Persistent Pulmonary Hypertension Syndrome Research Articles

Value of the natriuretic peptide level in diagnostics of newborns with heart failure

The article contains the first-ever data on correlation of the level of N-terminal fragment of natriuretic peptide in the serum of fullterm newborns with circulatory failure and persistent pulmonary hypertension syndrome; while the N-terminal fragment of natriuretic peptide can serve as a marker of circulatory failure in newborns. The study demonstrates that the dynamics of this peptide allows us to evaluate the effectiveness of the therapy.

Fetal and Neonatal Effects of Maternal Drug Treatment for Depression

Depression has a female sex predilection with 2 to 3% of the pregnant women population presently requiring treatment with selective serotonin reuptake inhibitors (SSRI). Exposure to SSRIs in late gestation leads to clinical manifestations in as much as 30% of the neonates. These include neurobehavioral, respiratory, gastrointestinal, and somatic symptoms. Among the respiratory manifestations, persistent pulmonary hypertension syndrome is a newly recognized and concerning side effect of SSRI exposure in utero. This causal association has been reproduced in an animal model where fluoxetine administration to pregnant rats induces fetal pulmonary hypertension. The pharmacological effects of SSRI on the fetus and newborn, available treatment, and prevention strategies are discussed in this review.

Human Meconium Has a Pulmonary Vascular and Airway Smooth Muscle Relaxant Effect

Meconium aspiration is believed to cause persistent pulmonary hypertension syndrome of the newborn (PPHN) via vasoconstriction, whereas meconium has a relaxant effect on rat tracheal muscle. We evaluated the meconium effect on lung vascular and airway muscle. Three-days old and adult rat 3rd-4th generation arteries and adjacent bronchi were studied in vitro. Fresh homogenized meconium did not induce arterial or airway muscle contraction. In precontracted arteries, meconium induced muscle relaxation that was greater (p < 0.01) in the newborn (53 +/- 5%), when compared with adult vessels (34 +/- 3%). This relaxant response was partially abrogated (p < 0.01) by L-NAME (28 +/- 4%) and enhanced by a superoxide scavenger (55 +/- 4%). Precontracted bronchial muscle relaxed to meconium in vitro and the magnitude of response was greater in the adult when compared with the newborn (p < 0.01). In vitro incubation with meconium (3 h) reduced agonist-stimulated force and enhanced endothelium-dependent relaxation (p < 0.01). Airway meconium instillation followed by mechanical ventilation enhanced thromboxane-induced newborn rat pulmonary arterial muscle contraction in vitro (p < 0.01). We conclude that meconium is a pulmonary vasodilator in vitro Meconium is first noted to be present at 12 wk gestation in humans. It is the by-product of fetal amniotic fluid, lanugo, skin cells, and vernix caseosa swallowing, as well it contains cells derived from the gastrointestinal tract (). Meconium composition also includes four different biliary acids (cholic, chenodeoxycholic, deoxycholic, and lithocholic) and minerals of which copper, zinc, magnesium, calcium iron, and phosphorus are the most common (). In addition, it contains plasmatic proteins such as alpha1-antitripsin and phospholipase A2 (4,5).

Prenatal Exposure to Fluoxetine Induces Fetal Pulmonary Hypertension in the Rat

Fluoxetine is a selective serotonin reuptake inhibitor antidepressant widely used by pregnant women. Epidemiological data suggest that fluoxetine exposure prenatally increases the prevalence of persistent pulmonary hypertension syndrome of the newborn. The mechanism responsible for this effect is unclear and paradoxical, considering the current evidence of a pulmonary hypertension protective fluoxetine effect in adult rodents. To evaluate the fluoxetine effect on fetal rat pulmonary vascular smooth muscle mechanical properties and cell proliferation rate. Pregnant rats were treated with fluoxetine (10 mg/kg) from Day 11 through Day 21 of gestation. Fetuses were delivered by cesarean section. As compared with controls, fluoxetine exposure resulted in fetal pulmonary hypertension as evidenced by an increase in the weight ratio of the right ventricle to the left ventricle plus septum (P = 0.02) and by an increase in pulmonary arterial medial thickness (P < 0.01). Postnatal mortality was increased among experimental animals, and arterial oxygen saturation was 96 +/- 1% in 1-day-old control animals and significantly lower (P < 0.01) in fluoxetine-exposed pups (79 +/- 2%). In vitro, fluoxetine induced pulmonary arterial muscle contraction in fetal, but not adult, animals (P < 0.01) and reduced serotonin-induced contraction at both ages (P < 0.01). After in utero exposure to a low fluoxetine concentration the pulmonary arterial smooth muscle cell proliferation rate was significantly increased in fetal, but not adult, cells (P < 0.01). In contrast to the adult, fluoxetine exposure in utero induces pulmonary hypertension in the fetal rat as a result of a developmentally regulated increase in pulmonary vascular smooth muscle proliferation.

