BARBITURATES INTOXICATION

BARBITURATES INTOXICATION

Background: Barbiturates are the earliest known class of sedative-hypnotic agents and were once extremely popular drugs to abuse. Benzodiazepines largely have replaced barbiturates for outpatient medical therapy, which has created a decline in barbiturate abuse. Stricter guidelines dictating barbiturate use have led to decreased availability as well.

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 neurotransmitter 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; barbiturates inhibit neuronal depolarization by potentiating and prolonging the 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 ultrashort, short, and intermediate-acting agents). Short-acting agents have an elimination half-life less than 40 hours compared to long-acting agents, which have an elimination half-life longer than 40 hours.

An ultrashort-acting agent mainly used for procedural sedation, propofol, deserves mention here. It is barbiturate-like 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. .

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 usually by increasing their metabolism (eg, Coumadin).

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 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. Barbiturate overdose fatality is usually secondary to respiratory depression.

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:

• In the US: Barbiturate abuse was popular in the 1960s and 1970s. Since then, however, its popularity has waned because of stricter guidelines for use and the advent 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

• As with any overdose, make and effort to ascertain the exact substance and quantity ingested, the time of ingestion, and possible co-intoxicants, especially alcohol. Remember that some barbiturates are included in combination drugs (eg, Fioricet [butalbital, acetaminophen]; Donnatal [phenobarbital, hyoscyamine, scopolamine, atropine]) with components that also may have toxicity.

• Investigate to 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 suggest potential 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) (A delirium of any fashion 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 craniofacial deformities and contribute to mental retardation.

DIFFERENTIAL DIAGNOSIS

Encephalitis
Hypoglycemia
Hypothermia
Hypothyroidism and Myxedema Coma
Shock, Cardiogenic
Stroke, Hemorrhagic
Toxicity, Benzodiazepine
Toxicity, Carbon Monoxide
Toxicity, Clonidine
Toxicity, Cyclic Antidepressants
Toxicity, Neuroleptic Agents

Lab Studies:

• Obtain a complete blood 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) may help determine 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 the aforementioned analgesics.

• Blood ethanol concentration may help establish co-ingestants.

• Be aware of alcohol co-ingestion; a synergistic effect between alcohol and barbiturates may exist.

• 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 is unfavorable.

• For long-acting barbiturates, a level of 90 mg/L is unfavorable.

• These levels do not apply to chronic barbiturate abusers.

Other Tests:

• Electrocardiogram

• In the hypothermic patient, awareness of any rhythm disturbances is important.

• When the core temperature is below 30sC (90sF), 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 IVs are necessary. Measure blood glucose and administer naloxone 2 mg IV to all patients with altered mental status.

Emergency Department Care: Treatment for the patient with barbiturate toxicity is predominantly supportive.

• Assess the airway and adequacy of respiration and perform ET intubation as necessary. Check ET tube placement if patient has been intubated. If patient has not been intubated, provide supplemental oxygen. Obtain IV access and an initial pulse oximeter reading and place patient on a 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 perform 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.

• GI decontamination

• Perform GI decontamination once the airway is protected and hemodynamic stabilization 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.

• Induction of emesis with ipecac syrup is contraindicated in these patients because the depressed neurologic response increases 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 for phenobarbital and butalbital. Phenobarbital's low pKa (7.2), higher water solubility, and slow hepatic metabolism and subsequently long half-life allow a larger proportion to be renally excreted.

• Urinary elimination may be accomplished by an infusion of dextrose and sodium bicarbonate at 200-300 cc/h.

MEDICATION:

GI decontamination (by multidose activated charcoal administration) and urinary alkalinization may be beneficial in patient management.

GI decontaminants -- 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 employed. Activated charcoal is beneficial in adsorbing the ingested agent and is considered safer than emetics.

Dose:1g/kg PO; may repeat in 2-4 h at one-half original dose

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.

Hemodialysis or hemoperfusion is recommended 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.

Complications:

• Several complications of barbiturate overdose exist, the most common of which is pneumonia. Other associated life-threatening complications include acute renal failure and pulmonary edema.

Prognosis:

• Mortality rates range from 1-10%.

Patient Education: