key: cord-0874333-na45nefd
authors: Seiler, Claudia; Klingberg, Cecilia; Hårdstedt, Maria
title: Lung Ultrasound for Identification of Patients Requiring Invasive Mechanical Ventilation in COVID‐19
date: 2021-01-26
journal: J Ultrasound Med
DOI: 10.1002/jum.15617
sha: 1703985e15794405731d20c5bfab01dbc4d8ddc8
doc_id: 874333
cord_uid: na45nefd

OBJECTIVES: Indication for invasive mechanical ventilation in COVID‐19 pneumonia has been a major challenge. This study aimed to evaluate if lung ultrasound (LUS) can assist identification of requirement of invasive mechanical ventilation in moderate to severe COVID‐19 pneumonia. MATERIALS AND METHODS: Between April 23 and November 12, 2020, hospitalized patients with moderate to severe COVID‐19 (oxygen demand ≥4 L/min) were included consecutively. Lung ultrasound was performed daily until invasive mechanical ventilation (IMV‐group) or spontaneous recovery (non‐IMV‐group). Clinical parameters and lung ultrasound findings were compared between groups, at intubation (IMV‐group) and highest oxygen demand (non‐IMV‐group). A reference group with oxygen demand <4 L/min was examined at hospital admission. RESULTS: Altogether 72 patients were included: 50 study patients (IMV‐group, n = 23; non‐IMV‐group, n = 27) and 22 reference patients. LUS‐score correlated to oxygen demand (SpO(2)/FiO(2)‐ratio) (r = 0.728; p < 0.0001) and was higher in the IMV‐group compared to the non‐IMV‐group (20.0 versus 18.0; p = 0.026). Based on receiver operating characteristic analysis, a LUS‐score of 19.5 was identified as cut‐off for requirement of invasive mechanical ventilation (area under the curve 0.68; sensitivity 56%, specificity 74%). In 6 patients, LUS identified critical coexisting conditions. Respiratory rate and oxygenation index ((SpO(2)/FiO(2))/respiratory rate) ≥4.88 identified no requirement of invasive mechanical ventilation with a positive predictive value of 87% and negative predictive value of 100%. CONCLUSIONS: LUS‐score had only a moderate diagnostic value for requirement of invasive mechanical ventilation in moderate to severe COVID‐19. However, LUS proved valuable as complement to respiratory parameters in guidance of disease severity and identifying critical coexisting conditions.

C oronavirus disease 2019 , caused by a previously unknown human pathogen (severe acute respiratory syndrome coronavirus 2; SARS-Cov-2), was declared a global pandemic on March 11, 2020. 1 Most patients express mild symptoms, but COVID-19 can develop into a severe condition with pneumonia, acute respiratory distress syndrome (ARDS) and multi-organ failure. 2 COVID-19 has challenged emergency medicine and intensive care worldwide by high numbers of critically ill patients together with deficient evidence for management and treatment of a novel condition. The clinical features of respiratory failure in COVID- 19 have confounded clinicianssevere hypoxia despite lack of respiratory distress (silent hypoxia) and unpredictable clinical deterioration. 3 Identification of requirement of and timing for initiation of invasive mechanical ventilation (IMV) has been a major challenge. 3, 4 Lung ultrasound (LUS) is an established method in diagnostics of acute respiratory failure. 5, 6 In COVID-19 pneumonia, interstitial lung pathologies have been described on LUS. [7] [8] [9] [10] In ARDS, a LUS-score has previously been developed to classify the severity of respiratory failure by a 36-point scale based on LUS findings of B-line artifacts (B-lines) and consolidations. 11 During the COVID-19 pandemic, studies exploring the role of LUS in the management of COVID-19 pneumonia and respiratory failure have been requested. [12] [13] [14] So far, only a few studies have evaluated LUS-score in hospitalized patients with COVID-19. [15] [16] [17] LUS has been found to be a valuable tool in assessment of disease severity and presumably also in guiding patient management, including decisions on mechanical ventilation. [15] [16] [17] By being a bedside method, LUS has obvious advantages compared to other radiological entities saving hospital resources and reducing virus transmission. 18 With the aim of determining the significance of LUS examination in identifying patients with requirement of IMV, we assessed a consecutive cohort of patients with moderate to severe (WHO 4-6) respiratory failure due to COVID-19 infection. 19 The primary objective was to evaluate the association between LUS-score and indication for IMV treatment. In addition, we assessed the association between LUS-score and peripheral oxygen saturation/inspired fraction of oxygen (SpO 2 / FiO 2 )-ratio as well as the distribution pattern of LUS findings in moderate to severe COVID-19 pneumonia.

