Lung Ultrasound for the Differential Diagnosis of Respiratory Distress in Neonates.

BACKGROUND: Respiratory distress (RD) is the most common neonatal illness. Lung ultrasound (LUS) is a technique previously tested in neonatal studies on RD, but literature regarding its routine clinical applicability is still lacking. OBJECTIVE: To assess the concordance between LUS performed by neonatologists with different training levels and chest X-ray (CXR) for the diagnosis of RD in newborns during the first 24 h of life. METHODS: We enrolled newborns with RD during the first 24 h of life. Patients underwent LUS and CXR. LUS and CXR diagnosis were compared to evaluate concordance. Twenty percent of patients received two LUS (one from an experienced and one from a novice sonographer) to calculate the interobserver agreement. The difference in time needed to reach a diagnosis with LUS and CXR, and from novice and expert operators, was measured. RESULTS: We studied 124 patients; 134 diagnoses were reported. The concordance between LUS and CXR diagnosis was 91% (95% CI 86-96%) with a κ statistic of 0.88 (95% CI 0.81-0.94). The median time to diagnosis was shorter for LUS (9.5 min, IQR 5-15) than for CXR (50 min, IQR 33-64) (p < 0.0001). In 25/124 patients, LUS was performed by both novice and experienced sonographers with complete concordance. The median time to diagnosis was shorter for expert (9 min, IQR 5-15) than novice operators (15 min, IQR 10-20) (p < 0.0002). CONCLUSION: LUS and CXR have a high concordance in the differential diagnosis of neonatal RD in the first 24 h of life. LUS has a shorter operation time than CXR.

Change of Cerebral Oxygenation during Surfactant Treatment in Preterm Infants: "LISA" versus "InSurE" Procedures.

Objectives The aim of the study was to compare the effects on cerebral oxygenation in preterm infants of two different procedures for surfactant administration: the LISA (low-invasive method of surfactant administration) and the InSurE (Intubation, SURfactant administration, Extubation). Study Design Twenty premature infants with respiratory distress syndrome were assigned to receive surfactant either by "LISA" (n = 10) or "InSurE" (n = 10) procedure. Patients were continuously studied by near-infrared spectroscopy (NIRS) for the measurement of cerebral regional oxygenation (rSO2C) and calculation of cerebral fractional oxygen extraction rate (cFTOE), and NIRS data were recorded 30 minutes before (T0) surfactant administration, during the procedure (Tproc), and 30 (T1), 60 (T2T2), and 120 minutes (T3) afterward. Cerebral blood flow velocity (CBFV) was studied in the anterior cerebral artery at T0, T1, and T3. Results SpO2 significantly decreased at Tproc in comparison with T0, T1, T2, and T3 and the decrease was higher in the LISA than in the InSurE group. rSO2C was lower at tproc and T3 in the LISA than in the InSurE group. cFTOE was higher at tproc, t2, and t3 in the LISA group than in the InSurE group. CBFV did not change during the study periods in both groups. Conclusions The LISA and InSurE procedures transiently decreased rSO2C in our population, and the decrease was higher in the LISA group. Consistently, there was a contemporary increase in cFTOE that was higher in the LISA than in the InSurE group, suggesting that it represents a compensatory mechanism.

Red blood cell transfusions can induce proinflammatory cytokines in preterm infants.

BACKGROUND: The risk of developing red blood cell (RBC) transfusion-associated necrotizing enterocolitis (TANEC) in preterm infants has recently been emphasized. Our aim was to assess changes in cytokine serum levels after RBC transfusions in a cohort of very preterm infants to evaluate their possible proinflammatory effect. STUDY DESIGN AND METHODS: We carried out a prospective observational study. One transfusion event was studied in infants less than 32 weeks' gestation and more than 7 days old (n = 20) admitted to a tertiary neonatal intensive care unit. Interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor-α, interferon-γ (IFN-γ), IL-17, monocyte chemoattractant protein-1 (MCP-1), interferon-γ-induced protein 10 (IP-10), intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule serum levels were measured in enrolled patients within 120 minutes before (T0 ) the RBC transfusion and then within 120 minutes (T1 ), 12 ± 3 hours (T2 ), 24 ± 6 hours (T3 ), and 48 ± 6 hours (T4 ) after the end of RBC transfusion. RESULTS: Infants received 19.8 ± 3.0 mL of RBCs at the mean age of 50 ± 18 days. Their hematocrit level increased from 24.1 ± 1.2% to 39.4 ± 2.9%. IL-1ß, IL-8, IFN-γ, IL-17, MCP-1, IP-10, and ICAM-1 increased significantly after RBC transfusions. CONCLUSION: Proinflammatory cytokines are increased after RBC transfusion. These findings may contribute to explaining the pathogenesis of TANEC and suggest the opportunity of adopting wise transfusion guidelines that would help to avoid detrimental risks of transfusion-related immunomodulation and of undertransfusion.

Peroxisome proliferator-activated receptor-γ agonist pioglitazone reduces the development of necrotizing enterocolitis in a neonatal preterm rat model.

BACKGROUND: Factors affecting innate immunity and acting as inflammatory regulators, such as the nuclear peroxisome proliferator-activated receptors (PPAR) could be crucial in the pathogenesis of necrotizing enterocolitis (NEC). We hypothesized that the PPARγ agonist pioglitazone (PIO) might be effective in preventing the development of NEC and/or reducing its severity. METHODS: We studied preterm rats in which NEC was induced using the hypoxia-hypothermia model. The treatment group (TG; n = 30) received enteral PIO (10 mg/kg/d) for 72 h and the control group (CG; n = 30) did not. Animals were sacrificed 96 h after birth. NEC was diagnosed evaluating histological ileum changes, and mRNA levels of IL-4, IL-12, IL-6, IL-10, INF-γ, and TNF-α cytokines were measured. RESULTS: NEC occurrence was higher in the CG (18/30; 60%) than in the TG (5/30; 16.7%) and was more severe. Proinflammatory IL-12 and INF-γ mRNA levels were significantly lower in the TG than in the CG; conversely, the anti-inflammatory IL-4 mRNA level was significantly higher in the TG than in the CG. CONCLUSION: Our results demonstrate for the first time that PIO is effective in reducing the incidence and severity of NEC and in decreasing renal injuries in a preterm rat model.

Genetic Contributions to the Development of Complications in Preterm Newborns.

AIM: We aimed to identify specific polymorphisms of genes encoding for vascular endothelial growth factor A (VEGFA), endothelial nitric oxide synthase (eNOS), renin-angiotensin system (angiotensinogen gene [AGT], angiotensinogen type 1 receptor [AGTR1], angiotensin-converting enzyme [ACE]), and heme oxygenase-1 (HMOX-1) in a cohort of preterm infants and correlate their presence with the development of respiratory distress syndrome (RDS) requiring mechanical ventilation (MV), bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH) and retinopathy of prematurity (ROP). STUDY DESIGN: We carried out a retrospective study to evaluate the allele frequency and genotype distribution of polymorphisms of VEGFA, eNOS, AGT, AGTR1, ACE, and HMOX-1 in a population of preterm neonates (n=342) with a gestational age ≤28 weeks according to the presence or absence of RDS requiring MV, BPD, IVH, or ROP. Moreover, we evaluated through the haplotype reconstruction analysis whether combinations of the selected polymorphisms are related to the occurrence of RDS, BPD, IVH and ROP. RESULTS: In our population 157 infants developed RDS requiring MV, 71 BPD, 70 IVH, and 43 ROP. We found that TC+CC rs2070744 eNOS (41.7 vs. 25.4%, p=0.01) and GT+TT rs1799983 eNOS (51.8 vs. 35.2%, p=0.01) polymorphisms are independent risk factors for BPD. Haplotype reconstruction showed that haplotypes in VEGF and eNOS are significantly associated with different effects on RDS, BPD, IVH, and ROP in our population. CONCLUSIONS: We found that TC+CC rs2070744 eNOS and GT+TT rs1799983 eNOS polymorphisms are independent predictors of an increased risk of developing BPD. Haplotypes of VEGFA and eNOS may be independent protective or risk markers for prematurity complications.

Presepsin for the detection of late-onset sepsis in preterm newborns.

