Low Doses of Ketamine and Postoperative Quality of Recovery

NCT ID: NCT02571153

Last Updated: 2017-03-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 135 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-09-30
• Study Completion Date: 2016-05-31

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.

Conditions

Postoperative Pain; Postoperative Nausea and Vomiting

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Saline group

Normal saline 0.9% (5 mL)

Group Type: PLACEBO_COMPARATOR

Normal saline

Intervention Type: DRUG

Intravenous normal saline 0.9% 5 mL

Ketamine 0.2

ketamine 0.2 mg/kg (5 mL)

Group Type: EXPERIMENTAL

Ketamine 0.2 mg/kg

Intervention Type: DRUG

Intravenous ketamine 0.2 mg/kg after induction of anesthesia

Ketamine 0.4

ketamine 0.4 mg/kg (5 mL)

Group Type: EXPERIMENTAL

Ketamine 0.4 mg/kg

Intervention Type: DRUG

Intravenous ketamine 0.4 mg/kg after induction of anesthesia

Interventions

Ketamine 0.4 mg/kg

Intravenous ketamine 0.4 mg/kg after induction of anesthesia

Intervention Type: DRUG

Normal saline

Intravenous normal saline 0.9% 5 mL

Intervention Type: DRUG

Ketamine 0.2 mg/kg

Intravenous ketamine 0.2 mg/kg after induction of anesthesia

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pontificia Universidade Catolica de Sao Paulo

OTHER

Sponsor Role: lead

Responsible Party

Eduardo Toshiyuki Moro

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Eduardo T Moro, PhD

Role: PRINCIPAL_INVESTIGATOR

School of Medical and Health Sciences, Pontificial Catholic University of São Paulo - PUCSP

Locations

Santa Lucinda Hospital

Sorocaba, São Paulo, Brazil

Countries

Brazil

References

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. doi: 10.1097/00002508-200309000-00006.

Reference Type: BACKGROUND

PMID: 12966258 (View on PubMed)

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. doi: 10.1093/oxfordjournals.bja.a013366.

Reference Type: BACKGROUND

PMID: 10740540 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25824051 (View on PubMed)

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. doi: 10.1097/00000542-200202000-00022.

Reference Type: BACKGROUND

PMID: 11818769 (View on PubMed)

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. doi: 10.1097/00000539-200012000-00035.

Reference Type: BACKGROUND

PMID: 11094005 (View on PubMed)

Other Identifiers

PUCSP 057539/2015

Identifier Type: -

Identifier Source: org_study_id