602
October 1975 TheJournalofPEDIATRICS
Necrotizing enterocolitis in low-birth-weight infants fed an elemental formula The incidence o f necrotizing enterocolitis in the newborn infant has increased within the same time period that increasing emphasis has been placed on oral alimentation o f very small infants. A prospective investigation was conducted to determine the nutritional efficacy as well as the incidence of necrotizing enterocolitis o f a standard cow milk formula compared with an elemental formula. Sixteen infants who weighed less than 1,200 gm were randomized and fed one of the two formulas. The clinical status o f the two groups was similar. Seven of eight (87.5%) infants f e d the elemental formula and two of eight (25%) fed the standard cow milk formula developed necrotizing enterocolitis (1o< 0.02). The hypertonir of the elemental diet may have contributed to the increased incidence of necrotizing enterocolitis in infants fed this formula.
Linda Sue Book, M.D.,* John J. Herbst, M.D., Stephen O. Atherton, M.D., and August L. Jung, M . D . , S a l t L a k e City, U t a h
NECROTIZING ENTEROCOLITIS is a serious and often
fatal disorder of the newborn infant which is being recognized with increasing frequency in many newborn intensive care centers?-" The incidence varies from 0.3% to 7.5% in various medical centers. 3-9 At the Intermountain Newborn Intensive Care Center the overall prevalence has increased from 0.5% of total admissions prior to 1972 to 5.2% in 1973-1974. Contributing to this dramatic increase may be longer survival and greater salvage of smaller and smaller infants. In our nursery 27% of all infants who weighed less than 1,200 gm developed necrotizing enterocolitis. Aggressive oral alimentation of very low-birth-weight infants may also contribute to the increased incidence of necrotizing enterocolitis. An aggressive feeding approach has been necessary because of the increased metabolic demands of very small premature infants and because of
From the Department of Pediatrics. University o f Utah. Supported in part by National Institutes of Health grant l i D 01478-01.Presented in part before the Society for Pediatric Research, May, 1974. *Reprint address: Department of Pediatrics, University of Utah, Salt Lake City, Utah.
Vol. 87, No. 4, pp. 602-605
their inability to completely assimilate the usual infant formulas. Fat absorption is markedly decreased in premature infants but can be significantly improved by feeding medium-chain triglycerides."-s A decreased absorptive capacity for carbohydrate occurs in up to 70% of all premature infants fed cow milk formulas who develop necrotizing enterocolitis but in less than 10% who do not See related article, p. 606.
Abbreviations used: CMF: cow milk formula EF: elemental formula develop the disorder2 Elemental formulas might be more efficiently absorbed and allow a less aggressive approach to oral alimentation. A study was therefore designed to compare the use of an elemental formula and a conventional infant formula in terms of nutritional efficacy as well as the incidence of necrotizing enterocolitis.
PATIENTS AND METHODS Because the prevalence of necrotizing enterocolitis is highest in very low-birth-weight infants, we studied only infants from the Intermountain Newborn Intensive Care
Volume 87 Number 4 Center whose birth weights were less than 1,200 gm. The investigation took place between August, 1973, and February, 1974. Written informed consent was obtained from the parents of all infants entered into the study. Both of the formulas studied were commercially available and were being widely used in our nursery for the oral nutrition of small premature infants. Sixteen infants were randomized at the time of their first oral feeding; eight were fed either a cow milk formula specially designed for premature infants (Premature Formula, Mead Johnson Laboratories), and eight were fed an elemental formula (Pregestimil, Mead Johnson Laboratories). The 0.8 cal/ml cow milk formula contained 2.8 gm/dl cow milk protein, 3.7 g m / d l corn oil, and 9.1 g m / d l sucrose and lactose. The 0.67 cal/ml elemental formula Contained 2.2 g m / d l casein hydrolysate, 2.8 gm/dl medium-chain triglycerides, and 8.8 gm/dl glucose. Oral feedings were initiated when the pulmonary status of the infant had stabilized. For most of the infants the first feeding was given by 48 hours-of age. Feedings were advanced from sterile water to full-strength formula over 24 hours. The volume was increased at an average rate of i9 m l / k g / d