- Email: [email protected]
Use of Continuous Venovenous Hemodiafiltration in a Case of Severe Phenobarbital Poisoning
CASE REPORT
Use of Continuous Venovenous Hemodiafiltration in a Case of Severe Phenobarbital Poisoning Rajiv Lal, MD, Saadia Faiz, MD, Rajeev K. Garg, MD, Kanwarpreet S. Baweja, MD, Jayarama Guntupalli, MD, and Kevin W. Finkel, MD ● Conventional hemodialysis and hemoperfusion have been used for life-threatening phenobarbital poisoning. We report the successful use of continuous renal replacement therapy in a case of severe phenobarbital poisoning associated with severe coma and hypotension. Use of this modality led to clearance of phenobarbital with improvement in the clinical status of the patient. Am J Kidney Dis 48:E13-E15. © 2006 by the National Kidney Foundation, Inc. INDEX WORDS: Phenobarbital poisoning; continuous venovenous hemodiafiltration (CVVHDF).
P
HENOBARBITAL is a long-acting barbiturate commonly used as an anticonvulsant since 1912.1 Phenobarbital overdose causes depression of the central nervous, cardiovascular, and respiratory systems, leading to coma, respiratory failure, and hemodynamic collapse. Treatment includes airway protection, vasopressor support, and drug elimination by gastric lavage, activated charcoal, forced alkaline diuresis, and renal replacement therapy. Both hemodialysis and hemoperfusion have been used for enhancing drug clearance. However, this may be difficult in patients with hemodynamic instability and hypotension. Continuous venovenous hemodiafiltration (CVVHDF) is a mode of renal replacement therapy commonly used in unstable critically ill patients Table 1. Laboratory Data Sodium (mEq/L) Potassium (mEq/L) Chloride (mEq/L) Bicarbonate (mEq/L) Blood urea nitrogen (mg/dL) Creatinine (mg/dL) Calcium (mg/dL) Phosphate (mg/dL) pH Bilirubin (mg/dL) Protime (s) White blood cells (⫻103/L) Hemoglobin (g/L) Platelets (⫻103/L)
136 3.9 109 19 21 1.5 8.3 3.7 7.27 2.1 17.3 22.6 181 181
NOTE. To convert serum sodium, potassium, chloride, and bicarbonate in mEq/L to mmol/L, multiply by 1; blood urea nitrogen in mg/dL to mmol/L, multiply by 0.357; creatinine in mg/dL to mol/L, multiply by 88.4; calcium in mg/dL to mmol/L, multiply by 0.2495; phosphorus in mg/dL to mmol/L, multiply by 0.3229; bilirubin in mg/dL to mol/L, multiply by 17.1; white blood cells and platelets in ⫻103/L to ⫻109/L, multiply by 1.
in intensive care units. We report the successful use of CVVHDF in a patient with severe coma and hypotension from phenobarbital overdose. Use of this modality led to clearance of phenobarbital and improvement in the clinical status of the patient. CASE REPORT A 58-year-old man was brought to the Emergency Center after a family member found the patient unresponsive on his couch. He apparently had not moved from his couch for 36 hours after a family argument. On presentation, the patient had a Glasgow Coma Scale score of 3 and was intubated and mechanically ventilated. Blood pressure was 89/74 mm Hg. Acute Physiology and Chronic Health Evaluation II score was 33. Results of serum chemistry tests at presentation are listed in Table 1. The patient was resuscitated in the Emergency Center with 2 L of 0.9% saline, followed by a 100-mmol solution of sodium bicarbonate at 100 mL/h. No inotropes or vasopressors were used. He was oliguric, with urine output of 20 mL/h. Toxicology studies showed a phenobarbital level of 106 g/mL. The patient had consumed approximately 50 pills (each 97 mg; total, 4.85 g) of phenobarbital. Benzodiazepine also was found in urine after the patient was administered a benzodiazepine before intubation. He was given activated charcoal in the Emergency Center, and renal replacement therapy was initiated. Because the patient was hypotensive, CVVHDF was the modality chosen. CVVHDF was performed through a dual-
From the University of Texas Health Science Center at Houston, TX. Received November 1, 2005; accepted in revised form April 24, 2006. Originally published online as doi:10.1053/j.ajkd.2006.04.081 on June 19, 2006. Support: None. Potential conflicts of interest: None. Address reprint requests to Rajiv Lal, MD, 6431 Fannin, Ste 4.148, Houston, TX 77030. E-mail: [email protected] © 2006 by the National Kidney Foundation, Inc. 0272-6386/06/4802-0025$32.00/0 doi:10.1053/j.ajkd.2006.04.081
American Journal of Kidney Diseases, Vol 48, No 2 (August), 2006: E13-E15
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LAL ET AL
Fig 1. Phenobarbital levels during hospitalization. Timing of the CVVHDF procedure is indicated.
lumen femoral catheter using the Prisma system (Hospal, Medolla, Italy) with a blood flow of 150 mL/h and dialysate flow rate of 2,500 mL/h with a biocompatible AN69 (Gambro, Meyzieu, France) membrane with 0.6-m2 filter. Hemofiltration at 1,000 mL/h was performed with 0.45% normal saline, with 50 mEq/L of sodium bicarbonate as the prefilter fluid. Anticoagulation was performed with regional citrate anticoagulation, as previously described. Flow rates remained constant during the entirety of therapy. Phenobarbital levels were measured simultaneously from a peripheral vein, arterial port, and venous port for the first 6 hours of therapy. Total duration of therapy was 31 hours 45 minutes. During therapy, phenobarbital level decreased from 93 g/mL at the start to 41 g/mL at the finish, as shown in Fig 1. After stopping CVVHDF, there was no rebound of phenobarbital levels. Approximately 6 hours into therapy, the patient started to improve. We calculated extraction ratios, clearances, amount of drug removed per hour (Table 2), elimination rate constant, and half-life. The patient then was transferred out of the intensive care unit on day 4 and discharged from the hospital on day 6.
DISCUSSION
Phenobarbital, a barbiturate, is a nonselective central nervous system depressant used primarily as an anticonvulsant. It has a molecular weight of 232 d and a relatively small volume of distribution (0.9 L/kg body weight). It is 40% to 60% protein bound. It is metabolized primarily by the hepatic microsomal enzyme system, and metabolic products are excreted in urine and, less commonly, feces. Approximately 25% to 50% of a dose of phenobarbital is eliminated unchanged in urine. Acute overdose with barbiturates is manifested by central nervous system and respiratory depression that can progress to CheyneStokes respiration, areflexia, oliguria, tachycardia, hypotension, hypothermia, and coma. Typical
Table 2. Phenobarbital Clearance Data During CVVHDF
Time
Peripheral Vein (g/mL)
Venous Port (V) (g/mL)
Arterial Port (A) (g/mL)
Extraction Ratio % E ⫽ (A ⫺ V)/A
Clearance (mL/min)
Drug Removed per Hour (mg)
12:52 AM 1:50 AM 2:44 AM 3:36 AM 4:45 AM 5:42 AM
93 94 88 82 84 79
68 72 69 64 62 65
72 85 81 79 79 79
5.5 15.2 14.8 18.9 21.5 17.7
8.25 22.8 22.2 28.35 32.25 26.55
46 128 117 139 162 125
SEVERE PHENOBARBITAL POISONING
shock syndrome with apnea, circulatory collapse, respiratory arrest, and death can occur. This case shows that CVVHDF can be used to treat severe phenobarbital poisoning. The normal half-life of phenobarbital ranges from 53 to 140 hours. While the patient was on CVVHDF therapy, we achieved an elimination rate constant of 0.025/h with a half-life of 27 hours. In a report by Palmer,2 the elimination rate constant achieved on hemodialysis therapy for 4 hours and forced alkaline diuresis was 0.220/h, with a half-life of 3.2 hours. In this case, the patient was hemodynamically unstable and CVVHDF offered a successful alternative. Bironneau et al3 also described the use of CVVHDF in a similar clinical setting of barbiturate overdose with total drug extraction of 2.7 g of pentobarbital (5% of ingested dose) during the 48-hour period of therapy. They used slower blood flows (100 mL/h) for the first 17 hours of therapy. For the remainder of the treatment (31 hours), blood flow rate was increased to 150 mL/h. Greater clearances were observed with the greater blood flow rate, with a range of 4 to 11 mL/min. Average effluent in their case was 750 mL/h, whereas it was 3,500 mL/h in this case. During the 48 hours of therapy, pentobarbital arterial concentration decreased from 176 to 71 mg/L, whereas in this case, phenobarbital peripheral vein concentration decreased from 93 to 41 g/mL at the end of approximately 28 hours of therapy, suggesting that both greater blood flows