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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
15
Ketamine drip at a subanesthetic infusion rate (low dose ketamine 5 - 10 mcg/kg/min)
Massachusetts General Hospital
Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
Inspiratory Airflow
Inspiratory airflow measured during spontaneous breathing trials without ventilator support using a calibrated pneumotachometer connected to the ventilatory circuit. Airflow signals were recorded along with airway and esophageal pressures and analyzed. Inspiratory airflow represents the rate of air entering the lungs during inspiration and is reported in liters per second (L/s). Higher values indicate greater inspiratory airflow during spontaneous breathing. Measurements were obtained during brief spontaneous breathing trials performed at predefined study time points.
Time frame: During spontaneous breathing trials at baseline (prior to ketamine infusion), after 60 minutes of ketamine infusion at 5 mcg/kg/min, and after 60 minutes of ketamine infusion at 10 mcg/kg/min
EEG Beta-gamma Power
Electroencephalogram (EEG) power spectrum density was measured using four frontal electrodes with the SedLine monitor and analyzed using multitaper spectral methods. Changes in beta-gamma power (19-44 Hz) were expressed in decibels (dB) relative to baseline using artifact-free \~3-minute segments at predefined time points. The reported value represents the maximum increase in spectral power across the frequency range, capturing the strongest frequency-specific effect, which may be diluted by averaging across the band if central tendency is used. This approach is standard in spectral analyses to detect peak effects and potential frequency shifts. Power spectra are continuous functions and peak values are the dominant signal components because they represent the strongest oscillatory activity the brain could achieve in a predefined frequency range.
Time frame: Baseline (prior to ketamine infusion), after 60 minutes of ketamine infusion at 5 mcg/kg/min, and after 60 minutes of ketamine infusion at 10 mcg/kg/min.
Minute Ventilation
Minute ventilation measured during spontaneous breathing trials without ventilator support using a calibrated pneumotachometer connected to the ventilatory circuit. Minute ventilation represents the total volume of air inhaled or exhaled per minute and is calculated as tidal volume multiplied by respiratory rate. Values are reported in liters per minute (L/min). Higher values indicate greater overall ventilation during spontaneous breathing. Measurements were derived from airflow recordings.
Time frame: During spontaneous breathing trials at baseline (prior to ketamine infusion), after 60 minutes of ketamine infusion at 5 mcg/kg/min, and after 60 minutes of ketamine infusion at 10 mcg/kg/min.
Tidal Volume
Tidal volume measured during spontaneous breathing trials without ventilator support using a calibrated pneumotachometer connected to the ventilatory circuit. Tidal volume represents the volume that enters the lungs during a single breath and is reported in liters (L). Values were derived from airflow recordings analyzed using spirometry software. Higher values indicate larger breath volumes during spontaneous breathing at the predefined study time points.
Time frame: During spontaneous breathing trials at baseline (prior to ketamine infusion), after 60 minutes of ketamine infusion at 5 mcg/kg/min, and after 60 minutes of ketamine infusion at 10 mcg/kg/min.
Work of Breathing
Inspiratory work of breathing measured during spontaneous breathing trials using esophageal pressure (Pes) and tidal volume recordings. Work of breathing was calculated from the area under the inspiratory limb of the esophageal pressure-volume loop for each breathing cycle. Values were averaged across breaths during the recording period and normalized to tidal volume. Work of breathing was expressed in joules per liter (J/L). Higher values indicate greater mechanical effort required to inhale.
Time frame: During spontaneous breathing trials at baseline (prior to ketamine infusion), after 60 minutes of ketamine infusion at 5 mcg/kg/min, and after 60 minutes of ketamine infusion at 10 mcg/kg/min.
Inspiratory Airway Resistance
Inspiratory airway resistance measured during spontaneous breathing trials using airway flow and esophageal pressure recordings. Resistance was estimated using the Mead and Whittenberger method, calculated as (Pes - PesLR)/V̇, where Pes is esophageal pressure, PesLR is the pressure on the lung elastic recoil curve at the same tidal volume, and V̇ is airflow. Measurements were made at an absolute tidal volume of 100 ml and averaged across breathing cycles during the recording period. Values are reported in cmH2O/L/s. Higher values indicate greater resistance to airflow during inspiration.
Time frame: During spontaneous breathing trials at baseline (prior to ketamine infusion), after 60 minutes of ketamine infusion at 5 mcg/kg/min, and after 60 minutes of ketamine infusion at 10 mcg/kg/min.
Lung Compliance
Lung compliance measured during spontaneous breathing trials using tidal volume and esophageal pressure recordings. Compliance was calculated as the change in tidal volume divided by the change in esophageal pressure (ΔVT/ΔPes) measured between zero-flow states at the beginning and end of inspiration. Values represent respiratory system compliance and are reported in milliliters per centimeter of water pressure (mL/cmH2O). Higher values indicate greater lung compliance, reflecting a larger volume change for a given pressure change.
Time frame: During spontaneous breathing trials at baseline (prior to ketamine infusion), after 60 minutes of ketamine infusion at 5 mcg/kg/min, and after 60 minutes of ketamine infusion at 10 mcg/kg/min.
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