Randomized Controlled Trial of urinE chemiStry Guided aCute heArt faiLure treATmEnt (ESCALATE)

Study Overview
=================
Brief Summary
-----------------
This is a randomized trial of protocolized diuretic therapy guided by urinary sodium compared to structured usual care in ED patients with AHF. Participants will be recruited following an initial standard evaluation in the ED and randomized in a 1:1 fashion to structured usual care or protocolized diuretic therapy guided by urinary sodium.

Detailed Description
-----------------
A standardized protocol driven treatment pathway for hospitalized patients started in the first few hours of ED evaluation and utilizing objective measures of diuretic response is needed. The investigators believe this would maximize diuretic efficiency, facilitate quicker resolution of congestion, avoid WHF and prolonged LOS, and reduce AHF readmissions. Propr data suggests low urine sodium predicts length of stay and outcomes after initial diuretic dosing in the outpatient and inpatient setting. Further, use of our pathway using spot urine sodium to titrate subsequent loop diuretic doses and maximize response in inpatients with AHF has shown compelling improvements in congestion and weight loss. However, a randomized trial is necessary to determine if initiating this protocol ,started in the ED, will improve AHF outcomes relative to structured usual care. Specifically, the investigators hypothesize use of spot urine sodium guided diuretic therapy will result in significant improvement in days of benefit over the 14 days after randomization. Days of benefit combines patient symptoms captured by global clinical status with clinical state quantifying the need for hospitalization and IV diuresis.

Official Title
-----------------
A Randomized Trial of Protocolized Diuretic Therapy Compared to Standard Care in Emergency Department Patients With Acute Heart Failure

Conditions
-----------------
Heart Failure, Acute Heart Failure

Intervention / Treatment
-----------------
* Drug: Protocolized diuretic therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age > 18 Emergency Department diagnosis of Acute Heart Failure (AHF) Any one of the following: i. Chest radiograph or lung ultrasound consistent with AHF ii. Jugular venous distension iii. Pulmonary rales on auscultation iv. Lower extremity edema v. S3 gallop > 10 pounds of volume overload physician estimate or historical dry weight IV diuretic ordered or planned to be during first 24 hours of ED or inpatient stay Exclusion Criteria: End Stage Renal Disease (ESRD) requiring dialysis Need for immediate intubation Acute Coronary Syndrome - presentation consistent with myocardial ischemia AND new ST-Segment elevation/depression Temperature > 100.5ºF End Stage Heart Failure: transplant list or ventricular assist device Concurrent use of ototoxic medications including intravenous aminoglycosides and cisplatin Systolic Blood Pressure < 90 mmHg at time of consent LV outflow obstruction, severe uncorrected stenotic valvular disease or severe restrictive cardiomyopathy Greater than 2 doses of IV diuretic administered at the time of screening from the time of the hospital presentation leading to this admission (outside hospital time is included) Severe, uncorrected serum electrolyte abnormalities at the time of consent (serum potassium <3.0 mEq/L, magnesium <1.0 mEq/L or sodium <125 or >150 mEq/l) Lack of informed consent

Ages Eligible for Study
-----------------
Minimum Age: 19 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
Interventional Model Description: Two-arm comparison of structured usual care vs urinary sodium guided diuresis
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Protocolized spot urine sodium guided diuretic therapy<br>Patients will have a spot urine sodium and urine creatinine obtained. The urine and creatinine results will be input into the diuretic calculator and the diuretic dose will be chosen based on daily goals for urine output and net negative fluid balance. Performed 3 times per day, diuretic dosing will be individualized based on the proportion of 24-hour diuresis achieved since the prior IV diuretic dose. Every 24 hours new goals for urine output and net negative fluid balance are established based on the study and treatment team's assessment of residual congestion until protocol completion. | Drug: Protocolized diuretic therapy<br>* The urine sodium, urine creatinine and serum creatinine results will be input into the diuretic calculator and the diuretic dose will be chosen based on daily goals for urine output and net negative fluid balance.<br>|
| No Intervention: Guideline-based care<br>Patients will be placed on guideline-based diuretic dosing consistent with usual practice. The initial dose will be two times their home dose and will be subsequently adjusted by the treating team based on renal function and symptom severity. The treating team can increase or decrease the frequency and dose of diuretic based on urine output and clinical assessment. Patients in this arm also have urine collected 3 times per day by the bedside nurse to mirror the intervention arm. | |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Status Score | Daily composite of the clinical state and global clinical status (GCS), expressed as an integer ranging in value from 0 (deceased) to 15 (outpatient; best possible GCS). | From the time of randomization through day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Congestion | Daily orthodema score | from the time of randomization until protocol transition to oral diuretics, approximately 14 days | 
| CV Death and AHF Readmission | Cardiovascular death and Acute Heart Failure Readmission | within 30 days of hospital discharge | 
| Global clinical status (GCS) | measured daily using a continuous scale of 1-100 | from the time of randomization through day 14 | 
| Change in natriuretic peptides | Blood measurement | from the time of randomization until protocol transition to oral diuretics, approximately 14 days | 
| Net fluid loss | difference between fluid input and urine output in ml | from the time of randomization until protocol transition to oral diuretics, approximately 14 days | 
| Total urine output | cumulative urine output in ml | from the time of randomization until protocol transition to oral diuretics, approximately 14 days | 
| Weight Loss | cumulative weight loss in pounds | from the time of randomization until protocol transition to oral diuretics, approximately 14 days | 
| Home days | Those days not in the hospital, rehab or a skilled nursing facility | within 30 days from randomization | 
| Shift in audiometry | Significant change in hearing threshold (dB) across frequencies from 250-8000 Hz | from the time of randomization until protocol transition to oral diuretics, approximately 14 days | 
| Cumulative natriuresis | cumulative sodium excretion estimated using the NRPE (based on spot urine creatinine and sodium) | from the time of randomization until protocol transition to oral diuretics, approximately 14 days | 
| Average daily natriuresis | mean daily sodium excretion estimated using the NRPE (based on spot urine creatinine and sodium) | from the time of randomization until protocol transition to oral diuretics, approximately 14 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diuretic Therapy, Emergency Department