Cerebral and systemic near infrared spectroscopy patterns in preterm infants treated by caffeine.

AIM: To investigate the effects of caffeine loading/maintenance administration on near-infrared spectroscopy cerebral, kidney and splanchnic patterns in preterm infants. METHODS: We conducted a multicentre case-control prospective study in 40 preterm infants (gestational age 29 ± 2 weeks) where each case acted as its own control. A caffeine loading dose of 20 mg/kg and a maintenance dose of 5 mg/kg after 24 h were administered intravenously. Near infrared spectroscopy monitoring parameters were monitored 30 min before, 30 min during and 180 min after caffeine therapy administration. RESULTS: A significant increase (p < 0.05) in splanchnic regional oxygenation and tissue function and a decrease (p < 0.05) in cerebral tissue function after loading dose was shown. A preferential hemodynamic redistribution from cerebral to splanchnic bloodstream was also observed. After caffeine maintenance dose regional oxygenation did not change in the monitored districts, while tissue function increased in kidney and splanchnic bloodstream. CONCLUSION: Different caffeine administration modalities affect cerebral/systemic oxygenation status, tissue function and hemodynamic pattern in preterm infants. Future studies correlating near infrared spectroscopy parameters and caffeine therapy are needed to determine the short/long-term effect of caffeine in preterm infants.

Study protocol: safety and efficacy of propranolol 0.2% eye drops in newborns with a precocious stage of retinopathy of prematurity (DROP-ROP-0.2%): a multicenter, open-label, single arm, phase II trial.

BACKGROUND: Retinopathy of prematurity (ROP) still represents one of the leading causes of visual impairment in childhood. Systemic propranolol has proven to be effective in reducing ROP progression in preterm newborns, although safety was not sufficiently guaranteed. On the contrary, topical treatment with propranolol eye micro-drops at a concentration of 0.1% had an optimal safety profile in preterm newborns with ROP, but was not sufficiently effective in reducing the disease progression if administered at an advanced stage (during stage 2). The aim of the present protocol is to evaluate the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns at a more precocious stage of ROP (stage 1). METHODS: A multicenter, open-label, phase II, clinical trial, planned according to the Simon optimal two-stage design, will be performed to analyze the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns with stage 1 ROP. Preterm newborns with a gestational age of 23-32 weeks, with a stage 1 ROP will receive propranolol 0.2% eye micro-drops treatment until retinal vascularization has been completed, but for no longer than 90 days. Hemodynamic and respiratory parameters will be continuously monitored. Blood samplings checking metabolic, renal and liver functions, as well as electrocardiogram and echocardiogram, will be periodically performed to investigate treatment safety. Additionally, propranolol plasma levels will be measured at the steady state, on the 10th day of treatment. To assess the efficacy of topical treatment, the ROP progression from stage 1 ROP to stage 2 or 3 with plus will be evaluated by serial ophthalmologic examinations. DISCUSSION: Propranolol eye micro-drops could represent an ideal strategy in counteracting ROP, because it is definitely safer than oral administration, inexpensive and an easily affordable treatment. Establishing the optimal dosage and treatment schedule is to date a crucial issue. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02504944, registered on July 19, 2015, updated July 12, 2016. EudraCT Number 2014-005472-29.

Impact of Continuous vs Bolus Feeding on Splanchnic Perfusion in Very Low Birth Weight Infants: A Randomized Trial.

