Prospective randomized trial of ketorolac after congenital heart surgery

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 chest-tube 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.     

Periventricular leukomalacia is common after neonatal cardiac surgery

OBJECTIVES: Periventricular leukomalacia is necrosis of the cerebral white matter adjacent to the lateral ventricles and results from injury to immature oligodendroglia. In infants without congenital heart disease, periventricular leukomalacia is associated with an increased incidence of developmental delay and attention deficit/hyperactivity disorder. The incidence of periventricular leukomalacia and the risk factors for development of periventricular leukomalacia after infant cardiac surgery are not known. METHODS: Magnetic resonance imaging of the brain was performed 6 to 14 days after cardiac surgery utilizing cardiopulmonary bypass with or without deep hypothermic circulatory arrest in 105 neonates and infants < or = 6 months of age. RESULTS: Median age at surgery was 6 days (range 1-178), with 82 neonates (age < or = 30 days). Periventricular leukomalacia was found in 44 of the neonates (54%) compared with 1 of 23 infants (4%). Forward logistic regression using age at surgery as a continuous variable identified a model containing longer total support time (cardiopulmonary bypass plus deep hypothermic circulatory arrest), lower systolic blood pressure at cardiac intensive care unit admission postoperatively, lower minimum diastolic blood pressure, and Po(2) in the first 48 hours after surgery. When age at surgery was considered as a dichotomous variable (neonate versus infant), younger age at surgery replaced systolic blood pressure, Po(2), and total support time in the model. Lower minimum diastolic blood pressure was a significant risk factor in both models. CONCLUSIONS: Periventricular leukomalacia was found in >50% of neonates after cardiac surgery but rarely in older infants. Hypoxemia and hypotension in the early postoperative period, particularly diastolic hypotension, may be important risk factors for periventricular leukomalacia.     

The effect of ketorolac and sevoflurane anesthesia on renal glomerular and tubular function.

We assessed the renal effects of the combination of ketorolac and sevoflurane anesthesia by using sensitive and specific markers of renal proximal and distal tubular and glomerular function. Thirty women (ASA physical status I and II) undergoing breast surgery received either ketorolac 30 mg IM or saline at premedication, at the end, and 6 h after anesthesia maintained with sevoflurane. Peak levels of serum fluoride at 2 h after the end of anesthesia were 30.1 micromol/L (21.0-50.0 micromol/L) in the Ketorolac group and 33.3 micromol/L (13.0-38.0 micromol/L) in the Control group (mean and range, not significant). Urine alpha1-microglobulin indexed to urine creatinine was increased from 2 h after the start of anesthesia until the first postoperative day in the Ketorolac group (peak level, 0.8 +/- 0.4 mg/mmol; upper limit of normal, 0.7 mg/mmol) but did not change in the Control group. Urine glutathione-S-transferase (GST)-alpha indexed to urine creatinine (GST-alpha/creatinine) and GST-pi/creatinine were increased 2 h after anesthesia and returned to baseline values thereafter in both groups. There were no changes in serum cystatin C and urine kallikrein or urine output per hour between groups. The perioperative administration of ketorolac to healthy, well hydrated patients anesthetized with sevoflurane did not produce renal glomerular or tubular dysfunction. IMPLICATIONS: Ketorolac 90 mg IM, given in divided doses over approximately 10 h to patients anesthetized with sevoflurane with a fresh gas flow rate of 4-6 L/min, did not result in clinically significant changes in renal glomerular or tubular function.     

Safety of ketorolac in the pediatric population after ureteroneocystostomy

PURPOSE: Ketorolac has been used to provide effective postoperative analgesia in children and decreases hospitalization for pediatric patients undergoing ureteroneocystostomy. However, it can cause severe side effects, including increased bleeding and renal insufficiency, which can be devastating in a child. Little has been reported on the safety of ketorolac by evaluating creatinine, hematocrit and complications. MATERIALS AND METHODS: An institutional retrospective review was performed during an 18-month period in which 118 patients underwent ureteroneocystostomy. One group containing 50 patients received caudal anesthetic preoperatively and narcotic analgesics postoperatively, while another 68 received caudal anesthetic preoperatively and ketorolac postoperatively. Patient ages, type of procedure, preoperative and postoperative creatinine and hematocrit, and complications were noted in each cohort. RESULTS: Average patient age of the control analgesic and ketorolac groups was 5.3 years (range 1 to 17) and 5.5 (1 to 12), respectively. There was no statistical difference between postoperative creatinine (0.68 and 0.65 mg./dl.) and hematocrit (33% and 34%) between the groups. One patient in each group had increased creatinine postoperatively. Minor complications, for example ileus and bladder spasms, were equivalent in both groups. No patient receiving ketorolac had any allergic or hypersensitivity reaction to the medication, and no major complications were reported. CONCLUSIONS: Ketorolac given after ureteroneocystostomy did not cause a significant decrease in hematocrit, increase in creatinine or overall complications. Because of the safety of ketorolac in our series, and ability to decrease hospital stay and narcotic requirements in children as reported previously, it is used as standard postoperative protocol after ureteroneocystostomy at our institution.     

