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Severe sepsis is frequently associated with microcirculatory abnormalities despite seemingly adequate hemodynamic resuscitation. As increased serum angiotensin II levels may play a role in this dysfunction, we evaluated the microcirculatory effects of enalaprilat in an experimental model of septic shock. One hour after injection of 1.5 g/kg body weight of feces into the abdominal cavity, 16 adult female anesthetized, mechanically ventilated sheep were randomized to receive 2.5 mg enalaprilat or saline. When fluid-resistant hypotension (mean arterial pressure, <65 mmHg) developed, norepinephrine was given up to a maximal dose of 3 μg·kg(-1)·min(-1). The sublingual microcirculation was evaluated using sidestream dark-field videomicroscopy. A cutoff of 20 μm was used to differentiate small and large vessels. Experiments were pursued until the sheep's spontaneous death or for a maximum of 30 h. There were progressive and significant reductions in the proportion of small perfused vessels and in the microvascular flow index for small vessels (both P < 0.01 for trend) during shock and the first 2 h of norepinephrine infusion in the placebo group, which were prevented by the administration of enalaprilat. There were no differences between treated and placebo groups in global hemodynamic variables, time to shock or median survival time (21.8 [18.6-28.8] vs. 22.9 [21.8-30.0] h; P = 0.45). However, oxygen exchange was worse (PaO2/FiO2 ratio, 224 [128-297] vs. 332 [187-450]; P < 0.05), and creatinine concentrations increased more in the treated group (from 0.51 [0.42-0.75] to 1.19 [0.64-1.50] mg·dL(-1); P = 0.04) than in the control group (from 0.55 [0.45-0.62] to 0.78 [0.46-1.78] mg·dL(-1); P = 0.12), Enalaprilat therefore prevented the worsening of sublingual microcirculatory variables in this fluid-resuscitated, hyperdynamic model of septic shock, without significant effect on arterial pressure, but with a possible deleterious effect on renal and lung function.

Objectives: A recent prospective study on beta-lactams levels in septic patients receiving continuous renal replacement therapy (CRRT) recommended the following dosage regimens: 2gq8h for ceftazidime or cefepime (CEF), 4gq6h for piperacillin-tazobactam (TZP), and 1gq8h for meropenem (MEM).1 We applied these regimens in our hospital since December 2009. The aim of our study was to evaluate the adequacy of this dosage strategy in a cohort of septic patients undergoing CRRT.Methods: Retrospective observational study from 01/01/2010 to 31/05/2011. Inclusion criteria were: a) sepsis, b) CRRT; c) treatment with CEF, TZP or MEM, and d) at least one measure of beta-lactam levels. Serum concentrations were measured by high-performance liquid chromatography (HPLC-UV). Blood samples were taken twice during the elimination phase after a 30-min intravenous administration of the drug. The two samples were used to calculate the time spent above the minimal inhibitory concentration (MIC), which was empirically considered as the clinical breakpoint for "difficult-to-treat" bacteria, such as Pseudomonas aeruginosa. Adequate therapy was defined as serum concentrations between 4 to 8 times the MIC during optimal periods of time for each drug: > 70% for CEF, > 50% for TZP, and > 40% for MEM. Underdosing and overdosing were defined as drug concentrations that were respectively < 4 times or > 8 times the MIC during optimal periods of time. Early and late phases of therapy were considered if drug levels measurement was performed within 48 hours or later on, respectively.Results: Fifty drugs levels were obtained from 36 patients; 15 during the early and 35 during the late septic phase. Drug levels obtained for each antibiotic are shown in Figure 1.Conclusions: Administering a higher beta-lactam dosage regimen for septic patients receiving CRRT avoided insufficient drug concentrations in most patients. Nevertheless, therapeutic drug monitoring should be performed routinely in order to adapt beta-lactam doses and to avoid drug accumulation .References: 1. Seyler L, Cotton F, Taccone FS, De Backer D, Macours P, Vincent JL, Jacobs F. Recommended beta-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy. Critical Care 2011, 15: R137.

info:eu-repo/semantics/nonPublished

AbstractINTRODUCTION. Patients with severe sepsis present high levels of angiotensin II (ang II), a hormone with vasoactive, proinflammatory, and procoagulant properties. Despite seemingly adequate hemodynamic resuscitation, microcirculatory abnormalities are frequently observed. Increased serum levels of ang II may play a role in this microcirculatory dysfunction during severe sepsis.OBJECTIVES. To evaluate the microcirculatory effects of enalaprilat in an experimental model of severe sepsis.METHODS. Prospective, randomized, double-blind, placebo controlled study including 16 adult female anesthetized, mechanically ventilated sheep. One hour after injection of 1.5 g/kg body weight of feces into the abdominal cavity, animals were randomized to receive either enalaprilat 2.5 mg or saline. A combination of Ringer's lactate (RL) and hydroxyethyl starch solutions was titrated to prevent hypovolemia. When fluid-resistant hypotension (MAP < 65 mmHg) developed, the animals were given norepinephrine up to a maximal dose of 3 µg/kg/min. The sublingual microcirculation was evaluated using sidestream dark-field videomicroscopy (Microscan, MicroVision Medical) at baseline (just before feces injection), before drug administration, before norepinephrine infusion (shock), and after the 1st and 2nd hour of norepinephrine infusion. Capillary density, proportion of perfused vessels, and microvascular flow index (MFI) were calculated. A cut-off of 20µm was used to differentiate small and large vessels. Experiments were pursued until the sheep's spontaneous death or a maximum of 30 hours. Results are presented as mean±SE.RESULTS. There were progressive and significant reductions in the proportion of small perfused vessels (p=0.006 for trend) and in the MFI (p=0.003 for trend) during shock and the first 2 hours of norepinephrine infusion in the placebo group, which were prevented by the administration of enalaprilat (p=0.83 and p=0.85 for trend in the proportion of small perfused vessels and MFI, respectively) (Figure). There were no differences between treated and placebo groups in global hemodynamic variables, time to shock (18.1±2.4 hours vs 17.6±2.1 hours, p=1.0) or median survival time (23±1.7 hours vs 24±1.9 hours, p=0.49). However creatinine concentrations increased more in the treated group (from 0.60±0.09 to 1.15±0.19, p=0.04) than in the control group (from 0.62±0.10 to 1.01±0.23, p=0.12).[figure]CONCLUSIONS. Enalaprilat prevented the worsening of microcirculatory variables in this fluid-resuscitated, hyperdynamic model of septic shock without significant effect on arterial pressure, but possibly associated with an earlier impairment of renal function.

A 72-hr, continuous intravenous infusion of rhIL-1ra failed to demonstrate a statistically significant reduction in mortality when compared with standard therapy in this multicenter clinical trial. If rhIL-1ra treatment has any therapeutic activity in severe sepsis, the incremental benefits are small and will be difficult to demonstrate in a patient population as defined by this clinical trial.