PRECISe: Personalised Resuscitation in Sepsis-Induced Hypotension (2023)

“Among adults with sepsis-induced hypotension in the emergency department, a personalised resuscitation protocol guided by capillary refill time, compared with usual care, did not significantly reduce the composite of all-cause mortality or persistent organ dysfunction at 30 days.”

  • The PRECISe Investigators

1. Publication Details

  • Trial Title: Personalised Resuscitation for Sepsis-Induced Hypotension: A Multicentre, Randomised Controlled Trial
  • Citation: Kuan WS, Ibrahim I, Le S, et al. Personalised resuscitation for sepsis-induced hypotension: a multicentre, randomised controlled trial. Lancet Respir Med. 2023;11(10):865-876. DOI: 10.1016/S2213-2600(23)00159-1
  • Published: October 2023, in The Lancet Respiratory Medicine
  • Author: Wang S. Kuan, M.B.B.S.
  • Funding: National Medical Research Council of Singapore.

2. Keywords

  • Sepsis, Septic Shock, Fluid Resuscitation, Personalized Medicine, Capillary Refill Time, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with sepsis-induced hypotension in the emergency department (Population), does a personalized resuscitation strategy guided by capillary refill time (CRT) (Intervention) compared to standard care (Comparison) reduce the composite of all-cause mortality or persistent organ dysfunction at 30 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Early fluid resuscitation is a cornerstone of sepsis management, but the optimal volume and strategy are unknown. A “one-size-fits-all” approach risks fluid overload in some patients and under-resuscitation in others. The ANDROMEDA-SHOCK trial (2019) had suggested a potential benefit for a resuscitation strategy guided by a simple clinical sign of peripheral perfusion (capillary refill time) in the ICU.
  • Knowledge Gap: It was unknown if this personalized, CRT-guided approach was superior to standard care when initiated very early in the course of illness, in the emergency department, before the patient was admitted to the ICU.
  • Proposed Hypothesis: The authors hypothesized that a personalized resuscitation strategy targeting CRT normalization would be superior to standard care in reducing the composite outcome of death or persistent organ dysfunction.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 5 emergency departments in Singapore.
  • Trial Period: Enrollment ran from April 2018 to August 2022.
  • Population:
    • Inclusion Criteria: Adult patients (≥21 years) with sepsis-induced hypotension (systolic BP < 100 mm Hg or MAP < 65 mm Hg) who had received less than 20 mL/kg of intravenous fluids.
    • Exclusion Criteria: Included pregnancy, active bleeding, and an immediate need for surgery.
  • Intervention: A personalized resuscitation protocol. Fluid boluses were guided by repeated measurements of capillary refill time. If CRT was abnormal (>3 seconds), patients received a 250-500 mL fluid bolus. If CRT was normal, further fluids were withheld.
  • Control: Standard care, where the volume and rate of fluid administration were at the discretion of the treating clinician.
  • Management Common to Both Groups: All patients received standard care for sepsis, including early antibiotics.
  • Power and Sample Size: The authors calculated that a sample size of 344 patients would provide 80% power to detect a 15% absolute risk reduction in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: A composite of all-cause mortality or persistent organ dysfunction at 30 days.
    • Secondary Outcomes: Included 30-day mortality, total fluid volume administered, and ICU length of stay.

6. Key Results

  • Enrollment and Baseline: 344 patients were randomized (172 to personalized care and 172 to standard care). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the primary composite outcome. The primary outcome occurred in 63 of 172 patients (37%) in the personalized care group, compared with 73 of 172 patients (43%) in the standard care group (p=0.27).
  • Secondary Outcomes: There was no significant difference in 30-day mortality. Patients in the personalized care group received significantly less intravenous fluid in the first 6 hours (a median of 1.4 L vs. 1.9 L).
  • Adverse Events: The incidence of adverse events, including fluid overload, was similar in both groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients who met the composite endpoint between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for the primary outcome: 0.86 (95% CI, 0.65 to 1.14; P-value: 0.27).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the result as 0.86.
      • Clinical Meaning: An RR of 0.86 suggests a non-significant 14% lower relative risk of the primary outcome in the personalized care group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.65 to 1.14.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. Clinically, this means the true effect could range from a 35% benefit to a 14% harm.
    • P-value: The p-value of 0.27 is much higher than the 0.05 threshold, indicating the result is not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided high-quality evidence on an important clinical question.
  • Generalizability: The pragmatic design and inclusion of patients from five different emergency departments increase the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The primary outcome was a composite of mortality and persistent organ dysfunction, which are highly relevant patient-centered endpoints.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which introduces a risk of performance bias.
  • External Validity (Generalizability): The study was conducted in a single country with a well-organized healthcare system. The “standard care” in the control group was not protocolized and could have been variable.
  • Other: The separation in the volume of fluid administered between the two groups was relatively small, which may have made it more difficult to detect a true difference in outcomes.

10. Conclusion of the Authors

  • The authors concluded that among adults with sepsis-induced hypotension in the emergency department, a personalized resuscitation protocol guided by capillary refill time did not significantly reduce the composite of mortality or persistent organ dysfunction compared to standard care.

11. To Summarize

  • Impact on Current Practice: This trial adds to the growing body of evidence that a more restrictive, personalized fluid strategy is safe in early sepsis but may not be superior to good quality standard care.
  • Specific Recommendations:
    • Patient Selection: For adult patients with sepsis-induced hypotension in the emergency department.
    • Actionable Intervention: A resuscitation strategy guided by capillary refill time is a reasonable and safe alternative to standard care and results in the administration of less intravenous fluid.
  • What This Trial Does NOT Mean: This trial does NOT mean that early fluid resuscitation is not important. It only suggests that a more cautious, physiologically guided approach is safe.
  • Implementation Caveats: The key to fluid management remains careful and frequent reassessment of the individual patient’s volume status and perfusion, whether guided by CRT or other clinical signs.

12. Context and Related Studies

  • Building on Previous Evidence: The PRECISe trial (2023) was designed to test the findings of the ANDROMEDA-SHOCK trial (2019) in an earlier phase of resuscitation (the emergency department).
  • Influence on Subsequent Research: The neutral findings of this trial, along with the larger CLOVERS (2023) and CLASSIC (2022) trials, have been highly influential. Together, they suggest that the focus of fluid resuscitation research should shift from “one-size-fits-all” volume protocols to more personalized, physiology-guided approaches.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is whether a CRT-guided strategy might be beneficial in different healthcare systems where standard care is less aggressive, or in specific subgroups of patients.
  • Future Directions: Future research is focused on combining multiple perfusion parameters (like CRT, lactate, and others) to create more sophisticated, personalized resuscitation strategies.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant and innovative, testing a simple, non-invasive, personalized resuscitation strategy at the earliest point of care.
  • Methods: The multicenter RCT design was appropriate and robust. The main methodological weakness is the open-label design.
  • Results: The study reported a clear neutral finding for its primary outcome. The finding that the personalized strategy resulted in less fluid administration without an increase in harm is a key secondary finding.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The trial provides strong evidence that a more cautious, CRT-guided approach to early fluid resuscitation is safe. Its findings are broadly applicable to most modern emergency departments.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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