Ceftazidime reduces pulmonary hypertension in an ovine model of sepsis following smoke inhalation injury

Objective

Our group recently developed an ovine model of Pseudomonas aeruginosa sepsis associated with acute lung injury (ALI) [1]. The aim of this study was to modify this model by the administration of Ceftazidime (Cef) to simulate a more clinically relevant situation. This modification could be the basis for future studies investigating new treatment strategies in sepsis.

Methods

Eighteen sheep (35–40 kg) were operatively prepared for chronic study. After 7 days of recovery, sheep were randomly allocated either to sham, control, or Cef groups (n = 6 each). After a tracheostomy had been performed, ALI was produced in the control and Cef group by insufflation of 48 breaths of cotton smoke under deep halothane anesthesia. Then, live P. aeruginosa were instilled into the lungs via a bronchoscope [1]. The sham group received the vehicle, 48 breaths of room air and 30 ml saline. Subsequently, anesthesia was discontinued. The sheep were studied for 24 hours in the awake state and were ventilated with 100% oxygen (tidal volume 15 ml/kg, 30 breaths/min). The mean pulmonary artery pressure (MPAP) and pulmonary artery occlusion pressure (PAOP = wedge pressure) were determined every 3 hours. Cef (3 g, intravenously) was administered 1 hour and 13 hours post injury. The animals were resuscitated with Ringer's lactate solution to maintain filling pressures and hematocrit. Lung tissues were taken after the experiment to determine the bloodless lung tissue wet to dry weight ratio (W/D). Statistical analysis: two-way analysis of variance, Student–Newman–Keuls post hoc comparisons, significance P < 0.05.

Results

MPAP and PAOP remained stable in sham animals. The control group showed a significant increase in MPAP (baseline [BL]: 19 ± 1 vs 24 hours: 31 ± 1) and PAOP (BL: 11 ± 1 vs 24 hours: 17 ± 1) versus BL over time. The Cef group also showed an increase in MPAP (BL: 20 ± 1 vs 24 hours: 26 ± 1) and PAOP (BL: 10 ± 1 vs 24 hours: 13 ± 1) vs BL, but this increase was significantly lower in comparison with the control group. The fluid balance (sham: -547 ± 38, control: +1266 ± 75, Cef: +382 ± 55) was significantly higher in the control and Cef groups compared with sham, but also significantly reduced in the Cef group compared with the control group. However, the W/D ratio after 24 hours (sham: 5.0 ± 0.1, control: 5.8 ± 0.2, Cef: 5.7 ± 0.2) increased significantly in the control and Cef groups compared with sham, but was not statistically different between those groups.

Conclusion

The application of Cef after ALI associated with bacterial challenge reduced pulmonary hypertension and fluid requirement. The addition of antibiotics to the protocol will make it more clinically relevant and is a useful new approach for further studies in this modified sepsis model.