Red blood cell transfusion management for people undergoing cardiac surgery for congenital heart disease

Abstract

Background

Congenital heart disease is the most common neonatal congenital condition. Surgery is often necessary. Patients with congenital heart disease are potentially exposed to red cell transfusion preoperatively, intraoperatively and postoperatively when admitted for cardiac surgery. There are a number of risks associated with red cell transfusion that may increase morbidity and mortality.

Objectives

To evaluate the association of red blood cell transfusion management with mortality and morbidity in people with congenital heart disease who are undergoing cardiac surgery.

Search methods

We searched multiple bibliographic databases and trials registries, including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCOhost), Transfusion Evidence Library, ClinicalTrials.gov and the World Health Organization (WHO) ICTRP. The most recent search was on 2 January 2024, with no limitation by language of publication.

Selection criteria

We included randomised controlled trials (RCTs) comparing red blood cell transfusion interventions in patients undergoing cardiac surgery for congenital heart disease. Participants of any age (neonates, paediatrics and adults) and with any type of congenital heart disease (cyanotic or acyanotic) were eligible for inclusion. No comorbidities were excluded.

Data collection and analysis

Two of five (AA, CK, KW, SB, SF) review authors independently extracted data and assessed the risk of bias in the trials. We contacted study authors for additional information. Two review authors (CK, KW) used GRADE methodology to assess evidence certainty for critical outcomes and comparisons.

Main results

We identified 19 relevant trials. The trials had 1606 participants, all of whom were neonates or children. No trials were conducted in the preoperative period or with adults. The trials compared different types of red blood cell transfusions. No trial compared red blood cell transfusion versus no red blood cell transfusion.

None of the trials was at low risk of bias overall. Eight trials had a high risk of bias in at least one domain, most commonly, blinding of participants and personnel.

For our critical outcomes, we judged the certainty of the evidence based on GRADE criteria to be low or very low.

Five trials (497 participants) compared a restrictive versus a liberal transfusion‐trigger.

It is very uncertain whether a restrictive transfusion‐trigger has an effect on all‐cause mortality in the short‐term (0 to 30 days post‐surgery) (risk ratio (RR) 1.12, 95% confidence interval (CI) 0.42 to 3.00; 3 RCTs, 347 participants; very low certainty evidence) or long term (31 days to two years post‐surgery) (RR 0.33, 95% CI 0.01 to 7.87; 1 RCT, 60 participants; very low certainty evidence). The evidence is also very uncertain on the incidence of severe adverse cardiac events (RR 1.00, 95% CI 0.73 to 1.37; 2 RCTs, 232 participants) and infection (RR 0.81, 95% CI 0.47 to 1.39; 2 RCTs, 232 participants) (both very low certainty evidence).

A restrictive transfusion‐trigger may have little to no effect on the duration of mechanical ventilation (mean difference (MD) −1.65, 95% CI −3.51 to 0.2; 2 RCTs, 168 participants; low‐certainty evidence) or of ICU stay (MD 0.15, 95% CI −0.72 to 1.01; 3 RCTs, 228 participants, low‐certainty evidence).

Five trials (231 participants) compared washed red blood cells in CPB prime versus unwashed red blood cells in CPB prime.

Washing red blood cells in CPB prime may have little to no effect on all‐cause mortality in the short term (0 to 30 days post‐surgery) (RR 0.25, 95% CI 0.03 to 2.18; 2 RCTs, 144 participants) or long term (31 days to 2 years post‐surgery) (RR 0.50, 95% CI 0.05 to 5.38; 1 RCT, 128 participants) (both low‐certainty evidence). The evidence is very uncertain about the effect of washed CPB prime on severe cardiac adverse events (RR 0.88, 95% CI 0.47 to 1.64), infection (RR 1.00, 95% CI 0.50 to 1.99) and duration of ICU stay (MD −0.3, 95% CI −4.32 to 3.72) (1 RCT, 128 participants; very low certainty evidence).

Two trials (76 participants) compared crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime.

It is very uncertain whether bloodless prime has an effect on the duration of mechanical ventilation (median 8.0 hours, interquartile range (IQR) 6.8 to 9.0 hours versus median 7.0 hours, IQR 6.0 to 8.0 hours; 1 RCT, 40 participants) or duration of ICU stay (median 23.0 hours, IQR 21.8 to 41.5 hours versus median 23.5 hours, IQR 21.0 to 29.0 hours; 1 RCT, 40 participants) (both very low certainty evidence).

Two trials (160 participants) compared ultrafiltration of CPB prime versus no ultrafiltration.

It is very uncertain whether ultrafiltration of CPB prime has an effect on all‐cause mortality in the short term (0 to 30 days post‐surgery) (RR not estimable; 1 RCT, 50 participants; very low certainty evidence). Ultrafiltration may reduce the duration of mechanical ventilation (MD −16.00, 95% CI −25.00 to −7.00) and the duration of ICU stay (MD −0.6, 95% CI −0.84 to −0.36) (1 RCT, 50 participants; low‐certainty evidence).

One trial (59 participants) compared retrograde autologous CPB prime versus standard CPB prime.

It is very uncertain whether retrograde autologous CPB prime has an effect on the duration of mechanical ventilation (MD 0.02, 95% CI −0.03 to 0.07) or duration of ICU stay (MD 0, 95% CI −0.01 to 0.01) (1 RCT, 59 participants; very low certainty evidence).

One trial (178 participants) compared 'fresh' (not near expiry date) versus 'old' (near expiry date) red blood cell transfusion but did not report on our outcomes.

Authors' conclusions

No randomised controlled trial compared red blood cell transfusion against no red blood cell transfusion in people with congential heart disease undergoing cardiac surgery. There are only small, heterogeneous trials in children that compare different forms of red blood cell transfusion, and there are no trials at all in adults. There is therefore insufficient evidence to accurately assess the association of red blood cell transfusion with the morbidity and mortality of patients with congenital heart disease undergoing cardiac surgery. It is possible that trial outcomes are affected by the presence or absence of cyanosis, so this should be considered in future trial design. Further adequately powered, high‐quality trials in both children and adults are required.

Plain language summary

Blood transfusions in people born with heart problems who require surgery on their heart

Key message

We found 19 studies that compared different ways of doing red blood cell transfusion in newborns and children requiring heart surgery for congenital heart disease (heart problems they were born with). However, we are unable to reach any reliable conclusions based on this evidence. More studies are required.

What is congenital heart disease?

Congenital heart disease is any problem with the heart's development that a person is born with. It means the heart has not formed properly. It affects between four and nine children out of every 1000 live births. In most cases, surgery is needed to allow a child to live and grow healthily. Adults often need surgery for congenital heart conditions.

Why is it important to manage blood transfusions during cardiac surgery?

Patients often need transfusions of red blood cells either before, during or after heart surgery. Most patients will have the surgery using a cardiopulmonary bypass (CPB) machine, which acts as their heart and lungs during the operation. More patients survive heart surgery now than in the past, and the aim is to make surgery even safer. Some research suggests that red blood cell transfusions may make people more ill. If so, it would be better to avoid unnecessary transfusions.

What did we want to find out?

We wanted to find out how the management of red blood cell transfusions affects patient outcomes after heart surgery. Do red blood cell transfusions have an impact on short‐term and longer‐term survival, serious side effects (e.g. stroke, kidney failure, infection, clots, bleeding) and the length of time patients stay in the intensive care unit and in hospital after their operation?

What did we do?

We searched medical databases for relevant studies. We looked for the most reliable type of studies, which are known as randomised controlled trials ('trials'). We compared and summarised the results of the trials and rated our confidence in the evidence, based on factors like their methods and the number of people involved.

What did we find?

We found 19 trials involving 1606 children. There were no trials involving adults. The trials examined eight treatments. We selected six comparisons as the key results. These are listed below. In the full review, we also present results for two other comparisons, which tested treatments that are now in common use.

1. Five trials compared giving a red blood cell transfusion only when the levels of haemoglobin in the blood fall below a certain concentration (a 'restrictive' versus a 'liberal' transfusion trigger). It is unclear if using a restrictive transfusion trigger has an effect on how many children die, develop severe side effects or develop an infection.

2. Five trials compared washing or not washing the red blood cells added to the heart‐lung machine. We do not know if washing the red blood cells has an effect on how many children die, develop severe side effects or infection, or how long children stay in the intensive care unit.

3. Two trials compared adding or omitting red cell transfusions into the fluid in the cardiopulmonary bypass machine. We do not know if not using blood in the heart‐lung machine has any effect on how long children stay on a ventilator, or how long they stay in the intensive care unit.

4. Two trials compared filtering the blood going through the heart‐lung bypass machine fluid to reduce high levels of minerals/salts and inflammation, which is sometimes a problem in transfused blood, versus not filtering it. It is unclear whether filtering the blood in the heart‐lung bypass machine has any effect on how many children die. Filtering may slightly reduce the time children spend on a ventilator, and may slightly reduce how long they stay in the intensive care unit.

5. One trial looked at using the child's own blood in the heart‐lung machine instead of a blood transfusion. The study did not give results on serious harmful events or how many children died. It is unclear if using the child's own blood in the heart‐lung machine instead of a transfusion has any effect on the time children spend on a ventilator or the time they spend in the intensive care unit.

6. One trial compared using very new blood compared with older blood to try to reduce harmful effects of older blood. This trial did not test the aspects we were interested in.

What are the limitations of the evidence?

The trials were small and measured many different aspects of red blood cell transfusion management in different children having heart surgery, so it is difficult to draw accurate conclusions about the benefits or risks of red blood cell transfusion. More research is needed to allow accurate conclusions to be drawn.

How up‐to‐date is the evidence?

We found all the published studies on this topic up to 2 January 2024. We also found all the trials that are in progress or due to be started soon.

Summary of findings

Summary of findings 1. Restrictive transfusion‐trigger versus liberal transfusion‐trigger.

Patient or population: individuals undergoing cardiac surgery for congenital heart disease Setting: inpatient Intervention: restrictive transfusion‐trigger Comparison: liberal transfusion‐trigger
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with liberal transfusion trigger	Risk with restrictive transfusion trigger
All‐cause mortality: short term (0 to 30 days post‐surgery)	41 per 1000	46 per 1000 (22 to 136)	RR 1.12 (0.42 to 3.00)	347 (3 RCTs)	⨁◯◯◯ Very lowa	The evidence is very uncertain about the effect of a restrictive transfusion trigger on mortality at 30 days.
All‐cause mortality: long term (31 days to 2 years post‐surgery)	33 per 1000	11 per 1000 (0 to 240)	RR 0.33 (0.01 to 7.87)	60 (1 RCT)	⨁◯◯◯ Very lowb	The evidence is very uncertain about the effect of a restrictive transfusion trigger on mortality at 31 days to 2 years.
Severe adverse events: cardiac events	302 per 1000	302 per 1000 (221 to 414)	RR 1.00 (0.73 to 1.37)	232 (2 RCTs)	⨁◯◯◯ Very lowb	The evidence is very uncertain about the effect of a restrictive transfusion trigger on severe cardiac adverse events.
Severe adverse events: infection	198 per 1000	160 per 1000 (55 to 237)	RR 0.81 (0.47 to 1.39	232 (2 RCTs)	⨁◯◯◯ Very lowb	The evidence is very uncertain about the effect of a restrictive transfusion trigger on infection.
Duration of mechanical ventilation	The mean duration of mechanical ventilation was 109.8 hours.	MD 1.65 hours lower (3.51 lower to 0.2 higher)	‐	168 (2 RCTs)	⨁⨁◯◯ Lowc	A restrictive transfusion trigger may have little to no effect on the duration of mechanical ventilation.
Duration of ICU stay	The mean duration of ICU stay was 4.6 days.	MD 0.15 days higher (0.72 lower to 1.01 higher)	‐	228 (3 RCTs)	⨁⨁◯◯ Lowc	A restrictive transfusion trigger may have little to no effect on the duration of ICU stay.

^aWe downgraded the certainty of evidence by one level for risk of bias, by one level for indirectness (one study reported "in hospital mortality", which included some deaths after 30 days) and by two levels for very serious imprecision.

^bWe downgraded the certainty of evidence by one level for risk of bias and by two levels for very serious imprecision.

^cWe downgraded the certainty of evidence by one level for risk of bias, and by one level for serious imprecision.

CI: confidence interval; ICU: intensive care unit; MD: mean difference; RCT: randomised controlled trials; RR: risk ratio

Summary of findings 2. Washed red blood cells in CPB prime versus unwashed red blood cells in CPB prime.

Patient or population: individuals undergoing cardiac surgery for congenital heart disease Setting: inpatient Intervention: washed red cells in CPB prime Comparison: unwashed red cells in CPB prime
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with unwashed CPB prime	Risk with washed CPB prime
All‐cause mortality: short term (0 to 30 days post‐surgery)	56 per 1000	14 per 1000 (2 to 122)	RR 0.25 (0.03 to 2.18)	144 (2 RCTs)	⨁⨁◯◯ Lowa	Washed packed red blood cells in cardiopulmonary bypass prime may have little to no effect on mortality at 30 days.
All‐cause mortality: long term (31 days to 2 years post‐surgery)	31 per 1000	15 per 1000 (1 to 168)	RR 0.50 (0.05 to 5.38)	128 (1 RCT)	⨁⨁◯◯ Lowa	Washed packed red blood cells in cardiopulmonary bypass prime may have little to no effect on mortality at 31 days to 2 years.
Severe adverse events: cardiac events	250 per 1000	220 per 1000 (117 to 410)	RR 0.88 (0.47 to 1.64)	128 (1 RCT)	⨁◯◯◯ Very lowb	The evidence is very uncertain about the effect of washed packed red blood cells in cardiopulmonary bypass prime on severe cardiac adverse events.
Severe adverse events: infection	203 per 1000	203 per 1000 (101 to 404)	RR 1.00 (0.50 to 1.99)	128 (1 RCT)	⨁◯◯◯ Very lowb	The evidence is very uncertain about the effect of washed packed red blood cells in cardiopulmonary bypass prime on infection.
Duration of mechanical ventilation	The median duration of mechanical ventilation was 51.5 hours (range 3 to 1200).	The median duration of mechanical ventilation was 45 hours (range 4 to 1008).	‐	128 (1 RCT)	⨁◯◯◯ Very lowc	The evidence is very uncertain about the effect of washed packed red blood cells in cardiopulmonary bypass prime on duration of mechanical ventilation.
Duration of ICU stay	The mean duration of ICU stay was 8.9 days.	MD 0.3 days lower (4.32 lower to 3.72 higher)	‐	128 (1 RCT)	⨁◯◯◯ Very lowb	The evidence is very uncertain about the effect of washed packed red blood cells in cardiopulmonary bypass prime on ICU stay.

^aWe downgraded the certainty of the evidence by two levels for very serious imprecision because of very wide confidence intervals and because the result was based on a single small study.

^bWe downgraded the certainty of the evidence by one level for risk of bias and by two levels for very serious imprecision because of very wide confidence intervals and because the result was based on a single small study.

^cWe downgraded the certainty of the evidence by one level for risk of bias and by two levels for very serious imprecision because the result was based on a single small study.

CI: confidence interval; CPB: cardiopulmonary bypass; ICU: intensive care unit; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio

Summary of findings 3. Crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime.

Patient or population: individuals undergoing cardiac surgery for congenital heart disease Setting: inpatient Intervention: crystalloid (bloodless) CPB prime Comparison: red‐blood‐cell‐containing CPB prime
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with blood‐containing CPB prime	Risk with crystalloid (bloodless) CPB prime
All‐cause mortality: short term (0 to 30 days post‐surgery)	We did not find any data for this outcome
All‐cause mortality: long term (31 days to 2 years post‐surgery)	We did not find any data for this outcome
Severe adverse events: cardiac events	We did not find any data for this outcome
Severe adverse events: infection	We did not find any data for this outcome
Duration of mechanical ventilation	The median duration of mechanical ventilation was 8.0 hours (IQR 6.8 to 9.0 hours).	The median duration of mechanical ventilation was 7.0 hours (IQR 6.0 to 8.0 hours).	‐	40 participants (1 RCT)	⨁◯◯◯ Very lowa	The evidence is very uncertain about the effect of crystalloid (bloodless) cardiopulmonary bypass prime on duration of mechanical ventilation.
Duration of ICU stay	The median duration of ICU stay was 23.0 hours (IQR 21.8 to 41.5).	The median duration of ICU stay was 23.5 hours (21.0 to 29.0).	‐	40 participants (1 RCT)	⨁◯◯◯ Very lowa	The evidence is very uncertain about the effect of crystalloid (bloodless) cardiopulmonary bypass prime on duration of ICU stay.

^aWe downgraded the certainty of the evidence by one level for risk of bias and by two levels for very serious imprecision because the result was based on a single, small study.

CPB: cardiopulmonary bypass; ICU: intensive care unit

CI: confidence interval; CPB: cardiopulmonary bypass; ICU: intensive care unit; IQR: interquartile range; RCT: randomised controlled trial

Summary of findings 4. Ultrafiltration of CPB prime versus no ultrafiltration.

Patient or population: individuals undergoing cardiac surgery for congenital heart disease Setting: inpatient Intervention: ultrafiltration of CPB prime Comparison: no ultrafiltration of of CPB prime
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with no ultrafiltration of CPB prime	Risk with ultrafiltration of CPB prime
All‐cause mortality: short term (0 to 30 days post‐surgery)	There were no deaths in either arm of this study.		Not estimable	50 (1 RCT)	⨁◯◯◯ Very lowa	The evidence is very uncertain about the effect of ultrafiltration in cardiopulmonary bypass prime on mortality at 30 days.
All‐cause mortality: long term (31 days to 2 years post‐surgery)	We did not find any data for this outcome
Severe adverse events: cardiac events	We did not find any data for this outcome
Severe adverse events: infection	We did not find any data for this outcome
Duration of mechanical ventilation	The mean duration of mechanical ventilation was 28 hours.	MD 16 hours lower (25 hours lower to 7 hours lower)	‐	50 (1 RCT)	⨁⨁◯◯ Lowb	Ultrafiltration may reduce the duration of mechanical ventilation.
Duration of ICU stay	The mean duration of ICU stay was 1.6 days.	MD 0.6 days lower (0.84 days lower to 0.36 days lower)	‐	50 (1 RCT)	⨁⨁◯◯ Lowb	Ultrafiltration may reduce the duration of ICU stay.

^aWe downgraded the certainty of the evidence by one level for risk of bias and by two levels for very serious imprecision because the relative risk was not estimable and the evidence was based on a single small study.

^bWe downgraded the certainty of the evidence by one level for risk of bias and by one level for imprecision because the result is based on a single small study.

CI: confidence interval; CPB: cardiopulmonary bypass; ICU: intensive care unit; MD: mean difference; RCT: randomised controlled trial

Summary of findings 5. Retrograde autologous CPB prime versus standard CPB prime.

Patient or population: individuals undergoing cardiac surgery for congenital heart disease Setting: inpatient Intervention: retrograde autologous CPB prime Comparison: standard CPB prime
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with standard CPB prime	Risk with retrograde autologous CPB prime
All‐cause mortality: short term (0 to 30 days post‐surgery)	We did not find any data for this outcome
All‐cause mortality: long term (31 days to 2 years post‐surgery)	We did not find any data for this outcome
Severe adverse events: cardiac events	We did not find any data for this outcome
Severe adverse events: infection	We did not find any data for this outcome
Duration of mechanical ventilation	The mean duration of mechanical ventilation was 4.67 hours.	MD 0.02 hours higher (0.03 lower to 0.07 higher)	‐	59 (1 RCT)	⨁◯◯◯ Very lowa	The evidence is very uncertain about the effect of retrograde autologous cardiopulmonary bypass prime on duration of mechanical ventilation.
Duration of ICU stay	The mean duration of ICU stay was 0.33 days.	MD 0 day higher (0.01 lower to 0.01 higher)	‐	59 (1 RCT)	⨁◯◯◯ Very lowa	The evidence is very uncertain about the effect of retrograde autologous cardiopulmonary bypass prime on duration of ICU stay.

^aWe downgraded the certainty of the evidence by one level for risk of bias and by two levels for very serious imprecision because of wide confidence intervals and the result being based on a single small study.

CI: confidence interval; CPB: cardiopulmonary bypass; MD: mean difference; ICU: intensive care unit; RCT: randomised controlled trial

Summary of findings 6. 'Fresh' (not near to expiry date) versus 'old' (near to expiry date) red blood cell transfusion.

Patient or population: individuals undergoing cardiac surgery for congenital heart disease Setting: inpatient Intervention: 'fresh' (not near to expiry date) red blood cell transfusion Comparison: 'old' (near to expiry date) red blood cell transfusion
Outcomes	Comments
All‐cause mortality: short term (0 to 30 days post‐surgery)	We did not find any data for this outcome
All‐cause mortality: long term (31 days to 2 years post‐surgery)	We did not find any data for this outcome
Severe adverse events: cardiac events	We did not find any data for this outcome
Severe adverse events: infection	We did not find any data for this outcome
Duration of mechanical ventilation	We did not find any data for this outcome
Duration of ICU stay	We did not find any data for this outcome

ICU: intensive care unit

Background

Congenital heart disease

Congenital heart disease is a general term for a birth defect that affects the structure or function of the heart, or both. It is a heterogenous condition that includes structural abnormalities of the cardiovascular system that are present from birth and derived from abnormal development of the heart in utero (Goldstein 2024).

Although there is worldwide variation in incidence, primarily due to the ability to detect trivial lesions (Hoffman 2002), congenital heart disease is the most frequent cause of severe birth defects, affecting 4 to 9 of 1000 live births each year worldwide (Dolk 2011; Van der Linde 2011). It is the most common congenital condition diagnosed in neonates (Gatzoulis 2005), with congenital heart defects accounting for 30% of all liveborn infants with a major congenital anomaly (EURO‐PERISTAT Project 2008). The impact of congenital heart disease on an individual is significant. About 10.4% of all UK infants who died in one UK‐based study population had a cardiovascular malformation (Wren 2012).

Congenital heart defects range from simple to complex. Some heart problems may not need treatment, whilst others can be treated pharmacologically. Some will require heart surgery (through a sternotomy or thoracotomy) or transcatheter intervention. These procedures may happen soon after the baby is born or later in life, with some people needing multiple operations and/or interventions throughout their life.

Types of congenital heart disease

Structural congenital heart disease may be broadly classified into acyanotic or cyanotic heart disease. Acyanotic heart disease describes patients with normal oxygen levels (e.g. congenital aortic stenosis, atrioseptal defect, ventricular septal defect) (Gatzoulis 2005). Cyanotic heart disease describes patients with hypoxaemia (low oxygen levels). These low oxygen levels are caused by an increased amount of haemoglobin that is carrying inadequate amounts of oxygen (non‐oxygenated blood) from either mixing of oxygenated and non‐oxygenated blood (right to left shunting or univentricular heart) or inadequate pulmonary blood flow (underdeveloped pulmonary vasculature or progressive pulmonary hypertension). Examples of cyanotic lesions are transposition of the great arteries, truncus arteriosus and hypoplastic left heart syndrome.

People with cyanotic heart disease tend to have higher haemoglobin levels as a result of the body's response to hypoxaemia‐induced erythrocytosis. The higher haemoglobin levels allow the body to transport a relatively lower amount of oxygen around the body to optimise tissue delivery of oxygen. However, higher preoperative haemoglobin and haematocrit levels have been associated with increased bleeding and blood product use in surgery for cyanotic heart disease (Williams 1999).

The presence or absence of cyanosis may alter the patient's response to any anaemia encountered during cardiac surgery, especially if a single haemoglobin level is used as a transfusion trigger for both groups. A restrictive transfusion trigger (where blood is not transfused until the patient's haemoglobin level has reached a predefined lower limit) that is the same for both acyanotic and cyanotic groups may have much more pronounced effects if the starting haemoglobin is significantly higher in the cyanotic groups.

Outcomes for people with congenital heart disease

Surgery for congenital heart disease aims to reduce mortality and morbidity. Historically, complex congenital heart disease was associated with near total mortality (Goldstein 2024). In the 1950s, without surgery, if 10 affected children were born alive, two would die by the end of the first week, a further one or two by the end of the first month, with five or six in total having died by the end of the first year; only three or four would survive to 10 years old (MacMahon 1953). Since this time, with the introduction of cardiopulmonary bypass and improved diagnostic, interventional and surgical techniques, there has been a dramatic decrease in mortality and morbidity rates (British Cardiac Society 2002). From 1965 to 1975, survival rates in the first month after surgery rose from 37% to 70% (Izukawa 1979). Between 1999 and 2006, overall mortality from congenital heart disease fell by 24.1% in the USA (Gilboa 2010), and surgical survival at one year in the UK was approximately 95% from 2006 to 2007 (CCAD 2008). The most recent (2022 to 2023) UK outcome data for surgery show a further improvement with a 30‐day survival of 98.3% (NCHDA 2024).

Around 80% to 85% of children with congenital heart disease are expected to reach adulthood, and this improved survival has resulted in a growing population of adults with congenital heart disease (ACHD) (Benzinger 2023; Khairy 2010; Majdalany 2023; Nieminen 2001; Wren 2001). This increase in survival has also resulted in an increase in the complexity of disease, with the prevalence of complex congenital heart disease amongst adults increasing by 85% between 1985 and 2000, compared with a 22% increase amongst children (Marelli 2014).

Surgical treatment for congenital heart disease

People present for surgery at differing ages depending on the underlying heart defect, but there are three main groups: neonates (within four weeks of birth), paediatrics (four weeks to 16 years of age) and adult congenital (over 16 years of age). The surgery may be either corrective (i.e. completely corrects the lesion into normal circulation) or palliative (i.e. changes the anatomy (and therefore circulation) to be compatible with life but does not completely correct the defect). The defect dictates the type of surgery undertaken. Some patients will undergo one single operation whilst others will require a sequence of surgeries (e.g. patients with hypoplastic left heart syndrome) or repeat operations.

Mortality and morbidity are variable depending on the defect present and where in the world the surgery is taking place. For some simple defects (e.g. atrioseptal defects), surgery is relatively routine. For other, more complex, defects, for example, hypoplastic left heart syndrome, the patient is critically unwell and surgery has very significant associated morbidity and mortality. Children with a single ventricle will undergo a palliative three‐stage repair during their early childhood. The first stage is the Norwood procedure, where early mortality is estimated at 5% to 20% (Kaplinski 2020). The second stage is the bidirectional Glenn procedure, with the third stage being the Fontan procedure (total cavopulmonary connection). One study in the USA cited hypoplastic left heart syndrome as the greatest specific diagnosis contributor to overall congenital heart disease mortality at 10.9% of all deaths (Gilboa 2010).

Despite excellent outcomes for many individuals, challenges remain in all patient groups, especially those at higher risk, such as neonates, premature infants and patients undergoing complex surgery (Van der Bom 2015; Cheng 2011; Padley 2011), as well as those in low‐income countries. Ninety per cent of the world's children born with congenital heart disease live in locations where care is suboptimal or even absent, and for these children, mortality remains high (Tchervenkov 2008).

Almost half of adult congenital cardiac surgical operations are repeat operations (Van der Bom 2011). These operations are associated with significant morbidity and mortality, with 15% to 24% of patients experiencing serious postoperative complications and early mortality rates between 3.6% and 7.6% (Berdat 2004; Giamberti 2009). Research now focusses on further reducing mortality and, maybe even more importantly, on defining important morbidity (Brown 2017) and decreasing it (Gatzoulis 2005).

Description of the intervention

Both paediatric and adult cardiac surgery for congenital heart disease have a high risk of causing anaemia. Adult congenital cardiac surgery often involves redo‐sternotomy procedures that have a considerable risk of bleeding (Dutta 2023). Both paediatric and adult patients undergoing cardiac surgery for congenital heart disease are potentially exposed to red blood cell transfusion at many points in the surgical pathway; transfusion may be used to treat anaemia preoperatively, intraoperatively or postoperatively. The likelihood of receiving a red blood cell transfusion whilst undergoing cardiac surgery for congenital heart disease is high with studies suggesting 25% to 100% of children receive a transfusion. The rate of transfusion is highest if the patient is less than 5 kg in weight, is undergoing complex operations or if their core temperature is less than 20 degrees Celsius (Chambers 1996, Kartha 2018).

Cardiopulmonary bypass (CPB) replaces the work of the heart and lungs, allowing the heart to be stopped during surgery to provide a still and bloodless field for the surgeon (Allman 2002). The blood is oxygenated, carbon dioxide is removed and then the blood is returned to the patient. The circuit provides continuous circulation between the venous cannula draining blood from the patient and the aortic cannula returning blood to the patient. The circuit tubing is primed with fluid to prevent air passing from the circuit into the patient. This fluid is known as the bypass prime, and it may have a number of components (Allman 2002). If it does not contain any red blood cells, it is known as a clear or bloodless prime. As the bypass prime mixes with the patient's own circulation, there is a risk of excessive haemodilution, so red blood cells may be added to prevent this. Red blood cells can be added into the prime volume before bypass or into the bypass pump once the patient is on bypass. A neonate is likely to undergo 60% haemodilution on bypass (Eaton 2005), so they are almost always likely to have donor red blood cells added to the CPB prime (Groom 2005). However, a number of centres have been investigating bloodless CPB prime to reduce exposure to red cell transfusion (Ging 2008; Golab 2009; Miyaji 2007; Olshove 2010).

Red blood cell transfusions have become safer, but there are still some associated risks, both infectious and non‐infectious. These risks can result in increased morbidity and mortality, especially in the critically ill patient population (Hebert 1999; Vincent 2002). The most recent UK Serious Hazards of Transfusion report has examined the safety of blood transfusion and subsequently raised concerns (SHOT 2022). The risk of death related to transfusion in the UK is 1 in 63,537 (1.57 per 100,000) components issued and the risk of serious harm is 1 in 15,450 (6.47 per 100,000) components issued.

After several years of improvement and continued safety in important areas, such as prevention of ABO‐incompatible transfusion, there has been a worrying upward trend in errors and harm. This may be due to improved reporting, but two deaths and one case of major morbidity due to ABO incompatible red blood cell transfusion were reported in 2022 in the UK; these three cases were attributed to portering and collection errors, stressful situations that led to shortcuts and failure to follow designated safety procedures. A series of errors resulted in patient harm. Paediatric reports account for 263 of 3499 reports (7.5%) to SHOT, including near‐miss events. More than a third of reports involved neonates (SHOT 2022).

In the past, the major concern about the safety of transfusion was the risk of transmission of infection, especially hepatitis C virus and human immunodeficiency virus (HIV) (Guzzetta 2011; Morley 2009). Through donor screening and donation testing, the risk of infection is now low in high‐income countries, with the estimated risk of hepatitis C being one in 50 million, hepatitis B one in 2.5 million and HIV one in 30 million (SHOT 2022). However, in countries that do not have the same rigorous testing systems, infection transmission remains a risk. The most recent World Health Organization (WHO) Blood Safety Survey showed that 10 out of 171 countries reported not being able to test one hundred per cent of the blood collected for one or more of the four transfusion‐transmissible infections (TTIs), i.e. HIV, hepatitis B, hepatitis C and syphilis (WHO Blood 2021).

As transfusion medicine practice has developed and improved, the focus of risks associated with red blood cell transfusion has shifted to non‐infectious sequelae, with the main current issues being transfusion‐associated circulatory overload (TACO) and delays in providing blood (SHOT 2022).

Adverse transfusion reactions are a real concern. Children under 18 years of age receive 4.2% of all red blood cell transfusions while children under the age of one year receive 1.7% (Wallis 2006). However, children have a disproportionately high number of adverse reactions compared to adults: 37 in 100,000 for children under one year, 18 in 100,000 transfusions for children under 18 years, while for adults, it is 13 in 100,000 (Stainsby 2008).

Transfusion‐related acute lung injury (TRALI), new acute lung injury occurring during or within six hours of a transfusion (Semple 2019; Vlaar 2013; Vlaar 2019), is estimated to have an incidence between 0.08% and 15% of patients receiving a transfusion (Benson 2010; Silliman 2003) and an adult mortality rate of 5% to 10% (Vlaar 2013). Although reported to be rare in children, it is probably under‐reported as it can be difficult to diagnose (Harrison 2011). Transfusion‐associated circulatory overload, TACO, is the most frequent pulmonary complication of transfusion, and has been estimated to occur in between 1.5% and 11% in a paediatric intensive care population (De Cloedt 2018).

The recognition of these risks associated with red cell transfusion has led to a more critical appraisal of the use of red cell transfusion. Although red cells are transfused more frequently than any other blood component, their overall usage in the UK has been declining (Tinegate 2013). The same also appears to be true for the USA (Nordestgaard 2020; Roubinian 2014).

Literature in critically unwell patient groups suggests that avoiding red blood cell transfusions may reduce morbidity, which explains the trend to reduce such exposure. Adult critical care patients cared for under a a restrictive transfusion policy were shown to have a similar 30‐day mortality during hospitalisation when compared with patients cared for under a liberal transfusion policy (18.7% versus 23.3%) (Hebert 1999). Several studies have assessed restrictive versus liberal transfusion policies in adult patients undergoing surgery for acquired heart disease (Carson 2023a; Mazer 2017; Murphy 2015; Patel 2015).

A recent Cochrane review examined the haemoglobin concentration (Hb) thresholds for guiding red blood cell transfusion and concluded that transfusing at a restrictive strategy of Hb between 7.0 g/dL to 8.0 g/dL, compared with a liberal Hb threshold of between 9.0 g/dL to 10.0 g/dL, across a broad range of hospitalised patients did not have an adverse effect on clinical outcomes. However, there was limited evidence for children and further research was recommended as uncertainty remains regarding best practice for children including those undergoing cardiac surgery (Carson 2021). Studies in this area continue. A very recent retrospective analysis that compared liberal and restrictive transfusion strategies in postoperative congenital heart disease surgery patients concluded that a restrictive transfusion strategy may be preferable (Tanyildiz 2024). Patients (who would be cyanotic) with single ventricle physiology were excluded from this study (Tanyildiz 2024).

Relatively few studies have examined the effects of red blood cell transfusion on critically ill children (Istaphanous 2011). Lacroix 2007 reported the results of a prospective randomised controlled trial (RCT) comparing a restrictive versus liberal transfusion strategy in critically ill children, which showed a decrease in transfusion requirements in the restrictive group without increasing adverse outcomes. However, the study did caution against the use of a restrictive strategy in children with cyanotic heart disease (Lacroix 2007). A number of studies have looked at the effects of haemodilution, and differing haematocrit levels in infants whilst on bypass. One study suggested that children on cardiopulmonary bypass with a haematocrit of 20% had worse outcomes than those with a haematocrit of 28% (Jonas 2003), while another study concluded that whether haematocrit levels were 35% or 25% had no major effect on the overall benefits or risks in infants (Newburger 2008). When these two trials were combined, a haematocrit of greater than 24% was associated with higher psychomotor development index scores and lower lactate levels (Wypij 2008). The NATA (Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis) guidelines suggest red blood cell transfusion to maintain a haematocrit of greater than 24% during cardiopulmonary bypass (Faraoni 2019).

A number of studies have also examined the impact of red blood cell transfusion on neonates as transfusion has been associated with higher rates of complications such as necrotising enterocolitis, bronchopulmonary dysplasia, retinopathy of prematurity and potentially abnormal neurodevelopment. Most of the studies have focused on premature neonates as transfusions are more common in this patient population (40% of low birth weight infants and up to 90% of extremely low birth weight infants require red cell transfusion (Villeneuve 2021)).

One of the largest studies, the Premature Infants in Need of Transfusion (PINT) study, suggested that a liberal transfusion strategy in extremely low birth weight neonates resulted in more infants receiving transfusions but conferred little evidence of benefit (Kirpalani 2006). This study was combined with three others (Bell 2005; Chen 2009; Connelly 1998) in a Cochrane review that concluded that restrictive Hb thresholds for transfusion resulted in modest reductions in transfusion and haemoglobin levels compared with liberal thresholds. Restrictive transfusion practice did not appear to have a significant impact on death or major morbidities at hospital discharge or first hospital follow‐up. However, there were uncertainties with these conclusions and the authors recommended further trials be conducted (Whyte 2011). A more recent randomised controlled trial examined higher or lower Hb transfusion thresholds for preterm infants. It showed that in extremely‐low‐birth‐weight infants, survival without neurodevelopmental impairment at 22 to 26 months of age, corrected for prematurity was not improved by a higher Hb threshold for red cell transfusion (Kirpalani 2020). A recent review article on neonatal blood transfusion concluded that further research is required to better define optimal transfusion practice in neonates and priority should be given to confirming that restrictive strategies are safe in neonates (Villeneuve 2021).

Guidelines have been developed to provide recommendations regarding anaemia management and blood transfusion practices in the paediatric population undergoing surgery for congenital heart disease (Carson 2023b; Faraoni 2019). However, both sets of guidelines acknowledge that the evidence base has low to moderate certainty for this patient population.

How the intervention might work

The most important physiological consequence of anaemia is reduced oxygen‐carrying capacity of the blood. The optimal concentration of haemoglobin for avoidance of severe morbidity is unknown, but animal experiments suggest the critical haemoglobin level for oxygen delivery to be 3 to 4 g/dL(Van der Linden 1998). Although healthy adult volunteers tolerate a haemoglobin of 5 g/dLwith no increase in lactate production or decrease in oxygen consumption, they do show an increase in heart rate and a decline in cognitive function, suggesting borderline tissue oxygen delivery (Weiskopf 2002). The physiological response to anaemia is to increase cardiac output, so anaemia effectively consumes some of the cardiac reserve (Morley 2009). Patients with congenital heart disease and a marginal cardiac reserve often have a precarious oxygen supply‐demand balance, and anaemia may adversely alter this balance. Red cell transfusion augments tissue oxygen delivery by increasing the oxygen‐carrying capacity of the blood (Guzzetta 2011). Many centres transfuse at a higher starting haemoglobin level for patients with congenital heart disease when they require surgery or intensive care (Morley 2009).

The red cells that are transfused can vary in age and nature. They may or may not be leucodepleted (white blood cells removed), they may be fresh or old, and they may come as red blood cell concentrates or whole blood. Each of these factors may be important in determining the outcome for the transfusion recipient and is further explained below.

Red blood cell function may become impaired with increased storage time (Morley 2009). Previously, there have been concerns with prolonged storage time leading to increases in mortality, pneumonia, infection, multiorgan failure and length of hospital stay (Tinmouth 2006). More recent research has concluded that there is no indication to preferentially use fresher red blood cell units in people over 12 years old (Steiner 2015). However, the evidence was scarce, absent or low quality for certain subgroups of patients, including neonates and children and those with additional risks for impaired microcirculation (Shah 2016; Shah 2018).

Theoretically, whole blood should improve haemostasis and decrease systemic inflammation in comparison with red blood cell concentrates. Manno 1991 compared the immediate post‐operative transfusion needs of children undergoing open‐heart surgery with CPB with either whole blood or reconstituted whole blood (red blood cells, fresh frozen plasma and platelets). Manno 1991 found that transfusion with reconstituted blood significantly increased mean 24‐hour postoperative blood loss in those less than two years old (85% more blood loss), but for those aged over two years undergoing surgery for simple defects, there was no significant difference between treatment groups. When whole blood was added into the bypass circuit prime, there were no significant differences in terms of bleeding and inflammatory mediator levels. There was a trend for longer intensive care unit (ICU) stays, greater positive fluid balance and longer hospital stays (Mou 2004).

In summary, the issues concerning red blood cell transfusion management in the perioperative period for patients with congenital heart disease undergoing cardiac surgery relate to the following questions.

• What haemoglobin level should trigger blood to be transfused ‐ can patients tolerate a lower (restrictive) haemoglobin concentration before they need to be transfused?

• How much blood to give ‐ what volume of red cell transfusion should be given to reach the intended haemoglobin target?

• Leukoreduced versus non‐leukoreduced ‐ is there a benefit to removing leukocytes from the transfused red cells?

• Whole blood versus red blood cell concentrates ‐ do patients benefit from whole blood more than red blood cell concentrates?

• The age of red cells transfused: new versus old ‐ do patients have better outcomes if 'fresher' (i.e. newer) red blood cells are transfused?

Why it is important to do this review

The patient population with congenital heart disease is small but growing. Epidemiological studies describe decreasing mortality and prolonged survival in young patients, resulting in a larger ‐ and ageing ‐ population with congenital heart disease (Khairy 2010; Knowles 2012; Majdalany 2023; Wren 2001).

Survival outcomes for cardiac surgery for congenital heart disease have improved, but there are still morbidity and mortality risks associated with cardiac surgery, especially in neonatal and premature patients and those undergoing complex surgery. Blood transfusion has been associated with adverse outcomes in critically unwell patients and the speciality of congenital heart disease has begun to address the specific risks to this population as some patients with congenital heart disease are critically unwell either before, during or after their operation (Guzzetta 2011). Studies have tried to identify the risk factors for adverse outcomes in patients undergoing surgery for congenital heart disease (Székely 2006). One secondary analysis suggested that intraoperative and early postoperative blood transfusion was a powerful independent predictor of duration of mechanical ventilation in infants undergoing reparative cardiac surgery (Kipps 2011). Infants who received the highest volume of transfusion were twice as likely as infants receiving the lowest volume of remaining intubated. The total amount of blood transfusion has been independently associated with infections but not mortality (Székely 2009). Red cell transfusions have also been associated with longer hospital stays, with the strongest association in the high transfusion group (Salvin 2011). This association was limited to patients with biventricular and not univentricular circulations. For patients with hypoplastic left heart syndrome, a higher haemoglobin nadir on postoperative days two to five was associated with higher early mortality, but neither haemoglobin concentrations nor transfusions were associated with two‐year mortality or neurodevelopmental outcomes. More transfusions two to five days postoperatively were associated with morbidity measured by ventilation days (Blackwood 2010).

