Non-invasive Goal-directed thErapy oN cIrcUlatory Shock

Study Overview
=================
Brief Summary
-----------------
Circulatory shock occurs when the supply of oxygen in the tissues decreases, which leads to cell damage and affects about one third of patients admitted to Intensive Care Units (ICU). Cardiac Output (CO) can be defined as the volume of blood ejected by the left ventricle per minute and is a very useful hemodynamic parameter in the monitoring of patients with signs of circulatory shock, since it can help define the etiology and management of such patients. Nevertheless, this parameter is underused in patients treated in Emergency Units, as its measurement usually involves invasive methods and few are available in this scenario. The pulmonary artery catheter is considered the gold standard method for determining the cardiac output, however, since it is an invasive method, in recent decades other devices capable of providing this hemodynamic variable in a less invasive way have been developed. Any method capable of providing CO without the need for pulmonary artery catheter insertion is called minimally invasive CO monitoring. The potential advantages of using these methods include the simplicity of measurements, faster acquisition of hemodynamic parameters and the possibility of implementing a monitoring strategy in places such as emergencies and emergency rooms. The evaluation of these parameters allows a faster determination of the etiology of circulatory shock, which enables the early initiation of goal-guided therapy. It is known that the use of goal-guided therapy proved to be effective in reducing peri- and postoperative morbidity and mortality in patients with high surgical risk; this strategy is also associated with reduced mortality, length of stay in the ICU and on mechanical ventilation in patients admitted to the ICU who are fluid responsive. To date, there is no data regarding the impact of a hemodynamic optimization strategy on patients in the first hours of shock. The investigators aim to assess whether goal-based hemodynamic therapy, through non-invasive hemodynamic monitoring, reduces the incidence of acute renal failure in patients with circulatory shock. A multicenter, randomized, open-label study will be carried out. The study will include patients over 18 years of age with signs of shock (systolic blood pressure less than 90 mmHg and/or mean arterial pressure less than 70 mmHg plus at least one of the following changes: lactate greater than 15 mg/dL, oliguria, neurological changes, and capillary refill time greater than 3 seconds) and who have signed an informed consent form (ICF). Included patients will be randomized in a 1:1 ratio into two groups. The Goal-Directed Therapy Group will be the one in which patients will be monitored by the ClearSight™ System (Edwards Life Sciences, Irvine, CA, USA) in the first 24 hours after randomization, where the parameters cardiac index (CI), systolic volume (SV), systolic blood pressure (SBP) and mean arterial pressure (MAP) will be used to determine medical management; if the CI is less than 2.2 L/min/m² and the SV less than 35 mL/beat, an aliquot of 500 mL of crystalloid solution will be administered; if the patient presents with CI less than 2.2 L/min/m², associated with SV greater than 35 mL/beat, dobutamine will be initiated; in patients with SBP less than 90 mmHg and/or MAP less than 70 mmHg, associated with SV greater than or equal to 35 mL/beat, norepinephrine will be initiated. In the Conventional Therapy group, the allocated patients will be treated according to the assistant team, where the following parameters will be evaluated: blood pressure, peripheral oximetry, heart rate, respiratory rate, and urine output; patients showing signs of hypovolemia will receive crystalloid solution; those who remain with hypotension refractory to volume replacement will be given vasoactive drugs; those with suggestive of cardiogenic shock will be given inotropic drugs; these procedures will be determined according to the clinical judgment of the assistant team.

Official Title
-----------------
The Effect of Non-invasive Hemodynamic Goal-directed Therapy on the Incidence of Acute Kidney Injury in Circulatory Shock: a Randomized Clinical Trial

