Potential pharmacological confounders in the setting of death determined by neurologic criteria: a narrative review

Abstract

Guidelines for the determination of death by neurologic criteria (DNC) require an absence of confounding factors if clinical examination alone is to be used. Drugs that depress the central nervous system suppress neurologic responses and spontaneous breathing and must be excluded or reversed prior to proceeding. If these confounding factors cannot be eliminated, ancillary testing is required. These drugs may be present after being administered as part of the treatment of critically ill patients. While measurement of serum drug concentrations can help guide the timing of assessments for DNC, they are not always available or feasible. In this article, we review sedative and opioid drugs that may confound DNC, along with pharmacokinetic factors that govern the duration of drug action. Pharmacokinetic parameters including a context-sensitive half-life of sedatives and opioids are highly variable in critically ill patients because of the multitude of clinical variables and conditions that can affect drug distribution and clearance. Patient-, disease-, and treatment-related factors that influence the distribution and clearance of these drugs are discussed including end organ function, age, obesity, hyperdynamic states, augmented renal clearance, fluid balance, hypothermia, and the role of prolonged drug infusions in critically ill patients. In these contexts, it is often difficult to predict how long after drug discontinuation the confounding effects will take to dissipate. We propose a conservative framework for evaluating when or if DNC can be determined by clinical criteria alone. When pharmacologic confounders cannot be reversed, or doing so is not feasible, ancillary testing to confirm the absence of brain blood flow should be obtained.

Keywords: death determination by neurologic criteria; drug confounders; opioids; pharmacokinetics sedatives.

Fig. 1

Variables that affect drug clearance and volume of distribution in the ICU. Artwork credit: Viktoriia Panchenko, www.dreamstime.com Cl = clearance; ICU = intensive care unit; V_d = volume of distribution

Fig. 2

Altered pharmacokinetics in ICU patients receiving prolonged continuous infusions of sedatives and analgesics. Figure is reproduced with permission from Tse AH, Ling L, Lee A, Joynt GM. Altered pharmacokinetics in prolonged infusions of sedatives and analgesics among adult critically ill patients: a systematic review. Clin Ther 2018; 40: 1598–615 (Elsevier; license number 5330910863857). Cl = clearance; T_1/2 = half-life; V_dss = volume of distribution at steady state