Phenylephrine Versus Norepinephrine for Septic Shock in Critically Ill Patients

A Randomized Controlled Pilot Trial of Phenylephrine Versus Norepinephrine for Septic Shock in Critically Ill Patients

Septic shock is a condition that is marked by severe infection causing hypotension requiring vasopressors to maintain adequate perfusion to vital organs. The Surviving Sepsis campaign, an international organization formed for the purpose of guiding the management of sepsis and septic shock, currently recommends norepinephrine as the first-choice vasopressor for septic shock. Phenylephrine, a vasopressor FDA-approved for use in septic shock, is recommended as an alternative vasopressor when septic shock is complicated by tachyarrhythmia to mitigate cardiac complications. This recommendation is based solely on experience with no scientific evidence to support this recommendation.

The investigators will conduct an open-label randomized controlled trial (RCT) directly comparing phenylephrine and norepinephrine, two FDA-approved vasopressors that are both used in clinical practice for the management of septic shock. The investigators will perform this study with a population of patients that have septic shock to complete the following aims:

Aim 1: Determine the incidence of tachyarrhythmias.

Aim 2: Determine which vasopressor, phenylephrine or norepinephrine, is associated with a lower heart rate.

Aim 3: Determine which vasopressor, phenylephrine or norepinephrine, is associated with a higher incidence of new tachyarrhythmias.

Aim 4: Determine which vasopressor, phenylephrine or norepinephrine, is associated with less time in tachyarrhythmia.

Aim 5: Determine which vasopressor, phenylephrine or norepinephrine, is associated with fewer complications, including cardiac complications.

The investigators hypothesize that in this setting, phenylephrine will improve the management of septic shock when used as a "first choice" vasopressor by:

1. Decreasing the mean heart rate
2. Decreasing the incidence of new tachyarrhythmias
3. Decreasing the amount of time spent in tachyarrhythmia for patients who develop new onset and recurrent tachyarrhythmias
4. Decreasing the number of cardiac complications

Study Overview

• Status: Terminated
• Conditions: Sepsis; Shock; Septic Shock; Arrhythmia; Tachycardia
• Intervention / Treatment: Drug: Phenylephrine; Drug: Norepinephrine

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adults 18 years of age or greater
• Intention to treat with vasopressor for diagnosis of septic shock
• Exclusion criteria not met

Exclusion Criteria:

• Emergent indication for surgery
• Patient possesses a terminal condition for which patient or medical decision maker has decided to de-escalate medical care (patients with Do Not Resuscitate order but for whom standard care is continued will not be excluded)
• Known allergy to phenylephrine or norepinephrine
• Treated with vasopressor >12 hours for current episode of shock
• Preference of specific vasopressor agent by patient's provider
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Phenylephrine; Phenylephrine will be administered as the primary vasopressor for the treatment of septic shock	Drug: Phenylephrine; Phenylephrine, in intravenous formulation, will be administered as the primary vasopressor for the treatment of septic shock; Other Names: Neosynephrine
Active Comparator: Norepinephrine; Norepinephrine will be administered as the primary vasopressor for the treatment of septic shock	Drug: Norepinephrine; Norepinephrine, in intravenous formulation, will be administered as the primary vasopressor for the treatment of septic shock; Other Names: Levophed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum Heart Rate	Up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Arrhythmia Events		Up to 28 days
Total Time in Arrhythmia		Up to 28 days
Number of Patients With ST-segment Abnormalities on ECG	ST Elevation of 1 mm in 2 or more consecutive leads or Horizontal or downsloping ST depression of 1 mm in 2 or more consecutive leads	Up to 28 days
Number of Uses of Rate-controlling Agent	includes use of Diltiazem, Esmolol, Metoprolol, Propranolol, Verapamil	Up to 28 days
Number of Times an Anti-arrhythmic Agent is Used		Up to 28 days
Use of Corticosteroid	number of days participants received a corticosteroid	Up to 28 days
Number of Direct Current (DC) Cardioversion Events		Up to 28 days
Number of Days Mechanical Ventilation Needed		Up to 28 days
Number of Days Hemodialysis Needed		Up to 28 days
Mean Sequential Organ Failure Assessment (SOFA) Score	Predicts ICU mortality based on lab results and clinical data. Range is 0-24 with higher numbers indicating a higher risk of mortality	Up to 28 days
Number of Participants Developing Peripheral Limb Ischemia		Up to 28 days
Number of Participants With Cardiac Arrest Events		Up to 28 days
Number of Days Without Vasopressor Use	Shock free days	Up to 28 days
Number of Days Without Mechanical Ventilation	Mechanical ventilation-free days	Up to 28 days
Days Without Dialysis	Dialysis-free days	Up to 28 days
Hospital Days Not in ICU	ICU free days	Up to 28 days
Days Spent Out of the Hospital	Hospital free days	Up to 28 days
Readmission to ICU		Up to 28 days
Number of Participants Rehospitalized After Discharge		Up to 28 days
Length of ICU Stay		Up to 28 days
Length of Hospital Stay		Up to 28 days
28-day Mortality		Up to 28 days
Location of Death		Up to 28 days
Cause of Death		Up to 28 days
Mean Troponin-I	From chart review (if available)	Up to 28 days
CK-MB	From chart review (if available)	Up to 28 days
Creatinine Kinase (CK)	From chart review (if available)	Up to 28 days
Number of Participants Receiving Non-study Vasopressors		Up to 28 days
Amount of Time Non-study Vasopressors Used		Up to 28 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Blood Pressure (Maximum and Minimum)		Up to 28 days
Mean Central Venous Pressure		Up to 28 days
Mean Metabolic Panel Laboratory Values	From chart review (if available)	Up to 28 days
Mean Central Venous Oxygen Saturation	From chart review (if available)	Up to 28 days
Anti-hypertensive Agents Used		Up to 28 days
Diuretic Agents Used		Up to 28 days
Inotropes Used		Up to 28 days

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Collaborators: National Center for Research Resources (NCRR); National Center for Advancing Translational Sciences (NCATS)
• Investigators: Principal Investigator: Raj Keriwala, MD, MPH, Vanderbilt University School of Medicine

Study record dates

Study Major Dates

• Study Start: August 1, 2014
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): January 1, 2016

Study Registration Dates

• First Submitted: July 22, 2014
• First Submitted That Met QC Criteria: July 28, 2014
• First Posted (Estimate): July 30, 2014

Study Record Updates

• Last Update Posted (Actual): June 13, 2018
• Last Update Submitted That Met QC Criteria: May 15, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Arrhythmia; Catecholamine; Septic shock; Norepinephrine; Tachycardia; Heart Rate; Phenylephrine; Vasopressor Agents
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Cardiac Conduction System Disease; Shock, Septic; Shock; Arrhythmias, Cardiac; Tachycardia; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Cardiotonic Agents; Respiratory System Agents; Sympathomimetics; Vasoconstrictor Agents; Mydriatics; Nasal Decongestants; Adrenergic alpha-1 Receptor Agonists; Norepinephrine; Phenylephrine; Oxymetazoline
• Other Study ID Numbers: IRB 140141; UL1RR024975-01 (U.S. NIH Grant/Contract); UL1TR000445-06 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No