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Neonatology

Uncovering the Role of the Pulmonary Microbiome in Chronic Respiratory Disease

Say the word microbiome and you probably think about the billions of microbes that inhabit the gut. But Children’s of Alabama neonatologist Charitharth Vivek Lal, M.D., wants you to consider another microbiome — the lung microbiome. Not only does it exist, he and his team have discovered, but it is present as early as birth, even at 24 weeks gestation, negating the long-held believe that the lungs are sterile before birth.

The question he is now trying to answer is what role it plays in the chronic lung disease bronchopulmonary dysplasia (BPD), which affects between 48% to 68% of babies born before 28 weeks of gestation. The condition is a major cause of morbidity and mortality in preterm infants, characterized by lung inflammation, injury and pulmonary hypertension, among other factors.[1]

A study from Lal clearly demonstrated that microbial imbalance, or dysbiosis, predicts the development of BPD in extremely low-birthweight newborns. He and his team evaluated the microbiome of several infants at birth and found diverse and similar airway microbiomes in both, which differed from older preterm infants with BPD.

They found that dysbiotic changes in the airway microbiome at birth correlated with the development of BPD, including lower levels of the “good” bacteria lactobacillus in infants born to mothers with chorioamnionitis, an infection of the membranes of the placenta that is an independent risk factor for BPD. They suggested in their paper that a microbiome signature possibly exists in utero, and that part of its role may be to prime the pulmonary immune system. If dysbiosis occurs, they wrote, “it may set the stage for subsequent lung disease.”

So, said Lal, what about a respiratory probiotic to restore the microbiome?

“If it relieves inflammation, could we use this to replace steroids in various childhood lung diseases?” he asked. Studies in mice using Dr. Lal’s patented ‘respiratory probiotics’ demonstrate benefits. “The next step is to test it in larger animals and then humans,” he said.


[1] Lal CV, Bhandari V, Ambalavanan N.Genomics, Microbiomics, Proteomics and Metabolomics in Bronchopulmonary Dysplasia. Semin Perinatol. 2018 Nov;42(7):425-431.

[2] Lal CV, Kandasamy J, Ramani M, Ambalavanan N. Metabolomic and Metagenomic Signatures of Bronchopulmonary Dysplasia. Am J Physiol Lung Cell Mol Physiol. 2018 Aug 16.

[3] Lal CV, Olave N, Travers C, Halloran H, Rezonzew G, Xu X, Genschmer K, Russell D, Gaggar A, Blalock E, Vineet Bhandari, Ambalavanan N. Exosomal MicroRNA 876-3p Predicts and Protects Against Severe Bronchopulmonary Dysplasia in Extremely Preterm Infants. JCI Insight, 2018; 3(5: e93994). PMID: 29515035

Care for the Tiniest Patients

Learn more about the Department of Neonatology at Children’s of Alabama.

Neonatology

NeuroNICU B.R.A.I.N. Program Aims to Improve Outcomes in High-Risk Neonates

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Preterm infants born at 30 weeks or earlier are at higher risk for developing intraventricular hemorrhage (IVH), which is associated with long-term neurocognitive deficits. The risk is also higher for infants with hypoxic-ischemic encephalopathy (HIE), those undergoing ECMO therapy, or those with seizures, metabolic disorders or stroke. Now, a new initiative in the University of Alabama at Birmingham (UAB) Division of Neonatology called NeuroNICU B.R.A.I.N. (Brain Rescue and Avoidance of Injury in Neonates) aims to prevent or reduce that risk.

The core of the initiative is a multidisciplinary team of professionals who work to provide neurodevelopmental care for infants at risk for developing brain injury and cognitive deficits. The team includes a pediatric neurologist, pediatric rehabilitation medicine specialist, pediatric neuro-radiologist, neonatal nurse practitioners, nurse manager, physical therapist, occupational therapist, speech therapist, respiratory therapist and nurse champions. The program also makes parents an integral part of the team.

“We all come together every week and discuss every baby on the unit,” said Allison Black, M.D., NICU associate medical director at Children’s of Alabama. “Before the NeuroNICU program, we would consult individually on an as-needed basis.”

Even though an infant may not need every aspect of care, she said, “everyone working together to integrate the different expertise we have in our field will result in better care for the babies.” The program also uses a standardized bundle of care designed to stabilize the infant and carefully monitor for clinical signs that can increase the risk of IVH.

“The process for the brain injury prevention program starts at birth and continues throughout the entire hospital stay,” said Maran Ramani, M.D., who directs the NeuroNICU program. The protocols call for preventing hypothermia, hypoglycemia and extreme variations in the blood pressure and carbon dioxide levels, and for maintaining fluid intake, all with minimal stimulation. Once discharged, all infants are followed long-term and continually assessed for developmental milestones, he said.

In addition to multidisciplinary care, the program provides near infrared spectroscopy monitoring for preterm and term infants to assess the oxygen saturations in the brain. It also uses transcutaneous CO2 monitoring for preterm infants to assess variations in serum CO2 levels, which plays a critical role in the development of IVH. Term and preterm infants also receive a head ultrasound in to screen for IVH, while preterm infants with grade III and IV IVH undergo   conventional electroencephalogram to detect subclinical seizures. Finally, infants with HIE have an MRI with spectroscopy to assess any damage.

Despite the multifactorial etiology of IVH, Ramani said, standardizing the neuroprotective care is reducing the overall rate of IVH in preterm infants (Figure 1).

Figure 1           Rate of IVH Before and After NeuroNICU B.R.A.I.N. Program

Neonatology Care Protocols Chart

Arrow indicates NeuroNICU roll out

Managing Neurologic Disorders
Visit www.uab.edu/medicine/peds/patient-care/neuro-related-programs-centers to learn about the Division of Pediatric Neurology’s subspecialty clinics at the University of Alabama at Birmingham.

 

Neonatology

Joined at the Hip

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The sky bridges connecting the University of Alabama at Birmingham (UAB) Women & Infants Center and Children’s of Alabama provide more than a means of travel from point A to B. For the UAB/Children’s Division of Neonatology, the sky bridges not only facilitate seamless clinical care, but also seamless research collaborations.

“It’s a tremendous benefit,” said Trent Tipple, M.D., UAB associate professor of pediatrics, director of neonatology faculty development and co-director of the Neonatal-Perinatal Medicine Fellowship Training Program. “The integration is one that just makes sense. It eliminates a lot of barriers that can make research frustrating and allows one to focus on designing the best study with the necessary personnel; to really think about how to execute a study rather than whether a study can be done.”

“It’s one of the unique features here. UAB’s Regional Neonatal Intensive Care Unit and Children’s NICU are literally joined at the hip,” said Namasivayam Ambalavanan, M.D., UAB professor of pediatrics, neonatology division co-director, director of the Translational Research in Normal & Disordered Development (TReNDD) Program at UAB and principal investigator of the UAB Research Center. “This makes clinical care a lot better and research also improves.”

Carl “Tim” Coghill, M.D., UAB professor of pediatrics and medical director of Children’s NICU, said the physical proximity not only serves as a benefit to clinicians and researchers, but also patient families facing what can be a stressful experience.

“Many freestanding children’s hospitals are blocks away from their associated delivery units, making it difficult for consultants to see the infants without transfer away from the mother,” Coghill said. “Children’s of Alabama used to be two blocks from UAB with no connecting bridge. With the present bridge, the closest NICU bed at UAB is only 75 feet from the nearest NICU bed at Children’s, which is closer than some beds are to each other in other respective units.”

Coghill continued, “The ability to stay with a nursing staff that you know and a hospital that you are familiar with while continuing to get the best care is a confidence builder, and delivering great care is only good enough if it is perceived to be great care by the patients and families as well.”

As a founding member of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN), part of the National Institutes of Health (NIH), UAB/Children’s is consistently one of the top centers in developing, leading, enrolling and analyzing randomized controlled trials and clinical studies. For example, neonatology division members have led three major innovative NRN studies – the SAVE Factorial Trial, the Cytokine Study and the SUPPORT Factorial Trial. A fourth trial led by UAB/Children’s neonatologists testing the effects of caffeine late in the neonatal course and at home to shorten hospitalization and decrease apparent life threatening events began enrollment this year.

In its more than 30 years of existence, the NRN has defined the standards of multi-institutional collaborative research resulting in increased survival and decreased morbidity rates of extremely low birth weight infants and other critically ill infants in the U.S. Wally Carlo, M.D., Edwin M. Dixon Endowed Chair in Neonatology and neonatology division co-director, and Ambalavanan are principal investigators for the NRN and have led nationwide studies on ventilator care, antenatal steroids, chronic lung disease and neurodevelopment outcomes. A study in the NRN published in the New England Journal of Medicine reported that neonatal mortality has been decreased over the last 10 years, including decreases in almost all specific causes of neonatal mortality, because of improvements in care implemented in the NRN centers.

