Sequential and Simultaneous “In Series” and Hemoperfusion in the Management of Theophylline Intoxication

Robert Hootkins, Sr., M.D., Ph.D.,1 Mark J. Lerman, M.D., F.A.C.P., and Jeffrey R. Thompson, M.D.

elimination by extracorporeal techniques is war- ranted. R. Hootkins, Sr. , M.J. Lerman, Nephrology/Metabolism Division, 3500 Gaston, Baylor University Medical Hemodialysis (HD) and hemoperfusion (HP) have Center, Dallas, TX been evaluated and are both effective in removing theophylhine. HD has been evaluated in uremic pa- JR. Thompson, University of Texas Southwestern tients but, surprisingly, not in the treatment of acute Medical School, Dallas overdose. Levy et at. (2) reported an average (J. Am. Soc. Nephrol. 1990; 1:923-926) plasma extraction ratio of 0.34 with a coil dialyzer using a flow rate (BFR) of 1 1 9 mL/min, result- ing in a plasma clearance of 32.8 mL/min. Lee et at. (3), by using a hollow fiber dialyzer and a higher BFR ABSTRACT of 180 to 250 mL/min, achieved a plasma extraction Hemodialysis and hemoperfusion have been evalu- ratio of 0.50 and a plasma clearance of 75 to 98 mL/ ated, and both are effective in removing theophyl- mm. HP with either resin (4) or activated charcoal line. We report two consecutive cases of theophyl- (5-8) increases theophylhine clearance as compared line intoxication in which the sequential treatment of with HD. The reported extraction ratios range from charcoal hemoperfusion and hemodialysis is con- 0. 1 9 to 0.99 with a maximum plasma theophylline trasted to the simultaneous ‘in series” treatment of clearance of 163 mL/min for charcoal HP and 225 hemodialysis and charcoal hemoperfusion. Analysis mL/min for resin HP. We report two consecutive cases of theophylhine of the two methodologies shows that the combined intoxication. Case 1 is a sequential study of charcoal in series technique offers several advantages, in- HP and HD under identical operating conditions. This cluding increased extraction efficiency, decreased allows for an accurate comparison of HP with HD time of hemoperfusion cartridge saturation, and and, in addition, an assessment of HP and HD as a rapid correction of electrolyte and acid-base ab- sequential technique. Case 2 is a study of simulta- normalities, and that it is well tolerated clinically. neous combined “in series” HD and charcoal HP (HD/ Simultaneous hemodialysis and charcoal hemoper- HP). fusion should be considered in cases of extreme theophylline intoxication. CASE I Key Words: , dialysis, extracorporeal ellmina- A 63-year-old 48.6-kg white female chronic hemo- tion dialysis patient was admitted for an acute theophyl- line overdose. She had a history of chronic obstruc- tive pulmonary disease and had been treated with theophyhhine sustained-release tablets (200 mg twice primary importance in the management of O a day). She acutely ingested an unknown number of theophylline intoxication is intense supportive these tablets 6 to 8 h before her presentation. Vital care, including maintenance of the respiratory and signs included a blood pressure of 1 40/90, a respi- cardiovascular status. Repeated administration of ratory rate of 26/mm, and an irregular pulse rate of oral doses of activated charcoal has been proven very 1 80/mm. Examination revealed clear lungs, a II/VI effective in removing theophylhine from the gastroin- systolic ejection murmur, and hyperreflexia. An dcc- testinal tract ( 1 ). When intoxications are severe or if trocardiogram revealed atrial fibrillation with a yen- endogenous clearances are decreased, enhanced tricuhar response of 180/mm. Her initial serum the- ophylhine level was 90 g/mL. She received p.o. acti- vated charcoal-sorbitoh at presentation and again

I Correspondence to Dr. R. Hootkins, 5r., Nephrology/Metabolism Division, Bay’ after 2 h. A left femoral double lumen dialysis cath- br University Medical Center, 3500 Gaston, Dallas, ix 75246. eter was inserted for vascular access (her native I046-6673/0 106-0923$02.00/0 access had thrombosed), and charcoal HP was per- Journal of the American Society of Nephrology Copyright © 1990 by the American Society of Nephrology formed for 2 h with a Gambro Adsorba 300C cartridge

