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Population pharmacokinetics and dose simulation of vancomycin in critically ill patients during high-volume haemofiltration

https://doi.org/10.1016/j.ijantimicag.2014.03.009Get rights and content

Abstract

This study aimed to describe the population pharmacokinetics of vancomycin in critically ill patients with refractory septic shock undergoing continuous venovenous high-volume haemofiltration (HVHF) and to define appropriate dosing for these patients. This was a prospective pharmacokinetic study in the ICU of a university hospital. Eight blood samples were taken over one vancomycin dosing interval. Samples were analysed by a validated liquid chromatography–tandem mass spectrometry assay. Non-linear mixed-effects modelling was used to describe the population pharmacokinetics. Dosing simulations were used to define therapeutic vancomycin doses for different HVHF settings. Nine patients were included (five male). The mean weight and SOFA score were 70 kg and 11, respectively. Mean HVHF settings were: blood flow rate, 240 mL/min; and haemofiltration exchange rate, 100 mL/kg/h. A linear two-compartment model with zero-order input adequately described the data. Mean parameter estimates were: clearance, 2.9 L/h; volume of distribution of central compartment (V1), 11.8 L; volume of distribution of peripheral compartment (V2), 18.0 L; and intercompartmental clearance, 9.3 L/h. HVHF intensity was strongly associated with vancomycin clearance (P < 0.05) and was a covariate in the final model. Simulations indicate that after a loading dose, vancomycin doses required for different HVHF intensities would be 750 mg every 12 h (q12 h) for 69 mL/kg/h, 1000 mg q12 h for 100 mL/kg/h and 1500 mg q12 h for 123 mL/kg/h. Continuous infusion would also be a valuable administration strategy. In conclusion, variable and much higher than standard vancomycin doses are required to achieve therapeutic concentrations during different HVHF settings.

Introduction

Continuous venovenous haemofiltration with high-volume exchange is used in intensive care units (ICUs) as part of the management of patients with refractory septic shock and/or acute kidney injury [1]. This form of renal replacement therapy (RRT) is commonly termed high-volume haemofiltration (HVHF) and employs haemofiltration rates that may exceed 100 mL/kg/h. Because HVHF removes pro-inflammatory mediators that are associated with haemodynamic compromise, it can be prescribed as either pulse 6-h treatments [2], as a continuous treatment for ≥12 h or as RRT to improve haemodynamics and other physiological conditions in critically ill patients with progressive refractory hypotension and lactic acidosis [3].

The amount of solute removed during HVHF is still uncertain. For antibiotics, effective dosing is a significant challenge because robust dosing recommendations in this context are scarce. A HVHF study of a hydrophilic antibiotic suggests that a higher dose is required in the presence of HVHF because of dramatically increased drug clearance [4].

Vancomycin is a widely used antibiotic in critically ill patients with sepsis. It is still the first-line treatment for meticillin-resistant Staphylococcus aureus (MRSA) infections in many countries. Previous studies of vancomycin pharmacokinetics during RRT have shown different vancomycin clearances [5], [6], resulting in variable achievement of target plasma concentrations [7], [8]. Dosing recommendations have been proposed for haemofiltration rates <45 mL/kg/h but not for higher substitution volumes. Therefore, if standard vancomycin doses are used during HVHF, subtherapeutic concentrations are highly likely to result.

To date, we are unaware of any studies investigating the effect of HVHF of ca. 100 mL/kg/h on vancomycin pharmacokinetics in critically ill septic patients and are not aware of any dosing guidelines in this scenario.

The aim of this study was to describe the population pharmacokinetics of vancomycin in patients undergoing HVHF for septic shock treatment and to propose appropriate doses for achievement of target concentrations.

Section snippets

Materials and methods

This was an observational prospective pharmacokinetic study performed in the ICU of Universidad Católica Clinical Hospital (Santiago, Chile). The institutional review board approved the study, and written informed consent was obtained from the legally authorised representative of each patient.

Eligible patients aged ≥18 years with sepsis or severe septic shock requiring HVHF who were prescribed vancomycin were recruited over a 1-year period (June 2011 to June 2012).

Clinical and demographic characteristics and high-volume haemofiltration prescription

As HVHF is not a frequently used rescue treatment in the ICU, only nine severe septic shock patients were included (five male). The mean ± S.D. age was 57 ± 14 years, weight 70 ± 18 kg and BMI 27 ± 9 kg/m2, respectively. The mean ± S.D. APACHE II and SOFA scores were 31 ± 7 and 11 ± 4, respectively. Six patients were anuric and three were oliguric before HVHF. The vancomycin prescription was 1000 mg intravenous daily as a 1-h infusion in all patients. The HVHF settings were a mean Qb of 240 ± 20 mL/min and a

Discussion

This study shows the inadequate vancomycin plasma concentrations achieved after a standard dose during HVHF rates close to 100 mL/kg/h. Even with much lower HVHF rates (ca. 56 mL/kg/h [8]), concentrations were insufficient.

This pharmacokinetic analysis showed a mean vancomycin clearance surprisingly similar to previous studies (<45 mL/kg/h) [7], [11], [12] despite the higher ultrafiltration rate. This observation might be explained by the residual renal function of the patients included in the

Acknowledgments

The authors thank the nurses of the Unit of Nephrology of Universidad Católica Clinical Hospital (Santiago, Chile) for assistance with sample collection.

Funding: This work was supported by a postgraduate grant from the National Commission of Science and Technology (CONICYT) of Chile [grant AT2012 no. 24121225] to LE and by the Faculty of Medicine of Universidad Católica for interdepartmental research (Departments of Intensive Medicine and Nephrology). JAR is funded by a Career Development

References (15)

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