Peripheral microcirculatory alterations are associated with the severity of acute respiratory distress syndrome in COVID-19 patients admitted to intermediate respiratory and intensive care units

COVID-19; Endothelial dysfunction; MicrocirculationCOVID-19; Disfunción endotelial; MicrocirculaciónCOVID-19; Disfunció endotelial; MicrocirculacióBackground COVID-19 is primarily a respiratory disease; however, there is also evidence that it causes endothelial damage in the microvasculature of several organs. The aim of the present study is to characterize in vivo the microvascular reactivity in peripheral skeletal muscle of severe COVID-19 patients. Methods This is a prospective observational study carried out in Spain, Mexico and Brazil. Healthy subjects and severe COVID-19 patients admitted to the intermediate respiratory (IRCU) and intensive care units (ICU) due to hypoxemia were studied. Local tissue/blood oxygen saturation (StO2) and local hemoglobin concentration (THC) were non-invasively measured on the forearm by near-infrared spectroscopy (NIRS). A vascular occlusion test (VOT), a three-minute induced ischemia, was performed in order to obtain dynamic StO2 parameters: deoxygenation rate (DeO2), reoxygenation rate (ReO2), and hyperemic response (HAUC). In COVID-19 patients, the severity of ARDS was evaluated by the ratio between peripheral arterial oxygen saturation (SpO2) and the fraction of inspired oxygen (FiO2) (SF ratio). Results Healthy controls (32) and COVID-19 patients (73) were studied. Baseline StO2 and THC did not differ between the two groups. Dynamic VOT-derived parameters were significantly impaired in COVID-19 patients showing lower metabolic rate (DeO2) and diminished endothelial reactivity. At enrollment, most COVID-19 patients were receiving invasive mechanical ventilation (MV) (53%) or high-flow nasal cannula support (32%). Patients on MV were also receiving sedative agents (100%) and vasopressors (29%). Baseline StO2 and DeO2 negatively correlated with SF ratio, while ReO2 showed a positive correlation with SF ratio. There were significant differences in baseline StO2 and ReO2 among the different ARDS groups according to SF ratio, but not among different respiratory support therapies. Conclusion Patients with severe COVID-19 show systemic microcirculatory alterations suggestive of endothelial dysfunction, and these alterations are associated with the severity of ARDS. Further evaluation is needed to determine whether these observations have prognostic implications. These results represent interim findings of the ongoing HEMOCOVID-19 trial. Trial registration ClinicalTrials.gov NCT04689477. Retrospectively registered 30 December 2020.The study has received funding from Fundació CELLEX Barcelona, Fundació Mir-Puig, Ajuntament de Barcelona, Agencia Estatal de Investigación (PHOTOMETABO, PID2019-106481RB-C31/10.13039/501100011033), the "Severo Ochoa" Programme for Centers of Excellence in R&D (CEX2019-000910-S), the Obra social “La Caixa” Foundation (LlumMedBcn), Generalitat de Catalunya (CERCA, AGAUR-2017-SGR-1380, RIS3CAT-001-P-001682 CECH), European Commission Horizon 2020 (FEDER, 688303/LUCA, 101016087/VASCOVID, 87114/LASERLAB-EUROPE V). We also acknowledge the collaboration and an instrument loan from Artinis (Netherlands)

Closed-loop oxygen control improves oxygen therapy in acute hypoxemic respiratory failure patients under high flow nasal oxygen: a randomized cross-over study (the HILOOP study)

Acute respiratory failure; High-flow nasal oxygenInsuficiencia respiratoria aguda; Oxígeno nasal de alto flujoInsuficiència respiratòria aguda; Oxigen nasal d'alt fluxBackground We aimed to assess the efficacy of a closed-loop oxygen control in critically ill patients with moderate to severe acute hypoxemic respiratory failure (AHRF) treated with high flow nasal oxygen (HFNO). Methods In this single-centre, single-blinded, randomized crossover study, adult patients with moderate to severe AHRF who were treated with HFNO (flow rate ≥ 40 L/min with FiO2 ≥ 0.30) were randomly assigned to start with a 4-h period of closed-loop oxygen control or 4-h period of manual oxygen titration, after which each patient was switched to the alternate therapy. The primary outcome was the percentage of time spent in the individualized optimal SpO2 range. Results Forty-five patients were included. Patients spent more time in the optimal SpO2 range with closed-loop oxygen control compared with manual titrations of oxygen (96.5 [93.5 to 98.9] % vs. 89 [77.4 to 95.9] %; p < 0.0001) (difference estimate, 10.4 (95% confidence interval 5.2 to 17.2). Patients spent less time in the suboptimal range during closed-loop oxygen control, both above and below the cut-offs of the optimal SpO2 range, and less time above the suboptimal range. Fewer number of manual adjustments per hour were needed with closed-loop oxygen control. The number of events of SpO2 < 88% and < 85% were not significantly different between groups. Conclusions Closed-loop oxygen control improves oxygen administration in patients with moderate-to-severe AHRF treated with HFNO, increasing the percentage of time in the optimal oxygenation range and decreasing the workload of healthcare personnel. These results are especially relevant in a context of limited oxygen supply and high medical demand, such as the COVID-19 pandemic. Trial registration The HILOOP study was registered at www.clinicaltrials.gov under the identifier NCT04965844.This study is partially supported by a research grant from Hamilton Medical AG. For each patient, an anonymised file containing the recorded data from the high-flow device was sent to Hamilton Medical AG, where these data were transformed into a database of raw data and sent back to the investigators for further analysis. Hamilton Medical AG did not have a role in statistical analysis beyond this point or data interpretation

Hemadsorption as a Treatment Option for Multisystem Inflammatory Syndrome in Children Associated With COVID-19: A Case Report

Hemoadsorció; Síndrome multisistèmica inflamatòria; Lesió del miocardi; Coronavirus SARS-CoV-2; COVID-19; 2019-nCoVHemoadsorción; Síndrome multisistémico inflamatorio; Lesión del miocardio; Coronavirus SARS-CoV-2; COVID-19; 2019-nCoVHemoadsorption; Inflammatory multisystemic syndrome; Myocardial injury; Coronavirus SARS-CoV-2; COVID-19; 2019-nCoVMultisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 is characterized by hypercytokinemia leading to overwhelming inflammation. We describe the use of a hemadsorption device as part of the supportive treatment for cytokine storm

Sigh in patients with acute hypoxemic respiratory failure and acute respiratory distress syndrome: the PROTECTION pilot randomized clinical trial

Background: Sigh is a cyclic brief recruitment manoeuvre: previous physiological studies showed that its use could be an interesting addition to pressure support ventilation to improve lung elastance, decrease regional heterogeneity and increase release of surfactant. Research question: Is the clinical application of sigh during pressure support ventilation (PSV) feasible? Study design and methods: We conducted a multi-center non-inferiority randomized clinical trial on adult intubated patients with acute hypoxemic respiratory failure or acute respiratory distress syndrome undergoing PSV. Patients were randomized to the No Sigh group and treated by PSV alone, or to the Sigh group, treated by PSV plus sigh (increase of airway pressure to 30 cmH2Ofor 3 seconds once per minute) until day 28 or death or successful spontaneous breathing trial. The primary endpoint of the study was feasibility, assessed as non-inferiority (5% tolerance) in the proportion of patients failing assisted ventilation. Secondary outcomes included safety, physiological parameters in the first week from randomization, 28-day mortality and ventilator-free days. Results: Two-hundred fifty-eight patients (31% women; median age 65 [54-75] years) were enrolled. In the Sigh group, 23% of patients failed to remain on assisted ventilation vs. 30% in the No Sigh group (absolute difference -7%, 95%CI -18% to 4%; p=0.015 for non-inferiority). Adverse events occurred in 12% vs. 13% in Sigh vs. No Sigh (p=0.852). Oxygenation was improved while tidal volume, respiratory rate and corrected minute ventilation were lower over the first 7 days from randomization in Sigh vs. No Sigh. There was no significant difference in terms of mortality (16% vs. 21%, p=0.342) and ventilator-free days (22 [7-26] vs. 22 [3-25] days, p=0.300) for Sigh vs. No Sigh. Interpretation: Among hypoxemic intubated ICU patients, application of sigh was feasible and without increased risk

Monitorización del paciente con oxigenoterapia de alto flujo nasal

L'oxigenoteràpia d'alt flux nasal (OAFN) ha esdevingut una tècnica útil en el maneig de pacients amb insuficiència respiratòria aguda (IRA). Les conseqüències negatives associades al retard de la intubació i el maneig clínic segueixen sent motiu de preocupació. La monitorització de marcadors biològics i paràmetres hemodinàmics podria ser útil per identificar de forma precoç els pacients de risc, establir un pronòstic i optimitzar el maneig. L'objectiu principal va ser estudiar la utilitat de diferents biomarcadors i sistemes de monitorització no invasiva, en el maneig de pacients amb IRA tractats amb OAFN. Els objectius secundaris van ser estudiar la utilitat de la monitorització de marcadors de lesió epitelial, endotelial i inflamació en pacients amb IRA i infiltrats bilaterals tractats amb OAFN i determinar la capacitat de l'índex de variabilitat pletismogràfica (PVi), de predir la precàrrega-dependència en pacients amb IRA i OAFN que presenten signes de hipoperfusió tissular. Mètodes: Es van incloure pacients intubats i no intubats amb hipoxèmia aguda i infiltrats bilaterals. Pacients amb ventilació mecànica invasiva (VMI) sense criteris radiològics ni d'oxigenació i voluntaris sans vas ser inclosos com a controls. Es van analitzar els nivells de marcadors de dany epitelial (receptor for advanced glycation end products i proteïna del surfactant-D), endotelial (angiopoyetina-2) i inflamació (interleuquina 6, 8 y 33, soluble suppression of tumorigenicity-2). Mitjançant l'anàlisi de propensió per aparellaments es van generar dos grups comparables en característiques basals i escales de gravetat. Per analitzar la utilitat del PVi es van incloure pacients amb IRA i OAFN que presentaven signes d'hipoperfusió. El grup control estava format per pacients amb IRA hipoxèmica i OAFN, sense signes d'hipoperfusió. Es va realitzar l'estudi de ecocardiografia transtoràcica (ETT) i la mesura de PVi. Posteriorment, es va realitzar l'elevació passiva de les cames (EPC) i es van repetir les mesures. La precàrrega-dependència es va definir com un augment del volum sistòlic (VS)≥10% després de la EPC. Els pacients responedors van rebre una càrrega de 250ml. Resultats: Es van analitzar 170 pacients amb IRA hipoxèmica i infiltrats bilaterals, dels quals 43 (25,3%) rebien OAFN. Es van seleccionar 39 parelles, que no van mostrar diferencies en els nivells dels biomarcadors. Els nivells de tots (excepte la interleuquina-33), van ser superiors en els dos grups en comparació amb els controsl. Vint-i-un pacients del grup OAFN (48,8%), van requerir intubació. Nivells d'interleuquina 8>67,16 ρg/mL van mostrar una forta associació amb la necessitat d'intubació (OR 9,21; p67,16 ρg/mL mostraron una fuerte asociación con la intubación (OR 9,21; p 67.16 ρg/mL were significantly associated with HFNC failure (OR 9.21; p<0.01). On the other hand, twenty ARF patients treated with HFNC who showed any sign of hypoperfusion were also analyzed. Twelve (60%) were preload-responders, and showed higher baseline PVi levels (24% vs. 13%; p=0.002) and PVi variation (δPVi) after PLR (6.8% vs. -1.7%; p<0.001) than non-responders. After fluid challenge, no differences in δPVi after PLR and δPVi after fluid administration were found (6.8% vs. 7.4%; p=0.24) and both values showed a strong correlation (r=0.84; p<0.001). Baseline PVi and δPVi after PLR showed excellent accuracy identifying preload responders (AUROC 0.92 and 1.00, respectively). Baseline PVi ≥ 16% had a sensitivity of 91.7% and a specificity of 87.5% for detecting preload responders, whereas δPVi ≥ 2% after PLR had a 100% sensitivity and specificity. Conclusions: Acute hypoxemic patients with bilateral opacities treated with HFNC, may show similar levels of biomarkers of inflammation and lung injury to acute respiratory distress syndrome (ARDS) patients and, therefore, they may be considered as ARDS patients. El PVi may predict preload responsiveness in patients treated with HFNC and it may be used to guide fluid administration in these patients

