Hospitalised COVID-19 outcomes are predicted by hypoxaemia and pneumonia phenotype irrespective of the timing of their emergence.

Despite the known clinical importance of hypoxemia and pneumonia, there is a paucity of evidence for these variables with respect to risk of mortality and short-term outcomes among those hospitalised with COVID-19. OBJECTIVE: Describe the prevalence and clinical course of patients hospitalised with COVID-19 based on oxygenation and pneumonia status at presentation and determine the incidence of emergent hypoxaemia or radiographic pneumonia during admission. METHODS: A retrospective study was conducted using a Canadian regional registry. Patients were stratified according to hypoxaemia/pneumonia phenotype and prevalence. Clinical parameters were compared between phenotypes using χ2 and one-way Analysis of variance (ANOVA). Cox analysis estimated adjusted Hazard Ratios (HR) for associations between disease outcomes and phenotypes. RESULTS: At emergency department (ED) admission, the prevalence of pneumonia and hypoxaemia was 43% and 50%, respectively, and when stratified to phenotypes: 28.2% hypoxaemia+/pneumonia+, 22.2% hypoxaemia+/pneumonia-, 14.5% hypoxaemia-/pneumonia+ and 35.1% hypoxaemia-/pneumonia-. Mortality was 31.1% in the hypoxaemia+/pneumonia- group and 26.3% in the hypoxaemia+/pneumonia+ group. Hypoxaemia with pneumonia and without pneumonia predicted higher probability of death. Hypoxaemia either <24 hours or ≥24 hours after hospitalisation predicted higher mortality and need for home oxygen compared with those without hypoxaemia. Patients with early hypoxaemia had higher probability of Intensive care unit (ICU) admission compared with those with late hypoxaemia. CONCLUSION: Mortality in COVID-19 infection is predicted by hypoxaemia with or without pneumonia and was greatest in patients who initially presented with hypoxaemia. The emergence of hypoxaemia was predicted by radiographic pneumonia. Patients with early and emergent hypoxaemia had similar mortality but were less likely to be admitted to ICU. There may be delayed identification of hypoxaemia, which prevents timely escalation of care.

Impact of a multifaceted and multidisciplinary intervention on pain, agitation and delirium management in an intensive care unit: an experience of a Canadian community hospital in conducting a quality improvement project.

BACKGROUND: Clinical guidelines suggest that routine assessment, treatment, and prevention of pain, agitation, and delirium (PAD) is essential to improving patient outcomes as delirium is associated with increased mortality and morbidity. Despite the well-established improvements on patient outcomes, adherence to PAD guidelines is poor in community intensive care units (ICU). This quality improvement (QI) project aims to evaluate the impact of a multifaceted and multidisciplinary intervention on PAD management in a Canadian community ICU and to describe the experience of a Canadian community hospital in conducting a QI project. METHODS: A ten-member PAD advisory committee was formed to develop and implement the intervention. The intervention consisted of a multidisciplinary rounds script, poster, interviews, visual reminders, educational modules, pamphlet and video. The 4-week intervention targeted nurses, family members, physicians, and the multidisciplinary team. An uncontrolled, before-and-after study methodology was used. Adherence to PAD assessment guidelines by nurses was measured over a 6-week pre-intervention and over a 6-week post-intervention periods. RESULTS: Data on 430 and 406 patient-days (PD) were available for analysis during the pre- and post- intervention periods, respectively. The intervention did not improve the proportion of PD with guideline compliance to the assessment of pain (23.4% vs. 22.4%, p=0.80), agitation (42.9% vs. 38.9%, p=0.28), nor delirium (35.2% vs. 29.6%, p=0.10) by nurses. DISCUSSION: The implementation of a multifaceted and multidisciplinary intervention on PAD assessment did not result in significant improvements in guideline adherence in a community ICU. Barriers to knowledge translation are apparent at multiple levels including the personal level (low completion rates on educational modules), interventional level (under-collection of data), and organisational level (coinciding with hospital accreditation education). Our next steps include reintroduction of education modules using organisation approved platforms, updating existing ICU policy, updating admission order sets, and conducting audit and feedback.

