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Pharmacology

Effect of parecoxib sodium on postoperative shivering: A randomised, double-blind clinical trial

Li, Xiuze; Zhou, Mengjun; Xia, Qing; Li, Wei; Zhang, Yonghong

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European Journal of Anaesthesiology: April 2014 - Volume 31 - Issue 4 - p 225-230
doi: 10.1097/01.EJA.0000436684.94403.1e
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Abstract

Introduction

Postoperative shivering is one of the most common problems in patients recovering from anaesthesia and surgery, with an incidence of up to 60%.1–3 It is very uncomfortable, can interfere with monitoring and may cause potential complications because of increased metabolic demand and oxygen consumption, lactic acidosis and carbon dioxide production. Patients with low cardiopulmonary reserves are at greatest potential risk.4–6

Although a variety of pharmacological therapies have been used to control postoperative shivering, including pethidine, tramadol and dexmedetomidine,3,7,8 the use of these drugs brought about many adverse effects, such as nausea and vomiting, sedation or respiratory depression. To date, no ideal drug has been found. Parecoxib sodium, a selective nonsteroidal anti-inflammatory drug, is frequently administered for postoperative pain treatment in a dose of 40 mg, and is well tolerated.9 As far as we know, there is no reported literature about the use of prophylactic parecoxib sodium for the prevention of postoperative shivering. The release of pyrogenic mediators from the surgical wound is associated with postoperative shivering,10 and we hypothesised that prophylactic parecoxib sodium might decrease the incidence and severity of postoperative shivering after general anaesthesia.

The present study was conducted to compare the effects of parecoxib sodium with the effects of tramadol and placebo on postoperative shivering, pain and sedation, and the incidence of postoperative nausea and vomiting (PONV) in patients undergoing abdominal surgery under general anaesthesia.

Materials and methods

Ethical approval for this study (Ethical Committee No. 201156) was provided by the Ethical Committee of Mianyang Central Hospital, Sichuan Province, China (Chairperson Prof. L. Cheng) on 14 October 2011. Written informed consent was obtained from each individual. One hundred and twenty adult patients graded as American Society of Anesthesiologists’ (ASA) physical status 1 or 2, aged 20 to 60 years and scheduled for elective abdominal surgery (open cholecystectomy with or without open common bile duct exploration) under general anaesthesia were enrolled in the prospective, randomised, double-blind clinical study. Patients who were allergic to any of the medications used, or who had severe cardiovascular disease, kidney or liver dysfunction, peptic ulcer, psychiatric disorders or muscle disease, received intraoperative blood or blood products, or had a history of convulsions or fever (temperature >37.5°C) were excluded from the study.

The patients did not receive premedication and received an infusion of Ringer's lactate solution after routine monitoring including ECG, noninvasive blood pressure and pulse oximetry. Intraoperatively, neuromuscular block was monitored by means of a peripheral nerve stimulator (TOF-Watch SX; Organon, Dublin, Ireland). Intravenous fluids were stored in the operating room, where the temperature was kept between 22°C and 24°C. Patients were covered with surgical drapes; none of the patients was actively warmed during or after anaesthesia.

Anaesthesia was induced with intravenous midazolam 2 mg, propofol 2 mg kg−1 and remifentanil 1 μg kg−1, and cisatracurium 0.2 mg kg−1 was administered to facilitate tracheal intubation. Anaesthesia was maintained with remifentanil 0.1 to 0.2 μg kg−1 min−1 and sevoflurane (end-tidal concentration 2 to 4%) in air/O2 to keep changes of blood pressure within 20% of the preincision values. Repeated doses of cisatracurium 0.05 mg kg−1 were given if required. Mechanical ventilation was used to maintain end-tidal carbon dioxide tension between 4.7 and 6.0 kPa. Remifentanil and sevoflurane were discontinued after the last skin suture and a bolus of fentanyl 1 μg kg−1 was administered intravenously for postoperative analgesia.

Patients were allocated randomly to one of three groups using a computer-generated random number assignment to receive parecoxib sodium 40 mg (Group P, n = 40), tramadol 2 mg kg−1 (Group T, n = 40) or an equal volume of isotonic saline (Group S, n = 40). Approximately 30 min before the end of surgery, the study drug was administered intravenously. The drugs were diluted to a volume of 5 ml and presented as coded syringes by a nurse anaesthetist who did not take part in the management of the patients. Both the patient and the person who observed the patient were unaware of the identity of the test drug or the group to which the patients were assigned. Heart rate, noninvasive blood pressure and peripheral oxygen saturation were recorded before and during surgery. Nasopharyngeal temperature was monitored continuously intraoperatively, and the temperatures at the start and end of surgery were recorded. Because no residual neuromuscular block was detected by the end of surgery (the T4/T1 values were over 90%), no reversal agents were administered. Tracheal extubation was performed after return of adequate spontaneous breathing, reflexes and responsiveness. Patients were transferred to the postanaesthetic care unit (PACU) for observation for about 1 h.

