Natural History of Uncorrected Anemia

Numerous laboratory experiments indicate that extreme hemodilution is well tolerated in healthy animals. Animals subjected to acute hemodilution tolerate decreasing hemoglobin concentrations down to 50 to 30 g/L, with ischemic electrocardiographic changes and depressed ventricular function, respectively, occurring at these levels of hemoglobin concentration.³ However, acute hemodilution is less well tolerated in experimental animal models of coronary stenosis, with ischemic electrocardiographic changes and depressed cardiac function occurring at hemoglobin concentrations between 70 and 100 g/L. Human data regarding the limits of anemia tolerance are inadequate and often conflicting. Leung et al.⁴ found electrocardiographic changes that may have been indicative of myocardial ischemia in 3 of 55 conscious resting volunteers subjected to acute isovolemic hemodilution to a hemoglobin concentration of 50 g/L.

While providing insight into the human physiologic response to acute anemia, the experimental data mentioned are of limited applicability to the perioperative setting, where many of the factors that influence oxygen consumption—muscle activity, body temperature, heart rate, sympathetic activity, metabolic state—are altered. Instead we need to determine the risk of withholding RBC transfusions in the perioperative setting. From a systematic review completed for the Canadian Guidelines on Red cells, Hébert and associates⁵ identified numerous reports of severe anemia being well tolerated in surgical patients.^6,7 Additional reports or case series^8,9–11 describe successful outcomes in patients with chronic anemia due to renal failure. Finally, descriptive studies in patients refusing red blood cell transfusion^12–1415 and from regions experiencing limited blood supplies^16,17 have demonstrated that patients can survive surgical interventions with hemoglobin levels as low as 45 g/L.

In examining some of these studies in more detail, there appears to be an association between preoperative hemoglobin concentrations, intraoperative estimated blood loss, and postoperative mortality.^13,14 Indeed, there were no reported deaths in more than 100 patients undergoing major elective surgery when preoperative hemoglobin concentrations were above 80 g/L and the estimated blood loss was less than 500 mL. In a single-center series of 542 Jehovah’s Witness patients undergoing a cardiac surgical procedure, the overall mortality rate was 10.7%; only 2.2% of the deaths observed were considered to be a direct consequence of anemia. More recently, Viele and Weiskopf ⁷ identified 134 Jehovah’s Witness patients with a hemoglobin concentration less than 80 g/L or a hematocrit below 24% who were treated for various medical and surgical conditions without the use of blood or blood components. There were 50 reported deaths, 23 of which were attributed primarily or exclusively to anemia (defined as deaths with hemoglobin concentration < 50 g/L). For those patients who died of their anemia, 60% were older than 50 years. However, in 27 survivors with hemoglobin concentration below 50 g/L, 65% were younger than 50. Although publication bias must be kept in mind in examining these data, young healthy patients may survive without transfusion at hemoglobin concentrations in the range of 50 g/L. From these data, it is clear that extreme anemia is often tolerated in the perioperative setting but also appears to increase the risk of death. However, these observations should not be interpreted as support for a restrictive or conservative transfusion strategy, especially because most of the literature related to tolerance of anemia has not explored patient characteristics that predispose patients to adverse outcomes from moderate to severe anemia.

Anemia in High-Risk Groups

A number of risk factors for adverse outcomes associated with anemia have been identified in clinical practice guidelines^18–20 and reviews.^21–23 Anemia is thought to be less tolerated in older patients, in the severely ill, and in patients with clinical conditions such as coronary, cerebrovascular, or respiratory disease. However, the clinical evidence confirming that these factors are independently associated with an increased risk of adverse outcome is lacking. One small case-control study following high-risk vascular surgery suggests an increase in postoperative cardiac events with increasing severity of anemia.²⁴ In perioperative²⁵ and critically ill patients,²⁶ two large cohort studies have documented that increasing degrees of anemia were associated with a disproportionate increase in mortality rate in the subgroup of patients with cardiac disease. In 1958 Jehovah’s Witness patients,²⁵ the adjusted odds of death increased from 2.3 (95% confidence interval [CI], 1.4-4.0) to 12.3 (95% CI, 2.5-62.1) as preoperative hemoglobin concentrations declined from the range of 100 to 109 g/L to the range of 60 to 69 g/L in patients with cardiac disease (Figure 150-1). There was no significant increase in mortality in noncardiac patients with comparable levels of anemia. In a separate study of critically ill patients,²⁶ those with cardiac disease and hemoglobin concentrations less than 95 g/L also had a trend toward an increased mortality rate (55% versus 42%; P = .09) as compared with anemic patients with other diagnoses. Although both cohort studies were retrospective in nature and may not have controlled for a number of important confounders, the evidence suggests that anemia increases the risk of death in patients with significant cardiac disease.