In addition, UAB/Children’s is the only facility in the U.S. to be awarded grants in all three perinatal networks from the NICHD – the NRN, the Maternal-Fetal Medicine Units Network and the Global Network for Women’s and Children’s Health Research. For more than two decades, these networks have awarded UAB/Children’s more than $20 million to fund research for pregnant women and babies. The most recent grants, awarded in 2016, will bring a total $1.1 million per year through 2021.

Under the Global Network, UAB/Children’s researchers have led seminal investigations of resuscitation and essential newborn care in 100 communities in six countries, which included almost 200,000 infants. These trials established the effectiveness of these interventions in reducing stillbirths and neonatal mortality, and led to worldwide implementation of training, including the globally-implemented Helping Babies Breathe Program and the Essential Care for Every Baby Program launched in 2014. The programs have been introduced in more than 75 countries to save babies’ lives at birth, with the potential to reduce infant deaths soon after birth by 1 million.

“It should save a million lives every single year at almost no cost,” Carlo said of the programs. “It will save the most lives in the world.”

Division of Neonatology
Learn more about the Division of Neonatology, including specialty clinics and faculty bios, at https://www.childrensal.org/neonatology.

Neonatology

STEPP-IN Initiative Improves Outcomes in Neonatal Surgical Patients

Neonatology_STEPP-IN

Newborns admitted to neonatal intensive care units (NICU) in freestanding children’s hospitals like Children’s of Alabama are typically sicker with much greater complications than those admitted to NICUs in delivery hospitals. Indeed, “All our patients are referred because of some type of complication that can’t be cared for at a delivery facility,” said NICU Associate Medical Director Allison Black, M.D. Most, she said, will require surgical procedures and/or care from pediatric subspecialists.

Thus, developing policies and procedures to improve the overall care and outcomes for these patients is paramount. One of the best ways to do that, research shows, is through a quality improvement approach, in which collaborative teams review current procedures, identify gaps, then redesign processes to close the gaps.

Which is exactly what Black and her team did to reduce perioperative stress in their tiny patients. Called the Safe Transitions and Euthermia in the Perioperative Period in Infants and Neonates (STEPP-IN), it is part of the Children’s Hospital Neonatal Consortium (CHNC).

“We know that going to the operating room creates significant physiological stress for these babies,” according to Black, in part because of the handoff between teams. The idea was to promote stability by improving and standardizing the handoff process. “There was a handoff through the charting, but not face-to-face,” she said.

So a multidisciplinary team of clinicians from the NICU, anesthesia and surgery worked together to create protocols and handoff forms to improve scores on the Post-Operative Management Score (POMS), which measures temperature, glucose, pH, pCO2 and intubation status, all of which can indicate infant stress. The score is calculated based on the number of times every parameter is within the target range. The goal is to reach each parameter at least 85 percent of the time.

The revamped protocol used today requires that the primary bedside nurse as well as nurse practitioner and/or neonatologist transport the infant to the pre-operative bay and provide an in-person handoff to the anesthesiologist or certified nurse anesthetist (CRNA), including written documentation of the baby’s status.

That face-to-face communication is important, Black said. “There are some things about the patient’s overall acuity and clinical course that can’t be expressed on paper and is better communicated verbally at the bedside with the patient,” she said. A similar process occurs postoperatively.

The team first tackled temperature. The handoff sheet requires temperature measures at six time points, including before and after transport to and from the operating room, as well as the highest and lowest temperature measurements during the procedure and the OR room temperature. “From this data we were able to pinpoint when our patients were getting cold and could work to address problems, such as providing education about thermoregulation in the OR as well as during transport,” Black said. Since implementing the new procedures, 90 percent or more of surgical patients have had postoperative temperatures within the accepted range.

Soon after Children’s began collecting data on the initiative, it received the CHNC Continuous Quality Improvement Initiative Golden Collaborative Award. In October, it also received a CHNC award for its work on improving euthermia in the postoperative process through the handoff procedure.

The team is now working to improve other POMS parameters. For instance, it found that it was only collecting full POMS data on about 10 to 20 percent of its postsurgical patients. So it developed a protocol and educated NICU and bedside nurses to obtain postoperative glucose as well as blood gases within one hour of the patient’s return to the NICU from the OR.

“Now that we’re collecting the data, we can take a hard look at where we could improve,” Black said. The team now evaluates the data every month and works to identify and address any problems.

“Looking at the parameters and understanding how they reflect the stability of the patient and how we can improve them in the postoperative period is improving the overall care,” she said.

Neonatology Clinics
Learn about some specialized neonatology services at Children’s of Alabama.