Clinical trial NCT03814564: ASSESSment of Perfusion, Oxygen Saturation, Endothelial Function and Coagulation in Circulatory SHOCK
Official title: ASSESSment of Peripheral Perfusion, Tissue Oxygen Saturation, Endothelial Function and Coagulation Disorder in Circulatory SHOCK, the ASSESS - SHOCK Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Circulatory Failure
Lead sponsor: Helsinki University Central Hospital
Sponsor class: OTHER
Collaborators: name: Tampere University Hospital
name: Kuopio University Hospital
name: Medtronic
First posted: 2019-01-24
Enrollment: 325
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population will comprise 400 critically ill patients with circulatory shock from 4 university hospitals during approximately 2 years between April 2019 and December 2021. Of the 400 patients, a subpopulation of the first 250 adult critically ill patients (≥18 years) requiring ICU care, including both surgical and medical ICU patients with circulatory shock will be included in the NIRS-substudy. All 400 patients will be analyzed for endotheliopathy incidence, metabolomics, genetic data (without NIRS monitoring). Representation of the study population will be ensured by enrolment of all consecutive patients at the study sites who meet the study enrollment criteria.

Brief summary: The objective of the observational cohort study is (1) to deduce whether measurements of peripheral near-infrared spectroscopy (NIRS) (lower limb) associate with the development of organ dysfunction as assessed by daily Sequential Orfgan Failure Score (SOFA) in the Intensive Care Unit (ICU), (2)whether cerebral (frontal) tissue haemoglobin oxygen saturation (StO2) values are associated with delirium in the ICU and (3) the association of frontal and peripheral StO2 with other micro- and macrohemodynamic parameters in this patient group , (4) to deduce the associations between shock, endotheliopathy, disseminated intravascular coagulation (DIC) and tissue perfusion and, last, the feasibility of central and peripheral NIRS monitoring in shock patients in the ICU using the Medtronic INVOS NIRS StO2 appliances. In addition, the investigators target to evaluate (5) the incidence, evolution, and outcome of sepsis-associated DIC, and (6) the associations between a) continuous hemodynamic data, b) laboratory data (such as syndecan-1 (SDC-1), vascular adhesion protein 1 (VAP1), CD73, heparin binding protein (HBP), endostatin, chromogranin, mitochondrial function tests,blood count d-dimer, international normalized ratio (INR), neuron specific enolase and metabolomics data) (7) and study associations of singlenucleotide polymorphisms with developing organ dysfunction and 90-day mortality. To compare the hemodynamic alterations of burn patients to septic patients with the intention to find new ways to monitor and manage hemodynamic and particularly microcirculation in burn patients.

Detailed description: Background:

Circulatory shock is a frequent condition in the intensive care unit, comprising roughly one of three patients in the intensive care unit (ICU), and associated with high mortality rates. Current treatment guidelines state that one of the main goals for therapeutic interventions is to improve tissue perfusion to prevent subsequent organ dysfunction and death. In acute critical illness, up to one fourth of the patients develop severe hemostatic aberrations and coagulopathy, called disseminated intravascular coagulation (DIC), which is associated with excess mortality.

Despite differences in the underlying cause, acutely critically ill patients share similar features that may be driven by shock. This response, potentially escalating to life-threatening conditions, is relatively homogenous. The shock induced sympatho-adrenal hyperactivation may be a critical driver this endotheliopathy. If allowed to proceed uncontrollably, damages to the microcirculation and organ dysfunction may follow.

Near-infrared spectroscopy (NIRS), a non-invasive method based on the principles of light transmission and absorption, offers a non-invasive and continuous bedside method to assess tissue haemoglobin oxygen saturation (StO2), which may serve as an indirect measure of the adequacy of tissue perfusion. NIRS could potentially be used for early identification of patients with tissue hypoperfusion and therefore high risk of developing organ dysfunction, and may also be used for assessing frontal cerebral oxygen saturation in circulatory failure and its use is well documented in general anaesthesia in many patient groups. There are some data showing an association between low frontal StO2 values and delirium in the ICU. The use of near-infrared spectroscopy to measure tissue oxygenation in healthy humans has been well validated. However, assessing tissue oxygenation using NIRS in critically ill patients is less well established. The hemodynamic and other systemic responses in burns are similar to those in septic shock. However, the mechanisms behind these responses have not been compared between burn and septic shock patients to our knowledge. Overall, the knowledge of microcirculation and how to monitor it in burn patients is limited.

Objectives:

The objective of the observational cohort study is (1) to deduce whether measurements of peripheral NIRS (lower limb registered proximal of the knee cap) associate with the development of organ dysfunction as assessed by daily sequential organ failure assessment score (SOFA) in the ICU during days 1 to 7 in the ICU, (2) whether cerebral (frontal) StO2 values are associated with delirium in the ICU and (3) the association of frontal and peripheral StO2 with other micro- and macrohemodynamic parameters in this patient group , (4) to deduce the associations between shock, endotheliopathy, DIC and tissue perfusion and, last, the feasibility of central and peripheral NIRS monitoring in shock patients in the ICU using the INVOS tm NIRS StO2 appliances. In addition, the investigators target to evaluate (5) the incidence, evolution, and outcome of sepsis-associated disseminated intravascular coagulation (DIC), and (6) the associations between a) continuous hemodynamic data, b) laboratory data (such as syndecan-1 (SDC-1), vascular adhesion protein 1 (VAP1), CD73, heparin binding protein (HBP), endostatin, chromogranin, mitochondrial function tests, blood count d-dimer, INR, neuron specific enolase and metabolomics data) (7) and study associations of singlenucleotide polymorphisms with developing organ dysfunction and 90-day mortality. To compare the hemodynamic alterations of burn patients to septic patients with the intention to find new ways to monitor and manage hemodynamic and particularly microcirculation in burn patients.

