Robert Grover

Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: Effect on survival in patients with septic shock

ObjectiveTo assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was survival at day 28. DesignMultiple-center, randomized, two-stage, double-blind, placebo-controlled, safety and efficacy study. SettingA total of 124 intensive care units in Europe, North America, South America, South Africa, and Australasia. PatientsA total of 797 patients with septic shock diagnosed for <24 hrs. InterventionsPatients with septic shock were allocated to receive 546C88 or placebo (5% dextrose) for up to 7 days (stage 1) or 14 days (stage 2) in addition to conventional therapy. Study drug was initiated at 0.05 mL·kg−1·hr−1 (2.5 mg·kg−1·hr−1 546C88) and titrated up to a maximum rate of 0.4 mL·kg−1·hr−1 to maintain mean arterial pressure between 70 and 90 mm Hg while attempting to withdraw concurrent vasopressors. Measurements and Main ResultsHemodynamic variables, organ function data, microbiological data, concomitant therapy, and adverse event data were recorded at baseline, throughout treatment, and at follow-up. The primary end point was day-28 survival. The trial was stopped early after review by the independent data safety monitoring board. Day-28 mortality was 59% (259/439) in the 546C88 group and 49% (174/358) in the placebo group (p < .001). The overall incidence of adverse events was similar in both groups, although a higher proportion of the events was considered possibly attributable to study drug in the 546C88 group. Most of the events accounting for the disparity between the groups were associated with the cardiovascular system (e.g., decreased cardiac output, pulmonary hypertension, systemic arterial hypertension, heart failure). The causes of death in the study were consistent with those expected in patients with septic shock, although there was a higher proportion of cardiovascular deaths and a lower incidence of deaths caused by multiple organ failure in the 546C88 group. ConclusionsIn this study, the nonselective nitric oxide synthase inhibitor 546C88 increased mortality in patients with septic shock.

An open-label dose escalation study of the nitric oxide synthase inhibitor, NG-methyl-L-arginine hydrochloride (546C88), in patients with septic shock

ObjectiveTo assess the effects of the nitric oxide synthase inhibitor, 546C88, in patients with septic shock and to evaluate the range of dose rates that sustain mean arterial pressure (MAP) of >or=to70 mmHg.DesignMulticenter, open-label, uncontrolled, dose range finding study.SettingTen intensive c

Administration of the nitric oxide synthase inhibitor NG-methyl- L-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: Results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002)

ObjectiveTo assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was resolution of shock, defined as a mean arterial pressure ≥70 mm Hg in the absence of both conventional vasopressors and study drug, determined at the end of the 72-hr treatment period. DesignMulticentered, randomized, placebo-controlled, safety and efficacy study. SettingForty-eight intensive care units in Europe, North America, and Australia. PatientsA total of 312 patients with septic shock diagnosed within 24 hr before randomization. InterventionsPatients were randomly allocated to receive either 546C88 or placebo (5% dextrose) by intravenous infusion for up to 72 hrs. Conventional vasoactive therapy was restricted to norepinephrine, dopamine, and dobutamine. Study drug was initiated at 0.1 mL/kg/hr (5 mg/kg/hr 546C88) and titrated according to response up to a maximum rate of 0.4 mL/kg/hr with the objective to maintain mean arterial pressure at 70 mm Hg while attempting to withdraw any concurrent vasopressor(s). Measurements and Main ResultsRequirement for vasopressors, systemic hemodynamics, indices of organ function and safety (including survival up to day 28) were assessed. The median mean arterial pressure for both groups was maintained >70 mm Hg. Administration of 546C88 was associated with a decrease in cardiac index while stroke index was maintained. Resolution of shock at 72 hr was achieved by 40% and 24% of the patients in the 546C88 and placebo cohorts, respectively (p = .004). There was no evidence that treatment with 546C88 had any major adverse effect on pulmonary, hepatic, or renal function. Day 28 survival was similar for both groups. ConclusionsIn this study, treatment with the nitric oxide synthase inhibitor 546C88 promoted the resolution of shock in patients with severe sepsis. This was associated with an acceptable overall safety profile.

Cardiovascular effects of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) in patients with septic shock: results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002).

