Barbiturate Toxicity

Back

Practice Essentials

Although barbiturates have largely been replaced, both medically and recreationally, by benzodiazepines, barbiturate toxicity still occurs. Clinicians need to be aware not only of the effects of barbiturates alone, but of compound drugs that include barbiturates and barbiturates taken together with alcohol or other synergistic sedatives (see Presentation). Treatment for poisoning remains supportive as there is no specific antidote (see Treatment and Medication).

Background

Barbiturates are the earliest class of sedative-hypnotic agents to be developed and were first used in medicine in the early 1900s and remained widely prescribed prior to the development of the less toxic hypnosedative drug class known as benzodiazepines. Their popularity peaked in the 1960s and 1970s for treatment of insomnia, anxiety, and seizures. Also known by street names such as, “reds”, “downers”, “barbs”, “yellow jackets”, “blue heavens”, and “nenbies”, barbiturates’ owe their various effects to a combination of a pyrimidinetrione ring structure and the overall size and structure of the C-5 position substituents.

Barbiturates once enjoyed a central place in the world of recreational drugs at the beginning of the 20th century and were used for a wide range of conditions until their liability for abuse led to an extensive number of barbiturate poisoning cases in the 1950s and 1960s. Today, barbiturates are commonly used in geriatric suicide involving medication overdose. In one New York City study, 27.2% of fatal overdose suicide cases in elderly persons were due to barbiturates.[1]

Interestingly, as abuse of phenobarbital wanes, cases of poisoning and abuse from other sedative-hypnotic drugs, such as propofol, ketamine, and gamma-hydroxybutyrate (GHB), have been reported to be steadily increasing. The effects that limit the clinical use of these drugs make them appealing to recreational drug users. In fact, 18% of academic anesthesiology departments surveyed have reported a case of propofol abuse or diversion in the past 10 years, a 5-fold increase from prior studies.[2] Recent high school surveys suggest abuse has been rising over the last 10 years, perhaps to counter the excitement caused by today’s synthetic stimulants.

Despite the decline in barbiturate use, cases of acute poisoning with severe toxicity are still noted at staggering rates in developing countries, where resource limitations and the affordability of barbiturates lend to their increased use as anticonvulsants.

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.

Toxicity within the barbiturate drug class varies depending on the onset and duration of the agent. For instance, patients with significant poisoning by short-acting barbiturates recover quickly (within 24-48h) in a setting devoid of complications, as opposed to those poisoned with longer-acting agents, such as phenobarbital, which requires more aggressive interventions such as ventilatory support and admission to the ICU.

Benzodiazepines have largely replaced barbiturates both medically and recreationally due to their wider therapeutic window, lower drug tolerance, and lower propensity for abuse. Although tolerance to the sedative-hypnotic effects does occur, no tolerance appears to develop to the level at which lethal toxicity occurs. Stricter guidelines dictating barbiturate use have also contributed to its decreased availability.

Procedural sedation and analgesia are essential to ameliorating painful procedures for both adults and children in the emergency department. The favorable pharmacokinetics and adverse effect profile of propofol allows it to be used clinically for procedural sedation. However, propofol contains a relatively narrow therapeutic window and is associated with a dose-dependent risk of bradypnea and hypotension, especially in elderly persons.

While clinically barbiturate use has been largely replaced by benzodiazepines and propofol, there are two distinct scenarios in which their use may still be warranted: status epilepticus and elevated intracranial pressure (ICP).

Being that status epilepticus is the second most frequent neurological emergency and that refractory status epilepticus (RSE) carries a 25% mortality rate, studies indicate that barbiturates still may have a role in this scenario.[3, 4] Supporting this, toxicological or withdraw seizures seem to be more amendable to GABA receptor activation, compared with idiopathic or traumatic seizures, which usually start with a focus of isolated abnormal neurons and are more amendable to blockade of voltage-dependent sodium channels.[5]

In a meta-analysis of the use of barbiturates, propofol, or midazolam in RSE there was no difference in short-term mortality, although immediate effectiveness favored barbiturates.[3] In addition, pentobarbital’s activity at the GABA receptor is less dependent on the presence of adequate normal quantities of GABA, a theoretical benefit in treating of seizures induced by toxins that deplete GABA. Propofol has the advantage of a short half-life which allows for rapid weaning; however, the risks of propofol infusion syndrome needs to be monitored. This has to be weighed against barbiturate long elimination time secondary to its lipophilic nature and high adipose storage (thiopental has a 36-hour elimination half life after continuous infusion).[3]

Although guidelines for management of traumatic brain injury (TBI) recommend that high-dose barbiturate therapy may be considered to lower ICP, the evidence for decreasing morbidity and mortality is lacking. In one study, high-dose barbiturate treatment caused a decrease in ICP in 69% of patients but also caused longer periods of a decreased mean arterial pressure (MAP) despite increased use of high-dose vasopressors. There was no significant effect on outcome.[6] Overall, there is no evidence that barbiturate therapy in patients with TBI improves outcome.[6] This probably is from the fact that cerebral perfusion pressure (CPP) remains unchanged as any benefit in decreasing ICP is offset by a decrease in MAP (CPP=MAP-ICP).

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. Although the clinical effects of barbiturates and benzodiazepines are similar and result from hyperpolarization of the neuron, there are subtle differences in terms of receptor binding. Barbiturates increase the duration of Cl ion channel opening at the GABA receptor, which, in turn, increases the efficacy of GABA. Benzodiazepines, on the other hand, increase the frequency of Cl ion channel openings at the GABA receptor, which, in turn, increases the potency of GABA.[7]

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 at the beta subunit is distinct from the GABA and benzodiazepine binding site and increases 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 (principle excitatory neurotransmitter) receptors (AMPA) in the CNS.

Barbiturates may be grouped functionally into long- and short-acting agents (consisting of ultrashort-, short-, and intermediate-acting agents). However, the relevance of this classification system in terms of prognosis remains to be well defined as the agents’ duration of action is only partially correlated with half-life (the remaining differences are accounted for with tissue binding and distribution).[8] 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

See image below.



View Image

Chemical compounds of barbiturates.

Short-acting agents have an elimination half-life of less than 40 hours compared with long-acting agents, which have an elimination half-life of longer than 40 hours.

Although technically not a barbiturate, the barbiturate-like sedative propofol deserves special mention. It is an ultra–short-acting agent usually used for general anesthesia, procedural sedation, or reduction of intracranial pressure after traumatic brain injury. Propofol binds to GABA A receptors directly and inhibits calcium flow through slow calcium ion channels.[9] Both barbiturates and propofol also interact with N -methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainite receptors.

Propofol is highly lipid soluble with an onset of less than 1 minute and a quick offset of action. 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 compared the efficacy and safety of propofol and etomidate for ED procedures.[10] 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.

Another agent widely used for procedural sedation and increasingly, as a drug of abuse is ketamine. Ketamine acts primarily on the NMDA receptor by noncompetitive antagonism that decreases the effect of the excitatory neurotransmitter glutamate as it is a derivative of PCP. It also binds to opioid receptors. At low doses (0.1-0.5 mg/kg/h), ketamine induces distortion of time and space, hallucinations, and mild dissociative effects. At larger doses, it induces a more severe dissociation wherein users experience intense detachment, such that their perceptions are completely disconnected from reality.[11] Ketamine causes a sympatheticlike response by inducing bronchodilatation and increasing heart rate and blood pressure. Increased salivation and minimal transient respiratory depression followed by respiratory stimulation may also occur.

GHB interacts with GHB-specific receptors and GABA B receptors. GHB also affects dopamine, opioid, serotonin, acetylcholine, and glutamate neurotransmitter systems. Additional GABA-like effects occur at high doses through the conversion of GHB to GABA. When consumed in oral doses as low as 25 mg/kg, confusion, sedation, respiratory depression, and dizziness have been shown to result. At higher dosages of 50-63 mg/kg, loss of consciousness and profound coma has been documented.[12] 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 long-term 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. Elderly people have proportionally more adipose tissue and therefore are more susceptible to this narrow therapeutic index. Barbiturates all have anticonvulsant activity because they hyperpolarize cell membranes. Therefore, they are effective adjuncts in the treatment of epilepsy.

The high doses of barbiturates used in the care of neurocritical patients have in recent years been reported to possibly lead to the accumulation of propylene glycol. Propylene glycol is a commonly used vehicle in the intravenous formulations of many medications, including phenobarbital and pentobarbital. Increased levels of propylene glycol may yield a less recognized complication of therapy, as propylene glycol may exacerbate existing complications associated with large doses of barbiturates, to include hypotension and respiratory depression. In addition, propylene glycol toxicity, ironically, may induce seizures that the barbiturates are intended to treat.[13]

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 and one must respect its narrow therapeutic index as even a slight overdose can cause coma or death.

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. The combination of the decreased vascular resistance by means of peripheral dilation and inherent negative ionotropic properties of barbiturates yields to the development of another recognized complication, hypotension.

Epidemiology

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. Street names for phenobarbital include "purple hearts" and "golfballs", while pentobarbital is called "nembies", "yellow jackets", "abbots", or "Mexican yellows".

Since 1965, ketamine has emerged as a common recreational drug among young people and adolescents. Often used in combination with other so-called club drugs such as gamma-hydroxybutyric acid, lysergic acid diethylamide (LSD), and ecstasy, ketamine is commonly called "special K", "kit kat", or "vitamin K".

Propofol abuse has been highlighted by the fatal case of the mega pop star Michael Jackson; however, propofol dependence has been a known problem, especially among anesthesiologists, who have constant access to it. Nearly 1 in 5 of all anesthesiology departments in the United States have reported a case of propofol abuse or diversion. Due to the drug's narrow therapeutic window, at least 7 physician fatalities were reported in 10 years. The trade name for propofol is Diprivan.

Mortality/Morbidity

Fatality associated with barbiturate overdose is rare, but complications are abundant.[14] Morbidity includes immunosuppression with frequent nosocomial infections such as pneumonia, acute respiratory distress syndrome (ARDS), shock, hypoxic damage secondary to prolonged hypotension, and coma. Other complications include iatrogenic ones from forced diuresis, gastric lavage, and central venous access.

Although propofol is generally considered a safe agent, an entity called propofol infusion syndrome (PRIS) has been recognized, describing acute onset of metabolic acidosis with refractory bradycardia progressing to asystole associated with propofol infusions greater than 48 hours.[15] More than 40 cases have been identified in the literature since 1992 with wide-varied clinical manifestations including rhabdomyolysis, myocardial failure, acute renal failure, cardiac arrest, dyslipidemias, and hypotension.

In a review of 153 case reports published between 1990 and 2014, the more recently published cases describe older patients developing PRIS at lower doses of propofol, in whom arrhythmia, hypertriglyceridaemia and fever are less frequently seen and survival more likely. The propofol infusion rate and duration, the presence of traumatic brain injury and fever were factors independently associated with mortality. Cardiac failure and metabolic acidosis occur early in a dose-dependent manner, while arrhythmia, other electrocardiographic changes and rhabdomyolysis appear more frequently after prolonged propofol infusions, irrespective of dose. Fatality rates decreased over time from 74% before 2001, to 64% between 2001 and 2006, and to 32% in cases reported after 2006.[16] Similarly,a European database of suspected adverse drug reactions run by The European Medicines Agency registered a total of 394 cases of PRIS between December 2001 and March 2015, of which 137 (35%) were fatal.[17]  

In addition, multiple cases have been reported in the literature concerning the presentation of ketamine-related bladder dysfunction and lower urinary tract destruction in association with chronic abuse of a new entity of street ketamine. However, no current studies demonstrate a statistically significant difference in urinary system presentations between ketamine and a control group.[9]

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 synergistic toxins such as 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.

