An Approach to Anemia in Critically Ill Patients: Transfusion or Tolerance?

Nika · #1 (**permalink**) 03-30-2005, 12:50 AM

Publisher:
Nata Publishing

Link:
http://tinyurl.com/3rn4u

Contact:
Gregor I. Kemming, MD,^1,2 and Oliver P. Habler, MD, PhD³
¹Institute for Surgical Research and
²Clinic of Anesthesiology
Ludwig-Maximilians-University
Munich, Germany
³Department of Anesthesiology, Intensive Care Medicine, and Pain Control
Johann-Wolfgang Goethe University Hospital
Frankfurt/Main, Germany

An Approach to Anemia in Critically Ill Patients: Transfusion or Tolerance?

Introduction
Anemia is defined as a reduction of a personâ€™s hemoglobin concentration below values considered normal (12-13 g/dL).1 Anemia is particularly common in the critically ill. Approximately half of the patients admitted to an intensive care unit are already anemic at the time of admission.2-4 Most of them will encounter anemia during intensive care treatment.3-6

Anemia in the Critically Ill: Mortality
Several large studies suggest that a preoperative hemoglobin concentration lower than 9-10 g/dL or major intraoperative blood loss are associated with an increased risk of death or serious morbidity.6-9 This finding is especially obvious in patients with preexisting cardiovascular disease.10 In a large combined retrospective and prospective analysis in 4,470 critically ill patients, overall mortality risk was associated with the degree of anemia.8

Causes of Anemia in Critically Ill Patients
In principle, anemia evolves from an increased turnover or reduced production of red cells. In the critically ill, this may be due to surgical blood loss, repeated phlebotomies, blood loss into extracorporeal circuits, decreased red cell production, and reduced erythropoietin response.6-11 One third of allogeneic blood transfusions (ABTs) are administered following traumatic or surgical blood losses.6 Renal failure is associated with pronounced anemia, in particular when extracorporeal circuits serve for renal replacement therapy.11 Chronic blood loss is to a great extent generated by frequent diagnostic blood sampling and may cause about 30% of all ABTs.6-11 It may also relate to gastrointestinal bleeding disorders, due to stress ulcer, anticoagulation and impaired gut mucosal integrity. An increased turnover of red cells occurs in the case of premature destruction. This could be caused by the therapeutic use of extracorporeal circuits (bypass, cardiac assist devices), by massive transfusion, and by hemolysis. Inappropriate formation of new red cells in the bone marrow is another issue in critically ill patients,12 since systemic inflammation blunts erythropoietin release and red cell maturation and hampers iron, folate, and vitamin B12 availability.11,12

Compensatory Response to Acute Anemia
Assuming that normovolemia is maintained (administration of colloids, crystalloids), hemoglobin concentration and therefore arterial O2 content are reduced during anemia. Adequate oxygenation of tissues in the presence of reduced O2 content is documented by a stable unchanged O2 consumption. The two main mechanisms contributing to the maintenance of O2 consumption are: 1) the increase of cardiac output, which temporarily augments O2 delivery during moderate hemodilution down to a hemoglobin concentration of 10 g/dL; and 2) the enhancement of tissue O2 extraction13 by the redistribution of regional microcirculatory organ blood flows in response to actual regional O2 needs.13,14 In the awake subject, cardiac output is increased via a sustained linear increase of heart rate,15 in the anesthetized subject it is increased via a rise in stroke volume.13 The latter is secondary to reduced blood viscosity and systemic afterload, to an increased venous return and enhanced myocardial contractility. Since under physiologic conditions O2 extraction is almost maximal in the myocardium and can hardly be increased during hemodilution, myocardial oxygenation under the condition of increased myocardial work predominantly depends on adequate increase of coronary blood flow.16,17 During hemodilution there is an increase and redistribution of organ blood flow between and within organs. Redistribution of bulk flow occurs mainly in favor of the heart in order to meet elevated myocardial O2 needs and to maintain the circulatory response to anemia. Redistribution of microcirculatory flow serves to regionally adapt regional O2 delivery to tissue O2 demands.14,18-20

