Sedative-Hypnotics

Clinical Features

Benzodiazepines are widely used medically for their antiepileptic, sedative, and anxiolytic properties. Prior to benzodiazepines, barbiturates were the primary sedative-hypnotics used, but they have been overwhelmingly supplanted by benzodiazepines and other, newer agents.

Benzodiazepines produce sedative, hypnotic, anxiolytic, and anticonvulsant effects by potentiating the GABA-A receptor in the presence of GABA. In contrast, barbiturates can directly increase Cl ⁻ conductance. This may account for the relative safety of benzodiazepines in comparison with barbiturates.

At therapeutic dosage, the GABA effects of benzodiazepines cause euphoria, anxiolysis, and drowsiness. Mild toxicity includes CNS depression, ataxia, slurred speech, nystagmus, and impaired cognition. Most benzodiazepine overdoses follow a relatively benign clinical course. Larger overdoses may cause respiratory depression, which may require intervention. The respiratory depression is less severe than with barbiturates, especially if benzodiazepines are the only substance ingested. Coingestants with sedative properties, particularly ethanol or opioids, can markedly potentiate the respiratory depression caused by benzodiazepines. Loss of muscle tone leads to upper airway obstruction and increased airway resistance. Hypoventilation is often the first sign of severe respiratory depression, and may be masked by oxygen supplementation, which can maintain adequate oxyhemoglobin saturation. Capnography can be useful in detecting early signs of hypoventilation.

Cardiac toxicity or hypotension from pure benzodiazepine overdose is rare. Other potential complications include aspiration pneumonia and pressure necrosis of skin and muscles. Intravenous solutions of diazepam and lorazepam contain the diluent propylene glycol, which is metabolized to lactate, and prolonged or high-dose infusions of these preparations can cause lactic acidosis. Patients with renal or hepatic insufficiency are at increased risk for this complication.

Most pediatric patients have symptoms within four hours of benzodiazepine ingestion. Ataxia is the most common sign of toxicity, occurring in 90% of pediatric patients. Respiratory depression occurs in fewer than 10% of pediatric cases, and hypotension is rarely reported in children.

Benzodiazepines were previously identified as pregnancy category D, noting some risk, but that they should be used when indicated based on a risk-benefit analysis (see Chapter 175 regarding drug therapy for the pregnant patient). There are some studies showing risks, but these are difficult to analyze as most patients involved were also exposed to other psychiatric medications. In the acute setting, when needed for management of emergent conditions including seizures, the benefits of short term acute use likely outweigh the complications to the mother and fetus. ^, Management of seizures during pregnancy is discussed in Chapter 173 . The management of benzodiazepine toxicity during pregnancy follows the standard approach, including supportive care and respiratory support, with the recognition of an increased risk of respiratory and mental status depression in the fetus if delivery is required.

Novel synthetic benzodiazepines are procured from a variety of internet sites or other illicit sources, and the true content of the product received is unknown to the user. Limited information is available about many of these agents. Management should be similar to the known pharmaceutical benzodiazepines, recognizing the increased likelihood of coingestants, as discussed in the following. ^,

Pharmacokinetics

Benzodiazepines are rapidly absorbed orally. Intramuscular use of chlordiazepoxide and diazepam is limited by erratic absorption, but lorazepam and midazolam are predictably absorbed after intramuscular injection. Parenteral and rectal administration of benzodiazepines provide faster time to onset than oral ingestion and can be used for antiepileptic and sedative indications. After absorption, benzodiazepines distribute readily, and rapidly penetrate the blood-brain barrier. In plasma, benzodiazepines are highly protein bound. ^,

Benzodiazepines are metabolized in the liver. Lorazepam, oxazepam, and temazepam are directly conjugated to an inactive, water-soluble glucuronide metabolite that is excreted by the kidney. Other benzodiazepines must first be converted by the hepatic cytochrome P450 system. Many benzodiazepines, including chlordiazepoxide and diazepam, are metabolized to active compounds that are then conjugated and excreted. The long elimination half-lives of up to 120 hours of these intermediates can cause accumulation in the body with repeated dosing and prolong the sedative effects of these benzodiazepines. Alprazolam and midazolam are converted to hydroxylated intermediates that are rapidly conjugated and excreted, but do not contribute significantly to the overall effect of the drug.

Cytochrome P450 metabolism may be significantly impaired in elderly patients or those with liver disease, leading to prolonged elimination of benzodiazepines. Coingestion of drugs that inhibit P450 metabolism (e.g., cimetidine, ethanol) also prolongs the half-lives of benzodiazepines.

Differential Diagnoses

Benzodiazepine overdose is usually suspected or diagnosed by clinical presentation. Many patients are able to interact appropriately with providers and can provide supporting information. Atypical or focal neurological findings suggest the presence of other conditions, such as intracranial events (e.g., intracerebral hemorrhage, cerebral ischemia). Profound coma or cardiopulmonary instability is rare with pure benzodiazepine overdose and should prompt the search for coingestants, such as opioids, ethanol, phenobarbital, choral hydrate, or a cyclic antidepressant. Non-toxicologic metabolic causes of CNS depression, such as hypoglycemia or hyponatremia should also be considered. The broader differential of CNS depression includes conditions described in Chapter 12, Chapter 13 .

Diagnostic Testing

Sedative-hypnotic toxidromes are clinical diagnoses, and most laboratory testing will not be helpful in determining the appropriate care for the patient. Any patient with altered mental status should have a blood glucose level rapidly determined. Qualitative immunoassays for benzodiazepines in urine are available, but do not aid management decisions and cannot provide definitive information regarding the cause of the altered mental status. Because most screening tests detect a specific benzodiazepine metabolite, including nordiazepam or oxazepam glucuronide, some benzodiazepines (including clonazepam, lorazepam, midazolam, and alprazolam) will not be detected on many standard urine drug tests. A positive urine drug screen for benzodiazepines indicates exposure or use but does not identify intoxication or indicate a specific agent and does not confirm benzodiazepine exposure as the cause of the clinical presentation. The positive screen also does not provide information regarding the timing of the benzodiazepine exposure. Serum drug concentrations are not routinely available and do not correlate with clinical severity.

Adjunct testing should be used as clinically indicated, including computerized topography (CT) imaging when concerned for head trauma or intracranial hemorrhage. The benzodiazepine antagonist flumazenil should not be routinely administered to patients with suspected benzodiazepine overdose or coma of unknown origin solely for diagnostic purposes.

Stabilization and Supportive Care

Initial stabilization, including endotracheal intubation when necessary, should not be delayed by the administration of an antidote. Most benzodiazepine overdoses can be managed expectantly with observation and supportive care alone. Neither gastrointestinal (GI) decontamination or administration of activated charcoal is indicated in benzodiazepine ingestion. Close respiratory monitoring is indicated to guide respiratory interventions and end tidal carbon dioxide (CO ₂ ) monitoring can be a useful adjunct. Naloxone should be administered in cases of suspected opioid coingestion (see further discussion of opioid overdoses in Chapter 151 ).

Antidote Therapy

Flumazenil, a nonspecific competitive antagonist at the benzodiazepine receptor, can reverse benzodiazepine-induced sedation after general anesthesia, procedural sedation, and confirmed benzodiazepine overdose. However, the risks of flumazenil usually outweigh the benefits in patients with benzodiazepine toxicity. Therefore, flumazenil is not recommended for the routine reversal of sedative overdose in the ED. Theoretic benefits of flumazenil use include cost savings and avoidance of procedures and tests (such as endotracheal intubation and CT scans). However, several clinical studies have failed to demonstrate these benefits in practice. Benzodiazepine toxicity has a low mortality rate with supportive care, shifting the risk benefit analysis away from the use of flumazenil in routine cases.

There are also risks associated with flumazenil; it can precipitate acute withdrawal in patients who are chronically dependent on benzodiazepines, leading to significant complications including status epilepticus. Similarly, this antidote is hazardous when it is given to patients who have coingested seizure-inducing drugs (such as cocaine or a tricyclic antidepressant) because of loss of the benzodiazepine’s protective anticonvulsant properties and the subsequent ineffectiveness of benzodiazepines to abort a seizure if one occurs. Seizures after the administration of flumazenil should be treated with the administration of barbiturates or propofol. Cardiac dysrhythmias (principally paroxysmal supraventricular tachycardia [PSVT]) can occur after flumazenil administration. Coingestants that cause dysrhythmias, such as carbamazepine or chloral hydrate, may increase the likelihood of cardiac effects. Fatalities after flumazenil administration have been reported. Other risk factors are summarized in Box 154.1 .

When benzodiazepine-naive patients ingest benzodiazepines alone in overdose (as occurs in young children), the risks associated with flumazenil are lower. In cases of benzodiazepine overdose by a non-benzodiazepine habituated patient, flumazenil use combined with close monitoring and repeated or infusion-based dosing, may obviate the need for intubation and mechanical ventilation. We recommend basing this decision on a balance of risks/benefits for the particular patient and the reliability that the patient is a novice benzodiazepine user. This approach extends to the setting of unintended over-sedation by benzodiazepines for procedural sedation. In these cases, as patients are often nonbenzodiazepine-dependent, flumazenil would likely have a lower risk of complications.

The initial adult dose of flumazenil is 0.2 mg given intravenously over 30 seconds. A second dose of 0.2 mg may be given, followed by 0.2 mg dose at 1-minute intervals to a total of 1 mg. In children, the initial dose is 0.01 mg/kg (up to 0.2 mg). Because the duration of action of flumazenil is short (45 to 75 minutes), re-sedation occurs in up to 65% of patients and requires either re-dosing or continuous infusion (0.25 to 1.0 mg/h). It is important to note that flumazenil reverses the CNS depressant effects of benzodiazepines more than it reverses the respiratory depression.

In summary, benzodiazepine overdose requires primarily supportive care, assisted ventilation, and if severe, intubation. Flumazenil may precipitate seizures or acute withdrawal and should be used only in highly selected cases (such as to reverse procedural sedation, or to treat young children with a clear history of inadvertent benzodiazepine ingestion). When flumazenil is used, close monitoring of oxy-hemoglobin saturation and overall ventilatory status (ideally including end-tidal CO ₂ ) is necessary because of the risk for recurrent respiratory depression or resedation.

Disposition

Patients remaining asymptomatic after 4 to 6 hours of ED observation following benzodiazepine ingestion may be medically cleared. For cases of deliberate overdose, appropriate psychiatric consultation should be obtained. Patients presenting with respiratory depression and coma should be given oxygen, ventilatory support, and admission to a monitored setting, such as an ED Observation Unit, or monitored inpatient unit.

Benzodiazepine Withdrawal Syndrome

Abrupt discontinuation of a benzodiazepine in a chronic user results in a characteristic constellation of symptoms similar to ethanol withdrawal ( Box 154.2 ). Risk for withdrawal is a function of both the dose of benzodiazepine and the duration of its use. Continuous treatment for more than 3 to 4 months is generally required before a patient is at risk for withdrawal. With abrupt discontinuation of a benzodiazepine, the most severe withdrawal symptoms occur within several days to a week. Treatment of withdrawal consists of restarting benzodiazepines in the acute setting and, if refractory, phenobarbital or propofol administration to treat withdrawal symptoms. Patients who have experienced withdrawal symptoms after cessation of benzodiazepine use may require benzodiazepine tapers to avoid symptomatic withdrawal.