Strange and Schafermeyer's Pediatric Emergency Medicine, Fourth Edition (Strange, Pediatric Emergency Medicine) 4th Ed.

CHAPTER

117

Sedative Hypnotics and Anticonvulsants

Suzan S. Mazor

HIGH-YIELD FACTS

• The hallmark of the care of children with sedative hypnotic poisoning is meticulous supportive care with particular attention to the support of airway and breathing.

• Severe anticonvulsant poisoning may require extracorporeal removal techniques.

Children with sedative hypnotic or anticonvulsant ingestions are relatively common emergency department presentations. For sedative hypnotics, the chief concern is respiratory insuficiency due to central nervous system depression. While morbidity may be significant, the provision of meticulous respiratory supportive care results in minimal mortality. Specific interventions such as antidotes and extracorporeal removal are rarely indicated. Indeed, supportive care as the mainstay for poison treatment was first promoted for sedative hypnotic poisoning more than a half of a century ago as the “Scandanavian Method.”1

Anticonvulsant poisoning has a greater morbidity and mortality because of cardiovascular toxicity. Extracorporeal removal techniques may be indicated for severe poisonings.

This chapter focuses upon benzodiazepines, phenobarbital, phenytoin, carbamazepine, and valproic acid.

BENZODIAZEPINES

Benzodiazepines are a large class of drugs with wide variation in potency and duration of action. They are used most commonly as anxiolytics, muscle relaxants, anti-epileptic medications, and as treatment of withdrawal states. They have an extreme wide margin of safety with respiratory failure being virtually unheard of in the absence of coingestants.2

image PATHOPHYSIOLOGY

Benzodiazepines enhance the action of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system (CNS) resulting in CNS depression after overdose.

image CLINICAL PRESENTATION

CNS depression is the most common finding after overdose. Coma and respiratory depression are typically due to the combined effects of the benzodiazepine and a coingestant. Respiratory depression or arrest may occur following rapid IV infusion of short-acting benzodiazepines. These patients may manifest coma, respiratory depression, hypotension, hypothermia, and rhabdomyolysis.

image LABORATORY STUDIES

Urine drug tests do not detect all benzodiazepines, including midazolam, so a negative screen does not rule out benzodiazepine ingestion.

image TREATMENT

Supportive care with attention to the airway, breathing, and circulation is the mainstay of treatment. Overdose of a benzodiazepine as a single agent may cause a depressed level of consciousness but generally does not cause loss of airway reflexes. Even with large overdoses, hemodynamic instability is unlikely. However, when benzodiazepines are combined with other sedating agents, airway protection and hemodynamic support may be necessary.

Although benzodiazepines are adsorbed by activated charcoal, its use is not recommended because of the low morbidity of this poisoning. Flumazenil is a benzodiazepine receptor antagonist that can rapidly reverse the benzodiazepine effect and is a potential antidote. However, its use is not recommended for the benzodiazepine-poisoned patient because of the risk of seizures and resedation.3

image DISPOSITION

Patients with symptoms of altered mental status, respiratory depression, or hypotension should be admitted to the hospital. Those who are asymptomatic at 4 hours after ingestion can be discharged from the emergency department. Purposeful ingestions require a mental health evaluation.

PHENOBARBITAL

Phenobarbital is a barbiturate drug used for the treatment of seizure disorders.

image PATHOPHYSIOLOGY

Barbiturates cause depression of neuronal activity by increasing the duration of opening of GABA-mediated chlorine channels. In overdose, phenobarbital causes CNS depression due to enhanced GABA activity and hypotension secondary to direct myocardial depression.

image CLINICAL PRESENTATION

With overdose, somnolence, confusion, nystagmus, slurred speech, and ataxia may occur. Severe effects include coma, hypotension, hypothermia, respiratory failure, and cardiovascular collapse. Pupils may be small or mid-position. Bullae on the skin may form secondary to prolonged immobilization from coma.

image LABORATORY STUDIES

Measure the serum phenobarbital concentration. In nontolerant individuals, concentrations of greater than 60 to 80 mg/L are associated with coma and concentrations of greater than 150 to 200 mg/L with hypotension. Obtain an ECG in patients with moderate-to-severe toxicity.

image TREATMENT

Provide meticulous supportive care with attention to the airway, breathing and circulation, including rewarming to correct hypothermia and vasopressors as needed. Clinical manifestations may be prolonged due to the long half-life of phenobarbital.

Consider activated charcoal in patients who have ingested a potentially toxic dose and have presented within 1 hour of ingestion.4 Urinary alkalinization can enhance the elimination of phenobarbital.5 Add 3 ampules of sodium bicarbonate to 1 L of D5W and run at 1.5 to 2 times maintenance fluid rates. Goal urine pH is 7.5 to 8. Follow urine pH, serum pH, and serum potassium, and add potassium chloride to IV bicarbonate if the serum potassium is low.

Multiple-dose–activated charcoal (MDAC) decreases the half-life of phenobarbital but has not been shown to improve outcome.6 MDAC should only be used in patients with an intact, functioning GI tract. For MDAC, activated charcoal (0.5 g/kg) is given every 4 to 6 hours. Hemodialysis or hemoperfusion should be performed in patients who have severe toxicity and refractory hemodynamic instability.7

image DISPOSITION

Patients with symptoms of altered mental status, respiratory depression, or hypotension should be admitted to the hospital. Those who are asymptomatic at 4 hours after ingestion can be discharged from the emergency department. Purposeful ingestions require a mental health evaluation.

PHENYTOIN

Phenytoin is used for the prevention and treatment of seizures.

image PATHOPHYSIOLOGY

Phenytoin decreases seizure activity by stabilizing neuronal membranes; increasing efflux or decreasing influx of sodium ions. Absorption of phenytoin may be slow and unpredictable.

image CLINICAL PRESENTATION

Vomiting, nystagmus, ataxia, dysarthria, and CNS depression may occur. Large oral ingestions can cause coma, and rarely, respiratory depression. Rapid infusion of the intravenous formulation can cause hypotension, bradycardia, conduction delays, and ventricular dysrhythmias. This is considered to be caused by the IV diluent, 40% propylene glycol, and not the phenytoin itself.

image LABORATORY STUDIES

Monitor serum phenytoin concentrations every 4 hours until they are clearly declining. At concentrations greater than 30 μg/mL, nystagmus and ataxia are common. Obtain an ECG and continuous cardiac monitoring during and after rapid intravenous phenytoin infusion or intravenous overdose. Obtain serum albumin concentration as phenytoin toxicity may occur in the setting of elevated free phenytoin concentrations, even though total phenytoin concentrations are normal.

image TREATMENT

Supportive care with attention to the airway, breathing, and circulation is the mainstay of treatment.

Consider activated charcoal in patients who have ingested a potentially toxic dose and have presented within 1 hour of ingestion.4

image DISPOSITION

Patients should be observed for at least 4 to 6 hours, and should not be cleared medically until symptoms are improving and serum concentrations are clearly declining. Patients with worsening symptoms after 4 to 6 hours, with significant ataxia or CNS depression, and those with rising serum concentrations should be admitted to the hospital.

CARBAMAZEPINE

Carbamazepine is used as an antiepileptic, for pain disorders and for several psychiatric conditions. It is available in both standard and controlled-release formulations. It is structurally and pharmacologically similar to tricyclic antidepressants.

image PATHOPHYSIOLOGY

Carbamazepine is slowly and erratically absorbed through the GI tract. With therapeutic dosing, peak concentrations are generally reached within 4 to 8 hours. There is a wider variation in time to peak concentration in overdose. With controlled-release formulation, concentrations may continue to rise for longer than 24 hours after overdose. Carbamazepine is metabolized by the liver; its primary metabolite is carbamazepine-10-11 epoxide, which also possesses anticonvulsant activity. Carbamazepine and its metabolite decrease repetitive action potential firing in the CNS via sodium channel inactivation.

image CLINICAL PRESENTATION

In acute overdose, common initial signs of toxicity include nystagmus, ataxia, ophthalmoplegia, hyperreflexia, CNS depression, dystonia, sinus tachycardia, and mild anticholinergic symptoms such as mydriasis, delirium, encephalopathy, and decreased bowel sounds. Less common effects include hepatotoxicity and hyponatremia secondary to the syndrome of inappropriate ADH secretion. Life-threatening effects include coma, seizures, and respiratory depression. Rhabdomyolysis and renal failure may occur rarely following large overdoses. Cardiac toxicity may occur with massive overdoses and may include decreased myocardial contractility, pulmonary edema, hypotension, dysrhythmias and conduction delays including PR, QRS, and QTc prolongation. Paradoxical seizures or cyclic coma may occur after overdose.

image LABORATORY STUDIES

Measure a serum carbamazepine concentration. Because peak levels may be delayed in overdose, serum carbamazepine concentration should be measured every 4 hours until the concentration has peaked and is clearly declining. ECG should be ordered to assess for arrhythmia and QTc prolongation.

Carbamazepine causes a false positive for tricyclic antidepressant on many urine drug screens.

image TREATMENT

Provide meticulous supportive care with attention to the airway, breathing, and circulation. Seizures should be treated with benzodiazepines as first-line therapy with phenobarbital for unresponsive or recurrent seizures. Consider activated charcoal in patients who have ingested a potentially toxic dose and have presented within 1 hour of ingestion.4

MDAC increases clearance of carbamazepine, but it has not been shown to improve clinical outcomes.6 MDAC should only be used in patients with an intact, functioning GI tract. For MDAC, activated charcoal (0.5 g/kg) is given every 4 to 6 hours. Charcoal hemoperfusion8 and high-flux hemodialysis9 have been used in severe, life-threatening carbamazepine overdose.

image DISPOSITION

Because of the risk of delayed drug absorption and toxicity, patients with significant ingestions should be observed for 6 to 8 hours, and have declining serum drug concentrations documented before they can be medically cleared. Symptomatic patients should be admitted to the hospital.

