Predictors of insufficient peak amikacin concentration in critically ill patients on extracorporeal membrane oxygenation

Abstract

Background: Amikacin infusion requires targeting a peak serum concentration (C_max) 8-10 times the minimal inhibitory concentration, corresponding to a C_max of 60-80 mg/L for the least susceptible bacteria to theoretically prevent therapeutic failure. Because drug pharmacokinetics on extracorporeal membrane oxygenation (ECMO) are challenging, we undertook this study to assess the frequency of insufficient amikacin C_max in critically ill patients on ECMO and to identify relative risk factors.

Methods: This was a prospective, observational, monocentric study in a university hospital. Patients on ECMO who received an amikacin loading dose for suspected Gram-negative infections were included. The amikacin loading dose of 25 mg/kg total body weight was administered intravenously and C_max was measured 30 min after the end of the infusion. Independent predicators of C_max < 60 mg/L after the first amikacin infusion were identified with mixed-model multivariable analyses. Various dosing simulations were performed to assess the probability of reaching 60 mg/L < C_max < 80 mg/L.

Results: A total of 106 patients on venoarterial ECMO (VA-ECMO) (68%) or venovenous-ECMO (32%) were included. At inclusion, their median (1st; 3rd quartile) Sequential Organ-Failure Assessment score was 15 (12; 18) and 54 patients (51%) were on renal replacement therapy. Overall ICU mortality was 54%. C_max was < 60 mg/L in 41 patients (39%). Independent risk factors for amikacin under-dosing were body mass index (BMI) < 22 kg/m² and a positive 24-h fluid balance. Using dosing simulation, increasing the amikacin dosing regimen to 30 mg/kg and 35 mg/kg of body weight when the 24-h fluid balance is positive and the BMI is ≥ 22 kg/m² or < 22 kg/m² (Table 3), respectively, would have potentially led to the therapeutic target being reached in 42% of patients while reducing under-dosing to 23% of patients.

Conclusions: ECMO-treated patients were under-dosed for amikacin in one third of cases. Increasing the dose to 35 mg/kg of body weight in low-BMI patients and those with positive 24-h fluid balance on ECMO to reach adequate targeted concentrations should be investigated.

Keywords: Acute respiratory distress syndrome; Amikacin; Cardiac failure; Pharmacokinetics; Shock; Volume of distribution.

Fig. 1

Study flow chart. ECMO, extracorporeal membrane oxygenation; C_max, peak serum concentration

Fig. 2

Amikacin peak serum concentration (C_max) after a single dose of 25 mg/kg total body weight according to 24-h fluid balance on extracorporeal membrane oxygenation (ECMO). Concentrations in patients with body mass index (BMI) < 22 kg/m² or > 22 kg/m² are represented by red dots and circles, respectively. Boxplots represent the distribution of the concentrations. The lower and upper borders correspond to the first and third quartiles. The upper whisker extends from the borders to the highest value that is within 1.5 * interquartile range (IQR) of the borders, or the distance between the first and third quartiles. The lower whisker extends from the borders to the lowest value within 1.5 * IQR of the hinge. Red dashed lines represent the therapeutic margin (60–80 mg/L)

Fig. 3

Simulated peak serum concentration (C_max) and probability of amikacin efficacy, under-dosing, and overdosing for various dosing regimens in a critically ill patient on extracorporeal membrane oxygenation (ECMO) with a negative 24-h fluid balance (a); a positive 24-h fluid balance (b); a positive 24-h fluid balance and body mass index (BMI) ≥ 22 kg/m² (c); or a positive 24-h fluid balance and BMI < 22 kg/m² (d)