Recommendations for the transfusion management of patients in the peri-operative period. II. The intra-operative period

Introduction

Elective surgery is the most common cause of major bleeding, that is, loss of 20% or more of the volume of blood; cardiovascular surgery and orthopaedic operations (hip and knee replacements, spinal surgery), as well as liver transplants and resections are particularly strongly associated with substantial intra-operative bleeding¹.

Post-partum haemorrhage is an important cause of maternal morbidity and mortality². Primary postpartum haemorrhage is defined by the World Health Organization as the loss of more than 500 mL of blood in the first 24 hours after delivery^3,4.

Management of the patient in the intra-operative period

The correct intra-operative management of the patient includes evaluation and monitoring of the following parameters⁵:

1. amount of blood lost;

2. haemoglobin (Hb) or haematocrit (Htc);

3. signs of inadequate perfusion and oxygenation of the vital organs;

4. platelet count;

5. prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, antithrombin (AT), D-dimer.

The evaluation of blood loss should be based on the volume of blood removed from the surgical field by aspirators and that absorbed by gauzes and swabs.

This estimate can be difficult in obstetric cases if the blood lost remains within the uterus, in the broad ligament or in the peritoneal cavity, with modest or no signs of external bleeding: it is, therefore, suggested that particular attention should be paid to evaluating clinical signs of haemorrhagic shock (Grade of recommendation: 2C)⁶.

It has also been suggested that the evaluation of the patient is targeted to detect the presence of abnormal microvascular bleeding, a sign of coagulopathy (Grade of recommendation: 2C)⁵.

The intracellular partial pressure of oxygen (pO₂) represents the decisional parameter “of choice” for evaluating tissue hypoxia^7–9; it cannot, however, be used in clinical practice and for this reason Hb and Htc, which are “surrogate” parameters, are used¹⁰.

Tissue oxygenation depends on various factors¹⁰:

• - the concentration of Hb;

• - the saturation of Hb, which in its turn is dependent on the oxygen (O₂) tension and the affinity of Hb for O₂;

• - the demand for O₂, that is, the volume of O₂ necessary for tissues to carry out their aerobic function.

The physiological mechanisms of adaptation to anaemia (increased cardiac output, increased coronary artery blood flow, redistribution of blood flow, increased O₂ extraction, increased red blood cell 2,3-diphosphoglycerate) can be affected by^7,10–16:

• - limited increase in the cardiac output: hypovolaemia, coronary artery disease, disorders of heart valves, congestive heart disease, negative inotropes;

• - impaired ability to increase O₂ extraction: acute respiratory distress syndrome (ARDS), sepsis, systemic inflammatory response syndrome (SIRS), syndrome of ischaemia-reperfusion injury;

• - altered gas exchange: chronic obstructive pulmonary disease (COPD), ARDS;

• - increased O₂ consumption: fever, pain, stress, sepsis, SIRS, hyperventilation syndromes.

The platelet count is one of the decisional parameters for platelet transfusion, along with the clinical evaluation of the patient (Grade of recommendation: 2C)^17–19.

PT and aPTT are fundamental laboratory parameters which, in the presence of haemorrhage, guide the therapeutic decision regarding transfusion of fresh-frozen plasma (FFP)¹⁸.

The diagnosis of disseminated intravascular coagulation (DIC) can be made or excluded on the basis of an integrated dynamic evaluation of the clinical picture, laboratory data [PT, aPTT, fibrinogen, AT, D-dimer] and of the patient’s underlying pathology (Grade of recommendation: 2C)²⁰.

In the case of suspected DIC, the fibrinogen level should be measured by the Clauss method (Grade of recommendation: 2C+)^20–22.

Physiological transfusion threshold

Table I shows the clinical and instrumental parameters that, in the anaemic and normovolaemic patient, are indicative of inadequate perfusion and oxygenation of vital organs (physiological transfusion triggers)^23–27.

Table I.

Clinical and instrumental parameters indicative of hypoxia in the anaemic, normovolaemic patient^27§.

Cardiopulmonary symptoms - Tachycardia* - Hypotension** - Acute hypotension of unknown origin - Dyspnoea Electrocardiographic signs typical of ischaemia - Newly occurring ST segment elevation or depression - Onset of arrhythmias - Newly occurring localised altered contractility of the myocardium Global indices of insufficient O2 release, evaluated by invasive methods - Increase in overall O2 extraction greater than 50% - Reduction of O2 uptake by more than 10% of the initial value - Reduction of mixed venous O2 saturation to below 50% - Reduction of peripheral mixed venous pO2 to below 32 mmHg - Reduction of central venous O2 saturation to below 60% - Lactate acidosis (lactates >2 mmol/L + acidosis)

Notes

^§:At term, pregnant women have about a 45% increase (about 1.5 L) in blood volume, with a greater increase in plasma than in red blood cells, leading to the so-called haemodilution anaemia of pregnancy which reduces the Htc by about 10%⁶.

^*:Tachycardia may already be present at baseline in pregnant women or develop as the result of an infusion of a tocolytic⁶.

^**:Placental perfusion in patients with hypertensive disorders during pregnancy, such as pre-eclampsia or haemolytic anaemia with elevated liver enzymes and low platelet count (HELLP) syndrome, can be inadequate at blood pressure values tolerated by other patients because of the increased peripheral resistance⁶.

Effect of anaesthesia on the cardiovascular response to acute anaemia

Acute normovolaemic anaemia in the conscious patient causes a physiological increase in cardiac output through effects of both increased systolic volume and heart rate^15,28–31; in the anaesthetised patient, on the other hand, cardiac output only increases as a result of an increase in systolic volume^{15,30,32–35} and, for this reason, the onset of tachycardia, or a further increase in already existing tachycardia in pregnant women (in whom it is already present at baseline)⁶, in the presence of acute anaemia is an indicator of hypovolaemia, which must be corrected with crystalloids/colloids^10,15.

The monitoring of adequate perfusion and oxygenation of vital organs should normally be based on evaluations of arterial blood pressure, heart rate, body temperature, O₂ saturation, pH, volume of urine and electrocardiographic traces but, in particular conditions, may be based on the evaluation of echocardiographic findings, mixed venous O₂ saturation or blood-gas analyses (Grade of recommendation: 2C)⁵.

Fluid therapy to restore intravascular blood volume

The main therapeutic strategy in the treatment of acute haemorrhage is to prevent or correct hypovolaemic shock¹⁰. In order to ensure tissue oxygenation it is essential to restore the circulating blood volume by an infusion of crystalloids/colloids, in sufficient amounts to maintain adequate blood flow and blood pressure.

Crystalloid and non-protein colloid solutions are the treatment of first choice^36–39; 5% albumin is used as a second choice when crystalloid and non-protein colloids have already been used at maximum doses, without having produced an adequate clinical response and in cases in which non-protein colloids are contra-indicated (Grade of recommendation: 1A)^36–39.

Albumin 5% and saline are clinically equivalent in terms of mortality and morbidity outcomes at 28 days in restoring intravascular blood volume in patients in intensive care⁴⁰.

