The Effects of Ketamine on Respiratory Stimulation and Transpulmonary Pressures

Overview

Impairment of airway patency is a common cause of extubation failure and opioids and hypnotics can adversely affect airway patency. Ketamine, a noncompetitive antagonist of N-methyl-D-aspartate (NMDA), unlike other anesthetics activates respiratory effort and promotes bronchodilation. At subanesthetic plasma concentration, ketamine reduces both opioid and propofol requirements.

The purpose of this pharmaco-physiological interaction trial is to evaluate the effects of ketamine on breathing and electroencephalography in mechanically ventilated patients.

Full Title of Study: “The Effects of Subanesthetic Ketamine on Respiratory Stimulation and Transpulmonary Pressures in Mechanically Ventilated Critically Ill Patients”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 2020

Detailed Description

Maintaining the patency of the upper airway in sedated and anesthetized patients is challenging especially when patients are ready to be weaned from mechanical ventilation. Spontaneous breathing trial (SBT) is used to expedite the weaning process, which oftentimes requires the reduction and/or discontinuation of sedatives and analgesics. In some surgical patients, reducing these medications can lead to pain associated agitation and inability to conduct SBTs, which may prolong the need for mechanical ventilation. Using medications with narcotic sparing effects and that do not cause respiratory depression may allow for the reduction or discontinuation of agents that depress respiratory drive and subsequently facilitate extubation.

Ketamine has been used for many years in critically ill patients for sedation and analgesia. This noncompetitive antagonist of N-methyl-D-aspartate (NMDA) is used as an anesthetic and analgesic and has been shown to reduce opioid consumption and to prevent the development of opioid tolerance. Unlike other anesthetics, ketamine activates respiratory effort and promotes bronchodilation. At subanesthetic plasma concentration, ketamine reduces both opioid and propofol requirements.

The goal of this pharmaco-physiological interaction trial is to evaluate the effects of ketamine at a subanesthetic dose on breathing and electroencephalography. The investigators hypothesize that ketamine drip at a subanesthetic infusion rate (low dose ketamine 5 – 10 mcg/kg/min) is associated with respiratory stimulating effects and does not markedly increase transpulmonary pressure in mechanically ventilated patients.

The primary outcome is respiratory function, assessed through peak inspiratory flow, tidal volume,respiratory rate, duty cycle, and minute ventilation measured 15 minutes prior to initiation of ketamine infusion (to serve as baseline), at 60 minutes of ketamine infusion at 5mcg/kg/min, at another 60 minutes of infusion at 10mcg/kg/min, at which point the infusion is stopped for 3 hours for a final set of measurements.

Interventions

  • Drug: Subanesthetic ketamine
    • Ketamine drip at a subanesthetic infusion rate (low dose ketamine 5 – 10 mcg/kg/min)

Arms, Groups and Cohorts

  • Experimental: Cohort
    • Adult mechanically ventilated patients who are deemed eligible for a spontaneous breathing trial and are candidates to receive subanesthetic ketamine by the primary critical care team.

Clinical Trial Outcome Measures

Primary Measures

  • Change in peak inspiratory flow
    • Time Frame: Measured 15 minutes prior to initiation of ketamine infusion, at 60 minutes of ketamine infusion at 5mcg/kg/min, at another 60 minutes of infusion at 10mcg/kg/min, and at 2 hours after stopping the infusion
    • Measured using a pneumotach (Hans Rudolph Inc., Shawnee, KS) connected to the ventilation tubing of the patient during the spontaneous breathing trials.
  • Change in tidal volume
    • Time Frame: Measured 15 minutes prior to initiation of ketamine infusion, at 60 minutes of ketamine infusion at 5mcg/kg/min, at another 60 minutes of infusion at 10mcg/kg/min, and at 2 hours after stopping the infusion
    • Measured using a pneumotach (Hans Rudolph Inc., Shawnee, KS) connected to the ventilation tubing of the patient during the spontaneous breathing trials.
  • Change in duty cycle
    • Time Frame: Measured 15 minutes prior to initiation of ketamine infusion, at 60 minutes of ketamine infusion at 5mcg/kg/min, at another 60 minutes of infusion at 10mcg/kg/min, and at 2 hours after stopping the infusion
    • Measured using a pneumotach (Hans Rudolph Inc., Shawnee, KS) connected to the ventilation tubing of the patient during the spontaneous breathing trials.
  • Change in respiratory rate
    • Time Frame: Measured 15 minutes prior to initiation of ketamine infusion, at 60 minutes of ketamine infusion at 5mcg/kg/min, at another 60 minutes of infusion at 10mcg/kg/min, and at 2 hours after stopping the infusion
    • Measured using a pneumotach (Hans Rudolph Inc., Shawnee, KS) connected to the ventilation tubing of the patient during the spontaneous breathing trials.
  • Change in minute ventilation
    • Time Frame: Measured 15 minutes prior to initiation of ketamine infusion, at 60 minutes of ketamine infusion at 5mcg/kg/min, at another 60 minutes of infusion at 10mcg/kg/min, and at 2 hours after stopping the infusion
    • Measured using a pneumotach (Hans Rudolph Inc., Shawnee, KS) connected to the ventilation tubing of the patient during the spontaneous breathing trials.

