Efficacy and pharmacokinetics of intravenous paracetamol in the critically ill patient

Introduction: Paracetamol (PCM) is a drug with analgesic and antipyretic properties. Despite its frequent use, little is known about its efficacy and pharmacokinetics (PK) when intravenously administered in the critically ill patient. A previous study suggests that therapeutic concentrations are not always reached [1]. The primary aim of this open-label, multiple-dose study was to evaluate intravenous PCM therapy in critically ill, secondary aim was to study the PK of intravenous PCM. Methods: Ventilated patients needing PCM treatment according to our ICU protocol (1 g PCM intravenously four times daily) were eligible for inclusion. Excluded were those with severe liver failure and those treated with PCM on the time of admission to the ICU. Blood samples were collected at 0, 30, 60, 180 and 300 minutes after the first and, if possible, the fifth and 21st doses. A computerized model was used to estimate population PK. Results: Nineteen patients were included of which 13 were male, with a mean APACHE IV score of 94.8. No antipyretic effect could be measured in any of the patients. PK parameters have been calculated for all patients after the first PCM dose. The half-life was 2.2 hours, the volume of distribution was 1.03 l/kg, and the clearance was 0.33 l/kg/hour. Data from 15 patients could be analysed after the fifth dose and from five patients after the 21st dose. The PK of intravenous PCM in our population show a biphasic profile (Figure 1). One hour after the dose, the mean serum concentration level was below the therapeutic level. In 18 out of 19 patients serum concentration dropped below 5 mg/ml before the next dose, resulting in a lack of build-up of a suitable therapeutic level of PCM after multiple dosages. Conclusions: The recommended dose of 1 g intravenous PCM four times daily is not sufficient to achieve a therapeutic effect in critically ill patients. This can be explained by the low serum levels reached. These results warrant the development of an adequate dosing scheme for intravenous PCM followed by a large clinical trial studying the effects and safety of this regimen in critically ill patients

Safe use of proton pump inhibitors in patients with cirrhosis

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Altered Micafungin Pharmacokinetics in Intensive Care Unit Patients.

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Evaluating the safety and dosing of drugs in patients with liver cirrhosis by literature review and expert opinion

Contains fulltext : 172495.pdf (publisher's version ) (Open Access)INTRODUCTION: Liver cirrhosis can have a major impact on drug pharmacokinetics and pharmacodynamics. Patients with cirrhosis often suffer from potentially preventable adverse drug reactions. Guidelines on safe prescribing for these patients are lacking. The aim of this study is to develop a systematic method for evaluating the safety and optimal dosage of drugs in patients with liver cirrhosis. METHODS AND ANALYSIS: For each drug, a six-step evaluation process will be followed. (1) Available evidence on the pharmacokinetics and safety of a drug in patients with liver cirrhosis will be collected from the Summary of Product Characteristics (SmPC) and a systematic literature review will be performed. (2) Data regarding two outcomes, namely pharmacokinetics and safety, will be extracted and presented in a standardised assessment report. (3) A safety classification and dosage suggestion will be proposed for each drug. (4) An expert panel will discuss the validity and clinical relevance of this suggested advice. (5) Advices will be implemented in all relevant Clinical Decision Support Systems in the Netherlands and published on a website for patients and healthcare professionals. (6) The continuity of the advices will be guaranteed by a yearly check of new literature and comments on the advices. This protocol will be applied in the evaluation of a selection of drugs: (A) drugs used to treat (complications of) liver cirrhosis, and (B) drugs frequently prescribed to the general population. ETHICS AND DISSEMINATION: Since this study does not directly involve human participants, it does not require ethical clearance. Besides implementation on a website and in clinical decision support systems, we aim to publish the generated advices of one or two drug classes in a peer-reviewed journal and at conference meetings

A comparison of the acid-inhibitory effects of esomeprazole and pantoprazole in relation to pharmacokinetics and CYP2C19 polymorphism

Background: Esomeprazole and pantoprazole are metabolized in the liver and the polymorphic CYP2C19 enzyme is involved in that process. This genetic polymorphism determines fast (70% of Caucasians), intermediate (25-30% of Caucasians) and slow (2-5% of Caucasians) metabolism of PPIs. Aim To compare the acid-inhibitory effects of esomeprazole 40 mg and pantoprazole 40 mg at 4, 24 and 120 h after oral administration in relation to CYP2C19 genotype and pharmacokinetics. Methods CYP2C19*2, *3, *4, *5 and *17 genotypes were determined in healthy Helicobacter pylori-negative Caucasian subjects. 7 wt/wt, 7 wt/*2, 2 wt/*17, 2 *2/*17 and 1 *2/*2 were included in a randomized investigator-blinded cross-over study with esomeprazole 40 mg and pantoprazole 40 mg. Intragastric 24-h pH-monitoring was performed on days 0, 1 and 5 of oral dosing. Results A total of 19 subjects (mean age 24 years, 7 male) completed the study. At day 1 and 5, acid-inhibition with esomeprazole was significantly greater and faster than with pantoprazole. Differences in acid-inhibition and pharmacokinetics between wt/wt and wt/*2 genotype were significant for pantoprazole at day 1 and 5. Conclusions Esomeprazole provides acid-inhibition faster than and superior to pantoprazole after single and repeated administration. The acid-inhibitory effect and the kinetics of pantoprazole are influenced by CYP2C19 genotype. © 2010 Blackwell Publishing Ltd

Efficacy of halopeRIdol to decrease the burden of Delirium In adult Critically ill patiEnts (EuRIDICE): study protocol for a prospective randomised multi-centre double-blind placebo-controlled clinical trial in the Netherlands

INTRODUCTION: Delirium in critically ill adults is associated with prolonged hospital stay, increased mortality and greater cognitive and functional decline. Current practice guideline recommendations advocate the use of non-pharmacological strategies to reduce delirium. The routine use of scheduled haloperidol to treat delirium is not recommended given a lack of evidence regarding its ability to resolve delirium nor improve relevant short-term and longer-term outcomes. This study aims to evaluate the efficacy and safety of haloperidol for the treatment of delirium in adult critically ill patients to reduce days spent with coma or delirium. METHODS AND ANALYSIS: EuRIDICE is a prospective, multi-centre, randomised, double-blind, placebo-controlled trial. Study population consists of adult intensive care unit (ICU) patients without acute neurological injury who have delirium based on a positive Intensive Care Delirium Screening Checklist (ICDSC) or Confusion Assessment Method for the ICU (CAM-ICU) assessment. Intervention is intravenous haloperidol 2.5 mg (or matching placebo) every 8 hours, titrated daily based on ICDSC or CAM-ICU positivity to a maximum of 5 mg every 8 hours, until delirium resolution or ICU discharge. Main study endpoint is delirium and coma-free days (DCFD) up to 14 days after randomisation. Secondary endpoints include (1) 28-day and 1-year mortality, (2) cognitive and functional performance at 3 and 12 months, (3) patient and family delirium and ICU experience, (4) psychological sequelae during and after ICU stay, (4) safety concerns associated with haloperidol use and (5) cost-effectiveness. Differences in DCFDs between haloperidol and placebo group will be analysed using Poisson regression analysis. Study recruitment started in February 2018 and continues. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee of the Erasmus University Medical Centre Rotterdam (MEC2017-511) and by the Institutional Review Boards of the participating sites. Its results will be disseminated via peer-reviewed publication and conference presentations. TRIAL REGISTRATION: NCT03628391