Abstract
Background and objectives Accumulation of fluid in the lung is the most concerning sequela of volume expansion in patients with ESRD. Lung auscultation is recommended to detect and monitor pulmonary congestion, but its reliability in ESRD is unknown.
Design, setting, participants, & measurements In a subproject of the ongoing Lung Water by Ultra-Sound Guided Treatment to Prevent Death and Cardiovascular Complications in High Risk ESRD Patients with Cardiomyopathy Trial, we compared a lung ultrasound–guided ultrafiltration prescription policy versus standard care in high-risk patients on hemodialysis. The reliability of peripheral edema was tested as well. This study was on the basis of 1106 pre– and postdialysis lung ultrasound studies (in 79 patients) simultaneous with standardized lung auscultation (crackles at the lung bases) and quantification of peripheral edema.
Results Lung congestion by crackles, edema, or a combination thereof poorly reflected the severity of congestion as detected by ultrasound B lines in various analyses, including standard regression analysis weighting for repeated measures in individual patients (shared variance of 12% and 4% for crackles and edema, respectively) and κ-statistics (κ ranging from 0.00 to 0.16). In general, auscultation had very low discriminatory power for the diagnosis of mild (area under the receiver operating curve =0.61), moderate (area under the receiver operating curve =0.65), and severe (area under the receiver operating curve =0.68) lung congestion, and the same was true for peripheral edema (receiver operating curve =0.56 or lower) and the combination of the two physical signs.
Conclusions Lung crackles, either alone or combined with peripheral edema, very poorly reflect interstitial lung edema in patients with ESRD. These findings reinforce the rationale underlying the Lung Water by Ultra-Sound Guided Treatment to Prevent Death and Cardiovascular Complications in High Risk ESRD Patients with Cardiomyopathy Trial, a trial adopting ultrasound B lines as an instrument to guide interventions aimed at mitigating lung congestion in high-risk patients on hemodialysis.
- end-stage renal disease
- chronic kidney disease
- hemodialysis
- clinical epidemiology
- Auscultation
- Cardiomyopathies
- Edema
- Humans
- Kidney Failure, Chronic
- Pulmonary Edema
- Regression Analysis
- renal dialysis
- Reproducibility of Results
- Respiratory Sounds
- Sound
- ultrafiltration
- Water
Introduction
In patients with ESRD, accumulation of fluid in the lung is the most concerning consequence of volume expansion, and the risk for pulmonary edema is very high in this population (1,2). Systematic application of lung auscultation for the detection of crackles at the bases of the lungs is recommended in clinical practice in both individuals with suspected heart failure (3) and patients with ESRD (4). However, the reliability of auscultation for the diagnosis of lung congestion has never been assessed in this population.
Lung water can be reliably estimated in clinical practice by applying lung ultrasound (US) (5–8). Importantly, lung US has been well validated as a measure of pulmonary water in patients with cardiovascular disease (6), and it has virtually no bias when tested against thermodilution and shows a reproducibility even higher than that of this gold standard in patients with heart disease. Furthermore, the same technique has also been extensively validated in patients on intensive care, in whom it holds very high discriminatory power for identifying moderate and severe congestion (areas under the receiver operating curves [ROCs] of 0.94 and 0.96, respectively) (9). In ESRD, the technique shows high intra- and interobserver reproducibility and also, high reproducibility when assessed with diverse echo tomography machines (10). In ESRD, lung congestion as detected by lung US holds strong prognostic power for death and cardiovascular events independent of traditional and ESRD–specific risk factors (11,12).
