Arrhythmia, Sepsis, Septic Shock, Shock, Tachycardia
Conditions
Keywords
Septic shock, Vasopressor Agents, Phenylephrine, Norepinephrine, Tachycardia, Heart Rate, Arrhythmia, Catecholamine
Brief summary
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
Interventions
DRUGPhenylephrine
Phenylephrine, in intravenous formulation, will be administered as the primary vasopressor for the treatment of septic shock
DRUGNorepinephrine
Norepinephrine, in intravenous formulation, will be administered as the primary vasopressor for the treatment of septic shock
Sponsors
National Center for Research Resources (NCRR)
National Center for Advancing Translational Sciences (NCATS)
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adults 18 years of age or greater * Intention to treat with vasopressor for diagnosis of septic shock *
Exclusion criteria
not met
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Maximum Heart Rate | Up to 28 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Receiving Non-study Vasopressors | Up to 28 days | — |
| Amount of Time Non-study Vasopressors Used | Up to 28 days | — |
| Number of Days Hemodialysis Needed | 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 | Up to 28 days | From chart review (if available) |
| CK-MB | Up to 28 days | From chart review (if available) |
| 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 | Up to 28 days | 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 |
| Number of Uses of Rate-controlling Agent | Up to 28 days | includes use of Diltiazem, Esmolol, Metoprolol, Propranolol, Verapamil |
| Number of Times an Anti-arrhythmic Agent is Used | Up to 28 days | — |
| Use of Corticosteroid | Up to 28 days | number of days participants received a corticosteroid |
| Number of Direct Current (DC) Cardioversion Events | Up to 28 days | — |
| Number of Days Mechanical Ventilation Needed | Up to 28 days | — |
| Creatinine Kinase (CK) | Up to 28 days | From chart review (if available) |
| Mean Sequential Organ Failure Assessment (SOFA) Score | Up to 28 days | Predicts ICU mortality based on lab results and clinical data. Range is 0-24 with higher numbers indicating a higher risk of mortality |
| 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 | Up to 28 days | Shock free days |
| Number of Days Without Mechanical Ventilation | Up to 28 days | Mechanical ventilation-free days |
| Days Without Dialysis | Up to 28 days | Dialysis-free days |
| Hospital Days Not in ICU | Up to 28 days | ICU free days |
| Days Spent Out of the Hospital | Up to 28 days | Hospital free days |
| Readmission to ICU | Up to 28 days | — |
| Number of Participants Rehospitalized After Discharge | Up to 28 days | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mean Central Venous Pressure | Up to 28 days | — |
| Mean Metabolic Panel Laboratory Values | Up to 28 days | From chart review (if available) |
| Mean Central Venous Oxygen Saturation | Up to 28 days | From chart review (if available) |
| Anti-hypertensive Agents Used | Up to 28 days | — |
| Diuretic Agents Used | Up to 28 days | — |
| Inotropes Used | Up to 28 days | — |
| Mean Blood Pressure (Maximum and Minimum) | Up to 28 days | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phenylephrine Phenylephrine will be administered as the primary vasopressor for the treatment of septic shock
Phenylephrine: Phenylephrine, in intravenous formulation, will be administered as the primary vasopressor for the treatment of septic shock | 8 |
| Norepinephrine Norepinephrine will be administered as the primary vasopressor for the treatment of septic shock
Norepinephrine: Norepinephrine, in intravenous formulation, will be administered as the primary vasopressor for the treatment of septic shock | 9 |
| Total | 17 |
Baseline characteristics
| Characteristic | Norepinephrine | Total | Phenylephrine |
|---|---|---|---|
| Age, Continuous | 58.4 years | 60.4 years | 63 years |
| Heart Rate | 97.3 beats/minute | 92.4 beats/minute | 86.3 beats/minute |
| Mean Blood Pressure | 66.2 mm/Hg | 66.7 mm/Hg | 67.4 mm/Hg |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 16 Participants | 8 Participants |
| Region of Enrollment United States | 9 participants | 17 participants | 8 participants |
| Sex: Female, Male Female | 4 Participants | 7 Participants | 3 Participants |
| Sex: Female, Male Male | 5 Participants | 10 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 8 | 3 / 9 |
| other Total, other adverse events | 0 / 8 | 0 / 9 |
| serious Total, serious adverse events | 0 / 8 | 0 / 9 |
Outcome results
Primary
Maximum Heart Rate
Time frame: Up to 28 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phenylephrine | Maximum Heart Rate | 96.7 beats/minute |
| Norepinephrine | Maximum Heart Rate | 108.6 beats/minute |
Secondary
28-day Mortality
Time frame: Up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phenylephrine | 28-day Mortality | 2 Participants |
| Norepinephrine | 28-day Mortality | 3 Participants |
Secondary
Amount of Time Non-study Vasopressors Used
Time frame: Up to 28 days
Population: participants receiving non-study vasopressors
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phenylephrine | Amount of Time Non-study Vasopressors Used | Phenylephrine | 0 hours |
| Phenylephrine | Amount of Time Non-study Vasopressors Used | Vasopressin | 8 hours |
| Phenylephrine | Amount of Time Non-study Vasopressors Used | Norepinephrine | 0 hours |
| Phenylephrine | Amount of Time Non-study Vasopressors Used | Epinephrine | 0 hours |
| Norepinephrine | Amount of Time Non-study Vasopressors Used | Norepinephrine | 0 hours |
| Norepinephrine | Amount of Time Non-study Vasopressors Used | Phenylephrine | 13 hours |
| Norepinephrine | Amount of Time Non-study Vasopressors Used | Epinephrine | 16 hours |
| Norepinephrine | Amount of Time Non-study Vasopressors Used | Vasopressin | 22 hours |
Secondary
Cause of Death
Time frame: Up to 28 days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phenylephrine | Cause of Death | E. coli bacteremia, aspiration pnemonia | 0 Participants |
| Phenylephrine | Cause of Death | Respiratory failure,hospital aquired pneumonia | 1 Participants |
| Phenylephrine | Cause of Death | septic shock | 1 Participants |
| Phenylephrine | Cause of Death | Hypoxemic respiratory failure | 0 Participants |
| Norepinephrine | Cause of Death | Hypoxemic respiratory failure | 1 Participants |
| Norepinephrine | Cause of Death | E. coli bacteremia, aspiration pnemonia | 1 Participants |
| Norepinephrine | Cause of Death | septic shock | 1 Participants |
| Norepinephrine | Cause of Death | Respiratory failure,hospital aquired pneumonia | 0 Participants |
Secondary
CK-MB
From chart review (if available)
Time frame: Up to 28 days
Population: patients with CK-MB levels
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phenylephrine | CK-MB | 8.87 ng/mL |
| Norepinephrine | CK-MB | 5.07 ng/mL |
Secondary
Creatinine Kinase (CK)
From chart review (if available)
Time frame: Up to 28 days
Population: patients with CK levels
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phenylephrine | Creatinine Kinase (CK) | 738 units/L |
| Norepinephrine | Creatinine Kinase (CK) | 6986.6 units/L |
Secondary
Days Spent Out of the Hospital
Hospital free days
Time frame: Up to 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phenylephrine | Days Spent Out of the Hospital | 103 days |
| Norepinephrine | Days Spent Out of the Hospital | 98 days |
Secondary
Days Without Dialysis
Dialysis-free days
Time frame: Up to 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phenylephrine | Days Without Dialysis | 168 days |
| Norepinephrine | Days Without Dialysis | 152 days |
Secondary
Hospital Days Not in ICU
ICU free days
Time frame: Up to 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phenylephrine | Hospital Days Not in ICU | 144 days |
| Norepinephrine | Hospital Days Not in ICU | 139 days |
Secondary
Length of Hospital Stay
Time frame: Up to 28 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phenylephrine | Length of Hospital Stay | 10 days |
| Norepinephrine | Length of Hospital Stay | 8.9 days |
Secondary
Length of ICU Stay
Time frame: Up to 28 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phenylephrine | Length of ICU Stay | 4.1 days |
| Norepinephrine | Length of ICU Stay | 5.2 days |
Secondary
Location of Death
Time frame: Up to 28 days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phenylephrine | Location of Death | ICU | 0 Participants |
| Phenylephrine | Location of Death | Not recorded | 1 Participants |
| Norepinephrine | Location of Death | ICU | 4 Participants |
| Norepinephrine | Location of Death | Not recorded | 0 Participants |
Secondary
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
Time frame: Up to 28 days
Population: data was not collected
Secondary
Mean Troponin-I
From chart review (if available)
Time frame: Up to 28 days
Population: patients with troponin levels
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phenylephrine | Mean Troponin-I | 0.22 ng/mL |
| Norepinephrine | Mean Troponin-I | 0.38 ng/mL |
Secondary
Number of Days Hemodialysis Needed
Time frame: Up to 28 days
Population: only participants that required dialysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phenylephrine | Number of Days Hemodialysis Needed | 1 days |
| Norepinephrine | Number of Days Hemodialysis Needed | 11 days |
Secondary
Number of Days Mechanical Ventilation Needed
Time frame: Up to 28 days
Population: only participants that required mechanical ventilation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phenylephrine | Number of Days Mechanical Ventilation Needed | 3 days |
| Norepinephrine | Number of Days Mechanical Ventilation Needed | 22 days |
Secondary
Number of Days Without Mechanical Ventilation
Mechanical ventilation-free days
Time frame: Up to 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phenylephrine | Number of Days Without Mechanical Ventilation | 165 days |
| Norepinephrine | Number of Days Without Mechanical Ventilation | 164 days |
Secondary
Number of Days Without Vasopressor Use
Shock free days
Time frame: Up to 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phenylephrine | Number of Days Without Vasopressor Use | 154 days |
