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.     

Familial association of primary pulmonary hypertension and a new low-oxygen affinity beta-chain hemoglobinopathy, Hb Washtenaw

A Hungarian-American kindred with familial primary pulmonary hypertension (PPH) and a new, low-oxygen affinity beta-chain variant hemoglobin, Hb Washtenaw, is described. The index case presented with severe PPH and was found to have the abnormal hemoglobin. Two siblings with the abnormal hemoglobin also demonstrated increased pulmonary artery pressures on exercise echocardiography suggestive of early PPH. The occurrence of PPH and the abnormal hemoglobin could be due to genetic or biochemical factors or simply coincidental. A previous study had described a possible association of an abnormal beta-chain variant hemoglobin, Hb Warsaw, and PPH. It was suggested that the putative gene for familial PPH may be located near the beta-globin gene on chromosome 11. The association of PPH and the beta-chain variant hemoglobin in this kindred adds further support to this hypothesis.     

Partitioning of pulmonary vascular resistance in primary pulmonary hypertension

OBJECTIVES: This study sought to determine the site of increased pulmonary vascular resistance (PVR) in primary pulmonary hypertension by standard bedside hemodynamic evaluation. BACKGROUND: The measurement of pulmonary vascular pressures at several levels of flow (Q) allows the discrimination between active and passive, flow-dependent changes in mean pulmonary artery pressure (Ppa), and may detect the presence of an increased pulmonary vascular closing pressure. The determination of a capillary pressure (Pc') from the analysis of a Ppa decay curve after balloon occlusion allows the partitioning of PVR in an arterial and a (capillary + venous) segment. These approaches have not been reported in primary pulmonary hypertension. METHODS: Ppa and Pc' were measured at baseline and after an increase in Q induced either by exercise or by an infusion of dobutamine, at a dosage up to 8 microg/kg body weight per min, in 11 patients with primary pulmonary hypertension. Reversibility of pulmonary hypertension was assessed by the inhalation of 20 ppm nitric oxide (NO), and, in 6 patients, by an infusion of prostacyclin. RESULTS: At baseline, Ppa was 52+/-3 mm Hg (mean value+/-SE), Q 2.2+/-0.2 liters/min per m2, and Pc' 29+/-3 mm Hg. Dobutamine did not affect Pc' and allowed the calculation of an averaged extrapolated pressure intercept of Ppa/Q plots of 34 mm Hg. Inhaled NO had no effect. Prostacyclin decreased Pc' and PVR. Exercise increased Pc' to 40+/-3 mm Hg but did not affect PVR. CONCLUSIONS:ns. These findings are compatible with a major increase of resistance and reactivity at the periphery of the pulmonary arterial tree.     

Noninvasive differential diagnosis between chronic pulmonary thromboembolism and primary pulmonary hypertension by means of Doppler ultrasound measurement

We examined the development of tolerance to the antiallodynic effect of chronic intrathecal (IT) administration of the adenosine analog R-phenylisopropyladenosine (R-PIA) in a rat model of central pain after ischemic spinal cord injury. After 10 days of IT R-PIA treatment, the effect of IT morphine was also assessed to examine whether cross-tolerance between R-PIA and morphine was present. IT R-PIA completely alleviated allodynia-like behaviors to mechanical and cold stimuli in spinally injured rats. The anti-allodynic effect of R-PIA was maintained for 6-7 days with twice-daily administration and was reduced thereafter, particularly with respect to cold allodynia. IT morphine alleviated mechanical and cold allodynia in rats rendered tolerant to R-PIA to a degree comparable to that in R-PIA-naive (control) rats, which indicates that the anti-allodynic property of R-PIA is independent of the mechanisms by which morphine acts. The possibility of using agonists of adenosine receptors in treating refractory pain in patients with spinal cord injury is discussed. IMPLICATIONS: There is often no satisfactory treatment for chronic pain after spinal cord injury. Our study suggests such pain can be treated with a spinal injection of R-phenylisopropyladenosine in rats. Reduced effect to R-phenylisopropyladenosine was noted with repeated administrations. However, there was no cross-tolerance to morphine.     

Relationship of newborn serum prolactin levels to the respiratory distress syndrome and maternal hypertension

Prolactin concentrations were measured in mixed cord blood of 782 newborn infants and related to the occurrence of the respiratory distress syndrome (RDS) and maternal cardiovascular condition. Infants of 30 to 33 weeks' gestational age who developed RDS had significantly lower serum concentrations of prolactin than non-RDS infants within this same age range. No difference was observed between RDS and non-RDS infants at 34 to 36 weeks. Prolactin levels in infants delivered by preeclamptic women were greater than the levels in infants of normotensive women from 30 to 39 weeks' gestation. The levels were higher in the 40 to 42 weeks age group as well; however, the difference was not statistically significant. Infants of mothers with gestational hypertension also tended to have elevated serum prolactin concentrations. No differences were observed in infants of women presenting with a history of chronic hypertension. Within the RDS subgroups, serum prolactin levels were significantly greater in infants of preeclamptic women than in infants of normotensive women, being approximately equal to the levels in the non-RDS normotensive group.     

The epidemiology of the association between hypertension and menopause

Menopause is a normal aging phenomenon in women and consists of the gradual transition from the reproductive to the non-reproductive phase of life. The median age at the menopause is currently around 50 years. As a result of the increasing life expectancy in the first and second worlds, many women will be postmenopausal for over one-third of their lives. The influence of menopause per se on blood pressure remains uncertain. Recent experimental and epidemiological evidence supports the hypothesis that oestrogen deficiency may induce endothelial and vascular dysfunction and potentiate the age-related increase in systolic pressure, possibly as a consequence of a reduced compliance of the large arteries. However, the latter hypothesis requires further investigation.     

Maternal treatment with indomethacin and severe neonatal pulmonary hypertension (author's transl)

The authors report five cases of premature newborns whose mothers had been treated with indomethacin. In all patients, clinical and biological symptoms were those of pulmonary hypertension with persistence of the fetal circulation. In two cases, autopsy showed an important reduction of the lumen of pulmonary arterioles due to a thickening of the tunica media. The role of indomethacin in such respiratory syndrome is very likely. Therefore, indications for that treatment in pregnant women should be reduced.     

Lung transplantation for primary pulmonary hypertension and giant pulmonary artery aneurysm

We report the case of an 18-year-old patient with a giant pulmonary artery aneurysm and primary pulmonary hypertension who was successfully treated with bilateral lung transplantation and complete reconstruction of the pulmonary artery.     

The influence of continuous intravenous prostacyclin therapy for primary pulmonary hypertension on the timing and outcome of transplantation

BACKGROUND: Primary pulmonary hypertension (PPH) is a progressive disease with a median survival of less than 3 years from diagnosis. Medical management has typically consisted of anticoagulation and oral calcium channel blocking agents, whereas lung transplantation (LT) has been reserved for patients who are unresponsive to medical therapy. Continuous intravenous prostacyclin was introduced for patients who did not respond to calcium channel blockers and who would have required LT. We reviewed our experience with prostacyclin in LT candidates to study its effects on the timing and outcome of LT. METHODS: We retrospectively reviewed the clinic and hospital records of patients with PPH who were both treated with prostacyclin and evaluated for LT. Additional information was obtained from the pulmonary vascular disease and lung transplantation databases. RESULTS: A total of 42 patients were identified who received prostacyclin for the treatment of PPH and were evaluated for LT. Thirty-seven patients were accepted as LT candidates, 22 at The University of Maryland Medical Center (UMMC), 15 at other LT programs. Overall, 70% (27/37) of LT candidates were removed from the LT waiting list or had listing for LT deferred because of clinical improvement. In patients listed for LT before initiation of prostacyclin therapy, 55% (12/22) were removed from the active waiting list for 27.2+/-17 months (range 8 to 60), and 92% (11/12) remain on the inactive status. In patients who received prostacyclin before listing for LT, listing for LT was deferred in 94% (14/15) for 17.4+/-9 months (range 6 to 33 months) because of clinical stability or improvement. In all, 93% of patients (39/42) experienced an improvement in 1 or more New York Heart Association functional class. The hemodynamic profiles of the eight patients removed from the active waiting list at UMMC demonstrated increases of 55%+/-18% in cardiac output, and decreases of 14.3%+/-4.9% in mean pulmonary artery pressure and 36%+/-8.3% in total pulmonary resistance (p < 0.05). The 1-year survival rate for LT after prostacyclin therapy was 88% (7/8) at UMMC and 60% (3/5) at the other centers. CONCLUSION: We conclude that prostacyclin therapy is an effective means of delaying, possibly indefinitely, the need for LT in patients with PPH and that excellent results can be obtained when LT is performed after prostacyclin therapy. Consideration should be given to initiating prostacyclin therapy in all patients whose conditions do not respond to conventional therapy before proceeding with transplantation.     

