- Email: [email protected]
Prospective randomized trial of ketorolac after congenital heart surgery
Prospective Randomized Trial of Ketorolac After Congenital Heart Surgery Anuja Gupta, MD,* Casey Daggett, MD,* Stacey Drant, MD,† Niurka Rivero, MD,* and Alan Lewis, MD* Objective: Ketorolac is a potent nonsteroidal analgesic agent used to treat postoperative pain. It produces excellent analgesia without the sedating side effects of opioid analgesics. Routine use of ketorolac after cardiac surgery is limited by concerns of bleeding complications. The purpose of this study was to evaluate the risk of bleeding complications of ketorolac for treatment of pain after congenital heart surgery in infants and children. Design: Prospective randomized, controlled trial. Setting: Pediatric cardiac intensive care unit in tertiary teaching hospital. Participants: Seventy infants and children, median age 10 months (range 2.5-174), who underwent congenital heart surgery requiring cardiopulmonary bypass were randomized in the trial. Intervention: Pain control was performed with ketorolac and opioid analgesics in one arm of the study and opioid analgesics alone in the other arm.
Outcome Measures: The main outcome evaluated was bleeding complications measured by chest-tube drainage and wound and gastrointestinal bleeding. Results: Thirty-five patients were randomized to each treatment arm. In the ketorolac group, the median chesttube drainage was 13.3 (range 4-22) mL/kg/d, no patient had significant wound bleeding, and 1 (0.03%) patient had gastrointestinal bleeding. In the control group, the median chest-tube drainage was 16.5 (range 3-24) mL/kg/d, 1 (0.03%) patient had wound bleeding, and no patient had gastrointestinal bleeding. Conclusion: Ketorolac can be used to treat pain after congenital heart surgery without an increased risk of bleeding complications. © 2004 Elsevier Inc. All rights reserved.
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in infants and children. The study was performed between February and May 2003 in the cardiac surgical intensive care unit at Childrens Hospital Los Angeles, Los Angeles, CA. Approval was obtained from the Food and Drug Administration to administer ketorolac in subjects less than 16 years of age. The study was then approved by the institutional review board at Childrens Hospital Los Angeles. Written informed consent was obtained from the parents, and assent was obtained from the subject when applicable. The subjects included infants and children between 2 days and 18 years of age who underwent surgery for congenital heart diseases at this institution. Only those procedures that required cardiopulmonary bypass were included. All diagnostic groups that are not listed in the exclusion criteria were included for the study. Table 1 shows the demographic and relevant clinical characteristics of the subjects involved. The exclusion criteria used were (1) previous history of allergy to aspirin or other nonsteroidal drugs because of risk of an exacerbated anaphylactic reaction; (2) previous history of chronic renal failure or immediate postoperative creatinine ⬎0.8 mg/dL because of the renal side effects of ketorolac; (3) previous history of recent GI bleed or perforation (within past 2 months), known bleeding diathesis, or immediate postoperative platelet count ⬍80,000 because of the hematologic side effects of ketorolac; (4) significant wound or chest-tube bleeding (requiring surgical intervention or recurrent requirement for blood or other blood product transfusion) in the first 6 hours postoperatively; (5) children undergoing cardiac transplantation, in view of a potential exacerbation of renal dysfunction caused by immunosuppressive medications; and (6) children with open sternum after cardiac surgery because they represent a particularly high-risk population for bleeding and renal insufficiency. All subjects who met the inclusion/exclusion criteria and who consented to participate in the study were included. A severity of illness score was developed for each patient to enable comparison of the degree of illness in the treatment and control groups. The score was based on the duration of ventilatory support and requirement for inotropic medications postoperatively. A grade of 0, 1, or 2 was assigned for ventilatory support lasting less than 6 hours, 6 to 24 hours, and greater than 24 hours, respectively. A grade of 1 was assigned for mild inotropic support (dopamine or dobutamine infusions at a dose of less than 5 g/kg/min or milrinone infusion at a dose of less than 0.3 g/kg/min). Any inotropic requirement greater than this was assigned a grade of 2. The severity of illness score was constituted by adding each grade point.
