Probiotic sepsis in preterm neonates-a systematic review.

Sepsis due to the administered probiotic strain/s is a barrier against adoption of prophylactic probiotic supplementation in preterm infants to reduce the risk of necrotising enterocolitis (NEC ≥ Stage II), all-cause mortality, late-onset sepsis, and feeding intolerance. We aimed to conduct a systematic review for reports of probiotic sepsis in preterm infants (gestation < 37 weeks). Databases including PubMed, Embase, Emcare, Cochrane Central library, and Google Scholar were searched in August 2021 and updated in Jan 2022. Probiotic sepsis was defined as positive blood/CSF culture isolating administered probiotic strain with symptoms suggestive of infection. Data collection included birth weight, gestation, comorbidities (e.g. gut surgery, NEC), presence of central venous catheters, treatment, and outcome. Literature search revealed 1569 studies. A total of 16 reports [randomised control trial (RCT): none; non-RCT: 1; case series: 8; case report: 7] involving 32 preterm infants with probiotic sepsis were included after exclusions for various reasons. Majority of the cases were born < 32 weeks' gestation. Bifidobacterium (N = 19) was the most commonly isolated organism followed by Lactobacillus (N = 10), and Saccharomyces (N = 3). A total of 25/32 cases were confirmed to be due to the administered probiotic strain on full genomic analysis. Two studies reported one neonatal death each. Twelve neonates had comorbidities. Majority were treated with antibiotics (29/32) whereas others (3/32) required antifungal treatment. CONCLUSION: Probiotics sepsis is relatively an uncommon event in preterm infants. Majority of the cases recovered after antibiotic or antifungal treatment. The importance of optimal surveillance and treatment of probiotic sepsis and research towards alternatives to probiotics (e.g. postbiotics) is emphasised. WHAT IS KNOWN: • Probiotics have been shown to reduce necrotising enterocolitis, late-onset sepsis, all-cause mortality, and time to reach full enteral feeds in preterm infants. • Despite the evidence, use of probiotics is not universal due to concerns regarding probiotic-associated sepsis in preterm infants. WHAT IS NEW: • This comprehensive systematic review showed that probiotic sepsis is a relatively rare phenomenon in preterm infants. • All except one case where the diagnosis was uncertain recovered after antimicrobial therapy.

Current Status of Probiotics for Preterm Infants.

Probiotics have been shown to reduce the risk of all-cause mortality, necrotizing enterocolitis (NEC ≥ stage II), late onset sepsis (LOS), and feeding intolerance in preterm infants. Considering the substantial health burden imposed by these conditions, the importance of probiotics in preterm infants cannot be overemphasized. Based on the data from experimental studies, and systematic reviews of randomized controlled trials (RCTs) and non-RCTs, the uptake of this intervention in neonatal medicine has been increasing over the last few years. However, many are still hesitating to adopt this intervention for various reasons, including concerns about probiotic sepsis, product quality, and lack of clarity on optimal strain/s or their combinations. Some question the validity of meta-analyses of studies involving different probiotic strains or their combinations because probiotics effects are considered to be strain-specific. Some of the early concerns about probiotics in preterm infants have been shown to be unjustified. However, the resistance to probiotics continues in many neonatal units around the world. The future of probiotics for preterm infants depends on continued efforts to develop high-quality probiotic products using stringent quality control, improving access to such products, and robust head-to-head comparisons to know the optimal strains or their combinations. Monitoring for adverse effects such as probiotic sepsis and development of antibiotic resistance is crucial. The authors review the current status of probiotics in preterm infants and discuss the scope for further research in this field.

Antenatal corticosteroids for impending late preterm (34-36+6 weeks) deliveries-A systematic review and meta-analysis of RCTs.

