Pharmacokinetic Assessment of Pre- and Post-Oxygenator Vancomycin Concentrations in Extracorporeal Membrane Oxygenation: A Prospective Observational Study

Abstract

Background

Extracorporeal membrane oxygenation (ECMO) is a form of cardiopulmonary life support frequently utilized in catastrophic lung and or cardiac failure. Patients on ECMO often receive vancomycin therapy for treatment or prophylaxis against Gram-positive organisms. It is unclear if ECMO affects vancomycin pharmacokinetics, thus we modeled the pharmacokinetic behavior of vancomycin according to ECMO-specific variables.

Methods

Adult patients receiving vancomycin and Veno-Arterial-ECMO between 12/1/2016 and 10/1/2017 were prospectively enrolled. Extracorporeal membrane oxygenation settings and four sets of pre- and post-oxygenator vancomycin concentrations were collected for each patient. Compartmental models were built and assessed ECMO flow rates on vancomycin clearance and potential circuit sequestration. Bayesian posterior concentrations of the pre- and post-oxygenator concentrations were obtained for each patient, and summary pharmacokinetic parameters were calculated. Simulations were performed from the final model for efficacy and toxicity predictions.

Results

Eight patients contributed 64 serum concentrations. Patients were a median (interquartile range) age of 58.5 years (50.8–62.3) with a calculated creatinine clearance of 39 mL/min (29.5–62.5) and ECMO flow rates of 3980 mL/min (interquartile range = 3493.75–4132.5). A three-compartment model best fit the data (Bayesian: plasma pre-oxygenation R² = 0.99, post-oxygenation R² = 0.99). Vancomycin clearance was not impacted by ECMO flow rate (p = 0.7). Simulations demonstrated that vancomycin 1 g twice daily was rarely sufficient for minimum inhibitory concentrations > 0.5 mg/L. Doses ≥ 1.5 g twice daily often exceeded toxicity thresholds for exposure.

Conclusions

Extracorporeal membrane oxygenation flow rates did not influence vancomycin clearance between flow rates of 3500 and 5000 mL/min and vancomycin was not sequestered in ECMO. Common vancomycin regimens resulted in suboptimal efficacy and/or excessive toxicity. Individual therapeutic drug monitoring is recommended for patients on ECMO.

Appendix

See Fig. 4 and Tables 4, 5, 6 and 7.

Fig. 4

Pre and post oxygenation vancomycin concentration differences over time (a) and pre and post oxygenation time-paired concentrations (b). Pre-oxygenator = before oxygenation by ECMO, Post-oxygenator = after oxygenation by ECMO

Concentrations did not significantly differ when comparing the time-matched pre- and post-oxygenator concentrations (mean difference − 0.22 mg/L, 0.90 mg/L SD, p = 0.18) indicating little sequestration (Fig. 4 of the Appendix). Results of the non-compartmental analysis from the Bayesian posterior-predicted concentrations (i.e., pre-oxygenator concentrations) for the eight patients are summarized in Table 3. Briefly, within the eight study patients, the median (IQR) clearance and volume of distribution at steady-state values were 3.4 (1–3.87) L/h and 43.91 (40.65–51.4) L, respectively.

Table 3 Non-compartmental pharmacokinetic analysis for the eight patients from the Bayesian posterior-predicted concentrations

Table 4 Model build comparison

Table 5 The probability of target attainment for different dosing regimens and ECMO rates

Table 6 The probability of toxic exposures as predicted by MCS for each simulated regimen at various EMCO rates

Table 7 Population parameter value covariance matrix