Figure 150-1 Adjusted odds ratio for mortality by cardiovascular disease and preoperative hemoglobin (Hgb).

(Adapted from Carson JL, Spence RK, Poses RM, Bonavita G. Severity of anemia and operative mortality and morbidity. Lancet 1988;1:727–9.)

Severity of illness also appears to be a risk factor in critically ill patients.^13,26 Two retrospective studies document that degree of blood loss contributes to perioperative mortality.^13,26 However, there are no studies examining the independent contributions of age, cerebrovascular disease, and respiratory disease to an increased mortality risk in anemic patients. This relationship may well be complex, given that age and cerebrovascular disease are risk factors associated with coronary artery disease. Smoking-related respiratory diseases may have similar associations to cardiac disease. Therefore, the association between anemia and increased rates of adverse outcomes in these patients can best be described as speculative at this time.

Risks and Benefits of Transfusion

Five large observational studies that were specifically designed to compare clinical outcomes at varying hemoglobin concentrations in transfused and nontransfused patients have been conducted in various clinical settings. In the first of these, Hébert and colleagues²⁶ used a combined retrospective and prospective cohort design to examine 4470 critically ill patients admitted to 6 Canadian tertiary-level ICUs during 1993. After controlling for disease severity, there remained a trend toward increased mortality when hemoglobin concentrations were less than 95 g/L in patients with cardiac diagnoses (ischemic heart disease, arrhythmia, cardiac arrest, or cardiac and vascular surgical procedures). Furthermore, analysis of a subgroup of 202 patients with anemia, an Acute Physiology and Chronic Health Evaluation (APACHE) II score above 20, and a cardiac diagnosis revealed that transfusion of 1 to 3 units or 4 to 6 units of RBCs was associated with a significantly lower mortality rate as compared with those patients who did not receive a transfusion (55% [no transfusions] versus 35% [1-3 units] or 32% [4-6 units]; P = .01).

Wu et al.²⁷ retrospectively studied Medicare records of 78,974 patients older than age 65 who were hospitalized with a primary diagnosis of acute myocardial infarction. The authors then categorized patients according to their admitting hematocrit. Although anemia, defined in the study as a hematocrit less than 39%, was present in nearly half the patients, only 3680 patients received an RBC transfusion. Lower admission hematocrit values were associated with increased 30-day mortality rate, with a mortality rate approaching 50% among patients with a hematocrit of 27% or lower who did not receive an RBC transfusion. Unfortunately, this study had no data on nadir hemoglobins and their relationship to mortality. Interestingly, RBC transfusion was associated with a reduction in 30-day mortality for patients who received at least one RBC transfusion if their admitting hematocrit was less than 33%, whereas RBC transfusion was associated with increased 30-day mortality for patients whose admitting hematocrit values were 36.1% or higher. These associations were present even when adjustments were made for clinical patient factors including APACHE II scores, location of myocardial infarction, and presence of congestive heart failure; as well as treatment factors including use of reperfusion therapies, aspirin, and β-adrenergic blockade.

In the only study exclusively focusing on the perioperative period, Carson and associates²⁸ attempted to determine the effect of perioperative transfusion on 30- and 90-day postoperative mortality with a retrospective cohort study involving 8787 patients with hip fractures undergoing repair between 1983 and 1993 in 20 different U.S. hospitals. This was a large, high-risk, elderly (median age 80.3 years) population with extensive coexisting disease and with an overall 30-day mortality rate of 4.6%. A total of 3699 patients (42%) received a perioperative transfusion within 7 days of the surgical repair. After controlling for trigger hemoglobin concentrations, cardiovascular disease, and other risk factors for death, the results suggested that patients who had hemoglobin concentrations as low as 80 g/L and did not receive transfusion were no more likely to die than those with similar hemoglobin concentration levels who received a transfusion. (With hemoglobin concentrations less than 80 g/L, nearly all patients received a transfusion, so investigators were unable to draw conclusions about the effect of transfusion at these lower hemoglobin concentrations levels.) However, as the authors point out, despite the large sample size, inadequate power may still explain the inability to detect a reduction in mortality related to transfusion, and they estimated that the study would need to be 10 times larger to detect a 10% difference in 30-day mortality with 80% power.

