Drop In Pulmonary Vascular Resistance Research Articles

Acute vasoreactivity testing during right heart catheterization in chronic thromboembolic pulmonary hypertension: Results from the pulmonary vascular disease phenomics study.

Chronic thromboembolic pulmonary hypertension (CTEPH) is believed to involve both vascular obstruction and vasoconstriction; hence, pulmonary vasodilators such as riociguat may be beneficial. Acute vasoreactivity testing (AVT) is seldom performed routinely in CTEPH patients, so there is limited understanding of the frequency and significance of an acute vasodilator response. Systematic vasodilator testing with oxygen (O2) and oxygen plus inhaled nitric oxide (O2 + iNO) was performed as part of the Pulmonary Vascular Disease Omics (PVDOMICS) NHLBI project, providing an opportunity to examine AVT responses in CTEPH. Patients with CTEPH enrolled in PVDOMICS (n = 49, 40 with prevalent CTEPH[82%])underwent right heart catheterization including AVT with O2 and O2 + iNO. Hemodynamics were obtained at baseline and with each challenge. Fourteen of 49 patients (29%) had >20% drop in pulmonary vascular resistance (PVR) with O2. With O2 + iNO, 30/49 (61%) had >20% drop in PVR, 20% had >20% drop in mean pulmonary artery pressure(mPAP) and PVR, and 8% had >10 mmHg decline in mPAP to mPAP < 40 with normal cardiac output. Patients on riociguat had less response to O2 + iNO than patients on phosphodiesterase-5inhibitors. Our findings shed light on the significant variability in vascular tone that is present in CTEPH, confirming that CTEPH represents a combination of mechanical obstruction and vasoconstriction that appears similar to that observed with Group 1 PAH. Additional study regarding whether results of acute vasodilator testing predict response to therapy and relate to prognosis is warranted.

ACUTE VASOREACTIVITY TESTING DURING RIGHT HEART CATHETERIZATION IN CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION: RESULTS FROM THE PULMONARY VASCULAR DISEASE OMICS PROJECT

