Evolution of Molecular Biomarkers in Acute Heart Failure Induced by Shock (Shockomics)

Multiscale Approach to Describe the Evolution of Molecular Biomarkers in Acute Heart Failure Induced by Shock

The relationship between shock, ischemia and reperfusion (I/R) injury, hemodynamic instability, systemic inflammatory response syndrome and multiorgan failure has been extensively investigated, but there is no consensus on the trigger mechanisms of tissue injury at the molecular level.

Current therapies are targeted to reduce symptoms of shock and multiorgan damage but they are unable to act at the "beginning of the cascade", because of the lack of a model explaining the molecular basis of shock induced tissue injury and ensuing organ damage.

The present observational study is aimed at identifying the molecular triggers of acute heart failure (HF) induced by shock and to identify inflammatory mediators and markers that are activated in shock, with a particular emphasis on the role of uncontrolled proteolytic activity.

Study Overview

• Status: Completed
• Conditions: Shock; Acute Heart Failure

• Study Type: Observational
• Enrollment (Actual): 70

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium
    • Department of Intensive Care, Erasme University Hospital
• Spain
  • Barcelona, Spain
    • Servei de Medicina Intensiva, Hospital Universitari Mútua Terrassa
• Switzerland
  • Geneva, Switzerland
    • Intensive Care Division, Geneva University Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

All the patients admitted to ICU

Description

Inclusion Criteria:

• For patients in septic shock, Severity: SOFA score > 5
• For patients in cardiogenic shock, Severity: SOFA score > 5
• First blood sample available within 16 hours from admission to the ICU.
• Only community medical acquired septic shock. We include patients with shock symptoms and shock diagnosis occurring within the first 48 hours from hospital admission
• Informed Consent available

Exclusion Criteria:

• Risk of rapidly fatal illness and death within 24 hours
• Patients already enrolled in other interventional studies
• N > 4 units of red blood cells transfused
• Patients treated with plasma or whole blood
• Active hematological malignancy
• Metastatic cancer
• Immunodepression, including transplant patients: HIV+, constitutive immune system deficiency, immunosuppressive therapy, systemic corticosteroids (aerosols allowed)
• Patients with pre-existing end stage renal disease needing renal replacement therapy (RRT). The introduction of continuous veno-venous hemofiltration (CVVH), from the day of admission onward is allowed.
• Cardiac surgery patients
• Cirrhosis Child C

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Hemorrhagic Shock; Hypovolemic shock characterized by: Hypotension: systolic blood pressure < 90 mm Hg or a drop of > 40 mm Hg from baseline or mean arterial pressure < 70 mm Hg persisting despite adequate fluid resuscitation.; Rapid loss of significant amount of blood; Lactate levels ≥ 2 mmol/L
Cardiogenic shock; State of inadequate circulation of blood because of ventricular failure due to acute cardiac conditions, concomitant presence of: Hypotension: systolic blood pressure < 90 mm Hg or a drop of > 40 mm Hg from baseline or mean arterial pressure < 70 mm Hg persisting despite adequate fluid resuscitation.; Need for a continuous infusion of inotropic drugs; Cardiac Index <2.2 L/min/m2 or use of inotropic drugs (dobutamine/isoprenaline/phosphodiesterase inhibitors or levosimendan); Signs of reduced heart function; Cardiac overload or altered left/right ventricular function
Septic shock; Septic shock is defined as sepsis-induced hypotension, defined as systolic blood pressure < 90 mm Hg or a drop of > 40 mm Hg from baseline or mean arterial pressure < 70 mm Hg persisting despite adequate fluid resuscitation. Only community medical acquired sepsis with a sepsis onset within 48 hours from hospital admission (i.e. different from nosocomial infection). Lactate levels ≥ 2mmol/L.
control group; The control group will consist on: 5 healthy blood donors: serving only for the purposes of obtaining reference values for proteomics analysis; a cohort of 20 patients hospitalized for sepsis OR cardiac syndromes not developing shock: will be recruited from patients admitted to the hospital during the study period. The clinical status of the patients will be assessed during hospitalization to ascertain shock and AHF development. Shock development will be an exclusion criteria.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression/occurrence of acute heart failure and changes in omics markers in acute phase of shock	The clinical endpoint will be Acute Heart Failure (AHF), assessed by a pool of measures/estimates of cardiac function and filling pressures, based on cardiac output monitoring, inotropic drugs requirements, left and right ventricles assessment using echocardiography. The molecular biomarkers changes will be evaluated by means of proteomics, transcriptomics and metabolomics analysis of blood samples collected at the ICU admission and within 48hr after admission.	within 48 hr after admission in ICU (acute phase of shock)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression/Occurence of Acute Heart Failure and changes in omics markers in survivors	The clinical endpoints will be: The Acute Heart Failure (AHF) assessed by a pool of measures/estimates of cardiac function and filling pressures, based on cardiac output monitoring, inotropic drugs requirements, left and right ventricles assessment using echocardiography. AHF will be at evaluated within 7 days after ICU admission.; Mechanical ventilation (MV)-free days or organ support (vasopressor, continuous renal replacement therapy (CRRT), etc.) free-days; Survival to ICU; Prognosis at discharge from the ICU (objective - dead or alive, morbidities - and subjective); Prognosis at discharge from the hospital (objective - dead or alive, morbidities - and subjective). The changes in molecular biomarkers will be evaluated by means of proteomics, transcriptomics and metabolomics analysis of blood samples collected within 7 days after ICU admission	within 7 days after admission in ICU (patient stabilization)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Long term effects of AHF in survivors assessed by changes in omics markers	Patients discharged after a shock episode have high morbidity and mortality rates, and evidences indicate that physiological condition is restored only after several months. The blood sample will be collected only in patients in healthy conditions, reporting no re-hospitalization associated to shock sequelae during the follow up.	at about 100 days from ICU admission and enrollment

