Kristina M. Reber

Newborn intestinal circulation: Physiology and pathophysiology

The physiologic characteristics of the newborn intestinal circulation are unique when compared with the adult condition. Most important, intestinal vascular resistance across newborn intestine is exceptionally low and this transient reduction is mediated by an increased constitutive and stimulated production of NO. The low vascular resistance characteristic of newborn intestine alters the capacity of this vasculature to respond to systemic circulatory perturbations, such as hypotension and arterial hypoxemia. The essential role of endothelial production of NO in maintaining newborn intestinal hemodynamics might be important in the pathogenesis of NEC, because endothelial dysfunction would limit, or possibly eliminate, NO production, leading to substantial intestinal ischemia.

Age‐Dependent Changes in the Postnatal Intestinal Microcirculation

Significant changes occur in intestinal hemodynamics during the transition from fetal to newborn life and then again during the first postnatal month. Most importantly, basal vascular resistance substantially decreases following birth. It then decreases further between postnatal days 1 and 3, plateaus, and then begins a slow, progressive increase between postnatal days 12 and 30. The basal rate of intestinal blood flow mirrors the changes in vascular resistance in an inverse manner. The postnatal changes in vascular resistance appear to be mediated, in large part, by an increase in the constitutive and stimulated production of nitric oxide. Most importantly, the diameter of terminal mesenteric arteries (150–300 µm diameter) in newborn (i.e., 1 day old) swine is determined by three intrinsic vascular control systems: endothelial production of nitric oxide and endothelin, and the inherent myogenic response of vascular smooth muscle. In contrast, these vessels in older subjects (i.e., 35 days old) are primarily passive in nature and fail to demonstrate significant diameter change in response to blockade of endogenous nitric oxide production or endothelin receptors, or applied perturbations of pressure or flow rate. The circulatory physiology of the perinatal and newborn intestine is exceptional when compared to the adult condition inasmuch as several hemodynamic variables change quite dramatically between fetal and neonatal life and during the first postnatal month. The unique hemodynamic conditions that characterize the perinatal and newborn intestine appear to be part of the overall physiological transition that occurs as the fetus, once born, replaces the placenta with his gastrointestinal tract to obtain nutrition. The goal of this review is to describe the circulatory physiology of the perinatal and newborn intestine, with a particular emphasis on those portions of the intestinal microcirculation that have thus far been studied. First, however, it is important to discuss the age‐dependent changes that occur within the intestinal circulation during perinatal and early newborn life.

The Children’s Hospitals Neonatal Database: an overview of patient complexity, outcomes and variation in care

The Childrens Hospitals Neonatal Consortium is a multicenter collaboration of leaders from 27 regional neonatal intensive care units (NICUs) who partnered with the Childrens Hospital Association to develop the Childrens Hospitals Neonatal Database (CHND), launched in 2010. The purpose of this report is to provide a first summary of the population of infants cared for in these NICUs, including representative diagnoses and short-term outcomes, as well as to characterize the participating NICUs and institutions. During the first 2 1/2 years of data collection, 40910 infants were eligible. Few were born inside these hospitals (2.8%) and the median gestational age at birth was 36 weeks. Surgical intervention (32%) was common; however, mortality (5.6%) was infrequent. Initial queries into diagnosis-specific inter-center variation in care practices and short-term outcomes, including length of stay, showed striking differences. The CHND provides a contemporary, national benchmark of short-term outcomes for infants with uncommon neonatal illnesses. These data will be valuable in counseling families and for conducting observational studies, clinical trials and collaborative quality improvement initiatives.

Short-term outcomes after perinatal hypoxic ischemic encephalopathy: a report from the Children’s Hospitals Neonatal Consortium HIE focus group

Objective:To characterize infants affected with perinatal hypoxic ischemic encephalopathy (HIE) who were referred to regional neonatal intensive care units (NICUs) and their related short-term outcomes.Study Design:This is a descriptive study evaluating the data collected prospectively in the Children’s Hospital Neonatal Database, comprised of 27 regional NICUs within their associated children’s hospitals. A consecutive sample of 945 referred infants born ⩾36 weeks’ gestation with perinatal HIE in the first 3 days of life over approximately 3 years (2010–July 2013) were included. Maternal and infant characteristics are described. Short-term outcomes were evaluated including medical comorbidities, mortality and status of survivors at discharge.Result:High relative frequencies of maternal predisposing conditions, cesarean and operative vaginal deliveries were observed. Low Apgar scores, profound metabolic acidosis, extensive resuscitation in the delivery room, clinical and electroencephalographic (EEG) seizures, abnormal EEG background and brain imaging directly correlated with the severity of HIE. Therapeutic hypothermia was provided to 85% of infants, 15% of whom were classified as having mild HIE. Electrographic seizures were observed in 26% of the infants. Rates of complications and morbidities were similar to those reported in prior clinical trials and overall mortality was 15%.Conclusion:Within this large contemporary cohort of newborns with perinatal HIE, the application of therapeutic hypothermia and associated neurodiagnostic studies appear to have expanded relative to reported clinical trials. Although seizure incidence and mortality were lower compared with those reported in the trials, it is unclear whether this represented improved outcomes or therapeutic drift with the treatment of milder disease.

