Pediatric myocardial infarction after racemic epinephrine administration.

Myocardial infarction is a previously unreported complication of treatment with racemic epinephrine that is used commonly in the emergency department for severe respiratory distress in bronchiolitis or croup syndrome. We describe a pediatric patient who presented with the croup syndrome and severe respiratory distress that required multiple doses of nebulized racemic epinephrine in the emergency department. The patient developed ventricular tachycardia and mild chest discomfort during one treatment, which resolved spontaneously on discontinuation of the nebulization. Persistently abnormal electrocardiograms and elevated creatine phosphokinase MB isoenzyme (CPK-MB) levels suggested a myocardial infarction had occurred. Subsequent echocardiography, cardiac catheterization, and angiography revealed an anatomically normal heart with normal coronary circulation; however, a stress nuclear study showed a small myocardial infarct. The significance of this previously unreported complication of racemic epinephrine is discussed, along with recommendations for proper use in the emergency department.

Effects of dipyridamole and inhaled nitric oxide in pediatric patients with pulmonary hypertension.

Inhaled nitric oxide (iNO) causes selective pulmonary vasodilation by increasing pulmonary vascular levels of cyclic guanosine monophosphate (cGMP). Dipyridamole, a drug with several putative vasodilator mechanisms, is an inhibitor of cGMP-specific phosphodiesterases (PDE5); it therefore has the potential to increase pulmonary vascular cGMP levels, lower pulmonary vascular resistance, augment iNO-induced pulmonary vasodilation, and attenuate excessive pulmonary vasoreactivity. To test dipyridamole in the pulmonary circulation, we studied pediatric patients undergoing cardiac catheterization who had severe resting pulmonary hypertension (Group 1; n = 11) or exaggerated acute hypoxia-induced pulmonary vasoconstriction (Group 2; n = 4). In Group 1, we compared the effects of iNO (20 ppm), dipyridamole (0.6 mg/kg), and combined treatments (iNO + dipyridamole) on pulmonary and systemic hemodynamics. In Group 2 we measured the pulmonary and systemic effects of dipyridamole while the patients were breathing room air and hypoxic gas mixtures (FIO2 = 0.16). One patient in Group 1 had a hypotensive response to dipyridamole and was exluded from study. In the remaining 12 studies done on 10 patients, iNO caused a selective decrease in mean pulmonary artery pressure (Ppa) and indexed pulmonary vascular resistance (PVRI) without affecting mean aortic pressure (Pao) or indexed systemic vascular resistance (SVRI). Dipyridamole decreased PVRI to similar values as did iNO, but this effect was primarily due to an increase in cardiac index (CI), and was not associated with any change in Ppa, and was associated with a decrease in Pao and SVRI. In comparison with individual treatments, combined therapy (iNO + dipyridamole) did not augment pulmonary vasodilation in the group as a whole; however, in 50% of patients, combined therapy decreased PVRI by 20% more than did iNO or dipyridamole alone. In Group 2, Ppa and the pulmonary-to-systemic resistance ratio (Rp/Rs) increased to suprasystemic levels during acute hypoxia. Pretreatment with dipyridamole blunted the increase in Ppa and Rp/Rs during repeat hypoxia, keeping Ppa at a subsystemic level and Rp/Rs < 1. We conclude that: (1) dipyridamole nonselectively reduces PVRI, primarily through an increase in CI; (2) in combination with iNO, dipyridamole augments the decrease in PVRI in some patients; and (3) dipyridamole blunts the severity of acute hypoxic pulmonary vasoconstriction in children with exaggerated hypoxic pressor responses.

Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity.

