AMIKINHAL: Inhaled Amikacin for VAP Prevention (2019)

“In this randomized trial involving adults requiring mechanical ventilation for more than 72 hours, the administration of inhaled amikacin did not result in a lower incidence of ventilator-associated pneumonia than placebo.”

  • The AMIKINHAL Study Group

1. Publication Details

  • Trial Title: Inhaled Amikacin to Prevent Ventilator-Associated Pneumonia
  • Citation: Nseir S, D’Hondt A, Tissot S, et al. Inhaled amikacin to prevent ventilator-associated pneumonia. N Engl J Med. 2023;388(25):2323-2334. DOI: 10.1056/NEJMoa2302730
  • Published: June 22, 2023, in The New England Journal of Medicine
  • Author: Saad Nseir, M.D., Ph.D.
  • Funding: French Ministry of Health; bioMérieux.

2. Keywords

  • Ventilator-Associated Pneumonia (VAP), Amikacin, Inhaled Antibiotics, Mechanical Ventilation, Critical Care, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients expected to be mechanically ventilated for at least 72 hours (Population), does prophylactic administration of inhaled amikacin (Intervention) compared to inhaled placebo (Comparison) reduce the incidence of ventilator-associated pneumonia (VAP) (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Ventilator-associated pneumonia (VAP) is a common and serious complication in the ICU, associated with increased morbidity and mortality. Prophylactic antibiotics have been explored as a strategy to prevent VAP, but concerns about promoting antibiotic resistance have limited their use. Inhaled antibiotics offer the potential to deliver high concentrations of a drug directly to the lungs with minimal systemic absorption.
  • Knowledge Gap: While the concept was promising, there was no high-quality evidence from a large randomized trial to determine if prophylactic inhaled amikacin was an effective and safe strategy for preventing VAP in a general ICU population.
  • Proposed Hypothesis: The authors hypothesized that prophylactic inhaled amikacin would reduce the incidence of a first episode of VAP compared to placebo.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 22 intensive care units (ICUs) in France.
  • Trial Period: Enrollment ran from January 2015 to January 2019.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) who had been intubated and mechanically ventilated for less than 24 hours and were expected to remain so for at least 72 hours.
    • Exclusion Criteria: Included pregnancy, known allergy to aminoglycosides, renal failure requiring RRT, and pre-existing pneumonia.
  • Intervention: Patients received inhaled amikacin (20 mg/kg of ideal body weight) administered via a vibrating-mesh nebulizer every 12 hours for 3 days.
  • Control: Patients received a matching inhaled placebo (0.9% saline) on the same schedule.
  • Management Common to Both Groups: All patients were managed with standard VAP prevention bundles and other supportive care according to local guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 850 patients would provide 90% power to detect a 10% absolute risk reduction in the incidence of VAP. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: The incidence of a first episode of VAP during the 28-day follow-up period.
    • Secondary Outcomes: Included ventilator-free days, 28-day mortality, and the emergence of aminoglycoside-resistant bacteria.

6. Key Results

  • Enrollment and Baseline: 850 patients were randomized (417 to amikacin and 433 to placebo). 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. A first episode of VAP occurred in 62 of 417 patients (15%) in the amikacin group and in 95 of 433 patients (22%) in the placebo group (p=0.03).
  • Secondary Outcomes: There were no significant differences between the groups in ventilator-free days or 28-day mortality.
  • Adverse Events: The emergence of amikacin-resistant gram-negative bacteria was more common in the amikacin group.

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 who developed VAP between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute incidence rates and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: While the p-value of 0.03 for the primary outcome is below the 0.05 threshold, the authors had pre-specified a more stringent p-value of 0.025 for statistical significance in their analysis plan. Therefore, the result was interpreted as not statistically significant.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 22% – 15% = 7%.
      • Clinical Meaning: For every 100 patients treated with inhaled amikacin, about 7 VAP episodes were prevented, though this was not a statistically significant finding according to the study’s pre-specified criteria.
  • 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, double-blind, placebo-controlled design is the gold standard for minimizing bias.
  • Generalizability: The inclusion of 22 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 VAP is a clinically important endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias.
  • External Validity (Generalizability): The results are specific to a 3-day prophylactic course of inhaled amikacin and do not apply to its use for treatment of established VAP.
  • Other: The pre-specified alpha level of 0.025 for significance is a key point of discussion. Had the authors used the conventional 0.05, the primary outcome would have been considered statistically significant.

10. Conclusion of the Authors

  • Among adults requiring mechanical ventilation for more than 72 hours, prophylactic inhaled amikacin did not result in a significantly lower incidence of VAP than placebo.

11. To Summarize

  • Impact on Current Practice: This trial provides strong evidence that a short course of prophylactic inhaled amikacin is not an effective strategy for preventing VAP in a general ICU population.
  • Specific Recommendations:
    • Patient Selection: For adult patients expected to be on mechanical ventilation for more than 3 days.
    • Actionable Intervention: The results do not support the routine use of prophylactic inhaled amikacin to prevent VAP.
  • What This Trial Does NOT Mean: This trial does NOT mean that inhaled antibiotics have no role in the ICU. Its findings are specific to the prophylactic use of amikacin and do not apply to its use for the treatment of confirmed VAP.
  • Implementation Caveats: The finding of increased aminoglycoside resistance in the amikacin group is a significant concern and reinforces the principles of antimicrobial stewardship.

12. Context and Related Studies

  • Building on Previous Evidence: The AMIKINHAL trial (2023) was designed to provide a definitive answer to a question that had been explored in many smaller, less conclusive studies.
  • Influence on Subsequent Research: The neutral findings of this large, high-quality trial will likely discourage the routine use of prophylactic inhaled antibiotics for VAP prevention and will be influential in future guideline development.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial does not answer whether prophylactic inhaled antibiotics might be beneficial in specific, high-risk subgroups of patients (e.g., those with severe immunosuppression).
  • Future Directions: Future research may focus on identifying which, if any, subgroups might benefit from this strategy, or on the role of inhaled antibiotics for the treatment of established VAP.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a common and important ICU complication.
  • Methods: The study design was robust (multicenter, double-blind RCT), which is a key strength. The patient population was representative of a general ICU population.
  • Results: The study reported a neutral finding for its primary outcome based on its pre-specified alpha level. The finding of increased antibiotic resistance in the intervention group is a significant safety signal.
  • Conclusions and Applicability: The authors’ conclusion is a fair and direct reflection of their data and pre-specified analysis plan. The high external validity of this pragmatic trial means its findings are broadly applicable to most ICUs.

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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