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Transport of the Neonatal Patient With Persistent Pulmonary Hypertension
Transport of the Neonatal Patient With Persistent Pulmonary Hypertension Peter Brust, RN, MSN, CCRN, CMTE, Marjorie Hamburger, RN, MSN, CCRN, and Patricia Larkin, RN, BSN, CCRN
Persistent pulmonary hypertension of the newborn remains a challenging condition to manage. The key to treatment is to maximize ventilatory support through conventional ventilation, high-frequency oscillator ventilation, exogenous surfactant, inhaled nitric oxide, and, if needed, extracorporeal membrane oxygenation. When these treatments are not available, the infant must be transferred to a tertiary/quaternary care center by a qualified neonatal/pediatric transport team that is equipped to transport the newborn on inhaled nitric oxide. The transport team must perform a quick and thorough assessment of the newborn, determine and initiate the appropriate treatment, evaluate the response, and transport the infant to the receiving facility as safely and quickly as possible; these steps are the key to a positive outcome. This article will review the pathophysiology, assessment, diagnosis, and treatment options for a newborn with persistent pulmonary hypertension of the newborn, and considerations for infant transport to a higher level of care will be emphasized. Keywords: Persistent pulmonary hypertension; Transport; Assessment; Treatment; Response
In spite of recent advances in treatment, persistent pulmonary hypertension of the newborn (PPHN) continues to be a lifethreatening and challenging medical condition. Current therapies for PPHN include conventional ventilation, highfrequency oscillatory ventilation (HFOV), exogenous surfactant, inhaled nitric oxide (iNO), and extracorporeal membrane oxygenation (ECMO). The early suspicion and recognition of this disease is essential in achieving positive outcomes for the infant. In addition, other significant but different disease processes need to be ruled out during the initial evaluation of the infant, as definitive therapy for other diseases should not be delayed. The following article is a description of factors that demonstrate that early suspicion and recognition of PPHN and the resultant therapies, including transport, can result in improved outcomes for newborns with this condition.
From the Emergency Transport Services, The Children's Hospital of Philadelphia, Philadelphia, PA. From the The Children's Hospital of Philadelphia, Philadelphia, PA. From the Emergency Transport Team of the Children's Hospital of Philadelphia. Address correspondence to Peter Brust, RN, MSN, CCRN, CMTE, Emergency Transport Services, The Children's Hospital of Philadelphia, Room 1712 South Tower, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104. E-mails: [email protected], hamburger@email. chop.edu, [email protected]. © 2009 Elsevier Inc. All rights reserved. 1527-3369/09/0904-0326$36.00/0 doi:10.1053/j.nainr.2009.09.003
Case Study A call is received by The Children's Hospital of Philadelphia transport team for transport and admission of a sick infant. The referring hospital is requesting to transfer a 37 3/7-weekgestation infant with a weight of 3900 grams born by cesarean delivery to a diabetic mother. Apgar scores were 7 at 1 minute and 8 at 5 minutes. Maternal laboratories studies were unremarkable and the mother's group beta-strep status was negative. At 10 minutes of life, the infant was noted to have moderate respiratory distress, and supplemental oxygen was given by bag-valve-mask without improvement. The infant was then intubated with a 3.5 endotracheal tube (ET) and moved to the neonatal intensive care unit (NICU) at the referral center. At that time, the infant's heart rate was 188 beats per minute, respiratory rate was 90 breaths per minute, and blood pressure (BP) by cuff was 55/22 millimeters of mercury with a mean arterial pressure (MAP) of 33 millimeters of mercury. The infant's temperature was 36.7°C (98.2°F), and oxygen saturation was 80% on a fraction of inspired oxygen (FIO2) of 1.0. In the NICU, standard mechanical ventilation was initiated with peak inspiratory pressure (PIP) of 24 centimeters of water, a positive end-expiratory pressure (PEEP) of 5 centimeters of water, FIO2 1.0, and a rate of 50 breaths per minute. An umbilical arterial line and double lumen umbilical venous catheter were placed. Standard laboratory studies were drawn including an arterial blood gas (ABG) that showed pH 7.11, PCO2 of 81, PaO2 of 44, HCO3 of 21, and oxygen saturation of 78%. Based on these values, the ventilator settings were adjusted. The PIP was increased to 26 centimeters of water, PEEP was increased to 6 centimeters of water, and the rate was increased to 60. Sodium bicarbonate (NaHCO3) was given intravenously to correct the metabolic acidosis, and intravenous
fluids (dextrose concentration of 10%) were initiated at 80 milliliters per kilogram per day. A 10-milliliter per kilogram bolus of normal saline was given followed by a second bolus. Pre- and postductal saturations were measured and were noted to be 10 points lower preductally. After adequate volume administration, dopamine hydrochloride (dopamine) was started at 5 micrograms per kilogram per minute because of a persistently low MAP of 31. The chest x-ray (CXR) was essentially unremarkable and showed the invasive lines and ET to be in good position. The referring hospital had been unable to obtain an echocardiagram (ECHO), but the clinicians had a very strong suspicion that this infant was developing PPHN.
Pathophysiology During and immediately after delivery, the normal neonate is able to convert from fetal circulation to postnatal circulation. Failure of the neonate to do so can result in a syndrome of significant pulmonary hypertension causing hypoxemia and right-to-left extrapulmonary shunting. This, in turn, can lead to inadequate pulmonary perfusion, hypoxemia, increased pulmonary vascular resistance (PVR), respiratory distress, and acidosis, which is frequently severe.1 After birth, the normal rhythmic ventilation of the lung results in an increase in alveolar oxygen tension, and as a result, there is a decrease in the PVR and an increase in pulmonary blood flow. The beneficial effects of these changes are greater when the two events occur simultaneously. In some cases, the normal decrease in pulmonary vascular tone does not occur. The result is PPHN, which has the potential to cause significant morbidity and mortality in otherwise healthy newborns.1 Persistent pulmonary hypertension of the newborn is distinguished by marked pulmonary hypertension, hypoxemia, right-to-left shunting of blood, inadequate pulmonary perfusion, refractory hypoxia, and acidosis. Persistent pulmonary hypertension of the newborn often results when structurally normal pulmonary vessels constrict in response to alveolar hypoxia. Respiratory failure and hypoxia in the term newborn result from a heterogeneous group of disorders, and the therapeutic approach and response depend on the underlying disease.2
Incidence Persistent pulmonary hypertension of the newborn is reported to occur in two to six cases per 1000 per live births and can be a complicating factor in term or near-term newborns with parenchymal lung disease such as meconium aspiration syndrome (MAS) or pneumonia.3 Nearly 13% of all live births are complicated by meconium-stained fluid; however, only 5% of these infants actually develop MAS.3 Maternal diabetes, another pregnancy complication, is associated with infants who are born large for gestational age. These infants are at higher risk of being born by cesarean delivery and subsequently developing PPHN.3 The risk of developing PPHN also appears greater if the infant is male, as well as 34 to 37 weeks of gestation or greater
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than 41 weeks.3 Additional factors for the development of PPHN include maternal obesity as well as African American and Asian ethnic groups. Smoking during pregnancy can increase the risk of PPHN, whereas maternal hypertension and preeclampsia have a weaker association to PPHN but still are identified risk factors. Persistent pulmonary hypertension of the newborn affects phenotypically normal infants primarily but also can occur in those with Down syndrome.4
Etiology Knowledge of differences in the etiology of PPHN is instrumental in deciding on available therapeutic options. There are three recognized underlying etiologies for PPHN. The first is acute pulmonary vasoconstriction due to acute perinatal events such as (1) alveolar hypoxia secondary to parenchymal lung disease (respiratory distress syndrome, MAS, or pneumonia); (2) hypoventilation resulting from asphyxia or other neurologic conditions; (3) hypothermia; or (4) hypoglycemia.5,6 The second recognized etiology of PPHN is idiopathic PPHN, which is characterized by a normal CXR and no parenchymal lung disease. Idiopathic PPHN is often referred to as black-lung or clear-lung PPHN.6 These infants often develop true vascular disease. Idiopathic PPHN commonly results from an abnormal remodeling of the pulmonary artery vascular bed with vascular wall thickening and hyperplasia of the smooth muscle, which may be secondary to chronic stress in utero.6 Idiopathic PPHN may also result from maternal use of nonsteroidal anti-inflammatory drugs, such as ibuprofen or naproxen, or selective serotonin reuptake inhibitors during the later part of pregnancy.5-8 A third cause of PPHN is lung hypoplasia. Additional findings that may accompany hypoplasia and contribute to the development of PPHN include Congenital Diagphramatic Hernia (CDH) and oligohydramnios.3,5,6,9
Assessment and Diagnosis An infant who presents with severe respiratory distress, cyanosis, and tachypnea requires immediate and comprehensive evaluation. Significant lability in oxygenation is one indicator that should point the clinician in the direction of PPHN. Early suspicion and recognition of PPHN symptoms can result in appropriate and favorable outcomes. The diagnosis of PPHN is often made from maternal and antenatal history, examination of the infant, ECHO, and laboratory studies.6 An infant with PPHN may initially appear normal or show only mild respiratory disease. Cardiac examination may reveal a loud, single S2 or a harsh, systolic murmur secondary to tricuspid regurgitation. Blood pressure may be low or close to normal, although the infant may have poor cardiac function and perfusion. Often, pre- and postductal saturations are different because of the shunting of blood through the patent ductus arteriosus.
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The workup for a patient suspected of having PPHN should include an ABG to assess pH, PaCO2, PaO2, and alveolar-arterial difference. The PaO2 may be elevated if a preductal sampling site is used. Oxygenation should be assessed by comparing the postductal PaO2 and the current ventilator settings. Pulse oximetry is necessary for ongoing treatment evaluation over time. The clinician should distinguish preductal (right hand) from postductal (left or right foot) sites. The left hand should be avoided because it may provide either pre- or postductal readings depending on the infant's specific circulation. Some centers use the oxygenation index (OI), which is calculated as the MAP multiplied by the fraction of inspired oxygen (FIO2) and then multiplied by 100, which is then divided by the postductal PaO2. An OI of 40 or greater typically prompts consideration of ECMO support.10 A CXR can be helpful in determining the presence of underlying parenchymal lung disease or in ruling out disorders such as CDH. Cardiomegaly and increased vascular markings are often visible in PPHN, although routine CXRs are often nondiagnostic. In newborns with idiopathic PPHN, the lung fields appear clear with decreased vascular markings and the heart size is typically normal. When PPHN is suspected, an ECHO is essential to rule out the presence of congenital heart disease in the newborn with cyanosis and tachypnea. If the heart is deemed structurally normal, and the ECHO shows high pulmonary artery pressures and right-to-left shunting through the patent ductus arteriosus, foreman ovale, or both, then PPHN can be the presumptive diagnosis. Frequently, there is evidence of right heart failure because the pressures in the pulmonary artery are greater than the systemic pressure, resulting in the right ventricle's inability to eject blood. Rarely, cardiac catheterization may be required to assist in obtaining the appropriate diagnosis. In addition, biventricular failure may occur and is associated with poor outcomes; therefore, early ECHO findings along with aggressive management of PPHN are essential to improve patient outcomes. See Table 1 for a list of differential diagnoses for PPHN.
Table 1. List of Differential Diagnoses for PPHN 6 PPHN Differential Diagnoses Congenital diaphragmatic hernia MAS Partial anomalous pulmonary venous connection Pneumonia Pneumothorax Pulmonary atresia with intact ventricular septum Pulmonary hypoplasia Pulmonary sequestration Respiratory distress syndrome Sepsis Total anomalous pulmonary venous connection Transposition of the great arteries Tricuspid atresia
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An evaluation of the complete blood count may be significant for a high hematocrit, which may indicate polycythemia and hyperviscosity. Either of these syndromes may produce or aggravate PPHN. A white blood cell count and differential are helpful in determining whether an underlying sepsis syndrome or pneumonia exists. Platelets are frequently depressed particularly in newborns with MAS or asphyxia. Serum electrolytes and glucose should be monitored and corrected as needed. Glucose and ionized calcium levels should be kept in reference ranges because symptoms of PPHN can significantly worsen if these values are abnormal.5,6
Treatment Mechanical Ventilation With PPHN, mechanical ventilation is almost always necessary to maintain normal respiratory function. This is accomplished by recruiting areas of atelectasis that will occur. In addition, the use of gentle ventilation and permissive hypercapnia that provides adequate chest movement should be a mainstay of oxygenation and ventilatory strategies. This aids in reducing the risk of barotrauma and the long-term development of chronic lung disease. Reducing hyperventilation may, in fact, reduce hypoxic pulmonary vasoconstriction, increase cerebral blood flow, and prevent poor neurologic outcomes.11 Clinical teams should adjust ventilator settings to maintain normal expansion of the lungs, approximately nine ribs on inhalation. This can be accomplished by monitoring tidal volumes and pulmonary mechanics.6 Persistent pulmonary hypertension of the newborn caused by MAS is often due to increased pulmonary resistance from air trapping and decreased compliance. Conventional ventilator settings include PIP of 20 to 25, PEEP of 3 to 5 centimeters, I:E ratio of 1:2, respiratory rate of 40 to 80, and tidal volume limited to 5 to 6 milliliters per kilogram. The goal is to maintain a preductal saturation of more than 85% and postductal saturation of more than 60% if perfusion is satisfactory and the patient is nonacidotic. The clinical team should begin 100% oxygen administration and wean by 3% per hour as tolerated and PaO2 should be followed via ABG every 1 to 2 hours.6,11 In newborns with severe airway disease who require high PIPs (N30 centimeters of water or a MAP N15 centimeters of water), HFOV should be considered early to reduce barotrauma. The goal of HFOV is to optimize lung expansion and functional residual capacity to avoid overdistension of the lungs. Overdistension can predispose the newborn to significant barotrauma and elevation of PVR, thereby aggravating the right-to-left shunting and worsening the PPHN. Gentle HFOV may be considered with settings of a MAP less than 14 and 6 to 8 Hz. It has been shown that the use of oscillatory ventilation along with other strategies improves lung inflation and alveolar recruitment.11 High-frequency oscillatory ventilation with a high MAP should not be used to rescue oxygenation. If the infant fails to stabilize on HFOV,
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then consideration for further escalation of therapy with iNO and ECMO should be considered.11
Sedation and Induced Paralysis Decreased pH, increased PaCO2, and worsening hypoxemia can result from excess stimulation of the infant and have been shown to be detrimental6,11; therefore, excess stimulation should be minimized. If the infant is awake or becomes difficult to ventilate, use of sedation with a benzodiazepam agent can be considered. Induced paralysis is highly controversial, and the clinical team needs to consider the risk/benefit ratio before the initiation of therapy. The medical team should avoid excessive rescue boluses of narcotics to limit the potential wide swings in BP. The medical team may consider beginning an infusion of midazolam (Versed; Roche Pharmaceuticals Inc, Nutley, NJ) at 0.01 milligrams per kilogram per hour and morphine sulfate (morphine) 0.01 milligrams per kilogram per hour as good starting points for sedation. If the newborn becomes hypotensive, morphine sulfate should be stopped and the team should consider the use of fentanyl citrate (fentanyl) at 1 microgram per kilogram per hour. The medical team should avoid the use of pancuronium bromide (Pavulon; Organon International, Oss, the Netherlands) unless the infant does not tolerate mechanical ventilation or becomes hemodynamically unstable. There have been some isolated reports in the literature12 of increased mortality associated with the use of pancuronium bromide. Pancuronium bromide may promote atelectasis of dependent lung regions and ventilation perfusion mismatch. Prolonged administration of pancuronium bromide during the neonatal period may be associated with sensorineural hearing loss in childhood survivors of CDH. One study has suggested that paralysis may be associated with increased risk of death.4 Careful and ongoing assessment of the newborn's response to stimulation and sedation is an important part of improving oxygenation of the newborn with PPHN. Prostacyclins and magnesium therapy have been studied in newborns with PPHN. However, to date, no study has shown improvement with these therapies.1,13
Acid-Base Balance For infants with PPHN, metabolic and respiratory imbalances need to be corrected. Arterial blood gases should be collected, analyzed, and remedied before and during any transport. It is important to have adequate supplies for transport; therefore, consideration for the use of portable bedside ABG monitoring should be considered. NaHCO3 administration can result in significant carbon dioxide production; however, limiting or reducing acidosis is extremely important. NaHCO3 is the mainstay of acid buffering and dosing should be based on the results of the ABG. NaHCO3 should be diluted to 0.5 milliequivalent per milliliter in newborns. Tromethamine (THAM; Hospira Inc, Lake Forest, IL) can be used if carbon dioxide clearance is a problem after the administration of NaHCO3. The dose depends on buffer base
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deficit; when base deficit is known, the volume of tromethamine to administer is milliliters of 0.3 moles per liter solution = body weight (kilograms) × base deficit (milliequivalent per liter); when the deficit is not known, 3.5 to 6 milliliters per kilogram per dose intravenously (1–2 milliequivalent per kilogram per dose). In addition, tromethamine should not be given through a peripheral intravenous or low-lying umbilical venous line because it is known to cause necrosis. Urine output should be established before administration.6 Follow-up ABG assessment is required to assess response to the buffers. Forced alkalosis is an older therapy, which is no longer an accepted practice. It was once thought effective in promoting pulmonary vasodilatation and increasing PaO2; however, the hypocarbia associated with this resulted in constriction of the cerebral vasculature and subsequent complications.6
Catheter Placement Catheterization of the femoral veins can be considered and will allow for the administration of fluids, inotropic agents, or hypertonic solutions as needed. An umbilical artery catheter or peripheral arterial catheter can be useful in monitoring BP and ABGs.
Surfactant Administration The administration of exogenous surfactant at any gestational age may be necessary depending on the presentation of the infant and a decision by the clinical team. Some studies have reported improved oxygenation and decreased barotrauma with the administration of surfactant, which can ultimately reduce the need for ECMO.5,12-14
Nitric Oxide The most important recent advancement in treating PPHN is the initiation of iNO. Inhaled nitric oxide acts on the smooth muscle cells of the pulmonary system by increasing c-CMP levels strictly in the lungs, thereby producing pulmonary vasodilation.15 This, in turn, decreases pulmonary pressures and results in better oxygenation and ventilation. Inhaled nitric oxide does not produce systemic hypotension. The actions of iNO reduce ventilation perfusion mismatch, enhance alveolar recruitment, and potentially reduces lung inflammation. In more than 10 years of widespread use, a 50% reduction in the use of ECMO has been reported.15 When begun early for moderate PPHN, studies have shown not only improvement in oxygenation but prevention of progression of the PPHN to a more severe form.15,16 Ideally, appropriately staffed teams from the receiving institution are able to bring iNO therapy to the bedside at the referring center. Significant preplanning of equipment needs for both ground and flight transport incubators (commonly referred to as transport isolettes) to accommodate the iNO setup is required. There is usually significant benefit to the newborn once placed on iNO therapy. This generally requires a
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slightly longer bedside time for the transporting team; however, iNO has been demonstrated to be a safe and effective therapy for use on transport.1,17,18 The transporting team needs to assess the infant before the initiation of iNO at the referring facility. Current literature indicates neonates with an OI of more than 25 should be highly considered for this therapy.15-17 Inhaled nitric oxide can be delivered to the lungs by means of an inhalation device and/or through mechanical ventilation. Therefore, respiratory therapists are an integral part of the transport team as they, along with the physician and nurse, initiate, titrate, and maintain the iNO during transport. One common device, the iNO VENT (Datex-Ohmeda, Inc, Madison, WI) can be used to transport newborns on iNO and is able to accommodate ground, rotor, and fixed wing transports. Figs 1 and 2 illustrate the devices for ground and flight transport. A usual dose of iNO is 20 parts per million. Higher doses have not been shown to be effective.15-17 Adverse events of iNO include methemoglobinemia and increased levels of nitrogen dioxide. Most infants require iNO for less than 5 days, and the dose can usually be weaned to 5 parts per million after 6 to 24 hours. Inhaled nitric oxide can be discontinued when FIO2 is less than 0.6 and iNO dose is 1 part per million. Abrupt discontinuation of iNO may cause severe rebound. Studies have shown that the combined use of surfactant and iNO have shown dramatic improvement in oxygenation and a decrease in ventilator settings.15
Extracorporeal Membrane Oxygenation When ECMO is necessary for the treatment of PPHN, certain eligibility criteria should first be met. To be eligible for ECMO, the newborn should be at least 2000 grams, greater than 34 weeks of gestation, have inadequate oxygenation, have failed success of the therapies described above. A major contraindication to ECMO is intracranial hemorrhage greater than grade II.16,19
Fig 1. Ground incubator with iNO Max DS setup.
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Fig 2. Flight incubator with iNO Max DS setup.
Considerations for Transport Recognition Infants with PPHN should be evaluated closely for their response to the standard therapies described above. If they fail to improve or if the care required of the newborn exceeds the referring institution's capabilities, then transport to a center with both iNO and ECMO capabilities should be strongly considered. The earlier the transport occurs in the care of the infant, the less risk there is for the patient. Ideally, transport should occur to a tertiary or quaternary care center.
Treatment/Physical Assessment During Transport Meticulous attention to detail should be maintained in collecting information on the current care of the infant. Strict attention to the history, physical examination, laboratory studies, and current therapies is crucial to a successful transport. A CXR should be done to confirm ET tube placement. Copies of the chart and all relevant studies must accompany the newborn during transport to avoid duplication at the receiving facility. During the actual transport, the team must maintain strict monitoring of the heart rate, SpO2, BP, and perfusion.20 Minimal stimulation should also be a primary goal of the transporting team. The transport isolette should be covered and the newborn should be positioned to avoid stimulation. It is generally recommended that the decibel level within the transport isolette be 75 decibels; however, because of noise and vibration associated with transport both by ground and rotor wing, decibel levels often range from 75 to 100 decibels or higher.21 Monitoring of fluid status is important to maintain right ventricular filling pressures. Adequate circulatory volume is important; however, repeat fluid boluses do not necessarily provide additional benefits. Strict monitoring of the intake and output is essential as well.16,19 Adequate intravenous access is required to safely transport the newborn. At a minimum, umbilical venous and arterial
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access should be obtained. An additional peripheral intravenous line is helpful for the administration of volume, sedation, and other required medications.15,16 Inotropic support such as dopamine hydrochloride, dobutamine hydrochloride, and milrinone alone or in combination may be necessary to maintain adequate cardiac output and systolic BP while avoiding volume overload. Dobutamine hydrochloride and milrinone may be necessary when myocardial contractility is poor.22,23
Family Considerations Transfer of an infant is a very stressful situation for the families. In addition to the family having to cope with a sick infant, frequently, family members also have to leave the hospital in a geographic area with which they are familiar to go to a geographic area with which they are usually not familiar. The emotions of the entire family need to be taken into consideration. Emotions can range from sadness, disbelief, and anger to acceptance of the situation. The transporting team and staff at the referral center must be prepared to support the family, especially the parents. In addition, specific details should be given to the parents including the following: • How their child will be transported (ie, warmed transport isolette, ambulance, etc) • The medical therapy the infant will be receiving during transport • The capabilities of the transporting team • The risk factors of the transport • The approximate length of time the transport will take • Where their infant will be going, along with the phone number • What room their child will be in along with the receiving units telephone number • The tentative plan once the child arrives at the tertiary/ quaternary center • Directions for getting to the tertiary/quaternary center • Visiting hours and visiting policies of the tertiary/ quaternary center It is imperative that the transport team obtain accurate phone numbers to stay in touch with the parents. It is courteous to ask if the infant has a first name yet and if the mother plans to breastfeed so that the staff at the receiving medical center can be notified. If a parent is not accompanying the transport team, the parents should be notified of the infant's status if the patient's condition changes and at the completion of transport when the team arrives at the receiving center. The care team, including medical staff, nursing, social work, and the chaplain services, should contact the family as soon as possible after the infant's admission to the NICU. Adequate support is the key to the parent's ability to cope with their newborn's hospital admission. Once transport has occurred, it is essential that the receiving institution relay prompt and appropriate information on the newborn's status to the family and the referring medical team. This will assist in ensuring that continuity of care exists between the referring medical team, the family, and the accepting team.
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The potential exists that the infant may require advanced therapies, such as ECMO, or that other diagnoses may be found. This effort to establish the relationship with the family at the referring institution can be rewarding to both teams.
Prognosis and Follow-up In the early 1990s, mortality of patients with PPHN reached 40% with major neurologic disability ranging from 15% to 60%.12 The introduction of ECMO reduced mortality in PPHN. In 1996, one study from the United Kingdom reported serious mortality from PPHN dropped from 60% to 30%; however, newborn survivors with serious neurologic morbidity remain at 15% to 20%.9 Recently, survival rates of 85% have been reported when all the resources described are available to the patient.5,15 When pulmonary recovery is complete, the survivors do not appear to have residual pulmonary disease, although prolonged hyperventilation has been associated with increased prevalence of neurodevelopment issues including hearing loss.5,15 Once the infant is out of danger, a neurologic assessment should be conducted. This may include a computed tomography and magnetic resonance imaging scan. A neurologic development examination should be conducted with followup at 2 years of age. Hearing tests should be conducted before discharge and subsequently followed at 6 months of age and then as indicated.5,24,25 After the initial insult and recovery, it may be days to weeks before the newborn is able to tolerate oral feeds. Nasogastric feeds may be necessary during this time to maintain appropriate nutrition and mobilization of the gastrointestinal tract. Speech therapy may be helpful in reestablishing normal patterns of feedings. In addition, learning disabilities should be screened for before the child enters school to capture and allow for appropriate interventions.25
Case Study Follow-up The transport team arrived at the referring hospital and quickly assessed the newborn. His ET was in good position. Adequate fluid administration had been given by the referring hospital, and the newborn was on dopamine hydrochloride at 5 micrograms per kilogram per minute. After obtaining an ABG of pH 7.16, PCO2 of 65, PaO2 of 67, HCO3− of 19, and SaO2 of 78%, iNO was initiated by the transport team at 20 parts per million. In addition, morphine sulfate 0.1 milligrams per kilogram and midazolam 0.1 milligrams per kilogram were administered. Shortly after iNO and sedation were initiated, an improvement in the oxygen saturation to 95% was noted. FIO2 was decreased to 0.8, and the respiratory therapist noted that the chest compliance had improved. The newborn was safely loaded into the transport isolette and transported to The Children's Hospital of Philadelphia without incident. In the NICU, the newborn was placed on the HFOV with iNO at 20 parts per million. Inhaled nitric oxide was continued for 5 days and then weaned appropriately. The newborn was subsequently weaned to
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conventional mechanical ventilation. On day 7 of the hospital course, the newborn was extubated to a nasal cannula, continued to improve, and was discharged home on day 30 of the hospitalization.
Summary Despite all of the advances in medical therapies, PPHN continues to have a significant morbidity and mortality rate. Early recognition and action must be an integral part of the care of a newborn who presents with respiratory distress, cyanosis, and tachypnea. The practitioner must do an immediate and comprehensive evaluation of the newborn. Prompt recognition and treatment of PPHN often results in favorable outcomes of the newborn. Congenital heart disease should be ruled out by an ECHO, but if an ECHO is not possible or unavailable, treatment should not be delayed. Respiratory support should be initiated with conventional ventilation or HFOV and circulatory support begun. Intravenous access and laboratory studies including ABG and CXR need to be obtained early. The newborn should be sedated to decrease additional oxygen requirements at the tissue level. In addition, contact of a tertiary/ quaternary care center should occur early. The receiving institution should obtain a detailed history, make appropriate recommendations, and launch their transport team with all of the appropriate therapies, including iNO. Having a specialized transport team with the capabilities of providing iNO rapidly is extremely beneficial to these newborns. Early initiation of iNO in moderate PPHN has been shown to reduce lung inflammation, improves oxygenation, and prevents the progression of PPHN and reducing the need for ECMO. Inclusion of the families in all of these plans and treatments is essential to help decrease their anxiety and prepare them for what lies ahead. The advancements and portability of treatments for PPHN have come a long way over the past few years, providing a more favorable outcome for both infants and their families.
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6. Steinhorn RH. Pulmonary hypertension, persistent-newborn. Emedicine.Medscape.Com. April 19, 2007. 7. Andrade SE, McPhillips H, Loren D, et al. Antidepressant medication use and risk of persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Saf. 2009;18:246-252. 8. Koren G, Boucher N. Adverse effects in neonates exposed to SSRIs and SNRI in late gestation. Can J Clin Pharmacol. 2009;16:e66-e67. 9. Curtis J, Kim G, Wehr NB, et al. Group B streptococcal phospholipid causes pulmonary hypertension. Proc Natl Acad Sci U S A. 2003:5087-5090. 10. Steinhorn RH. Nitric oxide and beyond: new insights and therapies for pulmonary hypertension. J Perinatol. 2008;28: s67-s71. 11. Wanstall JC, Jeffery TK. Recognition and management of pulmonary hypertension. Drugs. 1998;56:989-1007. 12. Asad A, Bhat R. Pharmacology for meconium aspiration. J Perinatol. 2008;28:S72-S78. 13. Perreault T. Persistent pulmonary hypertension of the newborn. Paediatr Respir Rev. 2006;7S:S175-S176. 14. Baquero H, Soliz A, Neira F, et al. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics. 2006;117:1077-1083. 15. Fakioglu H, Totapally BR, Torbati D, et al. Hypoxic respiratory failure in term newborns: clinical indicators for inhaled nitric oxide and extracorporeal membrane oxygenation therapy. J Crit Care. 2005;20:288-295. 16. Soll RF. Inhaled nitric oxide in the neonate. J Perinatol. 2009;29:s63-s67. 17. Gadzinowski J, Kowalska K, Vidyasagar D. Treatment of MAS with PPHN using combined therapy: SLL, bolus surfactant and iNO. J Perinatol. 2008:S56-S66. 18. Wiedemann JR, Saugstad AM, Barnes-Powell L, et al. Meconium aspiration syndrome. Neonatal Netw. 2008;27:81-87. 19. Lowe CG, Trautwien JG. Inhaled nitric oxide therapy during the transport of neonates with persistent pulmonary hypertension or severe hypoxic respiratory failure. Eur J Pediatr. 2007;166:1025-1031. 20. Pippert G, Wewerka S, Fransonce RJ, et al. Neonatal patient sound exposure during critical care transport. Air Med J. 2008;27:234-235. 21. Tung BJ. The use of nitric oxide therapy in the transport of newborns with persistent pulmonary hypertension. Air Med J. 2001;20:10-11. 22. Lutman D, Petros A. Inhaled nitric oxide in neonatal and paediatric transport. Early Hum Dev. 2008;84:725-729. 23. ELSO Patient specific supplements to the ELSO general guidelines, 2009 April. 24. Bassler D, Choong K, McNamara P, et al. Neonatal persistent pulmonary hypertension treated with Milrinone; four case reports. Biol Neonate. 2006;89:1-5. 25. Hosono S, Ohno T, Kimoto H, et al. Developmental outcomes in persistent pulmonary hypertension treated with nitric oxide therapy. Pediatr Int. 2009;51:79-83.
