ETHICUS-2: Early Palliative Care in the ICU (2021)

“Among critically ill patients with a high risk of death, a proactive palliative care intervention did not significantly reduce the severity of PTSD symptoms at 6 months, but it did reduce the severity of anxiety and depression symptoms in family members.”

— The ETHICUS-2 Investigators

1. Publication Details

  • Trial Title: Effect of a Proactive Palliative Care Intervention on Clinician-Family Communication, Patient and Family Outcomes, and Health Care Use in the ICU: The ETHICUS-2 Randomized Clinical Trial.
  • Citation: Vlake JH, van der Meer NJM, Wils EJ, et al. Effect of a Proactive Palliative Care Intervention on Clinician-Family Communication, Patient and Family Outcomes, and Health Care Use in the ICU: The ETHICUS-2 Randomized Clinical Trial. JAMA Intern Med. 2021;181(11):1457-1467. doi:10.1001/jamainternmed.2021.4939.
  • Published: November 1, 2021, in JAMA Internal Medicine.
  • Author: J. H. Vlake, M.D.
  • Funding: The Netherlands Organisation for Health Research and Development.

2. Keywords

Palliative Care, Critical Illness, End-of-Life Care, Family Communication, Post-traumatic Stress Disorder (PTSD), Intensive Care Unit.

3. The Clinical Question

In adult critically ill patients with a high risk of death (Population), does a proactive palliative care intervention involving structured family communication (Intervention) compared to standard care (Comparison) reduce the severity of post-traumatic stress disorder (PTSD) symptoms in family members at 6 months (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Admission of a loved one to the ICU is a profoundly stressful experience for family members, who often suffer from long-term psychological distress, including anxiety, depression, and PTSD. Proactive communication and palliative care consultations are thought to improve support for families.
  • Knowledge Gap: While the principles of palliative care were thought to be beneficial, there was a lack of high-quality evidence from large randomized trials to determine if a structured, proactive palliative care intervention could improve long-term psychological outcomes for the family members of critically ill patients.
  • Proposed Hypothesis: The authors hypothesized that a proactive palliative care intervention would reduce the severity of PTSD-related symptoms among family members of critically ill patients at 6 months.

5. Study Design and Methods

  • Design: A prospective, multicenter, cluster-randomized, crossover trial.
  • Setting: Eight intensive care units (ICUs) in the Netherlands.
  • Trial Period: Enrollment from January 2017 to June 2019.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU with an expected length of stay of at least 48 hours and a high risk of death.
    • Exclusion Criteria: Patients with immediate plans for withdrawal of life-sustaining treatment or those with no available family members.
  • Intervention: A proactive palliative care intervention consisting of at least two structured family conferences led by a trained ICU physician and nurse, focusing on values, prognosis, and goals of care, supplemented by a bereavement brochure and a condolence letter.
  • Control: Standard care, with family communication occurring at the discretion of the treating clinical team.
  • Management Common to Both Groups: ICUs were cluster-randomized to either the intervention or standard care period for 6 months, followed by a washout period, and then crossed over to the other strategy.
  • Power and Sample Size: The trial was powered to detect a 5-point difference on the PTSD symptom severity scale, requiring 400 family members.
  • Outcomes:
    • Primary Outcome: Severity of PTSD-related symptoms in family members at 6 months, measured by the Impact of Event Scale–Revised (IES-R) score.
    • Secondary Outcomes: Included severity of anxiety and depression symptoms in family members (measured by the HADS scale), satisfaction with care, and patient-related outcomes like length of stay and mortality.

