Correlation between Serum Biomarkers and Lung Ultrasound in COVID-19: An Observational Study.

Serum biomarkers and lung ultrasound are important measures for prognostication and treatment allocation in patients with COVID-19. Currently, there is a paucity of studies investigating relationships between serum biomarkers and ultrasonographic biomarkers derived from lung ultrasound. This study aims to assess correlations between serum biomarkers and lung ultrasound findings. This study is a secondary analysis of four prospective observational studies in adult patients with COVID-19. Serum biomarkers included markers of epithelial injury, endothelial dysfunction and immune activation. The primary outcome was the correlation between biomarker concentrations and lung ultrasound score assessed with Pearson's (r) or Spearman's (rs) correlations. Forty-four patients (67 [41-88] years old, 25% female, 52% ICU patients) were included. GAS6 (rs = 0.39), CRP (rs = 0.42) and SP-D (rs = 0.36) were correlated with lung ultrasound scores. ANG-1 (rs = -0.39) was inversely correlated with lung ultrasound scores. No correlations were found between lung ultrasound score and several other serum biomarkers. In patients with COVID-19, several serum biomarkers of epithelial injury, endothelial dysfunction and immune activation correlated with lung ultrasound findings. The lack of correlations with certain biomarkers could offer opportunities for precise prognostication and targeted therapeutic interventions by integrating these unlinked biomarkers.

Use of Lung Ultrasound in the New Definitions of Acute Respiratory Distress Syndrome Increases the Occurrence Rate of Acute Respiratory Distress Syndrome.

OBJECTIVES: To assess the effect of incorporating bilateral abnormalities as detected by lung ultrasound (LUS) in the Kigali modification and the New Global definition of acute respiratory distress syndrome (ARDS) on the occurrence rate of ARDS. DESIGN: Post hoc analysis of a previously published prospective cohort study. SETTING: An academic mixed medical-surgical ICU. PATIENTS: The original study included critically ill adults with any opacity on chest radiography in whom subsequent LUS was performed. Patients with ARDS according to the Berlin definition, COVID-19 patients and patients with major thorax trauma were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: LUS was performed within 24 hours of chest radiography and the presence of unilateral and bilateral abnormalities on LUS and chest radiograph (opacities) was scored. Subsequently, the Kigali modification and the New Global definition of ARDS were applied by two independent researchers on the patients with newly found bilateral opacities. Of 120 patients, 116 were included in this post hoc analysis. Thirty-three patients had bilateral opacities on LUS and unilateral opacities on chest radiograph. Fourteen of these patients had ARDS according to the Kigali modification and 12 had ARDS according to the New Global definition. The detected LUS patterns were significantly different between patients with and without ARDS ( p = 0.004). An A-profile with a positive PosteroLateral Alveolar and/or Pleural Syndrome was most prevalent in patients without ARDS, whereas heterogeneous and mixed A, B, and C patterns were most prevalent in patients with ARDS. CONCLUSION: The addition of bilateral abnormalities as detected by LUS to the Kigali modification and the New Global definition increases the occurrence rate of the ARDS. The nomenclature for LUS needs to be better defined as LUS patterns differ between patients with and without ARDS. Incorporating well-defined LUS criteria can increase specificity and sensitivity of new ARDS definitions.

Altitude Pre-Acclimatization with an Erythropoiesis-Stimulating Agent.

Introduction: High altitude illness is a complication of rapid ascent above 2,500 m elevation. Ventilatory, circulatory and haematological adjustments, known as acclimatization, occur to maintain adequate delivery of oxygen. Although (non-)pharmaceutical strategies that modulate ventilation and circulation have long been accepted, the haematological approach has not. Case description: This report describes the application of a comprehensive strategy, including prior pre-acclimatization using an erythropoiesis-stimulating agent (ESA), in two healthy subjects ascending from sea level to 6,268 m. Following ESA administration 30 days prior to ascent, the subjects had a cumulative haemoglobin rise of 7.1% and 11.9%, respectively. Both subjects experienced minimal symptoms during four incremental ascents to the final altitude and no adverse events occurred. Discussion: This report has limited external validity, lacking both a sample size and controls, but can serve as practical exploration of the concept. Administration of an ESA may be a safe and useful pre-acclimatization strategy but cannot be recommended based on current evidence. More comprehensive research is needed. LEARNING POINTS: High altitude illness (HAI) is a debilitating syndrome with potentially lethal consequences caused by ascent to a hypobaric atmosphere without acclimatization.Pharmacological strategies aimed at increasing oxygen delivery may be used to prevent and treat HAI.Administration of an erythropoiesis-stimulating agent may be a safe and useful pre-acclimatization strategy but cannot be recommended based on current evidence alone.

