Departments of 1Otorhinolaryngology, 2Anaesthesiology and Intensive Care and 3Pharmacy, Kuopio University Hospital, PO Box 1777, FIN-70211 Kuopio, Finland*Corresponding author
Accepted for publication: October 10, 2000
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Abstract |
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Br J Anaesth 2001; 86: 37781
Keywords: pain, post-operative; surgery, otolaryngological; analgesics non-opioid, ketoprofen; complications, post-operative; clinical trials
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Introduction |
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Non-steroidal anti-inflammatory drugs (NSAIDs) are potent analgesics and can reduce or even eliminate the need for post-operative opioids.4 However, they may also cause adverse effects, such as gastric irritation or renal dysfunction. It is also well known that NSAIDs prolong the bleeding time by inhibiting the biosynthesis of thromboxane A2 and can increase blood loss during and after surgery even in healthy patients.5
Ketoprofen, a phenylpropionic acid derivative, has been in clinical use since 1973.6 It is a widely used analgesic in many countries and has a good safety and efficacy record. A previous study demonstrated the efficacy of ketoprofen after tonsillectomy,7 but further evaluation of the optimal time of administration and safety of ketoprofen is needed.
The aim of the present study was to evaluate the safety and efficacy of ketoprofen during tonsillectomy. We compared administration of the same dose of ketoprofen, before incision and after surgery, with a placebo group. The main study variables were pain at rest and during swallowing, need for rescue analgesic and the amount of peri-operative bleeding.
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Materials and methods |
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One hundred and six ASA I adult patients undergoing elective tonsillectomy or adenotonsillectomy were studied. Patients were allocated randomly to one of two ketoprofen groups or a placebo group. The allocation was computer generated and a sealed envelope method was used to ensure blinding. Forty-one patients received ketoprofen at induction (pre ketoprofen group) and 40 patients after surgery (post ketoprofen group); 25 patients received normal saline (placebo group).
A standardized anaesthetic technique was used. Each patient was premedicated with diazepam 0.5 mg kg1 orally up to a maximum of 15 mg, 60 min before induction of anaesthesia. Fentanyl 2 µg kg1 was given intravenously and anaesthesia was induced with thiopental 5 mg kg1. Neuromuscular blockade was achieved with cis-atracurium 0.1 mg kg1. Anaesthesia was maintained with 23% sevoflurane (inspired concentration) in 65% nitrous oxide in oxygen with intermittent positive pressure ventilation. On completion of surgery, neuromuscular blockade was reversed with neostigmine 50 µg kg1 and glycopyrrolate 10 µg kg1. For intraoperative fluid maintenance, all patients were given 0.9% saline 10 ml kg1 h1 and, after surgery, 5% glucose in 0.3% saline 2 ml kg1 h1 until able to tolerate fluids by mouth.
In the pre ketoprofen group, patients were given ketoprofen 0.5 mg kg1 (Ketorin; Orion, Espoo, Finland) intravenously, mixed with 10 ml of normal saline and injected over 5 min after induction of anaesthesia but before surgical incision, and placebo (10 ml normal saline) injected over 5 min in the postanaesthesia care unit (PACU) followed by a continuous i.v. ketoprofen infusion of 3 mg kg1 over 24 h. In the post ketoprofen group, patients were given placebo (10 ml normal saline) after induction, and ketoprofen 0.5 mg kg1 i.v. in the PACU followed by a ketoprofen infusion of 3 mg kg1 over 24 h. In the placebo group, patients were given normal saline after induction and, in the PACU, normal saline infusion. The drug syringes were prepared by a nurse not otherwise involved in the study, ensuring blinding.
All tonsillectomies were performed between 11 a.m. and 2 p.m. by six surgeons with previous experience of over 50 procedures using an electrodissection technique. Blood loss was assessed by visual estimation of blood volume in sponges and the suction bottle. A study nurse recorded the length of surgery.
Pain intensity after surgery was assessed by asking patients to express their pain on a 100 mm visual analogue scale (VAS; 0=no pain, 100=worst possible pain). Pain scores were recorded at rest and on swallowing 1, 2, 3 and 4 h after surgery in the PACU. Thereafter, on the ward, pain scores were recorded at 8 p.m. and 8 a.m., and just before discharge. At discharge, patients were also asked to rate their worst pain and the average level of pain they had experienced on the ward.
Rescue analgesic medication consisted of oxycodone 0.05 mg kg1 i.v. during the first 4 h after surgery (in the PACU) and thereafter 0.1 mg kg1 i.m. (on the ward). Rescue analgesic was given if the pain score at rest was 30. The oxycodone dose was repeated at 1530 min intervals until the pain had diminished to slight (pain score at rest <30). All rescue analgesic doses were recorded. No other analgesic medication was permitted during the study. Time to the first voiding, nausea and vomiting and all adverse effects were recorded for each patient. Bleeding was classified as minor if medical attention was required and intravenous fluid or suction of the clot was initiated, and major if electrocautery or reoperation was required.
