Persistent Pulmonary Hypertension in the Neonate

review Persistent Pulmonary Hypertension in the Neonate Ernest D. Graves Ill, M.D .;· Clyde R. Redmond, M.D. ;t and Robert M. Arensman, M.D .·

Respiratory failure is the leading cause of death in the neonatalperiod. The anatomicand functional basisfor this, particularly in full-term infants, most often is persistent pulmonaryhypertensionofthe neonate (PPHN~ Thiscondition is reversible but can cause very severe and unrelenting respiratory failure and ultimate death when uncontrolled.

Recent technologic advances have expanded the scope of therapy available for PPHN, resulting in increasingtherapeutic success for these critically ill infants. This article reviews the anatomicand functional anomalies ofPPHN, as wen as the methods of diagnosis and discusses current treatment.

F;;rsistent pulmonary hypertension in the neonate (PPHN) leads to respiratory failure and death unless treated. It may be primary or secondary to meconium aspiration syndrome, hyaline membrane disease, neonatal sepsis with pneumonia, congenital diaphragmatic hernia, and certain congenital heart defects. The pathophysiologic key to this syndrome is increased pulmonary vascular resistance! that prevents normal pulmonary blood flow and causes a right-to-left shunt through persistent fatal channels (ie, the patent foramen ovale [PFO] and patent ductus arteriosus [PDA]). This may be seen in Figure 1. The result is lifethreatening hypoxia, cyanosis, and acidosis.

duced vascular compliance. Acidosis and hypercarbia contribute to the process. Thus, a vicious cycle may be initiated, maintained, and aggravated, causing further vasoconstriction and loss of compliance. Right-to-left shunting through the PFO and the PDA results, further worsening an already severe hypoxia. This maladaptation will occur in a pulmonary vascular bed that is structurally normal. The remaining types of

ANATOMIC CONSIDERATIONS

Geggel and Reid" described three anatomic types of PPHN, based on pulmonary vascular morphology. In all, there is increased pulmonary vascular resistance. These three types, which are not mutually exclusive, are maladaptation, excessive muscularization of the pulmonary vascular bed and underdevelopment of the pulmonary vascular bed.

Maladaptation When the normal neonate begins to breathe and the PV02 of the blood in the pulmonary bed rises, pulmonary vascular resistance decreases and compliance increases. Conversely, hypoxia (from any source including nuchal cord, airway obstruction, primary parenchymal disease) causes vasoconstriction and re-Department of Surgery. Ochsner Clinic and Alton Ochsner Medical Foundation. New Orleans . tDepartment of Surgery. Louisiana State University Medical Center, New Orleans . RefJ.rint requests: Dr. Graves, Ochsner Foundation Hospital . 1516 Jefferson Highway, New Orleans 70121

FIGURE 1. Diagram of right-to-left shunting (indicated by arrows) through PFO and PDA. which results from PPHN .

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Perslstent Pulmonary Hypertenslon In Neonate (Graves, Redmond, Arensman)

PPHN occur in structurally abnormal pulmonary vasculature. Excessive Muscuwrization of the Pulmonary Vascular Bed

In the normal fetus and neonate, muscular arteries extend no further distally than the terminal bronchiolus. Growth of muscular arteries occurs progressively so that by adulthood these arteries may be found at the alveolar wall level. Excessive in utero muscularization of the pulmonary bed may result in PPHN. Neonatal muscular arteries are found at the alveolar wall, similar to the adult configuration. This muscularization compromises the vessel lumen, adding to the increased pulmonary vascular resistance. Intrauterine exposure to indomethacin and aspirin may result in excessive muscularization, and congenital cardiac lesions that obstruct pulmonary veins (eg, aortic atresia, aortic stenosis, obstructed total anomalous pulmonary venous connection) may also promote excessive in utero muscularization. Underdevelopment of the Pulmonary Vascular Bed Bronchial branching is generally complete by the 16th gestational week. Intrauterine abnormalities that disturb lung development early in gestation may result in a reduced number of bronchial branches. Later disturbances may result in normal bronchial ramification, but reduced number and size of alveoli. In either case the end result is a hypoplastic lung and vasculature. Prognosis at birth of this condition is directly related to the lung volume present. A classic example of this type of PPHN is the neonate with congenital diaphragmatic hernia. The intrathoracically displaced abdominal contents retard lung development early in gestation and frequently result in irreversible PPHN. DIAGNOSIS

