Alprazolam and lorazepam overdose and the absence of brainstem reflexes

Background

Benzodiazepines (BZDs) are indirect gamma-aminobutyric acid (GABA) type A receptor agonists that exert their action by increasing GABA affinity for its receptor.1 BZDs rarely cause respiratory depression or death even after substantial ingestion.2 Herein, we describe a case of BZD overdose with profound sedation and abnormal brainstem reflexes mistakenly diagnosed and treated as a brainstem stroke.

Case presentation

A woman in her 70s was found unresponsive in a park 1.5 hours after texting her husband. On emergency medical service arrival, her vital signs were s follows: hypothermic (35°C) orally, blood pressure of 90/60 mm Hg, heart rate of 70 beats/min, rapid shallow breathing 16 times/min with oxygen saturation of 85%. Her Glasgow Coma Scale score was E1V1M4 (withdrawal to pain) with fixed 1 mm pupils in neutral positions. Corneal, oculocephalic reflex (doll’s eye) and oculovestibular reflex were absent. The tone was mildly increased with hyper-reflexia on the left side (2+) compared with the other (1+). Motor power was grade II/V bilaterally. There were no signs of traumas and toxidromes (such as flushing, urinary retention and myoclonus) other than depressed consciousness.

Investigations

Blood glucose and other laboratory investigations were normal. CT with perfusion of the brain was also unremarkable. Urine screening tests were negative for amphetamine derivatives, tricyclic antidepressants (TCAs), ketamine, tetrahydrocannabinol and opioids. Despite negative opioid screening, two doses of 0.4 mg naloxone were given as a therapeutic diagnosis for opioid overdose and yielded no response. The blood alcohol was not readily available and not tested. Because her symptoms (being comatose and the absence of brainstem reflexes) could suggest a brainstem stroke, a thrombolytic agent (alteplase) was delivered and the patient was admitted to the stroke unit. An electroencephalogram was scheduled for possible non-convulsive seizures. However, several hours later, her husband came to the hospital with empty zip bags containing 80 tablets of alprazolam and lorazepam. A toxicologist was then consulted for BZDs intoxication.

Differential diagnosis

This comatose patient demonstrated noteworthy presentations that hindered clinicians from diagnosing BZDs overdose: pinpoint pupils and loss of multiple brainstem reflexes. The pupils and brainstem reflex abnormalities in this patient implied a pontine-to-midbrain lesion. While the symptoms and signs are not fully compatible with the common lateral or medial pontine infarction syndrome, the acute alteration of consciousness with asymmetrical muscle tone and deep tendon reflexes still raised concern for basilar artery infarction.3 Timing within an eligible period for thrombolytics might conceivably influence the diagnosis and pressure the treatment decision. However, the absence of multiple brainstem reflexes at once with preserved motor functions (pain withdrawal) should urge physicians to consider other causes of extensive brainstem involvement.

The acuteness of symptoms also favours intoxications or poisoning. Miosis serves as an important clue of sedative–hypnotic, cholinergic or sympatholytic effects of xenobiotics.2 3 Common substances causing central nervous system depression and miosis include GABA agonists, opioids, alpha-2 agonists, some antipsychotics and cholinergic agents.4 5 Given no cardiovascular disturbances (hypotension/hypertension and bradycardia) that suggest alpha-2 agonist effects, anticholinergic toxidrome (flushing and urinary retention) that might arise from antipsychotic overdose, and cholinergic toxidrome (profound secretion), the latter three differentials were unlikely. Although miosis is a sign of opioid overdose triad, the lack of respiratory depression and negative naloxone response made this less likely. GABA agonist overdose, such as BZDs, barbiturates or ethanol, is by far the most plausible diagnosis as it usually causes sedation with preserved respiration like our patient. In this case, the tablets brought by her husband truly helped narrow down the differential.

Treatment

Following the patient’s possible history of BZDs overdose, she received a single dose of 0.25 mg intravenous flumazenil. Her unconsciousness and abnormal neurological findings improved dramatically within 30 s of antidote administration. She became fully conscious and extubated within the same day. There were no complications after flumazenil administration on close monitoring. During her hospital stay, she was diagnosed with major depressive disorder. She attended supportive psychotherapy regularly afterward but never told the detailed history of her overdose.

Outcome and follow-up

The following blood BZD concentration test (quantitative) showed alprazolam 268 ng/mL (20–40 ng/mL), lorazepam 861 ng/mL (20–250 ng/mL), nordiazepam 481 ng/mL (200–600 mg/mL) and oxazepam 14.9 ng/mL (500–2000 ng/mL). The urine drug confirmatory test (qualitative) detected alprazolam, lorazepam and metabolites, trazodone, clarithromycin and omeprazole. These blood and urine assays applied liquid chromatography–mass spectrometry technique. The results correlated with the overdose of alprazolam and lorazepam and corresponded to her previous medications: trazodone and diazepam for insomnia; clarithromycin, omeprazole and amoxicillin for Helicobacter pylori gastritis. Interestingly, diazepam or other parent compounds of nordiazepam and oxazepam were undetected. Thus, the coingestion of the drug was unproven.

She is currently doing well mentally and physically after multiple sessions of psychotherapy.