Development and Validation of the Hospital Medicine Safety Sepsis Initiative Mortality Model.

BACKGROUND: When comparing outcomes after sepsis, it is essential to account for patient case mix to make fair comparisons. We developed a model to assess risk-adjusted 30-day mortality in the Michigan Hospital Medicine Safety sepsis initiative (HMS-Sepsis). RESEARCH QUESTION: Can HMS-Sepsis registry data adequately predict risk of 30-day mortality? Do performance assessments using adjusted vs unadjusted data differ? STUDY DESIGN AND METHODS: Retrospective cohort of community-onset sepsis hospitalizations in the HMS-Sepsis registry (April 2022-September 2023), with split derivation (70%) and validation (30%) cohorts. We fit a risk-adjustment model (HMS-Sepsis mortality model) incorporating acute physiologic, demographic, and baseline health data and assessed model performance using concordance (C) statistics, Brier scores, and comparisons of predicted vs observed mortality by deciles of risk. We compared hospital performance (first quintile, middle quintiles, fifth quintile) using observed vs adjusted mortality to understand the extent to which risk adjustment impacted hospital performance assessment. RESULTS: Among 17,514 hospitalizations from 66 hospitals during the study period, 12,260 hospitalizations (70%) were used for model derivation and 5,254 hospitalizations (30%) were used for model validation. Thirty-day mortality for the total cohort was 19.4%. The final model included 13 physiologic variables, two physiologic interactions, and 16 demographic and chronic health variables. The most significant variables were age, metastatic solid tumor, temperature, altered mental status, and platelet count. The model C statistic was 0.82 for the derivation cohort, 0.81 for the validation cohort, and ≥ 0.78 for all subgroups assessed. Overall calibration error was 0.0%, and mean calibration error across deciles of risk was 1.5%. Standardized mortality ratios yielded different assessments than observed mortality for 33.9% of hospitals. INTERPRETATION: The HMS-Sepsis mortality model showed strong discrimination and adequate calibration and reclassified one-third of hospitals to a different performance category from unadjusted mortality. Based on its strong performance, the HMS-Sepsis mortality model can aid in fair hospital benchmarking, assessment of temporal changes, and observational causal inference analysis.

High-Flow Nasal Cannula Versus Noninvasive Ventilation as Initial Treatment in Acute Hypoxia: A Propensity Score-Matched Study.

IMPORTANCE: Patients presenting to the emergency department (ED) with hypoxemia often have mixed or uncertain causes of respiratory failure. The optimal treatment for such patients is unclear. Both high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) are used. OBJECTIVES: We sought to compare the effectiveness of initial treatment with HFNC versus NIV for acute hypoxemic respiratory failure. DESIGN SETTING AND PARTICIPANTS: We conducted a retrospective cohort study of patients with acute hypoxemic respiratory failure treated with HFNC or NIV within 24 hours of arrival to the University of Michigan adult ED from January 2018 to December 2022. We matched patients 1:1 using a propensity score for odds of receiving NIV. MAIN OUTCOMES AND MEASURES: The primary outcome was major adverse pulmonary events (28-d mortality, ventilator-free days, noninvasive respiratory support hours) calculated using a win ratio. RESULTS: A total of 1154 patients were included. Seven hundred twenty-six (62.9%) received HFNC and 428 (37.1%) received NIV. We propensity score matched 668 of 1154 (57.9%) patients. Patients on NIV versus HFNC had lower 28-day mortality (16.5% vs. 23.4%, p = 0.033) and required noninvasive treatment for fewer hours (median 7.5 vs. 13.5, p < 0.001), but had no difference in ventilator-free days (median [interquartile range]: 28 [26, 28] vs. 28 [10.5, 28], p = 0.199). Win ratio for composite major adverse pulmonary events favored NIV (1.38; 95% CI, 1.15-1.65; p < 0.001). CONCLUSIONS AND RELEVANCE: In this observational study of patients with acute hypoxemic respiratory failure, initial treatment with NIV compared with HFNC was associated with lower mortality and fewer composite major pulmonary adverse events calculated using a win ratio. These findings underscore the need for randomized controlled trials to further understand the impact of noninvasive respiratory support strategies.

Understanding How Clinicians Personalize Fluid and Vasopressor Decisions in Early Sepsis Management.

Importance: Recent sepsis trials suggest that fluid-liberal vs fluid-restrictive resuscitation has similar outcomes. These trials used generalized approaches to resuscitation, and little is known about how clinicians personalize fluid and vasopressor administration in practice. Objective: To understand how clinicians personalize decisions about resuscitation in practice. Design, Setting, and Participants: This survey study of US clinicians in the Society of Critical Care Medicine membership roster was conducted from November 2022 to January 2023. Surveys contained 10 vignettes of patients with sepsis where pertinent clinical factors (eg, fluid received and volume status) were randomized. Respondents selected the next steps in management. Data analysis was conducted from February to September 2023. Exposure: Online Qualtrics clinical vignette survey. Main Outcomes and Measures: Using multivariable logistic regression, the associations of clinical factors with decisions about fluid administration, vasopressor initiation, and vasopressor route were tested. Results are presented as adjusted proportions with 95% CIs. Results: Among 11 203 invited clinicians, 550 (4.9%; 261 men [47.5%] and 192 women [34.9%]; 173 with >15 years of practice [31.5%]) completed at least 1 vignette and were included. A majority were physicians (337 respondents [61.3%]) and critical care trained (369 respondents [67.1%]). Fluid volume already received by a patient was associated with resuscitation decisions. After 1 L of fluid, an adjusted 82.5% (95% CI, 80.2%-84.8%) of respondents prescribed additional fluid and an adjusted 55.0% (95% CI, 51.9%-58.1%) initiated vasopressors. After 5 L of fluid, an adjusted 17.5% (95% CI, 15.1%-19.9%) of respondents prescribed more fluid while an adjusted 92.7% (95% CI, 91.1%-94.3%) initiated vasopressors. More respondents prescribed fluid when the patient examination found dry vs wet (ie, overloaded) volume status (adjusted proportion, 66.9% [95% CI, 62.5%-71.2%] vs adjusted proportion, 26.5% [95% CI, 22.3%-30.6%]). Medical history, respiratory status, lactate trend, and acute kidney injury had small associations with fluid and vasopressor decisions. In 1023 of 1127 vignettes (90.8%) where the patient did not have central access, respondents were willing to start vasopressors through a peripheral intravenous catheter. In cases where patients were already receiving peripheral norepinephrine, respondents were more likely to place a central line at higher norepinephrine doses of 0.5 µg/kg/min (adjusted proportion, 78.0%; 95% CI, 74.7%-81.2%) vs 0.08 µg/kg/min (adjusted proportion, 25.2%; 95% CI, 21.8%-28.5%) and after 24 hours (adjusted proportion, 59.5%; 95% CI, 56.6%-62.5%) vs 8 hours (adjusted proportion, 47.1%; 95% CI, 44.0%-50.1%). Conclusions and Relevance: These findings suggest that fluid volume received is the predominant factor associated with ongoing fluid and vasopressor decisions, outweighing many other clinical factors. Peripheral vasopressor use is common. Future studies aimed at personalizing resuscitation must account for fluid volumes and should incorporate specific tools to help clinicians personalize resuscitation.

From ICU Syndromes to ICU Subphenotypes: Consensus Report and Recommendations for Developing Precision Medicine in the ICU.

Critical care uses syndromic definitions to describe patient groups for clinical practice and research. There is growing recognition that a "precision medicine" approach is required and that integrated biologic and physiologic data identify reproducible subpopulations that may respond differently to treatment. This article reviews the current state of the field and considers how to successfully transition to a precision medicine approach. To impact clinical care, identification of subpopulations must do more than differentiate prognosis. It must differentiate response to treatment, ideally by defining subgroups with distinct functional or pathobiological mechanisms (endotypes). There are now multiple examples of reproducible subpopulations of sepsis, acute respiratory distress syndrome, and acute kidney or brain injury described using clinical, physiological, and/or biological data. Many of these subpopulations have demonstrated the potential to define differential treatment response, largely in retrospective studies, and that the same treatment-responsive subpopulations may cross multiple clinical syndromes (treatable traits). To bring about a change in clinical practice, a precision medicine approach must be evaluated in prospective clinical studies requiring novel adaptive trial designs. Several such studies are underway, but there are multiple challenges to be tackled. Such subpopulations must be readily identifiable and be applicable to all critically ill populations around the world. Subdividing clinical syndromes into subpopulations will require large patient numbers. Global collaboration of investigators, clinicians, industry, and patients over many years will therefore be required to transition to a precision medicine approach and ultimately realize treatment advances seen in other medical fields.

Use and Outcomes of Peripheral Vasopressors in Early Sepsis-Induced Hypotension Across Michigan Hospitals: A Retrospective Cohort Study.

BACKGROUND: Vasopressors traditionally are administered via central access, but newer data suggest that peripheral administration may be safe and may avoid delays and complications associated with central line placement. RESEARCH QUESTION: How commonly are vasopressors initiated through peripheral IV lines in routine practice? Is vasopressor initiation route associated with in-hospital mortality? STUDY DESIGN AND METHODS: This retrospective cohort study included adults hospitalized with sepsis (November 2020-September 2022) at 29 hospitals in the Michigan Hospital Medicine Safety Consortium, a Collaborative Quality Initiative sponsored by Blue Cross Blue Shield of Michigan. We assessed route of early vasopressor initiation, factors and outcomes associated with peripheral initiation, and timing of central line placement. RESULTS: Five hundred ninety-four patients received vasopressors within 6 h of hospital arrival and were included in this study. Peripheral vasopressor initiation was common (400/594 [67.3%]). Patients with peripheral vs central initiation were similar; BMI was the only patient factor associated independently with initiation route (adjusted OR [aOR] of peripheral initiation [per 1-kg/m2 increase], 0.98; 95% CI, 0.97-1.00; P = .015). The specific hospital showed a large impact on initiation route (median OR, 2.19; 95% CI, 1.31-3.07). Compared with central initiation, peripheral initiation was faster (median, 2.5 h vs 2.7 h from hospital arrival; P = .002), but was associated with less initial norepinephrine use (84.3% vs 96.8%; P = .001). We found no independent association between initiation route and in-hospital mortality (32.3% vs 42.2%; aOR, 0.66; 95% CI, 0.39-1.12). No tissue injury from peripheral vasopressors was documented. Of patients with peripheral initiation, 135 of 400 patients (33.8%) never received a central line. INTERPRETATION: Peripheral vasopressor initiation was common across Michigan hospitals and had practical benefits, including expedited vasopressor administration and avoidance of central line placement in one-third of patients. However, the findings of wide practice variation that was not explained by patient case mix and lower use of first-line norepinephrine with peripheral administration suggest that additional standardization may be needed.

High-flow nasal cannula vs non-invasive ventilation in acute hypoxia: Propensity score matched study.

RATIONALE: The optimal treatment for early hypoxemic respiratory failure is unclear, and both high-flow nasal cannula and non-invasive ventilation are used. Determining clinically relevant outcomes for evaluating non-invasive respiratory support modalities remains a challenge. OBJECTIVES: To compare the effectiveness of initial treatment with high-flow nasal cannula versus non-invasive ventilation for acute hypoxemic respiratory failure. METHODS: We conducted a retrospective cohort study of patients with acute hypoxemic respiratory failure treated with high-flow nasal cannula or non-invasive ventilation within 24 hours of Emergency Department arrival (1/2018-12/2022). We matched patients 1:1 using a propensity score for odds of receiving non-invasive ventilation. The primary outcome was major adverse pulmonary events (28-day mortality, ventilator-free days, non-invasive respiratory support hours) calculated using a Win Ratio. MEASUREMENTS AND MAIN RESULTS: 1,265 patients met inclusion criteria. 795 (62.8%) received high-flow oxygen and 470 (37.2%) received non-invasive ventilation. We propensity score matched 736/1,265 (58.2%) patients. There was no difference between non-invasive ventilation vs high-flow nasal cannula in 28-day mortality (17.7% vs 23.1%, p=0.08) or ventilator-free days (median [Interquartile Range]: 28 [25, 28] vs 28 [13, 28], p=0.50), but patients on non-invasive ventilation required treatment for fewer hours (median 7 vs 13, p< 0.001). Win Ratio for composite major adverse pulmonary events favored non-invasive ventilation (1.26, 95%CI 1.06-1.49, p< 0.001). CONCLUSIONS: In this observational study of patients with acute hypoxemic respiratory failure, initial treatment with non-invasive ventilation was superior to high-flow nasal cannula for major pulmonary adverse events. Evaluation of composite outcomes is important in the assessment of respiratory support modalities.

Evolving Management Practices for Early Sepsis-induced Hypoperfusion: A Narrative Review.

Sepsis causes significant morbidity and mortality worldwide. Resuscitation is a cornerstone of management. This review covers five areas of evolving practice in the management of early sepsis-induced hypoperfusion: fluid resuscitation volume, timing of vasopressor initiation, resuscitation targets, route of vasopressor administration, and use of invasive blood pressure monitoring. For each topic, we review the seminal evidence, discuss the evolution of practice over time, and highlight questions for additional research. Intravenous fluids are a core component of early sepsis resuscitation. However, with growing concerns about the harms of fluid, practice is evolving toward smaller-volume resuscitation, which is often paired with earlier vasopressor initiation. Large trials of fluid-restrictive, vasopressor-early strategies are providing more information about the safety and potential benefit of these approaches. Lowering blood pressure targets is a means to prevent fluid overload and reduce exposure to vasopressors; mean arterial pressure targets of 60-65 mm Hg appear to be safe, at least in older patients. With the trend toward earlier vasopressor initiation, the need for central administration of vasopressors has been questioned, and peripheral vasopressor use is increasing, although it is not universally accepted. Similarly, although guidelines suggest the use of invasive blood pressure monitoring with arterial catheters in patients receiving vasopressors, blood pressure cuffs are less invasive and often sufficient. Overall, the management of early sepsis-induced hypoperfusion is evolving toward fluid-sparing and less-invasive strategies. However, many questions remain, and additional data are needed to further optimize our approach to resuscitation.