Other important aspects of the history include the following:

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 signs and symptoms listed delow.

Neurologic manifestations may include the following:

Psychiatric manifestations may include the following:

Respiratory manifestations may include the following:

Cardiovascular manifestations may include the following:

Other manifestations may include the following:

Laboratory Studies

See the list below:

Barbiturate plasma concentrations aid in diagnosis and help determine whether to institute methods to enhance elimination and if so, whether these methods are effective. They are not accurate for predicting the duration or severity of toxicity. Considerations are as follows:

Other Tests

 

 

Electrocardiography

Considerations regarding electrocardiography include the following:

Prehospital Care

Ensuring adequate airway, breathing, and circulation is essential. Emergency medical personnel should do the following:

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.

Supportive care

Assess the airway and adequacy of respiration and perform ET intubation if necessary. If the patient has not been intubated, provide supplemental oxygen and continue to monitor the 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) 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.

Gastrointestinal decontamination

Despite the fact that barbiturates are well adsorbed by activated charcoal and a study in which volunteers given 50 g of activated charcoal showed a mean reduction in absorption of 47.3%, 40.07%, and 16.5% when it was administered at 30 minutes, 60 minutes, and 120 minutes, respectively, current guidelines in overdose management question its benefit. There is no evidence that the administration of activated charcoal improves clinical outcome. Indeed, its use has decreased to less than 5% of all reported ingestions in recent years.[18]

A single dose of activated charcoal may be given within an hour of overdose if the clinician estimates that a clinically significant fraction of the ingested substance remains in the GI tract, the toxin is adsorbed by charcoal, further absorption may result in clinical deterioration, and the patient has no depression of his or her mental status. Activated charcoal is a hydrocarbon with a high aspiration ratio; hence, the administration of charcoal is contraindicated in any patient who does not have an intact or protected airway.

Of note, giving this noninnocuous substance to any patient with any ingestion must be weighed against the fact that general supportive care and the use of a few specific antidotes has decreased the mortality rate in unselected overdose patients to less than 1% if the patient arrives at the hospital in time for the clinician to intervene.[18]

Although multiple doses of activated charcoal (MDAC) have been shown to enhance elimination of phenobarbital and to reduce the serum half-life, a definite improvement in clinical outcome has not been shown in any studies using MDAC.

Induction of emesis with ipecac syrup is contraindicated in these patients because their depressed neurologic response increases the risk of aspiration.

Enhancement of elimination

The goal of enhanced elimination is to decrease the duration of ventilatory support, mitigate hypotension, and decrease morbidity/mortality. Since barbiturates are weak acids, enhanced renal elimination occurs through alkalinization of the urine. The presence of more protons and less additional substituents on the C-5 position decreases the pKa, thus increasing the acidity of the barbiturate structure. In this way, phenobarbital and, likely, other long-acting barbiturates, can be converted to water-soluble salts with the appropriate base and eliminated through ion trapping by decreasing tubular reabsorption, analogous to that of salicylate poisoning treatment.

Enhanced urinary elimination has been well established as a treatment for phenobarbital and butalbital. Phenobarbital's low pKa (4.2), higher water solubility, and slow hepatic metabolism with a subsequently long half-life allow a larger proportion of drug to be renally excreted. Urinary alkalinization is not recommended for short-acting barbiturates.

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 up to 30%, no controlled studies demonstrating a patient benefit are available.[8] Current literature suggests hemoperfusion is marginally preferable to hemodialysis in terms of absolute clearance rates (clearance decreases when the duration of treatment exceeds 2-3 h). 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.

While there remains no specific antidote for barbiturate toxicity, numerous publications have outlined the possible clinical use of intravenous lipid emulsion (ILE) as an antidote. The suggested mechanism of ILE in lipophilic drug toxidrome is the formation of a lipid sink that acts to sequester lipophilic toxins (such as local anesthetics), thereby decreasing the targeted drug concentration and toxicity.[19] However, although ILE continues to be a therapy of interest, its role at this time is limited. A review of approximately 42 case reports with ILE use showed a possible benefit. It has been used in patients with negative hemodynamics whose condition remains unresponsive to conventional supportive therapy.

Consultations

See the list below:

Medication Summary

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.

Activated charcoal (Liqui-Char)

Clinical Context:  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%).

Sodium bicarbonate (Neut)

Clinical Context:  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. This therapy is specific to long-acting barbiturates given their lower pKa, with ion trapping being the intended mechanism.

Norepinephrine (Levophed)

Clinical Context:  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.

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 withdrawal, barbiturate withdrawal may be refractory to standard-dose 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

With early supportive care, overall in-hospital mortality rates from barbiturate poisoning are less than 0.5-2%.

Patient Education

For patient education resources, see the Substance Abuse Center, Poisoning - First Aid and Emergency Center, and Drug Overdose Center, as well as Barbiturate Abuse, Drug Overdose, Drug Dependence and Abuse, and Substance Abuse.

Author

Keith A Lafferty, MD, Adjunct Assistant Professor of Emergency Medicine, Temple University School of Medicine; Medical Student Director, Department of Emergency Medicine, Gulf Coast Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Keisha Bonhomme, MD, Resident Physician, Department of Internal Medicine, St Vincent’s Medical Center

Disclosure: Nothing to disclose.

Piotr Kopinski, Perelman School of Medicine, University of Pennsylvania

Disclosure: Nothing to disclose.

Specialty Editors

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

Disclosure: Nothing to disclose.

Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Additional Contributors

David C Lee, MD, Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School

Disclosure: Nothing to disclose.

Rehab Abdel-Kariem, MD, Resident Physician, Department of Emergency Medicine, Temple University Hospital

Disclosure: Nothing to disclose.

References

  1. Harrison P. Barbiturates Still Drugs of Choice in Geriatric Suicide. Medscape Medical News. March 11, 2010.
  2. Wischmeyer PE, Johnson BR, Wilson JE, et al. A survey of propofol abuse in academic anesthesia programs. Anesth Analg. 2007 Oct. 105(4):1066-71, table of contents. [View Abstract]
  3. Rossetti AO, Lowenstein DH. Management of refractory status epilepticus in adults: still more questions than answers. Lancet Neurol. 2011 Oct. 10(10):922-30. [View Abstract]
  4. Cock HR. Drug-induced status epilepticus. Epilepsy Behav. 2015 Aug. 49:76-82. [View Abstract]
  5. Sharma AN, Hoffman RJ. Toxin-related seizures. Emerg Med Clin North Am. 2011 Feb. 29(1):125-39. [View Abstract]
  6. Majdan M, Mauritz W, Wilbacher I, Brazinova A, Rusnak M, Leitgeb J. Barbiturates use and its effects in patients with severe traumatic brain injury in five European countries. J Neurotrauma. 2013 Jan 1. 30(1):23-9. [View Abstract]
  7. Sharma AN, Hoffman RJ. Toxin-related seizures. Emerg Med Clin North Am. 2011 Feb. 29(1):125-39. [View Abstract]
  8. Roberts DM, Buckley NA. Enhanced elimination in acute barbiturate poisoning - a systematic review. Clin Toxicol (Phila). 2011 Jan. 49(1):2-12. [View Abstract]
  9. Ng SH, Tse ML, Ng HW, Lau FL. Emergency department presentation of ketamine abusers in Hong Kong: a review of 233 cases. Hong Kong Med J. 2010 Feb. 16(1):6-11. [View Abstract]
  10. Miner JR, Danahy M, Moch A, Biros M. Randomized clinical trial of etomidate versus propofol for procedural sedation in the emergency department. Ann Emerg Med. 2007 Jan. 49(1):15-22. [View Abstract]
  11. Morgan CJ, Curran HV. Ketamine use: a review. Addiction. 2012 Jan. 107(1):27-38. [View Abstract]
  12. Zvosec DL, Smith SW, Porrata T, Strobl AQ, Dyer JE. Case series of 226 gamma-hydroxybutyrate-associated deaths: lethal toxicity and trauma. Am J Emerg Med. 2011 Mar. 29(3):319-32. [View Abstract]
  13. Bledsoe KA, Kramer AH. Propylene glycol toxicity complicating use of barbiturate coma. Neurocrit Care. 2008. 9(1):122-4. [View Abstract]
  14. Mowry JB, Spyker DA, Brooks DE, Zimmerman A, Schauben JL. 2015 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 33rd Annual Report. Clin Toxicol (Phila). 2016 Dec. 54 (10):924-1109. [View Abstract]
  15. Fudickar A, Bein B. Propofol infusion syndrome: update of clinical manifestation and pathophysiology. Minerva Anestesiol. 2009 May. 75(5):339-44. [View Abstract]
  16. Krajčová A, Waldauf P, Anděl M, Duška F. Propofol infusion syndrome: a structured review of experimental studies and 153 published case reports. Crit Care. 2015 Nov 12. 19:398. [View Abstract]
  17. European database of suspected drug reaction reports. European Medicines Agency. Available at https://bi.ema.europa.eu/analyticsSOAP/saw.dll?PortalPages. Accessed: November 28, 2016.
  18. Chyka PA, Seger D, Krenzelok EP, Vale JA. Position paper: Single-dose activated charcoal. Clin Toxicol (Phila). 2005. 43(2):61-87. [View Abstract]
  19. Cave G, Harvey M, Graudins A. Intravenous lipid emulsion as antidote: a summary of published human experience. Emerg Med Australas. 2011 Apr. 23(2):123-41. [View Abstract]
  20. Barbiturates. In: Ford M, Delaney KA, Ling LJ, Erickson T. Clinical Toxicology. Elsevier Health Sciences; 2000. Chap 68.
  21. Barr J, Egan TD, Sandoval NF, et al. Propofol dosing regimens for ICU sedation based upon an integrated pharmacokinetic-pharmacodynamic model. Anesthesiology. 2001 Aug. 95(2):324-33. [View Abstract]
  22. Coupey SM. Barbiturates. Pediatr Rev. 1997 Aug. 18(8):260-4; quiz 265. [View Abstract]
  23. Devlin JW, Roberts RJ. Pharmacology of commonly used analgesics and sedatives in the ICU: benzodiazepines, propofol, and opioids. Crit Care Clin. 2009 Jul. 25(3):431-49, vii. [View Abstract]
  24. Fassoulaki A, Theodoraki K, Melemeni A. Pharmacology of sedation agents and reversal agents. Digestion. 2010. 82(2):80-3. [View Abstract]
  25. Feiner JR, Bickler PE, Estrada S, Donohoe PH, Fahlman CS, Schuyler JA. Mild hypothermia, but not propofol, is neuroprotective in organotypic hippocampal cultures. Anesth Analg. 2005 Jan. 100(1):215-25. [View Abstract]
