Hilary Wagner RN, BSN, SRNA Oakland University-Beaumont/MSN-Anesthesia Class of 2013

1. An Intraoperative Small Dose of Ketamine Prevents Remifentanil-Induced Postanesthetic Shivering Hilary Wagner RN, BSN, SRNA Oakland University-Beaumont/MSN-Anesthesia Class of 2013

2. Nakusuji, M., Nakamura, M., Imanaka, N., Tanaka, M., Nomura, M., & Suh, S. H. (2011). An intraoperative small dose of ketamine prevents remifentanil-induced postanesthetic shivering. Anesthesia & Analgesia, 113 (3).

3. Introduction • Published in the September 2011 edition of Anesthesia & Analgesia • The study was approved by the Human Ethics Review Committee of Kansai Denryoku Hospital in Japan

4. Study Objectives/Purpose • Postanesthetic shivering (PAS) is frequently encountered in patients after discontinuation of remifentanil infusion • Remifentanilis more likely to cause PAS than other opioids • However, the exact cause of remifentanil-induced PAS remains undetermined at this time

5. Study Objectives/Purpose • To investigate whether or not a ketamine infusion while using remifentanil during gynecological laparotomy cases reduces the incidence of PAS

6. Study • Patients were enrolled in this study from August 2009 to October 2010 • Randomized controlled trial • Prospective study • Dependent variable = Postanesthetic shivering • Independent variable = Ketamine infusion

7. Inclusion Criteria • ASA status of I or II • Under age 60 • Surgical time less than 3.5 hours (surgical times longer than 3.5 hours are correlated with PAS) • Patients were automatically excluded if they were: • undergoing emergency surgery • scheduled for radical hysterectomy

8. Methods • Signed written consent form was obtained from each subject • 64 patients meeting inclusion criteria were randomly assigned to receive either 0.5 mg/kg ketamine at induction followed by an infusion of 0.3 mg/kg/hr for the duration of surgery (n=32) or a similar volume of saline (n=32). • The patients were randomly assigned via envelope randomization

9. Methods (cont.) • In both groups, all patients received: • Midazolam IM (2.5-5 mg) 15 minutes before OR arrival • An epidural catheter at the T12-L1 interspace • Epidural ropivacaine titrated intraoperatively to maintain systolic arterial blood pressure within 20% or less of preoperative blood pressure • General anesthesia induced with propofol at 1.5-2 mg/kg IV and a remifentanil infusion at 0.25-0.5 mcg/kg/min (for analgesia) • Vecuronium bromide for tracheal intubation at 0.1 mg/kg IV

10. Methods (cont.) • Total IV anesthesia with propofol titrated to maintain a target Bispectral Index (BIS) value between 30-50 • FiO2 at 0.40 (a mix of oxygen and air, no nitrous oxide was used) • 100 mcg of fentanyl via the epidural catheter after closure of the peritoneum • 1.25 mg of droperidol at the end of the case to prevent postoperative nausea and vomiting • Forced air blanket to lower extremities at 32C which was discontinued when rectal temperature reached 37C • Lactated ringer’s solution infused at ambient temperature of 25-27C

11. Methods (cont.) • The OR staff were unaware as to which patients were part of the experimental and control groups • The staff monitored the patients for PAS while in the OR and for 30 minutes post-emergence

12. Outcome Measures(cont.) • Measured shivering with a 5-point rating scale 0: no shivering 1: peripheral vasoconstriction with no visible muscular activity 2: visible muscular activity confined to only 1 muscle group 3: visible muscular activity in more than 1 muscle group 4: gross muscular activity involving the whole body • A score between 3 and 4 indicated PAS

13. Methods (cont.) • The anesthesia provider remained absent during the PAS evaluation so as not to allow bias related to anesthetic regimen knowledge • Postoperative pain was also evaluated using the visual analog scale from 0 (no pain) to 10 (worst pain) • PAS was then treated using a warm blanket • If PAS persisted longer than 15 minutes, 50 mg of flurbiprofenaxetil was administered (COX inhibitor)

16. A flow diagram of inclusion and exclusion criteria applied in this study, based on the CONSORT (Consolidated Standards of Reporting Trials) statement. Nakasuji M et al. Anesth Analg 2011;113:484-487

17. Statistical Analysis • Student t test and the Mann-Whitney U test were used for statistical comparisons • Differences between the groups were considered statistically significant when the P value was <0.05 • Normality and equal variance tests were applied to all data (expressed as mean ± SD)

18. Results • No significant difference in temperature throughout anesthesia between both groups • All patients were found to be pain free for 30 minutes post emergence from anesthesia using the visual analog scale

19. Results (cont.) • Incidence of PAS in ketamine group • n=2, 6% • Incidence of PAS in control (saline) group • n=12, 38%, P=0.005

20. Discussion • The study showed that the incidence of remifentanil-induced PAS during the early recovery period was markedly reduced when ketamine was also administered intraoperatively • Exact mechanism of this remains to be discovered • Other factors which may have influenced the incidence of PAS were well controlled in this study (such as postoperative pain and hypothermia)

21. Strengths • Another study demonstrated decreased incidence of PAS when using intraoperative magnesium sulfate (a noncompetitive NMDA receptor antagonist) in patients receiving propofol/remifentanil based anesthesia • This suggests that the stimulation of NMDA receptors may be the underlying mechanism of remifentanil-induced PAS

22. Limitations • Small sample size (n=64) • Short duration of observation • Patients were only observed for 30 minutes after emergence • They may have developed PAS after transfer to the GYN floor • Cannot entirely exclude the possibility of residual sedative and analgesic effects being the cause of the differences observed

23. Conclusion • While the mechanism of the reduced incidence of PAS is still not fully understood, ketamine should be considered when using high dose remifentanil during surgery