Publications by authors named "David G Tingay"

80 Publications

Extubation generates lung volume inhomogeneity in preterm infants.

Arch Dis Child Fetal Neonatal Ed 2021 Jun 23. Epub 2021 Jun 23.

Newborn Research, The Royal Women's Hospital, Parkville, Victoria, Australia.

Objective: To evaluate the feasibility of electrical impedance tomography (EIT) to describe the regional tidal ventilation (V) and change in end-expiratory lung volume (EELV) patterns in preterm infants during the process of extubation from invasive to non-invasive respiratory support.

Design: Prospective observational study.

Setting: Single-centre tertiary neonatal intensive care unit.

Patients: Preterm infants born <32 weeks' gestation who were being extubated to nasal continuous positive airway pressure as per clinician discretion.

Interventions: EIT measurements were taken in supine infants during elective extubation from synchronised positive pressure ventilation (SIPPV) before extubation, during and then at 2 and 20 min after commencing nasal continuous positive applied pressure (nCPAP). Extubation and pressure settings were determined by clinicians.

Main Outcome Measures: Global and regional ΔEELV and ΔV, heart rate, respiratory rate and oxygen saturation were measured throughout.

Results: Thirty infants of median (range) 2 (1, 21) days were extubated to a median (range) CPAP 7 (6, 8) cm HO. SpO/FiO ratio was a mean (95% CI) 50 (35, 65) lower 20 min after nCPAP compared with SIPPV. EELV was lower at all points after extubation compared with SIPPV, and EELV loss was primarily in the ventral lung (p=0.04). V was increased immediately after extubation, especially in the central and ventral regions of the lung, but the application of nCPAP returned V to pre-extubation patterns.

Conclusions: EIT was able to describe the complex lung conditions occurring during extubation to nCPAP, specifically lung volume loss and greater use of the dorsal lung. EIT may have a role in guiding peri-extubation respiratory support.
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http://dx.doi.org/10.1136/archdischild-2021-321788DOI Listing
June 2021

Time to Lung Volume Stability After Pressure Change During High-Frequency Oscillatory Ventilation.

Crit Care Explor 2021 Jun 14;3(6):e0432. Epub 2021 Jun 14.

Neonatal Research, Murdoch Children's Research Institute, Parkville, VIC, Australia.

Clinicians have little guidance on the time needed before assessing the effect of a mean airway pressure change during high-frequency oscillatory ventilation. We aimed to determine: 1) time to stable lung volume after a mean airway pressure change during high-frequency oscillatory ventilation and 2) the relationship between time to volume stability and the volume state of the lung.

Design: Prospective observational study.

Setting: Regional quaternary teaching hospital neonatal ICU.

Patients: Thirteen term or near-term infants receiving high-frequency oscillatory ventilation and muscle relaxants.

Interventions: One to two cm HO mean airway pressure changes every 10 minutes as part of an open lung strategy based on oxygen response.

Measurements And Main Results: Continuous lung volume measurements (respiratory inductive plethysmography) were made during the mean airway pressure changes. Volume signals were analyzed with a biexponential model to calculate the time to stable lung volume if the model was greater than 0.6. If volume stability did not occur within 10 minutes, the model was extrapolated to maximum 3,600 s. One-hundred ninety-six mean airway pressure changes were made, with no volume change in 33 occurrences (17%). One-hundred twenty-five volume signals met modeling criteria for inclusion; median (interquartile range) , 0.96 (0.91-0.98). The time to stable lung volume was 1,131 seconds (718-1,959 s) (mean airway pressure increases) and 647 seconds (439-1,309 s) (mean airway pressure decreases), with only 17 (14%) occurring within 10 minutes and time to stability being longer when the lung was atelectatic.

Conclusions: During high-frequency oscillatory ventilation, the time to stable lung volume after a mean airway pressure change is variable, often requires more than 10 minutes, and is dependent on the preceding volume state.
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http://dx.doi.org/10.1097/CCE.0000000000000432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205213PMC
June 2021

Hemidiaphragmatic paralysis related to extravasation of parenteral solution in very low birthweight neonates.

BMJ Case Rep 2021 May 27;14(5). Epub 2021 May 27.

Neonatal Inetnsive Care, University of Alberta, Edmonton, Alberta, Canada

Central venous catheter (CVC) placement is common in the care of very low birthweight (VLBW) preterm neonates. Although it is generally considered to be safe, CVC placement is associated with complications, including extravasation that may lead to significant morbidity and mortality. We report the clinical course of an extremely preterm neonate born at 27 weeks gestation, and another 5 VLBW preterm neonates reported in the literature with hemidiaphragmatic paralysis related to extravasation of parenteral solution from CVC placement. In VLBW preterm neonates, spontaneous recovery of diaphragmatic paralysis related to extravasation of parenteral solution is possible.
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http://dx.doi.org/10.1136/bcr-2021-242390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162068PMC
May 2021

Personalized Medicine for the Management of RDS in Preterm Neonates.

Neonatology 2021 18;118(2):127-138. Epub 2021 Mar 18.

Division of Neonatology, "G. Salesi" Women and Children Hospital, Polytechnical University of Marche, Ancona, Italy.

Continuous positive airway pressure and surfactant represent the first- and second-line treatment for respiratory distress syndrome in preterm neonates, as European and American guidelines, since 2013 and 2014, respectively, started to recommend surfactant replacement only when continuous positive airway pressure fails. These recommendations, however, are not personalized to the individual physiopathology. Simple clinical algorithms may have improved the diffusion of neonatal care, but complex medical issues can hardly be addressed with simple solutions. The treatment of respiratory distress syndrome is a complex matter and can be only optimized with personalization. We performed a review of tools to individualize the management of respiratory distress syndrome based on physiopathology and actual patients' need, according to precision medicine principles. Advanced oxygenation metrics, lung ultrasound, electrical impedance tomography, and both quantitative and qualitative surfactant assays were examined. When these techniques were investigated with diagnostic accuracy studies, reliability measures have been meta-analysed. Amongst all these tools, quantitative lung ultrasound seems the more developed for the widespread use and has a higher diagnostic accuracy (meta-analytical AUC = 0.952 [95% CI: 0.951-0.953]). Surfactant adsorption (AUC = 0.840 [95% CI: 0.824-0.856]) and stable microbubble test (AUC = 0.800 [95% CI: 0.788-0.812]) also have good reliability, but need further industrial development. We advocate for a more accurate characterization and a personalized approach of respiratory distress syndrome. With the above-described currently available tools, it should be possible to personalize the treatment of respiratory distress syndrome according to physiopathol-ogy.
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http://dx.doi.org/10.1159/000513783DOI Listing
August 2021

The impact of steady streaming and conditional turbulence on gas transport during high-frequency ventilation.

Theor Comput Fluid Dyn 2021 Feb 15:1-27. Epub 2021 Feb 15.

Faculty of Science, Engineering and Technology, Swinburne University of Technology, Melbourne, VIC 3122 Australia.

High-frequency ventilation is a type of mechanical ventilation therapy applied on patients with damaged or delicate lungs. However, the transport of oxygen down, and carbon dioxide up, the airway is governed by subtle transport processes which hitherto have been difficult to quantify. We investigate one of these mechanisms in detail, nonlinear mean streaming, and the impact of the onset of turbulence on this streaming, via direct numerical simulations of a model 1:2 bifurcating pipe. This geometry is investigated as a minimal unit of the fractal structure of the airway. We first quantify the amount of gas recirculated via mean streaming by measuring the recirculating flux in both the upper and lower branches of the bifurcation. For conditions modeling the trachea-to-bronchi bifurcation of an infant, we find the recirculating flux is of the order of 3-5% of the peak flux . We also show that for conditions modeling the upper generations, the mean recirculation regions extend a significant distance away from the bifurcation, certainly far enough to recirculate gas between generations. We show that this mean streaming flow is driven by the formation of longitudinal vortices in the flow leaving the bifurcation. Second, we show that conditional turbulence arises in the upper generations of the airway. This turbulence appears only in the flow leaving the bifurcation, and at a point in the cycle centered around the maximum instantaneous flow rate. We hypothesize that its appearance is due to an instability of the longitudinal-vortices structure.
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http://dx.doi.org/10.1007/s00162-020-00559-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883339PMC
February 2021

Lung Ultrasound in Early Preterm Life: A Window into the Future?

Am J Respir Crit Care Med 2021 06;203(11):1338-1339

Neonatology/Pulmonary Biology Cincinnati Children's Hospital Cincinnati, Ohio and.

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http://dx.doi.org/10.1164/rccm.202101-0091EDDOI Listing
June 2021

Mechanism of bilirubin elimination in urine: insights and prospects for neonatal jaundice.

Clin Chem Lab Med 2021 May 15;59(6):1025-1033. Epub 2021 Jan 15.

New Vaccines, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

Despite a century of research, bilirubin metabolism and the transport mechanisms responsible for homeostasis of bilirubin in serum remain controversial. Emerging evidence on the hepatic membrane transporters and inherited disorders of bilirubin metabolism have contributed to a greater understanding of the various steps involved in bilirubin homeostasis and its associated excretory pathways. We discuss these recent research findings on hepatic membrane transporters and evaluate their significance on the newborn bilirubin metabolism and excretion. New insights gained speculate that a proportion of conjugated bilirubin is excreted via the renal system, as an alternative to the intestinal excretion, even in normal physiological jaundice with no associated pathological concerns. Finally, this paper discusses the clinical relevance of targeting the altered renal excretory pathway, as bilirubin in urine may hold diagnostic importance in screening for neonatal jaundice.
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http://dx.doi.org/10.1515/cclm-2020-1759DOI Listing
May 2021

Imaging the Respiratory Transition at Birth: Unraveling the Complexities of the First Breaths of Life.

Am J Respir Crit Care Med 2021 07;204(1):82-91

Department of Anaesthesiology and Intensive Care Medicine, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany.

The transition to air breathing at birth is a seminal respiratory event common to all humans, but the intrathoracic processes remain poorly understood. The objectives of this prospective, observational study were to describe the spatiotemporal gas flow, aeration, and ventilation patterns within the lung in term neonates undergoing successful respiratory transition. Electrical impedance tomography was used to image intrathoracic volume patterns for every breath until 6 minutes from birth in neonates born by elective cesearean section and not needing resuscitation. Breaths were classified by video data, and measures of lung aeration, tidal flow conditions, and intrathoracic volume distribution calculated for each inflation. A total of 1,401 breaths from 17 neonates met all eligibility and data analysis criteria. Stable FRC was obtained by median (interquartile range) 43 (21-77) breaths. Breathing patterns changed from predominantly crying (80.9% first min) to tidal breathing (65.3% sixth min). From birth, tidal ventilation was not uniform within the lung, favoring the right and nondependent regions;  < 0.001 versus left and dependent regions (mixed-effects model). Initial crying created a unique volumetric pattern with delayed midexpiratory gas flow associated with intrathoracic volume redistribution (pendelluft flow) within the lung. This preserved FRC, especially within the dorsal and right regions. The commencement of air breathing at birth generates unique flow and volume states associated with marked spatiotemporal ventilation inhomogeneity not seen elsewhere in respiratory physiology. At birth, neonates innately brake expiratory flow to defend FRC gains and redistribute gas to less aerated regions.
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http://dx.doi.org/10.1164/rccm.202007-2997OCDOI Listing
July 2021

Regional ventilation characteristics during non-invasive respiratory support in preterm infants.

Arch Dis Child Fetal Neonatal Ed 2021 Jul 27;106(4):370-375. Epub 2020 Nov 27.

Neonatal Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.

Objectives: To determine the regional ventilation characteristics during non-invasive ventilation (NIV) in stable preterm infants. The secondary aim was to explore the relationship between indicators of ventilation homogeneity and other clinical measures of respiratory status.

Design: Prospective observational study.

Setting: Two tertiary neonatal intensive care units.

Patients: Forty stable preterm infants born <30 weeks of gestation receiving either continuous positive airway pressure (n=32) or high-flow nasal cannulae (n=8) at least 24 hours after extubation at time of study.

Interventions: Continuous electrical impedance tomography imaging of regional ventilation during 60 min of quiet breathing on clinician-determined non-invasive settings.

Main Outcome Measures: Gravity-dependent and right-left centre of ventilation (CoV), percentage of whole lung tidal volume (V) by lung region and percentage of lung unventilated were determined for 120 artefact-free breaths/infant (4770 breaths included). Oxygen saturation, heart and respiratory rates were also measured.

Results: Ventilation was greater in the right lung (mean 69.1 (SD 14.9)%) total V and the gravity-non-dependent (ND) lung; ideal-actual CoV 1.4 (4.5)%. The central third of the lung received the most V, followed by the non-dependent and dependent regions (p<0.0001 repeated-measure analysis of variance). Ventilation inhomogeneity was associated with worse peripheral capillary oxygen saturation (SpO)/fraction of inspired oxygen (FiO) (p=0.031, r 0.12; linear regression). In those infants that later developed bronchopulmonary dysplasia (n=25), SpO/FiO was worse and non-dependent ventilation inhomogeneity was greater than in those that did not (both p<0.05, t-test Welch correction).

Conclusions: There is high breath-by-breath variability in regional ventilation patterns during NIV in preterm infants. Ventilation favoured the ND lung, with ventilation inhomogeneity associated with worse oxygenation.
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http://dx.doi.org/10.1136/archdischild-2020-320449DOI Listing
July 2021

Transmission of Oscillatory Volumes into the Preterm Lung during Noninvasive High-Frequency Ventilation.

Am J Respir Crit Care Med 2021 04;203(8):998-1005

Newborn Research, Department of Neonatology, University Hospital and University of Zürich, Zürich, Switzerland.

There is increasing evidence for a clinical benefit of noninvasive high-frequency oscillatory ventilation (nHFOV) in preterm infants. However, it is still unknown whether the generated oscillations are effectively transmitted to the alveoli. To assess magnitude and regional distribution of oscillatory volumes (V) at the lung level. In 30 prone preterm infants enrolled in a randomized crossover trial comparing nHFOV with nasal continuous positive airway pressure, electrical impedance tomography recordings were performed. During nHFOV, the smallest amplitude to achieve visible chest wall vibration was used, and the frequency was set at 8 hertz. Thirty consecutive breaths during artifact-free tidal ventilation were extracted for each of the 228 electrical impedance tomography recordings. After application of corresponding frequency filters, Vt and V were calculated. There was a signal at 8 and 16 Hz during nHFOV, which was not detectable during nasal continuous positive airway pressure, corresponding to the set oscillatory frequency and its second harmonic. During nHFOV, the mean (SD) V/Vt ratio was 0.20 (0.13). Oscillations were more likely to be transmitted to the non-gravity-dependent (mean difference [95% confidence interval], 0.041 [0.025-0.058];  < 0.001) and right-sided lung (mean difference [95% confidence interval], 0.040 [0.019-0.061];  < 0.001) when compared with spontaneous Vt. In preterm infants, V during nHFOV are transmitted to the lung. Compared with the regional distribution of tidal breaths, oscillations preferentially reach the right and non-gravity-dependent lung. These data increase our understanding of the physiological processes underpinning nHFOV and may lead to further refinement of this novel technique.
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http://dx.doi.org/10.1164/rccm.202007-2701OCDOI Listing
April 2021

Proteomics reveals region-specific hemostatic alterations in response to mechanical ventilation in a preterm lamb model of lung injury.

Thromb Res 2020 12 8;196:466-475. Epub 2020 Oct 8.