  26. Frank LR, Strote J, Hauff SR, Bigelow SK, Fay K. Propofol by infusion protocol for ED procedural sedation. Am J Emerg Med. 2006 Sep. 24(5):599-602. [View Abstract]
  27. Frazee BW, Park RS, Lowery D, Baire M. Propofol for deep procedural sedation in the ED. Am J Emerg Med. 2005 Mar. 23(2):190-5. [View Abstract]
  28. Frölich MA, Price DD, Robinson ME, Shuster JJ, Theriaque DW, Heft MW. The effect of propofol on thermal pain perception. Anesth Analg. 2005 Feb. 100(2):481-6. [View Abstract]
  29. Fujii Y, Uemura A. Effect of metoclopramide on pain on injection of propofol. Anaesth Intensive Care. 2004 Oct. 32(5):653-6. [View Abstract]
  30. Gary NE, Tresznewsky O. Clinical aspects of drug intoxication: barbiturates and a potpourri of other sedatives, hypnotics, and tranquilizers. Heart Lung. 1983 Mar. 12(2):122-7. [View Abstract]
  31. Lee DC. Sedative-hypnotic agents. In: Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR, eds. Goldfrank's Toxicologic Emergencies. 10th ed. New York, NY: McGraw-Hill Education; 2015. Chapter 74.
  32. Inagawa G, Sato K, Kikuchi T. Chronic ethanol consumption does not affect action of propofol on rat hippocampal acetylcholine release in vivo. Br J Anaesth. 2002. 93(5):737-9.
  33. Kanbak M, Saricaoglu F, Avci A, Ocal T, Koray Z, Aypar U. Propofol offers no advantage over isoflurane anesthesia for cerebral protection during cardiopulmonary bypass: a preliminary study of S-100beta protein levels. Can J Anaesth. 2004 Aug-Sep. 51(7):712-7. [View Abstract]
  34. Khantzian EJ, McKenna GJ. Acute toxic and withdrawal reactions associated with drug use and abuse. Ann Intern Med. 1979 Mar. 90(3):361-72. [View Abstract]
  35. Kotani Y, Shimazawa M, Yoshimura S, Iwama T, Hara H. The experimental and clinical pharmacology of propofol, an anesthetic agent with neuroprotective properties. CNS Neurosci Ther. 2008 Summer. 14(2):95-106. [View Abstract]
  36. Lowinson JH, Ruiz P, Millman RB, et al. Epidemiology. Substance Abuse: A Comprehensive Textbook. 3rd ed. Lippincott Williams & Wilkins; 1997. 10-16.
  37. Lowinson JH, Ruiz P, Millman RB, et al. Sedative hypnotics and tricyclics. Substance Abuse: A Comprehensive Textbook. 3rd ed. Lippincott Williams & Wilkins; 1997. 223-30.
  38. Miner JR, Danahy M, Moch A, Biros M. Randomized clinical trial of etomidate versus propofol for procedural sedation in the emergency department. Ann Emerg Med. 2007 Jan. 49(1):15-22. [View Abstract]
  39. Morgan CJ, Muetzelfeldt L, Curran HV. Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study. Addiction. 2010 Jan. 105(1):121-33. [View Abstract]
  40. Motsch J, Roggenbach J. [Propofol infusion syndrome]. Anaesthesist. 2004 Oct. 53(10):1009-22; quiz 1023-4. [View Abstract]
  41. Nishiyama T, Misawa K, Yokoyama T, Hanaoka K. Effects of combining midazolam and barbiturate on the response to tracheal intubation: changes in autonomic nervous system. J Clin Anesth. 2002 Aug. 14(5):344-8. [View Abstract]
  42. Roberts I. Barbiturates for acute traumatic brain injury. Cochrane Database Syst Rev. 2000. CD000033. [View Abstract]
  43. Romero CE, Baron JD, Knox AP, Hinchey JA, Ropper AH. Barbiturate withdrawal following Internet purchase of Fioricet. Arch Neurol. 2004 Jul. 61(7):1111-2. [View Abstract]
  44. Solomon S. Butalbital-containing agents: should they be banned? No. Curr Pain Headache Rep. 2002 Apr. 6(2):147-50. [View Abstract]
  45. Subramaniam K, Gowda RM, Jani K, Zewedie W, Ute R. Propofol combined with lorazepam for severe poly substance misuse and withdrawal states in intensive care unit: a case series and review. Emerg Med J. 2004 Sep. 21(5):632-4. [View Abstract]
  46. Young WB, Siow HC. Should butalbital-containing analgesics be banned? Yes. Curr Pain Headache Rep. 2002 Apr. 6(2):151-5. [View Abstract]
  47. Hayes BD, Gosselin S, Calello DP, Nacca N, Rollins CJ, Abourbih D, et al. Systematic review of clinical adverse events reported after acute intravenous lipid emulsion administration. Clin Toxicol (Phila). 2016 Jun. 54 (5):365-404. [View Abstract]

Chemical compounds of barbiturates.

Chemical compounds of barbiturates.