Hypoxemia will result from PPHN, which responds poorly to the administration of oxygen and positive pressure ventilation." A preductal (right radial artery) to postductal (umbilical artery) arterial oxygen pressure (PaOJ difference of 15 mm Hg or greater suggests significant right-to-left shunting. The diagnosis usually can be confirmed by echocardiography, which will demonstrate normal structural relationships with right-to-Ieft shunting at the atrial and ductal levels. If echocardiography does not rule out congenital cardiac lesions, cardiac catheterization may then be necessary for definitive visualization of cardiopulmonary anatomy. TREATMENT

Assisted Ventilation

Assisted ventilation is the mainstay of treatment for PPHN, the most common form being hyperventilation

and induced alkalosis. Hyperventilation maintains respiratory alkalosis with an arterial carbon dioxide pressure (PaCOJ in the 20 to 30 mm Hg, and a Pa02 of 120 mm Hg or greaten Most neonates will have a critical PaC02 above which Pa02 becomes labile, and below which good oxygenation can be maintained. The PaC02 must be maintained at or below this critical level. Hyperventilation requires rates in the range of100 to 140 breaths per minute. Low continuous distending pressures (CDP) in the range of 3 to 5 em H 20 are required, and often extreme peak inspiratory pressures (PIP) of 35 cm H 20 or greater will be required to achieve appropriate levels of PaC02 and Pa02 • The effect of hyperventilation is to interrupt the cycle of hypoxia and acidosis and allow relaxation of the pulmonary vascular bed. Once the neonate has stabilized, a gradual transition from maximum ventilation to spontaneous breathing begins. Greater variations of Pa02 and PaC02 are allowed once the PPHN cycle breaks." Hyperventilation is highly effective, and approximately 80 percent of neonates with PPHN can be treated with, and successfully weaned from, mechanical ventilation." The great disadvantage of hyperventilation is its traumatic effect on the delicate neonatal lung. In response to the barotrauma induced by hyperventilation, 4 to 38 percent of neonates will develop chronic and often debilitating bronchopulmonary dysplasia (BPD).6 Wung et al" have reported management of severe PPHN without hyperventilation. Their technique of minimal ventilation allows maintenance of a much lower Pa02 , in the range of 50 to 70 ton The PaC02 is not a controlled parameter and is allowed to increase to as high as 60 mm Hg. Thus, much lower ventilator settings are required as compared with those for conventional hyperventilation. Their method evolved through a long period of clinical evaluation and trial and error; and apparently considerable clinical expertise in this method is required for it to succeed. However; its distinct and important advantage is that ventilator-induced barotrauma and resultant BPD are minimized. In 15 patients reported, only one developed chronic lung disease. High frequency ventilators with rates ranging from 150 to 3,000 breaths per minute also are used in the treatment of PPHN. Such ventilators deliver small volumes of gas at high frequencies and require less airway pressure to achieve gas exchange equivalent to conventional assisted ventilation. Thus, pulmonary barotrauma and cardiovascular compromise, two frequent complications of hyperventilation, are reduced. 8 This makes high frequency ventilation an attractive alternative. There is evidence that high frequency ventilation .is associated with tracheal injury, and that CHEST I 93 I 3 I MARCH. 1988

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Fluids

Heparin

Heat Exchanger

02 Source Membrane

Lung

FIGURE 2. Infant attached to ECMO circuit AfTOW.t indicate direction of blood SCM lMeI, position of venous cannula in right abium (via right internal jugular vein) and arterial cannula in aortic arch (via right common carotid artery).

the severity of injury is directly proportional to ventilator rate." The use of high frequency ventilators in the treatment of PPHN is therefore controversial. Pulmonary

Vasodilators

There is currently no known drug that is a powerful and selective dilator of pulmonary vasculature. 10 When considering pharmacologic manipulation, it is, therefore, difficult to know if changes in PaO. are directly related to the action on the pulmonary vasculature or to overall hemodynamic effects. Following is a brief discussion of some of the more commonly used pharmacologic agents.

