Phenylephrine vs Norepinephrine for Blood Pressure Management During Surgery

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: The Cleveland Clinic

Must be taking: Antihypertensives

Disqualifiers: Dementia, Carotid surgery, Intracranial surgery, 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: Unknown

Duration: During surgery

6254 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Some patients participating in the underlying GUARDIAN trial (NCT04884802) will be additionally randomized to norepinephrine or phenylephrine infusion to maintain the designated target intraoperative mean arterial pressure.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, since participants must be chronically taking at least one anti-hypertensive medication, it seems you may continue those medications.

Is phenylephrine safe for use in humans?

Phenylephrine is generally considered safe, especially in nasal form, for people with controlled high blood pressure, but it can cause severe high blood pressure and lung issues if used in large doses or with certain other medications. ^{1 2 3 4 5}

How do phenylephrine and norepinephrine differ for blood pressure management during surgery?

Phenylephrine and norepinephrine are both used to manage blood pressure during surgery, but norepinephrine is gaining popularity because it causes less slowing of the heart rate and maintains better heart function compared to phenylephrine. This makes norepinephrine a potentially safer option for maintaining stable blood pressure without causing significant side effects like bradycardia (slow heart rate) during procedures such as cesarean sections. ^{5 6 7 8 9}

What data supports the effectiveness of the drugs phenylephrine and norepinephrine for blood pressure management during surgery?

Research shows that norepinephrine is effective in maintaining blood pressure during spinal anesthesia for cesarean delivery, with a lower risk of causing slow heart rate compared to phenylephrine. This suggests norepinephrine may be a safer option for managing blood pressure during surgery. ^{1 5 6 9 10}

Who Is on the Research Team?

Daniel I Sessler, MD

Principal Investigator

The Cleveland Clinic

Are You a Good Fit for This Trial?

This trial is for adults over 45 facing major noncardiac surgery lasting at least 2 hours, with certain health risks like heart disease or diabetes. They must be on blood pressure medication and able to have their blood pressure closely monitored during surgery.

Inclusion Criteria

I am over 65, have had vascular surgery, or have certain health conditions.

I am scheduled for a major surgery that is not heart-related and will last at least 2 hours.

I have a serious health condition that affects my daily life.

Exclusion Criteria

Have language, vision, or hearing impairments that may compromise cognitive assessments

I am scheduled for brain surgery.

I am scheduled for surgery on my carotid artery.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to norepinephrine or phenylephrine infusion to maintain intraoperative MAP

During surgery

Follow-up

Participants are monitored for major perfusion-related complications and postoperative delirium

30 days

What Are the Treatments Tested in This Trial?

Interventions

• Norepinephrine
• Phenylephrine

Trial Overview The study tests whether Phenylephrine or Norepinephrine is better at maintaining target blood pressure during major surgeries in patients who are already part of the GUARDIAN trial.

How Is the Trial Designed?

Group I: Tight Pressure Management with phenylephrine Active Control 1 Intervention

Pressure maintenance with phenylephrine infusion at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial.

Group II: Tight Pressure Management with norepinephrine Active Control 1 Intervention

Pressure maintenance with norepinephrine infusion at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial.

Group III: Routine Pressure Management with phenylephrine Active Control 1 Intervention

Pressure maintenance with phenylephrine infusion at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial

Group IV: Routine Pressure Management with norepinephrine Active Control 1 Intervention

Pressure maintenance with norepinephrine infusion at a rate sufficient to maintain the intraoperative MAP designated in the underlying GUARDIAN trial.

Who Is Running the Clinical Trial?

The Cleveland Clinic

Lead Sponsor

Trials

1,072

Recruited

1,377,000+

Published Research Related to This Trial

In a study of 86 pre-eclamptic women undergoing cesarean sections, both phenylephrine and norepinephrine were found to be equally effective in treating postspinal hypotension, with no significant differences in neonatal outcomes as measured by umbilical artery pH.

However, the phenylephrine group experienced fewer hypotensive episodes and lower heart rates compared to the norepinephrine group, suggesting it may be a safer option in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomised double-blind comparison of phenylephrine and norepinephrine for the management of postspinal hypotension in pre-eclamptic patients undergoing caesarean section. Mohta, M., R, L., Chilkoti, GT., et al.[2022]

Norepinephrine significantly reduces the incidence of bradycardia and reactive hypertension compared to phenylephrine in pregnant women undergoing elective cesarean delivery under spinal anesthesia, based on a systematic review of 12 studies.