SESSION TITLE: Advances in the Diagnosis and Management of Pulmonary Hypertension SESSION TYPE: Original Investigations PRESENTED ON: October 18-21, 2020 PURPOSE: Chronic thromboembolic pulmonary hypertension (CTEPH) is believed to involve both vascular obstruction and vasoconstriction; hence vasodilators such as riociguat may be beneficial. Acute vasoreactivity testing is seldom performed, so there is limited understanding of frequency and significance of acute response. Systematic vasodilator testing with oxygen and oxygen plus inhaled nitric oxide was performed as part of the Pulmonary Vascular Disease Omics (PVDOMICS) NHLBI project, providing opportunity to examine this issue. METHODS: Patients with CTEPH enrolled in PVDOMICS underwent right heart catheterization including vasodilator challenge with 100% oxygen (02) and 100% oxygen plus 40 PPM of inhaled nitric oxide (02 + NO). Mean pulmonary artery pressure, pulmonary artery wedge pressure, and cardiac output by thermodilution with calculation of pulmonary vascular resistance (PVR) was obtained at baseline and with each intervention. We examined acute vasoreactivity defined as > 20% drop in PVR, > 20% drop in both mPAP and PVR, and as a drop in mPAP > 10 mmHg to a value < 40 mmHg with normal cardiac output. RESULTS: Of the 61 patients who underwent vasoreactivity testing, 32 (52%) were on PH therapy (15 riociguat, 8 PDE5i, 9 other) and 29 (48%) were on no targeted PH therapy. Fourteen (23%) had prior pulmonary thromboendarterectomy, 1 (2%) had prior balloon pulmonary angioplasty. In the overall cohort, mean PVR was 5.49 WU at baseline, 4.81 with 02, and 4.01 with O2 + NO (mean ± SD change from baseline: -1.43 ± 1.32, 26%), p < .0001). In the subset who were on no PH therapy, mean PVR was 6.26 at baseline, 5.75 with 02, and 4.55 with 02 + NO (change from baseline of -1.62 ± 1.36, 26%), p < .0001). Overall, 25 (43%) had > 20% drop in PVR with 02. With 02 + NO, 36 (62%) had > 20% drop in PVR (decline of 1.43 ± 1.32 WU), including 9 (64%) of those with prior thromboendarterectomy and 19 who were on PH therapy. Six (10%) had a drop in mPAP by > 10 mmHg to < 40 mmHg with normal cardiac output. Thirteen (21%) had > 20% drop in both mPAP and PVR, 6 of whom were on no PH therapy and 4 out of 8 (50%) of those who were on PDE5i. Only 2/15 (13%) of those on riociguat had > 20% drop in both mPAP and PVR. CONCLUSIONS: An element of acute vasoreactivity is common in CTEPH including in those with prior pulmonary thromboendarterectomy. The 26% decline in PVR with acute testing for those who were on no PH therapy is similar to what was achieved chronically on average with riociguat in the pivotal randomized study [(29%, 226 dyn.sec.cm -5 = 2.83 WU,) from baseline of 791]. Whether acute vasoreactivity testing is predictive of clinical response to riociguat or other pulmonary vasodilators is worthy of additional investigation. CLINICAL IMPLICATIONS: Vasoconstriction is a significant contributor to the elevation in pulmonary artery pressure and resistance in the majority of patients with CTEPH. DISCLOSURES: No relevant relationships by Erika Berman Rosenzweig, source=Web Response Advisory Committee Member relationship with Liquidia Please note: $1001 - $5000 Added 03/19/2020 by Robert Frantz, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Altavant Please note: $1001 - $5000 Added 03/19/2020 by Robert Frantz, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Actelion Please note: $5001 - $20000 Added 07/16/2020 by Robert Frantz, source=Web Response, value=Consulting fee No relevant relationships by Paul Hassoun, source=Web Response Advisory Committee Member relationship with bayer Please note: $1001 - $5000 Added 04/14/2020 by Anna Hemnes, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Complexa Please note: $1-$1000 Added 04/14/2020 by Anna Hemnes, source=Web Response, value=Consulting fee Advisory Committee Member relationship with United Therapeutics Please note: $1001 - $5000 Added 04/14/2020 by Anna Hemnes, source=Web Response, value=Consulting fee Advisory Committee Member relationship with actelion Please note: $1001 - $5000 Added 04/14/2020 by Anna Hemnes, source=Web Response, value=Consulting fee Scientific Medical Advisor relationship with PHPreMedicine Please note: $1-$1000 Added 04/14/2020 by Anna Hemnes, source=Web Response, value=Ownership interest no disclosure on file for Evelyn Horn; No relevant relationships by Armand Larive, source=Web Response My spouse/partner as a Consultant relationship with Cellectis Please note: >$100000 Added 05/28/2020 by Jane Leopold, source=Web Response, value=Consulting fee no disclosure on file for Franz RIschard; Consultant relationship with Sequana Medical AG Please note: $5001 - $20000 Added 05/28/2020 by Wai Hong Tang, source=Web Response, value=Consulting fee Editor/Author relationship with Springer Nature Please note: $1-$1000 Added 05/29/2020 by Wai Hong Tang, source=Web Response, value=Honoraria My spouse/partner as a Consultant relationship with Cardiac Community Core Lab, LLC Please note: $1001 - $5000 Added 05/28/2020 by Wai Hong Tang, source=Web Response, value=Honoraria

The evolution of electrocardiographic signs of right ventricular overload after balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension.

Balloon pulmonary angioplasty (BPA) is a treatment option for a patient with chronic thromboembolic pulmonary hypertension. We aimed to investigate the evolution of electrocardiographic (ECG) markers of right ventricular hypertrophy (RVH) after BPA. Standard 12‑lead ECG was performed in 41 patients with chronic thromboembolic pulmonary hypertension before the first BPA and after completion of treatment. In the whole study group, the percentage change in the pulmonary vascular resistance (PVR) after BPA correlated with the percentage change in the values of the following ECG parameters (P <0.05): axis of the QRS (rho = 0.530) and T wave (rho = 0.372); P wave in leads II (rho = 0.340) and III (rho = 0.430); S wave in lead V5 (rho = 0.634); R/S ratio in lead V5 (rho = -0.636); S wave in lead V6 (rho = 0.508); S wave in lead I (rho = 0.496). Then, the group was divided into 2 subgroups: group A, defined as a drop in PVR greater than the median value (49%) for the whole study population; and group B, defined as a drop in PVR below the median value. In group A, the following parameters changed after BPA: T‑wave axis (P <0.001), P wave in lead II (P <0.001), S wave in lead V5 (P <0.001), R/S ratio in lead V5 (P <0.001). In group B, despite some hemodynamic and functional improvement, there were no differences in ECG mark ers of RVH after BPA. An improvement in RVH parameters can be observed on ECG after a hemodynamically effective BPA.