a y in infants fed the elemental formula and 17 m l / k g / d a y in infants fed the cow milk formula until adequate intake was attained, Infants remained in the study until they were discharged or developed necrotizing enterocolitis. A n infant was considered to have necrotizing enterocolitis when the characteristic features of ileus, abdominal distention, gastrointestinal bleeding, and pneumatosis intestinalis were present. The investigation was terminated when 16 infants had been entered into the study, because a large percentage of infants in one feeding group had developed necrotizing enterocolitis. After termination of the study results were analyzed using Fisher's exact test for small samples and the student t test. Because of the development of necrotizing enterocolitis in many of the infants entered into the investigation, meaningful comparison of the nutritional efficacy of the two formulas could not be made. RESULTS The two groups did not differ significantly in birth weight, gestational age, or 5-minute Apgar score (Table I). The infants fed C M F and EF required nearly the same degree of pulmonary support (Table II). Four infants in each group had extended periods of mechanical ventilation. One of the infants fed C M F required continuous positive airway pressure. Three infants fed C M F and four infants fed EF were maintained in headboxes with oxygen concentrations of less than 40%. Other clinical features
Necrotizing enterocolitis in LB W infants
603
Table I. Birth weights, gestational ages, and Apgar scores in infants fed cow milk formula and elemental formula
Eight infantsfed cow milk formula
Eight infantsfed elementalformula
Mean [SD [ Range Mean] SD
Range
Birth weight* 985 _+164 750-1200 930 _+ 185 680-1,120 (gm) Gestational 29 _+ 2.l 28-32 28 _ 2.5 24-32 age* (wk) 5-minute Ap5 -+ 1.98 3-8 5 _+ 1.42 2-8 gar* * Using student's t test no significantdifferencewas demonstrated. Table II. Clinical features of sixteen premature infants fed either a cow milk formula or an elemental formula
I Cow milk formula Number of patients Ventilatory assistance Continuous positive airway pressure Headbox < 40% O2 Congestive heart failure Exchange transfusion Umbilical artery catheter Documented sepsis
Elementalformula
8 4
8 4
1
0
3 3
4 3
0
1
6
7
0
0
were also similar in the two groups of infants. Three infants in each feeding group developed congestive heart failure. All of these infants required periods of ventilatory assistance and all had a patent ductus arteriosus. There were no other cardiac abnormalities present in the 16 infants. One infant fed EF received an exchange transfusion through an umbilical artery catheter for hyperbilirubinemia. Six infants fed CMF and seven infants fed EF had umbilical artery catheters. Sepsis was not documented in any infant prior to the development of necrotizing enterocolitis. Seven of eight infants (87.5%) fed EF developed necrotizing enterocolitis, whereas only two of eight infants (25%) fed C M F developed the disease ( p < 0.02 using Fisher's exact test). The 25% incidence of necrotizing enterocolitis in the group fed EF is similar to the 27% expected incidence of the disease in our nursery in infants weighing less than 1,200 gin. The diagnosis of necrotizing enterocolitis was confirmed at surgery in one infant fed C M F and four infants fed EF. Of the one infant fed C M F and three infants fed
604
B o o k et aL
The Journal of Pediatrics October 1975
DEVELOPMENT OFNECROTIZING ENTEROCOLITIS
Hypoxic 8~ hypotensive episodes
"-,,
L~
/
R Shunt e.g. PDA
Intestinol Ischernia Hypertonic feedings
unknown factors
~ ~ J Uucosol Injury t ~
Bacterial invasion
/
9
Necrotizing Enlerocolitis Fig. 1. Schematic diagram illustrating the possible pathogenesis of necrotizing enterocolitis. EF not requiting surgery the characteristic features of pneumatosis intestinalis, abdominal distention, and ileus were present. The mean age at diagnosis was 10.5 days in the group fed C M F and 18 days in the group fed EF. DISCUSSION Our prospective study illustrates that very low-birthweight infants fed the elemental formula have an increased risk of developing necrotizing enterocolitis when compared to similar infants fed a cow milk formula designed for feeding premature infants. The distribution of calories among protein, fat, and carbohydrate sources does not differ markedly in the two formulas. It seems unlikely that the amino acids, medium-chain triglycerides, or glucose would in themselves be deleterious to the premature infant. Since the elemental formula does provide protein as a predigested hydrolystate rather than large molecular weight polypeptides and carbohydrate as simple sugar rather than disaccharides, the osmolarity is much greater than conventional infant formulas. The osmolarity of EF, 650 m0sm/1, is over two times that of normal plasma. The osmolarity of C M F is 359 m0sm/1. It seems likely that the hyperosmolar effects of the elemental formula were responsible for the increased incidence of necrotizing enterocolitis. That the hypertonicity of EF can be implicated as the reason for the increased incidence of necrotizing enterocolitis in infants fed EF is supported by animal studies. Prematurely delivered goats fed hyperosmolar goat milk developed a disease closely resembling necrotizing enterocolitis.TM The early histologic lesion in necrotizing enterocolitis is mucosal necrosis? 1 Conceivably anything which alters the
integrity of the intestinal mucosa could predispose to the development of necrotizing enterocolitis. It has been shown in animal studies as well as in man that hypertonic solutions applied to the intestine produce microscopic damage of the mucosal lining cells. 1~, 13 Intestinal ischemia which can occur during asphyxia in young animals may initiate the pathologic processes in the development of necrotizing enterocolitis TM (Fig. 1). There is evidence that hypertonic solutions alter intestinal perfusion. Decreased venous outflow has been measured from rabbit ileal loops containing hypertonic solutions. 1~ If the ingestion of a hyperosmolar solution produced the equivalent o f the dumping syndrome, the circulating plasma volume of the small infant would be transiently decreased resulting in hypotension and decreased perfusion of the intestine. We have no clinical evidence from our investigation to support this hypothesis, because careful measurements of blood pressure during and after feedings were not included in our hwestigation. The investigations, which have been conducted on the cellular and cardiovascular effects of hypertonic solutions, have been performed in adult subjects. It is possible that the effects of orally ingested hypertonic solutions on very small premature infants are much more pronounced. It seems reasonable, therefore, that hyperosmolar formulas be used with great caution in small premature infants.
REFERENCES 1. Touloukian RS, Berdon WE, Armoury RA, et al: Surgical experience with necrotizing enterocolitis in the infant, J Pediatr Surg 2:388, 1967. 2. Stevenson JK, Oliver TK Sr, Graham B, et al: Aggressive treatment of neonatal necrotizing enterocolitis, J Pediatr Surg 6:28, 1971. 3. Bell RS, Graham B, and Stevenson JK: Roentgenologic and clinical manifestations of neonatal necrotizing enterocolitis, Am J Roentgol Radium Ther Nucl Med, 112:123, 1971. 4. Dudgeon, David, Caron AG, Lauppe FA, et ali Surgical management of acute necrotizing enterocolitis in infancy, J Pediatr Surg 8:607, 1973. 5". Frantz I, L'Heureux P, et ah Clinical correlates of necrotizing enterocolitis, Pediatr Res 8:381, 1974. 6. Katz L, and Hamilton R: Fat absorption in very low birthweight infants (abst), Pediatr Res 8:385, 1974. 7. Roy CC, St. Marie M, Weker A, and Bard H: Correction of the physiologic malabsorption of the premature by a medium chain triglyceridr formula (abst), Pediatr Res 8:385, 1974. 8. Andrews BF, and Lorch J: Improved fat and calcium absorption in L.B.W. infants fed a medium-chain triglyceride containing formula (abst), Pediatr Res 8:378, 1974. 9. Book LS, Herbst JJ, Jung AL, and Atherton S: Increased fecal reducing substances as a predictor of necrotizing enterocolitis (abst), Clin Res 22:238A, 1974. 10. Delemos R. Rogers, SH, and McLaughlin G: Experimental production of necrotizing enterocolitis in newborn goats (abst), Pediatr Res 8:380, 1974:
Vohtme 87 Number 4
11. Hopkins BG, Gould VE, et al: Necrotizing enterocolitis in premature infants, Am J Dis Child 120:229, 1970. 12. Nasrallah S, Coburn W, and lber F: The effect of mannitol on the intestine of man, John Hopkins Med J 123:134, 1968. 13. Kameda H, Abei T, et al: Functional and histological injury to intestinal mucosa produced by hypertonicity, Am J Physiol 214:1090, 1968.
Necrotizing enterocolitis in L B W infants
605
14. Touloukian RS, Posch JN, and Spencer R: The pathogenesis of ischemic gastroenterocolitis of the neonate: selective gut mucosa ischemia in asphyxiated neonatal piglets, J Pediatr Surg 7:194, 1973. 15. Norris H: Response of the small intestine to the application of a hypertonic solution, Am J Pathol 73:747, 1973.
October 1975 TheJournalofPEDIATRICS
Necrotizing enterocolitis in low-birth-weight infants fed an elemental formula The incidence o f necrotizing enterocolitis in the newborn infant has increased within the same time period that increasing emphasis has been placed on oral alimentation o f very small infants. A prospective investigation was conducted to determine the nutritional efficacy as well as the incidence of necrotizing enterocolitis o f a standard cow milk formula compared with an elemental formula. Sixteen infants who weighed less than 1,200 gm were randomized and fed one of the two formulas. The clinical status o f the two groups was similar. Seven of eight (87.5%) infants f e d the elemental formula and two of eight (25%) fed the standard cow milk formula developed necrotizing enterocolitis (1o< 0.02). The hypertonir of the elemental diet may have contributed to the increased incidence of necrotizing enterocolitis in infants fed this formula.
Linda Sue Book, M.D.,* John J. Herbst, M.D., Stephen O. Atherton, M.D., and August L. Jung, M . D . , S a l t L a k e City, U t a h
NECROTIZING ENTEROCOLITIS is a serious and often
fatal disorder of the newborn infant which is being recognized with increasing frequency in many newborn intensive care centers?-" The incidence varies from 0.3% to 7.5% in various medical centers. 3-9 At the Intermountain Newborn Intensive Care Center the overall prevalence has increased from 0.5% of total admissions prior to 1972 to 5.2% in 1973-1974. Contributing to this dramatic increase may be longer survival and greater salvage of smaller and smaller infants. In our nursery 27% of all infants who weighed less than 1,200 gm developed necrotizing enterocolitis. Aggressive oral alimentation of very low-birth-weight infants may also contribute to the increased incidence of necrotizing enterocolitis. An aggressive feeding approach has been necessary because of the increased metabolic demands of very small premature infants and because of
From the Department of Pediatrics. University o f Utah. Supported in part by National Institutes of Health grant l i D 01478-01.Presented in part before the Society for Pediatric Research, May, 1974. *Reprint address: Department of Pediatrics, University of Utah, Salt Lake City, Utah.
Vol. 87, No. 4, pp. 602-605
their inability to completely assimilate the usual infant formulas. Fat absorption is markedly decreased in premature infants but can be significantly improved by feeding medium-chain triglycerides."-s A decreased absorptive capacity for carbohydrate occurs in up to 70% of all premature infants fed cow milk formulas who develop necrotizing enterocolitis but in less than 10% who do not See related article, p. 606.
Abbreviations used: CMF: cow milk formula EF: elemental formula develop the disorder2 Elemental formulas might be more efficiently absorbed and allow a less aggressive approach to oral alimentation. A study was therefore designed to compare the use of an elemental formula and a conventional infant formula in terms of nutritional efficacy as well as the incidence of necrotizing enterocolitis.
PATIENTS AND METHODS Because the prevalence of necrotizing enterocolitis is highest in very low-birth-weight infants, we studied only infants from the Intermountain Newborn Intensive Care
Volume 87 Number 4 Center whose birth weights were less than 1,200 gm. The investigation took place between August, 1973, and February, 1974. Written informed consent was obtained from the parents of all infants entered into the study. Both of the formulas studied were commercially available and were being widely used in our nursery for the oral nutrition of small premature infants. Sixteen infants were randomized at the time of their first oral feeding; eight were fed either a cow milk formula specially designed for premature infants (Premature Formula, Mead Johnson Laboratories), and eight were fed an elemental formula (Pregestimil, Mead Johnson Laboratories). The 0.8 cal/ml cow milk formula contained 2.8 gm/dl cow milk protein, 3.7 g m / d l corn oil, and 9.1 g m / d l sucrose and lactose. The 0.67 cal/ml elemental formula Contained 2.2 g m / d l casein hydrolysate, 2.8 gm/dl medium-chain triglycerides, and 8.8 gm/dl glucose. Oral feedings were initiated when the pulmonary status of the infant had stabilized. For most of the infants the first feeding was given by 48 hours-of age. Feedings were advanced from sterile water to full-strength formula over 24 hours. The volume was increased at an average rate of i9 m l / k g / d