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Background: Calcium release-activated calcium (CRAC) channel inhibitors block proinflammatory cytokine release, preserve endothelial integrity and may effectively treat patients with severe COVID-19 pneumonia. Methods: CARDEA was a phase 2, randomized, double-blind, placebo-controlled trial evaluating the addition of Auxora, a CRAC channel inhibitor, to corticosteroids and standard of care in adults with severe COVID-19 pneumonia. The primary endpoint was time to recovery through Day 60, with secondary endpoints of all-cause mortality at Day 60 and Day 30. Due to declining rates of COVID-19 hospitalizations and encroachment of prohibited medications as standard of care, the trial was stopped early. Results: The pre-specified efficacy set consisted of the 261 patients with a baseline imputed PaO2/FiO2 £200 with 130 and 131 in the Auxora and placebo groups, respectively. Time to recovery was 7 vs. 10 days (P=0.0979) for patients who received Auxora vs. placebo, respectively. The all-cause mortality rate at Day 60 was 13.8% with Auxora vs. 20.6% with placebo (P=0.1449); Day 30 all-cause mortality was 7.7% and 17.6%, respectively (P=0.0165). Similar trends were noted in patients on high flow nasal cannula at baseline or those with a baseline imputed PaO2/FiO2 ≤100. Serious adverse events occurred less frequently in patients treated with Auxora vs. placebo. Conclusions: Auxora was safe and well tolerated with strong signals in both time to recovery and all-cause mortality through Day 60 in patients with severe COVID-19 pneumonia. Further studies of Auxora in combination with corticosteroids and other immunomodulatory agents are warranted.Trial registration: NCT04345614

Purpose To determine the feasibility of conducting a multicenter ICU RCT of AFS compared to either protocol-directed sedation (PDS) or both PDS and daily sedation interruption (DSI) in North America. Materials and methods This single-center RCT compared AFS [fentanyl (bolus ± infusions) to reach CPOT ≤2; if RASS ≥1, CPOT ≤2 and additional fentanyl failed to reach RASS goal (−2 to 0), low-dose propofol (up to 6 h) was given] with either PDS or both PDS and DSI daily in adults mechanically ventilated (MV) ≥48 h. Relevant feasibility, safety, and clinical outcomes were defined and evaluated. Results 90 of 160 eligible patients were enrolled [AFS = 27; PDS = 28; PDS + DSI = 31]; rate = 3/month. Time from intubation to randomization was 17.5 ± 11.6 h. Study days fully adherent to the study intervention [AFS = 95%; PDS = 99%; PDS + DSI = 96%] and time spent in the first 48 h after randomization without pain (CPOT ≤2)[AFS = 82%; PDS = 78%; PDS + DSI = 77%] and at goal RASS[AFS = 88%; PDS = 83%; PDS + DSI = 95%] were high and similar. Nurse-perceived [median (IQR)] study workload (10-point VAS) was higher with AFS [4(2–6)] than PDS [1(1–3)] or PDS + DSI [2(1–5)]; p = .002). Unplanned extubation was rare (AFS = 1; PDS = 0; PDS + DSI = 1). Days [median (IQR)] free of MV in the 28d after intubation [AFS 24(23,26); PDS 24(20,26); PDS + DSI 24(21,26)] was not different (p = .62). Conclusion A multicenter RCT evaluating AFS is feasible to conduct in North America.

Safe, effective, and easily implementable treatments that reduce the progression of respiratory failure in COVID-19 are urgently needed. Despite the increased adoption of prone positioning during the pandemic, the effectiveness of this technique on progression of respiratory failure among nonintubated patients is unclear.What is the effectiveness of smartphone-guided self-prone positioning recommendations and instructions compared with usual care in reducing progression of respiratory failure among nonintubated patients with COVID-19?Awake Prone Position for Early Hypoxemia in COVID-19 (APPEX-19) is a multicenter randomized clinical trial that randomized nonintubated adults with COVID-19 on 6 L/min of supplemental oxygen to receive a smartphone-guided self-prone positioning intervention or usual care. The primary outcome was the composite of respiratory deterioration (an increase in supplemental oxygen requirement) or ICU transfer. Using a Bayesian statistical approach, the posterior probability of superiority within each treatment arm (superiority threshold 95%) was calculated.The trial was stopped early for slow enrollment. A total of 293 participants were included in the modified intention-to-treat analysis (159 self-prone positioning intervention and 134 usual care). Among participants who self-reported body positioning (n = 139 [70 intervention, 69 usual care]), 71.4% in the intervention arm and 59.4% in the usual care arm attempted prone positioning. Thirty-one participants (posterior mean, 24.7%; 95% credible interval, 18.6-31.4) receiving usual care and 32 participants (posterior mean, 22.1%; 95% credible interval, 16.6-28.1) receiving the self-prone positioning intervention experienced the primary outcome; the posterior probability of superiority for the self-prone positioning intervention was 72.1%, less than the 95% threshold for superiority. Adverse events occurred in 26.9% of participants in the usual care arm and in 11.9% of participants in the intervention arm.Among nonintubated patients with COVID-19, smartphone-guided self-prone positioning recommendations and instructions did not promote strong adherence to prone positioning.ClinicalTrials.gov; No.: NCT04344587; URL: www.gov.