ETOROLAC IS A potent nonsteroidal analgesic agent that provides excellent pain control without the sedating side effects of opioid analgesics. The efficacy of ketorolac to treat pain in the postoperative setting is well established.1,2 Several previous studies have shown the advantages of using ketorolac either alone or in combination with opioid analgesics.3-5 Ketorolac significantly improves pain control, reduces duration of ventilatory support, and reduces intensive care unit and hospital length of stay.3,4 When used in combination with opioid analgesics, it significantly reduces the requirement for opioids.4 The major adverse effects associated with the use of ketorolac postoperatively are wound and gastrointestinal (GI) bleeding6 and renal dysfunction.7,8 The routine use of ketorolac after higher risk surgical procedures such as cardiac surgery is limited by concerns about these adverse effects. The purpose of this study was to evaluate the risk of bleeding complications associated with the use of ketorolac after congenital heart surgery in infants and children. Renal dysfunction caused by ketorolac occurs in a very small percentage of patients, and assessment of this adverse effect would require several thousand patients.8 Hence, the authors decided to focus on the evaluation of bleeding complications in this clinical trial. METHODS The study was a prospective randomized, controlled trial to assess the bleeding complications of ketorolac after congenital heart surgery
From *Childrens Hospital Los Angeles, University of Southern California, Los Angeles, CA; and †Mattel Childrens Hospital, University of California Los Angeles, Los Angeles, CA. Supported by departmental funds from the division of Cardiology at Childrens Hospital Los Angeles, Los Angeles, CA. Address reprint requests to Anuja Gupta, MD, Lupin Pharmaceuticals Inc, Harborplace Towers, 21st Floor, 111 S. Calvert Street, Baltimore, MD 21202. E-mail: [email protected] © 2004 Elsevier Inc. All rights reserved. 1053-0770/04/1804-0011$30.00/0 doi:10.1053/j.jvca.2004.05.024 454
KEY WORDS: ketorolac, nonsteroidal agents, pediatric analgesia, congenital heart surgery
Journal of Cardiothoracic and Vascular Anesthesia, Vol 18, No 4 (August), 2004: pp 454-457
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Table 1. Demographic and Clinical Characteristics of Study Patients
Patient Characteristic
Age (months), mean (SD) Weight (kg), mean (SD) Cyanotic heart diseases, n (%) Redo surgery, n (%) Cardiopulmonary bypass time (min), mean (SD) Severity of illness score, mean (SD)
Ketorolac Group (n ⫽ 35)
Non-Ketorolac Group (n ⫽ 35)
23.1 (⫾29.1) 9.9 (⫾5.7) 15 (43%) 15 (43%) 56.1 (⫾26.4)
25.1 (⫾38.4) 10.2 (⫾9.9) 17 (48%) 11 (29%) 54.3 (⫾20.6)
1.14 (⫾1.22)
1.42 (⫾1.4)
After initial recruitment, the subjects were screened for the inclusion/ exclusion criteria in the immediate postoperative period. Once the screening was complete, the subjects were randomized by using a random numbers table to receive 1 of 2 pain regimens. The first regimen consisted of the usual standard of care to treat pain after congenital heart surgery. At this institution, this consisted of using opioid analgesics such as morphine and/or fentanyl either by continuous infusion or as bolus doses. Most patients who did not require a continuous infusion of opioid analgesics were treated with bolus doses that were provided on an as-needed basis. Pain control was assessed by the patient’s bedside nurse, and pain medication was titrated accordingly. The second regimen consisted of using ketorolac in addition to the standard of care mentioned previously. Intravenous ketorolac (0.5 mg/kg/dose, maximum 15 mg/kg/dose) was administered every 6 hours without a separate loading dose. Ketorolac was started within 6 to 12 hours after arrival to the cardiothoracic intensive care unit. The duration of ketorolac therapy was limited to 36 to 48 hours because most patients were either discharged or did not require intravenous analgesics after that time period. The treatments were provided in a nonblinded fashion to satisfy requirements of the institutional review board and the US Food and Drug Administration. The main outcome measure selected was the incidence of bleeding complications. Bleeding was assessed by 3 markers: chest-tube drainage, wound bleeding, and GI bleeding. Chest-tube drainage was recorded from the pleural and mediastinal drains inserted during surgery. The total drainage was recorded for 48 hours and expressed as mL/ kg/d. Wound bleeding was evaluated by visual monitoring of the wound site and dressings for 48 hours and graded as clinically insignificant or clinically significant using practical judgment. GI bleeding was evaluated by monitoring of the GI drainage from nasogastric tubes or emesis for 48 hours and also graded as clinically insignificant or clinically significant. The secondary outcome measures included efficacy consisting of duration of intubation, hospital length of stay, and total morphine requirement. The total morphine requirement was measured in mg of morphine and g of fentanyl given and then expressed as mg/morphine/d. The incidence of pericardial effusion and renal dysfunction was also measured. Pericardial effusion was diagnosed by echocardiography. Not every patient in the study was evaluated by echocardiography. The decision to order an echocardiogram was made by the physicians caring for the patient based on clinical evidence suspicious for pericardial effusion. Renal dysfunction was measured by change in serum creatinine before and 24 hours after the pain medications were started. The hypothesis was tested that ketorolac did not increase the incidence of bleeding complications after congenital heart surgery. The estimation of sample size for the study was calculated based on the incidence of bleeding complications after use of ketorolac from previous studies6 and then modified to reflect the specific incidence of