A meta-analysis in 2008 concluded that all colloids are equally safe⁴¹, without, however, excluding clinically significant differences between albumin and dextran.

Care is recommended when using artificial colloids in patients with impaired renal function (Grade of recommendation: 1C+)^42,43.

High molecular weight hydroxyethyl starch solutions should not be used, in order to avoid alterations in haemostatis due to impaired platelet function (Grade of recommendation: 1C+)^44–50.

Transfusion therapy

Effect of bleeding on haemostasis

Intra-operative transfusion support is aimed at correcting acute anaemia and treating clotting disorders and secondary forms of thrombocytopenia⁵. In fact, a massive, acute haemorrhage can cause hypovolaemic shock with consequent tissue hypoxia, acidosis, hypothermia and a systemic inflammatory response, which can trigger DIC⁵¹.

Furthermore, the reduction of the Htc can “mechanically” affect platelet function, because it shifts blood flow towards the centre of the vessel’s lumen and reduces the interactions between the platelets themselves and the endothelium⁵¹; anaemia also acts on haemostasis, causing vasodilatation and inhibition of platelet function because of reduced production of adenosine-diphosphate and thromboxane and the lesser availability of Hb to eliminate nitric oxide⁵¹.

The available blood components and plasma-derived drugs

The blood components that can be used for transfusion support are whole blood from predeposit or pre-operative normovolaemic haemodilution, autologous red cell concentrates (RCC), derived from predeposit or intra-operative salvage, allogeneic RCC and platelet concentrates, allogeneic or autologous FFP and cryoprecipitate and allogeneic or autologous blood components for topical use (fibrin glue)^17,52,53; the plasma-derived drugs that can be used are albumin, AT and fibrinogen.

The pools of platelet concentrates from single units of whole blood and the platelet concentrates from apheresis contain approximately the same amount of platelets; comparative studies have shown that they are equivalent in terms of post-transfusion platelet increment and haemostatic efficacy, if transfused fresh, and also with regards incidence of side effects (Grade of recommendation: 1A)^48,54–58.

Likewise, FFP prepared from units of whole blood and that obtained by apheresis are equivalent in terms of haemostasis and side effects (Grade of recommendation: 1A)⁵⁹.

In cardiovascular surgery, the routine use of apheresis procedures in the immediate pre-operative period, in order to produce platelet concentrates or units of FFP from apheresis is not recommended because the documented superiority of benefits compared to the possible risks for the patient is marginal, because it is often impossible to produce therapeutic doses of autologous blood components and because of the costs of the procedure itself (Grade of recommendation: 1C+)^60–70.

Transfusion therapy of acute anaemia

The decision to transfuse allogeneic or autologous RCC or autologous whole blood in the intra-operative period depends on the concentration of Hb, the amount and speed of the blood loss and the clinical condition of the patient, in particular whether he or she is showing signs and symptoms of reduced local or general oxygenation (Table I)^{5,8,10,15,23–27,71–94}.

Rapid measurement of haematological parameters (Hb and Htc) by “point of care” (POC) analysers can raise the margins of safety and optimise transfusion support⁸². It is recommended that the POC instruments used for this purpose are automated systems that do not require the dilution of whole blood during the preanalytic phase (Grade of recommendation: 1C+)⁹⁵.

A loss of less than 15% of the blood volume does not usually produce symptoms or require transfusion, providing there is not pre-existing anaemia (Table II) (Grade of recommendation: 1C+)^{10,73,76,80,81,85,91,96}.

Table II.

Decisional criteria for transfusion in acute anaemia.

Class of haemorrhage	Reduction of volaemia %	Blood loss (mL)*	Indication for transfusion of RCC	GoR
Class I	<15%	<750	Non necessary, if no pre-existing anaemia	1C+
Class II	15–30%	750–1,500	Non necessary, unless pre-existing anaemia and/or cardiopulmonary disease	1C+
Class III	30–40%	1,500–2,000	Probably necessary	1C+
Class IV	>40%	>2,000	Necessary	1C+

Legend: RCC: red cell concentrate; GoR: grade of recommendation

*: in an adult person weighing 70 kg and with a circulating blood volume of 5,000 mL

When there is a loss of between 15% and 30% of the blood volume, compensatory tachycardia occurs and transfusion is indicated only in the presence of pre-existing anaemia or concomitant cardiopulmonary disease (Table II) (Grade of recommendation: 1C+)^{10,73,76,80,81,85,91,96,97}.

Blood losses of more than 30% can cause shock and, when the blood loss exceeds 40%, the shock becomes severe. The probability of having to use transfusion therapy with red blood cells increases notably with losses of 30–40%, even though, in previously healthy subjects, volume replacement alone may be sufficient (Table II) (Grade of recommendation: 1C+)^{10,73,76,79,80,81,85,91,96}.

Transfusion becomes a life-saving therapy when more than 40% of the patient’s blood is lost (Table II) (Grade of recommendation: 1C+)^{10,73,76,79,80,81,85,91,96}.

Patients with acute haemorrhage can have normal, or even raised, values of Htc and Hb until the plasma volume is restored; in these cases, therefore, the clinical examination of the patient becomes extremely important (Grade of recommendation: 2C+)^{10,73,76,79 81,85,91,92,96,97}.

However, as a guide, Hb values below 60 g/L almost always indicate the need for transfusion therapy (Table III) (Grade of recommendation: 1C+)^{5,10,27,70,73,78–81,83–85,89,92,96,97}.

Table III.

Indications for transfusion therapy with RCC in patients with acute anaemia.

Hb values	Presence of risk factors/mechanisms of compensation	TT with RCC	GoR
≤ 60 g/L	Transfusion therapy is almost always necessary*	YES*	1C+
60–80 g/L	Absence of risk factors/adequate mechanisms of compensation	NO	1C+
	Presence of risk factors (for example, coronary arterydisease, heart failure, cerebrovascular disease/limited mechanisms of compensation)	YES	1C+
	Presence of symptoms indicative of hypoxia (physiological transfusion triggers: tachycardia, hypotension, electrocardiographic signs of ischemia, lactic acidosis, etc.)	YES	1C+
80–100 g/L	Presence of symptoms indicative of hypoxia (physiological transfusion triggers: tachycardia, hypotension (physiological transfusion triggers: tachycardia, hypotension, electrocardiographic signs of ischemia, lactic acidosis, etc.)	YES	2C
>100 g/L	Transfusion therapy is required extremely rarely**	NO**	1A

Notes

- Hb values do not guarantee an adequate measure of the capacity to release O₂ to tissues.

- In the presence of hypovolaemia the Htc does not reflect blood loss.

- The presence of individual risk factors may make it necessary to use transfusion triggers other than those indicated.

Legend: RCC: red cell concentrate; GoR: grade of recommendation; TT, transfusion therapy.