Tolazoline Tolazoline has many pharmacologic effects; among them are alpha-adrenergic blockade and direct vasodilatation. Roughly 60 percent ofneonates treated with tolazoline will respond favorably, with a rise in PaO•. The complication rate associated with tolazoline is high (as high as 82 percent). The most common adverse effects are hypotension (up to 67 percent) and mild gastrointestinal bleeding (up to 55 percent). U

Prostaglandin E1 Prostaglandin E 1 (PGEJ is used to prevent closure of the ductus arteriosus in certain congenital cardiac lesions in which delivery of oxygenated blood to the systemic circulation is dependent on right-to-Ieft 840

shunting at the atrial and ductal levels (eg, total anomalous pulmonary venous connection). Prostaglandin E 1 also dilates pulmonary arterioles. Its effects, however, are not specific for pulmonary vasculature and it has not proven very useful in the treatment of PPHN.

Prostaglandin I J Prostaglandin I. (Prostacyclin) Reports vary widely concerning the use of this vasodilator; It has been very useful in some neonates," but equally unhelpful in others due to devastating complications. 13

Isoproterenol Isoproterenol is a l3-adrenergic agonist that dilates systemic and pulmonary arteries. Its theoretical advantages are its inotropic effect and the fact that alveolar hypoxemia may increase the number of J3-adrenergic receptors in the pulmonary vasculature. 14

Leu1cotriene Antagonists Leukotrienes are products of fatty acid metabolism that are pulmonary vasoconstrictors." Recent reports have implicated leukotrienes as a causative agent in PPHN18 and suggest a future role for leukotriene antagonists in the treatment of PPHN.

Enracorporeal Membrane Oxygenation Extracorporeal membrane oxygenation (ECMO) is a

'Dlble l-Baulta ojECMO t111hItmnenIfor Secere PPHN* Diagnosis

1btal

Survivors ("')

33 6 5

31 (94) 5 (83)

~ 48

~ (100)

11

6(55)

Primary parenchymal disorders MAS HMD Primary PPHN Sepsis Other Congenital diaphragmatic hernia CDR Congenital cardiac lesions TAPVC CCF

2

4

..! 5 64

Total

4 (SO) 2 (100)

44 (92)

3(75) (0) 3 (60) 53 (83)

..Q

• Abbreviations: ECMQ, enracorporeal membrane oxygenation; PPHN, persistent pulmonary hypertension of the neonate; MAS, meconium aspiration syndrome; HMO, hyaline membrane disease; CDH, congenital diaphragmatic hernia; TAPVC, totalanomalous pulmonary venous connection; CCF: coronary-cameral fistula.

method of partial cardiopulmonary bypass that maintains adequate oxygenation during a period of lung rest and recovery. Mechanical ventilation during ECMO is minimal and the risk of further barotrauma is, therefore, low This method is an invasive and extraordinary means of life support. It is used in the treatment of severe PPHN that has failed to respond to the more conventional and less invasive methods discussed previously. METHODS

Extracorporeal support is established by surgically cannulating the right internal jugular vein and right common carotid artery (Fig 2). Blood is removed (via the vein) from the right atrium, circulated and oxygenated by the extracorporeal circuit, and returned (via the artery) to the aortic arch. After the procedure, both vessels are permanently ligated. REsulXS

From September 1983 to August 1986, 64 neonates underwent ECMO in our institution for the treatment of severe PPHN unresponsive to conventional methods. There have been 53 (83 percent) survivors." As noted in Table 1, survival was greatest in the group of infants with primary parenchymal disease. These infants had structurally normal lungs; thus, their PPHN was of the maladaptation type. The clinical significance of the Geggel-Reid anatomic classification becomes obvious, as better survival would be expected in those neonates with structurally nonnallungs. Incontrast is the poor survival in the group with congenital diaphragmatic hernia, those neonates with underdevelopment of the pulmonary vascular bed. CONCLUSION

