Big problems for small lungs

Helping little ones breathe may lead to long-term problems

Carole Bartoo
Published: June, 2010

The lungs are the last critical support system to mature before a baby is born, so when a baby is born too early, the lungs struggle to work before they are ready.

Fortunately neonatal care is now very good at helping support the breathing of premature infants, so good, in fact, that a baby just a few weeks past the halfway point in gestation can survive… but at what cost?

Protection of tiny delicate lungs, threatened by premature birth, is one of the critical areas of research in the Vanderbilt University School of Medicine’s Department of Pediatrics.

Joshua Speck plays at Nashville’s
Dragon Park after his clinic visit at
Photo by Susan Urmy

Joshua Speck runs the hallways of his Sparta, Tenn., home tethered to a 50-foot-long oxygen tube. He plays happily, constantly in motion, except when he gets hopelessly tangled.

“He’s always getting hung up with his tubing and saying, ‘Me stuck,’” says his father, Dennis Speck. “Nothing stops him and he’s not afraid of anything. You turn your back and he’s ready to climb up and jump off the furniture.”

Joshua weighed 585 grams at birth, or 1 pound, 4 ounces. He was born just 27 weeks into his 40-week gestation. Somewhere along the rocky road to his discharge from the hospital he was diagnosed with a serious chronic breathing disorder called bronchopulmonary dysplasia, or BPD.

Today, at the age of 3, he still cannot go more than two hours without his oxygen tube.

BPD is a chronic lung disease that occurs in 10,000 to 15,000 premature infants in the United States every year. Many of them are born with respiratory distress syndrome and require mechanical ventilation to help them breathe. The pressure and oxygen mix delivered by a ventilator can irritate and inflame their delicate lung tissues. Prolonged ventilator use is the leading cause of BPD.

“You may save their life but do terrible things to their lungs,” says Mildred Stahlman, M.D., professor of Pediatrics and Pathology at Vanderbilt University Medical Center.

Mildred Stahlman, M.D., holds Cole
Petty, 101 days after he was born
prematurely weighing 470 grams
(a little over 1 pound).
Photo by Joe Howell
 Stahlman, a pioneer in the field of neonatology, is credited with setting up the nation’s first neonatal intensive care unit (NICU) at Vanderbilt in the 1960s. It was largely through her efforts that ventilators were adapted to meet the needs of premature infants more than 50 years ago.

“Early on we knew there was damage of some sort caused by the ventilation, but you don’t know exactly what you’re doing to the blood flow, or to the structure,” she says. “There are just a million questions. You answer one question and it asks another.”

Gentler approach

The questions doctors asked over the years led to the development of many important treatment advances: steroids to mature the lungs before delivery, surfactant to artificially lubricate and protect premature lungs, advanced infection control, and finely tuned ventilator settings and oxygen delivery systems.

Today, babies born even at 23 weeks of gestation can survive. But as smaller babies survive at earlier stages of gestation, a much more complex picture of lung damage is forming.

For Vanderbilt neonatologist Mario Rojas, M.D., M.P.H., one answer may lie in avoiding the use of ventilators unless absolutely necessary, and opting instead for the gentlest possible approach for premature respiratory support.

“When we breathe, our bodies use negative pressure to pull air in,” Rojas explains. “In artificial respiration, it’s very different. In these babies, it is just like blowing up a balloon. Positive air pressure creates sheer stress that damages the lung.”

Damage can occur in just the first few resuscitative breaths given to premature lungs through a ventilator. The longer a baby remains on a ventilator, the higher the risk of infection and a side effect called pneumothorax, in which the tiniest tubes leading to the deepest airways rupture.

Physicians and neonatal nurse practitioners must race to seal leaks in the lung -- like patching a tire on race day -- so that effective ventilation can resume. This collapsing and re-inflating, however, can tear up the sticky lung tissue.

Mario Rojas, M.D., examines a premature baby in the Neonatal Intensive Care Unit at the Monroe Carell Jr. Children’s Hospital at Vanderbilt.
Photo by Susan Urmy 

Studying the role of the ventilator in causing BPD is difficult to do in the United States, says Rojas, an associate professor of Pediatrics, “because we use ventilators so commonly here.”

But in Rojas’ native country Colombia, ventilators are in short supply. There, it is easier to study a less aggressive technique, called continuous positive airway pressure, or CPAP.

CPAP is frequently used in the United States to treat adults with sleep apnea, in which breathing is interrupted for long periods during sleep. The CPAP machine blows an oxygen mixture into the airways through the nose, and at a much lower pressure than do ventilators because the air can escape through the mouth if pressure gets too high.

Rojas and his colleagues in Colombia studied nearly 300 infants born at 27 to 32 weeks with signs of respiratory distress. “Our results showed that babies managed with nasal CPAP and very early surfactant, up to 74 percent of babies in this gestational age category with respiratory distress did well, and would not have required mechanical ventilation,” Rojas says.

Their study, published in the January 2009 journal Pediatrics, has helped fuel efforts to decrease ventilator use in premature infants.

“But even with the gentlest sorts of things we do, many times if the lungs are extremely premature, they simply don’t develop anatomically as they perhaps would if they had not been delivered so prematurely,” Stahlman says.

Thin line

Joshua Speck visits Odessa Settles,
R.N., who manages the BPD follow-up
program at Vanderbilt.
Photo by Susan Urmy
Odessa Settles, R.N., has been working with premature babies at Vanderbilt longer than almost anyone aside from Stahlman.

Settles helped the late Thomas Hazinski, M.D., establish the BPD clinic in 1984, and currently manages the BPD follow-up program at the Monroe Carell Jr. Children’s Hospital at Vanderbilt.

“The good news is some babies continue to grow and develop healthy lung tissue into their second year. The majority are able to come off of oxygen therapy by age 2,” she says. Others, like Joshua Speck, continue to struggle with serious chronic lung disease. 

Their numbers are growing.

Settles says the number of patients coming to the BPD clinic has more than doubled in the last five years from about 300 to more than 600.

“I am amazed at the strength and tenacity of the children who come to clinic,” she continues. “They still manage to smile, babble, laugh out loud, blow a kiss, play patty cake or reach out to be picked up.”

Advances in neonatal care have improved their chances for survival, yet “I want to know what you can do for ‘arrested development,’” Settles says. Arrested development, also called the “new BPD,” describes the abnormal lung tissue seen in very premature infants who inexplicably get worse after a “honeymoon” period in the NICU.

William Walsh, M.D., director of nurseries at the Monroe Carell Jr. Children’s Hospital, examines a preterm infant in the NICU.
Photo by John Russell
“We see it all the time,” said William Walsh, M.D., director of nurseries at the Monroe Carell Jr. Children’s Hospital. “Often these babies born at 24 or 26 weeks do well for a couple of weeks, and then they begin to decline, no matter what you do.”

Payton Wilson was supposed to be a miracle baby. She was delivered on Aug. 17, 2008, at a mere 24 weeks of gestation in order to save her mother, who had developed a heart problem in pregnancy. Payton was on the highest level of respiratory care since day one, yet somehow she kept bouncing back from crisis after crisis.

A year later, Payton was finally preparing to leave the NICU when she suddenly went into heart failure and could not be revived. Nikki Wilson says she lost her daughter less than 15 minutes before she would have turned 1. It was the day before she was to come home for the first time.

Losing babies like Payton is devastating for parents and incredibly hard on everyone who cares for them.

“We have at least one or two babies like Payton in our NICU all the time,” says Chris Lynn, RRT, who has been a respiratory therapist and educator at the Children’s Hospital for many years.

He is painfully and constantly aware of the thin line between supporting a baby and prolonging damaging treatments. Currently, however, it appears the new BPD may be a price of survival.

Role of infection

A retrospective study of 4,065 very low birth-weight infants treated in 1998, 2001 and 2006 at eight NICUs found that survival rates climbed after ventilator use was cut and CPAP and surfactant use increased. But the proportion of babies who developed BPD also rose -- from 25 percent to 29 percent, the researchers reported in the March 2010 issue of Pediatrics.

The study, sponsored by the Vermont Oxford Network, a NICU quality and information sharing organization, suggests that other factors besides mechanical ventilation are driving new BPD.

