A McLuckie

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.

Assessment of cardiac preload and extravascular lung water by single transpulmonary thermodilution

Objective: Transpulmonary double-indicator dilution is a useful monitoring technique for measurement of intrathoracic blood volume (ITBV) and extravascular lung water (EVLW). In this study, we compared a simpler approach using single arterial thermodilution derived measurements of ITBV and EVLW with the double-indicator dilution technique.¶Design: Prospective observational clinical study.¶Setting: Surgical intensive care units of two university hospitals.¶Patients and methods: Global end-diastolic volume (GEDV) derived from single thermodilution was used for calculation of ITBV. Structural regression analysis of the first two thermo-dye dilution measurements in a derivation population of 57 critically ill patients (38 male, 19 female, 18–79 years, 56 ± 15 years) revealed ITBV = (1.25 · GEDV)–28.4 (ml). This equation was then applied to all first measurements in a validation population of 209 critically ill patients (139 male, 70 female, 10–88 years, mean 53 ± 19 years), and single-thermodilution ITBV (ITBVST) and EVLW (EVLWST) was calculated and compared to thermo-dye dilution derived values (ITBVTD, EVLWTD). For inter-individual comparison, absolute values for ITBV and EVLW were normalised as indexed by body surface area (ITBVI) and body weight (EVLWI), respectively.¶Measurements and results: Linear regression analysis yielded a correlation of ITBVIST = (1.05 · ITBVITD)–58.0 (ml/m2), r = 0.97, P < 0.0001. Bias between ITBVITD and ITBVIST was 7.6 (ml/m2) with a standard deviation of 57.4 (ml/m2). Single-thermodilution EVLWI (EVLWIST) was calculated using ITBVIST and revealed the correlation EVLWIST = (0.83 · EVLWITD) + 1.6 (ml/kg), r = 0.96, P < 0.0001. Bias between EVLWITD and EVLWIST was –0.2 (ml/kg) with a standard deviation of 1.4 (ml/kg). In detail, EVLWIST systematically overestimated EVLWITD at low-normal values for EVLWI and underestimated EVLWI at higher values (above 12 ml/kg).¶Conclusion: Determinations of ITBV and EVLW by single thermodilution agreed closely with the corresponding values from the double-indicator technique. Since transpulmonary single thermodilution is simple to apply, less invasive and cheaper, all these features make it a promising technique for the bedside. Nevertheless, further validation studies are needed in the future.

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.

Pharmacokinetics of meropenem in intensive care unit patients receiving continuous veno-venous hemofiltration or hemodiafiltration.

Objective: To evaluate an intravenous meropenem dosage regimen in adult intensive care patients with acute renal failure treated by continuous renal replacement therapy. Design: A prospective, clinical study. Setting: General intensive care unit of a university hospital. Patients: Ten critically ill adult patients being treated with meropenem and receiving continuous veno‐venous hemofiltration (hemofiltration rates, 1‐2 L/hr) (n = 5) or continuous veno‐venous hemodiafiltration (hemofiltration rates, 1‐1.5 L/hr; dialysis rates, 1‐1.5 L/hr) (n = 5) via a polyacrylonitrile hollow fiber 0.9‐m2 filter. Interventions: Patients received a meropenem dose of 1 g iv every 12 hrs as a 5‐min bolus. Measurements and Main Results: Meropenem concentrations were measured by high‐performance liquid chromatography in serum taken at timed intervals and in ultrafiltrate/dialysate to determine serum concentration‐time profiles, derive pharmacokinetic variable estimates, and determine sieving coefficients and filter clearances. The serum concentrations were examined to see whether they were above the minimum inhibitory concentrations (MICs) for pathogens that may be encountered in intensive care patients. Serum concentrations exceeded 4 mg/L (MIC90 for Pseudomonas aeruginosa) during 67% of the dosage period in all patients. Sub‐MIC90 concentrations were obtained in three patients immediately before treatment and in one patient 12 hrs after treatment. Mean (SD) (n = 10) pharmacokinetic variable estimates were as follows: elimination half‐life, 5.16 hrs (1.83 hrs); volume of distribution, 0.35 L/kg (0.10 L/kg); and total clearance, 4.30 L/hr (1.38 L/hr). A sieving coefficient of 0.93 (0.06) (n = 9) indicated free flow across the filter. The fraction cleared by the extracorporeal route was 48% (13%) (n = 9), which is clinically important. Conclusions: A meropenem dose of 1 g iv every 12 hrs provides adequate serum concentrations in the majority of patients receiving continuous veno‐venous hemofiltration or continuous veno‐venous hemofiltration with a 0.9‐m2 polyacrylonitrile filter at combined ultrafiltrate/dialysate flow rates of up to 3 L/hr. A lower dose would not be sufficient for the empirical treatment of potentially life‐threatening infections in all patients.

Physiological predictors of survival during high-frequency oscillatory ventilation in adults with acute respiratory distress syndrome

IntroductionData that provide clinical criteria for the identification of patients likely torespond to high-frequency oscillatory ventilation (HFOV) are scarce. Our aim wasto describe physiological predictors of survival during HFOV in adults with severeacute respiratory distress syndrome (ARDS) admitted to a respiratory failurecenter in the United Kingdom.MethodsElectronic records of 102 adults treated with HFOV were reviewed retrospectively.We used logistic regression and receiving-operator characteristics curve to testassociations with oxygenation and mortality.ResultsPatients had severe ARDS with a mean (SD) Murrays score of 2.98 (0.7). Partialpressure of oxygen in arterial blood to fraction of inspired oxygen(PaO2/FiO2) ratio and oxygenation index improved only insurvivors. The earliest time point at which the two groups differed was at threehours after commencing HFOV. An improvement of >38% inPaO2/FiO2 occurring at any time within the first 72hours, was the best predictor of survival at 30 days (area under the curve (AUC)of 0.83, sensitivity 93%, specificity 78% and a positive likelihood ratio (LR) of4.3). These patients also had a 3.5 fold greater reduction in partial pressure ofcarbon dioxide in arterial blood (PaCO2). Multivariate analysis showedthat HFOV was more effective in younger patients, when instituted early, and inpatients with milder respiratory acidosis.ConclusionsHFOV is effective in improving oxygenation in adults with ARDS, particularly wheninstituted early. Changes in PaO2/FiO2 during the firstthree hours of HFOV can identify those patients more likely to survive.

H2 blockers in the intensive care unit: ignoring the evidence? Telephone survey

Stress ulcers are gastroduodenal erosions that occur commonly in critically ill patients. Although once thought to be due to excess acid production, they are now thought to result from gastric mucosal ischaemia and the value of using pH altering drugs to prevent them has been questioned.1 Cook et al showed that only critically ill patients who have a coagulopathy or who are ventilated for more than 48 hours are at increased risk of developing serious bleeding due to stress ulceration.2 Prophylaxis is usually with either an H2 receptor antagonist or sucralfate, and these agents appear equally efficacious in terms of reducing bleeding complications.3 A recent meta-analysis has, however, shown that sucralfate is associated with a lower …