Monitoring of pulmonary involvement in critically ill COVID-19 patients - should lung ultrasound be preferred over CT?

BACKGROUND: It is unclear if relevant changes in pulmonary involvement in critically ill COVID-19 patients can be reliably detected by the CT severity score (CTSS) and lung ultrasound score (LUSS), or if these changes have prognostic implications. In addition, it has been argued that adding pleural abnormalities to the LUSS could improve its prognostic value. The objective of this study was to compare LUSS and CTSS for the monitoring of COVID-19 pulmonary involvement through: first, establishing the correlation of LUSS (± pleural abnormalities) and CTSS throughout admission; second, assessing agreement and measurement error between raters for LUSS, pleural abnormalities, and CTSS; third, evaluating the association of the LUSS (± pleural abnormalities) and CTSS with mortality at different timepoints. METHODS: This is a prospective, observational study, conducted during the second COVID-19 wave at the AmsterdamUMC, location VUmc. Adult COVID-19 ICU patients were prospectively included when a CT or a 12-zone LUS was performed at admission or at weekly intervals according to local protocol. Patients were followed 90 days or until death. We calculated the: (1) Correlation of the LUSS (± pleural abnormalities) and CTSS throughout admission with mixed models; (2) Intra-class correlation coefficients (ICCs) and smallest detectable changes (SDCs) between raters; (3) Association between the LUSS (± pleural abnormalities) and CTSS with mixed models. RESULTS: 82 consecutive patients were included. Correlation between LUSS and CTSS was 0.45 (95% CI 0.31-0.59). ICCs for LUSS, pleural abnormalities, and CTSS were 0.88 (95% CI 0.73-0.95), 0.94 (95% CI 0.90-0.96), and 0.84 (95% CI 0.65-0.93), with SDCs of 4.8, 1.4, and 3.9. The LUSS was associated with mortality in week 2, with a score difference between patients who survived or died greater than its SDC. Addition of pleural abnormalities was not beneficial. The CTSS was associated with mortality only in week 1, but with a score difference less than its SDC. CONCLUSIONS: LUSS correlated with CTSS throughout ICU admission but performed similar or better at agreement between raters and mortality prognostication. Given the benefits of LUS over CT, it should be preferred as initial monitoring tool.

The Impact of Thoracic Ultrasound on Clinical Management of Critically Ill Patients (UltraMan): An International Prospective Observational Study.

OBJECTIVES: To investigate the impact of thoracic ultrasound (TUS) examinations on clinical management in adult ICU patients. DESIGN: A prospective international observational study. SETTING: Four centers in The Netherlands and Italy. PATIENTS: Adult ICU patients (> 18 yr) that received a clinically indicated lung ultrasound examination. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinicians performing TUS completed a pre- and post-examination case report form. Patient characteristics, TUS, and resulting clinical effects were recorded. First, change of management, defined as a TUS-induced change in clinical impression leading to a change in treatment plan, was reported. Second, execution of intended management changes within 8 hours was verified. Third, change in fluid balance after 8 hours was calculated. A total of 725 TUS performed by 111 operators across 534 patients (mean age 63 ± 15.0, 70% male) were included. Almost half of TUS caused a change in clinical impression, which resulted in change of management in 39% of cases. The remainder of TUS confirmed the clinical impression, while a minority (4%) did not contribute. Eighty-nine percent of management changes indicated by TUS were executed within 8 hours. TUS examinations that led to a change in fluid management also led to distinct and appropriate changes in patient's fluid balance. CONCLUSIONS: In this international observational study in adult ICU patients, use of TUS had a major impact on clinical management. These results provide grounds for future randomized controlled trials to determine if TUS-induced changes in decision-making also lead to improved health outcomes.

