PPHN: New Evidence-Based Approaches

Transcription

1 HOME CME/CE INFORMATION PROGRAM DIRECTORS NEWSLETTER ARCHIVE EDIT PROFILE RECOMMEND TO A COLLEAGUE VOLUME 10 ISSUE 10: TRANSCRIPT PPHN: New Evidence-Based Approaches Our guest authors are Jason Stoller, MD, Assistant Professor of Clinical Pediatrics, and Natalie Napolitano, MPH, RRT-NPS, FAARC at The Children s Hospital of Philadelphia. MEET THE AUTHOR Natalie Napolitano, MPH, RRT-NPS, FAARC After participating in this activity, the participant will demonstrate the ability to: Describe the risks and benefits of various therapeutic options for the treatment of PPHN, particularly in situations when ECMO and inhaled nitric oxide are not available. These include: n Aerosolized therapeutic options n IV therapeutic options n Oral therapeutic options. This discussion, offered as a downloadable audio file and companion transcript, covers the topic of treatment strategies for persistent pulmonary hypertension of the newborn in the format of case-study scenarios for the clinical practice. This program is a follow up to the Volume 10, Issue 9 eneonatal Review newsletter PPHN: New Evidence-Based Approaches. Unlabeled/Unapproved Uses Dr. Stoller and Natalie Napolitano have indicated that they will make references to the unlabeled/unapproved uses of iloprost, bosentan, milrinone, sildenafil, and treprostinil. PROGRAM DIRECTORS Edward E. Lawson, MD Professor of Pediatrics Chief, Division of Department of Pediatrics Johns Hopkins Children's Center Baltimore, Maryland Maureen M. Gilmore, MD Assistant Professor of Pediatrics Director of Neonatology Johns Hopkins Bayview Medical Center Baltimore, Maryland Research Clinical Specialist Respiratory Therapy Department The Children's Hospital of Philadelphia Philadelphia, Pennsylvania Jason Stoller, MD Assistant Professor of Clinical Pediatrics Perelman School of Medicine at the University of Pennsylvania Division of Neonatology Attending Neonatologist The Children's Hospital of Philadelphia Philadelphia, Pennsylvania Faculty Disclosure Dr. Stoller has disclosed that he has received grant/researching funding from Mallinckrodt Pharmaceuticals. Release Date August 27, 2015 Lawrence M. Nogee, MD Professor Department of Pediatrics Neonatology Johns Hopkins University School of Medicine Baltimore, Maryland Expiration Date August 26, 2017 Mary Terhaar, DNSc, RN Associate Professor Director, DNP Program Johns Hopkins University School of Nursing Baltimore, Maryland Anthony Bilenki, MA, RRT Director Respiratory Care/ECMO Services The Johns Hopkins Hospital Baltimore, Maryland

2 CME/CE INFORMATION _ PROGRAM BEGINS BELOW ACCREDITATION STATEMENTS Physicians: This activity has been planned and implemented in accordance with the accrediation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Johns Hopkins University School of Medicine and the Institute for Johns Hopkins Nursing. The Johns Hopkins University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. Nurses: The Institute for Johns Hopkins Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center s Commission on Accreditation. CREDIT DESIGNATIONS Physicians enewsletter: The Johns Hopkins University School of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Podcast: The Johns Hopkins University School of Medicine designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurses enewsletter: This 1 contact hour educational activity is provided by the Institute for Johns Hopkins Nursing. Each newsletter carries a maximum of 1 contact hour or a total of 6 contact hours for the six newsletters in this program. Podcast: This 0.5 contact hour educational activity is provided by the Institute for Johns Hopkins Nursing. Each podcast carries a maximum of 0.5 contact hours or a total of 3 contact hours for the six podcasts in this program. There are no fees or prerequisites for this activity. SUCCESSFUL COMPLETION To successfully complete this activity, participants must read the content, and then link to the Johns Hopkins University School of Medicine's CME website, or the Institute for Johns Hopkins Nursing to complete the post-test and evaluation. A passing grade of 70% or higher on the post-test/evaluation is required to receive CE credit. LAUNCH DATE August 27, 2015; activities expire two years from the date of each publication. INTERNET CME POLICY The Office of Continuing Medical Education (CME) at the Johns Hopkins University School of Medicine is committed to protecting the privacy of its members and customers. The Johns Hopkins University SOM CME maintains its Internet site as an information resource and service for physicians, other health professionals, and the public. Continuing Medical Education at the Johns Hopkins University School of Medicine will keep your personal and credit information confidential when you participate in an Internet-based CME program. Your information will never be given to anyone outside of the Johns Hopkins University School of Medicine's CME program. CME collects only the information necessary to provide you with the services that you request. To participate in additional CME activities presented by the Johns Hopkins University School of Medicine Continuing Medical Education Office, please visit DISCLAIMER STATEMENT The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of the Johns Hopkins University School of Medicine name implies review of educational format design and approach. Please review the complete prescribing information of specific drugs or combination of drugs, including indications, contraindications, warnings, and adverse effects before administering pharmacologic therapy to patients. STATEMENT OF RESPONSIBILITY The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity. INTENDED AUDIENCE The target audience (clinicians) for this initiative includes neonatologists, respiratory therapists, neonatal nurses, nurse practitioners, and other members of the NICU team. STATEMENT OF NEED Nutrition n Physicians may not be aware of recent evidence-based recommendations on recognizing and treating GERD in neonates. n Current neonatal nutritional management practices may be enhanced to optimize and meet the specific needs of low birth weight preterm infants. n Current neonatal nutritional management practices may be enhanced to optimize and meet the specific needs of low birth weight preterm infants. n Clinicians who treat neonates are uncertain of optimal strategies for prevention and early recognition and treatment of necrotizing enterocolitis. Respiratory-Related Issues n Clinicians may be unfamiliar with some of the newest evidence-based approaches for treating neonatal persistent pulmonary hypertension. n Clinicians treating preterm infants may not be fully aware of the most recent developments in optimal management of bronchopulmonary dysplasia and respiratory distress syndrome. POLICY ON FACULTY AND PROVIDER DISCLOSURE As a provider approved by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Johns Hopkins University School of Medicine Office of Continuing Medical Education (OCME) to require signed disclosure of the existence of financial relationships with industry from any individual in a position to control the content of a CME activity sponsored by OCME. Members of the Planning Committee are required to disclose all relationships regardless of their relevance to the content of the activity. Faculty are required to disclose only those relationships that are relevant to their specific presentation. The following relationships have been reported for this activity: Lawrence M. Nogee, MD discloses that he has served as a consultant for UpToDate, Inc. No other planners have indicated that they have any financial interest or relationships with a commercial entity whose products or services are relevant to the content of their presentation. Guest Author Dislcosures Note: Grants to investigators at The Johns Hopkins University are negotiated and administered by the institution which receives the grants, typically through the Office of Research Administration. Individual investigators who participate in the sponsored project(s) are not directly compensated by the sponsor, but may receive salary or other support from the institution to support their effort on the project(s). CONFIDENTIALTY DISCLAIMER FOR CONFERENCE ATTENDEES I certify that I am attending a Johns Hopkins University School of Medicine CME activity for accredited training and/or educational purposes. I understand that while I am attending in this capacity, I may be exposed to "protected health information," as that term is defined and used I Hopkins policies and in the federal HIPAA privacy regulations (the Privacy Regulations). Protected health information is information about a person s health or treatment that identifies the person. I pledge and agree to use and disclose any of this protected health information only for the training and/or educational purposes of my visit and to keep the information confidential. I agree not to post or discuss this protected health information, including pictures and/or videos, on any social media site (e.g. Facebook, Twitter, etc.), in any electronic messaging program or through any portable electronic device. I understand that I may direct to the Johns Hopkins Privacy Officer any questions I have about my obligations under this Confidentiality Pledge or under any of the Hopkins policies and procedures and applicable laws and regulations related to confidentiality. The contact information is Johns Hopkins Privacy Officer, telephone: HIPAA@jhmi.edu. The Office of Continuing Medical Education at The Johns Hopkins University School of Medicine, as provider or this activity, has relayed information with the CME attendees/participants and certifies that the visitor is attending for training, education and/or observation purposes only. For CME questions, please contact the CME Office at (410) or cmenet@jhmi.edu. Johns Hopkins University School of Medicine Office of Continuing Medical Education Turner 20/720 Rutland Avenue Baltimore, Maryland Reviewed and Approved by General Counsel, Johns Hopkins Medicine (4/1/03) Updated 4/09 and 3/14) HARDWARE & SOFTWARE REQUIREMENTS To access activities, users will need: -A computer with an internet connection -An HTML compliant web browser or Internet Explorer 8 (and higher)