We previously published a systematic review examining red blood cell transfusion in all patients with congenital heart disease undergoing cardiac surgery (Wilkinson 2014). The review identified only 11 small and heterogeneous trials, so there was insufficient evidence to assess the impact of red blood cell transfusion accurately. It concluded that further adequately powered, specific, high‐quality trials were warranted. The unanswered clinical questions included at what concentration of haemoglobin blood should be given, how much blood should be given, what storage age of blood should be used (i.e. 'fresh' versus stored blood) and what type of blood should be used (leukoreduced or non‐leukoreduced, irradiated or non‐irradiated, red blood cells or whole blood). This new review aims to update the previous review in order to address these knowledge gaps and direct future research and clinical practice.

Although the three patient groups of neonates, children (paediatrics) and adults appear different, the same questions exist for all of them, and it is likely that a neonate will survive to adulthood and possibly require further surgery at a later stage. We assessed the three groups separately but kept them in the same review. Clinicians often manage these patients from birth to adulthood, so this review will cover all ages.

Objectives

To evaluate the association of red blood cell transfusion management with mortality and morbidity in people with congenital heart disease who are undergoing cardiac surgery.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) in this review. We did not exclude cluster‐randomised controlled trials or quasi‐randomised controlled trials (i.e. trials that allocated participants using a method that was not truly random, e.g. by odd or even hospital number, or day of the week). This was to increase the number of trials eligible for inclusion in the review. We included data from all studies, regardless of whether the studies were published or unpublished.

Types of participants

We included all people undergoing cardiac surgery (via sternotomy or thoracotomy) for congenital heart disease, with no restriction on age. The congenital heart disease could be cyanotic or acyanotic. We did not exclude participants with comorbidities. We grouped study participants by age and analysed them separately: neonates (newborns up to four weeks old), paediatrics (children four weeks post birth to age 16 years) and adults (over 16 years of age).

We excluded people with congenital heart disease undergoing non‐cardiac surgery. Where a trial included only a subset of eligible participants, we included it if we were able to extract the data for the eligible participants, for example, if the relevant data had been presented as a subgroup. We did not include mixed populations if we were unable to extract the data for the participants with congenital heart disease.

Types of interventions

The intervention was red blood cell transfusion management at any point in the surgical pathway. This included red blood cell transfusion given preoperatively (during the admission for the surgery), intraoperatively directly into the patient or into the cardiopulmonary bypass (CPB) machine (either into the prime cardiopulmonary volume before bypass or subsequently into the cardiopulmonary pump volume during bypass) or postoperatively during the hospital stay.

We included the following comparisons.

• Restrictive transfusion‐trigger versus liberal transfusion‐trigger ‐ blood was transfused at two or more different haemoglobin (Hb) concentrations, with the liberal Hb trigger for transfusion being higher than restrictive (different studies chose different haemoglobin concentrations but were around haemoglobin 7 to 8 g/dL for restrictive and 9 to 10 g/dL for liberal).

• Standard cardiopulmonary bypass prime versus non‐standard cardiopulmonary bypass prime (e.g. washed red blood cells in CPB prime versus unwashed red blood cells in CPB prime; crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime; ultrafiltration of CPB prime versus no ultrafiltration; retrograde autologous CPB versus standard CPB prime; or different methods of processing the prime).

• 'Fresh' (not near to expiry date) versus 'old' (near to expiry date) red blood cell transfusion. In the UK, red blood cells up to five days old may be used for neonates and up to 35 days old for paediatric patients, so each group contained comparison groups appropriate to UK national guidelines (BCSH 2004).

• Cell salvage of CPB prime versus allogeneic red blood cells post‐CBP

• Leukoreduced red blood cell transfusion versus non‐leukoreduced red blood cell transfusion

• Volume A red blood cell transfusion versus volume B red blood cell transfusion (e.g. higher volume versus lower volume (different mL/kg)). The standard advised resuscitation volume for paediatric patients is 20 mL/kg, so the doses were likely to be factors of 20 mL/kg.

• Whole blood versus red blood cell transfusion

• Irradiated red blood cell transfusion versus non‐irradiated red blood cell transfusion

• Red blood cell transfusion versus placebo, non‐red‐blood‐cell‐containing solutions or no transfusion. Trials looking at red blood cell transfusion versus no transfusion may not be possible in certain groups of patients, for example, neonates or children who are low weight, or any age or size of patient with pre‐existing anaemia as the haemodilution from CPB may risk harmful, extreme anaemia.

Types of outcome measures

We included eligible trials even if they did not report any of the outcomes of this review.

Primary outcomes

• All‐cause mortality: short term ‐ 0 to 30 days post‐surgery

Secondary outcomes

• All‐cause mortality: long term ‐ 31 days to two years post‐surgery

• Severe adverse events: cardiac events, acute lung injury, stroke, thromboembolism, renal failure (needing renal replacement therapy), infection, haemorrhage (return to theatre for bleeding) at any point during hospitalisation

• Haematocrit/haemoglobin (g/dL) levels postoperatively and at discharge

• Volume or number of red blood cell units transfused at any point during hospitalisation; number of participants receiving any red blood cell transfusion

• Volume or number of other blood products transfused (i.e. fresh frozen plasma, platelets, cryoprecipitate) at any point during hospitalisation; number of participants receiving any fresh frozen plasma; number of participants receiving any platelet transfusion

• Postoperative chest drain output at any time point reported

• Duration of mechanical ventilation at any point during hospitalisation

• Duration of ICU stay at any point during hospitalisation

• Rate of rehospitalisation at any point reported in the studies

• Oxygen content difference

• Cerebral oxygen content post surgery (rSO₂)

• Blood lactate levels (mmol/L) at baseline, at CPB circuit prime, at up to 15 minutes after the start of CPB, at 28 degrees centigrade during rewarming, at 36 degrees centigrade after rewarming, immediately after CPB and clamp of arterial cannula, "peak" levels as defined by the study

• Blood sodium (Na⁺) levels (mmol/L) at baseline, at CPB circuit prime, at up to 15 minutes after the start of CPB, at 28 degrees centigrade during rewarming, at 36 degrees centigrade after rewarming, immediately after CPB and clamp of arterial cannula, "peak" levels as defined by the study

• Blood potassium (K⁺) levels (mmol/L) at baseline, at CPB circuit prime, at up to 15 minutes after the start of CPB, at 28 degrees centigrade during rewarming, at 36 degrees centigrade after rewarming, immediately after CPB and clamp of arterial cannula, "peak" levels as defined by the study

• Blood glucose (mg/dL) at baseline, at CPB circuit prime, at up to 15 minutes after the start of CPB, at 28 degrees centigrade during rewarming, at 36 degrees centigrade after rewarming, immediately after CPB and clamp of arterial cannula, "peak" levels as defined by the study

Search methods for identification of studies

Electronic searches

The Systematic Review Initiative's Information Specialist (CD) formulated the search strategies for the review in collaboration with the Cochrane Heart Group. We searched the following databases.

Bibliographic databases

• Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2024, Issue 1)

• MEDLINE (Ovid, 1946 to 2 January 2024)

• Embase (Ovid, 1974 to 2 January 2024)

• PubMed (epublications ahead of print only) (NLM, searched 2 January 2024)

• CINAHL (EBSCOhost 1981 to 2 January 2024)

• LILACS (Bireme, 1980 to 2 January 2024)

• Transfusion Evidence Library (Evidentia Publishing, 1950 to 2 January 2024)

• Web of Science Conference Proceedings Citation Index‐Science (CPCI‐S) (Clarivate, 1990 to 2 January 2024)

• KoreaMed (KAMJE, 1997 to 2 January 2024)

• PakMediNet (2001 to 2 January 2024)

Online databases of ongoing trials

• ClinicalTrials.gov (clinicaltrials.gov) (searched 2 January 2024)

• WHO International Clinical Trials Registry Platform (WHO ICTRP) (apps.who.int/trialsearch/AdvSearch.aspx) (searched 2 January 2024)

• HKU Clinical Trials Registry (www.hkuctr.com) (searched 2 January 2024)

The MEDLINE search strategy was adapted for the other databases, using appropriate syntax and controlled vocabulary. Searches in MEDLINE were combined with an expanded version of the Cochrane sensitivity‐ and precision‐maximizing RCT search filter, as detailed in Lefebvre 2023. We combined searches in Embase and CINAHL with adaptations of the relevant Scottish Intercollegiate Guidelines Network (SIGN) RCT filters (www.sign.ac.uk/methodology/filters.html). The search strategies for all databases are available in Appendix 1. We applied no restrictions for language of publication or publication status.

Searching other resources

We also undertook the following handsearching tasks.

• Handsearched reference lists

• Checked references of all identified trials and relevant review articles for further literature. We limited these searches to the 'first generation' reference lists.

• Handsearched conference proceedings

• Handsearched published abstract books (published between 2006 and January 2011) of the most relevant conferences for further studies, including the European Society of Cardiology, World Congress of Cardiology, American Heart Association, Society of Cardiothoracic Surgeons, British Cardiovascular Society, European Association of Cardiothoracic Surgeons, American Association for Thoracic Surgery and Association for European Paediatric and Congenital Cardiology. For this update of this review, we did not undertake handsearching of conference abstracts because they are now indexed by Embase and so appear in the electronic search results.

Data collection and analysis

Selection of studies

Two review authors (KW and SB, SF, AA or CK) independently assessed the titles and abstracts of all potentially relevant trials for eligibility. We obtained the full text of any papers where eligibility could not be assessed on title and abstract alone, and two review authors (KW and SB, AA, SF or CK) independently assessed eligibility. At all stages, we resolved any disagreements by discussion or by consultation with a third review author (MM). We sought further information from the study authors where articles contained insufficient data to make a decision about eligibility. We designed a study eligibility form to help in the assessment of relevance using the criteria outlined above.

Data extraction and management

Two review authors (KW and SB, CK or SF) independently conducted data extraction according to the guidelines proposed by The Cochrane Collaboration. We resolved disagreements by consensus. The review authors were not blinded to names of authors, institutions, journals or the outcomes of the trials. We extracted data from the studies using a standardised data extraction form. The form was initially piloted on a sample of the eligible papers. Any disagreements were resolved before the rest of the data extraction was completed.

We used both full‐text versions and abstracts, including additional information (e.g. slides) of eligible studies to retrieve the data. We extracted trials reported in more than one publication in one form only. Where these sources did not provide sufficient information, we requested additional details from the contact author.

Where articles required translation, we used Google Translate in the first instance, and clarified any points we were uncertain about with native speakers. None of the included studies required translation, but if any had been in a language other than English, we would have sought a full translation of the methods and results sections by a native speaker.

Assessment of risk of bias in included studies

Two review authors (KW and SB, CK or SF) independently assessed all included studies for possible risk of bias, using the 'Risk of bias' tool, as described in Chapter 8 of the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011). The assessment included information about the design, conduct and analysis of the trials. We evaluated the criteria using a three‐point scale: low, high or unclear risk of bias. Where review authors differed in their assessment of bias, we resolved disagreements by consensus. If we had been unable to resolve disagreements by consensus, we would have consulted an additional review author (LE).

Measures of treatment effect

For dichotomous outcomes, the numbers of outcomes in treatment and control groups were recorded, and the risk ratio (RR) was reported with a 95% confidence interval (CI), which was used for reporting the treatment effect measures across individual studies.

For continuous outcomes, the mean and standard deviations (SD) were recorded. For continuous outcomes measured using the same scale, the effect measure was the mean difference (MD) with 95% CIs, and we would have used the standardised mean difference (SMD) for any outcomes measured using different scales. We calculated SDs from the standard error of the mean (SEM) and used these for our calculations throughout this review.

We anticipated trials would report some of their outcome data as median and interquartile (IQR) ranges due to a skew in particular distributions. Such skew is commonplace in measures of duration (e.g. duration of mechanical ventilation and length of hospital stay). Where trials reported data as median IQR, we summarised these results in tables.

Two trials reported data that could have allowed a change from baseline analysis to be undertaken (Han 2004; Komai 1998). However, as no change from baseline SDs was reported by these trials, we chose not to calculate the change from baseline scores. We reported the findings from these studies using MDs with 95% CIs as per all other continuous outcomes in this review.

We had planned to calculate the number needed to treat for an additional beneficial outcome (NNTB) with 95% CI and the number needed to treat for an additional harmful outcome (NNTH) with 95% CI, but we were unable to do so as we had insufficient relevant data to undertake this calculation.

Unit of analysis issues

We did not encounter any unit of analysis issues, as we did not include any cluster‐randomised trials in this review, and the unit of analysis and randomisation was always the participant. If we had encountered any relevant multi‐arm trials, we would have presented the groups in separate analyses to avoid double‐counting participants, in accordance with the advice given in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Similarly, had multiple time points been reported, we would have reported all relevant time points as separate analyses.

Dealing with missing data

We successfully contacted three study authors by email to obtain missing data. We contacted one for more information on the randomisation sequence as it was unclear in the published report (Komai 1998). We contacted the second to request clarity on outcome data and information on whether study personnel were blinded to treatment allocation (Cholette 2012). We contacted the third to clarify some outcome data, and, in response, we received the mean and SD values for the baseline characteristics and outcomes they reported in their manuscript (Ye 2013).

Where possible, we used intention‐to‐treat (ITT) data, but if not, we included per‐protocol (PP) data. One trial stated that they analysed data by both ITT and PP, but the manuscript reported baseline data by ITT and outcome assessment data by PP (Cholette 2012). A second trial reported both ITT and PP data for their primary outcome, with the results being very similar in both analyses (Willems 2010). In accordance with our protocol, we used the ITT data from this trial in our review.

Assessment of heterogeneity

We performed very few meta‐analyses in this review, due to the limited number of studies, thus we did not make a formal assessment of heterogeneity. Had there been sufficient data to support full meta‐analyses, our decision about whether to combine the results of individual studies would have depended on an assessment of heterogeneity. We would have assessed statistical heterogeneity of treatment effects between trials using a Chi² test with a significance level at P value < 0.1. We would have used the I² statistic to quantify the percentage of heterogeneity (I² > 30% moderate heterogeneity, I² > 75% considerable heterogeneity). There were insufficient data to explore potential causes of heterogeneity using sensitivity and subgroup analyses. In any future updates of this review, assuming we find sufficient data, we will perform an assessment of heterogeneity as outlined.

Assessment of reporting biases

As there were no meta‐analyses with more than 10 trials, we did not perform an assessment of reporting biases. In future updates of this review, we will explore potential publication bias (small trial bias) by generating a funnel plot and doing statistical testing using a linear regression test. A P value of less than 0.1 would be considered significant for this test (Lau 2006; Sterne 2011).

Data synthesis

We performed analyses according to the recommendations of The Cochrane Collaboration (Schunemann 2011), with aggregated data used for analysis. For statistical analysis, we used Review Manager 5 (RevMan 2012) and RevMan Web (RevMan 2023).

We used a random‐effects model for our limited meta‐analysis, to account for heterogeneity in the data, and we employed the Mantel‐Haenszel method for dichotomous data outcomes. We would have used the generic inverse variance method for survival data outcomes, should this data have been available.

We created 'summary of findings' tables for each comparison in this review, which provided the results of the primary outcome and five other outcomes identified by clinical experts as being of critical importance. We used the GRADE profiler to assess the certainty of evidence, as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Schunemann 2011a).

Subgroup analysis and investigation of heterogeneity

For each of our critical outcomes, we intended to conduct subgroup analyses comparing patients with acyanotic or cyanotic congenital heart disease because patients with cyanotic congenital heart disease tend to have higher starting haemoglobin levels. As the effect of a restrictive transfusion trigger will be more pronounced in the cyanotic group, two different transfusion triggers would need to be used for the two different clinical groups. We also intended to compare different time points for receiving transfusion: preoperatively, intraoperatively, postoperatively. This is because transfusion may be given at various different stages of the surgical pathway and may not have the same effect across all time points.

We did not have sufficient data to conduct any subgroup analyses. However, in future updates of the review, we will explore these subgroup analyses if we have appropriate data.

Sensitivity analysis

We had intended to assess the robustness of our findings by the following sensitivity analyses for critical outcomes in all comparisons:

• including only those trials at low risk of bias on the dimensions of selection and performance bias (clinicians only);

• including only those trials in which loss to follow‐up was 25% of participants or less.

However, there were insufficient data to enable these assessments. In future updates of this review, we will explore these sensitivity analyses if we have appropriate data.

Summary of findings and assessment of the certainty of the evidence

We created separate summary of findings tables for six comparisons: restrictive transfusion‐trigger versus liberal transfusion‐trigger; washed red blood cells in CPB prime versus unwashed red blood cells in CPB prime; crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime; ultrafiltration of CPB prime versus no ultrafiltration; retrograde autologous CPB prime versus standard CPB prime; 'fresh' (not near expiry date) versus 'old' (near to expiry date) red cell transfusion. We also had data for two further comparisons, which we did not present in the summary of findings table: cell salvage of CPB prime versus allogeneic red blood cells post‐CPB; leukoreduced red blood cell transfusion versus non‐leukoreduced red blood cell transfusion. The reason for not presenting these in summary of findings tables is that both of these interventions have now become widely adopted practice.

We included the primary outcome and five secondary outcomes, which were identified as being outcomes of critical importance: all‐cause mortality: short term (30 days post‐surgery); all‐cause mortality: long term (31 days to 2 years); severe adverse events: cardiac events; severe adverse events: infection; duration of mechanical ventilation; duration of intensive care stay. CK and KW used the GRADE approach outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Schunemann 2011a) and GRADEpro software (GRADEpro GDT 2023) to assess the certainty of the evidence. We used the overall risk of bias judgement as the basis of our decision‐making for downgrading due to study limitations (risk of bias), but where blinding was the only domain at high risk of bias, we did not downgrade for bias in mortality outcomes, as these are objective measurements. We had planned to consult a third review (LE) in the event of any disagreement between review authors over the GRADE assessments.

Results

Description of studies

Results of the search

Our electronic database searches identified 6437 records (5028 references and 1409 trial registration records), which were reduced to 4714 records (3504 references and 1210 trial registration records) once duplicates were removed. We screened these 4714 records according to the criteria defined above and rejected a further 4626 records as clearly irrelevant (see Figure 1).

1.

Our handsearching of the abstracts from the annual conference proceedings identified 11,202 references. After initial screening, we excluded all but two as they were either not RCTs or did not evaluate the correct intervention. We excluded the two remaining abstracts after obtaining further information: one was not an RCT and the other did not solely use red blood cells as the intervention.

We screened the full text of the remaining 90 records against detailed eligibility criteria, 88 identified from the search and two records identified through handsearching. Of these, we deemed 42 records (35 records of published studies and 7 trial database records), which described 19 independent trials, to be eligible for inclusion in this review. Three records described ongoing trials and two studies await classification. Forty‐three records were not eligible for inclusion. We listed 27 of these (reporting 25 studies) as excluded studies (see Excluded studies below).

One study classified as an ongoing trial in the previous version of this review is now included as the trial has been completed and published (Cholette 2017). Two studies classified as ongoing trials in the previous version of this review have now been completed, but we excluded them from this update as congenital heart disease patients were not mentioned or distinguished from the general study patient population (ISRCTN70923932; Steiner 2010). One study that was included in a previous version of this review has been excluded from this version of the review (Cholette 2010). This is because we clarified our inclusion criteria to require at least one arm of a study to include transfusion. In Cholette 2010, there was no definite allogeneic blood transfusion arm, so we excluded the study.

Included studies

We found 19 trials (described in 35 published references and 8 trial database records) eligible for inclusion in this review (see Characteristics of included studies table).

Design

The trials were published between 1990 and 2022. All were published in English. One trial was described in a conference abstract only (Chkhaidze 2014), and one trial was a subgroup of a larger trial, with the subgroup data only available as an abstract (Martin 2022); the remaining trials were published as full journal articles. All trials were parallel RCTs. Two papers (Martin 2022; Willems 2010) were subgroup analyses of a larger RCT (Lacroix 2007; Spinella 2019). The larger trials were not eligible for inclusion in our review as they examined the general paediatric intensive care population and were not specific to children with congenital heart disease undergoing cardiac surgery (Lacroix 2007; Spinella 2019). The subgroup analyses of Martin 2022 and Willems 2010 explored transfusion strategies in our populations of interest: paediatric patients undergoing surgery for congenital heart disease in paediatric intensive care units (PICU).

Sample sizes

The trials included 1606 randomised participants. The number of participants ranged from 16 (Liu 2007) to 309 (Ye 2013). Four trials reported inadequate power of their studies with reference to testing for statistical differences in clinical outcomes (Borisenko 2022; Cholette 2011; Cholette 2012; Willems 2010).

Setting

The trials were conducted in several countries: four trials in the USA (Cholette 2011; Cholette 2012; Cholette 2017; Hosking 1990); three in China (Fu 2016; Liu 2007; Ye 2013); two in Germany (Busch 2017; Shimpo 2001), two in the Netherlands (De Gast‐Bakker 2013; De Vries 2004); and one in each of Georgia (Chkhaidze 2014), Iran (Gholampour Dehaki 2019), Japan (Komai 1998), Korea (Han 2004), Russia (Borisenko 2022) and the UK (Swindell 2007). Two trials were multi‐country: one included the USA, Canada, France, Israel and Italy (Martin 2022) and one in Belgium, Canada and the USA (Willems 2010).

Participants

The participants were all neonates or children. There were no trials including adults with congenital heart disease. One trial looked at neonates only (Liu 2007); five trials included both neonates and children (Cholette 2011; Cholette 2012; Cholette 2017; Martin 2022; Swindell 2007); and 13 trials included children only (Borisenko 2022; Busch 2017; Chkhaidze 2014; De Gast‐Bakker 2013; De Vries 2004; Fu 2016; Gholampour Dehaki 2019; Han 2004; Hosking 1990; Komai 1998; Shimpo 2001; Willems 2010; Ye 2013).

Three trials included only cyanotic patients (Cholette 2011; Liu 2007; Swindell 2007); six trials included only acyanotic patients (Chkhaidze 2014; De Gast‐Bakker 2013; Han 2004; Komai 1998; Shimpo 2001; Willems 2010); and nine trials included both cyanotic and acyanotic patients (Borisenko 2022; Busch 2017; ; Cholette 2012; Cholette 2017; De Gast‐Bakker 2013; De Vries 2004; Hosking 1990; Martin 2022; Ye 2013). One trial did not report whether patients were cyanotic or acyanotic (Fu 2016).

Interventions

The trials examined red blood cell transfusion management as an intervention in several different ways (see Table 7).

1. Included studies by intervention and age group.

Comparison	Cyanosis	Neonates	Neonates/paediatric	Paediatric	Adults
Restrictive transfusion‐trigger versus liberal transfusion‐trigger	Acyanotic	None	None	Chkhaidze 2014; De Gast‐Bakker 2013; Willems 2010	None
	Cyanotic	None	Cholette 2011	Cholette 2017
	Both	None	None	None
Washed red cells in CPB prime versus unwashed red cells in CPB prime	Acyanotic	None	None	None	None
	Cyanotic	Liu 2007	Swindell 2007	None
	Both	None	Cholette 2012	Busch 2017; Hosking 1990
Crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime	Acyanotic	None	None	Borisenko 2022; Han 2004	None
	Cyanotic	None	None	None
	Both	None	None	None
Ultrafiltration of CPB prime versus no ultrafiltration	Acyanotic	None	None	Shimpo 2001	None
	Cyanotic	None	None	None
	Both	None	None	Gholampour Dehaki 2019
Retrograde autologous CPB prime versus standard CPB prime	Acyanotic	None	None	None	None
	Cyanotic	None	None	None
	Both	None	None	Fu 2016
'Fresh' (not near expiry date) versus 'old' (near to expiry date) red cell transfusion	Acyanotic	None	None	None	None
	Cyanotic	None	None	None	None
	Both	None	Martin 2022*	None	None
Cell salvage of CPB prime versus allogeneic red cells post‐CPB	Acyanotic	None	None	None	None
	Cyanotic	None	None	None
	Both	None	None	Ye 2013
Leukoreduced red cell transfusion versus non‐leukoreduced red cell transfusion	Acyanotic	None	None	Komai 1998	None
	Cyanotic	None	None	None
	Both	None	None	De Vries 2004
Volume A red cell transfusion versus volume B red cell transfusion	Acyanotic	We did not find any studies for this comparison.
	Cyanotic
	Both
Whole blood versus red cell transfusion	Acyanotic	We did not find any studies for this comparison.
	Cyanotic
	Both
Irradiated red cell transfusion versus non‐irradiated red cell transfusion	Acyanotic	We did not find any studies for this comparison.
	Cyanotic
	Both
Transfusion versus no transfusion	Acyanotic	We did not find any studies for this comparison.
	Cyanotic
	Both

*Unclear whether the population includes both cyanotic and acyanotic patients, as subgroup analysis is reported only in abstract form

CPB: cardiopulmonary bypass

Five trials assessed restrictive transfusion‐trigger versus a liberal transfusion‐trigger (Chkhaidze 2014; Cholette 2011; Cholette 2017; De Gast‐Bakker 2013; Willems 2010). In the restrictive arm, children or neonates were transfused when their Hb concentration was less than 9.0 g/dL plus clinical indication for transfusion (Cholette 2011), less than 8.0 g/dL (Chkhaidze 2014; De Gast‐Bakker 2013), less than 7.0 g/dL (Willems 2010), less than 7.0 g/dL for biventricular repairs or less than 9.0 g/dL for palliative procedures plus a clinical indication (Cholette 2017). In the liberal arm, children or neonates were transfused when their Hb concentration was less than 13 g/dL regardless of clinical indication for transfusion (Cholette 2011), less than 10 g/dL (Chkhaidze 2014), less than 10.8 g/dL (De Gast‐Bakker 2013), less than 9.5 g/dL for biventricular repairs or less than 12.0 g/dL for palliative procedures regardless of clinical indications or less than 9.5 g/dL (Willems 2010).

Eleven trials assessed different aspects of non‐standard CPB prime, which we have presented in six different comparisons. Five trials assessed the impact of washed red blood cells in CPB prime versus unwashed red blood cells in CPB prime (Busch 2017; Cholette 2012; Hosking 1990; Liu 2007; Swindell 2007), and, in two of these trials, the red blood cells had also been irradiated in both arms (Cholette 2012; Swindell 2007). Two trials assessed crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime (Borisenko 2022; Han 2004). Two trials compared ultrafiltration of CPB prime versus no ultrafiltration (Gholampour Dehaki 2019; Shimpo 2001); one trial compared retrograde autologous CPB prime versus standard CPB prime (Fu 2016); and one trial assessed cell salvage of CPB prime blood versus allogenic red blood cells post‐CPB (Ye 2013).

One trial assessed the impact of fresher (stored less than seven days) versus older (standard issue blood, with no specific age requirement) blood (Martin 2022).

Two trials assessed leukoreduced red blood cell transfusion versus non‐leukoreduced red blood cell transfusion, but at different time points in the operation and in different patient populations. One trial, in acyanotic neonates and paediatric patients, explored the benefits (postoperative oxygenation and circulating leukocyte counts) of a leukoreduction filter for the blood in the bypass circuit at the end of the operation (De Vries 2004). The other trial, in acyanotic paediatric patients, reported on the clinical effect (lung function) of applying leukoreduction filters to stored donor red cells added to the CPB circuit at the beginning of the operation (Komai 1998).

Outcomes

No trial measured all outcomes of interest in this review. Six trials reported the primary outcome of this review (Cholette 2012; Cholette 2017; Liu 2007; Shimpo 2001; Willems 2010; Ye 2013). Three trials did not include any outcomes predefined as of interest to this review (Hosking 1990; Martin 2022; Swindell 2007). However, two of these included at least one biochemistry outcome that was deemed important to be added to this review post hoc (lactate levels, sodium levels, potassium levels, glucose levels) (Hosking 1990; Swindell 2007). We have added these outcomes to this review, clearly marking them as outcomes that were identified and added after the original review protocol was agreed (see Differences between protocol and review).

Excluded studies

We excluded 41 studies from the review following a full‐text eligibility assessment (see the Characteristics of excluded studies table). Fourteen studies were not RCTs and 19 had an ineligible intervention. Six had an ineligible patient population; of these, one was in the general neonatal population (Fergusson 2009), one contained neonates with cardiac neonates, but they did not undergo cardiac surgery (Gupta 2007), in one, people with congenital heart disease were excluded (Hajjar 2010), and in two studies, congenital heart disease patients were not mentioned or distinguished from the general study patient population (ISRCTN70923932; Steiner 2010). Finally, in another study there was a mixed PICU population but no cardiac surgery subgroup (Yay 2017). One study was withdrawn due to manufacturing issues, with no participants recruited (NCT03167788), while another study did not start as funding was withdrawn (NCT04537000).

Studies awaiting classification

We included two trials in the 'studies awaiting classification' section of the review (CTRI/2017/07/008972; Li 2020) (see Characteristics of studies awaiting classification table). One trial states it is comparing three interventions: N‐PRBC group: non‐leukoreduced red blood cells, S‐PRBC group: buffy coat depleted SAGM suspended red blood cells and L‐PRBC group: pre‐storage leukoreduced red blood cells using 3rd generation leukofilters (CTRI/2017/07/008972). We placed this trial in 'awaiting classification' because while the recruitment status states that it is open to recruitment, this status has not been updated since July 2017 and the expected trial end date was February 2019. The other trial describes a restrictive transfusion strategy in the intervention group, but we were unable to establish how transfusions were administered to the control group, or whether there were co‐interventions in both groups (Li 2020). We contacted the authors for clarification but did not receive a reply.

Ongoing studies

We identified three ongoing studies (see the Characteristics of ongoing studies table). One study will compare fresh whole blood, transfused within five days of collection with standard red blood cells (CTRI/2023/06/053544); it is estimated to be completed in May 2024. One study will compare pathogen reduced versus conventional red blood cells and is scheduled to complete in December 2023 (NCT03459287). This trial would need to present results for patients undergoing cardiac surgery for congenital cardiac disease as a separate group to be included in this systematic review. One study will compare bloodless CPB prime with blood containing CPB prime, and is estimated to be completed in May 2026 (NCT05881564). We will monitor the progress of this trial, and, if eligible, we will include it in future updates of this review.

Risk of bias in included studies

See Figure 2 for a graph of our overall summary of the risk of bias in the studies, and Figure 3 for details of our risk of bias assessment for each study.

2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

3.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Random sequence generation

Six trials reported details of the randomisation sequence (De Vries 2004; Fu 2016; Han 2004; Komai 1998; Martin 2022; Willems 2010). We judged five of these six trials as being at low risk of bias; they used computer‐generated lists (De Vries 2004; Han 2004; Martin 2022), random number tables (Fu 2016) and via centralised randomisation assigning patients to intervention groups in blocks of two or four (Willems 2010). We judged one trial as being at high risk of bias as an alternation method was used (Komai 1998).

We judged the generation of the randomisation sequence at unclear risk of bias in the other 13 trials (Borisenko 2022; Busch 2017; Chkhaidze 2014; Cholette 2017; De Gast‐Bakker 2013; Gholampour Dehaki 2019; Cholette 2011; Cholette 2012; Hosking 1990; Liu 2007; Shimpo 2001; Swindell 2007; Ye 2013). Three trials used block randomisation to randomise into either transfusion strategy, but no further description was provided as to how the random sequence was generated (Cholette 2011; Cholette 2012; Cholette 2017). Ten trials did not report details of their generation of the randomisation sequence methods (Borisenko 2022; Busch 2017; Chkhaidze 2014; De Gast‐Bakker 2013; Gholampour Dehaki 2019; Hosking 1990; Liu 2007; Shimpo 2001; Swindell 2007; Ye 2013), so we defined them as having an unclear risk of bias.

Concealment of treatment allocation

The method of randomisation (as described above) was deemed to be of low risk of bias for allocation concealment in four trials (De Gast‐Bakker 2013; Martin 2022; Shimpo 2001; Willems 2010), where only the perfusionist was informed of allocation in one trial (Shimpo 2001), physicians, nurses and research staff were unaware of the block‐randomisation strategy in the second trial (Willems 2010), sealed randomisation envelopes were used in the third trial (De Gast‐Bakker 2013), and in the fourth trial, only an independent study statistician at the data co‐ordinating centre had knowledge of randomisation codes (Martin 2022).

We deemed the method of randomisation to be inadequate (high risk of bias) to conceal treatment allocation in one trial, as the author confirmed directly by email that unsealed envelopes were used (De Vries 2004). Fourteen trials did not provide sufficient information for us to assess the adequacy of allocation concealment (Borisenko 2022; Busch 2017; Chkhaidze 2014; Cholette 2011; Cholette 2012; Cholette 2017; Fu 2016; Gholampour Dehaki 2019; Han 2004; Hosking 1990Komai 1998; Liu 2007; Swindell 2007; Ye 2013); therefore, we judged them as having unclear risk of bias.

Blinding of participants and personnel (performance bias)

Three studies were at low risk of performance bias (Cholette 2017; Martin 2022; Shimpo 2001). Twelve trials were at unclear risk of performance bias as the authors did not provide sufficient information to enable us to make a judgement on the adequacy of blinding (Busch 2017; Chkhaidze 2014; De Gast‐Bakker 2013; De Vries 2004; Fu 2016; Gholampour Dehaki 2019; Han 2004; Hosking 1990; Komai 1998; Liu 2007; Swindell 2007; Ye 2013). Four trials were at high risk of performance bias because treatment allocation was known to participants and personnel (Borisenko 2022; Cholette 2011; Cholette 2012; Willems 2010).

Blinding of outcome assessment (detection bias)

Three studies were at low risk of detection bias, reporting that they used outcome assessors who were unaware of the treatment allocation (Martin 2022; Shimpo 2001; Willems 2010). Fifteen studies did not report on the blinding of outcome assessors and were assessed as being at unclear risk of detection bias (Borisenko 2022; Busch 2017; Chkhaidze 2014; Cholette 2011; Cholette 2017; De Gast‐Bakker 2013; De Vries 2004; Fu 2016; Gholampour Dehaki 2019; Han 2004; Hosking 1990; Komai 1998; Liu 2007; Swindell 2007Ye 2013). We assessed one study as being at high risk of detection bias because outcome assessors were not blinded to treatment allocation (Cholette 2012).

Incomplete outcome data

Sixteen of the 19 included trials were at low risk of attrition bias; the other three were unclear.

Of the low‐risk‐of‐bias trials, 11 included all randomised participants in the analysis of outcome data and did not lose any participants during follow‐up (Chkhaidze 2014; Cholette 2017; De Vries 2004; Gholampour Dehaki 2019; Hosking 1990; Komai 1998; Liu 2007; Shimpo 2001; Swindell 2007; Willems 2010; Ye 2013). Five further trials did not include all randomised participants in the analysis of clinical, scientific or both clinical and scientific outcomes, but they reported the number of exclusions in each trial arm and provided reasons for this non‐inclusion (Cholette 2011; Cholette 2012; De Gast‐Bakker 2013; Fu 2016; Han 2004).

The reasons provided for not including some participants in data analysis were as follows. In Cholette 2011, two randomised participants (3% of participants in this trial) were excluded from the trial and from outcome analysis (one participant from each intervention arm). No other participant dropped out of the study or was lost to follow‐up. In Cholette 2012, no participant was lost to follow‐up, but six were excluded following randomisation for surgical reasons that were reported. Following randomisation, a further 34 participants (17 in each treatment arm) did not receive a transfusion and were therefore not included in the per protocol analysis. In De Gast‐Bakker 2013, the trial was discontinued in seven participants. Red blood cell transfusion was given in four participants and withheld in three participants, in contradiction to the randomisation protocol. All seven participants were included in the analyses using the intention‐to‐treat principle. In Fu 2016, one participant was excluded from analyses; this participant did not receive the allocated intervention as the operation time was longer than 120 minutes and was excluded from analysis. In Han 2004, one participant (3% of participants in this trial) in the intervention group was excluded for clinical reasons and this participant's data were not included in any outcome analyses.

Three trials were at unclear risk of attrition bias (Borisenko 2022; Busch 2017; Martin 2022). In Busch 2017, three randomised participants were excluded from the analyses. Although reasons were given for these exclusions, it was unclear to which trial arm these participants had been randomised. We therefore deemed the risk of attrition bias in this trial to be unclear. Similarly, we judged the attrition bias as unclear for Borisenko 2022. This was due to the fact that we were unable to work out how many participants were originally approached to be included in the study. Finally, we judged attrition bias in Martin 2022 as unclear, as there was some discrepancy in participant numbers: the number of participants in the subgroup analysis did not match the number stated for that same group in the full trial paper (178 versus 210), and no explanation for this discrepancy was provided.

Selective reporting

In three trials, all outcomes defined in the prospectively registered trial protocol were reported in the results, with a low risk of bias (Cholette 2011; Cholette 2012; Cholette 2017). In seven trials, all outcomes defined in the methods section were presented in the results, but no prospectively registered study protocol was identified. Therefore, we deemed these trials to have an unclear risk of bias (Borisenko 2022; De Gast‐Bakker 2013; De Vries 2004; Fu 2016; Liu 2007; Swindell 2007; Willems 2010). Seven additional trials did not define the outcomes they were interested in; therefore, it is impossible to identify whether there was reporting bias in these trials (Gholampour Dehaki 2019; Han 2004; Hosking 1990; Komai 1998; Martin 2022; Shimpo 2001; Ye 2013), and we judged them as having unclear risk of bias.

In one trial, several outcomes listed in the methods section were not reported in the results, and we considered this trial to have a high risk of reporting bias (Busch 2017). In a second trial, limited information was presented via a conference abstract, and we judged the risk of reporting bias as high (Chkhaidze 2014).

Protocol adherence

Thirteen trials reported protocol adherence (Busch 2017; Cholette 2011; Cholette 2012; Cholette 2017; De Gast‐Bakker 2013; De Vries 2004; Fu 2016; Gholampour Dehaki 2019; Han 2004; Hosking 1990; Swindell 2007; Willems 2010; Ye 2013). In one trial, there was 100% compliance with the trial protocol and the protocol was never suspended during the trial (Cholette 2011). Five trials described protocol violations (Cholette 2012; Cholette 2017; De Gast‐Bakker 2013; Fu 2016; Willems 2010). In Cholette 2012, there were three protocol violations: one in a neonate receiving washed red cells and two in neonates in the unwashed red cell group. In Cholette 2017, compliance was reported as 93% in the restrictive group and 100% in the liberal group. In De Gast‐Bakker 2013, red blood cell transfusion was given to three participants in the restrictive group, in contradiction to the randomisation protocol. In the liberal group, red blood cell transfusion was withheld in three participants and red cell transfusion was given in one participant, in contradiction to the randomisation protocol. In Fu 2016, one participant was excluded from the trial after randomisation because operation time was longer than 120 minutes. In Willems 2010, 10 participants did not reach pre‐defined criteria for good protocol adherence (80%), and seven participants in the restrictive group and one in the liberal group were suspended temporarily from the transfusion protocol.

Support and sponsorship

Twelve trials did not report the source of funding (Borisenko 2022; Chkhaidze 2014; De Gast‐Bakker 2013; De Vries 2004; Fu 2016; Gholampour Dehaki 2019; Han 2004; Hosking 1990; Komai 1998; Liu 2007; Shimpo 2001; Swindell 2007). In the seven trials that reported source of funding, three trials were supported in part by university grants (Busch 2017; Cholette 2011; Cholette 2012) and five received grants from government health departments or agencies (Busch 2017; Cholette 2017; Martin 2022; Willems 2010; Ye 2013). In two studies, at least one author declared a relevant conflict of interest with a manufacturer or pharmaceutical company (Cholette 2012; Willems 2010).

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5; Table 6

We identified eight comparisons of interest in our included studies. Of these, we selected six as main findings to be presented in our summary of findings tables: restrictive transfusion‐trigger versus liberal transfusion‐trigger; washed red blood cells in CPB prime versus unwashed red blood cells in CPB prime; crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime; ultrafiltration of CPB prime versus no ultrafiltration; retrograde autologous CPB prime versus standard CPB prime and 'fresh' (not near expiry date) versus 'old' (near to expiry date) red blood cell transfusion. However, the only trial we identified on 'fresh' (not near expiry date) versus 'old' (near to expiry date) red blood cell transfusion did not present any data that matched any of the outcomes of our review (Martin 2022).

We identified two further comparisons that we did not present in summary of findings tables as these interventions are now standard practice in most centres. The two additional comparisons were: cell salvage of CPB prime versus allogeneic red blood cells post‐CPB; leukoreduced red blood cell transfusion versus non‐leukoreduced red blood cell transfusion. We have presented a summary of the results for our most important outcomes in Table 8.

2. Additional results, not in summary of findings tables.

Patient or population: individuals undergoing cardiac surgery for congenital heart disease Setting: inpatient Intervention: cell salvage of CPB prime Comparison: allogeneic red cells post‐CPB
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with allogeneic red cells post cardiopulmonary bypass	Risk with cell salvage of CPB prime
All‐cause mortality: short term (0 to 30 days post‐ surgery)	22 per 1000	5 per 1000 (1 to 50)	RR 0.21 (0.02 to 2.31)	309 (1 RCT)	⨁◯◯◯ Very lowa	The evidence is very uncertain about the effect of cell salvage cardiopulmonary bypass prime on mortality at 30 days.
All‐cause mortality: long term (31 days to 2 years post‐surgery)	We did not find any data for this outcome.
Severe adverse events: cardiac events	We did not find any data for this outcome.
Severe adverse events: infection	We did not find any data for this outcome.
Duration of mechanical ventilation	Data for this outcome were only presented as medians (interquartile range) in one study of 309 participants. This result is reported in Table 14.
Duration of ICU stay	Data for this outcome were only presented as medians (interquartile range) in one study of 309 participants. This result is reported in Table 15.
Patient or population: individuals undergoing cardiac surgery for congenital heart disease Setting: inpatient Intervention: leukoreduced red cell transfusion Comparison: non‐leukoreduced red cell transfusion
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with non‐leukoreduced red cell transfusion	Risk with leukoreduced red cell transfusion
All‐cause mortality: short term (0 to 30 days post‐surgery)	We did not find any data for this outcome.
All‐cause mortality: long term (31 days to 2 years post‐surgery)	We did not find any data for this outcome.
Severe adverse events: cardiac events	We did not find any data for this outcome.
Severe adverse events: infection	We did not find any data for this outcome.
Duration of mechanical ventilation	The mean duration of mechanical ventilation was 23 hours.	MD 7.2 hours lower (20.72 lower to 6.32 higher)	‐	46 (1 RCT)	⨁◯◯◯ Very lowa	The evidence is very uncertain about the effect of leukoreduced red cell transfusion on duration of mechanical ventilation.
Duration of ICU stay	The mean duration of ICU stay was 4.1 days.	MD 1.1 days lower (7.72 lower to 5.52 higher)	‐	46 (1 RCT)	⨁◯◯◯ Very lowa	The evidence is very uncertain about the effect of leukoreduced red cell transfusion on duration of ICU stay.

^aWe downgraded the certainty of the evidence by one level for risk of bias and by two levels for very serious imprecision because of very wide confidence intervals and the result being based on a single study.

CI: confidence interval; CPB: cardiopulmonary bypass; ICU: Intensive care unit; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio

There was substantial clinical diversity in the participant groups (cyanotic and acyanotic, and paediatric and neonate), but we did not have sufficient numbers to undertake any planned subgroup analyses for these populations.

Restrictive transfusion‐trigger versus liberal transfusion‐trigger

Primary outcome

All‐cause mortality: short term (0 to 30 days post‐surgery)

Cholette 2011, Cholette 2017 and Willems 2010 reported data for this outcome. Cholette 2011 reported that there were no deaths in either arm. Only Cholette 2017 provided some details on the causes of death, but the time points at which the deaths occurred were unclear. There was no difference in the number of deaths between the restrictive and liberal thresholds, but the evidence is very uncertain (RR 1.12, 95% CI 0.42 to 3.00; 3 RCTs, 347 participants; very low certainty evidence; Table 9; Analysis 1.1).

3. Causes of mortality in the included trials.

All‐cause mortality: short term (0 to 30 days post‐surgery)
Restrictive transfusion‐trigger versus liberal transfusion‐trigger
Chkhaidze 2014	Mortality not reported
Cholette 2011	Not applicable: no deaths reported
Cholette 2017	Unclear, as some anomalies and discrepancies in reporting, with causes of death not fully reported
De Gast‐Bakker 2013	Mortality not reported
Willems 2010	2 deaths were reported, but there were no data on cause of death.
Washed red cells in CPB prime versus unwashed red cells in CPB prime
Busch 2017	Mortality not reported
Cholette 2012	Washed group (1 participant) 1 paediatric participant died on POD 0 secondary to a pulmonary hypertensive crisis. Unwashed group (4 participants) 1 neonate died in the operating room as a result of diffuse bleeding/coagulopathy. 1 neonate died on POD 4 after support was withdrawn as the participant had no LV function and was unable to come off ECMO. 1 neonate died on POD 11 following an arrest with acute desaturation, junctional rhythm, poor function on Echo and lactic acidosis. 1 neonate died on POD 23 as a result of an arrest stopping breathing and a subsequent inability to resuscitate the participant.
Hosking 1990	Mortality not reported
Liu 2007	Not applicable: no deaths reported (only in‐hospital mortality reported)
Swindell 2007	Mortality not reported
Crystalloid (bloodless) CPB prime versus red cell containing CPB prime
Borisenko 2022	Mortality not reported
Han 2004	Mortality not reported
Ultrafiltration of CPB prime versus no ultrafiltration
Gholampour Dehaki 2019	Mortality not reported
Shimpo 2001	Not applicable: no deaths reported (only operative mortality reported)
Retrograde autologous CPB prime versus standard CPB prime
Fu 2016	Mortality not reported
'Fresh' (not near to expiry date) versus 'old' (near to expiry date) red cell transfusion
Martin 2022	Mortality not reported
Cell salvage of CPB prime blood versus allogeneic red cells post CPB
Ye 2013	3 deaths were reported, but there were no data on cause of death.
‘Fresh' (not near expiry date) versus 'old' (near to expiry date) red cell transfusion
De Vries 2004	Mortality not reported
Komai 1998	Mortality not reported
All‐cause mortality: long term: 31 days to two years post‐surgery
Restrictive transfusion‐trigger versus a liberal transfusion‐trigger
Chkhaidze 2014	Mortality not reported
Cholette 2011	1 participant in the liberal transfusion strategy arm died on day 39 from staphylococcal sepsis.
Cholette 2017	Unclear, as some anomalies and discrepancies in reporting, with causes of death not fully reported.
De Gast‐Bakker 2013	Mortality not reported
Willems 2010	Late mortality not reported
Washed red cells in CPB prime versus unwashed red cells in CPB prime
Busch 2017	Mortality not reported
Cholette 2012	Washed group (1 participant) 1 neonate died on POD 57 after care was withdrawn in view of postoperative neurological disease. Unwashed group (2 participants) 1 neonate died on POD 61 following an acute arrest and inability to resuscitate the participant. 1 6‐month‐old participant arrested on POD 0 and subsequently arrested and died on POD 90. Autopsy revealed RSV bronchiolitis, acute Ischaemic neuronal necrosis in watershed regions, myocardial necrosis and chronic heart failure.
Hosking 1990	Mortality not reported
Liu 2007	Late mortality not reported
Swindell 2007	Mortality not reported
Crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime
Borisenko 2022	Mortality not reported
Han 2004	Mortality not reported
Ultrafiltration of CPB prime versus no ultrafiltration
Gholampour Dehaki 2019	Mortality not reported
Shimpo 2001	Late mortality not reported
Retrograde autologous CPB prime versus standard CPB prime
Fu 2016	Mortality not reported
‘Fresh' (not near expiry date) versus 'old' (near to expiry date) red cell transfusion
Martin 2022	Mortality not reported
Cell salvage of CPB prime versus allogeneic red cells post‐CPB
Ye 2013	Late mortality not reported
Leukoreduced red cell transfusion versus non‐leukoreduced red cell transfusion
De Vries 2004	Mortality not reported
Komai 1998	Mortality not reported

CPB: cardiopulmonary bypass; Echo: echocardiogram; ECMO: extracorporeal membrane oxygenation (machine); LV: left ventricular; POD: postoperative day; RSV: respiratory syncytial virus

1.1. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 1: All‐cause mortality: short term (0 to 30 days post surgery)

Secondary outcomes

All‐cause mortality: long term (31 days to two years post‐surgery)

Only Cholette 2011 fully reported data for this outcome. There was no evidence of a difference in the number of deaths up to two years post‐surgery between the restrictive and liberal threshold group (RR 0.33, 95% CI 0.01 to 7.87; 1 RCT, 60 participants; very low certainty evidence; Analysis 1.2). One further study provided some information about late mortality, but we were not able to extract exact numbers (Cholette 2017). Where reported, details of the cause and time of death are provided in Table 9.

1.2. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 2: All‐cause mortality: long term (31 days to two years post‐surgery)

Severe adverse events: cardiac events

Two RCTs reported data on this outcome (De Gast‐Bakker 2013; Willems 2010). There was little to no difference between the restrictive and liberal trigger arms in the number of participants who had cardiovascular dysfunction, but the evidence is very uncertain (RR 1.00 95% CI 0.73 to 1.37; 2 RCTs, 232 participants; very low certainty evidence; Analysis 1.3). No further details were given as to when the dysfunction occurred, how it was treated or the outcome for these participants.

1.3. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 3: Severe adverse events: cardiac events

Severe adverse events: acute lung injury

Two RCTs reported data on this outcome (De Gast‐Bakker 2013; Willems 2010). There was no evidence of a difference in the number of participants experiencing an acute lung injury between intervention arms (RR 1.03, 95% CI 0.74 to 1.45; 2 RCTs, 232 participants; Analysis 1.4). No further details were given as to when the acute lung injury occurred, how it was treated or the outcome for these participants.

1.4. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 4: Severe adverse events: acute lung injury

Severe adverse events: stroke

One RCT reported data on this outcome (Cholette 2017). There was one incident of stroke in the restrictive transfusion group and no stroke in the liberal transfusion group (RR 2.96, 95% CI 0.12 to 71.68; 1 RCT, 161 participants; Analysis 1.5).

1.5. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 5: Severe adverse events: stroke

Severe adverse events: thromboembolism

One RCT reported data for this outcome (Cholette 2017). There was little to no difference in the number of participants experiencing thromboembolism between the intervention arms (RR 1.71, 95% CI 0.52 to 5.61; 1 RCT, 162 participants; Analysis 1.6).

1.6. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 6: Severe adverse events: thromboembolism

Severe adverse events: renal failure (needing renal replacement therapy)

Two RCTs reported data on this outcome (Cholette 2017; Willems 2010). There was little to no difference in the number of participants experiencing renal failure between the intervention arms (RR 0.33, 95% CI 0.01 to 7.90; 2 RCTs, 287 participants; Analysis 1.7). No details as to the timing and severity of dysfunction were provided.

1.7. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 7: Severe adverse events: renal failure (needing renal replacement therapy)

Severe adverse events: infection

Two RCTs reported data on this outcome (De Gast‐Bakker 2013; Willems 2010). There was no evidence of a difference in the number of participants who had systemic inflammatory response syndrome between the intervention arms, but the evidence is very uncertain (RR 0.81, 95% CI 0.47 to 1.39; 2 RCTs, 232 participants; very low certainty evidence; Analysis 1.8).

1.8. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 8: Severe adverse events: infection

Severe adverse events: haemorrhage (return to theatre for bleeding)

Four RCTs reported data for this outcome (Cholette 2011; Cholette 2017; De Gast‐Bakker 2013; Willems 2010). There was little to no difference in the number of participants experiencing a haemorrhage requiring a return to theatre for bleeding between intervention arms (RR 2.33, 95% CI 0.35 to 15.57; 4 RCTs, 454 participants; Analysis 1.9).

1.9. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 9: Severe adverse events: haemorrhage (return to theatre for bleeding)

Haematocrit (%) levels postoperatively

No trial reported data for this outcome.

Haemoglobin (g/dL) levels postoperatively

Four trials reported data for this outcome (Cholette 2011; Cholette 2017; De Gast‐Bakker 2013; Willems 2010). We did not undertake a meta‐analysis due to clinical diversity and variation in timing of outcome measurement, but we have summarised all outcomes relating to haemoglobin levels in Table 10. There was a difference in haemoglobin concentrations after the first postoperative transfusion between the intervention arms favouring the liberal threshold group in three trials (MD −2.80 g/dL, 95% CI −3.30 to −2.30; 1 RCT, 60 participants (Cholette 2011); MD −1.90 g/dL, 95% CI −2.24 to −1.56; 1 RCT, 162 participants (Cholette 2017); MD ‐2.00 g/dL, 95% CI −2.45 to −1.55; 1 RCT, 107 participants (De Gast‐Bakker 2013)), and in one trial (Willems 2010), there was no clear difference in haemoglobin concentrations between the intervention arms (MD ‐1.20 g/dL, 95% CI ‐4.43 to 2.03; 1 RCT, 124 participants; Analysis 1.10).

4. Haemoglobin levels (g/dL) postoperatively.

Study name	Intervention	Comparator
Restrictive transfusion‐trigger versus liberal transfusion‐trigger
Cholette 2011	At baseline: 14.6 (1.8) On PICU admission, prior to intervention: 12.1 (1.3) At study end (time point slightly unclear): 11.1 (1.3)	At baseline: 14.6 (1.7) On PICU admission: 12.0 (11.4) At study end (time point slightly unclear): 13.9 (0.5)
Cholette 2017	At baseline (on PICU admission prior to intervention): 11.9 (1.4) g/dL At discharge from PICU: 10.3 (1.1) g/dL	At baseline (on PICU admission prior to intervention): 11.9 (1.7) g/dL At discharge from PICU: 12.2 g/dL
De Gast‐Bakker 2013	At baseline, prior to surgery: 12.2 (1.2) g/dL On admittance to PICU: 9.6 (1.1) g/dL At discharge from PICU: 10.2 (1.2) g/dL	At baseline prior to surgery: 11.9 (1.5) g/d/L On admittance to PICU: 10.3 (1.2) g/dL At discharge from PICU: 12.2 (1.2) g/dL
Willems 2010*	At randomisation: 8.3 (6.4) Prior to first transfusion: 7.1 (SEM 4.8) After first transfusion: 9.9 (SEM 10.3)	At randomisation: 8.0 (SEM 7.1) Prior to first transfusion: 8.2 (SEM 7.1) After first transfusion 11.1 (SEM 7.9)
Washed red cells in CPB prime versus unwashed red cells in CPB prime
No data reported for this outcome
Crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime
Borisenko 2022**	Immediately postoperatively 10.6.0 (10.2 to 11.0) Day 1: 10.1 (9.9 to 10.7)	Immediately postoperatively 13.1 (10.4 to 12.6) Day 1: 12.4 (11.3 to 12.7)
Busch 2017	Data reported only as figure
Ultrafiltration of CPB prime versus no ultrafiltration
No data reported for this outcome
Retrograde autologous CPB prime versus standard CPB prime
No data reported for this outcome
‘Fresh' (not near expiry date) versus 'old' (near to expiry date) red cell transfusion
No data reported for this outcome
Cell salvage of CPB prime versus allogeneic red cells post‐CPB
No data reported for this outcome
Leukoreduced red cell transfusion versus non‐leukoreduced red cell transfusion
No data reported for this outcome

*This outcome was reported as mean (SEM) and was converted to mean and SD by the review authors.

**This outcome is reported as median values (with 25 and 75 percentiles).

CPB: cardiopulmonary bypass; PICU: paediatric intensive care unit; SD: standard deviation; SEM: standard error of the means

1.10. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 10: Haemoglobin (g/dL) levels postoperatively

Haematocrit/haemoglobin (g/dL) levels at discharge

No trial reported data for this outcome.

Volume or number of red blood cell units transfused

Five RCTs reported data for this outcome (Chkhaidze 2014; Cholette 2011; Cholette 2017; De Gast‐Bakker 2013; Willems 2010). We did not undertake a meta‐analysis due to clinical diversity and how the outcome was measured. Where the outcome was presented in units, the authors did not specify the size of the units, so we could not be sure that the data were comparable. We have presented all outcomes relating to the volume or number of red blood cell units given in Table 11. We were able to combine results for the number of participants receiving any red blood cell transfusion for this outcome. Fewer participants received transfusion in the restrictive group (RR 0.26, 95% CI 0.12 to 0.56; 2 RCTs, 185 participants; Analysis 1.11).

5. Volume or number of red blood cell units transfused to discharge.

Study name	Intervention	Comparator
Restrictive transfusion‐trigger versus liberal transfusion‐trigger
Chkhaidze 2014	Volume of blood transfused: 164 (71) ml/kg	Volume of blood transfused: 264 (59) ml/kg
Cholette 2011	Number of units transfused in first 48 hours postoperatively: 0.43 (0.6) 11/30 participants received any transfusion.	Number of units transfused in first 48 hours postoperatively: 2.1 (1.2) 29/30 participants received any transfusion.
Cholette 2017*	Number of transfusions 0 (0 to 10) Number of RBC exposures 0 (0 to 4)	Number of transfusions 1 (0 to 10) Number of RBC exposures 1 (0 to 5)
De Gast‐Bakker 2013	Volume of transfusions given in PICU: 186 (70) ml	Volume of transfusions given in PICU: 259 (90) ml
Willems 2010	12.6 (3.7) volume per transfusion ml/kg 13 transfusions were given in total for this group of 63 participants. 11 participants received any transfusion.	13.6 (4) volume per transfusion ml/kg 82 transfusions were given in total for this group of 62 participants. 62 participants received any transfusion.
Washed red cells in CPB prime versus unwashed red cells in CPB prime
Cholette 2012	Number of units transfused: 2.97 (3.27)	Number of units transfused: 3.27 (4.3)
Crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime
No data reported for this outcome
Ultrafiltration of CPB prime versus no ultrafiltration
No data reported for this outcome
Retrograde autologous CPB prime versus standard CPB prime
No data reported for this outcome
‘Fresh' (not near expiry date) versus 'old' (near to expiry date) red cell transfusion
No data reported for this outcome
Cell salvage of CPB prime versus allogeneic red cells post‐CPB
No data reported for this outcome
Leukoreduced red cell transfusion versus non‐leukoreduced red cell transfusion
Komai 1998**	Number of units transfused: 6.3 (0.49) units	Number of units transfused: 6 (1.41) units

*This outcome is reported as median values (with range).

**This outcome was reported as mean (SEM) and was converted to mean and SD by the review authors.

CPB: cardiopulmonary bypass; PICU: paediatric intensive care unit; RBC: red blood cells; SD: standard deviation; SEM: standard error of the means

1.11. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 11: Number of participants receiving any red cell transfusion

Volume or number of other blood products transfused (i.e. fresh frozen plasma, platelets, cryoprecipitate)

Three RCTs reported on the volume or number of fresh frozen plasma transfusions (Cholette 2011; De Gast‐Bakker 2013; Willems 2010), and Willems 2010 reported the number of participants receiving platelets. We did not undertake a meta‐analysis due to clinical diversity and the timing of the outcome measurement. All results relating to this outcome are summarised in Table 12. There was no evidence of a difference between intervention arms in the number of participants receiving fresh frozen plasma in the first 48 hours after admission (RR 3.00, 95% CI 0.13 to 70.83; 1 RCT, 60 participants (Cholette 2011)); in the number of participants receiving fresh frozen plasma up to 28 days following randomisation (RR 1.97, 95% CI 0.37 to 10.36; 1 RCT, 125 participants (Willems 2010)), or in the number of participants receiving platelets up to 28 days following randomisation (RR 1.23, 95% CI 0.35 to 4.37; 1 RCT, 125 participants) (Willems 2010) (Analysis 1.13).

6. Volume or number of other blood products transfused to discharge.

Study name	Intervention	Comparator
Restrictive transfusion‐trigger versus liberal transfusion‐trigger
Cholette 2011	1 participant received FFP (reported up to 48 hours).	0 particpants received FFP (reported up to 48 hours).
De Gast‐Bakker 2013	Volume of FFP transfused:* 144 (77) Number of FFP units transfused:* 25	Volume of FFP transfused:* 152 (55) Number of FFP units transfused:* 32
Willems 2010	4 participants received FFP (up to 28 days post‐randomisation). 5 participants received platelets (up to 28 days post‐randomisation).	2 participants received FFP (up to 28 days post‐randomisation). 4 participants received platelets (up to 28 days post‐randomisation).
Washed red cells in CPB prime versus unwashed red cells in CPB prime
Cholette 2012	Number of FFP units transfused: 0.08 (0.324) Number of platelet units transfused: 0.06 (0.244) Number of cryoprecipitate units transfused: 0.03 (0.175)	Number of FFP units transfused: 0.25 (1.18) Number of platelet units transfused: 0.36 (1.5) Number of cryoprecipitate units transfused: 0.14 (0.639)
Crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime
No data reported for this outcome
Ultrafiltration of CPB prime versus no ultrafiltration
No data reported for this outcome
Retrograde autologous CPB prime versus standard CPB prime
No data reported for this outcome
‘Fresh' (not near expiry date) versus 'old' (near to expiry date) red cell transfusion
No data reported for this outcome
Cell salvage of CPB prime versus allogeneic red cells post‐CPB
No data reported for this outcome
Leukoreduced red cell transfusion versus non‐leukoreduced red cell transfusion
No data reported for this outcome

*It is unclear whether this is reported as volume transfused during hospital stay or during ICU stay only.

CBP: cardiopulmonary bypass; FFP: fresh frozen plasma; ICU: intensive care unit

1.13. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 13: Number of participants receiving any platelet transfusion

Postoperative chest drain output

One RCT with 60 participants reported postoperative mediastinal tube drainage on day 0, 1 and 2 postoperatively (Cholette 2011). There may be little to no difference in the effect of restrictive versus liberal transfusion‐trigger thresholds on day 0 (MD −0.20 mg/kg/hour (hr), 95% CI −0.88 to 0.48), day 1 (MD ‐0.20 mg/kg/hr 95% CI ‐1.19 to 0.79) or day 2 (MD ‐0.20 mg/kg/hr 95% CI ‐1.11 to 0.71) (Analysis 1.14). One RCT reported little to no difference in total blood loss in ml per participant (MD 9.00 ml, 95% CI −28.15 to 46.15; 1 RCT, 107 participants) (De Gast‐Bakker 2013). One RCT reported the number of days of mediastinal drainage as a median of nine days in the restrictive transfusion arm (full range 1 to 93; IQR not reported) and a median of eight days in the liberal transfusion arm (full range 1 to 33; IQR not reported) (Cholette 2017). We have summarised these results in Table 13.

1.14. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 14: Postoperative drain output mg/kg/hr

7. Postoperative chest drain output.

Study name	Intervention	Comparator
Restrictive transfusion‐trigger versus liberal transfusion‐trigger
Cholette 2011	MT drainage (mL/kg/hr) on postoperative day 0: 1.5 (1.3) MT drainage (mL/kg/hr) on postoperative day 1: 1.3 (1.8) MT drainage (mL/kg/hr) on postoperative day 2: 1.2 (1.3)	MT drainage (mL/kg/hr) on postoperative day 0: 1.7 (1.4) MT drainage (mL/kg/hr) on postoperative day 1: 1.5 (2.1) MT drainage (mL/kg/hr) on postoperative day 2: 1.4 (2.2)
Cholette 2017*	Number of days of mediastinal drainage: 9 (1 to 93)	Number of days of mediastinal drainage: 8 (1 to 33)
De Gast‐Bakker 2013	Volume of blood loss: 139 (95) mL per participant	Volume of blood loss: 130 (101) mL per participant
Washed red cells in CPB prime versus unwashed red cells in CPB prime
Cholette 2012	Number of days of mediastinal drainage: 8.75 (5.4)	Number of days of mediastinal drainage: 8.61 (5.0)
Crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime
Borisenko 2022**	Drainage loss on postoperative day 1: 54.6 (46.4 to 84) mL/kg	Drainage loss on postoperative day 1: 68 (53.3 to 82.4)
Ultrafiltration of CPB prime versus no ultrafiltration
No data reported for this outcome
Retrograde autologous CPB prime versus standard CPB prime
No data reported for this outcome
‘Fresh' (not near expiry date) versus 'old' (near to expiry date) red cell transfusion
No data reported for this outcome
Cell salvage of CPB prime versus allogeneic red cells post‐CPB
Ye 2013**	Volume of blood loss: 12.67 mL/kg (9.3875 to 17.43)	Volume of blood loss: 13.57 mL/kg (8.7300 to 18.45)
Leukoreduced red cell transfusion versus non‐leukoreduced red cell transfusion
De Vries 2004***	Volume of blood loss: 414 (340) ml/m2	Volume of blood loss: 324 (170) ml/m2

*This outcome is reported as median (range).

**This outcome is reported as median values (with 25 and 75 percentiles).

***This outcome was reported as mean (SEM) and has been converted to mean (SD) by the review authors

CBP: cardiopulmonary bypass; hr: hour; MT: mediastinal tube; POD: postoperative day; SD: standard deviation; SEM: standard eror of the means

Duration of mechanical ventilation

Cholette 2011, Chkhaidze 2014 and Willems 2010 reported data for this outcome. We were able to combine results for Chkhaidze 2014 and Willems 2010. There may be little to no difference in the duration of mechanical ventilation between intervention arms (MD −1.65, 95% CI −3.51 to 0.20; 2 RCTs, 168 participants; low‐certainty evidence; Analysis 1.16). Cholette 2011 reported the length of mechanical ventilation as median (plus IQR). The restrictive threshold group required a greater duration of mechanical ventilation than the liberal threshold group. The skew of this data prevents a conversion to mean (and SD). Median values are reported in Table 14.

1.16. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 16: Duration of mechanical ventilation (hours)

8. Duration of mechanical ventilation.

Study name	Intervention	Comparator
Restrictive transfusion‐trigger versus liberal transfusion‐trigger
Cholette 2011*	23 hours (5 to 625)	20 hours (4 to 216)
Willems 2010 (transfusion trigger)	4.6 hours (SD 3.1)	4.7 hours (SD 4.6)
Washed red cells in CPB prime versus unwashed red cells in CPB prime
Cholette 2012* (washed versus unwashed red blood cells)	45 hours (4 to 1008)	51.5 hours (3 to 1200)
Crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime
Borisenko 2022** (bloodless CPB prime versus blood‐containing CPB prime)	7.0 hours (6.0 to 8.0 hours)	8.0 hours (6.8 to 9.0)
Ultrafiltration of CPB prime versus no ultrafiltration
Gholampour Dehaki 2019**	17 hours (15 to 36)	20 hours (17 to 60)
Shimpo 2001 (ultrafiltration versus no ultrafiltration)	Exact figures not given but manuscript reports that the ultrafiltration arm had a significantly shorter duration of mechanical ventilation than the no ultrafiltration arm.	Exact figures not given but manuscript reports that the ultrafiltration arm had a significantly shorter duration of mechanical ventilation than the no ultrafiltration arm.
Retrograde autologous CPB prime versus standard CPB prime
No data reported for this outcome
‘Fresh' (not near expiry date) versus 'old' (near to expiry date) red cell transfusion
No data reported for this outcome
Cell salvage of CPB prime versus allogeneic red cells post‐CPB
Ye 2013** (cell salvage versus no cell salvage)	7.16 hours (4.5 to 24.5)	6.83 hours (4.69 to 25)
Leukoreduced red cell transfusion versus non‐leukoreduced red cell transfusion
Komai 1998***	15.8 hours (16.17)	23.0 hours (28.14)
De Vries 2004**	19 (9 to 48) hours	21 hours (16 to 54)

*This outcome is reported as median (range).

**This outcome is reported as median values (with 25 and 75 percentiles).

***This outcome is reported as mean (SD), where the SD has been calculated by the review authors from the standard error of the mean values reported by the study.

CPB: cardiopulmonary bypass; SD: standard deviation

Duration of intensive care unit stay

Chkhaidze 2014, Cholette 2011 and Willems 2010 reported data for this outcome. There may be little to no difference in the length of intensive care stay between the restrictive and liberal threshold (MD 0.15, 95% CI −0.72 to 1.01; 3 RCTs, 228 participants; low‐certainty evidence) (Table 15).

9. Duration of intensive care unit stay.

Study name	Intervention	Comparator
Restrictive transfusion‐trigger versus liberal transfusion‐trigger
Cholette 2011	mean 6.6 days (SD 6.4)	mean 5.4 days (SD 3.3)
Chkhaidze 2014	mean 3.8 days (SD 1.9)	mean 3.7 days (SD 2.2)
Willems 2010	mean 4.6 days (SD 3.1)	mean 4.7 days (SD 4.6)
Washed red cells in CPB prime versus unwashed red cells in CPB prime
Cholette 2012	mean 8.6 days (SD 10.8)	mean 8.9 days (SD 12.36)
Crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime
Borisenko 2022*	median 23.5 hours (IQR 21.0 to 29.0)	median 23.0 (IQR 21.8 to 41.5)
Ultrafiltration of CPB prime versus no ultrafiltration
Shimpo 2001 (ultrafiltration versus no ultrafiltration)	mean 24 hours (SD 13)	mean 40 hours (SD 8)
Retrograde autologous CPB prime versus standard CPB prime
No data reported for this outcome
‘Fresh' (not near expiry date) versus 'old' (near to expiry date) red cell transfusion
No data reported for this outcome
Cell salvage of CPB prime versus allogeneic red cells post‐CPB
No data reported for this outcome
Leukoreduced red cell transfusion versus non‐leukoreduced red cell transfusion
De Vries 2004*	1 day (1 to 3.7)	2 days (1 to 5)
Komai 1998**	mean 3 days (SD 14.49)	mean 4.1 days (SD 7.67)

*This outcome is reported as median values (with 25 and 75 percentiles).

**This outcome is reported as mean (SEM) and was converted to mean (SD) by the review authors.

CPB: cardiopulmonary bypass; IQR: interquartile range; SD: standard deviation; SEM standard error of the means

Rate of rehospitalisation

No trial reported data for this outcome.

Oxygen content difference

One trial reported this outcome as a figure (Cholette 2017). However, we were unable to extract the data.

Cerebral oxygen content post surgery (rSO₂)

One trial reported this outcome as a figure (Cholette 2011). However, we were unable to extract the data.

Blood lactate levels

Two trials reported 'peak' lactate levels (Cholette 2011; Cholette 2017), but Cholette 2017 reported the results only as a figure, so we were unable to extract the data. There was no clear difference in 'peak' lactate levels between the washed and unwashed groups (MD −0.10 mmol/L, 95% CI −0.81 to 0.61; 1 RCT, 60 participants; Analysis 1.19). Details of all results relating to lactate levels for this outcome are summarised in Table 16.

1.19. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 19: 'Peak' lactate levels (mmol/L)

10. Blood lactate levels mmol/L.

Study name	Intervention	Comparator
Restrictive transfusion‐trigger versus liberal transfusion‐trigger
Cholette 2011	At baseline: 1.5 (0.5 ) 'Peak' lactate: 3.1 (1.5)	At baseline: 1.4 (0.4) 'Peak' lactate: 3.2 (1.3)
Cholette 2017	At baseline: 5.3 (1.5) 'Peak' lactate: reported only as figure	At baseline: 5.8 (1.4) 'Peak' lactate: reported only as figure
Washed red cells in CPB prime versus unwashed red cells in CPB prime
Cholette 2012	'Peak' lactate: 4.0 (3.0)	'Peak' lactate: 4.0 (2.9)
Liu 2007*	At baseline: 11.2 (5.94) In CPB circuit prime after line connection and 5 min recirculation: 3.2 (2.26) At 10 min after start of CPB: 1.8 (2.26) Immediately after CPB and clamp of arterial cannula: 3.2 (1.41)	At baseline: 10.5 (5.94) In CPB circuit prime after line connection and 5 min recirculation: 10.5 (5.94) At 10 min after start of CPB: 3.8 (3.11) Immediately after CPB and clamp of arterial cannula: 4.8 (0.57)
Swindell 2007*	At baseline: 13.7 (1.66) 'Peak' lactate: 5.1 (1.66) Prior to CPB in CPB prime: 2.6 (0.66) Three min after start of CPB: Reported only as figure At 28˚C during cooling: reported only as figure At 28˚C during rewarming: 4.9 (1.66) At 36˚C after rewarming: 5.1 (1.66) Immediately after CPB and clamp of arterial cannula: reported only as figure	At baseline: 14.6 (0.66) 'Peak' lactate: 6.9 (2.65) Prior to CPB in CPB prime: 4.6 (0.99) Three min after start of CPB: Reported only as figure At 28˚C during cooling: reported only as figure At 28˚C during rewarming: 6.3 (1.66) At 36˚C after rewarming: reported only as figure Immediately after CPB and clamp of arterial cannula: at baseline: 6.9 (2.67)
Crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime
Borisenko 2022**	At 15 min after the start of CPB: 1.5 (1.3 to 1.8) At end of surgery, after skin closure: 1.5 (1.3 to 1.7)	At 15 min after start of CPB: 1.5 (1.2 to 1.9) At end of surgery, after skin closure: 1.5 (1.2 to 1.7)
Ultrafiltration of CPB prime versus no ultrafiltration
No data reported for this outcome
Retrograde autologous CPB prime versus standard CPB prime
Fu 2016	Baseline: 1.04 (0.26) At 15 min after the start of CPB: 0.96 (0.58) Immediately after CPB and clamp of arterial cannula: 1.7 (0.13)	Baseline: 0.95 (0.26) At 15 min after the start of CPB: 1.04 (0.66) Immediately after CPB and clamp of arterial cannula: 1.94 (0.17)
‘Fresh' (not near expiry date) versus 'old' (near to expiry date) red cell transfusion
No data reported for this outcome
Cell salvage of CPB prime versus allogeneic red cells post‐CPB
No data reported for this outcome
Leukoreduced red cell transfusion versus non‐leukoreduced red cell transfusion
No data reported for this outcome

*This outcome was reported as mean (standard error of the mean) and was converted by the review authors into mean (standard deviation).

**This outcome is reported as median values (with 25 and 75 percentiles).

C: Celsius; CPB: cardiopulmonary bypass; min: minutes

Blood sodium (Na+) levels

No trial reported data for this outcome.

Blood potassium (K+) levels

No trial reported data for this outcome.

Blood glucose levels

No trial reported data for this outcome.

Washed red blood cells in CPB prime versus unwashed red blood cells in CPB prime

Primary outcome

All‐cause mortality: short term (0 to 30 days post‐surgery)

Two trials reported data for this outcome (Cholette 2012; Liu 2007). There may be little to difference in mortality between intervention and control arms (RR 0.25, 95% CI 0.03 to 2.18; 2 RCTs, 144 participants; low‐certainty evidence; Analysis 2.1).

2.1. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 1: All‐cause mortality: short term (0 to 30 days post surgery)

Secondary outcomes

All‐cause mortality: long term (31 days to two years post‐surgery)

Data for this outcome were obtained directly from the study author for one trial (Cholette 2012). There may be little to no difference in the number of deaths over a long time period (31 days to two years) between the washed intervention and the unwashed intervention groups (RR 0.50, 95% CI 0.05 to 5.38; 1 RCT, 128 participants; low‐certainty evidence; Analysis 2.2). Details of the cause and time of death are provided in Table 9.

2.2. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 2: All‐cause mortality: long term (31 days to 2 years post‐surgery)

Severe adverse events: cardiac events

Cholette 2012 reported data for this outcome, defining a cardiac event as arrhythmia that was haemodynamically significant, required intervention or both. There was no little to no difference in the number of patients who had a cardiac event at any time during the hospital admission between the intervention arms, but the evidence is very uncertain (RR 0.88, 95% CI 0.47 to 1.64; 1 RCT, 128 participants; very low certainty evidence; Analysis 2.3).

2.3. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 3: Severe adverse events: cardiac events

Severe adverse events: acute lung injury

No trial reported data for this outcome.

Severe adverse events: stroke

No trial reported data for this outcome.

Severe adverse events: thromboembolism

One RCT reported data on this outcome (Cholette 2012). There was no evidence of a difference in the number of participants who had a thromboembolism, at any time during the hospital admission, between the washed intervention and unwashed intervention groups (RR 0.88, 95% CI 0.34 to 2.27; 1 RCT, 128 participants; Analysis 2.4).

2.4. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 4: Severe adverse event: thromboembolism

Severe adverse events: renal failure (needing renal replacement therapy)

No trial reported data for this outcome.

Severe adverse events: infection

One trial reported data for this outcome (Cholette 2012). There was little to no difference in the number of participants who had an infection at some time during their hospital admission between the washed and unwashed red blood cell intervention arms, but the evidence is very uncertain (RR 1.00, 95% CI 0.50 to 1.99; 1 RCT, 128 participants; very low certainty evidence; Analysis 2.5). In all cases, a diagnosis of an infection was supported by culture data.

2.5. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 5: Severe adverse events: infection

Severe adverse events: haemorrhage (return to theatre for bleeding)

Cholette 2012 reported data for this outcome. There was little to no difference in the number of participants experiencing a haemorrhage requiring a return to theatre for bleeding between the washed and unwashed red blood cell intervention groups (RR 0.33, 95% CI 0.01 to 8.06; 1 RCT, 162 participants; Analysis 2.6).

2.6. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 6: Severe adverse events: haemorrhage (return to theatre for bleeding)

Haematocrit (%) levels postoperatively

One RCT (Liu 2007) did not find evidence of a difference between the washed red blood cell group and the unwashed red blood cell group (MD 2.50%, 95% CI −1.44 to 6.44; 1 RCT, 16 participants; Analysis 2.7). One trial noted that haematocrit levels were "similar in both groups" but did not report data (Busch 2017).

2.7. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 7: Haematocrit (%) levels postoperatively

Haemoglobin (g/dL) levels postoperatively

No trial reported data for this outcome. One trial noted that haemoglobin levels were "similar in both groups" but did not report data (Busch 2017).

Haematocrit/haemoglobin (g/dL) levels at discharge

No trial reported data for this outcome.

Volume or number of red cell units transfused

Cholette 2012 reported the number of units transfused, with a mean of 2.97 units (standard deviation (SD) 3.27) transfused in the washed red blood cells group and a mean of 3.27 (SD 4.3) units transfused in the unwashed red blood cells group. We were unsure how many participants received any blood transfusion in each of these results, so we were not able to interpret the result or add to an analysis but have summarised all results relating to red blood cell transfusion outcomes in Table 11.

Volume or number of other blood products transfused (i.e. fresh frozen plasma, platelets, cryoprecipitate)

Cholette 2012 reported the mean number of platelets, fresh frozen plasma and cryoprecipitate units transfused over the entire hospitalisation period between the washed and unwashed red blood cell intervention groups. We were unsure how many participants received any transfusion in each of these results, so we were not able to interpret the result or add to an analysis but have summarised all results relating to fresh frozen plasma, platelet or cryoprecipitate transfusion outcomes in Table 12.

Postoperative chest drain output

One RCT reported data on this outcome (Cholette 2012). There was little to no difference in the mean duration of postoperative chest drain output (MD 0.14 days, 95% CI −1.66 to 1.94; 1 RCT, 128 participants; Analysis 2.9) (Table 13).

2.9. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 9: Postoperative chest drain output (number of days of mediastinal drainage)

Duration of mechanical ventilation

One trial reported intubation time as median (range) but did not report the interquartile range (Cholette 2012). The intervention group required a shorter duration of mechanical ventilation than the control group, 45 hours (range 4 to 1008) versus 51.5 hours (range 3 to 1200) (Table 14).

Duration of intensive care unit stay

One trial reported data for this outcome (Cholette 2012). There may be little to no difference in the mean length of stay in paediatric cardiac intensive care between the washed and unwashed red cell intervention groups, but the evidence is very uncertain (MD −0.30 days, 95% CI −4.32 to 3.72; 1 RCT, 128 participants; very low certainty evidence; Analysis 2.8).

2.8. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 8: Duration of intensive care unit stay (days)

Rate of rehospitalisation

No trial reported data for this outcome.

Oxygen content difference

No trial reported data for this outcome.

Cerebral oxygen content post surgery (rSO2)

No trial reported data for this outcome.

Blood lactate levels

Two trials reported 'peak' lactate levels (Cholette 2012, Swindell 2007). There was little to no difference between peak lactate levels (MD −0.73, 95% CI −2.46 to 1.00; 2 RCT, 150 participants; Analysis 2.10).

2.10. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 10: 'Peak' lactate levels (mmol/L)

One trial (Liu 2007) reported lactate levels in CPB circuit prime after line connection and five‐minute recirculation (MD −7.30 mmol/L, 95% CI −11.7.0 to −2.90; 1 RCT, 16 participants; Analysis 2.12); at 10 minutes after the start of cardiopulmonary bypass (MD −2.00 mmol/L, 95% CI ‐4.66 to 0.66; 1 RCT, 16 participants; Analysis 2.13); and immediately after cardiopulmonary bypass and clamp of arterial cannula (MD −1.60 mmol/L, 95% CI −2.65 to −0.55; 1 RCT, 16 participants; Analysis 2.15).

2.12. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 12: Lactate levels (mmol/L) in CPB circuit prime after line connection and 5 min recirculation

2.13. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 13: Lactate levels (mmol/L) at up to 15 minutes after the start of cardiopulmonary bypass

2.15. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 15: Lactate levels (mmol/L) immediately after cardiopulmonary bypass and clamp of arterial cannula

One trial (Swindell 2007) reported lactate levels prior to cardiopulmonary bypass in prime (MD −2.00, 95% CI −2.70 to −1.30; 1 RCT, 22 participants; Analysis 2.11) and at 28 degrees during rewarming (MD −1.40, 95% CI −2.79 to −0.01; 1 RCT, 22 participants; Analysis 2.14).

