Continuing Education Activity

Barbiturates have been used historically to treat insomnia and psychiatric disorders, provide anesthesia, and manage alcohol withdrawal, elevated intracranial pressure, and seizures. Once extremely popular for a broad spectrum of indications in the late 20th century, the use of these drugs has declined mainly in favor of agents with more favorable safety profiles. However, barbiturates are still prescribed or obtained illicitly, and their misuse, whether intentional or not, can lead to grave harm or death. The presentation of barbiturate toxicity includes a spectrum of effects ranging from sedation to coma, respiratory depression to apnea, and vasodilation to profound hypotension. Thus, emergent and intensive care is required with significant intoxication.

This activity reviews the pathophysiology, symptomatology, evaluation, and management of barbiturate toxicity and is pertinent to the multidisciplinary team that provides care for patients presenting with barbiturate toxicity.

Objectives:

• Determine the epidemiology of barbiturate toxicity.

• Identify the pathophysiology of barbiturate toxicity.

• Identify the symptomatology of barbiturate toxicity.

• Develop effective management decisions for patients who present with barbiturate toxicity.

Introduction

Barbiturates are sedative-hypnotic drugs. They are derivates of barbituric acid and were introduced clinically in the early 1900s. Over the past 120 years, barbiturates have been used for a broad spectrum of indications, including insomnia, psychiatric disorders, anesthesia, alcohol withdrawal, seizures, and elevated intracranial pressure.[1] These drugs have a narrow therapeutic index, are highly addictive, and carry a high risk for toxicity. Thus, the use of these drugs has declined mainly in the last several decades in favor of agents with more favorable safety profiles. Despite a lower rate of barbiturate utilization overall, barbiturate toxicity is still a prevalent cause of significant morbidity and mortality that requires prompt and effective care to mitigate.

Etiology

Owing to the narrow therapeutic index of barbiturates, toxicity often occurs when these drugs are used recreationally (ie, for a euphoric high) or in the context of self-medication for anxiety or psychological stress. Physical dependence can also develop with sustained barbiturate use and place patients at higher risk of toxicity due to the need for escalating doses to achieve the desired effect(s).[1] Additionally, barbiturates are used intentionally to end life in suicide attempts.[2]

Barbiturate toxicity can also be iatrogenic.  Patients with comorbid conditions are at higher risk for toxicity than patients without.  For example, patients with chronic obstructive pulmonary disease are more vulnerable to barbiturate-induced respiratory depression even when prescribed therapeutic doses, patients with congestive heart failure are more vulnerable to barbiturate-induced cardiovascular effects, and patients with liver disease are at higher risk for toxicity due to a decrease in hepatic metabolism of barbiturate drugs.[3][4][5] Other iatrogenic causes of toxicity include inappropriate prescribing practices and coadministration of drugs that increase the effects of barbiturates like other sedatives, opiates, and anticholinergic drugs.

Epidemiology

The incidence of barbiturate toxicity is directly proportional to access to barbiturate drugs. In 1939, 100 tons of barbiturates were sold in the United States. By the mid-1960s, the amount of barbiturates sold in the United States increased to 2000 tons. Amidst increased production, prescriptions, and ease of obtaining barbiturates during this period, hospitalizations and deaths caused by barbiturates increased proportionally.[2] Interestingly, those at highest risk for barbiturate toxicity and barbiturate use disorder during this time were females older than 45 years who became dependent on barbiturates and young men who abused multiple drugs.[6]   

In the 1970s, newer drugs with safer profiles (eg, benzodiazepines) began replacing barbiturates for many indications. At the same time, many sought to confront the dangers of barbiturates. Programs such as the Campaign for the Use and Restriction of Barbiturates advocated for awareness about the dangers of barbiturates and sponsored efforts to decrease prescriptions. Legislation like the Medicines Act of 1968 and The Controlled Substance Act also facilitated increased oversight and tighter control of barbiturates.[2] Both prescription rates of barbiturates and related poisonings decreased in the late 1980s.[7] By 2002, the American Association of Poison Control Centers noted only 375 cases and 21 deaths from barbiturate toxicity.[2]

