eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Barbiturate

Keith A Lafferty, MD, Adjunct Assistant Professor of Emergency Medicine, Temple University; Consulting Staff, Department of Emergency Medicine, South West Regional Medical Center

Updated: Oct 1, 2008

Introduction

Background

Barbiturates are the earliest class of sedative-hypnotic agents to be developed and were once extremely popular drugs of abuse. In general, sedative-hypnotic drugs are nonselective in their effects. At lower doses, a reduction in restlessness and emotional tension occurs. At increasingly higher doses, sedation is followed by increasing levels of anesthesia and eventually death.  

Benzodiazepines have largely replaced barbiturates for outpatient medical therapy, with a subsequent decline in barbiturate abuse. Stricter guidelines dictating barbiturate use have also contributed to their decreased availability.

Though tolerance occurs to the sedative-hypnotic effects, no tolerance appears to develop to the level at which lethal toxicity occurs.

Pathophysiology

Barbiturates bind to specific sites on gamma-aminobutyric acid (GABA)-sensitive ion channels found in the central nervous system (CNS), where they allow an influx of chloride into cell membranes and, subsequently, hyperpolarize the postsynaptic neuron.

GABA and glycine are the major inhibitory neurotransmitters in the CNS. Barbiturates enhance GABA-mediated chloride currents by binding to the GABA A receptor-ionophore complex and increasing the duration of ionophore opening. This potentiates and prolongs the inhibitory actions of GABA. At high doses, barbiturates stimulate GABA A receptors directly in the absence of GABA. Barbiturates also block glutamate (excitatory neurotransmitter) receptors in the CNS.

Barbiturates may be grouped functionally into long-acting and short-acting agents (consisting of ultra-short-, short-, and intermediate-acting agents). All of the drugs in this class are derivatives of barbituric acid, which was the original compound developed in 1864. However, the structure of each barbiturate differs and can be related to its effective duration of action.

Compared with long-acting agents, short-acting agents are more lipid soluble, more protein bound, have a higher pKa, a more rapid onset, shorter duration of action, and are metabolized almost entirely in the liver to inactive metabolites (which are excreted as glucuronides in the urine). Long-acting agents are less lipid soluble, accumulate more slowly in tissue, and are excreted more readily by the kidney as active drug. For instance, urinary excretion accounts for 20-30% of phenobarbital and 15-42% of primidone elimination (both long-acting agents). Specifically, the duration of action depends mainly on the alkyl groups attached to carbon #5. The structure of these alkyl groups determine lipid solubility of the drug in that the duration of action decreases as the total number of carbons at carbon #5 increases.

Chemical compounds of barbiturates.

An ultra–short-acting agent mainly used for procedural sedation, propofol, deserves mention. It is barbituratelike in its activity at the GABA receptor, its pharmacologic effects (respiratory depression and hypotension), and its lipophilic nature. However, its chemical structure is not analogous. Because of its short half-life of 3 minutes, it must be used in an intravenous infusion for long sedation. Additionally, its side effects, particularly respiratory depression, are compounded by benzodiazepines, opioids, and ethanol.

Propofol has specific pharmacokinetics that make it attractive for use in ED procedures. Notably, its rapid onset and short duration of action make it an excellent choice for this purpose. Miner et al recently compared the efficacy and safety of propofol and etomidate for ED procedures.¹ The success rate was 10% higher in the group given propofol, as 20% of the etomidate group experienced myoclonus. No significant increase in clinical respiratory depression or hypotension occurred in either arm of the study. 

Barbiturates stimulate the hepatic cytochrome P-450 mixed function oxidase microsomal enzyme system. Thus, barbiturates affect the drug levels of medications that are dependent on this system and typically increase their metabolism (eg, warfarin [Coumadin]). Note that barbiturates themselves are metabolized by this system, which may partially explain the drug tolerance often observed in chronic users.

Central nervous system effects

Barbiturates mainly act in the CNS, though they may indirectly affect other organ systems. Direct effects include sedation and hypnosis at lower dosages. The CNS depressant effect mimics that of ethanol. The lipophilic barbiturates, such as thiopental, cause rapid anesthesia because of their tendency to penetrate brain tissue quickly. Barbiturates all have anticonvulsant activity because they hyperpolarize cell membranes. Therefore, they are effective adjuncts in the treatment of epilepsy.

