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There is insufficient evidence supporting the theory that mechanical ventilation can replace the manual ventilation method during CPR. Is using automatic mechanical ventilation (MV) feasible and comparable to the manual ventilation method during CPR? This pilot randomized controlled trial compared MV and manual bag ventilation (BV) during CPR after out-of-hospital cardiac arrest (OHCA). Patients with medical OHCA arriving at the ED were randomly assigned to two groups: an MV group using a mechanical ventilator and a BV group using a bag valve mask. Primary outcome was any return of spontaneous circulation (ROSC). Secondary outcomes were changes of arterial blood gas analysis results during CPR. Tidal volume, minute volume, and peak airway pressure were also analyzed. A total of 60 patients were enrolled, and 30 patients were randomly assigned to each group. There were no statistically significant differences in basic characteristics of OHCA patients between the two groups. The rate of any return of spontaneous circulation was 56.7% in the MV group and 43.3% in the BV group, indicating no significant (P =.439) difference between the two groups. There were also no statistically significant differences in changes of PH, P co 2 , P o 2 , bicarbonate, or lactate levels during CPR between the two groups (P values =.798, 0.249,.515,.876, and.878, respectively). Significantly lower tidal volume (P <.001) and minute volume (P =.009) were observed in the MV group. In this pilot trial, the use of MV instead of BV during CPR was feasible and could serve as a viable alternative. A multicenter randomized controlled trial is needed to create sufficient evidence for ventilation guidelines during CPR. ClinicalTrials.gov ; No.: NCT05550454; URL: www.clinicaltrials.gov. [Display omitted] [ABSTRACT FROM AUTHOR]

Critical care survivors experience multiple care transitions, with no formal follow-up care pathway. What are the potential solutions to improve the communication between treating teams and integration of care following an ICU admission, from the perspective of patients, their caregivers, intensivists, and general practitioners (GPs) from diverse socioeconomic areas? This study included a qualitative design using semi-structured interviews with intensivists, GPs, and patients and caregivers. Framework analysis was used to analyze data and to identify solutions to improve the integration of care following hospital discharge. Patients were previously mechanically ventilated for > 24 h in the ICU and had access to a video-enabled device. Clinicians were recruited from hospital networks and a state-wide GP network. Forty-six interviews with clinicians, patients, and caregivers were completed (15 intensivists, eight GPs, 15 patients, and eight caregivers). Three higher level feedback loops were identified that comprised 10 themes. Feedback loop 1 was an ICU and primary care collaboration. It included the following: (1) developing collaborative relationships between the ICU and primary care; (2) providing interprofessional education and resources to support primary care; and (3) improving role clarity for patient follow-up care. Feedback loop 2 was developing mechanisms for improved communication across the care continuum. It included: (4) timely, concise information-sharing with primary care on post-ICU recovery; (5) survivorship-focused information-sharing across the continuum of care; (6) empowering patients and caregivers in self-management; and (7) creation of a care coordinator role for survivors. Feedback loop 3 was learning from post-ICU outcomes to improve future care. It included: (8) developing comprehensive post-ICU care pathways; (9) enhancing support for patients following a hospital stay; and (10) integration of post-ICU outcomes within the ICU to improve clinician morale and understanding. Practical solutions to enhance the quality of survivorship for critical care survivors and their caregivers were identified. These themes are mapped to a novel conceptual model that includes key feedback loops for health system improvements and foci for future interventional trials to improve ICU survivorship outcomes. [ABSTRACT FROM AUTHOR]

There is substantial evidence that patients with COVID-19 were treated with sustained deep sedation during the pandemic. However, it is unknown whether such guideline-discordant care had spillover effects to patients without COVID-19. Did patterns of early deep sedation change during the pandemic for patients on mechanical ventilation without COVID-19? We used electronic health record data from 4,237 patients who were intubated without COVID-19. We compared sedation practices in the first 48 h after intubation across prepandemic (February 1, 2018, to January 31, 2020), pandemic (April 1, 2020, to March 31, 2021), and late pandemic (April 1, 2021, to March 31, 2022) periods. In the prepandemic period, patients spent an average of 13.0 h deeply sedated in the first 48 h after intubation. This increased 1.9 h (95% CI, 1.0-2.8) during the pandemic period and 2.9 h (95% CI, 2.0-3.8) in the late pandemic period. The proportion of patients that spent over one-half of the first 48 h deeply sedated was 18.9% in the prepandemic period, 22.3% during the pandemic period, and 25.9% during the late pandemic period. Ventilator-free days decreased during the pandemic, with a subdistribution hazard ratio of being alive without mechanical ventilation at 28 days of 0.87 (95% CI, 0.79-0.95) compared with the prepandemic period. Tracheostomy placement increased during the pandemic period compared with the prepandemic period (OR, 1.41; 95% CI, 1.08-1.82). In the medical ICU, early deep sedation increased 2.5 h (95% CI, 0.6-4.4) during the pandemic period and 4.9 h (95% CI, 3.0-6.9) during the late pandemic period, compared with the prepandemic period. We found that among patients on mechanical ventilation without COVID-19, sedation use increased during the pandemic. In the subsequent year, these practices did not return to prepandemic standards. [ABSTRACT FROM AUTHOR]

Approximately one-third of acute ICU patients display atypical sleep patterns that cannot be interpreted by using standard EEG criteria for sleep. Atypical sleep patterns have been associated with poor weaning outcomes in acute ICUs. Do patients being weaned from prolonged mechanical ventilation experience atypical sleep EEG patterns, and are these patterns linked with weaning outcomes? EEG power spectral analysis during wakefulness and overnight polysomnogram were performed on alert, nondelirious patients at a long-term acute care facility. Forty-four patients had been ventilated for a median duration of 38 days at the time of the polysomnogram study. Eleven patients (25%) exhibited atypical sleep EEG. During wakefulness, relative EEG power spectral analysis revealed higher relative delta power in patients with atypical sleep than in patients with usual sleep (53% vs 41%; P <.001) and a higher slow-to-fast power ratio during wakefulness: 4.39 vs 2.17 (P <.001). Patients with atypical sleep displayed more subsyndromal delirium (36% vs 6%; P =.027) and less rapid eye movement sleep (4% vs 11% total sleep time; P <.02). Weaning failure was more common in the atypical sleep group than in the usual sleep group: 91% vs 45% (P =.013). This study provides the first evidence that patients in a long-term acute care facility being weaned from prolonged ventilation exhibit atypical sleep EEG patterns that are associated with weaning failure. Patients with atypical sleep EEG patterns had higher rates of subsyndromal delirium and slowing of the wakeful EEG, suggesting that these two findings represent a biological signal for brain dysfunction. [Display omitted] [ABSTRACT FROM AUTHOR]

