Effectiveness of hemodialysis in the extracorporeal therapy of phenobarbital overdose

Effectiveness of Hemodialysis in the Extracorporeal Therapy of Phenobarbital Overdose Bift F. Palmer, MD • Most patients with phenobarbital overdose can be adequately treated with general supportive care, cathartics, activated charcoal, and a forced alkaline diuresis. In severely compromised patients, both hemodialysis and hemoperfusion have been used to enhance elimination of the drug. Of these two therapies, hemoperfusion is generally considered to be more effective because phenobarbital shows significant protein binding. Prior reports describing the use of hemodialysis in the treatment of phenobarbital overdose used small low-efficiency dialyzers at much lower blood flow rates compared with what is available today. In this report, a patient with life-threatening phenobarbital overdose is described who was treated with hemodialysis. This is the first reported case describing the effects of a high-efficiency dialyzer using high blood flow rates on phenobarbital pharmakokinetics. Using this technique, the clearance of phenobarbital was found to be greater than what has been previously reported with hemodialysis and greater than most reported cases describing the use of hemoperfusion. The procedure was associated with a rapid fall in phenobarbital levels and a dramatic improvement in the patient's clinical condition. The findings in this case show that use of a high-efficiency dialyzer with high blood flow rates is an effective therapy for patients with life-threatening phenobarbital poisoning. The excellent clearance of phenobarbital shown in this case, combined with the lack of thrombocytopenia, more widespread availability, and greater familiarity by the staff who administer it, support the idea that hemodialysis should be considered the preferred mode of extracorporeal therapy for phenobarbital intoxication. © 2000 by the National Kidney Foundation, Inc. INDEX WORDS: Phenobarbital overdose; hemodialysis; phenobarbital clearance.

P

HENOBARBITAL is a long-acting barbiturate that is often used in the treatment of epilepsy. Toxic levels of the drug can profoundly suppress the central nervous system and potentially result in death or respiratory failure. As a result, deliberate overdose with phenobarbital constitutes a medical emergency. In addition to supportive care, the management of a patient with phenobarbital overdose involves therapy designed to decrease absorption and enhance elimination of the drug. Gastrointestinal absorption is reduced by the use of cathartics and activated charcoal, whereas establishment of an alkaline diuresis will enhance elimination of the drug. Although most patients can be managed with such noninvasive therapy, hemodialysis or hemoperfusion have both been From the Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX. Received February 4, 2000; accepted as submitted March 31,2000. Address reprint requests to Bift F. Palmer, MD, Professor of Internal Medicine. Director of Clinical Nephrology, Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas. TX 75235. E-mail: [email protected] © 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3603-0024$3.00/0 doi: I 0.1 053/ajkd.2000.16207 640

used in critically ill overdosed patients to enhance the elimination of phenobarbital. Because of the high degree of protein binding, hemoperfusion is generally viewed as a more effective means for the removal of phenobarbital than is hemodialysis.! However, unlike hemodialysis, hemoperfusion is not as widely available. In addition, the superiority of hemoperfusion over hemodialysis is largely based on older reports that used low-efficiency dialyzers and low blood flow rates as compared with what is available today.2-4 This report describes a patient with life-threatening phenobarbital toxicity who was treated successfully with hemodialysis, using a high-flux, high-efficiency dialyzer and high blood flow rates. The clearance of phenobarbital by use of this strategy was much greater than what has previously been reported with hemodialysis and greater than most values reported with hemoperfusion. The rapid fall in phenobarbital levels and the dramatic clinical response noted during the procedure would support that this technique is an effective therapy in patients with life-threatening phenobarbital intoxication. CASE REPORT A 33-year-old women was brought to the emergency room at Parkland Memorial Hospital after being found unconscious. A family member stated that the patient was depressed and had been drinking alcohol the night before. The following morning, the patient became less responsive, and

American Journal of Kidney Diseases, Vol 36, No 3 (September). 2000: pp 640-643

HD IN PHENOBARBITAL OVERDOSE

641 Table 1.

Hemodialysis 140

I

120

Phenobarbital Clearance Data During Hemodialysis

Concentration (p.gImL)

100

'ii

~ ~

.

:c III

,g

0

80 60 40

C

Gl

s;:

20

II. 0 0

5

10

15

Time (h)

Arterial

Venous

Extraction Ratio(%)

Clearance (mUmin)

0 1 2 3 4

130 90.9 79.4 62.4 53.5

70.2 58.2 43.2 32.8 29.7

46 36 45 47 44

184 144 180 188 176

20

Hours

Fig 1. Phenobarbital levels during the hospitalization. The timing of the hemodialysis procedure is indicated. The last phenobarbital level (39.7 ltg/mL) was obtanined 27 hours after the last data point and is not plotted in the figure. an empty medication bottle of unknown type was found in her room. On initial evaluation, she was comatose and required intravenous dopamine to maintain a systolic blood pressure of 90 to 100 mm Hg. Admission laboratory examination was significant for normal serum chemistries, blood counts, and osmolar gap. The ethanol level was 70 mg/dL, and a urine toxicology screen was positive for cocaine and barbiturates. The patient was admitted to the intensive care unit and was treated with several doses of activated charcoal administered through a nasogastric tube. A phenobarbital level obtained 18 hours after admission to the hospital showed a value of 147 Itg/mL. At this time, additional doses of activated charcoal were administered, and a forced alkaline diuresis was initiated. Given the extremely high level of phenobarbital and the severe clinical toxicity, the patient was initiated on hemodialysis approximately 23 hours after admission to the hospital. At the time of initiation, the patient was still comatose, although the blood pressure had stabilized off pressors. The patient was dialyzed for 4 hours with a femoral dual-lumen catheter. A high-flux, high-efficiency polysulfone hemodialysis membrane (F80, Fresenius) was used for the procedure. The blood flow rate was 400 mL/min, and the dialysate flow rate was 500 mUmin. Simultaneous blood samples for measurement of phenobarbital levels were obtained as blood entered (arterial) and exited (venous) the dialysis membrane and from a peripheral vein. Samples were obtained at the start of the procedure and hourly thereafter. Extraction ratio (E) was calculated from the formula E = (A-V)/A. Whole blood clearances were obtained by multiplying the whole blood flow rate by the extraction ratio. The elimination rate constant (1(.,,) was derived from the equation 1(.,1 = In (initial concentration / final concentration) / time. T1/2 was then calculated by using the equation T1/2 = .693/K.,1' At approximately 2 hours into the procedure, the patient began to show spontaneous movement and was able to say her name. Her mental status continued to improve, and by the end of the treatment, she was able to respond appropri-

ately to verbal commands. Her clinical condition remained stable, with no subsequent deterioration after discontinuation of the dialysis procedure. The alkaline diuresis was discontinued at the end of the dialysis procedure. The effect of hemodialysis on the concentration of phenobarbital is illustrated in Fig 1. During the course of the dialysis procedure, her phenobarbitallevel decreased from 130 to 53 ltg/mL. The extraction ratio and clearance values during the dialysis procedure are given in Table 1. The clearance of phenobarbital was fairly constant over the 4 hours and averaged 174 mL/min. For the 5 hours preceding hemodialysis when the patient was treated with activated charcoal and an alkaline diuresis, the 1(.,) was 0.024 per hour, and the T1/2 was 29 hours. The 1(.,) increased to 0.220 per hour, and the TJ12 decreased to 3.2 hours during the dialysis procedure. Over the next 32 hours, when all therapy was discontinued, the 1(.,1 decreased to 0.012 per hour and the TJ12 increased to 57 hours (Table 2).

DISCUSSION

This case illustrates that hemodialysis can rapidly lower toxic levels of phenobarbital and supports the use of this procedure in patients with life-threatening phenobarbital overdose. The effectiveness of the procedure in this case can be attributed to the use of a high-efficiency dialyzer and high blood flow rates. Although hemoperfusion is the generally recommended form of extracorporeal therapy for phenobarbital overdose, this report suggests that hemodialysis when emTable 2.

