Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

BARBITURATES-LONG ACTING

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Barbiturates have sedative hypnotic and anticonvulsant properties. Barbital is used in laboratories for its buffering properties.
    B) These compounds are divided according to their elimination half-lives in animals. The long acting barbiturates have elimination half-lives in humans greater than or equal to 48 hours.

Specific Substances

    A) CONSTITUENTS OF THE GROUP
    1) Barbital (not available in US) (synonym)
    2) Barbital buffer
    3) Mephobarbital (Mebaral) (synonym)
    4) Metharbital (Gemonil)(not available in the US) (synonym)
    5) Phenobarbital (Luminal) (synonym)
    6) Primidone (synonym)
    7) LONG-ACTING BARBITURATES

Available Forms Sources

    A) FORMS
    1) Phenobarbital:
    1) Tablets: 8,16, 32, 65, 100 mg
    2) Capsules: 16 mg
    3) Tablets: 8,16, 32, 65, 100 mg
    4) Elixir: 15 or 20 mg/5 mL
    5) Injection: 30, 60, 65, 130 mg/mL
    2) Mephobarbital:
    1) Tablets: 32, 50, 100 mg
    3) Metharbital (not available in the US):
    1) Tablets: 100 mg
    4) Primidone:
    1) Tablets: 50, 250 mg
    2) Oral suspension: 250 mg/5 mL

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Sedative hypnotics are used for sedation and the treatment of epilepsy, including status epilepticus (phenobarbital). Long acting barbiturates include mephobarbital, primidone, and phenobarbital.
    B) PHARMACOLOGY: Barbiturates cause depression of neuronal activity via alternation of gamma-aminobutyric acid (GABA) mediated chlorine currents. Specifically, barbiturates increase the duration of opening of the ligand gated chloride channel.
    C) TOXICOLOGY: Toxicology is the extension of the pharmacology. Central nervous system depression due to enhanced GABA activity is the primary effect, and may be accompanied by hypotension secondary to direct myocardial depression. CNS and respiratory depression may be exacerbated by co-ingestion of other sedatives.
    D) EPIDEMIOLOGY: Poisoning is uncommon; however, toxicity may be severe and may occur via oral or parenteral routes.
    E) WITH THERAPEUTIC USE
    1) Mild sedation, dizziness, and impaired coordination develop in some patients.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Somnolence, slurred speech, nystagmus, confusion, and ataxia may occur.
    2) SEVERE TOXICITY: Severe effects may include coma, hypotension, decreased myocardial contractility, hypothermia and respiratory failure. Blisters may occur secondary to prolonged immobilization from coma. Patients may have small to midpoint pupils and have very diminished reflexes. Death is most commonly caused by respiratory depression and cardiovascular collapse. Patients that present after prolonged coma are at risk for aspiration pneumonia, rhabdomyolysis, and renal failure.
    0.2.5) CARDIOVASCULAR
    A) Hypotension, cardiovascular collapse, and cardiac arrest may occur especially following intravenous administration.
    0.2.6) RESPIRATORY
    A) Respiratory arrest and pulmonary edema may occur especially following intravenous administration.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Ataxia, lethargy, and coma are frequently reported following overdose.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Isolated cases of hepatotoxicity have been reported secondary to idiosyncratic or hypersensitivity reactions.
    0.2.10) GENITOURINARY
    A) Massive crystalluria has been reported following primidone intoxication. Acute renal failure occurs rarely secondary to hypotension or rhabdomyolysis.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Thrombophlebosis has been reported following high-dose intravenous barbiturates but is rare.
    0.2.14) DERMATOLOGIC
    A) Clear, erythematous or hemorrhagic blisters ("barb burns", or barbiturate bullae) may occur on the skin, usually, but not necessarily restricted to areas over pressure points.
    B) Short-term therapy with phenobarbital has been associated with the development of Stevens-Johnson syndrome and toxic epidermal necrolysis.
    0.2.20) REPRODUCTIVE
    A) The manufacturer has classified belladonna alkaloids (atropine sulfate, hyoscyamine sulfate, and scopolamine hydrobromide) with phenobarbital as FDA pregnancy category C. Mephobarbital, phenobarbital, and primidone are classified as FDA pregnancy category D. One study found that the number of minor anomalies per infant was greater for the mothers taking antiepileptic medications than for the controls; however there was no difference in the number of major anomalies.
    0.2.22) OTHER
    A) Withdrawal symptoms may occur following discontinuation of chronic barbiturate therapy, but are rare following an acute overdose.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Routine monitoring of electrolytes, renal function, glucose, pulse oximetry, and blood gases may be helpful.
    C) PHENOBARBITAL: Serum phenobarbital concentrations are available in most hospitals. Generally, phenobarbital concentrations of 3 to 40 mg/L are associated with lethargy and ataxia in non-tolerant individuals, concentrations of greater than 60 to 80 mg/L are associated with coma and concentrations of greater than 150 to 200 mg/L with hypotension. Phenobarbital may be detected on urine immunoassays.
    D) Monitor creatinine phosphokinase in patients with prolonged immobilization from coma.
    E) Monitor renal function and urine output in patients with rhabdomyolysis.
    F) Monitor urine output and pH in patients treated with alkalinization.
    G) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity.
    H) Other causes of coma and hypotension should be ruled out.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Activated charcoal may be given if patients present shortly after ingestion, and are awake and alert with a protected airway.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Orotracheal intubation for airway protection should be performed if patient is increasingly drowsy or comatose. Administer activated charcoal (GI decontamination should be performed only in patients who can protect their airway or who are intubated). Severe hypotension and hypothermia may develop; aggressive supportive care is the mainstay of treatment including passive rewarming, administration of normal saline, and in severe cases vasopressors. Clinical manifestations may be prolonged due to long half-life of drug. Tetanus and routine wound care for blisters. A burn surgeon should be consulted for extensive skin blistering.
    C) DECONTAMINATION
    1) PREHOSPITAL: Not recommended because of potential for somnolence and loss of airway protection.
    2) HOSPITAL: Activated charcoal if recent, substantial ingestion, and patient able to protect airway, or if intubated.
    D) AIRWAY MANAGEMENT
    1) Perform early in patients with severe intoxication (i.e., coma, respiratory depression, hypotension).
    E) ANTIDOTE
    1) None
    F) HYPOTENSIVE EPISODE
    1) Secure intravenous access. Initiate treatment with intravenous fluids. Initiate vasopressors and titrate to a mean arterial pressure of at least 60 mmHg. Insert a bladder catheter and monitor urine output.
    G) COMA
    1) Treat symptomatically and supportively. Perform orotracheal intubation to protect airway.
    H) HYPOTHERMIA
    1) Monitor core temperature with rectal or bladder probe. Initiate external rewarming with warm blankets, IV fluids, and warm humidified oxygen until temperature is greater than 32.2 degrees C. For severe hypothermia, provide gastric or peritoneal lavage with warm fluids, consider warm fluids via chest tubes, and for very severe cases associated with cardiac arrest, perform rewarming with cardiopulmonary bypass.
    I) BRADYCARDIA
    1) Place on cardiac monitor. Correct hypothermia, if present, prior to initiating other treatment for bradycardia. Do not treat sinus bradycardia unless patient is symptomatic/hypotensive. Follow ACLS protocol including use of atropine, and, if necessary, epinephrine.
    J) ENHANCED ELIMINATION
    1) Urinary alkalinization can enhance the elimination of phenobarbital. Administer 1 to 2 mEq/kg (2 to 3 ampules in an adult) of bicarbonate IV initially followed by an infusion of 3 ampules of sodium bicarbonate mixed in 1 liter of D5W given at 1.5 to 2 times maintenance fluid rates. Goal urine pH is 7.5 to 8. Do not allow serum pH to exceed 7.55. Follow urine pH, serum pH and serum potassium carefully. Add potassium chloride to IV bicarbonate if the serum potassium is low. Repeat dose activated charcoal decreases the half life of phenobarbital but has not been shown to improve outcome; it should not be administered routinely. Charcoal 0.25 to 0.5 g/kg given every 2 to 4 hours (multiple dose charcoal should NOT be administered to any patient with ileus as it may cause bowel obstruction or infarction). End points include decreasing serum drug level and clinical improvement, this usually takes 24 hours. Hemodialysis or hemoperfusion should be performed in patients who have hemodynamic instability not responding to symptomatic supportive care. In addition, hemodialysis or hemoperfusion should be considered in symptomatic patients who are in renal failure or cannot tolerate a fluid load, such as patients with congestive heart failure.
    K) PATIENT DISPOSITION
    1) HOME CRITERIA: Phenobarbital doses as low as 8 mg/kg may produce toxicity in non-tolerant patients. Therefore, any child that ingests a phenobarbital dose of 8 mg/kg or greater should be evaluated by a healthcare professional.
    2) OBSERVATION CRITERIA: Patients with deliberate ingestions and symptomatic patients should be sent to a health care facility for observation for at least 6 to 8 hours. Anyone that ingests 8 mg/kg or greater of phenobarbital and is non-tolerant should be observed. Patients who do not develop more than mild drowsiness and have phenobarbital concentrations that have peaked and are clearly declining may be discharged following psychiatric evaluation.
    3) ADMISSION CRITERIA: Patients with significant persistent central nervous system toxicity (i.e., CNS depression, confusion or ataxia), or rising phenobarbital concentrations should be admitted. Patients with coma, hypotension, respiratory depression, or hypothermia should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (i.e., coma, respiratory depression, hypotension, or hypothermia), or in whom the diagnosis is not clear. Consult a nephrologist for hemodialysis in patients with severe poisoning not responding to supportive care.
    L) PITFALLS
    1) Failure to diagnose other causes of coma. Inadequate alkalinization of urine. Administration of multiple dose charcoal to a patient with ileus may cause bowel obstruction or infarction. Monitor arterial pH carefully in patients who are receiving bicarbonate for urine alkalinization, particularly those who are intubated, to avoid severe alkalemia.
    M) PHARMACOKINETICS
    1) These drugs are well absorbed. PHENOBARBITAL: volume of distribution 0.9 L/kg; 51% protein bound; half-life 40 to 70 hours in children, up to 100 hours in adults; renal elimination 25% to 33% as unchanged phenobarbital and the rest as metabolites. PRIMIDONE: volume of distribution 0.6 L/kg; 19% protein bound; half-life 10 to 12 hours (3 to 7 hours after chronic administration); hepatic metabolism. MEPHOBARBITAL: volume of distribution 2.6 L/kg; protein binding 40% to 60%; half-life 48 to 52 hours; hepatic metabolism. Both primidone and mephobarbital are metabolized in part to phenobarbital.
    N) TOXICOKINETICS
    1) Phenobarbital half life prolonged (4 to 7 days) after overdose.
    O) DIFFERENTIAL DIAGNOSIS
    1) Ethanol/benzodiazepine/opioid/other sedative-hypnotic or anticonvulsant poisoning, carbon monoxide or cyanide poisoning, hypoglycemia, infection, environmental hypothermia, metabolic derangement, biogenic amine syndrome (cocaine or methamphetamine washout), stroke, hypothyroidism.

Range Of Toxicity

    A) TOXICITY: The toxic dose varies depending on route and speed of administration as well as patient tolerance. Ingestion of 8 mg/kg phenobarbital generally causes some CNS depression in non-tolerant individuals.
    B) THERAPEUTIC DOSE: PHENOBARBITAL: ADULT: (Oral) 30 to 200 mg/day divided; (IV) (status epilepticus) 10 to 20 mg/kg. CHILDREN: (Oral) 5 to 8 mg/kg/day divided; (IV) (status epilepticus) 10 to 20 mg/kg. PRIMIDONE: ADULT: 500 mg/day divided. CHILDREN: less than 8-years-old, 10 to 25 mg/kg/day divided; more than 8-years-old, 750 to 1500 mg/day divided.

Clinical Effects

Summary Of Exposure

    A) USES: Sedative hypnotics are used for sedation and the treatment of epilepsy, including status epilepticus (phenobarbital). Long acting barbiturates include mephobarbital, primidone, and phenobarbital.
    B) PHARMACOLOGY: Barbiturates cause depression of neuronal activity via alternation of gamma-aminobutyric acid (GABA) mediated chlorine currents. Specifically, barbiturates increase the duration of opening of the ligand gated chloride channel.
    C) TOXICOLOGY: Toxicology is the extension of the pharmacology. Central nervous system depression due to enhanced GABA activity is the primary effect, and may be accompanied by hypotension secondary to direct myocardial depression. CNS and respiratory depression may be exacerbated by co-ingestion of other sedatives.
    D) EPIDEMIOLOGY: Poisoning is uncommon; however, toxicity may be severe and may occur via oral or parenteral routes.
    E) WITH THERAPEUTIC USE
    1) Mild sedation, dizziness, and impaired coordination develop in some patients.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Somnolence, slurred speech, nystagmus, confusion, and ataxia may occur.
    2) SEVERE TOXICITY: Severe effects may include coma, hypotension, decreased myocardial contractility, hypothermia and respiratory failure. Blisters may occur secondary to prolonged immobilization from coma. Patients may have small to midpoint pupils and have very diminished reflexes. Death is most commonly caused by respiratory depression and cardiovascular collapse. Patients that present after prolonged coma are at risk for aspiration pneumonia, rhabdomyolysis, and renal failure.

Vital Signs

    3.3.3) TEMPERATURE
    A) HYPOTHERMIA - May occur (Amitai & Degani, 1990; Pond et al, 1984).
    1) Hypothermia occurred in 17.7% of patients with acute barbiturate overdose in a large series (Matthew & Lawson, 1966).

Heent

    3.4.3) EYES
    A) NYSTAGMUS
    1) Periodic alternating nystagmus was reported in a patient with phenobarbital levels of 45 to 58 mcg/mL (Schwankhaus et al, 1989).
    2) Nystagmus developed in a 36-year-old man after ingestion of barbital buffer (Rodichok, 1992).

Cardiovascular

    3.5.1) SUMMARY
    A) Hypotension, cardiovascular collapse, and cardiac arrest may occur especially following intravenous administration.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension may occur and may be severe (Palmer, 2000; Ebid & Abdel-Rahman, 2001; Pond et al, 1984; Lin & Jeng, 1995).
    b) Severe hypotension occurred in 8.5% in a large series (Matthew & Lawson, 1966).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT - A 58-year-old man, with a history of type 2 diabetes mellitus and hypertension, became unresponsive with undetectable blood pressure and pulse following a phenobarbital overdose of an unknown amount. Following resuscitation with IV atropine and epinephrine, the patient presented to the ED comatose (Glasgow Coma Scale 3) with a blood pressure and pulse of 70/40 mmHg and 60 BPM, respectively. Initial laboratory data indicated hyperkalemia (potassium 7.1 mEq/L), hyperglycemia (blood glucose 350 mg/dL), and metabolic acidosis. Toxicologic analysis demonstrated a serum phenobarbital concentration of 151.5 mg/L. Following supportive therapy, including 2 hemodialysis sessions, the patient recovered without neurologic sequelae and was discharged to a psychiatric facility (Thompson & Aks, 2007).
    B) CARDIAC ARREST
    1) WITH POISONING/EXPOSURE
    a) Decreased cardiac output and cardiac arrest may occur. Cardiac arrest developed in 0.5% of acute overdoses of barbiturates (Matthew & Lawson, 1966).

Respiratory

    3.6.1) SUMMARY
    A) Respiratory arrest and pulmonary edema may occur especially following intravenous administration.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) WITH THERAPEUTIC USE
    a) Pulmonary edema may occur (Pond et al, 1984).
    B) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH THERAPEUTIC USE
    a) Respiratory depression, Cheyne-Stokes respiration, central hypoventilation, apnea, and respiratory failure may occur with subsequent respiratory acidosis (Lin & Jeng, 1995).
    C) PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) Pneumonia is common in patients with coma. In one series pneumonia occurred in 24 of 25 intubated patients and 13 of 117 non-intubated patients (Goodman et al, 1976).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Ataxia, lethargy, and coma are frequently reported following overdose.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) Alcohol and other CNS depressants enhance the toxic actions of barbiturates. Toxic effects include lethargy, slurred speech, ataxia, nystagmus, prolonged coma, with hyperactive, depressed or absent reflexes (Palmer, 2000; Ebid & Abdel-Rahman, 2001; Rodichok, 1992; Lin & Jeng, 1995). Coma may be cyclic with metharbital and mephobarbital overdoses, due to their toxic metabolites.
    b) CASE REPORT - A 58-year-old man, with a history of type 2 diabetes mellitus and hypertension, became unresponsive with undetectable blood pressure and pulse following a phenobarbital overdose of an unknown amount. Following resuscitation with IV atropine and epinephrine, the patient presented to the ED comatose (Glasgow Coma Scale 3) with a blood pressure and pulse of 70/40 mmHg and 60 BPM, respectively. A CT scan of the head was normal. Initial laboratory data indicated hyperkalemia (7.1 mEq/L), hyperglycemia (glucose 350 mg/dL), and metabolic acidosis. Toxicologic analysis demonstrated a serum phenobarbital concentration of 151.5 mg/L. Following supportive therapy, including 2 hemodialysis sessions, the patient recovered without neurologic sequelae and was discharged to a psychiatric facility (Thompson & Aks, 2007).
    B) CEREBROSPINAL FLUID: PROTEIN - INCREASED +
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 36-year-old man who had recurrent admissions for CNS depression secondary to unsuspected barbital ingestion had elevated CSF protein (64 to 132 mg/dL) on multiple lumbar punctures (Rodichok, 1992). The clinical significance of this is unclear.

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VASCULAR INSUFFICIENCY OF INTESTINE
    1) WITH POISONING/EXPOSURE
    a) Nonocclusive intestinal infarction was reported in a 29-year-old male following overdose of phenobarbital. The patient had no abdominal abnormalities at 72 hours post-ingestion, however, abdominal distention, ileus and gas within the intestinal wall and portal venous system occurred during the next 10 hours of hospitalization (Olson et al, 1984).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) GASTRIC DILATATION
    a) GI PROPULSION - Anesthetic doses of phenobarbital and pentobarbital reduce gastrointestinal propulsion in the rat (Holzer et al, 1987).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Isolated cases of hepatotoxicity have been reported secondary to idiosyncratic or hypersensitivity reactions.
    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 2-year-old child developed hepatic necrosis associated with administration of phenobarbital 2 mg/kg/day for approximately 2 weeks (Mockli et al, 1989). The reaction is believed to be an unusual hypersensitivity reaction.
    b) CASE REPORT - An 8-month-old child developed a rash 14 days after initiation of phenobarbital. Eight days after discontinuation, progressive liver dysfunction was documented, which responded to corticosteroids. The reaction was thought to be due to an idiosyncrasy in metabolism of phenobarbital (Roberts et al, 1990).

Genitourinary

    3.10.1) SUMMARY
    A) Massive crystalluria has been reported following primidone intoxication. Acute renal failure occurs rarely secondary to hypotension or rhabdomyolysis.
    3.10.2) CLINICAL EFFECTS
    A) CRYSTALLURIA
    1) WITH POISONING/EXPOSURE
    a) PRIMIDONE - Massive crystalluria (white cloudy urine containing hexagonal crystals) associated with proteinuria, hematuria and elevated specific gravity has been reported following PRIMIDONE intoxication (Turner, 1980).
    1) Another patient who had ingested primidone passed urine containing macroscopic, glistening whitish crystals that were composed predominantly of primidone (Lane et al, 1987).
    2) Other cases of massive crystalluria have been reported (Cate & Tenser, 1975) Bailey & Gatlow 1972; (van Heijst et al, 1983; Matzke et al, 1981).
    3) CASE REPORT - A 48-year-old female developed massive crystalluria following maintenance primidone dosing resulting in a primidone concentration of 125 mg/L (normal 5 to 12 mg/L) and a phenobarbital concentration of 62 mg/L (normal 20 to 40 mg/L). Hexagonal and plate-like urine crystals, compatible with primidone crystals, were seen. Crystalluria resolved following normalization of primidone concentrations 24 hours later. Nephrotoxicity was not observed in this patient (Sigg & Leikin, 1999).
    B) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Acute renal failure (acute tubular necrosis) was reported in 0.5% of acute barbiturate overdoses, and was secondary to severe hypotension not responsive to treatment (Matthew & Lawson, 1966).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Barbiturate overdose may cause respiratory acidosis secondary to hypoventilations, or lactic acidosis secondary to hypoxia, hypotension, and shock.
    b) CASE REPORT - A 58-year-old man developed metabolic acidosis (ph 7.18, pCO2 45 mmHg, HCO3 1.68 mEq/L) following a phenobarbital overdose which caused coma and hypotension. Toxicologic analysis revealed a serum phenobarbital concentration of 151.5 mg/L. Following supportive care, including 2 hemodialysis sessions, the patient recovered (Thompson & Aks, 2007).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Thrombophlebosis has been reported following high-dose intravenous barbiturates but is rare.
    3.13.2) CLINICAL EFFECTS
    A) THROMBOPHLEBITIS
    1) WITH THERAPEUTIC USE
    a) Three cases of thrombophlebosis have been reported in patients receiving high-dose intravenous barbiturate therapy (DeNicola & Hays, 1982).
    B) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Fatal agranulocytosis developed in a 40-year-old man on long term therapy with primidone and phenytoin (Laurenson et al, 1994).
    C) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Chronic leukopenia with normocellular bone marrow has been reported in patients on chronic phenobarbital therapy, usually in combination with another antiepileptic medication, most commonly carbamazepine (O'Connor et al, 1994).

