ILOPROST in Septic Shock With Persistent Microperfusion Defects (I-MICRO) (I-MICRO)

" ILOPROST for Treatment of Septic Shock With Persistent Microperfusion Defects ", a Double-blind, Randomized Controlled Trial:The I-MICRO Trial

Septic shock remains a major cause of death in critically ill patients. Alterations in microcirculation have long been proposed as a key pathophysiological factor of organ dysfunction and death in septic shock patients. Persistence of mottling, prolonged skin recoloration time and cyanosis of the extremities are the easily and frequently observed manifestations of these microcirculatory disorders. Ilomedin is a prostaglandin analog with a potent vasodilatory effect together with anti-thrombotic properties (inhibition of platelet aggregation) preferentially at the microcirculatory level. An increase in cardiac output with increased arterial oxygen delivery has been observed in clinical and preclinical studies with no episodes of hypotension. Improvement in mesenteric perfusion has moreover been observed in experimental sepsis using Ilomedin. Our group has furthermore reported that administration of Ilomedin in patients with refractory septic shock (peripheral hypoperfusion) resulted in a rapid and sustained improvement in peripheral perfusion. Altogether, Ilomedin may prevent or improve recovery of organ dysfunction in septic shock patients through recruitment of the microcirculation and, thereby, ultimately improve outcome.

Study Overview

• Status: Completed
• Conditions: Septic Shock Hyperdynamic
• Intervention / Treatment: Drug: NaCl; Drug: ILOPROST

Detailed Description

In the 32 participating centers: patients with septic shock and persistent peripheral hypoperfusion despite hemodynamic optimization (skin mottling and/or finger skin recoloration time > 3sec, and/or knee skin recoloration time > 4sec), after 6 to 24 hours of norepinephrine onset will be eligible for randomization.

Patients fulfilling the eligibility criteria will be included and randomized by the intensivist in two groups:

*Experimental group: The patient will receive treatment with intravenous Iloprost (blinded) therapy at a dose of 0.5 ng/kg/min with increments of 0.5 ng/kg/min every 30 minutes up to a maximum posology of 1.5ng/kg/min for 48h.

Placebo group: The patient will receive treatment with intravenous NaCl 0.9% (placebo-double blinded) therapy at a dose of 0.5ng/kg/min with increments of 0.5 ng/kg/min every 30 minutes according to body weight with a maximum posology of 1,5 ng/kg/min for 48h.

Primary outcome will be Delta Sequential Organ Failure Assessment (SOFA) score between infusion onset and day 7.

*within the 12 first hours after randomization : blood samples : 15 ml of blood will be collected at the same time as the sample routinely collected, within the 12 first hours after randomization in ICU, when the patients are perfused.

The blood will be drawn and worked as follows:

• 2 x EDTA tubes of 5 ml : After centrifugation each tube will be directly divided into 4 aliquots of 500 µL (8 aliquots per patient)
• 1 x aprotinine tube of 5 ml : After centrifugation, it will be directly divided into 4 aliquots of 500 µL

The aliquots previously will be stored locally, and will be transported to the "Centre de Ressources Biologiques" (CRB) of the Lariboisière Hospital.

• Study Type: Interventional
• Enrollment (Actual): 240
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 75010
    • Departement of Anesthesiology, Critical Care and Burn Unit; Saint-Louis hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients over 18 years of age
• Signed informed consent or inclusion under the emergency provisions of the law (Article L1122 -1-3 of the PHC / modified by Order n°2016-800 of June 16 2016 - art. 2).

• Patients with septic shock defined by the third international definition:

  • suspected or proven infection,
  • and organ dysfunction defined by an acute change in total SOFA score >or=2
  • and persistent hypotension requiring vasopressor treatment to maintain mean arterial pressure > 65 mmHg despite standard of care hemodynamic optimization
  • and serum lactate level > 2 mmol/L despite standard of care hemodynamic optimization
  • and persistence of peripheral hypoperfusion (skin mottling and/or finger skin recoloration time > 3sec, and/or knee skin recoloration time > 4sec) despite standard of care hemodynamic optimization
  • Within 6 to 24 hours after norepinephrine onset

Exclusion Criteria:

• Refusal to participate in the study
• Pregnancy, breastfeeding
• Hypersensitivity to Ilomedin or to any of the excipients.
• Conditions where the hemorrhagic risk may be increased due to the effects of Ilomedin on platelets (i.e., evolving hemorrhage, trauma, intracranial hemorrhage, active gastric ulcer).
• Platelet count < 10000 /mm3
• unstable angina.
• severe cardiac rhythm disorders since Norepinephrine onset
• severe hypoxemia (PaO2/FiO2 <100)
• myocardial infarction in the last 6 months
• lack of Social Insurance
• persons deprived of liberty
• persons of a protective measure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Intravenous Placebo; Treatment with intravenous NaCl 0.9% therapy with incremental infusion rate every 30 minutes for 48h	Drug: NaCl; The patient will receive treatment with intravenous NaCl 0.9% (placebo-double blinded) with increments of infusion rate every 30 minutes for 48h; Other Names: (Saline 0.9%)
Experimental: intravenous ILOPROST; a first dose of ILOPROST of 0.5ng/kg/ min with increments every 30 minutes up to a maximum of 1,5 ng/kg/min for 48h	Drug: ILOPROST; The patient will receive treatment with intravenous ILOPROST therapy at a dose of 0.5ng/kg/min with increments of 0.5 ng/kg/min every 30 minutes up to a maximum posology of 1,5 ng/kg/min for 48h.; Other Names: 50 microgrammes /0,5 ml vials

