Sedative-hypnotic drug overdose

Sedative-hypnotic drug overdose and/or poisoning can be intentional or unintentional. Affected individuals usually present with a sedative-hypnotic toxidrome, but the severity and features vary based on the specific agent, the amount taken, and the presence of any co-intoxicants. Diagnosis is primarily clinical because drug testing for sedative-hypnotics has limited utility in management. Diagnostic studies to exclude alternative diagnoses and/or confirm the presence of co-intoxicants are usually obtained. Treatment is primarily supportive with an emphasis on airway management and respiratory support while the drug is metabolized. Flumazenil can be used as an antidote for isolated benzodiazepine poisoning in benzodiazepine-naive patients but is often avoided because of the risk of adverse effects. Symptomatic patients generally require admission for further monitoring and treatment.

See “Sedative-hypnotic drugs” for more information on specific agents, their clinical uses, mechanisms of action, and adverse effects.

The sedative-hypnotic class of drugs comprises several agents that have similar effects at therapeutic levels, but the severity of overdose symptoms varies widely depending on the specific medication.

• Benzodiazepine overdose
  • Typically manifests with lethargy, somnolence, and slurred speech
  • Treatment includes supportive care and, in some cases, flumazenil.
• Barbiturate overdose
  • Typically manifests with profound CNS depression and respiratory depression
  • Treatment often includes endotracheal intubation and mechanical ventilation.
• Nonbenzodiazepine hypnotic overdose
  • Typically manifests with oversedation
  • Treatment is supportive care.
• Gamma-hydroxybutyrate overdose (GHB overdose)
  • Manifestations vary from euphoria to profound CNS depression, seizures, and respiratory depression.
  • Patients may rapidly cycle between different clinical presentations.
  • Treatment is supportive and may involve intermittent respiratory support with bag-mask ventilation.
• Xylazine intoxication
  • Most often seen alongside other recreational drug intoxication (e.g., fentanyl).
  • Typically manifests with a sedative-hypnotic toxidrome similar to opioid overdose but unresponsive to naloxone.
  • Treatment is supportive and often involves airway management and rescue breathing.

All sedative-hypnotic drug overdoses manifest with some features of sedative-hypnotic toxidrome, but the severity of symptoms varies with the specific medication.

Sedative-hypnotic drugs are a class of medications with primary CNS depressant effects that are typically prescribed for their sedating effects.

• Sedatives: substances that have a tranquilizing effect and mitigate agitation by limiting CNS excitability ^[1][2]
• Hypnotics: substances that induce, sustain, or prolong sleep ^[1][2]

Sedative-hypnotic toxidrome ^[2][3][4]

The severity of symptoms varies with the specific drug and quantity taken.

• CNS depression
  • Reduced level of consciousness: drowsiness, stupor, or coma
  • Ataxia
  • Nystagmus
  • Slurred speech
  • Hypotonia and/or hyporeflexia
• Respiratory failure
  • Upper airway obstruction: snoring, obstructive apnea ^[5][6]
  • Decreased respiratory drive: decreased respiratory rate and/or tidal volume ^[7][8]
• Hypotension
• Hypothermia

The manifestations of sedative-hypnotic overdose are nonspecific. Always consider alternative critical causes of altered mental status as well as causes of respiratory failure.

Clinical diagnosis ^[2][7]

Establish the diagnosis based on:

• Presence of a sedative-hypnotic toxidrome
• Suspected exposure to a sedative-hypnotic drug
• Toxicological history and physical examination

Do not delay initial management of sedative-hypnotic drug overdose for diagnostic testing or confirmation.

Supportive diagnostic studies ^[2][7]

The following are used to assess for complications and rule out alternative diagnoses.

