Sedative-Hypnotic Toxicity 

Updated: Oct 11, 2019
Author: Jeffrey S Cooper, MD, FAAEM, FACEP; Chief Editor: Asim Tarabar, MD 

Overview

Practice Essentials

Sedative-hypnotics are a group of drugs that cause central nervous system (CNS) depression. Benzodiazepines and barbiturates are the most commonly used agents in this class. Other agents include the nonbarbiturate nonbenzodiazepine sedative-hypnotics. Most cases of severe sedative-hypnotic poisoning are deliberate (suicidal). These agents are also commonly abused as recreational drugs.

Barbiturates include the following:

  • Ultrashort acting - Methohexital (Brevital) and thiopental (Pentothal)
  • Short and intermediate acting - Amobarbital (Amytal), pentobarbital (Nembutal), secobarbital (Seconal), butalbital (Fioricet, Fiorinal)
  • Long acting - Phenobarbital (Luminal)

Nonbarbiturates include the following:

  • Benzodiazepines
  • Carbamates - Meprobamate (Equanil, Miltown)
  • Chloral derivatives - Chloral hydrate (Noctec)
  • Ethchlorvynol (Placidyl)
  • Piperidines - Glutethimide (Doriden), methyprylon (Noludar)
  • Quinazolinone - Methaqualone (Quaalude)
  • Imidazopyridine - Zolpidem (Ambien), zaleplon (Sonata), eszopiclone (Lunesta)
  • Antihistamines (over-the-counter sleep aids) - Diphenhydramine, doxylamine
  • Gamma-hydroxybutyrate (GHB) and its analog gamma-butyrolactone (GBL)

Mild toxicity resembles ethanol intoxication. Severe respiratory depression is more likely to occur when the sedative-hypnotic is ingested with other CNS depressants or alcohol. Death from sedative-hypnotics is caused by respiratory arrest. Treatment is supportive or designed to limit absorption or enhance elimination. 

For patient education information, see Drugs and Medications, Drug Overdose and Poisoning, and Child-Proofing Basics.

Pathophysiology

All the sedative-hypnotics are general CNS depressants. Most stimulate the activity of gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the CNS. Benzodiazepines, which are one of the most frequently prescribed medications in the world, enhance the effect of GABA at the GABAA receptor.[1, 2]

GHB is a sedative-hypnotic that is banned for sale to the public because of frequent abuse (eg, "date rape") and serious toxic adverse effects. GHB is a neuroinhibitory neurotransmitter or neuromodulator in the CNS. It also appears to increase GABAB receptor activity and dopamine levels in the CNS. It binds to GABAB receptors in the brain, inhibits noradrenaline release in the hypothalamus, and mediates the release of an opiatelike substance in the striatum. It produces a biphasic dopamine response, increasing release at high doses and inhibiting release at lower doses.

Epidemiology

According to the 2017 Annual Report of the American Association of Poison Control Centers' National Poison Data System (AAPCC-NPDS), sedative/hypnotics/antipsychotics exposures as a class increased the most rapidly (4.91/year) over the last 17 years for cases showing more serious outcomes. It was the fourth most frequent exposure documented and the second most frequent exposure in adults aged 20 years or older. In 2017, there were with 53,419 single exposures resulting in 33 deaths. However, sedative/hypnotics/antipsychotics exposures were involved in 404 fatalies where more than one substance was present. This is the highest number of fatalities of any category.[3]  

 

Prognosis

In 2017, over 60% of ingestions were suicide related.[3]  These drugs are also used to offset the stimulatory effects of other drugs of abuse (eg, amphetamines, hallucinogens).[4]  Because they are prescribed so commonly, benzodiazepines have the highest morbidity and mortality of the sedative-hypnotics and represent nearly half of reported exposures.[3]  Alprazolam (Xanax) is relatively more toxic than other benzodiazepines in overdose and accounted for the majority of benzodiazepine fatalities in the 2017 AAPCC-NPDS annual report.[3]  

