ANEMIA, ALLOGENIC BLOOD TRANSFUSION, AND IMMUNOMODULATION IN THE CRITICALLY ILL

CHEST 2005; 127 (1) : 295-307

The study authors of this article sought to describe the epidemiology of anemia in critically ill patients, discuss the pathophysiology thereof, discuss the implications of red blood cell donation and storage, and discuss the effects of red blood cell transfusion in critically ill patients and what effects that may have on the immune system -- both infectious and immunomodulatory.

In the United States, a relatively static but slowly declining rate of blood donations exists. There are approximately 15 million units of blood donated each year in this country, of which 14 million units are consumed. A substantial proportion of blood transfusion occurs in the intensive care unit (ICU) and in critically ill patients. On average 16% of patients in medical ICUs and 27% of those in surgical ICUs receive a transfusion on any given day. By the third day of a patient's stay the ICU, more than 90% of patients will be anemic.[1] As many as 85% of patients with an ICU length of stay more than 7 days will receive at least 1 unit of blood, and on average these patients will receive 9.5 units during their ICU stay.[2]

The etiology of anemia in critically ill patients is multifactorial and complex. The etiology of anemia in critically ill patients is multifactorial and complex. Repeated phlebotomy contributes significantly to anemia, probably accounting for 25-50 mL of daily blood loss in ICU patients. Other smaller contributing factors include coagulopathy, pathogen-associated thrombolysis, reduced red blood cell survival, hypoadrenalism, and nutritional deficiencies.

Perhaps one of the more important determinants of anemia in critically ill patients is the decreased production of erythropoietin (EPO) and related impaired bone marrow sensitivity to the hormone. Critically ill patients have inappropriately low EPO concentrations, despite the presence or absence of renal failure.[3] Both a reduced production of EPO and resistance to EPO action are likely mediated through inflammatory mediators, such as interleukin and tumor necrosis factor (TNF). This results in reduced red blood cell synthesis and consequent anemia.

In large-scale trials studying transfusion strategies, it often appears that the transfusion trigger is highly variable and the reasons for transfusion are undefined.[4] Although transfusion of red blood cells is traditionally considered as a measure to ensure adequate tissue perfusion and oxygenation, there are data that question the effectiveness of red blood cell transfusion to increase oxygen delivery. In particular, it appears that the transfusion of older blood is less likely to improve oxygen delivery and more likely to cause splanchnic ischemia.[5] In a large cohort study of trauma patients, red blood cell transfusion was identified as an independent risk factor for multiple organ failure, with a clear dose-response relationship.[6] In multiply injured trauma patients, the age of blood was found to be an independent risk factor for the development of multiple organ failure.[7] In a study of postoperative cardiac surgery patients, the transfusion of red blood cells that had been stored for more than 28 days was an independent predictor of the development of nosocomial pneumonia.[8] A similar prospective cohort study of trauma patients demonstrated that the age of blood was an independent risk factor for the development of major infections.[9] More detailed analysis of stored red blood cells suggests that there is an association between the volume of red blood cell supernatant and the duration of mechanical ventilation, perhaps influenced by proinflammatory substances that accumulate during the storage of red blood cells.[10]

If transfusion of red blood cells may be ineffective or may in fact lead to harm, then more restrictive use of blood products may improve outcomes. In fact, in a large randomized trial conducted in Canada, critically ill patients who were randomized to maintain their hemoglobin levels between 7 g/dL and 9 g/dL appeared to fare better compared with patients whose hemoglobin levels were maintained at or above 10 g/dL.[11] The improved outcomes appeared to mostly relate to patients who were younger (< 55 years of age) and who were less severely ill (Acute Physiology And Chronic Health Evaluation [APACHE] II score < 25). Of note, there were fewer cardiac complications, including myocardial infarction and pulmonary edema, in the patients managed in the restrictive transfusion strategy group.

Storage of red blood cells may significantly alter the normal structure and function of the cells. Red blood cells stored from > 15 days have a reduced ability to deform and unload oxygen in the microcirculation. Complete depletion of 2,3-diphosphoglycerate concentrations occurs after approximately 2 weeks of storage, thereby also reducing by more than 50% the ability of transfused red blood cells to off-load oxygen. Stored red blood cells are also more likely to adhere to endothelial cells and potentially reduce perfusion. The normal antioxidant capacity of red blood cells may also be impaired through storage.

There are both immune and infectious complications of allergenic blood product transfusion. Infectious complications of red blood cell transfusion are rare, including viral and parasitic infections. Transfusion of red blood cells or any blood product also may modulate the immune system, known as transfusion-related immunomodulation. This may include adverse consequences, such as transfusion-related acute lung injury, transfusion-associated graft vs host disease, and the potential development of autoimmune diseases. Transfusion may modulate the immune system in humans either through alloimmunization or tolerance induction. Specifically, transfusion has been shown to cause a decrease in the helper-to-suppress T-cell ratio, a decrease in natural killer cell function, defective antigen presentation, the suppression of lymphocyte blastogenesis, and a reduction in delayed-type hypersensitivity and allograft tolerance. Leukodepletion may significantly reduce these risks, although it will not remove them altogether.

Excess morbidity and mortality associated with blood product transfusion are only beginning to be investigated. There are clearly rare but significant infectious complications of allergenic transfusion, although immunomodulation after transfusion is much more common, as it is likely to have significant consequences as well. Restricted transfusion strategies appear to be safe and probably effective in a large number of critically ill patients, permitting their hemoglobin levels to drop to as low as 7 g/dL prior to transfusion. Studies are ongoing to determine whether a true detriment can be assigned to old blood products, what blood-conservation strategies are most effective, and whether EPO is an effective alternative in the management of anemia.[12,13]