Both norepinephrine and phenylephrine show similar rates of hypotension, nausea, and vomiting, indicating that norepinephrine is a safe and effective alternative for maintaining blood pressure without adverse effects on maternal or fetal health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative efficacy and safety of prophylactic norepinephrine and phenylephrine in spinal anesthesia for cesarean section: A systematic review and meta-analysis with trial sequential analysis. Liu, P., He, H., Zhang, SS., et al.[2022]

The 'HYPOTENS' study is a national, multi-center trial comparing the effectiveness of cafedrine/theodrenaline versus ephedrine in treating intra-operative hypotension in patients aged 50 and older, as well as those undergoing Cesarean sections, ensuring real-world clinical practice conditions.

The primary goal is to evaluate how well each treatment restores blood pressure and affects post-operative outcomes, such as heart rate and delirium, with results expected to provide insights into the best management strategies for hypotensive patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A non-interventional comparative study of the 20:1 combination of cafedrine/theodrenaline versus ephedrine for the treatment of intra-operative arterial hypotension: the 'HYPOTENS' study design and rationale. Eberhart, L., Geldner, G., Huljic, S., et al.[2019]

Hypertensive patients should avoid using adrenergic agents for blood pressure control, with nasal phenylephrine hydrochloride being the safest option among them, while pseudoephedrine may also be safe.

Ibuprofen can raise blood pressure if taken at maximum over-the-counter doses for extended periods, highlighting the need for caution with nonprescription medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonprescription drugs and hypertension. Which ones affect blood pressure? Bradley, JG.[2019]

A review of 12 clinical studies found that intranasal phenylephrine appears to be safe for patients with controlled hypertension, based on one double-blind randomized trial.

The evidence regarding the safety of other sympathomimetic decongestants like phenylpropanolamine and pseudoephedrine in hypertensive patients is limited and unclear, suggesting that the belief they are unsafe is not strongly supported by research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Are oral decongestants safe in hypertension? An evaluation of the evidence and a framework for assessing clinical trials. Radack, K., Deck, CC.[2013]

Topical phenylephrine can cause severe hypertension due to its action on alpha-adrenergic receptors, which is a significant safety concern, especially in pediatric patients.

In this case, a pediatric patient experienced acute pulmonary edema after receiving a large dose of phenylephrine followed by beta-blockers, highlighting the potential risks of combining these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pulmonary edema following phenylephrine intranasal spray administration during the induction of general anesthesia in a child. Son, JS., Lee, SK.[2022]

Citations

1. England pubmed.ncbi.nlm.nih.gov

A randomised double-blind comparison of phenylephrine and norepinephrine for the management of postspinal hypotension in pre-eclamptic patients undergoing caesarean section. [2022]

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

A randomized open label, parallel-group study to evaluate the hemodynamic effects of Cafedrine/Theodrenaline vs Noradrenaline in the treatment of intraoperative hypotension after induction of general anesthesia: the "HERO" study design and rationale. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Comparative efficacy and safety of prophylactic norepinephrine and phenylephrine in spinal anesthesia for cesarean section: A systematic review and meta-analysis with trial sequential analysis. [2022]

4. England pubmed.ncbi.nlm.nih.gov

A non-interventional comparative study of the 20:1 combination of cafedrine/theodrenaline versus ephedrine for the treatment of intra-operative arterial hypotension: the 'HYPOTENS' study design and rationale. [2019]

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

A Random-allocation Graded Dose-Response Study of Norepinephrine and Phenylephrine for Treating Hypotension during Spinal Anesthesia for Cesarean Delivery. [2018]

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

Nonprescription drugs and hypertension. Which ones affect blood pressure? [2019]

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

Are oral decongestants safe in hypertension? An evaluation of the evidence and a framework for assessing clinical trials. [2013]

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

Pulmonary edema following phenylephrine intranasal spray administration during the induction of general anesthesia in a child. [2022]

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

Norepinephrine versus phenylephrine infusion for preventing postspinal hypotension during cesarean section for twin pregnancy: a double-blinded randomized controlled clinical trial. [2022]

10. Japan pubmed.ncbi.nlm.nih.gov

Comparative cardiovascular effects of SNP, ATP and phentolamine during norepinephrine-induced hypertension in dogs. [2018]