Aging Clin Exp Res DOI 10.1007/s40520-015-0373-9
ORIGINAL ARTICLE
Implications of palonosetron in elderly patients undergoing laparoscopic cholecystectomy with respect to its anti-shivering effect Youn Yi Jo1 • Yong Beom Kim1 • Dongchul Lee1 • Young Jin Chang1 Hyun Jeong Kwak1
•
Received: 17 February 2015 / Accepted: 5 May 2015 Ó Springer International Publishing Switzerland 2015
Abstract Background The elderly are vulnerable to hypothermia and have a higher risk of cardiovascular events induced by marked increases in oxygen consumption due to shivering. Five-hydroxytryptamine-3 (5-HT3) receptor antagonists have been previously reported to reduce post-anesthesia shivering. Aim In the present study, the authors investigated the effects of palonosetron, a new-generation 5-HT3 antagonist, on core hypothermia and the incidence of shivering after laparoscopic cholecystectomy in elderly patients. Methods Forty-eight patients (65–80 years) were randomly assigned to one of two groups and administered palonosetron 0.075 mg (palonosetron group, n = 24) or the same volume of normal saline (control group, n = 24) before anesthesia induction. Core body temperatures and hemodynamic variables were monitored during and after operation. Post-anesthetic shivering (PAS) and pain scores were obtained in a post-anesthetic care unit. Results Intraoperative esophageal temperature changed significantly over time (P = 0.010), but significant intergroup difference in change was not observed (P = 0.706). Furthermore, shivering frequencies were similar in the two groups (P = 0.610). However, postoperative pain scores at 30 min after entering the post-anesthesia care unit were significantly lower in the palonosetron group (P = 0.002).
& Hyun Jeong Kwak [email protected] 1
Department of Anesthesiology and Pain Medicine, Gil Medical Center, Gachon University, 1198 Guwol-dong, Namdong-gu, Incheon 405-760, South Korea
Discussion Regardless of the previously reported antishivering effect of 5-HT3 receptor antagonists, pre-operative palonosetron 0.075 mg did not influence perioperative hypothermia or PAS in this study. This discrepancy might be due to the dose responsiveness of palonosetron to PAS and relatively low incidence of PAS in the elderly. Conclusions Pre-operative administration of palonosetron 0.075 mg did not influence perioperative hypothermia or post-anesthesia shivering in elderly patients undergoing laparoscopic cholecystectomy. However, palonosetron might be beneficial for reducing early postoperative pain in elderly patients with opioid-based patient-controlled analgesia. Keywords Elderly
Post-anesthetic shivering Palonosetron
Introduction Many patients suffer from post-anesthesia shivering (PAS), which causes more metabolic changes than are immediately apparent, such as discomfort, greater surgical pain, and EKG disturbance [1]. In a previous comparative clinical study, it was reported that shivering reduced mixed venous oxygen saturation, but increased cardiac output after elective cardiac surgery, and suggested that this might indicate a discrepancy between body oxygen supply and demand [2]. In addition, profound oxygen consumption and carbon dioxide production during shivering lead to respiratory acidosis, hemodynamic instability, and substantial inotropic support [2, 3]. In particular, the elderly might be vulnerable to shivering-induced oxygen consumption, because of age-related cardiovascular structural changes and underlying comorbidities [4].
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Aging Clin Exp Res
Due to advantages of rapid recovery and less pain, laparoscopic procedures have replaced a variety of laparotomic procedures. However, incidences of shivering, due to heat loss from insufflation gas and irrigation fluid and heat redistribution after anesthesia, have been reported to be similar for laparoscopic and open procedures [5–7]. Furthermore, although the most commonly used drugs, meperidine and clonidine, have potent anti-shivering effects [8], these may cause hemodynamic and respiratory suppression due to their sympatholytic actions. Five-hydroxytryptamine-3 (5-HT3) receptor antagonists, which have been used to prevent or treat postoperative nausea and vomiting (PONV), have been reported to reduce PAS without inducing hemodynamic or respiratory disturbances [9]. In a recent meta-analysis of 6 trials and a total of 533 subjects, it was demonstrated that ondansetron reduces PAS [10], and in an earlier study, ramosetron (0.3 mg) was found to reduce the incidence of PAS after regional anesthesia significantly. In addition, it was suggested that the central inhibition of 5-HT reuptake might contribute to its effect [11]. Despite vulnerability to hypothermia and a higher risk of cardiovascular events associated with marked increases in oxygen consumption due to shivering, few studies have addressed the effects of 5-HT3 antagonists on thermoregulation in the elderly. We hypothesized that preanesthetic administration of palonosetron (a new-generation 5-HT3 antagonist) could modify thermoregulation and reduce the incidence of PAS in the elderly. Thus, the aim of this randomized controlled study was to investigate the effects of palonosetron on core hypothermia, peripheral thermal distribution, and the incidence of PAS after laparoscopic cholecystectomy under general anesthesia.
Materials and methods After obtaining approval from the institutional review board of Gachon University Gil Medical Center, written informed consent was obtained from all eligible subjects. Forty-eight patients, aged between 65 and 80 years of American Society of Anesthesiologists physical status I–II and scheduled for elective laparoscopic cholecystectomy, were enrolled in this prospective randomized trial. Patients with a tympanic temperature above 37.5 °C, uncontrolled hypertension, uncontrolled diabetes, cardiovascular morbidity, peripheral vascular disease, or progressive respiratory disease were excluded. Neither glycopyrrolate nor any other sedative was administered for premedication. On arrival at the operating room, electrocardiography, noninvasive blood pressure monitoring, and pulse oximetry were applied. Patients were randomized to receive either 1.5 ml of palonosetron
123
0.075 mg i.v. (palonosetron group, n = 24) or 1.5 ml of normal saline i.v. (control group, n = 24), before anesthesia induction with 5–10 lg/kg of alfentanil, 0.5 mg/kg of lidocaine, 1–1.5 mg/kg of propofol, and 0.6 mg/kg of rocuronium. After tracheal intubation, anesthesia was maintained with sevoflurane at 1.5–2.5 vol % in 60 % oxygen in medical air to maintain a Bispectral Index Score (BIS) between 40 and 50. An esophageal stethoscope with a temperature sensor (DeRoyal Inc., Powell, TN, USA) was inserted into mid-esophagus, and a skin temperature probe was attached to the radial side of the distal forearm not fitted with an intravenous cannula. All anesthetic circuits were electrically heated (Anesthesia controller and A4488 Heated and humidified anesthesia breathing circuitTM, Acemedical, Seoul, Korea), and room temperature was maintained at 20–22 °C throughout general anesthesia. Intravenous fluid was not warmed and when esophageal temperature dropped under 35 °C, we used a warming mattress laid on the operative table and equipped with circulating water at 38 °C. Hemodynamic data and esophageal and skin temperature values were measured immediately before anesthetic induction (Tbase), 5 min after anesthesia induction (T0) immediately after pneumoperitoneum (PP0), and then at 15-min intervals to the end of surgery (Tend). For patient-controlled analgesia, we used an infusion device (Accufuser, Wooyoung Meditech, Seoul, Korea) prefilled with fentanyl (700 lg) to a total volume of 100 ml connected to an intravenous line after induction (basal infusion rate 2 ml/h, intermittent bolus dose of 0.5 ml/15 min). After arrival in the post-anesthetic care unit (PACU), routine and tympanic temperature (ThermoScan IRT 1020; Braun, Germany) monitoring was initiated and recorded every 15 min. Room temperature in the PACU was maintained at 23–24 °C and when patients complained of being cold, a forced air-warming blanket (WarmTouch; Mallinckrodt Medical, St Louis, MO, USA) was applied. Incidences of postoperative nausea and vomiting (PONV) and of post-anesthesia shivering (PAS) were recorded. PAS was evaluated by two anesthesiologists unaware of group allocations and was graded as follows: grade 0, no visual shivering; grade 1, mild fasciculations of face or/and neck in the absence of voluntary limb activity; grade 2, visible tremors involving more than one muscle group; and grade 3, visible muscular activity over the entire body with bed shaking [12]. Postoperative pain was assessed using visual analog scale (VAS) scores, which were recorded 30 min after entry to the PACU. A sample size of 24 subjects per group was calculated by power analysis based on the findings of a previous study [13]. When the incidences of PAS in the palonosetron and control groups were predicted to be 15 and 57 %, respectively, 18 subjects per group were required with an a-error
Aging Clin Exp Res
of 0.05 and a power of 80 %, and thus, considering a dropout rate of 30 %, 24 patients were needed per group. Data were analyzed using SPSS ver. 17.0 (SPSS, Chicago, IL, USA). The independent t test or the Chi-square test, as appropriate, was used to compare group variables. Differences between hemodynamic variables and temperatures at different time points were analyzed using the paired t test, and intergroup changes in hemodynamic variables and temperature were analyzed using repeatedmeasures ANOVA with post hoc Bonferroni’s correction. Values are described as means ± SDs, medians (interquartile ranges), or as numbers of patients. P values of \0.05 were considered statistically significant.
Frequencies of intraoperative hypothermia and postanesthetic results are summarized in Table 2. Frequencies of hypothermia were similar in the two groups (P = 0.443). Frequencies of PAS were similar in the two groups (8 in the control group and 5 in the palonosetron group), and one patient in the control group experienced grade 3 PAS (P = 0.610). Incidences of PONV were comparable in the two groups after PACU arrival (P = 0.556). In terms of PONV incidents, three patients and one patient in the control and palonosetron groups, respectively, experienced severe PONV and required rescue anti-emetics. After 30 min in the PACU, median postoperative pain score was significantly lower in the palonosetron group [7 (5.25–8) vs. 8 (7–10) (median [interquartile range]); P = 0.002].
