Inhaled bronchodilators for the prevention and treatment of chronic lung disease in preterm infants.

BACKGROUND: Chronic lung disease (CLD) occurs frequently in preterm infants and is associated with respiratory morbidity. Bronchodilators have the potential effect of dilating small airways with muscle hypertrophy. Increased compliance and tidal volume, and decreased airway resistance, have been documented with the use of bronchodilators in infants with CLD. Therefore, bronchodilators are widely considered to have a role in the prevention and treatment of CLD, but there remains uncertainty as to whether they improve clinical outcomes. This is an update of the 2016 Cochrane review. OBJECTIVES: To determine the effect of inhaled bronchodilators given as prophylaxis or as treatment for chronic lung disease (CLD) on mortality and other complications of preterm birth in infants at risk for or identified as having CLD. SEARCH METHODS: An Information Specialist searched CENTRAL, MEDLINE, Embase, CINAHL and three trials registers from 2016 to May 2023. In addition, the review authors undertook reference checking, citation searching and contact with trial authors to identify additional studies. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials involving preterm infants less than 32 weeks old that compared bronchodilators to no intervention or placebo. CLD was defined as oxygen dependency at 28 days of life or at 36 weeks' postmenstrual age. Initiation of bronchodilator therapy for the prevention of CLD had to occur within two weeks of birth. Treatment of infants with CLD had to be initiated before discharge from the neonatal unit. The intervention had to include administration of a bronchodilator by nebulisation or metered dose inhaler. The comparator was no intervention or placebo. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Critical outcomes included: mortality within the trial period; CLD (defined as oxygen dependency at 28 days of life or at 36 weeks' postmenstrual age); adverse effects of bronchodilators, including hypokalaemia (low potassium levels in the blood), tachycardia, cardiac arrhythmia, tremor, hypertension and hyperglycaemia (high blood sugar); and pneumothorax. We used the GRADE approach to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included two randomised controlled trials in this review update. Only one trial provided useable outcome data. This trial was conducted in six neonatal intensive care units in France and Portugal, and involved 173 participants with a gestational age of less than 31 weeks. The infants in the intervention group received salbutamol for the prevention of CLD. The evidence suggests that salbutamol may result in little to no difference in mortality (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.50 to 2.31; risk difference (RD) 0.01, 95% CI -0.09 to 0.11; low-certainty evidence) or CLD at 28 days (RR 1.03, 95% CI 0.78 to 1.37; RD 0.02, 95% CI -0.13 to 0.17; low-certainty evidence), when compared to placebo. The evidence is very uncertain about the effect of salbutamol on pneumothorax. The one trial with usable data reported that there were no relevant differences between groups, without providing the number of events (very low-certainty evidence). Investigators in this study did not report if side effects occurred. We found no eligible trials that evaluated the use of bronchodilator therapy for the treatment of infants with CLD. We identified no ongoing studies. AUTHORS' CONCLUSIONS: Low-certainty evidence from one trial showed that inhaled bronchodilator prophylaxis may result in little or no difference in the incidence of mortality or CLD in preterm infants, when compared to placebo. The evidence is very uncertain about the effect of salbutamol on pneumothorax, and neither included study reported on the incidence of serious adverse effects. We identified no trials that studied the use of bronchodilator therapy for the treatment of CLD. Additional clinical trials are necessary to assess the role of bronchodilator agents in the prophylaxis or treatment of CLD. Researchers studying the effects of inhaled bronchodilators in preterm infants should include relevant clinical outcomes in addition to pulmonary mechanical outcomes.

Application of Video Laryngoscopy for Minimally Invasive Surfactant Therapy: A Retrospective Comparative Cohort Study.

Minimally invasive surfactant therapy (MIST) has emerged as a preferred method of surfactant delivery. Pioneers of this technique have described the use of direct laryngoscopy (DL) for MIST. With the increasing application of video laryngoscopy (VL) for neonatal airway management, it is speculated that MIST techniques can be adapted for use with VL. OBJECTIVE: To compare procedural success, operator ease of use, and complication of MIST using VL vs. MIST using DL. METHODS: This was a retrospective, observational cohort study conducted at a tertiary-level neonatal intensive care unit after obtaining ethical approval. We included neonates who received MIST between 1 October 2020 and 31 October 2022. Baseline demographic characteristics, along with procedural data, were collected. Primary outcome measures included the overall procedural success rate, the need for multiple attempts, and the total number of attempts. Secondary outcome measures included the occurrence of adverse events, the need for a second dose of surfactant, and the need for intubation within 7 days of the procedure. Means and SDs, independent t-tests, frequencies, and chi-square were used as appropriate. p-values < 0.05 were considered statistically significant. RESULTS: Of the 79 neonates included, 37 neonates received MIST via VL, while 42 received MIST via DL. The median gestational age was lower in the VL group at 29.0 weeks vs. 30.5 weeks (p = 0.011) in the DL group. The median birthweight in the VL group was 1260 g, IQR (1080, 1690), which was significantly lower than the DL group, which was 1575 g, IQR (1220, 2251), p = 0.028. Purpose-built catheter use was higher in the DL group. The overall procedural success was similar between groups. The need for multiple attempts was lower with VL in comparison to DL [4 (11%) vs. 13 (31%); p = 0.034)] at the univariate level but not significant at multivariate analysis (p = 0.131). Procedural complications, the need for a second dose of surfactant, the need for mechanical ventilation post-MIST, and operator ease of use were similar. User comments emphasized the value of VL in providing real-time visual information to confirm catheter placement and guide operators/trainees. CONCLUSION: Overall, in our cohort, despite VL being a more recently adapted technology used more in smaller, sicker, and more premature neonates, procedural success, complications, and operator ease of use for MIST using VL and DL were comparable. Our findings show the successful application of VL for MIST and suggest procedural advantages that might facilitate universal adoption.