BACKGROUND: Late-onset sepsis (LOS) is among the leading causes of morbidity and mortality in preterm newborns, and currently available diagnostic tools are inadequate. The objective of this study was to evaluate the accuracy of presepsin (P-SEP) as novel biomarker of bacterial infection for the diagnosis of LOS in preterm newborns. METHODS: We prospectively studied newborns ≤32 weeks' gestational age with LOS (n = 19) and noninfected controls (n = 21) at 4 to 60 days' postnatal age. At enrollment, and 1, 3, and 5 days later, we ascertained the C-reactive protein, procalcitonin, and P-SEP in the LOS group, whereas P-SEP alone was ascertained in the control group. RESULTS: P-SEP at enrollment was higher in the LOS than the control group (median 1295 vs 562 ng/L, P = .00001) and remained higher throughout the study period. In the LOS group, P-SEP had a borderline reduction at day 1 versus values at enrollment (median 1011 vs 1295 ng/L, P = .05), whereas C-reactive protein and procalcitonin at day 1 did not differ from baseline values. The receiver operating characteristic curve of P-SEP at enrollment shows an area under the curve of 0.972. The best calculated cutoff value was 885 ng/L, with 94% sensitivity and 100% specificity. Negative likelihood ratio was 0.05, and positive likelihood ratio was infinity. CONCLUSIONS: We demonstrated for the first time in a cohort of preterm newborns that P-SEP is an accurate biomarker for the diagnosis of possible LOS and may also provide useful information for monitoring the response to therapeutic interventions.

Splanchnic Tissue Oxygenation for Predicting Feeding Tolerance in Preterm Infants.

BACKGROUND: Feeding intolerance is very frequent in preterm infants, and the development of an early effective biomarker for its prediction could be useful for carrying out a proper feeding strategy. Our aim was to evaluate if the measurement of splanchnic regional oxygenation (rSO2S) and splanchnic fractional oxygen extraction ratio (FOES) using near-infrared spectroscopy (NIRS) is correlated with the time needed to achieve full enteral feeding and if it can predict the development of feeding intolerance. MATERIALS AND METHODS: We measured rSO2S and FOES in preterm infants 25 ± 0 to 31 ± 6 weeks of gestational age at 24-72 hours of life during continuous enteral feeding. RESULTS: Linear regression analysis did not evidence any relationship between rSO2S and FOES and the time for achievement of full enteral feeding. Multivariate logistic regression analysis showed that birth weight <1000 g (relative risk [RR], 4.5; 95% confidence interval [CI], 1.23-16.45) and patent ductus arteriosus occurrence (RR, 9.3; 95% CI, 1.31-66.06) increased the risk of developing feeding intolerance in our population. CONCLUSION: Splanchnic oxygenation and oxygen extraction measured in the first days of life are not correlated with the time needed to achieve full enteral feeding in preterm infants receiving continuous enteral nutrition.

Near-infrared spectroscopy measurements of splanchnic tissue oxygenation during continuous versus intermittent feeding method in preterm infants.

OBJECTIVES: The aim of the present study was to compare the effects of continuous and intermittent bolus milk feeding on splanchnic regional oxygenation (rSO2S) in small-for-gestational age (SGA) and appropriate-for-gestational age (AGA) preterm infants. METHODS: Infants with gestational age <32 weeks were prospectively studied by near-infrared spectroscopy. Each infant was given a milk bolus in ~10 minutes (intermittent feeding) followed after 3 hours by a 3-hour continuous feeding. rO2S and splanchnic fractional oxygen extraction ratio (FOES [S = splanchnic]) were recorded 30 minutes before (T0) and 30 minutes after the beginning of bolus feeding (T1), 30 minutes before (T2), at the end (T3), and 30 minutes after the continuous feeding period (T4). RESULTS: rSO2S increased at T1 in both AGA and SGA groups, whereas FOES did not vary during the study period. Moreover, we found that rSO2S was higher and FOES was lower at T1 and T3 in the AGA than in the SGA group. CONCLUSIONS: Bolus milk feeding increases splanchnic oxygenation in both AGA and SGA infants, whereas continuous feeding does not. Splanchnic oxygenation is higher in AGA than in SGA infants both during bolus and continuous feeding. Continuous enteral feeding could help to limit the risk of hypoxic-ischemic gut damage in preterm infants in critical condition, especially in AGA infants.

Hypothermia for neonatal hypoxic-ischemic encephalopathy: may an early amplitude-integrated EEG improve the selection of candidates for cooling?