In the PACU, all patients were monitored and received oxygen via facemask. Postoperative variables were assessed immediately after arrival (T1), and 15 (T2), 30 (T3), 45 min (T4) and 1 h (T5) after arrival in the PACU by the same PACU nurse. Observations included shivering, pain and sedation scores, the incidence of PONV and respiratory depression (a respiratory rate <8 breaths per minute). Postoperative shivering was assessed using a 5-point scale:5 0, no shivering; 1, piloerection or peripheral vasoconstriction but no visible shivering; 2, muscular activity in only one muscle group; 3, muscular activity in more than one muscle group but not generalised; 4, shivering involving the whole body. Postoperative pain intensity was assessed using a numerical rating scale: 0, no pain; 10, worst pain imaginable. Sedation was graded using a 5-point scale: 0, alert; 1, arouses to voice; 2, arouses with gentle tactile stimulation; 3, arouses with vigorous tactile stimulation; and 4, no awareness. A rescue dose of pethidine 25 mg was given for the treatment of shivering of grade at least 3. If pain score exceeded 4, an intravenous injection of fentanyl (1 μg kg−1) was given. The patients did not receive a continuous infusion of analgesic drug in the postoperative period. If patients developed nausea and vomiting, intravenous metoclopramide 10 mg was administered.

Statistical analysis

The primary outcome was the incidence of postoperative shivering. Secondary outcomes were postoperative pain and sedation scores, and the incidence of PONV. We hypothesised that the incidence of postoperative shivering in the isotonic saline group would be about 60% based on previous studies,1–3 and that a 50% reduction in shivering was considered to be clinically significant. We calculated that 34 patients were required in each group (at a level of significance of 0.05 and a power of 0.80). However, we recruited 40 patients in order to compensate for dropouts. Therefore, a total of 120 patients were involved in the study.

Quantitative variables including age, weight, surgery duration, anaesthesia duration, volume of intravenous fluid and irrigation fluid, the consumption of remifentanil and fentanyl, nasopharyngeal temperature, and postoperative pain and sedation scores were described as mean and SD or median and range, and qualitative variables including sex, ASA grade, the incidences of postoperative shivering, nausea and vomiting and the number of patients receiving rescue pethidine were described as number or percentage. The data among the three groups in terms of age, weight, surgery duration, anaesthesia duration, volume of intravenous fluid and irrigation fluid, the consumption of remifentanil and fentanyl, and nasopharyngeal temperature were compared by using analysis of variance. The Chi-squared test was used to compare the differences between sex, ASA grade, the incidences of postoperative shivering and nausea and vomiting, and the number of patients receiving rescue pethidine. The severity of postoperative shivering, pain scores and sedation scores were analysed using the Wilcoxon Rank Sum test. A P value of less than 0.05 was considered to be statistically significant in all tests. SPSS 17.0 program (SPSS Inc., Chicago, Illinois, USA) was used for statistical analysis.

Results

A total of 120 patients were selected and all completed the study, as shown in Fig. 1. The patients in the three groups were comparable with regard to age, weight, sex, ASA physical status, duration of surgery, duration of anaesthesia, volumes of intravenous fluid and irrigation fluid, the consumption of remifentanil and fentanyl, and the change of nasopharyngeal temperature from the beginning to the end of surgery (Table 1). There were also no significant differences in haemodynamic parameters among the groups. Twenty-six patients in Group P, 22 in Group T and 24 in Group S required supplementary doses of cisatracurium. The number of patients who required supplementary doses of cisatracurium was comparable among the three groups. Three patients in Group P, four in Group T and 16 in Group S received rescue pethidine; the number of patients who received pethidine was significantly higher in Group S than in Groups P and T (P < 0.001) (Table 2).

Fig. 1
Fig. 1:
No captions available.
Table 1
Table 1:
Patient characteristics and intraoperative data in patients who received parecoxib 40 mg (Group P), tramadol 2 mg kg−1 (Group T) or saline (Group S)
Table 2
Table 2:
Shivering scores and the number of patients receiving pethidine in patients who received parecoxib 40 mg (Group P), tramadol 2 mg kg−1 (Group T) or saline (Group S)

Table 2 shows the shivering scores in the three groups. The overall incidence of postoperative shivering was significantly lower (P < 0.001) in the parecoxib sodium (15%) and tramadol groups (17.5%) than that in the patients who received placebo (70%). The severity of postoperative shivering was also significantly reduced by parecoxib sodium and tramadol (P < 0.001). There were no significant differences between Groups P and T in respect of the incidence and severity of postoperative shivering.

Pain scores did not differ significantly among the three groups (Table 3). The sedation scores were significantly higher in Group T than in Groups P and S for 30 min after arrival at the PACU (P < 0.05), and became comparable after 45 min; there was no significant difference between Groups P and S in terms of sedation scores (Table 3). Sedation scores at level 3 or 4 were not observed in any of the patients during their stay in PACU. None of the patients in the three groups had respiratory depression during the study period.

Table 3
Table 3:
Pain and sedation scores 0 (T1), 15 (T2), 30 (T3), 45 (T4) and 60 (T5) min after arrival in the PACU in patients who received parecoxib 40 mg (Group P), tramadol 2 mg kg−1 (Group T) or saline (Group S)

Six patients in Group P (15%), 16 patients in Group T (40%) and seven patients in Group S (17.5%) had nausea and vomiting; the incidence of PONV was significantly higher in Group T than those in Groups P and S (P = 0.016), but there was no significant difference between Groups P and S.

Discussion

The present study demonstrates that the incidence and severity of postoperative shivering were significantly reduced by parecoxib sodium. However, the parecoxib sodium group and tramadol group were not significantly different from each other with respect to the incidence and severity of shivering.

The frequency of postoperative shivering of the patients who received placebo is inconsistent with the results of other studies;1–3 this is probably because remifentanil was used for maintenance of anaesthesia, resulting in an increase in the incidence of postoperative shivering.11,12 Opioids have been shown to be one important factor that affects postoperative shivering,13 but the consumption of remifentanil and fentanyl was comparable among the three groups. Inadequate pain control has been shown to be associated with shivering.14 However, in the present study, pain scores did not differ significantly among the groups.

Young age, core hypothermia and endoscopic surgery are major risk factors for postanaesthetic shivering.15 In this study, age and change in nasopharyngeal temperature were comparable in the three groups. All patients underwent cholecystectomy with or without common bile duct exploration, and the mean durations of operation were nearly identical in the three groups. According to a systematic review, room temperature irrigation fluid can decrease body temperature and increase the incidence of postoperative shivering.16 However, the volumes of irrigation fluid used in the three groups were comparable.

Tramadol 2 mg kg−1 is an effective drug in the control of postanaesthetic shivering.8,17 However, the sedation and emetic potential of tramadol confines its clinical appliance to a certain extent.18,19 The present study also showed that the sedation scores and the incidence of PONV in the tramadol group were higher than those in patients who received isotonic saline.

This study demonstrates that parecoxib sodium is also effective in reducing postoperative shivering and is well tolerated in respect of the side-effects of sedation, nausea and vomiting. To our knowledge, there has been no previous study of the use of prophylactic parecoxib sodium for the prevention of postoperative shivering. Cyclo-oxygenase-2 (COX-2) and prostaglandin E-2 are the main fever mediators of the hypothalamus.20 Therefore, the likely mechanism of action of parecoxib sodium for the reduction of postoperative shivering is that it inhibits COX-2 and the synthesis of prostaglandins, which subsequently reduce the set point of the thermoregulatory system in the anterior hypothalamus.21

The time to reach plasma peak concentrations for tramadol and the active metabolite of parecoxib sodium is about 30 min,22,23 which is why we chose the time of 30 min before skin closure for the therapeutic intervention in each group.

A limitation of the study is that the recording times of the primary and secondary outcomes lasted only 1 h. Further studies are needed to establish the optimal dose of parecoxib sodium for the prevention of postoperative shivering and whether parecoxib sodium has a treatment effect on postoperative shivering.

In conclusion, intraoperative intravenous administration of parecoxib sodium 40 mg is effective in reducing the incidence and severity of postoperative shivering in patients undergoing abdominal surgery under general anaesthesia. Although the mechanism of the reduced incidence of postoperative shivering is unclear, administration of parecoxib sodium can be used as an alternative to tramadol for the prevention of shivering in patients with no contraindication to its use.

Acknowledgements relating to this article

Assistance with the study: the staff of the operating theatre and PACU at Mianyang Central Hospital are thanked for their friendly assistance with the study.

Financial support and sponsorship: none.

Conflicts of interest: none.

Presentation: none.

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