Elimination occurs via first-order kinetics with a half-life of 5-20 hours; however, this can be prolonged up to 30 hours with toxicity.At toxic levels, VPA can cause central nervous system depression, respiratory depression, acute kidney injury, anion-gap metabolic acidosis, and electrolyte abnormalities . VPA is also associated with hepatotoxicity, pancreatitis, hyperammonemic encephalopathy, cerebral edema, and blood dyscrasias such as leukopenia, anemia, and thrombocytopenia. Treatment of VPA toxicity is largely supportive; however, it can include enhanced elimination methods such as charcoal hemoperfusion and hemodialysis . HD is known to clear toxins that are water soluble, have low volume of distribution, and are not highly bound to plasma proteins. VPA exhibits high plasma protein binding with therapeutic concentrations; however, saturation of plasma proteins may occur in the setting of acute intoxication and result in increased free VPA concentrations amenable to HD.While published data are limited, high-flux HD has been shown to be sufficient without the need for concomitant charcoal hemoperfusion.Furthermore, HD should be considered to remove ammonia or correct severe metabolic disturbances during VPA toxicity. Hyperammonemia caused by VPA toxicity is a complex process; it involves depletion of carnitine stores and ultimately results in inhibition of carbamoyl-phosphate synthetase,cannabis indoor growing the primary enzyme responsible for ammonia incorporation into the urea cycle. The use of L-carnitine in the treatment of VPA-induced hyperammonemia is secondary to its ability to assist in the metabolism of long-chain fatty acids. We present a patient with two presentations of VPA toxicity, eight months apart, each successfully treated with HD and L-carnitine.
The cases presented provide insight on the detrimental effects that VPA toxicity can cause and review current evidence-based treatment options. Additionally, the second presentation sheds light on the unfortunate repercussions that an incomplete discharge reconciliation can have, namely the lack of patient care transition from inpatient to outpatient when a significant medication event occurred in hospital and subsequent medication changes were made. A 32-year-old African-American male with a history of bipolar disorder, hypertension, and previous suicide attempts was brought to the emergency department with altered mental status . The patient ingested an unknown amount of his prescription medications with the timing unknown. He was prescribed lisinopril 10mg by mouth daily, hydrochlorothiazide 25mg PO daily, and divalproex sodium delayed release 500mg PO every morning and 1000mg PO nightly. Upon presentation, the patient was responsive only to painful stimuli with a Glasgow Coma Score of 12. Vitals included a blood pressure of 152/70 mmHg and heart rate of 110 beats per minute. Computed tomography of the brain/head was unremarkable. However, magnetic resonance imaging revealed cerebral edema and possible laminar necrosis. On presentation, pertinent laboratory values included the following: VPA 481.9 µg/dL, lactate 6.9 mmol/L, ammonia 303 µmol/L, and platelets 135 x 103 microL and serum creatinine 2.61 mg/dL. Other chemistries and liver function tests were within normal limits . The urine drug screen, serum alcohol level, acetaminophen level, and salicylate level were unremarkable. The patient required intubation for AMS and acute respiratory failure, and a temporary dialysis catheter was emergently placed for HD. Prior to HD and three hours after initial presentation, VPA level rose to greater than 600 µg/mL .
The patient was dialyzed six hours after presentation for a total of six hours; post HD he was started on intravenous L-carnitine 1,300 mg q4h based on literature recommendations and received lactulose 30 grams PO once.8 During his hospitalization, platelets reached a nadir of 63 x 103 microL, but other pertinent laboratory results remained WNL. The patient improved clinically to include a GCS of 15, allowing successful extubation on hospital day 2. VPA was not to be continued upon discharge and he was transferred to a psychiatric facility for further evaluation.During the second presentation, the patient was found unconscious and diaphoretic in his bedroom by his caregiver. He had AMS and was unable to communicate effectively. Home medications included venlafaxine 75 mg PO daily, benztropine 2 mg PO daily and divalproex sodium DR 500 mg PO twice daily. Although he was not discharged on divalproex sodium during his last visit, he had continued to refill this prescription at his outpatient pharmacy. Notably, the patient also had been using marijuana regularly the previous week. Baseline laboratory values on arrival include the following abnormalities: ammonia 48 µmol/L, VPA level 420 µg/mL, lactate 2.6 mmol/L, glucose 67 mg/dL, and platelets 127 x 103 microL. Other laboratory values were WNL. Although he did not immediately require HD, nephrology was emergently consulted in light of the complications of his previous admission. A repeat VPA level of 272 µg/mL was drawn five hours after the initial level before HD , and the patient was dialyzed for four hours. L-carnitine 2,640 mg PO q8h and lactulose 10 g PO four times a day were initiated. Laboratory findings one hour after HD included ammonia 84 µmol/L and VPA level 105 µg/ mL. His mental status and symptoms improved , and the patient was able to follow commands appropriately. He was discharged on hospital day 2 to a psychiatric facility with instructions to continue L-carnitine 2,640 mg PO every eight hours given continued elevation in ammonia levels. This presentation scored a 10 on the Naranjo scale indicating a definite adverse drug reaction.We present a unique patient with two separate presentations of VPA toxicity necessitating aggressive measures and treatment with HD and L-carnitine. On the first admission, cerebral edema was visualized on MRI and a peak VPA level of greater than 600 µg/mL was reduced to 199 µg/L at the end of a six-hour HD session.
During the second admission, a peak level of 420 µg/mL decreased to 105 µg/mL after a four-hour HD session. While VPA is highly protein bound, plasma proteins become saturated during VPA toxicity, causing an increase in unbound VPA that contributes to the signs and symptoms of toxicity. These small molecules become amenable to elimination via HD allowing for more rapid decline in the serum concentration and subsequent improvement in symptoms of toxicity, as evidenced by the patient’s first presentation. Historically, charcoal hemoperfusion was used for the treatment of VPA toxicity.However, previous case reports describe the effectiveness of using HD alone. What remains unclear is the threshold in VPA concentrations where HD may be useful. Based on the literature available,cannabis grow kit the EXtracorporeal TReatments in Poisoning workgroup recommends dialysis in patients with a VPA concentration greater than 1,300 mg/L, the presence of cerebral edema, or shock.Dialysis may be used when VPA concentrations are greater than 900 µg/mL, in the presence of coma, respiratory depression requiring mechanical ventilation, acute hyperammonemia, or pH less than 7.1.Similarly, a review article evaluating extracorporeal elimination of VPA advises HD in severe VPA toxicity and a plasma VPA level >850 µg/ mL.During our patient’s first presentation, the suggested criteria for HD were met due to the presence of cerebral edema on MRI and the need for mechanical ventilation. In the second presentation, AMS and his ingestion history drove the decision for HD. In a patient with therapeutic VPA concentrations, HD should not significantly impact VPA levels; it may be a viable option in acute toxicity by reducing free drug and improving clinical condition.VPA is metabolized primarily in the liver by means of glucuronic acid conjugation and oxidative pathways via the cytochrome P450 system. The major metabolites are 2-en-VPA, 4-en-VPA, and propionic acid derivatives which are active. 2-en-VPA has a long half-life and causes cerebral edema and coma, while 4-en-VPA causes reversible hepatotoxicity. Propionic acid is responsible for causing hyperammonemia by three proposed mechanisms. Its interaction with and depletion of carnitine impairs the transportation and metabolism of long-chain fatty acids. Also, it prevents glutamine production in the kidneys, which reduces ammonia levels in the brain. Lastly, it inhibits carbamoylphosphate synthetase, a hepatic mitochondrial enzyme responsible for eliminating ammonia within the urea cycle. The cumulative result is accumulation of ammonia, causing encephalopathy. L-carnitine has the ability to transport and metabolize long-chain fatty acids; thus, it has shown to be beneficial in VPA-induced hyperammonemia, especially in patients with hepatotoxicity, hyperammonemia, or significant CNS depression.An interesting aspect of our case was the reported increase in cannabis use during the week prior to the second VPA ingestion. To our knowledge, there are no reports of VPA toxicity caused by cannabis ingestion. However, cannabidiol, a component of marijuana, weakly inhibits the CYP2C9 pathway. In addition, delta-9-tetrahydrocannabinoid has high plasma lipoprotein binding.
The potential for weak inhibition of VPA metabolism via CYP2C9 and displacement of protein binding due to cannabis could have contributed to the toxicity, but this interaction has not been studied.Of most interest, is the demonstration of the importance of involving a patient’s outpatient pharmacy when a medication is discontinued for toxicity. This patient’s VPA was discontinued upon discharge after the first overdose; unfortunately, measures were not put in place to prevent patient access to medication. Thus, he continued to fill this medication from his outpatient pharmacy. Including a pharmacist in hospital discharge medication reconciliation has been previously shown to decrease 30-day hospital readmission.This service is commonly provided to patients with multiple comorbidities and complicated medication regimens; however, a second occurrence of toxicity in this patient demonstrates that coordinating discharge care for patients with high-risk overdoses should be performed. Methods for reliably informing outpatient pharmacies of discharge medication reconciliation after acute care episodes are expected to improve patient safety.Electronic cigarettes and vaping products are new devices for inhaling various substances such as nicotine and cannabinoids, with or without flavoring chemicals. “Vaping,” or “Juuling,” is a term used to describe the use of e-cigarettes and vaping products.These devices, also known as e-cigs, vape pens, vapes, mods, pod-mods, tanks and electronic nicotine delivery systems, are available in different shapes and sizes.All e-cigarettes and vaping products are made of three components. The first component is the cartridge that contains e-liquid and the atomizer, a coil that heats and converts e-liquid into aerosols. E-liquids can be broadly categorized into two types: regular e-liquids made of propylene glycolLoma Linda University, Department of Emergency Medicine, Loma Linda, California containing chemical flavors and vegetable glycerine used to dissolve nicotine or cannabis e-liquids containing tetrahydrocannabinol and cannabidiol. The second component is the sensor that activates the coil, and the third component is the battery.The hookah, also known as a water pipe, is an ancient method of smoking nicotine. In this method, the coal heats the tobacco and then the smoke passes through the water reservoir before it is inhaled.Contrary to public perception, hookah use is also associated with oral, lung, and esophageal cancers, similar to smoking cigarettes.In our study, we focused on e-cigarettes, and vaping, product-use associated lung injuries . According to the United States Centers for Disease Control and Prevention , in 2018 e-cigarettes were used by 3.05 million high school and 570,000 middle school students.EVALI is a diagnosis of exclusion, with a definition outlined by the CDC for confirmed and probable cases.6 EVALI was first identified in August 2019 after the Wisconsin Department of Health Services and the Illinois Department of Public Health received multiple reports of a pulmonary disease of unclear etiology, possibly associated with the use of e-cigarettes and related products.Since then, more than 2000 cases of EVALI have been reported, and in 80% tetrahydrocannabinol -containing products were used. Our study aimed to identify the clinical characteristics and hospital course of adolescents diagnosed with EVALI.We performed a retrospective chart review of adolescents presenting to our hospital between January– December 2019, with diagnosis of EVALI. Subjects were identified by the International Classification of Diseases, Tenth Revision diagnostic codes outlined by official ICD-10 guidelines.The data extracted from the medical records were age, gender, weight, and vital signs obtained in the ED. We also compiled data on duration of symptoms, history of cough, shortness of breath, chest pain, vomiting, wheezing, rales, use of accessory muscles, and presence of altered mental status. We also included data on respiratory support, duration of hospital stay, use of steroids during treatment, and laboratory tests and imaging obtained in the hospital and a negative infectious workup or the decision by the clinical care team to treat as a case of EVALI.