Limits of Compensation for Acute Anemia
When peripheral, microcirculatory, and coronary adaptation to anemia are exhausted, stroke volume response and adaptive microcirculatory flow distribution will fail and ischemic myocardial failure and peripheral tissue hypoxia will occur.21,22 The corresponding so-called â€œcriticalâ€ hemoglobin concentration varies considerably among individuals and depends on species, body temperature, age, and above all cardiac compensatory reserve. According to previous experimental data, the critical hemoglobin concentration varies between 2-5 g/dL with a corresponding critical O2 delivery of 5-15 mL/min/kg.21-24 The critical hemoglobin concentration for different organ systems may also vary due to the described redistribution of blood flow between organs, mainly in favor of the heart and brain.18 Little is known about the critical hemoglobin concentration in humans, and is the result of studying in large part healthy volunteers and patients who refuse transfusions:25 during profound hemodilution in human volunteers, hemoglobin concentrations between 5 and 6 g/dL were tolerated without changes in O2 consumption or plasma lactate levels.26 Light changes in cognitive function have been observed at hemoglobin concentrations between 5 and 6 g/dL.27,28 Mortality is suspected to significantly increase below a threshold value of 5 g/dL.25 A decline of O2 consumption secondary to a reduction in O2 delivery has been observed at a hemoglobin concentration of 4 g/dL in an anesthetized patient who refused allogeneic transfusion for religious reasons.29

Limitations to Anemia Compensation in Critically Ill Patients
Critically ill patients may present with various factors limiting their ability to tolerate low hemoglobin concentrations. An inadequate circulating blood volume does not allow for an adequate increase of stroke volume to maintain O2 delivery. Most importantly, a reduced compensatory reserve is encountered in elderly patients with congestive heart failure or coronary heart disease. There is evidence that mortality is associated with the extent of anemia in the presence of significant cardiovascular disease.8,10,30 Impaired pulmonary gas exchange might further limit arterial O2 content necessitating additional cardiac compensation. Finally, many intensive care patients suffer from systemic inflammation and sepsis. Not only is it possible that myocardial contractility may be reduced during inflammatory disorders, but it is generally accepted that these patients suffer impaired tissue O2 utilization mostly due to microvascular O2 shunts.31 Consequently, in cases of acute anemia and/or hypovolemia, tissue oxygenation cannot be maintained via a compensatory increase of tissue O2 extraction ratio. On the basis of the abovementioned considerations, the historical practice to ensure supranormal O2 delivery in patients was established and patients were transfused liberally. The beneficial effect of increasing O2 content via red cell transfusion on O2 delivery is well documented.32 In case of manifest tissue hypoxia in extreme anemia, e.g. documented by a reduced O2 consumption, the aim should be not to increase merely systemic O2 delivery, but to preferably improve tissue oxygenation, documented by a parallel increase in O2 consumption following administration of ABT.

Efficacy of ABT in Improving Tissue Oxygenation
There is indeed experimental evidence that the transfusion of red cells improves tissue oxygenation when administered under the condition of preexistent tissue hypoxia: Powell hemorrhaged rats by 30% of their blood volume and resuscitated the animals with fresh autologous whole blood, albumin or Ringerâ€™s lactate.33 Subcutaneous O2 partial pressure and mixed venous O2 saturation were most effectively restored in the whole blood group. Nolte and coworkers hemorrhaged hamsters of 54% of their blood volume and resuscitated either with 1:1 fresh whole blood or the same amount of 6% dextran 60%.34 Following therapy, the tissue O2 partial pressure was significantly higher in the whole blood group. Fitzgerald hemodiluted conscious septic rats until supply dependency of O2 consumption occurred.35 Transfusion of fresh red cells was followed by a significant increase of O2 consumption indicating the presence of supply-dependency prior the start of transfusion, while old red cells did not show the beneficial effect. Although there are numerous studies in patients reporting an increase of O2 delivery following red cell transfusion, in contrast to the cited experimental data, a simultaneous increase of O2 consumption, indicating an improvement of tissue oxygenation, was rarely observed in patient studies (overview in Ref. 32).

ABT and Mortality in the Critically Ill
In a multicenter trial published by HÃ©bert et al., two matched groups of patients were compared. In a group with a liberal transfusion regimen, hemoglobin concentration was kept above 10-12 g/dL. In a group with a more restrictive transfusion regimen hemoglobin concentration was allowed to fall to 7-9 g/dL.9 The overall rate of in-house mortality was lower in the group with the more restrictive transfusion regimen. Especially in young patients, who were less severely ill, the mortality risk was half as high as in liberally transfused patients. The reasons for these results may be a lack of efficacy of ABT, since in principle it has to be kept in mind, that the transfusion of red cells is not necessarily efficacious in improving tissue oxygenation;36 it seems somewhat logical, therefore, that it is not necessarily associated with an improved outcome.