Lung Ultrasound to Assess the Etiology of Persistent Pulmonary Hypertension of the Newborn (LUPPHYN Study): A Pilot Study

Introduction: Persistent pulmonary hypertension of the newborn (PPHN) is a neonatal syndrome associated with significant morbidity and mortality that is caused by the failure of postnatal drop in pulmonary vascular resistance. In extreme cases, patients may require extracorporeal membrane oxygenation therapy (ECMO). The aim of this study was to explore lung ultrasound (LUS) patterns in newborns with PPHN requiring ECMO. Patients and Methods: From January 2014 to January 2018, LUS was performed on patients with PPHN admitted for ECMO treatment. PPHN diagnosis was based on clinical and echocardiographic findings. LUS was performed before patients underwent ECMO cannulation. An underlying diagnosis was made taking into account the patient’s complete medical history, excluding LUS information. A blinded physician, unaware of the patient’s clinical condition, analyzed the stored ultrasound images. Results were then compared with chest x-ray (CXR) diagnoses. Results: Seventeen patients were recruited; 12 were male (70.6%). The median gestational age was 38.7 weeks, with 13 term newborns (76.5%). Twelve were cannulated for VA ECMO, with a median ECMO run of 111.2 h. Six patients (35%) survived. Patients with alveolar capillary dysplasia with misaligned pulmonary veins, fetal ductus arteriosus constriction, or sepsis had normal LUS patterns (A-lines with lung sliding). LUS showed a better sensitivity (88.9%) and specificity (85%) than CXR (55.6 and 77.5%, respectively) in identifying patients with nonparenchymal lung disease. Conclusions: LUS can provide essential information to help diagnose the underlying cause of PPHN in an earlier and more effective way than CXR. LUS is suitable for routine utilization in the intensive care unit.

Endothelial Phenotype Evoked by Low Dose Carvedilol in Pulmonary Hypertension.

Background: The therapeutic benefits of β-blockers are well established in left heart failure. The Pulmonary Arterial Hypertension Treatment with Carvedilol for Heart Failure [PAHTCH] study showed safety and possible benefit of carvedilol in pulmonary arterial hypertension (PAH) associated right heart failure over 6 months. This study aims at evaluating the short-term cardiovascular effects and early mechanistic biomarkers of carvedilol therapy.Methods: Thirty patients with pulmonary hypertension (PH) received low dose carvedilol (3.125 mg twice daily) for 1 week prior to randomization to placebo, low-dose, or dose-escalating carvedilol therapy. Echocardiography was performed at baseline and 1 week. Exercise capacity was assessed by 6 min walk distance (6MWD). The L-arginine/nitric oxide pathway and other biological markers of endothelial function were measured.Results: All participants tolerated 1 week of carvedilol without adverse effects. After 1 week of carvedilol, 6MWD and heart rate at peak exercise did not vary (both p > 0.1). Heart rate at rest and 1 min post walk dropped significantly (both p < 0.05) with a trend for increase in heart rate recovery (p = 0.08). Right ventricular systolic pressure (RVSP) decreased by an average of 13 mmHg (p = 0.002). Patients who had a decrease in RVSP of more than 10 mm Hg were defined as responders (n = 17), and those with a lesser drop as non-responders (n = 13). Responders had a significant drop in pulmonary vascular resistance (PVR) after 1 week of carvedilol (p = 0.004). In addition, responders had a greater decrease in heart rate at rest and 1 min post walk compared to non-responders (both p < 0.05). Responders had higher plasma arginine and global bioavailability of arginine at baseline compared to non-responders (p = 0.03 and p = 0.05, respectively). After 1 week of carvedilol, responders had greater increase in urinary nitrate (p = 0.04). Responders treated with carvedilol had a sustained drop in RVSP and PVR after 6 months of carvedilol with no change in cardiac output.Conclusions: Low-dose carvedilol for 1 week can potentially identify a PH responder phenotype that may benefit from β-blockers that is associated with less endothelial dysfunction.Clinical Trial Registration: http://www.clinicaltrials.gov. identifier: NCT01586156.