CPAP Versus NIPPV Postextubation in Preterm Neonates: A Comparative-Effectiveness Study.

BACKGROUND AND OBJECTIVES: Nasal intermittent positive pressure ventilation (NIPPV) has been shown to be superior to nasal continuous positive airway pressure (CPAP) postextubation in preterm neonates. However, studies have not permitted high CPAP pressures or rescue with other modes. We hypothesized that if CPAP pressures >8 cmH2O and rescue with other modes were permitted, CPAP would be noninferior to NIPPV. METHODS: We conducted a pragmatic, comparative-effectiveness, noninferiority study utilizing network-based real-world data from 22 Canadian NICUs. Centers self-selected CPAP or NIPPV as their standard postextubation mode for preterm neonates <29 weeks' gestation. The primary outcome was failure of the initial mode ≤72 hours. Secondary outcomes included failure ≤7 days, and reintubation ≤72 hours and ≤7 days. Groups were compared using a noninferiority adjusted risk-difference (aRD) margin of 0.05, and margin of no difference. RESULTS: A total of 843 infants extubated to CPAP and 974 extubated to NIPPV were included. CPAP was not noninferior (and inferior) to NIPPV for failure of the initial mode ≤72 hours (33.0% vs 26.3%; aRD 0.07 [0.03 to 0.12], Pnoninferiority(NI) = .86), and ≤7 days (40.7% vs 35.8%; aRD 0.09 [0.05 to 0.13], PNI = 0.97). However, CPAP was noninferior (and equivalent) to NIPPV for reintubation ≤72 hours (13.2% vs 16.1%; aRD 0.01 [-0.05 to 0.02], PNI < .01), and noninferior (and superior) for reintubation ≤7 days (16.4% vs 22.8%; aRD -0.04 [-0.07 to -0.001], PNI < .01). CONCLUSIONS: CPAP was not noninferior to NIPPV for failure ≤72 hours postextubation; however, it was noninferior to NIPPV for reintubation ≤72 hours and ≤7 days. This suggests CPAP may be a reasonable initial postextubation mode if alternate rescue strategies are available.

Impact of Catheter Choice on Procedural Success of Minimally Invasive Surfactant Therapy.

OBJECTIVE: Surfactant delivery via a thin endotracheal catheter during spontaneous breathing; a technique called minimally invasive surfactant therapy (MIST) is an alternative to intubation and surfactant administration. Procedural details among different centers vary, with marked differences in the choice of catheter to instill surfactant. Studies report use of feeding catheters, multiaccess suction catheters, vascular catheters, and more recently custom-built catheters for this purpose. The impact of choice of catheter on procedural success and procedural adverse effects has not been reported. Our present study compares the procedural success and adverse effects of MIST using a semirigid vascular catheter (16G Angiocath-Hobart Method) versus a flexible multiaccess catheter (MAC). STUDY DESIGN: This was a retrospective review of prospectively collected data at a tertiary care neonatal intensive care unit in Southwestern Ontario. All neonates who received surfactant via MIST between May 1, 2016 and September 30, 2020 were included in the study. Relevant baseline characteristics and data on procedural details (premedication, type of catheter, etc.) were collected. The procedural success, number of attempts, and adverse effects between neonates who received MIST via MAC and 16G Angiocath was compared by using Chi-square test or Fisher's test as appropriate. A p-value of less that 0.05 was considered significant. RESULTS: A total of 139 neonates received surfactant via MIST method during the study period. Moreover, 93 neonates received the surfactant via MAC, while 46 received it via Angiocath. The baseline demographic characteristics in the two group were similar. A higher proportion of neonates in Angiocath group received Atropine (100 vs. 76%, p = 0.002) and Fentanyl (98 vs. 36%, p < 0.001) than the MAC group.The procedural success was 91% in the Angiocath group and 89% in the MAC group (p > 0.99). Multiple attempts were needed in 24% of neonates in the Angiocath group and 37% in the MAC group (p = 0.158). More episodes of desaturations were noted in the Angiocath group (89%) than the MAC group (69%; p = 0.012). Other rates of common adverse effects were similar between the two groups. On exploratory analysis fentanyl use held significant association with less success, more desaturation, apneic episodes, and need of positive pressure ventilation /intubation. CONCLUSION: The overall procedural success of MIST is similar in both catheter groups. The proportion of neonates requiring multiple attempts was lower with the Angiocath, though difference was not statistically significant. Desaturation episodes were seen more frequently in the Angiocath group, which was related to higher use of procedural sedation in this group. KEY POINTS: · MIST is emerging as a less invasive method of surfactant delivery that has proven clinical benefits.. · Considerable, procedural variation is reported, particularly regarding choice of catheter.. · Our present study compares the procedural success and adverse effects of MIST using a semirigid vascular catheter (16G Angiocath-Hobart method) versus a flexible MAC.. · High and comparable procedural success was seen in both groups..

A survey of minimally invasive surfactant therapy in Canada.

Introduction: Minimally invasive surfactant therapy (MIST) can be used to treat neonatal respiratory distress syndrome in neonatal intensive care units (NICUs). Clinical and institutional variances in MIST utilization persist globally with little published research regarding MIST utilization in Canada. Therefore, the objective of this study was to survey MIST utilization in NICUs in Canada. Methods: An online survey was emailed to the 33 participating centres of Canadian Neonatal NetworkTM (CNN) Evidence-based Practice for Improving Quality (EPIQ) Lung Health Group (LHG). Site demographics and surfactant therapy procedural details were categorically collected. Free text and multiple-choice questions were utilized to capture perceived barriers and individual preferences for MIST use. Results: Twenty-eight of 33 participating members of the CNN EPIQ-LHG completed the survey between April 2021 and October 2021 (85%); 17/28 (61%) respondents reported ongoing MIST utilization at their center. Most centers that used MIST techniques administered bovine lipid extract surfactant (68%), commonly using angiocatheters (47%) and purpose-built catheters (41%). MIST was widely used for patients at 26-33 weeks gestational age (88%). Nine centres had never used MIST (32%), and 3 indicated a plan to implement MIST within the next 2 years. Common barriers to MIST use included lack of consensus amongst clinicians (78%), lack of training (56%), and lack of experience with MIST (56%). Conclusion: While MIST is being increasingly used in Canadian NICUs, universal use is yet to be seen. Clinician inexperience and lack of consensus, formal training, and local guidelines contribute to underutilization of MIST. Training workshops, country-wide data collection, and uniform operating protocols are needed to standardize practice.

Survey of Mode of Delivery and Maternal and Perinatal Outcomes in Canada.

OBJECTIVE: To identify determinants of cesarean delivery (CD) and examine associations between mode of delivery (MOD) and maternal and perinatal outcomes. METHODS: We conducted a retrospective analysis of a Canadian multicentre birth cohort derived from provincial data collected in 2008/2009. Maternal and perinatal characteristics and outcomes were compared between vaginal and cesarean birth and between the following MOD subgroups: spontaneous vaginal delivery (VD), assisted VD, planned cesarean delivery (CD), and intrapartum CD. Multivariate regression identified determinants of CD and the effects of MOD and previous CD on maternal and perinatal outcomes. RESULTS: The cohort included 264 755 births (72.1% VD and 27.9% CD) from 91 participating institutions. Determinants of CD included maternal age, parity, previous CD, chronic hypertension, diabetes, urinary tract infection or pyelonephritis, gestational hypertension, vaginal bleeding, labour induction, pre-term gestational age, low birth weight, large for gestational age, malpresentation, and male sex. CD was associated with greater risk of maternal and perinatal morbidity and mortality. Subgroup analysis demonstrated higher risk of adverse pregnancy outcomes with assisted VD and intrapartum CD than spontaneous VD. Planned CD reduced the risk of obstetric wound hematoma and perinatal mortality but increased maternal and neonatal morbidity. Previous CD increased the risk of maternal and neonatal morbidity among multiparous women. CONCLUSIONS: The CD rate in Canada is consistent with global trends reflecting demographic and obstetric intervention factors. The risk of adverse pregnancy outcomes with CD warrants evaluation of interventions to safely prevent nonessential cesarean birth.

Enteral supplementation with probiotics in preterm infants: A retrospective cohort study and 6-year follow-up.