The association between maternal cocaine use and placenta previa

We compared various diagnostic tests for their abilities to detect Mycobacterium ulcerans infection in specimens from patients with clinically active disease. Specimens from 10 patients from the area of Zangnanado (Department of Zou, Benin) with advanced, ulcerated active M. ulcerans infections were studied by direct smear, histopathology, culture, PCR, and oligonucleotide-specific capture plate hybridization (OSCPH). A total of 27 specimens, including 12 swabs of exudate collected before debridement and 15 fragments of tissue obtained during debridement, were submitted to bacteriologic and histopathologic analysis. The histopathologic evaluation of tissues from all six patients so tested revealed changes typical of those caused by M. ulcerans infection. Five specimens were contaminated, and M. ulcerans was cultivated on L?wenstein-Jensen medium from 12 of the remaining 22 (54.5%) specimens. Detection of mycobacteria was performed by PCR, and M. ulcerans was detected by OSCPH with a new probe (5'-CACGGGATTCATGTCCTGT-3') reacting with M. ulcerans and Mycobacterium marinum. In 10 of 22 (45.5%) specimens, M. ulcerans was identified by PCR-OSCPH. There was no statistically significant difference between the detection of M. ulcerans by culture and by PCR-OSCPH (P > 0.05). This is the first demonstration of an amplification system (PCR-OSCPH) with a sensitivity similar to that of culture for the direct and rapid recognition of M. ulcerans in clinical specimens. This system is capable of identifying M. ulcerans, even in paucibacillary lesions. Our findings suggest that PCR-OSCPH should be used in the quest for the elusive environmental reservoir(s) of M. ulcerans.     

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.     

Continuous therapy with intravenous prostacyclin for primary pulmonary hypertension: a bridge to heart-lung transplantation

Primary pulmonary hypertension (PPH) continues to be a major problem. Vasodilator therapy has been of variable success in selected patients. Recently, with the introduction of prostacyclin (Prostaglandin I2, epoprostenon) as a potent vasodilator, several reports have shown a positive effect in primary pulmonary hypertension. We report here two patients with PPH who responded favorably to continuous intravenous therapy with prostacyclin. Both patients responded with a reduction in pulmonary vascular resistance, increase in cardiac output and dramatic improvement of right heart failure. Although therapy with prostacyclin is extremely expensive it may be used as a bridge to heart-lung transplantation in patients with end-stage PPH who do not respond adequately to alternative therapy.     

Clinical primary pulmonary hypertension: three pathologic types

Clinically, there is a group of patients with elevated pulmonary arterial pressure in whom the underlying cause is not apparent. The pulmonary arterial wedge pressure is not elevated. For such cases, the designation of primary pulmonary hypertension may be made clinically. From the clinical categorization of primary pulmonary hypertension, three distinct pathologic entities emerge, namely 1) plexogenic pulmonary arteriopathy, 2) recurrent pulmonary thromboembolism, and 3) pulmonary veno-occlusive disease. The plexogenic type is characterized initially by pulmonary arterial vasoconstriction with medial hypertrophy. Secondary proliferative intimal lesions, including the plexiform lesion, develop. Recurrent pulmonary thromboembolism is characterized by the presence of arterial thrombi of varying ages involving the microscopic-sized pulmonary arteries. Thrombi may be embolic in nature or may develop in situ. Pulmonary veno-occlusive disease is characterized by obstructive lesions of pulmonary veins and venules. The clinical presentation of the three pathologic types may be so similar that definitive diagnosis depends upon histologic examination of the lung from tissue obtained either by biopsy or at necropsy.     

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.     

Exercise testing in children with primary pulmonary hypertension

Cardiopulmonary exercise testing is a useful noninvasive tool to assess physiological changes associated with exercise. Developing noninvasive methods to assess the severity of cardiopulmonary disorders, as well as the response to therapeutic interventions, is useful in conditions, such as primary pulmonary hypertension, in which invasive procedures carry significant risks. The 6-minute walk test is a simple measure of exercise endurance. Exercise studies that measure both hemodynamic and ventilatory responses provide additional information regarding the interaction of the circulatory and pulmonary systems. Subtle changes in exercise capacity may suggest deterioration prior to clinical manifestations. This may lead to an earlier reevaluation, including repeat cardiac catheterization, and subsequently changes in medical and/or surgical therapy.