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Key Questions Introduction References
Patient Outcome Annotated
Bibliography Questions A
23 Year Old Woman who Presents with New Onset SE Case Presentation A 23 year-old female presented to the emergency department following several generalized seizures. The patient was found at home by family members, initially in a somnolent state, followed by seizure activity. She arrived by EMS and was given diazepam en route. Upon arrival the patient was somnolent, could answer only simple questions, and proceeded to have another generalized seizure. Initial history was absent while awaiting family members arrival. Physical examination revealed a somnolent woman who responded only to simple questions with primarily unintelligible answers. Airway was open and intact. Pulse was 116, BP 90/50, respirations 24/minute, and oxygen saturation of 97% on non-rebreather mask. Temperature was 37.1. The patient moved all extremities and no facial asymmetry was seen. Pupils were equal, 5 mm, and reacted to light. The skin was warm, pink, and without rashes. Chest was clear, heart was tachycardic without murmur/ gallop/ or rub. While in the emergency department the patient was treated with several doses of benzodiazepines and continued to have brief, intermittent seizures. She was subsequently intubated for airway protection and placed on a diprovan infusion for sedation. Family members arrived and informed the emergency physician that the patient was recently started on INH prophylaxis and an empty bottle of 30 tablets were found at home.
A 23 Year Old Woman who Presents with New Onset SE Key Clinical Questions:
A 23 Year Old Woman who Presents with New Onset SE Isoniazid-Induced Seizures Background, Risk Factors and Epidemiology According to 2001 data from the American Association of Poison Control Centers Toxic Exposure Surveillance System (TESS)1, there were 426 reported cases of INH overdose. Of these, there were 70 moderate outcomes, 80 major outcomes, and one death. A therapeutic INH dose is 5-15 mg/kg. Toxicity may be seen with doses >20 mg/kg, and is common above 40 mg/kg. Peak serum concentrations are reached in two hours.
INH as well as toxins found in Gyromitra mushroom species, and even some types of rocket fuels are metabolized to hydrazines. In overdose, these cause a functional pyridoxine (vitamin B6) deficiency. This occurs by inhibition of pyridoxine phosphokinase, the enzyme that converts pyridoxine to active B6. Activated B6 is required by glutamic acid decarboxylase to convert glutamic acid to g-amino butyric acid (GABA), an inhibitory neurotransmitter. Decreased levels of GABA are believed to lead to seizures (see diagram below).
Severe lactic acidosis develops as a result of seizure activity. INH also inactivates NAD and interferes with NAD synthesis. This decrease in functional NAD inhibits the conversion of lactate to pyruvate resulting in more profound lactic acidosis.
Acute INH overdose is associated with a triad consisting of: seizures refractory to conventional therapy, severe metabolic acidosis, and coma. Initial manifestations may include: nausea/ vomiting, ataxia, tachycardia, mydriasis, and CNS depression, which could mimic an anticholinergic toxidrome. Patients often have improvement in mental status between seizures, or may be comatose. Metabolic acidosis can be severe, with pH ranging from 6.8-7.3 with elevated serum lactate levels. One retrospective chart review4 evaluated 52 cases of INH overdose and reported associated complications. Seizures were found in 100% of patients, CNS depression (53%), vomiting (45%), leukocytosis (75%), metabolic acidosis (29%), elevated hepatic enzymes (21%), and elevated CPK (60%). Chronic effects of INH include hepatotoxicity and peripheral neuropathy, however these are usually not clinically significant entities with an acute overdose.
A reasonable laboratory evaluation would include initial bedside glucose determination, and serum electrolytes. If a toxic overdose is suspected, additional studies to evaluate the poisoned patient could include: electrocardiogram, serum salicylate and acetaminophen levels, arterial blood gas, hepatic enzymes, CPK, and +/- drugs of abuse screen. The differential diagnosis for patients presenting with seizures is broad and includes both toxin-induced and non-toxin-induced etiologies. Patient history will guide much of the diagnostic evaluation. For example, if an underlying seizure disorder was suspected, serum anticonvulsant levels (valproate, carbamazepine, and phenytoin) may be sought. Please refer to the section on general approach to toxin-induced seizures for more details. INH levels are usually not available quickly enough to impact initial care but may be sought in an unknown ingestion consistent with INH intoxication.
The initial management of any patients presenting to the emergency department with seizures is attention to airway, breathing, and circulation. Patients should be placed in a monitored bed, IV established, placed on high-flow oxygen, and have cardiac monitoring. Rapid bedside glucose determination should be performed. Often it will take time to determine the etiology of the seizing patient, however history from EMS and family members should be vigorously pursued. Benzodiazepines should be first-line agents used for seizures. If benzodiazepines are unsuccessful, barbiturates may also be used. Phenytoin is not recommended for toxin-induced seizures. When INH overdose is suspected or confirmed by history, IV pyridoxine should be administered. Pyridoxine will terminate seizures, and may reverse coma5 and lactic acidosis. The dose for an unknown ingestion is 5 grams IV, at a rate of one gram given per two to three minutes. If the amount of INH ingested is known, pyridoxine should be given one gram IV for each gram of INH ingested. It is important to note that a hospital's supply of IV pyridoxine may be insufficient to treat a significant INH overdose. One study3 found that approximately 50% of pediatric institutions had less than 5 grams of IV pyridoxine available. It is important to contact your hospital pharmacy to find out the availability of pyridoxine. If IV pyridoxine is unavailable, contacting the regional poison center may reveal an institution in close proximity that could courier the antidote. It is not unreasonable that, while awaiting either transfer or arrival of IV pyridoxine that oral B6 tablets could be crushed and infused through a nasogastric tube.
Activated charcoal readily absorbs INH. When given concomitantly with INH, activated charcoal will prevent toxicity7; however, patients often present several hours after ingestion. One study of healthy volunteers found that administration of activated charcoal one hour after INH dose resulted in a 20% decrease in area under the plasma concentration-time curve, which was not statistically significant8. Additionally, INH toxicity is associated with both seizures and CNS depression, which can increase the risk for aspiration. For these reasons activated charcoal should be used cautiously when the airway is not protected. Gastric lavage is another modality that has been recommended in previous reviews9, however there are many reasons that gastric lavage should be reserved for a highly select group of patients. Gastric lavage carries an aspiration risk, consumes valuable time, may promote tablet passage past the pylorus, and is often ineffective at removing tablets2.
Patients presenting with significant toxicity from INH overdose should be admitted to an intensive care setting. Consultation with a medical toxicologist through a regional poison center may be helpful to guide therapy.
A 23 Year Old Woman who Presents with New Onset SE Patient Outcome Diagnosis: INH Overdose Toxicology consultation was obtained. Recommended IV pyridoxine 5 grams IV. Only 50 mg of IV pyridoxine was available at this institution. The Rush Medical Center antidote depot was contacted and 10 grams of IV pyridoxine was sent, via police to the medical center. Pt. was given an initial dose of 5 grams IV pyridoxine. Seizure activity terminated. Repeat ABG: 7.31/34/503/17. There was no subsequent seizure activity. Pt. was extubated the following day. On hospital day three, the patient was transferred to a psychiatric facility.
1. Initial management of patients presenting with seizures should include?
2. A seizure from INH overdose is due to?
3. All of the following compounds can be metabolized to hydrazines except?
4. Initial dose of IV pyridoxine for INH overdose should be?
5. Metabolic acidosis found in INH overdose is due to?
1. Answer e. 2. Answer e. 3. Answer d. 4. Answer e. 5. Answer e. |