Only a few barbiturate drugs are currently used therapeutically, and the incidence of unintentional toxicity has decreased.[8] However, over the past few decades, a concerning trend involving suicide attempts with barbiturates has developed. A 2022 study from Australia noted that although hospitalization rates for barbiturate toxicity have decreased, two-thirds of the hospitalizations for barbiturate toxicity were from a suicide attempt.[9] Deaths by suicide from barbiturate toxicity have involved both young and older adults. Younger individuals who attempt suicide with these agents tend to have mental health conditions, are more likely to have relationship difficulties, and are more likely to have substance use disorders.[10] 

Older individuals tend to have more physical diseases, issues with bereavement and palliative care, and requirements for physical assistance.[10] Increased awareness of the ability of barbiturates to end life by suicide and increased access to barbiturate drugs via the Internet have also influenced this concerning trend.[11][9] In addition, suicide attempts with barbiturates have also been reported that involve people who have access to veterinary practices where barbiturates are used to euthanize animals, access to laboratories where barbiturates are used and stored, and physicians with prescribing privileges.[12][13][14][15]

Pathophysiology

Barbiturates enhance the activation of gamma-amino-butyric-acid type A (GABA_A) receptors, extending the duration of GABA_A chloride channels are open.[16] This leads to hyperpolarization of the postsynaptic neuronal cell membrane, which causes inhibition of excitatory cells in the central nervous system. Barbiturates also diminish responses to the excitatory neurotransmitter, glutamate, by inhibiting the glutamate receptor subtype alpha-amino-3-hydoroxy-5-methyl-4-isoxalolepropionic acid (AMPA) in the central nervous system.[17] These drugs also decrease calcium conductance via their effect on membrane calcium channels.[1] 

Barbiturates’ effects on the brain include confusion, decreased mental status, ataxia, dysarthria, coma, and loss of brain stem reflexes.[18] Depression of the respiratory medullary centers can cause decreased ventilation and apnea.[19] Barbiturates affect the cardiovascular system via vasodilation of peripheral blood vessels, depression of the brain’s cardiac and vasomotor centers, and a direct negative ionotropic effect on the heart.[20][21] Gastrointestinal motility is also slowed, and ileus may develop. Barbiturates can also cause hypothermia by depressing the temperature-regulating mechanism in the pons.[20]

Toxicokinetics

Historically, barbiturates have been grouped by duration of action as ultra–short-acting, short-acting, intermediate-acting, and long-acting agents. This classification was developed based on the results of animal studies that assessed the duration of hypnosis after barbiturate injection.[22] However, this time-based classification can be misleading in toxicity. Any barbiturate can have long-lasting effects given favorable toxicokinetics, and all barbiturates can cause significant and life-threatening toxicities.[22]

Ultra–short-acting barbiturates (eg, thiopental and methohexital) are given intravenously and used as anesthetics. Due to their ultra–short duration of effect, these drugs are rarely misused.[23] Short-acting and intermediate-acting barbiturates (eg, pentobarbital and secobarbital) have durations of effect of 2 to 6 hours and are used as sleeping aids and sedatives.[23] These drugs have been the most frequently misused and are the most common barbiturate agents that contribute to substance use disorder.[23] Long-acting barbiturates (eg, phenobarbital) have durations of effect of greater than 6 hours and are used as antiepileptic agents and in the treatment of alcohol withdrawal. Owing to their longer durations of effect, these agents are not misused as frequently as short- and intermediate-acting agents.[23]

All barbiturates are absorbed rapidly after oral ingestion and undergo enterohepatic recirculation.[1] Saturable hepatic microsomal pathway enzymes complete hepatic metabolism, and only a small proportion of barbiturate drugs are excreted unchanged in the urine. Barbiturates also induce the hepatic cytochrome P450 (CYP) enzyme system, which increases the metabolism of drugs that are CYP substrates.[3] Compared to long-acting barbiturate agents, shorter-acting agents are more lipid soluble, protein-bound, and undergo more hepatic metabolism.[24]

