A multicentre neonatal interventional randomised controlled trial of nebulized surfactant for preterm infants with respiratory distress: Neo-INSPIRe trial protocol.

INTRODUCTION: Respiratory distress syndrome in preterm infants is an important cause of morbidity and mortality. Less invasive methods of surfactant administration, along with the use of continuous positive airway pressure (CPAP), have improved outcomes of preterm infants. Aerosolized surfactant can be given without the need for airway instrumentation and may be employed in areas where these skills are scarce. Recent trials from high-resourced countries utilising aerosolized surfactant have had a low quality of evidence and varying outcomes. METHODS AND ANALYSIS: The Neo-INSPIRe trial is an unblinded, multicentre, randomised trial of a novel aerosolized surfactant drug/device combination. Inclusion criteria include preterm infants of 27-34+6 weeks' gestational age who weigh 900-1999g and who require CPAP with a fraction of inspired oxygen (FiO2) of 0.25-0.35 in the first 2-24 h of age. Infants are randomised 1:1 to control (CPAP alone) or intervention (CPAP with aerosolized surfactant). The primary outcome is the need for intratracheal bolus surfactant instillation within 72 h of age. Secondary outcomes include the incidence of reaching failure criteria (persistent FiO2 of > 0.40, severe apnoea or severe work of breathing), the need for and duration of ventilation and respiratory support, bronchopulmonary dysplasia and selected co-morbidities of prematurity. Assuming a 40% relative risk reduction to reduce the proportion of infants requiring intratracheal bolus surfactant from 45 to 27%, the study will aim to enrol 232 infants for the study to have a power of 80% to detect a significant difference with a type 1 error of 0.05. ETHICS AND DISSEMINATION: Ethical approval has been granted by the relevant human research ethics committees at University of Cape Town (HREC 681/2022), University of the Witwatersrand HREC (221112) and Stellenbosch University (M23/02/004). TRIAL REGISTRATION: PACTR202307490670785.

Cryptosporidium infection and associated risk factors among children from rural areas in Peru: a nested case-control study.

This study aimed to detect the frequency of Cryptosporidium infection and associated risk factors among children from rural areas in Peru. A case-control study was conducted, nested in a cohort in two rural communities that included children between 6 and 13 months who were followed for 6 months. Cases were children whose fecal samples tested positive for Cryptosporidium infection using an immunochromatography test. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to analyze risk factors associated with Cryptosporidium infection. Among 72 children, 13 (18%) were cases. Cryptosporidium infection was associated with below secondary education of the mother (OR 7.62, 95% CI 1.50-36.72) and with having more siblings living at home (OR 1.71, 95% CI 1.04-2.82). An important frequency of Cryptosporidium infection among children from rural areas in Peru was reported, more research is needed to understand its true burden and risk factors among children in Peru.

Baby's first bath: Changes in skin barrier function after bathing full-term newborns with water vs liquid baby cleanser.

BACKGROUND: The impact of the newborn's first bath, whether given with water alone or water with skin cleansing products, on skin barrier function is unknown. METHODS: We evaluated skin barrier function, measured by skin surface pH (primary outcome), transepidermal water loss (TEWL), and hydration of the stratum corneum (SCH) in 100 newborns before and after their first bath, randomizing this cohort to bathing with water alone or with water and a liquid baby cleanser. Two consecutive measurements of each parameter were obtained at two anatomic locations, the volar forearm, and below the sternum. Randomization was by mode of delivery, with 50 vaginal and 50 cesarean section (C/S) delivered newborns. RESULTS: Skin pH decreased significantly following the first bath at both anatomic sites regardless of whether the bath was performed with water or with cleanser, and there was no significant effect on the change in pH in these two groups. Baseline TEWL and SCH measurements were significantly lower in the sternum area compared to the volar forearm. TEWL decreased significantly after the first bath except when the bath was given with water alone on the sternum site. SCH also decreased significantly after the first bath except in the forearm when the bath was given with water alone. CONCLUSIONS: We conclude that skin surface pH, TEWL, and SCH all decrease significantly following the first bath, an indication of the development of skin barrier function in the newly born infant. In addition, bathing with water alone or water and a liquid baby cleanser does not impact the developing skin barrier.

Utility of MRI for cervical spine clearance in blunt trauma patients after a negative CT.

PURPOSE: To determine the utility of cervical spine MRI in blunt trauma evaluation for instability after a negative non-contrast cervical spine CT. METHODS: A review of medical records identified all adult patients with blunt trauma who underwent CT cervical spine followed by MRI within 48 h over a 33-month period. Utility of subsequent MRI was assessed in terms of findings and impact on outcome. RESULTS: A total of 1,271 patients with blunt cervical spine trauma underwent both cervical spine CT and MRI within 48 h; 1,080 patients were included in the study analysis. Sixty-six percent of patients with a CT cervical spine study had a negative study. Of these, the subsequent cervical spine MRI had positive findings in 20.9%; 92.6% had stable ligamentous or osseous injuries, 6.0% had unstable injuries and 1.3% had potentially unstable injuries. For unstable injury, the NPV for CT was 98.5%. In all 712 patients undergoing both CT and MRI, only 1.5% had unstable injuries, and only 0.42% had significant change in management. CONCLUSIONS: MRI for blunt trauma evaluation remains not infrequent at our institution. MRI may have utility only in certain patients with persistent abnormal neurological examination. KEY POINTS: • MRI has limited utility after negative cervical CT in blunt trauma. • MRI is frequently positive for non-specific soft-tissue injury. • Unstable injury missed on CT is infrequent.

Progressive T1 Shortening of the Dentate Nucleus in Patients With Multiple Sclerosis: Result of Multiple Administrations of Linear Gadolinium Contrast Agents Versus Intrinsic Disease.

OBJECTIVE: The purpose of this article is to study the effect of the administration of multiple IV doses of gadolinium-based contrast agent on the intrinsic T1 hyperintensity in the dentate nucleus and globus pallidus in patients with multiple sclerosis (MS). MATERIALS AND METHODS: A retrospective review of imaging in patients with relapsing-remitting MS was performed. Images of 20 patients who received four or more doses of gadolinium-based contrast agent were reviewed. Patients received the linear agent gadopentetate dimeglumine before 2011 and the macrocyclic agent gadobutrol from 2011 onward. Dentate nucleus-to-pons and globus pallidus-to-thalamus signal intensity (SI) ratios were evaluated. SI ratios were compared over time with multiple injections of gadolinium. Similar SI ratios were evaluated for six patients who received gadopentetate dimeglumine and then underwent multiple subsequent MRI studies without contrast agent administration. RESULTS: The increase in the dentate nucleus-to-pons SI ratio after multiple administrations of the linear agent gadopentetate dimeglumine (mean = 1.44; SD = 2.50) was significantly higher than that with the macrocyclic agent gadobutrol (mean = -0.11; SD = 2.33) (p < 0.001). The globus pallidus-to-thalamus and dentate nucleus-to-CSF ratios also increased with multiple contrast injections over time, but the changes were not found to be statistically significant. The increase in SI in the dentate nucleus was not observed in patients who stopped receiving contrast injections, after showing a previous increase over time with gadolinium. CONCLUSION: In patients with MS, SI within the dentate nucleus and globus pallidus increased on unenhanced T1-weighted images and was significantly greater with the administration of a linear agent than with a macrocyclic agent. This increase in SI over time is likely a reflection of gadolinium deposition and not due to intrinsic disease, as previously postulated.

The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age.

OBJECTIVE: To determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control). STUDY DESIGN: Caregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys). RESULTS: Infants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM. CONCLUSION: Treatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

Pathogenicity Island O-122 in enteropathogenic Escherichia coli strains is associated with diarrhea severity in children from Lima Peru.

EPEC is an attaching and effacing diarrheal pathogen that carries a large pathogenicity island, locus for enterocyte effacement (LEE). Recently, the pathogenicity island PAI O-122 was described among non-LEE effectors and found to be associated with diarrhea among atypical EPEC strains. It is unknown if incomplete PAI O-122 could be associated with diarrhea duration and severity. To identify these virulence determinants we analyzed 379 EPEC strains isolated from Peruvian children. EPEC was diagnosed by PCR(eae+, stx-) and classified as typical(t-EPEC) or atypical(a-EPEC). To characterize PAI O-122 we amplified three modules by PCR: Module 1(pagC), Module 2(senA, nleB and nleE) and Module 3(lifA/efa-1). To characterize the large ORF lifA/efa-1 we amplified the regions known as efa-N, efa-M and efa-C. Clinical information was obtained from the cohort study. A total of 379 EPEC strains were able to analyze PAI O-122 genes, 128 (10.4%) EPEC strains were isolated from 1235 diarrhea episodes and 251(9.2%) from 2734 healthy controls. t-EPEC strains were isolated from 14.8% (19/128) of children with diarrhea and 25/251(10.0%) from healthy controls. The most frequent PAI O-122 genes were nleE(37.7%), senA(34.6%) and nleB(37.5%), with similar prevalence among diarrhea and control samples. However, lifA/efa-1 was more common among diarrhea cases than healthy control cases (30.5% vs. 21.1%, p<0.05). The presence of complete PAI O-122 was associated with diarrhea episodes of higher severity among single pathogen infection (33.3% vs. 1.8%, p<0.05) mainly due to the presence of a complete lifA/efa-1 gene. In summary, the gene lifA/efa-1 is significantly associated with diarrheal episodes of higher severity, suggesting to be an important virulent factor.