Vincent et al.²⁹ completed a prospective observational cross-sectional study involving 3534 patients admitted to 146 western European ICUs during a 2-week period in November 1999. Of these patients, 37% received an RBC transfusion during their ICU admission, with the overall transfusion rate increasing to 41.6% over a 28-day period. For those patients who received a transfusion, the mean pretransfusion hemoglobin concentration was 84 ± 13 g/L. In an effort to control for confounding factors created by illness severity and the need for transfusion, these investigators used a strategy of matching transfused and nontransfused patients based on their propensity to receive a transfusion, thereby defining two well-balanced groups (516 patients in each group) to determine the influence of RBC transfusions on mortality. Using this approach, the associated risk of death was increased instead of decreased by 33% for patients who received a transfusion compared to similar patients who did not receive blood. However, as pointed out in the accompanying editorial,³⁰ the results may have differed if the propensity scores were derived separately for categories of pretransfusion hemoglobin concentrations (e.g., <80, 80-100, and >100 g/L) instead of hemoglobin concentrations at ICU admission. For example, if one were to consider groups of patients with a pretransfusion hemoglobin concentration of less than 60 g/L, it is unlikely that the observed 33% increase in mortality would hold true, or blood transfusion would never be recommended.

Corwin and colleagues completed a similar prospective observational study evaluating 4486 patients admitted to 284 U.S. ICUs from August 2000 to April 2001. Overall, 44% patients were transfused RBCs, and the mean nadir hemoglobin was 8.6 ± 1.7 g/L. This study used logistic regression to evaluate the effects of transfusion on mortality. RBC transfusions of 1 to 2 units, 3 to 4 units, and more than 4 units were associated with increased odds ratio (OR) for mortality of 1.48 (95% CI, 1.07-2.05; P = 0.018), 2.62 (95% CI, 1.80-3.81; P < 0.001), and 4.01 (95% CI, 2.74-5.87; P < 0.001), respectively. Baseline hemoglobin levels were not significant in the logistic regression model, but a nadir hemoglobin below 9 g/L was associated with increased mortality (nadir hemoglobin < 8 g/L: OR, 1.49; 95% CI, 1.13-1.95; P = 0.004; and nadir hemoglobin 8 to < 9 g/L: OR, 1.54; 95% CI, 1.12-2.12; P = 0.009). A second analysis using propensity scores matched 1059 transfused patients on a 1 : 1 basis with non-transfused patients based on baseline characteristics associated with a likelihood of receiving transfusions. The transfused patients had an adjusted mortality ratio of 1.65 (95% CI, 1.35-2.03; P < 0.001).

Numerous observational studies have examined the relationship between RBC transfusions and morbidity and mortality in critically ill patients. These studies have been recently summarized in a systematic review by Marik and Corwin³¹; 45 studies (including the previous 4 studies) involving 272,596 trauma, surgery, cardiac, and ICU patients were identified. Overall, 42 studies showed an increase in at least one of the outcomes of interest. Of the 18 studies that reported the relationship between RBC transfusions and mortality, 17 found an association between RBC transfusion and mortality, with a pooled OR of 1.7; 95% CI, 1.4-1.9. While these findings suggest that the risks associated with RBC transfusion may outweigh the benefits, the authors suggest caution in interpreting these data. Multivariate analysis was used in many of the observational studies to control for other clinical variables, but it is not possible to control for all factors, especially the fact that blood transfusion itself is a marker for severity of illness. The complex interrelationship between disease severity, number of transfusions, and degree of anemia may result in a spurious association reported between increased mortality risk and anemia or RBC transfusion. Thus, randomized controlled trials are required to definitively determine the relationship between RBC transfusions and mortality.