2.11. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 11: Lactate levels prior to cardiopulmonary bypass in prime

2.14. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 14: Lactate levels at 28 degrees during rewarming

Details of all results relating to lactate levels for this outcome are summarised in Table 16.

Blood sodium (Na+) levels

One trial (Swindell 2007) reported data for this outcome prior to cardiopulmonary bypass in prime (MD 4.00 mmol/L, 95% CI 0.94 to 7.06; 1 RCT, 22 participants; Analysis 2.16); at 36 degrees Celsius after rewarming (MD 3.10 mmol/L, 95% CI 0.43 to 5.77; 1 RCT, 22 participants; Analysis 2.17); and immediately after cardiopulmonary bypass and clamp of arterial cannula (MD 3.50 mmol/L, 95% CI 0.69 to 6.31; 1 RCT, 22 participants; Analysis 2.18). We were unable to extract data for other time points, as these were reported only as figures.

2.16. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 16: Sodium (Na⁺) levels (mmol/L) prior to cardiopulmonary bypass in prime

2.17. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 17: Sodium (Na⁺) levels (mmol/L) at 36 degrees after rewarming

2.18. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 18: Sodium (Na⁺) levels (mmol/L) immediately after cardiopulmonary bypass and clamp of arterial cannula

One trial measured sodium levels before and after ultrafiltration in the participants who were treated with ultrafiltrated red cells only (Shimpo 2001). Sodium levels remained within a clinically accepted normal range following receipt of ultrafiltrated red cells. Shimpo 2001 did not report the sodium levels for patients not receiving ultrafiltrated red cells. Therefore, no further comparison of this outcome can be made.

One trial reported data as median with an interquartile range, so we were unable to analyse this data (Busch 2017).

Details of all results relating to sodium levels for this outcome are summarised in Table 17.

11. Blood sodium levels mmol/L.

Study name	Intervention	Comparator
Restrictive transfusion‐trigger versus liberal transfusion‐trigger
No data reported for this outcome
Washed red cells in CPB prime versus unwashed red cells in CPB prime
Busch 2017*	At baseline: 147 (146 to 147)	At baseline: 97 (95 to 100)
Swindell 2007**	At baseline: 126 (6.96) Prior to CPB in CPB prime: 151.5 (3.32) Three minutes after start of CPB: reported only as figure At 28˚C during cooling: reported only as figure At 28˚C reported only as figure At 36˚C after rewarming: 142 (3.65) Immediately after CPB and clamp of arterial cannula: 145 (4.31)	At baseline: 118.8 (14.59) Prior to CPB in CPB prime: 147.5 (3.98) Three minutes after start of CPB: reported only as figure At 28˚C during cooling: reported only as figure At 28˚C during rewarming: reported only as figure At 36˚C after rewarming: 138.9 (2.65) Immediately after CPB and clamp of arterial cannula: 141.5 (1.99)
Crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime
No data reported for this outcome
Ultrafiltration of CPB prime versus no ultrafiltration
Shimpo 2001	At baseline: 151 (17.7) After filtration: 139 (5)	NR
Retrograde autologous CPB prime versus standard CPB prime
No data reported for this outcome
‘Fresh' (not near expiry date) versus 'old' (near to expiry date) red cell transfusion
No data reported for this outcome
Cell salvage of CPB prime versus allogeneic red cells post‐CPB
No data reported for this outcome
Leukoreduced red cell transfusion versus non‐leukoreduced red cell transfusion
No data reported for this outcome

*This outcome is reported as median values (with 25 and 75 percentiles).

** This outcome was reported as mean (standard error of means) and was converted to mean and standard deviation by the review authors

C: Celsius; CPB: cardiopulmonary bypass; NR: not reported

Blood potassium (K+) levels

Two trials (Liu 2007, Swindell 2007) reported potassium levels prior to cardiopulmonary bypass in cardiopulmonary bypass prime (MD −6.21 mmol/L, 95% CI −8.36 to −4.06; 2 RCTS, 38 participants; Analysis 2.19).

2.19. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 19: Potassium (K⁺) levels (mmol/L) prior to cardiopulmonary bypass in prime

One trial (Swindell 2007) reported potassium levels at 28 degrees Celsius during rewarming (MD −1.90 mmol/L, 95% CI −2.71 to −1.09; 1 RCT, 22 participants; Analysis 2.20) and immediately after cardiopulmonary bypass with clamp of arterial cannula (MD −1.00 mmol/L, 95% CI −1.44 to −0.56; 1 RCT, 22 participants; Analysis 2.21).

2.20. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 20: Potassium (K⁺) levels (mmol/L) at 28 degrees during rewarming

2.21. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 21: Potassium (K⁺) levels (mmol/L) immediately after cardiopulmonary bypass and clamp of arterial cannula

One trial reported data as median with an interquartile range, so we were unable to analyse this data (Busch 2017).

Details of all results relating to potassium levels for this outcome are summarised in Table 18.

12. Blood potassium levels mmol/L.

Study name	Intervention	Comparator
Restrictive transfusion‐trigger versus liberal transfusion‐trigger
No data reported for this outcome
Washed red cells in CPB prime versus unwashed red cells in CPB prime
Busch 2017*	At baseline, measured from the transfused red blood cells: 0.8 (0.7 to 0.9)	At baseline, measured from the transfused red blood cells: 14.4 (11.6 to 16.3)
Liu 2007**	At baseline: 16.3 (7.92) Prior to CPB in CPB prime: 7.3 (7.92)	At baseline: 15.2 (9.9) Prior to CPB in CPB prime: 15.2 (9.9)
Swindell 2007**	At baseline: 20 Prior to CPB in CPB prime: 2.6 (0.33) Three minutes after start of CPB: reported only as figure At 28˚C during cooling: reported only as figure At 28˚C during rewarming: 3.0 (0.33) At 36˚C after rewarming: 3.8 (0.99) Immediately after CPB and clamp of arterial cannula: 3.2 (0.33)	At baseline: 20 Prior to CPB in CPB prime: 8.1 (1.33) Three minutes after start of CPB: 4.9 (0.99) At 28˚C during cooling: reported only as figure At 28˚C during rewarming: 4.9 (1.33) At 36˚C after rewarming: reported only as figure Immediately after CPB and clamp of arterial cannula: 4.2 (0.66)
Crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime
No data reported for this outcome
Ultrafiltration of CPB prime versus no ultrafiltration
Shimpo 2001	At baseline before ultrafiltration: 13.8 (5.9) After ultrafiltration; 3.0 (0.8)	NR
Retrograde autologous CPB prime versus standard CPB prime
Fu 2016	At baseline: 1.04 (0.26)	At baseline: 0.95 (0.26)
'Fresh' (not near to expiry date) versus 'old' (near to expiry date) red cell transfusion
No data reported for this outcome
Cell salvage of CPB prime versus allogeneic red cells post‐CPB
No data reported for this outcome
Leukoreduced red cell transfusion versus non‐leukoreduced red cell transfusion
No data reported for this outcome

*This outcome is reported as median values (with 25 and 75 percentiles).

** This outcome was reported as mean (standard error of the mean) and was converted by the review authors into mean (standard deviation).

CPB: cardiopulmonary bypass

Blood glucose levels

Two trials (Hosking 1990, Liu 2007) reported glucose levels prior to cardiopulmonary bypass in cardiopulmonary bypass prime (MD −212.14 mg/dL, 95% CI −349.14 to −75.14; 2 RCTS, 36 participants; Analysis 2.22).

2.22. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 22: Blood glucose (mg/dL) in prime prior to CPB

One trial (Hosking 1990) reported glucose levels at 10 minutes after the start of cardiopulmonary bypass (MD −132.00 mg/dL, 95% CI −147.64 to −116.36; 1 RCT, 20 participants; Analysis 2.23).

2.23. Analysis.

Comparison 2: Washed red cells in CPB prime versus unwashed red cells in CPB prime, Outcome 23: Blood glucose levels (mg/dL) at up to 15 minutes after the start of cardiopulmonary bypass

One trial reported data as median with an interquartile range, so we were unable to analyse this data (Busch 2017). Instead, we have summarised all data relating to blood glucose levels in Table 19.

13. Blood glucose levels mg/dL.

Study name	Intervention	Comparator
Restrictive transfusion‐trigger versus liberal transfusion‐trigger
No data reported for this outcome
Washed red cells in CPB prime versus unwashed red cells in CPB prime
Busch 2017*	Prior to CPB in CPB prime: 48 (26 to 69)	Prior to CPB in CPB prime: 403 (387 to 425)
Liu 2007**	Prior to CPB in CPB prime: 167.4 (86.55)	Prior to CPB in CPB prime: 309.6 (106.91)
Hosking 1990	Prior to CPB in CPB prime: 92 (27) At 10 minutes after the start of CPB: 78 (14)	Prior to CPB in CPB prime: 374 (46) At 10 minutes after the start of CPB: 210 (21)
Crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime
No data reported for this outcome
Ultrafiltration of CPB prime versus no ultrafiltration
No data reported for this outcome
Retrograde autologous CPB prime versus standard CPB prime
No data reported for this outcome
'Fresh' (not near to expiry date) versus 'old' (near to expiry date) red cell transfusion
No data reported for this outcome
Cell salvage of CPB prime versus allogeneic red cells post‐CPB
No data reported for this outcome
Leukoreduced red cell transfusion versus non‐leukoreduced red cell transfusion
No data reported for this outcome

*This outcome is reported as median values (with 25 and 75 percentiles).

**This outcome was reported in mmol/L and was converted by the authors into mg/dl, and was reported as mean (standard error of means) and was converted by the review authors into mg/dl.

CPB: cardiopulmonary bypass

Crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime

Primary outcome

All‐cause mortality: short term (0 to 30 days post‐surgery)

No trial reported data for this outcome.

Secondary outcomes

All‐cause mortality: long term (31 days to two years post‐surgery)

No trial reported data for this outcome.

Severe adverse events: cardiac events

No trial reported data for this outcome.

Severe adverse events: acute lung injury

No trial reported data for this outcome.

Severe adverse events: stroke

No trial reported data for this outcome.

Severe adverse events: thromboembolism

No trial reported data for this outcome.

Severe adverse events: renal failure (needing renal replacement therapy)

No trial reported data for this outcome.

Severe adverse events: infection

No trial reported data for this outcome.

Severe adverse events: haemorrhage (return to theatre for bleeding)

No trial reported data for this outcome.

Haematocrit (%) levels postoperatively

One RCT reported haematocrit levels for this outcome on postoperative day 1 (Han 2004), and found a difference favouring the CPB prime containing red blood cells (MD −3.90%, 95% CI −4.35 to −3.45; 1 RCT, 35 participants; Analysis 3.2). One trial reported haematocrit levels giving a median value with the interquartile range (Borisenko 2022). Haematocrit was higher on day 1 in the blood‐containing prime group (median 34% IQR 33 to 36) than in the bloodless prime group (median 30% IQR 29 to 32) (Table 20).

3.2. Analysis.

Comparison 3: Crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime, Outcome 2: Haematocrit (%) levels postoperatively

14. Haematocrit levels (%) postoperatively.

Study name	Intervention	Comparator
Restrictive transfusion‐trigger versus liberal transfusion‐trigger
No data reported for this outcome
Washed red cells in CPB prime versus unwashed red cells in CPB prime
Liu 2007*	At 10 min during CPB: 28.1 (2.55) At the end of CPB: 37.1 (1.41)	At 10 min during CPB: 25.6 (5.09) At the end of CPB: 33.4 (33.94)
Crystalloid (bloodless) CPB prime versus red‐cell‐containing CPB prime
Borisenko 2022**	Preoperative: 36.0 (34.0 to 38.0) Day 1: 30.0 (29.0 to 32.0)	Preoperative: 35.0 (33.0 to 37.0) Day 1: 34.0 (33.0 to 36.0)
Han 2004	Pre‐CPB: 36.8 (0.4) Post‐CPB 35.7 (0.9)	Pre‐CPB: 37.3 (0.3) Post‐CPB: 31.8 (0.4)
Ultrafiltration of CPB prime versus no ultrafiltration
No data reported for this outcome
Retrograde autologous CPB prime versus standard CPB prime
Fu 2016 (retrograde autologous priming versus conventional CPB)	Pre‐CPB: 35.72 (2.20) Start of surgery: 25.08 (0.50) Surgery end time: 26.04 (0.36) 2 hours after surgery end: 28.19 (0.62)	Pre‐CPB: 35.93 (2.23) Start of surgery: 26.81 (0.52) Surgery end time: 27.79 (0.51) 2 hours after surgery end: 26.87 (1.21)
‘Fresh' (not near expiry date) versus 'old' (near to expiry date) red cell transfusion
No data reported for this outcome
Cell salvage of CPB prime versus allogeneic red cells post‐CPB
Ye 2013** (Cell salvage versus no cell salvage)	Preoperative: 37.7 (34.8 to 39.9) Postoperative: 36.2 (33.6 to 39.6)	Preoperative: 36.8 (34.9 to 38.8) Postoperative: 34.8 (33.0 to 37.57)
Leukoreduced red cell transfusion versus non‐leukoreduced red cell transfusion
No data reported for this outcome

*This outcome was reported as mean (SEM) and was converted to mean and SD by review authors.

**This outcome is reported as median values (with 25 and 75 percentiles).

CPB: cardiopulmonary bypass; min: minutes; RBC: red blood cell; SD: standard deviation; SEM: standard error of the means

Haemoglobin (g/dL) levels postoperatively

Borisenko 2022 reported data for this outcome as a median with an interquartile range. The bloodless prime group had lower haemoglobin levels postoperatively, and on day one postoperatively (median 106.0, IQR 101.8 to 110.3 g/L versus median 130.5 IQR 104.0 to 125.5 g/L), and on day one postoperatively (median 101.0, IQR 98.8 to 107.0 g/L versus median 124.0, IQR 113.0 to 127.0 g/L).

Haematocrit/haemoglobin (g/dL) levels at discharge

No trial reported data for this outcome.

Volume or number of red cell units transfused

No trial reported data for this outcome.

Volume or number of other blood products transfused (i.e. fresh frozen plasma, platelets, cryoprecipitate)

No trial reported data for this outcome.

Postoperative chest drain output

One trial reported median volume of blood loss on day 1 of 54.6 (IQR 46.4 to 84) ml/kg in the bloodless CPB prime group and 68 (IQR 53.3 to 82.4) in the blood‐containing CPB prime group (Borisenko 2022) (Table 13).

Duration of mechanical ventilation

No trial reported data for this outcome.

Duration of intensive care unit stay

No trial reported data for this outcome.

Rate of rehospitalisation

No trial reported data for this outcome.

Oxygen content difference

One trial reported oxygen content difference (Han 2004). The difference favoured blood‐containing prime (MD −1.90, 95% CI −2.11 to −1.69; 1 RCT, 35 participants; Analysis 3.1).

3.1. Analysis.

Comparison 3: Crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime, Outcome 1: Oxygen content post surgery CaO₂ (ml dl^‐1)

Cerebral oxygen content post‐surgery (rSO2)

One trial of 40 participants reported cerebral oxygen saturation as median 70.5 (IQR 69.8 to 75) in the bloodless prime group and median 77 (IQR 74.5 to 78) in the blood‐containing prime group (Borisenko 2022).

Blood lactate levels

One trial reported lactate levels at 15 minutes after the start of cardiopulmonary bypass and at the end of surgery, after skin closure (Borisenko 2022). However, in both cases the data were reported as medians with interquartile ranges. Details of all results relating to lactate levels for this outcome are summarised in Table 16.

Blood sodium (Na+) levels

No trial reported data for this outcome.

Blood potassium (K+) levels

No trial reported data for this outcome.

Blood glucose levels

No trial reported data for this outcome.

Ultrafiltration of CPB prime versus no ultrafiltration

Primary outcome

All‐cause mortality: short term (0 to 30 days post‐surgery)

One trial reported data for this outcome (Shimpo 2001). There were no deaths in either intervention or control arms (RR not estimable; 1 RCT, 50 participants; very low certainty evidence; Analysis 4.1).

4.1. Analysis.

Comparison 4: Ultrafiltration in CPB prime versus no ultrafiltration, Outcome 1: All‐cause mortality: short term (0 to 30 days post‐surgery)

Secondary outcomes

All‐cause mortality: long term (31 days to two years post‐surgery)

No trial reported data for this outcome.

Severe adverse events: cardiac events

No trial reported data for this outcome.

Severe adverse events: acute lung injury

No trial reported data for this outcome.

Severe adverse events: stroke

No trial reported data for this outcome.

Severe adverse events: thromboembolism

No trial reported data for this outcome.

Severe adverse events: renal failure (needing renal replacement therapy)

No trial reported data for this outcome.

Severe adverse events: infection

No trial reported data for this outcome.

Severe adverse events: haemorrhage (return to theatre for bleeding)

No trial reported data for this outcome.

Haematocrit (%) levels postoperatively

No trial reported data for this outcome.

Haemoglobin (g/dL) levels postoperatively

No trial reported data for this outcome.

Haematocrit/haemoglobin (g/dL) levels at discharge

No trial reported data for this outcome.

Volume or number of red cell units transfused

No trial reported data for this outcome.

Volume or number of other blood products transfused (i.e. fresh frozen plasma, platelets, cryoprecipitate)

No trial reported data for this outcome.

Postoperative chest drain output

No trial reported data for this outcome.

Duration of mechanical ventilation

One trial reported data for this outcome (Shimpo 2001). Ultrafiltration may reduce the mean duration of mechanical ventilation compared to no ultrafiltration (MD −16.00 hours, 95% CI −25.00 to −7.00; 1 RCT, 50 participants; low‐certainty evidence). One trial reported this outcome as a median (plus IQR) of 17 hours (15 to 36) versus 20 hours (17 to 60) (Gholampour Dehaki 2019) (Table 14).

Duration of intensive care unit stay

One trial reported data on this outcome (Shimpo 2001). Ultrafiltration may reduce the mean length of intensive care stay compared to no ultrafiltration (MD ‐0.6 days, 95% CI ‐0.84 to ‐0.36; 1 RCT, 50 participants; low‐certainty evidence; Analysis 4.3).

4.3. Analysis.

Comparison 4: Ultrafiltration in CPB prime versus no ultrafiltration, Outcome 3: Duration of ICU stay (days)

Rate of rehospitalisation

No trial reported data for this outcome.

Oxygen content difference

No trial reported data for this outcome.

Cerebral oxygen content post surgery (rSO2)

No trial reported data for this outcome.

Blood lactate levels

No trial reported data for this outcome.

Blood sodium (Na+) levels

No trial reported data for this outcome.

Blood potassium (K+) levels

One trial measured potassium levels before and after ultrafiltration in the participants who were treated with ultrafiltrated red blood cells only (Shimpo 2001). Potassium levels fell to within a clinically accepted normal range following receipt of ultrafiltrated red blood cells. The trial did not report the potassium levels for participants not receiving ultrafiltrated red blood cells. Therefore, no further comparison of this outcome can be made. Details of all results relating to potassium levels for this outcome are summarised in Table 18.

Blood glucose levels

No trial reported data for this outcome.

Retrograde autologous CPB prime versus standard CPB prime

Primary outcome

All‐cause mortality: short term (0 to 30 days post‐surgery)

No trial reported data for this outcome.

Secondary outcomes

All‐cause mortality: long term (31 days to two years post‐surgery)

No trial reported data for this outcome.

Severe adverse events: cardiac events

No trial reported data for this outcome.

Severe adverse events: acute lung injury

No trial reported data for this outcome.

Severe adverse events: stroke

No trial reported data for this outcome.

Severe adverse events: thromboembolism

No trial reported data for this outcome.

Severe adverse events: renal failure (needing renal replacement therapy)

No trial reported data for this outcome.

Severe adverse events: infection

No trial reported data for this outcome.

Severe adverse events: haemorrhage (return to theatre for bleeding)

No trial reported data for this outcome.

Haematocrit (%) levels postoperatively

One study (Fu 2016) found a difference in postoperative haematocrit levels favouring the retrograde autologous priming group (MD 1.32, 95% CI 0.84 to 1.80; 1 RCT, 59 participants; Analysis 5.1).

5.1. Analysis.

Comparison 5: Retrograde autologous CPB prime versus standard CPB prime, Outcome 1: Haematocrit (%) levels postoperatively

Haemoglobin (g/dL) levels postoperatively

No trial reported data for this outcome.

Haematocrit/haemoglobin (g/dL) levels at discharge

No trial reported data for this outcome.

Volume or number of red cell units transfused

No trial reported data for this outcome.

Volume or number of other blood products transfused (i.e. fresh frozen plasma, platelets, cryoprecipitate)

No trial reported data for this outcome.

Postoperative chest drain output

No trial reported data for this outcome.

Duration of mechanical ventilation

One trial reported data for this outcome (Fu 2016). There may be little to no difference in the mean duration of ventilation between intervention arms, but the evidence is very uncertain (MD 0.02, 95% CI −0.03 to 0.07; 1 RCT, 59 participants; very low certainty evidence; Analysis 5.2).

5.2. Analysis.

Comparison 5: Retrograde autologous CPB prime versus standard CPB prime, Outcome 2: Duration of mechanical ventilation (hours)

Duration of intensive care unit stay

One trial reported data for this outcome (Fu 2016). There may be little to no difference in the mean duration of intensive care stay between the intervention arms, but the evidence is very uncertain (MD 0.00, 95% CI −0.01 to 0.01; 1 RCT, 59 participants; very low certainty evidence; Analysis 5.3).

5.3. Analysis.

Comparison 5: Retrograde autologous CPB prime versus standard CPB prime, Outcome 3: Duration of intensive care unit stay

Rate of rehospitalisation

No trial reported data for this outcome.

Oxygen content difference

No trial reported data for this outcome.

Cerebral oxygen content post surgery (rSO2)

No trial reported data for this outcome.

Blood lactate levels

One trial (Fu 2016) reported lactate levels at three minutes after the start of cardiopulmonary bypass (MD ‐0.08, 95% CI ‐0.40 to 0.24; 1 RCT, 59 participants; Analysis 5.4) and immediately after cardiopulmonary bypass and clamp of arterial cannula (MD ‐0.24, 95% CI ‐0.32 to ‐0.16; 1 RCT, 59 participants; Analysis 5.5). Details of all results relating to lactate levels for this outcome are summarised in Table 16.

5.4. Analysis.

Comparison 5: Retrograde autologous CPB prime versus standard CPB prime, Outcome 4: Lactate levels (mmol/L at up to 15 minutes after the start of cardiopulmonary bypass

5.5. Analysis.

Comparison 5: Retrograde autologous CPB prime versus standard CPB prime, Outcome 5: Lactate levels (mmol/L) immediately after cardiopulmonary bypass and clamp of arterial cannula

Blood sodium (Na+) levels

No trial reported data for this outcome.

Blood potassium (K+) levels

No trial reported data for this outcome.

Blood glucose levels

No trial reported data for this outcome.

'Fresh' (not near to expiry date) versus 'old' (near to expiry date) red blood cell transfusion

There was no extractable data on any of our review outcomes for this comparison.

Cell salvage of CPB prime blood versus allogeneic red blood cells post‐CPB

Primary outcome

All‐cause mortality: short term (0 to 30 days post‐surgery)

One trial reported data for this outcome (Ye 2013). There was no evidence of a difference in mortality between intervention and control arms, but the evidence is very uncertain (RR 0.21, 95% CI 0.02 to 2.31; 1 RCT, 309 participants; very low certainty evidence; Analysis 6.1).

6.1. Analysis.

Comparison 6: Cell salvage of CPB prime blood versus allogeneic red cells post‐CPB, Outcome 1: All‐cause mortality: short term (0 to 30 days post‐surgery)

Secondary outcomes

All‐cause mortality: long term (31 days to two years post‐surgery)

No trial reported data for this outcome.

Severe adverse events: cardiac events

No trial reported data for this outcome.

Severe adverse events: acute lung injury

Ye 2013 reported data for this outcome. There was little to no difference in the number of participants experiencing an acute lung injury between the cell salvage and the no‐cell salvage treated groups (RR 0.88, 95% CI 0.61 to 1.27; 1 RCT, 309 participants; Analysis 6.2). No further details were given as to when the acute lung injury occurred, how it was treated or the outcome for these participants.

6.2. Analysis.

Comparison 6: Cell salvage of CPB prime blood versus allogeneic red cells post‐CPB, Outcome 2: Severe adverse events: acute lung injury

Severe adverse events: stroke

No trial reported data for this outcome.

Severe adverse events: thromboembolism

No trial reported data for this outcome.

Severe adverse events: renal failure (needing renal replacement therapy)

In one trial, no participants required renal replacement therapy (Ye 2013). This trial reported the number of participants whose creatinine level increased twofold or more. Those receiving cell‐salvaged red blood cells during CPB were less likely to have renal failure than participants not exposed to cell salvage (RR 0.26, 95% CI 0.09 to 0.79; 1 RCT, 309 participants; Analysis 6.3).

6.3. Analysis.

Comparison 6: Cell salvage of CPB prime blood versus allogeneic red cells post‐CPB, Outcome 3: Severe adverse events: renal failure (creatinine increasing at least twofold within 72 hours of surgery)

Severe adverse events: infection

No trial reported data for this outcome.

Severe adverse events: haemorrhage (return to theatre for bleeding)

No trial reported data for this outcome.

Haematocrit (%) levels postoperatively

One RCT reported median and interquartile range results for postoperative haematocrit levels (Ye 2013). This study found a higher haematocrit level in the cell salvage group (median 36.2, IQR 33.6 to 39.6) than the allogeneic red cells group (median 34.8, IQR 33.0 to 37.57) (Table 20).

Haemoglobin (g/dL) levels postoperatively

No trial reported data for this outcome.

Haematocrit/haemoglobin (g/dL) levels at discharge

No trial reported data for this outcome.

Volume or number of red blood cell units transfused

No trial reported data for this outcome.

Volume or number of other blood products transfused (i.e. fresh frozen plasma, platelets, cryoprecipitate)

No trial reported data for this outcome.

Postoperative chest drain output

One trial reported a median volume of blood loss of 12.67 mL/kg (IQR 9.39 to 17.43) in the cell salvage group and 13.57 mL/kg (IQR 8.73 to 18.45) in the allogeneic red cells group (Ye 2013) (Table 13).

Duration of mechanical ventilation

One trial reported intubation time as median (plus interquartile range) (Ye 2013). The intervention group required a greater duration of mechanical ventilation than the control group, 7.16 hours (4.5 to 24.5) versus 6.83 hours (4.69 to 25) (Table 14).

Duration of intensive care unit stay

No trial reported data for this outcome.

Rate of rehospitalisation

No trial reported data for this outcome.

Oxygen content difference

No trial reported data for this outcome.

Cerebral oxygen content post surgery (rSO2)

No trial reported data for this outcome.

Blood lactate levels

No trial reported data for this outcome.

Blood sodium (Na+) levels

No trial reported data for this outcome.

Blood potassium (K+) levels

No trial reported data for this outcome.

Blood glucose levels

No trial reported data for this outcome.

Leukoreduced red blood cell transfusion versus non‐leukoreduced red blood cell transfusion

Primary outcome

All‐cause mortality: short term (0 to 30 days post‐surgery)

No trial reported data for this outcome.

Secondary outcomes

All‐cause mortality: long term (31 days to two years post‐surgery)

No trial reported data for this outcome.

Severe adverse events: cardiac events

No trial reported data for this outcome.

Severe adverse events: acute lung injury

No trial reported data for this outcome.

Severe adverse events: stroke

No trial reported data for this outcome.

Severe adverse events: thromboembolism

No trial reported data for this outcome.

Severe adverse events: renal failure (needing renal replacement therapy)

No trial reported data for this outcome.

Severe adverse events: infection

No trial reported data for this outcome.

Severe adverse events: haemorrhage (return to theatre for bleeding)

No trial reported data for this outcome.

Haematocrit (%) levels postoperatively

No trial reported data for this outcome.

Haemoglobin (g/dL) levels postoperatively

No trial reported data for this outcome.

Haematocrit/haemoglobin (g/dL) levels at discharge

No trial reported data for this outcome.

Volume or number of red cell units transfused

Komai 1998 reported data on this outcome. There was little to no difference in the mean number of red blood cell units transfused across the study period between the intervention arms (mean 6.3 units (SD 0.49) in the leukoreduced group compared to mean 6 units (SD 1.41) in the non‐leukoreduced group). We did not add this result to the analyses because it was unclear how many participants received any transfusion. The result is reported in Table 11.

Volume or number of other blood products transfused (i.e. fresh frozen plasma, platelets, cryoprecipitate)

No trial reported data for this outcome.

Postoperative chest drain output

No trial reported data for this outcome.

Duration of mechanical ventilation

De Vries 2004 and Komai 1998 reported data on this outcome. We did not undertake a meta‐analysis due to clinical diversity and the method of statistical analysis. De Vries 2004 reported intubation time as the median (plus interquartile range). The non‐leukoreduced group required a greater duration of mechanical ventilation than the leukoreduced group. The skew of these data prevents conversion to mean (and SD). Median values are reported in Table 14. In the second trial (Komai 1998), there was no evidence of a difference in intubation time between the two groups, but the evidence is very uncertain (MD −7.20 hours, 95% CI −20.72 to 6.32; 1 RCT, 46 participants; very low certainty evidence; Analysis 7.1).

7.1. Analysis.

Comparison 7: Leukoreduced red cell transfusion versus non‐leukoreduced red cell transfusion, Outcome 1: Duration of mechanical ventilation (hours)

Duration of intensive care unit stay

De Vries 2004 and Komai 1998 reported data on this outcome. De Vries 2004 reported similar lengths of median ICU stay for both groups. Median values are reported in Table 15. In Komai 1998, there may be little to no difference between the two groups in the duration of ICU stay, but the evidence is very uncertain (MD −1.10 days, 95% CI −7.72 to 5.52; 1 RCT, 46 participants; very low certainty evidence; Analysis 7.2).

7.2. Analysis.

Comparison 7: Leukoreduced red cell transfusion versus non‐leukoreduced red cell transfusion, Outcome 2: Duration of intensive care unit stay (days)

Rate of rehospitalisation

No trial reported data for this outcome.

Oxygen content difference

No trial reported data for this outcome.

Cerebral oxygen content post surgery (rSO2)

No trial reported data for this outcome.

Blood lactate levels

No trial reported data for this outcome.

Blood sodium (Na+) levels

No trial reported data for this outcome.

Blood potassium (K+) levels

No trial reported data for this outcome.

Blood glucose levels

No trial reported data for this outcome.

Discussion

The aim of this review was to evaluate the association of red blood cell transfusion management with mortality and morbidity in patients with congenital heart disease during their admission for cardiac surgery. We identified 19 completed RCTs involving 1606 participants, which evaluated red cell transfusion in eight intervention areas: five trials explored transfusion triggers (Chkhaidze 2014; Cholette 2011; Cholette 2017; De Gast‐Bakker 2013; Willems 2010), 11 trials explored non‐standard cardiopulmonary bypass (CPB) (Borisenko 2022; Busch 2017; Cholette 2012; Fu 2016; Gholampour Dehaki 2019; Han 2004; Hosking 1990; Liu 2007; Shimpo 2001; Swindell 2007; Ye 2013), two trials explored the benefit of leukoreduction (De Vries 2004; Komai 1998), and one trial explored the benefit of fresher blood compared to standard issue blood for transfusion (Martin 2022). All trials were in neonatal or paediatric populations, and there was a mix of cyanotic and acyanotic patients included in the trials. There were no trials specifically looking at the adult congenital heart disease population and no trials studied red blood cell transfusions versus no red blood cell transfusions.

Summary of main results

The 19 studies included in this review were heterogeneous in terms of study population, interventions, outcomes and data quality. We grouped them according to the following pre‐identified comparisons.

Restrictive transfusion‐trigger versus liberal transfusion‐trigger

The five included trials differed in terms of participant group and timing of interventions. Chkhaidze 2014, De Gast‐Bakker 2013 and Willems 2010 examined acyanotic participants; Cholette 2011 examined cyanotic participants; and Cholette 2017 examined a mix of acyanotic and cyanotic. One trial instituted the intervention from the time of induction of anaesthesia (De Gast‐Bakker 2013), whilst three instituted it postoperatively in the paediatric intensive care unit (Cholette 2011; Cholette 2017; Willems 2010). For the fifth trial, it appears the intervention was also instituted postoperatively, but the details are not clear (Chkhaidze 2014).

Restrictive versus liberal transfusion studies should aim to assess effects on mortality and morbidity. See Table 1.

Only three of the five included transfusion strategy trials examined our primary outcome of short‐term mortality (up to 30 days postoperatively). It is very uncertain whether a restrictive transfusion‐trigger impacts mortality at 30 days or mortality between 31 days and 2 years.

There may be little to no difference in the duration of mechanical ventilation. Cholette 2011 reported the length of mechanical ventilation as median (plus interquartile range). The restrictive threshold group required a greater duration of mechanical ventilation than the liberal threshold group. The skew of this data prevents a conversion to mean (and standard deviation (SD)).

There also may be little to no difference in the length of intensive care stay between the restrictive and liberal thresholds.

The evidence is very uncertain about the incidence of severe adverse cardiac events or infection.

One RCT reported data on the incidence of stroke (Cholette 2017), but we could not draw any conclusions due to there being only one study, so the results may not be generalisable.

Due to the small number of trials, plus clinical and methodological diversity, we were not able to perform meta‐analysis for the following specific important outcomes.

1. Renal failure

2. Postoperative haemorrhage rates

3. Postoperative haemoglobin levels

4. Rate of red cell transfusion (although, as expected, all five trials individually showed that the restrictive transfusion‐trigger group received fewer transfusions)

5. Rate/volume of blood product transfusion

The trials were small and heterogenous in terms of participant characteristics and timing of interventions, so we are uncertain whether restricting red blood cell transfusion has an effect on the outcomes of either acyanotic or cyanotic congenital cardiac patients in terms of mortality or incidence of some adverse events.

Washed red blood cells in CPB prime versus unwashed red blood cells in CPB prime

The aim of washing red blood cells that are added to the cardiopulmonary prime and returned to the patient is to reduce or eliminate potential adverse effects of the altered biochemistry of stored allogeneic red blood cells, especially raised potassium and lactate levels. See Table 2.

Washing red blood cells in the cardiopulmonary bypass prime may have little to no effect on mortality at 30 days and between 31 days and 2 years.

We were very uncertain about the impact of washing red blood cells in the cardiopulmonary bypass prime on the incidence of severe cardiac events, infection, duration of mechanical ventilation (no meta‐analysis) or duration of intensive care stay.

Lactate levels were variably affected by the washing techniques. Lactate levels were reported at different time points, making meta‐analysis difficult. There was no clear difference between peak lactate levels. For lactate levels prior to cardiopulmonary bypass in the cardiopulmonary bypass prime, one study showed washed red blood cells did have lower levels but the risk of bias in this study was unclear for most domains.

Washing red blood cells added to the cardiopulmonary bypass prime did appear to reduce potassium levels before cardiopulmonary bypass and at other time points in relation to cardiopulmonary bypass, but the study numbers were small, so there may be small‐study effects, making it difficult to accurately interpret the results.

Overall, the studies were too heterogeneous in terms of patient populations and exact intervention types to draw reliable conclusions about the impact of washing red cells. It does appear that washing reduces potassium levels. The data on lactate is less clear.

Crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime

Han 2004 and Borisenko 2022 (bloodless bypass prime) did not report mortality. See Table 3.

Unsurprisingly, a bloodless bypass prime showed lower haematocrit levels during bypass. For both studies, the haematocrit levels measured at the time points whilst on cardiopulmonary bypass and one time point after cardiopulmonary bypass were all higher in the blood‐containing prime group. Borisenko 2022 also showed a difference in haematocrit levels on the first day post‐surgery, with the blood‐containing prime group being higher. However, these differences were not clinically significant.

The haemoglobin/haematocrit levels at discharge were not reported by either study. Borisenko 2022 reported little to no difference in duration of mechanical ventilation or ITU stay between intervention groups. Han 2004 did not report these outcomes. Neither study reported any of the other secondary outcomes.

The important outcome for a bloodless bypass prime is intraoperative cerebral oxygen saturation, as reported by both trials (Borisenko 2022; Han 2004). Han 2004 found that the crystalloid prime group had lower cerebral oxygen saturations when compared with blood‐containing prime three minutes after initiating bypass and 15 minutes after the start of re‐warming. Borisenko 2022 found little to no difference in cerebral oxygen saturations during bypass between the intervention groups but did find a difference at the end of surgery with the blood‐containing prime group having higher cerebral oxygen saturations. This may suggest excessive haemodilution in the bloodless bypass prime, but the clinical significance of this is unknown as the trials did not specifically report neurological outcomes post‐surgery.

Overall, a bloodless bypass prime resulted in a lower haemoglobin level whilst on bypass and in 1 study, on postoperative day 1. These lower levels did not appear to increase the duration of mechanical ventilation or ICU stay. However, the studies did not report any secondary outcomes (e.g. neurological outcomes) that would have been relevant, and both studies had small sample sizes.

Ultrafiltration of CPB prime versus no ultrafiltration

Cardiopulmonary bypass priming solutions can often contain considerable amounts of stored allogenic blood. The process of ultrafiltration aims to reduce the negative effects of storage on the red blood cells by reducing the elevated levels of electrolytes and inflammatory mediators. We have identified two trials in this category, Gholampour Dehaki 2019 and Shimpo 2001. See Table 4.

Only Shimpo 2001 reported on early mortality, showing there may be little to no difference between treatment arms, but the evidence is very uncertain. Neither of the trials reported late mortality or adverse events.

Ultrafiltration may result in reduced duration of mechanical ventilation and ICU stay (Gholampour Dehaki 2019; Shimpo 2001). Ultrafiltration also reduced priming blood potassium and sodium levels, with Shimpo 2001 reporting ultrafiltrated priming blood had significantly lower levels when compared with pre‐ultrafiltration. No meta‐analysis was possible due to the different statistical methods used to report the results.

The two trials suggest that ultrafiltration of priming blood reduces the duration of ventilation and reduces potassium levels of the priming blood. However, both trials were small, and we graded the certainty of evidence as low, so the results should be interpreted with caution.

Retrograde autologous CPB prime versus standard CPB prime

Retrograde autologous priming of the cardiopulmonary bypass prime aims to reduce the exposure of participants to red cell transfusion by using the patient's own blood to prime the bypass circuit. Only one study examined this intervention (Fu 2016). See Table 5.

Mortality data and incidence of severe adverse events were not reported. The results showed there may be little to no difference in duration of mechanical ventilation or ICU stay between the two groups, but the evidence is from a single, small study and is very uncertain.

'Fresh' (not near to expiry date) versus 'old' (near to expiry date) red blood cell transfusion

There was only one study in this comparison. Martin 2022 aimed to determine if transfusion of fresh red blood cells reduced the incidence of new or progressive multiple organ dysfunction when compared to standard issue red blood cells. Unfortunately, the trial did not report any of the outcome data that we were interested in. See Table 6

This is an important area for research as there has been a suggestion that "older" red blood cell transfusions may be less effective than "fresh" red blood cell transfusions. Paediatric cardiac patients have a high risk of receiving red blood cell transfusions. Previous systematic reviews have highlighted that the effects of storage duration on clinically important outcomes have been investigated in high‐quality RCTs but predominantly in adults, and that the quality of evidence in neonates and children was low (Shah 2018). If the age of red blood cells used in transfusion had no impact on patient outcomes, it may change clinical practice and improve the logistics of providing blood from blood banks. It would be valuable to focus future studies on this intervention in this patient population.

Cell salvage of CPB prime versus allogeneic red blood cells post‐CPB

Only one trial was identified with this intervention (Ye 2013). See Table 8.

The trial showed there may be little to no difference in early mortality (up to 30 days postoperative), the incidence of cardiac events or acute lung injury, postoperative chest drain output or duration of mechanical ventilation, but the evidence is very uncertain.

Cell salvage significantly increased the haematocrit level on the first postoperative day but not at any other time point at baseline, during bypass or just after bypass.

Overall, these results would indicate cell salvage is a suitable alternative to allogeneic red blood cells post‐cardiopulmonary bypass, but this result should be interpreted with caution as the study risk of bias in the study was unclear for most domains.

Leukoreduced red blood cell transfusion versus non‐leukoreduced red blood cell transfusion

Leukoreduction aims to reduce the deleterious effects of leukocytes from allogeneic red cell transfusions.

For both duration of mechanical ventilation and length of intensive care, Komai 1998 (acyanotic population) showed there may be little to no difference between intervention groups, but the evidence is very uncertain. In contrast, De Vries 2004 (mixed cyanotic and acyanotic population) showed a shorter duration of mechanical ventilation for the leukoreduced group. Most of the other main outcomes of interest were not reported by the two studies in this comparison (De Vries 2004; Komai 1998).