This study was performed within the frame of the Lung Water by Ultra-Sound Guided Treatment to Prevent Death and Cardiovascular Complications in High Risk ESRD Patients with Cardiomyopathy (LUST) Trial (13), an ongoing clinical trial testing the usefulness of systematic application of lung US in the clinical care of high-risk patients on hemodialysis. In this LUST Trial subproject, we have adopted lung US as a reference method for testing the diagnostic reliability of pulmonary crackles as a clinical sign of pulmonary congestion and the prospectively collected, serial, well standardized (14) pulmonary auscultation data alongside with measurements of lung water by US. The diagnostic value of pulmonary auscultation for detecting moderate to severe degrees of lung congestion was assessed by comparing >1000 paired measurements of lung water by US with simultaneous standardized auscultation of the thorax. Because pitting edema is frequent in patients with pulmonary crackles attributable to heart failure and/or volume overload, a secondary aim of this study was that of assessing whether the combined detection of lung crackles and peripheral edema may improve the diagnostic performance of these physical signs for lung congestion.
Materials and Methods
The study protocol was approved by the ethical committees of the renal units participating in the LUST Trial. All participants gave informed consent before enrolment.
Patients
The LUST Trial is a multicenter, open, randomized, controlled trial aimed at assessing the usefulness of ultrasound B (US-B) lines in preventing adverse clinical outcomes (mortality, cardiovascular events, hospitalizations, and progression of left ventricular hypertrophy and left ventricular dysfunction) in patients on dialysis at high cardiovascular risk. This trial is registered at ClinicalTrials.gov (identifier no. NCT02310061). The inclusion criteria for the enrolment in the LUST Trial are age >18 years old; dialysis vintage >3 months; and a history of myocardial infarction with or without ST elevation or unstable angina, acute coronary syndrome documented by ECG recordings and cardiac troponins, or stable angina pectoris with documented coronary artery disease by prior coronary angiography, electrocardiogram, or dyspnea class 3 or 4 New York Heart Association. Patients with cancer or other advanced noncardiac disease or comorbidity (e.g., end stage liver failure) imposing a very poor short–term prognosis, active infections or relevant intercurrent disease, or inadequate lung scanning and echocardiographic studies were excluded from the trial. For the scope of this study, we focused on patients randomized into the active arm (no pre- and postdialysis lung US is contemplated in patients in the control arm in the LUST Trial). This subproject included 79 patients with simultaneous pre– and postdialysis US-B lines and peripheral edema and pulmonary crackles measurements. The total number of paired US lung scan and lung auscultation records was 1106 (on average, 14 per patient) over an observation period of 11 months.
US-B Lines Measurement
US-B lines are the sonographic equivalent of classic B lines detected in standard chest x-rays in patients with lung congestion/edema (15). US-B lines measurements have a high interobserver reliability (concordance index =0.96) as well as high interprobe concordance (concordance index =0.99) in patients on hemodialysis (10). US-B lines assessment was made immediately before and after dialysis in supine position. Scanning of the anterior and lateral chest was performed on both sides of the chest from the second to the fourth (on the right side to the fifth) intercostal space at parasternal to midaxillary lines as previously described (10). US-B lines were recorded in each intercostal space and defined as a hyperechoic, coherent US bundle at narrow basis going from the transducer to the limit of the screen. The sum of US-B lines produces a score reflecting the extent of lung water accumulation (5,6,16). Detailed description of the technique is available in a 2-minute movie on YouTube (the incredible ultrasound lung comets; http://www.youtube.com/watch?v=7y_hUFBHStM). Lung congestion was categorized according to the work by Frassi et al. (17) as absent: <5 US-B lines; mild: ≥5 to <15 US-B lines; moderate: ≥15 to ≤30 US-B lines; and severe: >30 US-B lines. All nephrologists participating into the LUST Trial were trained by a specific web–based educational program (L. Gargani, et al., unpublished data) and certified by the validation center at the Istituto di Fisiologia Clinica - Consiglio Nazionale delle Ricerche in Pisa, Italy. To be certified, assessors had to have an 85% or higher concordance in the assessment of lung US scans with the expert trainer at the validation center.
Clinical Evaluation of Volume Status and Lung Auscultation
In all patients included into the active arm of the LUST Trial, a standard pre– and postdialysis clinical evaluation of volume status was done immediately before the US-B lines measurements. Information about BP and BP changes over time, peripheral edema, presence/absence of dyspnea, crackles on lung auscultation, interdialysis body weight gain, and body weight trajectory data over time was collected. Lung auscultation was carefully done in anterior and posterior basilar sites in each hemithorax in the seated position. Patients were asked to perform periodic, slow, deep respirations. To evaluate crackles, the following scale (adapted from Kataoka and Matsuno [14]) was used: 1, no crackles; 2, I am uncertain about the presence of fine crackles; 3, definite fine crackles at lung bases; 4, moderate crackles; and 5, bilateral, diffuse crackles. For clinical edema, the following scale was used: 1, no clinical edema; 2, slight pitting (2-mm depth) with no visible distortion; 3, somewhat deeper pit (4 mm) with no readily detectable distortion; 4, noticeably deep pit (6 mm) with the dependent extremity full and swollen; and 5, very deep pit (8 mm) with the dependent extremity grossly distorted (18).
Statistical Analyses
Data are expressed as means±SD (normally distributed data), medians and interquartile ranges (IQRs; non–normally distributed data), or percent frequencies (categorical data). The correlation between US-B lines and pulmonary crackles/peripheral edema was assessed by using the Pearson correlation coefficient, and the shared variance was calculated by squaring the same correlation coefficient. To account for the fact that US-B lines were repeated measurements in the same patients, we performed weighted regression analyses (19). The discrimination power of crackles and peripheral edema for lung congestion as detected by US-B lines was investigated by analyzing the area under ROC curve. In this analysis, five categories of crackles (14) or peripheral edema (18) (as described before) were used to predict the presence of lung congestion as assessed by lung US (mild: ≥5 to <15 US-B lines; moderate: ≥15 to ≤30 US-B lines; and severe: >30 US-B lines) (17). Sensitivity, specificity, and positive and negative predictive values of crackles and edema were also calculated. Pre- and postdialysis variations of US-B lines were compared by the Wilcoxon test, and the relationship between pre- and postdialysis changes in crackles and peripheral edema was investigated by using the Wilcoxon test for dependent variables. The agreement between US-B lines and crackles/edema was also described by using the Cohen κ-coefficient. Statistical analysis was performed by using standard statistical packages (SPSS for Windows, Version 20 [IBM SPSS, Chicago, IL] and MedCalc Software, Version 15 [MedCalc, Ostend, Belgium]).
Results
The main demographic, anthropometric, clinical, and biochemical characteristics of the study population at baseline are detailed in Table 1. The categorization of patients refers to the baseline assessment of US-B lines; the number of paired US-B lines reported in Table 1 refers to the number of measurements falling in each category. Mean age was 72 years old, 65% of patients were men, and 20% were current smokers; 37% of patients had diabetes, and all patients had cardiovascular comorbidities. No differences in the other clinical data were found. These patients had been on regular hemodialysis for a median time of 52 months (IQR, 30–113) and were being treated with thrice weekly hemodialysis with various hemodialysis filters; 56% of patients were treated with various antihypertensive drugs (32% of patients on monotherapy with calcium channel blockers, angiotensin converting enzyme inhibitors, sartans, α- or β-blockers, clonidine, or furosemide; 36% of patients on double therapy; 18% of patients on triple therapy; and 14% of patients on multiple therapy with various combinations of these drugs).