Unfortunately, as evidenced by a recent systematic review, there is a paucity of clinical trials comparing restrictive to liberal transfusion studies to examine the efficacy of RBC transfusion. Carson et al.³² (Figure 150-2) were able to identify only 10 randomized clinical trials of adequate methodological quality in which different RBC transfusion triggers were evaluated. Included were a total of 1780 surgery, trauma, and ICU patients enrolled in trials conducted over the past 40 years. The transfusion triggers evaluated in these trials varied between 70 and 100 g/L. Data on mortality or hospital length of stay were available in only 6 of these trials. Conservative (low hemoglobin) transfusion triggers were not associated with an increase in mortality rate; on average, the rate of mortality was one-fifth lower (relative risk [RR], 0.80; 95% CI, 0.63-1.02) with conservative as compared with liberal transfusion triggers. Likewise, cardiac morbidity and length of hospital stay did not appear to be adversely affected by the lower rate of RBC transfusions. There were insufficient data on potentially relevant clinical outcomes such as stroke, thromboembolism, multiorgan failure, delirium, infection, and delayed wound healing to perform any pooled analysis. The Carson review²⁸ stated there were insufficient data to address the full range of risks and benefits associated with different transfusion thresholds, particularly in patients with coexisting disease. They also noted that their meta-analysis was dominated by a single trial: the Transfusion Requirements in Critical Care (TRICC) trial,³³ which enrolled 838 patients and was the only individual trial identified that was adequately powered to evaluate the impact of different transfusion strategies on mortality and morbidity.

Figure 150-2 Effect of restrictive transfusion triggers on the use of allogeneic blood transfusion. A, Number of red cell units transfused. B, Proportion transfused/receiving red cells.

(Adapted from Carson JL, Hill S, Carless P et al. Transfusion triggers a systematic review of the literature. Trans Med Rev 2002;16:187–99.) WMD, Weighted mean difference.

The TRICC Study³³ documented an overall non-significant trend toward decreased 30-day mortality (18.7 versus 23.3%; P = .11) and significant decreases in mortality among patients who were less acutely ill (8.7 versus 16.1%; P = .03) in the group treated using a hemoglobin transfusion trigger of 70 g/L compared with a more liberally transfused group that received 54% more RBC transfusions. The investigators also noted that the 30-day mortality rates were significantly lower with the restrictive transfusion strategy among patients who were less acutely ill (APACHE II scores less than 20) and among patients who were younger than 55 years of age (Figure 150-3).

Figure 150-3 ICU survival over 30 days in study patients in restrictive and liberal allogeneic RBC transfusion strategy groups. A, Kaplan-Meier survival curves for all patients in both study groups. There is a trend toward lower mortality in patients in the restrictive group (red line) as compared to the liberal group (purple line) (P = .10). B, In the subgroup with an APACHE II score less than 20, fewer patients died in the restrictive group than in the liberal group (P = .02). C, There were also significant differences in survival among groups in the subgroup with ages less than 55 years (P = .02).

(Adapted from Hébert PC, Wells G, Blajchmann MA et al. A multicentre, randomized, controlled trial of transfusion requirements in critical care. N Engl J Med 1999;340:409–17.)

A number of additional questions arose from the TRICC trial. The investigators were particularly interested in the risks and benefits of anemia and transfusion in patients with cardiovascular disease and in patients attempting to wean from mechanical ventilation. In the first of these subgroup analyses,³⁴ 357 patients (43%) were identified with cardiovascular disease. Of these, 160 had been in the restrictive RBC transfusion group and 197 in the liberal transfusion group. The two groups were fairly equally balanced with regard to baseline characteristics and concurrent therapies, with a few exceptions: there was less frequent diuretic use in the restrictive group (43% versus 58%; P < .01), and the use of epidural anesthetics was greater in the restrictive group (8% versus 2%; P < .01). Overall, in this subgroup analysis, there was no significant difference in the mortality rate between the two treatment groups. However, there was a non-significant (P = .3) decrease in overall survival rate in the restrictive group for patients with confirmed ischemic heart disease, severe peripheral vascular disease, or severe comorbid cardiac disease.