Echocardiographic Evaluation of Transitional Circulation for the Neonatologists.

The hemodynamic changes during the first few breaths after birth are probably the most significant and drastic adaptation in the human life. These changes are critical for a smooth transition of fetal to neonatal circulation. With the cord clamping, lungs take over as the source of oxygenation from placenta. A smooth transition of circulation is a complex mechanism and primarily depends upon the drop in pulmonary vascular resistance (PVR) and increase in systemic vascular resistance (SVR). Understanding the normal transition physiology and the adverse adaptation is of utmost importance to the clinicians looking after neonates. It may have a significant influence on the presentation of congenital heart defects (CHDs) in infants. Bedside echocardiography may help in understanding the transition physiology, especially the hemodynamic changes and shunting across ductus arteriosus and foramen ovale, and it may play an important role in making judicious clinical decisions based upon the altered physiology.

Effects of Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) on Fetal Pulmonary Circulation: An Experimental Study in Fetal Lambs

Background: Persistent pulmonary hypertension of the newborn (PPHN) causes significant morbidity and mortality in neonates. n-3 Poly-unsaturated fatty acids have vasodilatory properties in the perinatal lung. We studied the circulatory effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fetal sheep and in fetal pulmonary arterial rings. Methods: At 128 days of gestation, catheters were placed surgically in fetal systemic and pulmonary circulation, and a Doppler probe around the left pulmonary artery (LPA). Pulmonary arterial pressure and LPA flow were measured while infusing EPA or DHA for 120 min to the fetus, to compute pulmonary vascular resistance (PVR). The dose effects of EPA or DHA were studied in vascular rings pre-constricted with serotonin. Rings treated with EPA were separated into three groups: E+ (intact endothelium), E− (endothelium stripped) and LNA E+ (pretreatment of E+ rings with l-nitro-arginine). Results: EPA, but not DHA, induced a significant and prolonged 25% drop in PVR (n = 8, p < 0.001). Incubation of vascular rings with EPA (100 µM) caused a maximum relaxation of 60% in the E+ (n = 6), whereas vessel tone did not change in the E− (n = 6, p < 0.001). The vascular effects of EPA were significantly decreased in LNA E+ (n = 6). Incubation with DHA resulted in only a mild relaxation at the highest concentration of DHA (300 µM) compared to E+. Conclusions: EPA induces a sustained pulmonary vasodilatation in fetal lambs. This effect is endothelium- and dose-dependent and involves nitric oxide (NO) production. We speculate that EPA supplementation may improve pulmonary circulation in clinical conditions with PPHN.

Exercise during cardiac catheterization distinguishes between pulmonary and left ventricular causes of dyspnea in systemic sclerosis patients

The cause for shortness of breath among systemic sclerosis (SSc) patients is often lacking. We sought to characterize the hemodynamics of these patients by using simple isotonic arm exercise during cardiac catheterization. Catheterization was performed in 173 SSc patients when resting echocardiographic pulmonary systolic pressures were <40 but >40 mmHg post stress. Patients with resting mean pulmonary arterial pressures (mPAP) ≤ 25 and pulmonary arterial wedge pressures (PAWP) ≤ 15 mmHg exercised with 1-pound hand weights. Normal exercise was defined as a change in mPAP divided by the change in cardiac output (CO) (ΔmPAP/ΔCO) ratio ≤ 2 for patients <50 years (≤3 for >50). An abnormal ΔmPAP/ΔCO ratio, an exercise transpulmonary gradient (TPG) ≥ 15, a PAWP < 20, a ΔTPG > ΔPAWP and a pulmonary vascular resistance (PVR) which increased defined exercise-induced pulmonary arterial hypertension (EIPAH). An abnormal ΔmPAP/ΔCO ratio, an exercise TPG < 15, a PAWP ≥ 20, a ΔTPG < ΔPAWP and a drop in PVR defined left ventricular diastolic dysfunction (DD). Twelve patients without SSc served as controls. Pulmonary pressures increased with exercise in 53 patients. Six had EIPAH and 47 had DD. With exercise, mPAP and PAWP were 20 ± 4 and 13 ± 2 in controls, 36 ± 3 and 12 ± 4 in EIPAH and 34 ± 6 and 26 ± 4 in DD. Control ΔmPAP/ΔCO was 0.8 ± 0.7, 7.5 ± 3.9 in EIPAH and 9.1 ± 7.2 in DD. Rest and exercise TPG was normal for control and DD patients but increased (12 ± 4 to 23 ± 4) in EIPAH (P < 0.0001). PVR decreased in DD but increased in EIPAH with exercise. Exercise during catheterization elucidates the pathophysiology of dyspnea and distinguishes EIPAH from the more common DD in SSc patients.

PH and nitric oxide synthase activity and expression in bovine aortic endothelial cells

Abstract Aim: Nitric oxide (NO) plays an important role in the transition from intrauterine to extrauterine life. If this transition fails, a condition called persistent pulmonary hypertension of the neonate (PPHN) may develop. The current treatment modalities for this disease include induction of alkalosis by hyperventilation or alkali infusion, inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation. There is evidence from animal studies that the elevated pH, not the low pCO2 is responsible for the resultant pulmonary vasodilatation. In this study, we examined the effect of pH on the activity and expression of endothelial nitric oxide synthase (eNOS) in cultured bovine aortic endothelial cells (BAEC) as a possible explanation for the pH dependent drop in pulmonary vascular resistance. Methods: BAEC were exposed to a pH gradient of 7.1–7.6 for 4 h (short‐term) and 16 h (long‐term). Standard Western blotting technique was used to detect expression of eNOS. Activity was measured by an indirect assay using bovine aortic smooth muscle cells (BASM) as reporter cells and measuring cGMP levels as a marker of NO production. The cells were exposed to the pH gradient for a total of 4 h and measurement were made at 30, 60 and 90 min, and 2, 3 and 4 hours. Results: eNOS activity and expression remained unchanged during the four and sixteen hours of exposure. Conclusion: In this in vitro experiment, we could not demonstrate an alkalosis‐induced increase in eNOS activity and expression. The clinically observed pH dependent vasodilatation does not appear to be directly mediated through the induction of eNOS.

Effects of Phosphodiesterase 5 Inhibitor on Pulmonary Vascular Reactivity in the Fetal Lamb

Nitric oxide released by pulmonary vascular endothelium is a potent vasodilator related to increased cyclic guanosine monophosphate (cGMP) content. Hydrolysis of cGMP is achieved predominately by cGMP-specific phosphodiesterases. Sildenafil is a selective phosphodiesterase-5 (PDE5) inhibitor. The purpose of the study is to assess the effects of sildenafil on pulmonary vascular circulation during the perinatal period. Thirty-two pregnant ewes were operated on at the end of gestation, and fetal lambs were prepared with catheters placed into the aorta, vena cava, pulmonary artery, and left atrium. An ultrasonic flow transducer and an inflatable vascular occluder were placed respectively around the left pulmonary artery and the ductus arteriosus. Fetal lambs were randomly divided into two groups: (1) sildenafil group, infused continuously with sildenafil for 24 hours at a rate of 1 mg/h; or (2) control group, infused with saline for 24 hours. After 24 hours of infusion, we compared basal pulmonary vascular resistance and the pulmonary vascular responses to increase in fetal PaO2 and to acute ductus arteriosus compression causing "shear stress." Sildenafil infusion did not change mean aortic and pulmonary artery pressures, increased mean left pulmonary blood flow by 160%, and decreased pulmonary vascular resistance by 60% (p < 0.05). However, both mean flow (Q) and pulmonary vascular resistance returned to baseline values after 2 hours of sildenafil infusion. Despite similar baseline values, pulmonary vascular resistance during maternal O2 inhalation was lower in the sildenafil group than in the control group (0.21 +/- 0.03 versus 0.33 +/- 0.03 mm Hg.mL(-1).min(-1), respectively; p < 0.01). Furthermore, drop in pulmonary vascular resistance during acute ductus arteriosus compression was greater in the sildenafil group (from 0.56 +/- 0.06 to 0.26 +/- 0.04 mm Hg.mL(-1).min(-1)) than in the control group (from 0.55 +/- 0.05 to 0.39 +/- 0.03 mm Hg.mL(-1).min(-1); p < 0.01). Although sildenafil induces a transient pulmonary vasodilation, it mediates a sustained change in vascular reactivity, especially to birth-related stimuli in the ovine fetal lung. These data suggest that PDE5 is involved in the regulation of pulmonary vascular reactivity during the perinatal period and may potentiate birth-related pulmonary vasodilator stimuli.

