Valproic Acid Toxicity: Overview and Management

Matthew D. Sztajnkrycer*

Division of Toxicology, Department of Emergency Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio

ABSTRACT

Acute valproic acid intoxication is an increasing problem, accounting for more than 5000 calls to the American Association of Poison Control Centers in 2000. The purpose of this paper is to review the pharmacology and toxicology of valproic acid toxicity. Unlike earlier antiepileptic agents, valproic acid appears to function neither through sodium channel inhibition nor through direct g-aminobutyric acid agonism, but through an indirect increase in regional brain g-aminobutyric acid levels. Manifestations of acute valproic acid toxicity are myriad, and reflect both exaggerated therapeutic effect and impaired intermediary metabolism. Central nervous system depression is the most common finding noted in overdose, and may progress to coma and respiratory depression. Cerebral edema has also been observed. Although hepatotoxicity is rare in the acute overdose setting, pancreatitis and hyperammonemia have been reported. Metabolic and hematologic derangements have also been described. Management of acute valproic acid ingestion requires supportive care and close attention to the airway. The use of controversial adjunctive therapies, including extracorporeal drug elimination and L-carnitine supplementation, will be discussed.

Key Words: Valproic acid; Toxicology; Hyperammonemia; Carnitine; Cerebral edema

*Correspondence: Dr. Matthew D. Sztajnkrycer. Department of Emergency Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Fax: (507) 255-6592; E-mail: [email protected]

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DOI: 10.1081/CLT-120014645 0731-3810 (Print); 1097-9875 (Online)
Copyright q 2002 by Marcel Dekker, Inc. www.dekker.com

790 Sztajnkrycer

INTRODUCTION

Since its introduction in 1978, valproic acid (VPA) has been used as an antiepileptic drug in the management of both partial and generalized seizure disorder.[1]
Lambert first described the mood-stabilizing character- istic of VPA in patients with affective disorders in 1966.[2] In 1995, the Food and Drug Administration (FDA) approved VPA for use in the management of mania associated with bipolar disorder.[2] Due to its perceived improved side-effect profile and broader therapeutic index when compared with lithium, it has become the mood-stabilizing agent of choice in the
resulted in 373 cases of major toxicity and 16 deaths.[10]
In contrast, carbamazepine and phenytoin exposures resulted in eight and two fatalities, respectively. These data demonstrate that VPA toxicity represents an increasing concern for toxicologists. The purpose of this paper is to review the pharmacology and toxicology of VPA toxicity, as well as current management strategies.

PHARMACOKINETICS AND
TOXICOKINETICS

Valproic acid (N-dipropylacetic acid, sodium 2-n-

management of bipolar disorder.[3 –5] More recently, polyvalerate) is a simple branched chain carboxylic acid

VPA has been employed in both the prophylaxis and termination of migraine headache, and for control of neuropathic pain.[6– 9]
The increased use and availability of VPA have led to a steady increase in the number of cases reported to the American Association of Poison Control Centers’ (AAPCC) Toxic Exposure Surveillance System[10] (Fig. 1). Of particular note is the changing demographic of the cases, with fewer unintentional exposures and increasing intentional exposures. The first year that intentional exposures outnumbered unintentional exposures was 1995, the year the FDA granted approval for VPA use in patients with psychiatric illness.[11] Total VPA calls to the American Association of Poison Control Centers increased 129% between 1995 and 2000, and 707% between 1990 and 2000.[12] The most recent data from the TESS database recorded 5204 intentional VPA exposures and 3880 unintentional exposures. These exposures
(Fig. 2). It is a weak acid, with a pKa 4.8 and a report- ed volume of distribution ranging from 0.1 to 0.5 L/kg.[13– 17] After therapeutic dosing, VPA is rapidly absorbed from the gastrointestinal tract, with peak serum levels occurring 1–4 hours after ingestion.[13,18]
Although controversial, the range of therapeutic serum concentrations range from 50 mg/mL to between 100 and 150 mg/mL.[19– 22] In overdose, delayed peak levels have been documented. Graudins and Aaron reported the case of a 32-year-old female who developed peak serum levels 17 hours after ingestion of divalproex sodium and chlorpheniramine.[19] No evidence of anticholinergic toxicity was present to suggest chlorpheniramine- induced delayed gastric motility. A multi-center study by Spiller et al. demonstrated a range in time to peak drug level from 1 to 18 hours post-ingestion, with a mean of 7:4 ^ 3:9 hours:[23] Nineteen patients (14%) demon- strated a delay of greater than 10 hours prior to peak drug

Figure 1. Intentional vs. unintentional VPA ingestions 1983–2000.

Valproic Acid Toxicity

Figure 2. Structural similarities between VPA (N-dipropyla- cetic acid), the v-oxidation metabolite 4-en-VPA, and the hepatotoxins 4-pentenoic acid and methylenecyclopropylacetic acid (hypoglycin A metabolite).

level. Of these patients, nine had peak levels greater than 450 mg/mL, and four had levels greater than 850 mg/mL. Ingels et al. reported that 13% of patients who eventually developed toxic levels, defined as VPA level
$ 120 mg/mL, had low or unmeasurable levels upon presentation.[24] The authors recommended serial VPA levels with documented decline in levels prior to medical discharge of patients.
The degree of protein binding exhibited by the drug is a function of serum concentration, with 90% of the drug protein-bound at levels of 40 mg/mL, decreasing to 81.5% at 130 mg/mL.[13] Levels greater than 150 mg/mL saturate protein binding sites, resulting in increased free drug.[16] At levels greater than 150 mg/mL, protein binding ranges from 54 to 70% while at levels
. 300 mg/mL, only 35% of the drug is protein- bound.[16,25] It has been speculated that the increased free drug fraction in overdose allows for greater central nervous system (CNS) penetration and therefore
[26,27]
toxicity.
During elimination, the drug follows first-order kinetics.[15,28] Serum half-lives range from 8 to 21.5 hours with a mean half-life of 12:2 ^ 3:7 hours at therapeutic serum concentrations.[15,28,29] After over- dose, elimination half-life may be prolonged two- to three-fold with resultant half-lives greater than
[25,28,29]
30 hours.

METABOLISM

VPA undergoes extensive metabolism in the liver via direct glucuronidation, mitochondrial b oxidation, and

791

cytosolic v and v1 oxidation, with less than 3% of the initial dose excreted unchanged in the urine[14,16,25,31,32]
(Fig. 3). Glucuronide conjugation is the principal means of hepatic metabolism, accounting for as much as 80% of hepatic metabolism.[33] Of the phase I metabolic pathways, mitochondrial b-oxidation appears most important at therapeutic levels, accounting for nearly 70% of VPA metabolism. Despite being a short-chain fatty acid, VPA enters the mitochondria by way of the long-chain fatty acid transport system, which uses L- carnitine as a co-factor.[34] In this system, the fatty acid moiety is first attached to coenzyme-A (CoASH) to form valproyl-CoA. The valproyl-CoA is then esterified with L -carnitine to form valproyl-carnitine ester. The valproyl-carnitine ester is subsequently transported into the mitochondrial matrix by carnitine translocase in exchange for cytosolic movement of free carnitine. The principal b-oxidation products are 2-propyl-2 pentenoic acid (2-en-VPA), 3-hydroxy-2-propylpenta- noic acid (3-OH-VPA), and 3-oxo-2-propylpentanoic
[15,33,35]
acid (3-keto-VPA). Cytosolic v-oxidation (14%) and v1-oxidation (16%) pathways provide only minor
contributions.[21] v-oxidation products include
5-hydroxy-2-propylpentanoic acid (5-OH-VPA), 2-polyglutaric acid (PGA), and 2-propyl-4-pentenoic

Figure 3. Schematic representation of VPA metabolism, including glucuronidation and cytosolic v- and v1-oxidation and mitochondrial b-oxidation. 2-en-VPA: 2-propyl-2 pente- noic acid, 3-OH-VPA: 3-hydroxy-2-propylpentanoic acid, 3-keto-VPA: 3-oxo-2-propylpentanoic acid, 5-OH- VPA: 5-hydroxy-2-propylpentanoic acid, PGA: 2-polyglutaric acid, 4-en-VPA: 2-propyl-4-pentenoic acid, 4-OH-VPA: 4- hydroxy-2-propylpentanoic acid, 4-keto-VPA: 4-oxo-2-propyl- pentanoic acid, 3-en-VPA: 2-propyl-3-pentenoic acid.

792 Sztajnkrycer

acid (4-en-VPA), while v1-oxidation products include 4-hydroxy-2-propylpentanoic acid (4-OH-VPA), 4-oxo- 2-propylpentanoic acid (4-keto-VPA), and 2-propyl-3- pentenoic acid (3-en-VPA).[15,35]

MECHANISM OF ACTION

The mechanism of action of VPA remains to be fully elucidated. Unlike phenytoin and carbamazepine, sodium channel blockade does not appear to be a significant contributor to its antiepileptic effects. Murine tissue culture studies demonstrated the ability of valproate to
Increased levels of SSA inhibit the enzyme GABA-T, with resultant increased GABA concentrations.[36]

TOXICITY AND OVERDOSE CNS Toxicity
Even with therapeutic serum concentrations, VPA is associated with CNS depression.[43] In acute overdose, CNS depression is the most common manifestation of toxicity. Numerous case reports have described CNS depression and coma requiring intubation and mechan- ical ventilation as a consequence of acute inges-

inhibit voltage-dependent Naþ channels while rat studies tion.[19,25,28,29,44,45] A multi-center case series of VPA

demonstrated reduction in firing rate of neurons in the substantia nigra after 200 mg/kg VPA.[36– 38] More recent studies in rat hippocampal sections, however, have indicated that sodium channel blockade is not the principal mechanism of anticonvulsant activity.[39]
Valproic acid appears to function through regional changes in concentration of g-aminobutyric acid (GABA), the principal inhibitory brain neurotransmitter. Studies in the mouse and the rat have demonstrated elevations in whole brain GABA levels ranging from 15 to 45% after acute administration of VPA.[36,40] Tissue homogenization studies utilizing the VPA metabolite 2-en-VPA, noted to correlate with clinical anticonvulsant activity, have demonstrated that elevated brain GABA levels were localized to specific regions of the brain parenchyma, with larger increases noted in the substantia nigra (90%) than the hippocampus (10%).[15,41]
Current evidence does not suggest a direct role for VPA-mediated increase in brain GABA levels.[42] VPA does not appear to alter GABA uptake mechanisms nor does it appear to alter GABA complex receptor binding.[36] Rather, an indirect mechanism has been postulated, involving inhibition of the enzyme succinate semialdehyde dehydrogenase (SSA-DH) in the GABA
ingestions demonstrated that 71% of patients demon- strated lethargy while another 15% presented in coma.[23]
Higher drug levels were associated with an increased incidence of coma, with 100% of patients with levels greater than 850 mg/mL manifesting coma, as compared with 15% of total patients. Higher drug levels were also associated with respiratory depression requiring intuba- tion. Sixty-three percent of patients with serum VPA levels greater than 850 mg/mL required intubation, as compared with 8% of the total.[23] After acute overdose, coma has been noted to persist despite normal serum VPA levels, leading to speculation that metabolites rather than parent compound are responsible for at least part of the spectrum of CNS depression noted.[28]
Cerebral edema has been observed in both acute VPA overdose and chronic supratherapeutic dosing, with occasional fatal results.[44] The diagnosis has been made on clinical, radiological, and post-mortem basis. Khoo and Leyland reported the case of a comatose 19-year-old male who developed extensor plantar reflexes and bilateral papilledema 30 hours after ingestion of valpro- ate and salicylate. CT scan of the brain demonstrated gross cerebral edema.[44] Andersen and Ritland described the case of a 19-year-old female who, 4 days post-

shunt.[36,42] As a result of the GABA shunt, a- ingestion of 52 g VPA and 75 g clonazepam, developed

ketoglutarate undergoes transamination to glutamate, rather than continuing through the tricarboxylic acid (TCA) cycle to succinate. Glutamate is subsequently metabolized to GABA by the enzyme glutamate decarboxylase (GAD) and from GABA to succinate semialdehyde (SSA) via GABA-transminase (GABA-T). Finally, SSA is converted to succinate by SSA-DH, whereupon it re-enters the TCA cycle. VPA is a potent inhibitor of the enzyme SSA-DH and a weaker inhibitor of the enzymes GABA-T and a-ketoglutarate dehydro- genase, the enzyme responsible for forward metabolism of a-ketoglutarate towards succinate in the TCA cycle.
clinical evidence of cerebral edema.[28] CT scan of the head demonstrated only minor changes. Triggs et al. reported the case of a 27-year-old female, admitted to the hospital for refractory complex partial seizures and acutely administered VPA 35 mg/kg/day as part of an antiepileptic drug regimen.[46] By 36 hours after initiat- ing VPA therapy, the patient awoke only to painful stimuli. CT scan demonstrated evidence of massive cerebral edema with herniation. The patient died on hospital day 6. Janssen et al. reported the case of a 20- month-old male, previously healthy, who ingested 750 mg / kg VPA. Post-mortem findings demonstrated a

Valproic Acid Toxicity 793

high degree of cerebral edema.[47] Berthelot-Moritz et al. reported the case of a 34-year-old male who presented after a polysubstance overdose, including VPA, pheny- toin, and phenobarbital.[48] Clinical evidence of cerebral edema developed at 12 hours, and was confirmed by CT scan at 30 hours post-ingestion. Post-mortem findings confirmed cerebral edema with both temporal lobe and cerebellar herniation.
The etiology of the cerebral edema remains controversial. VPA-associated cerebral edema is described as occurring 48–72 hours post-inges-
expired 72 hours after arrival. Three percent of patients in a multi-center case series by Spiller et al. demonstrated hypotension as a manifestation of toxicity.[23] Twenty- five percent of patients with serum VPA levels
. 850 mg/mL developed episodes of hypotension. Tachycardia was present in 17% of patients with VPA intoxication.[23]

Gastrointestinal Toxicity

tion.[26,30,44] This delayed onset has previously been Pancreatitis has been associated with both chronic

attributed to the production of a neurotoxic metabolite, 2- en-VPA, a product of b-oxidation metabolism (Fig.
VPA therapy and acute overdose. First reported in 1979, the initial cases involved children chronically on VPA

3).[26,44,49] An alternate explanation may lie in the therapy, all of whom survived.[56 –58] Subsequent fatal-

finding that patients with cerebral edema have coincident hyperammonemia.[44] The case report by Berthelot- Moritz et al. is significant both for marked hyperammo- nemia (600 mmol/L, normal range 11–35 mmol/L) and for early development of cerebral edema (12 hours post- ingestion).[48] Further casting doubt upon the theory of 2- en-VPA as the etiology of cerebral edema is the observation of impaired b-oxidation in the setting of VPA toxicity, thus limiting the formation of 2-en-
ities have been reported.[59] Case reports have docu- mented pancreatitis in the setting of severe, acute overdose.[28,55]
In contrast with pancreatitis, cases of hepatotoxicity have been only rarely reported with acute overdose.[28,44]
With chronic administration, several distinct forms of hepatotoxicity have been described. As many as 44% of patients chronically treated with VPA develop a self- limited, reversible, and largely asymptomatic elevation

VPA.[34,35,50] Hyperammonemia, as a manifestation of of hepatic transaminases.[1,33] An idiosyncratic, rapidly

hepatic failure, is associated with cerebral edema under other circumstances.[51,52] Acute exposure to high levels of ammonia is directly toxic to neurons, causing
progressive hepatitis with histologic characteristics similar to Reye syndrome has also been reported.[60 –62]
Children under the age of 2 years on a multi-drug

stimulation of the NMDA receptor.[53,54] Hyperammo- antiepileptic regimen are most at risk, with a reported
nemia also caused decreased TCA cycle activity in incidence of 1/500–1/800 in contrast to the general
primary astrocyte cultures.[53] As a result of both NMDA population incidence of 1/5000–1/49,000.[33,34] The

activation and impaired energy production, disrupted regulation of cerebral osmotic gradients may result in cerebral edema.

Cardiovascular Toxicity

Hemodynamic instability, manifesting as hypoten- sion, has been reported in the setting of massive VPA ingestions. Andersen and Ritland described the case of a 27-year-old female who presented after ingestion of an unknown quantity of VPA.[28] Upon arrival, the patient was comatose, unresponsive to painful stimuli, with a
high incidence noted in young children with refractory seizure disorders requiring multiple drug regimens has led to the speculation that intrinsic mitochondrial abnormalities and other metabolic defects, with sub- sequent impaired VPA metabolism, underlie this form of hepatotoxicity.[63 –65] Altered VPA metabolism, mani- fest as markedly increased cytosolic v-oxidation products and absent mitochondrial b-oxidation products, have been demonstrated in patients with VPA-induced fulminant hepatic failure.[66,67] 4-en-VPA, a v-oxidation product normally present in low amounts, has been implicated in hepatotoxicity, possibly through metabolic

heart rate of 63 bpm and a blood pressure of
[67,68]
activation to an alkylating agent (Fig. 2).
It has been

70/45 mmHg. The initial serum VPA concentration was 1440 mg/mL. Connacher et al. reported the case of a 40- year-old female who presented after a witnessed generalized tonic–clonic seizure, and was subsequently
demonstrated to induce microvesicular steatosis in the rat.[68] Structurally, 4-en-VPA is similar to methylene- cyclopropylacetic acid, the hypoglycin A metabolite responsible for Jamaican vomiting sickness, and 4-

determined to have overdosed on VPA.[55] The patient pentenoic acid, a hepatotoxic agent, which produces a
developed progressive hypotension despite fluids, central Reye-like syndrome in rats (Fig. 2).[33,62] Concomitant
venous pressure monitoring, and pressor agents, and phenobarbital therapy, known to increase the incidence

794 Sztajnkrycer

of hepatotoxicity, also induces the cytosolic v-oxidation pathway.[69]
Both chronic use and acute overdose of VPA have been associated with hyperammonemia in the absence of
therapy.[83] VPA is esterified with carnitine to form valproyl-carntine ester as a means of translocating across the mitochondrial membrane. The valproyl-carnitine ester may subsequently cross the membrane into the

hepatotoxicity.[20,70 –74] Hyperammonemia, defined as cytosol, and be eliminated in the urine, resulting in a

plasma ammonia greater than 80 mg/dL, occurs in 35– 45% of patients chronically taking VPA.[34,75] The origin of the hyperammonemia noted with VPA therapy appears to be predominantly hepatic, from impaired urea cycle function and subsequent inability to metabolize nitrogen loads. A small contribution is made by the renal cortex, through enhanced glutamine uptake and increased glutaminase activity.[34,76]
The mechanism for excess hepatic ammonia pro- duction has been the source of much debate. Propionic acid had previously been demonstrated to inhibit the urea cycle enzyme carbamoyl phosphate synthetase I (CPS I) in vitro.[77] Coulter and Allen noted that propionic acid levels were elevated in patients treated with VPA who manifested hyperammonemia. They theorized that metabolic conversion of VPA to propionic acid or related compounds inhibited CPS I, with resultant impairment of the urea cycle and hyperammonemia. Coude et al. demonstrated in a rat model, however, that propionyl-CoA was not responsible for hyperammone- mia.[78] They further demonstrated a decrease in the level of N-acetylglutamate (NAGA), a required co-factor for CPS I activity, but preserved levels of CPS I, ornithine transcarbamylase (OTC), and NAGA synthetase activi- ties in the setting of VPA-induced hyperammonemia. Coude et al. concluded that valproyl-CoA or a closely related compound was the proximate inhibitor of mitochondrial ureagenesis. Clinical evidence that ele- vated levels of propionic acid did not cause hyper- ammonemia was provided by the case report of Mortensen et al.[30] Their patient, a 20-year-old female with a peak serum VPA concentration of 2120 mg/mL, demonstrated both elevated propionic acid levels and ammonia levels, however, elevations in ammonia preceded elevations in propionic acid. Studies examining 4-en-VPA have also failed to show any correlation between levels of 4-en-VPA and hyperammone-
relative carnitine deficiency and impairment of sub- sequent long-chain fatty acid metabolism.[84] A second potential mechanism for impaired b-oxidation is the formation of valproyl-CoA within the mitochondrial matrix, sequestering unbound CoASH and limiting availability.[85] Altered acyl-CoA / CoASH ratios result in impaired intermediary metabolism and energy production.[86 –88] Finally, the metabolite 2,4-dien-VPA appears to bind reversibly to the a-subunit of the trifunctional protein (TP), inhibiting b-oxidation.[89] As a result of effects on intermediary metabolism, VPA reduces levels of acetyl-CoA and glutamate, both of which are required for the synthesis of NAGA. The decreased NAGA, a co-factor for the enzyme CPS I, results in impaired urea production and subsequent hyperammonemia (Fig. 4a).[90,91]

