Primary Outcomes

Description: Symptoms of peritraumatic distress, as measured by the Peritraumatic Distress Inventory (adapted to fit the ICU experience), will be compared between groups at post-intervention assessment (T2). The PDI consists of 13 likert-style items and total score can range from 0 to 52. Higher total scores represent greater symptom burden. Lower scores represent better outcomes.

Measure: Peritraumatic Distress Inventory

Time: In the week following the intervention (T2)

---

Secondary Outcomes

Description: Anticipatory grief for patients who are not deceased, as measured by the Prolonged Grief-12, will be compared between groups at one-month and three-month follow up assessments (T3 and T4).The PG-12 consists of 12 items and total score can range from 0 to 57. Higher total scores represent greater symptom burden. Lower scores represent better outcomes.

Measure: Anticipatory Grief

Time: One month and three months from baseline (T3 and T4)

---

Description: Symptoms of prolonged grief disorder, as measured by the Prolonged Grief-13, will be compared between groups at one-month and three-month follow up assessments (T3 and T4). The PG-13 consists of 13 items and total score can range from 0 to 62. Higher total scores represent greater symptom burden. Lower scores represent better outcomes.

Measure: Prolonged Grief Disorder

Time: One month and three months from baseline (T3 and T4)

---

Description: Symptoms of experiential avoidance, as measured by the Brief Experiential Avoidance Questionnaire, will be compared between groups at one-month and three-month follow up assessments (T3 and T4). The BEAQ consists of 15 items and total score can range from 15 to 90. Higher total scores represent greater symptom burden. Lower scores represent better outcomes.

Measure: Experiential Avoidance

Time: One month and three months from baseline (T3 and T4)

---

Description: Symptoms of post-traumatic stress disorder, as measured by the Impact of Events Scale-Revised, will be compared between groups at one-month and three-month follow up assessments (T3 and T4). The IES-R consists of 22 items and total score can range from 0 to 88. Higher total scores represent greater symptom burden. Lower scores represent better outcomes.

Measure: Post-Traumatic Stress Disorder

Time: One month and three months from baseline (T3 and T4)

---

Other Outcomes

Description: Logistic regression models will regress patient quality of life for EMPOWER vs. the enhanced usual care condition. Patient quality of life will be assessed using three previously validated items. Total score can range from 0 to 30. Higher total scores represent better caregiver-assessed patient quality of life. Higher scores represent better outcomes.

Measure: Patient Quality of Life

Time: From baseline assessment to three-month follow up

---

Description: For patients who die during the study period, logistic regression models will regress patient quality of death for EMPOWER vs. the enhanced usual care condition. Quality of Death will be measured using the Caregiver Evaluation of the Quality of End-of-Life Care (CEQUEL). Total score can range from 13 to 26. Higher total scores represent better caregiver-assessed patient quality of death. Higher total scores represent better outcomes.

Measure: Patient Quality of Death

Time: From baseline assessment to three-month follow up

---

Description: Intensity of care (measured through indication of cardiopulmonary resuscitation, dialysis, mechanical ventilation, chemotherapy, parenteral nutrition, and palliative care in the medical record) will be matched with surrogate perceptions of patient treatment preferences to create a measure of value-concordant care. Logistic regression analyses will then model the effects of EMPOWER on the odds of patients' receipt of value-concordant care. Higher odds equal better outcomes.

Measure: Value-Concordant Care

Time: From baseline assessment to three-month follow up

---

Description: Symptoms of anxiety, as measured by the state scale of the State-Trait Anxiety Scale, will be compared between groups at one-month and three-month follow up assessments (T3 and T4).The STAI-Y state scale consists of 20 items and total score can range from 20 to 80. Higher total scores represent greater symptom burden. Lower scores represent better outcomes.

Measure: Anxiety

Time: One month and three months from baseline (T3 and T4)

---

Description: Symptoms of anxiety, as measured by the Patient Health Questionnaire - 9 , will be compared between groups at one-month and three-month follow up assessments (T3 and T4). The PHQ-9 consists of 9 items and total score can range from 0 to 27. Higher total scores represent greater symptom burden. Lower scores represent better outcomes.

Measure: Depression

Time: One month and three months from baseline (T3 and T4)

---

Description: Decision regret, as measured by the Decision Regret Scale, will be compared between groups at one-month and three-month follow up assessments (T3 and T4). The decision regret scale is a one-item likert-style measure. Total score can range from 1 to 10. Higher total scores represent greater symptom burden. Lower scores represent better outcomes.

Measure: Decision Regret

Time: One month and three months from baseline (T3 and T4)

---

Primary Outcomes

Measure: 28-day all cause mortality

Time: from admission to 28-day/discharge, an average of length of ICU stay is 28-day

---

Secondary Outcomes

Measure: All cause infection

Time: from admission to 28-day/discharge, an average of length of ICU stay is 28-day

---

Measure: The rate of complications

Time: from admission to 28-day/discharge, an average of length of ICU stay is 28-day

---

Measure: Length of ICU stay

Time: from admission to 28-day/discharge, an average of length of ICU stay is 28-day

---

Measure: Duration of mechanical ventilation

Time: from admission to 28-day/discharge, an average of length of ICU stay is 28-day

---

Primary Outcomes

Description: survival or death at 28 days

Measure: 28 day mortality

Time: 28 days

---

Secondary Outcomes

Description: days on vasopressor

Measure: vasopressor days

Time: 28 days

---

Description: days on mechanical ventilation during ICU stay

Measure: days on mechanical ventilation

Time: 28 days

---

Description: daily sequential organ function assessment score (0 minimum to 24 maximum), higher scores worse organ function

Measure: sequential organ function assessment score

Time: daily for first 5 days

---

Description: Percentage of patients requiring ECMO during ICU stay.

Measure: ECMO use

Time: 28 days

---

Description: percentage of patients requiring nitric oxide during ICU stay.

Measure: percentage nitric oxide use

Time: 28 days

---

Description: percentage not requiring oxygen therapy

Measure: percentage free from oxygen supplement

Time: 28 days

---

Primary Outcomes

Description: ratio of patients with acute encephalopathy among the total of patients with SARS-Cov-2 infection at Critical/Intensive care or Neurocritical care admission

Measure: prevalence

Time: at Critical/Intensive care or Neurocritical care admission

---

Secondary Outcomes

Description: A favorable outcome is defined by a Glasgow Outcome Scale (GOS) of 5. The Glasgow Outcome Scale (GOS) will be determined patients charts review, phone call, and/or general practitioner interview conducted by an independent assessor. The GOS score : [1: Death, 2: Persistent vegetative state, 3: Severe disability, 4: Moderate disability, 5 : Low disability]

Measure: Favorable outcome

Time: 3 months

---

Description: A favorable outcome is defined by a Glasgow Outcome Scale Extended (GOSe) >= 5. The Glasgow Outcome Scale Extended (GOSe) will be determined patients charts review, phone call, and/or general practitioner interview conducted by an independent assessor. The GOSe score : [1: Death, 2: Persistent vegetative state, 3: Severe disability Lower, 4: Severe disability Upper, 5: Moderate disability Lower, 6: Moderate disability Upper, 7 : Good recovery lower, 8 : Good recovery Upper]

Measure: Favorable outcome

Time: 3 months

---

Primary Outcomes

Measure: Survival

Time: up to 30 days

---

Secondary Outcomes

Description: Fragilty will be measured by using the Clinical frailty scale (CFS) a global clinical measure of fitness and frailty in elderly people (1=very fit to 9= terminally ill)

Measure: Fragilty

Time: pre-admission

---

Primary Outcomes

Measure: Mortality all causes at day30

Time: at day30

---

Secondary Outcomes

Measure: Number of days alive free of mechanical ventilation

Time: during 30 days after randomization

---

Measure: Number of days alive outside

Time: during 30 days after randomization

---

Measure: Number of days alive outside hospital

Time: during 30 days after randomization

---

Measure: Maximal changes in Sofa score

Time: in the first 7 days after randomization

---

Measure: Time to negativation of virus titer in the nasopharyngeal aspirate (NPA)

Time: during 90 days after randomization

---

Primary Outcomes

Description: Mortality at day 28

Measure: Mortality at day 28

Time: day 28

---

Secondary Outcomes

Description: severe complications (pulmonary embolism, acute kidney injury, myocarditis, cardiac arrest, liver failure, ventilator associated pneumonia) Yes / No

Measure: severe complications

Time: up to day 28

---

Description: Delay in imaging in hours

Measure: Imaging

Time: day 1

---

Description: delay in microbiological diagnosis in hours

Measure: Delay in Microbiological diagnosis

Time: day 1

---

Description: Antiviral therapy Yes / no

Measure: Antiviral therapy

Time: up to day 28

---

Description: Antibiotic therapy Yes / No

Measure: Antibiotic therapy

Time: day 28

---

Description: Covid-19 treatments Yes / No

Measure: Covid-19 treatments

Time: up to day 28

---

Description: number

Measure: Patients receiving renal replacement therapy

Time: up to day 28

---

Description: number

Measure: Patients receiving mechanical ventilation

Time: up to day 28

---

Description: Patient alive at day 28 : yes / No

Measure: Vital status

Time: day 28

---

Primary Outcomes

Description: To study the effect of Mw on recovery of organ function as assessed by Sequential Organ Failure Assessment (SOFA) which is based on six different scores, one for each of the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems each scored from 0 to 4 with an increasing score reflecting worsening organ dysfunction

Measure: Sequential Organ Failure Assessment (SOFA) scores

Time: Change in Sequential Organ Failure Assessment (SOFA) score from baseline to day 3

---

Description: To study the effect of Mw on recovery of organ function as assessed by Sequential Organ Failure Assessment (SOFA) scores which is based on six different scores, one for each of the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems each scored from 0 to 4 with an increasing score reflecting worsening organ dysfunction

Measure: Sequential Organ Failure Assessment (SOFA) scores

Time: Change in Sequential Organ Failure Assessment (SOFA) score from baseline to day 7

---

Description: To study the effect of Mw on recovery of organ function as assessed by Sequential Organ Failure Assessment (SOFA) scores which is based on six different scores, one for each of the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems each scored from 0 to 4 with an increasing score reflecting worsening organ dysfunction

Measure: Sequential Organ Failure Assessment (SOFA) scores

Time: Change in Sequential Organ Failure Assessment (SOFA) score from baseline to day 14

---

Description: To study the effect of Mw on recovery of organ function as assessed by Sequential Organ Failure Assessment (SOFA) scores which is based on six different scores, one for each of the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems each scored from 0 to 4 with an increasing score reflecting worsening organ dysfunction

Measure: Sequential Organ Failure Assessment (SOFA) scores

Time: Change in Sequential Organ Failure Assessment (SOFA) score from baseline to day 21

---

Description: To study the effect of Mw on recovery of organ function as assessed by Sequential Organ Failure Assessment (SOFA) scores which is based on six different scores, one for each of the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems each scored from 0 to 4 with an increasing score reflecting worsening organ dysfunction

Measure: Sequential Organ Failure Assessment (SOFA) scores

Time: Change in Sequential Organ Failure Assessment (SOFA) score from baseline to day 28

---

Description: To study the effect of Mw on recovery of organ function as assessed by Sequential Organ Failure Assessment (SOFA) scores which is based on six different scores, one for each of the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems each scored from 0 to 4 with an increasing score reflecting worsening organ dysfunction

Measure: Sequential Organ Failure Assessment (SOFA) scores

Time: Change in Sequential Organ Failure Assessment (SOFA) score from baseline to day of transfer from ICU, if earlier than 28 days.

---

Description: To study the effect of Mw on recovery of organ function as assessed by Ordinal scale

Measure: 7-category ordinal scale that ranges from 1 (not hospitalized with resumption of normal activities) to 7 (death)

Time: Change in Ordinal scale from baseline to day 3

---

Description: To study the effect of Mw on recovery of organ function as assessed by Ordinal scale

Measure: 7-category ordinal scale that ranges from 1 (not hospitalized with resumption of normal activities) to 7 (death)

Time: Change in Ordinal scale from baseline to day 7

---

Description: To study the effect of Mw on recovery of organ function as assessed by Ordinal scale

Measure: 7-category ordinal scale that ranges from 1 (not hospitalized with resumption of normal activities) to 7 (death)

Time: Change in Ordinal scale from baseline to day 14

---

Description: To study the effect of Mw on recovery of organ function as assessed by Ordinal scale

Measure: 7-category ordinal scale that ranges from 1 (not hospitalized with resumption of normal activities) to 7 (death)

Time: Change in Ordinal scale from baseline to day 21

---

Description: To study the effect of Mw on recovery of organ function as assessed by Ordinal scale

Measure: 7-category ordinal scale that ranges from 1 (not hospitalized with resumption of normal activities) to 7 (death)

Time: Change in Ordinal scale from baseline to day 28

---

Description: To study the effect of Mw on recovery of organ function as assessed by Ordinal scale

Measure: 7-category ordinal scale that ranges from 1 (not hospitalized with resumption of normal activities) to 7 (death)

Time: Change in Ordinal scale from baseline to day of transfer from ICU, if earlier than 28 days.

---

Secondary Outcomes

Description: All-cause mortality

Measure: All-cause mortality

Time: Till day 28

---

Description: Any AE / SAE or event of clinical significance observed during the study.

Measure: Incidence of AE / SAE or event of clinical significance

Time: Till day 28

---

Description: Percent of subjects with SARS-CoV-2 detectable in nasal or oropharyngeal (OP) sample.

Measure: SARS-CoV-2 detectable in nasal or oropharyngeal (OP) sample

Time: At days 3, 7, 14, 21, and 28

---

Description: ICU length of stay

Measure: ICU length of stay

Time: Till day 28

---

Description: Duration of mechanical ventilation

Measure: Duration of mechanical ventilation

Time: Till day 28

---

Description: Duration of hospitalization

Measure: Duration of hospitalization

Time: Till day 28

---

Description: Percentage of subjects having clinical improvement defined as two-point improvement on a seven category ordinal scale.

Measure: Clinical improvement

Time: From base line at day 14 & Day 28

---

Description: Time (in days) from treatment initiation to death.

Measure: Time (in days) from treatment initiation to death

Time: Till day 28

---

Primary Outcomes

Description: Troponin courses in the intensive care unit are analyzed in consideration of the respective cardiovascular risk.

Measure: ICU CV risk and Biomarker (e.g. Troponin)

Time: through study completion, up to 4 weeks

---

Secondary Outcomes

Description: The 30-day mortality during the ICU stay is determined and divided into appropriate cardiovascular risk groups.

Measure: CV risk and Outcome during ICU stay

Time: through study completion, up to 4 weeks

---

Primary Outcomes

Description: Variation of age between critically ill patients with SARS Cov2 admitted in ICU with non critically ill patients with SARS Cov2 admitted in ICU

Measure: Variation of age between critically ill patients with SARS Cov2 admitted in ICU with non critically ill patients with SARS Cov2 admitted in ICU

Time: from day 1 of admission

---

Description: Variation of medical history between critically ill patients with SARS Cov2 admitted in ICU with non critically ill patients with SARS Cov2 admitted in ICU

Measure: Variation of medical history between critically ill patients with SARS Cov2 admitted in ICU with non critically ill patients with SARS Cov2 admitted in ICU

Time: from day 1 of admission

---

Description: Variation of chronic drug used between critically ill patients with SARS Cov2 admitted in ICU with non critically ill patients with SARS Cov2 admitted in ICU

Measure: Variation of chronic drug used between critically ill patients with SARS Cov2 admitted in ICU with non critically ill patients with SARS Cov2 admitted in ICU

Time: from day 1 of admission

---

Description: Variation of chest CT scan at admission, between critically ill patients with SARS Cov2 admitted in ICU with non critically ill patients with SARS Cov2 admitted in ICU

Measure: Variation of chest CT scan at admission, between critically ill patients with SARS Cov2 admitted in ICU with non critically ill patients with SARS Cov2 admitted in ICU

Time: from day 1 of admission

---

Description: Variation of respiratory support at ICU admission, between critically ill patients with SARS Cov2 admitted in ICU with non critically ill patients with SARS Cov2 admitted in ICU

Measure: Variation of respiratory support at ICU admission, between critically ill patients with SARS Cov2 admitted in ICU with non critically ill patients with SARS Cov2 admitted in ICU

Time: from day 1 of admission

---

Primary Outcomes

Description: nM;

Measure: ETP (AUC) without rhThrombomodulin (rhTM)

Time: 6 months

---

Description: nM;

Measure: ETP (AUC) with rhThrombomodulin (rhTM)

Time: 6 months

---

Description: Ratio of endogenous thrombin potential (ETP) with rhTM to ETP without rhTM

Measure: ETP-ratio

Time: 6 months

---

Description: Comparison of ETP-ratios from ICU patients and ETP-ratios from citrated plasma samples from healthy donors

Measure: ETP-Normalisation

Time: 6 months

---

Primary Outcomes

Measure: ICU mortality

Time: During inclusion period

---

Secondary Outcomes

Measure: Hospital mortality

Time: During inclusion period

---

Measure: ICU length of stay

Time: During inclusion period

---

Primary Outcomes

Description: Plasma of covid-19 patients will be tested for endothelial injuries, notably with the measurement of InterCellular Adhesion Molecule 1 level by Enzym-Linked Immunosorbent Assay. The association of these levels with 28-days mortality will be evaluated as prognosis markers.

Measure: Association of InterCellular Adhesion Molecule-1 plasma level with 28 days mortality

Time: 24 hours

---

Secondary Outcomes

Description: Endothelin-1 will be assessed in blood as a maker of endothelial injuries, expressed in pg/mL. its association with 28 -days mortality will be evaluated.

Measure: Association of Endothelin-1 plasma level with 28 days mortality

Time: 24 hours

---

Description: Vascular Endothelial Growth Factor A plasma level will be measured in blood as a marker of endothelial injury expressed in pg/mL. its association with 28 -days mortality will be evaluated.

Measure: Association of Vascular Endothelial Growth Factor A plasma level with 28 days mortality

Time: 24 hours

---

Description: This soluble receptor is another marker of endothelial injury and will be measured in blood and expressed as pg/mL. Its association with 28-days mortality will be evaluated.

Measure: Association of soluble Vascular Endothelial Growth Factor Receptor type 1 with 28 days mortality

Time: 24 hours

---

Description: syndecan -1 is a marker of degradation of glycocalyx, raised during endothelial injury. It will be measured in blood and expressed as pg/mL. Its assocation with 28-days mortality will be evaluated.

Measure: Association of syndecan -1 plasma level with 28 days mortality

Time: 24 hours

---

Description: D-dimers si marker of enhanced thrombotic activity. It may be increased during covid-19 disease but its correlation with endothelial injury is not known. It will be measured in blood and expressed as microgrammes/L, and then correlated with ICAM-1 plasma levels

Measure: Association of D-dimers plasma levels with thrombotic events

Time: 24 hours

---

Description: This marker may be raised during endothelial injury and may explained thrombotic status of covid-19 patients. Its blood levels will be measured and expressed as international unit/dL, and correlated with ICAM-1 plasma levels

Measure: Association of von Willebrandt Factor with thrombotic events

Time: 24 hours

---

Description: Clot Stiffness and its fibrinogen and platelet contributions (expressed in kPa) will be measured as novative approach, using Quantra (Stago Inc) device, to explore hemostasis alterations of covid-19 patients.

Measure: Association of Viscoelastic testing with thrombotic events

Time: 24 hours

---

Primary Outcomes

Description: Mesured by STAY Scale

Measure: Anxiety

Time: 15 to 45 days after the beginning of the outbreak

---

Secondary Outcomes

Description: Participant suffering of Insomnia

Measure: Insomnia

Time: 15 to 45 days after the beginning of the outbreak

---

Description: Participant suffering of catastrophism

Measure: Catastrophism

Time: 15 to 45 days after the beginning of the outbreak

---

Primary Outcomes

Description: To compare the difference in proportion of patients with increased disease severity

Measure: Number of patients with increased disease severity

Time: From baseline to Day 3, Day 7, Day 14, Day 21, Day 28 or at any time during the study till 28 days post first dosing.

---

Secondary Outcomes

Description: To evaluate safety of Mw in COVID-19 patients admitted to hospital

Measure: Incidence of adverse events and serious adverse events (Safety)

Time: Till day 28

---

Description: To compare the proportion of patients discharged from hospital

Measure: Number of COVID-19 patients discharged from hospital

Time: From baseline to Day 3, Day 7, Day 14, Day 21, Day 28 or at any time during the study till 28 days post first dosing.

---

Description: To compare the proportion of patients transfer to ICU

Measure: Number of COVID-19 patients transfer to ICU

Time: From baseline to Day 3, Day 7, Day 14, Day 21, Day 28 or at any time during the study till 28 days post first dosing.

---

Description: To compare the proportion of patients with reduction in disease severity by 1 ordinal scale

Measure: Number of COVID-19 patients with reduction in disease severity by 1 ordinal scale

Time: From baseline to Day 3, Day 7, Day 14, Day 21, Day 28 or at any time during the study till 28 days post first dosing.

---

Description: To compare the proportion of symptom free patients

Measure: Number of of symptom free patients

Time: From baseline to Day 3, Day 7, Day 14, Day 21, Day 28 or at any time during the study till 28 days post first dosing.

---

Primary Outcomes

Description: Assessment of neurocognitive impairment using validated tools

Measure: Incidence of delirium/neurocognitive impairment in adult and pediatric patients with COVID-19 compared to patients without COVID-19

Time: Day 90

---

Description: Measurement of biomarker levels (e.g. NSE, S100B, neurofilament proteins) derived from blood samples

Measure: Change in neuroaxonal injury biomarker levels in patients with COVID-19 compared to patients without COVID-19

Time: Change from baseline biomarker levels at day 28

---

Description: Assessment of the neurocognitive performance of patients using validated tests (e.g. Short Blessed Test)

Measure: Neurocognitive 3-months outcome in patients with COVID-19 compared to patients without COVID-19

Time: Day 90

---

Description: Assessment of the change in the neurocognitive performance of patients using validated tests (e.g. IQCODE)

Measure: Neurocognitive 3-months outcome in patients with COVID-19 compared to patients without COVID-19

Time: Change from baseline IQCODE results at day 90

---

Secondary Outcomes

Description: Assessment of the overall quality of life using validated tests [e.g. Modified Rankin Scale with a range from 0 (no symptoms) to 6 (dead)]

Measure: Quality of life in patients with COVID-19 compared to patients without COVID-19 after hospital discharge

Time: Day 90

---

Description: Cumulative days in hospital

Measure: Length of hospital stay in patients with COVID-19 compared to patients without COVID-19

Time: 1 year

---

Description: Survival after 90 days

Measure: 90-day survival in patients with COVID-19 compared to patients without COVID-19

Time: Day 90

---

Primary Outcomes

Description: SF-36 score

Measure: Quality of Life score

Time: up to 12 months after discharge

---

Secondary Outcomes

Description: Montreal Cognitive Assessment (MoCA) score

Measure: cognitive dysfunction

Time: up to 12 months after discharge

---

Description: (FSS-ICU)

Measure: Functional Status Score

Time: up to 12 months after discharge

---

Description: MRC neuromuscular Assessment

Measure: Physical Disability

Time: up to 12 months after discharge

---

Description: Impact Event Score

Measure: Psychological Sequelae

Time: up to 12 months after discharge

---

Other Outcomes

Description: hospital anxiety and depression scale

Measure: hospital anxiety and depression

Time: up to 12 months after discharge

---

Description: including ventilator associated pneumonia, GI hemorrhage, Deep Vein Thrombosis (DVT) /Pulmonary Embolus (PE), sacral decubitus ulcer, delirium, ICU acquired weakness

Measure: ICU related complications

Time: hospitalization up to 6 weeks

---

Description: measure the location (home, rehabilitation center, nursing home

Measure: hospital discharge location

Time: hospital discharge up to 6 weeks

---

Description: number of days admitted to the ICU

Measure: lCU length of stay

Time: hospitalization up to 6 weeks

---

Description: number of days admitted to the hospital

Measure: hospital length of stay

Time: hospitalization up to 6 weeks

---

Primary Outcomes

Description: Improvement in knowledge item score of 2 points on follow up after intervention delivery and at final follow up

Measure: Improvement in knowledge surrounding SRA policy

Time: 1 month, 6 months

---

Description: Improvement in anxiety scale of 2 points responses on follow up after intervention delivery and at final follow up

Measure: Improvement in anxiety surrounding SRA policy

Time: 1 month, 6 months

---

Description: Improvement in trust scale of 2 points responses on follow up after intervention delivery and at final follow up

Measure: Improvement in trust surrounding SRA policy

Time: 1 month, 6 months

---

Primary Outcomes

Description: Patients with symptomatic pulmonary embolism confirmed on the CT-angiography and those with a swollen limb and confirmed deep venous thrombosis on compression ultrasound were considered to have "symptomatic venous thromboembolisms". The remaining patients with positive limb ultrasound or CT-angiography were considered to have "asymptomatic venous thrombembolism"

Measure: Venous thromboembolisms

Time: 7 days

---

Secondary Outcomes

Description: Deaths from all causes during the follow-up

Measure: Deaths

Time: 7 days

---

Primary Outcomes

Description: the proportion of patients who survive to ICU discharge or for 28 days in the ICU

Measure: ICU survival at 28 days

Time: 28 days

---

Secondary Outcomes

Description: the proportion of patients who survive to hospital discharge or for 60 days in the hospital

Measure: Hospital survival at 60 days

Time: 60 days

---

Description: Number of days under invasive ventilatory support

Measure: Duration of mechanical ventilation

Time: 28 days

---

Description: Proportion of patients who received renal replacement therapy during the ICU stay

Measure: Need for renal replacement therapy

Time: 28 days

---

Description: percentage of patients who developed complications during the ICU stay: thromboembolic events, ventilator associated pneumonia, secondary infections, cardiovascular complications

Measure: Complications during the ICU stay

Time: 28 days

---

Primary Outcomes

Description: percentage of patients with ICU acquired MDR bacteria colonization

Measure: Cumulative incidence of ICU-acquired colonization related multidrug resistant bacteria

Time: from D3 until day 28 after ICU admission

---

Secondary Outcomes

Description: percentage of patients with ICU acquired MDR bacteria infection

Measure: Cumulative incidence of ICU-acquired infection related to multidrug resistant bacteria

Time: from D3 until day 28 after ICU admission

---

Description: the number of days Under mechanical ventilation

Measure: Mechanical ventilation duration

Time: from D1 until day 28 after ICU admission

---

Description: death in the ICU

Measure: mortality

Time: from D1 until day 28 after ICU admission

---

Description: the number of days of hospitalization in the ICU

Measure: length of stay in intensive care unit

Time: from D1 until day 28 after ICU admission

---

Primary Outcomes

Description: rate (%)

Measure: ICU mortality

Time: events during the ICU stay, up to 3 months

---

Secondary Outcomes

Description: rate (%)

Measure: hospital mortality

Time: events through study completion during the hospital stay, up to 5 months

---

Description: rate (%)

Measure: 28-day mortality

Time: events through study completion considered from ICU admission up to 28 days

---

Description: rate (%). Incidence of outcome measures (ICU mortality), and appearance of complications (pneumonia or bacteriemia during ICU stay).

