Vasoactive Drugs for Shock

Overseen By John P Kress, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Chicago

Must be taking: Vasoactive drugs

Disqualifiers: Cardiopulmonary arrest, pregnancy, severe right heart failure

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

Duration: Duration not specified

836 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether the vasoactive drugs phenylephrine and vasopressin can reduce certain heart rhythm issues in ICU patients with shock, compared to norepinephrine and epinephrine. Shock is a serious condition where blood flow remains too low to keep organs functioning properly, even after IV fluids. The trial involves two groups: one receiving phenylephrine and vasopressin, and the other receiving norepinephrine and epinephrine. It seeks participants already in the ICU with low blood pressure and signs of poor circulation, such as confusion or low urine output, despite fluid administration. As a Phase 4 trial, this research aims to understand how these FDA-approved treatments benefit more patients.

Do I need to stop my current medications to join the trial?

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

What is the safety track record for these treatments?

Research has shown that norepinephrine is often chosen for treating septic shock due to its general safety. However, high doses can lead to heart-related side effects. In contrast, epinephrine may increase the risk of death within 30 days and can cause more severe shock than norepinephrine.

Phenylephrine effectively raises low blood pressure but does not enhance the heart's ability to pump more blood. Vasopressin does not protect the kidneys or reduce the need for dialysis in septic shock patients, but it may cause fewer irregular heartbeats.

Each treatment has its pros and cons, which are important to consider when deciding to join a trial. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about exploring these treatment combinations for shock because they offer a potentially more tailored approach to managing blood pressure in critically ill patients. Unlike the standard treatments that typically involve norepinephrine and epinephrine, the combination of phenylephrine and vasopressin introduces different mechanisms of action. Phenylephrine works primarily by constricting blood vessels, while vasopressin can increase blood pressure through its unique effect on kidney water retention and vascular tone. This approach could provide an alternative for patients who don't respond well to traditional vasopressors, potentially leading to improved outcomes.

What evidence suggests that this trial's treatments could be effective for shock?

Research has shown that norepinephrine and epinephrine, one of the treatment combinations in this trial, effectively treat shock by quickly raising blood pressure and improving urine flow. Studies indicate these drugs often help achieve target blood pressure levels and can be safe for patients. Another treatment combination in this trial is phenylephrine and vasopressin, also used to treat shock. Evidence suggests that phenylephrine with norepinephrine can be a good option, although some studies report higher death rates when phenylephrine is used with norepinephrine alone. Both drug combinations in this trial manage shock, but they have different effects and safety considerations. ^{1 2 6 7 8}

Who Is on the Research Team?

John P Kress, MD

Principal Investigator

University of Chicago

Are You a Good Fit for This Trial?

This trial is for adults in the ICU with shock not improved by IV fluids, needing drugs through a central vein to manage blood pressure. It's not for those with severe right heart failure, cardiopulmonary arrest, or pregnant women.

Inclusion Criteria

I need strong medication through a vein for severe low blood pressure.

Exclusion Criteria

Pregnancy

I have severe failure of the right side of my heart.

I have never had a cardiopulmonary arrest.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

Up to 12 hours

1 visit (in-person)

Treatment

Participants receive randomized vasoactive drug regimens to manage shock in the ICU

Duration not specified

Continuous monitoring in ICU

Follow-up

Participants are monitored for safety and effectiveness after treatment

Six months

Regular assessments

Long-term follow-up

Assessment of functional status and discharge outcomes

Up to twelve months

What Are the Treatments Tested in This Trial?

Interventions

• Epinephrine
• Norepinephrine
• Phenylephrine
• Vasopressin

Trial Overview

The study tests if phenylephrine and vasopressin can better reduce heart rhythm problems than norepinephrine and epinephrine in ICU patients with shock. It's a randomized double-blind trial where treatments are assigned by chance without patient or doctor knowing which one is given.

How Is the Trial Designed?

Group I: Norepinephrine and epinephrine Active Control 2 Interventions

Patients will receive norepinephrine infusion per standard protocol. Dose range will be 0.03-0.3 mcg/kg/minute. Norepinephrine concentration will be 16 mg/250 mL. If a second vasopressor is required, epinephrine will be added. Dose range of epinephrine will be 0.03-0.3 mcg/kg/minute. Epinephrine concentration will be 16 mg/250 mL. The drugs norepinephrine and epinephrine will be mixed and blinded by the research pharmacy. The research pharmacist will list the dose ranges in mL/hr; this will allow the bedside nurse to program the medication per standard protocol. If the patient's shock is not adequately treated with the highest doses of both norepinephrine and epinephrine, additional, open-label norepinephrine will be added, and titrated to achieve target blood pressure. If the patient's shock is not adequately treated with three vasopressors, additional open-label epinephrine will be added, and titrated to achieve target blood pressure.

Group II: Phenylephrine and vasopressin Active Control 2 Interventions

Patients will receive phenylephrine infusion per standard protocol. Dose range will be 0.3 to 3.0 mcg/kg/minute. Phenylephrine concentration will be 160 mg/250 mL. If a second vasopressor is required, vasopressin will be added. Dose range of vasopressin will be 0.1 to 0.6 milliunits/kg/minute. Vasopressin concentration will be 40 units/250 mL. The drugs phenylephrine and vasopressin will be mixed and blinded by the research pharmacy. The research pharmacist will list the dose ranges in mL/hr; this will allow the bedside nurse to program the medication per standard protocol. If the patient's shock is not adequately treated with the highest doses of both phenylephrine and vasopressin, additional, open-label norepinephrine will be added, and titrated to achieve target blood pressure. If the patient's shock is not adequately treated with three vasopressors, additional open-label epinephrine will be added, and titrated to achieve target blood pressure.