Though these differences exist, toxicologic management cannot be differentiated based on the duration of action alone due to the introduction of toxicokinetics. Respiratory acidosis brought about by respiratory depression may allow any barbiturate to cross the blood-brain barrier more easily. Additionally, even though short-acting agents undergo more hepatic metabolism than longer-acting agents, large ingestions of these agents may overwhelm saturable hepatic enzymes and prolong metabolism time. Finally, as barbiturate levels decrease, gastrointestinal motility may improve, which can lead to increased enterohepatic recirculation, barbiturate reabsorption, and further toxic effects.[20] However, hemodialysis is likely more effective for the removal of long-acting barbiturates because of their lower degree of protein binding and smaller volumes of distribution as compared to shorter-acting agents.[3]

Many times, coingestion of other substances can potentiate and complicate barbiturate toxicity. Such substances include ethanol,[24] marijuana,[25] opiates,[26][27] benzodiazepines,[28] disulfiram,[29] antihistamines,[30] histamines,[31] valerian extract,[32] anti-hypertensives,[33] and monoamine oxidase inhibitors.[34]

History and Physical

Assessment of the airway, breathing, circulation, and neurologic deficits should take priority for a patient with suspected barbiturate toxicity. Physical examination findings consistent with a sedative-hypnotic toxidrome include decreased ventilation, decreased blood pressure, abnormal heart rate, decreased bowel sounds, dry skin, and hypothermia.[3]

In addition, a thorough patient history should be obtained that includes the drugs taken, the amount taken, the route used for drug administration, past medical history, and other prescribed medications. Patients may not be able to provide an accurate history due to mental status alterations caused by barbiturate drugs. If the patient is unable to provide a history, providers should query information from other sources, including emergency medical services personnel, witnesses, relatives, and available medical and pharmacy records. Inspection of the patient’s belongings may also yield useful information.

Evaluation

The evaluation of the patient with barbiturate toxicity should confirm the diagnosis and assess the complications of toxicity, co-existing problems (eg, other ingestions, trauma), and complicating factors (eg, liver dysfunction, renal disease, pulmonary disease). A point-of-care glucose level should be determined for any patient with altered mental status to assess for hypoglycemia. A complete blood count and comprehensive metabolic panel should be obtained to further evaluate for hepatic disease, renal insufficiency, or other metabolic derangements. A pregnancy test should be conducted for any woman of childbearing age. A serum lactic acid level can help assess for cellular hypoperfusion. Creatine phosphokinase can identify rhabdomyolysis and should be drawn for unresponsive patients (ie, at risk for muscle compression) or present with physical trauma. Troponin can aid in assessing cardiac ischemia from hypoperfusion. An electrocardiogram can assess for abnormal heart rate and rhythm, and ischemia and give insight into the possibility of co-ingestion of other substances (eg, prolonged QTc interval and suspicion for tricyclic antidepressant co-ingestions). Laboratory screening for co-ingested agents should occur and include a blood ethanol level, urine drug screen inclusive of qualitative barbiturate testing, and acetaminophen and salicylate levels.  

Treatment / Management

Treatment of barbiturate toxicity consists mainly of supportive care as there is no specific antidote for barbiturate drugs.  However, clinicians should administer intravenous or intranasal naloxone if there is suspicion of opioid co-ingestion and impending respiratory failure. Endotracheal intubation and mechanical ventilation are necessary for patients who cannot protect their airways or progress to respiratory failure.  Hypotension should be treated with aggressive crystalloid fluid repletion and vasopressors. Hypothermia should be corrected with external rewarming.  

With appropriate supportive care alone, the mortality rate of barbiturate toxicity is low. However, select patients may benefit from treatment strategies to enhance barbiturate elimination. Current recommendations for enhanced elimination are based on the pharmacokinetic and toxicokinetic properties of each barbiturate drug, clinical trials, case reports, and expert opinion. Adequately controlled trials supporting these strategies are lacking, however.[35][3] Thus, enhanced elimination is only recommended for barbiturate toxicity with coma, need for respiratory support, or need for cardiovascular support (ie, when clinical benefits are likely to outweigh the risks of treatment).[35] 

Multiple-dose activated charcoal may decrease the elimination half-life in severe toxicity with long-acting barbiturates like phenobarbital.[35] Intermittent hemodialysis may benefit patients with toxicity from long-acting barbiturates as these agents may be more likely to be removed according to their pharmacokinetic properties.[3]  Urine alkalinization is no longer recommended for enhanced elimination of barbiturates because it may not significantly enhance renal clearance of these drugs and may cause complications.[3][36]