BACKGROUND: Administration of antenatal corticosteroids (ANC) for impending preterm delivery beyond 34 weeks of gestation continues to be a controversial issue despite various guidelines for obstetricians and gynaecologists. OBJECTIVE: To compare outcomes following exposure to ANC for infants born between 34-36+6 weeks' gestation. METHODS: A systematic review of randomised controlled trials (RCT) reporting neonatal outcomes after ANC exposure between 34-36+6 weeks' gestation using Cochrane methodology. Databases including PubMed, Embase, Emcare, Cochrane Central library and Google Scholar were searched in May 2020. Primary outcomes: (1) Need for respiratory support (Mechanical ventilation, CPAP, high flow) or oxygen (2) Hypoglycemia. Secondary outcomes included respiratory distress syndrome (RDS), transient tachypnoea of newborn (TTN), need for neonatal resuscitation at birth [only in the delivery room immediately after birth (not in neonatal intensive care unit (NICU)], admission to NICU, mortality and developmental follow up. Level of evidence (LOE) was summarised by GRADE guidelines. MAIN RESULTS: Seven RCTs (N = 4144) with low to high risk of bias were included. Only one RCT was from high income countries, Meta-analysis (random-effects model) showed (1) reduced need for respiratory support [5 RCTs (N = 3844); RR = 0.68 (0.47-0.98), p = 0.04; I2 = 55%; LOE: Moderate] and (2) higher risk of neonatal hypoglycaemia [4 RCTs (N = 3604); RR = 1.61(1.38-1.87), p<0.00001; I2 = 0%; LOE: High] after ANC exposure. Neonates exposed to ANC had reduced need for resuscitation at birth. The incidence of RDS, TTN and surfactant therapy did not differ significantly. None of the included studies reported long-term developmental follow up. CONCLUSIONS: Moderate quality evidence indicates that ANC exposure reduced need for respiratory support, and increased the risk of hypoglycaemia in late preterm neonates. Large definitive trials with adequate follow up for neurodevelopmental outcomes are required to assess benefits and risks of ANC in this population.

Prophylactic Probiotic Supplementation for Preterm Neonates-A Systematic Review and Meta-Analysis of Nonrandomized Studies.

Systematic review and meta-analyses of randomized controlled trials (RCTs) show that probiotics reduce the risk of necrotizing enterocolitis (NEC ≥ Stage II), late onset sepsis (LOS), all-cause mortality, and feeding intolerance in preterm neonates. Data from observational studies is important to confirm probiotic effects in clinical practice. We aimed to compare outcomes before and after implementing routine probiotic supplementation (RPS) in preterm neonates (<37 weeks of gestation) by performing a systematic review of non-RCTs using Cochrane methodology. Databases including PubMed, The Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Cochrane Central library, and Google Scholar were searched in May 2020. A meta-analysis was performed using a random effects model. Categorical measure of effect size was expressed as OR and 95% CI. Statistical heterogeneity was assessed by the chi-squared test, I2 statistic. The level of evidence (LOE) was summarized using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) guidelines. Primary outcomes were NEC ≥ Stage II, LOS, and all-cause mortality. Secondary outcomes included probiotic sepsis. Thirty good-quality non-RCTs (n = 77,018) from 18 countries were included. The meta-analysis showed RPS was associated with significantly reduced: 1) NEC ≥ Stage II (30 studies, n = 77,018; OR: 0.60; 95% CI: 0.50, 0.73; P <0.00001, I2: 65%; LOE: Moderate), 2) LOS: (21 studies, n = 65,858; OR: 0.85; 95% CI: 0.74, 0.97; P = 0.02, I2: 74%; LOE: Low), and 3) all-cause mortality (27 non-RCTs, n = 70,977; OR: 0.77; 95% CI: 0.68, 0.88; P = 0.0001, I2: 49%; LOE: Low). Subgroups: 1) extremely low birth weight (ELBW: birth weight <1000 g) neonates: RPS was associated with significantly reduced NEC ≥ Stage II (4.5% compared with 7.9%). However, there was no difference in LOS and mortality. 2) Multistrain RPS was more effective than single strain. One study reported 3 nonfatal cases of probiotic sepsis. In summary, moderate- to low-quality evidence indicates that RPS was associated with significantly reduced NEC ≥ Stage II, LOS, and all-cause mortality in neonates <37 weeks of gestation and NEC ≥ Stage II in ELBW neonates.

Sepsis calculator for neonatal early onset sepsis - a systematic review and meta-analysis.

BACKGROUND: Over investigation and overuse of empirical antibiotics is a concern in management of neonatal early onset sepsis (EOS) using the Centers for Disease Control and Prevention guidelines. "Sepsis calculator" is a risk-based prediction model for managing neonates at risk of EOS. OBJECTIVE: To compare outcomes of neonatal EOS using of sepsis calculator versus conventional approach. METHODS: A systematic review of randomized controlled trials (RCT) and non-RCTs reporting on outcomes after implementation of sepsis calculator for EOS for neonates >34-week gestation was conducted using the Cochrane methodology. Databases PubMed, CINAHL, Embase, Cochrane Central library and Google Scholar were searched in May 2019. Primary outcomes were antibiotics usage and laboratory tests for managing EOS. Secondary outcomes included hospital admissions and readmissions, blood culture positive EOS and mortality. The level of evidence (LOE) was summarized using the GRADE guidelines. RESULTS: A total of 387 articles were retrieved after initial search. Six high quality non-RCTs fulfilled inclusion criteria. Meta-analysis (random effects model) showed that implementation of sepsis calculator was associated with reduced antibiotic usage [N = 172,385; OR = 0.22 (0.14-0.36); p < .00001; heterogeneity (I2) = 97%, Number needed to treat (NNT): 22], laboratory tests [N = 168,432; OR = 0.14 (0.08-0.27); p < .00001; I2 = 99%, NNT = 8], and admissions to neonatal unit [N = 16,628; OR = 0.24 (0.11-0.51); p = .0002; I2 = 98%, NNT = 7]; LOE: moderate. There was no difference in mortality, culture positive EOS, and readmissions. CONCLUSION: Moderate quality evidence indicates that the implementation of a sepsis calculator was associated with reduced usage of antibiotics, laboratory tests and admission to neonatal unit with no increase in mortality and readmissions.

Probiotics for cow's milk protein allergy: a systematic review of randomized controlled trials.

Cow's milk protein allergy (CMPA) is the commonest food allergy in infancy and is associated with significant health burden. Given their immune modulatory properties, probiotics have been proposed as a strategy for management of CMPA. We aimed to systematically review efficacy and safety of probiotics in the management of CMPA. Databases PubMed, EMBASE, CINAHL, Cochrane Central Library, and Google scholar were searched in August 2018 for randomized controlled trials (RCT) of probiotic supplementation as an adjunct in the management of infants with suspected/proven CMPA. Primary outcomes were resolution of hematochezia and acquisition of tolerance to CMP at 6, 12, 24, and 36 months. Secondary outcomes included effect on allergic symptoms (SCORAD index), growth, gut microbiota, and adverse effects. A total of 10 RCTs (n = 845; probiotics, 422; control, 423) with low to unclear risk of bias were included. Meta-analysis showed probiotic supplementation was not associated with earlier resolution of hematochezia (n = 87; RR: 1.45 (95% CI: 0.96-2.18), p = 0.08; level of evidence (LOE), very low), in presumed CMPA. In confirmed CMPA, probiotics were associated with higher rate of acquisition of tolerance to CMP at the end of 3 years compared with placebo (N = 493; RR, 1.47; 95% CI, (1.17-1.84); p = 0.0009; LOE, low]. Meta-analysis was not possible for other outcomes. There were no probiotic related adverse effects. Conclusion: Limited low-quality evidence indicates that probiotic supplementation may be associated with earlier acquisition of tolerance to CMP in children with CMPA. Large well-designed trials are essential to confirm these findings. What is Known: • Cow's milk protein allergy (CMPA) is one of the commonest food allergies in children. CMPA is associated with significant socioeconomic burden. • Elimination diet and extensively hydrolyzed formula is the mainstay of the management of CMPA. What is New: • This first systematic review of randomized controlled trials shows that probiotics as an adjuvant can lead to earlier acquisition of tolerance to CMP in children at 36 months of age. However, the evidence is low quality and influenced by data from one large study. • Probiotic supplementation was not associated with earlier resolution of hematochezia.

Wastage of standardised parenteral nutrition solution - a challenge for neonatal units.