Dermatologic

    3.14.1) SUMMARY
    A) Clear, erythematous or hemorrhagic blisters ("barb burns", or barbiturate bullae) may occur on the skin, usually, but not necessarily restricted to areas over pressure points.
    B) Short-term therapy with phenobarbital has been associated with the development of Stevens-Johnson syndrome and toxic epidermal necrolysis.
    3.14.2) CLINICAL EFFECTS
    A) BULLOUS ERUPTION
    1) WITH POISONING/EXPOSURE
    a) INCIDENCE - Bullae have been reported in up to 6.5% of patients after barbiturate overdose, and usually appear within 24 hours of coma (Beveridge & Lawson, 1965).
    b) DESCRIPTION - Clear, erythematous or hemorrhagic blisters occur in various areas of the body, most typically on the hands, buttocks and between the ankles and knees, usually over pressure points. Bullous lesions have been reported over non-pressure points, such as dorsal surfaces of fingers and toes and ocular conjunctiva, and after extravasation of an intravenous dose of therapeutic phenobarbital (Haroun et al, 1987).
    c) However, bullae are not diagnostic of barbiturate poisoning, as other overdoses may cause the same type of lesions.
    B) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) A case-control study of 352 patients with Stevens-Johnson syndrome or toxic epidermal necrolysis determined that there was an increased association with short-term phenobarbital therapy. The period of increased risk was largely confined to the first 8 weeks of treatment (Rzany et al, 1999).
    C) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) A case-control study of 352 patients with Stevens-Johnson syndrome or toxic epidermal necrolysis determined that there was an increased association with short-term phenobarbital therapy. The period of increased risk was largely confined to the first 8 weeks of treatment (Rzany et al, 1999).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Rare hypersensitivity reactions may occur. A 2-year-old child developed fever and an erythematous, papular, pruritic rash approximately 2 weeks after being initiated on phenobarbital 2 mg/kg/day for two focal tonic-clonic seizures. The fever persisted after discontinuation of phenobarbital and hepatic necrosis was confirmed by liver biopsy. The child died from complications (intracranial hemorrhage) of liver failure (Mockli et al, 1989).
    b) Multisystem hypersensitivity reactions which may include mucocutaneous eruptions, fever, lymphadenopathy, eosinophilia, myopathy, hepatitis, and nephritis occur with phenobarbital, phenytoin, primidone, and carbamazepine. Clinically, these hypersensitivity reactions are often indistinguishable (Handfield-Jones et al, 1993).
    B) EOSINOPHILIC MYOCARDITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 37-year-old male developed dyspnea, annular skin eruptions, and peripheral eosinophilia approximately 1 month after beginning phenobarbital and phenytoin therapy. The patient's symptoms resolved after receiving steroid therapy, but two weeks after discontinuation of steroid treatment, the patient again developed dyspnea and peripheral eosinophilia, as well as cardiomegaly and elevated liver and cardiac enzyme levels. An endomyocardial biopsy showed extensive infiltration of lymphocytes with eosinophils and interstitial fibrosis, and a drug lymphocyte-stimulating test was positive for phenobarbital, indicating that the patient's condition may have been due to an allergic reaction to phenobarbital. The patient's eosinophilic myocarditis gradually improved with chronic oral prednisone therapy (Arima et al, 1998).

Reproductive

    3.20.1) SUMMARY
    A) The manufacturer has classified belladonna alkaloids (atropine sulfate, hyoscyamine sulfate, and scopolamine hydrobromide) with phenobarbital as FDA pregnancy category C. Mephobarbital, phenobarbital, and primidone are classified as FDA pregnancy category D. One study found that the number of minor anomalies per infant was greater for the mothers taking antiepileptic medications than for the controls; however there was no difference in the number of major anomalies.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified belladonna alkaloids (atropine sulfate, hyoscyamine sulfate, and scopolamine hydrobromide) with phenobarbital as FDA pregnancy category C (Prod Info DONNATAL(R) oral tablets, 2012; Prod Info DONNATAL(R) ELIXIR oral solution, 2011; Prod Info DONNATAL EXTENTABS(R) oral extended release tablets, 2007).
    2) Mephobarbital is classified as FDA pregnancy category D (Prod Info Mebaral(R) tablets, 2003).
    3) Phenobarbital is classified as FDA pregnancy category D (Prod Info phenobarbital oral solution, 2010).
    4) Primidone is classified as FDA pregnancy category D (Prod Info Mysoline(R), 1994).
    B) CASE STUDIES
    1) A prospective cohort study compared the children of pregnant females with epilepsy on antiepileptic drug therapy to the children of pregnant females who had no history of a seizure disorder. The study was small (64 epileptic women; 46 controls), but found that the number of minor anomalies per infant was greater for the mothers taking antiepileptic medications than for the controls (Yerby et al, 1992).
    2) However, there was NO difference in the number of major anomalies. Neither was there any difference in comparison between infants exposed to monotherapy with carbamazepine, phenytoin, and phenobarbital.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Phenobarbital breast milk concentration is approximately 1.5% of plasma concentration. The amount ingested by the infant can approach 2 to 4 milligrams/day (Horning et al, 1975; Briggs et al, 1998). Phenobarbital is eliminated more slowly in the neonate and may accumulate, resulting in sedation (Tyson et al, 1938) Nan et al, 1982; (Briggs et al, 1998).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Routine monitoring of electrolytes, renal function, glucose, pulse oximetry, and blood gases may be helpful.
    C) PHENOBARBITAL: Serum phenobarbital concentrations are available in most hospitals. Generally, phenobarbital concentrations of 3 to 40 mg/L are associated with lethargy and ataxia in non-tolerant individuals, concentrations of greater than 60 to 80 mg/L are associated with coma and concentrations of greater than 150 to 200 mg/L with hypotension. Phenobarbital may be detected on urine immunoassays.
    D) Monitor creatinine phosphokinase in patients with prolonged immobilization from coma.
    E) Monitor renal function and urine output in patients with rhabdomyolysis.
    F) Monitor urine output and pH in patients treated with alkalinization.
    G) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity.
    H) Other causes of coma and hypotension should be ruled out.
    4.1.2) SERUM/BLOOD
    A) SPECIFIC AGENT
    1) PHENOBARBITAL: Serum phenobarbital concentrations are available in most hospitals. Generally, phenobarbital concentrations of 3 to 40 mg/L are associated with lethargy and ataxia in non-tolerant individuals, concentrations of greater than 60 to 80 mg/L are associated with coma and concentrations of greater than 150 to 200 mg/L with hypotension.
    2) PRIMIDONE - Primidone levels of 5 to 15 mcg/mL may be considered therapeutic. Levels greater than 15 mcg/mL are associated with toxicity, and levels of 70 to 80 mcg/mL are associated with the development of crystalluria. A fatal case in a patient, not previously treated with primidone, occurred with a plasma level of 65 mcg/mL (Baselt, 2000).
    B) BLOOD/SERUM CHEMISTRY
    1) Monitor CBC, serum electrolytes, glucose, blood urea nitrogen, creatinine, and urine myoglobin in patients with significant intoxication.
    2) Monitor creatinine phosphokinase in patients with prolonged immobilization from coma.
    C) HEMATOLOGIC
    1) Monitor CBC in patients with significant intoxication.
    D) ACID/BASE
    1) Obtain serial blood gases in patients with hypotension or respiratory depression.
    4.1.3) URINE
    A) OTHER
    1) Monitor renal function and urine output in patients with rhabdomyolysis.
    2) Monitor urine output and pH in patients treated with alkalinization.
    3) Monitor urine for crystalluria in patients with significant primidone overdose.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs and mental status.
    2) ECG
    a) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity.

Radiographic Studies

    A) RADIOGRAPHIC-OTHER
    1) X-ray findings of radiopaque objects in the stomach may be intact phenobarbital tablets (Winek, 1967; Carroll, 1969; Yatzidis, 1971).

Methods

    A) IMMUNOASSAY
    1) BARBITURATE CLASS - Semiquantitative and qualitative EMIT(R) homogeneous enzyme immunoassays are available for measurement of the class of barbiturates in urine and in serum or plasma.
    a) Drugs detected include secobarbital, amobarbital, butabarbital, pentobarbital, phenobarbital, and talbutal. Assay responses for samples containing more than one barbiturate may be cumulative.
    b) Butalbital was found to cross-react with the phenobarbital EMIT(R) assay in two case reports (Nordt, 1997).
    2) PHENOBARBITAL - An EMIT(R) homogeneous enzyme immunoassay is available for quantitation of phenobarbital in serum or plasma. The assay's range of quantitation is 5 to 80 mcg/mL (21.5 to 34.4 mcmol/L) phenobarbital. Independent investigations have shown excellent correlation between this method and GC and RIA.
    3) PRIMIDONE - An EMIT(R) homogeneous enzyme immunoassay is available for quantitation of primidone in serum or plasma. The assay's range of quantitation is 2.5 to 20 mcg/mL (11.5 to 91.6 mcmol/L) for primidone. Clinical studies show excellent correlation between this method and GLC.
    B) CHROMATOGRAPHY
    1) A gas chromatography mass spectrometry method for detecting phenobarbital in hair has been described (Goulle et al, 1995).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with significant persistent central nervous system toxicity (i.e., CNS depression, confusion or ataxia), or rising phenobarbital concentrations should be admitted. Patients with coma, hypotension, respiratory depression, or hypothermia should be admitted to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Phenobarbital doses as low as 8 mg/kg may produce toxicity in non-tolerant patients. Therefore, any child that ingests a phenobarbital dose of 8 mg/kg or greater should be evaluated by a healthcare professional.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (i.e., coma, respiratory depression, hypotension, or hypothermia), or in whom the diagnosis is not clear. Consult a nephrologist for hemodialysis in patients with severe poisoning not responding to supportive care.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate ingestions and symptomatic patients should be sent to a health care facility for observation for at least 6 to 8 hours. Anyone that ingests 8 mg/kg or greater of phenobarbital and is non-tolerant should be observed. Patients who do not develop more than mild drowsiness and have phenobarbital concentrations that have peaked and are clearly declining may be discharged following psychiatric evaluation.

