High-altitude pulmonary edema (HAPE) is an acute and severe altitude disease, and its primary characteristic is pulmonary edema induced by hypoxic environment [
Until recently, the most valuable ancillary diagnostic tool for HAPE was chest radiography. However, X-ray examination may be unavailable or inconvenient in remote locations or under emergency conditions. Frequent exposure to radiation is also problematic, especially for pregnant women or children. Thus, a more convenient and reliable tool is needed for the diagnosis of HAPE.
Lung ultrasound (LUS) is a reliable diagnostic tool for pulmonary diseases [
The primary aim of our study was to determine the sensitivity and specificity of prehospital lung ultrasound for HAPE. The diagnosis at hospital discharge was used as the gold standard. The secondary aim was to assess the surveillance value of LUS for assessing the effect of treatment in HAPE patients. The design is showed in Figure
The study design.
A prospective study was conducted in the Department of High Altitude Diseases of Tibet Military General Hospital, China. This research was approved by the Ethics Committee of Tibet Military General Hospital (KY20160501).
We studied a consecutive sample of adult patients admitted to the Department of High Altitude Diseases for suspected HAPE. All patients were older than 10 years of age and were not pregnant.
Patients who met all of the following criteria were suspected of having HAPE: in a plateau location or higher altitude district within one week prior, cough, chest tightness, dyspnea, and obvious cyanosis. The exclusion criteria were the following: consciousness disorders; patients who were unable to follow the research plan and sign the consent form; a history of chronic pulmonary diseases, including interstitial lung disease, COPD, or other parenchymal lung disease; and a history of cardiac disease (ischemia, arrhythmia, valve dysfunction, or cardiomyopathy).
After enrollment, all patients were admitted to the high-altitude disease ward and underwent LUS, CXR, and a physical examination. Patients diagnosed with HAPE initially accepted the standard treatment for HAPE, and the non-HAPE patients accepted the corresponding treatment. If the diagnosis was changed during treatment, the program of treatment was changed according to the clinical needs.
LUS was performed using the LOGIQ 7 Pro Digital Premium Ultrasound System (GE Healthcare, USA) with a convex 3.5C broadband 2.0–5.0 MHz probe. Scanning was performed with the patient in the supine position, and the probe was placed perpendicular to the chest wall over the intercostal spaces. Both lungs were scanned along the parasternal, midclavicular, anterior axillary, and midaxillary lines. For the left lung, the scanning range was from the second to the fourth intercostal spaces, and for the right lung, the scanning range was from the second to the fifth intercostal spaces (Figure
Lung ultrasound scanning for B-lines (cited from L Gargani et al., “Ultrasound lung comets for the differential diagnosis of acute cardiogenic dyspnea: a comparison with natriuretic peptides,”
After the participants were admitted to the Department of High Altitude Diseases, a lung ultrasound was immediately performed prior to treatment. An experienced physician performed the LUS and determined the imaging diagnosis together with the B-line score. The LUS images were stored in DVD format.
In order to assess the reliability of LUS, intraobserver variability and interobserver variability were detected later. After the patients were discharged from the hospital, all identifying information was removed from the LUS images; then, the previous physician and another experienced physician read the handled images in a blinded manner to assess the intra and interobserver variability. Throughout the process, the two physicians were both blinded to any X-ray findings and clinical information.
CXR in the posteroanterior view was performed within 1 hour following ultrasound examination. Similar to LUS, CXR was performed before treatment and stored in DVD format. After the patients were discharged from the hospital, all identifying information was removed from the CXR images; then, two experienced radiologists read the images in a blinded manner. The first radiologist determined a diagnosis based on the X-ray images, and the second radiologist determined a radiologic score related to the extravascular lung fluid according to the reference [
The positive CXR results indicating HAPE were defined according to “Diagnostic Criteria of High Altitude Disease in China”: a patchy or cloudy infiltrate shadow centered on the hila and radiated to one or two sides of the lung fields [
For all patients, LUS and CXR were performed again after treatment. Reexaminations were performed on the day of hospital discharge. The CXR and LUS images obtained after treatment were read by the same physicians who read the images before treatment.
An independent experienced doctor who was blinded to any clinical information (including the LUS and CXR) recorded moist rales before treatment and on the day of discharge. The moist rales were auscultated in the same position that was scanned in the LUS and were recorded as positive or negative for each person.
Oxygen saturation was measured using a Fingertip pulse oximeter (ver1.0, the EMC of this product complies with the IEC60601-1-2 standard, Academy of Military Medical Sciences) before treatment and on the day of discharge.
All results of clinical research mentioned above, including LUS CXR and moist rales, were only used for clinical research and blinded to clinical doctors.
(1) Oxygen was delivered. (2). Aminophylline and/or dexamethasone were injected intravenously. The altitude where the remedy was performed for all patient s was 3700 m.
Participants who met all of the following criteria were diagnosed with HAPE.
(1) The CXR showed typical signs of pulmonary edema before treatment; (2) noted improvements in the pathogenic conditions and CXR images occurred rapidly after standard treatment for HAPE; and (3) other diseases were excluded.
The diagnosis and treatment were performed by experienced doctors who were blinded to the clinical research results.
Patients who met all of the following criteria were discharged from the hospital.
(1) Typical symptoms (including cough, sputum, and chest tightness) were completely relieved; (2) abnormal physical signs, including cyanosis and moist rales, vanished completely; and (3) the patients received the standard treatment for HAPE for at least 48 hours.
The diagnostic accuracy of the LUS, CXR, and moist rales before treatment for the diagnosis of HAPE was calculated. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and 95% confidence intervals (CIs) were calculated using standard formulas. The discrepancies in sensitivity and specificity between LUS and CXR and between LUS and moist rales were calculated using McNemar’s Chi-square test. The final diagnosis was the reference test for all calculations.
The intra- and interobserver variability of the LUS was measured by calculating intraclass correlation coefficient (ICC).
The concordance between the LUS and CXR of HAPE patients after treatment was also calculated. The result was reported using the statistic.
ROC curves with LUS score of all participants before treatment was calculated either.
Linear regression analysis was used to assess whether the independent variable B-line score had significant impact on the dependent variable oxygen saturation before treatment.
The McNemar, ICC, ROC curves, Linear regression analysis, and
From November 1, 2016, to March 31, 2017, 148 suspected HAPE patients, including 9 females and 139 males, were enrolled in the study. Overall, 126 cases were diagnosed with HAPE, and 22 patients received a different diagnosis. Of the patients who were not diagnosed with HAPE, 1 case had bronchitis, 4 cases had acute upper respiratory infections, and 17 cases were diagnosed with acute mild high-altitude disease (Tables
Characteristics of enrolling patients.
HAPE ( |
Non-HAPE ( |
| |
---|---|---|---|
General characteristics | |||
Age (years) | 31.09 ± 7.65 | 31.40 ± 9.73 | 0.886 |
Male | 119 (90.9) | 20 (94.4) | 0.000 |
Heart rate(beats per minute) | 108.50 ± 18.82 | 95.77 ± 10.51 | 0.000 |
Systolic arterial pressure (mmHg) | 113.79 ± 14.35 | 122.14 ± 18.34 | 0.000 |
Diastolic arterial pressure (mmHg) | 75.60 ± 11.61 | 78.77 ± 14.18 | 0.000 |
Time of high altitude exposed (days) | 3.14 ± 1.56 | 3.64 ± 1.89 | 0.000 |
Oxygen saturation (%, before treatment) | 65.12 ± 7.77 | 78.05 ± 2.40 | 0.000 |
Oxygen saturation (%, after treatment) | 88.10 ± 2.17 | 88.05 ± 1.91 | 0.479 |
Clinical characteristics | |||
Moist rales (positive) | 102 (80.95) | 3 (13.64) | 0.000 |
CXR (positive) | 117 (92.86) | 1 (4.55) | 0.000 |
LUS characteristics | |||
B-lines positive (B-lines score >5) | 124 (98.41) | 2 (9.09) | 0.000 |
Normal lung ultrasound | 2 (1.59) | 20 (90.91) | 0.000 |
Other abnormal | 0 (0) | 0 (0) | |
B-line score of HAPE (before treatment) | 57.14 ± 42.93 | 0.64 ± 1.79 | 0.000 |
B-line score of HAPE (after treatment) | 0.17 ± 1.13 | 0.00 ± 0.00 | 0.000 |
Data are presented as mean ± standard deviation or number (%).
Characteristics of enrolling patients.
HAPE severity according to HULTGREN grades | |
Grade 1 (mild) | 3 |
Grade 2 (moderate) | 21 |
Grade 3 (serious) | 93 |
Grade 4 (severe) | 9 |
Patients of non-HAPE (number %) | 22 (14.9) |
Bronchitis | 1 (0.7) |
Acute upper respiratory infection | 4 (2.7) |
Acute mild high-altitude disease | 17 (11.5) |
Radiologic score of extravascular lung water of HAPE (before treatment) | |
Median (IQR) |
39 (29–48) |
Range | 0–83 |
Of the 126 HAPE patients, 124 cases showed positive LUS results (B-line score >5). In the non-HAPE patients, only 2 cases diagnosed with acute mild high-altitude disease showed positive LUS results (B-line score >5). In all participants, no other abnormal signs except B-lines were detected on the LUS. ROC curve with LUS score was also established. The best critical value of B-line score for the diagnosis of HAPE was 6.5 and the ROC curve’s area was 0.995 (Figure
ROC curve with LUS score of all participants before treatment. The best critical value of B-line score for the diagnosis of HAPE was 6.5 and the ROC curve’s area was 0.995.
The intra- and interobserver variability in the B-line scores from the ultrasound images before treatment was assessed by 2 independent observers. The assessments had high ICC indicating excellent repeatability. The within and between observers ICC were 0.995 (95% CI 0.993–0.996) and 0.981 (95% CI 0.974–0.986) separately.
Moist rales were recorded in only 102 HAPE patients before treatment. Additionally, moist rales were recorded for 3 non-HAPE patients before treatment (Table
Results of LUS, CXR, and auscultation for moist rales before treatment.
HAPE+ | HAPE− | |
---|---|---|
LUS+ | 124 | 2 |
LUS− | 2 | 20 |
CXR+ | 117 | 1 |
CXR− | 9 | 21 |
Auscultation+ | 102 | 3 |
Auscultation− | 24 | 19 |
The sensitivity, specificity, PPV and NPV of LUS, CXR, and moist rales before treatment were calculated and compared with the final diagnosis (Table
Diagnostic value of LUS, CXR, and moist rales to HAPE.
LUS (95% CI) | CXR (95% CI) | Moist rales (95% CI) | |
---|---|---|---|
Sensitivity | 0.98 (1.01–0.96) | 0.93 (0.97–0.88) | 0.81 (0.88–0.74) |
Specificity | 0.91 (1.03–0.79) | 0.95 (1.04–0.87) | 0.86 (1.01–0.72) |
Positive predictive values | 0.98 (1.01–0.96) | 0.99 (1.01–0.98) | 0.97 (1.00–0.94) |
Negative predictive values | 0.91 (1.03–0.79) | 0.70 (0.86–0.54) | 0.44 (0.59–0.29) |
Positive likelihood ratio | 10.83 (64.07–4.56) | 20.43 (110.45–2.40) | 5.94 (14.29–1.73) |
Negative likelihood ratio | 0.0175 (0.0993–0.0063) | 0.0748 (0.1414–0.0396) | 0.2206 (0.2638–0.1194) |
Of the 126 cases diagnosed with HAPE, 10 patients were not reassessed by CXR at discharge. We compared the LUS and CXR results at discharge: of the 116 HAPE patients who finished the clinical study, 110 cases had negative results on LUS and CXR; 2 cases had positive results on both LUS and CXR; 1 case had negative results on CXR but positive results on LUS; and 3 patients had negative findings on LUS and positive CXR results (Table
Results of CXR compared with LUS in HAPE patients after treatment.
CXR+ | CXR− | Total | |
---|---|---|---|
LUS+ | 2 | 1 | 3 |
LUS− | 3 | 110 | 113 |
Total | 5 | 111 | 116 |
Before treatment, B-line score was correlated with oxygen saturation closely (adjusted
Distribution of oxygen saturation and B-line score in all participants (adjusted R2 for B-line score vs. oxygen saturation = 0.819;
We did not observe any adverse events related to LUS examination in this study.
HAPE is mainly characterized by a large amount of exudation in the pulmonary alveoli [
Fagenholz et al. observed that HAPE patients had higher B-line scores than healthy subjects [
Our experimental results were in accordance with previous studies. The main HAPE findings on LUS were multiple B-lines (Figure
Characteristic manifestations of HAPE on LUS. Patients showed intensive B-lines. The B-lines vanished along with absorption of the pulmonary edema. Typical images from one HAPE patient: (a) CXR before treatment: large flocculent infiltrates in the right lung; (b) CXR after treatment: pulmonary edema was entirely absorbed; (c) LUS before treatment: multiple B-lines; (d) LUS after treatment: normal image.
HAPE had multiple manifestations on CXR, whereas the LUS manifestations were only intensive B-lines. (a) Flake and trabs like shadow in inferior lobe of right lung; (a1), corresponding LUS image; (b) butterfly-shaped shadow; (b1), corresponding LUS image; (c) large infiltrates involving the entire lobar; (c1), corresponding LUS image.
Only 2 diagnosed cases of HAPE were negative on LUS. These cases all showed a small amount of pulmonary edema on the CXR, as evidenced by an enlarged hilar shadow or small patchy shadows (Figure
Examples of HAPE patients with negative manifestation of LUS. (a) CXR before treatment: enlarged hilar shadows can be observed; (a1) corresponding CXR after treatment: the image returned to normal; (a2) corresponding LUS before treatment: the images were normal, and no B-lines were detected; (b) CXR before treatment: densified hilar shadows and small patch shadows can be observed in the upper left lung (white arrow); (b1) corresponding CXR after treatment: the image returned to normal; (b2) corresponding LUS before treatment: only a few B-lines (B-line score = 2) were detected.
LUS also showed an improved negative diagnostic value for HAPE. The specificity of LUS had no significant difference compared with the specificity of moist rales or CXR.
B-lines are a sign of pulmonary edema but also a sign of interstitial pneumonia and severe pulmonary fibrosis, which may generate diffuse intensive B-lines [
We also found high coincidence rate between CXR and LUS results after treatment; the result indicates that LUS is valuable for the surveillance of HAPE. Compared to CXR, LUS is more convenient and faster and is especially suitable for use in emergency departments [
To the best of our knowledge, this study is the first to reveal the actual diagnostic value of LUS for HAPE through comparison with auscultation or CXR and this study is the largest study involving the diagnosis and monitoring of HAPE by LUS to date.
The main manifestation of HAPE was multiple B-lines. LUS had a high sensitivity and specificity for the diagnosis of HAPE. Otherwise, LUS showed a favorable surveillance effect for the treatment of HAPE. Thus, we recommend the use of LUS for the diagnosis and monitoring of HAPE.
As it has been mentioned before, B-lines is not the sign presented only in pulmonary edema, but it may also indicate interstitial lung diseases. The good results of LUS in our research are probably related to the high prevalence of HAPE in the population (126/(126 + 22)). Lack of larger sample size is no doubt a limitation of our research. However, according to the past researches, the incidence of interstitial lung diseases combined with acute high-altitude expose history was very rare, only limited to some case reports; meanwhile, accurate diagnosis of these cases can be gotten though comprehensive analysis for history, symptoms, and physical signs [
Due to the restriction of ethics and funds, CT was not performed widely in this study, especially when the LUS and CXR results did not match. We believe that the utilization of CT may enhance the persuasiveness of this research.
The monitoring by LUS during the process of treatment was not performed because of the lack of researchers. The relative research may better reveal the surveillance effect of LUS for HAPE.
The data of the research had been shared in the ResMan research manager (
Lung ultrasound (LUS) has proven to be a reliable tool for the diagnosis of pulmonary diseases. However, the actual diagnostic value of LUS for HAPE is still unknown. Our objective was to determine the feasibility of using LUS for the diagnosis of HAPE. Our study got the following results: LUS had higher sensitivity than moist rales and CXR for the diagnosis of HAPE. After treatment, LUS was consistent with CXR in 96.55% of HAPE patients. The results indicate that LUS is a reliable method for the diagnosis and surveillance of HAPE.
The funder is not involved in the manuscript writing, editing, approval, or decision to publish. Weibo Yang, Yuliang Wang, Xuewen Huang, Maoxia Lv, Bin Liu, Dingzhou Yang, Zhenhan Yang, and Tingshan Xie are currently at Xizang Military General Hospital, Lhasa City, China. Zewu Qiu is currently at Digestive System Department of Affiliated 307 Hospital, Beijing City, China.
The authors declare that they have no conflicts of interest.
The study was funded by China Post-Doctoral Science Foundation Grant (no. 2017M623356).