Anna Maria Hibbs

Dysfunction of pulmonary surfactant in chronically ventilated premature infants

Infants of <30 wk gestation often require respiratory support for several weeks and may develop bronchopulmonary dysplasia (BPD), which is associated with long-term pulmonary disability or death in severe cases. To examine the status of surfactant in infants at high risk for BPD, this prospective study analyzed 247 tracheal aspirate samples from 68 infants of 23–30 wk gestation who remained intubated for 7–84 d. Seventy-five percent of the infants had one or more surfactant samples with abnormal function (minimum surface tension 5.1–21.7 mN/m by pulsating bubble surfactometer), which were temporally associated with episodes of infection (p = 0.01) and respiratory deterioration (p = 0.005). Comparing normal and abnormal surfactant samples, there were no differences in amount of surfactant phospholipid, normalized to total protein that was recovered from tracheal aspirate, or in relative content of phosphatidylcholine and phosphatidylglycerol. Contents of surfactant proteins (SP) A, B, and C, measured in the surfactant pellet by immunoassay, were reduced by 50%, 80%, and 72%, respectively, in samples with abnormal surface tension (p ≤ 0.001). On multivariable analysis of all samples, SP-B content (r = −0.58, p < 0.0001) and SP-C content (r = −0.32, p < 0.001) were correlated with surfactant function. We conclude that most premature infants requiring continued respiratory support after 7 d of age experience transient episodes of dysfunctional surfactant that are associated with a deficiency of SP-B and SP-C.

Metoclopramide for the Treatment of Gastroesophageal Reflux Disease in Infants: A Systematic Review

OBJECTIVES. Metoclopramide is a commonly used drug to treat gastroesophageal reflux disease in infants. Given its widespread use and growing concern about toxicity in this population, we conducted a systematic review of metoclopramide for the treatment of gastroesophageal reflux disease in infants. METHODS. We performed a systematic search of PubMed and bibliographies of relevant review articles. We included cohort, case-control, and intervention studies of the efficacy, effectiveness, or toxicity of metoclopramide therapy for gastroesophageal reflux disease in infants. We excluded case reports, case series, review articles, and abstracts. RESULTS. Twelve articles met our inclusion criteria. Of these, 11 were prospective trials, and 5 were randomized, blinded clinical trials. Study size ranged from 6 to 77 patients. Eight studies showed patient improvement with metoclopramide in at least 1 measured outcome; 1 study showed worsening symptoms with metoclopramide. Of the 5 randomized, blinded trials, 2 showed no effect of metoclopramide on any outcome, and 2 showed a significant placebo effect. Four studies commented on adverse effects of therapy, with irritability being the most frequently reported potential adverse effect of therapy. Other reported adverse effects included dystonic reactions, drowsiness, oculogyric crisis, emesis, and apnea. Among studies, there was marked heterogeneity in the patient populations, dosing, and outcomes studied. Therefore, a meta-analysis was not performed. We both agreed on a US Preventive Service Task Force rating of “poor” for the level of evidence, leading to an “inconclusive” recommendation for the safety and efficacy of metoclopramide in infants. CONCLUSIONS. The current literature is insufficient to either support or oppose the use of metoclopramide for gastroesophageal reflux disease in infants. In the future, large blinded randomized clinical trials are needed to determine the efficacy and toxicity of metoclopramide in this population.

Prenatal and Neonatal Risk Factors for Sleep Disordered Breathing in School-Aged Children Born Preterm

OBJECTIVES Previously published data from the Cleveland Childrens Sleep and Health Study demonstrated that preterm infants are especially vulnerable both to sleep disordered breathing (SDB) and its neurocognitive sequelae at age 8 to 11 years. In this analysis, we aimed to identify the components of the neonatal medical history associated with childhood SDB among children born prematurely. STUDY DESIGN This analysis focuses on the 383 children in the population-based cohort from the Cleveland Childrens Sleep and Health Study who were born <37 weeks gestational age and who had technically acceptable sleep studies performed at ages 8 to 11 years (92% of all preterm children). Logistic regression was used to evaluate the associations between candidate perinatal and neonatal risk factors and the presence of childhood SDB by sleep study. RESULTS Twenty-eight preterm children (7.3%) met the definition for SDB at age 8 to 11 years. Having a single mother and mild maternal preeclampsia were strongly associated with SDB in unadjusted and race-adjusted models. Unadjusted analyses also identified xanthine use and cardiopulmonary resuscitation or intubation in the delivery room as potential risk-factors for SDB. We did not find a significant link between traditional markers of severity of neonatal illness-such as gestational age, birth weight, intraventricular hemorrhage, bronchopulmonary dysplasia, or duration of ventilation-and childhood SDB at school age. CONCLUSIONS These results represent a first step in identifying prenatal and neonatal characteristics that place preterm infants at higher risk for childhood SDB. The strong association between mild preeclampsia and childhood SDB underscores the importance of research aimed at understanding in utero risk factors for neurorespiratory development.

