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In an analysis including nearly 50,000 patients with sepsis treated at 149 New York hospitals, more rapid delivery of a 3-hour sepsis-care bundle (a protocol recommending blood cultures, broad-spectrum antibiotics, and lactate measurement within 3 hours) was associated with lower mortality. More than 1.5 million cases of sepsis occur in the United States annually, and many patients with sepsis present to the emergency department. 1 International clinical practice guidelines and the Centers for Medicare and Medicaid Services (CMS) recommend the prompt identification of sepsis and treatment with broad-spectrum antibiotic agents and intravenous fluids. 2 , 3 These recommendations are supported by preclinical and observational studies suggesting that early treatment with antibiotics and intravenous fluids could reduce the number of avoidable deaths. 4 , 5 Yet, considerable controversy exists about how rapidly sepsis must be treated. 6 Some clinicians question the potential benefit of rapid treatment, citing the . . .

Intensive care survivors often experience post-intensive care sequelae, which are frequently gathered together under the term “post-intensive care syndrome” (PICS). The consequences of PICS on quality of life, health-related costs and hospital readmissions are real public health problems. In the present Viewpoint, we summarize current knowledge and gaps in our understanding of PICS and approaches to management.

Alongside advances in understanding the pathophysiology of sepsis, there have been tremendous strides in understanding the pervasive role of the gut microbiota in systemic host resistance. In pre-clinical models, a diverse and balanced gut microbiota enhances host immunity to both enteric and systemic pathogens. Disturbance of this balance increases susceptibility to sepsis and sepsis-related organ dysfunction, while restoration of the gut microbiome is protective. Patients with sepsis have a profoundly distorted composition of the intestinal microbiota, but the impact and therapeutic potential of the microbiome is not well-established in human sepsis. Modulation of the microbiota consists of either resupplying the pool of beneficial microbes by administration of probiotics, improving the intestinal microenvironment to enhance the growth of beneficial species by dietary interventions and prebiotics, or by totally recolonizing the gut with a fecal microbiota transplantation (FMT). We propose that there are three potential opportunities to utilize these treatment modalities over the course of sepsis: to decrease sepsis incidence, to improve sepsis outcome, and to decrease late mortality after sepsis. Exploring these three avenues will provide insight into how disturbances of the microbiota can predispose to, or even perpetuate the dysregulated immune response associated with this syndrome, which in turn could be associated with improved sepsis management.

Both quality improvement and clinical research efforts over the past few decades have focused on consensus definition of sepsis and acute respiratory distress syndrome (ARDS). Although clinical definitions based on readily available clinical data have advanced recognition and timely use of broad supportive treatments, they likely hinder the identification of more targeted therapies that manipulate select biological mechanisms underlying critical illness. Sepsis and ARDS are by definition heterogeneous, and patients vary in both their underlying biology and their severity of illness. We have long been able to identify subtypes of sepsis and ARDS that confer different prognoses. The key is that we are now on the verge of identifying subtypes that may confer different response to therapy. In this perspective, inspired by a 2015 American Thoracic Society International Conference Symposium entitled \"Lumpers and Splitters: Phenotyping in Critical Illness,\" we highlight promising approaches to uncovering patient subtypes that may predict treatment responsiveness and not just differences in prognosis. We then discuss how this information can be leveraged to improve the success and translatability of clinical trials by using predictive enrichment and other design strategies. Last, we discuss the challenges and limitations to identifying biomarkers and endotypes and incorporating them into routine clinical practice.

Hospitalizations for severe sepsis are common, and a growing number of patients survive to hospital discharge. Nonetheless, little is known about survivors' post-discharge healthcare use. To measure inpatient healthcare use of severe sepsis survivors compared with patients' own presepsis resource use and the resource use of survivors of otherwise similar nonsepsis hospitalizations. This is an observational cohort study of survivors of severe sepsis and nonsepsis hospitalizations identified from participants in the Health and Retirement Study with linked Medicare claims, 1998-2005. We matched severe sepsis and nonsepsis hospitalizations by demographics, comorbidity burden, premorbid disability, hospitalization length, and intensive care use. Using Medicare claims, we measured patients' use of inpatient facilities (hospitals, long-term acute care hospitals, and skilled nursing facilities) in the 2 years surrounding hospitalization. Severe sepsis survivors spent more days (median, 16 [interquartile range, 3-45] vs. 7 [0-29]; P < 0.001) and a higher proportion of days alive (median, 9.6% [interquartile range, 1.4-33.8%] vs. 1.9% [0.0-7.9%]; P < 0.001) admitted to facilities in the year after hospitalization, compared with the year prior. The increase in facility-days was similar for nonsepsis hospitalizations. However, the severe sepsis cohort experienced greater post-discharge mortality (44.2% [95% confidence interval, 41.3-47.2%] vs. 31.4% [95% confidence interval, 28.6-34.2%] at 1 year), a steeper decline in days spent at home (difference-in-differences, -38.6 d [95% confidence interval, -50.9 to 26.3]; P < 0.001), and a greater increase in the proportion of days alive spent in a facility (difference-in-differences, 5.4% [95% confidence interval, 2.8-8.1%]; P < 0.001). Healthcare use is markedly elevated after severe sepsis, and post-discharge management may be an opportunity to reduce resource use.

Randomized clinical trials (RCTs) are conducted to guide clinicians' selection of therapies for individual patients. Currently, RCTs in critical care often report an overall mean effect and selected individual subgroups. Yet work in other fields suggests that such reporting practices can be improved. Specifically, this Critical Care Perspective reviews recent work on so-called \"heterogeneity of treatment effect\" (HTE) by baseline risk and extends that work to examine its applicability to trials of acute respiratory failure and severe sepsis. Because patients in RCTs in critical care medicine-and patients in intensive care units-have wide variability in their risk of death, these patients will have wide variability in the absolute benefit that they can derive from a given therapy. If the side effects of the therapy are not perfectly collinear with the treatment benefits, this will result in HTE, where different patients experience quite different expected benefits of a therapy. We use simulations of RCTs to demonstrate that such HTE could result in apparent paradoxes, including: (1) positive trials of therapies that are beneficial overall but consistently harm or have little benefit to low-risk patients who met enrollment criteria, and (2) overall negative trials of therapies that still consistently benefit high-risk patients. We further show that these results persist even in the presence of causes of death unmodified by the treatment under study. These results have implications for reporting and analyzing RCT data, both to better understand how our therapies work and to improve the bedside applicability of RCTs. We suggest a plan for measurement in future RCTs in the critically ill.

Background Acute hypoxemic respiratory failure (AHRF) and acute respiratory distress syndrome (ARDS) are associated with high in-hospital mortality. However, in cohorts of ARDS patients from the 1990s, patients more commonly died from sepsis or multi-organ failure rather than refractory hypoxemia. Given increased attention to lung-protective ventilation and sepsis treatment in the past 25 years, we hypothesized that causes of death may be different among contemporary cohorts. These differences may provide clinicians with insight into targets for future therapeutic interventions. Methods We identified adult patients hospitalized at a single tertiary care center (2016–2017) with AHRF, defined as PaO 2 /FiO 2 ≤ 300 while receiving invasive mechanical ventilation for > 12 h, who died during hospitalization. ARDS was adjudicated by multiple physicians using the Berlin definition. Separate abstractors blinded to ARDS status collected data on organ dysfunction and withdrawal of life support using a standardized tool. The primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support. Results We identified 385 decedents with AHRF, of whom 127 (33%) had ARDS. The most common primary causes of death were sepsis (26%), pulmonary dysfunction (22%), and neurologic dysfunction (19%). Multi-organ failure was present in 70% at time of death, most commonly due to sepsis (50% of all patients), and 70% were on significant respiratory support at the time of death. Only 2% of patients had insupportable oxygenation or ventilation. Eighty-five percent died following withdrawal of life support. Patients with ARDS more often had pulmonary dysfunction as the primary cause of death (28% vs 19%; p  = 0.04) and were also more likely to die while requiring significant respiratory support (82% vs 64%; p  <  0.01). Conclusions In this contemporary cohort of patients with AHRF, the most common primary causes of death were sepsis and pulmonary dysfunction, but few patients had insupportable oxygenation or ventilation. The vast majority of deaths occurred after withdrawal of life support. ARDS patients were more likely to have pulmonary dysfunction as the primary cause of death and die while requiring significant respiratory support compared to patients without ARDS.

In observational studies of the general population, higher body mass index (BMI) has been associated with increased incidence of and mortality from bloodstream infection (BSI) and sepsis. On the other hand, higher BMI has been observed to be apparently protective among patients with infection and sepsis. We aimed to evaluate the causal association of BMI with risk of and mortality from BSI. We used a population-based cohort in Norway followed from 1995 to 2017 (the Trøndelag Health Study [HUNT]), and carried out linear and nonlinear Mendelian randomization analyses. Among 55,908 participants, the mean age at enrollment was 48.3 years, 26,324 (47.1%) were men, and mean BMI was 26.3 kg/m2. During a median 21 years of follow-up, 2,547 (4.6%) participants experienced a BSI, and 451 (0.8%) died from BSI. Compared with a genetically predicted BMI of 25 kg/m2, a genetically predicted BMI of 30 kg/m2 was associated with a hazard ratio for BSI incidence of 1.78 (95% CI: 1.40 to 2.27; p < 0.001) and for BSI mortality of 2.56 (95% CI: 1.31 to 4.99; p = 0.006) in the general population, and a hazard ratio for BSI mortality of 2.34 (95% CI: 1.11 to 4.94; p = 0.025) in an inverse-probability-weighted analysis of patients with BSI. Limitations of this study include a risk of pleiotropic effects that may affect causal inference, and that only participants of European ancestry were considered. Supportive of a causal relationship, genetically predicted BMI was positively associated with BSI incidence and mortality in this cohort. Our findings contradict the \"obesity paradox,\" where previous traditional epidemiological studies have found increased BMI to be apparently protective in terms of mortality for patients with BSI or sepsis.

Background In patients with acute respiratory distress syndrome undergoing mechanical ventilation, positive end-expiratory pressure (PEEP) can lead to recruitment or overdistension. Current strategies utilized for PEEP titration do not permit the distinction. Electric impedance tomography (EIT) detects and quantifies the presence of both collapse and overdistension. We investigated whether using EIT-guided PEEP titration leads to decreased mechanical power compared to high-PEEP/FiO2 tables. Methods A single-center, randomized crossover pilot trial comparing EIT-guided PEEP selection versus PEEP selection using the High-PEEP/FiO 2 table in patients with moderate–severe acute respiratory distress syndrome. The primary outcome was the change in mechanical power after each PEEP selection strategy. Secondary outcomes included changes in the 4 × driving pressure + respiratory rate (4 ΔP, + RR index) index, driving pressure, plateau pressure, PaO 2 /FiO 2 ratio, and static compliance. Results EIT was consistently associated with a decrease in mechanical power compared to PEEP/FiO 2 tables (mean difference − 4.36 J/min, 95% CI − 6.7, − 1.95, p  = 0.002) and led to lower values in the 4ΔP + RR index (− 11.42 J/min, 95% CI − 19.01, − 3.82, p  = 0.007) mainly driven by a decrease in the elastic–dynamic power (− 1.61 J/min, − 2.99, − 0.22, p  = 0.027). The elastic–static and resistive powers were unchanged. Similarly, EIT led to a statistically significant change in set PEEP (− 2 cmH 2 O, p  = 0.046), driving pressure, (− 2.92 cmH2O, p  = 0.003), peak pressure (− 6.25 cmH 2 O, p  = 0.003), plateau pressure (− 4.53 cmH 2 O, p  = 0.006), and static respiratory system compliance (+ 7.93 ml/cmH 2 O, p  = 0.008). Conclusions In patients with moderate–severe acute respiratory distress syndrome, EIT-guided PEEP titration reduces mechanical power mainly through a reduction in elastic–dynamic power. Trial registration This trial was prospectively registered on Clinicaltrials.gov (NCT 03793842) on January 4th, 2019.

Importance To understand if the evaluation of incidental pulmonary nodules that follows an evidence-based management strategy is associated with fewer invasive procedures for benign lesions and/or fewer delays in cancer diagnosis. Retrospective cohort study. Large academic medical center. Adults ([greater than or equal to]18 years age) with an incidental pulmonary nodule discovered between January 2012 and December 2014. Patients with calcified nodules, prior nodules, prior diagnosis of cancer, high suspicion for pulmonary metastasis, or limited life expectancy were excluded. Of 314 patients that met inclusion criteria, median age was 61, 46.5% were men, and 66.5% had current or former tobacco use. The mean nodule size was 10.3 mm, mean probability of cancer was 11.8%, and 14.3% of nodules were malignant. Evaluation followed an evidence-based strategy in 245 patients (78.0%), and deviated in 69 patients (22%). The composite outcome occurred in 26 (8.3%) patients. Among patients whose nodule evaluation was concordant with an evidence-based evaluation, 6.1% (15/245) experienced the composite outcome versus 15.9% (11/69) of patients with an evaluation that deviated from evidence-based recommendations (P<0.01). At a large academic medical center, more than 1 in 5 patients with an incidental pulmonary nodule underwent evaluation that deviated from evidence-based practice recommendations. Nodule evaluation that deviated from an evidence-based strategy was associated with biopsy of benign lesions and delays in cancer diagnosis, suggesting a need to improve guideline uptake.