Groundbreaking Research Seeks to Combat Arterial Thromboembolic

Home , Bubble CPAP, Pediatric surgery

by by ranked innineclinicalspecialties andnationally of Medicine University ofPittsburgh School Pittsburgh isaffiliated withthe UPMC Children’s Hospitalof Spring 2019 • • • • In This Issue • • • U.S. News&World Report Neonates Medicine Anomaly inNeonatal Patients Surgery for Complex Airway Multidisciplinary Specialty Program in Neonatal Cardiac Patients Thromboembolic Disease Seeks to Combat Arterial The EXITProcedure: Continuity Care Faculty NICU Family Advisory Board Groundbreaking Research A First Graduation Ceremony Bubble CPAP andPreterm Clinical Trials inNeonatal Pediatric Insights

Platelet functioninneonates alsohasbeenunderstudied, andtheavailability anddevelopment efficacy, safety, pharmacodynamics, andoptimaldosage,” says Dr. Diacovo. these agents has ever beentested orconfirmed inpediatricpatients to understand their successful inpreventing clotformation inadultsandsaving lives. However, noneof virtually all theway backto thesynthesis ofaspirininthemid-1800s, whichhave proven to beextremely “There have beenmany anticoagulation agents developed for adultsover many decades,going these rates ofthromboembolic diseasehave been,andcontinue to be,completely unacceptable. mortality reflective ofsuchhigh rates ofbloodclots. For Dr. Diacovo andhisstudy companions, shunt thrombosis anywhere from 17percent to 34percent, withcorresponding morbidity and patients treated inspecialized centers. The current literature onthesubjectshows ranges of requiring placement ofasystemic shunt,are to pulmonaryartery thehighestofallpediatric Rates ofthrombosis inpost-operative neonatalcardiac those patients,andinparticular Disease inNeonatal Cardiac Patients Combat Arterial Thromboembolic Groundbreaking Research Seeksto cangrelor onP2Y of platelet agonists andantagonists, andtheirfindingsoftheefficacy andoptimalusageof their novel andgroundbreaking process analyzing responses to singleagents andcombinations In 2017 inthe With Microfluidic Devices andaNovel In Vivo MouseModel Uncovering Responses to Platelet Agonists andAntagonists new clinicaltrialsinhumansubjects. new findings, technological advances, andanimalmodelsthatare now leading to important However, Dr. Diacovo’s research hasbegunto upendthissuboptimaltreatment paradigm with antagonists haslagged indevelopment. of technologies to rapidly assess platelet response inpediatricpatientsto various agonists and Journal oftheAmerican College ofCardiology, 12 receptor functioninneonatal andpediatricCHDpatients. For thelastfour years, vascular Research, haslednew studies to combat thedevelopment UPMC Newborn MedicineProgram, anddirector ofNeonatal Cardio surgical repair for complex congenital conditions. heart of acute thromboembolic events (ATE) inneonates whorequire An Update from theUPMCNewborn MedicineProgram Thomas G.Diacovo, MD Dr. Diacovo andcolleagues outlined , division chief of the , divisionchiefofthe

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2 Pediatric Insights: Neonatology Spring 2019

The NICU Family Advisory Board

Very few expectant parents ever anticipate that their child will need admission to the neonatal intensive care unit after birth. However, when a NICU transport and admission is required, it is very often a traumatic and frightening experience for the entire family. UPMC Children’s operates a level IV NICU and routinely admits patients from up to four hours’ distance, many of whom arrive via helicopter. The NICU at UPMC Children’s is a bustling unit with more than 1,000 admissions each year, many for extended stays of several months.

To foster a continually evolving and improving Successes and Policy Changes room. Usually it would be the mother, and the patient and family experience for those who Spurred by the FAB father had to leave and sleep elsewhere in the are in need of a NICU admission, the NICU Mrs. MacPherson indicates that since the hospital. Within the first two months of the Family Advisory Board (FAB) was created in FAB’s founding, its members have been FAB’s existence, they were instrumental in 2014. Its creation was spearheaded by NICU involved with helping shape or change helping to get this policy changed to allow Quality Improvement Program Manager and approximately 17 different unit policies both parents to remain bedside at night if Family Experience Program Manager Mary Jo or equipment changes through the they wish,” says Mrs. MacPherson. MacPherson, BSN, RN, CBC, as a means of feedback process, and have offered more providing evidence-based best practice patient than 40 parent-to-parent events in the Contributing to the QI Process experience for visiting families. In addition to NICU for current inpatient families. her roles at UPMC Children’s, Mrs. MacPherson Quality improvement initiatives are a huge also is the quality improvement manager The projects have run the gamut from part of the day-to-day operation of virtually for the Children’s Hospitals Neonatal providing feedback when the NICU expanded every NICU in the United States. At UPMC Collaborative (CHNC). from 33 to 55 beds in 2014, to parent involve- Children’s, the FAB has taken an active part of ment in a central line infection prevention several QI projects that have had tremendous Entering its fifth year of operation, the FAB and handwashing protocol. The FAB also has success in improving clinical outcomes and consists of a rotating mix of individuals that advised on various NICU policies, including other aspects of the NICU experience for includes Mrs. MacPherson, two NICU floor allowing both parents to remain at their patients, parents, and staff. nurses, and NICU alumni parents and baby’s bedside 24/7. grandparents, along with individuals from “Our Breastmilk = Medicine project in the the surrounding Pittsburgh communities. Mrs. MacPherson also points out what NICU has increased the percentage of new The board meets monthly to discuss and she sees as the FAB’s most significant moms breastfeeding at the time of discharge provide firsthand perspectives on unit policies, contribution to date: the change in parent from 45 percent to 76 percent during its first and it helps guide the implementation of sleeping policy at the bedside. month. In the more than five years since its family-centered changes to procedures inception, the average rate of mothers breast and practices. Every other month there are “It used to be the case that only one parent feeding at discharge has been maintained parent-to-parent events where board was allowed to sleep over in their baby’s at 82 percent,” says Mrs. MacPherson. members or past NICU alumni will visit and interact with current families on the unit.

