Pharmacokinetics of Haloperidol in Critically Ill Patients: Is There an Association with Inflammation?

Letao Li,Henrik Endeman,Nicole G M Hunfeld,Birgit C P Koch,Mathieu Van Der Jagt,Sebastiaan D T Sassen

doi:10.3390/pharmaceutics14030549

Abstract

Haloperidol is considered the first-line treatment for delirium in critically ill patients. However, clinical evidence of efficacy is lacking and no pharmacokinetic studies have been performed in intensive care unit (ICU) patients. The aim of this study was to establish a pharmacokinetic model to describe the PK in this population to improve insight into dosing. One hundred and thirty-nine samples from 22 patients were collected in a single-center study in adults with ICU delirium who were treated with low-dose intravenous haloperidol (3–6 mg per day). We conducted a population pharmacokinetic analysis using Nonlinear Mixed Effects Modelling (NONMEM). A one-compartment model best described the data. The mean population estimates were 51.7 L/h (IIV 42.1%) for clearance and 1490 L for the volume of distribution. The calculated half-life was around 22 h (12.3–29.73 h) for an average patient. A negative correlation between C-Reactive Protein (CRP) and haloperidol clearance was observed, where clearance decreased significantly with increasing CRP up to a CRP concentration of 100 mg/L. This is the first step towards haloperidol precision dosing in ICU patients and our results indicate a possible role of inflammation.

Highlights

Delirium is quite common in intensive care unit (ICU) patients and is associated with poor clinical prognosis [1–5]
Data were collected at the adult ICU of Erasmus University Medical Centre (EMC), Rotterdam, the Netherlands, during a 3-year period
Patients who developed delirium received 1 mg every 8 h (q8h) by intravenous bolus infusion [or 0.5 mg q8h by intravenous bolus infusion for patients aged ≥ 80 years or 2 mg q8h by intravenous bolus infusion in case of agitation] within 8 h of delirium detection, which constituted the routine regimen in the EMC for the treatment of ICU delirium at that time

Summary

Introduction

Delirium is quite common in intensive care unit (ICU) patients and is associated with poor clinical prognosis [1–5]. The treatment of delirium may include pharmacological agents, including antipsychotics, melatonin, alpha-2 agonists (dexmedetomidine and clonidine), next to nonpharmacological interventions [6–8]. Clinical evidence for the effect of haloperidol in decreasing ICU delirium is scarce [8–11]. Pharmacokinetics (PK) can play an important role in understanding the effect of haloperidol in ICU patients. Ill patients tend to show large differences in PK [12,13]. In the case of haloperidol, this may lead to increased variability in haloperidol blood concentrations in ICU patients, compared to non-ICU patients [14,15]. The variable PK might explain the variability in the effect, adjusting the dose based on individual PK parameters might improve drug efficacy

Objectives

Methods

Results

Conclusion