An Evaluation of the Efficacy and Safety of Timolol Maleate 0.5% Microdrops Administered with the Nanodropper.

PURPOSE: To examine if 12.5 µl timolol maleate 0.5% microdrops dispensed with the Nanodropper Adaptor provide noninferior intraocular pressure (IOP) reduction compared with conventional 28 µl drops in patients with open-angle glaucoma (OAG) and ocular hypertension (OHT). DESIGN: Prospective, noninferiority, parallel, multicenter, single-masked, active-controlled, randomized trial. PARTICIPANTS: Treatment-naïve subjects who were recently diagnosed with OAG and OHT at the Aravind Eye Care System. METHODS: Both eyes of subjects received 1 commercially available drop or both eyes of subjects received 1 microdrop of timolol maleate 0.5%. We measured IOP, resting heart rate (HR), and blood pressure (BP) at baseline and 1, 2, 5, and 8 hours after timolol administration. MAIN OUTCOME MEASURES: The IOP was the primary outcome measure. Secondary outcomes were resting HR, systolic BP (sBP), and diastolic BP (dBP). RESULTS: Adaptor-mediated microdrops and conventional drops of timolol significantly decreased IOP compared with baseline at all timepoints. Noninferiority was established at 3 of 4 timepoints. Heart rate decreases with Nanodropper were approximately 3 beats per minute (bpm) less than with conventional drops. CONCLUSIONS: Timolol microdrops appear to be as effective in ocular hypotensive action as conventional drops with a slightly attenuated effect on resting HR and BP. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

A joint frailty model for recurrent and competing terminal events: Application to delirium in the ICU.

Joint models linking longitudinal biomarkers or recurrent event processes with a terminal event, for example, mortality, have been studied extensively. Motivated by studies of recurrent delirium events in patients receiving care in an intensive care unit (ICU), we devise a joint model for a recurrent event process and multiple terminal events. Being discharged alive from the ICU or experiencing mortality may be associated with a patient's hazard of delirium, violating the assumption of independent censoring. Moreover, the direction of the association between the hazards of delirium and mortality may be opposite of the direction of association between the hazards of delirium and ICU discharge. Hence treating either terminal event as independent censoring may bias inferences. We propose a competing joint model that uses a latent frailty to link a patient's recurrent and competing terminal event processes. We fit our model to data from a completed placebo-controlled clinical trial, which studied whether Haloperidol could prevent death and delirium among ICU patients. The clinical trial served as a foundation for a simulation study, in which we evaluate the properties, for example, bias and confidence interval coverage, of the competing joint model. As part of the simulation study, we demonstrate the shortcomings of using a joint model with a recurrent delirium process and a single terminal event to study delirium in the ICU. Lastly, we discuss limitations and possible extensions for the competing joint model. The competing joint model has been added to frailtypack, an R package for fitting an assortment of joint models.

A Survey of PICU Clinician Practices and Perceptions regarding Respiratory Cultures in the Evaluation of Ventilator-Associated Infections in the BrighT STAR Collaborative.

OBJECTIVES: To characterize respiratory culture practices for mechanically ventilated patients, and to identify drivers of culture use and potential barriers to changing practices across PICUs. DESIGN: Cross-sectional survey conducted May 2021-January 2022. SETTING: Sixteen academic pediatric hospitals across the United States participating in the BrighT STAR Collaborative. SUBJECTS: Pediatric critical care medicine physicians, advanced practice providers, respiratory therapists, and nurses. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We summarized the proportion of positive responses for each question within a hospital and calculated the median proportion and IQR across hospitals. We correlated responses with culture rates and compared responses by role. Sixteen invited institutions participated (100%). Five hundred sixty-eight of 1,301 (44%) e-mailed individuals completed the survey (median hospital response rate 60%). Saline lavage was common, but no PICUs had a standardized approach. There was the highest variability in perceived likelihood (median, IQR) to obtain cultures for isolated fever (49%, 38-61%), isolated laboratory changes (49%, 38-57%), fever and laboratory changes without respiratory symptoms (68%, 54-79%), isolated change in secretion characteristics (67%, 54-78%), and isolated increased secretions (55%, 40-65%). Respiratory cultures were likely to be obtained as a "pan culture" (75%, 70-86%). There was a significant correlation between higher culture rates and likelihood to obtain cultures for isolated fever, persistent fever, isolated hypotension, fever, and laboratory changes without respiratory symptoms, and "pan cultures." Respondents across hospitals would find clinical decision support (CDS) helpful (79%) and thought that CDS would help align ICU and/or consulting teams (82%). Anticipated barriers to change included reluctance to change (70%), opinion of consultants (64%), and concern for missing a diagnosis of ventilator-associated infections (62%). CONCLUSIONS: Respiratory culture collection and ordering practices were inconsistent, revealing opportunities for diagnostic stewardship. CDS would be generally well received; however, anticipated conceptual and psychologic barriers to change must be considered.

Instrument adaptation and preliminary validation study of the Laryngeal Hypersensitivity Questionnaire used for assessment of laryngeal symptoms in patients with artificial airways.

BACKGROUND: The Newcastle Laryngeal Hypersensitivity Questionnaire (LHQ) was developed to measure abnormal laryngeal sensation and was originally validated in a patient sample from otolaryngologic and respiratory outpatient clinics. Modification is needed for patients who are mechanically ventilated via an endotracheal tube or a tracheostomy tube. OBJECTIVES: We sought to adapt and preliminarily validate a modified version of the LHQ appropriate for nurses and other clinicians to administer in acute hospital settings called the LHQ-Acute (LHQ-A). METHODS: Internal consistency and construct validity analyses using secondary data from patients at a tertiary teaching hospital who presented with symptoms of laryngeal irritability/hypersensitivity between September 2012 and October 2013 were performed. RESULTS: A total of 131 patients, most complaining of coughing and dysphonia, with a median age of 58 (interquartile range: 48, 66) years and 29 healthy participants with a median age of 62 (interquartile range: 50, 66) years were analysed. The original LHQ was reduced from 14 questions with responses on a 7-point scale to the LHQ-A containing 13 questions with responses on a 4-point scale. Correlations between items of the LHQ and LHQ-A were similar, and internal consistency was excellent and highly comparable, with Cronbach's alpha = 0.906 and 0.902, respectively. CONCLUSIONS: The LHQ-A, which has been adapted for nurses and other clinicians to administer to a critically ill patient population, demonstrated comparable reliability and validity to the original LHQ. Validation of the LHQ-A in independent patient populations from acute settings is necessary to better understand norms and changes during recovery from acute illness.

Participant retention in follow-up studies of intensive care unit survivors - A scoping review.

OBJECTIVE: To synthesize participant retention data and related reporting in studies evaluating post-hospital outcomes of survivors of critical illness after an intensive care unit (ICU) stay. REVIEW METHOD USED: A synthesis of literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews checklist. DATA SOURCES: PubMed, EMBASE, PsycINFO, Cumulative Index of Nursing and Allied Health Literature, and the Cochrane Controlled Trials Registry. Hand searched reference lists and personal files of relevant narrative and systematic review articles. REVIEW METHODS: Articles were screened by pairs of independent reviewers. Similarly, data were abstracted by pairs of data collectors, with conflicts resolved by consensus or by a third reviewer. RESULTS: We included 243 publications, from 225 unique studies of 87,602 participants. Participant retention could not be calculated for any time-points in 13% of studies nor in 22% of all follow-up time-points. Retention ranged from 18-100%. When compared to follow-up before 1-month, retention at each later timepoint was not significantly different. Age and sex were not associated with retention and more recent studies had decreased retention (odds ratio: 0.94 [95% confidence interval: 0.92-0.96; p < 0.001]). Reporting of retention-related study methodology was inconsistent. CONCLUSION: Retention rate could not be calculated for 22% of study follow-up time-points, with retention at the remaining time-points generally being high (≥85%), but with high variability (18% - 100%). ICU survivorship research could be improved via: (i) more detailed guidance on reporting participant retention, and (ii) use of existing resources and best practices to facilitate better study design and to improve participant retention to preserve statistical power and reduce selection bias.

Post-extubation Assessment of Laryngeal Symptoms and Severity (PALSS) in the Intensive Care Unit: Protocol of a Prospective Cohort Study.