Persistent pulmonary hypertension of the neonate is a disorder that, when severe, may result in irreversible

respiratory failure and death. The pathophysiologic hallmark of PPHN is increased pulmonary vascular resistance with right-to-Ieft shunting at the atrial and ductal levels. Assisted ventilation and pharmacologic manipulation are the mainstays of treatment, and the great majority of infants with PPHN can be successfully treated with those two modalities. For those infants with good neurologic potential who fail to respond to the conventional modalities, ECMO should be considered. It provides adequate oxygenation dUJ'ing a period of lung rest and recovery, thus preventing further barotrauma. It is an invasive mode of therapy that requires considerable expertise as well as strong institutional support and should be reserved for those most critical infants who may benefit from it. REFERENCES 1 Gersony WM. Neonatal pulmonary hypertension: pathophysiology, classification, and etiology. Coo Perinatol 1984; 11:517-24 2 Geggel RL, Reid LM. The structural basis of PPHN. Coo Perinatoll984; 11:525-49 3 Goldsmith J~ Karot1dn FH. Assisted ventilation of the neonate. Philadelphia: WB Saunders Co, 1981:239 4 Goldsmith J~ Karotkin FH. Assisted ventilation of the neonate. Philadelphia: WB Saunders Co, 1981:122-25 5 Loe WA, Graves ED, Ochsner JL, Falterman ~ Arensman RM. Extracorporeal membrane oxygenation for newborn respiratory failure. J Pediatr Surg 1985;20:684-88 6 Markestad 'I: Fitzhardinge PM. Growth and development in children I'eCO\'eringfrom bronchopulmonary dysplasia. J Pediatr 1981; 98:597-602 7 Wong TI: James LS, ICilchevsky E, James E. Management of infants with severe respiratory 6Ulure and persistence of the fetal circulation, without hyperventilation. Pediatrics 1985;76:488-94 8 Carlo WA, Martin RJ. Principles of neonatal assisted ventilation. Pediatr Clio North Am 1986; 33:233-35 9 Mammel MC, Ophoven J~ Lewallen PIC, Gordon MJ, Sutton MC, Boros SJ. High-frequency ventilation and tracheal injuries. Pediatrics 1986; 77:608-13 10 Kulik 11 LockJE. Pulmonary vasodilator therapy in persistent pulmonary hypertension of the newborn. Coo Perinatol 1984; 11:693-701 11 Ward 8M. Pharmacology of tolazoline. Coo Perinatol 1984;11: 703-13 12 Lock JE, Olley PM, Coceani F: Swyer PR, Rowe RD. Use of prostacyclin in persistent fetal circulation. Lancet 1979; 1:1343 13 Dnmunond WH, Williams B], Blanchard WB, Bucholz CJ, Bucholz CL. Myocardial infarction after prostacyclin (PGI2) treatment of neonatal pulmonary hypertension (PH) (abstract). Pediatr Res 1982; 16:99 14 LockJE, Olley PM, Coceani It: Enhanced p-adrenergic-receptor responsiveness in hypoxic neonatal pulmonary circulation. Am J Physiol240 (Heart Cire Physiol 9) 1981; H697-703 15 Ahmed 'I: Oliver W. Does slow-reacting substance of anaphylaxis mediate hypoxic pulmonary vasoconstriction? Am Rev Respir Dis 1983; 127:566-71 16 Stenmark ICR, James SL, Voelkel NF: Toews WH, Reeves J1; Murphy RC. Leukotriene C4 and D4 in neonates with hypoxemia and pulmonary hypertension. N Eng! J Med 1983; 309:77-80 17 Redmond CR, Graves ED, Falterman ICW, Ochsner JL, Arensman 8M. Ext:racorporeal membrane oxygenation for respiratory and cardiac failure in infants and children. J Thone Cardiovasc Surg 1987; 93:199-204 CHEST I 83 I 3 I MARCH. 1888

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