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Departments of
*Anesthesiology and Intensive Care and
Pharmacy, Kuopio University Hospital, Kuopio, Finland
Address correspondence and reprint requests to Hannu Kokki, MD, Department of Anesthesiology and Intensive Care, Kuopio University Hospital, PO Box 1777, FIN-70211 Kuopio, Finland. Address e-mail to hannu.kokki{at}kuh.fi
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Abstract |
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Implications: We compared the effect of the IV nonsteroidal antiinflammatory drug ketoprofen versus placebo as adjuvants to epidural opioid analgesia with sufentanil. The continuous IV nonsteroidal antiinflammatory drug improved pain after major surgery in children receiving an epidural opioid. Although ketoprofen reduced epidural sufentanil requirements, the incidence of opioid-related adverse effects was not changed.
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Introduction |
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The high incidence of adverse effects of epidural opioid analgesia may be reduced by administering an adjunctive drug that acts synergistically with the opioid. Ketoprofen, a nonsteroidal antiinflammatory drug (NSAID) structurally similar to ibuprofen, has analgesic, antiinflammatory, and antipyretic properties (8). Ketoprofen has a synergistic effect with opioids, improving the degree and quality of analgesia and reducing the incidence of adverse effects (9,10). Although ketoprofen has been used clinically since 1974, we are unaware of any reports of ketoprofen use among children to treat pain after major surgery.
The aim of the present placebo-controlled study was to determine the efficacy and safety of IV ketoprofen as an adjuvant to epidural sufentanil in children after major surgery. We hypothesized that a bolus dose of ketoprofen, followed by a constant infusion, would reduce the epidural opioid requirement, reduce the intensity and duration of postoperative pain, and reduce the adverse effects of sufentanil.
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Methods |
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Fifty-four children, ASA physical status I or II, aged 1–15 yr, scheduled for major thoracic, abdominal, genitourinary, or orthopedic surgery were enrolled in the study. Patients with a known allergy to ketoprofen or other NSAIDs, as well as those with asthma, any kidney or liver dysfunction, or hemorrhagic diathesis, were excluded. Children with a known contraindication to epidural puncture, such as increased intracranial pressure, infection at the puncture site, or neurological disorder, were also excluded.
We used a prospective, randomized, double-blinded, placebo-controlled, parallel-group study design. Children were randomized to either the ketoprofen group (n = 27) or the placebo group (n = 27) in blocks of eight to keep the number of children balanced in the study groups. After the induction of anesthesia, the children in the ketoprofen group received 1 mg/kg ketoprofen (Orudis®; Rhone-Poulence Rorer, Copenhagen, Denmark) dissolved in 10 mL of 0.9% saline injected over 10 min IV as a loading dose, followed by an infusion of 4 mg/kg ketoprofen dissolved in 50 mL of 0.9% saline over 24 h up to 72 h. Children in the placebo group received a similar volume of 0.9% saline for a loading dose and infusion. The coded test syringes and infusions were prepared by a nurse who did not participate in the study.
The children were premedicated with oral flunitrasepam (Rohypnol®; Roche, Basel, Switzerland) 0.03 mg/kg (maximum 1 mg) 60 min before induction. EMLA cream (Astra, Sodertalje, Sweden) was used for skin analgesia at the venepuncture and epidural puncture sites.
The epidural catheters were placed before the induction of general anesthesia with the patients sedated with midazolam 0.1 mg/kg IV. For epidural analgesia, a Perifix Paed 18 (B. Braun, Melsungen, Germany) extradural set containing a 50-mm, 18-gauge Tuohy needle with a 20-gauge catheter was used. The epidural catheter was passed cephalad into the epidural space corresponding to the dermatome of the surgical incision; for thoracic and abdominal surgery, we used thoracic placement; and for genitourinary and orthopedic surgery, we used lumbar placement of the catheter. Intraoperatively, no local anesthetics were given epidurally.
