Anthony R. Dal Nogare

Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock

Summary Background Despite the availability of potent antibiotics and intensive care, mortality rates from septic shock are 40–70%. We assessed the safety and efficacy of murine monoclonal antibody to human tumour necrosis factor α (TNF α MAb) in the treatment of septic shock. Methods In a randomised, multicentre, double-blind, placebo-controlled clinical trial in 105 hospitals in the USA and Canada, we randomly assigned 1879 patients a single infusion of 7·5 mg/kg TNFα MAb (n=949) or placebo (0·25% human serum albumin n=930). Our main outcome measurement was the rate of all-cause mortality at 28 days. Findings 382 (40·3%) of 948 patients who received TNFα MAb and 398 (42·8%) of 930 who received placebo had died at 28 days (95% CI −0·02 to 0·07, p=0·27). We found no association between therapy with TNFα MAb and increased rapidity in reversal of initial shock or prevention of subsequent shock. Similarly, baseline plasma interleukin-6 concentrations of more than 1000 pg/mL or detectable circulating TNF concentrations were not associated with improvement in survival after TNFα MAb therapy. Coagulopathy but not other organ or system failures, was significantly decreased in the TNFα MAb group compared with placebo (day 7, p Interpretation We did not find an improvement in survival after septic shock with TNFα MAb. Therapy not solely dependent on TNFα blockade may be required to improve survival.

Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study.

Objective To identify a safe and potentially effective recombinant tissue factor pathway inhibitor (rTFPI) dose for further clinical evaluation in patients with severe sepsis. Design Prospective, randomized, single-blind, placebo-controlled, dose escalation, multicenter, multinational phase II clinical trial. Setting Thirty-eight intensive care units in the United States and Europe. Patients Two hundred and ten subjects with severe sepsis who received standard supportive care and antimicrobial therapy. Interventions Subjects received a continuous intravenous infusion of placebo or rTFPI at 0.025 or 0.05 mg/kg/hr for 4 days (96 hrs). Measurements and Main Results There were no significant imbalances in demographics, severity of illness, or source of infection in patients randomized to placebo or either dose of rTFPI. A 20% relative reduction in 28-day all-cause mortality was observed when all rTFPI-treated patients were compared with all placebo patients. An improvement in pulmonary organ dysfunction score and in a composite intensive care unit score (pulmonary, cardiovascular, and coagulation) were also noted in the rTFPI-treated patients. Logistic regression modeling indicated a substantial treatment by baseline laboratory international normalized ratio (INR) interaction effect when only treatment and INR were in the model (p = .037) and when baseline Acute Physiology and Chronic Health Evaluation (APACHE II) and log10 interleukin 6 were adjusted for (p = .026). This interaction effect indicates that higher baseline INR is associated with a more pronounced beneficial rTFPI effect. There was no increase in mortality in subjects treated with either dose of rTFPI compared with placebo. Biological activity, as detected by a statistically significant reduction in thrombin-antithrombin complexes (TATc), was noted in the all rTFPI-treated patients compared with those receiving placebo. There were no major imbalances across all treatment groups with respect to safety. The frequency of adverse events (AEs) and severe adverse events (SAEs) was similar among the treatment groups, with a slight increase in SAEs and SAEs involving bleeding in the 0.05 mg/kg/hr rTFPI group. The overall incidence of AEs involving bleeding was 28% of patients in the all placebo group and 23% of patients in the all rTFPI-treated group; a slight but statistically insignificant increase in incidence of SAEs involving bleeding was observed in the all rTFPI group (9%) as compared with the all placebo group (6%;p = .39). Conclusions Although the trial was not powered to show efficacy, a trend toward reduction in 28-day all-cause mortality was observed in the all rTFPI group compared with all placebo. This study demonstrates that rTFPI doses of 0.025 and 0.05 mg/kg/hr could be safely administered to severe sepsis patients. Additionally, rTFPI demonstrated bioactivity, as shown by reduction in TATc complexes and interleukin-6 levels. These findings warrant further evaluation of rTFPI in an adequately powered, placebo controlled, randomized trial for the treatment of severe sepsis.

Southwestern Internal Medicine Conference: Septic Shock

ABSTRACT Septic shock (SS) is the most common type of shock encountered by internists, and its prevalence appears to be increasing. SS complicates all types of infections. The hemodynamic characteristics of SS include a low systemic vascular resistance and an elevated, but relatively inadequate, cardiac output. A cardiomyopathy frequently occurs. The major endogenous mediator of SS is tumor necrosis factor, and interleukins-1 and -2 may also contribute. Important secondary phenomena include release of platelet activating factor, vasodilator prostaglandins, and upregulation of adhesion molecules on polymorphonuclear leukocytes and endothelial cells. Current therapy is often ineffectual, and potentially promising new therapeutic approaches are reviewed.