Aims: The Post-extubation Assessment of Laryngeal Symptoms and Severity (PALSS) study systematically evaluates patient symptoms related to endotracheal intubation with mechanical ventilation, assesses laryngeal injury and voice function after extubation, and develops a screening tool to identify patients with clinically important, post-extubation laryngeal injury. Design: Single-center, prospective observational cohort study conducted in 6 intensive care units (ICU). Methods: Patients ≥18 years old who are orally intubated and mechanically ventilated in an ICU and meet eligibility criteria will undergo flexible laryngoscopy, with a sample size goal of 300 completed laryngoscopies. Primary outcome measures include signs and symptoms of laryngeal injury, including voice symptoms and alterations in swallowing, measured using the Laryngeal Hypersensitivity Questionnaire-Acute and Voice Symptom Scale questionnaires respectively. Data will be collected within 72 hours post-extubation and at 7-day follow-up or hospital discharge (whichever occurs first). Data will be analyzed using descriptive statistics, regression models, and predictive modeling using machine learning. Discussion: The findings of this study will describe the clinical signs and symptoms of laryngeal injury post-extubation. Conclusion: The PALSS study will provide insights for future studies that explore laryngeal injuries using flexible laryngoscopy after endotracheal intubation. Implications for patient care: Identifying signs and symptoms of laryngeal injury after endotracheal intubation will facilitate the development of a screening tool that will assist in early identification of post-extubation laryngeal injury, and aid in decreasing short- and long-term complications of endotracheal intubation. Reporting Method: SPIRIT. Patient or Public Contribution: Patients were study participants; and family members provided informed consent when the patient lacked decision-making capacity.

Evaluating preschool linear growth velocities: an interim reference illustrated in Nepal.

OBJECTIVE: An annualised linear growth velocity (LGV) reference can identify groups of children at risk of growing poorly. As a single velocity reference for all preschool ages does not exist, we present an interim tool, derived from published, normative growth studies, for detecting growth faltering, illustrating its use in Nepali preschoolers. DESIGN: The WHO Child Growth Velocity Standard was adapted to derive 12-month increments and conjoined to the Tanner-Whitehouse Height Velocity Reference data yielding contiguous preschool linear growth annualised velocities. Linear restricted cubic spline regressions were fit to generate sex-specific median and standard normal deviate velocities for ages 0 through 59 months. LGV Z-scores (LGVZ) were constructed, and growth faltering was defined as LGVZ < ­2. SETTING: Use of the reference was illustrated with data from Nepal's Tarai region. PARTICIPANTS: Children contributing the existing growth references and a cohort of 4276 Nepali children assessed from 2013 to 2016. RESULTS: Fitted, smoothed LGV reference curves displayed monotonically decreasing 12-month LGV, exemplified by male/female annual medians of 26·4/25·3, 12·1/12·7, 9·1/9·4, 7·7/7·8 and 7/7 cm/years, starting at 0, 12, 24, 36 and 48 months, respectively. Applying the referent, 31·1 %, 28·6 % and 29·3 % of Nepali children <6, 6­11 and 12­23 months of age, and ∼6 % of children 24­59 months, exhibited growth faltering. Under 24 months, faltering velocities were more prevalent in girls (34·4 %) than boys (25·3 %) (P < 0·05) but comparable (∼6 %) in older preschoolers. CONCLUSIONS: A LGV reference, concatenated from extant data, can identify preschool groups at-risk of growth faltering. Application and limitations are discussed.

A unit-based, multi-center evaluation of adopting mobility measures and daily mobility goals in the hospital setting.

BACKGROUND: Promoting patient mobility helps improve patient outcomes, but mobility status is not widely tracked nor do patients have specific individualized mobility goals. PURPOSE: We evaluated nursing adoption of mobility measures and daily mobility goal achievement using the Johns Hopkins Mobility Goal Calculator (JH-MGC), a tool to guide an individualized patient mobility goal based on the level of mobility capacity. METHOD: Built on a translating research into practice framework, the Johns Hopkins Activity and Mobility Promotion (JH-AMP) program was the vehicle to promote use of the mobility measures and the JH-MGC. We evaluated a large-scale implementation effort of this program on 23 units across two medical centers. FINDINGS: Units significantly improved documentation compliance to mobility measures and achieving daily mobility goals. Units with the highest documentation compliance rates had higher rates of daily mobility goal achievement, especially for longer distance ambulation goals. DISCUSSION: The JH-AMP program improved adoption of mobility status tracking and higher nursing inpatient mobility levels.

