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. 2016 Dec 15;2016(12):CD012477. doi: 10.1002/14651858.CD012477

Effect of exchange transfusion on mortality in neonates with septicemia

Satish Mishra 1, Deepak Chawla 2, Ramesh Agarwal 3,✉
PMCID: PMC6611330

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To determine the efficacy of BET versus no BET in reducing the all‐cause mortality rate in neonates (up to 28 days of age) with septicemia, and to ascertain clinically important adverse effects associated with the BET procedure.

If we can procure sufficient data, we plan to perform the following subgroup analyses.

  • Term versus preterm neonates (term defined as infants ≥ 37 weeks' gestation, and preterm as < 37 weeks' gestation).

  • Early‐onset (systemic infection ≤ 48 hours of age) versus late‐onset (systemic infection > 48 hours of age) sepsis.

  • Single‐volume versus double‐volume exchange transfusion.

  • Infants with severe sepsis versus infants with less severe manifestations of sepsis.

Background

Description of the condition

Neonatal sepsis/infection is one of the most common causes of neonatal mortality and morbidity (WHO 2001). It has been estimated that 7.6 million children younger than five years of age died in 2010; of these deaths, 64% were attributed to infectious causes, and neonates contributed to a significant proportion (40.3%) (Liu 2012).

Owing to immaturity of the immune system, newborn infants are highly susceptible to systemic infection (Adkins 2004; Kapur 2002; Levy 2007; Lewis 2001; Wynn 2010). Studies have demonstrated a significant deficit across both innate and adaptive immunity. Neonatal adaptive immune function is hampered by deficiencies in T‐cell function and B‐cell function (weak immunoglobulin production) and by underdeveloped secondary lymphoid tissues (Adkins 2004; Wynn 2010). The innate immune system of these neonates is compromised by deficits in barrier integrity; circulating complement components; expression of antimicrobial proteins and peptides; quantitative and qualitative impairments in neutrophil, monocyte, macrophage, and dendritic cell functions; and decreased response to most Toll‐like receptor agonists (Levy 2007; Wynn 2010). Furthermore, recent research has unlocked a new angle on this issue. On the basis of experimental data from newborn mice, it has been conjectured that newborn infants have a fully developed immune system. However, in early infancy, to allow helpful bacteria to safely colonize the intestines, the immune system of newborn infants is actively suppressed, making them more vulnerable to infection. Suppressive cells in this case are CD71+ precursors of mature red blood cells (Elahi 2013).

Neonatal sepsis is divided into early‐onset neonatal sepsis (systemic infection within 48 hours of age) and late‐onset neonatal sepsis (systemic infection after 48 hours of age) on the basis of timing of the infection and presumed mode of transmission (Gordon 2005; Mtitimila 2004).

Although intravenous antibiotics are currently the mainstay of treatment in neonatal septicemia, reports of multidrug‐resistant bacteria causing neonatal sepsis are increasing (Ako‐Nai 1999; Karthikeyan 2001; Lim 1995; Rahman 2002; Tallur 2000; Viswanathan 2012). Greater understanding of the pathophysiology has led to multiple potential therapeutic targets for interventions to improve outcomes. Several types of immunomodulation/adjunct therapies including granulocyte transfusion (Mohan 2003), myeloid cell‐stimulating factors (Pammi 2011), intravenous pentoxifylline (Haque 2011), intravenous immunoglobulins (INIS 2011; Ohlsson 2013), and oral lactoferrin (Pammi 2009) have been utilized and studied in neonatal septicemia with varying degrees of success. Therapy that can assist in routine management of neonatal septicemia, especially in severe cases, is urgently needed.

Description of the intervention

Blood exchange transfusion (BET) was introduced in the late 1940s to decrease the mortality attributed to rhesus hemolytic disease of the newborn and to prevent kernicterus in surviving infants (Diamond 1947). Blood exchange transfusion is an invasive procedure that involves simultaneous removal of the patient's blood and replacement with donated blood. This procedure has occupied a unique place in the management of significant neonatal hyperbilirubinemia.

