Indomethacin administration after temporary ischemia causes bowel necrosis in mice

Several reports have suggested indomethacin administration causes necrotizing enterocolitis (NEC) in infants. Few experimental studies have addressed this relationship. We studied the effects of indomethacin after temporary intestinal ischemia in CD-1 mice, using a previously reported method of simulating NEC in mice. This involved occlusion of both superior mesenteric vessels for 15 minutes. Three groups were studied. In group 1, 12 mice had superior mesenteric vessels occluded for 15 minutes, followed by intravenous (IV) administration of saline for three doses over 3 days. In group 2, 12 mice had sham laparotomy, without occlusion of vessels, followed by IV administration of indomethacin for three doses over 3 days. In group 3, 36 mice had mesenteric vessel occlusion for 15 minutes, followed by IV administration of indomethacin for three doses over 3 days. The results were as follows: group 1, bowel necrosis developed in 1 of 12 animals (8%); group 2, all 12 animals survived without bowel damage (0%); and group 3, 22 of 36 animals developed bowel necrosis (61%) (Fisher's Exact Test: occlusion alone v occlusion and indomethacin, P = .002; indomethacin alone v occlusion and indomethacin, P = .00015.) We conclude that whereas occlusion alone or indomethacin alone does not cause bowel necrosis, temporary intestinal occlusion followed by indomethacin causes bowel necrosis in over 60% of animals studied. In the shocked preterm infant who may have suffered temporary intestinal ischemia, administration of indomethacin may be the second step to development of NEC.