and greater effluent rates decrease the drug concentration faster. Bonnardeaux et al4 showed improved clearances of small-molecularweight solutes in continuous arteriovenous hemodiafiltration by increasing diffusive fluxes with a dialysate flow rate up to 4 L/h and suggested its usefulness in treatment of patients with severe intoxication with low-molecular-weight substances. The modality of CVVHDF offers benefits compared with hemoperfusion, including volume and metabolic control, not limited by saturation of the hemoperfusion filter. CVVHD also was used in such poisonings as lithium,5-7 iodine,8 Nacetylprocainamide,9 methotrexate,10 and ethylene glycol.11 In life-threatening lithium and N-
e15
acetylprocainamide poisoning, CVVHDF offers the advantage of avoiding rebound of drug levels.5-7,9 At the same time, CVVHDF is more labor intensive and requires skilled nursing, which may not be available readily. In some cases, anticoagulation also may be needed. In conclusion, CVVHDF with high blood flow and high ultrafiltrate rates is a viable modality in the treatment of patients with severe phenobarbital poisoning when conventional hemodialysis or hemoperfusion may not be an option. REFERENCES 1. Hauptman A: Luminal bie epilepsia. Munch Med Wochenschr 59:1907-1909, 1912 2. Palmer BF: Effectiveness of hemodialysis in the extracorporeal therapy of phenobarbital overdose. Am J Kidney Dis 36:640-643, 2000 3. Bironneau E, Garrec F, Kergueris MF, Testa A, Nicolas F: Hemodiafiltration in pentobarbital poisoning. Ren Fail 18:299-303, 1996 4. Bonnardeaux A, Pichette V, Ouimet D, et al: Solute clearances with high dialysate flow rates and glucose absorption from the dialysate in continuous arteriovenous hemodialysis. Am J Kidney Dis 19:31-38, 1992 5. Meyer RJ, Flynn JT, Brophy PD, et al: Hemodialysis followed by continuous hemofiltration for treatment of lithium intoxication in children. Am J Kidney Dis 37:10441047, 2001 6. Leblanc M, Raymond M, Bonnardeaux A, et al: Lithium poisoning treated by high-performance continuous arteriovenous and venovenous hemodiafiltration. Am J Kidney Dis 27:365-372, 1996 7. Menghini VV, Albright RC Jr: Treatment of lithium intoxication with continuous venovenous hemodiafiltration. Am J Kidney Dis 36(3):E21, 2000 8. Kanakiriya S, De Chazal I, Nath KA, Haugen EN, Albright RC, Juncos LA: Iodine toxicity treated with hemodialysis and continuous venovenous hemodiafiltration. Am J Kidney Dis 41:702-708, 2003 9. Leblanc M, Pichette V, Madore F, Ouimet D, Geadah D, Cardinal J: N-Acetylprocainamide intoxication with torsades de pointes treated by high dialysate flow rate continuous arteriovenous hemodiafiltration. Crit Care Med 23:589593, 1995 10. Jambou P, Levraut J, Favier C, Ichai C, Milano G, Grimaud D: Removal of methotrexate by continuous venovenous hemodiafiltration. Contrib Nephrol 116:4852, 1995 11. Christiansson LK, Kaspersson KE, Kulling PE, Ovrebo S: Treatment of severe ethylene glycol intoxication with continuous arteriovenous hemofiltration dialysis. J Toxicol Clin Toxicol 33:267-270, 1995
Use of Continuous Venovenous Hemodiafiltration in a Case of Severe Phenobarbital Poisoning Rajiv Lal, MD, Saadia Faiz, MD, Rajeev K. Garg, MD, Kanwarpreet S. Baweja, MD, Jayarama Guntupalli, MD, and Kevin W. Finkel, MD ● Conventional hemodialysis and hemoperfusion have been used for life-threatening phenobarbital poisoning. We report the successful use of continuous renal replacement therapy in a case of severe phenobarbital poisoning associated with severe coma and hypotension. Use of this modality led to clearance of phenobarbital with improvement in the clinical status of the patient. Am J Kidney Dis 48:E13-E15. © 2006 by the National Kidney Foundation, Inc. INDEX WORDS: Phenobarbital poisoning; continuous venovenous hemodiafiltration (CVVHDF).
