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Saving the Newborn Brain

Saving the Newborn Brain

Brain Dtl

Pediatric neurologist Adam Hartman, neuroradiologist Thierry Huisman and neonatologist Frances Northington, co-directors of the NICN, consult over the care of a newborn.

Soon after boxes of Girl Scout cookies are passed around the table and pleasantries are exchanged, the weekly Neurosciences Intensive Care Nursery (NICN) Friday afternoon conference gets down to business. Over the next hour, a multidisciplinary team of neonatologists, pediatric neurologists and neuroradiologists, among other specialists, review the status of babies either at high risk of neurological injury or who already have signs of brain abnormalities.

They’ve come to Johns Hopkins Children’s Center because of a variety of circumstances—a baby diagnosed during the mother’s pregnancy with hydrocephalus, a buildup of fluid inside the skull that leads to brain swelling; an infant with seizures born to a drug-addicted mother; a baby born to a teen mother unaware she was pregnant. In that case, emergency medical services arrived at the home to find the baby limp, with its umbilical cord wrapped around its neck three times. About 85 percent of patients are transferred to Johns Hopkins from elsewhere.

Over the faint whirring noises from an MRI machine next door, the group hones in on a particularly challenging case: a 21-day-old infant with signs of a possible genetic disorder. The baby has wide- spaced eyes, a poor sucking reflex, poor muscle tone and ambiguous genitalia. Its body periodically has involuntary muscle contractions. Pediatric neuroradiologist Aylin Tekes-Brady shows the group images from head ultrasound and MRI studies, which illuminates areas where the mobility of interstitial water is altered within various regions of the neonatal brain. After some debate about the next steps in testing, the group suggests the residents in charge consult with genetics and check OMIM, a comprehensive online catalog of genetic disorders authored by Hopkins’ McKusick-Nathans Institute of Genetic Medicine.

The group shares thoughts about two other infants before closing. Then, neonatologist and NICN founder Frances Northington tells the two residents caring for the first baby that they have the most complex case, but not to worry: “Use your resources. You’ve got a lot of help.”

These meetings are central to the mission of the NICN, which has cared for hundreds of infants since forming in May 2009. Co-directed by Northington, pediatric neurologist Adam Hartman and pediatric neuroradiologist Thierry Huisman, the unit not only provides multidisciplinary, state-of-the-art care for babies to minimize brain damage, but also serves as on ongoing learning environment for the care team and a rich source of research ideas. Faculty associated with the NICN are pursuing at least 14 research projects, such as measuring blood-based biomarkers associated with brain injury in preterm infants and babies’ ability to regulate blood flow to their brains.

Originally three of the 45 private rooms in the neonatal intensive care nursery (NICU) were designated for NICN patients, but it immediately became clear that as many as a third to a half of infants in the NICU required NICN-type consultation at one time or another during their stay. Now, the NICN is available to any infant that has a neurologic issue.

The NICN’s origins date back to 2008, when Northington and colleagues had the opportunity to apply for funding for a formal neonatal neurosciences program from the Dana and Albert R. Broccoli Charitable Foundation. The organization, started by film producers known for their James Bond pictures, already had funded a heart disease center at Johns Hopkins. With Neonatology Division Director Edward Lawson, Northington pulled her colleagues across disciplines to put together a proposal.

Some other medical centers have a dedicated pediatric neurologist in the NICU, Northington says. “While that’s great, that wasn’t a possibility for us because of personnel demands and rather a low supply of neonatal neurologists,” she explains. “We decided to spread a wider net and try to advance the field, using our clinical cases as a core and then expand from there with educational and research missions.”

With the $170,000 grant, Northington was able to hire neonatal nurse Charlamaine Parkinson as the NICN nurse coordinator and move forward. Since then, the NICN has evolved into a highly consultative group that also includes specialists from maternal fetal medicine, pediatric anesthesiology and critical care, and neonatal respiratory care.

“The cases serve as the talking points for the meetings—we present the neuroimaging and neurophysiology from those cases and there’s always input from multiple other people who are not directly involved in the care, to give ideas about diagnostic workup, care management, and even some idea of what type of outcomes to expect,” she says. “But mostly it’s about doing things to improve the care of those infants.”

The NICN mentality “cuts across the silos” seen in other institutions where experts work independently in their own areas of expertise, adds Hartman: “The problem with the traditional model is that everyone weighs in on different points at different times in the day. You can have a situation where a radiology report can be misinterpreted or miscommunicated.

“I’m a better EEG reader because I know how it correlates with different imaging findings and clinical findings—it has made me a better bedside clinician,” he adds.

Talking about patients in a cross-disciplinary manner helps suggest potential research questions, too.

“I think that we are comfortable enough as a group that we’re OK saying, ‘I don’t know the answer to these questions,’ and either I have to look it up or it’s completely an unknown and that’s what drives some of the generation of new knowledge,” Hartman says. “In a sense I think we push each other a little bit to the limit of what is known and not known.”
Huisman adds, “It is patient care, in the most humane way of respecting each other and getting the input of all specialists into patient care, optimizing the interpretation of acute findings, evaluating treatments and giving some information on prognosis for all people involved.”

With Lawson’s support, an MRI-compatible incubator was purchased, allowing the neonate to be transported and imaged within the safe, well-controlled environment of the incubator. Neuroimaging includes both the bedside use of a dedicated brain ultrasound protocol as well as high-end, multisequence anatomical and functional MR imaging, allowing neuroradiologists to better characterize the quality and degree of brain injury. The advanced neuroimaging information has become an essential parameter in guiding and monitoring brain injury and treatment.

Central to the NICN’s care management offerings is therapeutic hypothermia, otherwise known as “brain cooling.” The treatment, which involves placing infants on a water-filled blanket to cool their core body temperature to 92.3 degrees fahrenheit, then gradually warming them after three days, is considered the standard of care for hypoxic ischemic encephalopathy (HIE), a condition in which oxygen supply to the brain is diminished. Cooling the baby, experts have found, interrupts the injurious metabolic processes that cause neurons to die. Johns Hopkins’ NICU has had a cooling protocol in place since 2007.

The group also incorporates biomarkers, measurable indicators of disease, in their treatment decisions. Work chaired by maternal-fetal medicine expert Ernest Graham determined that increased levels of a protein called glial fibrillary acidic protein in the blood of premature infants with HIE could help predict injury to part of the brain’s white matter, a precursor of cerebral palsy. Parkinson now takes into account those measures when she talks to parents, to give them a realistic picture of what to expect.

“We want to make sure we’re not just saving their body, but also their brain and quality of life,” she says.

The unit constantly evaluates how to improve care for its charges. In December 2014, the neurology group began performing continuous electroencephalography (EEG) on all babies undergoing therapeutic hypothermia to gain a broader perspective of brain activity than the limited sampling afforded by periodic bedside EEG monitoring or by using the simpler aEEG machines. This year nurses will be trialing a cooling head wrap to see if they can achieve better regulation of infants’ core body temperature.

After discharge, all babies are referred to Kennedy Krieger Institute for neurodevelopmental follow-up, and, if they have had a neurologic diagnosis, to Johns Hopkins’ pediatric neurology group. “If we see something that’s not looking good two years down the road, we have the potential to modify whatever it is,” Hartman says. “We don’t have to wait until they come back when they’re 10 or 12 years old, and having all kinds of school problems. We can see these things now and routinely get feedback from Kennedy Krieger. That’s something unusual.”

Recently, he says, a focus has been on what to offer the babies beyond cooling. And researchers here have been hard at work. Developing a neuroprotective bundle of interventions for premature infants has been the focus of one project, led by neonatal nurse practitioner Karen Dittman.

Due to advances in neonatal care, babies born at 25 weeks’ gestation routinely survive, and even those as young as 23 to 24 weeks’ gestation can be saved, Dittman says. But because the blood vessels in the brain are not fully developed, babies in this age group are at high risk for bleeding. Up to a quarter of infants born weighing less than 2.5 pounds experience intraventricular hemorrhage (IVH), which can lead to more serious conditions including hydrocephalus and periventricular leukomalacia—a brain injury involving the death and loss of brain tissue around the ventricles in the brain, which in turn can lead to cerebral palsy or other motor deficits, seizures, and severe developmental delays and cognitive impairments.

Dittman and colleagues are actively searching the medical literature for interventions that could decrease these fragile infants’ risk of IVH. Some ideas include keeping the baby’s head straight and slightly elevated, avoiding rapid administration of IV fluids and rapid blood drawing, and minimizing pain.

“There’s a lot of pseudoscience out there,” Dittman says. “We’re trying to sort through what’s pseudoscience, what’s real science, and what may have been based on somebody’s hunch.”

One intervention already in practice, identified by NICU nurse Karen Frank, is delaying the clamping of preterm infants’ umbilical cords. Waiting just 45 seconds before clamping the cord is enough to allow the placenta to bring more blood cells to the baby so there’s less chance of anemia and a lower risk of intracranial hemorrhage, Dittman says. Doctors also give laboring mothers a shot of betamethasone, a steroid that could decrease their babies’ risk of IVH. In addition, NICU staff work to keep the babies’ temperatures stable, and avoid swings in blood pressure. Upon completion of her review, Dittman will report back to the NICN team. “We want the best possible outcome for our babies.”

