The effect of low‐dose ketamine on postoperative quality of recovery in patients undergoing breast cancer surgery: A randomised, placebo‐controlled trial

Low‐dose ketamine has been proved to reduce opioid consumption, prevent depressant action and improve postoperative analgesia. Women undergoing mastectomy experience may not only have persistent postoperative pain syndromes but also emotional problems. However, the effect of intraoperative infusion of low‐dose ketamine on postoperative quality of recovery among these patients has not yet been fully studied.


| Subjects
We performed a prospective, randomised, single-centre clinical trial,

| Intervention
Patients were randomly assigned to one of two groups based on computer-generated codes that were maintained in sequentially numbered opaque envelopes: control group (group C) or ketamine group (group K) at a ratio of 1:1. On the day of surgery, a responsible anesthesiologist who was not involved in patient evaluation opened the envelope and prepared either 0.5% ketamine or normal saline in 20 ml syringes, then labelled them as 'study drug' for double-blind purposes.
After induction of anaesthesia and before surgical incision, a bolus dose of 0.5 mg/kg ketamine or an equivalent volume of normal saline was infused via a reliable intravenous catheter, followed by 0.25 mg·kg −1 ·h −1 ketamine or normal saline infusions until the end of surgery.
The ketamine diluents were mixed to concentrations of 5 mg/ml to ensure that all drugs were infused at a bolus of 0.1 ml/kg followed by 0.05 ml·kg −1 ·h −1 thereafter. None of the investigators involved in patient management or data collection were aware of the group assignments.

| Anaesthetic Management
All patients fasted for at least 6-8 hours before the surgery. After entering the operating room, venous access was opened. Heart rate (HR),

What's known
We have known that intraoperative low-dose ketamine could be an adjunct in the management of acute perioperative pain and may have a potential role in rescue depression.

What's new
Intraoperative infusion of low-dose ketamine did not improve the overall quality of recovery among patients undergoing modified radical mastectomy, whilst it may be beneficial for postoperative pain release.
As it is well known that the Bispectral Index (BIS) is not suitable for monitoring the anaesthesia depth regarding ketamine, the anaesthetic depth was titrated by an experienced attending anesthesiologist who is independent of the whole study, by adjusting the dosage of propofol and remifentanil based on the systolic blood pressure no greater or less than 20% compared with basal blood pressure. Also, the precise assumption of intraoperative propofol and also remifentanil in both groups were

| Primary outcome
The primary endpoint of the study was the global QoR-40 score on POD 1.

| Secondary outcomes
The secondary endpoints were the numeric rating scale (NRS) at

| Outcome assessment
A researcher who was unaware of the group assignments visited each patient to administer the QoR-40 survey the day before surgery and POD1. QoR-40 is a self-scoring questionnaire that examines the conditions associated with patients' recovery, including 5 subsections: physical comfort, emotional state, physical independence, psychological support and pain, for a total of 40 items. The scores of each item are added together as the final total score. The lowest score is 40 points and the highest score is 200 points, the higher the score, the better the patients recover. The pain score in QoR-40 is in opposition to other pain scores as we knew before, and high pain scores in QoR-40 mean that patients improve their pain. The QoR-40 survey has been widely used and validated for patients undergoing a variety of surgical procedures.

| Statistical analysis
All continuous variables data were assessed for normality using the Kolmogorov-Smirnov tests, and the Levene test was used to assess equality of variances. Group comparisons were made using two in- According to previous studies, a QoR-40 score of 10 or more differences was considered to be a clinically significant improvement or worsening of recovery quality. Based on our preliminary data, the variability (SD) of QoR-40 scores on the first day after breast cancer surgery was 15. The estimated sample size was 37 patients per group with a power of 80% at an α level of 0.05. We enrolled a final total of 50 patients per group, allowing for about a 30% drop-out rate.

| RE SULTS
Among 205 patients were screened between September 2018 and February 2019, 73 patients did not meet inclusion criteria, 10 patients satisfied the exclusion criteria, and 12 patients declined to participate. As 7 patients cancelled the operation and 3 patients withdrew consent, a total of 100 patients were finally randomly assigned to two groups. Primary outcome analysis is consisted of 49 patients in group C and 48 patients in group K, as 1 patient changed operation in group C, 1 patient changed surgery plan and 1 patient dropped out in group K (Figure 1). Demographic and baseline characteristics were generally comparable between the two groups (Table 1).

| Primary outcome
The global QoR-40 scores and subsections for the two groups are shown in Table 2. There were no differences in global QoR-40 scores on POD1 between the patients in group C and group K (169.8 ± 10.7 vs. 172.7 ± 7.5, 95% CI −1.35 (−5.50, 2.80), p = .519). In a post hoc analysis, among the subsection of QoR-40, pain scores were significantly higher in group K than in group C (29.8 ± 3.8 vs. 31.7 ± 2.1, 95% CI −1.81 (−3.00, −0.62), p = .003), which indicates patients may have better performance in pain in group K. Scores for the 4 other subsections on POD 1 were not significantly different between group C and group K (p value for each >.10) ( Table 2).

| Secondary outcomes
Postoperative recovery elements, such as NRS at rest and when moving at 4, 24, 48 h postoperatively, were not significantly different between groups (p value for each >.40). ICFS scores at 3 and 7 days after operation were similar between groups (p = .159 and 0.911, respectively). HADS scores at 2 days and 3 months after operation were also similar between groups (p = .764 and 0.727, respectively). Chronic pain at 3 months postoperatively was comparable between groups (p = .359) ( Table 3).

| Other parameters
Other surgery-related data and safety outcomes related to the usage of ketamine are presented in Tables 4 and 5. The vital signs, propofol and remifentanil consumption, the emergence time and duration of PACU stay, the analgesics required frequency, and safety outcomes had no difference between groups. No hallucinations or chills were observed in any of the participants.

| DISCUSS ION
In this study, we did not observe any significant difference in patients who received continuous intraoperative low-dose ketamine and control patients who did not receive ketamine, in terms of the global core of QoR following mastectomy. We did not find any improvements in NRS scores, ICFS scores, HADS scores and chronic pain regarding the ketamine intervention, either. However, among the 5 subsections of QoR-40, the pain score was significantly higher in the group that received ketamine. To our knowledge, the present study is the first to report the effects of continuous intraoperatively administered low-dose ketamine on quality of recovery using the QoR-40 survey among women undergoing modified radical mastectomy.
When defining the quality of postoperative recovery, not only pain control, but also patients' emotional and psychological state, physical comfort and physical independence should be considered.

The global QoR-40 is the first established and verified clinical tool
for measuring functional recovery in the immediate postoperative period. Its scoring system contains five different subsections and assesses pain as well as the aforementioned aspects. Whilst it is F I G U R E 1 CONSORT flow diagram of participants suggested that a minimum 10-point difference represents a clinically relevant improvement in quality of recovery, 11 a recent study reported that a change of 6.3 can be the minimum clinically important difference. 12 In the present study, even median QoR-40 scores in group K were ~3 higher than those in group C at POD1, this difference was not statistically significant. Further statistical analysis of each QoR-40 dimension may offer additional valuable information. Thus, we conducted post hoc statistical analysis of each subsection of QoR-40 between groups. This revealed that the ketamine group has higher pain scores than those in the control group. These data indicate that ketamine may help to improve patients' analgesia but may not be beneficial for other aspects of the recovery.
By activating NMDA receptors, persistent nociceptive input can lead to pain sensitisation. The mechanism of ketamine-induced antihyperalgesia is predominantly by noncompetitive antagonism of the NMDA receptor. This promotes structural synaptic connectivity thereby leading to prolonged antidepressant effects. 13 Opioidinduced hyperalgesia (OIH) refers to the long-term application of opioid analgesics, and the damage caused by peripheral tissue damage or inflammation has a strong nociceptive response to noxious stimuli, and NMDA receptors play a key role in OIH. As an NMDA receptor antagonist, ketamine is thought to prevent or reduce OIH through antagonising the NMDA receptor. Ketamine was also shown TA B L E 1 Patients' characteristics  Note: Data are presented as mean (SD, standard deviation).

TA B L E 2 The Global QoR-40 scores between groups
to reduce hyperalgesia, prevent opioid tolerance in animals, 14 reduce morphine resistance in humans 15 and decrease morphine consumption after transthoracic lung and heart surgery. 16  So in the present study, considering the potential side effects caused by higher and long-term administration of ketamine, we administered subanaesthetic ketamine during the surgery. Although the dosage we selected in this article mainly referred to the study in rectal adenocarcinoma surgery. 20 We did not observe similar positive effects related to ketamine partially because of the difference in surgery types. In future study, the dose of ketamine or the length of infusion may have to be increased or prolonged to achieve better outcomes.
Second, other analgesics, such as nonsteroidal anti-inflammatory drugs and glucocorticoids, were not restricted between groups in our study, which may also have the ability to block NMDA receptors and thus reduce the differences in recovery quality and analgesic effects between groups.
There are several limitations of our study. First, we excluded subjects with a history of chronic pain or those taking analgesics before surgery as this population would introduce a bias in the assessment of  Note: Data are presented as mean (SD, standard deviation).
Abbreviations: Emergence time, from discontinuation of anaesthetics to extubation; Group C, control group; Group K, ketamine group; HR, heart rate; MAP, mean arterial blood pressure; PACU, postanaesthetic care unit; SpO 2 , peripheral oxygen saturation; T1, 10 min after ketamine infusion; T2, the moment of extubation; T3, 10 min after extubation. Note: Data are presented as median (IQR, interquartile range) or numbers (proportion, %). Hallucinations and chill are not found in this study. Analgesics refer to flurbiprofen axetil or dezocine.

TA B L E 5 Postoperative safety outcomes
Abbreviations: Group C, control group; Group K, ketamine group. postoperative recovery quality. A recent study has highlighted a possible role for ketamine in opioid-dependent chronic pain patients. 2 Patients in the ketamine group had significantly reduced postoperative morphine consumption and better outcomes at 6 months, so the effect of ketamine in opioid-dependent patients is worth exploring. Second, we did not perform regional nerve block in both groups. On the one hand, the main purpose of the trial was to observe the effect of ketamine on the total score of QoR40, which involved acute pain as an important component.
On the other hand, NAISIDS and other drugs for analgesic remediation were allowed to be used as the rescue of insufficient analgesia effect postoperatively. Third, nevertheless, as the median difference in QoR-40 between the two groups was only 3 and the minimum clinically important difference is at least 6.3, expanding the sample size to observe a greater effect may be worthwhile and should be considered in the future studies.
Further studies should evaluate higher doses or extend the administration of ketamine into the recovery period in both male and female patients.

| CON CLUS ION
In conclusion, based on this study, intravenous low-dose ketamine did not benefit female patients' overall quality of recovery on POD 1 undergoing breast cancer surgery.

D I SCLOS U R E S
The authors have declared no conflicts of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available because of privacy or ethical restrictions.