3 eneonatal REVIEW PODCAST TRANSCRIPT MR. BOB BUSKER: Welcome to this first eneonatal Review podcast. Today s program is a follow-up to our newsletter on New Evidence-Based Approaches to Persistent Pulmonary Hypertension of the Newborn. With us today are both that issue s authors: Dr. Jason Stoller, Assistant Professor of Clinical Pediatrics, and Research Respiratory Therapist Natalie Napolitano. Both our guests are from The Children s Hospital of Philadelphia. eneonatal Review is jointly presented by the Johns Hopkins University School of Medicine and the Institute for Johns Hopkins Nursing. This program is supported by educational grants from Abbott Nutrition, Ikaria, and Mead Johnson Nutrition. Learning objectives for this audio program focus on describing the risks and benefits of various therapeutic options for the treatment of PPHN, particularly in situations when ECMO and inhaled nitric oxide are not available. These include: n Aerosolized therapeutic options n IV therapeutic options n Oral therapeutic options. Dr. Stoller has indicated that he has received grant and/or research funding from Mallinckrodt Pharmaceuticals. Natalie Napolitano had indicated that she has no financial interests or relationships with any commercial entity whose products or services are relevant to the content of her presentation. Further, the authors have indicated that there will be references to the unlabeled or unapproved uses of iloprost, bosentan, milrinone, sildenafil, and treprostinil. MR. BUSKER: I m Bob Busker, managing editor of eneonatal Review. Dr. Stoller, Natalie, thank you both for joining us today. DR. JASON STOLLER: Thank you for having us today. NATALIE NAPOLITANO: Good afternoon Bob, thank you. MR. BUSKER: I think most clinicians are aware that the treatment of PPHN needs to focus on maximizing ventilation. The most common treatments are adding inhaled nitric oxide ino and, if necessary, placing the baby on ECMO. In your newsletter issue you reviewed recent publications investigating the use of other options when ino and ECMO might not be available or appropriate. Today I d like to discuss the diagnosis and treatment of PPHN, and which options might be best used in clinical practice. So if you would, Natalie, start us out with a patient scenario. NATALIE NAPOLITANO: Our first case is a two-dayold female infant born at 39 weeks gestation who is transferred to the NICU because of hypoxemic respiratory failure. The mother had an unremarkable prenatal history, including prenatal screening lab. The baby was born via vaginal delivery. The amniotic fluid was clear at rupture of membrane, and no resuscitation was required. She had Apgar scores of 9 at one minute and 9 at five minutes of age. She was initially admitted to the newborn nursery, where she developed central cyanosis. She was given supplemental oxygen and transferred to the NICU at that time. On admission to the NICU, she had increased work of breathing. She was initially placed on high-flow nasal cannula and subsequently intubated for progressive respiratory failure. Blood cultures were drawn, and she was started on ampicillin and gentamicin. Her initial chest x-ray was diffusely hazy with air bronchograms. She was given surfactant twice. The initial echocardiogram showed normal structure with a left-to-right shunting across the ductus arteriosus. On day two of life, pre- and post-ductal pulse oximetry gradient was greater than 5 percent, which is consistent with right-to-left shunting across the ductus, and she was started on inhaled nitric oxide and dopamine. Her PaO 2 initially improved but by the next morning had worsened again. Her PaO 2 was 58 on 100 percent oxygen on the ventilator setting of volume control mode, had a volume of 23, PEEP of 8, a rate of 55, pressure support of 20. Just prior to transfer to a regional care, she was still on those settings. 1

4 On admission to a quaternary care NICU, her first PaO 2 was 107 on 100 percent FIO2. MR. BUSKER: Thank you for that description, Natalie. Now I want to turn to you, Dr. Stoller. And I want to ask you: based on what we ve just heard, what factors influence making the differential diagnosis for this infant? DR. STOLLER: A large number of diseases could cause symptoms like this. Although this baby was born at term, a certain percentage of these babies can have respiratory distress syndrome, or RDS, so that would definitely be on the differential. And this baby had the appropriate treatment for this disease with the surfactant administration. Amniotic fluid aspiration or pneumonia could also cause a picture like this. Congenital heart disease would always be considered on our differential with a baby presenting with these symptoms. In this baby heart disease is unlikely, since they got an echocardiogram. Sometimes we do repeat echocardiograms on referral to a quaternary care NICU just because we re unsure of the quality at an outside hospital, but that seems less likely in this baby. Sepsis is always on our differential, or if there s some event that occurred before birth leading to a systemic acidosis, we know that acidosis can cause high pulmonary vascular resistance, and thus the baby could have symptoms of pulmonary hypertension such as shunting that was described in this baby. We then can think about rarer conditions like disorders of surfactant production. Several genetic disorders can cause surfactant synthetic dysfunction. We can think about rare diseases such as alveolar capillary dysplasia. Those babies can sometimes present with reasonable oxygenation in the beginning, but over the next several days can have progressively worsening hypoxemia. Several rare interstitial lung diseases could cause a picture like this, and recent research is elucidating many of these new interstitial lung diseases. And then this could be just PPHN, or a persistent pulmonary hypertension of the newborn, which can have many