a y in infants fed the elemental formula and 17 m l / k g / d a y in infants fed the cow milk formula until adequate intake was attained, Infants remained in the study until they were discharged or developed necrotizing enterocolitis. A n infant was considered to have necrotizing enterocolitis when the characteristic features of ileus, abdominal distention, gastrointestinal bleeding, and pneumatosis intestinalis were present. The investigation was terminated when 16 infants had been entered into the study, because a large percentage of infants in one feeding group had developed necrotizing enterocolitis. After termination of the study results were analyzed using Fisher's exact test for small samples and the student t test. Because of the development of necrotizing enterocolitis in many of the infants entered into the investigation, meaningful comparison of the nutritional efficacy of the two formulas could not be made. RESULTS The two groups did not differ significantly in birth weight, gestational age, or 5-minute Apgar score (Table I). The infants fed C M F and EF required nearly the same degree of pulmonary support (Table II). Four infants in each group had extended periods of mechanical ventilation. One of the infants fed C M F required continuous positive airway pressure. Three infants fed C M F and four infants fed EF were maintained in headboxes with oxygen concentrations of less than 40%. Other clinical features
Necrotizing enterocolitis in LB W infants
603
Table I. Birth weights, gestational ages, and Apgar scores in infants fed cow milk formula and elemental formula
Eight infantsfed cow milk formula
Eight infantsfed elementalformula
Mean [SD [ Range Mean] SD
Range
Birth weight* 985 _+164 750-1200 930 _+ 185 680-1,120 (gm) Gestational 29 _+ 2.l 28-32 28 _ 2.5 24-32 age* (wk) 5-minute Ap5 -+ 1.98 3-8 5 _+ 1.42 2-8 gar* * Using student's t test no significantdifferencewas demonstrated. Table II. Clinical features of sixteen premature infants fed either a cow milk formula or an elemental formula
I Cow milk formula Number of patients Ventilatory assistance Continuous positive airway pressure Headbox < 40% O2 Congestive heart failure Exchange transfusion Umbilical artery catheter Documented sepsis
Elementalformula
8 4
8 4
1
0
3 3
4 3
0
1
6
7
0
0
were also similar in the two groups of infants. Three infants in each feeding group developed congestive heart failure. All of these infants required periods of ventilatory assistance and all had a patent ductus arteriosus. There were no other cardiac abnormalities present in the 16 infants. One infant fed EF received an exchange transfusion through an umbilical artery catheter for hyperbilirubinemia. Six infants fed CMF and seven infants fed EF had umbilical artery catheters. Sepsis was not documented in any infant prior to the development of necrotizing enterocolitis. Seven of eight infants (87.5%) fed EF developed necrotizing enterocolitis, whereas only two of eight infants (25%) fed C M F developed the disease ( p < 0.02 using Fisher's exact test). The 25% incidence of necrotizing enterocolitis in the group fed EF is similar to the 27% expected incidence of the disease in our nursery in infants weighing less than 1,200 gin. The diagnosis of necrotizing enterocolitis was confirmed at surgery in one infant fed C M F and four infants fed EF. Of the one infant fed C M F and three infants fed
604
B o o k et aL
The Journal of Pediatrics October 1975
DEVELOPMENT OFNECROTIZING ENTEROCOLITIS
Hypoxic 8~ hypotensive episodes
"-,,
L~
/
R Shunt e.g. PDA
Intestinol Ischernia Hypertonic feedings
unknown factors
~ ~ J Uucosol Injury t ~
Bacterial invasion
/
9
Necrotizing Enlerocolitis Fig. 1. Schematic diagram illustrating the possible pathogenesis of necrotizing enterocolitis. EF not requiting surgery the characteristic features of pneumatosis intestinalis, abdominal distention, and ileus were present. The mean age at diagnosis was 10.5 days in the group fed C M F and 18 days in the group fed EF. DISCUSSION Our prospective study illustrates that very low-birthweight infants fed the elemental formula have an increased risk of developing necrotizing enterocolitis when compared to similar infants fed a cow milk formula designed for feeding premature infants. The distribution of calories among protein, fat, and carbohydrate sources does not differ markedly in the two formulas. It seems unlikely that the amino acids, medium-chain triglycerides, or glucose would in themselves be deleterious to the premature infant. Since the elemental formula does provide protein as a predigested hydrolystate rather than large molecular weight polypeptides and carbohydrate as simple sugar rather than disaccharides, the osmolarity is much greater than conventional infant formulas. The osmolarity of EF, 650 m0sm/1, is over two times that of normal plasma. The osmolarity of C M F is 359 m0sm/1. It seems likely that the hyperosmolar effects of the elemental formula were responsible for the increased incidence of necrotizing enterocolitis. That the hypertonicity of EF can be implicated as the reason for the increased incidence of necrotizing enterocolitis in infants fed EF is supported by animal studies. Prematurely delivered goats fed hyperosmolar goat milk developed a disease closely resembling necrotizing enterocolitis.TM The early histologic lesion in necrotizing enterocolitis is mucosal necrosis? 1 Conceivably anything which alters the
integrity of the intestinal mucosa could predispose to the development of necrotizing enterocolitis. It has been shown in animal studies as well as in man that hypertonic solutions applied to the intestine produce microscopic damage of the mucosal lining cells. 1~, 13 Intestinal ischemia which can occur during asphyxia in young animals may initiate the pathologic processes in the development of necrotizing enterocolitis TM (Fig. 1). There is evidence that hypertonic solutions alter intestinal perfusion. Decreased venous outflow has been measured from rabbit ileal loops containing hypertonic solutions. 1~ If the ingestion of a hyperosmolar solution produced the equivalent o f the dumping syndrome, the circulating plasma volume of the small infant would be transiently decreased resulting in hypotension and decreased perfusion of the intestine. We have no clinical evidence from our investigation to support this hypothesis, because careful measurements of blood pressure during and after feedings were not included in our hwestigation. The investigations, which have been conducted on the cellular and cardiovascular effects of hypertonic solutions, have been performed in adult subjects. It is possible that the effects of orally ingested hypertonic solutions on very small premature infants are much more pronounced. It seems reasonable, therefore, that hyperosmolar formulas be used with great caution in small premature infants.
REFERENCES 1. Touloukian RS, Berdon WE, Armoury RA, et al: Surgical experience with necrotizing enterocolitis in the infant, J Pediatr Surg 2:388, 1967. 2. Stevenson JK, Oliver TK Sr, Graham B, et al: Aggressive treatment of neonatal necrotizing enterocolitis, J Pediatr Surg 6:28, 1971. 3. Bell RS, Graham B, and Stevenson JK: Roentgenologic and clinical manifestations of neonatal necrotizing enterocolitis, Am J Roentgol Radium Ther Nucl Med, 112:123, 1971. 4. Dudgeon, David, Caron AG, Lauppe FA, et ali Surgical management of acute necrotizing enterocolitis in infancy, J Pediatr Surg 8:607, 1973. 5". Frantz I, L'Heureux P, et ah Clinical correlates of necrotizing enterocolitis, Pediatr Res 8:381, 1974. 6. Katz L, and Hamilton R: Fat absorption in very low birthweight infants (abst), Pediatr Res 8:385, 1974. 7. Roy CC, St. Marie M, Weker A, and Bard H: Correction of the physiologic malabsorption of the premature by a medium chain triglyceridr formula (abst), Pediatr Res 8:385, 1974. 8. Andrews BF, and Lorch J: Improved fat and calcium absorption in L.B.W. infants fed a medium-chain triglyceride containing formula (abst), Pediatr Res 8:378, 1974. 9. Book LS, Herbst JJ, Jung AL, and Atherton S: Increased fecal reducing substances as a predictor of necrotizing enterocolitis (abst), Clin Res 22:238A, 1974. 10. Delemos R. Rogers, SH, and McLaughlin G: Experimental production of necrotizing enterocolitis in newborn goats (abst), Pediatr Res 8:380, 1974:
Vohtme 87 Number 4
11. Hopkins BG, Gould VE, et al: Necrotizing enterocolitis in premature infants, Am J Dis Child 120:229, 1970. 12. Nasrallah S, Coburn W, and lber F: The effect of mannitol on the intestine of man, John Hopkins Med J 123:134, 1968. 13. Kameda H, Abei T, et al: Functional and histological injury to intestinal mucosa produced by hypertonicity, Am J Physiol 214:1090, 1968.
Necrotizing enterocolitis in L B W infants
605
14. Touloukian RS, Posch JN, and Spencer R: The pathogenesis of ischemic gastroenterocolitis of the neonate: selective gut mucosa ischemia in asphyxiated neonatal piglets, J Pediatr Surg 7:194, 1973. 15. Norris H: Response of the small intestine to the application of a hypertonic solution, Am J Pathol 73:747, 1973.
