Cornelia Hagmann

Therapeutic hypothermia for birth asphyxia in low-resource settings: a pilot randomised controlled trial

This letter describes a study done at Mulago Hospital Kampala Uganda aimed at determining the feasibility of whole-body cooling by use of simple methods in a low-resource setting. The study performed after written informed parental consent randomly assigned standard care plus therapeutic hypothermia or standard care alone on infants within 3 hours of birth. Data suggests that therapeutic hypothermia with whole-body cooling screening informed consent and randomisation are feasible and inexpensive in a special-care baby unit in a low-resource setting. Rigorous randomised trials to determine the safety and efficacy of therapeutic hypothermia in this context are urgently needed so that any benefi ts of this novel therapy can reach areas of the world that might need it most. (excerpt)

Cerebral near infrared spectroscopy oximetry in extremely preterm infants : Phase II randomised clinical trial

Objective To determine if it is possible to stabilise the cerebral oxygenation of extremely preterm infants monitored by cerebral near infrared spectroscopy (NIRS) oximetry. Design Phase II randomised, single blinded, parallel clinical trial. Setting Eight tertiary neonatal intensive care units in eight European countries. Participants 166 extremely preterm infants born before 28 weeks of gestation: 86 were randomised to cerebral NIRS monitoring and 80 to blinded NIRS monitoring. The only exclusion criterion was a decision not to provide life support. Interventions Monitoring of cerebral oxygenation using NIRS in combination with a dedicated treatment guideline during the first 72 hours of life (experimental) compared with blinded NIRS oxygenation monitoring with standard care (control). Main outcome measures The primary outcome measure was the time spent outside the target range of 55-85% for cerebral oxygenation multiplied by the mean absolute deviation, expressed in %hours (burden of hypoxia and hyperoxia). One hour with an oxygenation of 50% gives 5%hours of hypoxia. Secondary outcomes were all cause mortality at term equivalent age and a brain injury score assessed by cerebral ultrasonography. Randomisation Allocation sequence 1:1 with block sizes 4 and 6 in random order concealed for the investigators. The allocation was stratified for gestational age (<26 weeks or ≥26 weeks). Blinding Cerebral oxygenation measurements were blinded in the control group. All outcome assessors were blinded to group allocation. Results The 86 infants randomised to the NIRS group had a median burden of hypoxia and hyperoxia of 36.1%hours (interquartile range 9.2-79.5%hours) compared with 81.3 (38.5-181.3) %hours in the control group, a reduction of 58% (95% confidence interval 35% to 73%, P<0.001). In the experimental group the median burden of hypoxia was 16.6 (interquartile range 5.4-68.1) %hours, compared with 53.6 (17.4-171.3) %hours in the control group (P=0.0012). The median burden of hyperoxia was similar between the groups: 1.2 (interquartile range 0.3-9.6) %hours in the experimental group compared with 1.1 (0.1-23.4) %hours in the control group (P=0.98). We found no statistically significant differences between the two groups at term corrected age. No severe adverse reactions were associated with the device. Conclusions Cerebral oxygenation was stabilised in extremely preterm infants using a dedicated treatment guideline in combination with cerebral NIRS monitoring. Trial registration ClinicalTrial.gov NCT01590316.

Association between early administration of high-dose erythropoietin in preterm infants and brain MRI abnormality at term-equivalent age.

IMPORTANCE Premature infants are at risk of developing encephalopathy of prematurity, which is associated with long-term neurodevelopmental delay. Erythropoietin was shown to be neuroprotective in experimental and retrospective clinical studies. OBJECTIVE To determine if there is an association between early high-dose recombinant human erythropoietin treatment in preterm infants and biomarkers of encephalopathy of prematurity on magnetic resonance imaging (MRI) at term-equivalent age. DESIGN, SETTING, AND PARTICIPANTS A total of 495 infants were included in a randomized, double-blind, placebo-controlled study conducted in Switzerland between 2005 and 2012. In a nonrandomized subset of 165 infants (n=77 erythropoietin; n=88 placebo), brain abnormalities were evaluated on MRI acquired at term-equivalent age. INTERVENTIONS Participants were randomly assigned to receive recombinant human erythropoietin (3000 IU/kg; n=256) or placebo (n=239) intravenously before 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth. MAIN OUTCOMES AND MEASURES The primary outcome of the trial, neurodevelopment at 24 months, has not yet been assessed. The secondary outcome, white matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method. The resulting white matter injury and gray matter injury scores were categorized as normal or abnormal according to thresholds established in the literature by correlation with neurodevelopmental outcome. RESULTS At term-equivalent age, compared with untreated controls, fewer infants treated with recombinant human erythropoietin had abnormal scores for white matter injury (22% [17/77] vs 36% [32/88]; adjusted risk ratio [RR], 0.58; 95% CI, 0.35-0.96), white matter signal intensity (3% [2/77] vs 11% [10/88]; adjusted RR, 0.20; 95% CI, 0.05-0.90), periventricular white matter loss (18% [14/77] vs 33% [29/88]; adjusted RR, 0.53; 95% CI, 0.30-0.92), and gray matter injury (7% [5/77] vs 19% [17/88]; adjusted RR, 0.34; 95% CI, 0.13-0.89). CONCLUSIONS AND RELEVANCE In an analysis of secondary outcomes of a randomized clinical trial of preterm infants, high-dose erythropoietin treatment within 42 hours after birth was associated with a reduced risk of brain injury on MRI. These findings require assessment in a randomized trial designed primarily to assess this outcome as well as investigation of the association with neurodevelopmental outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00413946.

Brain volumes predict neurodevelopment in adolescents after surgery for congenital heart disease

Patients with complex congenital heart disease are at risk for neurodevelopmental impairments. Evidence suggests that brain maturation can be delayed and pre- and postoperative brain injury may occur, and there is limited information on the long-term effect of congenital heart disease on brain development and function in adolescent patients. At a mean age of 13.8 years, 39 adolescent survivors of childhood cardiopulmonary bypass surgery with no structural brain lesions evident through conventional cerebral magnetic resonance imaging and 32 healthy control subjects underwent extensive neurodevelopmental assessment and cerebral magnetic resonance imaging. Cerebral scans were analysed quantitatively using surface-based and voxel-based morphometry. Compared with control subjects, patients had lower total brain (P = 0.003), white matter (P = 0.004) and cortical grey matter (P = 0.005) volumes, whereas cerebrospinal fluid volumes were not different. Regional brain volume reduction ranged from 5.3% (cortical grey matter) to 11% (corpus callosum). Adolescents with cyanotic heart disease showed more brain volume loss than those with acyanotic heart disease, particularly in the white matter, thalami, hippocampi and corpus callosum (all P-values < 0.05). Brain volume reduction correlated significantly with cognitive, motor and executive functions (grey matter: P < 0.05, white matter: P < 0.01). Our findings suggest that there are long-lasting cerebral changes in adolescent survivors of cardiopulmonary bypass surgery for congenital heart disease and that these changes are associated with functional outcome.

Artifacts on electroencephalograms may influence the amplitude-integrated EEG classification: a qualitative analysis in neonatal encephalopathy.

This is a case report and a descriptive study demonstrating that artifacts are common during long-term recording of amplitude-integrated electroencephalograms and may lead to erroneous classification of the amplitude-integrated electroencephalogram trace. Artifacts occurred in 12% of 200 hours of recording time sampled from a representative sample of 20 infants with neonatal encephalopathy. Artifacts derived from electrical or movement interference occurred with similar frequency; both types of artifacts influenced the voltage and width of the amplitude-integrated electroencephalogram band. This is important knowledge especially if amplitude-integrated electroencephalogram is used as a selection tool for neuroprotection intervention studies.

The SafeBoosC Phase II Randomised Clinical Trial: A Treatment Guideline for Targeted Near-Infrared-Derived Cerebral Tissue Oxygenation versus Standard Treatment in Extremely Preterm Infants

Near-infrared spectroscopy-derived regional tissue oxygen saturation of haemoglobin (rStO2) reflects venous oxygen saturation. If cerebral metabolism is stable, rStO2 can be used as an estimate of cerebral oxygen delivery. The SafeBoosC phase II randomised clinical trial hypothesises that the burden of hypo- and hyperoxia can be reduced by the combined use of close monitoring of the cerebral rStO2 and a treatment guideline to correct deviations in rStO2 outside a predefined target range. Aims: To describe the rationale for and content of this treatment guideline. Methods: Review of the literature and assessment of the quality of evidence and the grade of recommendation for each of the interventions. Results and Conclusions: A clinical intervention algorithm based on the main determinants of cerebral perfusion-oxygenation changes during the first hours after birth was generated. The treatment guideline is presented to assist neonatologists in making decisions in relation to cerebral oximetry readings in preterm infants within the SafeBoosC phase II randomised clinical trial. The evidence grades were relatively low and the guideline cannot be recommended outside a research setting.