Six-month and 12-month patient outcomes based on inflammatory subphenotypes in sepsis-associated ARDS: secondary analysis of SAILS-ALTOS trial.

BACKGROUND: Prior acute respiratory distress syndrome (ARDS) trials have identified hypoinflammatory and hyperinflammatory subphenotypes, with distinct differences in short-term outcomes. It is unknown if such differences extend beyond 90 days or are associated with physical, mental health or cognitive outcomes. METHODS: 568 patients in the multicentre Statins for Acutely Injured Lungs from Sepsis trial of rosuvastatin versus placebo were included and assigned a subphenotype. Among 6-month and 12-month survivors (N=232 and 219, respectively, representing 243 unique survivors), subphenotype status was evaluated for association with a range of patient-reported outcomes (eg, mental health symptoms, quality of life). Patient subsets also were evaluated with performance-based tests of physical function (eg, 6 min walk test) and cognition. FINDINGS: The hyperinflammatory versus hypoinflammatory subphenotype had lower overall 12-month cumulative survival (58% vs 72%, p<0.01); however, there was no significant difference in survival beyond 90 days (86% vs 89%, p=0.70). Most survivors had impairment across the range of outcomes, with little difference between subphenotypes at 6-month and 12-month assessments. For instance, at 6 months, in comparing the hypoinflammatory versus hyperinflammatory subphenotypes, respectively, the median (IQR) patient-reported SF-36 mental health domain score was 47 (33-56) vs 44 (35-56) (p=0.99), and the per cent predicted 6 min walk distance was 66% (48%, 80%) vs 66% (49%, 79%) (p=0.76). INTERPRETATION: Comparing the hyperinflammatory versus hypoinflammatory ARDS subphenotype, there was no significant difference in survival beyond 90 days and no consistent findings of important differences in 6-month or 12-month physical, cognitive and mental health outcomes. These findings, when considered with prior results, suggest that inflammatory subphenotypes largely reflect the acute phase of illness and its short-term impact.

Perioperative Neurofilament Light Plasma Concentrations and Cognition before and after Cardiac Surgery: A Prospective Nested Cohort Study.

BACKGROUND: Neurofilament light is a marker of neuronal injury and can be measured in blood. Postoperative increases in neurofilament light have been associated with delirium after noncardiac surgery. However, few studies have examined the association of neurofilament light changes with postdischarge cognition in cardiac surgery patients, who are at highest risk for neuronal injury and cognitive decline. The authors hypothesized that increased neurofilament light (both baseline and change) would be associated with worse neuropsychological status up to 1 yr after cardiac surgery. METHODS: This observational study was nested in a trial of cardiac surgery patients, in which blood pressure during bypass was targeted using cerebral autoregulation monitoring. Plasma concentrations of neurofilament light were measured at baseline and postoperative day 1. Neuropsychological testing was performed at baseline, 1 month after surgery, and 1 yr after surgery. Primary outcomes were baseline and change from baseline in a composite z-score of all cognitive tests. RESULTS: Among 167 patients, cognitive outcomes were available in 80% (134 of 167) and 61% (102 of 167) at 1 month and 1 yr after surgery, respectively. The median baseline concentration of neurofilament light was 18.2 pg/ml (interquartile range, 13.4 to 28.1), and on postoperative day 1 was 28.5 pg/ml (interquartile range, 19.3 to 45.0). Higher baseline log neurofilament light was associated with worse baseline cognitive z-score (adjusted slope, -0.60; 95% CI, -0.90 to -0.30; P < 0.001), no change in z-score from baseline to 1 month (0.11; 95% CI, -0.19 to 0.41; P = 0.475), and improvement in z-score from baseline to 1 yr (0.56; 95% CI, 0.31 to 0.81; P < 0.001). Whereas some patients had an improvement in cognition at 1 yr and others a decline, an increase in neurofilament light from baseline to postoperative day 1 was associated with a greater decline in cognition at 1 yr. CONCLUSIONS: Higher baseline neurofilament light concentration was associated with worse baseline cognition but improvement in cognition at 1 yr. A postoperative increase in neurofilament light was associated with a greater cognitive decline at 1 yr.

Frailty subtypes and recovery in older survivors of acute respiratory failure: a pilot study.

