Barbiturate (phenobarbital) poisoning

INTRODUCTION — Barbiturates were first synthesized in 1903 as an alternative to existing sedative and hypnotic medications such as chloral hydrate, paraldehyde, and bromides [1]. They were increasingly used over the first half of the 20^th century for treatment of psychiatric disease, seizures, insomnia, and induction of anesthesia, but patterns of misuse and dependence evolved concurrently [2,3]. Compared with benzodiazepines, barbiturates are more likely to cause respiratory depression in overdose. The evaluation and management of phenobarbital poisoning has unique considerations compared with the other barbiturates.

This topic will discuss the evaluation and management of barbiturate poisoning, focusing on phenobarbital. A rapid overview table to facilitate emergency management is provided (table 1). The following related content is discussed in separate topics:

●General discussion of the evaluation and management of the poisoned patient (see "General approach to drug poisoning in adults" and "Initial management of the critically ill adult with an unknown overdose" and "Approach to the child with occult toxic exposure")

●The evaluation of stupor and coma (see "Stupor and coma in adults" and "Evaluation of stupor and coma in children")

●The pharmacology of antiseizure medications (see "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects")

EPIDEMIOLOGY — Barbiturate poisoning has declined since the worldwide peak in the 1950 to 1960s, at one point accounting for over 3000 deaths per year in the United Kingdom [4,5]. This trend is likely due to the clinical use and popularization of benzodiazepines starting in 1960 coupled with the notoriety from high-profile overdose deaths, such as those of Marilyn Monroe and Jimi Hendrix. Approximately 1200 to 1400 single-substance barbiturate exposures are reported annually to United States poison control centers [6-10].

Barbiturates remain in clinical use with diverse indications, despite concerns over their safety profile. There has been renewed interest in phenobarbital for treatment of alcohol withdrawal [11-14]. In Australia and some European countries, barbiturate-related deaths have increased, likely from use in self-harm attempts, despite an overall decline in poisoning cases and hospitalizations [15-18].

PHARMACOLOGY

Mechanism of action — Barbiturates enhance gamma-aminobutyric acid (GABA) receptor signaling, which is the primary inhibitory neurotransmitter in the central nervous system. Barbiturates increase the duration of GABA-A receptor subtype opening (an ionotropic chloride channel), thus increasing chloride influx and hyperpolarizing postsynaptic cell membranes [19,20]. At higher doses, barbiturates may act as direct agonists and open the receptor chloride channel, even in the absence of GABA [21,22]. Barbiturates also inhibit excitatory N-methyl-d-aspartate (NMDA) receptor signaling by indirect mechanisms [23,24].

Commonly available agents

●Phenobarbital – Phenobarbital is a long-acting agent used to treat status epilepticus and seizure disorders. It is used as a sedative agent, such as to treat alcohol withdrawal syndrome and occasionally for mechanically ventilated patients [25-27]. Phenobarbital is a potent cytochrome P450 (CYP) inducer. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Phenobarbital' and "Treatment of neonatal seizures", section on 'Antiseizure medication therapy' and "Management of moderate and severe alcohol withdrawal syndromes", section on 'Refractory delirium tremens, including use of phenobarbital' and "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects", section on 'Barbiturates'.)

Phenobarbital doses >40 mg/kg are considered potentially toxic (typical loading is 15 to 20 mg/kg), but sedation can occur even with therapeutic dosing.

●Butalbital – Butalbital is found primarily in combination products used for headache treatment alongside acetaminophen, caffeine, and/or aspirin. (See "Acute treatment of migraine in adults", section on 'Opioids and barbiturates' and "Tension-type headache in adults: Acute treatment", section on 'Limited role of combination analgesics containing barbiturates or opioids'.)

●Primidone – Even though primidone is classified as a barbiturate, its effect on the GABA receptor is primarily from metabolism to phenobarbital [28]. Primidone is used to treat essential tremor and several seizure disorders [29]. Primidone can cause dose-related sedation and an acute neurotoxic reaction that includes dizziness, ataxia, nausea, and vomiting, likely unrelated to the phenobarbital metabolite [28]. Primidone does not appear to prolong the QT interval [30,31]. (See "Essential tremor: Treatment and prognosis", section on 'Primidone' and "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Primidone'.)

●Methohexital – Methohexital is an ultrashort-acting agent used for procedural sedation and induction of anesthesia, particularly for electroconvulsive therapy [32]. It may have some intrinsic proconvulsant effects [33,34]. (See "General anesthesia: Intravenous induction agents", section on 'Methohexital' and "Procedural sedation in adults in the emergency department: Medication selection, dosing, and discharge criteria", section on 'Barbiturates'.)

●Thiopental – Thiopental is an ultrashort-acting agent used for induction of anesthesia, especially in patients with conditions that can elevate intracranial pressure (ICP) and seizure control in refractory status epilepticus. It is a venodilator with negative cardiac inotropic effects and can induce profound hypotension. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Barbiturates' and "Refractory status epilepticus in adults", section on 'Infusion therapies and other treatments'.)

●Pentobarbital – Pentobarbital is used as an adjunct for refractory status epilepticus and to induce coma in patients requiring aggressive control of elevated ICP [35,36]. (See "Refractory status epilepticus in adults", section on 'Pentobarbital' and "Evaluation and management of elevated intracranial pressure in adults", section on 'Barbiturates'.)

Pharmacokinetics

●Absorption – Barbiturates and barbiturate salts generally have good oral bioavailability and are primarily absorbed in the small intestine. Phenobarbital has >95 percent oral bioavailability with a time-to-peak concentration of 0.5 to 4 hours [37].

●Distribution – Barbiturates generally have a low volume of distribution (table 2). The long-acting barbiturates such as phenobarbital have lower volumes of distribution (0.6 to 1.0 L/kg) compared with the short-acting barbiturates, such as thiopental (4.4 L/kg) [38-40]. Barbiturates are weak acids, with pKa generally ranging from 7.3 (phenobarbital) to 8.1 (pentobarbital). There is varied serum protein binding; phenobarbital is 48 percent protein bound, but these binding sites are saturated in overdose, resulting in a greater free fraction [41].

●Metabolism – Barbiturates are primarily metabolized via the hepatic CYP system and n-glucuronidation [42]. They also undergo extensive enterohepatic recirculation; biliary concentrations can be tenfold greater than those in the plasma [43]. Chronic phenobarbital use can enhance its own elimination and that of many other agents because it is a potent inducer of several CYP isoenzymes and uridine diphosphate-glucuronosyltransferase-glucuronidation [44,45].

●Elimination – Barbiturate elimination half-life only partially correlates with duration of action, which is largely determined by rate of distribution out of the central nervous system. Highly lipid soluble and highly protein-bound barbiturates, such as thiopental and methohexital, redistribute quickly and have a duration of effect of only several minutes despite long terminal elimination half-lives (eg, 9 to 11 hours for thiopental) [46]. Less lipid soluble drugs with lower protein binding, such as phenobarbital, have longer durations of effect (eg, 10 to 12 hours), with an elimination half-life of 70 to 140 hours [42,47]. Elimination is renal following hepatic metabolism. A minor fraction of many barbiturates (generally <30 percent; 25 percent for phenobarbital) are excreted unchanged in the urine. Phenobarbital elimination can be enhanced by urinary alkalinization since it is a weak acid and by multidose activated charcoal since it undergoes enterohepatic recirculation [48-50]. (See "Enhanced elimination of poisons".)

CLINICAL MANIFESTATIONS

Sedation/coma — Barbiturates produce dose-dependent sedation ranging from decreased alertness and ataxia to coma and suppression of brainstem reflexes [51]. They can cause a neurologic examination that mimics brain death (table 3) and may even perturb cerebral flow studies [52,53]. The duration of their sedative effects following intentional overdose may be vastly prolonged compared with therapeutic use; for example, a patient was comatose with suppressed brainstem reflexes for five days following an intentional pentobarbital ingestion [54].

However, the degree of sedation often does not correlate with the serum drug concentration, which is discussed further below. (See 'Specific serum drug concentrations' below.)

Respiratory depression — Barbiturates are potent central respiratory depressants, initially characterized by decreased tidal volume that can proceed to apnea with sufficient doses [55-58]. This dose-dependent respiratory depression contributes to the relatively narrow therapeutic index of barbiturates compared with benzodiazepines [59]. Respiratory depression is synergistic when barbiturates are combined with other sedatives and/or opioids [60].

Cardiovascular depression — Barbiturates can cause hypotension following overdose, likely due to insensible fluid losses, increased venous capacitance, and preload dependence with an associated reduction in cardiac output [61-64]. The peripheral vascular resistance is often normal or increased. Some agents such as thiopental may cause more profound cardiovascular depression [65-69]. Barbiturates do not appear to be intrinsically arrhythmogenic, but bradycardia and compensatory tachycardia have been reported [62-64]. Barbiturate poisoning may induce a hypometabolic state characterized by decreased myocardial and systemic oxygen demand [70-72].

Hypothermia — Thermoregulatory dysfunction, specifically hypothermia, is common following barbiturate poisoning [73-76]. Temperatures as low as 21ºC (70ºF) have been reported with severe poisoning [73]. Rebound hyperthermia also commonly occurs, likely from physiologic heat conservation [77].

Skin bullae (barb blisters) — Barbiturate poisoning can cause drug-induced bullae, often called "coma blisters" or "barb blisters," which are characteristically tense, subepidermal, sterile bullae typically occurring 24 to 72 hours following intoxication [78-80]. These are self-limited, resolving in weeks [81]. Bullae formation is likely from pressure and hypoxia since they often occur at dependent sites, but they have also been reported in noncomatose patients (picture 1) and at nondependent sites [82-85]. Although coma blisters can occur following poisoning with other sedatives [86-89], they are most closely associated with barbiturates [80,90]. (See "Approach to the patient with cutaneous blisters", section on 'Localized distribution'.)

Others

●Idiosyncratic drug reactions – Although typically occurring with therapeutic use and not poisoning, barbiturates are a rare cause (6 percent) of drug reaction with eosinophilia and systemic symptoms (DRESS), similar to other aromatic antiseizure medications [91-94]. Phenobarbital has been implicated in up to 10 percent of cases of Stevens Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), accounting for half of cases caused by antiseizure medications [95]. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

Phenobarbital, unlike other barbiturates, has been implicated in cases of drug-induced liver injury, usually in conjunction with other manifestations of drug hypersensitivity (eg, DRESS, SJS, TEN) [96]. Aminotransferase elevation is typically mild and resolves with drug discontinuation. (See "Drug-induced liver injury".)

●Intravenous formulation diluent toxicity – Intravenous administration of high doses of barbiturates that may contain propylene glycol (eg, pentobarbital, phenobarbital) predisposes patients to propylene glycol toxicity [1,97-99]. Manifestations include hypotension, bradycardia, depressed mental status, and a metabolic acidosis with hyperlactemia and increased serum osmolality. Substitution with an intravenous benzodiazepine may not obviate this problem since some formulations (eg, lorazepam, diazepam) may also contain propylene glycol. (See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects", section on 'Propylene glycol toxicity'.)

●Hypokalemia – Hypokalemia commonly occurs with therapeutic use of thiopental, which may be profound (eg, serum potassium concentration <2.0 mEq/L) in one-quarter of patients [100-105]. Hypokalemia can also occur less frequently with pentobarbital [106,107]. The mechanism is likely multifactorial, potentially involving neuronal potassium currents, metabolic interactions, and catecholamine-mediated pathways [105,108]. Rebound hyperkalemia is common and can be life threatening [102,105].

●Crystalluria – Primidone overdose has been reported to cause crystalluria [109].

DIFFERENTIAL DIAGNOSIS — Barbiturate poisoning produces a sedative-hypnotic toxidrome, which is characterized by depressed mental status and either mostly normal vital signs or a varying degree of respiratory and/or cardiovascular depression depending on the agent (table 4). In any suspected ingestion when the patient cannot provide a history, an exploration of alternative sources of information is warranted, including but not exclusive to emergency medical services, family members, pill bottles if available, medical records, and pharmacy information. Other common ingestions that present similarly to barbiturate poisoning include:

●Ethanol intoxication, which can be assessed by obtaining serum concentrations or using an alcohol breathalyzer. (See "Ethanol intoxication in adults" and "Ethanol intoxication in children: Clinical features, evaluation, and management".)

●Opioid intoxication causes depressed mental status, decreased respiratory rate, and miotic pupils that improve after naloxone administration. (See "Acute opioid intoxication in adults" and "Opioid intoxication in children and adolescents".)

●Benzodiazepine, zolpidem, zopiclone, gabapentin, and trazodone are examples of commonly misused sedatives that can only be excluded by history. (See "Benzodiazepine poisoning" and "Gabapentinoid poisoning and withdrawal".)

●Gamma hydroxybutyrate (GHB) intoxication, which often manifests as coma followed by abrupt awakening. GHB intoxication is difficult to distinguish from other causes of obtundation without a clear history. Baclofen, also a gamma-aminobutyric acid (GABA)-B agonist, can cause profound sedation with more indolent and prolonged time course. (See "Gamma hydroxybutyrate (GHB) intoxication" and "GABA-B agonist (baclofen, phenibut) poisoning and withdrawal".)

●Atypical antipsychotic agents (eg, quetiapine), which are commonly misused and intentionally ingested, can cause sedation as well as tachycardia and anticholinergic delirium. (See "Second-generation antipsychotic medications: Pharmacology, administration, and side effects" and "Anticholinergic poisoning".)

Sedation and coma (table 5) are found in a wide range of medical and toxicologic conditions (see "Stupor and coma in adults" and "Evaluation of stupor and coma in children"). Unless the diagnosis of barbiturate poisoning is obvious, other life-threatening nontoxicologic causes must be considered in the differential diagnosis:

●Hypoglycemia must be excluded in every patient with altered mental status, even if barbiturate poisoning is suspected.

