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Sodium Valproate

Sodium Valproate
23.Nov.2019-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
Decontamination
Ingestion
Antidote(s)
Enhanced Elimination
Supportive Care
Neurologic
Hepatic
Metabolic
Fluid and electrolytes
Respiratory
Cardiovascular
Hematologic
 

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 ToxicityModerate Valproate ToxicitySevere 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.
[8] Schrettl V, Felgenhauer N, Rabe C, Fernando M, Eyer F. l-Arginine in the treatment of valproate overdose - five clinical cases. Clin Toxicol (Phila) 2017 Apr; 55 (4): 260-266.
[9] Su M, Fong J, Howland MA, Nelson LS. Multiple-dose activated charcoal used to treat valproic acid overdose [abstract]. J Toxicol Clin Toxicol 2002; 40 (3): 381-2.
[10] Vannaprasaht S, Tiamkao S, Sirivongs D, Piyavhatkul N. Acute valproic acid overdose: enhance elimination with multiple-doses activated charcoal. J Med Assoc Thai 2009 Aug; 92 (8): 1113-5.
[11] Ghannoum M, Laliberté M, Nolin TD, MacTier R, Lavergne V, Hoffman RS, Gosselin S. Extracorporeal treatment for valproic acid poisoning: Systematic review and recommendations from the EXTRIP workgroup. Clin Toxicol (Phila) 2015 Jun; 53 (5): 454-65.
[12] Engbersen R, Kramers C. Enhanced extracorporeal elimination of valproic acid in overdose. [Editorial] Neth J Med 2004 Oct; 62 (9): 307-8.
[13] Gerstner T, Bauer MO, Longin E, Bell N, Koenig SA. Reversible hepatotoxicity, pancreatitis, coagulation disorder and simultaneous bone marrow suppression with valproate in a 2-year-old girl. Seizure 2007 Sep; 16 (6): 554-6.
[14] Star K, Edwards IR, Choonara I. Valproic acid and fatalities in children: a review of individual case safety reports in VigiBase. PLoS One 2014; 9 (10): e108970.
[15] Schmid MM, Freudenmann RW, Keller F, Connemann BJ, Hiemke C, Gahr M, Kratzer W, Fuchs M, Schönfeldt-Lecuona C. Non-fatal and fatal liver failure associated with valproic acid. Pharmacopsychiatry 2013 Mar; 46 (2): 63-8.
[16] Chen HY, Albertson TE, Olson KR. Treatment of drug-induced seizures. Br J Clin Pharmacol 2016 Mar; 81 (3): 412-9.
[17] Fountain JS, Beasley DM. Activated charcoal supercedes ipecac as gastric decontaminant. N Z Med J 1998 Oct 23; 111 (1076): 402-4.
[18] Rankin RJ, Edwards IR. Overdose of sustained release verapamil. [Letter] N Z Med J 1990 Apr 11; 103 (887): 165.
[19] Ishikura H, Matsuo N, Matsubara M, Ishihara T, Takeyama N, Tanaka T. Valproic acid overdose and L-carnitine therapy. J Anal Toxicol 1996 Jan-Feb; 20 (1): 55-8.
[20] Lheureux PE, Penaloza A, Zahir S, Gris M. Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence? Crit Care 2005 Oct 5; 9 (5): 431-40.
[21] Raskind JY, El-Chaar GM. The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother 2000 May; 34 (5): 630-8.
[22] De Vivo DC, Bohan TP, Coulter DL, Dreifuss FE, Greenwood RS, Nordli DR Jr, Shields WD, Stafstrom CE, Tein I. L-carnitine supplementation in childhood epilepsy: current perspectives. Epilepsia 1998 Nov; 39 (11): 1216-25.
[23] Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila) 2009 Feb; 47 (2): 101-11.
[24] Chan YC, Tse ML, Lau FL. Two cases of valproic acid poisoning treated with L-carnitine. Hum Exp Toxicol 2007 Dec; 26 (12): 967-9.
[25] Auinger K, Müller V, Rudiger A, Maggiorini M. Valproic acid intoxication imitating brain death. Am J Emerg Med 2009 Nov; 27 (9): 1177.e5-6.
[26] Sztajnkrycer MD. Valproic acid toxicity: overview and management. J Toxicol Clin Toxicol 2002; 40 (6): 789-801.
[27] LoVecchio F, Shriki J, Samaddar R. L-carnitine was safely administered in the setting of valproate toxicity. Am J Emerg Med 2005 May; 23 (3): 321-2.
[28] Perez A, McKay CA. Role of carnitine in valproic acid toxicity. [Letter] J Toxicol Clin Toxicol 2003; 41 (6): 899; author reply 901-2.
[29] Carnitor IV Prescribing Information, United States of America: Leadiant Biosciences, Inc; 2018; [cited 26 January 2019]. URL: http://leadiant.com
[30] Carnitor Oral Prescribing Information, United States of America: Leadiant Biosciences, Inc; 2018; [cited 26 January 2019]. URL: http://leadiant.com
[31] Montero FJ. Naloxone in the reversal of coma induced by sodium valproate. [Letter] Ann Emerg Med 1999 Mar; 33 (3): 357-8.
[32] 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.
[33] 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.