Progressive lung and cardiac changes associated with pulmonary hypertension in the fetal rat.

To determine the natural history of lung vascular remodeling and cardiac changes in the rat model of persistent pulmonary hypertension syndrome (PPHN) of the newborn, we studied fetal rats subjected to maternal indomethacin administration initiated on day 19 of gestation and continued for 2, 3, or 4 days. Animals receiving a similar volume of water or alcohol served as controls. Significant pulmonary hypertension was noted in the experimental group, as evidenced by a significantly increased right to left ventricular wall ratio to 1.6 +/- 0.1 in the 4-day treatment group, as compared with 1.2 +/- 0.4 in the control group (P < 0.01). The smooth muscle area for <25 microm external diameter arterial vessels was significantly increased (12.7 +/- 0.6 vs. 10.0 +/- 0.6 microm; P < 0.01) and the adventitial area of all diameters vessels was significantly greater (P < 0.01) following 3 days of indomethacin treatment, as compared with water controls. Associated with these changes, the 4-day treatment group's lung/body weight ratio was 0.021 +/- 0.001, and was significantly less (P < 0.01) than for the control group (0.035 +/- 0.001). This reduction in lung weight was not associated with changes in lung protein content or wet/dry weight ratio, indicating that pulmonary hypertension in the fetal rat induced lung hypoplasia. In conclusion, closure of the ductus arteriosus in the fetal rat results in early-onset right ventricular hypertrophy, followed by pulmonary vascular remodeling and lung hypoplasia. We speculate that lung growth in late gestation is adversely affected by pulmonary hypertension.

Fetal ductus arteriosus ligation. Pulmonary vascular smooth muscle biochemical and mechanical changes.

To evaluate the smooth muscle mechanical and biochemical changes associated with persistent pulmonary hypertension syndrome of the newborn, we studied 31 fetal sheep in which the ductus arteriosus was ligated at 125 days of gestation. Sixty-one noninstrumented and six sham-operated fetuses served as controls. All animals were delivered by cesarean section at 137-140 days of gestation, and the experimental group had the ductus arteriosus ligated for 12 +/- 3 days. The ligated group demonstrated a higher mean (+/- SEM) pulmonary artery pressure (72.3 +/- 3.8 versus 54.1 +/- 2 mm Hg, p < 0.01) and right ventricular mean free wall weight (12.5 +/- 0.7 versus 6.8 +/- 0.3 g, p < 0.01) as compared with the sham-operated group. Significant changes in the pulmonary vascular smooth muscle of the ligated group were observed. The myosin content of vessels from the second through fifth generation demonstrated a significant increase in actin and myosin content (p < 0.01), but given their disproportional changes, the noninstrumented group demonstrated a lower actin/myosin ratio than the experimental group (p < 0.01). Changes in the myosin heavy chain isoform stoichiometry, characterized by an increase in both the mean high/low myosin heavy chain isoform ratio (1.8 +/- 0.3 versus 1.0 +/- 0.1, p < 0.05) and the nonmuscle isoform as a percentage of the total myosin heavy chain (12.4 +/- 0.7% versus 2.7 +/- 0.9%, p < 0.01), were also observed in the ligated as compared with the noninstrumented animals. In addition, the muscle Mg-ATPase activity was significantly (p < 0.05) reduced in the experimental group.(ABSTRACT TRUNCATED AT 250 WORDS)

Ligating the ductus arteriosus before birth remodels the pulmonary vasculature of the lamb.

