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294 EXPERIENCE AND REASON

Ketorolac-induced

Acute

Renal

Failure

in a Previously

Healthy

Adolescent

ABBREVIATIONS. IM, intramuscularly; BUN, blood urea nitro-gen; HPF, high-power field; NSAID, nonsteroidal antiinflamatory drug, PC, prostaglandin.

Ketorolac has become an important component of

analgesic regimens for children as well as adults because of its lack of adverse effects on respiratory,

cardiovascular, and neurologic function. Although

initially used parenterally in hospitalized patients,

the development of an oral ketorolac dose form

ex-tended its use to the outpatient setting, where its

potency has been considered an advantage over

Ira-ditional therapies.’3

Several cases of hyperkalemia and oliguric acute

renal failure associated with ketorolac use have been reported in the medical literature.4’2 Elderly hospi-talized patients receiving large doses of ketorolac

intramuscularly (IM) after major surgery seem to be

at greatest risk. Patients with congestive heart fail-ure, diabetes, or underlying renal disease also seem to be predisposed to this adverse effect. We report an unusual case of oliguric acute renal failure in a

pre-viously healthy adolescent being treated with oral

ketorolac for pain after minor surgery. This is the

first published account of ketorolac-induced

nephro-toxicity in a child.

CASE REPORT

A 17-year-old girl was referred to the Children’s Medical

Cen-ter of the University of Virginia for treatment of acute renal

failure. She had been healthy until 3 days before admission, when

she underwent extraction of her two lower wisdom teeth. She had

taken no food or fluids for 12 hours before the procedure. After

surgery, she was given penicillin C, 500 mg orally every 6 hours, for bacterial prophylaxis because of the presence of mitral valve prolapse and ketorolac, 10 mg orally every 4 to 6 hours as needed,

for pain.

On the following day, the patient began to have repeated

periods of nausea with emesis. This lasted throughout the night

and next morning. She continued to take her prescribed

medica-tions and at this point had taken 10 doses of ketorolac in

approx-isnately 30 hours. Because of persistent nausea, abdominal pain,

and poor oral intake, she was taken to a local emergency

depart-ment by her parents. She seemed to be mildly dehydrated and was

given 2 L of intravenous fluids at arrival. Initial laboratory

eva!-uation revealed a blood urea nitrogen (BUN) level of 44 mg/dL

(15.7 mmol/L) and a serum creatinine level of 7.0 mg/dL (534

Mmol/L). Her serum bicarbonate level was 19 mEq/L (19 mmo!/

L), and potassium was 4.5 mEq/L (4.5 mmol/L). A complete

blood count, including white cell differential, hematocrit, and

platelet count, were within normal limits. Urinalysis revealed a 3+ protein, three to five white blood cells per high-power field (HPF),

and one to three red blood cells per HPF.

The patient was then admitted to a local hospital, where her

physical examination revealed a weight of 50.4 kg, blood pressure of 130/90 mm Hg (100/60 mm Hg at previous medical visits), dry

mucous membranes, bilateral costovertebral angle tenderness,

and no evidence of peripheral or pulmonary edema. Ketorolac

Received for publication May 16, 1995; accepted Oct 25, 1995.

Reprint requests to (M.L.B.) Box 274-1 1, Children’s Medical Center, Univer-sity of Virginia Health Sciences Center, Charlottesville, VA 22908. PEDIATRICS (ISSN 0031 4005). Copyright © 1996 by the American Acad-emy of Pediatrics.

was discontinued. She received another 2 L of intravenous fluid

replacement in 8 hours, during which time her urine output was

only 150 mL. Her weight increased to 52.3 kg. Subsequent

!abo-ratory evaluation revealed a BUN level of 54 mg/dL (19.3

mmol/L) and a creatinine level of 7.3 mg/dL (557 j.unol/L), but electrolytes were in the normal range.

She was transferred to our institution for further diagnosis and treatment of her renal failure. Her physical examination was un-remarkable, with the exception of mild periorbital edema. Labo-ratory evaluation revealed the following serum concentrations:

sodium, 139 mEq/L (139 mmol/L); potassium, 4.1 mEq/L (4.1

mmol/L); chloride, 106 mEq/L (106 mmol/L); bicarbonate, 17

mEq/L (17 mmol/L); BUN, 54 mg/dL (19.3 mmol/L); and creat-mine, 8.4 mg/dL (641 .tmol/L). Serum calcium and magnesium

concentrations were in the normal range; however, phosphorus

was mildly elevated (5.6 mg/dL [1.81 mmol/L]; normal range, 2.4

to 4.5 mg/dL). A complete blood count, liver function tests, and

serum albumin were within normal limits. The sedimentation rate

was slightly elevated at 27 mm/h. Urinalysis showed a specific

gravity of 1.015, a pH of 5.5, 1+ protein, small ketones, one to five red blood cells per HPF, occasional white blood cells, and no casts.

Urine eosinophils were unremarkable at 3%, identical to

periph-eral blood. Complement fractions and antineutrophilic cytoplas-mic antibody were in the normal range. Antinuclear antibody

(human) was mildly elevated at 1:320. Ultrasound revealed kid-neys of normal size with mild increased echogenicity.

Acute tubular necrosis was confirmed by biopsy without

evi-dence of preexisting kidney disease. Ught microscopy revealed

normal glomeruli and blood vessels. There was obvious dysplasia

of tubular epithelial cells, mild tubular dilatation, and tubular atrophy. Mitotic figures were noted, as were scattered pigmented inclusions within tubular cells, reflecting tubular regeneration. There was a mild monocytic interstitial infiltrate and

extramedul-lary hematopoiesis. No eosinophils were present.

Immunofluores-cence studies were negative. Electron microscopy revealed a

nor-mal glomerular basement membrane and no fusion of the foot

processes.

During the first 3 days, the patient was treated with strict

control of fluid intake, potassium and phosphate restriction, and

bicarbonate supplementation. She remained normotensive but

oli-guric, producing less than 250 mL of urine/d. BUN and creatinine

levels continued to rise, reaching peak values of 110 and 16.3

mg/dL (39.3 mmo!/L and 1243 jmol/L), respectively. Because of

persistent severe nausea and worsening lethargy, hemodialysis was initiated 4 days after admission and was repeated the follow-ing day. A nonoliguric phase of recovery began shortly thereafter,

7 days after discontinuing ketorolac. The patient was discharged

17 days after her oral surgery with a BUN level of 40 mg/dL (14.3 mmol/L) and a creatinine level of 4.4 mg/dL (336 mol/L). At a follow-up visit 2 weeks later, she was in good health, with a BUN

level of 16 mg/dL (5.7 mmol/L) and a creatinine level of 1.1

mg/dL (84 jmol/L). The results of this case were submitted to the

Food and Drug Administration through the MedWatch system.

DISCUSSION

Renal dysfunction has been estimated to occur in

less than I % of patients treated with ketorolac

(pack-age insert, Toradol [ketorolac tromethamine]; Syntex

Laboratories, Palo Alto, CA, 1994). Aitken and

col-leagues” found that routine use of ketorolac had

little clinical impact on renal function in adults

with-out underlying kidney disease. Similarly, a review of

children and adolescents treated with ketorolac at

our institution failed to reveal any significant effect

on urinary output, BUN, or serum creatimne.3

De-spite these studies, the number of cases of

ketorolac-induced nephrotoxicity continues to increase.4’2 The

signs and symptoms observed range from isolated

hyperkalemia to anuric acute renal failure.

In 1992, Boras-Uber and Brackett’ published the

first account of ketorolac-associated acute renal

fail-ure. They described a 61-year-old woman receiving

ketorolac, 60 mg IM, after mitral valve replacement

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EXPERIENCE AND REASON 295

in whom anuria developed. A causal relationship

with ketorolac became apparent when symptoms

worsened after a second dose. Two additional cases

documented that year also involved patients older

than 50 years.5’6

Hemolytic uremic syndrome potentially

associ-ated with ketorolac occurred in a 58-year-old

woman. The patient had received three 10-mg oral

doses when vomiting and bloody diarrhea

devel-oped. Despite the discontinuation of ketorolac,

he-molytic anemia, thrombocytopenia, and renal

insuf-ficiency developed.7 Pearce and coworkers8 reported three more cases of ketorolac-induced

nephrotoxic-ity. The patients, ages 48, 53, and 58 years, had

received ketorolac for more than 5 days. Although

two patients had full recovery, fatal oliguna with

hyperkalemia developed in one patient. Corelli and

Gericke9 identified six patients with probable ketoro-lac-induced renal insufficiency. The average patient

age was 58 years. Only one patient required

hemo-dialysis; in all cases, renal function recovered. Since

that report, three additional cases have been

pub-lished, including oliguric renal failure occurring after a single 60-mg IM dose.’#{176}’2

The nephrotoxic effects of nonsteroidal

antiinflam-matory drugs (NSAIDs) may be the result of

inhibi-tion of prostaglandin (PC) synthesis. A number of

different prostaglandins, including PCI2

(prostacy-din), PGE2, PGF2a, and thromboxane A2, are

pro-duced in renal tissues. Both PCI2 and PGE2 function

as vasodilators of renal arterioles. When the

circulat-ing blood volume is reduced by hypotension or

vol-ume depletion, prostaglandins become major factors

in maintaining renal function by counteracting the

vasoconstrictive effects of epinephrine and angioten-sin II and regulating electrolyte balance.’4”5

As a result of blocking the production of PCI2 and

PGE2, NSAIDs can decrease renal blood flow and the

glomerular filtration rate, producing acute ischemic

damage. These drugs also block the ability of

pros-taglandins to inhibit tubular resorption of sodium, resulting in sodium and water retention. In addition,

NSAIDs can suppress the PGI2-controlled release of

renin, creating a reduction in aldosterone secretion

and inducing hyperkalemia.’4”5 These mechanisms

may explain, in part, why NSAID-induced

nephro-toxicity is observed more frequently in patients with altered hemodynamics, such as in the postoperative period.”3”5

In addition to the nephrotoxic effects of

prosta-glandin inhibition, NSAIDs also have been linked to

the development of an allergic-type interstitial

ne-phritis. This reaction is rare, with an estimated mci-dence of one case per 5000 to 10 000 patients treated.

Patients present with edema, elevated serum

creati-nine concentrations, and proteinuria. Unlike the

re-ports of acute renal failure, interstitial nephritis typ-ically occurs after several months to years of chronic

NSAID use.’5

Although the incidence of nephrotoxicity among

NSAIDs is too small to allow for comparisons

be-tween individual agents, the increasing number of

case reports involving ketorolac is of concern.

5ev-eral theories have been proposed for the

predomi-nance of ketorolac in cases of NSAID-induced acute

renal dysfunction.9’11”5 The pharmacokinetics of

ke-torolac may make it more prone to cause

nephrotox-icity than other NSAIDs. Ketorolac is extensively

metabolized via hepatic glucuronidation. In the

pres-ence of reduced renal blood flow, the metabolite

accumulates in the kidney, where it can be

hydro-lyzed to reform active drug. In effect, this process can form a cycle of further increasing the amount of the

potential nephrotoxin and prolonging its

opportu-nity to induce damage.’5 In addition, the increased

potency of ketorolac compared with other NSAIDs

may make it more likely to exacerbate underlying

renal insufficiency. Contributing factors, including

advanced age, chronic diseases such as congestive

heart failure or diabetes, and fluid and electrolyte

imbalance associated with surgery, were present in

many of the case reports cited. Our patient was

un-usual in that she had none of these recognized risk

factors before her surgery. She received oral

ketoro-lac at a dosage recommended by the manufacturer

(one 10-mg tablet every 4 to 6 hours); however, it

seems that she exceeded the recommended daily

maximum of 40 mg/d. Of note, symptoms appeared

when she had received ketorolac for less than 2 days,

well within the recommended duration (package

in-sert, Toradol [ketorolac tromethaminel; Syntex

Lab-oratories, Palo Alto, CA, 1994). Potential

complicat-ing factors may have included preoperative fluid

restriction as well as poor postoperative fluid intake,

nausea, and vomiting. Other complicating factors

may have been unrecognized intraoperative

hypo-tension from intravenous sedation, resulting in renal

ischemia before the initiation of ketorolac, and a

possible reaction to penicillin. Although an allergic-type reaction cannot be ruled out, our patient’s

din-ical presentation and biopsy were more consistent

with acute tubular necrosis.