BACKGROUND: Identifying subtypes of acute respiratory failure survivors may facilitate patient selection for post-intensive care unit (ICU) follow-up clinics and trials. METHODS: We conducted a single-centre prospective cohort study of 185 acute respiratory failure survivors, aged ≥ 65 years. We applied latent class modelling to identify frailty subtypes using frailty phenotype and cognitive impairment measurements made during the week before hospital discharge. We used Fine-Gray competing risks survival regression to test associations between frailty subtypes and recovery, defined as returning to a basic Activities of Daily Living disability count less than or equal to the pre-hospitalisation count within 6 months. We characterised subtypes by pre-ICU frailty (Clinical Frailty Scale score ≥ 5), the post-ICU frailty phenotype, and serum inflammatory cytokines, hormones and exosome proteomics during the week before hospital discharge. RESULTS: We identified five frailty subtypes. The recovery rate decreased 49% across each subtype independent of age, sex, pre-existing disability, comorbidity and Acute Physiology and Chronic Health Evaluation II score (recovery rate ratio: 0.51, 95% CI 0.41 to 0.63). Post-ICU frailty phenotype prevalence increased across subtypes, but pre-ICU frailty prevalence did not. In the subtype with the slowest recovery, all had cognitive impairment. The three subtypes with the slowest recovery had higher interleukin-6 levels (p=0.03) and a higher prevalence of ≥ 2 deficiencies in insulin growth factor-1, dehydroepiandrostersone-sulfate, or free-testosterone (p=0.02). Exosome proteomics revealed impaired innate immunity in subtypes with slower recovery. CONCLUSIONS: Frailty subtypes varied by prehospitalisation frailty and cognitive impairment at hospital discharge. Subtypes with the slowest recovery were similarly characterised by greater systemic inflammation and more anabolic hormone deficiencies at hospital discharge.

Functional electrical stimulation in-bed cycle ergometry in mechanically ventilated patients: a multicentre randomised controlled trial.

PURPOSE: To investigate the effect of functional electrical stimulation-assisted cycle ergometry (FES-cycling) on muscle strength, cognitive impairment and related outcomes. METHODS: Mechanically ventilated patients aged ≥18 years with sepsis or systemic inflammatory response syndrome were randomised to either 60 min of FES-cycling >5 days/week while in the intensive care unit (ICU) plus usual care rehabilitation versus usual care rehabilitation alone, with evaluation of two primary outcomes: (1) muscle strength at hospital discharge and (2) cognitive impairment at 6-month follow-up. RESULTS: We enrolled 162 participants, across four study sites experienced in ICU rehabilitation in Australia and the USA, to FES-cycling (n=80; mean age±SD 59±15) versus control (n=82; 56±14). Intervention participants received a median (IQR) of 5 (3-9) FES-cycling sessions with duration of 56 (34-63) min/day plus 15 (10-23) min/day of usual care rehabilitation. The control group received 15 (8-15) min/day of usual care rehabilitation. In the intervention versus control group, there was no significant differences for muscle strength at hospital discharge (mean difference (95% CI) 3.3 (-5.0 to 12.1) Nm), prevalence of cognitive impairment at 6 months (OR 1.1 (95% CI 0.30 to 3.8)) or secondary outcomes measured in-hospital and at 6 and 12 months follow-up. CONCLUSION: In this randomised controlled trial, undertaken at four centres with established rehabilitation programmes, the addition of FES-cycling to usual care rehabilitation did not substantially increase muscle strength at hospital discharge. At 6 months, the incidence of cognitive impairment was almost identical between groups, but potential benefit or harm of the intervention on cognition cannot be excluded due to imprecision of the estimated effect. TRIAL REGISTRATION NUMBER: ACTRN 12612000528853, NCT02214823.

Design of Clinical Trials Evaluating Sedation in Critically Ill Adults Undergoing Mechanical Ventilation: Recommendations From Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) Recommendation III.

