Low Doses of Ketamine and Postoperative Quality of Recovery

• ClinicalTrials.gov Identifier: NCT02571153
• Recruitment Status: Completed
• First Posted: October 8, 2015
• Results First Posted: March 6, 2017
• Last Update Posted: March 6, 2017
• Sponsor: Pontificia Universidade Catolica de Sao Paulo
• Information provided by (Responsible Party): Eduardo Toshiyuki Moro, Pontificia Universidade Catolica de Sao Paulo

Tracking Information

• First Submitted Date: October 2, 2015
• First Posted Date: October 8, 2015
• Results First Submitted Date: September 28, 2016
• Results First Posted Date: March 6, 2017
• Last Update Posted Date: March 6, 2017
• Study Start Date: September 2015
• Actual Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 12, 2017)

Quality of Postoperative Recovery Assessed by QoR-40 Questionnaire 24 Hours After Surgery [ Time Frame: 24 hours ]

Quality of postoperative functional recovery assessed by the questionnaire QoR40 The quality of postoperative functional recovery was assessed by the QoR-40 questionnaire, which assesses five dimensions of recovery (physical comfort - 12 items; emotional state - 7 items; physical independence - 5 items; physiological support - 7 items; and pain - 7 items). Each item was rated on a five-point Likert scale: none of the time, some of the time, usually, most of the time, and all the time. The total score on the QoR-40 ranges from 40 (poorest quality of recovery) to 200 (best quality of recovery). The QoR-40 was administered by a blind investigator 24 hours after surgery.

Original Primary Outcome Measures (submitted: October 6, 2015)

QoR-40 [ Time Frame: 24 hours ]

Quality of postoperative functional recovery assessed by the questionnaire QoR40

Current Secondary Outcome Measures (submitted: January 12, 2017)

• Length of PACU Stay [ Time Frame: During the stay at postanesthesia recovery room (about 90 to 120 minutes) ]
  Length of stay at postanesthesia recovery room
• Occurrence of Postoperative, Nausea and Vomiting [ Time Frame: 24 hours ]
  Percentage of participants with postoperative nausea and vomiting at the PACU and during the hospital ward stay
• Occurrence of Pain at PACU Using a 0-10 Numeric Pain Rating Scale [ Time Frame: 90 minutes postanesthesia at recovery room ]
  Occurrence of pain at the PACU. Average Pain will be calculated. The pain score will be evaluated using a 0-10 numeric pain rating scale, where zero mean no pain and 10 the worst imaginable pain.
• Morphine Consumption (mg) at PACU [ Time Frame: During the stay at postanesthesia recovery room (about 90 to 120 minutes) ]
  Morphine consumption (mg) at PACU (about 90 to 120 minutes)
• The Severity of Postoperative Pain [ Time Frame: 24 hours ]
  The severity of postoperative pain was rated the higher score of pain (NRS) during the hospital ward stay. Pain was evaluated using a 0-10 numeric pain rating scale (NRS), where zero meant no pain and 10 the worst imaginable pain.
• Percentage of Participants With Tramadol Consumption [ Time Frame: 24 hours ]
  Percentage of Participants with Tramadol during the ward stay

Original Secondary Outcome Measures (submitted: October 6, 2015)

• Length of PACU Stay [ Time Frame: 5 minutes ]
  Length of stay at postanesthesia recovery room
• PONV [ Time Frame: 24 hours ]
  Occurrence of nausea and vomiting at the PACU and during the hospital ward stay
• Pain [ Time Frame: 24 hours ]
  Occurrence of pain at the PACU and during the hospital ward stay

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Low Doses of Ketamine and Postoperative Quality of Recovery
• Official Title: Effects of Low Doses of Ketamine on Postoperative Quality of Recovery After Total Intravenous Anesthesia
• Brief Summary: There are evidences that intraoperative administration of low doses of ketamine may contribute to control the postoperative pain by acting on the N-methyl-D-aspartate (NMDA) channel, reducing the effects related to the tolerance and hyperalgesia induced by opioids. This study aims to evaluate the effects of administration of this agent not only as an analgesic but also its role in the quality of recovery from anesthesia, which includes observation of emotional, psychological and physical aspects. Patients who were scheduled to undergo total intravenous anesthesia (TIVA) for laparoscopic cholecystectomy will be enrolled in this clinical study. After induction of anesthesia, patients will receive one of three solutions according to the randomly selected group: ketamine 0,2 mg/kg; ketamine 0,4 mg/kg or saline. In the recovery room and on the ward, data related to the presence of pain, analgesic consumption, the incidence of nausea and vomiting, dizziness or hallucinations will be recorded. The next day, the quality of recovery will be evaluated by application of the questionnaire QoR40 (Quality of Recovery Questionnaire-40).

Detailed Description

Introduction It is known that nociceptive stimuli, triggered by surgery and tissue inflammation can cause peripheral sensitization and primary hyperalgesia, increases spinal responsiveness to stimuli, whether harmful or not, due to the wind-up phenomenon, and other mechanisms, with induction central sensitization. Additionally, opioids commonly employed during general anesthesia may activate, both, the antinociceptive system and the pro-nociceptive system which can lead to acute tolerance and hyperalgesia. There is evidence that NMDA receptors are involved in the development of these changes and that low doses of ketamine (< 1mg/kg) may control of postoperative pain to bind to the receptor phencyclidine the NMDA channel and inhibit the activation of the channel by glutamate non-competitively. Recently, there has been a change in pain management, which includes the observation of non-traditional variables such as those related to the concepts of satisfaction and quality of life related to health. To this end, a growing number of authors went on to assess the opinion of patients as a way to determine the quality of recovery from anesthesia, meaning the observation not only of pain intensity, but also aspects related to emotional state, comfort and independence physical. The QoR-40 questionnaire (Quality of recovery-40), a validated instrument for this purpose, allows an objective approach of these factors that can influence the perception of the patient and allows you to compare different therapeutic ways. There are no recent data on the application of this instrument to assess the effects of giving, or not, of low doses of ketamine on the quality of recovery of patients undergoing total intravenous anesthesia.

Methods After arrival in the operating room, standard American Society of Anesthesiologists (ASA) monitors will be applied. Midazolam 0.06 mg/kg and 1% lidocaine (30 mg) will be administered intravenously immediately after venoclysis. After anesthesia induction, capnographic monitoring will be added and the neuromuscular blockade will be evaluated using acceleromyography (TOF Watch). Induction and maintenance of anesthesia will be performed as follows: remifentanil, induction dose 0.5 μg/kg/min, followed by a maintenance dose of 0.3 μg/kg/min. Propofol, initial bolus (2.0 mg/kg) followed by infusion at 4 to 6 mg/kg/h. Each patient will receive rocuronium (0.6 mg/kg) before tracheal intubation. Ventilation will be controlled by adjusting the flow volume and respiratory rate to keep the end-tidal carbon dioxid (CO2) level between 30 and 40 mmHg. In the case of inadequate depth of anesthesia (movements, sweating, tachycardia, blood pressure increase >10% of the pre-induction value), propofol infusion or sevoflurane rate will be increased (by 1%); if this was not sufficient, the remifentanil infusion rate will be also increased (by 0,1 μg/kg/min). Patients who exhibit reductions in systolic arterial pressure (SAP) greater than 30% or heart rate (HR) reductions to less than 50 bpm will be given ephedrine (10 mg) and atropine (0.5 mg), respectively. After induction patients will receive one of three intravenous solutions: ketamine 0.2 mg/kg - diluted in saline until the volume of 5 mililiters (mL) (k2 group); ketamine 0.4 mg/kg diluted in saline until the volume of 5 ml (k4 group) or 5mL of 0.9% normal saline (K0 group). Hydration will be maintained with 0.9% normal saline 2 ml/kg/h. All of the participants were given dexamethasone (8 mg) and ketoprofen (100 mg) at the onset of surgery and dimenhydrinate (30 mg), dipyrone (1 g) and morphine (0.1 mg/kg) 15 minutes prior the end of the procedure. Atropine (0.01 mg/kg) and neostigmine (0.05 mg/kg) were used to achieve T4/T1>0.9 on the TOF monitor. Extubation was performed after awakening. When stable vital signs and respiration was confirmed, all patients were transferred to the postanesthesia care unit (PACU). Data related to the occurrence of pain, nausea, vomiting, dizziness or hallucinations at the PACU will be recorded as will be the length of stay in the PACU. Pain will be assessed every 15 minutes using a 0-10 numeric pain rating scale, where zero meant no pain and 10 the worst imaginable pain. Morphine (1 to 2 mg) will be administered intravenously every 10 minutes to maintain the pain score below 4 (1 mg when the pain score was <7 and 2 mg when it was ≥7). Following discharge from the PACU (minimum stay 60 minutes and Aldrete & Kroulik index >9), all of the participants will be given ketoprofen (100 mg) every 12 hours and dipyrone (30 mg/kg, maximum 1 g) every six hours intravenously. Whenever patients judged that their analgesia was insufficient, tramadol (100 mg) will be administered intravenously at eight-hour minimum intervals as needed. Postoperative nausea and vomiting (PONV) will be treated with dimenhydrinate (30 mg) intravenously. Pain score, use of analgesics, and the occurrence of nausea, vomiting, and other complications during the hospital ward stay will be recorded.