VALPROIC ACID

Valproic acid is used as an anticonvulsant, a mood stabilizer, for the treatment of chronic pain and as prophylaxis for migraine headaches.

image PATHOPHYSIOLOGY

Valproic acid inhibits GABA transaminase, increasing GABA concentrations in the brain. Valproic acid also depletes coenzyme A (CoA) stores in the liver by trapping CoA in the mitochondria. Depletion of CoA affects the activation of the carbamyl phosphate synthetase I, leading to disruption of the urea cycle, which may cause hyperammonemia. Valproic acid depletes carnitine levels resulting in decreased transport of fatty acids and their accumulation in the cytoplasm. This process may result in development of fatty liver.

image CLINICAL PRESENTATION

The most common effects of valproic acid overdose are vomiting, tachycardia, and CNS depression. With severe poisoning, patients may develop coma, miotic pupils, tachycardia, hypotension, QTc prolongation, and respiratory depression. Paradoxic seizures and cerebral edema may occur. Laboratory abnormalities may include hypernatremia, hypocalcemia, elevation of transaminases, and bone marrow suppression. Hyperammonemic encephalopathy can develop after overdose or therapeutic use.

image LABORATORY STUDIES

Valproic acid concentration should be measured and repeated every 4 to 6 hours until the level is decreasing. The therapeutic serum concentration is generally considered to be 50 to 100 μg/mL. Values greater than 450 μg/mL are associated with drowsiness and obtundation; those greater than 850 μg/mL are associated with coma. Useful studies may include complete blood count, liver enzymes, ammonia concentration, lactic acid, electrolytes, blood sugar, renal function, and ECG. Consider obtaining a CT scan of the head if cerebral edema is suspected.

image TREATMENT

Provide meticulous supportive care with attention to the airway, breathing, and circulation.

Consider activated charcoal in patients who have ingested a potentially toxic dose and have presented within 1 hour of ingestion.4

Hemodialysis10 or charcoal hemoperfusion11 should be considered in patients with severe symptoms, severe metabolic disturbance or serum valproic acid concentration greater than 1000 μg/mL.

L-carnitine may be considered for patients with coma, hepatotoxicity, hyperammonemia, or serum valproic acid concentration greater than 450 μg/mL.12 Although there are no controlled studies to support its use after acute overdose, reports suggest it lowers serum ammonia concentrations, and it is associated with few adverse effects.

image DISPOSITION

Patients should be observed for at least 6 hours after immediate-release valproic acid ingestions, and for 12 hours following ingestion of delayed-release preparations. Patients may be medically cleared if valproic acid concentrations are declining, and symptoms are resolved. Patients with persistent altered mental status, abnormal vital signs, acidosis, renal or hepatic involvement should be admitted to the hospital.

REFERENCES

1. Clemmensen C, Nilsson E. Therapeutic trends in the treatment of barbiturate poisoning. The Scandinavian method. Clin Pharmacol Ther. 1961;2:220–229.

2. Greenblatt DJ, Allen MD, Noel BJ, Schader RI. Acute overdosage with benzodiazepine derivatives. Clin Pharmacol Ther. 1977;21:497–514.

3. Seger DL. Flumazenil – treatment or toxin. J Toxicol Clin Toxicol. 2004;42:209–216.

4. American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists. Position paper: Single-dose activated charcoal. J Toxicol Clin Toxicol. 2005;43:61–87.

5. Proudfoot AT, Krenzelok EP, Vale JA. Position paper on urinary alkalinization. J Toxicol Clin Toxicol. 2004;42:1–26.

6. American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists. Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol. 1999;37:731–751.

7. Palmer BF. Effectiveness of hemodialysis in the extracorporeal therapy of phenobarbital overdose. Am J Kid Dis. 2000;36:640–643.

8. Deshpande G, Meert KL, Valentini RP. Repeat charcoal hemoperfusion treatments in life threatening carbamazepine overdose. Pediatr Nephrol. 1999;13:775–777.

9. Schuerer DJE, Brophy PD, Maxvold NJ. High-efficiency dialysis for carbamazepine overdose. Clin Toxicol. 2000;38:321–323.

10. Guillaume CP, Stolk L, Dejagere TF, Kooman JP. Successful use of hemodialysis in acute Valproic acid intoxication. J Toxicol Clin Toxicol. 2004;42:335–336.

11. Graudins A, Aaron CK. Delayed peak serum valproic acid level in massive divalproex overdose–treatment with charcoal hemoperfusion. J Toxicol Clin Toxicol. 1996;34:335–341.

12. L'Heureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol. 2009;47:101–111.