OBJECTIVES: Clinical trials evaluating the safety and effectiveness of sedative medication use in critically ill adults undergoing mechanical ventilation differ considerably in their methodological approach. This heterogeneity impedes the ability to compare results across studies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations convened a meeting of multidisciplinary experts to develop recommendations for key methodologic elements of sedation trials in the ICU to help guide academic and industry clinical investigators. DESIGN: A 2-day in-person meeting was held in Washington, DC, on March 28-29, 2019, followed by a three-round, online modified Delphi consensus process. PARTICIPANTS: Thirty-six participants from academia, industry, and the Food and Drug Administration with expertise in relevant content areas, including two former ICU patients attended the in-person meeting, and the majority completed an online follow-up survey and participated in the modified Delphi process. MEASUREMENTS AND MAIN RESULTS: The final recommendations were iteratively refined based on the survey results, participants' reactions to those results, summaries written by panel moderators, and a review of the meeting transcripts made from audio recordings. Fifteen recommendations were developed for study design and conduct, subject enrollment, outcomes, and measurement instruments. Consensus recommendations included obtaining input from ICU survivors and/or their families, ensuring adequate training for personnel using validated instruments for assessments of sedation, pain, and delirium in the ICU environment, and the need for methodological standardization. CONCLUSIONS: These recommendations are intended to assist researchers in the design, conduct, selection of endpoints, and reporting of clinical trials involving sedative medications and/or sedation protocols for adult ICU patients who require mechanical ventilation. These recommendations should be viewed as a starting point to improve clinical trials and help reduce methodological heterogeneity in future clinical trials.

Spinal Anesthesia with Targeted Sedation based on Bispectral Index Values Compared with General Anesthesia with Masked Bispectral Index Values to Reduce Delirium: The SHARP Randomized Controlled Trial.

BACKGROUND: Reducing depth of anesthesia and anesthetic exposure may help prevent delirium, but trials have been conflicting. Most studies were conducted under general anesthesia or in cognitively impaired patients. It is unclear whether reducing depth of anesthesia beyond levels consistent with general anesthesia reduces delirium in cognitively intact patients. The authors' objective was to determine whether a bundled approach to reduce anesthetic agent exposure as determined by Bispectral Index (BIS) values (spinal anesthesia with targeted sedation based on BIS values) compared with general anesthesia (masked BIS) reduces delirium. METHODS: Important eligibility criteria for this parallel-arm randomized trial were patients 65 yr or greater undergoing lumbar spine fusion. The intervention group received spinal anesthesia with targeted sedation to BIS greater than 60 to 70. The control group received general anesthesia (masked BIS). The primary outcome was delirium using the Confusion Assessment Method daily through postoperative day 3, with blinded assessment. RESULTS: The median age of 217 patients in the analysis was 72 (interquartile range, 69 to 77). The median BIS value in the spinal anesthesia with targeted sedation based on BIS values group was 62 (interquartile range, 53 to 70) and in the general anesthesia with masked BIS values group was 45 (interquartile range, 41 to 50; P < 0.001). Incident delirium was not different in the spinal anesthesia with targeted sedation based on BIS values group (25.2% [28 of 111] vs. the general anesthesia with masked BIS values group (18.9% [20 of 106]; P = 0.259; relative risk, 1.22 [95% CI, 0.85 to 1.76]). In prespecified subgroup analyses, the effect of anesthetic strategy differed according to the Mini-Mental State Examination, but not the Charlson Comorbidity Index or age. Two strokes occurred among patients receiving spinal anesthesia and one death among patients receiving general anesthesia. CONCLUSIONS: Spinal anesthesia with targeted sedation based on BIS values compared with general anesthesia with masked BIS values did not reduce delirium after lumbar fusion.

Cerebral autoregulation in the operating room and intensive care unit after cardiac surgery.

BACKGROUND: Cerebral autoregulation monitoring is a proposed method to monitor perfusion during cardiac surgery. However, limited data exist from the ICU as prior studies have focused on intraoperative measurements. Our objective was to characterise cerebral autoregulation during surgery and early ICU care, and as a secondary analysis to explore associations with delirium. METHODS: In patients undergoing cardiac surgery (n=134), cerebral oximetry values and arterial BP were monitored and recorded until the morning after surgery. A moving Pearson's correlation coefficient between mean arterial proessure (MAP) and near-infrared spectroscopy signals generated the cerebral oximetry index (COx). Three metrics were derived: (1) globally impaired autoregulation, (2) MAP time and duration outside limits of autoregulation (MAP dose), and (3) average COx. Delirium was assessed using the 3-Minute Diagnostic Interview for CAM-defined Delirium (3D-CAM) and the Confusion Assessment Method for the ICU (CAM-ICU). Autoregulation metrics were compared using χ2 and rank-sum tests, and associations with delirium were estimated using regression models, adjusted for age, bypass time, and logEuroSCORE. RESULTS: The prevalence of globally impaired autoregulation was higher in the operating room vs ICU (40% vs 13%, P<0.001). The MAP dose outside limits of autoregulation was similar in the operating room and ICU (median 16.9 mm Hg×h; inter-quartile range [IQR] 10.1-38.8 vs 16.9 mm Hg×h; IQR 5.4-35.1, P=0.20). In exploratory adjusted analyses, globally impaired autoregulation in the ICU, but not the operating room, was associated with delirium. The MAP dose outside limits of autoregulation in the operating room and ICU was also associated with delirium. CONCLUSIONS: Metrics of cerebral autoregulation are altered in the ICU, and may be clinically relevant with respect to delirium. Further studies are needed to investigate these findings and determine possible benefits of autoregulation-based MAP targeting in the ICU.