Influence of Storage on ABT Efficacy
Today it is known that a lack of efficacy in terms of restoring tissue oxygenation might be related to the time of storage. In the above-mentioned experimental study, Fitzgerald transfused the supply-dependent septic rats either with fresh (3 days) or old (28 days of storage) red cells.35 Whereas the transfusion of fresh red cells was capable of improving O2 consumption, at the time when the critical hemoglobin concentration had been reached, the transfusion of â€œoldâ€ red cells was not. In a similar protocol, SielenkÃ¤mper also induced supply dependency by hemodiluting septic rats.37 Supply dependency of O2 consumption was assumed with a 40% reduction of O2 consumption. Due to a significantly lower survival in the group receiving â€œold red cells,â€ changes in O2 consumption could not be analyzed. Marik and Sibbald investigated the influence of the transfusion of three units of packed red cells on gastric mucosal oxygenation in septic patients, who presented with a hemoglobin concentration of 9 g/dL and an increased serum lactate concentration.38 Not surprisingly, the maximal improvement in gastric mucosal oxygenation was significantly correlated to the age of the red cell units. In those patients who received blood of an age of more than 15 days splanchnic ischemia was induced by transfusion. Several reasons may account for the lack of efficacy of â€œoldâ€ red cells.39 Acidosis and loss of high energetic phosphates lead to changes in shape, loss of membrane deformability, and surface antigen pattern. By that, slugding of red cells in the microcirculation occurs. The loss of 2,3-bisphosphoglycerate leads to a reduction of the p50 value of the hemoglobin within the transfused red cell and a consecutive left shift of the hemoglobin O2 dissociation curve.39 Taken together, these factors might hamper optimal convective O2 transport within the microcirculation and unloading of O2 from transfused red cells to hypoxic tissues. Unexpectedly, in a recent study in 22 euvolemic, anemic, critically ill patients, Walsh and colleagues did not observe an increased incidence of adverse events in response to administration of allogeneic red cells, older than 20 days, when compared to red cells that were stored for only 5 days or less.40 However, due to limitations in methodology, results from large prospective trials should be awaited before a conclusive statement on the clinical consequences of the storage lesion might be given.41

Side Effects of ABT
Not only a lack of efficacy, but also the well-known unwanted side effects of allogeneic transfusion might contribute to the increased mortality with a more liberal transfusion practice: besides the most frequent and serious clerical error,42 transfusion-transmitted infections, allergic and immunologic reactions, transfusion-related immunomodulation, transfusion-related lung injury, and post-transfusion purpura still remain important issues today.42-46 Of particular relevance is the increased risk of serious bacterial infection and pneumonia observed in patients receiving ABT.47 The risk of infection is associated which the number of units transfused.47 Furthermore, this increased risk of infection is also associated with considerable mortality.48 ABT-related immunosuppression is the suspected underlying reason.49,50 In analogy to febrile non-hemolytic transfusion reactions it is attributed to circulating plasmatic antibodies of the recipient against surface antigens of donor-leucocytes.50,54

Effect of Leukocyte Depletion
As a consequence, considerable effort has been undertaken to reduce ABT-related adverse reactions by removing donor leukocytes from the preparations. Numerous techniques of leukoreduction at different points in time have been investigated, and there has been a lively debate on controversial results.55-60 Febrile, non-hemolytic transfusion reactions, as indicators of interaction of donor white cells with the recipients immune system, may be significantly reduced using (prestorage) universal white blood cell reduction.61-63 There is new evidence from retrospective studies in adults and neonates, that this is associated with improved clinical outcome.64,65 Convincing evidence for the effect of leukoreduction on patient mortality is still lacking.

ABT: Numeric â€œTransfusion Triggersâ€
In summary, under various preconditions anemia may be associated with an increased mortality of the critically ill. The same is true with ABT. The decision to whether transfuse or not must be taken after weighing up the potential consequences of anemia against ABT-associated risks.66 Based on the experimental and clinical data the American Association of Anesthesiologists Task Force on Blood Component Therapy recommended in 1996 that red blood cell transfusion should be rarely indicated above a hemoglobin concentration of 10 g/dL and should be almost always indicated when it is less than 6 g/dL.67 As outlined, every single patientâ€™s ability to compensate for anemia is different, based on the actual O2 requirements, the cardiovascular reserve, depth of analgosedation and coexistent inflammation. Therefore, the data on the hemoglobin threshold at which tissue hypoxia and myocardial ischemia occur may vary considerably. The question of whether a potential transfusion is capable of positively affecting the clinical outcome of a given patient is related to the question of whether tissue hypoxia is in fact prevailing at a certain hemoglobin concentration. Therefore, an individual symptomatic indication for ABT, based on the presence of symptomatic anemia, is a more reasonable approach than searching for a numeric transfusion trigger. This, however, requires reliable information in order to judge at the bedside whether tissue hypoxia is really present, requiring ABT to increase arterial O2 content.

