Non-interventional Follow-up Versus Fluid Bolus in RESPONSE to Oliguria in the Critically Ill

Study Overview
=================
Brief Summary
-----------------
Background: After hypotension, oliguria (urine output less than 0.5 mL/kg/h) was the most common trigger to administer fluid bolus in a multinational practice survey in intensive care. The effect of fluid bolus on cardiovascular variables can be very short-lived among patients in shock suggesting that fluid boluses in the optimization phase are unlikely to improve patient-centered outcomes. Moreover, a growing body of evidence suggests a poor renal response to fluid bolus. Objective: To investigate, whether fluid bolus - as a standard of care - improves urine output in oliguric patients compared to a non-interventional follow-up approach without fluid bolus. Design: Investigator-initiated, open, randomized, controlled study Interventions: Intervention group - follow-up without intervention Control group - fluid bolus (500mL of balanced crystalloid over 30 minutes) Randomization: 1:1 stratified according to the site, presence of acute kidney injury, and sepsis Trial size: 130 patients randomized in 2 ICUs

Detailed Description
-----------------
Study hypothesis: The investigators hypothesize that fluid bolus given due to oliguria does not improve urine output in a majority of patients, especially among those with acute kidney injury. Another study hypothesis is that patients receiving fluid bolus will have higher levels of endothelial damage biomarkers. Intervention description: Intervention group -follow-up without intervention; No intervention to increase the urine output within 2 hours will be done. Standard group - Fluid bolus group: Patient will receive 500mL of balanced crystalloid intravenously over 30 minutes. In both groups, if severe hemodynamic instability occurs, a rescue bolus of 500mL over 30 minutes may be given according to the decision of the treating clinician. In both groups, all other ongoing infusions (nutrition and on-going clear fluids) will be held constant during the 2-hour period. Vasoactive medications, sedation, short-acting insulin, and other medications can be modified according the clinical need. No diuretics during the 2-hour study period are allowed. After two hours from randomization, treating clinician can modify the fluid and drug therapy according to the clinical needs of the patient. All administered fluids will be recorded 6 h from randomization. Except for the study intervention period of 2 hours, no attempt to control fluid therapy will be done. During the study period, all other aspects of critical care will follow the ICU's standard operating procedures and clinician's prescription.

Official Title
-----------------
Non-interventional Follow-up Versus Fluid Bolus in RESPONSE to Oliguria in the Optimization Phase of Fluid Therapy in the Critically Ill (the RESPONSE Trial)

Conditions
-----------------
Critically Ill, Acute Kidney Injury, Sepsis, Oliguria

Intervention / Treatment
-----------------
* Other: follow-up without intervention
* Other: fluid bolus


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age over 18 Emergency admission to an ICU Mean arterial pressure (MAP) >65 mmHg (with vasopressors if needed) and initial fluid resuscitation for shock/hypovolemia has been given Oliguria (urine output less than 0.5mL/kg/h) for at least 2 consecutive hours Exclusion Criteria: Marked fluctuations in hemodynamics within last 2 hours (cardiac arrhythmias, increase in norepinephrine need over 0.2ug/kg/min, need for initiation of inotrope/inodilator) Administration of furosemide within last 6 hours Chronic kidney disease (estimated pre-critical illness GFR < 60ml/min/1.73m2) Renal replacement therapy Among patients with acute kidney injury, urgent indications for commencing renal replacement therapy Fluid overload (cumulative fluid accumulation exceeds 10% of baseline body weight) Pulmonary edema (bilateral infiltrates in chest x-ray) Active bleeding (need for transfusion, platelets, or fresh frozen plasma) Suspected or known intra-abdominal hypertension (IAP >16mmHg) Pregnant or lactating Expected survival less than 24h Obtaining informed consent is not possible/consent is denied

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 100 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: follow-up without intervention<br>No intervention to increase the urine output within 2 hours will be done. | Other: follow-up without intervention<br> <br> |
| Active Comparator: Standard group - fluid bolus<br>Patient will receive 500mL of balanced crystalloid intravenously over 30 minutes. | Other: fluid bolus<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in individual mean cumulative urine output (mL/kg/h) | Doubling of the urine output is defined as clinically meaningful response | 2 hours after randomization compared to urine output 2 hours preceding randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The difference between groups in the change in individual urine output |  | 2 hours after randomization compared to urine output 2 hours preceding randomization | 
| Duration of consecutive oliguria (urine output <0.5 mL/kg) |  | during ICU stay, i.e. as long as urine output stays below 0.5 mL/kg/h while the patient is in the ICU (an average of 5 to 7 days) or until renal replacement therapy is commenced | 
| Cumulative fluid balance |  | six hours from randomization | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
fluid therapy, oliguria, endothelial injury