Chad Andersen

High-Flow Nasal Cannulae in Very Preterm Infants after Extubation

BACKGROUND The use of high-flow nasal cannulae is an increasingly popular alternative to nasal continuous positive airway pressure (CPAP) for noninvasive respiratory support of very preterm infants (gestational age, <32 weeks) after extubation. However, data on the efficacy or safety of such cannulae in this population are lacking. METHODS In this multicenter, randomized, noninferiority trial, we assigned 303 very preterm infants to receive treatment with either high-flow nasal cannulae (5 to 6 liters per minute) or nasal CPAP (7 cm of water) after extubation. The primary outcome was treatment failure within 7 days. Noninferiority was determined by calculating the absolute difference in the risk of the primary outcome; the margin of noninferiority was 20 percentage points. Infants in whom treatment with high-flow nasal cannulae failed could be treated with nasal CPAP; infants in whom nasal CPAP failed were reintubated. RESULTS The use of high-flow nasal cannulae was noninferior to the use of nasal CPAP, with treatment failure occurring in 52 of 152 infants (34.2%) in the nasal-cannulae group and in 39 of 151 infants (25.8%) in the CPAP group (risk difference, 8.4 percentage points; 95% confidence interval, -1.9 to 18.7). Almost half the infants in whom treatment with high-flow nasal cannulae failed were successfully treated with CPAP without reintubation. The incidence of nasal trauma was significantly lower in the nasal-cannulae group than in the CPAP group (P=0.01), but there were no significant differences in rates of serious adverse events or other complications. CONCLUSIONS Although the result for the primary outcome was close to the margin of noninferiority, the efficacy of high-flow nasal cannulae was similar to that of CPAP as respiratory support for very preterm infants after extubation. (Funded by the National Health and Medical Research Council; Australian New Zealand Clinical Trials Network number, ACTRN12610000166077.).

Neurodevelopmental outcome of extremely low birth weight infants randomly assigned to restrictive or liberal hemoglobin thresholds for blood transfusion

BACKGROUND AND OBJECTIVE. Extremely low birth weight infants frequently receive red cell transfusions. We sought to determine whether a restrictive versus liberal hemoglobin transfusion threshold results in differences in death or adverse neurodevelopmental outcomes of extremely low birth weight infants. PATIENTS AND METHODS. Extremely low birth weight infants previously enrolled in the Preterm Infants in Need of Transfusion Trial, a randomized, controlled trial of low versus high hemoglobin transfusion thresholds, were followed up at 18 to 21 months’ corrected age. Erythrocyte transfusion was determined by an algorithm of low (restrictive) or high (liberal) hemoglobin transfusion thresholds, differing by 10 to 20 g/L and maintained until first hospital discharge. The primary composite outcome was death or the presence of cerebral palsy, cognitive delay, or severe visual or hearing impairment. RESULTS. Of 451 enrolled infants, the primary outcome was available in 430. There was no statistically significant difference in the primary outcome, found in 94 (45%) of 208 in the restrictive group and 82 (38%) of 213 in the liberal group. There were no statistically significant differences in preplanned secondary outcomes. However, the difference in cognitive delay (Mental Development Index score < 70) approached statistical significance. A posthoc analysis with cognitive delay redefined (Mental Development Index score < 85) showed a significant difference favoring the liberal threshold group. CONCLUSIONS. Maintaining the hemoglobin of extremely low birth weight infants at these restrictive rather than liberal transfusion thresholds did not result in a statistically significant difference in combined death or severe adverse neurodevelopmental outcome.

Plasma cytokines and markers of endothelial activation increase after packed red blood cell transfusion in the preterm infant

Background:Transfusion of packed red blood cells (PRBCs) saves lives in the neonatal critical care setting and is one of the most common interventions in the preterm infant. The number and volume of PRBC transfusions are associated with several major neonatal morbidities, although a direct causal link between transfusion and major neonatal morbidity is still to be proven. Transfusion-related immunomodulation (TRIM) may underlie these adverse outcomes, yet it has received little attention in the high-risk preterm infant.Methods:One transfusion event was studied in infants ≤28 wk gestation between 2 and 6 wk postnatal age (n = 28). Plasma inflammatory cytokines and markers of endothelial activation were measured in the infants before and 2–4 h after transfusion, as well as in the donor pack.Results:Median (range) age at transfusion was 18 (14–39) days with the pretransfusion hemoglobin level at 9.8 (7.4–10.2) g/dl. Interleukin (IL)-1β (P = 0.01), IL-8 (P = <0.001), tumor necrosis factor-α (P = 0.008), and monocyte chemoattractant protein (P = 0.01) were increased after transfusion. A similar elevation in markers of endothelial activation was seen after transfusion with increased plasma macrophage inhibitory factor (P = 0.005) and soluble intracellular adhesion molecule-1 (P = <0.001).Conclusion:Production of inflammatory cytokines and immunoactivation of the endothelium observed after the transfusion of PRBCs in the preterm infant may be a manifestation of TRIM. The implications of this emerging phenomenon within the preterm neonatal population warrant further investigation.

Early cerebral oxygen extraction and the risk of death or sonographic brain injury in very preterm infants.

OBJECTIVE To evaluate the relationship between cerebral fractional tissue oxygen extraction (cFTOE), a measure of oxygen delivery-consumption equilibrium, and the risk of early poor outcome in very preterm infants. STUDY DESIGN Cerebral blood flow, tissue oxygenation index (by near-infrared spectroscopy), and arterial oxygen content were measured, and cerebral oxygen delivery, consumption, and cFTOE were calculated at 3 intervals in the first 72 hours of life in infants ≤ 30 weeks gestational age (GA). A receiver operating characteristic curve was derived with an a priori defined dichotomized outcome of good or poor, defined as death or sonographic brain injury (grade ≥ II intraventricular hemorrhage) by day 7. RESULTS Seventy-one infants were enrolled, with a mean (SD) GA of 27 (2) weeks. cFTOE demonstrated better discrimination for the study outcome at <24 hours of age than at 48 or 72 hours of age (P = .01). The area under the curve for cFTOE at the initial measurement was no different from that for GA alone (0.87; 95% CI, 0.77-0.95 vs 0.81; 95% CI, 0.69-0.92), but the combined measure of cFTOE and GA had better discrimination (0.96; 95% CI, 0.91-1.0) than either cFTOE (P = .03) or GA (P = .016) alone. A cFTOE of 0.4 had a sensitivity of 82% and specificity of 75% for risk of early poor outcome. CONCLUSION Elevated cFTOE values are associated with increased risk of early poor outcome in very preterm infants. Its predictive value is further improved with the addition of GA.

Australasian randomised trial to evaluate the role of maternal intramuscular dexamethasone versus betamethasone prior to preterm birth to increase survival free of childhood neurosensory disability (A*STEROID): study protocol

AbstractBackgroundBoth dexamethasone and betamethasone, given to women at risk of preterm birth, substantially improve short-term neonatal health, increase the chance of the baby being discharged home alive, and reduce childhood neurosensory disability, remaining safe into adulthood. However, it is unclear which corticosteroid is of greater benefit to mother and child.This study aims to determine whether giving dexamethasone to women at risk of preterm birth at less than 34 weeks’ gestation increases the chance of their children surviving free of neurosensory disability at two years’ corrected age, compared with betamethasone.Methods/DesignDesign randomised, multicentre, placebo controlled trial. Inclusion criteria women at risk of preterm birth at less than 34 weeks’ gestation with a singleton or twin pregnancy and no contraindications to the use of antenatal corticosteroids and who give informed consent. Trial entry & randomisation at telephone randomisation eligible women will be randomly allocated to either the dexamethasone group or the betamethasone group, allocated a study number and corresponding treatment pack. Study groups women in the dexamethasone group will be administered two syringes of 12 mg dexamethasone (dexamethasone sodium phosphate) and women in the betamethasone group will be administered two syringes of 11.4 mg betamethasone (Celestone Chronodose). Both study groups consist of intramuscular treatments 24 hours apart. Primary study outcome death or any neurosensory disability measured in children at two years’ corrected age. Sample size a sample size of 1449 children is required to detect either a decrease in death or any neurosensory disability from 27.0% to 20.1% with dexamethasone compared with betamethasone, or an increase from 27.0% to 34.5% (two-sided alpha 0.05, 80% power, 5% loss to follow up, design effect 1.2).DiscussionThis study will provide high-level evidence of direct relevance for clinical practice. If one drug clearly results in significantly fewer deaths and fewer disabled children then it should be used consistently in women at risk of preterm birth and would be of great importance to women at risk of preterm birth, their children, health services and communities.Trial registrationTrial registration number: ACTRN12608000631303

Does non-transferrin bound iron contribute to transfusion related immune-modulation in preterms?

