BRIEF CLINICAL
OBSERVATIONS
TABLE I CryptococcalMeningitis Cerebrospinal Fluid (CSF) Parametersand Therapy 2119189
3/l/89
713189 1
8131189
l/4/90
3/16/90
4124190
0
2
1
0
WBC (no./mm3)
1
3
RBC (no./mm3)
28
2
214
3
0
1
2
Protein (g/dL)
Unavailable
36
52
46
41
66
56
Glucose (g/dL)
Unavailable
36
53
42
44
48
38
CSF cryptoantigen
+1:8,192
t 1:512
+1:64
+1:64
+1:8
Unavailable
CSFculture
Positive
Positive
Positive
Negative
Negative
Negative
Blood culture
Positive
Negative
Negative
Negative
Negative
Therapy
None
Amphotericin
Fluconazole
Fluconazole
Fluconazole
2g
200 mgid
200 mgid
200 mg/d
IV
PO
PO
PO
+1:1,024
B
Amphotericin
Dosage Route
IV
B
Positive Positive Stopped fluconazole on 4118
NBC = white bloodcell count; RBC = red blood cellcount; IV = intravenously; PO = orally.
conazole 200 mg daily was continued orally. One month later, on April 18, 1990, he stopped takiig his fluconazole for unknown reasons. His CSF and blood again grew C. neoformans when sampled 10 days after his last dose of fluconazole. A head CT scan was unchanged from the previous month. Because of projectile vomiting, fluconazole 400 mg/day was administered intravenously. The patient lost vision, became confused, had seizures, and became unresponsive. An emergent head CT scan was unchanged, and the patient died before lumbar puncture could be repeated. No postmortem examination was obtained. Comments. In a recent study [l], one patient receiving oral fluconazole maintenance therapy for cryptococcal meningitis had recurrence in the urinary tract, and none had a relapse of meningitis. Other studies have reported relapses [2,3], including rapid relapses after termination of fluconazole therapy [4]. Our patient had an unusual course of prolonged suppression before relapse. It is possible that the new lesions on CT scans of the head 450
April
1992
The American
Journal
that appeared a month before his death represented cryptococcomas that developed during therapy [4 (Patient 13)], although the decreasing CSF cryptococcal antigen titer was interpreted as evidence against that possibility. This case illustrates the problem of complacency about adequate cryptococcal suppressive therapy in patients with acquired immunodeficiency syndrome. It is likely that underdosing played some role in the failure of this patient’s suppressive therapy. Fluconazole has been well tolerated, and toxicity does not appear to increase at higher doses, although this has not been well studied. Trials of fluconazole maintenance in cryptococcal meningitis utilizing higher-dosage schedules should be pursued.
2. Chuck S, Sande M. Infections with Crypfococcus neoformansin the acquired immunodeficiency syndrome. N Engl J Med 1989; 321: 794-9. 3. Sugar A, Saunders C. Oral fluconazole as suppressive therapy of disseminated cryptococcosis in patients with acquired immunodeficiency syndrome. Am J Med 1988; 85: 481-9. 4. Stern J, Hartman B, Sharkey P, et a/.Oral fluconazole therapy for patients with acquired immunodeficiency syndrome and cryptococcosis: experience with 22 patients. Am J Med 1988; 85: 477-80. Submitted
July 10, 1991, and accepted
August 1, 1991
KETOROLAC-INDUCEDACUTE RENAL FAILURE
Recently, a new nonsteroidal anti-inflammatory drug (NSAID), ketorolac tromethamine (Toradol), has been released and approved by the Food and Drug Administration (FDA) for intramuscular administration in the treatment of acute pain. KetoroLISA A. HAGLUND, M.D. lac is well absorbed and has a rapRONALD A. GREENFIELD,M.D. id onset of action. Maximum University of Oklahoma Health plasma concentrations are Sciences Center Oklahoma City, Oklahoma achieved in 45 to 50 minutes, and peak analgesic effects in 1 to 2 1. Bouette S, Larsen R. Chiu J, et al. A placebohours following intramuscular incontrolled trial of maintenance therapy with fluconjection. It is more than 99% azole after treatment of cryptococcal meningitis in bound to plasma proteins and has the acquired immunodeficiency syndrome. N Engl J Med 1991; 324: 580-4. a mean volume of distribution of of Medicine
Volume
92
BRIEF CLINICAL
