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Ambulatory Anesthesiology: Brief Report

An Intraoperative Small Dose of Ketamine Prevents Remifentanil-Induced Postanesthetic Shivering

Nakasuji, Masato, MD; Nakamura, Mitsuyo, MD; Imanaka, Norie, MD; Tanaka, Masuji, MD; Nomura, Masataka, MD; Suh, Soon Hak, MD

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doi: 10.1213/ANE.0b013e318224ac4e

Remifentanil is often used for intraoperative analgesia. Postanesthetic shivering (PAS) is often encountered in patients after discontinuation of remifentanil. Some reports have described an increase in the incidence of PAS with remifentanil,13 and remifentanil is more likely to cause PAS than other opioids, even though the exact underlying mechanism of remifentanil-induced PAS remains undetermined.4 We previously reported that remifentanil-induced PAS is not a phenomenon of intraoperative hypothermia and that high-dose remifentanil increased PAS.5 We consider that patients administered high doses of remifentanil during surgery are more likely to experience shivering after sudden discontinuation in a manner similar to the increased incidence of hyperalgesia after high-dose remifentanil administration.6 Ketamine, a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has been reported to inhibit opiate-induced PAS.79 We hypothesized that, in the absence of pain and similar intraoperative temperature, ketamine would reduce the incidence of remifentanil-induced PAS.


The study protocol was approved by the Human Ethics Review Committee of Kansai Denryoku Hospital and a signed consent form was obtained from each subject. The study subjects were consecutive patients who underwent laparotomy for a gynecological procedure between August 2009 and October 2010 at Kansai Denryoku Hospital. Patients were excluded if they were ASA physical status III or more, older than 60 years, undergoing emergency surgery, or scheduled for radical hysterectomy. When surgery exceeded 3.5 hours, the study was discontinued and the patient was excluded because the duration of surgery is reported to correlate with the incidence of PAS.10,11

Sixty-four patients meeting inclusion criteria were randomly (envelope randomization) assigned to receive either 0.5 mg/kg ketamine at induction followed by intraoperative infusion of 0.3 mg/kg/h until the end of surgery (ketamine group, n = 32), or a similar volume of normal saline (control group, n = 32). In both groups, patients were premedicated with IM midazolam (2.5–5 mg) 15 minutes before arrival in the operating room (OR). An epidural catheter was placed at the T12-L1 interspace. General anesthesia was then initiated. Anesthesia was induced with propofol 1.5 to 2 mg/kg and remifentanil 0.25 to 0.5 μg/kg/min. Vecuronium bromide 0.1 mg/kg was administered for endotracheal intubation. Patients' lungs were ventilated using oxygen in air (fraction of inspired oxygen, 0.4). Nitrous oxide was not used during surgery. Anesthesia was maintained with propofol 5 to 10 mg/kg/h, remifentanil 0.25 μg/kg/min, and vecuronium bromide. The intraoperative remifentanil infusion rate was fixed. To ensure adequate and similar analgesia between the groups, epidural ropivacaine was titrated intraoperatively to maintain systolic arterial blood pressure between −20% and 0% of its value measured at the preoperative anesthetic interview (defined as baseline arterial blood pressure). Propofol was titrated to maintain a target Bispectral Index (BIS) value between 30 and 50. When systolic arterial blood pressure decreased below 80 mm Hg or by 30% from the baseline value, 5 mg ephedrine was injected IV. Intraoperative remifentanil and propofol were discontinued at the end of surgery. Epidural ropivacaine was administered at 8 mg/h postoperatively. Fentanyl 100 μg was administered via the epidural catheter after closure of the peritoneum. Droperidol 1.25 mg was administered to prevent postoperative nausea and vomiting at the end of surgery. Body temperature was measured at the rectum and palm skin surface (thumb). Ambient temperature was 22°C to 24°C during surgery and 25°C to 27°C postoperatively. The lower extremities were covered by a forced air blanket at 32°C, and warming was discontinued when rectal temperature reached 37°C. Acetated Ringer solution was infused at ambient temperature.

The OR nursing staff who were blinded to the anesthetic regimen checked the patients for PAS while in the OR for 30 minutes after emergence from anesthesia. The nursing staff judged PAS using a 5-point rating scale described by Wrench et al.12 (0 = no shivering, 1 = peripheral vasoconstriction without visible muscular activity, 2 = visible muscular activity confined to 1 muscle group, 3 = visible muscular activity in >1 muscle group, and 4 = gross muscular activity involving the entire body). Grade 3 and 4 represented the occurrence of PAS and the “Incidence of PAS” was written in the postoperative record by the nursing staff. During the same 30 minutes after emergence, with the patient reclining comfortably on the bed, the nursing staff evaluated postoperative pain using a visual analog scale from 0 cm (no pain) to 10 cm (worst pain ever). The anesthesiologist in charge of the patient was absent during PAS assessment to avoid bias related to knowledge of the anesthetic regimen. PAS was treated initially using a warm blanket, and then if the shivering persisted for >15 minutes despite warming, flurbiprofen axetil 50 mg was administered.