different causes. Sometimes we can t put our finger on the exact cause. I think it s less likely in this baby, but it could be pulmonary hypoplasia, but because her conditions was initially not as severe as it was on referral, I think that s less likely. But these are the major diseases that I would be thinking about in this baby. MR. BUSKER: Determining the differential, as you ve described, can be quite a complex process. Summarize your diagnosis for us, if you would, please. DR. STOLLER: So in summary, this baby definitely has the symptoms and findings of persistent pulmonary hypertension of the newborn, which can be caused by several problems. But I definitely would give this baby a diagnosis of PPHN. MR. BUSKER: Natalie, let me ask you: from the respiratory therapist s perspective, this patient is already on ino. What are the options if she doesn t improve or if she worsens? NATALIE NAPOLITANO: One of the things that we always try to do first is optimize our ventilation. Generally, if we know we re ventilating and oxygenating well, that greatly enhances the ability to treat the pulmonary hypertension. We may look at alternative ventilation strategies, maybe highfrequency ventilation if necessary and concentrate on treating the acidosis, which may or may not be done from a respiratory standpoint with the different options we can use for ventilation. Often, they might look at improving the preload if the echo shows that it needs to be done. We will also sedate and sometimes paralyze the infant for a period of time until we can get a good handle on the ventilation and make sure that this will fix the problem. If we re able to oxygenate and ventilate better with all of our advanced modes, we can help the lungs heal in that timeframe. If those approaches do not work, sometimes we will try another dose of surfactant administration. That seemed to help in the past, especially if we re trying to rule out one of the surfactant disorders that Dr. Stoller mentioned. After that, we don t have too many more options. We would start to consider ECMO, which is very invasive and not a decision made lightly. Often we might want to consider some off-label use of medication that could help to alleviate the pulmonary hypertension. 2

5 But usually how you decide which one to use starts with the primary diagnosis, which as Dr. Stoller mentioned is most likely PPHN, but if we can determine what exactly caused the PPHN, then treating the cause as well. MR. BUSKER: Dr. Stoller, the safety concerns with ino. What do clinicians need to be aware of? DR. STOLLER: Inhaled nitric oxide is a remarkably safe medication. The side effect we talk most about is methemoglobinemia, but that s only a concern if a patient is on high doses or is on inhaled nitric oxide for a very long period of time. By high doses I mean if they re on more than 20 ppm of nitric oxide. Nowadays most centers, if patients are on 20 ppm or less, do not even check for methemoglobinemia. The other side effects of inhaled nitric oxide are theoretical at this point. Nitric oxide has many different effects that have been shown in the laboratory: for example, on cell-signaling, inflammation, metabolism, growth and differentiation. The mechanism of these effects is probably through nitrosylation of proteins which can either upregulate or downregulate their function, but at this point these effects have just been shown in the lab and not been shown to be causing any problems in infants being treated in the NICU. MR. BUSKER: Now Natalie mentioned the potential use of other medications off-label. Let me ask you to follow up on that. DR. STOLLER: Unfortunately, we do not have many choices in medications when it comes to newborns and PPHN. The only medications we have other than inhaled nitric oxide and a treatment such as ECMO are medications that are being given off-label. Examples of those would be sildenafil or bosentan. Those two for the most part are only given orally or enterally. Other choices, if a patient is unable to get oral medication, would be iloprost, milrinone, or treprostinil. Those, again, are off-label medications, and are the only other options if a baby cannot be put on ECMO and has failed inhaled nitric oxide therapy and other medical treatments such as correcting acidosis, etc. MR. BUSKER: Thank you, Dr. Stoller. Natalie, anything to add? NATALIE NAPOLITANO: Just that all of the discussions about the off-label medications with the exception of treprostinil were all discussed in the newsletter in greater detail. MR. BUSKER: Thank you. And we ll return, with Dr. Jason Stoller and Natalie Napolitano from The Children s Hospital of Philadelphia, in just a moment. DR. MAUREEN GILMORE: Hello. I m Maureen Gilmore, assistant professor of pediatrics and director of neonatology at Johns Hopkins Bayview Medical Center. I m one of the program directors of eneonatal Review. eneonatal Review is a combination newsletter and podcast program delivered via to subscribers. Newsletters are published every other month. Each issue reviews the current literature in areas of importance to neonatologists, respiratory therapists, neonatal nurses and nurse practitioners, and other health care practitioners whose work/practice includes treating neonates. Bimonthly podcasts are also available as downloadable transcripts, providing case-based scenarios to help bring that new clinical information into practice in the delivery room and at the bedside. Subscription to eneonatal Review is provided without charge or prerequisite. Continuing education credit for each issue, and each podcast is provided by the Johns Hopkins University School of Medicine and the Institute for Johns Hopkins Nursing. For more information on this educational activity, to subscribe and receive eneonatal Review without charge, and access back-issues, please go to our website; Thank you. MR. BUSKER: Welcome back to this eneonatal Review podcast. I m Bob Busker, managing editor of the program. Our guests are Dr. Jason Stoller and Research Respiratory Therapist Natalie Napolitano from The Children s Hospital of Philadelphia. And our topic is New Evidence-Based Approaches to Treating Persistent Pulmonary Hypertension of the Newborn. We ve looking at how some of the information presented in our guests newsletter issue can be 3

6 applied in the clinic. So let s continue, if you would, Natalie, with another patient scenario. NATALIE NAPOLITANO: Our next case is a 39-week gestation male infant who presents with hypoxemic respiratory failure. He had an unremarkable prenatal history, including prenatal screening lab. The mother had a fever and was treated with one dose of antibiotics four hours prior to his delivery. At delivery the amniotic fluid contained some thick meconium when they ruptured the membranes, and he was born via vaginal delivery. He was very vigorous at delivery and thus was not intubated to suction for meconium. However, in the delivery room he started grunting and had some nasal flaring, so the team gave him some nasal CPAP. His Apgar scores were 6 at one minute of age and 8 at five minutes of age, and then he was transferred to the NICU. In the NICU, he was initially placed on nasal CPAP, but because of his lack of improvement with his respiratory distress, they intubated him and gave him surfactant. His respiratory failure and hypoxemia continued to worsen, and they then converted him from conventional ventilation to high frequency oscillator ventilation. At that time, his oxygen index was 26, so he was started on inhaled nitric oxide. He was started also on dopamine for his hypotension. Blood cultures were drawn, and he was treated with ampicillin and gentamicin. They drew an ABG which was a ph of 7.16, CO2 of 47, PO2 of 40, and a base deficit of -11, and this was on 100 percent oxygen prior to his transfer to a regional quaternary care NICU. No echocardiogram was performed at the referral hospital. His initial chest x-ray on admission to the NICU showed some patchy alveolar pattern with hyperinflation. The echocardiogram showed a normal heart structure, with a large PDA that had bidirectional blood flow. In addition, moderate left and right sided pleural effusions were seen. The pulmonary pressures were estimated at two-thirds systolic, and he was started on therapeutic hypothermia because they had some concerns for hypoxic ischemic encephalopathy (HIE) because of his initial blood gases and moderate encephalopathy seen on his neurological exam. MR. BUSKER: Thank you, Natalie. Now PPHN due to meconium aspiration syndrome that would appear to rate pretty high in the differential. Dr. Stoller, would you agree? And what other management therapies might you consider? DR. STOLLER: Good question. Yes, I think it s clear, given this patient s history and the symptoms he s displaying, that this baby has PPHN probably from meconium aspiration syndrome. The first few things I would do when this baby was transferred would be to correct any acidosis and thus decrease his pulmonary vascular resistance. I would try to adjust his ventilator settings to do whatever we could to recruit lung volumes because we know that also will decrease pulmonary vascular resistance. We know with meconium aspiration syndrome that having meconium in the alveoli can cause surfactant inactivation. So even though the other hospital did administer surfactant, I would consider repeating that surfactant administration. It is possible after administering it that we could recruit more lung and decrease the pulmonary vascular resistance, thus improving his oxygenation. It is worth noting that anecdotally some babies do much worse during the process of surfactant administration, so we usually have the ECMO team notified that the baby may be heading toward ECMO. We ve had a couple of babies who crashed onto ECMO right after administering surfactant. So it should be done cautiously, but in some babies it definitely helps. MR. BUSKER: Natalie, the potential use of off-label treatments in this patient in what circumstances would you turn to those? NATALIE NAPOLITANO: It really depends on your local practice environment and what you have available to you. Not everyone has inhaled nitric oxide and/or ECMO available, so they may be more aggressive to go to some of the off-label medications, and some centers may be doing studies with these off-label medications. So it really depends on your center and the preferred practice of that center with the other options you have available and treatment of PPHN. MR. BUSKER: And how aggressive would your approach likely be? 4

7 NATALIE NAPOLITANO: The deciding factor as to how aggressive any center would be to using some of these off-label treatment options would be whether inhaled nitric oxide and/or ECMO are available. MR. BUSKER: Dr. Stoller, in Natalie s case description of this patient, she noted that he was started on therapeutic hypothermia due to some concerns for HIE. How would this cooling affect his treatment of PPHN? DR. STOLLER: That s a great question. We think about several things when we re treating baby with PPHN and giving the baby therapeutic hypothermia. We know that therapeutic hypothermia can affect coagulation, and it can also affect heart rhythm. So we carefully monitor the heart rhythm; the cardiac function needs to be optimized for PPHN, so we keep a close eye on that. The coagulation issues are routinely monitored while cooling. There is a rather weak association between worsening of PPHN and cooling, and several studies have looked at that. Most of the studies found no worsening, but one study did find that in babies who are hypothermic, PPHN can be worse. So we do watch that, although therapeutic hypothermia is one of the only treatments we know of that can improve neurodevelopmental outcomes in babies who have HIE. So I would think very carefully about stopping cooling, even in a baby with PPHN. Other things that we think about in PPHN is, we want to maximize our oxygen delivery, but when you re cooling a baby, they can start to shiver, and shivering increases oxygen consumption. So we have to keep an eye on shivering, but again, we have very good evidence that we should cool babies who have symptoms of HIE. Another thing that we consider in this scenario is how bad the HIE is. In a baby who seems to be extremely severely affected by HIE, depending on the center, they might not be considered a candidate for ECMO. But that is very center-dependent and also depends on conversations with the entire treatment team as well as the parents when considering that issue. MR. BUSKER: Thank you, doctor. Natalie, if you would, please, bring us one more patient scenario. NATALIE NAPOLITANO: Our last case is a 41-weekgestation male infant, presenting with meconium aspiration syndrome, PPHN, and respiratory failure. The mother has a history of substance abuse, including daily tobacco smoke. She is currently incarcerated and recently transitioned to methadone. The prenatal labs were unremarkable. The amniotic fluid did contain some thick meconium at delivery with the rupture of the membrane. The baby was born by repeat cesarean section because of a prior C-section for a breech birth. At birth he initially started to cry and so was not intubated to suction for meconium. Subsequently he stopped breathing, became apneic, developed bradycardia, and required intubation in the delivery room. At that time they did not note any meconium below the vocal cords. His Apgar scores were 1 at one minute of age and 3 at five minutes of age and 5 at ten minutes of age. His initial blood gas was a ph of 7.08, CO2 of 59, PO2 of 51, and base deficit of -12. He was admitted to the NICU. The mother s postoperative course was complicated by seizures and postpartum hemorrhage requiring admission into the intensive care unit. The baby was initially managed on a pressure controlled ventilation because of a progressive hypoxemia. He was then placed on the high frequency oscillator. Blood cultures were drawn, and he was started on ampicillin and gentamicin. His initial chest x-ray showed a complete bilateral opacification. He was then given surfactant at about 45 minutes of life and started on nitric oxide at about 90 minutes of life. An echocardiogram performed while he was on nitric oxide showed a structurally normal heart with left-toright shunting through a PFO and bidirectional shunting through his PDA. He was sedated and paralyzed, and his follow-up blood gas had a ph of 7.23, CO2 of 54, O2 of 44, and a base deficit of -5. MR. BUSKER: Thank you, Natalie. Dr. Stoller, let me ask you about the mother s history substance abuse, smoking, etc. How does that affect your thinking about management? DR. STOLLER: A couple of things stand out to me in this case with regard to the mother. One is the tobacco and substance abuse, and the other is the post-delivery seizures. All of these things lead me to worry that the 5

8 placenta was being affected in utero. We know that tobacco use can cause placental dysfunction, in addition to illicit drugs, particularly cocaine. If there was placental insufficiency, this could cause chronic prenatal hypoxemia, leading to pulmonary vascular remodeling and thus symptoms of PPHN after birth. The other thing in the mother s history that concerns me is the seizure she had after birth. Sometimes maternal seizures can indicate eclampsia, which involves maternal hypertension. We know that chronic maternal hypertension can also affect the placenta, and this could lead to pulmonary vascular remodeling, which may explain this baby s symptoms. MR. BUSKER: So what you ve just described: how would that change the course of treatment you d undertake? DR. STOLLER: I would think about a couple of things. One is, if this baby s symptoms were truly due to pulmonary vascular remodeling, that problem does not reverse quickly. So this baby may be sick for several days if not a couple of weeks. The other thing I would think about would be if this mother had taken opiates, for example, methadone or heroin. We know that signs of neonatal withdrawal from those medications does not occur right after birth. It typically occurs around day of life two to five. So if this baby started having worse hypoxia because of agitation around day of life two to five, I d consider treating this baby for neonatal abstinence syndrome and administering morphine to the baby to prevent the baby s withdrawal symptoms. Sometimes these babies are so sick that they re already sedated and/or paralyzed, but if that were not the case, I would consider adding morphine to this baby s medication regimen. MR. BUSKER: Now his initial chest x-ray showed a complete bilateral opacification. How does that affect your thinking in treating this child? DR. STOLLER: That s an interesting point. Even though this baby had thick meconium at delivery, an x-ray that shows bilateral opacification is not typical for meconium aspiration syndrome. The typical x-ray in meconium aspiration syndrome is patchy and hyperinflated. Sometimes people wonder why the x-ray would be hyperinflated, and the answer is that you can have a ball-valve effect with thick meconium fluid plugging the airways, so air can get in but it can t get out, giving a hyperinflated appearance on x-ray. So this x-ray would not be consistent with that, and I would think more of other causes. For example, could this have been a massive pulmonary aspiration? Could this be overwhelming infection causing bilateral alveolar infiltrates? Could this x-ray be consistent with bilateral massive effusions? Those are several things other than meconium aspiration syndrome I would think of with this x-ray. MR. BUSKER: Natalie, let me ask you a hypothetical question. Let s assume that this child, for whatever reason, is unable to be transferred to an ECMO center. What would be your first choice for an offlabel treatment? NATALIE NAPOLITANO: Generally we prefer to use inhaled methods of treating pulmonary hypertension. We start with inhaled nitric oxide, primarily because anything going into the lungs generally stays within the lungs and doesn t have as much of a systemic absorption for more side effects to the baby. However, with this child s ventilatory status, it s definitely in question, and when you re trying to give any sort of inhaled medications, like inhaled iloprost, you re not really sure what dose will actually get across to the patient. That may change from minute to minute, especially if there is an infection or aspiration as we re able to clear some of that out of the lungs. I would generally stay away from the inhaled options in this case, because we re not sure how good our ventilation is. Two potentially good options would be sildenafil, the PO route, or IV iloprost. Sildenafil is preferably given with some food, not on an empty stomach, although it has been done. It depends on the overall condition of this infant whether they think they can feed the baby or can trickle in some food so we don t have any other problems, or if it s safe to give it on an empty stomach. With the IV iloprost, one common side effect is hypotension. Depending on the condition, if the baby is already hypotensive, you don t want to make that worse by adding a medication that could potentially give you greater reduction in your blood pressure. However, that would be the decision of the team at 6

9 the time and how likely they felt the side effect would even occur, and if they re willing to give vasopressors if needed to treat the side effect of the medication. MR. BUSKER: Natalie, Dr. Stoller I want to thank you both for today s cases and discussion. I d like to take a moment now and ask you to look to the future for us. Dr. Stoller what might clinicians expect to see happening for the treatment of PPHN? DR. STOLLER: Our current treatment is inhaled nitric oxide, and in the 30 to 40 percent of patients who do not respond to inhaled nitric oxide, the only available option is ECMO. These other medications we ve discussed today that some centers use in an off-label manner, we have no good data on both efficacy and side effects. This is not a huge problem for centers that have access to inhaled nitric oxide and ECMO, but it s a major, major problem for both providers and babies who are born in centers without access to those options. Although nitric oxide and ECMO are available in a large number of developed countries, most of the world does not have access to them but may have access to enteral and IV medication. As with all medications, it takes a very long time and a lot of money to complete clinical trials. Often times pediatric patients and neonates are neglected in this process, but more and more we re realizing the need to perform rigorous trials in these patients. I think in the future we may have better data with these unlabeled medications and have the opportunity to use them in babies who fail nitric oxide and maybe then as first-line therapies to help these babies. That will have huge benefit for patients around the world who don t have access to these other high technology therapies. MR. BUSKER: Thank you for sharing your thoughts, doctor. Let s wrap things up now by reviewing what we ve talked about today in light of our learning objectives. So to begin: the challenges of delivering inhaled medication for PPHN. Natalie? NATALIE NAPOLITANO: One of our biggest challenges in delivering any sort of inhaled medication for treating PPHN is ventilation status. Obviously, medication being inhaled is potentially safer because there is less systemic absorption, as we discussed; however, often some of our newborn population develops PPHN because of meconium aspiration syndrome and other pulmonary issues. So if you haven't optimized your ventilation, it s difficult to add an inhaled medication because you re not certain what the dose will be from day to day or hour to hour as the ventilation status changes. However, in an older infant where pulmonary problems aren t the concern and you re very confident you have stable ventilation, then inhaled options definitely would be considered as a safer option to any of the systemic medications. Then we have to think about the delivery method of inhaling these medications if they are not properly investigated to be aerosolized. We re not sure what the particle size is, what needs to be used to get dosing to the right portion of the lungs for absorption and if that medication is even stable when aerosolized, to know that any of it gets across. We need some better research on aerosolizing any sort of medication before it s given so that we know what type of nebulizer to use, what particle size we re trying to achieve, and that the medication is stable at the particle size for the duration of the therapy so that the intended dose of medication is actually being delivered to the patient. MR. BUSKER: And our second learning objective: the safety concerns for the delivery of IV medication in PPHN. Dr. Stoller? DR. STOLLER: Some of these patients typically or often have difficult IV access, which is a technical problem with delivering the medication. The babies are typically on several different infusions TPN, intralipids, dextrose, sedation medications, and paralysis medications so we need better data on IV compatibility with some of these agents. With all of these agents there s the concern of systemic hypotension. For the most part, these medications are not specific for the blood vessels in the lungs, so any time we administer these agents intravenously, there s a risk of decreasing systemic vascular resistance and causing hypotension. Some centers have decided to give additional fluid prophylactically while administering the initial doses to protect against hypotension, but we don t know if this should be done in every patient at this point. MR. BUSKER: And finally: the safety concerns with the delivery of oral medications in PPHN. 7

10 DR. STOLLER: Of the four medications discussed in the newsletter, two are oral. The first is sildenafil and the second is bosentan. Sildenafil is the off-label medication we know most about at this point, but it can only really be given orally. There is an IV preparation, but it s not in widespread use at this point. Most of these patients are so sick during this treatment that they re not being fed, and we worry about giving anything enterally because they re at risk of bowel compromise or necrotizing enterocolitis. So that limits us when we re thinking about giving oral medications. If a baby did get an oral medication such as sildenafil or bosentan, the biggest safety concern is similar to the IV forms, in that we worry about hypotension and would need to carefully monitor that when treating a patient with these off-label oral medications. MR. BUSKER: From the Children s Hospital of Philadelphia, Dr. Jason Stoller, Research Respiratory Therapist Natalie Napolitano thank you both for participating in this eneonatal Review Podcast. NATALIE NAPOLITANO: Thanks, Bob, it was a great discussion. DR. STOLLER: Thank you for the opportunity to talk with you today. MR. BUSKER: To receive CME credit for this activity, please take the post-test at This podcast is presented in conjunction with the eneonatal Review Newsletter, a peer-reviewed literature review certified for CME/CE credit, ed monthly to clinicians treating patients in the NICU. This activity has been developed for neonatologists, respiratory therapists, neonatal nurses, nurse practitioners, and other members of the NICU team. This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education, through the joint sponsorship of the Johns Hopkins University School of Medicine and the Institute for Johns Hopkins Nursing. The Johns Hopkins University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. The Johns Hopkins University School of Medicine designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in this activity. The Institute for Johns Hopkins Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center s Commission on Accreditation. For nurses, this 0.5 contact hour Educational Activity is provided by the Institute for Johns Hopkins Nursing. Each podcast carries a maximum of 0.5 contact hour. This educational resource is provided without charge, but registration is required. To register to receive eneonatal Review via , please go to our website: The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of the names of the Johns Hopkins University School of Medicine and the Institute for Johns Hopkins Nursing implies review of educational format, design, and approach. Please review the complete prescribing information for specific drugs, combinations of drugs, or use of medical equipment, including indication, contraindications, warnings, and adverse effects, before administering therapy to patients. eneonatal Review is supported by educational grants from Abbott Nutrition, Ikaria, and Mead Johnson Nutrition. This program is copyright with all rights reserved by the Johns Hopkins University School of Medicine and the Institute for Johns Hopkins Nursing. 8