Phenylephrine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Neo-Synephrine for:

• Nasal congestion
• Hypotension
• Burn injury management

Approved in European Union as Phenylephrine for:

• Nasal congestion
• Hypotension
• Burn injury management

Approved in Canada as Sudafed PE for:

• Nasal congestion
• Hypotension

Who Is Running the Clinical Trial?

University of Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

Published Research Related to This Trial

Norepinephrine combined with dobutamine was found to be the most effective treatment for reducing 28-day mortality in patients with septic shock, based on a network meta-analysis of 33 trials involving 4,966 patients.

Dopamine was linked to a higher risk of 28-day mortality compared to norepinephrine, terlipressin, and vasopressin, and it also had the highest incidence of cardiac arrhythmias among the vasoactive medications studied.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of vasopressors for septic shock patients: A systemic review and network meta-analysis. Jia, L., Wang, P., Li, C., et al.[2023]

In a study of 98 patients with septic shock, both dopamine and metaraminol were effective in stabilizing blood circulation and improving renal function, as indicated by normalized urine output and blood parameters after treatment.

Despite improvements, certain kidney function markers (like urine albumin and beta(2)-microglobulin) remained abnormal post-treatment, suggesting that while these drugs help, they may not fully restore kidney health in septic shock patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of dopamine and metaraminol on the renal function of patients with septic shock. Hou, LC., Li, SZ., Xiong, LZ., et al.[2013]

In a study of 64 CABG patients, fenoldopam (DA1-receptor agonist) was found to significantly reduce mean arterial pressure (MAP) more quickly than nifedipine (Ca-channel antagonist), achieving target MAP levels faster.

Both drugs effectively lowered systemic vascular resistance and improved heart rate and cardiac output, but fenoldopam showed a stronger decrease in pulmonary vascular resistance, making it a promising alternative for managing postoperative hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DA1-receptor stimulation by fenoldopam in the treatment of postcardiac surgical hypertension. Gombotz, H., Plaza, J., Mahla, E., et al.[2019]

In a study of 29 adult septic shock patients receiving high-dose noradrenalin (≥0.25 μg/kg/min), those treated with vasopressin had a significantly lower survival rate (33%) compared to those receiving noradrenalin alone (82%).

The addition of vasopressin did not improve lactate clearance, a marker of tissue perfusion, indicating that it may not provide additional benefits in managing septic shock alongside high-dose noradrenalin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does vasopressin improve the mortality of septic shock patients treated with high-dose NA. Ohsugi, K., Kotani, T., Fukuda, S., et al.[2020]

In a study of 270 patients with vasodilatory shock, 67% responded positively to synthetic angiotensin II, showing significant increases in mean arterial pressure and reductions in vasopressor dosage after 3 hours.

Responders to angiotensin II had a lower likelihood of 30-day mortality, indicating that this treatment may improve survival rates in patients with refractory shock, while the most common side effects were arrhythmias in 10% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin II Infusion for Shock: A Multicenter Study of Postmarketing Use. Wieruszewski, PM., Wittwer, ED., Kashani, KB., et al.[2022]

The management of shock is complex due to its various types (cardiogenic, septic, hypovolemic) and the limitations of current treatments, which primarily include endogenous catecholamines and traditional vasopressors.

Newer agents like vasopressin, levosimendan, and omecamtiv mecarbil show promise in enhancing shock therapy, but their effectiveness in improving clinical outcomes still needs further validation through clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Shock - Classification and Pathophysiological Principles of Therapeutics. Kislitsina, ON., Rich, JD., Wilcox, JE., et al.[2020]

Vasopressin is effective in treating vasoplegic shock, particularly when traditional catecholamine treatments fail, as it works through a different receptor pathway to improve organ perfusion.

In a case study of a 49-year-old woman who overdosed on diabetes medications and developed severe lactic acidosis and shock, the addition of vasopressin to her treatment regimen helped stabilize her hemodynamic status after other treatments were ineffective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin intoxication: Vasopressin's key role in the management of severe lactic acidosis. Galiero, F., Consani, G., Biancofiore, G., et al.[2018]

Vasoactive medications, including inotropes and vasopressors, are crucial in treating shock by either increasing vascular tone or enhancing cardiac output, with norepinephrine being preferred as a first-line therapy for various shock states, especially septic shock.

Understanding the pharmacologic properties and hemodynamic effects of these medications is essential for optimizing treatment and minimizing adverse effects, as their efficacy can vary significantly based on the dose and the specific patient's condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy update on the use of vasopressors and inotropes in the intensive care unit. Jentzer, JC., Coons, JC., Link, CB., et al.[2015]

In a study of 287 patients with septic shock, combining norepinephrine with phenylephrine did not show a significant difference in in-hospital mortality compared to combining norepinephrine with vasopressin, indicating similar safety profiles for both combinations.

The study suggests that using phenylephrine as a second-line treatment alongside norepinephrine may be a viable alternative to vasopressin, but further validation through randomized controlled trials is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of norepinephrine with phenylephrine versus norepinephrine with vasopressin in critically ill patients with septic shock: A retrospective study. Arishi, H., AlQahtani, S., Tamim, H., et al.[2023]

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