Measure: effectiveness of treatment

Time: through study completion considered from ICU admission until ICU discharge, up to 3 months

---

Description: days

Measure: length of ICU stay

Time: through study completion during ICU stay considered from ICU admission until ICU discharge as date of inclusion until the date of first documented discharge or date of death from any cause, whichever came first, assessed up to 3 months

---

Description: days

Measure: length of hospital stay

Time: through study completion during ICU stay considered from ICU admission until ICU discharge as date of inclusion until the date of first documented hospital discharge or date of death from any cause, whichever came first, assessed up to 5 months

---

Description: rate (%)

Measure: ventilator-associated pneumonia

Time: through duration of invasive ventilatory support period (from intubation date until date of successful extubation) through study completion up to 3 months

---

Description: rate (%)

Measure: bacteriemia

Time: through study completion, up to 28-days

---

Description: rate (%)

Measure: barotrauma

Time: through study completion, up to 28-days

---

Description: days

Measure: duration of mechanical ventilation

Time: period of invasive controlled ventilatory support from date of orotraqueal intubation until date of successful extubation or assessed up to 3 months whichever came first

---

Primary Outcomes

Description: days of ICU stay

Measure: Length of ICU stay

Time: up to 60 days

---

Secondary Outcomes

Description: days of hospital stay

Measure: Length of hospital stay

Time: up to 90 days

---

Primary Outcomes

Measure: Demographic characteristics of patients with Covid-19 receiving intensive care

Time: Until 30 days after admittance to Intensive Care

---

Secondary Outcomes

Measure: Survival rate in patients with Covid-19 receiving intensive care

Time: 30 days and 6 months after admission to intensive care

---

Measure: Clinical course characteristics of patients with Covid-19 receiving intensive care

Time: Until 30 days after admittance to Intensive Care

---

Measure: Number of days on mechanical ventilation

Time: Until 30 days after admittance to Intensive Care

---

Primary Outcomes

Description: Number and characteristics of patients with COVID-19 admitted in Intensive Care Units every week.

Measure: Overall number and characteristics of patients with COVID-19 in ICU

Time: 22nd February - 22nd August 2020

---

Primary Outcomes

Description: Odds ratio of intensive care treated patients with COVID-19 having ongoing treatment with drugs blocking the Renin-Angiotensin-Aldosterone-System (RAAS), statins, immunosuppressant drugs, oral anticoagulant drugs, oral thrombocyte aggregation inhibitors or antiviral drugs.

Measure: Chronic medications as risk factor of intensive care for COVID-19

Time: Drug dispensation within 6 months prior inclusion

---

Description: Odds ratio of intensive care treated patients with COVID-19 having been diagnosed with diabetes typ I, diabetes type II, ischemic heart disease, other heart disease, cerebrovascular disease, cancer, chronic renal failure, chronic obstructive pulmonary disease (COPD) asthma, obesity, immunosuppressed disease or systemic inflammatory disease.

Measure: Comorbidities as risk factor of intensive care for COVID-19

Time: 5 years prior to inclusion

---

Secondary Outcomes

Description: Odds ratio of patients who have died during intensive care with COVID-19 having ongoing treatment with drugs blocking the Renin-Angiotensin-Aldosterone-System (RAAS), statins, immunosuppressant drugs, oral anticoagulant drugs, oral thrombocyte aggregation inhibitors or antiviral drugs.

Measure: Chronic medications as risk factor of death during intensive care for COVID-19

Time: Drug dispensation within 6 months prior inclusion

---

Description: Odds ratio of patients who have died during intensive care with COVID-19 having been diagnosed with diabetes typ I, diabetes type II, ischemic heart disease, other heart disease, cerebrovascular disease, cancer, chronic renal failure, chronic obstructive pulmonary disease (COPD) asthma, obesity, immunosuppressed disease or systemic inflammatory disease.

Measure: Comorbidities as risk factor of death during intensive care for COVID-19

Time: 5 years prior to inclusion

---

Primary Outcomes

Description: Highest level of mobility achieved at the point of ICU discharge

Measure: Mobility level

Time: At ICU discharge, an average of 3 weeks

---

Description: Time taken to first mobilise, defined as sitting on the edge of the bed or higher

Measure: Time taken to first mobilise

Time: during ICU admission, up to 3 weeks

---

Secondary Outcomes

Description: Discharged to home, home with rehab, or a community rehab facility

Measure: Discharge location

Time: Hospital discharge, up to 2 months

---

Primary Outcomes

Description: a composite measure of WHODAS 2.0 - 12 level and hospital survival

Measure: Disability-free survival

Time: 6 months

---

Description: The physiotherapy interventions provided to patients with COVID-19 admitted to the ICU and health outcomes

Measure: Physiotherapy intervention

Time: During the ICU stay until 3 months

---

Secondary Outcomes

Description: Health related quality of life measured with EQ5D-5L score from 0 to 100

Measure: Health status

Time: 6 months

---

Description: World Health Organization Disability Assessment Schedule 2.0 12L

Measure: Global function

Time: 6 months

---

Description: Montreal Cognitive Assessment Blind

Measure: Cognitive function

Time: 6 months

---

Description: Hospital Anxiety and Depression Scale

Measure: Anxiety and depression

Time: 6 months

---

Description: Impact of Events Scale Revised

Measure: Screening for post-traumatic distress

Time: 6 months

---

Description: WHODAS 2.0

Measure: Work Status

Time: 6 months

---

Measure: Proportion of patients with COVID-19 who received physiotherapy in ICU

Time: During the ICU stay until 28 days

---

Description: Physiotherapist reported barriers to delivering the intervention

Measure: The reported barriers to delivering physiotherapy interventions

Time: During the ICU stay until 28 days

---

Description: Adverse events that require the intervention to be ceased for medical intervention

Measure: Adverse events during physiotherapy interventions

Time: During the ICU stay until 28 days

---

Description: Qualitative interviews

Measure: Phenomenological data of the patient and family experience

Time: 6 months

---

Primary Outcomes

Description: Comparison of number of COVID-19 positive patients who have died within 30 days of starting treatment on each treatment arm

Measure: 30-day mortality

Time: 30 days

---

Secondary Outcomes

Description: Comparison of length of ICU stay in days between each treatment arm.

Measure: Length of Intensive Care Unit (ICU) Stay in Days

Time: 6 months

---

Description: Comparison of number of documented VTE, arterial thrombosis and microthrombosis events on each treatment arm

Measure: Number of documented venous thromboembolism (VTE), arterial thrombosis (stroke, myocardial infarction, other) and microthrombosis events

Time: 6 months

---

Description: Comparison of major and clinically-relevant non-major bleeding events on each treatment arm, as defined by the International Society of Thrombosis and Haemostasis (ISTH) criteria.

Measure: Number of major and clinically relevant non-major bleeding events

Time: 6 months

---

Primary Outcomes

Description: Incidence of adverse events, quantified by pain or discomfort that causes termination of interventions; a fall (with or without injury) during interventions or directly related to interventions such as fall due to fatigue; and physiologic event/abnormality that warrants termination of interventions or medical follow-up including bradycardia, tachycardia, and emergent hypertension

Measure: Adverse events (safety)

Time: through study completion, an average of 3-months

---

Secondary Outcomes

Description: Feasibility will be assessed by the consent rate (number of patients agreed to participate/number of patients approached for consent) and adherence attendance measured by the percentage of sessions patient participated divided total number of scheduled appointments. Adherence will also be prospectively assessed by total duration of exercise, dosage and intensity of exercises as described above. Attrition will be quantified by number of patients lost to follow-up.

Measure: Feasibility (success of consent process, adherence, and attrition)

Time: through study completion, an average of 3-months

---

Description: Distance walked on six-minute walk test performed in line with the ATS/ERS Guidelines as measure of exercise capacity

Measure: Six minute walk test

Time: Assessed at baseline, and repeated 3- and 6-months post hospital discharge

---

Description: Short Performance Physical Battery (SPPB) is a performance-based physical function test with components of balance, repetitive five times sit-to-stand for time, and 4-meter habitual gait speed. Higher scores on SPPB indicate better physical function.

Measure: Short Performance Physical Battery

Time: Assessed at baseline, and repeated 3- and 6-months post hospital discharge

---

Description: Health-related quality of life (HRQoL) will be measured by self-report questionnaire, the Five Dimension Euro-Quality of Life (EQ-5D) that includes a visual analog scale with rating for overall HRQoL (0-100)

Measure: Quality of life (EQ-5DL)

Time: Assessed at baseline, and repeated 3- and 6-months post hospital discharge

---

Description: Cognitive function will be assessed by the Montreal Cognitive Assessment (MOCA) with <23/30 distinguishing mild cognitive impairment. If the patient participating in telemedicine through Zoom then the MOCA-Blind version will be completed.

Measure: Cognitive function

Time: Assessed at baseline, and repeated 3- and 6-months post hospital discharge

---

Description: Anxiety and depression will be assessed with the Hospital Anxiety and Depression Scale (HADS), a fourteen-item scale with subset scores of >8/21 indicating anxiety or depression

Measure: Anxiety and Depression

Time: Assessed at baseline, and repeated 3- and 6-months post hospital discharge

---

Description: Distress and Post-traumatic stress disorder (PTSD) will be assessed through the Impact of Events Scale-Revised (IES-R), a 22-item self-report measure, with scores >35/88 recommending provisional diagnosis of PTSD

Measure: PTSD and distress

Time: Assessed at baseline, and repeated 3- and 6-months post hospital discharge

---

Description: For patients previously employed, the return to work will be assessed using the self-report survey instrument designed for ICU follow-up

Measure: Return to work

Time: Assessed at baseline, and repeated 3- and 6-months post hospital discharge

---

Description: Readmission rate and morality with be assessed

Measure: Secondary complication

Time: Assessed 3 and 6-months post hospital discharge

---

Primary Outcomes

Description: To compare confirmed COVID-19 cases with suspected COVID-19 cases in critical care units.

Measure: Polymerase Chain Reaction (PCR) test

Time: 5 days

---

Secondary Outcomes

Description: To use symptoms, medical history, computed tomography and laboratory examinations for scoring system to detect suspected COVID-19 cases admitted to the intensive care units.

Measure: A scoring system for patients to be admitted to the intensive care unit

Time: 5 days

---

Primary Outcomes

Description: Does the use of inhaled volatile anesthetic-based sedation regimen improve participant hospital mortality as compared to standard intravenous sedation regimen with a 10% difference between groups for 752 participants.

Measure: Hospital Mortality

Time: 2 years

---

Description: Does the use of inhaled volatile anesthetic-based sedation regimen improve participant ventilation outcomes after 30 days post enrollment, as compared to standard intravenous sedation regimen for 200 participants

Measure: Ventilator-Free Days

Time: 30 days

---

Description: Does the use of inhaled volatile anesthetic-based sedation regimen improve participant time spent in ICU, 30 days post enrollment, as compared to standard intravenous sedation regimen for 128 participants

Measure: ICU-Free Days

Time: 30 days

---

Description: Does the use of inhaled volatile anesthetic-based sedation regimen improve participant quality of life outcomes at 3 and 12 months post discharge as compared to standard intravenous sedation regimen for 144 participants. The EQ-5D questionnaire will be completed at both time points

Measure: Participant Quality of Life at 3 and 12 months after discharge

Time: 365 days

---

Secondary Outcomes

Description: To evaluate participant median daily oxygenation (PaO2/FiO2) at 3 days post enrollment

Measure: Median Daily Oxygenation

Time: 3 days

---

Description: To evaluate participant need for adjunctive ARDS therapies (prone, nitric oxide, paralysis, ECMO) during ICU stay

Measure: Adjunctive ARDS therapies

Time: 30 days

---

Description: To evaluate the number of hospital-free days for participants, 60 days after enrollment

Measure: Hospital-Free Days

Time: 60 days

---

Description: To evaluate participant disability at 3 and 12 months post discharge. The World Health Organization Disabiltity Assessment Score (WHODAS 2.0) will be completed at both timepoints. The scores assigned to each of the items - "none" (0), "mild" (1) "moderate" (2), "severe" (3) and "extreme" (4) - are summed. This method is referred to as simple scoring because the scores from each of the items are simply added up without recoding or collapsing of response categories; thus, there is no weighting of individual items.

Measure: Disability

Time: 365 days

---

Description: Quality of Life (QALY) assessment to be calculated using the EQ-5D, comparison costs at 3 and 12 months post discharge, costs associated with hospital stay, devices and sedative costs

Measure: Cost Utility Analysis

Time: 365 days

---

Description: Life Year Gained (LYG) to be calculated using the EQ-5D, total costs during hospitalization, and health care utilization for 1 year after discharge.

Measure: Cost Effectiveness Analysis

Time: 365 days

---

Primary Outcomes

Description: Adequate endotracheal tube position in agreement with chest radiograph

Measure: Concordance with next occurring chest radiograph

Time: within 24 hours

---

Secondary Outcomes

Description: Number of esophageal intubations detected during intubation attempt

Measure: Esophageal Intubation detection

Time: within intubation attempt

---

Description: Number of right main stem intubations detected with ultrasonography

Measure: Right main or endobronchial intubation

Time: within intubation attempt

---

Primary Outcomes

Description: number of fatal cases

Measure: ICU mortality

Time: through study completion, an average of 14 days

---

Secondary Outcomes

Description: number of patients with invasive mechanical ventilation

Measure: Invasive mechanical ventilation

Time: through study completion, an average of 14 days

---

Description: number of fatal cases

Measure: In-hospital mortality

Time: through study completion, an average of 21 days

---

Primary Outcomes

Description: Anxiety for relative of ICU patient will be measured by the Hospital Anxiety and depression scale (HADS) assessed 3 months after the ICU discharge of patient. HADS ranges from 0 to 42; higher scores indicate worse symptoms.

Measure: Anxiety

Time: at 3 months

---

Description: Anxiety for relative of ICU patient will be measured by the Hospital Anxiety and depression scale (HADS) assessed 3 months after the ICU discharge of patient. HADS ranges from 0 to 42; higher scores indicate worse symptoms.

Measure: Depression

Time: at 3 months

---

Secondary Outcomes

Description: Impact of post traumatic stress disorder for relative of ICU patient will be measured with the Event scale revised (IES-R) assessed 3 months after the ICU discharge of patient. IES-R ranges from 0 to 88; higher scores indicate worse symptoms

Measure: post-traumatic stress disorder

Time: at 3 months

---

Primary Outcomes

Description: to evaluate mortality

Measure: number of death

Time: at Intensive Care Units discharge, an average of 1 months

---

Secondary Outcomes

Description: to evaluate morbidity

Measure: number of infections

Time: from date of admission until Intensive Care Units discharge, assessed up to 1 months

---

Measure: number of days of mechanical ventilation

Time: from date of admission until Intensive Care Units discharge, assessed up to 1 months

---

Measure: number of days of sedation

Time: from date of admission until Intensive Care Units discharge, assessed up to 1 months

---

Measure: number of days of use of neuromuscular blocking agents

Time: from date of admission until Intensive Care Units discharge, assessed up to 1 months

---

Measure: number of days of vasopressor use

Time: from date of admission until Intensive Care Units discharge, assessed up to 1 months

---

Measure: number of days in Intensive Care Units

Time: from date of admission until Intensive Care Units discharge, assessed up to 1 months

---

Measure: number of days in hospital

Time: from date of admission until hospital discharge, assessed up to 1 months

---

Primary Outcomes

Description: Hand grip strength is an indicator of overall muscle strength that predicts mortality in older patients. Handgrip strength was measured using a handheld dynamometer according to the instructions of the American Society of Hand Therapists.Patients were seated placing their arms by their sides with the elbow flexed to 90°, the forearm mid-prone, and the wrist in neutral position. Patients were asked to grip the dynamometer with maximal effort using standard verbal encouragement. Three trials were performed in the dominant hand with a 30 sec rest between trials and the highest value was recorded in kg. The cut-off values of grip strength is 28.6 kg in men and 16.4 kg in women. The measurement was performed 1 month after discharge.

Measure: Hand grip strength

Time: 1 month after discharge from hospital

---

Secondary Outcomes

Description: Short form - 36 measures health related quality of life. It is a self-reported survey that evaluates individual health status with eight parameters consisting of physical function, pain, role limitations attributed to physical problems, role limitations attributed to emotional problems, mental health, social functioning, energy/ vitality, general health perception. There is not a summary score, each section is scored between 0-100, 0 indicates the worst condition, 100 indicates the best. The measurement was performed 1 month after discharge.

Measure: Short form - 36

Time: 1 month after discharge from hospital

---

Description: Number of days of stay in intensive care unit from admission to discharge

Measure: Length of stay in intensive care unit

Time: through study completion, an average of 3 months

---

Description: Number of days of stay in hospital from admission to hospital to discharge from hospital

Measure: Length of stay in hospital

Time: through study completion, an average of 3 months

---

Description: Number of days of invasive mechanical ventilation during intensive care unit

Measure: Duration of invasive mechanical ventilation

Time: through study completion, an average of 3 months

---

Description: Manual muscle strength was graded via a composite of Medical Research Council Scale score which has an excellent inter-rater reliability in survivors of critical illness. This scale range from 0 point (no muscle contraction) to 5 points (normal muscle strength). Through examination of 3 muscle groups in each limb (arm abduction, forearm flexion, wrist extension, hip flexion, knee extension and ankle dorsiflexion), clinical important muscle weakness has been defined as a composite score < 48 out of maximum 60 points. The measurement was performed 1 month after discharge.

Measure: Manual muscle strength

Time: 1 month after discharge from hospital

---

Description: Range of joint motion was evaluated in upper and lower extremity joints by physical examination and the results were recorded as normal or restricted for each joint. The measurement was performed 1 month after discharge.

Measure: Range of joint motion

Time: 1 month after discharge from hospital

---

Primary Outcomes

Description: evaluate the role of convalescent plasma in saving life of treated patients by measuring the final outcome whether treated patients survived or died

Measure: Death versus survival of treated patients

Time: Up to 8 weeks

---

Secondary Outcomes

Description: this outcome is about measuring the length of stay (in days) of treated patients with convalescent plasma versus tose who were treated with conventional therapies

Measure: The length of stay in hospitals

Time: Up to 8 weeks

---

Primary Outcomes

Description: As defined by Kidney Diseases: Improving Global Outcomes (KDIGO) criteria

Measure: Incidence of any stage of acute kidney injury

Time: 14 days

---

Secondary Outcomes

Description: Mortality

Measure: Mortality

Time: 14-day, hospital, and intensive care unit (ICU) mortality

---

Description: Defined by return of creatinine to < 1.5 times of baseline

Measure: Renal recovery

Time: 14 days

---

Description: Percentage

Measure: Percentage of patients who receive renal replacement therapy

Time: 14 days

---

Description: Percentage of participants who are dialysis dependent

Measure: Percentage of participants who are dialysis dependent

Time: Through study completion, an average of 90 days

---

Description: Days without vasoactive medications and mechanical ventilation

Measure: Free-days of vasoactive medications and mechanical ventilation

Time: Day 30

---

Description: Length of intensive care unit and hospital stay

Measure: Length of intensive care unit and hospital stay

Time: Through study completion, an average of 90 days

---

Description: Congestive heart failure, Arrhythmia, Acute respiratory distress syndrome, Septic shock, Acute cardiac injury, pneumonia

Measure: Number of participants with consequences following AKI

Time: Through study completion, an average of 90 days

---

Description: Time from illness onset to need for mechanical ventilator support

Measure: Time from illness onset to need for mechanical ventilator support

Time: Through study completion, an average of 30 days

---

Primary Outcomes

Description: pCLE images are assessed morphometrically. Such criteria as quantity of alveolar macrophages, quantity of floating intraalveolar substances etc. are measured using a 6-point score, where zero means the absence of the symptom and 5 means the maximal expressiveness. Thickness of interalveolar septum, diameter of microvessels and thickness of elastic fibers are measured using a special tool with the included software for the endomicroscopic system. Radiologic signs e.g. low-density areas and consolidation areas are assessed in Hounsfield Units. Other radiologic signs e.g. groundglass opacity, crazy paving patterns etc. are measured by a 5-point scale, where zero means the absence of the symptom and 4 means the maximal expressiveness. The morphological analysis of the lung tissue specimens (received as a result of autopsy/transbronchial biopsy) is made according to the structures in pCLE images for 20 fields of view.

Measure: Number of COVID-19 Participants With Notable Differences in the pCLE images in comparison with the pCLE images of non-COVID-19 Participants

Time: up to one year

---

Secondary Outcomes

Description: pCLE images are assessed morphometrically. Such criteria as quantity of alveolar macrophages, quantity of floating intraalveolar substances etc. are measured using a 6-point score, where zero means the absence of the symptom and 5 means the maximal expressiveness. Thickness of interalveolar septum, diameter of microvessels and thickness of elastic fibers are measured using a special tool with the included software for the endomicroscopic system. Radiologic signs e.g. low-density areas and consolidation areas are assessed in Hounsfield Units. Other radiologic signs e.g. groundglass opacity, crazy paving patterns etc. are measured by a 5-point scale, where zero means the absence of the symptom and 4 means the maximal expressiveness. The morphological analysis of the lung tissue specimens (received as a result of autopsy/transbronchial biopsy) is made according to the structures in pCLE images for 20 fields of view.

Measure: Number of Participants With the Correspondence of pCLE Images to High Resolution Computer Tomography and Morphologic Data as a Measure of Specificity and Sensitivity of the Method

Time: up to one year

---

Primary Outcomes

Measure: occurrence of severe cardiac arrhythmia: torsade de pointes and cardiac arrest or sudden death

Time: 30 days after admission in ICU

---

Secondary Outcomes

Description: QTc (corrected QT interval) > 500 ms and ΔQTc > 60 ms

Measure: assessment of QTc interval prolongation during the treatment period compared to baseline ECG

Time: daily

---

Primary Outcomes

Description: A seven-category ordinal scale consisting of: 1. Death; 2. hospitalized, on invasive mechanical ventilation; 3. hospitalized, on non-invasive ventilation; 4. hospitalized, requiring supplemental oxygen; 5. hospitalized not requiring supplemental oxygen; 6. hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care. 7 Not hospitalized

Measure: Outcome 30 days after ICU admission

Time: 30 days after admission

---

Primary Outcomes

Description: Feasibility will be determined by the following measures: Able to recruit >30% of eligible patients approached Complete early EMDR intervention programme in 75% or more of trial participants randomised to intervention. Protocol adherence Assignment of causality of serious events will be assessed by the chief investigator. Events attributable to trial procedures will be reviewed by trial management board, study sponsor and the research ethics committee, in order to determine ongoing feasibility. Outcome measures completed in 75% or more of trial participants

Measure: Feasibility of recruitment, intervention adherence, incidence of treatment related adverse events and trial completion to final assessment timepoints

Time: 12 months

---

Secondary Outcomes

Description: The PTSD Checklist-Civilian Version (PCL-C) is a validated, standardised self-reporting questionnaire for PTSD comprising of 17 items that correspond to key PTSD symptoms

Measure: Post-Traumatic stress disorder

Time: 6 months post-hospital discharge

---

Description: Hospital Anxiety and Depression Scale (HADS) is a 14-item, self-reported measure with 7-items relating to symptoms of anxiety and 7-items relating to depression

Measure: Anxiety and depression

Time: 6 months

---

Description: Montreal Cognitive Assessment (MoCA) is a validated tool, used to detect cogntive impairment

Measure: Cognitive function

Time: 6 months post-hospital discharge

---

Description: EQ5D -5L comprises five quality-of-life dimensions; mobility, self-care, usual activities, pain/discomfort andanxiety/depression.

Measure: Health Related Quality of Life

Time: 6 months post-hospital discharge

---

Description: WHODAS 2.0 is a generic assessment tool that produces standarised disability levels and profiles

Measure: Health and disability

Time: 6 months post-hospital discharge

---

Description: Wrist worn physical activity monitoring

Measure: Physical activity

Time: 6 months post-hospital discharge

---

Description: Patient generated subjective global assessment

Measure: Nutritional status

Time: 6 months post-hospital discharge

---

Primary Outcomes

Description: Assessing whether the patients still have dyspnea, one of cardinal symptoms of Covid-19, assessed from the respiratory rate

Measure: Clinical improvement: Presence of dyspnea

Time: 15 days

---

Description: Assessing whether the patients still have productive cough, one of cardinal symptoms of Covid-19, assessed from lung auscultation

Measure: Clinical improvement: presence of sputum

Time: 15 days

---

Description: Assessing the presence of fever from measurement of body temperature checking, assessed on daily basis

Measure: Clinical improvement: fever

Time: 15 days

---

Description: Assessing whether the patients still require ventilation, one of cardinal symptoms of ARDS in Covid-19, assessed from patients' ability during ventilation weaning phase

Measure: Clinical improvement: ventilation status

Time: 15 days

---

Description: Assessing the patients' blood pressure on daily basis

Measure: Clinical improvement: blood pressure

Time: 15 days

---

Description: Assessing the patients' heart rate on daily basis

Measure: Clinical improvement: heart rate

Time: 15 days

---

Description: Assessing the patients' respiratory rate on daily basis

Measure: Clinical improvement: respiratory rate

Time: 15 days

---

Description: Assessing the patients' oxygen saturation on daily basis

Measure: Clinical improvement: oxygen saturation

Time: 15 days

---

Secondary Outcomes

Description: Assessing the changes in total leukocyte upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: General laboratory outcome from leukocyte level

Time: 15 days

---

Description: Assessing the changes in lymphocytes level upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: General laboratory outcome from lymphocytes level

Time: 15 days

---

Description: Assessing the changes in blood pH level upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: General laboratory outcome from blood pH

Time: 15 days

---

Description: Assessing the changes in blood pH level upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: General laboratory outcome from blood level of CO2

