WORD COUNT: 286 1 AbstractPurpose: Ventilator-induced diaphragm dysfunction or damage (VIDD) is highly prevalent in patients under mechanical ventilation (MV), but its analysis is limited by the difficulty of obtaining histological samples. In this study we compared diaphragm histological characteristics in Maastricht III (MSIII) and brain-dead (BD) organ donors and in control subjects undergoing thoracic surgery (CTL) after a period of either controlled or spontaneous MV (CMV or SMV).Methods: In this prospective study, biopsies were obtained from diaphragm and quadriceps.Demographic variables, comorbidities, severity on admission, treatment and ventilatory variables were evaluated. Immunohistochemical analysis (fiber size and type percentages) and quantification of abnormal fibers (a surrogate of muscle damage) were performed.Results: Muscle samples were obtained from 35 patients. MSIII (n=16) had more hours on MV (either CMV or SMV) than BD (n=14) and also spent more hours, and a greater percentage of time with diaphragm stimuli (time in assisted and spontaneous modalities). Cross sectional area (CSA) was significantly reduced in the diaphragm and quadriceps in both groups in comparison with CTL (n=5).Quadriceps CSA was significantly decreased in MSIII compared to BD but there were no differences in the diaphragm CSA between the two groups. Those MSIII who spent 100 or more hours without diaphragm stimuli presented reduced diaphragm CSA without changes in their quadriceps CSA.Proportion of internal nuclei in diaphragms of MSIII tended to be higher than BD, and their proportion of lipofuscin deposits tended to be lower, though there were no differences in the quadriceps fiber evaluation. Conclusions:This study provides the first evidence in humans about the effects of different modalities of MV (controlled, assisted and spontaneous) on diaphragm myofiber damage showing that diaphragm inactivity during mechanical ventilation is associated with the development of VIDD. KeywordsVentilator-induced Diaphragm Dysfunction or damage (VIDD), Atrophy, Mechanical Ventilation, Brain Death, Maastricht III, Muscle dysfunction.Most critically ill patients admitted to the Intensive Care Unit (ICU) require mechanical ventilation (MV) due to respiratory failure. MV may be associated with adverse effects on respiratory muscles, and disuse atrophy may be the most important mechanism in patients under controlled mechanical ventilation (CMV) [1]. During CMV, the electromyographic activity of the respiratory muscle fibers is diminished or may even stop [2], resulting in a rapid development of respiratory muscle dysfunction, especially diaphragm weakness. Ventilator-induced diaphragm dysfunction (VIDD) is defined as the loss of the diaphragm's capacity to generate force, together with muscle injury and fiber atrophy, and the same acronym has been used before to describe ventilator-induced diaphragm damage [3]. Both VIDD are associated particularly with the use of MV, typically after periods of CMV [4,5,6].VIDD may play a key role in th...

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Background Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0–171.2] to 180.0 [135.4–227.9] mmHg and the ventilatory ratio from 1.73 [1.33–2.25] to 1.96 [1.61–2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01–1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01–1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93–1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation.