Role of Active Deresuscitation After Resuscitation-2

Study Overview
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Brief Summary
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RADAR-2 will be a randomised, open-label, allocation concealed, pilot trial of conservative fluid administration and deresuscitation compared with usual care in patients who are critically ill.

Detailed Description
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The optimal approach to fluid balance in critically ill patients is uncertain. A recent systematic review found low quality evidence in favour of a conservative fluid or deresuscitative approach (active removal of accumulated fluid using diuretics and/or renal replacement therapy) compared with a liberal strategy or usual care. The RADAR-2 pilot randomised trial will compare conservative fluid and deresuscitation with usual care in patients who are mechanically ventilated in an intensive care unit. The main hypothesis is that in critically ill patients, a post-resuscitation fluid strategy comprising conservative fluid administration and active deresuscitation reduces net fluid balance, is safe and improves clinical outcomes.

Official Title
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Role of Active Deresuscitation After Resuscitation- 2: a Pilot Randomised Controlled Trial of Conservative Fluid Management Versus Usual Care in Critical Illness

Conditions
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Critical Illness, Sepsis, Trauma

Intervention / Treatment
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* Other: Conservative fluid and deresuscitation strategy
* Other: Usual care strategy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Invasive mechanical ventilation Treating ICU doctor expects patient to require treatment in an ICU beyond the next calendar day Between 24 and 48 hours from ICU admission at the time of randomisation Exclusion Criteria: Age < 16 years Body weight <40kg (measured or estimated) Diabetic ketoacidosis or Hyperosmolar hyperglycaemic state Non-traumatic subarachnoid haemorrhage Acute cardiac failure or cardiogenic shock End-stage renal failure (on dialysis) Known to be pregnant Suspected or proven active diabetes insipidus (DDAVP within 24 hours) Not expected to survive for 72 hours Active 'Do not attempt resuscitation' order Refusal of consent Inability of personal consultee to understand written or verbal information and for whom no interpreter is available Known allergy to one or more of the study drugs Inability to measure fluid balance

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomised, open-label, allocation concealed, pilot trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Conservative fluid and deresuscitation<br>Fluid restriction (avoidance of maintenance intravenous fluid and minimisation of drug diluent volumes) Daily assessment of eligibility for deresuscitation for 3 days (eligible if oedema in more than 1 site and cumulative fluid balance > 2 litres) Deresuscitation to target negative daily fluid balance of 1 to 3 litres: 5mg Indapamide daily (enteral) 100mg Spironolactone daily (enteral) 0.5mg/kg furosemide once (intravenous, max 40mg) 2.5-20mg/hr furosemide infusion titrated to effect OR continuous renal replacement therapy with fluid removal | Other: Conservative fluid and deresuscitation strategy<br>* Conservative administration of intravenous fluid and active deresuscitation using diuretics or renal replacement therapy for eligible patients<br>|
| Active Comparator: Usual care<br>Usual care at the discretion of the treating team | Other: Usual care strategy<br>* Usual care at the discretion of the clinical team<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Day 3 fluid balance | Change in fluid balance (mL) between the beginning of study day 2 and the beginning of study day 3. | From beginning of day 2 to the beginning of study day 3. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative fluid balance | Cumulative fluid balance (mL) from ICU admission | Up to the beginning of days 3 and 5, and at ICU discharge (estimated median day 7) | 
| Incidence of significant protocol violations | Incidence of significant protocol violations (total number of patients, per site, and by nature of protocol violation) up to day 5 (intervention period) | Up to study day 5 | 
| Incidence of reported adverse events | Incidence of reported adverse events up to day 5 (intervention period) | Up to study day 5 | 
| Change in Sequential Organ Function Assessment scores | Change in Sequential Organ Function Assessment scores from baseline, overall (0-24) and 6 individual organ sub scores (respiratory, cardiovascular, neurological, coagulation, renal and liver, each scored 0-4 which are added to give a total score). Higher values represent more deranged physiology and predict mortality for critically ill patients. | From baseline until day 3 and day 5 | 
| Mortality | Mortality | 28 and 180 days | 
| Duration of mechanical ventilation | Duration of mechanical ventilation in survivors and non-survivors (number of days or part thereof from initiation of mechanical ventilatory support until unassisted breathing) | 28 days | 
| Length of ICU stay | Length of ICU stay (number of days or part thereof from admission to an ICU or being under the care of a critical care team or consultant until ICU discharge) | 28 days | 
| Acute kidney injury | Incidence of new acute kidney injury defined as estimated KDIGO Stage 3 (before and after correction for fluid balance) | Up to day 5. | 
| Cognitive function | Cognitive function score (assessed using the Montreal Cognitive Assessment (MoCA-blind) instrument) | 180 days | 
| Health-related quality of life | Health-related quality of life (HR-QoL) (assessed using absolute values of a telephone-administered EQ-5D (EuroQoL 5 Dimension Scale) questionnaire). This has 5 domains: mobility, self-care, usual activities, pain/discomfort, anxiety/depression, each of which are scored 1-5, with 1 being best and 5 being worst health. Each domain is reported separately. A total score is generated and is indexed to population reference values for that country (in this case UK) according to the time of data collection. It is therefore not possible to pre-specify a range for the indexed score. | 180 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fluid therapy, furosemide, diuretics, Injections, Intravenous, Infusions, Intravenous, Spironolactone, Indapamide