Single‐volume BET (80‐90 mL/kg of blood volume) or double‐volume BET (160‐180 mL/kg of blood volume) can be done by a central or peripheral route by means of the push‐pull technique through the umbilical vein, or as an isovolumetric exchange transfusion with peripheral arterial access used to pull out the patient's blood, and a peripheral venous access used for simultaneous infusion of donated blood. The volume of aliquots for each cycle of BET is variable and depends on weight, gestational age, and cardiovascular status of the infant. Often, the aliquot volume used is 5 to 10 mL/kg body weight (Watchko 2012). Blood exchange transfusions are most readily performed via the umbilical venous route with a 4 to 8 French umbilical catheter inserted just far enough to obtain free flow of blood. The push‐pull technique with a single syringe and a four‐way stopcock assembly requires a single operator to complete the procedure (Watchko 2012). The whole procedure must be performed with continuous monitoring of vital signs, temperature regulation, asepsis, and correct position of the catheter. The entire procedure ideally should be completed within 60 to 90 minutes, with about 30 to 35 cycles of completed isovolumetric infusions and withdrawals.

Several studies have reported that in neonates, BET provided via peripheral vessels is an effective and safe alternative to BET provided by the umbilical venous route (Campbell 1979; Chen 2008; Raichur 1999).

Choice and use of donor blood

The medical decision to select donor blood type is dependent on mother‐infant blood and Rh grouping. Fresh citrate‐phosphate‐dextrose blood (< 72 hours old) is usually preferred to avoid the risk of neonatal hyperkalemia. Reconstitution of packed red blood cells (RBCs) and fresh frozen plasma (3:1) is conducted in the blood bank and ideally is performed within a closed system to ensure asepsis and an optimal hematocrit for donor blood. Before transfusion, donor blood should be tested for infection (hepatitis, CMV, malaria, etc.), and only irradiated donor blood should be used to prevent graft‐versus‐host disease (Dwyre 2008). Blood should be warmed to body temperature before transfusion.

How the intervention might work

Although BET has been used traditionally to treat neonates with hyperbilirubinemia, indications for use of this procedure have expanded over time. Blood exchange transfusion performed in experimental studies on two different animal models has been found to be a useful procedure for treatment of individuals in endotoxin shock (through removal of bacterial toxins such as circulating cytokines and other inflammatory molecules) (Levinson 1972; Nakamura 1976). Delivoria‐Papadopoulos et al have suggested the effectiveness of BET with fresh blood in improving the oxygenation of organs and tissues of the body by improving circulation and shifting the oxygen dissociation curve to the right (Delivoria‐Papadopoulos 1971; Delivoria‐Papadopoulos 1976).

Studies have reported that BET with fresh anticoagulated blood increases serum opsonic activity in septic neonates (Belohradsky 1978); increases serum immunoglobulin (Ig)G, IgA, and IgM levels (Sadana 1997; Vain 1980); and improves pulmonary perfusion and ventilation in low birth weight infants (Gottuso 1976). This procedure helps replenish neutrophils in neutropenic infants (Mathur 1993); increases platelet counts and clotting factors; enhances humoral and cellular inflammatory responses; and decreases the requirement for oxygen and assisted ventilation (Vain 1980). Gross and Melhorn have demonstrated that BET with citrated blood is a readily available, effective, and safe means of treating patients with disseminated intravascular coagulation (Gross 1971).

However, as of now, BET is an experimental adjuvant therapy for neonatal septicemia that is often used only in poorly responding fulminant cases.