Patients were discharged 2430 h after surgery when they had no or mild pain, were able to tolerate clear fluids and soft food, had no bleeding and had no nausea or vomiting. On discharge, all patients received a ketoprofen capsule (2 mg kg1). For post-operative pain relief at home, all patients were given ketoprofen 50 or 100 mg capsules (Ketorin) and were instructed to take two or three capsules over 24 h (35 mg kg1 day1) for 510 days. For rescue analgesia at home patients were prescribed Panacod tablets (Sanofi-Winthrop, Solna, Sweden) containing, per tablet, 500 mg paracetamol and 30 mg codeine.
The sample size was based on detecting a difference of 35% in the need for rescue analgesia between the pre and post ketoprofen groups at a 0.05 significance level with 80% power.
Statistical analysis of continuous variables was performed using the KruskalWallis test. The MannWhitney test with Bonferonni correction was used for post hoc analysis. The 2 test was used for categorical variables. Correlation between independent variables was tested with the Pearson correlation coefficient. Differences were considered statistically significant when the P value was <0.05. Results are presented as number of cases (%), mean (SD) with 10th and 90th percentiles, correlation coefficient (R) or mean difference (95% confidence intervals (CI)) as appropriate.
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Results |
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Thirty-four patients (83%) in the pre ketoprofen group, 34 (85%) in the post ketoprofen group and all 25 in the placebo group received rescue analgesia. There was no difference between the study groups with respect to the proportion of patients receiving oxycodone in the PACU. During the next 20 h, significantly more patients in the placebo group (24 patients (96%)) received oxycodone compared with the pre ketoprofen group (27 patients (66%)) (difference 30%, 95% CI: 1447%) and with the post ketoprofen group (22 patients (55%)) (difference 41%, 95% CI: 2458%) (P=0.002).
There was no statistically significant difference between the two ketoprofen groups with respect to the mean dose of rescue analgesia, but patients in the placebo group received significantly more oxycodone doses than patients in the two ketoprofen groups (P=0.001). The mean difference between the placebo group and the other two groups was the same (pre ketoprofen group, 2.6 (95% CI: 1.33.9) doses; post ketoprofen group, 2.6 (95% CI: 1.14.0) doses) (Table 2).
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Discussion |
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Pre-emptive or proactive administration of NSAIDs is justified because of the delayed action of these drugs. However, in this study, ketoprofen administered after surgery performed as well as the same dose administered before incision. This is consistent with assumptions that, in addition to its peripheral action, ketoprofen has a rapid central analgesic action.8
NSAIDs increase bleeding time but usually within normal limits.9 The reduction in thromboxane A2 biosynthesis produced by NSAIDs prevents platelet aggregation and therefore inhibits haemostasis. Whether or not the increase in blood loss during surgery is clinically significant is controversial. Ketoprofen has been used successfully in children undergoing adenoidectomy without any major peri-operative bleeding.10 The safety of ketoprofen during throat surgery may be supported by the present study, as no significant differences were found between the study groups in the amount of peri-operative bleeding. Post-tonsillectomy haemorrhage continues to pose serious problems. Over the years, the incidence of significant bleeding has decreased, but it still occurs in approximately 23% of patients.1116 In contrast to two recent studies where peri-operative use of ketoprofen did not cause post-operative bleeding,7 17 three cases of haemorrhage occurred 414 h after surgery in our study. Most studies have investigated small numbers of patients, introducing a large risk of type II error. However, some conclusions may be drawn. (i) Studies suggest that the risk of bleeding varies between different NSAIDS. In many studies, ketorolac has been associated with a higher incidence of bleeding than propionic acid derivatives (ibuprofen, naproxen or ketoprofen).7 10 15 1825 (ii) Post-tonsillectomy bleeding seems to occur with a similar incidence when paracetamol (with or without codeine) is used instead of propionic acid derivatives.20 2631 (iii) When opioids are used alone, bleeding still occurs.7 2124 Moreover, when opioids are used without background analgesia, post-operative nausea and vomiting are common. This may delay discharge.24 29 (iv) Nerve blocks and periotonsillar infiltrations with local anaesthetics have not improved anaesthesia after tonsillectomy and studies have shown that post-operative bleeding occurs as often as with other analgesic techniques.27 28 31 (v) Unlike Stoeckli and colleagues,32 we supposed that fibrin glue did not decrease post-operative pain and bleeding.
Vomiting is common after tonsillectomy and may be induced not only by swallowed blood and oropharyngeal irritation but also by opioids.7 33 We did not find any difference between the groups with respect to the incidence of vomiting, but overall it was less than reported previously.33 Opioids may have different emetic properties. We have found that fentanyl induces less vomiting than morphine.34 The present study suggests that oxycodone is also associated with a fairly low incidence of vomiting, as only 23% of our patients vomited, compared with 41% in a previous study.33
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References |
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