OBJECTIVE: To detect changes in splanchnic perfusion and oxygenation induced by 2 different feeding regimens in infants with intrauterine growth restriction (IUGR) and those without IUGR. STUDY DESIGN: This was a randomized trial in 40 very low birth weight infants. When an enteral intake of 100 mL/kg/day was achieved, patients with IUGR and those without IUGR were randomized into 2 groups. Group A (n = 20) received a feed by bolus (in 10 minutes), then, after at least 3 hours, received the same amount of formula by continuous nutrition over 3 hours. Group B (n = 20) received a feed administered continuously over 3 hours, followed by a bolus administration (in 10 minutes) of the same amount of formula after at least 3 hours. On the day of randomization, intestinal and cerebral regional oximetry was measured via near-infrared spectroscopy and Doppler ultrasound (US) of the superior mesenteric artery was performed. Examinations were performed before the feed and at 30 minutes after the feed by bolus and before the feed, at 30 minutes after the start of the feed, and at 30 minutes after the end of the feed for the 3-hour continuous feed. RESULTS: Superior mesenteric artery Doppler US showed significantly higher perfusion values after the bolus feeds than after the continuous feeds. Near-infrared spectroscopy values remained stable before and after feeds. Infants with IUGR and those without IUGR showed the same perfusion and oxygenation patterns. CONCLUSION: According to our Doppler US results, bolus feeding is more effective than continuous feeding in increasing splanchnic perfusion. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01341236.

Monitoring Doppler patterns and clinical parameters may predict feeding tolerance in intrauterine growth-restricted infants.

AIM: To detect predictors of feeding tolerance in intrauterine growth restriction (IUGR) infants with or without brain-sparing effect (BS). METHODS: We conducted a case-control study in 70 IUGR infants (35 IUGR with BS, matched for gestational age with 35 IUGR infants with no BS). BS was classified as pulsatility index (PI) ratio [umbilical artery (UAPI) to middle cerebral artery (MCAPI) (U/C ratio)] > 1. Clinical parameters of feeding tolerance - days to achieve full enteral feeding (FEF) - were compared between the IUGR with BS and IUGR without BS infants. Age at the start of minimal enteral feeding (MEF) was analysed. RESULTS: Achievement of FEF was significantly shorter in IUGR infants without BS than in IUGR with BS. IUGR with BS started MEF later than IUGR without BS infants. Significant correlation of MEF and FEF with UA PI, U/C ratio and CRIB score was found. Multiple linear regression analysis showed significant correlations with CRIB score and caffeine administration (MEF only), and sepsis (FEF only) and U/C ratio (for both). CONCLUSION: Impaired gut function can be early detected by monitoring Doppler patterns and clinical parameters.

Evaluation of splanchnic oximetry, Doppler flow velocimetry in the superior mesenteric artery and feeding tolerance in very low birth weight IUGR and non-IUGR infants receiving bolus versus continuous enteral nutrition.

BACKGROUND: IUGR infants are thought to have impaired gut function after birth, which may result in intestinal disturbances, ranging from temporary intolerance to the enteral feeding to full-blown NEC.In literature there is no consensus regarding the impact of enteral feeding on intestinal blood flow and hence regarding the best regimen and the best rate of delivering the enteral nutrition. METHODS/DESIGN: This is a randomized, non-pharmacological, single-center, cross-over study including 20 VLBW infants. Inclusion criteria * Weight at birth ranging: 700-1501 grams * Gestational age up to 25 weeks and 6 days * Written informed consent from parents or guardians Exclusion criteria * Major congenital abnormality * Patients enrolled in other trials * Significant multi-organ failure prior to trial entry * Pre-existing cutaneous disease not allowing the placement of the NIRS' probe. In the first 24 hours of life, between the 48th and 72nd hours of life, and during Minimal Enteral Feeding, all infants' intestinal perfusion will be evaluated with NIRS and a Doppler of the superior mesenteric artery will be executed.At the achievement of an enteral intake of 100 mL/Kg/day the patients (IUGR and NON IUGR separately) will be randomized in 2 groups: Group A (n=10) will receive a feed by bolus (in 10 minutes); then, after at least 3 hours, they will receive the same amount of formula administered in 3 hours. Group B (n=10) will receive a feed administered in 3 hours followed by a bolus administration of the same amount of formula (in 10 minutes) after at least 3 hours. On the randomization day intestinal and cerebral regional oximetry will be measured via NIRS. Intestinal and celebral oximetry will be measured before the feed and 30 minutes after the feed by bolus during the 3 hours nutrition the measurements will be performed before the feed, 30 minutes from the start of the nutrition and 30 minutes after the end of the gavage. An evaluation of blood flow velocity of the superior mesenteric artery will be performed meanwhile. The infants of the Group A will be fed with continuous nutrition until the achievement of full enteral feeding. The infants of the Group B will be fed by bolus until the achievement of full enteral feeding. DISCUSSION: Evaluations of intestinal oximetry and superior mesenteric artery blood flow after the feed may help in differentiating how the feeding regimen alters the splanchnic blood flow and oxygenation and if the changes induced by feeding are different in IUGR versus NON IUGR infants. TRIAL REGISTRATION NUMBER: NCT01341236.

