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1 2 3 4 5 6 journal homepage: www.JournalofSurgicalResearch.com 7 8 9 10 11 12 13 14 15 a,1 Yan Chen,b,1 Kai-zhi Lu,b and Jie Chenb,* 16 Q19 Q1 Hong Shen, 17 a Department of Radiology, Chongqing Fifth Hospital, Chongqing, China 18 Q2 Q3 b Department of Anaesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China 19 20 21 article info abstract 22 23 Background: Shivering is the most common complication during the recovery period after 24 Q4 Article history: general anesthesia, and there is no clear consensus about the best strategy for its pro25 Received 29 April 2014 26 phylactic. The aim of the study was to evaluate the efficacy of parecoxib in prevention of Received in revised form 27 postoperative shivering. 26 January 2015 28 Methods: Eighty patients with American Society of Anesthesiologists physical status IeII, Accepted 10 March 2015 29 who were scheduled for minor urological surgeries under general anesthesia, were Available online xxx 30 randomly assigned to two groups (n ¼ 40 in each group): group P received 40 mg of par31 ecoxib by intravenous bolus injection and group S received the same volume of normal Keywords: 32 saline in the same way just after the induction of anesthesia. Hemodynamic parameters Parecoxib 33 and body temperatures including tympanic and axillary temperature were monitored. The Postoperative shivering 34 occurrence of shivering and pain intensity score were recorded during the recovery period. General anesthesia 35 Results: Parecoxib significantly reduced the incidence and severity of shivering in com36 37 parison with the placebo. Postoperative shivering was observed in 22 patients in group S 38 (55%), compared with nine in group P (22.5%) (P ¼ 0.003). In addition, pain intensity scores 39 were lower in group P during recovery period; consequently, less rescue analgesics were 40 required in group P when compared with group S (P ¼ 0.001). Regarding the body tem41 perature, it was found that core temperature decreased but peripheral temperature 42 increased significantly in both groups. There was no significant difference between groups 43 in all time intervals. 44 Conclusions: Prophylactic administration of parecoxib produces dual effects on antishiver45 ing and postoperative analgesia. This implies that cyclooxygenase 2/prostaglandin H2 46 pathways may be involved in the regulation of shivering. 47 Q5 ª 2015 Elsevier Inc. All rights reserved. 48 49 50 51 1. Introduction postoperative pain, increased oxygen consumption, carbon di52 53 oxide production, and raised intraocular and intracranial pres54 Postoperative shivering is a common complication that occurs in sures [1e4]. Hence, the best way to avoid these secondary 55 30%e60% of patients during their recovery period [1]. This unundesirable effects is to prevent shivering in the first place. 56 pleasant physiological response may cause a lot of physiological Cyclooxygenase 2 (COX-2) is a rate-limiting enzyme in the 57 disturbances such as hypoxemia, lactic acidosis, aggravated conversion of arachidonic acid to prostaglandins, and its 58 59 60 * Corresponding author. Department of Anaesthesiology, Southwest Hospital, Third Military Medical University, Gaotanyan 30 Street, 61 Shapingba, Chongqing 400038, PR China. Tel.: þ86 23 65463270; fax: þ86 23 65463285. 62 E-mail address: [email protected] (J. Chen). 1 63 These authors contributed equally to this work. 64 0022-4804/$ e see front matter ª 2015 Elsevier Inc. All rights reserved. 65 http://dx.doi.org/10.1016/j.jss.2015.03.011
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Parecoxib for the prevention of shivering after general anesthesia
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product prostaglandin E2 (PGE2) plays a key role in thermo131 regulatory pathways [5,6]. In animal models, direct injections 132 influenced body temperature and shivering [7,8]. of PGE 2 133 Overexpression of COX-2 in the brain exacerbated febrile 134 response induced by lipopolysaccharide in mouse [9]. All 135 136 these observations suggest that the COX-2/PGE2 pathway 137 plays a critical role in body temperature and shivering 138 process. Parecoxib is the first injectable and highly selective 139 COX-2 inhibitor [10,11] that may affect perioperative thermo140 regulation and shivering. Therefore, we evaluated the efficacy 141 of prophylactic administration of parecoxib in preventing the 142 postoperative shivering and pain in patients undergoing 143 general anesthesia, in a randomized, placebo-controlled, 144 double-blind study. 145 146 147 148 2. Materials and methods 149 150 This was a prospective, randomized and blinded study, which 151 had been registered (UMIN000008532) in UMIN Clinical Trials 152 Q6 Registry. Ethical approval for the study was obtained from the 153 Ethics Committee of Southwest Hospital, Third Military 154 Medical University, Chongqing, China (Chairperson Prof. Jun 155 Wu) and written informed consents were obtained from all 156 participants. 157 Inclusion criteria were age between 20 and 60 y and 158 159 American Society of Anesthesiologists (ASA) physical status 160 IeII. Patients with cardiac, pulmonary, hepatic, renal, thyroid, 161 or neuromuscular disease, body mass index 35, and 162 those who took chronic drug or abused alcohol were excluded. 163 Additionally, operations that were anticipated to be more than 164 90 min were excluded. Patients with anemia (Hb 40 U/L, alanine amino166 transferase >40 U/L) and renal insufficiency (serum creatinine 167 >1.5 mg/dL), hypertension, gastrointestinal bleeding, an 168 initial core temperature >37.5 C or 40 mm received a single dose of fentanyl (50 mg) IV. If patient suffered from severe nausea and vomiting, a dose of metoclopramide was administered IV (normally 10 mg and a maximum of 30 mg according to the situation of patient).
