Pain Medicine 2011; 12: 1418–1426 Wiley Periodicals, Inc. ACUTE PAIN SECTION Original Research Article Pre-Incisional Analgesia with Intravenous or Subcutaneous Infiltration of Ketamine Reduces Downloaded from https://academic.oup.com/painmedicine/article/12/9/1418/1899516 by guest on 01 October 2021 Postoperative Pain in Patients after Open Cholecystectomy: A Randomized, Double-Blind, Placebo-Controlled Studypme_1205 1418..1426 Mohammadreza Safavi, MD, Azim Honarmand, MD, VAS scores were significantly lower than Group KS1 and Zahra Nematollahy, MD (P < 0.05). Postoperative VAS scores were signifi- cantly lower at 1, 2, 3, 4, 8, 12, and 24 hours after Department of Anesthesiology and Intensive Care operation in Group KS1, Group KS2, and Group KI < Unit, Anesthesiology and Critical Care Research compared with Group C (P 0.05). In Group KS2, Center, Isfahan University of Medical Sciences, VAS scores were significantly lower than Group KS1 (P < 0.05). Isfahan, Iran Conclusion. A 2 mg/kg dose of subcutaneous infil- Reprint requests to: Azim Honarmand, MD, tration ketamine or 1 mg/kg dose of intravenous ket- Anesthesiology and Critical Care Research Center, amine given at approximately 15 minutes before Isfahan University of Medical Sciences, Isfahan, Iran. surgery provides an adjunctive analgesia during 24 Tel: 00989131102327; Fax: 00983112361594; E-mail: hours after surgery in patients undergoing chole- [email protected]. cystectomy surgery. Key Words. Pain; Acute; Postoperative; Preemp- Abstract tive; Ketamine; Open Cholecystectomy Background. In literature, there is controversy on the use of ketamine for management of postopera- Introduction tive pain. The aim of the present study was to evalu- ate the efficacy of pre-incisional intravenous or One of important factors in patient recovery is postopera- subcutaneous infiltration of ketamine on postopera- tive analgesia. Although many studies [1] confirmed that tive pain relief after open cholecystectomy. effective analgesia decreases postoperative complica- tions, pain often is overlooked and its control unsatisfac- Methods. One hundred twenty patients, aged 18–60 tory [2]. Releases of proteolytic and inflammatory years, scheduled for open cholecystectomy was mediators after surgical trauma generate powerful nocice- enrolled in this randomized, double-blind, placebo- ptive impulses that trigger pain [3]. controlled study. Patients were divided into four groups of 30 each and received subcutaneous infil- The most important phenomenon in transmission of tration of ketamine 1 mg/kg (group KS1), subcutane- inflammatory pain is sensitization of spinal cord with active ous infiltration of ketamine 2 mg/kg (group KS2), contribution of glutamate and aspartate aminoacids on intravenous ketamine 1 mg/kg (group KI), or subcu- the N-methyl-dimethyl-aspartate receptors (NMDA) [4]. taneous infiltration of normal saline 20 mL (group C) before surgery. Visual analog scale (VAS) values Ketamine, a non-competitive NMDA antagonist, prevents and analgesic consumption were evaluated for 24 central sensitization of nociceptors at subanesthetic doses hours after operation. by elimination of peripheral afferent noxious stimulation [5–7]. Stubhaug et al. [8] showed that ketamine decreases Results. VAS scores were significantly lower at acute postoperative pain by inhibiting C-fiber activity. arrival to the postanesthesia care unit, 15 and 30 minutes in Group KS1, Group KS2, and Group KI Moreover, Tan et al. [9] showed that the pre-incisional compared with Group C (P < 0.05). In Group KS2, treatment with subcutaneous infiltration of ketamine 1418 Pre-Incisional Ketamine for Pain after Cholecystectomy prolongs the time to first analgesic requirement, Sealed envelopes were prepared by an anesthesia decreases the total dosage of analgesics used and pain research nurse who did not involve in data collection. She score after circumcision surgery. prepared one envelope for each patient. The name of group was specified on each envelope. Then after, the Additionally, Aida et al. [10] showed that the pre-incisional envelopes were sealed and randomly ordered. These administration of subanesthetic doses of intravenous (IV) envelopes were stored in research nurse box in operating ketamine significantly improved postoperative analgesia. room. On the day of surgery, after taking informed consent, the first anesthesiologist who did not participate In view of the above conclusions, it seems reasonable to in data collection pull out one of the envelopes. He then suggest that preemptive infiltration of ketamine into the prepared and labeled similar syringes containing either intended line of surgical incision or IV administration of it normal saline or the study medications for each subject Downloaded from https://academic.oup.com/painmedicine/article/12/9/1418/1899516 by guest on 01 October 2021 may be a useful method for preventing postoperative according to the group that was specified in the envelope. somatic (wound) and visceral pain in some other surgeries All medications were 20 mL in volume. such as open cholecystectomy. So, we designed this randomized, double-blind, placebo