L. Keith French
BARBITURATES
EPIDEMIOLOGY
Barbiturate use has declined with the adoption of safer sedative-hypnotic agents and second-generation anticonvulsants.
In 2008, the American Association of Poison Control Centers (AAPCC) received 1523 reports of isolated barbiturate exposures with only four indentified deaths.
PATHOPHYSIOLOGY
Barbiturates depress activity in the nervous and musculoskeletal systems.
Within the central nervous system, barbiturates enhance the action of the neurotransmitter γ-aminobutryic acid (GABA). This leads to prolonged opening of chloride channels on postsynaptic neurons, decreasing the resting membrane potential and making it more difficult to bring the neuron to an excitatory threshold.
Barbiturates decrease vascular tone, which can lead to hypotension.
Barbiturates are classified according to their duration of action: long-acting (barbital, phenobarbital, duration of action >6 hours), intermediate-acting (amobarbital, butalbital, duration of action 3-6 hours), short-acting (pentobarbital, secobarbital, duration of action <3 hours), and ultrashort-acting (thiopental, methohexital, duration of action <10 minutes).
Elimination half-life can be shortened in the very young and extended in the very old.
Chronic barbiturate use induces hepatic P-450 enzymes and may be responsible for several adverse drug-drug interactions (including oral contraceptives, anticoagulants, and corticosteroids).
CLINICAL FEATURES
Mild to moderate barbiturate toxicity resembles acute intoxication with ethanol or other sedative-hypnotics: drowsiness, disinhibition, ataxia, slurred speech, and confusion.
Severe intoxication manifests as a range of cognitive decline from stupor to coma, and may include absent corneal and deep tendon reflexes.
The most common vital sign abnormalities are respiratory depression (usually the first altered vital sign), hypothermia, and hypotension.
Gastrointestinal (GI) motility is slowed and gastric emptying is delayed.
Hypoglycemia can occur.
Heart rate, nystagmus, pupil size, and reactivity are variable.
Common complications include aspiration pneumonia, pulmonary edema, and acute lung injury.
Skin bullae, also known as “barbiturate blisters,” can be present, but are neither sensitive nor specific for barbiturate overdoses.
Severe poisoning is likely to occur following ingestion often or more times the therapeutic dose.
DIAGNOSIS AND DIFFERENTIAL
Serum barbiturate concentrations can help establish a diagnosis, but do not exclude alternative etiologies for altered mental status or hypotension; serum levels of potential coingestants (eg, acetaminophen and aspirin) should be obtained.
Additional tests to consider included ECG, chest radiography, a complete blood count, serum chemistries, creatinine phosphokinase concentration, blood ethanol concentrations, and arterial blood gas analysis.
The differential diagnosis includes acute ethanol intoxication or toxicity from other sedative-hypnotic agents.
EMERGENCY DEPARTMENT CARE AND DISPOSITION
Assessment and stabilization of the airway, breathing, and circulation remain the priority for all patients with barbiturate poisoning.
Activated charcoal (1 gram/kg) may decrease the absorption of barbiturates and should be given to cooperative, stable patients if presenting <1 hour after overdose.
In life-threatening phenobarbital overdoses, consider multidose activated charcoal (12.5-25 grams via nasogastric tube every 4 hours × 3 doses) once the airway has been secured (generally via endotracheal intubation).
Treat hypotension with isotonic crystalloids; administer norepinephrine or dopamine for refractory hypotension.
Treat hypothermia <36°C with aggressive rewarming measures.
Urinary alkalinization is not considered a first-line therapy, but may be considered in serious phenobarbital or primidone overdoses.
There is no role for forced dieresis.
Consider extracorporeal elimination (hemodialysis, hemoperfusion, and hemodiafiltration) in patients with life-threatening phenobarbital overdoses who deteriorate despite aggressive supportive care.
Observe patients for at least 6 to 8 hours following barbiturate overdose; patients can be safely discharged if they are improving, are minimally symptomatic, and have stable vital signs without supportive measures.
Evidence of toxicity beyond 6 hours following overdose requires hospital admission, potentially to intensive care.
BENZODIAZEPINES
EPIDEMIOLOGY
In 2008, the AAPCC received 30,856 reports of isolated benzodiazepine exposures.
Mortality from isolated benzodiazepine overdoses is rare. However, when benzodiazepines are combined with other sedative-hypnotics, morbidity increases.
PATHOPHYSIOLOGY
Benzodiazepines stimulate the α-subunit of the posts-ynaptic GABA receptor in the central nervous system rendering neurons less excitable.
Benzodiazepines are relatively lipid soluble, but differ individually in time to peak effect, elimination half-life, and duration of action. Many benzodiazepines have active metabolites.
Most benzodiazepines are classified as category D for teratogenicity, except for flurazepam, quazepam, temazepam, and triazolam, which are characterized as category X.
CLINICAL FEATURES
Stimulation of the GABA receptor leads to inhibitory effects, typically producing sedation, anxiolysis, anti-convulsant activity, and striated muscle relaxation.
The predominant clinical features include somnolence, dizziness, slurred speech, confusion, ataxia, incoordination, and general impairment of intellectual function.
Paradoxical reactions consisting of anxiety, aggression, hostile behavior, rage, and delirium are uncommon but can occur.
Deaths from isolated benzodiazepine overdoses are more common with short-acting agents such as alpra-zolam, temazepam, and triazolam.
The effects of benzodiazepines may be prolonged in patients with liver disease, with protein deficiencies, or at the extremes of age.
Short-term anterograde amnesia, a potentially desirable effect, is common with lorazepam, midazolam, and triazolam, but may occur with any benzodiazepine.
Respiratory depression and hypotension may occur after IV administration or in the presence of co-ingestants.
Metabolic acidosis following high-dose infusions of lorazepam or diazepam may result as a complication of the diluent propylene glycol.
DIAGNOSIS AND DIFFERENTIAL
The clinical presentation of benzodiazepine intoxication is nonspecific and shares many features of intoxication from other sedative-hypnotics.
Urine drug screens may detect the presence of benzodiazepines; however, remote exposure may not be the etiology of an acute sedative-hypnotic toxidrome.
Serum drug screens have no role in active management of a patient with an unknown sedative-hypnotic overdose, but may play a role in forensic investigations or potential child endangerment cases.
EMERGENCY DEPARTMENT CARE AND DISPOSITION
Assessment and stabilization of the airway, breathing, and circulation remain the priority in management of all patients with benzodiazepine poisoning.
Endotracheal intubation and mechanical ventilation may be necessary in the obtunded patient.
Activated charcoal (1 gram/kg) may decrease the absorption of benzodiazepines and should be given to cooperative, stable patients if presenting <1 hour after overdose. There is no role for multidose activated charcoal.
Gastric lavage, forced dieresis, and hemodialysis are ineffective and generally unwarranted.
Flumazenil (0.2 milligram IV titrated to effect or a total dose of 3 milligrams), a selective antagonist of the central effects of benzodiazepines, has a limited role in the management of benzodiazepine poisoning.
Contraindications to the use of flumazenil include overdoses of unknown agents, suspected or known dependence on benzodiazepines, suspected co-ingestions with another seizure-inducing agent (such as tricyclic antidepressants), a known seizure disorder, or suspected increased intracranial pressure.
If used and effective, benzodiazepine toxicity may recur once the effects of flumazenil have worn off.
Admit all patients with significant alterations in mental status, respiratory depression, and hypotension to the hospital.
Although many clinicians use the 6-hour principle for observation and discharge of asymptomatic patients, there is limited data regarding the specific duration of ED observation following benzodiazepine exposure.
NONBENZODIAZEPINE SEDATIVES
EPIDEMIOLOGY
In 2008, the AAPCC received 13,054 reports of isolated exposures to nonbenzodiazepine sedatives.
Three sedative-hypnotics, ethchlorvynol, glutethim-ide, and methaqualone, have been removed from US and Canadian markets.
PATHOPHYSIOLOGY
The sedative-hypnotic effects of the many nonben-zodiazepines do not share a common mechanism of action, and with some agents, the underlying mechanism of action is unknown.
CLINICAL FEATURES
BUPIRONE
Common adverse effects include sedation, GI discomfort, vomiting, and dizziness.
The effects in overdose exaggerate the clinical effects observed with therapeutic dosing.
Seizures are rare.
Buspirone has been associated with serotonin syndrome.
CARISOPRODOL AND MEPROBAMATE1
Meprobamate is the active metabolite of carisoprodol.
Following carisoprodol and meprobamate overdose, sedation, coma, cardiovascular collapse, and pulmonary edema have been reported.
Myoclonic jerks are commonly observed following carisoprodol overdose, but are not seen with meprobamate.
Meprobamate overdose has resulted in gastric bezoar formation and prolonged coma.
CHLORAL HYDRATE
At therapeutic doses, chloral hydrate produces mental status depression, but airway and respiratory reflexes are maintained. In overdose, however, chloral hydrate can produce coma.
Vomiting and paradoxical hyperactivity occur in approximately 5% of children.
Cardiovascular toxicity, specifically decreased cardiac contractility, myocardial electrical instability, and increased sensitivity to catecholamines are important features of chloral hydrate toxicity. Cardiac arrhythmias include premature ventricular contractions, ventricular fibrillation, torsades de pointes, and asystole.
The sedative effects of chloral hydrate are exaggerated when co-ingested with ethanol.
A pear-like odor is often present and may be a diagnostic clue in a patient presenting with a sedative-hypnotic toxidrome.
γ-HYDROXYBUTYRATE
γ-Hydroxybutyrate (GHB) effects are dose dependent and range from short-term amnesia and sedation at low doses to seizures, coma, respiratory depression, and cardiac depression with higher doses.
Bradycardia, hypothermia, and either miosis or mydriasis can occur.
Agitation with stimulation or sternal rub is common.
During recovery, which is generally within 6 hours, a patient may suddenly awaken and become aggressive.
GHB has a very short half-life and is difficult to detect in urine >6 hours after ingestion; thus urine or serum drug screening has a limited role in management.
Two other compounds, 1,4-butanediol and γ-butyrolactone, are metabolized to GHB and may produce similar effects.
ZOLPIDEM, ZALEPLON, AND ZOPICLONE
All three agents are used for the treatment of insomnia and are generally considered safer than benzodiazepines.
Adverse effects include somnolence, nausea, and psychomotor impairment. Sleep walking/driving and vivid dreams are commonly reported.
DIAGNOSIS AND DIFFERENTIAL
Poisoning from nonbenzodiazepines share many overlapping features and can be difficult to distinguish from one another.
Diagnostic adjuncts to consider included electrocardi-ography; chest radiography; a complete blood count; serum chemistries; creatinine phosphokinase concentration; salicylate, acetaminophen, and blood ethanol concentrations; and arterial blood gas analysis.
There is almost no role for serum or urine drug screening in the management of poisonings from nonbenzodiazepines.
EMERGENCY DEPARTMENT CARE AND DISPOSITION
Assessment and stabilization of the airway, breathing, and circulation remain the priority in management of all patients with nonbenzodiazepine poisoning.
Routine use of flumazenil or fomepizole for managing overdoses of any of the nonbenzodiazepine sedatives is not recommended.
IV β-adrenergic blockers should be used to treat ventricular arrhythmias seen with chloral hydrate overdose.
SEDATIVE-HYPNOTIC WITHDRAWAL
Withdrawal states have been described with chronic use of barbiturates, benzodiazepines, carisoprodol and meprobamate, chloral hydrate, GHB, and zal-eplon/zopiclone/zolpidem.
Within a given class, shorter acting agents are more likely to produce withdrawal states.
The onset or duration of withdrawal symptoms vary among agents and may occur hours to days after last use, and last days to weeks.
Common features of sedative-hypnotic withdrawal include agitation, tremor, insomnia, anxiety, GI distress, and anorexia, and in severe states, may be associated with delirium and seizures.
Barbiturate withdrawal can occur in neonates born to dependent mothers.
Treatment requires reintroduction of the dependent drug with a slow, controlled taper. Barbiturate, benzodi-azepine, and GHB withdrawal may require hospitalization for management.
For further reading in Tintinalli’s Emergency Medicine: A Comprehensive Guide, 7th ed., see Chapter 176, “Barbiturates,” by Chip Gresham and Frank LoVecchio; Chapter 177, “Benzodiazepines,” by Dan Quan; and Chapter 178, “Nonbenzodiazepine Sedatives” by Michael Levine and Dan Quan.