The endogenous circadian system worsens asthma at night independent of sleep and other daily behavioral or environmental cycles.

Asthma often worsens at night. To determine if the endogenous circadian system contributes to the nocturnal worsening of asthma, independent of sleep and other behavioral and environmental day/night cycles, we studied patients with asthma (without steroid use) over 3 wk in an ambulatory setting (with combined circadian, environmental, and behavioral effects) and across the circadian cycle in two complementary laboratory protocols performed in dim light, which separated circadian from environmental and behavioral effects: 1) a 38-h "constant routine," with continuous wakefulness, constant posture, 2-hourly isocaloric snacks, and 2) a 196-h "forced desynchrony" incorporating seven identical recurring 28-h sleep/wake cycles with all behaviors evenly scheduled across the circadian cycle. Indices of pulmonary function varied across the day in the ambulatory setting, and both laboratory protocols revealed significant circadian rhythms, with lowest function during the biological night, around 4:00 AM, uncovering a nocturnal exacerbation of asthma usually unnoticed or hidden by the presence of sleep. We also discovered a circadian rhythm in symptom-based rescue bronchodilator use (ß2-adrenergic agonist inhaler) whereby inhaler use was four times more likely during the circadian night than day. There were additive influences on asthma from the circadian system plus sleep and other behavioral or environmental effects. Individuals with the lowest average pulmonary function tended to have the largest daily circadian variations and the largest behavioral cycle effects on asthma. When sleep was modeled to occur at night, the summed circadian, behavioral/environmental cycle effects almost perfectly matched the ambulatory data. Thus, the circadian system contributes to the common nocturnal worsening of asthma, implying that internal biological time should be considered for optimal therapy.

Evaluation of the Efficacy and Safety of Inhaled Epoprostenol and Inhaled Nitric Oxide for Refractory Hypoxemia in Patients With Coronavirus Disease 2019.

OBJECTIVES: The objectives of this study were to evaluate the efficacy and safety of inhaled epoprostenol and inhaled nitric oxide in patients with refractory hypoxemia secondary to coronavirus disease 2019. DESIGN: Retrospective single-center study. SETTING: ICUs at a large academic medical center in the United States. PATIENTS: Thirty-eight adult critically ill patients with coronavirus disease 2019 and refractory hypoxemia treated with either inhaled epoprostenol or inhaled nitric oxide for at least 1 hour between March 1, 2020, and June 30, 2020. INTERVENTIONS: Electronic chart review. MEASUREMENTS AND MAIN RESULTS: Of 93 patients screened, 38 were included in the analysis, with mild (4, 10.5%), moderate (24, 63.2%), or severe (10, 26.3%), with acute respiratory distress syndrome. All patients were initiated on inhaled epoprostenol as the initial pulmonary vasodilator and the median time from intubation to initiation was 137 hours (68-228 h). The median change in Pao2/Fio2 was 0 (-12.8 to 31.6) immediately following administration of inhaled epoprostenol. Sixteen patients were classified as responders (increase Pao2/Fio2 > 10%) to inhaled epoprostenol, with a median increase in Pao2/Fio2 of 34.1 (24.3-53.9). The mean change in Pao2 and Spo2 was -0.55 ± 41.8 and -0.6 ± 4.7, respectively. Eleven patients transitioned to inhaled nitric oxide with a median change of 11 (3.6-24.8) in Pao2/Fio2. A logistic regression analysis did not identify any differences in outcomes or characteristics between the responders and the nonresponders. Minimal adverse events were seen in patients who received either inhaled epoprostenol or inhaled nitric oxide. CONCLUSIONS: We found that the initiation of inhaled epoprostenol and inhaled nitric oxide in patients with refractory hypoxemia secondary to coronavirus disease 2019, on average, did not produce significant increases in oxygenation metrics. However, a group of patients had significant improvement with inhaled epoprostenol and inhaled nitric oxide. Administration of inhaled epoprostenol or inhaled nitric oxide may be considered in patients with severe respiratory failure secondary to coronavirus disease 2019.

