Persistent pulmonary hypertension in newborn infants

On the basis of a review of the literature, a survey is presented concerning persistent pulmonary hypertension of the newborn. In this article the authors focus on the pathophysiology, diagnostic criteria and treatment, including mechanical ventilation, pharmacological vasodilation and extracorporal membrane oxygenation. Particular emphasis is placed on the treatment of the condition with inhaled nitric oxide. Nitric oxide is a selective pulmonary vasodilator and able to improve ventilation/ perfusion mismatching in cases where there is an affection of the pulmonary parenchyma. Data from randomized trials with close long-term follow-up is necessary before routine nitrogen oxide treatment can be recommended.     

Persistent pulmonary hypertension of the neonate and asymmetric growth restriction

OBJECTIVE: To evaluate the possible associations between persistent pulmonary hypertension of the neonate, need for extra-corporeal membranous oxygenation, small for gestational age (SGA), and low ponderal index for gestational age in infants with persistent pulmonary hypertension of the neonate and in matched controls. METHODS: Eighty-six infants with persistent pulmonary hypertension of the neonate delivered from 1991 to 1994 at our hospital were matched with 430 contemporaneous control singleton neonates. Birth weight and ponderal indices (100 x weight/length3) less than the tenth percentile for gestational age and gender were defined as SGA and low ponderal index, respectively. We assessed associations between these markers, the presence of persistent pulmonary hypertension of the neonate, and the need for extracorporeal membranous oxygenation. RESULTS: Low ponderal index was associated with persistent pulmonary hypertension of the neonate (odds ratio [OR] 5.4), whereas SGA was not. Low ponderal index (OR 4.0) was an independent correlate of persistent pulmonary hypertension of the neonate after adjustment with logistic regression for 5-minute Apgar scores less than 7, umbilical arterial pH less than 7.10, and presence of meconium. Low ponderal index was associated with need for extracorporeal membranous oxygenation in neonates with persistent pulmonary hypertension (P < .001). CONCLUSION: Fetal developmental events may significantly affect neonatal pulmonary status. Diminished neonatal nutritional status, as measured by low ponderal index for gestational age, is associated with increased risk of persistent pulmonary hypertension of the neonate and severity of the disease process.     

Persistence of fetal cardiopulmonary circulation: one manifestation of transient tachypnea of the newborn

Five cyanotic newborn infants underwent cardiac catheterization between 8 and 36 hours of age with a tentative diagnosis of cyanotic congenital heart disease. All had normal cardiovascular anatomy. Cyanosis was the result of persistence of fetal cardiopulmonary circulation with right-to-left shunting across the ductus arteriosus. In all infants, cyanosis resolved spontaneously and the infants survived without sequelae. Admission chest roentgenograms of all infants showed marked hyperinflation of the lungs. Except for severe hypoxemia, the clinical presentation, chest films, and course of illness of these infants were consistent with transient tachypnea of the newborn. It is proposed that an increase in pulmonary vascular resistance, due to hyperinflation of the lungs, was the mechanism which reopened the fetal cardiopulmonary circulatory channels and produced hypoxemia, and that these infants suffered from a rare manifestation of a usually benign newborn respiratory condition. Further, given these pathophysiologic mechanisms, the use of continuous transpulmonary pressure gradients in the management of such infants would be contraindicated.     

Phosphodiesterase isoforms in the pulmonary arterial circulation of the rat: changes in pulmonary hypertension

Phosphodiesterase (PDE) activity was determined in pulmonary arteries removed from control and chronic hypoxia-induced pulmonary hypertensive rats. The main, first-branch, intrapulmonary and resistance pulmonary arteries were studied. We measured total cAMP PDE activity and cGMP PDE activity, as well as that of individual isoforms (PDE1-5). cAMP PDE activity in chronic hypoxic rats was increased in first-branch and intrapulmonary arteries from hypoxic rats. No changes were observed in the main or resistance pulmonary arteries. Similarly, cGMP PDE activity was increased in the main, first-branch and intra-pulmonary arteries of the hypoxic rats. No changes in cGMP PDE activity were observed in resistance arteries. There was evidence for PDE1-5 activity in all pulmonary arteries. The increased cAMP PDE activity in first-branch and intrapulmonary vessels was associated with an increase in cilostimide-inhibited PDE (PDE3) activity. Increased total cGMP PDE in main pulmonary artery was associated with increases in Ca++/calmodulin-stimulated (PDE1) activity. An increase in zaprinast-inhibited (PDE5) activity was observed in first-branch and intrapulmonary arteries. Our results suggest that decreases in intracellular cyclic nucleotide levels in pulmonary arteries from pulmonary hypertensive rats are associated with increased PDE activity. Further, these changes may reflect alterations at the level of specific types of PDE isoforms.     