P
HENOBARBITAL is a long-acting barbiturate commonly used as an anticonvulsant since 1912.1 Phenobarbital overdose causes depression of the central nervous, cardiovascular, and respiratory systems, leading to coma, respiratory failure, and hemodynamic collapse. Treatment includes airway protection, vasopressor support, and drug elimination by gastric lavage, activated charcoal, forced alkaline diuresis, and renal replacement therapy. Both hemodialysis and hemoperfusion have been used for enhancing drug clearance. However, this may be difficult in patients with hemodynamic instability and hypotension. Continuous venovenous hemodiafiltration (CVVHDF) is a mode of renal replacement therapy commonly used in unstable critically ill patients Table 1. Laboratory Data Sodium (mEq/L) Potassium (mEq/L) Chloride (mEq/L) Bicarbonate (mEq/L) Blood urea nitrogen (mg/dL) Creatinine (mg/dL) Calcium (mg/dL) Phosphate (mg/dL) pH Bilirubin (mg/dL) Protime (s) White blood cells (⫻103/L) Hemoglobin (g/L) Platelets (⫻103/L)
136 3.9 109 19 21 1.5 8.3 3.7 7.27 2.1 17.3 22.6 181 181
NOTE. To convert serum sodium, potassium, chloride, and bicarbonate in mEq/L to mmol/L, multiply by 1; blood urea nitrogen in mg/dL to mmol/L, multiply by 0.357; creatinine in mg/dL to mol/L, multiply by 88.4; calcium in mg/dL to mmol/L, multiply by 0.2495; phosphorus in mg/dL to mmol/L, multiply by 0.3229; bilirubin in mg/dL to mol/L, multiply by 17.1; white blood cells and platelets in ⫻103/L to ⫻109/L, multiply by 1.
in intensive care units. We report the successful use of CVVHDF in a patient with severe coma and hypotension from phenobarbital overdose. Use of this modality led to clearance of phenobarbital and improvement in the clinical status of the patient. CASE REPORT A 58-year-old man was brought to the Emergency Center after a family member found the patient unresponsive on his couch. He apparently had not moved from his couch for 36 hours after a family argument. On presentation, the patient had a Glasgow Coma Scale score of 3 and was intubated and mechanically ventilated. Blood pressure was 89/74 mm Hg. Acute Physiology and Chronic Health Evaluation II score was 33. Results of serum chemistry tests at presentation are listed in Table 1. The patient was resuscitated in the Emergency Center with 2 L of 0.9% saline, followed by a 100-mmol solution of sodium bicarbonate at 100 mL/h. No inotropes or vasopressors were used. He was oliguric, with urine output of 20 mL/h. Toxicology studies showed a phenobarbital level of 106 g/mL. The patient had consumed approximately 50 pills (each 97 mg; total, 4.85 g) of phenobarbital. Benzodiazepine also was found in urine after the patient was administered a benzodiazepine before intubation. He was given activated charcoal in the Emergency Center, and renal replacement therapy was initiated. Because the patient was hypotensive, CVVHDF was the modality chosen. CVVHDF was performed through a dual-
From the University of Texas Health Science Center at Houston, TX. Received November 1, 2005; accepted in revised form April 24, 2006. Originally published online as doi:10.1053/j.ajkd.2006.04.081 on June 19, 2006. Support: None. Potential conflicts of interest: None. Address reprint requests to Rajiv Lal, MD, 6431 Fannin, Ste 4.148, Houston, TX 77030. E-mail: [email protected] © 2006 by the National Kidney Foundation, Inc. 0272-6386/06/4802-0025$32.00/0 doi:10.1053/j.ajkd.2006.04.081
American Journal of Kidney Diseases, Vol 48, No 2 (August), 2006: E13-E15
e13
e14
LAL ET AL
Fig 1. Phenobarbital levels during hospitalization. Timing of the CVVHDF procedure is indicated.