Infants undergoing the cooling protocol are routinely given the pain medication morphine to prevent shivering, but neonatologist Estelle Gauda and colleagues are investigating whether clonidine, a blood pressure medication, might better improve neurological outcomes. Beyond lowering blood pressure, the agent also has been shown to have some neuroprotective effects in newborn rats recovering from stroke. It suppresses output from the sympathetic nervous system that activates our innate “fight or flight” response, reducing agitation, excitation, and is quite effective in reducing shivering. As an added bonus, while morphine decreases respiration, which causes the need for additional interventions in some infants, clonidine does not suppress breathing, increasing the probability that the infant can breathe without ventilator support.

Gauda’s group has finished the first part of her study, testing NICN babies’ tolerance of clonidine and the optimal dose, with good success. Next, they’ll study a larger group of infants to better understand how the babies metabolize clonidine during cooling. Ultimately, she says, she’d like to conduct a doubleblinded, randomized controlled trial comparing morphine and clonidine on neurological outcomes.

Also, work directed by pediatric anesthesiologist Jennifer Lee is finding that NICN babies’ ability to regulate blood flow in the brain in the first few days of life can predict how they will do in the next two years. In conjunction with cooling, Lee has been studying cerebral autoregulation, a natural process that maintains stable blood flow to the brain. Within a normal blood pressure range, the brain controls its own blood flow and adapts to changes in blood pressure. So if blood pressure drops, the brain should regulate its own blood flow to prevent a stroke. By contrast, if blood pressure rises, the brain should compensate so it doesn’t hemorrhage.

But babies born with brain injuries may have low oxygen levels and may need medication to support proper blood pressure. Using cerebral near infrared spectroscopy (NIRS), a technology that monitors the concentration of oxygen in the brain, Lee and colleagues can estimate blood flow to the brain and determine the safest range of blood pressure for an individual baby. NIRS uses just a small sticker placed on the forehead, so “it’s an ideal technology for babies,” she says.

Babies who can’t regulate their own blood flow are more likely to show signs of brain injury on an MRI scan at age two weeks, and more likely to have signs of neurocognitive injury at age two years, according to Lee's research.

The NICN will also participate in national clinical trials like the PENUT (Preterm Epo Neuroprotection) study, funded by the National Institute for Neurological Disorders and Stroke. This study, led locally by neonatologist Maureen Gilmore, is studying whether a high dose of a medicine called erythropoietin (Epo) can help protect premature infants’ brains from injury and reduce the occurrence of later developmental problems. They are just beginning recruiting for the study, which will give either Epo or a placebo three times a week until the baby reaches 32 weeks’ gestational age, and follow the babies until they are 2 years old.

Education also is a major focus for the NICN. Parkinson trains all new nurses and fellows in bedside technologies like brain cooling. The NICN faculty organizes regular in-service training workshops on care management for the babies, and every other year partners with Children’s National Medical Center in Washington, D.C., to teach a continuing medical education course covering updates and advances in neonatology. Hartman started a rotation through the NICN that is now required for pediatric neurology residents from Johns Hopkins and neurodevelopmental disabilities residents from Kennedy Krieger Institute. One pediatric neurology resident, Monica Lemmon, was so inspired that she has chosen neonatal neuroscience as a career. She is now the NICN’s first fellow.

“For me, there is no more exciting population to work with,” Lemmon says. “First, you’re working with families at a critical and vulnerable time in their baby’s life. There is a lot of uncertainty. Fortunately, the newborn brain can recover in ways that the adult brain cannot. It is hugely rewarding to work with these children as they grow and develop.”

Among other duties, Lemmon organizes the weekly NICN conferences. A research project she’s undertaking will survey parents of former NICN babies to find out what worked and didn’t work in terms of communication between the families and the NICN teams; their responses may inspire additional changes to the program.

“This fellowship has set the stage for how I’d like to spend my career,” she says. “There is a big interest nationwide in setting up programs like the NICN. People want to replicate it.”

“I tell audiences when I talk about the NICN that everybody needs an NICN because every baby in the neonatal intensive care unit either has a primary neurologic problem or they are at risk for neurologic injury,” says Northington. “Every single patient. That’s how important it is to pay attention.”

Parkinson keeps a log of patients and outcomes so she can communicate with parents. “I tell them, ‘I know it’s scary now, but let me tell you about someone in a similar situation, and how they are doing.’” She keeps in touch with many of the NICN “graduates” and their families. Even some parents whose children have passed away come back to say hello, she says.

“I like seeing how we made a difference,” Parkinson says, “because I know how they would have turned out if we hadn’t intervened.”
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