Canadian Critical Care Society clinical practice guideline: The use of vasopressin and vasopressin analogues in critically ill adults with distributive shock.

PURPOSE: Hemodynamic management of adults with distributive shock often includes the use of catecholamine-based vasoconstricting medications. It is unclear whether adding vasopressin or vasopressin analogues to catecholamine therapy is beneficial in the management of patients with distributive shock. The purpose of this guideline was to develop an evidence-based recommendation regarding the addition of vasopressin to catecholamine vasopressors in the management of adults with distributive shock. METHODS: We summarized the evidence informing this recommendation by updating a recently published meta-analysis. Then, a multidisciplinary panel from the Canadian Critical Care Society developed the recommendation using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. RESULTS: The updated systematic review identified 25 randomized controlled trials including a total of 3,737 patients with distributive shock. Compared with catecholamine therapy alone, the addition of vasopressin or its analogues was associated with a reduced risk of mortality (relative risk [RR], 0.91; 95% confidence interval [CI], 0.85 to 0.99; low certainty), reduced risk of atrial fibrillation (RR, 0.77; 95% CI, 0.67 to 0.88; high certainty), and increased risk of digital ischemia (RR, 2.56; 95% CI, 1.24 to 5.25; moderate certainty). CONCLUSIONS: After considering certainty in the evidence, values and preferences, cost, and other factors, the expert guideline panel suggests using vasopressin or vasopressin analogues in addition to catecholamines over catecholamine vasopressors alone for the management of distributive shock (conditional recommendation, low certainty evidence).

Canadian Critical Care Society clinical practice guideline: The use of vasopressin and vasopressin analogues in critically ill adults with distributive shock / Recommandation de pratique clinique de la Société canadienne de soins intensifs: utilisation de vasopressine et d'analogues de la vasopressine chez l'adulte en état critique souffrant de choc distributif

Purpose: Hemodynamic management of adults with distributive shock often includes the use of catecholamine-based vasoconstricting medications. It is unclear whether adding vasopressin or vasopressin analogues to catecholamine therapy is beneficial in the management of patients with distributive shock. The purpose of this guideline was to develop an evidence-based recommendation regarding the addition of vasopressin to catecholamine vasopressors in the management of adults with distributive shock. Methods: We summarized the evidence informing this recommendation by updating a recently published meta-analysis. Then, a multidisciplinary panel from the Canadian Critical Care Society developed the recommendation using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Results: The updated systematic review identified 25 randomized controlled trials including a total of 3,737 patients with distributive shock. Compared with catecholamine therapy alone, the addition of vasopressin or its analogues was associated with a reduced risk of mortality (relative risk [RR], 0.91; 95% confidence interval [CI], 0.85 to 0.99; low certainty), reduced risk of atrial fibrillation (RR, 0.77; 95% CI, 0.67 to 0.88; high certainty), and increased risk of digital ischemia (RR, 2.56; 95% CI, 1.24 to 5.25; moderate certainty). Conclusions: After considering certainty in the evidence, values and preferences, cost, and other factors, the expert guideline panel suggests using vasopressin or vasopressin analogues in addition to catecholamines over catecholamine vasopressors alone for the management of distributive shock (conditional recommendation, low certainty evidence).

