EXPERIENCE AND REASON |
Management of a Severe Carbamazepine Overdose Using Albumin-Enhanced Continuous Venovenous Hemodialysis
* Renal Section
Pharmacy, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
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ABSTRACT |
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 TOP ABSTRACT CASE REPORTSDISCUSSIONREFERENCES |
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Carbamazepine intoxication is common in the pediatric population. Highly protein-bound, carbamazepine is not removed efficiently through conventional hemodialysis. We describe the use of albumin-enhanced continuous venovenous hemodialysis (CVVHD) in a 10-year-old girl who developed coma and respiratory depression due to an intentional carbamazepine overdose (peak drug level of 44.8 µg/ml; therapeutic range: 8–12 µg/ml). Without intervention, the half-life of drug elimination is 25 to 60 hours in patients who are naive to carbamazepine and 12 to 20 hours in children on chronic carbamazepine therapy. In contrast, with albumin-enhanced CVVHD, we observed a half-life of 7 to 8 hours. The patient recovered rapidly and was discharged from hospital <4 days from the time of ingestion with no complications or neurologic impairment. Because the cost-benefit analysis was also favorable relative to other therapeutic options, albumin-enhanced CVVHD may be the optimal treatment of toxic-level ingestion of carbamazepine.
Key Words: dialysis • CVVHD • CRRT • carbamazepine • overdose
Abbreviations: ICU, intensive care unit • CVVHD, continuous venovenous hemodialysis
Because of its availability, carbamazepine is a drug commonly involved in accidental and intentional overdoses. Carbamazepine, approved by the Food and Drug Administration in 1968, is indicated as first-line therapy for simple partial, complex partial, and general tonic-clonic seizures. Carbamazepine is also approved by the Food and Drug Administration for trigeminal neuralgia, and off-label indications include bipolar disorder, neuropathic pain, and attention-deficit/hyperactivity disorder.1 Because this drug is present in many households, there is a high incidence of accidental as well as intentional poisoning. The American Association of Poison Control Centers reported a total number of 18 201 carbamazepine overdoses from 1999 to 2001. Of these, 48% occurred in children <19 years of age. Among antiepileptic drugs involved in toxic ingestion, carbamazepine is the second most common, after valproic acid. Although carbamazepine overdose led to only 18 deaths between 1999 and 2001, moderate to severe disability occurred in 3813 (21%) patients, revealing a tremendous need for improvements in management and detoxification regimens.2–4
Acute carbamazepine toxicity presents with cardiac, respiratory, and neurologic effects. Cardiac effects can include hypertension, hypotension, tachycardia, and cardiac conduction delays. Respiratory depression requiring mechanical ventilation is extremely common, and other neurologic signs include loss of consciousness, seizures, ataxia, choreoathetosis, myoclonus, motor restlessness, opisthotonus, mydriasis, and nystagmus.5 The observed toxicity increases as plasma carbamazepine concentrations increase above the therapeutic range; however, an individual child’s prognosis is unpredictable. Some comatose patients demonstrate complete recovery, whereas 5% to 38% of patients die. Patients with serum carbamazepine levels >28 µg/ml are likely to develop apnea, coma, and dystonic reactions.5
Carbamazepine distribution and metabolism are complex. Carbamazepine is reasonably bioavailable and rapidly absorbed from the gastrointestinal tract, leading to peak drug concentrations in 1 to 3 hours. Carbamazepine is highly bound to plasma proteins (75–80%) with a moderately large volume of distribution (Vd = 1.0–2.0 L/kg) and has a half-life (T1/2) between 12 and 20 hours. Hepatic metabolism is the major route of elimination, with renal excretion accounting for only 1% to 3% of its elimination. When children are started on carbamazepine, hepatic cytochrome p450 (CYP3A4) induction occurs over 2 to 3 weeks. This induction reduces the plasma T1/2 of the drug from 25 to 65 hours to 12 to 20 hours. Consequently, patients who are naive to carbamazepine can overdose on much lower doses. Once p450 induction has occurred, peak levels are usually achieved 1.5 hours after administration. The extended-release form of carbamazepine, which has been available for several years, peaks in 3 to 12 hours and has an oral availability 15% less than its original formulation.6
Carbamazepine ingestion management is generally supportive. Patients receive endotracheal intubation and mechanical ventilation as well as intravenous volume expansion and pressors to maintain hemodynamic stability.5 Multiple doses of activated charcoal have been shown to be useful in enhancing the elimination of carbamazepine by binding the drug and preventing primary absorption as well as increasing biliary excretion.7 Unfortunately, the efficacy of activated charcoal is reduced dramatically when given >1 hour postingestion.8 Drug elimination by other methods is clearly needed to decrease the morbidity and mortality of carbamazepine intoxication.
Several modalities have been proposed to enhance drug clearance of carbamazepine using hemodialysis circuits. Because carbamazepine is highly protein-bound and has a resultant large volume of distribution, conventional hemodialysis and peritoneal dialysis have not been efficacious in acute carbamazepine toxicity.9 Charcoal hemoperfusion is somewhat effective in removing highly protein-bound substances, because this procedure allows circulating blood to come into direct contact with substances capable of absorbing toxins.10 Many authors recommend charcoal hemoperfusion for enhanced clearance in patients who are intubated or severely impaired after carbamazepine toxicity.10 Deshpande et al11 reported successful treatment of a 16-month-old with carbamazepine toxicity with 3 sessions of charcoal hemoperfusion. Others have calculated a 6-hour T1/2 with charcoal hemoperfusion.10 Charcoal hemoperfusion is not ideal, however, because it is not readily used or available in many pediatric institutions and because of potential side effects and potential rebound in drug levels, especially in overdoses involving the extended-release formulation.
Others report the use of high-flux dialyzers for carbamazepine overdose.12 Tapolyai et al13 reported an adult who underwent both high-flux dialysis and charcoal hemofiltration for 3 hours and showed a similar clearance (27% vs 25%) for the 2 modalities. Schuerer et al12 used high-flux dialysis in an 18-month-old with carbamazepine toxicity and reported blood levels from 27 µg/ml to therapeutic 4.5 hours after the start of treatment. This modality also has shortcomings, because rebound toxicity of the drug is expected as protein-bound stores reequilibrate into the plasma and would entail high risk in a patient who was hemodynamically unstable. The use of plasmapheresis14 has also been advocated but gained little widespread acceptance.
The addition of physiologic concentrations of albumin to the dialysate fluid during hemodialysis has been shown to enhance clearance of protein-bound drugs.15 As the small amount of nonbound drug is exposed to the dialysate fluid with albumin, it quickly binds to albumin and thereby optimizes the diffusion gradient of unbound drug across the dialysis membrane. Such a system potentially could provide improved elimination rates of highly bound drug. Chadha et al15 reported using albumin-enhanced dialysis to treat a 6.5-month-old with valproic acid (a drug that is also heavily protein-bound) toxicity. They showed a 48% improvement in drug clearance with the addition of albumin to the dialysate. Although it was a promising result, convection-mediated clearance will have a greater relative effect in an infant, and the vast majority of toxic ingestions are in older, larger children. To the best of our knowledge, the use of albumin-enhanced dialysis has not been reported previously in school-aged children or adolescents or for carbamazepine ingestion in any age group.
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CASE REPORTS |
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TOPABSTRACTCASE REPORTSDISCUSSIONREFERENCES |
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A 10-year-old 30-kg Hispanic female was brought to the emergency center after her mother found her unresponsive at home. Two months before admission she was started on carbamazepine for a newly diagnosed seizure disorder. Compliance with the medical regimen had been problematic, and pill counts indicated that she had been taking less than half of her prescribed doses (200 mg, twice a day). She did not have any drug levels checked before the admission. After an argument in her home, the patient intentionally took 7 extended-release carbamazepine 200-mg tablets. The time of ingestion was estimated at 4 hours before arrival to the emergency center. She had 1 episode of emesis, but no pill fragments were present. She had a brief seizure in the emergency department.
On physical examination, her blood pressure was 107/57 mm Hg, heart rate was 121 per minute, respiratory rate was 21 per minute, O2 saturation was 98% on room air, and body surface area was 1.0 m2. She was unresponsive to pain. Glasgow Coma score was 3. Her pupils were fixed at 3 mm bilaterally. She had a regular heart rate and rhythm and no murmurs. Her abdomen was not distended, and she had no peripheral edema.
Initial laboratory analysis, 4 hours after ingestion, showed a carbamazepine level of 44.8 µL/ml (therapeutic range: 8–12 µL/dL). Her serum electrolytes were: sodium = 140 mmol/L; potassium = 2.8 mmol/L; chloride = 106 mmol/L; HCO2 = 25 mmol/L; glucose = 242 mg/dL; blood urea nitrogen = 13 mg/dL; and creatinine = 0.6 mg/dL. Her ionized calcium was 1.18 mmol/L, her arterial pH was 7.41, and drugs of abuse were not detected. Her Acetaminophen level was <0.5 µg/ml and salicylate level was <0.5 mg/dL. Urinalysis was unremarkable.
The patient underwent endotracheal intubation and received 2 doses of activated charcoal before admission to the pediatric intensive care unit (ICU). Despite the use of repeated doses of activated charcoal, carbamazepine levels remained stable (43–44 µg/ml) over the first 12 hours in the hospital. In an effort to increase the rate of drug clearance, reduce the neurologic morbidity, and avoid very prolonged mechanical ventilation, we chose to initiate albumin-enhanced continuous venovenous hemodialysis (CVVHD). The patient had a 10-F, 15-cm, Tyco-Kendall dual-lumen catheter placed in the right femoral vein. CVVHD was started 12 hours after arrival to the hospital (16 hours after ingestion). The composition of the dialysis fluid was adjusted to 4.5 g/dL of albumin using a 25% albumin solution.
CVVHD was administered by using a PRIMSA CRRT M60 circuit (Gambro Renal Products, Inc, Lakewood, CO) using an in-line blood warmer set at 35 to 36°C. The extracorporeal circuit was primed with 
118 mL of 5% albumin (5.4% of the patient’s circulating volume). The blood-pump flow rate (QB) was 120 mL per minute (4 mL/kg per minute). Normocarb (Dialysis Solutions, Inc, Toronto, Canada), 240 mL in 3 L of sterile water with 3 mEq/L of potassium chloride, 2 mmol/L potassium phosphate, and 4.5 g/dL of albumin (prepared by using the addition of 25% albumin), was used continuously as the dialysate fluid with a flow rate (QD) of 3000 mL/1.73 m2 per hour (her body surface area was 1.0 m2). Anticoagulation of the extracorporeal circuit was achieved by using the citrate regional anticoagulation protocol as described by Bunchman.16 Despite the theoretical possibility that addition of albumin to the dialysis solution would alter citrate or calcium clearance, effecting the anticoagulation procedure, no such changes were observed, and anticoagulation was maintained without difficulty by standard procedures.16
During the initiation of the procedure, the patient had a brief episode of hypotension. The lowest blood pressure attained was 60/40 mm Hg. The patient’s ionized calcium was found to be 1.04 after initiation of dialysis. The patient responded to increased CaCl2 administration and 100 mL of normal saline bolus. The CVVHD circuit clotted 4 hours after the initiation of CVVHD and was restarted by using the same parameters as described above. No complications occurred after initiation of the second circuit.
During CVVHD, carbamazepine levels were measured every 3 hours. At the start, her carbamazepine level was 43.8 µg/ml. Fig 1 shows drug clearance using continuous albumin-enhanced CVVHD compared with the estimated clearance without treatment. Because the patient had been taking carbamazepine for >1 month with no recent dose changes, induction of p450 was assumed to be complete. We therefore estimated the T1/2 for carbamazepine without hemodialysis to be 15 hours, although elimination times reported in the literature vary between 12 and 20 hours. We conservatively assumed first-order kinetics, although there is potential saturation of the cytochrome p450 system that would slow metabolism in severe overdoses as in this child’s case. These assumptions almost certainly overestimate the patient’s endogenous clearance rate but are useful for comparison.
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Twelve hours after albumin-enhanced CVVHD was initiated, drug levels reached a normal therapeutic range of 10.4 µg/ml. CVVHD was terminated 17 hours after initiation, when the serum carbamazepine level was 6.6 µg/ml. The T1/2 during the entire CVVHD course was 7 hours. Because of interruption in CVVHD, this is actually an underestimate of true clearance efficiency. Furthermore, no rebound drug effect was seen. The addition of albumin into dialysate fluid did not cause any clinically significant effects on other medical therapies. The patient was weaned successfully from ventilator support, had her carbamazepine restarted, and was transferred to the floor. She fully recovered and was discharged from the hospital in good condition 90 hours after the ingestion occurred. We estimate that albumin-enhanced CVVHD reduced her mechanical ventilation time by between 24 and 36 hours and shortened her ICU admission by between 1 and 3 days.
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DISCUSSION |
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TOPABSTRACTCASE REPORTSDISCUSSIONREFERENCES |
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This case illustrates some of the difficulties of managing life-threatening toxic ingestion with agents that are highly protein-bound. Delays in seeking or reaching treatment and or diagnosis will attenuate the utility of bowel decontamination procedures. Drugs that are highly protein-bound and have a large volume of distribution are also cleared poorly with traditional peritoneal dialysis or hemodialysis.
Our patient was comatose and intubated and had critically high drug levels that had not responded to multiple administrations of activated charcoal. In addition, the form of drug ingested was a sustained-release formulation, and the very high drug levels could be sustained for a significant duration, increasing neurologic risks and time of mechanical ventilation. Enhanced clearance of this drug could have been attempted with the use of charcoal hemoperfusion and high-flux dialysis, but the potential risks and significant rebound effect with the sustained-release formulation made these 2 methods less than optimal. Consequently, we elected to use albumin-enhanced CVVHD to assist in the elimination of carbamazepine, with the goal of clearing sufficient quantities of the drug to prevent further seizures, shorten mechanical ventilation time, shorten ICU time, and decrease risk of infectious or neurologic complications. We achieved relatively rapid drug clearance without subsequent rebound, and the child woke and regained normal neurologic function rapidly, compared with the expected hepatic metabolism of the drug.
Albumin-enhanced CVVHD worked as well or better than other innovative dialysis therapies that have been reported and had several advantages. The T1/2 of elimination of the drug was 7 hours despite interruption of therapy. The T1/2 of elimination while the circuit was functioning was 4.5 hours. The T1/2 of elimination for high-flux hemofiltration and charcoal hemoperfusion varies between 4 and 8 hours. However, unlike the albumin-enhanced CVVHD, both of the other modalities may have less overall clearance because of a substantial drug rebound. Furthermore, the clearance of drug in charcoal hemoperfusion decreased during the procedure because of saturation of the adsorbing resin. Cameron et al10 estimated that the cartridge would need to be changed every 5 to 7 hours.
Another advantage of albumin-enhanced CVVHD for enhanced elimination of protein-bound drug toxicities is the minimal side effects of the treatment compared with those seen with other modalities. Because of the smaller lines, smaller filter, and slower rate of blood flow, continuous hemodialysis has a smaller risk of hypotension and hemodynamic instability, especially in those patients who are already hemodynamically unstable before initiation of therapy. Unlike hemoperfusion, CVVHD can also correct fluid and electrolyte abnormalities when present. By using citrate anticoagulation in the extracorporeal circuit as opposed to heparin in the other modalities, the risk of bleeding is less when using CVVHD with albumin, as compared with acute hemodialysis or acute hemoperfusion. Charcoal hemoperfusion also has the substantial risk of thrombocytopenia, which is not an issue with other modalities.
Because albumin-enhanced CVVHD is a novel therapy, there may be unforeseeable adverse reactions in some children. The predictable side effects are those related to the use of albumin including, nausea, vomiting, chills, fever, rash, and hypotension. The effect of albumin-enhanced CVVHD on calcium and citrate fluxes is not clearly established. However, using routine protocols for citrate anticoagulation16 allows detection of changes in serum and circuit calcium concentrations to make appropriate adjustments of citrate and calcium infusions. The inherent risks of CVVHD in infants may be higher than in adults due to the greater proportion of blood volume in an extracorporeal circuit. These risks generally are easily managed in experienced hands.
The most significant potential drawback of albumin-enhanced CVVHD is its very high cost due to the use of large quantities of albumin. For this reason, we undertook a comparative cost-benefit analysis and compared the added cost of the albumin used (approximately $15 000) compared with the cost savings of reduced ventilator and ICU time. To do this we analyzed the actual charges of 5 comparable ICU patients at our institution to generate a composite estimated mean cost for care of a child with neurologic impairment on mechanical ventilation. The mean daily ICU cost for 5 similar patients was $4172 ± 1194. We estimate that albumin-enhanced CVVHD reduced ventilation/ICU time in our patient by 1 to 3 days, assuming no additional complications occurred due to her toxic ingestion. Thus, for this child, albumin-enhanced CVVHD may have resulted in a moderate cost increase ($10 828) to no significant cost change over traditional therapies. If, however, the child developed complications from sustained toxic drug levels or secondary to prolonged ventilation and hospitalization, the savings would be substantial. At higher levels of intoxication or in children pharmacologically naive to carbamazepine who will have an endogenous clearance rate 2 to 4 times slower than those on chronic therapy, the decrease in ICU time would be much greater. Most importantly, albumin-enhanced CVVHD resulted in safer care, more rapid return to normal health, and much earlier discharge from the ICU and the hospital.
We conclude that albumin-enhanced CVVHD may be an optimal and cost-effective option for the treatment of toxic-level ingestion of protein-bound drugs that are not amenable to clearance by conventional dialysis protocols. We have demonstrated the rapid clearance of carbamazepine and resolution of toxic symptoms with this modality and shown that its efficacy is not unique to the treatment of valproic acid overdose.15 The albumin in the dialysis fluid provides an alternative binding site for the drug, thereby maintaining a large diffusion gradient, allowing for maximal drug clearance. The observed effectiveness would be expected to pertain to many highly protein-bound drugs. However, additional testing of this technique is needed before the recommendation of new practice guidelines.
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ACKNOWLEDGMENTS |
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We thank Carolyn M. Smith (Senior Analyst, Decision Support Services, Texas Children’s Hospital, Houston, TX) for assistance with cost analysis. We are indebted to the physicians, nurses, and pharmacists at the Texas Children’s Hospital.
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FOOTNOTES |
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Received for publication Jan 30, 2003; Accepted Apr 28, 2003.
Reprint requests to (D.I.F.) Baylor College of Medicine, Renal Section, Department of Pediatrics, MC3-2482, 6621 Fannin St, Houston, TX 77030. E-mail dfeig{at}bcm.tmc.edu
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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
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