Fluid Responsiveness Evaluation in Sepsis-associated Hypotension (FRESH)

Evaluation of Fluid Volume in Patients With Sepsis and Refractory Hypotension

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.

Study Overview

• Status: Completed
• Conditions: Sepsis; Hypotension
• Intervention / Treatment: Device: Treatment Starling SV monitor

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.

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Guildford, United Kingdom
    • Royal Surrey County Hospital
• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California San Francisco Medical Center
  • Colorado
    • Denver, Colorado, United States, 80204
      • Denver Health
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Grady Memorial Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Methodist Hospital
  • New York
    • New York, New York, United States, 10016
      • NYU School of Medicine
    • New York, New York, United States, 11215
      • New York Presbyterian Brooklyn Methodist Hospital
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College Of Medicine

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:

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

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
Experimental: 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) to guide corresponding treatment.	Device: Treatment 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.
No Intervention: Control; No required therapeutic protocol will be used for patient treatment, and is determined per the discretion of the physician and hospital standards.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Day 1 to Day 30
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.	Day 1 to Day 30
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.	Day 1 to Day 30
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).	Day 1 to Day 30
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.	Day 1 to Day 30
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	Baseline, 72 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	72 hours
Percentage of Participants With Major Adverse Cardiac Event (MACE)	Incidence of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.	Day 1 to Day 30
Number of Participants Experiencing an Adverse Event (AE) Related to Study Device	Adverse events associated with the treatment procedure.	Day 1 to Day 30
Percentage of Participants With Hospital Discharge Without ICU Readmission		Day 1 to Day 30
Percentage of Participants Within Overall 30 Day Mortality Rate	Incidence of death.	Day 1 to Day 30
Number of Participants by Hospital Discharge Location	Patient location (either "home" or "other") following hospital discharge.	Day 1 to Day 30

Collaborators and Investigators

• Sponsor: Cheetah Medical Inc.

Publications and helpful links

General Publications

• Douglas IS, Alapat PM, Corl KA, Exline MC, Forni LG, Holder AL, Kaufman DA, Khan A, Levy MM, Martin GS, Sahatjian JA, Seeley E, Self WH, Weingarten JA, Williams M, Hansell DM. Fluid Response Evaluation in Sepsis Hypotension and Shock: A Randomized Clinical Trial. Chest. 2020 Oct;158(4):1431-1445. doi: 10.1016/j.chest.2020.04.025. Epub 2020 Apr 27.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2016
• Primary Completion (Actual): March 1, 2019
• Study Completion (Actual): March 13, 2019

Study Registration Dates

• First Submitted: July 14, 2016
• First Submitted That Met QC Criteria: July 15, 2016
• First Posted (Estimate): July 20, 2016

Study Record Updates

• Last Update Posted (Actual): December 3, 2020
• Last Update Submitted That Met QC Criteria: November 10, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Hypotension
• Other Study ID Numbers: PRO-OOO1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Summary data will be reviewed periodically

Drug and device information, study documents

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