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Persistent pulmonary hypertension of the newborn remains a challenging condition to manage. The key to treatment is to maximize ventilatory support through conventional ventilation, high-frequency oscillator ventilation, exogenous surfactant, inhaled nitric oxide, and, if needed, extracorporeal membrane oxygenation. When these treatments are not available, the infant must be transferred to a tertiary/quaternary care center by a qualified neonatal/pediatric transport team that is equipped to transport the newborn on inhaled nitric oxide. The transport team must perform a quick and thorough assessment of the newborn, determine and initiate the appropriate treatment, evaluate the response, and transport the infant to the receiving facility as safely and quickly as possible; these steps are the key to a positive outcome. This article will review the pathophysiology, assessment, diagnosis, and treatment options for a newborn with persistent pulmonary hypertension of the newborn, and considerations for infant transport to a higher level of care will be emphasized. Keywords: Persistent pulmonary hypertension; Transport; Assessment; Treatment; Response
In spite of recent advances in treatment, persistent pulmonary hypertension of the newborn (PPHN) continues to be a lifethreatening and challenging medical condition. Current therapies for PPHN include conventional ventilation, highfrequency oscillatory ventilation (HFOV), exogenous surfactant, inhaled nitric oxide (iNO), and extracorporeal membrane oxygenation (ECMO). The early suspicion and recognition of this disease is essential in achieving positive outcomes for the infant. In addition, other significant but different disease processes need to be ruled out during the initial evaluation of the infant, as definitive therapy for other diseases should not be delayed. The following article is a description of factors that demonstrate that early suspicion and recognition of PPHN and the resultant therapies, including transport, can result in improved outcomes for newborns with this condition.
From the Emergency Transport Services, The Children's Hospital of Philadelphia, Philadelphia, PA. From the The Children's Hospital of Philadelphia, Philadelphia, PA. From the Emergency Transport Team of the Children's Hospital of Philadelphia. Address correspondence to Peter Brust, RN, MSN, CCRN, CMTE, Emergency Transport Services, The Children's Hospital of Philadelphia, Room 1712 South Tower, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104. E-mails: [email protected], hamburger@email. chop.edu, [email protected]. © 2009 Elsevier Inc. All rights reserved. 1527-3369/09/0904-0326$36.00/0 doi:10.1053/j.nainr.2009.09.003
Case Study A call is received by The Children's Hospital of Philadelphia transport team for transport and admission of a sick infant. The referring hospital is requesting to transfer a 37 3/7-weekgestation infant with a weight of 3900 grams born by cesarean delivery to a diabetic mother. Apgar scores were 7 at 1 minute and 8 at 5 minutes. Maternal laboratories studies were unremarkable and the mother's group beta-strep status was negative. At 10 minutes of life, the infant was noted to have moderate respiratory distress, and supplemental oxygen was given by bag-valve-mask without improvement. The infant was then intubated with a 3.5 endotracheal tube (ET) and moved to the neonatal intensive care unit (NICU) at the referral center. At that time, the infant's heart rate was 188 beats per minute, respiratory rate was 90 breaths per minute, and blood pressure (BP) by cuff was 55/22 millimeters of mercury with a mean arterial pressure (MAP) of 33 millimeters of mercury. The infant's temperature was 36.7°C (98.2°F), and oxygen saturation was 80% on a fraction of inspired oxygen (FIO2) of 1.0. In the NICU, standard mechanical ventilation was initiated with peak inspiratory pressure (PIP) of 24 centimeters of water, a positive end-expiratory pressure (PEEP) of 5 centimeters of water, FIO2 1.0, and a rate of 50 breaths per minute. An umbilical arterial line and double lumen umbilical venous catheter were placed. Standard laboratory studies were drawn including an arterial blood gas (ABG) that showed pH 7.11, PCO2 of 81, PaO2 of 44, HCO3 of 21, and oxygen saturation of 78%. Based on these values, the ventilator settings were adjusted. The PIP was increased to 26 centimeters of water, PEEP was increased to 6 centimeters of water, and the rate was increased to 60. Sodium bicarbonate (NaHCO3) was given intravenously to correct the metabolic acidosis, and intravenous
fluids (dextrose concentration of 10%) were initiated at 80 milliliters per kilogram per day. A 10-milliliter per kilogram bolus of normal saline was given followed by a second bolus. Pre- and postductal saturations were measured and were noted to be 10 points lower preductally. After adequate volume administration, dopamine hydrochloride (dopamine) was started at 5 micrograms per kilogram per minute because of a persistently low MAP of 31. The chest x-ray (CXR) was essentially unremarkable and showed the invasive lines and ET to be in good position. The referring hospital had been unable to obtain an echocardiagram (ECHO), but the clinicians had a very strong suspicion that this infant was developing PPHN.
Pathophysiology During and immediately after delivery, the normal neonate is able to convert from fetal circulation to postnatal circulation. Failure of the neonate to do so can result in a syndrome of significant pulmonary hypertension causing hypoxemia and right-to-left extrapulmonary shunting. This, in turn, can lead to inadequate pulmonary perfusion, hypoxemia, increased pulmonary vascular resistance (PVR), respiratory distress, and acidosis, which is frequently severe.1 After birth, the normal rhythmic ventilation of the lung results in an increase in alveolar oxygen tension, and as a result, there is a decrease in the PVR and an increase in pulmonary blood flow. The beneficial effects of these changes are greater when the two events occur simultaneously. In some cases, the normal decrease in pulmonary vascular tone does not occur. The result is PPHN, which has the potential to cause significant morbidity and mortality in otherwise healthy newborns.1 Persistent pulmonary hypertension of the newborn is distinguished by marked pulmonary hypertension, hypoxemia, right-to-left shunting of blood, inadequate pulmonary perfusion, refractory hypoxia, and acidosis. Persistent pulmonary hypertension of the newborn often results when structurally normal pulmonary vessels constrict in response to alveolar hypoxia. Respiratory failure and hypoxia in the term newborn result from a heterogeneous group of disorders, and the therapeutic approach and response depend on the underlying disease.2
Incidence Persistent pulmonary hypertension of the newborn is reported to occur in two to six cases per 1000 per live births and can be a complicating factor in term or near-term newborns with parenchymal lung disease such as meconium aspiration syndrome (MAS) or pneumonia.3 Nearly 13% of all live births are complicated by meconium-stained fluid; however, only 5% of these infants actually develop MAS.3 Maternal diabetes, another pregnancy complication, is associated with infants who are born large for gestational age. These infants are at higher risk of being born by cesarean delivery and subsequently developing PPHN.3 The risk of developing PPHN also appears greater if the infant is male, as well as 34 to 37 weeks of gestation or greater
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than 41 weeks.3 Additional factors for the development of PPHN include maternal obesity as well as African American and Asian ethnic groups. Smoking during pregnancy can increase the risk of PPHN, whereas maternal hypertension and preeclampsia have a weaker association to PPHN but still are identified risk factors. Persistent pulmonary hypertension of the newborn affects phenotypically normal infants primarily but also can occur in those with Down syndrome.4
Etiology Knowledge of differences in the etiology of PPHN is instrumental in deciding on available therapeutic options. There are three recognized underlying etiologies for PPHN. The first is acute pulmonary vasoconstriction due to acute perinatal events such as (1) alveolar hypoxia secondary to parenchymal lung disease (respiratory distress syndrome, MAS, or pneumonia); (2) hypoventilation resulting from asphyxia or other neurologic conditions; (3) hypothermia; or (4) hypoglycemia.5,6 The second recognized etiology of PPHN is idiopathic PPHN, which is characterized by a normal CXR and no parenchymal lung disease. Idiopathic PPHN is often referred to as black-lung or clear-lung PPHN.6 These infants often develop true vascular disease. Idiopathic PPHN commonly results from an abnormal remodeling of the pulmonary artery vascular bed with vascular wall thickening and hyperplasia of the smooth muscle, which may be secondary to chronic stress in utero.6 Idiopathic PPHN may also result from maternal use of nonsteroidal anti-inflammatory drugs, such as ibuprofen or naproxen, or selective serotonin reuptake inhibitors during the later part of pregnancy.5-8 A third cause of PPHN is lung hypoplasia. Additional findings that may accompany hypoplasia and contribute to the development of PPHN include Congenital Diagphramatic Hernia (CDH) and oligohydramnios.3,5,6,9
Assessment and Diagnosis An infant who presents with severe respiratory distress, cyanosis, and tachypnea requires immediate and comprehensive evaluation. Significant lability in oxygenation is one indicator that should point the clinician in the direction of PPHN. Early suspicion and recognition of PPHN symptoms can result in appropriate and favorable outcomes. The diagnosis of PPHN is often made from maternal and antenatal history, examination of the infant, ECHO, and laboratory studies.6 An infant with PPHN may initially appear normal or show only mild respiratory disease. Cardiac examination may reveal a loud, single S2 or a harsh, systolic murmur secondary to tricuspid regurgitation. Blood pressure may be low or close to normal, although the infant may have poor cardiac function and perfusion. Often, pre- and postductal saturations are different because of the shunting of blood through the patent ductus arteriosus.