The objective of this retrospective cohort study was to assess the impact of an enteral probiotics supplementation protocol on the incidence of necrotizing enterocolitis (NEC) in infants born <33 weeks gestational age (GA) or birth weight (BW) <1,500 g. In addition, a 6-year follow-up is presented after instigation of probiotic use. In October 2014, our NICU introduced an enteral probiotics supplementation protocol for infants born <33 weeks GA or BW <1,500 g. Infants received 0.5 g of Bifidobacterium breve HA-129, Lacticaseibacillus rhamnosus HA-111, Bifidobacterium bifidum HA-132, Bifidobacterium longum subsp. infantis HA-116, and Bifidobacterium longum subsp. longum HA-135 (FloraBABYⓇ) daily until discharge or transfer from hospital. The incidence of NEC was compared among infants for 2 years pre- and post implementation of the protocol then 6-years following continuous implementation of the probiotic use. In total, 370 infants not treated with probiotics between 2012 and 2014 were included with an incidence of NEC at 4.9%. In comparison, the 367 infants who received had a 67% reduction (4.9-1.6%, p = 0.01) in our Neonatal Intensive Care Unit (NICU). The results remained significant (aOR = 0.26; 95% CI: 0.09, 0.72; p < 0.01) after adjusting for GA, small for gestational age, and antenatal corticosteroid use. Data from the Canadian Neonatal Network not only showed a consistently high rate of NEC in October 2014, but also identified exceedingly high rates (8.7-15.6%) in some hospitals up to 2021, while our rates have been consistently low with using the probiotic as standard therapy for low BW premature babies, with no serious side effects reported. In conclusion, the introduction of a five-strain probiotic natural health product has coincided with a reduced incidence and complications of NEC in our NICU setting.

Airway injury and pneumomediastinum associated with less invasive surfactant administration in a premature neonate: a case report.

BACKGROUND: The use of less invasive surfactant administration (LISA)/minimally invasive surfactant therapy (MIST) has increased due to its potential advantage over traditional surfactant delivery methods through an endotracheal tube. Known complications for this procedure include failure of the first attempt at insertion, desaturation, and bradycardia. To the best of our knowledge, this is the first reported case of pneumomediastinum and subcutaneous emphysema following LISA. CASE PRESENTATION: A preterm newborn born at 27 weeks of gestation presented with respiratory distress syndrome requiring surfactant replacement. LISA using the Hobart method was completed. There was a report of procedural difficulty related to increased resistance to insertion of the 16G angiocath. The newborn was subsequently noted to have subcutaneous emphysema over the anterior aspect of the neck and substantial pneumomediastinum on radiological assessment. Associated complications included hypotension requiring inotropic support. The newborn was successfully managed conservatively, with complete resolution of the air leak. CONCLUSIONS: Upper airway injury leading to air leak syndrome is a rare complication of the Hobart method for LISA. Awareness of such procedural complications is important as the use of the LISA method increases.

Actuarial Survival Based on Gestational Age in Days at Birth for Infants Born at <26 Weeks of Gestation.

OBJECTIVE: To provide comprehensive, contemporary information on the actuarial survival of infants born at 22-25 weeks of gestation in Canada. STUDY DESIGN: In a retrospective cohort study, we included data from preterm infants of 22-25 weeks of gestation admitted to neonatal intensive care units participating in the Canadian Neonatal Network between 2010 and 2017. Infants with major congenital anomalies were excluded. We calculated gestational age using in vitro fertilization date, antenatal ultrasound dating, last menstrual period, obstetrical estimate, or neonatal estimate (in that order). Infants were followed until either discharge or death. Each day of gestational age was considered a category except for births at 22 weeks, where the first 4 days were grouped into one category and the last 3 days were grouped into another category. For each day of life, an actuarial survival rate was obtained by calculating how many infants survived to discharge out of those who had survived up to that day. RESULTS: Of 4335 included infants, 85, 679, 1504, and 2067 were born at 22, 23, 24, and 25 weeks of gestation, respectively. Survival increased from 32% at 22 weeks to 83% at 254-6/7 weeks. Graphs of actuarial survival developed for the first 6 weeks after birth in male and female children indicated a steep increase in survival during the first 7-10 days postnatally. CONCLUSIONS: Survival increased steadily with postnatal survival and was dependent on gestational age in days and sex of the child.

Epidemiology of thrombosis in Canadian neonatal intensive care units.

OBJECTIVE: To assess the rate, location, risk factors, management, and outcomes of neonatal thrombosis (NT). DESIGN: A retrospective study investigating infants admitted to NICUs in Canadian Neonatal Network between January 2014 and December 2016 and diagnosed with NT. Each infant with NT was matched with an infant without NT. RESULTS: Of 39,971 infants, 587 (1.5%) were diagnosed with NT: 440 (75%) venous, 112 (19%) arterial, 29 (5%) both. NT rate was 1.4% in full-term and 1.7% in preterm infants. Venous thrombi occurred most commonly in the portal vein and arterial thrombi in the cerebral artery. Conservative management and low molecular weight heparin were the most common treatment modalities. Hospital stay was longer (p < 0.001) in the NT patients, but mortality was similar. CONCLUSIONS: NT was diagnosed in ~15/1000 NICU admissions and most commonly in the portal vein and cerebral arteries. Management varied based on the type and location of thrombi. Large multicenter trials are needed to address the best management strategies.

High-volume surfactant administration using a minimally invasive technique: Experience from a Canadian Neonatal Intensive Care Unit.

BACKGROUND: Surfactant delivery via a thin endotracheal catheter during spontaneous breathing, a technique called minimally invasive surfactant therapy (MIST), is an alternative to intubation and surfactant administration. There is paucity of data regarding the administration of high-volume surfactant using this technique. METHODS: We conducted a retrospective cohort study to review the safety, efficacy, and procedural details pertaining to the delivery of 5 mL/kg of BLES® via MIST approach. In 2016, our centre initiated a practice change allowing the use of MIST as an alternative method of surfactant delivery in infants born at ≥28 weeks and/or with a birth weight ≥ 1,000 g with respiratory distress syndrome. In this study, we identified all neonates who received surfactant via MIST between May 1, 2016 and July 30, 2018 and collected relevant procedural data. RESULTS: Since this practice change, MIST technique was attempted in 43 neonates with successful instillation of surfactant in 41 (95.3%) of the neonates. Intubation and positive pressure ventilation was avoided in 35 neonates (85.3%). No serious adverse effect was noted. CONCLUSIONS: Our study reports successful use of higher volume surfactant via MIST. This should encourage other similar centres to consider this technique, in order to avoid unnecessary intubation and positive pressure ventilation.

Pregnancy gestation at delivery and breast milk production: a secondary analysis from the EMPOWER trial.

BACKGROUND: Preterm birth alters the normal sequence of lactogenesis. Lactogenesis I may not yet have started when mothers of very preterm infants (≤ 29 weeks gestation) have given birth. Preterm infants are too small or too ill to initiate suckling in the immediate postpartum period thus altering the normal cascade of event for lactogenesis II. With an increasing demand for mother's own milk as a primary source of nutritional support in the care of very small and preterm infants, mothers of these infants are often at risk of expressing inadequate amounts of milk. The use of galactogogues is often considered when mothers of preterm infants are still having challenges in breast milk production. What is not clear in the literature is the role that pregnancy gestation at birth plays in successful response to galactogogues. Our objective for this study was to evaluate the role of pregnancy gestation at birth on a mother's response to the treatment interventions in the EMPOWER trial. METHODS: For this analysis, the study participants are the 90 mothers who participated in the EMPOWER trial and were in the stratified in two gestational age groups, 230/7-266/7 weeks and 270/7-296/7 weeks at the time of randomization. The primary outcome measures were the proportion of mothers in each of the gestational age groupings who achieved a 50% increase in breast milk volume on day 14 and day 28 of the study treatment period. RESULTS: On day 14 of the study treatment, there was no significant difference in the proportion of mothers in the 23-26 weeks gestation group (72.9%) compared to those in the 27-29 weeks gestation group (64.2%), OR 1.51 (95% CI 0.60, 3.78; p = 0.38). Similarly, there was no difference in the proportion of mothers between the two gestational age groupings on day 28 of the study treatment, 70.3% compared to 62.3%, OR 1.43 (95% CI 0.58, 3.51; p = 0.43). CONCLUSION: This secondary analysis was able to demonstrate that mothers of very preterm infants, < 30 weeks gestation at birth, were able to respond to the study treatment in a similar fashion regardless of gestation at birth. If non-pharmacologic approaches are unsuccessful, then a 14-day treatment of domperidone may be considered to enhance breast milk production, even in the lowest gestational ages at delivery. TRIAL REGISTRATION: EMPOWER has been registered at www.clinicaltrials.gov (identifier NCT 01512225) on January 10, 2012.

Effectiveness of Family Integrated Care in neonatal intensive care units on infant and parent outcomes: a multicentre, multinational, cluster-randomised controlled trial.

BACKGROUND: Despite evidence suggesting that parent involvement was beneficial for infant and parent outcomes, the Family Integrated Care (FICare) programme was one of the first pragmatic approaches to enable parents to become primary caregivers in the neonatal intensive care unit (NICU). We aimed to analyse the effect of FICare on infant and parent outcomes, safety, and resource use. METHODS: In this multicentre, cluster-randomised controlled trial, we stratified 26 tertiary NICUs from Canada, Australia, and New Zealand by country and size, and assigned them, using a computer-generated random allocation sequence, to provide FICare or standard NICU care. Eligible infants were born at 33 weeks' gestation or earlier, and had no or low-level respiratory support; parents gave written informed consent for enrolment. To be eligible, parents in the FICare group had to commit to be present for at least 6 h a day, attend educational sessions, and actively care for their infant. The primary outcome, analysed at the individual level, was infant weight gain at day 21 after enrolment. Secondary outcomes were weight gain velocity, high frequency breastfeeding (≥6 times a day) at hospital discharge, parental stress and anxiety at enrolment and day 21, NICU mortality and major neonatal morbidities, safety, and resource use (including duration of oxygen therapy and hospital stay). This trial is registered with ClinicalTrials.gov, number NCT01852695. FINDINGS: From Oct 1, 2012, 26 sites were randomly assigned to provide FICare (n=14) or standard care (n=12). One site assigned to FICare discontinued because of poor site enrolment. Parents and infants were enrolled between April 1, 2013, and Aug 31, 2015, with 895 infants being eligible in the FICare group and 891 in the standard care group. At day 21, weight gain was greater in the FICare group than in the standard care group (mean change in Z scores -0·071 [SD 0·42] vs -0·155 [0·42]; p<0·0002). Average daily weight gain was significantly higher in infants receiving FICare than those receiving standard care (mean daily weight gain 26·7 g [SD 9·4] vs 24·8 g [9·5]; p<0·0001). The high-frequency exclusive breastmilk feeding rate at discharge was higher for infants in the FICare group (279 [70%] of 396) than those in the standard care group (394 [63%] of 624; p=0·016). At day 21, parents in the FICare group had lower mean stress scores than did parents in the standard care group (2·3 [SD 0·8] vs 2·5 [0·8]; p<0·00043), and lower mean anxiety scores (70·8 [20·1] vs 74·2 [19·9]; p=0·0045). There were no significant differences between groups in the rates of the secondary outcomes of mortality, major morbidity, duration of oxygen therapy, and duration of hospital stay. Although the safety assessment was not completed, there were no adverse events. INTERPRETATION: FICare improved infant weight gain, decreased parent stress and anxiety, and increased high-frequency exclusive breastmilk feeding at discharge, which together suggest that FICare is an important advancement in neonatal care. Further research is required to examine if these results translate into better long-term outcomes for families. FUNDING: Canadian Institutes of Health Research Partnerships for Health System Improvement, and Ontario Ministry of Health and Long-Term Care.

Neonatal outcomes of extremely preterm infants exposed to maternal hypertension and cigarette smoking.

OBJECTIVE: To study the outcomes of extremely preterm infants of hypertensive mothers who smoke. STUDY DESIGN: This retrospective cohort study included infants born between 2003 and 2012 at <29 weeks' gestation and admitted to neonatal intensive care units participating in the Canadian Neonatal Network. Infants were divided into four mutually exclusive groups. Infants of hypertensive mothers who smoked; infants of hypertensive, non-smoking mothers; infants of normotensive mothers who smoked; and infants of normotensive, non-smoking mothers. Using infants of normotensive, non-smoking mothers as the reference group, neonatal outcomes were compared between the groups. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated using univariate and multivariate regression analysis. RESULTS: Of the 12,307 eligible infants, 172 had hypertensive mothers who smoked, 1689 had hypertensive non-smoking mothers, 1535 had normotensive mothers who smoked, and 8911 had normotensive non-smoking mothers. Compared to infants of normotensive non-smoking mothers, infants of hypertensive mothers, regardless of smoking status, had higher odds of developing bronchopulmonary dysplasia (AORs of smokers 1.62; 95% CI 1.12-2.35 and of non-smokers 1.43; 95% CI 1.24-1.64). There was no difference in the odds of mortality and retinopathy of prematurity stage ≥3 between the groups. Infants of hypertensive, non-smoking mothers had decreased odds of intraventricular hemorrhage >grade 2 and higher odds of necrotizing enterocolitis. There was decreased odds of hypertension if the mother was a smoker (AOR 0.71; 95% CI 0.59-0.85). CONCLUSION: Maternal hypertension is associated with increased rates of bronchopulmonary dysplasia, irrespective of smoking status.

Effects of bovine lipid extract surfactant administration in preterm infants treated for respiratory distress syndrome.

AIM: To review the initial effectiveness of bovine lipid extract surfactant (BLES) for the treatment of respiratory distress syndrome in preterm infants. METHODS AND RESULTS: A retrospective review of data collected from infants born <37-week gestation with respiratory distress syndrome treated with BLES between February 1, 2015 and March 1, 2016. Data were analyzed to determine the timing of initial dose, the length of time to wean the fraction of inspired oxygen (FiO2) concentration to 0.21 following initial dose, and the number of repeated doses given during hospital admission. Infants were subgrouped by gestational age stratum, 230 to 276 weeks (group 1), 280 to 316 weeks (group 2), and 320 to 366 weeks (group 3). Ninety-eight infants received the surfactant during the study period. After applying exclusion criteria, 77 infants were analyzed. Mean (SD) gestational age was 28 (4) weeks, and mean (SD) birth weight was 1250 (602) g. Initial dose of BLES was given at a median (interquartile range) time of 29 (19-43) minutes in group 1, 150 (20-615) minutes in group 2, and 990 (53-2025) minutes in group 3. Median (interquartile range) length of time to wean the FiO2 concentration to 0.21 was 14 (5-56) minutes, 10 (5-53) minutes, and 10 (5-38) minutes in groups 1, 2, and 3, respectively. Ten infants required repeated doses. CONCLUSION: Given the rapid response of BLES in all the groups, careful monitoring of ventilator parameters is paramount to allow for rapid weaning and early extubation to avoid lung injury associated with mechanical ventilation.

Enhancing Human Milk Production With Domperidone in Mothers of Preterm Infants.

