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Valproic acid (VPA) overdose most commonly presents with gradations of central nervous system (CNS) depression, but in the most severe forms can lead to fatal cerebral edema and coma.1-3 Typical management includes supportive therapy and consideration of carnitine supplementation or dialysis. We present a case of massive VPA overdose that was managed using a combination of standard of care therapies with an unusual therapy, meropenem. We then discuss the risks and benefits of using meropenem for VPA toxicity.
A 28-year-old male (58 kg) with a history of seizure disorder status post ventriculoperitoneal (VP) shunt, depression, anxiety, atrial fibrillation, and prior overdose presented to the Emergency Department (ED) due to altered mental status and possible overdose. He was found unresponsive at his homeless shelter with empty bottles of VPA and levetiracetam. Review of the patient’s medical record found that he had also previously been prescribed fluoxetine (20 mg QD) and gabapentin (300 mg TID).
The patient presented unresponsive with a GCS of 8. His initial vitals were blood pressure 124/81 mmHg, heart rate 116 beats/minute, respiratory rate 19 respirations/ minute, oxygen saturation 100%, and glucose 76 mg/dL. He had an elevated ammonia concentration of 99 µmol/L (ref range 6-47 µmol/L), lactic acid concentration of 3.5 mmol/L (ref range 0.9-1.7 mmol/L), and VPA concentration of 984 mcg/mL (reference range 50-100 mcg/mL). Other pertinent labs included a normal comprehensive metabolic panel (CMP), undetectable acetaminophen and salicylate concentrations, a negative urine drug screen, and an ethanol concentration of 16 mg/dL (ref range <10 mg/dL). His chest x-ray and CT head were negative for significant findings. His electrocardiogram revealed no significant abnormalities.
The patient was intubated due to CNS depression and inability to maintain his airway. Poison Control, the ED pharmacy team, the medical intensive care unit (MICU), and nephrology were consulted. He received 50 g activated charcoal via nasogastric tube (NG), 2 g meropenem intravenously (IV), 6,300 g L-carnitine (IV), and emergent hemodialysis.
He required norepinephrine due to progressively worsening hypotension that persisted after being intubated. He had mean arterial pressures (MAP) ranging from 48-60. He received a bolus of D10 via IV. Approximately 40 minutes after this hypotensive episode, his vitals stabilized with MAP consistently greater than 100. He was given 2 mg of IV lorazepam and 2 mg of IV midazolam due to seizures. Sixteen hours after his presentation, his VPA concentration was therapeutic at 62 mcg/mL and at 19 hours he was extubated. Upon discharge from the MICU, he was transferred to the psychiatry service.
Valproic acid acid is a branched chain carboxylic acid used for treating seizures, mania, bipolar disorder, and migraines. Reported mechanisms of action include blocking voltage gated sodium channels, increasing brain GABA concentrations, and inhibiting T-type calcium channels.4 Patients who ingest more than 200 mg/kg and/or have serum concentrations greater than 180 mcg/mL are at risk for CNS effects and metabolic derangements.4,5 Significant CNS depression can lead to respiratory depression and hypoventilation, potentially requiring intubation and mechanical ventilation.5,6 Other life-threatening complications from VPA overdose include cerebral edema and hemorrhagic pancreatitis, although these occur infrequently.6 Metabolic derangements associated with VPA overdose include anion gap metabolic acidosis, hypernatremia, hypocalcemia, and hyperammonemia.5,7,8
VPA is metabolized via three primary methods, including glucuronidation, beta-oxidation in the mitochondria, and cytochrome P450. Glucuronidation is the primary route, accounting for nearly 50% of total metabolism.9 In-vitro studies of human liver microsomes have identified a host of enzymes that are responsible for glucuronidation of VPA, thereby enabling its excretion by converting it to its water soluble form (VPA-G).9,10 VPA is a fatty acid, and therefore undergoes similar metabolism as free fatty acid (FFA). This occurs in the mitochondria via beta-oxidation and accounts for roughly 40% of VPA metabolism. The remaining 10% of VPA metabolism is through the CYP-450 system and is considered a minor pathway. Some of the mitochondrial metabolites generated in this process are hepatotoxic.9
VPA decreases the concentration of carnitine by increasing urine excretion, decreasing tubular reabsorption, reducing endogenous synthesis, inhibiting carnitine transporters into the cell, and inhibiting carnitine storage.11,12 With reduced carnitine available for fatty acid metabolism, hyperammonemia ensues.13 This occurs because carnitine is an essential cofactor in the metabolism of long-chain fatty acids. Specifically, carnitine plays a key role in transporting fatty acids to the mitochondrial matrix, where beta-oxidation occurs. Therefore, reduced carnitine availability will lead to an accumulation of unmetabolized fatty acids that disrupt the urea cycle.13 Prior research has established an association between decreased carnitine levels and VPA associated hyperammonemia.14,15
Traditional overdose therapies include gastrointestinal decontamination, supplementation with carnitine, and consideration for dialysis. Researchers theorize that supplementing depleted carnitine levels may improve VPA associated encephalopathy (VPE) by mitigating hyperammonemia.11 This is believed to occur by restoring the carnitine transport chain needed for beta-oxidation of VPA and thereby reducing the accumulation of cytosolic fatty acids that interferes with the urea cycle.11 Bohles et al. identified 14 patients with hyperammonemia who were undergoing treatment with VPA. They had ammonia concentrations greater than 50 µmol/L. They were treated with L-carnitine 500 mg/m2 twice daily and experienced normalization of serum ammonia.16 A 2010 systematic review concluded that it is reasonable to use L-carnitine in patients with VPA overdose and CNS effects.17
As for the use of hemodialysis in treating VPA-induced hyperammonemia, this mechanism has been well researched by the Extracorporeal Treatment in Poisoning (EXTRIP) workgroup and these studies have found that VPA is moderately dialyzable.18,19 A systematic review of 79 articles found that patients with VPA-induced hyperammonemia experienced clinical improvement in regard to mental status, respiratory depression, and hemodynamics.19 In recent years, the interaction of carbapenem antibiotics and VPA serum concentration has been explored.20-23 While this research provided the foundation for using carbapenems for VPA overdose, it is also important to consider the associated risks. As such, we reviewed the available evidence to better understand the benefits and risks of this emerging therapy.
Carbapenem antibiotics, specifically meropenem, are a novel treatment for VPA overdose as they lower VPA concentration.20-23 This occurs because carbapenems inhibit acylpeptide hydrolase. Acylpeptide hydrolase, located in the hepatocytes, removes the glucuronic acid group from VPA-G. In doing so, VPA-G is converted back into its active form, VPA, thus reducing its excretion in urine and bile.20,24 Without this enzyme, the recycling process is inhibited and more rapid elimination occurs. Wu et al. recorded VPA concentrations before and after carbapenem administration. These patients were receiving maintenance anti-epileptic treatment primarily for seizure prevention (79% of patients) and antibiotic therapy for pneumonia (54%). This study found that VPA concentrations were subtherapeutic in 90% of subjects within 24 hours.23 In another study, researchers analyzed VPA levels of patients receiving both VPA and meropenem and saw a reduction of > 70% of VPA levels compared to values before initiating meropenem.21 Another retrospective analysis of 36 patients found that the mean reduction of serum VPA levels was > 80% after starting meropenem.22 These findings suggest that carbapenem antibiotics may play a role in the management of VPA overdose.
Given that L-carnitine, hemodialysis, and supportive care demonstrated adequate results in treating VPA overdose, the addition of meropenem requires careful consideration as there are associated risks.1,11,17,19,25 The primary concern with the use of meropenem in serum VPA concentration reduction revolves around the prolonged inhibition of acylpeptide hydrolase.26 This inhibition increases the risk of seizure-like activity in patients on VPA for anti-epileptic purposes, as the therapeutic serum levels are not maintained due to decreased recycling of the VPA.23,27 As a result of the reduction in serum VPA concentration after carbapenem administration, one study found that 48% of patients being treated for epilepsy with maintenance VPA experienced increased seizure frequency.27
This study demonstrated the potential effect of carbapenem on VPA concentration and the resulting clinical outcome. Therefore, providers must weigh these risks against the existing treatment modalities that have demonstrated effectiveness. On one hand, meropenem has been shown to reduce VPA concentration by 50-80% within 24-48 hours.21,23,27 However, when hemodialysis alone was used, valproic serum half-life was markedly reduced, and clinical improvement was rapid.19 These studies support the theory that hemodialysis is an effective treatment, thus raising the question of the need for an intervention which may have uncertain consequences.
In the case being reviewed above, the patient had reduction of VPA levels from 984 mcg/mL to 109 mcg/mL over 7 hours after 1 course of hemodialysis and 2 g of meropenem. During this time, the patient’s clinical status improved. However, it is uncertain which treatment method contributed more to the changes in the patient’s status. With this in mind, it is important to consider the risk profile of each intervention. There are risks to the use of hemodialysis in all patients, including blood pressure changes, metabolic derangements, access site complications, and several others. Although after reviewing the EXTRIP guidelines, there were no specific risks for hemodialysis in VPA overdose patients.19 As such, hemodialysis may be considered the safer option. Conversely, there is data to support the risk of precipitating seizure- activity with the use of carbapenems.
In summary, this case raised the question of whether the addition of meropenem to an already proven VPA overdose treatment regimen was worth the ongoing risk of precipitating seizure activity. While studies have not been done to specifically examine this question, it is a valuable consideration when determining the best course of treatment for a patient.
Emergency Medicine physicians must be able to diagnose and manage toxicologic emergencies, such as VPA overdose. Additionally, they must be able to lead and collaborate with multidisciplinary teams in order to weigh the risks and benefits of therapies, including L-carnitine, meropenem, and emergent hemodialysis for VPA overdose. Future research is needed to better understand the role, if any, of using meropenem for VPA overdose among patients with a known seizure disorder.
- G. O. Andersen and S. Ritland, “Life threatening intoxication with sodium valproate,” J. Toxicol. Clin. Toxicol., vol. 33, no. 3, pp. 279–284, 1995, doi: 10.3109/15563659509018000.
- S. H. Khoo and M. J. Leyland, “Cerebral edema following acute sodium valproate overdose,” J. Toxicol. Clin. Toxicol., vol. 30, no. 2, pp. 209–214, 1992, doi: 10.3109/15563659209038632.
- R. E. Dupuis, S. N. Lichtman, and G. M. Pollack, “Acute valproic acid overdose. Clinical course and pharmacokinetic disposition of valproic acid and metabolites,” Drug Saf, vol. 5, no. 1, pp. 65–71, Feb. 1990, doi: 10.2165/00002018-199005010-00006.
- M. D. Sztajnkrycer, “Valproic acid toxicity: overview and management,” J. Toxicol. Clin. Toxicol., vol. 40, no. 6, pp. 789–801, 2002, doi: 10.1081/ clt-120014645.
- H. A. Spiller et al., “Multicenter case series of valproic acid ingestion: serum concentrations and toxicity,” J. Toxicol. Clin. Toxicol., vol. 38, no. 7, pp. 755–760, 2000, doi: 10.1081/clt-100102388.
- F. Eyer, N. Felgenhauer, K. Gempel, W. Steimer, K.-D. Gerbitz, and T. Zilker, “Acute Valproate Poisoning: Pharmacokinetics, Alteration in Fatty Acid Metabolism, and Changes During Therapy,” Journal of Clinical Psychopharmacology, vol. 25, no. 4, pp. 376–380, Aug. 2005, doi: 10.1097/01.jcp.0000168485.76397.5c.
- R. J. Evans, R. N. Miranda, J. Jordan, and F. J. Krolikowski, “Fatal Acute Pancreatitis Caused by Valproic Acid,” The American Journal of Forensic Medicine and Pathology, vol. 16, no. 1, pp. 62–65, Mar. 1995.
- S. A. Antoniuk, I. Bruck, L. R. Hönnicke, L. T. Martins, J. E. Carreiro, and R. Cat, “[Acute hepatic failure associated with valproic acid in children. Report of 3 cases],” Arq Neuropsiquiatr, vol. 54, no. 4, pp. 652–654, Dec. 1996, doi: 10.1590/s0004-282x1996000400015.
- Y. Ghodke-Puranik et al., “Valproic acid pathway: pharmacokinetics and pharmacodynamics,” Pharmacogenet Genomics, vol. 23, no. 4, pp. 236–241, Apr. 2013, doi: 10.1097/FPC.0b013e32835ea0b2.
- PubChem, “Valproic acid glucuronide.” https://pubchem.ncbi.nlm. nih.gov/compound/88111 (accessed Jun. 15, 2020).
- P. E. R. Lheureux and P. Hantson, “Carnitine in the treatment of valproic acid-induced toxicity,” Clin Toxicol (Phila), vol. 47, no. 2, pp. 101–111, Feb. 2009, doi: 10.1080/15563650902752376.
- F. A. Moreno, H. Macey, and B. Schreiber, “Carnitine levels in valproic acid-treated psychiatric patients: a cross-sectional study,” J Clin Psychiatry, vol. 66, no. 5, pp. 555–558, May 2005, doi: 10.4088/jcp. v66n0502.
- B. N. Limketkai and S. D. Zucker, “Hyperammonemic encephalopathy caused by carnitine deficiency,” J Gen Intern Med, vol. 23, no. 2, pp. 210–213, Feb. 2008, doi: 10.1007/s11606-007-0473-0.
