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Procalcitonin-Guided Sepsis Care Reduces 28-Day Mortality Without Changing Early Antibiotic Rates
In a large phase 3 randomised trial of suspected sepsis patients in English and Welsh emergency departments, adding procalcitonin testing to standard NEWS2-based assessment was associated with a significantly lower 28-day mortality — 13.6% versus 16.6% in usual care — representing an adjusted risk difference of approximately 3 percentage points (adjusted risk difference −3.12 pp, 90% CI −4.68 to −1.57; p=0.0009). Critically, this mortality benefit occurred without any detectable change in intravenous antibiotic initiation at 3 hours, leaving the mechanism of benefit unexplained and the finding in need of further investigation.
What Was Studied
The PRONTO trial investigated whether supplementing standard emergency department practice — centred on the National Early Warning Score 2 (NEWS2) — with rapid procalcitonin blood testing could improve two outcomes simultaneously: earlier and more accurate antibiotic prescribing, and patient survival at 28 days. This question is clinically important because sepsis is difficult to distinguish from non-infectious conditions at triage, and existing tools carry the risk of both under-treatment and antibiotic overuse.
How It Was Studied
PRONTO was a multicentre, parallel, two-arm, open-label, individually randomised controlled trial conducted across 20 emergency departments within 17 NHS Trusts or Health Boards in England and Wales. A total of 7,667 patients aged 16 years or older with clinically suspected sepsis were enrolled between November 2020 and November 2023, with final 28-day follow-up completed in late November 2023. Participants were assigned in a 1:1 ratio to either usual care based solely on NEWS2 assessment, or to a procalcitonin-guided care pathway in which rapid procalcitonin results were combined with NEWS2 using a guidance-only clinical algorithm — one that clinicians were permitted to follow, modify, or disregard. The primary analysis population comprised 5,453 participants with complete data for both co-primary outcomes.
What Was Observed
- No reduction in early antibiotic prescribing: Intravenous antibiotic initiation within 3 hours of triage was virtually identical between groups — 48.4% in the procalcitonin-guided group versus 48.2% in usual care — a negligible and statistically non-significant difference (adjusted risk difference −0.08 percentage points, 95% CI −2.58 to 2.42; p=0.95). The superiority hypothesis for this outcome was not met.
- Lower 28-day mortality with procalcitonin guidance: Mortality at 28 days was meaningfully lower in the procalcitonin-guided group — about 3 percentage points fewer deaths (13.6% vs 16.6%; adjusted risk difference −3.12 pp, 90% CI −4.68 to −1.57; p=0.0009). The upper bound of the 90% confidence interval fell below both the pre-specified non-inferiority margin of 2.5 percentage points and the null, satisfying criteria for both non-inferiority and superiority.
- Limited algorithm uptake: Procalcitonin results were formally incorporated into clinical decision-making in only 64.7% of participants in the intervention group, indicating that the guidance-only design resulted in meaningful variation in protocol adherence.
- Adverse event profile was low and similar: Adverse events were rare in both groups — recorded in 1.9% of usual care participants and 2.2% of procalcitonin-guided participants — and only one serious adverse event was considered probably or definitely attributable to the procalcitonin test itself.
Why This Matters
The trial demonstrates that embedding procalcitonin testing within an emergency sepsis pathway can be associated with a clinically meaningful reduction in 28-day mortality, even when it does not alter rates of early antibiotic administration. This decoupling of the two co-primary outcomes challenges the assumption that mortality benefit from biomarker-guided sepsis care flows primarily through changes in antibiotic timing or volume. The authors acknowledge that no planned subgroup, sensitivity, or secondary analysis explains the mortality signal, meaning the pathway through which procalcitonin guidance may have influenced outcomes remains an open scientific question requiring dedicated follow-up research.
How to Read This Result
Although this is a well-powered, high-quality phase 3 trial, the mortality benefit is an unexpected finding whose underlying mechanism is unexplained by any supporting analysis, which warrants cautious interpretation and further prospective investigation before the result can be considered definitive or translated into practice changes.
Limitations
The trial was open-label, with no masking of participants, research staff, outcome assessors, or the statisticians conducting the primary analysis, introducing the possibility of performance or ascertainment bias. The central mortality finding was not elucidated by any planned subgroup, sensitivity, or secondary analyses, leaving the biological and clinical mechanism entirely unclear. Additionally, clinicians were explicitly permitted to deviate from or ignore the procalcitonin-based algorithm, and the test result was actually used in clinical decision-making in only about two-thirds of intervention participants, making it difficult to assess the true effect of consistent protocol adherence.