BACKGROUND: Mothers of preterm infants often are at risk of expressing an inadequate amount of milk for their infants and the use of galactogogues is often considered. Domperidone is a widely used galactogogue with little information available to guide clinicians regarding initiation, timing, and duration of treatment. Research aim: The primary objective of this study was to determine whether administration of domperidone within the first 21 days after delivery would lead to a higher proportion of mothers achieving a 50% increase in the volume of milk at the end of 14 days of treatment compared with mothers receiving placebo. METHODS: Eligible mothers were randomized to one of two treatment arms: Group A-domperidone 10 mg orally three times daily for 28 days; or Group B-placebo 10 mg orally three times daily for 14 days followed by domperidone 10 mg orally three times daily for 14 days. RESULTS: A total of 90 mothers of infants ≤ 29 weeks gestation were randomized. Mean milk volumes at entry were similar for both groups. More mothers achieved a 50% increase in milk volume after 14 days in Group A (77.8%) compared with Group B (57.8%), odds ratio = 2.56, 95% confidence interval [1.02, 6.25], p = .04. CONCLUSION: A greater number of mothers experienced a 50% or more increase in human milk volume, but the absolute increase in milk volume was modest.

Bronchodilators for the prevention and treatment of chronic lung disease in preterm infants.

BACKGROUND: Chronic lung disease (CLD) occurs frequently in preterm infants. Bronchodilators have the potential effect of dilating small airways with muscle hypertrophy. Increased compliance and tidal volume and decreased pulmonary resistance have been documented with the use of bronchodilators in infants with CLD. Therefore, bronchodilators might have a role in the prevention and treatment of CLD. OBJECTIVES: To determine the effect of bronchodilators given as prophylaxis or as treatment for CLD on mortality and other complications of preterm birth in infants at risk for or identified as having CLD. SEARCH METHODS: On 2016 March 7, we used the standard strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2), MEDLINE (from 1966), Embase (from 1980) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; from 1982). We searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. We applied no language restrictions. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials involving preterm infants were eligible for inclusion. Initiation of bronchodilator therapy for prevention of CLD had to occur within two weeks of birth. Treatment of patients with CLD had to be initiated before discharge from the neonatal unit. The intervention had to include administration of a bronchodilator by nebulisation, by metered dose inhaler (with or without a spacer device) or by intravenous or oral administration versus placebo or no intervention. Eligible studies had to include at least one of the following predefined clinical outcomes: mortality, CLD, number of days on oxygen, number of days on ventilator, patent ductus arteriosus (PDA), pulmonary interstitial emphysema (PIE), pneumothorax, intraventricular haemorrhage (IVH) of any grade, necrotising enterocolitis (NEC), sepsis and adverse effects of bronchodilators. DATA COLLECTION AND ANALYSIS: We used the standard method described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Two review authors extracted and assessed all data provided by each study. We reported risk ratio (RR), risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB) with 95% confidence interval (CI) for dichotomous outcomes and mean difference (MD) for continuous data. We assessed the quality of the evidence by using the GRADE approach. MAIN RESULTS: For this update, we identified one new randomised controlled trial investigating effects of bronchodilators in preterm infants. This study, which enrolled 73 infants but reported on 52 infants, examined prevention of CLD with the use of aminophylline. According to GRADE, the quality of the evidence was very low. One previously included study enrolled 173 infants to look at prevention of CLD with the use of salbutamol. According to GRADE, the quality of the evidence was moderate. We found no eligible trial that studied the use of bronchodilator therapy for treatment of individuals with CLD. Prophylaxis with salbutamol led to no statistically significant differences in mortality (RR 1.08, 95% CI 0.50 to 2.31; RD 0.01, 95% CI -0.09 to 0.11) nor in CLD (RR 1.03, 95% CI 0.78 to 1.37; RD 0.02, 95% CI -0.13 to 0.17). Results showed no statistically significant differences in other complications associated with CLD nor in preterm birth. Investigators in this study did not comment on side effects due to salbutamol. Prophylaxis with aminophylline led to a significant reduction in CLD at 28 days of life (RR 0.18, 95% CI 0.04 to 0.74; RD -0.35, 95% CI -0.56 to -0.13; NNTB 3, 95% CI 2 to 8) and no significant difference in mortality (RR 3.0, 95% CI 0.33 to 26.99; RD 0.08, 95% CI -0.07 to 0.22), along with a significantly shorter dependency on supplementary oxygen in the aminophylline group compared with the no treatment group (MD -17.75 days, 95% CI -27.56 to -7.94). Tests for heterogeneity were not applicable for any of the analyses, as each meta-analysis included only one study. AUTHORS' CONCLUSIONS: Data are insufficient for reliable assessment of the use of salbutamol for prevention of CLD. One trial of poor quality reported a reduction in the incidence of CLD and shorter duration of supplementary oxygen with prophylactic aminophylline, but these results must be interpreted with caution. Additional clinical trials are necessary to assess the role of bronchodilator agents in prophylaxis or treatment of CLD. Researchers studying the effects of bronchodilators in preterm infants should include relevant clinical outcomes in addition to pulmonary mechanical outcomes. We identified no trials that studied the use of bronchodilator therapy for treatment of CLD.

Online Calculator to Improve Counseling of Short-Term Neonatal Morbidity and Mortality Outcomes at Extremely Low Gestational Age (23-28 Weeks).

Objective Extremely low gestational age (ELGA) infants are at high risk of perinatal and neonatal morbidity and mortality. Accurate and relevant data are essential for developing a health care plan and providing realistic estimates of infants' outcomes. Study Design Retrospective analysis of all infants delivered between 23(0/7) and 28(6/7) weeks' gestation over 11 years at a single center. Using logistic regression analysis, gestational age (GA)-specific mortality and morbidity rates, and the effects of gender, antenatal corticosteroids, multiple gestation, and birth weight (BW) were determined. Results Of the 766 study infants, 644 (84.1%) were admitted to the neonatal intensive care unit, of which 502 (75.8%) survived to discharge. GA, antenatal corticosteroids, and BW were significant predictors of survival (GA: odds ratio [OR] = 1.83, 95% confidence interval [CI] = 1.64-2.04; corticosteroids: OR = 7.62, 95% CI = 5.19-11.18; BW: OR = 1.56, 95% CI = 1.44-1.69). Increasing BW correlated with a decreasing mortality rate. Conclusion This study provides recent outcome data of ELGA infants delivered at a tertiary level center. The results have been translated into an online counseling tool (http://murmuring-brook-6600.herokuapp.com/ELGA.html).

Evaluation of the Family Integrated Care model of neonatal intensive care: a cluster randomized controlled trial in Canada and Australia.

BACKGROUND: Admission to the neonatal intensive care unit (NICU) may disrupt parent-infant interaction with adverse consequences for infants and their families. Several family-centered care programs promote parent-infant interaction in the NICU; however, all of these retain the premise that health-care professionals should provide most of the infant's care. Parents play a mainly supportive role in the NICU and continue to feel anxious and unprepared to care for their infant after discharge. In the Family Integrated Care (FICare) model, parents provide all except the most advanced medical care for their infants with support from the medical team. Our hypothesis is that infants whose families complete the FICare program will have greater weight gain and better clinical and parental outcomes compared with infants provided with standard NICU care. METHODS/DESIGN: FICare is being evaluated in a cluster randomized controlled trial among infants born at ≤ 33 weeks' gestation admitted to 19 Canadian, 6 Australian, and 1 New Zealand tertiary-level NICU. Trial enrollment began in April, 2013, with a target sample size of 675 infants in each arm, to be completed by August, 2015. Participating sites were stratified by country, and by NICU size within Canada, for randomization to either the FICare intervention or control arm. In intervention sites, parents are taught how to provide most of their infant's care and supported by nursing staff, veteran parents, a program coordinator, and education sessions. In control sites standard NICU care is provided. The primary outcome is infants' weight gain at 21 days after enrollment, which will be compared between the FICare and control groups using Student's t-test adjusted for site-level clustering, and multi-level hierarchical models accounting for both clustering and potential confounders. Similar analyses will examine secondary outcomes including breastfeeding, clinical outcomes, safety, parental stress and anxiety, and resource use. The trial was designed, is being conducted, and will be reported according to the CONSORT 2010 guidelines for cluster randomized controlled trials. DISCUSSION: By evaluating the impact of integrating parents into the care of their infant in the NICU, this trial may transform the delivery of neonatal care. TRIAL REGISTRATION: NCT01852695 , registered December 19, 2012.

Adverse Impact of Maternal Cigarette Smoking on Preterm Infants: A Population-Based Cohort Study.

OBJECTIVE: The aim of the study is to examine the impact of exposure to maternal cigarette smoking on neonatal outcomes of very preterm infants. STUDY DESIGN: A retrospective cohort study examined preterm infants (<33 weeks gestational age) admitted to the Canadian Neonatal Network centers between 2003 and 2011. Mortality and major morbidities (bronchopulmonary dysplasia, severe intraventricular hemorrhage, necrotizing enterocolitis, and retinopathy) were compared between infants exposed and unexposed to maternal smoking during pregnancy after adjusting for confounders. RESULTS: Among 29,051 study infants, 4,053 (14%) were exposed to maternal smoking during pregnancy. Multivariable analysis revealed higher odds of grade 3 or 4 intraventricular hemorrhage or periventricular leukomalacia (adjusted odds ratio [OR]: 1.21, 95% confidence interval [CI]: 1.04-1.41) and bronchopulmonary dysplasia (adjusted OR: 1.16, 95% CI: 1.02-1.33) in the smoking group, while mortality, severe retinopathy, and necrotizing enterocolitis were not significantly different. CONCLUSION: Maternal smoking during pregnancy is associated with severe neurological injury and bronchopulmonary dysplasia in preterm infants.