Background: Standardised parental nutrition (PN) has been used in many neonatal intensive care unit (NICU). Easy accessibility, better provision of nutrients, reduced prescription errors and cost savings are some of its benefits. Fixed large volume (e.g. 750-1000 mL) and short expiry limit (48 hrs) along with changing metabolic needs of neonates leads to significant wastage of PN solution. Objective: To evaluate wastage of PN solution in our 22-bedded NICU. Methods: The audit was conducted over 21-month period (July 2015-April 2017). Data on PN use (e.g. type, duration, infused volume, residual after use) was obtained from hospital records. The discarded volume of PN was estimated after subtracting the administered volume based on the rate of infusion from the total volume in the bag. Cumulative "discarded" volume as percentage of the total "supplied" volume was calculated. Results: A total of 305-PN bags (Standardised: Preterm: 222, Term: 83) were used. The estimated total used, discarded, and percentage discarded volumes for standard preterm and term PN were 78.1, 88 L, 53% and 33.5, 49.7 L, and 59.8%, respectively. Conclusions: There was more than 50% wastage of PN solution in our NICU. The estimated cost of this PN wastage was around 21,000 AUD over 21 months. Strategies such as minipack should be explored to prevent such losses.

Probiotics for the management of neonatal hyperbilirubinemia: a systematic review of randomized controlled trials.

BACKGROUND: Neonatal jaundice requiring phototherapy is associated with significant socioeconomic burden including hospital readmission, prolonged hospital stay, and separation of the baby from mother. OBJECTIVES: To assess the efficacy and safety of probiotics in reducing the need for phototherapy and its duration in neonatal hyperbilirubinemia. METHODS: A systematic review of randomized controlled trials (RCTs) of probiotic supplementation for prevention or treatment of jaundice in neonates (any gestation or weight) using the Cochrane methodology. Primary outcome was the duration of phototherapy. Secondary outcomes included incidence of jaundice, total serum bilirubin (TSB) level at 24, 48, 72, 96 h, and day 7, duration of hospital stay, and adverse effects (e.g. probiotic sepsis). Results were summarized as per GRADE guidelines. RESULTS: Nine RCTs (prophylactic: six trials, N = 1761; therapeutic: three trials, N = 279) with low to high risk of bias were included. Meta-analysis (random-effects model) showed probiotic supplementation reduced duration of phototherapy [N = 415, mean difference (MD): -11.80 (-17.47, -6.13); p < .0001; level of evidence (LOE): low]. TSB was significantly reduced at 96 h [MD: -1.74 (-2.92, -0.57); p = .004] and 7 d [MD: -1.71 (-2.25, -1.17); p < .00001; LOE: low] after probiotic treatment. Prophylactic probiotics did not reduce the incidence of jaundice significantly [N = 1582, relative risk (RR): 0.56 (0.25, 1.27); p = .16; LOE: low]. There were no probiotic-related adverse effects. CONCLUSION: Limited low-quality evidence indicates that probiotic supplementation may reduce the duration of phototherapy in neonates with jaundice. Routine use of probiotics to prevent or treat neonatal jaundice cannot be recommended. Large well-designed trials are essential to confirm these findings.

Antenatal corticosteroids in impending preterm deliveries before 25 weeks' gestation.

Antenatal corticosteroid (ANC) use before 25 weeks' gestation is controversial. Our previous systematic review (eight observational studies, n=10 109) showed that ANC exposure was associated with significantly reduced mortality and severe intraventricular haemorrhage (IVH)/periventricular leukomalacia (PVL) in neonates born <25 weeks. We update our review by adding data (n=3334) from a recent study. We used Cochrane methodology and summarised the results using GRADE (The Grading of Recommendations Assessment, Development and Evaluation) guidelines. Nine high-quality observational studies were included. Meta-analysis (random effects model) showed reduced mortality (n=13 443; OR=0.48 (95% CI 0.42 to 0.55) P<0.00001; level of evidence (LOE): moderate) and IVH or PVL (n=8418; OR=0.70 (95% CI 0.63 to 0.79), P<0.00001; LOE: moderate) in neonates born <25 weeks exposed to ANC. There was no difference in necrotising enterocolitis (NEC) ≥stage II (n=8737; OR=1.01 (95% CI 0.84 to 1.22), P=0.89; LOE: low); incidence of chronic lung disease (CLD) was higher (n=7983; OR=1.32 (95% CI 1.04 to 1.67), P=0.02; LOE: low) in ANC group. Composite outcomes of death/major morbidities (eg, severe IVH, NEC, CLD) were improved after ANC exposure.

Antenatal corticosteroids for neonates born before 25 Weeks-A systematic review and meta-analysis.

BACKGROUND: Efficacy of antenatal corticosteroids before 25 weeks of gestation is unclear. OBJECTIVE: To assess and compare neonatal outcomes following ANC exposure at 22, 23 and 24 weeks of gestation by conducting systematic review and meta- analysis. METHODS: A systematic review of randomised controlled trials (RCT) and non-RCTs reporting on neonatal outcomes after exposure to ANC up to 246 weeks of gestation using the Cochrane systematic review methodology. Databases Pubmed, CINAHL, Embase, Cochrane Central library, and online abstracts of conference proceedings including the Pediatric Academic Society (PAS) were searched in Feb 2017. Primary outcome was in-hospital mortality defined as death before discharge during the first admission. Secondary outcomes included severe intraventricular hemorrhage (IVH> grade III and IV)/or periventricular leukomalacia (PVL), necrotising enterocolitis (NEC >stage II) and chronic lung disease (CLD). Meta-analysis was performed using a random-effects model. The level of evidence (LOE) was summarised using the GRADE guidelines. MAIN RESULTS: There were no RCTs; 8 high quality non-RCTs were included in the review. Meta-analysis showed reduction in mortality [N = 10109; OR = 0.47(0.39-0.56), p<0.00001; LOE: Moderate] and severe IVH and PVL [N = 5084; OR = 0.71(0.61-0.82), p<0.00001; LOE: Low] after exposure to ANC in neonates born <25 weeks. There was no significant difference in CLD [N = 4649; OR = 1.19(0.85-1.65) p = 0.31; LOE: Low] and NEC [N = 5403; OR = 0.95 (0.76-1.19) p = 0.65; LOE: Low]. Mortality was comparable in neonates born at 22, 23 or 24 weeks. CONCLUSION: Moderate to low quality evidence indicates that exposure to ANC is associated with reduction in mortality and IVH/or PVL in neonates born before 25 weeks.

Strategies for managing transient tachypnoea of the newborn - a systematic review.

OBJECTIVE: To conduct a systematic review of strategies for the management of transient tachypnoea of the newborn (TTN). METHODS: The Cochrane Collaboration and PRISMA guidelines were used for conducting and reporting this systematic review, respectively. The Cochrane Central Register of Controlled Trials, PubMed, CINAHL and EMBASE databases were searched in February 2016. Only randomised and quasi-randomised controlled trials (RCTs) assessing any intervention for the management of TTN in infants <7 days of age, born at 35 or more weeks with a clinical diagnosis of TTN were eligible for inclusion. Primary outcomes included the duration of respiratory support, oxygen support, tachypnoea and hospitalisation. RESULTS: Nine RCTs with moderate risk of bias were included. The interventions assessed included furosemide (2 trials, n = 100), inhaled salbutamol (2 trials, n = 94), inhaled epinephrine (1 trial, n = 20), restrictive fluids (2 trials, n = 146) and non-invasive ventilation (2 trials, n = 80). Amongst all interventions, inhaled salbutamol significantly reduced the duration of hospitalisation (2 trials, n = 94) [mean difference (MD) - 1.63 days (95% CI -2.71 to -0.55); p = 0.003] and duration of oxygen requirement (1 trial, n = 37) [MD - 43.10 h (95% CI -81.82 to -4.38; p = 0.03] without adverse effects. CONCLUSION: Limited low-quality evidence exists on the effects of different management strategies for TTN. The safety and efficacy of inhaled salbutamol in the treatment of TTN can be assessed in a large RCT.

Strategies for Medical Management of Pediatric Eosinophilic Esophagitis.