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Delta (Sequential Organ Failure Assessment (SOFA)) score between infusion onset and day 7. SOFA score assesses organ failure (respiratory, hemodynamics, liver, coagulation, neurological and kidney) in ICU patients.	SOFA and Delta SOFA calculation will be performed by the Intensivist. Patients deceased before day 7 will be attributed a maximum SOFA score. SOFA score range from 0 (no organ failure) to a maximum of 24 (worst SOFA score).	7 days after randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean SOFA score during the first 7 days after randomization	SOFA and Delta SOFA calculation will be performed by the Intensivist.	7 days after randomization
Number of survival days outside ICU in the 28 days post randomization	It will be calculated by the number of days between ICU discharge and day 28 in survivors of ICU stay.	Between ICU discharge and day 28
Number of ventilation-free survival days in the 28 days post randomization	It will be calculated as the number of survival days without mechanical ventilation	Between randomization and day 28.
Number of renal replacement therapy-free survival days in the 28 days post randomization -	It will be calculated as the number of survival days without renal replacement therapy	Between randomization and day 28.
Number of vasopressor-free survival days in the 28 days post randomization	It will be calculated as the number of survival days without vasopressor therapy	Between randomization and day 28.
Molting score at day 1 after randomization.	In order to identifying and quantifying microcirculatory dysfunction in septic shock. A picture of patient's knees will be taken. Molting score range from 0 to a maximum of 5 : 0. - No mottling; - Coin sized mottling area on the knee.; - To the superior area of the knee cap.; - Mottling up to the middle thigh; - Mottling up to the fold of the groin; - Severe mottling that extends beyond the the groin.	At day 1 after randomization
Conservation of plasma for future biological measurements	15 ml of blood will be collected at the same time as the sample routinely collected, within the 12 first hours after randomization, when the patients are perfused.	within 10 years after the end of the study.
Microcirculation	Monitoring of microcirculation using non-invasive monitoring devices including: photoplethysmography,cutaneous Doppler coupled with iontophoresis, near-infrared spectroscopy, videomicroscopy, tissular PCO2, urethral photoplethysmography, perfusion index using phtoplethysmography	At the baseline, and between day 2 and day 7
mortality		At day 28

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: François DEPRET, MD, APHP-Hôpital saint Louis; Study Director: Matthieu LEGRAND, MD,PhD, APHP-Hôpital saint Louis

Publications and helpful links

General Publications

• Ait-Oufella H, Lemoinne S, Boelle PY, Galbois A, Baudel JL, Lemant J, Joffre J, Margetis D, Guidet B, Maury E, Offenstadt G. Mottling score predicts survival in septic shock. Intensive Care Med. 2011 May;37(5):801-7. doi: 10.1007/s00134-011-2163-y. Epub 2011 Mar 4.
• Lara B, Enberg L, Ortega M, Leon P, Kripper C, Aguilera P, Kattan E, Castro R, Bakker J, Hernandez G. Capillary refill time during fluid resuscitation in patients with sepsis-related hyperlactatemia at the emergency department is related to mortality. PLoS One. 2017 Nov 27;12(11):e0188548. doi: 10.1371/journal.pone.0188548. eCollection 2017.
• De Backer D, Donadello K. Assessment of microperfusion in sepsis. Minerva Anestesiol. 2015 May;81(5):533-40. Epub 2014 Jun 19.
• Muller B, Schmidtke M. Microvascular effects of iloprost in the hamster cheek pouch. Adv Prostaglandin Thromboxane Leukot Res. 1987;17A:455-8.
• Johannes T, Ince C, Klingel K, Unertl KE, Mik EG. Iloprost preserves renal oxygenation and restores kidney function in endotoxemia-related acute renal failure in the rat. Crit Care Med. 2009 Apr;37(4):1423-32. doi: 10.1097/CCM.0b013e31819b5f4e.
• Hoeper MM, Gall H, Seyfarth HJ, Halank M, Ghofrani HA, Winkler J, Golpon H, Olsson KM, Nickel N, Opitz C, Ewert R. Long-term outcome with intravenous iloprost in pulmonary arterial hypertension. Eur Respir J. 2009 Jul;34(1):132-7. doi: 10.1183/09031936.00130408. Epub 2009 Feb 27.
• Depret F, Sitbon A, Soussi S, De Tymowski C, Blet A, Fratani A, Legrand M. Intravenous iloprost to recruit the microcirculation in septic shock patients? Intensive Care Med. 2018 Jan;44(1):121-122. doi: 10.1007/s00134-017-4935-5. Epub 2017 Sep 18. No abstract available.
• Legrand M, Oufella HA, De Backer D, Duranteau J, Leone M, Levy B, Rossignol P, Vicaut E, Depret F; I-MICRO trial investigators. The I-MICRO trial, Ilomedin for treatment of septic shock with persistent microperfusion defects: a double-blind, randomized controlled trial-study protocol for a randomized controlled trial. Trials. 2020 Jul 1;21(1):601. doi: 10.1186/s13063-020-04549-y.

Study record dates

Study Major Dates

• Study Start (Actual): July 3, 2019
• Primary Completion (Actual): January 5, 2024
• Study Completion (Actual): January 18, 2024

Study Registration Dates

• First Submitted: November 20, 2018
• First Submitted That Met QC Criteria: December 26, 2018
• First Posted (Actual): December 28, 2018

Study Record Updates

• Last Update Posted (Actual): July 3, 2024
• Last Update Submitted That Met QC Criteria: July 2, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Septic shock; SOFA score; Microcirculatory defects; hemodynamic macroparameters; mottling
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Vasodilator Agents; Platelet Aggregation Inhibitors; Iloprost
• Other Study ID Numbers: P170924J

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

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