Detection of Lung Pathologies Among Dialysis Patients Using Pulsenmore MC™ Device - Feasibility Study

Background Patients with end-stage renal disease (ESRD) and heart failure (HF) have a high risk to suffer from pulmonary congestion (PC) (1,2). PC in HF and ESRD patients is a common cause of admission, mortality, and cardiac events )3-6(. Extravascular lung water (EVLW), which leads to PC, can be subclinical among normo-hydrated dialysis patients (1,7).

PC exact mechanism in ESRD is under debate )8( but occurs in a combination of two forces mechanism - changes in hydrostatic pressure due to HF and volume overload and increase in lung permeability with retention of uremic product and chronic inflammation (1,2,6,8). Chronic load of extracellular volume and increased LV filling pressure is mainly the cause of EVLW accumulation leading to clinical PC (1,2). Volume overload builds gradually during the interval between the dialysis treatments (6,7) and maybe asymptomatic (1,6). PC can also occur in ESRD patients, even with normal cardiac filling pressure or mild volume overload )8( and can be explained by volume redistribution (2). Untreated or suboptimal treated PC can cause respiratory distress. Volume overload is an independent risk factor for death and cardiovascular events in ESRD patients (2,9). Therefore, volume removal is crucial to prevent PC events (2). Dialysis reduces the severity of PC immediately )8(, and delay in treatment can increase the frequency and the severity of the events (8,9).

Lung ultrasound (LUS) is an effective, bedside, imaging tool for the detection and monitoring of PC (2,7-12). Alveolar interstitial syndrome, which can be caused by an increase of EVLW, is diagnosed by the detection of ultrasonographic B-lines in both lung zones (2,3,5,7,9,10). Lung ultrasound was found at least sensitive and effective as other traditional modalities to diagnose PC (1,4,5,8,10,13).

B-lines are hyperechoic reverberation, relatively simple to teach and conduct (3,8,11), which can be detected by LUS (5,8,14). Some studies quantified B-lines using the B-line score (BLS). The score is calculated by the number of lung zones that are dichotomously positive for B-lines (10,11). Furthermore, B-lines are an important prognostic factor for death, cardiovascular events, and readmission in ESRD and HF patients (2-4,10-12).

Changes in BLS seen during volume removal by dialysis treatment or diuresis (2,7-10) represents the dynamic changes in EVLW (7,9-11). Studies found a distinct real-time decrease in the number of B-line and BLS that correlated with the traditional examination for EVLW (2,9- 11,13). Data suggests that B-lines monitoring is used for the assessment of volume overload removal adequacy (2,4,10,11).

A tool that can help the patients to manage their disease better, by early, self- identification of evolving PC, can shorten time to definite treatment (2,9). This may lead to reduced hospitalization and improved patients' clinical outcome.

In the present study, the investigators sought to check the feasibility of a new mobile US probe device that connects to a mobile phone, on hemodialysis patients. The investigators will compare the results measured by the new device to the traditional US device.

Ultrasound is very potent in the identification of these lung pathologies. The investigators would like to identify the sensitivity and specificity of this device in the detection of these other lung pathologies.

5 Method: Prospective, single center, pilot study will be carried out at the SUMC, and Soroka Clinical Research Center (SCRC), will oversee and manage the study.

5.1 Working Hypothesis

1. The study device, a novel mobile phone-based ultrasound device, Pulsenmore MC can identify B lines in high sensitivity and specificity and can replace traditional bigger and more expensive ultrasound machines for this diagnosis. 5.2 Objective 5.2.1 Primary Objective To measure success rate and identification of pathological lung B-lines, using novel mobile phone, Pulsenmore MC device, in chronic renal failure patients, pre and post dialysis. 5.2.2 Secondary Objective