Objectif: La prise en charge hémodynamique des adultes atteints de choc distributif comprend souvent le recours à des agents vasoconstricteurs à base de catécholamines. Nous ne savons pas si l'ajout de vasopressine ou d'analogues de la vasopressine au traitement de catécholamines est bénéfique pour la prise en charge des patients atteints de choc distributif. L'objectif de cette ligne directrice était de mettre au point une recommandation fondée sur des données probantes concernant l'ajout de vasopressine aux vasopresseurs à base de catécholamines pour la prise en charge des adultes touchés par un choc distributif. Méthode: Nous avons résumé les données probantes sur lesquelles se fonde cette recommandation en mettant à jour une méta-analyse publiée récemment. Par la suite, un panel multidisciplinaire de la Société canadienne de soins intensifs a mis au point une recommandation en se fondant sur la méthodologie GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Résultats: La revue systématique mise à jour a identifié 25 études randomisées contrôlées, comptant un total de 3737 patients atteints de choc distributif. Par rapport à un traitement à base de catécholamines seulement, l'ajout de vasopressine ou de ses analogues a été associé à une réduction du risque de mortalité (risque relatif [RR], 0,91; intervalle de confiance [IC] 95 %, 0,85 à 0,99; certitude faible), une réduction du risque de fibrillation auriculaire (RR, 0,77; IC 95 %, 0,67 à 0,88; certitude forte), et une augmentation du risque d'ischémie digitale (RR, 2,56; IC 95 %, 1,24 à 5,25; certitude modérée). Conclusion: Après avoir examiné le niveau de certitude des données probantes, les valeurs et préférences, le coût et d'autres facteurs, le panel d'experts pour l'élaboration des directives suggère d'utiliser des vasopressines ou des analogues de la vasopressine en plus des catécholamines, plutôt que seulement des vasopresseurs à base de catécholamines, pour la prise en charge du choc distributif (recommandation conditionnelle, données probantes de certitude faible).

Impact of a nurse engagement intervention on pain, agitation and delirium assessment in a community intensive care unit.

BACKGROUND: In 2013, the Society of Critical Care Medicine published a revised version of the ICU Pain, Agitation, and Delirium (PAD) guidelines. Immobility and sleep were subsequently added in 2018. Despite the well-established advantages of implementing these guidelines, adoption and adherence remain suboptimal. This is especially true in community settings, where PAD assessment is performed less often, and the implementation of PAD guidelines has not yet been studied. The purpose of this prospective interventional study is to evaluate the effect of a multifaceted nurse engagement intervention on PAD assessment in a community intensive care unit (ICU). METHODS: All patients admitted to our community ICU for over 24 hours were included. A 20-week baseline audit was performed, followed by the intervention, and a 20-week postintervention audit. The intervention consisted of a survey, focus groups and education sessions. Primary outcomes included rates of daily PAD assessment using validated tools. RESULTS: There were improvements in the number of patients with at least one assessment per day of pain (67.5% vs 59.3%, p=0.04), agitation (93.1% vs 78.7%, p<0.001) and delirium (54.2% vs 39.4%, p<0.001), and the number of patients with target Richmond Agitation-Sedation Scale ordered (63.1% vs 46.8%, p=0.002). There was a decrease in the rate of physical restraint use (10.0% vs 30.9%, p<0.001) and no change in self-extubation rate (0.9% vs 2.5%, p=0.2). CONCLUSION: The implementation of a multifaceted nurse engagement intervention has the potential to improve rates of PAD assessment in community ICUs. Screening rates in our ICU remain suboptimal despite these improvements. We plan to implement multidisciplinary interventions targeting physicians, nurses and families to close the observed care gap.

Tyrosine Phosphorylation of Caspase-8 Abrogates Its Apoptotic Activity and Promotes Activation of c-Src.

Src family tyrosine kinases (SFKs) phosphorylate caspase-8A at tyrosine (Y) 397 resulting in suppression of apoptosis. In addition, the phosphorylation of caspase-8A at other sites including Y465 has been implicated in the regulation of caspase-8 activity. However, the functional consequences of these modifications on caspase-8 processing/activity have not been elucidated. Moreover, various Src substrates are known to act as potent Src regulators, but no such role has been explored for caspase-8. We asked whether the newly identified caspase-8 phosphorylation sites might regulate caspase-8 activation and conversely, whether caspase-8 phosphorylation might affect Src activity. Here we show that Src phosphorylates caspase-8A at multiple tyrosine sites; of these, we have focused on Y397 within the linker region and Y465 within the p12 subunit of caspase-8A. We show that phosphomimetic mutation of caspase-8A at Y465 prevents its cleavage and the subsequent activation of caspase-3 and suppresses apoptosis. Furthermore, simultaneous phosphomimetic mutation of caspase-8A at Y397 and Y465 promotes the phosphorylation of c-Src at Y416 and increases c-Src activity. Finally, we demonstrate that caspase-8 activity prevents its own tyrosine phosphorylation by Src. Together these data reveal that dual phosphorylation converts caspase-8 from a pro-apoptotic to a pro-survival mediator. Specifically, tyrosine phosphorylation by Src renders caspase-8 uncleavable and thereby inactive, and at the same time converts it to a Src activator. This novel dynamic interplay between Src and caspase-8 likely acts as a potent signal-integrating switch directing the cell towards apoptosis or survival.

