Neonatal Pulmonary Hypertension Research Articles

Cellular adaptation during chronic neonatal hypoxic pulmonary hypertension

Newborn animals develop more severe hypoxic pulmonary hypertension than do adults, their vascular changes are greater, and both the hypertension and vascular changes occur more rapidly. We hypothesize that this differential developmentally controlled response may arise from either a difference in the type or quantity of endogenously secreted mediators in response to a given injury or a difference in the replicative and/or matrix-producing response of the vascular cells to physical or chemical stimuli. We investigated the effect of chronic hypoxia (14 days) on the proliferative and matrix-producing phenotype of the neonatal (14-day-old) pulmonary artery smooth muscle cell (SMC) and examined the heterogeneity and potential mechanisms responsible for this response. In situ hybridization studies demonstrated a remarkable change in the distribution of cells hybridizing with a tropoelastin cRNA probe after 14 days of hypoxia. Studies also demonstrated a population of SMC that did not hybridize with the elastin or collagen probes, indicating that the pulmonary artery contains SMC of multiple phenotypes and that the response to hypoxic and hemodynamic stress is not uniform for the various types. Bromodeoxyuridine labeling experiments indicated a large increase in DNA synthesis in hypertensive vessels, which, again, was not uniform either across or along the arterial wall. In vitro experiments with neonatal SMC suggested that hypoxia alone could not be responsible for the proliferative or matrix changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma prostanoids in neonates with pulmonary hypertension treated with conventional therapy and with extracorporeal membrane oxygenation

Thromboxane may be a mediator of pulmonary hypertension in the neonate. Acute thromboxane-mediated pulmonary hypertension has been described in sheep receiving extracorporeal membrane oxygenation, which raises concerns about a potential thromboxane-mediated exacerbation of pulmonary hypertension in human neonates with severe pulmonary hypertension who are treated with extracorporeal membrane oxygenation. We measured plasma levels of thromboxane, prostaglandin F2 alpha, and 6-keto-prostaglandin F1 alpha in infants with pulmonary hypertension, some of whom were treated medically and some of whom were treated with extracorporeal membrane oxygenation. Plasma levels of all three prostanoids were elevated in infants with pulmonary hypertension and decreased with time, whether the neonates were treated with extracorporeal membrane oxygenation or with medical management alone. In infants treated with extracorporeal membrane oxygenation, we collected samples simultaneously from preoxygenator sites, postoxygenator sites, and umbilical artery catheter. We could demonstrate no significant difference in plasma prostanoid levels across the oxygenator. In two patients, plasma thromboxane and prostaglandin F2 alpha levels measured shortly after a platelet transfusion were distinctly higher in the umbilical artery catheter than in venous samples.

Plasma prostanoids in neonatal extracorporeal membrane oxygenation: Influence of meconium aspiration

Thromboxane B2 may be a mediator of neonatal persistent pulmonary hypertension. Elevated levels of plasma thromboxane and prostacyclin have been described previously in hypoxic newborn infants with neonatal pulmonary hypertension. We measured serial plasma levels of thromboxane B2 and 6-keto-prostaglandin F1 alpha (stable metabolite of prostacyclin) in 21 newborn infants with severe respiratory failure and pulmonary hypertension who required extracorporeal membrane oxygenation support. We sought to study (1) the evolution of plasma prostanoids in pulmonary hypertensive infants treated with extracorporeal membrane oxygenation and (2) whether different pulmonary hypertensive diagnostic subgroups have distinctive prostanoid profiles. Our data indicated that infants with meconium aspiration had significantly lower levels of plasma thromboxane B2 and 6-keto-prostaglandin F1 alpha while receiving extracorporeal membrane oxygenation than did infants with persistent pulmonary hypertension but no meconium aspiration. Levels of all infants decreased progressively as extracorporeal membrane oxygenation support continued.

Pulmonary vascular resistance in neonatal swine: Response to right pulmonary artery occlusion, isoproterenol, and prostaglandin E 1

