Chapter 182: Barbiturates

Barbiturate toxicity has historically been associated with the highest risk of morbidity and mortality among all sedative-hypnotics. Barbiturates are still the most common class of antiepileptic drugs used in developing countries, but their use is declining due to the introduction of safer, less toxic sedative-hypnotics, such as benzodiazepines, and second-generation anticonvulsants.¹ Status epilepticus,² severe ethanol and sedative withdrawal syndromes,^3,4,5 and toxicologic seizures⁶ are typically managed with benzodiazepines, but barbiturates have a useful role as a second-line agent. They are still used in combination drugs (i.e., butalbital) and alone (i.e., secobarbital) for the treatment of tension and migraine headaches,^7,8 although the efficacy of either is controversial.⁹ Barbiturates are used in the pharmacologic management of refractory intracranial hypertension from focal and diffuse brain injury, but evidence of improved outcomes has been modest.¹⁰

Barbiturates are generally classified according to their duration of action, which is primarily dependent on lipid solubility and tissue distribution rather than the elimination half-life (Table 182-1).

Barbiturates readily distribute throughout the body to most tissues, crossing the blood–brain barrier and placenta, and are excreted in breast milk. Fetal blood barbiturate concentrations closely reflect maternal plasma levels, creating the potential for fetal withdrawal syndrome.¹¹ Most barbiturates are metabolized in the liver to inactive metabolites primarily through routes involving the cytochrome P450 system. The elimination half-life of barbiturates can be greatly shortened in infants and children and very prolonged in the elderly and in patients with liver or renal disease. Chronic barbiturate use induces activity of the cytochrome P450 enzymes and may accelerate the metabolism of other therapeutic drugs, such as oral contraceptives, anticoagulants, and corticosteroids, when taken concurrently.

Barbiturates' main action is the depression of activity in the CNS and musculoskeletal system. In the CNS, this is accomplished by enhancing the action of the primary inhibitory neurotransmitter γ-aminobutyric acid at its receptor.¹² When γ-aminobutyric acid binds to its chloride channel receptor, it causes it to open, resulting in depolarization, which temporarily stabilizes the resting membrane potential and inhibits the firing of new action potentials. Barbiturates bind to the α subunit of the γ-aminobutyric acid receptor, causing an increase in the duration of time that the cell membrane chloride channel is open, resulting in prolonged depolarization and prolonged inactivity.

Benzodiazepines bind to a different site on the α subunit of the γ-aminobutyric acid receptor and increase the frequency with which the chloride channel opens. Increased duration, as opposed to increased frequency, is one of the reasons cited for increased morbidity and mortality with barbiturate overdoses compared to benzodiazepines.

Barbiturates inhibit both the activity of the excitatory neurotransmitter, glutamate, at the glutamate receptor and calcium-mediated excitatory neurotransmitter release at the presynaptic terminal. Blockade of the calcium channel may contribute to the cardiac contractility impairment seen with barbiturate overdoses. Barbiturates also have effects on voltage-dependent sodium and potassium channels, but in concentrations typically far above the therapeutic range.¹³ These effects may contribute to the toxicity or paradoxical actions seen with some barbiturate drugs in overdoses.

Mild to moderate barbiturate intoxication closely resembles alcohol intoxication and toxicity of other sedative-hypnotics; drowsiness, disinhibition, ataxia, slurred speech, and mental confusion are common features that escalate with increasing dose. The progressive neurologic depression seen with severe barbiturate intoxication predictably manifests as a range from stupor to coma to complete neurologic unresponsiveness, including the absence of a corneal reflex and deep tendon reflexes.

The most common vital sign abnormalities seen in overdose are respiratory depression, hypothermia, and hypotension, with respiratory depression usually occurring first. Abnormal temperature control and respiratory depression are centrally mediated phenomena, whereas hypotension is primarily a result of decreased vascular tone. Pulse rate, pupil size, light reactivity, and nystagmus are variable. GI tract motility is slowed, resulting in delayed gastric emptying and ileus. Skin bullae, sometimes referred to as "barb blisters" or "coma blisters," are uncommon and may indicate nothing more than the effects of local skin pressure, although hypoxia has been implicated as well.¹⁴ Coma blisters are not specific to sedative-induced coma; they have been reported after surgery,¹⁵ from other causes of coma,¹⁶ and even without coma.¹⁷

Early deaths in barbiturate overdose result from respiratory arrest and cardiovascular collapse. Common complications include hypoglycemia (perhaps due to starvation), pulmonary edema, aspiration pneumonia, and acute lung injury. Current mortality rates range between 1% and 3%; death usually results from multiple organ system failure. Lethal doses are estimates (Table 182-1), but severe poisoning can be assumed if more than 10 times the hypnotic dose has been ingested in a single exposure in an intolerant patient.¹⁸ As with other sedative-hypnotics, the toxic properties of barbiturates may be enhanced in the presence of benzodiazepines or alcohol. Conversely, the depressive effects may be protective in a mixed-stimulant overdose.¹⁹

Laboratory evaluation in barbiturate overdose should include determination of glucose levels, blood chemistries, CBC, arterial blood gas (if indicated), toxicology screen, chest radiograph, and an electrocardiogram. Urine drug screens most commonly use the immunoassay methodology, and a false-positive result on the barbiturate screen has been reported with ibuprofen and naproxen.²⁰ If important, confirm a positive urine screen using a more accurate method, such as gas chromatography–mass spectrometry.

