Pulse Photoplethysmography as an Early Tool for the Diagnosis of Sepsis (PROUD-1)

Early management of sepsis is associated with better outcome. However, this requires early recognition of the sepsis host. One recently developed customized pulse photoplethysmography (PPG) device manages to measure nitric oxide (NO) that is released from vascular endothelium and seems promising for earlier sepsis diagnosis than conventional approaches. Aim of the project To evaluate the diagnostic performance of the PPG device for the early diagnosis of sepsis is to evaluate the diagnostic performance of the PPG device for the early diagnosis of sepsis

Study Overview

• Status: Completed
• Conditions: Sepsis
• Intervention / Treatment: Device: pulse photoplethysmography (PPG); Diagnostic test: Measurements of nitric oxide (NO) and malondialdehyde (MDA)

Detailed Description

Sepsis is a life-threatening syndrome and the most common cause of death nowadays. This syndrome develops as a result of the dysregulated host response to an infectious insult. As such the mainstay of treatment is the early administration of antimicrobials leading to early eradication of the offending pathogen. However, in this statement the key-feature is the definition of what "early" means. Using the retrospective analysis of data associating final outcome from septic shock with the delay in start of antimicrobials from the start of vasopressors in 2713 patients with septic shock, it was found that 79.1% of patients in which this delay was less than one hour survived. Every further hour of delay in start of antibiotics led to 7.6% increase of the risk for unfavorable outcome. These findings were later confirmed from two other analyses. These findings generate two thoughts: a) the above results are based on early recognition of hospital-acquired sepsis that was achievable only because these studies were done in an Intensive Care Unit (ICU) environment in patients under close monitoring. However, early sepsis recognition for a newly admitted patient remains an unmet need; b) all the above results are coming from patients with septic shock where diagnosis had already been established since patients were already on vasopressors.

It is reasonable to hypothesize that if sepsis had been recognized even earlier final outcome would have been even better. Sanmina have developed a non-invasive technique for the measurement of endothelial released nitric oxide (NO) through customized pulse photoplethysmography (PPG). Since NO is released by the vascular endothelium early in the pathogenesis of sepsis it is reasonable to hypothesize that PPG is a technique that can early inform on the risk for a patient with suspicion of an infection to develop sepsis. The time of measurement is less than two minutes. Preliminary data show that the reading of a healthy subject of eight consecutive minutes cannot trace any increase of NO; in sepsis a peak of more than 200 units is shown within the first 40 seconds of measurement.

The development of PPG as a tool for the early diagnosis of sepsis requires a two-stage approach. The first stage is based on the association of PPG readings with the change of the SOFA (sequential organ failure assessment) score and vital signs to define if among patients who eventually develop sepsis, PPG changes will be produced earlier than changes of SOFA scores and of vital signs.

• Study Type: Observational
• Enrollment (Actual): 200

Contacts and Locations

Study Locations

• Greece
  • Athens, Greece, 12462
    • 4th Department of Internal Medicine, "Attikon" University Hospital, National and Kapodistrian University of Athens, Medical School
  • Athens, Greece, 11526
    • Intensive Care Unit, "Korgialenio - Benakio" General Hospital of Athens
  • Athens, Greece, 11528
    • Department of Clinical Therapeutics, "Alexandra" General Hospital of Athens, National and Kapodistrian University of Athens, Medical School
  • Athens, Greece, 12462
    • 2nd Department of Critical Care, "Attikon" University Hospital, National and Kapodistrian University of Athens, Medical School

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Probability Sample

Study Population

Screening will be done for the inclusion and exclusion criteria in all patients admitted or hospitalized in the participating sites. Participants will be patients meeting all inclusion criteria and none of the exclusion criteria

Description

Inclusion Criteria:

• Age equal to or greater than 18 years
• Both genders
• Written informed consent provided by the patients or by first-degree relatives in case of patients unable to consent.
• Any of two:

Any infection in a patient with total SOFA score equal to 0 or 1 Patient without sepsis prone to the development of sepsis defined as patients with Charlson's Comorbidity Index (CCI) more than 2 irrespective the reason of admission. These patients are considered prone to infection based on previous findings of our group showing that CCI more than 2 is an independent predisposing factor for sepsis

Exclusion Criteria:

• Age below 18 years
• Denial to consent
• Any stage 4 malignancy
• Any do not resuscitate decision
• Active tuberculosis (TB) as defined by the co-administration of drugs for the treatment of TB
• Pregnancy or lactation

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Patients without sepsis; Patients admitted and hospitalized for infections without sepsis and for other reasons in departments of Internal Medicine and Intensive Care Units

Device: pulse photoplethysmography (PPG); PPG and systolic blood pressure recording will be performed every two hours for three consecutive days. PPG reading will last two minutes and peaks of NO productions will be captured. Day 1 is considered the day of signing the informed consent followed by the first recording. On the first PPG recording of the same days i.e. on days 1, 2 and 3 the investigators will collect blood from the patients; Diagnostic test: Measurements of nitric oxide (NO) and malondialdehyde (MDA); On the first PPG recording of the same days i.e. on days 1, 2 and 3 the investigators will collect blood from the patients. NO will be measured in serum samples by the Griess reaction. MDA that is considered an index of oxidant status will be measured in serum samples by the thiobarbiturate assay and analysis by high-performance liquid chromatography (HPLC)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sensitivity of PPG for the diagnosis of sepsis.	Sensitivity of PPG for the diagnosis of sepsis.	72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of PPG (absolute number) with qSOFA score (absolute number)	Correlation of PPG (absolute number) with qSOFA score (absolute number)	72 hours
Correlation of PPG (absolute number) with SOFA score (absolute number)	Correlation of PPG (absolute number) with SOFA score (absolute number)	72 hours
Correlation of time (in minutes) of sepsis diagnosis between PPG (absolute number) and SOFA score (absolute number)	Correlation of time (in minutes) of sepsis diagnosis between PPG (absolute number) and SOFA score (absolute number)	72 hours
Correlation of time (in minutes) of sepsis diagnosis between PPG (absolute number) and hypotension (mmHg)	Correlation of time (in minutes) of sepsis diagnosis between PPG (absolute number) and hypotension (mmHg)	72 hours
The specificity, positive predictive value (PPV) and negative predictive value (NPV) of PPG for the diagnosis of sepsis	The specificity, positive predictive value (PPV) and negative predictive value (NPV) of PPG for the diagnosis of sepsis	72 hours
The sensitivity, specificity, PPV and NPV of PPG for the prognosis of 28-day outcome	The sensitivity, specificity, PPV and NPV of PPG for the prognosis of 28-day outcome	28 days
Correlation of PPG (absolute number) with circulating levels of NO (μmol/l) and MDA (μmol/l)	The association between PPG and circulating levels of NO and MDA	72 hours

Collaborators and Investigators

• Sponsor: Hellenic Institute for the Study of Sepsis
• Investigators: Principal Investigator: Antonios Papadopoulos, MD, PhD, 4th Department of Internal Medicine

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2019
• Primary Completion (Actual): May 30, 2020
• Study Completion (Actual): June 30, 2020

Study Registration Dates

• First Submitted: October 29, 2019
• First Submitted That Met QC Criteria: October 30, 2019
• First Posted (Actual): November 4, 2019

Study Record Updates

• Last Update Posted (Actual): July 29, 2020
• Last Update Submitted That Met QC Criteria: July 28, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: infection; early diagnosis; pulse photoplethysmography
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Antioxidants; Free Radical Scavengers; Endothelium-Dependent Relaxing Factors; Gasotransmitters; Nitric Oxide
• Other Study ID Numbers: PROUD-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

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