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W4231055819 abstract "Introduction The peri-operative use of blood and blood products accounts for two-thirds of all units issued by the blood transfusion services [1]. It is clear from the recent European multi-centre study - Sanguis [2] - that there is a wide variability in peri-operative transfusion practice with regard to the level of haemoglobin (Hb) or haematocrit (Hct) at which transfusion is initiated - even when considering similar patients undergoing similar surgical procedures. Of more concern, in as many as 75% of cases, the indications for the transfusions are not recorded; this may represent casual record keeping or a reluctance to record an ill defined rationale for prescribing. Several reviews of transfusion practice [3-7] between 1965 and 1991 have demonstrated similar variability; when examined retrospectively a large proportion of transfusions were regarded as unnecessary. A recent survey [8] presented hypothetical cases to medical practitioners of varying experience, working in separate specialities in two unlinked medical centres. Once again this demonstrated marked variation in practice not only between the centres but also between specialists and, strikingly, junior doctors were far more likely to transfuse than their senior colleagues. This may reflect an erroneous reliance on 'transfusion triggers' or a failure to appreciate the risks of transfusion coupled with over concern about the risks of anaemia. Furthermore Sanguis [2] highlighted the fact that blood is ordered pre-operatively on the basis of the perceived requirement for a given procedure, rather than on the probability of an individual patient requiring blood (as indicated by age, pre-operative haematocrit, concomitant use of anticoagulants, etc). Thus 50% of patients presenting for cholecystectomy had blood ordered pre-operatively (type and screen or group and cross-match), while only 4% actually had blood transfused. These facts have significant implications given current concern regarding the transmission of infection, immunosuppression, and tumour recurrence associated with blood transfusion and the increasing difficulty and cost of maintaining blood transfusion services. Clearly there are two broad areas of concern: the efficient use of the blood transfusion services (requests for cross-match) and the appropriate use of red blood cells by clinicians. The concept of a 'transfusion trigger' was established in the 1940s by Adams and Lundy [9]. They recommended a minimum acceptable Hb level of 10 g dL−1 (corresponding to Hct 30%). This became widely accepted practice as the '10/30' rule. It has been repeatedly challenged in recent years as too conservative [10,11]. Is there an acceptable minimum for Hb in the perioperative period? Implicit in this is the concept of risk/benefit analysis in balancing the risks incurred as a consequence of anaemia against those arising as a result of transfusion. A rational approach involves establishing a risk profile: Is there an increased mortality/morbidity associated with anaemia? If so, is it related to the degree of anaemia? Are the risks alleviated by transfusion? What are the risks of transfusion? Is there an increased mortality/morbidity associated with anaemia? If so, is it related to the degree of anaemia? Anaemia may be simply defined as a red cell concentration corresponding to an Hb <13.0 g dL−1 (Hct 40%) in males and <11.5 g dL−1 (37%) in females. These values derived from population studies, describe the lower limit of the accepted normal range for that population. Clearly there are two significant variables: the nature of the population studied and the definition of 'normal range'. Furthermore comparing such a value with an individual's Hb may be of limited use; the significant factor being the deviation from the individual's norm not from the population norm. In clinical practice, the important consideration is the functional disturbance and morbidity associated with a given level of Hb rather than a somewhat arbitrary definition of normality. It is important to differentiate between acute and chronic anaemia. This discussion will consider anaemia arising as a consequence of acute blood loss and also chronic anaemia, without considering complex red cell defects, haemoglobinopathies, enzyme deficiencies or autoimmune disorders, which in themselves affect morbidity and mortality. Initial consideration will be given to anaemia as an acute event in the peri-operative period. There is a wealth of experience relating to intentional haemodilution: this technique involves the normovolaemic dilution of all the constituents of blood rather than just a reduction in red cell concentration; this is comparable to the situation intra-operatively in which blood loss is replaced by crystalloid or colloid solutions, or both. What are the physiological effects of haemodilution? Reduction in blood viscosity. Viscosity depends on red cell concentration and the interaction between the red blood cells and plasma proteins. As red cell concentration falls viscosity decreases [12,13]. Reduction in systemic vascular resistance (SVR). Is almost entirely because of the reduction in viscosity described above [14]. Increase in venous return (VR). Probably occurs as a result of an α adrenergic mediated increase in venous tone with movement of blood from the peripheral to central compartment [15,16]. Increase in cardiac output (CO). Occurs principally as a result of an increase in stroke volume (SV) which in part is because of the increase in VR in accordance with Starling's law; if normovolaemia is maintained and the Hct is greater than 25% then increased heart rate is not a feature [17]. Maximal response depends on sympathetic activity which may be attenuated if for example the patient is given β adrenergic blocking agents [18]. Redistribution of flow. From areas of low to high metabolic demand which may cause preferential flow to both the heart and brain. This can lead to a critical reduction in oxygen delivery to other organs such as the kidney [19] during marked haemodilution/anaemia. Increased oxygen extraction. As the absolute amount of oxygen delivered falls demand may be satisfied by an increase in the extraction ratio. At rest this is about 20% but may increase four-fold with rising demand. Thus there is a considerable reserve, the exception being the myocardium in which the extraction ratio is between 50-70% at rest. Release of oxygen in the tissues. May be enhanced by a right shift of the oxy-haemoglobin dissociation curve because of a rise in hydrogen ion concentration occurring as a result of a reduction in red cell buffering capacity. 2-3-Di-Phospho-Glycerate (2-3-DPG). In chronic anaemia oxygen release is further augmented by an increase in the level of 2-3-DPG with subsequent rightward shift of the oxy-haemoglobin dissociation curve. As a net result of all these changes there is an increase in flow as a result of improved flow dynamics and increased cardiac output together with an increase in oxygen extraction ratio such that tissue oxygenation can be maintained, although inevitably the physiological reserve is being diminished. The influence of haemodilution on systemic oxygen transport capacity remains controversial. The reduction in viscosity improves flow in resistance vessels, there is a rise in cardiac output and therefore in bulk flow. The effect in the microcirculation is contentious. Under normal conditions the Fahraeus-Lindqvist effect results in the viscosity in vessels with a diameter of less than 1.5 mm being lower than that in the general circulation. However, rouleaux formation and obstruction by single red blood cells at vessel branch points may effectively increase viscosity. These factors conflict and the resultant effect on flow is difficult to predict. Initial data suggested that maximal oxygen transport capacity would be achieved at an Hct of 30% [20] and did not fall below control values until an Hct of 20%. Although the latter value has been challenged by Lundsgaard-Hansen [21], who advocated a safe lower limit for the Hct of 35%, it has been supported by both clinical [22] and model analysis [23]. What are the limits of normovolaemic haemodilution? Global consideration of oxygen delivery indicates that oxygen consumption (V˙O2) at rest is approximately 140 mL min−1 m−2 whilst oxygen delivery (DO2) is approximately 550 mL min−1 m−2. As oxygen delivery falls V˙O2 becomes dependent on DO2, at which point adequate tissue oxygenation is threatened. The critical value at which this occurs is not known. In one case report [24] V˙O2/DO2 dependency was demonstrated at a DO2 of 184 mL min−1 m−2 in a patient anaesthetized and haemodiluted to an Hb of 4 g dL−1. This is considerably lower than the value of 330 mL min−1 m−2 quoted by Shibutani [25] in anaesthetized patients prior to cardiac surgery. The relevance of such a value is questionable because it may not reflect regional oxygen delivery and consumption. A study of the effect of haemodilution on the splanchnic circulation of anaesthetized pigs [26] showed that although hepatic oxygen delivery was maintained at a haematocrit of 14% there was a marked reduction in portal vein oxygen delivery with impaired tissue oxygenation. Of particular concern is the oxygen supply to the myocardium because it has an extraction ratio of 50-70% at rest. Therefore increasing oxygen supply is almost entirely dependent on increasing flow and therefore on coronary vasodilatation. Thus the presence of stenosis within the coronary vasculature, impaired diastolic relaxation (as a consequence of ischaemia) or myocardial oedema may impair coronary flow sufficiently to cause ischaemia. This problem has recently been addressed in a review by Kettler [27] in which he attempted to define a critical Hct based on functional coronary reserve at different levels of global and myocardial oxygen demand using a theoretical model. Considering myocardial demand during anaesthesia and at a level approximately four times this, as may occur in the post-operative period, he calculated that, in the presence of coronary stenosis, while an Hb of 9.2 g dL−1 was adequate to sustain oxygen delivery under anaesthesia, it would require an Hb of 12.8 g dL−1 when oxygen demand increased. Even in the patient with normal coronary vasculature supply/demand would be critically placed at an Hb of 7.0 g dL−1. In summary when red cell mass is reduced oxygen carrying capacity per unit volume is reduced but global oxygen delivery can be maintained by a combination of increased CO, inter organ flow redistribution and increased oxygen extraction. Fit and healthy individuals may tolerate extreme haemodilution using these compensatory mechanisms. However, this compensation is dependent on: Maintaining normovolaemia; Normal myocardial/ventricular function; An intact autonomic nervous system; Normal vascular beds. These ideal circumstances may not always be met in the post-operative period: The response may be impaired by limited left ventricular function, concomitant medications (β-blockers and α-blockers), residual effects of anaesthesia, and hypovolaemia. Oxygen delivery may be reduced by impaired respiratory function, hypothermia and alkalosis. Oxygen demands may be increased, particularly by shivering during recovery from anaesthesia [28]. In addition the increase in CO results in an increase in cardiac work (volume and rate dependent). It has been argued that this increase is small because of the decrease in afterload arising as a result of the decrease in SVR, but this is a dangerous assumption to make in the post-operative period. At this time afterload may be increased by vasoconstriction (secondary to pain, anxiety, hypothermia) and so further increase myocardial oxygen demand. Thus there are implications for standards of care both intra- and post-operatively if one accepts a lower Hb/Hct. These include: Maintenance of intravascular normovolaemia; Maintenance of adequate oxygenation; Avoidance of hypothermia; Access to rapid reliable estimation of Hb/Hct; Adequate pain control; Rapid and reliable access to blood/blood products when required; In patients with very low Hb levels or in those at particular risk the ability to assess oxygen delivery/consumption may be required. (This may include measurements of serum lactate, mixed venous oxygen saturation (SvO2) and V˙O2/DO2 - remembering of course that these are global measures and may not reflect specific organ function.) The use of on-line ST segment analysis and the development of devices for measuring the redox state of individual tissues (such as Near-Infra-Red-Spectroscopy) may be of benefit in monitoring the effects of anaemia [29]. What clinical evidence is available regarding the effect of anaemia on morbidity and mortality? The following information is derived from retrospective studies involving relatively small numbers of patients, combined reviews of such studies and individual case reports. Carson and Spence [30] reported a study of 125 patients who refused blood transfusion and demonstrated a significant relation between the degree of pre-operative anaemia and mortality (Hb<6 g dL−1=61.5%; Hb>10 gdL−1=7.1%). There was also an independent relation between the degree of blood loss and mortality (>2000 mL = 42.9%; <500 mL = 8%). No patient with a Hb>8 g dL−1 and blood loss <500 mL died. These relations were independent of other potentially confounding variables such as ischaemic heart disease, chronic obstructive airways disease, diabetes mellitus, etc. However, the significance of blood loss is not clearly separated from the extent/duration of surgery and underlying pathology which may independently have affected mortality. The same authors [31] demonstrated that surgery could be performed in patients whose Hb was as low as 6 g dL−1. This study again highlighted the association between operative blood loss and mortality (>500 mL = 8.4%; <500 mL = 0%). They concede that the relatively young age of their patient population (average age 47 years) may have had a beneficial effect, although this was not demonstrated in their initial study. Both of these studies showed a strong correlation between the degree of blood loss and mortality irrespective of the pre-operative Hb. It is possible that this reflects the degree of compensation required in response to an acute fall in Hb; thus not only is the absolute Hb important but also the acute change. A review of experience with Jehovah's Witnesses [32] showed that of 134 cases, who satisfied the criteria of moderate to severe anaemia pre-operatively and who were not transfused peri-operatively, 23 patients died from anaemia (as reported by original authors). In 20 of these the Hb was <5 g dL−1. Conversely 27 patients survived with Hb <5 g dL−1. There were no deaths when Hb was between 5 and 7 g dL−1. There were three deaths in the range Hb 7-8 g dL−1 all following major cardiac surgery. It was noted that of the survivors with a Hb <5 g dL−1 65% were aged less than 50 years; of those who died 60% were aged over 50. The authors stressed that this group was heterogenous with regard to age and intercurrent disease. Some of these studies were performed under exceptional circumstances with regard to the anaesthetic techniques, intra- and post-operative monitoring and post-operative care, so that their results may not be a true representation of everyday clinical practice. Two studies have shown that in high risk vascular surgery patients the incidence of myocardial ischaemia, shown by continuous ambulatory electrocardiograph monitoring, correlated significantly with an Hct <28% [33] and an Hct <29% [34]. Similarly a case report [35] involving a patient presenting for vascular surgery demonstrated several episodes of silent ischaemia pre-operatively in association with a Hct of 27% which resolved completely when the Hct was raised by transfusion to 36%. Is it possible to make recommendations regarding a minimum acceptable level of Hb? The previous discussion has demonstrated that it is possible for individuals to survive with exceedingly low levels of Hb. Indeed mortality may not be excessive until the level of Hb falls to <5 g dL−1 - allowing for the fact that this may involve intensive support and increased levels of post-operative care. This is reassuring and provides a basis for informed discussion particularly with patients who, for religious or other reasons, refuse transfusion. However, the question should not be what can be achieved by specialists, but rather what it is reasonable to expect in routine clinical practice. The emphasis should be on the maintenance of an adequate Hb during the peri-operative period as opposed to the often quoted 'starting' Hb. Such an approach requires consideration of the patients age, general health (with particular reference to cardio-respiratory status), use of drugs interfering with the autonomic nervous system or haemostasis, intercurrent disease associated with increased oxygen demands (e.g. sepsis) and prediction of blood loss, either expected or ongoing. Clearly the necessity for transfusion, the volume of blood required and the time at which transfusion is initiated are influenced by the Hb at the outset. With these principles in mind we would propose the following as guide values against which we might begin to audit both practice and clinical outcomes, without inhibiting the flexibility in clinical decision making for an individual patient: In fit otherwise healthy individuals in whom the ability to compensate should be intact, a Hb of >7 g dL−1 is adequate. Individuals with known or suspected intercurrent disease (including drug therapy) likely to impair their ability to compensate require a Hb of >9.5 g dL−1. In individuals with chronic anaemia (if compensatory mechanisms are intact) a Hb of >6 g dL−1 is adequate. Individuals with evidence of an increased oxygen demand require a Hb of >10 g dL−1. These are recommendations. The clinical condition of the patient must be observed in order to alter treatment as appropriate. Are the risks associated with anaemia alleviated by transfusion? Red blood cells should be administered with the aim of increasing oxygen carrying capacity, thereby increasing oxygen delivery at a given cardiac output. The associated rise in Hct will result in an increase in blood viscosity and SVR, thus increasing afterload, myocardial work and oxygen demand. If transfusion is excessive, the combination of volume load may result in left ventricular dysfunction and pulmonary oedema, further compromising oxygenation with the risk of aggravating myocardial ischaemia [10]. Clearly excessive transfusion is inappropriate. The aim should be to raise the Hb/Hct to achieve optimal oxygen delivery. In many clinical situations relief of symptoms - fatigue, dyspnoea, chest pain - is a useful guide to the adequacy of oxygen delivery. However, this is not always the case. Of particular concern are those patients with ischaemic heart disease in whom silent myocardial ischaemia is known to occur frequently in the peri-operative period [36] and has been shown to be associated with a low Hb [35]. What are the risks associated with transfusion of blood? Clearly the major risks (haemolytic reasons - see Table 1) are those associated with mismatched transfusion which usually arise from errors in patient identification [37,38]. Morbidity arising from over transfusion (volume overload) is also thought to be significant. Risks of infection from blood transfusion are low (see Table 2). Less clear are the risks arising from the postulated association between blood transfusion, increased susceptibility to infection and the risk of tumour recurrence. There is convincing evidence that trauma/surgery results in a period of decreased immune competence [39,40] and that the transfusion of blood [41] may amplify this response. It would seem that this depends on the presence of leucocytes in the transfused blood [42]. Intuitively this suggests the potential for an increased incidence of post-operative septic complications and an impaired ability to remove disseminated malignant cells resulting in an increased tumour recurrence rate. This was originally high-lighted by Burrows and Tartter [43] and a large metaanalysis [44] provides evidence to support this theory. Recently this has been questioned in a retrospective analysis of patients undergoing surgery for colorectal cancer [45]. Although both showed an increase in tumour recurrence associated with blood transfusion neither could demonstrate a cause and effect relation between the two and it may be that other independent variables associated with blood transfusion are involved. A smaller study [46] involving 216 patients with cancer of the colon, rectum, cervix and prostate produced results, which although consistent with the hypothesis that transfusion impairs host defence against cancer, again could not prove it. Furthermore there may be no difference in recurrence rate regardless of whether autologous or homologous blood is used [47]. The meta-analysis [44] demonstrated a point estimate of 69% increase in the odds of suffering a negative outcome. If one were to assume that the adverse outcome was solely because of the administration of blood, which is clearly doubtful, this would represent an unacceptable risk. However, this is not supported by the available evidence, therefore any quantification of risk is impossible.Table 1: Acute adverse reactions [10]Table 2: Transmission of infection [1]There is also controversy regarding blood transfusions and increased post-operative septic complications: numerous clinical studies [47-52] have demonstrated a link, this has been challenged by others. A recent qualitative statistical review [53] (including the above papers) concluded that 'research to unequivocally link blood transfusion with an increased rate of post-operative infection has not yet been published'. There is evidence only of an association not a causal link. Comment and Conclusion In the light of this information is it possible to perform a risk benefit analysis? Consideration of a young adult is markedly different from that of an elderly individual: for example; a fit 35-year-old undergoing surgical resection of a colonic carcinoma (Dukes B) will tolerate a low Hb and can expect a 5-year survival rate of about 80% with a recurrence rate of about 10% (54). In contrast a 70-year-old with known ischaemic heart disease undergoing a similar procedure is at greater risk of complications as a result of anaemia and although the risks of transfusion are the same the consequences of those risks are significantly different. This should result in a different threshold for transfusion in the two cases. It might be argued that this is no more than common sense, it is at best an analysis in very broad terms. Unfortunately as has been demonstrated in the foregoing discussion there is a paucity of information on which to make this assessment. There are no prospective randomized controlled trials assessing the influence of differing levels of anaemia on morbidity. There is controversy regarding the effect of transfusion on tumour recurrence and infective complications. There is reasonably reliable information regarding the incidences of both the transmission of infective agents and immunologically based reactions. However, recent experience with HIV demonstrates that complacency with regard to the possibility of further occult infective agents should be avoided. Can clinical practice be improved using the information currently available? Initially the problem of inappropriate overtransfusion was identified [2]. However, it would seem that in certain areas (such as cancer surgery) transfusion is inappropriately with-held. It is clear therefore that polarized attitudes exist. The decision to transfuse red blood cells should be a balanced clinical decisions taking into account the known risks of having a low Hb peri-operatively, the risks associated with transfusion and the wishes of the patient. Ideally one could identify finite risks and make a fully informed decision for each individual. At present there is insufficient information to do this. Experience with risk analysis in other areas of medical practice (e.g. Goldmann cardiac risk index [55] and APACHE scoring) demonstrates that when there are multiple variables influencing the outcome we may at best be able to identify at risk groups and assign a degree of risk to that group. It would be unwise to rely on 'transfusion triggers', indeed this may encourage rigid thinking which is the antithesis of good clinical practice. Guidelines relating to the use of blood in the peri-operative period have already been published [11,56,57]. These do not appear to be widely used. Whether this is because of reluctance to accept such guidelines, concern over their validity, failure to propagate them or simply reluctance to change existing practice is unclear. Experience elsewhere suggests that acceptance is more likely if guidelines are based on sound scientific evidence (controlled trials), some would regard this as a requirement [1]. At present it is not possible to satisfy these demands with regard to blood transfusions in the peri-operative period. However, the broad approach by Grimshaw and Russell [58] which assigns a value to the evidence used (from level one, that derived from control trials, to level five, that derived from case reports with no control data) is possible and should be used if progress is to be made in this area. Effective implementation requires dissemination of information, support of recognized authorities and local incentives (teaching, audit, etc). If inappropriate transfusion is to be reduced then education of the clinicians involved in making those decisions is essential; widely accepted guidelines would form a basis for this. In addition although we are limited in our ability to assess the relative risks and benefits of transfusion, the concept of risk benefit analysis is an important one in that it reinforces the idea of a balanced clinical decision and should serve to emphasise that polarised attitudes are inappropriate. Further progress can be made through large scale prospective controlled studies looking at the relation between anaemia and outcome and transfusion and outcome. In the interim further systematic review of the information currently available is required. Acknowledgments This review was originally prepared for the Quality of Practice Committee of the Royal College of Anaesthetists (London, UK). We would like to thank Dr D. B. L. McClelland (Regional Director, Edinburgh and South East Scotland Blood Transfusion Service, Lauriston Place, Edinburgh), Professor A. A. Spence and Dr E. Watson (Department of Anaesthetics, Royal Infirmary Edinburgh) for their assistance in the pre-paration of this paper." @default.
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W4231055819 title "Peri-operative haemoglobin: an overview of current opinion regarding the acceptable level of haemoglobin in the peri-operative period" @default.
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