The surge in clinical demand, shortage in personal protective equipment and high-exposure risk for healthcare workers during the COVID-19 pandemic has challenged hospital common practices and forced a reassessment of care delivery models. Code blue teams are highly specialised units that partake in life-saving situations that can jeopardise the safety of team members. There is a paucity of guidance in regards to proper infection control measures to protect the responders.This study describes a methodical approach to assessing vulnerabilities to transmission of SARS-CoV-2 within existing code blue practices, modalities to limit the number of code blue team responders and modifications to the protocol at a large community teaching hospital. The effort undertaken faced challenges due to the nature of the pandemic and the increased demand on healthcare workers. Quality improvement methods facilitated our protocol design and implementation. To this date, there has been no identified COVID-19 disease in any protected code blue (PCB) team members. We recommend that similar practices be considered and adopted widely and practised periodically.

Rationale In critically ill patients receiving invasive mechanical ventilation (MV), research supports the use of daily screening to identify patients who are ready to undergo a spontaneous breathing trial (SBT) followed by conduct of an SBT. However, once daily (OD) screening is poorly aligned with the continuous care provided in most intensive care units (ICUs) and the best SBT technique for clinicians to use remains controversial. Objectives To identify the optimal screening frequency and SBT technique to wean critically ill adults in the ICU. Methods We aim to conduct a multicenter, factorial design randomized controlled trial with concealed allocation, comparing the effect of both screening frequency (once versus at least twice daily [ALTD]) and SBT technique (Pressure Support [PS] + Positive End-Expiratory Pressure [PEEP] vs T-piece) on the time to successful extubation (primary outcome) in 760 critically ill adults who are invasively ventilated for at least 24 h in 20 North American ICUs. In the OD arm, respiratory therapists (RTs) will screen study patients between 06:00 and 08:00 h. In the ALTD arm, patients will be screened at least twice daily between 06:00 and 08:00 h and between 13:00 and 15:00 h with additional screens permitted at the clinician’s discretion. When the SBT screen is passed, an SBT will be conducted using the assigned technique (PS + PEEP or T-piece). We will follow patients until successful extubation, death, ICU discharge, or until day 60 after randomization. We will contact patients or their surrogates six months after randomization to assess health-related quality of life and functional status. Relevance The around-the-clock availability of RTs in North American ICUs presents an important opportunity to identify the optimal SBT screening frequency and SBT technique to minimize patients’ exposure to invasive ventilation and ventilator-related complications. Trial registration Clinical Trials.gov, NCT02399267. Registered on Nov 21, 2016 first registered.

Purpose The purpose was to describe characteristics and outcomes of restrained and nonrestrained patients enrolled in a randomized trial of protocolized sedation compared with protocolized sedation plus daily sedation interruption and to identify patient and treatment factors associated with physical restraint. Methods This was a post hoc secondary analysis using Cox proportional hazards modeling adjusted for center- and time-varying covariates to evaluate predictors of restraint use. Results A total of 328 (76%) of 430 patients were restrained for a median of 4 days. Restrained patients received higher daily doses of benzodiazepines (105 vs 41 mg midazolam equivalent, P μ g fentanyl equivalents, P P P = .02), and more daily benzodiazepine boluses (0.2 vs 0.1, P P = .02) and atypical antipsychotics (17% vs 4%, P = .003). More restrained patients experienced unintentional device removal (26% vs 3%, P P = .01). In the multivariable analysis, alcohol use was associated with decreased risk of restraint (hazard ratio, 0.22; 95% confidence interval, 0.08-0.58). Conclusions Physical restraint was common in mechanically ventilated adults managed with a sedation protocol. Restrained patients received more opioids and benzodiazepines. Except for alcohol use, patient characteristics and treatment factors did not predict restraint use.

