Journal of Clinical Apheresis 29:178–180 (2014)
Case Report Plasma-Exchange Treatment for Severe Carbamazepine Intoxication: A Case Study Ilknur Kozanoglu,1,2* Suat Kahveci,3 Suheyl Asma,4 Mahmut Yeral,1 Aytul Noyan,3 Can Boga,1 and Hakan Ozdogu1 1
2
Department of Physiology, Faculty of Medicine, Baskent University, Ankara, Turkey Adana Adult Bone Marrow Transplantation Center, Apheresis Unit, Baskent University, Ankara, Turkey 3 Department of Pediatrics, Faculty of Medicine, Baskent University, Ankara, Turkey 4 Department of Family Medicine, Faculty of Medicine, Baskent University, Ankara, Turkey Acute poisoning is an important cause of morbidity and mortality during childhood. This manuscript reports the positive outcome of a pediatric case with a history of accidental carbamazepine intake treated using plasma exchange. A 3-year-old male presented with severe carbamazepine intoxication. He was comatose and had generalized tonic clonic seizure, ventricular tachycardia, and hypotension. Although he did not respond to classical therapies, we performed two sessions of plasma exchange. The patient recovered rapidly and was discharged from the hospital six days from the time of carbamazepine ingestion with no complication or neurologic impairment. Plasma exchange can be performed safely in very small children, and it might be the first line treatment, particularly for intoxication with drugs that have high plasma-protein-binding properties. J. Clin. Apheresis C 2013 Wiley Periodicals, Inc. 29:178–180, 2014. V Key words: plasma exchange; acute poisoning; carbamazepine; childhood
INTRODUCTION
Poisoning is one of the most common medical problems in children. Approximately 80% of accidental poisoning cases involve children under the age of 5 years, and 87% of childhood poisoning cases occur within the home environment [1,2]. Poisoning in children aged one year or younger is usually caused by improper use of medications, whereas poisoning of older children involves ingestion of accessible household items due to curiosity. Toxic substances may enter the body through the gastrointestinal system and skin and mucous membranes by inhalation or parenterally [1,2]. Carbamazepine intoxication is one of the most common causes of poisoning in children. Because of its availability, carbamazepine is commonly involved in accidental and deliberate overdoses. Carbamazepine, which was approved by the Food and Drug Administration in 1968, is indicated as first-line therapy for simple, complex partial, general tonic-clonic seizures and trigeminal neuralgia, bipolar disorders, neuropathic pain, and attention-deficit/hyperactivity disorders [3]. Because this drug is present in many households, there is a high incidence of accidental poisoning, particularly in children. Acute carbamazepine toxicity presents with cardiac, respiratory, and neurologic effects [2,3]. C 2013 Wiley Periodicals, Inc. V
Carbamazepine distribution and metabolism are complex. It is reasonably bioavailable and rapidly absorbed from the gastrointestinal (GI) tract, leading to peak drug concentrations in 1–3 h. Carbamazepine is highly bound to plasma proteins (75–80%) with a moderately large volume of distribution and has a half-life between 12 h and 20 h. Carbamazepine intoxication management is generally supportive [4]. The treatment options include activated charcoal, alkalinization, and hemoperfusion or plasma exchange, if necessary [5–9]. We aimed to emphasize the importance of plasma exchange for the treatment of intoxication with high plasma-protein-binding agents such as carbamazepine. CASE
A 3-year-old male patient who was being followed at another center for status epilepticus was referred to *Correspondence to: Ilknur Kozanoglu, Department of Physiology, Faculty of Medicine, Baskent University, Ankara, Turkey. E-mail: [email protected] Received 2 April 2013; Accepted 20 September 2013 Published online 18 October 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jca.21305
Severe Carbamazepine Intoxication
our hospital for plasma exchange treatment. A review of the patient’s history showed that he had taken 20 tablets R 400 mg (carbamazepine) 6 h earlier. His of TegretolV serum carbamazepine level was 37 mg/ml, indicating carbamazepine intoxication (therapeutic range: 8–12 mg/ml) [10]. After the diagnosis, gastric lavage was performed, and activated charcoal was administered. The patient was then referred for plasma exchange treatment. Physical examination showed that he was unconscious and had dilated pupils, a weak response to light with a Glasgow coma score of 4, tachycardia (134/ min), and hypotension (80/40 mmHg). His hemoglobin and hematocrit levels were 11.6 g/dl and 36.2%, respectively. Other physical and laboratory findings were unremarkable. The patient was started on activated charcoal, administered every 4 h and continuous electrocardiographic monitoring was instituted. The Pediatric Nephrology Department was consulted, and emergency hemodialysis was planned. After hemodialysis, his carbamazepine levels remained high. The patient had severe facial edema and eyelid swelling. Because his clinical status did not improve after hemodialysis, emergency plasma exchange was planned. Two sessions of plasma exchange were performed using a Spectra Optia Apheresis System (Terumo BCT, Lakewood, CO). The total blood volume (1200 ml) of the patient was calculated based on his weight, and his plasma volume (768 ml) was calculated based on the total blood volume and hematocrit [11]. Considering the extracorporeal volume, the plasma exchange set was primed with one unit of typed and cross-matched leukoreduced packed red cells prior to the run. A central venous catheter was used. The inlet flow rate was 15 ml/ min for both procedures, and 2195 ml and 1980 ml of blood were processed in the first and the second procedures, respectively. The total plasma volume exchanged was 1250 ml (1.4 plasma volumes) in the first procedure and 1083 ml (1.3 plasma volumes) in the second. The replacement fluid used was ABO-compatible fresh frozen plasma. The duration of the first procedure was 148 min, and the second procedure lasted 115 min. No technical problem related to the cell separators was noted. No minor or severe complication was observed during or after the plasma exchange procedures. The patient was hospitalized as a tertiary care pediatric intensive care unit (ICU) patient and underwent plasma exchange 12 h after admission. After the treatment, his carbamazepine levels decreased gradually to 28 and 25 mg/ml. We observed an increase in spontaneous activity, although he was still unconscious. The initial albumin was 2.05 g/dl and plasma albumin level increased to 3.01 g/dl. The second plasma exchange was performed 36 h after admission. After the treatment, his carbamazepine level was less than 10 mg/ml. His activity increased more, and his response to light stimuli was stronger. He started opening his eyes spon-
179
taneously. He was extubated at the third day of his hospitalization. Because sufficient spontaneous respiration was returned, an oxygen mask was used during the follow up. He gained consciousness and responded verbally at day 4. Oral feeding was started, and he was transferred to the pediatric ward. He was discharged at day 6 after regaining his physical and mental activity. DISCUSSION
Acute poisoning during childhood is an important cause of morbidity and mortality [1]. When epidemiological data are examined, it is obvious that, in addition to preventive measures for drug intoxications, fast planning of treatment and intervention is crucial and may be life saving [1,2]. Carbamazepine is an antiepileptic drug with a tricyclic structure. It is used for the treatment of complex and partial epilepsies, bipolar disorder, trigeminal neuralgia, post-therapeutic neuralgia, and phantom extremity pain [3,4]. Carbamazepine inhibits presynaptic voltage-sensitive Na1 channels in the central nervous system, inhibiting high-frequency epileptic foci. It has no effect on normal neuronal discharge [3,4]. Due to its lipophilic properties, after oral ingestion, carbamazepine is absorbed in different amounts and quickly passes the blood brain barrier. The peak plasma level of carbamazepine may be reached in 6 to 8 h, and it binds to plasma proteins [4]. Carbamazepine levels exceeding the therapeutic dose range cause a proportional increase in complaints and severe clinical symptoms. A concentration higher than 40 mg/L is usually fatal [5,7,8]. Considering the pharmacokinetic characteristics of carbamazepine, plasma exchange treatment may be useful for cases of carbamazepine poisoning. For carbamazepine intoxication, gastric lavage and activated charcoal administration within 1 h is recommended. Because the effects of carbamazepine are dose dependent, and it has high plasma-protein-binding properties, hemodialysis and hemoperfusion are not adequate for elimination [7]. Thus, plasma exchange therapy must be considered for the treatment of highdose carbamazepine intoxication or other similar plasma-protein-binding drug intoxications. When the current literature was searched for carbamazepine intoxication and plasma exchange therapy, studies involving two adult patients and one adolescent patient were found [9,12,13]. Duzova et al. reported a case of an adolescent (15 years old) who had taken a lethal dose of carbamezapine and was treated by plasma exchange in the ICU. At the end of the procedure, the patient started to respond to verbal stimuli, her neurological status improved, gradually and she was discharged on the fourth day after the ICU admission [13]. Another case with severe carbamazepine poisoning was reported by Gambi et al. They treated the patient Journal of Clinical Apheresis DOI 10.1002/jca
180
Kozanoglu et al.
