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Critical care uses syndromic definitions to describe patient groups for clinical practice and research. There is growing recognition that a "precision medicine" approach is required and that integrated biologic and physiologic data identify reproducible subpopulations that may respond differently to treatment. This article reviews the current state of the field and considers how to successfully transition to a precision medicine approach. To impact clinical care, identification of subpopulations must do more than differentiate prognosis. It must differentiate response to treatment, ideally by defining subgroups with distinct functional or pathobiological mechanisms (endotypes). There are now multiple examples of reproducible subpopulations of sepsis, acute respiratory distress syndrome, and acute kidney or brain injury described using clinical, physiological, and/or biological data. Many of these subpopulations have demonstrated the potential to define differential treatment response, largely in retrospective studies, and that the same treatment-responsive subpopulations may cross multiple clinical syndromes (treatable traits). To bring about a change in clinical practice, a precision medicine approach must be evaluated in prospective clinical studies requiring novel adaptive trial designs. Several such studies are underway, but there are multiple challenges to be tackled. Such subpopulations must be readily identifiable and be applicable to all critically ill populations around the world. Subdividing clinical syndromes into subpopulations will require large patient numbers. Global collaboration of investigators, clinicians, industry, and patients over many years will therefore be required to transition to a precision medicine approach and ultimately realize treatment advances seen in other medical fields.
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Cuidados Críticos , Unidades de Cuidados Intensivos , Medicina de Precisión , Humanos , Medicina de Precisión/métodos , Cuidados Críticos/métodos , Cuidados Críticos/normas , Consenso , Síndrome , Enfermedad Crítica/terapia , Fenotipo , Síndrome de Dificultad Respiratoria/terapia , Síndrome de Dificultad Respiratoria/diagnóstico , Síndrome de Dificultad Respiratoria/clasificaciónRESUMEN
BACKGROUND: Lung ultrasound (LUS) in an emerging technique used in the intensive care unit (ICU). The derivative LUS aeration score has been shown to have associations with mortality in invasively ventilated patients. This study assessed the predictive value of baseline and early changes in LUS aeration scores in critically ill invasively ventilated patients with and without ARDS (Acute Respiratory Distress Syndrome) on 30- and 90-day mortality. METHODS: This is a post hoc analysis of a multicenter prospective observational cohort study, which included patients admitted to the ICU with an expected duration of ventilation for at least 24 h. We restricted participation to patients who underwent a 12-region LUS exam at baseline and had the primary endpoint (30-day mortality) available. Logistic regression was used to analyze the primary and secondary endpoints. The analysis was performed for the complete patient cohort and for predefined subgroups (ARDS and no ARDS). RESULTS: A total of 442 patients were included, of whom 245 had a second LUS exam. The baseline LUS aeration score was not associated with mortality (1.02 (95% CI: 0.99 - 1.06), p = 0.143). This finding was not different in patients with and in patients without ARDS. Early deterioration of the LUS score was associated with mortality (2.09 (95% CI: 1.01 - 4.3), p = 0.046) in patients without ARDS, but not in patients with ARDS or in the complete patient cohort. CONCLUSION: In this cohort of critically ill invasively ventilated patients, the baseline LUS aeration score was not associated with 30- and 90-day mortality. An early change in the LUS aeration score was associated with mortality, but only in patients without ARDS. TRIAL REGISTRATION: ClinicalTrials.gov, ID NCT04482621.
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Pulmón , Respiración Artificial , Síndrome de Dificultad Respiratoria , Ultrasonografía , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Pulmón/diagnóstico por imagen , Ultrasonografía/métodos , Síndrome de Dificultad Respiratoria/mortalidad , Síndrome de Dificultad Respiratoria/diagnóstico por imagen , Síndrome de Dificultad Respiratoria/terapia , Estudios de Cohortes , Enfermedad Crítica/mortalidad , Factores de Tiempo , Unidades de Cuidados IntensivosRESUMEN
BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening respiratory condition with high mortality rates, accounting for 10% of all intensive care unit admissions. Lung ultrasound (LUS) as diagnostic tool for acute respiratory failure has garnered widespread recognition and was recently incorporated into the updated definitions of ARDS. This raised the hypothesis that LUS is a reliable method for diagnosing ARDS. OBJECTIVES: We aimed to establish the accuracy of LUS for ARDS diagnosis and classification of focal versus non-focal ARDS subphenotypes. METHODS: This systematic review and meta-analysis used a systematic search strategy, which was applied to PubMed, EMBASE and cochrane databases. Studies investigating the diagnostic accuracy of LUS compared to thoracic CT or chest radiography (CXR) in ARDS diagnosis or focal versus non-focal subphenotypes in adult patients were included. Quality of studies was evaluated using the QUADAS-2 tool. Statistical analyses were performed using "Mada" in Rstudio, version 4.0.3. Sensitivity and specificity with 95% confidence interval of each separate study were summarized in a Forest plot. RESULTS: The search resulted in 2648 unique records. After selection, 11 reports were included, involving 2075 patients and 598 ARDS cases (29%). Nine studies reported on ARDS diagnosis and two reported on focal versus non-focal ARDS subphenotypes classification. Meta-analysis showed a pooled sensitivity of 0.631 (95% CI 0.450-0.782) and pooled specificity of 0.942 (95% CI 0.856-0.978) of LUS for ARDS diagnosis. In two studies, LUS could accurately differentiate between focal versus non-focal ARDS subphenotypes. Insufficient data was available to perform a meta-analysis. CONCLUSION: This review confirms the hypothesis that LUS is a reliable method for diagnosing ARDS in adult patients. For the classification of focal or non-focal subphenotypes, LUS showed promising results, but more research is needed.
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Pulmón , Síndrome de Dificultad Respiratoria , Ultrasonografía , Humanos , Síndrome de Dificultad Respiratoria/diagnóstico por imagen , Síndrome de Dificultad Respiratoria/clasificación , Ultrasonografía/métodos , Ultrasonografía/normas , Pulmón/diagnóstico por imagen , FenotipoRESUMEN
BACKGROUND: Acute respiratory distress syndrome (ARDS) poses challenges in early identification. Exhaled breath contains metabolites reflective of pulmonary inflammation. AIM: To evaluate the diagnostic accuracy of breath metabolites for ARDS in invasively ventilated intensive care unit (ICU) patients. METHODS: This two-center observational study included critically ill patients receiving invasive ventilation. Gas chromatography and mass spectrometry (GC-MS) was used to quantify the exhaled metabolites. The Berlin definition of ARDS was assessed by three experts to categorize all patients into "certain ARDS", "certain no ARDS" and "uncertain ARDS" groups. The patients with "certain" labels from one hospital formed the derivation cohort used to train a classifier built based on the five most significant breath metabolites. The diagnostic accuracy of the classifier was assessed in all patients from the second hospital and combined with the lung injury prediction score (LIPS). RESULTS: A total of 499 patients were included in this study. Three hundred fifty-seven patients were included in the derivation cohort (60 with certain ARDS; 17%), and 142 patients in the validation cohort (47 with certain ARDS; 33%). The metabolites 1-methylpyrrole, 1,3,5-trifluorobenzene, methoxyacetic acid, 2-methylfuran and 2-methyl-1-propanol were included in the classifier. The classifier had an area under the receiver operating characteristics curve (AUROCC) of 0.71 (CI 0.63-0.78) in the derivation cohort and 0.63 (CI 0.52-0.74) in the validation cohort. Combining the breath test with the LIPS does not significantly enhance the diagnostic performance. CONCLUSION: An exhaled breath metabolomics-based classifier has moderate diagnostic accuracy for ARDS but was not sufficiently accurate for clinical use, even after combination with a clinical prediction score.
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Lesión Pulmonar , Neumonía , Síndrome de Dificultad Respiratoria , Humanos , Cuidados Críticos , Pulmón , Síndrome de Dificultad Respiratoria/diagnósticoRESUMEN
Rationale: Lung ultrasound (LUS) is a promising tool for diagnosis of acute respiratory distress syndrome (ARDS), but adequately sized studies with external validation are lacking. Objectives: To develop and validate a data-driven LUS score for diagnosis of ARDS and compare its performance with that of chest radiography (CXR). Methods: This multicenter prospective observational study included invasively ventilated ICU patients who were divided into a derivation cohort and a validation cohort. Three raters scored ARDS according to the Berlin criteria, resulting in a classification of "certain no ARDS," or "certain ARDS" when experts agreed or "uncertain ARDS" when evaluations conflicted. Uncertain cases were classified in a consensus meeting. Results of a 12-region LUS exam were used in a logistic regression model to develop the LUS-ARDS score. Measurements and Main Results: Three hundred twenty-four (16% certain ARDS) and 129 (34% certain ARDS) patients were included in the derivation cohort and the validation cohort, respectively. With an ARDS diagnosis by the expert panel as the reference test, the LUS-ARDS score, including the left and right LUS aeration scores and anterolateral pleural line abnormalities, had an area under the receiver operating characteristic (ROC) curve of 0.90 (95% confidence interval [CI], 0.85-0.95) in certain patients of the derivation cohort and 0.80 (95% CI, 0.72-0.87) in all patients of the validation cohort. Within patients who had imaging-gold standard chest computed tomography available, diagnostic accuracy of eight independent CXR readers followed the ROC curve of the LUS-ARDS score. Conclusions: The LUS-ARDS score can be used to accurately diagnose ARDS also after external validation. The LUS-ARDS score may be a useful adjunct to a diagnosis of ARDS after further validation, as it showed performance comparable with that of the current practice with experienced CXR readers but more objectifiable diagnostic accuracy at each cutoff.
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Pulmón , Síndrome de Dificultad Respiratoria , Humanos , Pulmón/diagnóstico por imagen , Síndrome de Dificultad Respiratoria/diagnóstico por imagen , Ultrasonografía , Tórax , RadiografíaRESUMEN
Pulmonary edema is a central hallmark of acute respiratory distress syndrome (ARDS). Endothelial dysfunction and epithelial injury contribute to alveolar-capillary permeability but their differential contribution to pulmonary edema development remains understudied. Plasma levels of surfactant protein-D (SP-D), soluble receptor for advanced glycation end products (sRAGE), and angiopoietin-2 (Ang-2) were measured in a prospective, multicenter cohort of invasively ventilated patients. Pulmonary edema was quantified using the radiographic assessment of lung edema (RALE) and global lung ultrasound (LUS) score. Variables were collected within 48 h after intubation. Linear regression was used to examine the association of the biomarkers with pulmonary edema. In 362 patients, higher SP-D, sRAGE, and Ang-2 concentrations were significantly associated with higher RALE and global LUS scores. After stratification by ARDS subgroups (pulmonary, nonpulmonary, COVID, non-COVID), the positive association of SP-D levels with pulmonary edema remained, whereas sRAGE and Ang-2 showed less consistent associations throughout the subgroups. In a multivariable analysis, SP-D levels were most strongly associated with pulmonary edema when combined with sRAGE (RALE score: ßSP-D = 6.79 units/log10 pg/mL, ßsRAGE = 3.84 units/log10 pg/mL, R2 = 0.23; global LUS score: ßSP-D = 3.28 units/log10 pg/mL, ßsRAGE = 2.06 units/log10 pg/mL, R2 = 0.086), whereas Ang-2 did not further improve the model. Biomarkers of epithelial injury and endothelial dysfunction were associated with pulmonary edema in invasively ventilated patients. SP-D and sRAGE showed the strongest association, suggesting that epithelial injury may form a final common pathway in the alveolar-capillary barrier dysfunction underlying pulmonary edema.
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COVID-19 , Edema Pulmonar , Síndrome de Dificultad Respiratoria , Enfermedades Vasculares , Humanos , Edema Pulmonar/etiología , Estudios Prospectivos , Proteína D Asociada a Surfactante Pulmonar , Respiración Artificial/efectos adversos , Ruidos Respiratorios , Biomarcadores/metabolismo , Receptor para Productos Finales de Glicación AvanzadaRESUMEN
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.
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Pulmón , Edema Pulmonar , Adulto , Humanos , Unidades de Cuidados Intensivos , Pulmón/diagnóstico por imagen , Estudios Prospectivos , Sensibilidad y Especificidad , Ultrasonografía/métodosRESUMEN
BACKGROUND: Patients with COVID-19-related acute respiratory distress syndrome (ARDS) require respiratory support with invasive mechanical ventilation and show varying responses to recruitment manoeuvres. In patients with ARDS not related to COVID-19, two pulmonary subphenotypes that differed in recruitability were identified using latent class analysis (LCA) of imaging and clinical respiratory parameters. We aimed to evaluate if similar subphenotypes are present in patients with COVID-19-related ARDS. METHODS: This is the retrospective analysis of mechanically ventilated patients with COVID-19-related ARDS who underwent CT scans at positive end-expiratory pressure of 10 cmH2O and after a recruitment manoeuvre at 20 cmH2O. LCA was applied to quantitative CT-derived parameters, clinical respiratory parameters, blood gas analysis and routine laboratory values before recruitment to identify subphenotypes. RESULTS: 99 patients were included. Using 12 variables, a two-class LCA model was identified as best fitting. Subphenotype 2 (recruitable) was characterized by a lower PaO2/FiO2, lower normally aerated lung volume and lower compliance as opposed to a higher non-aerated lung mass and higher mechanical power when compared to subphenotype 1 (non-recruitable). Patients with subphenotype 2 had more decrease in non-aerated lung mass in response to a standardized recruitment manoeuvre (p = 0.024) and were mechanically ventilated longer until successful extubation (adjusted SHR 0.46, 95% CI 0.23-0.91, p = 0.026), while no difference in survival was found (p = 0.814). CONCLUSIONS: A recruitable and non-recruitable subphenotype were identified in patients with COVID-19-related ARDS. These findings are in line with previous studies in non-COVID-19-related ARDS and suggest that a combination of imaging and clinical respiratory parameters could facilitate the identification of recruitable lungs before the manoeuvre.
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COVID-19 , Síndrome de Dificultad Respiratoria , Humanos , Análisis de Clases Latentes , Estudios Retrospectivos , COVID-19/complicaciones , Síndrome de Dificultad Respiratoria/diagnóstico por imagen , Respiración con Presión Positiva/métodosRESUMEN
Rationale: Recent studies showed that biological subphenotypes in acute respiratory distress syndrome (ARDS) provide prognostic enrichment and show potential for predictive enrichment. Objectives: To determine whether these subphenotypes and their prognostic and potential for predictive enrichment could be extended to other patients in the ICU, irrespective of fulfilling the definition of ARDS. Methods: This is a secondary analysis of a prospective observational study of adult patients admitted to the ICU. We tested the prognostic enrichment of both cluster-derived and latent-class analysis (LCA)-derived biological ARDS subphenotypes by evaluating the association with clinical outcome (ICU-day, 30-day mortality, and ventilator-free days) using logistic regression and Cox regression analysis. We performed a principal component analysis to compare blood leukocyte gene expression profiles between subphenotypes and the presence of ARDS. Measurements and Main Results: We included 2,499 mechanically ventilated patients (674 with and 1,825 without ARDS). The cluster-derived "reactive" subphenotype was, independently of ARDS, significantly associated with a higher probability of ICU mortality, higher 30-day mortality, and a lower probability of successful extubation while alive compared with the "uninflamed" subphenotype. The blood leukocyte gene expression profiles of individual subphenotypes were similar for patients with and without ARDS. LCA-derived subphenotypes also showed similar profiles. Conclusions: The prognostic and potential for predictive enrichment of biological ARDS subphenotypes may be extended to mechanically ventilated critically ill patients without ARDS. Using the concept of biological subphenotypes for splitting cohorts of critically ill patients could add to improving future precision-based trial strategies and lead to identifying treatable traits for all critically ill patients.
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Fenotipo , Respiración con Presión Positiva/métodos , ARN/análisis , Síndrome de Dificultad Respiratoria/genética , Síndrome de Dificultad Respiratoria/fisiopatología , Síndrome de Dificultad Respiratoria/terapia , Anciano , Femenino , Variación Genética , Humanos , Análisis de Clases Latentes , Modelos Logísticos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: There is a demand for a non-invasive bedside method to diagnose Acute Respiratory Distress Syndrome (ARDS). Octane was discovered and validated as the most important breath biomarker for diagnosis of ARDS using gas-chromatography and mass-spectrometry (GC-MS). However, GC-MS is unsuitable as a point-of-care (POC) test in the intensive care unit (ICU). Therefore, we determined if a newly developed POC breath test can reliably detect octane in exhaled breath of invasively ventilated ICU patients. METHODS: Two developmental steps were taken to design a POC breath test that relies on gas-chromatography using air as carrier gas with a photoionization detector. Calibration measurements were performed with a laboratory prototype in healthy subjects. Subsequently, invasively ventilated patients were included for validation and assessment of repeatability. After evolving to a POC breath test, this device was validated in a second group of invasively ventilated patients. Octane concentration was based on the area under the curve, which was extracted from the chromatogram and compared to known values from calibration measurements. RESULTS: Five healthy subjects and 53 invasively ventilated patients were included. Calibration showed a linear relation (R2 = 1.0) between the octane concentration and the quantified octane peak in the low parts per billion (ppb) range. For the POC breath test the repeatability was excellent (R2 = 0.98, ICC = 0.97 (95% CI 0.94-0.99)). CONCLUSION: This is the first study to show that a POC breath test can rapidly and reliably detect octane, with excellent repeatability, at clinically relevant levels of low ppb in exhaled breath of ventilated ICU patients. This opens possibilities for targeted exhaled breath analysis to be used as a bedside test and makes it a potential diagnostic tool for the early detection of ARDS.
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Pruebas Respiratorias , Octanos , Espiración , Cromatografía de Gases y Espectrometría de Masas , Humanos , Sistemas de Atención de PuntoRESUMEN
BACKGROUND: Exhaled volatile organic compounds (VOCs), particularly hydrocarbons from oxidative stress-induced lipid peroxidation, are associated with hyperoxia exposure. However, important heterogeneity amongst identified VOCs and concerns about their precise pathophysiological origins warrant translational studies assessing their validity as a marker of hyperoxia-induced oxidative stress. Therefore, this study sought to examine changes in VOCs previously associated with the oxidative stress response in hyperoxia-exposed lung epithelial cells. METHODS: A549 alveolar epithelial cells were exposed to hyperoxia for 24 h, or to room air as normoxia controls, or hydrogen peroxide as oxidative-stress positive controls. VOCs were sampled from the headspace, analysed by gas chromatography coupled with mass spectrometry and compared by targeted and untargeted analyses. A secondary analysis of breath samples from a large cohort of critically ill adult patients assessed the association of identified VOCs with clinical oxygen exposure. RESULTS: Following cellular hyperoxia exposure, none of the targeted VOCs, previously proposed as breath markers of oxidative stress, were increased, and decane was significantly decreased. Untargeted analysis did not reveal novel identifiable hyperoxia-associated VOCs. Within the clinical cohort, three previously proposed breath markers of oxidative stress, hexane, octane, and decane had no real diagnostic value in discriminating patients exposed to hyperoxia. CONCLUSIONS: Hyperoxia exposure of alveolar epithelial cells did not result in an increase in identifiable VOCs, whilst VOCs previously linked to oxidative stress were not associated with oxygen exposure in a cohort of critically ill patients. These findings suggest that the pathophysiological origin of previously proposed breath markers of oxidative stress is more complex than just oxidative stress from hyperoxia at the lung epithelial cellular level.
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Patients with acute exacerbation of lung fibrosis with usual interstitial pneumonia (EUIP) pattern are at increased risk for ventilator-induced lung injury (VILI) and mortality when exposed to mechanical ventilation (MV). Yet, lack of a mechanical model describing UIP-lung deformation during MV represents a research gap. Aim of this study was to develop a constitutive mathematical model for UIP-lung deformation during lung protective MV based on the stress-strain behavior and the specific elastance of patients with EUIP as compared to that of acute respiratory distress syndrome (ARDS) and healthy lung. Partitioned lung and chest wall mechanics were assessed for patients with EUIP and primary ARDS (1:1 matched based on body mass index and PaO2/FiO2 ratio) during a PEEP trial performed within 24 h from intubation. Patient's stress-strain curve and the lung specific elastance were computed and compared with those of healthy lungs, derived from literature. Respiratory mechanics were used to fit a novel mathematical model of the lung describing mechanical-inflation-induced lung parenchyma deformation, differentiating the contributions of elastin and collagen, the main components of lung extracellular matrix. Five patients with EUIP and 5 matched with primary ARDS were included and analyzed. Global strain was not different at low PEEP between the groups. Overall specific elastance was significantly higher in EUIP as compared to ARDS (28.9 [22.8-33.2] cmH2O versus 11.4 [10.3-14.6] cmH2O, respectively). Compared to ARDS and healthy lung, the stress/strain curve of EUIP showed a steeper increase, crossing the VILI threshold stress risk for strain values greater than 0.55. The contribution of elastin was prevalent at lower strains, while the contribution of collagen was prevalent at large strains. The stress/strain curve for collagen showed an upward shift passing from ARDS and healthy lungs to EUIP lungs. During MV, patients with EUIP showed different respiratory mechanics, stress-strain curve and specific elastance as compared to ARDS patients and healthy subjects and may experience VILI even when protective MV is applied. According to our mathematical model of lung deformation during mechanical inflation, the elastic response of UIP-lung is peculiar and different from ARDS. Our data suggest that patients with EUIP experience VILI with ventilatory setting that are lung-protective for patients with ARDS.
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Pulmón , Respiración Artificial , Síndrome de Dificultad Respiratoria , Humanos , Masculino , Femenino , Persona de Mediana Edad , Respiración Artificial/efectos adversos , Síndrome de Dificultad Respiratoria/fisiopatología , Anciano , Pulmón/fisiopatología , Pulmón/patología , Elasticidad , Lesión Pulmonar Inducida por Ventilación Mecánica/fisiopatología , Fibrosis Pulmonar/fisiopatología , Fibrosis Pulmonar/metabolismo , Mecánica Respiratoria/fisiología , Estrés Mecánico , Enfermedades Pulmonares Intersticiales/fisiopatología , Modelos TeóricosRESUMEN
BACKGROUND: Acute respiratory distress syndrome (ARDS) is a frequent cause of hypoxemic respiratory failure with a mortality rate of approximately 30%. Identifying ARDS subphenotypes based on "focal" or "non-focal" lung morphology has the potential to better target mechanical ventilation strategies of individual patients. However, classifying morphology through chest radiography or computed tomography is either inaccurate or impractical. Lung ultrasound (LUS) is a non-invasive bedside tool that can accurately distinguish "focal" from "non-focal" lung morphology. We hypothesize that LUS-guided personalized mechanical ventilation in ARDS patients leads to a reduction in 90-day mortality compared to conventional mechanical ventilation. METHODS: The Personalized Mechanical Ventilation Guided by UltraSound in Patients with Acute Respiratory Distress Syndrome (PEGASUS) study is an investigator-initiated, international, randomized clinical trial (RCT) that plans to enroll 538 invasively ventilated adult intensive care unit (ICU) patients with moderate to severe ARDS. Eligible patients will receive a LUS exam to classify lung morphology as "focal" or "non-focal". Thereafter, patients will be randomized within 12 h after ARDS diagnosis to receive standard care or personalized ventilation where the ventilation strategy is adjusted to the morphology subphenotype, i.e., higher positive end-expiratory pressure (PEEP) and recruitment maneuvers for "non-focal" ARDS and lower PEEP and prone positioning for "focal" ARDS. The primary endpoint is all-cause mortality at day 90. Secondary outcomes are mortality at day 28, ventilator-free days at day 28, ICU length of stay, ICU mortality, hospital length of stay, hospital mortality, and number of complications (ventilator-associated pneumonia, pneumothorax, and need for rescue therapy). After a pilot phase of 80 patients, the correct interpretation of LUS images and correct application of the intervention within the safe limits of mechanical ventilation will be evaluated. DISCUSSION: PEGASUS is the first RCT that compares LUS-guided personalized mechanical ventilation with conventional ventilation in invasively ventilated patients with moderate and severe ARDS. If this study demonstrates that personalized ventilation guided by LUS can improve the outcomes of ARDS patients, it has the potential to shift the existing one-size-fits-all ventilation strategy towards a more individualized approach. TRIAL REGISTRATION: The PEGASUS trial was registered before the inclusion of the first patient, https://clinicaltrials.gov/ (ID: NCT05492344).
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Pulmón , Ensayos Clínicos Controlados Aleatorios como Asunto , Respiración Artificial , Síndrome de Dificultad Respiratoria , Ultrasonografía Intervencional , Humanos , Síndrome de Dificultad Respiratoria/terapia , Síndrome de Dificultad Respiratoria/diagnóstico por imagen , Síndrome de Dificultad Respiratoria/mortalidad , Respiración Artificial/métodos , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Resultado del Tratamiento , Ultrasonografía Intervencional/métodos , Factores de Tiempo , Estudios Multicéntricos como Asunto , Valor Predictivo de las Pruebas , Medicina de Precisión/métodosRESUMEN
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.
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BACKGROUND: Lung ultrasound (LUS) can detect pulmonary edema and it is under consideration to be added to updated acute respiratory distress syndrome (ARDS) criteria. However, it remains uncertain whether different LUS scores can be used to quantify pulmonary edema in patient with ARDS. OBJECTIVES: This study examined the diagnostic accuracy of four LUS scores with the extravascular lung water index (EVLWi) assessed by transpulmonary thermodilution in patients with moderate-to-severe COVID-19 ARDS. METHODS: In this predefined secondary analysis of a multicenter randomized-controlled trial (InventCOVID), patients were enrolled within 48 hours after intubation and underwent LUS and EVLWi measurement on the first and fourth day after enrolment. EVLWi and ∆EVLWi were used as reference standards. Two 12-region scores (global LUS and LUS-ARDS), an 8-region anterior-lateral score and a 4-region B-line score were used as index tests. Pearson correlation was performed and the area under the receiver operating characteristics curve (AUROCC) for severe pulmonary edema (EVLWi > 15 mL/kg) was calculated. RESULTS: 26 out of 30 patients (87%) had complete LUS and EVLWi measurements at time point 1 and 24 out of 29 patients (83%) at time point 2. The global LUS (r = 0.54), LUS-ARDS (r = 0.58) and anterior-lateral score (r = 0.54) correlated significantly with EVLWi, while the B-line score did not (r = 0.32). ∆global LUS (r = 0.49) and ∆anterior-lateral LUS (r = 0.52) correlated significantly with ∆EVLWi. AUROCC for EVLWi > 15 ml/kg was 0.73 for the global LUS, 0.79 for the anterior-lateral and 0.85 for the LUS-ARDS score. CONCLUSIONS: Overall, LUS demonstrated an acceptable diagnostic accuracy for detection of pulmonary edema in moderate-to-severe COVID-19 ARDS when compared with PICCO. For identifying patients at risk of severe pulmonary edema, an extended score considering pleural morphology may be of added value. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04794088, registered on 11 March 2021. European Clinical Trials Database number 2020-005447-23.
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INTRODUCTION: The Radiographic Assessment of Lung Edema (RALE) score provides a semi-quantitative measure of pulmonary edema. In patients with acute respiratory distress syndrome (ARDS), the RALE score is associated with mortality. In mechanically ventilated patients in the intensive care unit (ICU) with respiratory failure not due to ARDS, a variable degree of lung edema is observed as well. We aimed to evaluate the prognostic value of RALE in mechanically ventilated ICU patients. METHODS: Secondary analysis of patients enrolled in the 'Diagnosis of Acute Respiratory Distress Syndrome' (DARTS) project with an available chest X-ray (CXR) at baseline. Where present, additional CXRs at day 1 were analysed. The primary endpoint was 30-day mortality. Outcomes were also stratified for ARDS subgroups (no ARDS, non-COVID-ARDS and COVID-ARDS). RESULTS: 422 patients were included, of which 84 had an additional CXR the following day. Baseline RALE scores were not associated with 30-day mortality in the entire cohort (OR: 1.01, 95% CI: 0.98-1.03, p = 0.66), nor in subgroups of ARDS patients. Early changes in RALE score (baseline to day 1) were only associated with mortality in a subgroup of ARDS patients (OR: 1.21, 95% CI: 1.02-1.51, p = 0.04), after correcting for other known prognostic factors. CONCLUSIONS: The prognostic value of the RALE score cannot be extended to mechanically ventilated ICU patients in general. Only in ARDS patients, early changes in RALE score were associated with mortality.
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Background: Changes in exhaled volatile organic compounds (VOCs) can be used to discriminate between respiratory diseases, and increased concentrations of hydrocarbons are commonly linked to oxidative stress. However, the VOCs identified are inconsistent between studies, and translational studies are lacking. Methods: In this bench to bedside study, we captured VOCs in the headspace of A549 epithelial cells after exposure to hydrogen peroxide (H2O2), to induce oxidative stress, using high-capacity polydimethylsiloxane sorbent fibres. Exposed and unexposed cells were compared using targeted and untargeted analysis. Breath samples of invasively ventilated intensive care unit patients (n=489) were collected on sorbent tubes and associated with the inspiratory oxygen fraction (F IO2 ) to reflect pulmonary oxidative stress. Headspace samples and breath samples were analysed using gas chromatography and mass spectrometry. Results: In the cell, headspace octane concentration was decreased after oxidative stress (p=0.0013), while the other VOCs were not affected. 2-ethyl-1-hexanol showed an increased concentration in the headspace of cells undergoing oxidative stress in untargeted analysis (p=0.00014). None of the VOCs that were linked to oxidative stress showed a significant correlation with F IO2 (Rs range: -0.015 to -0.065) or discriminated between patients with F IO2 ≥0.6 or below (area under the curve range: 0.48 to 0.55). Conclusion: Despite a comprehensive translational approach, validation of known and novel volatile biomarkers of oxidative stress was not possible in patients at risk of pulmonary oxidative injury. The inconsistencies observed highlight the difficulties faced in VOC biomarker validation, and that caution is warranted in the interpretation of the pathophysiological origin of discovered exhaled breath biomarkers.