Longitudinal Monitoring of Clinician-Patient Video Visits During the Peak of the COVID-19 Pandemic: Adoption and Sustained Challenges in an Integrated Health Care Delivery System.

BACKGROUND: Numerous prior opinion papers, administrative electronic health record data studies, and cross-sectional surveys of telehealth during the pandemic have been published, but none have combined assessments of video visit success monitoring with longitudinal assessments of perceived challenges to the rapid adoption of video visits during the pandemic. OBJECTIVE: This study aims to quantify (1) the use of video visits (compared with in-person and telephone visits) over time during the pandemic, (2) video visit successful connection rates, and (3) changes in perceived video visit challenges. METHODS: A web-based survey was developed for the dual purpose of monitoring and improving video visit implementation in our health care system during the COVID-19 pandemic. The survey included questions regarding rates of in-person, telephone, and video visits for clinician-patient encounters; the rate of successful connection for video visits; and perceived challenges to video visits (eg, software, hardware, bandwidth, and technology literacy). The survey was distributed via email to physicians, advanced practice professionals, and clinicians in May 2020. The survey was repeated in March 2021. Differences between the 2020 and 2021 responses were adjusted for within-respondent correlation across surveys and tested using generalized estimating equations. RESULTS: A total of 1126 surveys were completed (511 surveys in 2020 and 615 surveys in 2021). In 2020, only 21.7% (73/336) of clinicians reported no difficulty connecting with patients during video visits and 28.6% (93/325) of clinicians reported no difficulty in 2021. The distribution of the percentage of successfully connected video visits ("Over the past two weeks of scheduled visits, what percentage did you successfully connect with patients by video?") was not significantly different between 2020 and 2021 (P=.74). Challenges in conducting video visits persisted over time. Poor connectivity was the most common challenge reported by clinicians. This response increased over time, with 30.5% (156/511) selecting it as a challenge in 2020 and 37.1% (228/615) in 2021 (P=.01). Patients not having access to their electronic health record portals was also a commonly reported challenge (109/511, 21.3% in 2020 and 137/615, 22.3% in 2021, P=.73). CONCLUSIONS: During the pandemic, our health care delivery system rapidly adopted synchronous patient-clinician communication using video visits. As experience with video visits increased, the reported failure rate did not significantly decline, and clinicians continued to report challenges related to general network connectivity and patient access to technology.

Tackling Brain and Muscle Dysfunction in Acute Respiratory Distress Syndrome Survivors: National Heart, Lung, and Blood Institute Workshop Report.

Acute respiratory distress syndrome (ARDS) is associated with long-term impairments in brain and muscle function that significantly impact the quality of life of those who survive the acute illness. The mechanisms underlying these impairments are not yet well understood, and evidence-based interventions to minimize the burden on patients remain unproven. The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health assembled a workshop in April 2023 to review the state of the science regarding ARDS-associated brain and muscle dysfunction, to identify gaps in current knowledge, and to determine priorities for future investigation. The workshop included presentations by scientific leaders across the translational science spectrum and was open to the public as well as the scientific community. This report describes the themes discussed at the workshop as well as recommendations to advance the field toward the goal of improving the health and wellbeing of ARDS survivors.

Video versus Direct Laryngoscopy for Tracheal Intubation of Critically Ill Adults.