Low tidal volume ventilation (LTVV; < 8 mL/kg predicted body weight [PBW]) is a well-established standard of care associated with improved outcomes. This study used data collated in multicenter electronic health record ICU databases from the United Kingdom and the United States to analyze the use of LTVV in routine clinical practice. What factors are associated with adherence to LTVV in the United Kingdom and North America? This was a retrospective, multicenter study across the United Kingdom and United States of patients who were mechanically ventilated. Factors associated with adherence to LTVV were assessed in all patients in both databases who were mechanically ventilated for > 48 h. We observed trends over time and investigated whether LTVV was associated with patient outcomes (30-day mortality and duration of ventilation) and identified strategies to improve adherence to LTVV. A total of 5,466 (Critical Care Health Informatics Collaborative [CCHIC]) and 7,384 electronic ICU collaborative research database [eICU-CRD] patients were ventilated for > 48 h and had data of suitable quality for analysis. The median tidal volume (V T) values were 7.48 mL/kg PBW (CCHIC) and 7.91 mL/kg PBW (eICU-CRD). The patients at highest risk of not receiving LTVV were shorter than 160 cm (CCHIC) and 165 cm (eICU-CRD). Those with BMI > 30 kg/m2 (CCHIC OR, 1.9 [95% CI, 1.7-2.13]; eICU-CRD OR, 1.61 [95% CI, 1.49-1.75]) and female patients (CCHIC OR, 2.39 [95% CI, 2.16-2.65]; eICU-CRD OR, 2.29 [95% CI, 2.26-2.31]) were at increased risk of having median V T > 8 mL/kg PBW. Patients with median V T < 8 mL/kg PBW had decreased 30-day mortality in the CCHIC database (CCHIC cause-specific hazard ratio, 0.86 [95% CI, 0.76-0.97]; eICU-CRD cause-specific hazard ratio, 0.9 [95% CI, 0.86-1.00]). There was a significant reduction in V T over time in the CCHIC database. There has been limited implementation of LTVV in routine clinical practice in the United Kingdom and the United States. V T > 8 mL/kg PBW was associated with worse patient outcomes. [ABSTRACT FROM AUTHOR]

A 37-year-old man presented to the ED with symptoms of productive cough, self-reported fever, and shortness of breath for the past 15 days. He was placed on noninvasive mechanical ventilation for respiratory distress. IV piperacillin-tazobactam and inhaled bronchodilators were promptly administered, and he was subsequently transferred to the respiratory ICU for further care. He had no history of bowel and bladder disturbance, altered sensorium, swelling of feet, or abdominal distention. He never used tobacco and denied a history of TB. Medical history was notable for recurrent hospitalizations and administration of multiple courses of antibiotics in the past for similar complaints. He often used inhaled bronchodilators/corticosteroids when clinically stable to relieve symptoms. [ABSTRACT FROM AUTHOR]

Airway closure is an underestimated phenomenon reported in hypoxemic respiratory failure under mechanical ventilation, during cardiac arrest, and in patients who are obese. Because airway and alveolar pressure are not communicating, it leads to an overestimation of driving pressure and an underestimation of respiratory system compliance. Airway closure also favors denitrogenation atelectasis. To date, it has been described mainly in patients with ARDS and those with obesity. We describe three cases of airway closure in patients with hydrostatic pulmonary edema caused by cardiogenic shock, highlighting its resolution in a limited period of time (24 h) as pulmonary edema resolved. The waveforms show a biphasic reopening that we refer to as the "uncorking effect". The detection of airway closure may require setting positive end-expiratory pressure at or above the airway opening pressure to avoid the overestimation of driving pressure. [ABSTRACT FROM AUTHOR]

Several recently published randomized controlled trials have evaluated various noninvasive oxygenation strategies for the treatment of acute hypoxemic respiratory failure. Which available noninvasive oxygen strategies are effective for acute hypoxic respiratory failure? A systematic review of Medline, Embase, Cochrane CENTRAL, CINAHL, Web of Science, MedRxiv, and Research Square was conducted from inception to October 1, 2022. A random effects frequentist network meta-analysis was performed, and the results are presented using absolute risk difference per 1,000 patients. The Grading of Recommendations, Assessment, Development and Evaluation framework was used to rate the certainty of the evidence. Mortality, invasive mechanical ventilation, duration of hospitalization and ICU stay, ventilator-free days, and level of comfort are reported. Thirty-six trials (7,046 patients) were included. It was found that helmet CPAP probably reduces mortality compared with standard oxygen therapy (SOT) (231 fewer deaths per 1,000; 95% CI, 126-273 fewer) (moderate certainty). A high-flow nasal cannula (HFNC) probably reduces the need for invasive mechanical ventilation (103.5 fewer events per 1,000; 95% CI, 40.5-157.5 fewer) (moderate certainty). All noninvasive oxygenation strategies may reduce the duration of hospitalization as compared with SOT (low certainty). Helmet bilevel ventilation (4.84 days fewer; 95% CI, 2.33-7.36 days fewer) and helmet CPAP (1.74 days fewer; 95% CI, 4.49 fewer-1.01 more) may reduce the duration of ICU stay as compared with SOT (both low certainty). SOT may be more comfortable than face mask noninvasive ventilation and no different in comfort compared with an HFNC (both low certainty). A helmet interface for noninvasive ventilation probably reduces mortality and the risk of mechanical ventilation, as well as the duration of hospital and ICU stay. An HFNC probably reduces the risk of invasive mechanical ventilation and may be as comfortable as SOT. Further research is necessary to understand the role of these interfaces in acute hypoxemic respiratory failure. [Display omitted] [ABSTRACT FROM AUTHOR]