OBJECTIVE: To report our experience in the selection of newborns candidate to therapeutic hypothermia. METHODS: Retrospective study involving 47 newborns suffering from perinatal asphyxia from January 2008 to September 2011. RESULTS: Thirty-five of 47 newborns admitted to our hospital fulfilled metabolic and neurological criteria for recruitment and were cooled. aEEG was carried out in 26 of them and resulted always abnormal. In three of the 12 newborns with only metabolic criteria, aEEG was moderately abnormal. They were cooled and their outcome (evaluated by General Movements and Griffiths Mental Development Scales for children aged 0-2 years) is good. Three additional newborns who only met the metabolic criterion reached our hospital after the therapeutic window for hypothermia and exhibited seizures; their outcome is poor. CONCLUSIONS: In our experience, the inclusion of aEEG in the entry criteria would not have precluded newborns with neurological criteria from cooling. On the contrary, without an early aEEG, we would have excluded from hypothermia infants with moderate hypoxic-ischemic encephalopathy without precocious neurological signs who exhibited only the metabolic criterion, but with abnormal aEEG. If further studies will confirm that early aEEG might identify newborns suitable for cooling even in the absence of clinical signs, a revision of the entry criteria should be considered.

Rescue treatment with terlipressin in different scenarios of refractory hypotension in newborns and infants.

OBJECTIVE: Terlipressin has been successfully used as rescue treatment in hypotensive adults and children with septic shock, but only exceptionally in neonates. The aim of this study is to describe original clinical scenarios in which terlipressin, in newborns and infants, resolved the catecholamine-refractory hypotension. DESIGN: Retrospective study. SETTING: Neonatal intensive care unit. PATIENTS: All newborns with hypotension unresponsive to volume replacement and catecholamines, and treated with terlipressin, from January 2008 to December 2009. In this study, also an infant (11 months old) born extremely preterm was included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Four hypotensive patients received as rescue therapy terlipressin, which produced a dramatic increase in mean arterial pressure, diuresis, and reduction of lactate levels. In three newborns, hypotension, associated with pulmonary hypertension, was resolved with terlipressin. Two of them (one with systemic inflammatory response syndrome, the other with congenital diaphragmatic hernia) died in the following days for causes unrelated to hypotension; the third (on mild hypothermia for hypoxic-ischemic encephalopathy) recovered. We report furthermore an infant with septic shock and on treatment with ß-blockers in whom terlipressin normalized blood pressure. In two patients, cranial Doppler ultrasonography showed the recovery of diastolic cerebral flow in the anterior cerebral artery and the normalization of resistance index within 30 mins from the first dose of terlipressin. In two infants, hyponatremia was detected. CONCLUSION: Although the number of reported infants is little, terlipressin appears to be an effective rescue treatment in different scenarios of refractory neonatal hypotension. Further controlled studies are required to confirm its efficacy and safety.

N-carbamylglutamate in emergency management of hyperammonemia in neonatal acute onset propionic and methylmalonic aciduria.

In propionic aciduria and methylmalonic aciduria, hyperammonemia as a symptom of metabolic decompensation is one of the major clinical problems. Hyperammonemia is a true neonatal emergency with high mortality and neurological complications in most survivors. It requires a rapid and vigorous treatment in order to normalize the ammonia concentration as fast as possible. We report on two full-term neonates, one with propionic aciduria and the other with methylmalonic aciduria, whose plasma ammonia concentrations responded dramatically to oral N-carbamylglutamate. N-carbamylglutamate, added to the classic treatment, quickly normalized plasma ammonia levels in both patients and avoided the need of hemodialysis or peritoneal dialysis. A particularly sudden fall of ammonia was obtained in one patient through beginning N-carbamylglutamate treatment precociously.

Neonatal liver abscesses due to Candida infection effectively treated with caspofungin.

UNLABELLED: Candidiasis is relatively frequent in neonatal and pediatric intensive care units (ICUs), particularly in preterm infants less than 28 weeks of gestational age. Neonatal candidiasis shows high mortality and is often associated to poor neurodevelopmental prognosis in survivor patients. Amphotericin B and fluconazole are the first choice drugs for the treatment of neonatal candidiasis. Caspofungin is an alternative antifungal agent, which is recommended for invasive candidiasis in adults, but has been poorly experienced in neonates and infants as far as now. We report the first two infants with Candida liver abscesses treated with caspofungin. In the first infant bloodstream and liver lesions were cleared by combination therapy with fluconazole, liposomal amphotericin and caspofungin, while in the second one by caspofungin alone. CONCLUSION: Our observations confirm the efficacy and tolerability of caspofungin in the treatment of neonatal candidiasis refractory to conventional antifungal drugs. More extensive data are recommended in order to asses a specific neonatal schedule.