ANDROMEDA-SHOCK: Capillary Refill Time vs. Lactate in Septic Shock (2019)

“Among patients with septic shock, a resuscitation strategy targeting normalization of capillary refill time, compared with a strategy targeting normalization of serum lactate levels, did not reduce 28-day mortality.”

  • The ANDROMEDA-SHOCK Investigators

1. Publication Details

  • Trial Title: Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial
  • Citation: Hernández G, Ospina-Tascón GA, Damiani LP, et al. Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA. 2019;321(7):654–664. DOI: 10.1001/jama.2019.0071
  • Published: February 19, 2019, in The Journal of the American Medical Association (JAMA)
  • Author: Glenn Hernández, M.D., Ph.D.
  • Funding: Unrestricted grants from the Pontificia Universidad Católica de Chile and others.

2. Keywords

  • Septic Shock, Resuscitation, Capillary Refill Time, Lactate, Perfusion, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with early septic shock (Population), does a resuscitation strategy targeting normalization of capillary refill time (CRT) (Intervention) compared to a strategy targeting normalization of serum lactate levels (Comparison) reduce 28-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The Surviving Sepsis Campaign guidelines recommended guiding resuscitation to normalize lactate in patients with elevated levels. However, lactate can be influenced by factors other than tissue hypoperfusion (e.g., liver dysfunction, epinephrine effect), and its clearance can be slow, potentially leading to unnecessary fluid administration. Capillary refill time (CRT) is a simple, readily available clinical sign of peripheral perfusion.
  • Knowledge Gap: It was unknown if a resuscitation strategy guided by a simple clinical sign of peripheral perfusion (CRT) could be a safe and effective alternative to a lactate-guided strategy, potentially leading to a more personalized and less aggressive resuscitation.
  • Proposed Hypothesis: The authors hypothesized that a resuscitation strategy targeting normalization of CRT would be superior to a lactate-guided strategy in reducing 28-day mortality.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 28 intensive care units (ICUs) in 5 countries in South America.
  • Trial Period: Enrollment ran from March 2017 to March 2018.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with septic shock diagnosed within 4 hours, who had an elevated lactate level (≥2 mmol/L) and required vasopressors after a fluid bolus.
    • Exclusion Criteria: Included active bleeding and contraindications to any of the potential resuscitation interventions.
  • Intervention: A peripheral perfusion-targeted strategy. Every 30 minutes for 8 hours, clinicians assessed CRT. If abnormal (>3 seconds), they performed a fluid challenge, a vasopressor test, or an inotrope test according to a structured protocol.
  • Control: A lactate-targeted strategy. Every 2 hours for 8 hours, serum lactate was measured. If elevated, the goal was to decrease it by 20% every 2 hours, guided by the same structured interventions as the CRT group.
  • Management Common to Both Groups: Both groups were managed with an identical, protocolized algorithm of interventions (fluids, vasopressors, inotropes) to reach their respective targets.
  • Power and Sample Size: The authors calculated that a sample size of 422 patients would provide 80% power to detect a 15% absolute risk reduction in 28-day mortality. (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: All-cause mortality at 28 days.
    • Secondary Outcomes: Included 90-day mortality, organ dysfunction (SOFA score) at 72 hours, and total fluid and vasopressor doses during the 8-hour intervention period.

