Hypotension, Sepsis
Conditions
Brief summary
This study assesses the mean difference in fluid balance at ICU discharge and associated patient outcomes, based on a dynamic assessment of fluid responsiveness in septic patients with refractory hypotension in an ICU setting.
Detailed description
Multi-center randomized study comparing dynamic assessment of fluid responsiveness utilizing Starling SV monitor compared to a control group. Subjects will be randomized in a 2:1 treatment to control group ratio to increase power for sub-analysis by patient population. Patients randomized to the Starling SV arm will have treatment guided by a dynamic assessment of fluid responsiveness (measured by a change in stroke volume index \> 10%) as assessed by passive leg raise (PLR). Patients randomized to the control group will receive standard of care treatment.
Interventions
DEVICETreatment Starling SV monitor
A dynamic assessment of fluid responsiveness will be performed at every clinical decision point for the first 72 hours of study enrollment. Fluid responsiveness will be assessed using a passive leg raise (PLR) and Starling SV hemodynamic monitor to guide corresponding treatment.
Sponsors
Cheetah Medical Inc.
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
1. Diagnosis of sepsis, as exhibited by 2 or more of the following systemic inflammatory response syndrome (SIRS) criteria and a known or presumed infection at time of screening: * Temperature of \> 38 C or \< 36 C * Heart rate of \> 90/min * Respiratory rate of \> 20/min or PaCO2 \< 32 mm Hg (4.3 kPA) * White blood cell count \> 12000/mm3 or \< 4000/mm3 or \>10% immature bands 2. Refractory hypotension despite initial fluid resuscitation (1L of treatment fluid) 3. Patient enrolled in study as soon as possible (ideal window of 0-12 hours) and within 24 hours of arrival to the hospital 4. Anticipated ICU admission 5. Able to provide signed informed consent or consent can be obtained from the patient's authorized representative
Exclusion criteria
1. Primary diagnosis of: acute cerebral vascular event, acute coronary syndrome, acute pulmonary edema, status asthmaticus, major cardiac arrhythmia, drug overdose, or injury from burn or trauma 2. Known aortic insufficiency, or aortic abnormalities 3. Hemodynamic instability due to active gastrointestinal hemorrhage 4. Patient has received \>3 liters of IV fluid prior to study randomization 5. Requires immediate surgery 6. Patient transferred to the ICU from another hospital unit 7. Do not attempt resuscitation (DNAR or DNR) order 8. Advanced directives restricting implementation of the resuscitation protocol 9. Contraindication to blood transfusion 10. Attending clinician deems aggressive resuscitation unsuitable 11. Transferred from another in-hospital setting 12. Not able to commence treatment protocol within 1 hour after randomization 13. Known intraventricular heart defect, such as ventral septal defect or atrial septal defect 14. Use of additional hemodynamic monitoring involving stroke volume variation (SVV) to determine fluid responsiveness 15. Seizure in the last 24 hours 16. Prisoner 17. Pregnancy 18. Age \<18 19. Known allergy to sensor material or gel 20. Inability or contraindication to doing a passive leg raise with both extremities, such as inability to interrupt venous compression boots 21. Patient has an epidural catheter in place 22. Suspected intra-abdominal hypertension 23. Inability to obtain IV access 24. Diabetic ketoacidosis 25. Hyper-osmolarity syndrome 26. Patient uncouples from treatment algorithm 27. Patient should be excluded based on the opinion of the Clinician/Investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fluid Balance | 72 hours | Fluid balance is defined as all intravenous fluids administered over a 72 hour period (or ICU discharge, whichever occurred first), minus all fluid output. Urine output was measured in the ICU in 12 hour increments. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Requiring Renal Replacement Therapy | Day 1 to Day 30 | Renal replacement therapy (RRT) is therapy that replaces the normal blood-filtering function of the kidneys. It is used when the kidneys are not working well, which is called kidney failure and includes acute kidney injury and chronic kidney disease. Patient receives new treatment with dialysis. |
| Percentage of Participants Requiring Ventilator Use | Day 1 to Day 30 | Patients did not enter the study on ventilation, but required ventilator use during the study are included in the analysis. |
| Length of ICU Stay | Day 1 to Day 30 | Intensive Car Unit (ICU) length of stay will be calculated using the earliest of date that the subject is medically ready for discharge when captured, the date of discharge, or the study exit date. |
| Number of Hours of Ventilator Use | Day 1 to Day 30 | Patients that did not enter the study on ventilation, but required ventilator use during the study are included in the analysis.Ventilator use might have improved (less use of ventilator support), had no change, or worsened (more use of ventilator support). |
| Number of Hours of Vasopressor Use | Day 1 to Day 30 | Vasopressor drugs are provided to restore and maintain blood pressure in patients with septic shock. Patients that have vasopressors initiated throughout the trial are included in this analysis. |
| Change From Baseline in Serum Creatinine Levels at 72 Hours | Baseline, 72 hours | The diagnosis of Acute Kidney Injury (AKI) is traditionally based on a rise in serum creatinine |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Major Adverse Cardiac Event (MACE) | Day 1 to Day 30 | Incidence of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. |
| Number of Participants Experiencing an Adverse Event (AE) Related to Study Device | Day 1 to Day 30 | Adverse events associated with the treatment procedure. |
| Percentage of Participants With Hospital Discharge Without ICU Readmission | Day 1 to Day 30 | — |
| Percentage of Participants Within Overall 30 Day Mortality Rate | Day 1 to Day 30 | Incidence of death. |
| Number of Participants by Hospital Discharge Location | Day 1 to Day 30 | Patient location (either home or other) following hospital discharge. |
| Volume of Fluid | 72 hours | Traditional methods of assessing fluid responsiveness (FR) such as vital signs, physical examination, and static measurements of circulatory pressure have shown not to reliably correlate with fluid responsiveness. In contrast, dynamic measurement of stroke volume (SV) following an intravenous (IV) fluid bolus or passive leg raise (PLR) is a safe and feasible method of rapidly assessing the effectiveness of fluid-induced augmentation of SV and cardiac output (CO). Mean volume of treatment fluid Administered (ml) at 72 hours or ICU discharge, whichever occurs first, between the two treatment groups |
Countries
United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Starling SV Monitor A dynamic assessment of fluid responsiveness using the Starling SV monitor will be performed at every clinical decision point for the first 72 hours of study enrollment. Examples of a clinical decision point include a mean arterial pressure (MAP) of \< 65, the decision to give additional fluid volume, and the decision to either escalate or wean vasopressors. Fluid responsiveness will be assessed using a passive leg raise (PLR) and Starling SV hemodynamic monitor to guide corresponding treatment. | 83 |
| Usual Care No required therapeutic protocol will be used for patient treatment, and is determined per the discretion of the physician and hospital standards. | 41 |
| Total | 124 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Allocation | Admitted to General Floor | 3 | 4 |
| Allocation | Device not available | 1 | 0 |
| Allocation | Diabetic Ketoacidosis/withdrew | 1 | 0 |
| Allocation | Did not meet sepsis criteria | 1 | 2 |
| Allocation | Immediate surgery/withdrew | 2 | 0 |
| Allocation | Known aortic abnormalities | 0 | 1 |
| Allocation | Moribund/Do not resuscitate | 2 | 0 |
| Allocation | Protocol not implemented | 7 | 0 |
| Allocation | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Treatment Starling SV Monitor | Usual Care | Total |
|---|---|---|---|
| Age, Continuous | 61.8 years STANDARD_DEVIATION 16.9 | 62.7 years STANDARD_DEVIATION 15 | 62.1 years STANDARD_DEVIATION 16.24 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Black or African American | 17 Participants | 9 Participants | 26 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 61 Participants | 31 Participants | 92 Participants |
| Sex: Female, Male Female | 51 Participants | 13 Participants | 64 Participants |
| Sex: Female, Male Male | 32 Participants | 28 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 20 / 102 | 10 / 48 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 10 / 102 | 7 / 48 |
Outcome results
Primary
Fluid Balance
Fluid balance is defined as all intravenous fluids administered over a 72 hour period (or ICU discharge, whichever occurred first), minus all fluid output. Urine output was measured in the ICU in 12 hour increments.
Time frame: 72 hours
Population: mITT population was predefined as including all patients who signed consent, met study eligibility criteria, were randomized and received monitoring for 72 hours or ICU discharge if earlier. mITT (n=83,41).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Starling SV Monitor | Fluid Balance | 0.65 Liters | Standard Deviation 2.85 |
| Usual Care | Fluid Balance | 2.02 Liters | Standard Deviation 3.44 |
p-value: 0.02195% CI: [-2.53, 0.21]t-test, 2 sided
Secondary
Change From Baseline in Serum Creatinine Levels at 72 Hours
The diagnosis of Acute Kidney Injury (AKI) is traditionally based on a rise in serum creatinine
Time frame: Baseline, 72 hours
Population: mITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Starling SV Monitor | Change From Baseline in Serum Creatinine Levels at 72 Hours | 0.13 mg/dL | Standard Deviation 1.1 |
| Usual Care | Change From Baseline in Serum Creatinine Levels at 72 Hours | 0.04 mg/dL | Standard Deviation 0.97 |
p-value: 0.45395% CI: [-0.34, 0.52]ANCOVA
Secondary
Length of ICU Stay
Intensive Car Unit (ICU) length of stay will be calculated using the earliest of date that the subject is medically ready for discharge when captured, the date of discharge, or the study exit date.
Time frame: Day 1 to Day 30
Population: mITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Starling SV Monitor | Length of ICU Stay | 3.31 days | Standard Deviation 3.51 |
| Usual Care | Length of ICU Stay | 6.22 days | Standard Deviation 10.72 |
p-value: 0.11395% CI: [-6.67, 0.85]Fisher Exact
Secondary
Number of Hours of Vasopressor Use
Vasopressor drugs are provided to restore and maintain blood pressure in patients with septic shock. Patients that have vasopressors initiated throughout the trial are included in this analysis.