●In patients with an intentional ingestion, the presence of coingestants should be investigated. (See "General approach to drug poisoning in adults", section on 'Diagnosis of poisoning'.)

●Altered mental status in association with fever or leukocytosis raises concern for meningitis or other infections and warrants a thorough evaluation, often including assessment of the cerebral spinal fluid. (See "Clinical features and diagnosis of acute bacterial meningitis in adults" and "Bacterial meningitis in children older than one month: Clinical features and diagnosis" and "Viral encephalitis in adults" and "Acute viral encephalitis in children: Pathogenesis, epidemiology, and etiology".)

●Any focal neurologic findings or seizures raise concern for a central nervous system process such as stroke, intracranial hemorrhage, or encephalitis. (See "Overview of the evaluation of stroke" and "Evaluation and management of the first seizure in adults".)

●A history of trauma or clinical findings of injuries should prompt obtaining a head computed tomography (CT) scan. (See "Initial management of trauma in adults".)

EVALUATION AND DIAGNOSTIC TESTING

History and examination — A patient with barbiturate poisoning may have sedation and be unable to provide a history, which may need to be obtained from family, caregivers, emergency medical personnel, or bystanders. In a patient with suspected poisoning, try to ascertain the reason to suspect an overdose (eg, suicide note, witnessed), time of ingestion, intent (eg, self-harm versus misuse), potential coingestants, other accessible medications, last time patient was seen without signs of toxicity, prior medical history, and prior history of self-harm attempts. If the ingested agent is unclear, checking electronic medical records or drug monitoring databases, where available, may reveal an active barbiturate prescription. A history of a condition that is treated with barbiturates (eg, seizure disorder, alcohol use disorder, essential tremor, migraine headache) in the patient or a family member may also provide a clue to poisoning with a barbiturate.

We perform a targeted physical examination assessing vital signs, mental status, ability to protect airway, respirations, focal neurologic deficits, evidence of self-injury, and presence of specific toxidromes (table 4). Ensure that a core temperature is measured. A patient with an unknown downtime should be evaluated for signs of compartment syndrome or traumatic myositis (eg, palpation of muscle compartments, including paraspinal and gluteal muscles). Examine the skin for bullae, which may provide a clue of barbiturate poisoning if the diagnosis is in doubt. (See 'Skin bullae (barb blisters)' above.)

Routine laboratory studies and electrocardiogram — In a patient with somnolence, including when a barbiturate ingestion is suspected, we obtain the following, aimed at excluding other diagnoses:

●Fingerstick blood glucose to rule out hypoglycemia as the cause of altered mental status

●Serum acetaminophen, salicylate, and ethanol concentrations to rule out these common coingestants

●An electrocardiogram to evaluate for drug-induced cardiotoxic effects (more likely to occur from a coingestant)

●Serum chemistries, creatinine, and creatine kinase to assess for metabolic derangements, kidney function, and exclude rhabdomyolysis

●Pregnancy test in females of childbearing age

Specific serum drug concentrations

Phenobarbital — In a patient with a history of phenobarbital ingestion or a patient with depressed mental status and potential phenobarbital exposure, we obtain a serum phenobarbital concentration. Most clinical hospital laboratories can provide a quantitative result within two hours [110]. The therapeutic range is 10 to 40 mcg/mL (43 to 172 micromole/L). Concentrations >80 mcg/mL (344 micromole/L) are considered potentially fatal and >100 mcg/mL (430 micromole/L) are typically fatal without intervention [64,111,112].

In a patient with phenobarbital poisoning or a supratherapeutic concentration, we obtain serial concentrations (eg, every 8 to 12 hours) to monitor trajectory. Serum concentrations often do not correlate with the degree of coma and cardiorespiratory collapse [113]. Possible reasons include presence of coingestants, development of tolerance to the barbiturate, and discordance between serum and central nervous system (the active compartment) concentrations. An increasing concentration may reflect redistribution (and thus correlate with earlier clinical effects) or continued absorption.

Other barbiturates — Quantitative testing for other barbiturates is not useful in the acute management of the somnolent patient since these assays are not readily available at most clinical laboratories and have long turnaround times. Testing performed at a reference laboratory might still be helpful if confirmatory forensic testing is needed (eg, child with altered mental status in whom poisoning is suspected), a brain death declaration is considered in a patient with suspected barbiturate overdose, or to exclude barbiturate poisoning as a cause of prolonged coma [114]. Serum concentrations of short-acting barbiturates >35 mcg/mL (150 micromole/L) are associated with potentially fatal ingestions [64].

Role of urine drug immunoassays — Urine "drug of abuse" (DOA) testing can often be misleading and typically has a very limited role in the acute management of the poisoned patient (table 6). These immunoassays are a test of use and not intoxication, have many false-positive and false-negative results, and thus can lead to premature diagnostic closure. Even though clinically available urine drug immunoassays will reveal the presence of most barbiturates with good sensitivity and specificity, these qualitative tests do not confirm barbiturate poisoning as the sole cause of the patient's signs and symptoms [115]. (See "Testing for drugs of abuse (DOAs)".)

In young children, some experts will obtain a urine DOA screen since a positive result is suggestive of poisoning [116]. However, a positive result can also occur from prescribed barbiturates or from a cross-reaction with ibuprofen, naproxen, or ethosuximide, and thus should be confirmed with advanced laboratory methods (eg, gas chromatography with mass spectrophotometry) [117-119]. (See "The substance-exposed child: Clinical features and diagnosis", section on 'Toxicology testing'.)

Role of imaging and other studies — We obtain other studies based on clinical indication. As examples, CT scan of the head is indicated in a patient with altered mental status if there is a history of trauma or if the history of drug intoxication is uncertain. A chest radiograph should be obtained if there is concern for aspiration (eg, hypoxia).

DIAGNOSIS

●Phenobarbital – The diagnosis of phenobarbital poisoning is suspected in a patient with a depressed mental status and a history of exposure to phenobarbital. The diagnosis of phenobarbital poisoning is confirmed in a patient with depressed mental status and a supratherapeutic serum phenobarbital concentration (>40 mcg/mL [172 micromole/L]). However, the concentration does not reliably predict the severity or duration of toxicity [120].

●Other barbiturates – Barbiturate poisoning (other than phenobarbital) is a clinical diagnosis and usually suspected in a patient with depressed mental status and corroborating history (eg, access to barbiturates) or a urine drug screen (if obtained) that detects a barbiturate. In the absence of clear corroborating history, barbiturate poisoning should still be considered a diagnosis of exclusion since confirmatory serum concentrations are not readily available. Nontoxicologic and other toxicologic etiologies must be ruled out, especially conditions in which diagnostic delay will hold up critical interventions and definitive care. (See 'Differential diagnosis' above.)

MANAGEMENT

All patients/barbiturates: supportive care — As with any potentially critically ill patient, initial management begins with rapidly assessing and addressing the patient's airway, breathing, and circulation. In a patient who presents with anything more than trivial sedation, we suggest establishing intravenous access and continuous cardiac monitoring. End tidal carbon dioxide (E_tCO₂; ie, capnography) is useful for monitoring patients at risk for hypoventilation. Supplemental oxygen should be administered as needed. Placing a nasopharyngeal airway (ie, nasal trumpet) may help overcome upper airway obstruction from central nervous system depression in a patient who is breathing spontaneously. (See "Basic airway management in adults" and "Basic airway management in children" and "Carbon dioxide monitoring (capnography)".)

We suggest not administering flumazenil to a patient with suspected barbiturate poisoning. Flumazenil is a nonspecific competitive antagonist of the benzodiazepine receptor on the gamma-aminobutyric acid (GABA) channel. It would not be expected to improve barbiturate intoxication and may precipitate benzodiazepine withdrawal if the patient has a benzodiazepine coingestion. Its use in the somnolent patient with benzodiazepine poisoning is discussed elsewhere. (See "Benzodiazepine poisoning", section on 'Role of antidote (flumazenil)'.)

Respiratory depression — In a somnolent patient with suspected barbiturate poisoning who has a low respiratory rate, we suggest a trial of parenteral or intranasal naloxone given the possibility of opioid coingestion. Naloxone would not be expected to reverse the effects of the barbiturate itself but may improve mental status or respiration if the patient is also suffering opioid intoxication. (See "Acute opioid intoxication in adults", section on 'Basic measures and antidotal therapy' and "Opioid intoxication in children and adolescents", section on 'Naloxone'.)

Tracheal intubation and mechanical ventilation will most likely be required in a patient with respiratory depression from barbiturate poisoning, especially if there is no improvement following naloxone (if administered). (See "Mechanical ventilation of adults in the emergency department" and "Initiating mechanical ventilation in children".)

Hypotension — Hypotension is treated with a rapid infusion of isotonic crystalloid, followed by vasopressors (eg, norepinephrine, phenylephrine) if needed. Increase in plasma volume has been associated with increased cardiac output and improved blood pressure [63]. (See "Initial management of the critically ill adult with an unknown overdose", section on 'Hypotension' and "Use of vasopressors and inotropes".)

Modalities with limited roles

Gastrointestinal decontamination — We suggest not performing routine gastrointestinal decontamination with activated charcoal (AC) in a patient with an isolated barbiturate ingestion (except for phenobarbital, discussed below) since intoxication will often improve with supportive care and metabolism of the barbiturate. Administering single-dose AC may not provide additional benefits but can increase the risk of aspiration and complicate airway management if the patient loses airway protective reflexes. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Activated charcoal'.)

Enhanced elimination — Urinary alkalinization may increase elimination of any long-acting barbiturate (eg, phenobarbital, barbital, primidone) since they are weak acids and less lipophilic (compared with short- and medium-acting barbiturates) [50]. However, there is insufficient evidence to routinely recommend this modality for a patient poisoned by barbiturates other than phenobarbital. For a patient with long-acting barbiturate poisoning and hemodynamic instability or deep sedation (eg, does not awaken with verbal stimuli), we recommend consultation with a poison center or medical toxicologist to discuss modalities to increase elimination. (See "Enhanced elimination of poisons", section on 'Urinary alkalinization' and 'Regional poison centers' below.)

There is insufficient evidence to routinely recommend multidose activated charcoal (MDAC) or hemodialysis for a patient poisoned by barbiturates other than phenobarbital. The use of these modalities for phenobarbital poisoning is discussed immediately below.

Patient with phenobarbital poisoning and moderate to severe toxicity — In a patient with phenobarbital poisoning and moderate to severe toxicity, we suggest MDAC and urinary alkalinization in addition to supportive care. We consider moderate toxicity as depressed mental status that does not improve with verbal stimuli and a phenobarbital concentration >40 mcg/mL (172 micromole/L) and severe toxicity as hypotension requiring the use of vasopressors or cardiovascular collapse. Severe toxicity typically occurs with concentrations >80 mcg/mL (344 micromole/L) but may occur with lower concentrations [120].

In a patient with phenobarbital poisoning and severe toxicity or prolonged coma and/or increasing serum phenobarbital concentrations despite MDAC and urinary alkalinization, we recommend hemodialysis in addition to MDAC, urinary alkalinization, and supportive care. (See 'Hemodialysis' below.)

Multidose activate charcoal (MDAC) — MDAC increases phenobarbital clearance but should only be performed in a patient with a protected airway (ie, tracheally intubated). However, tracheal intubation should not be performed for the sole purpose of providing MDAC. We also do not perform MDAC if there are signs of bowel obstruction or ileus (eg, lack of bowel sounds). (See "Gastrointestinal decontamination of the poisoned patient", section on 'Multidose activated charcoal'.)

We place a nasogastric or orogastric tube to facilitate administration of AC. The initial dose is 50 g (adults) or 1 g/kg (pediatric) with or without cathartic. Subsequent doses are 12.5 g (or 0.25 g/kg) per hour, which can be administered continuously or in divided doses every two, four, or six hours (eg, 50 g every four hours) without a cathartic. Serial phenobarbital concentrations (eg, every 8 to 12 hours) should be obtained to guide duration of MDAC. We continue MDAC until the patient is clinically improving and the phenobarbital serum concentration is less than 40 mcg/mL (172 micromole/L).

A trial of 20 comatose, mechanically ventilated patients with phenobarbital poisoning found that MDAC reduced the elimination half-life of phenobarbital (36 versus 93 hours) but did not significantly reduce the time of mechanical ventilation (39 versus 48 hours) [121]. A study of 30 patients (15 with mechanical ventilation) with phenobarbital poisoning found that, compared with urinary alkalinization alone, treatment with MDAC alone or MDAC with urinary alkalinization was associated with a decreased time of mechanical ventilation (40 and 52 versus 79 hours) and shorter phenobarbital plasma half-life (39 and 51 versus 81 hours) [48]. A study of six patients with moderate to severe phenobarbital poisoning treated with MDAC found that the elimination half-life was 12 hours immediately following MDAC (the typical half-life is 70 to 140 hours), and all patients had faster recovery in mental status than expected [122]. Animal and volunteer evidence has found that MDAC increases clearance of intravenous phenobarbital, suggesting the mechanism is more than just limiting gastrointestinal absorption [123,124]. A study of volunteers who received therapeutic doses of phenobarbital found that MDAC reduced the half-life up to 59 and 82 percent for intravenous and oral administration, respectively [124].

A workgroup composed of members from the American Academy of Clinical Toxicology (AACT) and European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) estimated a phenobarbital clearance of 84 mL/min with MDAC, compared with 49, 7, and 4 mL/min for hemodialysis, urine alkalinization, and endogenous, respectively [125].

