TL;DR: ⚪ Clean null — balanced fluid vs 0.9% saline in pediatric septic shock: MAKE30 identical (3.4% vs 3.0%, P=0.85) despite confirmed biochemical separation; fluid choice doesn't matter here.
1. Publication
- Title: Balanced Fluid or 0.9% Saline in Children Treated for Septic Shock
- Acronym: PRoMPT BOLUS (PRagMatic Pediatric Trial of Balanced vs nOrmaL Saline flUid in Sepsis)
- Year & Journal: New England Journal of Medicine, published online April 24, 2026
- Citation: Balamuth F, Weiss SL, Long E, et al; PRoMPT BOLUS Investigators of the PECARN, PERC, and PREDICT Networks. Balanced Fluid or 0.9% Saline in Children Treated for Septic Shock. N Engl J Med. 2026. doi:10.1056/NEJMoa2601969
2. Context & Rationale
Background: 0.9% saline contains a supraphysiologic chloride concentration linked to hyperchloremic metabolic acidosis and reduced renal blood flow; balanced/buffered fluids (lactated Ringer's, Plasma-Lyte) have a more physiologic electrolyte composition. Adult trials (e.g., SMART) and some smaller pediatric studies suggested balanced fluids reduce major adverse kidney events (MAKE) and mortality, but pediatric-specific evidence remained inconsistent, leading guidelines to issue only weak, very-low-certainty recommendations favoring balanced fluids.
Research Question/Hypothesis: In children treated for suspected septic shock in the ED, does resuscitation/maintenance hydration with balanced crystalloid reduce Major Adverse Kidney Events within 30 days (MAKE30) compared with 0.9% saline?
Why This Matters: ~25 million children worldwide receive crystalloid resuscitation for septic shock annually (per trial protocol background); ~18,000 US pediatric sepsis cases and ~1,800 attributable deaths occur annually. The intervention (fluid type) is cheap, immediately available, and globally familiar — even a small effect would matter at this scale.
3. Design & Methods
- Study Type: Randomized, multicenter, pragmatic, open-label, international trial
- Setting & Centers: 47 EDs across the United States, Canada, Australia, New Zealand, and Costa Rica (PECARN, PERC, PREDICT networks); enrolled August 25, 2020 – October 31, 2025
- Population:
- Inclusion: Children 2 months to <18 years with suspected septic shock and abnormal perfusion, for whom clinicians planned more than one fluid bolus
- Exclusions: Not detailed in available trial text
- Intervention: Balanced/buffered crystalloid fluid for bolus resuscitation and maintenance hydration, up to 48 hours
- Comparator: 0.9% saline, same duration/use pattern
- Blinding: Open-label (clinicians not blinded to fluid type, for pragmatic reasons); enrollment used exception from informed consent (US) / deferred consent (Canada, Australia/NZ) given the narrow therapeutic window
- Statistical Power & Follow-Up: Anticipated enrollment 8800 (protocol); actual enrollment 9041. Primary outcome MAKE30 (composite of death, new RRT, or persistent kidney dysfunction) assessed at 30 days or hospital discharge, whichever came first.
4. Key Results
Outcome | Balanced Fluid | 0.9% Saline | Effect Size | 95% CI | p-value | Clinical Notes |
MAKE30 (primary) | 3.4% | 3.0% | RR 1.10 | 0.88–1.40 | 0.85 | Decisively neutral — no benefit from balanced fluid |
Hyperchloremia | 31.4% | 49.0% | Not reported | Not reported | Described as significant biochemical difference | Strong biochemical separation without clinical benefit |
Hyperlactatemia | 19.8% | 16.7% | Not reported | Not reported | Reported as higher in balanced-fluid group | Direction opposite to hypothesized mechanism |
Death, new RRT, persistent kidney dysfunction, hospital-free days, overall safety | Similar between groups | Similar between groups | Not reported | Not reported | Not reported | No difference in any component outcome |
Arterial/venous thrombosis, cerebral edema, electrolyte abnormalities (4-day safety) | No difference | No difference | Not reported | Not reported | Not reported | No safety signal either direction |
Enrollment: 9,041 children (2 months–<18 years; 50.8% boys).
5. Internal Validity Assessment
- Randomization & Allocation: Randomized, site-stratified, patient-level allocation across 47 international sites; specific sequence-generation/concealment mechanics not detailed in available trial text.
- Protocol Adherence & Separation: Strong biochemical separation was achieved (hyperchloremia 49.0%→31.4%), confirming the intervention was actually delivered as intended, even though this did not translate into clinical outcome separation.