Monitoring

    A) Monitor vital signs and mental status.
    B) Routine monitoring of electrolytes, renal function, glucose, pulse oximetry, and blood gases may be helpful.
    C) PHENOBARBITAL: Serum phenobarbital concentrations are available in most hospitals. Generally, phenobarbital concentrations of 3 to 40 mg/L are associated with lethargy and ataxia in non-tolerant individuals, concentrations of greater than 60 to 80 mg/L are associated with coma and concentrations of greater than 150 to 200 mg/L with hypotension. Phenobarbital may be detected on urine immunoassays.
    D) Monitor creatinine phosphokinase in patients with prolonged immobilization from coma.
    E) Monitor renal function and urine output in patients with rhabdomyolysis.
    F) Monitor urine output and pH in patients treated with alkalinization.
    G) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity.
    H) Other causes of coma and hypotension should be ruled out.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT INDICATED
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) Activated charcoal effectively adsorbs phenobarbital in vitro and in vivo (Berg et al, 1993; Cooney, 1995). Activated charcoal with greater surface area and more surface hydroxyl groups appears to be more effective (Modi et al, 1994; Cooney, 1995).
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    B) MULTIPLE DOSE ACTIVATED CHARCOAL
    1) SUMMARY
    a) Multiple dose activated charcoal has been shown to increase phenobarbital elimination in animal studies (Arimori & Nakano, 1986), volunteers (Neuvonen & Elonen, 1980; Berg et al, 1982; Frenia et al, 1996; Berg et al, 1987), and overdose patients (Thompson & Aks, 2007; Ebid & Abdel-Rahman, 2001; Goldberg & Berlinger, 1982; Pond et al, 1984; Boldy et al, 1986; Veerman et al, 1991). This has NOT been shown to alter severity or outcome of poisoning. It should be considered in patients with severe poisoning.
    2) MULTIPLE DOSE ACTIVATED CHARCOAL
    a) ADULT DOSE: Optimal dose not established. After an initial dose of 50 to 100 grams of activated charcoal, subsequent doses may be administered every 1, 2 or 4 hours at a dose equivalent to 12.5 grams/hour (Vale et al, 1999), do not exceed: 0.5 g/kg charcoal every 2 hours (Ghannoum & Gosselin, 2013; Mauro et al, 1994). There is some evidence that smaller more frequent doses are more effective at enhancing drug elimination than larger less frequent doses (Park et al, 1983; Ilkhanipour et al, 1992). PEDIATRIC DOSE: Optimal dose not established. After an initial dose of 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) (Chyka & Seger, 1997), subsequent doses may be administered every 1, 2 or 4 hours (Vale et al, 1999) in a dose equivalent to 6.25 grams/hour in children 1 to 12 years old.
    b) Activated charcoal should be continued until the patient's clinical and laboratory parameters, including drug concentrations if available, are improving (Vale et al, 1999). The patient should be frequently assessed for the ability to protect the airway and evidence of decreased peristalsis or intestinal obstruction.
    c) Use of cathartics has not been shown to increase drug elimination and may increase the likelihood of vomiting. Routine coadministration of a cathartic is NOT recommended (Vale et al, 1999).
    d) AGENTS AMENABLE TO MDAC THERAPY: The following properties of a drug that are likely to allow MDAC therapy to be effective include: small volume of distribution, low protein binding, prolonged half-life, low intrinsic clearance, and a nonionized state at physiologic pH (Chyka, 1995; Ghannoum & Gosselin, 2013).
    e) Vomiting is a common adverse effect; antiemetics may be necessary.
    f) CONTRAINDICATIONS: Absolute contraindications include an unprotected airway, intestinal obstruction, a gastrointestinal tract that is not intact and agents that may increase the risk of aspiration (eg, hydrocarbons). Relative contraindications include decreased peristalsis (eg, decreased bowel sounds, abdominal distention, ileus, severe constipation) (Vale et al, 1999; Mauro et al, 1994).
    g) COMPLICATIONS: Include constipation, intestinal bleeding, bowel obstruction, appendicitis, charcoal bezoars, and aspiration which may be complicated by acute respiratory failure, adult respiratory distress syndrome or bronchiolitis obliterans (Ghannoum & Gosselin, 2013; Ray et al, 1988; Atkinson et al, 1992; Gomez et al, 1994; Mizutani et al, 1991; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Mina et al, 2002; Harsch, 1986; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002).
    3) STUDIES
    a) Multiple doses of activated charcoal have been shown to significantly decrease the serum half-life and increase the total body clearance of phenobarbital (Ebid & Abdel-Rahman, 2001; Berg et al, 1982; Goldberg & Berlinger, 1982; Neuvonen & Elonen, 1980; Pond et al, 1984; Boldy et al, 1986; Gillespie et al, 1986; Veerman et al, 1991; Frenia et al, 1993; Frenia et al, 1996).
    b) In one study (Berg et al, 1982) this mode of therapy increased total body clearance of phenobarbital by a factor of 2.8 and decreased its elimination half-life by a factor of 0.4.
    c) Repeated doses of activated charcoal initiated 10 hours after ingestion of therapeutic doses of phenobarbital in 5 healthy volunteers resulted in a plasma half-life of 18.8 to 20.8 hours compared to a control value of 87 to 133 hours. Total body clearance increased from 4.6 milliliters/minute (controls) to 23 milliliters/minute following multiple dose charcoal therapy (Neuvonen & Elonen, 1980).
    d) In a crossover study multiple dose activated charcoal decreased the elimination half life of intravenously administered phenobarbital to 19 hours compared to half lives of 47 hours with urinary alkalinization and 148 hours with no intervention (Frenia et al, 1993).
    e) In a prospective study of patients with phenobarbital overdose, multiple dose charcoal significantly increased total body clearance, decreased serum half life, decreased time to mental alertness and orientation, and decreased the duration of mechanical ventilation and time to extubation compared with urinary alkalinization and urinary alkalinization combined with multiple dose activated charcoal (Ebid & Abdel-Rahman, 2001).
    4) CASE REPORTS
    a) Serum half-lives in 2 patients of less than 24 hours following multiple doses of activated charcoal were demonstrated. Serum half-lives of phenobarbital reported in the literature vary from 55 to 220 hours (Goldberg & Berlinger, 1982).
    b) A 28-day-old infant with a serum phenobarbital concentration of 103 micrograms/milliliter was treated with 1 gram/kilogram aqueous super activated charcoal followed by 3 additional doses of 0.5 gram/kilogram 4 hours apart, and one dose of 1 milliliter/kilogram of 20 percent sorbitol. The calculated elimination half-life was 11.2 hours in this infant (Amitai & Degani, 1990).
    c) Six 2-gram doses of activated charcoal (0.7 gram/kilogram) administered in 10 milliliters of normal saline via an orogastric tube every 6 hours was associated with a decrease of serum phenobarbital concentration from 79 to less than 30 nanograms/milliliter, and a decrease in the elimination half-life from 250 to 30 hours in a 2610-gram, 36 weeks gestation neonate (Veerman et al, 1991).
    5) COMPLICATIONS
    a) CASE REPORT - Following a polydrug overdose which included Tuinal (amylobarbitone sodium 50 mg and quinalbarbitone sodium 50 mg), temazepam, and diazepam a 24 year-old comatose male was administered 25 grams of activated charcoal every four hours for four doses. Approximately, 4 days after the first dose of activated charcoal was administered the patient still had not passed charcoal per rectum (Atkinson et al, 1992).
    1) The patient subsequently was noted to have an intestinal obstruction which on laparotomy was determined to be caused by a solid charcoal bolus. The patient had a limited right hemicolectomy and recovered (Atkinson et al, 1992).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Most patients, except for those in Coma 3 or 4, may be safely managed with conservative, supportive care. Debilitated patients may tolerate prolonged coma poorly.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Routine monitoring of electrolytes, renal function, glucose, pulse oximetry, and blood gases may be helpful.
    3) PHENOBARBITAL: Serum phenobarbital concentrations are available in most hospitals. Generally, phenobarbital concentrations of 3 to 40 mg/L are associated with lethargy and ataxia in non-tolerant individuals, concentrations of greater than 60 to 80 mg/L are associated with coma and concentrations of greater than 150 to 200 mg/L with hypotension. Phenobarbital may be detected on urine immunoassays.
    4) Monitor creatinine phosphokinase in patients with prolonged immobilization from coma.
    5) Monitor renal function and urine output in patients with rhabdomyolysis.
    6) Monitor urine output and pH in patients treated with alkalinization.
    7) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity.
    8) Other causes of coma and hypotension should be ruled out.
    C) HYPOTENSIVE EPISODE
    1) First administer 10 to 20 milliliters/kilogram of isotonic intravenous fluids and place in Trendelenburg position. Repeat boluses of isotonic intravenous fluids should be administered prior to initiating vasopressor therapy. If the patient is unresponsive to isotonic fluid therapy administer a vasopressor. Dopamine or norepinephrine should be titrated to desired response.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) HYPOTHERMIA
    1) Monitor core temperature with rectal or bladder probe. Initiate external rewarming with warm blankets, IV fluids, and warm humidified oxygen until temperature is greater than 32.2 degrees C. For severe hypothermia, provide gastric or peritoneal lavage with warm fluids, consider warm fluids via chest tubes, and for very severe cases associated with cardiac arrest, perform rewarming with cardiopulmonary bypass.
    E) DRUG WITHDRAWAL
    1) Withdrawal symptoms may occur following discontinuation of chronic barbiturate therapy, but are rare following an acute overdose.
    2) Withdrawal may be treated by reinstitution of the phenobarbital and a program of gradual reduction over three weeks. A tapering schedule of 10 percent every 3 days has been used successfully (Smith & Wesson, 1970).
    3) NEONATE - Neonatal withdrawal may be treated by administration of phenobarbital 3 to 5 milligrams/kilogram/24 hours divided every 6 hours. A gradual reduction in dosage over 3 to 4 weeks may then be instituted. Patients may continue to demonstrate jitteriness up to 4 to 6 months of age.
    a) A second method of detoxification is to rapidly dose phenobarbital to the point of intoxication and then administer no more drug. The slow endogenous elimination reduces the risk of severe withdrawal signs and symptoms (Janecek et al, 1987).