Conditions
-----------------
Acute Kidney Injury Due to Circulatory Failure

Intervention / Treatment
-----------------
* Device: Goal-Directed Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age > 18 years; Patients with shock defined as: Systolic Blood Pressure (SBP) < 90 mmHg and/or Mean Arterial Pressure (MAP) < 70 mmHg and At least one of the following alterations: Lactate > 18 mg/dL; Oliguria (diuresis < 0.5 mL/Kg/min for at least 6 hours); Neurological alteration (mental confusion, lowered level of consciousness, psychomotor agitation, temporal-spatial disorientation); Capillary refill time > 3 s (after 10 seconds of fingertip compression). Exclusion Criteria: Significant edema in the fingers; Significant peripheral vasoconstriction; Use of Noradrenaline at a dose greater than or equal to 0.2 mcg/Kg/min; Presence of Aortic Insufficiency; Patients on Renal Replacement Therapy; Patients with acute ST-elevation Myocardial Infarction; Patients in need of Invasive Mechanical Ventilation; Patients already participating in another study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Goal-Directed Therapy Group<br>Patients allocated to the Goal-Directed Therapy group will be monitored by the ClearSight™ System (Edwards Life Sciences, Irvine, CA, USA) in the first 24 hours after randomization, where the parameters Cardiac Index (CI), Stroke Volume (SV), Systolic Blood Pressure (SBP) and Mean Arterial Pressure (MAP) will be acquired continuously. | Device: Goal-Directed Therapy<br>* Patients will be monitored by the ClearSight™ System (Edwards Life Sciences, Irvine, CA, USA) in the first 24 hours, where the parameters Cardiac Index (CI), Stroke Volume (SV), Systolic Blood Pressure (SBP) and Mean Arterial Pressure (MAP) will be acquired continuously. The treatment goal will be to keep the CI greater than or equal to 2.2 L/min/m2, the SV greater than or equal to 35 mL/beat, and the SBP greater than or equal to 90 mmHg and/or the MAP greater than or equal to 70 mmHg. If the CI is below 2.2 L/min/m2 and the SV less than 35 mL/beat, an aliquot of 500 mL of crystalloid solution will be administered; if there is not an increase by 10% in the CI and SV values, a new aliquot of 250 mL may be administered; if this 10% increase does not occur for at least 20 minutes, inotropic medications will be started, with doses titrated periodically. If the pre-established goal is not reached, it is suggested to consider transfusion of a concentrated red blood cell.<br>* Other names: ClearSight™ System;|
| No Intervention: Conventional Therapy Group<br>Patients allocated to the Conventional Therapy Group will be treated according to the assistant team of the Emergency Unit, where will be measured the following parameters: invasive or non-invasive blood pressure (decided by the assistant team), peripheral oximetry, heart and respiratory rate, urinary output, in association with clinical history, complete physical examination and laboratory and imaging tests. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Acute Kidney Injury | According to the AKIN classification, acute kidney injury is defined as an abrupt reduction (within 72 hours) in renal function, characterized by an absolute creatinine elevation greater than or equal to 0.3 mg/dL; or a percentage increase in creatinine greater than or equal to 50% (1.5 times baseline creatinine); or a reduction in urine output to less than 0.5 mL/Kg/h for six hours or more. | 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Myocardial Injury | Presence of elevated troponin levels to values above the 99th percentile. | 30 days | 
| Number of Participants with Acute Myocardial Infarction | Presence of Myocardial Injury, associated with at least one of the following factors: Symptoms of acute myocardial ischemia; Dynamic alteration on Electrocardiogram; Evidence of new myocardial segmental contractility loss, diagnosed by Echocardiogram and/or Cardiac Resonance. | 30 days | 
| Number of Participants with need for invasive Intra Aortic Balloon-type | Intra aortic balloon is a short term ventricular assist device, indicated in cases of cardiogenic shock refractory to the use of high doses of inotropic drugs. | 30 days | 
| Assessment of health costs | The health costs will be measured in US dollars using the Brazilian Public Health database, which contains data on procedures, medicines, and hospital stay prices. | 1 year | 
| SOFA (Sequential Organ Failure Assessment) score | The SOFA score (Sequential Organ Failure Assessment score) is a scale composed of 6 parameters (PaO2/FiO2; Glasgow Coma Scale; mean arterial pressure (MAP) or administration of vasopressors required; bilirubin; platelets and creatinine or urine output), with a final value ranging between 0 and 24, where higher values indicate worsening of organ dysfunction. | 1st, 3rd, 7th and 30th day of hospital admission | 
| Assessment of finger capillary refill time | The use of the ClearSight™ System monitor (Edwards Life Sciences, Irvine, CA, USA) can cause a decrease in the peripheral perfusion of the involved finger, therefore, the capillary refill time in seconds of the fingers of all involved patients will be evaluated (where a greater filling time shows worse peripheral perfusion), to observe if there is a difference between the protocol groups. | 1st, 3rd, 7th and 30th day of hospital admission | 
| Number of Participants needing Mechanical Ventilation |  | 30 days | 
| Number of Participants needing Vasopressors |  | 30 days | 
| Number of Participants needing Inotropics |  | 30 days | 
| Length of hospital stay |  | 30 days | 
| Length of stay in the Intensive Care Unit |  | 30 days | 
| Number of Participants with need for Renal Replacement Therapy |  | 30 days | 
| Venous blood glucose measurement | Venous blood glucose will be measured using an enzymatic method (glucose dehydrogenase). | 1st, 3rd, 7th and 30th day of hospital admission | 
| Quality of life assessment | The assessment of quality of life will be made using the EQ-5D Dimensions questionnaire (EQ-5D), which consists of an instrument that assesses five dimensions (mobility, personal care, usual activities, pain/discomfort and anxiety/depression), where the patient indicates the degree of impairment in each dimension, in addition to a visual scale that varies from zero to one hundred, in relation to their perception of health on the day of the test, with one hundred indicating the best possible level of health, and zero indicating the worst possible level. This questionnaire was validated for use in the Brazilian population. | Hospital admission and at 30 days | 
| Rate of mortality |  | 30 days, 6 months and 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Acute Kidney Injury, Shock, Early Goal Directed Therapy