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Impact of Bedside Combined Cardiopulmonary Ultrasound on Etiological Diagnosis and Treatment of Acute Respiratory Failure in Critically Ill Patients

Ab s t r Ac t Aims and objectives: To prospectively evaluate the impact of cardiopulmonary ultrasound (CPUS) on etiological diagnosis and treatment of critically ill acute respiratory failure (ARF) patients. Design: This is a prospective observational study conducted in a general intensive care unit (ICU) of a tertiary care center in India. Patients over 18 years old with presence of one of the objective criteria of ARF. Patients either consecutively admitted for ARF to ICU or already admitted to ICU for a different reason but later developed ARF during their hospital stay. Written informed consent in local language was obtained from next of kin. Interventions: All included patients underwent bedside CPUS including lung ultrasound (US) and transthoracic echocardiography plus targeted venous US by single investigator, blinded to clinical data. The US diagnosis of ARF etiology was shared with treating intensivist. Initial clinical diagnosis (ICD) and treatment plan (made before US) of each patient were compared with post-US clinical diagnosis and treatment plan. The changes in diagnosis and treatment up to 24 hours post-US were considered as impact of US. Results: Mean age of 108 included patients was 45.7 ± 20.4 years (standard deviation). The ICD was correct in 67.5% (73/108) cases, whereas the combined CPUS yielded correct etiological diagnosis in 88% (95/108) cases. Among the 108 included patients, etiological diagnosis of ARF was altered after CPUS in 40 (37%) patients, which included “diagnosis changed” in 18 (17%) and “diagnosis added” in 22 (20%). Treatment plan was changed in 39 (36%) patients after CPUS, which included surgical interventions in 17 (16%), changes in medical therapy in 12 (11%), and changes in ventilation strategy in 4 (3.5%) patients. Conclusion: This study demonstrates that use of combined US approach as an initial test in ARF, improves diagnostic accuracy for identification of underlying etiology, and frequently changes clinical diagnosis and/or treatment.


IntroductIon
Acute respiratory failure (ARF) is a life-threatening condition that results from acute impairment in gas exchange between lungs and blood resulting in hypoxia with or without hypercapnia. 1 Around half of all admitted patients in intensive care unit (ICU) suffer from ARF, 2 which is associated with 30-65% mortality rates. [2][3][4][5][6][7] There are multiple causes of ARF, which can be grouped as respiratory and nonrespiratory causes. Early diagnosis of etiological factor(s) and appropriate therapeutic strategy is essential to improve outcome of ARF patients. 8 Diagnosis of etiological factor of ARF is challenging for physicians. Traditionally, physical examination, arterial blood gas (ABG) analysis, bedside radiography, and computed tomography (CT) are used. Physical examination has low accuracy, 9,10 while ABG analysis provides limited information about etiology of ARF. 11 Bedside chest X-rays (CXRs) has low diagnostic efficacy. 9 Although diagnostic accuracy of CT is high, CT in critically ill patients has several limitations such as risk of radiation exposure, high cost, and moving critically ill patients to scanning room can be associated with inadvertent extubations.
Bedside ultrasound (US) is now emerging as a valuable tool in dynamic assessment of lungs and hemodynamic status. Bedside US is readily available, noninvasive, convenient, and cost effective can be repeated at will and has shown better diagnostic efficacy compared to physical examination and CXR for diagnosis of lung conditions in critically ill patients. 9,10,12 There have been several studies in the field of point of care US for assessment of ARF patients in ICU and emergency settings. Few studies showed potential of combining lung ultrasound (LUS) and transthoracic echocardiography (TTE) as a single integrated assessment method for etiological diagnosis of ARF in ICU. 13,14 These studies have limited applicability in clinical practice due to some important limitations, such as none of the studies reported acute respiratory distress syndrome (ARDS), which is quite surprising, as ARDS is considered a common cause of ARF. 15 Therefore, results of these studies may not be applicable in cohorts where ARDS is prevalent. Till now only few studies have reported therapeutic impact of combined US approach in ICU. 16,17 However, to our knowledge, specific data focusing on therapeutic impact of combined US approach in ARF patients is lacking.
The aim of our study was to prospectively evaluate the impact of bedside cardiopulmonary ultrasound (CPUS) on etiological diagnosis and treatment plan of critically ill ARF patients.

Study Design and Patients
This prospective observational study was conducted with approval from Institutional Ethics Committee of King George's Medical University (Ref. code: 90th ECM II B-Thesis/PI). We prospectively recruited patients admitted to an ICU during September 2017 to August 2018. Patients were either consecutively admitted for ARF to ICU, or already admitted to ICU for a different reason but later developed ARF during their hospital stay. Any patients aged ≥18 years with one of the objective criteria of ARF, including oxygen saturation by pulse oximetry (SaO 2 ) ≤90% while breathing room air, PaO 2 /FiO 2 ratio of ≤200 mm Hg, respiratory rate of ≥25/minute, PaCO 2 of >45 mm Hg with an arterial pH <7.35, were included and screened for exclusion criteria (Table 1). Written informed consent in local language was obtained from next of kin of all participants.

Lung and Cardiac Ultrasound
All included patients underwent bedside combined CPUS including LUS and focused TTE by single investigator (B. Barman). The investigator was blinded to clinical data, and had no role in decision-making or clinical management of patients. Scans were performed with My Lab™ Seven (Esaote, Italy) US machine, using 3-10 MHz microconvex array, 3-5 MHz convex array, and 3-12 MHz linear array probes for LUS and 1-4 MHz phased array probe for TTE.
For LUS scanning, eight region/zone methods 18,19 were used which included scanning of anterior and lateral chest wall on both sides with patients in supine (n = 92) or semirecumbent position. TTE was performed by taking 5-10 seconds acquisitions of following: parasternal long axis (PLAX), parasternal short axis views, apical four-chamber (A4C) views, and subcostal four-chamber views. LUS and echocardiography results were interpreted using standardized criteria for etiological diagnosis of ARF, as depicted in Table 2. After CPUS, venous US scan of lower extremity for deep venous thrombosis (DVT) was done with a linear probe, in a proportion of included patients (n = 55, 51%) suspected for pulmonary embolism (PE) on US. PE was suspected on US after ruling out cardiogenic pulmonary edema, ARDS, and pneumothorax on CPUS; or in cases showing (a) presence of wedge shaped or rounded pleura-based hypoechoic consolidation on LUS; (b) A-profile or C-profile on LUS; or (c) acute RV dysfunction on TTE. The scans were performed without interrupting management within 24 hours of ICU admission or developing ARF (average 8 ± 5 hours). Average scan time was 15 ± 6 minutes per case. Imaging data were recorded for further assessment. The US performance bias of the investigator was reduced by quality assurance check on recorded images by an independent observer, who checked for interpretability of images obtained and that the correct diagnosis was made.
The investigator followed the methodology as depicted in Table 3. The primary outcome was any change in initial clinical diagnosis (ICD) and/or treatment plan after combined CPUS. For this, ICD and treatment plans of each patient were compared with post-US clinical diagnosis and treatment plan. "ICD and treatment plan" was defined as etiological diagnosis and treatment plan of ARF made by primary treating intensivist before US test on day 1; utilizing patient's history, physical examination, chest radiography, and available emergency laboratory tests. "Post-US clinical diagnosis and treatment plan" was defined as etiological diagnosis of ARF and treatment plan made by treating intensivist after US test, utilizing all the clinical data available before US scan plus US data. The changes in diagnosis and treatment plans up to 24 hours post-US scan were considered as impact of US. The following changes in treatment plan after US scan were taken as impact of CPUS test: (a) surgical interventions including drainage of pleural effusion (thoracentesis) under US guidance, intercostal chest tube (ICT) placement for pneumothorax; (b) changes in ventilation strategy including use of lung protective ventilation, escalation from noninvasive ventilation (NIV) to invasive mechanical ventilation (IMV) or downgrading from IMV to NIV; (c) changes in medical therapy including restriction/escalation of fluid therapy, addition/removal of diuretics, inotropes, and use of thrombolytic/anticoagulants for treatment of PE. However, vasopressor use was not taken as impact of US.

Final Etiological Diagnosis of Acute Respiratory Failure
Final etiological diagnosis (FD) of ARF in all patients was obtained from the final clinical diagnosis on day 7 (assuming the day of US test as day 1). FD was made by a team comprising of three senior intensivists. Their FD was made on basis of complete clinical history and examinations, laboratory investigations, chest radiography and US data, chest CT (done in 49 or 45% patients), response to treatment, and independent TTE by a cardiologist whenever indicated (done in  (Table 4). The main diagnoses finally proposed were pneumonia (n = 34, including community and hospital acquired pneumonias, ventilator-associated pneumonia); hydrostatic or cardiogenic pulmonary edema (n = 22); nonhydrostatic pulmonary edema or ARDS (n = 19); acute bronchospasm [n = 13, including cases of decompensated chronic obstructive pulmonary disease (COPD) and acute asthma], pneumothorax (n = 12), and PE (n = 8).

Statistical Analysis
Statistical analysis was performed using SPSS statistics V23 (IBM SPSS Inc, Chicago, IL, USA). We calculated our sample size based on the outcome of assessing diagnostic accuracy of bedside CPUS to accurately assess the common causes of ARF in critically ill patients. We calculated sample size of 108 ARF patients to yield a minimum 80% sensitivity and 80% power with type I error (α ) = 0.05.

Participant Characteristics
Out of the 123 patients with ARF enrolled in the study over 1-year period, final diagnosis was not established in four patients because of unknown diagnosis at the end of seventh day of hospitalization, five patients had multiple etiological diagnoses for ARF, and two patients had miscellaneous diagnoses (Table 4). US scan was not possible or incomplete in four patients due to thoracotomy, subcutaneous emphysema, or inadequate sonographic window. These 15 patients were subsequently excluded from the analysis. So a total of 108 patients were considered for analysis.
Age of patients ranged from 18 to 87 years with a mean age of 45.7±20.4 years (standard deviation). At the time of inclusion, patients had a mean PaO 2 /FiO 2 ratio of 142 ± 53 (range 56-200). About 78 of 108 (72%) patients were intubated at the time of  TTE assessment methods: a) Visual estimation of left ventricular ejection fraction (LVEF) was done on PLAX and A4C views, as <30%, 30% to <50%, and ≥50%. LVEF <50% was considered as systolic dysfunction 14,17,35 b) LV diastolic dysfunction was considered in cases of elevated left ventricular filling pressure (LVFP). LVFP was estimated using pulsedwave and tissue Doppler of mitral inflow and lateral annulus, following standard guidelines and recommendations 13,36,37 c) On visual estimation, acute RV dysfunction was considered when there was RV dilatation and/or abnormal inter-ventricular septal configuration. Chronic RV dysfunction was considered when there was RV hypertrophy without RV dilatation or abnormal septal configuration 13,37,38 d) Presence of mitral valve disease (MVD) was evaluated using color Doppler for reverse flow indicating mitral regurgitation (MR) and visual assessment of the mitral valve for reduced leaflet movement indicating mitral stenosis (MS) e) Presence and size of pericardial effusion was also evaluated inclusion. Out of 108 patients, 68 (63%) were males and remaining 40 (37%) were females.

Diagnostic Accuracy
Accuracy of two diagnostic approaches, ICD and combined CPUS diagnosis were compared against the final diagnosis. The ICD was correct in 68% (73/108) cases, whereas the focused CPUS test yielded a correct etiological diagnosis in 88% (95/108) cases (Fig. 1). Sensitivity and specificity of CPUS for each etiological entity were as follows: 88% and 92% for pneumonia; 95% and 98% for cardiogenic pulmonary edema; 89% and 97% for ARDS; 83% and 100% for pneumothorax; 85% and 99% for decompensated COPD/acute asthma; and 75% and 99% for PE. CPUS findings in a case of ARDS, cardiogenic pulmonary edema, pneumothorax, and pneumonia are shown in Figures 2 and 3.

Changes in Diagnosis
Of the 108 ARF patients included in our study, etiological diagnosis of ARF was altered or modified after the CPUS in 40 (37%) patients, which included "diagnosis changed" in 18 (17%) and "diagnosis added" in 22 (20%) patients (Flowchart 1).
Cases of "diagnosis changed" represented complete change in etiological diagnosis of ARF after US. In all these cases, primary treating intensivist's ICD was different from that suspected before US. This included five cases of cardiogenic pulmonary edema, four cases of ARDS, three cases of pneumothorax, three cases of consolidation, two cases of PE, and one case of acute bronchospasm (decompensated COPD/acute asthma). Cases of "diagnosis added" represented cases where primary treating intensivist's ICD was correct, but some additional unsuspected finding/diagnosis had been added after US. On the next day investigator did CPUS scan on subsequent patients with ARF, b and shared US data with treating intensivist ↓ Investigator then recorded the ICD and treatment plan of the patients, who were scanned on the same day; and also recorded the postultrasound clinical diagnosis and treatment plan of those patients, who were scanned on the previous day ↓ Day 7 Final etiological diagnosis (FD) was recorded from the treatment plan Same events were repeated during the study period for all the included patient a Applied to patients admitted to the ICU for a different reason other than ARF but subsequently developed ARF during ICU stay b These are new patients admitted with ARF or developed ARF, since after the investigator left the ICU on previous day; and also within the last 24 hours time period

Changes in Treatment Plan
After combined US, treatment plan changed in 39 (36%) patients (Flowchart 2). Among the surgical interventions thoracentesis under US guidance was done in 17 (16%) patients; ICT was placed for pneumothorax in 5 patients; and 1 procedure (ICT placement) was cancelled based on the US results. Ventilation strategy changed in four (3.5%) patients, which included two cases where lung protective IMV started for ARDS and two cases of escalation from NIV to IMV. Changes in medical therapy was made in 12 (11%) patients which included fluid restriction in 3 (2.5%), fluid restriction plus addition of diuretics in 3 (2.5%), fluid restriction plus addition of inotropes in 2 (2%), only inotropes addition in 2 (2%), and only diuretics addition in 1 (1%). Most of changes in medical therapy occurred in patients with cardiogenic pulmonary edema. Anticoagulants had to be started in two (2%) cases for treatment of PE, not suspected in initial clinical assessment.

dIscussIon
The main results of our study were (i) significant improvement in the diagnostic accuracy of early CPUS compared with usual care (i.e., physical examination, chest radiography, and emergency laboratory tests) for the etiological diagnosis of ARF in critically ill patient; and (ii) high incidence of change in clinician's initial diagnosis and treatment after early CPUS in critically ill patient with ARF indicating significant impact of CPUS on management of ARF patients. While most of the previous studies on critical care ultrasonography in ARF focused on diagnostic efficacy; only few studies 13,17,35 evaluated the therapeutic impact of a combined ultrasonography approach in critically ill patients. In our study, among the 108 included patients with ARF, CPUS test yielded a correct etiological diagnosis in 88% of ARF cases, whereas primary treating intensivists' ICD was correct only in 68% of ARF cases. The higher accuracy of CPUS over clinical examination and CXR is supported by results of previous studies. 10,16,25 Furthermore, higher diagnostic accuracy of the early combined CPUS approach was found when six main etiological entities of ARF were analyzed independently. We found similar sensitivity and specificity as were described in previous studies using combined CPUS for etiological diagnosis of ARF in critical care. 13,14 Our data showed that ICD of ARF (made before US scan) was altered in 37% cases after sharing combined CPUS findings with the treating intensivists. This included 17% cases, where ICD was changed to a different type or previously unsuspected pathology; and 20% cases, where some additional finding had been added after Flowchart 1: Changes in etiological diagnosis of ARF after CPUS. Data represents n (%). "Diagnosis changed" represented cases where the ICD (made before US) was completely different from the modified diagnosis made by the treating intensivist after US test; and indicated complete change in etiological diagnosis of ARF. "Diagnosis added" represented cases where the ICD was part of modified diagnosis (made by the treating intensivist after US), but some additional finding/diagnosis had been added after ultrasound test US test. Most of these cases were cardiogenic pulmonary edema and ARDS. This can be justified as previous studies have shown low accuracy of physical examination and bedside CXR compared to US for detection of origin of pulmonary edema. 10,13,19,25 In few patients in our study, pneumothorax, consolidation, PE, and pleural and pericardial effusions were missed by the treating intensivists on clinical evaluation. These changes in diagnosis cautioned the treating intensivist and in some cases triggered a change in treatment plan, while in cases, where there was concordance in CPUS and ICD, the intensivists were reassured.
In our study, CPUS test resulted in a change of treatment plan in about 36% of patients. CPUS scan led to drainage of pleural effusion in significant percentage of patients (15%), and change in ventilation strategy in a small proportion of patients (4%). Most of the changes in medical therapy occurred in patients, when cardiogenic pulmonary edema (missed on clinical evaluation and CXR) was detected in CPUS. This type of change in diagnosis and treatment has been reported in few previous studies in ICU setting 16,17,39 as well as in anesthetic preoperative assessment and emergency setting. 40,41 However, our results are specific for ARF patients, which has been lacking in most of the previous studies.
Our data suggest that lung ultrasonography provides quick assessment of common etiologies of ARF but addition of cardiac US helps in accurate differentiation of some pathological factors, having somewhat similar pattern in LUS. For example, both cardiogenic pulmonary edema and ARDS show diffuse bilateral B-lines pattern on LUS but addition of cardiac US helps in differentiating between them. This is in agreement with previous studies 13,14 that showed combined CPUS is more accurate in differentiating ARDS from cardiogenic pulmonary edema and, in disagreement with previous studies 12,25 suggesting that lung ultrasonography without echocardiography could be used to estimate cardiogenic pulmonary edema. Our study highlights the potential limitations of isolated LUS and provides a comprehensive and feasible diagnostic alternative by combining LUS and TTE. Our data also show that CPUS findings suggestive of PE in the absence of other lung pathology in ARF may alert the treating clinician, and assist in diagnosis, risk stratification, and management.
Our study has some limitations. Firstly, interobserver variability could not be assessed as single operator did all US scans. However, the investigator had 1 year of experience in ultrasonography, took supervised training in critical care ultrasonography; and followed a standard predefined algorithm. Secondly, we evaluated LVEF and mitral valve disease based on visual assessment; however, we did not calculate LVEF and mitral valve area. So, it might be possible that we were not able to diagnose mild changes in LVEF and mild mitral stenosis. Thirdly, patients with multiple etiological diagnoses for ARF such as ARDS plus congestive heart failure were subsequently excluded. The reference standard was final diagnosis on patient assessment file. Although a team comprising of three senior intensivists established the FD, there could have been diagnostic errors. Finally, it is possible that changes in diagnosis and treatment plan, which occurred after US, may have occurred without US. The treating intensivist may have changed diagnosis and treatment based on response to treatment, or after internal discussion with other intensivists.
Despite these limitations, our study has several advantages. Our study shows that addition of combined US approach as a supplement to clinical evaluation not only improves the diagnostic accuracy but also changes diagnosis and treatment plan in significant proportion of ARF cases. Feasibility was demonstrated, as investigator was able to obtain interpretable images in the majority of patients.

conclusIon
This study demonstrates that use of combined US approach (CPUS and targeted venous US) as an initial test in ARF improves diagnostic accuracy for identification of underlying etiology and frequently changes clinical diagnosis and/or treatment. We conclude that routine screening of ARF patients at admission to ICU with Flowchart 2: Changes in treatment plan after combined focused lung and heart ultrasound. Data represents n (%). "Lung protective ventilation" in ARDS represents mechanical ventilation using lower tidal volumes, lower inspiratory pressures, prone positioning and alveolar recruitment options by higher PEEP levels. ICT, intercostal chest tube; IMV, invasive mechanical ventilation; NIV, noninvasive ventilation combined US approach is feasible and has significant diagnostic as well as therapeutic impact.