Effect of fluid loading during hypovolaemic shock on caspofungin pharmacokinetic parameters in pigReport as inadecuate




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Critical Care

, 15:R219

First Online: 20 September 2011Received: 04 May 2011Revised: 20 June 2011Accepted: 20 September 2011

Abstract

IntroductionCaspofungin treatment is frequently initiated in shock patients. In the present study, we investigated the influence of hypovolaemic shock requiring fluid loading on the plasma and pulmonary pharmacokinetic parameters of caspofungin in the pig.

MethodsAfter being anaesthetised and mechanically ventilated, 12 pigs were bled to induce a two-hour deep shock and resuscitated using normal saline based on haemodynamic goals. A one-hour infusion of 70 mg of caspofungin was started at the beginning of the resuscitation period. The lungs were removed four hours after caspofungin administration. Sixteen animals served as controls without haemorrhage. Caspofungin concentrations were measured by using high-performance liquid chromatography, and a two-compartment population pharmacokinetic analysis was performed.

ResultsIn the shock group, the volume of blood removed was 39 ± 7 mL-kg and a volume of 90 ± 17 mL-kg saline was infused throughout the resuscitation period. The extravascular lung water index was higher in the shock group 9.3 ± 1.6 mL-kg vs 5.7 ± 1 mL-kg in the control group; P < 0.01. In the shock group, the median interquartile range maximal plasma concentration was 37% lower than in the control group 21.6 μg-mL 20.7 to 22.3 vs 33.1 μg-mL 28.1 to 38.3; P < 0.01. The median area under curve AUC from zero to four hours was 25% lower in the shock group than in the control group 60.3 hours × μg-mL 58.4 to 66.4 vs 80.8 hours × μg-mL 78.3 to 96.9; P < 0.01, as was the median lung caspofungin concentration 1.22 μg-g 0.89 to 1.46 vs 1.64 μg-g 1.22 to 2.01; P < 0.01. However, the plasma-to-tissue ratios were not different between the groups, indicating that lung diffusion of caspofungin was not affected after shock followed by fluid loading. Pharmacokinetic analysis showed that the peripheral volume of distribution of caspofungin and intercompartmental clearance were significantly higher in the shock group, as was the total apparent volume of distribution.

ConclusionsHypovolaemic shock followed by fluid loading in the pig results in a significant increase in the apparent volume of distribution of caspofungin and in a decrease in its plasma and pulmonary exposition. Although our model was associated with capillary leakage and pulmonary oedema, our results should be generalised to the septic shock with caution. Future investigations should focus on monitoring plasma caspofungin concentrations and optimal caspofungin dosing in shock patients.

Keywordsechinocandin pharmacokinetics intensive care unit lung Abbreviationsσresidual variability of the model

ωinterindividual variability

AUC0→4 hoursarea under the curve of caspofungin plasma concentration from zero to four hours

CIcardiac index

CLelimination clearance of caspofungin

Cmaxmaximal plasma concentration of caspofungin

Cpcaspofungin plasma concentration at four hours

Ctlung caspofungin concentration at four hours

EVLWIextravascular lung water indexed to body weight

MAPmean arterial pressure

Qintercompartmental clearance of caspofungin

SVO2mixed venous oxygen saturation

V1central volume of distribution of caspofungin

V2peripheral volume of distribution of caspofungin

Vdtotal apparent volume of distribution of caspofungin.

Electronic supplementary materialThe online version of this article doi:10.1186-cc10455 contains supplementary material, which is available to authorized users.

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Author: Antoine Roch - Christian Woloch - Dorothée Blayac - Caroline Solas - Sylvie Quaranta - Vincent Mardelle - Matthias Castani

Source: https://link.springer.com/







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