bleeding complications after congenital heart surgery. The sample size of this study was not powered to detect a significant difference in the secondary outcome measures. It also was not powered to detect significant differences in the incidence of pericardial effusion and renal dysfunction between the 2 arms of the study. Data were expressed as mean ⫾ standard deviation or median with range. The Fisher exact test was used for comparison of the outcome measures in the 2 groups. A p value of 0.05 was considered as the acceptable level of significance. All statistical analysis was performed using the STATA statistical software package (Stata Corp, College Station, TX). RESULTS
Seventy-three patients were randomized to the 2 treatment groups in the study. One patient each in the ketorolac and non-ketorolac group were withdrawn after randomization but before initiation of treatment because the parents of these patients decided to terminate their participation after initial consent. One patient randomized to the ketorolac group was withdrawn after treatment was initiated because of a medication error performed by the pharmacy responsible for dispensing the study drug. Thirty-five patients were finally randomized and treated in each group of the study. Table 1 shows the demographic and relevant clinical characteristics of the patients in the 2 groups. The ketorolac and non-ketorolac groups were comparable with respect to age, weight, and diagnosis. The mean age and weight of the 70 randomized infants and children were 24 (⫾34) months (median 10 months, range 1-174 months) and 10 (⫾8) kg (median 8.2 kg, range 3.5-60.9 kg), respectively. The diagnostic categories randomized included 7 (10%) patients with atrial septal defect closure, 9 (12.8%) with atrial and ventricular septal defect closures, 7 (10%) with atrioventricular canal repair, 1 (1.4%) with right ventricle to pulmonary artery conduit revision, 8 (11.4%) with Fontan surgery, 10 (14.3%) with Glenn surgery, 2 (2.8%) with mitral valve repair, 2 (2.8%) with pulmonary valve repair, 2 (2.8%) with partial anomalous pulmonary venous repair, 1 (1.4%) with Ross procedure, 1 (1.4%) with resection of right ventricular aneurysm, 2 (2.8%) with resection of subaortic membrane, 1 (1.4%) with total anomalous pulmonary venous repair, 6 (8.6%) with tetralogy of Fallot repair, and 13 (18.6%) patients with ventricular septal defect closure. Twenty-six (37%) of the surgical procedures included were revision of previous repairs. The mean severity of illness score was 1.28 (⫾1.3). In the ketorolac arm of the study, 22 (62.8%) patients received 6 doses of ketorolac, 1 (2.9%) patient received 7, and 12 (34.3%) patients received 8 doses. The mean time interval between arrival to the cardiac intensive care unit postoperatively and initiation of ketorolac therapy was 8.1 (⫾1.2) hours (median 6 hours, range 4-12 hours). There were no deaths in the 70 children randomized in the trial. No patient was noted to develop any allergic or anaphylactic reaction to ketorolac. Table 2 shows the comparison of the main outcome measures between the patients treated with and without ketorolac. In the ketorolac arm of the study, the median chest-tube drainage was 13.3 (range 4-22) mL/kg/d, no patient had wound bleeding, and 1 (0.03%) patient had GI bleeding. The severity of the GI bleeding was limited to mild coffee-ground nasogas-
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Table 2. Incidence of Bleeding Complications With the Use of Ketorolac After Congenital Heart Surgery Complication
Ketorolac Group (n ⫽ 35)
Non-Ketorolac Group (n ⫽ 35)
p Value
Chest-tube drainage (mL/kg/d), median (range) Wound bleeding, n (%) GI bleeding, n (%)
13.3 (4-22) 0 1 (0.03%)
16.5 (3-24) 1 (0.03%) 0
0.05 0.7 0.56
tric aspirate. In the non-ketorolac arm, the median chest-tube drainage was 16.5 (range 3-24) mL/kg/d, 1 (0.03%) patient had wound bleeding, and no patient had GI bleeding. The wound bleeding was recorded as soaking of sternal wound dressing requiring dressing change. Table 3 shows the results of the secondary outcome measures used in the study. In the ketorolac arm, the median duration of intubation was 4 hours (range 0-24), the median hospital length of stay was 5 days (range 1-49), and the median morphine requirement was 0.3 (range 0.1-1) mg/kg/d. One (0.03%) patient treated with ketorolac had pericardial effusion, and the median change in serum creatinine was 0 (range ⫹0.3 to ⫺0.2) In the non-ketorolac arm, the median duration of intubation was 3 hours (range 0-48), the median hospital length of stay was 4 days (range 2-21) and the median morphine requirement was 0.4 (range 0.1-1.05) mg/kg/d. Two (0.06%) patients had pericardial effusion and the median change in serum creatinine was 0 (range ⫹0.4 to ⫺0.1). The pericardial effusions occurring in both arms were moderate sized but did not cause hemodynamic compromise and resolved with conservative care. DISCUSSION
The routine use of ketorolac to treat pain after congenital heart surgery is limited by concerns of bleeding complications and renal dysfunction. The authors performed a prospective randomized trial of ketorolac in infants and children after congenital heart surgery to evaluate the risk of bleeding complications. This study showed that the short-term (less than 48 hours) use of intravenous ketorolac was not associated with a significantly increased risk of postoperative bleeding complications in this patient population. The volume of chest-tube drainage was lower in patients treated with ketorolac compared with patients treated with opioid analgesics alone. The incidence of wound and GI bleeding complications were similar in the 2 groups. The results presented in this report confirm the findings of other previous studies9-11 performed in pediatric patients. However, the major strength of this study is the prospective randomized nature of the clinical trial. Previous studies that have
reported the use of ketorolac in a similar subset of pediatric surgical procedures have been retrospective studies.9-11 The main limitation of applying the results of these retrospective studies in clinical practice has been the issue of bias caused by patient selection. In the authors’ past experience, ketorolac has been used as an analgesic to treat postoperative pain only in patients who had a low likelihood of bleeding complications. This made selection of a comparable control group difficult because the patients who received ketorolac differed from the patients who did not. In the present study, patients after congenital heart surgery were prospectively randomized to receive either ketorolac in addition to opioid analgesics or opioid analgesics alone. Although inclusion and screening criteria were used for patient selection, the treatment and control groups were comparable with respect to clinical diagnosis, severity of illness and the risk for bleeding complications postoperatively. There are several limitations to these data. Ketorolac was used only for a short period of time, not exceeding 48 hours postoperatively. Previous studies7 have reported a causal association between the duration of ketorolac therapy and the risk of bleeding complications. The reason a short-term treatment course was selected was that most patients in this practice did not require potent analgesia after that time period. Secondly, the use of ketorolac was limited to patients without a high-risk of postoperative bleeding complications. The authors believe that appropriate patient selection is essential for the safe and successful use of this drug in this patient population. The severity of illness score used to indicate the degree of illness in this study has not been previously used or validated by other studies. The authors developed this score simply to enable comparison of the degree of illness in both groups of the study. Other severity of illness scores used in previous studies did not apply meaningfully to describe this patient population. The authors do not advocate using this score for any other purpose. Because the allocation of treatments in the two groups of the study was not blinded, there may be a bias in terms of total opioid requirements for patients in each group. However, the objective of this study was to assess safety and not efficacy of
Table 3. Secondary Outcome Measures With the Use of Ketorolac After Congenital Heart Surgery Outcome Measure
Ketorolac Group (n ⫽ 35)
Non-Ketorolac Group (n ⫽ 35)
p Value
Duration of intubation (hours), median (range) Hospital length of stay (days), median (range) Morphine requirement (mg/kg/day), median (range) Pericardial effusion, n(%) Change in creatinine, median (range)
4 (0-24) 5 (1-49) 0.3 (0.1-1) 1 (0.03%) 0 (⫹0.3 to ⫺0.2)
3 (0-48) 4 (2-21) 0.4 (0.1-1.05) 2 (0.06%) 0 (⫹0.4 to ⫺0.1)
0.3 0.06 0.13 0.5 0.06
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ketorolac after congenital heart surgery. Most outcomes measures in the study were objectively assessed. In addition, both the institutional review board and the Food and Drug Administration who approved the study recommended that the study be performed in a nonblinded fashion to minimize the potential and ensure prompt recognition of any untoward side effects of using ketorolac in this particular patient population. The use of ketorolac postoperatively is associated with a small risk of renal failure. Previous studies have estimated this risk to be 1 in 1,000 to 1 in 100,000. The sample size of this study was estimated based on the risk of bleeding complications, and, consequently, the study did not have sufficient power to detect a significant difference in the incidence of adverse renal effects. One patient randomized to the ketorolac arm developed hyperkalemia with a 100% increase in serum creatinine. This was noted to happen shortly after the second dose of ketorolac was administered. There was no other apparent clinical reason for this complication to develop. The hyperkalemia and elevated creatinine resolved spontaneously within 6 hours. The authors are skeptical that this reaction was caused by ketorolac because the renal dysfunction caused by this drug through its antiprostaglandin mechanism usually does not occur or resolve within such a short duration. However, no further ketorolac was administered to this patient. The sample size of this study also limited the ability to establish the efficacy of ketorolac compared with opioid anal-
gesics alone. Previous studies have reported2-5 several beneficial effects of using ketorolac, either alone or as a supplement to opioid analgesics, in terms of improved analgesia, faster recovery, shorter duration of ventilatory support, and shorter hospital length of stay. In this study, the 2 groups were not statistically different with respect to duration of intubation, hospital length of stay, or requirement of narcotic analgesics. This difference in findings is attributed to inadequate sample size. Lastly, because the sample size of this study was specifically selected based on the incidence of bleeding complications after congenital heart surgery, the results may not apply to other surgical groups with different risk of bleeding complications, such as tonsillectomy patients. This study shows that ketorolac can be used to treat early postoperative pain after congenital heart surgery in infants and children without significantly increasing the risk of bleeding complications. Caution must be used in selecting the type of patients who may be at higher risk for the side effects of this drug. Patients with higher than usual risk for early postoperative bleeding or renal dysfunction must be excluded. Ketorolac is an excellent analgesic to treat postoperative pain without the sedating side effects of opioid analgesics. Previous studies1-5 have recommended its use as a supplement or adjunct to opioid analgesics to treat postoperative pain, and this study shows that, with appropriate patient selection, it is possible to minimize the potential for serious side effects.
