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Introduction Many patients who pass a spontaneous awakening trial (SAT) and spontaneous breathing trial (SBT) do not undergo extubation that day. We aimed to identify predictors of extubation on the day of passing an SBT and to develop prediction models for extubation among mechanically ventilated patients. Methods In a cohort of mechanically ventilated patients who had passed an SBT in a single, academic medical intensive care unit (ICU) from 2018 to 2019, we developed a logistic regression model for identifying predictors of extubation. Results Of 745 patients in our study, 77% were extubated the day they passed a SBT. Independent predictors of extubation included higher Richmond Agitation Sedation Scale (RASS) (−2 compared to −4: odds ratio (OR) 1.83, 95% confidence interval (CI) 1.56 to 2.14), receipt of sedation on the day prior (OR 2.12, 95% CI 1.63 to 2.74), absence of diagnosis of sepsis or septic shock (OR 0.77, 95% CI 0.59 to 1), absence of neurological illness (OR 0.59, 95% CI 0.37 to 0.96), indication for intubation of altered mental status, seizure, or agitation (OR 1.67, 95% CI 1.05 to 2.65), and absence of hemodynamic instability or cardiac arrest (OR 0.67, 95% CI 0.47 to 0.95). Conclusion and Relevance Patients on mechanical ventilation were more likely to be extubated on the day they passed an SBT if they had higher RASS scores, received sedation the day prior, or did not have diagnosis of sepsis, neurological illness, or hemodynamic instability. Future research should attempt to identify and address modifiable risk factors for failure to extubate after passing an SBT.

Balanced crystalloids may improve outcomes compared with saline for some critically ill adults. Lower tonicity of balanced crystalloids could worsen cerebral edema in patients with intracranial pathology. The effect of balanced crystalloids versus saline on clinical outcomes in patients with traumatic brain injury (TBI) requires further study. We planned an

Sepsis is the dysregulated immune response to severe infection that is common and lethal among critically ill patients. Fluid administration is a common treatment for hypotension and shock in early sepsis. Fluid therapy can also cause edema and organ dysfunction. Research on the best treatment strategies for sepsis has provided insights on the optimal timing, dose, and type of fluid to treat patients with sepsis. Initial research on early goal-directed therapy for sepsis included an initial bolus of 30 ml/kg of fluid, but more recent research has supported use of smaller volumes. After initial fluid resuscitation, minimizing additional fluid administration may be beneficial, but no single measure has been established as the best method to guide ongoing fluid management in sepsis. Dynamic measures of "fluid responsiveness" can predict which patients will experience an increase in cardiac output from a fluid bolus. Use of such a measure in clinical care remains limited by applicability to patient populations and uncertainty regarding the effect on clinical outcomes. Recent research informs the effect of fluid composition on outcomes for patients with sepsis. Current data support the use of balanced crystalloids, rather than saline, and the use of crystalloids, rather than semisynthetic colloids. The role for albumin administration in sepsis remains uncertain. Future research should focus on determining the optimal volume of fluid during sepsis resuscitation, the effectiveness of measures of "fluid responsiveness" in improving outcomes, the optimal composition of crystalloid solutions, the role of albumin, and the effects of "deresuscitation" after septic shock.

BACKGROUND: Invasive mechanical ventilation in critically ill adults involves adjusting the fraction of inspired oxygen to maintain arterial oxygen saturation. The oxygen-saturation target that will optimize clinical outcomes in this patient population remains unknown. METHODS: In a pragmatic, cluster-randomized, cluster-crossover trial conducted in the emergency department and medical intensive care unit at an academic center, we assigned adults who were receiving mechanical ventilation to a lower target for oxygen saturation as measured by pulse oximetry (Spo(2)) (90%; goal range, 88 to 92%), an intermediate target (94%; goal range, 92 to 96%), or a higher target (98%; goal range, 96 to 100%). The primary outcome was the number of days alive and free of mechanical ventilation (ventilator-free days) through day 28. The secondary outcome was death by day 28, with data censored at hospital discharge. RESULTS: A total of 2541 patients were included in the primary analysis. The median number of ventilator-free days was 20 (interquartile range, 0 to 25) in the lower-target group, 21 (interquartile range, 0 to 25) in the intermediate-target group, and 21 (interquartile range, 0 to 26) in the higher-target group (P = 0.81). In-hospital death by day 28 occurred in 281 of the 808 patients (34.8%) in the lower-target group, 292 of the 859 patients (34.0%) in the intermediate-target group, and 290 of the 874 patients (33.2%) in the higher-target group. The incidences of cardiac arrest, arrhythmia, myocardial infarction, stroke, and pneumothorax were similar in the three groups. CONCLUSIONS: Among critically ill adults receiving invasive mechanical ventilation, the number of ventilator-free days did not differ among groups in which a lower, intermediate, or higher Spo(2) target was used. (Supported by the National Heart, Lung, and Blood Institute and others; PILOT ClinicalTrials.gov number, NCT03537937.)

Sepsis causes significant morbidity and mortality worldwide, yet the optimal approach to resuscitation remains unclear. This review covers 5 areas of evolving practice in the management of early sepsis-induced hypoperfusion: fluid resuscitation volume, timing of vasopressor initiation, resuscitation targets, route of vasopressor administration, and use of invasive blood pressure monitoring. For each topic, we review the seminal evidence, discuss the evolution of practice over time, and highlight questions for additional research. Intravenous fluids are a core component of early sepsis resuscitation. However, with growing concerns about harms of fluid, practice is evolving towards smaller-volume resuscitation, which is often paired with earlier vasopressor initiation. Large trials of fluid-restrictive, vasopressor-early strategies are providing more information about the safety and potential benefit of these approaches. Lowering blood pressure targets is a means to prevent fluid overload and reduce exposure to vasopressors; mean arterial pressure targets of 60-65mmHg appear to be safe, at least in older patients. With the trend toward earlier vasopressor initiation, the need for central administration of vasopressors has been questioned, and peripheral vasopressor use is increasing, though is not universally accepted. Similarly, while guidelines suggest use of invasive blood pressure monitoring with arterial catheters in patients receiving vasopressors, blood pressure cuffs are less invasive and often sufficient. Overall, the management of early sepsis-induced hypoperfusion is evolving towards fluid-sparing and less-invasive strategies. However, many questions remain, and additional data are needed to further optimize our approach to resuscitation.

Background: Hypoxemia is common during tracheal intubation in intensive care units. To prevent hypoxemia during intubation, 2 methods of delivering oxygen between induction and laryngoscopy have been proposed: bag-mask ventilation and supplemental oxygen delivered by nasal cannula without ventilation (apneic oxygenation). Whether one of these approaches is more effective for preventing hypoxemia during intubation of critically ill patients is unknown. Methods: We performed a secondary analysis of data from 138 patients enrolled in 2, consecutive randomized trials of airway management in an academic intensive care unit. A total of 61 patients were randomized to receive bag-mask ventilation in a trial comparing bag-mask ventilation to none, and 77 patients were randomized to receive 100% oxygen at 15 L/min by nasal cannula in a trial comparing apneic oxygenation to none. Using multivariable linear regression accounting for age, body mass index, severity of illness, and oxygen saturation at induction, we compared patients assigned to bag-mask ventilation with those assigned to apneic oxygenation regarding lowest oxygen saturations from induction to 2 min after intubation. Results: Patients assigned to bag-mask ventilation and apneic oxygenation were similar at baseline. The median lowest oxygen saturation was 96% (interquartile range [IQR] 89%-100%) in the bag-mask ventilation group and 92% (IQR 84%-99%) in the apneic oxygenation group. After adjustment for prespecified confounders, bag-mask ventilation was associated with a higher lowest oxygen saturation compared to apneic oxygenation (mean difference, 4.2%; 95% confidence interval, 0.7%-7.8%; P = .02). The incidence of severe hypoxemia (oxygen saturation