Diagnostic guidelines for pediatric ARDS (PARDS) were developed at the 2015 Pediatric Acute Lung Injury Consensus Conference (PALICC). Although this was an improvement in creating pediatric-specific diagnostic criteria, there remains potential for variability in identification of PARDS. What is the interrater reliability of the 2015 PALICC criteria for diagnosing moderate to severe PARDS? What clinical criteria and patient factors are associated with diagnostic disagreements? Patients with acute hypoxic respiratory failure admitted from 2016 to 2021 who received invasive mechanical ventilation were retrospectively reviewed by two pediatric ICU physicians. Reviewers evaluated whether the patient met the 2015 PALICC definition of moderate to severe PARDS and rated their diagnostic confidence. Interrater reliability was measured using Gwet's agreement coefficient. Thirty-seven of 191 encounters had a diagnostic disagreement. Interrater reliability was substantial (Gwet's agreement coefficient, 0.74; 95% CI, 0.65-0.83). Disagreements were caused by different interpretations of chest radiographs (56.8%), ambiguity in origin of pulmonary edema (37.8%), or lack of clarity if patient's current condition was significantly different from baseline (27.0%). Disagreement was more likely in patients who were chronically ventilated (OR, 4.66; 95% CI, 2.16-10.08; P <.001), had a primary cardiac admission diagnosis (OR, 3.36; 95% CI, 1.18-9.53; P =.02), or underwent cardiothoracic surgery during the admission (OR, 4.90; 95% CI, 1.60-15.00; P =.005). Reviewers were at least moderately confident in their decision 73% of the time; however, they were less likely to be confident if the patient had cardiac disease or chronic respiratory failure. The interrater reliability of the 2015 PALICC criteria for diagnosing moderate to severe PARDS in this cohort was substantial, with diagnostic disagreements commonly caused by differences in chest radiograph interpretations. Patients with cardiac disease or chronic respiratory failure were more vulnerable to diagnostic disagreements. More guidance is needed on interpreting chest radiographs and diagnosing PARDS in these subgroups. [Display omitted] [ABSTRACT FROM AUTHOR]

A 37-year-old woman with a medical history of myasthenia gravis resulting in progressive respiratory failure requiring continuous mechanical ventilation via tracheostomy, as well as multiple cardiac arrests leading to severe anoxic brain injury, was brought to the hospital from a nursing home because of difficulties with ventilation and oxygenation. On presentation to the ED, the patient was found to be agitated and tachypneic on a ventilator, generating low tidal volumes despite elevated peak airway pressures. Before the current presentation, the patient had been mechanically ventilated at a long-term acute care facility for the past 5 years. More recently, staff has noted intermittent loss of tidal volumes, temporarily responding to overinflation of tracheostomy cuff. Additionally, the tracheostomy tube was exchanged for an extra-long tracheostomy tube to improve tidal volumes; however, the problem persisted, prompting the current presentation. [ABSTRACT FROM AUTHOR]

BackgroundObjective and early identification of hospitalized patients, and particularly those with novel coronavirus disease 2019 (COVID-19), who may require mechanical ventilation (MV) may aid in delivering timely treatment.Research questionCan a transparent deep learning (DL) model predict the need for MV in hospitalized patients and those with COVID-19 up to 24 h in advance?Study design and methodsWe trained and externally validated a transparent DL algorithm to predict the future need for MV in hospitalized patients, including those with COVID-19, using commonly available data in electronic health records. Additionally, commonly used clinical criteria (heart rate, oxygen saturation, respiratory rate, Fio2, and pH) were used to assess future need for MV. Performance of the algorithm was evaluated using the area under receiver operating characteristic curve (AUC), sensitivity, specificity, and positive predictive value.ResultsWe obtained data from more than 30,000 ICU patients (including more than 700 patients with COVID-19) from two academic medical centers. The performance of the model with a 24-h prediction horizon at the development and validation sites was comparable (AUC, 0.895 vs 0.882, respectively), providing significant improvement over traditional clinical criteria (P < .001). Prospective validation of the algorithm among patients with COVID-19 yielded AUCs in the range of 0.918 to 0.943.InterpretationA transparent deep learning algorithm improves on traditional clinical criteria to predict the need for MV in hospitalized patients, including in those with COVID-19. Such an algorithm may help clinicians to optimize timing of tracheal intubation, to allocate resources and staff better, and to improve patient care.

Common, operational definitions are crucial to assess interventions and outcomes related to pediatric mechanical ventilation. These definitions can reduce unnecessary variability among research and quality improvement efforts, to ensure findings are generalizable, and can be pooled to establish best practices. Can we establish operational definitions for key elements related to pediatric ventilator liberation using a combination of detailed literature review and consensus-based approaches? A panel of 26 international experts in pediatric ventilator liberation, two methodologists, and two librarians conducted systematic reviews on eight topic areas related to pediatric ventilator liberation. Through a series of virtual meetings, we established draft definitions that were voted upon using an anonymous web-based process. Definitions were revised by incorporating extracted data gathered during the systematic review and discussed in another consensus meeting. A second round of voting was conducted to confirm the final definitions. In eight topic areas identified by the experts, 16 preliminary definitions were established. Based on initial discussion and the first round of voting, modifications were suggested for 11 of the 16 definitions. There was significant variability in how these items were defined in the literature reviewed. The final round of voting achieved ≥ 80% agreement for all 16 definitions in the following areas: what constitutes respiratory support (invasive mechanical ventilation and noninvasive respiratory support), liberation and failed attempts to liberate from invasive mechanical ventilation, liberation from respiratory support, duration of noninvasive respiratory support, total duration of invasive mechanical ventilation, spontaneous breathing trials, extubation readiness testing, 28 ventilator-free days, and planned vs rescue use of post-extubation noninvasive respiratory support. We propose that these consensus-based definitions for elements of pediatric ventilator liberation, informed by evidence, be used for future quality improvement initiatives and research studies to improve generalizability and facilitate comparison. [ABSTRACT FROM AUTHOR]

Respiratory therapists (RTs) are credentialed health professionals who specialize in assessment of pulmonary conditions, performing assessment of pulmonary function and delivering pulmonary therapeutics including aerosol therapy, and noninvasive and invasive mechanical ventilation. Respiratory therapists work closely with various clinicians including physicians, nurses, and therapy staff in a number of different settings including outpatient clinics, long-term facilities, EDs, and ICUs. RTs are integral in the treatment of patients with several acute and chronic conditions. In this review, we outline the importance, the elements of, and an approach to building a comprehensive RT program that allows delivery of high-quality care while ensuring RTs practice at the full scope of their licensure. Over the last two decades, we have implemented a suite of changes to the training, functioning, deployment, continuing education, and capacity building in our Lung Partners Program practice, under the supervision of a medical director, that have allowed us to create an effective inpatient and outpatient model of primary respiratory care. [ABSTRACT FROM AUTHOR]

