Sodium Valproate 7.Aug.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 100 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 100 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 for 12 hours in the care of a reliable observer.   The patient should be medically assessed if any symptoms develop, including: Vomiting Lethargy/drowsiness Confusion Agitation Tremor Ataxia Racing heart   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, they may be: Discharged into the care of a reliable observer, or Referred for psychological assessment if the overdose or exposure was with intent of self-harm   If the patient is symptomatic on presentation, or develops symptoms during the initial observation period, they should be observed until there has been resolution of signs of valproate toxicity and serum concentrations have fallen into the therapeutic range.   Investigations Concentrations 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 2 to 3 hourly intervals initially and 4 to 6 hourly intervals later (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, or large numbers of tablets/capsules, 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] 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 100 mg/kg. Whole bowel irrigation may be a useful adjunct in the treatment of overdoses of enteric coated formulations or patients with rising concentrations despite activated charcoal.   There are no proven antidotes for valproate capable of immediately reversing its toxic effects, however, 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 regularly monitored.[3]   Further treatment is primarily symptomatic and supportive. CNS depression is a common manifestation of toxicity requiring treatment. 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 Whole bowel irrigation 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 possible but 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 100 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.   Whole Bowel Irrigation Whole bowel irrigation may be a useful adjunct in the treatment of overdoses of enteric coated formulations or patients with rising concentrations despite activated charcoal.   Whole Bowel Irrigation Procedure   When performed optimally, whole bowel irrigation is a labor intensive task that is more likely to be successful with 1:1 nursing care and can take 4 to 6 hours to complete. Use of a nasogastric (NG) tube is recommended over oral administration as it can be difficult for patients to drink the appropriate amount of irrigation fluid over several hours.   Before commencing ensure the airway is adequately protected, the NG tube is confirmed to be in the stomach, and there is no ileus or intestinal obstruction. The patient should be in an upright position with easy access to a commode (or use a rectal tube).[18][19]   The only irrigant recommended is an iso-osmotic polyethylene glycol electrolyte solution approved for GI cleansing and administered at the following rates until the rectal effluent is clear.[18][19]   CHILD < 9 months: There is limited evidence for use in this age group, consultation with a medical toxicologist is advised 9 months to 6 years: 500 mL/hour (or 25 mL/kg/hour) via NG tube 6 to 12 years: 1,000 mL/hour (or 25 mL/kg/hour) via NG tube ADOLESCENT or ADULT 1,500 to 2,000 mL/hour via NG tube   To achieve desired infusion rates it may be helpful to start at a slower rate and increase as tolerated over the first 10 to 15 minutes. Enteral feeding pumps may not be able to achieve target rates for adults even on the “flush” setting (if considering use of an enteral feeding pump check the device manual to see what rates can be achieved). A gravity infusion, i.e. hanging the irrigant solution bag to gravity, will typically be able to achieve a rate up to 2,000 mL/hour via NG tube.   Monitor the patient for abdominal distension or vomiting during the procedure. Pre-treatment with antiemetics can be considered. If vomiting occurs, and ileus or obstruction are not suspected, decrease the infusion rate by 50% for 30 to 60 minutes then attempt to increase back to the full rate.[18]   After completion of the procedure the patient should be expected to have additional liquid bowel movements for a period of time.[18]   Exclude Bezoar While bezoar formation is unlikely following most cases of valproate overdose, the possibility should be considered with the ingestion of enteric-coated or modified-release formulations or in situations where high numbers of tablets/capsule are ingested. Valproate tablets are not radiopaque and are unlikely to be seen on plain x-ray imaging.   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.[20]   Investigation for the presence of a tablet mass in the upper GI tract may be of benefit in the patient with life-threatening toxicity.   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 can be impossible to remove without laparotomy.   ANTIDOTE(S) There Are No Antidotes For This Substance No clinically established antidotes capable of immediately reversing toxic effects 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,[21] a state which is commonly observed in chronic, supratherapeutic valproic acid poisoning. Hypocarnitemia may favor the production of toxic metabolites, and contribute to the development of hyperammonemia.[11] Administration of L-carnitine is thought to normalize metabolism and has well established clinical benefit in reversing hyperammonemia in these patients.[22] It is recommended prophylactically in “at-risk” patients on valproic acid therapy.[8][23][24]   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.[5][21][25] There are also anecdotal reports of reversal of hyperammonemia in acute poisoning.[6][8][26][27] L-carnitine does not appear to have any direct effect on neurological toxicity.[25]   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][8]   Indications L-carnitine administration is indicated in patients with:[5][7][8][25][28][29] 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][30] Hepatotoxicity[24][25]   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][21][24][26][28] L-carnitine infusion may be required for up to 3 to 4 days.[5][26]   L-Carnitine Dosage in Acute Valproic Acid Poisoning   CHILD and ADULT[5][7] IV Loading dose: 100 mg/kg Doses given as an infusion over 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 as an infusion over 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.[31][32]   Contra-indications L-carnitine does not have any absolute contraindications other than known previous hypersensitivity.[31][32]   Adverse Effects Seizures are reported, both in patients with or without a prior history of convulsive disorder.[31][32] Tachydysrhythmias, hypertension, and hypotension are also noted.[5] Gastrointestinal upset[32] and an unpleasant, fishy body odor may occur.[25][28] No allergic reactions or adverse effects were observed when L-carnitine was administered in 215 acute valproic acid poisoning cases.[29]   Naloxone Naloxone has been used anecdotally in a small number of cases to reverse valproate-induced CNS depression.[33][34][35][36][37][38][39] This appears to have been more effective with minimally elevated serum concentrations,[39][40][41] with other reports showing no effect with much higher concentrations.[42][43][44] Any effect may be due to reversal of valproate blockade of GABA cellular uptake or reversal of valproate-induced release of endogenous opioids.[39][40][45]   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][46][47] Ingestions from 200 to 400 mg/kg are likely to develop varying degress of decreased consciousness (lethargy, sedation, ataxia). 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.[48][49][50]   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.[27][51][52]Delayed cerebral edema may occur though it is not common.[53][54] Death is rare, and usually results from cardiac or respiratory arrest.[55]   Individuals with underlying genetic urea cycle disorders, such as ornithine transcarbamylase deficiency, are at increased risk of developing hyperammonemic encephalopathy.[56][57] Pancreatitis and other adverse effects seen with therapeutic doses may occasionally occur with overdose.[58]   Onset/Duration of Symptoms Symptoms would usually be expected to develop within 1 to 6 hours of ingestion with most standard preparations.[36][59][53][55][60][61][62][63] Delayed toxicity may occur with ingestion of sustained release or enteric-coated formulations,[2][52][64] or with the prodrug valpromide,[1] with CNS depression developing as late as 8 hours post-ingestion. Ingestion of high numbers of tablets/capsules may also be associated with delayed or prolonged absorption. 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.[59][65]   Depending on the severity, the duration of intoxication can range from 24 hours to 7 days or longer.[48][66][55][61][63][67]   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. [2] Graudins A, Aaron CK. Delayed peak serum valproic acid in massive divalproex overdose--treatment with charcoal hemoperfusion. J Toxicol Clin Toxicol 1996; 34 (3): 335-41. [3] Ingels M, Beauchamp J, Clark RF, Williams SR. Delayed valproic acid toxicity: a retrospective case series. Ann Emerg Med 2002 Jun; 39 (6): 616-21. [4] Isbister GK, Balit CR, Whyte IM, Dawson A. Valproate overdose: a comparative cohort study of self poisonings. Br J Clin Pharmacol 2003 Apr; 55 (4): 398-404. [5] Perrott J, Murphy NG, Zed PJ. L-carnitine for acute valproic acid overdose: a systematic review of published cases. Ann Pharmacother 2010 Jul-Aug; 44 (7-8): 1287-93. [6] Jung J, Eo E, Ahn KO. A case of hemoperfusion and L-carnitine management in valproic acid overdose. Am J Emerg Med 2008 Mar; 26 (3): 388.e3-4. [7] Russell S. Carnitine as an antidote for acute valproate toxicity in children. Curr Opin Pediatr 2007 Apr; 19 (2): 206-10. 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[Letter] J Toxicol Clin Toxicol 2003; 41 (6): 899; author reply 901-2. [31] Carnitor IV Prescribing Information, United States of America: Leadiant Biosciences, Inc; 2018; [cited 26 January 2019]. URL: http://leadiant.com [32] Carnitor Oral Prescribing Information, United States of America: Leadiant Biosciences, Inc; 2018; [cited 26 January 2019]. URL: http://leadiant.com [33] Montero FJ. Naloxone in the reversal of coma induced by sodium valproate. [Letter] Ann Emerg Med 1999 Mar; 33 (3): 357-8. [34] Alberto G, Erickson T, Popiel R, Narayanan M, Hryhorczuk D. Central nervous system manifestations of a valproic acid overdose responsive to naloxone. Ann Emerg Med 1989 Aug; 18 (8): 889-91. [35] Espinoza O, Maradei I, Ramirez M, Pascuzzo-Lima C. An unusual presentation of opioid-like syndrome in pediatric valproic acid poisoning. Vet Hum Toxicol 2001 Jun; 43 (3): 178-9. [36] Steiman GS, Woerpel RW, Sherard ES Jr. Treatment of accidental sodium valproate overdose with an opiate antagonist. Ann Neurol 1979 Sep; 6 (3): 274. [37] Roberge RJ, Francis EH 3rd. Use of naloxone in valproic acid overdose: case report and review. J Emerg Med 2002 Jan; 22 (1): 67-70. [38] Popiel R, Erickson T, Leikin JB. Valproic acid overdose: response to naloxone [abstract]. Vet Hum Toxicol 1989; 31: 368. [39] Thanacoody HK. Chronic valproic acid intoxication: reversal by naloxone. Emerg Med J 2007 Sep; 24 (9): 677-8. [40] Dingledine R, Iversen LL, Breuker E. Naloxone as a GABA antagonist: evidence from iontophoretic, receptor binding and convulsant studies. Eur J Pharmacol 1978 Jan 1; 47 (1): 19-27. [41] Hyden H, Cupello A, Palm A. Naloxone reverses the inhibition by sodium valproate of GABA transport across the Deiters' neuronal plasma membrane. [Letter] Ann Neurol 1987 Apr; 21 (4): 416-7. [42] Connacher AA, Macnab MS, Moody JP, Jung RT. 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Neurointensive care management of raised intracranial pressure caused by severe valproic acid intoxication. Neurocrit Care 2007; 7 (2): 160-4. [54] Hintze G, Klein HH, Prange H, Kreuzer H. A case of valproate intoxication with excessive brain edema. Klin Wochenschr 1987 May 4; 65 (9): 424-7. [55] Eyer F, Felgenhauer N, Gempel K, Steimer W, Gerbitz KD, Zilker T. Acute valproate poisoning: pharmacokinetics, alteration in fatty acid metabolism, and changes during therapy. J Clin Psychopharmacol 2005 Aug; 25 (4): 376-80. [56] Honeycutt D, Callahan K, Rutledge L, Evans B. Heterozygote ornithine transcarbamylase deficiency presenting as symptomatic hyperammonemia during initiation of valproate therapy. Neurology 1992 Mar; 42 (3 Pt 1): 666-8. [57] Kay JD, Hilton-Jones D, Hyman N. Valproate toxicity and ornithine carbamoyltransferase deficiency. [Letter] Lancet 1986 Nov 29; 2 (8518): 1283-4. [58] Andersen GO, Ritland S. Life threatening intoxication with sodium valproate. 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Delayed toxicity following ingestion of enteric-coated divalproex sodium (Epival). J Emerg Med 1999 May-Jun; 17 (3): 463-7. [65] Khoo SH, Leyland MJ. Cerebral edema following acute sodium valproate overdose. J Toxicol Clin Toxicol 1992; 30 (2): 209-14. [66] Kielstein JT, Woywodt A, Schumann G, Haller H, Fliser D. Efficiency of high-flux hemodialysis in the treatment of valproic acid intoxication. J Toxicol Clin Toxicol 2003; 41 (6): 873-6. [67] Grynnerup A, Fernández IS, Hernández JC, Martínez AD, López JM, García-Alix A. A severe valproate overdose with complete recovery in a newborn. J Child Neurol 2012 Aug; 27 (8): 1072-6. Do Not Archive. This document is current on day of issue, NZ: 7.Aug.2020

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