266 Acta Med Indones - Indones J Intern Med • Vol 54 • Number 2 • April 2022 ORIGINAL ARTICLE Accuracy of Bedside Lung Ultrasound in Emergency (BLUE) Protocol to Diagnose the Cause of Acute Respiratory Distress Syndrome (ARDS): A Meta-Analysis Oke Dimas Asmara1*, Ceva Wicaksono Pitoyo1, Vally Wulani2, Kuntjoro Harimurti3, Abrianty P. Araminta4 1 Division of Pulmonology, Department of Internal Medicine, Faculty of Medicine University of Indonesia - Cipto Mangunkusumo Hospital, Jakarta, Indonesia. 2 Division of Thoracic Imaging, Department of Radiology, Faculty of Medicine University of Indonesia, Jakarta, Indonesia. 3 Division of Geriatric, Department of Internal Medicine, Faculty of Medicine University of Indonesia - Cipto Mangunkusumo Hospital, Jakarta, Indonesia. 4 Departement of Internal Medicine, Faculty of Medicine University of Indonesia, Jakarta, Indonesia. * Corresponding Authors: Oke Dimas Asmara, MD. Division of Pulmonology, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital. Jl. Salemba Raya no. 6, Jakarta Pusat 10430, Indonesia. Email: okeasmara16@gmail.com. ABSTRACT Background: There is a stigma that ultrasound cannot be used to see abnormalities in the air-filled organs makes ultrasound rarely used to identify lung abnormalities. This study purpose comparing diagnostic accuracy of BLUE protocol with gold standard for each diagnosis causing acute respiratory failure. Methods: Systematic search was done in 6 databases (Pubmed/MEDLINE, Embase, Cochrane Central, Scopus, Ebscohost/CINAHL dan Proquest) and multiple grey-literature sources for cross-sectional studies. We manually extracted the data from eligible studies and calculated pooled sensitivity, pooled specificity, likelihood ratio (LR) and diagnostic odds ratio (DOR). We follow PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guideline throughout these processes. Results: Four studies has been picked from total 509 studies involved. The results yield parameters indicating BLUE protocol as a reliable modality to diagnose pneumonia with pooled sensitivity 84% (95% CI, 76-89%), pooled specificity 98% (95% CI, 93-99%), LR+ 42 (95% CI, 12-147), LR- 0.12 (95% CI, 0.07-0.2) and DOR 252 (95% CI, 81-788), respectively. It also considerably applicable to diagnose pulmonary oedema with pooled sensitivity 89% (95% CI, 81-93%), pooled specificity 94% (95% CI, 89-96%), LR+ 14 (95% CI, 8-25), LR- 0.165 (95% CI, 0.11-0.24), and DOR 116 (95% CI, 42-320), respectively. Conclusion: BLUE protocol has good diagnostic accuracy to diagnose pneumonia and pulmonary oedema. We recommend implementing BLUE protocol as a tool in evaluating cause of ARF. Keywords: Ultrasonography, BLUE protocol, Accuracy, Respiratory Failure, Meta-analysis Vol 54 • Number 2 • April 2022 Accuracy of Bedside Lung Ultrasound in Emergency (BLUE) Protocol 267 INTRODUCTION Dyspnea is a common symptom and is an important sign of acute respiratory failure (ARF). This condition is a life-threatening situation and it is not uncommon for patients with ARF to require intensive oxygen therapy such as a mechanical ventilator. The case of ARF continues to increase every year with a mortality rate reaching 37%. Determining the cause of respiratory failure is an important step in the management of ARF.1-3 The BLUE (Bedside Lung Ultrasound in Emergency) protocol is an ultrasound examination algorithm of the lung to assist in searching for the diagnosis of various lung disorders by combining various artefacts.4-9 The accuracy of the BLUE protocol reaches 90.5% with a duration of approximately 3 minutes, so this Protocol very suitable for use in patients with ARF. However, the stigma that ultrasound cannot be used to see abnormalities in the air- filled organs makes ultrasound rarely used to identify lung abnormalities.9-10 Through this meta-analysis, the authors are going to assess several previous studies regarding the accuracy of the BLUE Protocol in diagnosing pulmonary disorders. With prompt and precise diagnosis, appropriate management for the patient can also be achieved. This study aims to determine the accuracy of the BLUE protocol in diagnosing the causes of ARF. METHODS Search Strategy A comprehensive search was carried out from six online databases namely Pubmed/ MEDLINE, Embase, Cochrane Central, Scopus, Ebscohost/CINAHL, and Proquest on 6-13 September 2020 . The search is performed with a combination of keywords based on MESH and text word combined with the Boolean operator. The keywords used come from the Population and Index Test components of the research questions that have been formulated. The keyword used from the Population component is Acute Respiratory Failure with its synonym and examples of the diagnosis of the cause of respiratory failure. The keyword used in the Index Test component is the BLUE protocol or Bedside Lung Ultrasound in Emergency. A manual search for grey-literature was carried out at various sources on September 7, 2020. The search was carried out on several portals, namely the GARUDA portal (Indonesia Ministry of Research and Technology Portal), Proquest (focus on thesis results, dissertations, scientific posters, or proceeding books), abstracts from the scientific book Jakarta International Chest and Critical Care Internal Medicine (JICCIM) in the last 5 years, snowballing method, the repository of the Library of the University of Indonesia and the National Library as well as the Global Index Medicus (GIM). Study Selection Inclusion criteria are diagnostic studies with a cross-sectional design, study subject age > 18 years, and comparing the diagnostic ability of the BLUE protocol with the gold standard. No language or year limits were applied. Exclusion criteria were studies that didn’t include data to calculate overall accuracy. The assessment of risk of bias and study quality was carried out by APA dan CWP. If there are differences of opinion regarding the selection criteria of an article, it will be resolved through consensus and reviewed by KH. The authors use the Covidence® software to assist in the selection stages of articles in this meta-analysis. Ethics Approval and Consent to Participate PROSPERO Systematic Review Registry number: CRD42020203208. BLUE Protocol Method Bedside lung ultrasound examination was introduced by Dr. Lichtenstein in 1989 to monitor critically ill patients in ICU setting. It has been widely used for detecting many lung disorders such as pleural effusion, pulmonary oedema, pneumothorax, pneumonia, and pulmonary embolism. He formulized the lung ultrasound findings into one framework called BLUE Protocol and become one of the most important parts of Point of Care Ultrasound (POCUS). In BLUE Protocol, patients were positioned in semi recumbent or supine position. Scans were done longitudinally and evaluated based on artefacts finding on some certain anatomical landmarks. The normal Oke Dimas Asmara Acta Med Indones-Indones J Intern Med 268 lung is characterized by normal A or B Line with lung sliding. BLUE Protocol also evaluate the presence of alveolar consolidation and/ or pleural effusion.10 Details of the BLUE protocol’s component is shown in Figure 1. Data Extraction and Quality Assessment Data extraction was carried out independently by two researchers. Basic characteristics data such as name of the principal investigator, type of study, place/country, year of publication, basic demographic characteristics of study subjects, population eligibility, eligibility of the gold standard used, sample size, characteristics of the ultrasound device, The characteristics of the ultrasound operator, duration of lung ultrasound, blinding, and comparison of outcomes from selected studies will be displayed in the form of a descriptive table. The output is written in a 2x2 table form and is displayed in terms of sensitivity and specificity. The performance of the BLUE protocol is displayed in the form of a receiver operating characteristic (ROC) curve. Assessment of the quality and risk of bias of selected studies was carried out using the Quality Assessment of Diagnostic Accuracy Study - 2 (QUADAS - 2). Data Synthesis and Statistical Analysis Statistical analysis on this meta-analysis was performed using RevMan software version 5.4 (Cochrane Collaboration, the Nordic Cochrane Center, Copenhagen) and STATA 14. The results of data analysis are presented in the form of a forrest plot if meta-analysis can be done. Heterogeneity assessed using I2 or X2 test with result of I2 <25%, 26-50%, and >50% reflecting low or insignificant, moderate, and significant heterogeneity, respectively. Fixed-effect model was chosen for insignificant heterogeneity, otherwise random-effect model was used. The expected results are in the form of accuracy, sensitivity, and specificity along with the confidence interval, likelihood ratio, diagnostic odds ratio, and the area under the ROC curve. The analysis was carried out in the form of an accumulation of all diagnoses and then continued with the analysis of each diagnosis. 483 studies identified through database searching 26 additional studies identified through other sources (grey-literature) 312 studies after duplicates removed 312 studies screened by title and abstract 210 studies excluded 98 studies excluded, with reasons: 46 wrong study design 22 wrong index test/intervention 10 wrong outcome 10 wrong population n = 1 wrong reference test 9 data were incomplete 102 full-text studies assessed for eligibility 5 studies included in qualitative synthesis 4 studies included in quantitative synthesis Id e n ti fi c a ti o n S c re e n in g E li g ib il it y In c lu s io n Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Flow Diagram for Study Selection Vol 54 • Number 2 • April 2022 Accuracy of Bedside Lung Ultrasound in Emergency (BLUE) Protocol 269 RESULTS Literature search Based on the systematic search carried out, a total of 509 articles were obtained and after adjusting for the eligibility criteria only 4 studies could be continued for the meta-analysis process (Figure 1). Study Characteristics In general, these studies classified as homogenous because most of the important characteristics were almost the same such as population eligibility, the unit site of the study, BLUE protocol implementation, ultrasound device/specification, gold standard used, and the presented output (Table 1 and 2). The unit/site used for Lichtenstein, Neto, and Danish study is the ICU whereas Patel and Bekgoz study takes place at the ER. The ICU and ER has almost the same characteristics, both taking care patient with breathing problem which life-threatening cases and require immediate care. From the origin of the country of the study, the findings from this meta-analysis could represent various types of major populations in the world.11-14 The population eligibility used by the five studies is almost the same which is patients with breathing problem and admitted into the criteria of breathing failure with indication intensive care. Patel’s research used population age above 12 years which is different from the other four studies which used adult population. The author had sent email correspondence on requisition for research data by Patel et al. however, to the date of this report is finished, the author had not received any reply therefore the author excluded Patel et al. research in both qualitative and quantitative synthesis. However, the author tried to include Patel et al research in sensitivity analysis to see if its exclusion from this research would produce significant output relative to the findings of this meta-analysis. The total samples used in the 4 studies is 770 patients. There is a difference in the ultrasound operator which performs the BLUE protocol. In the Lichtenstein, Bekgoz, and Danish studies, they used certified ultrasound operators with 2 years minimum experience on lung ultrasound. Neto et al used ultrasound operators who had received 5 hours theoretical training and performed 10 times lung ultrasound under supervision. The probes used in the five studies have similar characteristics, they are the probes with low frequency (curvilinear and microconvex) which frequency range 2-6 MHz. Low-frequency probes is the best option for lung ultrasound because it has broader and deeper exploration area than high-frequency probes.11-14. Assessment of Risk of Bias Two reviewers (O.D.A and A.P.A) evaluate the methodological quality of included studies according to Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) criteria. The assessment shown in Figure 2. Any discrepancies found would be resolved by consultation with the third expert reviewer (K.H). Data synthesis and analysis The results of t he included studies can be seen in Table 3. From all of the studies, it was found that the sensitivity of the BLUE protocol in diagnosing pneumonia was in the range of 83% to 97% with the combined sensitivity calculation being 84% (95% CI 76-89%). Whereas the specificity of the BLUE protocol in diagnosing pneumonia was in the range of 86% to 100% with the combined specificity calculation was 98% (95% CI 93-99%). Forest plot for pneumonia can be seen in Figure 3 and summary receiving operating characteristic (SROC) curve can be seen in Figure 4. The combined result of LR + is 42 (95% CI 12-147) and and LR- 0.12 (95% CI 0.07–0.2) respectively with DOR of 252 (95% CI 81–788). In diagnosing pulmonary edema, the sensitivity of the BLUE protocol was found to be in the range of 76% to 94% with a combined sensitivity calculation of 89% (95% CI, 81- 93%). Meanwhile, the specificity of the BLUE protocol in diagnosing pneumonia is in the range of 90% to 100% with the calculation of the combined sensitivity is 94% (95% CI, 89-96%). The combined results for LR+ were 14 (95% CI, 8-25) and LR- 0.165 (95% CI, 0.11-0.24), respectively, with a DOR number of 116 (95% CI, 42-320). Forest plot for pulmonary edema can be seen in Figure 5 and summary receiving operating characteristic (SROC) curve can be seen in Figure 6. Oke Dimas Asmara Acta Med Indones-Indones J Intern Med 270 Ta bl e 1. S tu dy C ha ra ct er is tic s. S tu dy Ye ar C ou nt ry U ni t S tu dy D es ig n N um be r of P at ie nt s In cl us io n C ri te ri a M ea n A ge U ltr as ou nd O pe ra to r U ltr as ou nd D ev ic e N um be r of A re a B lin de d Li ch te ns te in et a l11 20 08 Fr an ce IC U C ro ss se ct io na l 26 0 ad ul t p at ie nt s w ith a cu te re sp ira to ry fa ilu re 68 In ve st ig at or s (s ev er al y ea rs o f e xp er ie nc e) M ic ro co nv ex pr ob e 5- M H z (H ita ch i-4 05 ; H ita ch i M ed ic al ; To ky o, J ap an ) 6 po in ts N o, in ve st ig at or s w er e no t bl in de d to th e pa tie nt ’s c lin ic al pr es en ta tio n N et o et a l12 20 15 B ra zi l IC U C ro ss se ct io na l 37 ag e ≥ 18 y ea rs a nd ad m is si on to th e IC U fo r A R F, d efi ne d by o ne o f th e fo llo w in g: a re sp ira to ry ra te ≥ 3 0 br ea th s/ m in ; a P aO 2 ≤ 60 m m H g; a n ox yg en s at ur at io n on ro om ai r ≤ 9 0% , a s m ea su re d by pu ls e ox im et ry ; o r a c ar bo n di ox id e te ns io n (P C O 2) ≥ 45 m m H g w ith a n ar te ria l pH ≤ 7 .3 5 73 .2 N ew ly tr ai ne d op er at or s (a tte nd in g 5 ho ur s of th eo re tic al tr ai ni ng a nd p er fo rm in g 10 su pe rv is ed L U S e xa m in at io ns ) C ur vi lin ie r P ro be 3- 5 M H z (T os hi ba To sb ee ; T os hi ba , To ky o, J ap an ) 6 po in ts Ye s P at el e t a l15 20 18 In di a E R C ro ss se ct io na l 50 P at ie nt s ha vi ng a ge > 12 ye ar s, P at ie nt s an d/ or re la tiv es g iv in g in fo rm ed co ns en t, P at ie nt s of ac ut e re sp ira to ry d is tre ss re qu iri ng IC U ad m is si on w er e in cl ud ed . 59 .6 4 U ltr as ou nd w as p er fo rm ed in e m er ge nc y de pa rtm en t b y sa m e em er ge nc y ph ys ic ia n C ur vi lin ie r ( 2- 5 M H z) a nd L in ea r pr ob e (5 -1 0 M H z) , M ic ro m ax ul tra so un d sy st em , S on os ite 6 po in ts N o B ek go z et al 13 20 19 Tu rk ey E R C ro ss se ct io na l 38 3 A ll co ns ec ut iv e pa tie nt s ag ed > 18 y ea rs a dm itt ed to th e E D w ith a p rim ar y co m pl ai nt o f a cu te dy sp ne a an d w ho co ns en te d to p ar ic ip at e 65 .5 LU S w as c on du ct ed b y 5 E D p hy si ci an s w ho ha d be en p re vi ou sl y ce rti fie d by b as ic a nd ad va nc ed U S e du ca tio n an d ha d at le as t 2 ye ar s of E D a nd U S e xp er ie nc e. T he se E D p hy si ci an s w er e al so in fo rm ed b y 2 h of th eo re tic al le ct ur es re ga rd in g LU S a nd th e B LU E p ro to co l. Th ey a ls o pe rfo rm ed 1 0 su pe rv is ed L U S e xa m in at io ns a cc or di ng to th e B LU E p ro to co l M ic ro co nv ex pr ob e 2- 6 M H z (F uj ifi lm F az on e C B , J ap an ) 4 po in ts Ye s D an is h et al 14 20 19 In di a IC U C ro ss se ct io na l 90 A du lt pa tie nt s ad m itt ed to m ed ic al -s ur gi - c al IC U w ho h ad e vi de nc e of lu ng pa th ol og y as d em on st ra te d by a n ac ut e lu ng in ju ry (A LI ) s co re o f ≥ 1 47 .6 6 Th e in te ns iv is t p er fo rm in g LU S h ad > 2 ye ar s of e xp er ie nc e in p er fo rm in g LU S C ur vi lin ie r P ro be (2 -5 M H z) S on oS ite M -tu rb o (F uj ifi lm S on oS ite In c. , B ot he ll, W A , U S A ) 3 po in ts Ye s Vol 54 • Number 2 • April 2022 Accuracy of Bedside Lung Ultrasound in Emergency (BLUE) Protocol 271 Ta bl e 2 . G ol d S ta nd ar ds U se d in In cl ud ed S tu di es . Li ch te ns te in e t a l11 N et o et a l12 P at el e t a l15 B ek go z et a l13 D an is h et a l14 P ne um on ia In fe ct io us p ro fil e, ra di ol og ic as ym m et ry , m ic ro or ga ni sm is ol at ed (b lo od , i nv as iv e te st s) , r ec ov er y w ith an tib io tic s. In cl ud ed w er e in fe ct io us , a sp ira tio n, co m m un ity , o r h os pi ta l- ac qu ire d pn eu m on ia . P ne um on ia c om pl ic at in g ch ro ni c re sp ira to ry d is ea se w as c la ss ifi ed a s pn eu m on ia N ot s ta te d In fe ct io us p ro fil e, ra di ol og ic as ym m et ry , m ic ro or ga ni sm is ol at ed (b lo od ), re co ve ry w ith a nt ib io tic s in fe ct io n fin di ng s, c he st X -r ay s, m ic ro or ga ni sm is ol at io n (if p os si bl e) , C T (if n ec es sa ry ) N ot s ta te d P ul m on ar y E de m a E va lu at io n of c ar di ac fu nc tio n us in g ec ho ca rd io gr ap hy , fu nc tio na l t es ts , a nd A m er ic an H ea rt A ss oc ia tio n re co m m en da tio ns N ot s ta te d C he st ra di og ra ph y, e va lu at io n of c ar di ac fu nc tio n us in g ec ho ca rd io gr ap hy , r es po nd in g to di ur et ic s el ec tro ca rd io gr ap hy , c ar di ac b io m ar ke rs ec ho ca rd io gr ap hy (b y a ca rd io lo gi st ) N ot s ta te d P ne um ot ho ra x R ad io gr ap hy (C T if ne ce ss ar y) - C he st ra di og ra ph y (C T if ne ce ss ar y) C he st X -r ay s an d C T (if n ec es sa ry ) N ot s ta te d P ul m on ar y E m bo lis m H el ic al C T - H el ic al C T Th or ax C T an gi og ra ph y - A st hm a/ C O P D A st hm a (H is to ry , r es po nd s to b ro nc ho di la to r t re at m en t) C O P D (C on di tio n de fin ed as e xa ce rb at io n of c hr on ic re sp ira to ry d is ea se w ith ou t pn eu m on ia , p ne um ot ho ra x, pu lm on ar y ed em a, p le ur is y, o r pu lm on ar y em bo lis m . C O P D w as c on fir m ed b y fu nc tio na l te st s. ) N ot s ta te d H is to ry , r es po nd s to b ro nc ho di la to r tre at m en t, ch es t r ad io gr ap hy , a nd C O P D w as c on fir m ed b y fu nc tio na l te st s H is to ry , r es pi ra to ry fu nc tio na l t es ts , a nd re sp on se s to b ro nc ho di la to r t re at m en t - Fo r a ll pa tie nt s H is to ry , c lin ic al e xa m in at io n, ra di og ra ph y re ad b y ra di ol og is ts , C T w he n av ai la bl e, fa vo ra bl e cl in ic al pr og re ss io n un de r t re at m en t Th e fin al d ia gn os is o f t he ep is od e of A R F m ad e by th e IC U te am b ef or e pa tie nt s w er e di sc ha rg ed fr om th e IC U w as c on si de re d th e go ld s ta nd ar d Fo r a ll pa tie nt s: H is to ry , c lin ic al ex am in at io n, b as ic b lo od te st s an d sp ec ifi c bl oo d in ve st ig at io ns (a rte ria l bl oo d ga s an al ys is , D -d im er ), el ec tro ca rd io gr ap hy , r ad io gr ap hy re po rti ng b y ra di ol og is ts , C T as ne ed ed , f av or ab le c lin ic al p ro gr es si on un de r t re at m en t w as fo llo w ed a lo ng w ith Th e fin al c lin ic al d ia gn os is w as m ad e by a tte nd in g em er ge nc y ph ys ic ia ns (fo r 2 15 E D p at ie nt s be fo re d is ch ar ge fro m th e E D ), at te nd in g co ns ul ta nt ph ys ic ia ns (f or 1 26 h os pi ta liz ed p at ie nt s be fo re d is ch ar ge fr om th e ho sp ita l), a nd an IC U te am (f or 4 6 IC U p at ie nt s be fo re di sc ha rg e fro m th e IC U ) T ho ra x C T sc an Oke Dimas Asmara Acta Med Indones-Indones J Intern Med 272 Table 3. Results of Included Studies Lichtenstein et.al11 Neto et.al12 Patel et.al15 Bekgoz et.al13 Danish et.al14 Sn (%) Sp (%) Sn (%) Sp (%) Sn (%) Sp (%) Sn (%) Sp (%) Sn (%) Sp (%) Pneumonia 89 94 88 90 94.11 93.93 82 98 75.9 100 Pulmonary Edema 97 95 85 87 92.3 100 87 97 83.3 88.5 Pneumothorax 88 100 - - 80 100 85 100 88.9 100 Pulmonary Embolism 81 100 - - 100 100 46.2 100 - - Asthma/ COPD 89 97 67 100 85.17 88.88 96 75 - - Table 4. The Grading of Recommendations Assessment, Development and Evaluation (GRADE ) of Each Outcome16 GRADE Recommendations for BLUE Protocol Accuracy by Each Outcomes GRADE Domain Pneumonia (4 cross- sectional studies) Pulmonary Edema (4 cross-sectional studies) Pneumothorax (3 cross- sectional studies) Pulmonary Emboly (2 cross-sectional studies) Asthma/COPD (3 cross- sectional studies) Risk of Bias None None None None None Inconsistency None None None Serious (-1) Serious (-1) Indirectness None None None None None Imprecision None None Serious (-1) Serious (-1) Serious (-1) Publication Bias None None Serious (-1) Serious (-1) Serious (-1) Certainty of Evidence Results Sensitivity 84% 89% 71-89% 46-81% 50-98% Specificity 98% 94% 100% 99-100% 69-100% High certainty (we are very confident that the true effect lies close to that of the estimate of the effect) Moderate certainty (we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different) Low certainty (our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect) Very low certainty (we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect Vol 54 • Number 2 • April 2022 Accuracy of Bedside Lung Ultrasound in Emergency (BLUE) Protocol 273 Fig 3. Forest Plot and Diagnostic Accuracy of BLUE Protocol for Pneumonia Figure 2. Quality of Assessment of Included Studies by QUADAS-2 Tool. Figure 3. Forest Plot and Diagnostic Accuracy of BLUE Protocol for Pneumonia. Oke Dimas Asmara Acta Med Indones-Indones J Intern Med 274 Figure 4. Summary Receiving Operating Characteristic Curve of BLUE Protocol for Pneumonia Figure 5. Forest Plot and Diagnostic Accuracy of BLUE Protocol for Pulmonary Edema Vol 54 • Number 2 • April 2022 Accuracy of Bedside Lung Ultrasound in Emergency (BLUE) Protocol 275 Fig 6. Summary Receiving Operating Characteristic Curve of BLUE Protocol for Pulmonary Edema Figure 6. Summary Receiving Operating Characteristic Curve of BLUE Protocol for Pulmonary Edema Figure 7. Forest Plot and Diagnostic Accuracy of BLUE Protocol for Pneumothorax, Pulmonary Emboly, Asthma/ COPD Oke Dimas Asmara Acta Med Indones-Indones J Intern Med 276 Figure 8. Area Under Curve (AUC) BLUE Protocol for A) Pneumonia B). Subgroup Analysis: Ultrasound Operator C) Subgroup Analysis: Number of Ultrasound Zone. Vol 54 • Number 2 • April 2022 Accuracy of Bedside Lung Ultrasound in Emergency (BLUE) Protocol 277 Figure 9. Area Under Curve (AUC) BLUE Protocol for A) Pulmonary Edema B) Subgrup Analysis: Ultrasound Operator C) Subgroup Analysis: Number of Ultrasound Zone. Oke Dimas Asmara Acta Med Indones-Indones J Intern Med 278 B’ Profile Pneumonia Present A ProfileB Profile Pulmonary Edema Any A/B or C Profile Pneumonia Lung Sliding Abolished A lines Plus Lung Point Without Lung Point Venous Analysis Free VeinsThrombosed Vein Pulmonary Embolism Stage 3 COPD or Asthma PLAPS Pneumonia No PLAPS Figure 10. BLUE Protocol Alghoritm Not all studies have examined every diagnosis used by Lichtenstein as the original author of the BLUE protocol. The sensitivity and specificity ranges of the BLUE protocol in pneumothorax are 71-89% and 50-98%, in pulmonary emboli it ranges from 46-81% and 100%, and in asthma/COPD ranges from 50- 98% and 69-100%, respectively. Forest plot for pneumothorax, pulmonary emboli, and asthma/ COPD can be seen in Figure 7. DISCUSSION Several meta-analyses on the roles of lung ultrasound for diagnosing lung abnormalities had been conducted by previous researchers. The author recorded that there are at least 4 meta-analysis with lung ultrasound topics in diagnosing pneumonia. The main difference of this meta-analysis with previous study is in the population. This study enrolled all patients with breathing problems whereas the previous 4 meta- analysis studies specifically enrolled population suspected with pneumonia. During the search process, the authors found 14 original studies that discussed the accuracy of BLUE protocol but among them, there were 9 studies in the form of gray-literature that could not be included in the analysis because there was no complete text. Another limitation is that there are studies that did not include findings of pleural effusions. The discovery of a pleural effusion may guide the diagnosis of pulmonary disorders.32-35 In addition, the intervention/index test used by those meta- analysis studies were not standardized, whereas this study specified the assessment on the accuracy of the BLUE Protocol. However, the Vol 54 • Number 2 • April 2022 Accuracy of Bedside Lung Ultrasound in Emergency (BLUE) Protocol 279 accuracy of this 4 meta-analyses are nearly even with current study. The range of sensitivity and specificity of the lung ultrasound in pneumonia diagnosis by meta-analysis conducted by Chavez et al. is 80-95%, Ye et al., Long et.al, Llamas- Alvarez et al. is 70-96%, consecutively.7, 15-17 Three of five studies analyzed by this study included the operator who didn’t know the patient’s clinical and still produce good accuracy because the ultrasound output is objective. Ultrasound accuracy might be better if it is adjusted with patient’s clinical examination data. History taking and physical examination is mandatory and irreplaceable. Lung ultrasound is complimentary of history taking and physical examination to enhance the physician’s diagnosis probability. A study in Italy by Peris et al. shows that lung ultrasound could reduce the need for thorax X-Ray imaging by 26% and thorax CT scan by 47%.1, 28-31. We use GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach to summarize our recommendations. Summary of this approach for this meta-analysis is shown in Table 4.36 In sensitivity analysis calculation, the author included Patel et al. study and compared it to the analysis results without Patel et al. The author analyzed the accuracy of pneumonia diagnosis using the 5 studies in total and obtained the aggregate sensitivity 85% (95%CI 78-90%), specificity 97% (95%CI 93-99%), LR positive 34 (95%CI 12-94%), LR negative 0.15 (95%CI 0.1-0.23%) and the DOR 222 (95%CI 89-554%). These findings is not much different with the findings of the 4 studies which qualified the inclusion criteria presented in this paper.14 The sensitivity of the BLUE Protocol for pulmonary emboli and asthma/COPD has varied range from 46% to 98%. This inconsistent result might be caused by the BLUE Protocol algorithm to diagnose lung emboli and asthma/ COPD which is based on exclusion criteria and it needs to be confirmed with emboli findings in extremity’s vein. Performing ultrasound on the extremity’s vein requires a skilled operator and longer ultrasound procedure. From the date, the author did not recommend lung ultrasound to screen asthma/COPD or lung emboli, but if emboli was found in the vein extremities and no lung image abnormality in any case this might lead to emboli diagnosis. This is also found in pneumothorax cases which image shows the loss of lung sliding and the presence of lung point and barcode sign which is specifically found in pneumothorax.18-20 The ultrasound area used in the five studies is almost the same except in the study by Danish et al. and Bekgoz et al. Lichtenstein et al., Neto et al., and Patel et al., in performing lung ultrasound at 6 points of each hemithorax, therefore, resulted 12 examined points in total. Danish et al. performed lung ultrasound at 3 points of each hemithorax and the total is 6 points and Bekgoz et al. performed it at 4 points and the total is 8 points of all lung areas. This variability might explain the lower sensitivity value of pneumonia and lung edema in the research by Danish et al. and Bekgoz et al. when compared to other researches. Lung edema yield better AUC value in 6 points examination of each hemithorax (Figure 8 and 9). This is slightly different on pneumonia which shows that the lung ultrasound at 6 locations did not any better than 3 or 4 locations.11-15 The four studies also show that the lung ultrasound can be performed within the first 20 minutes when the patient is admitted to the intensive unit or emergency unit without any necessary interruption to the standard procedure because the duration of the examination is brief and performed beside the patient’s bed. Lichtenstein et al. and Bekgoz et al. only need less than 3-5 minutes, sequentially to complete the BLUE protocol. The lung ultrasound can be performed while other medic or paramedic doing other procedures. For any patient who needs advanced breathing support, lung ultrasound can also be performed right after the procedure without having to remove the patient to radiology unit.21-23 Operator bias tends to be found in ultrasound examination. Subgroup analysis with operator competence as a variable showed an experienced and certified operator yield better accuracy than newly trained operators, in both groups. However, the accuracy level of newly trained operators is considerably good in both groups. The operator in Neto et al. research is a rookie doctor in lung ultrasound who received 5 hours BLUE Oke Dimas Asmara Acta Med Indones-Indones J Intern Med 280 protocol theoretical training and performed 10 lung ultrasounds under supervision. The research shows sensitivity 85-88% and specificity 87-90% to detect lung edema and pneumonia. Certain shows that the BLUE protocol can be learned in relatively short time by any doctor who possesses basic knowledge of ultrasound. It is feasible for any on-duty doctor in intensive or emergency unit to be trained with BLUE protocol to help them manage patients with acute breathing problem (Figure 8 and 9). The study to assess the time needed training duration could be the subject for future research.24-27 CONCLUSION In conclusion, the BLUE protocol has high sensitivity and specificity in diagnosing pneumonia and pulmonary edema. These high diagnostic accuracy values came from a good quality study based on the GRADE approach. The BLUE protocol has high specificity in diagnose pneumothorax and pulmonary embolism but with varying sensitivity. This accuracy assessment comes from a poor-quality study based on the GRADE approach. ABBREVIATION BLUE Bedside Lung Ultrasound in Emergency ARF Acute Respiratory Failure LR Likelihood Ratio DOR Diagnostic Odds Ratio PRISMA Preferred Reporting Items for Systematic reviews and Meta- Analyses JICCIM Jakarta International Chest and Critical Care Internal Medicine GIM Global Index Medicus ROC Receiver Operating Characteristic QUADAS - 2 Q u a l i t y A s s e s s m e n t o f Diagnostic Accuracy Study - 2 ICU Intensive Care Unit ER Emergency Room SROC Summary Receiving Operating Characteristic COPD Chronic Obstructive Pulmonary Disease AUC Area Under Curve GRADE Grading of Recommendations, Assessment, Development and Evaluations COMPETING INTERESTS The authors declare that there is no competing interest. FUNDING This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. AUTHORS’ CONTRIBUTIONS ODA is the chief principle of the study and also the coordinator of the Study. ODA, CWP, VW conceived the Idea and developed the theory and design of the study. KH help to finalize the study conception and design, verified the analytical method and supervised the analytical calculation ODA and APA carried out the data collection and analyze the result. CWP and VW review the data collection and gave revision regarding interpretation of the data. ODA, APA and KH made draft manuscript preparation.All authors reviewed the results and approved the final version of the manuscript. ACKNOWLEDGMENTS The Authors would like to extend our sincere thanks to all the staff of Internal Medicine Residency Program, Department of Internal Medicine Faculty of Medicine Univesity of Indonesia and other supporting parties for helping us finishing the study. It would not have been possible without their support. REFERENCES 1. Peris A, Tutino L, Zagli G, et al. 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