A 52-year-old White man, who currently smokes, was admitted to the medical ICU with worsening shortness of breath. The patient was dyspneic for a month and had been clinically diagnosed with COPD by his primary care doctor and started on bronchodilators and supplemental oxygen. He had no known medical history or recent illness. His dyspnea worsened rapidly over the next month, prompting admission to the medical ICU. He was on high-flow oxygen followed by noninvasive positive pressure ventilation and then mechanical ventilation. He denied cough, fever, night sweats, or weight loss at the time of admission. There was no history of work-related or occupational exposures, drug intake, or recent travel. Review of systems was negative for arthralgia, myalgia, or skin rash. [ABSTRACT FROM AUTHOR]

A 25-year-old man with cerebral palsy, scoliosis, and ventilator dependence since SARS-CoV-2 infection 11 months earlier presented with a 2-week history of chest redness and swelling. The area of erythema and edema was located on the left side of the anterior chest and had grown to approximately 9 cm in diameter over the 2 weeks. It was tender to palpation. There was no history of trauma, injury, or bug bites at that site. He had not had a rash or similar lesions elsewhere on his body and had not taken any new medications. He did have increased, thick, yellow secretions from his tracheostomy, but no fevers. He was born in the Dominican Republic and moved to the United States as a child. He had not traveled anywhere outside the United States in more than a decade. [ABSTRACT FROM AUTHOR]

Critically ill patients sometimes remember periods of neuromuscular blockade. What is the prevalence of recalled awareness during paralysis in patients who underwent emergency tracheal intubation and mechanical ventilation, and what clinical variables are associated with this outcome? This study analyzed data from a prospectively collected continuous quality improvement database of emergency tracheal intubation in an urban, county hospital. Patients who received a neuromuscular blocking agent to facilitate emergency tracheal intubation in the ED were included. The database contained details of intubation management, including medications received and patient mental status prior to intubation. Patient recall of awareness of paralysis was assessed by trained staff during an in-person interview following extubation using a modified Brice questionnaire. For this analysis, three expert reviewers used these data to adjudicate whether patients may have had awareness of paralysis, the primary outcome. A logistic regression model was constructed to determine whether clinical variables were associated with the primary outcome. A total of 886 patients were analyzed. There were 66 patients (7.4%; 95% CI, 5.8-9.4) determined to possibly (61 patients) or definitely (5 patients) have experienced and recalled awareness of paralysis. A logistic regression model revealed that a decreased level of consciousness prior to intubation was associated with lower odds of awareness (adjusted OR, 0.39; 95% CI, 0.22-0.69), whereas the class of neuromuscular blocking agent used, sedative used, preintubation shock index, and postintubation sedation were not significantly associated with recall of this outcome. Among patients intubated emergently using a neuromuscular blocking agent, 7.4% of patients recalled awareness without being able to move, which was more likely when patients had a normal level of consciousness prior to intubation. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: The inhaled vasodilators nitric oxide and epoprostenol may be initiated to improve oxygenation in mechanically ventilated patients with severe acute respiratory failure (ARF); however, practice patterns and head-to-head comparisons of effectiveness are unclear.Research Question: What are the practice patterns and comparative effectiveness for inhaled nitric oxide and epoprostenol in severe ARF?Study Design and Methods: Using a large US database (Premier Healthcare Database), we identified adult patients with ARF or ARDS who were mechanically ventilated and started on inhaled nitric oxide, epoprostenol, or both. Leveraging large hospital variation in the choice of initial inhaled vasodilator, we compared the effectiveness of inhaled nitric oxide with that of epoprostenol by limiting analysis to patients admitted to hospitals that exclusively used either inhaled nitric oxide or epoprostenol. The primary outcome of successful extubation was modeled using multivariate Fine-Grey competing risk (death or hospice discharge) time-to-event models.Results: Among 11,200 patients (303 hospitals), 6,366 patients (56.8%) received inhaled nitric oxide first, 4,720 patients (42.1%) received inhaled epoprostenol first, and 114 patients (1.0%) received both therapies on the same day. One hundred four hospitals (34.3%; 1,666 patients) exclusively used nitric oxide and 118 hospitals (38.9%; 1,812 patients) exclusively used epoprostenol. No differences were found in the likelihood of successful extubation between patients admitted to nitric oxide-only hospitals vs those admitted to epoprostenol-only hospitals (subdistribution hazard ratio, 0.97; 95% CI, 0.80-1.18). Also no differences were found in total hospital costs or death. Results were robust to multiple sensitivity analyses.Interpretation: Large variation exists in the use of initial inhaled vasodilator for respiratory failure across US hospitals. Comparative effectiveness analyses identified no differences in outcomes based on inhaled vasodilator type. [ABSTRACT FROM AUTHOR]

Asthma exacerbations can be life-threatening, with 25,000 to 50,000 such patients per year requiring admission to an ICU in the United States. Appropriate triage of life-threatening asthma is dependent on both static assessment of airway function and dynamic assessment of response to therapy. Treatment strategies focus on achieving effective bronchodilation with inhaled β2-agonists, muscarinic antagonists, and magnesium sulphate while reducing inflammation with systemic corticosteroids. Correction of hypoxemia and hypercapnia, a key in managing life-threatening asthma, occasionally requires the incorporation of noninvasive mechanical ventilation to decrease the work of breathing. Endotracheal intubation and mechanical ventilation should not be delayed if clinical improvement is not achieved with conservative therapies. However, mechanical ventilation in these patients often requires controlled hypoventilation, adequate sedation, and occasional use of muscle relaxation to avoid dynamic hyperinflation, which can result in barotrauma or volutrauma. Sedation with ketamine or propofol is preferred because of their potential bronchodilation properties. In this review, we outline strategies for the assessment and management of patients with acute life-threatening asthma focusing on those requiring admission to the ICU. [ABSTRACT FROM AUTHOR]

