Hyperammonemia

Anemia occurs in virtually all critically ill patients receiving long-term mechanical ventilation and has been associated with increased mortality and poor outcomes. Allogeneic RBC transfusions are routinely administered to critically ill anemic patients, especially during lengthy stays in ICUs or in long-term acute care facilities. Although RBC transfusions are a physiologically rational approach to raising hemoglobin levels, they may increase the risk of complications and have been associated with higher mortality in critically ill patients. Treatment with epoetin alfa, an erythropoiesis-stimulating agent, as a means of reducing transfusion requirements has been studied in the critically ill and in patients receiving long-term mechanical ventilation. Promising results have been reported, including a potential survival benefit, although larger and more definitive studies are needed in order to establish whether raising hemoglobin levels affects clinical outcomes in patients receiving mechanical ventilation.

Key words: epoetin alfa; long-term acute care; mechanical ventilation; RBC transfusion; weaning

Abbreviation: LTAC = long-term acute care

Learning Objectives: 1. To understand the risks and benefits of managing, with RBC transfusions, the increased oxygen requirements of anemic patients receiving mechanical ventilation. 2. To review data regarding, epoetin alfa as a potential transfusion alternative in long-term acute care patients. 3. To discuss predictive variables for the possibility of weaning and time to wean from long-term mechanical ventilation.

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ANEMIA AND TRANSFUSION PRACTICE IN THE ICU

Anemia is a common comorbid condition in the ICU. In virtually all critically ill patients, hemoglobin levels are either below normal at the time of admission or decline during the course of an ICU stay. (1-4) In studies (1,3) of anemia and transfusion practices in the critically ill, patients with lower hemoglobin levels were more likely to receive RBC transfusions; had a higher incidence of hemodynamic instability, sepsis, GI bleeding, and complication rates; and had a higher risk of mortality. Severity of anemia correlated with operative mortality rates in surgical patients who refused blood transfusions, (5) and anemia beyond the second preoperative day was one of the significant factors associated with poor outcomes in elderly cardiac surgical patients. (6) Because anemia has been associated with poor outcomes, administration of RBC transfusions is routine practice in the setting of critical illness. Studies (7,8) have reported that 37 to 50% of patients receive at least 1 U of RBCs during an ICU stay. Additionally, Corwin et al (9) reported that 85% of patients who remained in the ICU for > 1 week received [greater than or equal to] 1 U of RBCs.

In one study (3) of anemia and transfusion practice in critically ill patients, 61% of the population required mechanical ventilation and almost two thirds of patients had a baseline hemoglobin level < 12 g/dL, which continued to decline throughout the ICU stay. In patients receiving long-term mechanical ventilation, the presence of anemia may interfere with the ability to wean from ventilatory support. Due to the extra workload imposed on respiratory muscles during the process of weaning from mechanical ventilation, the demand for oxygen is increased. (10) Increasing oxygen-carrying capacity by raising hemoglobin levels with RBC transfusions should improve oxygen delivery to vital organs, which is especially critical for the subset of patients in whom coronary artery disease is present. (2) Administration of RBC transfusions to improve oxygenation would therefore appear to be physiologically rational. Indeed, the frequent use of RBC transfusions might be perceived as a testimonial to their relative safety and clinical benefit. The belief that RBC transfusions are efficacious and risk free, however, is not supported by the bulk of emerging clinical evidence.

Starting in the early 1980s, concerns regarding transfusion-related HIV and hepatitis C infections stimulated numerous investigations (11-15) that have since uncovered a variety of risks associated with allogeneic RBC transfusions. In critically ill patients supported by long-term mechanical ventilation, complications of RBC transfusion--including immunosuppression, infection, volume overload, and pulmonary edema--may be magnified. Although it seems counterintuitive, transfusions with RBCs that are intended to improve oxygenation can actually hinder oxygen uptake as a result of changes in RBC function during storage. (16,17) Any of these factors may explain why RBC transfusions have been associated with an increased probability of morbidity and mortality in this patient population.