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The workup for a patient suspected of having PPHN should include an ABG to assess pH, PaCO2, PaO2, and alveolar-arterial difference. The PaO2 may be elevated if a preductal sampling site is used. Oxygenation should be assessed by comparing the postductal PaO2 and the current ventilator settings. Pulse oximetry is necessary for ongoing treatment evaluation over time. The clinician should distinguish preductal (right hand) from postductal (left or right foot) sites. The left hand should be avoided because it may provide either pre- or postductal readings depending on the infant's specific circulation. Some centers use the oxygenation index (OI), which is calculated as the MAP multiplied by the fraction of inspired oxygen (FIO2) and then multiplied by 100, which is then divided by the postductal PaO2. An OI of 40 or greater typically prompts consideration of ECMO support.10 A CXR can be helpful in determining the presence of underlying parenchymal lung disease or in ruling out disorders such as CDH. Cardiomegaly and increased vascular markings are often visible in PPHN, although routine CXRs are often nondiagnostic. In newborns with idiopathic PPHN, the lung fields appear clear with decreased vascular markings and the heart size is typically normal. When PPHN is suspected, an ECHO is essential to rule out the presence of congenital heart disease in the newborn with cyanosis and tachypnea. If the heart is deemed structurally normal, and the ECHO shows high pulmonary artery pressures and right-to-left shunting through the patent ductus arteriosus, foreman ovale, or both, then PPHN can be the presumptive diagnosis. Frequently, there is evidence of right heart failure because the pressures in the pulmonary artery are greater than the systemic pressure, resulting in the right ventricle's inability to eject blood. Rarely, cardiac catheterization may be required to assist in obtaining the appropriate diagnosis. In addition, biventricular failure may occur and is associated with poor outcomes; therefore, early ECHO findings along with aggressive management of PPHN are essential to improve patient outcomes. See Table 1 for a list of differential diagnoses for PPHN.
Table 1. List of Differential Diagnoses for PPHN 6 PPHN Differential Diagnoses Congenital diaphragmatic hernia MAS Partial anomalous pulmonary venous connection Pneumonia Pneumothorax Pulmonary atresia with intact ventricular septum Pulmonary hypoplasia Pulmonary sequestration Respiratory distress syndrome Sepsis Total anomalous pulmonary venous connection Transposition of the great arteries Tricuspid atresia
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An evaluation of the complete blood count may be significant for a high hematocrit, which may indicate polycythemia and hyperviscosity. Either of these syndromes may produce or aggravate PPHN. A white blood cell count and differential are helpful in determining whether an underlying sepsis syndrome or pneumonia exists. Platelets are frequently depressed particularly in newborns with MAS or asphyxia. Serum electrolytes and glucose should be monitored and corrected as needed. Glucose and ionized calcium levels should be kept in reference ranges because symptoms of PPHN can significantly worsen if these values are abnormal.5,6
Treatment Mechanical Ventilation With PPHN, mechanical ventilation is almost always necessary to maintain normal respiratory function. This is accomplished by recruiting areas of atelectasis that will occur. In addition, the use of gentle ventilation and permissive hypercapnia that provides adequate chest movement should be a mainstay of oxygenation and ventilatory strategies. This aids in reducing the risk of barotrauma and the long-term development of chronic lung disease. Reducing hyperventilation may, in fact, reduce hypoxic pulmonary vasoconstriction, increase cerebral blood flow, and prevent poor neurologic outcomes.11 Clinical teams should adjust ventilator settings to maintain normal expansion of the lungs, approximately nine ribs on inhalation. This can be accomplished by monitoring tidal volumes and pulmonary mechanics.6 Persistent pulmonary hypertension of the newborn caused by MAS is often due to increased pulmonary resistance from air trapping and decreased compliance. Conventional ventilator settings include PIP of 20 to 25, PEEP of 3 to 5 centimeters, I:E ratio of 1:2, respiratory rate of 40 to 80, and tidal volume limited to 5 to 6 milliliters per kilogram. The goal is to maintain a preductal saturation of more than 85% and postductal saturation of more than 60% if perfusion is satisfactory and the patient is nonacidotic. The clinical team should begin 100% oxygen administration and wean by 3% per hour as tolerated and PaO2 should be followed via ABG every 1 to 2 hours.6,11 In newborns with severe airway disease who require high PIPs (N30 centimeters of water or a MAP N15 centimeters of water), HFOV should be considered early to reduce barotrauma. The goal of HFOV is to optimize lung expansion and functional residual capacity to avoid overdistension of the lungs. Overdistension can predispose the newborn to significant barotrauma and elevation of PVR, thereby aggravating the right-to-left shunting and worsening the PPHN. Gentle HFOV may be considered with settings of a MAP less than 14 and 6 to 8 Hz. It has been shown that the use of oscillatory ventilation along with other strategies improves lung inflation and alveolar recruitment.11 High-frequency oscillatory ventilation with a high MAP should not be used to rescue oxygenation. If the infant fails to stabilize on HFOV,
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then consideration for further escalation of therapy with iNO and ECMO should be considered.11
Sedation and Induced Paralysis Decreased pH, increased PaCO2, and worsening hypoxemia can result from excess stimulation of the infant and have been shown to be detrimental6,11; therefore, excess stimulation should be minimized. If the infant is awake or becomes difficult to ventilate, use of sedation with a benzodiazepam agent can be considered. Induced paralysis is highly controversial, and the clinical team needs to consider the risk/benefit ratio before the initiation of therapy. The medical team should avoid excessive rescue boluses of narcotics to limit the potential wide swings in BP. The medical team may consider beginning an infusion of midazolam (Versed; Roche Pharmaceuticals Inc, Nutley, NJ) at 0.01 milligrams per kilogram per hour and morphine sulfate (morphine) 0.01 milligrams per kilogram per hour as good starting points for sedation. If the newborn becomes hypotensive, morphine sulfate should be stopped and the team should consider the use of fentanyl citrate (fentanyl) at 1 microgram per kilogram per hour. The medical team should avoid the use of pancuronium bromide (Pavulon; Organon International, Oss, the Netherlands) unless the infant does not tolerate mechanical ventilation or becomes hemodynamically unstable. There have been some isolated reports in the literature12 of increased mortality associated with the use of pancuronium bromide. Pancuronium bromide may promote atelectasis of dependent lung regions and ventilation perfusion mismatch. Prolonged administration of pancuronium bromide during the neonatal period may be associated with sensorineural hearing loss in childhood survivors of CDH. One study has suggested that paralysis may be associated with increased risk of death.4 Careful and ongoing assessment of the newborn's response to stimulation and sedation is an important part of improving oxygenation of the newborn with PPHN. Prostacyclins and magnesium therapy have been studied in newborns with PPHN. However, to date, no study has shown improvement with these therapies.1,13
Acid-Base Balance For infants with PPHN, metabolic and respiratory imbalances need to be corrected. Arterial blood gases should be collected, analyzed, and remedied before and during any transport. It is important to have adequate supplies for transport; therefore, consideration for the use of portable bedside ABG monitoring should be considered. NaHCO3 administration can result in significant carbon dioxide production; however, limiting or reducing acidosis is extremely important. NaHCO3 is the mainstay of acid buffering and dosing should be based on the results of the ABG. NaHCO3 should be diluted to 0.5 milliequivalent per milliliter in newborns. Tromethamine (THAM; Hospira Inc, Lake Forest, IL) can be used if carbon dioxide clearance is a problem after the administration of NaHCO3. The dose depends on buffer base
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deficit; when base deficit is known, the volume of tromethamine to administer is milliliters of 0.3 moles per liter solution = body weight (kilograms) × base deficit (milliequivalent per liter); when the deficit is not known, 3.5 to 6 milliliters per kilogram per dose intravenously (1–2 milliequivalent per kilogram per dose). In addition, tromethamine should not be given through a peripheral intravenous or low-lying umbilical venous line because it is known to cause necrosis. Urine output should be established before administration.6 Follow-up ABG assessment is required to assess response to the buffers. Forced alkalosis is an older therapy, which is no longer an accepted practice. It was once thought effective in promoting pulmonary vasodilatation and increasing PaO2; however, the hypocarbia associated with this resulted in constriction of the cerebral vasculature and subsequent complications.6
Catheter Placement Catheterization of the femoral veins can be considered and will allow for the administration of fluids, inotropic agents, or hypertonic solutions as needed. An umbilical artery catheter or peripheral arterial catheter can be useful in monitoring BP and ABGs.
Surfactant Administration The administration of exogenous surfactant at any gestational age may be necessary depending on the presentation of the infant and a decision by the clinical team. Some studies have reported improved oxygenation and decreased barotrauma with the administration of surfactant, which can ultimately reduce the need for ECMO.5,12-14
Nitric Oxide The most important recent advancement in treating PPHN is the initiation of iNO. Inhaled nitric oxide acts on the smooth muscle cells of the pulmonary system by increasing c-CMP levels strictly in the lungs, thereby producing pulmonary vasodilation.15 This, in turn, decreases pulmonary pressures and results in better oxygenation and ventilation. Inhaled nitric oxide does not produce systemic hypotension. The actions of iNO reduce ventilation perfusion mismatch, enhance alveolar recruitment, and potentially reduces lung inflammation. In more than 10 years of widespread use, a 50% reduction in the use of ECMO has been reported.15 When begun early for moderate PPHN, studies have shown not only improvement in oxygenation but prevention of progression of the PPHN to a more severe form.15,16 Ideally, appropriately staffed teams from the receiving institution are able to bring iNO therapy to the bedside at the referring center. Significant preplanning of equipment needs for both ground and flight transport incubators (commonly referred to as transport isolettes) to accommodate the iNO setup is required. There is usually significant benefit to the newborn once placed on iNO therapy. This generally requires a
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slightly longer bedside time for the transporting team; however, iNO has been demonstrated to be a safe and effective therapy for use on transport.1,17,18 The transporting team needs to assess the infant before the initiation of iNO at the referring facility. Current literature indicates neonates with an OI of more than 25 should be highly considered for this therapy.15-17 Inhaled nitric oxide can be delivered to the lungs by means of an inhalation device and/or through mechanical ventilation. Therefore, respiratory therapists are an integral part of the transport team as they, along with the physician and nurse, initiate, titrate, and maintain the iNO during transport. One common device, the iNO VENT (Datex-Ohmeda, Inc, Madison, WI) can be used to transport newborns on iNO and is able to accommodate ground, rotor, and fixed wing transports. Figs 1 and 2 illustrate the devices for ground and flight transport. A usual dose of iNO is 20 parts per million. Higher doses have not been shown to be effective.15-17 Adverse events of iNO include methemoglobinemia and increased levels of nitrogen dioxide. Most infants require iNO for less than 5 days, and the dose can usually be weaned to 5 parts per million after 6 to 24 hours. Inhaled nitric oxide can be discontinued when FIO2 is less than 0.6 and iNO dose is 1 part per million. Abrupt discontinuation of iNO may cause severe rebound. Studies have shown that the combined use of surfactant and iNO have shown dramatic improvement in oxygenation and a decrease in ventilator settings.15
Extracorporeal Membrane Oxygenation When ECMO is necessary for the treatment of PPHN, certain eligibility criteria should first be met. To be eligible for ECMO, the newborn should be at least 2000 grams, greater than 34 weeks of gestation, have inadequate oxygenation, have failed success of the therapies described above. A major contraindication to ECMO is intracranial hemorrhage greater than grade II.16,19
Fig 1. Ground incubator with iNO Max DS setup.
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Fig 2. Flight incubator with iNO Max DS setup.
Considerations for Transport Recognition Infants with PPHN should be evaluated closely for their response to the standard therapies described above. If they fail to improve or if the care required of the newborn exceeds the referring institution's capabilities, then transport to a center with both iNO and ECMO capabilities should be strongly considered. The earlier the transport occurs in the care of the infant, the less risk there is for the patient. Ideally, transport should occur to a tertiary or quaternary care center.
Treatment/Physical Assessment During Transport Meticulous attention to detail should be maintained in collecting information on the current care of the infant. Strict attention to the history, physical examination, laboratory studies, and current therapies is crucial to a successful transport. A CXR should be done to confirm ET tube placement. Copies of the chart and all relevant studies must accompany the newborn during transport to avoid duplication at the receiving facility. During the actual transport, the team must maintain strict monitoring of the heart rate, SpO2, BP, and perfusion.20 Minimal stimulation should also be a primary goal of the transporting team. The transport isolette should be covered and the newborn should be positioned to avoid stimulation. It is generally recommended that the decibel level within the transport isolette be 75 decibels; however, because of noise and vibration associated with transport both by ground and rotor wing, decibel levels often range from 75 to 100 decibels or higher.21 Monitoring of fluid status is important to maintain right ventricular filling pressures. Adequate circulatory volume is important; however, repeat fluid boluses do not necessarily provide additional benefits. Strict monitoring of the intake and output is essential as well.16,19 Adequate intravenous access is required to safely transport the newborn. At a minimum, umbilical venous and arterial
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access should be obtained. An additional peripheral intravenous line is helpful for the administration of volume, sedation, and other required medications.15,16 Inotropic support such as dopamine hydrochloride, dobutamine hydrochloride, and milrinone alone or in combination may be necessary to maintain adequate cardiac output and systolic BP while avoiding volume overload. Dobutamine hydrochloride and milrinone may be necessary when myocardial contractility is poor.22,23
Family Considerations Transfer of an infant is a very stressful situation for the families. In addition to the family having to cope with a sick infant, frequently, family members also have to leave the hospital in a geographic area with which they are familiar to go to a geographic area with which they are usually not familiar. The emotions of the entire family need to be taken into consideration. Emotions can range from sadness, disbelief, and anger to acceptance of the situation. The transporting team and staff at the referral center must be prepared to support the family, especially the parents. In addition, specific details should be given to the parents including the following: • How their child will be transported (ie, warmed transport isolette, ambulance, etc) • The medical therapy the infant will be receiving during transport • The capabilities of the transporting team • The risk factors of the transport • The approximate length of time the transport will take • Where their infant will be going, along with the phone number • What room their child will be in along with the receiving units telephone number • The tentative plan once the child arrives at the tertiary/ quaternary center • Directions for getting to the tertiary/quaternary center • Visiting hours and visiting policies of the tertiary/ quaternary center It is imperative that the transport team obtain accurate phone numbers to stay in touch with the parents. It is courteous to ask if the infant has a first name yet and if the mother plans to breastfeed so that the staff at the receiving medical center can be notified. If a parent is not accompanying the transport team, the parents should be notified of the infant's status if the patient's condition changes and at the completion of transport when the team arrives at the receiving center. The care team, including medical staff, nursing, social work, and the chaplain services, should contact the family as soon as possible after the infant's admission to the NICU. Adequate support is the key to the parent's ability to cope with their newborn's hospital admission. Once transport has occurred, it is essential that the receiving institution relay prompt and appropriate information on the newborn's status to the family and the referring medical team. This will assist in ensuring that continuity of care exists between the referring medical team, the family, and the accepting team.
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The potential exists that the infant may require advanced therapies, such as ECMO, or that other diagnoses may be found. This effort to establish the relationship with the family at the referring institution can be rewarding to both teams.
Prognosis and Follow-up In the early 1990s, mortality of patients with PPHN reached 40% with major neurologic disability ranging from 15% to 60%.12 The introduction of ECMO reduced mortality in PPHN. In 1996, one study from the United Kingdom reported serious mortality from PPHN dropped from 60% to 30%; however, newborn survivors with serious neurologic morbidity remain at 15% to 20%.9 Recently, survival rates of 85% have been reported when all the resources described are available to the patient.5,15 When pulmonary recovery is complete, the survivors do not appear to have residual pulmonary disease, although prolonged hyperventilation has been associated with increased prevalence of neurodevelopment issues including hearing loss.5,15 Once the infant is out of danger, a neurologic assessment should be conducted. This may include a computed tomography and magnetic resonance imaging scan. A neurologic development examination should be conducted with followup at 2 years of age. Hearing tests should be conducted before discharge and subsequently followed at 6 months of age and then as indicated.5,24,25 After the initial insult and recovery, it may be days to weeks before the newborn is able to tolerate oral feeds. Nasogastric feeds may be necessary during this time to maintain appropriate nutrition and mobilization of the gastrointestinal tract. Speech therapy may be helpful in reestablishing normal patterns of feedings. In addition, learning disabilities should be screened for before the child enters school to capture and allow for appropriate interventions.25
Case Study Follow-up The transport team arrived at the referring hospital and quickly assessed the newborn. His ET was in good position. Adequate fluid administration had been given by the referring hospital, and the newborn was on dopamine hydrochloride at 5 micrograms per kilogram per minute. After obtaining an ABG of pH 7.16, PCO2 of 65, PaO2 of 67, HCO3− of 19, and SaO2 of 78%, iNO was initiated by the transport team at 20 parts per million. In addition, morphine sulfate 0.1 milligrams per kilogram and midazolam 0.1 milligrams per kilogram were administered. Shortly after iNO and sedation were initiated, an improvement in the oxygen saturation to 95% was noted. FIO2 was decreased to 0.8, and the respiratory therapist noted that the chest compliance had improved. The newborn was safely loaded into the transport isolette and transported to The Children's Hospital of Philadelphia without incident. In the NICU, the newborn was placed on the HFOV with iNO at 20 parts per million. Inhaled nitric oxide was continued for 5 days and then weaned appropriately. The newborn was subsequently weaned to
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conventional mechanical ventilation. On day 7 of the hospital course, the newborn was extubated to a nasal cannula, continued to improve, and was discharged home on day 30 of the hospitalization.
Summary Despite all of the advances in medical therapies, PPHN continues to have a significant morbidity and mortality rate. Early recognition and action must be an integral part of the care of a newborn who presents with respiratory distress, cyanosis, and tachypnea. The practitioner must do an immediate and comprehensive evaluation of the newborn. Prompt recognition and treatment of PPHN often results in favorable outcomes of the newborn. Congenital heart disease should be ruled out by an ECHO, but if an ECHO is not possible or unavailable, treatment should not be delayed. Respiratory support should be initiated with conventional ventilation or HFOV and circulatory support begun. Intravenous access and laboratory studies including ABG and CXR need to be obtained early. The newborn should be sedated to decrease additional oxygen requirements at the tissue level. In addition, contact of a tertiary/ quaternary care center should occur early. The receiving institution should obtain a detailed history, make appropriate recommendations, and launch their transport team with all of the appropriate therapies, including iNO. Having a specialized transport team with the capabilities of providing iNO rapidly is extremely beneficial to these newborns. Early initiation of iNO in moderate PPHN has been shown to reduce lung inflammation, improves oxygenation, and prevents the progression of PPHN and reducing the need for ECMO. Inclusion of the families in all of these plans and treatments is essential to help decrease their anxiety and prepare them for what lies ahead. The advancements and portability of treatments for PPHN have come a long way over the past few years, providing a more favorable outcome for both infants and their families.
References 1. Abman SH. Recent advances in the pathogenesis and treatment of persistent pulmonary hypertension of the newborn. Neonatology. 2007;91:283-290. 2. Graves III ED, Redmond CR, Arensman RM. Persistent pulmonary hypertension in the neonate. Chest. 1988;93:638-641. 3. Hernandez-Diaz S, Van Marter LJ, Werier MM, et al. Risk Factors for persistent pulmonary hypertension of the newborn. Pediatrics. 2007;120:e272-e282. 4. Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics. 2000;105:1-14. 5. Ostrea Jr EM, Villanueva-Uy ET, Natarajan G, et al. Persistent pulmonary hypertension of the newborn, pathogenesis, etiology and management. Pediatr Drugs. 2006;8:179-188.
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6. Steinhorn RH. Pulmonary hypertension, persistent-newborn. Emedicine.Medscape.Com. April 19, 2007. 7. Andrade SE, McPhillips H, Loren D, et al. Antidepressant medication use and risk of persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Saf. 2009;18:246-252. 8. Koren G, Boucher N. Adverse effects in neonates exposed to SSRIs and SNRI in late gestation. Can J Clin Pharmacol. 2009;16:e66-e67. 9. Curtis J, Kim G, Wehr NB, et al. Group B streptococcal phospholipid causes pulmonary hypertension. Proc Natl Acad Sci U S A. 2003:5087-5090. 10. Steinhorn RH. Nitric oxide and beyond: new insights and therapies for pulmonary hypertension. J Perinatol. 2008;28: s67-s71. 11. Wanstall JC, Jeffery TK. Recognition and management of pulmonary hypertension. Drugs. 1998;56:989-1007. 12. Asad A, Bhat R. Pharmacology for meconium aspiration. J Perinatol. 2008;28:S72-S78. 13. Perreault T. Persistent pulmonary hypertension of the newborn. Paediatr Respir Rev. 2006;7S:S175-S176. 14. Baquero H, Soliz A, Neira F, et al. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics. 2006;117:1077-1083. 15. Fakioglu H, Totapally BR, Torbati D, et al. Hypoxic respiratory failure in term newborns: clinical indicators for inhaled nitric oxide and extracorporeal membrane oxygenation therapy. J Crit Care. 2005;20:288-295. 16. Soll RF. Inhaled nitric oxide in the neonate. J Perinatol. 2009;29:s63-s67. 17. Gadzinowski J, Kowalska K, Vidyasagar D. Treatment of MAS with PPHN using combined therapy: SLL, bolus surfactant and iNO. J Perinatol. 2008:S56-S66. 18. Wiedemann JR, Saugstad AM, Barnes-Powell L, et al. Meconium aspiration syndrome. Neonatal Netw. 2008;27:81-87. 19. Lowe CG, Trautwien JG. Inhaled nitric oxide therapy during the transport of neonates with persistent pulmonary hypertension or severe hypoxic respiratory failure. Eur J Pediatr. 2007;166:1025-1031. 20. Pippert G, Wewerka S, Fransonce RJ, et al. Neonatal patient sound exposure during critical care transport. Air Med J. 2008;27:234-235. 21. Tung BJ. The use of nitric oxide therapy in the transport of newborns with persistent pulmonary hypertension. Air Med J. 2001;20:10-11. 22. Lutman D, Petros A. Inhaled nitric oxide in neonatal and paediatric transport. Early Hum Dev. 2008;84:725-729. 23. ELSO Patient specific supplements to the ELSO general guidelines, 2009 April. 24. Bassler D, Choong K, McNamara P, et al. Neonatal persistent pulmonary hypertension treated with Milrinone; four case reports. Biol Neonate. 2006;89:1-5. 25. Hosono S, Ohno T, Kimoto H, et al. Developmental outcomes in persistent pulmonary hypertension treated with nitric oxide therapy. Pediatr Int. 2009;51:79-83.
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