Six-Minute Walk Distance After Critical Illness: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Impaired physical functioning is common and long lasting after an intensive care unit (ICU) admission. The 6-minute walk test (6MWT) is a validated and widely used test of functional capacity. This systematic review synthesizes existing data in order to: (1) evaluate 6-minute walk distance (6MWD) in meters over longitudinal follow-up after critical illness, (2) compare 6MWD between acute respiratory distress syndrome (ARDS) versus non-ARDS survivors, and (3) evaluate patient- and ICU-related factors associated with 6MWD. DATA SOURCES: Five databases (PubMed, EMBASE, Cumulative Index of Nursing and Allied Health Literature, PsychINFO, and Cochrane Controlled Trials Registry) were searched to identify studies reporting 6MWT after hospital discharge in survivors from general (ie, nonspeciality) ICUs. The last search was run on February 14, 2018. Databases were accessed via Johns Hopkins University Library. DATA EXTRACTION AND SYNTHESIS: Pooled mean 6MWD were reported, with separate linear random effects models used to evaluate associations of 6MWD with ARDS status, and patient- and ICU-related variables. Twenty-six eligible articles on 16 unique participant groups were included. The pooled mean (95% confidence interval [CI]) 6MWD results at 3- and 12-months post discharge were 361 (321-401) and 436 (391-481) meters, respectively. There was a significant increase in 6MWD at 12 months compared to 3 months (P = .017). In ARDS versus non-ARDS survivors, the mean (95% CI) 6MWD difference over 3-, 6-, and 12-month follow-up was 73 [13-133] meters lower. Female sex and preexisting comorbidity also were significantly associated with lower 6MWD, with ICU-related variables having no consistent associations. CONCLUSIONS: Compared to initial assessment at 3 months, significant improvement in 6MWD was reported at 12 months. Female sex, preexisting comorbidity, and ARDS (vs non-ARDS) were associated with lower 6MWT results. Such factors warrant consideration in the design of clinical research studies and in the interpretation of patient status using the 6MWT.

Identifying Clinical Research Priorities in Adult Pulmonary and Critical Care. NHLBI Working Group Report.

Preventing, treating, and promoting recovery from critical illness due to pulmonary disease are foundational goals of the critical care community and the NHLBI. 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 preclinical 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, preclinical disease modeling, and understanding of recovery from acute illness promise to transform the methods of pulmonary and critical care clinical research. To assess the current state of, research priorities for, and future directions in 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 preclinical models by incorporating comorbidities, cointerventions, and organ support; 3) developing and applying novel clinical trial designs; and 4) advancing mechanistic understanding of injury and recovery 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.

Racial and ethnic disparities in hospital observation in Maryland.

OBJECTIVES: Hospital observation is a key disposition option from the emergency department (ED) and encompasses up to one third of patients requiring post-ED care. Observation has been associated with higher incidence of catastrophic financial costs and has downstream effects on post-discharge clinical services. Yet little is known about the non-clinical determinants of observation assignment. We sought to evaluate the impact of patient-level demographic factors on observation designation among Maryland patients. METHODS: We conducted a retrospective analysis of all ED encounters in Maryland between July 2012 and January 2017 for four priority diagnoses (heart failure, chronic obstructive pulmonary disease [COPD], pneumonia, and acute chest pain) using multilevel logistic models allowing for heterogeneity of the effects across hospitals. The primary exposure was self-reported race and ethnicity. The primary outcome was the initial status assignment from the ED: hospital observation versus inpatient admission. RESULTS: Across 46 Maryland hospitals, 259,788 patient encounters resulted in a disposition of inpatient admission (65%) or observation designation (35%). Black (adjusted odds ratio [aOR]: 1.19; 95% confidence interval [CI]: 1.16-1.23) and Hispanic (aOR: 1.11; 95% CI: 1.01-1.21) patients were significantly more likely to be placed in observation than white, non-Hispanic patients. These differences were consistent across the majority of acute-care hospitals in Maryland (27/46). CONCLUSION: Black and Hispanic patients in Maryland are more likely to be treated under the observation designation than white, non-Hispanic patients independent of clinical presentation. Race agnostic, time-based status assignments may be key in eliminating these disparities.