^*:Values of Hb below 60 g/L can be tolerated provided an evaluation of the individual patient has excluded risk factors and inadequate mechanisms of compensation;

^**:The individual patient must be evaluated to establish whether transfusion therapy is indicated to raise the values of Hb above 100 g/L.

In stable patients with Hb values between 60 and 100 g/L, an evaluation of the patients’ clinical status is necessary (Table III) (Grade of recommendation: 1C+)^{5,10,27,70,73,78–81,83–85,89,92,96,97}.

It is very rarely necessary to transfuse patients whose Hb concentration is higher than 100 g/L (Table III) (Grade of recommendation: 1A)^{5,10,27,70,73,78–85,89,92,96,97}.

Inappropriate indications

Inappropriate indications for the use of RCC or whole blood in the intra-operative period are¹⁰:

• - anaemia with a Hb above 100 g/L (in the absence of specific risk factors related to the patient’s clinical characteristics);

• - expansion of the blood volume.

Adverse events

Transfusion therapy with RCC or whole blood can cause adverse events which are classified according to their aetiopathogenesis and the time of onset with respect to the transfusion¹⁰.

1. Immediate reactions with an immunological mechanism:

   • - acute haemolytic reactions;
   • - non-haemolytic febrile reactions;
   • - allergic reactions (anaphylaxis, urticaria);
   • - non-cardiogenic acute pulmonary oedema (Transfusion-Related Acute Lung Injury - TRALI), which develops within 6–8 hours after the transfusion.
2. Delayed reactions with an immunological mechanism:

   • - delayed haemolytic reactions;
   • - Graft-versus-Host Disease;
   • - post-transfusion purpura;
   • - alloimmunisation.
3. Immediate reactions with a non-immunological mechanism:

   • - reactions to bacterial contamination;
   • - circulatory overload;
   • - non-immunological haemolysis.
4. Delayed reactions with a non-immunological mechanism:

   • - iron overload;
   • - post-transfusion infections: viral or protozoan (in particular malaria) diseases are possible, but very rare.

Acute normovolaemic haemodiluition

Acute normovolaemic haemodilution is an autotransfusion procedure that was introduced in the 1970s^98–100. It consists in removing at least three or four units of autologous blood while maintaining isovolaemia immediately before elective surgery^{16,66,101–104}.

Volaemia should be maintained by infusing crystalloids at a dose of 2–3 mL for every 1 mL of blood removed, or colloids, at a 1:1 ratio with the volume of the blood removed (Grade of recommendation: 2C)¹⁰³.

Acute normovolaemic haemodilution is generally performed after the induction of anaesthesia¹⁰¹, immediately before the surgical incision¹⁰⁵. The responsibility for managing this activity and other procedures that do not involve the storage of blood components, such as intra-operative and post-operative blood salvage, is usually that of the anaesthetists^53,66,106.

Candidates for acute normovolaemic haemodilution must have Hb values at least near the upper limit of the norm, must fulfil the same clinical criteria as those for suitability for autologous predeposit^66,103 and the predicted blood loss during the operation must be more than 50% of the circulating volume or, at any rate, not less than 1,500 mL (Grade of recommendation: 1C+)^{16,27,82,101–104,107–109}.

The rationale of acute normovolaemic haemodilution is to reduce the Htc before the intraoperative bleeding, in order to limit the loss of red blood cells¹⁰³. The efficacy of acute normovolaemic haemodilution in reducing the need for allogeneic blood transfusion does, however, remain doubtful¹¹⁰. Various clinical studies, including prospective randomised ones, have demonstrated that acute normovolaemic haemodilution can reduce the use of allogeneic transfusion therapy in patients undergoing elective heart surgery, orthopaedic surgery (knee replacements), abdominal, vascular, urological, maxillo-facial and hepatic operations and even in patients undergoing surgery for burns^111–122; other studies, however, did not show any substantial benefit or even found an increased use of allogeneic blood^123–125.

The doubts on the real benefits of this procedure were further reinforced by some meta-analyses^126–129. The relative risk of receiving allogeneic blood at any peri-operative moment were not, in fact, significantly reduced by using acute normovolaemic haemodilution and, likewise, there was no reduction in a comparison of acute normovolaemic haemodilution with other pharmacological techniques for blood saving, such as tranexamic acid which, in elective orthopaedic surgery, was found to be more effective than acute normovolaemic haemodilution in containing the use of allogeneic transfusion^128,130. The relative risk of allogeneic transfusion was not reduced significantly in relation to the degree of haemodilution used, the type of surgery (orthopaedic, cardiac, urological, thoracic or vascular operations), the Htc taken as the transfusion threshold, the number of patients enrolled in the studies analysed or the year in which these were performed; indeed, the strategy seemed to be less effective in the more recent studies¹²⁸. As regards secondary outcomes, such as intra-operative and post-operative bleeding and the incidence of adverse events, acute normovolaemic haemodilution reduced total bleeding (weighted mean difference = 91 mL), but increased intra-operative bleeding in heart surgery, liver surgery and thoracic surgery^{115,128,131–133}; furthermore, there are reports of an increase in the relative risk of repeat surgery because of bleeding¹³⁴, as well as a general lack of information on the safety of the procedure^{126,128,129,134}.

The use of acute normovolaemic haemodilution cannot be recommended as a routine method for sparing the use of allogeneic blood (Grade of recommendation: 1A)^{70,104,126–129}.

Acute normovolaemic haemodilution could be used in selected groups of patients (those with rare blood groups or multiple alloimmunisation), in whom it is absolutely necessary to avoid giving an allogeneic transfusion, and/or in the context of local protocols that integrate various different strategies (surgical, anaesthesiological, pharmacological) of saving blood (Grade of recommendation: 2B)^{70,102,104,110,126–129}.

Furthermore, it has been suggested that “restrictive” transfusion protocols should be adopted in order to reduce the exposure of patients to autologous and/or homologous transfusion therapy (Grade of recommendation: 1C+)¹³⁴.

Acute normovolaemic haemodilution may be taken into consideration in the management of Jehovah’s Witnesses, who can accept this technique provided that the blood removed remains within a closed circuit in continuity with the patient’s own blood circulation (Grade of recommendation: 2C)^102,135.

The autologous units must be collected using procedures that comply with current legislation⁵², must be identified unequivocally and should be maintained at room temperature for no more than 6 hours (Grade of recommendation: 1C+)^{27,66,101,103,104,136}.

The volume of blood to remove can be calculated using the formula proposed by Gross^{101,103,104,137}.

The units of blood should be re-infused in the reverse order from that of their withdrawal, since the first units have a higher Htc and greater content of clotting factors and platelets (Grade of recommendation: 2C)^{101,103,138,139}.

Whenever, for selected types of operation and patients, acute normovolaemic haemodilution is combined with intra-operative blood salvage (IOBS), the salvaged units of red cells should be reinfused first, followed by the units of whole blood from acute normovolaemic haemodilution (Grade of recommendation: 2C)^{101,103,138–140}.

