Sloane, Mark; Brake, Helga; Jacobi, Judith; Kahn, Jeremy; Pingleton, Susan; Steinberg, Kenneth Author Information

OBJECTIVE:Phase III study to confirm a trend observed in a previous phase II study showing that a single dose of lenercept, human recombinant p55 tumor necrosis factor receptor-immunoglobulin G1 (TNFR55-IgG1) fusion protein, decreased mortality in patients with severe sepsis or early septic shock. DESIGN:Multicenter, double-blind, phase III, placebo-controlled, randomized study. SETTING:A total of 108 community and university-affiliated hospitals in the United States (60), Canada (6) and Europe (42). PATIENTS:A total of 1,342 patients were recruited who fulfilled the entry criteria within the 12-hr period preceding the study drug administration. INTERVENTION:After randomization, an intravenous dose of 0.125 mg/kg lenercept or placebo was given. The patient was monitored for up to 28 days, during which standard diagnostic, supportive, and therapeutic care was provided. MEASUREMENTS AND MAIN RESULTS:The primary outcome measure was 28-day all-cause mortality. Baseline characteristics were as follows: a total of 1,342 patients were randomized; 662 received lenercept and 680 received placebo. The mean age was 60.5 yrs (range, 17-96 yrs); 39% were female; 65% had medical admissions, 8% had scheduled surgical admissions, and 27% had unscheduled surgical admissions; 73% had severe sepsis without shock, and 27% had severe sepsis with early septic shock. Lenercept and placebo groups were similar at baseline with respect to demographic characteristics, simplified acute physiology score II-predicted mortality, profiles of clinical site of infection and microbiological documentation, number of dysfunctioning organs, and interleukin-6 (IL-6) plasma concentration. Lenercept pharmacokinetics were similar in severe sepsis and early septic shock patients. Tumor necrosis factor was bound in a stable manner to lenercept as reflected by the accumulation of total serum tumor necrosis factor alpha concentrations. There were 369 deaths, 177 on lenercept (27% mortality) and 192 on placebo (28% mortality). A one-sided Cochran-Armitage test, stratified by geographic region and baseline, predicted 28-day all-cause mortality (simplified acute physiology score II), gave a p value of .141 (one-sided). Lenercept treatment had no effect on incidence or resolution of organ dysfunctions. There was no evidence that lenercept was detrimental in the overall population. CONCLUSION:Lenercept had no significant effect on mortality in the study population.

SUMMARY OF APPROACH The approach to surgery in the patient with COPD is summa-rized below. Surgery Definitely indicated Lung resection. Pulmonary function studies should be performedbefore lung resection. Simple spirometry has the greatest utilityin documenting physiologic operability. FEV, > 2 L in an adultman or > 60% of predicted is acceptable for pneumonectomy.Values below this suggest that further studies, such as split func-tion assessment by quantitative lung scintigraphy and exercisetesting, are warranted.FEV, predicted after lung resection to be less than 40 to 50%of normal for the patient’s sex, age, and height suggests highermorbidity and mortality. An exercise 90, of less than 10 to 15ml/min per kg of body weight is associated with higher mor-bidity and mortality after lung resection.All elective surgery Prophylaxis against deep venous throm-bosis should be given before most procedures that will requirepostoperative bed rest or significantly reduce mobility. Heparinin low doses seems well accepted for most procedures. Externalpneumatic compression of the lower legs can be used when anti-coagulants are contraindicated.

The effects of malnutrition and refeeding on nutritional indices, pulmonary function, and diaphragmatic contractile properties were studied in severely malnourished patients with anorexia nervosa. Fifteen patients were evaluated upon hospital admission (Day 0) and on Days 7, 30, and 45 after starting feeding. Spirometry, lung volumes, and arterial blood gases were measured at each time interval, as were contractile properties of the diaphragm as assessed by transdiaphragmatic pressure generated during electrical phrenic nerve stimulation (Pdistim) and a maximal sniff maneuver (Pdisniff). Anthropomorphic and biochemical measurements were performed at each time interval. Patients were severely malnourished upon admission; mean body weight was 37.1 +/- 4.7 kg (63% ideal body weight). During nutritional support, body weight increased significantly to 42.9 +/- 4.6 kg on Day 45 (p < 0.01), as did muscle mass: 11.2 +/- 4.1 kg on Day 0, to 16.6 +/- 4.9 kg on Day 45 (p < 0.01). Vital capacity and FEV1 increased significantly by Day 30 (p < 0.05). Lung volumes were unchanged. Mean arterial blood gas values were also within the normal range at Day 0; PaO2, 92.6 +/- 2.4 mm Hg and PacO2, 41.0 +/- 1.5 mm Hg. Four patients, however, had an increased PacO2 (> 42 mm Hg) at Day 0, which returned to normal by Day 30. Diaphragmatic contractility was severely depressed initially; Pdistim, 15.9 +/- 1.4 cm H2O; Pdisniff, 65.4 +/- 5 cm H2O; but it significantly increased with nutritional support by Day 30 to 22.5 +/- 1.9 and 84.6 +/- 4.7 cm H2O, respectively. We conclude that diaphragmatic function is severely impaired in malnuorished patients free of other coexisting