Adverse effects of BET

Blood exchange transfusion is an invasive procedure that has been associated with an extensive list of complications related to the use of blood products (infection, hemolysis of transfused blood, thromboembolization, graft‐vs‐host reaction, etc.), as well as metabolic derangement, cardiorespiratory compromise, and other miscellaneous complications (Edwards 1993; Watchko 2000). The complications most commonly related to BET procedures are thrombocytopenia (platelet count < 100,000) and hypocalcemia (Jackson 1997; Patra 2004). In a retrospective chart review of 107 patients who underwent 141 single‐ or double‐volume exchange transfusions from 1986 to 2006, Steiner reported that the overall BET‐related adverse event rate including hypocalcemia and thrombocytopenia was up to 73% (Steiner 2007). Necrotizing enterocolitis (NEC) is one of the major life‐threatening complications associated with BET (Campbell 1979; Hovi 1985; Jackson 1997; Palmer 1983). In a large case series of jaundiced infants, including 248 umbilical venous BET procedures for hyperbilirubinemia, Guaran reported two deaths due to necrotizing enterocolitis after a BET procedure (Guaran 1992). Studies have reported significant hypotension during BET (Aranda 1977; Gupta 1965; Wallgren 1964; Young 1966). Among a total of 81 umbilicus venous BET procedures, Jackson reported 21 cases of catheter malfunction (Jackson 1997). In a study of BET via peripheral vessels, Chen reported adverse events such as catheter malfunction, transient ischemic changes, and suspected occlusion of radial arteries (Chen 2008). Other complications associated with the BET procedure include portal vein thrombosis; portal hypertension (Yadav 1993); hypoglycemia (Jackson 1997; Vain 1980); hyponatremia (Jackson 1997); desaturation episodes (percutaneous oxygen < 90 mmHg) leading to severe apnea; bradycardia with cyanosis (Chen 2008); cardiac dilation, pericardial effusion, and hydrothorax (Weldon 1968); bilateral pulmonary edema (Singh 1969); metabolic acidosis (Patra 2004); and cardiac arrhythmia and air embolism (Boggs 1960; Dincsoy 1982; Nelson 1988; Vain 1980). Moreover, BET always carries some risk of infection (Aranda 1977; Jackson 1997), including acute omphalitis and purpuric eruptions (Chen 2008; Jackson 1997; Weldon 1968).

Among 106 BET procedures performed for hyperbilirubinemia, Jackson reported that the rate of severe complications observed in ill infants undergoing BET (12%; 3/25) was significantly greater (P < 0.05) than that observed in healthy infants receiving BET (1.2%; 1/81) (Jackson 1997).

The mortality rate attributable to the BET procedure has been reported as 0.4% to 8% in various studies. This rate was reported as 0.65% to 3.2% during the 1960s (Boggs 1960; Kitchen 1970; Panagopoulos 1969; Weldon 1968); 0.4% to 3.2% during the 1970s and the 1980s (Dikshit 1989; Guaran 1992; Hovi 1985); approximately 2.8% in the 1990s (Narang 1997); and up to 8% between 2000 and 2010 (Chitty 2013).

Why it is important to do this review

Neonatal sepsis is a frequent and serious event associated with varying degrees of multiorgan dysfunction, including consumption coagulopathy. Although few studies have reported a reduction in mortality in neonatal sepsis with the use of BET, no definitive recommendations have been provided on use of the BET procedure in neonates with septicemia. The primary aim of this review is to assess and systematically compile available evidence from randomized and quasi‐randomized trials comparing the efficacy of BET versus no BET to guide clinicians on use of this procedure for optimal management of neonatal septicemia, and to ascertain potential risks associated with this procedure.

Objectives

To determine the efficacy of BET versus no BET in reducing the all‐cause mortality rate in neonates (up to 28 days of age) with septicemia, and to ascertain clinically important adverse effects associated with the BET procedure.

If we can procure sufficient data, we plan to perform the following subgroup analyses.

  • Term versus preterm neonates (term defined as infants ≥ 37 weeks' gestation, and preterm as < 37 weeks' gestation).

  • Early‐onset (systemic infection ≤ 48 hours of age) versus late‐onset (systemic infection > 48 hours of age) sepsis.

  • Single‐volume versus double‐volume exchange transfusion.

  • Infants with severe sepsis versus infants with less severe manifestations of sepsis.

Methods

Criteria for considering studies for this review

Types of studies

We will include in this review randomized, quasi‐randomized, and cluster‐randomized trials comparing the efficacy of BET versus no BET in reducing the all‐cause neonatal mortality rate among neonates with septicemia.

Types of participants

Neonates (up to 28 days of age) of any gestational age or birth weight with confirmed or suspected sepsis who are being treated with antimicrobials.

  • Confirmed sepsis is defined as clinical sepsis (signs and symptoms consistent with infection) that is microbiologically proven (positive blood culture).

  • Suspected sepsis is defined as clinical sepsis without isolation of a causative organism.

  • Severe sepsis is defined as clinical sepsis, along with evidence of organ dysfunction (need for mechanical ventilation; hypotension or perfusion abnormalities, or need for inotrope or vasopressors; signs of dysfunction of two or more organs ‐ liver, renal, coagulation, neurological or hematological abnormalities, etc.).

Types of interventions

Comparison of BET versus no BET as adjunctive treatment, along with standard intravenous antibiotic therapy (antibiotic therapy of any kind depending on infant's postnatal age, gestational age, clinical condition, and laboratory parameters, and the antibiotic policy of the hospital), in the management of neonatal septicemia. We will include both single‐volume and double‐volume BETs.

Blood exchange transfusion is defined as any procedure in which whole blood was removed from the circulation and was replaced with fresh whole blood or diluted packed red blood cells.

Types of outcome measures

Primary outcomes

  • All‐cause neonatal mortality (during initial hospital stay and up to 28 days' postnatal age)

Secondary outcomes

  • Sepsis‐related mortality (death attributed to sepsis or its complications, including disseminated intravascular coagulation, refractory shock, multiorgan dysfunction, severe pneumonia, necrotizing enterocolitis, etc.) up to 28 days' postnatal age

  • Duration of hospital stay (days)

  • Adverse effects of BET

    • Thrombocytopenia (defined as platelet count < 150,000/mm3) (Chavda 2012)

    • Hypocalcemia (defined as total serum calcium concentration < 7 mg/dL, or as an ionized calcium concentration < 4 mg/dL (1 mmol/L)) (Abrams 2008)

    • Necrotizing enterocolitis (NEC) (defined as an acute gastrointestinal disorder that manifests clinically with systemic signs (temperature instability, apnea, bradycardia, lethargy, hypotension, metabolic acidosis, hyponatremia, thrombocytopenia, disseminated intravascular coagulation, etc.), intestinal signs (feed intolerance, gastrointestinal bleeding, abdominal tenderness, abdominal wall cellulitis, abdominal distention, etc.), and radiological features (nonspecific intestinal dilation and ileus in stage I, pneumatosis intestinalis and air in the portal tree in stage II, or pneumoperitoneum in stage III), and pathologically with intestinal necrosis} (Bell 1978; Walsh 1986)

    • Metabolic acidosis (defined as arterial or capillary pH < 7.25 and base excess worse than ‐6 mmol/L)

    • Air embolism (diagnosed as cutaneous blanching, air in intravascular catheters, an air‐filled heart and vessels on chest roentgenogram, etc.) (Carlo 2011)

    • Cardiac arrhythmia (defined as abnormal rhythm on electrocardiogram)

    • Hypotension (defined as blood pressure < 10th percentile that is appropriate for gestation and postnatally) (Nuntnarumit 1999)

    • Desaturation episode (defined as oxygen saturation as measured by pulse oximeter < 85%)

    • Adverse effects not predefined by us but reported by study authors

  • Duration of antibiotic therapy in days (counted from the day antibiotics were started for the sepsis episode for which BET was done up to the day when antibiotics were stopped because the infant was declared sepsis free or the infant died)

  • Long‐term neurological morbidity (long‐term outcome will be reported for all studies that have evaluated children between 18 and 24 months' or later postnatal age. Major neurological morbidity will include cerebral palsy and developmental delay (Baley or Griffith assessment > 2 standard deviations (SDs) below the mean) or intellectual impairment (intelligence quotient (IQ) > 2 SDs below the mean), blindness (vision < 6/60 in both eyes), and sensorineural deafness (requiring amplification)

Search methods for identification of studies

We will use the standard search strategy of the Cochrane Neonatal Review Group, as outlined in the Cochrane Library.

Electronic searches

We will search the Cochrane Central Register of Controlled Trials (CENTRAL, in the Cochrane Library) and PubMed (1966 to current) using the medical subject heading (MeSH) terms infant‐newborn AND bacteraemia/sepsis AND exchange transfusion, whole blood. We will additionally search clinical trial registries (clinicalTrial.gov, controlled‐trials.com) and will apply no language restrictions.

Searching other resources

  • Reference lists from the above, and from review articles

  • Personal communication with primary study authors from the above to retrieve unpublished data related to published articles

  • Proceedings of annual meetings of the European Society for Paediatric Research and the Society for Pediatric Research: handsearches of abstracts (up to and including 2014)

Data collection and analysis

We will use the standard methods of the Cochrane Neonatal Review Group when performing data collection and analysis.

Selection of studies

Two review authors will independently examine the title and abstract of each retrieved study to assess eligibility. In cases of uncertainty, we will retrieve the full paper and will examine it to evaluate the methodological quality of the study and to consider the trial for inclusion.

Data extraction and management

Two review authors will independently obtain data from the study (text or electronic assessment) using a data collection form. We will resolve differences in interpretation by discussion with the other review authors.

Assessment of risk of bias in included studies

We will use the standard methods of the Cochrane Neonatal Review Group to assess the methodological quality of studies. All review authors will independently assess risk of bias for each study using criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We will resolve disagreements by discussion among all review authors. We will assess the methodological quality of studies using the following criteria.

Sequence generation (selection bias)

For each study, we will assess the method of sequence generation as:

  • low risk: when sequences were generated using a true randomisation process;

  • high risk: when any nonrandom process was used for sequence generation; or

  • unclear risk: when the method of sequence generation is unclear.

Allocation concealment (selection bias)

For each study, we will assess the method of allocation concealment as:

  • low risk: when adequate methods were used for allocation concealment (eg, consecutively numbered sealed, opaque envelopes);

  • high risk: when allocation concealment was inadequately done; or

  • unclear risk: when the method of allocation concealment is unclear.

Blinding (performance bias and detection bias)

For each study, we will categorize the methods used to blind study participants and personnel from knowledge of which intervention a participant received. We will assess the process of blinding separately for different outcomes and will categorize methods as:

  • low risk, high risk or unclear risk for participants;

  • low risk, high risk or unclear risk for personnel; and

  • low risk, high risk or unclear risk for outcome assessors.

Incomplete outcome data (attrition bias)

For each study, we will examine the completeness of data including attrition and exclusion from analysis. We will note whether attrition and exclusions were reported, numbers included in the analysis at each stage (compared with the total number of randomized participants), whether reasons for attrition or exclusion were reported, and whether missing data were balanced across groups or were related to outcomes. We will categorize the method as:

  • low risk: < 20% missing data;

  • high risk: ≥ 20% missing data; or

  • unclear risk.

Selective reporting (reporting bias)

For each study, we will investigate the possibility of selective outcome reporting and will categorize the method as:

  • low risk: when all prespecified study outcomes and expected outcomes of interest were reported;

  • high risk: when not all prespecified study outcomes were reported or one or more primary outcomes were not prespecified; or

  • unclear risk: when information provided is unclear.

Other source of bias

For each included study, we will describe our concerns about other possible sources of bias. On the basis of potential sources of bias, we will describe the included study as:

  • low risk;

  • high risk; or

  • unclear risk.

Measures of treatment effect

We will use risk ratio (RR) or risk difference (RD) for dichotomous data, and mean difference (MD) or standardized mean difference (SMD) for continuous data (when outcome measurements in all studies are made on the same scale, we will use MD; when all studies assess the same outcome but measure it in a variety of ways, we will use SMD). We will calculate the number needed to treat for an additional beneficial outcome (NNTB) and the number needed to treat for an additional harmful outcome (NNTH) for significant differences and will use 95% confidence intervals (CIs) for all estimates. When possible, we will perform intention‐to‐treat (ITT) analysis.

Unit of analysis issues

The unit of analysis will be the individual participant. We will appropriately adjust data obtained from cluster trials for clustering (as per guidelines of the Cochrane Handbook for Systematic Reviews of Interventions).

Dealing with missing data

We will try to contact the original study authors to obtain details of any missing data.

Assessment of heterogeneity

We will assess all eligible studies for variability in participants, interventions, and outcomes studied (clinical heterogeneity) and for variability in study design and risk of bias (methodological heterogeneity). Two review authors will recheck variability in intervention effects evaluated in different studies (statistical heterogeneity) and will explore other causes of heterogeneity. We will use the I2 statistic (< 25% none, 25%‐49% low, 50%‐74% moderate, and 75%+ high heterogeneity) in measuring heterogeneity.

Assessment of reporting biases

We will conduct a comprehensive search of eligible study protocols from prospective clinical trial registries and conference proceedings to decrease reporting bias and will use funnel plots to investigate publication bias.

Data synthesis

We will synthesize data using the fixed‐effect model and will use RR, RD, NNTB, NNTH, WMD, SMD, and 95% CIs as per applicability.

Quality of evidence

We will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the quality of evidence for the following (clinically relevant) outcomes.

  • All‐cause neonatal mortality (during initial hospital stay and up to 28 days' postnatal age).

  • Sepsis‐related mortality (death attributed to sepsis or its complications, including disseminated intravascular coagulation, refractory shock, multiorgan dysfunction, severe pneumonia, necrotizing enterocolitis, etc.) up to 28 days' postnatal age.

  • Duration of hospital stay (days).

  • Long‐term neurological morbidity (long‐term outcome will be reported for all studies that have evaluated children between 18 and 24 months' or later postnatal age). Major neurological morbidity will include cerebral palsy and developmental delay (Baley or Griffith assessment > 2 SDs below the mean) or intellectual impairment (IQ > 2 SDs below the mean), blindness (vision < 6/60 in both eyes), and sensorineural deafness (requiring amplification).

Two review authors will independently assess the quality of the evidence for each of the outcomes above. We will consider evidence from randomized controlled trials as high quality but will downgrade the evidence one level for serious (or two levels for very serious) limitations on the basis of the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates and presence of publication bias. We will use the GRADEpro Guideline Development Tool to create a "Summary of findings" table to report the quality of the evidence.

The GRADE approach results in an assessment of the quality of a body of evidence according to one of four grades.

  • High: We are very confident that the true effect lies close to that of the estimate of effect.

  • Moderate: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of effect but may be substantially different.

  • Low: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of effect.

  • Very low: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Subgroup analysis and investigation of heterogeneity

Subgroup comparisons will include:

  • term versus preterm neonates;

  • early‐onset versus late‐onset sepsis;

  • single‐volume versus double‐volume exchange transfusion; and

  • infants with severe sepsis versus infants with less severe manifestations of sepsis.

Sensitivity analysis

We will perform sensitivity analysis according to the methodological quality of included studies.

Acknowledgements

None.

Contributions of authors

Satish Mishra, Cheema Aminderjit, Deepak Chawla, and Ramesh Agarwal participated in preparing the protocol.

Sources of support

Internal sources

  • None, Other.

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA.

    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201600005C.

Declarations of interest

All review authors declare that they have no conflicts of interest.

New

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