Hailing all sepsis providers, great and small!

Sepsis and septic shock are life-threatening medical emergencies in which organ dysfunction is caused by a dysregulated host response to infection (1). The recently established Phoenix criteria differentiate children with sepsis as those having a higher risk for mortality than children with infections without sepsis (2). Specifically, groups of children with at least moderate cardiovascular, respiratory, coagulation, and/or neurologic dysfunction exhibited in-hospital mortality of 7.1% in higher-resource settings (e.g., United States) and 28.5% in lower-resource settings (e.g., Bangladesh, China, Colombia, Kenya).

Numerous studies have demonstrated that early recognition and treatment of sepsis and septic shock limit the progression of organ dysfunction, reduce hospital length of stay, improve chances of survival, and optimize long-term outcomes after hospitalization (3-5). In 2020, the Surviving Sepsis Campaign published broad evidence-based recommendations to guide clinicians on the optimal management of children with septic shock and other sepsis-associated organ dysfunction (6). These recommendations included six key initial management steps: (I) obtain intravenous/intraosseous access, (II) collect a blood culture (and other diagnostic tests for most likely sites of infection), (III) start empiric broad-spectrum antibiotics, (IV) measure blood lactate, (V) administer fluid bolus(es) if shock is present, and (VI) start vasoactive agents if shock persists. Other studies have validated that a bundle of care that includes at least early blood culture collection, antibiotics, and a fluid bolus is associated with improved outcomes for children with sepsis and septic shock (7). However, much less is known about how often care delivered meets these recommendations, especially outside of pediatric specialty hospitals where sepsis is an infrequent event in children.

Dr. Halden Scott and colleagues recently sought to address this knowledge gap by testing whether the annual volume of pediatric sepsis encounters is associated with care concordant with the Surviving Sepsis Campaign at 29 general emergency departments (ED) in Colorado and Wyoming (8). The authors identified 1,527 ED encounters from 1,402 distinct patients aged 30 days to 18 years between January 1, 2015 and September 30, 2021 who were hospitalized within 72 hours of presentation and had at least one of three criteria to support a presentation with sepsis or septic shock: (I) ED diagnostic code of sepsis (R65.20 or R65.21), (II) ED sepsis order set used, or (III) blood culture in the first 12 hours with ED intravenous fluid bolus and ED intravenous antibiotic administration. Additional chart review was performed by these experienced investigators to exclude encounters with an alternative non-sepsis etiology, and a high level of interrater reliability for the chart reviews was achieved. Notably, because all EDs were connected within one large, university-affiliated extended health system, patients could be followed after transfer from the presenting ED, which is a common limiting factor in pediatric sepsis epidemiology and research. Each ED was categorized based on its annual ED volume of pediatric patients with sepsis, assessed as a continuous variable. Acknowledging a lack of consensus on definitions of low pediatric sepsis volume or low pediatric ED volume, the authors ultimately grouped EDs as lowest (0–10 cases of pediatric sepsis/year), middle (<10–100 cases/year), and highest (>100 cases/year) volumes. Most EDs fell into the lowest volume (25 of 29), with three middle and one highest volume ED. The primary outcome was concordance with three of the six elements of initial sepsis resuscitation recommended by the Surviving Sepsis Campaign, including intravenous antibiotics within 3 hours, intravenous fluid bolus within 3 hours, and measurement of blood lactate. A subgroup analysis was performed for children with systolic hypotension in the ED to assess concordance with these same interventions delivered within one hour, as recommended for children with septic shock.

The main finding of this analysis was a small, but significant, association of annual volume of pediatric sepsis encounters with concordant care overall (odds ratio 1.002, 95% CI: 1.001–1.003) (8). However, when the one high-volume ED was removed, annual volume of pediatric sepsis encounters was no longer associated with concordant care (odds ratio 0.99, 95% CI: 0.987–1.01), suggesting this one high-volume site drove this association. Similarly, the authors found a small association of ED pediatric sepsis volume with hospital length of stay (incident rate ratio 1.002, 95% CI: 1.002–1.003 with all sites included and 1.004, 95% CI: 0.999–1.01 with the one highest volume site removed). It is worth noting that, because the annual volume of pediatric sepsis encounters was analyzed as a continuous variable, the interpretation of the odds and incident rate ratios is that of a small increase in the probability of concordant care with each increase in annual sepsis volume of one patient. Given that most EDs fell into the lowest volume, it is difficult to generalize the actual magnitude of this effect size across a wider array of middle and larger-volume sites.

A secondary finding of this analysis is that concordant care improved significantly over time from 23.1% in 2015 to 52.8% in 2021 across all EDs (8). Concordant care was even higher, at 59%, in the small subgroup of hypotensive patients. Although only 13.3% of hypotensive patients met the stricter 1-hour goals for septic shock, few details are available on this relatively small cohort.

The volume-outcome relationship has been studied extensively in health care, with many studies demonstrating that higher volume hospitals more often achieve desirable patient outcomes (9-11), though this is not a universal finding (12). However, there remains debate as to whether this association is a true causal effect due to a “practice-makes-perfect” principle or a proxy for patients’ preferences to seek care at hospitals with better outcomes. Other studies have noted that hospitals with lower annual patient volumes tend to be located further away from the patients treated there (e.g., small rural hospitals serving patients living across broad geographic areas) and have different case-mix severity of illness profiles than high-volume centers (13). Because of the difficulty in discerning whether high volumes cause better care/outcomes or better care/outcomes drive increased volume, several studies have employed instrumental variables, such as distance from patients’ homes to their hospital, to help interpret the meaning of a volume-outcome relationship. An instrumental variable is a measured factor that has no direct effect on the outcome, but rather only impacts the outcome through the exposure variable (14). Thus, an observed association of the instrumental variable with an outcome is taken to mean that a causal association exists between the exposure of interest and the outcome. Of course, such interpretations require a valid instrument, which is difficult to prove with confidence. Nonetheless, studies taking this approach have tended to conclude that higher volumes do lead to better care, i.e., “practice-makes-perfect”.

In their study of pediatric sepsis annual volumes and care concordance with guidelines, Dr. Scott and colleagues did attempt to control for differences in case-mix through inclusion of age, hypotension, mode of arrival to the ED, oxygen saturation, temperature, heart rate, and respiratory rate in their general estimating equations (8). It is not clear, however, how successful this approach was in reducing potential confounding, as it is very likely that the case-mix varied considerably across hospitals beyond the factors included in the analysis. Moreover, given the location of the hospitals throughout Colorado and Wyoming, it is also likely distance from the hospital affected when and where patients sought treatment and influenced illness severity at presentation. For example, if low-volume EDs tend to see fewer children with sepsis in part because they happen to be in less populated areas with patients traveling greater distances, it is possible they their patients more often present at later stages of septic illness, making recognition easier and driving faster treatment. Notably, a recent study of 9,013 pediatric sepsis encounters treated at 153 hospitals across the Commonwealth of Pennsylvania found that 69% of hospitals had treated fewer than 10 children with sepsis over the three-year study period (15). Of the remaining 24 evaluable hospitals, pediatric sepsis volumes continued to range from a low of 35 to a high of 1,861. While unadjusted hospital mortality also varied widely from 1.5% to 11.9%, risk-standardized mortality rates showed much less variation (6.2% to 7%) after adjustment for differences in case-mix and reliability that accounted for small numbers of patients at most hospitals. The experience in Pennsylvania illustrates the importance of accounting for case-mix differences when trying to decipher the reasons underlying volume-outcome relationships in pediatric sepsis.

Despite challenges in interpreting the volume-outcome relationship in Dr. Scott’s study, it is overall reassuring that ED providers in general are increasingly providing fast treatment to children who present with concern for sepsis or septic shock. Although <10% of the total cohort is likely to have met the new Phoenix Sepsis Criteria (2), one cannot know how many children might have suffered clinical deterioration to the point of life-threatening organ dysfunction had such early recognition and treatment been delayed. Moreover, as noted by the authors, these data also lay bare the challenge borne by general ED providers who must be ready to identify and treat children with early signs of sepsis and septic shock despite rarely encountering these patients. Optimizing early warning and sepsis recognition tools is clearly an area for urgency to provide the most efficient clinical decision support across different healthcare settings (16). While the majority of patients in this study for whom clinicians intended to administer intravenous antibiotics and fluids received these treatments quickly, it is not known how many children with sepsis were not recognized because this study required that patients be diagnosed with sepsis or treated with antibiotics/fluids as inclusion criteria; consequently, cases of “missed sepsis” would be excluded.

Dr. Scott and colleagues should be commended for applying such a rigorous methodology to a difficult epidemiologic question to better understand how often care delivered in an ED setting outside of a pediatric specialty center complies with basic, evidence-based recommendations for children with sepsis and septic shock. From these data, we learned that while initial overall care for children with sepsis has improved over time, both low- and high-volume EDs can still benefit from focused quality improvement efforts and implementation of early recognition tools. Consequently, while we must hail the great work of front-line clinicians who bear the challenge of recognizing and treating sepsis at its earliest stages, from both high- and low-volume healthcare settings, we also know that there remains work to do!

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Public Health and Emergency. The article has undergone external peer review.

Peer Review File: Available at https://jphe.amegroups.com/article/view/10.21037/jphe-24-29/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://jphe.amegroups.com/article/view/10.21037/jphe-24-29/coif). The author serves as Co-Vice Chair of Surviving Sepsis Campaign in Children and is a member of the Phoenix Pediatric Sepsis Definition Taskforce. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315:801-10. [Crossref] [PubMed]
2. Schlapbach LJ, Watson RS, Sorce LR, et al. International Consensus Criteria for Pediatric Sepsis and Septic Shock. JAMA 2024;331:665-74. [Crossref] [PubMed]
3. Paul R, Niedner M, Riggs R, et al. Bundled Care to Reduce Sepsis Mortality: The Improving Pediatric Sepsis Outcomes (IPSO) Collaborative. Pediatrics 2023;152:e2022059938. [Crossref] [PubMed]
4. Lane RD, Funai T, Reeder R, et al. High Reliability Pediatric Septic Shock Quality Improvement Initiative and Decreasing Mortality. Pediatrics 2016;138:e20154153. [Crossref] [PubMed]
5. Balamuth F, Weiss SL, Fitzgerald JC, et al. Protocolized Treatment Is Associated With Decreased Organ Dysfunction in Pediatric Severe Sepsis. Pediatr Crit Care Med 2016;17:817-22. [Crossref] [PubMed]
6. Weiss SL, Peters MJ, Alhazzani W, et al. Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children. Pediatr Crit Care Med 2020;21:e52-e106. [Crossref] [PubMed]
7. Evans IVR, Phillips GS, Alpern ER, et al. Association Between the New York Sepsis Care Mandate and In-Hospital Mortality for Pediatric Sepsis. JAMA 2018;320:358-67. [Crossref] [PubMed]
8. Scott HF, Lindberg DM, Brackman S, et al. Pediatric Sepsis in General Emergency Departments: Association Between Pediatric Sepsis Case Volume, Care Quality, and Outcome. Ann Emerg Med 2024;83:318-26. [Crossref] [PubMed]
9. Chowdhury MM, Dagash H, Pierro A. A systematic review of the impact of volume of surgery and specialization on patient outcome. Br J Surg 2007;94:145-61. [Crossref] [PubMed]
10. Gonzalez AA, Dimick JB, Birkmeyer JD, et al. Understanding the volume-outcome effect in cardiovascular surgery: the role of failure to rescue. JAMA Surg 2014;149:119-23. [Crossref] [PubMed]
11. McLeod L, French B, Dai D, et al. Patient volume and quality of care for young children hospitalized with acute gastroenteritis. Arch Pediatr Adolesc Med 2011;165:857-63. [Crossref] [PubMed]
12. Frosch ZAK, Illenberger N, Mitra N, et al. Trends in Patient Volume by Hospital Type and the Association of These Trends With Time to Cancer Treatment Initiation. JAMA Netw Open 2021;4:e2115675. [Crossref] [PubMed]
13. Huguet M, Joutard X, Ray-Coquard I, et al. What underlies the observed hospital volume-outcome relationship? BMC Health Serv Res 2022;22:70. [Crossref] [PubMed]
14. Lousdal ML. An introduction to instrumental variable assumptions, validation and estimation. Emerg Themes Epidemiol 2018;15:1. [Crossref] [PubMed]
15. Ames SG, Davis BS, Angus DC, et al. Hospital Variation in Risk-Adjusted Pediatric Sepsis Mortality. Pediatr Crit Care Med 2018;19:390-6. [Crossref] [PubMed]
16. Eisenberg MA, Balamuth F. Pediatric sepsis screening in US hospitals. Pediatr Res 2022;91:351-8. [Crossref] [PubMed]