One-Year Respiratory Outcomes of Preterm Infants Enrolled in the Nitric Oxide (to Prevent) Chronic Lung Disease Trial

OBJECTIVE To identify whether inhaled nitric oxide treatment decreased indicators of long-term pulmonary morbidities after discharge from the neonatal intensive care unit. STUDY DESIGN The Nitric Oxide (to Prevent) Chronic Lung Disease trial enrolled preterm infants (<1250 g) between 7 to 21 days of age who were ventilated and at high risk for bronchopulmonary dysplasia. Follow-up occurred at 12 +/- 3 months of age adjusted for prematurity; long-term pulmonary morbidity and other outcomes were reported by parents during structured blinded interviews. RESULTS A total of 456 infants (85%) were seen at 1 year. Compared with control infants, infants randomized to inhaled nitric oxide received significantly less bronchodilators (odds ratio [OR] 0.53 [95% confidence interval 0.36-0.78]), inhaled steroids (OR 0.50 [0.32-0.77]), systemic steroids (OR 0.56 [0.32-0.97]), diuretics (OR 0.54 [0.34-0.85]), and supplemental oxygen (OR 0.65 [0.44-0.95]) after discharge from the neonatal intensive care unit. There were no significant differences between parental report of rehospitalizations (OR 0.83 [0.57-1.21]) or wheezing or whistling in the chest (OR 0.70 [0.48-1.03]). CONCLUSIONS Infants treated with inhaled nitric oxide received fewer outpatient respiratory medications than the control group. However, any decision to institute routine use of this dosing regimen should also take into account the results of the 24-month neurodevelopmental assessment.

Apnea, bradycardia and desaturation in preterm infants before and after feeding

Objective:A common clinical impression is that both gastroesophageal reflux (GER) and cardiorespiratory events increase after feeding in preterm infants. We aimed to measure objectively the effects of feeding on GER, apnea, bradycardia and desaturations.Study Design:We conducted a retrospective review of premature infants with a gestational age of 23 to 37 weeks at birth and a post-conceptional age of 34 to 48 weeks, who were referred for multichannel intraluminal impedance (MII), pH probe and 12-h apnea evaluation. Cardiorespiratory and GER event rates during pre- and post-feeding intervals were compared.Result:Thirty-six infants met the inclusion criteria. More GER events occurred after a feed than before (P=0.012). After feeds, reflux was less acidic and higher in the esophagus (P<0.05). In contrast, the rates of apnea, bradycardia and desaturations were not altered by infant feeding. Apnea of >5 s occurred at a median frequency of 0 (range 0 to 3) events per hour before a feed and 0 (0 to2) events per hour after a feed (P=0.61).Conclusion:The frequency, height and pH of GER are significantly altered by feedings in preterm infants. However, the common clinical impression that apnea, bradycardia and desaturations are more prevalent after feeding is not supported.

Characterization of cardiorespiratory events following gastroesophageal reflux in preterm infants.

Objective:The aim of this study was to characterize cardiorespiratory events in preterm infants after both acid and nonacid gastroesophageal reflux (GER) as detected by pH and multiple intraluminal impedance (MII).Study Design:Twelve hour overnight studies were performed in 71 preterm infants (gestational age 29.4±3.0 weeks, birth weight 1319±496 g). Apnea ⩾10 s in duration, bradycardia ⩽80 b.p.m. and oxygen desaturation ⩽85% that occurred within 30 s after the initiation of GER were classified as associated with GER.Result:A total of 12 957 cardiorespiratory events and 4164 GER episodes were documented. Less than 3% of all cardiorespiratory events were preceded by GER constituting 3.4% of apnea, 2.8% of oxygen desaturation and 2.9% of bradycardia events. GER did not prolong cardiorespiratory event duration or increase severity. In contrast, GER was associated with a shorter duration of oxygen desaturation events (7.8±4.6 vs 6.3±5.6 s, P<0.05).Conclusion:GER is rarely associated with cardiorespiratory events, and has no detrimental effect on cardiorespiratory event duration or severity.

Two-Year Neurodevelopmental Outcomes of Ventilated Preterm Infants Treated with Inhaled Nitric Oxide

OBJECTIVE In a randomized multi-center trial, we demonstrated that inhaled nitric oxide begun between 7 and 21 days and given for 24 days significantly increased survival without bronchopulmonary dysplasia (BPD) in ventilated premature infants weighing <1250 g. Because some preventative BPD treatments are associated with neurodevelopmental impairment, we designed a follow-up study to assess the safety of nitric oxide. STUDY DESIGN Our hypothesis was that inhaled nitric oxide would not increase neurodevelopmental impairment compared with placebo. We prospectively evaluated neurodevelopmental and growth outcomes at 24 months postmenstrual age in 477 of 535 surviving infants (89%) enrolled in the trial. RESULTS In the treated group, 109 of 243 children (45%) had neurodevelopmental impairment (moderate or severe cerebral palsy, bilateral blindness, bilateral hearing loss, or score <70 on the Bayley Scales II), compared with 114 of 234 (49%) in the placebo group (relative risk, 0.92; 95% CI, 0.75-1.12; P = .39). No differences on any subcomponent of neurodevelopmental impairment or growth variables were found between inhaled nitric oxide or placebo. CONCLUSIONS Inhaled nitric oxide improved survival free of BPD, with no adverse neurodevelopmental effects at 2 years of age.

Accounting for Multiple Births in Neonatal and Perinatal Trials: Systematic Review and Case Study

OBJECTIVES To determine the prevalence in the neonatal literature of statistical approaches accounting for the unique clustering patterns of multiple births and to explore the sensitivity of an actual trial to several analytic approaches to multiples. STUDY DESIGN A systematic review of recent perinatal trials assessed the prevalence of studies accounting for clustering of multiples. The Nitric Oxide to Prevent Chronic Lung Disease (NO CLD) trial served as a case study of the sensitivity of the outcome to several statistical strategies. We calculated odds ratios using nonclustered (logistic regression) and clustered (generalized estimating equations, multiple outputation) analyses. RESULTS In the systematic review, most studies did not describe the random assignment of twins and did not account for clustering. Of those studies that did, exclusion of multiples and generalized estimating equations were the most common strategies. The NO CLD study included 84 infants with a sibling enrolled in the study. Multiples were more likely than singletons to be white and were born to older mothers (P < .01). Analyses that accounted for clustering were statistically significant; analyses assuming independence were not. CONCLUSIONS The statistical approach to multiples can influence the odds ratio and width of confidence intervals, thereby affecting the interpretation of a study outcome. A minority of perinatal studies address this issue.

Inhaled Nitric Oxide in preterm infants: a systematic review and individual patient data meta-analysis

BackgroundPreterm infants requiring assisted ventilation are at significant risk of both pulmonary and cerebral injury. Inhaled Nitric Oxide, an effective therapy for pulmonary hypertension and hypoxic respiratory failure in the full term infant, has also been studied in preterm infants. The most recent Cochrane review of preterm infants includes 11 studies and 3,370 participants. The results show a statistically significant reduction in the combined outcome of death or chronic lung disease (CLD) in two studies with routine use of iNO in intubated preterm infants. However, uncertainty remains as a larger study (Kinsella 2006) showed no significant benefit for iNO for this combined outcome. Also, trials that included very ill infants do not demonstrate significant benefit. One trial of iNO treatment at a later postnatal age reported a decrease in the incidence of CLD. The aim of this individual patient meta-analysis is to confirm or refute these potentially conflicting results and to determine the extent to which patient or treatment characteristics may explain the results and/or may predict benefit from inhaled Nitric Oxide in preterm infants.Methods/DesignThe Meta-Analysis of Preterm Patients on inhaled Nitric Oxide (MAPPiNO) Collaboration will perform an individual patient data meta-analysis to answer these important clinical questions. Studies will be included if preterm infants receiving assisted ventilation are randomized to receive inhaled Nitric Oxide or to a control group. The individual patient data provided by the Collaborators will be analyzed on an intention-to-treat basis where possible. Binary outcomes will be analyzed using log-binomial regression models and continuous outcomes will be analyzed using linear fixed effects models. Adjustments for trial differences will be made by including the trial variable in the model specification.DiscussionThirteen (13) trials, with a total of 3567 infants are eligible for inclusion in the MAPPiNO systematic review. To date 11 trials (n = 3298, 92% of available patients) have agreed to participate. Funding was successfully granted from Ikaria Inc as an unrestricted grant. A collaborative group was formed in 2006 with data collection commencing in 2007. It is anticipated that data analysis will commence in late 2009 with results being publicly available in 2010.

Technical limitations in detection of gastroesophageal reflux in neonates.

Objective: Characterize the incidence and possible etiologies of acid reflux events detected by pH and not identified by multiple intraluminal impedance (MII) monitoring. Materials and Methods: Acid reflux events detected by pH but not identified by MII (pH-only) were documented in 80 preterm and 39 term infants. Reasons for failure of MII to detect these events were classified as failure to meet MII scoring criteria, presence of an air bolus, technical artifact, and no change in impedance. Events with no change in impedance were stratified to low impedance throughout the study (possible esophageal inflammation), transient decrease in pre-event impedance (presence of refluxate), occurrence <30 seconds of a preceding event, and no explanation. Results: A total of 2572 events were detected by pH, with 59% of events not identified by MII. A higher incidence of pH-only events occurred in preterm versus term infants (54 ± 27% versus 42 ± 23%, P = .025, respectively). Thirteen percent of pH-only events were missed due to MII scoring criteria, 12% due to technical artifact, 11% due to an air bolus, and 64% had no change in impedance. Of the 978 events with no change in impedance, 154 were associated with low impedance throughout the study, 430 with a transient decrease in pre-event impedance, and 175 were preceded by a reflux episode within 30 seconds. Conclusions: There was a high incidence of acid reflux events detected by pH but not identified by MII. This occurred more often in the least mature infants, and we speculate that delayed esophageal fluid clearance is the major underlying mechanism.