Neonatal Research, Murdoch Childrens Research Institute, Parkville, Australia; Department of Paediatrics, University of Melbourne, Parkville, Australia. Electronic address:

Introduction: Preterm infants often require assisted ventilation, however ventilation when applied to the immature lung can initiate ventilator-induced lung injury (VILI). The biotrauma which underscores VILI is largely undefined, and is likely to involve vascular injury responses, including hemostasis. We aimed to use a ventilated, preterm lamb model to: (1) characterize regional alterations in hemostatic mediators within the lung and (2) assess the functional impact of protein alterations on hemostasis by analyzing temporal thrombin generation.

Materials And Methods: Preterm lambs delivered at 124 to 127 days gestation received 90 min of mechanical ventilation (positive end-expiratory pressure = 8 cm HO, V = 6-8 ml/kg) and were compared with unventilated control lambs. At study completion, lung tissue was taken from standardized nondependent and gravity-dependent regions, and Orbitrap-mass spectrometry and KEGG were used to identify and map regional alterations in hemostasis pathway members. Temporal alterations in plasma thrombin generation were assessed.

Results: Ventilation was distributed towards the nondependent lung. Significant changes in hemostatic protein abundance, were detected at a two-fold higher rate in the nondependent lung when compared with the gravity-dependent lung. Seven proteins were uniquely altered in non-dependent lung (SERPINA1, MYL12A, RAP1B, RHOA, ITGB1, A2M, GNAI2), compared with a single proteins in gravity-dependent lung (COL1A2). Four proteins were altered in both regions (VTN, FGG, FGA, and ACTB). Tissue protein alterations were mirrored by plasma hypocoagulability at 90-minutes of ventilation.

Conclusions: We observed regionally specific, hemostatic alterations within the preterm lung together with disturbed fibrinolysis following a short period of mechanical ventilation.
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http://dx.doi.org/10.1016/j.thromres.2020.09.036DOI Listing
December 2020

COVID-19 surveillance for all newborns at the NICU; conditio sine qua non?

Eur J Pediatr 2020 12;179(12):1945-1947

Neonatal Research, Murdoch Children's Research Institute, Melbourne, VIC, Australia.

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http://dx.doi.org/10.1007/s00431-020-03773-7DOI Listing
December 2020

Skin-to-skin care alters regional ventilation in stable neonates.

Arch Dis Child Fetal Neonatal Ed 2021 Jan 30;106(1):76-80. Epub 2020 Jul 30.

Neonatal Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia.

Objective: Skin-to-skin care (SSC) has proven psychological benefits; however, the physiological effects are less clearly defined. Regional ventilation patterns during SSC have not previously been reported. This study aimed to compare regional ventilation indices and other cardiorespiratory parameters during prone SSC with supine and prone position cot-nursing.

Design: Prospective observational study.

Setting: Single quaternary neonatal intensive care unit in Australia.

Patients: 20 infants spontaneously breathing (n=17) or on non-invasive ventilation (n=3), with mean (SD) gestational age at birth of 33 (5) weeks.

Interventions: Thirty-minute episodes of care in each position: supine cot care, prone SSC and prone cot care preceding a 10 min period of continuous electrical impedance tomography measurements of regional ventilation.

Main Outcome Measures: In each position, ventral-dorsal and right-left centre of ventilation (CoV), percentage of whole lung ventilation by region and percentage of apparent unventilated lung regions were determined. Heart and respiratory rates, oxygen saturation and axillary temperature were also measured.

Results: Heart and respiratory rates, oxygen saturation, temperature and right-left lung ventilation did not differ between the three positions (mixed-effects model). Ventilation generally favoured the dorsal lung, but the mean (95% CI) ventrodorsal CoV was -2.0 (-0.4 to -3.6)% more dorsal during SSC compared with prone. Supine position resulted in 5.0 (1.5 to 5.3)% and 4.5 (3.9 to 5.1)% less apparently unventilated lung regions compared with SSC and prone, respectively.

Conclusions: In clinically stable infants, SSC generates a distinct regional ventilation pattern that is independent of prone position and results in greater distribution of ventilation towards the dorsal lung.
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http://dx.doi.org/10.1136/archdischild-2020-319136DOI Listing
January 2021

The EPICENTRE (ESPNIC Covid pEdiatric Neonatal Registry) initiative: background and protocol for the international SARS-CoV-2 infections registry.

Eur J Pediatr 2020 Aug 22;179(8):1271-1278. Epub 2020 May 22.

Neonatal Research, Murdoch Children's Research Institute, Melbourne, VIC, Australia.

The outbreak of SARS-CoV-2 is the worst healthcare emergency of this century, and its impact on pediatrics and neonatology is still largely unknown. The European Society for Pediatric and Neonatal Intensive Care (ESPNIC) launched the EPICENTRE (ESPNIC Covid pEdiatric Neonatal Registry) international, multicenter, and multidisciplinary initiative to study the epidemiology, clinical course, and outcomes of pediatric and neonatal SARS-CoV-2 infections. EPICENTRE background and aims are presented together with protocol details. EPICENTRE is open to centers all over the world, and this will allow to provide a pragmatic picture of the epidemic, with a particular attention to pediatric and neonatal critical care issues.Conclusions: EPICENTRE will allow researchers to clarify the epidemiology, clinical presentation, and outcomes of pediatric and neonatal SARS-CoV-2 infection, refining its clinical management and hopefully providing new insights for clinicians. What is Known: • COVID19 is the new disease caused by SARS-CoV-2 infection and is spreading around the globe. • Majority of data available about SARS-CoV-2 infections originates from adult patients. What is New: • EPICENTRE is the first international, multicenter, multidisciplinary, meta-data driven, hospital-based, online, prospective cohort registry dedicated to neonatal and pediatric SARS-CoV-2 infections. • EPICENTRE will allow to understand epidemiology and physiopathology of COVID19.
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http://dx.doi.org/10.1007/s00431-020-03690-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242019PMC
August 2020

Respiratory mechanics during initial lung aeration at birth in the preterm lamb.