Collaborators and Investigators

• Sponsor: Shockomics Consortium
• Collaborators: Seventh Framework Programme
• Investigators: Principal Investigator: Giuseppe Baselli, MS, Politecnico di Milano

Publications and helpful links

General Publications

• Carrara M, Bollen Pinto B, Baselli G, Bendjelid K, Ferrario M. Baroreflex Sensitivity and Blood Pressure Variability can Help in Understanding the Different Response to Therapy During Acute Phase of Septic Shock. Shock. 2018 Jul;50(1):78-86. doi: 10.1097/SHK.0000000000001046.
• Cambiaghi A, Pinto BB, Brunelli L, Falcetta F, Aletti F, Bendjelid K, Pastorelli R, Ferrario M. Characterization of a metabolomic profile associated with responsiveness to therapy in the acute phase of septic shock. Sci Rep. 2017 Aug 29;7(1):9748. doi: 10.1038/s41598-017-09619-x.
• Braga D, Barcella M, Herpain A, Aletti F, Kistler EB, Bollen Pinto B, Bendjelid K, Barlassina C. A longitudinal study highlights shared aspects of the transcriptomic response to cardiogenic and septic shock. Crit Care. 2019 Dec 19;23(1):414. doi: 10.1186/s13054-019-2670-8.
• Bauza-Martinez J, Aletti F, Pinto BB, Ribas V, Odena MA, Diaz R, Romay E, Ferrer R, Kistler EB, Tedeschi G, Schmid-Schonbein GW, Herpain A, Bendjelid K, de Oliveira E. Proteolysis in septic shock patients: plasma peptidomic patterns are associated with mortality. Br J Anaesth. 2018 Nov;121(5):1065-1074. doi: 10.1016/j.bja.2018.05.072. Epub 2018 Jul 26.
• Aletti F, Conti C, Ferrario M, Ribas V, Bollen Pinto B, Herpain A, Post E, Romay Medina E, Barlassina C, de Oliveira E, Pastorelli R, Tedeschi G, Ristagno G, Taccone FS, Schmid-Schonbein GW, Ferrer R, De Backer D, Bendjelid K, Baselli G. ShockOmics: multiscale approach to the identification of molecular biomarkers in acute heart failure induced by shock. Scand J Trauma Resusc Emerg Med. 2016 Jan 28;24:9. doi: 10.1186/s13049-016-0197-4.
• Carrara M, Baselli G, Ferrario M. Mortality prediction in septic shock patients: Towards new personalized models in critical care. Annu Int Conf IEEE Eng Med Biol Soc. 2015 Aug;2015:2792-5. doi: 10.1109/EMBC.2015.7318971.

Helpful Links

• EU project website

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): September 1, 2017

Study Registration Dates

• First Submitted: May 8, 2014
• First Submitted That Met QC Criteria: May 14, 2014
• First Posted (Estimate): May 19, 2014

Study Record Updates

• Last Update Posted (Actual): June 15, 2018
• Last Update Submitted That Met QC Criteria: June 13, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: biomarkers; heart failure; shock; inflammation; cardiovascular instability; metabolic pathways; proteolysis
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Heart Failure; Shock
• Other Study ID Numbers: FP7#602706; 602706 (Other Grant/Funding Number: FP7-HEALTH-2013-INNOVATION-1)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO