CENSER: Early Use of Norepinephrine in Septic Shock (2019)

“Early norepinephrine administration in patients with septic shock was associated with a higher rate of shock control.”

— The CENSER Study Investigators

1. Publication Details

  • Trial Title: Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER): A Randomized Trial.
  • Citation: Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T, Udompanturak S. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER): A Randomized Trial. Am J Respir Crit Care Med. 2019;199(9):1097-1105. doi:10.1164/rccm.201806-1034OC.
  • Published: May 1, 2019, in the American Journal of Respiratory and Critical Care Medicine.
  • Author: Chairat Permpikul, M.D.
  • Funding: Siriraj Research Development Fund, Mahidol University.

2. Keywords

Septic Shock, Norepinephrine, Vasopressors, Early Resuscitation, Hypotension, Fluid Resuscitation.

3. The Clinical Question

In adult patients with septic shock (Population), does the early administration of norepinephrine (within 1 hour of diagnosis) (Intervention) compared to standard care (norepinephrine after initial fluid resuscitation) (Comparison) increase the rate of shock control at 6 hours (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Septic shock is defined by persistent hypotension despite adequate fluid resuscitation. The cornerstones of management are fluids and vasopressors (primarily norepinephrine). Standard practice was to administer a large fluid bolus first and only start vasopressors if hypotension persisted.
  • Knowledge Gap: There was a growing concern that delaying vasopressors while giving large volumes of fluid could be harmful, leading to prolonged hypotension and fluid overload. It was unknown if starting norepinephrine much earlier, alongside initial fluid resuscitation, could stabilize patients faster and improve outcomes.
  • Proposed Hypothesis: The authors hypothesized that early administration of norepinephrine would lead to a higher rate of shock control and better clinical outcomes compared to standard care.

5. Study Design and Methods

  • Design: A single-center, open-label, randomized controlled trial.
  • Setting: A single tertiary care medical center in Thailand.
  • Trial Period: Enrollment from June 2013 to March 2017.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with septic shock, defined as hypotension (MAP < 65 mmHg) not responding to an initial 1,000 mL fluid bolus.
    • Exclusion Criteria: Patients who had received vasopressors before screening, had contraindications to vasopressors, or had limitations on life-sustaining treatment.
  • Intervention: Early Norepinephrine Group: Norepinephrine was started within 1 hour of septic shock diagnosis, concurrently with fluid resuscitation.
  • Control: Standard Care Group: Norepinephrine was started only after fluid resuscitation was deemed complete by the treating physician (typically after receiving 30 mL/kg).
  • Management Common to Both Groups: All patients were targeted to a MAP of ≥ 65 mmHg. Other aspects of sepsis management followed Surviving Sepsis Campaign guidelines.

6. Key Results

  • Enrollment and Baseline: 310 patients were randomized (155 to each group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: The early norepinephrine group had a significantly higher rate of shock control by 6 hours (defined as achieving MAP ≥ 65 mmHg with adequate urine output or decreased lactate) compared to the standard care group (76.1% vs. 48.4%; P < 0.001).
  • Secondary Outcomes: The early norepinephrine group had significantly lower rates of cardiogenic pulmonary edema (14.2% vs. 27.7%) and new-onset arrhythmias (11.0% vs. 20.0%). 28-day mortality was also lower in the early group, although this difference was not statistically significant (15.5% vs. 21.9%; P=0.15).
  • Adverse Events: There was no difference in other adverse events, such as limb ischemia.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Key Statistic(s) Reported:
    • Primary Outcome (Shock Control at 6h): 76.1% (early) vs. 48.4% (standard); P < 0.001.
    • Secondary Outcome (28-day mortality): Relative Risk (RR) 0.71 (95% CI, 0.44 to 1.15; P=0.15).
  • Interpretation of Key Statistic(s) for Primary Outcome:
    • P-value: The p-value of < 0.001 is far below the 0.05 threshold, indicating a highly statistically significant difference in the rate of early shock control. This result is very unlikely to be due to chance.
  • Interpretation of Key Statistic(s) for Secondary Outcome (Mortality):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: RR = 15.5% / 21.9% = 0.71.
      • Clinical Meaning: An RR of 0.71 means there was a 29% lower relative risk of death at 28 days in the early norepinephrine group, but this difference was not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.44 to 1.15.
      • Clinical Meaning: The confidence interval suggests the true effect could be anywhere from a 56% benefit to a 15% harm. Because it crosses the line of no effect (1.0), the result is not statistically significant.
    • P-value:
      • Calculation: The reported p-value was 0.15.
      • Clinical Meaning: The p-value of 0.15 is above the conventional threshold of 0.05, indicating that the observed difference in mortality could be due to chance.
  • Clinical Impact Measures (for Shock Control at 6h):
    • Absolute Risk Reduction (ARR) (or Absolute Benefit Increase):
      • Formula: ARR = (Risk in Intervention Group) – (Risk in Control Group).
      • Calculation: ARR = 76.1% – 48.4% = 27.7%.
      • Clinical Meaning: For every 100 patients with septic shock treated with early norepinephrine, approximately 28 more will achieve shock control within 6 hours.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR.
      • Calculation: NNT = 1 / 0.277 ≈ 3.6, rounded to 4.
      • Clinical Meaning: Approximately 4 patients with septic shock need to be treated with early norepinephrine to achieve one additional instance of shock control by 6 hours.

8. Strengths of the Study

  • Randomized Controlled Design: The study used a strong methodology to test a critical timing question in resuscitation.
  • Important Clinical Question: It was one of the first RCTs to provide high-quality evidence supporting the concept of early vasopressor use.
  • Patient-Centered Outcomes: The study included important outcomes like mortality and organ dysfunction (pulmonary edema).

9. Limitations and Weaknesses

  • Single-Center Study: Being conducted at a single institution in Thailand limits the external validity and generalizability of the findings to other healthcare systems.
  • Open-Label Design: Clinicians were aware of the treatment allocation, which could have introduced performance bias in co-interventions and clinical assessments.
  • Surrogate Primary Outcome: The primary outcome, “shock control,” is a physiological surrogate, not a direct patient-centered outcome like mortality.

10. Conclusion of the Authors

“Early norepinephrine in septic shock is safe and more effective than standard treatment in achieving hemodynamic stability. This may prevent fluid overload and reduce the incidence of cardiogenic pulmonary edema and new-onset arrhythmia.”

11. To Summarize

  • Impact on Current Practice: This was a highly influential trial that provided the first strong randomized evidence to challenge the “fluids first” dogma. It demonstrated that starting norepinephrine early is not only safe but also more effective at achieving hemodynamic stability. This has contributed to a major shift in practice and guidelines, supporting a more balanced approach of “fluids and vasopressors together” from the outset of resuscitation.
  • Specific Recommendations:
    • Patient Selection: For adult patients with septic shock who remain hypotensive after an initial fluid challenge.
    • Actionable Intervention: Do not delay starting norepinephrine until a full 30 mL/kg of fluid has been administered. Start norepinephrine early (within the first hour) to restore MAP, while continuing fluid resuscitation.
    • Expected Benefit: Faster shock control (NNT ~4) and a lower risk of fluid overload complications like pulmonary edema.
  • What This Trial Does NOT Mean: This trial does not mean that fluids are unimportant. It means that vasopressors should be seen as a concurrent, not a sequential, therapy. Patients still require judicious fluid administration.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was designed to test the hypothesis generated from physiological principles and observational studies that prolonged hypotension and excessive fluid volumes are harmful.
  • Influence on Subsequent Research: The findings of CENSER provided the foundation for the much larger, multicenter CLOVERS trial (2023), which compared a restrictive fluid/early vasopressor strategy to a liberal fluid strategy. While CLOVERS did not find a difference in mortality, the CENSER trial remains a key piece of evidence supporting the safety and physiological benefit of early vasopressor initiation.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: What is the optimal MAP target? What is the best way to guide ongoing fluid resuscitation once vasopressors have been started?
  • Future Directions: Research continues to focus on personalized resuscitation strategies, using dynamic assessments of fluid responsiveness to guide therapy and avoid the harms of both under- and over-resuscitation.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was of fundamental importance, addressing the timing of one of the most critical interventions in septic shock management.
  • Methods: The randomized design was appropriate. However, the single-center, open-label nature are significant limitations that temper the strength of the conclusions.
  • Results: The trial had a clear and highly statistically significant positive result for its primary physiological outcome. The positive signals in important secondary outcomes (pulmonary edema, arrhythmias) further strengthen the case for the intervention.
  • Conclusions and Applicability: The authors’ conclusion is a reasonable interpretation of the data. Despite its limitations, the trial’s results are physiologically compelling and have been widely applied, forming a key part of the evidence base that has shifted global practice toward earlier vasopressor use in septic shock.

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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