Metabolic Toxicity

Hypernatremia and anion gap metabolic acidosis have
[16,23,25,92]
been noted in patients with VPA toxicity. Hypernatremia was noted in only 2 of 81 cases (2.5%) with a VPA level , 450 mg/mL compared with 5 of 27 patients (18.5%) with a peak drug level $ 450 mg/mL.[92]
Six percent of patients in a multi-center review of VPA ingestions manifested a metabolic acidosis, defined as serum bicarbonate , 20 mEq / L.[23] Anion gap greater than 15 mmol / L was noted in 26% of patients with serum levels $ 450 mg/mL. No patient with a level , 450 mg/mL demonstrated an anion gap.[92] Franssen et al. have speculated that the elevated anion gap is directly attributable to the VPA, rather than to lactic acidosis.[25] Lactic acidosis has also been reported, however, and attributed to circulatory compromise and

mia.[79,80] In fact, 4-en-VPA showed a negative hypotension.[16] Marked hypocalcemia has also been

correlation with plasma ammonia levels in patients on VPA monotherapy.[80]
Recent attention has turned to the role of L-carnitine in hepatic b-oxidation of fatty acids as a possible explanation for the observed hyperammonemia. Long-
noted, although the etiology remains unclear.[30]
Hypocalcemia (Ca # 3.4 mmol/L) was observed in six of 108 cases of acute VPA overdose, with 83% of episodes occurring in patients with serum VPA concentrations $ 450 mg/mL.[92] Acute renal failure has

term or high-dose VPA therapy has been associated with been associated with VPA intoxication.[23,28,44,93] One
carnitine deficiency. [34,81,82] Carnitine deficiency has percent of patients in the multi-center study by Spiller
been noted in nearly 80% of adults receiving VPA et al. manifested acute renal failure.[23]

Valproic Acid Toxicity

Figure 4. (a) Putative schematic of VPA-induced impaired mitochondrial b-oxidation with subsequent hyperammonemia. Gray lines indicate areas of impaired metabolic function. Gray arrows indicate loss of carnitine and ammonia from the cell, respectively. See text for details. NAGA: N-acetylglutamic acid, CPS I: carbamoyl phosphate synthetase I, Glu: glutamic acid, CoASH: coenzyme A. (b) Putative schematic of reversal of VPA-impaired mitochondrial b-oxidation with supplemental L-carnitine. Gray arrow indicates loss of valproyl-carnitine ester. See text for details. NAGA: N-acetylglutamic acid, CPS I: carbamoyl phosphate synthetase I, Glu: glutamic acid, CoASH: Coenzyme A.

Hematologic Toxicity

Thrombocytopenia is the most commonly observed hematologic toxicity.[28] Leukopenia has been reported to occur in several case reports, but anemia is uncommon. Both patients reported by Andersen and Ritland manifested a moderate anemia requiring

795

penia and leukopenia in a multi-center study of VPA ingestion were 8 and 3%, respectively.[23]

MANAGEMENT OF TOXICITY

Basic toxicologic principles should be applied to the clinical management of patients suffering from VPA intoxication. Close attention should be given to the airway, given the incidence of CNS depression and coma. Endotracheal intubation was required in 63% of patients with serum VPA concentrations above 450 mg/mL in one case series.[92] Due to delayed peak serum levels in overdose, serial levels should be obtained.[19,24] Patients should not be considered medically stable for discharge until levels are documen- ted to be in the therapeutic range, serial levels are noted to be declining, and clinical evidence of toxicity has resolved. Patients have been noted to be comatose with normal serum VPA concentrations, a finding attributed to the presence of unmeasured metabolites, such as 2-en-
[20,28,70,74,94,95]
VPA, or to hyperammonemia. For this reason, serum ammonia concentrations should also be measured in all patients presenting after VPA ingestion and in all patients on VPA therapy presenting with alterations in level of consciousness.

Decontamination

In accordance with current ACCT/EAPCC guide- lines, all patients presenting within 1 hour of ingestion and without evidence of contraindications should be administered a dose of activated charcoal.[96] Whole bowel irrigation has also been used, although change in patient outcome has not been demonstrated.[19] How- ever, initiation of whole bowel irrigation in this case report was delayed 14 hours until a peak VPA serum concentration of 1380 mg/mL was reached. Given the delay to peak serum concentration with significant ingestions, and the presence of sustained release and enteric-coated preparations, whole bowel irrigation may have a role in decontamination of selected cases. Further studies are needed to determine the indications for this gastric decontamination modality in VPA intoxication.