Use of thoracic ultrasound in acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a significant cause of morbidity and mortality in critically ill patients, yet it is often underrecognized. Current imaging techniques, such as CT scan and X-ray, have several limitations, including inter-observer reliability, limited accessibility, radiation and the need for transportation. Ultrasound has become an essential bedside tool in the critical care setting and the emergency room, offering several advantages over traditional imaging techniques. It is nowadays widely used for diagnosis and early management of acute respiratory and circulatory failure. Lung ultrasound (LUS) provides non-invasively valuable information regarding lung aeration, ventilation distribution and respiratory complications in ARDS patients at the bedside. Moreover, a holistic ultrasound approach, combining LUS, echocardiography, and diaphragm ultrasound offers physiological information that could help the clinician to personalize ventilator settings and guide fluid resuscitation in these patients. Ultrasound techniques could also inform about possible causes of weaning failure in difficult-to-wean patients. However, it is uncertain whether clinical decisions based on ultrasound assessment can improve outcomes in ARDS patients and this clinical approach requires further investigation. In this article, we review the use of thoracic ultrasound, including lung and diaphragm examination, for the clinical assessment of patients with ARDS, and discuss its limitations and future perspectives

Subphenotypes in patients with acute respiratory distress syndrome treated with high-flow oxygen

Background: Acute respiratory distress syndrome (ARDS) subphenotypes differ in outcomes and treatment responses. Subphenotypes in high-flow nasal oxygen (HFNO)-treated ARDS patients have not been investigated. Objectives: To identify biological subphenotypes in HFNO-treated ARDS patients. Methods: Secondary analysis of a prospective multicenter observational study including ARDS patients supported with HFNO. Plasma inflammation markers (interleukin [IL]-6, IL-8, and IL-33 and soluble suppression of tumorigenicity-2 [sST2]) and lung epithelial (receptor for advanced glycation end products [RAGE] and surfactant protein D [SP-D]) and endothelial (angiopoietin-2 [Ang-2]) injury were measured. These biomarkers and bicarbonate were used in K-means cluster analysis to identify subphenotypes. Logistic regression was performed on biomarker combinations to predict clustering. We chose the model with the best AUROC and the lowest number of variables. This model was used to describe the HAIS (High-flow ARDS Inflammatory Subphenotype) score. Results: Among 41 HFNO patients, two subphenotypes were identified. Hyperinflammatory subphenotype (n = 17) showed higher biomarker levels than hypoinflammatory (n = 24). Despite similar baseline characteristics, the hyperinflammatory subphenotype had higher 60-day mortality (47 vs 8.3% p = 0.014) and longer ICU length of stay (22.0 days [18.0-30.0] vs 39.5 [25.5-60.0], p = 0.034). The HAIS score, based on IL-8 and sST2, accurately distinguished subphenotypes (AUROC 0.96 [95%CI: 0.90-1.00]). A HAIS score ≥ 7.45 was predictor of hyperinflammatory subphenotype. Conclusion: ARDS patients treated with HFNO exhibit two biological subphenotypes that have similar clinical characteristics, but hyperinflammatory patients have worse outcomes. The HAIS score may identify patients with hyperinflammatory subphenotype and might be used for enrichment strategies in future clinical trials

Closed-loop oxygen control improves oxygen therapy in acute hypoxemic respiratory failure patients under high flow nasal oxygen: a randomized cross-over study (the HILOOP study)

Background: We aimed to assess the efficacy of a closed-loop oxygen control in critically ill patients with moderate to severe acute hypoxemic respiratory failure (AHRF) treated with high flow nasal oxygen (HFNO). Methods: In this single-centre, single-blinded, randomized crossover study, adult patients with moderate to severe AHRF who were treated with HFNO (flow rate ≥ 40 L/min with FiO2 ≥ 0.30) were randomly assigned to start with a 4-h period of closed-loop oxygen control or 4-h period of manual oxygen titration, after which each patient was switched to the alternate therapy. The primary outcome was the percentage of time spent in the individualized optimal SpO2 range. Results: Forty-five patients were included. Patients spent more time in the optimal SpO2 range with closed-loop oxygen control compared with manual titrations of oxygen (96.5 [93.5 to 98.9] % vs. 89 [77.4 to 95.9] %; p < 0.0001) (difference estimate, 10.4 (95% confidence interval 5.2 to 17.2). Patients spent less time in the suboptimal range during closed-loop oxygen control, both above and below the cut-offs of the optimal SpO2 range, and less time above the suboptimal range. Fewer number of manual adjustments per hour were needed with closed-loop oxygen control. The number of events of SpO2 < 88% and < 85% were not significantly different between groups. Conclusions: Closed-loop oxygen control improves oxygen administration in patients with moderate-to-severe AHRF treated with HFNO, increasing the percentage of time in the optimal oxygenation range and decreasing the workload of healthcare personnel. These results are especially relevant in a context of limited oxygen supply and high medical demand, such as the COVID-19 pandemic. Trial registration The HILOOP study was registered at www.clinicaltrials.gov under the identifier NCT04965844