173 Effects of Phosphodiesterase 5 Inhibitor on Pulmonary Vascular Reactivity in The Fetal Lamb

Background: Nitric Oxide (NO) released by pulmonary vascular endothelium is a potent vasodilator related to increased cGMP content. Hydrolysis of cGMP is achieved predominantly by cGMP–specific phosphodiesterases (PDEs). Sildenafil (SILD) is a selective phosphodiesterase–5 (PDE–5) inhibitor. The purpose of the study was to assess the effects of sildenafil on pulmonary vascular circulation during the perinatal period.Methods: 12 pregnant ewes were operated on between 128 and 130 days gestation (term = 145 d). Catheters were placed into the ascending aorta, superior vena cava, main pulmonary artery and left atrium. An ultrasonic flow transducer was placed around left pulmonary artery (LPA). An inflatable vascular occluder was placed around ductus arteriosus (DA). Acute DA compression increases pulmonary artery pressure (PAP) causing an increase in pulmonary blood flow (Q) and a progressive decline in pulmonary vascular resistance (PVR). Fetal lambs were divided in two groups: 1) a SILD group infused continuously with SILD at a rate of 24 mg/day (n=6) and; 2/ control group (CONT) infused with saline (n=6). After 24 hrs of infusion, we compared the hemodynamic response of LPA to: 1) increased fetal PaO2 (maternal O2 inhalation for 30 min), and; 2) increase in vascular shear-stress (flow-induced pulmonary vasodilatation related to DA compression).Results: Mean PAP, Q and PVR were similar in both groups before and after 24 h of SILD or saline infusion. Despite similar baseline values, PVR during maternal O2 inhalation was lower in SILD than in CONT group (0.23±0.01 vs 0.27±0.01 mmHg/ml.min−1 respectively) (p<0.01). Furthermore, drop in PVR during acute DA compression was greater in the SILD group (from 0.54±0.03 to 0.26±0.02 mmHg/ml.min−1) than in the CONT group (from 0.55±0.04 to 0.39±0.02 mmHg/ml.min−1) (p<0.01).Conclusion: Although no difference was found in the basal pulmonary vascular tone, sildenafil increases pulmonary vascular reactivity in the ovine fetus. These data suggest that PDE–5 is involved in the regulation of pulmonary vascular reactivity during the perinatal period. We further speculate that specific inhibitor of PDE–5 may potentiate birth related pulmonary vasodilator stimuli and could improve conditions associated with failure to circulatory adaptation at birth.

Haemodynamic requirements for an ideal pulmonary vasodilator.

An ideal vasodilator should be selective for the pulmonary vascular bed, thus minimizing side-effects from reduced systemic resistance. It must achieve not only a drop in pulmonary vascular resistance but also a marked decrease in pulmonary arterial pressure. The ideal drug should increase cardiac output and pulmonary venous oxygen saturation. An increase in oxygen delivery to the peripheral tissues should be achieved at a lower right ventricular afterload both at rest and during exercise. Right ventricular function should be improved. The effects of vasodilator therapy should be so marked that it should be possible to follow them non-invasively by radionuclide methods and exercise tolerance tests. The aim of vasodilator therapy is a regression of pulmonary hypertension and of right ventricular hypertrophy, an improved quality of life, and above all a longer survival.

Acute and Chronic Fetal Pulmonary Hypertension Alter Pulmonary Vasoreactivity

Persistent pulmonary hypertension of the newborn (PPHN) is the failure of the pulmonary circulation to adapt successfully to postnatal conditions. Associated with a wide variety of neonatal cardiopulmonary disorders, PPHN represents the inability to achieve or sustain a drop in pulmonary vascular resistance during the immediate newborn period. Previous clinical and experimental studies suggested that intrauterine events may play important roles in its pathogenesis. Supportive evidence includes: (1) the timing of onset of disease within hours of birth; (2) the severity of histologic findings at autopsy of infants with severe PPHN dying within the first few days, including marked smooth muscle and perivascular adventitial thickening;1 and (3) animal studies suggesting that fetal stresses, such as hypoxia or hypertension, can cause smooth muscle thickening of small pulmonary arteries.