Study design and setting Between April 23 and November 12, 2020 a prospective single-center study was conducted at Falun Hospital, Sweden. During the study period, Falun Hospital supplied care for all hospitalized patients with COVID-19 in the county of Dalarna, with a population of about 270,000. A majority of patients with COVID-19 were admitted to the hospital due to respiratory failure. In isolation rooms at the care units, oxygen therapy was provided by nasal cannula, face mask or high flow nasal cannula. Patients in need of IMV were admitted to the intensive care unit. Indication for IMV treatment was respiratory failure with impending exhaustion, high oxygen demand with deranged clinical parameters such as respiratory rate, work of breathing and impaired consciousness. Due to aerosol dispersion and risk of virus transmission in open areas at the intensive care unit, high flow nasal cannula and noninvasive ventilation were not utilized for patients with COVID-19 at the intensive care unit.

All admitted patients (age ≥ 18 years) with the following criteria were eligible for the study: (1) positive for SARS-CoV-2 by reverse transcription polymerase chain reaction on nasopharyngeal swab and (2) moderate to severe respiratory failure corresponding to oxygen requirement ≥4 liters/minute (L/min) or high flow nasal cannula with a FiO 2 of ≥30% (Airvo 2, Fisher & Paykel) (WHO 4-6). 19, 20 Exclusion criteria were documented treatment limitation of "not eligible for IMV "and inability to participate in LUS examination or daily follow-ups. Also patients with the following conditions were excluded to avoid false-positive findings: interstitial lung diseases (for example pulmonary fibrosis), congestive heart failure, kidney failure on dialysis or age > 80 years. 5, 21 Patients with pneumothorax or history of pneumonectomy or pleurodesis were excluded due to interference with LUS examination. Between May 21 and June 13 a group of reference patients admitted to the hospital with no or mild respiratory failure (oxygen requirement of <4 L/min, were included based on the same criteria. 19 All patients approved participation by written informed consent. Ethical approval was received from the Swedish Ethical Review Authority (Dnr 2020-02184).

Patients eligible for the study were identified through daily contact with all care units. Included patients with oxygen requirement ≥4 L/min were examined daily with LUS until either initiation of IMV treatment or spontaneous improvement to oxygen demand of ≤1-2 L/min. For reference patients, LUS was performed at one occasion within 48 hours after admission to hospital. Clinical respiratory status was noted along with the LUS examination. For patients receiving IMV, data right before initiation of IMV were used for analysis. If LUS data were missing from the time right before intubation, data within 24 hours prior to, or after initiation of IMV were used. For patients who did not receive IMV treatment, data at the day of highest oxygen demand (based on lowest SpO 2 /FiO 2 -ratio) were used for further analysis. To define severity of ARDS (Berlin criteria) for patients on IMV, the lowest arterial partial pressure of oxygen/FiO 2 -ratio (PaO 2 /FiO 2 -ratio) within 24 hours after intubation was used. 22 Peripheral oxygen saturation was measured by a pulse oximeter (Nellcor Oximax N-65; Covidien, Boulder, CO, USA). Respiratory rate, oxygen requirement (L/min) and Glasgow Coma Scale were noted and patients were asked for dyspnea at rest ("yes/no"). Medical history and clinical parameters together with relevant laboratory results were collected from patient charts. A conversion table for estimation of FiO 2 provided by oxygen delivery devices was used. 23, 24 An estimate of PaO 2 / FiO 2 -ratio was obtained from SpO 2 /FiO 2. 20 Severity of respiratory failure was defined by cut-off values used for ARDS; a SpO 2 /FiO 2 -ratio of 315, 235 and 148 reflecting mild, moderate and severe ARDS, respectively. 20, 22 In order to evaluate clinical criteria for intubation, we used the respiration rate and oxygenation index (ROX index) based on Roca et al. ((SpO 2 /FiO 2 )/respiratory rate). 25 A ROX index of ≥4.88 has been suggested as cut-off for low risk of requirement of IMV. 25 Lung ultrasound An ultrasound machine aimed for point-of-care examinations with a lung preset adjusted to a depth of 12 cm was used (BK Medical flex focus 500 with a curved probe [BK medical type 8823] of 2-6 MHz, BK Medical AB, Herley, Denmark). Six lung regions on the left and right hemithorax, respectively, were scanned: upper and basal anterior/lateral/posterior regions. Anterior, lateral and posterior regions were separated by the anterior and posterior axillary lines. 11 For each region, findings of B-line artifacts (B-lines) and consolidations were noted. Each region was assessed and added up to a LUS-score (0-36) based on previously described protocol in ARDS 11, 26 : score 0 -normal findings with A-lines or ≤ two B-lines; score 1 -3 or more well-separated B-lines covering ≤50% of the region; score 2 -coalescent B-lines covering >50% of the region; score 3 -large consolidation with air bronchogram. Our data were also used to evaluate an alternative LUS-score developed for COVID-19 pneumonia by Manivel et al. 12 Therefore, the presence of small (<1 cm) or large (>1 cm) subpleural consolidations was noted for each region. Scanning was performed by carefully sliding sagittal and/or transversal over each region, and the highest score found was considered representative for the region. LUS was performed by 5 consultant anaesthesiologists experienced in LUS examination technique, not blinded for the patients' clinical status. Consensus on interpretation and scoring of LUSfindings were sought among 2 physicians present at each LUS examination.

Demographics, clinical parameters and LUS findings were presented as absolute numbers and percentages for categorical variables and as medians with interquartile range (IQR) for continuous variables. The Chi-square test or Fisher's exact test was used for comparisons of categorical outcomes and Mann-Whitney U test for unrelated continuous outcomes. The Friedman test compared ordinal data between 3 related samples and Wilcoxon signed rank test was used for post hoc analysis. Pearson correlation was used to estimate association between continuous variables. Receiveroperating characteristic curve analysis was used to evaluate LUS-score and ROX index for identification of requirement of IMV treatment. The optimal cut-off values were identified using the Youden index. P-value <0.05 was considered statistically significant. A sample size of 50 patients was estimated prior to initiation of the present study, based on previous LUS-data for mild and moderate ARDS (significance level of 0.05, 80% power). 27 

During the study period, 50 patients with COVID-19 with an oxygen demand of ≥4 L/min were included. Of these, 23 received IMV treatment (IMV-group) and 27 did not (non-IMV-group) ( Figure 1 ). In addition, a reference group of 22 patients with an oxygen requirement of <4 L/min was recruited. Four of these later developed an oxygen requirement of ≥4 L/min and were included as study patients. Medical history and clinical parameters at admission to hospital are presented in Table 1 . The median number of days from onset of symptoms to hospital admission was 9-10 days for all groups.

Clinical parameters associated with IMV Time from hospital admission to intubation (IMVgroup) or highest oxygen demand (non-IMV-group) showed large individual differences within both groups (0-10 days) ( Table 2 ). On the day of intubation (IMV-group) or of highest oxygen demand (non-IMV-group), all patients were hemodynamically stable and all but 4 patients were fully oriented. Before intubation, patients in the IMV-group had lower SpO 2 /FiO 2 -ratio and ROX index, higher respiratory rate and reported dyspnea more often compared to the non-IMV-group (Table 2, Figure 2 ). Based on previously presented cut-off for ROX index indicating lower risk for requirement of IMV (≥4.88), 4 of 23 (17%) patients in the IMV-group and all patients in the non-IMV-group fulfilled criteria for low risk of IMV treatment (positive predictive value 87%, negative predictive value 100%) ( Figure 3C ). Median PaO 2 / FiO 2 -ratio in patients on IMV was 140 (IQR 68) after intubation. According to Berlin definition, 20 of these patients (87%), were classified as moderate ARDS and 3 patients (13%) as mild ARDS. 22 Lung ultrasound findings LUS data for the IMV-group was obtained as close as possible in relation to intubation. Twelve patients (52%) were examined right before intubation and 8 (35%) and 3 (13%) patients were scanned within 24 hours prior to, or after intubation respectively. The 3 patients scanned after intubation presented with a LUS-score of 17, 20 and 25, respectively.

All 72 patients with COVID-19 infection, except 3 patients in the reference group, had pathological LUS findings including thickening or irregularity of the pleural line, different distributions of B-lines, subpleural consolidations and/or large consolidations with air bronchogram (Table 2) . Based on all examined patients, LUS-score correlated to SpO 2 /FiO 2ratio (r = 0.728, p < 0.0001) (Figure 2 ). However, this correlation did not remain when analyzing only patients with oxygen demand ≥4 L/min (r = 0.266, p = 0.062). Patients in the IMV-group had an overall higher LUS-score compared to the non-IMV-group (20.0 versus 18.0; p = 0.026) ( Figure 3A ). This difference was more pronounced when also including reference patients in the non-IMV-group (20.0 versus 12.0; p < 0.0001). Using the scoring system proposed for COVID-19 by Manivel et al., no difference was found between patients in the IMV-and non-IMVgroup (Table 2) . 12 The total number of regions with pathological LUS-findings (Score 1, 2 or 3) for each patient showed significant difference between the IMV-and non-IMV group even though the median numbers were the same in both groups (11 regions of 12 examined, p = 0.008) ( Table 2 ; Figure 3B ). Ten patients (43%) presented with pathological findings (LUS-score 1, 2 or 3) in every region in the IMVgroup, compared to 5 patients (19%) in the non-IMV group (p = 0.055) ( Figure 3B , Table 2 ). Distribution of B-lines and different categories of consolidations over anterior, lateral and posterior lung fields are presented in Figure 4 . The number of large consolidations increased gradually from anterior to posterior fields in both IMV-and non-IMV-groups ( Figure 4 ). For B-lines and subpleural consolidations, there was no difference between anterior, lateral and posterior lung fields (Figure 4) . Photos of representative LUS findings are presented in Figure 5 .

LUS identified important differential diagnoses in 6 patients. One IMV patient with high procalcitonin and one non-IMV patient showed compact basal consolidations and pleural effusions on LUS. They were diagnosed with bacterial pneumonia in addition to COVID-19 infection. Two IMV-patients with low Figure 1 legend for definition of groups. P-values given for comparison between fields of large consolidations (score 3) using Friedman's test. Post hoc test for comparison of score 3 between anterior and posterior field using Wilcoxon signed rank test (IMV p = 0.013; non-IMV p = 0.015). LUS = Lung ultrasound; IMV = invasive mechanical ventilation.

LUS-score (17 and 15, respectively) despite low PaO 2 /FiO 2 -ratio (116 and 129, respectively) raised the concern of pulmonary embolus, which was later confirmed by computed tomography. One non-IMV patient had a history of dyspnea for several months. In this patient, an elevated hemidiaphragm was seen on LUS, which was confirmed by computed tomography. In one patient, excluded due to pneumothorax, LUS revealed a large pleural effusion later diagnosed as empyema.

The diagnostic value of LUS-score and ROX index for requirement of IMV were evaluated with receiver operating characteristic curve analysis. Based on patients with oxygen requirement of ≥4 L/min, an optimal cut-off value of 19.5 for LUS-score was identified with a sensitivity of 56% and specificity of 74% for IMV treatment (area under the curve 0.68, 95% CI 0.54-0.83; p = 0.026) ( Figure 6A ). For the same group of patients, a cut-off value for ROX index of 5.57 identified patients with requirement for IMV with a sensitivity of 96% and specificity of 96% based on receiver operating characteristic curve analysis (area under the curve, 0.98, 95% CI, 0.94-1.00; p < 0.0001) ( Figure 6B ). Receiver operating characteristic curve analysis was also performed including the reference group, that is, patients with an oxygen demand of <4 L/min for comparison ( Figures 6A,B ).

In line with previous findings in ARDS and recent reports in COVID-19, LUS-score correlated to overall severity of respiratory failure. [15] [16] [17] 27, 28 However, LUS-score had a limited diagnostic value for identification of patients with requirement of IMV treatment in a group of patients with moderate to severe COVID-19 infection (WHO scale 4-6). LUS proved an important bedside instrument for identification of critical differential diagnoses.

In COVID-19 pneumonia, there are a few studies describing the association between LUS-findings and severity of disease. [15] [16] [17] 29, 30 In 3 recent reports, a much higher difference in LUS-score was presented between patients requiring IMV treatment and patients without IMV compared to our data. [15] [16] [17] LUS-score was also suggested a useful predictor for IMV. [15] [16] [17] In all 3 studies, LUS examinations were performed at hospital admission for patients with a wide range of disease severity, including milder conditions. [15] [16] [17] When also including reference patients with less severe respiratory failure in our analysis, the diagnostic value of LUS was consistent with previous reports. [15] [16] [17] In evaluation of requirement of IMV, selecting patients with an impending risk for mechanical ventilation was relevant for our purpose. Therefore, only patients with a high oxygen demand eligible for IMV treatment were included in our primary study group. Patients with a mild condition were examined foremost to ensure that LUS, in our hands, correlated to disease severity as previously shown in ARDS. 27, 28 Timing of LUS examination in this study was based on the rationale that clinical assessment for requirement of IMV is routinely performed when patients deteriorate with increasing oxygen demand. It is important to consider that LUS findings in COVID-19 correlate with disease severity and will change with the clinical course. 15, 30, 31 To match the clinical course between groups, all patients were followed daily and LUS findings closest to the time of intubation or at the day of highest oxygen demand were used for analysis. The onset of severe respiratory distress in patients with COVID-19 has been reported about 5 days into hospitalization, however, with large individual differences. 32 In the presented data, time from admission to start of IMV treatment or highest oxygen demand also showed large variation. Altogether, patient selection and timing of LUS examination will determine the clinical implication of conclusions.

Our data confirmed the typical pattern of COVID-19 pneumonia on LUS: bilateral B-lines, thickened pleural lines and consolidations of various sizes mixed with spared areas. 7, 9, 26, 29 Pleural effusions were rare. 29, 30 As previously reported, large consolidations were predominantly found in posterior lung regions. 8, 30 Based on this, it is of value to include also posterior regions in the ultrasound examination. In accordance to previous studies, the overall presence of large consolidations was not associated with requirement for IMV treatment in COVID-19 pneumonia. 15, 30 Differential diagnoses always need to be considered since the described LUS findings are not specific for COVID-19. 33, 34 Unexpected LUS findings assisted in identifying coexisting conditions that required urgent treatment in our study.

Patients requiring IMV treatment presented with higher LUS-score and higher number of pathologic regions, compared to patients not requiring IMV treatment. However, a LUS-score cut-off to identify IMV requirement had only a moderate diagnostic value due to high individual variation among patients with moderate to severe respiratory failure. Also in ARDS, attempts to identify a LUS-score cut-off to separate mild, moderate and severe ARDS have been conflicting. [26] [27] [28] 35, 36 IMV requirement partially depends on patient related factors beyond lung pathology identified on LUS. Moreover, individual variations of LUS-score might be based on the fact that COVID-19 pneumonia seems to differ from ARDS in general. Compared to ARDS, a discrepancy between degree of lung compliance and hypoxia has been described in COVID-19. Based on a theoretical model, 2 phenotypes depending on lung compliance have been suggested. 37, 38 The low compliance type (L-type) is characterized by a predominant B-line pattern and the high compliance type (H-type) presents mainly with large consolidations. 26, 38 Variation in LUS-score for individuals with similar oxygen demand might be explained by a comparatively low LUS-score, for the L-type, and a high LUS-score, for the H-type. Another explanation of the discrepancy of oxygen demand and findings on LUS-score could be a V/Q-mismatch due to alveolar capillary microthrombi described in COVID-19. 39 So far, there is no consensus regarding a LUS-protocol for COVID-19 pneumonia. 12, 13, 26, 40 In our cohort, LUS-score proved valuable by correlation to disease severity. 11, 26 Manivel et al. have suggested a modified protocol for COVID-19, adding subpleural consolidations to the score. 12 This scoring system seemed inferior to LUSscore in our patients. Frequent findings of minor subpleural consolidations in the non-IMV-group resulted in a higher score according to Manivel et al., while these findings had no obvious impact on respiratory status. 12 By natural means, respiratory parameters were strong predictors for identification of patients requiring IMV treatment. A majority of patients in the IMV-group reported dyspnea and had high respiratory rate, low SpO 2 despite high oxygen delivery previous to intubation and a PaO 2 /FiO 2 -ratio corresponding to moderate ARDS. 22 ROX index, based on oxygen demand and respiratory rate, has previously proved a high diagnostic value for prediction of lower risk for IMV in pneumonia. 25 ROX index has been suggested to also be useful in COVID-19 pneumonia but has not been validated so far. 38 Our data confirmed that the previously validated ROX index cut-off for prediction of IMV treatment in pneumonia can be used also in COVID-19. 25 In summary, we agree with the panel opinion reported by Liu et al. on using LUS for guidance of severity of disease and differential diagnosis but to "decide on level of care on clinical appearance." 14 There are some limitations of this study. False low LUS-score in the IMV-group might have been recorded due to examination too far prior to intubation or due to improved aeration after initiation of IMV-treatment. It was not possible to blind the physicians performing LUS examination for the clinical respiratory status of the patients, which could have added bias to the interpretation of LUSfindings. As a single-center-study, with a small number of patients, the findings should be verified in other populations.

LUS-score had only a moderate diagnostic value for identification of requirement of invasive mechanical ventilation in patients with moderate to severe COVID-19. Lung ultrasound served as complement to bedside assessment by guidance of disease severity and was an important tool for differential diagnostics. Respiratory rate and oxygenation index (ROX index) proved applicable for guiding need of IMV-treatment in COVID-19.

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We want to thank all patients for their participation and health personnel at the intensive care unit and care units of Falun hospital for help with patient recruitment. A special acknowledgement is given to Jeanette Vestling (MD), Ida Mattsson (MD), Lars Dittlau (MD) and Oskar Ostwald (MD) for LUS examinations. Torbjörn Roos (MD) and Erik Degerman (MD) are acknowledged for supporting and facilitating the study during the hectic time of the pandemic.