REFERENCES 1. Jelinek GA: Ketorolac versus morphine for severe pain: Ketorolac is more effective, cheaper, and has fewer side effects. Br Med J 321:1236-1237, 2000 2. Moote C: Efficacy of nonsteroidal anti-inflammatory drugs in the management of postoperative pain. Drugs 44:14-29, 1992 3. Forrest JB, Heitlinger EL, Revell S: Ketorolac for postoperative pain management in children. Drug Safety 16:309-329, 1997 4. Munro HM, Walton SR, Malviya S, et al: Low-dose ketorolac improves analgesia and reduces morphine requirements following posterior spinal fusion in adolescents. Can J Anaesth 49:461-466, 2002 5. Gonzalez A, Smith DP: Minimizing hospital length of stay in children undergoing ureteroneocystostomy. Urology 52:501-504, 1998 6. Strom BL, Berlin JA, Kinman JL, et al: Parenteral ketorolac and risk of gastrointestinal and operative site bleeding. A postmarketing surveillance study. JAMA 275:376-382, 1996
7. Feldman HI, Kinman JL, Berlin JA, et al: Parenteral ketorolac: The risk for acute renal failure. Ann Intern Med 126:193-199, 1997 8. Myles PS, Power I: Does ketorolac cause postoperative renal failure: How do we assess the evidence? Br J Anaesth 80:420-421, 1998 9. Buck ML: Clinical experience with ketorolac in children. Ann Pharmacother 28:1009-1013, 1994 10. Houck CS, Wilder RT, McDermott JS, et al: Safety of intravenous ketorolac therapy in children and cost savings with a unit dosing system. J Pediatr 129:292-296, 1996 11. Romsing J, Walther-Larsen S: Perioperative use of nonsteroidal anti-inflammatory drugs in children: Analgesic efficacy and bleeding. Anaesthesia 52:673-683, 1997
Outcome Measures: The main outcome evaluated was bleeding complications measured by chest-tube drainage and wound and gastrointestinal bleeding. Results: Thirty-five patients were randomized to each treatment arm. In the ketorolac group, the median chesttube drainage was 13.3 (range 4-22) mL/kg/d, no patient had significant wound bleeding, and 1 (0.03%) patient had gastrointestinal bleeding. In the control group, the median chest-tube drainage was 16.5 (range 3-24) mL/kg/d, 1 (0.03%) patient had wound bleeding, and no patient had gastrointestinal bleeding. Conclusion: Ketorolac can be used to treat pain after congenital heart surgery without an increased risk of bleeding complications. © 2004 Elsevier Inc. All rights reserved.
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in infants and children. The study was performed between February and May 2003 in the cardiac surgical intensive care unit at Childrens Hospital Los Angeles, Los Angeles, CA. Approval was obtained from the Food and Drug Administration to administer ketorolac in subjects less than 16 years of age. The study was then approved by the institutional review board at Childrens Hospital Los Angeles. Written informed consent was obtained from the parents, and assent was obtained from the subject when applicable. The subjects included infants and children between 2 days and 18 years of age who underwent surgery for congenital heart diseases at this institution. Only those procedures that required cardiopulmonary bypass were included. All diagnostic groups that are not listed in the exclusion criteria were included for the study. Table 1 shows the demographic and relevant clinical characteristics of the subjects involved. The exclusion criteria used were (1) previous history of allergy to aspirin or other nonsteroidal drugs because of risk of an exacerbated anaphylactic reaction; (2) previous history of chronic renal failure or immediate postoperative creatinine ⬎0.8 mg/dL because of the renal side effects of ketorolac; (3) previous history of recent GI bleed or perforation (within past 2 months), known bleeding diathesis, or immediate postoperative platelet count ⬍80,000 because of the hematologic side effects of ketorolac; (4) significant wound or chest-tube bleeding (requiring surgical intervention or recurrent requirement for blood or other blood product transfusion) in the first 6 hours postoperatively; (5) children undergoing cardiac transplantation, in view of a potential exacerbation of renal dysfunction caused by immunosuppressive medications; and (6) children with open sternum after cardiac surgery because they represent a particularly high-risk population for bleeding and renal insufficiency. All subjects who met the inclusion/exclusion criteria and who consented to participate in the study were included. A severity of illness score was developed for each patient to enable comparison of the degree of illness in the treatment and control groups. The score was based on the duration of ventilatory support and requirement for inotropic medications postoperatively. A grade of 0, 1, or 2 was assigned for ventilatory support lasting less than 6 hours, 6 to 24 hours, and greater than 24 hours, respectively. A grade of 1 was assigned for mild inotropic support (dopamine or dobutamine infusions at a dose of less than 5 g/kg/min or milrinone infusion at a dose of less than 0.3 g/kg/min). Any inotropic requirement greater than this was assigned a grade of 2. The severity of illness score was constituted by adding each grade point.