A standard anesthetic technique was used. Anesthesia was induced with thiopental 5 mg/kg IV, and tracheal intubation was facilitated with atracurium 0.5 mg/kg. Anesthesia was maintained with 1.5%–2.5% isoflurane (inspired concentration) in 35% oxygen in air with intermittent positive-pressure ventilation and bolus doses of atracurium. The inhaled anesthesia was supplemented with epidural sufentanil 5 µg/mL (Sufenta®; Janssen Cilag, Beerse, The Netherlands). Sufentanil was diluted to a concentration of 1 µg/mL, and the infusion was started at the induction of the anesthesia. During surgery, the infusion rate was 0.2 µg · kg-1 · h-1. After the procedure, neuromuscular block was antagonized with neostigmine 50 µg/kg and glycopyrronium 10 µg/kg.
All children were given 0.9% saline 10 mL · kg-1 · h-1 IV for intraoperative fluid maintenance during surgery and 5% glucose in 0.3% saline 2–4 mL · kg-1 · h-1 IV after surgery until they were able to drink.
The children were transferred to a postanesthesia care unit for the first 24 h postoperatively for continuous monitoring of vital signs and assessment of pain and adverse effects. The children were observed by specially trained study nurses. The epidural sufentanil infusion was started at the induction of anesthesia with an initial infusion rate of 0.2 µg · kg-1 · h-1. If analgesia was inadequate, a bolus dose of 0.1 µg/kg was given, and the infusion rate was increased by 20%–30%. The infusion rate of epidural sufentanil was adjusted stepwise by 30% to keep the pain score 
3 at rest and 5 during activity using the modified Maunuksela pain scale (11) or on a 100-mm visual analog scale (VAS) on two subsequent observations. The maximal infusion rate was set at 0.3 µg · kg-1 · h-1. If adequate pain relief was not achieved with the maximal infusion rate and two extra boluses in an hour, a 0.25-mg/kg bolus dose of bupivacaine 2.5 mg/mL was administered epidurally for rescue analgesia. The epidural infusion was discontinued when the child was pain-free for 6 h with an infusion rate of 0.03 µg · kg-1 · h-1. No other analgesics were permitted during the study.
During the first 24 h, the following variables were recorded on a follow-up chart every hour and thereafter every 1–4 h: epidural infusion rate, epidural bolus doses, respiratory rate, SpO2, sedation on a 5-point scale (0 = full alert to 4 = not arousable), blood pressure, and pulse rate. Pain at rest and during activity was evaluated by using a 100-mm VAS and the modified Maunuksela pain scale. The modification consisted of expansion of the original scale from 0–9 to 0–10 (0 = no pain, 10 = worst possible pain) to facilitate comparisons with the 100-mm VAS scale. The need for epidural sufentanil was calculated for each child, and the number of dose adjustments of the epidural infusion was counted. All adverse effects were recorded.
Based on our previous experiences with epidural sufentanil analgesia in children, we made a power analysis that suggested that 24 children would need to be enrolled in both study groups to provide an 80% chance of detecting a 30% reduction in the use of epidural sufentanil at the 0.05 level of significance. For statistical analysis of the categorical data (gender, ASA physical status, need for rescue analgesia, and number of children with adverse effects) and proportions of children receiving epidural pain treatment, a 
2 test of independence and Fisher's exact test were used. For continuous data with uneven distribution (height, weight, and age of the children; amount of epidural sufentanil administered; observed pain scores; and epidural dose adjustments), the Mann-Whitney U-test was used. Within the study groups, the differences in the use of sufentanil at 24, 48, and 72 h compared with the use at 6 h were tested using Wilcoxon's signed ranks test. Wilcoxon's signed ranks test was used also to compare the observed and expressed pain scores. For repeated comparisons, the Bonferroni correction was used. For post hoc analysis among the three different types of surgery, the Kruskall-Wallis test was used. A P value of 0.05 was considered statistically significant. The results are presented as number of cases, mean, median, range, or 10th–90th percentiles as appropriate.