Peripheral microcirculatory alterations are associated with the severity of acute respiratory distress syndrome in COVID-19 patients admitted to intermediate respiratory and intensive care units

Background: COVID-19 is primarily a respiratory disease; however, there is also evidence that it causes endothelial damage in the microvasculature of several organs. The aim of the present study is to characterize in vivo the microvas‑ cular reactivity in peripheral skeletal muscle of severe COVID-19 patients. Methods: This is a prospective observational study carried out in Spain, Mexico and Brazil. Healthy subjects and severe COVID-19 patients admitted to the intermediate respiratory (IRCU) and intensive care units (ICU) due to hypox‑ emia were studied. Local tissue/blood oxygen saturation (StO2) and local hemoglobin concentration (THC) were non-invasively measured on the forearm by near-infrared spectroscopy (NIRS). A vascular occlusion test (VOT), a threeminute induced ischemia, was performed in order to obtain dynamic StO2 parameters: deoxygenation rate (DeO2), reoxygenation rate (ReO2), and hyperemic response (HAUC). In COVID-19 patients, the severity of ARDS was evaluated by the ratio between peripheral arterial oxygen saturation (SpO2) and the fraction of inspired oxygen (FiO2) (SF ratio). Results: Healthy controls (32) and COVID-19 patients (73) were studied. Baseline StO2 and THC did not difer between the two groups. Dynamic VOT-derived parameters were signifcantly impaired in COVID-19 patients showing lower metabolic rate (DeO2) and diminished endothelial reactivity. At enrollment, most COVID-19 patients were receiving invasive mechanical ventilation (MV) (53%) or high-fow nasal cannula support (32%). Patients on MV were also receiv‑ ing sedative agents (100%) and vasopressors (29%). Baseline StO2 and DeO2 negatively correlated with SF ratio, while ReO2 showed a positive correlation with SF ratio. There were signifcant diferences in baseline StO2 and ReO2 among the diferent ARDS groups according to SF ratio, but not among diferent respiratory support therapies. Conclusion: Patients with severe COVID-19 show systemic microcirculatory alterations suggestive of endothelial dysfunction, and these alterations are associated with the severity of ARDS. Further evaluation is needed to determin

Pressure support ventilation + sigh in acute hypoxemic respiratory failure patients: Study protocol for a pilot randomized controlled trial, the PROTECTION trial

Background: Adding cyclic short sustained inflations (sigh) to assisted ventilation yields optimizes lung recruitment, decreases heterogeneity and reduces inspiratory effort in patients with acute hypoxemic respiratory failure (AHRF). These findings suggest that adding sigh to pressure support ventilation (PSV) might decrease the risk of lung injury, shorten weaning and improve clinical outcomes. Thus, we conceived a pilot trial to test the feasibility of adding sigh to PSV (the PROTECTION study). Methods: PROTECTION is an international randomized controlled trial that will be conducted in 23 intensive care units (ICUs). Patients with AHRF who have been intubated from 24 h to 7 days and undergoing PSV from 4 to 24 h will be enrolled. All patients will first undergo a 30-min sigh test by adding sigh to clinical PSV for 30 min to identify early oxygenation responders. Then, patients will be randomized to PSV or PSV + sigh until extubation, ICU discharge, death or day 28. Sigh will be delivered as a 3-s pressure control breath delivered once per minute at 30 cmH2O. Standardized protocols will guide ventilation settings, switch back to controlled ventilation, use of rescue treatments, performance of spontaneous breathing trial, extubation and reintubation. The primary endpoint of the study will be to verify the feasibility of PSV + sigh evaluated through reduction of failure to remain on assisted ventilation during the first 28 days in the PSV + sigh group versus standard PSV (15 vs. 22%). Failure will be defined by switch back to controlled ventilation for more than 24 h or use of rescue treatments or reintubation within 48 h from elective extubation. Setting the power to 80% and first-risk order to 5%, the computed size of the trial is 129 patients per arm. Discussion: PROTECTION is a pilot randomized controlled trial testing the feasibility of adding sigh to PSV. If positive, it will provide physicians with an effective addition to standard PSV for lung protection, able to reduce failure of assisted ventilation. PROTECTION will provide the basis for a future larger trial aimed at verifying the impact of PSV + sigh on 28-day survival and ventilator-free days. Trial registration: ClinicalTrials.gov, NCT03201263. Registered on 28 June 2017