• Laboratory studies
  • CMP, TFTs: to evaluate for alternative or associated causes of AMS
  • VBG or ABG: to evaluate the severity of respiratory failure
  • Acetaminophen level: to rule out an overdose of this commonly co-ingested medication
  • Drug tests for sedative-hypnotic drugs have limited utility in clinical management. ^[7]
• ECG: : to look for signs of cardiotoxicity from commonly co-ingested medications
• Imaging studies: if clinically indicated
  • CXR: to evaluate for suspected aspiration pneumonia or acute lung injury
  • CT head: to evaluate for suspected head injury or for alternative causes of AMS

Consider testing for co-ingested CNS depressants (e.g., alcohol, opioids) if the patient has significant respiratory depression, hypotension, and/or prolonged coma. ^[1]

Initial management ^[2][7]

• Follow the ABCDE approach in poisoning and initiate resuscitation (e.g., oxygen therapy, IV fluid resuscitation) as needed.
• Perform a toxicological risk assessment and obtain diagnostic studies.
• Call the local Poison Control Center: In the US, the Poison Help line is 1-800-222-1222.
• Provide supportive care for the poisoned patient; (e.g., treat hypoglycemia, replete electrolytes).
• Treat concurrent drug intoxications if indicated, e.g., psychiatric drug poisoning.

Respiratory support ^[2][7]

• Secure the airway in patients with reduced level of consciousness or airway obstruction
  • Airway opening maneuvers and/or recovery position: relieve most mild or moderate airway obstruction due to transient CNS depression
  • Bag mask ventilation (BMV) provides temporary ventilation if:
    • Antidote is indicated, e.g., flumazenil for severe benzodiazepine overdose.
    • Respiratory depression is expected to be short-lived, e.g., GHB overdose.
  • Endotracheal intubation: may be required for poisoning with long-acting agents with no known antidote, e.g., barbiturate overdose
• Monitor for respiratory depression with pulse oximetry, capnography, and serial examinations.
• Provide mechanical ventilation if the patient develops respiratory failure.

Supportive cardiorespiratory care with frequent reevaluation of respiratory and neurologic status is the cornerstone of sedative-hypnotic overdose management. ^[1][2]

Monitor respiratory status with capnography because supplemental oxygen can mask worsening hypoventilation. ^[7]

Antidotes ^[2][7]

• Consider flumazenil only in patients with severe isolated benzodiazepine overdose who are not benzodiazepine-dependent. ^[2]
• Consider naloxone for opioid overdose in patients with concurrent opioid use and respiratory suppression.

GI decontamination and enhanced elimination ^[2][7]

Consider based on causative agent and patient factors. ^[9]

• Not recommended for benzodiazepine overdose ^[7]
• May be considered with expert consultation for barbiturate overdose ^[2][10]

Disposition ^[2][7]

• Asymptomatic patients: may be medically cleared if no symptoms develop within 6 hours of ingestion
• Mildly symptomatic patients: Observe until mental status returns to normal and the risk of respiratory depression has resolved (agent-specific).
• Severely symptomatic patients: Admit to ICU for ongoing care.
• All patients: Consult psychiatry if overdose was intentional.

Poisoning and/or overdose due to other CNS depressants

• Opioid overdose
• Alcohol intoxication
• Tricyclic antidepressant overdose
• Baclofen overdose
• Clonidine overdose
• Cannabis intoxication

Severe symptoms (e.g., respiratory depression, hypotension, coma) often indicate polysubstance poisoning. ^[1]

Nonpharmacological conditions

Consider other potential causes of altered mental status.

• Primary CNS pathology: e.g., encephalitis, stroke, seizures
• Primary respiratory problem: e.g., hypoxia, hypercarbia
• Electrolyte disturbance: e.g., hyponatremia, hypernatremia, hypercalcemia
• Metabolic abnormality: e.g., hypoglycemia, hepatic encephalopathy, myxedema coma
• Hypoperfusion: e.g., sepsis, shock
• Psychiatric: e.g., psychosis, catatonia
• Environmental: e.g., hypothermia, hyperthermia

The differential diagnoses listed here are not exhaustive.

General principles ^[4][7]

• Benzodiazepines have a wide therapeutic index and are therefore safer than barbiturates.
• Overdose is rarely life-threatening unless other respiratory or CNS depressants have been coingested (e.g., alcohol, opioids, barbiturates, antihistamines).
• Older adults are at particularly high risk because of pharmacokinetic changes and potential drug interactions. ^[11]
• See “Benzodiazepines” for information on specific agents, their clinical uses, mechanisms of action, and adverse effects.

Clinical features ^[4][7]

Benzodiazepine overdose manifests with a sedative-hypnotic toxidrome.