Randomized Trial of Late Surfactant Treatment in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide.

OBJECTIVE: To assess whether late surfactant treatment in extremely low gestational age (GA) newborn infants requiring ventilation at 7-14 days, who often have surfactant deficiency and dysfunction, safely improves survival without bronchopulmonary dysplasia (BPD). STUDY DESIGN: Extremely low GA newborn infants (GA ≤28 0/7 weeks) who required mechanical ventilation at 7-14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide and either surfactant (calfactant/Infasurf) or sham instillation every 1-3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, as evaluated by physiological oxygen/flow reduction. RESULTS: A total of 511 infants were enrolled between January 2010 and September 2013. There were no differences between the treated and control groups in mean birth weight (701 ± 164 g), GA (25.2 ± 1.2 weeks), percentage born at GA <26 weeks (70.6%), race, sex, severity of lung disease at enrollment, or comorbidities of prematurity. Survival without BPD did not differ between the treated and control groups at 36 weeks PMA (31.3% vs 31.7%; relative benefit, 0.98; 95% CI, 0.75-1.28; P = .89) or 40 weeks PMA (58.7% vs 54.1%; relative benefit, 1.08; 95% CI, 0.92-1.27; P = .33). There were no between-group differences in serious adverse events, comorbidities of prematurity, or severity of lung disease to 36 weeks. CONCLUSION: Late treatment with up to 5 doses of surfactant in ventilated premature infants receiving inhaled nitric oxide was well tolerated, but did not improve survival without BPD at 36 or 40 weeks. Pulmonary and neurodevelopmental assessments are ongoing. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

Utility analysis of management strategies for suspected subarachnoid haemorrhage in patients with thunderclap headache with negative CT result.

PURPOSE: To determine the most effective follow-up strategy for evaluation of patients with thunderclap headache and negative initial non-contrast CT for acute subarachnoid haemorrhage (SAH). MATERIALS AND METHODS: Institutional review was performed to assess the frequency of CT angiography (CTA) in screening patients with negative non-contrast CT. A comparative effectiveness analysis based on decision tree modelling was subsequently performed to assess three different strategies--no follow-up, lumbar puncture (LP) and CTA. The clinical probabilities and utilities from literature were used to design the decision tree. Base-case scenario utility calculations, sensitivity analyses and probabilistic Monte Carlo simulation were performed. RESULTS: Institutional review of recent data in the last two years demonstrates frequent use of CTA in patients with thunderclap headache with limited utility. The decision tree analysis shows CT with LP follow-up to be the most effective strategy with the highest expected utility of 0.79926 quality-adjusted life-year (QALY) compared with 0.79875 QALY for no follow-up and 0.79869 QALY for CTA follow-up. Monte Carlo simulation showed LP was the best strategy in 86.4% of all iterations. Sensitivity analyses demonstrate that CT without follow-up is the best strategy only when the sensitivity of CT is very high (99.6%) or the pre-test probability of SAH in a patients with thunderclap headache with negative initial CT is low (1.6%). CONCLUSIONS: CT with no follow-up was shown to be the best strategy when the pre-test probability of SAH is low (<1.6%) or the sensitivity of initial non-contrast CT for blood is high (>99.6%). Otherwise, LP should be the preferred strategy for follow-up.

Virulence factors and mechanisms of antimicrobial resistance in Shigella strains from periurban areas of Lima (Peru).

