Understanding Clinical Literature Relevant to Spontaneous Intestinal Perforations

ABSTRACT

Spontaneous intestinal perforation (SIP) has emerged as a disease of extremely low-birth-weight (ELBW) infants over the last two decades. Several risk factors have been associated with this disease including early postnatal steroids (EPS; use within the first week of life), early use of indomethacin (EUI; use within the first 3 postnatal days), and the synergistic combination of the two. These two risk factors are thought to play a causal role in the etiology of SIP through their effects on ileal trophism and motility. Two infectious agents (Candida and Staphylococcus epidermidis) are commonly grown from peritoneal cultures of patients with SIP. It is less clear whether these infections play a causal role or if they represent comorbitities of perforation. Chorioamnionitis is thought to be a risk factor for SIP, as is the stress and elevated cortisol that accompanies it. Recent analyses suggest that antenatal indomethacin may also be a risk factor for SIP, particularly when given close to birth. These latter variables are more challenging to rank in importance compared with EPS and EUI, which have been repeatedly associated with SIP in both retrospective cohorts and randomized controlled trials. Because neonatal care of the ELBW infant is commonly standardized, the habitual combination of any of these risk factors potentially amplifies the risk of SIP. Many of these factors are medicines, thus SIP risk is exacerbated by select forms of polypharmacy. Our challenge lies in understanding how these drug interactions lead to harm.

