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Observational Study
. 2018 Aug 19;22(1):199.
doi: 10.1186/s13054-018-2122-x.

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

Cyril Touchard  1 , Alexandra Aubry  2 , Philippine Eloy  3 , Nicolas Bréchot  1 , Guillaume Lebreton  4 , Guillaume Franchineau  1 , Sebastien Besset  1 , Guillaume Hékimian  1 , Ania Nieszkowska  1 , Pascal Leprince  4 , Charles-Edouard Luyt  1 , Alain Combes  1 , Matthieu Schmidt  5
Affiliations
Observational Study

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

Cyril Touchard et al. Crit Care. .

Abstract

Background: Amikacin infusion requires targeting a peak serum concentration (Cmax) 8-10 times the minimal inhibitory concentration, corresponding to a Cmax 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 Cmax 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 Cmax was measured 30 min after the end of the infusion. Independent predicators of Cmax < 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 < Cmax < 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%. Cmax 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.

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Conflict of interest statement

Ethics approval and consent to participate

The study protocol was in accordance with the ethical standards of our hospital’s Institutional Review Board (Committee for the Protection of Human Subjects). In accordance with French law, informed consent was not obtained for demographic, physiological and hospital-outcome data analyses because this observational study did not modify existing diagnostic or therapeutic strategies. However, patients and/or relatives were informed about the anonymous data collection and that they could decline inclusion. This database was registered at the Commission Nationale l’Informatique et des Libertés (CNIL, registration number 1950673).

Consent for publication

In accordance with French law, informed consent was not obtained for demographic, physiological and hospital-outcome data analyses because this observational study did not modify existing diagnostic or therapeutic strategies. However, patients and/or relatives were informed about the anonymous data collection and that they could decline inclusion.

Competing interests

Alain Combes has received lecture fees from Baxter and Gettinge and is the primary investigator of the EOLIA trial (NCT01470703), partly supported by Maquet-Gettinge. Matthieu Schmidt has received lectures fees from Gettinge and Dräger. The remaining authors have no conflicts of interest.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Study flow chart. ECMO, extracorporeal membrane oxygenation; Cmax, peak serum concentration
Fig. 2
Fig. 2
Amikacin peak serum concentration (Cmax) 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
Fig. 3
Simulated peak serum concentration (Cmax) 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)
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