Am J Physiol Lung Cell Mol Physiol 2020 03 8;318(3):L525-L532. Epub 2020 Jan 8.

Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano University, Milan, Italy.

Despite recent insights into the dynamic processes during lung aeration at birth, several aspects remain poorly understood. We aimed to characterize changes in lung mechanics during the first inflation at birth and their relationship to changes in lung volume. Intubated preterm lambs (gestational age, 124-127 days; = 17) were studied at birth. Lung volume changes were measured by electrical impedance tomography (V). Respiratory system resistance (R) and oscillatory compliance (C) were monitored with the forced oscillation technique at 5 Hz. Lambs received 3-7 s of 8 cmHO of continuous distending pressure (CDP) before delivery of a sustained inflation (SI) of 40 cmHO. The SI was then applied until either C or the V or the airway opening volume was stable. CDP was resumed for 3-7 s before commencement of mechanical ventilation. The exponential increases with time of C and V from commencement of the SI were characterized by estimating their time constants (τC and τV, respectively). During SI, a fast decrease in R and an exponential increase in C and V were observed. C and V provided comparable information on the dynamics of lung aeration in all lambs, with τC and τV being highly linearly correlated ( = 0.87, < 0.001). C and V decreased immediately after SI. Despite the standardization of the animal model, changes in C and R both during and after SI were highly variable. Lung aeration at birth is characterized by a fast reduction in resistance and a slower increase in oscillatory compliance, the latter being a direct reflection of the amount of lung aeration.
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http://dx.doi.org/10.1152/ajplung.00302.2019DOI Listing
March 2020

Heart of the Matter? Early Ventricular Dysfunction in Congenital Diaphragmatic Hernia.

Am J Respir Crit Care Med 2019 12;200(12):1462-1464

Department of PediatricsUniversity of Colorado School of MedicineAurora, Coloradoand.

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http://dx.doi.org/10.1164/rccm.201909-1737EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909840PMC
December 2019

Gestational Age Influences the Early Microarchitectural Changes in Response to Mechanical Ventilation in the Preterm Lamb Lung.

Front Pediatr 2019 21;7:325. Epub 2019 Aug 21.

Neonatal Research Group, Murdoch Children's Research Institute, Parkville, VIC, Australia.

Preterm birth is associated with abnormal lung architecture, and a reduction in pulmonary function related to the degree of prematurity. A thorough understanding of the impact of gestational age on lung microarchitecture requires reproducible quantitative analysis of lung structure abnormalities. The objectives of this study were (1) to use quantitative histological software (ImageJ) to map morphological patterns of injury resulting from delivery of an identical ventilation strategy to the lung at varying gestational ages and (2) to identify associations between gestational age-specific morphological alterations and key functional outcomes. Lung morphology was compared after 60 min of a standardized ventilation protocol (40 cm HO sustained inflation and then volume-targeted positive pressure ventilation with positive end-expiratory pressure 8 cm HO) in lambs at different gestations (119, 124, 128, 133, 140d) representing the spectrum of premature developmental lung states and the term lung. Age-matched controls were compared at 124 and 128d gestation. Automated and manual functions of Image J were used to measure key histological features. Correlation analysis compared morphological and functional outcomes in lambs aged ≤128 and >128d. In initial studies, unventilated lung was indistinguishable at 124 and 128d. Ventilated lung from lambs aged 124d gestation exhibited increased numbers of detached epithelial cells and lung tissue compared with 128d lambs. Comparing results from saccular to alveolar development (120-140d), lambs aged ≤124d exhibited increased lung tissue, average alveolar area, and increased numbers of detached epithelial cells. Alveolar septal width was increased in lambs aged ≤128d. These findings were mirrored in the measures of gas exchange, lung mechanics, and molecular markers of lung injury. Correlation analysis confirmed the gestation-specific relationships between the histological assessments and functional measures in ventilated lambs at gestation ≤128 vs. >128d. Image J allowed rapid, quantitative assessment of alveolar morphology, and lung injury in the preterm lamb model. Gestational age-specific patterns of injury in response to delivery of an identical ventilation strategy were identified, with 128d being a transition point for associations between morphological alterations and functional outcomes. These results further support the need to develop individualized respiratory support approaches tailored to both the gestational age of the infant and their underlying injury response.
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http://dx.doi.org/10.3389/fped.2019.00325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712425PMC
August 2019

A dedicated respiratory function monitor to improve tidal volume delivery during neonatal anesthesia.

Paediatr Anaesth 2019 09 12;29(9):920-926. Epub 2019 Aug 12.

Neonatal Research, Murdoch Children's Research Institute, Parkville, Vic., Australia.

Background: Tight control of tidal volume using accurate monitoring may improve neonatal outcomes. However, respiratory function monitors incorporated in current anesthetic workstations are generally inaccurate at tidal volumes used for infants.

Aims: To determine if a specific respiratory function monitor for neonatal infants improved expired tidal volume delivery during anesthesia.

Method: Infants <3 months old requiring intubation for surgery in the operating theater were studied. After intubation a Phillips NM3, Acutronic Florian, or Novametrix Ventcheck Respiratory Function Monitor was integrated into the circuit, and clinicians given access to the display for the duration of anesthesia. Breath-to-breath expired tidal volume delivery, leak, and delivered pressure were recorded, with cardiorespiratory parameters. These were compared with a matched control group with clinicians blinded to respiratory function monitor display.

Results: A total of 10 055 and 2569 inflations were measured in the respiratory function monitor visible (n = 32) and masked (n = 33) groups, respectively, with mean (standard deviation) delivered expired tidal volume 7.5 (2.4) mL/kg and 7.7 (3.0) mL/kg, respectively; mean difference (95% confidence interval) -0.2 (-1.1, 0.8) mL/kg (Welch's t test). In the visible group, 55.6% of expired tidal volumes were between 4 and 8 mL/kg compared to 51.7% in the masked group; relative benefit (95% confidence interval), 1.08 (1.03, 1.12). Expired tidal volume was less likely to be <4 mL/kg in the visible group compared to masked group; 6.4% vs 9.8%, 1.53 (1.33, 1.76). The use of a respiratory function monitor also reduced the number of inflations >10 mL/kg; 13.0% vs 22.0%, 1.11 (1.09, 1.14).

Conclusion: Tidal volumes <4 mL/kg and >10 mL/kg are frequently delivered during neonatal anesthesia. The inclusion of an accurate respiratory function monitor may reduce the risk of exposure to potentially harmful tidal volumes.
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http://dx.doi.org/10.1111/pan.13707DOI Listing
September 2019

Electrical impedance tomography identifies a distinct change in regional phase angle delay pattern in ventilation filling immediately prior to a spontaneous pneumothorax.

J Appl Physiol (1985) 2019 09 3;127(3):707-712. Epub 2019 Jul 3.

Neonatal Research, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

Pneumothoraxes are common in preterm infants and are a major cause of morbidity. Early detection and treatment of pneumothoraxes are vital to minimize further respiratory compromise. Electrical impedance tomography (EIT) has been suggested as a method of rapidly detecting pneumothoraxes at the bedside. Our objective was to define the EIT-derived regional phase angle differences in filling characteristics before and during spontaneous pneumothoraxes in preterm lambs. Preterm lambs (124-127-day gestation) were ventilated with high-frequency oscillatory ventilation for 120 min. EIT data and cardiorespiratory parameters were monitored continuously and recorded for 3 min every 15 min. Six animals spontaneously developed a pneumothorax within a gravity-nondependent quadrant of the lung and were included for this analysis. Changes in end-expiratory lung impedance (EELI), ventilation, and phase angle delay were calculated in the four lung quadrants at the onset of the pneumothorax and 15 and 30 min prior. At the onset of the pneumothorax, all animals showed a clear increase in EELI in the affected lung quadrant. Fifteen and thirty minutes before the pneumothorax there was a significant phase angle delay between the nondependent and dependent lung. At 1 min before pneumothorax this phase angle delay was isolated just to the affected quadrant (nondependent). These findings are the first description of the events within the lung at initiation of a pneumothorax, demonstrating distinct predictive changes in air-filling characteristics before the occurrence of pneumothorax. This suggests that EIT may be able to accurately identify the onset of a pneumothorax. In this article we describe for the first time predictive changes in electrical impedance tomography-based regional filling characteristics of the lung before the onset of a one-sided pneumothorax in six preterm lambs ventilated with high-frequency oscillatory ventilation. This can give clinicians bedside information to change treatment of preterm infants and prevent pneumothorax as life-threatening event from happening.
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http://dx.doi.org/10.1152/japplphysiol.00973.2018DOI Listing
September 2019

Preterm Lung Exhibits Distinct Spatiotemporal Proteome Expression at Initiation of Lung Injury.

Am J Respir Cell Mol Biol 2019 11;61(5):631-642

Neonatal Research, and.

The development of regional lung injury in the preterm lung is not well understood. This study aimed to characterize time-dependent and regionally specific injury patterns associated with early ventilation of the preterm lung using a mass spectrometry-based proteomic approach. Preterm lambs delivered at 124-127 days gestation received 15 or 90 minutes of mechanical ventilation (positive end-expiratory pressure = 8 cm HO, Vt = 6-8 ml/kg) and were compared with unventilated control lambs. At study completion, lung tissue was taken from standardized nondependent and dependent regions, and assessed for lung injury via histology, quantitative PCR, and proteomic analysis using Orbitrap-mass spectrometry. Ingenuity pathway analysis software was used to identify temporal and region-specific enrichments in pathways and functions. Apoptotic cell numbers were ninefold higher in nondependent lung at 15 and 90 minutes compared with controls, whereas proliferative cells were increased fourfold in the dependent lung at 90 minutes. The relative gene expression of lung injury markers was increased at 90 minutes in nondependent lung and unchanged in gravity-dependent lung. Within the proteome, the number of differentially expressed proteins was fourfold higher in the nondependent lung than the dependent lung. The number of differential proteins increased over time in both lung regions. A total of 95% of enriched canonical pathways and 94% of enriched cellular and molecular functions were identified only in nondependent lung tissue from the 90-minute ventilation group. In conclusion, complex injury pathways are initiated within the preterm lung after 15 minutes of ventilation and amplified by continuing ventilation. Injury development is region specific, with greater alterations within the proteome of nondependent lung.
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http://dx.doi.org/10.1165/rcmb.2019-0084OCDOI Listing
November 2019

Inhaled surfactant plus budesonide reduces early preterm lung injury, but is there an effect beyond the lung?