Enhanced Elimination

Post-mortem findings have demonstrated high VPA concentrations in bile, suggesting the presence of

transfusion.[28] The overall incidences of thrombocyto- enterohepatic recirculation of drug.[55] This has led to

796 Sztajnkrycer

the use of multiple-dose activated charcoal adminis- tration in acute VPA intoxication, with mixed results. Graudins and Aarons reported the case of a 32-year-old female who presented after ingestion of 30 g of VPA.[19]
An initial VPA level of 105 mg/mL continued to rise despite three doses of activated charcoal over 14 hours. At this point, the patient’s serum VPA concentration was noted to be 1380 mg/mL, and multiple-dose activated charcoal and whole bowel irrigation were started. Three hours later, due to continued lack of clinical effect or change in serum drug concentration, charcoal hemoper- fusion was initiated. In contrast, Farrar et al. reported the case of a 26-month-old previously healthy male who
hemodialysis decreased serum half-life from 23.41 to 2.74 hours, coincident with improved mental status and cardiovascular function.[100] Absolute serum VPA level or coma should not be used as an indication for extracorporeal elimination.[102] Rather, the decision should be based upon the presence of persistent hemodynamic instability or persistent metabolic acidosis unresponsive to fluids.

Antidotal Therapy

Several case reports have examined the utility of naloxone in the management of acute VPA intoxi-

ingested at least 4.5 g VPA and subsequently presented to
[103 –106]
cation.
In the initial case report, Steiman et al.

the ICU comatose and acidotic.[17] The patient received continuous activated charcoal by nasogastric tube at 3 g/h. The half-life with continuous activated charcoal was determined to be 4.8 hours, in contrast to typical half-lives of 10–16 hours. The patient awoke 24 hours later without sequelae, after the serum VPA concen- tration fell to 56 mg/mL from a peak of 815 mg/mL. A single controlled study examined the effects of multiple-dose activated charcoal in seven healthy volunteers after administration of VPA 300 mg.[18] In the setting of therapeutic VPA dosing, multiple-dose activated charcoal did not enhance the rate of drug elimination. Multiple-dose activated charcoal has not been demonstrated to alter clinical course or outcome, and has been associated with adverse events including aspiration and bowel obstruction.[97] Therefore, on the basis of current information, the routine use of multiple- dose activated charcoal in VPA intoxication cannot be recommended.

Extracorporeal Elimination
reported the use of naloxone 0.01 mg/kg IV in a patient with an apparent opioid toxidrome after accidental VPA ingestion.[103] Within 3 minutes of receiving the dose, the patient was alert and conversant. Twenty minutes later, as the patient became somnolent, a second dose of naloxone provided similar response. No opiate agents were detected on a serum toxicologic screen. Espinoza et al. described the case of a 3-year-old male who developed ataxia and coma after accidental ingestion of VPA 500 mg.[106] On arrival, the patient was noted to be in deep coma, with pin-point pupils and depressed respirations. Within a few minutes of receiving 0.1 mg naloxone, the patient returned to an acceptably consciousness level. In other cases, however, naloxone administration has been demonstrated to have no effect.[30]
L-carnitine has been increasingly recommended in the management of VPA-induced hyperammonemia. The 1996 Pediatric Neurology Advisory Committee con- sensus guidelines classify intravenous L -carnitine administration as clearly indicated for all cases of VPA overdose, and strongly recommend the administration of carnitine in symptomatic VPA-induced hyperammone-

At therapeutic concentrations, VPA is 90% protein- mia.[84] Case reports have documented correction of
bound and therefore not readily amenable to extra- impaired b-oxidation with supplemental L -carni-
corporeal elimination. The degree of protein binding tine.[35,50] Cell culture experiments have demonstrated

reflects serum concentration, however, with saturation of protein binding sites occurring at levels greater than 150 mg/mL.[13,16] At levels greater than 300 mg/mL, only
inhibition of hyperammonemia and presence of ketone body formation in primary rat hepatocytes grown in VPA-containing culture media supplemented with L-

35% of the drug is protein-bound.[16,25] In this setting, carnitine.[107] The mechanism of action of L-carnitine

extracorporeal elimination becomes a viable option and has been used with success. Initial case reports demon- strated success with hemoperfusion or combined hemo- dialysis–hemoperfusion modalities.[14,25,29,30,45,98 – 100]
Serum half-lives fell from predialysis levels of 13 hours to as low as 1.7 hours with extracorporeal removal.[100]
supplementation in reversing VPA-induced hyperammo- nemia remains speculative. It has been suggested that carnitine, required to allow long-chain fatty acids to cross the mitochondrial membrane, is relatively depleted in patients on VPA therapy.[34,85] Supplemental carnitine is speculated to work by acting as an acceptor of toxic acyl

More recently, high-flux hemodialysis has been groups, such as valproyl-CoA.[34,107] The valproyl-
used as monotherapy.[16,101] In one study, high-flux carnitine ester is subsequently excreted in the urine.