To 1) describe factual, emotional, and delusional memories of ICU stay for patients enrolled in the SLEAP (Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol) trial; 2) compare characteristics of patients with and without ICU recall, and patients with and without delusional memories; and 3) determine factors associated with delusional memories 28 days after ICU discharge.Prospective cohort.Sixteen North American medical and surgical ICUs.Critically ill, mechanically ventilated adults randomized in the SLEAP trial.Post-ICU interviews on days 3, 28, and 90 using the validated ICU Memory Tool.Overall, 289 of 297 ICU survivors (97%) (146 protocolized sedation and 143 protocolized sedation plus daily interruption patients) were interviewed at least once. Because there were no differences in recall status or types of memories between the two sedation groups, we present the findings for all patients rather than by study group. On days 3, 28, and 90, 28%, 26%, and 36% of patients, respectively, reported no recall of being in the ICU (overall perception, self-reported) (p = 0.75). Mean daily doses of benzodiazepines and opioids were lower in patients with no ICU recall than those with recall (p0.0001 for both). Despite one third of patients reporting no recall of ICU stay on day 3, 97% and 90% reported at least one factual and one emotional memory from ICU, respectively. Emotional memories declined with time after ICU discharge, particularly panic and confusion. Delusional memories 28 days after discharge were common (70%) yet unrelated to delirium (p = 0.84), recall status (p = 0.15), total dose of benzodiazepine (p = 0.78), or opioid (p = 0.21). Delusional memories were less likely with longer duration of mechanical ventilation (odds ratio, 0.955; 95% CI, 0.91-1.00; p = 0.04).Recall of ICU stay and types of memories reported were not influenced by the trial sedation strategy. Lack of ICU recall and delusional memories were common after ICU discharge despite the use of sedation strategies that promoted wakefulness.

Background:Various intensivist staffing models have been suggested, but the long-term sustainability and outcomes vary and may not be sustained. We examined the impact of implementing a high-intensity intensivist coverage model with a nighttime in-house nocturnist (non-intensivist) and its effect on intensive care unit (ICU) outcomes.Methods:We obtained historical control baseline data from 2007 to 2011 and compared the same data from 2011 to 2015. The Acute Physiological and Chronic Health Evaluation outcomes system was utilized to collect clinical, physiological, and outcome data on all adult patients in the medical ICU and to provide severity-adjusted outcome predictions. The model consists of a mandatory in-house daytime intensivist service that leads multidisciplinary rounds, and an in-house nighttime coverage is provided by nocturnist (nonintensivists) with current procedural skills in airways management, vascular access, and commitment to supervise house staff as needed. The intensivist continues to be available remotely at nighttime for house staff and consultation with the nocturnist. A backup intensivist is available for surge management.Results:First year yielded improved throughput (2428 patients/year to 2627 then 2724 at fifth year). Case mix stable at 53.7 versus 55.2. The ICU length of stay decreased from 4.7 days (predicted 4.25 days) to 3.8 days (4.15) in first year; second year: 3.63 days (4.29 days); third year: 3.24 days (4.37), fourth year: 3.34 days (4.45), and fifth year: 3.61 days (4.42). Intensive care unit 24 hours increased from 4% to 6%. Low-risk monitoring admissions remained at an average 17% (benchmark 17.18%). Intensive care unit mortality improved with standardized mortality ration averaging at 0.84. Resident satisfaction surveys improved.Conclusions:Implementing an intensivist service with nighttime nocturnist staffing in a high-intensity large teaching hospital is feasible and improved ICU outcomes in a sustained manner that persisted after the initial implementation phase. The model resulted in reduced and sustained observed-to-predicted length of ICU stay.