TRANSFUSION RISKS

Infection

Patients who receive allogeneic blood experience increased morbidity and longer and more costly hospital stays. (18) Among the risks associated with allogeneic BBC transfusions are viral infections (most commonly hepatitis) (19-22) and bacterial infections, (23,24) Fortunately, the risk of acquiring an infection directly from a blood transfusion is now lower than in the past. (12) The lowered risk has resulted from the implementation of more comprehensive testing, increasingly stringent donor deferrals, and improvements in the reliability and sophistication of detection methods. (25,26) Despite these improvements, infectious risks can never be entirely eliminated. This is because new transmissible diseases are always emerging, and even when risks are foreseeable and eliminated with careful screening there will always be a window period between infection and seroconversion during which the potential infection cannot be detected in the donor. (27)

Complications of Stored Blood

The shelf life of erythrocytes is 35 days in whole blood and 42 days when preserved in adenine-saline solution. (28) The benefits of administering RBCs that were stored > 15 days was first questioned by Marik and Sibbald. (16) The demonstration by these investigators that systemic oxygen uptake in patients with sepsis was not improved when older RBCs were infused led them to hypothesize that poorly deformable RBC membranes might occlude the microcirculation and potentially exacerbate end-organ ischemia. There is also mounting evidence that RBCs that have been stored > 14 days are associated with poor outcomes, including higher mortality, increased risk of infection and multiple organ failure, and longer hospital and ICU lengths of stay. (29) Other complications that may arise from the use of older blood include hypocalcemia caused by citrate binding, hyperkalemia caused by cell lysis, hyperammonemia and hyperbilirubinemia due to breakdown of RBCs, and acidosis. (30) In addition to erythrocytes, a unit of packed RBCs also contains platelets, leukocytes, and plasma. Degenerating leukocytes and platelets may release bioactive substances that are toxic to BBCs, (17,29) and the use of older blood containing leukocytes has been shown to be an independent risk factor for multiple organ failure. (30) A recent clinical trial (31) evaluating the impact of the storage age of blood (units stored [less than or equal to] 5 days vs [greater than or equal to] 20 days) found no significant difference in tissue oxygenation or in adverse effects on gastric tonometry. However, the RBCs used in this study had been leukoreduced, consistent with the hypothesis that removal of leukocytes from stored blood may limit the adverse consequences of RBC transfusions. Additionally, a report (32) describing the mandatory leukoreduction program in Canada indicated that there has been a trend toward lower mortality rates since implementation. Because blood banks generally fill transfusion orders with the oldest RBC units first, the risk of serious posttransfusion complications might be increased in certain patients if the leukocytes are not depleted prior to storing the blood. Thus, although the evidence is relatively convincing that the detrimental effects of stored blood are mediated primarily by the presence of lymphocytes, the blood banks in the United States have still not adopted universal leukoreduction and the problem will likely persist. Moreover, based on earlier data, (16) poor deformability of older RBC membranes and the byproducts of their degradation may contribute to poor efficacy and risks in ways that are independent of leukocytes. (16) These hypotheses, however, have yet to be tested in prospective, randomized clinical trials. Specifically, studies have yet to investigate whether leukoreduction of blood improves outcome in critically ill patients. (33)

Potential Immunologic Sequelae of Blood Transfusions

It is likely that the greatest consequences of RBC transfusions in critically ill patients may be mediated through the actions of transfused blood elements on the immune system, (34-37) The clinical sequelae are diverse, and in many cases the mechanism is incompletely understood or conflicting evidence exists regarding cause and effect. Some of the immunologic complications noted in association with transfusions are reactivation of latent viruses,as diminished capacity for wound healing, (39) predisposition to postoperative infection, (38,40-42) sepsis, (43,44) cancer recurrence, (40) down-regulation of macrophage and T-cell function, (45) and alloimmunization. (46) It is not completely clear how immunomodulation occurs, but this phenomenon has the potential to be particularly troubling for the critically ill, in whom any of these complications, infectious or otherwise, will be magnified.

Questionable Efficacy of RBC Transfusions

The efficacy of blood transfusions in critically ill patients may be limited since there is evidence that stored RBCs are less effective at unloading oxygen. One study (16) of patients with sepsis receiving mechanical ventilation not only failed to demonstrate an acute improvement in oxygen uptake after transfusion of 3 U of RBCs, but also found that patients who received RBCs > 15 days old had evidence of splanchnic ischemia. Blood transfusions may hinder oxygen delivery in patients receiving mechanical ventilation and during weaning, when oxygen consumption further increases. (10) This lack of effect could possibly result in an insufficient supply of oxygen to vital organs including the heart, (47,48) the respiratory muscles, (49) and the splanchnic circulation. (50)

Do RBC TRANSFUSIONS IMPROVE OUTCOMES IN SOME CRITICALLY ILL PATIENTS?

Specifically designed to investigate transfusion outcomes in ICU patients, the Transfusion Requirements in Critical Care trial conducted by Hebert and colleagues (2) randomly assigned patients to receive RBC transfusions based on a restrictive strategy (transfusion initiated at hemoglobin level of 7.0 g/dL and maintained between 7.0 g/dL and 9.0 g/dL) or a liberal strategy (transfusion initiated at hemoglobin level of 10.0 g/dL and maintained between 10.0 g/dL and 19.0 g/dL). Overall, 30-day mortality was similar in the two groups (restrictive vs liberal transfusions), and patients in the restrictive group tended to have better outcomes than those in the liberal group. The superiority of a restrictive transfusion strategy was clear in patients who were less severely ill, but not as clear in patients with serious cardiac disease, severe infections, septic shock, and trauma.

The outcome of the trail by Hebert et al (2) has since stimulated discussion about transfusion triggers in specific subpopulations who may be particularly vulnerable to the adverse consequences of anemia and insufficient oxygen delivery, ie, patients with cardiac disease and patients receiving mechanical ventilation. Recently, Rao and colleagues (51) reported results from a large observational study of patients who had experienced an acute myocardial infarction, demonstrating that the risk of 30-day death was fourfold greater in patients who received transfusions compared to those who did not. In this study, (51) 30-day mortality was higher in patients transfused at nadir hematocrit levels > 25%. In an accompanying editorial, Hebert and Fergusson (52) cautioned against foregoing transfusions in cardiac patients altogether, noting that the population in the analysis of Rao et al (51) was younger and may therefore have seen less transfusion benefit than would have been expected in more elderly patients. Their editorial concludes, however, that transfusion triggers of 8 to 10 g/dL of hemoglobin remain controversial.

Anemia may be a key factor interfering with a patient's ability to safely wean from mechanical ventilation, (9) although the relationship of hemoglobin levels to successful weaning and outcomes has not been investigated thoroughly enough to draw conclusions. Hebert et al (53) conducted a post hoc evaluation of the effects of RBC transfusions on mechanical ventilation outcomes in a subset of patients enrolled in the Transfusion Requirements in Critical Care trial. (2) Of those enrolled, 713 patients (85%) required mechanical ventilation; 219 patients (26%) required mechanical ventilation for > 7 days. The restrictive group (n = 357) had a similar (p = 0.09) number of ventilator-free days as the liberal group (n = 356), and no significant difference was detected in the duration of mechanical ventilation (measured as ventilator-days). The likelihood of successful extubation was approximately 10% greater in the restrictive group vs the liberal group, but the difference was also not statistically significant. Higher rates of pulmonary edema, ARDS, cardiac complications, and in-hospital mortality were, in fact, associated with a liberal RBC transfusion strategy in the 713 patients receiving mechanical ventilation. In the smaller subgroup of patients who required mechanical ventilation > 7 clays (n = 219), neither the duration of ventilation, ventilator-free days, nor time to wean were different between the restrictive and liberal transfusion groups. (53) Therefore, in this study, (53) BBC transfusions administered liberally did not reduce the duration of mechanical ventilation or improve any other mechanical ventilation outcome. The authors (53) hypothesized that any benefit of increased oxygen delivery from liberal transfusions was likely to have been negated by the pulmonary edema that resulted from increased circulating volume. Even though this may represent the largest investigation of outcomes to date in this population, it should be noted that the study was neither designed nor powered to examine outcomes with and without transfusions in mechanically ventilated patients. Specifically, there was no protocol for weaning and extubation, and the observations were based on a subset of patients from a larger trial, thus limiting the strength of inferences made about anemia, transfusions, weaning patients from mechanical ventilation, and outcomes. Thus, although it seems reasonable to speculate that improving oxygen delivery will facilitate weaning from mechanical ventilation, the therapeutic intervention that can best help achieve this goal is still undetermined.

TREATMENT OF ANEMIA WITH EPOETIN ALFA IN PATIENTS RECEIVING LONG-TERM ACUTE CARE

In light of the evidence that the benefits of transfusions may not outweigh their risks, treatment of anemia with an erythropoietic agent may be an alternative strategy in critically ill patients. To investigate this concept, a randomized, double-blind, placebo-controlled, two-center trial (54) was conducted in patients who had been transferred to long-term acute care (LTAC) facilities. The study was designed primarily to evaluate the cumulative number of RBC units transfused in epoetin alfa-treated patients vs those who received placebo injections. A restrictive RBC transfusion strategy was implemented, using a hemoglobin concentration of 8 g/dL as the transfusion trigger. The demographics and baseline characteristics of the patients included in this study (n = 86) were well balanced across treatment groups with respect to age, gender, and admission diagnosis. Diagnoses included postoperative, trauma, neurologic, cardiovascular, pneumonia, ARDS, sepsis, deep vein thrombosis, pulmonary embolus, or other respiratory conditions with some overlap (ie, some patients had multiple admitting diagnoses). Baseline hemoglobin levels, however, were significantly different (p = 0.02) between groups (9.9 in the epoetin alfa group, vs 9.3 in the placebo group). Fifty-five percent (n = 47) of these patients were receiving mechanical ventilation.

Administration of epoctin alfa weekly for up to 12 doses resulted in a statistically significant decrease in the likelihood of receiving RBC transfusions compared to patients receiving placebo. Thirty-one percent of patients in the epoetin alfa group received transfusions, compared with 61.4% in the placebo group (p = 0.006) [Table 1], although the epoetin alfa group had significantly higher hemoglobin levels at baseline, possibly accounting for the fewer number of BBC transfiisions. However, after adjusting for the baseline hemoglobin differences with a multiple regression analysis, the odds ratio for risk of receiving a RBC transfusion was 0.28, still significantly lower (p = 0.03) for epoetin alfa-treated vs placebo-treated patients. Transfusion rates normalized per patient and per days alive were also significantly lower in epoetin alfa-treated patients (Table 1). The likelihood of receiving the first transfusion increased over time in the ICU for both groups (Fig 1). Treatment with epoetin alfa significantly increased the hemoglobin concentration over baseline compared to placebo (1.0 g/dL and 0.4 g/dL, respectively) and markedly reduced the requirements for allogeneic RBC transfusions. Compared with placebo-treated patients, those treated with epoetin alfa had more than a 50% reduction in the likelihood of receiving RBC transfusions and also a > 50% reduction in the cumulative number of RBCs transfused. The effect of epoetin alfa treatment had a delayed onset of 5 to 7 days, presumably because of the time needed to generate new erythrocytes. The maximum benefits of epoetin alfa were not observed until day 42 but persisted through day 84 vs placebo.

[FIGURE 1 OMITTED]

The cumulative probability of mortality (Fig 2) for the two treatment groups followed a similar pattern to the cumulative probability of transfusion. The data depicted in Figure 2 suggest a survival benefit with epoetin alfa treatment compared to placebo. The difference did not reach statistical significance however (p = 0.1673). Thus, studies to date examining epoetin alfa in the critically ill have not been able to demonstrate a significant effect on mortality.

[FIGURE 2 OMITTED]

The rationale for the use of epoetin alfa in this setting is that, in critically ill patients, endogenous erythropoietin levels are low and do not increase in response to the physiologic stimuli. (55-59) These results in patients receiving LTAC demonstrated correction of anemia and reduction of transfusion requirements and are consistent with previous studies (60,61) of epoetin alfa in the general population of critically ill patients.

The availability of iron is critical for erythropoiesis, and in critically ill patients iron metabolism is often abnormal as a result of inflammatory conditions.(62) A recent cross-sectional sttldy (63) assessed the prevalence of iron deficiency in a random sample of critically ill ICU patients. Anemia (hemoglobin level < 12 g/dL) was present in 76% of patients, and a functional iron deficiency was correlated with the inflammatory status and the length of ICU stay. Moreover, a real iron deficiency was present in 21% of the ICU patients who had immune-associated functional iron deficiency (transferrin saturation < 20%; ferritin < 100 ng/mL, and serum transferrin receptor levels > 2.3 mg/dL). Thus, if therapy with an erythropoietie agent is being considered as a means to reduce RBC transfusion requirements in the critically ill or in long-term care patients, the patient's iron status should be ascertained. (63) If the results of such screening indicate the need for supplemental iron, oral iron may be inadequate because of poor absorption and GI adverse effects. Caution is warranted, however, if parenteral iron is to be used, since there are data to suggest that bacteria may be encouraged to proliferate in an iron-rich environment. (64,65) In a recent review of the topic of iron metabolism in the critically ill, Darveau and colleagues (62) concluded that there are insufficient data to support administration of oral or parenteral iron in critically ill patients, but the authors also note the scarcity of data in this population. An assessment of risk and benefit should be made for individual patients with careful monitoring of iron, hemoglobin, and infection risk.

