Optimising the dose of clonidine to achieve sedation in intensive care unit patients with population pharmacokinetics.

AIMS: The aim of this study was to investigate the population pharmacokinetics (PK) of clonidine in intensive care unit (ICU) patients in order to develop a dosing regimen for sedation. METHODS: We included 24 adult mechanically ventilated, sedated patients from a mixed medical and surgical ICU. Intravenous clonidine was added to standard sedation in doses of 600, 1200 or 1800 µg/d. Within each treatment group, 4 patients received a loading dose of half the daily dose administered in 4 hours. Patients gave an average of 12 samples per individual. In total, 286 samples were available for analysis. Model development was conducted with NONMEM and various covariates were tested. After modelling, doses to achieve a target steady-state plasma concentration of >1.5 µg/L were explored using stochastic Monte Carlo simulations for 1000 virtual patients. RESULTS: A 2-compartment model was the best fit for the concentration-time data. Clearance (CL) increased linearly with 0.213%/h; using allometric scaling, body weight was a significant covariate on the central volume of distribution (V1). Population PK parameters were: CL 17.1 (L/h), V1 124 (L/70 kg), intercompartmental CL 83.7 (L/h), and peripheral volume of distribution 178 (L), with 33.3% CV interindividual variability on CL and 66.8% CV interindividual variability on V1. Simulations revealed that a maintenance dose of 1200 µg/d provides target sedation concentrations of >1.5 µg/L in 95% of the patients. CONCLUSION: A population PK model for clonidine was developed in an adult ICU. A dosing regimen of 1200 µg/d provided a target sedation concentration of >1.5 µg/L.

In vivo Elimination of Clonidine by Continuous Venovenous Hemofiltration in Critically Ill Patients.

BACKGROUND: Clonidine is an α2-agonist that is commonly used for sedation in the intensive care unit. When patients are on continuous venovenous hemofiltration (CVVH) in the presence of kidney dysfunction, the sieving coefficient of clonidine is required to estimate how much drug is removed by CVVH. In the present study, we measured the sieving coefficient of clonidine in critically ill, ventilated patients receiving CVVH. METHODS: A total of 20 samples of plasma and ultrafiltrate of 3 patients on CVVH, using a standard 1.5 m2 polyacrylonitrile AN69 membrane, during continuous clonidine infusion were collected. After correction for the effect of predilution, we calculated the sieving coefficient for clonidine. RESULTS: The mean sieving coefficient of clonidine was 0.52 (SD 0.097). CONCLUSION: Using a polyacrylonitrile AN69 membrane in a CVVH machine, the in vivo sieving coefficient of clonidine was 0.52.

The safety and efficacy of nicotine replacement therapy in the intensive care unit: a randomised controlled pilot study.

BACKGROUND: Studies evaluating nicotine replacement therapy (NRT) to prevent nicotine withdrawal symptoms in ICU patients have yielded conflicting results. We performed a randomised controlled double-blind pilot study to assess the safety and efficacy of NRT in critically ill patients. Mechanically ventilated patients admitted to two medical-surgical intensive care units and smoking more than 10 cigarettes per day before ICU admission were enrolled in this study. Participants were randomised to transdermal NRT (14 or 21 mg per day) or placebo until ICU discharge or day 30. Smoking status was confirmed by the biomarkers serum cotinine and urinary NNAL. The primary endpoint was 30-day mortality. Among secondary endpoints and post hoc endpoints, 90-day mortality, safety, time spent without delirium, sedation and coma, and patient destination at day 30 were addressed. RESULTS: We enrolled 47 patients. No differences were found between NRT and control group patients concerning 30-day mortality (9.5 vs. 7.7%, p = 0.84) and 90-day mortality (14.3 vs. 19.2%, p = 0.67). The number of serious adverse events was comparable between groups (NRT: 4, control: 11, p = 0.13). At day 20, average time alive without delirium, sedation and coma was 16.6 days among NRT patients versus 12.6 days among control patients (p = 0.03). At day 30, more NRT group patients were discharged from the ICU or hospital compared with controls (p = 0.03). CONCLUSIONS: NRT did not affect mortality or the number of (serious) adverse events compared with placebo. Time alive without delirium, sedation and coma at day 20 in NRT patients was longer than in control patients. An adequately powered randomised controlled trial to further study safety and efficacy of NRT in ICU patients seems feasible and is warranted. Trial registration ClinicalTrials.gov, number NCT01362959, registered 1 June 2011.