Objective There is increasing awareness that allogeneic transfusion is potentially harmful in preterm neonates secondary to transfusion related immunomodulation (TRIM). Non-transferrin bound iron (NTBI) may contribute to TRIM by promoting oxidative damage and pro-inflammatory cytokine release. The current study aimed to determine if transfusion early in the neonatal period resulted in an increase in circulating NTBI, oxidative stress and immune activation. Design Prospective observational study. Setting One transfusion event was studied in infants ≤28 weeks gestation between 2 and 6 weeks postnatal age (n=33) admitted to a tertiary neonatal intensive care unit. Methods Serum NTBI, inflammatory cytokines and malondialdehyde (MDA) were measured from the donor pack, prior to and at 2–4 and 24 h post-transfusion. Results Median (range) age at transfusion was 17 (14–39) days with the pretransfusion haemoglobin level 9.6 (7.4–10.4) g/dl. NTBI was detectable in 18 (51%) of the transfusion packs. NTBI levels were higher after transfusion (p<0.01) returning to pretransfusion levels by 24 h. Post-transfusion NTBI level correlated with the age of transfused blood (p<0.001) and was positively correlated with plasma MDA (p=0.01) but not IL-1β, IL-6, IL8 or TNFα. Conclusions Circulating NTBI is transiently elevated following blood transfusion in preterm newborns. This increase was related to the age of blood transfused and correlated with increases in oxidative stress but not pro-inflammatory cytokines. While further studies are necessary to determine whether these transient effects influence clinical outcome, the current data do not support a significant role in the very preterm neonate for NTBI in TRIM.

Intrauterine inflammation, cerebral oxygen consumption and susceptibility to early brain injury in very preterm newborns

Background In utero exposure to inflammation results in elevated cerebral oxygen consumption. This increased metabolic demand may contribute to the association between chorioamnionitis and intraventricular haemorrhage (P/IVH). We hypothesised that intrauterine inflammation imposes an elevated cerebral metabolic load and increased fractional oxygen extraction (cFTOE) with cFTOE further increased in the presence of early P/IVH. Methods Eighty-three infants ≤30 weeks gestation were recruited. Exposure to intrauterine inflammation was determined by placental histology. Total internal carotid blood flow (Doppler ultrasound) and near infrared spectroscopy were measured and cerebral oxygen delivery (mcerbDO2), consumption (mcerbVO2) and cFTOE were calculated on days 1 and 3 of life. Primary outcome was defined as death or P/IVH >grade II (cranial sonograph) by day 3. Results Infants exposed to intrauterine inflammation had higher total internal carotid blood flow (92 vs 63 mL/kg/min) and mcerbDO2 (13.7 vs 10.1 mL/kg/min) than those not exposed to inflammation. Newborns with P/IVH had both higher oxygen consumption and extraction compared with those without sonographic injury regardless of exposure to intrauterine inflammation. Further, in preterms exposed to inflammation, those with P/IVH had higher consumption (6.1 vs 4.8 mL/kg/min) and extraction than those without injury. These differences were observed only on day 1 of life. Conclusions Although P/IVH is multifactorial in preterm newborns, it is likely that cerebral hypoxic-ischaemia plays a central pathophysiological role. These data provide a mechanistic insight into this process and suggests that the increased cerebral metabolic load imposed by the presence of inflammation results in a higher risk of critical hypoxic ischaemia in the preterm with increased susceptibility to significant P/IVH.

Hypothermia: A Neuroprotective Therapy for Neonatal Hypoxic-Ischemic Encephalopathy

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Effects of antenatal magnesium sulfate treatment for neonatal neuro-protection on cerebral oxygen kinetics

Background:The underlying neuro-protective mechanisms of antenatal magnesium sulfate (MgSO4) in infants born preterm remain poorly understood. Early neonatal brain injury may be preceded by low cerebral blood flow (CBF) and elevated cerebral fractional tissue oxygen extraction (cFTOE). This study investigated the effect of antenatal MgSO4 on cerebral oxygen delivery, consumption, and cFTOE in preterm infants.Methods:CBF and tissue oxygenation index were measured, and oxygen delivery, consumption, and cFTOE calculated within 24 h of birth and at 48 and 72 h of life in 36 infants ≤ 30 wk gestation exposed to MgSO4 and 29 unexposed infants.Results:Total internal carotid blood flow and cerebral oxygen delivery did not differ between the groups at the three study time-points. Cerebral oxygen consumption and cFTOE were lower in infants exposed to antenatal MgSO4 (P = 0.012) compared to unexposed infants within 24 h of delivery. This difference was not evident by 48 h of age. Fewer infants in the MgSO4 group developed P/IVH by 72 h of age (P = 0.03).Conclusion:Infants exposed to MgSO4 had similar systemic and cerebral hemodynamics but lower cFTOE compared to nonexposed. These findings suggest reduced cerebral metabolism maybe a component of the neuro-protective actions of antenatal MgSO4.

Vitamin D in preterm infants: A prospective observational study

Preterm infants are at increased risk of vitamin D deficiency as a result of both maternal deficiency and inadequate supplementation. The quantity and effectiveness of vitamin D supplementation in preterm infants are unclear. The aim of this study was to evaluate the natural history of vitamin D status in preterm infants and the effectiveness of the hospitals nutritional practices in meeting current supplementation recommendations.