Journal of the American Society of Nephrology 923 Management of Theophylline Intoxication

followed by HD for 2 additional h with a CDAK- 135 dialyzer (KoA = 525). Each technique was performed at a BFR of 300 mL/min and a dialysate flow rate of 500 mL/min. Her serum theophylhine concentration decreased from 65.7 to 24.8 g/mL during HP and Hemodialysis decreased further to 6. 1 ,g/mL after completion of HD (Table 1 ). Assuming a volume of distribution (Va) of theophylline of 0.5 liters/kg, HP removed 0.99 g and HD removed 0.48 g of theophylline. Minimal drug “rebound” was observed post-HD, and recircuhation of the dialysis catheter was determined to be less Hemoperfusion than 10%.

Case 2

A 50-year-old 47.5-kg white female with a history of depression and asthma was admitted for an acute Figure 1 . Schematic representation of simultaneous HD/HP theophylline overdose. She had ingested 1 5 g of theo- technique employed in Case 2. A, I, and V ports defined phylhine sustained-release tablets with a peak serum as depicted. level of 227 tg/mL 7 h postingestion. She received supportive treatment and p.o. activated charcoal (100 g) with magnesium citrate. Examination revealed her to be tremulous and diaphoretic with a blood pressure vice over the 4-h period (Figure 1 ). Her serum theo- of 100/65, a pulse rate of 180/mm (sinus tachy- phylline concentration decreased from 1 50 to 13.1 cardla), and a respiratory rate of 30/mm. Other cx- g/mL (Table 2). Assuming a VD of theophylline of amination findings included a hyperdynamic precor- 0.5 liters/kg, simultaneous HD/HP removed 3.25 g of dium and hyperreflexia. Laboratory evaluation re- theophylhine over 4 h. Minimal drug “rebound” was vealed hypokalemia and a metabolic acidosis. A left observed post-HD/HP, and recirculation of the di- femoral double lumen dialysis catheter was inserted alysis catheter was determined to be less than 8%. for vascular access, and simultaneous “in series” HD

(Cobe HF-140; KoA = 589) and charcoal HP (Gambro Adsorba 300C) were initiated. BFR was 250 mL/min, DISCUSSION and dialysate flow rate was 600 mL/min. A stopcock A number of factors influence the overall extrac- was placed “in line” between the dialyzer and HP tion efficiency of HP and the calculated theophylhine cartridge to facilitate blood sampling for calculation clearances. Charcoal HP cartridges progressively sat- of the individual extraction efficiencies of each de- urate with use. The rate of saturation is influenced by both the theophylline concentration and the BFR TABLE 1. Theophylline clearance data for Case 1#{176} through the device. Manufacturers recommend changing the cartridge every 2 h to prevent satura- tion and the resultant loss of efficiency. In the report Theophylline Blood by Ehlers et at. (6), the extraction efficiency de- Serum Extraction Time Theophylline creased from 0.88 to 0.65 in 90 mm with an initial Concentrations Efficiency (mm) (,g/mL) Clearance serum theophylline concentration of 1 70 g/mL and (A - V)/A (mi/kg/h) a BFR of 1 1 0 to 1 70 mL/min. Russo (7) showed a AV decrease in extraction efficiency from 0.83 to 0.19 after 60 mm with an initial plasma theophylline HP 0 65.7 5.2 0.92 341 concentration of 36 g/mL and a BFR of 200 ml/min. 30 44.1 14.7 0.67 248 We examined this saturation phenomenon with a 60 33.2 16.9 0.49 182 sequential study of charcoal HP and HD by using 120 24.8 16.8 0.32 119 identical operating conditions (Case 1 ). At a BFR of HD 135 25.7 11.9 0.54 200 300 mL/min and DFR of 500 mL/min, consistent 180 17.8 10.1 0.43 159 with current dialysis practices, extraction efficien- 240 6.1 3.2 0.48 176 des of 0.40 to 0.50 were obtained with a high effi- ciency (K0A 500) hollow fiber cellulose dialyzer and Theophylline serum concentrations were determined by Abbott TDx these rates remained relatively constant. In contrast, assay. A, arterial port of the extraction device; V. venous port of the although initially very effective, the charcoal HP car- extraction device. Clearance = extraction efficiency x BFR (300 mL/ mm) x 60 min/48.6 kg. tridge extraction efficiency deteriorated in less than