Organoid technologies for the study of intestinal microbiota-host interactions.

Postbiotics have recently emerged as critical effectors of the activity of probiotics and, because of their safety profile, they are considered potential therapeutics for the treatment of fragile patients. Here, we present recent studies on probiotics and postbiotics in the context of novel discovery tools, such as organoids and organoid-based platforms, and nontransformed preclinical models, that can be generated from intestinal stem cells. The implementation of organoid-related techniques is the next gold standard for unraveling the effect of microbial communities on homeostasis, inflammation, idiopathic diseases, and cancer in the gut. We also summarize recent studies on biotics in organoid-based models and offer our perspective on future directions.

Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity: A Prospective Phase IIB Study.

Background: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. Propranolol 0.1% eye micro-drops administered to newborns with stage 2 ROP are well-tolerated, but not sufficiently effective. Methods: A multi-center open-label trial was conducted to assess the safety and efficacy of propranolol 0.2% eye micro-drops in newborns with stage 1 ROP. The progression of the disease was evaluated with serial ophthalmologic examinations. Hemodynamic, respiratory, biochemical parameters, and propranolol plasma levels were monitored. Demographic and perinatal characteristics, co-morbidities and co-intervention incidences, together with ROP progression, were compared with a historical control group in the same centers participating in the trial. Results: Ninety-eight newborns were enrolled and compared with the historical control group. Populations were not perfectly homogeneous (as demonstrated by the differences in the Apgar score and the different incidence rate in surfactant administration and oxygen exposure). The progression to ROP stage 2 or 3 plus was significantly lower than the incidence expected on the basis of historical data (Risk Ratio 0.521, 95% CI 0.297- 0.916). No adverse effects related to propranolol were observed and the mean propranolol plasma level was significantly lower than the safety cut-off of 20 ng/mL. Unexpectedly, three newborns treated with oral propranolol before the appearance of ROP, showed a ROP that was unresponsive to propranolol eye micro-drops and required laser photocoagulation treatment. Conclusion: Propranolol 0.2% eye micro-drops were well-tolerated and appeared to reduce the ROP progression expected on the basis of a comparison with a historical control group. Propranolol administered too early appears to favor a more aggressive ROP, suggesting that a ß-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results. Clinical Trial Registration  The trial was registered at ClinicalTrials.gov with Identifier NCT02504944 and with EudraCT Number 2014-005472-29.

Enteral nutrition for preterm infants: by bolus or continuous? An update.

Optimization of nutritional management of preterm infants is crucial for achievement of their long-term health. Enteral nutrition is preferred to total parenteral nutrition (TPN) because the former avoids complications related to vascular catheterization, sepsis, adverse effects of TPN, and fasting. Due to the lack of ability of preterm infants to coordinate suckling, swallowing, and breathing, tube feeding is necessary for most infants less than 1500 g to ensure sufficient feeding tolerance, to support optimal growth and to reduce the risk of aspiration. Therefore, feeding by orogastric or nasogastric tube using either continuous or intermittent bolus delivery of formula or human milk is common practice for these infants. Theoretical risks and benefits of both continuous nasogastric milk feeding and intermittent bolus milk feeding have been proposed. According to the literature, continuous nutrition could be preferred in smaller infants (as those with a birthweight below 1250 g) or hemodynamically impaired infants; in stable growing infants nutrition can be administered intermittently as in healthy term infants.

Enteral feeding of intrauterine growth restriction preterm infants: theoretical risks and practical implications.

Intrauterine growth restriction (IUGR) infants are thought to have impaired gut function after birth secondary to intrauterine redistribution of the blood flow, due to placental insufficiency, with a consequent reduction of gut perfusion. For this reason, infants complicated by IUGR have been considered at higher risk of feeding intolerance. Postnatal evaluation of splanchnic perfusion, through Doppler of the superior mesenteric artery, and of splanchnic oxygenation, through near infrared spectroscopy measurements, may be useful in evaluating the persistence (or not) of the redistribution of blood flow occurred in utero.

Nutritional approach to preterm infants on noninvasive ventilation: An update.

Nutrition and pulmonary function in very-low-birth-weight infants (VLBWIs) are strictly related. Preterm infants on noninvasive ventilation may have respiratory instability that can interfere with feeding tolerance. Moreover, feeding may impair pulmonary function. These infants have nutritional requirements different from nonventilated infants. The main challenge of the nutritional support in such patients is to guarantee adequate caloric intake while avoiding episodes of feeding intolerance. The aim of this study was to review the issues and strategies of enteral feeding of preterm infants on noninvasive ventilation.

Cerebral and somatic NIRS-determined oxygenation in IUGR preterm infants during transition.

BACKGROUND: Fetal growth restriction (intra-uterine growth restriction [IUGR]) has a considerable impact on perinatal morbidity. Preterm IUGR infants are prone to impaired intestine function. Near-infrared spectroscopy (NIRS) has been used to monitor oxygenation status of the brain and of the intestine. PATIENTS AND METHODS: We conducted a prospective case-control study at our NICU in 20 preterm infants of whom 10 infants complicated by compared with 10 non-IUGR preterm infants. Splanchnic and cerebral regional oximetry values were measured with NIRS. Three hours of consecutive recordings were performed in the first 24 h of life, T0, and during the transitional period, T1. The cerebral/splanchnic oxygenation ratio, CSOR, (cerebral regional saturations [rScO2]/splanchnic regional saturations [rSsO2]) was also calculated. RESULTS: Both in the IUGR and the non-IUGR infants, at T0 and T1 monitoring time-points, the rSO2 values were higher in the cerebral district when compared to those of the splanchnic area. Comparison of the NIRS parameters between the IUGR and non-IUGR infants at T0 showed no difference in rScO2, while rSsO2 was significantly lower in the IUGR group. At T1, rScO2 was significantly lower and rSsO2 higher in the IUGR group. CONCLUSIONS: Cerebral/splanchnic vascular adaptation of IUGR infants to the extra-uterine environment is characterized by a postnatal persistence of the brain sparing effect with reperfusion in the transitional period.

Impact of a dedicated enteral feeding system in an Italian NICU.

The inadvertent connection between an enteral feeding system and a nonenteral system such as a vascular line may occur. Intravenous administration of an enteral admixture may lead to severe, sometimes lethal, complications. We report our experience with a new set of enteral devices that may prevent any risk of misconnection.

Is the intravenous supplementation of amino acid to cancer patients adequate? A critical appraisal of literature.

