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[FG] Schulzke Sven

Projects & Collaborations

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Predictive value of heart rate variability on cardiorespiratory events of preterm infants routinely immunised in the hospital

Research Project  | 2 Project Members

Preterm birth is a major challenge of health care systems across the globe, affecting about 10% of all infants born worldwide, resulting in almost 13 million preterm births per year. The autonomic nervous system of preterm infants is characterized by instability of heart rate and breathing, requiring continuous monitoring of vital signs over several months and long-term respiratory support. Cardiorespiratory events due to this instability, summarised under the term 'apnoea of prematurity' (AOP), affect at least 80% of very preterm infants born before 32 weeks of gestation. AOP may lead to severe hypoxaemia requiring immediate resuscitation and recent data show that repetitive episodes of AOP increase the risk of post-discharge death and long-term neurodevelopmental impairment. Most importantly, severity and frequency of AOP may drastically increase upon challenging the autonomic system by routine immunisation. It is, however, very important to provide timely immunisation and establish early immunity against typical vaccine-preventable diseases in preterm infants as they are particularly vulnerable to complications arising from those diseases. Current recommendations are to initially immunise preterm infants in the hospital under continuous monitoring of vital signs if the treating physician considers an infant to be at risk of post-immunisation AOP. However, there are no objective criteria to predict post-immunisation AOP. Although the first immunisation of very preterm infants typically takes place in the hospital under continuous monitoring of vital signs, immunisations of infants at risk of AOP are often delayed due to fear of AOP or may be initiated in non-intensive care settings (normal wards) where adequate respiratory support cannot be provided but may be needed due to post-immunisation AOP. Also, due to an international trend of early discharge home of preterm infants, immunisations may be arranged in the rooms of the family paediatrician without further monitoring of vital signs and no specific knowledge of the individual risk of post-immunisation AOP. Thus, developing of new biomarkers and objective criteria to better understand and assess the risk of post-immunisation AOP is urgently needed. We recently developed a systematic quality control algorithm for assessing heart rate variability data in a standardised manner and demonstrated that the sample entropy (SampEn) of interbeat intervals, a parameter of heart rate variability derived from nonlinear time series analysis, predicts cardiorespiratory stability in preterm infants. SampEn reflects the regularity of heart rate and the presence of spikes in a given time series of heart beats and has been validated to be a reliable predictor of incipient events such as sepsis. SampEn of heart rate can be obtained non-invasively from electrocardiogram monitors, which are routinely used to monitor preterm infants immunised in the hospital. We aim to evaluate whether real-time calculation of SampEn at a) 32 and 36 weeks corrected age, b) upon primary routine immunisation in the hospital, c) at discharge from the hospital after initial prematurity-related hospital stay, and d) on readmission for immunisation in the hospital based on previous post-immunisation AOP or referral of the family paediatrician has prognostic utility for the risk of post-immunisation AOP in very preterm infants. We will further assess whether immunisation itself initiates a step response in SampEn and compare SampEn values from preterm infants to those of term healthy infants to study maturational effects. The biomarker SampEn provides a unique opportunity to objectively prognosticate autonomic stability with the goal of optimising risk stratification and establishing timely immunisation in preterm infants. Such real-time display of SampEn thus could become a valuable tool to better understand autonomic regulation in preterm infants and guide physicians in providing an optimal level of care for immunisation based on personalised risk assessment in order to provide an adequate setting and staffing. This approach combines both novel scientific aspects on prognostic value of nonlinear time series analysis and pragmatic utility of SampEn for decision-making on within hospital risk-stratification and necessity of readmission for immunisation.

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Erythropoietin for the repair of cerebral injury in very preterm infants (EpoRepair)