The only two studies testing this intervention gave contrasting results (in differing patient populations) with respect to the impact of leukoreduction, making it difficult to draw definite conclusions about leukoreduction.

However, high‐income countries have largely stopped using non‐leucocyte reduced red blood cell concentrates. In addition, there were no new trials in this area since our original review, so we may not include this intervention in any future updates.

Overall completeness and applicability of evidence

The trials included in this review are insufficient to address the objectives of our systematic review. There are gaps in the evidence base in terms of patient population (no trials in adults with congenital heart disease), interventions (no trials examined the interventions of volumes of red blood cell transfusion or whole blood versus packed red blood cells), and the completeness of outcomes measured and reported by the included trials. Moreover, no trials evaluated red blood cell transfusion versus no red blood cell transfusion.

Our primary outcome was reported in only seven included trials. No trials reported data on re‐hospitalisation rates and only one trial reported the incidence of stroke. The number of trials providing data for individual outcomes ranged from one (thromboembolism) to eight (duration of intensive care stay).

We were not able to pool results for many of the outcomes of interest in this review. This was because there were too few trials, and the existing trials varied in their interventions and outcomes. This may limit the applicability of the evidence within this review. However, we are encouraged that eight RCTs have been completed since the original review was published in 2014. This area of medicine is small and includes a very heterogenous population, but red blood cell transfusion is used frequently, so future research should continue in this area.

Quality of the evidence

We used GRADE to assess the quality and certainty of the evidence. Overall, the certainty of the evidence was low or very low for all outcomes. We downgraded certainty because of the risk of bias, imprecision and indirectness. In terms of the risk of bias, there was a high or unclear risk of bias in the randomisation, allocation concealment, blinding and selective outcome domains, with many studies not fully describing their methods or not publishing a trial protocol with details of primary and secondary outcomes. In terms of imprecision, many results had very wide confidence intervals, and many results were also based on a single small study. We downgraded for indirectness in the restrictive transfusion‐trigger versus liberal transfusion‐trigger comparison because, for one trial (Cholette 2017), deaths were only reported as "in‐hospital mortality" and we were unable to establish at exactly which time point deaths occurred. We were unable to assess publication bias in any comparison due to having too few studies.

Overall, it was difficult to assess the quality of the evidence accurately as much information was lacking; we had to mark many domains of risk of bias in each trial as having an unclear risk of bias.

We downgraded for imprecision in all meta‐analysed outcomes presented in the summary of findings. This is because the sample size of the 19 included trials was generally small. Only nine trials had more than 50 participants in each treatment arm included in the analysis of outcome data (Cholette 2011; Cholette 2012; Cholette 2017; De Gast‐Bakker 2013; Gholampour Dehaki 2019; Martin 2022; Shimpo 2001; Willems 2010; Ye 2013). This may well reflect the difficulty of performing trials for this condition, but it does limit the statistical power of these trials to detect differences in outcomes of interest in this clinical area.

As has already been noted, the substantial clinical diversity in the included trials and the variability in outcome data reported limited our ability to pool outcome data. Thus, for many individual comparisons, there is little or no data to present. Addressing such variability should be a key component of future research in this area.

Potential biases in the review process

The strengths of this review lie in the robust and comprehensive methodology employed to find and assess all relevant trials. In this review update, we stipulated that, in order for a study to be included, at least one arm of the study had to involve a red blood cell transfusion management intervention. This meant we excluded a previously included study, Cholette 2010, because, although the intervention group was assigned to a cell salvage procedure, the control participants were not assigned to a red blood cell transfusion management intervention. For one study (Li 2020), we were unable to ascertain the exact nature of the intervention and control arms, despite contacting the authors for information. In order to avoid biasing the results, we categorised this study as 'awaiting classification'.

We anticipated finding studies with a mixed population that included some participants from the relevant population, and we planned to contact authors where possible to obtain subgroup data. However, we did not identify any studies with mixed populations in this update. We followed standard Cochrane methods for data extraction and results analysis with reference to the Cochrane Handbook for Systematic Reviews of Interventions(Higgins 2011), referring to a statistician where necessary. We had a clinician and methodologist working on all stages, independently of each other, to control any bias that might ensue due to clinical or systematic review methodology knowledge. When we were limited by a lack of reporting data to allow inclusion and assessment of trials, we successfully contacted authors directly to obtain the necessary data.

Agreements and disagreements with other studies or reviews

Prior to the publication of the original version of this review (Wilkinson 2014), there had been no other systematic reviews specifically examining the effects of red blood cell transfusion on mortality and morbidity in the congenital heart disease population at the time of cardiac surgery (Dorée 2010). Guzzetta 2011 reviewed the risks and benefits of red cell transfusion and concluded that the efficacy of red blood cell transfusion has never been equivocally shown, even in well‐designed trials, and that further well‐designed trials are needed in this heterogeneous population.

More recently, Carson 2021 looked at transfusion thresholds across numerous patient populations and concluded that no evidence suggests that a restrictive transfusion strategy has impacted mortality or morbidity compared with a liberal transfusion strategy. However, Carson 2021 felt that the data remain insufficient to inform the safety of transfusion policies in some patient subgroups and that further research efforts are needed.

Duan 2021 performed a meta‐analysis of five RCTs assessing liberal versus restrictive transfusion thresholds in cyanotic and acyanotic patients. Duan 2021 concluded that a liberal transfusion strategy does not lead to a better outcome, but the data are extremely sparse, and clearer transfusion guidelines specific to this specific population are needed.

Our review agrees with these conclusions in relation to the effect of liberal and restrictive red cell transfusion in patients with congenital heart disease. We have not found any other reviews looking at other aspects of the practice of red blood cell transfusion in this patient population.

Authors' conclusions

Implications for practice.

We are unable to draw any reliable conclusions from the evidence identified in this review. Transfusion practice in children with congenital heart disease undergoing cardiac surgery will continue to be based on expert opinion‐based recommendations and individual centre practice.

This review found 19 randomised controlled studies, including 1606 participants, which studied the impact of red cell transfusion on children undergoing cardiac surgery for congenital heart disease, but these studies did not assess red blood cell transfusion versus no red cell transfusion. Moreover, the trials did not assess the key important clinical outcomes. We are therefore unable to determine whether red blood cell transfusion plays a role in reducing or increasing morbidity and mortality.

The reason that none of the studies examined red blood cell transfusion versus no red blood cell transfusion may be because there are likely only a very small group of stable, non‐complex patients with congenital heart disease undergoing cardiac surgery where it would be ethical and safe to conduct such a trial. Smaller babies and children and those with pre‐existing anaemia may be put at risk of the harmful effects of excessive haemodilution and profound anaemia from the start of cardiopulmonary bypass if assigned to a no‐red‐cell‐transfusion study arm.

Congenital heart disease remains an outlier within transfusion practice guidelines. Patients with congenital heart disease undergoing cardiac surgery have a high incidence of red blood cell transfusion. However, the absence of evidence from randomised controlled trials on the benefits or harms of red blood cell transfusion management means that, by necessity, clinical practice is based only on expert opinion.

Implications for research.

There are gaps and deficiencies in the current evidence base. Disappointingly, only eight further trials have been reported in the nine years since the original version of this review was published. However, new trials have studied new clinical outcomes of red blood cell transfusion, suggesting recognition that the overall effect of red blood cell transfusion may be multifactorial. No studies were found which specifically assessed the association of patient morbidity and mortality with red blood cell transfusion management in the fast‐growing adult congenital population.

Future randomised controlled trials should be designed that are adequately powered and specific both for age (neonates, paediatrics and adult age groups) and type of congenital heart disease (cyanotic and acyanotic groups). The main areas of clinical interest are haemoglobin transfusion triggers and the age of red blood cells in the preoperative, intraoperative and postoperative periods (including in the cardiopulmonary bypass prime). The most important outcomes are mortality, duration of ventilation, length of intensive care and hospital stay, plus the incidence of adverse events (cardiac, renal failure and bleeding).

What's new

Date	Event	Description
19 March 2025	New citation required but conclusions have not changed	There is insufficient evidence to accurately assess the impact of red cell transfusion on people with congenital heart disease undergoing cardiac surgery.
19 March 2025	New search has been performed	We updated the search for this review on 2 January 2024 and included a further eight studies, which involved 698 participants. We refined our inclusion criteria, which led to the exclusion of one previously included study of 106 participants. We updated the analysis and results throughout to add data from the new studies. Three review authors who are no longer working on the review (Sheila A Fisher, Ravi Gill, Marialena Trivella) were removed from the byline and added to the acknowledgements section. Three new review authors (Alisha Allana, Rita Champaneria and Catherine Kimber) were added to the byine.

History

Protocol first published: Issue 3, 2012
Review first published: Issue 2, 2014

Appendices

Appendix 1. Search strategies

CENTRAL

#1 MeSH descriptor: [Heart Defects, Congenital] explode all trees

#2 MeSH descriptor: [Heart Diseases] explode all trees and with qualifier(s): [congenital ‐ CN]

#3 ((heart* or cardiac* or coronary or septal* or aortopulmonary or aorticopulmonary or atrial or ventricular or intraventricular) near/3 (congenital* or neonat* or defect* or abnormal* or anomal*))

#4 (digeorge next (syndrome* or anomal* or sequenc*))

#5 (transpos* near/3 (arteries or artery or vessel*))

#6 (alagille near/2 syndrome)

#7 arteriohepatic dysplasia* or gonadal dysgenesis or subdivided left atrium* or cardiovertebral syndrome* or pharyngeal pouch syndrome* or thymic aplasia syndrome* or conotruncal anomaly face syndrome

#8 hepatic hypoplasia or arteriohepatic dysplasia* or turner* syndrome or noonan syndrome or arteriohepatic dysplasia* or bicuspid aortic valve

#9 (taussig* near/2 anomal*)

#10 (pulmon* or aortic or subaortic or valve or mitral) next stenosis

#11 ((aortic or aorta*) near/3 coarctation*)

#12 (ventricular near/2 dysplasia*)

#13 (barth syndrome or cor triatriatum or cortriatriatum or triatrial heart*)

#14 (velo* near/3 syndrome*)

#15 (myocardial bridging* or arterial switch* or crisscross heart* or criss‐cross heart*)

#16 (dextrocardia* or kartagener* syndrome or kartagener* triad or siewert* syndrome or primary ciliary dyskinesia)

#17 "patent ductus arteriosus" or "scimitar syndrome" or "anomalous pulmonary venous connection" or "double inlet left ventricle" or "double outlet right ventricle" or "interrupted aortic arch"

#18 (ebstein* anomaly or ebstein* malformation* or ectopia cordis)

#19 (eisenmenger* next (complex or syndrome))

#20 (persistent truncus arteriosus or persistent ostium primum)

#21 endocardial cushion defect* or "atrioventricular canal"

#22 (foramen oval* or lutembacher* syndrome)

#23 (heart near/3 hypoplas*)

#24 ((noncompaction near/3 ventricular myocardium) or (noncompaction near/3 ventricular myocardium))

#25 ((leopard or multiple lentigines) next syndrome*)

#26 levocardia or marfan* syndrome

#27 ((tetralogy or trilogy or syndrome) near/2 fallot*) or cantrell* or "shone's"

#28 (tricuspid atresia* or valve atresia* or pulmonary atresia or absent right atrioventricular connection)

#29 single ventricle physiology or GUCH or fontan procedure or cavopulmonary connection

#30 ((reparative or repair*) near/2 (cardiac surgery or heart surgery))

#31 (taussig* near/2 anomal*) or (bonnevie near/2 (syndrome* or status)) or polynesian bronchiectas* or gonadal dysgenesis

#32 ((congenital* or birth or born neonat* or newborn* or infant* or pediatric* or paediatric* or child* or prematur*) and (heart* or cardiac* or cardiomyopath* or coronary or myocard* or septal* or aortopulmonary or aorticopulmonary or atrial or ventricular or intraventricular or ventricle* or surg* or operat* or preoperat* or postoperat* or perioperat* or bypass* or intensive care or critical care or ICU or PICU)):ti

#33 ((congenital* or birth or born or neonat* or newborn* or infant* or pediatric* or paediatric* or child* or prematur*) near/5 (heart* or cardiac* or cardiomyopath* or coronary or myocard* or septal* or aortopulmonary or aorticopulmonary or atrial or ventricular or intraventricular or ventricle* or surg* or operat* or preoperat* or postoperat* or perioperat* or bypass* or intensive care or critical care or ICU or PICU)):ab

#34 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33

#35 MeSH descriptor: [Blood Transfusion] this term only

#36 MeSH descriptor: [Blood Component Transfusion] this term only

#37 MeSH descriptor: [Erythrocyte Transfusion] this term only

#38 MeSH descriptor: [Erythrocytes] this term only

#39 ((blood or erythrocyte* or red cell* or red blood cell* or RBC*) near/3 (transfus* or infus* or hypertransfus* or retransfus*))

#40 ((transfus* or retransfus*) near/1 (trigger* or level* or threshold* or rule* or restrict*))

#41 (transfusion* near/2 (management or practice* or polic* or strateg* or guideline* or indication* or protocol* or criteri* or autologous))

#42 ((blood near/2 management) or "blood sparing" or "cell salvage" or "cell saver" or "blood support" or (blood near/2 requirement*) or (blood near/2 need*) or autotransfus* or "whole blood" or "blood product" or "blood products" or "blood component" or "blood components")

#43 (red cell* management or red cell* sparing or red cell* support or (red cell* near/3 requirement*))

#44 (leukodeplet* or leukoreduc* or leucodeplet* or leucoreduc* or leukofiltrat* or leucofiltrat*):ti

#45 ((leukocyte* or leucocyte*) near/2 (remov* or deplet* or reduc* or poor or filtrat*)):ti

#46 hemotransfus* or haemotransfus* or hemotherap* or haemotherap*

#47 (red cell* or red blood cell* or erythrocyte* or RBC* or transfus*):ti

#48 (bypass near/5 (prime or priming))

#49 ((blood or erythrocyte* or red cell* or red blood cell* or RBC*) near/3 (exchang* or replac*))

#50 #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46 or #47 or #48 or #49

#51 #34 and #50 in Trials

MEDLINE (Ovid)

1. exp Heart Defects, Congenital/

2. exp Heart Diseases/cn

3. ((heart* or cardiac* or coronary or septal* or aortopulmonary or aorticopulmonary or atrial or ventricular or intraventricular) adj3 (congenital* or defect* or abnormal* or anomal*)).tw,kf.

4. (digeorge adj (syndrome* or anomal* or sequenc*)).tw,kf.

5. (transpos* adj3 (arteries or artery or vessel*)).tw,kf.

6. (alagille adj2 syndrome).tw,kf.

7. (arteriohepatic dysplasia* or gonadal dysgenesis or subdivided left atrium* or cardiovertebral syndrome* or pharyngeal pouch syndrome* or thymic aplasia syndrome* or conotruncal anomaly face syndrome).tw,kf.

8. (hepatic hypoplasia or arteriohepatic dysplasia* or turner* syndrome or noonan syndrome or arteriohepatic dysplasia* or bicuspid aortic valve).tw,kf.

9. (taussig* adj2 anomal*).tw,kf.

10. ((pulmon* or aortic or subaortic or valve or mitral) adj stenosis).tw,kf.

11. ((aortic or aorta*) adj3 coarctation*).tw,kf.

12. (ventricular adj2 dysplasia*).tw,kf.

13. (barth syndrome or cor triatriatum or cortriatriatum or triatrial heart*).tw,kf.

14. (velo* adj3 syndrome*).tw,kf.

15. (myocardial bridging* or crisscross heart* or criss‐cross heart*).tw,kf.

16. (dextrocardia* or kartagener* syndrome or kartagener* triad or siewert* syndrome or primary ciliary dyskinesia).tw,kf.

17. ("patent ductus arteriosus" or "scimitar syndrome" or "anomalous pulmonary venous connection" or "double inlet left ventricle" or "double outlet right ventricle" or "interrupted aortic arch").tw,kf.

18. (ebstein* anomaly or ebstein* malformation* or ectopia cordis).tw,kf.

19. (eisenmenger* adj (complex or syndrome)).tw,kf.

20. (persistent truncus arteriosus or persistent ostium primum).tw,kf.

21. (endocardial cushion defect* or atrioventricular canal).tw,kf.

22. (foramen oval* or lutembacher* syndrome).tw,kf.

23. (heart adj3 hypoplas*).tw,kf.

24. ((noncompaction adj3 ventricular myocardium) or (non compaction adj3 ventricular myocardium)).tw,kf.

25. ((leopard or multiple lentigines) adj syndrome*).tw,kf.

26. (levocardia or marfan* syndrome).tw,kf.

27. (((tetralogy or trilogy or syndrome) adj2 fallot*) or cantrell* or shon?s).tw,kf.

28. (tricuspid atresia* or valve atresia* or pulmonary atresia or absent right atrioventricular connection).tw,kf.

29. (single ventricle physiology or GUCH or fontan procedure or cavopulmonary connection).tw,kf.

30. ((reparative or repair*) adj2 (cardiac surgery or heart surgery)).tw,kf.

31. arterial switch.tw,kf.

32. ((bonnevie adj2 (syndrome* or status)) or polynesian bronchiectas*).tw,kf.

33. ((congenital* or birth or born or neonat* or newborn* or infant* or pediatric* or paediatric* or child* or prematur*) and (heart* or cardiac* or cardiomyopath* or coronary or myocard* or septal* or aortopulmonary or aorticopulmonary or atrial or ventricular or intraventricular or ventricle* or surg* or operat* or preoperat* or postoperat* or perioperat* or bypass* or intensive care or critical care or ICU or PICU)).ti,kf.

34. ((congenital* or birth or born or neonat* or newborn* or infant* or pediatric* or paediatric* or child* or prematur*) adj5 (heart* or cardiac* or cardiomyopath* or coronary or myocard* or septal* or aortopulmonary or aorticopulmonary or atrial or ventricular or intraventricular or ventricle* or surg* or operat* or preoperat* or postoperat* or perioperat* or bypass* or intensive care or critical care or ICU or PICU)).ab.

35. or/1‐34

36. BLOOD TRANSFUSION/

37. BLOOD COMPONENT TRANSFUSION/

38. ERYTHROCYTE TRANSFUSION/

39. ERYTHROCYTES/

40. ((blood or erythrocyte* or red cell* or red blood cell* or RBC* or PRBC*) adj3 (transfus* or infus* or hypertransfus* or retransfus*)).tw,kf.

41. ((transfus* or retransfus*) adj2 (trigger* or level* or threshold* or rule* or restrict*)).tw,kf.

42. ((blood or erythrocyte* or red cell* or red blood cell* or RBC*) adj3 (exchang* or replac*)).tw,kf.

43. (transfusion* adj2 (management or practice* or polic* or strateg* or guideline* or indication* or protocol* or criteri* or autologous)).tw,kf.

44. ((blood adj2 management) or blood sparing or cell salvage or cell saver* or (blood adj2 salvag*) or blood support or (blood adj2 requirement*) or autotransfus*).tw,kf.

45. (red cell* management or red cell* sparing or red cell* support or (red cell* adj3 requirement*)).tw,kf.

46. ((blood adj1 need*) or whole blood or blood product* or blood component*).tw,kf.

47. (leukodeplet* or leukoreduc* or leucodeplet* or leucoreduc* or leukofiltrat* or leucofiltrat*).ti,kf.

48. ((leukocyte* or leucocyte*) adj2 (remov* or deplet* or reduc* or poor or filtrat*)).ti,kf.

49. (hemotransfus* or haemotransfus* or hemotherap* or haemotherap*).tw,kf.

50. (red cell* or red blood cell* or erythrocyte* or whole blood or RBC* or transfus*).ti,kf.

51. (bypass adj5 (prime or priming)).tw,kf.

52. or/36‐51

53. 35 and 52

54. Meta‐Analysis.pt.

55. Systematic Review.pt.

56. "Systematic Reviews as Topic"/

57. ((meta analy* or metaanaly*) and (trials or studies)).ab.

58. (meta analy* or metaanaly* or evidence‐based).ti.

59. ((systematic* or evidence‐based) adj2 (review* or overview*)).tw,kf.

60. (evidence synthes* or cochrane or medline or pubmed or embase or cinahl or cinhal or lilacs or "web of science" or science citation index or scopus or search terms or literature search or electronic search* or comprehensive search* or systematic search* or published articles or search strateg* or reference list* or bibliograph* or handsearch* or hand search* or manual* search*).ab.

61. Cochrane Database of systematic reviews.jn.

62. (additional adj (papers or articles or sources)).ab.

63. ((electronic* or online) adj (sources or resources or databases)).ab.

64. (relevant adj (journals or articles)).ab.

65. or/54‐64

66. Review.pt.

67. Randomized Controlled Trials as Topic/

68. selection criteria.ab. or critical appraisal.ti.

69. (data adj (abstraction or extraction or analys*)).ab.

70. Randomized Controlled Trial/

71. or/67‐70

72. 66 and 71

73. 65 or 72

74. exp Controlled Clinical Trial/

75. (randomi* or randomly or placebo or groups).tw,kf.

76. trial.ti,kf.

77. Clinical Trials as Topic/

78. or/74‐77

79. 73 or 78

80. (Animals/ or exp Animal Experimentation/ or exp Models, Animal/) not Humans/

81. Editorial.pt.

82. 80 or 81

83. 79 not 82

84. 53 and 83

Embase (Ovid)

1. exp Congenital Heart Disease/

2. exp Congenital Blood Vessel Malformation/

3. exp Heart Disease/cn

4. ((heart* or cardiac* or coronary or septal* or aortopulmonary or aorticopulmonary or atrial or ventricular or intraventricular) adj3 (congenital* or defect* or abnormal* or anomal*)).tw,kf.

5. (digeorge adj (syndrome* or anomal* or sequenc*)).tw,kf.

6. (transpos* adj3 (arteries or artery or vessel*)).tw,kf.

7. (alagille adj2 syndrome).tw,kf.

8. (arteriohepatic dysplasia* or gonadal dysgenesis or subdivided left atrium* or cardiovertebral syndrome* or pharyngeal pouch syndrome* or thymic aplasia syndrome* or conotruncal anomaly face syndrome).tw,kf.

9. (hepatic hypoplasia or arteriohepatic dysplasia* or turner* syndrome or noonan syndrome or arteriohepatic dysplasia* or bicuspid aortic valve).tw,kf.

10. (taussig* adj2 anomal*).tw,kf.

11. ((pulmon* or aortic or subaortic or valve or mitral) adj stenosis).tw,kf.

12. ((aortic or aorta*) adj3 coarctation*).tw,kf.

13. (ventricular adj2 dysplasia*).tw,kf.

14. (barth syndrome or cor triatriatum or cortriatriatum or triatrial heart*).tw,kf.

15. (velo* adj3 syndrome*).tw,kf.

16. (myocardial bridging* or crisscross heart* or criss‐cross heart*).tw,kf.

17. (dextrocardia* or kartagener* syndrome or kartagener* triad or siewert* syndrome or primary ciliary dyskinesia).tw,kf.

18. ("patent ductus arteriosus" or "scimitar syndrome" or "anomalous pulmonary venous connection" or "double inlet left ventricle" or "double outlet right ventricle" or "interrupted aortic arch").tw,kf.

19. (ebstein* anomaly or ebstein* malformation* or ectopia cordis).tw,kf.

20. (eisenmenger* adj (complex or syndrome)).tw,kf.

21. (persistent truncus arteriosus or persistent ostium primum).tw,kf.

22. (endocardial cushion defect* or atrioventricular canal).tw,kf.

23. (foramen oval* or lutembacher* syndrome).tw,kf.

24. (heart adj3 hypoplas*).tw,kf.

25. ((noncompaction adj3 ventricular myocardium) or (non compaction adj3 ventricular myocardium)).tw,kf.

26. ((leopard or multiple lentigines) adj syndrome*).tw,kf.

27. (levocardia or marfan* syndrome).tw,kf.

28. (((tetralogy or trilogy or syndrome) adj2 fallot*) or cantrell* or shon?s).tw,kf.

29. (tricuspid atresia* or valve atresia* or pulmonary atresia or absent right atrioventricular connection).tw,kf.

30. (single ventricle physiology or GUCH or fontan procedure or cavopulmonary connection).tw,kf.

31. ((reparative or repair*) adj2 (cardiac surgery or heart surgery)).tw,kf.

32. arterial switch.tw,kf.

33. ((bonnevie adj2 (syndrome* or status)) or polynesian bronchiectas*).tw,kf.

34. ((congenital* or birth or born or neonat* or newborn* or infant* or pediatric* or paediatric* or child* or prematur*) and (heart* or cardiac* or cardiomyopath* or coronary or myocard* or septal* or aortopulmonary or aorticopulmonary or atrial or ventricular or intraventricular or ventricle* or surg* or operat* or preoperat* or postoperat* or perioperat* or bypass* or intensive care or critical care or ICU or PICU)).ti,kf.

35. ((congenital* or birth or born or neonat* or newborn* or infant* or pediatric* or paediatric* or child* or prematur*) adj5 (heart* or cardiac* or cardiomyopath* or coronary or myocard* or septal* or aortopulmonary or aorticopulmonary or atrial or ventricular or intraventricular or ventricle* or surg* or operat* or preoperat* or postoperat* or perioperat* or bypass* or intensive care or critical care or ICU or PICU)).ab.

36. or/1‐35

37. Blood Transfusion/

38. Blood Component Therapy/

39. Erythrocyte Transfusion/

40. Erythrocyte/

41. ((blood or erythrocyte* or red cell* or red blood cell* or RBC*) adj3 (transfus* or infus* or hypertransfus* or retransfus*)).tw,kf.

42. ((transfus* or retransfus*) adj1 (trigger* or level* or threshold* or rule* or restrict*)).tw,kf.

43. (transfusion* adj2 (management or practice* or polic* or strateg* or guideline* or indication* or protocol* or criteri*)).tw,kf.

44. ((blood adj2 management) or blood sparing or cell salvage or cell saver* or (blood adj2 salvag*) or blood support or (blood adj2 requirement*)).tw,kf.

45. (red cell* management or red cell* sparing or red cell* support or (red cell* adj3 requirement*)).tw,kf.

46. ((blood adj1 need*) or whole blood or blood product* or blood component*).tw,kf.

47. ((blood or erythrocyte* or red cell* or red blood cell* or RBC*) adj3 (exchang* or replac*)).tw,kf.

48. (leukodeplet* or leukoreduc* or leucodeplet* or leucoreduc* or leukofiltrat* or leucofiltrat*).ti,kf.

49. ((leukocyte* or leucocyte*) adj2 (remov* or deplet* or reduc* or poor or filtrat*)).ti,kf.

50. (hemotransfus* or haemotransfus* or hemotherap* or haemotherap*).tw,kf.

51. (red cell* or red blood cell* or erythrocyte* or whole blood or RBC* or transfus* or retransfus*).ti,kf.

52. (bypass adj5 (prime or priming)).tw,kf.

53. or/37‐52

54. 36 and 53

55. Meta Analysis/

56. (meta analy* or metaanaly* or evidence‐based).ti.

57. ((meta analy* or metaanaly*) and (trials or studies)).ab.

58. Systematic Review/

59. ((systematic* or evidence‐based) adj2 (review* or overview*)).tw,kf.

60. (evidence synthes* or cochrane or medline or pubmed or embase or cinahl or cinhal or lilacs or "web of science" or science citation index or scopus or search terms or literature search or electronic search* or comprehensive search* or systematic search* or published articles or search strateg* or reference list* or bibliograph* or handsearch* or hand search* or manual* search*).ab.

61. ((electronic* or online) adj (sources or resources or databases)).ab.

62. ((additional adj (papers or articles or sources)) or (relevant adj (journals or articles))).ab.

63. or/55‐62

64. Review.pt.

65. (data extraction or selection criteria).ab.

66. 64 and 65

67. 63 or 66

68. Editorial.pt.

69. 67 not 68

70. crossover‐procedure/ or double‐blind procedure/ or randomized controlled trial/ or single‐blind procedure/

71. (random* or factorial* or crossover* or cross over* or cross‐over* or placebo* or doubl* blind* or singl* blind* or assign* or allocat* or volunteer*).mp.

72. 70 or 71

73. 69 or 72

74. limit 73 to (conference abstracts or embase)

75. 54 and 74

PubMed (epublications only)

#1 ((blood[TI] OR erythrocyte*[TI] OR red cell*[TI] OR red blood cell*[TI] OR RBC*[TI]) AND (transfus*[TI] OR infus*[TI] OR hypertransfus*[TI] OR retransfus*[TI])) OR ((transfus*[TI] OR retransfus*[TI]) AND (trigger*[TI] OR level*[TI] OR threshold*[TI] OR rule*[TI] OR restrict*[TI])) OR (transfusion*[TI] AND (management[TI] OR practice*[TI] OR polic*[TI] OR strateg*[TI] OR guideline*[TI] OR indication*[TI] OR protocol*[TI] OR criteri*[TI]))

#2 ("blood management" OR "blood sparing" OR "cell salvage" OR "blood salvage" OR "blood support" OR blood requirement*[TI] OR "blood product" OR "blood products" OR "blood component" OR "blood components") OR (("red cell"[TI] OR "red cells"[TI]) AND (management[TI] OR sparing[TI] OR support[TI] OR requirement*[TI])) OR ("need for blood"[TI] OR whole blood[TI] OR "use of blood"[TI])

#3 (leukodeplet*[TI] OR leukoreduc*[TI] OR leucodeplet*[TI] OR leucoreduc*[TI] OR leukofiltrat*[TI] OR leucofiltrat*[TI]) OR ((leukocyte*[TI] OR leucocyte*[TI]) AND (remov*[TI] OR deplet*[TI] OR reduc*[TI] OR poor[TI] OR filtrat*[TI])) OR (hemotransfus*[TI] OR haemotransfus*[TI] OR red cell*[TI] OR red blood cell*[TI] OR erythrocyte*[TI] OR RBC*[TI] OR transfus*[TI]) OR (bypass[TI] AND (prime*[TI] OR priming[TI]))

#4 #1 OR #2 OR #3

#5 ((congenital*[TI] OR birth[TI] OR born[TI] OR neonat*[TI] OR newborn*[TI] OR infant*[TI] OR pediatric*[TI] OR paediatric*[TI] OR child*[TI] OR prematur*[TI] OR defect*[TI] OR abnormal*[TI] OR anomal*[TI]) AND (heart*[TI] OR cardiac*[TI] OR cardiomyopath*[TI] OR coronary[TI] OR myocard*[TI] OR septal*[TI] OR aortopulmonary[TI] OR aorticopulmonary[TI] OR atrial[TI] OR ventricular[TI] OR intraventricular[TI] OR ventricle*[TI] OR surg*[TI] OR operat*[TI] OR preoperat*[TI] OR postoperat*[TI] OR perioperat*[TI] OR bypass*[TI] OR intensive care[TI] OR critical care[TI] OR ICU[TI] OR PICU[TI]))

#6 #4 AND #5

#7 (random* OR blind* OR "control group" OR placebo* OR controlled OR groups OR trial* OR "systematic review" OR "meta‐analysis" OR metaanalysis OR “evidence synthesis” OR "literature search" OR medline OR pubmed OR cochrane OR embase) AND (publisher[sb] OR inprocess[sb] OR pubmednotmedline[sb])

#8 #6 AND #7

CINAHL (EBSCOhost)

1. (MH “Heart Defects, Congenital+”)

2. TI ((heart* or cardiac* or coronary or septal* or aortopulmonary or aorticopulmonary or atrial or ventricular or intraventricular) N3 (congenital* or neonat* or defect* or abnormal* or anomal*)) OR AB ((heart* or cardiac* or coronary or septal* or aortopulmonary or aorticopulmonary or atrial or ventricular or intraventricular) N3 (congenital* or neonat* or defect* or abnormal* or anomal*))

3. TI (transpos* N3 (arteries or artery or vessel*)) OR AB (transpos* N3 (arteries or artery or vessel*))

4. TI (alagille N2 syndrome) OR AB (alagille N2 syndrome)

5. TI ((hepatic hypoplasia) OR (arteriohepatic dysplasia*) OR (turner* syndrome) OR (noonan syndrome) OR (arteriohepatic dysplasia*) OR (bicuspid aortic valve)) OR AB ((hepatic hypoplasia) OR (arteriohepatic dysplasia*) OR (turner* syndrome) OR (noonan syndrome) OR (arteriohepatic dysplasia*) OR (bicuspid aortic valve))

6. TI ((pulmon* or aortic or subaortic or valve or mitral) N1 stenosis) OR AB ((pulmon* or aortic or subaortic or valve or mitral) N1 stenosis)

7. TI ((aortic or aorta*) N3 coarctation) OR AB ((aortic or aorta*) N3 coarctation)

8. TI (ventricular N2 dysplasia*) OR AB (ventricular N2 dysplasia*)

9. TI ((barth syndrome) or (cor triatriatum) or cortriatriatum or (triatrial heart*)) OR AB ((barth syndrome) or (cor triatriatum) or cortriatriatum or (triatrial heart*))

10. TI (coronary vessel* N2 anomal*) OR AB (coronary vessel* N2 anomal*)

11. TX (myocardial bridging) or TX (arterial switch*) or TX (crisscross heart*) or TX (criss‐cross heart*)

12. TI (dextrocardia*) or TX (kartagener* syndrome) or TX (kartagener* triad) or TX (siewert* syndrome) or TX (primary ciliary dyskinesia)

13. TI (“patent ductus arteriosus” or “scimitar syndrome” or “anomalous pulmonary venous connection” or “double inlet left ventricle” or “double outlet right ventricle” or “interrupted aortic arch”) OR AB (“patent ductus arteriosus” or “scimitar syndrome” or “anomalous pulmonary venous connection” or “double inlet left ventricle” or “double outlet right ventricle” or “interrupted aortic arch”)

14. TI (“ebstein* anomaly” or “ebstein* malformation*” or “ectopia cordis”) OR AB (“ebstein* anomaly” or “ebstein* malformation*” or “ectopia cordis”)

15. TI (eisenmenger* N1 (complex or syndrome)) OR AB (eisenmenger* N1 (complex or syndrome))

16. TI (“persistent truncus arteriosus” or “persistent ostium primum” or “endocardial cushion defect*” or “atrioventricular canal” or “foramen oval*” or “lutembacher* syndrome”) OR AB (“persistent truncus arteriosus” or “persistent ostium primum” or “endocardial cushion defect*” or “atrioventricular canal” or “foramen oval*” or “lutembacher* syndrome”)

17. TI (heart N3 hypoplas*) OR AB (heart N3 hypoplas*)

18. TI ((noncompaction N3 “ventricular myocardium”) or TI (“non compaction” N3 “ventricular myocardium”))

19. AB ((noncompaction N3 “ventricular myocardium”) or AB (“non compaction” N3 “ventricular myocardium”))

20. TI ((leopard or multiple lentigines) N1 syndrome*) OR AB ((leopard or multiple lentigines) N1 syndrome*)

21. TI (levocardia or marfan* syndrome) OR AB (levocardia or marfan* syndrome)

22. TI (((tetralogy or trilogy or syndrome) N2 fallot*) or cantrell* or shone?s) OR AB (((tetralogy or trilogy or syndrome) N2 fallot*) or cantrell* or shone?s)

23. TI ((double outlet N3 ventricle) or taussig bing anomaly) OR AB ((double outlet N3 ventricle) or taussig bing anomaly)

24. TI (tricuspid atresia* or valve atresia* or pulmonary atresia* or absent right atrioventricular connection) OR AB (tricuspid atresia* or valve atresia* or pulmonary atresia* or absent right atrioventricular connection)

25. TI (single ventricle physiology or GUCH or fontan procedure or cavopulmonary connection) OR AB (single ventricle physiology or GUCH or fontan procedure or cavopulmonary connection)

26. TI ((reparative or repair*) N2 TX (cardiac surgery or heart surgery)) OR AB ((reparative or repair*) N2 TX (cardiac surgery or heart surgery))

27. TI ((bonnevie N2 TX (syndrome* or status)) or polynesian bronchiectas*) OR AB ((bonnevie N2 TX (syndrome* or status)) or polynesian bronchiectas*)

28. TI ((congenital* or birth or born or neonat* or newborn* or infant* or pediatric* or paediatric* or child* or prematur*) N5 (heart* or cardiac* or cardiomyopath* or coronary or myocard* or septal* or aortopulmonary or aorticopulmonary or atrial or ventricular or intraventricular or ventricle* or surg* or operat* or preoperat* or postoperat* or perioperat* or bypass* or intensive care or critical care or ICU or PICU))

29. AB ((congenital* or birth or born or neonat* or newborn* or infant* or pediatric* or paediatric* or child* or prematur*) N5 (heart* or cardiac* or cardiomyopath* or coronary or myocard* or septal* or aortopulmonary or aorticopulmonary or atrial or ventricular or intraventricular or ventricle* or surg* or operat* or preoperat* or postoperat* or perioperat* or bypass* or intensive care or critical care or ICU or PICU))

30. S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29

31. (MH BLOOD TRANSFUSION)

32. (MH BLOOD COMPONENT TRANSFUSION)

33. (MH ERYTHROCYTE TRANSFUSION)

34. (MH ERYTHROCYTES)

35. TI ((blood or erythrocyte* or red cell* or red blood cell* or RBC*) N3 (transfus* or infus* or hypertransfus* or retransfus*)) OR AB ((blood or erythrocyte* or red cell* or red blood cell* or RBC*) N3 (transfus* or infus* or hypertransfus* or retransfus*))

36. TI ((transfus* or retransfus*) N2 (trigger* or level* or threshold* or rule* or restrict*)) OR AB ((transfus* or retransfus*) N2 (trigger* or level* or threshold* or rule* or restrict*))

37. TI (transfusion* N2 (management or practice* or polic* or strateg* or guideline* or indication* or protocol* or criteri* or autologous)) OR (transfusion* N2 (management or practice* or polic* or strateg* or guideline* or indication* or protocol* or criteri* or autologous))

38. TI ((blood N2 management) or blood sparing or cell salvage or (blood N2 salvag*) or blood support or (blood N2 requirement*) or autotransfus*) OR AB ((blood N2 management) or blood sparing or cell salvage or (blood N2 salvag*) or blood support or (blood N2 requirement*) or autotransfus*)

39. TI (red cell* management or red cell* sparing or red cell* support or (red cell* N3 requirement*)) OR AB (red cell* management or red cell* sparing or red cell* support or (red cell* N3 requirement*))

40. TI ((blood N1 need*) or whole blood or blood product* or blood component*) OR AB ((blood N1 need*) or whole blood or blood product* or blood component*)

41. TI (leukodeplet* or leukoreduc* or leucodeplet* or leucoreduc* or leukofiltrat* or leucofiltrat*)

42. TI ((leukocyte* or leucocyte*) N2 (remov* or deplet* or reduc* or poor or filtrat

43. TI (hemotransfus* or haemotransfus*) OR AB (hemotransfus* or haemotransfus*)

44. TI (red cell* or red blood cell* or erythrocyte* or whole blood or RBC* or transfus*)

45. TI (bypass N5 (prime or priming)) OR AB (bypass N5 (prime or priming))

46. S31 OR S32 OR S33 OR S34 OR S35 OR S36 OR S37 OR S38 OR S39 OR S40 OR S41 OR S42 OR S43 OR S44 OR S45

52. S30 AND S46

LILACS

(db:("LILACS") AND (tw:(congenital heart disease) OR mh:("Heart Defects, Congenital")) AND type_of_study:("clinical_trials" OR "systematic_reviews")) AND (instance:"regional") AND (instance:"regional") AND (instance:"regional")

Web of Science Conference Proceedings Citation Index ‐ Science (CPCI‐S)

#1 TI=(heart* OR cardiac* OR cardiomyopath* OR coronary OR myocard* OR septal* OR aortic OR aorta OR aortopulmonary OR aorticopulmonary OR atrial OR ventricular OR intraventricular)

#2 TS=(surg* OR operat* OR preoperat* OR postoperat* OR perioperat* OR bypass* OR intensive care OR critical care OR ICU OR PICU)

#3 TS=(congenital* OR birth OR born OR neonat* OR newborn* OR infant* OR pediatric* OR paediatric* OR child* OR prematur*)

#4 TS=(blood OR erythrocyte* OR red cell* OR RBC* OR transfus* OR retransfus* OR cell salvage)

#5 TS=(systematic* OR random* OR blind* OR trial* OR controlled OR control group* OR groups)

#6 #1 AND #2 and #3 AND #4 AND #5

Transfusion Evidence Library

Clinical Specialty: Surgery / Cardiovascular Surgery

Subject Area: Blood Components / Red Cells

Patient Type: Neonates and Paediatrics

KOREAMED

(congenital [ALL]) AND (heart [ALL]) AND ("Randomized Controlled Trial" [PT])
(congenital [ALL]) AND (cardiac [ALL]) AND ("Randomized Controlled Trial" [PT])

(congenital [ALL]) AND (septal [ALL]) AND ("Randomized Controlled Trial" [PT])

(congenital [ALL]) AND (myocardial [ALL]) AND ("Randomized Controlled Trial" [PT])

PAKMEDINET

congenital AND heart AND (randomized OR randomised OR randomly)

congenital AND cardiac AND (randomized OR randomised OR randomly)

congenital AND septal AND (randomized OR randomised OR randomly)

congenital AND myocardial AND (randomized OR randomised OR randomly)