INCIDENCE, RISK FACTORS, AND OUTCOME OF SUSPECTED CENTRAL VENOUS CATHETER-RELATED INFECTIONS IN CRITICALLY ILL COVID-19 PATIENTS: A MULTICENTER RETROSPECTIVE COHORT STUDY.

ABSTRACT: Background: Aims of this study were to investigate the prevalence and incidence of catheter-related infection, identify risk factors, and determine the relation of catheter-related infection with mortality in critically ill COVID-19 patients. Methods: This was a retrospective cohort study of central venous catheters (CVCs) in critically ill COVID-19 patients. Eligible CVC insertions required an indwelling time of at least 48 hours and were identified using a full-admission electronic health record database. Risk factors were identified using logistic regression. Differences in survival rates at day 28 of follow-up were assessed using a log-rank test and proportional hazard model. Results: In 538 patients, a total of 914 CVCs were included. Prevalence and incidence of suspected catheter-related infection were 7.9% and 9.4 infections per 1,000 catheter indwelling days, respectively. Prone ventilation for more than 5 days was associated with increased risk of suspected catheter-related infection; odds ratio, 5.05 (95% confidence interval 2.12-11.0). Risk of death was significantly higher in patients with suspected catheter-related infection (hazard ratio, 1.78; 95% confidence interval, 1.25-2.53). Conclusions: This study shows that in critically ill patients with COVID-19, prevalence and incidence of suspected catheter-related infection are high, prone ventilation is a risk factor, and mortality is higher in case of catheter-related infection.

Lung Ultrasound Signs to Diagnose and Discriminate Interstitial Syndromes in ICU Patients: A Diagnostic Accuracy Study in Two Cohorts.

OBJECTIVES: To determine the diagnostic accuracy of lung ultrasound signs for both the diagnosis of interstitial syndrome and for the discrimination of noncardiogenic interstitial syndrome (NCIS) from cardiogenic pulmonary edema (CPE) in a mixed ICU population. DESIGN: A prospective diagnostic accuracy study with derivation and validation cohorts. SETTING: Three academic mixed ICUs in the Netherlands. PATIENTS: Consecutive adult ICU patients that received a lung ultrasound examination. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULT: The reference standard was the diagnosis of interstitial syndrome (NCIS or CPE) or noninterstitial syndromes (other pulmonary diagnoses and no pulmonary diagnoses) based on full post-hoc clinical chart review except lung ultrasound. The index test was a lung ultrasound examination performed and scored by a researcher blinded to clinical information. A total of 101 patients were included in the derivation and 122 in validation cohort. In the derivation cohort, patients with interstitial syndrome ( n = 56) were reliably discriminated from other patients based on the presence of a B-pattern (defined as greater than or equal to 3 B-lines in one frame) with an accuracy of 94.7% (sensitivity, 90.9%; specificity, 91.1%). For discrimination of NCIS ( n = 29) from CPE ( n = 27), the presence of bilateral pleural line abnormalities (at least two: fragmented, thickened or irregular) had the highest diagnostic accuracy (94.6%; sensitivity, 89.3%; specificity, 100%). A diagnostic algorithm (Bedside Lung Ultrasound for Interstitial Syndrome Hierarchy protocol) using B-pattern and bilateral pleural abnormalities had an accuracy of 0.86 (95% CI, 0.77-0.95) for diagnosis and discrimination of interstitial syndromes. In the validation cohort, which included 122 patients with interstitial syndrome, bilateral pleural line abnormalities discriminated NCIS ( n = 98) from CPE ( n = 24) with a sensitivity of 31% (95% CI, 21-40%) and a specificity of 100% (95% CI, 86-100%). CONCLUSIONS: Lung ultrasound can diagnose and discriminate interstitial syndromes in ICU patients with moderate-to-good accuracy. Pleural line abnormalities are highly specific for NCIS, but sensitivity is limited.

Evolution of Respiratory Muscles Thickness in Mechanically Ventilated Patients With COVID-19.

BACKGROUND: Given the long ventilation times of patients with COVID-19 that can cause atrophy and contractile weakness of respiratory muscle fibers, assessment of changes at the bedside would be interesting. As such, the aim of this study was to determine the evolution of respiratory muscle thickness assessed by ultrasound. METHODS: Adult (> 18 y old) patients admitted to the ICU who tested positive for SARS-CoV-2 and were ventilated for < 24 h were consecutively included. The first ultrasound examination (diaphragm, rectus abdominis, and lateral abdominal wall muscles) was performed within 24 h of intubation and regarded as baseline measurement. After that, each following day an additional examination was performed, for a maximum of 8 examinations per subject. RESULTS: In total, 30 subjects were included, of which 11 showed ≥ 10% decrease in diaphragm thickness from baseline; 10 showed < 10% change, and 9 showed ≥ 10% increase from baseline. Symptom duration before intubation was highest in the decrease group (12 [11-14] d, P = .03). Total time ventilated within the first week was lowest in the increase group (156 [129-172] h, P = .03). Average initial diaphragm thickness was 1.4 (1.1-1.6) mm and did not differ from final average thickness (1.3 [1.1-1.5] mm, P = .54). The rectus abdominis did not show statistically significant changes, whereas lateral abdominal wall thickness decreased from 14 [10-16] mm at baseline to 11 [9-13] mm on the last day of mechanical ventilation (P = .08). Mixed-effect linear regression demonstrated an association of atrophy and neuromuscular-blocking agent (NMBA) use (P = .01). CONCLUSIONS: In ventilated subjects with COVID-19, overall no change in diaphragm thickness was observed. Subjects with decreased or unchanged thickness had a longer ventilation time than those with increased thickness. NMBA use was associated with decreased thickness. Rectus muscle thickness did not change over time, whereas lateral abdominal muscle thickness decreased but this change was not statistically significant.

Bacterial Contamination of Ultrasound and Stethoscope Surfaces in Low- and High-Resource Settings.

Point-of-care ultrasound is an accurate diagnostic and monitoring tool. Its increasing affordability, portability, and versatility make it an excellent component of standard clinical evaluation alongside the stethoscope. However, like the stethoscope, ultrasound carries risks of surface contamination and potential cross-infection. In this international observational study, we compared the surface contamination of ultrasound equipment to stethoscopes in two medical centers: a tropical low-resource hospital and academic high-resource hospital. Ultrasound equipment and coupling gel had similar prevalence of microbial surface contamination compared with observed stethoscopes. Most microbes were commensal Gram-positive, but some were opportunistic and pathogenic microbes (such as Escherichia coli and Staphylococcus aureus). In conclusion, it is crucial to appreciate and reduce the risk of ultrasound device contaminations. When ultrasound is used bedside, similar to stethoscopes, conscientious hygiene measures are equally fundamental.

Anatomical Variation in Diaphragm Thickness Assessed with Ultrasound in Healthy Volunteers.

Ultrasonography of the diaphragm in the zone of apposition has become increasingly popular to evaluate muscle thickness and thickening fraction. However, measurements in this anatomical location are frequently hindered by factors that constrain physical accessibility or that alter diaphragm position. Therefore, other anatomical positions at the chest wall for transducer placement are used, but the variability in diaphragm thickness across the dome has not been systematically studied. The aim of this study was to evaluate anatomical variation of diaphragm thickness in 46 healthy volunteers on three ventrodorsal lines and two craniocaudal positions on these three lines. The intraclass correlation coefficient (ICC) for diaphragm thickness in the craniocaudal direction on the mid-axillary line was significantly higher than those on the posterior axillary and midclavicular lines, suggesting it had the lowest variability (ICCmidaxillary = .89, 95% confidence interval [CI]: 0.83-0.93, ICCposterior axillary = 0.74, 95% CI: 0.62-0.85, ICCmidclavicular = 0.62, 95% CI: 0.43-0.47, p < 0.05). Average diaphragm thickness was comparable on the posterior axillary and midaxillary lines and substantially larger on the midclavicular line (1.24 mm [1.06-1.47], 1.27 mm [1.10-1.42] and 2.32 [1.97-2.70], p < 0.01). We conclude that the normal diaphragm has a large variability in thickness, especially in the ventrodorsal direction. Variability in craniocaudal position is the lowest at the midaxillary line, which therefore appears to be the preferred site for diaphragm thickness measurement.

The impact of lung ultrasound on clinical-decision making across departments: a systematic review.

BACKGROUND: Lung ultrasound has established itself as an accurate diagnostic tool in different clinical settings. However, its effects on clinical-decision making are insufficiently described. This systematic review aims to investigate the impact of lung ultrasound, exclusively or as part of an integrated thoracic ultrasound examination, on clinical-decision making in different departments, especially the emergency department (ED), intensive care unit (ICU), and general ward (GW). METHODS: This systematic review was registered at PROSPERO (CRD42021242977). PubMed, EMBASE, and Web of Science were searched for original studies reporting changes in clinical-decision making (e.g. diagnosis, management, or therapy) after using lung ultrasound. Inclusion criteria were a recorded change of management (in percentage of cases) and with a clinical presentation to the ED, ICU, or GW. Studies were excluded if examinations were beyond the scope of thoracic ultrasound or to guide procedures. Mean changes with range (%) in clinical-decision making were reported. Methodological data on lung ultrasound were also collected. Study quality was scored using the Newcastle-Ottawa scale. RESULTS: A total of 13 studies were included: five studies on the ED (546 patients), five studies on the ICU (504 patients), two studies on the GW (1150 patients), and one study across all three wards (41 patients). Lung ultrasound changed the diagnosis in mean 33% (15-44%) and 44% (34-58%) of patients in the ED and ICU, respectively. Lung ultrasound changed the management in mean 48% (20-80%), 42% (30-68%) and 48% (48-48%) of patients in the ED, in the ICU and in the GW, respectively. Changes in management were non-invasive in 92% and 51% of patients in the ED and ICU, respectively. Lung ultrasound methodology was heterogeneous across studies. Risk of bias was moderate to high in all studies. CONCLUSIONS: Lung ultrasound, exclusively or as a part of thoracic ultrasound, has substantial impact on clinical-decision making by changing diagnosis and management in the EDs, ICUs, and GWs. The current evidence level and methodological heterogeneity underline the necessity for well-designed trials and standardization of methodology.

Extended Lung Ultrasound to Differentiate Between Pneumonia and Atelectasis in Critically Ill Patients: A Diagnostic Accuracy Study.

OBJECTIVES: To determine the diagnostic accuracy of extended lung ultrasonographic assessment, including evaluation of dynamic air bronchograms and color Doppler imaging to differentiate pneumonia and atelectasis in patients with consolidation on chest radiograph. Compare this approach to the Simplified Clinical Pulmonary Infection Score, Lung Ultrasound Clinical Pulmonary Infection Score, and the Bedside Lung Ultrasound in Emergency protocol. DESIGN: Prospective diagnostic accuracy study. SETTING: Adult ICU applying selective digestive decontamination. PATIENTS: Adult patients that underwent a chest radiograph for any indication at any time during admission. Patients with acute respiratory distress syndrome, coronavirus disease 2019, severe thoracic trauma, and infectious isolation measures were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Lung ultrasound was performed within 24 hours of chest radiograph. Consolidated tissue was assessed for presence of dynamic air bronchograms and with color Doppler imaging for presence of flow. Clinical data were recorded after ultrasonographic assessment. The primary outcome was diagnostic accuracy of dynamic air bronchogram and color Doppler imaging alone and within a decision tree to differentiate pneumonia from atelectasis. Of 120 patients included, 51 (42.5%) were diagnosed with pneumonia. The dynamic air bronchogram had a 45% (95% CI, 31-60%) sensitivity and 99% (95% CI, 92-100%) specificity. Color Doppler imaging had a 90% (95% CI, 79-97%) sensitivity and 68% (95% CI, 56-79%) specificity. The combined decision tree had an 86% (95% CI, 74-94%) sensitivity and an 86% (95% CI, 75-93%) specificity. The Bedside Lung Ultrasound in Emergency protocol had a 100% (95% CI, 93-100%) sensitivity and 0% (95% CI, 0-5%) specificity, while the Simplified Clinical Pulmonary Infection Score and Lung Ultrasound Clinical Pulmonary Infection Score had a 41% (95% CI, 28-56%) sensitivity, 84% (95% CI, 73-92%) specificity and 68% (95% CI, 54-81%) sensitivity, 81% (95% CI, 70-90%) specificity, respectively. CONCLUSIONS: In critically ill patients with pulmonary consolidation on chest radiograph, an extended lung ultrasound protocol is an accurate and directly bedside available tool to differentiate pneumonia from atelectasis. It outperforms standard lung ultrasound and clinical scores.

Lung ultrasound in a tertiary intensive care unit population: a diagnostic accuracy study.

BACKGROUND: Evidence from previous studies comparing lung ultrasound to thoracic computed tomography (CT) in intensive care unit (ICU) patients is limited due to multiple methodologic weaknesses. While addressing methodologic weaknesses of previous studies, the primary aim of this study is to investigate the diagnostic accuracy of lung ultrasound in a tertiary ICU population. METHODS: This is a single-center, prospective diagnostic accuracy study conducted at a tertiary ICU in the Netherlands. Critically ill patients undergoing thoracic CT for any clinical indication were included. Patients were excluded if time between the index and reference test was over eight hours. Index test and reference test consisted of 6-zone lung ultrasound and thoracic CT, respectively. Hemithoraces were classified by the index and reference test as follows: consolidation, interstitial syndrome, pneumothorax and pleural effusion. Sensitivity, specificity, positive and negative likelihood ratio were estimated. RESULTS: In total, 87 patients were included of which eight exceeded the time limit and were subsequently excluded. In total, there were 147 respiratory conditions in 79 patients. The estimated sensitivity and specificity to detect consolidation were 0.76 (95%CI: 0.68 to 0.82) and 0.92 (0.87 to 0.96), respectively. For interstitial syndrome they were 0.60 (95%CI: 0.48 to 0.71) and 0.69 (95%CI: 0.58 to 0.79). For pneumothorax they were 0.59 (95%CI: 0.33 to 0.82) and 0.97 (95%CI: 0.93 to 0.99). For pleural effusion they were 0.85 (95%CI: 0.77 to 0.91) and 0.77 (95%CI: 0.62 to 0.88). CONCLUSIONS: In conclusion, lung ultrasound is an adequate diagnostic modality in a tertiary ICU population to detect consolidations, interstitial syndrome, pneumothorax and pleural effusion. Moreover, one should be careful not to interpret lung ultrasound results in deterministic fashion as multiple respiratory conditions can be present in one patient. Trial registration This study was retrospectively registered at Netherlands Trial Register on March 17, 2021, with registration number NL9344.

Effects of Lung Ultrasonography-Guided Management on Cumulative Fluid Balance and Other Clinical Outcomes: A Systematic Review.

Lung ultrasonography is accurate in detecting pulmonary edema and overcomes most limitations of traditional diagnostic modalities. Whether use of lung ultrasonography-guided management has an effect on cumulative fluid balances and other clinical outcomes remains unclear. In this systematic review, we included 12 studies using ultrasonography guided-management with a total of 2290 patients. Four in-patient studies found a reduced cumulative fluid balance (ranging from -0.3 L to -2.4 L), whereas three out-patient studies found reduction in dialysis dry weight (ranging from -2.6 kg to -0.2 kg) compared with conventionally managed patients. None of the studies found adverse effects related to hypoperfusion. The use of lung ultrasonography-guided management was not associated with other clinical outcomes. This systematic review shows that lung ultrasonography-guided management, exclusively or in concert with other diagnostic modalities, is associated with a reduced cumulative fluid balance. Studies thus far have not shown a consistent effect on clinical outcomes.