mellitus, mitral valve insufficiency, and a myocardial infarction. Her presentation on admission was consistent with systolic myocardial dysfunction and congestive heart failure, including progressive dyspnea and long-standing five-pillow orthopnea. Her mitral valve was replaced -WP to with a no. 29 St. Jude prosthesis without complication. During her postoperative course, she maintained stable blood pressures of 90-100/40-52 mm Hg. Monitored hemodynamic parameters (Figure 1) included a cardiac output of 4.2 to 5.9 L/minute, pulmonary capillary wedge pressure (PCWP) of 12 to 13 mm Hg, and systemic vascular resistance (SVR) of 650 to 800 dynessecond*cm+‘. She also had a steady urine output of 30 to 50 mL/hour. On postoperative Day 2, she received a 60-mg intramuscular dose of ketorolac for pain, and 1 hour later became essentially anuric. Concomitantly, the serum creatinine level increased from 0.9 mg/dL to 2.2 mg/dL, and the blood urea nitrogen level from 10 mg/dL to 25 mg/dL. With the decrease in urine volume and continued intravenous fluid administration, the PCWP increased and SVR increased with the addireceiving ketorolac. tion of dobutamine, while other hemodynamic parameters remained essentially unchanged. those that are hemodynamically Furosemide and albumin were compromised. given with no response. Five We describe a patient who, while maintaining stable hemohours later, a second intramuscular dose of 30 mg of ketorolac was dynamic parameters, developed given, and anuria persisted deacute anuria temporally related spite increasing intravenous to the administration of intradoses of furosemide. Urine outmuscular ketorolac. There seemed to be an association be- put resumed at 50 ml/hour after the administration of 200 mg of tween the estimated pharmacokiintravenous furosemide and 25 g netics of the drug in our patient of mannitol, approximately 4 and the time-related decrease hours after the 30 mg of ketoroand recovery of renal function. lac; the serum creatinine level reCase Report. A Bl-year-old obese woman was referred for mi- turned to 1.0 mg/dL 48 hours lattral valve replacement. She had a er. The role of the furosemide and mannitol is unclear since the impast medical history of hypertenprovement in urine flow and resion, insulin-dependent diabetes --
S”R
-Q---
Figure
1. Hemodynamic
parameters
in patient
0.11 to 0.25 L/kg. About 91% of the drug is excreted in urine, mostly as inactive metabolites. The elimination half-life, approximately 4 to 6 hours, increases in elderly patients and those with renal functional impairment [ 1,2]. Ketorolac appears effective in the treatment of moderate to severe pain, especially postoperative pain, and compares favorably to meperidine and morphine [1,2]. Due to its potency, it might be predicted that this drug, like other NSAIDs, could lead to a deterioration in renal function in certain patients, particularly
OBSERVATIONS
April
1992
“0
The American
Journal
of Medicine
Volume
92
451
nal function was temporally associated with the decreasing blood level of ketorolac as projected by estimated pharmacokinetics. Thus, the clinical course and associated recovery of renal function in the presence of stable hemodynamic parameters strongly suggest a relationship to the NSAID effects of ketorolac. Comments. NSAIDs constitute one of the most frequently prescribed classes of prescription drugs. In addition, ibuprofen has been approved by the FDA for nonprescription use. It is well recognized that renal dysfunction is a potentially serious side effect of NSAIDs, which decrease production of prostaglandins known to be important in maintaining renal blood flow, sodium and water excretion, and potassium balance. The inhibition of prostaglandins may be especially important in disease states associated with a decrease
452
April
1992
The American
Journal
in effective plasma volume (e.g., hypovolemia, congestive heart failure, nephrotic syndrome, and cirrhosis of the liver with ascites) or in patients with chronic renal insufficiency. Inhibition of renal prostaglandin activity has been shown to be associated with acute renal dysfunction in these patients and in some instances interstitial nephritis associated with heavy proteinuria [3,4]. In previous studies, the effects of NSAIDs on renal hemodynamits and renal prostaglandin production as reflected by urinary prostaglandin excretion have been shown to correlate with systemic drug kinetics [5]. In one report, patients with asymptomatic renal failure developed acute deterioration of renal function during an llday course of ibuprofen [5]. Since intramuscularly administered ketorolac has a rapid onset of action and a relatively short half-life, acute changes in renal
of Medicine
Volume
92
function in patients at risk may occur. Therefore, ketorolac should be used with caution and renal function should be closely monitored in patients with conditions likely associated with decreased prostaglandin activity. LYNN A. BORAS-UBER,
B.S., Pharm.D.