Differential Diagnosis

The differential diagnosis of barbiturate toxicity includes intoxication from other substances that may cause altered mental status including benzodiazepines, sleeping aids, alcohol, opioids, anticonvulsants, anticholinergic medications, and gamma-hydroxybutyric acid. Metabolic disorders should also be considered including hypoglycemia, myxedema coma, hypo- and hypernatremia, uremic encephalopathy, and hypercarbia. Meningitis, encephalitis, sepsis, seizures, brain masses, cerebral edema, and intracranial hemorrhages may cause altered mental status and should be investigated if deemed likely according to the patient's history. Psychiatric disorders such as functional coma and catatonia may also be considered.

Prognosis

In-hospital mortality for barbiturate toxicity with appropriate supportive care is 0.5 to 2%.[35] Older patients and patients with heart or pulmonary disease may experience more complications of barbiturate toxicity as compared to younger patients and patients without comorbid conditions.

Complications

Complications of barbiturate toxicity include aspiration pneumonia, myocardial infarction, cerebral edema, pulmonary edema, and multiorgan failure.[37] Barbiturate withdrawal may occur with the treatment of barbiturate toxicity and can be life-threatening.  Chronic users of barbiturates and patients who undergo enhanced elimination as part of toxicity management are most at risk for withdrawal.[35] Rebound barbiturate toxicity may also occur with treatment and over time. As barbiturate drugs are eliminated from the body, gastrointestinal motility and blood supply increase, which may result in increased residual-drug absorption.[20]

Consultations

Consultation with a toxicologist or poison center can greatly assist with management and treatment decisions for barbiturate toxicity. Patients with severe barbiturate toxicity, cardiovascular collapse, or respiratory failure will need care in an intensive care unit. In the case of a suicide attempt, consultation with a psychiatrist should occur after the patient’s physical medical condition improves.

Deterrence and Patient Education

Strategies employed to deter barbiturate misuse and toxicity include government action, drug safety initiatives, and education to the public and prescribers.  Under the Controlled Substances Act of 1970, the Drug Enforcement Administration began to regulate the production, distribution, and prescription of barbiturate drugs to improve patient safety.[38] Many countries have further reduced access to barbiturate drugs by withdrawing barbiturate-containing analgesics from the market.[39] Prescription drug monitoring programs have also been implemented to help deter individuals from obtaining prescriptions from multiple prescribers.[38] 

Development of abuse-deterrent drug formulations and the use of safer drug packaging (eg, blister packs, child-resistant caps, and cautionary labeling) have also been employed to deter misuse.[40] Finally, educational campaigns aimed at prescribers, public health advisories, and evidence-based clinical guidelines have assisted in increasing knowledge regarding the dangers of barbiturate drugs and safer treatment alternatives.[41][42]

Enhancing Healthcare Team Outcomes

Mortality rates associated with barbiturate toxicity are low with prompt and appropriate management by a well-prepared interprofessional team. Interprofessional team members essential in caring for patients who experience barbiturate toxicity include emergency medicine personnel, specialists in poison information, nurses, phlebotomists, laboratory technicians, radiology technicians, respiratory therapists, pharmacists, and physicians/advanced practice providers. Emergency medicine personnel obtain ingestion and past medical history, check the scene for pertinent information, and monitor and treat the patient during transport. Emergency department staff assess, further stabilize, and start to coordinate necessary care for the patient, including the involvement of specialists in poison information and toxicology. Nursing staff are fundamental in monitoring the patient, administering medications, assisting with procedures, and obtaining relevant patient information. Phlebotomists, laboratory technicians, and radiology technicians help obtain critical information needed for the comprehensive management of patients. Respiratory therapists assess and support oxygenation and ventilation, including assistance in initiating mechanical ventilation. Pharmacists assist with obtaining the patient's medication use history, assessing overdose severity, adjudicating medication therapy decisions, and obtaining medications efficiently. Physicians and advanced practice providers, including specialists in emergency medicine, toxicology, radiology, nephrology, and critical care medicine, lead the interprofessional team and make treatment decisions.