BACKGROUND: Whether video laryngoscopy as compared with direct laryngoscopy increases the likelihood of successful tracheal intubation on the first attempt among critically ill adults is uncertain. METHODS: In a multicenter, randomized trial conducted at 17 emergency departments and intensive care units (ICUs), we randomly assigned critically ill adults undergoing tracheal intubation to the video-laryngoscope group or the direct-laryngoscope group. The primary outcome was successful intubation on the first attempt. The secondary outcome was the occurrence of severe complications during intubation; severe complications were defined as severe hypoxemia, severe hypotension, new or increased vasopressor use, cardiac arrest, or death. RESULTS: The trial was stopped for efficacy at the time of the single preplanned interim analysis. Among 1417 patients who were included in the final analysis (91.5% of whom underwent intubation that was performed by an emergency medicine resident or a critical care fellow), successful intubation on the first attempt occurred in 600 of the 705 patients (85.1%) in the video-laryngoscope group and in 504 of the 712 patients (70.8%) in the direct-laryngoscope group (absolute risk difference, 14.3 percentage points; 95% confidence interval [CI], 9.9 to 18.7; P<0.001). A total of 151 patients (21.4%) in the video-laryngoscope group and 149 patients (20.9%) in the direct-laryngoscope group had a severe complication during intubation (absolute risk difference, 0.5 percentage points; 95% CI, -3.9 to 4.9). Safety outcomes, including esophageal intubation, injury to the teeth, and aspiration, were similar in the two groups. CONCLUSIONS: Among critically ill adults undergoing tracheal intubation in an emergency department or ICU, the use of a video laryngoscope resulted in a higher incidence of successful intubation on the first attempt than the use of a direct laryngoscope. (Funded by the U.S. Department of Defense; DEVICE ClinicalTrials.gov number, NCT05239195.).

Older Adults' Perspectives on Screening for Cognitive Impairment Following Critical Illness: Pre-Implementation Qualitative Study.

Screening for cognitive impairment following ICU discharge is recommended but not part of routine care. We sought to understand older adults' perspectives on screening for cognitive impairment following an ICU admission to inform the design and delivery of a cognitive screening intervention. DESIGN: Qualitative study using semi-structured interviews. SUBJECTS: Adults 60 years and older within 3 months of discharge from an ICU in an academic health system. INTERVENTIONS: Interviews were conducted via telephone, audio recorded and transcribed verbatim. All transcripts were coded in duplicate. Discrepancies were resolved by consensus. Codes were organized into themes and subthemes inductively. MEASUREMENTS AND MAIN RESULTS: We completed 22 interviews. The mean age of participants was 71 ± 6 years, 14 (63.6%) were men, 16 (72.7%) were White, and 6 (27.3%) were Black. Thematic analysis was organized around four themes: 1) receptivity to screening, 2) communication preferences, 3) information needs, and 4) provider involvement. Most participants were receptive to cognitive screening; this was influenced by trust in their providers and prior experience with cognitive screening and impairment. Participants preferred simple, direct, compassionate communication. They wanted to understand the screening procedure, the rationale for screening, and expectations for recovery. Participants desired input from their primary care provider to have their cognitive screening results placed in the context of their overall health, because they had a trusted relationship, and for convenience. CONCLUSIONS: Participants demonstrated limited understanding of and exposure to cognitive screening but see it as potentially beneficial following an ICU stay. Providers should use simple, straightforward language and place emphasis on expectations. Resources may be needed to assist primary care providers with capacity to provide cognitive screening and interpret results for ICU survivors. Implementation strategies can include educational materials for clinicians and patients on rationale for screening and recovery expectations.

Protocol and statistical analysis plan for the PREOXI trial of preoxygenation with noninvasive ventilation vs oxygen mask.

Background: Hypoxemia is a common and life-threatening complication during emergency tracheal intubation of critically ill adults. The administration of supplemental oxygen prior to the procedure ("preoxygenation") decreases the risk of hypoxemia during intubation. Research Question: Whether preoxygenation with noninvasive ventilation prevents hypoxemia during tracheal intubation of critically ill adults, compared to preoxygenation with oxygen mask, remains uncertain. Study Design and Methods: The PRagmatic trial Examining OXygenation prior to Intubation (PREOXI) is a prospective, multicenter, non-blinded randomized comparative effectiveness trial being conducted in 7 emergency departments and 17 intensive care units across the United States. The trial compares preoxygenation with noninvasive ventilation versus oxygen mask among 1300 critically ill adults undergoing emergency tracheal intubation. Eligible patients are randomized in a 1:1 ratio to receive either noninvasive ventilation or an oxygen mask prior to induction. The primary outcome is the incidence of hypoxemia, defined as a peripheral oxygen saturation <85% between induction and 2 minutes after intubation. The secondary outcome is the lowest oxygen saturation between induction and 2 minutes after intubation. Enrollment began on 10 March 2022 and is expected to conclude in 2023. Interpretation: The PREOXI trial will provide important data on the effectiveness of noninvasive ventilation and oxygen mask preoxygenation for the prevention of hypoxemia during emergency tracheal intubation. Specifying the protocol and statistical analysis plan prior to the conclusion of enrollment increases the rigor, reproducibility, and interpretability of the trial. Clinical trial registration number: NCT05267652.

A Pragmatic Pilot Trial Comparing Patient-Triggered Adaptive Pressure Control to Patient-Triggered Volume Control Ventilation in Critically Ill Adults.

BACKGROUND: Patient-triggered adaptive pressure control (APC) continuous mandatory ventilation (CMV) (APC-CMV) has been widely adopted as an alternative ventilator mode to patient-triggered volume control (VC) CMV (VC-CMV). However, the comparative effectiveness of the 2 ventilator modes remains uncertain. We sought to explore clinical and implementation factors pertinent to a future definitive randomized controlled trial assessing APC-CMV versus VC-CMV as an initial ventilator mode strategy. The research objectives in our pilot trial tested clinician adherence and explored clinical outcomes. METHODS: In a single-center pragmatic sequential cluster crossover pilot trial, we enrolled all eligible adults with acute respiratory failure requiring mechanical ventilation admitted during a 9-week period to the medical ICU. Two-week time epochs were assigned a priori in which subjects received either APC-CMV or VC-CMV The primary outcome of the trial was feasibility, defined as 80% of subjects receiving the assigned mode within 1 h of initiation of ICU ventilation. The secondary outcome was proportion of the first 24 h on the assigned mode. Finally, we surveyed clinician stakeholders to understand potential facilitators and barriers to conducting a definitive randomized trial. RESULTS: We enrolled 137 subjects who received 152 discreet episodes of mechanical ventilation during time epochs assigned to APC-CMV (n = 61) and VC-CMV (n = 91). One hundred and thirty-one episodes were included in the prespecified primary outcome. One hundred and twenty-six (96%) received the assigned mode within the first hour of ICU admission (60 of 61 subjects assigned APC-CMV and 66 of 70 assigned VC-CMV). VC-CMV subjects spent a lower proportion of first 24 h (84% [95% CI 78-89]) on the assigned mode than APC-CMV recipients (95% [95% CI 91-100]). Mixed-methods analyses identified preconceived perceptions of subject comfort by clinicians and need for real-time education to address this concern. CONCLUSIONS: In this pilot pragmatic, sequential crossover trial, unit-wide allocation to a ventilator mode was feasible and acceptable to clinicians.

DirEct versus VIdeo LaryngosCopE (DEVICE): protocol and statistical analysis plan for a randomised clinical trial in critically ill adults undergoing emergency tracheal intubation.

INTRODUCTION: Among 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 ANALYSIS: The DirEct versus VIdeo 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 <80%); severe hypotension (systolic blood pressure <65 mm Hg or new or increased vasopressor administration); cardiac arrest or death. Enrolment began on 19 March 2022 and is expected to be completed in 2023. ETHICS AND DISSEMINATION: The 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 NUMBER: ClinicalTrials.gov Registry (NCT05239195).

Functional, imaging, and respiratory evaluation (FIRE) of patients post-hospitalization for COVID-19: protocol for a pilot observational study.

INTRODUCTION: We describe a protocol for FIRE CORAL, an observational cohort study that examines the recovery from COVID-19 disease following acute hospitalization with an emphasis on functional, imaging, and respiratory evaluation. METHODS AND ANALYSIS: FIRE CORAL is a multicenter prospective cohort study of participants recovering from COVID-19 disease with in-person follow-up for functional and pulmonary phenotyping conducted by the National Heart, Lung and Blood Institute (NHLBI) Prevention and Early Treatment of Acute Lung Injury (PETAL) Network. FIRE CORAL will include a subset of participants enrolled in Biology and Longitudinal Epidemiology of PETAL COVID-19 Observational Study (BLUE CORAL), an NHLBI-funded prospective cohort study describing the clinical characteristics, treatments, biology, and outcomes of hospitalized patients with COVID-19 across the PETAL Network. FIRE CORAL consists of a battery of in-person assessments objectively measuring pulmonary function, abnormalities on lung imaging, physical functional status, and biospecimen analyses. Participants will attend and perform initial in-person testing at 3 to 9 months after hospitalization. The primary objective of the study is to determine the feasibility of longitudinal assessments investigating multiple domains of recovery from COVID-19. Secondarily, we will perform descriptive statistics, including the prevalence and characterization of abnormalities on pulmonary function, chest imaging, and functional status. We will also identify potential clinical and biologic factors that predict recovery or the occurrence of persistent impairment of pulmonary function, chest imaging, and functional status. ETHICS AND DISSEMINATION: FIRE CORAL is approved via the Vanderbilt University central institutional review board (IRB) and via reliance agreement with the site IRBs. Results will be disseminated via the writing group for the protocol committee and reviewed by the PETAL Network publications committee prior to publication. Data obtained via the study will subsequently be made publicly available via NHLBI's biorepository. STRENGTHS AND LIMITATIONS OF THE STUDY: Strengths: First US-based multicenter cohort of pulmonary and functional outcomes in patients previously hospitalized for COVID-19 infection Longitudinal biospecimen measurement allowing for biologic phenotyping of abnormalities Geographically diverse cohort allowing for a more generalizable understanding of post-COVID pulmonary sequela Limitations: Selected cohort given proximity to a participating center Small cohort which may be underpowered to identify small changes in pulmonary function.

Systematic Review of the "Pragmatism" of Pragmatic Critical Care Trials.

To assess the pragmatism of published critical care randomized controlled trials self-described as pragmatic using a validated tool. DATA SOURCES: Medical Literature Analysis and Retrieval Online database and PubMed interface from inception to November 1, 2021. STUDY SELECTION: We performed a systematic search of randomized controlled trials evaluating interventions for critically ill adults that self-identified as pragmatic in title or abstract. DATA EXTRACTION: Reviewers independently performed study selection and data extraction in duplicate; discrepancies were resolved by consensus. Pragmatism was assessed independently in duplicate by trained reviewers using the Pragmatic-Explanatory Continuum Indicator Summary 2 (PRECIS-2), a validated tool designed to represent how explanatory/pragmatic a trial is on the pragmatic to explanatory continuum. Trials were scored in nine domains on a 5-point continuum (from 1 = very explanatory to 5 = very pragmatic). Discrepancies of greater than 2 points were adjudicated by consensus discussion. DATA SYNTHESIS: The search resulted in 284 studies; 56 met eligibility criteria. Forty-one of the trials had a discrepancy in at least one domain that required consensus discussion, most commonly in domains of eligibility and follow-up. Twelve studies (21.4%) were scored as "overall pragmatic," defined as score of greater than 4 in five domains provided the scores in the remaining domains were three. The overall PRECIS-2 score of self-identified pragmatic studies increased from 1995 to 2021 suggesting increasing pragmatism over time. Pragmatic trials were more likely to have a waiver of informed consent (p = 0.05). CONCLUSIONS: The number and pragmatism of self-identified pragmatic trials have increased, particularly in the past decade. However, less than one-quarter of these trials that use the term pragmatic in title or abstract were retrospectively rated as pragmatic. Our results support the concept that trials are designed on a spectrum of pragmatic to explanatory. Advances in the design and reporting of critical care trials are needed to ensure their real-world applicability.