NEWTON C. BRACKETT,Jr., M.D. Medical University of South Carolina Charleston, South Carolina 1. Resman-Targoff BH. Ketorolac: a parenteral nonsteroidal anti-inflammatory drug. DICP 1990; 24: 1098-104. 2. Buckley M. Brogden RN. Ketorolac: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs 1990; 39: 86-109. 3. D’Angio RG. Nonsteroidal anti-inflammatory drug induced renal dysfunction of renal prostaglandins. DICP 1987; 21: 954-8. 4. Murray MD, Brataer DC. Adverse effects of nonsteroidal anti-inflammatory drugs on renal function. Ann Intern Med 1990; 15: 559-60. 5. Whelton A, Stuot RL. Spilman PS. Klassen DK. Renal effects of ibuprofen, piroxicam, and sulindac in patients with asymptomatic renal failure. Ann Intern Med 1990; 112: 568-76. Submitted
May 22, 1991, and accepted
August 12. 1991
OBSERVATIONS
TABLE I CryptococcalMeningitis Cerebrospinal Fluid (CSF) Parametersand Therapy 2119189
3/l/89
713189 1
8131189
l/4/90
3/16/90
4124190
0
2
1
0
WBC (no./mm3)
1
3
RBC (no./mm3)
28
2
214
3
0
1
2
Protein (g/dL)
Unavailable
36
52
46
41
66
56
Glucose (g/dL)
Unavailable
36
53
42
44
48
38
CSF cryptoantigen
+1:8,192
t 1:512
+1:64
+1:64
+1:8
Unavailable
CSFculture
Positive
Positive
Positive
Negative
Negative
Negative
Blood culture
Positive
Negative
Negative
Negative
Negative
Therapy
None
Amphotericin
Fluconazole
Fluconazole
Fluconazole
2g
200 mgid
200 mgid
200 mg/d
IV
PO
PO
PO
+1:1,024
B
Amphotericin
Dosage Route
IV
B
Positive Positive Stopped fluconazole on 4118
NBC = white bloodcell count; RBC = red blood cellcount; IV = intravenously; PO = orally.
conazole 200 mg daily was continued orally. One month later, on April 18, 1990, he stopped takiig his fluconazole for unknown reasons. His CSF and blood again grew C. neoformans when sampled 10 days after his last dose of fluconazole. A head CT scan was unchanged from the previous month. Because of projectile vomiting, fluconazole 400 mg/day was administered intravenously. The patient lost vision, became confused, had seizures, and became unresponsive. An emergent head CT scan was unchanged, and the patient died before lumbar puncture could be repeated. No postmortem examination was obtained. Comments. In a recent study [l], one patient receiving oral fluconazole maintenance therapy for cryptococcal meningitis had recurrence in the urinary tract, and none had a relapse of meningitis. Other studies have reported relapses [2,3], including rapid relapses after termination of fluconazole therapy [4]. Our patient had an unusual course of prolonged suppression before relapse. It is possible that the new lesions on CT scans of the head 450
April
1992
The American
Journal
that appeared a month before his death represented cryptococcomas that developed during therapy [4 (Patient 13)], although the decreasing CSF cryptococcal antigen titer was interpreted as evidence against that possibility. This case illustrates the problem of complacency about adequate cryptococcal suppressive therapy in patients with acquired immunodeficiency syndrome. It is likely that underdosing played some role in the failure of this patient’s suppressive therapy. Fluconazole has been well tolerated, and toxicity does not appear to increase at higher doses, although this has not been well studied. Trials of fluconazole maintenance in cryptococcal meningitis utilizing higher-dosage schedules should be pursued.