Enhanced Elimination

    A) MULTIPLE DOSE ACTIVATED CHARCOAL
    1) SUMMARY
    a) Multiple dose activated charcoal has been shown to increase phenobarbital elimination in animal studies (Arimori & Nakano, 1986)(Arimori & Nakano, 1986), volunteers (Neuvonen & Elonen, 1980; Berg et al, 1982; Frenia et al, 1996; Berg et al, 1987) , and overdose patients (Thompson & Aks, 2007; Ebid & Abdel-Rahman, 2001; Goldberg & Berlinger, 1982; Pond et al, 1984; Boldy et al, 1986; Veerman et al, 1991). This has NOT been shown to alter outcome of poisoning. It should be considered in patients with severe poisoning.
    2) MULTIPLE DOSE ACTIVATED CHARCOAL
    a) ADULT DOSE: Optimal dose not established. After an initial dose of 50 to 100 grams of activated charcoal, subsequent doses may be administered every 1, 2 or 4 hours at a dose equivalent to 12.5 grams/hour (Vale et al, 1999), do not exceed: 0.5 g/kg charcoal every 2 hours (Ghannoum & Gosselin, 2013; Mauro et al, 1994). There is some evidence that smaller more frequent doses are more effective at enhancing drug elimination than larger less frequent doses (Park et al, 1983; Ilkhanipour et al, 1992). PEDIATRIC DOSE: Optimal dose not established. After an initial dose of 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) (Chyka & Seger, 1997), subsequent doses may be administered every 1, 2 or 4 hours (Vale et al, 1999) in a dose equivalent to 6.25 grams/hour in children 1 to 12 years old.
    b) Activated charcoal should be continued until the patient's clinical and laboratory parameters, including drug concentrations if available, are improving (Vale et al, 1999). The patient should be frequently assessed for the ability to protect the airway and evidence of decreased peristalsis or intestinal obstruction.
    c) Use of cathartics has not been shown to increase drug elimination and may increase the likelihood of vomiting. Routine coadministration of a cathartic is NOT recommended (Vale et al, 1999).
    d) AGENTS AMENABLE TO MDAC THERAPY: The following properties of a drug that are likely to allow MDAC therapy to be effective include: small volume of distribution, low protein binding, prolonged half-life, low intrinsic clearance, and a nonionized state at physiologic pH (Chyka, 1995; Ghannoum & Gosselin, 2013).
    e) Vomiting is a common adverse effect; antiemetics may be necessary.
    f) CONTRAINDICATIONS: Absolute contraindications include an unprotected airway, intestinal obstruction, a gastrointestinal tract that is not intact and agents that may increase the risk of aspiration (eg, hydrocarbons). Relative contraindications include decreased peristalsis (eg, decreased bowel sounds, abdominal distention, ileus, severe constipation) (Vale et al, 1999; Mauro et al, 1994).
    g) COMPLICATIONS: Include constipation, intestinal bleeding, bowel obstruction, appendicitis, charcoal bezoars, and aspiration which may be complicated by acute respiratory failure, adult respiratory distress syndrome or bronchiolitis obliterans (Ghannoum & Gosselin, 2013; Ray et al, 1988; Atkinson et al, 1992; Gomez et al, 1994; Mizutani et al, 1991; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Mina et al, 2002; Harsch, 1986; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002).
    3) STUDIES
    a) Multiple doses of activated charcoal have been shown to significantly decrease the serum half-life and increase the total body clearance of phenobarbital (Ebid & Abdel-Rahman, 2001; Berg et al, 1982; Goldberg & Berlinger, 1982; Neuvonen & Elonen, 1980; Pond et al, 1984; Boldy et al, 1986; Gillespie et al, 1986; Veerman et al, 1991; Frenia et al, 1993; Frenia et al, 1996).
    b) In one study (Berg et al, 1982) this mode of therapy increased total body clearance of phenobarbital by a factor of 2.8 and decreased its elimination half-life by a factor of 0.4.
    c) Repeated doses of activated charcoal initiated 10 hours after ingestion of therapeutic doses of phenobarbital in 5 healthy volunteers resulted in a plasma half-life of 18.8 to 20.8 hours compared to a control value of 87 to 133 hours. Total body clearance increased from 4.6 milliliters/minute (controls) to 23 milliliters/minute following multiple dose charcoal therapy (Neuvonen & Elonen, 1980).
    d) In a crossover study multiple dose activated charcoal decreased the elimination half life of intravenously administered phenobarbital to 19 hours compared to half lives of 47 hours with urinary alkalinization and 148 hours with no intervention (Frenia et al, 1993).
    e) In a prospective study of patients with phenobarbital overdose, multiple dose charcoal significantly increased total body clearance, decreased serum half life, decreased time to mental alertness and orientation, and decreased the duration of mechanical ventilation and time to extubation compared with urinary alkalinization and urinary alkalinization combined with multiple dose activated charcoal (Ebid & Abdel-Rahman, 2001).
    1) Plasma phenobarbital half life was 38.6 +/- 6.6 hr with MDAC alone, 81.1 +/- 14.6 hr with urinary alkalinization, and 51.4 +/- 9.8 hr in patients treated with both.
    2) Total body clearance was 10.8 +/- 1.8 mL/kg/hr in patients treated with MDAC alone, 5.1 +/- 0.9 ml/kg/hr in patients treated with urinary alkalinization alone, and 8.1 +/- 1.5 mL/kg/hr in patients treated with both.
    3) Duration of mechanical ventilation was 40.2 +/- 12.5 hr in patients treated with MDAC alone, 79.4 +/- 20.9 hr in patients treated with urinary alkalinization alone, and 51.7 +/- 17.3 hr in patients treated with both.
    4) Time to alertness and orientation was 24.4 +/- 9.6 hr in patients treated with MDAC alone, 50.6 +/- 12.5 hr in patients treated with urinary alkalinization alone, and 37.2 +/- 11.4 hr in patients treated with both.
    5) Time to extubation was 29.7 +/- 10.3 hr in patients treated with MDAC alone, 54.2 +/- 12.8 hr in patients treated with urinary alkalinization alone, and 43.2 +/- 11.6 hr in patients treated with both.
    6) The authors postulated that the addition of urinary alkalinization may have decreased the efficacy of MDAC alone by causing increased serum pH and ion trapping of phenobarbital in serum.
    4) CASE REPORTS
    a) Serum half-lives in 2 patients of less than 24 hours following multiple doses of activated charcoal were demonstrated. Serum half-lives of phenobarbital reported in the literature vary from 55 to 220 hours (Goldberg & Berlinger, 1982).
    b) A 28-day-old infant with a serum phenobarbital concentration of 103 micrograms/milliliter was treated with 1 gram/kilogram aqueous super activated charcoal followed by 3 additional doses of 0.5 gram/kilogram 4 hours apart, and one dose of 1 milliliter/kilogram of 20 percent sorbitol. The calculated elimination half-life was 11.2 hours in this infant (Amitai & Degani, 1990).
    c) Six 2-gram doses of activated charcoal (0.7 gram/kilogram) administered in 10 milliliters of normal saline via an orogastric tube every 6 hours was associated with a decrease of serum phenobarbital concentration from 79 to less than 30 nanograms/milliliter, and a decrease in the elimination half-life from 250 to 30 hours in a 2610-gram, 36 weeks gestation neonate (Veerman et al, 1991).
    5) COMPLICATIONS
    a) CASE REPORT - Following a polydrug overdose which included Tuinal (amylobarbitone sodium 50 mg and quinalbarbitone sodium 50 mg), temazepam, and diazepam a 24 year-old comatose male was administered 25 grams of activated charcoal every four hours for four doses. Approximately, 4 days after the first dose of activated charcoal was administered the patient still had not passed charcoal per rectum (Atkinson et al, 1992).
    1) The patient subsequently was noted to have an intestinal obstruction which on laparotomy was determined to be caused by a solid charcoal bolus. The patient had a limited right hemicolectomy and recovered (Atkinson et al, 1992).
    B) URINE ALKALINIZATION
    1) Alkalinizing the urine will enhance the renal excretion of phenobarbital but this does not correlate with improved clinical outcome. Urine alkalinization should be considered only in severe barbiturate toxicity with life-threatening signs and symptoms. It appears to be LESS effective at enhancing phenobarbital elimination than multiple dose activated charcoal (Ebid & Abdel-Rahman, 2001; Frenia et al, 1996; Frenia et al, 1993) and is generally NOT the preferred method of elimination enhancement.
    2) In a crossover study urinary alkalinization decreased the elimination half life of intravenously administered phenobarbital to 47 hours compared to half lives of 19 hours with multiple dose activated charcoal and 148 hours with no intervention (Frenia et al, 1993).
    3) In a study the effectiveness of urinary alkalinization to multiple-dose activated charcoal for enhancement of phenobarbital elimination was compared (Frenia et al, 1996a). The elimination half-life of intravenously administered phenobarbital following urinary alkalinization was 47 hours as compared to 19 hours with multiple-dose activated charcoal and 148 hours with no intervention.
    4) Administer 1 mEq/kg of NaHCO3 by intravenous bolus. Place 88 to 132 milliequivalents/liter of D5W (2 to 3 ampules) sodium bicarbonate and 20 to 40 milliequivalents/liter potassium chloride (as needed to maintain normal serum potassium concentrations) in dextrose 5 percent in water or similar appropriate fluid should be given at a rate sufficient to produce a urine pH of at least 7.5.
    5) SODIUM BICARBONATE/REPEAT DOSES -
    a) Additional sodium bicarbonate (1 to 2 milliequivalents per kilogram) and potassium chloride (20 to 40 milliequivalents per liter) may be needed to achieve an alkaline urine.
    6) CAUTION - Obtain hourly intake/output and urine pH. Assure adequate hydration and renal function prior to alkalinization. Do not administer potassium to an oliguric or anuric patient. Monitor fluid and electrolyte balance carefully.
    C) HEMOPERFUSION
    1) Barbiturate elimination can be increased by hemodialysis or charcoal hemoperfusion. These techniques are rarely needed when managing even severe barbiturate intoxication and should be reserved for patients with hemodynamic compromise refractory to aggressive supportive care.
    a) During hemoperfusion, plasma half-lives were reduced by 78 to 88 percent in 3 patients overdosed on phenobarbital (Jacobsen et al, 1984). Rebound in serum levels may occur after discontinuation of hemoperfusion, as drug is released from tissue stores.
    2) ADVERSE EFFECTS - Even though hemoperfusion will clear barbiturates two to four times more rapidly than dialysis, hemoperfusion will not correct electrolyte imbalances and has been associated with platelet consumption, hypothermia, hypotension, and decreased serum calcium (Lindberg et al, 1992).
    3) CASE REPORT - A 40-year-old man developed coma, respiratory failure and hypotension after phenobarbital overdose and was treated with continuous arteriovenous hemoperfusion (CAVHP) for 8 hours (Lin & Jeng, 1995). Phenobarbital level dropped from 80.2 micrograms/milliliter to 6.4 micrograms/milliliter in 8 hours; calculated mean CAVHP phenobarbital clearance was 290 milliliter/minute. Mild thrombocytopenia developed and the patient recovered uneventfully.
    D) HEMODIALYSIS
    1) In most US health care facilities, hemodialysis is more readily available than is hemoperfusion. Newer high efficiency dialyzers with high blood flow rates may be as effective as hemoperfusion in clearing phenobarbital.
    2) Hemodialysis was used in a 43-year-old male following a phenobarbital overdose resulted in a decrease in the half-life of phenobarbital (8.33 hours during dialysis compared to 86.6 hours after dialysis) and an increase in the clearance of phenobarbital (29 to 62.4 milliliters/minute during dialysis compared to 7.4 milliliters/minute after dialysis) (Zawada et al, 1983).
    3) In a patient with severe phenobarbital overdose, hemodialysis was performed with a high-flux, high-efficiency polysulfone hemodialysis membrane (F80, Fresenius) with a blood flow rate of 400 mL/min and a dialysate flow rate of 500 mL/min achieved phenobarbital clearance rates of 144 to 188 mL/min over a 4 hour dialysis session (average 174 mL/min) with an extraction ratio of 36% to 47% and a half life of 3.2 hours (Palmer, 2000).
    4) CASE REPORT - Two hemodialysis sessions were performed on a 58-year-old man who was comatose following a phenobarbital overdose of an unknown amount. Toxicologic analysis demonstrated a serum phenobarbital concentration of 151.5 mg/L. Following the second hemodialysis session, the patient's serum phenobarbital concentration decreased to 30 mg/L. Over the next several days, his mental status returned to baseline and he was discharged to a psychiatric facility (Thompson & Aks, 2007).
    E) HEMODIAFILTRATION
    1) A 47-year-old woman was successfully treated with hemodiafiltration for acute phenobarbital intoxication (phenobarbital serum concentration, 106 mg/L). Using a high-flux, high efficiency membrane, the patient was treated with 4 hours of hemodiafiltration 16 hours after admission. Dialysate flow rate, blood flow rate, and filtration rate were 500 mL/min, 400 mL/min, and 2 L/hr, respectively. The calculated half-life during, before, and after hemodiafiltration were 2.4 hours, 64 hours, and 26 hours, respectively. She fully recovered and was discharged 72 hours after admission. In this case, the half-life of phenobarbital during hemodiafiltration (2.4 hours) was comparable or shorter compared to other reports during hemoperfusion (4.5 to 16.4 hours) and hemodialysis (3.2 to 8.3 hours) (vandePlas et al, 2006).
    2) A 58-year-old man with severe phenobarbital overdose (coma, respiratory failure, hypotension, oliguria, phenobarbital concentration 106 mcg/mL) was treated for almost 32 hours with continuous venovenous hemodiafiltration (CVVHDF). Blood phenobarbital concentration decreased from 93 mcg/mL to 41 mcg/mL during the procedure. The extraction ratio ranged from 5.5% to 21.5% and clearance ranged from 8.25 mL/min to 32.35 mL/min. The patient began to improve clinically 6 hours after the start of CVVHDF (Lal et al, 2006).
    F) EXCHANGE TRANSFUSION
    1) Exchange transfusion was successful in decreasing plasma phenobarbital levels from 112 mcg/mL to 50 mcg/mL in a comatose 14-day-old infant (Sancak et al, 1999).

Abstracts

Case Reports

    A) ADULT
    1) PRIMIDONE
    a) Primidone overdose usually presents with coma and loss of deep tendon reflexes, nystagmus, strabismus, ankle and knee clonus, and positive Babinski, Hoffman, and Chaddock signs. Supportive therapy usually results in recovery.
    b) A 48-year-old female presented with lethargy and ataxia after chronic therapeutic use of primidone. Her initial primidone level was 125 mg/mL (normal = 5 to 12 mg/L) and phenobarbital level was 62 mg/mL (normal = 20 to 40 mg/L). Six hours later, after initiation of urine alkalinization, her urine specimen was found to contain large amounts of hexagonal and plate-like crystals containing primidone. Crystals were still present 20 hours after presentation but resolved by the next day. Renal function remained normal (Sigg & Leikin, 1999).
    B) PEDIATRIC
    1) PHENOBARBITAL
    a) A previously healthy 2-year-old child developed a fever (102 degrees F) and an erythematous, papular, pruritic rash on his extremities (including soles and palms) and trunk 2 weeks after initiation of 2 mg/kg/day of oral phenobarbital for 2 focal tonic-clonic seizures. Two days after hospital admission the phenobarbital was discontinued. Acetaminophen 80 mg was administered every 4 hours while the child was febrile. The child developed diffuse adenopathy and hepatomegaly. Clinical laboratory tests revealed alkaline phosphatase 1458 International Units/L, ALT 3880 International Units/L, CK 790 International Units/L, albumin 3.8 g/dL, PT 12.9 s, and PTT 39 s. This child failed to improve and was transferred to another health care facility for a possible liver transplant. Hepatocyte necrosis was reported on liver biopsy. The child died after an intercranial hemorrhage was detected by CT exam (Mockli et al, 1989).