Inflammatory Biomarker Trends Predict Respiratory Decline in COVID-19 Patients.

In this single-center, retrospective cohort analysis of hospitalized coronavirus disease 2019 (COVID-19) patients, we investigate whether inflammatory biomarker levels predict respiratory decline in patients who initially present with stable disease. Examination of C-reactive protein (CRP) trends reveals that a rapid rise in CRP levels precedes respiratory deterioration and intubation, although CRP levels plateau in patients who remain stable. Increasing CRP during the first 48 h of hospitalization is a better predictor (with higher sensitivity) of respiratory decline than initial CRP levels or ROX indices (a physiological score of respiratory function). CRP, the proinflammatory cytokine interleukin-6 (IL-6), and physiological measures of hypoxemic respiratory failure are correlated, which suggests a mechanistic link. Our work shows that rising CRP predicts subsequent respiratory deterioration in COVID-19 and may suggest mechanistic insight and a potential role for targeted immunomodulation in a subset of patients early during hospitalization.

Early clinical and sociodemographic experience with patients hospitalized with COVID-19 at a large American healthcare system.

BACKGROUND: Despite over 4 million cases of novel coronavirus disease 2019 (COVID-19) in the United States, limited data exist including socioeconomic background and post-discharge outcomes for patients hospitalized with this disease. METHODS: In this case series, we identified patients with COVID-19 admitted to 3 Partners Healthcare hospitals in Boston, Massachusetts between March 7th, 2020, and March 30th, 2020. Patient characteristics, treatment strategies, and outcomes were determined. FINDINGS: A total of 247 patients hospitalized with COVID-19 were identified; the median age was 61 (interquartile range [IQR]: 50-76 years), 58% were men, 30% of Hispanic ethnicity, 21% enrolled in Medicaid, and 12% dual-enrolled Medicare/Medicaid. The median estimated household income was $66,701 [IQR: $50,336-$86,601]. Most patients were treated with hydroxychloroquine (72%), and statins (76%; newly initiated in 34%). During their admission, 103 patients (42%) required intensive care. At the end of the data collection period (June 24, 2020), 213 patients (86.2%) were discharged alive, 2 patients (0.8%) remain admitted, and 32 patients (13%) have died. Among those discharged alive (n = 213), 70 (32.9%) were discharged to a post-acute facility, 31 (14.6%) newly required supplemental oxygen, 19 (8.9%) newly required tube feeding, and 34 (16%) required new prescriptions for antipsychotics, benzodiazepines, methadone, or opioids. Over a median post-discharge follow-up of 80 days (IQR, 68-84), 22 patients (10.3%) were readmitted. INTERPRETATION: Patients hospitalized with COVID-19 are frequently of vulnerable socioeconomic status and often require intensive care. Patients who survive COVID-19 hospitalization have substantial need for post-acute services.

Semi-quantitative visual assessment of chest radiography is associated with clinical outcomes in critically ill patients.

BACKGROUND: Respiratory pathology is a major driver of mortality in the intensive care unit (ICU), even in the absence of a primary respiratory diagnosis. Prior work has demonstrated that a visual scoring system applied to chest radiographs (CXR) is associated with adverse outcomes in ICU patients with Acute Respiratory Distress Syndrome (ARDS). We hypothesized that a simple, semi-quantitative CXR score would be associated with clinical outcomes for the general ICU population, regardless of underlying diagnosis. METHODS: All individuals enrolled in the Registry of Critical Illness at Brigham and Women's Hospital between June 2008 and August 2018 who had a CXR within 24 h of admission were included. Each patient's CXR was assigned an opacification score of 0-4 in each of four quadrants with the total score being the sum of all four quadrants. Multivariable negative binomial, logistic, and Cox regression, adjusted for age, sex, race, immunosuppression, a history of chronic obstructive pulmonary disease, a history of congestive heart failure, and APACHE II scores, were used to assess the total score's association with ICU length of stay (LOS), duration of mechanical ventilation, in-hospital mortality, 60-day mortality, and overall mortality, respectively. RESULTS: A total of 560 patients were included. Higher CXR scores were associated with increased mortality; for every one-point increase in score, in-hospital mortality increased 10% (OR 1.10, CI 1.05-1.16, p < 0.001) and 60-day mortality increased by 12% (OR 1.12, CI 1.07-1.17, p < 0.001). CXR scores were also independently associated with both ICU length of stay (rate ratio 1.06, CI 1.04-1.07, p < 0.001) and duration of mechanical ventilation (rate ratio 1.05, CI 1.02-1.07, p < 0.001). CONCLUSIONS: Higher values on a simple visual score of a patient's CXR on admission to the medical ICU are associated with increased in-hospital mortality, 60-day mortality, overall mortality, length of ICU stay, and duration of mechanical ventilation.

