R. Bruce Light

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.

The clinical evaluation committee in a large multicenter phase 3 trial of drotrecogin alfa (activated) in patients with severe sepsis (PROWESS): role, methodology, and results.

ObjectiveIn the multinational PROWESS trial, drotrecogin alfa (activated) significantly reduced mortality rate in patients with severe sepsis compared with placebo. The use of large multiple-center trials can potentially complicate interpretation of results in severe sepsis populations because of variability in medical attitudes and practices and the frequency of confounding events such as protocol violations. The objective of this study was to perform a blinded, critical, integrated review of data from the 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial using a Clinical Evaluation Committee. DesignBlinded, critical, integrated review of data. SettingParticipating sites. PatientsThe 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial. InterventionsWe performed analyses of the optimal cohort, defined as patients who had full compliance with the protocol, had evidence of an infection, and received adequate anti-infective therapy. We also performed other analyses, including significant underlying disorders, life support measures, and causes of death. Measurements and Main ResultsThe optimal cohort of 81.4% of the intention-to-treat population [drotrecogin alfa (activated), n = 695; placebo, n = 680] had similar baseline severity of illness between the two groups, a similar pharmacodynamic effect, and a relative risk of death estimate consistent with that observed in the overall PROWESS trial (0.83, 95% confidence interval 0.69–0.99 vs. 0.806, 95% confidence interval 0.69–0.94). A beneficial effect of drotrecogin alfa (activated) similarly was observed in patients with significant underlying disorders (0.73, 95% confidence interval 0.57–0.93) who were more severely ill and had a higher percentage of patients forgoing life-sustaining therapy. In contrast with the original investigator determinations, a benefit associated with drotrecogin alfa (activated) treatment in urinary tract infection adjudicated by the Clinical Evaluation Committee was observed. ConclusionsThe survival benefit associated with drotrecogin alfa (activated) use was consistent with the results of the overall trial regardless of whether patients met criteria of the optimal cohort or had a significant underlying disorder.

Epidemiology and Clinical Spectrum of Blastomycosis Diagnosed at Manitoba Hospitals

Blastomyces dermatitidis is a dimorphic fungus endemic to Canada and the United States. Few reports regarding blastomycosis in Canada have been published. We retrospectively reviewed the medical charts of 143 patients with confirmed cases of blastomycosis diagnosed in hospitals in Manitoba, Canada, from 1988 through 1999. The annual incidence rate of blastomycosis in Manitoba was 0.62 cases per 100,000 population, compared with 7.11 cases per 100,000 population in the Kenora, Ontario district. The average age of patients was 38.0 years, and males accounted for 65.0% of cases. An increased incidence of blastomycosis was observed in the Aboriginal subpopulation. Organ systems involved were as follows: respiratory system (93.0% of cases), skin (21.0%), bone (13.3%), genitourinary tract (1.4%), and the central nervous system (1.4%); 6.3% of patients died, and death was associated with a short clinical course. This study provides a summary of the current status of blastomycosis in this area of endemicity in Canada.

EFFECT OF INDOMETHACIN ON ARTERIAL OXYGENATION IN CRITICALLY ILL PATIENTS WITH SEVERE BACTERIAL PNEUMONIA

The effect of indomethacin (1 mg/kg) on gas exchange was studied in ten patients with hypoxaemic respiratory failure precipitated by bacterial pneumonia. Mean arterial oxygen tension (PaO2) improved significantly (79 +/- 16 mm Hg to 98 +/- 20 mm Hg) but the response varied between patients: five showed substantial responses (27-42 mm Hg), three lesser responses (7-9 mm Hg), and two no response. Similar changes were found in the alveolar-arterial oxygen gradient and the ratio of PaO2 to fractional inspired oxygen concentration. In two responders studied further, PaO2 had fallen to baseline values 4-6 h later and a repeat indomethacin challenge again increased PaO2 by greater than 25 mm Hg with concomitant changes in pulmonary shunt. There were no significant changes in the other gas-exchange or haemodynamic variables measured and there was no clear reason for the variability in response to indomethacin. These results suggest a role for products of the cyclo-oxygenase pathway of arachidonic acid metabolism in the pathogenesis of hypoxaemia in patients with severe bacterial pneumonia.