| Norepinephrine | Number of Days Without Vasopressor Use | 151 days |
Secondary
Number of Direct Current (DC) Cardioversion Events
Time frame: Up to 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phenylephrine | Number of Direct Current (DC) Cardioversion Events | 0 DC cardioversion events |
| Norepinephrine | Number of Direct Current (DC) Cardioversion Events | 0 DC cardioversion events |
Secondary
Number of Participants Developing Peripheral Limb Ischemia
Time frame: Up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phenylephrine | Number of Participants Developing Peripheral Limb Ischemia | 0 Participants |
| Norepinephrine | Number of Participants Developing Peripheral Limb Ischemia | 0 Participants |
Secondary
Number of Participants Receiving Non-study Vasopressors
Time frame: Up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phenylephrine | Number of Participants Receiving Non-study Vasopressors | 3 Participants |
| Norepinephrine | Number of Participants Receiving Non-study Vasopressors | 3 Participants |
Secondary
Number of Participants Rehospitalized After Discharge
Time frame: Up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phenylephrine | Number of Participants Rehospitalized After Discharge | 0 Participants |
| Norepinephrine | Number of Participants Rehospitalized After Discharge | 0 Participants |
Secondary
Number of Participants With Arrhythmia Events
Time frame: Up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phenylephrine | Number of Participants With Arrhythmia Events | 1 Participants |
| Norepinephrine | Number of Participants With Arrhythmia Events | 2 Participants |
Secondary
Number of Participants With Cardiac Arrest Events
Time frame: Up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phenylephrine | Number of Participants With Cardiac Arrest Events | 0 Participants |
| Norepinephrine | Number of Participants With Cardiac Arrest Events | 0 Participants |
Secondary
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
Time frame: Up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phenylephrine | Number of Patients With ST-segment Abnormalities on ECG | 0 Participants |
| Norepinephrine | Number of Patients With ST-segment Abnormalities on ECG | 0 Participants |
Secondary
Number of Times an Anti-arrhythmic Agent is Used
Time frame: Up to 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phenylephrine | Number of Times an Anti-arrhythmic Agent is Used | 2 events |
| Norepinephrine | Number of Times an Anti-arrhythmic Agent is Used | 1 events |
Secondary
Number of Uses of Rate-controlling Agent
includes use of Diltiazem, Esmolol, Metoprolol, Propranolol, Verapamil
Time frame: Up to 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phenylephrine | Number of Uses of Rate-controlling Agent | 0 number of uses |
| Norepinephrine | Number of Uses of Rate-controlling Agent | 0 number of uses |
Secondary
Readmission to ICU
Time frame: Up to 28 days
Population: data was not collected
Secondary
Total Time in Arrhythmia
Time frame: Up to 28 days
Population: only participants with arrhythmias included
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phenylephrine | Total Time in Arrhythmia | atrial fibrillation | 1224 minutes |
| Phenylephrine | Total Time in Arrhythmia | Other (undetermined) arrthymia | 0 minutes |
| Norepinephrine | Total Time in Arrhythmia | atrial fibrillation | 209 minutes |
| Norepinephrine | Total Time in Arrhythmia | Other (undetermined) arrthymia | 2332 minutes |
Secondary
Use of Corticosteroid
number of days participants received a corticosteroid
Time frame: Up to 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phenylephrine | Use of Corticosteroid | 1 days |
| Norepinephrine | Use of Corticosteroid | 10 days |
Other Pre-specified
Anti-hypertensive Agents Used
Time frame: Up to 28 days
Other Pre-specified
Diuretic Agents Used
Time frame: Up to 28 days
Other Pre-specified
Inotropes Used
Time frame: Up to 28 days
Other Pre-specified
Mean Blood Pressure (Maximum and Minimum)
Time frame: Up to 28 days
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Phenylephrine | Mean Blood Pressure (Maximum and Minimum) | minimum | 55.8 mm/Hg |
| Phenylephrine | Mean Blood Pressure (Maximum and Minimum) | maximum | 88.6 mm/Hg |
| Norepinephrine | Mean Blood Pressure (Maximum and Minimum) | minimum | 53.8 mm/Hg |
| Norepinephrine | Mean Blood Pressure (Maximum and Minimum) | maximum | 79.5 mm/Hg |
Other Pre-specified
Mean Central Venous Oxygen Saturation
From chart review (if available)
Time frame: Up to 28 days
Population: patients with central venous pressure readings
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phenylephrine | Mean Central Venous Oxygen Saturation | 10.4 mm/Hg |
| Norepinephrine | Mean Central Venous Oxygen Saturation | 11.7 mm/Hg |
Other Pre-specified
Mean Central Venous Pressure
Time frame: Up to 28 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phenylephrine | Mean Central Venous Pressure | 10.4 mm/Hg |
| Norepinephrine | Mean Central Venous Pressure | 11.7 mm/Hg |
Other Pre-specified
Mean Metabolic Panel Laboratory Values
From chart review (if available)
Time frame: Up to 28 days