The Effects of Ketamine on Respiratory Stimulation and Transpulmonary Pressures

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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The Effects of Subanesthetic Ketamine on Respiratory Stimulation and Transpulmonary Pressures in Mechanically Ventilated Critically Ill Patients

Conditions
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Mechanical Ventilation, Airway Patency, Respiratory Depression

Intervention / Treatment
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* Drug: Subanesthetic ketamine


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort<br>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<br>* Ketamine drip at a subanesthetic infusion rate (low dose ketamine 5 - 10 mcg/kg/min)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in peak inspiratory flow | Measured using a pneumotach (Hans Rudolph Inc., Shawnee, KS) connected to the ventilation tubing of the patient during the spontaneous breathing trials. | 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 | 
| Change in tidal volume | Measured using a pneumotach (Hans Rudolph Inc., Shawnee, KS) connected to the ventilation tubing of the patient during the spontaneous breathing trials. | 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 | 
| Change in duty cycle | Measured using a pneumotach (Hans Rudolph Inc., Shawnee, KS) connected to the ventilation tubing of the patient during the spontaneous breathing trials. | 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 | 
| Change in respiratory rate | Measured using a pneumotach (Hans Rudolph Inc., Shawnee, KS) connected to the ventilation tubing of the patient during the spontaneous breathing trials. | 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 | 
| Change in minute ventilation | Measured using a pneumotach (Hans Rudolph Inc., Shawnee, KS) connected to the ventilation tubing of the patient during the spontaneous breathing trials. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transpulmonary pressure | 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) | Continuously throughout the study until stopping the ketamine infusion. | 
| Changes in power spectrum densities | Electroencephalography (EEG)-based power spectrum densities will be measured using the Sedline brain function monitor (Masimo Corporation, Irvine, CA) | Continuously throughout the ketamine infusion until 3 hours after stopping the ketamine infusion. | 
| Oxygen blood saturation | Pulse oxymetry | Continuously throughout the ketamine infusion until 3 hours after stopping the ketamine infusion. | 
| Changes in volumetric capnography | Measures through volumetric capnography: NICO© device from Respironics (Hartford, CT). | Periods of at least five minutes during steady state breathing before and after administration of ketamine. | 
| Total narcotic consumption | Obtained from the medical record and flow sheets. | 3 hours after stopping the ketamine infusion | 
| Number of days mechanically ventilated | Difference in days between intubation and extubation. Obtained from the medical record and flow sheets. | 3 hours after stopping the ketamine infusion | 
| Richmond Agitation Sedation Scale (RASS) | Obtained from the medical record and flow sheets. | 3 hours after stopping the ketamine infusion | 
| Critical care pain observation tool (CPOT) | Obtained from the medical record and flow sheets. | 3 hours after stopping the ketamine infusion | 
| Confusion Assessment Measurement for the ICU (CAM-ICU) | Obtained from the medical record and flow sheets. | 3 hours after stopping the ketamine infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Subanesthetic ketamine, Mechanical ventilation, Transpulmonary pressure, Spontaneous breathing trial, Extubation