EFFECTS OF PROLONGED NALOXONE INFUSION IN SEPTIC SHOCK

Fourteen patients suffering sixteen episodes of septic shock requiring inotrope and/or vasopressor support were randomised to receive a 30 micrograms/kg naloxone intravenous bolus followed by a 30 micrograms/kg/h infusion or an equivalent volume placebo bolus and infusion for 8-16 h in a double-blind study. pH and pulmonary wedge pressure were kept constant, and inotrope and/or vasopressor were titrated to maintain a preselected mean blood pressure. Inotrope/vasopressor requirements in the naloxone-treated group were significantly lower than those in the control group at 8 h (eight patients in each group, p less than 0.005) and at 16 h (five patients in each group, p less than 0.02). Late but significant improvements in stroke volume (p less than 0.02) and heart rate (p less than 0.05) were also noted in the eight naloxone-treated patients.

Lysozyme: a mediator of myocardial depression and adrenergic dysfunction in septic shock in dogs

The objective of the present study was to identify the nature of a filterable cardiodepressant substance (FCS) that contributes to myocardial dysfunction in a canine model of Escherichia coli septic shock. In a previous study, it was found that FCS increased in plasma after 4 h of bacteremia (Am J Physiol 1993;264:H1402) in which FCS was identified by a bioassay that included a right ventricular trabecular (RVT) preparation. In that study, FCS was only partially identified by pore filtration techniques and was found to be a protein of molecular weight between 10 and 30 K. In the present study, FCS was further purified by size exclusion high-pressure liquid chromatography, until a single band was identified on one-dimensional gel electrophoresis. This band was then subjected to tandem mass spectrometry and protein-sequencing techniques and both techniques identified FCS as lysozyme c (Lzm-S), consistent with that originating from the canine spleen. Confirmatory tests showed that purified Lzm-S produced myocardial depression in the RVT preparation at concentrations achieved during sepsis in the in vivo preparation. In addition, Lzm-S inhibited the adrenergic response induced by field stimulation and the beta- agonist isoproterenol in in vitro preparations, these results suggesting that Lzm-S may inhibit the sympathetic response in sepsis. The present findings indicate that Lzm-S originating from disintegrating leukocytes from organs such as the spleen contributes to myocardial dysfunction in this model. The mechanism may relate to its binding or hydrolysis of a cardiac membrane glycoprotein thereby interfering with myocardial excitation-contraction coupling in sepsis.

Seasonal variations in the clinical presentation of pulmonary and extrapulmonary blastomycosis.

Blastomycosis is a granulomatous infection caused by the thermally dimorphic fungus, Blastomyces dermatitidis, for which seasonal variation has been proposed. We conducted a retrospective review of medical records of 324 patients with blastomycosis in Manitoba and northwestern Ontario. The average age of patients at the time of diagnosis was 39+/-20 (range, 0-85) years. Symptoms referable to blastomycosis were first noted in the autumn and winter (September to February) by 63% of the patients. The seasonal distribution of cases was different for localized pulmonary infection than the disseminated disease (P<0.0001). For localized lung disease, the peak incidence of symptom onset occurred in the autumn, and lowest incidence in the spring; one half (50%) of the patients with diffuse lung disease had onset of symptoms in the spring months and a few (11%) cases occurred during the summer. We noted a distinct seasonal variation in the clinical presentation of blastomycosis. The observed pattern suggests that summer environmental exposure and acquisition of the infection results in an early (1-6 months) localized pneumonia in the majority of cases, followed by later (4-9 months) reactivation or slow progression of asymptomatic infection resulting in isolated extrapulmonary or disseminated hematogenous disease in the minority.

N,n′,n′-triacetylglucosamine, an inhibitor of lysozyme, prevents myocardial depression in escherichia coli sepsis in dogs*

