Identifying and Measuring Administrative Harms Experienced by Hospitalists and Administrative Leaders.

Importance: Administrative harm (AH), defined as the adverse consequences of administrative decisions within health care that impact work structure, processes, and programs, is pervasive in medicine, yet poorly understood and described. Objective: To explore common AHs experienced by hospitalist clinicians and administrative leaders, understand the challenges that exist in identifying and measuring AH, and identify potential approaches to mitigate AH. Design, Setting, and Participants: A qualitative study using a mixed-methods approach with a 12-question survey and semistructured virtual focus groups was held on June 13 and August 11, 2023. Rapid qualitative methods including templated summaries and matrix analysis were applied. The participants included 2 consortiums comprising hospitalist clinicians, researchers, administrative leaders, and members of a patient and family advisory council. Main Outcomes and Measures: Quantitative data from the survey on specific aspects of experiences related to AH were collected. Focus groups were conducted using a semistructured focus group guide. Themes and subthemes were identified. Results: Forty-one individuals from 32 different organizations participated in the focus groups, with 32 participants (78%) responding to a brief survey. Survey participants included physicians (91%), administrative professionals (6%), an advanced practice clinician (3%), and those in leadership roles (44%), with participants able to select more than one role. Only 6% of participants were familiar with the term administrative harm to a great extent, 100% felt that collaboration between administrators and clinicians is crucial for reducing AH, and 81% had personally participated in a decision that led to AH to some degree. Three main themes were identified: (1) AH is pervasive and comes from all levels of leadership, and the phenomenon was felt to be widespread and arose from multiple sources within health care systems; (2) organizations lack mechanisms for identification, measurement, and feedback, and these challenges stem from a lack of psychological safety, workplace cultures, and ambiguity in who owns a decision; and (3) organizational pressures were recognized as contributors to AHs. Many ideas were proposed as solutions. Conclusions and Relevance: The findings of this study suggest that AH is widespread with wide-reaching impact, yet organizations do not have mechanisms to identify or address it.

Distinct pulmonary and systemic effects of dexamethasone in severe COVID-19.

Dexamethasone is the standard of care for critically ill patients with COVID-19, but the mechanisms by which it decreases mortality and its immunological effects in this setting are not understood. Here we perform bulk and single-cell RNA sequencing of samples from the lower respiratory tract and blood, and assess plasma cytokine profiling to study the effects of dexamethasone on both systemic and pulmonary immune cell compartments. In blood samples, dexamethasone is associated with decreased expression of genes associated with T cell activation, including TNFSFR4 and IL21R. We also identify decreased expression of several immune pathways, including major histocompatibility complex-II signaling, selectin P ligand signaling, and T cell recruitment by intercellular adhesion molecule and integrin activation, suggesting these are potential mechanisms of the therapeutic benefit of steroids in COVID-19. We identify additional compartment- and cell- specific differences in the effect of dexamethasone that are reproducible in publicly available datasets, including steroid-resistant interferon pathway expression in the respiratory tract, which may be additional therapeutic targets. In summary, we demonstrate compartment-specific effects of dexamethasone in critically ill COVID-19 patients, providing mechanistic insights with potential therapeutic relevance. Our results highlight the importance of studying compartmentalized inflammation in critically ill patients.

Causes and attributable fraction of death from ARDS in inflammatory phenotypes of sepsis.

BACKGROUND: Hypoinflammatory and hyperinflammatory phenotypes have been identified in both Acute Respiratory Distress Syndrome (ARDS) and sepsis. Attributable mortality of ARDS in each phenotype of sepsis is yet to be determined. We aimed to estimate the population attributable fraction of death from ARDS (PAFARDS) in hypoinflammatory and hyperinflammatory sepsis, and to determine the primary cause of death within each phenotype. METHODS: We studied 1737 patients with sepsis from two prospective cohorts. Patients were previously assigned to the hyperinflammatory or hypoinflammatory phenotype using latent class analysis. The PAFARDS in patients with sepsis was estimated separately in the hypo and hyperinflammatory phenotypes. Organ dysfunction, severe comorbidities, and withdrawal of life support were abstracted from the medical record in a subset of patients from the EARLI cohort who died (n = 130/179). Primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support. RESULTS: The PAFARDS was 19% (95%CI 10,28%) in hypoinflammatory sepsis and, 14% (95%CI 6,20%) in hyperinflammatory sepsis. Cause of death differed between the two phenotypes (p < 0.001). Respiratory failure was the most common cause of death in hypoinflammatory sepsis, whereas circulatory shock was the most common cause in hyperinflammatory sepsis. Death with severe underlying comorbidities was more frequent in hypoinflammatory sepsis (81% vs. 67%, p = 0.004). CONCLUSIONS: The PAFARDS is modest in both phenotypes whereas primary cause of death among patients with sepsis differed substantially by phenotype. This study identifies challenges in powering future clinical trials to detect changes in mortality outcomes among patients with sepsis and ARDS.

