Sodium Valproate 22.Jan.2020-Expires: 7 days - Do not archive DESCRIPTION SUBSTANCE NAME Sodium Valproate   SUBSTANCE CLASS Antiepileptic   Carboxylic Acid Derivative   Antipsychotic   INTERVENTION CRITERIA Intervention Level Acute Child and Adult Medical assessment and observation at an emergency department is recommended for: - Ingestions greater than 50 mg/kg - Symptomatic cases - Exposures with intent to self-harm   Decontamination, if appropriate, and medical observation at an emergency department is recommended for: - Ingestions greater than 200 mg/kg   Acute On Chronic Medical assessment and observation at an emergency department is recommended for: - Ingestions 50 mg/kg greater than the patients usual single therapeutic dose - Symptomatic cases - Exposures with intent to self-harm   Decontamination, if appropriate, and medical observation at an emergency department is recommended for: - Ingestions 200 mg/kg greater than the patients usual single therapeutic dose is ingested   Chronic Medical assessment and observation is recommended for:  - Any symptomatic chronic ingestion   Observation Period Observation at Home If the patient does not require medical observation they can be monitored at home in the care of a reliable observer. The patient should be observed for 6 hours following ingestion of a standard preparation or for 12 hours if a sustained release formulation has been ingested.   The patient should be medically assessed if any symptoms develop, including: Vomiting Drowsiness Confusion Unconsciousness Tremor   Medical Observation If the patient’s ingested dose is above the intervention criteria: - Observe for development of symptoms for a minimum period of 6 hours when a standard-release preparation has been ingested - Observe for development of symptoms for a minimum period of 12 hours when an enteric-coated or sustained-release preparation has been ingested   If the patient remains asymptomatic throughout the observation period, and any necessary decontamination and investigations have been carried out: - Discharge into the care of a reliable observer, or - Refer for psychiatric assessment (if the overdose was intentional)   If the patient is symptomatic on presentation they should be observed until there has been resolution of signs of valproate toxicity and serum concentrations have fallen into the therapeutic range.   Investigations Levels Valproic acid serum concentrations should be measured following ingestion of immediate- and sustained release-preparations when the suspected dose is > 100 mg/kg.   Serum concentrations should be taken on presentation and repeated at 4 to 6 hour intervals (to help identify the time of peak concentration and to ensure that a downward trend is observed)[1][2][3] In particular, patients ingesting enteric coated formulations of valproic acid may have slowed absorption or form concretions in the GI tract. Absorption may be delayed and prolonged. Hence, serial serum valproic acid estimations may be useful to ascertain on-going absorption and guide the need for further GI decontamination and extracorporeal elimination.[3]   Click here to link to toxic serum concentrations   Monitoring Monitor: Level of consciousness Heart rate Blood pressure ECG Respiratory rate Blood gas analysis Seizure activity Urea and electrolytes Serum ammonia Serum lactate Full blood count Liver function tests Blood glucose   Admission Criteria Admission to an intensive care environment is recommended when: - 400 mg/kg or more is ingested - Serum concentration is greater than 6,250 umol/L (900 mg/L) valproic acid - Following symptoms occur  Coma or respiratory depression requiring mechanical ventilation Recurrent seizures - Following conditions are present Severe electrolyte disturbances (e.g. marked hypernatremia) Hyperammonemia Metabolic acidosis Encephalopathy Hepatotoxicity   TREATMENT TREATMENT SUMMARY Severe toxicity is unlikely in the majority of overdoses.[4] However, emergency stabilization may occasionally be required following exposure to massive amounts of valproate, when treatment of cardio-respiratory arrest, seizures, or metabolic acidosis may be necessary. Decontamination with activated charcoal may be warranted for ingestions over 200 mg/kg.   There are no proven antidotes for valproate intoxication, although L-carnitine may be considered an adjunct to standard management.[5][6][7][8] Multiple dose activated charcoal[9][10] and hemodialysis may be useful in severe toxicity.[11][12] Valproic acid concentrations should be monitored.[3]   Further treatment is primarily symptomatic and supportive, focussing mainly on CNS and respiratory depression. Treatment of encephalopathy, seizures, hypotension, electrolyte disturbances, thrombocytopenia, metabolic acidosis, and delayed cerebral edema may sometimes be required following large to massive overdoses. Ammonia concentrations should be checked if encephalopathy is suspected. Hepatotoxicity and pancreatitis are uncommon with overdose, but can occur even with regular therapeutic doses and may be fatal.[13][14][15]   Patients with chronic valproate toxicity will require referral to a neurologist for dosage adjustment and monitoring of their on-going therapy.   