Chloral hydrate overdose

aka Toxicology Conundrum 020

A 25 year-old woman with a history of depression was found by her flatmate. An empty 200mL bottle of chloral hydrate was present at the scene. She arrived at your emergency department with the following vital signs:

T 36.0 C
P 140 /min
BP 80/50 mmHg
RR 14 /min
SO2 93% on 15 L/min O2 via a non-rebreather mask
GCS3 with pin-point pupils

Her breath smells like something from the tin of fruit salad you gulped down as you were dragged to the resus room…


Questions

Q1. What are the toxicodynamics of chloral hydrate overdose?

Answer and interpretation

Chloral hydrate has an active metabolite trichloroethanol (TCE) that binds the GABA-A receptor in the central nervous system (CNS). CNS depression and sedation results from potentiation of the effects of endogenous GABA.

Chloral hydrate/ TCE- mediated toxicity also results from:

  • catecholamine-hypersensitivity leading to tachydysrhythmias
  • corrosive effects on the gastrointestinal mucosa
  • hepatotoxicity and nephrotoxicity

Q2. What are the toxicokinetics of chloral hydrate overdose?

Answer and interpretation
  • Absorption:
    • Usually rapid with peak plasma concentrations in 30-60 minutes, but may be delayed in overdose. Bioavailability is high. IV overdoses are clinically similar to oral overdoses.
  • Distribution:
    • Voulme of distribution is low (~1 L/kg) and there is ~ 35% protein binding.
  • Metabolism –
    • Rapid hepatic metabolism (the half-life of therapeutic doses of chloral hydrate is only ~5 minutes).
    • There are reactive metabolites (trichloroethanol (TCE) (10%)) and inactive metabolites (trichloroacetic acid (TCAA) (67%)).
  • Elimination:
    • TCE has a half-life of 8 to 12 hours, perhaps even longer in overdose.

Q3. What is the toxic dose of chloral hydrate?

Answer and interpretation

The dose-related risk assessment of chloral hydrate is not well defined. In general, the following effects are expected in adults:

  • 0.5 to 1.0g — sedation
  • 1.5-2.0g — ‘excessive’ sedation
  • 3-10g — potentially lethal dose (primarily due to cardiovascular effects)

Potentially lethal dysrhythmias may occur in near-therapeutic doses – as little as 1.5g in young children. There have been adult survivors of ingestions up to 35g.


Q4. What are the potential clinical manifestations of chloral hydrate overdose?

Answer and interpretation

It may be helpful to think of choral hydrate as a hybrid of a barbiturate-like sedative and a halogenated hydrocarbon when considering its potential clinical effects.

  • Neurological:
    • Sedation, ataxia, coma, miosis
  • Gastrointestinal and renal:
    • Erosive injuries to the esophageal or gastric mucosa resulting in hemorrhage or perforation or stricture formation, hepatitis, breath odour resembles the smell of pears.
    • Nephrotoxicity and proteinuria may occur.
  • Cardiovascular:
    • Hypotension, myocardial depression, catecholamine hypersensitivity and dysrhythmias including sinus tachycardia, ventricular premature beats (VPBs), ventricular tachycardia (VT), ventricular fibrillation (VF), and torsades de pointes (TdP).
  • Respiratory:
    • Airway obstruction from skeletal muscle relaxation, respiratory depression, aspiration pneumonitis
  • Skin:
    • Rashes such as bullae or eyrthema mulitforme

Chronic users who discontinue chloral hydrate use may develop a withdrawal syndrome. Tolerance develops with 1-2 weeks of regular use.


Q5. Would you consider using any antidotes in this case?

Answer and interpretation

Two antidotes might be considered – naloxone and flumazemil. I would not administer either of them in this case.

Naloxone could be considered due to the possibility of opioid coingestion.  The patient has pinpoint pupils characteristic of opioid toxicity, but this is also a feature of chloral hydrate toxicity. The absence of marked respiratory depression makes opiate overdose less likely. Naloxone administration can result in sympathetic stimulation, that might aggravate chloral hydrate-induced catecholamine hypersensitivity, and non-cardiogenic pulmonary edema.

Flumazenil reversed chloral hydrate-induced sedation following toxicity in at least one case report. However, flumazenil use has potential risks:

  • may exacerbate dysrhythmias due to catecholamine-hypersensitivity
  • may lead to seizures if the patient has an underlying seizure disorder or has coingested tricyclic antidepressants
  • may precipitate a severe withdrawal syndrome in people with benzodiazepine dependence.

Q6. Describe your management plan.

Answer and interpretation

Risk assessment:

This is a potentially lethal ingestion of chloral hydrate – the patient already has coma and evidence of cardiovascular toxicity (tachycardia, hypotension).

Gastrointestinal injury and the presence of coingestants cannot be excluded.

Resuscitation, supportive care and monitoring –

Manage patient in an appropriately resourced resuscitation area with continuous monitoring.

Treat immediate life-threats:

  • Airway compromise due to CNS depression
    • intubate and ventilate.
  • Hypotension
    • crystalloid boluses (up to 2L)
    • avoid catecholaminergic agents if possible due to risk of catecholamine-induced dysrhythmias.
    • consider GI perforation as a cause of hypotension. Keep NBM until corrosive GI injury ruled out.
  • Ventricular dysrhythmias (especially VT and VF)
    • manage according ACLS guidelines but avoid catecholaminergic agents if possible.
    • Corect hypoxia, acidosis and electrolyte disturbances (e.g. hypokalaemia, hypomagnesaemia).
    • Administer beta blockers  – e.g. propanolol 1-2 mg IV or metoprolol 5mg IV (0.1mg/kg in children) or esmolol infusion.
  • Torsades de pointes

Investigations –

Screening tests- paracetamol level, BSL.

Specific tests –

  • ECG – potentially lethal tachydysrhythmias
  • CXR – pulmonary edema or pneumonitis
  • AXR – chloral hydrate is radio-opaque – may help confirm recent ingestion.
  • ABG – confirm hypoxia, metabolic acidosis. lactaemia
  • UEC – electrolyte abnormalities must be ruled out in the event of dysrhtymia, acute renal impairment from shock or rhabdomyolysis.
  • LFTs, INR, glucose – hepatic injury
  • CK, trop – rhabomyolysis or myocardial ischemia
  • bHCG – pregnancy?
  • urinalysis – proteinuria, myoglobin, bHCG
  • upper GI endoscopy – to identify corrosive injury

Other investigations may be needed depending on how the situation evolves…

Decontamination – nil.

  • Decontamination is unlikely to be helpful unless there are coingestants as chloral hydrate is rapidly absorbed and the patient already has evidence of severe toxicity.
  • One might think about administering activated charcoal following intubation if AXR showed the presence of radio-opaque chloral hydrate in the patients stomach or if other findings suggested a coingestion. However, chloral hydrate also has the risk of causing corrosive injury to the gastrointestinal tract, so the risk-benefit balance probably leans against the administration of AC or gastric lavage.

Enhanced elimination and antidotes – nil

  • Renal dialysis may increase the elimination of chloral hydrate, given its low volume of distribution and has been used in massive overdoses of chloral hydrate. Clinical efficacy is uncertain.

Disposition

  • This patient needs admission to intensive care for ongoing management. Surgical intervention if evidence of GI perforation. Psychiatric assessment prior to discharge from hospital.

Disposition is different in other situations:

  • The asymptomatic patient should be observed for at least 4 hours following ingestion. Do not discharge at night.
  • Patients with possible corrosive gastrointestinal injury (e.g. drooling, odynophagia, vomiting, abdominal pain) should be kept nil-by-mouth and have upper GI endoscopy performed within 24 hours of ingestion.
  • Discharged patients should be warned of the potential for re-sedation up to 24 hours post-ingestion.

Q7. What are the clinical uses of chloral hydrate?

Answer and interpretation

Although it has been used since the mid-1800s, clinical use of chloral hydrate is controversial. Many have called for the drug to be banned. However chloral hydrate may be used to safely sedate children for procedures or diagnostic imaging. Other uses of chloral hydrate include use as a second-line treatment for status epilepticus in children, and it might still be found being used as a sedative in the elderly.

Here are some pointers distilled from the recommendations of the ‘EMSC Panel on Critical Issues in the Sedation of Pediatric Patients in the Emergency Department’ for the use of chloral hydrate for the sedation of children:

  • Administration
    • dose 50-100 mg/kg po (maximum 2g), with the option of a repeat dose
    • children should not be fasted – chloral hydrate works more quickly in the unfasted child (sounds paradoxical I know…)
  • Patient selection
    • should not be used for children >48 months-old due to decreased efficacy
    • avoid if child has neurodevelopmental delay (decreased efficacy and more adverse events)
  • Adverse events
    • patient must be supervised by skilled staff able to manage potential complications of sedation (e.g airway obstruction).
    • Vomiting and paradoxical excitement can occur
    • be aware of the potential for re-sedation up to 24 hours after administration due to circulating active metabolites

Q8. What is a ‘Mickey Finn’?

Answer and interpretation

A ‘Mickey Finn’ is a slang term for a drink surreptitiously laced with a sedative – a “knockout drink”. Most commonly it refers to a mixture of ethanol and chloral hydrate, ingestion of which can lead to rapid loss of consciousness as the two sedative potentiate one another.

“He slipped him a Mickey.”

The name ‘Mickey Finn‘ probably originates from a Chicago bartender who, around the turn of the last century, had a reputation for knocking out customers with spiked drinks so that he could rob them without a fuss.

Chloral hydrate overdoses were all the rage in the 1980s, but have since died out (no pun intended…) – at least in this part of the world. Its clinical use has also greatly declined, in favour of “safer” sedatives.


References
  • Donovan KL, Fisher DJ. Reversal of chloral hydrate overdose with flumazenil. BMJ 1989 May 6;298(6682):1253. PMID: 2502241 [fulltext]
  • Graham SR et al. Overdose with chloral hydrate: a pharmacological and therapeutic review. Med J Aust. 1988 Dec 5-19;149(11-12):686-8. PMID: 3059159
  • Mace SE and the EMSC Panel on Critical Issues in the Sedation of Pediatric Patients in the Emergency. Clinical policy: Critical issues in the sedation of pediatric patients in the emergency department. Ann Emerg Med. 2008 Apr;51(4):378-99, 399.e1-57. PMID: 18359378
  • Whyte IM. Chapter 140 Miscellaneous Anziolytics, Sedatives and Hypnotics; in Dart R, Medical Toxicology (3rd edition), Philadelphia: Lippincott Williams and Wilkins, 2004. [Google Books Preview]
  • Zahedi A, et al: Successful treatment of chloral hydrate cardiac toxicity with propranolol.  Am J Emerg Med 1999; 17:490. PMID: 10496517

CLINICAL CASES

Toxicology Conundrum

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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