ObjectiveTo assess the hemodynamic effects of the nitric oxide synthase inhibitor 546C88 in patients with septic shock, although this was not a stated aim of the protocol. The predefined primary efficacy objective of the protocol was resolution of shock determined at the end of a 72-hr treatment period. DesignMulticentered, randomized, placebo-controlled, safety and efficacy study. SettingForty-eight intensive care units in Europe, North America, and Australia. PatientsA total of 312 patients with septic shock diagnosed within 24 hr before randomization. InterventionsPatients were randomly allocated to receive either 546C88 or placebo (5% dextrose) by intravenous infusion for up to 72 hrs. Conventional vasoactive therapy was restricted to norepinephrine, dopamine, and dobutamine. Study drug was initiated at 0.1 mL/kg/hr (5 mg/kg/hr 546C88) and titrated according to response up to a maximum rate of 0.4 mL/kg/hr with the objective to maintain mean arterial pressure at 70 mm Hg while attempting to withdraw any concurrent vasopressor(s). Measurements and Main ResultsRequirement for vasopressors, systemic and pulmonary hemodynamics, indices of oxygen transport, and plasma concentrations of arginine and nitrate were assessed over time. The median mean arterial pressure for both groups was maintained ≥70 mm Hg. There was an early increase in systemic and pulmonary vascular tone and oxygen extraction, whereas both cardiac index and oxygen delivery decreased for patients in the 546C88 cohort. Although these parameters subsequently returned toward baseline values, the observed differences between the treatment groups, except for pulmonary vascular resistance and oxygen extraction, persisted throughout the treatment period, despite a reduced requirement for vasopressors in the 546C88 cohort. These changes were associated with a reduction in plasma nitrate concentrations, which were elevated in both groups before the start of therapy. ConclusionsThe nitric oxide synthase inhibitor 546C88 can reduce the elevated plasma nitrate concentrations observed in patients with septic shock. In this study, treatment with 546C88 for up to 72 hrs was associated with an increase in vascular tone and a reduction in both cardiac index and oxygen delivery. The successful maintenance of a target mean arterial blood pressure ≥70 mm Hg was achieved with a reduction in the requirement for, or withdrawal of, conventional inotropic vasoconstrictor agents (i.e., dopamine and norepinephrine). There were no substantive untoward consequences accompanying these hemodynamic effects. An international, randomized, double-blind, placebo-controlled phase III study has since been conducted in patients with septic shock. Recruitment into the study was discontinued due to the emergence of increased mortality in the 546C88-treated group.

Pharmacokinetics of the nitric oxide synthase inhibitor L‐NG‐methylarginine hydrochloride in patients with septic shock

To characterize the pharmacokinetics of L‐N G‐methylarginine in patients with septic shock.

Norepinephrine and N(G)-monomethyl-L-arginine in hyperdynamic septic shock in pigs: effects on intestinal oxygen exchange and energy balance.

OBJECTIVES To compare the effects of norepinephrine (NOR) and the nonselective nitric oxide synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), on intestinal blood flow, oxygen exchange, and energy metabolism over 24 hrs of hyperdynamic, normotensive porcine endotoxic shock. DESIGN Prospective, randomized, experimental study with repeated measures. SETTING Investigational animal laboratory. SUBJECTS Twenty-seven pigs were divided into three groups: seven animals received no vasopressor therapy (ETX) during endotoxic shock; ten animals were treated with NOR; and ten animals were treated with L-NMMA. INTERVENTIONS Pigs were anesthetized, mechanically ventilated, and instrumented. Eight hours later, endotoxic shock was initiated by an infusion of Escherichia coli lipopolysaccharide. Animals were resuscitated by hetastarch directed to maintain the intrathoracic blood volume and a mean arterial pressure (MAP) of >60 mm Hg. Twelve hours after the start of the endotoxin infusion, NOR or L-NMMA was administered for 12 hrs in the treatment groups to maintain a MAP at preshock levels. MEASUREMENTS AND MAIN RESULTS ETX caused a continuous fall in MAP, despite a sustained increase in the cardiac output achieved by fluid resuscitation. NOR maintained MAP at preshock levels because of a further rise in cardiac output, whereas hemodynamic stabilization during L-NMMA resulted from systemic vasoconstriction. NOR increased portal venous blood flow concomitant with decreased intestinal oxygen extraction, whereas L-NMMA influenced neither portal venous blood flow nor intestinal oxygen extraction. Mean capillary hemoglobin oxygen saturation of the ileal mucosa as well as the frequency distributions reflecting microcirculatory oxygen availability remained unchanged as well. Nevertheless, portal venous pH similarly decreased and portal venous lactate/pyruvate ratios increased in all three groups. The arterial-ileal mucosal PCO2 gap progressively increased in the ETX and L-NMMA groups, whereas NOR blunted this response. CONCLUSIONS Neither treatment could reverse the ETX-induced derangements of cellular energy metabolism as reflected by the increased portal venous lactate/pyruvate ratios. The NOR-induced attenuation of ileal mucosal acidosis was possibly caused by a different pattern of blood flow redistribution compared with L-NMMA.