Early versus late parenteral nutrition in term and late preterm infants: a randomised controlled trial.

BACKGROUND: There is limited evidence regarding the optimal time to commence parenteral nutrition (PN) in term and late preterm infants. DESIGN: Single-centre, non-blinded, exploratory randomised controlled trial. SETTING: A level-3 neonatal unit in a stand-alone paediatric hospital. PATIENTS: Infants born ≥34 weeks of gestation and ≤28 days, who needed PN. Eligible infants were randomised on day 1 or day 2 of admission. INTERVENTIONS: Early (day 1 or day 2 of admission, N=30) or late (day 6 of admission, N=30) PN. MAIN OUTCOME MEASURES: Plasma phenylalanine and F2-isoprostane levels on day 4 and day 8 of admission. Secondary outcomes were amino-acid and fatty-acid profiles on day 4 and day 8, and clinical outcomes. RESULTS: The postnatal age at randomisation was similar between the groups (2.3 (SD 0.8) vs 2.3 (0.7) days, p=0.90). On day 4, phenylalanine levels in early-PN infants were higher than in late-PN (mean (SD) 62.9 (26.7) vs 45.5 (15.3) µmol/L; baseline-adjusted percentage difference 25.8% (95% CI 11.6% to 39.9%), p<0.001). There was no significant difference in phenylalanine levels between the two groups on day 8. There was no significant difference between the groups for F2-isoprostane levels on day 4 (early-PN mean (SD) 389 (176) vs late-PN 419 (291) pg/mL; baseline-adjusted percentage difference: -4.4% (95% CI -21.5% to 12.8%) p=0.62) and day 8 (mean (SD) 305 (125) vs 354 (113) pg/mL; adjusted mean percentage difference -16.1 (95% CI -34.1 to 1.9) p=0.09).Postnatal growth restriction for weight was less severe in the early-PN group (change in weight z-score from baseline to discharge: -0.6 (0.6) vs -1.0 (0.6); p=0.02). The incidence of hyperglycaemia was greater in the early-PN group (20/30 (66.7%) vs 11/30 (36.7%), p=0.02). CONCLUSIONS: The timing of the commencement of PN did not seem to affect the degree of oxidative stress in critically ill term and late preterm infants. The effect of transiently high plasma phenylalanine with early PN on clinical outcomes requires further investigation. TRIAL REGISTRATION NUMBER: ACTRN12620000324910.

Current parenteral nutrition practice and clinical outcomes of term and late preterm infants: A retrospective study.

BACKGROUND AND AIMS: Limited studies have described parenteral nutrition (PN) practices and clinical outcomes in term and late preterm infants. The aim of this study was to describe the current practice of PN in term and late preterm infants and their short-term clinical outcomes. METHODS: We conducted a retrospective study in a tertiary NICU between October 2018 and September 2019. Infants (gestation ≥34 weeks) admitted on the day of birth or the following day and received PN were included. We collected data on patient characteristics, daily nutrition, clinical and biochemical outcomes until discharge. RESULTS: A total of 124 infants [mean (SD) gestation: 38 (1.92) weeks] were included; 115 (93%) and 77 (77%) commenced on parenteral amino acids and lipids, respectively, by day 2 of admission. The mean parenteral amino acid and lipid intake on day 1 of admission was 1.0 (0.7) g/kg/day and 0.8 (0.6) g/kg/day respectively and increased to 1.5 (1.0) g/kg/day and 2.1 (0.7) g/kg/day by day 5, respectively. Eight (6.5%) infants accounted for 9 episodes of hospital-acquired infections. The mean z-scores for anthropometrics at discharge were significantly lower than at birth (Weight: -0.72 (1.13) vs - 0.04 (1.11); p < 0.001; Head circumference: -0.14 (1.17) vs 0.34 (1.05); p < 0.001; Length: -0.17 (1.69) vs 0.22 (1.34); p < 0.001). A total of 28 (22.6%) and 16 (12.9%) infants had mild and moderate postnatal growth restriction (PNGR), respectively. None had severe PNGR. Thirteen infants (11%) experienced hypoglycaemia, whereas 53 (43%) experienced hyperglycaemia. CONCLUSION: The intakes of parenteral amino acids and lipids in term and late preterm infants were at the lower end of the currently recommended doses, especially in the first five days of admission. One third of the study population had mild to moderate PNGR. Randomised trials investigating the impact of initial PN intakes on clinical, growth and developmental outcomes are recommended.

Oral agents for acute severe hypertension in children with minimal or no symptoms.

Acute hypertension is common among children admitted to hospital, and large or rapid increases in blood pressure place children at risk of complications such as posterior reversible encephalopathy syndrome. Guidelines in the United States and Europe now include definitions guiding the identification of acute severe hypertension (otherwise known as hypertensive crisis) and its management. This review discusses these recommendations and the appropriate use of oral antihypertensive agents for children with minimal or no symptoms. We focus on the role of oral calcium channel blockers, including isradipine (a second-generation dihydropyridine), given recent changes to regulatory approvals in Australia. The differing pharmacokinetic and pharmacodynamic properties of agents are compared, with the aim of facilitating directed drug selection and dosing.

Early versus late parenteral nutrition in term and late preterm infants: study protocol for a randomised controlled trial.

BACKGROUND: Despite the wide use of parenteral nutrition (PN) in neonatal intensive care units (NICU), there is limited evidence regarding the optimal time to commence PN in term and late preterm infants. The recommendations from the recently published ESPGHAN/ESPEN/ESPR/CPEN and NICE guidelines are substantially different in this area, and surveys have reported variations in clinical practice. The aim of this randomised controlled trial (RCT) is to evaluate the benefits and risks of early versus late PN in term and late preterm infants. METHODS/DESIGN: This study is a single-centre, non-blinded RCT in the NICU of Perth Children's Hospital, Western Australia.A total of 60 infants born ≥34 weeks of gestation who have a high likelihood of intolerance to enteral nutrition (EN) for at least 3-5 days will be randomised to early (day 1 or day 2 of admission) or late commencement (day 6 of admission) of PN after informed parental consent. In both groups, EN will be commenced as early as clinically feasible. Primary outcomes are plasma phenylalanine and plasma F2-isoprostane levels on Day 4 and Day 8 of admission. Secondary outcomes are total and individual plasma amino acid profiles, plasma and red blood cell fatty acid profiles, in-hospital all-cause mortality, hospital-acquired infections, length of hospital/NICU stay, z scores and changes in z scores at discharge for weight, height and head circumference, time to full EN, duration of respiratory (mechanical, non-invasive) support, duration of inotropic support, the incidence of hyper and hypoglycaemia, incidence of metabolic acidosis, liver function, blood urea nitrogen, and C-reactive protein (CRP). DISCUSSION: This RCT will examine the effects of early versus late PN in term and late preterm infants by comparing key biochemical and clinical outcomes and has the potential to identify underlying pathways for beneficial or harmful effects related to the timing of commencement of PN in such infants. TRIAL REGISTRATION: ANZCTR; ACTRN12620000324910 (3rd March 2020).

Use of parenteral nutrition in term and late preterm infants: an Australian and New Zealand survey.

There is limited information regarding the use of parenteral nutrition (PN) in term and late preterm infants. We conducted a survey to study the current clinical practices within Australia and New Zealand (ANZ). A fifteen-question online survey was distributed to 232 neonatologists and fifty-five paediatric intensivists across ANZ between September and November 2019. At least one neonatologist from twenty-seven out of thirty tertiary neonatal intensive care units responded (90 %). Responses were received from sixty-nine neonatologists (30 %) and seven paediatric intensivists (13 %). The overall response rate was 26 % (76/287). Thirty-three percent (25/76) commenced PN within 24 h of admission, 27 % (20/75) between 24 and 48 h, 24 % (18/75) between 48 and 72 h, 9 % (7/75) between 72 and 96 h and 4 % (3/75) between 96 h and 7 days. None of the respondents commenced PN after 7 d of admission. Sixty-one percent (46/75) aimed for 1·5-3 g/kg per d of parenteral amino acids, whereas 27 % (20/75) aimed for 2-3 g/kg per d. Renal failure (59 %; 38/64) and high plasma urea (44 %; 28/64) were the major indications for withholding/decreasing the amino acid intake. Eighty-three percent (63/76) aimed for a dose of 2·5g-3·5 g/kg per d of parenteral lipids; about 9 % (7/76) targeted a dose of 1-2·5 g/kg per d and 4 % (3/76) for > 3·5 g/kg per d. Thirty-two percent (24/74) reported that they would withhold/decrease the dose of parenteral lipids in infants with sepsis. The variations in clinicians' practices with respect to the use of PN in term and late preterm infants highlight the need for high-quality research in this population.

Early or delayed parenteral nutrition for infants: what evidence is available?

PURPOSE OF REVIEW: To review the current evidence evaluating early versus delayed commencement of parenteral nutrition in infants. RECENT FINDINGS: Recent studies in very premature infants (<32 weeks gestation) have shown that early commencement of parenteral nutrition immediately after birth improves physical growth. However, there are concerns that early use of very high dose of amino-acids (>3.5 g/kg/day immediately after birth) may cause metabolic acidosis, elevated blood urea, slower head growth and refeeding-hypophosphatemia syndrome. A recent multicentre randomized controlled trial found that commencement of parenteral nutrition within 24-h of admission increases the risk of infections and prolongs the duration of ventilation and ICU stay in full-term neonates, older infants and children. The study also found that delaying to day 8 of admission increased the risk of hypoglycaemia. SUMMARY: Benefits of commencing parenteral nutrition on the first day of life appear to outweigh risks in very premature infants; however, it is prudent to avoid early very high doses of amino acids (>3.5 g/kg/day) in the first few days of life. In moderate to late preterm infants, if enteral feeds are not tolerated by 72 h, it is reasonable to commence parenteral nutrition. In full-term and older infants, it is preferable to avoid parenteral nutrition within 24 h of admission and consider delaying by further few days. Diligent monitoring of blood glucose, serum phosphate and other parameters is essential while on parenteral nutrition.

Early versus late parenteral nutrition for critically ill term and late preterm infants.

BACKGROUND: Recently conducted randomised controlled trials (RCTs) suggest that late commencement of parenteral nutrition (PN) may have clinical benefits in critically ill adults and children. However, there is currently limited evidence regarding the optimal timing of commencement of PN in critically ill term and late preterm infants. OBJECTIVES: To evaluate the benefits and safety of early versus late PN in critically ill term and late preterm infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (5 April 2019), MEDLINE Ovid (1966 to 5 April 2019), Embase Ovid (1980 to 5 April 2019), EMCare (1995 to 5 April 2019) and MEDLINE via PubMed (1966 to 5 April 2019). We searched for ongoing or recently completed clinical trials, and also searched the grey literature and reference lists of relevant publications. SELECTION CRITERIA: We included RCTs comparing early versus late initiation of PN in term and late preterm infants. We defined early PN as commencing within 72 hours of admission, and late PN as commencing after 72 hours of admission. Infants born at 37 weeks' gestation or more were defined as term, and infants born between 34 and 36+6 weeks' gestation were defined as late preterm. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the trials, extracted the data and assessed the risk of bias. Treatment effects were expressed using risk ratio (RR) and risk difference (RD) for dichotomous outcomes and mean difference (MD) for continuous data. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: Two RCTs were eligible for inclusion. Data were only available from a subgroup (including 209 term infants) from one RCT in children (aged from birth to 17 years) conducted in Belgium, the Netherlands and Canada. In that RCT, children with medium to high risk of malnutrition were included if a stay of 24 hours or more in the paediatric intensive care unit (PICU) was expected. Early PN and late PN were defined as initiation of PN within 24 hours and after day 7 of admission to PICU, respectively. The risk of bias for the study was considered to be low for five domains and high for two domains. The subgroup of term infants that received late PN had significantly lower risk of in-hospital all-cause mortality (RR 0.35, 95% confidence interval (CI) 0.14 to 0.87; RD -0.10, 95% CI -0.18 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) = 10; 1 trial, 209 participants) and neonatal mortality (death from any cause in the first 28 days since birth) (RR 0.29, 95% CI 0.10 to 0.88; RD -0.09, 95% CI -0.16 to -0.01; NNTB = 11; 1 trial, 209 participants). There were no significant differences in rates of healthcare-associated blood stream infections, growth parameters and duration of hospital stay between the two groups. Neurodevelopmental outcomes were not reported. The quality of evidence was considered to be low for all outcomes, due to imprecision (owing to the small sample size and wide confidence intervals) and high risk of bias in the included studies. AUTHORS' CONCLUSIONS: Whilst late commencement of PN in term and late preterm infants may have some benefits, the quality of the evidence was low and hence our confidence in the results is limited. Adequately powered RCTs, which evaluate short-term as well as long-term neurodevelopmental outcomes, are needed.

Longchain polyunsaturated fatty acid supplementation in preterm infants.

BACKGROUND: Controversy exists over whether longchain polyunsaturated fatty acids (LCPUFA) are essential nutrients for preterm infants because they may not be able to synthesise sufficient amounts of LCPUFA to meet the needs of the developing brain and retina. OBJECTIVES: To assess whether supplementation of formula milk with LCPUFA is safe and of benefit to preterm infants. The main areas of interest were the effects of supplementation on the visual function, development and growth of preterm infants. SEARCH METHODS: Trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2) in the Cochrane Library (searched 28 February 2016), MEDLINE Ovid (1966 to 28 February 2016), Embase Ovid (1980 to 28 February 2016), CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1980 to 28 February 2016), MEDLINE In Process & Other Non-indexed Citations (1966 to 28 February 2016) and by checking reference lists of articles and conference proceedings. We also searched ClinicalTrials.gov (13 April 2016). No language restrictions were applied. SELECTION CRITERIA: All randomised trials evaluating the effect of LCPUFA-supplemented formula in enterally-fed preterm infants (compared with standard formula) on visual development, neurodevelopment and physical growth. Trials reporting only biochemical outcomes were not included. DATA COLLECTION AND ANALYSIS: All authors assessed eligibility and trial quality, two authors extracted data separately. Study authors were contacted for additional information. MAIN RESULTS: Seventeen trials involving 2260 preterm infants were included in the review. The risk of bias varied across the included trials with 10 studies having low risk of bias in a majority of the domains. The median gestational age (GA) in the included trials was 30 weeks and median birth weight (BW) was 1300 g. The median concentration of docosahexaenoic acid (DHA) was 0.33% (range: 0.15% to 1%) and arachidonic acid (AA) 0.37% (range: 0.02% to 0.84%). Visual acuity Visual acuity over the first year was measured by Teller or Lea acuity cards in eight studies, by visual evoked potential (VEP) in six studies and by electroretinogram (ERG) in two studies. Most studies found no significant differences in visual acuity between supplemented and control infants. The form of data presentation and the varying assessment methods precluded the use of meta-analysis. A GRADE analysis for this outcome indicated that the overall quality of evidence was low. Neurodevelopment Three out of seven studies reported some benefit of LCPUFA on neurodevelopment at different postnatal ages. Meta-analysis of four studies evaluating Bayley Scales of Infant Development at 12 months (N = 364) showed no significant effect of supplementation (Mental Development Index (MDI): MD 0.96, 95% CI -1.42 to 3.34; P = 0.43; I² = 71% - Psychomotor DeveIopment Index (PDI): MD 0.23, 95% CI -2.77 to 3.22; P = 0.88; I² = 81%). Furthermore, three studies at 18 months (N = 494) also revealed no significant effect of LCPUFA on neurodevelopment (MDI: MD 2.40, 95% CI -0.33 to 5.12; P = 0.08; I² = 0% - PDI: MD 0.74, 95% CI -1.90 to 3.37; P = 0.58; I² = 54%). A GRADE analysis for these outcomes indicated that the overall quality of evidence was low. Physical growth Four out of 15 studies reported benefits of LCPUFA on growth of supplemented infants at different postmenstrual ages (PMAs), whereas two trials suggested that LCPUFA-supplemented infants grow less well. One trial reported mild reductions in length and weight z scores at 18 months. Meta-analysis of five studies (N = 297) showed increased weight and length at two months post-term in supplemented infants (Weight: MD 0.21, 95% CI 0.08 to 0.33; P = 0.0010; I² = 69% - Length: MD 0.47, 95% CI 0.00 to 0.94; P = 0.05; I² = 0%). Meta-analysis of four studies at a corrected age of 12 months (N = 271) showed no significant effect of supplementation on growth outcomes (Weight: MD -0.10, 95% CI -0.31 to 0.12; P = 0.34; I² = 65% - Length: MD 0.25; 95% CI -0.33 to 0.84; P = 0.40; I² = 71% - Head circumference: MD -0.15, 95% CI -0.53 to 0.23; P = 0.45; I² = 0%). No significant effect of LCPUFA on weight, length or head circumference was observed on meta-analysis of two studies (n = 396 infants) at 18 months (Weight: MD -0.14, 95% CI -0.39 to 0.10; P = 0.26; I² = 66% - Length: MD -0.28, 95% CI -0.91 to 0.35; P = 0.38; I² = 90% - Head circumference: MD -0.18, 95% CI -0.53 to 0.18; P = 0.32; I² = 0%). A GRADE analysis for this outcome indicated that the overall quality of evidence was low. AUTHORS' CONCLUSIONS: Infants enrolled in the trials were relatively mature and healthy preterm infants. Assessment schedule and methodology, dose and source of supplementation and fatty acid composition of the control formula varied between trials. On pooling of results, no clear long-term benefits or harms were demonstrated for preterm infants receiving LCPUFA-supplemented formula.

One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates.

BACKGROUND: Animal studies and trials in older children and adults suggest that a 'one dose per day' regimen of gentamicin is superior to a 'multiple doses per day' regimen. OBJECTIVES: To compare the efficacy and safety of one dose per day compared to multiple doses per day of gentamicin in suspected or proven sepsis in neonates. SEARCH METHODS: Eligible studies were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 3) in the Cochrane Library (searched 8 April 2016), MEDLINE (1966 to 8 April 2016), Embase (1980 to 8 April 2016), and CINAHL (December 1982 to 8 April 2016). SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing one dose per day ('once a day') compared to multiple doses per day ('multiple doses a day') of gentamicin to newborn infants. DATA COLLECTION AND ANALYSIS: Data collection and analysis was performed according to the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Eleven RCTs were included (N = 574) and 28 excluded. All except one study enrolled infants of more than 32 weeks' gestation. Limited information suggested that infants in both 'once a day' as well as 'multiple doses a day' regimens showed adequate clearance of sepsis (typical RR 1.00, 95% CI 0.84 to 1.19; typical RD 0.00, 95% CI -0.19 to 0.19; 3 trials; N = 37). 'Once a day' gentamicin regimen was associated with fewer failures to attain peak level of at least 5 µg/ml (typical RR 0.22, 95% CI 0.11 to 0.47; typical RD -0.13, 95% CI -0.19 to -0.08; number needed to treat for an additional beneficial outcome (NNTB) = 8; 9 trials; N = 422); and fewer failures to achieve trough levels of 2 µg/ml or less (typical RR 0.38, 95% CI 0.27 to 0.55; typical RD -0.22, 95% CI -0.29 to -0.15; NNTB = 4; 11 trials; N = 503). 'Once a day' gentamicin achieved higher peak levels (MD 2.58, 95% CI 2.26 to 2.89; 10 trials; N = 440) and lower trough levels (MD -0.57, 95% CI -0.69 to -0.44; 10 trials; N = 440) than 'multiple doses a day' regimen. There was no significant difference in ototoxicity between two groups (typical RR 1.69, 95% CI 0.18 to 16.25; typical RD 0.01, 95% CI -0.04 to 0.05; 5 trials; N = 214). Nephrotoxicity was not noted with either of the treatment regimens. Overall, the quality of evidence was considered to be moderate on GRADE analysis, given the small sample size and unclear/high risk of bias in some of the domains in a few of the included studies. AUTHORS' CONCLUSIONS: There is insufficient evidence from the currently available RCTs to conclude whether a 'once a day' or a 'multiple doses a day' regimen of gentamicin is superior in treating proven neonatal sepsis. However, data suggest that pharmacokinetic properties of a 'once a day' gentamicin regimen are superior to a 'multiple doses a day' regimen in that it achieves higher peak levels while avoiding toxic trough levels. There was no change in nephrotoxicity or auditory toxicity. Based on the assessment of pharmacokinetics, a 'once a day regimen' may be superior in treating sepsis in neonates of more than 32 weeks' gestation.