Long delay in antibiotic administration increases mortality risk in kids with sepsis

A study of pediatric sepsis patients suggests long delays in initiation of antibiotic therapy increase the risk of mortality, researchers reported yesterday in JAMA Network Open.

The study, which used data from 51 US children’s hospitals, found that children with sepsis who received antibiotics more than 5.5 hours after emergency department (ED) arrival had a more than three-fold increase in the odds of sepsis-attributable 3- and 30-day mortality.

The study authors say the findings support guideline recommendations for timely antibiotic administration in pediatric sepsis patients. 

Defining timely antibiotic administration

For the study, a team of researchers from US children’s hospitals analyzed data from the Children’s Hospital Association’s Improving Pediatric Sepsis Outcomes (IPSO) quality-improvement collaborative, which maintains a database of pediatric patients treated for sepsis—the leading cause of death in children worldwide. Sepsis occurs when the immune system overreacts to an infection, triggering a chain of events that can lead to tissue damage, organ failure, and death. 

The collaborative’s goal is to reduce pediatric sepsis mortality in children’s hospitals by emphasizing earlier recognition and treatment. Although not all cases of sepsis are caused by bacteria, early antibiotic administration is a core feature of timely sepsis management. The Pediatric Surviving Sepsis Campaign guidelines recommend antibiotic administration within 1 hour of recognition of septic shock and within 3 hours of recognition of sepsis-associated organ dysfunction without shock. 

While the importance of timely antibiotics is not in question, the researchers note, a precise understanding of timeliness has not been established for children. Their aim was to determine how long antibiotic administration can be delayed before there is a change in sepsis-attributable mortality rates.

Participants in the retrospective study included patients aged 29 days to 18 years who had sepsis recognized within 1 hour of ED arrival from 2017 through 2021. The 1-hour cutoff time was chosen to minimize the impact of delayed sepsis recognition on outcomes. The primary outcome was sepsis-attributable 3-day mortality. The secondary outcome was sepsis-attributable 30-day mortality.

A total of 19,515 sepsis patients were included in the study (median age, 6 years). The median time to antibiotic administration was 69 minutes. The sepsis-attributable mortality rate among the entire cohort was less than 1%.

“Overall, sepsis was recognized quickly, and IV [intravenous] antibiotics and fluids were administered promptly,” the study authors wrote.

The analysis found that the estimated time to antibiotic administration at which 3-day mortality increased was 330 minutes. For patients who received antibiotics in less than 330 minutes, sepsis-attributable mortality was 0.5% at 3 days and 0.9% at 30 days. For those who received antibiotics at 330 minutes or later, 3-day and 30-day sepsis-attributable mortality was 1.2% and 2.0%, respectively. 

In an adjusted analysis, antibiotic administration at 330 minutes or later was associated with increased odds of sepsis-attributable mortality at 3 days (odds ratio [OR], 3.44; 95% confidence interval [CI], 1.20 to 9.93) and 30 days (OR, 3.63; 95% CI, 1.59 to 8.30) compared with antibiotics given before 330 minutes. 

Who benefits most from early intervention?

A subgroup analysis of patients with bacteremia identified an inflection point in time to antibiotic administration of 90 minutes. Although this finding was not considered statistically significant, the authors say patients with bacteremia are most likely to benefit from timely antibiotic administration and should be a focus of future research.

“The findings are congruent with previous work and guidelines emphasizing that long delays in antibiotic therapy are associated with harm in pediatric sepsis,” they wrote. “Future investigation should involve prospectively identifying patients with bacterial blood infections and studying the effect of antibiotic administration time on outcomes.”

This message is echoed in an accompanying commentary by pediatric infectious disease experts from the University of Zurich and the University of Queensland, who say that while the study provides new insights into antibiotic timing in pediatric sepsis patients, the optimization of sepsis management should ideally focus on identifying patients with predicted bacterial infection who are likely to deteriorate and need rapid antibiotic therapy.

“Future studies should attempt to assess temporal relationships by focusing on patients who are most likely to benefit from early intervention,” they wrote. “The question to balance will then be to decide on the acceptable number of children with uncertain sepsis who get treated as a result of mandates for early care, vs the benefit of timely treatment in those most likely to have bacterial infection progressing to organ or multiorgan dysfunction.”

The findings are congruent with previous work and guidelines emphasizing that long delays in antibiotic therapy are associated with harm in pediatric sepsis.