[34] Steiman GS, Woerpel RW, Sherard ES Jr. Treatment of accidental sodium valproate overdose with an opiate antagonist. Ann Neurol 1979 Sep; 6 (3): 274.
[35] 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.
[36] Popiel R, Erickson T, Leikin JB. Valproic acid overdose: response to naloxone [abstract]. Vet Hum Toxicol 1989; 31: 368.
[37] Thanacoody HK. Chronic valproic acid intoxication: reversal by naloxone. Emerg Med J 2007 Sep; 24 (9): 677-8.
[38] 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.
[39] 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.
[40] Connacher AA, Macnab MS, Moody JP, Jung RT. Fatality due to massive overdose of sodium valproate. Scott Med J 1987 Jun; 32 (3): 85-6.
[41] Mortensen PB, Hansen HE, Pedersen B, Hartmann-Andersen F, Husted SE. Acute valproate intoxication: biochemical investigations and hemodialysis treatment. Int J Clin Pharmacol Ther Toxicol 1983 Feb; 21 (2): 64-8.
[42] Palatnick W, Honcharik N, Roberts D. Coma, anion gap, and metabolic derangements associated with massive valproic acid overdose [abstract] Vet Hum Toxicol 1989; 31:368.
[43] Gruol DL, Barker JL, Smith TG. Naloxone antagonism of GABA-evoked membrane polarizations in cultured mouse spinal cord neurons. Brain Res 1980 Oct 6; 198 (2): 323-32.
[44] Garnier R, Boudignat O, Fournier PE. Valproate poisoning. [Letter] Lancet 1982 Jul 10; 2 (8289): 97.
[45] Manoguerra AS, Erdman AR, Woolf AD, Chyka PA, Caravati EM, Scharman EJ, Booze LL, Christianson G, Nelson LS, Cobaugh DJ, Troutman WG. Valproic acid poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2008 Aug; 46 (7): 661-76.
[46] Farrar HC, Herold DA, Reed MD. Acute valproic acid intoxication: enhanced drug clearance with oral-activated charcoal. Crit Care Med 1993 Feb; 21 (2): 299-301.
[47] Dupuis RE, Lichtman SN, Pollack GM. Acute valproic acid overdose. Clinical course and pharmacokinetic disposition of valproic acid and metabolites. Drug Saf 1990 Jan-Feb; 5 (1): 65-71.
[48] Ge Y, Xu B, Zhu S, Li C, He Q, Zhu T, Fan R, Gong D. Severe acute valproic acid intoxication successfully treated with liver support therapy. Basic Clin Pharmacol Toxicol 2017 Oct; 121 (4): 368-70.
[49] Bigler D. Neurological sequelae after intoxication with sodium valproate. Acta Neurol Scand 1985 Sep; 72 (3): 351-2.
[50] Mestrovic J, Filipovic T, Polic B, Stricevic L, Omazic A, Kuzmanic-Samija R, Markic J. Life-threatening valproate overdose successfully treated with haemodialysis. Arh Hig Rada Toksikol 2008 Dec; 59 (4): 295-8.
[51] Marklund N, Enblad P, Ronne-Engström E. Neurointensive care management of raised intracranial pressure caused by severe valproic acid intoxication. Neurocrit Care 2007; 7 (2): 160-4.
[52] 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.
[53] 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.
[54] 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.
[55] Kay JD, Hilton-Jones D, Hyman N. Valproate toxicity and ornithine carbamoyltransferase deficiency. [Letter] Lancet 1986 Nov 29; 2 (8518): 1283-4.
[56] Andersen GO, Ritland S. Life threatening intoxication with sodium valproate. J Toxicol Clin Toxicol 1995; 33 (3): 279-84.
[57] Thabet H, Brahmi N, Amamou M, Ben Salah N, Hedhili A. Hyperlactatemia and hyperammonemia as secondary effects of valproic acid poisoning. [Letter] Am J Emerg Med 2000 Jul; 18 (4): 508.
[58] Al Aly Z, Yalamanchili P, Gonzalez E. Extracorporeal management of valproic acid toxicity: a case report and review of the literature. Semin Dial 2005 Jan-Feb; 18 (1): 62-6.
[59] Lynch A, Tobias JD. Acute valproate ingestion induces symptomatic methemoglobinemia. Pediatr Emerg Care 1998 Jun; 14 (3): 205-7.
[60] Min YG, Tse ML. Image in toxicology: Pseudo-subarachnoid hemorrhage in a case of severe valproic acid poisoning. Clin Toxicol (Phila) 2011 Aug; 49 (7): 699-700.
[61] Colak A, Memis D, Guzel A, Cerci H, Gurkaynak B. Valproic acid intoxication with suicide attempt in a pediatric patient. Pediatr Int 2011 Oct; 53 (5): 781-3.
[62] Brubacher JR, Dahghani P, McKnight D. Delayed toxicity following ingestion of enteric-coated divalproex sodium (Epival). J Emerg Med 1999 May-Jun; 17 (3): 463-7.
[63] Khoo SH, Leyland MJ. Cerebral edema following acute sodium valproate overdose. J Toxicol Clin Toxicol 1992; 30 (2): 209-14.
[64] 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.
[65] 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.

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