2.1.
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Statistical analysis
The primary outcome variable was the incidence of postoperative shivering. The secondary outcome variables included (1) pain intensity assessed through VAS scores during the first postoperative hour; (2) change in core and peripheral temperature during perioperative period; (3) change in hemodynamic parameters during perioperative period; (4) the number of patients requiring rescue medication during the first postoperative hour; and (5) the frequency of adverse events during the first postoperative hour. The power of the study was calculated from previous investigations, which found that the incidence of postoperative shivering could be up to 40%e65% [1,14]. We anticipated an incidence of shivering as 60% in the placebo group and a reduction to 20% with an effective medication such as parecoxib. On the basis of a two-sided alpha of 0.05 and a beta error of 0.2, we prospectively calculated that a minimum of 29 patients in each group were needed to allow the detection of a difference between groups with a power of 80%. In our study, 40 patients were recruited in each group in case there were expulsion cases. Statistical analysis was performed by SPSS version 17.0 (SPSS Inc, Chicago, IL). Data distribution was evaluated with the Shapiro-Wilk’s test. Parametric data were analyzed by a two-tailed independent t-test or an analysis of variance for repeated measures as needed. Nonparametric data were assessed by the Wilcoxon rank sum test. Category data were analyzed by the chi-square test or the Fisher exact test, as appropriate. Values were reported as the mean standard deviation, absolute number (n), or percentages. A P value ＜0.05 was set as statistically significant.
3.
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Results
A total of 80 patients were selected and all completed the study, as shown in Figure 1. There were no significant differences between the groups regarding patient demographic characteristics, ASA physical status, duration of surgery and anesthesia, and extubation time (Table 1). Rescue antiemetics were required by two patients in the saline group and three patients in the parecoxib group, with no significant differences observed between the two groups (Table 1). However, none of the patients in the parecoxib group were given fentanyl during the postoperative recovery period, whereas six patients in the saline group needed fentanyl rescue to treat postoperative pain (P ¼ 0.026; Table 1). Postoperative shivering was observed in 22 patients in the saline group (55%) and nine in the parecoxib group (22.5%) (Table 2). The overall incidence of shivering was higher in the saline group than in the parecoxib group (P ¼ 0.003). Sixteen percent of the patients (13/80) experienced shivering at grade 2 and 3 and required treatment. It is noted that the number of patients with a shivering grade of 2 and 3 was significantly higher in the saline group than that in the parecoxib group (P ¼ 0.006). In addition, there was no shivering at grade 3 noted in the parecoxib group (Table 2). However, there were no statistical significant differences in the duration of shivering between the parecoxib and saline groups (Table 2). Figures 2 and 3 showed the changes in tympanic and axillary temperatures during anesthesia and recovery periods, respectively. It could be observed in both groups that the tympanic temperature decreased but the axillary temperature increased significantly when compared with their baselines (P < 0.0001 and P < 0.005, respectively); however, there were no significant differences in temperature between the two groups at any time interval. Throughout the study period, there were no significant differences in mean arterial pressure (MAP) and heart rate between the groups at any measured data point (Table 3). MAP was significantly lower at T0 in the parecoxib group compared with all other time points (P < 0.05). In the saline group, MAP
Fig. 1 e Flowchart of patients through the trial study. 5.2.0 DTD YJSRE13190_proof 9 April 2015 8:49 pm ce
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Table 1 e Demographic characteristics and perioperative data.
Age (y) Weight (kg) Gender (Male/Female) American Society of Anesthesiologists physical status I/II Body mass index (kg/m2) Anesthetics Fentanyl (mg) Midazolam (mg) Propofol (mg) Volume of Ringer’s solution (mL) Duration of surgery (min) Duration of anesthesia (min) Extubation time (min) Patients receiving fentanyl rescue (n) Patients receiving metoclopramide rescue (n)
Group P (n ¼ 40)
Group S (n ¼ 40)
49.9 15.3 60.9 9.6 23/17 35/5
51.9 13.6 61.7 10.3 27/13 38/2
23.5 3.0
23.6 3.6
121.8 6.1 121.8 779.0 42.8 51.5 7.2 0
19.2 1.0 19.2 221.1 12.7 14.0 2.0
3
123.4 6.2 123.4 877.2 44.5 57.1 7.3
20.7 1.0 20.7 229.4 12.6 12.8 1.9 6* 2
Data are expressed the as mean standard deviation or number of patients. * P < 0.05 compared with the group P.
was significantly lower at T0 compared with T1e3 (P < 0.01). Heart rate was significantly lower at T0 compared with other time points in the parecoxib group (P < 0.05). The average pain intensity scores (VAS) in the recovery room were higher in the saline group than that in the parecoxib group at all time points (P < 0.0001; Table 3). No patient with a VAS >40 mm was observed in the parecoxib group. There were no statistically significant differences with respect to postoperative nausea and vomiting between the two groups. No other serious adverse events, such as undesired sedation, respiratory depression, strokes, or fatal and nonfatal myocardial infarctions, were observed during the trial period (Table 4).
