Combination Clearance Therapy Asya Agulnik, MD, MPH, a Daniel P. Kelly, MD, b Rebecca Bruccoleri, MD, c Christopher Yuskaitis, MD, d Darius andEbrahimi-Fakhari, Barbiturate MD, PhD, d Mustafa Sahin, MD, PhD, Coma d Michele M. Burns, for MD, c Daniel Severe S. Kohane, MD, PhD b Carbamazepine Overdose abstract ∼ A 15-year-old female subject presented comatose, in respiratory failure and shock, after the intentional ingestion of 280 extended-release 200- mg carbamazepine tablets with a peak serum concentration of 138 µg/mL (583.‍74 µmol/L).‍ The patient developed clinical seizures and an EEG pattern of stimulus-induced rhythmic, periodic, or ictal discharges, suggestive of significant cortical dysfunction.‍ Due to the extremely high drug serum concentration and clinical instability, a combination of therapies was used, aDepartment of Global Pediatric Medicine and Division of Critical Care, St. Jude Children's Research Hospital, including lipid emulsion therapy, plasmapheresis, hemodialysis, continuous Memphis, Tennessee; and Divisions of bMedicine Critical venovenous hemodiafiltration, and endoscopic intestinal decontamination.‍ Care, cEmergency Medicine, and dNeurology, Boston The patient’s elevated serum lactate level with a high mixed venous Children’s Hospital, Boston, Massachusetts saturation suggested possible mitochondrial dysfunction, prompting Dr Agulnik reviewed the clinical data for this treatment with barbiturate coma to reduce cerebral metabolic demand.‍ case as well as the available literature, drafted the initial manuscript, and critically reviewed The serum carbamazepine concentration declined steadily, with resolution all versions of the manuscript; Dr Kelly reviewed of lactic acidosis, no long-term end-organ damage, and return to baseline the pheresis and hemodialysis clinical data for neurologic function.‍ The patient was eventually discharged in her usual this case as well as the available literature, and critically reviewed the manuscript; Dr Bruccoleri state of health.‍ In the laboratory, we demonstrated in vitro that the active reviewed the toxicology and lipid emulsion therapy metabolite of carbamazepine hyperpolarized the mitochondrial membrane clinical data for this case as well as the available potential, supporting the hypothesis that the drug caused mitochondrial literature, and critically reviewed the manuscript; Dr Yuskaitis reviewed the neurologic clinical data dysfunction.‍ We thus successfully treated a life-threatening carbamazepine for this case as well as the available literature, and overdose with a combination of modalities.‍ Future studies are required critically reviewed the manuscript; Dr Ebrahimi- to validate this aggressive approach.‍ The occurrence of mitochondrial Fakhari designed and conducted the in vitro study dysfunction must be confirmed in patients with carbamazepine toxicity and presented in the manuscript and critically reviewed the manuscript; Dr Sahin oversaw the in vitro the need to treat it validated.‍ study presented in the manuscript and critically reviewed the manuscript; Dr Bruccoleri reviewed the toxicology and lipid emulsion therapy clinical data for this case as well as the available literature, Carbamazepine is a lipophilic drug clearance.‍ Barbiturate coma ∼ and critically reviewed the manuscript; and anticonvulsant with peak absorption1 was induced for cerebral protection Dr Kohane reviewed the clinical data for this at 12 to 24 hours after ingestion.‍ despite the patient being comatose; case and critically reviewed all versions of the manuscript; and all authors approved the It is a sodium channel blocker 2 preliminary data are provided to final manuscript as submitted and agree to be with anticholinergic properties.‍ support the hypothesis of functional accountable for all aspects of the work. Carbamazepine poisoning can tissue hypoxia in carbamazepine present with altered mental status overdose.‍ DOI: 10.1542/peds.2016-1560 Accepted for publication Nov 16, 2016 leading to coma, respiratory failure,3 CASE PRESENTATION cardiac arrhythmias, and seizures.‍ Serum concentrations >39 µg/mL To cite: Agulnik A, Kelly DP, Bruccoleri R, et al. (165 µmol/L) are associated with A confused 15-year-old female 3–5 ≤ Combination Clearance Therapy and Barbitu- fatalities.‍ We report a life- was found by her parents with an rate Coma for Severe Carbamazepine Overdose. threatening intentional overdose empty carbamazepine bottle ( 285 Pediatrics. 2017;139(5):e20161560 of carbamazepine treated with a tablets, 200-mg extended-release combination of therapies to enhance formulation).‍ She was brought to the Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 139, number 5, May 2017:e20161560 CASE REPORT emergency department, where she was unresponsive (Glasgow Coma Scale score, 5).‍ She was intubated for airway protection, and charcoal was delivered via an orogastric tube.‍ The initial carbamazepine serum concentration exceeded the assay upper limit (>20 µg/mL).‍ The patient was transferred to the PICU of a tertiary referral hospital 9 hours after the ingestion.‍ On arrival at the PICU, the patient was hypotensive, requiring volume resuscitation and a norepinephrine infusion.‍ Her electrocardiogram showed a normal QRS interval (90 milliseconds) and a prolonged QTc (504 milliseconds).‍ Initially, the patient demonstrated motor response to painful stimuli and had dilated but responsive pupils; she then quickly developed decerebrate posturing with no brainstem reflexes and pupils that were fixed and 9 mm dilated bilaterally.‍ Her initial head computed tomography scan was normal.‍ She developed generalized FIGURE 1 tonic-clonic seizures treated with EEG of the study patient demonstrating low voltages with bursts of SIRPIDs during stimulation (pinch lorazepam, propofol boluses, and a right thumb and stroke left foot). A, Compressed EEG. B, Uncompressed EEG. midazolam infusion.‍ Continuous EEG monitoring showed low voltages with bursts of stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs) (Fig 1).‍ The initial venous blood gas analysis showed the following: pH, 7.‍33; CO P 2, 42.‍7 mm Hg; bicarbonate, 22 mmol/L; and oxygen saturation, 98% (from a femoral catheter tip at L2).‍ Her lactate level was 7.‍3 mmol/L.‍ The initial carbamazepine serum concentration was 86 µg/mL (364 µmol/L).‍ Extended urine and blood drug screens were otherwise positive only for midazolam and lorazepam, which had been administered to the patient.‍ The time course of the FIGURE 2 patient’s carbamazepine serum Total carbamazepine serum concentration over time. OSH, outside hospital; ED, emergency department; concentration and interventions are IL, lipid emulsion therapy; IHD, intermittent hemodialysis; CVVHD, continuous venovenous hemodialysis. shown in Fig 2.‍ The patient deteriorated clinically with worsening lactic acidemia (lactate level, 10.‍6 mmol/L) and a Downloaded from www.aappublications.org/news by guest on October 1, 2021 e2 AGULNIK et al peak carbamazepine concentration of a brain and spine MRI on day 7 Plasmapheresis is an extracorporeal ∼ of 138 µg/mL (584 µmol/L) were normal.‍ She was extubated procedure that allows removal 13 hours after the suspected that day but exhibited self-injurious and replacement of selected blood ingestion.‍ Because of her worsening behaviors necessitating reintubation.‍ components, including highly protein condition and rapidly increasing She was successfully extubated on bound substances.‍ Although the carbamazepine serum concentration, day 10 in her baseline condition.‍ On American Society for Apheresis does the patient was given lipid emulsion day 14, the patient was discharged not offer recommendations regarding therapy (1.‍5 mL/kg bolus of a to a psychiatric facility, where she plasmapheresis12 in carbamazepine 20% fat emulsion, then infusion of reportedly did well.‍ overdose, the use and variable 0.‍25 mL/kg/min for 60 minutes), DISCUSSION effectiveness of plasmapheresis13 have–15 followed by plasmapheresis of 1.‍5 been described in case reports.‍ plasma volume with 5% albumin Significant rebound in carbamazepine replacement, and intermittent serum concentrations have been The patient presented with 13 high-flux hemodialysis followed reported after plasmapheresis.‍ This many characteristic symptoms of by continuous venovenous scenario was not observed in our carbamazepine overdose.‍ Fixed, hemodiafiltration (CVVHDF).‍ The patient, possibly because we used dilated pupils, tachycardia, and pheresate was clear except after CVVHDF after plasmapheresis.‍ Lipid decreased gastric motility with lipid treatment, when there was a emulsion therapy can increase blood ileus were likely the result of separate lipemic phase.‍ The patient clot formation and fat deposition in carbamazepine’s anticholinergic 16, 17 had decreased bowel sounds and 2 extracorporeal circuits, which effects.‍ Other reported an ileus, preventing intestinal was not observed in this case.‍ cardiovascular manifestations decontamination with motility agents include hypotension, myocardial Plasmapheresis was followed or further use of activated charcoal.‍ 6 depression, and QRS and QTc by 1 cycle of hemodialysis, then To prevent ongoing carbamazepine 7 prolongation.‍ Carbamazepine by CVVHDF, to remove free absorption from a potentially large frequently causes neurologic carbamazepine from the serum.‍ number of ingested extended- dysfunction such as dystonia, apnea, Hemodialysis, hemofiltration, and release capsules, an endoscopic 8 and coma.‍ Seizures