Return to work after critical illness: a systematic review and meta-analysis.

BACKGROUND: Survivors of critical illness often experience poor outcomes after hospitalisation, including delayed return to work, which carries substantial economic consequences. OBJECTIVE: To conduct a systematic review and meta-analysis of return to work after critical illness. METHODS: We searched PubMed, Embase, PsycINFO, CINAHL and Cochrane Library from 1970 to February 2018. Data were extracted, in duplicate, and random-effects meta-regression used to obtain pooled estimates. RESULTS: Fifty-two studies evaluated return to work in 10 015 previously employed survivors of critical illness, over a median (IQR) follow-up of 12 (6.25-38.5) months. By 1-3, 12 and 42-60 months' follow-up, pooled return to work prevalence (95% CI) was 36% (23% to 49%), 60% (50% to 69%) and 68% (51% to 85%), respectively (τ2=0.55, I2=87%, p=0.03). No significant difference was observed based on diagnosis (acute respiratory distress syndrome (ARDS) vs non-ARDS) or region (Europe vs North America vs Australia/New Zealand), but was observed when comparing mode of employment evaluation (in-person vs telephone vs mail). Following return to work, 20%-36% of survivors experienced job loss, 17%-66% occupation change and 5%-84% worsening employment status (eg, fewer work hours). Potential risk factors for delayed return to work include pre-existing comorbidities and post-hospital impairments (eg, mental health). CONCLUSION: Approximately two-thirds, two-fifths and one-third of previously employed intensive care unit survivors are jobless up to 3, 12 and 60 months following hospital discharge. Survivors returning to work often experience job loss, occupation change or worse employment status. Interventions should be designed and evaluated to reduce the burden of this common and important problem for survivors of critical illness. TRIAL REGISTRATION NUMBER: PROSPERO CRD42018093135.

Associations Between Violence and HIV Risk Behaviors Differ by Perpetrator Among Russian Sex Workers.

Violence is associated with HIV and HIV risk behaviors among female sex workers (FSW). However, few studies assess multiple forms of violence and multiple HIV risk behaviors to build a comprehensive picture of how violence is implicated in HIV risk. Using respondent-driven sampling, 754 FSW were recruited in the Russian Federation. Surveys collected data on lifetime exposure to client, police, intimate partner, and pimp violence, as well as recent HIV risk behavior in the forms of injecting drug use (IDU), and inconsistent condom use with intimate partners and clients. Multivariable log-binomial and Poisson regression were used to assess associations between violence and HIV risk behavior outcomes. Lifetime client (31.7%), police (16.0%), intimate partner (15.7%), and pimp (11.4%) violence were prevalent. IDU (10.7%) and inconsistent condom use with intimate partners (45.1%) and clients (22.5%) were common. Intimate partner violence (IPV) and client violence were associated with IDU (ARRIPV 2.12, 95% CI 1.10, 4.10; ARRClient 2.75, 95% CI 1.19, 6.32), IPV and police violence were associated with inconsistent condom use with intimate partners (ARRIPV 1.10, 95% CI 1.01, 1.19; ARRPolice 1.11, 95% CI 1.01, 1.21), and IPV and police violence were associated with inconsistent condom use with clients (ARRIPV 1.49, 95% CI 1.02, 2.17; ARRPolice 1.65, 95% CI 1.19, 2.29). Each perpetrator-specific type of violence was associated with a unique set of HIV risk behaviors. Comprehensive violence prevention programming that addresses multiple perpetrators of violence against FSW, including clients, intimate partners and police, is critical for reducing sexual and drug-related HIV risk in FSW.