Design:

Observational multi-center study

Patient population:

Patients with circulatory shock admitted to the intensive care units (ICU) fulfilling the inclusion criteria.

Sample size:

A minimum of 250patients with circulatory shock with NIRS registration A minimum of 400 patients with sepsis for evaluation of incidence of DIC and metabolomics and genetic tests (genome-wide association study, GWAS)

Methods:

Patients with circulatory shock admitted to the intensive care unit (ICU) fulfilling the inclusion criteria but none of the exclusion criteria within 4 hours of vasopressor inititation in the ICU and signs of clinical hypoperfusion or elevated lactate levels. Frontal and peripheral NIRS StO2 registration is performed using the Medtronic INVOS appliances and bilateral central and peripheral sensors for 48 hours from study inclusion. The INVOS NIRS registration is blinded and cannot be used for clinical decision making. The frontal and peripheral StO2 registrations will be collected for further analyses. Blood samples will be taken from an arterial cannula at inclusion, and at 12 h, 24h and 48h, blood gas samples will be drawn every 2 hours. Data on demographic data, health status, chronic illnesses and medications prior to ICU admission will be collected during the study. Hemodynamic data, information on vasopressor and inotrope medication, need and use of sedatives, fluid balance and specific ICU interventions during the ICU stay will also be collected, as well as daily intensive care delirium screening checklist (ICDSC) and SOFA-score registrations. An electronic case report form (CRF) will be used in the study. In addition to clinical data, data of feasibility and reported problems considering the use of NIRS StO2 registrations will be collected. Blood samples will be frozen and stored locally for further processing and analyses.

Eligibility criteria: Inclusion Criteria:

Age ≥ 18 Critically ill patients requiring Intensive Care Unit (ICU) care with circulatory shock within 4 hours (≤ hours) of ICU admission or with circulatory shock developing in the ICU within 24 hours from ICU admission and within 4 hours of initiation of vasopressor treatment presenting with the below listed signs of for circulatory shock

1. Hypotension - need for vasopressor to achieve mean arterial pressure (MAP) ≥65 mmHg after 1L of crystalloid solution

   and
2. Any sign of hypoperfusion (at least one of the signs below)

   * blood lactate ≥2 mmol/L
   * mottling score ≥ 2
   * Base Excess (BE) ≤ - 5 mEq/L
   * prolonged capillary refill time ≥ 2 s
   * cool periphery beyond elbows or knees bilaterally
   * altered mentation

   OR

   Confirmed or suspected infection and anti-microbial treatment

   OR as an independent criteria for the ASSESS-SHOCK BURNS substudy
3. Burn injury ≥30% total body surface area(TBSA), ICU admission within 12h of the injury, with or without hypotension and signs of hypoperfusion within 4 hours of ICU admission

Exclusion Criteria:

* Age \< 18 years
* Pregnant or lactating
* Known refusal to any clinical study or this specific study
* Consent not obtained (according to local regulatory statements for ethical conduct of research)
* Out-of-hospital cardiac arrest (OHCA) patients
* Terminal illness and not considered for full intensive care support
* Planned postoperative admission
* Postoperative intensive care after organ transplantation
* Patients who are likely to be transferred to the ward in 24 hours
* Defects of skin, underlying tissues or extremities preventing the use of the central or peripheral NIRS probes (the first 250 enrolled patients)

Primary outcomes:
measure: Change in severity of Organ dysfunction during the first week in ICU (study period)
timeFrame: At 7 days in ICU
measure: Average severity of Organ dysfunction during the first 7 days in the ICU (study period)
timeFrame: First week in the Intensive Care Unit after admission
measure: New organ dysfunctions
timeFrame: First week in the Intensive Care Unit after admission
measure: 90-day mortality
timeFrame: 90 days
Secondary outcomes:
measure: Intensive care delirium incidence
timeFrame: First week in the Intensive Care Unit after admission
measure: Intensive care delirium severity
timeFrame: First week in the Intensive Care Unit after admission
measure: Intensive care delirium scoring checklist aggregate and average score during first week in intensive care
timeFrame: First week in the Intensive Care Unit after admission
measure: INVOS NIRS feasibility and safety questionnaire
timeFrame: 0-48 hours in Intensive Care Unit after enrolment into study
measure: Time to Extubation
timeFrame: 28 days
measure: Days off ventilator in 28 days
timeFrame: 28 days
measure: Days without vasoactive medication in 28 days
timeFrame: 28 days
measure: Days without RRT in 28 days
timeFrame: 28 days
measure: ICU length of stay
timeFrame: 90 days
measure: 28-day mortality
timeFrame: 28 days
measure: Cognitive dysfunction after ICU discharge
timeFrame: 6 months
Other outcomes:
measure: Glycocalyx and endothelial injury biomarkers such as: Syndecan-1 (SDC-1), vascular adhesion protein 1 (VAP1), CD73, heparin binding protein (HBP), angiopoietin-2, endostatin, chromogranin
timeFrame: First week in the Intensive Care Unit after admission
Locations:
city: Helsinki
country: Finland
facility: Helsinki University Hospital
city: Kuopio
country: Finland
facility: Kuopio University Hospital
city: Tampere
country: Finland
facility: Tampere University Hospital
Study officials:
affiliation: Helsinki University Central Hospital
name: Erika Wilkman, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: