B-lines Lung Ultrasound Guided ED Management of Acute Heart Failure Pilot Trial

The primary goal of the BLUSHED AHF pilot trial is to determine whether an early lung ultrasound (LUS) guided, protocol-driven ED AHF strategy-of-care leads to more rapid and sustained resolution of congestion, as measured by LUS B-lines. If the investigators are able to demonstrate this necessary and sufficient information - targeted strategy-of-care is more effective than usual care - they will apply for a follow on study to achieve the following aim.

Aim 1: To demonstrate the effectiveness of a targeted decongestion strategy - LUS guided, protocol-driven ED AHF management - will result in improved 30-day outcomes vs. usual care. This aim will be tested using a randomized, controlled, unblinded, pragmatic, multi-center, simple trial design.

The pilot trial may determine that ED management alone is insufficient to impact the outcome. Thus, the investigators may need to modify their subsequent trial design to include targeted therapy throughout hospitalization. However, the pilot study will demonstrate whether targeted therapy effectively reduces B-lines.

PUBLIC HEALTH IMPACT Over one million hospitalizations for AHF occur every year in the US. Within 30 days after hospitalization, over 25% of AHF patients will be dead or re-hospitalized.4 Up to 67% of patients will be re-hospitalized and 36% will be dead by one year. For patients aged 65 years and older, AHF is the most common and most expensive reason for hospitalization. Despite major reductions in morbidity and mortality for chronic HF, considerably less progress has been seen in AHF.

Congestion is the primary reason why AHF patients present to the ED seeking medical care. Congestion is manifest by signs and symptoms of heart failure (HF); dyspnea, orthopnea, edema, and weight gain. Yet, how to best assess, grade, and manage congestion is not well established.

Freedom from congestion is associated with improved outcomes; Yet many patients leave the hospital inadequately decongested. The absence of robust, reliable methods to assess congestion is a primary reason why it is not well-assessed. A recent consensus statement published in 2010 highlights this fact: "…no method to assess congestion…has been validated." The investigators would argue many ED AHF patients are poorly assessed prior to treatment. In addition, they are poorly re-assessed prior to hospitalization to gauge the success or failure of initial management. While physical exam is currently the cornerstone of congestion assessment, it lacks sensitivity and inter-rater reliability.

The investigators challenge the current paradigm of relying on insensitive methods of congestion to guide therapy. Furthermore, they argue the lack of a robust evidence base for ED management of congestion contributes to poor outcomes.

• LUS-guided strategy-of-care (Other): For patients randomized to the strategy-of-care arm, the LUS guided protocol will be initiated and continued until there is a decrease in B-lines to ≤ 15 or 6 hours of care has been delivered, whichever comes first. Treatment protocol: 1. IV furosemide (unless already given): 2x single oral dose if on chronic therapy or 20-40 mg if diuretic naive. 2. Optional therapies: non-invasive ventilation, vasodilators (SL, topical, or IV) 3. Reassessment every 2 hours
• Usual Care (Other): Patients will receive usual AHF care
• Intravenous Loop Diuretic (Drug): IV loop diuretic
• Vasodilator (Drug): IV, topical, or SL Vasodilator
• Non invasive Ventilation (NIV) (Device): Face, mouth, or nasal mask applied to provide positive pressure ventilation

Primary outcomes

• Number of Participants With B-lines ≤ 15 at the Conclusion of ED AHF Management [During the ED phase of management, usually no more than 6 hours]: B-lines ≤ 15 at the conclusion of ED AHF management or maximum of 6 hours after enrollment, whichever comes first.

Other outcomes

• Total Days Alive and Out Of Hospital (DAOOH) [Up through 90 days, with specific reporting of events through 30 and 90 days]: Total days alive and out of hospital through 30 and 90 days post-discharge
• Association of B-lines at Discharge and 30-day / 90-day Outcomes [Up through 90 days, with specific reporting of events through 30 and 90 days]
• Change in Biomarkers From Presentation to Pre-discharge [From admission to pre-discharge from the hospital, on average 5 to 7 days.]
• Time to Reach B-lines <15 [Throughout hospitalization, on average 5-7 days]
• B Lines < 15 at 24 Hours and at Discharge [Through the first 24 hours and then prior to discharge, on average 5-7 days after admission]
• Composite of 30-day and 90-day All-cause Mortality, Cardiovascular (CV) Re-hospitalizations, and CV Emergency Department (ED) Revisits. [Up through 90 days, with specific reporting of events through 30 and 90 days]: CV endpoints are defined according to the 2014 American College of Cardiology/American Heart Association (ACC/AHA) Key Data Elements and Definitions for Cardiovascular Endpoint Events.
• All Cause Readmissions, All Cause ED Re-visits [Up through 90 days, with specific reporting of events through 30 and 90 days]: 30- day and 90-day
• Number of Participants With Physical Exam Findings of Heart Failure When Discharge is Compared to Baseline [From admission throughout hospitalization, usually 5-7 days.]: Physical exam includes body weight, peripheral edema, jugular venous distention, pulmonary and cardiac auscultation
• Count of Pharmacologic Therapies the Patient Received in the ED [From admission throughout hospitalization, usually 5-7 days.]: This is a description of which pharmacologic therapies the patient has received.
• Count of Pharmacologic and Device Therapies the Patient Received During Hospitalization [From admission throughout hospitalization, usually 5-7 days.]: This is a description of which pharmacologic and device therapies the patient has received.
• Comparison of LUS Interpretation Within and Between Trained Investigators as Well as the Core Lab [From admission throughout hospitalization, usually 5-7 days.]: Calculation of intra and inter-agreement between investigators and also the Core Lab to determine the reproducibility of LUS
• Association of Baseline, Discharge, and Change With 30 and 90 Day Outcomes [Up through 90 days, with specific reporting of events through 30 and 90 days]

Sex: All, ages: 21 Years to any

Inclusion Criteria:

* Age ≥ 21 years
* Presents with shortness of breath at rest or with minimal exertion
* Clinical diagnosis of AHF and presence of > 15 total bilateral B-lines distributed in at least 4 zones on initial LUS
* Hx of chronic HF and any one of the following:

  * Chest radiograph consistent with AHF
  * Jugular venous distension
  * Pulmonary rales on auscultation
  * Lower extremity edema

Exclusion Criteria:

* Chronic renal dysfunction, including end-stage renal disease (ESRD) or estimated glomerular filtration rate (eGFR) < 45ml//min/1.73m2.
* Shock of any kind. Any requirement for vasopressors or inotropes.
* Systolic blood pressure (SBP) < 100 or >175 mmHg
* Need for immediate intubation
* Acute Coronary Syndrome- Presentation consistent with myocardial ischemia AND either new ST-segment elevation/depression
* Fever >101.5 ºF or chest radiograph or clinical picture of pneumonia
* End stage HF: transplant list, ventricular assist device
* Anemia requiring transfusion
* Known interstitial lung disease
* Suspected acute lung injury or acute respiratory distress syndrome (ARDS)
* Pregnant or recently pregnant within the last 6 months

Participant flow

Outcome results

• Number of Participants With B-lines ≤ 15 at the Conclusion of ED AHF Management (Primary), Count of participants, Participants: LUS-guided Strategy-of-care 7; Usual Care 10
• Total Days Alive and Out Of Hospital (DAOOH) (Other pre specified)
• Association of B-lines at Discharge and 30-day / 90-day Outcomes (Other pre specified)
• Change in Biomarkers From Presentation to Pre-discharge (Other pre specified)
• Time to Reach B-lines <15 (Other pre specified)
• B Lines < 15 at 24 Hours and at Discharge (Other pre specified)
• Composite of 30-day and 90-day All-cause Mortality, Cardiovascular (CV) Re-hospitalizations, and CV Emergency Department (ED) Revisits. (Other pre specified)
• All Cause Readmissions, All Cause ED Re-visits (Other pre specified)
• Number of Participants With Physical Exam Findings of Heart Failure When Discharge is Compared to Baseline (Other pre specified)
• Count of Pharmacologic Therapies the Patient Received in the ED (Other pre specified)
• Count of Pharmacologic and Device Therapies the Patient Received During Hospitalization (Other pre specified)
• Comparison of LUS Interpretation Within and Between Trained Investigators as Well as the Core Lab (Other pre specified)
• Association of Baseline, Discharge, and Change With 30 and 90 Day Outcomes (Other pre specified)

Adverse events

Time frame: 7 days from consent

Serious adverse events by term

Other adverse events by term

• Results publication: Pang PS, Russell FM, Ehrman R, Ferre R, Gargani L, Levy PD, Noble V, Lane KA, Li X, Collins SP. Lung Ultrasound-Guided Emergency Department Management of Acute Heart Failure (BLUSHED-AHF): A Randomized Controlled Pilot Trial. JACC Heart Fail. 2021 Sep;9(9):638-648. doi: 10.1016/j.jchf.2021.05.008. Epub 2021 Jul 7. PMID 34246609
• Results publication: Russell FM, Ehrman RR, Ferre R, Gargani L, Noble V, Rupp J, Collins SP, Hunter B, Lane KA, Levy P, Li X, O'Connor C, Pang PS. Design and rationale of the B-lines lung ultrasound guided emergency department management of acute heart failure (BLUSHED-AHF) pilot trial. Heart Lung. 2019 May-Jun;48(3):186-192. doi: 10.1016/j.hrtlng.2018.10.027. Epub 2018 Nov 15. PMID 30448355

• Study Protocol and Statistical Analysis Plan (PDF, 2018-01-23)
• Informed Consent Form (PDF, 2018-11-08)

• Peter S Pang, MD, Principal investigator, Indiana University