Background Decannulation from venovenous extracorporeal membrane oxygenation (ECMO) at the earliest and safest possible time may improve outcomes and reduce cost. Yet, no prospective studies have compared weaning strategies for liberation from ECMO. Research Question Is a protocolized daily assessment of readiness to liberate from venovenous ECMO safe and feasible? Study Design and Methods We conducted a prospective, single-arm safety and feasibility study of a protocol for daily assessment of readiness to liberate from venovenous ECMO among consecutive adult patients receiving venovenous ECMO across four ICUs at a single center between June 20, 2020, and November 24, 2020. The ECMO-free protocol included three phases: (1) the safety screening, (2) non-ECMO F io 2 titration, and (3) the ECMO-free trial. Enrollment, interventions, and data collection were performed prospectively by trained study staff. Results Twenty-six patients received the ECMO-free protocol on 385 patient-days. The safety screening was passed during a total of 59 ECMO-free daily assessments (15.3%) among 20 patients. Every passed safety screening proceeded to an ECMO-free trial. Twenty-eight passed ECMO-free trials (47.5%) occurred among 16 patients (61.5%). No missed safety screenings, protocol deviations, or adverse events occurred. Of the 16 patients who passed an ECMO-free trial, 14 patients (87.5%) were decannulated. Among decannulated patients, 12 patients (85.7%) were decannulated on the same day as a passed ECMO-free trial, 6 patients (42.9%) were decannulated on the first day that they passed an ECMO-free trial, and 6 patients (42.9%) passed an ECMO-free trial at least twice consecutively before decannulation. The median time from first passed ECMO-free trial to decannulation was 2 days (interquartile range, 0-3 days). Interpretation The ECMO-free protocol is feasible and may identify patients for decannulation earlier than gradual approaches to weaning.

Oxygen supplementation is one of the most common interventions in critically ill patients. Despite over a century of data suggesting both beneficial and detrimental effects of supplemental oxygen, optimal arterial oxygenation targets in adult patients remain unclear. Laboratory animal studies have consistently showed that exposure to a high Fi(O(2)) causes respiratory failure and early death. Human autopsy studies from the 1960s purported to provide histologic evidence of pulmonary oxygen toxicity in the form of diffuse alveolar damage. However, concomitant ventilator-induced lung injury and/or other causes of acute lung injury may explain these findings. Although some observational studies in general populations of critically adults showed higher mortality in association with higher oxygen exposures, this finding has not been consistent. For some specific populations, such as those with cardiac arrest, studies have suggested harm from targeting supraphysiologic Pa(O(2)) levels. More recently, randomized clinical trials of arterial oxygenation targets in narrower physiologic ranges were conducted in critically ill adult patients. Although two smaller trials came to opposite conclusions, the two largest of these trials showed no differences in clinical outcomes in study groups that received conservative versus liberal oxygen targets, suggesting that either strategy is reasonable. It is possible that some strategies are of benefit in some subpopulations, and this remains an important ongoing area of research. Because of the ubiquity of oxygen supplementation in critically ill adults, even small treatment effects could have a large impact on a global scale.

PURPOSE OF REVIEW: This review describes the learning healthcare system paradigm, recent examples, and future directions. Patients, clinicians, and health systems frequently encounter decisions between available treatments, technologies, and healthcare delivery methods with little or no evidence about the comparative effectiveness and safety of the available options. Learning healthcare systems endeavor to recognize such knowledge gaps, integrate comparative effectiveness research – including clinical trials – into clinical care to address the knowledge gaps, and seamlessly implement the results into practice to improve care and patient outcomes. RECENT FINDINGS: Recent studies comparing the effectiveness of diagnostic tests and treatments, using information technology to identify patients likely to experience an outcome or benefit from an intervention, and evaluating models of healthcare delivery have demonstrated how a learning healthcare system approach can reduce arbitrary variation in care, decrease cost, and improve patient outcomes. SUMMARY: Learning healthcare systems have the potential to answer questions of importance to patients, clinicians, and health system leaders, improve efficiency of healthcare delivery, and improve patient outcomes. Achieving this goal will require realignment of the culture around clinical care, institutional and federal investment, expanded stakeholder engagement, tailored ethical and regulatory guidance, and methodologic advances in information technology and biostatistics.

This review article summarizes current scientific evidence regarding the treatment of sepsis. We highlight recent advances in sepsis management with a focus on antibiotics, fluids, vasopressors, and adjunctive therapies such as corticosteroids and renal replacement therapy.

PurposeThe Balanced versus Saline Trialists (BEST) -Living Study is an ongoing living systematic review with aggregated and individual patient data meta-analysis (IPDMA) from eligible trials that assessed the effects of using balanced solutions compared with saline in critically ill adults. We herein present the search strategies for the BEST-Living Study and provide details for future analysis and presentation.MethodsThe report will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Individual Participant Data (PRISMA-IPD) recommendations. Search was performed in Pubmed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL). The primary endpoint will be hospital mortality, which will be analyzed using a Bayesian hierarchical model. Secondary endpoints include nurvival until longest follow-up available, use of kidney replacement therapy, and intensive care unit and hospital length-of-stay. Details on the analysis plan are provided in this statistical analysis plan.ConclusionThe study will provide the most up-to-date and comprehensive assessment using the best evidence available for the use of balanced solutions in critically ill patients.ApprovalsThe undersigned and all authors have reviewed this plan and approve it as final. They find it to be consistent with the requirements of the protocol as it applies to their respective areas. They also find it to be compliant with ICH-E9 principles and, in particular, confirm that this analysis plan was final prior to any analysis of the aggregated data.

Background Whether the composition of intravenous crystalloid solutions affects outcomes in adults with aneurysmal subarachnoid hemorrhage (aSAH) remains unknown. Therefore, we determined whether the use of saline is associated with a lower risk of disability and death in patients with aSAH compared with balanced crystalloids. Methods We conducted a post hoc subgroup analysis of SMART (Isotonic S olutions and M ajor A dverse R enal Events T rial), a pragmatic, unblinded, cluster‐randomized, multiple‐crossover clinical trial that enrolled 15 802 adults between June 2015 and April 2017. We compared IV administration of saline to balanced crystalloids in consecutively enrolled patients with aSAH aged 18 years or older whose ruptured aneurysm was procedurally secured at a single academic center in the United States. The primary outcome was the score on the modified Rankin scale (range, 0 [no symptoms]–6 [death]) at 90 days obtained from a prospective institutional stroke registry. Secondary outcome included death by 90 days. Logistic or proportional odds regression models were used to test for between‐group differences adjusted for age, hypertension, aSAH grade, and procedure type. Results Of the 79 patients with aSAH procedurally treated during the Isotonic Solutions and Major Adverse Renal Events Trial study period, 78 were enrolled (median age, 58 years; interquartile range, 49–64.5; 64% female), with 41 (53%) assigned to saline and 37 (47%) to balanced crystalloids. Plasma‐Lyte was the primary balanced crystalloid used. Among 72 patients with 90‐day modified Rankin scale assessment, the adjusted common odds ratio, for the modified Rankin scale was 0.68 (95% CI, 0.28–1.63; P =0.39), with values P =0.02). Conclusions Among procedurally treated patients with aSAH, the risk of disability or death at 90 days did not significantly differ between saline and balanced crystalloids. Death occurred less frequently with saline than balanced crystalloids.

PURPOSE: We aimed to determine if balanced crystalloids compared with saline improve outcomes in critically ill adults admitted with low plasma bicarbonate. MATERIALS AND METHODS: We performed a secondary analysis of the Isotonic Solutions and Major Adverse Renal Events Trial (SMART). We included patients who presented to the Emergency Department with a first measured plasma bicarbonate less than 20mmol/L. Among these patients, we compared the effect of balanced crystalloid versus saline on the primary outcome of major adverse kidney events within 30 days (MAKE30), defined as a composite of death, new renal-replacement therapy, or persistent renal dysfunction (final inpatient creatinine ≥ 200% baseline). Secondary outcomes included 30 day in-hospital mortality, receipt of new RRT, persistent renal dysfunction, incident AKI, and vasopressor-free days. RESULTS: Among the 2029 patients with an initial plasma bicarbonate concentration < 20 mmol/L, there was no difference in the incidence of MAKE30 between those assigned to balanced crystalloid versus saline (21.8% vs 21.3%; P = 0.93). Secondary outcomes were similar between the balanced crystalloid and saline groups. CONCLUSIONS: Among critically ill adults presenting to the Emergency Department, initial plasma bicarbonate concentration does not appear to be a useful marker to guide the selection of balanced crystalloid versus saline.

Refractory hypoxemia can occur in patients with acute respiratory distress syndrome from COVID-19 despite support with venovenous (VV) extracorporeal membrane oxygenation (ECMO). Parallel ECMO circuits can be used to increase physiologic support. We report our clinical experience using ECMO circuits in parallel for select patients with persistent severe hypoxemia despite the use of a single ECMO circuit.We performed a retrospective cohort study of all patients with COVID-19-related acute respiratory distress syndrome who received VV-ECMO with an additional circuit in parallel at Vanderbilt University Medical Center between March 1, 2020, and March 1, 2022. We report demographic characteristics and clinical characteristics including ECMO settings, mechanical ventilator settings, use of adjunctive therapies, and arterial blood gas results after initial cannulation, before and after receipt of a second ECMO circuit in parallel, and before removal of the circuit in parallel, and outcomes.Of 84 patients with COVID-19 who received VV-ECMO during the study period, 22 patients (26.2%) received a circuit in parallel. The median duration of ECMO was 40.0 days (interquartile range, 31.6-53.1 days), of which 19.0 days (interquartile range, 13.0-33.0 days) were spent with a circuit in parallel. Of the 22 patients who received a circuit in parallel, 16 (72.7%) survived to hospital discharge and 6 (27.3%) died before discharge.In select patients, the additional use of an ECMO circuit in parallel can increase ECMO blood flow and improve oxygenation while allowing for lung-protective mechanical ventilation and excellent outcomes.