2. Chuck S, Sande M. Infections with Crypfococcus neoformansin the acquired immunodeficiency syndrome. N Engl J Med 1989; 321: 794-9. 3. Sugar A, Saunders C. Oral fluconazole as suppressive therapy of disseminated cryptococcosis in patients with acquired immunodeficiency syndrome. Am J Med 1988; 85: 481-9. 4. Stern J, Hartman B, Sharkey P, et a/.Oral fluconazole therapy for patients with acquired immunodeficiency syndrome and cryptococcosis: experience with 22 patients. Am J Med 1988; 85: 477-80. Submitted
July 10, 1991, and accepted
August 1, 1991
KETOROLAC-INDUCEDACUTE RENAL FAILURE
Recently, a new nonsteroidal anti-inflammatory drug (NSAID), ketorolac tromethamine (Toradol), has been released and approved by the Food and Drug Administration (FDA) for intramuscular administration in the treatment of acute pain. KetoroLISA A. HAGLUND, M.D. lac is well absorbed and has a rapRONALD A. GREENFIELD,M.D. id onset of action. Maximum University of Oklahoma Health plasma concentrations are Sciences Center Oklahoma City, Oklahoma achieved in 45 to 50 minutes, and peak analgesic effects in 1 to 2 1. Bouette S, Larsen R. Chiu J, et al. A placebohours following intramuscular incontrolled trial of maintenance therapy with fluconjection. It is more than 99% azole after treatment of cryptococcal meningitis in bound to plasma proteins and has the acquired immunodeficiency syndrome. N Engl J Med 1991; 324: 580-4. a mean volume of distribution of of Medicine
Volume
92
BRIEF CLINICAL
mellitus, mitral valve insufficiency, and a myocardial infarction. Her presentation on admission was consistent with systolic myocardial dysfunction and congestive heart failure, including progressive dyspnea and long-standing five-pillow orthopnea. Her mitral valve was replaced -WP to with a no. 29 St. Jude prosthesis without complication. During her postoperative course, she maintained stable blood pressures of 90-100/40-52 mm Hg. Monitored hemodynamic parameters (Figure 1) included a cardiac output of 4.2 to 5.9 L/minute, pulmonary capillary wedge pressure (PCWP) of 12 to 13 mm Hg, and systemic vascular resistance (SVR) of 650 to 800 dynessecond*cm+‘. She also had a steady urine output of 30 to 50 mL/hour. On postoperative Day 2, she received a 60-mg intramuscular dose of ketorolac for pain, and 1 hour later became essentially anuric. Concomitantly, the serum creatinine level increased from 0.9 mg/dL to 2.2 mg/dL, and the blood urea nitrogen level from 10 mg/dL to 25 mg/dL. With the decrease in urine volume and continued intravenous fluid administration, the PCWP increased and SVR increased with the addireceiving ketorolac. tion of dobutamine, while other hemodynamic parameters remained essentially unchanged. those that are hemodynamically Furosemide and albumin were compromised. given with no response. Five We describe a patient who, while maintaining stable hemohours later, a second intramuscular dose of 30 mg of ketorolac was dynamic parameters, developed given, and anuria persisted deacute anuria temporally related spite increasing intravenous to the administration of intradoses of furosemide. Urine outmuscular ketorolac. There seemed to be an association be- put resumed at 50 ml/hour after the administration of 200 mg of tween the estimated pharmacokiintravenous furosemide and 25 g netics of the drug in our patient of mannitol, approximately 4 and the time-related decrease hours after the 30 mg of ketoroand recovery of renal function. lac; the serum creatinine level reCase Report. A Bl-year-old obese woman was referred for mi- turned to 1.0 mg/dL 48 hours lattral valve replacement. She had a er. The role of the furosemide and mannitol is unclear since the impast medical history of hypertenprovement in urine flow and resion, insulin-dependent diabetes --
