Low Doses of Ketamine and Postoperative Quality of Recovery
Condition: Postoperative Pain; Postoperative Nausea and Vomiting
MeSH terms: Pain, Postoperative; Nausea; Vomiting; Postoperative Nausea and Vomiting
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Ketamine 0.4 mg/kg; Normal saline; Ketamine 0.2 mg/kg
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Intravenous ketamine 0.4 mg/kg after induction of anesthesia; Intravenous normal saline 0.9% 5 mL; Intravenous ketamine 0.2 mg/kg after induction of anesthesia
Intervention MeSH terms: Ketamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Intravenous anesthesia; Postoperative nausea vomiting; Postoperative pain; Patient satisfaction; Quality of health care; Ketamine