Neonatal respiratory disorders, pathophysiology and treatment

The extremely preterm infant has immature lungs and the transition to air breathing is often difficult. The situation is confounded by the immature developmental stage of the lung and thorax plus surfactant deficiency in the lung parenchyma.

The infant’s initial respiration after birth can be absent, inadequate or gradually failing. Several types of respiratory support treatments are used to aid this transition to air breathing. Infants that do not breathe need to be ventilated with positive pressure. Breathing infants receive continuous positive airway pressure support (CPAP), which aids the development of the infant’s pulmonary functional residual capacity. Infants who do not establish stable spontaneous breathing need intubation and subsequent mechanical ventilation.

Chronic lung disease of prematurity (bronchopulmonary dysplasia, BPD) is the most common morbidity in the extremely preterm infant population. It is increasingly appreciated that BPD is a result from a combination of several antenatal and perinatal factors. The initiation of mechanical ventilation is the major risk factor for the development of the disease. The Disease process starts with the acute lung injury to the immature lung. There is a strong component of inflammation that interrupts lung development in preterm infants. Infants with BPD have a simplified parenchymal architecture and a decreased alveolar area that limits gas exchange.

As mechanical ventilation is a major risk factor the avoidance of it is a major focus in our research. The focus revolves around stabilization of infants and the management of respiratory problems at birth and during the neonatal period.

Another focus are the resulting pulmonary sequels of treatment resulting in a possibly lifelong reduction in the individuals´ pulmonary capacity.  Visualizing areas of mismatched perfusion and ventilation (V/Q) in the BPD lung are a part of this research strategy.

The effect of different respiratory care strategies on the need for intubation and mechanical ventilation of extremely preterm infants.

A major focus for our research is respiratory support, specifically CPAP, for newborn infants from 0,5 to 5 kg birth weight. This basically applies to all newborn infants worldwide. Every year an estimated 15 million babies are born preterm (WHO). Complications of preterm birth are the leading cause for neonatal mortality and WHO estimates that 3 out of 4 of these babies can be saved with improved maternal and neonatal care. The use of continuous positive airway pressure (CPAP) is one of the key recommended interventions to reduce morbidity and mortality in preterm infants. (WHO recommendations).  Many CPAP devices are in the “homemade” category; several low-cost bubble CPAP devices are being developed specifically for low-income countries but need to be tested for durability, reliability and safety’ [WHO 2012]. Our research can help in this regard with testing of other designs and the introduction of more stable properly designed and tested CPAP equipment. 

Please follow the link to our group homepage for a more detailed description of our subgroup NEAR. This is a truly collaborative effort where the design innovations are mostly developed by Thomas Drevhammar and Kjell Nilsson anesthesiologists based in Östersund, Sweden while the connection to neonatal practice, clinical modifications/testing and trials is done at the Karolinska University Hospital in Stockholm, Sweden.

Thomas Drevhammar thesie 2016;

Performance of NCPAP systems for neonatal use and development of a new system for infant resuscitation

The pathophysiology, clinical aspects and treatment of bronchopulmonary dysplasia (BPD)

We developed a unique method to simultaneously map the ventilation-perfusion (V/Q) in newborn infants using 3-D SPECT. This enables us to study the ventilation/perfusion relationship in BPD longitudinally from infancy to adulthood. Using the SPECT technique, we are also able to study the effect of different respiratory treatment strategies on the incidence and severity of BPD in extremely preterm infants

The figure shows transverse section of the lung using single photon emission computed tomography (SPECT) technique that measures the ventilation (V) and perfusion (Q) as well as matching (V/Q) in 3 individuals with different severity of BPD, mild (column A), moderate (column B) and severe (column C). A worsening V/Q is illustrated by a gradually increasing blue color.  Oxygen need increases with increasing severity grade and decreasing V/Q

Malin Kjellberg thesis 2019;

Lung function measured with SPECT in infants and children with bronchopulmonary dysplasia : correlation with respiratory management and clinical grading 

BPD is a multifactorial disease and we have ongoing projects to define the effect of other risk factors, such as PDA, that contribute to the development of the disease. The effects of different respiratory strategies and care practices over time are a significant contributing factor to the BPD clinical spectrum and epidemiology of disease. Risk factors that need further study.