Compliance With the National SEP-1 Quality Measure and Association With Sepsis Outcomes: A Multicenter Retrospective Cohort Study.

OBJECTIVES: Many septic patients receive care that fails the Centers for Medicare and Medicaid Services' SEP-1 measure, but it is unclear whether this reflects meaningful lapses in care, differences in clinical characteristics, or excessive rigidity of the "all-or-nothing" measure. We compared outcomes in cases that passed versus failed SEP-1 during the first 2 years after the measure was implemented. DESIGN: Retrospective cohort study. SETTING: Seven U.S. hospitals. PATIENTS: Adult patients included in SEP-1 reporting between October 2015 and September 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 851 sepsis cases in the cohort, 281 (33%) passed SEP-1 and 570 (67%) failed. SEP-1 failures had higher rates of septic shock (20% vs 9%; p < 0.001), hospital-onset sepsis (11% vs 4%; p = 0.001), and vague presenting symptoms (46% vs 30%; p < 0.001). The most common reasons for failure were omission of 3- and 6-hour lactate measurements (228/570 failures, 40%). Only 86 of 570 failures (15.1%) had greater than 3-hour delays until broad-spectrum antibiotics. Cases that failed SEP-1 had higher in-hospital mortality rates (18.4% vs 11.0%; odds ratio, 1.82; 95% CI, 1.19-2.80; p = 0.006), but this association was no longer significant after adjusting for differences in clinical characteristics and severity of illness (adjusted odds ratio, 1.36; 95% CI, 0.85-2.18; p = 0.205). Delays of greater than 3 hours until antibiotics were significantly associated with death (adjusted odds ratio, 1.94; 95% CI, 1.04-3.62; p = 0.038), whereas failing SEP-1 for any other reason was not (adjusted odds ratio, 1.10; 95% CI, 0.70-1.72; p = 0.674). CONCLUSIONS: Crude mortality rates were higher in sepsis cases that failed versus passed SEP-1, but there was no difference after adjusting for clinical characteristics and severity of illness. Delays in antibiotic administration were associated with higher mortality but only accounted for a small fraction of SEP-1 failures. SEP-1 may not clearly differentiate between high- and low-quality care, and detailed risk adjustment is necessary to properly interpret associations between SEP-1 compliance and mortality.

Variability in determining sepsis time zero and bundle compliance rates for the centers for medicare and medicaid services SEP-1 measure.

We compared sepsis "time zero" and Centers for Medicare and Medicaid Services (CMS) SEP-1 pass rates among 3 abstractors in 3 hospitals. Abstractors agreed on time zero in 29 of 80 (36%) cases. Perceived pass rates ranged from 9 of 80 cases (11%) to 19 of 80 cases (23%). Variability in time zero and perceived pass rates limits the utility of SEP-1 for measuring quality.

User-Centered Collaborative Design and Development of an Inpatient Safety Dashboard.

Patient safety remains a key concern in hospital care. This article summarizes the iterative participatory development, features, functions, and preliminary evaluation of a patient safety dashboard for interdisciplinary rounding teams on inpatient medical services. This electronic health record (EHR)-embedded dashboard collects real-time data covering 13 safety domains through web services and applies logic to generate stratified alerts with an interactive check-box function. The technological infrastructure is adaptable to other EHR environments. Surveyed users perceived the tool as highly usable and useful. Integration of the dashboard into clinical care is intended to promote communication about patient safety and facilitate identification and management of safety concerns.

