Sevoflurane for procedural sedation in critically ill patients: A pharmacokinetic comparative study between burn and non-burn patients.

BACKGROUND: Sevoflurane has anti-inflammatory proprieties and short lasting effects making it of interest for procedural sedation in critically ill patients. We evaluated the pharmacokinetics of sevoflurane and metabolites in severely ill burn patients and controls. The secondary objective was to assess potential kidney injury. METHODS: Prospective interventional study in a burn and a surgical intensive care unit; 24 mechanically ventilated critically ill patients (12 burns, 12 controls) were included. The sevoflurane was administered with an expired fraction target of 2% during short-term procedural sedation. Plasma concentrations of sevoflurane, hexafluoroisopropanolol (HFIP) and free fluoride ions were recorded at different times. Kinetic Pro (Wgroupe, France) was used for pharmacokinetic analysis. Kidney injury was assessed with neutrophil gelatinase-associated lipocalin (NGAL). RESULTS: The mean total burn surface area was 36±11%. The average plasma concentration of sevoflurane was 70.4±37.5mg·L-1 in burns and 57.2±28.1mg·L-1 in controls at the end of the procedure (P=0.58). The volume of distribution was higher (46.8±7.2 vs 22.2±2.50L, P<0.001), and the drug half-life longer in burns (1.19±0.28h vs 0.65±0.04h, P<0.0001). Free metabolite HFIP was higher in burns. Plasma fluoride was not different between burns and controls. NGAL did not rise after procedures. CONCLUSION: We observed an increased volume of distribution, slower elimination rate, and altered metabolism of sevoflurane in burn patients compared to controls. Repeated use for procedural sedation in burn patients needs further evaluation. No renal toxicity was detected. TRIAL REGISTRY NUMBER: ClinicalTrials.gov Identifier NCT02048683.

The Dose-Dependent Effects of Ketoprofen on Dynamic Pain after Open Heart Surgery.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) can reduce postoperative pain, in both static (i.e., at rest) and dynamic contexts (e.g., during coughing or mobilization), and reduced doses could improve their efficacy/tolerance balance. OBJECTIVES: To test this hypothesis of efficacy after open heart surgery, in which NSAIDs are poorly used, particularly for safety concerns. STUDY DESIGN: Randomized, double-blind trial. SETTING: Single-center, French university hospital. METHODS: Patients. One hundred patients at low risk of postoperative complications undergoing scheduled open heart surgery (97 analyzed). We tested intravenous ketoprofen, at a dose of 0.5 mg/kg-1 every 6 hours during the 48 hours following the end of sedation, after surgery. This standard protocol was compared to a similar one in which half doses were administered, to one with quarter doses, as well as to a placebo group. Analgesia was supplemented by acetaminophen plus self- and nurse-administered intravenous morphine. The primary outcome was the intensity of dynamic pain, assessed over 48 hours on an 11-point numerical rating scale (NRS). RESULTS: Only the full-dose ketoprofen group showed reduced dynamic and static postoperative pain vs. placebo (P < 0.00001 for both). The evolution of dynamic pain suggested a delayed and therefore non-significant effect with the low doses. Ketoprofen did not affect either the postoperative morphine consumption or the tolerance outcomes, such as the volumes of chest tube drainage and the renal function. LIMITATIONS: This pilot trial was undersized to test major tolerance outcomes. CONCLUSIONS: Although we failed to demonstrate any analgesic effects with low doses of ketoprofen, we confirmed the good efficacy/tolerance balance with this propionic NSAID of intermediate COX2-selectivity. Lower doses of NSAIDs, potentiated by a loading dose, should be tested in the future.IRB approval: CPP Sud-Est VI (Clermont-Ferrand, France), on 12/23/2013.Clinical trial registry: EudraCT (2013-003878-27); ClinicalTrials.gov (NCT02180087).Key words: Non-steroidal anti-inflammatory drugs, ketoprofen, cyclooxygenase, pain, postoperative, sternotomy, postoperative rehabilitation, analgesia, side effects.