Acute massive gentamicin intoxication in a patient with end-stage renal disease

Acute Massive Gentamicin Intoxication in a Patient With End-Stage Renal Disease Chao-Ming

C. Lu, MD, Sam H. James, MD, and Yeong-Hau

H. Lien, MD, PhD

0 A 65-year-old man with end-stage renal disease on continuous ambulatory peritoneal dialysis accidentally received an acute massive overdose of gentamicin as a treatment of peritonitis. The patient developed acute vestibular dysfunction and hearing loss following the overdose. His serum gentamicin had reached the extremely toxic level of 220 &mL. To remove the gentamicin, the patient received hemodialysis and hemoperfusion immediately. This was followed by two more courses of hemodialysis during the following 2 days. The gentamicin level was brought down to 10 pg/mL after the third hemodialysis. Moderate and persistent high-frequency hearing loss was documented with serial audiograms. The patient made a gradual but incomplete recovery from the vestibular dysfunction. The complications of gentamicin toxicity and its management are discussed with respect to our patient. 0 1996

by the

National

Kidney

INDEX WORDS: Gentamicin;

Foundation,

hemodialysis;

Inc.

hemoperfusion;

G

ENTAMICIN, an aminoglycoside antibiotic derived from Micromonaspora purpurea, is widely used for treating gram-negative bacilli infection because of its effectiveness, especially against Pseudomonas aeruginosa. The convenience of intraperitoneal administration and excellent coverage of aerobic gram-negative bacilli make gentamicin a popular choice for empiric treatment of peritonitis in peritoneal dialysis patients.’ Unfortunately, gentamicin is associated with two serious and potentially irreversible side effects: nephrotoxicity and ototoxicity. In patients with normal renal function, gentamicin may cause renal failure and rarely, hypomagnesemia, hypocalcemia, and hypokalemia as a result of renal wasting.2’3 Other adverse reactions reported to be associated with gentamicin therapy include increased serum transaminase, skin rash, urticaria, granulocytopenia, anemia, and thrombocytopenia, which are all rare and usually reversible.* Apart from the eighth cranial nerve involvement, neurotoxicity induced by gentamitin includes numbness, skin tingling, muscle twitching, convulsion, and acute organic brain syndrome.* In animals receiving a lethal dose of gentamicin, the cause of death is usually respiratory arrest due to neuromuscular blockade.4 This curare-like effect has been reported in patients with overdose of gentamicin, neuromuscular disorders, or simultaneous use of neuromuscular blocking agents, such as tubocurarine.5~6 We report a case of accidental acute gentamitin overdose given intraperitoneally to a patient with end-stage renal disease. The patient presented with a serum gentamicin level of 220 pg/

American

Journal

of Kidney

Diseases,

Vol 26, No 5 (November),

ototoxicity.

mL, an extremely elevated level that has not been previously reported in the literature. He was treated with intermittent hemodialysis, initially combined with charcoal hemoperfusion and subsequently hemodialysis alone, for 3 consecutive days to remove the gentamicin. CASE

REPORT

Our patient, a 65year-old black man, was admitted to the hospital because of an unsteady gait and hearing loss. He had a history of end-stage renal disease secondary to diabetic nephropathy and had been on continuous ambulatory peritoneal dialysis without peritonitis for more than 2 years. His dialysis prescription was four 2-L exchanges with 1.5% Dianeal solution during the day and one 3-L, 1.5% Dianeal overnight. His dry weight was maintained at 81 kg. Two days prior to admission, he developed symptomatic peritonitis and reported to an emergency room of a rural hospital. He was mistakenly instructed to administer and dwell 2 g of vancomycin and 8 g of gentamicin in a 2-L, 1.5% Dianeal for 3 hours on 2 consecutive days after receiving 100 mg of gentamicin intravenously at the emergency room. Twenty-four hours following the second dose of gentamicin, he presented to our dialysis unit complaining of an unsteady gait and hearing loss for 1 day. His wife reported that she had to repeat herself frequently, which was quite unusual. On physical examination, the patient was alert and oriented to time, place, and person. Blood pressure was 120176 mm Hg, pulse 120 beatslmin, and respiratory rate 12 breaths/min.