“These peer-to-peer support opportunities NICU Family Advisory Board Goals are incredibly helpful for families. They are able to visit with and interact with people • Improve family-centered care through solicitation of feedback on new projects, who have gone through a similar experience policies, and procedures from NICU alumni parents. with their child and come out the other side. • Provide parent-to-parent support for current NICU families from individuals If a family has been in the NICU for several with a previous NICU stay and discharge. months, they can begin to feel as though they will never be going home. Having the • Support quality improvement initiatives within the UPMC Children’s NICU and chance to interact with NICU “Alumni” promote the NICU’s community presence and outreach work. families can be very beneficial emotionally,” says Mrs. MacPherson. UPMCPhysicianResources.com/Pediatrics 3

The FAB also has been instrumental in increase participation and the number of overcoming barriers to change. It has another QI initiative called the Kangaroo-a- hours of STS, the better. Ideas from FAB given the NICU an effective strategy for the thon Project that sought to substantially members and their perspective that including provision of evidence-based, best-practice increase the amount of skin-to-skin (STS) fathers needed to be more of a priority parent-to-parent emotional support, and it time between parents and their NICU babies. has directly benefited many families,” has been a key driver for implementation of says Mrs. MacPherson. transformational family-centered policy “The FAB realized that sometimes fathers can improvements that have shown significant be left out of the picture in everything that impact on the overall patient experience An Instrument for Practice Change happens in the NICU, so they emphasized in the UPMC Children’s NICU. the importance of fathers in this aspect of Formation of a unit-based family advisory parent-child interaction. It provides nothing board has proven to be an effective tool for but positive benefits. The more we can

Arterial Thromboembolic Disease in Neonatal Cardiac Patients Continued from Page 1

Using a novel mouse model created by the evidence-based guidance and real-time “Our preliminary work shows a vast difference Diacovo lab while at Columbia University, analysis of platelet function in individuals, the between the two age groups, which you and microfluidic devices by colleagues at the most appropriate course of pharmacologic may understand intuitively, but because no University of Pennsylvania capable of assessing therapy to mitigate clot formation risk may one has been able to do these studies in the clotting using 20-times less blood than in be predicted. past we lack basic, concrete knowledge of standard testing platforms (a significant how these agents work in the very young. advancement and desirous approach, “A large part of our research agenda from Knowing what the true pharmacokinetics or particularly in neonates where blood draw the outset has been to test these novel pharmacodynamics are of these drugs in our amounts are limited for safety concerns), drugs in animal models in order to make neonatal patients, again, is the crux of our the researchers were able to not only show better predictions of how these pharma entire research endeavor,” says Dr. Diacovo. efficacy of the entire testing platform for ceutical agents will actually work before determining platelet reactivity in these introducing them into a child. Just looking at References and Further Reading subject, but they were also able to show the laboratory values has little bearing on actual 1 in vivo efficacy of cangrelor setting the stage function. This functionality is a crucial part of Kaza EA, Egalka MC, Zhou H, Chen J, Evans D, Prats J, Li R, Diamond SL, Vincent JA, Bacha A, for the first trial in neonatal cardiac patients. the equation we must work to understand,” says Dr. Diacovo. Diacovo TG. P2Y12 Receptor Function and “A major success of our work during the first Response to Cangrelor in Neonates With three years was our ability to go from our The existing methodologies and dearth of Cyanotic Congenital Heart Disease. J Am Coll Cardiol. 2017; 2(4): 465-476. basic science studies to preclinical and then evidence to support treatments to combat arterial thromboembolic disease have relied rapidly translate it into a phase 1 clinical trial Neonatal and Pediatric Platelet Function mainly on extrapolation. that we are in the process of finishing,” and Pharmacology. NIH Project Number: says Dr. Diacovo. 7R01HD081281-04. Principal Investigator: Preparations for a New Clinical Trial Thomas G. Diacovo, MD.