DOES TREATING ANEMIA AFFECT WEANING FROM MECHANICAL VENTILATION?

Maintaining critically ill patients on long-term mechanical ventilation has economic implications, and thus an understanding of the key predictive variables for the possibility of weaning and the time to wean is of considerable interest. We therefore undertook a study to examine the electronic medical records from 3,001 consecutive patients receiving mechanical ventilation from five LTAC facilities. (66) This data set comprises the largest patient population utilized for this type of statistical analysis to date. After analyzing > 120 demographic, clinical, and physiologic data elements, we found that 30 variables were suitable for model development (Table 2).

A prior hospital length of stay, albumin concentration, and peak inspiratory pressure were three factors predictive of both the possibility of weaning and the time to wean. In addition, we observed that the patient's age and BUN concentration accounted for variations in the possibility of weaning, while the presence of cancer in the patient and the Glasgow coma score were key variables for the time to wean. Interestingly, we could not conclude that the hematocrit was a factor in either predicting the possibility of weaning or the time to wean. The strength of the model was quantified for consistency, based on this large sample size, in which a receiver operator curve value of 71% was obtained.

Other studies, (67-69) however, have shown that higher hemoglobin levels may facilitate weaning. Subsequent studies designed to directly qualify the effect of hemoglobin on clinical outcomes of these patients are necessary. Because anemia is common, easy to detect, and treatment options exist, this information would be valuable for intensivists and physicians at LTAC facilities and would facilitate management and weaning of patients requiring mechanical ventilation.

CONCLUSION

Anemia is common in critically iii patients receiving long-term mechanical ventilation. Although it is possible that treatment of anemia may have a positive impact on outcomes, further study is required. The traditional approach to managing critically ill patients with low hemoglobin levels has been to administer RBC transfusions. Evidence has emerged that RBC transfusions pose a variety of risks, including an increased risk of pulmonary complications in patients receiving mechanical ventilation. Questions also exist about the relative efficacy of stored RBCs and whether RBC transfusions improve oxygen delivery and outcomes. Endogenous erythropoietin levels are low in critically ill patients, and epoetin alfa has been shown to improve hemoglobin levels and to reduce the need for transfusions in this population. Data from a small clinical trial (54) indicated that it is possible to reduce transfusion requirements in longterm acute care patients, many of whom were mechanically ventilated, by administering epoetin alfa. However, there is insufficient evidence to understand whether this treatment, by virtue of its ability to reduce BBC transfusion requirements, improves outcomes. Larger and more detailed studies are also necessary to determine whether correction of anemia by any means--RBC transfusions or erythropoietic agents--affects weaning from mechanical ventilation, length of ICU stay, or mortality in this patient subtype. Future studies focused on the management of anemic patients receiving long-term mechanical ventilation will help establish clear criteria for reducing risks and improving clinical outcomes.

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* From the Division of Pulmonary and Critical Care Medicine, Rush University Medical Center, Chicago, IL.

The following authors have indicated to the ACCP that no significant relationships exist with any company/organization whose products or services may be discussed in their article: Michael R. Silver, MD, FCCP.

The following authors have disclosed that he or she may be discussing information about a product/procedure/technique that is considered research and is not yet approved for any purpose: Michael R. Silver, MD, FCCP: Use of erythropoeitin in chronically critically ill patients.

This publication was supported by an educational grant from Ortho Biotech Products, L.P.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).

Correspondence to: Michael R. Silver, MD, FCCP, Associate Vice President, Medical Affairs, Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Rush University Medical Center, 1653 West Congress Parkway, Chicago, IL 60612; e-mail: msilver2@rush.edu

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