Sepsis Presenting in Hospitals versus Emergency Departments: Demographic, Resuscitation, and Outcome Patterns in a Multicenter Retrospective Cohort

Patient Outcomes

HPS patients had higher mortality (31.2% vs19.3%), mechanical ventilation (51.5% vs27.4%), and ICU admission (60.6% vs 46.5%) (Table 1 and Supplemental Table 6). Figure 2b shows propensity-matched and covariate-adjusted differences in patient outcomes before and after adjusting for initial resuscitation. aORs corresponded to approximate relative risk differences¹⁸ of 1.38 (CI: 1.28-1.48), 1.68 (CI: 1.57-1.79), and 1.72 (CI: 1.61-1.84) for mortality, mechanical ventilation, and ICU admission, respectively. HPS was associated with 83% longer mortality-censored ICU stays (five vs nine days, HR^–1: 1.83, CI: 1.65-2.03), and 108% longer hospital stay (eight vs 17 days, HR^–1: 2.08, CI: 1.93-2.24). After adjustment for resuscitation, all effect sizes decreased but persisted. The initial crystalloid volume was a significant negative effect modifier for mortality (Supplemental Table 7). That is, the magnitude of the association between HPS and greater mortality decreased by a factor of 0.89 per 10 mL/kg given (CI: 0.82-0.97). We did not observe significant interaction from other interventions, or overall bundle compliance, meaning these interventions’ association with mortality did not significantly differ between HPS versus EDPS.

The implied attributable risk difference from discrepancies in initial resuscitation was 23.3% for mortality, 35.2% for mechanical ventilation, and 7.6% for ICU admission (Figure 2B). Resuscitation explained 26.5% of longer ICU LOS and 16.7% of longer hospital LOS associated with HPS.

Figure 2C shows sensitivity analysis excluding ICU-presenting sepsis from propensity matching (ie, limiting HPS to hospital ward presentations). Again, HPS was associated with all adverse outcomes, though effect sizes were smaller than in the primary cohort for all outcomes except hospital LOS. In this cohort, resuscitation factors now explained 16.5% of HPS’ association with mortality, and 14.5% of the association with longer ICU LOS. However, they explained a greater proportion (13.0%) of ICU admissions. Attributable risk differences were comparable to the primary cohort for mechanical ventilation (37.6%) and hospital LOS (15.3%).

In this analysis of 11,182 sepsis and septic shock patients, HPS contributed 22% of prevalence but >35% of total sepsis mortalities, ICU utilization, and hospital days. HPS patients had higher comorbidity burdens and had clinical presentations less obviously attributable to infection with more severe organ dysfunction. EDPS received antibiotics within three hours about 1.62 times more often than do HPS patients. EDPS patients also receive fluids initiated within two hours about 1.82 times more often than HPS patients do. HPS had nearly 1.5-fold greater mortality and LOS, and nearly two-fold greater mechanical ventilation and ICU utilization. Resuscitation disparities could partially explain these associations. These patterns persisted when comparing only wards presenting HPS with EDPS.

Our analysis revealed several notable findings. First, these data confirm that HPS represents a potentially high-impact target population that contributes adverse outcomes disproportionately frequently with respect to case prevalence.

Our findings, unsurprisingly, revealed HPS and EDPS reflect dramatically different patient populations. We found that the two groups significantly differed by the majority of the baseline factors we compared. It may be worth asking if and how these substantial differences in illness etiology, chronic health, and acute physiology impact what we consider an optimal approach to management. Significant interaction effects of fluid volume on the association between HPS and mortality suggest differential treatment effects may exist between patients. Indeed, patients who newly arrive from the community and those who are several days into admission likely have different volume status. However, no interactions were noted with other bundle elements, such as timeliness of antibiotics or timeliness of initial fluids.

Another potentially concerning observation was that HPS patients were admitted much less frequently from skilled nursing facilities, as it could imply that this poorer-fairing population had a comparatively higher baseline functional status. The fact that 25% of EDPS cases were admitted from these facilities also underscores the need to engage skilled nursing facility providers in future sepsis initiatives.

We found marked disparities in resuscitation. Timely delivery of interventions, such as antibiotics and initial fluid resuscitation, occurred less than half as often for HPS, especially on hospital wards. While evidence supporting the efficacy of specific 3-hour bundle elements remains unsettled,¹⁹ a wealth of literature demonstrates a correlation between bundle uptake and decreased sepsis mortality, especially for early antibiotic administration.^13,20-26 Some analysis suggests that differing initial resuscitation practices explain different mortality rates in the early goal-directed therapy trials.²⁷ The comparatively poor performance for non-ICU HPS indicates further QI efforts are better focused on inpatient wards, rather than on EDs or ICUs where resuscitation is already delivered with substantially greater fidelity.

While resuscitation differences partially explained outcome discrepancies between groups, they did not account for as much variation as expected. Though resuscitation accounted for >35% of attributable mechanical ventilation risk, it explained only 16.5% of mortality differences for non-ICU HPS vs EDPS. We speculate that several factors may contribute.

First, HPS patients are already hospitalized for another acute insult and may be too physiologically brittle to derive equal benefit from initial resuscitation. Some literature suggests protocolized sepsis resuscitation may paradoxically be more effective in milder/earlier disease.²⁸

Second, clinical information indicating septic organ dysfunction may become available too late in HPS—a possible data limitation where inpatient providers are counterintuitively more likely to miss early signs of patients’ deterioration and a subsequent therapeutic window. Several studies found that fluid resuscitation is associated with improved sepsis outcomes only when it is administered very early.^11,29-31 In inpatient wards, decreased monitoring³² and human factors (eg, hospital workflow, provider-to-patient ratios, electronic documentation burdens)^33,34 may hinder early diagnosis. In contrast, ED environments are explicitly designed to identify acutely ill patients and deliver intervention rapidly. If HPS patients were sicker when they were identified, this would also explain their more severe organ dysfunctions. Our data seems to support this possibility. HPS patients had tachypnea less frequently but more often had impaired gas exchange. This finding may suggest that early tachypnea was either less often detected or documented, or that it had progressed further by the time of detection.

Third, inpatients with sepsis may more often present with greater diagnostic complexity. We observed that HPS patients were more often euthermic and less often tachypneic. Beyond suggesting a greater diagnostic challenge, this also raises questions as to whether differences reflect patient physiology (response to infection) or iatrogenic factors (eg, prior antipyretics). Higher comorbidity and acute physiological burdens also limit the degree to which new organ dysfunction can be clearly attributed to infection. We note differences in the proportion of patients who received antibiotics increased over time, suggesting that HPS patients who received delayed antibiotics did so much later than their EDPS counterparts. This lag could also arise from diagnostic difficulty.

All three possibilities highlight a potential lead time effect, where the same measured three-hour period on the wards, between meeting sepsis criteria and starting treatment, actually reflects a longer period between (as yet unmeasurable) pathobiologic “time zero” and treatment versus the ED. The time of sepsis detection, as distinct from the time of sepsis onset, therefore proves difficult to evaluate and impossible to account for statistically.

Regardless, our findings suggest additional difficulty in both the recognition and resuscitation of inpatient sepsis. Inpatients, especially with infections, may need closer monitoring. How to cost effectively implement this monitoring is a challenge that deserves attention.

A more rational systems approach to HPS likely combines efforts to improve initial resuscitation with other initiatives aimed at both improving monitoring and preventing infection.

To be clear, we do not imply that timely initial resuscitation does not matter on the wards. Rather, resuscitation-focused QI alone does not appear to be sufficient to overcome differences in outcomes for HPS. The 23.3% attributable mortality risk we observed still implies that resuscitation differences could explain nearly one in four excess HPS mortalities. We previously showed that timely resuscitation is strongly associated with better outcomes.^11,13,30 As discussed above, the unclear degree to which better resuscitation is a marker for more obvious presentations is a persistent limitation of prior investigations and the present study.

Taken together, the ultimate question that this study raises but cannot answer is whether the timely recognition of sepsis, rather than any specific treatment, is what truly improves outcomes.

In addition to those above, this study has several limitations. Our study did not differentiate HPS with respect to patients admitted for noninfectious reasons and who subsequently became septic versus nonseptic patients admitted for an infection who subsequently became septic from that infection. Nor could we discriminate between missed ED diagnoses and true delayed presentations. We note distinguishing these entities clinically can be equally challenging. Additionally, this was a propensity-matched retrospective analysis of an existing sepsis cohort, and the many limitations of both retrospective study and propensity matching apply.^35,36 We note that randomizing patients to develop sepsis in the community versus hospital is not feasible and that two of our aims intended to describe overall patterns rather than causal effects. We could not ascertain robust measures of severity of illness (eg, SOFA) because a real world setting precludes required data points—eg, urine output is unreliably recorded. We also note incomplete overlap between inclusion criteria and either Sepsis-2 or -3 definitions,^1,37 because we designed and populated our database prior to publication of Sepsis-3. Further, we could not account for surgical source control, the appropriateness of antimicrobial therapy, mechanical ventilation before sepsis onset, or most treatments given after initial resuscitation.

In conclusion, hospital-presenting sepsis accounted for adverse patient outcomes disproportionately to prevalence. HPS patients had more complex presentations, received timely antibiotics half as often ED-presenting sepsis, and had nearly twice the mortality odds. Resuscitation disparities explained roughly 25% of this difference.