Urinary alkalinization — Urinary alkalinization increases phenobarbital clearance but to a lesser extent compared with MDAC [50]. We alkalinize urine in combination with MDAC or alone when MDAC is contraindicated or cannot be performed. The urine is alkalinized by administering an intravenous bolus of 1 to 2 mEq/kg of an 8.4 percent solution of sodium bicarbonate followed by an infusion of 150 mEq/L solution of sodium bicarbonate at 200 to 250 mL/hour (adults) or 1.5 times maintenance (children). The administration, monitoring, and urine pH goal are described in detail separately. (See "Enhanced elimination of poisons", section on 'Technique'.)

We continue urinary alkalinization until the patient is clinically improving and the phenobarbital serum concentration is less than 40 mcg/mL (172 micromole/L). Potassium supplementation may be required during a sodium bicarbonate infusion. (See "Enhanced elimination of poisons", section on 'Complications'.)

Alkalinizing the urine leads to a marked excretion of weak acids such as phenobarbital; the mechanism is discussed in detail separately. (See "Enhanced elimination of poisons", section on 'General concepts and mechanism' and "Salicylate (aspirin) poisoning: Management", section on 'Serum and urine alkalinization'.)

In a study of volunteers who received a therapeutic intravenous phenobarbital dose, urinary alkalinization decreased the elimination half-life compared with control (47 versus 148 hours) but to a lesser extent compared with MDAC (19 hours) [49]. Several small studies have found that urine alkalinization is associated with increased phenobarbital clearance [126-128].

Hemodialysis — Extracorporeal removal (ie, hemodialysis) should be reserved for a phenobarbital-poisoned patient with hemodynamic instability or prolonged coma not improving with MDAC and urinary alkalinization. Intermittent hemodialysis is the preferred technique, but continuous renal replacement therapy is an alternative in cases where intermittent hemodialysis might not be tolerated [129-132]. (See "Enhanced elimination of poisons", section on 'Extracorporeal removal'.)

The evidence for hemodialysis in phenobarbital poisoning is based on case reports, case series, and measured hemodialysis clearance [111,132-134]. For example, in a case report, the phenobarbital clearance was an average of 174 mL/min during hemodialysis with a high-flux, high-efficiency membrane and blood flow rate of 400 mL/min [120]. This is significantly greater than prior reported hemodialysis or hemoperfusion clearance rates (approximately 50 to 90 mL/min), likely due to the high-efficiency dialyzer technique. A study of 25 patients with coma following phenobarbital overdose found that, compared with forced alkaline diuresis, hemodialysis was associated with a higher mean reduction in serum concentrations (63 versus 40 percent) and a shorter duration of coma (12 versus 61 hours) [134].

However, studies or trials comparing the effectiveness of hemodialysis with MDAC do not exist. Since MDAC is generally safe (in a patient with a protected airway) and effectively increases clearance of phenobarbital, we suggest MDAC and urinary alkalinization as first-line therapy in a hemodynamically stable patient. When MDAC specifically is contraindicated (eg, ileus) or has failed (eg, has not improved mental status or decreased serum concentrations), hemodialysis is a reasonable alternative to increase clearance. If prolonged coma is expected, shortening the duration of coma outweighs potential complications of hemodialysis since prolonged mechanical ventilation has potential complications (eg, ventilator-associated pneumonia). Additionally, toxicity affecting autonomic control of circulatory function and causing hemodynamic instability (eg, hypotension requiring vasopressor, malignant dysrhythmias) suggests a high mortality, thus warranting aggressive measures to increase elimination. Our recommendations are consistent with those from the Extracorporeal Treatments In Poisoning (EXTRIP) workgroup, who similarly prefer hemodialysis for cases of severe or prolonged long-acting barbiturate poisoning or cases where MDAC and supportive therapy have failed [111].

DISPOSITION — A patient with significant respiratory depression, an inability for airway protection, hypotension, or exposure to a dangerous coingestant should be admitted to a critical care setting.

Most patients with an isolated barbiturate ingestion can be safely discharged or cleared for psychiatric evaluation following an observation period of six hours, provided that any concerning symptoms, such as central nervous system depression, have resolved. The patient should be able to ambulate safely prior to discharge. If the patient has an opioid coingestion or opioid use disorder, they should be counseled about the risk of respiratory depression from barbiturate coingestion and offered referral to substance use disorder treatment. A patient with persistent signs of intoxication beyond six hours should be admitted to a monitored setting until symptoms resolve. A patient with a coingestion of an opioid, anticholinergic agent, or medication that may form a bezoar (eg, aspirin) should be closely monitored until the peak clinical effect has been reached, as drug absorption can be delayed.

SPECIAL POPULATIONS

Pediatrics — Clearance of barbiturates in children is prolonged compared with adults [42]. This difference may be even more exaggerated in neonates and infants, who have relatively higher volumes of distribution and poorly developed cytochrome P450 (CYP) systems [135].

Pregnancy — Treatment of a pregnant patient with barbiturate poisoning is the same as for a nonpregnant patient. However, phenobarbital readily crosses the placenta and may be a teratogen; thus, the patient should be referred for appropriate obstetrical evaluation and counseling following the acute intoxication [136]. (See "Risks associated with epilepsy during pregnancy and the postpartum period", section on 'Phenobarbital'.)

ADDITIONAL RESOURCES

Regional poison centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment" and "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse".)

SUMMARY AND RECOMMENDATIONS

●Pharmacology – Barbiturates enhance gamma-aminobutyric acid (GABA)-A receptor signaling. Compared with benzodiazepines, barbiturates are more likely to cause respiratory depression in overdose. They are weak acids. The management of long-acting barbiturate (phenobarbital, primidone) (table 2) poisoning has unique considerations compared with other barbiturates. (See 'Pharmacology' above.)

●Clinical manifestations of overdose – Barbiturates produce central nervous system depression, respiratory depression, hypotension, and thermoregulatory dysfunction (ie, hypothermia). Severe poisoning can produce coma (occasionally with suppression of brainstem reflexes that mimics brain death), apnea, and cardiovascular collapse. (See 'Clinical manifestations' above.)

●Evaluation – Routine laboratory and diagnostic testing is aimed at excluding other diagnoses and includes serum chemistries, creatinine, complete blood count, serum acetaminophen, salicylate, and ethanol concentrations, creatine kinase, and an electrocardiogram. Obtain a serum phenobarbital concentration in a patient with potential phenobarbital exposure. The therapeutic range is 10 to 40 mcg/mL (43 to 172 micromole/L) and concentrations >80 mcg/mL (344 micromole/L) are potentially fatal. Quantitative testing for other barbiturates is not useful in the acute management of the somnolent patient since these assays are not readily available at most clinical laboratories and have long turnaround times. (See 'Evaluation and diagnostic testing' above.)

●Diagnosis – Barbiturate poisoning should be suspected in a patient with depressed mental status and a history of exposure to a barbiturate. The diagnosis of phenobarbital poisoning is confirmed by a supratherapeutic serum phenobarbital concentration (>40 mcg/mL [172 micromole/L]). Other than phenobarbital, barbiturate poisoning is a clinical diagnosis in a patient with depressed mental status and corroborating history (eg, access to barbiturates) or a urine drug screen (if obtained) that detects a barbiturate. In the absence of clear corroborating history, it is a diagnosis of exclusion. (See 'Diagnosis' above.)

●Management – Initial management is with supportive care. A rapid overview table to facilitate emergency management is provided (table 1). We do not administer flumazenil since it may precipitate benzodiazepine withdrawal if the patient has a benzodiazepine coingestion. We do not routinely administer a single dose of activated charcoal in a patient with isolated barbiturate ingestion since intoxication will often improve with supportive care. (See 'All patients/barbiturates: supportive care' above and 'Gastrointestinal decontamination' above.)

•Respiratory depression – In a somnolent patient with a low respiratory rate, we administer a trial of parenteral or intranasal naloxone, which would not be expected to reverse the effects of the barbiturate itself. Naloxone may improve mental status or respiration if the patient is also suffering opioid intoxication. Tracheal intubation and mechanical ventilation will most likely be required in a patient with respiratory depression or an inability for airway protection. (See 'Respiratory depression' above.)

•Hypotension – Hypotension is treated with a rapid infusion of isotonic crystalloid, followed by vasopressors (eg, norepinephrine, phenylephrine) if needed. (See 'Hypotension' above.)

•Phenobarbital ingestion with moderate to severe toxicity – We consider moderate toxicity as depressed mental status that does not improve with verbal stimuli and a phenobarbital concentration >40 mcg/mL [172 micromole/L] and severe toxicity as hypotension requiring the use of vasopressors or cardiovascular collapse. In a patient with moderate to severe toxicity, we suggest multidose activated charcoal (MDAC) and urinary alkalinization in addition to supportive care (Grade 2C). MDAC increases phenobarbital clearance but should only be performed in a patient with a protected airway, but tracheal intubation should not be performed for the sole purpose of providing MDAC. Urinary alkalinization increases phenobarbital clearance but to a lesser extent compared with MDAC. (See 'Patient with phenobarbital poisoning and moderate to severe toxicity' above.)

In a patient with severe toxicity or prolonged coma and/or increasing serum phenobarbital concentrations despite MDAC and urinary alkalinization, we recommend hemodialysis in addition to MDAC, urinary alkalinization, and supportive care (Grade 1C). Intermittent hemodialysis or continuous renal replacement therapy increase phenobarbital clearance but has more potential complications compared with MDAC. (See 'Hemodialysis' above.)