Intra-operative blood salvage

IOBS is a blood-saving technique in which blood lost from the operating field is re-used; this blood is aspirated and anticoagulated before passing into a collection reservoir and from here, through filters for microaggregates of various diameter, into the bowl of the specific cell separators, to be concentrated by centrifugation and subsequently washed with saline before being reinfused into the patient^81,135,140. A higher degree of flow turbulence of blood aspirated from the operating field is a cause of haemolysis and can be the result of high suction pressures^{135,140–145}, or an incorrect method of aspiration (generation of foam, suction at the interface between blood and air, use of aspirators whose suction holes are too narrow)^135–140.

It is suggested that the pressure of suction of the blood from the operating field should be kept between 80 and 120 mmHg, avoiding levels higher than 150 mmHg, unless for brief periods to clear the operating field if rapid and unexpected bleeding occurs (Grade of recommendation: 2C)^{135,140–143,145}.

The formation of foam should be avoided during IOBS and the aspirator should be immersed directly in the blood; instruments with the widest possible suction holes should be used (Grade of recommendation: 2C)¹³⁵.

If the aspiration field is shallow and flat, as for example, in surgery of the vertebral column, the formation of foam during the aspiration and mechanical stress to red blood cells can be reduced by irrigating the surgical field with physiological saline (Grade of recommendation: 2C+)¹⁴⁶.

The blood recovered is anticoagulated with heparin, at a dose of 30,000 IU/L of saline, or with citrate-based solutions [citric acid/sodium citrate/dextrose (ACD), citrate/phosphate/dextrose/adenine (CPD-A)]; there is still controversy regarding the optimal anticoagulant^135,140. Both the anticoagulant solutions are generally used, through the aspiration systems, at a fixed ratio of 15 mL per 100 mL of blood aspirated^135,140,141.

The process of concentration by centrifugation of the bowls enables the plasma, platelets, and irrigating solutions to be removed, as well as 70–90% of the soluble contaminants present in the salvaged blood^110,140.

The subsequent washing with saline removes the remaining soluble contaminants and the socalled “biochemical debris”^{104,129,134,140,141,145,147} (fibrinogen and fibrin degradation products, D-dimer, tissue plasminogen activator, activated fibrinolysis products such as plasmin, components of the activated complement cascade such as C3a and C5a, cytokines, proteolytic enzymes, cardiac or other enyzmes, cell stroma and cell fragments, activated leucocytes, free Hb, bacteria and endotoxins, fat, anticoagulant solutions, metal ions and fragments deriving from orthopaedic prostheses) and prevents the onset of a broad range of complications (DIC, multiorgan failure, microembolism, acute renal failure, respiratory or circulatory failure, electrolyte disturbances, immunosuppression, thrombosis, haemorrhage)^{81,110,129,134,135,140,141,145,147–149}.

It is recommended that IOBS procedures are not used for autologous blood which will not be washed before reinfusion (Grade of recommendation: 1A)^{81,104,110,129,134,135,140,141,145,147–150}.

IOBS should be used with caution in orthopaedic revision surgery of metal-metal prostheses because of the possible contamination by Co or Cr ions or by metal particles, despite appropriate washing prior to reinfusion (Grade of recommendation: 2C)¹⁵¹.

The process of washing can generally be considered completed if the fluid exiting from the cell separator appears clear and transparent and the volume of fluid used for the washing (1–2 litres) is at least three times the volume of the bowl (Grade of recommendation: 2C)^104,140,145.

The Htc of autologous RCC obtained by IOBS depends on the washing programme used by the cell separator and can vary from 55% to 80%^16,104,152. The recirculation of blood salvaged and returned to the patient through IOBS makes it difficult to calculate the real blood loss that occurs during the surgical procedure¹³⁵. However, the following formula can be used to estimate this loss¹⁵³:

The accuracy of the calculation of blood loss depends on the efficiency of the collection. The efficiency of the IOBS varies depending on several factors including, mainly, the size of the suction holes of the aspirator, the precision of the operator responsible for the IOBS, the duration of the contact between the blood and the operating field; however, if the IOBS procedure is carried out carefully, its efficiency can reach 60–70%^135,140.

If the estimated collection efficiency is not considered reliable, using the same formula, the blood loss can in any case be determined to lie within a range between a minimum volume (maximum collection efficiency) and maximum volume (minimum collection efficiency)¹³⁵.

Autologous RCC obtained by IOBS are usually transfused immediately; in special circumstances they can be stored, for a maximum of 6 hours, at 4±2 °C, but must be identified unequivocally (Grade of recommendation: 1C+)^27,66,81.

Indications

IOBS may be indicated in many types of elective and emergency surgery, when blood loss is expected to be at least 800–1,000 mL of 20% of more of the patient’s circulating blood volume^16,154.

The fields of use (heart surgery, orthopaedic surgery, vascular surgery, emergency surgery, neurosurgery, obstetrics, cancer surgery [in selected cases], liver transplantation) should be identified according to local protocols that take into account the patients’ characteristics (haemorrhagic risk, multiple alloimmunisation) and expectations, type of operation, requirements of the surgical and anaesthetic teams, a cost-efficiency evaluation carried out in the setting of the individual hospital, as well as any local programmes aimed at achieving self-sufficiency in blood components (Grade of recommendation: 2C)¹⁴⁰.

IOBS can be taken into consideration in the management of Jehovah’s Witnesses, who can accept the technique provided that the blood collection circuit, the cell separator and the units of RCC salvaged remain within a closed circuit in continuity with the patient’s own blood circulation (Grade of recommendation: 2C)^16,155.

Heart surgery

Between 2004 and 2006, three systematic reviews analysed the role of intra- and post-operative blood recovery in reducing allogeneic transfusion needs in adults patients undergoing elective heart surgery, orthopaedic surgery and vascular surgery^129,134,150. In heart surgery and orthopaedic surgery the relative risk of receiving allogeneic transfusion therapy was reduced more by using IOBS procedures in which the blood returned was washed. The reduction in the relative risk of allogeneic transfusion in vascular operations was not statistically significant. The authors concluded that the use of blood salvage techniques that involve washing the collected blood is justified in heart surgery and in orthopaedic surgery, although the trials included in the reviews were not of high methodological quality and the number of patients enrolled was limited. The efficacy of the salvage decreased where the use of transfusion therapy was guided by specific guidelines and protocols.

A meta-analysis in 2009¹⁵⁶ confirmed that IOBS guarantees the safety and quality of the recovered blood¹⁵⁷ and significantly reduces the need for allogeneic transfusions during heart surgery; it is, therefore, recommended that this strategy is used for recovering blood lost throughout the operation, whether this involves beating heart surgery or for operations with cardiopulmonary bypass (before, during and after this), as well as for washing residual blood in the heart-lung machine in the case of cardiopulmonary bypass operations (Grade of recommendation: 1A)^{70,129,134,150,156,157}.