Main demographic, anthropometric, and clinical characteristics in patients as divided according to ultrasound B lines number
Association of Crackles and Peripheral Edema with Lung Congestion as Measured by US-B Lung
No patient had intercurrent inflammatory or infectious broncopulmonary disease when simultaneous assessment of US-B lines and crackles was done. Overall, 1106 paired assessments (in 79 patients) of lung congestion by auscultation and lung US were performed. Thus, on average, each patient had 14 paired assessments. In 144 assessments (13%), there was evidence of moderate congestion (≥15 to ≤30 US-B lines), and in 118 assessments (11%), severe lung congestion (>30 US-B lines) was documented. Overall, in the vast majority (61%) of these assessments, evidence of moderate or severe lung congestion by US was not accompanied by the presence of crackles. In severe lung congestion (as defined by US), the prevalence of crackles (49%) was higher (P=0.003) than that registered in patients with moderate (by US) congestion (31%). Table 2 shows the number of US-B lines across crackles-number strata of increasing severity.
Ultrasound B lines number across lung crackles strata of increasing severity
By the same token, peripheral edema was conspicuously absent in as many as 87% and 80% of assessments where lung US indicated moderate and severe lung congestion, respectively. The severity of lung congestion by crackles correlated very weakly with the severity of lung congestion as detected by US-B lines (shared variance of 12%) (Figure 1A). The correlation between peripheral edema and the number of US-B lines was even weaker, and the shared variance was minuscule, being a mere 4% (Figure 1B). The combination of crackles and edema (i.e., the sum of the two scores) did not improve the degree of the association of these signs with US-B lines (shared variance of 10%).
Poor correlation between ultrasound (US) B lines and clinical signs of lung congestion. Correlation between the severity of lung congestion as detected by US-B lines with (A) pulmonary crackles and (B) peripheral edema.
Postdialysis Changes of US-B Lines, Pulmonary Crackles, and Peripheral Edema
Lung congestion as detected by lung US was modified by dialysis treatment. The median number of US-B lines before dialysis was nine (IQR, 5–19), and it fell to five (IQR, 2–10; P<0.001) after dialysis. In detail, the number of US-B lines decreased in 79% of patients and did not change in 21% of patients (i.e., remained exactly the same or changed by two US-B lines at most). Before dialysis, in 39 of 79 patients (49% of patients) and a total of 439 assessments in the same patients (79% of assessments), no crackles were detected. Similarly, in 31 of 79 patients (39% of patients) and 495 assessments (90% of assessments) in the same patients, no peripheral edema was registered. In the remaining assessments (i.e., those where these alterations were noted), both crackles (from a median predialysis score of 2.00 [IQR, 1.00–2.25] to a postdialysis score of 1.00 [IQR, 0.00–2.00]; P<0.001) and peripheral edema (from 1.00 [IQR, 1.00–1.25] to 1.00 [IQR, 1.00–1.00]; P<0.001) reduced after dialysis. After dialysis, the degree of association of crackles and peripheral edema with US-B lines remained very poor (shared variances of 13% and 8%, respectively).
Agreement between US B Lines and Clinical Examination
In line with the previous analysis showing a modest shared variance between US-B lines and pulmonary crackles/peripheral edema (see above), we found a poor agreement (by the κ-weighted statistics) between US-B lines and pulmonary crackles in both analyses considering the average number of US-B lines and the average grading of crackles and peripheral edema across the observation period or the whole series of measurements considered individually (Table 3).
Agreement (weighted-κ [95% confidence interval]) between ultrasound B lines and pulmonary crackles, peripheral edema, and a combination thereof considering the individual average number of ultrasound B lines in the 79 patients and the simultaneous average grading of crackles and peripheral edema or the whole series of measurements considered one by one (n=1106)
Discrimination Analyses and Standard Diagnostic Tests
On discriminant analysis (ROC curve), crackles had a limited discriminatory power for the diagnosis of mild, moderate, or severe lung congestion as assessed by US (mild lung congestion: area under the receiver operating curve [AUC] =0.61; 95% confidence interval [95% CI], 0.57 to 0.64; P<0.001; moderate congestion: AUC=0.65; 95% CI, 0.61 to 0.70; P<0.001; severe congestion: AUC=0.68; 95% CI, 0.62 to 0.74; P<0.001). Peripheral edema had virtually no discriminatory power (mild lung congestion: AUC=0.51; 95% CI, 0.48 to 0.55; P=0.54; moderate congestion: AUC=0.54; 95% CI, 0.50 to 0.58; P=0.05; severe congestion: AUC=0.56; 95% CI, 0.50 to 0.62; P=0.03). The use of a composite score (the sum of crackles and edema) failed to materially increase the discrimination power of crackles and peripheral edema considered as separated physical signs (mild lung congestion: AUC=0.60; 95% CI, 0.57 to 0.64; P<0.001; moderate congestion: AUC=0.65; 95% CI, 0.61 to 0.70; P<0.001; severe congestion: AUC=0.68; 95% CI, 0.62 to 0.74; P<0.001). The sensitivity, specificity, and positive and negative predictive values of crackles and peripheral edema for lung congestion are reported in Table 4. In general, both clinical signs had very low sensitivity but high specificity for lung congestion. However the false negative rate was exceedingly high for both lung crackles and peripheral edema, ranging from 69% to 99% (Table 4). The likelihood ratios clearly indicated that crackles and peripheral edema had modest value for ruling in or out lung congestion.
Diagnostic value of pulmonary crackles and peripheral edema for the diagnosis of moderate and severe lung congestion in the 1106 paired measurements (in 79 patients) of these clinical signs and simultaneous ultrasound B lines
Discussion
This study shows that two time–honored clinical signs, like lung crackles and peripheral edema, that are universally applied to detect and monitor volume excess and/or fluid translocation to tissues and organs in disease states, including ESRD, have an unsuspectedly low sensitivity for detecting interstitial edema in a most critical organ, like the lungs, in this population. These findings have potential implications for clinical practice and suggest that these clinical signs only remotely reflect the degree of lung congestion as measured by an objective, well validated method, like lung US scanning.
Lung auscultation is a cornerstone of physical examination. This procedure provides important clinical information about the respiratory system. Although expertise in auscultation requires standardization and specific training, the technique is simple, low cost, and widely available, and it can be repeated whenever required to monitor patients (20). In patients with heart failure, the presence of crackles is considered indicative of pulmonary congestion secondary to left ventricular dysfunction and/or volume overload, and this physical sign guides physicians to implement or change therapy in patients with heart disease (21). The presence of ankle edema and basal lung crackles helps to identify patients with suspected heart failure who should be referred for echocardiography (3). However, compared with imaging techniques, lung auscultation is notoriously insensitive to capture an increased quantity of fluid in the lungs in patients with acute heart failure (22) and ambulatory patients with chronic heart failure (23,24), where the technique has both low sensitivity and low specificity as well (23). Furthermore, in the acute care setting, the diagnosis of interstitial edema by auscultation is substantially inferior to those of chest radiography and lung US (25).
Patients with ESRD maintained on chronic dialysis have an exceedingly high risk of hospitalization and death from pulmonary edema (1), and the differentiation of congestive heart failure from volume expansion may be problematic in these patients (26). Lung congestion is an insidious phenomenon that builds up gradually over weeks before frank, symptomatic pulmonary edema (27). Furthermore, the degree of lung congestion only weakly associates with estimates of volume excess in ESRD, like total body water by Body Impedance Analysis BIA and interdialysis weight gain/ultrafiltration volume (10). Subclinical congestion is of peculiar relevance, because these patients have increased alveolocapillary permeability (28), which make them vulnerable to volume overload that gradually builds up during the dialysis interval. In this study, the median number of US-B lines before a regular hemodialysis session was nine, and the IQR spanned from five to 19 lines. These estimates underlie a median accumulation of water in the lungs of about 1.2 L in a range comprised between 0.5 and about 2.2 L, which is a substantial degree of congestion (6). Of note, the majority of these patients with ESRD had no or very mild effort dyspnea, indicating that clinical symptoms may be conspicuously absent, even at relevant levels of water accumulation in the lung. At peak of volume expansion (i.e., before dialysis), crackles and peripheral edema were relatively rare, being present just in 21% and 10% of patients, respectively. The agreement between US-B lines and pulmonary crackles, between the same parameter with peripheral edema, or between a combination of crackles/edema was poor. As one may expect from the relatively rare occurrence and the low sensitivity of lung crackles and peripheral edema, the specificity of these signs for the diagnosis of lung congestion was very high indeed, but this high negative diagnostic power was counterbalanced by almost equally high false negative rates. Considering crackles and edema in aggregate (which conforms to clinical practice and maximizes the discriminant power for lung congestion of these signs), the combination of these two signs showed a satisfactory to low positive predictive value (Table 4) (ranging from 79% [mild congestion] to 33% [severe congestion]) and a high to moderate negative predictive power (ranging from 90% [severe congestion] to 48% [severe congestion]). However, this alteration went unnoticed in a substantial proportion of patients without crackles and/or peripheral edema (false negative rate ranging from 69% to 87%). Overall, the discriminant ability of crackles and peripheral edema for the diagnosis of moderate and severe lung congestion ranged from 0.54 to 0.68, which is a poor discrimination power (29). Findings in this study support the contention that crackles and edema provide only modest information on interstitial edema in a critical organ, like the lung, and reinforce the rationale underpinning the LUST Trial (13). Lung US is a highly reliable, low–cost, and easy to learn technique that can be performed with whatever echotomographic machine is available from a handheld one to echocardiography machines and machines applied for the sonography of abdominal organs (8). The ongoing LUST Trial will establish whether systematic application of lung US may help preventing excessive water accumulation in the lung and ultimately, improve clinical outcomes in high-risk patients on dialysis.
This study has limitations. First, we repeatedly measured US-B lines and quantified crackles and peripheral edema in patients in the active arm of a clinical trial enrolling patients at high cardiovascular risk. Therefore, our results cannot be generalized to the whole dialysis population. However, it is precisely in this population that the risk of lung congestion is highest. Second, we focused on lung auscultation as traditionally performed by standard stethoscopes by trained physicians. Novel acoustic devices for use at the bedside are being proposed (e.g., electronic stethoscopes synchronized with small recorders in the form of smartphone applications) to record lung sounds and enhance the usefulness of auscultation (20). Therefore, the value of these novel devices has potential for the detection of lung congestion far superior to conventional auscultation. Third, although the measurements of crackles and peripheral edema in the LUST Trial were well standardized and performed with a high degree of attention by physicians, we have not specifically measured the interobserver variability of these clinical signs in the LUST Trial.
In conclusion, two classic physical signs, like lung crackles and peripheral edema, have a very low sensitivity for detecting interstitial lung edema in patients with ESRD. These findings reinforce the rationale underlying the LUST Trial, a trial testing US-B lines as an instrument to guide interventions aimed at mitigating lung congestion in high-risk patients on hemodialysis.
Disclosures
None.
Acknowledgments
We thank Sarah Rocchi and Gennaro D’Angelo for their invaluable support during the Lung Water by Ultra-Sound Guided Treatment to Prevent Death and Cardiovascular Complications in High Risk ESRD Patients with Cardiomyopathy (LUST) Trial.
The LUST Trial is a study entirely funded by the European Renal Association - European Dialysis Transplant Association. We thank Nancy CHRU University Hospital, which sponsored the trial in the French centers.
The LUST Trial collaborators can be found in the Supplemental Appendix.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
See related editorial, “Crackles and Comets: Lung Ultrasound to Detect Pulmonary Congestion in Patients on Dialysis is Coming of Age,” on pages 1924–1926.
This article contains supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.03890416/-/DCSupplemental.
- Received April 6, 2016.
- Accepted July 14, 2016.
- Copyright © 2016 by the American Society of Nephrology