924 Volume I a Number 6 ‘ 1990 Hootkins et al

TABLE 2. Theophylline clearance data for Case 2#{176}

Theophylline Serum Blood heophylline Clearance Concentrations Extraction Efficiency Time (mL/kg/h) (mm) (g/mL) A I V HD HP Combined HD HP Combined

0 150.0 47.1 0.4 0.69 0.99 1.00 219 313 316 15’ 30 97.4 51.0 2.0 0.48 0.96 0.98 152 303 310 45 82.8 45.4 2.6 0.45 0.94 0.97 142 297 307 60 76.1 30.7 1.9 0.60 0.94 0.98 190 297 310 90 61.9 26.0 3.7 0.58 0.86 0.94 183 272 297 120’ 56.9 0.8 0.99 313 180 39.6 0.8 0.98 310 240 13.1

0 Theophylline serum concentration determined by Abbott TDx assay. Extraction efficiency = (A - 1)/A for HD. (I - V)/A for HP, and (A - V)/A for the combined HD/HP. (A, I, and V. ports as defined on Figure 1.) Clearance = extraction efficiency x BFP (250 mL/min) x oO min/47.5 kg. . Hemoperfusion cartridge replaced.

2 h (the saturation phenomenon). When HP was con- tinued beyond 75 mm, this technique became tess efficient than HD. This period of reduced efficiency of HP in comparison with HD is represented as the

C) shaded area in Figure 2. C 5) Case 2 illustrates the advantages of employing both C)

HD and charcoal HP simultaneously, “in series”. U) C First, by placing the dialyzer before placing the HP 0

C) cartridge, we can decrease the incident serum the- 5) ophylhine concentration on the HP cartridge, thus ‘C U) prolonging the time to saturation and maintaining the overall effectiveness of the combined technique.

The higher extraction efficiency of simultaneous HD/ 15 30 45 60 75 90 105 120

HP versus HP alone is depicted as the shaded area in Time (mm) Figure 3. Although the BFR is slightly reduced in Figure 2. Extraction efficiency versus time. HD and HP data comparison with that in Case 1 , the overall extraction are from Case 1; simultaneous HD/HP data are from Case efficiency after 60 mm exceeds 94% and is much 2. Shaded area represents the time period over which the greater than would be expected by a small decrease extraction efficiency of HD exceeded charcoal HP after In BFR. A second major advantage of simultaneous cartridge saturation. HD/HP is the ability to minimize the complication of hypocalcemla in HP by adding calcium to the dialy- sate. In Case 1 , the serum calcium concentration plasma flow rates because the erythrocyte theophyl- decreased during HP from 9.7 to 7. 1 mg/dL (a 27% line concentration is comparable to that of plasma reduction). In Case 2, the serum calcium remained in and transport occurs rapidly across erythrocyte the 8.5- to 9.5-mg/dL range with a diahysate calcium membranes. In comparing techniques, we have fo- concentration of 1 0 mEq/liter. Finally, theophyhhine cused on the extraction efficiency, as it Is lndepcnd- Intoxication frequently results in hypokalemia and ent of these considerations. metabolic acidosis (9) (as evidenced in Case 2), which Although extraction efficiency is an accurate can be more easily corrected by HD with bicarbonate measure of the elimination of a drug by a device, the dialysate. extraction efficiency itself is a function of BFR. Of We have reported theophyhline clearances as the greater importance is the total body elimination of a product of the extraction efficiency and blood flow drug. Assuming a constant VD of theophylhine of 0.5 rate. Theophylline clearances may also be calculated liters/kg and no disequilibrium, we can approximate by using ptasma flow rates. However, Van Kesteren the total theophylline removal from each technique et at. (1 0) argue that the total amount of drug re- (Table 3). In terms of drug elimination (In mlhhigrams/ moved can be determined by blood rather than hour), in increasing order of effectiveness are HD,