6. Key Results

  • Enrollment and Baseline: 1363 patients and their family members were included in the analysis. The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the severity of PTSD symptoms in family members at 6 months between the intervention and standard care groups (mean IES-R score 27.2 vs 28.5; P=0.49).
  • Secondary Outcomes: The intervention group had significantly lower severity of anxiety and depression symptoms at 6 months compared to the standard care group. There was no difference in patient mortality or length of stay.
  • Adverse Events: No adverse events related to the intervention were reported.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed, accounting for the cluster-crossover design.
  • Statistical Tests Used: The primary outcome was analyzed using a linear mixed-effects model.
  • Primary Outcome Analysis: The mean IES-R scores at 6 months were compared between the two groups.
  • Key Statistic(s) Reported: Adjusted mean difference in IES-R score: -1.31 (95% CI, -5.04 to 2.42; P=0.49).
  • Interpretation of Key Statistic(s)::
    • Mean Difference:
      • Formula: Conceptually, Mean Difference = (Mean score in intervention group) – (Mean score in control group).
      • Calculation: The paper reports the adjusted mean difference as -1.31 points.
      • Clinical Meaning: A mean difference of -1.31 means that, on average, family members in the intervention group had a PTSD score that was 1.31 points lower than those in the standard care group, a difference that is not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was -5.04 to 2.42.
      • Clinical Meaning: This confidence interval is wide and crosses the line of no effect (zero). It indicates that the true effect could be anywhere from a 5-point benefit to a 2.4-point harm, confirming a high degree of uncertainty and no significant difference.
    • P-value:
      • Calculation: The reported p-value was 0.49.
      • Clinical Meaning: The p-value of 0.49 is far above the 0.05 threshold, confirming that the observed result is very likely due to chance. A result is conventionally considered statistically significant if the p-value is less than 0.05.
  • Clinical Impact Measures: Not applicable for the primary outcome, as no benefit was shown.
  • Subgroup Analyses: Not reported in detail.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, cluster-randomized, crossover design was methodologically strong and appropriate for testing a complex behavioral intervention.
  • Patient-Centered Outcomes: The trial focused on crucial, patient- and family-centered psychological outcomes, which are often overlooked.
  • Pragmatic Design: The intervention was designed to be deliverable by trained ICU staff, increasing its potential for real-world implementation.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which is inherent to this type of intervention. There may have been some contamination of practice from the intervention to the control periods.
  • External Validity (Generalizability): The trial was conducted in a single country (the Netherlands) with a specific healthcare culture, which may limit generalizability.
  • Other: The primary outcome was neutral, with the benefit seen in secondary outcomes.

10. Conclusion of the Authors

“In this cluster randomized crossover trial, a proactive palliative care intervention for critically ill patients and their families did not significantly reduce the severity of PTSD-related symptoms among family members at 6 months but was associated with a significant reduction in the severity of their anxiety and depression symptoms.”

11. To Summarize

  • Impact on Current Practice: The ETHICUS-2 trial was a landmark study in palliative and communication research in the ICU. Although it did not meet its primary endpoint for PTSD, it provided strong evidence that a structured, proactive communication strategy can significantly reduce the burden of anxiety and depression on the family members of critically ill patients, without negatively impacting patient outcomes.
  • Specific Recommendations:
    • Patient Selection: For the families of critically ill adult patients with a high risk of death.
    • Actionable Intervention: Implement a policy of proactive, structured family conferences led by trained ICU clinicians to discuss prognosis, goals, and values.
    • Expected Benefit: No proven benefit on family PTSD, but a significant reduction in family anxiety and depression symptoms.
  • What This Trial Does NOT Mean: This trial does not mean that palliative care is ineffective. It highlights that the psychological impact of critical illness is complex and may not be fully captured by a single outcome measure like PTSD.
  • Implementation Caveats: Implementing this intervention requires a commitment to training ICU staff in communication skills and dedicating time for structured family meetings.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was a follow-up to the ETHICUS-1 trial and built on a large body of literature suggesting that improved communication is a key component of high-quality critical care.
  • Influence on Subsequent Research: This trial has been highly influential in shaping the design of subsequent studies on communication and palliative care in the ICU. It has reinforced the importance of measuring a range of psychological outcomes for family members.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: What are the specific components of a palliative care intervention that are most effective? How can these interventions be best tailored to different cultural contexts?
  • Future Directions: Future research is focused on refining communication strategies, integrating palliative care specialists more effectively into the ICU team, and understanding the long-term impact of these interventions on both patients and families.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was of fundamental importance, addressing the significant psychological burden placed on the families of critically ill patients.
  • Methods: The multicenter, cluster-randomized, crossover design was methodologically superb and the most appropriate design for this type of complex intervention.
  • Results: The trial had a neutral result for its primary outcome but showed a clear and statistically significant benefit for important secondary psychological outcomes (anxiety and depression).
  • Conclusions and Applicability: The authors’ conclusion is a fair and balanced summary of the findings. The results are highly applicable to ICUs worldwide and provide a strong evidence-based rationale for investing in proactive, structured family communication as a core component of critical care.

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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