The LUST Trial in Hemodialysis: Can Lung Ultrasound Guide Decongestive Therapy?

For this edition of NephJC, we invited the POCUS experts from the nephrology community to provide some more context for the rest of us. Read on.

In 1996, Dr. Daniel Lichtenstein described the significance of the comet tail artifact in a series of patients with cardiogenic and non-cardiogenic pulmonary edema (1). This artifact arises from micro-reflections at the sub-pleural end which are interpreted by the ultrasound machine as distance thus appearing on the screen as a narrow-based laser-like ray.

Fast forward to 2021: This artifact, now designated as the B-Line, has revolutionized our ability to detect clinical and sub-clinical pulmonary edema in a way that makes lung auscultation or chest x-ray seem obsolete (2,3). Lung ultrasound (LUS) has demonstrated excellent sensitivity and specificity (94.1% and 92.4% respectively) for the diagnosis of acute cardiogenic pulmonary edema (ACPE). B-lines are tallied across multiple intercostal spaces with higher B-line counts corresponding to worse pulmonary edema.

As expected, the number of B-lines improves in response to decongestive treatment. For example, in a study including 45 hemodialysis patients, Noble, et al., showed that ultrafiltration decreases the number of pulmonary B-lines in real time (7). Several studies have found a dose-dependent relationship between subclinical pulmonary congestion evidenced by an increased number of B-lines and adverse clinical outcomes in patients with heart failure (5) and in patients undergoing hemodialysis (6).

As the quest for objective methods to determine optimal dry weight continues, the adoption of lung ultrasound in hemodialysis clinics has the potential to become a practical tool to improve not just determination of appropriate dry weight, but patient outcomes. We believe this to be true first because the technical skills are easy to acquire and highly reproducible and second because using LUS to titrate diuretic doses reduces acute care utilization in patients with heart failure. Let’s expand a little bit more on these points.

How easy is it to become proficient at performing lung ultrasound (LUS)?

For the LUST trial, a detailed 28-zone lung ultrasound protocol was used encompassing 16 zones in the right hemithorax and 12 in the left. To learn to perform the LUS study, nephrologists were trained remotely using a 3-step training process8. First, they watched a 26-minute educational video showing how to perform LUS B-lines assessment. Then they watched 44 clips of LUS where the number of B-Lines was already given. Finally, trainees reviewed 47 non-scored clips where they had to estimate the number of B-lines on each video. After this training, the average intraclass correlation coefficient (ICC) was high (0.81). Out of the 44 trainees, in only 5 cases was the ICC <0.7. These trainees were able to improve after a brief targeted retraining via video chat. These findings resonate with our experience, learning how to accurately perform LUS is not hard! A 6-minute video by one of the LUST trial investigators on how to perform 28-zone LUS can be found here.

Clinical Trials using Lung Ultrasound (LUS) in Heart Failure

Before the publication of the LUST trial, 3 clinical trials were published comparing the use of LUS versus usual care in patients with congestive heart failure. LUS-HF9 and CLUSTER-HF10 are similar studies that recruited 123 and 126 hospitalized patients with heart failure (HFrEF and HFpEF) that were randomized at discharge to either the non-LUS-guided group (control group) or the LUS-guided group (LUS group). The LUS protocol consisted in evaluating 8 chest zones (4 per side) using a pocket ultrasound device. Lung congestion was considered present when a total of more than 3 B-lines were observed. In the LUS group, treating physicians were encouraged to adjust diuretic treatment incorporating LUS to their overall clinical assessment.  After 6-month follow-up period, both trials showed similar results: A significant reduction in the primary endpoint that was driven by a reduced number of urgent HF visits with no difference in death or hospitalizations.

The third is a study from Italy involving 244 ambulatory patients with HFrEF (11). The LUS protocol consisted of scanning the apical, middle, and basal lung fields from the parasternal to the midaxillary line. Lung congestion was graded on the lung field height were B-lines were visualized (1 point if B-lines were detected only in the basal fields, 2 points if up to the middle fields, 3 points if up to the apex). Again, data from LUS were incorporated into clinical decisions incorporating diuretic regimen. After a 3-month follow-up, hospitalizations for ADHF were significantly reduced in the LUS group however no difference in mortality was observed.

These three studies used LUS to detect subclinical congestion in the outpatient setting. In contrast, the BLUSHED-AHF trial investigated the use of LUS in guiding decongestion in patients presenting to the ED with ADHF. The intervention consisted of a LUS guided decision to administer a second dose of diuretics 6 hours after enrolling. 100% of patients assigned to the LUS group got the additional dose of diuretics, however 92% of the control group also got this additional dose. With the intervention being similar between the two groups, this trial had a null outcome as expected.

The LUST trial: A negative trial?

The LUST trial randomized 367 patients at high cardiovascular risk (history of coronary artery disease and/or New York Heart Association (NYHA) class III-IV heart failure) to a LUS guided intervention versus standard clinical care (12). Approximately 40% of included patients had the diagnosis of heart failure and this was almost exclusively HFpEF. The LUS protocol consisted of examining 28 lung zones and congestion was defined as a total B-line count of >15 B-Lines. This information was used by treating physicians to gradually decrease dry weight. If this intervention failed to decrease the number of B-Lines, the next step was to optimize or add anti-hypertensive drugs.

Despite the higher number of lung zones scanned, the LUS protocol highly resembles that of LUS-HF and CLUSTER-HF studies, especially since the definition of lung congestion can be simplified as finding ≈ 0.5 B-Lines per lung field. In fact, a recent study in hemodialysis patients showed that abbreviated LUS protocols using 4-, 6-, or 8-zone scanning were comparable to 28-zone method for the assessment of congestion (13). As opposed to LUS-HF and CLUSTER-HF studies, the primary endpoint of this study consisted of a composite of death, myocardial infarction, or de novo decompensated heart failure.

In this study, intensifying ultrafiltration resulted in a significant decrease in the number of B-lines in patients assigned to LUS-guided intervention. This reduction was most likely due to a sustained decrease in total body water even though there was no difference in weight at the end of the study. A similar finding was noted on the frequent hemodialysis trial where the decrease in total body water was accompanied by an increase in body fat (14). Reduction in lung congestion however was not immediate, and it reached its maximum near the end of the follow-up period.

Despite improvement in pulmonary congestion, the LUS-guided intervention did not result in a lower probability of the primary end point. And thus, this is a negative trial. However, based on the results from LUS-HF and CLUSTER-HF studies, a post hoc analysis on the number of repeated episodes of decompensated HF was added. In this analysis, the intervention group displayed significantly fewer episodes of decompensated HF and recurrent cardiovascular events. Even though this is a post hoc analysis, these results are very similar to previously published studies and strongly suggest biological plausibility. As the authors point out in their discussion, it is possible that decongestion is a slow process and the effects on this intervention on hard outcomes might take longer to become apparent. Interestingly, there were were significantly fewer episodes of intra-dialytic hypotension in the LUS guided intervention group (320 versus 473 events per 100 person-years) lending credence to the idea that LUS might identify those who will tolerate more ultrafiltration.

Considering the non-invasive nature of LUS, the relative ease of image acquisition, and interpretation of B-line focused LUS and the demonstrated absence of harm LUS-guided management strategy, it is our opinion that, while awaiting further trials, LUS could be considered as an adjuvant to our current clinical evaluation of dry weight in hemodialysis. This tool readily identifies patients with significant pre-clinical pulmonary congestion predicting those who are tolerant of additional ultrafiltration and, if acted on, reduces acute care utilization due to recurrent cardiovascular events.

 

Eduardo Argaiz, MD (@ArgaizR)

National Institute of Medical Sciences and Nutrition Salvador Zubirán,

Mexico City, Mexico

Abhilash Koratala, MD (@NephroP)

Medical College of Wisconsin, Milwaukee, Wisconsin, USA

Nathaniel Reisinger, MD (@nephrothaniel)

University of Pennsylvania, Philadelphia, Pennsylvania, USA

References:

1.      Lichtenstein, D., Mézière, G., Biderman, P., Gepner, A. & Barré, O. The Comet-tail Artifact: An Ultrasound Sign of Alveolar-Interstitial Syndrome. Am J Respir Crit Care Med 156, 1640–1646 (1997).

2.      Torino, C. et al. The Agreement between Auscultation and Lung Ultrasound in Hemodialysis Patients: The LUST Study. Clin J Am Soc Nephrol 11, 2005–2011 (2016).

3.      Maw, A. M. et al. Diagnostic Accuracy of Point-of-Care Lung Ultrasonography and Chest Radiography in Adults With Symptoms Suggestive of Acute Decompensated Heart Failure: A Systematic Review and Meta-analysis. JAMA Netw Open 2, e190703 (2019).

4.      Al Deeb, M., Barbic, S., Featherstone, R., Dankoff, J. & Barbic, D. Point-of-care ultrasonography for the diagnosis of acute cardiogenic pulmonary edema in patients presenting with acute dyspnea: a systematic review and meta-analysis. Acad Emerg Med 21, 843–852 (2014).

5.      Platz, E. et al. Detection and prognostic value of pulmonary congestion by lung ultrasound in ambulatory heart failure patients. Eur Heart J 37, 1244–1251 (2016).

6.      Zoccali, C. et al. Pulmonary congestion predicts cardiac events and mortality in ESRD. J Am Soc Nephrol 24, 639–646 (2013).

7.      Noble, V. E. et al. Ultrasound assessment for extravascular lung water in patients undergoing hemodialysis. Time course for resolution. Chest 135, 1433–1439 (2009).

8.      Gargani, L. et al. Efficacy of a remote web-based lung ultrasound training for nephrologists and cardiologists: a LUST trial sub-project. Nephrol Dial Transplant 31, 1982–1988 (2016).

9.      Rivas-Lasarte, M. et al. Lung ultrasound-guided treatment in ambulatory patients with heart failure: a randomized controlled clinical trial (LUS-HF study). Eur. J. Heart Fail. 21, 1605–1613 (2019).

10.  Araiza-Garaygordobil, D. et al. A randomized controlled trial of lung ultrasound guided therapy in heart failure (CLUSTER-HF study). American Heart Journal (2020) doi:10.1016/j.ahj.2020.06.003.

11.  Marini, C. et al. Lung ultrasound-guided therapy reduces acute decompensation events in chronic heart failure. Heart 106, 1934–1939 (2020).

12.  Zoccali, C. et al. A randomized multicenter trial on a lung ultrasound–guided treatment strategy in patients on chronic hemodialysis with high cardiovascular risk. Kidney International 100, 1325–1333 (2021).

13.  Reisinger, N., Lohani, S., Hagemeier, J., Panebianco, N. & Baston, C. Lung Ultrasound to Diagnose Pulmonary Congestion Among Patients on Hemodialysis: Comparison of Full Versus Abbreviated Scanning Protocols. Am J Kidney Dis S0272-6386(21)00632–6 (2021) doi:10.1053/j.ajkd.2021.04.007.

14.  Kaysen, G. A. et al. The effect of frequent hemodialysis on nutrition and body composition: frequent Hemodialysis Network Trial. Kidney Int 82, 90–99 (2012).

15.  Loutradis, C. et al. The effect of dry-weight reduction guided by lung ultrasound on ambulatory blood pressure in hemodialysis patients: a randomized controlled trial. Kidney Int 95, 1505–1513 (2019).