OBJECTIVES: Prone position ventilation is a potentially life-saving ancillary intervention but is not widely adopted for coronavirus disease 2019 or acute respiratory distress syndrome from other causes. Implementation of lung-protective ventilation including prone positioning for coronavirus disease 2019 acute respiratory distress syndrome is limited by isolation precautions and personal protective equipment scarcity. We sought to determine the safety and associated clinical outcomes for coronavirus disease 2019 acute respiratory distress syndrome treated with prolonged prone position ventilation without daily repositioning. DESIGN: Retrospective single-center study. SETTING: Community academic medical ICU. PATIENTS: Sequential mechanically ventilated patients with coronavirus disease 2019 acute respiratory distress syndrome. INTERVENTIONS: Lung-protective ventilation and prolonged protocolized prone position ventilation without daily supine repositioning. Supine repositioning was performed only when Fio 2 less than 60% with positive end-expiratory pressure less than 10 cm H2O for greater than or equal to 4 hours. MEASUREMENTS AND MAIN RESULTS: Primary safety outcome: proportion with pressure wounds by Grades (0–4). Secondary outcomes: hospital survival, length of stay, rates of facial and limb edema, hospital-acquired infections, device displacement, and measures of lung mechanics and oxygenation. Eighty-seven coronavirus disease 2019 patients were mechanically ventilated. Sixty-one were treated with prone position ventilation, whereas 26 did not meet criteria. Forty-two survived (68.9%). Median (interquartile range) time from intubation to prone position ventilation was 0.28 d (0.11–0.80 d). Total prone position ventilation duration was 4.87 d (2.08–9.97 d). Prone position ventilation was applied for 30.3% (18.2–42.2%) of the first 28 days. Pao 2:Fio 2 diverged significantly by day 3 between survivors 147 (108–164) and nonsurvivors 107 (85–146), mean difference –9.632 (95% CI, –48.3 to 0.0; p = 0·05). Age, driving pressure, day 1, and day 3 Pao 2:Fio 2 were predictive of time to death. Thirty-eight (71.7%) developed ventral pressure wounds that were associated with prone position ventilation duration and day 3 Sequential Organ Failure Assessment. Limb weakness occurred in 58 (95.1%) with brachial plexus palsies in five (8.2%). Hospital-acquired infections other than central line–associated blood stream infections were infrequent. CONCLUSIONS: Prolonged prone position ventilation was feasible and relatively safe with implications for wider adoption in treating critically ill coronavirus disease 2019 patients and acute respiratory distress syndrome of other etiologies.

Luckey SW, Mansoori J, Fair K, Antos CL, Olson EN, Leinwand LA. Blocking cardiac growth in hypertrophic cardiomyopathy induces cardiac dysfunction and decreased survival only in males. Am J Physiol Heart Circ Physiol 292: H838 -H845, 2007. First published September 29, 2006; doi:10.1152/ajpheart.00615.2006.-Mutations in myosin heavy chain (MyHC) can cause hypertrophic cardiomyopathy (HCM) that is characterized by hypertrophy, histopathology, contractile dysfunction, and sudden death. The signaling pathways involved in the pathology of HCM have not been elucidated, and an unresolved question is whether blocking hypertrophic growth in HCM may be maladaptive or beneficial. To address these questions, a mouse model of HCM was crossed with an antihypertrophic mouse model of constitutive activated glycogen synthase kinase-3␤ (caGSK-3␤). Active GSK-3␤ blocked cardiac hypertrophy in both male and female HCM mice. However, doubly transgenic males (HCM/GSK-3␤) demonstrated depressed contractile function, reduced sarcoplasmic (endo) reticulum Ca 2ϩ -ATPase (SERCA) expression, elevated atrial natriuretic factor (ANF) expression, and premature death. In contrast, female HCM/GSK-3␤ double transgenic mice exhibited similar cardiac histology, function, and survival to their female HCM littermates. Remarkably, dietary modification from a soy-based diet to a casein-based diet significantly improved survival in HCM/GSK-3␤ males. These findings indicate that activation of GSK-3␤ is sufficient to limit cardiac growth in this HCM model and the consequence of caGSK-3␤ was sexually dimorphic. Furthermore, these results show that blocking hypertrophy by active GSK-3␤ in this HCM model is not therapeutic. cardiac hypertrophy; glycogen synthase kinase-

Mutations in cardiac troponin T (TnT) are a cause of familial hypertrophic cardiomyopathy (FHC). Transgenic mice expressing a missense mutation (R92Q) or a splice site donor mutation (Trunc) in the cardiac TnT gene have mutation-specific phenotypes but mice of both models have smaller hearts compared to wild type and exhibit hemodynamic dysfunction. Because growth-related signaling pathways in the hearts of mice expressing TnT mutations are not known, we evaluated the impact of increased Akt or glycogen synthase kinase-3β (GSK-3β) activity in both mutant TnT mice; molecules that increase heart size via physiologic pathways and block pathologic growth, respectively. Expression of activated Akt dramatically augments heart size in both R92Q and Trunc mice; however, this increase in heart size is not beneficial, since Akt also increases fibrosis in both TnT mutants and causes some pathologic gene expression shifts in the R92Q mice. Activated GSK-3β results in further decreases in left ventricular size in both R92Q and Trunc hearts, but this decrease is associated with significant mutation-specific phenotypes. Among many pathologic consequences, activating GSK-3β in R92Q hearts decreases phosphorylation of troponin I and results in early mortality. In contrast, increased GSK-3β activity in Trunc hearts does not significantly impact cardiac phenotypes. These findings demonstrate that increased Akt and its downstream target, GSK-3β can impact both cardiac size and phenotype in a mutation-specific manner. Moreover, increased activity of these molecules implicated in beneficial cardiac phenotypes exacerbates the progression of disease in the R92Q TnT mutant.

Rationale: There remains significant controversy regarding the optimal approach to fluid resuscitation for patients in shock. The magnitude of care variability in shock resuscitation, the confounding effects of disease severity and comorbidity, and the relative impact on sepsis survival are poorly understood. Objective: To evaluate usual care variability and determine the differential effect of observed and predicted fluid resuscitation volumes on risk-adjusted hospital mortality for mechanically ventilated patients in shock. Methods: We performed a retrospective outcome analysis of mechanically ventilated patients admitted to intensive care units using the 2013 Premier Hospital Database (Premier, Inc.). Observed and predicted hospital mortality were evaluated by observed and predicted day 1 fluid administration, using the difference in predicted and observed outcomes to adjust for disease severity between groups. Both predictive models were validated using a second large administrative database (Truven Health Analytics Inc.). Secondary outcomes included duration of mechanical ventilation, hospital and ICU length of stay, and cost. Results: Among 33,831 patients, observed hospital mortality was incrementally higher than predicted for each additional liter of day 1 fluid beginning at 7 L (40.9% vs. 37.2%, p = 0.008). Compared to patients that received expected (± 1.5 L predicted) day 1 fluid volumes, greater-than-expected fluid resuscitation was associated with increased risk-adjusted hospital mortality (52.3% vs. 45.0%, p < 0.0001) among all patients with shock and among a subgroup of shock patients with comorbid conditions predictive of lower fluid volume administration (47.1% vs. 41.5%, p < 0.0001). However, in patients with shock but without such conditions, both greater-than-expected (57.5% vs. 49.2%, p < 0.0001) and less-than-expected (52.1% vs. 49.2%, p = 0.037) day 1 fluid resuscitation were associated with increased risk-adjusted hospital mortality. Conclusions: Highly variable day 1 fluid resuscitation was associated with a non-uniform impact on risk-adjusted hospital mortality among distinct subgroups of mechanically ventilated patients with shock. These findings support closer evaluation of fluid resuscitation strategies that include broadly applied fluid volume targets in the early phase of shock resuscitation.