Roberto Paludetto

Ranitidine is associated with infections, necrotizing enterocolitis, and fatal outcome in newborns

Background And Objective: Gastric acidity is a major nonimmune defense mechanism against infections. The objective of this study was to investigate whether ranitidine treatment in very low birth weight (VLBW) infants is associated with an increased risk of infections, necrotizing enterocolitis (NEC), and fatal outcome. Methods: Newborns with birth weight between 401 and 1500 g or gestational age between 24 and 32 weeks, consecutively observed in neonatal intensive care units, were enrolled in a multicenter prospective observational study. The rates of infectious diseases, NEC, and death in enrolled subjects exposed or not to ranitidine were recorded. Results: We evaluated 274 VLBW infants: 91 had taken ranitidine and 183 had not. The main clinical and demographic characteristics did not differ between the 2 groups. Thirty-four (37.4%) of the 91 children exposed to ranitidine and 18 (9.8%) of the 183 not exposed to ranitidine had contracted infections (odds ratio 5.5, 95% confidence interval 2.9–10.4, P < .001). The risk of NEC was 6.6-fold higher in ranitidine-treated VLBW infants (95% confidence interval 1.7–25.0, P = .003) than in control subjects. Mortality rate was significantly higher in newborns receiving ranitidine (9.9% vs 1.6%, P = .003). Conclusions: Ranitidine therapy is associated with an increased risk of infections, NEC, and fatal outcome in VLBW infants. Caution is advocated in the use of this drug in neonatal age.

Bile acids modulate tight junction structure and barrier function of Caco-2 monolayers via EGFR activation

Intestinal and systemic illnesses have been linked to increased gut permeability. Bile acids, whose luminal profile can be altered in human disease, modulate intestinal paracellular permeability. We investigated the mechanism by which selected bile acids increase gut permeability using a validated in vitro model. Human intestinal Caco-2 cells were grown in monolayers and challenged with a panel of bile acids. Transepithelial electrical resistance and luminal-to-basolateral fluxes of 10-kDa Cascade blue-conjugated dextran were used to monitor paracellular permeability. Immunoprecipitation and immunoblot analyses were employed to investigate the intracellular pathway. Redistribution of tight junction proteins was studied by confocal laser microscopy. Micromolar concentrations of cholic acid, deoxycholic acid (DCA), and chenodeoxycholic acid (CDCA) but not ursodeoxycholic acid decreased transepithelial electrical resistance and increased dextran flux in a reversible fashion. Coincubation of 50 muM CDCA or DCA with EGF, anti-EGF monoclonal antibody, or specific src inhibitor 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP-2) abolished the effect. A concentration of 50 muM of either CDCA or DCA also induced EGF receptor phosphorylation, occludin dephosphorylation, and occludin redistribution at the tight junction level in the same time frame and in a reversible fashion. We conclude that selected bile acids modulate intestinal permeability via EGF receptor autophosphorylation, occludin dephosphorylation, and rearrangement at the tight junction level. The effect is mediated by the src family kinases and is abolished by EGF treatment. These data also support the role of bile acids in the genesis of necrotizing enterocolitis and the protective effect of EGF treatment.

Nonnutritive Sucking during Heelstick Procedures Decreases Behavioral Distress in the Newborn Infant

We investigated if nonnutritive sucking (NNS) during heelstick procedures alleviates behavioral distress in neonates. In our NICU, 26 neonates without severe complications (mean Minde score 0.8, range 0–3), undergoing heelstick procedures at least twice a day, in the first 2 weeks of life, were enrolled in the trial (mean gestational age 33.9 weeks, range 26–39 weeks, mean birth weight 1,988.5 g, range 1,200–4,010 g, mean Apgar score at the first minute 6.7, range 4–10, at the fifth minute 8.5, range 6–10). Two heelpricks were performed in each neonate with NNS randomly assigned. Behavioral states, transcutaneous oxygen tension (TcPO2), heart rate, and respiratory rate were monitored before, during and after the heelstick procedures. Heelstick procedures lasted for a mean of 109 s (range 50–230 s) with NNS, and a mean of 128.8 s (range 20–420 s) without NNS. Compared with baseline, heart rate and behavioral distress increased and respiratory rate decreased during heelstick and after heelstick. Oxygen tension did not change. Nonnutritive sucking had no effect on respiratory rate or transcutaneous oxygen tension, but reduced the time of crying and the heart rate increase during the procedure. In conclusion, NNS can be recommended to reduce distress in newborns undergoing invasive routine procedures. Further studies are needed to evaluate the effects of NNS on respiratory rate and blood gas levels.

Neonatal Onset Intestinal Failure: An Italian Multicenter Study

OBJECTIVE To describe the natural course of intestinal failure with onset in the neonatal period to provide data regarding the occurrence and to provide a population-based survey regarding the spectrum of underlying diseases. STUDY DESIGN We performed a retrospective chart review including infants admitted to the neonatal intensive care unit of 7 Italian tertiary care centers. Intestinal failure was defined as a primary intestinal disease that induces the need of total parenteral nutrition (PN) for more than 4 weeks or the need of partial PN for more than 3 months. RESULTS The total number of live births during the study time within the enrolled institutions was 30 353, and the number of newborns admitted to the neonatal intensive care unit was 5088. Twenty-six patients satisfied the definition of intestinal failure; thus the occurrence rate of intestinal failure was 0.1% among live-birth newborns and 0.5% among infants at high risk. The main underlying diseases leading to intestinal failure in neonatal age were congenital intestinal defects (42.3%), necrotizing enterocolitis (30.8%), severe intestinal motility disorder (11.5%), intestinal obstruction (7.7%), structural enterocyte defects (3.8%), and meconium peritonitis (3.8%). After a follow-up of 36 months, 84.6% of patients achieved intestinal competence, 1 patient was still receiving home PN, 1 patient underwent transplantation, and 2 patients died. Cholestatic liver disease was diagnosed in 54% of observed children. CONCLUSION An understanding of the incidence, causes, and natural history of intestinal failure would be helpful to appropriately allocate resources and to plan clinical trials.

Neonatal Urinary Cotinine Correlates With Behavioral Alterations in Newborns Prenatally Exposed to Tobacco Smoke

Altered behavior due to prenatal smoke exposure was examined in 25 neonates born from smoking mothers who consumed at least 5 cigarettes/d during the entire gestation. Data were compared with 25 matched neonates born from nonsmoking mothers. Neonatal behavior was evaluated using the Brazelton Neonatal Behavioral Assessment Scale (BNBAS). Antenatal exposure to tobacco smoke at the end of the pregnancy was determined by measurement of urinary cotinine. Newborns from smoking mothers showed significant lower scores in various BNBAS items compared with neonates from nonsmoking mothers. A strong correlation was observed between infant irritability and urinary cotinine in newborns from smoker and nonsmoking mothers and with number of daily smoked cigarettes and maternal nicotine daily intake of infants exposed to active maternal smoking. Linear regression analysis showed that urinary cotinine was the best predictor of infant irritability (r2 = 0.727). The latter was also associated to the neonates low level of attention and poor response to inanimate auditory stimuli. Among infants from nonsmoking mothers, paternal smoking significantly correlated with infant urinary cotinine and infant irritability, being also the best predictor of irritability (r2 = 0.364). Neonatal behavior can be significantly altered in a dose-dependent manner even after modest prenatal exposure to tobacco smoke.

Minimal enteral feeding reduces the risk of sepsis in feed-intolerant very low birth weight newborns

Aims: To evaluate the efficacy and safety of minimal enteral feeding (MEF) nutritional practice in feed‐intolerant very low birth weight (VLBW) infants.