6. Key Results

  • Enrollment and Baseline: 424 patients were randomized (212 to the CRT group and 212 to the lactate group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no statistically significant difference in 28-day mortality. 74 of 212 patients (34.9%) in the CRT group died, compared with 92 of 212 patients (43.4%) in the lactate group (p=0.06).
  • Secondary Outcomes: Patients in the CRT-targeted group had a greater improvement in their SOFA scores at 72 hours and received less intravenous fluid during the 8-hour intervention period.
  • Adverse Events: There were no significant differences in adverse events between the 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 death between the two groups.
  • Key Statistic(s) Reported: Hazard Ratio (HR) for death at 28 days: 0.75 (95% CI, 0.55 to 1.02; P-value: 0.06).
  • Interpretation of Key Statistic(s):
    • Hazard Ratio (HR):
      • Formula: Conceptually, HR = (Hazard Rate in Intervention Group) / (Hazard Rate in Control Group).
      • Calculation: The paper reports the result as 0.75.
      • Clinical Meaning: The HR of 0.75 suggests a 25% lower risk of death at any given time point in the CRT group, but this result was not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.55 to 1.02.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. The true effect could range from a 45% benefit to a 2% harm.
    • P-value: The p-value of 0.06 is just above the 0.05 threshold, meaning the result did not meet the conventional criteria for statistical significance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 43.4% – 34.9% = 8.5%.
      • Clinical Meaning: For every 100 patients treated with a CRT-guided strategy, there was a non-significant trend towards about 9 fewer deaths.
  • Subgroup Analyses: No significant differences were found in the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided high-quality evidence on a novel resuscitation strategy.
  • Generalizability: The pragmatic design across 28 diverse ICUs increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The primary outcome of 28-day mortality is a robust and patient-centered endpoint.

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 South America, and the results may not be fully generalizable to other healthcare systems. The resuscitation algorithm was complex and may be difficult to replicate without specific training.
  • Other: The trial was arguably underpowered to detect a smaller, but still clinically important, difference in mortality. The p-value of 0.06 is a major point of discussion.

10. Conclusion of the Authors

  • Among patients with septic shock, a resuscitation strategy targeting normalization of capillary refill time did not significantly reduce 28-day mortality as compared with a strategy targeting normalization of serum lactate levels.

11. To Summarize

  • Impact on Current Practice: This trial provided strong evidence that a resuscitation strategy guided by a simple, non-invasive clinical sign (CRT) is a safe and reasonable alternative to a lactate-guided strategy, and may be associated with less fluid administration and faster organ function recovery.
  • Specific Recommendations:
    • Patient Selection: For adult patients in the early hours of septic shock resuscitation.
    • Actionable Intervention: A resuscitation strategy targeting normalization of CRT (<3 seconds) is a valid alternative to a lactate-clearance strategy.
  • What This Trial Does NOT Mean: This trial does NOT mean that lactate should be ignored. It remains an essential marker for diagnosis and prognostication in sepsis.
  • Implementation Caveats: A CRT-guided strategy requires a standardized measurement technique and a structured algorithm for interventions, as was used in the trial.

12. Context and Related Studies

  • Building on Previous Evidence: The ANDROMEDA-SHOCK trial (2019) was the first large RCT to directly compare a clinical perfusion target to a biochemical target for resuscitation in septic shock.
  • Influence on Subsequent Research: The intriguing, near-significant result of this trial has spurred significant interest in peripheral perfusion-guided resuscitation and has led to the design of the ongoing ANDROMEDA-2 trial, which is larger and powered to detect a smaller difference in mortality.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is whether the 8.5% absolute risk reduction in mortality seen in this trial was a real, albeit statistically non-significant, effect, or simply due to chance.
  • Future Directions: The ongoing ANDROMEDA-2 trial aims to provide a more definitive answer. Future research is also exploring the role of other peripheral perfusion markers.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant and innovative, testing a novel, non-invasive resuscitation strategy against the established standard of care.
  • Methods: The multicenter RCT design was appropriate. The main methodological weakness is the open-label design, which introduces a risk of performance bias. The use of a highly structured intervention algorithm in both arms is a strength.
  • Results: The study reported a non-significant difference in its primary outcome, but with a strong trend towards benefit in the CRT group (p=0.06). The secondary outcomes of faster organ function recovery and less fluid administration in the CRT group provide supportive evidence for a real physiological effect.
  • Conclusions and Applicability: The authors’ conclusion is a fair and accurate reflection of the primary outcome data. The trial provides strong evidence that a CRT-guided strategy is at least as good as a lactate-guided strategy, and may be superior. The findings are highly applicable to most ICU settings, as CRT is a universally available assessment.

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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