Relationship between diabetes control and pulmonary function in insulin-dependent diabetes mellitus

PURPOSE To evaluate the effect of different levels of glycemic control on the pulmonary function of subjects with type I insulin-dependent diabetes mellitus. PATIENTS AND METHODS Eighteen subjects with type I insulin-dependent diabetes mellitus with no history or physical findings of respiratory disease. Patients were given insulin therapy with a standard twice-daily insulin injection regimen (standard treatment group) or a subcutaneous insulin infusion device (insulin pump) (intensive treatment group). Glycosylated hemoglobin (HbA1c) levels were determined at quarterly intervals in both groups of patients (standard treatment group, n = 10; intensive treatment group, n = 8). Pulmonary function and diffusing capacity for carbon monoxide (DLCO) were measured after 6 years of continuous follow-up. RESULTS The average HbA1c in the standard treatment group was significantly higher than that of the intensive treatment group throughout the 6 years of follow-up (p less than 0.001). The forced vital capacity of the standard treatment group was 85 +/- 3% of predicted as compared with 106 +/- 4% of predicted in the intensive treatment group (p less than 0.001). The DLCO was also significantly diminished in the standard treatment group as compared with that in the intensive treatment group (65 +/- 2% versus 87 +/- 4% of predicted) (p less than 0.001). CONCLUSION These data confirm previous reports of abnormal respiratory function in subjects with insulin-dependent diabetes mellitus and suggest that long-term near-normoglycemia may be beneficial in preventing the deterioration of pulmonary function associated with diabetes mellitus.

Case report: transverse myelitis associated with Epstein-Barr virus infection.

Transverse myelitis is a rare complication of Epstein-Barr virus (EBV) infection. This article describes a case of a previously healthy patient with a subacute transverse myelopathy. The cerebrospinal fluid showed lymphocytic pleocytosis and protein elevation. A magnetic resonance imaging scan demonstrated abnormal spinal cord signal intensity over several cervical and thoracic segments, suggesting the diagnosis of transverse myelitis. The patient was treated with high-dose corticosteroids and had a rapid improvement. Serologic studies for other viruses were negative; antibody tests indicated acute EBV infection. It is thought this represents a case of transverse myelitis associated with acute EBV infection. Although a few similar patients have been reported previously, this case is the first where EBV serology suggested the etiology at the time of diagnosis, when EBV antibody titers and polymerase-chain reaction for EBV DNA in the cerebrospinal fluid were performed, and when a magnetic resonance imaging scan was used for diagnosis and follow-up.

Southwestern Internal Medicine Conference: Adult Respiratory Distress Syndrome

ABSTRACT The Adult Respiratory Distress Syndrome (ARDS) is a fulminant form of respiratory failure affecting many seriously ill patients. The early manifestations of ARDS are caused by increased permeability of the alveo-lo-capillary barrier leading to pulmonary edema, stiff lungs, and a large right-to-left intrapulmonary shunt. Polymorphonuclear leukocytes (PMNS) are involved in the pathogenesis of most ARDS, and multiple PMN mechanisms can effect pulmonary injury; interactions between PMN adherence, proteolytic enzyme release, and oxygen radical production are emphasized. ARDS therapy remains largely supportive and has had little impact on mortality. The complications of infection and multiorgan failure play important roles in determining ARDS outcome.

Gastrointestinal gram-negative bacillary colonization accompanies oropharyngeal colonization but is not adversely affected by elevation of gastric pH☆☆☆

Abstract Colonization of the oropharynx with gram-negative bacilli (GNB) is a frequent forerunner of nosocomial pneumonia in critically ill patients. To investigate the patterns of colonization and possible endogenous reservoirs of infection, we used an established animal model of pharyngeal colonization and quantitated GNB in several sites in the respiratory and gastrointestinal tracts. Adult Sprague-Dawley rats underwent a 75% surgical renal infarction and postoperative food deprivation. Control (normal) animals had no surgery and were fed. Normal and infarcted animals were killed at either 24 or 48 hours after surgery. Oropharyngeal cultures were obtained and the trachea, left lung, distal esophagus, stomach, and a segment of the jejunum were removed and quantitatively cultured for GNB. Postoperatively, pharyngeal GNB increased markedly compared with control values. The GNB isolated were indigenous gastrointestinal tract flora. Gram-negative bacilli were not isolated from either the trachea or the lung. In contrast, animals with GNB pharyngeal colonization had increases in the number of GNB isolated from the esophagus and stomach. There were no GNB isolated from the jejunal segments in any of the animals. The magnitude of the gastrointestinal colonization did not change when the gastric pH of the colonized animals was raised by administration of the H 2 -receptor antagonist cimetidine. Our results suggest that enteric GNB rapidly colonize the oropharynx and upper gastrointestinal tract in this model of renal infarction, and that gastric acidity plays a minor role in the pathogenesis of this process.