ClinicalTrials.gov

Search Terms: infant OR infants OR neonate OR neonates OR neonatal OR newborn OR newborns OR congenital

Condition: heart OR cardiac OR cardiomyopathy OR cardiothoracic OR coronary OR myocardial OR septal OR aortic OR atrial OR ventricular OR intraventricular OR aortopulmonary OR aorticopulmonary

Intervention: blood OR erythrocyte OR "red cell" OR "red blood cell" OR "red cells" OR "red blood cells" OR RBC OR PRBC OR transfusion OR retransfusion OR "cell salvage" OR "cell saver" OR autotransfusion OR auto‐transfusion OR bypass

WHO ICTRP

Title/Condition: infant OR infants OR birth OR neonate OR neonates OR neonatal OR newborn OR newborns OR premature OR prematurity OR congenital

Condition/Title: heart OR cardiac OR cardiomyopathy OR coronary OR myocardial OR septal OR aortic OR atrial OR ventricular OR intraventricular OR aortopulmonary OR aorticopulmonary OR congenital

Intervention: blood OR erythrocyte OR red cell OR red blood cells OR red blood cell OR red blood cells OR RBC OR PRBC OR cell salvage" OR cell saver OR transfusion OR retransfusion OR autotransfusion OR auto‐transfusion OR bypass

OR

(infant OR infants OR birth OR neonate OR neonates OR neonatal OR newborn OR newborns OR premature OR prematurity OR congenital) AND (cardiac OR cardiomyopathy OR coronary OR myocardial OR septal OR aortic OR atrial OR ventricular OR intraventricular OR aortopulmonary OR aorticopulmonary OR congenital) AND (blood OR erythrocyte OR red cell OR red cells OR red blood cell OR red blood cells OR RBC OR PRBC OR cell salvage OR cell saver OR transfusion OR retransfusion OR autotransfusion OR auto‐transfusion OR bypass)

Data and analyses

Comparison 1. Restrictive transfusion‐trigger versus liberal transfusion‐trigger.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 All‐cause mortality: short term (0 to 30 days post surgery)	3	347	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.42, 3.00]
1.2 All‐cause mortality: long term (31 days to two years post‐surgery)	1	60	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.87]
1.3 Severe adverse events: cardiac events	2	232	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.73, 1.37]
1.4 Severe adverse events: acute lung injury	2	232	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.74, 1.45]
1.5 Severe adverse events: stroke	1	161	Risk Ratio (M‐H, Random, 95% CI)	2.96 [0.12, 71.68]
1.6 Severe adverse events: thromboembolism	1	162	Risk Ratio (M‐H, Random, 95% CI)	1.71 [0.52, 5.61]
1.7 Severe adverse events: renal failure (needing renal replacement therapy)	2	287	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.90]
1.8 Severe adverse events: infection	2	232	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.47, 1.39]
1.9 Severe adverse events: haemorrhage (return to theatre for bleeding)	4	454	Risk Ratio (M‐H, Random, 95% CI)	2.33 [0.35, 15.57]
1.10 Haemoglobin (g/dL) levels postoperatively	4		Mean Difference (IV, Random, 95% CI)	Totals not selected
1.11 Number of participants receiving any red cell transfusion	2	185	Risk Ratio (M‐H, Random, 95% CI)	0.26 [0.12, 0.56]
1.12 Number of participants receiving any fresh frozen plasma	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.13 Number of participants receiving any platelet transfusion	1	125	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.35, 4.37]
1.14 Postoperative drain output mg/kg/hr	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
1.14.1 Postoperative day 0	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
1.14.2 Postoperative day 1	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
1.14.3 Postoperative day 2	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
1.15 Postoperative chest drain output mL per participant	1	107	Mean Difference (IV, Fixed, 95% CI)	9.00 [‐28.15, 46.15]
1.16 Duration of mechanical ventilation (hours)	2	168	Mean Difference (IV, Random, 95% CI)	‐1.65 [‐3.51, 0.20]
1.17 Duration of ICU stay (days)	3	228	Mean Difference (IV, Random, 95% CI)	0.15 [‐0.72, 1.01]
1.18 Cerebral oxygen content post surgery (rSO2)	1	60	Mean Difference (IV, Fixed, 95% CI)	1.00 [‐6.45, 8.45]
1.19 'Peak' lactate levels (mmol/L)	1	60	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.81, 0.61]

1.12. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 12: Number of participants receiving any fresh frozen plasma

1.15. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 15: Postoperative chest drain output mL per participant

1.17. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 17: Duration of ICU stay (days)

1.18. Analysis.

Comparison 1: Restrictive transfusion‐trigger versus liberal transfusion‐trigger, Outcome 18: Cerebral oxygen content post surgery (rSO₂)

Comparison 2. Washed red cells in CPB prime versus unwashed red cells in CPB prime.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 All‐cause mortality: short term (0 to 30 days post surgery)	2	144	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.03, 2.18]
2.2 All‐cause mortality: long term (31 days to 2 years post‐surgery)	1	128	Risk Ratio (M‐H, Random, 95% CI)	0.50 [0.05, 5.38]
2.3 Severe adverse events: cardiac events	1	128	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.47, 1.64]
2.4 Severe adverse event: thromboembolism	1	128	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.34, 2.27]
2.5 Severe adverse events: infection	1	128	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.50, 1.99]
2.6 Severe adverse events: haemorrhage (return to theatre for bleeding)	1	162	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 8.06]
2.7 Haematocrit (%) levels postoperatively	1	16	Mean Difference (IV, Fixed, 95% CI)	2.50 [‐1.44, 6.44]
2.8 Duration of intensive care unit stay (days)	1	128	Mean Difference (IV, Random, 95% CI)	‐0.30 [‐4.32, 3.72]
2.9 Postoperative chest drain output (number of days of mediastinal drainage)	1	128	Mean Difference (IV, Random, 95% CI)	0.14 [‐1.66, 1.94]
2.10 'Peak' lactate levels (mmol/L)	2	150	Mean Difference (IV, Random, 95% CI)	‐0.73 [‐2.46, 1.00]
2.11 Lactate levels prior to cardiopulmonary bypass in prime	1	22	Mean Difference (IV, Random, 95% CI)	‐2.00 [‐2.70, ‐1.30]
2.12 Lactate levels (mmol/L) in CPB circuit prime after line connection and 5 min recirculation	1	16	Mean Difference (IV, Random, 95% CI)	‐7.30 [‐11.70, ‐2.90]
2.13 Lactate levels (mmol/L) at up to 15 minutes after the start of cardiopulmonary bypass	1	16	Mean Difference (IV, Random, 95% CI)	‐2.00 [‐4.66, 0.66]
2.14 Lactate levels at 28 degrees during rewarming	1	22	Mean Difference (IV, Random, 95% CI)	‐1.40 [‐2.79, ‐0.01]
2.15 Lactate levels (mmol/L) immediately after cardiopulmonary bypass and clamp of arterial cannula	1	16	Mean Difference (IV, Random, 95% CI)	‐1.60 [‐2.65, ‐0.55]
2.16 Sodium (Na+) levels (mmol/L) prior to cardiopulmonary bypass in prime	1	22	Mean Difference (IV, Random, 95% CI)	4.00 [0.94, 7.06]
2.17 Sodium (Na+) levels (mmol/L) at 36 degrees after rewarming	1	22	Mean Difference (IV, Random, 95% CI)	3.10 [0.43, 5.77]
2.18 Sodium (Na+) levels (mmol/L) immediately after cardiopulmonary bypass and clamp of arterial cannula	1	22	Mean Difference (IV, Random, 95% CI)	3.50 [0.69, 6.31]
2.19 Potassium (K+) levels (mmol/L) prior to cardiopulmonary bypass in prime	2	38	Mean Difference (IV, Random, 95% CI)	‐6.21 [‐8.36, ‐4.06]
2.20 Potassium (K+) levels (mmol/L) at 28 degrees during rewarming	1	22	Mean Difference (IV, Random, 95% CI)	‐1.90 [‐2.71, ‐1.09]
2.21 Potassium (K+) levels (mmol/L) immediately after cardiopulmonary bypass and clamp of arterial cannula	1	22	Mean Difference (IV, Random, 95% CI)	‐1.00 [‐1.44, ‐0.56]
2.22 Blood glucose (mg/dL) in prime prior to CPB	2	36	Mean Difference (IV, Random, 95% CI)	‐212.14 [‐349.14, ‐75.14]
2.23 Blood glucose levels (mg/dL) at up to 15 minutes after the start of cardiopulmonary bypass	1	20	Mean Difference (IV, Random, 95% CI)	‐132.00 [‐147.64, ‐116.36]

Comparison 3. Crystalloid (bloodless) CPB prime versus red‐blood‐cell‐containing CPB prime.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Oxygen content post surgery CaO2 (ml dl‐1)	1	35	Mean Difference (IV, Random, 95% CI)	‐1.90 [‐2.11, ‐1.69]
3.2 Haematocrit (%) levels postoperatively	1	35	Mean Difference (IV, Fixed, 95% CI)	‐3.90 [‐4.36, ‐3.44]

Comparison 4. Ultrafiltration in CPB prime versus no ultrafiltration.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 All‐cause mortality: short term (0 to 30 days post‐surgery)	1	50	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
4.2 Duration of mechanical ventilation (hours)	1	50	Mean Difference (IV, Random, 95% CI)	‐16.00 [‐25.00, ‐7.00]
4.3 Duration of ICU stay (days)	1	50	Mean Difference (IV, Random, 95% CI)	‐0.60 [‐0.84, ‐0.36]

4.2. Analysis.

Comparison 4: Ultrafiltration in CPB prime versus no ultrafiltration, Outcome 2: Duration of mechanical ventilation (hours)

Comparison 5. Retrograde autologous CPB prime versus standard CPB prime.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Haematocrit (%) levels postoperatively	1	59	Mean Difference (IV, Random, 95% CI)	1.32 [0.84, 1.80]
5.2 Duration of mechanical ventilation (hours)	1	59	Mean Difference (IV, Random, 95% CI)	0.02 [‐0.03, 0.07]
5.3 Duration of intensive care unit stay	1	59	Mean Difference (IV, Random, 95% CI)	0.00 [‐0.01, 0.01]
5.4 Lactate levels (mmol/L at up to 15 minutes after the start of cardiopulmonary bypass	1	59	Mean Difference (IV, Random, 95% CI)	‐0.08 [‐0.40, 0.24]
5.5 Lactate levels (mmol/L) immediately after cardiopulmonary bypass and clamp of arterial cannula	1	59	Mean Difference (IV, Random, 95% CI)	‐0.24 [‐0.32, ‐0.16]

Comparison 6. Cell salvage of CPB prime blood versus allogeneic red cells post‐CPB.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 All‐cause mortality: short term (0 to 30 days post‐surgery)	1	309	Risk Ratio (M‐H, Random, 95% CI)	0.21 [0.02, 2.31]
6.2 Severe adverse events: acute lung injury	1	309	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.61, 1.27]
6.3 Severe adverse events: renal failure (creatinine increasing at least twofold within 72 hours of surgery)	1	309	Risk Ratio (M‐H, Random, 95% CI)	0.26 [0.09, 0.79]

Comparison 7. Leukoreduced red cell transfusion versus non‐leukoreduced red cell transfusion.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Duration of mechanical ventilation (hours)	1	46	Mean Difference (IV, Random, 95% CI)	‐7.20 [‐20.72, 6.32]
7.2 Duration of intensive care unit stay (days)	1	46	Mean Difference (IV, Random, 95% CI)	‐1.10 [‐7.72, 5.52]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Borisenko 2022.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: full Setting: Research Institute of Complex Problems of Cardiovascular Disease Number of centres: 1 Dates of trial (start and end): NR Follow‐up: 1 day post‐surgery, but results also given for duration of hospital stay Number randomised: 40 Number analysed (primary outcome): intervention group: 20, control group: 20
Participants	Inclusion criteria: children undergoing planned radical correction of interventricular or interatrial septal defect under CPB Age: median 14 months IQR 12 to 22.5 Sex: 40% male Exclusion criteria: NR Statistically significant baseline imbalances between the groups: no
Interventions	2 groups: ‐ CPB priming solution based on colloid/crystalloid solutions without red blood cell mass ‐ CPB priming solution based on colloid/crystalloid solutions with red blood cell mass Intervention arm: CPB priming solution based on colloid/crystalloid solutions without red blood cell mass Comparator arm: CPB priming solution based on colloid/crystalloid solutions with red blood cell mass Quantity of RBCs received: intervention: 0; control: 10ml/kg Timing of RBC transfusion: in CPB prime solution Any other comments about type of blood: removed WBC and platelets layer, storage time not exceeding 5 days Was there compliance with the intervention? Not stated Any deviations from treatment? Not stated Percentage reaching the stated intervention target: not stated Co‐interventions: nil
Outcomes	Trial primary outcome To determine the effect of not using donor blood components in the priming of the CPB circuit in children with septal congenital heart defects, operated under CPB, on the severity of SIR Trial secondary outcomes Laboratory parameters: haemoglobin g/l; haematocrit; O2 saturation in venous blood; blood lactate mmol/l; RBC count; WBC count; direct bilirubin; indirect bilirubin; creatinine, urea, postoperative NGAL Monitored parameters: drainage loss day 1; duration of ICU stay; duration of mechanical ventilation; inotropic drugs: number of participants on inotropic drugs Water balance: volume of fluid infusions during ICU stay; urine output in ICU Changes in SIR markers: interleukin 1 (IL‐1); interleukin 6 (IL‐6); interleukin 10 (IL‐10); tumour necrosis factor alpha (TNF‐α) Review outcomes All‐cause mortality up to 30 days: NR All‐cause mortality 31 days to 2 years: NR Serious adverse event: cardiac events: NR Serious adverse event: acute lung injury: NR Serious adverse event: stroke: NR Serious adverse event: thromboembolism: NR Serious adverse event: renal failure: NR (actual renal failure incidence not stated, only measured urea and electrolyte levels with no comment on renal failure events) Serious adverse event: infection: NR Serious adverse event: haemorrhage, defined as return to theatre for bleeding: NR (but drainage ouput measured) Haematocrit levels: reported as median IQR Haemoglobin levels: reported as median IQR RBC units used to discharge: NR Other blood products transfused to discharge: NR Postoperative chest drain output: reported as median IQR Duration of mechanical ventilation: reported as median IQR Duration of intensive care stay: reported as median IQR Rate of rehospitalisation: NR Oxygen content difference: NR Cerebral O2 status: reported as median IQR Blood lactate levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: reported as median IQR at 15 minutes at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: reported as median IQR "peak" lactate, as defined by the study: NR Blood sodium (Na+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR Blood potassium (K+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: NR up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: NR
Notes	Study objective: to determine the effect of not using donor blood components in the priming of the CPB circuit in children with septal congenital heart defects, operated under CPB, on the severity of SIR Funding: NR, but authors declare no conflict of interest. Sample size: study was underpowered. Unclear what effect was used to reduce the sample size from 196 to 40. "However, since the effect of limiting red blood cell transfusion in reducing the severity of SIR was significant, a smaller sample of patients participating in the study was sufficient to prove that this effect was not random." Compliance: NR Trial registration: we did not find a trial registration.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Sequence generation is described as "random", but no further details are given.
Allocation concealment (selection bias)	Unclear risk	Authors refer to the "envelope method," but the envelopes are not described as sealed, opaque and sequentially numbered.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding of personnel was not possible due to the nature of the intervention. No description of any blinding in relation to caregivers outside theatre.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No description of blinded outcome assessors
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear how many patients were originally approached to be included in the study
Selective reporting (reporting bias)	Unclear risk	There was no published trial protocol, so it was impossible to tell if all planned outcomes were reported.
Other bias	Low risk	No other concerns not addressed elsewhere in this assessment

Busch 2017.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: full Setting: Deutsches Herzzentrum Berlin, Germany Number of centres: 1 Dates of trial (start and end): September 2009 to May 2011 Follow‐up: 24 hours post‐transfusion Number randomised: 48 (number in each trial arm not reported) Number analysed (primary outcome): washed RBC group 22, unwashed RBC group 23
Participants	Inclusion criteria: children who have undergone cardiac surgery with CPB at the Deutsches Herzzentrum Berlin (DHZB, German Heart Institute Berlin) were consecutively enroled in the study from the period of September 2009 to May 2011. The participants ranged in age from one month to 15 years old. The period between transfusion and end of the operation was at least six hours to reduce the possible influence of CPB, interaction with anaesthetic and previous transfusions. Age: washed RBC group median 4.8 months (IQR 3.6 to 16.4), unwashed RBC group median 5.5 months (IQR 3.3 to 8.8) Sex: washed RBC group 45% male, unwashed RBC group 57% male Exclusion criteria: acute bleeding, immunosuppressive therapy, congenital immunodeficiency syndromes, simultaneous transfusion with fresh frozen plasma or platelets, extracorporeal membrane oxygenation, and lack of consent Statistically significant baseline imbalances between the groups: no
Interventions	2 groups: ‐ washed RBCs ‐ unwashed RBCs Intervention arm: washed RBCs. Packed RBCs were reduced of leukocytes and ABO identical. The washing procedure was performed with an Electra autotransfusion device (Sorin Group, Mirandola, Italy) using 0.9% sodium chloride wash solution. Comparator arm: unwashed RBCs. Packed RBCs were reduced of leukocytes and ABO identical. No washing procedure was performed. Quantity of RBCs received: median 100 ml Timing of RBC transfusion: within 4 hours Any other comments about type of blood: leukoreduced and ABO identical Was there compliance with the intervention? Yes Any deviations from treatment? No Percentage reaching the stated intervention target: 100% Co‐interventions: nil
Outcomes	Trial primary outcome Not stated Trial secondary outcomes Vital parameters (SBP, DBP, HR, temperature, O2 saturation) Haemoglobin Haematocrit Erythrocyte counts Coagulation parameters Creatinine Liver function Cytokine levels Review outcomes All‐cause mortality up to 30 days: NR All‐cause mortality 31 days to 2 years: NR Serious adverse event: cardiac events: NR Serious adverse event: acute lung injury: NR Serious adverse event: stroke: NR Serious adverse event: thromboembolism: NR Serious adverse event: renal failure: NR Serious adverse event: infection: NR Serious adverse event: haemorrhage, defined as return to theatre for bleeding: NR Haematocrit levels: reported only as a figure Haemoglobin levels: reported only as a figure RBC units used to discharge: NR Other blood products transfused to discharge: NR Postoperative chest drain output: NR Duration of mechanical ventilation: NR Duration of intensive care stay: NR Rate of rehospitalisation: NR Oxygen content difference: NR Cerebral O2 status: NR Blood lactate levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" lactate, as defined by the study: NR Blood sodium (Na+) levels: at baseline: reported at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR Blood potassium (K+) levels: at baseline: reported at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: reported as median IQR up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: NR
Notes	Study objective: the aim of this study was to evaluate the inflammatory response and clinical effect of RBC transfusion in children. Funding: supported by Deutsche Stiftung für Herzforschung, the Germany Kaltenbach‐Stipendium for Sonja Raschzok and the Gerd Kilian Preis (2012) of the Deutsche Stiftung für Herzforschung, Germany (Award Winner Dr. Oliver Miera). Dr Constanze Pfitzer is a participant in the BIH Charité Junior Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. The authors declare that they have no conflict of interest. Sample size: NR Compliance: yes Trial registration: we did not find a trial registration. Notes: 4 female and 6 male participants were included twice in the study (the period between the inclusion of the participants was at least seven days) and were analysed as two separate participants.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information was provided to enable an assessment of random sequence generation.
Allocation concealment (selection bias)	Unclear risk	No information was provided to enable an assessment of adequate allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not reported so insufficient information to make a definite judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported so insufficient information to make a definite judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Three participants were excluded from analyses: two children received more than one RBC transfusion within a 24‐hour period and one participant suffered a cardiac arrest and was resuscitated during the study period. Which group these three participants had been randomised to was not stated.
Selective reporting (reporting bias)	High risk	No published study protocol was identified. Coagulation parameters, creatinine and liver function test results were not reported.
Other bias	Low risk	None reported

Chkhaidze 2014.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: conference abstract Setting: Jo Ann Medical Center, Tbilisi, Georgia Number of centres: 1 Dates of trial (start and end): March 2013 to May 2013 Follow‐up: hospital discharge Number randomised: 43 (restrictive group 23, liberal group 20) Number analysed (primary outcome): restrictive group 23, liberal group 20
Participants	Inclusion criteria: patients with non‐cyanotic congenital heart defects, age from 1 to 7 years, underwent elective cardiac surgery, in stable postoperative condition, written informed consent, approval by the institutional Ethics Committee Age: range 1 to 7 years Sex: NR Exclusion criteria: NR Statistically significant baseline imbalances between the groups: no
Interventions	2 groups: ‐ restrictive transfusion strategy ‐ liberal transfusion strategy Intervention arm: restrictive RBC transfusion policy (Hb transfusion threshold < 8 g/kdL) Comparator arm: liberal RBC transfusion policy (Hb transfusion threshold < 10 g/kdL) Quantity of RBCs received: restrictive group: mean 164 SD 71 ml/kg; liberal group: mean 264 SD 59 ml/kg Timing of RBC transfusion: perioperative Any other comments about type of blood: none Was there compliance with the intervention? NR Any deviations from treatment? NR Percentage reaching the stated intervention target: NR Co‐interventions: nil
Outcomes	Trial primary outcome Not stated Trial secondary outcomes Volume of RBC transfused perioperatively In‐hospital length of stay LOS in the PICU Duration of mechanical ventilation In‐hospital morbidity Review outcomes All‐cause mortality up to 30 days: NR All‐cause mortality 31 days to 2 years: NR Serious adverse event: cardiac events: NR Serious adverse event: acute lung injury: NR Serious adverse event: stroke: NR Serious adverse event: thromboembolism: NR Serious adverse event: renal failure: NR Serious adverse event: infection: NR Serious adverse event: haemorrhage, defined as return to theatre for bleeding: NR Haematocrit levels: NR Haemoglobin levels: NR RBC units used to discharge: reported ‐ as volume of RBC transfused Other blood products transfused to discharge: NR Postoperative chest drain output: NR Duration of mechanical ventilation: reported Duration of intensive care stay: reported Rate of rehospitalisation: NR Oxygen content difference: NR Cerebral O2 status: NR Blood lactate levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" lactate, as defined by the study: NR Blood sodium (Na+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR Blood potassium (K+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: NR up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: NR
Notes	Study objective: to compare outcomes of two transfusion strategies in paediatric cardiac surgery patients: "restrictive" (RBC transfusion threshold haemoglobin level < 8 g/dL) and "liberal" (Hb < 10 g/dL) Funding: NR, no details of author conflicts were reported. Sample size: NR Trial registration: we did not find a trial registration. Compliance: NR Notes: this conference abstract was lacking in detail. No subsequent publications of this trial have been identified.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Patients were "randomly divided" into two groups. No information was provided to enable an assessment of random sequence generation.
Allocation concealment (selection bias)	Unclear risk	No information was provided to enable an assessment of adequate allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not reported so insufficient information to make a definite judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported so insufficient information to make a definite judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	No randomised participant withdrawals were reported.
Selective reporting (reporting bias)	High risk	No published study protocol was identified. This conference abstract provided limited information to assess whether measured outcomes were fully reported.
Other bias	Unclear risk	None reported. It would be difficult to rule out as very little methodological detail was provided in the trial report.

Cholette 2011.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: full Setting: URMC, Rochester, NY, USA Number of centres: 1 Dates of trial (start and end): August 2006 to September 2009 Follow‐up: until hospital discharge Number randomised: 62 (31 in each group) Number analysed (primary outcome): 30 in each group
Participants	Inclusion criteria: neonates and children presenting for elective partial or total cavopulmonary connection (bidirectional Glenn or Fontan procedures). The children had single ventricle physiology (including hypoplastic left heart syndrome, double inlet left ventricle, tricuspid atresia, pulmonary atresia, double outlet right ventricle, Ebstein's anomaly, unbalanced atrioventricular septal defect, hypoplastic right ventricle variant). Age: restrictive group mean 27 months (SD 23), liberal group mean 32.5 months (SD 27) Sex (M/F): 34/26 Exclusion criteria: those from whom consent could not be obtained Statistically significant baseline imbalances between the groups: no
Interventions	2 groups: ‐ restrictive ‐ liberal Intervention arm: restrictive transfusion strategy = 10 mL/kg of leukoreduced, irradiated red blood cells for any Hb < 9.0 g/dL accompanied by clinical findings suggestive of symptomatic anaemia for 48 hours postoperation Comparator arm: liberal transfusion strategy = 10 mL/kg of leukoreduced, irradiated red blood cells for Hb < 13.0 g/dL regardless of whether there was a clinical indication for transfusion for 48 hours postoperation Quantity of RBCs received: restrictive group: mean 0.43 (SD 0.6); liberal group: 2.1 (SD 1.2) Timing of RBC transfusion: first 48 hours postoperatively. Transfusions were given within 1 hour of reaching Hb threshold. Any other comments: blood was leukoreduced and irradiated. Was there compliance with the intervention? Yes Were there any deviations from treatment? No Percentage reaching the stated intervention target: 100% Co‐interventions: "Current PCICU standard of care aside from their transfusion strategy". Five participants received red cell transfusion after the 48‐hour study period and before hospital discharge.
Outcomes	Trial primary outcome Mean and peak arterial lactate level during initial 48 hours postoperation Other trial outcomes C(a‐v) O2, C(a‐c) O2 (ateriovenous and arteriocerebral oxygen) Clinical outcomes Length of mechanical ventilation Length and dose of vasoactive agent administration PCICU and hospital length of stay Mediastinal chest tube drainage Volume of crystalloid and albumin infused during the study period Outcome assessment points: on PCICU admission and every 4 hours for 48 hours Review outcomes All‐cause mortality up to 30 days: NR All‐cause mortality 31 days to 2 years: reported Serious adverse event: cardiac events: NR Serious adverse event: acute lung injury: NR Serious adverse event: stroke: reported Serious adverse event: thromboembolism: NR Serious adverse event: renal failure: NR Serious adverse event: infection: NR Serious adverse event: haemorrhage, defined as return to theatre for bleeding: reported Postoperative chest drain output: reported Haematocrit levels: NR Haemoglobin levels: reported RBC units used to discharge: reported as number of units transfused Other blood products transfused to discharge: reported as number of units transfused for FFP, platelets and cryoprecipitate Duration of mechanical ventilation: reported as median (range) Duration of intensive care stay: reported as median (range) Rate of rehospitalisation: NR Oxygen content difference: reported Cerebral O2 status: reported as figure, data not extractable Blood lactate levels: at baseline: reported at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" lactate, as defined by the study: reported Blood sodium (Na+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR Blood potassium (K+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR Immediately after CPB and clamp of arterial cannula: NR "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: NR up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: NR
Notes	Study objective: (1) to compare peak and mean arterial lactate in children post cavopulmonary connection randomised to a restrictive versus a liberal transfusion protocol, and (2) to compare surrogate markers of oxygen delivery, specifically the ateriovenous and arteriocerebral oxygen content differences and clinical outcomes between transfusion groups Funding: University of Rochester Strong Children's Research Centre Research Development Award 2006 to 2007 (JMC). The authors declare that they have no conflict of interest. Sample size: Cholette 2011 determined that 29 participants would be needed per group to have 80% power to reject the null hypothesis that the 2 treatment arms would be equivalent in terms of mean and peak lactate levels. The type 1 error rate was set at 0.05. 60 participants (30 in each group) were analysed, so the calculated requisite numbers were attained. However, the study was not powered to assess for clinical outcome differences, only lactate differences. Compliance: there was 100% compliance with the trial protocol and the protocol was not suspended during the trial period. Trial registration: this trial was prospectively registered. Notes: the study was only carried out for 48 hours postoperation in PCICU and then transfusion strategies were relaxed. The participants stayed in PICU for a mean of 6.6 (SD 6.4) days (restrictive) and 5.4 (SD 3.3) days (liberal), so they were in PICU for longer than the defined study duration. As stated above, a significant number of children in both groups were transfused after the 48‐hour period. Significantly, mean Hb in the groups was not markedly different, and it may be argued that a mean Hb of 11.1 g/dL is not truly restrictive.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Block randomisation (block size 8) was used to randomise into either transfusion strategy. Insufficient information about sequence generation process to permit a judgement of 'yes' or 'no'
Allocation concealment (selection bias)	Unclear risk	No information was provided to enable an assessment of adequate allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Clinical staff and participants' families were aware of transfusion group assignment.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported so insufficient information to permit judgement of 'yes' or 'no'
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data. 2 participants (3%) who were randomised were excluded, 1 from each group. Both could not have surgery: 1 could not be endotracheally intubated and 1 had bleeding complications before going onto CPB. The authors did not include these data in their outcome analyses. No other participant dropped out of the study or was lost to follow‐up.
Selective reporting (reporting bias)	Low risk	All outcomes defined in the prospectively registered protocol were reported in the results section.
Other bias	Low risk	None reported

Cholette 2012.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: full Setting: URMC, Rochester, NY, USA Number of centres: 1 Dates of trial (start and end): October 2008 to September 2010 Follow‐up: not clearly stated, but duration of hospital stay was up to 78 days Number randomised: 162 (81 in each group) Number analysed (primary outcome): 64 in each group Only those randomised participants who received a transfusion on study entrance were included in the analysis of outcomes. No participants were lost to follow‐up.
Participants	Inclusion criteria: children up to 18 years presenting to the URMC for cardiac surgical repair/palliation with CPB The surgical procedures undergone by the study participants included stage 1 palliation; arterial switch operation; bidirectional Glenn; tetralogy of Fallot repair; atrial, ventricular or atrioventricular septal defect repair; aortic arch reconstruction and Fontan. Age: washed group: median 6 months (IQR 3 days to 17 years); unwashed group: median 7 months (IQR range 2 days to 17 years) Sex (M/F): washed group: 63/18; unwashed group: 64/17 Exclusion criteria: patent ductus arteriosus repair, if parent/guardian did not speak English, if consent could not be obtained or if patient was participating in another clinical trial Statistically significant baseline imbalances between the groups? No
Interventions	2 groups: ‐ washed ‐ unwashed Intervention arm: all red cell and platelets transfusions were washed after storage for the duration of the hospital stay. The protocol could be temporarily suspended at the discretion of the attending physician if the time taken to wash blood products (2 hours for platelets, 30 minutes for red blood cells) interfered with patient care. The protocol was resumed promptly once the participant's condition no longer fulfilled the suspension criteria. Comparator arm: all red cell and platelet transfusions were prepared according to standard protocol at the URMC for the duration of the hospital admission. The study transfusion strategy was initiated for the operating room and maintained until hospital discharge. All blood products were leukoreduced before storage, irradiated and ABO‐blood‐group identical, without restrictions on storage age. Quantity of RBCs received: washed group: 2.48 ± 3.5 transfusions (n = 64); unwashed group: 3.22 ± 6.5 transfusions (n = 64) Timing of RBC transfusion: during CPB and postoperatively Was there compliance with the intervention? Yes Were there any deviations from treatment? Yes: washed group n = 1; unwashed group n = 2 Percentage reaching the stated intervention target: washed group 99%; unwashed group: 98% Co‐interventions: nil
Outcomes	Trial primary outcome 12 hours post CPB IL‐6:IL‐10 ratio Other trial outcomes Mortality up to 30 days Severe adverse events: cardiac, thromboembolism, infection, haemorrhage Red blood cell units and other blood products transfused to discharge Duration of mechanical ventilation Duration of ICU stay In addition, the following outcomes were reported by the trial (but not included in this review): inotropic/vasopressor hours, central venous line duration, mediastinal tube days, antibiotics, PCICU admission lactate, peak lactate, volume, highest white blood count postoperatively on days 0 to 2, PCICU complication and ECMO duration. Review outcomes All‐cause mortality up to 30 days: reported All‐cause mortality 31 days to 2 years: NR Serious adverse event: cardiac events: reported Serious adverse event: acute lung injury: NR Serious adverse event: stroke: NR Serious adverse event: thromboembolism: reported Serious adverse event: renal failure: NR Serious adverse event: infection: reported Serious adverse event: haemorrhage, defined as return to theatre for bleeding: reported Haematocrit levels: NR Haemoglobin levels: NR RBC units used to discharge: reported Other blood products transfused to discharge: reported as volume transfused for FFP, platelets and cryoprecipitate Postoperative chest drain output: reported Duration of mechanical ventilation: NR Duration of intensive care stay: reported Rate of rehospitalisation: NR Oxygen content difference: NR Cerebral O2 status: NR Blood lactate levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" lactate, as defined by the study: reported Blood sodium (Na+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR Blood potassium (K+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: NR up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: NR
Notes	Study objective: to investigate the hypothesis that washing red blood cells (RBC) and platelets transfused to these participants will reduce postoperative transfusion‐related immune modulation and inflammation. Funding: Strong Children's Research development award from URMC ‐ Department of Pediatrics, National Institute of Environmental Health Sciences/National Institute of Health (ESO1247) and the National Heart Lung and Blood Institute/National Institute of Health (HL100051, HL095467). Dr Blumberg has served as a consultant to and research grant recipient from manufacturers of leukoreduction filters (Pall Biomedical, Fenwall) and cell washing devices (Caridian). Caridian provided a small proportion of the cell washing sets for people in the washed arm of the study. No other author has any financial or personal relationship with other people or organisations that could inappropriately influence his/her work. Sample size: Cholette 2012 calculated that a sample of 64 participants per group would provide 80% power to detect a relatively small group difference of 2 units (one half of SD) of the mean IL‐6:IL‐10 ratio. 64 participants were included in each group, making the study adequately powered for differences in IL‐6:IL‐10 ratios. However, these study numbers were not large enough to power the study to test for clinical outcomes. Compliance: yes, but there were 2 protocol violations: 1 in the washed group (a neonate who received 1 unwashed platelet transfusion) and 2 in the unwashed group (both participants required ECMO and all products for ECMO were washed to prevent hyperkalaemia) Trial registration: this trial was prospectively registered.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote (p. 291): "...block randomisation was used to randomise to the unwashed or washed transfusion strategy". Insufficient information about sequence generation process to permit a judgement of 'yes' or 'no'
Allocation concealment (selection bias)	Unclear risk	No information was provided to enable an assessment of adequate allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Email communication with the main author identified that no one involved in patient care could be blinded to treatment allocation due to packaging differences of the blood products that were not allowed to be concealed under FDA, New York state and hospital regulations. The blood bank sent blood appropriate to the allocation (washed or unwashed). When blood was not hanging, the treatment allocation was not obvious and the clinician would not have been aware of trial assignment.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Email communication with the main author identified that outcome assessment was determined from inpatient notes from the PCICU attending physician and cardiothoracic surgery nurse practitioner, both of whom were not blinded to treatment allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The trial authors report that there were no missing outcome data: no participants were lost to follow‐up and data were analysed by both ITT and per‐protocol principles. 34 randomised participants (17 from each treatment group) did not receive a transfusion and were thus excluded from the per‐protocol analysis. 6 participants were excluded following randomisation: 3 because shunts were performed off bypass, 2 because surgical palliation was not offered and 1 patient as surgery was not performed. These participants did not receive a transfusion and were excluded from all outcome analyses.
Selective reporting (reporting bias)	Low risk	The trial protocol is available. All outcomes prespecified (IL‐6:IL‐10 ratio and wide‐range C‐reactive protein levels) in the protocol have been reported in the trial as prespecified.
Other bias	Low risk	None reported

Cholette 2017.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: full Setting: URMC, Rochester, NY, USA Number of centres: 1 Dates of trial (start and end): March 2012 to July 2014 Follow‐up: hospital discharge Number randomised: 162 (restrictive group 82, liberal group 80) Number analysed (primary outcome): restrictive group 82, liberal group 80
Participants	Inclusion criteria: children ≤ 6 months of age with congenital cardiac disease undergoing cardiac surgery with CPB Age: restrictive group median 84 (range 2 to 914) days; liberal group median 43 (range 1 to 730) days Sex: restrictive group 49% male; liberal group 56% male Exclusion criteria: presence of a known bleeding disorder or coagulopathy; age > 6 months or lack of informed consent Statistically significant baseline imbalances between the groups: no
Interventions	2 groups: ‐ restrictive ‐ liberal Intervention arm: restrictive RBC transfusion strategy: RBC transfusion for Hb < 7.0 g/dL for biventricular repairs or < 9.0 g/dL for palliative procedures plus a clinical indication Comparator arm: liberal RBC transfusion strategy: RBC transfusion for Hb < 9.5 g/dL for biventricular repairs or < 12.0 g/dL for palliative procedures regardless of clinical indications Quantity of RBCs received: 10 ml/kg Timing of RBC transfusion: from admission to PCICU and maintained until 1) transfer from PCICU, 2) postoperative day 28, 3) decision to cannulate for ECMO or 4) death. Transfusion initiated within 60 minutes for breaching Hb threshold. Any other comments: pre‐stored, leukoreduced, irradiated, ABO identical and Rh matched, stored for less than 14 days Was there compliance with the intervention? Restrictive group: 93% compliance. Reasons for non‐compliance were chest closure (n = 1) or perceived clinical indication (n = 5). Liberal group: 100% compliance Were there any deviations from treatment? None apart from transfusion non‐compliance as above Percentage reaching the stated intervention target: restrictive group: 93%; liberal group: 100% Co‐interventions: nil
Outcomes	Trial primary outcome Oxygen utilisation derived from the arterio‐venous oxygen difference (arterial and venous oxygen saturations measured every 4 hours for 48‐72 hours and used to calculate arterio‐venous oxygen content differences Trial secondary outcomes Total number of RBC transfusions given during the immediate postoperative period (first 7 days) Review outcomes All‐cause mortality up to 30 days: reported All‐cause mortality 31 days to 2 years: NR Serious adverse event: cardiac events: NR Serious adverse event: acute lung injury: NR Serious adverse event: stroke: NR Serious adverse event: thromboembolism: reported Serious adverse event: renal failure: reported Serious adverse event: infection: NR Serious adverse event: haemorrhage, defined as return to theatre for bleeding: reported Haematocrit levels: NR Haemoglobin levels: reported RBC units used to discharge: reported as median IQR Other blood products transfused to discharge: NR Postoperative chest drain output: reported Duration of mechanical ventilation: reported as median (range) Duration of intensive care stay: reported Rate of rehospitalisation: NR Oxygen content difference: reported in graph form, data not extractable Cerebral O2 status: NR Blood lactate levels: at baseline: reported at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" lactate, as defined by the study: reported only as figure, data not extractable Blood sodium (Na+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR Blood potassium (K+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: NR up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: NR
Notes	Study objective: to assess safety, frequency of RBC transfusion, daily Hb concentration and oxygen utilisation of infants randomly assigned to either a conservative or liberal RBC transfusion strategy Funding: this work was funded in part by the National Institute of Environmental Health Sciences (grant ES01247) and National Heart Lung and Blood Institute (grants HL100051, HL095467). The authors declare that they have no conflict of interest. Sample size: given the hypothesis that infants managed with a conservative transfusion strategy would receive fewer red blood cell transfusions than those treated with a liberal strategy, a 30% reduction in number of RBC transfusions was determined to be clinically relevant. Based on preliminary data from 75 liberally‐treated participants, there were 170 transfusions made, resulting in 1.3 transfusions per participant on average. A sample size of 160 participants has 80% power to detect a 31% reduction in number of RBC transfusions, with a significance level (alpha) of 0.05 (two‐tailed) using a Poisson regression with a binary independent variable indicating treatment groups (in 1:1 ratio). Compliance: in the restrictive group, transfusion compliance occurred within 93% of participants (100% compliance after biventricular repair, 79.3% compliance after palliative procedures). 100% compliance was observed in the liberal group. Trial registration: this trial was prospectively registered.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote (p. 207): "Block randomization (block size 8) divided patients to either a conservative or liberal transfusion strategy (stratified randomization). Patients were further divided into two strata based on the type of operation as follows: biventricular repair or palliative (nonseptated) procedure." Insufficient information about sequence generation process to permit judgement of 'yes' or 'no'
Allocation concealment (selection bias)	Unclear risk	No information was provided to enable an assessment of adequate allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The cardiac surgeon, anaesthesiologist and perfusionist were blinded to study assignment. Blinding of participants was not reported, but participants were aged < 6 months.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported so insufficient information to permit judgement of 'yes' or 'no'
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomised participants were included in the analyses under the ITT principle.
Selective reporting (reporting bias)	Low risk	All outcomes defined in the prospectively registered protocol were reported in the results section.
Other bias	Low risk	None reported