Effects of prenatal lipopolysaccharide exposure on epithelial development and function in newborn rat intestine.

Background: Maternal infection during pregnancy is associated with several neonatal morbidities, including periventricular leukomalacia and lung maldevelopment and injury. Objective: To test the hypothesis that responses to prenatal maternal exposure to lipopolysaccharide (LPS) alter intestinal epithelial development and function in newborn rats. Design/Methods: Timed-pregnancy female Sprague-Dawley rats were administered either 2 mg LPS or an equal volume of isotonic saline by intraperitoneal injection at E16 and allowed to deliver naturally. Pups were weighed and then killed at days of life (DOL) 0, 3, 7 and 14. Morphometric parameters were measured on standard hematoxylin and eosin-stained sections using ImagePro software. Immunohistochemistry was performed with antibody specific for inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine on distal ileal intestinal samples analyzed at each time point. Optical density was determined and quantified for site-specific regions of intestinal sections. On DOL 14, in vivo mucosal permeability was measured by feeding rats fluorescein isothiocyanate (FITC) via orogastric tube; and then serum FITC was measured. Results: There were no significant differences in pup weights. Mucosal thicknesses were significantly less in the distal ileum from pups born to LPS-exposed dams on DOL 0, 3 and 7 (P < 0.001). On DOL 0, iNOS protein concentrations in the prenatal LPS treatment group were significantly greater than iNOS protein concentrations in the distal villus (P < 0.001), proximal villus/crypts (P < 0.01), submucosa (P < 0.001) and muscularis (P < 0.01) in the distal small intestine of the control group. On DOL 3, 7 and 14, significant differences were observed in iNOS protein concentrations in the distal villus and submucosal regions between groups (P < 0.001). On DOL 0, 3, 7 and 14, 3-nitrotyrosine immunostaining was significantly elevated in the prenatal LPS-exposed pups in the distal villus on (P < 0.001) as well as in the submucosa on DOL 3 (P < 0.001). Serum FITC measurement was significantly greater in prenatal LPS exposure group at DOL 14 (P < 0.001). Conclusions: Maternal exposure to LPS during pregnancy alters intestinal growth and regulation of iNOS in the newborn rat intestine.

Probiotics and Prebiotics for the Prevention of Necrotizing Enterocolitis

Necrotizing enterocolitis (NEC) continues to be a major cause of morbidity and mortality in premature infants. Although the pathogenesis of NEC remains unclear, abnormal bacterial colonization has been postulated as playing a central role. Various factors impact bacterial colonization following delivery. Compared to term infants, the bacterial colonization pattern in prematurely born infants is markedly different, with a greater predilection for colonization with pathogenic bacteria. Probiotic and prebiotic administration offers the opportunity to manipulate the intestinal bacterial environment, favoring the growth of commensal bacteria. Experimental data from animal studies and data from human trials suggest that probiotics decrease the incidence of NEC. These preliminary studies support the need for a large, randomized, controlled trial to further investigate the role of probiotics in the prevention of NEC.

Quality Improvement Initiative to Reduce the Necrotizing Enterocolitis Rate in Premature Infants

OBJECTIVE: To reduce the incidence of necrotizing enterocolitis (NEC) among very low birth weight (VLBW) infants admitted to 8 intensive care nurseries from a 2010 baseline of 8.0% to <4.0% by 2012 and sustain for 6 months using quality improvement (QI) methodology. METHODS: A multidisciplinary NEC QI team used the Vermont Oxford Network definition of NEC and the Institute for Healthcare Improvement model. The specific aims were evidenced based and included (1) standardized early human milk feedings, (2) conservative feeding guidelines during blood transfusions and indomethacin treatment, and (3) restriction of ranitidine use in VLBW infants. Inclusion criteria included VLBW infants admitted within the study period without NEC. Exclusion criteria included established NEC or spontaneous intestinal perforation unrelated to NEC. The incidence of NEC and NEC-related surgery were tracked using statistical process control methodology. RESULTS: The baseline NEC rate in 2010 was 8% (27 NEC cases in 335 VLBW infants). After initiation of early human-milk feeding and conservative feeds during blood transfusions guidelines in November 2011, only 3.1% (19 of 606 VLBW infants) had developed NEC through December 2013 (P = .001). Special cause variation was noted in June 2012 establishing a new centerline at 3.1%. NEC-related mortality decreased from a 2010 baseline mean of 2.7% to a new baseline mean of 0.9% from January 2011 to December 2013. CONCLUSIONS: Implementation of QI initiatives decreased the NEC rate from 8.0% to <4.0%. Early human milk feedings and conservative feeding during blood transfusion policies appear to have significant impact on NEC reduction.

Therapeutic interventions and short-term outcomes for infants with severe bronchopulmonary dysplasia born at <32 weeks' gestation.

Objective:To characterize the treatments and short-term outcomes in infants with severe bronchopulmonary dysplasia (sBPD) referred to regional neonatal intensive care units.Study Design:Infants born <32 weeks’ gestation with sBPD were identified using the Children’s Hospital Neonatal Database. Descriptive outcomes are reported.Result:A total of 867 patients were eligible. On average, infants were born at 26 weeks’ gestation and referred 43 days after birth. Infants frequently experienced lung injury (pneumonia: 24.1%; air leak: 9%) and received systemic corticosteroids (61%) and mechanical ventilation (median duration 37 days). Although 91% survived to discharge, the mean post-menstrual age was 47 weeks. Ongoing care such as supplemental oxygen (66%) and tracheostomy (5%) were frequently needed.Conclusion:Referred infants with sBPD sustain multiple insults to lung function and development. Because affected infants have no proven, safe or efficacious therapy and endure an exceptional burden of care even after referral, urgent work is required to observe and improve their outcomes.

Predicting death or extended length of stay in infants with congenital diaphragmatic hernia

Objective:To predict mortality or length of stay (LOS) >109 days (90th percentile) among infants with congenital diaphragmatic hernia (CDH).Study Design:We conducted a retrospective analysis using the Childrens Hospital Neonatal Database during 2010 to 2014. Infants born >34 weeks gestation with CDH admitted at 22 participating regional neonatal intensive care units were included; patients who were repaired or were at home before admission were excluded. The primary outcome was death before discharge or LOS >109 days. Factors associated with this outcome were used to develop a multivariable equation using 80% of the cohort. Validation was performed in the remaining 20% of infants.Results:The median gestation and age at referral in this cohort (n=677) were 38 weeks and 6 h, respectively. The primary outcome occurred in 242 (35.7%) infants, and was distributed between mortality (n=180, 27%) and LOS >109 days (n=66, 10%). Regression analyses showed that small for gestational age (odds ratio (OR) 2.5, P=0.008), presence of major birth anomalies (OR 5.9, P<0.0001), 5- min Apgar score ⩽3 (OR 7.0, P=0.0002), gradient of acidosis at the time of referral (P<0.001), the receipt of extracorporeal support (OR 8.4, P<0.0001) and bloodstream infections (OR 2.2, P=0.004) were independently associated with death or LOS >109 days. This model performed well in the validation cohort (area under curve (AUC)=0.856, goodness-of-fit (GF) χ2, P=0.16) and acted similarly even after omitting extracorporeal support (AUC=0.82, GF χ2, P=0.05).Conclusions:Six variables predicted death or LOS ⩾109 days in this large, contemporary cohort with CDH. These results can assist in risk adjustment for comparative benchmarking and for counseling affected families.

Intestinal O2 consumption in necrotizing enterocolitis : Role of nitric oxide

We tested the hypothesis that inducible isoform of nitric oxide synthase (iNOS)-derived nitric oxide (NO) inhibits oxygen consumption (Vo2) in human intestine resected for necrotizing enterocolitis (NEC). Each NEC resection specimen was divided into two sections based on histologic appearance: healthy or diseased. Intestine removed from infants for reasons other than NEC was used as control. The tissue injury score (0–6, with 6 indicating complete necrosis) was 0.4 ± 0.2 in control tissue, 1.2 ± 0.4 in NEC-healthy tissue, and 4.6 ± 0.5 in NEC-diseased tissue. Prominent iNOS staining was present in villus enterocytes in NEC-healthy tissue but not in the other tissue types. Intestinal Vo2 (per direct oximetry, in nM O2/min/g) was significantly greater in control tissue than in NEC-healthy or NEC-diseased tissues. Accumulation of NO into buffer bathing intestinal slices (in nM NO/μL/g) was greater in NEC-healthy tissue than control or NEC-diseased tissues. The specific iNOS antagonist l-Nω-(1-iminoethyl)-lysine (l-NIL) reduced buffer NO concentration 76% and increased Vo2 by 90% in NEC-healthy tissue; however, l-NIL had no effect on NO or Vo2 in control or NEC-diseased tissue. Addition of exogenous NO via S-nitroso-N-acetylpenicillamine depressed Vo2 in NEC-healthy and control tissues but not NEC-diseased tissue. A significant correlation was present between buffer NO concentration and Vo2 in NEC-healthy tissue. We conclude that iNOS-derived NO suppresses Vo2 in intestine resected for NEC that demonstrates a relatively normal histology on light microscopy.