Results Twenty-four patients were initially enrolled in each of the two study groups. However, one patient in the control group was excluded from the analysis due to conversion to another operative method. Patient characteristics and perioperative data are described in Table 1. No significant intergroup differences were observed in body surface area and anesthesia, operation, and pneumoperitoneum time. The intraoperative changes in mean arterial pressure (MAP), heart rate (HR), and esophageal and skin temperatures are illustrated in Fig. 1. No intergroup differences were observed in the hemodynamic variables at any time points (all P values [0.05), and the changes in MAP and HR over time were not significantly different between the groups. Esophageal and skin temperatures had no intergroup differences at any time points. Esophageal and skin temperatures changed significantly over time (P = 0.010 and P = 0.043, respectively), but these changes were similar between the groups (P = 0.706 and P = 0.240, respectively). Table 1 Patient characteristics
Discussion In the present study, we found that the pre-operative administration of palonosetron 0.075 mg had no beneficial effect in terms of preventing intraoperative hypothermia or PAS, but that pre-operative palonosetron might reduce early postoperative pain scores in elderly (65–80 years) after laparoscopic cholecystectomy under general anesthesia. The elderly experience more profound and longer hypothermia due to a reduced ability to compensate for hypothermia [14]. In addition, the discrimination of temperature is poorer and elderly are less likely to shiver than the young [15–17]. In the present study, we found a PAS incidence of 35 % (8/23) in the control group. The reported incidence of PAS varies from 5 to 65 % [1], and its incidence in the elderly population has been reported of 25 % during routine thermal care [18] in previous report. Taken together, our result is comparable to the previous studies [1, 18].
Palonosetron (n = 24)
Control (n = 23)
P value 0.521
Age (years)
72 ± 6
71 ± 5
Sex (M/F)
11/13
10/13
0.552
Weight (kg)
59 ± 11
57 ± 11
0.386
157 ± 9
157 ± 12
0.852
Height (cm) 2
Body surface area (m )
1.59 ± 0.18
1.59 ± 0.18
0.966
Diabetics (n)
2
4
0.312
Hypertension (n)
18
16
0.464
Anesthesia time (min)
80 ± 25
89 ± 25
0.315
Operation time (min)
57 ± 18
63 ± 20
0.390
Pneumoperitoneum time (min)
37 ± 18
39 ± 21
0.707
Values are means ± SDs or number of patients
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Aging Clin Exp Res
Fig. 1 Intraoperative changes in hemodynamics and core and skin temperatures. MAP mean arterial pressure, HR heart rate, PACU postanesthesia care unit. Tbase, immediately before anesthetic induction;
T0, 5 min after anesthesia induction; PP0-30, from immediately to 30 min after pneumoperitoneum; and Tend, at the end of surgery
Antagonists of 5-HT3 receptor inhibit the neurotransmission required for thermoregulation in the hypothalamus, which is the primary locus of thermoregulatory control [19]. In a previous clinical study, it was suggested that the classic 5-HT3 receptor antagonist, ondansetron, inhibits thermoregulatory responses centrally and independently of core hypothermia induced by core-to-peripheral redistribution of heat after anesthetic induction [13]. However, in the present study, pre-operative administration of palonosetron 0.075 mg did not influence perioperative hypothermia or PAS in elderly patients undergoing laparoscopic cholecystectomy. We propose two possible explanations for this apparent discrepancy. In the previous clinical study, ondansetron was found to effectively prevent PAS in a dose-dependent manner, and at 8 mg, but not at 4 mg, ondansetron prevented PAS after general anesthesia [14]. In another study, although palonosetron at 0.075 mg (the usual dose used to prevent PONV) was superior to ondansetron 8 mg in terms of preventing PONV after
gynecologic laparoscopy [20], this dose may have been insufficient to control thermoregulation. Another possible explanation is that the relatively low incidence of PAS in our cohort might prevent proper statistical analysis. In a previous regression analysis of 1340 patients, it was found that an older age independently predicted a lower rate of PAS (odds ratio 0.59, P \ 0.001) [21]. Thus, we suggest that further dose–response study and comparisons of different age groups might help elucidate the effects of palonosetron on PAS and thermoregulation. There is the possibility that the lack of anti-shivering effect of palonosetron may not be limited to the elderly. Palonosetron shows the unique molecular interactions with 5-HT3 receptors [22]. Older drugs are based on a 3-substituted indole structure resembling serotonin, whereas palonosetron has a fused tricyclic ring system attached to quinuclidine moiety. Accordingly, palonosetron interacts with 5-HT3 receptors at sites different from or additional to those involved in ondansetron and granisetron binding