Aortic and pulmonary blood velocities during the first 3 days of life.

Newborn infants undergo major cardiovascular changes to accomplish the transition from fetal to newborn circulation. These include a drop in pulmonary vascular resistance and closure of the ductus arteriosus. We measured blood velocities by pulsed-Doppler ultrasound in the great vessels of normal newborns during this transition period. Our goals were to understand the timing of these changes and to assess cardiac function as measured by flow velocities. We concluded that shunting of blood through the ductus arteriosus continues for 1-2 days after birth without apparent hemodynamic consequences, cardiac function, as assessed by the Doppler technique, remains remarkably stable during this time period, the timing of ductal closure is not affected by the mode of delivery, and Doppler ultrasound is a portable, reproducible method which is useful in assessing the cardiovascular system of the neonate.

Indomethacin and the cardiopulmonary adaptations of transition.

The present investigation examines the biochemical and physiologic changes produced in fetal rabbit lungs by adding a prostaglandin synthetase inhibitor, sodium indomethacin trihydrate, to the pulmonary perfusate. A control group was similarly perfused without adding indomethacin. The ductus arteriosus was ligated and perfusion was then continued for 2 h while pulmonary artery pressures were monitored. At the end of this period, with perfusion continuing, the lungs were inflated with air at 5 cm H2O increments. Volume changes were recorded. After deflation, the lungs were lavaged with normal saline. Phospholipids were extracted from lung homogenates and lavage. Total lipid phosphorus was determined. Pulmonary vascular resistances in both groups manifested a sharp increase in pressure with ligation of the ductus. After 2 h of perfusion, pulmonary pressures in the control groups had returned very nearly to preligation levels, while in the indomethacin-treated group, pulmonary pressures remained significantly elevated. The first full inflation produced a slight fall in pulmonary vascular resistance in all control animals and a slight rise in all the treated rabbits. Perfused but untreated lungs had higher volumes during inflation as compared to both indomethacin-perfused lungs and unperfused untreated lungs. In this model, prostaglandins appear to have a significant role at two key points in transition: 1) the gradual accommodation to mechanically or hemodynamically mediated increases in pulmonary vascular resistance and 2) the drop in pulmonary vascular resistance which occurs with the first inflation of the lungs. No direct effect of prostaglandin inhibition on surfactant production was documented.

Increased shunt through the patent ductus arteriosus after surfactant replacement therapy

Instillation of surfactant into the trachea of preterm infants with respiratory distress syndrome is associated with a 90% incidence of patent ductus arteriosus. We studied the effects of surfactant therapy on the ductus arteriosus in 12 preterm lambs. Flow across the ductus arteriosus and systemic blood flow were calculated from radioactive microsphere injections. All developed respiratory failure (pH less than 7.1, Paco2 greater than 60) by 30 minutes after birth. Between 30 and 60 minutes after birth, six lambs were treated with tracheal instillation of 50 mg/kg surfactant lipid. By two hours after birth, treated lambs differed significantly from controls in pH (7.27 +0.02 vs 6.97 +0.08) and Paco2 (43.3 +4.1 vs 85 + 15). There were no differences in Pao2 or PGE2 concentrations or ductus arteriosus resistance, but there was a significantly larger shunt through the ductus arteriosus in treated lambs. This increased shunt resulted from the significant drop in pulmonary vascular resistance and not from a change in patency of the ductus arteriosus. Surfactant replacement may require interventions directed specifically at the patent ductus arteriosus in sick preterm infants.