Preemptive analgesic effects of ketorolac in ankle fracture surgery

BACKGROUND: Preemptive analgesia has been difficult to show in human experiments. If ketorolac has preemptive effects, then there may be an advantage to administering it at the beginning of surgery despite the potential for increased blood loss. METHODS: The authors performed a randomized, double-blind, controlled trial of 48 patients scheduled for ankle fracture surgery in a county trauma hospital. Anesthesia management was standardized and included adequate opioid analgesia (5 microg/kg fentanyl and 0.1 mg/kg morphine). Intravenous 30 mg ketorolac was administered to 23 patients before tourniquet inflation and to 25 patients after tourniquet inflation. Visual analog scale pain scores, morphine patient-controlled analgesia consumption, nausea-vomiting, and postoperative bleeding were measured. RESULTS: The 23 patients given ketorolac before tourniquet inflation had no increase in pain postoperatively compared with their preoperative baseline (P = 0.280). The 25 patients who received ketorolac minutes later after tourniquet inflation had significant increases in their postoperative pain compared with their preoperative baseline (P = 0.00116). This effect was short-lived, and by 6 h the pain score in this group was not significantly more than it was preoperatively. Intergroup comparison showed a lower visual analog scale score at 2 (P = 0.0203) and 4 h (P = 0.00549) in the preemptive group and lower nausea scores at hour 6 (P = 0.00704). There was no difference in patient-controlled analgesia consumption between groups. CONCLUSIONS: Intravenous 30 mg ketorolac appears to have preemptive analgesic effects in patients undergoing ankle fracture repair. Ketorolac administered before tourniquet inflation prevents postoperative pain being perceived as more intense than preoperative pain.     

Ketorolac: safe and effective analgesia for the management of renal cortical tumors with partial nephrectomy

PURPOSE: Ketorolac has demonstrated advantages as a supplement to opioid based analgesia in several surgical settings, including donor nephrectomy. To our knowledge there has been no published data to date on the use of ketorolac in patients undergoing partial nephrectomy. We compared analgesia with ketorolac and opioids to analgesia with opioids alone with regard to pain control, postoperative recovery and effects on renal function in patients with renal cortical tumors surgically managed by partial nephrectomy. MATERIALS AND METHODS: Records for 154 patients treated with partial nephrectomy for renal cortical tumors were retrospectively analyzed. Clinicopathological variables examined were age, gender, medication use, comorbidity profile, operation side, estimated blood loss, hospital stay, operative duration, American Society of Anesthesiologists class, histopathology results, perioperative transfusion status, ischemia type (warm vs cold vs none), duration of renal artery cross clamping, tumor size and intraparenchymal location, pathological stage and perioperative complications. Postoperative duration to the initiation of solid diet, discontinuation of patient controlled analgesia and overall pain control were assessed. Serum creatinine was measured during the preoperative period, and at 1, 3 or greater and 30 or greater days postoperatively. RESULTS: Patients who received ketorolac demonstrated superior postoperative recovery with an earlier return to solid diet and earlier discontinuation of patient controlled analgesia. Treatment groups were similar with respect to changes in serum creatinine, blood loss, transfusion rates and complication rates. Ketorolac was not associated with an increased risk of acute renal failure. CONCLUSIONS: Ketorolac is a safe and effective supplement to opioid based analgesia for pain control after partial nephrectomy.     