S”R
-Q---
Figure
1. Hemodynamic
parameters
in patient
0.11 to 0.25 L/kg. About 91% of the drug is excreted in urine, mostly as inactive metabolites. The elimination half-life, approximately 4 to 6 hours, increases in elderly patients and those with renal functional impairment [ 1,2]. Ketorolac appears effective in the treatment of moderate to severe pain, especially postoperative pain, and compares favorably to meperidine and morphine [1,2]. Due to its potency, it might be predicted that this drug, like other NSAIDs, could lead to a deterioration in renal function in certain patients, particularly
OBSERVATIONS
April
1992
“0
The American
Journal
of Medicine
Volume
92
451
nal function was temporally associated with the decreasing blood level of ketorolac as projected by estimated pharmacokinetics. Thus, the clinical course and associated recovery of renal function in the presence of stable hemodynamic parameters strongly suggest a relationship to the NSAID effects of ketorolac. Comments. NSAIDs constitute one of the most frequently prescribed classes of prescription drugs. In addition, ibuprofen has been approved by the FDA for nonprescription use. It is well recognized that renal dysfunction is a potentially serious side effect of NSAIDs, which decrease production of prostaglandins known to be important in maintaining renal blood flow, sodium and water excretion, and potassium balance. The inhibition of prostaglandins may be especially important in disease states associated with a decrease
452
April
1992
The American
Journal
in effective plasma volume (e.g., hypovolemia, congestive heart failure, nephrotic syndrome, and cirrhosis of the liver with ascites) or in patients with chronic renal insufficiency. Inhibition of renal prostaglandin activity has been shown to be associated with acute renal dysfunction in these patients and in some instances interstitial nephritis associated with heavy proteinuria [3,4]. In previous studies, the effects of NSAIDs on renal hemodynamits and renal prostaglandin production as reflected by urinary prostaglandin excretion have been shown to correlate with systemic drug kinetics [5]. In one report, patients with asymptomatic renal failure developed acute deterioration of renal function during an llday course of ibuprofen [5]. Since intramuscularly administered ketorolac has a rapid onset of action and a relatively short half-life, acute changes in renal
of Medicine
Volume
92
function in patients at risk may occur. Therefore, ketorolac should be used with caution and renal function should be closely monitored in patients with conditions likely associated with decreased prostaglandin activity. LYNN A. BORAS-UBER,
B.S., Pharm.D.
NEWTON C. BRACKETT,Jr., M.D. Medical University of South Carolina Charleston, South Carolina 1. Resman-Targoff BH. Ketorolac: a parenteral nonsteroidal anti-inflammatory drug. DICP 1990; 24: 1098-104. 2. Buckley M. Brogden RN. Ketorolac: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs 1990; 39: 86-109. 3. D’Angio RG. Nonsteroidal anti-inflammatory drug induced renal dysfunction of renal prostaglandins. DICP 1987; 21: 954-8. 4. Murray MD, Brataer DC. Adverse effects of nonsteroidal anti-inflammatory drugs on renal function. Ann Intern Med 1990; 15: 559-60. 5. Whelton A, Stuot RL. Spilman PS. Klassen DK. Renal effects of ibuprofen, piroxicam, and sulindac in patients with asymptomatic renal failure. Ann Intern Med 1990; 112: 568-76. Submitted
May 22, 1991, and accepted
August 12. 1991