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Aging Clin Exp Res Table 2 Intraoperative hypothermia and post-anesthetic results
Variables
Palonosetron (n = 24)
Control (n = 23)
P value
Intraoperative hypothermia (n)
0.443
9
12
C36 °C
15
11
35.5–35.9 °C
6
5
35.0–35.4 °C
2
6
\35.0 °C
1
1
Post-anesthetic results after 30 min in PACU Mean arterial pressure (mmHg)
105 ± 18
103 ± 15
0.681
Heart rate (beats/min)
86 ± 15
89 ± 16
0.457
Tympanic temperature (°C)
36.4 ± 0.6
36.1 ± 0.5
0.147
Postoperative pain score
7 (5.25–8)
8 (7–10)
0.002
6.7 ± 1.9
8.3 ± 1.3
5
8
Grade 1
4
6
Grade 2
1
1
Grade 3 PONV (n)
0 8
1 6
Post-anesthesia shivering (n)
0.610
0.556
Values are means ± SDs, number of patients, or medians (interquartile ranges) PACU post-anesthetic care unit, PONV postoperative nausea and vomiting
[22]. These characteristics might partly explain our result. In addition, palonosetron of 0.075 has already been reported for its negative effect on PAS in young female patients (mean age 45 years) with a higher incidence of shivering in the control and palonosetron groups (33 vs. 27 %, respectively) [23]. The previous study has suggested that the lack of anti-shivering effect might result from remifentanil-induced PAS [24] and the molecular structure of palonosetron [23]. Because we did not use remifentanil, our result is not associated with remifentanil-induced PAS. In the present study, pre-operative palonosetron significantly reduced postoperative pain scores in elderly undergoing laparoscopic cholecystectomy. Selective 5-HT3 receptor antagonists are known to have good analgesic properties in backgrounds of fibromyalgia and chronic neuropathic pain by modulating the nociceptive pathway [25, 26]. Furthermore, in man, ondansetron ligates with lopioid receptors and acts as an agonist [27]. Our results suggest that the administration of palonosetron before anesthetic induction might modulate postoperative pain and enhance opioid-based patient-controlled analgesia in the elderly. Our result is supported by prior clinical studies. Pretreatment of palonosetron 0.075 mg could effectively reduce early postoperative pain after thyroid and breast cancer as well as propofol-induced injection pain [28, 29]. Summarizing, the pre-operative administration of palonosetron 0.075 mg did not influence perioperative hypothermia or post-anesthesia shivering in elderly patients after laparoscopic cholecystectomy under sevoflurane anesthesia. However, our findings show that palonosetron might be beneficial for reducing early postoperative pain in
elderly patients with opioid-based patient-controlled analgesia. Conflict of interest terest to declare.
The authors have no potential conflict of in-
Human and Animal Rights The study was conducted according to standards derived from the Declaration of Helsinki. Informed consent A written informed consent was obtained from every patient.
References 1. Alfonsi P (2003) Postanaesthetic shivering. Epidemiology, pathophysiology and approaches to prevention and management. Minerva Anestesiol 69(5):438–442 2. Ralley FE, Wynands JE, Ramsay JG et al (1988) The effects of shivering on oxygen consumption and carbon dioxide production in patients rewarming from hypothermic cardiopulmonary bypass. Can J Anaesth 35(4):332–337 3. Zwischenberger JB, Kirsh MM, Dechert RE et al (1987) Suppression of shivering decreases oxygen consumption and improves hemodynamic stability during postoperative rewarming. Ann Thorac Surg 43(4):428–431 4. Lakatta EG, Levy D (2003) Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation 107(2):346–354 5. Berber E, String A, Garland A et al (2001) Intraoperative thermal regulation in patients undergoing laparoscopic vs. open surgical procedures. Surg Endosc 15(3):281–285 6. Huntington TR, LeMaster CB (1997) Laparoscopic hypothermia: heat loss from insufflation gas flow. Surg Laparosc Endosc 7(2):153–155 7. Moore SS, Green CR, Wang FL et al (1997) The role of irrigation in the development of hypothermia during laparoscopic surgery. Am J Obstet Gynecol 176(3):598–602
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Aging Clin Exp Res 8. Park SM, Mangat HS, Berger K et al (2012) Efficacy spectrum of antishivering medications: meta-analysis of randomized controlled trials. Crit Care Med 40(11):3070–3082. doi:10.1097/ CCM.0b013e31825b931e 9. Diemunsh P, Conseiller C, Clyti N et al (1997) Ondansetron compared with metoclopramide in the treatment of established postoperative nausea and vomiting: the French Ondansetron Study Group. Br J Anaesth 79:322–326 10. Tie HT, Su GZ, He K et al (2014) Efficacy and safety of ondansetron in preventing postanesthesia shivering: a meta-analysis of randomized controlled trials. BMC Anesthesiol 14:12. doi:10. 1186/1471-2253-14-12 11. Kim MS, Kim DW, Woo SH et al (2010) Effect of ramosetron on shivering during spinal anesthesia. Korean J Anesthesiol 58(3):256–259. doi:10.4097/kjae.2010.58.3.256 12. Mohta M, Kumari N, Tyagi A et al (2009) Tramadol for prevention of postanaesthetic shivering: a randomised double-blind comparison with pethidine. Anaesthesia 64(2):141–146. doi:10. 