Jones et al: Preemptive Resuscitation in Intermediate-Risk Sepsis (2017)

“Among patients with suspected infection and an intermediate lactate level, a preemptive resuscitation strategy did not reduce the incidence of worsening organ dysfunction at 72 hours.”

  • Adapted from Jones AE, et al.

1. Publication Details

  • Trial Title: A Randomized Trial of a Preemptive Intravenous Fluid and Vasopressor Infusion Strategy for Sepsis-Induced Tissue Hypoperfusion
  • Citation: Jones AE, Puskarich MA, Shapiro NI, et al. A randomized trial of a preemptive intravenous fluid and vasopressor infusion strategy for sepsis-induced tissue hypoperfusion. Am J Respir Crit Care Med. 2017;195(12):1621-1631. DOI: 10.1164/rccm.201608-1615OC
  • Published: June 15, 2017, in The American Journal of Respiratory and Critical Care Medicine
  • Author: Alan E. Jones, M.D.
  • Funding: United States National Institute of General Medical Sciences.

2. Keywords

  • Sepsis, Tissue Hypoperfusion, Lactate, Fluid Resuscitation, Vasopressors, Randomized Controlled Trial

3. The Clinical Question

  • In adult emergency department patients with sepsis and intermediate hyperlactatemia (lactate 2-4 mmol/L) without hypotension (Population), does a preemptive, aggressive resuscitation strategy (Intervention) compared to standard care (Comparison) reduce the incidence of worsening organ dysfunction at 72 hours (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Early and aggressive resuscitation is a cornerstone of care for patients with septic shock (defined by hypotension or lactate >4 mmol/L). However, patients with an intermediate lactate level (2-4 mmol/L) without hypotension represent a large group with an intermediate risk of deterioration.
  • Knowledge Gap: It was unknown if applying the same aggressive resuscitation strategies used in septic shock to this lower-risk “pre-shock” population would be beneficial. The potential benefits of preventing progression to shock had to be weighed against the risks of fluid overload and unnecessary vasopressor use.
  • Proposed Hypothesis: The authors hypothesized that a preemptive, aggressive resuscitation strategy would be superior to standard care in reducing the incidence of worsening organ dysfunction in this intermediate-risk population.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 7 academic emergency departments in the United States.
  • Trial Period: Enrollment ran from March 2012 to January 2015.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with a suspected infection, two or more SIRS criteria, and a lactate level between 2.0 and 4.0 mmol/L, without hypotension (systolic BP > 90 mm Hg).
    • Exclusion Criteria: Included an immediate need for vasopressors, obvious fluid overload, or pregnancy.
  • Intervention: A preemptive, aggressive resuscitation strategy. This involved a protocolized 2-liter intravenous crystalloid bolus and the initiation of a vasopressor infusion (norepinephrine) if needed to maintain a MAP of 65-75 mm Hg.
  • Control: Standard care, where all treatment decisions, including the volume of intravenous fluids and the use of vasopressors, were at the discretion of the treating clinicians.
  • Management Common to Both Groups: All patients received standard care for sepsis, including antibiotics.
  • Power and Sample Size: The authors calculated that a sample size of 200 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: Worsening organ dysfunction at 72 hours, defined as an increase in the SOFA score of ≥1 point.
    • Secondary Outcomes: Included the development of cardiovascular collapse, the need for mechanical ventilation, and 28-day mortality.

6. Key Results

  • Enrollment and Baseline: 200 patients were randomized (100 to the preemptive group and 100 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 outcome. Worsening organ dysfunction occurred in 22 of 100 patients (22%) in the preemptive group and in 18 of 100 patients (18%) in the standard care group (p=0.48).
  • Secondary Outcomes: There were no significant differences between the groups in the rates of cardiovascular collapse, need for mechanical ventilation, or 28-day mortality.
  • Adverse Events: Patients in the preemptive group received significantly more intravenous fluids. There was no significant difference in the rates of fluid overload-related complications.

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 with worsening organ dysfunction between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates of the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.48 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was 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 inclusion of 7 diverse academic centers increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The study included important patient-centered outcomes like mortality and the need for organ support.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias.
  • External Validity (Generalizability): The study population was a specific group of “intermediate-risk” sepsis patients, and the findings do not apply to patients who present with overt septic shock.
  • Other: The “standard care” provided in the control group was likely of high quality, which may have made it more difficult for the protocolized intervention to show a benefit.

10. Conclusion of the Authors

  • The authors concluded that in patients with sepsis-induced tissue hypoperfusion without hypotension, a preemptive, aggressive resuscitation strategy did not reduce the incidence of worsening organ dysfunction.

11. To Summarize

  • Impact on Current Practice: This was an important “negative” trial that provided strong evidence against the strategy of applying aggressive septic shock resuscitation protocols to a lower-risk, pre-shock population.
  • Specific Recommendations:
    • Patient Selection: For adult patients with sepsis and an intermediate lactate level (2-4 mmol/L) who are not hypotensive.
    • Actionable Intervention: The results do not support the routine use of a preemptive, aggressive fluid and vasopressor strategy in this population.
  • What This Trial Does NOT Mean: This trial does NOT mean that these patients do not require careful monitoring and resuscitation. It only suggests that a “one-size-fits-all” aggressive protocol is not beneficial.
  • Implementation Caveats: The findings of this trial support a more individualized and cautious approach to fluid resuscitation in patients with intermediate-risk sepsis, avoiding the potential harms of fluid overload.

12. Context and Related Studies

  • Building on Previous Evidence: The Jones et al. trial (2017) was designed to test whether the principles of early, aggressive resuscitation from the EGDT era should be applied to a less sick patient population.
  • Influence on Subsequent Research: The definitive neutral result of this trial has been influential in shaping sepsis guidelines and in reinforcing the idea that resuscitation strategies should be tailored to the patient’s severity of illness.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal monitoring and resuscitation strategy for this large group of intermediate-risk sepsis patients remains an area of active investigation.
  • Future Directions: Future research is focused on using other markers of perfusion (beyond lactate) to identify which patients in this intermediate-risk group are most likely to benefit from more aggressive therapy.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and important clinical dilemma in the emergency department and ICU.
  • 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 and all major secondary outcomes.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable. This is a classic example of a high-quality “negative” trial that was practice-changing by providing strong evidence to not adopt a more aggressive strategy in a lower-risk population.

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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