Use of intravenous ketorolac in the neonate and premature babies

BACKGROUND: Ketorolac is a powerful nonsteroidal anti-inflammatory drug widely used for pain control in children and adults. The aim of this study was to evaluate its safety and analgesic efficacy in the neonate. METHODS: Ketorolac was used in a group of 18 spontaneously breathing neonates presenting with chronic lung disease, for the control of postsurgical pain and pain from invasive procedures. Pain scores (Neonatal Infant Pain Scale) were assessed before and after i.v. administration of 1 mg.kg(-1) of ketorolac. RESULTS: Total pain control was achieved in 94.4% of the neonates. None of the neonates had haematological, renal or hepatic changes prior to treatment, and these complications did not occur after treatment. No neonate had systemic haemorrhage or bleeding from injection and blood withdrawal sites. CONCLUSIONS: Ketorolac could represent an efficacious analgesic alternative to opioids, particularly in neonates. It would avoid the side-effects associated with opioid analgesics, especially respiratory depression.     

Prospective double-blind study of effect of ketorolac administration after laparoscopic urologic surgery

BACKGROUND AND PURPOSE: To decrease postoperative dependence on narcotics for analgesia, we have evaluated ketorolac as an adjunct to perioperative pain control in patients undergoing laparoscopic urologic surgery. PATIENTS AND METHODS: Sixty-five patients (34 male, 31 female) were randomized to receive either ketorolac tromethamine (15-30 mg IV q 6 h) or placebo prior to laparoscopic surgery. Patient-controlled analgesia in the form of morphine sulfate was provided. Operative factors such as the type of surgery, operative time, and estimated blood loss were recorded. Postoperative factors such as analog pain score (range 0-10), narcotic usage, and length of stay were evaluated. RESULTS: Fifty-five patients completed the study. The average pain score was 2.2 and 4.5 for the ketorolac and placebo groups, respectively (P < 0.005). The mean amounts of total morphine used were 39.2 mg (ketorolac) and 62.5 mg (placebo) (P = 0.077). The length of stay was not significantly different in the ketorolac (2.5 days) and placebo (2.6 days) groups (P = 0.74). Operative times (P = 0.21) and estimated blood loss (P = 0.60) were not significantly different in the two groups. Ketorolac did not adversely affect renal function; serum creatinine changes were not significantly different from those in the patients receiving placebo (P = 0.50). Laparoscopic pyeloplasty necessitated more narcotic analgesia than did other laparoscopic procedures (P = 0.05). CONCLUSION: Ketorolac decreases the subjective perception of pain after laparoscopic urologic surgery. It is suggested that ketorolac administration decreases the amount of narcotic usage as well. Time to resumption of oral intake and length of hospital stay were not influenced by use of ketorolac.     

Comparative effects of intravenous ketorolac and pethidine on perioperative analgesia and postoperative nausea and vomiting (PONV) for paediatric strabismus surgery

BACKGROUND: Corrective strabismus surgery is associated with moderate pain and a very high incidence of postoperative nausea and vomiting (PONV). Ketorolac tromethamine, a nonsteroidal anti-inflammatory drug, is a popular analgesic in adults. There are only limited published data on the use of intravenous ketorolac for paediatric analgesia perioperatively. This study evaluated and compared the emetic and analgesic effect of ketorolac with pethidine and its suitability for this kind of surgery. METHODS: Following institutional ethics committee approval and parental consent, 52 ASA class I children of age 2.5 to 15 yr were randomised to receive either ketorolac 0.9 mg kg-1 or pethidine 0.5 mg kg-1 given intravenously (i.v.). A blinded observer assessed recovery by Steward's method immediately after arrival at the post anaesthesia care unit (PACU), pain by validated Objective Pain Score (OPS) at 0 h, 1/2 h and 1 h after arrival at the PACU and PONV by Numeric Rank Score at specified time intervals. RESULTS: There were no differences in demographic data, anaesthesia time or surgery duration. Recovery scores, OPS and postoperative analgesic requirement were similar in both groups. PONV at various time intervals for the first 24 h, occurred more frequently in the pethidine group as compared to the ketorolac group (P < 0.001) There were no side effects observed with either drug. CONCLUSION: Ketorolac in a dose of 0.9 mg kg-1 i.v. at the induction of anaesthesia is as effective as pethidine 0.5 mg kg-1 i.v. as an analgesic and is associated with significantly less PONV.     

Ketorolac after congenital heart surgery: does it increase the risk of significant bleeding complications?