1111/j.1365-2044.2008.05711.x 13. Powell RM, Buggy DJ (2000) Ondansetron given before induction of anesthesia reduces shivering after general anesthesia. Anesth Analg 90(6):1423–1427 14. Vaughan MS, Vaughan RW, Cork RC (1981) Postoperative hypothermia in adults: relationship of age, anesthesia, and shivering to rewarming. Anesth Analg 60(10):746–751 15. Collins KJ, Exton-Smith AN, Dore´ C (1981) Urban hypothermia: preferred temperature and thermal perception in old age. Br Med J (Clin Res Ed) 282(6259):175–177 16. Frank SM, Raja SN, Bulcao C et al (2000) Age-related thermoregulatory differences during core cooling in humans. Am J Physiol Regul Integr Comp Physiol 279(1):R349–R354 17. Frank SM, Raja SN, Bulcao C et al (2000) Age-related thermoregulatory differences during core cooling in humans. Am J Physiol Regul Integr Comp Physiol 279(1):R349–R354 18. Frank SM, Fleisher LA, Olson KF et al (1995) Multivariate determinants of early postoperative oxygen consumption in elderly patients. Effects of shivering, body temperature, and gender. Anesthesiology 83(2):241–249 19. Saudou F, Hen R (1994) 5-Hydroxytryptamine receptor subtypes: molecular and functional diversity. Adv Pharmacol 30:327–380
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20. Park SK, Cho EJ (2011) A randomized, double-blind trial of palonosetron compared with ondansetron in preventing postoperative nausea and vomiting after gynaecological laparoscopic surgery. J Int Med Res 39(2):399–407 21. Eberhart LH, Do¨derlein F, Eisenhardt G et al (2005) Independent risk factors for postoperative shivering. Anesth Analg 101(6):1849–1857 22. Rojas C, Stathis M, Thomas AG et al (2008) Palonosetron exhibits unique molecular interactions with the 5-HT3 receptor. Anesth Analg 107(2):469–4778. doi:10.1213/ane. 0b013e318172fa74 23. Jo YY, Kwak HJ, Lee MG et al (2013) Effect of palonosetron on postanesthetic shivering after propofol-remifentanil total intravenous anesthesia. J Anesth 27(4):535–540. doi:10.1007/s00540013-1556-1 24. Nakasuji M, Nakamura M, Imanaka N et al (2010) Intraoperative high-dose remifentanil increases post-anaesthetic shivering. Br J Anaesth 105(2):162–167. doi:10.1093/bja/aeq121 25. McCleane GJ, Suzuki R, Dickenson AH (2003) Does a single intravenous injection of the 5HT3 receptor antagonist ondansetron have an analgesic effect in neuropathic pain? A doubleblinded, placebo-controlled cross-over study. Anesth Analg 97(5):1474–1478 26. Spa¨th M (2002) Current experience with 5-HT3 receptor antagonists in fibromyalgia. Rheum Dis Clin North Am 28(2):319–328 27. Gregory RE, Ettinger DS (1998) 5HT3 receptor antagonists for the prevention of chemotherapy induced nausea and vomiting a comparison of their pharmacology and clinical efficacy. Drugs 55(2):173–189 28. Ryu HB, Kim SJ (2014) Analgesic effects of palonosetron in the intravenous propofol injection. Korean J Anesthesiol 66(2):99–104. doi:10.4097/kjae.2014.66.2.99 29. Lee KH, Rim SK, Lee JY et al (2014) Effects of pretreatment with intravenous palonosetron for propofol-remifentanil-based anesthesia in breast and thyroid cancer surgery: a double-blind, randomized, controlled study. Korean J Anesthesiol 67(1):13–19. doi:10.4097/kjae.2014.67.1.13
ORIGINAL ARTICLE
Implications of palonosetron in elderly patients undergoing laparoscopic cholecystectomy with respect to its anti-shivering effect Youn Yi Jo1 • Yong Beom Kim1 • Dongchul Lee1 • Young Jin Chang1 Hyun Jeong Kwak1
•
Received: 17 February 2015 / Accepted: 5 May 2015 Ó Springer International Publishing Switzerland 2015
Abstract Background The elderly are vulnerable to hypothermia and have a higher risk of cardiovascular events induced by marked increases in oxygen consumption due to shivering. Five-hydroxytryptamine-3 (5-HT3) receptor antagonists have been previously reported to reduce post-anesthesia shivering. Aim In the present study, the authors investigated the effects of palonosetron, a new-generation 5-HT3 antagonist, on core hypothermia and the incidence of shivering after laparoscopic cholecystectomy in elderly patients. Methods Forty-eight patients (65–80 years) were randomly assigned to one of two groups and administered palonosetron 0.075 mg (palonosetron group, n = 24) or the same volume of normal saline (control group, n = 24) before anesthesia induction. Core body temperatures and hemodynamic variables were monitored during and after operation. Post-anesthetic shivering (PAS) and pain scores were obtained in a post-anesthetic care unit. Results Intraoperative esophageal temperature changed significantly over time (P = 0.010), but significant intergroup difference in change was not observed (P = 0.706). Furthermore, shivering frequencies were similar in the two groups (P = 0.610). However, postoperative pain scores at 30 min after entering the post-anesthesia care unit were significantly lower in the palonosetron group (P = 0.002).
& Hyun Jeong Kwak [email protected] 1
Department of Anesthesiology and Pain Medicine, Gil Medical Center, Gachon University, 1198 Guwol-dong, Namdong-gu, Incheon 405-760, South Korea
Discussion Regardless of the previously reported antishivering effect of 5-HT3 receptor antagonists, pre-operative palonosetron 0.075 mg did not influence perioperative hypothermia or PAS in this study. This discrepancy might be due to the dose responsiveness of palonosetron to PAS and relatively low incidence of PAS in the elderly. Conclusions Pre-operative administration of palonosetron 0.075 mg did not influence perioperative hypothermia or post-anesthesia shivering in elderly patients undergoing laparoscopic cholecystectomy. However, palonosetron might be beneficial for reducing early postoperative pain in elderly patients with opioid-based patient-controlled analgesia. Keywords Elderly
Post-anesthetic shivering Palonosetron
Introduction Many patients suffer from post-anesthesia shivering (PAS), which causes more metabolic changes than are immediately apparent, such as discomfort, greater surgical pain, and EKG disturbance [1]. In a previous comparative clinical study, it was reported that shivering reduced mixed venous oxygen saturation, but increased cardiac output after elective cardiac surgery, and suggested that this might indicate a discrepancy between body oxygen supply and demand [2]. In addition, profound oxygen consumption and carbon dioxide production during shivering lead to respiratory acidosis, hemodynamic instability, and substantial inotropic support [2, 3]. In particular, the elderly might be vulnerable to shivering-induced oxygen consumption, because of age-related cardiovascular structural changes and underlying comorbidities [4].
123
Aging Clin Exp Res
Due to advantages of rapid recovery and less pain, laparoscopic procedures have replaced a variety of laparotomic procedures. However, incidences of shivering, due to heat loss from insufflation gas and irrigation fluid and heat redistribution after anesthesia, have been reported to be similar for laparoscopic and open procedures [5–7]. Furthermore, although the most commonly used drugs, meperidine and clonidine, have potent anti-shivering effects [8], these may cause hemodynamic and respiratory suppression due to their sympatholytic actions. Five-hydroxytryptamine-3 (5-HT3) receptor antagonists, which have been used to prevent or treat postoperative nausea and vomiting (PONV), have been reported to reduce PAS without inducing hemodynamic or respiratory disturbances [9]. In a recent meta-analysis of 6 trials and a total of 533 subjects, it was demonstrated that ondansetron reduces PAS [10], and in an earlier study, ramosetron (0.3 mg) was found to reduce the incidence of PAS after regional anesthesia significantly. In addition, it was suggested that the central inhibition of 5-HT reuptake might contribute to its effect [11]. Despite vulnerability to hypothermia and a higher risk of cardiovascular events associated with marked increases in oxygen consumption due to shivering, few studies have addressed the effects of 5-HT3 antagonists on thermoregulation in the elderly. We hypothesized that preanesthetic administration of palonosetron (a new-generation 5-HT3 antagonist) could modify thermoregulation and reduce the incidence of PAS in the elderly. Thus, the aim of this randomized controlled study was to investigate the effects of palonosetron on core hypothermia, peripheral thermal distribution, and the incidence of PAS after laparoscopic cholecystectomy under general anesthesia.
Materials and methods After obtaining approval from the institutional review board of Gachon University Gil Medical Center, written informed consent was obtained from all eligible subjects. Forty-eight patients, aged between 65 and 80 years of American Society of Anesthesiologists physical status I–II and scheduled for elective laparoscopic cholecystectomy, were enrolled in this prospective randomized trial. Patients with a tympanic temperature above 37.5 °C, uncontrolled hypertension, uncontrolled diabetes, cardiovascular morbidity, peripheral vascular disease, or progressive respiratory disease were excluded. Neither glycopyrrolate nor any other sedative was administered for premedication. On arrival at the operating room, electrocardiography, noninvasive blood pressure monitoring, and pulse oximetry were applied. Patients were randomized to receive either 1.5 ml of palonosetron
123
0.075 mg i.v. (palonosetron group, n = 24) or 1.5 ml of normal saline i.v. (control group, n = 24), before anesthesia induction with 5–10 lg/kg of alfentanil, 0.5 mg/kg of lidocaine, 1–1.5 mg/kg of propofol, and 0.6 mg/kg of rocuronium. After tracheal intubation, anesthesia was maintained with sevoflurane at 1.5–2.5 vol % in 60 % oxygen in medical air to maintain a Bispectral Index Score (BIS) between 40 and 50. An esophageal stethoscope with a temperature sensor (DeRoyal Inc., Powell, TN, USA) was inserted into mid-esophagus, and a skin temperature probe was attached to the radial side of the distal forearm not fitted with an intravenous cannula. All anesthetic circuits were electrically heated (Anesthesia controller and A4488 Heated and humidified anesthesia breathing circuitTM, Acemedical, Seoul, Korea), and room temperature was maintained at 20–22 °C throughout general anesthesia. Intravenous fluid was not warmed and when esophageal