Time: 15 days

---

Description: Assessing the changes in blood base excess level upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: General laboratory outcome from blood base excess level

Time: 15 days

---

Description: Assessing the changes in blood oxygen partial pressure upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: General laboratory outcome from blood oxygen partial pressure

Time: 15 days

---

Description: Assessing the changes in blood level of HCO3 upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: General laboratory outcome from blood level of HCO3

Time: 15 days

---

Description: Assessing the changes in blood level of O2 saturation upon MSCs administration, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: General laboratory outcome from blood level of O2 saturation

Time: 15 days

---

Description: Assessing the changes in level of CRP, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: General laboratory outcome from level of CRP

Time: 15 days

---

Description: Assessing the changes in laboratory parameter, consist of SGOT/SGPT (AST/ALT) level, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: General laboratory outcome from level of SGOT/SGPT (AST/ALT)

Time: 15 days

---

Description: Assessing the changes in laboratory parameter, consist of ureum/creatinine level, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: General laboratory outcome from the level of ureum/creatinine level

Time: 15 days

---

Description: Assessing the changes in laboratory parameter, consist of eGFR, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: General laboratory outcome from the level of eGFR

Time: 15 days

---

Description: Assessing the changes in level of sodium, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: General laboratory outcome from the level of sodium

Time: 15 days

---

Description: Assessing the changes in level of potassium, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: General laboratory outcome from the level of potassium

Time: 15 days

---

Description: Assessing the changes in level of chloride, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: General laboratory outcome from the level of chloride

Time: 15 days

---

Description: Assessing the changes in procalcitonin level to assess the anti-inflammatory properties of MSCs, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: Changes in procalcitonin level

Time: 15 days

---

Description: Assessing the changes in albumin level, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: General laboratory outcome from albumin level

Time: 15 days

---

Description: Assessing the changes in total bilirubin level, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: General laboratory outcome from total bilirubin level

Time: 15 days

---

Description: Assessing the changes in D-Dimer to assess the anti-inflammatory properties of MSCs, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: Changes in D-Dimer level

Time: 15 days

---

Description: Assessing the changes in fibrinogen to assess the anti-inflammatory properties of MSCs, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: Changes in fibrinogen level

Time: 15 days

---

Description: Assessing the changes in troponin level to assess the anti-inflammatory properties of MSCs and their effect in cardiac remodelling, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: Cardiac changes from troponin level

Time: 15 days

---

Description: Assessing the changes in NT proBNP to assess the anti-inflammatory properties of MSCs and their effect in cardiac remodelling, assessed prior to and 1st day after implantation, then once every 3 days post implantation

Measure: Cardiac changes from NT proBNP level

Time: 15 days

---

Description: Assessing the changes in leukemia inhibiting factor (LIF) to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation

Measure: Changes in Leukemia Inhibiting Factor

Time: 7 days

---

Description: Assessing the changes in level of IL-6 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation

Measure: Changes in level of IL-6

Time: 7 days

---

Description: Assessing the changes in level of IL-10 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation

Measure: Changes in level of IL-10

Time: 7 days

---

Description: Assessing the changes in vascular endothelial growth factor (VEGF) to assess the effect of growth factors in the MSCs, assessed prior to implantation and on the 7th day post-implantation

Measure: Changes in level of vascular endothelial growth factor (VEGF)

Time: 7 days

---

Description: Assessing the changes in level of ferritin to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation

Measure: Changes in level of ferritin

Time: 7 days

---

Description: Assessing the changes in level of CXCR3 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation

Measure: Changes in level of CXCR3

Time: 7 days

---

Description: Assessing the changes in level of CD4 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation

Measure: Changes in level of CD4

Time: 7 days

---

Description: Assessing the changes in level of CD8 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation

Measure: Changes in level of CD8

Time: 7 days

---

Description: Assessing the changes in CD56 to assess the anti-inflammatory properties of MSCs, assessed prior to implantation and on the 7th day post-implantation

Measure: Changes in level of CD56

Time: 7 days

---

Description: Assessing the changes in radiology examination (Chest X-Ray/CT Scan) for any increased in lung infiltration or ground glass opacity, assessed prior to implantation and once every 3 days post-implantation

Measure: Radiologic Improvement from Chest X-Ray/CT Scan

Time: 15 days

---

Primary Outcomes

Description: all-cause

Measure: 30-day mortality

Time: 30 days

---

Secondary Outcomes

Description: all cause

Measure: ICU mortality

Time: 30 days

---

Primary Outcomes

Description: measurements of arterial blood gas

Measure: clinical characteristics

Time: 48 hours

---

Primary Outcomes

Description: Change from baseline in total daily dose of primary sedative on Day 3

Measure: Primary sedative dose change

Time: 24 hours prior to enrollment to Day 3 of the study (60-84hrs after enrollment)

---

Secondary Outcomes

Description: Proportion of measured sedation scores within target range (to be defined a priori by treating team): Richmond Agitation-Sedation Scale and/or the Sedation-Agitation Scale

Measure: Sedation scores

Time: Daily upon enrollment until study completion (discharge from ICU, 28 days, or death - whichever is first)

---

Description: Proportion of participants whose sedative dose on day 3 are below a minimum level (propofol <0.5mg/kg/h or midazolam <1.9mg/h)

Measure: Primary sedative dose

Time: Day 3 of study (60-84hrs after enrollment)

---

Description: Change from baseline in total daily dose of all sedatives (in mg of midazolam equivalents) on Day 3

Measure: Total sedative daily dose change

Time: 24 hours prior to enrollment to Day 3 of the study (60-84hrs after enrollment)

---

Description: Change from baseline in total daily dose of all opioids (in mcg of fentanyl equivalents) on Day 3

Measure: Total opioid daily dose change

Time: 24 hours prior to enrollment to Day 3 of the study (60-84hrs after enrollment)

---

Description: Incidence of bradycardia (HR <50 or requiring intervention)

Measure: Adverse event - bradycardia

Time: Daily from study enrollment until study completion (discharge from ICU, 28 days, or death - whichever is first)

---

Description: Incidence of hypotension (MAP <60 requiring new vasopressor agents or an increase of >0.1 mcg/kg/min of norepinephrine or epinephrine persisting more than 2h after reducing sedative doses)

Measure: Adverse event - hypotension

Time: Daily from study enrollment until study completion (discharge from ICU, 28 days, or death - whichever is first)

---

Description: Incidence of clinically-important bronchospasm requiring a change in mechanical ventilation settings

Measure: Adverse event - bronchospasm

Time: Daily from study enrollment until study completion (discharge from ICU, 28 days, or death - whichever is first)

---

Description: Incidence of new ECG conduction delays

Measure: Adverse event - ECG conduction delays

Time: Daily from study enrollment until study completion (discharge from ICU, 28 days, or death - whichever is first)

---

Other Outcomes

Description: Total number of days of propranolol use

Measure: Duration of propranolol use

Time: Daily from enrollment to study withdrawal/completion (last day of propranolol dose given; discharge from ICU, 28 days, or death - whichever is first)

---

Description: Mean propranolol dose on day 3

Measure: Propranolol dose

Time: Day 3 of study (60-84hrs after enrollment)

---

Description: Mean number of ventilator-free days in first 30 days of hospital intensive care unit admission

Measure: Ventilator-free days

Time: Day 1 of admission to the intensive care unit until 30 days, discharge from intensive care, or death (whichever is first)

---

Description: Mean number of delirium-free days in first 30 days of hospital intensive care unit admission, measured using the Intensive Care Delirium Screening Checklist

Measure: Delirium-free days

Time: Day 1 of admission to the intensive care unit until 30 days, discharge from intensive care, or death (whichever is first)

---

Description: Mean length of stay in hospital

Measure: Hospital Length of Stay

Time: Day 1 of hospital admission until hospital discharge date or date of death (whichever is first)

---

Description: Mean length of stay in the intensive care unit

Measure: Intensive Care Unit Length of Stay

Time: Day 1 of intensive care unit admission until discharge date from intensive care unit or date of death (whichever is first)

---

Description: Mortality rate among participants while in hospital

Measure: Hospital Mortality

Time: Upon study completion (after all 108 participants have completed the study, estimated at 6 months) and after 50 patients have been enrolled (estimated at 3 months)

---

Description: Mean cost of sedative medication used in the intensive care unit among the intervention and control arms

Measure: Direct Costs

Time: Upon study completion (after all 108 participants have completed the study, estimated at 6 months)

---

Primary Outcomes

Description: Comparison of lesions from patients that are neurologically affected to non-affected individuals in terms of CNS involvement to describe encephalitic changes due to COVID-19 infection.

Measure: MRI imaging data

Time: Project duration for each patient takes 1 hour for the MRI at baseline

---

Description: Description of proteomic biomarkers (CSF and Plasma) in comparison with control reference sample.

Measure: Proteomic analysis

Time: 10 minutes for blood draw at baseline

---

Description: Mass cytometry will be performed form peripheral blood mononuclear cells to count cell population frequency.

Measure: Peripheral blood leukocyte Cytof Mass Cytometry Analysis for cell population frequency

Time: 10 minutes for blood draw at baseline

---

Description: In situ distribution assessment of marker expression (CD147 protein, ACE2 protein, Transmembrane protease serine subtype 2 (TMPRSS2))

Measure: CODEX (high dimensional microscopy) workflow analysis of defined regions on brain autopsy specimens

Time: at baseline

---

Primary Outcomes

Description: The distribution of ventilation measured by EIT at PEEP 5 and 15.

Measure: The distribution of ventilation

Time: Through study completion (up to 24 hours)

---

Secondary Outcomes

Description: The changes in dependent and non-dependent silent spaces measured by EIT in PEEP 5 and 15.

Measure: Silent spaces

Time: Through study completion (up to 24 hours)

---

Description: Respiratory system compliance in PEEP 5 and 15.

Measure: Respiratory system compliance

Time: Through study completion (up to 24 hours)

---

Description: Oxygenation in PEEP 5 and 15.

Measure: Oxygenation

Time: Through study completion (up to 24 hours)

---

Description: Dead space ventilation ratio in PEEP 5 and 15.

Measure: Dead space ventilation ratio

Time: Through study completion (up to 24 hours)

---

Primary Outcomes

Description: Mortality 90 days post randomization

Measure: 90 day-all cause mortality

Time: 90 days

---

Secondary Outcomes

Description: use of vasopressor/inotropic support, invasive mechanical ventilation and/or renal replacement therapy

Measure: Days alive at day 90 without life support

Time: 90 days

---

Description: 90 day survival after randomization

Measure: Days alive and out of hospital at day 90

Time: 90 days

---

Description: Any symptoms of bacteremia

Measure: Bacteremia until 2 days of ICU stay

Time: until 2 days post ICU.

---

Description: anytime during ICU stay

Measure: New or progression of Skin Pressure Ulcers

Time: ICU stay

---

Description: SARC-F screen for sarcopenia and EuroQoL

Measure: Functional assessment at day 90

Time: Day 90

---

Other Outcomes

Description: New episode of stage 2 or higher AKI by KDIGO criteria; 2. Pneumonia defined as episodes of newly confirmed pneumonia according to the modified CDC criteria; 3. Grade IV Acute Gastrointestinal injury (AGI)

Measure: Safety outcomes during ICU stay

Time: ICU stay

---

Description: Feeding tolerance; Diarrhoea; Refeeding syndrome

Measure: Minor safety outcomes during ICU stay

Time: ICU stay

---

Primary Outcomes

Description: Comparison between the duration and number of tries needed to intubate a patient, or achieve ROSC in patients requiring cardiopulmonary resuscitation, in resuscitation area and negative pressure isolation rooms.

Measure: The success rate of tracheal intubation between resuscitation area and negative pressure isolation rooms

Time: 6 months

---

Description: Comparison between the survival rate of patients who were intubated in the resuscitation area and negative pressure isolation rooms, taking into account the duration of hospital stay, respiratory status (successful extubation, post tracheostomy, etc), and neurological state (using the Glasgow coma score, cerebral performance categories, and overall performance categories) upon discharge from the hospital.

Measure: The patient prognosis between resuscitation area and negative pressure isolation rooms

Time: 6 months

---

Description: The medical staff involved in the intubation and/or cardiopulmonary resuscitation procedures will be asked to voluntarily fill up a survey form to determine their level of psychological stress. They will also be followed up within 14 days post exposure for covid-19 symptoms and undergo testing and quarantine if needed.

Measure: The physical and psychological stress of medical staff

Time: 14 days

---

Description: The facilities in both resuscitation area and negative pressure isolation rooms will be sampled and compared for the presence of the coronavirus after each intubation or cardiopulmonary resuscitation procedure.

Measure: The amount of environmental contamination between resuscitation area and negative pressure isolation rooms

Time: 14 days

---

Primary Outcomes

Description: In-hospital mortality after administration of ABO compatible convalescent plasma or indication (but not plasmapheresis for absence of compatible convalescent plasma) for comparison group

Measure: In-hospital mortality

Time: 30 days

---

Secondary Outcomes

Description: Number of patients with medical indication of hemodialysis or peritoneal dialysis for acute renal failure

Measure: Incidence of renal replacement therapy

Time: 30 days

---

Description: Number of patients with Alergic reaction, Anaphylaxis, Severe thrombotic events, Transfusion-related acute lung injury (TRALI)], Transfusion-associated circulatory overload (TACO)], Antibody-Dependent Enhancement (ADE)]

Measure: Incidece of adverse events

Time: During tranfusion until 24 hours after.