The pulmonary physiological response of adults to unilateral pulmonary artery (PA) occlusion has been well-characterized as resulting in a decrease in the pulmonary vascular resistance (PVR), in order to maintain the same PA pressure and accommodate the entire cardiac output (CO). We evaluated the response of the neonate to unilateral PA occlusion and how this response is altered by infusions of isoproterenol (isuprel) and prostaglandin E 1 (PGE 1) in the neonatal swine model. Twenty farm piglets (five at 1 day, three at 5 days, seven at 14 days, and five at 60 days as controls) underwent left lateral thoracotomy and measurement of PA and left atrial (LA) pressures, CO, and PVR with the right PA open and occluded. To determine if neonatal PVR could be influenced by a vasodilator (indicating the vascular capacity is not fixed) or by an inotrope (indicating the lung is not maximally recruited) this experiment was then repeated with infusions of PGE 1 (a vasodilator) at doses of 0.1, 0.5, and 1.0 μg/kg/min and subsequently with Isuprel (an inotrope and vasodilator) at doses of 0.1, 0.5, 1.0 μg/kg/min. Control measurements taken without unilateral PA occlusion showed that PVR is high at 1 day of age but progressively decreases to a level 89% lower by 60 days of age. The vascular capacity of the neonatal lung is fixed and responds to unilateral PA occlusion with a dramatic increases in PVR. This response cannot be altered by either a vasodilator (PGE 1) or an inotrope (Isuprel) thereby limiting the utility of these drugs in treating neonatal pulmonary hypertension. The adult response pattern to unilateral PA occlusion first appears at 60 days in the pig. These results may have implications for the management of newborns with pulmonary hypertension or neonates undergoing pulmonary resection.

Tumor Necrosis Factor-Induced Neonatal Pulmonary Hypertension: Effects of Dazmegrel Pretreatment

The endogenously produced cytokine, tumor necrosis factor-alpha (TNF-alpha), has been shown in adult animal models to be associated with many of the pathophysiologic effects of sepsis, including systemic hypotension and hemorrhagic necrosis. TNF-alpha can induce the release of various vasoactive arachidonic acid metabolites, suggesting that TNF-alpha may act either directly or via intermediary substances in producing its effects. The pathophysiologic role of TNF-alpha in neonatal sepsis, especially its potential effect on pulmonary vascular tone, is presently unknown. To assess the role of TNF-alpha in neonatal sepsis, 19 piglets (19 +/- 5 d old) were anesthetized, intubated, paralyzed, mechanically ventilated, and catheterized to assess pulmonary and systemic vascular hemodynamics and pulmonary gas exchange. The multiple inert gas elimination technique was used to assess ventilation perfusion matching. A 30-min infusion of human recombinant TNF-alpha (250 micrograms/kg total dose) was administered to animals pretreated with either 10 mg/kg dazmegrel, a thromboxane synthase inhibitor (n = 9) or placebo (n = 10). TNF-alpha alone induced a prompt and sustained rise in pulmonary arterial pressure and pulmonary vascular resistance that continued at least for 2 h after onset of the infusion. In contrast, the animals pretreated with dazmegrel demonstrated no rise in pulmonary vascular resistance until 2 h after the onset of the infusion. Neither group of animals demonstrated a significant decline in arterial PO2 or evidence from inert gas analysis of VA/Q mismatching or increase in intrapulmonary shunt.(ABSTRACT TRUNCATED AT 250 WORDS)

Vascular remodeling in neonatal pulmonary hypertension. Role of the smooth muscle cell

Vascular remodeling in neonatal pulmonary hypertension. Role of the smooth muscle cell

Vascular Remodeling in Neonatal Pulmonary Hypertension: Role of the Smooth Muscle Cell

We suggest that hypoxia-induced pulmonary hypertension in the newborn calf is an attractive model for studying the mechanisms underlying alterations in extracellular matrix accumulation which occur in pulmonary vascular disease. Our data support a model (Fig 7) in which the SMC, perhaps as a result of hypoxic and/or pressure-induced vessel wall injury, becomes phenotypically altered. This phenotypically altered SMC generates a factor, termed smooth muscle derived extracellular matrix factor (SMEF), and possibly other factors. SMEF, in turn, stimulates or induces elastin and collagen synthesis in fibroblasts and endothelial cells. SMEF, or an associated activity derived from phenotypically altered smooth muscle cells, also induces elastin receptor expression on the cell surface and affects the chemotactic responsiveness of vascular cells. Thus, the SMC may be able to affect both the secretory and responsive properties of cell types in the vascular wall. The SMC may be critical in the vascular remodeling in pulmonary hypertension. The possible autocrine or paracrine alteration of cellular phenotypes by smooth muscle-derived mediators provides an important new direction for future research into molecular and cellular mechanisms of connective tissue regulation in diseased vessels.

Pulmonary Vascular Remodeling in Neonatal Pulmonary Hypertension: State of the Art

Pulmonary Vascular Remodeling in Neonatal Pulmonary Hypertension: State of the Art

Pulmonary vascular remodeling in neonatal pulmonary hypertension. State of the art

Pulmonary vascular remodeling in neonatal pulmonary hypertension. State of the art

Adaptation of fetal pulmonary blood flow to local infusion of tolazoline.

