Kalim Habet

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.

CRITICAL CARE IN THE UNITED STATES : Who Are We and How Did We Get Here?

Critical care medicine has progressed significantly over the past two to three decades. We will review the history and evolution of critical care medicine and ICUs in the United States. The evolving health care delivery system and the changing and important role of the intensivist will be addressed. Finally, a discussion about what critical care physicians must do to prepare for the future is presented.

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.

Interleukin-10 blunts the human inflammatory response to lipopolysaccharide without affecting the cardiovascular response

Objective:The objective of this study was to assess the efficacy of variations in dose and timing of administration of recombinant human IL-10 (rhIL-10) on inflammatory and cardiovascular responses in a human endotoxemia model of sepsis. Design:The authors conducted a randomized, placebo-controlled, double-blind trial. Setting:The study was conducted in a procedure room of an intensive-care unit. Participants:The study comprised 24 healthy male volunteers. Interventions:Interventions consisted of intravenous administration of rhIL-10 at 1, 10, or 25 &mgr;g/kg either 2 mins or 2 hrs before Escherichia coli lipopolysaccharide (4 ng/kg) or placebo. Measurements and Results:The placebo group receiving lipopolysaccharide alone demonstrated significant, time-dependent changes in vital signs, white blood cell counts, inflammatory cytokine/cortisol levels, and hemodynamic/cardiovascular (including echocardiographic) parameters over the duration of the study. rhIL-10, administered immediately before (concurrent) lipopolysaccharide resulted in decreased temperature and heart rate responses as well as decreased serum levels of proinflammatory cytokines (tumor necrosis factor-&agr;, IL-6), IL-1 receptor antagonist, cortisol, and total leukocytes/neutrophils compared with lipopolysaccharide alone. Dose-dependent effects were absent. In contrast, rhIL-10 administration 2 hrs before endotoxin augmented the endotoxin-induced IL-&bgr; and IL-1 receptor antagonist response. rhIL-10 failed to modulate major cardiovascular responses (cardiac output, stroke volume index, ejection fraction, peak systolic pressure/end-systolic volume ratio) to endotoxin in both study groups as assessed by echocardiography. Conclusion:Concurrent administration of rhIL-10 suppresses the human inflammatory/stress response but has no effect on the hemodynamic/cardiovascular response to endotoxin. Early administration of rhIL-10 can potentially augment elements of the cytokine inflammatory response to lipopolysaccharide. These findings suggest significant limitations of rhIL-10 as a potential immunomodulatory therapy for sepsis.