Background: Broad-scale adoption of spontaneous awakening trials (SATs) and spontaneous breathing trials (SBTs) into everyday practice has been slow, and uncertainty exists regarding what factors facilitate or impede their routine delivery.Research Question: What patient, practice, and pharmacologic factors are associated with SAT and SBT performance and to what extent do they predict overall SAT/SBT performance?Study Design and Methods: This secondary analysis used data collected from a national quality improvement collaborative composed of 68 diverse ICUs. Adults with critical illness adults who received mechanical ventilation and/or continuously infused sedative medications were included. We performed mixed-effects logistic regression modeling, created receiver operating characteristic curves, and calculated the area under the curve (AUC).Results: Included in the SAT and SBT analysis were 4,847 and 4,938 patients, respectively. In multivariable models controlling for admitting patient characteristics, factors independently associated with higher odds of a next-day SAT and SBT included physical restraint use (adjusted odds ratio [AOR], 1.63; 95% CI, 1.42-1.87; AOR, 1.83; 95% CI, 1.60-2.09), documented target sedation level (AOR, 1.68; 95% CI, 1.41-2.01; AOR, 1.46; 95% CI, 1.24-1.72), more frequent level of arousal assessments (AOR, 1.22; 95% CI, 1.03-1.43; AOR, 1.32; 95% CI, 1.13-1.54), and dexmedetomidine administration (AOR, 1.23; 95% CI, 1.05-1.45; AOR, 1.52; 95% CI, 1.27-1.80). Factors independently associated with lower odds of a next-day SAT and SBT included deep sedation/coma (AOR, 0.69; 95% CI, 0.60-0.80; AOR, 0.33; 95% CI, 0.28-0.37) and benzodiazepine (AOR, 0.83; 95% CI, 0.72-0.95; AOR, 0.67; 95% CI, 0.59-0.77) or ketamine (AOR, 0.34; 95% CI, 0.16-0.71; AOR, 0.40; 95% CI, 0.18-0.88) administration. Models incorporating admitting, daily, and unit variations displayed moderate discriminant accuracy in predicting next-day SAT (AUC, 0.73) and SBT (AUC, 0.72) performance.Interpretation: There are a number of modifiable factors associated with SAT/SBT performance that are amenable to the development and testing of implementation interventions. [ABSTRACT FROM AUTHOR]

In critically ill patients receiving mechanical ventilation, expiratory muscles are recruited with high respiratory loading and/or low inspiratory muscle capacity. In this case report, we describe a previously unrecognized patient-ventilator dyssynchrony characterized by ventilator triggering by expiratory muscle relaxation, an observation that we termed expiratory muscle relaxation-induced ventilator triggering (ERIT). ERIT can be recognized with in-depth respiratory muscle monitoring as (1) an increase in gastric pressure (Pga) during expiration, resulting from expiratory muscle recruitment; (2) a drop in Pga (and hence, esophageal pressure) at the time of ventilator triggering; and (3) diaphragm electrical activity onset occurring after ventilator triggering. Future studies should focus on the incidence of ERIT and the impact in the patient receiving mechanical ventilation. [ABSTRACT FROM AUTHOR]

Patients admitted to the ICU with critical COVID-19 often require prolonged periods of mechanical ventilation. Difficulty weaning, lack of progress, and clinical deterioration are commonly encountered. These conditions should prompt a thorough evaluation for persistent or untreated manifestations of COVID-19, as well as complications from COVID-19 and its various treatments. Inflammation may persist and lead to fibroproliferative changes in the lungs. Infectious complications may arise including bacterial superinfection in the earlier stages of disease. Use of immunosuppressants may lead to the dissemination of latent infections, and to opportunistic infections. Venous thromboembolic disease is common, as are certain neurologic manifestations of COVID-19 including delirium and stroke. High levels of ventilatory support may lead to ventilator-induced injury to the lungs and diaphragm. We present diagnostic and therapeutic considerations for the mechanically ventilated patient with COVID-19 who shows persistent or worsening signs of critical illness, and we offer an approach to treating this complex but common scenario. [ABSTRACT FROM AUTHOR]

Background: Sarcoidosis-related hospitalizations have been increasing in the past decade. There is a paucity of data on mortality trends over time in patients with pulmonary sarcoidosis and respiratory failure who are hospitalized.Research Question: What are the national temporal trends over time in hospitalization and inpatient mortality rates in patients with pulmonary sarcoidosis and respiratory failure hospitalized in the United States between 2007 and 2018?Study Design and Methods: Hospitalization data between 2007 and 2018 were extracted from the National Inpatient Sample for subjects with pulmonary sarcoidosis. Inpatient mortality was stratified by age, respiratory failure, mechanical ventilation (MV), hospital location, and setting (rural vs urban, academic vs nonacademic). A Cochran-Armitage test for trend was used to assess the linear trend in mortality, respiratory failure, and need for MV.Results: Hospitalizations in patients with pulmonary sarcoidosis increased from 258.5 per 1,000,000 hospitalizations in 2007 to 705.7 per 1,000,000 in 2018. Hospitalizations for respiratory failure increased ninefold from 25.9 to 239.4 per 1,000,000 hospitalizations, and the need for MV increased threefold from 9.4 per 1,000,000 in 2007 to 29.4 per 1,000,000 in 2018. All-cause inpatient mortality was 2.6%; however, mortality was 13 times higher in patients with respiratory failure (10.6% vs 0.8%) and 26 times higher in patients who required MV (31.2% vs 1.2%). Inpatient mortality associated with respiratory failure declined 50% from 17.2% in 2007 to 6.6% in 2018. Independent inpatient mortality predictors were older age (adjusted hazard ratio [aHR], 1.025), respiratory failure (aHR, 3.12), need for MV (aHR, 6.01), pulmonary hypertension (pHTN; aHR, 1.44), pulmonary embolism (aHR, 1.61), and frailty (aHR, 3.10).Interpretation: Hospitalizations for respiratory failure in patients with pulmonary sarcoidosis are increasing; however, inpatient mortality from respiratory failure has declined. Older age, respiratory failure, pHTN, and frailty are important predictors of inpatient mortality in patients with pulmonary sarcoidosis who are hospitalized. [ABSTRACT FROM AUTHOR]

Background: Clinicians use several measures to ascertain whether individual patients will tolerate liberation from mechanical ventilation, including the rapid shallow breathing index (RSBI).Research Question: Given varied use of different thresholds, patient populations, and measurement characteristics, how well does RSBI predict successful extubation?Study Design and Methods: We searched six databases from inception through September 2019 and selected studies reporting the accuracy of RSBI in the prediction of successful extubation. We extracted study data and assessed quality independently and in duplicate.Results: We included 48 studies involving RSBI measurements of 10,946 patients. Pooled sensitivity for RSBI of < 105 in predicting extubation success was moderate (0.83 [95% CI, 0.78-0.87], moderate certainty), whereas specificity was poor (0.58 [95% CI, 0.49-0.66], moderate certainty) with diagnostic ORs (DORs) of 5.91 (95% CI, 4.09-8.52). RSBI thresholds of < 80 or 80 to 105 yielded similar sensitivity, specificity, and DOR. These findings were consistent across multiple subgroup analyses reflecting different patient characteristics and operational differences in RSBI measurement.Interpretation: As a stand-alone test, the RSBI has moderate sensitivity and poor specificity for predicting extubation success. Future research should evaluate its role as a permissive criterion to undergo a spontaneous breathing trial (SBT) for patients who are at intermediate pretest probability of passing an SBT.Trial Registry: PROSPERO; No.: CRD42020149196; URL: www.crd.york.ac.uk/prospero/. [ABSTRACT FROM AUTHOR]

Background: During the first wave of the COVID-19 pandemic, shortages of ventilators and ICU beds overwhelmed health care systems. Whether early tracheostomy reduces the duration of mechanical ventilation and ICU stay is controversial.Research Question: Can failure-free day outcomes focused on ICU resources help to decide the optimal timing of tracheostomy in overburdened health care systems during viral epidemics?Study Design and Methods: This retrospective cohort study included consecutive patients with COVID-19 pneumonia who had undergone tracheostomy in 15 Spanish ICUs during the surge, when ICU occupancy modified clinician criteria to perform tracheostomy in Patients with COVID-19. We compared ventilator-free days at 28 and 60 days and ICU- and hospital bed-free days at 28 and 60 days in propensity score-matched cohorts who underwent tracheostomy at different timings (≤ 7 days, 8-10 days, and 11-14 days after intubation).Results: Of 1,939 patients admitted with COVID-19 pneumonia, 682 (35.2%) underwent tracheostomy, 382 (56%) within 14 days. Earlier tracheostomy was associated with more ventilator-free days at 28 days (≤ 7 days vs > 7 days [116 patients included in the analysis]: median, 9 days [interquartile range (IQR), 0-15 days] vs 3 days [IQR, 0-7 days]; difference between groups, 4.5 days; 95% CI, 2.3-6.7 days; 8-10 days vs > 10 days [222 patients analyzed]: 6 days [IQR, 0-10 days] vs 0 days [IQR, 0-6 days]; difference, 3.1 days; 95% CI, 1.7-4.5 days; 11-14 days vs > 14 days [318 patients analyzed]: 4 days [IQR, 0-9 days] vs 0 days [IQR, 0-2 days]; difference, 3 days; 95% CI, 2.1-3.9 days). Except hospital bed-free days at 28 days, all other end points were better with early tracheostomy.Interpretation: Optimal timing of tracheostomy may improve patient outcomes and may alleviate ICU capacity strain during the COVID-19 pandemic without increasing mortality. Tracheostomy within the first work on a ventilator in particular may improve ICU availability. [ABSTRACT FROM AUTHOR]

The prevalence of obesity is rising worldwide. Adipose tissue exerts anatomic and physiological effects with significant implications for critical illness. Changes in respiratory mechanics cause expiratory flow limitation, atelectasis, and V̇/Q̇ mismatch with resultant hypoxemia. Altered work of breathing and obesity hypoventilation syndrome may cause hypercapnia. Challenging mask ventilation and peri-intubation hypoxemia may complicate intubation. Patients with obesity are at increased risk of ARDS and should receive lung-protective ventilation based on predicted body weight. Increased positive end expiratory pressure (PEEP), coupled with appropriate patient positioning, may overcome the alveolar decruitment and intrinsic PEEP caused by elevated baseline pleural pressure; however, evidence is insufficient regarding the impact of high PEEP strategies on outcomes. Venovenous extracorporeal membrane oxygenation may be safely performed in patients with obesity. Fluid management should account for increased prevalence of chronic heart and kidney disease, expanded blood volume, and elevated acute kidney injury risk. Medication pharmacodynamics and pharmacokinetics may be altered by hydrophobic drug distribution to adipose depots and comorbid liver or kidney disease. Obesity is associated with increased risk of VTE and infection; appropriate dosing of prophylactic anticoagulation and early removal of indwelling catheters may decrease these risks. Obesity is associated with improved critical illness survival in some studies. It is unclear whether this reflects a protective effect or limitations inherent to observational research. Obesity is associated with increased risk of intubation and death in SARS-CoV-2 infection. Ongoing molecular studies of adipose tissue may deepen our understanding of how obesity impacts critical illness pathophysiology. [ABSTRACT FROM AUTHOR]

Case Presentation: A 17-year-old previously healthy Taiwanese girl presented with syncope on a background of 1 month of weakness, polyarthritis, and heliotrope rash. Her presentation and investigations, which included an elevated creatine phosphokinase level and diffuse myositis on lower limb MRI, were consistent with juvenile dermatomyositis (JDM). [ABSTRACT FROM AUTHOR]

The existing coverage criteria for home noninvasive ventilation (NIV) do not recognize the diversity of hypoventilation syndromes and advances in technologies. This document summarizes the work of the hypoventilation syndromes Technical Expert Panel working group. The most pressing current coverage barriers identified were: (1) overreliance on arterial blood gases (particularly during sleep); (2) need to perform testing on prescribed oxygen; (3) requiring a sleep study to rule out OSA as the cause of sustained hypoxemia; (4) need for spirometry; (5) need to show bilevel positive airway pressure (BPAP) without a backup rate failure to qualify for BPAP spontaneous/timed; and (6) qualifying hospitalized patients for home NIV therapy at the time of discharge. Critical evidence support for changes to current policies includes randomized controlled trial evidence and clinical practice guidelines. To decrease morbidity and mortality by achieving timely access to NIV for patients with hypoventilation, particularly those with obesity hypoventilation syndrome, we make the following key suggestions: (1) given the significant technological advances, we advise acceptance of surrogate noninvasive end-tidal and transcutaneous Pco2 and venous blood gases in lieu of arterial blood gases; (2) not requiring Pco2 measures while on prescribed oxygen; (3) not requiring a sleep study to avoid delays in care in patients being discharged from the hospital; (4) remove spirometry as a requirement; and (5) not requiring BPAP without a backup rate failure to approve BPAP spontaneous/timed. The overarching goal of the Technical Expert Panel is to establish pathways that improve clinicians' management capability to provide Medicare beneficiaries access to appropriate home NIV therapy. Adoption of these proposed suggestions would result in the right device, for the right type of patient with hypoventilation syndromes, at the right time. [ABSTRACT FROM AUTHOR]

The current national coverage determinations (NCDs) for noninvasive ventilation for patients with thoracic restrictive disorders, COPD, and hypoventilation syndromes were formulated in 1998. New original research, updated formal practice guidelines, and current consensus expert opinion have accrued that are in conflict with the existing NCDs. Some inconsistencies in the NCDs have been noted, and the diagnostic and therapeutic technology has also advanced in the last quarter century. Thus, these and related NCDs relevant to bilevel positive airway pressure for the treatment of OSA and central sleep apnea need to be updated to ensure the optimal health of patients with these disorders. To that end, the American College of Chest Physicians organized a multisociety (American Thoracic Society, American Academy of Sleep Medicine, and American Association for Respiratory Care) effort to engage experts in the field to: (1) identify current barriers to optimal care; (2) highlight compelling scientific evidence that would justify changes from current policies incorporating best evidence and practice; and (3) propose suggestions that would form the basis for a revised NCD in each of these 5 areas (thoracic restrictive disorders, COPD, hypoventilation syndromes, OSA, and central sleep apnea). The expert panel met during a 2-day virtual summit in October 2020 and subsequently crafted written documents designed to achieve provision of "the right device to the right patient at the right time." These documents have been endorsed by the participating societies following peer review and publication in CHEST and will be used to inform efforts to revise the current NCDs. [ABSTRACT FROM AUTHOR]

This document summarizes the work of the COPD Technical Expert Panel working group. For patients with COPD, the most pressing current coverage barriers identified were onerous diagnostic requirements focused on oxygenation (rather than ventilation) and difficulty obtaining bilevel devices with backup rate capabilities. Because of these difficulties, many patients with COPD were instead sometimes prescribed home mechanical ventilators. Critical evidence supports changes to current policies, including randomized controlled trial evidence suggesting a mortality benefit from bilevel positive airway pressure with backup rate and updated clinical practice guidelines from the American Thoracic Society as well as the European Respiratory Society. To achieve optimal access to noninvasive ventilation for patients with COPD, we make the following key recommendations: (1) removal of the need for overnight oximetry testing; (2) the ability to initiate therapy using bilevel devices with backup rate capability; and (3) increased duration of time to meet adherence criteria (ie, a second 90-day trial period) in those patients actively engaged in their care. Clear guidelines based on medical necessity are also included for patients who require initiation of or switch to a home mechanical ventilator. Adoption of these proposed recommendations would result in the right device, for the right type of patient with COPD, at the right time. Finally, we emphasize the need for adequate clinical support during initiation and maintenance of home noninvasive ventilation in such patients. [ABSTRACT FROM AUTHOR]

Case Presentation: An 8-month-old previously healthy, full-term girl presented with altered mental status after falling approximately 3 feet from a bed, landing on her head. In the ED, she had a CT scan of her head (Fig 1) and was intubated for airway protection. While in the PICU, initial chest radiography showed bilateral infiltrates that were consistent with ARDS, which subsequently resolved. Her respiratory status continued to improve, which allowed a trial on CPAP with invasive neurally adjusted ventilatory assist (NAVA) support, which she was unable to tolerate because of the need for increased support during sleep. On hospital day 8, she was extubated to noninvasive NAVA and was noted to have poor truncal tone and inability to lift or rotate her head. Repeat head CT scans were unchanged. Despite nasal CPAP and NAVA support, she experienced hypercapnia to 83 mm Hg that required reintubation. Brain MRI was completed on hospital day 10 (Fig 1). Lumbar puncture results were obtained, which were unremarkable. Extubation was attempted again on hospital days 15 and 22 with subsequent hypercapnia that required reintubation. She was able to gradually lengthen her CPAP trials but continued to have periods of hypercapnia and bradypnea. [ABSTRACT FROM AUTHOR]

Background: Pseudomonas aeruginosa (PA) is a common cause of respiratory infection and morbidity. Pseudomonas elastase is an important virulence factor regulated by the lasR gene. Whether PA elastase activity is associated with worse clinical outcomes in ICU patients is unknown.Research Question: Is there an association between PA elastase activity and worse host outcomes in a cohort of ICU patients?Methods: PA respiratory isolates from 238 unique ICU patients from two tertiary-care centers within the University of Pittsburgh Medical Center health system were prospectively collected and screened for total protease and elastase activity, biofilm production, antimicrobial resistance, and polymicrobial status. The association between pathogen characteristics and 30-day and 90-day mortality was calculated using logistic regression. For subgroup analysis, two patterns of early (≤72 h) and late sample (>72 h) collection from the index ICU admission were distinguished using a finite mixture model. Lung inflammation and injury was evaluated in a mouse model using a PA high elastase vs low elastase producer.Results: PA elastase activity was common in ICU respiratory isolates representing 75% of samples and was associated with increased 30-day mortality (adjusted OR [95% CI]: 1.39 [1.05-1.83]). Subgroup analysis demonstrated that elastase activity was a risk factor for 30- and 90-day mortality in the early sample group, whereas antimicrobial resistance was a risk factor for 90-day mortality in the late sample group. Whole genome sequencing of high and low elastase producers showed that predicted loss-of-function lasR genotypes were less common among high elastase producers. Mice infected with a high elastase producer showed increased lung bacterial burden and inflammatory profile compared with mice infected with a low elastase producer.Interpretation: Elastase activity is associated with 30-day ICU mortality. A high elastase producing clinical isolate confers increased lung tissue inflammation compared with a low elastase producer in vivo. [ABSTRACT FROM AUTHOR]