- Blinding & Detection Bias: Open-label by design (pragmatic trial, clinicians manage all other care as usual) — introduces potential performance bias, though the primary outcome (MAKE30) is relatively objective/laboratory-based.
- Missing Data & Sensitivity Analyses: Not reported in available trial text.
- Overall Internal Validity Conclusion: High — very large sample size (9041, exceeding the protocol's 8800 target), pragmatic multinational design, and demonstrated biochemical separation support a robust, well-powered null result rather than an underpowered non-finding.
6. External Validity Assessment
- Population Representativeness: Broad, real-world pediatric ED population (2 months–<18 years) with suspected septic shock across 5 countries and 3 major pediatric research networks — among the most externally valid pediatric sepsis trials to date.
- Practice Context: Pragmatic design (clinicians manage all other aspects of care per usual practice) directly supports real-world applicability; fluids studied are both cheap and globally available.
- Overall External Validity Conclusion: High — largest pediatric sepsis fluid trial to date, explicitly designed and powered for generalizability across high-income multinational ED settings.
7. Strengths & Limitations
Strengths:
- Largest pediatric sepsis fluid RCT to date (n=9041)
- Multinational, multi-network pragmatic design (PECARN, PERC, PREDICT)
- Clear, well-powered null result with confirmed biochemical separation (ruling out "the intervention wasn't really delivered" as an explanation)
- Addresses a genuine, previously unresolved pediatric-specific evidence gap despite adult data suggesting benefit
Limitations:
- Open-label design (inherent to pragmatic trials)
- Specific exclusion criteria and detailed safety/adverse event breakdowns not fully available in accessible trial text
- Paradoxical higher hyperlactatemia in the balanced-fluid arm is unexplained mechanistically
8. Interpretation & Practice Impact
- Clinical Implications: Does not support preferential use of balanced fluid over 0.9% saline for reducing kidney complications in pediatric septic shock — both fluids appear clinically equivalent for this outcome.
- Mechanistic Coherence: Despite achieving the expected biochemical separation (lower hyperchloremia with balanced fluid, consistent with its mechanism of action), this did not translate into the hypothesized reduction in kidney injury — a genuine dissociation between biochemical and patient-centered outcomes.
- Systems-Level Takeaway: Given equivalent outcomes, fluid choice for pediatric septic shock resuscitation can reasonably be guided by cost, availability, and institutional preference rather than presumed kidney-protective benefit.
9. Controversies & Subsequent Evidence
- Editorial Commentary/Debates: Investigators explicitly frame the result as evidence that "the care already being delivered" (i.e., either fluid) is appropriate — a notable contrast to some adult literature (e.g., SMART secondary analysis in sepsis, showing balanced fluids reduced 30-day MAKE from 40.1% to 35.4% and reduced mortality) that had suggested benefit.
- Guideline Integration: The 2026 Surviving Sepsis Campaign guideline (issued before this trial's full publication) suggested balanced/buffered crystalloids over 0.9% saline for pediatric septic shock fluid boluses, but explicitly rated the certainty of evidence as very low and stated saline remained a suitable alternative — PRoMPT BOLUS now provides the definitive, adequately powered pediatric-specific data that guideline lacked.
10. Summary & Executive Takeaway
Summary: PRoMPT BOLUS randomized 9,041 children with suspected septic shock across 47 EDs in 5 countries to balanced crystalloid versus 0.9% saline for resuscitation/maintenance fluid over 48 hours. MAKE30 occurred in 3.4% (balanced) vs 3.0% (saline) (RR 1.10, 95% CI 0.88–1.40, P=0.85) — a clear null result despite confirmed biochemical separation (hyperchloremia 31.4% vs 49.0%).
Overall Takeaway: The largest pediatric sepsis fluid trial to date shows balanced crystalloid and 0.9% saline are clinically equivalent for kidney and safety outcomes in pediatric septic shock — resolving a long-standing pediatric-specific evidence gap and indicating fluid choice need not be dictated by presumed kidney-protective benefit.
11. Bibliography
- Weiss SL, Balamuth F, Long E, et al. PRoMPT BOLUS study protocol. Trials. 2021;22(1). Correction: 2025. doi:10.1186/s13063-021-05717-4
- Brown RM, Wang L, Coston TD, et al. Balanced Crystalloids versus Saline in Sepsis: A Secondary Analysis of the SMART Clinical Trial. Am J Respir Crit Care Med. 2019.