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Results |
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There was no significant difference in the resting pain scores between the groups. However, during activity, the observed pain scores were lower in the ketoprofen group at 24 h (P = 0.01) and at 72 h (P = 0.033) (Table 2). In the placebo group, inadequate pain relief was significantly more frequent at 24 h, as judged using pain scores during activity (P = 0.037) (Table 3). In those 31 children who were able to use the VAS, the correlation between the observed and expressed pain scores was high at every observation time (P = 0.001). Although the observed scores were slightly lower compared with the reported pain scores, the differences were not significant.
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The incidence of adverse effects is presented in Table 4. There was a significantly higher occurrence of desaturation (SpO2 <90%) in the placebo group (P < 0.035). Postoperative fever was detected more often in the placebo group (P < 0.008). The other adverse effects were similar in both groups. One patient in the placebo group underwent a reoperation because of postoperative fever and possible bleeding 16 h after the study infusion.
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Discussion |
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The use of NSAIDs reduces the need for opioids after surgery by approximately one-third (12,13). In the present study, such a reduction was shown just after 36 h. We can only speculate whether a more marked reduction could have been produced with a larger dose of ketoprofen, as there is no dose recommendation for a continuous infusion in children. After adenoidectomy, intraoperative bolus doses of 0.5 mg/kg and 2.0 mg/kg ketoprofen were shown to be equianalgesic (10). Further investigations are required to determine the optimal IV ketoprofen dose regimen for children after major surgery.
Accurate pain assessment is important when the epidural opioid infusion is tailored individually. Pain assessment in children is difficult because of their limited understanding and verbal abilities. In this study, we used the Maunuksela pain scale, which has been validated for use in children of both genders aged 1–17 yr (11). Because accurate pain assessment is difficult among children of different ages and cognitive abilities, using a multidimensional pain measurement such as the Maunuksela pain scale has been recommended (14). Not all variability of the Maunuksela pain scale can be related to pain: operation stress can also cause changes in both behavioral and cardiorespiratory variables. However, the high correlation between the observed and expressed pain scores in the present study support the findings of Maunuksela et al. (11) that these pain scores can be used in clinical analgesic studies in children.
The most feared complication of an epidural opioidinfusion is respiratory depression. In the present study, we did not notice a low respiratory rate in any children. Mild desaturations while the patients breathed room air after thoracoplasty/thoracotomy recovered with oxygen administration. Desaturations were more common among children in the placebo group. This could be explained by the increased need for epidural sufentanil in the placebo group.
In previous reports, the incidence of pruritus during an epidural opioid infusion in children has varied between 0% and 5% (15,16), in contrast to the 34% incidence in the present study and a 20%–93% incidence in adults (17). This difference can be explained by the close monitoring of the children in the present study, because itching may be difficult to detect unless special attention is paid to scratching. The incidence of pruritus was not less in the ketoprofen group, although prostaglandins E1 and E2 are involved in perception of pruritus by modulating C-fiber transmission, and opioid-induced pruritus is suggested to be less with smaller doses of epidural opioid (18).
Like other NSAIDs, ketoprofen has antipyretic activity. Hence, it was not a surprise that the incidence of fever was less in the ketoprofen group. However, ketoprofen did not mask clinically important fever, because one child in the ketoprofen group was diagnosed as having an acute otitis media. In the present study, most of the children had a urinary catheter; of those 18 without catheters, one-third had difficulties in passing urine. Thus, the use of a bladder catheter or regular checking of the bladder is essential to avoid urinary retention whenever an epidural opioid is used.
In conclusion, continuous IV ketoprofen improved postoperative pain and reduced epidural sufentanil requirements. However, the incidence of opioid-related adverse effects was not changed.
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This article has been cited by other articles:
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  G. B. Hammer Pediatric Thoracic Anesthesia Anesth. Analg., June 1, 2001; 92(6): 1449 - 1464. [Full Text] [PDF]
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 C. Lejus, D. Schwoerer, I. Furic, J.-P. Le Moing, J.-C. Levron, and M. Pinaud Fentanyl versus sufentanil: plasma concentrations during continuous epidural postoperative infusion in children Br. J. Anaesth., October 1, 2000; 85(4): 615 - 617. [Abstract] [Full Text] [PDF]
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