Elimination Rate Constant (Kel ) 0.024/h 0.220/h 0.012/h

Pharmacokinetic Parameters During Different Treatments Half-Life (T 1I2 ) (h) 29 3.2 57

Treatment Activated charcoal, forced alkaline diuresis Hemodialysis, forced alkaline diuresis None

642

ployed in this manner is also a highly effective treatment for acute phenobarbital poisoning. A number of factors playa role in determining whether a drug can be removed by hemodialysis or hemoperfusion. 5 Dialysis is most effective when a substance has a low molecular weight, a high water solubility, and a small volume of distribution. Drugs that are highly protein bound are not effectively removed with hemodialysis. By contrast, hemoperfusion is effective in removing drugs that are highly protein bound because this procedure allows circulating blood to come into direct contact with substances capable of adsorbing toxins. Phenobarbital has a relatively small volume of distribution (0.9 L/kg body weight) but is 40% to 60% protein bound. 6 It is this latter characteristic that has resulted in hemoperfusion becoming the preferred mode of extracorporeal therapy in barbiturate poisoning. Limited data are available on the effect of hemoperfusion on the pharmacokinetics of phenobarbital in the overdose setting. Jacobson et aF described 3 patients with phenobarbital overdose who were simultaneously treated with hemoperfusion and a forced alkaline diuresis. The median clearance values for the three patients were 93, 77, and 68 mUmin. It was noted that clearance values declined during the procedure, reflecting saturation of the hemoperfusion cartridge. During the procedure, the plasma T 1/2 values were 10, 11, and 7 hours. The plasma T 1/2 increased to 82, 51, and 48 hours after the procedure while only receiving the alkaline diuresis. The procedure was complicated by significant declines in the platelet count, with one patient requiring a platelet transfusion. Raper et al 8 described two patients with phenobarbitone overdose who were treated with hemoperfusion by use of a cartridge containing 160 g petroleum-based activated charcoal carbon beads coated with polyhydroxymethylacrylate. 8 The initial clearance values in these two patients was as high as 286 and 212 mUmin but progressively declined during the 7and 5.25-hour procedure to 140 and 183 mU min. In seven additional patients treated with other types of cartridges, the average clearance values for phenobarbitone ranged from 41 to 102 mL/min. Once again, clearance values were noted to decline during the hemoperfusion procedure. It was not specifically mentioned in these reports

BIFF F. PALMER

as to whether the patients were treated with forced alkaline diuresis or oral activated charcoal during the procedure. Previous reports describing the effect of hemodialysis on the pharmacokinetics of phenobarbital is also somewhat limited. Zawada et al 9 described a patient with phenobarbital poisoning treated with 6.5 hours of hemodialysis with a 1.5 m2 hollow fiber dialyzer and a blood flow rate of 200 mL/min. 9 During the procedure, the extraction ratio ranged from 14.7% to 27.8%, with clearance values ranging from 29.4 to 62 mL/ min. There was no decline in the extraction ratio or clearance of phenobarbital during the procedure. The Kel during dialysis was 0.0832 per hour. The T 1I2 during dialysis was 8.33 hours as compared with 86.6 hours while treated with a forced alkalinization diuresis. Additional reports in which much less detail is given regarding the dialysis procedure have reported phenobarbital clearance values of 60 to 82 mUmin. 10.11 The clearance of phenobarbital in this case is much higher than previously reported with hemodialysis. In addition, the phenobarbital clearance in this case also exceeds most values that have been previously reported with hemoperfusion. As noted above, Raper et al 8 described two cases treated with hemoperfusion in which the initial clearance of phenobarbital was greater than in this case; however, it should be noted that these values progressively declined over the course of the procedure. 8 Given that phenobarbital is significantly protein bound, it is somewhat surprising that hemodialysis even with the use of a high-efficiency dialyzer was found so effective in removing the drug. In this regard, it is of interest that in vitro experiments examining the barbiturate pentobarbital did not show any important differences in the dialysis of the drug in plasma as compared with dialysis in a proteinfree solution. 4 There are several reasons to suggest that hemodialysis as implemented in this case is preferable to hemoperfusion in the therapy of phenobarbital overdose. The high clearance of phenobarbital observed in this case was sustained over the course of the 4 hours of treatment. By contrast, most reports of phenobarbital clearance in hemoperfusion have been much lower than observed in this case and have progressively de-

