Toxicologic Confounders of Brain Death Determination: A Narrative Review

Abstract

The aim of this narrative review is to describe the toxicologic confounders of brain death currently reported in the literature to offer guidance for physicians assessing brain death after a toxic exposure. We established an a priori definition of a "brain death mimic" as an unresponsive, intubated patient missing some, but not all brainstem reflexes. We completed a review of the literature utilizing MEDLINE and EMBASE to find case reports of patients of all ages in English, French, and Spanish meeting the criteria and hand searched the references of the results. We recorded xenobiotic dose, duration of physical exam suggesting brain death, and how the cases failed to meet full brain death criteria, when available. Fifty-six cases representing 19 different substances met the a priori definition of brain death mimic. Xenobiotic toxicities included: snake envenomation (13), baclofen (11), tricyclic antidepressants (8), bupropion (7), alcohols (4), antiepileptic agents (3), barbiturates (2), antidysrhythmics (2), organophosphates (2), and one case each of magnesium, succinylcholine, tetrodotoxin, and zolpidem. All patients except one survived to discharge and the majority at their baseline physical health. The most common means by which the cases failed brain death examination prerequisites was via normal neuroimaging. The xenobiotics in this review should be considered in cases of poisoning resulting in loss of brainstem reflexes and addressed before brain death determination. Brain death diagnosis should not be pursued in the setting of normal cerebral imaging or incomplete evaluation of brain death prerequisites.

Brain death: a clinical overview

“…Potential confounders are vast and can be thought of by placing them into general categories such as clinical disease states (demyelinating polyneuropathy [ 18 – 20 ], botulism [ 21 ]), hemodynamics and body temperature [ 22 ], metabolic derangements [ 23 ], toxicities [ 24 – 29 ], sedation effects [ 30 ], and other medication effects). Extensive descriptions of potential confounders are beyond the scope of this review and have been described elsewhere [ 6 , 31 ].…”

Burst Suppression Electroencephalography (EEG) Pattern with Coma and Loss of Brain Stem Reflexes Following a Baclofen Overdose with Subsequent Full Recovery

“…While the differential is broad, toxicological causes are not uncommon. Significant sedation is common following overdose of many substances, although a thorough physical examination and neurologic assessment will typically identify preservation of very basic neurologic function and, often, maintenance of higher degrees of cortical functioning [ 1 ]. In their absence, an alternative diagnosis, including the possibility of anoxic brain injury occurring in relationship to medication or substance misuse, will often be considered.…”

Machine Learning with Objective Serum Markers and Algorithmic Deep Learning CT Scan Analysis Predicts Brain Death Due to Trauma and Hypoxia

“…Nineteen different xenobiotic agents have been implicated in causing a transient neurologic mimic of brain death. 3 Some survivors of coldwater drowning and avalanche suffocations with hypothermic arrest may experience neurologic recovery. 4 Recent advances in whole body temperature-controlled perfusion allowed for full neurological recovery after 10 minutes of prolonged asystole with hypothermia.…”

“…Serum biomarkers offer potential to aid in objective measurement and prognostication of brain injury 11 , and have been examined in various brain injury cohorts including brain death. 12 In particular, glial fibrillary acidic protein (GFAP), the predominant filament protein in the astrocytic skeleton has demonstrated potential as a marker of astrocytic injury 3, 14 , and is markedly upregulated during astrogliosis, a process in which astrocytes increase in size and number in response to traumatic and anoxic injury. 15,16 Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is a neuron-specific protein, known for its role in the addition and removal of ubiquitin from proteins.…”