There are systems for aspirating blood that is shed into the thoracic cavity. Such systems, which were introduced in the 1960s, are designed to return the blood lost from the operating field into the cardiopulmonary bypass¹⁵⁸; given the principle on which they are based and the construction of the equipment, these systems are very haemolytic^159–161 and a possible cause of acute renal damage, thrombocytopenia and secondary platelet defects^162,163. Furthermore, the salvaged blood contains large amounts of cell debris and lipid microparticles^164,165, which, in animal models, are responsible for cerebral microemboli¹⁶⁶. The use of such blood, even when washed with a cell separator specific for IOBS, has been associated with greater bleeding in the post-operative period and a greater need for FFP^156,167,168.

It is, therefore, recommended that the use of blood recovered with suction systems from the operating field during cardiopulmonary bypass is limited to emergency circumstances, even if the blood is washed with a cell separator specific for IOBS (Grade of recommendation: 1C+)^70,156–168.

Other intra-operative techniques for saving blood during heart surgery

Retrograde priming of the cardiopulmonary bypass circuit with autologous blood (up to 1,100 mL) can be used as a complementary intra-operative method of saving blood (Grade of recommendation: 2B)^{70,105,169–176}. This strategy is used with the purpose of replacing the crystalloids used to fill the circuitry of the heart-lung machine and, thereby, avoid the risk of excessive haemodilution and minimise transfusion needs, particularly of patients with small intravascular blood volumes.

Beating heart surgery for coronary artery bypass, if feasible in the light of the patient’s characteristics and the experience of the surgical and anaesthetic team, is a recommended strategy for reducing the incidence of clotting disorders and transfusion needs, particularly if combined with IOBS (Grade of recommendation: 1C+)^{70,105,110,177–184}.

Orthopaedic surgery

The meta-analyses currently available show that both autologous predeposit and IOBS significantly reduce allogeneic transfusion needs in elective surgery^{129,149,150,185–194}; however, the use of predeposited blood leads to an increase in the total number of units (autologous and/or allogeneic) transfused^185,186.

The use of IOBS and the consequent reinfusion of washed RCC reduces the relative risk of receiving allogeneic transfusion therapy^129,134,150.

In major orthopaedic surgery, IOBS can be a cost-effective procedure and better than autologous predeposit in reducing allogeneic transfusion, especially if the predoposit, when indicated, is not carried out respecting optimal time intervals^187–195.

IOBS should be used in major orthopaedic surgery in all those cases in which the use of predeposit is not indicated, not practicable for religious reasons, or not possible with respect to the time needed for the patient’s haematological recovery: in these cases IOBS should be used, also on the basis of local protocols that include integrated recourse to other techniques of saving blood (pharmacological, surgical and anaesthesiological), taking into consideration the characteristics of the individual patients (haemorrhagic risk, multiple alloimmunisation) and the experience of the surgical and anaesthetic team (Grade of recommendation: 2C+)^{105,110,129,134,149,150,194–198}.

Vascular surgery

The use of IOBS in vascular surgery does not significantly reduce the relative risk of requiring allogeneic transfusion^129,134,150.

In abdominal vascular surgery (aorto-femoral bypass and infrarenal aneurysms of the abdominal aorta) there is not sufficient evidence to recommend systematic adoption of IOBS with the purpose of containing allogeneic transfusion needs¹⁹⁹. Observational or retrospective studies indicate that it can reduce the use of allogeneic transfusion and be cost-effective, particularly for operations with an intra-operative blood loss of ≥1,000 mL which allow the re-infusion of at least two or three units of RCC, or for emergency operations for a ruptured aneurysm, always on the basis of the pre-operative assessment of the individual patient carried out by the surgical team^200–203 (Grade of recommendation: 2B)^{129,134,150,199–203}.

In the subgroup of operations for infrarenal abdominal aortic aneurysm, a recent meta-analysis showed that IOBS can significantly reduce the relative risk of allogeneic transfusion, although the confidence interval is wide and the number of patients limited (Grade of recommendation: 2B)^204–207.

Emergency surgery

IOBS can be used in cases of abdominal trauma with liver and/or splenic lesions, in cases of thoracic trauma, for haemoperitoneum following an ectopic pregnancy and for unexpected bleeding during laparoscopic surgery (Grade of recommendation: 2C)^{140,154,208–217}.

Neurosurgery

IOBS should be used in neurosurgery (vertebral column fusion operations or intracranial surgery for giant aneurysms of the basilar artery) in the context of local protocols which, with the aim of minimising allogeneic transfusion needs and optimising the cost-efficacy ratio, take into account the characteristics of the individual patient (haemorrhagic risk, multiple alloimmunisation) and the experience of the surgical and anaesthetic team (Grade of recommendation: 2C)^{140,218–220}.

Obstetrics

The use of IOBS in obstetrics does not seem to be related to an increased incidence of amniotic fluid embolism, infectious complications or DIC^221–223.

Amniotic fluid embolism is currently considered a syndrome with an immunological pathogenesis; indeed, in 1995²²⁴ the new name of “anaphylactoid syndrome of pregnancy” was proposed^{104,224–227}.

The risk of Rh isoimmunisation deriving from contamination of the salvaged blood by foetal red blood can be prevented by administering the mother an adequate dose^228–230 of immunoglobulin G (IgG) anti-D [20–25 μg (100–125 UI) of IgG per mL of Rh(D)-positive red blood cells or per 2 mL of whole Rh(D) positive blood] (Grade of recommendation: 1A)^{104,154,231,232}.

The use of leucodepletion filters when reinfusing RCC efficiently removes squamous cells and other contaminants derived from the amniotic fluid^{16,104,154,223,233}.

In the context of obstetrics it is suggested that IOBS be used for the management of haemorrhagic emergencies or for cases with a high risk of bleeding (e. g. placenta previa, or other cases of abnormal placentation such as placenta accreta or percreta), provided that it possible to use leucodepletion filters for the transfusion of the RCC recovered (Grade of recommendation: 2B)^{16,104,154,221–227,231–235}.

Cancer surgery

Various prospective and retrospective studies have shown that IOBS can be used with the purpose of reducing the use of allogeneic transfusion, without increasing the risk of recurrences, in surgery of urological malignancies (radical prostatectomy, radical cystectomy)^236–243, gynaecological operations²⁴⁴, in liver resections²⁴⁵or in liver transplants²⁴⁶, in thoracic surgery²⁴⁷ and in combined oncological and cardiovascular surgery²⁴⁸.

A high percentage of these patients have malignant cells in the circulation, without this, however, being related to a worse survival after the surgical procedure^154,249; in fact, only a limited percentage of these cells has the capacity to metastasise (from 1/10⁴ to 1/10⁸)^154,250.

Leucodepletion filters have been used to reduce the number of malignant cells in the blood recovered during cancer surgery^{154,243,244,246,247,251–253}. Such filtration has been successfully combined with irradiation of the RCC obtained by IOBS^{16,251,253–257}.

In cancer surgery, in the context of local protocols that take into account the characteristics of the individual patient (haemorrhagic risk, multiple alloimmunisation) and of the experience of the surgical and anaesthetic team, is it suggested that IOBS be used, provided that the recovered RCC are filtered through leucodepletion filters and irradiated (25 Gy) prior to transfusion (Grade of recommendation: 2C)^{16,27,154,236–257}.