Barbiturate serum levels are useful in establishing the diagnosis of a comatose patient; however, acute treatment decisions should be clinically based. Serum barbiturate levels reported in lethal overdoses vary widely, and measurements are not reliable in predicting clinical course after an overdose because they do not reflect brain barbiturate concentrations and may underestimate the clinical condition of a patient in the setting of polydrug exposure.²¹ Barbiturate levels are also invalid in chronic barbiturate abusers who have developed physiologic tolerance and in patients with renal or hepatic disease who have decreased clearance.¹⁸

In a barbiturate overdose, the initial priorities are airway management and supportive care. Once pulmonary and cardiovascular function has been stabilized, options for increasing drug clearance are considered.

AIRWAY ASSESSMENT AND INITIAL STABILIZATION

Assess the patient's mental status and airway stability. Intubation with mechanical ventilation in severe sedative-hypnotic overdose is often required. Barbiturate toxicity results in decreased cardiac output and vascular tone, often resulting in profound hypotension. Volume expansion with intravenous crystalloids is the mainstay for circulatory support in the absence of cardiac failure. If fluid resuscitation fails to correct hypotension, administer vasopressors such as dopamine or norepinephrine. Hypothermia between 30°C (86°F) and 36°C (96.8°F) is common and should be monitored via continuous core temperature and treated with rewarming measures.

ACTIVATED CHARCOAL

A single dose of activated charcoal should be given to cooperative, clinically sTable patients who present within 1 hour of acute oral overdose.²² Multidose activated charcoal is beneficial in reducing serum phenobarbital concentrations; however, no significant difference in clinical outcome has ever been demonstrated. Current consensus guidelines are to consider multidose activated charcoal if a patient has ingested a life-threatening amount of phenobarbital.²³ A typical adult regimen for multidose activated charcoal is an initial dose of 50 to 100 grams PO followed by 12.5 to 25 grams PO every 4 hours. Concurrent administration of cathartic agents remains unproven and is discouraged (see chapter 176, General Management of Poisoned Patients). Careful attention to and monitoring of the patient's airway is important to decrease the risk of aspiration or bowel obstruction.

FORCED DIURESIS

Forced diuresis is not recommended because of the risks of sodium and fluid overload and lack of proven efficacy.

URINARY ALKALIZATION

Urinary alkalization (see chapter 176) does enhance the clearance of phenobarbital and primidone (which is metabolized to phenobarbital). The treatment is less effective than multidose activated charcoal in reducing serum levels, does not improve clinical outcomes, and is not effective for shorter-acting barbiturates.²⁴ In barbiturate poisoning, urinary alkalization is not a first-line treatment and has only a minor, if any, role.^25,26

EXTRACORPOREAL ELIMINATION

Hemodialysis, hemoperfusion, and hemodiafiltration can enhance elimination of phenobarbital but are reserved for patients who are deteriorating despite aggressive supportive care.^26,27,28 These modalities are not useful for poisoning from barbiturates other than phenobarbital. Exchange transfusion has also been reported to be useful in neonatal phenobarbital toxicity.²⁹

Mild to moderate barbiturate intoxication responds well to general supportive care, including a single dose of activated charcoal, if appropriate. Improvement in neurologic status and vital signs over 6 to 8 hours signals eventual patient discharge or transfer. When indicated, obtain mental health assessment. For a long-acting agent such as phenobarbital, serial serum levels should be obtained during the initial 6 hours after an overdose before concluding the patient can be safely discharged or transferred. Evidence of toxicity after 6 hours will require hospital admission, and patients with severe toxicity should go to the intensive care unit. Consult with a medical toxicologist or local poison center to assist in the care of barbiturate-poisoned patients.

BARBITURATE WITHDRAWAL SYNDROME

Barbiturates are notorious for their rapid development of tolerance, high liability for physical dependence and abuse, and multiple drug interactions. Abrupt discontinuation of barbiturates in a chronically dependent user will produce minor withdrawal symptoms within 24 hours and major life-threatening symptoms within 2 to 8 days. The severity of the withdrawal reflects the degree of physical dependence and drug half-life. Cessation of short-acting barbiturates results in more severe abstinence symptoms than stopping long-acting barbiturates. Such effects are consistent with the clinical observation that the brain has more time to adapt to gradually declining drug concentrations.

Clinical manifestations of barbiturate withdrawal mimic those described for alcohol withdrawal. Minor symptoms include anxiety, restlessness, depression, insomnia, anorexia, nausea, vomiting, muscle twitching, abdominal cramping, and sweating. Major symptoms include psychosis, hallucinations, delirium, generalized seizures, hyperthermia, and cardiovascular collapse.

Priorities in the treatment of major withdrawal symptoms are cardiovascular stabilization and seizure control. Seizures may be treated with benzodiazepines but are more effectively treated with barbiturates. Due to the associated mortality, gradual in-hospital detoxification is needed.

NEONATAL WITHDRAWAL

Infants born to mothers physically dependent on barbiturates are at risk for dependence and subsequently withdrawal. Withdrawal may manifest within the first to third days of life.¹¹ Signs and symptoms include high-pitched crying, vomiting, diarrhea, tremors, and, possibly, seizures. Withdrawal is treated with gradually decreasing doses of phenobarbital.¹¹