Susan E. Jacobs

Newer approaches to the diagnosis of early onset neonatal sepsis.

Accurate and timely diagnosis of early onset neonatal sepsis remains challenging to the clinician and the laboratory. A test with a rapid turnaround time with 100% sensitivity, rather than high specificity, which allows accurate diagnosis and appropriate antimicrobial treatment or which allows antibiotics to be safely withheld in non-infected infants, is desirable. Many potential markers (acute phase reactants, cell surface markers, cytokines) are not routinely available to the laboratory, and most likely combinations of markers will ensure greater diagnostic accuracy. In the future, molecular biology techniques offer the prospect of rapid identification of both pathogens and antimicrobial resistance markers.

Hypothermia and other treatment options for neonatal encephalopathy: an executive summary of the Eunice Kennedy Shriver NICHD workshop.

HIE is not a single disease from a single cause, and is characterized by great diversity in the timing and magnitude of brain injury. It is therefore unreasonable to expect any single intervention to provide uniformly favorable outcome. The known heterogeneity in neuropathological changes after perinatal HIE combined with potential regional heterogeneity of treatment effects will lead to marked differential effects on outcomes among survivors of HIE (e.g. physical disability versus cognitive deficits). This underscores the need for longer term follow up of all infants with HIE undergoing any treatment. In spite of rapidly accumulating clinical and laboratory data related to hypothermia as a neuroprotective strategy for HIE, the speakers and discussants at the workshop underscored numerous gaps in knowledge in this field summarized in the Table, which compares the gaps identified at the 2005 NICHD workshop8 with current gaps. The participants noted that with only six completed studies1-6 providing information on follow-up for up to 18 months of age, the longer-term neurodevelopmental impact of hypothermia for HIE are pending.23,24 This, they concluded, should lead to an overall measure of caution in applying the new therapy of hypothermia indiscriminately for all cases of HIE. Table 1 Comparison of Categories of Gaps in Knowledge and Change from 2005 to 2010 Based on the available data and large knowledge gaps, the expert panel suggested that although hypothermia is unequivocally a promising therapy for HIE, a substantial proportion of infants still suffer from death or disability despite treatment. Further analysis of existing trial data, development of adjuvant therapies to hypothermia, development of biomarkers and further refinements of hypothermia therapy for use in infants suffering from HIE and clinical trials of therapeutic hypothermia in mid resource settings with different risk factors but adequate facilities and infrastructure are all urgently needed and were identified as areas of high priority for study.

Probiotic Effects on Late-onset Sepsis in Very Preterm Infants: A Randomized Controlled Trial

BACKGROUND AND OBJECTIVE: Late-onset sepsis frequently complicates prematurity, contributing to morbidity and mortality. Probiotics may reduce mortality and necrotizing enterocolitis (NEC) in preterm infants, with unclear effect on late-onset sepsis. This study aimed to determine the effect of administering a specific combination of probiotics to very preterm infants on culture-proven late-onset sepsis. METHODS: A prospective multicenter, double-blinded, placebo-controlled, randomized trial compared daily administration of a probiotic combination (Bifidobacterium infantis, Streptococcus thermophilus, and Bifidobacterium lactis, containing 1 × 109 total organisms) with placebo (maltodextrin) in infants born before 32 completed weeks’ gestation weighing <1500 g. The primary outcome was at least 1 episode of definite late-onset sepsis. RESULTS: Between October 2007 and November 2011, 1099 very preterm infants from Australia and New Zealand were randomized. Rates of definite late-onset sepsis (16.2%), NEC of Bell stage 2 or more (4.4%), and mortality (5.1%) were low in controls, with high breast milk feeding rates (96.9%). No significant difference in definite late-onset sepsis or all-cause mortality was found, but this probiotic combination reduced NEC of Bell stage 2 or more (2.0% versus 4.4%; relative risk 0.46, 95% confidence interval 0.23 to 0.93, P = .03; number needed to treat 43, 95% confidence interval 23 to 333). CONCLUSIONS: The probiotics B infantis, S thermophilus, and B lactis significantly reduced NEC of Bell stage 2 or more in very preterm infants, but not definite late-onset sepsis or mortality. Treatment with this combination of probiotics appears to be safe.

Hypothermia and other treatment options for neonatal encephalopathy

HIE is not a single disease from a single cause, and is characterized by great diversity in the timing and magnitude of brain injury. It is therefore unreasonable to expect any single intervention to provide uniformly favorable outcome. The known heterogeneity in neuropathological changes after perinatal HIE combined with potential regional heterogeneity of treatment effects will lead to marked differential effects on outcomes among survivors of HIE (e.g. physical disability versus cognitive deficits). This underscores the need for longer term follow up of all infants with HIE undergoing any treatment. In spite of rapidly accumulating clinical and laboratory data related to hypothermia as a neuroprotective strategy for HIE, the speakers and discussants at the workshop underscored numerous gaps in knowledge in this field summarized in the Table, which compares the gaps identified at the 2005 NICHD workshop8 with current gaps. The participants noted that with only six completed studies1-6 providing information on follow-up for up to 18 months of age, the longer-term neurodevelopmental impact of hypothermia for HIE are pending.23,24 This, they concluded, should lead to an overall measure of caution in applying the new therapy of hypothermia indiscriminately for all cases of HIE. Table 1 Comparison of Categories of Gaps in Knowledge and Change from 2005 to 2010 Based on the available data and large knowledge gaps, the expert panel suggested that although hypothermia is unequivocally a promising therapy for HIE, a substantial proportion of infants still suffer from death or disability despite treatment. Further analysis of existing trial data, development of adjuvant therapies to hypothermia, development of biomarkers and further refinements of hypothermia therapy for use in infants suffering from HIE and clinical trials of therapeutic hypothermia in mid resource settings with different risk factors but adequate facilities and infrastructure are all urgently needed and were identified as areas of high priority for study.

Inhaled nitric oxide for acute hypoxic respiratory failure in children and adults : a meta-analysis

We systematically reviewed randomized controlled trials examining inhaled nitric oxide (INO) for the treatment of acute respiratory distress syndrome or acute lung injury in children and adults. Qualitative assessments of identified trials were made, and metaanalyses were performed according to Cochrane methodology. Five randomized controlled trials (n = 535) met entry criteria. One study demonstrated significant improvement in oxygenation in the first 4 days of treatment, with no difference after this. There was no difference in ventilator-free days between treatment and placebo groups, and no specific dose of INO was more advantageous than any other. INO had no effect on mortality in trials without crossover of treatment failures to open-label INO (relative risk, 0.98; 95% confidence interval, 0.66–1.44). Other clinical indicators of effectiveness, such as duration of hospital and intensive care stay, were inconsistently reported. Lack of data prevented assessment of all outcomes. If further trials assessing INO in acute respiratory distress syndrome or acute lung injury are to proceed, they should be stratified for primary etiology, incorporate other modalities that may affect outcome, and evaluate clinically relevant outcomes before any benefit of INO can be excluded.

Prognostic Utility of Magnetic Resonance Imaging in Neonatal Hypoxic-Ischemic Encephalopathy: Substudy of a Randomized Trial

OBJECTIVE To investigate the effects of hypothermia treatment on magnetic resonance imaging (MRI) patterns of brain injury in newborns with hypoxic-ischemic encephalopathy compared with normothermia, including the prognostic utility of MRI for death and/or disability at a postnatal age of 2 years. DESIGN Substudy of a randomized controlled trial. SETTING Participating centers in the Infant Cooling Evaluation trial. PARTICIPANTS Trial participants (gestational age ≥35 weeks with moderate to severe hypoxic-ischemic encephalopathy, randomized to whole-body hypothermia or normothermia) with available MRIs. MAIN EXPOSURE We performed qualitative evaluation of T1- and T2-weighted and diffusion MRIs. The posterior limb of the internal capsule was classified as normal or abnormal, whereas the basal ganglia and thalami, white matter, and cortical gray matter were classified as normal or mildly abnormal or moderately/severely abnormal. MAIN OUTCOME MEASURES Death or major disability at 2 years. RESULTS We evaluated 127 MRIs (66 patients treated with hypothermia and 61 with normothermia; mean age at scan, 6 postnatal days). The odds of having moderate/severe white matter or cortical gray matter abnormalities on T1- and T2-weighted MRI were reduced by hypothermia (white matter odds ratio, 0.28 [95% CI, 0.09-0.82]; gray matter odds ratio, 0.41 [0.17-1.00]). Abnormal MRI findings predicted adverse outcomes, with T1- and T2-weighted and diffusion MRI abnormalities in the posterior limb of the internal capsule and basal ganglia and thalami demonstrating the greatest predictive value. There was little evidence that prognostic value of the MRI was modified by therapeutic hypothermia (all interactions, P > .05). CONCLUSIONS Brain injury on T1- and T2-weighted MRI is reduced in hypothermia-treated newborns. Abnormal MRI findings are prognostic of long-term outcome in moderate to severe hypoxic-ischemic encephalopathy regardless of treatment with hypothermia.

NIDCAP: A Systematic Review and Meta-analyses of Randomized Controlled Trials

BACKGROUND AND OBJECTIVE: The “synactive” theory of neurobehavioral development forms the basis of the Newborn Individualized Developmental Care and Assessment Program (NIDCAP). Our objective was to assess the effectiveness of NIDCAP in improving outcomes in preterm infants. METHODS: Medline, CINAHL, Embase, PsychInfo, The Cochrane Library, Pediatric Academic Societies’ Abstracts and Web of Science were searched in July 2010 and February 2012. The studies selected were randomized controlled trials testing the effectiveness of NIDCAP on medical and neurodevelopmental outcomes. The authors abstracted baseline characteristics of infants and outcomes. The risk of bias was assessed by using Cochrane criteria. RevMan 5.1 was used to synthesize data by the use of relative risk and risk difference for dichotomous outcomes and mean or standardized mean difference for continuous outcomes. RESULTS: Eleven primary and 7 secondary studies enrolling 627 neonates were included, with 2 of high quality. The composite primary outcomes of death or major sensorineural disability at 18 months corrected age or later in childhood (3 trials, 302 children; relative risk 0.89 [95% confidence interval 0.61 to 1.29]) and survival free of disability at 18 months corrected age or later in childhood (2 trials, 192 infants; relative risk 0.97 [95% confidence interval 0.69 to 1.35]), were not significantly different between the NIDCAP and control groups. With the sensitivity analysis that excluded the 2 statistically heterogeneous outlying studies, there were no significant differences between groups for short-term medical outcomes. CONCLUSIONS: This systematic review including 627 preterm infants did not find any evidence that NIDCAP improves long-term neurodevelopmental or short-term medical outcomes.

Outcomes following prolonged preterm premature rupture of the membranes.

Objective: Rupture of the membranes in the second trimester is reported to be associated with high rates of pregnancy loss, neonatal mortality and morbidity. This article describes the outcomes of liveborn infants delivered following a prolonged period of membrane rupture occurring before 24 weeks’ gestation. Patients and setting: Over a 5-year period, consecutive pregnancies complicated by spontaneous rupture of the membranes before 24 weeks’ gestation were identified. Evaluation of short-term outcomes before discharge of liveborn infants delivered, in a tertiary referral centre, following prolonged rupture of membranes of duration greater than 2 weeks. Results: Of 98 pregnancies identified with rupture of the membranes before 24 weeks’ gestation, 40 (41%) women progressed to deliver a liveborn infant following a latent period of at least 14 days. Although most liveborn infants required neonatal intensive care including mechanical ventilation (n = 38; 78%), the survival rate to hospital discharge was 70% (n = 28). Airleak occurred in 7 (25%) survivors and 8 (67%) deaths. Among the survivors, 12 (43%) required supplemental oxygen at 36 weeks’ postmenstrual age and no infant had grade 3 or 4 intraventricular haemorrhage. One infant had a postmortem diagnosis of pulmonary hypoplasia and nine others had clinical features consistent with this diagnosis. Low liquor volume was not uniformly associated with a poor outcome. Conclusion: With full contemporary neonatal intensive care, the outcome for liveborn infants in the present cohort delivered following membrane rupture occurring before 24 weeks’ gestation, of at least 14 days duration, was better than previously reported.

Pseudomonas aeruginosa outbreak associated with a contaminated blood-gas analyser in a neonatal intensive care unit

Over a 10 month period in a neonatal intensive care unit there was an outbreak of infection caused by Pseudomonas aeruginosa (resistant to ticarcillin, timentin) which involved 24 newborns. There was extensive morbidity and mortality (38%) associated with the infections, which presented as septicaemia (N = 6) (five succumbed and four had coexisting pneumonia), pneumonia (N = 6), meningitis (one, died), conjunctivitis (N = 1), otitis externa (N = 1), conjunctivitis plus otitis externa (N = 1). In addition there were two pseudosepticaemias and six colonized infants, three of whom were treated for the presence of P. aeruginosa in endotracheal aspirates. There was always at least one baby colonized or infected with P. aeruginosa during the outbreak. Environmental surveillance and genomic DNA fingerprinting of isolates identified the blood gas analyzer port as the likely reservoir for the outbreak. Further spread of the organism did not occur after commencement of staff education on vigilant and careful handwashing, especially after use of the blood-gas analyser.

Therapeutic hypothermia for newborn infants with hypoxic-ischaemic encephalopathy.

Peripartum asphyxia complicated by moderate or severe hypoxic–ischaemic encephalopathy is a devastating global health issue. A therapeutic ‘window of opportunity’ exists after resuscitation of the asphyxiated newborn and before the delayed phase of neuronal loss. Animal studies demonstrated that neuronal injury following hypoxia–ischaemia can be prevented or reduced by a mild reduction in brain temperature. Human infant pilot studies confirmed feasibility, without major adverse effects. Randomised trials and systematic reviews comprising term infants with moderate or severe encephalopathy and peripartum asphyxia have established the neuroprotective benefit of therapeutic hypothermia. Hypothermia reduces mortality or major disability to 18 months of age, as well as cerebral palsy, and neuromotor and cognitive delay. Importantly, mortality is reduced without any increase in major neurodevelopmental disability in survivors, and with only minor adverse effects. The evidence supports therapeutic hypothermia when used within strict protocols in tertiary centres to improve the outcome for term and near‐term newborns with moderate or severe hypoxic–ischaemic encephalopathy. Equally strict protocols in non‐tertiary nurseries will enable earlier initiation of hypothermia under guidance of the regional neonatal intensive care unit and transport team.