Cerebral Hemodynamic and Metabolic Responses to Anesthesia and Vasopressors in Adult Surgery: A 2x2 Factorial Design Randomized Controlled Trial With Light-based Neuromonitoring (CHEM-FACT Study)
Trial Snapshot
- Phase
- Phase 4
- Status
- Recruiting
- Sponsor
- Enrollment
- 80
- Locations
- 1
- Primary Endpoint
- Effects of anesthetic maintenance agents and vasopressors on cerebral hemodynamics and metabolism.
Study Overview
Brief Summary
The brain is a highly active organ that requires a large blood flow to function properly. Normally, blood flow is tightly linked to the brain's energy demands. However, during surgery, anesthesia can affect this relationship in different ways. Some types of anesthesia can decrease blood flow to the brain, while others can increase it. Anesthesiologists need to be careful to maintain adequate blood flow to the brain during surgery, especially when blood pressure drops. Drugs may be used to increase blood pressure, but some of these drugs can also affect blood flow to the brain. It is still unclear how to best maintain blood flow to the brain during surgery and how different types of anesthesia and drugs affect this process.
The study aims to assess the clinical utility of a new technique that uses light-based neuromonitoring to measure changes in cerebral blood flow and metabolism. The investigators will recruit 80 adult patients undergoing surgery under general anesthesia and randomize them into one of four groups to evaluate the effects of different anesthetic agents and vasopressors on brain hemodynamics and metabolism. The study will include patients over 18 years of age with no history of neurological conditions, substance abuse, or contraindications to cerebral oximetry devices or specific anesthetic agents. The patients will receive standard anesthesia care and be monitored with our light-based neuromonitoring system. This study aims to demonstrate the device's ability to detect changes in cerebral hemodynamic parameters related to anesthesia induction and systemic hypotension. This study will also evaluate the effects of anesthetic maintenance agents and vasopressors on cerebral hemodynamics and neurovascular coupling.
Detailed Description
The brain is a highly metabolic active organ, which receives approximately 15% of cardiac output with a normal cerebral blood flow (CBF) of approximately 50 mL/100 g/min. In normal circumstances, CBF is tightly coupled to local cerebral metabolism. An increase of cerebral metabolic activity of one region of the brain will trigger a corresponding increase of blood flow to that brain region. Conversely, a reduction of cerebral metabolic activity will lead to a reduction in blood flow. This tightly controlled physiological phenomenon is known as flow-metabolism coupling.
Flow-metabolism coupling is thought to be a feed-forward physiological protective mechanism wherein neuronal activity directly increases CBF, thereby matching the increased energy supply. In the event of cerebral hypoperfusion (i.e. reduction in CBF), brain vessels would be dilated in compensation and the local oxygen extraction fraction (OEF) would be increased. If cerebral hypoperfusion persists and is below the threshold, the activity of the brain cells would be suppressed, thereby resulting in the reduction of the cerebral metabolic rate (CMR) and cerebral metabolic requirement of oxygen (CMRO2). This flow-metabolism coupling mechanism is well studied using a PET scan in both healthy volunteers and patients with pathological conditions. Importantly, this physiological property of flow-metabolism in response to brain ischemia may be used as an earlier indicator of cerebral ischemia during surgery. In other words, monitoring that indicates a sudden drop in CMRO2 or increase in OEF may serve as an early marker of brain ischemia. However, due to technical limitations, bedside detection of such subtle physiological changes is challenging, especially in the intraoperative settings. In addition, many physiological, pathological, and pharmacological factors may affect this flow-metabolism coupling relationship and hence affect the interpretation of CMRO2/OEF changes as an indicator of brain ischemia. Additional studies are required to address how anesthetics may confound the interpretation.