Emergency Stabilization Ensure adequate cardiorespiratory function Cardiac arrest Seizure Metabolic acidosis Emergency monitoring Decontamination Ingestion Single dose activated charcoal Exclude bezoar Antidote(s) None recommended L-Carnitine Enhanced Elimination Multiple dose activated charcoal Hemodialysis Supportive Care Monitoring Neurologic CNS depression Encephalopathy Cerebral edema Seizure Hepatic Hepatotoxicity Metabolic Metabolic acidosis Fluid and electrolytes Electrolyte abnormalities Respiratory Respiratory depression Cardiovascular Hypotension Hematologic Thrombocytopenia EMERGENCY STABILIZATION Ensure Adequate Cardiopulmonary Function Endotracheal intubation may be required for airway protection and adequate ventilation of the obtunded patient following overdose. Ensure that the patient is well perfused and hemodynamically stable.   Immediately establish secure intravenous access.   Seizure Seizures are uncommon with valproate overdose.   Administer a benzodiazepine as first-line treatment to patients with seizure activity.[16]   Blood glucose concentration should be promptly determined. If the result indicates hypoglycemia, or is unobtainable, supplemental dextrose should be administered IV.   If seizure activity continues or if there is need for maintenance dosing proceed to further supportive care of toxic seizure.   Metabolic Acidosis Follow standard protocols for the management of metabolic acidosis. Emergency Monitoring Level of consciousness Heart rate Blood pressure ECG Respiratory rate Blood gas analysis Seizure activity Urea and electrolytes Serum ammonia Serum lactate Full blood count Liver function tests Blood glucose   DECONTAMINATION Ingestion Single Dose Activated Charcoal Decontamination with activated charcoal is recommended for ingestions over 200 mg/kg.   CNS depression is a likely consequence of significant overdose. Gastrointestinal decontamination should be undertaken with appropriate airway protection in those who are CNS depressed.[4]   Administration of activated charcoal may be considered if a patient has ingested a potentially toxic amount of a solid formulation (e.g. tablet or capsule) up to 4 hours previously.   Single dose activated charcoal[17] CHILD 1 to 2 g/kg orally ADULT 50 to 100 g orally   Nasogastric Administration Nasogastric instillation of activated charcoal is not recommended unless the ingestion is considered potentially severely toxic. If endotracheal intubation is otherwise required, activated charcoal can be administered following intubation, however, intubation should not be performed solely for the purpose of then administering charcoal.   Exclude Bezoar While bezoar formation is unlikely following valproate overdose, the possibility should be considered with the ingestion of enteric-coated or modified-release formulations.   Suspect a bezoar or tablet concretion where serum valproate concentration remains persistently elevated or plateaued despite apparently adequate GI decontamination.   Pharmacobezoars (drug concretions) may occur following an ingested overdose of various drugs and, particularly, modified release (e.g. sustained release) or enteric-coated preparations. Such masses may significantly extend or increase the duration of toxicity.[18]   Investigation for the presence of a tablet mass in the upper GI tract may be of benefit in the patient with life-threatening toxicity, but negative imaging studies do not exclude the presence of a bezoar.   Bezoars may be detected by: - Gastroscopy (can only view stomach and duodenum and impractical if charcoal has been administered as the bezoar may be hidden) - Abdominal CT scanning with oral contrast - Plain X-ray examination (but only for radio-opaque concretions) - Ultrasound examination   If found, the risk and practicality of removal should be weighed against use of supportive care with or without the addition of whole bowel irrigation.   If the bezoar is located in the stomach or duodenum, removal may be attempted endoscopically. Bezoars in the small intestine are inherently difficult to localize and impossible to remove without laparotomy.   ANTIDOTE(S) There Are No Antidotes For This Substance No clinically established antidotes exist for the treatment of valproic acid overdose. However, L-carnitine and naloxone have both been used in a number of cases with varying results.   L-Carnitine Evidence supporting clinical efficacy and safety of L-carnitine in acute valproic acid poisoning is limited.[5] The primary route of metabolism of valproic acid by beta-oxidation is inhibited by hypocarnitemia,[19] a state which is commonly observed in chronic, supratherapeutic valproic acid poisoning. Administration of L-carnitine is thought to normalize metabolism[20]  and has well established clinical benefit in reversing hyperammonemia in these patients. It is strongly recommended prophylactically in “at-risk” patients on valproic acid therapy.[21][22]   In acute poisoning there is some, albeit scant, evidence that valproic acid metabolism is similarly inhibited and that administration of L-carnitine similarly normalizes metabolism.[19][23][5] There are also anecdotal reports of reversal of hyperammonemia in acute poisoning.[6][24][25] L-carnitine does not appear to have any effect on neurological toxicity.[23]   L-carnitine may be considered in acute valproic acid poisoning as an adjunct to standard management where hyperammonemia or decreased level of consciousness is present.