The clinical syndrome of persistent pulmonary hypertension of the newborn includes a developmentally abnormal pulmonary microvasculature which contains excessive amounts of muscle and which cannot adapt to air breathing in the perinatal period. Surgical ligation of the ductus arteriosus of the fetal lamb has produced a physiologic model of pulmonary hypertension of the newborn. The aim of the present investigation is to determine whether surgical ligation of the ductus arteriosus in fetal sheep produces anatomic changes in the pulmonary blood vessels. The pulmonary vasculature of seven neonatal lambs that underwent surgical ligation of the ductus arteriosus from 6 to 17 d before birth was compared to that of five control lambs with a patent ductus arteriosus without fetal surgery and three control lambs with a patent ductus arteriosus that underwent sham surgery. Quantitative microscopic analysis of the barium gelatin-filled peripheral pulmonary vascular bed revealed an increase in the proportion of partially and fully muscularized pulmonary arteries at the level of the terminal bronchiole and within the acinus (p less than 0.0001). This finding demonstrates that medial muscle develops in areas of the distal pulmonary vascular bed where it is normally absent. Periadventitial fibrosis surrounding intraacinar pulmonary arteries was also present. No change in the number of small intraacinar arteries was detected. This structural remodeling of the peripheral pulmonary vascular bed was initiated in utero by ductus arteriosus occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Ligating the Ductus Arteriosus before Birth Causes Persistent Pulmonary Hypertension in the Newborn Lamb

We determined whether closing the ductus arteriosus of the fetal lamb several d before birth would cause persistent pulmonary hypertension after birth. Six experimental fetuses who had their ductus arteriosus ligated 3-17 d before delivery, three control fetuses who had sham ligation of the ductus arteriosus 14 d before delivery, and six control fetuses who had no prenatal surgery were delivered by cesarean section between 138 and 144 d of gestation. Each was instrumented to measure pulmonary and systemic arterial pressures and pulmonary blood flow. Each newborn lamb was ventilated with room air during the first 45 min after birth and then with decreasing amounts of inspired oxygen from 100 to 9%. Pulmonary arterial pressure decreased significantly when ventilation was begun in the control lambs but not in the lambs who had their ductus arteriosus ligated before delivery. Throughout the experiment, pulmonary arterial pressure and total pulmonary resistance were significantly higher, and pulmonary blood flow was significantly lower in the lambs who had their ductus arteriosus ligated before delivery. In two of them, pulmonary arterial pressure was greater than or equal to systemic arterial pressure, even during ventilation with 100% oxygen. This animal preparation provides a method of investigating persistent pulmonary hypertension in the newborn lamb and may provide insight into an etiology of the syndrome of persistent pulmonary hypertension of the newborn.

Effects of prostaglandin D 2 on pulmonary arterial pressure and oxygenation in newborn infants with persistent pulmonary hypertension

We studied the effects of prostaglandin D2 (PGD2) in six newborn infants, 1 to 2 days of age, who had persistent pulmonary hypertension syndrome and a PaO2 less than 75 torr during mechanical hyperventilation with an inspired oxygen concentration of 100%. Tolazoline and dopamine were used to treat some of the patients. No patients had congenital heart disease or sepsis. Catheters were placed to measure pulmonary and systemic arterial blood pressures. PGD2 was infused intravenously at doses of 1 to 25 micrograms/kg/min. Pulmonary and systemic arterial blood pressures, heart rate, and descending aortic blood gas values were measured before each dose change. Only two of six patients had a transient increase in PaO2. All had an increase in heart rate. Two of six patients had an increase in pulmonary arterial blood pressure. No deleterious effects occurred during the infusion. Four of six patients subsequently died. Although PGD2 is a specific pulmonary vasodilator in fetal and newborn animals, it did not lower pulmonary arterial blood pressure nor improve oxygenation in newborn infants with persistent pulmonary hypertension syndrome.

Hemodynamic responses of chronically instrumented piglets to bolus injections of group B streptococci.

Group B beta-hemolytic Streptotocci cause pulmonary hypertension when injected into animals and may precipitate the persistent pulmonary hypertension syndrome in infected human neonates. We used chronically instrumented piglets to study the effects of repeated injections of heat-killed group B Streptococcus (GBS) type III. Daily exposure to GBS was associated with a 2-fold or greater potentiation of pulmonary and systemic hypertensive responses after 1 wk. Throughout experimentation, pulmonary pressure changes were more marked than systemic changes. After establishing a dose-response relationship, we chose a control dose that produced intermediate hypertensive responses. We then evaluated the effects of antibody and various drugs on the hypertensive responses. Preincubation of organisms with rabbit antiserum containing type-specific antibody enhanced the responses. Beta endorphin blockade with naloxone had little or no effect; leukotriene synthesis inhibition also did not affect responses. Both indomethacin, a cyclooxygenase inhibitor, and dazmegrel, a specific thromboxane synthesis inhibitor, blocked the hypertensive responses to GBS. It appears that repeated doses of GBS potentiate the hypertensive responses, a process that we hypothesize may be mediated by development of type-specific antibody as type-specific antibody levels rose during potentiation. It is likely that thromboxane A2 is the effector of the pulmonary and systemic hypertensive responses to GBS injection, because thromboxane inhibition by dazmegrel was as effective as indomethacin in blocking these effects. Thromboxane synthesis blockade may prove useful in management of hemodynamic disturbances accompanying severe bacterial infections in humans.

Effects of indomethacin in utero on the pulmonary vasculature of the newborn guinea pig.

The clinical syndrome of persistent pulmonary hypertension of the newborn results from failure of the normal perinatal vascular adaptation, and functionally is characterized by persistent right to left shunting of blood through the foramen ovale and ductus arteriosus. Exposure of the fetus to drugs that inhibit prostaglandin synthesis and cause closure of the ductus arteriosus has been suggested as one cause of persistent pulmonary hypertension of the newborn. We attempted to produce a functional and structural model of persistent pulmonary hypertension of the newborn by administration of indomethacin, a cyclooxygenase inhibitor, to pregnant guinea pigs. Five pregnant guinea pigs received 3.5 mg/kg indomethacin intravenously twice each day for the 12 to 19 days before delivery and seven controls received saline. Hemodynamic studies were performed in eight "treated" newborns and in 12 controls. After sacrifice, the ductus was ligated and, for morphometric studies, the pulmonary arteries were distended with barium/gelatin. The treated animals did not show the intraacinar structural or hemodynamic changes of persistent pulmonary hypertension of the newborn. It seems that the indomethacin did cross the placenta because lung structure was modified. The radical alveolar count and alveolar/artery ratio were increased and the preacinar arteries dilated, with more increase in muscle mass. This could be explained by increased pulmonary blood flow because of ductal constriction but direct effect of indomethacin cannot be excluded.

Thromboxane synthesis inhibition reverses group B Streptococcus-induced pulmonary hypertension.

Group B Streptococcus (GBS) sepsis in humans may cause the persistent pulmonary hypertension syndrome. Infusions of GBS in animals elevate pulmonary artery pressure (PAP) and resistance and are associated with elevated thromboxane levels. We investigated the hemodynamic effects of the specific thromboxane synthesis inhibitor, dazmegrel, in a piglet model of GBS-induced pulmonary hypertension. PAP rose from 22 +/- 6 to 42 +/- 11 (SD) mm Hg during infusion of heat-killed GBS; pulmonary vascular resistance increased from 1440 +/- 400 to 4000 +/- 1040 dyne X sec/cm5. No significant changes in cardiac output, mean arterial pressure, or left atrial pressure were noted. Treatment with 1 mg/kg of dazmegrel resulted in a rapid return of PAP and resistance to control values. No other hemodynamic effects of either bacteria or drug were observed despite continued infusion of GBS.

Non-narcotic analgesics. Use in pregnancy and fetal and perinatal effects.

Aspirin and related non-narcotic analgesics such as paracetamol (acetaminophen) are present in almost every 'Western' household and are so commonly used that the public often does not think of them as drugs. Although the toxic effects of overdoses are well recognised by the medical and related professions, the potential adverse effects of repetitive dosing, within the commonly recommended therapeutic range, are not. This is particularly true during pregnancy, where the relative overall general safety of the agents is overshadowed by the possible subtle but potentially pervasive effects on the fetus. Marketing publicity, particularly about recently introduced related agents, has at times failed to take into account these less obvious, but nevertheless potentially lethal, side effects. It is now likely that aspirin and/or paracetamol are used during pregnancy by most women and that the earlier figures are underestimates. Although animal studies have shown significant effects of non-steroidal anti-inflammatory agents (NSAIDs) on the fetal circulation, particularly on the developing pulmonary circulation, the data on human pregnancy are less convincing. Nevertheless, the possible association of these drugs with prolonged gestation, and an increased incidence of the syndrome of persistent pulmonary hypertension of the newborn and of intracranial haemorrhage, demand that prudence be exercised when using these drugs during pregnancy. At the very least, more conclusive evidence is necessary that fetal and neonatal complications are not increased.