T2 at MR Imaging Is an Objective Quantitative Measure of Cerebral White Matter Signal Intensity Abnormality in Preterm Infants at Term-equivalent Age

PURPOSE To compare quantitative T2 relaxometry of cerebral white matter (WM) with qualitative assessment of conventional T2-weighted magnetic resonance (MR) images, to assess the relationship between cerebral WM T2 and region-specific apparent diffusion coefficient (ADC), and to examine WM T2 regional variation in preterm infants at term. MATERIALS AND METHODS The local ethical committee granted ethical permission for this study; informed parental consent was obtained for each infant. Sixty-two preterm infants born at less than 32 weeks gestation and nine control infants were examined at 1.5 T; T2-weighted fast spin-echo MR images, T2 relaxometry data, and diffusion-weighted MR images were acquired. Conventional T2-weighted MR images were assessed by a pediatric neuroradiologist for diffuse excessive high signal intensity (DEHSI) in WM. Regions of interest were positioned in frontal WM, central WM, and posterior WM at the level of the centrum semiovale. RESULTS In preterm infants at term, T2 was longer in all WM regions than in control infants; in infants with DEHSI, T2 was longer than in infants without DEHSI and control infants, with posterior WM T2 being longer than central or frontal WM T2. In control infants, T2 was similar in all WM regions. Frontal and posterior WM ADCs were higher in preterm infants at term than in control infants. CONCLUSION Cerebral WM T2 is an objective quantitative measurement that can easily and rapidly be obtained during clinical MR imaging in preterm infants at term.

Severe Congenital Heart Defects Are Associated with Global Reduction of Neonatal Brain Volumes

OBJECTIVES To determine neonatal global and regional brain volumes in infants with congenital heart disease (CHD) in comparison with healthy controls and to determine brain growth. STUDY DESIGN Prospective cohort study in infants undergoing open-heart surgery for complex CHD. Global and regional volumetric measurements on preoperative cerebral magnetic resonance imaging were manually segmented in children without overt brain lesions. RESULTS Preoperative brain volumetry of 19 patients demonstrates reduction in total and regional brain volumes, without any specific regional predilection compared with 19 healthy control infants (total brain volume reduction: 21%, regional brain volume reduction 8%-28%, all P < .001). CONCLUSIONS Infants with CHD undergoing bypass surgery have smaller brain volumes prior to surgery without a specific regional predilection. This suggests a fetal origin of reduced brain growth.

MRI in fetal necropsy

The fetal autopsy involves a series of investigations of the corpse, most of which are noninvasive and acceptable to the majority of parents and their physicians. The value of the perinatal autopsy is manyfold and well established, and the results can provide a basis for parental and family counseling, inform future obstetric management, and provide audit for prenatal care. Many techniques originally developed for diagnosis, such as histology, biochemical tests, photography, x‐rays, and cytogenetic karyotyping, have become standard tools in perinatal autopsies. However, there has been an inexorable decline in the autopsy consent rate over the last 30 years due to social and cultural factors, and perhaps ignorance of the benefits to be derived from the examination. Growing evidence suggests that postmortem fetal MRI can assist the pathologist at autopsy, and in many cases can obviate the need for dissection or at least minimize and focus it. For the majority of cases in which no consent for surgical autopsy is given, MRI together with other noninvasive postmortem tests can provide a great deal of the information that was previously available only from autopsy. J. Magn. Reson. Imaging 2006.

The SafeBoosC II randomized trial : Treatment guided by near-infrared spectroscopy reduces cerebral hypoxia without changing early biomarkers of brain injury

Background:The SafeBoosC phase II multicentre randomized clinical trial investigated the benefits and harms of monitoring cerebral oxygenation by near-infrared spectroscopy (NIRS) combined with an evidence-based treatment guideline vs. no NIRS data and treatment as usual in the control group during the first 72 h of life. The trial demonstrated a significant reduction in the burden of cerebral hypoxia in the experimental group. We now report the blindly assessed and analyzed treatment effects on electroencephalographic (EEG) outcomes (burst rate and spectral edge frequency 95% (SEF95)) and blood biomarkers of brain injury (S100β, brain fatty acid-binding protein, and neuroketal).Methods:One hundred and sixty-six extremely preterm infants were randomized to either experimental or control group. EEG was recorded at 64 h of age and blood samples were collected at 6 and 64 h of age.Results:One hundred and thirty-three EEGs were evaluated. The two groups did not differ regarding burst rates (experimental 7.2 vs. control 7.7 burst/min) or SEF95 (experimental 18.1 vs. control 18.0 Hz). The two groups did not differ regarding blood S100β, brain fatty acid-binding protein, and neuroketal concentrations at 6 and 64 h (n = 123 participants).Conclusion:Treatment guided by NIRS reduced the cerebral burden of hypoxia without affecting EEG or the selected blood biomarkers.