play_arrow

keyboard_arrow_right

skip_previous play_arrow skip_next
00:00 00:00
playlist_play chevron_left
volume_up
play_arrow

Featured

AMIKINHAL – Inhaled Amikacin to prevent VAP

Dr Swapnil Pawar February 27, 2024 182


Background
share close
  • cover play_arrow

    AMIKINHAL – Inhaled Amikacin to prevent VAP
    Dr Swapnil Pawar

 

Blog written by Dr Jose Chacko

 

Research question

The question addressed by the AMIKINHAL trial was: does a 3-day course of nebulized amikacin reduce the incidence of ventilator-associated pneumonia?

Population and design

The AMIKINHAL trial was conducted between July 2017 and March 2021, across 19 ICUs in France. The study population included patients who had undergone at least 72 hours of invasive ventilation.

Excluded

 

  • More than 96 hours had elapsed since commencement of invasive ventilation
  • Suspected or confirmed ventilator-associated pneumonia (VAP)
  • Severe acute kidney injury, not on renal replacement therapy
  • Chronic kidney disease (glomerular filtration rate <30 ml/min)
  • Extubation expected within 24 hours
  • On systemic aminoglycosides
  • Had undergone tracheostomy

 

Patients were randomized in a 1:1 ratio to receive inhaled amikacin or placebo. Randomization was stratified by center and based on treatment with systemic antibiotics on the day of randomization.

 

Amikacin group

A vibrating mesh nebulizer (Aerogen) was used to administer inhaled amikacin. A dose of 20 mg/kg ideal body weight was administered once a day for 3 consecutive days.

Saline group

Patients were nebulized with an equivalent volume of normal saline

Both groups

The second and third dose of nebulization was not administered if patients were extubated, developed acute kidney injury, or had an indication for systemic aminoglycoside as judged by the clinician. The nebulizer was positioned in the inspiratory limb of the circuit; active humidification was provided based on clinician preference. Ventilator settings, sedative medication, and muscle relaxant administration was based on clinician judgment. International guidelines were followed towards the prevention of VAP. Blinding was ensured throughout the trial.

VAP was diagnosed based on a positive quantitative culture on the pulmonary sample with at least two of the following: leukocytosis, leukopenia, fever, or purulent secretions with a new infiltrate on the chest radiograph. A centralized committee blinded to the study arm were the adjudicators of the diagnosis of VAP.

Sample size

The authors assumed a 6% incidence of VAP in the amikacin group and 12% in the placebo group. A sample size of 850 patients provided the study with 80% power at a two-sided alpha level of 0.05.

Results

A total of 6419 patients were screened, and 850 were randomized. In the final analysis, there were 417 patients in the amikacin group (three had withdrawn consent) and 430 in the placebo group. Patient characteristics were well matched at baseline. Most patients were medical (87%); the SOFA score was 8±4 at baseline in both groups. The mean duration of invasive mechanical ventilation before randomization was 3.5±0.3 days in both groups; systemic antibiotic therapy was being administered in nearly 78% of all patients at baseline.

Most patients received all three scheduled nebulizations – 81% in the amikacin group and 83% in the placebo group.

The primary outcome: the first episode of VAP at 28 days

Significantly fewer patients developed VAP in the amikacin group compared to placebo at 28 days of follow-up. By day 28, 62 patients (15%) in the amikacin group had developed VAP compared with 95 patients (22%) in the placebo group [difference in restricted mean

survival time to VAP: 1.5 days; 95% CI (0.6–2.5); P = 0.004]. The first episode of VAP occurred at a median of 10 days in the amikacin group and 9 days in the placebo group. The incidence of the first episode of VAP was 16 per 1000 ventilation days in the amikacin group and 23 in the placebo group. The first episode of VAP due to a gram-negative organism was less common in the amikacin group (7% vs. 14%).

Secondary outcomes

Among ventilator-associated events, ventilator-associated conditions (worsening oxygenation over 2 days after a period of stability), infection-related ventilator-associated complications (worsening oxygenation, signs of infection, and initiation of antibiotics), and possible VAP (infection-related ventilator-associated complication with positive cultures) occurred significantly more often in the placebo group. Systemic antibiotic use was similar in both groups. There was no significant difference between groups in the duration before the first successful spontaneous breathing trial, the duration of mechanical ventilation, duration of stay in the ICU and in hospital, and the ICU and hospital mortality.

Safety outcomes

A serious adverse event occurred in 11 patients overall – seven in the amikacin group and four in the placebo group. These included increased resistance in the expiratory limb filter, obstructed endotracheal tube, and bronchospasm. Among patients with normal renal function at baseline, acute kidney injury occurred by day 28 in 11 patients (4%) in the amikacin group and 24 patients (8%) in the placebo group.

Main study outcomes are summarized in Table 1.

Table 1. Main study outcomes

 

Outcome Amikacin (417 patients) Placebo (430 patients) Hazard Ratio, Rate

Ratio, or Difference

First episode of VAP at 28 d 62 (15%) 95 (22) 1.5 (0.6 to 2.5)

P = 0.004

Ventilator-associated events 230 (56%) 323 (76%)  
Antibiotic-days per 1000 patient-days of ICU 887 968 0.92 (0.81 to 1.03) (NS)
Duration to first successful SBT (median, IQR) 7 (5 to 12) 8 (6 to 12) 0.96 (0.81 to 1.14) (NS)
Invasive ventilation days 9 (6 to 16) 9 (6 to 15) 0 (−2 to 1) (NS)
ICU LOS 12 (9 to 20) 13 (9 to 19) −1 (−3 to 1) (NS)
Hospital LOS 27 (17 to 45) 27 (18 to 43) 0 (−3 to 4) (NS)
ICU mortality 99 (24%) 112 (26%) 0.89 (0.68 to 1.17) (NS)
Hospital mortality 123 (29) 136 (32%) 0.91 (0.71 to 1.16) (NS)

Abbreviations: VAP, ventilator-associated pneumonia; NS, not significant; SBT, spontaneous breathing trial; LOS, length of stay

Study conclusion

A 3-day course of inhaled amikacin resulted in a lower incidence of VAP at 28 days of follow-up among patients on mechanical ventilation for at least 3 days.

 

Strengths

  • Relevant clinical question
  • Double blinded, multicentric study
  • Adequate sample size

Limitations

  • No significant difference in hard core clinical outcomes, including mortality, duration of ventilation, and ICU stay
  • The use of systemic antibiotics similar in both groups
  • Would the use of inhaled amikacin increase the resistance burden?
  • The study evaluated only the first episode of VAP – it does not apply to later onset infections
  • The incidence VAP (22% in the control group) was higher than generally encountered; a 12% incidence was assumed for sample size calculation
  • Applicability depends on local microbiological flora and resistance patterns
  • Is it possible that amikacin may have sterilized the upper airway secretions, leading to underdiagnosis of VAP?

Our view – 

Although this trial demonstrated a significant decrease in VAP incidence, it is premature to adopt these practices widely in intensive care units. We express caution against the intervention as the external validity of this approach is limited and might lead to an increased incidence of MRO.

 

Rate it
Previous episode
eCritCare Podcast
1
play_arrow
share playlist_add
close
  • 843
  • 1

Featured

NICO Trial – Intubation in Acute Drug Overdose – Does Intubation Matter?

Dr Swapnil Pawar December 23, 2023

play_arrow NICO Trial – Intubation in Acute Drug Overdose – Does Intubation Matter? Dr Swapnil Pawar   Blog Written by Dr Jose Chacko  Effect of Noninvasive Airway Management of Comatose […]

Read more trending_flat