Range Of Toxicity

Summary

    A) TOXICITY: The toxic dose varies depending on route and speed of administration as well as patient tolerance. Ingestion of 8 mg/kg phenobarbital generally causes some CNS depression in non-tolerant individuals.
    B) THERAPEUTIC DOSE: PHENOBARBITAL: ADULT: (Oral) 30 to 200 mg/day divided; (IV) (status epilepticus) 10 to 20 mg/kg. CHILDREN: (Oral) 5 to 8 mg/kg/day divided; (IV) (status epilepticus) 10 to 20 mg/kg. PRIMIDONE: ADULT: 500 mg/day divided. CHILDREN: less than 8-years-old, 10 to 25 mg/kg/day divided; more than 8-years-old, 750 to 1500 mg/day divided.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) BELLADONNA ALKALOIDS/PHENOBARBITAL
    a) ELIXIR: One or 2 teaspoonfuls of elixir 3 to 4 times daily based on severity of symptoms and current conditions (Prod Info DONNATAL(R) ELIXIR oral solution, 2011).
    b) EXTENDED RELEASE TABLETS: One tablet orally every 12 hours. If indicated, one tablet every 8 hours may be administered (Prod Info DONNATAL EXTENTABS(R) oral extended release tablets, 2007).
    c) TABLETS: One or 2 tablets 3 to 4 times daily based on severity of symptoms and current conditions (Prod Info DONNATAL(R) oral tablets, 2012).
    2) PHENOBARBITAL
    a) EPILEPSY: (tablet) 50 mg to 100 mg ORALLY 2 or 3 times daily (Prod Info phenobarbital oral tablets, 2006) or (solution) 60 to 200 mg/day ORALLY (Prod Info phenobarbital oral solution, 2005)
    b) SEDATION: daytime sedation, 30 mg to 120 mg ORALLY divided into 2 or 3 doses (Prod Info phenobarbital oral tablets, 2006), up to MAX 400 mg in 24 hours (Prod Info phenobarbital oral solution, 2005); hypnotic, (tablet) 100 to 320 mg ORALLY as a single dose (Prod Info phenobarbital oral tablets, 2006) or (solution) 100 to 200 mg/day ORALLY; up to MAX 400 mg in 24 hours (Prod Info phenobarbital oral solution, 2005)
    c) STATUS EPILEPTICUS: average dose, 100 to 320 mg slow IV or IM; larger doses may be required in patients with status epilepticus, psychoses, and pronounced excitement and in mental patients with insomnia; however, the total MAX dose 600 mg/24 hrs (Prod Info LUMINAL(R)SODIUM powder for IV injection, 2008)
    3) PRIMIDONE
    a) Initial: Day 1 to 3: 100 to 125 mg at bedtime; Day 4 to 6: 100 to 125 mg twice daily; Day 7 to 9: 100 to 125 mg three times daily; Day 10 to maintenance: 250 mg three times daily (Prod Info Mysoline(R) oral tablets, 2010).
    b) Maintenance: 250 mg three or four times daily; max 500 mg four times daily (Prod Info Mysoline(R) oral tablets, 2010).
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) BELLADONNA ALKALOIDS/PHENOBARBITAL
    a) ELIXIR: Dosed 4 to 6 times daily based on body weight (Prod Info DONNATAL(R) ELIXIR oral solution, 2011).
    2) PHENOBARBITAL
    a) ANTICONVULSANT
    1) NEONATES
    a) In the treatment of neonatal seizures, a loading dose of 15 to 20 milligrams/kilogram intravenously, followed by a maintenance dose of 3 to 4 milligrams/kilogram is recommended to maintain a plasma concentration of 20 micrograms/milliliter (Legido et al, 1988). However, a maintenance dose of 2.9 to 4.9 milligrams/kilogram/day is recommended in newborns younger than 1 month; newborns over 30 days should receive 6.0 milligrams/kilogram/day (n=17) (Gonzalez et al, 1993).
    2) PEDIATRIC
    a) Initial: 1 to 1.5 mg/kg/day orally for two weeks followed by maintenance dose of 3 to 6 mg/kg/day orally in 1 or 2 divided doses (Coppola, 2004; Pal et al, 1998). Maintenance doses greater than 5 mg/kg/day may be necessary to achieve serum phenobarbital concentrations of 20 to 40 mcg/mL (Suzuki et al, 1991).
    b) STATUS EPILEPTICUS
    1) INFANTS AND CHILDREN
    a) Initially, give 10 to 20 milligrams/kilogram over 10 to 15 minutes (2 mg/kg/minute) to a maximum of 30 mg/min, followed by 5 to 10 milligrams/kilogram/dose at intervals of 20 to 30 minutes, until seizures are controlled, up to a total of 40 milligrams/ kilogram. Maximum cumulative daily doses up to 80 mg/kg have been given (Lee et al, 2006; Crawford et al, 1988; Hanhan et al, 2001; De Negri & Baglietto, 2001; Mitchell, 1996; Crawford et al, 1988; Shaner et al, 1988; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) HYPNOTIC OR SEDATIVE
    1) 2 mg/kg orally three times daily (Prod Info phenobarbital oral tablets, 2006).
    d) NEONATAL ABSTINENCE SYNDROME
    1) Loading dose: 16 mg/kg orally on day 1 (Burgos & Burke, 2009; Finnegan et al, 1984; Finnegan et al, 1979). Maintenance dose: 1 to 4 mg/kg/dose orally every 12 hours (Burgos & Burke, 2009; Finnegan et al, 1984; Finnegan et al, 1979).
    3) PRIMIDONE
    a) CHILDREN LESS THAN 8 YEARS OLD
    1) Initial: Day 1 to 3: 50 mg orally at bedtime; Day 4 to 6: 50 mg twice daily; Day 7 to 9: 100 mg twice daily; Day 10 to maintenance: 125 to 250 mg three times daily (Prod Info Mysoline(R) oral tablets, 2010).
    2) Maintenance: 125 to 250 mg orally three times daily or 10 to 25 mg/kg/day in divided doses (Prod Info Mysoline(R) oral tablets, 2010).
    b) CHILDREN 8 YEARS AND OLDER
    1) Initial: Day 1 to 3: 100 to 125 mg orally at bedtime; Day 4 to 6: 100 to 125 mg twice daily; Day 7 to 9: 100 to 125 mg three times daily; Day 10 to maintenance: 250 mg three times daily (Prod Info Mysoline(R) oral tablets, 2010).
    2) Maintenance: 250 mg orally three or four times daily; max 500 mg four times daily (Prod Info Mysoline(R) oral tablets, 2010).

Minimum Lethal Exposure

    A) SUMMARY
    1) Death following oral phenobarbital overdose, without coingestants, is rare. Deaths are usually due to complications of altered mental status, such as trauma, aspiration pneumonia. The mortality rate is low with aggressive supportive care and treatment.

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) PHENOBARBITAL: Dosages in excess of 8 milligrams/kilogram may produce some toxic symptomatology depending upon whether the patient has had previous exposure or is addicted to the agent. Addicts have been known to utilize 1000 milligrams/day.

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) PHENOBARBITAL -
    1) Levels above 30 to 40 micrograms/milliliter are often associated with toxic symptoms (Hvidberg & Dam, 1976; Gallagher, 1973) although psychomotor slowing and intellectual deterioration may occur at levels between 15 to 20 micrograms/milliliter (Reynolds & Travers, 1974).
    2) Levels ranging from 5 to 13.4 milligrams/deciliter (50 to 130 micrograms/milliliter) have been found in fatal poisonings (McBay, 1966) 1973).
    b) PRIMIDONE -
    1) Concentration of 15 micrograms/milliliter of primidone with therapeutic concentrations of phenobarbital have been reported to be associated with ataxia and/or somnolence (Hvidberg & Dam, 1976; Gallagher, 1973; Gallagher & Baumel, 1971).
    2) Plasma levels exceeding 8 mg/dL (80 mcg/mL) (344 mcmol/L) are generally associated with some degree of coma. In the absence of tolerance, plasma levels exceeding 2 to 3 mg/dL may be associated with CNS depression.

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Barbiturates depress the central nervous system but differ widely in dosage, duration of action and in margin of safety between the therapeutic dose and the toxic dose. They are mainly used in epilepsy.

Physicochemical

Molecular Weight

    A) Varies

Animal Toxicology

Clinical Effects

    11.1.13) OTHER
    A) OTHER
    1) Shallow respiration, incoordination, lethargy, coma, loss of reflexes, and dilated pupils.

Treatment

    11.2.1) SUMMARY
    A) GENERAL TREATMENT
    1) SUMMARY
    a) Begin treatment immediately.
    b) Keep animal warm and do not handle unnecessarily.
    c) Remove the patient and other animals from the source of contamination or remove dietary sources.
    2) Treatment should always be done on the advice and with the consultation of a veterinarian.
    3) Additional information regarding treatment of poisoned animals may be obtained from a Veterinary Toxicologist or the National Animal Poison Control Center.
    4) ASPCA ANIMAL POISON CONTROL CENTER
    a) ASPCA Animal Poison Control Center, 1717 S Philo Road, Suite 36 Urbana, IL 61802
    b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    c) Contact information: (888) 426-4435 (hotline) or www.aspca.org (A fee may apply. Please inquire with the poison center). The agency will make follow-up calls as needed in critical cases at no extra charge.
    5) SMALL ANIMALS: Due to lack of reports of large animal intoxication with this substance, the following sections address small animals (dogs and cats) only.
    6) In the case of a poisoning involving large animals, consult a veterinary poison control center.
    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) EMESIS/GASTRIC LAVAGE -
    1) Induce emesis only within 30 minutes of ingestion and with extreme caution. CNS depression may occur before emesis is completed.
    2) CAUTION: Carefully examine patients with chemical exposure before inducing emesis. If signs of oral, pharyngeal, or esophageal irritation, a depressed gag reflex, or central nervous system excitation or depression are present, EMESIS SHOULD NOT BE INDUCED.
    3) HORSES OR CATTLE: DO NOT attempt to induce emesis in ruminants (cattle) or equids (horses).
    4) DOGS AND CATS
    a) IPECAC: If within 2 hours of exposure: induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.
    b) APOMORPHINE: Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
    1) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram, although this route may not be as effective.
    5) LAVAGE: In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
    a) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times.
    b) ACTIVATED CHARCOAL/CATHARTIC -
    1) ACTIVATED CHARCOAL: Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
    2) CATHARTIC: Administer a dose of a saline or sorbitol cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.
    3) NOTE - Activated charcoal may be used even after parenteral exposure.
    11.2.5) TREATMENT
    A) GENERAL TREATMENT
    1) MAINTAIN VITAL FUNCTIONS - as necessary.
    2) FLUIDS -
    a) Begin electrolyte and fluid therapy with isotonic solutions as needed at maintenance doses (66 milliliters solution/kilogram body weight/day intravenously) or, in hypotensive patients, at high doses (up to shock dose 60 milliliters/kilogram/hour). Monitor for urine production and pulmonary edema.
    3) DIURESIS -
    a) Alkaline diuresis with sodium bicarbonate may increase urinary excretion rate in carnivores (Klaasen et al, 1986; Haddad et al, 1983).
    4) DOXAPRAM -
    a) Doxapram may be used to stimulate the respiratory and cardiovasular systems at a rate of 5.5 to 11 milligrams/kilograms slowly intravenously for dogs and cats.
    1) In neonates it can be given subcutaneously or sublingually at a total dose of 1 to 5 milligrams in pups and 1 to 2 milligrams in kittens. This also may be given slowly in the umbilical vein in pups.
    b) When stimulants are used, including doxapram, it is essential to monitor the animal closely to avoid the effects of rebound depression and possible respiratory arrest (Booth et al, 1988).
    5) MONITORING -
    a) Symptomatic patients must be monitored continuously. Refer to an emergency hospital or critical care clinic for 24 hour monitoring.