4.
Discussion
The main finding of this study was that prophylactic administration of parecoxib could effectively decrease the incidence
Fig. 2 e Change in core temperature with time. Data are shown as the mean with standard deviation error bars. io0, io10, io20, io30, and io40 indicate the zeroth, 10th, 20th, 30th, and 40th minute after induction of anesthesia, respectively. Similarly, po1, po20, and po60 indicate the first, 20th, and 60th minute after removal of the laryngeal mask airway. Temperature in both groups decreased significantly from their baselines (*P < 0.0001), but there were no significant differences between groups. io, intraoperative; po, postoperative.
and severity of shivering related to general anesthesia without significant adverse effects in the postoperative period. Intraoperative hypothermia is the major risk factor for postoperative shivering, but shivering can occur in normothermic patients as well [15,16]. More risk factors may accompany with shivering, such as decreased sympathetic activity, recovery of spinal activity, adrenal suppression, the release of pyrogenic substances during surgery, pain or opiate withdrawal, administration of volatile anesthetics, blood loss, and duration of surgery [1,4,13e17]. Regarding the mechanism of shivering, its birthplace is considered to be posterior hypothalamus and its activity is modulated by inputs from the cold receptors. It is normally inhibited by impulses from the preoptic anterior hypothalamic area, but if the cold impulses exceed the rate at which the former impulses may be received, the starting point for shivering is activated and sends impulses bilaterally into the anterior motor neurons of the spinal cord [1]. During general anesthesia, patients are protected against thermoregulatory responses by an increase of warm-response thresholds and a decrease of cold-response thresholds, such that the normal
Table 2 e Number and grades of postoperative shivering in the postanesthetic care unit.
Number of patients with shivering Grade of shivering (0/1/2/3) Duration of shivering (min) 95% CI of the occurrence of shivering (OR)
Group P (n ¼ 40)
Group S (n ¼ 40)
9
22*
31/7/2/0 18/11/5/6 12.9 3.8 14.4 4.3 1.60e11.09 (4.21)
CI ¼ confidence interval; OR ¼ odds ratio. Data are expressed as the mean standard deviation or number of patients. * P < 0.05 compared with the group P.
Fig. 3 e Change in peripheral temperature with time. Data, label, and caption are shown in the same way as Figure 2. Temperature in both groups increased significantly from their baselines (*P < 0.005), but there were no significant differences between groups.
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Table 3 e Hemodynamic parameters and VAS. Group P (n ¼ 40) MAP (mm Hg) T0 T1 T2 T3 T4 HR (beats/min) T0 T1 T2 T3 T4 VAS (mm) T2 T3 T4
Group S (n ¼ 40)
83.1 89.8 99.5 96.9 91.3
12.8* 15.6 11.8 16.7 19.9
83.2 88.0 96.7 92.7 85.9
14.6y 18.0 13.5 17.6 14.2
79.5 83.8 86.8 85.8 87.0
17.0* 18.5 13.7 14.1 16.7
78.0 82.4 80.1 80.4 83.0
14.2 11.2 14.5 14.4 13.6
33.9 17.3z 34.3 14.4z 32.4 12.6z
15.3 8.9 14.2 7.7 13.5 6.9
Data are shown as the mean standard deviation. HR ¼ heart rate; MAP ¼ mean arterial pressure; PACU ¼ postanesthetic care unit; T0 ¼ before induction of anesthesia; T1 ¼ end of surgery; T2 ¼ 1 min after arrival in the PACU; T3 ¼ 20 min after arrival in the PACU; T4 ¼ 60 min after arrival in the PACU; VAS ¼ visual analog scale. * P < 0.05, when compared with other time points in the same group. y P < 0.01, when compared with T1e3 in the same group. z P < 0.0001, when compared with the group P.