[5][7]   Indications L-carnitine administration is indicated in patients with:[5][7][8][23][26][27] Decreased level of consciousness Hyperammonemia Some authors also recommend considering L-carnitine administration if severe toxicity is present or likely: Ingestions > 100 mg/kg valproic acid[5] Serum valproic acid concentrations > 3,128 umol/L (> 450 mg/L)[5][7][28] Hepatotoxicity[22][23]   Dose and Administration The recommended L-carnitine dose for acute valproic acid poisoning is higher than that used for chronic, supratherapeutic poisoning or mild hypocarnitemia.[5][6][7][19][22][24][26] L-carnitine infusion may be required for up to 3 to 4 days.[5][24]   L-Carnitine Dosage in Acute Valproic Acid Poisoning   CHILD and ADULT[5][7] IV Loading dose: 100 mg/kg Doses given either as bolus over 2 to 3 minutes or infusion over 15 to 30 minutes Maximum dose 3 g (up to 6 g has been given) Maintenance dose: 50 mg/kg every 8 hours or 15 mg/kg every 4 hours Doses given either as bolus over 2 to 3 minutes or infusion over 15 to 30 minutes Maximum single dose 3 g End Point: Ammonia concentrations decreasing, patient demonstrates clinical improvement, or significant adverse effects occur   Precautions Seizures have occurred in patients taking L-carnitine therapeutically; caution is recommended in patients with underlying seizure disorder. Adequate hydration and a good renal output must be maintained as there is potential for accumulation of toxic metabolites of L-carnitine (trimethylamine and trimethylamine-N-oxide) in patients with renal impairment.[29][30]   Contra-indications L-carnitine does not have any absolute contraindications other than known previous hypersensitivity.[29][30]   Adverse Effects Seizures are reported, both in patients with or without a prior history of convulsive disorder.[29][30] Tachydysrhythmias, hypertension, and hypotension are also noted.[5] Gastrointestinal upset[30] and an unpleasant, fishy body odor may occur.[23][26] No allergic reactions or adverse effects were observed when L-carnitine was administered in 215 acute valproic acid poisoning cases.[27]   Naloxone Naloxone has been used successfully in a small number of cases to reverse valproate-induced CNS depression.[31][32][33][34][35][36][37] This appears to have been more effective with minimally elevated serum concentrations,[37][38][39] with other reports showing no effect with much higher concentrations.[40][41][42] Any effect may be due to reversal of valproate blockade of GABA cellular uptake or reversal of valproate-induced release of endogenous opioids.[37][38][43]   SIGNS AND SYMPTOMS Sodium valproate is rapidly metabolized to valproic acid in vivo.   Common clinical symptoms of valproic acid toxicity vary in severity, depending on the ingested dose, from mild confusion and drowsiness to deep coma and rarely, death.   With ingestions less than 200 mg/kg, effects are generally mild or the patient may remain asymptomatic.[4][44][45] Ingestions from 200 to 400 mg/kg are likely to develop varying levels of decreased consciousness. Additionally gastrointestinal disturbances, tachycardia, hyperammonemia, hypothermia, and rarely hepatic or renal toxicity may develop. Significant CNS depression is likely, with multi-organ involvement as the dose increases.[46][47][48]   Massive overdoses (typically > 800 mg/kg) can result in serious CNS and respiratory depression, hypotension, and metabolic acidosis. Severe hyperammonemic encephalopathy, cerebral edema, and clinically significant thrombocytopenia may develop; hypernatremia, hypocalcemia, and other electrolyte disturbances may be severe and prolonged.[25][49][50]Delayed cerebral edema may occur though it is not common.[51][52] Death is rare, and usually results from cardiac or respiratory arrest.[53]   Individuals with underlying genetic urea cycle disorders, such as ornithine transcarbamylase deficiency, are at increased risk of developing hyperammonemic encephalopathy.[54][55] Pancreatitis and other adverse effects seen with therapeutic doses may occasionally occur with overdose.[56]   Onset/Duration of Symptoms Symptoms would usually be expected to develop within 1 to 6 hours of ingestion with most standard preparations.[34][57][51][53][58][59][60][61] Delayed toxicity may occur with ingestion of sustained release or enteric-coated formulations,[2][50][62] or with the prodrug valpromide,[1] with CNS depression developing as late as 8 hours post-ingestion. Metabolic disturbances usually present early, and may be severe and prolonged. The development of cerebral edema is generally delayed, presenting 2 to 3 days or more post-ingestion, and is associated with a higher mortality.[57][63]   Depending on the severity, the duration of intoxication can range from 24 hours to 7 days or longer.[46][64][53][59][61][65]   Severity of Poisoning Mild Valproate Toxicity Moderate Valproate Toxicity Severe Valproate Toxicity Mild drowsiness Confusion Nausea Vomiting Tachycardia Moderate to severe drowsiness Agitation Hyperammonemia Hypocalcemia Hypernatremia Thrombocytopenia Hypotension Miosis Unconsciousness / coma Respiratory depression Metabolic acidosis Elevated creatnine kinase Hepatotoxicity Seizure Encephalopathy Cerebral edema Cardiac or respiratory arrest   REFERENCES [1] Payen C, Frantz P, Martin O, Parant F, Moulsma M, Pulce C, Descotes J. Delayed toxicity following acute ingestion of valpromide. Hum Exp Toxicol 2004 Mar; 23 (3): 145-8. 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