HD IN PHENOBARBITAL OVERDOSE

elined during the procedure because of saturation of the adsorbing resin. Hemodialysis is not associated with thrombocytopenia, although this is a well-known complication of hemoperfusion that may be severe enough to require platelet transfusion. Unlike hemoperfusion, hemodialysis will correct fluid and electrolyte abnormalities when present. Finally, hemodialysis is much more widely available than is hemoperfusion. As a result, both physicians and nursing staff have greater familiarity with the procedure and its attendant complications. The purpose of this report is not to suggest that all patients with phenobarbital overdose should be treated with hemodialysis. In fact, most cases of phenobarbital overdose can be treated by less invasive methods. Both forced alkaline diuresis and multiple-dose activated charcoal can significantly reduce the plasma T 1/2 and increase the Kel for phenobarbital. 12-15 The effectiveness of these measures is evident in this case by comparing the T 1/2 and the Kel during the 5 hours before hemodialysis during treatment with both activated charcoal and an alkaline diuresis with the values posthemodialysis when all therapy was discontinued. Rather, this case simply illustrates that hemodialysis with use of a high-efficiency dialyzer and high blood flow rates is an effective means to treat a patient with phenobarbital overdose in whom extracorporeal therapy is indicated.

REFERENCES 1. Gelfand M: Hemoperfusion in drug overdose. JAMA 240:2761-2762,1978 2. Setter J, Freeman R, Maher J, Schreiner G: Factors

643 influencing the dialysis of barbituates. Trans Am Soc Artif Internal Organs 10:340-344, 1964 3. Kennedy A, Briggs J, Yound N, Lindsay R, Luke R, Campbell D: Successful treatment of three cases of very severe barbituate poisoning. Lancet 1:995-998, 1969 4. Berman L, Jeghers H, Schreiner G, Pallotta A: Hemodialysis: An effective therapy for acute barbituate poisoning. JAMA 161:820-827,1956 5. Garella S: Extracorporeal techniques in the treatment of exogenous intoxications. Kidney Int 33:735-754, 1988 6. Lindberg MC, Cunningham A, Lindburg N: Acute phenobarbital intoxication. South Med J 85:803-807, 1992 7. Jacobsen D, Wiik-Larsen E, Dahl T, Enger E, Lunde P: Pharmacokinetic evaluation ofhaemoperfusion in phenobarbital poisoning. Eur J Clin PharmacoI26:109-112, 1984 8. Raper S, Crome P, Vale A, Helliwell M, Widdop B: Experience with activated Carbon-bead haemoperfusion columns in the treatment of severe drug intoxication. Arch ToxicoI49:303-31O, 1982 9. Zawada E, Nappi J, Done G, Rollins D: Advance in the hemodialysis management of phenobarbital overdose. South Med J 76:6-8, 1983 10. Streete J, Berry D, Jones J, Groggin M: Clearance of phenylethylmalonarnide during haemodialysis of a patient with renalfailure. Ther Drug Monit 12:281-283, 1990 11. Bradberry S, Vale J: Multiple-dose activated charcoal: A review of relevant clinical studies. Clin Toxicol 33:407-416, 1995 12. Strickler J: Forced diuresis in the management ofbarbituate intoxication. Clin Pharmacol Ther 6:693-698, 1965 13. Bloomer H: A critical evaluation of diuresis in the treatment ofbarbituate intoxication. J Lab Clin Med 67:898905, 1966 14. Pond S, Olson K, Osterich J, Tong T: Randomized study of the treatment of phenobarbital overdose with repeated doses of activated charcoal. JAMA 251:3104-3108, 1984 15. Frenia M, Schauben J, Wears R, Karlix J, Tucker C, Kunisaki T: Multiple-dose activated charcoal compared to urinary alkalinization for the enhancement of phenobarbital elimination. Clin ToxicoI34:169-175, 1996