Pulmonary effects

Barbiturates can cause a depression of the medullary respiratory center and induce a respiratory depression. Patients with underlying chronic obstructive pulmonary disease (COPD) are more susceptible to these effects, even at doses that would be considered therapeutic in healthy individuals. Fatality from barbiturate overdose is usually secondary to respiratory depression and subsequent pneumonia.

Cardiovascular effects

Cardiovascular depression may occur following depression of the medullary vasomotor centers; patients with underlying congestive heart failure (CHF) are more susceptible to these effects. At higher doses, cardiac contractility and vascular tone are compromised, which may cause cardiovascular collapse.

Frequency

United States

Barbiturate abuse was popular in the 1960s and 1970s. Since then, however, its popularity has waned because of stricter guidelines for use and the introduction of benzodiazepines, which inherently have lower cardiorespiratory toxicity. These two factors have decreased barbiturate availability significantly and have led to less abuse. However, a recent gradual increase in barbiturate abuse has been observed among high school seniors.

Mortality/Morbidity

Fatality associated with barbiturate overdose is rare, but complications are abundant. Morbidity includes pneumonia, acute respiratory distress syndrome (ARDS), shock, hypoxia, and coma.

Clinical

History

• As with any overdose, it is important to attempt to ascertain the exact substance and quantity ingested, the time of ingestion and possible co-intoxicants, especially alcohol or other sedatives. Remember that some barbiturates are included in combination drugs (eg, Fioricet [butalbital, acetaminophen]; Donnatal [phenobarbital, hyoscyamine, scopolamine, atropine]) with components that have their own toxicity profile.
• Determine if the barbiturate overdose represents a suicide attempt.
• Do not overlook the patient's medical history. Most notably, a history of liver disease could potentially result in prolongation of toxic effects.

Physical

A full physical examination is warranted in any overdose. Record vital signs. The patient with barbiturate toxicity may present with any or all of the following symptoms:

• Neurologic
  • Lethargy
  • Coma
  • Hypothermia
  • Decreased pupillary light reflex
  • Nystagmus
  • Strabismus
  • Vertigo
  • Slurred speech
  • Ataxia
  • Decreased deep tendon reflexes
• Psychiatric
  • Impairment in thinking (eg, memory disturbances, poor judgment, limited attention span) (Delirium of any kind is a cardinal feature.)
  • Irritability
  • Combativeness
  • Paranoia
• Respiratory
  • Respiratory depression
  • Apnea
  • Hypoxia
  • Acute respiratory distress syndrome
• Cardiovascular
  • Tachycardia
  • Bradycardia
  • Hypotension
  • Diaphoresis
  • Shock
• Gastrointestinal - Decreased bowel sounds
• Skin - Barbiturate blisters (ie, bullous lesions typically found on the hands, buttocks, and knees)
• Mutagenicity - Barbiturates cause fetal craniofacial deformities and contribute to mental retardation.

Differential Diagnoses

Other Problems to Be Considered

Encephalopathy
Head trauma

Workup

Laboratory Studies

• Obtain a complete blood cell count (CBC), electrolytes, BUN, creatinine, and glucose screen to distinguish barbiturate toxicity from metabolic derangements that can cause similar symptoms.
• An arterial blood gas (ABG) measurement may help establish the presence and progress of ventilatory failure, hypoxia, and metabolic acidosis.
• Quantify serum alcohol and barbiturate concentrations (particularly phenobarbital), if possible. Phenobarbital concentrations may be useful to determine the appropriate treatment and, once initiated, efficacy of treatment (eg, urinary alkalinization, multidose charcoal, hemodialysis).
• A urine drug screen may help establish co-ingestants. Many clinicians routinely obtain acetaminophen and salicylate levels in all overdoses. This is particularly important because barbiturates/combination drugs may contain these analgesics.
• Blood ethanol concentration may help establish the presence of an important co-ingestant.
• Be aware of alcohol co-ingestion since a synergistic effect between alcohol and barbiturates may be expected.
• Obtain a pregnancy test in women of childbearing age.
• Barbiturate plasma concentrations
  • Barbiturate plasma concentrations aid in diagnosis and help determine whether to institute methods to enhance elimination and whether these methods are effective. They are not accurate for predicting the duration or severity of toxicity.
  • For short-acting barbiturates, a level of 35 mg/L carries an unfavorable prognosis.
  • For long-acting barbiturates, a level of 90 mg/L carries an unfavorable prognosis.
  • These levels do not apply to chronic barbiturate abusers.

Other Tests

• Electrocardiography
  • In the hypothermic patient, awareness of any rhythm disturbances is important.
  • When the core temperature is below 30ºC (90ºF), risk of ventricular fibrillation is increased.

Treatment

Prehospital Care

• Ensuring adequate airway, breathing, and circulation is essential.
  • Secure the airway and make sure the patient has good breath sounds bilaterally and is not hypotensive.
  • Perform an emergent endotracheal (ET) intubation if the patient has a significantly depressed level of consciousness and is not able to maintain the airway or has signs of increased intracranial pressure, ventilatory failure, or hypoxia.
  • Administer supplemental oxygen and obtain venous access.
  • In cases of hypotension, 2 large-bore intravenous lines are necessary for the administration of intravenous fluids and medications. Measure blood glucose level, and administer naloxone 2 mg IV to all patients with an altered mental status.

Emergency Department Care

Treatment of the patient with barbiturate toxicity is predominantly supportive. The mainstay of treatment underscores the importance of preventing hypoxemia and hypotension. Management strategies generally fall into 3 major areas: supportive care, decontamination, and enhancement of elimination. 

• Assess the airway and adequacy of respiration, and perform ET intubation if necessary. Check ET tube placement if the patient has been intubated. If the patient has not been intubated, provide supplemental oxygen and continue to monitor his or her airway status. Obtain intravenous access and an initial pulse oximeter reading, and place the patient on a cardiac monitor. Measure blood glucose, and administer naloxone 2 mg IV to all patients with altered mental status.
• Obtain a rectal temperature to check for hypothermia. If the patient is hypothermic, immediately initiate a careful rewarming (to avoid precipitating a fall in blood pressure).
• Aggressively initiate fluid therapy if the patient has a low blood pressure or appears to be in hypovolemic shock.
• Initiate treatment with pressors (eg, norepinephrine, dopamine) if shock persists or worsens. In general, initiate pressors after aggressive and adequate fluid resuscitation has been attempted and the patient is determined to be euvolemic.   
• GI decontamination
  • Since barbiturates are well adsorbed by activated charcoal, an initial dose of 1 g/kg should be administered. A cathartic is often administered to prevent constipation and to facilitate more rapid passage of the charcoal because barbiturates slow intestinal motility. Only perform GI decontamination after the airway is protected and hemodynamic stabilization has been addressed. Large-bore orogastric tube placement and gastric lavage have not been proven beneficial. They may increase risk of aspiration and have the added deleterious effect of delaying activated charcoal delivery. Activated charcoal orally or by nasogastric tube is recommended for all patients with potential barbiturate toxicity.
  • Multiple doses of activated charcoal (MDAC) have been shown to enhance elimination of phenobarbital and to reduce the serum half-life. The recommended adult dose is 15-20 g given orally every 6 hours. Note that a definite improvement in clinical outcome has not been shown in any studies using MDAC and that patients with barbiturate toxicity are at increased risk of impaction and gut perforation with the use of MDAC due to decreased GI motility.
  • Induction of emesis with ipecac syrup is contraindicated in these patients because their depressed neurologic response increases the risk of aspiration.
• Alkalinization of the urine enhances the elimination of phenobarbital and, likely, other long-acting barbiturates by ion trapping. Urinary alkalinization is not recommended for short-acting barbiturate toxicity.
  • Enhanced urinary elimination has been well established as a treatment for phenobarbital and butalbital. Phenobarbital's low pKa (7.2), higher water solubility, and slow hepatic metabolism with a subsequently long half-life allow a larger proportion of drug to be renally excreted.
  • Enhancement of urinary elimination may be accomplished with an initial sodium bicarbonate bolus of 1 mEq/kg followed by a constant infusion. This infusion may be made by adding 100-150 mEq of sodium bicarbonate to 850 mL of D5 and titrating to maintain a urine pH of greater than 7.5 with an arterial pH of less than 7.50. The goal should be a urine output of 150-250 mL/h.
  • Risks include hypokalemia, fluid overload, tetany, and the possibility of excessive elevations in arterial pH. 
• Extracorporeal elimination is rarely advised. Even though plasma clearance and elimination half-life has been shown to be decreased, no controlled studies demonstrating a patient benefit are available. Current literature suggests hemoperfusion is preferable to hemodialysis in terms of absolute clearance rates. Because the majority of patients do well with supportive care alone and blood levels do not correlate with duration of coma/ventilatory time, routine extracorporeal drug removal is not recommended. An argument can be made for this procedure in a patient who remains unstable despite aggressive supportive care, especially in a patient with rising drug blood levels. 

