The Effects of Ketamine on Respiratory Stimulation and Transpulmonary Pressures

Mechanical Ventilation Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01969227
• Other study ID #: 2013P001690
• Status: Completed
• Phase: N/A
• Start date: January 2014
• Est. completion date: December 2022

Study information

• Verified date: March 2023
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: December 2022
• Est. primary completion date: December 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Airway Patency
• Mechanical Ventilation
• Respiratory Depression
• Respiratory Insufficiency

Intervention

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

Locations

Country	Name	City	State
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Massachusetts General Hospital	Beth Israel Deaconess Medical Center

Country where clinical trial is conducted

United States, 

References & Publications (6)

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. — View Citation

Esteban A, Frutos F, Tobin MJ, Alia I, Solsona JF, Valverdu I, Fernandez R, de la Cal MA, Benito S, Tomas 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. doi: 10.1056/NEJM199502093320601. — View Citation

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. doi: 10.1111/j.1399-6576.1998.tb05106.x. — View Citation

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. — View Citation

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. doi: 10.1097/00000539-200001000-00029. — View Citation

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. doi: 10.1097/00000542-198610000-00008. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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.
Secondary	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.
Secondary	Oxygen blood saturation	Pulse oxymetry	Continuously throughout the ketamine infusion until 3 hours after stopping the ketamine infusion.
Secondary	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.
Secondary	Total narcotic consumption	Obtained from the medical record and flow sheets.	3 hours after stopping the ketamine infusion
Secondary	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
Secondary	Richmond Agitation Sedation Scale (RASS)	Obtained from the medical record and flow sheets.	3 hours after stopping the ketamine infusion
Secondary	Critical care pain observation tool (CPOT)	Obtained from the medical record and flow sheets.	3 hours after stopping the ketamine infusion
Secondary	Confusion Assessment Measurement for the ICU (CAM-ICU)	Obtained from the medical record and flow sheets.	3 hours after stopping the ketamine infusion