• Mild CNS depression (e.g., lethargy, somnolence, slurred speech, cognitive impairment) and ataxia are most common. ^[4]
• Respiratory depression (uncommon in isolated benzodiazepine overdose)
• Hypotonia and hyporeflexia
• Vital signs are often normal (hypotension is uncommon). ^[12]

Benzodiazepine overdose most commonly manifests with mild CNS symptoms, and vital signs are often normal. ^[4][12]

Severe symptoms (e.g., coma, respiratory suppression, hypotension) suggest a very large ingestion and/or the co-ingestion of another intoxicant. ^[4][7]

Management ^[2][4][7]

• Follow the approach to sedative-hypnotic drug overdose.
• Supportive care is the mainstay of treatment.
• Endotracheal intubation is seldom required for pure benzodiazepine overdose.
• GI decontamination is usually not recommended.
• Flumazenil administration may be considered in select cases.

Avoid flumazenil in patients on chronic benzodiazepine therapy because of the risk of precipitating withdrawal symptoms and seizures. ^[2][7]

Flumazenil ^[2][7][12]

Flumazenil is a specific antidote to benzodiazepines, but its risks often outweigh its benefits. ^[12]

Mechanism of action ^[12]

• Flumazenil is a competitive antagonist to benzodiazepines at the GABA receptor.
• It rapidly reverses CNS depression.
• It does not reliably reverse respiratory depression.

Adverse effects ^[12][13]

• Seizures, tachyarrythmias: especially in patients with proconvulsive or proarrythmic co-ingestions ^[12]
• Acute benzodiazepine withdrawal: in patients with benzodiazepine dependence
• Other: aggressive behavior, agitation, nausea, vomiting, abdominal cramping

Indications ^[2][7][12]

• Severe benzodiazepine-induced CNS depression in benzodiazepine-naive patients who meet all the following criteria:
  • Absence of other neurologic findings
  • Absence of ECG abnormalities
  • Presence of normal vital signs
• Severe benzodiazepine-induced respiratory depression (controversial) ^[2][7]
• Reversal of oversedation with a benzodiazepine (mostly in perioperative settings)

Flumazenil is not routinely recommended for reversal of sedative overdose in the emergency department. Expert consultation is advised. ^[7]

Contraindications ^[2][7]

• Chronic benzodiazepine use
• History of seizure disorder
• Suspected co-ingestion of proconvulsive or proarrythmic substances

Administration ^[2][7]

• Dose: flumazenil (for benzodiazepine overdose)
• Carefully monitor for resedation and recurrent respiratory depression: Readministration may be necessary. ^[2]

Flumazenil can increase the risk of seizures, supraventricular arrhythmias, and/or benzodiazepine withdrawal. Be prepared to manage these complications. ^[13]

General principles ^[1][7]

• Barbiturates have a narrow therapeutic index making them less safe than other sedative-hypnotics.
• Overdose is often caused by dose escalation due to rapid tolerance.
• See “Barbiturates” for information on specific agents, their clinical uses, mechanisms of action, and adverse effects.

Clinical features ^[7][14]

Barbiturate overdose manifests with a sedative-hypnotic toxidrome. Manifestations of severe toxicity include:

• Respiratory failure: due to severe hypoventilation or respiratory arrest
• Profound CNS depression: e.g., stupor, coma
• Cardiovascular depression: hypotension, often with normal or increased heart rate
• Noncardiogenic pulmonary edema or acute lung injury

Barbiturate toxicity can manifest with potentially fatal respiratory failure and/or cardiogenic shock. ^[7]

Management ^[7]

• Follow the approach to sedative-hypnotic drug overdose.
• Aggressive supportive care is the mainstay of treatment.
• Endotracheal intubation and mechanical ventilation are often required.
• No specific antidotes are available.
• Enhanced elimination: Consider with expert consultation. ^[10]
  • Multidose activated charcoal: for severe phenobarbital or primidone toxicity ^[10][15]
  • Urine alkalinization (with sodium bicarbonate): for severe phenobarbital toxicity ^[2][10][16]
  • Charcoal hemoperfusion or hemodialysis: for life-threatening barbiturate toxicity ^[7][10]

Monitor all patients with pulse oximetry and capnography; rapid shallow respirations frequently mask clinically significant hypoventilation. ^[7]

General principles ^{[7][17][18][19]}

• Z-drugs (e.g., zolpidem, zaleplon, and zopiclone) have a better safety profile than benzodiazepines.
• Serious toxicity is more likely when Z-drugs are co-ingested with other CNS depressants.
• See “Nonbenzodiazepine hypnotics” for information on specific agents, clinical use, mechanisms of action, and adverse effects.

Clinical features ^[17]

Nonbenzodiazepine hypnotic overdose causes a sedative-hypnotic toxidrome.

• Sedation is the most common symptom.
• Coma, respiratory depression, and cardiovascular instability are rare.

Management ^[7][17]

• Follow the approach to sedative-hypnotic drug overdose.
• Supportive care is the mainstay of treatment.
• Respiratory support is usually unnecessary.
• Gastric decontamination is typically not indicated.
• Flumazenil may be considered with caution for isolated nonbenzodiazepine hypnotic overdose. ^[17]

Nonbenzodiazepine overdose typically manifests with sedation only. Consider co-ingestion in patients with more severe manifestations. ^[7][17]

General principles ^[7][20]

• GHB has a low margin of safety between recreational use and fatal overdoses.
• It is frequently co-ingested with other intoxicating substances (e.g., ethanol, amphetamines, cocaine). ^[20][21]
• See “Gamma-hydroxybutyrate” for information on use, mechanisms of action, and GHB withdrawal.

Fatal GHB overdoses most commonly occur with co-ingestion of alcohol. ^[7][20]

Clinical features ^[7][20][21]

GHB causes a sedative-hypnotic toxidrome characterized by alternating somnolence and agitation or abrupt recovery from CNS depression with emergence delirium.

• CNS
  • Minor intoxication: euphoria, somnolence, aggression, amnesia, ataxia, nystagmus
  • Severe intoxication: loss of consciousness, coma, seizures, self-injurious behavior
• Cardiovascular: sinus bradycardia with or without hypotension
• Respiratory: mild bradypnea to respiratory arrest ^[21]
• Other: hypothermia, nausea, vomiting, miosis

Rapid symptom resolution (typically within 3–4 hours of ingestion) is typical, given the short half-life of GHB. ^[7]

Prolonged coma, refractory seizures, and/or significant ECG abnormalities (e.g., conduction delays) suggest the presence of a co-intoxicant. ^[7][21]

Management ^[7][20][21]

• Follow the approach to sedative-hypnotic drug overdose.
• Supportive care is the mainstay of treatment.
• BMV is preferred for transient hypoventilation. ^[22]
• Gastric decontamination is not indicated. ^[7]
• No specific antidotes are available.
• Consider atropine for clinically significant bradycardia.

Overview ^[23][24][25]

• Epidemiology
  • > 1200% increase in xylazine-associated overdose deaths in the U.S. from 2018 to 2021 ^[23]
  • High prevalence in Puerto Rico and New England ^[23]
• Etiology: consumption of recreational drugs (e.g., fentanyl) adulterated with xylazine ^[23]
• Mechanism of action: alpha-2 receptor agonist activity → inhibition of norepinephrine and dopamine release → peripheral vasoconstriction and CNS depression ^[26]

Clinical features ^[23][24][25]

• Acute effects
  • Sedation, analgesia, euphoria
  • Bradycardia, hypotension, miosis, hypothermia
  • Respiratory depression
• Effects of prolonged use
  • Drug tolerance
  • Necrotic skin ulcerations
• Withdrawal syndrome
  • Severe if discontinuation is abrupt after prolonged use
  • Mimics opioid withdrawal syndrome but not alleviated by opioid administration

Using xylazine in combination with opioids increases the risk of airway compromise and respiratory depression. ^[23]

Diagnostics ^[23][24][25]

• Mass spectrometry: using serum or urine specimens
• Blood glucose: possible hyperglycemia ^[25]

Management ^[23][24][25]

Because xylazine is typically an adulterant in recreational opioids, most patients with xylazine intoxication require concurrent management of opioid overdose.

• Follow the approach to sedative-hypnotic drug overdose.
• Supportive care is the mainstay of treatment.
• Airway management and rescue breathing (e.g., BMV) are often required. ^[27]
• No specific antidotes are available.
• Patient education on harm reduction strategies

Sedation caused by xylazine does not resolve with naloxone for opioid overdose. ^[23]