Although tolazoline is the most commonly used drug in the treatment of neonatal pulmonary hypertension, its mode of action and efficacy remain incompletely understood. In order to study the effects of tolazoline on a high resistance pulmonary circulation and to better understand mechanisms that control pulmonary vascular tone and reactivity in the fetus, we infused tolazoline either continuously or as bolus into the left pulmonary artery of 15 chronically instrumented, normoxic fetal lambs during late gestation. The vasodilatory effects of bolus injections of tolazoline (2.5 mg) were inhibited by the prior administration of the histaminergic receptor blockers, cimetidine (56%), diphenhydramine (56%), or both (100%). During the continuous infusion of tolazoline (4.5 mg/h for 9 min), pulmonary blood flow to the left lung increased from 61 +/- 6 ml/min (mean +/- SE; control) to 100 +/- 10 (peak) at 30 min (p less than 0.001). However, following this initial vasodilatation, pulmonary blood flow steadily decreased toward control values by 90 min, despite the continued infusion of tolazoline (p less than 0.001). Although the calcium channel blocker, verapamil, and the alpha-adrenergic blocker, phentolamine, had little effect on fetal pulmonary blood flow when infused alone, both drugs increased the vasodilatory response to tolazoline (p less than 0.001). We conclude that tolazoline effects pulmonary vasodilatation by a histaminergic mechanism and that subsequent refractoriness to the drug is a calcium-dependent process which may be partially mediated by an alpha-adrenergic mechanism.

Misalignment of lung vessels: A syndrome causing persistent neonatal pulmonary hypertension

The cases of two female infants with persistent neonatal pulmonary hypertension are described. Combinations of pulmonary parenchymal lesions were present, including underdevelopment of alveoli and interstitial fibrosis as well as misalignment of lung vessels. As a result of the misalignment, the pulmonary veins joined the pulmonary arteries, rather than following a course away from them. One of the infants had additional congenital malformations. This syndrome should be considered in the evaluation of infants with persistent fetal circulation.

Alkalosis attenuates hypoxic pulmonary vasoconstriction in neonatal lambs.

Hyperventilation (respiratory alkalosis) is an important treatment for persistent pulmonary hypertension in neonates. The precise way that hyperventilation attenuates hypoxic pulmonary vasoconstriction is unclear. We studied the effect of alkalosis on hypoxia-induced pulmonary vasoconstriction in 13 acutely instrumented, pentobarbital anesthetized, neonatal lambs. We specifically examined the relative effects of a metabolic alkalosis versus a respiratory alkalosis on hypoxic pulmonary vasoconstriction and compared these results to the control response to hypoxia without alkalosis. Hypoxic pulmonary vasoconstriction was significantly milder whenever the animal was alkalotic, regardless of whether the alkalosis was respiratory of metabolic. Thus, the elevated pHa rather than decreased PaCO2 during hyperventilation appears to be the major factor in moderating the response of the pulmonary vessels to acute hypoxia in this neonatal lamb model.

Prostacyclin in the treatment of neonatal pulmonary hypertension

PERSISTENT pulmonary hypertension often complicates a variety of neonatal distrubances, 1 leads to right-to-left shunting across the ductus arteriosus or foramen ovale, and may thereby cause or exacerbate neonatal hypoxemia. ~ Although vasodilating agents, such as tolazoline, have been used with variable success in the treatment of neonatal pulmonary vasoconstriction, 2 a generally acceptable therapy is still lacking. Prostacyclin (epoprostenol, PGI2) is a potent vasodilatory and antiaggregatory agent that may participate in postnatal pulmonary vasodilation. 3, 4 It has been used successfully in the management of pulmonary hypertension in adults 5 and in one newborn infant. 6 We describe five newborn infants with pulmonary hypertension who received intravascular infusion of PGI2.

357 TOLAZOLINE INHIBITION OF PLATELET AGGREGATION

Tolazoline (TZ), an imidazoline compound with vasodilatory and histaminic properties, is used in the therapy of neonatal persistent pulmonary hypertension (PPH). Inhibition of thromboxane A2 (TBX-A) synthesis by TZ has been reported. The in-vitro effects of TZ on platelet aggregation were studied. Platelet rich plasma obtained from 6 healthy adults and from cord blood samples of 6 healthy term infants was incubated with TZ and aggregated with ADP (10μM). At increasing concentrations of TZ, decreases in maximal aggregation occurred, followed by disaggregation (mean±SEM): The relationship between TZ concentration and both maximal and 10-minute aggregation was linear up to 103 μg/ml (r≥0.88). The inhibition of primary aggregation at the highest TZ concentrations is inconsistent with TBX-A inhibition alone. Preliminary data, using a radioimmunoassay, suggest an increase in platelet cyclic AMP when incubated with TZ, perhaps mediated by hist-amine receptors. In-vivo inhibition of platelet aggregation and TBX-A release by TZ may be benefical in some forms of PPH.