Associations Between Volume of Early Intravenous Fluid and Hospital Outcomes in Septic Patients With and Without Heart Failure: A Retrospective Cohort Study.

OBJECTIVES: To evaluate the relationship between early IV fluid volume and hospital outcomes, including death in-hospital or discharge to hospice, in septic patients with and without heart failure (HF). DESIGN: A retrospective cohort study using logistic regression with restricted cubic splines to assess for nonlinear relationships between fluid volume and outcomes, stratified by HF status and adjusted for propensity to receive a given fluid volume in the first 6 hours. An ICU subgroup analysis was performed. Secondary outcomes of vasopressor use, mechanical ventilation, and length of stay in survivors were assessed. SETTING: An urban university-based hospital. PATIENTS: A total of 9613 adult patients were admitted from the emergency department from 2012 to 2021 that met electronic health record-based Sepsis-3 criteria. Preexisting HF diagnosis was identified by the International Classification of Diseases codes. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 1449 admissions from patients with HF. The relationship between fluid volume and death or discharge to hospice was nonlinear in patients without HF, and approximately linear in patients with HF. Receiving 0-15 mL/kg in the first 6 hours was associated with lower likelihood of death or discharge to hospice compared with 30-45 mL/kg (odds ratio = 0.61; 95% CI, 0.41-0.90; p = 0.01) in HF patients, but no significant difference for non-HF patients. A similar pattern was identified in ICU admissions and some secondary outcomes. Volumes larger than 15-30 mL/kg for non-HF patients and 30-45 mL/kg for ICU-admitted non-HF patients were not associated with improved outcomes. CONCLUSIONS: Early fluid resuscitation showed distinct patterns of potential harm and benefit between patients with and without HF who met Sepsis-3 criteria. Restricted cubic splines analysis highlighted the importance of considering nonlinear fluid outcomes relationships and identified potential points of diminishing returns (15-30 mL/kg across all patients without HF and 30-45 mL/kg when admitted to the ICU). Receiving less than 15 mL/kg was associated with better outcomes in HF patients, suggesting small volumes may be appropriate in select patients. Future studies may benefit from investigating nonlinear fluid-outcome associations and a focus on other conditions like HF.

Rapidly improving ARDS differs clinically and biologically from persistent ARDS.

BACKGROUND: Rapidly improving acute respiratory distress syndrome (RIARDS) is an increasingly appreciated subgroup of ARDS in which hypoxemia improves within 24 h after initiation of mechanical ventilation. Detailed clinical and biological features of RIARDS have not been clearly defined, and it is unknown whether RIARDS is associated with the hypoinflammatory or hyperinflammatory phenotype of ARDS. The purpose of this study was to define the clinical and biological features of RIARDS and its association with inflammatory subphenotypes. METHODS: We analyzed data from 215 patients who met Berlin criteria for ARDS (endotracheally intubated) and were enrolled in a prospective observational cohort conducted at two sites, one tertiary care center and one urban safety net hospital. RIARDS was defined according to previous studies as improvement of hypoxemia defined as (i) PaO2:FiO2 > 300 or (ii) SpO2: FiO2 > 315 on the day following diagnosis of ARDS (day 2) or (iii) unassisted breathing by day 2 and for the next 48 h (defined as absence of endotracheal intubation on day 2 through day 4). Plasma biomarkers were measured on samples collected on the day of study enrollment, and ARDS phenotypes were allocated as previously described. RESULTS: RIARDS accounted for 21% of all ARDS participants. Patients with RIARDS had better clinical outcomes compared to those with persistent ARDS, with lower hospital mortality (13% vs. 57%; p value < 0.001) and more ICU-free days (median 24 vs. 0; p value < 0.001). Plasma levels of interleukin-6, interleukin-8, and plasminogen activator inhibitor-1 were significantly lower among patients with RIARDS. The hypoinflammatory phenotype of ARDS was more common among patients with RIARDS (78% vs. 51% in persistent ARDS; p value = 0.001). CONCLUSIONS: This study identifies a high prevalence of RIARDS in a multicenter observational cohort and confirms the more benign clinical course of these patients. We report the novel finding that RIARDS is characterized by lower concentrations of plasma biomarkers of inflammation compared to persistent ARDS, and that hypoinflammatory ARDS is more prevalent among patients with RIARDS. Identification and exclusion of RIARDS could potentially improve prognostic and predictive enrichment in clinical trials.

Timing of antibiotic treatment identifies distinct clinical presentations among patients presenting with suspected septic shock.

Objective: Recent clinical guidelines for sepsis management emphasize immediate antibiotic initiation for suspected septic shock. Though hypotension is a high-risk marker of sepsis severity, prior studies have not considered the precise timing of hypotension in relation to antibiotic initiation and how clinical characteristics and outcomes may differ. Our objective was to evaluate antibiotic initiation in relation to hypotension to characterize differences in sepsis presentation and outcomes in patients with suspected septic shock. Methods: Adults presenting to the emergency department (ED) June 2012-December 2018 diagnosed with sepsis (Sepsis-III electronic health record [EHR] criteria) and hypotension (non-resolving for ≥30 min, systolic blood pressure <90 mmHg) within 24 h. We categorized patients who received antibiotics before hypotension ("early"), 0-60 min after ("immediate"), and >60 min after ("late") treatment. Results: Among 2219 patients, 55% received early treatment, 13% immediate, and 32% late. The late subgroup often presented to the ED with hypotension (median 0 min) but received antibiotics a median of 191 min post-ED presentation. Clinical characteristics notable for this subgroup included higher prevalence of heart failure and liver disease (p < 0.05) and later onset of systemic inflammatory response syndrome (SIRS) criteria compared to early/immediate treatment subgroups (median 87 vs. 35 vs. 20 min, p < 0.0001). After adjustment, there was no difference in clinical outcomes among treatment subgroups. Conclusions: There was significant heterogeneity in presentation and timing of antibiotic initiation for suspected septic shock. Patients with later treatment commonly had hypotension on presentation, had more hypotension-associated comorbidities, and developed overt markers of infection (eg, SIRS) later. While these factors likely contribute to delays in clinician recognition of suspected septic shock, it may not impact sepsis outcomes.

Host and Microbe Blood Metagenomics Reveals Key Pathways Characterizing Critical Illness Phenotypes.

Rationale: Two molecular phenotypes of sepsis and acute respiratory distress syndrome, termed hyperinflammatory and hypoinflammatory, have been consistently identified by latent class analysis in numerous cohorts, with widely divergent clinical outcomes and differential responses to some treatments; however, the key biological differences between these phenotypes remain poorly understood.Objectives: We used host and microbe metagenomic sequencing data from blood to deepen our understanding of biological differences between latent class analysis-derived phenotypes and to assess concordance between the latent class analysis-derived phenotypes and phenotypes reported by other investigative groups (e.g., Sepsis Response Signature [SRS1-2], molecular diagnosis and risk stratification of sepsis [MARS1-4], reactive and uninflamed).Methods: We analyzed data from 113 patients with hypoinflammatory sepsis and 76 patients with hyperinflammatory sepsis enrolled in a two-hospital prospective cohort study. Molecular phenotypes had been previously assigned using latent class analysis.Measurements and Main Results: The hyperinflammatory and hypoinflammatory phenotypes of sepsis had distinct gene expression signatures, with 5,755 genes (31%) differentially expressed. The hyperinflammatory phenotype was associated with elevated expression of innate immune response genes, whereas the hypoinflammatory phenotype was associated with elevated expression of adaptive immune response genes and, notably, T cell response genes. Plasma metagenomic analysis identified differences in prevalence of bacteremia, bacterial DNA abundance, and composition between the phenotypes, with an increased presence and abundance of Enterobacteriaceae in the hyperinflammatory phenotype. Significant overlap was observed between these phenotypes and previously identified transcriptional subtypes of acute respiratory distress syndrome (reactive and uninflamed) and sepsis (SRS1-2). Analysis of data from the VANISH trial indicated that corticosteroids might have a detrimental effect in patients with the hypoinflammatory phenotype.Conclusions: The hyperinflammatory and hypoinflammatory phenotypes have distinct transcriptional and metagenomic features that could be leveraged for precision treatment strategies.