ObjectiveReversible myocardial depression in sepsis has been ascribed to the release of inflammatory mediators. We recently found that lysozyme c (Lzm-S), consistent with that originating from the spleen, was a mediator of myocardial depression in an Escherichia coli model of septic shock in dogs. We further showed in a right ventricular trabecular (RVT) preparation that Lzm-S’s depressant activity could be blocked by N,N′,N’ triacetylglucosamine (TAC), a competitive inhibitor of Lzm-S. We hypothesized that Lzm-S binds to or cleaves a cardiac membrane glycoprotein, thereby interfering with myocardial contraction in sepsis. In the present study, we examined whether TAC could prevent myocardial depression in an in vivo preparation and whether other related N-acetylglucosamine (NAG) structures could also inhibit Lzm-S’s effect in RVT. DesignRandomized experimental study. SettingUniversity laboratory. SubjectsAnesthetized, mechanically ventilated dogs. InterventionsWe produced sepsis by infusion of E. coli over an approximately 6-hr period. Measurements and Main ResultsWe examined the effect of TAC on stroke work, our primary index of myocardial function, when treatment was administered before sepsis (pretreatment) and after 1.5 hrs (early treatment study) and 3.5 hrs of sepsis (late treatment study; LTS). In the pretreatment study and early treatment study, myocardial depression would have not yet occurred but would have already been present in the late treatment study. In RVT, we assessed the effect of other NAG oligosaccharides and variants to the NAG structure on Lzm-S’s depressant activity. In pretreatment and the early treatment study, TAC prevented the reduction in stroke work observed in nontreated septic groups but did not reverse the reduction found in the late treatment study. In RVT, of the compounds tested, only N,N′-diacetylglucosamine showed an inhibitory effect. ConclusionsWe found that TAC, a competitive inhibitor of Lzm-S, prevented myocardial depression in experimental sepsis. Only specific NAG structures are inhibitory to Lzm-S’s depressant activity. TAC may be useful in attenuating cardiovascular collapse in sepsis.

Mycobacterium tuberculosis Septic Shock

BACKGROUND Septic shock due to Mycobacterium tuberculosis (MTB) is an uncommon but well-recognized clinical syndrome. The objective of this study was to describe the unique clinical characteristics, epidemiologic risk factors, and covariates of survival of patients with MTB septic shock in comparison with other bacterial septic shock. METHODS A retrospective nested cohort study was conducted of patients given a diagnosis of MTB septic shock derived from a trinational, 8,670-patient database of patients with septic shock between 1996 and 2007. RESULTS In the database, 53 patients had been given a diagnosis of MTB shock compared with 5,419 with septic shock associated with isolation of more common bacterial pathogens. Patients with MTB and other bacterial septic shock had in-hospital mortality rates of 79.2% and 49.7%, respectively (P < .0001). Of the cases of MTB shock, all but five patients had recognized respiratory tract involvement. Fifty-five percent of patients (29 of 53) were documented (by direct culture or stain) as having disseminated extrapulmonary involvement. Inappropriate and appropriate initial empirical therapy was delivered in 28 patients (52.8%) and 25 patients (47.2%); survival was 7.1% and 36.0%, respectively (P = .0114). Ten patients (18.9%) did not receive anti-MTB therapy; all died. The median time to appropriate antimicrobial therapy for MTB septic shock was 31.0 h (interquartile range, 18.9-71.9 h). Only 11 patients received anti-MTB therapy within 24 h of documentation of hypotension; six of these (54.5%) survived. Only one of 21 patients (4.8%) who started anti-MTB therapy after 24 h survived (P = .0003 vs < 24 h). Survival differences between these time intervals are not significantly different from those seen with bacterial septic shock due to more common bacterial pathogens. CONCLUSIONS MTB septic shock behaves similarly to bacterial septic shock. As with bacterial septic shock, early appropriate antimicrobial therapy appears to improve mortality.

Characterization of membrane N-glycan binding sites of lysozyme for cardiac depression in sepsis.

Purpose In sepsis, reversible myocardial depression has been ascribed to the release of mediators of inflammation. We previously found that lysozyme released from leukocytes from the spleen and other organs mediated myocardial depression in an Escherichia coli model of septic shock in dogs. We hypothesize that lysozyme binds to or cleaves a cardiac surface membrane N-glycoprotein to cause depression. The objectives of the present study were: 1) to determine whether the binding of lysozyme is reversible; 2) to assess the N-glycan structure to which lysozyme binds; 3) to examine whether nonenzymatic proteins, termed lectins, with a binding specificity similar to that of lysozyme could also cause depression; and 4) to assess whether the membrane to which lysozyme binds is affected by the enzymes protease type XIV and collagenase A, that are used to prepare single cell myocyte experiments.Methods We measured isometric contraction in a right ventricular trabecular preparation.Results We found that lysozyme binds in a reversible manner to the Man β(1–4) GlcNAc β(1–4)GlcNAc moiety in the tri-mannosyl core structure of high mannose/hybrid and tri-antennary carbohydrate classes where GlcNAc is N-acetylglucosamine and Man is mannose. Lectins with a specificity similar to that of lysozyme also caused depression, and lysozyme’s depressant activity was eliminated by protease type XIV and collagenase A.Conclusions These results indicate that lysozyme reversibly binds to a membrane glycoprotein to cause myocardial depression in sepsis. We further localize its binding site to a variant of the chitotriose structure in the tri-mannosyl core of the membrane glycoprotein.