Leukotriene inhibition prevents and reverses hypoxic pulmonary vasoconstriction in newborn lambs.

The effects of the leukotriene antagonist FPL 57231 on the circulation were studied in spontaneously breathing normoxic and hypoxic newborn lambs in order to evaluate the role of leukotrienes in the perinatal control of hypoxic pulmonary vasoconstriction. Hypoxia produced a 58% increase in pulmonary arterial pressure (p less than 0.05) and a 37% increase in pulmonary vascular resistance (p less than 0.05). Hypoxic pulmonary vasoconstriction was abolished by the prior infusion of FPL 57231. Pulmonary arterial pressure increased by only 8% and pulmonary vascular resistance decreased by 10% from normoxia. The infusion of FPL 57231 during hypoxia-induced pulmonary vasoconstriction reversed the increase in pulmonary arterial pressure (p less than 0.05) and pulmonary vascular resistance (p less than 0.05). The hypoxia-induced increase in cardiac output was maintained during the infusion of FPL 57231. Leukotrienes may play a significant role in the mediation of hypoxic pulmonary vasoconstriction. Leukotriene inhibition with FPL 57231 may be useful in the management of infants with persistent pulmonary hypertension syndrome.

Utility of M-Mode Echocardiography for Early Identification of Infants with Persistent Pulmonary Hypertension of the Newborn

The clinical syndrome of persistent pulmonary hypertension of the newborn (PPHN) still carries high mortality in spite of improved neonatal care. The purpose of this prospective study was to assess the utility of M-mode echocardiography for the early identification of infants with PPHN prior to clinical deterioration. Echocardiograms of 51 infants who needed fractional inspiratory oxygen (FIO2) greater than or equal to 0.25 to maintain adequate PaO2 within 36 hours of life were compared to those of 115 healthy full-term and preterm newborns. Of the 51 infants, ten had elevated systolic time interval ratios of both ventricles simultaneously (ventricular pre-ejection period to ventricular ejection time [RPEP/RVET greater than or equal to 0.50, LPEP/LVET greater than 0.38]). All of these newborns had PPHN that was manifest clinically by 11 to 30 hours of age. The echocardiographic findings preceded clinical deterioration by at least one to five hours in all cases. The other 41 infants had clinical courses consistent with uncomplicated pulmonary disease. These data indicate that systolic time interval ratios, although not accurate measures of pulmonary arterial pressure and/or pulmonary vascular resistance, permit early identification of infants with PPHN and separation from others with uncomplicated pulmonary disease.

Fetal hypertension and the development ofincreased pulmonary vascular smooth muscle: A possible mechanism for persistent pulmonary hypertension of the newborn infant

Chronic pulmonary arterial hypertension was produced in six fetal lambs. In four (126 to 139 days' gestation) unilateral fetal renal artery constriction caused systemic arterial mean blood pressure elevations. In another fetus, constriction of the umbilical artery caused a systemic mean blood pressure elevation; in the sixth, partial occlusion of the ductus arteriosus caused isolated pulmonary arterial hypertension. The right lung of each fetus was perfused with fixative at the in vivo mean arterial pressure and the amount of smooth muscle in the fifth generation (resistance) vessels analyzed using the medial width/external diameter ratio. There was a significant increase in the medial width/external diameter ratio in the six experimental animals as compared to that in six normal fetuses. In separate fetuses the increased ratios were due to a decreased external diameter, increased smooth muscle, or both these factors. The total number of resistance vessels was counted in the right lung of each fetus and no significant difference from normal was observed. We postulate that either fetal systemic hypertension or constriction of the ductus arteriosus causes fetal pulmonary hypertension in utero and that this produces increased smooth muscle development in pulmonary arterial resistance vessels; this may be a pathogenic mechanism for the syndrome of persistent pulmonary hypertension of the newborn infant.