BACKGROUND: The routine use of ketorolac after congenital heart surgery in infants and children is limited by concerns for postoperative bleeding complications. The object of this study was to determine if the use of ketorolac is associated with an increased risk of significant postoperative bleeding after congenital heart surgery in infants and children. METHODS: A retrospective chart review was performed. The exposure of interest was postoperative use of ketorolac after congenital heart surgery in infants and children. The outcome measured was postoperative bleeding requiring surgical exploration. The patients who received ketorolac were compared with an age- and diagnosis-matched comparison group who did not receive ketorolac. RESULTS: Records of 842 infants and children who underwent congenital heart surgery between July 2001 and October 2002 were reviewed. 94 (11.1%) patients were treated with ketorolac postoperatively. The comparison group consisted of 94 matched subjects selected from the patients that did not receive ketorolac. The mean age of patient in the ketorolac group was 8.5 (+/-6.1) years. No (0%) patients in the ketorolac group and four (4.2%) patients in the nonketorolac group developed postoperative bleeding requiring surgical exploration. The relative risk for postoperative bleeding that required surgical exploration in the ketorolac group compared with the nonketorolac group was 0.2 (95% CI 0.02-1.67). CONCLUSIONS: The use of ketorolac after congenital heart surgery in infants and children does not significantly increase the risk of bleeding complications requiring surgical exploration.     

Ketorolac effectively inhibits ureteral contractility in vitro

INTRODUCTION: The use of ketorolac in the management of painful symptoms associated with urinary stones is well supported in the literature; however, the gastric and renal adverse effects limit the dose and duration of administration. As a nonselective cyclooxygenase inhibitor, ketorolac can act locally to help control renal colic by inhibiting smooth muscle contractions and inflammation. We sought to confirm ketorolac's inhibition of ureteral contractility and determine a dose response relationship to identify an effectiveness range. MATERIALS AND METHODS: Porcine ureter strips attached to force displacement transducers were suspended in organ tissue baths that contained aerated Krebs buffer. Tissues equilibrated for 1 hour, and a spontaneous contractility rate was established. Tissues were incubated with a concentration-response curve of ketorolac (0.1 nM-10 microM) for 90 minutes and compared with indomethacin (1 muM) and dimethyl sulfoxide (DMSO) 0.1%. Contractility rates were recorded on a polygraph and analyzed for changes over exposure time. RESULTS: Ketorolac inhibition of ureteral contractility was dose dependent. At 90 minutes, the average percent decrease from the spontaneous contraction rate for 0.1 nM ketorolac was 18.2%; 1 nM, 34.3%; 10 nM, 56.0%; 100 nM, 69.9%; 1 microM, 88.7%; and 10 microM, 98.3%. Ureteral contractility was significantly reduced by 1 microM ketorolac (39.0%; P = 0.016) at 15 minutes when compared with DMSO. In addition, 1 microM ketorolac was not significantly different at any time point from any of the higher doses studied. CONCLUSION: Ketorolac inhibition of stretch-induced ureteral contractility is concentration-dependent between 1 nM and 1 microM. Local administration of ketorolac at these doses may be useful during the management of stones while at the same time limiting the risk for adverse effects.     

Peritoneal dialysis in neonates and infants after open heart surgery

Peritoneal dialysis was required in 20 (12.8%) of 156 neonates and infants for acute renal failure following open heart surgery using cardiopulmonary bypass. Cardiac diagnosis was TAPVD (7 cases), PA with IVS (2), ECD (2), coarctation of the aorta with VSD (2) and other cardiac malformations (7). The indication for dialysis was oliguria of less than 1.0 ml/kg over 4 hours resistant to volume repletion, inotropic agent and diuretics. Peritoneal dialysis was performed using dialysis catheter and glucose containing dialysis solutions. The mean predialysis BUN and serum creatinine were 30.4 mg/dl and 2.7 mg/dl respectively. The highest serum creatinine during dialysis was 4.5 mg/dl, and all but one patient had BUN level of under 100 mg/dl. Dialysis with glucose containing solution could allow sufficient fluid removal as a result, fluid overload was restored. Plasma protein and electrolytes balance were corrected within 48 hours. Two neonates and 4 infants survived. Thirteen patients died on dialysis: nine of those deaths were related to low cardiac output, 2 death were attributable to respiratory insufficiency, and 2 cases died due to sepsis. One infant died of an unexplained cardiac arrhythmia after renal failure had been improved. It is concluded that peritoneal dialysis is beneficial in neonates and infants who become oliguria following open heart surgery.     