Predicting Response and While Dr. Diacovo and colleagues are still Determining Functionality and working to finish their first phase 1 trial, Functional Changes planning currently is underway for a second The types of studies Dr. Diacovo and trial that will examine specific Xa inhibitory colleagues are engaged in are providing agents like apixaban. Dr. Diacovo’s team is the framework and foundation for a new working to finish various ex vivo studies paradigm of treatment determination to using their microfluidic devices and mouse combat the scourge of arterial thrombo modeling technologies to assess the embolic disease. By providing sound, differences between adults and neonates. 4 Pediatric Insights: Neonatology Spring 2019

Continuity Care Faculty Program

All families and babies admitted to the NICU endure significant stress, time away from home, uncertainty about the future, and much more. Families of babies in the NICU who are inpatients for longer than three months deal with these and other issues much longer than most. Over extended periods of time, and because of the natural flow of staff changes and physician service periods (every two weeks at the UPMC Children’s NICU), communications between families and providers also can become fragmented or inconsistent and can lead to stress and potential negative patient experiences.

In November 2018, at the suggestion of Thomas Diacovo, MD, chief of the UPMC Newborn Medicine Program, the UPMC Carrie Rubino, MSN, RN, CCRN Children’s NICU developed and instituted a new program for any family/patient unit who need stays on the NICU for longer than three months.

Dubbed the Continuity Care Faculty Program, every long-term NICU patient is assigned one physician who oversees the entirety of their communication with families, and enable a Diane Ankney, MSN, RN, NEA-BC care, regardless of whether or not the physician better understanding of family needs and the is assigned to be attending for a given week. family’s understanding of the care their child is receiving or will need in the future. Carrie Rubino, MSN, RN, CCRN, and Diane Ankney, MSN, RN, NEA-BC, unit “In terms of patient volume, we have approx directors of the UPMC Children’s NICU, imately three or four of these longer-term worked to implement the program NICU stays at any given time. And we try to and continue to oversee its elements. limit the number of continuity cases that Ms. Rubino and Ms. Ankney work to identify Beverly Brozanski, MD each physician has at one time to just two,” the patients who are or will be in need of says Ms. Rubino. greater than 90-day-stays, and coordinate with the physician staff who will be assigned to the patients. Consistency of Communication Is Key to Family Satisfaction

“Our physicians work together to determine The program was successful immediately who will be the best fit to oversee care for upon implementation, ensuring communica any particular patient, and we facilitate and tions to families from one team or physician help to coordinate all the necessary logistics. to the next is seamless and consistent. This includes holding a patient/family care conference at two-week intervals,” “Some of our patients are here for a long says Ms. Ankney. time — and oftentimes it is the families who know their babies best and can sense when These have become vitally important for something may be changing or an issue is family members in a short period of time. The arising. Valuing and respecting the parent’s families have access to a consistent voice who insights and opinions is something that we oversees the care of their baby, and the family work diligently on so the family understands is included in all of the communications and that we value their input,” says Beverly major decisions or plans. The conferences and Brozanski, MD, medical director of the single point of communication from one NICU at UPMC Children’s. dedicated physician have been able to break down communication barriers, enhance UPMCPhysicianResources.com/Pediatrics 5

The EXIT Procedure: Multidisciplinary Specialty Surgery for Complex Airway Anomaly in Neonatal Patients

Ex utero intrapartum treatment (EXIT) is a highly specialized, multidisciplinary surgical procedure used to deliver babies who have been diagnosed prenatally with various airway anomalies leading to airway compression or blockage, making a normal vaginal birth or traditional Caesarean section delivery unviable for the baby. Anomalies or conditions leading to airway compression for which the EXIT procedure may be needed include cervical teratomas, cystic hygromas, or a blockage of the airway from congenital high airway obstruction syndrome (CHAOS).

Diagnosing and treating some of rarest, most complex prenatal The Center for Advanced Fetal Diagnostics conditions amenable to in utero surgical intervention is a collaboration The CAFD is a multidisciplinary service primarily housed at UPMC between the UPMC Newborn Medicine Program, the Fetal Diagnosis Magee. This service provides comprehensive care to patients and their and Treatment Center, the Center for Innovative Fetal Intervention (CIFI), providers following the prenatal diagnosis of fetal anomalies. and the Center for Advanced Fetal Diagnostics (CAFD). Primary components of this service include prenatal ultrasound; “Achieving good outcomes for these highly complex genetics (including both genetic counseling and reproductive geneticist cases is not something every hospital or even services); maternal-fetal medicine; neonatology; pediatric surgery. academic medical center can accomplish. It takes Additionally, the CAFD works closely and coordinates care with various a tremendous amount of resources, planning, pediatric subspecialties, that include cardiology, urology, neurology, procedural skill, and the technical expertise neurosurgery, radiology, and others. The CAFD also works closely of dozens of individuals before, during, and after with the CIFI to provide comprehensive fetal surgery. the surgery to perform this procedure safely and effectively,” says Kalyani Vats, MD, assistant In a true multidisciplinary fashion, weekly meetings review CAFD professor of pediatrics, a neonatologist with the UPMC Newborn patients and provide an opportunity for input from multiple specialties Medicine Program, co-Director of the CAFD at UPMC Magee-Womens into the care of each patient. This coordination of care promotes Hospital, and director of triage and antenatal consult services, also seamless continuity from prenatal diagnosis and counseling through at UPMC Magee. delivery and postnatal care.