Consultations

• Consider consulting a toxicology service if available.
• Patients requiring admission are generally admitted to the ICU after consultation with an intensivist.
• If a patient is considered for hemodialysis or hemoperfusion, a nephrologist should be consulted.

Medication

GI decontamination with activated charcoal and urinary alkalinization may be beneficial in patient management. Also, pharmacologic support may be required in hypotensive patients with the use of pressor agents.

GI decontaminants

These agents are used to minimize the amount of toxin absorbed from the GI tract into systemic circulation. Depending upon the amount of drug ingested and time from ingestion to treatment, gastric lavage may be used. Activated charcoal is beneficial in adsorbing the ingested agent and is considered safer than emetics.

Activated charcoal (Liqui-Char)

Prevents absorption by adsorbing drug in the intestine. Multidose charcoal may interrupt enterohepatic recirculation and enhance elimination by enterocapillary exsorption. Theoretically, by constantly bathing the GI tract with charcoal, the intestinal lumen serves as a dialysis membrane for reverse-absorption of drug from intestinal villous capillary blood back into the intestine.
Supplied as an aqueous mixture or in combination with a cathartic (usually sorbitol 70%).

Dosing

Adult

1 g/kg PO; may repeat without cathartic in 2-4 h at one-half the original dose

Pediatric

1 g/kg PO (typical 12.5-25 g); <2 y, use without cathartic

Interactions

May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases adsorptive properties)

Contraindications

Documented hypersensitivity; poisoning or overdosage of mineral acids and alkalis; unprotected airway and absent gag reflex

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not very effective in poisonings of ethanol, methanol, and iron salts; induce emesis before administering; after emesis with ipecac, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns are black; protect airway in patients with depressed level of consciousness; if using multiple dose charcoal, monitor for presence of bowel sounds to minimize risk of charcoal ileus and vomiting with subsequent pulmonary aspiration

Alkalinizing agent

Sodium bicarbonate is the primary agent used clinically to enhance elimination. The goal of use is to alkalinize the urine to promote renal excretion and decrease elimination half-life of the barbiturate.

Sodium bicarbonate (Neut)

Goal is to maintain a urinary pH >7.5 and urine output >2 mL/kg/h. Monitor arterial or venous pH; a blood pH >7.55 may increase patient morbidity.

Dosing

Adult

1-2 mEq/kg IV bolus, followed by an IV drip of 1000 mL of D5W to which 100-150 mEq of sodium bicarbonate has been added; initiate drip rate at 3 times maintenance IVF rate and titrate drip rate to urinary pH

Pediatric

Administer as in adults

Interactions

Urinary alkalinization, induced by increased sodium bicarbonate concentrations, may cause decreased levels of lithium, tetracyclines, chlorpropamide, methotrexate, and salicylates; increases levels of amphetamines, pseudoephedrine, flecainide, anorexiants, mecamylamine, ephedrine, quinidine, and quinine; may inactivate sympathomimetic agents (eg, epinephrine, norepinephrine)

Contraindications

Documented hypersensitivity; alkalosis (pH >7.5); volume overload; severe hypernatremia; hypocalcemia; severe pulmonary edema; unknown abdominal pain

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Serum potassium level must be >4 mEq/L because urinary alkalinization cannot occur in the presence of hypokalemia; can cause alkalosis, decreased plasma potassium, hypocalcemia, and hypernatremia; caution in electrolyte imbalances such as in patients with CHF, cirrhosis, edema, corticosteroid use, or renal failure; when administering, avoid extravasation, which can cause tissue necrosis

Adrenergic Agonist Agents

These agents improve the hemodynamic status by increasing myocardial contractility and heart rate. This results in an increase in cardiac output. They also increase peripheral resistance by inducing vasoconstriction. Increased cardiac output and increased peripheral resistance lead to increased blood pressure.

Norepinephrine (Levophed)

Stimulates beta1-adrenergic and alpha-adrenergic receptors, which, in turn, increases cardiac muscle contractility, heart rate, and vasoconstriction. As a result, systemic blood pressure and coronary blood flow increase.

Dosing

Adult

0.5-30 mcg/min IV, titrate to effect

Pediatric

0.1 mcg/kg/min IV; titrate to effect

Interactions

Effects increase when administered concurrently with tricyclic antidepressants, MAO inhibitors, antihistamines, guanethidine, methyldopa, ergot alkaloids; atropine may block reflex tachycardia caused by norepinephrine and enhances pressor response

Contraindications

Documented hypersensitivity; peripheral or mesenteric vascular thrombosis because ischemia may be increased and the area of the infarct extended

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Correct blood-volume depletion, if possible, before giving norepinephrine therapy; extravasation may cause severe tissue necrosis and, thus, should be administered into a large vein; caution in occlusive vascular disease

Follow-up

Further Inpatient Care

• Patients with barbiturate toxicity generally need to be monitored closely and should be in an ICU setting.
• Hemodialysis and hemoperfusion enhance elimination of barbiturates (this is best established with phenobarbital). Hemoperfusion is more efficacious than hemodialysis but is associated with a higher incidence of complications. Hemodialysis or hemoperfusion may be of benefit for patients resistant to standard supportive care, in stage IV coma, or with shock, severe hypothermia, renal failure, and pulmonary edema. Some recommend extracorporeal removal to shorten the duration of coma when patients are apneic or have serum concentrations of barbiturate >100 mg/L.
• Barbiturate withdrawal is very similar to ethanol withdrawal. Specifically, one may see a reduction in intoxication and an apparent improvement in condition. This may be quickly followed by anxiety, weakness, tremors, nausea, vomiting, and abdominal cramps. In chronic, heavy users, 1.5-5 days after the last dose the patient may develop seizures, and, between 3 and 7 days after the last dose, delirium tremens may occur. Like ethanol, barbiturate withdrawal may be refractory to benzodiazepine therapy though these medications are first-line therapy.

Complications

• Overdose with barbiturate may be associated with multiple complications, the most common of which is pneumonia. Other life-threatening complications may include acute renal failure, pulmonary edema, and the sequelae of hypotension and respiratory depression. Survivors may develop dermal bullae.

Prognosis

• Mortality rates range from 1-10%.

Patient Education

• For excellent patient education resources, visit eMedicine's Substance Abuse Center, Poisoning - First Aid and Emergency Center, and Drug Overdose Center. Also, see eMedicine's patient education articles Barbiturate Abuse, Drug Overdose, Drug Dependence and Abuse, and Substance Abuse.

Miscellaneous

Medicolegal Pitfalls

• Failure to consider the presence of concomitant intoxicants: Polypharmacy is a key feature of many drug overdoses, and coingestion of CNS depressants exacerbates the effects of a barbiturate overdose. Also, combination drugs may contain acetaminophen, salicylates, and other drugs that may contribute their own significant toxicities.
• Failure to adequately address and secure an airway
• Failure to aggressively support blood pressure in hypotensive patients
• Failure to recognize and treat barbiturate withdrawal in patients at risk
• Failure to recognize and treat depression in suicidal patients

Special Concerns

• Pregnancy
  • Barbiturates freely cross the placenta and can have adverse effects on the fetus.
  • Barbiturate exposure is associated with a decrease in fetal intelligence, possible addiction, and possible withdrawal.
  • Overactivity, visible tremors, hypertonicity, hyperphagia, and vasomotor instability characterize neonatal withdrawal syndrome.
  • Withdrawal begins 4-7 days after birth and may last up to 4 months.
  • Support an infant with withdrawal symptoms by decreasing environmental stimulation and by increasing feedings.

Multimedia

Media file 1: Chemical compounds of barbiturates.

References

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Keywords

sedative-hypnotic drugs, barbiturate use, barbiturate overdose, barbiturate poisoning, barbiturate toxicity

Contributor Information and Disclosures

Author

Keith A Lafferty, MD, Adjunct Assistant Professor of Emergency Medicine, Temple University; Consulting Staff, Department of Emergency Medicine, South West Regional Medical Center
Keith A Lafferty, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Medical Association, and Pennsylvania Medical Society
Disclosure: Nothing to disclose.

Medical Editor

David C Lee, MD, Research Director, Department of Emergency Medicine, Assistant Professor, North Shore University Hospital and New York University Medical School
David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, ABAT, Director of Pharmacy, Sacred Heart Hospital
John T VanDeVoort, PharmD, ABAT is a member of the following medical societies: American Academy of Clinical Toxicology and American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center
Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the medical review of this article by Lada Kokan, MD.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Tucker Greene, MD, and Manisha Khatiwala, MD, to the development and writing of this article.

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