FIG 15.12 Management algorithm for intensive care support of preterm infants with acute pulmonary hypertension BP, Blood pressure; HIE, hypoxic-ischemic encephalopathy; HRF, heart rate fluctuations; iNO, Inhaled nitric oxide; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; R/O, rule out; RV, right ventricle; SVR, systemic vascular resistance; TnECHO; targeted neonatal echocardiography (From Giesinger RE, More K, Odame J, Jain A, Jankov RP, McNamara PJ Controversies in the identification and management of acute pulmonary hypertension in preterm neonates Pediatr Res 2017;82[6]:901–914.) Pulmonary Vasodilator Therapy Acute administration of iNO leads to improved oxygenation in premature infants.244,245 Weight and gestational age have been suggested as predictors of responsiveness246,247; however, studies of infants with pulmonary hypoplasia suggest that nitric oxide is effective independent of gestational age.248–250 Rescue therapy for hypoxic preterm infants with echocardiography documented pulmonary hypertension is recommended.222 A prior history of prolonged oligohydramnios or pulmonary hypoplasia may increase the likelihood of response Although nitric oxide has not been shown to improve long-term outcomes, responders to therapy may have improved disability-free survival compared with nonresponders.251 There is some evidence in support of alternative vasodilator treatments in premature infants For example, milrinone is associated with improved oxygenation and right ventricular function.252 Cardiovascular Support Blood pressure support for preterm infants with pulmonary hypertension should focus on agents that increase systemic vascular resistance without corresponding increase in pulmonary vascular resistance Vasopressin, a potent systemic vasoconstrictor with nitric oxide mediated pulmonary vasodilator effects, has an ideal pharmacologic profile, although published literature is limited.253 Treatment for right ventricular dysfunction may include dobutamine, which provides positive inotropy without vasoconstriction,209 or epinephrine, which raises systemic and pulmonary vascular resistance proportionally and therefore is less likely to exacerbate extracardiac shunting (see Fig 15.9).254 Chronic Lung Disease, Pulmonary Vascular Remodeling, and Pulmonary Hypertension Preterm lung injury is characterized by injury to both the air spaces and vasculature.255 The former is characterized by alveolar simplification, whereas the latter is characterized by impaired angiogenesis and pulmonary hypertension The abnormal pulmonary vascular bed is characterized by increased muscularization of vascular smooth muscle cells, distal extension of muscle into nonmuscularized vessels, and arrested vascular growth The vasoactivity of pulmonary vessels is characterized by increased basal vascular tone and impaired potential to relax Factors contributing to pulmonary vascular remodeling include oxygen toxicity, hypoxemia, and mechanical ventilation.256 Injury to the pulmonary vascular bed may also play a role in the development of impaired alveolarization Pulmonary angiogenesis is modulated by vascular endothelial-derived growth factor The administration of a receptor antagonist leads to impaired angiogenesis and alveologenesis in neonatal rodents.257 Echocardiography screening is currently the subject of comprehensive investigation in at-risk populations because the natural history of pulmonary vascular disease in extreme preterm infants is poorly understood Magnetic resonance imaging may provide an opportunity to study pulmonary flow and pressure more effectively Nitric oxide has been explored as a preventative strategy due to its ability to protect surfactant258 and promote both angiogenesis and alveolarization.259 Several randomized controlled trials of iNO in premature infants have been conducted.260 Neither early or late treatment strategies improve survival or long-term outcomes, suggesting routine administration to all preterm infants for prevention of chronic lung disease to be ineffective Early routine use for less-sick preterm infants may reduce the risk of severe cerebral injury and may improve survival without chronic lung disease.260 The clinical trials of iNO in premature infants are limited by variable methodology and the lack of standardization of outcome measures Systemic Hypertension and Prematurity Neonatal hypertension is defined as a sustained systolic blood pressure greater than the 97th percentile for age, gender, and size according to published nomograms The incidence of systemic hypertension is between 0.2% and 3%.261,262 Of these, 9% had indwelling arterial catheters Causes of Neonatal Hypertension In most cases the finding is coincidental on routine monitoring Occasionally some neonates present insidiously with nonspecific symptoms, such as difficulty in feeding, tachypnea, or lethargy In more extreme cases, seizures or congestive cardiac failure may occur It is important to take a thorough history, to make a complete cardiovascular evaluation, including testing of blood pressure in all limbs, and to screen for dysmorphisms, ambiguous genital organs, abdominal masses such as Wilms tumor, and bruits such as produced by renal arterial stenosis There are many causes of hypertension, of which renovascular disease and renal parenchymal disease are the most common (Table 15.8)