Ketorolac reduces postoperative narcotic requirements

BACKGROUND/PURPOSE: Adverse effects from narcotics complicate pain management in children. Ketorolac, a potent nonsteroidal antiinflammatory agent can be used as an adjuvant analgesic, yet concerns of bleeding and nephrotoxicity have limited routine use. The authors hypothesized that postoperative use of ketorolac in healthy pediatric surgical patients would limit narcotic requirements without increasing morbidity. METHODS: A case-control clinical trial was conducted of 29 pediatric surgical cases prospectively administered ketorolac (0.5 mg/kg intravenously every 6 hours) supplemented with morphine. Controls receiving morphine only were matched for age (+/- 6 months) and surgical procedure. Incidence of respiratory depression, urinary retention, emesis, nephrotoxicity, and bleeding were recorded. RESULTS: Patients receiving ketorolac plus morphine had significantly less morphine requirements in the first 48 postoperative hours (Ketorolac plus Morphine: 0.36+/-0.16 mg/kg/d, Morphine only: 1.08+/-0.16 mg/kg/d [P<.05, analysis by paired t test]). This decrease was noted despite mode of analgesia (patient controlled or nurse administered). Adverse effects of morphine including respiratory depression, emesis, and urinary retention were not affected by ketorolac. Patients administered ketorolac had no significant increase in bleeding or nephrotoxicity. CONCLUSION: Ketorolac exhibits significant opiate-sparing effects in the immediate postoperative period without introducing additional morbidity to pediatric surgical procedures.     

Ketorolac tromethamine: stereo-specific pharmacokinetics and single-dose use in postoperative infants aged 2-6 months

Objective: We determined the postoperative pharmacokinetics (PK), safety, and analgesic effects of ketorolac in 14 infants (aged <6 months) receiving a single intravenous (IV) administration of racemic ketorolac or placebo. Background: Information on the PK of ketorolac in infants is limited. Unblinded studies suggest ketorolac may be useful in infants. Methods: This double‐blinded, placebo‐controlled study enrolled 14 infants (aged <6 months) postoperatively. At 6–18 h after surgery, infants were randomized to receive placebo, 0.5 mg·kg^?1, or 1 mg·kg^?1 ketorolac IV. All infants received morphine sulfate as needed for pain control. Blood was collected up to 12‐h postdosing. Analysis used noncompartmental and compartmental population modeling methods. Results: In addition to noncompartmental and empirical Bayes PK modeling, data were integrated with a previously studied data set comprising 25 infants and toddlers (aged 6–18 months). A two‐compartmental model described the comprehensive data set. The population estimates of the R (+) isomer were (%CV): central volume of distribution 1130 (10%) ml, peripheral volume of distribution 626 (25%) ml, and clearance from the central compartment 7.40 (8%) ml·min^?1. Those of the S (?) isomer were 1930 (15%) ml, 319 (58%) ml, and 39.5 (13%) ml·min^?1. Typical elimination half‐lives were 191 and 33 min, respectively. There was a trend for increased clearance and central volume with increasing age and weight. The base model suggested that clearance of the S (?) isomer was weakly related to age; however, when body size adjustment was added to the model, no covariates were significant. Safety assessment showed no changes in renal or hepatic function tests, surgical drain output, or continuous oximetry between groups. Cumulative morphine administration showed large inter‐patient variability and was not different between groups. Conclusion: Stereo‐isomer‐specific clearance of ketorolac in infants (aged 2–6 months) shows rapid elimination of the analgesic S (?) isomer as reported in infants aged 6–18 months. No adverse effects were seen after a single IV ketorolac dose.     

Ketorolac, diclofenac, and ketoprofen are equally safe for pain relief after major surgery