temperature dropped under 35 °C, we used a warming mattress laid on the operative table and equipped with circulating water at 38 °C. Hemodynamic data and esophageal and skin temperature values were measured immediately before anesthetic induction (Tbase), 5 min after anesthesia induction (T0) immediately after pneumoperitoneum (PP0), and then at 15-min intervals to the end of surgery (Tend). For patient-controlled analgesia, we used an infusion device (Accufuser, Wooyoung Meditech, Seoul, Korea) prefilled with fentanyl (700 lg) to a total volume of 100 ml connected to an intravenous line after induction (basal infusion rate 2 ml/h, intermittent bolus dose of 0.5 ml/15 min). After arrival in the post-anesthetic care unit (PACU), routine and tympanic temperature (ThermoScan IRT 1020; Braun, Germany) monitoring was initiated and recorded every 15 min. Room temperature in the PACU was maintained at 23–24 °C and when patients complained of being cold, a forced air-warming blanket (WarmTouch; Mallinckrodt Medical, St Louis, MO, USA) was applied. Incidences of postoperative nausea and vomiting (PONV) and of post-anesthesia shivering (PAS) were recorded. PAS was evaluated by two anesthesiologists unaware of group allocations and was graded as follows: grade 0, no visual shivering; grade 1, mild fasciculations of face or/and neck in the absence of voluntary limb activity; grade 2, visible tremors involving more than one muscle group; and grade 3, visible muscular activity over the entire body with bed shaking [12]. Postoperative pain was assessed using visual analog scale (VAS) scores, which were recorded 30 min after entry to the PACU. A sample size of 24 subjects per group was calculated by power analysis based on the findings of a previous study [13]. When the incidences of PAS in the palonosetron and control groups were predicted to be 15 and 57 %, respectively, 18 subjects per group were required with an a-error
Aging Clin Exp Res
of 0.05 and a power of 80 %, and thus, considering a dropout rate of 30 %, 24 patients were needed per group. Data were analyzed using SPSS ver. 17.0 (SPSS, Chicago, IL, USA). The independent t test or the Chi-square test, as appropriate, was used to compare group variables. Differences between hemodynamic variables and temperatures at different time points were analyzed using the paired t test, and intergroup changes in hemodynamic variables and temperature were analyzed using repeatedmeasures ANOVA with post hoc Bonferroni’s correction. Values are described as means ± SDs, medians (interquartile ranges), or as numbers of patients. P values of \0.05 were considered statistically significant.
Frequencies of intraoperative hypothermia and postanesthetic results are summarized in Table 2. Frequencies of hypothermia were similar in the two groups (P = 0.443). Frequencies of PAS were similar in the two groups (8 in the control group and 5 in the palonosetron group), and one patient in the control group experienced grade 3 PAS (P = 0.610). Incidences of PONV were comparable in the two groups after PACU arrival (P = 0.556). In terms of PONV incidents, three patients and one patient in the control and palonosetron groups, respectively, experienced severe PONV and required rescue anti-emetics. After 30 min in the PACU, median postoperative pain score was significantly lower in the palonosetron group [7 (5.25–8) vs. 8 (7–10) (median [interquartile range]); P = 0.002].
Results Twenty-four patients were initially enrolled in each of the two study groups. However, one patient in the control group was excluded from the analysis due to conversion to another operative method. Patient characteristics and perioperative data are described in Table 1. No significant intergroup differences were observed in body surface area and anesthesia, operation, and pneumoperitoneum time. The intraoperative changes in mean arterial pressure (MAP), heart rate (HR), and esophageal and skin temperatures are illustrated in Fig. 1. No intergroup differences were observed in the hemodynamic variables at any time points (all P values [0.05), and the changes in MAP and HR over time were not significantly different between the groups. Esophageal and skin temperatures had no intergroup differences at any time points. Esophageal and skin temperatures changed significantly over time (P = 0.010 and P = 0.043, respectively), but these changes were similar between the groups (P = 0.706 and P = 0.240, respectively). Table 1 Patient characteristics
Discussion In the present study, we found that the pre-operative administration of palonosetron 0.075 mg had no beneficial effect in terms of preventing intraoperative hypothermia or PAS, but that pre-operative palonosetron might reduce early postoperative pain scores in elderly (65–80 years) after laparoscopic cholecystectomy under general anesthesia. The elderly experience more profound and longer hypothermia due to a reduced ability to compensate for hypothermia [14]. In addition, the discrimination of temperature is poorer and elderly are less likely to shiver than the young [15–17]. In the present study, we found a PAS incidence of 35 % (8/23) in the control group. The reported incidence of PAS varies from 5 to 65 % [1], and its incidence in the elderly population has been reported of 25 % during routine thermal care [18] in previous report. Taken together, our result is comparable to the previous studies [1, 18].
Palonosetron (n = 24)
Control (n = 23)
P value 0.521
Age (years)
72 ± 6
71 ± 5
Sex (M/F)
11/13
10/13
0.552
Weight (kg)
59 ± 11
57 ± 11
0.386
157 ± 9
157 ± 12
0.852
Height (cm) 2
Body surface area (m )
1.59 ± 0.18
1.59 ± 0.18
0.966
Diabetics (n)
2
4
0.312
Hypertension (n)
18
16
0.464
Anesthesia time (min)
80 ± 25
89 ± 25
0.315
Operation time (min)
57 ± 18
63 ± 20
0.390
Pneumoperitoneum time (min)
37 ± 18
39 ± 21
0.707
Values are means ± SDs or number of patients
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Aging Clin Exp Res
Fig. 1 Intraoperative changes in hemodynamics and core and skin temperatures. MAP mean arterial pressure, HR heart rate, PACU postanesthesia care unit. Tbase, immediately before anesthetic induction;
T0, 5 min after anesthesia induction; PP0-30, from immediately to 30 min after pneumoperitoneum; and Tend, at the end of surgery
Antagonists of 5-HT3 receptor inhibit the neurotransmission required for thermoregulation in the hypothalamus, which is the primary locus of thermoregulatory control [19]. In a previous clinical study, it was suggested that the classic 5-HT3 receptor antagonist, ondansetron, inhibits thermoregulatory responses centrally and independently of core hypothermia induced by core-to-peripheral redistribution of heat after anesthetic induction [13]. However, in the present study, pre-operative administration of palonosetron 0.075 mg did not influence perioperative hypothermia or PAS in elderly patients undergoing laparoscopic cholecystectomy. We propose two possible explanations for this apparent discrepancy. In the previous clinical study, ondansetron was found to effectively prevent PAS in a dose-dependent manner, and at 8 mg, but not at 4 mg, ondansetron prevented PAS after general anesthesia [14]. In another study, although palonosetron at 0.075 mg (the usual dose used to prevent PONV) was superior to ondansetron 8 mg in terms of preventing PONV after
gynecologic laparoscopy [20], this dose may have been insufficient to control thermoregulation. Another possible explanation is that the relatively low incidence of PAS in our cohort might prevent proper statistical analysis. In a previous regression analysis of 1340 patients, it was found that an older age independently predicted a lower rate of PAS (odds ratio 0.59, P \ 0.001) [21]. Thus, we suggest that further dose–response study and comparisons of different age groups might help elucidate the effects of palonosetron on PAS and thermoregulation. There is the possibility that the lack of anti-shivering effect of palonosetron may not be limited to the elderly. Palonosetron shows the unique molecular interactions with 5-HT3 receptors [22]. Older drugs are based on a 3-substituted indole structure resembling serotonin, whereas palonosetron has a fused tricyclic ring system attached to quinuclidine moiety. Accordingly, palonosetron interacts with 5-HT3 receptors at sites different from or additional to those involved in ondansetron and granisetron binding
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Aging Clin Exp Res Table 2 Intraoperative hypothermia and post-anesthetic results
Variables
Palonosetron (n = 24)
Control (n = 23)
P value
Intraoperative hypothermia (n)
0.443
9
12
C36 °C
15
11
35.5–35.9 °C
6
5
35.0–35.4 °C
2
6
\35.0 °C
1
1
Post-anesthetic results after 30 min in PACU Mean arterial pressure (mmHg)
105 ± 18
103 ± 15
0.681
Heart rate (beats/min)
86 ± 15
89 ± 16
0.457
Tympanic temperature (°C)
36.4 ± 0.6
36.1 ± 0.5
0.147
Postoperative pain score
7 (5.25–8)
8 (7–10)
0.002
6.7 ± 1.9
8.3 ± 1.3
5
8
Grade 1
4
6
Grade 2
1
1
Grade 3 PONV (n)
0 8
1 6
Post-anesthesia shivering (n)
0.610
0.556
Values are means ± SDs, number of patients, or medians (interquartile ranges) PACU post-anesthetic care unit, PONV postoperative nausea and vomiting
[22]. These characteristics might partly explain our result. In addition, palonosetron of 0.075 has already been reported for its negative effect on PAS in young female patients (mean age 45 years) with a higher incidence of shivering in the control and palonosetron groups (33 vs. 27 %, respectively) [23]. The previous study has suggested that the lack of anti-shivering effect might result from remifentanil-induced PAS [24] and the molecular structure of palonosetron [23]. Because we did not use remifentanil, our result is not associated with remifentanil-induced PAS. In the present study, pre-operative palonosetron significantly reduced postoperative pain scores in elderly undergoing laparoscopic cholecystectomy. Selective 5-HT3 receptor antagonists are known to have good analgesic properties in backgrounds of fibromyalgia and chronic neuropathic pain by modulating the nociceptive pathway [25, 26]. Furthermore, in man, ondansetron ligates with lopioid receptors and acts as an agonist [27]. Our results suggest that the administration of palonosetron before anesthetic induction might modulate postoperative pain and enhance opioid-based patient-controlled analgesia in the elderly. Our result is supported by prior clinical studies. Pretreatment of palonosetron 0.075 mg could effectively reduce early postoperative pain after thyroid and breast cancer as well as propofol-induced injection pain [28, 29]. Summarizing, the pre-operative administration of palonosetron 0.075 mg did not influence perioperative hypothermia or post-anesthesia shivering in elderly patients after laparoscopic cholecystectomy under sevoflurane anesthesia. However, our findings show that palonosetron might be beneficial for reducing early postoperative pain in
elderly patients with opioid-based patient-controlled analgesia. Conflict of interest terest to declare.
The authors have no potential conflict of in-
Human and Animal Rights The study was conducted according to standards derived from the Declaration of Helsinki. Informed consent A written informed consent was obtained from every patient.
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