Coronavirus disease 2019 (COVID-19) has increased the demand for extracorporeal membrane oxygenation (ECMO) and introduced distinct challenges to patient selection for ECMO. Standardized processes for patient selection amidst resource limitations are lacking, and data on ECMO consults are underreported. We retrospectively reviewed consecutive adult ECMO consults for acute respiratory failure received at a single academic medical center from April 1, 2020, to February 28, 2021, and evaluated the implementation of a multidisciplinary selection committee (ECMO Council) and standardized framework for patient selection for ECMO. During the 334-day period, there were 202 total ECMO consults; 174 (86.1%) included a diagnosis of COVID-19. Among all consults, 157 (77.7%) were declined and 41 (20.3%) resulted in the initiation of ECMO. Frequent reasons for decline included the presence of multiple relative contraindications (n = 33), age greater than 60 years (n = 32), and resource limitations (n = 27). The ECMO Council deliberated on every case in which an absolute contraindication was not present (n = 96) via an electronic teleconference platform. Utilizing multidisciplinary consensus together with a standardized process for patient selection in ECMO is feasible during a pandemic and may be reliably exercised over time. Whether such an approach is feasible at other centers remains unknown.

Purpose Limited data are available on venovenous extracorporeal membrane oxygenation (ECMO) in patients with severe hypoxemic respiratory failure from coronavirus disease 2019 (COVID-19). Methods We examined the clinical features and outcomes of 190 patients treated with ECMO within 14 days of ICU admission, using data from a multicenter cohort study of 5122 critically ill adults with COVID-19 admitted to 68 hospitals across the United States. To estimate the effect of ECMO on mortality, we emulated a target trial of ECMO receipt versus no ECMO receipt within 7 days of ICU admission among mechanically ventilated patients with severe hypoxemia (PaO2/FiO2

Background Recent trials have suggested use of balanced crystalloids may decrease the incidence of major adverse kidney events compared to saline in critically ill adults. The effect of crystalloid composition on biomarkers of early acute kidney injury remains unknown. Methods From February 15 to July 15, 2016, we conducted an ancillary study to the Isotonic Solutions and Major Adverse Renal Events Trial (SMART) comparing the effect of balanced crystalloids versus saline on urinary levels of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) among 261 consecutively-enrolled critically ill adults admitted from the emergency department to the medical ICU. After informed consent, we collected urine 36 ± 12 h after hospital admission and measured NGAL and KIM-1 levels using commercially available ELISAs. Levels of NGAL and KIM-1 at 36 ± 12 h were compared between patients assigned to balanced crystalloids versus saline using a Mann-Whitney U test. Results The 131 patients (50.2%) assigned to the balanced crystalloid group and the 130 patients (49.8%) assigned to the saline group were similar at baseline. Urinary NGAL levels were significantly lower in the balanced crystalloid group (median, 39.4 ng/mg [IQR 9.9 to 133.2]) compared with the saline group (median, 64.4 ng/mg [IQR 27.6 to 339.9]) (P P = 0.36). Conclusions In this ancillary analysis of a clinical trial comparing balanced crystalloids to saline among critically ill adults, balanced crystalloids were associated with lower urinary concentrations of NGAL and similar urinary concentrations of KIM-1, compared with saline. These results suggest only a modest reduction in early biomarkers of acute kidney injury with use of balanced crystalloids compared with saline. Trial registration ClinicalTrials.gov number: NCT02444988. Date registered: May 15, 2015.

