Eugene Bunnell

A lipid A analog, E5531, blocks the endotoxin response in human volunteers with experimental endotoxemia.

BackgroundEndotoxin (lipopolysaccharide [LPS]) has been associated with sepsis and the high mortality rate seen in septic shock. The administration of a small amount of LPS to healthy subjects produces a mild syndrome qualitatively similar to that seen in clinical sepsis. We used this model to test the efficacy of an endotoxin antagonist, E5531, in blocking this LPS-induced syndrome. MethodsIn a placebo-controlled, double-blind study, we randomly assigned 32 healthy volunteers to four sequential groups (100, 250, 500, or 1000 &mgr;g of E5531). Each group of eight subjects (six assigned to E5531, two assigned to placebo) received a 30-min intravenous infusion of study drug. LPS (4 ng/kg) was administered to all subjects as an intravenous bolus in the contralateral arm at the midpoint of the infusion. Symptoms, signs, laboratory values, and hemodynamics (by echocardiogram) were evaluated at prospectively defined times. ResultsIn subjects receiving placebo, LPS caused headache, nausea, chills, and myalgias. E5531 led to a dose-dependent decrease in these symptoms that was statistically significant (p < .05) except for myalgias. The signs of endotoxemia (fever, tachycardia, and hypotension) were consistently inhibited at the three higher doses (250, 500, and 1000 &mgr;g, p < .05). Tumor necrosis factor-&agr; and interleukin-6 blood levels were both lower in those who received E5531 (p < .0001). The C-reactive protein level and white blood cell count response were decreased at all doses (p < .0001). The hyperdynamic cardiovascular state (high cardiac index and low systemic vascular resistance) associated with endotoxin challenge was significantly inhibited at the higher doses of E5531. ConclusionsE5531 blocks the symptoms and signs and cytokine, white blood cell count, C-reactive protein, and cardiovascular response seen in experimental endotoxemia. This agent is a potent inhibitor of endotoxin challenge in humans and may be of benefit in the prevention or treatment of sepsis and septic shock.

Preload-independent mechanisms contribute to increased stroke volume following large volume saline infusion in normal volunteers: a prospective interventional study

IntroductionResuscitation with saline is a standard initial response to hypotension or shock of almost any cause. Saline resuscitation is thought to generate an increase in cardiac output through a preload-dependent (increased end-diastolic volume) augmentation of stroke volume. We sought to confirm this to be the mechanism by which high-volume saline administration (comparable to that used in resuscitation of shock) results in improved cardiac output in normal healthy volunteers.MethodsUsing a standardized protocol, 24 healthy male (group 1) and 12 healthy mixed sex (group 2) volunteers were infused with 3 l normal (0.9%) saline over 3 hours in a prospective interventional study. Individuals were studied at baseline and following volume infusion using volumetric echocardiography (group 1) or a combination of pulmonary artery catheterization and radionuclide cineangiography (group 2).ResultsSaline infusion resulted in minor effects on heart rate and arterial pressures. Stroke volume index increased significantly (by approximately 15–25%; P < 0.0001). Biventricular end-diastolic volumes were only inconsistently increased, whereas end-systolic volumes decreased almost uniformly. Decreased end-systolic volume contributed as much as 40–90% to the stroke volume index response. Indices of ventricular contractility including ejection fraction, ventricular stroke work and peak systolic pressure/end-systolic volume index ratio all increased significantly (minimum P < 0.01).ConclusionThe increase in stroke volume associated with high-volume saline infusion into normal individuals is not only mediated by an increase in end-diastolic volume, as standard teaching suggests, but also involves a consistent and substantial decrease in end-systolic volumes and increases in basic indices of cardiac contractility. This phenomenon may be consistent with either an increase in biventricular contractility or a decrease in afterload.

CARDIAC DYSFUNCTION DURING SEPTIC SHOCK

Cardiac dysfunction is common in sepsis and septic shock. An understanding of this pathophysiology is crucial in treatment of this disorder. This article reviews the numerous studies of septic shock in humans that focus on cardiovascular physiology, briefly addresses the possible etiology, and concludes with therapeutic implications.