Background. Ketorolac is approved for the relief of postoperativepain but concerns have been raised over a possible risk of seriousadverse effects and death. Two regulatory reviews in Europeon the safety of ketorolac found the data were inconclusiveand lacked comparison with other non-steroidal anti-inflammatorydrugs. The aim of this study was to compare the risk of seriousadverse effects with ketorolac vs diclofenac or ketoprofen inadult patients after elective major surgery. Methods. This prospective, randomized multicentre trial evaluatedthe risks of death, increased surgical site bleeding, gastrointestinalbleeding, acute renal failure, and allergic reactions, withketorolac vs diclofenac or ketoprofen administered accordingto their approved parenteral and oral dose and duration of treatment.Patients were followed for 30 days after surgery. Results. A total of 11 245 patients completed the trial at 49European hospitals. Of these, 5634 patients received ketorolacand 5611 patients received one of the comparators. 155 patients(1.38%) had a serious adverse outcome, with 19 deaths (0.17%),117 patients with surgical site bleeding (1.04%), 12 patientswith allergic reactions (0.12%), 10 patients with acute renalfailure (0.09%), and four patients with gastrointestinal bleeding(0.04%). There were no differences between ketorolac and ketoprofenor diclofenac. Postoperative anticoagulants increased the riskof surgical site bleeding equally with ketorolac (odds ratio=2.65,95% CI=1.51–4.67) and the comparators (odds ratio=3.58,95% CI=1.93–6.70). Other risk factors for serious adverseoutcomes were age, ASA score, and some types of surgery (plastic/ear,nose and throat, gynaecology, and urology). Conclusion. We conclude that ketorolac is as safe as ketoprofenand diclofenac for the treatment of pain after major surgery. Br J Anaesth 2002; 88: 227–33     

Utility and limitations of serum creatinine as a measure of renal function in experimental renal ischemia-reperfusion injury

BACKGROUND: Ischemia-reperfusion injury (IRI) is the major cause of delayed graft function in renal allografts. The present study was performed to investigate the validity of serum creatinine (SCr) level as an indicator of postischemic renal dysfunction in mice. METHODS: Renal IRI or sham surgery was induced in C57BL/6 mice, and SCr level and inulin clearance (Cin) were measured between 24 hr and 7 days after ischemia. RESULTS: Cin in IRI mice was reduced 75% at 72 hr after ischemia in association with a nearly threefold increase in SCr level. Cin in IRI mice did not recover between 72 hr and 7 days after ischemia, even though SCr level at 7 days was not different between control and IRI mice. In IRI mice, SCr level measured at 24, 48, and 72 hr after ischemia correlated inversely with Cin measured at 72 hr, but not 7 days, after ischemia. CONCLUSIONS: SCr level in the early postischemic period (24-72 hr) seems to be a valid indicator of early postischemic renal dysfunction, and that renal function remains markedly depressed at 7 days despite suggestion from the SCr value that renal function is improving.     

Pharmacokinetics of bupivacaine after continuous epidural infusion in infants with and without biliary atresia

BACKGROUND: Continuous epidural infusion of bupivacaine is widely practiced for postoperative pain relief in pediatric patients. However, bupivacaine may induce adverse effects in infants (convulsions or cardiac arrhythmias), likely because of decreased hepatic clearance and serum protein binding capacity. The authors wanted to examine the complex relations between age, alpha-1 acid glycoprotein (AAG) concentration, and unbound and total bupivacaine serum concentrations in infants receiving bupivacaine epidurally for 2 days. METHODS: Twenty-two infants aged 1-7 months (12 with biliary atresia and 10 with another disease) received a continuous epidural infusion of 0.375 mg x kg(-1) x h(-1) bupivacaine during 2 days (during and after surgery). Unbound and total bupivacaine concentration in serum was measured 0.5, 4, 24, and 48 h after infusion initiation. AAG concentration was measured in serum before and 2 days after surgery. In eight additional infants, the blood/plasma concentration ratio was measured in vitro at whole blood concentrations of 2 and 20 microg/ml. Bupivacaine concentration was fitted to a one-compartment model to calculate basic pharmacokinetic parameters. RESULTS: No adverse effects were observed. AAG increased markedly after surgery, and the increase was correlated to both age and preoperative AAG concentration. Two infants aged 1.8 months had unbound concentrations greater than 0.2 microg/ml. Clearance of unbound drug significantly increased with age. Because of increased drug binding, clearance of bound drug decreased both with time (from 0.5 to 48 h) and with age. Blood/plasma ratio was 0.77+/-0.08 and 0.85+/-0.24 at 2 and 20 microg/ml, respectively. CONCLUSIONS: Because of a low AAG concentration and a low intrinsic clearance, unbound bupivacaine increased to concentrations greater than 0.2 microg/ml in two infants younger than 2 months, after 2 days of infusion at a rate of 0.375 mg x kg(-1) x h(-1). The increase in AAG observed after surgery did not fully buffer this unbound fraction. Similarly, the buffer capacity of erythrocytes did not sufficiently increase at high concentration to compensate the saturation of the AAG system. Thus, we propose the use of a maximum dose of 0.25 mg x kg(-1) x h(-1) in infants younger than 4 months and a maximum of 0.3 mg x kg(-1) x h(-1) in infants older than 4 months.     