QoR40 The quality of postoperative functional recovery will be assessed by the QoR40 questionnaire, which assesses five dimensions of recovery (physical comfort - 12 items; emotional state - 7 items; physical independence - 5 items; physiological support - 7 items; and pain - 7 items). Each item is rated on a five-point Likert scale: none of the time, some of the time, usually, most of the time, and all the time. The total score on the QoR40 ranges from 40 (poorest quality of recovery) to 200 (best quality of recovery). The QoR40 will be administered by a blind investigator 24 hours after surgery.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention

Condition

• Postoperative Pain
• Postoperative Nausea and Vomiting

Intervention

• Drug: Ketamine 0.4 mg/kg
  Intravenous ketamine 0.4 mg/kg after induction of anesthesia
• Drug: Normal saline
  Intravenous normal saline 0.9% 5 mL
• Drug: Ketamine 0.2 mg/kg
  Intravenous ketamine 0.2 mg/kg after induction of anesthesia

Study Arms

• Placebo Comparator: Saline group
  Normal saline 0.9% (5 mL)
  Intervention: Drug: Normal saline
• Experimental: Ketamine 0.2
  ketamine 0.2 mg/kg (5 mL)
  Intervention: Drug: Ketamine 0.2 mg/kg
• Experimental: Ketamine 0.4
  ketamine 0.4 mg/kg (5 mL)
  Intervention: Drug: Ketamine 0.4 mg/kg

Publications *

• Xie H, Wang X, Liu G, Wang G. Analgesic effects and pharmacokinetics of a low dose of ketamine preoperatively administered epidurally or intravenously. Clin J Pain. 2003 Sep-Oct;19(5):317-22.
• Myles PS, Weitkamp B, Jones K, Melick J, Hensen S. Validity and reliability of a postoperative quality of recovery score: the QoR-40. Br J Anaesth. 2000 Jan;84(1):11-5.
• Wu L, Huang X, Sun L. The efficacy of N-methyl-D-aspartate receptor antagonists on improving the postoperative pain intensity and satisfaction after remifentanil-based anesthesia in adults: a meta-analysis. J Clin Anesth. 2015 Jun;27(4):311-24. doi: 10.1016/j.jclinane.2015.03.020. Epub 2015 Mar 29.
• Pfenninger EG, Durieux ME, Himmelseher S. Cognitive impairment after small-dose ketamine isomers in comparison to equianalgesic racemic ketamine in human volunteers. Anesthesiology. 2002 Feb;96(2):357-66.
• Kissin I, Bright CA, Bradley EL Jr. The effect of ketamine on opioid-induced acute tolerance: can it explain reduction of opioid consumption with ketamine-opioid analgesic combinations? Anesth Analg. 2000 Dec;91(6):1483-8.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 12, 2017): 135
• Original Estimated Enrollment (submitted: October 6, 2015): 150
• Actual Study Completion Date: May 2016
• Actual Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• American Society of Anesthesiologists physical status I or II
• Patients scheduled to undergo laparoscopic cholecystectomy

Exclusion Criteria:

• Patients who refuse to participate in the study
• Patients who are not able to communicate due to alterations in the level of consciousness, or neurologic, or psychiatric disease
• Contraindication of any of the drugs used in the study
• Patients who are superobese (BMI>40)
• History of alcohol or drug dependence

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Brazil

Administrative Information

• NCT Number: NCT02571153
• Other Study ID Numbers: PUCSP 057539/2015
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Eduardo Toshiyuki Moro, Pontificia Universidade Catolica de Sao Paulo
• Study Sponsor: Pontificia Universidade Catolica de Sao Paulo
• Collaborators: Not Provided

Investigators

• Principal Investigator: Eduardo T Moro, PhD; School of Medical and Health Sciences, Pontificial Catholic University of São Paulo - PUCSP

• PRS Account: Pontificia Universidade Catolica de Sao Paulo
• Verification Date: January 2017