Association of early sedation level with patient outcomes in moderate-to-severe acute respiratory distress syndrome: Propensity-score matched analysis.

PURPOSE: Studies of early depth of sedation in mixed critically ill populations have suggested benefit to light sedation; however, the relationship of early depth of sedation with outcomes in patients with acute respiratory distress syndrome (ARDS) is unknown. MATERIALS AND METHODS: We performed a propensity-score matched analysis of early light sedation (Richmond Agitation Sedation Scale Score, RASS 0 to -1 or equivalent) versus deep sedation (RASS -2 or lower) in patients enrolled in the non-intervention group of The Reevaluation of Systemic Early Neuromuscular Blockade trial. Primary outcome was 90 day mortality. Secondary outcomes included days free of mechanical ventilation, days not in ICU, days not in hospital at day 28. RESULTS: 137 of 486 participants (28.2%) received early light sedation. Vasopressor usage and Apache III scores significantly differed between groups. Prior to matching, 90-day mortality was higher in the early deep sedation (45.3%) compared to light sedation (34.2%) group. In the propensity score matched cohort, there was no difference in 90-day mortality (Odds Ratio (OR) 0.72, 95% CI 0.41, 1.27, p = 0.26) or secondary outcomes between the groups. CONCLUSIONS: We did not find an association between early depth of sedation and clinical outcomes in this cohort of patients with moderate-to-severe ARDS.

Long-Term Outcomes in Acute Respiratory Distress Syndrome: Epidemiology, Mechanisms, and Patient Evaluation.

Survivors of acute respiratory distress syndrome (ARDS) experience challenges that persist well beyond the time of hospital discharge. Impairment in physical function, cognitive function, and mental health are common and may last for years. The current coronavirus disease 2019 pandemic is drastically increasing the incidence of ARDS worldwide, and long-term impairments will remain lasting effects of the pandemic. Evaluation of the ARDS survivor should be comprehensive, and common domains of impairment that have emerged from long-term outcomes research over the past 2 decades should be systematically evaluated.

How We Prevent and Treat Delirium in the ICU.

Delirium is a serious and complex problem facing critically ill patients, their families, and the health care system. When delirium develops, it is associated with prolonged hospital stays, increased costs, and long-term cognitive impairment in many patients. This article uses a clinical case to discuss our approach to delirium prevention and treatment in the ICU. We believe that an effective strategy to combat delirium requires implementation and adherence to a pain and sedation protocol as part of bundled care, use of a validated tool to detect delirium when present, and a focus on nonpharmacologic care strategies, including reorientation, early mobility, and incorporating family into care when possible. At present, the evidence does not support the routine administration of medications to prevent or treat delirium. A pharmacologic approach may be needed for agitated delirium, and we discuss our evaluation of the evidence for and against particular medications. Although delirium can be a distressing problem, there is evidence that it can be addressed through careful attention to prevention, detection, and minimizing the long-term impact on patients and their families.

Detection of Cognitive Impairment after Critical Illness with the Medicare Annual Wellness Visit: A Cohort Study.

Rationale: Cognitive impairment after critical illness is common in observational studies of older intensive care unit (ICU) survivors. The rate of screening for and diagnosis of cognitive impairment in ICU survivors in nonresearch settings is unknown. Objectives: To determine how often cognitive impairment was detected in older adults in the year after critical illness at an academic medical center as part of 1) the Medicare Annual Wellness Visit (AWV) and 2) routine clinical care. Methods: This study was a retrospective cohort study conducted at an urban academic medical center. The study included 696 patients aged 65 years and older admitted to the medical ICU between October 1, 2016, and October 1, 2018, and discharged alive. Patients were also required to have a health system-affiliated primary care provider. Patients were followed for 1 year. We defined cognitive impairment detected in the AWV as either an indicated diagnosis of cognitive impairment or dementia or patient, family, or provider indication of memory concerns during the AWV. We modeled the incidence of AWV completion and the detection of cognitive impairment using semiparametric additive models accounting for the competing risk of death. Results: Over 1 year of follow-up, the cumulative incidence of mortality was 23.0% (95% confidence interval [CI], 19.9-26.1%), with 24.7% (95% CI, 21.5-27.9%) completing the AWV. The cumulative incidence of cognitive impairment first detected through the AWV was 3.4% (95% CI, 1.8-5.0%) at 1 year, with a higher cumulative incidence for diagnoses of cognitive impairment or dementia first indicated via encounter diagnosis codes or the electronic health record problem list (5.9%; 95% CI, 3.9-7.9%). Conclusions: The results of our study suggest that the currently implemented AWV is unlikely to be an adequate mechanism for detecting cognitive impairment in a high-risk population such as those recovering from critical illness.