Authors:
David G Tingay

Am J Physiol Lung Cell Mol Physiol 2019 May 3;316(5):L886-L887. Epub 2019 Apr 3.

Neonatal Research Group, Murdoch Children's Research Institute , Parkville, Victoria , Australia.

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http://dx.doi.org/10.1152/ajplung.00138.2019DOI Listing
May 2019

Gradual Aeration at Birth Is More Lung Protective Than a Sustained Inflation in Preterm Lambs.

Am J Respir Crit Care Med 2019 09;200(5):608-616

Neonatal Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.

The preterm lung is susceptible to injury during transition to air breathing at birth. It remains unclear whether rapid or gradual lung aeration at birth causes less lung injury. To examine the effect of gradual and rapid aeration at birth on: ) the spatiotemporal volume conditions of the lung; and ) resultant regional lung injury. Preterm lambs (125 ± 1 d gestation) were randomized at birth to receive: ) tidal ventilation without an intentional recruitment (no-recruitment maneuver [No-RM];  = 19); ) sustained inflation (SI) until full aeration ( = 26); or ) tidal ventilation with an initial escalating/de-escalating (dynamic) positive end-expiratory pressure (DynPEEP;  = 26). Ventilation thereafter continued for 90 minutes at standardized settings, including PEEP of 8 cm HO. Lung mechanics and regional aeration and ventilation (electrical impedance tomography) were measured throughout and correlated with histological and gene markers of early lung injury. DynPEEP significantly improved dynamic compliance ( < 0.0001). An SI, but not DynPEEP or No-RM, resulted in preferential nondependent lung aeration that became less uniform with time ( = 0.0006). The nondependent lung was preferential ventilated by 5 minutes in all groups, with ventilation only becoming uniform with time in the No-RM and DynPEEP groups. All strategies generated similar nondependent lung injury patterns. Only an SI caused greater upregulation of dependent lung gene markers compared with unventilated fetal controls ( < 0.05). Rapidly aerating the preterm lung at birth creates heterogeneous volume states, producing distinct regional injury patterns that affect subsequent tidal ventilation. Gradual aeration with tidal ventilation and PEEP produced the least lung injury.
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http://dx.doi.org/10.1164/rccm.201807-1397OCDOI Listing
September 2019

Lung Recruitment Strategies During High Frequency Oscillatory Ventilation in Preterm Lambs.

Front Pediatr 2018 22;6:436. Epub 2019 Jan 22.

Department of Neonatology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

High frequency oscillatory ventilation (HFOV) is considered a lung protective ventilation mode in preterm infants only if lung volume is optimized. However, whilst a "high lung volume strategy" is advocated for HFOV in preterm infants this strategy is not precisely defined. It is not known to what extent lung recruitment should be pursued to provide lung protection. In this study we aimed to determine the relationship between the magnitude of lung volume optimization and its effect on gas exchange and lung injury in preterm lambs. 36 surfactant-deficient 124-127 d lambs commenced HFOV immediately following a sustained inflation at birth and were allocated to either (1) no recruitment (low lung volume; LLV), (2) medium- (MLV), or (3) high lung volume (HLV) recruitment strategy. Gas exchange and lung volume changes over time were measured. Lung injury was analyzed by post mortem pressure-volume curves, alveolar protein leakage, gene expression, and histological injury score. More animals in the LLV developed a pneumothorax compared to both recruitment groups. Gas exchange was superior in both recruitment groups compared to LLV. Total lung capacity tended to be lower in the LLV group. Other parameters of lung injury were not different. Lung recruitment during HFOV optimizes gas exchange but has only modest effects on lung injury in a preterm animal model. In the HLV group aiming at a more extensive lung recruitment gas exchange was better without affecting lung injury.
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http://dx.doi.org/10.3389/fped.2018.00436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349831PMC
January 2019

Electrical Impedance Tomography Can Identify Ventilation and Perfusion Defects: A Neonatal Case.

Am J Respir Crit Care Med 2019 02;199(3):384-386

6 Systems and Computer Engineering Carleton University, Ottawa, Ontario, Canada.

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http://dx.doi.org/10.1164/rccm.201808-1551LEDOI Listing
February 2019

Plasma proteomics reveals gestational age-specific responses to mechanical ventilation and identifies the mechanistic pathways that initiate preterm lung injury.

Sci Rep 2018 08 22;8(1):12616. Epub 2018 Aug 22.

Neonatal Research, Murdoch Childrens Research Institute, Parkville, Australia.