Background Mechanically ventilated patients may receive more sedation during the night than during the day, potentially delaying extubation. We compared nighttime and daytime benzodiazepine and opioid administration in adult patients enrolled in a multicenter sedation trial comparing protocolized sedation alone or protocolized sedation combined with daily sedation interruption; and we evaluated whether nighttime and daytime doses were associated with liberation from mechanical ventilation. Methods This is a secondary analysis of a randomized trial which was conducted in 16 North American medical-surgical ICUs. In all 423 patients, nurses applied a validated sedation scale hourly to titrate benzodiazepine and opioid infusions to achieve a light level of sedation. Using fentanyl equivalents and midazolam equivalents, we compared dosages administered during night (19:00 to 07:00) and day (07:00 to 19:00) shifts. Using multivariable logistic regression we evaluated the association between nighttime and daytime opioid and sedative doses, and spontaneous breathing trial (SBT) conduct, SBT success, and extubation. Results Nighttime benzodiazepine and opioid doses were significantly higher than daytime doses (mean difference midazolam equivalents 23.3 mg, 95 % CI 12.9, 33.8, p

Background Cardiac dysfunction is one of many causes for unsuccessful weaning from mechanical ventilation. Although cardiac dysfunction can be detected via direct measurement of cardiac output during weaning, available methods are not feasible. Objective To investigate the role of noninvasive monitoring of cardiac output during weaning and determine if a relationship exists between serial measurements during the spontaneous breathing trial and weaning outcomes. Methods A prospective, observational study was conducted in the intensive care unit at a university-affiliated teaching hospital. The sample consisted of patients intubated for more than 24 hours who were being weaned off of mechanical ventilation according to a validated weaning protocol. Before the first spontaneous breathing trial, a noninvasive cardiac output monitor was connected to the ventilator circuit. Measurements were made before, at the beginning of, and at the end of the trial. Results Among the 85 patients tested, baseline cardiac output was similar (P = .93) for those in whom the first trial was successful (mean [SD], 5.7 [2.1] L/min) and those in whom the trial was unsuccessful (5.6 [1.8] L/ min). Unlike patients with unsuccessful trials, patients with successful trials were able to augment their cardiac output from baseline. Mean cardiac output increased to 7.1 (SD, 3.1) L/min for patients in whom weaning was successful and to 6.2 (SD, 2.3) L/min for those in whom weaning was unsuccessful (P = .001). Conclusion A noninvasive method of monitoring cardiac output can be easily applied while patients are being weaned off of mechanical ventilation.

Rationale: Research supports the use of screening protocols to identify patients who are candidates for weaning from mechanical ventilation, and the use of spontaneous breathing trials (SBTs) to predict ability to breathe spontaneously. However, once daily screening is poorly aligned with 24-hour continuous care in the intensive care unit (ICU) environment and the most effective SBT technique is not known. The optimal strategy to liberate our sickest patients from ventilators remains to be determined. Objectives: To assess our ability to recruit critically ill adults and adhere to the screening and SBT protocols. Methods: We propose a pilot, factorial design, randomized trial comparing once-daily versus at least twice daily screening and pressure support (PS) ± positive end-expiratory pressure (PEEP) (inspiratory ± expiratory support) or T-piece (no support) as the SBT technique in critically ill adults who are invasively ventilated for at least 24 hours in 11 North American ICUs. Respiratory Therapists (RTs) will screen all enrolled patients between 06:00 and 08:00 hours daily to identify SBT candidates. Patients in the at least twice daily screening arms will also be screened between 13:00 and 15:00 hours; additional screening will be permitted at clinician’s discretion. Once a screening assessment is passed, an SBT will be conducted with the assigned technique. Outcomes: The study will be considered feasible if at least 1 to 2 patients per ICU per month are recruited and if the screening and SBT protocols are adhered to >80% of the time. Relevance: The availability of RTs in ICUs presents an important opportunity to screen patients more frequently, conduct more frequent SBTs, and reduce the duration of invasive ventilation and ICU stay. FAST Trial Registration: Clinical Trials.gov NCT02399267.

Neurofibromatosis type 1 (NF1)-related lung disease is a rare but increasingly recognised, high morbidity associated feature of the condition. We present a 48-year-old male patient with NF1, who was initially admitted for a subarachnoid haemorrhage requiring aneurysmal coil embolisation. During his recovery, he developed a left-sided pneumothorax requiring chest tube placement followed by concerns for re-expansion pulmonary oedema requiring intubation. Subsequently, the patient also developed a right-sided pneumothorax requiring additional chest tube placement but did not develop right-sided pulmonary oedema. During his hospitalisation, the patient also exemplified other important NF1-related pathophysiology including pheochromocytoma, cerebrovascular abnormalities and cardiovascular manifestations. Due to his multiple comorbidities and poor prognosis, we held a goals of care discussion with the patient's mother, and with her agreement, the patient underwent compassionate withdrawal of artificial life support.