The study was aimed to describe the serotype, mechanisms of antimicrobial resistance, and virulence determinants in Shigella spp. isolated from Peruvian children. Eighty three Shigella spp. were serogrouped and serotyped being established the antibiotic susceptibility. The presence of 12 virulence factors (VF) and integrase 1 and 2, along with commonly found antibiotic resistance genes was established by PCR. S. flexneri was the most relevant serogroup (55 isolates, 66%), with serotype 2a most frequently detected (27 of 55, 49%), followed by S. boydii and S. sonnei at 12 isolates each (14%) and S. dysenteriae (four isolates, 5%). Fifty isolates (60%) were multi-drug resistant (MDR) including 100% of S. sonnei and 64% of S. flexneri. Resistance levels were high to trimethoprim-sulfamethoxazole (86%), tetracycline (74%), ampicillin (67%), and chloramphenicol (65%). Six isolates showed decreased azithromycin susceptibility. No isolate was resistant to nalidixic acid, ciprofloxacin, nitrofurantoin, or ceftriaxone. The most frequent resistance genes were sul2 (95%), tet(B) (92%), cat (80%), dfrA1 (47%), blaOXA-1like (40%), with intl1 and intl2 detected in 51 and 52% of the isolates, respectively. Thirty-one different VF profiles were observed, being the ipaH (100%), sen (77%), virA and icsA (75%) genes the most frequently found. Differences in the prevalence of VF were observed between species with S. flexneri isolates, particularly serotype 2a, possessing high numbers of VF. In conclusion, this study highlights the high heterogeneity of Shigella VF and resistance genes, and prevalence of MDR organisms within this geographic region.

Hospital variation in medical and surgical treatment of patent ductus arteriosus.

OBJECTIVE: This study aims to characterize population risks for diagnosis, medical treatment, and surgical ligation of patent ductus arteriosus (PDA) in very low-birth-weight infants. STUDY DESIGN: Maternal and neonatal data were collected in 40 hospitals in California during 2011 for infants with birth weight ≤ 1,500 g without any congenital malformation, with a diagnosis of PDA. Multivariable logistic regression was used to determine independent risks for PDA diagnosis and for surgical ligation. RESULTS: There were 770/1,902 (40.4%) infants diagnosed with PDA. Low birth weight, gestational age, respiratory distress syndrome, and surfactant administration were associated with PDA diagnosis. Ligation occurred in 43% of patients with birth weight ≤ 750 g, in 24% of patients weighing between 715 and 1,000 g, and in 12% of patients weighing from 1,001 to 1,500 g. Older gestational age (1 week, odds ratio 0.55, 95% confidence interval 0.48-0.63) and absence of respiratory distress syndrome (odds ratio 0.14, 95% confidence interval 0.03-0.59) were associated with lower ligation risk. The median hospital ligation rate was 14% (interquartile range 0-38%). CONCLUSION: Most patients with PDA receive treatment for closure. Practice variation may set the stage for further exploration of experimental trials.

Inhaled nitric oxide increases urinary nitric oxide metabolites and cyclic guanosine monophosphate in premature infants: relationship to pulmonary outcome.

OBJECTIVE: Inhaled nitric oxide (iNO) has been tested to prevent bronchopulmonary dysplasia (BPD) in premature infants, however, the role of cyclic guanosine monophosphate (cGMP) is not known. We hypothesized that levels of NO metabolites (NOx) and cGMP in urine, as a noninvasive source for biospecimen collection, would reflect the dose of iNO and relate to pulmonary outcome. STUDY DESIGN: Studies were performed on 125 infants who required mechanical ventilation at 7 to 14 days and received 24 days of iNO at 20-2 ppm. A control group of 19 infants did not receive iNO. RESULTS: In NO-treated infants there was a dose-dependent increase of both NOx and cGMP per creatinine (maximal 3.1- and 2-fold, respectively, at 10-20 ppm iNO) compared with off iNO. NOx and cGMP concentrations at both 2 ppm and off iNO were inversely related to severity of lung disease during the 1st month, and the NOx levels were lower in infants who died or developed BPD at term. NOx was higher in Caucasian compared with other infants at all iNO doses. CONCLUSION: Urinary NOx and cGMP are biomarkers of endogenous NO production and lung uptake of iNO, and some levels reflect the severity of lung disease. These results support a role of the NO-cGMP pathway in lung development.

Postnatal weight gain in preterm infants with severe bronchopulmonary dysplasia.

OBJECTIVES: To characterize postnatal growth failure (PGF), defined as weight < 10th percentile for postmenstrual age (PMA) in preterm (≤ 27 weeks' gestation) infants with severe bronchopulmonary dysplasia (sBPD) at specified time points during hospitalization, and to compare these in subgroups of infants who died/underwent tracheostomy and others. STUDY DESIGN: Retrospective review of data from the multicenter Children's Hospital Neonatal Database (CHND). RESULTS: Our cohort (n = 375) had a mean ± standard deviation gestation of 25 ± 1.2 weeks and birth weight of 744 ± 196 g. At birth, 20% of infants were small for gestational age (SGA); age at referral to the CHND neonatal intensive care unit (NICU) was 46 ± 50 days. PGF rates at admission and at 36, 40, 44, and 48 weeks' PMA were 33, 53, 67, 66, and 79% of infants, respectively. Tube feedings were administered to > 70% and parenteral nutrition to a third of infants between 36 and 44 weeks' PMA. At discharge, 34% of infants required tube feedings and 50% had PGF. A significantly greater (38 versus 17%) proportion of infants who died/underwent tracheostomy (n = 69) were SGA, compared with those who did not (n = 306; p < 0.01). CONCLUSIONS: Infants with sBPD commonly had progressive PGF during their NICU hospitalization. Fetal growth restriction may be a marker of adverse outcomes in this population.

Clinical prediction models for bronchopulmonary dysplasia: a systematic review and external validation study.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Very different models using clinical parameters at an early postnatal age to predict BPD have been developed with little extensive quantitative validation. The objective of this study is to review and validate clinical prediction models for BPD. METHODS: We searched the main electronic databases and abstracts from annual meetings. The STROBE instrument was used to assess the methodological quality. External validation of the retrieved models was performed using an individual patient dataset of 3229 patients at risk for BPD. Receiver operating characteristic curves were used to assess discrimination for each model by calculating the area under the curve (AUC). Calibration was assessed for the best discriminating models by visually comparing predicted and observed BPD probabilities. RESULTS: We identified 26 clinical prediction models for BPD. Although the STROBE instrument judged the quality from moderate to excellent, only four models utilised external validation and none presented calibration of the predictive value. For 19 prediction models with variables matched to our dataset, the AUCs ranged from 0.50 to 0.76 for the outcome BPD. Only two of the five best discriminating models showed good calibration. CONCLUSIONS: External validation demonstrates that, except for two promising models, most existing clinical prediction models are poor to moderate predictors for BPD. To improve the predictive accuracy and identify preterm infants for future intervention studies aiming to reduce the risk of BPD, additional variables are required. Subsequently, that model should be externally validated using a proper impact analysis before its clinical implementation.

Class 1 and 2 Integrons in Escherichia coli Strains Isolated from Diarrhea and Bacteremia in Children Less Than 2 Years of Age from Peru.

Class 1 and Class 2 integrons are mobilizable elements able to carry a variety of antibiotic resistance determinants. In the present study, Class 1 and 2 integrons present in 355 pathogenic Escherichia coli (285 diarrheagenic, of these 129 were enteropathogenic, 90 enteroaggregative, 66 enterotoxigenic, and 70 bacteremic) isolated from healthy and ill children under age 5 from periurban areas of Lima, Peru, were characterized. The presence of integrase 1 and 2 was established by polymerase chain reaction (PCR), and variable regions were grouped by PCR-restriction fragment length polymorphism and subsequent sequencing. Antimicrobial resistance was established by disk diffusion. Ninety-seven isolates (27.3%) presented integrase 1, and 16 (4.5%) presented integrase 2 (P < 0.0001); in addition, seven (2.0%) isolates, six diarrheagenic and one bacteremic, presented both integrase genes. The presence of integrase 1 was more frequent among bacteremic isolates (P = 0.0004). Variable regions were amplified in 76/120 (63.3%) isolates with up to 14 gene arrangements. The most prevalent gene cassettes were those encoding dihydrofolate reductases as well as aminoglycoside modifying enzymes. Of note, Class 1 integrons tended to be associated with the presence of extended-spectrum ß-lactamases (ESBLs). A variety of Class 1 and 2 integrons were detected in diarrheagenic and bacteremic E. coli, demonstrating the heterogeneity of variable regions circulating in the area. The association of integrons with ESBLs is worrisome and has an impact on the development of multidrug resistance.

Extra-genital Neisseria gonorrhoeae infections with genetic mutations conferring ciprofloxacin resistance among men who have sex with men and transgender women in Lima, Peru.

BACKGROUND: The increasing prevalence of drug-resistant Neisseria gonorrhoeae (NG) infections has caused great concern. Ciprofloxacin remains the empiric antimicrobial recommended to treat NG infections in Peru disregarding the susceptibility profile of circulating NG strains. We report the prevalence of individuals infected with NG strains presenting mutations in the gyrA gene that confers ciprofloxacin resistance. METHODS: We conducted a descriptive study assessing extragenital swab samples collected from a cohort of men who have sex with men and transgender women in Lima, Peru. Anal and pharyngeal NG positive swabs for Aptima Combo 2 assay (Hologic Inc., USA) were used for DNA extraction. We performed TaqMan real time PCR assays to detect a point mutation at codon Ser91 of the gyrase A (gyrA) gene. RESULTS: From 156 individuals who had at least one positive sample for NG reported by the Aptima assay, 80 individuals had at least one amplified DNA for the gyrA gene. We found that 67 of them (84.0%) were infected with a gyrA-mutated NG strain at the Ser91 codon. CONCLUSIONS: We report a high prevalence of gyrA mutation conferring ciprofloxacin resistance among individuals with extragenital NG infection. Empirical treatment of NG needs to be urgently updated in Peru in concordance with international guidelines.

Late administration of surfactant replacement therapy increases surfactant protein-B content: a randomized pilot study.

BACKGROUND: Surfactant dysfunction may contribute to the development of bronchopulmonary dysplasia (BPD) in persistently ventilated preterm infants. We conducted a multicenter randomized, blinded, pilot study to assess the safety and efficacy of late administration of doses of a surfactant protein-B (SP-B)-containing surfactant (calfactant) in combination with prolonged inhaled nitric oxide (iNO) in infants ≤1,000 g birth weight (BW). METHODS: We randomized 85 preterm infants ventilated at 7-14 d after birth to receive either late administration of surfactant (up to 5 doses) plus prolonged iNO or iNO alone. Large aggregate surfactant was isolated from daily tracheal aspirates (TAs) for measurement of SP-B content, total protein, and phospholipid (PL). RESULTS: Late administration of surfactant had minimal acute adverse effects. Clinical status as well as surfactant recovery and SP-B content in tracheal aspirate were transiently improved as compared to the controls; these effects waned after 1 d. The change in SP-B content with surfactant dosing was positively correlated with SP-B levels during treatment (r = 0.50, P = 0.02). CONCLUSION: Low SP-B values increased with calfactant administration, but the relationship of this response to SP-B levels suggests that degradation is a contributing mechanism for SP-B deficiency and surfactant dysfunction. We conclude that late therapy with surfactant in combination with iNO is safe and transiently increases surfactant SP-B content, possibly leading to improved short- and long-term respiratory outcomes.

Trial of aerosolised surfactant for preterm infants with respiratory distress syndrome.

OBJECTIVE: To evaluate the safety of an aerosolised surfactant, SF-RI 1, administered via nasal continuous positive airway pressure (nCPAP) and a prototype breath synchronisation device (AeroFact), to preterm infants with respiratory distress syndrome (RDS). DESIGN: Multicentre, open-label, dose-escalation study with historical controls. SETTING: Newborn intensive care units at Mater Mothers' Hospital, Brisbane, and Royal Hospital for Women, Sydney, Australia. PATIENTS: Infants 26 weeks through 30 weeks gestation who required nCPAP 6-8 cmH2O and fraction of inspired oxygen (FiO2) <0.30 at <2 hours of age. INTERVENTIONS: In part 1, infants received a single dose of 216 mg/kg of aerosolised surfactant. In part 2, infants could receive up to four doses of aerosolised surfactant. Three historical control infants were matched for each enrolled infant. MAIN OUTCOME MEASURES: Treatment failure was defined as Respiratory Severity Score (FiO2×cmH2O nCPAP) >2.4, nCPAP >8 cmH2O, arterial carbon dioxide >65 mm Hg, pH <7.20 or three severe apnoeas within 6 hours during the first 72 hours of life. Other outcomes included tolerance of the AeroFact treatment and complications of prematurity. RESULTS: 10 infants were enrolled in part 1 and 21 in part 2 and were compared with 93 historical controls. No safety issues were identified. In part 2, 6 of 21 (29%) AeroFact-treated infants compared with 30 of 63 (48%) control infants met failure criteria. Kaplan-Meier analysis of patients in part 2 showed a trend towards decreased rate of study failure in the AeroFact-treated infants compared with historical controls (p=0.10). CONCLUSION: The AeroFact system can safely deliver aerosolised surfactant to preterm infants with RDS who are on nCPAP. TRIAL REGISTRATION NUMBER: ACTRN12617001458325.