Propofol for Anesthesia

Overseen By Zirui Huang

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Michigan

Disqualifiers: Pregnancy, Cardiopulmonary disease, Neurological illness, 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores changes in mental function during different anesthesia levels and examines whether ultrasonic brain stimulation, a new technology, can speed up recovery after anesthesia. The study focuses on using propofol, a common anesthetic, paired with this technology to potentially improve recovery times. Healthy individuals who are right-handed, English-speaking, and have a BMI under 30 are suitable for participation. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to advancements in anesthesia recovery.

Do I need to stop taking my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. However, it does mention that participants should not have a history of drug use or a positive drug screen, and must abstain from alcohol for 24 hours before dosing.

What prior data suggests that ultrasonic brain stimulation is safe for use in this trial?

Research has shown that ultrasonic brain stimulation is generally safe and non-invasive. It can target specific brain areas, which is beneficial. However, some minor side effects have been reported, including headaches (4% of people), mood changes (3%), pain (8%), and a feeling of pressure without pain (17%).

This study uses ultrasonic brain stimulation with propofol, a drug approved by the FDA for anesthesia during medical procedures. Although propofol is not approved for use in healthy volunteers, its safety is well-established in anesthesia.

Overall, the safety data for ultrasonic brain stimulation appears promising, but like any treatment, possible side effects exist. Prospective participants should consider these and discuss them with the study team if considering joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about ultrasonic brain stimulation for anesthesia because it offers a non-invasive alternative to traditional drugs like propofol. Unlike propofol, which is administered intravenously and can have systemic side effects, ultrasonic brain stimulation targets specific brain areas without the need for needles or chemicals. This method could lead to fewer side effects, faster recovery times, and potentially even more precise control over anesthesia levels. By focusing on the brain directly, it could revolutionize how anesthesia is delivered, making procedures safer and more comfortable for patients.

What evidence suggests that ultrasonic brain stimulation is effective for accelerating return to consciousness?

Research has shown that sound waves on the brain might help people wake up faster after anesthesia. In one study, gentle ultrasound waves helped mice recover more quickly from the effects of a common anesthetic called propofol. Another study found that this method is safe and can effectively change brain activity. This trial will explore ultrasonic brain stimulation to potentially speed up waking. Although more research is needed, early results are promising. ^{6 7 8 9 10}

Who Is on the Research Team?

Zirui Huang

Principal Investigator

University of Michigan

Are You a Good Fit for This Trial?

This trial is for individuals undergoing anesthesia with propofol, a common sedative. It's not for healthy volunteers since propofol isn't approved for them. Participants will have their brain activity monitored using fMRI to understand mental function at different anesthesia levels.

Inclusion Criteria

Right-handed

I am in good health as per the ASA-1 status.

Body mass index (BMI) less than 30

Exclusion Criteria

I do not have allergies to propofol, eggs, soy, or a history of major health issues listed.

Tattoos in the head or neck region, unless determined safe by investigators, recent food or liquid intake within 8 hours to eliminate aspiration risk, history of drug use, positive drug screen, unwillingness to abstain from alcohol for 24 hours prior to dosing, current history of nicotine use, and pregnancy

Medical contraindication to magnetic resonance imaging (MRI) scanning including possible pregnancy or currently breastfeeding, BMI>30, metallic substances in the body, claustrophobia, anxiety, or cardiopulmonary disease, or intracranial structural abnormality on T1-weighted MRI scans

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Anesthetic Sedation

Participants undergo anesthetic sedation with propofol to study mental function and perception during different levels of anesthesia

Up to 90 minutes

1 visit (in-person)

Image Recognition Task

Participants perform an image recognition task with real and scrambled images to assess neural response during sedation

16 minutes per session

Follow-up

Participants are monitored for safety and effectiveness after the anesthetic sedation

1-2 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ultrasonic Brain Stimulation

Trial Overview The study tests how the brain perceives stimuli while under varying levels of sedation from propofol. Researchers are also looking into whether ultrasonic brain stimulation can help patients wake up faster after sedation.

How Is the Trial Designed?

Group I: Image recognition task Experimental Treatment 1 Intervention

The stimulus set will include real and scrambled images, where the scrambled images will be created by phase-shuffling a randomly chosen real image from each category to preserve category specific low-level image features. Each object category will include four unique real images and one scrambled image. Each image will be repeated 10 times (i.e., trials) for each 16-min session. The pre-stimulus interval will vary randomly from trial to trial between 4 and 8 seconds to prevent stimulus timing predictability. The stimuli will be presented in a randomized order to prevent category predictability.

Who Is Running the Clinical Trial?

University of Michigan

Lead Sponsor

Trials

1,891

Recruited

6,458,000+

National Institute of General Medical Sciences (NIGMS)

Collaborator

Trials

315

Recruited

251,000+

Published Research Related to This Trial

Propofol is a short-acting intravenous anesthetic that is widely used for sedation in mechanically ventilated patients in the ICU due to its rapid onset and termination of action.