KEYWORDS

spontaneous intestinal perforation - steroids - indomethacin

REFERENCES

• 1 Aschner J L, Deluga K S, Metlay L A, Emmens R W, Hendricks-Munoz K D. Spontaneous focal gastrointestinal perforation in very low birth weight infants.  J Pediatr. 1988;  113 364-367
• 2 Nagaraj H S, Sandhu A S, Cook L N, Buchino J J, Groff D B. Gastrointestinal perforation following indomethacin therapy in very low birth weight infants.  J Pediatr Surg. 1981;  16 1003-1007
• 3 Alpan G, Eyal F, Vinograd I et al.. Localized intestinal perforations after enteral administration of indomethacin in premature infants.  J Pediatr. 1985;  106 277-281
• 4 Kühl G, Seyberth H W. Intestinal perforations after enteral administration of indomethacin in premature infants.  J Pediatr. 1986;  108 327-328
• 5 Tatli M M, Kumral A, Duman N, Demir K, Gurcu O, Ozkan H. Spontaneous intestinal perforation after oral ibuprofen treatment of patent ductus arteriosus in two very-low-birthweight infants.  Acta Paediatr. 2004;  93 999-1001
• 6 Lloyd J R. The etiology of gastrointestinal perforations in the newborn.  J Pediatr Surg. 1969;  4 77-84
• 7 Steiner D H, Maxwell J G, Rasmussen B L, Jones R. Segmental absence of intestinal musculature. An unusual cause of intestinal obstruction in the neonate.  Am J Surg. 1969;  118 964-967
• 8 Miserez M, Barten S, Geboes K, Naulaers G, Devlieger H, Penninckx F. Surgical therapy and histological abnormalities in functional isolated small bowel obstruction and idiopathic gastrointestinal perforation in the very low birth weight infant.  World J Surg. 2003;  27 350-355
• 9 Huang S F, Vacanti J, Kozakewich H. Segmental defect of the intestinal musculature of a newborn: evidence of acquired pathogenesis.  J Pediatr Surg. 1996;  31 721-725
• 10 Tatekawa Y, Muraji T, Imai Y, Nishijima E, Tsugawa C. The mechanism of focal intestinal perforations in neonates with low birth weight.  Pediatr Surg Int. 1999;  15 549-552
• 11 Hwang H, Murphy J J, Gow K W, Magee J F, Bekhit E, Jamieson D. Are localized intestinal perforations distinct from necrotizing enterocolitis?.  J Pediatr Surg. 2003;  38 763-767
• 12 Holland A J, Shun A, Martin H C, Cooke-Yarborough C, Holland J. Small bowel perforation in the premature neonate: congenital or acquired?.  Pediatr Surg Int. 2003;  19 489-494
• 13 Mintz A C, Applebaum H. Focal gastrointestinal perforations not associated with necrotizing enterocolitis in very low birth weight neonates.  J Pediatr Surg. 1993;  28 857-860
• 14 Gordon P, Rutledge J, Sawin R, Thomas S, Woodrum D. Early postnatal dexamethasone increases the risk of focal small bowel perforation in extremely low birth weight infants.  J Perinatol. 1999;  19(8 Pt 1) 573-577
• 15 Attridge J T, Clark R, Walker M W, Gordon P V. New insights into spontaneous intestinal perforation using a national data set: (2) two populations of patients with perforations.  J Perinatol. 2006;  26 185-188
• 16 Garland J S, Alex C P, Pauly T H et al.. A three-day course of dexamethasone therapy to prevent chronic lung disease in ventilated neonates: a randomized trial.  Pediatrics. 1999;  104(1 Pt 1) 91-99
• 17 Anttila E, Peltoniemi O, Haumont D et al.. Early neonatal dexamethasone treatment for prevention of bronchopulmonary dysplasia. Randomised trial and meta-analysis evaluating the duration of dexamethasone therapy.  Eur J Pediatr. 2005;  164 472-481
• 18 Stark A R, Carlo W A, Tyson J E National Institute of Child Health and Human Development Neonatal Research Network et al. Adverse effects of early dexamethasone in extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network.  N Engl J Med. 2001;  344 95-101
• 19 Efird M M, Heerens A T, Gordon P V, Bose C L, Young D A. A randomized-controlled trial of prophylactic hydrocortisone supplementation for the prevention of hypotension in extremely low birth weight infants.  J Perinatol. 2005;  25 119-124
• 20 Peltoniemi O, Kari M A, Heinonen K et al.. Pretreatment cortisol values may predict responses to hydrocortisone administration for the prevention of bronchopulmonary dysplasia in high-risk infants.  J Pediatr. 2005;  146 632-637
• 21 Vermont Oxford Network Steroid Study Group . Early postnatal dexamethasone therapy for the prevention of chronic lung disease.  Pediatrics. 2001;  108 741-748
• 22 Kopelman A E, Moise A A, Holbert D, Hegemier S E. A single very early dexamethasone dose improves respiratory and cardiovascular adaptation in preterm infants.  J Pediatr. 1999;  135 345-350
• 23 Yeh T F, Torre J A, Rastogi A, Anyebuno M A, Pildes R S. Early postnatal dexamethasone therapy in premature infants with severe respiratory distress syndrome: a double-blind, controlled study.  J Pediatr. 1990;  117(2 Pt 1) 273-282
• 24 Shinwell E S, Karplus M, Zmora E et al.. Failure of early postnatal dexamethasone to prevent chronic lung disease in infants with respiratory distress syndrome.  Arch Dis Child Fetal Neonatal Ed. 1996;  74 F33-F37
• 25 Watterberg K L, Gerdes J S, Gifford K L, Lin H M. Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants.  Pediatrics. 1999;  104 1258-1263
• 26 Watterberg K L, Gerdes J S, Cole C H et al.. Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial.  Pediatrics. 2004;  114 1649-1657
• 27 Ng P C, Lee C H, Bnur F L et al.. A double-blind, randomized, controlled study of a “stress dose” of hydrocortisone for rescue treatment of refractory hypotension in preterm infants.  Pediatrics. 2006;  117 367-375
• 28 Rastogi A, Akintorin S M, Bez M L, Morales P, Pildes R S. A controlled trial of dexamethasone to prevent bronchopulmonary dysplasia in surfactant-treated infants.  Pediatrics. 1996;  98(2 Pt 1) 204-210
• 29 Sinkin R A, Dweck H S, Horgan M J et al.. Early dexamethasone-attempting to prevent chronic lung disease.  Pediatrics. 2000;  105(3 Pt 1) 542-548
• 30 Roberts R S. Early closure of the Watterberg Trial pediatrics.  Pediatrics. 2004;  114 1670-1671
• 31 Gordon P V. Weighing statistical certainty against ethical, clinical, and biologic expediency: the contributions of the Watterberg Trial tip the scales in the right direction pediatrics.  Pediatrics. 2005;  115 1446-1447
• 32 Jobe A H. Postnatal corticosteroids for preterm infants—do what we say, not what we do.  N Engl J Med. 2004;  350 1349-1351
• 33 Gordon P V. Postnatal dexamethasone for lung disease of prematurity.  N Engl J Med. 2004;  350 2715-2718
• 34 Gordon P V, Price W A, Stiles A D, Rutledge J C. Early postnatal dexamethasone diminishes transforming growth factor alpha localization within the ileal muscularis propria of newborn mice and extremely low-birth-weight infants.  Pediatr Dev Pathol. 2001;  4 532-537
• 35 Herman A C, Carlisle E M, Paxton J B, Gordon P V. Insulin-like growth factor-I governs submucosal growth and thickness in the newborn mouse ileum.  Pediatr Res. 2004;  55 507-513
• 36 Gordon P V, Paxton J B, Herman A C, Carlisle E M, Fox N S. Igf-I accelerates ileal epithelial cell migration in culture and newborn mice and may be a mediator of steroid-induced maturation.  Pediatr Res. 2004;  55 34-41
• 37 Gordon P V, Price W A, Stiles A D. Dexamethasone administration to newborn mice alters mucosal and muscular morphology in the ileum and modulates IGF-I localization.  Pediatr Res. 2001;  49 93-100
• 38 Gordon P V, Herman A C, Marcinkiewicz M, Gaston B M, Laubach V E, Aschner J L. A neonatal mouse model of intestinal perforation: investigating the harmful synergism between glucocorticoids and indomethacin.  J Pediatr Gastroenterol Nutr. 2007;  45 509-519
• 39 Kajanne R, Leppä S, Luukkainen P et al.. Hydrocortisone and indomethacin negatively modulate EGF-R signaling in human fetal intestine.  Pediatr Res. 2007;  62 570-575
• 40 Watterberg KL Weighing Statistical Certainty Against Ethical . Clinical, and biologic expediency: the contributions of the Watterberg Trial tip the scales in the right direction: in reply.  Pediatrics. 2005;  115 1447
• 41 Ragouilliaux C J, Keeney S E, Hawkins H K, Rowen J L. Maternal factors in extremely low birth weight infants who develop spontaneous intestinal perforation.  Pediatrics. 2007;  120 e1458-e1464
• 42 Schmidt B, Roberts R S, Fanaroff A et al.. TIPP Investigators. Indomethacin prophylaxis, patent ductus arteriosus, and the risk of bronchopulmonary dysplasia: further analyses from the Trial of Indomethacin Prophylaxis in Preterms (TIPP).  J Pediatr. 2006;  148 730-734
• 43 Attridge J T, Clark R, Walker M W, Gordon P V. New insights into spontaneous intestinal perforation using a national data set: (1) SIP is associated with early indomethacin exposure.  J Perinatol. 2006;  26 93-99
• 44 Amin S B, Sinkin R A, Glantz J C. Metaanalysis of the effect of antenatal indomethacin on neonatal outcomes.  Am J Obstet Gynecol. 2007;  197 486.e1-10
• 45 Gordon P V, Swanson J R, Clark R. Antenatal indomethacin is more likely associated with spontaneous intestinal perforation rather than NEC.  Am J Obstet Gynecol. 2008;  198 725
• 46 Adesanya O A, O'Shea T M, Turner C S, Amoroso R M, Morgan T M, Aschner J L. Intestinal perforation in very low birth weight infants: growth and neurodevelopment at 1 year of age.  J Perinatol. 2005;  25 583-589
• 47 Attridge J T, Clark R, Gordon P V. New insights into spontaneous intestinal perforation using a national data set (3): antenatal steroids have no adverse association with spontaneous intestinal perforation.  J Perinatol. 2006;  26 667-670
• 48 Coates E W, Karlowicz M G, Croitoru D P, Buescher E S. Distinctive distribution of pathogens associated with peritonitis in neonates with focal intestinal perforation compared with necrotizing enterocolitis.  Pediatrics. 2005;  116 e241-e246
• 49 Robertson N J, Kuna J, Cox P M, Lakhoo K. Spontaneous intestinal perforation and Candida peritonitis presenting as extensive necrotizing enterocolitis.  Acta Paediatr. 2003;  92 258-261
• 50 Bond S, Stewart D L, Bendon R W. Invasive Candida enteritis of the newborn.  J Pediatr Surg. 2000;  35 1496-1498
• 51 Anderson E E, Pappin A, Pavia A T. Spontaneous intestinal perforation in premature infants: a distinct clinical entity associated with systemic candidiasis.  J Pediatr Surg. 1998;  33 1463-1467
• 52 Novack C M, Waffarn F, Sills J H, Pousti T J, Warden M J, Cunningham M D. Focal intestinal perforation in the extremely-low-birth-weight infant.  J Perinatol. 1994;  14 450-453
• 53 Meyer C L, Payne N R, Roback S A. Spontaneous, isolated intestinal perforations in neonates with birth weight less than 1,000 g not associated with necrotizing enterocolitis.  J Pediatr Surg. 1991;  26 714-717
• 54 Attridge J T, Herman A C, Gurka M J, Griffin M P, McGahren E D, Gordon P V. Discharge outcomes of extremely low birth weight infants with spontaneous intestinal perforations.  J Perinatol. 2006;  26 49-54
• 55 Blakely M L, Tyson J E, Lally K P NICHD Neonatal Research Network et al. Laparotomy versus peritoneal drainage for necrotizing enterocolitis or isolated intestinal perforation in extremely low birth weight infants: outcomes through 18 months adjusted age.  Pediatrics. 2006;  117 e680-e687
• 56 Hintz S R, Kendrick D E, Stoll B J NICHD Neonatal Research Network. et al. Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis.  Pediatrics. 2005;  115 696-703
• 57 Grimes D A, Nanda K. Magnesium sulfate tocolysis: time to quit.  Obstet Gynecol. 2006;  108 986-989
• 58 Ohlsson A, Walia R, Shah S. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants.  Cochrane Database Syst Rev. 2008;  23 CD003481
• 59 Rees C M, Eaton S, Kiely E M, Wade A M, McHugh K, Pierro A. Peritoneal drainage or laparotomy for neonatal bowel perforation? A randomized controlled trial.  Ann Surg. 2008;  248 44-51