Effect of ductus ligation on cardiopulmonary function in premature baboons

Abstract

Rationale: The role of the patent ductus arteriosus in the development of chronic lung disease in surfactant-treated premature newborns remains unclear.

Objective: To examine the effects of ductus ligation on cardiopulmonary function and lung histopathology in premature primates.

Methods: Baboons were delivered at 125 d, (term = 185 d) treated with surfactant, and ventilated for 14 d. Serial echocardiograms and pulmonary function tests were performed. Animals were randomized to ligation (n = 12) or no ligation (controls, n = 13) on Day 6 of life. Necropsy was performed on Day 14.

Results: Compared with nonligated control animals, ligated animals had lower pulmonary-to-systemic flow ratios, higher systemic blood pressures, and improved indices of right and left ventricular performance. The ligated animals tended to have better compliance and ventilation indices for the last 3 d of the study. There were no differences between the groups in proinflammatory tracheal cytokines (interleukin [IL] 6 and IL-8), static lung compliance, or lung histology.

Conclusion: Although a persistent patent ductus arteriosus results in diminished cardiac function and increased ventilatory requirements at the end of the second week of life, ligation on Day 6 had no measurable effect on the histologic evolution of chronic lung injury in this 14-d baboon model.

Figure 1.

(A) Pulmonary-to-systemic blood flow (Q̇P/Q̇S), (B) mean systemic blood pressure (BP), and (C) ratio of pulmonary-to-systemic systolic BP in ligated (n = 12; solid circles) and control (unligated, n = 13; open circles) animals. Surgical ligation was performed on Day 6 in the ligated group. Values are mean ± SD. Values between the study groups were similar before ductus ligation (Day 5) in A, B, and C. Values between the study groups were significantly different for Days 7–13 (ligated vs. control, analysis of variance, p < 0.05) in A, B, and C.

Figure 2.

Comparison of indices of right ventricular performance for (A) acceleration time (AT) and (B) peak Doppler velocity at the pulmonary valve (Pvel[P]) and left ventricular performance for (C) shortening fraction (SF) and (D) rate-corrected velocity of circumferential shortening (VCFc) in ligated (hatched bars) and control (open bars) animals. Indices were compared during three time periods: before ligation (values on Day 5), the early postoperative period (values on Days 7–10), and the late postoperative period (values on Days 11–13). Values are mean ± SD. ^*p < 0.05, ligated versus control.

Figure 3.

Comparison of (A) oxygenation index (OI), (B) ventilation index (VI), and (C) dynamic compliance per kilogram of bodyweight (C/kg) in ligated (hatched bars) and control (open bars) animals. Indices were compared during three time periods: before ligation (values on Day 5), the early postoperative period (values on Days 7–10), and the late postoperative period (values on Days 11–13). Values are mean ± SD. OI in the ligation group tended (p < 0.09) to be higher than that of the control group during the early postoperative period (Days 7–10) but was similar during the later part of the study (Days 11–13). VI tended to be lower (p = 0.08) and dynamic compliance tended to be higher (p < 0.08) in the ligated animals during Days 11–13 of the study.

Figure 4.

Comparison of cytokines interleukin (IL)-6 (A) and IL-8 (B) concentrations in tracheal aspirates obtained on Days 3–4, Days 5–7, Days 9–11, and Ddays 12–13 in ligated (hatched bars) and control (open bars) animals. Values are mean ± SD. There were no significant differences between the groups.

Figure 5.

Comparison of static inflation and deflation lung pressure–volume curves performed after necropsy in ligated and control animals (see METHODS). Values are mean ± SD. Open circles, control inflation; open triangles, control deflation; solid circles, ligated inflation; solid triangles, ligated deflation.

Figure 6.

Box and whisker plot of panel of standards comparison of ligated (n = 12) and control (unligated; n = 13) animals. Each photograph was graded independently by three different observers using the derived panel of standards (see Methods). Shown are median (thick bar), mean (solid squares), interquartile spread (box), and range (whiskers). There were no significant differences between the groups.