What Are Reliable Physiologic â€œTransfusion Triggersâ€?
As outlined, tissue hypoxia as well as myocardial ischemia may prevail if the critical hemoglobin concentration is reached in a given patient. Easily available clinical parameters to verify the actual presence of a critical level of acute isovolemic anemia, namely symptomatic transfusion triggers, have already been used in clinical studies.36 Changes in hemodynamic parameters like blood pressure, heart rate or cardiac output may indicate variations in compensatory response to anemia. However, they are by no means specific indicators that verify the presence of tissue hypoxia. Surrogate parameters for tissue oxygenation like venous O2 partial pressure or mixed venous O2 saturation are sensitive to changes in tissue oxygenation. They are, however, scarcely representative in indicating regional tissue hypoxia which may develop at distinct hemoglobin concentrations, e.g. in the heart and the intestinal mucosa. The same is true for the ECG: ST-segment deviations indicate a disturbed myocardial O2 balance. However, any tachycardia, e.g., secondary to inadequate analgosedation, or systemic inflammation as well may cause changes of the ST-segment in presence of an unchanged hemoglobin concentration. It has been proposed that a beneficial effect of red cell transfusion is dependent upon a preexistent reduction in O2 consumption (O2 debt).7,36 Given that patients with jeopardized tissue oxygenation will mostly be ventilated on high respiratory O2 concentrations (> 60%), gasometrical determination of O2 consumption with a metabolic monitor is technically impossible and O2 consumption can only be determined by calculation using the reversed Fick principle. However, in the presence of O2 supply dependency the calculation of O2 consumption is unreliable and imprecise,68 which in principle prevents valid detection of relative changes < 20-30%. In summary, the ability to timely and correctly verify the presence of tissue hypoxia and thus to decide when to transfuse based on symptomatic transfusion triggers requires profound knowledge of O2 transport physiology, clinical experience, and critical interpretation of data.

Strategies to Reduce Transfusion
Besides the attempt to minimize the risk of undesired side effects of ABT another strategy is to reduce the number of ABT administered in a given patient by the use of blood-sparing strategies.69,70 In the perioperative setting, this includes bloodless surgery, preoperative autologous donation of blood, acute normovolemic hemodilution, cell salvage, and the tolerance of extremely low hemoglobin concentrations during normovolemic hemodilution.70 Hemodilution may be further extended while arterial O2 content is augmented by administration of artificial oxygen carriers36,71,72 or by increasing the amount of O2 physically dissolved in plasma during hyperoxic ventilation,73,74 which may restore O2 supply to tissues when tissue oxygenation is jeopardized at the critical hemoglobin concentration.24,75-78 By use of such interim measures precollected autologous blood might be spared until surgical control of bleeding has been achieved, resulting in a reduced amount of ABT required for the maintenance of tissue oxygenation.73,79 Such short-term measures are only one point of improving care of the critically ill. The majority of ABTs in the critically ill relate to low hemoglobin concentration in the absence of active bleeding.4 Of note, the administration of recombinant human erythropoietin (rHuEPO) efficaciously increases hematocrit and reduces the cumulative units of ABT administered.80 However, since approximately one-third of ABTs are due to repeated blood sampling (41 mL per patient and per day3), a rational approach to diagnostic phlebotomies appears both safe and cost-effective. The amount of blood discarded during phlebotomies could be reduced by 50% when using closed-loop systems that allow sterile venous reinjection of collected blood.81

Conclusion
Anemia in the critically ill is associated with increased mortality and morbidity; so is allogeneic blood transfusion. The cardiovascular compensatory reserve towards anemia is limited. A critical threshold may be expected at a hemoglobin concentration of approximately 5 g/dL. The cardiovascular reserve to compensate for the reduction in O2 content is different for each individual and may already be reduced in intensive care patients. In conclusion, there is no numeric hemoglobin threshold below which an allogeneic red cell transfusion may guarantee efficacious improvement of tissue oxygenation or survival. In absence of tissue hypoxia, ABT is associated with increased morbidity and therefore should be restricted. Below 6 g/dL, ABT may be considered to be beneficial. Above a hemoglobin concentration of 10 g/dL ABT rarely needs to be indicated. Within these limits, the decision to transfuse or to tolerate the hemoglobin level must be made for each single individual based on the patientâ€™s underlying disease, hemodynamic stability, cardiac compensatory reserve, as well as on clinical judgment and on the presence of carefully interpreted symptomatic transfusion triggers suggesting tissue hypoxia in a given clinical scenario.

References
For full transcript on references, please see .pdf file attached.

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An Approach to Anemia in Critically Ill Patients: Transfusion or Tolerance?

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