Life-threatening complications of acute renal fail-ure developed in our patient after a minor surgical

procedure and the use of routine postoperative

med-ications. Although the severity of our patient’s renal

dysfunction may be unusual, we hope to alert other

clinicians to the potential for severe adverse

reac-tions with ketorolac, including its use on an outpa-tient basis. Whenever possible, preoperative evalua-lion of renal function should be performed as well as close monitoring for early signs suggesting dehydra-tion or acute renal failure. Therapy should be

discon-tinued immediately if any abnormalities are

discov-ered. Although in increasingly common use in the

pediatric population, ketorolac and all other NSAIDS carry nephrotoxicity risks that are not well recognized.

MARCIA L. BUCK, PHARMD

VICTORIA F. NoRwooD, MD

Department of Pediatrics Children’s Medical Center University of Virginia

Charlottesville, VA 22908

REFERENCES

I. Forbes JA, Butterworth GA, Burchfield WH, Beaver WT. Evaluation of ketorolac, aspirin, and an acetaminophen-codeine combination in post-operative oral surgery pain. Phannacotherapy. 1990;6(pt 2):77S-93S

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296 EXPERIENCE AND REASON

2. Forbes JA, Kehm CJ, GrOdin CD, Beaver WT. Evaluation of ketorolac, ibuprofen, acetaminophen, and an acetaminophen-codeine combination

in postoperative oral surgery pain. Pharmacotherapy. 1990;6(pt

2)94S-105S

3. Buck ML. Clinical experience with ketorolac in children. Ann Pharma-cother. 1994;28:1009-1013

4. Boras-Uber LA, Brackett NC. Ketorolac-induced acute renal failure. Am

IMed. 199292:450-452. Erratum published in Am JMed. 1992;93:117 5. Rotenberg FA, Giannini VS. Hyperkalemia associated with ketorolac.

Ann Pharmacother. 199226:778-779

6. Schoch PA, Ranno A, North DS. Acute renal failure in an elderly woman following intramuscular ketorolac administration. Ann Pharma-cother. 199226:1233-1236

7. Randi ML, Tison T, Luzzatto G, GirOlami A. Haemolytic uraemic syn-drome during treatment with ketorolac trometamoL Br Med I.1993306:186 8. Pearce CJ, Gonzalez FM, Wallin JD. Renal failure and hyperkalemia associated with ketorolac tromethamine. Arch Intern Med. 1993;153: 1000-1002

9. Corelli RL, Gericke KR. Renal insufficiency associated with intramus-cular administration of ketorolac tromethamine. Ann Pharmacother.

199327:1055-1057

10. Murray RP, Watson RC. Acute renal failure and gastrointestinal bleed associated with postoperative Toradol and vancomycin. Orthopedics.

1993;16:1361-1363

I I. Quan DJ, Kayser SR. Ketoro!ac induced acute renal failure following a single dose. Clin Toxicol. 199432:305-309

12. Haragsim L, Dalal R, Bagga H, Bastani B.Ketorolac-induced acute renal

failure and hyperkalemia: report of three cases. Am JKidney Dis. 1994; 24:578-580

13. Aitken HA, Burns JW, McArdle CS, Kenny GNC. Effects of ketorolac trometamol on renal function. Br JAnaesth. 1992;68:481-485

14. Seyberth HW, Leonhardt A, Tonshoff B, GOrdjani N. Prostanoids in pediatric kidney diseases. Pediatr Nephrol. 19915:639-M9

15. Murray MD, Brater DC. Renal toxicity of the nonsteroidal anti-inflammatory drugs. Annu Rev Pharmacol Toxicol. 199322:435-465

AIS SELF-HELP GROUP

Androgen Insensitivity Syndrome

(AIS) Support Group

United Kingdom Representative

Mrs Jackie Burrows 2 Shirburn Avenue

Mansfield Nottinghamshire

NG18 2BY UK

Tel/Fax: +44 (0) 1623 661749

United States Representative

Ms Sherri Groveman

4297 Mt Herbert Avenue

San Diego, CA 92117

Tel: (619) 569-5254

Started in the United Kingdom in 1988 by the mother of an infant with AIS, this

is a small seif-help group providing information and support to parents of AIS

youngsters and to adults with AIS on an informal basis.

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1996;98;294

Pediatrics

Marcia L. Buck and Victoria F. Norwood

Ketorolac-induced Acute Renal Failure in a Previously Healthy Adolescent

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1996;98;294

Pediatrics

Marcia L. Buck and Victoria F. Norwood

Ketorolac-induced Acute Renal Failure in a Previously Healthy Adolescent

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