Secondary Measures

  • Transpulmonary pressure
    • Time Frame: Continuously throughout the study until stopping the ketamine infusion.
    • Standard nutritional nasogastric tube with an integrated esophageal balloon will be inserted if not already in place by a trained physician or respiratory therapist prior to initiation of ketamine drip and will be used for measurement of transpulmonary pressure. for the study period (approximately 5 hours)
  • Changes in power spectrum densities
    • Time Frame: Continuously throughout the ketamine infusion until 3 hours after stopping the ketamine infusion.
    • Electroencephalography (EEG)-based power spectrum densities will be measured using the Sedline brain function monitor (Masimo Corporation, Irvine, CA)
  • Oxygen blood saturation
    • Time Frame: Continuously throughout the ketamine infusion until 3 hours after stopping the ketamine infusion.
    • Pulse oxymetry
  • Changes in volumetric capnography
    • Time Frame: Periods of at least five minutes during steady state breathing before and after administration of ketamine.
    • Measures through volumetric capnography: NICO© device from Respironics (Hartford, CT).
  • Total narcotic consumption
    • Time Frame: 3 hours after stopping the ketamine infusion
    • Obtained from the medical record and flow sheets.
  • Number of days mechanically ventilated
    • Time Frame: 3 hours after stopping the ketamine infusion
    • Difference in days between intubation and extubation. Obtained from the medical record and flow sheets.
  • Richmond Agitation Sedation Scale (RASS)
    • Time Frame: 3 hours after stopping the ketamine infusion
    • Obtained from the medical record and flow sheets.
  • Critical care pain observation tool (CPOT)
    • Time Frame: 3 hours after stopping the ketamine infusion
    • Obtained from the medical record and flow sheets.
  • Confusion Assessment Measurement for the ICU (CAM-ICU)
    • Time Frame: 3 hours after stopping the ketamine infusion
    • Obtained from the medical record and flow sheets.

Participating in This Clinical Trial

Inclusion Criteria

  • Age ≥ 18 years admitted to ICU requiring mechanical ventilation
  • Suitable for spontaneous breathing trial
  • Candidate to received low dose ketamine by the primary critical care team

Exclusion Criteria

  • Esophageal injury
  • Allergic to ketamine
  • Known neurodegenerative disorders
  • Major neurologic disorders (elevated ICP)

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Massachusetts General Hospital
  • Collaborator
    • Beth Israel Deaconess Medical Center
  • Provider of Information About this Clinical Study
    • Principal Investigator: Lorenzo Berra, MD, Medical Director, Respiratory Care – Massachusetts General Hospital
  • Overall Official(s)
    • Lorenzo Berra, MD, Principal Investigator, Massachusetts General Hospital
    • Matthias Eikermann, MD, PhD, Study Director, Beth Israel Deaconess Medical Center
  • Overall Contact(s)
    • Matthias Eikermann, MD. PhD, meikerma@bidmc.harvard.edu

References

Eikermann M, Grosse-Sundrup M, Zaremba S, Henry ME, Bittner EA, Hoffmann U, Chamberlin NL. Ketamine activates breathing and abolishes the coupling between loss of consciousness and upper airway dilator muscle dysfunction. Anesthesiology. 2012 Jan;116(1):35-46. doi: 10.1097/ALN.0b013e31823d010a.

Esteban A, Frutos F, Tobin MJ, Alía I, Solsona JF, Valverdú I, Fernández R, de la Cal MA, Benito S, Tomás R, et al. A comparison of four methods of weaning patients from mechanical ventilation. Spanish Lung Failure Collaborative Group. N Engl J Med. 1995 Feb 9;332(6):345-50.

Menigaux C, Fletcher D, Dupont X, Guignard B, Guirimand F, Chauvin M. The benefits of intraoperative small-dose ketamine on postoperative pain after anterior cruciate ligament repair. Anesth Analg. 2000 Jan;90(1):129-35.

Hirota K, Hashimoto Y, Sakai T, Sato T, Ishihara H, Matsuki A. In vivo spasmolytic effect of ketamine and adrenaline on histamine-induced airway constriction. Direct visualization method with a superfine fibreoptic bronchoscope. Acta Anaesthesiol Scand. 1998 Feb;42(2):184-8.

Morel DR, Forster A, Gemperle M. Noninvasive evaluation of breathing pattern and thoraco-abdominal motion following the infusion of ketamine or droperidol in humans. Anesthesiology. 1986 Oct;65(4):392-8.

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.

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