Valproic Acid Toxicity 797

The resultant normalization of acyl-CoA/CoASH ratios within the mitochondrion reverses the inhibition of b- oxidation, which in turn generates acetyl-CoA. The generation of acetyl-CoA allows for the formation of NAGA, and the subsequent detoxification of ammonia to urea, thereby correcting hyperammonemia (Fig. 4b).[107]
L-carnitine supplementation appears to be well tolerated, with few adverse reactions reported.[34,108]
A fishy body odor has been observed, as have gas- trointestinal disturbances. The appropriate dose and route of carnitine supplementation remains to be determined. The 1996 Pediatric Neurology Advisory Committee consensus guidelines recommended oral administration of 100 mg/kg/day up to 2 g/day in divided doses for supplementation.[84] In overdose or hyperammonemia, intravenous carnitine 150–500 mg/kg/day up to 3 g/day has been recommended. Ishikura et al. reported the use of 100 mg/kg L-carnitine IV, followed by 250 mg/kg IV every 8 hours for 4 days, a dose that has since been
given the relative safety profile of L-carnitine, and the potential for cerebral edema secondary to the hyper- ammonemia, it remains reasonable to provide L-carnitine supplementation to patients with acute VPA intoxication and hyperammonemia.

CONCLUSION

VPA intoxication is an increasing problem facing the medical community. AAPCC TESS database figures demonstrate a greater than 700% increase in calls regarding VPA in the past decade.[10,12] Since the FDA granted approval to utilize VPA as a mood stabilizer in 1995, the number of intentional exposures has surpassed the number of accidental exposures.
Despite these facts, there is still much that is unknown regarding the pharmacology and toxicology of VPA. Fundamental questions about the mechanism of drug

employed in adults.[35,95,109] Though this dose exceeds action have yet to be answered. Appropriate management

the maximum recommended daily dose, no adverse reactions have been reported to date. Murakami et al. reported the use of L-carnitine 100 mg/kg/day by nasogastric tube for 3 days.[50] Thole et al. recommended 25 mg/kg IV every 6 hours in acute overdose.[110] In the case series reported by Sztajnkrycer et al., one patient received 150 mg/kg IV followed by 500 mg IV every 8 hours, while another patient received 3000 mg po load followed by 660 mg po every 8 hours.[109]
Although L-carnitine supplementation is recom- mended for VPA-induced hyperammonemia and acute overdose, there is no evidence that L-carnitine sup- plementation changes clinical outcome. The 15-month- old male described by Murakami et al. regained consciousness on hospital day 3 despite L-carnitine administration for 3 days.[50] Similarly, the 16-month-old male treated by Ishikura et al. remained comatose until his serum VPA concentration reached therapeutic levels on day 4, despite 4 days of L-carnitine supplemen- tation.[35] Analysis of urine metabolites in both cases did document reversal of inhibition of b-oxidation by the second day. A kinetic study of ammonia metabolism in the presence and absence of L-carnitine supplementation demonstrated a serum ammonia half-life of 6:1 ^ 3:6 hours for the L-carnitine-supplemented group and
[109]
42:1 ^ 42:1 hours in the control group. The differ- ence was not significant. The study was limited by small sample sizes, the lack of consistent L-carnitine dosing regimens, the use of additional treatment modalities including hemodialysis, and the use of literature-based historical controls. Despite of the lack of available data,
strategies remain elusive. Which patients would benefit from whole bowel irrigation? Who requires extracorpo- real elimination? At what point should such therapy be instituted? Although serum VPA concentrations are not felt to be an indication, extracorporeal removal would ideally be instituted prior to development of hemody- namic instability.[102] Is there a role for naloxone and L-carnitine in the management of the VPA-intoxicated patient? It is clear that further studies are needed to answer these questions satisfactorily.

ACKNOWLEDGMENTS

Aspects of this paper were initially presented during the AACT Acute and Intensive Care Symposium: Toxicology Diagnostic and Treatment Dilemmas, 2001 North American Congress of Clinical Toxicology, Montreal.

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