---

Primary Outcomes

Description: The median ventilator-free days will be calculated as calendar days with no ventilator support to day 28 . Participants who die before day 28 are assigned zero free days.

Measure: Ventilator-Free Days

Time: Up to Day 28

---

Secondary Outcomes

Description: From Intubation to extubation date and off Mechanical Ventilation or until ICU discharge, death, or 28 days whichever occurs first.

Measure: Median duration of ventilation

Time: Up to Day 28

---

Description: Ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2)

Measure: Median change in the PaO2/FiO2

Time: Up to Day 28

---

Description: The median vasopressor-free days will be calculated as calendar days with no vasopressor support to day 28. Participants who die before day 28 are assigned zero free days.

Measure: Vasopressor-Free days

Time: Up to Day 28

---

Description: To compare ICU LOS

Measure: Duration of ICU Stay

Time: Up to 28 days

---

Description: To compare hospital LOS

Measure: Duration of Hospital Stay

Time: Up to 28 days

---

Description: Death that occurs during 28 days

Measure: Mortality Rate

Time: Up to Day 28

---

Description: adverse events that occurs during 28 days

Measure: Percentage of participants with adverse events [transaminitis, hyperglycemia]

Time: Up to 28 days

---

Description: Concentration of inflammatory markers

Measure: Concentration of Ferritin, IL6, D dimer, fibrinogen, C-reactive protein (CRP), Lactate dehydrogenase (LDH) and absolute lymphocyte count and their correlation with the effectiveness of the treatment

Time: Up to 28 days

---

Measure: Rate of superinfection (bacterial, viral, invasive fungal infections)

Time: Up to 28 days

---

Measure: Time to the first COVID 19 test negative

Time: Up to 28 days

---

Primary Outcomes

Description: Time to achieve durable change in COVID-19 to ordinal level 4 or less for at least 48 hours

Measure: Identify agents that will result in substantial improvements to the clinical condition of participants with COVID-19

Time: Up to 28 days

---

Secondary Outcomes

Description: % of COVID-19 level 5 who never progress to COVID-19 level 6/7

Measure: Improvement in disease severity

Time: Up to 60 days

---

Description: Ventilator-free Days

Measure: Health care utilization

Time: Up to 60 days

---

Description: Total grade 3 or higher AEs by arm and total number of patients with grade 3 or higher AEs by arm. ● Total grade 3 or higher AEs of special interest by arm and total number of patients with grade 3 or higher AEs of special interest by arms (based upon lab assessments)

Measure: Frequency of serious AEs

Time: Up to 60 days

---

Description: Mortality at 28 days after study enrollment

Measure: Mortality

Time: Up to 28 days

---

Primary Outcomes

Description: death or recovery

Measure: survival

Time: 28 days

---

Secondary Outcomes

Description: duration in days

Measure: duration of hospitalization

Time: 28 days

---

Description: duration in days to normalize symptoms and laboratory parameters

Measure: Time to resolution of cytokine release storm

Time: 28 days

---

Description: Time in days to turn PCR negative

Measure: Time of viral clearance

Time: 45 days

---

Description: incidence of Post Covid lung fibrosis

Measure: Complications

Time: 90 days

---

Primary Outcomes

Description: sub scores of HADS questionnaire >7

Measure: occurence of anxiety and depression

Time: one month after ICU discharge

---

Description: sub scores of HADS questionnaire >7

Measure: occurence of anxiety and depression

Time: three months after ICU discharge

---

Description: IES-R score > 22

Measure: occurence of acute stress

Time: one month after ICU discharge

---

Description: IES-R score > 36

Measure: occurence of post-traumatic stress disorder

Time: three months after ICU discharge

---

Description: assessed using the EQ-5D questionnaire

Measure: quality of life

Time: one month after ICU discharge

---

Description: assessed using the EQ-5D questionnaire

Measure: quality of life

Time: three months after ICU discharge

---

Primary Outcomes

Description: The primary prognostic outcome will be the maximum SOFA score during ICU stay. The daily maximum SOFA score will be considered up to a maximum of 90 days.

Measure: Severity of organ failure observed during ICU stay

Time: During ICU admission with a maximum of 90 days

---

Secondary Outcomes

Description: Patients will be evaluated by questionnaires at 6 and 12 months follow-up.Follow-up data will include survival status and data on quality of life. Patients psychological functioning will be evaluated using the Short Form 20 and the Hospital Anxiety and Depression Scale (HADS). Patients physical functioning data will be measured by the KATZ ADL index and the Clinical Frailty Score. In addition, the Euro-Qol (EQ-5d) will be used. Social functioning data will be collected using the General Functioning 6 scale (GF6) which is a subscale of the GF12 and is a quick and effective tool to assess the overall functioning of families. Data will be collected from both patients and family members. Return to work will only be evaluated at 12 months follow-up by 4 extra questions concerning the patients return to work. In addition we will explore and validate extended modifications on the total and domain level of the organ failure assessment score (SOFA+).

Measure: Follow-up Quality of life data

Time: 6 and 12 months after ICU discharge

---

Primary Outcomes

Description: PCL - 5 (Post-Traumatic Stress Disorder Checklist Scale, version DSM-5)

Measure: Post-Traumatic Stress Disorder

Time: 3-6 month after the Covid-19 outbreak

---

Secondary Outcomes

Description: HADS scale (Hospital Anxiety and Depression Scale)

Measure: anxiety and depression

Time: 3-6 month after the Covid-19 outbreak

---

Description: Score MBI (Burn out syndrome)

Measure: Burn out

Time: 3-6 month after the Covid-19 outbreak

---

Primary Outcomes

Description: Clinical cranial nerves anomalies using validated scale (BRASS score- ranges from 0 to 7 - ) in deeply sedated patient (RASS <-3)

Measure: Brainstem dysfunction prevalence

Time: At inclusion or in patients with neuromuscular blockade 12h-72h following neuromuscular blocking agent cessation

---

Secondary Outcomes

Description: Clinical cranial nerves anomalies using validated scale (BRASS score)

Measure: Brainstem dysfunction prevalence after sedation weaning

Time: Day 4 to day 7 after sedation weaning

---

Description: Analysis of the sympathico-parasympathetic ratio (using spectral analysis of the EKG signal) according to the presence or absence of brainstem dysfunction and its severity

Measure: Link between brainstem dysfunction and clinical dysautonomia

Time: At inclusion or in patients with neuromuscular blockade 12h-72h following neuromuscular blocking agent cessationn

---

Description: Analysis of the sympathico-parasympathetic ratio (using spectral analysis of the EKG signal) according to the presence or absence of brainstem dysfunction and its severity

Measure: Link between brainstem dysfunction and clinical dysautonomia after sedation weaning

Time: 4 to 7 days after sedation weaning

---

Description: EEG power in delta, theta, alpha, beta and gamma frequency bands according to the presence or absence of brainstem dysfunction and its severity

Measure: Characterization of brainstem dysfunction in COVID-19 patients: EEG power

Time: At inclusion or in patients with neuromuscular blockade 12h-72h following neuromuscular blocking agent cessation

---

Description: EEG power in delta, theta, alpha, beta and gamma frequency bands according to the presence or absence of brainstem dysfunction and its severity

Measure: Characterization of brainstem dysfunction in COVID-19 patients: EEG power after sedation weaning

Time: Day 4 to day 7 after sedation weaning.

---

Description: EEG functional connectivity using weighted Symbolic Mutual Information and weighted Phase Lag Index according to the presence or absence of brainstem dysfunction and its severity

Measure: Characterization of brainstem dysfunction in COVID-19 patients: EEG functional connectivity

Time: At inclusion or in patients with neuromuscular blockade 12h-72h following neuromuscular blocking agent cessation

---

Description: EEG functional connectivity using weighted Symbolic Mutual Information and weighted Phase Lag Index according to the presence or absence of brainstem dysfunction and its severity

Measure: Characterization of brainstem dysfunction in COVID-19 patients: EEG functional connectivity, after sedation weaning

Time: Day 4 to day 7 after sedation weaning.

---

Description: EEG complexity using Kolmogorov complexity and permutation entropy according to the presence or absence of brainstem dysfunction and its severity

Measure: Characterization of brainstem dysfunction in COVID-19 patients: EEG complexity

Time: At inclusion or in patients with neuromuscular blockade 12h-72h following neuromuscular blocking agent cessation

---

Description: EEG complexity using Kolmogorov complexity and permutation entropy according to the presence or absence of brainstem dysfunction and its severity

Measure: Characterization of brainstem dysfunction in COVID-19 patients: EEG complexity after sedation weaning

Time: Day 4 to day 7 after sedation weaning.

---

Description: Multivariate classification of the presence or absence of brainstem dysfunction using support vector machine and extra-trees algorithm based on the EEG derived quantitative features presented above

Measure: Characterization of brainstem dysfunction in COVID-19 patients: multivariate classification

Time: At inclusion or in patients with neuromuscular blockade 12h-72h following neuromuscular blocking agent cessation

---

Description: Multivariate classification of the presence or absence of brainstem dysfunction using support vector machine and extra-trees algorithm based on the EEG derived quantitative features presented above

Measure: Characterization of brainstem dysfunction in COVID-19 patients: multivariate classification after sedation weaning

Time: Day 4 to day 7 after sedation weaning.

---

Measure: Duration of mechanical ventilation

Time: at ICU discharge up to 28 days

---

Measure: Mortality

Time: at ICU discharge up to 28 days

---

Measure: Duration of hospitalisation

Time: at hospital discharge up to 90 days

---

Measure: Duration of coma, disturbance of consciousness, delirium

Time: at ICU discharge up to 28 days

---

Description: Using validated functional scale modified Rankin (mRankin) for independence assessment (mRankin ranges from 0 to 6 with higher scores indicating more severe disability)

Measure: Neurological functional evolution with mRankin

Time: 90 days after inclusion

---

Description: Using validated functional scale Glasgow Outcome Scale Extended (GOSE) for independence assessment (GOSE ranges from 1 to 8 with higher scores indicating less severe disability outcome)

Measure: Neurological functional evolution with GOSE

Time: 90 days after inclusion

---

Primary Outcomes

Description: All-cause mortality at day 28, defined as the comparison of proportions of patients death for any cause at day 28 from randomization.

Measure: All-cause mortality at day 28

Time: Day 28 from randomization

---

Secondary Outcomes

Description: All-cause mortality at ICU discharge, defined as the comparison of proportions of patients death for any cause at ICU discharge.

Measure: All-cause mortality at ICU discharge

Time: from randomization to ICU discharge, censored at day 30

---

Description: All-cause mortality at Hospital discharge, defined as the comparison of proportions of patients death for any cause at hospital discharge

Measure: All-cause mortality at hospital discharge

Time: from randomization to ICU discharge, censored at day 90

---

Description: Occurrence of rescue administration of high-dose steroids or immune-modulatory drugs

Measure: Need of rescue administration of high-dose steroids or immune-modulatory drugs

Time: from randomization to ICU discharge, censored at day 28

---

Description: Occurrence of new organ dysfunction during ICU stay. Organ dysfunction is defined as a Sequential Organ Failure Assessment (SOFA) score ≥3 for the corresponding organ occurring after randomization.

Measure: New organ dysfunction during ICU stay

Time: From randomization to ICU discharge, censored at day 28

---

Description: Grade of organ dysfunction during ICU stay, grade of dysfunction is measured with Sequential Organ Failure Assessment (SOFA) score daily from randomization to day 28 or ICU discharge.

Measure: Grade of organ dysfunction during ICU stay

Time: From randomization to ICU discharge, censored at day 28

---

Description: Total number of days between ICU discharge and day 28. If death occurs during the ICU stay before day 28 the ICU free days calculation will be 0. The ICU readmission before day 28 after randomization will be considered.

Measure: ICU free days at day 28

Time: From randomization to day 28

---

Description: Occurrence of new infections including bacterial infections, fungal infections by Candida, Aspergillus, and viral reactivations including Adenovirus, Herpes Virus e Cytomegalovirus

Measure: Occurrence of new infections

Time: from randomization to day 28

---

Description: Total number of days that patient is alive and free of ventilation between randomisation and day 28. Ventilation is considered as positive pressure ventilation, either invasive or non-invasive. Periods of assisted breathing lasting less than 24 hours for surgical procedures will not count against the ventilation free days calculation.

Measure: Ventilation free days at day 28

Time: From randomization to day 28, censored at hospital discharge

---

Description: Total number of days that patient is alive and free of vasopressors between randomisation and day 28.

Measure: Vasopressors free-days at day 28

Time: From randomization to day 28, censored at hospital discharge

---

Description: Occurrence of switch from non-invasive to invasive mechanical ventilation

Measure: Switch from non-invasive to invasive mechanical ventilation

Time: from randomization to ICU discharge, censored at day 28

---

Description: Total number of hours from start of non-invasive to invasive ventilation to switch to invasive ventilation

Measure: Delay from start of non-invasive ventilation to switch to invasive ventilation

Time: from randomization to ICU discharge, censored at day 28

---

Description: Adverse events occurred from randomization to day 28. Events that are part of the natural history of the primary disease process or expected complications of critical illness will not be reported as adverse events.

Measure: Occurrence of protocol related adverse events

Time: From randomization to day 28

---

Description: Occurrence of objectively confirmed venous thromboembolism, stroke or myocardial infarction

Measure: Occurrence of venous thromboembolism, stroke or myocardial infarction

Time: from randomization to ICU discharge, censored at day 28

---

Description: Occurrence of major bleeding defined as transfusion of 2 or more units of packed red blood cells in a day, bleeding that occurs in at least one of the following critical sites [intracranial, intraspinal, intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal], bleeding that necessitates surgical intervention and bleeding that is fatal (defined as a bleeding event that was the primary cause of death or contributed directly to death)

Measure: Occurrence of major bleeding (safety end point)

Time: from randomization to ICU discharge, censored at day 28

---

Description: Occurrence of clinically relevant non-major bleeding defined ad acute clinically overt bleeding that does not meet the criteria for major and consists of any bleeding compromising hemodynamic; spontaneous hematoma larger than 25 cm2, or 100 cm2, intramuscular hematoma documented by ultrasonography, haematuria that was macroscopic and was spontaneous or lasted for more than 24 hours after invasive procedures; haemoptysis, hematemesis or spontaneous rectal bleeding requiring endoscopy or other medical intervention or any other bleeding requiring temporary cessation of a study drug.

Measure: Occurrence of clinically relevant non-major bleeding (safety end point)

Time: from randomization to ICU discharge, censored at day 28

---

Other Outcomes

Description: Mean arterial pressure will be measured in millimeters of mercury

Measure: Mean arterial pressure

Time: Daily from inclusion until ICU discharge, censored day 28

---

Description: hearth rate will be measured in beats per minute

Measure: hearth rate

Time: Daily from inclusion until ICU discharge, censored day 28

---

Description: respiratory rate will be measured in breaths per minute

Measure: respiratory rate

Time: Daily from inclusion until ICU discharge, censored day 28

---

Description: diuresis will be measured daily in milliliters of urine output in the previous 24 hours

Measure: diuresis

Time: Daily from inclusion until ICU discharge, censored day 28

---

Description: systemic body temperature will be measured in celsius degrees

Measure: systemic body temperature

Time: Daily from inclusion until ICU discharge, censored day 28

---

Description: fluid balance will be measured in milliliters of fluids input and output in the previous 24 hours

Measure: fluid balance

Time: Daily from inclusion until ICU discharge, censored day 28

---

Description: Haemoglobin will be measured in mg/dl

Measure: Haemoglobin concentration

Time: Daily from inclusion to ICU discharge (censored at day 28)

---

Description: platelets count will be measured in U 10^3/mm^3

Measure: platelets count

Time: Daily from inclusion to ICU discharge (censored at day 28)

---

Description: white blood cells count will be measured in U per 10^9/L

Measure: white blood cells count

Time: Daily from inclusion to ICU discharge (censored at day 28)

---

Description: troponin will be measured in µg/L

Measure: troponin

Time: Daily from inclusion to ICU discharge (censored at day 28)

---

Description: coagulative function will be measured with parameters INR, PT, aPTT

Measure: coagulative function

Time: Daily from inclusion to ICU discharge (censored at day 28)

---

Description: D-dimer will be measured in µg/ml

Measure: D-dimer

Time: Daily from inclusion to ICU discharge (censored at day 28)

---

Description: anti-thrombin will be measured as a percentage

Measure: anti-thrombin

Time: Daily from inclusion to ICU discharge (censored at day 28)

---

Description: liver function will be assessed through measurement of AST, ALT in U/L

Measure: Liver function

Time: Daily from inclusion to ICU discharge (censored at day 28)

---

Description: Bilirubin will be measured in mg/dL

Measure: Bilirubin

Time: Daily from inclusion to ICU discharge (censored at day 28)

---

Description: Creatinine will be measured in mg/dL

Measure: Creatinine

Time: Daily from inclusion to ICU discharge (censored at day 28)

---

Description: Blood cells count will be measured in Units per x 10^9/L of blood

Measure: Blood cells count

Time: daily from inclusion to ICU discharge (censored at day 28)

---

Description: C-reactive protein (CRP) will be measured in mg/dl

Measure: C-reactive protein (CRP)

Time: daily from inclusion to ICU discharge (censored at day 28)

---

Description: procalcitonin(PCT) wiull be measured in ng/ml

Measure: procalcitonin(PCT)

Time: daily from inclusion to ICU discharge (censored at day 28)

---

Description: interleukin 6 (IL-6) will be measured in pg/ml

Measure: interleukin 6 (IL-6)

Time: daily from inclusion to ICU discharge (censored at day 28)

---

Description: Ventilation mode will be cathegorized in spontaneous breathing, invasive or non invasive ventilation

Measure: Ventilation mode

Time: Daily from inclusion to ICU discharge (censored at day 28)

---

Description: inspired oxygen fraction will be measured in percentage of oxygen in inspired air

Measure: inspired oxygen fraction

Time: Daily from inclusion to ICU discharge (censored at day 28)

---

Description: Gas exchanges will be assessed by measurement of PaO2, PaCO2 in mmHg by arterial blood gas analysis

Measure: Gas exchanges

Time: Daily from inclusion to ICU discharge (censored at day 28)

---

Description: lactates will be measured in mMol/L

Measure: lactates

Time: Daily from inclusion to ICU discharge (censored at day 28)

---

Description: pH will be measured in pH scale

Measure: pH

Time: Daily from inclusion to ICU discharge (censored at day 28)

---

Description: oxygen saturation in blood will be measured in arterial and venous samples in percentage values

Measure: oxygen saturation in blood

Time: Daily from inclusion to ICU discharge (censored at day 28)

---

Description: New blood, respiratory and urinary-tract infections will be recorded

Measure: New infections

Time: From randomization to day 28

---

Description: Viral reactivation measured by CMV DNA titres will be recorded.

Measure: Viral reactivation

Time: From randomization to day 28

---

Description: Need of new renal replacement therapy (intermittent haemodialysis or continuous veno-venous hemofiltration) will be recorded.

Measure: Need of new renal replacement therapy

Time: from randomization to day 28

---

Description: Adjunctive treatment such as pronation cycles, Nitric Oxide or ECMO will be recorded

Measure: Adjunctive treatments

Time: from randomization to ICU discharge (censored at day 28);

---

Primary Outcomes

Description: Number of days patient found to have delirium using the Confusion Assessment Method for the ICU (CAM-ICU)

Measure: Duration of delirium

Time: From the date of admission to the Intensive Care Unit (ICU) until discharge from the ICU or death, whichever came first, up to 12 months.

---

Secondary Outcomes

Description: CAM-ICU

Measure: Incidence of delirium

Time: From the date of admission to the Intensive Care Unit (ICU) until discharge from the ICU or death, whichever came first, up to 12 months.

---

Description: Days

Measure: Length of critical care stay

Time: From the date of admission to the ICU until discharge from the ICU or death, whichever came first, up to 12 months.

---

Description: Days

Measure: Length of hospital stay

Time: From the date of admission to the hospital until discharge from the hospital or death, whichever came first, up to 12 months.

---

Measure: Doses of specified drugs during ICU admission

Time: From the date of admission to the ICU until discharge from the ICU or death, whichever came first, up to 12 months.

---

Description: Days

Measure: Length of time ventilated

Time: From the date of admission to the ICU until discharge from the ICU or death, whichever came first, up to 12 months.

---

Measure: Mortality

Time: 6 months

---

Other Outcomes

Description: Semi structured interviews

Measure: Exploring the experiences of patients, relatives and staff of the visitation restrictions during the COVID-19 pandemic

Time: 18 months

---

Primary Outcomes

Description: Secondary infection will include healthcare associated infections as well as sepsis, and septic shock

Measure: Number of patient with secondary infection

Time: 2 weeks

---

Secondary Outcomes

Description: mortality

Measure: Number of patients dying

Time: 7-day, 28-day and 60-day

---

Description: Description of the variable clinical phenotypes of COVID-19 in adults and children. This include COVID-19 respiratory failure, acute myocarditis and multi system inflammatory syndrome in children (MIS-C)

Measure: Description of clinical phenotypes

Time: through study completion, an average of 4 weeks

---

Description: Measure circulating cell phenotypes (relative percentage and monocyte classII histocompatibility complex

Measure: Description of immunological phenotypes

Time: through study completion, an average of 4 weeks

---

Primary Outcomes

Measure: 28 day all-cause mortality

Time: 28 days

---

Primary Outcomes

Description: Determine if the WFIT Program is cost-effective by measuring INB in the intervention arm (WFIT program) compared to an attention control arm. Incremental net benefit ($) = [Change in Quality of Adjusted Life Year (QALY) *100,000] - [Change in health care spending] INB is defined as the difference between change in quality of life evaluated at monetary valuation of 1 QALY (currently $100,000) and change in health care spending. Using this measure, even if WFIT does not affect patient quality of life, then INB will equal the reduction in health care spending.

Measure: Incremental Net Benefit (INB) Cost Effectiveness

Time: 6 months post hospital discharge

---

Secondary Outcomes

Description: evaluated monthly through to 6 months.

Measure: Number of Emergency Room (ER) Visits

Time: 6 months post hospital discharge

---

Description: Readmissions to a hospital evaluated monthly through to 6 months.

Measure: Number of hospital readmissions

Time: 6 months post hospital discharge

---

Measure: Mortality Rate

Time: Through 6 months post hospital discharge

---

Description: Satisfaction with care evaluated monthly through to 6 months. Scores range from 18-90 with a higher score denoting more satisfaction.

Measure: Patient Satisfaction Questionnaire 18 (PSQ-18)

Time: 6 months post hospital discharge

---

Description: Quality of life evaluated monthly through to 6 months. Scores range from 5-25 with higher scores indicating poorer health status.

Measure: Euro Quality of Life, 5 Dimension, 5 Level (EQ-5D-5L) Questionnaire

Time: 6 months post hospital discharge

---

Primary Outcomes

Description: Define the possible clusters of critically ill patients - treated with extracorporeal blood purification therapies worldwide - that are homogeneous regarding both clinical and treatment characteristics thanks all the treatment and baseline clinical variables extracted from the patient Case Report Forms (CRFs).

Measure: Define the possible clusters of critically ill patients

Time: 10 days after Extracorporeal Blood Purification Therapy (EBPT) initiation

---

Secondary Outcomes

Description: Define as ≥ 20% decrease in Vasoactive-Inotropic Score (VIS) at 48 hours with respect to baseline to assess the correlation between cluster membership and positive short-term outcome (i.e. an improvement in hemodynamic stability and inflammatory status).

Measure: To assess the correlation between cluster membership and positive short-term outcome.

Time: 48 hours after EBPT initiation

---

Description: To assess the correlation between cluster membership and positive long-term outcome, defined as patient survival at ICU discharge.

Measure: To assess the correlation between cluster membership and positive long-term outcome.

Time: 10 days after EBPT initiation

---

Description: To assess the correlation between positive short-term outcome and changes from baseline in clinical parameters and all treatment at 12 and 24 hours (as from the patient CRFs).

Measure: To assess the correlation between positive short-term outcome and changes from baseline.

Time: 24 hours after EBPT initiation

---

Description: Timing of initiation of a specific Extracorporeal Blood Purification (EBT) treatment will be described.

Measure: To describe the clinical circumstances under which clinicians opt for specific techniques of extracorporeal blood purification therapy worldwide.

Time: 10 days after EBPT initiation

---

Description: Absolute and relative frequencies of those clinical variables relevant to the application of a specific EBP treatment will be described.

Measure: To describe the clinical circumstances under which clinicians opt for specific techniques of extracorporeal blood purification therapy worldwide in terms of absolute and relative frequencies of clinical variables.

Time: 10 days after EBPT initiation

---

Description: EBP utilization will be described in terms of cumulative incidence among all the enrolled patients from all participating centers

Measure: To describe EBP utilization rates in intensive care units worldwide.

Time: 10 days after EBPT initiation

---

Description: EBP utilization will be described in terms of of yearly absolute frequencies and cumulative incidence among all the enrolled patients from all participating centers.

Measure: To describe EBP utilization rates in intensive care units worldwide in terms of absolute frequency

Time: 10 days after EBPT initiation

---

Description: Utilization of Continuous Renal Replacement Therapy(CRRT), Intermittent Hemodialysis (IHD), and Hybrid Renal Replacement Therapies as well as of the different membranes will be described in terms of relative frequencies.

Measure: To describe EBP in terms of relative frequencies for treatment type in intensive care units worldwide.

Time: 10 days after EBPT initiation

---

Description: For each EBP treatment will be described absolute and relative frequency of chosen anticoagulation strategy

Measure: To describe EBP in terms of technical characteristics in intensive care units worldwide.

Time: 10 days after EBPT initiation

---

Description: For each EBP treatment will be described average flow rates (variables: blood flow rate, dialysate flow rate, replacement flow rate pre-filter, replacement flow rate post-filter, effluent flow rate, net ultrafiltration rate).

Measure: To describe EBP in terms of average flow rates in intensive care units worldwide.

Time: 10 days after EBPT initiation

---

Primary Outcomes

Measure: time to complete intubation

Time: immediately after intervention

---

Secondary Outcomes

Description: Team Emergency Assessment Measure, minimal score is 0 and the maximal score is 4. Higher score means a better outcome.

Measure: teamwork score

Time: immediately after intervention

---

Measure: exposure time in isolation rooms

Time: immediately after intervention

---

Primary Outcomes

Description: Medical Research Council (MRC)-sum score evaluates global muscle strength, and it has been proposed in PICS syndrome post-COVID-19. Manual strength of six muscle groups (shoulder abduction, elbow flexion, wrist extension, hip flexion, knee extension, and ankle dorsiflexion) is evaluated on both sides using the MRC-sumscore. The summation of scores gives MRC-sumscore, ranging from 0 to 60. This score reliably identifies significant weakness (< 48) and even better in severe weakness (<36).

Measure: Medical Research Council (MRC) sum score

Time: 3 months

---

Description: Medical Research Council (MRC)-sum score evaluates global muscle strength, and it has been proposed in PICS syndrome post-COVID-19. Manual strength of six muscle groups (shoulder abduction, elbow flexion, wrist extension, hip flexion, knee extension, and ankle dorsiflexion) is evaluated on both sides using the MRC-sumscore. The summation of scores gives MRC-sumscore, ranging from 0 to 60. This score reliably identifies significant weakness (< 48) and even better in severe weakness (<36).

Measure: Medical Research Council (MRC) sum score

Time: 6 months

---

Description: Medical Research Council (MRC)-sum score evaluates global muscle strength, and it has been proposed in PICS syndrome post-COVID-19. Manual strength of six muscle groups (shoulder abduction, elbow flexion, wrist extension, hip flexion, knee extension, and ankle dorsiflexion) is evaluated on both sides using the MRC-sumscore. The summation of scores gives MRC-sumscore, ranging from 0 to 60. This score reliably identifies significant weakness (< 48) and even better in severe weakness (<36).

Measure: Medical Research Council (MRC) sum score

Time: 12 months

---

Description: Dynamometry will be considered normal if >11Kg in Male and 7.5 kg in Female. Moreover, the researcher will standardized the result as percentage of the predicted normal value (PNV) as follow: <20% PNV; 20%<=PNV< 40%; 40%<=PNV< 60%; 60%<= PNV< 80%, and >=80 PNV. [DOI: 10.1016/j.clnu.2008.04.004]

Measure: Dominand Handgrip Test

Time: 3 months

---

Description: Dynamometry will be considered normal if >11Kg in Male and 7.5 kg in Female. Moreover, the researcher will standardized the result as percentage of the predicted normal value (PNV) as follow: <20% PNV; 20%<=PNV< 40%; 40%<=PNV< 60%; 60%<= PNV< 80%, and >=80 PNV. [DOI: 10.1016/j.clnu.2008.04.004]

Measure: Dominand Handgrip Test

Time: 6 months

---

Description: Dynamometry will be considered normal if >11Kg in Male and 7.5 kg in Female. Moreover, the researcher will standardized the result as percentage of the predicted normal value (PNV) as follow: <20% PNV; 20%<=PNV< 40%; 40%<=PNV< 60%; 60%<= PNV< 80%, and >=80 PNV. [DOI: 10.1016/j.clnu.2008.04.004]

Measure: Dominand Handgrip Test

Time: 12 months

---

Description: Six-minute walking test will be performed in accordance with the America Thoracic Society recommendations and it will be adjusted for age, sex, height, and body weight

Measure: Six Minutes Walking Test

Time: 3 months

---

Description: Six-minute walking test will be performed in accordance with the America Thoracic Society recommendations and it will be adjusted for age, sex, height, and body weight

Measure: Six Minutes Walking Test

Time: 6 months

---

Description: Six-minute walking test will be performed in accordance with the America Thoracic Society recommendations and it will be adjusted for age, sex, height, and body weight

Measure: SIX Minutes Walking Test

Time: 12 months

---

Description: The Fatigue severity score is a nine-item unidimensional questionnaire that measures the severity of fatigue symptoms on a seven-point ordinal scale (maximum score of seven). An FSS ≥36 will be considered as an indicator of fatigue.

Measure: Fatigue Severity Scale (FSS)

Time: 3 months

---

Description: The Fatigue severity score is a nine-item unidimensional questionnaire that measures the severity of fatigue symptoms on a seven-point ordinal scale (maximum score of seven). An FSS ≥36 will be considered as an indicator of fatigue.

Measure: Fatigue Severity Scale (FSS)

Time: 6 months

---

Description: The Fatigue severity score is a nine-item unidimensional questionnaire that measures the severity of fatigue symptoms on a seven-point ordinal scale (maximum score of seven). An FSS ≥36 will be considered as an indicator of fatigue.

Measure: Fatigue Severity Scale (FSS)

Time: 12 months

---

Description: Simplified peroneal nerve test (PENT)wiil be used to diagnose a critical illness polyneuropathy and myopathy; a value <5.26 mV present in both legs was considered as abnormal.

Measure: Elettromyography

Time: 3 months

---

Description: Simplified peroneal nerve test (PENT)wiil be used to diagnose a critical illness polyneuropathy and myopathy; a value <5.26 mV present in both legs was considered as abnormal.

Measure: Elettromyography

Time: 6 months

---

Description: Simplified peroneal nerve test (PENT)wiil be used to diagnose a critical illness polyneuropathy and myopathy; a value <5.26 mV present in both legs was considered as abnormal.

Measure: Elettromyography

Time: 12 months

---

Description: Montreal Cognitive Assessment (MoCA) is divided into several cognitive domains with variable scoring among them, adding up to a maximum total of 30 points if all responses are correct. The scale is divided into Visuospatial and executive functioning (5 points), animal naming (3 points), attention (6 points), language (3 points), abstraction (2 points), delayed recall (short-term memory, 5 points), and orientation (6 points). To correct for educational effects found in the original study, one point is added if the subject has less than 12 years of education. The suggested cutoff score for normalcy in the MoCA is 26/30. When patients scored less than 26, we used the following classification: 18-25 = mild cognitive impairment, 10-17= moderate cognitive impairment, and less than 10= severe cognitive impairment

Measure: Montreal Cognitive Assessment Test (MoCA)

Time: 3 months

---

Description: Montreal Cognitive Assessment (MoCA) is divided into several cognitive domains with variable scoring among them, adding up to a maximum total of 30 points if all responses are correct. The scale is divided into Visuospatial and executive functioning (5 points), animal naming (3 points), attention (6 points), language (3 points), abstraction (2 points), delayed recall (short-term memory, 5 points), and orientation (6 points). To correct for educational effects found in the original study, one point is added if the subject has less than 12 years of education. The suggested cutoff score for normalcy in the MoCA is 26/30. When patients scored less than 26, we used the following classification: 18-25 = mild cognitive impairment, 10-17= moderate cognitive impairment, and less than 10= severe cognitive impairment

Measure: Montreal Cognitive Assessment Test (MoCA)

Time: 6 months

---

Description: Montreal Cognitive Assessment (MoCA) is divided into several cognitive domains with variable scoring among them, adding up to a maximum total of 30 points if all responses are correct. The scale is divided into Visuospatial and executive functioning (5 points), animal naming (3 points), attention (6 points), language (3 points), abstraction (2 points), delayed recall (short-term memory, 5 points), and orientation (6 points). To correct for educational effects found in the original study, one point is added if the subject has less than 12 years of education. The suggested cutoff score for normalcy in the MoCA is 26/30. When patients scored less than 26, we used the following classification: 18-25 = mild cognitive impairment, 10-17= moderate cognitive impairment, and less than 10= severe cognitive impairment

Measure: Montreal Cognitive Assessment Test (MoCA)

Time: 12 months

---

Description: Hospital Anxiety and Depression Scale (HADS) was classified as follow: HADS for depression: 0-7 = Normal 8-10 = Borderline abnormal (borderline case) 11-21 = Abnormal (case) and HADS Anxiety: 0-7 = Normal 8-10 = Borderline abnormal (borderline case) 11-21 = Abnormal (case).

Measure: Hospital Anxiety and Depression Scale (HADS)

Time: 3 months

---

Description: Hospital Anxiety and Depression Scale (HADS) was classified as follow: HADS for depression: 0-7 = Normal 8-10 = Borderline abnormal (borderline case) 11-21 = Abnormal (case) and HADS Anxiety: 0-7 = Normal 8-10 = Borderline abnormal (borderline case) 11-21 = Abnormal (case).

Measure: Hospital Anxiety and Depression Scale (HADS)

Time: 6 months

---

Description: Hospital Anxiety and Depression Scale (HADS) was classified as follow: HADS for depression: 0-7 = Normal 8-10 = Borderline abnormal (borderline case) 11-21 = Abnormal (case) and HADS Anxiety: 0-7 = Normal 8-10 = Borderline abnormal (borderline case) 11-21 = Abnormal (case).

Measure: Hospital Anxiety and Depression Scale (HADS)

Time: 12 months

---

Description: The PCL-5 is a self-report measure that assesses the presence and severity of Post Traumatic Stress Disorder (PTSD) symptoms. Items on the PCL-5 correspond with DSM-5 criteria for PTSD. PTSD >32 is strongly associated with the presence of PTSD.

Measure: The The Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5)

Time: 3 months

---

Description: The PCL-5 is a self-report measure that assesses the presence and severity of Post Traumatic Stress Disorder (PTSD) symptoms. Items on the PCL-5 correspond with DSM-5 criteria for PTSD. PTSD >32 is strongly associated with the presence of PTSD.

Measure: The The Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5)

Time: 6 months

---

Description: The PCL-5 is a self-report measure that assesses the presence and severity of Post Traumatic Stress Disorder (PTSD) symptoms. Items on the PCL-5 correspond with DSM-5 criteria for PTSD. PTSD >32 is strongly associated with the presence of PTSD.

Measure: The The Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5)

Time: 12 months

---

Description: Insomnia Severity Index (ISI) is a brief instrument that was designed to assess the severity of both nighttime and daytime components of insomnia. It is available in several languages and is increasingly used as a metric of treatment response in clinical research. ISI will be classified as follows: No clinically significant insomnia (0-7), Subthreshold insomnia (8-14), Moderate insomnia (15-21), and severe insomnia (22-28).

Measure: Insomnia Severity Index (ISI)

Time: 3 months

---

Description: Insomnia Severity Index (ISI) is a brief instrument that was designed to assess the severity of both nighttime and daytime components of insomnia. It is available in several languages and is increasingly used as a metric of treatment response in clinical research. ISI will be classified as follows: No clinically significant insomnia (0-7), Subthreshold insomnia (8-14), Moderate insomnia (15-21), and severe insomnia (22-28).

Measure: Insomnia Severity Index (ISI)

Time: 6 months

---

Description: Insomnia Severity Index (ISI) is a brief instrument that was designed to assess the severity of both nighttime and daytime components of insomnia. It is available in several languages and is increasingly used as a metric of treatment response in clinical research. ISI will be classified as follows: No clinically significant insomnia (0-7), Subthreshold insomnia (8-14), Moderate insomnia (15-21), and severe insomnia (22-28).

Measure: Insomnia Severity Index (ISI)

Time: 12 months

---

Description: The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) is a widely used and extensively validated generic QOL measure that consists of 8 multiple-item domains. We applied two different methods for scoring. Firstly, for each item, a scale between 0-100 will be calculated and the percentage of predicted value has been calculated, based on the Italian normalized value. The second method will be been the calculation ofthe physical component summary (PCS) and the mental component summary (MCS), as described by Taft et al. After the eight scale scores are calculated, a z-score is determined for each by subtracting the scale mean of a sample of the Italian general population from an individual's scale score and then dividing by the standard deviation from the Italian general population. Each of the eight z-scores is then multiplied by the corresponding factor scoring coefficient for the scale.

Measure: The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36)

Time: 3 months

---

Description: The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) is a widely used and extensively validated generic QOL measure that consists of 8 multiple-item domains. We applied two different methods for scoring. Firstly, for each item, a scale between 0-100 will be calculated and the percentage of predicted value has been calculated, based on the Italian normalized value. The second method will be been the calculation ofthe physical component summary (PCS) and the mental component summary (MCS), as described by Taft et al. After the eight scale scores are calculated, a z-score is determined for each by subtracting the scale mean of a sample of the Italian general population from an individual's scale score and then dividing by the standard deviation from the Italian general population. Each of the eight z-scores is then multiplied by the corresponding factor scoring coefficient for the scale.

Measure: The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36)

Time: 6 months

---

Description: The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) is a widely used and extensively validated generic QOL measure that consists of 8 multiple-item domains. We applied two different methods for scoring. Firstly, for each item, a scale between 0-100 will be calculated and the percentage of predicted value has been calculated, based on the Italian normalized value. The second method will be been the calculation ofthe physical component summary (PCS) and the mental component summary (MCS), as described by Taft et al. After the eight scale scores are calculated, a z-score is determined for each by subtracting the scale mean of a sample of the Italian general population from an individual's scale score and then dividing by the standard deviation from the Italian general population. Each of the eight z-scores is then multiplied by the corresponding factor scoring coefficient for the scale.

Measure: The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36)

Time: 12 months

---

Description: BI will be classified as follow: Independent (80-100); Minimally dependent (60-79);, Partially dependent (40-59), Very dependent (20-39); and Totally dependent (<20).

Measure: Barthel Index (BI)

Time: 3 months

---

Description: BI will be classified as follow: Independent (80-100); Minimally dependent (60-79);, Partially dependent (40-59), Very dependent (20-39); and Totally dependent (<20).

Measure: Barthel Index (BI)

Time: 6 months

---

Description: BI will be classified as follow: Independent (80-100); Minimally dependent (60-79);, Partially dependent (40-59), Very dependent (20-39); and Totally dependent (<20).

Measure: Barthel Index (BI)

Time: 12 months

---