exchange transfusion and multidose activated charcoal following ...

CLINICAL TOXICOLOGY, 30(2), 285-294 (1992)

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EXCHANGE TRANSFUSION AND MULTIDOSE ACTIVATED CHARCOAL FOLLOWING VANCOMYCIN OVERDOSE

Keith K. Burkhart, M.D.; Steve Metcalf, M.D.; Elizabeth Shurnas, M.D.; Owen O’Meara, M.D.; Jeffrey Brent, M.D.; Kenneth Kulig, M.D.; Barry H. Rumack, M.D. Denver General Hospital; University of Colorado Health Sciences Center; Rocky Mountain Poison and Drug Center; Denver, Colorado

ABSTRACT The inadvertent administration of a concentrated vancomycin solution to a 47 day-old premature male twin resulted in extremely high vancomycin levels and altered renal function. A 1.5 volume exchange transfusion did not change the measured vancomycin level. Multiple doses of oral activated charcoal, 1 g/kg, were administered beginning 5 h after the exchange transfusion. A calculated half-life of vancomycin before the exchange transfusion was 35 h. The half-life after the exchange transfusion and during charcoal administration was calculated to be 12 h. The only apparent adverse effect of this vancomycin overdose was reversible nephrotoxicity . The infant’s hearing, tested by brainstem auditory responses, was normal. The higher volume of distribution of vancomycin in infants may preclude removing significant amounts of this drug by exchange transfusion. Gastrointestinal dialysis with activated charcoal warrants consideration in

Address reprint requests to: Dr. Kenneth W.Kulig, Rocky Mountain Poison and Drug Center, 645 Bannock St., Denver, CO 80204-4507. 2 85 Copyright

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1992 by Marcel Defier, Inc.

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cases of vancomycin overdose in neonates. (Key Words: exchange transficsion, whole blood; churcoal.)

vancornycin;


INTRODUCTION Nephrotoxicity and ototoxicity are potential adverse effects that may develop after vancomycin overdose. This report describes an infant who was iatrogenically overdosed with vancomycin. Our attempts to enhance the elimination of vancomycin included an exchange transfusion and the administration of multiple doses of oral activated charcoal. To our knowledge neither of these treatment modalities has previously been reported following vancomycin overdose. Case ReDoq A 35 week postconceptual age male twin had a neonatal course that included many complications. He required prolonged ventilatory support for hyaline membrane disease and developed bronchopulmonary dysplasia. He was treated for presumed sepsis with an antibiotic course of ampicillin and gentamicin for the first five days of life (DOL). On the 29th DOL the neonate developed necrotizing enterocolitis. A urine culture from this time period grew E. coli. The antibiotic regimen for these infections included both ampicillin and gentamycin. The neonate subsequently received an aminoglycoside on 16 of the 17 days (DOL 29 to 46) prior to a vancomycin overdose. Vancomycin therapy was started on the 46th DOL, because of S. epidennidis, oxacillin-resistant, bacteremia. The vancomycin order was written as 12 mg intravenously every 8 h. This 10 mg/kg dose by NICU protocol was to be mixed by the nurse and administered as 2.4 mL from a 5 mg/mL solution. The standard vancomycin solution prepared by the pharmacy was 100 mg/mL. On the second day of vancomycin therapy this undiluted mislabelled solution was sent to the neonatal intensive care unit and administered to the infant. A vancomycin trough level of 7.5 mcg/mL (normal therapeutic trough level < 10 mcg/mL) was determined after the administration of two correct doses. Levels were determined by the TDx Fluorescence Polarization


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Immunoassay. After the fourth dose, which was the first incorrect dose, a peak level of 261.4 mcg/mL was measured (peak therapeutic levels 30-40 mcglml). The laboratory stated that this value was an error and requested that another peak level be sent. After the seventh dose, the fourth incorrect dose, the peak level was measured at 207 mcg/mL. Vancomycin was discontinued after nine doses. A total of 1476 mg of vancomycin, three 12 mg doses and six 240 mg doses, were given. A vancomycin level obtained 9 h after the final dose was 427 mcg/mL. Because of potential nephrotoxicity and ototoxicity from this overdose, an exchange transfusion of 1.5 blood volumes was performed over a period of 3.25 h, beginning 32 h after the last dose. Blood was administered through two peripheral intravenous lines at a rate of 60 mL/h. Simultaneously, blood was withdrawn at this same rate through a radial arterial line. A radial arterial line was utilized, because umbilical vessels were no longer accessible and peripheral vein flow rates were too slow in this neonate. A 2.0 volume exchange was planned, but the blood bank only sent the 1.5 volume. Because of the apparent ineffectiveness of the exchange transfusion, the 2.0 volume exchange was not completed. Vancomycin levels, measured immediately before and 30 min after this procedure, were both 230 mcg/mL. After the exchange transfusion, activated charcoal 1 g/kg, was administered through a nasogastric tube every 4 h. A total of 10 doses of charcoal, one before the exchange transfusion, were administered. The calculated half-life prior to the exchange transfusion was 35 h. After the exchange and during multidose activated charcoal therapy the half-life was 12 h (Figure 1). Prior to vancomycin therapy the serum creatinine level was 0.3 mg/dL (normal range = 0.2 - 0.6 mg/dL). The creatinine level increased to 1.4mg/dL on the two days after vancomycin was discontinued (Figure 1). Unfortunately, only blood urea nitrogen and serum creatinine levels were followed as measures of renal function. Recorded daily input and outputs are presented in Table 1. Analysis of urinary sediment was not done. Ten days after the last vancomycin dose the creatinine was 0.6 mg/dL. Peripheral blood counts did not demonstrate evidence of neutropenia following the vancomycin overdose. Repeat blood cultures obtained prior to

Figure 1.

Serum vancomycin levels and serum creatinine following vancomycin overdose treated with exchange transfusion and multiple dose activated charcoal therapy.

DAYS AFlER START OFVANCOYYCINTREATMENT


x

00 00

h)

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Daily Input and Output Recordings


~-

Vancomycin Day 1 2

Input mL 229 200

output mL 138 53

Creatinine mg/dL 0.3 0.6

3 4

217 229

108 34 +

0.7

5

232

97

1.4

6 7

184 179

208 175

1.2 0.7

Comment

1600 first dosing error Output void x 2 1st shift Exchange performed

~~

~-

beginning vancomycin therapy did not produce any growth. Therefore, additional antibiotic therapy was not administered during or after the vancomycin overdose. The hearing of this infant was tested on the 62nd DOL by brainstem auditory evoke responses. His hearing was determined to be normal and better than his twin sibling. The infant has continued to do well and has been discharged. Additional hearing tests are planned for the next year.

DISCUSSION Many procedures have been suggested to enhance the elimination of vancomycin because of its potential for causing nephrotoxicity and ototoxicity following overdose. Continuous arteriovenous hernofiltration (CAVH) and charcoal hemoperfusion have often been suggested as extracorporeal removal procedures (1-3). Peritoneal dialysis has also been reported to remove significant amounts of vancomycin (4). Increased vancomycin clearance has been demonstrated when new highly permeable dialyzing membranes have been used (5). The potential neurotoxic and nephrotoxic effects of vancomycin, a bacteriocidal glycopeptide antibiotic, are controversial. The purity of the


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pharmaceutical preparation of vancomycin has increased from 70 % to 95 96 since being introduced in 1956 (6). The impurity of the early preparations is believed to have contributed to a higher incidence of toxicity. Vancomycin nephrotoxicity has been demonstrated in rats and dogs (7,8). The concomitant administration of an aminoglycoside had a synergistic effect on nephrotoxicity (73). Our neonate had received gentamycin immediately prior to the vancomycin overdose. The true incidence of toxicity in humans following therapeutic administration is not known. In one prospective study of 34 adult patients the incidence of nephrotoxicity was 996, while the incidence of ototoxicity was 6% (9). Nephrotoxicity was defined as an elevation of the serum creatinine by at least 0.5 mg/dl. Audiometric testing was performed in these patients, although serum levels were not done in all patients. In another large retrospective series of 98 children and adults the incidence of nephrotoxicity was 5 % (10). In patients treated with vancomycin alone, normal renal function returned when therapy was discontinued (10). The pharmacokinetics of vancomycin exhibit individual and age-related variability (3,ll). After rapid distribution vancomycin elimination in healthy patients with normal renal function is dependent upon glomerular filtration. The elimination half-life of vancomycin decreases with increasing age: 5.9 to 9.8 h in neonates, 4.1 h in infants, and 2.2 to 3.0 h in children (11). Prematdre infants, weighing less than 1 kg, have larger volumes of distribution, 1 L/kg, than do older children, 0.45 L/kg, or adults, 0.1 L/kg (3,12). Protein binding in adults has been reported to range from 10-82%,although in most subjects has been less than 50% (3). Hemodialysis enhances the elimination of drugs that have the following properties: small volume of distribution, low percentage of protein binding, and small molecular weight. Vancomycin meets these criteria except for its large molecular weight of 1448. A new dialyzer membrane that is more permeable and has a larger surface area increased vancomycin clearance and reduced the TI,, of 5 vancomycin from 30 to 4.5 h (5). Hemodialysis or CAVH would have been technically difficult procedures in our small premature infant.