De Gast‐Bakker 2013.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: full Setting: Leiden University Medical Centre, Leiden, The Netherlands Number of centres: 1 Dates of trial (start and end): April 2009 to January 2012 Follow‐up: hospital discharge Number randomised: 107 (restrictive group 53, liberal group 54) Number analysed (primary outcome): restrictive group 53, liberal group 54 (ITT)
Participants	Inclusion criteria: elective surgery for a congenital heart defect; between 6 weeks and 6 years of age and peripheral oxygen saturation above 95% on admission; written informed consent Age: restrictive group median 9.5 (IQR 3.6 to 30.4) months, liberal group median 7.3 (IQR 3.0 to 29.7) months Sex: restrictive group 64.2% male; liberal group 42.6% male All participants had non‐cyanotic congenital heart defects. Exclusion criteria: NR Statistically significant baseline imbalances between the groups: no
Interventions	2 groups: ‐ restrictive ‐ liberal Intervention arm: restrictive transfusion strategy: RBC transfusion given if Hb < 8.0 g/dL Comparator arm: liberal transfusion strategy: RBC transfusion given if Hb < 10.8 g/dL Quantity of RBCs received: restrictive group: in surgery: mean 148 (53) ml, in PICU: mean 90 (SD 50) ml, total: 186 (70) ml; liberal group: in surgery: mean 158 (SD 54) ml, in PICU: mean 120 (72) ml, total: 259 (90) ml* (*results do not tally with text: 258 (87) ml) Timing of RBC transfusion: start/during/after CPB, in PICU. Numbers for each not reported Any other comments: leukocyte depleted blood Was there compliance with the intervention? No (see Notes section below) Were there any deviations from treatment? Yes (see Notes section below) Percentage reaching the stated intervention target: restrictive group: 94%; liberal group: 93% Co‐interventions: nil
Outcomes	Trial primary outcome In‐hospital length of stay (days) Trial secondary outcomes PICU length of stay (days) Duration of mechanical ventilatory support (time between induction of anaesthesia and extubation at the PICU in hours) Incidence of all reported (serious) adverse events, complications and transfusion costs Other trial outcomes Respiratory infections (fever, leucocytosis, signs on chest X‐ray and a positive sputum culture) were noted as a complication. Review outcomes All‐cause mortality up to 30 days: NR All‐cause mortality 31 days to 2 years: NR Serious adverse event: cardiac events: reported Serious adverse event: acute lung injury: reported Serious adverse event: stroke: NR Serious adverse event: thromboembolism: NR Serious adverse event: renal failure: NR Serious adverse event: infection: reported ‐ respiratory infections Serious adverse event: haemorrhage, defined as return to theatre for bleeding: reported Haematocrit levels: NR Haemoglobin levels: reported RBC units used to discharge: reported Other blood products transfused to discharge: reported as volume transfused and number of units transfused for FFP Postoperative chest drain output: reported Duration of mechanical ventilation: reported as median IQR Duration of intensive care stay: reported as median IQR Rate of rehospitalisation: NR Oxygen content difference: NR Cerebral O2 status: NR, only pre‐surgery values reported Blood lactate levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" lactate, as defined by the study: NR Blood sodium (Na+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR Blood potassium (K+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: NR up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: NR
Notes	Study objective: to investigate the safety and effects of a restrictive red blood cell transfusion strategy in paediatric cardiac surgery patients Funding: NR. The authors declare that they have no conflict of interest. Sample size: assuming a significant difference in hospital LOS from 20.1 (± 21.8) (group A) to 10.1 (± 10.9) (group B), it was estimated that 48 participants would be needed per group for a power of 0.8 and an alpha of 0.05. Compliance: no, as there were protocol violations. In the restrictive group, RBC transfusion was given in 3 participants in contradiction with the randomisation protocol. In the liberal group, RBC transfusion was withheld in 3 participants and RBC transfusion was given in 1 participant in contradiction with the randomisation protocol. Analysis was performed using the ITT principle. Trial registration: trial registration was available, but we were unable to tell if it was prospective or retrospective.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information was provided to enable an assessment of random sequence generation.
Allocation concealment (selection bias)	Low risk	Sealed randomisation envelopes were used.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not reported so insufficient information to make a definite judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported so insufficient information to make a definite judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	The study was discontinued in 7 participants. In the restrictive group, RBC transfusion was given in 3 participants in contradiction with the randomisation protocol. In the liberal group, RBC transfusion was withheld in 3 participants and RBC transfusion given in 1 participant in contradiction with the randomisation protocol. All 7 participants were included in the analyses using the ITT principle.
Selective reporting (reporting bias)	Unclear risk	All outcomes described in the methods were reported in the results.
Other bias	Low risk	None reported

De Vries 2004.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: full Setting: University Hospital Groningen, the Netherlands Number of centres: 1 Dates of trial (start and end): not stated Follow‐up: until hospital discharge Number randomised: 50 (25 in each group) Number analysed (primary outcome): 25 in each group
Participants	Inclusion criteria: children who were undergoing congenital open‐heart surgery. Procedures selected were correction of tetralogy of Fallot, simple closure of ventricular septal defect, correction of atrioventricular septal defect, arterial switch operation of transposition of the great arteries and completion of the Fontan procedure. Age: filtration group: median 13 months (IQR 2 to 31.5), control group: median 6 months (IQR 1 to 28.5) Sex: NR Exclusion criteria: NR Statistically significant baseline imbalances between the groups: no
Interventions	2 groups: ‐ filtration ‐ control After CPB and disconnection of the system, the residual blood in the heart‐lung machine was collected in a transfusion bag and re‐transfused in the child during wound closure and the first 2 hours in the ICU. Intervention arm: filtration group: the re‐transfused blood was filtered with one leukoreduction filter (Pall RS 1, Pall, Portsmouth, UK) for each participant. Comparator arm: control group: no filtration of re‐transfused blood Quantity of RBCs received: NR Timing of RBC transfusion: NR Any other comments: packed cells added to priming solution if calculated Hb on bypass was less than 4.5 mmol/l. May not all have had packed cells added to bypass priming solution Was there compliance with the intervention? NR, but results suggest yes Were there any deviations from treatment? NR Percentage reaching the stated intervention target: 100% Co‐interventions: NR
Outcomes	Trial primary outcome PaO2 on the first postoperative day Trial other outcomes Leukocyte counts after induction of anaesthesia and on the first 4 postoperative days Platelet counts and PaO2 after induction of anaesthesia and after arrival on the ICU (in addition to primary outcome) In 10 children, additional blood samples were taken from the residual heart‐lung machine blood. In these samples, leukocyte and platelet counts and levels of Hb and elastase as a measure of leukocyte activation, were determined. Review outcomes All‐cause mortality up to 30 days: NR All‐cause mortality 31 days to 2 years: NR Serious adverse event: cardiac events: NR Serious adverse event: acute lung injury: NR Serious adverse event: stroke: NR Serious adverse event: thromboembolism: NR Serious adverse event: renal failure: NR Serious adverse event: infection: NR Serious adverse event: haemorrhage, defined as return to theatre for bleeding: NR Haematocrit levels: NR Haemoglobin levels: NR RBC units used to discharge: NR Other blood products transfused to discharge: NR Postoperative chest drain output: reported Duration of mechanical ventilation: reported as median (IQR) Duration of intensive care stay: reported as median (IQR) Rate of rehospitalisation: NR Oxygen content difference: NR Cerebral O2 status: NR Blood lactate levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" lactate, as defined by the study: NR Blood sodium (Na+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR Blood potassium (K+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: NR up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: NR
Notes	Study objective: the study was designed to examine the effect of leukoreduction of residual heart‐lung machine blood on postoperative oxygenation and circulating leukocyte counts in children undergoing congenital heart surgery. Funding: not stated. No details of author conflicts were reported. Sample size: NR Compliance: yes Trial registration: we did not find a trial registration.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated list
Allocation concealment (selection bias)	High risk	Unsealed envelopes (information direct from trialist by email)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not reported so insufficient information to permit a judgement of 'yes' or 'no'
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported so insufficient information to permit a judgement of 'yes' or 'no'
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing data identified
Selective reporting (reporting bias)	Unclear risk	All outcomes described in the methods were reported in the results. However, no prospectively registered study protocol was identified, and we cannot exclude the possibility of selective reporting.
Other bias	Low risk	None reported

Fu 2016.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: full Setting:The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China Number of centres: 1 Dates of trial (start and end): September 2013 to June 2014 Follow‐up: hospital discharge Number randomised: 60 (RAP group 27, non‐RAP group 33) Number analysed (primary outcome): RAP group 26, non‐RAP group 33
Participants	Inclusion criteria: body weight of 15 to 20kg, preoperative Hb higher than or equal to 100g/L, elective for CPB intracardiac correction Age: RAP group 49.92 (SD 20.07) months; non‐RAP group 50.09 (SD 19.50) months Sex: RAP group 57.7% male; non‐RAP group 54.5% male Exclusion criteria: CPB longer than 120 minutes and exhibited difficulties in removing treatment instruments Statistically significant baseline imbalances between the groups: no
Interventions	2 groups: ‐ retrograde autologous priming (RAP) ‐ conventional CPB Intervention arm: retrograde autologous priming (RAP) Comparator arm: conventional CPB Quantity of RBCs received: RAP group: NR (2 participants required intraoperative blood transfusion); CPB group: NR (26 participants required intraoperative blood transfusion) Timing of RBC transfusion: intraoperative Any other comments: none Was there compliance with the intervention? RAP group: no; CPB group: yes Were there any deviations from treatment? RAP group: yes, 1 participant excluded from study because operation time was longer than 120 minutes; CPB group: no Percentage reaching the stated intervention target: RAP group: 96%; CPB group 100% Co‐interventions: ultrafiltration
Outcomes	Trial primary outcome Not reported Trial secondary outcomes CPB time, aortic blocking time and intraoperative blood transfusion Haematocrit and lactate values at 15 minutes after the beginning and at the end of CPB Post‐surgery mechanical ventilation time ICU time Hospitalisation duration and postoperative blood transfusion Haematocrit value 2 hours after surgery Statistically significant baseline imbalances between the groups: no Review outcomes: NR All‐cause mortality up to 30 days: NR All‐cause mortality 31 days to 2 years: NR Serious adverse event: cardiac events: NR Serious adverse event: acute lung injury: NR Serious adverse event: stroke: NR Serious adverse event: thromboembolism: NR Serious adverse event: renal failure: NR Serious adverse event: infection: NR Serious adverse event: haemorrhage, defined as return to theatre for bleeding: NR Haematocrit levels: reported Haemoglobin levels: NR RBC units used to discharge: NR Other blood products transfused to discharge: NR Postoperative chest drain output: NR Duration of mechanical ventilation: reported Duration of intensive care stay: reported Rate of rehospitalisation: NR Oxygen content difference: NR Cerebral O2 status: NR Blood lactate levels: at baseline: reported at CPB circuit prime: NR at up to 15 minutes after start of CPB: reported at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: reported "peak" lactate, as defined by the study: NR Blood sodium (Na+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR Blood potassium (K+) levels: at baseline: reported at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: NR up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: NR
Notes	Study objective: this study explored the clinical application of RAP in CPB in paediatric patients undergoing cardiac surgery. Funding: NR. No details of author conflicts were reported. Sample size: 40 excluded (32 did not meet inclusion criteria, 6 declined to participate, 2 for "other reasons") Compliance: yes (1 participant excluded from study because operation time was longer than 120 minutes.) Trial registration: we did not find a trial registration.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random number table
Allocation concealment (selection bias)	Unclear risk	No information was provided to enable an assessment of adequate allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	The trial was described as single‐blinded, but no further details of blinding were given. Participants were young paediatric patients.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported so insufficient information to permit a judgement of 'yes' or 'no'
Incomplete outcome data (attrition bias) All outcomes	Low risk	1 participant in RAP group was excluded from analyses; this participant did not receive the allocated intervention as the operation time was longer than 120 minutes and was excluded from analyses.
Selective reporting (reporting bias)	Unclear risk	All outcomes described in the methods were reported in the results. However, no prospectively registered study protocol was identified, and we cannot exclude the possibility of selective reporting.
Other bias	Low risk	None reported

Gholampour Dehaki 2019.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: full Setting: Rajaie Cardiovascular, Medical and Research Centre ‐ Perfusion, Tehran Province, Tehran, Iran Number of centres: 1 Dates of trial (start and end): not reported Follow‐up: 24 hours postoperative Number randomised: 60 (30 in each group) Number analysed (primary outcome): 30 in each group
Participants	Inclusion criteria: to assess the effects of zero‐balance ultrafiltration priming method on the procalcitonin concentration and the postoperative pulmonary function amongst infants following CPB Age: Z‐BUF group mean 9 (SD 5.7) months; non Z‐BUF group mean 5.1 (SD 6) months Sex: Z‐BUF group 50% male; non Z‐BUF group 66.6% male Exclusion criteria: older than 18 months at the time of surgery and had preoperative mechanical ventilation Statistically significant baseline imbalances between the groups: no
Interventions	2 groups: ‐ zero‐balance ultrafiltration (Z‐BUF) ‐ no Z‐BUF Intervention arm: Z‐BUF: CPB with zero‐balance ultrafiltration of priming blood Comparator arm: non‐Z‐BUF: CPB without Z‐BUF Quantity of RBCs received: not stated but PRBC added to reach a haematocrit 25% to 28% Timing of RBC transfusion: in CPB prime Any other comments: none Was there compliance with the intervention? Yes Were there any deviations from treatment? No Percentage reaching the stated intervention target: 100% Co‐interventions: 20 mg heparin. The volume of replacement fluid (Ringer's and NaCl 0.45%) used was 40 mL per 10 mL of PRBCs. An additional 1000 U of heparin was given after the Z‐BUF of priming blood, and a NaHCO3 7.5% solution was injected as needed according to the blood gas analysis of the priming solution.
Outcomes	Trial primary outcome NR Other trial outcomes Mean procalcitonin level (ng/ml) Respiratory index and pulmonary compliance Time to extubation duration of ICU stay Postoperative mechanical ventilation time Review outcomes All‐cause mortality up to 30 days: NR All‐cause mortality 31 days to 2 years: NR Serious adverse event: cardiac events: NR Serious adverse event: acute lung injury: NR Serious adverse event: stroke: NR Serious adverse event: thromboembolism: NR Serious adverse event: renal failure: NR Serious adverse event: infection: NR Serious adverse event: haemorrhage, defined as return to theatre for bleeding: NR Haematocrit levels: NR Haemoglobin levels: NR RBC units used to discharge: NR Other blood products transfused to discharge: NR Postoperative chest drain output: NR Duration of mechanical ventilation: reported as median (IQR) Duration of intensive care stay: NR Rate of rehospitalisation: NR Oxygen content difference: NR Cerebral O2 status: NR Blood lactate levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" lactate, as defined by the study: NR Blood sodium (Na+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR Blood potassium (K+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: NR up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: NR
Notes	Study objective: to assess the effects of zero‐balance ultrafiltration priming method on the procalcitonin concentration and the postoperative pulmonary function amongst infants following CPB Funding: NR. The authors declare that they have no conflict of interest. Sample size: NR Compliance: yes Trial registration: trial registration was available (retrospective).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported so insufficient information to permit a judgement of 'yes' or 'no'
Allocation concealment (selection bias)	Unclear risk	Not reported so insufficient information to permit a judgement of 'yes' or 'no'
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not reported so insufficient information to permit a judgement of 'yes' or 'no'
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported so insufficient information to permit a judgement of 'yes' or 'no'
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomised participants were included in the analysis of outcome data and no participants were lost during follow‐up.
Selective reporting (reporting bias)	Unclear risk	The trial did not define the outcomes they were interested in; therefore, there is insufficient information to identify whether there was reporting bias in these trials. The trial was registered but only retrospectively.
Other bias	Low risk	None reported

Han 2004.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: full Setting: Seoul National University, Seoul, Korea Number of centres: 1 Dates of trial (start and end): not reported Follow‐up: during operative period Number randomised: 36 (18 in each group) Number analysed (primary outcome): 17 in blood‐containing prime group, 18 in crystalloid group
Participants	Inclusion criteria: children weighing 8 to 12 kg who were scheduled for elective surgical repair of ventricular or atrial septal defect Age: intervention group: median 19.5 months (IQR 10 to 29); control group: median 22 months (IQR 9 to 35) Sex (M/F): 20/15 Exclusion criteria: children with a preoperative haematocrit < 35%, children who needed preoperative inotropic support or children with a known neurological problem Statistically significant baseline imbalances between the groups: no
Interventions	2 groups: ‐ blood‐containing prime group ‐ crystalloid. The priming volume was 600 mL for both groups Intervention arm: pump prime consisted of Normosol Comparator arm: PRBCs were added to the prime to achieve a haematocrit of 20% on initiation of CPB Both groups had perfusion maintained at 150 mL/kg/minute with moderate hypothermia and alpha stat management. Conventional and modified ultrafiltrations were performed. Intraoperative cell salvage was performed in the control group and salvaged red cells were re‐infused after surgery. During CPB, transfusion was initiated if rSO2 decreased below 20% of pre‐bypass value. After finishing modified ultrafiltration, transfusion was performed if haematocrit was < 28%. Quantity of RBCs received: blood‐containing prime group: NR, but enough to achieve a haematocrit of 20% on initiation of CPB; crystalloid group: NR Timing of RBC transfusion: during CPB (blood‐containing prime group only) Any other comments: packed red cells Was there compliance with the intervention? Yes Were there any deviations from treatment? Yes. In crystalloid prime group, after initiation of CPB, regional cerebral oxygen saturation decreased to 53% of that before CPB with a haematocrit of 13%. RBCs were given and regional cerebral oxygen saturation improved within seconds, but the participant was excluded from the study. Percentage reaching the stated intervention target: blood‐containing prime group 100%; crystalloid group: 94% Co‐interventions: blood‐containing prime group: NR; crystalloid group: intraoperative cell salvage was performed and salvaged red cells were re‐infused after surgery.
Outcomes	Trial primary outcome rSO2 (assumed to be primary outcome but not specifically stated) Other trial outcomes Mean arterial pressure Nasopharyngeal temperature Haematocrit Arterial blood gas measurement Arterial oxygen content Review outcomes All‐cause mortality up to 30 days: NR All‐cause mortality 31 days to 2 years: NR Serious adverse event: cardiac events: NR Serious adverse event: acute lung injury: NR Serious adverse event: stroke: NR Serious adverse event: thromboembolism: NR Serious adverse event: renal failure: NR Serious adverse event: infection: NR Serious adverse event: haemorrhage, defined as return to theatre for bleeding: NR Haematocrit levels: reported Haemoglobin levels: NR RBC units used to discharge: NR Other blood products transfused to discharge: NR Postoperative chest drain output: NR Duration of mechanical ventilation: NR Duration of intensive care stay: NR Rate of rehospitalisation: NR Oxygen content difference: reported Cerebral O2 status: reported in a figure, but data not extractable Blood lactate levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" lactate, as defined by the study: NR Blood sodium (Na+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR Blood potassium (K+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: NR up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: NR
Notes	Study objective: to compare the effect of bloodless CPB prime with that of red‐blood‐cell‐containing prime on rSO2 value, as measured by near infrared spectroscopy Funding: NR. No details of author conflicts were reported. Sample size: NR Compliance: yes Trial registration: we did not find a trial registration. Notes: 1 participant in the crystalloid group was excluded from analysis as, after initiation of CPB, rSO2 decreased to 53% of that before bypass, with a haematocrit of 13%. RBCs were transfused and rSO2 improved within seconds.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated table
Allocation concealment (selection bias)	Unclear risk	No information was provided to enable an assessment of adequate allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not reported, but participants were asleep so unlikely to know but anaesthetist, surgeon and perfusionist likely to know. Insufficient information provided to make a definite judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported so insufficient information provided to make a definite judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	One participant (3% of trial participants) in the intervention group was excluded for clinical reasons. After initiation of CPB, the rSO2 saturations level dropped to an unacceptable level and red cell transfusion was required. rSO2 saturations improved within seconds. The authors did not include this participant's data in their outcome analyses. No other participants were excluded or withdrew from the trial.
Selective reporting (reporting bias)	Unclear risk	The trial did not define the outcomes they were interested in; therefore, there is insufficient information to identify whether there was reporting bias in the trial.
Other bias	Unclear risk	None reported. It would be difficult to rule out as very little methodological detail was provided in the trial report.

Hosking 1990.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: full Setting: Mayo Clinic, Rochester, MN, USA Number of centres: 1 Dates of trial (start and end): NR Follow‐up: intraoperatively Number randomised: 20 (10 in each group) Number analysed (primary outcome): 10 in each group
Participants	Inclusion criteria: infants weighing < 10 kg scheduled for cardiac surgical procedures (acyanotic and cyanotic) Age: washed red blood cell group: mean 7 months (SD 4.9); packed red blood cells: mean 8.3 months (SD 4) Sex: not stated Exclusion criteria: infants with diabetes mellitus or other endocrine disturbances that could result in an abnormal response to glucose Statistically significant baseline imbalances between the groups: no
Interventions	2 groups: ‐ washed red blood cells ‐ packed red blood cells Intervention arm: washed packed red blood cells (with isotonic saline to decrease blood glucose concentrations to 30 to 60 mg/dL) added into CPB prime to yield a haematocrit of 25% during CPB Comparator arm: packed red blood cells added into CPB prime to yield a haematocrit 25% during CPB. Red blood cells were suspended in AS‐1 preservative solution (adenine‐glucose‐mannitol‐saline) and added into the CPB prime prior to the child going onto CPB and intraoperatively to replace intraoperative losses. Quantity of RBCs received: NR Timing of RBC transfusion: into the CPB prime prior to the child going onto CPB and intraoperatively to replace intraoperative losses Any other comments: red blood cells suspended in AS‐1 preservative solution (adenine‐glucose‐mannitol‐saline) Was there compliance with the intervention? Yes Were there any deviations from treatment? NR Percentage reaching the stated intervention target: 100% Co‐interventions: none
Outcomes	Trial primary outcome Not stated Other trial outcomes Blood glucose concentrations after induction, prior to initiation of CPB, 10 minutes after initiation of CPB, 10 minutes prior to separation from CPB and after protamine administration Review outcomes All‐cause mortality up to 30 days: NR All‐cause mortality 31 days to 2 years: NR Serious adverse event: cardiac events: NR Serious adverse event: acute lung injury: NR Serious adverse event: stroke: NR Serious adverse event: thromboembolism: NR Serious adverse event: renal failure: NR Serious adverse event: infection: NR Serious adverse event: haemorrhage, defined as return to theatre for bleeding: NR Haematocrit levels: NR Haemoglobin levels: NR RBC units used to discharge: NR Other blood products transfused to discharge: NR Postoperative chest drain output: NR Duration of mechanical ventilation: NR Duration of intensive care stay: NR Rate of rehospitalisation: NR Oxygen content difference: NR Cerebral O2 status: NR Blood lactate levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" lactate, as defined by the study: NR Blood sodium (Na+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR Blood potassium (K+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: Reported up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: reported
Notes	Study objective: to determine if washed red cells when used for bypass prime in infants can prevent the large increase in blood glucose concentrations during CPB observed when red blood cells suspended in AS‐1 preservative solution are used. Funding: NR. No details of author conflicts were reported. Sample size: NR Compliance: yes Trial registration: we did not find a trial registration.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information was provided to enable an assessment of random sequence generation.
Allocation concealment (selection bias)	Unclear risk	No information was provided to enable an assessment of adequate allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not reported so insufficient information to make a definite judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported so insufficient information to make a definite judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomised participants were included in the analysis of outcome data and no participants were lost during follow‐up.
Selective reporting (reporting bias)	Unclear risk	The trial did not define the outcomes they were interested in; therefore, there is insufficient information to identify whether there was reporting bias in the trial.
Other bias	Unclear risk	None reported. It would be difficult to rule out as very little methodological detail was provided in the trial report.

Komai 1998.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: full Setting: Department of Thoracic and Cardiovascular Surgery, Wakayama Medical College, Wakayama, Japan Number of centres: 1 Dates of trial (start): from April 1991. End date not reported Follow‐up: duration of ITU stay Number randomised: 46 (24 in leukocyte removal group, 22 in control group) Number analysed: 24 in leukocyte removal group, 22 in control group
Participants	Inclusion criteria: undergoing elective open‐heart surgery for radical correction of ventricular septal defect Age: leukoreduction group: median 22.5 months (range 7 months to 10 years); control group: median 22.5 months (range 3 months to 8 years) Sex:(M/F): 25/21 Exclusion criteria: NR, but no participant had been intubated or on catecholamines before the operation Statistically significant baseline imbalances between the groups: no
Interventions	2 groups: surgical technique and anaesthesia were uniform for both groups. For both groups, the priming fluid of the CPB circuit consisted of crystalloid solution (Ringer's lactate), colloid solution (albumin or plasma protein fraction) and banked blood. The number of blood units used was determined individually to give an estimated haematocrit level during bypass of around 25%. Intervention arm: leukoreduction group: a leukoreduction filter (Pall RC100 or 400, Pall Biomedical, Glen Cove, USA) was used for priming, as well as in every supplement of banked blood used during and after the operation. Comparator arm: control group: banked blood was primed without using any leukoreduction technique. Quantity of RBCs received: leukocyte removal group: mean 6.0 (SEM = 0.3) units; control group: 6.3 (SEM = 0.1) units Timing of RBC transfusion: intraoperative and postoperative Any other comments: number of blood units used was determined individually to give an estimated haematocrit level during bypass of around 25%. Transfusion trigger for post‐operation not stated. Was there compliance with the intervention? NR Were there any deviations from treatment? Yes, 1 of 3 possible oxygenators was used ‐ does not state which one or numbers in each treatment arm Percentage reaching the stated intervention target: assumed 100% Co‐interventions: none reported
Outcomes	Trial primary outcome Not stated Other trial outcomes Perioperative changes in Pp:Pp and Ps measured simultaneously just before and after CPB to calculate the percentage decrease in Pp/Ps Respiratory index after intracardiac repair Intubation time and duration of stay in the ICU Blood analysis and blood chemistry test: white blood cell count, platelet count, creatinine, total bilirubin, serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase 1 week before, 1 day after and 7 days after operation Review outcomes All‐cause mortality up to 30 days: NR All‐cause mortality 31 days to 2 years: NR Serious adverse event: cardiac events: NR Serious adverse event: acute lung injury: NR Serious adverse event: stroke: NR Serious adverse event: thromboembolism: NR Serious adverse event: renal failure: NR Serious adverse event: infection: NR Serious adverse event: haemorrhage, defined as return to theatre for bleeding: NR Haematocrit levels: NR Haemoglobin levels: NR RBC units used to discharge: reported as number of units transfused Other blood products transfused to discharge: NR Postoperative chest drain output: NR Duration of mechanical ventilation: reported as mean (SEM) Duration of intensive care stay: NR Rate of rehospitalisation: NR Oxygen content difference: NR Cerebral O2 status: NR Blood lactate levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" lactate, as defined by the study: NR Blood sodium (Na+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR Blood potassium (K+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: NR up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: NR
Notes	Study objective: the trial was designed to determine the clinical effect on lung function of reducing allogeneic leukocytes for children with ventricular septal defects undergoing open‐heart surgery. Funding: NR. No details of author conflicts were reported. Sample size: NR Compliance: NR, but there were some protocol deviations, 1 of 3 possible oxygenators was used ‐ does not state which one or numbers in each treatment arm Trial registration: we did not find a trial registration.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Used an alternation method: this information was provided through direct email contact with the authors.
Allocation concealment (selection bias)	Unclear risk	No information was provided to enable an assessment of adequate allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not reported so insufficient information to make a definite judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported so insufficient information to make a definite judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomised participants were included in the analysis of outcome data and no participants were lost during follow‐up.
Selective reporting (reporting bias)	Unclear risk	The trial did not define the outcomes they were interested in; therefore, there is insufficient information to identify whether there was reporting bias in the trial.
Other bias	Low risk	None reported

Liu 2007.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: full Setting: Fuwai Hospital, Beijing, China Number of centres: 1 Dates of trial (start and end): May 2005 to December 2006 Follow‐up: operative period Number randomised: 16 (8 in each group) Number analysed: 8 in each group
Participants	Inclusion criteria: neonates with congenital heart disease undergoing cardiac surgery with CPB. Diagnoses were transposition of the great arteries with ventricular septal defect and patent ductus arteriosus (13 participants) or interrupted aortic arch with patent ductus arteriosus (3 participants). Age: processed packed red cells group: mean 14 days (SEM 3); unprocessed packed red blood cells: mean 12 days (SEM 4) Sex (M/F): not clearly reported Exclusion criteria: NR Statistically significant baseline imbalances between the groups: no
Interventions	2 groups: ‐ processed ‐ unprocessed packed red blood cells Intervention arm: received processed packed red blood cells before priming with CATS (Fresenius, Bad Homborg, Germany). The washing procedure by CATS lasted approximately 7 minutes and used 1000 mL of 0.9% sodium chloride wash solution. Comparator arm: received unprocessed packed red cells for priming. All packed red blood cells were acquired from a standard donor bank. Quantity of RBCs received: processed group: priming volume: 212.5 +/‐ 24.8 mL; unprocessed group: priming volume: 420.6 +/‐ 18.9 mL Timing of RBC transfusion: intraoperatively, in bypass prime Any other comments: packed red blood cells Was there compliance with the intervention? NR Were there any deviations from treatment? NR Percentage reaching the stated intervention target: assumed 100% Co‐interventions: none stated
Outcomes	Trial primary outcome Not stated Other trial outcomes Series laboratory and clinical parameters of haematocrit, blood potassium, blood glucose, blood lactate, acid‐base and total priming volume of packed red blood cells. Levels were measured pre‐processing (i.e. baseline for both groups), post‐processing (in intervention arm only), at 10 minutes during CPB and at the end of CPB. Review outcomes All‐cause mortality up to 30 days: reported All‐cause mortality 31 days to 2 years: NR Serious adverse event: cardiac events: NR Serious adverse event: acute lung injury: NR Serious adverse event: stroke: NR Serious adverse event: thromboembolism: NR Serious adverse event: renal failure: NR Serious adverse event: infection: NR Serious adverse event: haemorrhage, defined as return to theatre for bleeding: NR Haematocrit levels: reported Haemoglobin levels: NR RBC units used to discharge: NR Other blood products transfused to discharge: NR Postoperative chest drain output: NR Duration of mechanical ventilation: NR Duration of intensive care stay: NR Rate of rehospitalisation: NR Oxygen content difference: NR Cerebral O2 status: NR Blood lactate levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" lactate, as defined by the study: NR Blood sodium (Na+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR Blood potassium (K+) levels: at baseline: reported at CPB circuit prime: reported at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: reported up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: NR
Notes	Study objective: the objective of the trial was to compare the effect of unprocessed and processed packed red blood cells with CATS on neonates undergoing corrective cardiac surgery. Funding: NR. No details of author conflicts were reported. Sample size: NR Compliance: NR Trial registration: we did not find a trial registration.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation not reported
Allocation concealment (selection bias)	Unclear risk	No information was provided to enable an assessment of adequate allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	The blinding of participants and personnel was not reported.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	The blinding of outcome assessors was not reported.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants randomised were included in the analysis and no participants were lost during follow‐up.
Selective reporting (reporting bias)	Unclear risk	All outcomes described in the methods were reported in the results. However, no prospectively registered study protocol was identified and we cannot exclude the possibility of selective reporting.
Other bias	Low risk	None reported

Martin 2022.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: abstract only for subgroup; trial protocol and full report of main trial. Setting: multicentre Number of centres: 50 Dates of trial (start and end): 2014 to 2018 Follow‐up: 28 days or at discharge or death Number randomised: 178 (89 in each group) Number analysed (primary outcome): fresh group: 89; standard issue group: 89
Participants	Inclusion criteria: patients enroled in ABC‐PICU study and admitted to PICU/cardiac PICU after cardiac surgery with CPB. From original paper: "patients admitted to participating PICUs or in the process of being admitted from the operating room, aged 3 days to 16 years, if first transfusion was administered within 7 days of PICU admission and if they were expected by the attending physician to stay in the PICU for at least 24hrs." Age: median 0.6 years Sex: NR for subgroup Exclusion criteria: age at time of enrolment < 3 days from birth or has reached their 16th birthday; post‐conception age < 36 weeks at time of enrolment; documented RBC transfusion within the 28 days prior to fulfilling the eligibility criteria; previously randomised in this study; weight < 3.0 kg at ICU admission; pregnant; conscious objection or unwillingness to receive blood products; not expected to survive beyond 24 hours, brain death or suspected brain death; limitation or withdrawal of care decisions have been made; enrolment in another randomised clinical trial that has not been approved for co‐enrolment; patients for whom autologous and/or directed donation RBCs will be provided; patients for whom the treating physician routinely and systematically requests RBC ≤ 14 days of storage; patients for whom there systematically exist RBC aliquoting policies that mandate the initial use of units stored ≤ 14 days (ex: Pedi‐Pack); on ECMO or plan to be immediately placed on ECMO at time of enrolment; patient predicted or presumed to require a massive transfusion (> 40ml/kg of all blood components in a 24‐hour period) according to treating physician judgment; refusal by physician; inability to obtain consent; blood bank personnel experience difficulties in securing blood products (difficult cross‐matches, rare blood groups and diseases like IgA deficiency); insufficient number of ABO type compatible RBC units available in the blood bank at randomisation with a storage time ≤ 7 days (minimum 1 unit regardless of patient age); all RBC units available for the patient are not leukocyte‐reduced prior to storage Statistically significant baseline imbalances between the groups: unclear
Interventions	2 groups: ‐ fresh blood ‐ standard issue blood Intervention arm: fresh blood, stored less than or up to 7 days Comparator arm: standard issue blood, no specific age requirement Quantity of RBCs received: not stated Timing of RBC transfusion: NR for subgroup. In full study, red cells were given up to 28 days after randomisation or until hospital discharge or death, whichever occurred first. Any other comments: none Was there compliance with the intervention? NR in this subgroup analysis (original paper states 59 protocol violations in the fresh red blood group out of 728 included) Were there any deviations from treatment? Not reported in subgroup. In full trial, 25/768 did not receive transfusion as randomised in fresh group. Percentage reaching the stated intervention target: NR Co‐interventions: nil
Outcomes	Trial primary outcome 28‐day NPMODS (multiple organ dysfunction syndrome), defined as the proportion of participants who die during the 28 days after randomisation or who develop NPMODS including mortality Trial secondary outcomes PICU and hospital mortality 28‐ and 90‐day all‐cause mortality Highest number of organ dysfunctions, Pediatric Logistic Organ Dysfunction 2 (PELOD‐2) score Nosocomial infections (pneumonia, blood stream infection, urinary tract infections, sepsis) Acute lung injury Acute respiratory distress syndrome (ARDS) Mechanical ventilation–free and PICU‐free days Use of haemodynamic support (vasoactive drugs or extracorporeal support) Renal support (renal replacement therapy) Symptomatic deep vein thrombosis Reported transfusion reactions Other adverse events. Review outcomes All‐cause mortality up to 30 days: NR All‐cause mortality 31 days to 2 years: NR Serious adverse event: cardiac events: NR Serious adverse event: acute lung injury: NR Serious adverse event: stroke: NR Serious adverse event: thromboembolism: NR Serious adverse event: renal failure: NR Serious adverse event: infection: NR Serious adverse event: haemorrhage, defined as return to theatre for bleeding: NR Haematocrit levels: NR Haemoglobin levels: NR RBC units used to discharge: NR Other blood products transfused to discharge: NR Postoperative chest drain output: NR Duration of mechanical ventilation: NR Duration of intensive care stay: NR Rate of rehospitalisation: NR Oxygen content difference: NR Cerebral O2 status: NR Blood lactate levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" lactate, as defined by the study: NR Blood sodium (Na+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR Blood potassium (K+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: NR up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: NR
Notes	Study objective: to determine if transfusion of fresh RBC units reduced the incidence of NPMODS compared with the use of standard‐issue RBC in paediatric cardiac surgical patients. Funding: "Funding support was provided for the trial by the NIH/NHLBI, Institute of Circulatory and Respiratory Health of the Canadian Institutes Health Research, Washington University in St Louis, the French Ministry of Health Programme Hospitalier de Recherche Clinique, the Quebec Ministry of Health and Social Services, the GFRUP, and the Établissement Français du Sang. The Canadian Critical CareTrials Group (CCCTG) received funding through the Community Development Grant from CIHR’s Institute of Circulatory and Respiratory Health." The authors declare that they have no conflict of interest. Sample size: NR for subgroup. Main paper reports 210 participants in cardiac surgery group, but subgroup only reports on 178. No reasons given Compliance: NR in this subgroup analysis (original paper states 59 protocol violations in the fresh red blood group out of 728 included). Unclear for cardiac surgery subgroup. Adherence to transfusion protocol was considered present if 80% or more transfusions occurred with units stored for 7 days or less and if no units were stored for more than 14 days during the 28‐day follow‐up period. No cross‐over to the other study group occurred: from original paper. Not reported in subgroup. In full trial, 25/768 did not receive transfusion as randomised in fresh group. Trial registration: we did not find a trial registration, but there is a published protocol.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Centralised computer‐generated assignment sequence using variable permuted block sizes of 2, 4 and 6 and were stratified according to participant age (< 29 days, 29 to 365 days, > 365 days) and study site.
Allocation concealment (selection bias)	Low risk	Only the independent study statistician at the data co‐ordinating centre had knowledge of randomisation codes.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding was achieved using a sticker over expiration date prior to blood issue.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	From protocol: "The diagnosis of NPMODS and the determination of the PELOD score will be done by research assistants who will be kept unaware of treatment allocation". Statisticians conducting analysis were also blinded, with the use of dummy codes to designate treatment allocation.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	178 participants are reported in the subgroup analysis, but the cardiac surgery group in the full trial appears to be 210. No explanation for the difference in numbers
Selective reporting (reporting bias)	Unclear risk	Reporting of subgroup analysis does not include most trial outcomes
Other bias	Low risk	No other concerns

Shimpo 2001.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: full Setting: Edobashi Tsu, Japan Number of centres: 1 Dates of trial (start and end): not reported Follow‐up: not stated Number randomised: 100 (50 in each group) Number analysed (primary outcome): 50 in each group
Participants	Inclusion criteria: children undergoing cardiac operations to correct congenital heart defects Age: ultrafiltration group: mean 9.7 months (SD 1.8); control group: mean 10.6 months (SD 1.9) Sex (M/F): ultrafiltration group: 15/12; control group: 11/12 Exclusion criteria: not stated Statistically significant baseline imbalances between the groups: no
Interventions	2 groups: ‐ ultrafiltration ‐ no ultrafiltration Intervention arm: ultrafiltration group: stored packed red blood cells priming solution was treated with ultrafiltration before CPB was initiated. Comparator arm: no ‐ ultrafiltration group Very little methodological detail provided in trial report
Outcomes	Trial primary outcome Not stated Other trial outcomes Electrolytes NH3 Prekallikrein Kininogen Bradykinin Blood gases before and after ultrafiltration Review outcomes All‐cause mortality up to 30 days: only intraoperative deaths reported All‐cause mortality 31 days to 2 years: NR Serious adverse event: cardiac events: NR Serious adverse event: acute lung injury: NR Serious adverse event: stroke: NR Serious adverse event: thromboembolism: NR Serious adverse event: renal failure: NR Serious adverse event: infection: NR Serious adverse event: haemorrhage, defined as return to theatre for bleeding: NR Haematocrit levels: NR Haemoglobin levels: NR RBC units used to discharge: NR Other blood products transfused to discharge: NR Postoperative chest drain output: NR Duration of mechanical ventilation: not fully reported, but authors note that the ultrafiltration group had significantly shorter duration of ventilator support. Duration of intensive care stay: reported Rate of rehospitalisation: NR. Ultrafiltration of the priming blood before CPB attenuates inflammatory response and improves postoperative clinical course in paediatric patients. Oxygen content difference: NR Cerebral O2 status: NR Blood lactate levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR Immediately after CPB and clamp of arterial cannula: NR "peak" lactate, as defined by the study: NR Blood sodium (Na+) levels: at baseline: reported at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR Blood potassium (K+) levels: at baseline: reported at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: NR up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: NR
Notes	Study objective: to test the hypothesis that ultrafiltration of the stored blood before CPB reduces the unfavourable effects of stored blood and the production of inflammatory cytokines Funding: NR. No details of author conflicts were reported. Sample size: NR Compliance: yes Trial registration: we did not find a trial registration.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information was provided to enable an assessment of random sequence generation.
Allocation concealment (selection bias)	Low risk	Quote (p. 52): "Just before setting up the operating room, the randomisation process was performed. Only the perfusionist was informed which method to use."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote (p. 52): "Just before setting up the operating room, the randomisation process was performed. Only the perfusionist was informed which method to use."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote (p. 52): "Just before setting up the operating room, the randomisation process was performed. Only the perfusionist was informed which method to use."
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomised participants were included in the analysis of outcome data and no participants were lost during follow‐up.
Selective reporting (reporting bias)	Unclear risk	The trial did not define the outcomes they were interested in; therefore, there is insufficient information to identify whether there was reporting bias in the trial.
Other bias	Unclear risk	None reported. It would be difficult to rule out as very little methodological detail was provided in the trial report.

