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.

Extracorporeal treatment of metforminassociated lactic acidosis in clinical practice: a retrospective cohort study.

PURPOSE: To assess whether extracorporeal treatment (ECTR) improves outcome of patients with metformin-associated lactic acidosis (MALA) and to evaluate the clinical applicability of the Extracorporeal Treatments in Poisoning Workgroup (EXTRIP) criteria for starting ECTR in metformin poisoning. METHODS: Patients with metformin serum concentrations above 2 mg/l who were admitted in the Deventer Teaching Hospital between January 2000 and July 2019 and complied with the definition of MALA (pH < 7.35 and lactate concentration > 5 mmol/l) were included. Mortality and clinical parameters of patients treated with ECTR or not were compared. In addition, treatment of MALA in clinical practice was verified against the criteria of EXTRIP. RESULTS: Forty-two patients were included. Lactate (13.8 versus 10.5 mmol/l, p = 0.01), creatinine (575 versus 254 umol/l, p < 0.01)), metformin (29.4 versus 8.6 mg/l, p < 0.01) concentrations, and vasopressor requirement (72% versus 23%, p < 0.01) were significantly higher in the ECTR-group. Blood pH (7.05 versus 7.19, p = 0.03) and bicarbonate (6 versus 11 mmol/l, p < 0.01) were significantly lower. Mortality, length of hospital stay, and mechanical ventilation requirement were not statistically different. In 83% of patients, treatment of MALA was in accordance with the EXTRIP criteria. CONCLUSIONS: Although there was no statistical benefit in mortality shown from ECTR, ECTR might be lifesaving in MALA, considering the ECTR-group was significantly sicker than the non-ECTR-group. The majority of patients were treated in line with the EXTRIP criteria. Severity of lactic acidosis and renal impairment were the main indications for initiating ECTR.

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.

Serum creatine kinase as predictor of clinical course in rhabdomyolysis: a 5-year intensive care survey.

OBJECTIVE: To evaluate the risk factors for the development of acute renal failure (ARF) in severe rhabdomyolysis. DESIGN: Observational historical cohort study. SETTING: General intensive care unit of a university hospital. PATIENTS: Twenty-six patients with severe rhabdomyolysis, who were admitted between July 1996 and July 2001. MEASUREMENTS AND RESULTS: Clinical and laboratory data were reviewed and groups were stratified according to presence or absence of acute renal failure. The underlying cause of rhabdomyolysis was ischemia by vascular obstruction (50%), crush injury by trauma (23%), sepsis (11.5%), heatstroke/hyperthermia (11.5%) and hyponatremia in a single patient. Mean creatine kinase (CK) level was 38,351+/-35,354 U/l on admission and rose further in all patients (mean: 59,747+/-67,514 U/l). Renal failure developed in 17 patients (65%). Serum CK levels correlated with onset of ARF, as these patients had significantly higher admission and peak serum CK concentrations. Patients with ARF had a higher mortality (59% vs 22%). CONCLUSION: In our cohort of patients with severe rhabdomyolysis the level of serum CK predicted the development of ARF. Although our results suggest that series of CK determination might be beneficial for the evaluation of the effect of therapy, the value of CK determination as a prognostic tool is limited, given the wide range of CK levels.