Based on our previous study, we estimated the incidence of PAS as 5% after intraoperative ketamine versus 32% in the absence of ketamine.5 Power analysis indicated a minimum sample size of 32 patients in each group would be necessary to detect this difference with a power of 80% and an α of 0.05. Because the incidence of PAS may increase with increasing duration of surgery, we reviewed 46 records from August 2008 to July 2009 in patients undergoing gynecological laparotomy with propofol/remifentanil-based anesthesia, and we calculated the sensitivity and specificity related to the proportion of PAS and duration of surgery (every 30 minutes). The area under the receiver operating characteristic curves was 0.851 with an optimal threshold value of 3.5 hours, yielding a sensitivity of 89% and specificity of 74%. Thus, in patients whose procedure lasted longer than 3.5 hours, the study was stopped and they were excluded from further analysis. Normality (Kolmogorov-Smirnov) and equal-variance tests were applied to all data, which were expressed as mean ± SD or median values (interquartile range). The Student t test and the Mann-Whitney U test were used for statistical comparisons. χ2 and Fisher exact tests were also used to compare category data. Repeated-measure analysis of variance was performed to compare time lapse of rectal and palm skin temperatures during general anesthesia between the 2 groups. Differences between groups were considered statistically significant when the P value was <0.05.


Eighty patients were approached during the observation period. Sixteen patients were excluded preoperatively and 7 patients were later excluded (Fig. 1). The incidence of PAS during the observation period was significantly less frequent in the ketamine group (n = 2, 6%) than in the control group (n = 12, 38%, P = 0.005, power = 0.882). Analysis of patients' baseline characteristics and intraoperative factors showed no differences between groups except for BIS values (Table 1). None of the patients received blood or transfusion of blood products and there was no significant difference between groups with regard to the proportion of patients who required intraoperative ephedrine (41% in control group vs 25% in ketamine group). There was no significant difference in rectal or palm skin temperature throughout anesthesia between groups. All patients in both groups were evaluated as being pain-free (visual analog scale score 0 cm) for 30 minutes after emergence from anesthesia.

Figure 1
Figure 1:
A flow diagram of inclusion and exclusion criteria applied in this study, based on the CONSORT (Consolidated Standards of Reporting Trials) statement. Six patients were later excluded because of prolonged surgery after the start of the protocol. One patient was also excluded because 0.25 μg/kg/min remifentanil could not be administered continuously as a result of circulatory instability requiring phenylephrine in addition to ephedrine.
Table 1
Table 1:
Comparison of Perioperative Clinical Variables Between the Ketamine and Control Groups


We found that the incidence of remifentanil-induced PAS during early recovery was markedly reduced when ketamine was administered intraoperatively. The exact underlying mechanism for this finding (residual sedative and analgesic effects after discontinuation or stimulation of the NMDA receptors79) remains to be determined. In this study, other factors such as postoperative pain and hypothermia, which might have influenced the incidence of PAS,4 were well controlled. Although ketamine has analgesic and anesthetic effects, it also induces vasoconstriction13 and increases BIS values.14,15 This may explain why intraoperative propofol and epidural ropivacaine doses were not lower in the ketamine group than in the control group. Ryu et al.16 reported a similar reduction in PAS using intraoperative magnesium sulfate, a noncompetitive NMDA receptor antagonist, in patients undergoing propofol/ remifentanil-based general anesthesia. Therefore, we consider that stimulation of the NMDA receptors is the more likely underlying mechanism of remifentanil-induced PAS rather than residual sedative and analgesic effects.

In choosing the dose of ketamine, the highest priority was given to minimizing tracheal extubation time. We thus chose the dose used by Joly et al.,17 as described in their article concerning the effect of continuous intraoperative small-dose ketamine on remifentanil-induced postoperative hyperalgesia.

A weakness of our study is the short duration of observation. We cannot exclude the possibility that shivering occurred in additional patients in the ketamine group after transfer to the gynecological floors.

In conclusion, an intraoperative small dose of ketamine reduced the early incidence of remifentanil-induced PAS. We cannot completely exclude the possibility of the residual sedative and analgesic effects after discontinuation of ketamine as being the reason for the differences observed. However, based on the results of this study and our previous findings,5 we suggest that the sudden discontinuation of high-dose remifentanil may be associated with stimulation of NMDA receptors as part of acute opioid tolerance leading to both hyperalgesia and PAS. Although the underlying mechanism of the reduced incidence of PAS has not been resolved, intraoperative administration of ketamine should be considered when a high dose of remifentanil is used during surgery.


Name: Masato Nakasuji, MD.

Contribution: Study design, conduct of the study, data collection, data analysis, manuscript preparation.

Name: Mitsuyo Nakamura, MD.

Contribution: Conduct of the study, data collection.

Name: Norie Imanaka, MD.

Contribution: Conduct of the study, data collection.

Name: Masuji Tanaka, MD.

Contribution: Conduct of the study, data collection.

Name: Masataka Nomura, MD.

Contribution: Conduct of the study, data collection.

Name: Soon Hak Suh, MD.

Contribution: Conduct of the study, data collection, data analysis.


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