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
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Pediatrics
Marcia L. Buck and Victoria F. Norwood
Ketorolac-induced Acute Renal Failure in a Previously Healthy Adolescent
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