Airway Patency, Mechanical Ventilation, Respiratory Depression
Conditions
Keywords
Subanesthetic ketamine, Mechanical ventilation, Transpulmonary pressure, Spontaneous breathing trial, Extubation
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.
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
DRUGSubanesthetic ketamine
Ketamine drip at a subanesthetic infusion rate (low dose ketamine 5 - 10 mcg/kg/min)
Sponsors
Massachusetts General Hospital
Beth Israel Deaconess Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Inspiratory Airflow | 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 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| EEG Beta-gamma Power | 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. | 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. |
| Minute Ventilation | 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. | 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. |
| Tidal Volume | 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 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. |
| Work of Breathing | 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 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. |
| Inspiratory Airway Resistance | 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 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. |
| Lung Compliance | 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 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORLorenzo Berra, MD
Massachusetts General Hospital
STUDY_DIRECTORMatthias Eikermann, MD, PhD
Beth Israel Deaconess Medical Center
Participant flow
Recruitment details
Participants were recruited in the surgical ICUs of two Boston academic medical centers (Massachusetts General Hospital and Beth Israel Deaconess Medical Center). Study personnel screened ICU censuses daily (7:30am-10:00pm) and through clinician referral. Eligible intubated adults suitable for SBT and on stable sedation ≥3 hours were approached via a clinician, with surrogate written consent obtained.
Pre-assignment details
No specific pre-assignment run-in or washout period occurred. After enrollment and confirmation of eligibility, participants proceeded directly to the study intervention and measurements according to the protocol.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 62 years STANDARD_DEVIATION 20 |
| APACHE II (Acute Physiology and Chronic Health Evaluation II) score | 15 points |
| Body Mass Index (BMI) | 26 kg/m^2 |
| History of pulmonary disease | 6 Participants |
| Primary ICU admission diagnosis / reason for mechanical ventilation Cardiovascular | 1 Participants |
| Primary ICU admission diagnosis / reason for mechanical ventilation Infection | 3 Participants |
| Primary ICU admission diagnosis / reason for mechanical ventilation Postoperative | 1 Participants |
| Primary ICU admission diagnosis / reason for mechanical ventilation Respiratory | 4 Participants |
| Primary ICU admission diagnosis / reason for mechanical ventilation Trauma | 3 Participants |
| RASS (Richmond Agitation-Sedation Scale) at study start | -1 score |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 5 Participants |
| SOFA (Sequential Organ Failure Assessment) score | 5 points |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 0 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
None listed