Benzodiazepines are commonly misused by individuals with opioid dependence, with prevalence rates of 45–70% for patients in opioid maintenance treatment.[5] Concomitant benzodiazepine use is a known risk factor for fatal and non-fatal opioid overdose; benzodiazepine co-ingestion is involved in 40–80% of heroin- and methadone-related deaths, and in 80% or more of buprenorphine-related deaths.[6]

Death from sedative-hypnotics is caused by respiratory arrest. Some sedative-hypnotics may have teratogenic or mutagenic effects. Complications associated with mortality in patients requiring intubation include difficulties with intubation, shock, and evidence of gastric aspiration.[7]

 

Presentation

History

The history should include the following information:

  • Agent(s) ingested
  • Amount of ingestion
  • Time of ingestion
  • Cause and/or reason for ingestion (eg, accidental, intentional, suicide attempt, recreational)
  • Whether ingestion is acute or chronic
  • Past medical history and history of drug abuse
  • Circumstances surrounding the overdose

Physical Examination

Focus the physical examination on vital signs and neurologic and cardiopulmonary status. Mild toxicity resembles ethanol intoxication. Severe respiratory depression is more likely to occur when the sedative-hypnotic is ingested with other CNS depressants or alcohol. Flexor or extensor posturing can be present in coma resulting from sedative drug ingestion. It does not imply structural damage in this setting.

Barbiturates

Mild intoxication is characterized by ataxia, incoordination, nystagmus, slurred speech, and altered level of consciousness. Moderate poisoning leads to respiratory depression and hyporeflexia. Severe poisoning leads to flaccid areflexic coma, apnea, and hypotension. Generally, 10 times the hypnotic dose produces severe toxicity.

Occasionally, hyperreflexia, rigidity, clonus, and Babinski signs are present. Miosis is common, but mydriasis may be present with certain agents. However, the nonbarbiturates, such as methyprylon and glutethimide, more commonly produce mydriasis. Hypotension is usually secondary to vasodilation and negative cardiac inotropic effects.

Complications include the following:

  • Noncardiogenic pulmonary edema
  • Hypothermia
  • Delayed gastric emptying (therefore, late lavage and multiple charcoal is effective)
  • Skin lesions (clear vesicles and bullae on an erythematous base at contact surfaces) occur in 6% of ingestions and in approximately 50% of lethal ingestions.

Methaqualone (Quaalude)

Methaqualone intoxication resembles barbiturate poisoning but has more pronounced motor problems (eg, ataxia); the drug is known as wallbanger because of this phenomenon. Progression to severe muscular hypertonicity and seizures is possible.

Glutethimide (Doriden)

Signs and symptoms of glutethimide toxicity include the following:

  • Loss of brainstem reflexes
  • Flaccidity
  • Anticholinergic effects
  • Delayed gastric emptying
  • May cause hyperthermia or heatstroke

Ethchlorvynol (Placidyl)

Ethchlorvynol toxicity is characterized by a pungent odor of breath and gastric contents and prolonged coma (up to 2 weeks). Acute respiratory distress syndrome (ARDS) predominates in IV use.

Chloral hydrate

Signs and symptoms of chloral hydrate toxicity include the following:

  • Synergistic with alcohol (knockout drops, Mickey Finn)
  • Cerebellar incoordination
  • Severe gastritis and GI bleeding
  • Multiple dermatologic effects, including purpura, bullae, urticaria, and erythema multiforme (EM)
  • CNS depression with cardiopulmonary collapse
  • Associated with hepatitis, gastritis, proteinuria, and dysrhythmias
  • Odor of pears

Z-drugs (Imidazopyridine)

Sleepwalking or other complex bizarre behaviors have been reported in patients taking z-drugs (ie, zopiclone, zaleplon, zolpidem); prolonged coma and respiratory failure are possible. Chromaturia (blue-green urine discoloration) has been reported with zaleplon (Sonata) overdose.

Meprobamate

Meprobamate toxicity is characterized by hypotension and CNS and respiratory depression. 

