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The Effects of Ketamine on Respiratory Stimulation and Transpulmonary Pressures

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ClinicalTrials.gov Identifier: NCT01969227
Recruitment Status : Recruiting
First Posted : October 25, 2013
Last Update Posted : September 3, 2019
Sponsor:
Collaborator:
Beth Israel Deaconess Medical Center
Information provided by (Responsible Party):
Lorenzo Berra, MD, Massachusetts General Hospital

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Mechanical Ventilation Airway Patency Respiratory Depression Drug: Subanesthetic ketamine Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Effects of Subanesthetic Ketamine on Respiratory Stimulation and Transpulmonary Pressures in Mechanically Ventilated Critically Ill Patients
Study Start Date : January 2014
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Ketamine

Arm Intervention/treatment
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.
Drug: Subanesthetic ketamine
Ketamine drip at a subanesthetic infusion rate (low dose ketamine 5 - 10 mcg/kg/min)




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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 Outcome Measures :
  1. 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)

  2. 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)

  3. Oxygen blood saturation [ Time Frame: Continuously throughout the ketamine infusion until 3 hours after stopping the ketamine infusion. ]
    Pulse oxymetry

  4. 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).

  5. Total narcotic consumption [ Time Frame: 3 hours after stopping the ketamine infusion ]
    Obtained from the medical record and flow sheets.

  6. 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.

  7. Richmond Agitation Sedation Scale (RASS) [ Time Frame: 3 hours after stopping the ketamine infusion ]
    Obtained from the medical record and flow sheets.

  8. Critical care pain observation tool (CPOT) [ Time Frame: 3 hours after stopping the ketamine infusion ]
    Obtained from the medical record and flow sheets.

  9. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01969227


Contacts
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Contact: Matthias Eikermann, MD. PhD meikerma@bidmc.harvard.edu
Contact: Lorenzo Berra, MD lberra@partners.org

Locations
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United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Lorenzo Berra, MD, PhD       lberra@partners.org   
Beth Israel Deaconess Medical Center Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Matthias Eikermann, MD, PhD       meikerma@bidmc.harvard.edu   
Sponsors and Collaborators
Massachusetts General Hospital
Beth Israel Deaconess Medical Center
Investigators
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Principal Investigator: Lorenzo Berra, MD Massachusetts General Hospital
Study Director: Matthias Eikermann, MD, PhD Beth Israel Deaconess Medical Center

Publications:

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Responsible Party: Lorenzo Berra, MD, Medical Director, Respiratory Care, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT01969227    
Other Study ID Numbers: 2013P001690
First Posted: October 25, 2013    Key Record Dates
Last Update Posted: September 3, 2019
Last Verified: August 2019
Keywords provided by Lorenzo Berra, MD, Massachusetts General Hospital:
Subanesthetic ketamine
Mechanical ventilation
Transpulmonary pressure
Spontaneous breathing trial
Extubation
Additional relevant MeSH terms:
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Respiratory Insufficiency
Respiration Disorders
Respiratory Tract Diseases
Ketamine
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anesthetics, Dissociative
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Central Nervous System Depressants
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action