Acute refractory hypoxemia after chest trauma reversed by high-frequency oscillatory ventilation: a case report.

INTRODUCTION: Polytrauma often results in significant hypoxemia secondary to direct lung contusion or indirectly through atelectasis, systemic inflammatory response, large volume fluid resuscitation and blood product transfusion. In addition to causing hypoxemia, atelectasis and acute lung injury can lead to right ventricular failure through an acute increase in pulmonary vascular resistance. Mechanical ventilation is often applied, accompanied with recruitment maneuvers and positive end-expiratory pressure in order to recruit alveoli and reverse atelectasis, while preventing excessive alveolar damage. This strategy should lead to the reversal of the hypoxemic condition and the detrimental heart-lung interaction that may occur. However, as described in this case report, hemodynamic instability and intractable alveolar atelectasis sometimes do not respond to conventional ventilation strategies. CASE PRESENTATION: We describe the case of a 21-year-old Caucasian man with severe chest trauma requiring surgical interventions, who developed refractory hypoxemia and overt right ventricular failure. After multiple failed attempts of recruitment using conventional ventilation, the patient was ventilated with high-frequency oscillatory ventilation. This mode of ventilation allowed the reversal of the hemodynamic effects of severe hypoxemia and of the acute cor pulmonale. We use this case report to describe the physiological advantages of high-frequency oscillatory ventilation in patients with chest trauma, and formulate the arguments to explain the positive effect observed in our patient. CONCLUSIONS: High-frequency oscillatory ventilation can be used in the context of a blunt chest trauma accompanied by severe hypoxemia due to atelectasis. The positive effect is due to its capacity to recruit the collapsed alveoli and, as a result, the relief of increased pulmonary vascular resistance and subsequently the reversal of acute cor pulmonale. This approach may represent an alternative in case of failure of the conventional ventilation strategy.

Regulation of apoptosis and priming of neutrophil oxidative burst by diisopropyl fluorophosphate.

BACKGROUND: Diisopropyl fluorophosphate (DFP) is a serine protease inhibitor that is widely used as an inhibitor of endogenous proteases in in vitro neutrophil studies. Its effects on neutrophil function are unclear. We sought to determine the biological effects of DFP on human neutrophil apoptosis and oxidative burst. METHODS: We isolated neutrophils from healthy volunteers, incubated them with DFP (2.5 mM), and evaluated neutrophil elastase (NE) activity, neutrophil degranulation, apoptosis as reflected in hypodiploid DNA formation and exteriorization of phosphatidylserine (PS), processing and activity of caspases-3 and -8, oxidative burst activity and hydrogen peroxide release. RESULTS: Consistent with its activity as a serine protease inhibitor, DFP significantly inhibited NE activity but not the degranulation of azurophilic granules. DFP inhibited constitutive neutrophil apoptosis as reflected in DNA fragmentation, and the processing and activity of caspases-3 and -8. DFP also inhibited priming of neutrophils for oxidative burst activity and hydrogen peroxide release. However, DFP enhanced the exteriorization of PS in a dose-dependent manner. CONCLUSION: We conclude that DFP exerts significant effects on neutrophil inflammatory function that may confound the interpretation of studies that use it for its antiprotease activity. We further conclude that endogenous proteases play a role in the biology of constitutive neutrophil apoptosis.