From the Department of Medicine, University of Arizona Health Sciences Center, Tucson, AZ. Received January 16, 1996; accepted in revised form July 9, 1996. Address reprint requests to Yeong-Hau H. Lien, MD, PhD, Renal Section, Department of Medicine, University of Arizona Health Sciences Center, Tucson, AZ 85724. 0 1996 by the National Kidney Foundation, Inc. 0272-6386/96/2805-0018$3.00/O

1996:

pp 767-771

767

768 Despite bilateral cataracts, fundoscopic examination revealed bilateral retinal pigmentation and scarring as a result of multiple laser treatments. Neurology examinations revealed diminished deep tendon reflexes in the lower limbs, which were not new findings and were presumed to be secondary to diabetic neuropathy. The patient had obvious truncal ataxia and could walk only when his legs were spread apart. There was no nystagmus. His muscle strength was normal. The remainder of the physical examinations was unremarkable. Laboratory results revealed a gentamicin level of 220 hg/ mL (48 hours after the first 8 g, and 24 hours after the second), a vancomycin level of 24.8 pg/mL, white blood cell count of 8,1OO/pL, hemoglobin of 9.9 g/dL, hematocrit of 29.9%, platelet count of 278,OOO/pL, sodium 132 mEq/L, potassium 2.9 &q/L, CO, 28 mEq/L, chlorine 89 mEq/L, blood urea nitrogen 65 mg/dL, creatinine 13.1 mg/dL, calcium 8.6 mgl dL, phosphorus 4.1 mg/dL, asparate aminotransferase (AST) 23 IU/L, alanine aminotransferase (ALT) 19 IU/L, and alkaline phosphatase 43 Iv/L. An electrocardiogram showed sinus tachycardia. Hemodialysis with a TAF 175 dialyzer (Terumo Corp, Somerset, NJ) was immediately initiated through a doublelumen dialysis catheter placed in the left femoral vein. After 3 hours, it was converted to combined charcoal hemoperfusion and hemodialysis using an Adsorba 150C charcoal column (Gambro Corp. Williamsburg, VA) and a Hemoflow F80 hemodialyzer (Fresenius, Concord, MA) for 3 additional hours. The treatment was provided with a Cobe Century 2 machine (Lakewood, CO), with a dialysate and blood flow rate of 550 mL/min and 300 mL/min, respectively. Due to the potential curare-like neuromuscular blocking effect of high-dose gentamicin, the patient was monitored with a pulse oxygenator throughout the course of dialysis and for the following 2 days. His oxygen saturation was 95% or above on room air, and he never showed any signs of respiratory depression. The time course of the change in serum gentamicin levels in relation to the treatment is shown in Fig 1. Initial hemodialysis for 3 hours with a TAF 175 dialyzer resulted in the serum gentamicin level decreasing from 220 pg/mL to 76 PglmL. The combined charcoal perfusion and hemodialysis resulted in a further decrease of serum gentamicin from 76 PglmL to 52 pg/mL after 1.5 hours and to 47.5 PglmL after 3 hours. The gentamicin level had increased to 59.7 PglmL 12 hours after stopping hemodialysis and hemoperfusion. The patient received 6 hours of hemodialysis with a TAF 175 dialyzer, which reduced the gentamicin level to 25 pg/dL. The following day he received the same dialysis treatment, and the serum gentamicin level was decreased to 10.5 pg/ mL. During the entire hospital course, the patient remained on his regular peritoneal dialysis to facilitate the removal of gentamicin. The vestibular function gradually improved with physical therapy. The patient was able to ambulate and maintain his balance with visual and proprioceptive adaptations 2 months after discharge. Serial pure-tone audiograms were obtained 4 days, 1 week, and 3 weeks after the final dose of gentamicin was given, as shown in Fig 2. A persistent moderate hearing loss was detected that was greatest at frequencies above 2,000 Hz.

LU, AB

JAMES,

C

AND

LIEN

D

i 0

10 40

50

60

70

a0

90

100

110

120

Time (hours) Fig 1. Time course of the change in gentamicin concentration in relationship to treatment (A to 0). Serum gentamicin levels are plotted in a log scale. The first dose of gentamicin was given at 0 hours and the second at 24 hours. The beginning and end of each treatment is indicated by dash lines. (A) Hemodialysis (TAF 175 dialyzer) for 3 hours, (8) combined charcoal hemoperfusion (Adsorba 16OC charcoal column) and hemodialysis (F60 dialyzer) for 3 hours, and (C and D) hemodialysis (TAF 175 dialyzer) for 6 hours.

DISCUSSION

Our patient’s serum gentamicin level reached an enormously elevated level of 220 &mL. A computer Medline search failed to reveal any previous report of this order of magnitude of gentamicin overdose. An error of this magnitude is due to the combination of physician’s ineptness and seriously flawed mechanisms regarding drug prescribing and dispensing. This error could and should have been prevented if procedural protections, such as pharmacist review or dispensing, were executed properly. Our patient presented with acute vestibular and cochlear toxicity. The primary cause of gentamitin ototoxicity is degeneration of vestibular sensory cells and cochlear hair cells.7 The incidence of ototoxicity in the general population receiving gentamicin is approximately 1.8% with two thirds of patients as isolated vestibular dysfunction, and as combined vestibular and cochlear, or isolated cochlear dysfunction in the remainder.7Ss However, Gailiunas et al reported that the incidence of gentamicin ototoxicity in dialysis patients is as high as 30%.’ All their patients received gentamicin 1.O to 1.5 mg/kg intravenously three times a week, as suggested by Christopher et al.” The ototoxicity is related to the total dose

GENTAMICIN

OVERDOSE

769

Frequency

A

in Hz Frequency in Hz 250

500

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20 8

30

.-c

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3 u F

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Fig 2. (triangles)

Pure tone after the

audiograms last dose

of the right of gentamicin.

(A) and left

per kilogram of body weight. Based on regression analyses, the critical cumulative dose is estimated to be 17.5 mg/kg.’ Our patient received a total of 1.2 mg/kg intravenously and 200 mg/kg intraperitoneally within 2 days. The effects of such a massive dose of gentamicin have been reported only in animal studies. In mice with normal renal function, the LD50 of gentamicin is approximately 380 mg/kg when given intraperitoneally.4 The gentamicininduced lethality can be reduced with simultaneous administration of neostigmine, indicating that neuromuscular blockade is the cause of death. Neuromuscular blockade was also observed in cats receiving 40 mg/kg gentamicin intravenously.4 In another study, Waitz et al” reported that cats receiving gentamicin 40 mgl kg/d developed ataxia and irreversible vestibular damage in 20 days. The trough gentamicin levels in those cats with complete ataxia were in the range of 21 to 42 PglmL.” Fortunately, our patient did not have any clinical evidence of neuromuscular blockade. He had moderate high-frequency hearing loss, which may not be totally attributed to gentamicin because no previous audiograms were available for comparison. In addition, although the vancomycin level was within

(6) ears

4 days

(diamonds),

1 week

(squares),

and

3 weeks

the therapeutic range, the concomitant use of excessive vancomycin may augment gentamicin ototoxicity.” The patient’s follow-up audiograms did not show further deterioration of high-frequency hearing loss, and his truncal ataxia due to vestibular toxicity has gradually recovered with physical therapy, as well as concomitant visual and proprioceptive adjustments. We speculate that our patient may have suffered less damage than what might have been expected from the total dose given because of rapid removal of gentamicin and the acuteness of the intoxication, which may have resulted in less gentamicin accumulation in the inner ear than with chronic intoxication. There is a paucity of literature on the treatment of gentamicin overdose, particularly in patients with end-stage renal disease. The half-life of gentamicin is prolonged from 2 to 3 hours in normal individuals to 69 hours in anephric patients,” In continuous ambulatory peritoneal dialysis patients, approximately 50% of an intraperitoneal dose is absorbed during a 6-hour dwell. The mass transfer coefficients are higher in patients with peritonitis, resulting in an increases absorption rate.13 The apparent volume of distribution for gentamicin has been reported to be 24% of body

770

weight,14 and its plasma protein binding is negligible.” Baue? first reported the gentamicin rebound phenomenon after hemodialysis. He observed a mean 25% increase in gentamicin level one hour after hemodialysis. The rebound of gentamicin level seen after hemodialysis is most likely due to the same phenomenon reported for other drugs that show tissue penetration and multicompartment pharmacokinetics. During dialysis, gentamicin is removed rapidly from the serum, whereas the tissue release lags behind. The slow redistribution of gentamicin out of slowly equilibrating tissues results in the rebound of serum levels after hemodialysis. This process mostly applies to chronic intoxication following long periods of gentamicin accumulation. In our case of acute toxicity, we also witnessed a 25.7% rebound in gentamicin level 12 hours after dialysis, which indicates that the severe tissue accumulation of gentamicin can occur in the setting of acute intoxication. Gentamicin can be removed by hemodialysis with a dialyzer clearance (Kiil dialyzer, Oslo, Norway) of approximately 24 rnL/min.” Wright and Bhamjee17 used a 6-hour period of combined charcoal hemoperfusion and hemodialysis for a toxic gentamicin level of 15 pg/mL and were able to reduce the level to 7.2 pg/mL. These investigators indicated that similar extraction could be achieved by hemodialysis alone for at least 12 hours. This is why we switched to combined hemodialysis and hemoperfusion after 3 hours of hemodialysis. When the gentamicin levels were available, we found that the initial hemodialysis with a TAF 175 dialyzer resulted in a 65% reduction of serum gentamicin level, while combined therapy was able to remove 37.5% of the remaining serum gentamicin. Subsequently, we decided to use high-efficiency hemodialysis alone to avoid potential side effects from charcoal hemoperfusion, such as hemolysis, hypocalcemia, and thrombocytopenia. Agarwal and Toto” reported that the TAF 175 dialyzer is almost twice as efficient in removing gentamicin as a conventional cellulose ester hemodialyzer, which is consistent with the notion that TAF 175, a high-efficiency dialyzer, has superior permeability to middle molecules (500 to 2,000 d), such as gentamicin (molecular weight, 518 d). How-

LU,

JAMES,

AND

LIEN

ever, there is heterogeneity in gentamicin clearhemodialyzers. ance among high-efficiency Agarwal and Cronin” reported that the TAF 175, a cuprammonium rayon dialyzer, is significantly better than the F8 (Fresenius, Concord, CA), a polysulfone dialyzer, for gentamicin clearance. Despite the improved clearance with a cuprammonium rayon dialyzer, the rate of clearance decreases during the latter half of dialysis, as can be seen in Fig 1 (dialyses B and C). Since we know that plasma protein binding of gentamitin is negligibleI and that our patient’s blood level remained excessively high, it is possible to speculate that the reduced clearance could be on the basis of altered dialyzer membrane characteristics. Clearance is driven by the concentration gradient between the intracellular space and the extracellular space as well as between the blood and dialysate compartments. Based on these facts, it seems reasonable to attempt continuous dialysis with the view to maintaining a wide concentration gradient that would result in greater solute load removal. Continuous dialysis could be provided with the recommendation that the dialyzer be changed out on a 2- to 3-hour basis to avoid reduced clearance as a result of altered dialyzer membrane characteristics. Progress should be monitored with gentamicin blood levels measured every 6 hours. Dialysis should be discontinued when the gentamicin level decreases into the therapeutic trough range. It should be checked 6 hours later for possible rebound. In view of the increased resources and time required, as well as the increased risk of adverse events on dialysis, results of continuous forms of treatment for gentamicin toxicity would have to be evaluated in the future. In summary, our patient represents the most serious case of acute gentamicin overdose reported in humans. The patient presented with acute ototoxicity and was treated with repeated acute hemodialyses with and without hemoperfusion. Severe tissue accumulation can occur in acute gentamicin intoxication. Based on our experience and the literature review, we recommend that acute gentamicin overdose be treated with hemodialysis using cuprammonium rayon membrane, a high-efficiency dialyzer, or combined hemodialysis and hemoperfusion if the cu-