ETOROLAC IS A potent nonsteroidal analgesic agent that provides excellent pain control without the sedating side effects of opioid analgesics. The efficacy of ketorolac to treat pain in the postoperative setting is well established.1,2 Several previous studies have shown the advantages of using ketorolac either alone or in combination with opioid analgesics.3-5 Ketorolac significantly improves pain control, reduces duration of ventilatory support, and reduces intensive care unit and hospital length of stay.3,4 When used in combination with opioid analgesics, it significantly reduces the requirement for opioids.4 The major adverse effects associated with the use of ketorolac postoperatively are wound and gastrointestinal (GI) bleeding6 and renal dysfunction.7,8 The routine use of ketorolac after higher risk surgical procedures such as cardiac surgery is limited by concerns about these adverse effects. The purpose of this study was to evaluate the risk of bleeding complications associated with the use of ketorolac after congenital heart surgery in infants and children. Renal dysfunction caused by ketorolac occurs in a very small percentage of patients, and assessment of this adverse effect would require several thousand patients.8 Hence, the authors decided to focus on the evaluation of bleeding complications in this clinical trial. METHODS The study was a prospective randomized, controlled trial to assess the bleeding complications of ketorolac after congenital heart surgery
From *Childrens Hospital Los Angeles, University of Southern California, Los Angeles, CA; and †Mattel Childrens Hospital, University of California Los Angeles, Los Angeles, CA. Supported by departmental funds from the division of Cardiology at Childrens Hospital Los Angeles, Los Angeles, CA. Address reprint requests to Anuja Gupta, MD, Lupin Pharmaceuticals Inc, Harborplace Towers, 21st Floor, 111 S. Calvert Street, Baltimore, MD 21202. E-mail: [email protected] © 2004 Elsevier Inc. All rights reserved. 1053-0770/04/1804-0011$30.00/0 doi:10.1053/j.jvca.2004.05.024 454
KEY WORDS: ketorolac, nonsteroidal agents, pediatric analgesia, congenital heart surgery
Journal of Cardiothoracic and Vascular Anesthesia, Vol 18, No 4 (August), 2004: pp 454-457
CONGENITAL HEART SURGERY
455
Table 1. Demographic and Clinical Characteristics of Study Patients
Patient Characteristic
Age (months), mean (SD) Weight (kg), mean (SD) Cyanotic heart diseases, n (%) Redo surgery, n (%) Cardiopulmonary bypass time (min), mean (SD) Severity of illness score, mean (SD)
Ketorolac Group (n ⫽ 35)
Non-Ketorolac Group (n ⫽ 35)
23.1 (⫾29.1) 9.9 (⫾5.7) 15 (43%) 15 (43%) 56.1 (⫾26.4)
25.1 (⫾38.4) 10.2 (⫾9.9) 17 (48%) 11 (29%) 54.3 (⫾20.6)
1.14 (⫾1.22)
1.42 (⫾1.4)
After initial recruitment, the subjects were screened for the inclusion/ exclusion criteria in the immediate postoperative period. Once the screening was complete, the subjects were randomized by using a random numbers table to receive 1 of 2 pain regimens. The first regimen consisted of the usual standard of care to treat pain after congenital heart surgery. At this institution, this consisted of using opioid analgesics such as morphine and/or fentanyl either by continuous infusion or as bolus doses. Most patients who did not require a continuous infusion of opioid analgesics were treated with bolus doses that were provided on an as-needed basis. Pain control was assessed by the patient’s bedside nurse, and pain medication was titrated accordingly. The second regimen consisted of using ketorolac in addition to the standard of care mentioned previously. Intravenous ketorolac (0.5 mg/kg/dose, maximum 15 mg/kg/dose) was administered every 6 hours without a separate loading dose. Ketorolac was started within 6 to 12 hours after arrival to the cardiothoracic intensive care unit. The duration of ketorolac therapy was limited to 36 to 48 hours because most patients were either discharged or did not require intravenous analgesics after that time period. The treatments were provided in a nonblinded fashion to satisfy requirements of the institutional review board and the US Food and Drug Administration. The main outcome measure selected was the incidence of bleeding complications. Bleeding was assessed by 3 markers: chest-tube drainage, wound bleeding, and GI bleeding. Chest-tube drainage was recorded from the pleural and mediastinal drains inserted during surgery. The total drainage was recorded for 48 hours and expressed as mL/ kg/d. Wound bleeding was evaluated by visual monitoring of the wound site and dressings for 48 hours and graded as clinically insignificant or clinically significant using practical judgment. GI bleeding was evaluated by monitoring of the GI drainage from nasogastric tubes or emesis for 48 hours and also graded as clinically insignificant or clinically significant. The secondary outcome measures included efficacy consisting of duration of intubation, hospital length of stay, and total morphine requirement. The total morphine requirement was measured in mg of morphine and g of fentanyl given and then expressed as mg/morphine/d. The incidence of pericardial effusion and renal dysfunction was also measured. Pericardial effusion was diagnosed by echocardiography. Not every patient in the study was evaluated by echocardiography. The decision to order an echocardiogram was made by the physicians caring for the patient based on clinical evidence suspicious for pericardial effusion. Renal dysfunction was measured by change in serum creatinine before and 24 hours after the pain medications were started. The hypothesis was tested that ketorolac did not increase the incidence of bleeding complications after congenital heart surgery. The estimation of sample size for the study was calculated based on the incidence of bleeding complications after use of ketorolac from previous studies6 and then modified to reflect the specific incidence of