Time frame: Day 1 to Day 30
Population: mITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Starling SV Monitor | Number of Hours of Vasopressor Use | 40.74 hours | Standard Deviation 51.23 |
| Usual Care | Number of Hours of Vasopressor Use | 55.64 hours | Standard Deviation 87.42 |
p-value: 0.42695% CI: [-52.5, 22.68]Wilcoxon (Mann-Whitney)
Secondary
Number of Hours of Ventilator Use
Patients that did not enter the study on ventilation, but required ventilator use during the study are included in the analysis.Ventilator use might have improved (less use of ventilator support), had no change, or worsened (more use of ventilator support).
Time frame: Day 1 to Day 30
Population: mITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Starling SV Monitor | Number of Hours of Ventilator Use | 46.99 hours | Standard Deviation 52.33 |
| Usual Care | Number of Hours of Ventilator Use | 119.42 hours | Standard Deviation 134.9 |
95% CI: [-154.08, 9.22]Wilcoxon (Mann-Whitney)
Secondary
Percentage of Participants Requiring Renal Replacement Therapy
Renal replacement therapy (RRT) is therapy that replaces the normal blood-filtering function of the kidneys. It is used when the kidneys are not working well, which is called kidney failure and includes acute kidney injury and chronic kidney disease. Patient receives new treatment with dialysis.
Time frame: Day 1 to Day 30
Population: mITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Starling SV Monitor | Percentage of Participants Requiring Renal Replacement Therapy | 5.1 percentage of participants |
| Usual Care | Percentage of Participants Requiring Renal Replacement Therapy | 17.5 percentage of participants |
p-value: 0.04295% CI: [-0.27, -0.01]Fisher Exact
Secondary
Percentage of Participants Requiring Ventilator Use
Patients did not enter the study on ventilation, but required ventilator use during the study are included in the analysis.
Time frame: Day 1 to Day 30
Population: mITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Starling SV Monitor | Percentage of Participants Requiring Ventilator Use | 17.7 percentage of participants |
| Usual Care | Percentage of Participants Requiring Ventilator Use | 34.1 percentage of participants |
p-value: 0.04495% CI: [-0.33, 0]Chi-squared
Other Pre-specified
Number of Participants by Hospital Discharge Location
Patient location (either home or other) following hospital discharge.
Time frame: Day 1 to Day 30
Population: mITT
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment Starling SV Monitor | Number of Participants by Hospital Discharge Location | Home | 53 Participants |
| Treatment Starling SV Monitor | Number of Participants by Hospital Discharge Location | Other | 30 Participants |
| Usual Care | Number of Participants by Hospital Discharge Location | Home | 18 Participants |
| Usual Care | Number of Participants by Hospital Discharge Location | Other | 23 Participants |
Other Pre-specified
Number of Participants Experiencing an Adverse Event (AE) Related to Study Device
Adverse events associated with the treatment procedure.
Time frame: Day 1 to Day 30
Population: ITT-all randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Starling SV Monitor | Number of Participants Experiencing an Adverse Event (AE) Related to Study Device | 1 participants |
| Usual Care | Number of Participants Experiencing an Adverse Event (AE) Related to Study Device | 0 participants |
Other Pre-specified
Percentage of Participants With Hospital Discharge Without ICU Readmission
Time frame: Day 1 to Day 30
Population: mITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Starling SV Monitor | Percentage of Participants With Hospital Discharge Without ICU Readmission | 94.9 percentage of participants |
| Usual Care | Percentage of Participants With Hospital Discharge Without ICU Readmission | 97.8 percentage of participants |
Other Pre-specified
Percentage of Participants Within Overall 30 Day Mortality Rate
Incidence of death.
Time frame: Day 1 to Day 30
Population: mITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Starling SV Monitor | Percentage of Participants Within Overall 30 Day Mortality Rate | 15.7 percentage of participants |
| Usual Care | Percentage of Participants Within Overall 30 Day Mortality Rate | 22 percentage of participants |
Other Pre-specified
Percentage of Participants With Major Adverse Cardiac Event (MACE)
Incidence of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.
Time frame: Day 1 to Day 30
Population: mITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Starling SV Monitor | Percentage of Participants With Major Adverse Cardiac Event (MACE) | 6 percentage of participants |
| Usual Care | Percentage of Participants With Major Adverse Cardiac Event (MACE) | 12.2 percentage of participants |
Other Pre-specified
Volume of Fluid
Traditional methods of assessing fluid responsiveness (FR) such as vital signs, physical examination, and static measurements of circulatory pressure have shown not to reliably correlate with fluid responsiveness. In contrast, dynamic measurement of stroke volume (SV) following an intravenous (IV) fluid bolus or passive leg raise (PLR) is a safe and feasible method of rapidly assessing the effectiveness of fluid-induced augmentation of SV and cardiac output (CO). Mean volume of treatment fluid Administered (ml) at 72 hours or ICU discharge, whichever occurs first, between the two treatment groups
Time frame: 72 hours
Population: mITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Starling SV Monitor | Volume of Fluid | 5759.2 ml | Standard Deviation 2246.8 |
| Usual Care | Volume of Fluid | 6865.5 ml | Standard Deviation 3348.5 |