Liver transplantation

IOBS should be used in liver transplant operations, with the purpose of limiting the use of allogeneic transfusion therapy (Grade of recommendation: 2B)^{92,246,258–261}.

Leucodepletion filters

Units of RCC obtained from IOBS are often contaminated by bacteria even when the type of operation is not one in which contamination is predicted²⁶².

RCC obtained from IOBS should be transfused through leucodepletion filters in order to reduce bacterial contamination (Grade of recommendation: 2C)^16,154,263.

Contraindications

Recent studies in obstetrics^{16,104,154,221–227,231–235} and cancer surgery^{154,236–250} have re-evaluated the possibility of using IOBS in these settings; RCC salvaged from the operating field must be filtered through leucodepletion filters^{16,104,154,223,233,243,244,246,247,251–253} and, in the case of cancer surgery, must also be irradiated^{16,251,253–257}.

There are, however, numerous contraindications to the use of IOBS (Table IV), most of which are related to the presence of possible contaminants or solutions/drugs in the operating field, which can cause haemolysis^16,140,154.

Table IV.

Contraindications to intra-operative recovery of blood.

Condition	Cause or contaminant
Presence of solutions and drugs in the operating field	Haemostatic agents for topical use
	Synthetic resins (methylmetacrylate)
	Irrigating solutions of disinfectants for topical use (oxygenated water, betadine, distilled water, alcohol)
	Anticoagulant drugs
Presence of contaminants in the operating field	Urine
	Bone fragments
	Adipose tissue
	Faeces
	Infection of areas of the operating field
	Amniotic fluid*
Malignant tumours	Neoplastic cells**
Haematological diseases	Sickle cell anaemia
	Thalassaemia
Miscellaneous	Carbon monoxide (electrocautery smoke)
	Catecholamines (phaeochromocytoma)
	Decongestant drugs (oxymetazoline)

Note

^*:the passage of the recovered blood through leucodepletion filters effectively removes squamous cells and other contaminants derived from amniotic fluid¹⁶,¹⁰⁴,¹⁵⁴,²²³,²³³.

^**:Intra-operative recovery can be carried out in cancer surgery for malignant neoplasia provided the subsequent reinfusion of the intra-operative recovered red cell concentrates occurs through leucodepletion filters and after irradiation (25 Gy) of the product to be reinfused⁶,²⁷,¹⁵⁴,²³⁶–²⁵⁷.

In these circumstances it has been suggested using a supplementary aspirator in order to remove contaminants and prevent their entry into the reservoir (Grade of recommendation: 2C)^{140,154,222,264,265}.

Complications

The main complication of IOBS is gas embolism which can occur when the primary reinfusion bag is directly connected to the patient’s vascular access^135,140,266. Massive haemolysis can be caused by the mistaken use of distilled water as a washing solution^135,140.

Treatment of thrombocytopenia and platelet disorders

Intra-operative transfusion of platelets is indicated for the treatment of bleeding^17,18, in patients with thrombocytopenia or primary or secondary platelet function disorders.

The decision to transfuse platelet concentrates must not be based exclusively on the platelet count, but must also take into account the patient’s clinical condition, in particular fever above 38.5 °C, plasma coagulation disorders, recent haemorrhages and neurological deficits (Grade of recommendation: 2C)^17,18.

An absolute indication for transfusion of platelets is severe thrombocytopenia together with clinically relevant bleeding. Human leucocyte antigen (HLA)- and/or human platelet antigen (HPA)-compatible platelets can be used in the treatment of immunised patients¹⁸.

Following a validated procedure of leucodepletion, platelet concentrates from apheresis are an acceptable alternative to cytomegalovirus-negative platelet concentrates for the prevention of infections by cytomegalovirus¹⁸.

Indications for the intra-operative transfusion of platelet concentrates

The need for platelet concentrates, in the presence of thrombocytopenia (platelets <100x10⁹/L) or functional defects (including iatrogenic ones) of the platelets, depends on the type and site of the bleeding, the presence or absence of clotting disorders, intercurrent treatments, as well as the clinical condition of the patient¹⁸.

The following approach is recommended:

• - In the surgical patient with ongoing bleeding, transfusion of platelets if the count is <50x10⁹/L; if, however, the count is >100x10⁹/L a transfusion should not be given, except in particular circumstances (Grade of recommendation: 2C)^{18,54,58,85,96,267–270}.

• - During massive transfusions a transfusion threshold of 75x10⁹/L is suggested to prevent the platelet count from falling below 50x10⁹/L, the critical threshold for haemostasis (Grade of recommendation: 2C)^18,54,91; for patients with multiple trauma from high velocity accidents or with lesions involving the central nervous system, it is suggested that a higher transfusion threshold is adopted (Grade of recommendation: 2C)^18,54,91.

• - In acute DIC, in the presence of substantial haemorrhage and thrombocytopenia, it is advised that the platelet count is maintained around 50x10⁹/L (Grade of recommendation: 2C)^{18,20,54,85,271}.

• - Extracorporeal circulation: platelet transfusion is recommended for patients who, at the end of the operation, have bleeding that is not related to the surgery or other clotting disorders (Grade of recommendation: 1C+)^18,54. In these patients, given the secondary functional platelet disorders, the decision to transfuse platelets should be based on clinical criteria (microvascular bleeding and excessive post-surgical anaemia) (Grade of recommendation: 2C)^18,54.

• - Platelet function disorders (congenital or acquired): transfusion of platelets is indicated, independently of the platelet count, in the presence of haemorrhage (Grade of recommendation: 2C)^18,54,85,269.

Transfusion practice

In anaemic and thrombocytopenic patients (platelet count ≤20x10⁹/L), without ongoing bleeding, an increase of about 30% in the Htc can reduce the risk of haemorrhage (Grade of recommendation: 1C+)^{18,51,58,272–283}.

Mean dose of platelets for each transfusion^54,85

About 3x10¹¹ platelets (1 platelet concentrate from apheresis or 1 platelet concentrate from pools of 5–8 platelet concentrates from whole blood or from buffy coat pools).

Calculation of the dose of platelets to transfuse

The dose of platelets to transfuse can be calculated using the following formula¹⁸:

ABO/RhD compatibility

The platelet concentrates transfused should be ABO-identical, or at least ABO-compatible, for an efficient yield^{18,53,54,85,267,284–294}.

Adverse reactions

Acute adverse reactions to transfusion therapy with platelets are¹⁸:

• - non-haemolytic transfusion reactions (usually manifested by shivers, fever and urticaria);

• - sepsis, due to bacterial contamination of the blood;

• - TRALI.

Transfusion therapy with fresh-frozen plasma

The main indication for transfusion of FFP is correction of deficiencies of clotting factors for which a specific concentrate is not available, in patients with ongoing bleeding¹⁸.