Safety of ketorolac in surgical neonates and infants 0 to 3 months old

Background

Ketorolac is a nonsteroidal antiinflammatory drug widely used as an adjunct to postoperative pain control in adult and pediatric patients. Minimal safety data exist regarding the use of ketorolac in neonates.

Methods

The charts of 57 postsurgical neonates between 0 and 3 months of age were retrospectively reviewed for bleeding events associated with ketorolac. Data included gestational age (GA), corrected gestational age (CGA) at the time of ketorolac, serum creatinine, platelet count, urine output (in milliliters per kilogram per hour), concomitant medications, enteral feeds, number of ketorolac doses, and surgical procedure performed.

Results

Of 57 patients, 10 (17.2%) demonstrated a bleeding event. Mean CGA and serum creatinine for those with bleeding events was 39.4 weeks (P = .69) and 0.64 mg/dL (P = .03), respectively. Patients with a bleeding event received ketorolac at a mean of 20.7 days of life with 70% receiving the drug at less than 14 days of age, whereas those without a bleeding event received ketorolac at a mean of 31.9 days (P = .04). Bleeding events correlated with glomerular filtration rate of less than 30 mL/min/1.73 m² or concomitant medications in all but 1 patient.

Conclusions

Infants younger than 21 days and less than 37 weeks CGA are at significantly increased risk for bleeding events and should not be candidates for ketorolac therapy.     

Comparison of intramuscular ketorolac and morphine in pain control after laparotomy

Ketorolac, a prostaglandin synthetase-inhibiting analgesic, was compared with morphine for relief of pain after laparotomy for gynaecological surgery. Eighty patients were studied; they were given either ketorolac 30 mg intramuscularly followed by 10 mg 4-hourly as required, or morphine 10 mg intramuscularly 4-hourly as required, administered in a double-blind, randomised fashion. Pain scores (verbal and visual analogue) were recorded at baseline and assessed at 30 and 60 minutes and then hourly for 6 hours. Pain relief was measured at the same times. Pain and pain-relief scores were further assessed on the evening of day 1 and at 24 hours. Pain scores were similar in the two groups but pain-relief scores were better in the morphine group. A considerable number of patients suffered postoperative nausea and vomiting but there was no difference between the groups. One patient in the ketorolac group had unexplained hypotension. It is concluded that ketorolac can provide effective postoperative analgesia.     

Intra-operative ketorolac 15 mg versus 30 mg for analgesia following cesarean delivery: a retrospective study

BackgroundKetorolac is a nonsteroidal anti-inflammatory drug used as part of multimodal analgesia in women undergoing cesarean delivery. The lowest effective dose of ketorolac that best optimizes analgesia without increasing side effects is unclear. We performed this retrospective study to compare the analgesic efficacy of 15 mg or 30 mg ketorolac administered intra-operatively to our obstetric population.MethodsWe included patients who underwent cesarean delivery under neuraxial anesthesia and received 15 mg or 30 mg of ketorolac intra-operatively. Our multimodal analgesic regimen is standardized and includes 150 µg spinal or 3 mg epidural morphine, 975 mg rectal acetaminophen, and 15–30 mg intravenous ketorolac within 15 min of surgery completion. The primary outcome was opioid use in the first 6 h after surgery. Secondary outcomes were opioid use at 24 and 48 h, opioid dose, pain scores, breastfeeding, postoperative serum creatinine and need for rescue anti-emetics.ResultsOne-thousand-three-hundred and forty-nine patients were analyzed (15 mg ketorolac n=999; 30 mg n=350). There was no difference between the two groups in patient demographics or intra-operative characteristics. There was no significant difference between groups for opioid use at 6 h after surgery (50.3% vs 52.0%, odds ratio [95% confidence interval] 1.13 [0.87 to 1.47]). There were also no significant differences between the groups for secondary outcomes.ConclusionsThere was no difference in opioid use between patients receiving either a 15 mg or a 30 mg dose of ketorolac given intra-operatively for postoperative analgesia following cesarean delivery.