Herbal or Dietary Supplement Use and Hypertensive Medications: Does the Combination Relate to Medication Adherence and Blood Pressure Control?

Introduction: Medication nonadherence contributes to poor blood pressure control and increases cardiovascular disease risk in patients with hypertension. Identifying modifiable risk factors for low or nonadherence to antihypertensive medication is needed. Studies that have examined the relationship between herbal or dietary supplement (HDS) use and antihypertensive medication nonadherence provide inconsistent findings. Data from the National Health and Nutrition Examination Survey were used to examine the association between HDS use, current use of prescribed antihypertensive medication, and blood pressure status. Methods: The study sample included hypertensive adults (n = 5,478) who have been told by a health professional to take prescribed medication for their health condition. Respondents were classified as either HDS users or HDS nonusers. Depending on the kind of supplement used, HDS users were further divided into three mutually exclusive groups: hypertension HDS users, nonhypertension HDS users, and those who used both kinds of supplements. Supplements groupings were based on reports in the literature. Blood pressure status definition was based on Eighth Joint National Committee (JNC 8) recommendations. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were obtained from logistic models. Results: Overall HDS use prevalence was 62%. Current medication use did not significantly differ between patients reporting no HDS use and those reporting HDS use (aOR: 1.45; 95% CI: 0.78-2.69). No observable differences were found in current medication use between patients reporting no HDS use and those taking nonhypertension HDS or both kinds of supplements. Use of hypertension HDS was associated with improved blood pressure (aOR: 1.90; 95% CI: 1.07-3.36) compared with no HDS use. Conclusion: In a nationally representative U.S. sample, HDS use did not compromise current use of prescribed medication and was associated with improved blood pressure control. More research is needed to better understand why HDS use is associated with better blood pressure control.

Long-Term Outcomes After Extracorporeal Life Support for Acute Respiratory Failure.

OBJECTIVE: This study aims to determine the prevalence of functional and psychological impairment in survivors of extracorporeal life support (ECLS) and assess the needs of survivors to guide development of an effective follow-up program. DESIGN: This mixed-methods outcomes study used quantitative assessment via standardized instruments (Katz Index of Independence of Activities of Daily Living [Katz ADL], the Lawton Instrumental Activities of Daily Living [Lawton IADL], Hospital Anxiety and Depression Scale, and the Post Traumatic Growth Inventory) and qualitative interview to identify challenges experienced by survivors. SETTING: A single institutional experience in an academic medical center in the United States. PATIENTS: Patient selection targeted patients who underwent veno-venous ECLS for acute respiratory failure between January 1, 2015, and April 1, 2017. Forty-two patients (21 male, 21 female; median age of 49 years; interquartile range 36-57 years) completed the interview a median of 14.6 (interquartile range 7.7-21.1) months after ECLS decannulation. INTERVENTIONS: This was an observational follow-up study for which no intervention was made. MEASUREMENTS AND MAIN RESULTS: The Katz ADL and Lawton IADL revealed high independence and functionality in 62% of patients (26 of 42). Clinically significant anxiety was present in 48% (20 of 42) of patients and depression in 26% (11 of 42). There was a correlation between the number of ADL and IADL deficiencies and depression (rho 0.61, p < 0.001) and anxiety (rho 0.29, p = 0.033) subscales of the Hospital Anxiety and Depression Scale. High levels of posttraumatic growth were noted in 50% (21 of 42) of patients. Nearly all survivors noted that a clinic designed for post-ECLS follow-up would be beneficial. Patients desired access to education, improved coordination of care, and additional mental health resources. CONCLUSIONS: This study demonstrated persistent physical and psychological impairments in survivors of ECLS. Patients consistently expressed a desire to debrief on their hospital course and receive education on possible long-term effects. Study findings suggest that structured follow-up may allow for early identification of psychological and physical impairments to improve outcomes. Future studies should focus on investigating the effect of rehabilitation and follow-up clinics in preventing these issues.

