Respiratory distress syndrome is the poster child for neonatology

My goal is to discuss the significant improvement in mortality rates for respiratory distress syndrome (RDS) due to new therapies. In the 1950s and 1960s, mortality rates were approximately 50% (Fig. 1); however, with the introduction of CPAP, surfactant therapy, antenatal steroids, and mechanical ventilation, today’s mortality rate has dropped to less than 2%. This is a remarkable advancement, and the 2% figure may be overestimated due to misdiagnosis of RDS in some instances. My primary interests have been to understand surfactant metabolism and physiology.¹ I collaborated on this research for over two decades with Machiko Ikegami,² Harris Jacobs,³ Andrea Petennazzo,⁴ and Jim Lewis.

I failed in two important life transitions. I flunked the 5th grade, and I got kicked out of hospice care last year since I was doing too well with my glioblastoma (now 4.5 years into diagnosis). The fact that I made it to Toronto to receive the Howland Medal – is surprising. I need to thank my parents for recognizing that I could not read in the 5th grade. They decided to enroll me in a preparatory school, where I repeated the 5th grade and found support to overcome my reading challenges.

I wish to express gratitude to my first scientific mentor, Del Fisher, during my tenure as a faculty member for two decades from 1987 to 1997 at Harbor UCLA. While I was a junior faculty member, I learned a crucial lesson from Del Fisher: that comprehending human diseases necessitates dependable animal models, as conducting mechanistic studies in humans is frequently too difficult. Thankfully, we had access to exceptional animal models for RDS, such as preterm sheep, rabbits, and monkeys. Harbor UCLA provided me with invaluable research space, dedicated time, exemption from extensive clinical duties, and financial support, laying the foundation for my academic journey. Thanks also to the two exceptional junior neonatal faculty members at Harbor UCLA, Jim Padbury and J. Usha Raj, who had their own highly successful academic careers at UCLA. Del’s remarkable achievements, including receiving the Howland Medal in 2001 for his groundbreaking work in fetal endocrinology, were truly inspiring.

Key Points

1. Historical Mortality Trends: In the 1950s and 1960s, RDS was associated with mortality rates of approximately 50%, primarily due to a lack of effective therapies. However, the introduction of CPAP, surfactant therapy, and antenatal steroids has reduced the mortality rate to less than 2%, marking one of the most significant achievements in neonatology.
2. Surfactant Deficiency in RDS: The primary cause of RDS is surfactant deficiency in preterm infants, leading to alveolar collapse, hypoxemia, and respiratory failure. Research on surfactant metabolism and function was crucial in obtaining FDA approval for surfactant therapy in 1990.
3. Role of CPAP: CPAP, introduced by George Gregory, was a pivotal advancement in RDS treatment. It effectively maintains lung volume and oxygenation by preventing alveolar collapse, reducing the need for invasive mechanical ventilation and its associated complications.
4. Surfactant Therapy: The development of exogenous surfactant replacement therapy revolutionized neonatal care. Early studies in animal models demonstrated that surfactant administration significantly improved lung compliance, reduced oxygen requirements, and lowered mortality in preterm infants with RDS.
5. Surfactant Inactivation: Inflammatory mediators and serum proteins can inactivate surfactant, limiting its effectiveness in some cases. Early studies demonstrated that airway samples from infants with severe RDS exhibited high surface tension, underscoring the importance of surfactant quality and function in treatment success.
6. Antenatal Steroids and Lung Maturation: The use of antenatal corticosteroids in mothers at risk for preterm birth has significantly improved neonatal lung function. However, concerns remain regarding the optimal dosage and long-term effects, particularly in terms of neurodevelopmental outcomes.
7. CPAP as a Primary Therapy: Clinical data suggest that CPAP alone can effectively manage most cases of RDS, particularly in resource-limited settings. In South Africa, CPAP has been successfully used as the primary treatment, reducing the need for surfactant therapy and mechanical ventilation.
8. Advances in Surfactant Research: Studies on surfactant pool sizes, secretion mechanisms, and metabolic pathways have contributed to refining surfactant therapy. Research using stable isotopes has shown that surfactant recycling in preterm infants is highly efficient, supporting the long-term sustainability of surfactant therapy.
9. Challenges in Antenatal Steroid Use: Although antenatal steroids are widely used, there is growing evidence that current dosing regimens may be excessive, leading to prolonged adrenal suppression and potential long-term health risks. Ongoing research aims to optimize steroid dosing while minimizing adverse effects.
10. Future Directions in Neonatology: The continued evolution of neonatal care will focus on improving RDS treatment strategies, refining CPAP techniques, optimizing surfactant therapy, and reassessing the long-term effects of antenatal steroids. Research into alternative lung maturation pathways may lead to new therapies that do not rely on glucocorticoids.