Keith J. Barrington

The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs

BackgroundRecent reports have raised concerns that postnatal steroids may cause neuro-developmental impairment in preterm infants. This systematic review was performed with the objective of determining whether glucocorticoid therapy, to prevent or treat bronchopulmonary dysplasia, impairs neuro-developmental outcomes in preterm infants.MethodA systematic review of the literature was performed. Medline was searched and articles retrieved using predefined criteria. Data from randomized controlled trials with adequate neuro-developmental follow up (to at least one year) were entered into a meta-analysis to determine the effects of postnatal treatment of preterm infants with glucocorticoids. Cerebral palsy rates, and neuro-developmental impairment (developmental score more than 2SD below the mean, or cerebral palsy or blindness) were analyzed. The studies were divided into 2 groups according to the extent of contamination of the results by treatment of controls with steroids after the initial study period, those with less than 30% contamination, and those with more than 30% contamination or size of contamination not reported.ResultsPostnatal steroid therapy is associated with an increase in cerebral palsy and neuro-developmental impairment. The studies with less contamination show a greater effect of the steroids, consistent with a real direct toxic effect of steroids on the developing central nervous system. The typical relative risk for the development of cerebral palsy derived from studies with less than 30% contamination is 2.86 (95% CI 1.95, 4.19). The typical relative risk for the development of neuro-developmental disability among followed up infants from studies with less than 30% contamination is 1.66 (95% CI 1.26, 2.19). From this subgroup of studies, the number of premature infants who need to be treated to have one more infant with cerebral palsy (number needed to harm, NNH) is 7; to have one more infant with neuro-developmental impairment the NNH is 11.ConclusionsPostnatal pharmacologic steroid treatment for prevention or treatment of bronchopulmonary dysplasia is associated with dramatic increases in neuro-developmental impairment. As there is no clear evidence in the literature of long term benefit, their use for this indication should be abandoned.

Survival Without Disability to Age 5 Years After Neonatal Caffeine Therapy for Apnea of Prematurity

CONTEXT Very preterm infants are prone to apnea and have an increased risk of death or disability. Caffeine therapy for apnea of prematurity reduces the rates of cerebral palsy and cognitive delay at 18 months of age. OBJECTIVE To determine whether neonatal caffeine therapy has lasting benefits or newly apparent risks at early school age. DESIGN, SETTING, AND PARTICIPANTS Five-year follow-up from 2005 to 2011 in 31 of 35 academic hospitals in Canada, Australia, Europe, and Israel, where 1932 of 2006 participants (96.3%) had been enrolled in the randomized, placebo-controlled Caffeine for Apnea of Prematurity trial between 1999 and 2004. A total of 1640 children (84.9%) with birth weights of 500 to 1250 g had adequate data for the main outcome at 5 years. MAIN OUTCOME MEASURES Combined outcome of death or survival to 5 years with 1 or more of motor impairment (defined as a Gross Motor Function Classification System level of 3 to 5), cognitive impairment (defined as a Full Scale IQ<70), behavior problems, poor general health, deafness, and blindness. RESULTS The combined outcome of death or disability was not significantly different for the 833 children assigned to caffeine from that for the 807 children assigned to placebo (21.1% vs 24.8%; odds ratio adjusted for center, 0.82; 95% CI, 0.65-1.03; P = .09). The rates of death, motor impairment, behavior problems, poor general health, deafness, and blindness did not differ significantly between the 2 groups. The incidence of cognitive impairment was lower at 5 years than at 18 months and similar in the 2 groups (4.9% vs 5.1%; odds ratio adjusted for center, 0.97; 95% CI, 0.61-1.55; P = .89). CONCLUSION Neonatal caffeine therapy was no longer associated with a significantly improved rate of survival without disability in children with very low birth weights who were assessed at 5 years.

Randomized Trial of Nasal Synchronized Intermittent Mandatory Ventilation Compared With Continuous Positive Airway Pressure After Extubation of Very Low Birth Weight Infants

Objective. To determine whether noninvasive, nasal synchronized intermittent mandatory ventilation (nSIMV) improves the likelihood that very low birth weight infants will be successfully extubated. Methods. Infants of <1251-g birth weight who were due to be extubated before 6 weeks of age were eligible once they were receiving <35% oxygen and were on a ventilator rate of <18 breaths per minute (bpm). Extubation was performed following intravenous loading with aminophylline, after a successful trial of 12 hours of endotracheal synchronized intermittent mandatory ventilation at a rate of 8. Infants were randomized to either nasal continuous positive airway pressure (nCPAP) at 6 cm H2O or nSIMV after extubation. nSIMV was commenced at a rate of 12 bpm with pressure on the ventilator set to achieve a delivered pressure of at least 12 cm H2O and a peak end expiratory pressure of 6 cm H2O. Continuous recording for diagnosis of apnea was performed for 72 hours after extubation. Objective criteria for failure of extubation were as follows: a Paco 2 >70; Fio 2 >0.7; or severe recurrent apnea (>2 apneas requiring intermittent positive-pressure ventilation in 24 hours or >6 apneas >20 seconds per day). The study ended after 72 hours postextubation or when infants satisfied failure criteria. A sample size of 54 was determined by power analysis. Results. Mean birth weight (831 standard deviation [SD]: 193 g) and gestation (26.3 SD: 1.8 weeks) did not differ between groups. Mean age at extubation was 7.6 (SD: 9.7) days, range 1 to 40 days. The nSIMV group had a lower incidence of failed extubation 4/27 compared with the continuous positive airway pressure group, 12/27. This was attributable to both a decreased incidence of apnea and a decreased incidence of hypercarbia. There was no increase in the incidence of abdominal distension or feeding intolerance. Discussion. nSIMV is effective in preventing extubation failure in very low birth weight infants in the first 72 hours after extubation. Noninvasive ventilation may have other roles in the care of the very low birth weight infant.

Apnea Is Associated with Neurodevelopmental Impairment in Very Low Birth Weight Infants

OBJECTIVE: To determine whether apnea in preterm infants is associated with abnormal neurodevelopmental outcome.METHODS: We determined the number of days that apnea and bradycardia spells were noted by the nursing staff, during the initial hospitalization of 175 preterm infants of less than <1250 g birth weight or <32 weeks gestation who had been enrolled in the follow-up program of the Royal Victoria Hospital. Multiple logistic and multiple linear regression models were constructed to determine the relationships between apnea days and neurodevelopmental impairment at 3 years of age, after correcting for gestation, sex, intrauterine growth restriction, intraventricular hemorrhage, periventricular leukomalacia, pre- and postnatal steroids, and maternal education.RESULTS: A total of 41 infants had neurodevelopmental impairment (Bayley MDI or PDI <70, cerebral palsy or blindness). By multiple logistic regression, an increasing number of days on which at least one apnea occurred, “total apnea days”, and male sex were significantly associated with increasing probability of neurodevelopmental impairment, p<0.01, the sum of days of assisted ventilation and apnea days occurring after extubation was also associated with impairment in a separate regression model, p<0.001. Lower MDI at 3 years was significantly associated with postnatal steroid use, p=0.004. Lower PDI was associated with increasing apnea days, male sex, and postnatal steroid use, p<0.001. Functional impairment (a score on any one of the four dimensions of the Vineland scale <70), found in 17% of the infants, was associated with increasing apnea days, p<0.05. Caffeine treatment was not independently associated with any outcome.CONCLUSION: An increasing number of days that apnea was recorded during hospitalization was associated with a worse outcome. Among the potential explanations for this finding is the possibility that multiple recurrent hypoxic and bradycardic spells may cause brain injury.

Periodic Breathing and Apnea in Preterm Infants

ABSTRACT: The relationship between periodic breathing and idiopathic apnea of prematurity was investigated. We recorded respiratory impedance, heart rate, pulse oximetry and end-tidal CO2 from 68 untreated infants of less than or equal to 34 wk gestation with a diagnosis of idiopathic apnea of prematurity. Mean birth wt was 1476 g (SD 420) and mean gestational age was 29.9 wk (SD 2.6). Apneas of more than 15 s duration that were associated with hypoxemia or bradycardia were identified by semiautomated analysis of computerized records. A total of 1116 significant apneic spells were identified, only one of which occurred during an epoch of periodic breathing, five others occurred within 2 min of the end of an epoch of periodic breathing. Less than 0.6% of significant apneic spells occur within 2 min of periodic breathing. In all of the 12 infants that were monitored starting in the first 12 h or life, significant apneic spells were identified before 36 h of age and no precipitating factors were identified. Periodic breathing did not occur during the first 48 h of life, a finding that supports the concept that the peripheral chemoreceptor is inactive in the first 48 h of life. Periodic breathing in the premature infant is not a precursor to significant apnea.

Permissive hypotension in the extremely low birthweight infant with signs of good perfusion

Introduction: Many practitioners routinely treat infants whose mean arterial blood pressure in mm Hg is less than their gestational age in weeks (GA). Objective: To assess the effectiveness of utilising a combined approach of clinical signs, metabolic acidosis and absolute blood pressure (BP) values when deciding to treat hypotension in the extremely low birthweight (ELBW) infant. Methods: Retrospective cohort study of all live born ELBW infants admitted to our neonatal intensive care unit over a 4-year period. Patients were grouped as either normotensive (BP never less than GA), hypotensive and not treated (BP<GA but signs of good perfusion; we termed this permissive hypotension) and hypotensive treated (BP<GA with signs of poor perfusion). Results: 118 patients were admitted during this period. Blood pressure data were available on 108 patients. 53% of patients were hypotensive (mean BP in mm Hg less than GA in weeks). Treated patients had lower birth weight and GA, and significantly lower blood pressure at 6, 12, 18 and 24 h. Normotensive patients and patients designated as having permissive hypotension had similar outcomes. Mean blood pressure in the permissive group increased from 26 mm Hg at 6 h to 31 mm Hg at 24 h. In a logistic regression model, treated hypotension is independently associated with mortality, odds ratio 8.0 (95% CI 2.3 to 28, p<0.001). Conclusions: Blood pressure spontaneously improves in ELBW infants during the first 24 h. Infants hypotensive on GA criteria but with clinical evidence of good perfusion had as good an outcome as normotensive patients. Treated low blood pressure was associated with adverse outcome.

Treating hypotension in the preterm infant: when and with what: a critical and systematic review

Methods:We performed systematic reviews of the literature in order to determine which preterm infants may benefit from treatment with interventions to elevate blood pressure (BP), and which interventions improve clinically important outcomes.Results:Our review was not able to define a threshold BP that was significantly predictive of a poor outcome, nor whether any interventions for hypotensive infants improved outcomes, nor which interventions were more likely to be beneficial.Conclusions:There is a distinct lack of prospective research of this issue, which prevents good clinical care. It is possible that a simple BP threshold that indicates the need for therapy does not exist, and other factors, such as the clinical status or systemic blood flow measurements, may be much more informative. Such a paradigm shift will also require careful prospective study.A very large proportion of extremely preterm infants receive treatments for hypotension. There are, however, marked variations in indications for treatment, and in the interventions used, between neonatal intensive care units and between neonatologists.

Pain in Canadian NICUs: have we improved over the past 12 years?

ObjectivesTo determine the incidence of and factors predicting management strategies used for procedural pain in Canadian neonatal intensive care units and to determine whether the incidence of procedures and their management has changed since our 1997 study. PatientsFive hundred eighty-two neonates who were hospitalized in any of the participating study centers were included. MethodsA prospective observational study was conducted in 14 Canadian neonatal intensive care units (level III A and III B). Infants were followed for 1 week regarding all invasive procedures. Data were collected prospectively by unit staff using a checklist and verified by research assistants. ResultsA total of 3508 tissue damaging (mean=5.8, SD=15) and 14,085 (mean=25.6, SD=15) nontissue damaging procedures were recorded. Half of procedures (46% tissue damaging and 57% nontissue damaging) had no analgesic interventions. Opiates were used for 14.5% of tissue-damaging procedures and sweet taste was used for 14.3% of the tissue-damaging procedures. Factors predicting use of pharmacologic management of tissue-damaging procedures were being less ill at birth, receiving high frequency ventilatory support, and being transferred to the study center. Parental presence predicted use of sweet taste or nonpharmacologic analgesia for tissue-damaging procedures. Study site practices varied widely with 1 unit providing analgesia for 90% of tissue-damaging procedures. InterpretationAlthough the number of tissue-damaging procedures has decreased from 1997 and the use of analgesics has increased, the management of these procedures falls far below the recommended guidelines of the Canadian Pediatric Society. That 1 unit reached a high level of analgesic use suggests that it is possible to achieve this goal. That parental presence had a positive influence on comfort strategies supports offering encouragement and support for parents to remain with their infant during procedures.

Outcomes of preterm infants <29 weeks gestation over 10-year period in Canada: a cause for concern?

Objective:To compare risk-adjusted changes in outcomes of preterm infants <29 weeks gestation born in 1996 to 1997 with those born in 2006 to 2007.Study Design:Observational retrospective comparison of data from 15 units that participated in the Canadian Neonatal Network during 1996 to 1997 and 2006 to 2007 was performed. Rates of mortality and common neonatal morbidities were compared after adjustment for confounders.Result:Data on 1897 infants in 1996 to 1997 and 1866 infants in 2006 to 2007 were analyzed. A higher proportion of patients in the later cohort received antenatal steroids and had lower acuity of illness on admission. Unadjusted analyses revealed reduction in mortality (unadjusted odds ratio (UAOR): 0.83, 95% confidence interval (CI): 0.63, 0.98), severe retinopathy (UAOR: 0.68, 95% CI: 0.50 to 0.92), but increase in bronchopulmonary dysplasia (UAOR: 1.61, 95% CI: 1.39 to 1.86) and patent ductus arteriosus (UAOR: 1.22, 95% CI: 1.07 to 1.39). Adjusted analyses revealed increases in the later cohort for bronchopulmonary dysplasia (adjusted odds ratio (AOR): 1.88, 95% CI: 1.60 to 2.20) and severe neurological injury (AOR: 1.49, 95% CI: 1.22 to 1.80). However, the ascertainment methods for neurological findings and ductus arteriosus differed between the two time periods.Conclusion:Improvements in prenatal care has resulted in improvement in the quality of care, as reflected by reduced severity of illness and mortality. However, after adjustment of prenatal factors, no improvement in any of the outcomes was observed and on the contrary bronchopulmonary dysplasia increased. There is need for identification and application of postnatal strategies to improve outcomes of extreme preterm infants.

The Natural History of the Appearance of Apnea of Prematurity

ABSTRACT: Twenty healthy preterm infants of less than 34 wk gestation were studied with continuous recordings, commencing within 8 h of birth, for up to 1 wk of age to determine the usual time course of the appearance of apnea and to classify apnea types. Airway occlusion studies were also performed on a regular basis to determine whether apneic spells were preceded or followed by a reduction in central respiratory drive. Apneic spells of greater than 15 s duration accompanied by hypoxia or bradycardia occurred in all infants before 24 h of age. The frequency of apneic spells was highest in the first 24 h after birth with a mean frequency of 0.9/h and gradually reduced thereafter, falling to 0.2/h by 5 d of age (p < 0.01). Apneic spells were more likely to be obstructive in the first 2 d of life than thereafter (p < 0.05). Central apnea was proportionately significantly less frequent during this time period. Reduced respiratory drive, as demonstrated by airway occlusion pressures, was associated with more frequent apnea and was evident at the first occlusion study, which frequently preceded the first significant apnea.