• To describe the difference in B-lines score (BLS), pre and post dialysis as measured by the new device.
• Examine the degree of agreement in the BLS performed by the new mobile Pulsenmore MC device to the traditional ultrasound device. 5.4 The study population will be screened at SUMC nephrology ward before scheduled dialysis. Population will be enrolled according to the following inclusion and exclusion criteria. 5.4.1 Inclusion Criteria • Patients diagnosed with End-stage renal disease (ESRD) and treated with chronic dialysis center at Soroka University Medical Center (SUMC)
• Cognitive intact and can sign informed consent as decided by their treating nephrologist.
• have smart phone and any social app- like WhatsApp- his or her main care giver 5.4.2 Exclusion Criteria
• Morbid obese - BMI>35
• History of lung resection or lung transplant. 5.4.3 Withdrawal Criteria All patients should be encouraged to remain in the study through both of the ultrasound test. However, if a patient decides to discontinue study participation, the reason for discontinuation must be recorded in the medical record and the Case Report Form (CRF). 5.5 Enrollment 5.6 Patient Screening Screening will be performed at the dialysis center located in the nephrology. Interested patients will be asked to provide written consent prior to performing any study procedure. 5.7 Study Procedures 5.7.1 Screening informed consent and Enrollment, training patient on the Pulsenmore MC device and then save the images from new mobile MC device and from the traditional POCUS device (Standard of care US equipment). After the enrollment of the first 10 patients, Additional 20 patients will be enrolled and receive the new ultrasound device, MC, that connects to the mobile phone. Till 24 hours before dialysis treatment, those patients will perform a self-examination at home using the demo or the video guided mode. . . The patients will receive instruction on how to use the device. The duration of the study, for these patients, will be up to three weeks (6-10 dialysis). At Screening and enrollment visit: The patient will be consented after examination with inclusion and exclusion criteria. Demographics, Medical History, Clinical data, device details, and vital signs data will be collected. The patient will be trained on Pulsenmore MC device. Patient will receive instructions how to use the new ultrasound device and when to self-scan himself. First dialysis treatment in the study can be performed on the same day of subject consent. Dialysis treatments (6-10): US images will be recorded and documented before and after the dialysis from 3 zones (and both sides - right and left) Two physicians will analyze the data from the Self-scan ultrasound device compared to the traditional ultrasound device. AE and CCMED will be reviewed. Phase I: In- clinic: dialysis unit, enrolment of max 10 patients receiving ES or MC for up to 3 weeks of use (6-10 dialysis sessions). Each patient will be weighed Before \& after Dialysis Study procedure -Before Dialysis:
• Physician training
• Physician with Patient: watching the tutorials
• Physician scanning the patient for B lines and lung pathologists using the Demo or the video guided mode MC - scanning both sides.
• Patient scanning for B lines using the Pulsenmore MC Demo or the video guided mode - scanning both sides.
• Later, on the same day, the patients will have an in-person clinic visit and will be scanned by a physician/technician for lung pathologies using the Standard of care US equipment. The scanned images, from demo or the video guided mode, will be uploaded to the cloud from the patient 's device and interpreted by 2 physicians. Study procedure - After Dialysis:
• Physician scanning for B lines using MC
• Physician scanning for B lines using the Standard of care US. Phase II: At Home: enrolment of 20 patients receiving MC for up to 3 weeks of use (6-10 dialysis). *A patient who participate in the first phase will also be able to participate in the second phase of the study. Each patient will be weighed Before \& after Dialysis Study procedure -Before Dialysis:
• Physician training in clinic using the Demo or the video guided mode.
• Physician with Patient: watching the tutorials or Practice scan.
• Patient scanning for B lines using MC in Demo or video guided mode, scanning both sides. This procedure will be performed at home, till 24 hours before dialysis treatment.
• Later, on the same day, the patients will have an in-person clinic visit and will be scanned by a physician/technician for lung pathologies using the Standard of care US equipment. Study procedure - After Dialysis:
• Physician scanning for B lines using MC
• After using the MC, Physician scanning for B lines using the Standard of care US.
• The in-clinic scan serves as Ground truth (GT).
• At the end of phase 1 or 2, the images from the Demo scan or the video guided mode, will be uploaded to the cloud from the patient 's device and interpreted by 2 physicians. 5.8 Study Duration: the investigators expect that enrollment to the study will be for a period of 10 months. 5.9 Data to Capture 5.9.1 Required Data All required data for this study will be collected via electronic case report forms (eCRF). 5.9.2 Data Collection The final set of CRFs is designed to accommodate the specific features of the trial design. Modification of CRFs will only be made if deemed necessary by Soroka CRC. The CRFs will be filled out manually by the study personal and or will be collected through the computer services database. The following data will be collected:
• Demographic factors: age, gender, ethnicity
• Medical history: medications, diabetes mellitus, hypertension, systemic diseases, Congestive Heart Failure (CHF), Chronic Obstructive Pulmonary Disease (COPD), height and weight
• Clinical data: -Dates of admission -Treatment: dialysis duration (years) -Essential: heart rate, blood pressure, saturation, weight in Kg, Before and after session, Dry weight and BMI. US results - from pictures collected from New mobile Pulsenmore MC and standard device (Traditional US POCUS) before and after the dialysis from 3 zones (and both sides right and left) -BLS, pleural effusion and lung atelectasis from each device and each zone Each patient will receive the same code for both devices' records for blinded comparison that All the analysis of BLS will be decided by an independent blinded reviewer.

1. Statistical Considerations and Analysis Plan 6.1 Statistical Analyses Data will be expressed as mean SD, median, and interquartile range, or as percent and frequency, as appropriate.

All statistical tests and/or confidence intervals, as appropriate, will be performed at α=0.05 (2-sided). All p-values reported will be rounded to three decimal places.

6.2 Sample Size Considerations We will analyze data of all relevant patients who meet all the inclusion criteria and none of the exclusion criteria. This feasibility research we will perform on 30 different patients.

6.3 Primary Endpoints Comparison between the devices in the b-lines test. Number of b lines, more than 2, more than 5, confluent 6.4 Secondary Analyses and Endpoints

Secondary end point:

6.4.1. Comparison of lung pathologies of both sides, right and left, between Pulsenmore MC and Standard of care US devices for pleural effusion, atelectasis, and consolidation.