IntroductionAntibiotics are time-critical in the management of sepsis. When infectious organisms are unknown, patients are treated with empiric antibiotics to include coverage for gram-negative organisms, such as antipseudomonal cephalosporins and penicillins. However, in observational studies, some antipseudomonal cephalosporins (eg, cefepime) are associated with neurologic dysfunction while the most common antipseudomonal penicillin (piperacillin–tazobactam) is associated with acute kidney injury (AKI). No randomised control trials have compared these regimens. This manuscript describes the protocol and analysis plan for a trial designed to compare the effects of antipseudomonal cephalosporins and antipseudomonal penicillins among acutely ill patients receiving empiric antibiotics.Methods and analysisThe Antibiotic Choice On ReNal outcomes trial is a prospective, single-centre, non-blinded randomised trial being conducted at Vanderbilt University Medical Center. The trial will enrol 2500 acutely ill adults receiving gram-negative coverage for treatment of infection. Eligible patients are randomised 1:1 to receive cefepime or piperacillin–tazobactam on first order entry of a broad-spectrum antibiotic covering gram-negative organisms. The primary outcome is the highest stage of AKI and death occurring between enrolment and 14 days after enrolment. This will be compared between patients randomised to cefepime and randomised to piperacillin–tazobactam using an unadjusted proportional odds regression model. The secondary outcomes are major adverse kidney events through day 14 and number of days alive and free of delirium and coma in 14 days after enrolment. Enrolment began on 10 November 2021 and is expected to be completed in December 2022.Ethics and disseminationThe trial was approved by the Vanderbilt University Medical Center institutional review board (IRB#210591) with a waiver of informed consent. Results will be submitted to a peer-reviewed journal and presented at scientific conferences.Trial registration numberNCT05094154.

Purpose/Background: Pharmacists have been shown to play an important role in the medication management of critically ill patients. Pharmacist interventions in the care of critically ill patients with coronavirus disease 2019 (COVID-19) have not been quantitatively described. Methodology: A single center, retrospective, observational study was conducted at Vanderbilt University Medical Center in Nashville, Tennessee. All adult patients admitted to the COVID-19 intensive care unit (ICU) or Medical ICU with a COVID-19 diagnosis between March 1, 2020, and June 30, 2021, were included. All interventions made by pharmacists were documented electronically, collected, categorized, and analyzed. The primary outcome of this study was the median number of interventions by pharmacists per patient. The secondary outcome was the number of different types of interventions performed. Results: A total of 768 patients were included in the analysis. The median age was 63 years old; 63% of patients were male and 71% were Caucasian. Median hospital length of stay (LOS) was 12 days (interquartile range (IQR) 7-21) and ICU LOS was 5 days (IQR 1-11). The median Sequential Organ Failure Assessment score was 4 (IQR 2-7) and Charlson Comorbidity Index was 3 (IQR 2-5). Mortality at 60 days occurred in 352 patients (46%). Pharmacists performed a total of 7027 interventions for 655 patients with a median number of pharmacist interventions per patient of 6 (IQR 3-14). The most common pharmacist interventions were medication discontinuation (24%), completion of components of the ICU liberation bundle (19%), medication dose adjustment (18%), therapeutic drug monitoring (15%), and medication initiation (10%). Conclusions: Pharmacists made multiple interventions related to medication use and management in critically ill patients with COVID-19. This study adds important information of the evolving role clinical pharmacists play in the care of critical illness, specifically during the COVID-19 pandemic.

IntroductionAmong critically ill patients undergoing orotracheal intubation in the emergency department (ED) or intensive care unit (ICU), failure to visualise the vocal cords and intubate the trachea on the first attempt is associated with an increased risk of complications. Two types of laryngoscopes are commonly available: direct laryngoscopes and video laryngoscopes. For critically ill adults undergoing emergency tracheal intubation, it remains uncertain whether the use of a video laryngoscope increases the incidence of successful intubation on the first attempt compared with the use of a direct laryngoscope.Methods and analysisTheDirEct versusVIdeo LaryngosCopE(DEVICE) trial is a prospective, multicentre, non-blinded, randomised trial being conducted in 7 EDs and 10 ICUs in the USA. The trial plans to enrol up to 2000 critically ill adults undergoing orotracheal intubation with a laryngoscope. Eligible patients are randomised 1:1 to the use of a video laryngoscope or a direct laryngoscope for the first intubation attempt. The primary outcome is successful intubation on the first attempt. The secondary outcome is the incidence of severe complications between induction and 2 min after intubation, defined as the occurrence of one or more of the following: severe hypoxaemia (lowest oxygen saturation Ethics and disseminationThe trial protocol was approved with waiver of informed consent by the single institutional review board at Vanderbilt University Medical Center and the Human Research Protection Office of the Department of Defense. The results will be presented at scientific conferences and submitted for publication in a peer-reviewed journal.Trial registration numberClinicalTrials.gov Registry (NCT05239195).

Background: Despite the rapid integration of extracorporeal membrane oxygenation (ECMO) into intensive care units over the past decade, established programs for training critical care clinicians to provide ECMO are lacking. Objective: To evaluate the development and implementation of a multidisciplinary ECMO training program for the rapid deployment of ECMO training for a high volume of critical care clinicians. Methods: We performed a prospective cohort study examining a program for rapid training of multiple disciplines of critical care clinicians to deliver ECMO during the implementation of ECMO services across the intensive care units of an academic tertiary care center between October 2018 and January 2019. The multidisciplinary ECMO training program included didactic and simulation-based teaching and emphasized new, universal clinical protocols to improve consistency of care across the institution. Pre- and post-program written examinations evaluated knowledge acquisition, and an electronically distributed program evaluation assessed perceptions of content and delivery. Results: Among the 97 clinicians who completed the program, 49 (51%) were physicians and 48 (49%) were advanced practice providers from the departments of surgery (n = 42), medicine (n = 29), and anesthesia (n = 26). There was a significant difference in knowledge about ECMO between the pre- and post-program examination score (median [interquartile range] 70% [60–80%] vs. 90% [80–90%], respectively, P

Mortality historically has been the primary outcome of choice for acute and critical care clinical trials. However, undue reliance on mortality can limit the scope of trials that can be performed. Large sample sizes are usually needed for trials powered for a mortality outcome, and focusing solely on mortality fails to recognize the importance that reducing morbidity can have on patients' lives. The COVID-19 pandemic has highlighted the need for rapid, efficient trials to rigorously evaluate new therapies for hospitalized patients with acute lung injury. Oxygen-free days (OFDs) is a novel outcome for clinical trials that is a composite of mortality and duration of new supplemental oxygen use. It is designed to characterize recovery from acute lung injury in populations with a high prevalence of new hypoxemia and supplemental oxygen use. In these populations, OFDs captures two patient-centered consequences of acute lung injury: mortality and hypoxemic lung dysfunction. Power to detect differences in OFDs typically is greater than that for other clinical trial outcomes, such as mortality and ventilator-free days. OFDs is the primary outcome for the Fourth Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-4) Host Tissue platform, which evaluates novel therapies targeting the host response to COVID-19 among adults hospitalized with COVID-19 and new hypoxemia. This article outlines the rationale for use of OFDs as an outcome for clinical trials, proposes a standardized method for defining and analyzing OFDs, and provides a framework for sample size calculations using the OFD outcome.

Supplemental Digital Content is available in the text., OBJECTIVES: This systematic review and meta-analysis compared the use of saline to balanced crystalloid for fluid resuscitation in patients with diabetic ketoacidosis (DKA). DATA SOURCES: We searched databases including Medline, Embase, and the Cochrane registry. STUDY SELECTION: We included randomized controlled trials (RCTs) that compared saline to balanced crystalloid in patients with DKA. DATA EXTRACTION: We pooled estimates of effect using relative risk for dichotomous outcomes and mean differences (MDs) for continuous outcomes, both with 95% CIs. We assessed risk of bias for included RCTs using the modified Cochrane tool and certainty of evidence using Grading of Recommendations, Assessment, Development, and Evaluation methodology. DATA SYNTHESIS: We included eight RCTs (n = 482 patients). Both time to DKA resolution (MD, 3.51 hr longer; 95% CI, 0.90 longer to 6.12 longer; moderate certainty) and length of hospital stay (MD, 0.89 d longer in saline group; 95% CI, 0.34 longer to 1.43 d longer; moderate certainty) are probably longer in the saline group compared with the balanced crystalloid group, although for the latter, the absolute difference (under 1 d) is small. Post-resuscitation serum chloride level may be higher (MD, 1.62 mmol/L higher; 95% CI, 0.40 lower to 3.64 higher; low certainty), and post-resuscitation serum bicarbonate is probably lower (MD, 1.50 mmol/L; 95% CI, 2.33 lower to 0.67 lower; moderate certainty) in those receiving saline. CONCLUSIONS: In patients with DKA, the use of saline may be associated with longer time to DKA resolution, higher post-resuscitation serum chloride levels, lower post-resuscitation serum bicarbonate levels, and longer hospital stay compared with balanced crystalloids. Pending further data, low to moderate certainty data support using balanced crystalloid over saline for fluid resuscitation in patients with DKA.

The ORCHID (Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease) trial is a multicenter, blinded, randomized trial of hydroxychloroquine versus placebo for the treatment of adults hospitalized with coronavirus disease (COVID-19). This document provides the rationale and background for the trial and highlights key design features. We discuss five novel challenges to the design and conduct of a large, multicenter, randomized trial during a pandemic, including 1) widespread, off-label use of the study drug before the availability of safety and efficacy data; 2) the need to adapt traditional procedures for documentation of informed consent during an infectious pandemic; 3) developing a flexible and robust Bayesian analysis incorporating significant uncertainty about the disease, outcomes, and treatment; 4) obtaining indistinguishable drug and placebo without delaying enrollment; and 5) rapidly obtaining administrative and regulatory approvals. Our goals in describing how the ORCHID trial progressed from study conception to enrollment of the first patient in 15 days are to inform the development of other high-quality, multicenter trials targeting COVID-19. We describe lessons learned to improve the efficiency of future clinical trials, particularly in the setting of pandemics. The ORCHID trial will provide high-quality, clinically relevant data on the safety and efficacy of hydroxychloroquine for the treatment of COVID-19 among hospitalized adults.Clinical trial registered with www.clinicaltrials.gov (NCT04332991).

Preventing, treating, and promoting recovery from critical illness due to pulmonary disease are foundational goals of the critical care community and the National Heart, Lung, and Blood Institute. Decades of clinical research in acute respiratory distress syndrome, acute respiratory failure, pneumonia, and sepsis have yielded improvements in supportive care, which have translated into improved patient outcomes. Novel therapeutics have largely failed to translate from promising pre-clinical findings into improved patient outcomes in late-phase clinical trials. Recent advances in personalized medicine, "big data", causal inference using observational data, novel clinical trial designs, pre-clinical disease modeling, and understanding recovery from acute illness promise to transform the methods of pulmonary and critical care clinical research. To assess the current state, research priorities, and future directions for adult pulmonary and critical care research, the NHLBI assembled a multidisciplinary working group of investigators. This working group identified recommendations for future research, including: (1) focusing on understanding the clinical, physiological, and biological underpinnings of heterogeneity in syndromes, diseases, and treatment-response with the goal of developing targeted, personalized interventions; (2) optimizing pre-clinical models by incorporating comorbidities, co-interventions, and organ support; (3) developing and applying novel clinical trial designs; and (4) advancing mechanistic understanding of injury and recovery in order to develop and test interventions targeted at achieving long-term improvements in the lives of patients and families. Specific areas of research are highlighted as especially promising for making advances in pneumonia, acute hypoxemic respiratory failure, and acute respiratory distress syndrome.

Objective To determine whether surge conditions were associated with increased mortality. Design Multicenter cohort study. Setting U.S. ICUs participating in STOP-COVID. Patients Consecutive adults with COVID-19 admitted to participating ICUs between March 4 and July 1, 2020. Interventions None Measurements and Main Results The main outcome was 28-day in-hospital mortality. To assess the association between admission to an ICU during a surge period and mortality, we used two different strategies: (1) an inverse probability weighted difference-in-differences model limited to appropriately matched surge and non-surge patients and (2) a meta-regression of 50 multivariable difference-in-differences models (each based on sets of randomly matched surge- and non-surge hospitals). In the first analysis, we considered a single surge period for the cohort (March 23 – May 6). In the second, each surge hospital had its own surge period (which was compared to the same time periods in matched non-surge hospitals). Our cohort consisted of 4342 ICU patients (average age 60.8 [sd 14.8], 63.5% men) in 53 U.S. hospitals. Of these, 13 hospitals encountered surge conditions. In analysis 1, the increase in mortality seen during surge was not statistically significant (odds ratio [95% CI]: 1.30 [0.47-3.58], p = .6). In analysis 2, surge was associated with an increased odds of death (odds ratio 1.39 [95% CI, 1.34-1.43], p Conclusions Admission to an ICU with COVID-19 in a hospital that is experiencing surge conditions may be associated with an increased odds of death. Given the high incidence of COVID-19, such increases would translate into substantial excess mortality.