The subgroup analysis of patients receiving mechanical ventilation was limited to 713 (85% of the 838 patients in the TRICC trial who required invasive mechanical ventilatory support).³⁵ Of these, 357 had been in the restrictive RBC transfusion group and 356 in the liberal group. The mean duration of mechanical ventilation was 8.3 ± 8.1 days in the restrictive group and 8.8 ± 8.7 days in the liberal group (P = .48). Ventilator-free days were 17.5 ± 10.9 and 16.1 ± 11.4 in the restrictive and liberal RBC transfusion groups, respectively (P = .09); 82% of the patients in the restrictive transfusion group were considered successfully weaned and extubated for at least 24 hours, compared with 78% in the liberal group (P = .19). Among the 219 patients who required mechanical ventilation for more than 7 days, there were no differences in the time to successful weaning (Figure 150-4). The independent effects of RBC transfusions and hemoglobin concentration were also examined. Each additional transfusion was associated with an increased duration of mechanical ventilation (RR, 1.10; 95% CI, 1.14-1.06; P < .01) after adjusting for the effect of age, APACHE II score, and comorbid illnesses. Hemoglobin concentrations did not influence the duration of mechanical ventilation (RR, 0.99; 95% CI, 1.01-0.98; P = .45). Complications including pulmonary edema and acute respiratory distress syndrome (ARDS) were increased in patients in the liberal strategy group.

Figure 150-4 Time remaining on mechanical ventilation in 283 patients requiring mechanical ventilation for more than 1 week. Time to successful weaning from mechanical ventilation is illustrated using Kaplan-Meier survival curves in patients who required mechanical ventilation for more than 1 week. Weaning success is defined as remaining off mechanical ventilation once extubated during the 30 days of observation. Red line = restrictive group; purple line = liberal group. Survival curves were not statistically different when compared using a log rank test (P = .08).

(Adapted from Hébert PC, Blajchmann MA, Cook DJ et al. Do blood transfusions improve outcomes related to mechanical ventilation? Chest 2001;119:1850–7.)

Recently, two other large randomized clinical trials have compared liberal and restrictive transfusion strategies in different populations. Lacroix and colleagues³⁶ undertook a non-inferiority trial comparing a restrictive (7.0 g/L) and a liberal (9.5 g/L) transfusion threshold in 648 pediatric ICU patients. There were no differences in new or progressive multiple-organ dysfunction (12% in both groups; absolute RR, 0.4%; 95% CI, −4.6 to 5.4) or the number of deaths (14 in each group).

Results from the recently completed FOCUS trial have also been reported. Carson et al. (Carson, ASH annual meeting 2010) randomized 2016 patients with a history or risk factors for cardiovascular disease who underwent surgery for hip fracture to symptomatic RBC transfusion (permitted if hemoglobin < 8 g/L) or a transfusion threshold of 10 g/L. The percentage of patients who were dead or unable to walk without assistance were identical in the two groups (35%), and there were no differences in 60-day mortality (OR, 1.19; 99% CI, 0.76-1.86).

Even though three large randomized controlled trials have been completed, a number of questions remain to be answered. One of the most important questions is why the liberal RBC transfusion strategy failed to improve 30-day mortality rate and rates of organ failure in critically ill patients. It is conceivable that the greater number of allogeneic RBC units in the liberal group significantly depressed host immune responses^35,37 or resulted in altered microcirculatory flow as a consequence of prolonged storage times.

Subsequent to the publication of the TRICC trial, a study by Rivers et al.³⁸ documented that the use of early goal-directed care based on a mixed central venous saturation (ScvO₂) decreased mortality from 46.5% in the control group to 30.5% in the goal-directed therapy group (P = .009). As one of the many interventions in patients with early septic shock, hematocrits were increased to greater than 30% if the ScvO₂ fell to less than 70%. As a consequence of goal-directed therapy, 64% of patients, compared to 18.5% of the control group, received RBC transfusions (P < .0001). The significant differences in patient populations studied by Rivers and colleagues and the TRICC trial may account for the apparently conflicting results between the studies. Results from the early goal-directed therapy study should be reproduced and better understood. In the interim, they highlight the need for further studies in subpopulations of critically ill patients.

Alternatives to Transfusion

Numerous strategies have been explored and are recommended to decrease or to eliminate the need for blood transfusions during major surgery and critical illness. Some are relatively benign, but others carry their own risks that must be weighed against the administration of RBCs. Alternatives include decreasing the use of medications that result in perioperative bleeding (e.g., nonsteroidal antiinflammatory drugs and acetylsalicylic acid), avoidance of unnecessary phlebotomy, use of blood conservation strategies (e.g., pediatric test tubes and arterial catheter reinfusion setups), medications to decrease blood loss (e.g., antifibrinolytic agents), and medications to increase hemoglobin production. In addition to a restrictive transfusion strategy, the two most useful approaches to decreasing RBC transfusions in critically ill patients appear to be blood conservation techniques such as decreased phlebotomies and erythropoietin therapy. Other therapeutic strategies are better suited to patients undergoing high-risk surgical procedures.

Decreased RBC production is one of the causes of anemia observed in the critically ill. Indeed, critical illness is characterized by blunted erythropoietin production and response.³⁹ This blunted erythropoietin response observed in critically ill patients appears to result from inhibition of the erythropoietin gene by inflammatory mediators.^40,41 It has also been shown that these same inflammatory cytokines directly inhibit RBC production by the bone marrow and may produce distinct abnormalities of iron metabolism.^42,43 In patients with multiple organ failure, recombinant human erythropoietin therapy (600 units/kg) has been shown to stimulate erythropoiesis.⁴⁴ Similarly, in a small randomized placebo-controlled trial (160 patients), therapy with recombinant human erythropoietin resulted in an almost 50% reduction in RBC transfusions compared to patients treated with a placebo.⁴⁵ Erythropoietin was given at a dose of 300 units/kg daily for 5 days followed by every-other-day dosing until ICU discharge. Despite receiving fewer RBC transfusions, patients in the recombinant human erythropoietin group had a significantly greater increase in hematocrit.

Recently the efficacy of recombinant human erythropoietin in critically ill patients was evaluated in two similar large randomized controlled trials involving a total of 2762 patients.^46,47 In the first trial, recombinant human erythropoietin was given weekly at a dose of 40,000 units. All patients received three weekly doses, and patients who remained in the ICU on study day 21 received a fourth dose. Treatment with recombinant human erythropoietin resulted in a 10% reduction in the number of patients receiving any RBC transfusions. The authors reported a 60.4% rate of transfusions following randomization in the placebo group, as compared with 50.5% in the recombinant human erythropoietin group (OR, 0.67; 95% CI, 0.54-0.83; P < .0004) and a 20% reduction in the total number of RBC units transfused in patients receiving recombinant human erythropoietin (P < .001). All clinical outcomes including mortality rates, rates of organ failure, and lengths of stay in the ICU and the hospital were comparable between groups (all P values > .05). A second large trial in 1460 critically ill patients randomly allocated patients to receive either 40,000 units/wk versus a placebo for a maximum of 3 weeks. This confirmatory trial did not find a significant decrease in mortality (OR, 0.72; 95% CI, 0.51-1.02). A systematic review incorporating results from 9 trials in 3326 critically ill patients documented a decrease in transfusions without affecting mortality rates (OR, 0.86; 95% CI, 0.71-1.05).⁴⁸ These studies and the systematic review^45–49 demonstrate that recombinant human erythropoietin therapy in critically ill patients can decrease in RBC transfusions and increase hemoglobin levels. This is consistent with the hypothesis that the anemia in critically ill patients is similar to the anemia of patients with chronic disease and is characterized at least in part by a relative erythropoietin deficiency.⁵⁰ However, given the high costs of erythropoietin and the lack of clinical benefit demonstrated in the randomized controlled trial, its use is not recommended as a blood conservation strategy in routine practice.

Conclusions

Despite the frequent use of RBC transfusions, only three large randomized trials have examined RBC administration in postoperative and critically ill patients. Together, they consistently document that a restrictive transfusion strategy is safe and minimizes red cell use in critically ill adults and children as well as postoperative patients. However, there is insufficient evidence in early septic shock or in patients with a myocardial infarction or acute coronary syndromes. In addition, most transfusion practice guidelines published prior to completion of the TRICC trial^32–34 are now dated and warrant expert opinion by solid evidence in diverse clinical settings. Still, high-quality clinical evidence is not yet available for many decisions related to RBC transfusions. In terms of alternatives, human recombinant erythropoietin should not be widely used in critically ill patients. We anticipate that risks and benefits of red cells and alternatives will be better elucidated in the coming years.

Recommendations

Key Points