Different anesthetic agents may alter flow-metabolism coupling in different ways. Cerebral metabolic rate is determined by a number of factors, including the functional state of the nervous system, anesthetic drugs and body temperature. The effect of individual anesthetic drugs on the CMR has been well studied. In short, most anesthetic drugs suppress the CMR in a dose-dependent manner, with the exception of ketamine and nitrous oxide (N2O). The anesthetic suppression of the CMR is mainly driven by the reduction of electrophysiologic activities. Previous studies have showed several anesthetics, including barbiturates, isoflurane, sevoflurane, desflurane, propofol, and etomidate can increase plasma concentrations and cause progressive suppression of EEG activity and a concomitant reduction in the CMR.
To further complicate the issue, during surgery, the anesthesiologist is required to maintain adequate cerebral perfusion pressure to ensure that there is sufficient CBF to meet metabolic demands. Induction of general anesthesia is often associated with a reduction in the mean arterial blood pressure(MAP) and cerebral perfusion pressure which is attributable to a decrease in cardiac output (CO) and systemic vascular resistance (SVR). Many intraoperative conditions such as blood loss and surgical positioning, may further compromise patient blood pressure and hence, CBF. Phenylephrine and ephedrine are commonly administered during neurosurgical procedures to counteract cardiovascular depression and treat anesthesia-related hypotension. Near-infrared spectroscopy (NIRS) studies in anesthetized patients suggest that phenylephrine reduces regional cerebral oxygen saturation (StO2) compared with ephedrine, despite a marked increase in the MAP. The results of these studies are conflicting and are various limitations.
NIRS has long been recognized as a promising neuromonitor due to the relative transparency of tissue to light in the near-infrared range and the dependency of light absorption on the oxygenation of haemoglobin, which provides a non-invasive method of measuring StO2. In addition, NIRS is extremely safe, inexpensive and provides real-time monitoring. Commercial systems are available and have been used for neuromonitoring during a variety of surgical procedures with an associated risk of brain injury, including coronary artery bypass and carotid endarterectomy.1,2 Despite the advantages of NIRS, its diagnostic accuracy for detecting intra-operative ischemia is controversial.3 A recent systematic review concluded that:
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Factorial
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Outcomes Assessor)
Masking Description
Participants and outcomes assessors will be blinded to the combination of anesthetic maintenance agents (propofol or sevoflurane) and vasopressors (phenylephrine or ephedrine) that were used during surgery.
Eligibility Criteria
- Ages
- 19 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Adult patients over the age of 18 years old.
- •Undergoing surgery under general anesthesia at London Health Sciences Centre or St. Joseph's Healthcare that is scheduled to last longer than 1 hour.
Exclusion Criteria
- •Had any neurological conditions such as history of stroke, TIA, neurodegenerative disease, or carotid stenosis
- •Had a history of substance abuse such as heavy cannabis users
- •Have a contraindication of applying the cerebral oximetry device (e.g., skin lesions in the forehead)
- •Have contraindications to receive specific anesthetic agents or vasopressors such as malignant hyperthermia or an allergy.
- •Unable to communicate with the research staff
Arms & Interventions
Propofol-based anesthetic maintenance with phenylephrine used as the vasopressor
Propofol-based anesthetic maintenance with phenylephrine used as the vasopressor. Patient will receive propofol as their maintenance agent during surgery. The typical dose is 150-200 mg/kg/min. Patient will receive phenylephrine infusion as the primary vasopressor of choice. The typical dose of phenylephrine infusion is 10-40 mcg/min (dilution 100 mcg/ml).
Intervention: Phenylephrine (Drug)
Propofol-based anesthetic maintenance with phenylephrine used as the vasopressor
Propofol-based anesthetic maintenance with phenylephrine used as the vasopressor. Patient will receive propofol as their maintenance agent during surgery. The typical dose is 150-200 mg/kg/min. Patient will receive phenylephrine infusion as the primary vasopressor of choice. The typical dose of phenylephrine infusion is 10-40 mcg/min (dilution 100 mcg/ml).
Intervention: Propofol (Drug)
Propofol-based anesthetic maintenance with ephedrine used as the vasopressor
Propofol-based anesthetic maintenance with ephedrine used as the vasopressor. Patient will receive propofol as their maintenance agent during surgery. The typical dose is 150-200 mg/kg/min. The patient will receive ephedrine infusion as the primary vasopressor of choice. The typical dose of ephedrine infusion is 10-50 mg/hr (dilution 2 mg/ml).
Intervention: Propofol (Drug)
Propofol-based anesthetic maintenance with ephedrine used as the vasopressor
Propofol-based anesthetic maintenance with ephedrine used as the vasopressor. Patient will receive propofol as their maintenance agent during surgery. The typical dose is 150-200 mg/kg/min. The patient will receive ephedrine infusion as the primary vasopressor of choice. The typical dose of ephedrine infusion is 10-50 mg/hr (dilution 2 mg/ml).
Intervention: Ephedrine (Drug)
Sevoflurane-based anesthetic maintenance with phenylephrine used as the vasopressor
Sevoflurane-based anesthetic maintenance with phenylephrine used as the vasopressor.
Patient's anesthesia will be maintained with 1 MAC of sevoflurane during surgery. Patient will receive phenylephrine infusion as the primary vasopressor of choice. The typical dose of phenylephrine infusion is 10-40 mcg/min (dilution 100 mcg/ml).
Intervention: Sevoflurane (Drug)
Sevoflurane-based anesthetic maintenance with phenylephrine used as the vasopressor
Sevoflurane-based anesthetic maintenance with phenylephrine used as the vasopressor.
Patient's anesthesia will be maintained with 1 MAC of sevoflurane during surgery. Patient will receive phenylephrine infusion as the primary vasopressor of choice. The typical dose of phenylephrine infusion is 10-40 mcg/min (dilution 100 mcg/ml).
Intervention: Phenylephrine (Drug)
Sevoflurane-based anesthetic maintenance with ephedrine used as the vasopressor
Sevoflurane-based anesthetic maintenance with ephedrine used as the vasopressor. Patient's anesthesia will be maintained with 1 MAC of sevoflurane during surgery. The patient will receive ephedrine infusion as the primary vasopressor of choice. The typical dose of ephedrine infusion is 10-50 mg/hr (dilution 2 mg/ml).
Intervention: Sevoflurane (Drug)
Sevoflurane-based anesthetic maintenance with ephedrine used as the vasopressor
Sevoflurane-based anesthetic maintenance with ephedrine used as the vasopressor. Patient's anesthesia will be maintained with 1 MAC of sevoflurane during surgery. The patient will receive ephedrine infusion as the primary vasopressor of choice. The typical dose of ephedrine infusion is 10-50 mg/hr (dilution 2 mg/ml).
Intervention: Ephedrine (Drug)
Outcomes
Primary Outcomes
Effects of anesthetic maintenance agents and vasopressors on cerebral hemodynamics and metabolism.
Time Frame: Duration of surgery
Differences in CMRO2 during surgery between sevoflurane and propofol groups will be analyzed by repeated measures ANOVA. Next, differences in CMRO2 during surgery between the phenylephrine and ephedrine groups will be compared by repeated measures ANOVA. To explore any interaction, we will examine whether the effect of one independent variable depends on the level of the other independent variable by conducting a two-way ANOVA. A two-way ANOVA will allow us to examine the main effects of each independent variable and the interaction effect. The interaction effect can be examined by looking at the F-value and p-value associated with the interaction term in the ANOVA output. If the p-value is significant (i.e., less than the alpha level), then there is evidence of an interaction effect.
Secondary Outcomes
- Effects of anesthetic maintenance agents and vasopressors on cerebral hemodynamics and metabolism during induction(Anesthesia induction)
Investigators
Jason Chui
Anesthesiologist, Associate Professor
Lawson Health Research Institute