144 SERIM ARGININE VASOPRESSIN RESPONSES IN CONGENITAL HEART DISEASE

In addition to its antidiuretic properties, arginine vasopressin (AVP) is a potent vasoactive homone. If unopposed by baroreceptor mediated reflexes, even low serun levels of AVP nay exert pressor effects. Since early life is associated with an enhanced ability to release AVP and with an increase in its cardiovascular effects, we evaluated whether congestive heart failure (CHF) is a stimulus for AVP release. AVP levels were measured by RIA using the modified Bentonite technique in 40 infants and children divided into 5 groups: Group I (n = 7) with CHF; Group II (n = 6) with cyanotic heart disease; Group III(n = 3) with persistent neonatal pulmonary hypertension; Group IV (n = 12) stressed infants with respiratory disease but no heart disease; and Group V (n = 12) healthy unstressed controls. Group IV had statistically higher AVP levels (13 pcg/ml ± 6) when compared to Group V normals (6 peg/ml ± 2)(p ≤ 0.05). Groups II & III were not significantly different from Group V (7 pcg/ml ± 5 and 6 peg/ml ± 2 respectively). CHF patients (Group I) had variable AVP levels with peak levels markedly elevated above other groups (102 peg/ml ± 135), (p<0.05) and further increased with worsening clinical status. Additional data suggest that hyperosrrotic angiographic contrast madia increase AVP levels by 2 to 10 times pre-dye levels in most instances (n = 12 of 15 patients, p < 0.02). We conclude that AVP levels are increased in children with CHF and that diagnostic interventions such as angiography may further elevate AVP. This may result in increased cardiac afterload further impairing already diminished cardiac function.

Hemodynamic consequences of tolazoline in neonatal group B streptococcal bacteremia: an animal model.

Using a piglet model of neonatal sepsis, we have determined that Group B streptococcal (GBS) bacteremia is associated with a state of vascular hyper-resistance in both the pulmonary and systemic circulations. This elevated vascular resistance is accompanied by a significant fall in cardiac output despite the assurance of constant intravascular fluid volume. Pulmonary artery pressure rises extensively while systemic blood pressure remains essentially unchanged during this GBS infusion protocol. We report here our attempts to relieve the vascular hyperresistance of GBS infusion by administration of an alpha-sympathetic antagonist, tolazoline (Tz). We found that Tz, in a dose-related fashion, decreased both systemic and pulmonary vascular resistance over the entire range from 2 to 25 mg/kg. Further, at all doses tested, the resistance-reducing effect of Tz was equal in the systemic and pulmonary vascular beds. No selective pulmonary or systemic vasodilatory effect was demonstrated by Tz in this model of neonatal pulmonary hypertension. The reduction of systemic vascular resistance was accompanied by a significant elevation in total body cardiac output at all Tz doses. Compared to pre-Tz values, cardiac output rose by 24, 55, and 55% after Tz at 2, 8.3, and 25 mg/kg respectively. In addition, administration of Tz to septic normovolemic piglets reliably produced a transient decrease of systemic blood pressure. For Tz doses of 2 and 8.3 mg/kg, steady state systemic blood pressure returned to pre-Tz levels within 10 min. However, after Tz at 25 mg/kg, steady state systemic blood pressure remained significantly below pre-Tz levels.

AIKALOSIS ATIENUATES HYPOXIC PULYONARY VASOCONSTRICTION IN NEO NATAL LAMBS

Hyperventilation (respiratory alkalosis)is an important treatment for persistent pulmonary hypertension in neonates. The precise way that hyperventilation attenuates hypoxic pulmonary vasoconstriction is unclear. We studied the effect of alkalosis on hypoxia-induced pulmonary vasoconstriction in 13 acutely instrumented neonatal lambs. We specifically examined the relative roles of a metabolic alkalosis (MA) vs a respiratory alkalosis (RA). After stabilization in each experimental situation, the lambs were made acutely hypoxic by a 1-minute inhalation of 5% O2-95% N2. The control pulmonary vasoconstrictor response to hypoxia was measured at both the beginning and end of each experiment and was compared to the responses observed after hyperventilation (RA) and after bicarbonate infusion (MA-normal PaCO2). The table gives the mean changes before and during hypoxia. Data consider different from control 1 when p<.05 by 2-way ANOVA. Hypoxic pulmonary vasoconstriction was significantly milder whenever the animal was alkalotic - regardless of whether the alkalosis was respiratory or metabolic. Although the rise in PVR was smaller during MA than during RA, there was no significant difference between the effects of the two types of alkalosis. In summary, the elevated pH rather than decreased PaCO2 during hyperventilation appears to be the major factor in blunting hypoxic pulmonary vasoconstriction.