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A piglet model of advanced necrotising enterocolitis following exposure to hypoxia and endotoxin

Presented at the Neonatal Society 2003 Summer Meeting (programme).

Dhillon AS1,2, Al-Salti W3, Marshall JM1, Lander AD4, Booth IW4, Ewer AK2,4

1 Department of Physiology, University of Birmingham, UK
2 Department of Neonatology, Birmingham Women's Hospital, UK
3 Department of Pathology, Birmingham Children's Hospital, UK
4 Institute of Child Health, Birmingham, UK

Background: We recently developed a piglet model for early necrotising enterocolitis (NEC) using a combination of hypoxia and endotoxin (Lipopolysaccharide, LPS) (1). Using this model, we have shown that the intestinal lesions produced were ameliorated by prophylactic platelet-activating factor (PAF) antagonist administration (2), suggesting a role for PAF in the pathogenesis of NEC.
Aim: To develop a model for more advanced NEC using similar insults (hypoxia and LPS), but increasing the post-insult period.

Methods: 19 anaesthetised piglets median (range) age 2 days (2-4), weight 1975g (1260-2710) were studied. The animals formed 3 groups: Controls (n=9); Hypoxia + low dose LPS group (n=5); and Hypoxia + high dose LPS group (n=5). Controls breathed room air throughout. Both the low and high dose groups were given intravenous LPS (2mg/kg and 4mg/kg, respectively) and breathed 10% O2 for a 45 minute period. Physiological parameters, including heart rate (HR), arterial blood pressure (ABP), respiratory rate (RR), and arterial acid-base status were recorded. Experiments were terminated after 6 hours and the internal organs were removed, examined macroscopically and then fixed in formalin for histological examination.

Results: All physiological parameters were stable in controls. The 'high dose' group became significantly more acidaemic: mean pH 7.10 compared with the 'low dose' group (7.37) and controls (7.43) (p<0.01 and <0.0001, respectively). Mean blood pressure (mmHg) decreased from 88.4 to 63.2 (p<0.0001) in 'low dose' group and from 95.3 to 48.8 (p<0.0001) in 'high dose' group. During the hypoxic phase of the experiment mean arterial PaO2 (mmHg) decreased in both the 'low dose' and 'high dose' groups (from 67.3 to 34.7 and from 62.0 to 37.3, respectively).
Histological examination of the intestines in controls was normal in 8/9 and showed mild neutrophil infiltration in 1/9. Examination of the 'low dose' group showed congestion and patchy intraluminal and mucosal haemorrhage in the small and large intestine in 2/5; additionally, there was mucosal ulceration in 3/5. The 'high dose' group showed extensive severe congestion and epithelial apoptosis with inflammation in 1/5; villous irregularity and mucosal haemorrhage in 1/5; and mucosal ulceration and transmural haemorrhagic necrosis of ileum and caecum in 3/5. Pneumatosis intestinalis was present in 2/5 in the 'low dose' group and 2/5 in the 'high dose' group.

Conclusion: To our knowledge, our unique model is the first to demonstrate pneumatosis intestinalis, a feature which is pathognomonic for NEC, making it the closest model for the condition seen in humans. This will enable further study of the role of PAF in the pathogenesis of NEC, and importantly, the role of PAF antagonists as possible rescue treatment for this devastating disease.

1. Ewer AK, et al. J Pediatr Gastroenterol Nutr 1999; 28: 553.
2. Ewer AK, et al. Arch Dis Child 2001; 84 (suppl 1): A31. (submitted to Gut 2003)

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