In the intra-operative period the transfusion of FFP is indicated to correct congenital deficiencies of clotting factors, for which a specific concentrate is not available, or of multiple clotting factor deficits, when the PT or aPTT, expressed as a ratio is >1.5, in the following circumstances^{5,17,18,27,59,74,85,91,271,295–306}:

• - in the presence of acute or chronic liver disease and ongoing bleeding (Grade of recommendation: 1C+)^{5,27,74,85,296–306};

• - in the presence of DIC and active bleeding, together with correction of the underlying cause (Grade of recommendation: 1C+)^{5,20,74,85,296–306};

• - prevention of intra-operative bleeding, in patients with DIC²⁰ and/or acute or chronic liver disease without active bleeding^{5,27,74,85,296–312} (Grade of recommendation: 2C);

• - correction of microvascular bleeding in patients undergoing massive transfusion. If the PT and aPTT cannot be determined within a reasonable time, the FFP can be transfused in any case, in an attempt to halt the bleeding (Grade of recommendation: 1C+)^{5,27,74,85,91,295–306};

• - deficiencies of single clotting factors, in the absence of specific concentrates (for example, factor V deficiency), in the presence of active bleeding or to prevent bleeding, during surgery (Grade of recommendation: 1C+)^{5,27,74,85,296–306}.

Transfusion practice

Method of use

FFP must be thawed between 30 °C and 37 °C in a water bath under continuous agitation or with other appropriate equipment, in order that the temperature can be controlled. After thawing, the plasma must be transfused as soon as possible and in any case within 24 hours, if stored at 4±2 °C^52,59. Thawed FFP must not be refrozen (Grade of recommendation: 1C+)⁵⁹.

Posology

The recommended initial dose of FFP is 10–15 mL/kg of body weight^5,59,74,301. The dose of FFP depends in any case on the patient’s clinical situation and laboratory parameters (Grade of recommendation: 1C+)^{5,59,74,85,301}, which can justify the administration of higher doses (up to 30 mL/kg) of FFP^20,313–315.

ABO/RhD compatibility

Plasma that is ABO-compatible with the recipient must be used (Grade of recommendation: 1C+)^18,53.

FFP can be administered regardless of Rh compatibility; anti-D prophylaxis is not necessary in Rh(D)-negative recipients given Rh(D)-positive FFP (Grade of recommendation: 1C+)^18,59.

Inappropriate indications for the transfusion of fresh-frozen plasma

The main inappropriate indication for using FFP in surgical patients is as a blood volume expander¹⁸.

Contraindications

Absolute contraindications to the use of FFP are documentated intolerance to plasma or its components and congenital deficiency of immunoglobulin A (IgA) in the presence of anti-IgA antibodies^18,59.

Relative contraindications are heart failure and pulmonary oedema.

Adverse reactions to the transfusion of fresh-frozen plasma

The acute adverse reactions to transfusion therapy with FFP are mild allergic reactions (urticaria) or severe, anaphylactic allergic reactions, TRALI, febrile reactions, citrate toxicity and circulatory overload¹⁸.

Use of cryoprecipitate and fibrinogen

A specific acquired deficiency of fibrinogen, in the presence of haemorrhage, can be corrected by the transfusion of autologous or allogeneic cryoprecipitate, if available, or of fibrinogen concentrate (not registered in Italy, but can be obtained)²⁰. A dose of 10 units of cryoprecipitate prepared from FFP from whole blood or 3 g of fibrinogen concentrate should raise the plasma fibrinogen by about 1 g/L^20,27,316 in an adult person weighing 70 kg and with a plasma volume of about 3,000 mL²⁷.

The response to treatment should be monitored, both clinically and by coagulation tests (PT, aPTT, fibrinogen) (Grade of recommendation: 2C)²⁰.

The Clauss method should be used to determine the fibrinogen concentration (Grade of recommendation: 2C+)^20–22.

Persistent, severe hypofibrinogenaemia (<1 g/L) despite treatment with FFP, in the presence of clinically relevant ongoing bleeding and together with correction of the underlying cause, can be treated with cryoprecipitate or fibrinogen concentrate, if available (Grade of recommendation: 2C)^{20,59,91,317–341}.

ABO/RhD compatibility

Fibrinogen can be infused independently of the recipient’s blood group. The same criteria for FFP also apply to cryoprecipitate^17,18,53,59.

Side effects and adverse reactions

The acute adverse reactions associated with the administration of cryoprecipitate have mostly been described in case reports and can be attributed to haemolytic reactions caused by anti-A/B antibodies, allergic and febrile reactions, respiratory distress and thrombotic events³¹⁶.

Allergic and anaphylactic reactions, as well as thrombotic events have also been described following the administration of fibrinogen concentrates^337,342,343.

Use of antithrombin concentrates

Almost the only indication for antithrombin (AT), used as replacement therapy, is correction of congenital deficiency in certain circumstances^27,344,345. There is no clinical evidence that higher than normal levels of AT guarantee better protection than physiological levels^344,346,347.

A recent meta-analysis of the use of AT in critically ill patients did not show any significant effect on a global reduction of mortality, even in subgroups of studies carried out in obstetric or trauma patients^346,347; in contrast, it was seen that the use of AT was associated with an increased risk of bleeding.

Acute haemorrhage in the intra-operative period can be associated with an acquired deficiency of AT³⁴⁴; however, the use of AT concentrates in this case is not indicated, even when the levels of AT are considerably below the norm (Grade of recommendation: 2C+)^344,346,347.

In the absence of further evidence from randomised, controlled trials, which could demonstrate a favourable effect on clinically relevant end-points, the use of AT cannot be recommended in patients with DIC who are not being contemporaneously also treated with heparin (Grade of recommendation: 1C+)²⁰.

Calculation of the dose of antithrombin to administer

Before starting replacement therapy with the specific concentrate, the amount of functional AT should be assayed (Grade of recommendation: 2C)³⁴⁴.

Given that the administration of 1 IU/kg of weight increases plasma AT activity by 1.5%, the dose to administer can be calculated as follows:

The dose and timing of subsequent administrations should be adapted to the plasma activity of AT, monitored every 12–48 hours.

Side effects and adverse reactions

AT infusions are generally well tolerated although allergic type reactions are possible³⁴⁴.

The use of AT concentrates contemporaneously with the administration of heparin increases the risk of haemorrhage and careful clinical and laboratory monitoring is, therefore, necessary in these circumstances (Grade of recommendation: 2C)³⁴⁴.

Blood components for topical use

Fibrin glue

Fibrin glue is a blood component for topical use that has been employed in surgery for more than 20 years³⁴⁸; it is available as a commercial product derived from pools of inactivated plasma, or can be produced from autologous or homologous whole blood or plasma, following protocols for manual or automated production³⁴⁹. The main components are fibrinogen, factor XIII and thrombin (and calcium chloride with or without antifibrinolytics) which can be applied contemporaneously or in succession to the surfaces to be treated. The application of fibrin glue reproduces in situ the final phase of the coagulation cascade through activation of fibrinogen by the thrombin³⁵⁰.

Given its haemostatic potential, this blood component for topical use has been used in cardiovascular, orthopaedic, thoracic, hepatic, splenic and urological surgery with the aim of containing the consumption of blood^1,351–354.

Although based on studies of methodologically modest quality, three systematic reviews suggest that fibrin glue can be effective in reducing allogeneic transfusion needs in the peri-operative period^134,353,354; however, the adoption of restrictive transfusion protocols reduces this effect¹³⁴ and greater benefit in terms of saving blood is obtained in the post-operative period^353,354.

Recent studies in liver surgery have challenged the role of fibrin glue in reducing intra-operative bleeding in this context and the cost-efficacy ratio of the strategy^355,356.

Fibrin glue in heart surgery should only be used in the operations at highest risk (rupture of the external wall of the left ventricle and dissecting aorta)⁷⁰, because of the possible complications associated with this product^357–359.

It has been suggested that fibrin glue could be used, applying it to areas of bleeding parenchyma to facilitate local haemostasis, as a possible complementary therapeutic approach to contain intra-operative consumption of blood, on the basis of local protocols which take into consideration the characteristics of the individual patient (haemorrhagic risk, multiple alloimmunisation), the type of operation, the experience of the surgical and anaesthetic team, as well as the appropriateness of integrating the use of this blood component with other strategies of saving blood, taking into account the cost-efficacy ratio (Grade of recommendation: 2C)^{1,27,70,134,351–356}.

Intra-operative pharmacological strategies for saving blood

Recombinant activated factor VII

The main indications for the use of recombinant activated factor VII (rFVIIa) are peri-operative prophylaxis and the treatment of haemorrhage in patients with haemophilia A or B with inhibitors, in whom replacement treatment with the specific deficient factor is either not possible or not indicated (Grade of recommendation: 2C)^360,361 and in patients with acquired haemophilia (Grade of recommendation: 2C+)³⁶¹, congenital FVII deficiency (Grade of recommendation: 2C+)^362–364, or Glanzmann’s thromboasthenia associated with refractariness to platelet transfusion (Grade of recommendation: 2C)^18,54,85.

In recent years there has been a notable increase in the use of rFVIIa for the off-label indication of treatment of haemorrhage events due to secondary clotting defects in patients undergoing surgery or those with multiple trauma³⁶⁵, despite the uncertainty of the real risk of thrombotic complications associated with the use of this drug for indications that have not been registered^1,110.

The use of rFVIIa, mainly in uncontrolled studies, has been the subject of recommendations, based on the consensus of experts, for the treatment of massive haemorrhage in the fields of surgery, obstetrics and gynaecology^366–368.

A recent systematic Cochrane review recommended that rFVIIa be used only in the context of clinical trials, since there is still uncertainty regarding its real efficacy as a haemostatic agent, whether for prophylaxis or for the treatment of major bleeding³⁶⁹. However, records of arterial thromboembolic adverse reactions have recently led the EMEA to contraindicate the use of rFVIIa except for its already approved indications^370,371.

Antifibrinolytics

Following the worldwide withdrawal of aprotinin from the market, which occurred on 5 November 2007¹¹⁰, because of the greater mortality associated with the use of this product in heart surgery compared to its lysine analogues (tranexamic acid and epsilon-aminocaproic acid [EACA])^372–374, and since EACA has not been marketed in Italy since 2006, tranexamic acid is, currently, the only antifibrinolytic available.

A systematic Cochrane review in 2007 indicated the efficacy of antifibrinolytic agents in reducing the consumption of blood products in major surgery³⁷⁵, finding stronger evidence for tranexamic acid; a subsequent update³⁷³ recommended the use of tranexamic acid and AEAC to prevent bleeding in heart surgery.

The use of tranexamic acid and AEAC in orthopaedic surgery (hip and knee replacement) has been shown to be effective in reducing transfusion therapy, without increasing the risk of thromboembolic complications, provided that antithrombotic prophylaxis is given normally; also in this type of surgery, despite the large variability in doses and methods of infusion used in the pre-, intra- and post-operative periods, tranexamic acid was found to be superior to EACA^{110,375–381}.

Tranexamic acid and AEAC have also been used successfully in liver transplants, achieving a reduction in the use of blood without increasing thromboembolic complications^382–385; once again, tranexamic acid was found to be superior to EACA^384,385.

Tranexamic acid could be a possible complementary pharmacological approach to help to limit intra-operative use of blood during heart surgery, major orthopaedic operations (hip and knee replacements) and liver transplants, on the basis of local protocols taking into consideration the characteristics of the individual patients (haemorrhagic risk, multiple alloimmunisation) and the experience of the surgical and anaesthetic team, provided that normal prophylaxis against venous thromboembolism is given (Grade of recommendation: 2C+)^{1,2,51,70,110,134,365–371}.

Surgical and anaesthesiological techniques of saving blood

The use of surgical techniques and instruments aimed at limiting trauma to tissues and vessels and facilitating local haemostasis is effective in containing intra-operative bleeding (Grade of recommendation: 2C)^{105,110,155,386–392}.

Controlled hypotension (a reduction of systolic blood pressure down to 80–90 mmHg, a reduction in mean blood pressure down to 50–65 mmHg, or a 30% reduction of the mean baseline blood pressure) can be obtained pharmacologically or by spinal or epidural anaesthesia³⁹⁰ and is a commonly used technique which, depending on the experience of the team of anaesthetists, can be used in selected patients to help to limit intra-operative blood loss (Grade of recommendation: 2C)^110,393.

A reduction in central venous pressure (1–5 mmHg) can contribute to reducing intra-operative bleeding during liver resection in selected patients and depending on the experience of the surgical and anaesthetic team (Grade of recommendation: 2C)^110,394.

Peri-operative hypothermia increases the risk of organ failure, coagulation disorders and intraoperative bleeding^95,395–400.

Hypothermia should be prevented, with the purpose of limiting intra-operative bleeding, by prewarming solutions to be infused^401,402 and by warming the patient himself (Grade of recommendation: 2C)^95,395–400.

Addendum

The process of developing these Recommendations, in conformity with the indications in the methodological manual of the national programme for guidelines (Istituto Superiore di Sanità, Agenzia per i Servizi Sanitari Regionali. Programma Nazionale per le Linee Guida – Manuale Metodologico. Milano, Italia, Arti Grafiche Passoni srl; 2002. Available at: http://www.snlg-iss.it/cms/files/Manuale_PNLG_0.pdf. Last accessed: 03/25/2010), made use of systematic literature reviews and updates of already existing recommendations on the subject.

The methodology used to determine the grades of recommendation drew on that presented at the 2004 Consensus Conference of the American College of Chest Physicians (Guyatt G, Schünemann HJ, Cook D, et al. Applying the grades of recommendation for antithrombotic and thrombolytic therapy. Chest 2004; 126: S179–87).

The recommendations are classified by grades, expressed in Arabic numbers (1, 2), according to their strength, and in letters (A, B, C), reflecting the type of study and evidence provided.