While propofol has a well-established safety profile, clinicians should be aware of potential adverse reactions associated with its use, emphasizing the importance of monitoring patients during administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Propofol for sedation in the intensive care unit: essentials for the clinician. Marinella, MA.[2019]

In a study involving 5 rats, propofol was found to significantly increase the latencies of auditory brainstem response (ABR) waves III and V, indicating that propofol affects auditory processing at the brainstem level.

Despite these changes in ABR latencies, propofol did not significantly alter the postsynaptic currents at the MNTB-LSO synapses, suggesting that glycinergic and glutamatergic neurotransmission may not be responsible for the observed effects on ABR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The correlation between the effects of propofol on the auditory brainstem response and the postsynaptic currents of the auditory circuit in brainstem slices in the rat. Kang, BJ., Kim, SK., Lee, GW., et al.[2019]

In a study involving 49,836 pediatric sedation/anesthesia encounters using propofol, there were no deaths reported, indicating a high level of safety in this practice across various institutions.

While serious adverse events were rare, less serious complications such as oxygen desaturation and airway obstruction occurred, highlighting the importance of effective management systems to handle these issues during propofol sedation/anesthesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The incidence and nature of adverse events during pediatric sedation/anesthesia with propofol for procedures outside the operating room: a report from the Pediatric Sedation Research Consortium. Cravero, JP., Beach, ML., Blike, GT., et al.[2022]

In a study of 20 patients undergoing lumbar disk surgery, the effectiveness of motor-evoked potentials (MEPs) elicited by transcranial magnetoelectric stimulation changed with varying levels of propofol anesthesia, indicating that stimulation patterns need to be adjusted based on the drug's concentration.

At lower propofol levels (<3 microg/mL), the best MEP responses were achieved with quadruple stimulation at 100 Hz, while at higher levels (≥3 microg/mL), the optimal frequency shifted to 200 Hz, suggesting a dose-dependent effect of propofol on cortical interneurons.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Motor-evoked potential facilitation during progressive cortical suppression by propofol. Scheufler, KM., Zentner, J.[2019]

Propofol enhances sedation by increasing the frequency of excitatory signals to GABAergic neurons in the ventrolateral preoptic area (VLPO), which are crucial for inducing sleep.

This effect is mediated through GABA(A) receptors on glutamatergic inputs, leading to increased glutamate release and greater activation of VLPO neurons, thereby promoting sedation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Propofol facilitates glutamatergic transmission to neurons of the ventrolateral preoptic nucleus. Li, KY., Guan, YZ., Krnjević, K., et al.[2021]

Anesthesia, specifically with propofol, disrupts auditory processing in higher-order association cortices while preserving some responses in the primary auditory cortex (PAC), indicating a selective effect on sensory processing during loss of consciousness (LOC).

The study utilized intracranial electroencephalogram (iEEG) and local field potentials (LFPs) in patients, revealing that while neuronal spiking in higher-order regions decreased significantly after LOC, gamma power responses to auditory stimuli persisted, suggesting complex changes in brain activity during anesthesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anesthesia-induced loss of consciousness disrupts auditory responses beyond primary cortex. Krom, AJ., Marmelshtein, A., Gelbard-Sagiv, H., et al.[2020]

In a study of 128 patients undergoing deep brain surgery for Parkinsonism, 78.9% experienced adverse events, with the most common being hemodynamic issues like arterial hypertension, which poses a risk for serious complications such as brain hemorrhage.

The use of propofol for anesthesia during these lengthy surgeries (averaging 8.3 hours) was found to be safe and did not interfere with neurophysiological monitoring, allowing for effective patient oversight throughout the procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Preoperative adverse events during stereotactic microelectrode-guided deep brain surgery in Parkinson's disease]. Santos, P., Valero, R., Arguis, MJ., et al.[2014]

This study used intracranial electroencephalography to investigate how general anesthesia with propofol affects auditory processing in the brain, revealing that sedation significantly reduces the magnitude of auditory evoked potentials (AEPs) and alters brain activity in auditory-related areas.

The findings suggest that specific changes in auditory cortical activity could serve as biomarkers for loss of consciousness (LOC), providing insights into how sensory processing is altered during different states of consciousness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cortical Responses to Vowel Sequences in Awake and Anesthetized States: A Human Intracranial Electrophysiology Study. Nourski, KV., Steinschneider, M., Rhone, AE., et al.[2023]

Propofol is a safe and effective anesthetic agent, with induction doses of 2-2.5 mg/kg and maintenance doses of about 9 mg/kg per hour, leading to rapid and predictable emergence from anesthesia.

The use of propofol alone can significantly reduce post-induction hypotension and minimize apnea when pre-induction hyperventilation is avoided, making it a reliable choice for anesthesia without major complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Propofol as an intravenous agent in general anesthesia and conscious sedation. McNeir, DA., Mainous, EG., Trieger, N.[2018]

Propofol primarily acts as a hypnotic agent by enhancing the inhibitory effects of GABAA receptors in the cerebral cortex, which is crucial for its use in anesthesia and sedation.

In addition to its main action on GABAA receptors, propofol also influences various ion channels, including voltage-gated sodium and potassium channels, indicating a complex mechanism of action at the cellular level.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Actions of Propofol on Neurons in the Cerebral Cortex. Kobayashi, M., Oi, Y.[2018]

Using focused ultrasound to temporarily open the blood-brain barrier in non-human primates allows for effective delivery of GABA, leading to a significant decrease in visual cortex activity in a dose-dependent manner.

The study demonstrated that the GABA-induced inhibition was much more effective than the effects of ultrasound alone, highlighting the potential of this method for non-invasive brain modulation while ensuring safety through monitoring cavitation levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-invasive ultrasonic modulation of visual evoked response by GABA delivery through the blood brain barrier. Constans, C., Ahnine, H., Santin, M., et al.[2021]

The FDA has issued a warning about the potential risks of certain anesthetic agents on brain development in fetuses and young children, particularly highlighting inhalational anesthetics like isoflurane and sevoflurane, as well as intravenous agents like propofol and midazolam, especially during prolonged procedures.

To mitigate risks, healthcare professionals are advised to consider alternative sedation methods, minimize exposure duration to anesthetics, and ensure prompt surgery start times, particularly for nonobstetric and fetal surgeries in pregnant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Food and Drug Administration warning on anesthesia and brain development: implications for obstetric and fetal surgery. Olutoye, OA., Baker, BW., Belfort, MA., et al.[2018]

Transcranial high-frequency electrical stimulation can effectively record myogenic motor evoked potentials (MEPs) during general anesthesia, which was previously not possible with single pulse stimulation, demonstrating its potential for intraoperative monitoring.

In a study involving 10 patients, specific stimulation parameters were identified as necessary for eliciting MEPs, including a minimum intensity of 60-80 mA and a frequency of 100-200 Hz, indicating a precise method for monitoring motor pathways during surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial high-frequency repetitive electrical stimulation for recording myogenic motor evoked potentials with the patient under general anesthesia. Pechstein, U., Cedzich, C., Nadstawek, J., et al.[2019]

Researchers have created biodegradable nanoparticles that can noninvasively release the anesthetic propofol in the brain using focused ultrasound, which could change how we approach brain treatments.

In tests on rats, these nanoparticles effectively silenced seizures without causing any damage to brain tissue or disrupting the blood-brain barrier, indicating a safe method for neuromodulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Noninvasive Targeted Transcranial Neuromodulation via Focused Ultrasound Gated Drug Release from Nanoemulsions. Airan, RD., Meyer, RA., Ellens, NP., et al.[2022]

Citations

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High Intensity Focused Ultrasound – Longitudinal Data on ... When a subgroup analysis was done to account for this, DBS remained more effective in terms of tremor control –61.2% vs 56.4%. Notably, however, ...

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Low-intensity transcranial ultrasound stimulation ... Transcranial ultrasound stimulation has the advantages of non-invasiveness, higher spatial resolution and deeper penetration.

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Ultrasonic Deep Brain Stimulation During Anesthetic ... Primary Outcome Measure: Blood Oxygen Level Dependent (BOLD) response to visual stimuli ... LIFUP has been shown to be a safe and effective method to modulate ...

4. bmcneurosci.biomedcentral.com bmcneurosci.biomedcentral.com/articles/10.1186/s12868-018-0476-2

The effect of anesthetic dose on the motor response induced ... Their results showed that the stimulation success rates were 10%, 98.7%, and 94.6% when the mice had anesthesia levels of 0.5%, 0.1%, and 0.02% ...

5. withpower.com withpower.com/trial/phase-2-mental-function-7-2022-abd55

Ultrasound Brain Stimulation for Anesthetic Sedation Low-intensity transcranial ultrasound stimulation (TUS) significantly reduced the time to emerge from propofol anaesthesia in mice, with an average recovery ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S1935861X19303389

Safety of transcranial focused ultrasound stimulation At high stimulation intensity and/or rate, TFUS may cause haemorrhage, cell death or damage, and unintentional blood-brain barrier (BBB) opening. TFUS may also ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT07221539

Restoration of Consciousness With Ultrasonic Deep Brain ... The purpose of this study is to see if mental functions take place during different levels of anesthesia using two commonly used drug (propofol ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6996285/

Ultrasound Neuromodulation: A Review of Results ... In conclusion, the literature supports the use of US as a safe, non-invasive brain stimulation modality with improved spatial localization and depth targeting ...

9. mdpi.com mdpi.com/2076-3425/12/10/1277

Safety of Clinical Ultrasound Neuromodulation Minor adverse events were noted with free reporting, namely headache (4%), mood deterioration (3%), pain (8%) and painless pressure sensations (17%) [57].

10. link.springer.com link.springer.com/article/10.1007/s12630-016-0794-8

Anesthesia considerations for patients with an implanted ... Neurostimulators should be turned off intraoperatively to minimize electromagnetic interference, and precautions should be taken when using ...