Does fentanyl or remifentanil provide better postoperative recovery after laparoscopic surgery? a randomized controlled trial

This study was prospective, patient and investigator-blinded, controlled, parallel-group clinical trial with equal randomization performed at the Yokohama City University Hospital. Ethical approval for this study (approval number: B120510058) was provided by the Ethics Committee of Yokohama City University Hospital (Chairperson Prof K. Ohashi), Yokohama, Japan on May 2012. The trial was registered at www.​umin.​ac.​jp (UMIN000010464) and enrolment started from April 2013. The enrolment ended at March 2015, and the follow-up completed at July 2015.

Adult patients aged 20 to 79 years, with ASA physical status (PS) 1 and 2, who were scheduled to undergo a laparoscopic or retroperitoneoscopic renal or ureteral surgery were enrolled to the study. Patients using corticosteroid, antiemetics, opioids, or immunosuppressants; those with severe liver or renal dysfunction, poor Japanese comprehension, psychiatric disturbances, or massive blood loss during surgery; and pregnant subjects were excluded from enrolment. Written informed consent was obtained from all participants.

Subjects were randomized to either fentanyl or remifentanil based anesthesia groups, using a randomization plan with a 1:1 allocation using random block size of 10, obtained from www.​randomization.​com. Group assignments were sealed in sequentially numbered opaque envelopes, which were opened after the patients provided informed consent. The attending anesthesiologists were aware of the allocated arm; however, they did not take outcome measurements, and the patients, data collectors (ward nursing staffs), and data analysts were kept blinded to the allocation. In addition, all investigators, staffs, and patients were kept masked to outcome measurement and trial results.

The study subjects received no premedication. All patients received fentanyl 2 μg/kg and target controlled infusion (TCI) propofol 3–6 μg/ml for inducing anesthesia, and rocuronium 0.6 mg/kg to ease tracheal intubation. After the intubation, TCI propofol was adjusted to keep a bispectral index between 40 and 60 throughout the surgery. No volatile anesthetic was used. Rocuronium was appropriately added during the surgery to maintain the train-of-four count of 1 and 2. A catheter was placed in the radial artery to monitor blood pressure continuously and to draw blood for blood samples. In the remifentanil group, remifentanil 0.2 μg/kg/min was commenced at the induction, and was infused continuously during the surgery until the end of the insufflation. The infusing rate was controlled between 0.05 and 0.5 μg/kg/min by the attending anesthesiologist to regulate the mean arterial pressure (MAP) within 20% of preoperative values. Considering the postoperative pain after termination of remifentanil, which may lead to lower QoR-40 score, fentanyl 1 μg/kg was administered every hour, to load for postoperative patient-controlled anesthesia (PCA). In the fentanyl group, fentanyl 2 μg/kg was administered before the surgery began, and fentanyl 1 μg/kg was additionally given at any time to maintain the MAP as written above. During maintenance, F_IO₂ was kept between 0.4 and 0.6 and end tidal CO₂ between 30 and 45. Core body temperature was maintained at 36–37 °C. The CO₂ insufflation pressure was basically 10 mmHg, and was occasionally raised to 12 mmHg. At the end of the insufflation, both groups received 50 mg flurbiprofen, and PCA (CADD Legacy™, Smiths Medical Japan, Tokyo, Japan) with fentanyl (15–30 μg/ml, 1 ml/h, bolus dose 1 ml, lockout 30 min) was started. Droperidol 2.5 mg was added into PCA as PONV prophylaxis, but no other prophylaxis was administered in the operating room. No local anesthesia was administered in the ports or surgical field. Neostigmine and atropine were administered to reverse neuromuscular blocks. We confirmed that patients were not in pain before leaving the operating room. Patients were free to use non-opioid analgesics in the wards, if the pain could not be controlled by PCA.

The QoR-40 questionnaire [12] (Japanese version [13]) was presented to the participants 24 h after the surgical procedure. The QoR-40, as Myles introduced, “is a 40-item quality of recovery score measuring five dimensions: emotional state, physical comfort, psychological support, physical independence, and pain. Each item is rated on a 5-point Likert scale” [9], so the scores are from 40 to 200, with a higher score indicating the better QoR.

The SF-36 (Japanese version [14, 15]) was sent by mail to the subjects 1 and 3 months after surgery and was sent back by the subjects using enclosed return envelope. The SF-36 is “widely used to measure health related QoL, which consists of eight scales: physical function (PF), role limitations due to physical problems (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role limitations due to emotional problems (RE), and mental health (MH)” [16]. Scores are from 0 to 100 points, with the higher score indicating the better QoL. To minimize the loss to follow up, we sent a reminder to the subjects who had not returned the questionnaire.

Additional postoperative data collected were adrenocorticotropic hormone (ACTH), adrenaline, noradrenaline, dopamine, and cort (The samples were immediately taken to the clinical laboratory). Furthermore, data of the postoperative nausea and vomiting (PONV) and antiemetics use were collected when leaving the operating room, on 6 h and 24 h after the surgery. The pain score at rest and in motion using the numerical rating scale (NRS) from 0 (no pain) to 10 (worst pain imaginable) were asked on 6 h, 24 h, and 48 h after the surgery. The time when the patients started drinking and walking, and the total amount of bolus fentanyl consumed using the PCA were also checked.

Normally distributed data are reported as the mean (± SD) and were analyzed using unpaired t test. Non-normally distributed data are reported as the median (interquartile range [IQR]) and were analyzed using Mann-Whitney test. Categorical data were compared using Fisher’s exact test. The SF-36 scores, hormones, and the pain score were compared using two-way repeated-measures analysis of variance (ANOVA) followed by between-group post hoc Student t tests with Bonferroni correction if significant differences revealed. Sample size analysis was performed using the R statistical software package, version 3.0.2 (R Foundation for Statistical Computing, Vienna, Austria). All other statistical analyses were performed using the GraphPad PRISM version 6.0 (La Jolla, CA), and P-values < 0.05 were considered statistically significant.