Anna Gudmundsdóttir thesis 2019;

Patent ductus arteriosus in extremely preterm infants : characteristics, risk factors and treatment decisions 

Members of the research group

Research team members affiliated with KBH, KI

Baldvin Jonsson

Adjunct Professor in neonatology, group leader
Jonsson
K6 Kvinnors och barns hälsa

Thomas Drevhammar

PhD, anesthesiologist, post doc
Jonsson
K6 Kvinnors och barns hälsa

Malin Kjellberg

MD, PhD, neonatologist, postdoc

Anna Gudmundsdottir

MD, PhD, neonatologist, post doc
Jonsson
K6 Kvinnors och barns hälsa

PhD students in the group at KBH, KI

Snorri Donaldsson

MD, neonatologist
Jonsson
K6 Kvinnors och barns hälsa

Sonja Baldursdottir

MD, neonatologist
Jonsson
K6 Kvinnors och barns hälsa

Markus Falk

anestesiologist
Jonsson
K6 Kvinnors och barns hälsa

Kolbrún Gunnarsdóttir

MD, neonatologist
Jonsson
K6 Kvinnors och barns hälsa

Methods and competences within our group

We use a wide range of methods ranging from design and bench studies with lung simulators that are run in Östersund by Thomas Drevhammar, Markus Falk and Kjell Nilsson. Computational fluid dynamics in collaboration with doc. Lisa Prahl at KTH. State-of-the art imaging technology in nuclear medicine (SPECT) with doc. Alejandro Sanchez Crespo at the Karolinska and extending to our own sponsored and collaborative multi- and national RCT´s in patients that are managed from the department of Neonatology at the Karolinska University Hospital.

Important recent research results

The design and development of a new resuscitation device (rPAP) for the smallest infants has been tested in a feasibility study and found to be safe.

We were awarded the Medtech4Health Innovation Award in 2019 for the development of the device and the Swedish Athena prize for innovation and clinical research later in 2019.

We have described ventilation-perfusion abnormalities in infants with BPD at 36 weeks corrected gestational age and shown that these abnormalities partly persist at 10 years of age.

Ongoing projects

We are currently sponsoring a large RCT on new our new rPAP resuscitation device with the aim to further reduce the use of invasive mechanical ventilation. The device has the potential to change the standard of care for respiratory stabilization of extremely preterm infants after delivery (Heart-Lung Foundation grant).

Develop new CPAP system for use in newborn stabilization in low income settings, worldwide (VINNOVA grant).

To describe the ventilation perfusion relationship in BPD longitudinally from infancy to adulthood. Also, to continue to study the effects of different respiratory strategies during the neonatal period on the longitudinal development of lung function.

We are active participants in international clinical RCT´s for preterm and term infants. The RCT on the use of iNO. The 7 year follow up for infants in the EUNO RCT for iNO as prophylaxis against BPD is ongoing. An RCT studying the clinical effects of using a concomitant infusion of Sildenafil to iNO for PPHN non-responders is ongoing.

Past and Present Research collaborations  

KI & Sweden: Docent Alejandro Sanchez Crespo Department of Oncology-Pathology, Department of Medical Radiation Physics and Nuclear Medicine (SPECT), Karolinska Trial Alliance (support), prof. Birgitta Agerberth KI (antibacterial CPAP application), docent Lisa Prahl KTH (computational fluid dynamics, CPAP), Kjell Nilsson, Ventivent AB Östersund (CPAP development)

International: Resuscitation devices (Mark Tracy, University of Sydney). Non-invasive ventilation (prof. Haresh Kirpalani, Philadelphia USA), EUNO group (prof. Jean Christophe Mercier, Paris), UKOS group (Prof. Anne Greenough, Kings college, London).