Conversations About Goals and Values Are Feasible and Acceptable in Long-Term Acute Care Hospitals: A Pilot Study.

RATIONALE: The chronically critically ill have survived acute critical illness but require prolonged mechanical ventilation. These patients are frequently transferred from acute care to long-term acute care hospitals (LTACHs) for prolonged recovery, yet many suffer setbacks requiring readmission to acute care. The patient's relatively improved condition while at the LTACH might be an opportunity for communication regarding care goals; however, there have been no prior studies of the feasibility of such conversations in the LTACH. OBJECTIVES: To determine the feasibility, acceptability, and potential usefulness of conversations about serious illness with chronic critical illness patients or their surrogate decision makers after LTACH admission. METHODS: We adapted an existing conversation guide for use in chronically critically ill (defined by tracheotomy for prolonged ventilation) LTACH patients or their surrogates to explore views about quality of life, understanding of medical conditions, expectations, and planning for setbacks. These conversations were conducted by one interviewer and summarized for the patients' clinicians. We surveyed patients, surrogates, and clinicians to assess acceptability. MEASUREMENT AND MAIN RESULTS: A total of 70 subjects were approached and 50 (71%) were enrolled, including 30 patients and 20 surrogates. The median duration of the conversation was 14 minutes 45 seconds [IQR 12:46, 19]. The presence of ongoing mechanical ventilation did not lead to longer conversations; in fact, conversations with patients were shorter than those with surrogates. The majority of subjects (81%) described the conversation as worthwhile. The majority of clinicians (73%) reported that the conversation offered a new and significant understanding of the patient's preferences if a setback were to occur. CONCLUSIONS: Conversations about serious illness care goals can be accomplished in a relatively short period of time, are acceptable to chronically critically ill patients and their surrogate decision makers in the LTACH, and are perceived as worthwhile by patients, surrogates, and clinicians.

Opening the Door: The Experience of Chronic Critical Illness in a Long-Term Acute Care Hospital.

OBJECTIVE: Chronically critically ill patients have recurrent infections, organ dysfunction, and at least half die within 1 year. They are frequently cared for in long-term acute care hospitals, yet little is known about their experience in this setting. Our objective was to explore the understanding and expectations and goals of these patients and surrogates. DESIGN: We conducted semi-structured interviews with chronically critically ill long-term acute care hospital patients or surrogates. Conversations were recorded, transcribed, and analyzed. SETTING: One long-term acute care hospital. SUBJECTS: Chronically critically ill patients, defined by tracheotomy for prolonged mechanical ventilation, or surrogates. INTERVENTION: Semi-structured conversation about quality of life, expectations, and planning for setbacks. MEASUREMENTS AND MAIN RESULTS: A total of 50 subjects (30 patients and 20 surrogates) were enrolled. Thematic analyses demonstrated: 1) poor quality of life for patients; 2) surrogate stress and anxiety; 3) optimistic health expectations; 4) poor planning for medical setbacks; and 5) disruptive care transitions. Nearly 80% of patient and their surrogate decision makers identified going home as a goal; 38% were at home at 1 year. CONCLUSIONS: Our study describes the experience of chronically critically ill patients and surrogates in an long-term acute care hospital and the feasibility of patient-focused research in this setting. Our findings indicate overly optimistic expectations about return home and unmet palliative care needs, suggesting the need for integration of palliative care within the long-term acute care hospital. Further research is also needed to more fully understand the challenges of this growing population of ICU survivors.

Associations Between Ventilator Bundle Components and Outcomes.

IMPORTANCE: Ventilator bundles, including head-of-bed elevation, sedative infusion interruptions, spontaneous breathing trials, thromboprophylaxis, stress ulcer prophylaxis, and oral care with chlorhexidine gluconate, are ubiquitous, but the absolute and relative value of each bundle component is unclear. OBJECTIVE: To evaluate associations between individual and collective ventilator bundle components and ventilator-associated events, time to extubation, ventilator mortality, time to hospital discharge, and hospital death. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included all 5539 consecutive patients who underwent mechanical ventilation for at least 3 days from January 1, 2009, to December 31, 2013, at Brigham and Women's Hospital. EXPOSURES: Head-of-bed elevation, sedative infusion interruptions, spontaneous breathing trials, thromboprophylaxis, stress ulcer prophylaxis, and oral care with chlorhexidine. MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) for ventilator-associated events, extubation alive vs ventilator mortality, and hospital discharge vs hospital death. Effects were modeled using Cox proportional hazards regression and Fine-Gray competing risk models adjusted for patients' demographic characteristics, comorbidities, unit type, severity of illness, recent procedures, process measure contraindications, day-to-day markers of clinical status, and calendar year. RESULTS: Of 5539 consecutive patients undergoing mechanical ventilation, 3208 were male (57.9%), 2331 female (42.1%), and the mean (SD) age was 61.2 (16.1) years. Sedative infusion interruptions were associated with less time to extubation (HR, 1.81; 95% CI, 1.54-2.12; P < .001) and a lower hazard for ventilator mortality (HR, 0.51, 95% CI, 0.38-0.68; P < .001). Similar associations were found for spontaneous breathing trials (HR for extubation, 2.48; 95% CI 2.23-2.76; P < .001; HR for mortality, 0.28; 95% CI, 0.20-0.38; P = .001). Spontaneous breathing trials were also associated with lower hazards for ventilator-associated events (HR, 0.55; 95% CI, 0.40-0.76; P < .001). Associations with less time to extubation were found for head-of-bed elevation (HR, 1.38, 95% CI, 1.14-1.68; P = .001) and thromboembolism prophylaxis (HR, 2.57; 95% CI, 1.80-3.66; P < .001) but not ventilator mortality. Oral care with chlorhexidine was associated with an increased risk for ventilator mortality (HR, 1.63; 95% CI, 1.15-2.31; P = .006), and stress ulcer prophylaxis was associated with an increased risk for ventilator-associated pneumonia (HR, 7.69; 95% CI, 1.44-41.10; P = .02). CONCLUSIONS AND RELEVANCE: Standard ventilator bundle components vary in their associations with patient-centered outcomes. Head-of-bed elevation, sedative infusion interruptions, spontaneous breathing trials, and thromboembolism prophylaxis appear beneficial, whereas daily oral care with chlorhexidine and stress ulcer prophylaxis may be harmful in some patients.

Diagnosing sepsis is subjective and highly variable: a survey of intensivists using case vignettes.

BACKGROUND: Sepsis is the focus of national quality improvement programs and a recent public reporting measure from the Centers for Medicare and Medicaid Services. However, diagnosing sepsis requires interpreting nonspecific signs and can therefore be subjective. We sought to quantify interobserver variability in diagnosing sepsis. METHODS: We distributed five case vignettes of patients with suspected or confirmed infection and organ dysfunction to a sample of practicing intensivists. Respondents classified cases as systemic inflammatory response syndrome, sepsis, severe sepsis, septic shock, or none of the above. Interobserver variability was calculated using Fleiss' κ for the five-level classification, and for answers dichotomized as severe sepsis/septic shock versus not-severe sepsis/septic shock and any sepsis category (sepsis, severe sepsis, or septic shock) versus not-sepsis. RESULTS: Ninety-four physicians completed the survey. Most respondents (88%) identified as critical care specialists; other specialties included pulmonology (39%), anesthesia (19%), surgery (9%), and emergency medicine (9%). Respondents had been in practice for a median of 8 years, and 90% practiced at academic hospitals. Almost all respondents (83%) felt strongly or somewhat confident in their ability to apply the traditional consensus sepsis definitions. However, overall interrater agreement in sepsis diagnoses was poor (Fleiss' κ 0.29). When responses were dichotomized into severe sepsis/septic shock versus not-severe sepsis/septic shock or any sepsis category versus not-sepsis, agreement was still poor (Fleiss' κ 0.23 and 0.18, respectively). Seventeen percent of respondents classified one of the five cases as severe sepsis/septic shock, 27.7% rated two cases, 33.0% respondents rated three cases, 19.2% rated four cases, and 3.2% rated all five cases as severe sepsis/septic shock. Among respondents who felt strongly confident in their ability to use sepsis definitions (n = 45), agreement was no better (Fleiss' κ 0.28 for the five-category classification, and Fleiss' κ 0.21 for the dichotomized severe sepsis/septic shock classification). Cases were felt to be extremely or very realistic in 74% of responses; only 3% were deemed unrealistic. CONCLUSIONS: Diagnosing sepsis is extremely subjective and variable. Objective criteria and standardized methodology are needed to enhance consistency and comparability in sepsis research, surveillance, benchmarking, and reporting.

Strategies for Managing Mobile Devices for Use by Hospitalized Inpatients.

Despite the potential advantages, implementation of mobile devices and ongoing management pose challenges in the hospital environment. Our team implemented the PROSPECT (Promoting Respect and Ongoing Safety through Patient-centeredness, Engagement, Communication and Technology) project at Brigham and Women's Hospital. The goal of PROSPECT is to transform the hospital environment by providing a suite of e-tools to facilitate teamwork among nurses, physicians, patients and to engage patients and care partners in their plan of care. In this paper, we describe the device-related decisions and challenges faced including device and accessory selection, integration, information and device security, infection control, user access, and ongoing operation and maintenance. We relate the strategies that we used for managing mobile devices and lessons learned based on our experiences.

Integrative "omic" analysis of experimental bacteremia identifies a metabolic signature that distinguishes human sepsis from systemic inflammatory response syndromes.

RATIONALE: Sepsis is a leading cause of morbidity and mortality. Currently, early diagnosis and the progression of the disease are difficult to make. The integration of metabolomic and transcriptomic data in a primate model of sepsis may provide a novel molecular signature of clinical sepsis. OBJECTIVES: To develop a biomarker panel to characterize sepsis in primates and ascertain its relevance to early diagnosis and progression of human sepsis. METHODS: Intravenous inoculation of Macaca fascicularis with Escherichia coli produced mild to severe sepsis, lung injury, and death. Plasma samples were obtained before and after 1, 3, and 5 days of E. coli challenge and at the time of killing. At necropsy, blood, lung, kidney, and spleen samples were collected. An integrative analysis of the metabolomic and transcriptomic datasets was performed to identify a panel of sepsis biomarkers. MEASUREMENTS AND MAIN RESULTS: The extent of E. coli invasion, respiratory distress, lethargy, and mortality was dependent on the bacterial dose. Metabolomic and transcriptomic changes characterized severe infections and death, and indicated impaired mitochondrial, peroxisomal, and liver functions. Analysis of the pulmonary transcriptome and plasma metabolome suggested impaired fatty acid catabolism regulated by peroxisome-proliferator activated receptor signaling. A representative four-metabolite model effectively diagnosed sepsis in primates (area under the curve, 0.966) and in two human sepsis cohorts (area under the curve, 0.78 and 0.82). CONCLUSIONS: A model of sepsis based on reciprocal metabolomic and transcriptomic data was developed in primates and validated in two human patient cohorts. It is anticipated that the identified parameters will facilitate early diagnosis and management of sepsis.

Participatory Design and Development of a Patient-centered Toolkit to Engage Hospitalized Patients and Care Partners in their Plan of Care.

Patient engagement has been identified as a key strategy for improving patient outcomes. In this paper, we describe the development and pilot testing of a web-based patient centered toolkit (PCTK) prototype to improve access to health information and to engage hospitalized patients and caregivers in the plan of care. Individual and group interviews were used to identify plan of care functional and workflow requirements and user interface design enhancements. Qualitative methods within a participatory design approach supported the development of a PCTK prototype that will be implemented on intensive care and oncology units to engage patients and professional care team members developing their plan of care during an acute hospitalization.

An integrated clinico-metabolomic model improves prediction of death in sepsis.

Sepsis is a common cause of death, but outcomes in individual patients are difficult to predict. Elucidating the molecular processes that differ between sepsis patients who survive and those who die may permit more appropriate treatments to be deployed. We examined the clinical features and the plasma metabolome and proteome of patients with and without community-acquired sepsis, upon their arrival at hospital emergency departments and 24 hours later. The metabolomes and proteomes of patients at hospital admittance who would ultimately die differed markedly from those of patients who would survive. The different profiles of proteins and metabolites clustered into the following groups: fatty acid transport and ß-oxidation, gluconeogenesis, and the citric acid cycle. They differed consistently among several sets of patients, and diverged more as death approached. In contrast, the metabolomes and proteomes of surviving patients with mild sepsis did not differ from survivors with severe sepsis or septic shock. An algorithm derived from clinical features together with measurements of five metabolites predicted patient survival. This algorithm may help to guide the treatment of individual patients with sepsis.

Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation.

BACKGROUND: Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. METHODS AND FINDINGS: Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. CONCLUSIONS: Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.

Inflammasome-regulated cytokines are critical mediators of acute lung injury.

RATIONALE: Despite advances in clinical management, there are currently no reliable diagnostic and therapeutic targets for acute respiratory distress syndrome (ARDS). The inflammasome/caspase-1 pathway regulates the maturation and secretion of proinflammatory cytokines (e.g., IL-18). IL-18 is associated with injury in animal models of systemic inflammation. OBJECTIVES: We sought to determine the contribution of the inflammasome pathway in experimental acute lung injury and human ARDS. METHODS: We performed comprehensive gene expression profiling on peripheral blood from patients with critical illness. Gene expression changes were assessed using real-time polymerase chain reaction, and IL-18 levels were measured in the plasma of the critically ill patients. Wild-type mice or mice genetically deficient in IL-18 or caspase-1 were mechanically ventilated using moderate tidal volume (12 ml/kg). Lung injury parameters were assessed in lung tissue, serum, and bronchoalveolar lavage fluid. MEASUREMENTS AND MAIN RESULTS: In mice, mechanical ventilation enhanced IL-18 levels in the lung, serum, and bronchoalveolar lavage fluid. IL-18-neutralizing antibody treatment, or genetic deletion of IL-18 or caspase-1, reduced lung injury in response to mechanical ventilation. In human patients with ARDS, inflammasome-related mRNA transcripts (CASP1, IL1B, and IL18) were increased in peripheral blood. In samples from four clinical centers, IL-18 was elevated in the plasma of patients with ARDS (sepsis or trauma-induced ARDS) and served as a novel biomarker of intensive care unit morbidity and mortality. CONCLUSIONS: The inflammasome pathway and its downstream cytokines play critical roles in ARDS development.

Evaluation of a local ICU sedation guideline on goal-directed administration of sedatives and analgesics.

PURPOSE: Sedatives and analgesics are commonly used in mechanically ventilated patients in the intensive care unit. Sedation guidelines have been shown to improve sedation management as well as various patient outcomes. The main objective was to evaluate adherence to a sedation guideline with both sedative prescribing and documentation of Richmond Agitation-Sedation Scale (RASS) scores. METHODS: In a retrospective chart review, data was collected on 111 medical intensive care unit patients mechanically ventilated via endotracheal tube for 12 hours or greater at Brigham and Women's Hospital. Fifty-seven patients were evaluated pre-guideline implementation and 54 patients were evaluated post-guideline. RESULTS: Significant increases were seen in the post-guideline group in goal-directed sedation with a patient-specific RASS goal in the sedation order: 21.3 vs 85.4% (P < 0.001), and mean number of sedation assessments per 24 hours using the RASS: 4.7 vs 11.4 (P < 0.001). Similarly, this group experienced a higher percentage of RASS scores at their sedation goal: 31.4 vs 44.1% (P < 0.001). No difference was seen in other clinical endpoints. CONCLUSION: Implementation and routine application of a hospital pain and sedation guideline was associated with significantly improved sedation metrics, such as goal-directed sedation, as well as frequency of sedation level assessment and documentation. An increase was observed in the time that post-guideline patients spent at or near their RASS goal.