Effect of fluid loading during hypovolaemic shock on caspofungin pharmacokinetic parameters in pig

Critical Care

Emmanuelle Sampol-Manos²  Laurent Papazian³  Matthias Castanier³  Vincent Mardelle¹  Sylvie Quaranta²  Caroline Solas²  Dorothée Blayac³  Christian Woloch²  Antoine Roch³ 

[1] Institut de médecine tropicale du service de santé des armées, 58 boulevard Charles Livon, 13007, Marseille, France;Laboratoire de Pharmacocinétique et de Toxicologie, Hôpital de la Timone, 264 rue Saint Pierre, 13005, Marseille, France;APHM, Hôpital Nord, Réanimation, Chemin des Bourrely 13915, Marseille, France

关键词: lung;    intensive care unit;    pharmacokinetics;    echinocandin;   

Others  :  1093849
DOI  :  10.1186/cc10455

 received in 2011-05-04, accepted in 2011-09-20,  发布年份 2011

【 摘 要 】

Introduction

Caspofungin 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.

Methods

After 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.

Results

In 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.

Conclusions

Hypovolaemic 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.

【 授权许可】

   
2011 Roch et al.; licensee BioMed Central Ltd.

【 图 表 】

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