BACKGROUND & AIMS: International guidelines are quite vague regarding the optimal doses of amino acid to administer to cancer patients and standard practice appears not to be supported by specific investigations. The purpose of this study is to determine from the literature whether there are some correlates among amino acid infusions and nutritional-metabolic or clinical outcomes. METHODS: Through the help of PubMed (www.ncbi.nlm.nih.gov) and the use of a personal database we analysed papers reporting details of infused amino acid and metabolic-nutritional or clinical effects. RESULTS: Five short-term metabolic studies using isotopes showed that infusion of about 2 g amino acid/kg/day (including high doses of branched chain amino acid) positively affects protein metabolism of severely malnourished cancer patients. In eight studies in less malnourished patients receiving longer periods of parenteral nutrition, to allow the administration of oncologic therapy or to compensate for a decline in oral alimentation, the intravenous addition of 1.5 g amino acid/kg/day to the oral diet achieved positive results. These findings are concordant with recent metabolic results achieved in cancer patients receiving amino acid orally. CONCLUSION: We think that a higher quantity of parenteral amino acids than that usually administered might be useful to cancer patients and further studies on this issue are warranted.

Feeding issues in IUGR preterm infants.

Intra-uterine growth restriction (IUGR) is a severe and quite common problem in obstetrics. A condition of placental dysfunction can lead to a cardiovascular adaptation in the fetus characterized by a redistribution of cardiac output to maintain oxygen supply to the heart, adrenal glands and brain - the so-called brain sparing effect - at the expense of visceral organs (such as the gastrointestinal system). This condition may predispose IUGR infants to impaired gut function after birth. A higher incidence of necrotizing enterocolitis (NEC) is documented in IUGR preterm infants. Therefore, a common practice in neonatal intensive care units is to delay feeds to reduce the risk of feeding intolerance. Recent trials, however, have shown that early enteral feeding in IUGR infants is safe and it would appear, on the basis of the few available data, that breast milk could offer protection against NEC. This mini-review offers an update on feeding in IUGR infants. Future perspectives on the usefulness of Doppler and regional splanchnic and cerebral saturation monitoring for deciding when to start feeding are also provided.

Feeding tolerance of preterm infants appropriate for gestational age (AGA) as compared to those small for gestational age (SGA).

Preterm infants are often considered too unstable to be fed enterally so they are exposed to complications related to a prolonged enteral fasting. Our study aims to compare feeding tolerance of adequate for gestational age (AGA) versus small for gestational age (SGA) infants and to evaluate which perinatal factors affect feeding tolerance (measured as time to achieve full enteral feeding, FEF). Inborn infants with a gestational age (GA) less than 32 weeks, born from January 2006 to December 2010, were eligible for this study. We enrolled 310 infants. The time to FEF was longer for SGA infants than for AGA, while a longer GA was associated to a reduced time to FEF. A beneficial effect was observed for antenatal steroids, while Apgar score below 7, the administration of inotrops or caffeine, the occurrence of sepsis or NEC and the presence of PDA were associated to a longer time to FEF. When evaluated jointly with a multivariate analysis, GA (p < 0.0001), antenatal steroids prophylaxis (p = 0.002), SGA (p < 0.0001) and occurrence of NEC (p = 0.0002) proved to have independent prognostic impact on the time to FEF. Feeding tolerance is better as GA increases, and worsen in SGA infants. Antenatal betamethasone is effective in reducing the time to FEF in both AGA and SGA.

Survey on retinopathy of prematurity (ROP) in Italy.

BACKGROUND: This study aims to investigate the incidence and the relative risk factors of retinopathy of prematurity (ROP) and posterior-ROP (P-ROP): ROP in Zone I and posterior Zone II, as well as to analyze the occurrence of surgical treatment of ROP and to evaluate the short term outcome of the disease in Italy. METHODS: It is a prospective multicenter observational study; all infants with a birth weight (BW) ≤ 750 g and/or a gestational age (GA) ≤27 weeks born between January 1st 2008 and December 31st 2009 in 25 III level Italian neonatal intensive care units were eligible for the study. RESULTS: 421 infants were examined: 265 (62.9%) developed ROP and 102 (24.2%) P-ROP. CONCLUSIONS: P-ROP is the most aggressive type of ROP. It associates with lower GA and sepsis. Obstetricians and Neonatologists must focus on the reduction of severe preterm births and on the prevention of neonatal early and late onset sepsis in order to reduce the incidence of P-ROP.