title: Effect of fluid loading during hypovolaemic shock on caspofungin pharmacokinetic parameters in pig.
abstract: BACKGROUND
  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.
authors.affiliation: Aix-Marseille Univ, URMITE CNRS-UMR 6236, 27 boulevard Jean Moulin, 13005 Marseille, France. antoine.roch@mail.ap-hm.fr
authors.forename: Antoine
authors.initials: A
authors.lastname: Roch
authors.forename: Christian
authors.initials: C
authors.lastname: Woloch
authors.forename: Dorothée
authors.initials: D
authors.lastname: Blayac
authors.forename: Caroline
authors.initials: C
authors.lastname: Solas
authors.forename: Sylvie
authors.initials: S
authors.lastname: Quaranta
authors.forename: Vincent
authors.initials: V
authors.lastname: Mardelle
authors.forename: Matthias
authors.initials: M
authors.lastname: Castanier
authors.forename: Laurent
authors.initials: L
authors.lastname: Papazian
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Sampol-Manos
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics*; D000077336:Caspofungin; D004195:Disease Models, Animal; D054714:Echinocandins / Q000097:blood / Q000493:pharmacokinetics*; D005440:Fluid Therapy; D055666:Lipopeptides; D008168:Lung / Q000378:metabolism; D012769:Shock / Q000378:metabolism / Q000628:therapy*; D013552:Swine; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000077336:Caspofungin