Background: Ultrasound may be useful to assess the structure, activity, and function of the abdominal muscles in patients who are mechanically ventilated.Research Question: Does measurement of abdominal muscle thickening on ultrasound in patients who are mechanically ventilated provide clinically relevant information about abdominal muscle function and weaning outcomes?Study Design and Methods: This study consisted of two parts, a physiological study conducted in healthy subjects and a prospective observational study in patients who were mechanically ventilated. Abdominal muscle thickness and thickening fraction were measured during cough and expiratory efforts in 20 healthy subjects, and prior to and during a spontaneous breathing trial in 57 patients being ventilated.Results: In healthy subjects, internal oblique and rectus abdominis thickening fraction correlated with pressure generated during expiratory efforts (P < .001). In patients being ventilated, abdominal muscle thickness and thickening fraction were feasible to measure in all patients, and reproducibility was moderately acceptable. During a failed spontaneous breathing trial, thickening fraction of transversus abdominis and internal oblique increased substantially from baseline (13.2% [95% CI, 0.9-24.8] and 7.2% [95% CI, 2.2-13.2], respectively). The combined thickening fraction of transversus abdominis, internal oblique, and rectus abdominis measured during cough was associated with an increased risk of reintubation or reconnection to the ventilator following attempted liberation (OR, 2.1; 95% CI, 1.1-4.4 per 10% decrease in thickening fraction).Interpretation: Abdominal muscle thickening on ultrasound was correlated to the airway pressure generated by expiratory efforts. In patients who were mechanically ventilated, abdominal muscle ultrasound measurements are feasible and moderately reproducible. Among patients who passed a spontaneous breathing trial, reduced abdominal muscle thickening during cough was associated with a high risk of liberation failure.Clinical Trial Registration: ClinicalTrials.gov; No.: NCT03567564; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Although bilateral lung volume reduction surgery has been shown to be safe and effective in carefully selected patients with upper lobe-predominant emphysema and hyperinflation, bronchoscopic lung volume reduction via placement of endobronchial valves is conventionally performed only unilaterally. Furthermore, it is not offered to patients with interlobar collateral ventilation because of the lack of clinical efficacy. We describe two novel management approaches including (1) bilateral bronchoscopic lung volume reduction, and (2) a combined thoracic surgical and interventional pulmonary procedure involving surgical fissure completion followed by endobronchial valve placement, which culminated in safe and effective lung volume reduction of both lungs along with an excellent patient outcome. [ABSTRACT FROM AUTHOR]

Case Presentation: A 58-year-old man presented to the ED with a 1-week history of progressive weight loss, generalized weakness, unsteadiness, and dizziness. In hospital, he experienced a witnessed episode of loss of consciousness with no observable respirations that lasted for 15 minutes. His arterial blood gas demonstrated hypercapnic respiratory failure, and he required mask ventilation and vasoactive medications. Similar episodes occurred several more times over the course of the night that required the patient to be intubated. The paroxysmal episodes persisted necessitating continued invasive ventilatory support and admission to the ICU. The episodes occurred in both awake and asleep states and required the ventilator settings to dictate a minimum rate, but minimal ventilatory support otherwise. Further history revealed other symptomatic complaints of vertigo, dysphagia, and hypophonia that had progressed over a 2-month period. The patient's medical history was pertinent for a diagnosis of prostatic carcinoma 3 years previously that was found to be castrate resistant. He had metastases to his hip, ribs, and thoracic spine. Previous treatments had included bicalutamide, docetaxel, and abiraterone; he was receiving leuprolide therapy on presentation. [ABSTRACT FROM AUTHOR]

Background: Ventilator-associated pneumonia (VAP) is the most frequent health care-associated infection in severely ill patients, and aspiration of contaminated oropharyngeal content around the cuff of the tracheal tube is the main route of contamination.Research Question: Is continuous regulation of tracheal cuff pressure using a pneumatic device superior to manual assessment three times daily using a portable manometer (routine care) in preventing VAP in patients with severe trauma?Study Design and Methods: In this open-label, randomized controlled superiority trial conducted in 13 French ICUs, adults (age ≥ 18 years) with severe trauma (Injury Severity Score > 15) and requiring invasive mechanical ventilation for ≥ 48 h were enrolled. Patients were randomly assigned (1:1) via a secure Web-based random number generator in permuted blocks of variable sizes to one of two groups according to the method of tracheal cuff pressure control. The primary outcome was the proportion of patients developing VAP within 28 days following the tracheal intubation, as determined by two assessors masked to group assignment, in the modified intention-to-treat population. This study is closed to new participants.Results: A total of 434 patients were recruited between July 31, 2015, and February 15, 2018, of whom 216 were assigned to the intervention group and 218 to the control group. Seventy-three patients (33.8%) developed at least one episode of VAP within 28 days following the tracheal intubation in the intervention group compared with 64 patients (29.4%) in the control group (adjusted subdistribution hazard ratio, 0.96; 95% CI, 0.76-1.20; P = .71). No serious adverse events related to the use of the pneumatic device were noted.Interpretation: Continuous regulation of cuff pressure of the tracheal tube using a pneumatic device was not superior to routine care in preventing VAP in patients with severe trauma.Clinical Trial Registration: ClinicalTrials.gov; No.: NCT02534974; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Background: The resting of the respiratory musculature after undergoing the spontaneous breathing trial (SBT) to prevent extubation failures in critically ill patients needs to be studied further.Research Question: Is the reconnection to mechanical ventilation (MV) for 1 h after a successful SBT able to reduce the risk of reintubation?Study Design and Methods: Randomized clinical trial conducted in four ICUs between August 2018 and July 2019. Candidates for tracheal extubation who met all screening criteria for weaning were included. After achieving success in the SBT using a T-tube, the patients were randomized to the following groups: direct extubation (DE) or extubation after reconnection to MV for 1 h (R1h). The primary outcome was reintubation within 48 h.Results: Among the 336 patients studied (women, 41.1%; median age, 59 years [interquartile range, 45-70 years]), 12.9% (22/171) in the R1h group required reintubation within 48 h vs 18.2% (30/165) in the DE group (risk difference, 5.3 [95% CI, -2.49 to 13.12]; P = .18). No differences were found in mortality, length of ICU or hospital stay, causes of reintubation, or signs of extubation failure. A prespecified exploratory analysis showed that among the 233 patients (69.3%) who were ventilated for more than 72 h, the incidence of reintubation was 12.7% (15/118) in the R1h group compared with 22.6% (26/115) observed in the DE group (P = .04).Interpretation: Reconnection to MV after a successful SBT, compared with DE, did not result in a statistically significant reduction in the risk of reintubation in mechanically ventilated patients. Subgroup exploratory findings suggest that the strategy may benefit patients who were ventilated for more than 72 h, which should be confirmed in further studies.Trial Registry: Brazilian Clinical Trials Registry; No.: RBR-3x8nxn; URL: www.ensaiosclinicos.gov.br. [ABSTRACT FROM AUTHOR]