Anesthetics Impact on Brain Blood Flow During Surgery

Overseen By Jason Chui, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Jason Chui

Disqualifiers: Neurological conditions, Substance abuse, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

80 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the research staff or your doctor.

What data supports the effectiveness of the drugs Ephedrine and Phenylephrine on brain blood flow during surgery?

Research indicates that Ephedrine may maintain better cerebral blood flow compared to Phenylephrine during surgery, as it results in less capillary transit time heterogeneity, which is linked to improved oxygen delivery to the brain. ^{1 2 3 4 5}

Is Ephedra safe for use in humans?

Ephedra Herb, which contains ephedrine alkaloids, can cause adverse effects like palpitations, insomnia, and excitation. However, an ephedrine alkaloid-free Ephedra Herb extract (EFE) has been shown to be safer, with fewer adverse effects and no toxicity in healthy volunteers. ^{6 7 8 9 10}

How does this drug affect brain blood flow during surgery?

This treatment is unique because it combines drugs like ephedrine and phenylephrine, which help maintain stable blood flow to the brain during surgery, with anesthetics like propofol and sevoflurane that reduce brain pressure and have anti-nausea effects. The use of light-based neuromonitoring to track brain oxygen levels adds an innovative approach to ensure adequate brain perfusion. ^{2 11 12 13 14}

What is the purpose of this trial?

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.

Research Team

Jason Chui, MD

Principal Investigator

Western University

Eligibility Criteria

This trial is for adults over 18 who need general anesthesia for surgery lasting more than an hour. It's not for those with neurological conditions, substance abuse history, skin issues on the forehead, or allergies to certain anesthesia drugs.

Inclusion Criteria

ASA I-IV

I am scheduled for surgery under general anesthesia lasting over an hour at a specified hospital.

I am over 18 years old.

Exclusion Criteria

I cannot communicate with the research team.

History of substance abuse such as heavy cannabis use

I have a history of stroke, TIA, neurodegenerative disease, or carotid stenosis.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Anesthesia Induction

Preoperative baseline cerebral hemodynamic and metabolic parameters are measured, followed by anesthesia induction and monitoring of cerebral hemodynamics and metabolism.

Approximately 5-10 minutes

1 visit (in-person)

Surgery and Treatment

Participants undergo surgery with randomized anesthetic maintenance and vasopressor agents. Continuous monitoring of cerebral blood flow and metabolism using trNIRS/DCS.

Duration of surgery

Post-Anesthesia Care

Patients are extubated and transferred to the PACU. Neurological outcomes are collected via routine physical exam.

Immediate post-surgery period

Follow-up

Participants are monitored for safety and effectiveness after treatment.

4 weeks

Treatment Details

Interventions

• Ephedrine
• Light-based neuromonitoring
• Phenylephrine
• Propofol
• Sevoflurane

Trial Overview The study tests how different anesthetics and blood pressure drugs affect brain blood flow and energy use during surgery. Patients are randomly assigned to receive Propofol, Phenylephrine, Sevoflurane, or Ephedrine while being monitored with a new light-based device.

Participant Groups

Group I: Sevoflurane-based anesthetic maintenance with phenylephrine used as the vasopressor Experimental Treatment 2 Interventions

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).

Group II: Sevoflurane-based anesthetic maintenance with ephedrine used as the vasopressor Experimental Treatment 2 Interventions

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).

Group III: Propofol-based anesthetic maintenance with phenylephrine used as the vasopressor Experimental Treatment 2 Interventions

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).

Group IV: Propofol-based anesthetic maintenance with ephedrine used as the vasopressor Experimental Treatment 2 Interventions

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).

Ephedrine is already approved in United States, Canada for the following indications:

Approved in United States as Ephedrine for:

• Hypotension
• Bronchial asthma
• Narcolepsy
• Myasthenia gravis
• Allergic disorders

Approved in Canada as Ephedrine for:

• Nasal decongestant
• Asthma
• Bronchitis

Who Is Running the Clinical Trial?

Jason Chui

Lead Sponsor

Trials

1

Recruited

80+

Findings from Research

In a study involving six healthy Welsh Mountain ponies, ephedrine significantly increased heart rate, arterial blood pressure, cardiac index, and intramuscular blood flow during halothane anesthesia, particularly after a higher dose of 0.2 mg/kg.

While ephedrine improved hemodynamic parameters, one pony experienced an arrhythmia, highlighting a potential safety concern despite the overall positive effects on blood flow and circulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of ephedrine on intramuscular blood flow and other cardiopulmonary parameters in halothane-anesthetized ponies. Lee, YL., Clarke, KW., Alibhai, HI., et al.[2019]

In a study of 70 elderly orthopedic patients, immediate infusion of either ephedrine or phenylephrine after spinal anesthesia effectively maintained blood pressure and prevented significant hemodynamic changes compared to a saline control group.

Ephedrine not only maintained blood pressure but also increased cardiac index and heart rate, demonstrating its potential advantages over phenylephrine in managing hemodynamics post-anesthesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The influence of the infusion of ephedrine and phenylephrine on the hemodynamic stability after subarachnoid anesthesia in senior adults - a controlled randomized trial. Žunić, M., Krčevski Škvarč, N., Kamenik, M.[2020]

In a study of 24 anesthetized brain tumor patients, ephedrine was found to significantly improve cerebral blood flow and brain tissue oxygenation compared to phenylephrine, which worsened microcirculation as indicated by increased capillary transit time heterogeneity.

Despite both drugs achieving similar mean arterial pressure, ephedrine demonstrated superior effects on cerebral macro- and microcirculation, suggesting it may be a better choice for maintaining cerebral oxygen levels during anesthesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cerebral Macro- and Microcirculation during Ephedrine versus Phenylephrine Treatment in Anesthetized Brain Tumor Patients: A Randomized Clinical Trial Using Magnetic Resonance Imaging. Koch, KU., Mikkelsen, IK., Espelund, US., et al.[2022]

In a study of 24 patients undergoing spine surgery, the infusion of ephedrine helped maintain core body temperature during anesthesia, while the control group experienced a significant drop in temperature.

Ephedrine also stabilized hemodynamic variables like blood pressure and heart rate, suggesting it effectively prevents core-to-peripheral heat redistribution during surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of ephedrine on intraoperative hypothermia. Jo, YY., Kim, JY., Kim, JS., et al.[2021]

In a study of over 103,000 patients undergoing general anesthesia, the use of phenylephrine was linked to a higher risk of postoperative delirium compared to ephedrine, with an adjusted odds ratio of 1.35.

The risk of delirium increased with higher doses of phenylephrine, suggesting a dose-dependent relationship, which indicates that using ephedrine may be a safer option to reduce the incidence of delirium after surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraoperative use of phenylephrine versus ephedrine and postoperative delirium: A multicenter retrospective cohort study. Ma, H., Ahrens, E., Wachtendorf, LJ., et al.[2023]

A new sensitive and validated LC-MS/MS method was developed to detect and quantify multiple phenalkylamines, including ephedrine and cathinone, in plasma, demonstrating high accuracy and precision across a range of concentrations (10 to 1000 ng/ml).

The method effectively distinguished between alkaloids from cold medications and those from herbal sources, showing that ingestion of an Ephedra extract resulted in the detection of multiple ephedrines, highlighting the potential for abuse and the importance of monitoring these substances.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Detection and validated quantification of nine herbal phenalkylamines and methcathinone in human blood plasma by LC-MS/MS with electrospray ionization. Beyer, J., Peters, FT., Kraemer, T., et al.[2019]

The study used HPLC-MS to analyze the pharmacokinetics and tissue distribution of five Ephedra alkaloids in rats, revealing that the compatibility of Ephedrae Herba with Atractylodis Macrocephalae Rhizoma alters their distribution in plasma and tissues.

This compatibility may enhance the therapeutic efficacy of Ephedra alkaloids while simultaneously reducing their toxicity, suggesting a potential for safer and more effective herbal treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacokinetic and Tissue Distribution Study of Ephedrae Herba and Herbal Pair of Ephedrae Herba-Atractylodis Macrocephalae Rhizoma in Rats]. Zhu, ZM., Li, HC., Luo, JB.[2018]

An ephedrine alkaloid-free extract of Ephedra Herb (EFE) demonstrated analgesic, anti-influenza, and anticancer activities similar to the standard extract (EHE) but without the adverse effects associated with ephedrine alkaloids, such as excitation and insomnia.

In a safety evaluation involving healthy volunteers, EFE showed fewer adverse events compared to the standard extract EHE, suggesting that EFE is a safer alternative for therapeutic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The Adverse Effects of Ephedra Herb and the Safety of Ephedrine Alkaloids-free Ephedra Herb Extract (EFE)]. Odaguchi, H., Hyuga, S., Sekine, M., et al.[2020]

Ephedra, traditionally used for thousands of years, has become controversial in the U.S. due to concerns about its composition, particularly regarding the levels of ephedrine and related alkaloids in dietary supplements.

The review highlights potential health risks associated with Ephedra, especially for sensitive individuals or those abusing it for its stimulant effects, raising important questions about its safety and regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ephedra in perspective--a current review. Abourashed, EA., El-Alfy, AT., Khan, IA., et al.[2013]

A study of 56 concentrated powder products in Taiwan revealed that many Chinese herbal formulae containing Herba Ephedrae could exceed World Anti-Doping Agency (WADA) thresholds for Ephedra alkaloids, particularly ephedrine and norpseudoephedrine.

The analysis showed that a significant percentage of these products could lead to violations of WADA regulations, highlighting the need for athletes and medical personnel to be cautious when using herbal remedies alongside other medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ephedra alkaloid contents of Chinese herbal formulae sold in Taiwan. Chang, CW., Hsu, SY., Huang, GQ., et al.[2018]

Thiopental and propofol are both favorable anesthetics for brain-injured patients due to their positive effects on cerebral blood flow and metabolism, but neither has been shown to improve outcomes in head injury cases.

Isoflurane is recommended as the best inhalational agent for neuroanesthesia because it has minimal impact on cerebral blood flow and intracranial pressure, while nitrous oxide remains popular despite variable effects, as its impact can be mitigated by other agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cerebrovascular and cerebral metabolic effects of commonly used anaesthetics. Chong, KY., Gelb, AW.[2020]

A network meta-analysis of 9 randomized controlled trials involving adult surgical patients found that dopamine and ephedrine are more effective at preserving cerebral oxygen saturation (ScO2) during treatment for intraoperative hypotension compared to norepinephrine and phenylephrine.

The study suggests a rank order for maintaining ScO2, with dopamine and ephedrine being the best options, while phenylephrine was associated with the greatest reduction in ScO2, indicating potential risks in its use during surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Regional Cerebral Oxygen Saturation Effect of Inotropes/Vasopressors Administered to Treat Intraoperative Hypotension: A Bayesian Network Meta-analysis. Bombardieri, AM., Singh, NP., Yaeger, L., et al.[2023]

Ephedrine significantly accelerates psychomotor recovery from anesthesia in rhesus monkeys, reducing recovery time from an average of 80.4 minutes to about 14.8 minutes.

The administration of ephedrine also improved oxygen saturation and systolic blood pressure, while causing a notable decrease in pulse rate shortly after administration, indicating its potential benefits and effects on cardiorespiratory functions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ephedrine accelerates psychomotor recovery from anesthesia in macaque monkeys. Hess, L., Votava, M., Slíva, J., et al.[2013]

In a study involving 10 healthy males, phenylephrine significantly reduced oxygenation levels in both the forehead and cerebral regions while increasing blood flow to the internal carotid artery, indicating a complex effect on cerebral oxygenation despite overall stable oxygen levels.

Conversely, ephedrine maintained forehead oxygenation and increased blood flow to extracerebral tissues, while slightly decreasing cerebral oxygenation, suggesting it may be a safer option for preserving oxygen levels in the brain during blood pressure management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

External carotid artery flow maintains near infrared spectroscopy-determined frontal lobe oxygenation during ephedrine administration. Sørensen, H., Rasmussen, P., Sato, K., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

The effects of ephedrine on intramuscular blood flow and other cardiopulmonary parameters in halothane-anesthetized ponies. [2019]

2. England pubmed.ncbi.nlm.nih.gov

The influence of the infusion of ephedrine and phenylephrine on the hemodynamic stability after subarachnoid anesthesia in senior adults - a controlled randomized trial. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Cerebral Macro- and Microcirculation during Ephedrine versus Phenylephrine Treatment in Anesthetized Brain Tumor Patients: A Randomized Clinical Trial Using Magnetic Resonance Imaging. [2022]

4. Korea (South) pubmed.ncbi.nlm.nih.gov

The effect of ephedrine on intraoperative hypothermia. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Intraoperative use of phenylephrine versus ephedrine and postoperative delirium: A multicenter retrospective cohort study. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Detection and validated quantification of nine herbal phenalkylamines and methcathinone in human blood plasma by LC-MS/MS with electrospray ionization. [2019]

7. China pubmed.ncbi.nlm.nih.gov

[Pharmacokinetic and Tissue Distribution Study of Ephedrae Herba and Herbal Pair of Ephedrae Herba-Atractylodis Macrocephalae Rhizoma in Rats]. [2018]

8. Japan pubmed.ncbi.nlm.nih.gov

[The Adverse Effects of Ephedra Herb and the Safety of Ephedrine Alkaloids-free Ephedra Herb Extract (EFE)]. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Ephedra in perspective--a current review. [2013]

10. England pubmed.ncbi.nlm.nih.gov

Ephedra alkaloid contents of Chinese herbal formulae sold in Taiwan. [2018]

11. Singapore pubmed.ncbi.nlm.nih.gov

Cerebrovascular and cerebral metabolic effects of commonly used anaesthetics. [2020]

12. United States pubmed.ncbi.nlm.nih.gov

The Regional Cerebral Oxygen Saturation Effect of Inotropes/Vasopressors Administered to Treat Intraoperative Hypotension: A Bayesian Network Meta-analysis. [2023]

13. Denmark pubmed.ncbi.nlm.nih.gov

Ephedrine accelerates psychomotor recovery from anesthesia in macaque monkeys. [2013]

14. England pubmed.ncbi.nlm.nih.gov

External carotid artery flow maintains near infrared spectroscopy-determined frontal lobe oxygenation during ephedrine administration. [2022]