The ability to conduct EXIT procedures, and to conduct them safely and EXIT Procedure Indications, Variations, and successfully, can be accomplished only by a multidisciplinary team of Best Practice Guidelines at UPMC highly skilled, physicians, surgeons, and nurses operating in an environ- ment with the necessary infrastructure and expertise to transform a The most common indication for the EXIT procedure is a fetus with potentially fatal neonatal emergency into a controlled situation. an airway compromised by a neck mass such as a cervical teratoma or lymphangioma, tracheal or laryngeal atresia (resulting in CHAOS), UPMC is one such place with the ability to successfully navigate the or severe micrognathia. The EXIT procedure allows time to secure complexities of the EXIT procedure, and it has been doing so for close the fetal airway by laryngoscopy, bronchoscopy, endotracheal to 15 years. The EXIT team at UPMC comprises experienced, highly intubation, or tracheostomy, depending upon the nature of the skilled clinicians from multiple specialties and hospitals, including condition and the surgical preplanning and can have several maternal-fetal medicine, maternal-fetal anesthesia, neonatology, variations (See Table 1 on Page 6). pediatric surgery, otolaryngology, obstetrics, and nursing, along with an operating room that is specifically designed for performing fetal EXIT-to-Airway turns an airway emergency into a controlled, planned procedures. Clinicians at UPMC performed their first EXIT procedure procedure. The EXIT-to-ECMO strategy is useful in cases of severe in 2004, and have since conducted several EXIT and PRESTO (Presence pulmonary or cardiac malformations in which separation from of Extra Surgical Team at Operation) procedures (PRESTO is similar to EXIT, yet is a less extensive procedure). EXIT is a rare procedure; however, Continued on Page 6 when it is called for it may be the only way to save the life of the baby. 6 Pediatric Insights: Neonatology Spring 2019

The EXIT Procedure Continued from Page 5 Table 1. Variations of the EXIT Procedure and Their Indications uteroplacental circulation will lead to immediate instability in the newborn. In such cases, EXIT-to-ECMO strategy can be applied to Procedure: EXIT-to-Airway secure the airway and insert venous and arterial cannulas for ECMO Indications: while on placental support. This approach avoids a possible period • Cervical teratoma/lymphangioma of hypoxia or acidosis during neonatal resuscitation. • Congenital high airway obstruction syndrome (CHAOS) Not all babies with airway obstructions will be candidates for the • Micrognathia (small chin) EXIT procedure. Some conditions may be able to be handled through Procedure: EXIT-to-Extra-Corporeal Membrane Oxygenation (ECMO) alternative procedures or airway management protocols. Indications: • Congenital diaphragmatic hernia (CDH) “Not every compromised airway calls for an EXIT procedure, nor does every mass in the neck. We look at all the signs and clues for the well- Procedure: EXIT-to-Resection being of the fetus to determine airway function in advance. If it appears Indications: to be a life-threatening condition, then EXIT may be an option, but • Congenital pulmonary airway malformation of the lung (CPAM) many other factors contribute to the final determination,” says Dr. Vats. • Bronchopulmonary sequestrations (BPS) • Mediastinal, cervical, or oral teratoma

Planning and Preparations for an EXIT Procedure

Virtually all cases of significant high airway obstruction are diagnosed prenatally via ultrasonography and confirmed by fetal magnetic “If the mother is fine, and the baby is fine, and no complications arise, resonance imaging (MRI) during the mother’s pregnancy. Fetal MRI is an we will expect to allow the pregnancy to continue for as long as possible important aspect of the consultation and planning process for when an so the fetus can grow and develop as much as possible, or until there is EXIT procedure may be a viable surgical option for both mother and baby. a change in status that warrants immediate intervention. The older and more mature the fetus is, when EXIT is performed, typically the better Sufficient time is needed to assess both the mother and fetus, determine the outcomes will be. However, if we have an EXIT case that we are the extent of the airway anomaly, and uncover other issues that may be monitoring, the entire team must be on call and ready to go at a compromising the health or viability of the fetus. A plan for the nature of moment’s notice should the mother arrive in premature labor. This the EXIT procedure is needed. Also, alternate plans for care, should an aspect factors heavily into our planning process,” says Dr. Vats. EXIT procedure not be warranted, desired, or are considered safe. This process takes significant time and coordination between many clinical A few days before the procedure is anticipated to occur, the entire specialties, and then the family must be informed and counselled on all team performs a walk-through of the procedure in a special operating the options, risks, and unknowns that factor into such highly complex room used for EXIT. Every element of the procedure is choreographed in medical and surgical decisions. advance, including where everyone will be positioned, and where equipment will be placed. Every specialty taking part in the procedure “There are cases where we could perform an EXIT procedure, but other has a dedicated area for their needs in the operating suite. underlying issues may render securing the airway and ultimately repairing it moot. However, if the airway anomaly is the only major issue affecting “Because these procedures are so rare, they present an excellent the fetus, we can secure the airway through the EXIT procedure, and our teaching and observational opportunity for all levels of medical trainee ENT surgeons can continue to follow, evaluate, and reconstruct the and care providers. We direct a live feed of the procedure to another airway later,” says Dr. Vats. room set up specifically to view our EXIT cases, where residents, fellows, students, and others can observe, in real-time, the progression Planning for an EXIT procedure typically begins early, usually at 24 to and details of the procedure,” says Dr. Vats. 25-weeks gestation. Planning includes diagnostics through the CAFD, consultations and case reviews with maternal-fetal medicine, ENT, Surgical Details of EXIT at UPMC Magee neonatology, surgery, anesthesia, and any other specialties that may and UPMC Children’s be needed based on the baby’s underlying conditions. At a fundamental level, the EXIT procedure serves a simple function. Premature babies — especially those under 32-weeks gestation — are By keeping the baby attached through the umbilical cord to the placenta not good candidates for an EXIT procedure. The complications and to sustain perfusion and respiration, the EXIT procedure allows the contributing factors in a fetus at that gestation generally outweigh team the time they need to deliver the baby via C-section, work to benefits of the EXIT procedure, according to Dr. Vats. establish or secure an airway through whatever means are called for, and then separate baby from mother. UPMCPhysicianResources.com/Pediatrics 7