control study to evalu- Patients received either: subcutaneous infiltration of ket- ate the analgesic effect of pre-incisional IV or subcutane- amine 1 mg/kg (group KS1) plus IV saline, subcutaneous ous infiltration of two low doses of ketamine on visceral infiltration of ketamine 2 mg/kg (group KS2) plus IV saline, and wound pain after open cholecystectomy. IV ketamine 1 mg/kg (group KI) plus subcutaneous infil- tration of saline, or subcutaneous infiltration of normal saline 20 mL (group C) plus IV saline before surgery. Sub- Materials and Methods cutaneous infiltration of study drugs was at the actual site of the incision. All the cholecystectomy incisions were One hundred twenty American Society of Anesthesiolo- subcostal. gists (ASA) physical status I-II patients, aged 18–60 years old, scheduled for open cholecystectomy gave Induction of anesthesia was performed by second anes- written informed consent to participate in the present thesiologist who was not aware from the group alloca- study, which was approved by our institute Ethics tion. After induction of anesthesia with 5 mg/kg of Committee. thiopental sodium, 3 mg/kg fentanyl and 0.6 mg/kg of atracurium for facilitation of tracheal intubation, the study The written informed consent was obtained on the day of drugs were administered by a surgeon who was not surgery by the anesthesiologist. The enrolled patients had involved in the group assignment. All the surgical inci- contraindication for laparoscopic cholecystectomy (i.e., sions were made only after 15 minutes had elapsed since acute cholangitis, severe acute-cholecystitis, acute pan- study drug administration. Anesthesia was maintained creatitis, peritonitis portal hypertension, and serious with 1.2% isoflurane, nitrous oxide 50% in oxygen. Mor- bleeding disorder as absolute contraindications and acute phine 0.1 mg/kg was administered for intraoperative cholecystitis, prior upper abdominal operation, minor analgesia intravenously. At the end of the operation, neu- bleeding disorder, common duct stones, and morbid romuscular blockade was reversed by IV neostigmine obesity as relative contraindications). 0.04 mg/kg and IV atropine 0.02 mg/kg. Consequently, anesthesia was discontinued and the tracheal tube was Exclusion criteria included patients with a known history removed in the operating room when airway reflexes had of hypertension, hyperthyroidism, psychiatric disorders, returned. allergy to ketamine, chronic pain syndrome, renal or hepatic insufficiency, history of seizure or intracranial HR, SpO2, SAP, DAP, and MAP were recorded at hypertension, or drug or alcohol abuse in the preceding 6 15-minute intervals during surgery, at the time of arrival to months. the PACU, at 15 minutes, and 30 minutes after that. These variables also were recorded at 1, 2, 3, 4, 8, 12, and 24 The patients were visited on the day before surgery and hours after operation at arrival to the ward. After extuba- were informed how to evaluate their pain by a 10-cm tion, the patients were transferred to the PACU where an visual analog scale (VAS), ranging from 0 (none) to 10 anesthetist and nurse who were unaware of the study (worst possible pain). No premedication was given to the drug observed the patients. In the PACU, pain scores patients. were assessed by a blinded observer physician at the time of arrival, 15, and 30 minutes using a VAS (0–10 cm: Noninvasive arterial blood pressure (systolic arterial pres- 0 = no pain, 10 = the worst pain possible). sure [SAP], diastolic arterial pressure [DAP], mean arterial blood pressure [MAP]), heart rate (HR), respiratory rate, During the postoperative period, pain score were evalu- and peripheral oxygen saturation (SpO2) level were moni- ated by an investigator who was blinded to the treatment tored in the operation room. assignment, at 1, 2, 3, 4, 8, 12, and 24 hours. The pain that we asked was both somatic (incision) and visceral in Using random selection of sealed envelopes, patients origin. In addition, the sedation level of patients was evalu- were randomized into one of four test groups with 30 ated with using a sedation scale (0, awake; 1, drowsy but patients in each group. responsive to verbal orders; 2, drowsy but responsive to 1419 Safavi et al. physical stimulus; 3 sleepy but responsive to pain stimu- comparing between groups for nonparametric variables. lus) at the all above mentioned times. If the VAS score was Mann–Whitney U-test would be used to compare for >4 cm, then 0.4 mg/kg meperidine was given intrave- pairs of groups. Sex, ASA physical status, and complica- nously and, if the score did not decrease within 10 tion rates were assessed by Pearson chi-square test and minutes, an additional 0.2 mg/kg meperidine was admin- by Fisher’s exact test when the anticipated number was istered. The total meperidine dose did not exceed a <5. P < 0.05 was considered statistically significant. All maximum of 2 mg/kg in any 4 hours. Meperidine was statistical analyses were performed using SPSS 16.0 for only analgesic drugs we used for postoperative pain man- Windows statistical package (SPSS Inc., Chicago, IL, agement.