lumen femoral catheter using the Prisma system (Hospal, Medolla, Italy) with a blood flow of 150 mL/h and dialysate flow rate of 2,500 mL/h with a biocompatible AN69 (Gambro, Meyzieu, France) membrane with 0.6-m2 filter. Hemofiltration at 1,000 mL/h was performed with 0.45% normal saline, with 50 mEq/L of sodium bicarbonate as the prefilter fluid. Anticoagulation was performed with regional citrate anticoagulation, as previously described. Flow rates remained constant during the entirety of therapy. Phenobarbital levels were measured simultaneously from a peripheral vein, arterial port, and venous port for the first 6 hours of therapy. Total duration of therapy was 31 hours 45 minutes. During therapy, phenobarbital level decreased from 93 g/mL at the start to 41 g/mL at the finish, as shown in Fig 1. After stopping CVVHDF, there was no rebound of phenobarbital levels. Approximately 6 hours into therapy, the patient started to improve. We calculated extraction ratios, clearances, amount of drug removed per hour (Table 2), elimination rate constant, and half-life. The patient then was transferred out of the intensive care unit on day 4 and discharged from the hospital on day 6.
DISCUSSION
Phenobarbital, a barbiturate, is a nonselective central nervous system depressant used primarily as an anticonvulsant. It has a molecular weight of 232 d and a relatively small volume of distribution (0.9 L/kg body weight). It is 40% to 60% protein bound. It is metabolized primarily by the hepatic microsomal enzyme system, and metabolic products are excreted in urine and, less commonly, feces. Approximately 25% to 50% of a dose of phenobarbital is eliminated unchanged in urine. Acute overdose with barbiturates is manifested by central nervous system and respiratory depression that can progress to CheyneStokes respiration, areflexia, oliguria, tachycardia, hypotension, hypothermia, and coma. Typical
Table 2. Phenobarbital Clearance Data During CVVHDF
Time
Peripheral Vein (g/mL)
Venous Port (V) (g/mL)
Arterial Port (A) (g/mL)
Extraction Ratio % E ⫽ (A ⫺ V)/A
Clearance (mL/min)
Drug Removed per Hour (mg)
12:52 AM 1:50 AM 2:44 AM 3:36 AM 4:45 AM 5:42 AM
93 94 88 82 84 79
68 72 69 64 62 65
72 85 81 79 79 79
5.5 15.2 14.8 18.9 21.5 17.7
8.25 22.8 22.2 28.35 32.25 26.55
46 128 117 139 162 125
SEVERE PHENOBARBITAL POISONING
shock syndrome with apnea, circulatory collapse, respiratory arrest, and death can occur. This case shows that CVVHDF can be used to treat severe phenobarbital poisoning. The normal half-life of phenobarbital ranges from 53 to 140 hours. While the patient was on CVVHDF therapy, we achieved an elimination rate constant of 0.025/h with a half-life of 27 hours. In a report by Palmer,2 the elimination rate constant achieved on hemodialysis therapy for 4 hours and forced alkaline diuresis was 0.220/h, with a half-life of 3.2 hours. In this case, the patient was hemodynamically unstable and CVVHDF offered a successful alternative. Bironneau et al3 also described the use of CVVHDF in a similar clinical setting of barbiturate overdose with total drug extraction of 2.7 g of pentobarbital (5% of ingested dose) during the 48-hour period of therapy. They used slower blood flows (100 mL/h) for the first 17 hours of therapy. For the remainder of the treatment (31 hours), blood flow rate was increased to 150 mL/h. Greater clearances were observed with the greater blood flow rate, with a range of 4 to 11 