- H. Ishikura, N. Matsuo, M. Matsubara, T. Ishihara, N. Takeyama, and T. Tanaka, “Valproic acid overdose and L-carnitine therapy,” J Anal Toxicol, vol. 20, no. 1, pp. 55–58, Feb. 1996, doi: 10.1093/jat/20.1.55.
- I. Matsuda and Y. Ohtani, “Carnitine status in Reye and Reye-like syndromes,” Pediatr. Neurol., vol. 2, no. 2, pp. 90–94, Apr. 1986, doi: 10.1016/0887-8994(86)90062-7.
- H. Böhles, A. C. Sewell, and D. Wenzel, “The effect of carnitine supplementation in valproate-induced hyperammonaemia,” Acta Paediatr., vol. 85, no. 4, pp. 446–449, Apr. 1996, doi: 10.1111/j.1651- 2227.1996.tb14058.x.
- J. Perrott, N. G. Murphy, and P. J. Zed, “L-carnitine for acute valproic acid overdose: a systematic review of published cases,” Ann Pharmacother, vol. 44, no. 7–8, pp. 1287–1293, Aug. 2010, doi: 10.1345/aph.1P135.
- S. Gupta, A. Z. Fenves, and R. Hootkins, “The Role of RRT in Hyperammonemic Patients,” CJASN, vol. 11, no. 10, pp. 1872–1878, Oct. 2016, doi: 10.2215/CJN.01320216.
- M. Ghannoum et al., “Extracorporeal treatment for valproic acid poisoning: systematic review and recommendations from the EXTRIP workgroup,” Clin Toxicol (Phila), vol. 53, no. 5, pp. 454–465, Jun. 2015, doi: 10.3109/15563650.2015.1035441.
- D. Dreucean, K. Beres, A. McNierney-Moore, and D. Gravino, “Use of meropenem to treat valproic acid overdose,” Am J Emerg Med, vol. 37, no. 11, p. 2120.e5-2120.e7, 2019, doi: 10.1016/j.ajem.2019.158426.
- Z.-P. Wen et al., “Drug-drug interaction between valproic acid and meropenem: a retrospective analysis of electronic medical records from neurosurgery inpatients,” J Clin Pharm Ther, vol. 42, no. 2, pp. 221–227, Apr. 2017, doi: 10.1111/jcpt.12501.
- S. Haroutiunian, Y. Ratz, B. Rabinovich, M. Adam, and A. Hoffman, “Valproic acid plasma concentration decreases in a dose-independent manner following administration of meropenem: a retrospective study,” J Clin Pharmacol, vol. 49, no. 11, pp. 1363–1369, Nov. 2009, doi: 10.1177/0091270009334377.
- C.-C. Wu, T.-Y. Pai, F.-Y. Hsiao, L.-J. Shen, and F.-L. L. Wu, “The Effect of Different Carbapenem Antibiotics (Ertapenem, Imipenem/ Cilastatin, and Meropenem) on Serum Valproic Acid Concentrations,” Ther Drug Monit, vol. 38, no. 5, pp. 587–592, 2016, doi: 10.1097/ FTD.0000000000000316.
- E. Suzuki, D. Nakai, N. Yamamura, N. Kobayashi, O. Okazaki, and T. Izumi, “Inhibition mechanism of carbapenem antibiotics on acylpeptide hydrolase, a key enzyme in the interaction with valproic acid,” Xenobiotica, vol. 41, no. 11, pp. 958–963, Nov. 2011, doi: 10.3109/00498254.2011.596582.
- A. Graudins and C. K. Aaron, “Delayed peak serum valproic acid in massive divalproex overdose--treatment with charcoal hemoperfusion,” J. Toxicol. Clin. Toxicol., vol. 34, no. 3, pp. 335–341, 1996, doi: 10.3109/15563659609013799.
- Y. Masuo, K. Ito, T. Yamamoto, A. Hisaka, M. Honma, and H. Suzuki, “Characterization of inhibitory effect of carbapenem antibiotics on the deconjugation of valproic acid glucuronide,” Drug Metab. Dispos., vol. 38, no. 10, pp. 1828–1835, Oct. 2010, doi: 10.1124/dmd.110.034231.
- C.-R. Huang et al., “Drug interaction between valproic acid and carbapenems in patients with epileptic seizures,” Kaohsiung J. Med. Sci., vol. 33, no. 3, pp. 130–136, Mar. 2017, doi: 10.1016/j.kjms.2016.12.001.