Gamma-hydroxybutyrate and gamma-butyrolactone

Mild intoxication includes the following:

  • Slurred speech
  • Disinhibition
  • Euphoria
  • Mild lethargy
  • Moderate intoxication
  • CNS and mild respiratory depression
  • Agitation when stimulated
  • Myoclonus

Severe intoxication includes the following:

  • Unresponsive coma
  • Miosis
  • Bradycardia
  • Mild hypotension
  • Seizures
  • Respiratory depression and apnea

After ingestion, the onset of effects occurs within 15 minutes and peaks in 1.5-2 hours. Elimination of GHB is rapid (elimination half-life 1-2 h). The duration of clinical effects is 2-8 hours.

 

DDx

 

Workup

Laboratory Studies

Obtain a complete blood count (CBC), arterial blood gas (ABG) sampling, glucose, chemistry, and toxicology screen. Screen for alcohol, salicylate, and acetaminophen with all intentional exposures. Quantitative serum drug concentrations are recommended for patients with serious toxicity. Significant results for specific agents include the following:

  • Barbiturates: For short-acting drugs, the lethal dose is 3 g or a serum concentration higher than 3.5 mg/dL. For long-acting drugs, the lethal dose is 5-10 g or a concentration higher than 8 mg/dL.

  • Methaqualone: A serum concentration higher than 8 mg/L is life threatening.

  • Glutethimide: Consider hemodialysis if the serum concentration is higher than 3 mg/dL.

  • Methyprylon: A serum concentration higher than 3 mg/dL is associated with severe toxicity and concentration higher than 6 mg/dL is typically fatal.

  • Ethchlorvynol: Perform charcoal hemoperfusion for an ingestion more than 100 mg/kg or a serum concentration higher than 10 mg/dL.

  • Chloral hydrate: The lethal dose is 10 g and a concentration higher than 100 mcg/mL is toxic.

  • Meprobamate: Coma occurs at 6-20 mg/dL. The drug is fatal at serum concentrations higher than 20 mg/dL.

On urinalysis, blue-green urine has been reported with zaleplon (Sonata) overdose.

Imaging Studies

Obtain an abdominal radiograph. Chloral hydrate is radiopaque.

Other Tests

Obtain an electrocardiogram (ECG); co-ingested drugs may have direct cardiac effects (eg, tricyclic antidepressants).

 

Treatment

Approach Considerations

The only available antidote-like drug is flumazenil for benzodiazepine intoxication. Flumazenil should not be used routinely, and the harms and benefits should be considered carefully in every patient.[8]  All other therapy is supportive or designed to limit absorption or enhance elimination. Given that the major issues in an overdose are aspiration, respiratory depression or failure, hypoxia, hypotension, and cardiac arrhythmias, the most important aspects in managing an overdose situation are, as usual, the ABCs—airway, breathing, and circulation.

Prior to arrival in the emergency department obtain IV access, provide oxygen, and perform aggressive supportive care with airway protection as necessary. Ensure adequate airway and ventilation. Consider and reassess the need for endotracheal intubation. Ipecac syrup is not recommended for home use because of the fear of emesis after onset of respiratory depression. 

Emergency Department Care

Gastric lavage may be performed if the patient presents obtunded within 1 hour of ingestion or rapidly deteriorates while in the emergency department. The airway should be secured in such instances prior to gastric intubation and lavage.

The use of activated charcoal has come under debate, and its liberal use is discouraged. In general, measures to prevent absorption (eg, emesis, gastric lavage) or increase excretion (eg, diuresis, catharsis) of ingested drugs have not been shown consistently to reduce mortality associated with drug toxicity. Considerable morbidity is associated with charcoal aspiration. Its use should be limited to substances that would be well absorbed and have a high likelihood of toxic dose ingestion. It is not recommended in instances in which GHB or GBL are known to be the only intoxicants.

Multi-dose activated charcoal (20-50 g q4h) is recommended for overdoses with barbiturates, glutethimide, and meprobamate.

Alkaline diuresis enhances elimination of phenobarbital and other long-acting barbiturates. It is recommended for all symptomatic patients with long-acting barbiturate toxicity. Consider hemodialysis or hemoperfusion in glutethimide, methyprylon, phenobarbital, meprobamate, and chloral hydrate poisoning.

