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

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.

Forty-minute endovascular aortic occlusion increases survival in an experimental model of uncontrolled hemorrhagic shock caused by abdominal trauma.

BACKGROUND: To evaluate the feasibility of aortic balloon catheter occlusion in intra-abdominal hemorrhage. METHODS: Effects of transfemoral diaphragmatic aortic balloon occlusion (ABO) have been evaluated in 25 pigs. The animals were submitted to incontrollable hemorrhage by a splenic trauma. Group 1 (n = 9) received fluid resuscitation with normal saline (NS) without aortic occlusion; group 2 (n = 8) underwent 60 minutes ABO and NS. Groups 3 (n = 4) and 4 (n = 4) underwent ABO during 40 minutes and 60 minutes, respectively, NS, and splenectomy. RESULTS: Aortic balloon location was adequate in all animals. ABO increased the portion of 2-hour survivors significantly (7/16 vs. 0/9; p = 0.03). ABO increased mean arterial blood pressures (p < 0.05). There was a significant decrease of bleeding and volume of fluid resuscitation (p < 0.05) in ABO groups. Blood potassium and lactate levels at death were significantly higher in groups 2 and 4 compared with those of the control group: 29 ± 0.54 and 6.08 mmol/L ± 0.44 mmol/L versus 4.16 mmol/L ± 0.35 mmol/L (p < 0.02), and 11.39 mmol/L ± 0.37 mmol/L and 9.59 mmol/L ± 1.19 mmol/L versus 6.43 mmol/L ± 0.57 mmol/L (p < 0.001), respectively. There were no significant differences between group 3 and the control group: 4.83 mmol/L ± 0.32 mmol/L versus 6.43 mmol/L ± 0.57 mmol/L and 5.2 mmol/L ± 0.13 mmol/L versus 4.16 mmol/L ± 0.35 mmol/L, respectively. At necropsy, there were no significant differences in terms of visceral (bowel and kidney) ischemia between the different experimental groups. CONCLUSION: A 40-minute ABO followed by surgical damage control improved survival in this animal model of uncontrolled hemorrhagic shock caused by abdominal trauma. ABO could be considered for the management of severe abdominal trauma.

Effect of hypertonic saline pre-treatment on ischemia-reperfusion lung injury in pig.

BACKGROUND: Hypertonic saline may be administered in the setting of lung transplantation but may affect the development of ischemia-reperfusion lung injury. This study investigated the effects of the pre-treatment by intravenous hypertonic saline in a pig model of single lung ischemia-reperfusion. METHODS: Forty-three pigs (34 +/- 4 kg) under mechanical ventilation were randomly assigned to a left lung ischemia-reperfusion alone or preceded by 4-ml/kg 7.5% hypertonic saline, 33-ml/kg normal saline, or by the infusion of the vasodilator nicardipine. Animals without ischemia served as controls. After euthanasia, the left lung was sampled for histologic analysis and measurement of lung water and alveolar-capillary permeability. RESULTS: Ischemia-reperfusion resulted in high-permeability pulmonary edema, hypoxemia, and increased interleukin-6 serum level. Hypertonic saline pre-treatment worsened pulmonary edema of the left lung (6.6 +/- 0.7 vs 4.8 +/- 0.8 ml/kg of body weight, p < 0.05) and resulted in a higher ratio of the protein level in the alveolar fluid to the serum protein level (0.41 +/- 0.04 vs 0.21 +/- 0.09, p < 0.05) and in a higher histologic damage score (11 [range, 9-11.75] vs 6.5 [range, 4.5-7.5], p < 0.05) without promoting pulmonary or systemic inflammation. Lung injury was affected neither by normal saline nor by nicardipine pre-treatment. Nicardipine did not influence the deleterious effect of hypertonic saline. CONCLUSIONS: Pre-treatment by intravenous hypertonic saline worsened ischemia-reperfusion lung injury independently of its effects on the cardiac index or pulmonary circulation but probably through a direct effect of hyperosmolarity on endothelial permeability.