using plasmapheresis techniques for three consecutive days. The patient recovered and was discharged without complications after a 6-day stay in the ICU [9]. Kale et al. reported a 21-year-old male with acute overdose, and performed plasma exchange therapy; however, the procedure did not seem to affect the clinical status of the patient because a significant rebound occurred after plasmapheresis [12]. The youth of our patient (3 years) and his rapid and remarkable response to plasma exchange were significant. The present case illustrates some of the difficulties of managing life-threatening toxic ingestion using agents that are highly protein-bound. Thus, we suggest that simple plasma exchange by plasma replacement might be a less costly and more effective method for the treatment of intoxication with carbamazepine. No technical problem related to the cell separators was noted, and no minor or severe complication was observed during or after the plasma exchange procedures. Our results also suggest that plasma exchange is effective for the treatment of intoxication with high plasma-protein-binding agents such as carbamazepine, particularly in children. REFERENCES 1. Ozdemir R, Bayrakci B, Teksam O, Yalcin B, Kale G. Thirtythree-year experience on childhood poisoning. Turk J Pediatr 2012;54:251–259.
Journal of Clinical Apheresis DOI 10.1002/jca
2. Neilson ZE, Morrison W. Childhood self-poisoning: a one-year review. Scott Med J 2012;57:196–199. 3. Holland KD. Efficacy, pharmacology, and adverse effects of antiepileptic drugs. Neurol Clin 2001;19:313–345. 4. Bertilsson L, Tomson T. Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11epoxide. An update. Clin Pharmacokinet 1986;11:177–198. 5. Spiller HA, Carlisle RD. Status epilepticus after massive carbamazepine overdose. J Toxicol Clin Toxicol 2002;40:81–90. 6. American Academy of Clinical Toxicology, European Association of Poisons Centres and Clinical Toxicologists. Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol 1999;37:731–751. 7. Durelli L, Massazza U, Cavallo R. Carbamazepine toxicity and poisoning: incidence, clinical features and management. Med Toxicol Adverse Drug Exp 1989;4:95–107. 8. Soderstrom J, Murray L, Little M, Daly FM. Toxicology case of the month: carbamazepine overdose. Emerg Med J 2006;23: 869–871. 9. Gambi D, Oggioni R, Mangani V, Librenti M, Manescalchi F, Tulli G Acute carbamazepine poisoning treated with plasmapheresis. Description of a clinical case. Minerva Anestesiol 1993;59:547–552. 10. Tibbals J. Acute toxic reaction to carbamazepine: clinical effects and serum concentrations. J Pediatr 1992;121:295–299. 11. McLeod Bruce C. Apheresis Principles and Practice, 2nd ed. Bethesda: AABB Press; 2003. 12. Kale PB, Thomson PA, Provenzano R, Higgins MJ. Evaluation of plasmapheresis in the treatment of an acute overdose of carbamazepine. Ann Pharmacother 1993;27:866–870. 13. Duzova A. Carbamazepine poisoning: treatment with plasma exchange. Hum Exp Toxicol 2001;20:175.
Case Report Plasma-Exchange Treatment for Severe Carbamazepine Intoxication: A Case Study Ilknur Kozanoglu,1,2* Suat Kahveci,3 Suheyl Asma,4 Mahmut Yeral,1 Aytul Noyan,3 Can Boga,1 and Hakan Ozdogu1 1
2
Department of Physiology, Faculty of Medicine, Baskent University, Ankara, Turkey Adana Adult Bone Marrow Transplantation Center, Apheresis Unit, Baskent University, Ankara, Turkey 3 Department of Pediatrics, Faculty of Medicine, Baskent University, Ankara, Turkey 4 Department of Family Medicine, Faculty of Medicine, Baskent University, Ankara, Turkey Acute poisoning is an important cause of morbidity and mortality during childhood. This manuscript reports the positive outcome of a pediatric case with a history of accidental carbamazepine intake treated using plasma exchange. A 3-year-old male presented with severe carbamazepine intoxication. He was comatose and had generalized tonic clonic seizure, ventricular tachycardia, and hypotension. Although he did not respond to classical therapies, we performed two sessions of plasma exchange. The patient recovered rapidly and was discharged from the hospital six days from the time of carbamazepine ingestion with no complication or neurologic impairment. Plasma exchange can be performed safely in very small children, and it might be the first line treatment, particularly for intoxication with drugs that have high plasma-protein-binding properties. J. Clin. Apheresis C 2013 Wiley Periodicals, Inc. 29:178–180, 2014. V Key words: plasma exchange; acute poisoning; carbamazepine; childhood
INTRODUCTION
Poisoning is one of the most common medical problems in children. Approximately 80% of accidental poisoning cases involve children under the age of 5 years, and 87% of childhood poisoning cases occur within the home environment [1,2]. Poisoning in children aged one year or younger is usually caused by improper use of medications, whereas poisoning of older children involves ingestion of accessible household items due to curiosity. Toxic substances may enter the body through the gastrointestinal system and skin and mucous membranes by inhalation or parenterally [1,2]. Carbamazepine intoxication is one of the most common causes of poisoning in children. Because of its availability, carbamazepine is commonly involved in accidental and deliberate overdoses. Carbamazepine, which was approved by the Food and Drug Administration in 1968, is indicated as first-line therapy for simple, complex partial, general tonic-clonic seizures and trigeminal neuralgia, bipolar disorders, neuropathic pain, and attention-deficit/hyperactivity disorders [3]. Because this drug is present in many households, there is a high incidence of accidental poisoning, particularly in children. Acute carbamazepine toxicity presents with cardiac, respiratory, and neurologic effects [2,3]. C 2013 Wiley Periodicals, Inc. V
Carbamazepine distribution and metabolism are complex. It is reasonably bioavailable and rapidly absorbed from the gastrointestinal (GI) tract, leading to peak drug concentrations in 1–3 h. Carbamazepine is highly bound to plasma proteins (75–80%) with a moderately large volume of distribution and has a half-life between 12 h and 20 h. Carbamazepine intoxication management is generally supportive [4]. The treatment options include activated charcoal, alkalinization, and hemoperfusion or plasma exchange, if necessary [5–9]. We aimed to emphasize the importance of plasma exchange for the treatment of intoxication with high plasma-protein-binding agents such as carbamazepine. CASE
A 3-year-old male patient who was being followed at another center for status epilepticus was referred to *Correspondence to: Ilknur Kozanoglu, Department of Physiology, Faculty of Medicine, Baskent University, Ankara, Turkey. E-mail: [email protected] Received 2 April 2013; Accepted 20 September 2013 Published online 18 October 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jca.21305
Severe Carbamazepine Intoxication
our hospital for plasma exchange treatment. A review of the patient’s history showed that he had taken 20 tablets R 400 mg (carbamazepine) 6 h earlier. His of TegretolV serum carbamazepine level was 37 mg/ml, indicating carbamazepine intoxication (therapeutic range: 8–12 mg/ml) [10]. After the diagnosis, gastric lavage was performed, and activated charcoal was administered. The patient was then referred for plasma exchange treatment. Physical examination showed that he was unconscious and had dilated pupils, a weak response to light with a Glasgow coma score of 4, tachycardia (134/ min), and hypotension (80/40 mmHg). His hemoglobin and hematocrit levels were 11.6 g/dl and 36.2%, respectively. Other physical and laboratory findings were unremarkable. The patient was started on activated charcoal, administered every 4 h and continuous electrocardiographic monitoring was instituted. The Pediatric Nephrology Department was consulted, and emergency hemodialysis was planned. After hemodialysis, his carbamazepine levels remained high. The patient had severe facial edema and eyelid swelling. Because his clinical status did not improve after hemodialysis, emergency plasma exchange was planned. Two sessions of plasma exchange were performed using a Spectra Optia Apheresis System (Terumo BCT, Lakewood, CO). The total blood volume (1200 ml) of the patient was calculated based on his weight, and his plasma volume (768 ml) was calculated based on the total blood volume and hematocrit [11]. Considering the extracorporeal volume, the plasma exchange set was primed with one unit of typed and cross-matched leukoreduced packed red cells prior to the run. A central venous catheter was used. The inlet flow rate was 15 ml/ min for both procedures, and 2195 ml and 1980 ml of blood were processed in the first and the second procedures, respectively. The total plasma volume exchanged was 1250 ml (1.4 plasma volumes) in the first procedure and 1083 ml (1.3 plasma volumes) in the second. The replacement fluid used was ABO-compatible fresh frozen plasma. The duration of the first procedure was 148 min, and the second procedure lasted 115 min. No technical problem related to the cell separators was noted. No minor or severe complication was observed during or after the plasma exchange procedures. The patient was hospitalized as a tertiary care pediatric intensive care unit (ICU) patient and underwent plasma exchange 12 h after admission. After the treatment, his carbamazepine levels decreased gradually to 28 and 25 mg/ml. We observed an increase in spontaneous activity, although he was still unconscious. The initial albumin was 2.05 g/dl and plasma albumin level increased to 3.01 g/dl. The second plasma exchange was performed 36 h after admission. After the treatment, his carbamazepine level was less than 10 mg/ml. His activity increased more, and his response to light stimuli was stronger. He started opening his eyes spon-
179
taneously. He was extubated at the third day of his hospitalization. Because sufficient spontaneous respiration was returned, an oxygen mask was used during the follow up. He gained consciousness and responded verbally at day 4. Oral feeding was started, and he was transferred to the pediatric ward. He was discharged at day 6 after regaining his physical and mental activity. DISCUSSION
Acute poisoning during childhood is an important cause of morbidity and mortality [1]. When epidemiological data are examined, it is obvious that, in addition to preventive measures for drug intoxications, fast planning of treatment and intervention is crucial and may be life saving [1,2]. Carbamazepine is an antiepileptic drug with a tricyclic structure. It is used for the treatment of complex and partial epilepsies, bipolar disorder, trigeminal neuralgia, post-therapeutic neuralgia, and phantom extremity pain [3,4]. Carbamazepine inhibits presynaptic voltage-sensitive Na1 channels in the central nervous system, inhibiting high-frequency epileptic foci. It has no effect on normal neuronal discharge [3,4]. Due to its lipophilic properties, after oral ingestion, carbamazepine is absorbed in different amounts and quickly passes the blood brain barrier. The peak plasma level of carbamazepine may be reached in 6 to 8 h, and it binds to plasma proteins [4]. Carbamazepine levels exceeding the therapeutic dose range cause a proportional increase in complaints and severe clinical symptoms. A concentration higher than 40 mg/L is usually fatal [5,7,8]. Considering the pharmacokinetic characteristics of carbamazepine, plasma exchange treatment may be useful for cases of carbamazepine poisoning. For carbamazepine intoxication, gastric lavage and activated charcoal administration within 1 h is recommended. Because the effects of carbamazepine are dose dependent, and it has high plasma-protein-binding properties, hemodialysis and hemoperfusion are not adequate for elimination [7]. Thus, plasma exchange therapy must be considered for the treatment of highdose carbamazepine intoxication or other similar plasma-protein-binding drug intoxications. When the current literature was searched for carbamazepine intoxication and plasma exchange therapy, studies involving two adult patients and one adolescent patient were found [9,12,13]. Duzova et al. reported a case of an adolescent (15 years old) who had taken a lethal dose of carbamezapine and was treated by plasma exchange in the ICU. At the end of the procedure, the patient started to respond to verbal stimuli, her neurological status improved, gradually and she was discharged on the fourth day after the ICU admission [13]. Another case with severe carbamazepine poisoning was reported by Gambi et al. They treated the patient Journal of Clinical Apheresis DOI 10.1002/jca
180
Kozanoglu et al.
using plasmapheresis techniques for three consecutive days. The patient recovered and was discharged without complications after a 6-day stay in the ICU [9]. Kale et al. reported a 21-year-old male with acute overdose, and performed plasma exchange therapy; however, the procedure did not seem to affect the clinical status of the patient because a significant rebound occurred after plasmapheresis [12]. The youth of our patient (3 years) and his rapid and remarkable response to plasma exchange were significant. The present case illustrates some of the difficulties of managing life-threatening toxic ingestion using agents that are highly protein-bound. Thus, we suggest that simple plasma exchange by plasma replacement might be a less costly and more effective method for the treatment of intoxication with carbamazepine. No technical problem related to the cell separators was noted, and no minor or severe complication was observed during or after the plasma exchange procedures. Our results also suggest that plasma exchange is effective for the treatment of intoxication with high plasma-protein-binding agents such as carbamazepine, particularly in children. REFERENCES 1. Ozdemir R, Bayrakci B, Teksam O, Yalcin B, Kale G. Thirtythree-year experience on childhood poisoning. Turk J Pediatr 2012;54:251–259.
Journal of Clinical Apheresis DOI 10.1002/jca
2. Neilson ZE, Morrison W. Childhood self-poisoning: a one-year review. Scott Med J 2012;57:196–199. 3. Holland KD. Efficacy, pharmacology, and adverse effects of antiepileptic drugs. Neurol Clin 2001;19:313–345. 4. Bertilsson L, Tomson T. Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11epoxide. An update. Clin Pharmacokinet 1986;11:177–198. 5. Spiller HA, Carlisle RD. Status epilepticus after massive carbamazepine overdose. J Toxicol Clin Toxicol 2002;40:81–90. 6. American Academy of Clinical Toxicology, European Association of Poisons Centres and Clinical Toxicologists. Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol 1999;37:731–751. 7. Durelli L, Massazza U, Cavallo R. Carbamazepine toxicity and poisoning: incidence, clinical features and management. Med Toxicol Adverse Drug Exp 1989;4:95–107. 8. Soderstrom J, Murray L, Little M, Daly FM. Toxicology case of the month: carbamazepine overdose. Emerg Med J 2006;23: 869–871. 9. Gambi D, Oggioni R, Mangani V, Librenti M, Manescalchi F, Tulli G Acute carbamazepine poisoning treated with plasmapheresis. Description of a clinical case. Minerva Anestesiol 1993;59:547–552. 10. Tibbals J. Acute toxic reaction to carbamazepine: clinical effects and serum concentrations. J Pediatr 1992;121:295–299. 11. McLeod Bruce C. Apheresis Principles and Practice, 2nd ed. Bethesda: AABB Press; 2003. 12. Kale PB, Thomson PA, Provenzano R, Higgins MJ. Evaluation of plasmapheresis in the treatment of an acute overdose of carbamazepine. Ann Pharmacother 1993;27:866–870. 13. Duzova A. Carbamazepine poisoning: treatment with plasma exchange. Hum Exp Toxicol 2001;20:175.
