Micro and Macro Circulation in Sepsis (DAISY)

Clinical Utility of Longitudinal Measurement of Hemodynamic Incoherence and Endothelial

Purpose: To assess the prognostic role of Handheld Vital Microscopy (HVM) and evaluate levels of endothelial glycocalyx (eGC) breakdown in patients demonstrating Hemodynamic Incoherence (HI), to elucidate a mechanistic link between the eGC and HI in order to inform prognostic enrichment of future resuscitation trials. We will serially evaluate microhemodynamics (MiH) and macro hemodynamics (maH) and the perfused boundary region (PBR, an visual proxy for eGC thickness) using HVM, and a validated circulating biomarker of eGC integrity.

Study Overview

• Status: Completed
• Conditions: Sepsis; Septic Shock
• Intervention / Treatment: Diagnostic test: Starling Stroke Volume (Starling SV)- Passive Leg Raise; Diagnostic test: Microscan Sublingual Microscopy; Diagnostic test: Venous Excess Ultrasound Scoring (VExUS); Other: Urine Collection

Detailed Description

There are few reliable prognostic indicators in early sepsis to predict disease progression, in part because the pathophysiologic mechanism of vascular dysregulation remains incompletely understood. The global Coronavirus Disease 2019 (COVID-19) pandemic has increased the number of patients with sepsis, straining hospital systems and illustrating the need for research into prognostic and therapeutic strategies. An important area of research is the role of the eGC, a thin vascular lining composed of proteoglycans, glycosaminoglycan side-chains, and plasma proteins that play a central role in microvascular homeostasis, the function of which is compromised in sepsis. Another growing field of inquiry is the phenomenon of HI, a condition in which MiH remain dysfunctional despite normalization of conventionally targeted MaH measures such as mean arterial pressure (MAP), leading to poor end-organ perfusion. It has been hypothesized that HI due to persistently deranged MiH and reduced end-organ perfusion result in an ongoing state of "microvascular shock", leading to worsening end-organ damage despite apparent normalization of conventionally targeted parameters. Importantly, HI has been shown to predict poor patient outcomes, with abnormal MiH predicting patient mortality despite normalization of MAP after administration of vasoactive medications. MiH measures have also been shown to differ significantly between septic patients and healthy controls. In one study of a large sepsis cohort, MiH parameters were predictive of adverse outcomes, while MaH parameters were not, suggesting that MiH measurements, and HI in particular may be more sensitive than conventional measures for predicting outcomes in sepsis. One hypothesis is that HI in sepsis is mediated by degradation of the eGC, with subsequent loss of microvascular homeostasis, though the role of the eGC as a vascular barrier remains controversial.

One question that remains is whether or not microvascular changes can predict patient outcomes in patients judged to be adequately fluid resuscitated, as measured by MAP or Starling Stroke Volume/Non-invasive cardiac monitor (NICOM) testing.

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80204
      • Denver Health Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Septic Patient Cohort:

1. Greater than or equal to 18 years of age
2. Diagnosed with sepsis or septic shock
3. Require admission to the Hospital

Control Cohort:

1. Greater than or equal to 18 years of age
2. Undergoing elective surgery requiring intubation and general anesthesia

Exclusion Criteria:

Patients with any of the following characteristics will be excluded

1. Less than 18 years old
2. Chronic Kidney disease on dialysis
3. Currently pregnant
4. Incarcerated persons

Control Cohort:

1. Less than 18 years old
2. History of Chronic Kidney disease on dialysis, uncontrolled diabetes, cirrhosis, heart failure, or nephritic or nephrotic syndromes.
3. Currently pregnant
4. Incarcerated persons

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Septic Patient Interventions; Septic Patients will have all interventions performed: Urine collection, Passive Leg Raise, Ultrasound and sublingual microscopy	Diagnostic test: Starling Stroke Volume (Starling SV)- Passive Leg Raise; All septic patients will have a passive leg raise performed with the assistance of an Starling SV device to look at Stroke Volume change. This will be performed at admission and 4 hours after admission. This intervention will not be performed on healthy controls; Other Names: Baxter Starling Stroke Volume (SV); Diagnostic test: Microscan Sublingual Microscopy; All septic patients will have sublingual microscopic images performed at admission, 8-16 hours, 48 hours and 72 hours. Control patients will have a sublingual microscope imaging performed after intubation for the elective procedure. This is a process of a 2cm probe tip gently placed on patients' mouth and 3 different images of 5-8 seconds are recorded.; Other Names: Microvision Sublingual Microscopy; Diagnostic test: Venous Excess Ultrasound Scoring (VExUS); All septic Patients will have this performed on all patients at admission, 8-16 hours, 48 hours and 72 hours. Ultrasound images and blood flow waves will be collected of the Inferior Vena Cava diameter, hepatic vein, portal vein, renal veins and scored using the Venous Excess Ultrasound (VExUS scale). Healthy controls will not have ultrasound performed; Other: Urine Collection; The urine assay is collected passively from the patient will be ran through a Dimethylmethylene blue (DMMB assay)- could provide future beneficial information to resuscitation efforts. This will be performed on all septic patients at admission, 8-16 hours, 48 hours and 72 hours. Urine will be collected on healthy controls at time of intubation for elective procedure.
Other: Control Patient Interventions; Control patients will have urine collection and sublingual microscopy performed when intubated	Diagnostic test: Starling Stroke Volume (Starling SV)- Passive Leg Raise; All septic patients will have a passive leg raise performed with the assistance of an Starling SV device to look at Stroke Volume change. This will be performed at admission and 4 hours after admission. This intervention will not be performed on healthy controls; Other Names: Baxter Starling Stroke Volume (SV); Other: Urine Collection; The urine assay is collected passively from the patient will be ran through a Dimethylmethylene blue (DMMB assay)- could provide future beneficial information to resuscitation efforts. This will be performed on all septic patients at admission, 8-16 hours, 48 hours and 72 hours. Urine will be collected on healthy controls at time of intubation for elective procedure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Initiation and Duration Renal Replacement Therapy	Renal Replacement Therapy will be monitored while hospitalized for Sepsis/Septic Shock for initiation and days receiving Renal replacement will be counted.	90 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Inpatient Mortality	Patient Death while hospitalized for the admission of Sepsis/Septic Shock	90 day
Rate of 90 day survival	Patient death within 90 days of admission to the hospital for Sepsis/Septic Shock	90 day

Collaborators and Investigators

• Sponsor: Denver Health and Hospital Authority
• Collaborators: National Institutes of Health (NIH)

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2022
• Primary Completion (Actual): May 31, 2025
• Study Completion (Actual): May 31, 2025

Study Registration Dates

• First Submitted: January 5, 2023
• First Submitted That Met QC Criteria: January 13, 2023
• First Posted (Actual): January 23, 2023

Study Record Updates

• Last Update Posted (Actual): December 5, 2025
• Last Update Submitted That Met QC Criteria: December 1, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Pathological Conditions, Signs and Symptoms; Sepsis; Shock, Septic; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Urine Specimen Collection
• Other Study ID Numbers: 22-0349

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: currently individual participant data will not be made available to other researchers

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes