Charles L. Sprung

Treatment of gram-negative bacteremia and septic shock with ha-1a human monoclonal antibody against endotoxin: A randomized, double-blind, placebo-controlled trial

BACKGROUNDnHA-1A is a human monoclonal IgM antibody that binds specifically to the lipid A domain of endotoxin and prevents death in laboratory animals with gram-negative bacteremia and endotoxemia.nnnMETHODSnTo evaluate the efficacy and safety of HA-1A, we conducted a randomized, double-blind trial in patients with sepsis and a presumed diagnosis of gram-negative infection. The patients received either a single 100-mg intravenous dose of HA-1A (in 3.5 g of albumin) or placebo (3.5 g of albumin). Other interventions, including the administration of antibiotics and fluids, were not affected by the study protocol.nnnRESULTSnOf 543 patients with sepsis who were treated, 200 (37 percent) had gram-negative bacteremia as proved by blood culture. For the patients with gram-negative bacteremia followed to death or day 28, there were 45 deaths among the 92 recipients of placebo (49 percent) and 32 deaths among the 105 recipients of HA-1A (30 percent; P = 0.014). For the patients with gram-negative bacteremia and shock at entry, there were 27 deaths among the 47 recipients of placebo (57 percent) and 18 deaths among the 54 recipients of HA-1A (33 percent; P = 0.017). Analyses that stratified according to the severity of illness at entry showed improved survival with HA-1A treatment in both severely ill and less severely ill patients. Of the 196 patients with gram-negative bacteremia who were followed to hospital discharge or death, 45 of the 93 given placebo (48 percent) were discharged alive, as compared with 65 of the 103 treated with HA-1A (63 percent; P = 0.038). No benefit of treatment with HA-1A was demonstrated in the 343 patients with sepsis who did not prove to have gram-negative bacteremia. For all 543 patients with sepsis who were treated, the mortality rate was 43 percent among the recipients of placebo and 39 percent among those given HA-1A (P = 0.24). All patients tolerated HA-1A well, and no anti-HA-1A antibodies were detected.nnnCONCLUSIONSnHA-1A is safe and effective for the treatment of patients with sepsis and gram-negative bacteremia.

The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study.

To determine whether corticosteroids are efficacious in severe septic shock, we conducted a prospective study of 59 patients randomly assigned to a methylprednisolone, dexamethasone, or control group. Patients were treated 17.5 +/- 5.4 hours (mean +/- S.E.M.) after the onset of shock, and 55 patients required vasopressor agents. Early in the hospital course, reversal of shock was more likely in patients who received corticosteroids than in those who did not. Four (19 per cent) of 21 methylprednisolone-treated, 7 (32 per cent) of 22 dexamethasone-treated, and none of 16 control patients had reversal of shock 24 hours after drug administration (corticosteroid groups vs. control group, P less than 0.05). Patients treated with corticosteroids within four hours after the onset of shock had a higher incidence of shock reversal (P less than 0.05). At 133 hours after drug administration, 17 (40 per cent) of 43 corticosteroid-treated patients had died, and 11 (69 per cent) of 16 control patients had died (P less than 0.05). However, these differences in reversal of shock and survival disappeared later in the course. Overall, 16 (76 per cent) of 21 patients receiving methylprednisolone, 17 (77 per cent) of 22 patients receiving dexamethasone, and 11 (69 per cent) of 16 controls in the hospital died. We conclude that corticosteroids do not improve the overall survival of patients with severe, late septic shock but may be helpful early in the course and in certain subgroups of patients.

Treatment of Gram-Negative Bacteremia and Septic Shock with HA-1A Human Monoclonal Antibody against Endotoxin

BACKGROUNDnHA-1A is a human monoclonal IgM antibody that binds specifically to the lipid A domain of endotoxin and prevents death in laboratory animals with gram-negative bacteremia and endotoxemia.nnnMETHODSnTo evaluate the efficacy and safety of HA-1A, we conducted a randomized, double-blind trial in patients with sepsis and a presumed diagnosis of gram-negative infection. The patients received either a single 100-mg intravenous dose of HA-1A (in 3.5 g of albumin) or placebo (3.5 g of albumin). Other interventions, including the administration of antibiotics and fluids, were not affected by the study protocol.nnnRESULTSnOf 543 patients with sepsis who were treated, 200 (37 percent) had gram-negative bacteremia as proved by blood culture. For the patients with gram-negative bacteremia followed to death or day 28, there were 45 deaths among the 92 recipients of placebo (49 percent) and 32 deaths among the 105 recipients of HA-1A (30 percent; P = 0.014). For the patients with gram-negative bacteremia and shock at entry, there were 27 deaths among the 47 recipients of placebo (57 percent) and 18 deaths among the 54 recipients of HA-1A (33 percent; P = 0.017). Analyses that stratified according to the severity of illness at entry showed improved survival with HA-1A treatment in both severely ill and less severely ill patients. Of the 196 patients with gram-negative bacteremia who were followed to hospital discharge or death, 45 of the 93 given placebo (48 percent) were discharged alive, as compared with 65 of the 103 treated with HA-1A (63 percent; P = 0.038). No benefit of treatment with HA-1A was demonstrated in the 343 patients with sepsis who did not prove to have gram-negative bacteremia. For all 543 patients with sepsis who were treated, the mortality rate was 43 percent among the recipients of placebo and 39 percent among those given HA-1A (P = 0.24). All patients tolerated HA-1A well, and no anti-HA-1A antibodies were detected.nnnCONCLUSIONSnHA-1A is safe and effective for the treatment of patients with sepsis and gram-negative bacteremia.

Risk of right bundle-branch block and complete heart block during pulmonary artery catheterization

The need for the prophylactic insertion of a pacemaker before pulmonary artery catheterization in patients with pre-existing left bundle-branch block (LBBB) is controversial. To determine the incidence of new right bundle-branch block (RBBB) and complete heart block during bedside pulmonary artery catheterization, 293 patients undergoing 307 pulmonary artery catheterizations were prospectively studied. Nine patients had pacemaker rhythms and 19 patients had an RBBB on their precatheterization ECGs and therefore were excluded from analysis. In the remaining 279 pulmonary artery catheterizations, eight (3%) were associated with the development of a new RBBB. None of the 14 patients with a pre-existing LBBB developed complete heart block. The incidence of complete heart block during pulmonary artery catheterization of patients with previous LBBB was not higher than the incidence of RBBB in patients without underlying conduction defects. Because of the rare but grave consequences of RBBB in patients with pre-existing LBBB, we recommend the use of standby external pacemakers and equipment for transvenous pacemaker insertion in these patients during pulmonary artery catheterization. We do not recommend prophylactic pacemaker insertion.

The new sepsis consensus definitions: the good, the bad and the ugly

Introduction Despite improvements in diagnosis and management, sepsis and septic shock remain frequent causes of morbidity and mortality. Singer and colleagues [1–3] recently updated the consensus definitions of sepsis and septic shock to improve both sensitivity and specificity compared with the previous definitions [4]. We present here our opinions of the potential ramifications of this important work (Table 1).

Pacemaker Inhibition by Myopotentials Detected by Holter Monitoring

Ambulatory eiectrocardiography revealed myopoiential inhibition of a demand ventricular pacemaker in each of two patients. Although it was first regarded as artifact, fine baseline osciliations observed during apparent pacemaker malfunction actualiy signalled skeletal muscie‐induced pacemaker inhibition. Though not widely recognized, myopotential inhibition may be a common occurrence in unipolar lead systems. As greater numbers of patients undergo ambulatory monitoring, awareness of this phenomenon should become more widespread

HA-1A in septic patients with ARDS: Results from the pivotal trial

ObjectiveTo evaluate the effects of HA-1A, a human monoclonal antiendotoxin antibody, in septic patients with ARDS.DesignSubstudy of a multicenter, double-blinded, placebo-controlled trial of HA-1A in septic patients.Patients63 septic patients with ARDS at the time of study entry.InterventionA single intravenous injection of HA-1A (100 mg) or placebo.ResultsA quantitative radiographic score, the PaO2/FIO2 ratio and an index of the severity of ARDS did not show a significant difference between the treatment and placebo groups at 3, 5 and 7 days after treatment. The duration of endotracheal intubation did not differ between the two groups. 15 of 30 HA-1A treated patients (50%) and 23 of 33 placebo-treated patients (69.7%) died within 28 days. The daily mortality was always lower in the HA-1A group, but this difference was not statistically significant at 28 days. The 28-day survival curves for the two treatment groups adjusted by covariate analysis were not significantly different (p=0.07). Using logistic regression, a significant independent effect of HA-1A treatment was detected upon the early survival rate at 7 days (p=0.03) but not at 14 and 28 days.ConclusionA single injection of HA-1A in septic patients with ARDS did not reverse acute respiratory failure or improve long-term survival.

Corticosteroids, Nonsteroidal Anti-Inflammatory Drugs, and Naloxone in the Sepsis Syndrome

Corticosteroids have proven to be effective as adjunctive treatment in sepsis and severe typhoid fever when used early and in high doses. If corticosteroids are given in high doses (30 mg/kg), they should be administered in 1–2 doses, and not to exceed 4 total doses within 24 hours. The efficacy of the drug may be diminished in more severe sepsis, but use of corticosteroids in severe sepsis may delay death. If the benefit of corticosteroid use in late sepsis is only to prolong impending death, then steroid administration is probably futile; however, the alternative view is that corticosteroid use may constitute one step in a series leading to shock reversal and recovery. Risks and benefits of corticosteroid use should be tailored to the individual patient with consideration given to the nature and extent of the underlying disease. Although the pathophysiology of the sepsis syndrome remains elusive, new therapeutic regimens may evolve using nonsteroidal anti-inflammatory drugs and neuropeptide antagonists. As with corticosteroids, their application before or early after the onset of shock appears more beneficial; however, the patient population that will benefit most from treatment with these drugs remains, for the most part, unidentified, and more clinical trials are needed.RésuméLes corticostéroïdes ont fait leur preuve en tant quagent thérapeutique complémentaire quand ils sont employés précocement et à hautes doses dans linfection et la fièvre typhoïde. Si les corticostéroïdes sont donnés à hautes doses (30 mg/kg), ils doivent être administrés en 1–2 doses et ne jamais dépasser 4 doses par 24 heures. Lefficacité du médicament peut être faible dans les infections graves, il est alors seulement susceptible de retarder le décès. En fait, si lemploi se limite à ce seul bénéfice, il paraît inutile dy avoir recours. A linverse, la corticothérapie peut représenter une étape utile et efficace du traitement du choc. Les bénéfices et les risques de la corticothérapie doivent être appréciés en fonction de chaque malade et plus particulièrement de la nature et de lintensité de laffection dont il est victime. Bien que la physiopathologie du syndrome infectieux reste insaisissable, de nouveaux protocoles thérapeutiques comportant des anti-inflammatoires non stéroïdiens et des antagonistes neuropeptidiques peuvent être employés. Comme pour les corticoïdes leur usage avant ou au début du choc donne les meilleurs résultats. En fait, la population des malades qui peut bénéficier de lemploi de ces agents médicamenteux nest pas parfaitement définie et de très nombreux essais cliniques sont indispensables pour définir les meilleures indications.ResumenLos corticosteroides han probado ser efectivos como tratamiento adyuvante cuando se utilizan precozmente y en altas dosis en la sepsis y en la fiebre tifoidea grave. Si los corticosteroides son administrados en altas dosis (30 mg/kg), éstos deben darse en 1–2 dosis y no exceder un total de 4 dosis en 24 horas. La eficacia de la droga puede verse disminuida en casos de sepsis mas severa, pero su uso en el estado séptico puede diferir la mortalidad. Si el beneficio del uso de los corticosteroides en sepsis tardía es únicamente el de retardar una muerte inminente, entonces la administración de esteroides sería fútil; sinembargo, la perspectiva alterna es que el uso de corticosteroides constituye un escalón de una serie de eventos que resultan en la reversion del shock y la recuperation. Los riesgos y los beneficios del uso de corticosteroides deben ser ajustados a cada paciente individual con la debida consideración a la naturaleza y gravedad de la enfermedad de base. Aunque la patofisiología del síndrome de sepsis se mantiene elusivo, es previsible que nuevos regimenes terapéuticos puedan ser desarrollados con el uso de drogas anti-inflamatorias no esteroides y antagonistas neuropéptidos. Al igual que con los corticosteroides, su aplicación antes o muy pronto después de la iniciacion del shock parece ser de mayor beneficio; sinembargo, todavía no ha sido posible establecer cual es la población de patientes que se puede beneficiar mayormente de la terapia con estas drogas, y son necesarios mas estudios y ensayos clínicos.