Swindell 2007.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: full Setting: Birmingham Children's Hospital, Birmingham, UK Number of centres: 1 Dates (start and end): January 2005 to May 2006 Follow‐up: not stated but measurements taken intraoperatively Number randomised: 22 (11 in each group) Number analysed (primary outcome): 11 in each group
Participants	Inclusion criteria: infants (< 1 year old) and neonates undergoing CPB for complex congenital heart surgery Diagnoses were hypoplastic left heart syndrome (12 participants), multiple complex defects (5 participants), transposition of the great arteries (3 participants), pulmonary atresia and ventricular septal defect (1 participant), hypoplastic aortic arch (1 participant). The operations they underwent were modified Norwood Stage 1 (12 participants), cavo‐pulmonary shunt (4 participants), arterial switch (3 participants), aortic arch repair (2 participants), pulmonary atresia repair (1 participant) Age: washed group: mean 45 days (range 1 to 180); unwashed group: mean 62 days (range 2 to 300) Weight: washed group: mean 4.2 kg (range 2.62 to 8.2); unwashed group: mean 4.0 kg (range 2.4 to 8.3) Sex (M/F): 12/10 Exclusion criteria: NR Statistically significant baseline imbalances between groups: not stated, but control group have a higher mean age: 62 days versus 45 days
Interventions	2 groups: ‐ washed ‐ unwashed in the CPB circuit prime Intervention arm: washed received the processed volume from 2 units of irradiated pre‐washed in a cell‐saver before addition to the CPB circuit prime. They received 2 units to compensate for the volume loss during processing. Comparator arm: unwashed received 1 unit of unwashed irradiated red cells in the CPB circuit prime. They also received a second unit of unwashed irradiated red cells as required during CPB. Quantity of RBCs received: 1 unit into prime initially +/‐ another 1 unit as needed Timing of RBC transfusion: into bypass prime Any other comments: irradiated red cells ‐ gamma irradiated with dose of 25 Gy within 14 days of donation and given to pt within 14 days of irradiation Was there compliance with the intervention? Yes Were there any deviations from treatment? No Percentage reaching the stated intervention target: 100% Co‐interventions: nil
Outcomes	Trial primary outcome Potassium and lactate levels in the irradiated red cells and inpatient samples Other trial outcomes Sodium concentrations Samples were taken before addition to the prime (for the intervention group this meant pre‐ and post‐washing), after connection of lines and 5 minutes of re‐circulation in bypass prime, from patient arterial blood prior to bypass, bypass circuit sample after start of bypass, at 28°C during cooling then re‐warming, then at 36°C after re‐warming. A final sample was taken from participant arterial blood immediately after bypass and clamping of arterial cannula. Review outcomes All‐cause mortality up to 30 days: NR All‐cause mortality 31 days to 2 years: NR Serious adverse event: cardiac events: NR Serious adverse event: acute lung injury: NR Serious adverse event: stroke: NR Serious adverse event: thromboembolism: NR Serious adverse event: renal failure: NR Serious adverse event: infection: NR Serious adverse event: haemorrhage, defined as return to theatre for bleeding: NR Haematocrit levels: NR Haemoglobin levels: NR RBC units used to discharge: NR Other blood products transfused to discharge: NR Postoperative chest drain output: NR Duration of mechanical ventilation: NR Duration of intensive care stay: NR Rate of rehospitalisation: NR Oxygen content difference: NR Cerebral O2 status: NR Blood lactate levels: at baseline: reported at CPB circuit prime: reported at up to 15 minutes after start of CPB: reported only as figure at 28 degrees centigrade during cooling: reported only as figure at 28 degrees centigrade during rewarming: reported at 36 degrees centigrade after rewarming: reported only for intervention group; control group reported as only as figure immediately after CPB and clamp of arterial cannula: reported only as figure "peak" lactate, as defined by the study: reported Blood sodium (Na+) levels: at baseline: reported at CPB circuit prime: reported at up to 15 minutes after start of CPB: reported only as figure at 28 degrees centigrade during cooling: reported only as figure at 28 degrees centigrade during rewarming: reported at 36 degrees centigrade after rewarming: reported immediately after CPB and clamp of arterial cannula: reported Blood potassium (K+) levels: at baseline: reported at CPB circuit prime: reported at up to 15 minutes after start of CPB: reported as figure for control group, data not extractable at 28 degrees centigrade during cooling: reported only as figure at 28 degrees centigrade during rewarming: reported at 36 degrees centigrade after rewarming: reported immediately after CPB and clamp of arterial cannula: reported "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: NR up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: NR
Notes	Study objective: the study aimed to identify whether cell‐saver washing of irradiated red cells prior to transfusion reduced potassium and lactate levels in the donor blood. In addition, it aimed to identify whether transfusion of washed red cells prevented hyperkalaemia and hypercalcaemia in the serum of neonates and infants undergoing open‐heart surgery. In an appendix at the end of the paper, a conference discussion was reported and the issue of the need to give all of this patient population irradiated red cells. The authors agree that not all of their patients may have needed irradiated red cells, so the issue of high potassium and lactate levels may not be relevant to all. Funding: NR. No details of author conflicts were reported. Sample size: NR Compliance: yes Trial registration: trial registration was available.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation not reported
Allocation concealment (selection bias)	Unclear risk	No information was provided to enable an assessment of adequate allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not reported but theatre staff unlikely to be blinded as washing equipment would be visible to all
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported so insufficient information to make a definite judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomised participants were included in the analysis of outcome data and no participants were lost during follow‐up.
Selective reporting (reporting bias)	Unclear risk	All outcomes described in the methods were reported in the results. However, no prospectively registered study protocol was identified, and we cannot exclude the possibility of selective reporting.
Other bias	Low risk	None reported

Willems 2010.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: subgroup analysis of TRIPICU study (Lacroix 2007) Setting: tertiary care paediatric ICUs in Belgium, Canada and the USA Number of centres: 7 (TRIPICU study had 19 participating centres) Dates: November 2001 to August 2008 (information from original TRIPICU publication) Follow‐up: 28 days post randomisation Number randomised: 125 (63 in restrictive group, 62 in liberal group) Number analysed (primary outcome): 63 in restrictive group, 62 in liberal group
Participants	Inclusion criteria: subgroup of paediatric patients post cardiac surgery from the TRIPICU study (125 participants, representing 19.6% of all the TRIPICU participants). The participants had undergone cardiac surgery or cardiac catheterisation. All patients with at least 1 Hb concentration ≤ 9.5 g/dL within the first 7 days after paediatric ICU admission were considered for inclusion. The most common surgeries were coarctation repair (13 participants), ventricular septal defect repair (16 participants), repair of tetralogy of Fallot (24 participants), repair of atrioventricular canal defect (11 participants), mitral valve surgery (8 participants), Rastelli procedure (8 participants), arterial switch procedure (5 participants). Age: restrictive mean 31.4 months (SD 38.1), liberal mean 26.4 months (SD 39.1) Sex (% male): restrictive group: 57, liberal group: 57 Weight: restrictive mean 11.5 kg (SD 10.4), liberal mean 10.0 kg (SD 8.5) Exclusion criteria specific to cardiac surgery subgroup: age < 28 days, patients with cyanotic heart disease (with right‐to‐left shunt) who had a palliative intervention (procedures such as Norwood, Glenn, Fontan or a shunt between a systemic and a pulmonary artery were considered palliative) Statistically significant baseline imbalances between groups: no
Interventions	2 groups: pre‐storage leukoreduced allogeneic red cell units were transfused when transfusion thresholds were reached. Intervention arm: restrictive: transfusion threshold 7.0 g/dL. Transfusion strategies were applied for up to 28 days post‐randomisation. Comparator arm: liberal: transfusion threshold 9.5 g/dL. Transfusion strategies were applied for up to 28 days post‐randomisation. Quantity of RBCs received: NR Timing of RBC transfusion: transfusion strategies applied for up to 28 days post‐randomisation. Restrictive group: 1.8 +/‐ 1.8 days from randomisation to first transfusion; liberal group: 0.6 +/‐ 0.25 days from randomisation to first transfusion Any other comments: the research protocol allowed temporary suspension during active blood loss, surgery, severe hypoxaemia or haemodynamic instability. Was there compliance with the intervention? Yes Were there any deviations from treatment? Yes. Restrictive group: 7 participants were temporarily suspended from the transfusion protocol for 1.1 +/‐ 0.4 days and received 7 red cell transfusions, but these were not considered to be a breach of protocol. Reasons for suspension: shock 1, acute blood loss 1, surgery 2, others 3. Liberal group: 1 participant was suspended temporarily from the transfusion protocol for 1 day and received 1 red cell transfusion. This was not considered to be a breach of protocol. Reason for suspension: surgery 1. Percentage reaching the stated intervention target: NR? Co‐interventions: NR?
Outcomes	Trial primary outcome Proportion of participants who developed or had progression of MODS Other trial outcomes Markers of severity of MODS (highest number of organ dysfunction per patient and paediatric Logistic Organ Dysfunction Score) Nosocomial infections Oxygenation markers Duration of mechanical ventilation Length of ICU stay Number of red cell transfusion reactions 28‐day mortality Vasoactive drugs and corticosteroid use Review outcomes All‐cause mortality up to 30 days: reported All‐cause mortality 31 days to 2 years: NR Serious adverse event: cardiac events: reported Serious adverse event: acute lung injury: reported Serious adverse event: stroke: NR Serious adverse event: thromboembolism: NR Serious adverse event: renal failure: reported Serious adverse event: infection: reported Serious adverse event: haemorrhage, defined as return to theatre for bleeding: reported Haematocrit levels: NR Haemoglobin levels: reported RBC units used to discharge: reported as volume transfused Other blood products transfused to discharge: reported as volume transfused for FFP, platelets and cryoprecipitate Postoperative chest drain output: NR Duration of mechanical ventilation: reported Duration of intensive care stay: NR Rate of rehospitalisation: NR Oxygen content difference: NR Cerebral O2 status: NR Blood lactate levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" lactate, as defined by the study: NR Blood sodium (Na+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR Blood potassium (K+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: NR up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: NR
Notes	Study objective: this study aimed to determine the impact of a restrictive versus a liberal transfusion strategy on new or progressive multiple organ dysfunction in children post cardiac surgery. It is difficult to determine from this paper the exact methodology used, but this is well documented in the original TRIPICU paper. Funding: supported in part by grants 84300 and 130770 from the Canadian Institutes of Health Research (CIHR) and Grant 13904 from the Fonds de la Recherche en Sante du Quebec. Drs Lacroix and Hebert have received consulting fees and grant support from Johnson and Johnson; Dr Hebert also received consulting fees and unrestricted funds from Novo Nordisk and Amgen serving as a career scientist of the Ontario Ministry of Health (1994 to 2004), and received unrestricted training funds from Canadian Blood Services. The remaining authors did not disclose any potential conflicts of interest. Sample size: Willems 2010 was a subgroup analysis of the larger RCT, the TRIPICU study (Lacroix 2007). The original TRIPICU paper estimated they would need to enrol 626 participants to detect an absolute reduction of 10% in the risk of new or progressive organ dysfunction in the group treated according to the restrictive transfusion strategy, with an overall one‐sided alpha of 5% and a power of 90%. 637 participants were included in analysis, giving the TRIPICU study the requisite numbers to attain the desired power. As Willems 2010 is a subgroup analysis, the power calculations of the main trial are not relevant. The subgroup analysis was based on 125 participants: the paper states that the power of this subgroup analysis was not optimal and the number of participants was too small to permit any conclusions. The study reports results for the 125 participants randomised (ITT analysis). Compliance: yes, but there were protocol violations. 10 participants did not reach their predefined criteria for good protocol adherence (80%), and these participants were excluded from a per‐protocol analysis performed for their primary outcome (MODS). The results of the ITT and per‐protocol analysis differed slightly, but neither analysis resulted in a difference in the number of participants developing or experiencing a worsening of MODS between the 2 study treatment arms. The actual protocol adherence rates were not stated for other outcomes and a per‐protocol analysis was similarly not reported for any other outcome. In this review, we have used the ITT data the study reported. In addition, 7 participants in the restrictive group and 1 in the liberal group were suspended temporarily from the transfusion protocol (1.1 ± 0.4 days and 1.0 days, respectively): during this time, 7 red cell transfusions were given in the restrictive group and 1 red cell transfusion in the liberal group. All products received while suspended were accounted for in the outcome analysis. Trial registration: trial registration was available.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Unclear from subgroup analysis paper, but full TRIPICU paper states block randomisation (Lacroix 2007): randomisation was centralised with assignment data posted on the Internet. Patients were assigned to study groups in blocks of 2 or 4 that were randomly distributed and stratified according to centre and 3 age groups (< 28 days, 29 to 364 days and > 364 days).
Allocation concealment (selection bias)	Low risk	Unclear from subgroup analysis paper, but full TRIPICU paper states block randomisation (Lacroix 2007): randomisation was centralised with assignment data posted on the Internet. Patients were assigned to study groups in blocks of 2 or 4 that were randomly distributed and stratified according to centre and 3 age groups (< 28 days, 29 to 364 days and > 364 days).
Blinding of participants and personnel (performance bias) All outcomes	High risk	Clinicians and carers were reported as being not blinded to treatment allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The statistician and members of the data and safety monitoring committee were reported as being blinded to treatment allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants randomised were included in the analysis. No participants were lost to follow‐up. A per‐protocol analysis was performed on the primary outcome data, excluding 15 participants from the analysis: 10 who did not meet their predefined criteria for good adherence (i.e. 80%), 1 who was younger than 28 days and should not have been included, and 4 who could not be categorised according to the Risk Adjustment for Congenital Heart Surgery (RACHS‐1) method. The publication reported that the results of this per‐protocol analysis differed slightly from the ITT analysis (where all trial participants were included). As per this review's protocol, the ITT data have been used in the analysis of the primary outcome for this trial.
Selective reporting (reporting bias)	Unclear risk	All outcomes described in the methods were reported in the results. However, no prospectively registered study protocol was identified and we cannot exclude the possibility of selective reporting.
Other bias	Low risk	None reported

Ye 2013.

Study characteristics
Methods	Type of study: parallel RCT Type of publication: full Setting: Children's Hospital, Hangzhou, China Number of centres: 1 Dates (start and end): October 2010 to April 2011 Follow‐up: not stated Number randomised: 309 (217 in the cell saver group, 92 in the control group) Number analysed (primary outcome): 217 in the cell saver group, 92 in the control group
Participants	Inclusion criteria: Chinese paediatric patients undergoing open heart operations with CPB Age: cell salvage: median 1.167 years (IQR 0.637 to 3.833), mean 2.55 years (SD 2.55); control: median 1.250 years (IQR 0.555 to 2.479), mean 2.05 years (SD 2.27) Weight: cell salvage: mean 11.09 kg (SD 6.48); control: mean 10.03 kg (SD 4.973) Sex (M/F): cell salvage: 108/109; control group: 42/50 Exclusion criteria: not reported Statistically significant baseline imbalances between the groups: no
Interventions	2 groups: ‐ cell salvage ‐ control Intervention arm: cell salvage group The residual CPB circuit blood was re‐infused after the cell saving procedure. Comparator arm: control group Participants were directly transfused with allogenic red cells after their operation and the residual CPB circuit blood was discarded. Red cells added to circuit prime during CPB and in ICU postoperatively. Quantity of RBCs received: cell salvage group: median 1.5 units (IQR 1.5 to 2.5); control group: median 2.5 units (IQR 2.5 to 3.0) Timing of RBC transfusion: during CPB and postoperatively Any other comments: none Was there compliance with the intervention? Yes Were there any deviations from treatment? NR Percentage reaching the stated intervention target: 100% Co‐interventions: nil
Outcomes	Trial primary outcome Postoperative clinical outcome Other trial outcomes Allogenic red cell requirements Haematocrit on the first day in ICU Postoperative chest tube drainage Intrahospital mortality Respiratory morbidity Renal dysfunction Review outcomes All‐cause mortality up to 30 days: reported as in‐hospital mortality All‐cause mortality 31 days to 2 years: NR Serious adverse event: cardiac events: NR Serious adverse event: acute lung injury: reported for events during ICU stay Serious adverse event: stroke: NR Serious adverse event: thromboembolism: NR Serious adverse event: renal failure: reported for events during ICU stay Serious adverse event: infection: NR Serious adverse event: haemorrhage, defined as return to theatre for bleeding: NR Haematocrit levels: reported as median IQR Haemoglobin levels: NR RBC units used to discharge: NR Other blood products transfused to discharge: NR Postoperative chest drain output: reported as median (IQR) Duration of mechanical ventilation: reported as median (IQR) Duration of intensive care stay: NR Rate of rehospitalisation: NR Oxygen content difference: NR Cerebral O2 status: NR Blood lactate levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" lactate, as defined by the study: NR Blood sodium (Na+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR Blood potassium (K+) levels: at baseline: NR at CPB circuit prime: NR at up to 15 minutes after start of CPB: NR at 28 degrees centigrade during cooling: NR at 28 degrees centigrade during rewarming: NR at 36 degrees centigrade after rewarming: NR immediately after CPB and clamp of arterial cannula: NR "peak" potassium, as defined by the study: NR Blood glucose levels (mg/dL): in priming solution prior to bypass: NR up to 15 minutes after start of CPB: NR "peak" glucose, as defined by the study: NR
Notes	Study objective: to evaluate the effect of cell salvage on postoperative clinical outcome by investigating allogenic RBC requirements, haematocrit on the first day in ICU, postoperative chest tube drainage, intrahospital mortality, respiratory morbidity and renal dysfunction after washed residual volume salvage transfusion in paediatric patients undergoing cardiac surgery Funding: supported by the National Science and Technology Foundation of China (2102BA105B05), the Zhejiang Province innovation team for the early screening and intervention of birth defects (2010R50045), the Health Bureau of Zhejiang Provincial Key Program (2012ZDA030; 2012ZDA031) and the Fundamental Research Funds for the Central Universities, Ministry of Education (2011KYJD008; 2012QNA7041). No details of author conflicts were reported. Sample size: although the participants were randomly divided into 2 groups, the numbers of participants in the 2 groups were not equal. This was because, in the early stage of the study, they only had one cell‐saver machine. Later, they bought a second machine, which ultimately led to a significant difference in the numbers of participants in the 2 arms of the trial. Compliance: yes Trial registration: we did not find a trial registration.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information was provided to allow an assessment of random sequence generation.
Allocation concealment (selection bias)	Unclear risk	No information was provided to allow an assessment of adequate allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not reported so insufficient information to make a definite judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported so insufficient information to make a definite judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomised participants were included in the analysis of outcome data and no participants were lost during follow‐up.
Selective reporting (reporting bias)	Unclear risk	The trial did not define the outcomes they were interested in; therefore, there is insufficient information to identify whether there was reporting bias in these trials.
Other bias	Unclear risk	None reported. It would be difficult to rule out as very little methodological detail was provided in the trial report.

ABO: the ABO blood group system; CATS: continuous autotransfusion system; CPB: cardiopulmonary bypass; DBP: diastolic blood pressure; ECMO: extracorporeal membrane oxygenation; FDA: Food and Drug Administration (US); FFP: fresh frozen plasma; Gy: gray; Hb: haemoglobin; HR: heart rate; IgA: immunoglobulin A; ICU: intensive care unit; IL: interleukin; IQR: interquartile range; ITT: intention to treat; LOS: length of stay; MODS: multiple organ dysfunction syndrome; n: number of participants; NGAL: neutrophil gelatinase‐associated lipocalin; NaCl: sodium chloride; NaHCO3: sodium bicarbonate; NPMODS: new or progressive multiple organ dysfunction syndrome; NR: not reported; PaO₂: partial oxygen pressure of the arterial blood; O_2: oxygen; PaO₂: partial pressure; PCICU: paediatric cardiac intensive care unit; PICU: paediatric intensive care unit; P_p: pulmonary arterial pressure; P_p/P_s: pulmonary to systemic arterial pressure ratio; P_s: systemic arterial pressure; PRBC: packed red blood cell; RBC: red blood cell; RCT: randomised controlled trial; rSO₂: regional cerebral oxygen saturation; SPB: systolic blood pressure; SD: standard deviation; SEM: standard error of the mean; SIR: systemic inflammatory response; TRIPICU: Transfusion Requirements in Pediatric Intensive Care Units; URMC: University of Rochester Medical Center; WBC: white blood cell

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Chamberlain 2018	Ineligible intervention: autologous cord blood
Chasovskyi 2015	Ineligible type of study: observational study and retrospective analysis
Cholette 2010	Ineligible intervention: no definite allogeneic blood transfusion intervention arm
Cholette 2013	Ineligible intervention: no definite allogeneic blood transfusion intervention arm. The primary intervention in the trial was cell salvage blood and the control arm received crystalloid/albumin with or without red cell transfusion (depending if anaemic). It is likely that a significant proportion of participants in the control arm would not have received an allogeneic red cell transfusion. The intervention of cell salvage could be examined in a future review.
CTRI/2017/11/010512	Ineligible intervention: modified ultrafiltration of cardiopulmonary bypass prime versus no modified ultrafiltration
Fergusson 2009	Ineligible participant group: based on a general neonatal population and not specifically in neonates with congenital heart disease undergoing cardiac surgery
Gruenwald 2008	Ineligible intervention: reconstituted fresh whole blood compared with standard blood component therapy
Gupta 2007	Ineligible participant group: patients with congenital heart disease (patent ductus arteriosus) did not undergo cardiac surgery.
Hajjar 2010	Ineligible participant group: people with congenital heart disease were excluded.
ISRCTN70923932	Ineligible participant group: no mention of congenital heart disease and no results presented by participant diagnosis upon completion of study
Kaltmann 2010	Ineligible type of study: a commentary not an RCT (further details obtained to assess eligibility)
Kipps 2011	Ineligible type of study: data taken from 2 related studies to explore and analyse the duration of mechanical ventilation in infants undergoing reparative cardiac surgery.
Manno 1991	Ineligible intervention: red cells were not an independent intervention as very fresh whole blood was compared with older whole blood and then compared with red blood cells, platelets and fresh frozen plasma.
Moritz 2000	Ineligible intervention: red cell data not presented independently of other blood products used. Blood components (packed red cells, fresh frozen plasma and platelets) were compared with fresh whole blood.
Mou 2004	Ineligible intervention: the reconstituted blood (0.5 units of packed red cells) was mixed with 0.5 units of fresh frozen plasma to achieve a haematocrit of 25%. Reconstituted blood was then compared with fresh whole blood, so red cell data were not presented independently of the other blood products used.
Nakayama 2015	Ineligible intervention: RCT of thrombelastography or conventional blood product management
NCT02751645	Ineligible intervention: removing blood prior to operation then replacing with clear fluid
NCT02761564	Ineligible intervention: use of central venous oxygen saturation as an indicator of need for RBC transfusion
NCT03167788	Study was withdrawn (manufacturing issues) with no participants recruited
NCT03469440	Ineligible intervention: continuous central venous saturations versus standard protocol
NCT04537000	Trial did not begin (funding withdrawn). No participants randomised
Steiner 2010	Ineligible participant group: no mention of congenital heart disease and no results presented by patient diagnosis upon completion of study
Valente 2018	Ineligible intervention: myocardial protection (different cardioplegia solutions)
Wu 2018	Ineligible intervention: variables (e.g. position, oxygenator type, UF etc) aimed at reducing the need for PRBC transfusion
Yay 2017	Ineligible participant group: mixed PICU population with no cardiac surgery subgroup

PICU: paediatric intensive care unit; PRBC: packed red blood cells; RBC: red blood cell; RCT: randomised controlled trial; UF: ultrafiltration

Characteristics of studies awaiting classification [ordered by study ID]

CTRI/2017/07/008972.

Methods	Randomised, parallel‐group, multiple‐arm trial
Participants	Inclusion criteria: age 1 to 10 years; undergoing cardiac surgery for congenital disease Exclusion criteria: receipt of blood transfusion in the past 3 months; Rh (D) negative blood group Estimated enrolment: 90 participants
Interventions	Three groups N‐PRBC group: non‐leukoreduced packed red blood cells S‐PRBC group: buffy coat depleted SAGM suspended packed red blood cells L‐PRBC group: pre‐storage leukoreduced packed red blood cells using 3rd generation leukofilters
Outcomes	Primary outcome Mortality at 90 days Secondary outcomes In‐hospital mortality (up to 30 days) Postoperative development of multiple organ dysfunction syndrome (up to 30 days) Postoperative infections (up to 30 days) Length of ICU stay Length of hospital stay
Notes	Estimated study completion date: 1 February 2019. Status "open to recruitment" checked 8 November 2023

Li 2020.

Methods	Randomised, parallel groups
Participants	Inclusion criteria Preoperative haemoglobin (Hb) ≥ 110 g/L Preoperative Hct ≥ 0.35 Preoperative haemodynamics are stable, and cardiac function is grade I to II Exclusion criteria Liver or kidney function or coagulation dysfunction before surgery Use of drugs affecting coagulation function before surgery Concurrent infection Actual enrolment: 72 participants
Interventions	Two groups Blood transfusion reduction group: "(1) After anesthesia, slowly bleed 5 mL/kg through the central vein according to the blood pressure, store it in a special citrate anticoagulant blood storage bag and store it in a constant temperature refrigerator at 4°C; (2) Stop bleeding strictly from the time of skin incision. , after sawing the sternum to stop bleeding, heparinize the whole body, recover the wound bleeding, and use an autologous blood recovery device; (3) Try to shorten the extracorporeal circulation line as much as possible, and do not transfuse red blood cells when the Hct is above 0.18 to 0.20 during the operation. After stopping the extracorporeal circulation, return Transfuse residual blood into the membrane lung and pipeline; (4) Use sufficient antifibrinolytic drugs during the operation, and use an autologous blood recovery device to recover blood after neutralization of protamine; (5) Apply hemostatic drugs and hemostatic materials; (6) Postoperatively After admission to the ICU, control blood pressure at an appropriate level to avoid bleeding caused by high blood pressure, avoid blind rehydration, and reduce unnecessary hemodilution; (7) Encourage children to get out of bed in the early postoperative period to improve gastrointestinal activity in order to achieve Nutritional enhancement purposes." Control group: "The control group: (1) Unconventional preoperative preparation of autologous blood; (2) Systemic heparinization before aortic cannulation; (3) Conventional extracorporeal circulation device; (4) Conventional ICU treatment."
Outcomes	Operation time CPB time Aortic cross‐clamping time ICU admission time Postoperative hospitalisation time Pulmonary infection rate Secondary endotracheal intubation rate Secondary surgery rate Hospitalisation expenses Preoperative Hb Preoperative Hct Hb at postoperative admission to ICU Hct at postoperative admission to ICU Hb at discharge Hct at discharge Postoperative drainage volume Red blood cell consumption Blood transfusion rate
Notes	After consultation with native speakers, we were unable to establish exactly what the intervention was, and, in particular, how the control group participants were managed. We contacted the authors on 25 January 2024 and 5 February 2024 but received no reply.

CPB: cardiopulmonary bypass; CRP: C‐reactive protein; Hb: haemoglobin; Hct: haematocrit; ICU: intensive care unit; IL: interleukin; PCICU: paediatric cardiac intensive care unit; SAGM: saline‐adenine‐glucose‐mannitol; URMC: University of Rochester Medical Center

Characteristics of ongoing studies [ordered by study ID]

CTRI/2023/06/053544.

Study name	A randomised controlled trial on short term outcomes of using fresh whole blood and packed red blood cells for priming in cardiopulmonary bypass in neonatal and pediatric cardiac surgery
Methods	Randomised, parallel‐group, 2‐arm trial
Participants	Inclusion criteria Age less than 1 year Undergoing elective cardiac surgery Requiring cardiopulmonary bypass during cardiac surgery Children of parents who provide consent for the study Exclusion criteria Inability to give parental consent for the study Unavailability for follow‐up during the study period. Pre‐existing blood dyscrasias Emergency surgery Patients not requiring CPB Patient not fit to receive the blood product as per randomisation for clinical reasons Recent antiplatelet or anticoagulation therapy Scheduled for complex surgery or repeat open heart surgery Patients with rare blood groups and alloantibodies Estimated enrolment: 34 participants
Interventions	Two groups: fresh whole blood versus packed RBCs Intervention arm: whole blood transfusion group: participants will be transfused during cardiopulmonary bypass with fresh whole blood, transfused within 5 days of collection. Comparator arm: packed RBCs group: participants will be transfused during cardiopulmonary bypass with packed RBCs.
Outcomes	Primary outcome Difference in mean donor exposures 24 hours postoperatively Secondary outcomes Mean transfusion requirement (ml/kg) at 4, 12 and 24 hours Mean length of stay in the ICU Mean length of stay in the hospital Mean chest tube loss mL/kg at 4, 12 and 24 hours Difference in mean haemoglobin, coagulogram (PT, aPTT, INR, serum fibrinogen) and platelet count at 4, 12 and 24 hours
Starting date	15 May 2023
Contact information	Dr Sheetal Malhotra, Department of Transfusion Medicine, PGIMER, Chandigarh, India sheetalmalhotra50@gmail.com
Notes	Estimated study completion date: May 2024

NCT03459287.

Study name	Study to evaluate the efficacy & safety of the INTERCEPT blood system for RBCs in complex cardiac surgery patients (ReCePI)
Methods	A randomised, double‐blinded (participant, care provider, investigator, outcomes assessor), controlled, parallel group, non‐inferiority, phase III multicentre study
Participants	Inclusion criteria Age ≥ 11 years of age Weight ≥ 40 kg Scheduled complex cardiac surgery with planned use of median sternotomy. The procedure may be performed either on‐pump or off‐pump. TRUST probability score ≥ 3, or currently on a regimen of aspirin, clopidogrel (or analogues) and/or GPIIb/IIIa inhibitors Females of childbearing potential must meet the 2 criteria below: negative serum or urine pregnancy test use at least one method of birth control that results in a low failure rate Informed consent Exclusion criteria Confirmed negative anti‐human globulin crossmatch with IBS RBCs to detect antibodies to IBS‐treated RBCs prior to receiving first study transfusion Pregnant or breastfeeding Refusal of blood products or other inability to comply with the protocol in the opinion of the investigator or the treating physician Treatment with any medication that is known to adversely affect RBC viability, such as dapsone, levodopa, methyldopa, nitrofurantoin, and its derivatives, phenazopyridine and quinidine Planned surgery is minimally invasive. Planned cardiac transplantation Active autoimmune haemolytic anaemia Left ventricular assist device or extracorporeal membrane oxygenation support preoperatively or planned need postoperatively Cardiogenic shock requiring preoperative placement of an intra‐aortic balloon pump. Planned deep hypothermic circulatory arrest Planned use of autologous or directed donations RBC transfusion during current hospitalisation prior to enrolment and randomisation (within 14 days) Participation in any one of the following types of clinical studies either concurrently or within the previous 28 days: investigational blood products, pharmacological agents or imaging materials, including dyes, investigational surgical techniques or devices. Studies of nutrition, psychology or socioeconomic issues are not grounds for exclusion. Current diagnosis of either chronic kidney disease or acute kidney injury with sCr ≥ 1.8 mg/dL at screening or requiring RRT Current diagnosis of either chronic or acute hepatic insufficiency Pre‐existing antibody to RBC antigens that may make the provision of compatible study RBC components difficult. History of transfusion reactions requiring washed RBCs, volume reduced RBC, or RBCs with additive solution removed. Patients with documented IgA deficiency or a history of severe allergic reactions to blood products Requirement for gamma‐irradiated RBC blood components Estimated enrolment: 600 participants
Interventions	2 groups: pathogen reduced RBCs (INTERCEPT) versus conventional RBCs Intervention arm: the INTERCEPT treatment process uses amustaline and glutathione together with a processing solution in a single‐use disposable set and results in pathogen and leukocyte inactivated RBCs suspended in SAG‐M additive solution (INTERCEPT RBCs). The INTERCEPT treatment will be performed on leukocyte reduced RBC components prepared from whole blood collections and suspended in AS‐5 additive solution within 24 hours of collection. The test component is allogeneic INTERCEPT RBCs suspended in SAG‐M and stored at 1°C to 6 for up to 35 days post‐donation and administered intravenously. Dose and schedule of RBC transfusions will be determined by the treating physician. Comparator arm: the control transfusion component is a conventional leukocyte‐reduced RBC component in an FDA approved additive solution (AS‐1, AS‐3 or AS‐5) stored at 1°C to 6°C for up to 35 days post‐donation and administered intravenously. The control RBC components will be handled and labelled in a manner so as to maintain blinding. Dose and schedule of RBC transfusions will be determined by the treating physician.
Outcomes	Primary outcome Proportion of participants with renal impairment: an increase in sCr ≥0.3 mg/dL (or 26.5 mol/L) from the pre‐surgery baseline within 48 hours after the end of surgery Proportion of participants with any treatment‐emergent AEs possibly, probably or definitely related to study RBC transfusion through 28 days after the last study transfusion Treatment‐emergent antibodies: proportion of participants with treatment‐emergent antibodies with confirmed specificity to IBS RBCs by end of study (i.e. 75 days after the last study transfusion) Secondary outcomes Proportion of participants with a diagnosis of stage I, II or III Acute Kidney Injury (KDIGO 2012) based on changes in sCr levels from pre‐surgery baseline and the need for RRT Mortality or the need for RRT by 30 days post completion of the surgery Treatment‐emergent AEs through 28 days after the last study transfusion Treatment‐emergent SAEs through 28 days after the last study transfusion Transfusion reactions (as defined by the CDC National Healthcare Safety Network Hemovigilance Module protocol) through 28 days after last study transfusion Treatment‐emergent immunisation to RBC alloantigens through 28 days after the last study transfusion Treatment‐emergent immunisation to HLA alloantigens through 28 days after the last study transfusion
Starting date	5 December 2018
Contact information	Richard J Benjamin, MD (Principal Investigator), Cerus Corporation, USA Contacts: Alison Coombs, acoombs@cerus.com; Chris Marston, cmarston@cirus.com
Notes	Estimated study completion date: December 2023 The trial would need to present results for participants undergoing cardiac surgery for congenital cardiac disease as a separate group to be included in this systematic review. Details correct as of 8 November 2023

NCT05881564.

Study name	Blood conservation in patients (3.5 to 12kg) undergoing congenital cardiac surgery
Methods	RCT with parallel‐group assignment
Participants	Inclusion criteria Patient weight 3.5 to 12kg Elective and urgent cardiac surgery with cardiopulmonary bypass Cases within the STS STAT categories of 1 to 4 Exclusion criteria Patients who weigh more than 12kg or less than 3.5kg Patients undergoing emergency surgery STAT category 5 cases Patients whose surgery does not require cardiopulmonary bypass Patients presenting preoperatively in shock Patients with known blood dyscrasias Estimated enrolment: 150
Interventions	2 groups: clear prime versus blood prime for cardiopulmonary bypass Intervention arm: cardiopulmonary bypass primed without blood Comparator arm: cardiopulmonary bypass primed with blood
Outcomes	Primary outcomes Blood received during bloodless cardiac surgery Volume transfused during bloodless cardiac surgery Number of participants with unplanned reoperation in bloodless cardiac surgery Number of participants with unplanned cardiac catheterisation in bloodless cardiac surgery Number of participants with a neurologic complication in bloodless cardiac surgery Number of participants with chylothorax in bloodless cardiac surgery Number of participants with vocal cord injury in bloodless cardiac surgery Number of participants with diaphragm paralysis in bloodless cardiac surgery Number of participants with pacemaker implantation in bloodless cardiac surgery Number of participants with postoperative pneumothorax in bloodless cardiac surgery Number of participants with wound infection in bloodless cardiac surgery Number of participants with bleeding requiring reoperation in bloodless cardiac surgery Number of participants with pericardial effusion in bloodless cardiac surgery Number of participants who died following bloodless cardiac surgery Time frame: 30 days Secondary outcomes: NR
Starting date	10 May 2023
Contact information	Principal Investigator Brian Bateson, Children's Hospital of Georgia, Augusta, Georgia, United States lauallen@augusta.edu
Notes	Estimated study completion date: 12 May 2026 Details correct as of 22 January 2024

AEs: adverse events; aPTT: activated partial thromboplastin time; CDC: US Centers for Disease Control and Prevention; FDA: US Food and Drug Administration; GPIIb/IIIa: glycoprotein IIb/IIIa; Hb: haemoglobin; HDU: high dependency unit; HLA: human leukocyte antigen; IBS: INTERCEPT blood system; ICU: intensive care unit; IgA: immunoglobulin A; INR: international normalised ratio; KDIGO: Kidney Disease Improving Global Outcomes; NR: not reported; PCICU: paediatric cardiac intensive care unit; PTT: partial thromboplastin time; RBC: red blood cell; RCT: randomised controlled trial; RRT: renal replacement therapy; SAEs: serious adverse events; SAG‐M: saline‐adenine‐glucose‐mannitol; sCr: serum creatinine; STS STAT: Society of Thoracic Surgery The Society of Thoracic Surgeons‐European Association for Cardio‐Thoracic Surgery

Differences between protocol and review

2025 version

We made two minor edits to the title, changing it from 'Red cell transfusion management for patients undergoing cardiac surgery for congenital heart disease' to 'Red blood cell transfusion management for people undergoing cardiac surgery for congenital heart disease'.

We were unable to use the following methods due to insufficient data.

• We had planned to conduct subgroup analyses comparing participants with acyanotic or cyanotic congenital heart disease, and comparing transfusion given at different time points, but we did not have enough data to do these analyses in any comparison for any of our critical outcomes.

• We had intended to calculate the number needed to treat for an additional beneficial outcome (NNTB) with 95% confidence interval (CI) and the number needed to treat for an additional harmful outcome (NNTH) with 95% CI, if the data were sufficient, but no comparison had enough data for this calculation.

• We were unable to conduct formal assessments of heterogeneity, or any sensitivity analyses, owing to the small number of studies. As there were fewer than 10 studies in any comparison, we were unable to produce any funnel plots to test for publication bias as we had planned.

• We refined our inclusion criteria, which led to the exclusion of one previously included study of 106 participants.

We were limited in the amount of meta‐analysis we could carry out, owing to lack of data. Where we have been unable to conduct meta‐analyses, we have noted this in the text of the review.

2014 version

In February 2013, we added in a new (post hoc) outcome, biochemistry levels. While only one of our included trials measured this outcome, we are aware that this could be an important outcome both in this version of the review and in future updates. We overlooked the outcome at the protocol stage, hence its addition now as below.

• Blood lactate levels (mmol/L) at baseline, at CPB circuit prime, at up to 15 minutes after the start of CPB, at 28 degrees centigrade during rewarming, at 36 degrees centigrade after rewarming, immediately after CPB and clamp of arterial cannula, "peak" levels as defined by the study

• Blood sodium (Na⁺) levels (mmol/L) at baseline, at CPB circuit prime, at up to 15 minutes after the start of CPB, at 28 degrees centigrade during rewarming, at 36 degrees centigrade after rewarming, immediately after CPB and clamp of arterial cannula, "peak" levels as defined by the study

• Blood potassium (K⁺) levels (mmol/L) at baseline, at CPB circuit prime, at up to 15 minutes after the start of CPB, at 28 degrees centigrade during rewarming, at 36 degrees centigrade after rewarming, immediately after CPB and clamp of arterial cannula, "peak" levels as defined by the study

• Blood glucose (mg/dL) at baseline, at CPB circuit prime, at up to 15 minutes after the start of CPB, at 28 degrees centigrade during rewarming, at 36 degrees centigrade after rewarming, immediately after CPB and clamp of arterial cannula, "peak" levels as defined by the study

Contributions of authors

Kirstin Wilkinson was the content expert for this review (congenital heart disease) and undertook the screening and selection of trials, data extraction, assessment of risk of bias, analysis of results, and preparation of the protocol and both published versions of this review.

Catherine Kimber was a systematic reviewer on this review who undertook screening and selection of trials, data extraction and assessment of risk of bias, analysis of results and contributed to the updated version of this review.

Alisha Allana was a content expert for this review (congenital heart disease) and undertook the screening and selection of trials, data extraction, assessment of risk of bias and contributed to the updated version of this review.

Carolyn Dorée was the information specialist who developed and implemented the search strategies, undertook the first sift of identified references, and contributed to the preparation of the protocol and both published versions of this review.

Rita Champaneria was a systematic reviewer on this review who assisted with the analysis of results and contributed to the updated version of this review.

Susan Brunskill was the methodological expert for this review and initially project managed the review, provided support and training to KW, undertook data extraction and assessment of risk bias, provided support with data analysis and the initial preparation of the protocol, and contributed to both published versions of this review.

Mike Murphy was a content expert for this review (red cells and transfusion) who contributed to the preparation of the protocol and both published versions of this review.

Sources of support

Internal sources

• NHS Blood and Transplant, Research and Development, UK

  Funds the work of the Systematic Review Initiative (SRI)

External sources

• UK Forum, UK

  UK Blood Services (NHS Blood and Transplant, Welsh Blood Service, Scottish National Blood Transfusion Service, and the Northern Ireland Blood Transfusion Service) provide infrastructure funding for the Systematic Reviews Initiative (SRI).

Declarations of interest

Kirstin Wilkinson: nothing to declare

Catherine Kimber: nothing to declare

Alisha Allana: nothing to declare

Carolyn Dorée: nothing to declare

Rita Champaneria: nothing to declare

Susan Brunskill is a Cochrane editor. She was not involved in the editorial process for this review.

Michael F Murphy: nothing to declare

New search for studies and content updated (no change to conclusions)