1271 PDA WITH SURFACTANT REPLACEMENT THERAPY

Surfactant instillation into the trachea of preterm infants with RDS is associated with a 90% incidence of PDA. We studied the effects of surfactant therapy on the ductus arteriosus (DA) in 12 preterm lambs (.89 gestation). Flow (Q) across the DA and systemic blood flow were calculated from microsphere injections. All 12 lambs were paralyzed and ventilated with 100% O2. All developed respiratory failure (pH<7.1, PCO>60) by 30 min after birth. Between 30-60 mins after birth, 6 lambs were treated with tracheal instillation of 50 mg/kg surfactant lipid (purified from alveolar washes from adult sheep). There were no significant differences between control and treated animals prior to surfactant instillation for PCO2, pH, prostaglandin (PG) E2 concentrations, the ratio of L→R shunt through the DA vs systemic flow (Q shunt/Q syst), DA resistance, or the ratio of pulmonary to systemic vascular resistance (RP/RS). By 2 hr after birth treated lambs differed significantly from controls in pH (7.27±02 vs 6.97±08) and PCO2 (43.3±4.1 vs 85±15). There were no differences in PO2 (146±50 vs 84±44), PGE2 concentrations or DA resistance. However, there was a significantly larger shunt through the DA in treated lambs (Q shunt/syst=.70±.14 vs .25±10). This increased DA shunt was due to the significant drop in pulmonary vascular resistance (RP/RS=.47±.08 vs .76±.08) and not to a change in patency of the DA. Surfactant replacement may require interventions directed at the PDA to adequately treated sick preterm infants.

PROSTAGLANDIN E-1 (PGE-1) &amp; PULMONARY VASCULAR RESIS- TANCE IN NEONATAL LAMBS

PGE-1, a known pulmonary vasodilator in isolated lungs, has been proposed as a mediator of the rapid fall in pulmonary vascular resistance (PVR) in neonates. A previous study found that in fetal animals a 50% drop in PVR was accompained by severe systemic effects including a 44% drop in placental flow. To exclude such effects we studied chronic PGE-1 infusion directly into the pulmonary circulation of 7 neonatal lambs. Animals were instrumented in utero under maternal anesthesia. Peripheral arterial and venous catheters were placed. Thoracotomy was performed with placement of a pulmonary arterial catheter and a pulmonary trunk electromagnetic flow transducer. The ductus was ligated, the animal delivered, and mechanical ventilation instituted. Systemic and pulmonary arterial pressures, pulmonary arterial flows, heart rate, and arterial blood gases were monitored. PVR was calculated before and during infusion under normoxemic and hypoxemic conditions. In 9 infusions in 7 animals, basal PVR was 0.225 mm/Hg/ml/min and rose to 0.521 with hypoxia. Basal systemic vascular resistance (SVR) was 0.534, and rose to 0.568 with hypoxia. With PGE-1 infusion at a mean dose of 1.6 mcg/kg/min PVR fell 27% to 0.185 in room air while SVR fell 25% to 0.400. Under hypoxic conditions PVR fell 49% to 0.264 while SVR fell 44% to 0.319. We conclude that PGE-1 is a nonspecific vasodilator which during infusion is not degraded in a single pass through the lungs. It decreases PVR and SVR equally during both normoxemia and hypoxemia.

The Pulmonary Blood Volume in Rheumatic Heart Disease and Its Alteration by Isoproterenol

Pulmonary blood volume was measured in five hemodynamically normal subjects and 37 patients with heart disease. Mean pulmonary blood volume in 25 of these patients with moderate to severe mitral stenosis, alone or complicated by other valvular lesions, was 359 ml. per M.2 (SE = +/-24 ml. per M.2), which was significantly higher than the average value of 230 ml. per M.2 (SE = +/-14 ml. per M.2) in the five normal subjects (p < 0.025). Multiple correlation of pulmonary blood volume with left atrial mean pressure, pulmonary vascular resistance, and stroke volume showed that each of these factors was significantly related to pulmonary blood volume, independently of the others. Increased left atrial pressure or stroke volume was associated with relatively high, and increased pulmonary vascular resistance with relatively low pulmonary blood volume. In seven subjects 10 to 20 mg. of isoproterenol administered sublingually led to a marked increase in pulmonary blood volume and a small decrease in pulmonary vascular resistance. The average increase in pulmonary blood volume was 78 ml. per M.2, or 35 per cent of the control value (SE = +/-15 ml. per M.2), while the average drop in pulmonary vascular resistance was 1.3 R.U.M.2 (SE = +/-0.5 R.U.M.2). Since the change in volume was too large to be accounted for by arteriolar dilatation alone, and there was a simultaneous decrease in pulmonary arterial and left atrial pressures, isoproterenol apparently increased the distensibility of a large but as yet unidentified segment of the pulmonary vascular bed.