Probiotics for Prevention of Severe Necrotizing Enterocolitis: Experience of New Zealand Neonatal Intensive Care Units.

Introduction: Necrotizing enterocolitis (NEC) affects mainly preterm infants, has a multifactorial etiology and is associated with intestinal dysbiosis and disordered immunity. Use of probiotics for prophylaxis is beneficial with studies indicating reduction in NEC ≥ stage 2, late onset sepsis (LOS) and mortality. However, not all studies have shown a reduction, there are questions regarding which probiotic to use, whether infants <1,000 g benefit and the risk of probiotic sepsis. All neonatal intensive care units in New Zealand (NZ) use probiotics and contribute to an international database (Australian and New Zealand Neonatal Network or ANZNN). Objective: To use ANZNN data to investigate the experience of NZ neonatal units with probiotics for NEC prevention in a setting where the baseline incidence of severe NEC was low, to compare results of 2 commonly used probiotic regimes and report on the extremely low birth weight subgroup. Method: Outcomes before (Pre group 2007-2010) and after (Probiotic group 2013-2015) starting routine probiotics for preterm infants <1,500 g or <32 weeks were compared. Clinicians reviewed cases to ensure they met database criteria. Five units used Infloran (Bifidobacterium bifidum and Lactobacillus acidophilus) and 1 unit used Lactobacillus GG (LGG) and bovine lactoferrin (bLF). Results: Four thousand five hundred and twenty nine infants were included and Pre and Probiotic groups were well-balanced with regard to gestation, birth weight and gender. The incidence of NEC in the Probiotic group was 1.6 and 2.7% in the pre group (corrected OR 0.62 CI 0.41-0.94). There was one case of probiotic sepsis. There was no significant difference between the Infloran and LGG/bLF combinations in regard to observed NEC rates. Late onset sepsis rates were significantly lower in the Probiotic group (p < 0.01). Conclusions: Introduction of probiotics for preterm infants in NZ has been associated with significant reductions in NEC and late onset sepsis.

Safe and effective glycaemic control in premature infants: observational clinical results from the computerised STAR-GRYPHON protocol.

OBJECTIVE: Previous studies examine clinical outcomes of insulin therapy in neonatal intensive care units (NICUs), without first developing safe and effective control protocols. This research quantifies the safety and performance of a computerised model-based control algorithmSTAR-GRYPHON (Stochastic TARgeted Glucose Regulation sYstem to Prevent Hyper- and hypO-glycaemia in Neonates). DESIGN: Retrospective observational study of glycaemic control in very/extremely low birthweight infants treated with insulin from Christchurch Women's Hospital NICU between January 2013 and June 2017. Blood glucose (BG) outcomes and control performance is compared with retrospective data (n=22) and literature. INTERVENTIONS: Insulin infusion doses were calculated from 3 to 4 hourly BG measurements using a computerised model-based control algorithm, STAR-GRYPHON. MAIN OUTCOME MEASURES: Mean BG, time in targeted range and incidence of hypoglycaemia. RESULTS: STAR-GRYPHON (n=35) had lower mean BG concentration (7.0mmol/L vs 7.9 mmol/L), higher %BG within the 4.0-8.0 mmol/L target range (71.1% vs 50.9%) and lower %BG <4.0 mmol/L (0.6% vs 2.1%). There were only 2 BG <2.6 mmol/L (over n=2, 5.5% of patients, 0.03% of all BG outcomes), one of which may be attributed to clinical error. These results show better control to target and lower incidence of hypoglycaemia than most literature results from intensive insulin therapy protocols or study groups in children and infants. CONCLUSIONS: Model-based protocols can safely and effectively control BG in very premature infants and should be used in future studies to determine the effect of insulin therapy on clinical outcomes.

Electrolytes in sick neonates - which sodium is the right answer?

INTRODUCTION: Hypoproteinaemia leads to spuriously high-sodium values when measured by indirect ion-selective electrodes (ISE) as used in main laboratory analysers compared with direct ISE employed in point-of-care analysers (POCT). The authors, therefore, investigated the occurrence of hypoalbuminaemia and its effect on measured sodium from POCT and the main laboratory analyser of neonatal intensive-care samples. METHOD: Sodium, in paired retrospective samples, measured by the main laboratory and neonatal unit blood-gas (POCT) analysers were compared. RESULTS: Hypoalbuminaemia (<30 g/l) was present in 1400/2420 paired results. Sodium was higher when measured by laboratory analyser, the difference increased with decreasing albumin; sodium (laboratory - POCT)=7.6 (±1.1)-0.22 (±0.04)×albumin. A difference >3 mmol/l was present in 31% and consequently underestimated (9.4%) hyponatraemia and overestimated (3.8%) hypernatraemia. CONCLUSION: Hypoalbuminaemia is common in sick neonates and monitoring electrolytes using POCT and laboratory analysers frequently yield significantly different results with consequent misclassification. In these patients, measurement of electrolytes by direct ISE (blood-gas analyser) may be more accurate.

Pilot study of a model-based approach to blood glucose control in very-low-birthweight neonates.

BACKGROUND: Hyperglycemia often occurs in premature, very low birthweight infants (VLBW) due to immaturity of endogenous regulatory systems and the stress of their condition. Hyperglycemia in neonates has been linked to increased morbidities and mortality and occurs at increasing rates with decreasing birthweight. In this cohort, the emerging use of insulin to manage hyperglycemia has carried a significant risk of hypoglycemia. The efficacy of blood glucose control using a computer metabolic system model to determine insulin infusion rates was assessed in very-low-birth-weight infants. METHODS: Initial short-term 24-hour trials were performed on 8 VLBW infants with hyperglycemia followed by long-term trials of several days performed on 22 infants. Median birthweight was 745 g and 760 g for short-term and long-term trial infants, and median gestational age at birth was 25.6 and 25.4 weeks respectively. Blood glucose control is compared to 21 retrospective patients from the same unit who received insulin infusions determined by sliding scales and clinician intuition. This study was approved by the Upper South A Regional Ethics Committee, New Zealand (ClinicalTrials.gov registration NCT01419873). RESULTS: Reduction in hyperglycemia towards the target glucose band was achieved safely in all cases during the short-term trials with no hypoglycemic episodes. Lower median blood glucose concentration was achieved during clinical implementation at 6.6 mmol/L (IQR: 5.5 - 8.2 mmol/L, 1,003 measurements), compared to 8.0 mmol/L achieved in similar infants previously (p < 0.01). No significant difference in incidence of hypoglycemia during long-term trials was observed (0.25% vs 0.25%, p = 0.51). Percentage of blood glucose within the 4.0 - 8.0 mmol/L range was increased by 41% compared to the retrospective cohort (68.4% vs 48.4%, p < 0.01). CONCLUSIONS: A computer model that accurately captures the dynamics of neonatal metabolism can provide safe and effective blood glucose control without increasing hypoglycemia. TRIAL REGISTRATION: ClinicalTrials.gov registration NCT01419873.

BCS1L gene mutation presenting with GRACILE-like syndrome and complex III deficiency.

The clinical presentation of a neonate with GRACILE-like syndrome, complex III deficiency and BCS1L mutations is discussed. This case is compared and contrasted with the original Finnish reports of GRACILE syndrome and other cases with a similar phenotype. This case confirms the pathogenicity of the BCS1L gene mutation c.166C>T, and provides support for the pathogenicity of a sequence variation, c.-588T>A, previously reported.

Are gentamicin and/or vancomycin associated with ototoxicity in the neonate? A retrospective audit.

BACKGROUND: Aminoglycoside-induced ototoxicity has been reported in neonates but its incidence is poorly defined, whereas vancomycin-induced ototoxicity has not been reported in neonates. OBJECTIVE: To compare hearing test results in infants in a neonatal intensive care unit (NICU) who were or were not treated with extended interval gentamicin dosing and/or standard vancomycin dosing. METHOD: A database of otoacoustic emissions (OAE), over a 5-year period of NICU admissions, was combined with databases of gentamicin and vancomycin dosing to compare patients treated or not treated with these antibiotics. RESULTS: A total of 2,347 OAE results was available. OAE failure rates were: no gentamicin and no vancomycin (noGnoV), 7% (85/1,233); gentamicin but no vancomycin (GnoV), 4% (42/949); vancomycin but no gentamicin (VnoG), 22% (9/41) and gentamicin and vancomycin (GandV), 14% (17/124). Compared to noGnoV there was a decreased risk of OAE failure in GnoV (p = 0.022, OR 0.64, 95% CI 0.44-0.94) and an increased risk in VnoG (p = 0.003, OR 3.46, 95% CI 1.54-7.75) and GandV, (p = 0.006, OR 2.20, 95% CI 1.26-3.83). CONCLUSIONS: Gentamicin, as used and evaluated in this audit, showed no evidence of an increased risk of ototoxicity; what was observed was a statistically significant decrease in OAE failure rate. Vancomycin, by contrast, was associated with ototoxicity.

Amino-terminal proCNP: a putative marker of cartilage activity in postnatal growth.

Recent evidence from rodents and humans shows that C-type natriuretic peptide (CNP) plays an essential role in endochondral bone growth. We recently identified a stable product of proCNP, amino-terminal proCNP (NT-proCNP), which unlike CNP is readily measurable in human and ovine plasma. Hypothesizing that plasma NT-proCNP concentrations reflect in part CNP synthesis within growth plates of rapidly growing cartilage, we studied levels of CNP forms in both children and lambs and related these to age, growth velocity, and biochemical markers of bone turnover. Plasma NT-proCNP levels were elevated at birth and fell progressively with age. Significant associations between plasma NT-proCNP and height velocity, alkaline phosphatase, and type 1 collagen C telopeptide were identified in children (aged 5-18 y). In longitudinal animal studies, elevated plasma concentration of NT-proCNP in 1-wk-old lambs fell progressively to mature adult levels at age 27 wk. Plasma NT-proCNP showed a highly significant association with alkaline phosphatase and metacarpal growth velocity. Glucocorticoids, a treatment known to inhibit cartilage proliferation, reduced metacarpal growth elongation in 4-wk-old lambs and markedly lowered circulating NT-proCNP levels during the treatment period. In summary, NT-proCNP levels in blood show a strong association with growth velocity and markers of bone formation and may well serve as a useful marker of growth plate activity in humans and other mammals.