mL/min. Average effluent in their case was 750 mL/h, whereas it was 3,500 mL/h in this case. During the 48 hours of therapy, pentobarbital arterial concentration decreased from 176 to 71 mg/L, whereas in this case, phenobarbital peripheral vein concentration decreased from 93 to 41 g/mL at the end of approximately 28 hours of therapy, suggesting that both greater blood flows and greater effluent rates decrease the drug concentration faster. Bonnardeaux et al4 showed improved clearances of small-molecularweight solutes in continuous arteriovenous hemodiafiltration by increasing diffusive fluxes with a dialysate flow rate up to 4 L/h and suggested its usefulness in treatment of patients with severe intoxication with low-molecular-weight substances. The modality of CVVHDF offers benefits compared with hemoperfusion, including volume and metabolic control, not limited by saturation of the hemoperfusion filter. CVVHD also was used in such poisonings as lithium,5-7 iodine,8 Nacetylprocainamide,9 methotrexate,10 and ethylene glycol.11 In life-threatening lithium and N-
e15
acetylprocainamide poisoning, CVVHDF offers the advantage of avoiding rebound of drug levels.5-7,9 At the same time, CVVHDF is more labor intensive and requires skilled nursing, which may not be available readily. In some cases, anticoagulation also may be needed. In conclusion, CVVHDF with high blood flow and high ultrafiltrate rates is a viable modality in the treatment of patients with severe phenobarbital poisoning when conventional hemodialysis or hemoperfusion may not be an option. REFERENCES 1. Hauptman A: Luminal bie epilepsia. Munch Med Wochenschr 59:1907-1909, 1912 2. Palmer BF: Effectiveness of hemodialysis in the extracorporeal therapy of phenobarbital overdose. Am J Kidney Dis 36:640-643, 2000 3. Bironneau E, Garrec F, Kergueris MF, Testa A, Nicolas F: Hemodiafiltration in pentobarbital poisoning. Ren Fail 18:299-303, 1996 4. Bonnardeaux A, Pichette V, Ouimet D, et al: Solute clearances with high dialysate flow rates and glucose absorption from the dialysate in continuous arteriovenous hemodialysis. Am J Kidney Dis 19:31-38, 1992 5. Meyer RJ, Flynn JT, Brophy PD, et al: Hemodialysis followed by continuous hemofiltration for treatment of lithium intoxication in children. Am J Kidney Dis 37:10441047, 2001 6. Leblanc M, Raymond M, Bonnardeaux A, et al: Lithium poisoning treated by high-performance continuous arteriovenous and venovenous hemodiafiltration. Am J Kidney Dis 27:365-372, 1996 7. Menghini VV, Albright RC Jr: Treatment of lithium intoxication with continuous venovenous hemodiafiltration. Am J Kidney Dis 36(3):E21, 2000 8. Kanakiriya S, De Chazal I, Nath KA, Haugen EN, Albright RC, Juncos LA: Iodine toxicity treated with hemodialysis and continuous venovenous hemodiafiltration. Am J Kidney Dis 41:702-708, 2003 9. Leblanc M, Pichette V, Madore F, Ouimet D, Geadah D, Cardinal J: N-Acetylprocainamide intoxication with torsades de pointes treated by high dialysate flow rate continuous arteriovenous hemodiafiltration. Crit Care Med 23:589593, 1995 10. Jambou P, Levraut J, Favier C, Ichai C, Milano G, Grimaud D: Removal of methotrexate by continuous venovenous hemodiafiltration. Contrib Nephrol 116:4852, 1995 11. Christiansson LK, Kaspersson KE, Kulling PE, Ovrebo S: Treatment of severe ethylene glycol intoxication with continuous arteriovenous hemofiltration dialysis. J Toxicol Clin Toxicol 33:267-270, 1995