Journal of the American Society of Nephrology 925 Management of Theophylline Intoxication

100 h. By using simultaneous in series HD/HP, we can obtain the highest extraction efficiency and drug removal, minimize complications of HP alone, and 80 more easily correct acid-base and electrolyte abnor- C) C malities associated with theophylline intoxication. 5) Simultaneous HD/HP is very well tolerated and should be considered in cases of extreme theophyl- line intoxication.

60 C I 40 U) HP ACKNOWLEDGMENTS

20 We acknowledge the secretarial assistance in manuscript prepa- 0 15 30 45 60 75 90 105 120 ration provided by Ann Drew and the technical assistance of Roy Time (mm) McKinney. RN. We also acknowledge Michael Emmett. M.D., for his critical review and helpful suggestions. Figure 3. Extraction efficiency versus time. Similar to Figure 2 except here, shaded area represents the time period over which the extraction efficiency of simultaneous HD/HP REFERENCES exceeded charcoal HP alone. 1 . Sinter C, Hendeles L, Weinberger M: Inhibition of theophylline by activated charcoal. J Pediatr 1979: TABLE 3. Theophylline removal and relative 94:3 14. improvement with each technique used#{176} 2. Levy G, Gibson TP, Whitman W, Procknal J: Hemodialysis clearance of theophylline. JAMA 1977: 237:1466-1467. Theophylline 3. Lee CS, Marbury TC, Perrin JH, Fuller TJ: He- Relative Technique Removal modialysis of theophylline in uremic patients. J Clin Improvement (mg/h) Pharmacol 1979:19:219. 4. Lawyer CH, Aitchison J, Sutton J, Bennett W: Treatment of theophylline neurotoxicity with resin HD 240 1.0 hemoperfusion. Ann Intern Med 1978:88:5 16. Sequential HD/HP 370 1.5x 5, Chang TMS, Espinosa-Melendez E, Francoeur TE, Eade NR: Albumin-collodion activated charcoal HP 500 2.lx hemoperfusion in the treatment of severe theophylline Combined 810 3.4x HD/HP intoxication in a 3-year-old patient. Pediatrics 1980: 65:811. 6. Ehlers SM, Zaske DE, Sawchuk RJ: Massive theo- ,, Theophylline removal is based on VD = 0.5 liters/kg and the experi- mental conditions defined in the text. HD, sequential HD/HP. and HP phylline overdose-rapid elimination by charcoal theophylline removal are derived from Case I . Simultaneous HD/HP hemoperfusion. JAMA 1978:240:474-475. theophylline removal is derived from Case 2. 7. Russo ME: Management of theophylline intoxication with charcoal-column hemoperfusion. N Engl J Med 1979:300:24-26. sequential HD/HP, HP, and simultaneous in series 8. Park GD, Spector R, Roberts RJ, et at. : Use of HD/HP. hemoperfusion for treatment of theophylline intoxi- cation. Am J Med 1983:74:961-966. In conclusion, with high-efficiency dialyzers and 9. Kearney TE, Manoguerra AS, Curtis GP, Ziegler current dialysis operating conditions, the extraction MG: Theophylline toxicity and the beta-adrenergic efficiency of HD in theophylhine intoxication can ap- system. Ann Intern Med 1985:102:766-769. proach 50% with a constant drug removal of 240 mg/ 1 0. van Kesteren RG, van Dijk A, Klein SW, van Heijst ANP: Massive theophylline intoxication: Ef- h. To exceed this extraction efficiency and achieve fects of charcoal haemoperfusion on plasma and eryth- faster rates of drug removal, HP can be performed rocyte theophylline concentrations. Ann Toxicol but HP cartridges should be changed in less than 2 1985:4:127-134.

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