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The use of peritoneal dialysis was considered. In one report 40% of an intravenous dose of vancomycin was eliminated during 15 h of peritoneal dialysis (4). Moellering, however, concluded that vancomycin undergoes excellent transfer from the peritoneum to the plasma, but is poorly transferred in the opposite direction (13). We decided not to attempt peritoneal dialysis, because of the inconclusiveness of these data and the recent recovery of our infant from necrotizing enterocolitis. Although there are many reports of poisonings that have been treated with exchange transfusion (14-21), a clear benefit from the procedure is not generally discernable. In some cases the patient's intrinsic clearance or concurrent elimination procedures may account for the apparent drug removal (14-16). Exchange transfusion has been used to treat a few cases of perinatal toxicity which have resulted from medications taken by or administered to the mother prior to delivery (17-19). A caffeine poisoned neonate's clinical condition improved following significant decreases in serum levels during an exchange transfusion (20). In our case vancomycin levels did not change following a 1.5 volume exchange. The vancomycin level of the exchanged blood was not analyzed, and therefore, the actual vancomycin clearance by the exchange transfusion could not be calculated. Exchange transfusions are most effective for drugs with slow clearance rates, small volumes of distribution, or disproportionate binding by red blood cells (22). In a recent report only 396 of another therapeutically administered aminoglycoside, kanamycin, was removed by exchange transfusion (22). The administration of multiple doses of activated charcoal to enhance drug elimination has been termed "gastrointestinal dialysis. " It is believed that many drugs passively diffuse or are secreted into the gut lumen. Activated charcoal adsorbs the drug maintaining a gradient for the continued diffusion of the drug into the gut with eventual elimination in the feces. Vancomycin, although it does have a large molecular weight of 1448, does diffuse across the gut wall. When administered parenterally, vancomycin is excreted in the feces (1 1,23). In patients with renal insufficiency significant serum levels have been reported following the oral administration of vancomycin (24,25).

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Charcoal impaction, electrolyte disturbances, and hyperosmolality would be potential complications of multiple dose charcoal and cathartic therapy. Therefore, only one dose of a magnesium cathartic was administered with the first dose of charcoal. (Sorbitol is not recommended for this age group.) Serial abdominal and stool exams were performed to observe for the development of a charcoal impaction.


CONCLUSION In this case of vancomycin overdose a 1.5 volume exchange transfusion did not change the serum level of vancomycin. After the exchange and during charcoal administration, the serum half-life of vancomycin was reduced. The infant's renal function was also improving, although the fall in serum creatinine occurred after the reduction in vancomycin half-life. Charcoal therapy, by reducing renal tissue levels, may have contributed to the improved renal function. Because we do not know the impact renal function had on vancomycin elimination, we cannot conclude that multiple dose charcoal therapy produced the significant reduction in the serum half-life. Multiple dose charcoal therapy is a generally safe procedure, and its administration warrants consideration in future cases of vancomycin overdose.

ACKNOW LEDGEMEN" Doctor Burkhart's fellowship was supported in part by a grant from Smith, Kline & French Laboratories.

REFERENCES 1.

Walczyk MH, Hill D, Arai A, Wolfson M. Acute renal failure owing to inadvertent vancomycin overdose. Vancomycin removal by continuous arteriovenous hemofiltration. Ann Clin Lab Sci 1988;18:440-443.

VANCOMYCIN OVERDOSE

2.

3. 4.

5.


6. 7. 8.

