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© 1999 International Anesthesia Research Society
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Abstract |
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We compared the effect of IV ketoprofen and placebo as an adjuvant to epidural sufentanil analgesia after major surgery. We used a prospective, randomized, double-blinded, placebo-controlled, parallel-group study design in 54 children aged 1–15 yr who received a standardized anesthetic. Either IV ketoprofen or saline was administered in addition to an epidural sufentanil infusion, which was adjusted as required clinically. The study drug infusions were discontinued when pain scores were <3 on 0–10 scale for 6 h at a sufentanil infusion rate of 0.03 µg · kg-1 · h-1. Children in the ketoprofen group had a better analgesic effect, as shown by decreased need for sufentanil (mean [10th—90th percentiles] 8.3 [3.1–15.1] µg/kg vs 12.5 [6.2–18.9] µg/kg; P = 0.002) and earlier possibility to discontinuation of the epidural sufentanil (11 [46%] vs 3 [13%]; P = 0.014) before the end of the 72-h study period. In the ketoprofen group, median (range) pain scores were lower during activity at 24 h (2 [0–5] vs 5 [0–7]; P = 0.01) and at 72 h (0 [0–3] vs 2 [0–6]; P = 0.033), and fewer children had inadequate pain relief during activity at 24 h (0 vs 5; P = 0.037). Children who received ketoprofen required fewer infusion rate adjustments (12 [4–20] vs 17 [6–42]; P = 0.016). In the ketoprofen group, the incidence of desaturation (1 [4%] vs 6 [26%]; P = 0.035) and fever (3 [12%] vs 11 [48%]; P = 0.008) was less than that in the placebo group. We conclude that ketoprofen improved postoperative pain in children.
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 administration of epidural opioids is a safe and effective technique to manage severe pain after major surgery in children (1–4). Some studies have observed better pain relief with epidural opioid analgesia than with systemic opioids. This is particularly evident when analgesia is assessed during activity (5). When lipophilic opioids, such as sufentanil, are infused epidurally close to the spinal cord opioid receptors corresponding to the dermatome of the surgical incision, similar pain relief is achieved with a smaller dose compared with the IV infusion (6,7). However, epidural opioids are associated with adverse effects such as respiratory depression, excessive sedation, protracted vomiting, urinary retention, and pruritus (5).
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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The study protocol was approved by our ethics committee and was conducted in accordance with the Declaration of Helsinki. The parents of the patients and those children old enough to understand the planned study gave their written, informed consent.
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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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Fifty-four children were enrolled in the study. In both groups, there was one dislodged catheter. In the ketoprofen group, one infusion was stopped because of excessive sedation and one because the IV line was dislodged. In the placebo group, three infusions were stopped because pain relief was judged inadequate with the study infusions or because of the parents' request. Forty-seven children—24 in the ketoprofen group and 23 in the placebo group—completed the study following the protocol. Patient characteristics of the study groups are summarized in Table 1. There were no significant differences between the two groups with respect to age, height, weight, gender, ASA physical status, or surgery performed. No signs of local infections or infectious catheters were noted in either study group.
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Less epidural sufentanil was used in the ketoprofen group (mean [10th–90th percentiles] 8.3 [3.1–15.1] µg/kg) compared with the placebo group (12.5 [6.2–18.9] µg/kg; P = 0.002). The criteria for termination of epidural sufentanil (VAS score <3 for 6 hours with an infusion rate of 0.03 µg · kg-1 · h-1) were met in 11 (46%) children in the ketoprofen group and in 3 (13%) children in the placebo group before the planned end of the 72-h study period (P = 0.014) (Fig. 1). The use of epidural sufentanil decreased successively after 6 h in both the placebo (P < 0.05) and the ketoprofen groups (P < 0.01) (Fig. 2).
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The median (range) need for epidural infusion rate adjustment was less in the ketoprofen group (12 [4–20]) compared with the placebo group (17 [6–42]; P = 0.016). Four children (17%) in the placebo group and 3 (12%) in the ketoprofen group required bupivacaine epidurally for rescue analgesia. Epidural bupivacaine was effective in every administration, confirming the correct position of the catheter.
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 type of surgery did not seem to affect the postoperative analgesic requirements. There was no significant difference in the need for sufentanil, duration of epidural infusion, or time to meet the criteria for termination of epidural sufentanil among patients undergoing penile, lower abdominal, thoracic, and orthopedic surgery (data not shown).
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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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The results of this study show that intraoperative ketoprofen IV, followed by a constant infusion, reduced the need for epidural segmental sufentanil after major surgery in children. Simultaneously, the pain relief was more stable, especially during activity. There was also less need for infusion rate adjustments when ketoprofen was administered as an adjuvant analgesic. These findings confirm that ketoprofen is a potent analgesic in children after major surgery.
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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References |
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[Free Full Text] - Wilson PTJ, Lloyd-Thomas AR. An audit of extradural infusion analgesia in children using bupivacaine and diamorphine. Anesthesiology 1993;48:718–23.
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[Abstract/Free Full Text] - Maunuksela E-L, Olkkola KT, Korpela R. Measurement of pain in children with self-reporting and behavioral assessment. Clin Pharmacol Ther 1987;42:137–41.[Web of Science][Medline]
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- Sweet SD, McGrath PJ. Physiological measures of pain. In: Finley GA, McGrath PJ, eds. Measurement of pain in infants and children. Seattle, WA:IASP, 1998:59–81.
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