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) GENERAL TREATMENT
    1) SUMMARY
    a) Begin treatment immediately.
    b) Keep animal warm and do not handle unnecessarily.
    c) Remove the patient and other animals from the source of contamination or remove dietary sources.
    2) Treatment should always be done on the advice and with the consultation of a veterinarian.
    3) Additional information regarding treatment of poisoned animals may be obtained from a Veterinary Toxicologist or the National Animal Poison Control Center.
    4) ASPCA ANIMAL POISON CONTROL CENTER
    a) ASPCA Animal Poison Control Center, 1717 S Philo Road, Suite 36 Urbana, IL 61802
    b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    c) Contact information: (888) 426-4435 (hotline) or www.aspca.org (A fee may apply. Please inquire with the poison center). The agency will make follow-up calls as needed in critical cases at no extra charge.
    5) SMALL ANIMALS: Due to lack of reports of large animal intoxication with this substance, the following sections address small animals (dogs and cats) only.
    6) In the case of a poisoning involving large animals, consult a veterinary poison control center.
    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) EMESIS/GASTRIC LAVAGE -
    1) Induce emesis only within 30 minutes of ingestion and with extreme caution. CNS depression may occur before emesis is completed.
    2) CAUTION: Carefully examine patients with chemical exposure before inducing emesis. If signs of oral, pharyngeal, or esophageal irritation, a depressed gag reflex, or central nervous system excitation or depression are present, EMESIS SHOULD NOT BE INDUCED.
    3) HORSES OR CATTLE: DO NOT attempt to induce emesis in ruminants (cattle) or equids (horses).
    4) DOGS AND CATS
    a) IPECAC: If within 2 hours of exposure: induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.
    b) APOMORPHINE: Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
    1) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram, although this route may not be as effective.
    5) LAVAGE: In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
    a) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times.
    b) ACTIVATED CHARCOAL/CATHARTIC -
    1) ACTIVATED CHARCOAL: Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
    2) CATHARTIC: Administer a dose of a saline or sorbitol cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.
    3) NOTE - Activated charcoal may be used even after parenteral exposure.

