A Model of Pediatric End-Stage Lung Failure in Small Lambs <20 kg

Abstract

One in five children with end-stage lung failure (ESLF) die while awaiting lung transplant. No suitable animal model of ESLF exists for the development of artificial lung devices for bridging to transplant. Small lambs weighing 15.7 ± 3.1 kg (n = 5) underwent ligation of the left anterior pulmonary artery (PA) branch, and gradual occlusion of the right main PA over 48 hours. All animals remained hemodynamically stable. Over seven days of disease model conditions, they developed pulmonary hypertension (mean PA pressure 20 ± 5 vs. 33 ± 4 mm Hg), decreased perfusion (SvO2 66 ± 3 vs. 55 ± 8%) with supplemental oxygen requirement, and severe tachypneic response (45 ± 9 vs. 82 ± 23 breaths/min) (all p < 0.05). Severe right heart dysfunction developed (tricuspid annular plane systolic excursion 13 ± 3 vs. 7 ± 2 mm, fractional area change 36 ± 6 vs. 22 ± 10 mm, ejection fraction 51 ± 9 vs. 27 ± 17%, all p < 0.05) with severe tricuspid regurgitation and balloon-shaped dilation of the right ventricle. This model of pediatric ESLF reliably produces pulmonary hypertension, right heart strain, and impaired gas exchange, and will be used to develop a pediatric artificial lung.

Figure 1. Surgical Instrumentation, Diagram, And Intraoperative Photo

A = Adjustable tourniquet controlling the right pulmonary artery; B = Ligated anterior branch of the left pulmonary artery; C = vascular flow probe around the main pulmonary artery.

Figure 2

Experimental Timeline

Figure 3. Systemic Hemodynamics

Mean arterial pressure (A), heart rate (B), and main PA flow (C) remained stable, while mean PA pressure (D) significantly increased after occlusion. * p<0.05 and ** p<0.01 compared to Baseline

Figure 4. Respiratory Variables (Ventilation)

Animals experienced a transient increase in pCO₂ (A) and compensated with significantly increased respiratory rate (B). * p<0.05 and ** p<0.01 compared to Baseline

Figure 5. Oxygenation and Oxygen Requirements

Mixed venous saturation decreased significantly after occlusion (A), but paO₂ and oxygen saturation remained stable with supplemental O₂ via nasal cannula (B, C, and D). * p<0.05 and ** p<0.01 compared to Baseline

Figure 6. Effects Of The Disease Model On Right Ventricular Function

Over 7 days of 100% right pulmonary artery occlusion, right ventricular size significantly increased, while contractility significantly decreased (p < 0.05 for all parameters). RV EDA = right ventricular end-diastolic area; RV ESA = right ventricular end-systolic area; FAC = fractional area change

Figure 7. Histology Of Lung And Cardiac Tissue

Histologic findings of left lung (A and B), right lung (C and D), right atrium (E), and right ventricle (F). Left lung: thickening and disruption of tunica media of small arteries (arrowhead) with mixed perivascular inflammation (A); Left lung: smooth muscle hyperplasia (arrowheads) and focal interstitial fibrosis (B); Right lung: diffuse fibrin deposition in alveoli (arrowhead), and indistinct alveolar septae with diffuse congestion (C); Right lung: multifocal areas of acellular material (arrowheads), with edema and thickening of alveolar septae and alveolar spaces (D); Right atrium: locally extensive edema separating myofiber bundles (E); Right ventricle: multifocal zones of myofiber degeneration and mineralization within the papillary muscles (arrowhead), with hypertrophied interstitial cells, granulation tissue, and scant inflammatory cells (F).