The preterm lung is particularly vulnerable to ventilator-induced lung injury (VILI) as a result of mechanical ventilation. However the developmental and pathological cellular mechanisms influencing the changing patterns of VILI have not been comprehensively delineated, preventing the advancement of targeted lung protective therapies. This study aimed to use SWATH-MS to comprehensively map the plasma proteome alterations associated with the initiation of VILI following 60 minutes of standardized mechanical ventilation from birth in three distinctly different developmental lung states; the extremely preterm, preterm and term lung using the ventilated lamb model. Across these gestations, 34 proteins were differentially altered in matched plasma samples taken at birth and 60 minutes. Multivariate analysis of the plasma proteomes confirmed a gestation-specific response to mechanical ventilation with 79% of differentially-expressed proteins altered in a single gestation group only. Six cellular and molecular functions and two physiological functions were uniquely enriched in either the extremely preterm or preterm group. Correlation analysis supported gestation-specific protein-function associations within each group. In identifying the gestation-specific proteome and functional responses to ventilation we provide the founding evidence required for the potential development of individualized respiratory support approaches tailored to both the developmental and pathological state of the lung.
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http://dx.doi.org/10.1038/s41598-018-30868-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105628PMC
August 2018

The Effect of Noninvasive High-Frequency Oscillatory Ventilation on Desaturations and Bradycardia in Very Preterm Infants: A Randomized Crossover Trial.

J Pediatr 2018 10 25;201:269-273.e2. Epub 2018 Jun 25.

Newborn Research Center and Neonatal Services, The Royal Women's Hospital, Melbourne, Victoria, Australia; Department of Obstetrics and Gynecology, The University of Melbourne, Melbourne, Victoria, Australia; Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

Noninvasive high-frequency oscillatory ventilation compared with nasal continuous positive airway pressure significantly reduced the number of desaturations and bradycardia in preterm infants. However, noninvasive high-frequency oscillatory ventilation was associated with increased oxygen requirements and higher heart rates.

Trial Registration: Australian and New Zealand Clinical Trial Registry: ACTRN12616001516471.
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http://dx.doi.org/10.1016/j.jpeds.2018.05.029DOI Listing
October 2018

How best to capture the respiratory consequences of prematurity?

Eur Respir Rev 2018 Mar 14;27(147). Epub 2018 Mar 14.

Dept of Paediatrics, University of Melbourne, Melbourne, Australia.

Chronic respiratory morbidity is a common complication of premature birth, generally defined by the presence of bronchopulmonary dysplasia, both clinically and in trials of respiratory therapies. However, recent data have highlighted that bronchopulmonary dysplasia does not correlate with chronic respiratory morbidity in older children born preterm. Longitudinally evaluating pulmonary morbidity from early life through to childhood provides a more rational method of defining the continuum of chronic respiratory morbidity of prematurity, and offers new insights into the efficacy of neonatal respiratory interventions. The changing nature of preterm lung disease suggests that a multimodal approach using dynamic lung function assessment will be needed to assess the efficacy of a neonatal respiratory therapy and predict the long-term respiratory consequences of premature birth. Our aim is to review the literature regarding the long-term respiratory outcomes of neonatal respiratory strategies, the difficulties of assessing dynamic lung function in infants, and potential new solutions.
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http://dx.doi.org/10.1183/16000617.0108-2017DOI Listing
March 2018

Surgery and magnetic resonance imaging increase the risk of hypothermia in infants.

J Paediatr Child Health 2018 Apr 13;54(4):426-431. Epub 2018 Jan 13.

Neonatal Research, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

Aim: Maintaining normothermia is a tenet of neonatal care. However, neonatal thermal care guidelines applicable to intra-hospital transport beyond the neonatal intensive care unit (NICU) and during surgery or magnetic resonance imaging (MRI) are lacking. The aim of this study is to determine the proportion of infants normothermic (36.5-37.5°C) on return to NICU after management during surgery and MRI, and during standard clinical care in both environments.

Methods: Sixty-two newborns requiring either surgery in the operating theatre (OT) (n = 41) or an MRI scan (n = 21) at the Royal Children's Hospital (Melbourne) NICU were prospectively studied. Core temperature, along with cardiorespiratory parameters, was continuously measured from 15 min prior to leaving the NICU until 60 min after returning. Passive and active warming (intra-operatively) was at clinician discretion.

Results: The study reported 90% of infants were normothermic before leaving NICU: 86% (MRI) and 93% (OT). Only 52% of infants were normothermic on return to NICU (relative risk (RR) 1.75; 95% confidence interval (CI) 1.39-2.31; number needed to harm (NNH) 2.6). Between departure from the NICU and commencement of surgery, core temperature decreased by mean 0.81°C (95% CI 0.30-1.33; P = 0.0001, analysis of variance), with only 24% of infants normothermic when surgery began (P < 0.0001; RR 3.80 (95% CI 2.33-6.74); NNH 1.5). After an MRI, infants were a mean 0.41°C (95% CI 0.16-0.67) colder than immediately before entering the scanner (P = 0.001, analysis of variance), with only 43% being normothermic (P = 0.003; RR 2.11 (95% CI 1.35-3.74); NNH 2.1).

Conclusion: Unintentional hypothermia is a common occurrence during surgery in the OT and MRI in neonates, indicating that evidence-based warming strategies to prevent hypothermia should be developed.
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http://dx.doi.org/10.1111/jpc.13824DOI Listing
April 2018
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