interthreshold range, between which no effector response occurs, is expanded to 0.4 Cd4.0 C [18]. During recovery from anesthesia, thermoregulation is no longer inhibited so that the shivering is triggered when the temperature is reduced less than the thermoregulatory threshold [19]. The exact mechanism by which parecoxib prevents shivering is still not clear. A possible explanation is that COX-2/PGE2 pathway is involved in the action of parecoxib. It is generally known that COX-2/PGE2 pathway plays a critical role in thermoregulatory pathways [5,6]. Peng et al. [20] reported that parecoxib inhibited hippocampal COX-2 expression and PGH2 synthesis through downregulation of the COX-2/PGH2 pathway during perioperative period. We suppose that the effect of parecoxib on postoperative shivering is likely to be secondary to its anti-inflammatory activity through inhibition of COX-2 expression and PGH2 synthesis at the level of hypothalamus, where the bulk of thermoregulatory control occurs. The inhibitory effect probably results in a generalized thermoregulatory inhibition in
the hypothalamus during perioperative period. This explanation was supported by our clinical data on perioperative temperature. The anticipated core-to-peripheral tissue temperature gradient after the induction of general anesthesia was characterized by an approximate 1 C decrease in core temperature within the first 20e30 min, followed by an increase in peripheral skin temperature [21,22]. This phenomenon was unchanged in our patients who received parecoxib. Thus, the antishivering effect of parecoxib may be independent of intraoperative core hypothermia, suggesting that it inhibits thermoregulatory responses by a central mechanism [22]. In addition, the analgesic effects of parecoxib may be another reason for the reduction of postoperative shivering. Postoperative surgical pain has been shown to make the nonthermoregulatory shivering happen [23]. Analgesic agents, such as meperidine and sufentanil, have been shown to prevent postoperative shivering via the m- or b-receptors [24]. Parecoxib is known to produce analgesia by inhibiting COX-2 expression and PGH2 synthesis, and has been recommended for postoperative analgesia [10,11]. In the present study, the pain scores and analgesic requirements were significant reductions in the parecoxib group during recovery from anesthesia. The antishivering effect of parecoxib might result from a downregulation of the COX-2/PGH2 pathway. Parecoxib appears to be a safe and rapidly effective agent with some minor adverse effects such as hemodynamic changes associated with its administration [10,11,25]. However, these adverse effects were not observed in our study, possibly because of our study protocol. Parecoxib was administered as a bolus for one-time-only and contraindicated in patients with hypertension or at high risk for cardiovascular disease. In the present study, we did not observe any detrimental effect in recovery time after general anesthesia in the parecoxib group. None of our patients had major adverse events such as undesired sedation, respiratory depression, strokes, or fatal and nonfatal myocardial infarctions during the trial period. A limitation of our study was that we did not evaluate the effects of parecoxib with various doses, and a standard dose (40 mg) was given to all patients. It remains unclear whether a higher or lower dose of parecoxib will be more effective in preventing shivering in some patients. Furthermore, we did not include a positive control group using an established agent such as meperidine. To include another group with positive agent in future study may provide more useful information.
5. Table 4 e Incidence of adverse events during the first postoperative hour.
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Nausea, n (%) Vomiting, n (%) Undesired sedation, n Respiratory depression, n Strokes, n Myocardial infarction, n
Group P (n ¼ 40)
Group S (n ¼ 40)
P value
12 (30%) 8 (20%) 0 0 0 0
14 (35%) 7 (17.5%) 0 0 0 0
0.812 1.000 NA NA NA NA
Data are presented as the number (percent).
5
Conclusions
Prophylactic administration of parecoxib provides dual advantage of antishivering and analgesic effect without influencing hemodynamics and postoperative recovery. COX2/PGH2 pathways seem to be involved in the central thermoregulation, leading to an effective reduction of shivering.
Acknowledgment Author contributions: All authors were involved in the form and/or study design and contributed critically to the final
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preparation of the article, including approving the final version of the manuscript. In particular, J.C. conceived and designed the study, wrote the final study protocol, collected the results, analyzed the data, and drafted the manuscript. Y.C. assisted in implementing the study, advised at various stages, from protocol design to data interpretation, and assisted revising the manuscript. H.S. analyzed and interpreted the data. K.Z.L. was as a general advisor most helpful in assisting throughout and in the interpretation of data.
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.
references
[1] Buggy DJ, Crossley AWA. Thermoregulation, mild perioperative hypothermia and postanaesthic shivering. Br J Anaesth 2000;84:615. [2] Ciofolo MJ, Clergue F, Devilliers C, Ben Ammar M, Viars P. Changes in ventilation, oxygen uptake, and carbon dioxide output during recovery from isoflurance anesthesia. Anesthesiology 1989;70:737. [3] Macintyre PE, Pavlin EG, Dwersteg JF. Effect of meperidine on oxygen consumption, carbon dioxide production, and respiratory gas exchange in postanesthesia shivering. Anesth Analg 1987;66:751. [4] Alfonsi P. Postanaesthetic shivering. Epidemiology, pathophysiology, and approaches to prevention and management. Drugs 2001;61:2193. [5] Saper CB. Neurobiological basis of fever. Ann N Y Acad Sci 1998;29:90. [6] Morrison SF, Nakamura K. Central neural pathways for thermoregulation. Front Biosci (Landmark Ed) 2011;16:74. [7] De Saedeleer V, Wechsung E, Houvenaghel A. Effect of infusion of a diarrheogenic dose of PGE2 on gastrointestinal electrical activity in the conscious piglet. Prostaglandins Leukot Essent Fatty Acids 1992;45:67. [8] Amir S, Schiavetto A. Injection of prostaglandin E2 into the anterior hypothalamic preoptic area activates brown adipose tissue thermogenesis in the rat. Brain Res 1990;24:138. [9] Vidensky S, Zhang Y, Hand T, et al. Neuronal overexpression of COX-2 results in dominant production of PGE2 and altered fever response. Neuromolecular Med 2003;3:15.