Patients who have made a suicide attempt should be evaluated by a psychiatrist after the intoxication has resolved to determine if they need inpatient psychiatric care.

With barbiturate toxicity, patients may be discharged after 6 hours of observation, provided that they are asymptomatic or minimally symptomatic. Patients with glutethimide (Doriden) toxicity require 24 hours of observation in the hospital.

Flumazenil Therarpy

Benzodiazepines promote the binding of GABA to its receptor. The z-drugs (zopiclone, zaleplon and zolpidem) act in a similar manner. Flumazenil is a benzodiazepine analogue with minimal intrinsic activity. It binds to the extracellular surface of GABAA receptors and competitively displaces benzodiazepine molecules, preventing further benzodiazepine binding.[9]  Flumazenil can reverse respiratory depression in the rare patient with severe, isolated benzodiazepine or z-drug toxicity who does not have contraindications to its use. It is most often considered in accidental pediatric ingestions or reversal of iatrogenic oversedation.[10]  

Contraindications to flumazenil use include the following[10] :

  • Increased intracranial pressure (ICP) or closed head injury (CHI)
  • History of epilepsy
  • Unknown or mixed overdose,
  • Benzodiazepine tolerance
  • Prolonged QRS interval

In a meta-analysis, serious adverse events were significantly more common among patients with suspected benzodiazepine overdose treated with flumazenil than among those in the placebo group (12/498 versus 2/492; risk ratio: 3.81; 95% CI: 1.28–11.39; P = 0.02). The most common adverse events in the flumazenil group were agitation and gastrointestinal symptoms, and the most common severe adverse events were supraventricular arrhythmia and convulsions.[8]  Seizures may become more difficult to manage and may require the use of propofol or barbiturates. A poison control center should be consulted if the use of flumazenil is being considered.[10]

If used, flumazenil should be administered slowly (0.2 mg/min up to 3-5 mg) because large doses cause agitation and withdrawal. The half-life of flumazenil is about 50 minutes and sedation often recurs. Cardiorespiratory monitoring is necessary, and repeat dosing or infusion may be required.[10]

Agent-specific interventions

Meprobamate: Force diuresis and provide hemodialysis in severe intoxication.  Whole bowel irrigation is recommended for serious meprobamate poisoning because of the high predilection for bezoar formation.

Methaqualone (Quaalude): Do not provide diuresis. Diazepam can be administered for severe tonicity or seizures. Phenytoin may be strongly considered as an anticonvulsant because barbiturates potentiate this drug.

Chloral hydrate: Consider hemodialysis. Strictly avoid beta-adrenergic agonists (eg, dopamine) because they increase risk of fatal dysrhythmias. Beta-blockers (eg, propranolol) and overdrive pacing have also been reported to be effective. Intravenous propranolol is, perhaps, the drug of choice for chloral hydrate-associated ventricular dysrhythmias. Chloral hydrate sensitizes the myocardium to catecholamines, and propranolol blocks this effect. Lidocaine may also be used to treat ventricular dysrhythmias. 

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Use of flumenazil may sbe considered for reversal of benzodiazepine toxicity in selected cases.

GI decontaminant

Class Summary

Empirically used to minimize systemic absorption of the toxin. May only be of benefit if administered within 1-2 h of ingestion.

Activated charcoal (Liqui-Char)

Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.

For maximum effect, administer within 30 min of ingesting poison. The initial dose may be given with water or a cathartic (such as 70% sorbitol). Sorbitol should not be given to children < 2 y.

Antagonist

Class Summary

Reverses benzodiazepine sedation and respiratory depression.

Flumazenil (Romazicon)

Competitively and reversibly binds benzodiazepine receptors (GABA). Administer slowly; large doses cause agitation and withdrawal.

Usually effective after 0.4-1 mg. Although up to 3-5 mg in massive ingestions have been required.

In cases of resedation, IV drip at 0.01-0.05 mg/kg/h may be used. Only consider a flumazenil drip if the patient is not habituated to sedative-hypnotic agents.