GENTAMICIN

OVERDOSE

prammonium rayon dialyzer is not available. Serum gentamicin levels should be closely monitored after dialysis because of the rebound phenomenon. Prolonged dialyses may be the optimal treatment for the removal of the total body load of gentamicin. REFERENCES 1. Keane WF, Everett ED, Fine RN, Golper TA, Vas S, Peterson PK, Gokal R, Matzke GR: Continuous ambulatory peritoneal dialysis peritonitis treatment recommendations: 1989 Update. Petit Dial Int 9:247-2X, 1989 2. Hewitt WL: Gentamicin toxicity in perspective. Postgrad Med J 5055-61, 1974 (suppl 7) 3. Kelnar CJ, Taor WS, Reynolds DJ, Smith DR, Slavin BM, Brook CG: Hypomagnesemic hypocalcaemia with hypokalemia caused by treatment with high dose gentamicin. Arch Dis Child 53:817-820, 1978 4. Bamett A, Ackermann E: Neuromuscular blocking activity of gentamicin in cats and mice. Arch Pharmacodyn 181:109-117, 1969 5. Holtzman JL: Gentamicin and neuromuscular blockade. Ann Intern Med 84:55, 1976 (letter) 6. Warner WA, Sanders E: Neuromuscular blockade associated with gentamicin. JAMA 215:1153-l 154, 1971 7. Keene M, Hawke M, Barber HO, Farkashidy J: Histopathological findings in clinical gentamicin ototoxicity. Arch Otolaryngol 108:65-70, 1982 8. Jackson GG, Arcieri G: Ototoxicity of gentamicin in man: A survey and controlled analysis of clinical experience in the U.S. J Infect Dis 124:130-137, 1971 (suppl)

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9. Gailiunas P, Jr, Dominguez-Moreno M, Lazarus M, Lowrie EG, Gottlieb MN, Merrill JP: Vestibular toxicity of gentamicin. Incidence in patients receiving long-term hemodialysis therapy. Arch Intern Med 138:1621-1624, 1978 10. Christopher TG, Kom D, Blair AD, Forrey AW, O’Neill MA, Cutler RE: Gentamicin pharmacokinetics during hemodialysis. Kidney Int 6:38-44, 1974 11. Waitz JA, Moss EL, Jr, Weinstein MJ: Aspects of the chronic toxicity of gentamicin sulfate in cats. J Infect Dis 124:S125-129, 1971 (suppl) 12. Brummett RE: Ototoxicity of vancomycin and analogues. Otolaryngol Clin North Am 26:821-829, 1993 13. DePaepe M, Lameire N, Belpaire F, Bogaert M: Peritoneal pharmacokinetics of gentamicin in man. Clin Nephrol 19:107-109, 1983 14. Gyselynck AM, Forrey A, Cutler RE: Pharmacokinetits of gentamicin distribution and plasma and renal clearance. J Infect Dis 124:70-76, 1971 (suppl) 15. Gorgon R, Regamey C, Kirby W: Serum protein binding of the aminoglycoside antibiotics. Antimicrob Agents Chemother 2:214-216, 1972 16. Bauer LA: Rebound gentamicin levels after hemodialysis. Ther Drug Monit 4:99-101, 1982 17. Wright N, Bhamjee A: Gentamicin extraction from an anuric patient by combined haemodialysis and charcoal haemoperfusion. Postgrad Med J 56:140-141, 1980 18. Agarwal R, Toto RD: Gentamicin clearance during hemodialysis: A comparison of high-efficiency cuprammonium rayon and conventional cellulose ester hemodialyzers. Am J Kidney Dis 22:296-299, 1993 19. Agarwal R, Cronin RE: Heterogeneity in gentamicin clearance between high-efficiency hemodialyzers. Am J Kidney Dis 23:47-51, 1994