[10] Nong L, Sun Y, Tian Y, Li H, Li H. Effects of parecoxib on morphine analgesia after gynecology tumor operation: a randomized trial of parecoxib used in postsurgical pain management. J Surg Res 2013;183:821. [11] Bunyavejchevin S, Prayoonwech C, Sriprajittichai P. Preemptive analgesic efficacy of parecoxib vs placebo in infertile women undergoing diagnostic laparoscopy: randomized controlled trial. J Minim Invasive Gynecol 2012; 19:585. [12] Du Manoir B, Aubrun F, Langlois M, et al. Randomized prospective study of the analgesic effect of nefopam after orthopaedic surgery. Br J Anaesth 2003;91:836. [13] Bicer C, Esmaoglu A, Akin A, Boyaci A. Dexmedetomidine and meperidine prevent postanaesthetic shivering. Eur J Anaesthesiol 2006;23:149. [14] Sessler DI. Perioperative heat balance. Anesthesiology 2000; 92:578. [15] Horn EP, Sessler DI, Staandl T, et al. Non-thermoregulatory shivering in patients recovering from isoflurane or desflurane anesthesia. Anesthesiology 1998;89:878. [16] Panzer O, Ghazanfari N, Sessler DI, et al. Shivering and shivering-like tremor during labor with and without epidural analgesia. Anesthesiology 1999;90:1609. [17] Elvan EG, Oc B, Uzun S, Karabulut E, Coskun F, Aypar U. Dexmedetomidine and postoperative shivering in patients undergoing elective abdominal hysterectomy. Eur J Anaesthesiol 2008;25:357. [18] Sessler DI. Central thermoregulatory inhibition by general anesthesia. Anesthesiology 1991;75:557. [19] Cheong KF, Low TC. Propofol and postanaesthetic shivering. Anaesthesia 1995;50:550. [20] Peng M, Wang YL, Wang FF, Chen C, Wang CY. The cyclooxygenase-2 inhibitor parecoxib inhibits surgeryinduced proinflammatory cytokine expression in the hippocampus in aged rats. J Surg Res 2012;178:e1. [21] Matsukawa T, Sessler DI, Sessler AM, et al. Heat flow and distribution during induction of general anesthesia. Anesthesiology 1995;82:662. [22] Powell RM, Buggy DJ. Ondansetron given before induction of anesthesia reduces shivering after general anesthesia. Anesth Analg 2000;90:1423. [23] Horn EP, Schroeder F, Wilhelm S, et al. Postoperative pain facilitates nonthermoregulatory tremor. Anesthesiology 1999;91:979. [24] Alfonsi P, Sessler DI, Du Manoir B, Levron JC, Le Moing JP, Chauvin M. The effect of meperidine and sufentanil on the shivering threshold in postoperative patients. Anesthesiology 1998;89:43. [25] Zhan J, Ding EL, Song Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials. JAMA 2006;296:1619.
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1 2 3 4 5 6 journal homepage: www.JournalofSurgicalResearch.com 7 8 9 10 11 12 13 14 15 a,1 Yan Chen,b,1 Kai-zhi Lu,b and Jie Chenb,* 16 Q19 Q1 Hong Shen, 17 a Department of Radiology, Chongqing Fifth Hospital, Chongqing, China 18 Q2 Q3 b Department of Anaesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China 19 20 21 article info abstract 22 23 Background: Shivering is the most common complication during the recovery period after 24 Q4 Article history: general anesthesia, and there is no clear consensus about the best strategy for its pro25 Received 29 April 2014 26 phylactic. The aim of the study was to evaluate the efficacy of parecoxib in prevention of Received in revised form 27 postoperative shivering. 26 January 2015 28 Methods: Eighty patients with American Society of Anesthesiologists physical status IeII, Accepted 10 March 2015 29 who were scheduled for minor urological surgeries under general anesthesia, were Available online xxx 30 randomly assigned to two groups (n ¼ 40 in each group): group P received 40 mg of par31 ecoxib by intravenous bolus injection and group S received the same volume of normal Keywords: 32 saline in the same way just after the induction of anesthesia. Hemodynamic parameters Parecoxib 33 and body temperatures including tympanic and axillary temperature were monitored. The Postoperative shivering 34 occurrence of shivering and pain intensity score were recorded during the recovery period. General anesthesia 35 Results: Parecoxib significantly reduced the incidence and severity of shivering in com36 37 parison with the placebo. Postoperative shivering was observed in 22 patients in group S 38 (55%), compared with nine in group P (22.5%) (P ¼ 0.003). In addition, pain intensity scores 39 were lower in group P during recovery period; consequently, less rescue analgesics were 40 required in group P when compared with group S (P ¼ 0.001). Regarding the body tem41 perature, it was found that core temperature decreased but peripheral temperature 42 increased significantly in both groups. There was no significant difference between groups 43 in all time intervals. 44 Conclusions: Prophylactic administration of parecoxib produces dual effects on antishiver45 ing and postoperative analgesia. This implies that cyclooxygenase 2/prostaglandin H2 46 pathways may be involved in the regulation of shivering. 47 Q5 ª 2015 Elsevier Inc. All rights reserved. 48 49 50 51 1. Introduction postoperative pain, increased oxygen consumption, carbon di52 53 oxide production, and raised intraocular and intracranial pres54 Postoperative shivering is a common complication that occurs in sures [1e4]. Hence, the best way to avoid these secondary 55 30%e60% of patients during their recovery period [1]. This unundesirable effects is to prevent shivering in the first place. 56 pleasant physiological response may cause a lot of physiological Cyclooxygenase 2 (COX-2) is a rate-limiting enzyme in the 57 disturbances such as hypoxemia, lactic acidosis, aggravated conversion of arachidonic acid to prostaglandins, and its 58 59 60 * Corresponding author. Department of Anaesthesiology, Southwest Hospital, Third Military Medical University, Gaotanyan 30 Street, 61 Shapingba, Chongqing 400038, PR China. Tel.: þ86 23 65463270; fax: þ86 23 65463285. 62 E-mail address: [email protected] (J. Chen). 1 63 These authors contributed equally to this work. 64 0022-4804/$ e see front matter ª 2015 Elsevier Inc. All rights reserved. 65 http://dx.doi.org/10.1016/j.jss.2015.03.011
ScienceDirect
Parecoxib for the prevention of shivering after general anesthesia
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product prostaglandin E2 (PGE2) plays a key role in thermo131 regulatory pathways [5,6]. In animal models, direct injections 132 influenced body temperature and shivering [7,8]. of PGE 2 133 Overexpression of COX-2 in the brain exacerbated febrile 134 response induced by lipopolysaccharide in mouse [9]. All 135 136 these observations suggest that the COX-2/PGE2 pathway 137 plays a critical role in body temperature and shivering 138 process. Parecoxib is the first injectable and highly selective 139 COX-2 inhibitor [10,11] that may affect perioperative thermo140 regulation and shivering. Therefore, we evaluated the efficacy 141 of prophylactic administration of parecoxib in preventing the 142 postoperative shivering and pain in patients undergoing 143 general anesthesia, in a randomized, placebo-controlled, 144 double-blind study. 145 146 147 148 2. Materials and methods 149 150 This was a prospective, randomized and blinded study, which 151 had been registered (UMIN000008532) in UMIN Clinical Trials 152 Q6 Registry. Ethical approval for the study was obtained from the 153 Ethics Committee of Southwest Hospital, Third Military 154 Medical University, Chongqing, China (Chairperson Prof. Jun 155 Wu) and written informed consents were obtained from all 156 participants. 157 Inclusion criteria were age between 20 and 60 y and 158 159 American Society of Anesthesiologists (ASA) physical status 160 IeII. Patients with cardiac, pulmonary, hepatic, renal, thyroid, 161 or neuromuscular disease, body mass index 35, and 162 those who took chronic drug or abused alcohol were excluded. 163 Additionally, operations that were anticipated to be more than 164 90 min were excluded. Patients with anemia (Hb 40 U/L, alanine amino166 transferase >40 U/L) and renal insufficiency (serum creatinine 167 >1.5 mg/dL), hypertension, gastrointestinal bleeding, an 168 initial core temperature >37.5 C or 40 mm received a single dose of fentanyl (50 mg) IV. If patient suffered from severe nausea and vomiting, a dose of metoclopramide was administered IV (normally 10 mg and a maximum of 30 mg according to the situation of patient).
2.1.
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Statistical analysis
The primary outcome variable was the incidence of postoperative shivering. The secondary outcome variables included (1) pain intensity assessed through VAS scores during the first postoperative hour; (2) change in core and peripheral temperature during perioperative period; (3) change in hemodynamic parameters during perioperative period; (4) the number of patients requiring rescue medication during the first postoperative hour; and (5) the frequency of adverse events during the first postoperative hour. The power of the study was calculated from previous investigations, which found that the incidence of postoperative shivering could be up to 40%e65% [1,14]. We anticipated an incidence of shivering as 60% in the placebo group and a reduction to 20% with an effective medication such as parecoxib. On the basis of a two-sided alpha of 0.05 and a beta error of 0.2, we prospectively calculated that a minimum of 29 patients in each group were needed to allow the detection of a difference between groups with a power of 80%. In our study, 40 patients were recruited in each group in case there were expulsion cases. Statistical analysis was performed by SPSS version 17.0 (SPSS Inc, Chicago, IL). Data distribution was evaluated with the Shapiro-Wilk’s test. Parametric data were analyzed by a two-tailed independent t-test or an analysis of variance for repeated measures as needed. Nonparametric data were assessed by the Wilcoxon rank sum test. Category data were analyzed by the chi-square test or the Fisher exact test, as appropriate. Values were reported as the mean standard deviation, absolute number (n), or percentages. A P value ＜0.05 was set as statistically significant.
3.
3
Results
A total of 80 patients were selected and all completed the study, as shown in Figure 1. There were no significant differences between the groups regarding patient demographic characteristics, ASA physical status, duration of surgery and anesthesia, and extubation time (Table 1). Rescue antiemetics were required by two patients in the saline group and three patients in the parecoxib group, with no significant differences observed between the two groups (Table 1). However, none of the patients in the parecoxib group were given fentanyl during the postoperative recovery period, whereas six patients in the saline group needed fentanyl rescue to treat postoperative pain (P ¼ 0.026; Table 1). Postoperative shivering was observed in 22 patients in the saline group (55%) and nine in the parecoxib group (22.5%) (Table 2). The overall incidence of shivering was higher in the saline group than in the parecoxib group (P ¼ 0.003). Sixteen percent of the patients (13/80) experienced shivering at grade 2 and 3 and required treatment. It is noted that the number of patients with a shivering grade of 2 and 3 was significantly higher in the saline group than that in the parecoxib group (P ¼ 0.006). In addition, there was no shivering at grade 3 noted in the parecoxib group (Table 2). However, there were no statistical significant differences in the duration of shivering between the parecoxib and saline groups (Table 2). Figures 2 and 3 showed the changes in tympanic and axillary temperatures during anesthesia and recovery periods, respectively. It could be observed in both groups that the tympanic temperature decreased but the axillary temperature increased significantly when compared with their baselines (P < 0.0001 and P < 0.005, respectively); however, there were no significant differences in temperature between the two groups at any time interval. Throughout the study period, there were no significant differences in mean arterial pressure (MAP) and heart rate between the groups at any measured data point (Table 3). MAP was significantly lower at T0 in the parecoxib group compared with all other time points (P < 0.05). In the saline group, MAP
Fig. 1 e Flowchart of patients through the trial study. 5.2.0 DTD YJSRE13190_proof 9 April 2015 8:49 pm ce
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4
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Table 1 e Demographic characteristics and perioperative data.
Age (y) Weight (kg) Gender (Male/Female) American Society of Anesthesiologists physical status I/II Body mass index (kg/m2) Anesthetics Fentanyl (mg) Midazolam (mg) Propofol (mg) Volume of Ringer’s solution (mL) Duration of surgery (min) Duration of anesthesia (min) Extubation time (min) Patients receiving fentanyl rescue (n) Patients receiving metoclopramide rescue (n)
Group P (n ¼ 40)
Group S (n ¼ 40)
49.9 15.3 60.9 9.6 23/17 35/5
51.9 13.6 61.7 10.3 27/13 38/2
23.5 3.0
23.6 3.6
121.8 6.1 121.8 779.0 42.8 51.5 7.2 0
19.2 1.0 19.2 221.1 12.7 14.0 2.0
3
123.4 6.2 123.4 877.2 44.5 57.1 7.3
20.7 1.0 20.7 229.4 12.6 12.8 1.9 6* 2
Data are expressed the as mean standard deviation or number of patients. * P < 0.05 compared with the group P.
was significantly lower at T0 compared with T1e3 (P < 0.01). Heart rate was significantly lower at T0 compared with other time points in the parecoxib group (P < 0.05). The average pain intensity scores (VAS) in the recovery room were higher in the saline group than that in the parecoxib group at all time points (P < 0.0001; Table 3). No patient with a VAS >40 mm was observed in the parecoxib group. There were no statistically significant differences with respect to postoperative nausea and vomiting between the two groups. No other serious adverse events, such as undesired sedation, respiratory depression, strokes, or fatal and nonfatal myocardial infarctions, were observed during the trial period (Table 4).
4.
Discussion
The main finding of this study was that prophylactic administration of parecoxib could effectively decrease the incidence
Fig. 2 e Change in core temperature with time. Data are shown as the mean with standard deviation error bars. io0, io10, io20, io30, and io40 indicate the zeroth, 10th, 20th, 30th, and 40th minute after induction of anesthesia, respectively. Similarly, po1, po20, and po60 indicate the first, 20th, and 60th minute after removal of the laryngeal mask airway. Temperature in both groups decreased significantly from their baselines (*P < 0.0001), but there were no significant differences between groups. io, intraoperative; po, postoperative.
and severity of shivering related to general anesthesia without significant adverse effects in the postoperative period. Intraoperative hypothermia is the major risk factor for postoperative shivering, but shivering can occur in normothermic patients as well [15,16]. More risk factors may accompany with shivering, such as decreased sympathetic activity, recovery of spinal activity, adrenal suppression, the release of pyrogenic substances during surgery, pain or opiate withdrawal, administration of volatile anesthetics, blood loss, and duration of surgery [1,4,13e17]. Regarding the mechanism of shivering, its birthplace is considered to be posterior hypothalamus and its activity is modulated by inputs from the cold receptors. It is normally inhibited by impulses from the preoptic anterior hypothalamic area, but if the cold impulses exceed the rate at which the former impulses may be received, the starting point for shivering is activated and sends impulses bilaterally into the anterior motor neurons of the spinal cord [1]. During general anesthesia, patients are protected against thermoregulatory responses by an increase of warm-response thresholds and a decrease of cold-response thresholds, such that the normal
Table 2 e Number and grades of postoperative shivering in the postanesthetic care unit.
Number of patients with shivering Grade of shivering (0/1/2/3) Duration of shivering (min) 95% CI of the occurrence of shivering (OR)
Group P (n ¼ 40)
Group S (n ¼ 40)
9
22*
31/7/2/0 18/11/5/6 12.9 3.8 14.4 4.3 1.60e11.09 (4.21)
CI ¼ confidence interval; OR ¼ odds ratio. Data are expressed as the mean standard deviation or number of patients. * P < 0.05 compared with the group P.
Fig. 3 e Change in peripheral temperature with time. Data, label, and caption are shown in the same way as Figure 2. Temperature in both groups increased significantly from their baselines (*P < 0.005), but there were no significant differences between groups.
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Table 3 e Hemodynamic parameters and VAS. Group P (n ¼ 40) MAP (mm Hg) T0 T1 T2 T3 T4 HR (beats/min) T0 T1 T2 T3 T4 VAS (mm) T2 T3 T4
Group S (n ¼ 40)
83.1 89.8 99.5 96.9 91.3
12.8* 15.6 11.8 16.7 19.9
83.2 88.0 96.7 92.7 85.9
14.6y 18.0 13.5 17.6 14.2
79.5 83.8 86.8 85.8 87.0
17.0* 18.5 13.7 14.1 16.7
78.0 82.4 80.1 80.4 83.0
14.2 11.2 14.5 14.4 13.6
33.9 17.3z 34.3 14.4z 32.4 12.6z
15.3 8.9 14.2 7.7 13.5 6.9
Data are shown as the mean standard deviation. HR ¼ heart rate; MAP ¼ mean arterial pressure; PACU ¼ postanesthetic care unit; T0 ¼ before induction of anesthesia; T1 ¼ end of surgery; T2 ¼ 1 min after arrival in the PACU; T3 ¼ 20 min after arrival in the PACU; T4 ¼ 60 min after arrival in the PACU; VAS ¼ visual analog scale. * P < 0.05, when compared with other time points in the same group. y P < 0.01, when compared with T1e3 in the same group. z P < 0.0001, when compared with the group P.
interthreshold range, between which no effector response occurs, is expanded to 0.4 Cd4.0 C [18]. During recovery from anesthesia, thermoregulation is no longer inhibited so that the shivering is triggered when the temperature is reduced less than the thermoregulatory threshold [19]. The exact mechanism by which parecoxib prevents shivering is still not clear. A possible explanation is that COX-2/PGE2 pathway is involved in the action of parecoxib. It is generally known that COX-2/PGE2 pathway plays a critical role in thermoregulatory pathways [5,6]. Peng et al. [20] reported that parecoxib inhibited hippocampal COX-2 expression and PGH2 synthesis through downregulation of the COX-2/PGH2 pathway during perioperative period. We suppose that the effect of parecoxib on postoperative shivering is likely to be secondary to its anti-inflammatory activity through inhibition of COX-2 expression and PGH2 synthesis at the level of hypothalamus, where the bulk of thermoregulatory control occurs. The inhibitory effect probably results in a generalized thermoregulatory inhibition in
the hypothalamus during perioperative period. This explanation was supported by our clinical data on perioperative temperature. The anticipated core-to-peripheral tissue temperature gradient after the induction of general anesthesia was characterized by an approximate 1 C decrease in core temperature within the first 20e30 min, followed by an increase in peripheral skin temperature [21,22]. This phenomenon was unchanged in our patients who received parecoxib. Thus, the antishivering effect of parecoxib may be independent of intraoperative core hypothermia, suggesting that it inhibits thermoregulatory responses by a central mechanism [22]. In addition, the analgesic effects of parecoxib may be another reason for the reduction of postoperative shivering. Postoperative surgical pain has been shown to make the nonthermoregulatory shivering happen [23]. Analgesic agents, such as meperidine and sufentanil, have been shown to prevent postoperative shivering via the m- or b-receptors [24]. Parecoxib is known to produce analgesia by inhibiting COX-2 expression and PGH2 synthesis, and has been recommended for postoperative analgesia [10,11]. In the present study, the pain scores and analgesic requirements were significant reductions in the parecoxib group during recovery from anesthesia. The antishivering effect of parecoxib might result from a downregulation of the COX-2/PGH2 pathway. Parecoxib appears to be a safe and rapidly effective agent with some minor adverse effects such as hemodynamic changes associated with its administration [10,11,25]. However, these adverse effects were not observed in our study, possibly because of our study protocol. Parecoxib was administered as a bolus for one-time-only and contraindicated in patients with hypertension or at high risk for cardiovascular disease. In the present study, we did not observe any detrimental effect in recovery time after general anesthesia in the parecoxib group. None of our patients had major adverse events such as undesired sedation, respiratory depression, strokes, or fatal and nonfatal myocardial infarctions during the trial period. A limitation of our study was that we did not evaluate the effects of parecoxib with various doses, and a standard dose (40 mg) was given to all patients. It remains unclear whether a higher or lower dose of parecoxib will be more effective in preventing shivering in some patients. Furthermore, we did not include a positive control group using an established agent such as meperidine. To include another group with positive agent in future study may provide more useful information.
5. Table 4 e Incidence of adverse events during the first postoperative hour.
Q18
Nausea, n (%) Vomiting, n (%) Undesired sedation, n Respiratory depression, n Strokes, n Myocardial infarction, n
Group P (n ¼ 40)
Group S (n ¼ 40)
P value
12 (30%) 8 (20%) 0 0 0 0
14 (35%) 7 (17.5%) 0 0 0 0
0.812 1.000 NA NA NA NA
Data are presented as the number (percent).
5
Conclusions
Prophylactic administration of parecoxib provides dual advantage of antishivering and analgesic effect without influencing hemodynamics and postoperative recovery. COX2/PGH2 pathways seem to be involved in the central thermoregulation, leading to an effective reduction of shivering.
Acknowledgment Author contributions: All authors were involved in the form and/or study design and contributed critically to the final
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6
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preparation of the article, including approving the final version of the manuscript. In particular, J.C. conceived and designed the study, wrote the final study protocol, collected the results, analyzed the data, and drafted the manuscript. Y.C. assisted in implementing the study, advised at various stages, from protocol design to data interpretation, and assisted revising the manuscript. H.S. analyzed and interpreted the data. K.Z.L. was as a general advisor most helpful in assisting throughout and in the interpretation of data.
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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