bleeding complications after congenital heart surgery. The sample size of this study was not powered to detect a significant difference in the secondary outcome measures. It also was not powered to detect significant differences in the incidence of pericardial effusion and renal dysfunction between the 2 arms of the study. Data were expressed as mean ⫾ standard deviation or median with range. The Fisher exact test was used for comparison of the outcome measures in the 2 groups. A p value of 0.05 was considered as the acceptable level of significance. All statistical analysis was performed using the STATA statistical software package (Stata Corp, College Station, TX). RESULTS
Seventy-three patients were randomized to the 2 treatment groups in the study. One patient each in the ketorolac and non-ketorolac group were withdrawn after randomization but before initiation of treatment because the parents of these patients decided to terminate their participation after initial consent. One patient randomized to the ketorolac group was withdrawn after treatment was initiated because of a medication error performed by the pharmacy responsible for dispensing the study drug. Thirty-five patients were finally randomized and treated in each group of the study. Table 1 shows the demographic and relevant clinical characteristics of the patients in the 2 groups. The ketorolac and non-ketorolac groups were comparable with respect to age, weight, and diagnosis. The mean age and weight of the 70 randomized infants and children were 24 (⫾34) months (median 10 months, range 1-174 months) and 10 (⫾8) kg (median 8.2 kg, range 3.5-60.9 kg), respectively. The diagnostic categories randomized included 7 (10%) patients with atrial septal defect closure, 9 (12.8%) with atrial and ventricular septal defect closures, 7 (10%) with atrioventricular canal repair, 1 (1.4%) with right ventricle to pulmonary artery conduit revision, 8 (11.4%) with Fontan surgery, 10 (14.3%) with Glenn surgery, 2 (2.8%) with mitral valve repair, 2 (2.8%) with pulmonary valve repair, 2 (2.8%) with partial anomalous pulmonary venous repair, 1 (1.4%) with Ross procedure, 1 (1.4%) with resection of right ventricular aneurysm, 2 (2.8%) with resection of subaortic membrane, 1 (1.4%) with total anomalous pulmonary venous repair, 6 (8.6%) with tetralogy of Fallot repair, and 13 (18.6%) patients with ventricular septal defect closure. Twenty-six (37%) of the surgical procedures included were revision of previous repairs. The mean severity of illness score was 1.28 (⫾1.3). In the ketorolac arm of the study, 22 (62.8%) patients received 6 doses of ketorolac, 1 (2.9%) patient received 7, and 12 (34.3%) patients received 8 doses. The mean time interval between arrival to the cardiac intensive care unit postoperatively and initiation of ketorolac therapy was 8.1 (⫾1.2) hours (median 6 hours, range 4-12 hours). There were no deaths in the 70 children randomized in the trial. No patient was noted to develop any allergic or anaphylactic reaction to ketorolac. Table 2 shows the comparison of the main outcome measures between the patients treated with and without ketorolac. In the ketorolac arm of the study, the median chest-tube drainage was 13.3 (range 4-22) mL/kg/d, no patient had wound bleeding, and 1 (0.03%) patient had GI bleeding. The severity of the GI bleeding was limited to mild coffee-ground nasogas-
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Table 2. Incidence of Bleeding Complications With the Use of Ketorolac After Congenital Heart Surgery Complication
Ketorolac Group (n ⫽ 35)
Non-Ketorolac Group (n ⫽ 35)
p Value
Chest-tube drainage (mL/kg/d), median (range) Wound bleeding, n (%) GI bleeding, n (%)
13.3 (4-22) 0 1 (0.03%)
16.5 (3-24) 1 (0.03%) 0
0.05 0.7 0.56
tric aspirate. In the non-ketorolac arm, the median chest-tube drainage was 16.5 (range 3-24) mL/kg/d, 1 (0.03%) patient had wound bleeding, and no patient had GI bleeding. The wound bleeding was recorded as soaking of sternal wound dressing requiring dressing change. Table 3 shows the results of the secondary outcome measures used in the study. In the ketorolac arm, the median duration of intubation was 4 hours (range 0-24), the median hospital length of stay was 5 days (range 1-49), and the median morphine requirement was 0.3 (range 0.1-1) mg/kg/d. One (0.03%) patient treated with ketorolac had pericardial effusion, and the median change in serum creatinine was 0 (range ⫹0.3 to ⫺0.2) In the non-ketorolac arm, the median duration of intubation was 3 hours (range 0-48), the median hospital length of stay was 4 days (range 2-21) and the median morphine requirement was 0.4 (range 0.1-1.05) mg/kg/d. Two (0.06%) patients had pericardial effusion and the median change in serum creatinine was 0 (range ⫹0.4 to ⫺0.1). The pericardial effusions occurring in both arms were moderate sized but did not cause hemodynamic compromise and resolved with conservative care. DISCUSSION
The routine use of ketorolac to treat pain after congenital heart surgery is limited by concerns of bleeding complications and renal dysfunction. The authors performed a prospective randomized trial of ketorolac in infants and children after congenital heart surgery to evaluate the risk of bleeding complications. This study showed that the short-term (less than 48 hours) use of intravenous ketorolac was not associated with a significantly increased risk of postoperative bleeding complications in this patient population. The volume of chest-tube drainage was lower in patients treated with ketorolac compared with patients treated with opioid analgesics alone. The incidence of wound and GI bleeding complications were similar in the 2 groups. The results presented in this report confirm the findings of other previous studies9-11 performed in pediatric patients. However, the major strength of this study is the prospective randomized nature of the clinical trial. Previous studies that have