Disturbances of the transitional circulation: spectrum of pulmonary hypertension and myocardial dysfunction

The possible role of the adrenergic nervous system in the intoxicant effects of ethanol was examined in studies of the interaction or propranolol and phentolamine with ethanol. Propranolol teneded to increase the effect of lower doses of ethanol in a dose-dependent manner. However, the effect of higher doses of ethanol (over 2.0 g/kg) tended to be diminished by low doses of propranolol, whereas higher doses of propranolol were ineffective or actually increased the ethanol effect. Phentolamine tended to decrease the effect of the lower ethanol doses. These findings are inconsistent with any simple adrenergic mechanism in the mediation of the intoxicant effect of ethanol.     

Persistence of fetal circulation syndrome: an echocardiographic study

Serial echocardiograms were performed on 17 infants with persistence of fetal circulation syndrome to measure right ventricular systolic time intervals from pulmonic valve echograms and left ventricular systolic time intervals from aortic valve echograms. Right ventricular pre-ejection period/right ventricular ejection time ratio was prolonged in PFCS when compared to that in normal newborn infants, and diminished with clinical improvement. Left ventricular pre-ejection period/left ventricular ejection time ratio was prolonged in infants with PFCS. Echographic RPEP/RVET was consistent with the elevated pulmonary artery pressure and pulmonary vascular resistance of PFCS; elevated LPEP/LVET suggested left ventricular dysfunction.     

Possible association between maternal indomethacin therapy and primary pulmonary hypertension of the newborn

Indomethacin purportedly arrests premature labor by inhibiting the production of prostaglandins. Animal experimentation has demonstrated that prostaglandins are involved in the neonatal rerouting of the circulation. Experience with two neonates with disorders circulatory adjustment at birth following prenatal exposure to indomethacin indicates that indomethacin may interfere with these adjustments in man and favor the development of the serious oxygen dependency known as primary pulmonary hypertension of the newborn.     

Idiopathic pulmonary hilar fibrosis: an unusual cause of pulmonary hypertension

A 37-year-old man with progressive exertional dyspnea had pulmonary hypertension associated with pulmonary arterial and venous obstruction. An autopsy revealed that the cause of death was idiopathic pulmonary hilar fibrosis, a variant of mediastinal fibrosis. Pulmonary hilar fibrosis can mimic thromboembolic pulmonary hypertension, pulmonary veno-occlusive disease, and pulmonary venous hypertension.     

Inhaled nitric oxide: a physiologic treatment of persistent pulmonary arterial hypertension in the newborn

Fetal pulmonary circulation is characterized by high resistance and low pulmonary blood flow. Right-to-left shunting through the foramen ovale and/or patent ductus arteriosus is necessary to perfuse the placenta and insure fetal life. At birth, pulmonary arterial blood flow increases immediately by 8- to 10-fold, and allows pulmonary gas exchange and postnatal life. In some circumstances, this adaptation to extra-uterine life is inadequate, because of persistent high pulmonary resistance (PPHN). Due to the lack of a selective pulmonary vasodilator, the treatment of this syndrome remained purely symptomatic using high oxygen levels and barotraumatic mechanical hyperventilation. When this medical treatment failed, the only alternative was extracorporeal membrane oxygenation (ECMO). The discovery of the major role of various endothelium-derived factors including nitric oxide (NO) in the control of vascular reactivity led to dramatic switches in the concepts of severe neonatal respiratory failure and the therapeutic approach of PPHN. It was shown, first in experimental animals then in a few infants with hypoxemic respiratory failure, that NO inhalation selectively vasodilated the vasoconstricted pulmonary vessels, and reversed right-to-left shunting and refractory hypoxemia. Whether inhaled NO also reduces mortality and/or morbidity in hypoxic infants remains to be proven by appropriate randomized clinical trials. However, not only PPHN is associated with pulmonary diseases of various etiologies and underlying pathophysiologic mechanisms, but also inhaled NO is used in conjunction with other validated therapeutic strategies including ante- or postnatal steroids, exogenous surfactants, and high-frequency oscillatory ventilation. Thus, the relevant primary endpoint might be not only crude survival but the most physiological and economical way of obtaining it.     

Unusual cause of pulmonary hypertension and congestive heart failure in a newborn

Anomalous systemic arterial supply to a lobe of the lung is a rare cause of pulmonary hypertension and congestive heart failure in the newborn period. We report the presentation and successful treatment of a neonate with this unusual anatomy. Proper diagnosis required both echocardiography and aortography, and surgical resection of the involved lobe was curative.     

Persistence of the fetal circulation

A 43-year-old woman with bilateral Adie's tonic pupils had a segment of one iris sphincter that contracted spontaneously every few seconds, but was not influenced by light, near vision, or eye movements.     

Persistent hyperinsulinemic hypoglycemia in the newborn and infants

Persistent hyperinsulinemic hypoglycaemia of infancy (PHHI) is the most frequent cause of hypoglycaemia in infancy. Clinical presentation is heterogeneous, with variable onset of hypoglycaemia and response to diazoxide, and presence of sporadic or familial forms. Underlying histopathological lesions can be focal or diffuse. Focal lesions are characterised by focal hyperplasia of pancreatic islet-like cells, whereas diffuse lesions implicate the whole pancreas. The distinction between the two forms is important because surgical treatment and genetic counselling are radically different. Focal lesions correspond to somatic defects which are totally cured by limited pancreatic resection, whereas diffuse lesions require a subtotal pancreatectomy exposing to high risk of diabetes mellitus. Diffuse lesions are due to functional abnormalities involving several genes and different transmission forms. Recessively inherited PHHI have been attributed to homozygote mutations for the beta-cell sulfonylurea receptor (SUR1) or the inward-rectifying potassium-channel (Kir6.2) genes. Dominantly inherited PHHI can implicate the glucokinase gene, particularly when PHHI is associated with diabetes, the glutamate dehydrogenase gene when hyperammonaemia is associated, or another locus.     

Clinical response to inhaled nitric oxide in persistent pulmonary hypertension of the newborn

We observed clinical response to inhaled nitric oxide (iNO) in 12 neonates with persistent pulmonary hypertension of the newborn (PPHN). Clinical response was defined as a decrease in oxygenation index (OI) by 40%. Ten of 12 neonates had response to iNO showing decrease OI from 46.1+/-7.6 to 14.4+/-6.8 at 1 hour after inhalation. Sustained improvement of OI was achieved in 8 neonates and two neonates were relapsed. In the group of neonates who had OI above 40 (n=7), 6 of them showed the decrease of OI from 66.1+/-4.8 to 18.3+/-8.0 at 1 hour. In two groups, one had OI of 40 or greater, and the other OI of 40 or less, there were no differences in pattern of response and early death rate. The response rates according to underlying diseases were as follows; idiopathic PPHN 100%, respiratory distress syndrome 100%, and diaphragmatic hernia 66.7%. Relapse was observed in one neonate with sepsis caused by pneumonia and in one infant with meconium aspiration syndrome. Two infants showed no response to iNO (one diaphragmatic hernia and one suspected pulmonary hypoplasia). We conclude that iNO therapy could improve oxygenation in high percentage of newborn infants with severe PPHN of various underlying conditions except pulmonary hypoplasia.     

Plasma immunoreactive endothelin-1 concentrations in infants with persistent pulmonary hypertension of the newborn

Plasma concentrations of endothelin-1 (ET-1) have been reported to be elevated in children and adults with pulmonary hypertension. We hypothesized that infants with persistent pulmonary hypertension of the newborn (PPHN) have elevated plasma concentrations of ET-1. Plasma concentrations of immunoreactive-endothelin-1 (ir-ET-1) were measured using a radioimmunoassay in 20 infants with PPHN and 20 normal term infants. Mean birthweight and gestational age of the infants were comparable in the two groups. The mean plasma ir-ET-1 concentrations were significantly elevated in neonates with PPHN compared to those of normal term infants (2.04 +/- 0.30 versus 1.04 +/- 0.29 pg/mL, p = 0.02). A linear regression analysis demonstrated a significant relationship between ir-ET-1 concentrations and alveolar-arterial oxygen gradient (r = 0.49, p = 0.02) and mean airway pressure (r = 0.49, p = 0.02). There was also a significant correlation between ir-ET-1 concentrations and duration of extracorporeal membrane oxygenation among infants with PPHN (r = 0.44, p = 0.05). We conclude that plasma ir-ET-1 concentrations are elevated in infants with PPHN. The presence of elevated ir-ET-1 concentrations and their positive correlation with disease severity suggests that ET-1 may serve as a marker of the disease severity in these infants. However, further studies are needed to elucidate the role of ET-1 in the pathophysiology of PPHN.     

Adrenoleukodystrophy: unusual clinical and radiographic manifestation

Adrenoleukodystrophy is an X-linked recessive peroxisomal disorder, characterized by progressive neurologic deterioration due to cerebral white matter demyelination and adrenal insufficiency. Onset is usually in childhood between ages 5 and 10, and its course is fatal within approximately 5 years. Initial symptoms are behavioral, gait, and auditory disturbances and may be a diagnostic dilemma. Abnormally raised plasma very long chain fatty acids (VLCFA) are diagnostic; computed tomography and magnetic resonance imaging findings show symmetrical occipital white matter lesions which progress in a rostralcaudal direction.