Research Project  | 3 Project Members

Survival of premature infants has improved over the past decades, but neurodevelopmental outcome did not. One of the most consistent predictors of long-term developmental disabilities in preterm infants is brain injury, namely intraventricular haemorrhage (IVH) or periventricular haemorrhagic infarction (PVHI). Recombinant erythropoietin (rEPO) enhances repair in a variety of animal models with brain injury. Observational data suggest that rEPO improves long-term cognitive outcome in infants with IVH/PVHI. Recent magnetic resonance imaging (MRI) studies of our group revealed improved white matter (WM) development of high-dose rEPO given with a preventive strategy to preterm infants immediately after birth. Based on these findings we designed a new randomized control trial (RCT) following a therapeutic strategy to investigate rEPO in preterm infants with established IVH/PVHI. Working hypotheses: High dose rEPO treatment after IVH/PVHI compared with control treatment (placebo) leads to: (1) increased neuronal regeneration, restored neuronal integrity, and decreased brain injury; (2) improved short- and long-term neurodevelopment.Specific aims, objectives: (1) to determine the effect of rEPO on brain development in preterm infants with established brain damage, namely IVH/PVHI; (2) to understand the mechanisms of rEPO on brain development and neuronal integrity; (3) to improve cognitive abilities and motor function in those infants treated with rEPO.Experimental methods: (1) Execution of an investigator initiated, randomized, double blind, and multicentre trial of high-dose rEPO in very preterm infants suffering from IVH/PVHI (www.eporepair.ch). (2) Quantifying axonal injury in blood samples, sleep-wake-cycling by aEEG and brain MRI at term equivalent age (TEA) to assess brain growth and development, brain injury and functional network connectivity. (3) Standardized neurological and formal psychological examinations at various time points up to five years of age.Expected value of project: Since there is no specific treatment to ameliorate the neurodevelopmental sequelae of IVH/PVHI in preterm infants, this RCT is the first to test prospectively a promising drug in infants with IVH/PVHI. Recent MRI results showing improved WM development and less WM injuries in preterm infants who received prophylactic rEPO will be verified and MRI sequences, in order to assess functional connectivity, will be acquired.

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Impact of early maturation, immunisation and caffeine on control of breathing in preterm infants with and without chronic lung disease

Research Project  | 1 Project Members

This study aims to provide further insight into the early maturation of respiratory control in infants born preterm. In addition, quanitification of breathing regulation in preterm infants with and without chronic lung disease using new analytical techniques may give improved insight into the impact that CLDI has upon this process. Examination of the impact of two common interventions known to affect respiratory control (i.e. caffeine administration and immunisation) may provide a mechanism for quantifying control impairments in infants affected by CLDI. Early identification of those infants most at risk for abnormal control may prove useful in assessing the necessity for ongoing clinical monitoring during the pre- and post-discharge care of infants born preterm.

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Physiological deadspace measurements in ventilated preterm infants

Research Project  | 1 Project Members

Should ventilator target tidal volumes be adjusted for gestational age? Authors: Roland Neumann, roland.neumann@health.wa.gov.au1, Alexander Larcombe, alexanderl@ichr.uwa.edu.au2, Graham Hall, graham.hall@health.wa.gov.au2,3, J. Jane Pillow, jpillow@meddent.uwa.edu.au4, Sven Schulzke, sven.schulzke@health.wa.gov.au1,4. Author Affiliations: 1King Edward Memorial Hospital and 2Telethon Institute for Child Health Research Perth, Australia; 3School of Paediatrics and Child Health and 4School of Women s and Infants Health, University of Western Australia, Perth, Australia. Background: Preterm infants are susceptible to volutrauma, but lung volumes capacities may vary. The relationship between gestation and the alveolar deadspace and tidal volumes is unknown. Aims: To measure Vd,MM on day 1 of life in ventilated very preterm infants. We hypothesized that after adjusting for set target tidal volume on the ventilator ( volume guarantee ) and respiratory rate, the ratio of alveolar to total tidal volume (Valv/VT) increases with gestational age at birth. Methods: 120 s of tidal breathing was recorded from unsedated, sleeping preterm infants (n=43; gestation 23-31 w, mean (SD) birth weight 1.1 (0.4) kg, postnatal age 14.3 (7.2) h) receiving patient-triggered ventilation (Babylog 8000 plus, Draeger Medical, Luebeck, Germany) using a mainstream ultrasonic flowmeter (Spiroson Exhalyzer D, Ecomedics AG, CH). Airway deadspace was calculated from the molar mass signal (Vd,MM). Alveolar volume (Valv) was calculated as VT Vd,MM. Arterial blood gases were obtained immediately after lung function testing. Multiple linear regression was used to analyse outcomes. Results: Mean (SD) values for Vd,MM, VT, and Valv/VT were 2.51 (0.61) mL/kg, 6.57 (1.54) mL/kg, and 0.62 (0.06) respectively. Mean (SD) arterial PaCO2 was 42.9 (5.8) mmHg. Valv/VT was positively associated with gestational age (R2 = 0.26, p = 0.012) after adjusting for set volume guarantee (range 3.8-5.1 mL/kg) and respiratory rate. Conclusions: In ventilated very preterm infants, Valv/VT on day 1 increases with gestational age. Ventilator target tidal volumes should be adjusted for maturity as well as body size at birth to avoid potential alveolar overdistension.