According to Vanderbilt neonatologist Lance Prince, M.D., Ph.D., infection may play a role.

Lance Prince, M.D., Ph.D.
Photo by Joe Howell

“We have made great strides in understanding the mechanisms involved in inflammation,” says Prince, an assistant professor of Pediatrics. “At the same time, we have a lot more knowledge of normal fetal development. In this work with new BPD, we are trying to find the intersection of the two.”

Prince began by examining the lungs of babies who died from BPD.

“Lung development of the babies who had been exposed to infection was months behind. We were looking at lungs that appeared to be remodeled with large, dilated or boggy air sacs,” he says. “But in a premature baby not exposed to inflammation, lungs still continue to develop outside the womb.”

Using a mouse model, Prince has identified some of the chemical changes that occur when lungs are exposed to infection before they fully develop.

In a 2006 study, he exposed fetal mouse lungs at the equivalent of 27 weeks of human gestation to endotoxin released by the common bacterium E. coli. The alveoli, the tiny air sacs in the lungs, stopped developing, and levels of FGF10, a chemical known to be important to normal lung development, dropped precipitously.

The latest in microscopic video imaging techniques showed for the first time how normal cells lay down the structure of the innermost airways, and then what happens to them if FGF10 goes away in the face of infection. Prince says that without the crucial chemical the cells responsible for alveolar construction appear to “wander aimlessly.”

Prince teamed up with Vanderbilt’s Tim Blackwell, M.D., Rudolph H. Kampmeier Professor of Medicine and chief of the Division of Allergy, Pulmonary and Critical Care, for the next phase of his work: honing in on the pathway involved.

Blackwell had developed a way to borrow nature’s florescence and luminescence -- from jellyfish and fireflies -- to illuminate activation of a common inflammatory pathway involved in adult chronic lung disease.

When this technology was applied to Prince’s fetal mouse lung model, the researchers observed macrophage cells involved in the fetal mouse’s inflammatory response glowing “like a firefly” as FGF10 levels dropped.

Best strategy

Prince and Blackwell believe infection triggers an inflammatory response that is common in mature lungs, but ultimately is devastating to fetal lung development.

To pursue their theory, they have received a government grant to collect evidence of macrophage inflammatory activity and FGF10 levels in premature infants on ventilators in Vanderbilt’s NICU. Cellular and chemical signs of inflammation will be correlated with the clinical course of the babies’ respiratory distress.

If their hunch is correct, therapies could be developed, perhaps something to calm the inflammation, or even replace the chemical that goes missing.

“You could inhale something that would start the FGF10 again to heal and develop the lungs, or continue along the pathway that stopped, (and) that would be a way to potentially prevent BPD,” Prince says.

It is likely each case of BPD has a complex set of contributors. Genetics may also play a role. Stahlman and colleagues at Cincinnati Children's Hospital Medical Center, for example, have identified genetic mutations that may prevent normal surfactant development.

Another contributor to lung damage in premature infants is the immaturity of their “anti-oxidant systems,” including enzymes, which normally convert toxic forms of oxygen into harmless oxygen gas and water.

“A premature infant has not had time to fully develop the mechanisms within the lungs to deal with higher levels of oxygen,” says Judy Aschner, M.D., Julia Carell Stadler Professor and director of the Mildred Stahlman Division of Neonatology.

Aschner and colleagues recently received a large research grant from the National Institutes of Health and the National Heart, Lung, and Blood Institute (NHLBI) to collaborate nationally on prematurity outcomes.

Vanderbilt researchers will search for biomarkers in the blood, urine or other body fluids that may help predict which babies are at higher risk for BPD. Aschner hopes this will lead to development of nutrition-based supplements to boost antioxidant protection in premature infants.

Ultimately, the best strategy is to prevent premature delivery in the first place.

“The lung in utero prepares itself for extra-uterine life in a very precise fashion, and if we interfere with that you don’t have the same sequence of events,” Stahlman points out. “For some babies it is a disaster no matter how you look at it. It is an emotional disaster for the parent.”

Respiratory therapist Chris Lynn agrees that prevention of preterm birth is a must. “Our goal is to put me out of business,” he says. “There is no other way.” 

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