A case control study of necrotizing enterocolitis occurring over 8 years in a neonatal intensive care unit

The perinatal histories of 27 newborn infants with NEC were compared to those of 54 infants of equivalent birth weight who did not have NEC during an 8-year study period to see if possible predisposing factors were independent of the confounding effect of birth weight. No differences were observed in gestational age, degree of intrauterine growth retardation, premature rupture of membranes, perinatal asphyxia, skin temperature at admission, haematocrit, presence or absence of respiratory distress syndrome, umbilical catheter placement, start and type of feeding or presence of positive blood cultures. Prematurity is the greatest risk factor predisposing to the development of NEC and the perinatal problems which precede the onset of NEC are common among all premature infants.

A randomized trial comparing oxygen delivery on intermittent positive pressure with nasal cannulae versus facial mask in neonatal primary resuscitation

Aim: To compare, in a prospective clinical trial, oxygen delivery on intermittent positive pressure with nasal cannulae versus facial mask in primary resuscitation of the newborn with moderate asphyxia. Methods: 617 neonates with moderate asphyxia at birth were randomized: 303 were resuscitated by oxygen on intermittent positive pressure with nasal cannuale and 314 neonates by mask. Resuscitation followed the Neonatal Resuscitation Program guidelines of the American Academy of Pediatrics, 3rd edition. Results: Resuscitation through the nasal route less frequently requires chest compressions and intubations (26 neonates needed chest compression and 20 needed intubation out of 314 resuscitated by mask; five neonates needed chest compression and two needed intubation out of 303 resuscitated by nasal cannulae). Apgar scores, admission rates to neonatal intensive care units, air‐leak syndromes, birthweight, gestational age, use of prenatal steroids and deaths did not differ between groups.

Behaviour of preterm newborns reaching term without any serious disorder

We studied the behaviour of 20 preterm infants (average gestational age 33 weeks) brought to term, without any serious disorder. These infants were compared with a group of 21 healthy term infants. To evaluate behaviour we used the 26 items of the Brazelton Neonatal Behavioural Assessment Scale (BNBAS). Our preterm infants had on the whole better scores than those reported in the literature for preterm infants with various disorders. Apart from lower ability to bring hand to mouth and in getting used to visual stimuli (these differences are statistically significant) they had, in the items of orientation a lower score only in ability to follow a voice and a face (not statistically significant). These results show that preterm infants reaching term without any serious disorder do on the whole as well as full-term infants. This correlates with the observations of Dubowitz on behaviour and particularly on visual function of preterm infants and confirms the preliminary report of Daum regarding the influence of the type of neonatal pathology on the ability of orientation at the moment of term.

Unconjugated Bilirubin Modulates the Intestinal Epithelial Barrier Function in a Human-Derived In Vitro Model

Unconjugated bilirubin promotes intestinal secretion without affecting nutrient digestion or absorption. In the current study, the effects of unconjugated bilirubin (UCB) on the barrier function of the intestinal epithelium were investigated. The apical side of human intestinal cell line Caco-2 monolayers was challenged with purified UCB. Transepithelial electrical resistance and paracellular fluxes of 10 kD Cascade blue conjugate dextran were measured. Cell monolayer viability was studied using LDH release and trypan blue exclusion tests. Redistribution of enterocyte tight junction occludin was studied by confocal microscopy. Bilirubin induced a dose-dependent decrease of transepithelial electrical resistance (TEER). This effect was maximal at 6 h and tended to be reversed at 48 h. Oxidated bilirubin was ineffective. Bilirubin significantly increased fluorescent dextran paracellular passage. Cell viability was not affected by UCB over the 5–200 nmol/L concentration range. Finally, bilirubin triggered a reversible redistribution of tight junctional occludin. UCB increases the permeability of intestinal epithelium. This effect is reversible, dependent on the redox status of the molecule and the rearrangement of the tight junction. These data attribute to bilirubin a novel role of functional modulator of intestinal paracellular permeability in vitro.