It is a simple concept, but one that requires some of the most Likewise, the mother will be monitored closely for hemorrhage, thorough and complex planning to execute that is likely to be seen infection, or other postdelivery complications for an appropriate time in a surgical procedure. period based on the specific nature of the case.

“Our colleagues in anesthesia and maternal-fetal medicine play a A debriefing session occurs upon conclusion of the procedure and critical role in the success of this procedure. The mother must receive before the team members depart. Team leaders from the various general anesthesia for the C-section. The deep anesthesia she receives specialties involved in the case meet to briefly review the entire is done to achieve and maintain a state of uterine relaxation to preserve procedure and report their perspectives and opinions of how the entire uteroplacental circulation, and a special uterine stapling device is used case proceeded and any anticipated or unanticipated issues that arose. to open the uterus to prevent bleeding,” says Dr. Vats. This initial debriefing is typically followed a few days later by another more detailed session where all team members, including nursing, The team also must ensure that normal maternal blood pressure is participate to discuss the case. The entire EXIT team receives an update maintained and that appropriate levels of fetal anesthesia are achieved on how the mother and baby are progressing in their postoperative care, without triggering cardiac depression. It is a delicate balance that must and the team also reviews the procedure notes and findings to identify, be struck, and the teams at UPMC have perfected their anesthesia address, and collaboratively solve any issues that arose. The entire protocols for the procedure. debriefing process is intended to inform and guide future cases, learning from any unique aspects that the cases provide and contributes to the Once the C-section is performed, the baby is then partially (the head evolution of best practices for these rare and complex deliveries. and upper torso) delivered through the incision while remaining attached to the placenta through the umbilical cord. Anesthesia keeps the uterus soft and relaxed, which allows the placenta to continue to perform its function. The procedure preserves uteroplacental gas exchange so that the baby can continue to receive oxygen and nutrients from the mother EXIT Procedure — Key Team Members at UPMC while the team works to establish an airway that will permit the infant Stephen P. Emery, MD — Associate Professor and Director, to breathe and obtain oxygen once he or she is fully delivered. Center for Innovative Fetal Intervention (CIFI) — UPMC Magee The baby is only partially delivered through the incision to naturally Kalyani Vats, MD — Co-Director Center for Advanced Fetal keep the baby warm without the need for other interventions to Diagnostics (CAFD) — UPMC Magee prevent hypothermia. Jeffrey P. Simons, MD, FAAP — Professor, Pediatric Potential risks to the EXIT procedure include intrauterine bleeding for Otolaryngology — UPMC Children’s the mother. For the baby, if endotracheal intubation fails, the surgical team will need to perform a tracheostomy to establish an airway before Allison Tobey, MD — Assistant Professor, Pediatric the procedure is completed and the baby whisked away to the NICU Otolaryngology — UPMC Children’s for follow-up care. Jonathan H. Waters, MD — Chief, Department of Once the baby’s airway is established, and the delivery concludes, Anesthesiology — UPMC Magee Dr. Vats and her neonatology team takes over and transfers the infant to the NICU where other procedures and care will take place. Further into Linda S. Dudas, RNC, MSN, CNL — Unit Director, Labor, the care plan, once the infant is stabilized in the UPMC Magee NICU, Delivery, and Antepartum — UPMC Magee he or she is then transferred to the UPMC Children’s NICU for the Barb Eichhorn, RN, BSN — Nurse Coordinator, CAFD balance of their care and follow-up procedures based on their needs. and CIFI — UPMC Magee

Postprocedural Care Douglas A. Potoka, MD, FACS, FAAP — Assistant Professor of Surgery, Division of Pediatric General and Thoracic After the delivery, the baby receives specialized care in the neonatal Surgery — UPMC Children’s intensive care units of the UPMC Newborn Medicine Program, either at UPMC Magee or UPMC Children’s. Babies who need help with respiration but do not require ECMO may be placed on a ventilator for respiratory support.

If called for as part of the surgical preplanning process, a pediatric surgeon also may perform additional procedure(s) to correct an underlying congenital anomaly that may be amenable to surgery. 8 Pediatric Insights: Neonatology Spring 2019

Clinical Trials in Neonatal Medicine: Shrinking the Ninety Percent Gap

Ninety percent of pharmaceutical agents that are used to treat or prevent various conditions in neonatal patients — medications that have been approved for similar usage in adult patients — have never actually been tested in neonates to determine their pharmacokinetics, pharmacodynamics, optimal dosing patterns, and other criteria.

Use of these agents in this patient population Cangrelor Use in Neonates Dr. Diacovo is serving as the site primary is largely driven by empirical evidence of how investigator for this study, and is collaborating This investigator-initiated study being they work in adults and physician discretion internally with colleagues from the UPMC conducted at UPMC Children’s and led by based on the available clinical guidance or Heart Institute at UPMC Children’s Hospital Dr. Diacovo, will assess the pharmaco institutional protocols. of Pittsburgh. dynamics and pharmacokinetics of cangrelor “The fact that most of the drugs we use in our used in neonatal patients who are at risk for This apixaban study is being conducted in neonatal patients have not undergone prior thrombosis related to the use of pulmonary pediatric patients from age 3 months to 18 testing in this group is unsatisfactory at best,” arterial shunting. years. Various aspects of pharmacokinetics says Thomas Diacovo, MD, chief of the and safety will be examined, as well as Dr. Diacovo and his study collaborators will UPMC Newborn Medicine outcomes related to bleeding events, fatal seek to enroll up to 20 participants up to 28 Program at UPMC bleeding, and bleeding that requires some days in age in this trial analyzing the safety Children’s Hospital of form of medical or surgical intervention to and mechanistic properties of cangrelor in Pittsburgh. “Yes, it is restore hemostasis. four discrete doses. The trial will start with a exceptionally difficult to cohort of four subjects receiving the lowest conduct many of these dose and progress over time to additional Searching for High-Risk Markers studies. However, it is cohorts of four — each receiving subsequently for Necrotizing Enterocolitis incumbent upon the field larger doses of the agent. Liza Konnikova, MD, PhD, FAAP, assistant to do more and do better by our patients, professor of pediatrics and developmental regardless of the difficulty or barriers we face Apixaban and Heart Disease biology at UPMC Children’s Hospital, is a in building this badly needed evidence base.” in Children physician-scientist who broadly investigates Increasing the evidence base for the use of how neonatal mucosal UPMC Children’s is now participating in a pharmaceutical agents in neonatal patients is immunity develops and its multicenter, randomized study investigating a priority for Dr. Diacovo and his colleagues in role in the pathogenesis the use of apixaban to prevent thrombo the UPMC Newborn Medicine Program. The of diseases, including embolism in pediatric patients with congenital program is currently participating in ongoing necrotizing enterocolitis heart disease or an acquired version of multicenter investigations examining the (NEC) and very-early- heart disease. efficacy of various medications in neonates. onset inflammatory bowel Sponsored by Bristol-Myers Squibb in In addition to the pharmaceutical clinical disease (VEOIBD). collaboration with the Pediatric Heart trials in progress, several new basic and NEC is the leading cause of death in preterm Network and Pfizer, the study — titled translational investigations are examining infants. Despite advances in neonatal care, “Safety and Pharmacokinetics of Apixaban aspects of necrotizing enterocolitis, immune the survival of infants with NEC remains Versus Vitamin K Antagonist or LMWH and microbial development in the neonatal low — less than 50 percent in many cases. in Pediatric Subjects with Congenital or gastrointestinal tract, and a novel approach to In part, this is due to an inability to predict Acquired Heart Disease for Thrombo using precision medicine in the diagnosis of which infants are at risk for the development embolism Prevention” — is a badly needed genetic disorders in neonates. of NEC and the subsequent failure to utilize examination of how this antithrombotic preventative strategies. Below are summaries of these promising new functions in pediatric patients, and how it trials currently in progress that seek to improve compares in usage and efficacy with low the care of neonatal patients everywhere. molecular weight warfarin (LMWH) or vitamin K antagonist (VKA). UPMCPhysicianResources.com/Pediatrics 9

