General algorithm for the approach to a patient with both chronic lung disease and anemia. Often iron-deficiency anemia or the anemia of chronic disease, or both, can be present.
Evaluating the etiology of anemia in the patient with chronic lung disease
“Usual normal” ranges
Red cell parameters
MCV (mean corpuscular volume)
• As in other settings, anemia of chronic disease (ACD) is a normochromic, normocytic anemia.
MCHC (mean corpuscular hemoglobin concentration)
• Consider other causes of anemia, especially iron-deficiency anemia (IDA), if these parameters are outside of their normal ranges
MCH (mean corpuscular hemoglobin)
• IDA (iron deficiency anemia) is relatively common among persons with ACD and chronic lung disease. This is a treatable anemia
• Ferritin is an acute phase reactant. Among persons with chronic lung disease, acute or chronic inflammatory processes may elevate the serum ferritin, even in the co-presence of iron deficiency.
Content of hemoglobin in reticulocytes (CHR)
• Important to reassess periodically
• Assesses internal distribution of iron (i.e., “availability” for incorporation into Hgb and reticulocytes)
Absolute reticulocyte count
• Reticulocyte index = observed absolute reticulocyte count/normal absolute reticulocyte count.
Vitamin B12, Folate
• Manifests as a macrocytosis
Coexistence of iron-deficiency anemia (IDA) and ACD is relatively common. For cases where there is diagnostic uncertainty, there are two reasonable approaches. Direct staining of a bone marrow aspirate reveals features of ACD, IDA, or both. Iron supplementation (see Table 8.1) is recommended for both simple IDA and IDA in combination with ACD, and should be followed by repeat evaluation of the hematological profile. A positive response to a 4-week trial of iron supplementation therapy is diagnostically useful. However, lack of a response is possible when IDA coexists with ACD because ACD involves abnormal iron absorption due to deficient export by ferroportin in the duodenal enterocytes. If a patient has an unsatisfactory response to oral iron therapy, a clinician should consider intravenous iron therapy.
Transfusing the Anemic Patient with Lung Disease
The evidence is generally lacking to guide the clinician in decision-making regarding RBC transfusion triggers or thresholds for the patient with acute or chronic lung disease. Consideration should be given to whether the anemia is functionally limiting or whether the lung disease is so severe that transfusions will have very little impact on quality of life. Some insight into transfusion threshold in the acute setting comes from the seminal TRICC (Transfusion Requirements in Critical Care) trial, which demonstrated no benefit of a liberal RBC transfusion strategy (threshold of Hgb 10 g/dL) as compared to a restrictive (Hgb 7 g/dL) RBC transfusion threshold in nonbleeding adults with critical illness . The study population in this randomized trial included a broad cross-section of ICU patients, including those with acute respiratory insufficiency. Significantly, in subgroup analyses, younger patients (<55 years) and those with lower severity of illness (APACHE <20) fared significantly worse when assigned to the liberal-transfusion arm, and mortality and pulmonary morbidity were among the events represented excessively in this group.
More broadly, pulmonary morbidity has been documented in a number of clinical trials of “when to transfuse” in the acute care setting, or the RBC transfusion threshold . A clinically important question, recently asked anew with increasing intensity, is whether the duration of RBC storage influences clinical outcomes in potentially vulnerable transfused patients such as critically ill patients and those with acute coronary syndromes. Koch and colleagues’ retrospective analysis of patients undergoing cardiac surgery at the Cleveland Clinic demonstrated increased mortality among patients receiving RBC units stored greater than 14 days, as compared with patients receiving exclusively RBC units stored less than 14 days . Again, adverse pulmonary events, such as number of ventilator days, were among the morbidity excessively seen in patients receiving the older RBC units . Despite a carefully conducted multivariable regression upholding the findings, the retrospective nature of this study limits drawing inferences about causality, let alone calling for changes in the pattern of transfusion practice. But this study and others have led to sufficient concern over the consequences of transfusing older RBCs that randomized clinical trials were completed to compare clinical outcomes in patients assigned to “older” vs. “fresher” RBC-transfusion strategies [24, 25]. Lacroix and colleagues performed a randomized, blinded trial of critically ill adults receiving transfusions of either fresh RBCs (<8 days; stored 6.1 ± 4.9 days (mean ± SD)) or standard-issue RBCs (stored 22.0 ± 8.4 days). The 90-day mortality rate was similar for both groups (37% fresh vs. 35.3% standard) . Other complications like ARDS were similar between the two groups (5.7% fresh, 6.6% standard). Additionally, the fraction of patients who required invasive mechanical ventilation was comparable (97.5% in the fresh-RBC arm vs. 97.3% in the standard-issue RBC arm). Fergusson and colleagues performed a randomized, double-blind controlled trial in premature infants who were transfused either fresh RBCs (<7 days) or standard-issue (“dedicated donor”) RBCs. Fresh and standard RBC transfusion strategies were associated with similar rates of neonatal morbidities and mortality . Specifically, pulmonary complications like bronchopulmonary dysplasia occurred at similar rates in the two groups (31.9% fresh vs. 33.3% standard). Steiner and colleagues completed a randomized controlled trial that compared outcomes after the transfusion of fresher (<10 days) vs. older RBCs (>21 days) in patients undergoing complex cardiac surgery. The rates of mortality and adverse events were comparable between the two groups . At this time, the use of fresh RBCs to reduce morbidity and mortality is not justified.
Transfusing for Anemia in COPD
Interest in specifically detecting and treating anemia in the ill COPD patient was intensified by a frequently cited early report that RBC transfusion led to significant reductions in the work of breathing and minute ventilation in 20 anemic, COPD patients in an intensive care setting [29, 30]. In a smaller group of five ventilator-dependent COPD patients with anemia, the same authors reported successfully extubating the patients after raising the Hgb levels to 12 g/dL by transfusion . However, these results have not been replicated in a large, randomized controlled trial. Currently, there is no specific recommended RBC transfusion threshold in COPD, but rather it is recommended that symptoms attributable to the anemia should prompt transfusion if the clinician believes there is insufficient time to await other measures (e.g., iron replacement or EPO) .
Erythropoietin for Anemia in Chronic Lung Disease
There is no role for the routine use of erythropoiesis-stimulating agents (ESAs) in the typical patient with the chronic lung disease and ACD. Use of an ESA should in fact be avoided in patients whose anemia is related to concomitant lung cancer or other solid malignancy and its treatment (myelosuppressive chemotherapy) . The reader is referred to the corresponding chapters of this handbook for discussion and treatment algorithms.
Anemia as an Adaptive Response
The disappointing clinical outcomes in studies of RBC transfusion of anemic patients have generally (and appropriately) raised the question of whether RBCs stored for transfusion may be inferior to native RBCs. A case has also been made that anemia in chronic pulmonary and other diseases represents an adaptive state or response. Specifically, it has been argued that anemia benefits those with chronic illness via the following mechanisms: (a) the sequestration of iron in ACD serves to limit iron availability to microorganisms that require it for growth and proliferation in vivo; (b) minimizing the availability of free iron means avoiding toxic chemistry associated with oxidant responses typical of a chronic inflammatory state ; (c) the lower blood viscosity associated with anemia places a smaller load on the vulnerable cardiovascular system of the ACD/COPD patient.