Transfusion practice in the critically ill : Can we do better ? *

Efforts by intensivists to define acute lung injury (ALI) must make cardiologists smile. ALI is a clinical syndrome that affects 200,000 patients annually in the United States, and current estimates place the overall mortality at approximately 40%, or 80,000 deaths each year. For comparison, approximately 50,000 people die of breast cancer, and 150,000 deaths occur from lung cancer each year. ALI is both common and life threatening, yet we lack simple clinical tests to accurately diagnose and categorize patients according to etiology, pathophysiology, and probable outcome. By contrast, more than one million people each year experience myocardial infarctions, with an in-hospital mortality rate of approximately 12% (1). Cardiologists have developed simple and remarkably rapid diagnostic tests that can be done at or near the point of care. The electrocardiogram provides an accurate and noninvasive report about the electrical activity of the myocardium, and a sensitive and specific blood test, serum troponin T, can be returned in 1 hr in most centers. Ventricular function can be estimated using noninvasive echocardiography at the patient’s bedside. Specific medical treatment begins within minutes of the time the patient reaches an emergency center, and complex interventional treatments that improve outcome can be applied within a few hours. In contrast, ALI is a clinical syndrome that is diagnosed when a patient develops critical hypoxemia, bilateral pulmonary infiltrates consistent with edema, normal measured or estimated left atrial filling pressure, and no other obvious cause for the radiographic findings, such as pulmonary masses or pleural effusions. We understand the major aspects of pathophysiology, but in the same 3 decades in which cardiologists have made remarkable progress in myocardial infarction, we have not developed specific biochemical tests for serum or plasma that can detect cellular injury to the pulmonary capillary endothelium or epithelium, and we lack a simple and accurate bedside test that tells clinicians about the nature of the injury that is occurring in the lungs. Even computed tomography of the lungs, which can detect regions of increased alveolar density with great sensitivity, cannot easily differentiate alveolar collapse from alveolar flooding, nor can it assess the degree of injury to pulmonary tissues. We know that ALI is associated with severe acute inflammation in the lungs, injury to the alveolar epithelium, and loss of the tight permeability barrier that restricts movement of extravascular fluid and proteins into the airspaces (2). Patients with relatively preserved alveolar epithelial function have a better prognosis (3). Inflammatory exudates fill alveolar spaces and impair surfactant function, oxidation reactions damage intraand extracellular proteins, and there is a major and sustained increase in liquid and protein permeability across the alveolar epithelial/endothelial barrier. Lung compliance is markedly reduced, and severe alterations in ventilation-perfusion relationships cause life-threatening hypoxemia. The repair process begins almost immediately, as markers of increased collagen production are detectable as soon as lung injury is clinically defined (4). At the same time, inflammation in the systemic circulation is reflected by fever, leukocytosis, and circulating cytokines in the plasma compartment (5, 6). Until recently, specific strategies to improve lung physiology and/or reduce lung inflammation have not been particularly successful. Surfactant replacement has not been beneficial in large randomized trials, and small trials of systemic antioxidants have not shown a protective effect, even though lung glutathione deficiency is a major risk factor for lung injury in humans (7–10). Ketoconazole, lysophylline, and prolonged treatment with a neutrophil elastase inhibitor all have failed to affect mortality (11, 12). Similarly, strategies to improve physiologic abnormalities with inhaled nitric oxide or prone positioning have not affected mortality in controlled randomized trials (13, 14). None of these trials specifically examined the direct effect of the treatment on lung pathophysiology, as reflected by inflammation, so we do not know why they failed. One of the great limitations in acute lung injury research has been the lack of validated markers of lung injury or systemic inflammation that can be used to predict the severity, outcome, or response to therapy (15). Such markers would be particularly useful in smaller trials designed to test the biological relevance of new treatment strategies— before commitments are made to a larger multiple-center randomized clinical trial. This concept was supported in principle by a small clinical trial in which cytokine concentrations in bronchoalveolar lavage and plasma were used as an intermediate end point to show that a lung-protective ventilation strategy reduced pulmonary and systemic inflammation in patients with ALI (6). This trial correctly predicted the results of the large National Institutes of Health (NIH) Acute Respiratory Distress Syndrome Network (ARDSnet) study, which showed that patients ventilated with a low tidal volume had better survival than patients ventilated with a higher tidal volume (16). However, what has been lacking in order to move this field forward has been a concurrent analysis of lung and blood inflammatory markers in a large trial in which an intervention produces a clear separation between two treatment groups. The NIH ARDSnet clinical research network has provided an important opportunity to close this gap. In this issue, Dr. Parsons and colleagues (17) report the results of plasma measurements of key proand anti-inflammatory cytokines in patients enrolled in the ARDSnet trial of lower vs. higher tidal volumes in patients with lung injury. The primary hypothesis was that at the onset of clinically defined lung injury, patients with more *See also p. 1.