Plasma angiopoietin-2 as a potential causal marker in sepsis-associated ARDS development: evidence from Mendelian randomization and mediation analysis.

PURPOSE: A causal biomarker for acute respiratory distress syndrome (ARDS) could fuel precision therapy options. Plasma angiopoietin-2 (ANG2), a vascular permeability marker, is a strong candidate on the basis of experimental and observational evidence. We used genetic causal inference methods-Mendelian randomization and mediation-to infer potential effects of plasma ANG2. METHODS: We genotyped 703 septic subjects, measured ICU admission plasma ANG2, and performed a quantitative trait loci (QTL) analysis to determine variants in the ANGPT2 gene associated with plasma ANG2 (p < 0.005). We then used linear regression and post-estimation analysis to genetically predict plasma ANG2 and tested genetically predicted ANG2 for ARDS association using logistic regression. We estimated the proportion of the genetic effect explained by plasma ANG2 using mediation analysis. RESULTS: Plasma ANG2 was strongly associated with ARDS (OR 1.59 (95% CI 1.35, 1.88) per log). Five ANGPT2 variants were associated with ANG2 in European ancestry subjects (n = 404). Rs2442608C, the most extreme cis QTL (coefficient 0.22, 95% CI 0.09-0.36, p = 0.001), was associated with higher ARDS risk: adjusted OR 1.38 (95% CI 1.01, 1.87), p = 0.042. No significant QTL were identified in African ancestry subjects. Genetically predicted plasma ANG2 was associated with ARDS risk: adjusted OR 2.25 (95% CI 1.06-4.78), p = 0.035. Plasma ANG2 mediated 34% of the rs2442608C-related ARDS risk. CONCLUSIONS: In septic European ancestry subjects, the strongest ANG2-determining ANGPT2 genetic variant is associated with higher ARDS risk. Plasma ANG2 may be a causal factor in ARDS development. Strategies to reduce plasma ANG2 warrant testing to prevent or treat sepsis-associated ARDS.

Quantitative peripheral muscle ultrasound in sepsis: Muscle area superior to thickness.

PURPOSE: The objective of this study is to describe the relationship between two quantitative muscle ultrasound measures, the rectus femoris cross-sectional area (RF-CSA) and quadriceps muscle thickness, with volitional measures of strength and function in critically ill patients with sepsis. MATERIALS AND METHODS: We performed a prospective study of patients admitted to a medical ICU with sepsis and shock or respiratory failure. We examined the association of two ultrasound measurements - the RF-CSA and quadriceps muscle thickness - with strength and function at day 7. Strength was determined using the Medical Research Council Score and function using Physical Function in the ICU Test, scored. RESULTS: Twenty-nine patients were enrolled; 19 patients had outcome testing performed. Over 7days, RF-CSA and thickness decreased by an average of 23.2% and 17.9%, respectively. The rate of change per day of RF-CSA displayed a moderate correlation with strength (ρ 0.51, p-value 0.03) on day 7. Baseline and day 7 RF-CSA did not show a significant correlation with either outcome. Quadriceps muscle thickness did not significantly correlate with either outcome. CONCLUSIONS: Muscle atrophy as detected by the rate of change in RF-CSA moderately correlated with strength one week after sepsis admission.