Hypercapnia limits β-catenin mediated alveolar type 2 cell progenitor function by altering Wnt production from adjacent fibroblasts

Persistent symptoms and radiographic abnormalities suggestive of failed lung repair are among the most common symptoms in patients with COVID-19 after hospital discharge. In mechanically ventilated patients with ARDS secondary to SARS-CoV-2 pneumonia, low tidal volume ventilation to reduce ventilator-induced lung injury necessarily elevate blood CO2 levels, often leading to hypercapnia. The role of hypercapnia on lung repair after injury is not completely understood. Here, we show that hypercapnia limits β-catenin signaling in alveolar type 2 (AT2) cells, leading to reduced proliferative capacity. Hypercapnia alters expression of major Wnts in PDGFRα-fibroblasts from those maintaining AT2 progenitor activity and towards those that antagonize β-catenin signaling and limit progenitor function. Activation of β-catenin signaling in AT2 cells, rescues the effects of hypercapnia on proliferation. Inhibition of AT2 proliferation in hypercapnic patients may contribute to impaired lung repair after injury, preventing sealing of the epithelial barrier, increasing lung flooding, ventilator dependency and mortality.

Hyaluronic acid plasma levels during high versus low tidal volume ventilation in a porcine sepsis model

Background Shedding of the endothelial glycocalyx can be observed regularly during sepsis. Moreover, sepsis may be associated with acute respiratory distress syndrome (ARDS), which requires lung protective ventilation with the two cornerstones of application of low tidal volume and positive end-expiratory pressure. This study investigated the effect of a lung protective ventilation on the integrity of the endothelial glycocalyx in comparison to a high tidal volume ventilation mode in a porcine model of sepsis-induced ARDS. Methods After approval by the State and Institutional Animal Care Committee, 20 male pigs were anesthetized and received a continuous infusion of lipopolysaccharide to induce septic shock. The animals were randomly assigned to either low tidal volume ventilation, high tidal volume ventilation, or no-LPS-group groups and observed for 6 h. In addition to the gas exchange parameters and hematologic analyses, the serum hyaluronic acid concentrations were determined from central venous blood and from pre- and postpulmonary and pre- and postcerebral circulation. Post-mortem analysis included histopathological evaluation and determination of the pulmonary and cerebral wet-to-dry ratios. Results Both sepsis groups developed ARDS within 6 h of the experiment and showed significantly increased serum levels of hyaluronic acid in comparison to the no-LPS-group. No significant differences in the hyaluronic acid concentrations were detected before and after pulmonary and cerebral circulation. There was also no significant difference in the serum hyaluronic acid concentrations between the two sepsis groups. Post-mortem analysis showed no significant difference between the two sepsis groups. Conclusion In a porcine model of septic shock and ARDS, the serum hyaluronic acid levels were significantly elevated in both sepsis groups in comparison to the no-LPS-group. Intergroup comparison between lung protective ventilated and high tidal ventilated animals revealed no significant differences in the serum hyaluronic acid levels.

Effects of individualized positive end-expiratory pressure combined with recruitment maneuver on intraoperative ventilation during abdominal surgery: a systematic review and network meta-analysis of randomized controlled trials

Low tidal volume ventilation strategy may lead to atelectasis without proper positive end-expiratory pressure (PEEP) and recruitment maneuver (RM) settings. RM followed by individualized PEEP was a new method to optimize the intraoperative pulmonary function. We conducted a systematic review and network meta-analysis of randomized clinical trials to compare the effects of individualized PEEP + RM on intraoperative pulmonary function and hemodynamic with other PEEP and RM settings. The primary outcomes were intraoperative oxygenation index and dynamic compliance, while the secondary outcomes were intraoperative heart rate and mean arterial pressure. In total, we identified 15 clinical trials containing 36 randomized groups with 3634 participants. Ventilation strategies were divided into eight groups by four PEEP (L: low, M: moderate, H: high, and I: individualized) and two RM (yes or no) settings. The main results showed that IPEEP + RM group was superior to all other groups regarding to both oxygenation index and dynamic compliance. LPEEP group was inferior to LPEEP + RM, MPEEP, MPEEP + RM, and IPEEP + RM in terms of oxygenation index and LPEEP + RM, MPEEP, MPEEP + RM, HPEEP + RM, IPEEP, and IPEEP + RM in terms of dynamic compliance. All comparisons were similar for secondary outcomes. Our analysis suggested that individualized PEEP and RM may be the optimal low tidal volume ventilation strategy at present, while low PEEP without RM is not suggested.

Locked-in Guillain-Barré syndrome: ‘my living nightmare’

A 48-year-old man with severe Guillain-Barré syndrome suffered complete paralysis, and for 31 days could not communicate with the outside world, while remaining fully conscious. After recovery, he provided feedback on aspects of his care, such as mechanical ventilation, physical therapy, and communication. Conventional low tidal volume normocapnic ventilation induced ongoing and profound dyspnoea, occasionally relieved by modest increases in minute ventilation. Routine and apparently benign physical therapy was extremely painful, which was not reflected in heart rate or blood pressure changes. When he eventually re-established communication after many weeks, via slight eye movements, his first message was to express a particular distressing symptom. His case is a valuable reminder of the sometimes large gap between clinical measurements and assumptions and the subjective patient experience. We propose several approaches to address such issues in other paralysed but conscious patients.