One of Dr. Konnikova’s current studies and colleagues have adapted mass cytometry The usual therapy for HIE involves the use seeks to understand Toll-like receptor (CyTOF) to perform deep immunophenotyping of hypothermia. The HEAL trial (High-dose (TLR) biomarkers in necrotizing enterocolitis and functional analysis of immune cells at Erythropoietin for Asphyxia and Enceph and how to use these markers to identify mucosal surfaces. These advances have alopathy) is a multicenter, randomized premature neonates who are at high risk allowed Dr. Konnikova to study immune investigation of the efficacy of erythropoietin for developing NEC. dysregulation in various diseases such as (EPO) that is being conducted to see if its use NEC and VEOIBD. can improve outcomes when given in tandem Dr. Konnikova’s lab has identified that innate with the use of hypothermia. immune signaling via the Toll-like receptor 4 (TLR4) plays a key role in the development The PreMOD2 Study EPO acts both as a neuroprotective agent and of NEC. Her team now is searching for novel Toby D. Yanowitz, MD, MS, associate as a growth factor in the brain. The study biomarkers for NEC in a longitudinal cohort professor of pediatrics, obstetrics, gynecology, seeks to determine if EPO given in five doses study of infants with NEC by assessing the and productive sciences of 1,000 units per kilogram, in combination TLR4 signaling capacity of these neonates, at UPMC Children’s, with hypothermia, will reduce neurocognitive using combined in vitro and in silico serves as the site primary deficits and mortality in newborns. approaches. In so doing, Dr. Konnikova and investigator for the Dr. Yanowitz is the site primary investigator her team hope to advance the field by PreMOD2 study. This for this trial at UPMC Children’s. identifying newborns that are at risk for NEC study is investigating the development, thus creating a window for early benefits of delayed cord Ceftobiprole Use in Neonates prophylactic and interventional therapies. clamping (DCC) versus the use of umbilical cord milking (UCM) to Kathleen Schwabenbauer, MD, assistant Uncovering the Mysteries mitigate bleeding in the brain in premature professor of pediatrics and a neonatologist of Immune and Microbial neonates and to prevent mortality. The trial is with the UPMC Newborn Development in the GI Tract currently enrolling neonatal patients that are Medicine program, is the 30 to 32 + six weeks gestational age. site primary investigator The gastrointestinal (GI) tract is one of the for a multicenter study body’s largest immune organs. It is also host Dr. Yanowitz and the other study leaders designed to characterize to 500 to 1,000 different bacterial species are primarily interested in both short- and the pharmacokinetics of and as many as 1014 bacteria. The majority long-term outcomes of the use of UCM or ceftobiprole — a broad- of these bacteria represent commensals that DCC in those neonatal subjects delivered spectrum antibiotic in the play an important role in the development before 32-weeks gestation. cephalosporin family that is used to treat a and maintenance of the host immune system. In this randomized study, patients will either range of Gram-positive and Gram-negative The interplay between the immune cells and receive UCM at the time of delivery (four bacterial pathogens. the commensal bacteria allows for host’s times during a 15 to 20 second period) or immune system to respond to pathogenic The dynamics of the medication are being DCC for a minimum of 60 seconds. The bacteria while being tolerant of the com tested in neonates and infants who are up to goal is to see if either method is better at mensal ones. However, how homeostasis is three months of age but greater than or equal preventing intraventricular hemorrhage or established and maintained in humans is to 28 weeks gestation. death in premature newborns. very poorly understood. This open-label interventional study will Through translational studies of human tissue Combatting HIE with EPO: evaluate the dynamics and safety of a single throughout gestation, as well as tissue from The HEAL Trial dose of ceftobiprole given to patients neonates and young children, Dr. Konnikova currently undergoing some form of systemic Hypoxic-ischemic encephalopathy (HIE) is working to decipher how homeostasis is antibiotic treatment at a dose of 7.5 mg/kg is a consequence of reduced blood flow and, established and maintained. body weight via a four-hour infusion. ultimately, a reduced flow of oxygen to the Dysregulation of the GI immune homeostasis brain that occurs close to the time of birth. Dr. Diacovo is serving as the co-primary leads to a number of diseases, such as Affecting approximately 12,000 babies investigator of this trial. ClinicalTrials.gov necrotizing enterocolitis (NEC), very-early- each year in the United States, HIE has the Identifier: NCT02527681. onset inflammatory bowel disease (VEOIBD) potential to inflict devastating, permanent and IBD. To facilitate studying mucosal neurologic impairments. It leads to mortality immunity in health and diseases, Dr. Konnikova in nearly 10 percent of cases, with higher rates attributable to more severe cases. Continued on Page 11 10 Pediatric Insights: Neonatology Spring 2019

Bubble CPAP and Preterm Neonates: A Noninvasive Ventilation Approach to Quality Improvement — Six-Month Implementation Results Update

Preterm neonates — and particularly extremely preterm neonates who are less than 28-weeks gestational age — are at a high risk for developing bronchopulmonary dysplasia (BPD), which carries with it significant rates of morbidity and mortality. The use of mechanical ventilation for respiratory support, coupled with the use of pulmonary surfactants, increases these risks.

“In those neonates with a Vigilant monitoring of the positioning of the days and corresponding fleet size, secondary gestational age less than breathing apparatus and airway pressure is care costs associated with BPD (short- and 28-weeks, the literature required to ensure the proper levels of positive long-term), and other financial benefits. shows a nearly 40 percent pressure ventilation are delivered at all times. rate of BPD. This has both For the first six months of the short- and long-term Implementing the Protocol Bubble CPAP initiative: complications for the Bubble CPAP protocol development • Surfactant use has declined by more than patients and their families. began in February 2018. At that time, 50 percent. With the implementation and use of bubble the implementation of a multidisciplinary CPAP, a noninvasive, safe, and effective Within just the first two weeks of the committee was formed, consultations and method of respiratory support for spontan Bubble CPAP initiative, surfactant use training occurred with experts in the field eously breathing babies, we believe rates of dropped by more than 50 percent. from Columbia University in New York, and an BPD will be dramatically reduced, along with That trend in decreases versus baseline extensive literature review of the established overall use of mechanical ventilation and statistics has continued. evidence of bubble CPAP use in preterm other support measures that have been neonates was undertaken. • Unplanned extubations have dropped part of our existing standard of care,” says considerably. James Kiger, MD, MS, medical director for The protocol moved into active use in the Newborn Respiratory Care and Bubble NICUs at UPMC Children’s and UPMC From September 2018 through January CPAP implementation lead. Magee-Womens Hospital on September 11, 2019, there were just five unplanned 2018, after all the necessary equipment, extubations. By comparison, in the five Implementation of the bubble CPAP protocol training, education, and protocol outcomes months preceding the use of bubble CPAP is not without its risks and challenges. Because and practices were established and executed. there were 12 unplanned extubations. the protocol entails its use in neonates up to 32-weeks gestational age (more or less time • The total number of ventilator days has Outcomes and Benefits of the on the device is possible depending on the decreased even more dramatically. Protocol — Six-Month Metrics specific needs of the patient), there is the Since the bubble CPAP protocol began in potential that it may be required to support The Bubble CPAP initiative in the UPMC September 2018, the number of ventilator infants for up to nine weeks. Newborn Medicine Program is designed to days has totaled 297 compared to 1,025 provide a number of clinical benefits for “The changes needed to administer this in the five months before implementation. preterm neonates. Achieving marked protocol are fairly intensive and require strict That represents a nearly three-fold reductions in oxygen exposure, mechanical adherence to the use and safety measures decrease in ventilator days. ventilation, morbidities associated with BPD, that we have put in place,” says Dr. Kiger. length of hospitalization, and the use of agents needed to treat the condition is paramount. Continued on Page 11

