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.
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.
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.
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.
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.
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.
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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 (β2-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.
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.
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.
We sought to determine the contribution of the inflammasome pathway in experimental acute lung injury and human ARDS.
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.
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.
The inflammasome pathway and its downstream cytokines play critical roles in ARDS development.
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.
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Rising CRP levels predict intubation in COVID-19 inpatients stable at admissionEarly CRP trend outperforms initial CRP level in prediction of respiratory failureCRP trend outperforms a physiological index (ROX) in prediction of respiratory failureCRP and IL-6 levels correlate with each other and with hypoxemia (PaO2/FiO2)
Mueller et al. demonstrate in hospitalized COVID-19 patients that trending C-reactive protein (CRP), an inflammatory biomarker, is a simple and accessible strategy for predicting respiratory deterioration. An early rise in CRP predicts intubation, and CRP levels correlate with IL-6 levels and physiological measures of hypoxemic respiratory failure.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PURPOSE: We sought to determine the effects of a communication process that was designed to encourage the use of advanced supportive technology when it is of benefit, but to limit its burdens when it ...is ineffective. We compared usual care with a proactive, multidisciplinary method of communicating that prospectively identified for patients and families the criteria that would determine whether a care plan was effective at meeting the goals of the patient. This process allowed caregivers to be informed of patient preferences about continued advanced supportive technology when its continuation would result in a compromised functional outcome or death.
MATERIALS AND METHODS: We performed a before-and-after study in 530 adult medical patients who were consecutively admitted to a university tertiary care hospital for intensive care. Multidisciplinary meetings were held within 72 hours of critical care admission. Patients, families, and the critical care team discussed the care plan and the patients’ goals and expectations for the outcome of critical care. Clinical “milestones” indicative of recovery were identified with time frames for their occurrence. Follow-up meetings were held to discuss palliative care options when continued advanced supportive technology was not achieving the patient’s goals. We measured length of stay, mortality, and provider team and family consensus in 134 patients before the intensive communication intervention and in 396 patients after the intervention.
RESULTS: Intensive communication significantly reduced the median length of stay from 4 days (interquartile range, 2 to 11 days) to 3 days (2 to 6 days,
P = 0.01 by survival analysis). This reduction remained significant after adjustment for acute physiology and chronic health evaluation (APACHE) 3 score risk ratio (RR) = 0.81; 95% confidence interval (CI), 0.66 to 0.99;
P = 0.04). Subgroup analysis revealed that this reduction occurred in our target group, patients with acuity scores in the highest quartile who died (RR = 0.60; 95% CI, 0.38 to 0.92;
P = 0.02). The intervention, which allowed dying patients earlier access to palliative care, was not associated with increased mortality.
CONCLUSIONS: Intensive communication was associated with a reduction in critical care use by patients who died. Our multidisciplinary process targeted advanced supportive technology to patients who survived and allowed the earlier withdrawal of advanced supportive technology when it was ineffective.
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GEOZS, IJS, NUK, OILJ, UL, UM
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