CRISTAL: Colloids vs. Crystalloids in Hypovolemic Shock (2013)

“Among ICU patients with hypovolemia, the use of colloids vs crystalloids did not result in a significant difference in 28-day mortality. Although 90-day mortality was lower among patients receiving colloids, this finding should be considered exploratory.”

  • The CRISTAL Investigators

1. Publication Details

  • Trial Title: Colloids versus Crystalloids for Fluid Resuscitation in Critically Ill Patients
  • Citation: Annane D, Siami S, Jaber S, et al. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA. 2013;310(17):1809-1817. DOI: 10.1001/jama.2013.280502
  • Published: November 6, 2013, in The Journal of the American Medical Association (JAMA)
  • Author: Djillali Annane, M.D., Ph.D.
  • Funding: French Ministry of Health

2. Keywords

  • Fluid Resuscitation, Hypovolemic Shock, Sepsis, Colloids, Crystalloids, Albumin, Randomized Controlled Trial

3. The Clinical Question

  • In critically ill adult patients with hypovolemic shock (Population), does fluid resuscitation with colloids (Intervention) compared to crystalloids (Comparison) reduce 28-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The debate over the optimal type of fluid for resuscitation (colloids vs. crystalloids) was one of the longest-standing controversies in critical care. Colloids were thought to be better plasma volume expanders, but were more expensive and had potential side effects. The large SAFE trial (2004) had shown no overall difference between albumin and saline, but questions remained about other types of colloids and different patient populations.
  • Knowledge Gap: A large, pragmatic trial was needed to compare a strategy of using any type of colloid versus any type of crystalloid in a broad population of ICU patients with hypovolemic shock.
  • Proposed Hypothesis: The authors hypothesized that a resuscitation strategy using colloids would be superior to a strategy using crystalloids in reducing 28-day mortality.

5. Study Design and Methods

  • Design: A multicenter, prospective, open-label, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 57 intensive care units (ICUs) in France, Belgium, North Africa, and Canada.
  • Trial Period: Enrollment ran from February 2003 to August 2012.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU with hypovolemic shock, defined by hypotension and signs of hypoperfusion.
    • Exclusion Criteria: Included traumatic brain injury, burns, and end-stage renal disease.
  • Intervention: Patients were randomized to receive fluid resuscitation with colloids (gelatins, dextrans, hydroxyethyl starches, or albumin).
  • Control: Patients were randomized to receive fluid resuscitation with crystalloids (isotonic or hypertonic saline or Ringer’s lactate solution).
  • Management Common to Both Groups: The choice of the specific fluid within the assigned class was at the discretion of the treating clinician. All other aspects of care were managed according to local guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 2800 patients would provide 80% power to detect a 5% 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, need for renal-replacement therapy (RRT), and ventilator-free days.

6. Key Results

  • Enrollment and Baseline: 2857 patients were randomized (1414 to colloids and 1443 to crystalloids). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 28-day mortality. 359 of 1414 patients (25.4%) in the colloid group died, compared with 390 of 1443 patients (27.0%) in the crystalloid group (p=0.26).
  • Secondary Outcomes: 90-day mortality was significantly lower in the colloid group (30.7% vs. 34.2%; p=0.03). Patients in the colloid group also had more days alive without vasopressors. There was no difference in the need for RRT.
  • Adverse Events: The incidence of adverse events 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 death between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-values.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.26 for the primary outcome of 28-day mortality is much higher than the 0.05 threshold, indicating the result was not statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05). The p-value of 0.03 for the secondary outcome of 90-day mortality was statistically significant.
  • Clinical Impact Measures (for the secondary outcome of 90-day mortality):
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 34.2% – 30.7% = 3.5%.
      • Clinical Meaning: For every 100 patients treated with a colloid-based strategy, about 3-4 additional deaths were prevented at 90 days.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.035 = 28.6, which is rounded up to 29.
      • Clinical Meaning: You would need to treat 29 patients with a colloid-based strategy to prevent one additional death at 90 days.
  • Subgroup Analyses: No significant differences were found in the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized controlled design provided high-quality evidence.
  • Generalizability: The pragmatic design, allowing clinicians to choose specific fluids within each class, makes the findings highly generalizable to real-world practice.
  • Statistical Power: The study was large and adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The study focused on mortality, 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 colloid group was very heterogeneous, including synthetic colloids (like HES) and albumin. The findings cannot be attributed to any single type of colloid.
  • Other: The primary outcome was negative. The positive finding for the secondary outcome of 90-day mortality should be interpreted with caution and is generally considered hypothesis-generating rather than definitive.

10. Conclusion of the Authors

  • The authors concluded that there was no significant difference in 28-day mortality between patients resuscitated with colloids versus crystalloids. They noted that 90-day mortality was lower in the colloid group, but that this finding requires further study.

11. To Summarize

  • Impact on Current Practice: This large trial added to the body of evidence suggesting no clear survival benefit of a routine colloid-based strategy over a crystalloid-based strategy in a general ICU population with shock.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients with hypovolemic shock.
    • Actionable Intervention: The results support the use of crystalloids as the first-line fluid for resuscitation.
  • What This Trial Does NOT Mean: This trial does NOT mean that colloids (particularly albumin) have no role in resuscitation. It only suggests that a strategy of using them routinely for all patients is not superior to using crystalloids.
  • Implementation Caveats: Given the higher cost of colloids and the lack of a definitive benefit for the primary outcome, crystalloids remain the standard first-line resuscitation fluid.

12. Context and Related Studies

  • Building on Previous Evidence: The CRISTAL trial (2013) was designed to provide a more pragmatic and generalizable answer to the question addressed by the SAFE trial (2004), which had specifically compared albumin to saline.
  • Influence on Subsequent Research: The neutral finding of this trial, along with the concurrent findings of harm with HES in the 6S (2012) and CHEST (2012) trials, further solidified the role of crystalloids as first-line therapy and shifted the focus of the fluid debate to the question of balanced crystalloids versus saline.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question from this trial is whether the signal of benefit for 90-day mortality was real, and if so, which specific type of colloid (e.g., albumin) was driving this effect.
  • Future Directions: Subsequent research has focused more on the role of albumin in specific subgroups (e.g., the ALBIOS trial (2014) in sepsis) and on comparing different types of crystalloids.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a fundamental and long-standing controversy in critical care.
  • Methods: The large, multicenter, pragmatic RCT design was a major strength. The main methodological weaknesses are the open-label design and the significant heterogeneity of the fluids used in the colloid arm, which makes it difficult to draw conclusions about any specific agent.
  • Results: The study reported a clear neutral finding for its primary outcome. The positive finding for the secondary outcome of 90-day mortality is intriguing but must be interpreted with caution, as secondary outcomes are not powered for definitive conclusions and are at higher risk of being false-positive findings.
  • Conclusions and Applicability: The authors’ cautious conclusion is a fair reflection of the data. The trial provides strong evidence that a routine strategy of using any type of colloid is not superior to using crystalloids for 28-day mortality. The applicability of the 90-day mortality finding remains a subject of debate.

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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