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Recent studies have indicated that protective lung strategies may improve outcomes in acute lung injury. We hypothesized that the use of a lower tidal volume early during septic shock may protect against the subsequent development of acute lung injury. Fourteen fasted, anesthetized, invasively monitored, mechanically ventilated, female sheep (26.4 +/- 4.5 kg) underwent cecal ligation and perforation to induce sepsis. Sheep were then randomized to ventilation with low (6 mL/kg) or high (12 mL/kg) tidal volumes. A positive end-expiratory pressure of 10 cm H(2)O was applied in each case. Ringer's lactate was titrated to maintain pulmonary artery occlusion pressure at baseline levels. No vasoactive agents or antibiotics were used. Survival time was longer in the low- than in the high-tidal-volume group (21.8 +/- 2.4 vs. 17.6 +/- 4.1 h, respectively, P < 0.05). The times to develop hypotension and anuria were longer in the low-tidal-volume group (18.1 +/- 3.1 vs. 12.0 +/- 2.8 h, P < 0.05, and 17.6 +/- 1.6 vs. 14.1 +/- 3.8 h, P < 0.05). Although the Pao2/Fio2 tended to be lower in the low- than in the high-tidal-volume group (P = 0.06), postmortem examination showed a lower lung tissue wet/dry ratio in the low- than in the high-tidal-volume group (7.1 +/- 0.5 vs. 9.1 +/- 0.7, P < 0.05). A low-tidal-volume ventilation strategy applied early during septic shock may be beneficial in terms of reducing the amount of lung edema and prolonging survival time.

Castilho, Marco A; Buchele, Gustavo L; Sales, Joao A Jr; OspinaTascón, Gustavo A; Oliveira, Telmo A; Creteur, Jacques; Vincent, Jean-Louis Author Information

Critically ill patients are frequently at risk of neurological dysfunction as a result of primary neurological conditions or secondary insults. Determining which aspects of brain function are affected and how best to manage the neurological dysfunction can often be difficult and is complicated by the limited information that can be gained from clinical examination in such patients and the effects of therapies, notably sedation, on neurological function. Methods to measure and monitor brain function have evolved considerably in recent years and now play an important role in the evaluation and management of patients with brain injury. Importantly, no single technique is ideal for all patients and different variables will need to be monitored in different patients; in many patients, a combination of monitoring techniques will be needed. Although clinical studies support the physiologic feasibility and biologic plausibility of management based on information from various monitors, data supporting this concept from randomized trials are still required.

The effects of reversal of hypotension on the cerebral microcirculation, oxygenation, and metabolism in septic shock remain unclear. In 12 sheep, peritonitis was induced by injection of feces into the abdominal cavity. At the onset of septic shock (mean arterial pressure (MAP) < 65 mmHg, unresponsive to fluid challenge), a norepinephrine infusion was titrated in eight sheep to restore a MAP ≥ 75 mmHg; the other four sheep were kept hypotensive. The microcirculation of the cerebral cortex was evaluated using side-stream dark-field video-microscopy. Brain partial pressure of oxygen (PbtO2) was measured, and cerebral metabolism was assessed using microdialysis. All animals developed septic shock after a median of 15 (14−19) h. When MAP was raised using norepinephrine, the PbtO2 increased significantly (from 41 ± 4 to 55 ± 5 mmHg), and the cerebral lactate/pyruvate ratio decreased (from 47 ± 13 to 28 ± 4) compared with values at shock onset. Changes in the microcirculation were unchanged with restoration of MAP and the glutamate increased further (from 17 ± 11 to 23 ± 16 μM), as it did in the untreated animals. In septic shock, the correction of hypotension with vasopressors may improve cerebral oxygenation but does not reverse the alterations in brain microcirculation or cerebral metabolism.

Introduction: Voriconazole (VRC) is essential for the treatment of invasive fungal diseases in critically ill patients; however, data are scarce on VRC concentrations in this population. The aim of this study was to evaluate VRC concentrations and their relationship with clinical variables in a cohort of ICU patients. Methods: We reviewed all patients in whom VRC levels were measured during treatment in the ICU from January 2010 to December 2012. VRC levels were measured just before (trough, C0) drug administration using a high-performance liquid chromatography (HPLC) technique. Optimal C0 was between 1.0 and 5.0 mg/L. Early therapy was defined as a measurement within 4 days of VRC treatment. Results: We obtained 65 VRC levels from 41 patients (median age 56 years; 24 male). Median APACHE II score on ICU admission was 15 [12-16] and median SOFA score on the day of measurement was 5 [3-7]. All patients were also treated with proton pump inhibitors. Median VRC daily dose was 400 [400-600] mg, which corresponded to 6.9 [5.3-8.7] mg/kg per day. Median time from VRC initiation and VRC levels measurement was 6 [4-8] days. Median drug trough concentration was 2.1 [1.4-4] mg/L. C0 were adequate in 38 (58%) of measurements, insufficient in 13 (20%) and excessive in 14 (22%), without significant differences related to timing (early and late). Also, we found no differences in C0 between intravenous and oral administration. Furthermore, drug concentrations were not correlated to daily drug dose (indexed to body weight), even when only the first drug level was analyzed. Intravenous therapy had higher proportion of adequate C0 (23/32) than oral therapy (15/33, p = 0.04). Also, patients with more severe organ dysfunction (SOFA > 5) had higher C0 than those with lower score (3.8 [1.7-6.0] vs. 2.1 [1-3.6] mg/L, p = 0.03). Conclusions: Blood concentrations of VRC are highly variable in critically ill patients. Drug concentrations are higher in patients with more severe organ impairment. Intravenous therapy resulted in a higher proportion of adequate C0 when compared to oral doses.