9. 10. 11.

12.

13. 14. 15. 16. 17.

293

Dupuis RE, Matzke GR, Maddux FW, O’Neil MG. Vancomycin disposition during continuous arteriovenous hemofiltration. Clin P h a m 1989;8:371-374. Matzke GR, Zhanel GG, Guay DR. Clinical pharmacokinetics of vancomycin. Clin Pharmucokinet 1986;11:257-282. Nielsen HE, Sorensen I, Hansen HE. Peritoneal transport of vancomycin during peritoneal dialysis. Nephron 1979;24:274-277. Lanese DM, Alfrey PS, Molitoris BA. Markedly increased clearance of vancomycin during hemodialysis using polysulfone dialyzers. Kidney Int 1989;35:1409-1412. Bailie GR, Neal D. Vancomycin ototoxicity and nephrotoxicity, a review. Med Toxic01 Adverse Drug Ejcp 1988;3:376-386. Wold JS, Turnipseed SA. Toxicology of vancomycin in laboratory animals. Rev Infect Dis 1981 ;3 Suppl:S224-S229. Nelson JD. New antibiotics and new ways of using older drugs. Pediatr Infect Dis 1984;3 Suppl:S2-S5. Mellor JA, Kingdom J, Cafferkey M, Keane CT. Vancomycin toxicity: a prospective study. J Antimicrob Chemother 198535:773-780. Farber BF, Moellering RC Jr. Retrospective study of the toxicity of preparations of vancomycin from 1974 to 1981. Antimicrob Agents Chemother 1983;23:138-141. Schaad UB, McCracken GH, Nelson JD. Clinical pharmacology and efficacy of vancomycin in pediatric patients. J Pediatr 1980;96: 119-126. Gross JR, Kaplan SL, Kramer WG, Mason EO Jr. Vancomycin pharmacokinetics in premature infants. Ped Pharmucol1985;5:17-22. Moellering RC Jr. Pharmacokinetics of vancomycin. J Antimicrob Chemother 1984;14 Suppl:43-52. Kessler DL, Smith AL, Woodrum DE. Chloramphenicol toxicity in a neonate treated with exchange transfusion. J Pediatr 1980;96: 140-141. Stevens DC, Kleiman MB, Lietman PS, Schreiner RL. Exchange transfusion in acute chloramphenicol toxicity. J Pediatr 1981;99: 651-653. Hyde JS, Lawrence AG, Moles JB. Ethchlorovynol intoxication. Successful treatment by exchange transfusion and peritoneal dialysis. Clin Pediatr 1968;7:739-741. Asnes RS, Lamb JM. Neonatal respiratory depression secondary to maternal analgesics, treated by exchange transfusion. Pediatrics 1969;43:94-96.

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BURKHART ET AL.

18.

Thearle MJ, Dunn PM, Hailey DM. Exchange transfusion for diazepam intoxication at birth followed by jejunal stenosis. Proc Roy Soc Med 1973;66:349-350. Lederman S , Fysh WJ,Tredger M, Gamsu HR. Neonatal paracetamol poisoning: treatment by exchange transfusion. Arch Dis Child 1983;58:63 1-633. Perrin C, Debruyne D, Lacotte J, et al. Treatment of caffeine intoxication by exchange transfusion in a newborn. Acta Pediatr Scand 1987;76:679-681. Burrows AW, Hambleton G, Hardman MJ, Wilson BD. Quinine intoxication in a child treated by exchange transfusion. Arch Dis mild 1972;47:304-305. Yakatan GJ, Smith RB, Leff RD, Kay JL. Pharmacokinetic considerations in exchange transfusion in neonates. Clin Pharmacol mer 1978;24:90-94. Geraci JE, Heilman FR, Nichols DR, Wellman WE, Ross GT. Some laboratory and clinical experiences with a new antibiotic. Vancomycin Antibiotics Annual. New York: Medical Encyclopedia, Inc., 1956-1957:90-106. Cheung RPF, Dipiro JT. Vancomycin. An update. Phamcotherapy 1986;6: 153-169. Thompson CM, Long SS, Gilligan PH, Prebis JW. Absorption of oral vancomycin - possible associated toxicity. Int J Pediatr Nephrol 1983;4:1-4.

19. 20.


21. 22. 23.

24. 25.