reported the use of ketorolac in a similar subset of pediatric surgical procedures have been retrospective studies.9-11 The main limitation of applying the results of these retrospective studies in clinical practice has been the issue of bias caused by patient selection. In the authors’ past experience, ketorolac has been used as an analgesic to treat postoperative pain only in patients who had a low likelihood of bleeding complications. This made selection of a comparable control group difficult because the patients who received ketorolac differed from the patients who did not. In the present study, patients after congenital heart surgery were prospectively randomized to receive either ketorolac in addition to opioid analgesics or opioid analgesics alone. Although inclusion and screening criteria were used for patient selection, the treatment and control groups were comparable with respect to clinical diagnosis, severity of illness and the risk for bleeding complications postoperatively. There are several limitations to these data. Ketorolac was used only for a short period of time, not exceeding 48 hours postoperatively. Previous studies7 have reported a causal association between the duration of ketorolac therapy and the risk of bleeding complications. The reason a short-term treatment course was selected was that most patients in this practice did not require potent analgesia after that time period. Secondly, the use of ketorolac was limited to patients without a high-risk of postoperative bleeding complications. The authors believe that appropriate patient selection is essential for the safe and successful use of this drug in this patient population. The severity of illness score used to indicate the degree of illness in this study has not been previously used or validated by other studies. The authors developed this score simply to enable comparison of the degree of illness in both groups of the study. Other severity of illness scores used in previous studies did not apply meaningfully to describe this patient population. The authors do not advocate using this score for any other purpose. Because the allocation of treatments in the two groups of the study was not blinded, there may be a bias in terms of total opioid requirements for patients in each group. However, the objective of this study was to assess safety and not efficacy of
Table 3. Secondary Outcome Measures With the Use of Ketorolac After Congenital Heart Surgery Outcome Measure
Ketorolac Group (n ⫽ 35)
Non-Ketorolac Group (n ⫽ 35)
p Value
Duration of intubation (hours), median (range) Hospital length of stay (days), median (range) Morphine requirement (mg/kg/day), median (range) Pericardial effusion, n(%) Change in creatinine, median (range)
4 (0-24) 5 (1-49) 0.3 (0.1-1) 1 (0.03%) 0 (⫹0.3 to ⫺0.2)
3 (0-48) 4 (2-21) 0.4 (0.1-1.05) 2 (0.06%) 0 (⫹0.4 to ⫺0.1)
0.3 0.06 0.13 0.5 0.06
CONGENITAL HEART SURGERY
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ketorolac after congenital heart surgery. Most outcomes measures in the study were objectively assessed. In addition, both the institutional review board and the Food and Drug Administration who approved the study recommended that the study be performed in a nonblinded fashion to minimize the potential and ensure prompt recognition of any untoward side effects of using ketorolac in this particular patient population. The use of ketorolac postoperatively is associated with a small risk of renal failure. Previous studies have estimated this risk to be 1 in 1,000 to 1 in 100,000. The sample size of this study was estimated based on the risk of bleeding complications, and, consequently, the study did not have sufficient power to detect a significant difference in the incidence of adverse renal effects. One patient randomized to the ketorolac arm developed hyperkalemia with a 100% increase in serum creatinine. This was noted to happen shortly after the second dose of ketorolac was administered. There was no other apparent clinical reason for this complication to develop. The hyperkalemia and elevated creatinine resolved spontaneously within 6 hours. The authors are skeptical that this reaction was caused by ketorolac because the renal dysfunction caused by this drug through its antiprostaglandin mechanism usually does not occur or resolve within such a short duration. However, no further ketorolac was administered to this patient. The sample size of this study also limited the ability to establish the efficacy of ketorolac compared with opioid anal-
gesics alone. Previous studies have reported2-5 several beneficial effects of using ketorolac, either alone or as a supplement to opioid analgesics, in terms of improved analgesia, faster recovery, shorter duration of ventilatory support, and shorter hospital length of stay. In this study, the 2 groups were not statistically different with respect to duration of intubation, hospital length of stay, or requirement of narcotic analgesics. This difference in findings is attributed to inadequate sample size. Lastly, because the sample size of this study was specifically selected based on the incidence of bleeding complications after congenital heart surgery, the results may not apply to other surgical groups with different risk of bleeding complications, such as tonsillectomy patients. This study shows that ketorolac can be used to treat early postoperative pain after congenital heart surgery in infants and children without significantly increasing the risk of bleeding complications. Caution must be used in selecting the type of patients who may be at higher risk for the side effects of this drug. Patients with higher than usual risk for early postoperative bleeding or renal dysfunction must be excluded. Ketorolac is an excellent analgesic to treat postoperative pain without the sedating side effects of opioid analgesics. Previous studies1-5 have recommended its use as a supplement or adjunct to opioid analgesics to treat postoperative pain, and this study shows that, with appropriate patient selection, it is possible to minimize the potential for serious side effects.
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7. Feldman HI, Kinman JL, Berlin JA, et al: Parenteral ketorolac: The risk for acute renal failure. Ann Intern Med 126:193-199, 1997 8. Myles PS, Power I: Does ketorolac cause postoperative renal failure: How do we assess the evidence? Br J Anaesth 80:420-421, 1998 9. Buck ML: Clinical experience with ketorolac in children. Ann Pharmacother 28:1009-1013, 1994 10. Houck CS, Wilder RT, McDermott JS, et al: Safety of intravenous ketorolac therapy in children and cost savings with a unit dosing system. J Pediatr 129:292-296, 1996 11. Romsing J, Walther-Larsen S: Perioperative use of nonsteroidal anti-inflammatory drugs in children: Analgesic efficacy and bleeding. Anaesthesia 52:673-683, 1997