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) Amitai Y & Degani Y: Treatment of phenobarbital poisoning with multiple dose activated charcoal in an infant. J Emerg Med 1990; 8:449-450.
    3) Arima M, Kanoh T, & Yamasaki A: Eosinophilic myocarditis associated with toxicodermia caused by phenobarbital. Jpn Circ J 1998; 62:132-135.
    4) Arimori K & Nakano M: Accelerated clearance of intravenously administered theophylline and phenobarbital by oral doses of activated charcoal in rats. A possibility of the intestinal dialysis. J Pharmacobiodyn 1986; 9(5):437-441.
    5) Atkinson SW, Young Y, & Trotter GA: Treatment with activated charcoal complicated by gastrointestinal obstruction requiring surgery. Br Med J 1992; 305:563.
    6) Baselt RC: Disposition of Toxic Drugs and Chemicals in Man, 5th ed, Chemical Toxicology Institute, Foster City, CA, 2000.
    7) Berg MJ, Berlinger WG, & Goldberg MJ: Acceleration of the body clearance of phenobarbital by oral activated charcoal. N Engl J Med 1982; 307:642-644.
    8) Berg MJ, Rose JQ, & Wurster DE: Effect of charcoal and sorbitol-charcoal suspension on the elimination of intravenous phenobarbital. Ther Drug Monitor 1987; 9:41-47.
    9) Berg MJ, Wurster DE, & Kolling WM: Effect of three charcoal preparations on oral and intravenous phenobarbital. Clin Res Reg Affairs 1993; 10:81-98.
    10) Beveridge GW & Lawson AAH: Occurrence of bullous lesions in acute barbiturate poisoning. Br Med J 1965; 1:835-837.
    11) Boldy DAR, Vale JA, & Prescott PI: Treatment of phenobarbitone poisoning with repeated oral administraiton of activated charcoal. Quar J Med 1986; 235:997-1002.
    12) Booth, Nicholas H, & McDonald: Veterinary Pharmacology and Therapeutics, 6th ed, Iowa State University Press, Ames, IA, 1988.
    13) Brent DA, Crumrine PK, & Varma RR: Phenobarbital treatment and major depressive disorder in children with epilepsy. Pediatrics 1987; 80:909-917.
    14) Briggs GG, Freeman RK, & Yaffe SJ: Drugs in Pregnancy and Lactation. 5th ed, Williams and Wilkins, Baltimore, MD, 1998.
    15) Burgos AE & Burke BL: Neonatal Abstinence Syndrome. Neoreviews 2009; 10(5):e222-e229.
    16) Butler TC: Quantitative studies of the metabolic fate of mephobarbital (N-methylphenobarbital). J Pharm Exp Ther 1952; 106:235-245.
    17) Carroll BJ: Barbiturate overdosage: presentation with focal neurological signs. Med J Aust 1969; 1:1133.
    18) Cate JC & Tenser R: Acute primidone overdosage with massive crystalluria. Clin Toxicol 1975; 8:385-389.
    19) Chyka PA & Seger D: Position statement: single-dose activated charcoal. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol 1997; 35:721-741.
    20) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    21) Chyka PA: Multiple-dose activated charcoal and enhancement of systemic drug clearance: summary of studies in animals and human volunteers. J Toxicol Clin Toxicol 1995; 33(5):399-405.
    22) Cooney DO: In vitro adsorption of phenobarbital, chlorpheniramine maleate, and theophylline by four commercially available activated charcoal suspensions. Clin Toxicol 1995; 33:213-217.
    23) Coppola G : Treatment of partial seizures in childhood : an overview. CNS Drugs 2004; 18(3):133-156.
    24) Craig GP: Systems of Measurement and Common Equivalents. In: Clinical Calculations Made Easy: Solving Problems Using Dimensional Analysis, 3rd ed. Lippincott Williams & Wilkins, Philadelphia, PA, 2005.
    25) Crawford TO, Mitchell WG, & Fishman LS: Very-high-dose phenobarbital for refractory status epilepticus in children. Neurology 1988; 38:1035-1040.
    26) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    27) De Negri M & Baglietto MG: Treatment of status epilepticus in children. Paediatr Drugs 2001; 3(6):411-420.
    28) DeNicola LK & Hays DP: Thrombophebosis due to high-dose barbiturates. Drug Intell Clin Pharm 1982; 16:880.
    29) Desmond MM, Schwanecke RP, & Wilson GS: Maternal barbiturate utilization in neonatal withdrawal symptomatology. J Pediatr 1972; 80:190-197.
    30) Ebid AH & Abdel-Rahman HM: Pharmacokinetics of phenobarbital during certain enhanced elimination modalities to evaluate their clinical efficacy in management of drug overdose. Ther Drug Mon 2001; 23:209-216.
    31) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    32) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    33) Finnegan LP, Michael H, Leifer B, et al: An evaluation of neonatal abstinence treatment modalities. NIDA Res Monogr 1984; 49:282-288.
    34) Finnegan LP, Mitros TF, & Hopkins LE: Management of neonatal narcotic abstinence utilizing a phenobarbital loading dose method. NIDA Res Monogr 1979; 27:247-253.
    35) Frenia ML, Schauben JL, & Wears RL: Multiple-dose activated charcoal compared to urinary alkalinization for the enhancement of phenobarbital elimination. Clin Toxicol 1996; 34:169-175.
    36) Frenia ML, Schauben JL, & Wears RL: Multiple-dose activated charcoal compared to urinary alkalinization for the enhancement of phenobarbital elimination. J Toxicol Clin Toxicol 1996a; 34:169-175.
    37) Frenia ML, Schauben JS, & Tucker C: Multiple dose activated charcoal compared to urinary alkalinization for the enhancement of phenobarbital elimination. Vet Hum Toxicol 1993; 35:367.
    38) Gallagher BB & Baumel IP: Diphenylhydantoin, phenobarbital, and primidone: serum concentrations, distribution, and toxicity in a large population of epileptic patients. Neurology 1971; 21:395.
    39) Gallagher BB: Primidone, diphenylhydantoin and phenobarbital. Aspects of acute and chronic toxicity. Neurology 1973; 23:145.
    40) Ghannoum M & Gosselin S: Enhanced poison elimination in critical care. Adv Chronic Kidney Dis 2013; 20(1):94-101.
    41) Gillespie WR, Veng-Pedersen P, & Berg MJ: Linear systems approach to the analysis of an induced drug process. phenobarbital removal by oral activated charcoal. J Pharmacokinet Biopharm 1986; 14:19-28.
    42) Goldberg MJ & Berlinger WG: Treatment of phenobarbital overdose with activated charcoal. JAMA 1982; 247:2400-2401.
    43) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    44) Gomez HF, Brent JA, & Munoz DC: Charcoal stercolith with intestinal perforation in a patient treated for amitriptyline ingestion. J Emerg Med 1994; 12:57-60.
    45) Gonzalez ACA, Valin LO, Buelga DS, et al: Dosage programming of phenobarbital in neonatal seizures. J Clin Pharm Ther 1993; 18:267-270.
    46) Goodman JM, Bischel MD, & Wagers PW: Barbituate intoxication: morbidity and mortality. West J Med 1976; 124:179-186.
    47) Goulle JP, Noyon J, & Layet A: Phenobarbital in hair and drug monitoring. Forensic Sci Int 1995; 70:191-202.
    48) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    49) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    50) Haddad, Lester M, & Winchester: Clinical Management of Poisoning and Drug Overdose, WB Saunders Company, Philadelphia, PA, 1983.
    51) Handfield-Jones SE, Jenkins RE, & Whittaker SJ: The anticonvulsant hypersensitivity syndrome. Br J Dermatol 1993; 129:175-177.
    52) Hanhan UA, Fiallos MR, & Orlowski JP: Status epilepticus. Pediatr Clin North Am 2001; 48(3):683-694.
    53) Haroun M, Jakubovic HR, & Nethercott JR: Localized subepidermal bullae after intravenous phenobarbital. Cutis 1987; 39:233-234.
    54) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    55) Harsch HH: Aspiration of activated charcoal. N Engl J Med 1986; 314:318.
    56) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    57) Holzer P, Beubler E, & Dirnhofer R: Barbituate poisoning and gastrointestinal propulsion. Arch Toxicol 1987; 60:394-396.
    58) Hooper WD, Kunze HE, & Eadie MJ: Pharmacokinetics and bioavailability of methylphenobarbital in man. Ther Drug Monit 1981a; 3:39-44.
    59) Hooper WD, Kunze HE, & Eadie MJ: Qualitative and quantitative studies of methylphenobarbital metabolism in man. Drug Metab Disp 1981b; 9:381-385.
    60) Horning MG, Stillwell WG, & Nowling J: Identification and quantification of drugs and drug metabolites in human breast milk using GC-MS-COM methods. Mod Probl Paediatr 1975; 15:73-79.
    61) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    62) Ilkhanipour K, Yealy DM, & Krenzelok EP: The comparative efficacy of various multiple-dose activated charcoal regimens. Am J Emerg Med 1992; 10:298-300.
    63) Jacobsen D, Wiik-Larsen E, & Dahl T: Pharmacokinetic evaluation of haemoperfusion in phenobarbital poisoning. Eur J Clin Pharmacol 1984; 26:109-112.
    64) Janecek E, Kapur B, & Devenyi P: Oral phenobarbital loading: A safe method of barbiturate and nonbarbiturate hypnosedative withdrawal. Can Med Assoc J 1987; 137:410-412.
    65) Klaasen, Curtis D, & Amdur: Cassarett and Doull's Toxicology: The Basic Science of Poisons, 3rd ed, Macmillan Publishing Company, New York, NY, 1986.
    66) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    67) Lal R, Faiz S, Garg RK, et al: Use of continuous venovenous hemodiafiltration in a case of severe phenobarbital poisoning. Am J Kidney Dis 2006; 48(2):13-15.
    68) Lane GP, Lewis CJ, & Zail SC: Macroscopic crystalluria after primidone overdosage. Med J Aust 1987; 147:624-625.
    69) Laurenson IF, Buckoke C, & Davidson C: Delayed fatal agranulocytosis in an epileptic taking primidone and phenytoin (letter). Lancet 1994; 344:332-333.
    70) Lee WK, Liu KT, & Young BW: Very-high-dose phenobarbital for childhood refractory status epilepticus. Pediatr Neurol 2006; 34(1):63-65.
    71) Legido A, Clancy RR, & Berman PH: Recent advances in the diagnosis, treatment, and prognosis of neonatal seizures. J Pediatr Neurol 1988; 4:79-86.
    72) Lin J-L & Jeng L-B: Critical, acutely poisoned patients treated with continuous arteriovenous hemoperfusion in the emergency department. Ann Emerg Med 1995; 25:75-80.
    73) Lindberg MC, Cunningham A, & Lindberg NH: Acute phenobarbital intoxication. South Med J 1992; 85:803-807.
    74) Lous P: Plasma levels and urinary excretion of three barbituric acids after oral administration to man. Acta Pharmacol Toxicol 1954; 10:147-165.
    75) Matthew H & Lawson AAH: Acute barbituate poisoning - a review of two years experience. Q J Med 1966; 35:539-551.
    76) Matzke GR, Cloyd JC, & Sawchuk RJ: Acute phenytoin and primidone intoxication: A pharmacokinetic analysis. J Clin Pharmacol 1981; 21:92-99.
    77) Mauro LS, Nawarskas JJ, & Mauro VF: Misadventures with activated charcoal and recommendations for safe use. Ann Pharmacother 1994; 28(7-8):915-924.
    78) McBay A: Chemical findings in poisonings. N Engl J Med 1966; 274:1257.
    79) Mina B, Dym JP, & Kuepper F: Fatal inhalational anthrax with unknown source of exposure in a 61-year-old woman in New York City. J Am Med Assoc 2002; 287:858-862.
    80) Mitchell WG: Status epilepticus and acute repetitive seizures in children, adolescents, and young adults: etiology, outcome, and treatment. Epilepsia 1996; 37(S1):S74-S80.
    81) Mizutani T, Naito H, & Oohashi N: Rectal ulcer with massive hemorrhage due to activated charcoal treatment in oral organophosphate poisoning. Hum Exp Toxicol 1991; 10:385-386.
    82) Mockli G, Crowley M, & Stern R: Massive hepatic necrosis in a child after administration of phenobarbital. Am J Gastroenterol 1989; 84:820-822.
    83) Modi NB, Veng-Pedersen P, & Wurster DE: Phenobarbital removal characteristics of three brands of activated charcoals: a system analysis approach. Pharm Res 1994; 11:318-323.
    84) Neuvonen PJ & Elonen E: Effect of activated charcoal on absorption and elimination of phenobarbitone, carbamazepine and phenylbutazone in man. Eur J Clin Pharmacol 1980; 17:51-57.
    85) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    86) Nordt SP: Butalbital cross-reactivity to an Emit assay for phenobarbital (letter). Ann Pharmacother 1997; 31:254-255.
    87) O'Connor CR, Schraeder PL, & Kurland AH: Evaluation of the mechanisms of antiepileptic drug-related chronic leukopenia. Epilepsia 1994; 35:149-154.
    88) Olson KR, Pond SM, & Verrier ED: Intestinal infarction complicating phenobarbital overdose. Arch Intern Med 1984; 144:407-408.
    89) Pal DK, Das T, Chaudhury G, et al: Randomised controlled trial to assess acceptability of phenobarbital for childhood epilepsy in rural India. Lancet 1998; 351(9095):19-23.
    90) Palmer BF: Effectiveness of hemodialysis in the extracorporeal therapy of phenobarbital overdose. Am J Kid Dis 2000; 36:640-643.
    91) Park GD, Radomski L, & Goldberg MJ: Effects of size and frequency of oral doses of charcoal on theophylline clearance. Clin Pharmacol Ther 1983; 34:663-666.
    92) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    93) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    94) Pond SM, Olson KR, & Osterloh JD: Randomized study of the treatment of phenobarbital overdose with repeated doses of activated charcoal. JAMA 1984; 251:3104-3108.
    95) Product Information: DONNATAL EXTENTABS(R) oral extended release tablets, phenobarbital hyoscyamine sulfate atropine sulfate scopolamine hydrobromide oral extended release tablets. PBM Pharmaceuticals, Inc. (per DailyMed), Charlottesville, VA, 2007.
    96) Product Information: DONNATAL(R) ELIXIR oral solution, phenobarbital hyoscyamine sulfate atropine sulfate scopolamine hydrobromide oral solution. PBM Pharmaceuticals, Inc. (per Manufacturer), Charlottesville, VA, 2011.
    97) Product Information: DONNATAL(R) oral tablets, phenobarbital hyoscyamine sulfate atropine sulfate scopolamine hydrobromide oral tablets. PBM Pharmaceuticals, Inc. (per Manufacturer), Charlottesville, VA, 2012.
    98) Product Information: LUMINAL(R)SODIUM powder for IV injection, phenobarbital sodium powder for IV injection. Hospira, Lake Forest, IL, 2008.
    99) Product Information: Mebaral(R) tablets, mephobarbital. Ovation Pharmaceuticals, Deerfield, IL, 2003.
    100) Product Information: Mysoline(R) oral tablets, primidone oral tablets. Valeant Pharmaceuticals North America (per DailyMed), Aliso Viejo, CA, 2010.
    101) Product Information: Mysoline(R), primidone. Wyeth-Ayerst Laboratories, Philadelphia, PA, 1994.
    102) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    103) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    104) Product Information: phenobarbital oral solution, phenobarbital oral solution. Pharmaceutical Associates, Inc (per manufacturer), Greenville, SC, 2010.
    105) Product Information: phenobarbital oral solution, phenobarbital oral solution. Pharmaceutical Associates,Inc, Greenville, SC, 2005.
    106) Product Information: phenobarbital oral tablets, phenobarbital oral tablets. West-ward Pharmaceutical,Corp, Eatontown, NJ, 2006.
    107) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    108) Ray MJ, Padin DR, & Condie JD: Charcoal bezoar. Small-bowel obstruction secondary to amitriptyline overdose therapy. Dig Dis Sci 1988; 33:106-107.
    109) Reynolds EH & Travers RD: Serum anticonvulsants concentrations in epileptic patients with mental symptoms. Br J Psychiatry 1974; 124:440.
    110) Roberts EA, Spielberg SP, & Goldbach M: Phenobarbital hepatotoxicity in an 8-month-old infant. J Hepatol 1990; 10:235-239.
    111) Rodichok LD: A case of barbiturate poisoning with a readily-accessible laboratory reagent (abstract). Clin Toxicol 1992; 30:455-458.
    112) Rzany B, Correia O, & Kelly JP: Risk of stevens johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy: a case-control study. Lancet 1999; 353:2190-2194.
    113) Sancak R, Kucukoduk S, & Tasdemir HA: Exchange transfusion treatment in a newborn with phenobarbital intoxication. Pediatr Emerg Care 1999; 15:268-270.
    114) Schwankhaus JD, Kattah JC, & Lux WE: Primidone/phenobarbital-induced peiodic alternating nystagmus. Ann Ophthalmol 1989; 21:230-232.
    115) Shaner DM, McCurdy SA, & Herring MO: Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin. Neurology 1988; 38:202-207.
    116) Sigg T & Leikin JB: Massive crystalluria in a patient taking primidone (letter). Ann Emerg Med 1999; 33:726-727.
    117) Smith DE & Wesson DR: A new method for treatment of barbiturate dependence. JAMA 1970; 213:294-295.
    118) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    119) Suzuki Y, Cox S, Hayes J, et al: Phenobarbital doses necessary to achieve 'therapeutic' concentrations in children. Dev Pharmacol Ther 1991; 17(1-2):79-87.
    120) Svendsen AB & Brochmann-Hanssen E: Gas chromatography of barbiturates II. Application to the study of their metabolites and excretion in humans. J Pharm Sci 1962; 494-495.
    121) Tang BK, Kalow W, & Grey AA: Metabolic fate of phenobarbital in man. Drug Metab Dispos 1979; 7:315-318.
    122) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    123) Thompson TM & Aks SE: Case files of the toxikon medical toxicology fellowship in chicago: the poisoned anesthesiologist. J Med Toxicol 2007; 3(1):31-36.
    124) Turner CR: Primidone intoxication and massive crystalluria. Clin Pediatr 1980; 19:706-710.
    125) Tyson RM, Shrader EA, & Perlman HN: Drugs transmitted throug breast-milk. II. Barbituates. J Pediatr 1938; 13:86-90.
    126) Vale JA, Krenzelok EP, & Barceloux GD: Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol 1999; 37:731-751.
    127) Veerman M, Espejo MG, & Christopher MA: Use of activated charcoal to reduce elevated serum phenobarbital concentration in a neonate. Clin Toxicol 1991; 29:53-58.
    128) Whyte MP & Dekaban AS: Metabolic fate of phenobarbital. Drug Metab Dispos 1977; 5:63-70.
    129) Winek CL: Sustained-release-barbiturate risk. Lancet 1967; 2:155.
    130) Yatzidis H: Bullous lesions in acute barbiturate poisoning. JAMA 1971; 27:211.
    131) Yerby MS, Leavitt A, & Erickson DM: Antiepileptics and the development of congenital anomalies. Neurology 1992; 42(suppl 5):132-140.
    132) Zawada ET, Nappi J, Done G, et al: Advances in the hemodialysis management of phenobarbital overdose. South Med J 1983; 76(1):6-8.
    133) van Heijst ANP, de Jong W, & Seldenrijk R: Coma and crystalluria: a massive primidone intoxication treated with haemoperfusion. J Toxicol Clin Toxicol 1983; 20:307-318.
    134) vandePlas A, Stolk L, Verhoeven MAM, et al: Successful treatment of acute phenobarbital intoxication by hemodiafiltration. Clin Toxicol (Phila) 2006; 44(1):93-94.