Gram-negative sepsis and the adult respiratory distress syndrome

Gram-negative sepsis has dramatically increased in frequency throughout the twentieth century in the United States. Currently, approximately 200,000 patients develop gram-negative sepsis each year in this country. Of these, about one-quarter develop the adult respiratory distress syndrome (ARDS). Among these critically ill patients, mortality is estimated at 60%-90%. In the complex series of events leading to acute lung injury in gram-negative sepsis, endotoxin is the proximal mediator. Although endotoxin may be capable of causing direct injury to the pulmonary endothelium, its primary role is as a trigger activating inflammatory agents, including complement, neutrophils, and platelets, and inducing the production of cytokines and arachidonic acid metabolites. The end results are impairment of the endothelial barrier, diffusely increased capillary permeability, and adherence of neutrophils to the endothelium with subsequent migration into the tissues. The consequent clinical syndrome is one of acute respiratory distress with pulmonary edema, poorly compliant lungs, and refractory hypoxemia. Endothelial injury often becomes widespread, leading to the failure of multiple organs, including the kidneys, brain, intestine, and liver. Conventional therapy consists of supplemental oxygen, positive end-expiratory pressure, inotropic agents, fluid management, and antibiotics aimed at the offending pathogen. Recent discoveries regarding the mediators of sepsis as well as the expansion of the biotechnological armamentarium have provided clinicians with a plethora of new tools with which to manipulate the host's inflammatory response. The challenge for the next decade will be to ensure the safety, efficacy, and cost-effective use of these expensive but potentially lifesaving immunomodulators, singly or in combination, as adjuvant therapy.