Biotrauma during ultra-low tidal volume ventilation and venoarterial extracorporeal membrane oxygenation in cardiogenic shock: a randomized crossover clinical trial

Background Cardiogenic pulmonary oedema (CPE) may contribute to ventilator-associated lung injury (VALI) in patients with cardiogenic shock. The appropriate ventilatory strategy remains unclear. We aimed to evaluate the impact of ultra-low tidal volume ventilation with tidal volume of 3 ml/kg predicted body weight (PBW) in patients with CPE and veno–arterial extracorporeal membrane oxygenation (V–A ECMO) on lung inflammation compared to conventional ventilation. Methods A single-centre randomized crossover trial was performed in the Cardiac Intensive Care Unit (ICU) at a tertiary university hospital. Seventeen adults requiring V–A ECMO and mechanical ventilation due to cardiogenic shock were included from February 2017 to December 2018. Patients were ventilated for two consecutive periods of 24 h with tidal volumes of 6 and 3 ml/kg of PBW, respectively, applied in random order. Primary outcome was the change in proinflammatory mediators in bronchoalveolar lavage fluid (BALF) between both ventilatory strategies. Results Ventilation with 3 ml/kg PBW yielded lower driving pressures and end-expiratory lung volumes. Overall, there were no differences in BALF cytokines. Post hoc analyses revealed that patients with high baseline levels of IL-6 showed statistically significant lower levels of IL-6 and IL-8 during ultra-low tidal volume ventilation. This reduction was significantly proportional to the decrease in driving pressure. In contrast, those with lower IL-6 baseline levels showed a significant increase in these biomarkers. Conclusions Ultra-low tidal volume ventilation in patients with CPE and V–A ECMO may attenuate inflammation in selected cases. VALI may be driven by an interaction between the individual proinflammatory profile and the mechanical load overimposed by the ventilator. Trial registration The trial was registered in ClinicalTrials.gov (identifier NCT03041428, Registration date: 2nd February 2017).

Implementing nudges to promote utilization of low tidal volume ventilation (INPUT): a stepped-wedge, hybrid type III trial of strategies to improve evidence-based mechanical ventilation management

Background Behavioral economic insights have yielded strategies to overcome implementation barriers. For example, default strategies and accountable justification strategies have improved adherence to best practices in clinical settings. Embedding such strategies in the electronic health record (EHR) holds promise for simple and scalable approaches to facilitating implementation. A proven-effective but under-utilized treatment for patients who undergo mechanical ventilation involves prescribing low tidal volumes, which protects the lungs from injury. We will evaluate EHR-based implementation strategies grounded in behavioral economic theory to improve evidence-based management of mechanical ventilation. Methods The Implementing Nudges to Promote Utilization of low Tidal volume ventilation (INPUT) study is a pragmatic, stepped-wedge, hybrid type III effectiveness implementation trial of three strategies to improve adherence to low tidal volume ventilation. The strategies target clinicians who enter electronic orders and respiratory therapists who manage the mechanical ventilator, two key stakeholder groups. INPUT has five study arms: usual care, a default strategy within the mechanical ventilation order, an accountable justification strategy within the mechanical ventilation order, and each of the order strategies combined with an accountable justification strategy within flowsheet documentation. We will create six matched pairs of twelve intensive care units (ICUs) in five hospitals in one large health system to balance patient volume and baseline adherence to low tidal volume ventilation. We will randomly assign ICUs within each matched pair to one of the order panels, and each pair to one of six wedges, which will determine date of adoption of the order panel strategy. All ICUs will adopt the flowsheet documentation strategy 6 months afterwards. The primary outcome will be fidelity to low tidal volume ventilation. The secondary effectiveness outcomes will include in-hospital mortality, duration of mechanical ventilation, ICU and hospital length of stay, and occurrence of potential adverse events. Discussion This stepped-wedge, hybrid type III trial will provide evidence regarding the role of EHR-based behavioral economic strategies to improve adherence to evidence-based practices among patients who undergo mechanical ventilation in ICUs, thereby advancing the field of implementation science, as well as testing the effectiveness of low tidal volume ventilation among broad patient populations. Trial registration ClinicalTrials.gov, NCT04663802. Registered 11 December 2020.

Audit of low tidal volume ventilation in patients with hypoxic respiratory failure in a tertiary Australian intensive care unit

A low tidal volume ventilation (LTVV) strategy improves outcomes in patients with acute respiratory distress syndrome (ARDS). Subsequently, a LTVV strategy has become the standard of care for patients receiving mechanical ventilation. This strategy is poorly adhered to within intensive care units (ICUs). A retrospective analysis was conducted of prescribed tidal volumes in mechanically ventilated patients with hypoxic respiratory failure between April 2013 and March 2017. Data collection included the establishment of a new data-entry box for patient height in March 2016, aimed at assisting the calculation of LTVV. We reviewed 836 ICU admissions, comprising 19,884 hours of ventilation. A total of 92% of admissions lacked patient height recording. When height was recorded, 54% of hours of ventilation were LTVV adherent. Non-LTVV hours for both groups involved higher tidal volumes (38%) rather than lower tidal volumes (8%). Non–LTVV-adherent hours were significantly ( P<0.001) more likely to be associated with patient mortality than LTVV-adherent hours were. For all hours of ventilation, mean tidal volume before March 2016 was significantly higher (496 (standard deviation (SD) 101) ml, compared to after March 2016 (451 (SD 107) ml, P<0.001, 95% confidence interval for true difference in means 42 to 48 ml). However, this trend gradually reversed over time. There was a clinician preference for multiples of 50 ml. There was poor adherence to LTVV strategy in patients with hypoxic respiratory failure, which was associated with an increase in patient mortality. An electronic medical record intervention was successful in producing change, but this was not sustainable over time. Clinician ventilation prescribing habits were based on numerical simplicity rather than evidence-based practice.