OBJECTIVE: Eosinophilic esophagitis (EoE) is associated with significant morbidity in children. Strategies for optimizing its outcomes are hence essential. We aimed to review the strategies for medical management of EoE in children. METHODS: We conducted a systematic review of randomized controlled trials (RCTs) of medical interventions in children with EoE, using the Cochrane methodology. Databases including PubMed, EMBASE, CINAHL, Cochrane Central Library, and Google scholar were searched up to March 2016. Primary outcomes included histological (peak eosinophil count) and symptomatic remission. Secondary outcomes were improvement in endoscopic and other histological parameters and adverse effects. RESULTS: A total of 5 RCTs (N = 448) with low to unclear risk of bias were included. The interventions included topical oral steroids, swallowed enteral steroids and anti- interleukin (IL)5 agent. Pooling of data from all trials was not possible owing to significant heterogeneity in interventions. Meta-analysis of data (N = 141) from 3 RCTs (oral viscous budesonide: 2, fluticasone: 1) showed significant histological remission in the intervention versus control group participants (risk difference: 10.32 [95% confidence interval: 3.04, 35.03]; P = 0.0002), level of evidence-low. Compared with anti-IL5 agent, the trials assessing steroids reported high rates of clinical remission. Clinical remission did not correlate with histological improvement in any trial. Except for systemic corticosteroids, there were no significant adverse effects related to other interventions. CONCLUSIONS: Limited low-quality evidence exists on the effects of various interventions in children with EoE. The beneficial effects of swallowed steroid need to be confirmed in large well-designed RCTs.

Meconium Evacuation for Facilitating Feed Tolerance in Preterm Neonates: A Systematic Review and Meta-Analysis.

BACKGROUND: A delayed passage of meconium is considered as a risk factor for feed intolerance in preterm neonates. OBJECTIVES: The aim of this study was to review the effects of different therapeutic agents for meconium evacuation on feed tolerance in preterm neonates. METHODS: A systematic review of randomised controlled trials (RCTs) of different therapeutic agents for meconium evacuation in preterm neonates (gestation <32 weeks and/or birth weight <1,500 g) using the Cochrane systematic review methodology was undertaken. Databases including Google Scholar were searched in January 2016. The primary outcome was the time to reach full feeds (TFF; ≥120 ml/kg feeds with stoppage of parenteral nutrition >24 h). Secondary outcomes included necrotising enterocolitis (NEC), weight at discharge and adverse effects. The results were summarised as per the GRADE guidelines. RESULTS: Six RCTs (2 each of glycerine suppository and enema, 1 normal saline enema and 1 oral osmotic contrast agent; n = 442) with a low or unclear risk of bias were included. The pooled estimate (random effects model) showed no reduction in TFF [mean difference (MD) -0.03, 95% CI -2.47, 2.41, p = 0.98; level of evidence: low]. No differences in NEC [risk ratio (RR) 1.71, 95% CI 0.63, 4.65, p = 0.30; level of evidence: low] and weight at discharge (MD -0.08, 95% CI -0.30, 0.15, p = 0.50; level of evidence: low) were found. The trial assessing oral osmotic contrast agents reported a trend towards a higher incidence of NEC ≥ stage II. There were no other adverse effects. CONCLUSION: Limited low-quality evidence indicates that prophylactic glycerine suppository, small volume glycerine/normal saline enema or oral osmotic contrast agents to evacuate meconium did not reduce TFF in preterm neonates. Large, well-designed trials are essential to study this clinically significant issue.

Effect of gastric lavage on feeding in neonates born through meconium-stained liquor: a systematic review.

OBJECTIVE: To evaluate the efficacy and safety of gastric lavage (GL) in neonates born through meconium-stained liquor (MSL). DESIGN: A systematic review of randomised controlled trials by searching databases MEDLINE (from 1966), EMBASE (from1980), CINAHL, Cochrane Central Register of Controlled Trials, Google Scholar and proceedings of Pediatric Academic Society meetings (2002-2014). SETTING: Delivery room/Neonatal ward. PATIENTS: Neonates with gestation >34 weeks and birth weight ≥1800 g born through MSL. INTERVENTIONS: Prophylactic GL versus no intervention before first feed. MAIN OUTCOME MEASURE: Feeding intolerance, defined as inability to initiate/upgrade feeds due to problems such as retching, vomiting, regurgitation and gastric residuals. RESULTS: A total of six studies (GL: 918, no GL: 966) were included in the review. Meta-analysis using fixed-effects model showed decreased incidence of feed intolerance following GL ((81/918 (8.8%) vs 114/966 (11.8%); risk ratio (RR): 0.71 (95% CI 0.55 to 0.93)). However, the results were not significant when random-effects model was used (RR: 0.78 (95% CI 0.55 to 1.09)). No significant adverse effects of GL were reported. CONCLUSIONS: Routine GL immediately after birth may improve feed tolerance in neonates born through MSL. However, the evidence is limited, with probable small-study bias and high risk of bias in a number of the included studies. Well-designed studies with adequate sample size are essential to confirm these findings.

Nebulized pentoxifylline for reducing the duration of oxygen supplementation in extremely preterm neonates.

OBJECTIVE: To evaluate the efficacy and safety of nebulized pentoxifylline for reducing the duration of oxygen supplementation in extremely preterm neonates at high risk of bronchopulmonary dysplasia (BPD). STUDY DESIGN: Single-center, randomized, double-blind, placebo-controlled trial was conducted. Infants of 23(0) to 27(6) weeks' gestational age requiring mechanical ventilation or ≥30% supplemental oxygen on continuous positive airway pressure at 72-168 hours were randomized to receive 20 mg/kg (1 mL/kg) nebulized pentoxifylline or an equal volume of normal saline placebo every 6 hours for 10 consecutive days via a vibrating mesh nebulizer. The primary outcome was the duration of oxygen supplementation at 40 weeks' postmenstrual age. We used Cox proportional hazards regression modeling to analyze outcomes. RESULTS: All infants had adequate data for analysis of the primary outcome. Intention-to-treat analysis revealed no differences in duration of oxygen supplementation at 40 weeks' postmenstrual age between pentoxifylline (n=41) and placebo (n=40) groups (median 2262 vs 2160 hours, adjusted hazard ratio: 1.14, 95% CI 0.72-1.80, P=.63). There was no difference in mortality and further secondary outcomes. No adverse effects were noted. CONCLUSIONS: Nebulized pentoxifylline is safe but did not reduce the duration of oxygen supplementation in extremely preterm infants at high risk of BPD. Dose-ranging studies and large, well-designed clinical trials are required to determine whether the use of nebulized or systemic pentoxifylline as a prophylactic therapy offers small but relevant benefits for prevention of BPD. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12611000145909.

Fish Oil (SMOFlipid) and olive oil lipid (Clinoleic) in very preterm neonates.

OBJECTIVES: Fat emulsions used in Australia for parenteral nutrition in preterm neonates have been based on either soybean oil or olive oil (OO). OO lipid Clinoleic has a high ratio of n-6 to n-3 fatty acids (9:1); this may not be ideal for long-chain polyunsaturated fatty acids supply. Newly available SMOFlipid has an appropriate ratio of n-6 to n-3 fatty acids (2.5:1). SMOFlipid also contains OO (25%), coconut oil (30%), and soybean oil (30%). The aims of the study were to evaluate the safety of the SMOFlipid and to test the hypothesis that SMOFlipid would lead to increased omega-3 long-chain polyunsaturated fatty acid levels and reduced oxidative stress as compared with Clinoleic in preterm neonates (<30 weeks). METHODS: Preterm neonates (23-30 weeks) were randomised to receive Clinoleic or SMOFlipid emulsion for 7 days. Investigators and outcome assessors were masked to allocation. Plasma F2-isoprostanes (lipid peroxidation marker), red blood cell fatty acids, and vitamin E were measured before and after the study. Blood culture positive sepsis and growth were monitored for safety. RESULTS: Thirty of 34 participants completed the study. Both emulsions were well tolerated without any adverse events. F2-isoprostane levels were reduced in the SMOFlipid group as compared with baseline. Eicosapentanoic acid and vitamin E levels were significantly increased in the SMOFlipid group. Oleic acid and linoleic acid levels were increased in both groups. No significant differences were noted in poststudy docosahexaenoic acid levels in both groups despite higher levels of docosahexaenoic acid in SMOFlipid. CONCLUSIONS: SMOFlipid was safe, well tolerated, and showed beneficial effect in terms of reduction of oxidative stress by reducing lipid peroxidation levels in high-risk preterm neonates.