Pharmacodynamic Effect of Different Dosage Regimes of Oseltamivir in Severe Influenza Patients Requiring Mechanical Ventilation: A Multicentre Randomised Controlled Trial

Abstract

Background and objectives: This randomised controlled trial evaluated whether higher doses of oseltamivir would improve virological and clinical outcomes in severe influenza patients requiring invasive mechanical ventilation.

Methods: Forty intubated adult patients with severe influenza A or B from four intensive care units in Hong Kong were enrolled and randomised to receive either a double dose (300 mg/day) or a triple dose (450 mg/day) of oseltamivir for 10 days. Baseline data were collected, and outcomes were assessed daily using SOFA and Murray scores. Viral RNA was quantified from nasopharyngeal and tracheal aspirates. The primary outcome was the viral clearance rate after 5 days of treatment; secondary outcomes included 28-day and hospital mortality rates, changes in viral load, and serial SOFA and Murray scores.

Results: Viral clearance rates after 5 days of treatment were low and similar between the double (3/20, 15%) and triple-dose groups (2/20, 10%). No significant differences were observed in 28-day mortality, hospital mortality, ICU length of stay or duration of mechanical ventilation between the double and triple-dose groups. However, patients receiving triple doses exhibited a faster decline in influenza A viral load but had a longer hospital length of stay.

Conclusions: Triple doses of oseltamivir did not significantly improve virological or clinical outcomes compared with double doses in severe influenza.

Keywords: mechanical ventilation; oseltamivir; severe influenza.

FIGURE 1

CONSORT flow diagram of patient enrolment. “*” represents 26 patients did not require invasive ventilator support; 29 patients required renal replacement therapy; 5 patients died shortly after ICU admission/adopted limitation of support; 4 patients had delayed screening and consent (> 48 h after ICU admission); 3 refused to participate; 1 patient was pregnant. “§” represents 2 patients who had the missing virological outcome due to early discharge and early death, and viral clearance and viral persistence were assumed based on the clinical ground, respectively (N = 18).

FIGURE 2

(A, B) Influenza A and B viral load. Viral load from day 0 to day 10 of recruited Influenza A patients (N = 35) and Influenza B patients (N = 5). The longitudinal viral load was analysed by a generalised mixed‐effect model adjusting for gender, Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II score, Charlson's score and bacterial coinfection status (Influenza A patients: p = 0.048 and Influenza B patients: insufficient data to analyse).

FIGURE 3

(A, B) SOFA and Murray scores. SOFA and Murray scores from day 0 to day 10 of all influenza patients (Influenza A and Influenza B, N = 40). The longitudinal SOFA score was analysed by a generalised mixed‐effect model adjusting for gender, Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II score, Charlson's score, influenza type and bacterial coinfection status (SOFA score: p = 0.144, Murray score: p = 0.624).