The administrative and cost-benefit potentials from the adoption of the bubble CPAP protocol includes reductions in the number of ventilator UPMCPhysicianResources.com/Pediatrics 11

The Future of Bubble CPAP at UPMC Clinical Trials in Neonatal Medicine Continued from Page 9 The UPMC Newborn Medicine Program will at the National Institutes of Health. This continue its use of bubble CPAP, and the Genetics and Precision Medicine trial is studying the use of rapid, targeted, protocol will eventually be implemented Co-primary investigators Thomas Diacovo, next-generation sequencing technology to system-wide at all UPMC NICUs, even in MD, and Jerry Vockley, MD, PhD, chief diagnose underlying genetic causes for Level II units for late- or mid-term infants. of medical genetics at UPMC Children’s, disease in high-risk neonates. currently are engaged in a collaborative effort Led by researchers at Floating Hospital Bubble CPAP between the UPMC for Children at Tufts Medical Center, Implementation Team Newborn Medicine researchers at UPMC Children’s will enroll Program, the Division neonates who may have a variety of genetic James Kiger, MD, MS — of Medical Genetics disorders, but whose diagnoses are unable Implementation Lead at UPMC Children’s to be determined through the use of Kalyani Vats, MD Hospital of Pittsburgh, standard testing. The new five-year study Abeer Azzuqa, MD and the Institute for Precision Medicine entails the conduction of whole-genome Jennifer Kloesz, MD (IPM) — a collaborative effort between the sequencing of the neonates, as well as a Laura Jackson, MD University of Pittsburgh and UPMC — to targeted examination of 1,722 genetic Thomas Diacovo, MD provide rapid genomic testing for NICU disorders known to afflict newborns. Karen Ewing, NNP patients who present with rare and The study will then compare the results difficult-to-diagnose conditions that may Roberta Bell, RN, MSN between the targeted screening and the have an underlying genetic cause. Jordan Kalivoda, RRT whole-genome sequencing to determine the William Vehovic, RRT UPMC Children’s also is participating in a viability of the targeted panel approach. Kristen Brenneman, RN new national precision medicine clinical Amy Farren, RN trial sponsored by the National Center for Bradley Kuch, BS, RRT-NPS, FAARC Advancing Translational Sciences (NCATS)

A First Graduation Ceremony

NICU patients and their families are a special group. a graduation ceremony for all of its patients who have The complexities of care needed to treat these had admissions of 90 days or longer. medically fragile cases are difficult and emotionally demanding for both families and providers. Upon discharge from the NICU, patients and families are presented with a diploma announcing their graduation, While the average NICU stay at UPMC Children’s is balloons, and a cap knitted by NICU volunteers. The approximately 14 days, there is a small subset of traditional music played at graduation ceremonies — patients whose conditions and complexities of care Pomp and Circumstance — is played as the family says requires substantially longer hospital stays. During their goodbyes to the NICU staff who have worked these long days and weeks of working toward the best tirelessly to make this outcome possible. outcome possible, families endure what may be one Bridget S. — Recent NICU graduate. of the most emotionally and physically demanding An alert is sent out to staff via pickle phone when a experiences they may ever have to face. discharge is happening so that anyone who is able to get away from their duties for a few minutes can join To celebrate the good outcomes of these extended NICU stays, the event and wish the family well on their continuing journey in recent months the NICU staff at UPMC Children’s instituted and recovery at home. 4401 Penn Ave. Pittsburgh, PA 15224

About UPMC Children’s Hospital of Pittsburgh Regionally, nationally, and globally, UPMC Children’s Hospital of Pittsburgh is a leader in the treatment of childhood conditions and diseases, a pioneer in the development of new and improved therapies, and a top educator of the next generation of pediatricians and pediatric subspecialists. With generous community support, UPMC Children’s Hospital has fulfilled this mission since its founding in 1890. UPMC Children’s is recognized consistently for its clinical, research, educational, and advocacy-related accomplishments, including ranking 15th among children’s hospitals and schools of medicine in funding for pediatric research provided by the National Institutes of Health (FY2018).