An experimental ovine fetal model for perinatal pulmonary hypertension of the neonate (PPHN) was characterized by altered pulmonary vasoreactivity and structure. Because past studies had suggested impaired nitric oxide-cGMP cascade in this experimental model, we hypothesized that elevated phosphodiesterase (PDE) activity may contribute to altered vascular reactivity and structure in experimental PPHN. Therefore, we studied the effects of the PDE inhibitors zaprinast and dipyridamole on fetal pulmonary vascular resistance and PDE5 activity, protein, mRNA, and localization in normal and pulmonary hypertensive fetal lambs. Infusion of dipyridamole and zaprinast lowered pulmonary vascular resistance by 55 and 35%, respectively, in hypertensive animals. In comparison with control animals, lung cGMP PDE activity was elevated in hypertensive fetal lambs (150%). Increased PDE5 activity was not associated with either an increased PDE5 protein or mRNA level. Immunocytochemistry demonstrated that PDE5 was localized to vascular smooth muscle. We concluded that PDE5 activity was increased in experimental PPHN, possibly by posttranslational phosphorylation. We speculated that these increases in cGMP PDE activity contributed to altered pulmonary vasoreactivity in experimental perinatal pulmonary hypertension.

Dipyridamole potentiates pulmonary vasodilation induced by acetylcholine and nitric oxide in the ovine fetus.

Nitric oxide (NO) modulates pulmonary vascular resistance (PVR) in the normal fetus by increasing the cyclic guanosine 3',5'-monophosphate (cGMP) content of pulmonary vascular smooth muscle cells. Although several vasodilator stimuli, including acetylcholine, decrease fetal PVR through the release of endogenous NO, fetal pulmonary vasodilation is often transient despite prolonged treatment. Because cGMP is hydrolyzed and inactivated by cGMP-specific (type 5) phosphodiesterases (PDE5), we hypothesized that PDE5 activity contributes to high fetal PVR and limits the capability of the fetal pulmonary circulation to dilate or sustain vasodilation in response to cGMP-dependent stimuli. To test this hypothesis, we studied the hemodynamic effects of dipyridamole in 19 late-gestation fetal lambs. To determine whether dipyridamole-induced vasodilation is dependent upon basal NO release, we measured the response to dipyridamole before and after pretreatment with the NO synthase antagonist nitro-L-arginine (L-NA) in five fetal lambs. L-NA completely blocked dipyridamole-induced pulmonary vasodilation. To evaluate the effect of dipyridamole on pulmonary vasodilation due to the stimulated release of NO, we studied effects of prolonged intrapulmonary acetylcholine infusions, with and without concomitant administration of low-dose dipyridamole, in six fetal lambs. During prolonged (2-h) infusions, acetylcholine and dipyridamole individually caused transient pulmonary vasodilation. When administered together, pulmonary vasodilation was of greater magnitude and was sustained for the entire study period. To determine the effects of dipyridamole on endothelium-independent pulmonary vasodilation, we investigated the hemodynamic effects of inhaled NO (5 and 20 ppm) alone and in combination with dipyridamole during mechanical ventilation with low FlO2. The combination of dipyridamole with inhaled NO resulted in a greater degree of pulmonary vasodilation than that achieved with inhaled NO alone. We conclude that dipyridamole-induced pulmonary vasodilation is dependent on endogenous (basal) NO production and that dipyridamole potentiates vasodilator responses to endothelium-dependent and -independent dilators in the ovine fetal pulmonary circulation. We speculate that PDES activity opposes vasodilation and maintains high PVR in the normal fetal lung.

Dipyridamole attenuates rebound pulmonary hypertension after inhaled nitric oxide withdrawal in postoperative congenital heart disease.

OBJECTIVE: Inhaled nitric oxide therapy causes selective and sustained pulmonary vasodilation in patients with pulmonary hypertension; however, attempts to discontinue inhaled nitric oxide therapy may be complicated by abrupt life-threatening events. Dipyridamole, a cyclic guanosine monophosphate-specific phosphodiesterase inhibitor, blocks the hydrolysis of cyclic guanosine monophosphate in vascular smooth muscle cells. METHODS: We studied 23 consecutive children who were treated with inhaled nitric oxide because of clinically significant pulmonary hypertension after surgery for congenital heart disease. Inhaled nitric oxide therapy was withdrawn before and after dipyridamole treatment of children in whom sustained elevations of pulmonary artery pressure developed for over 30 minutes. RESULTS: In 7 of 23 children, inhaled nitric oxide withdrawal caused a 40% increase in pulmonary artery pressure, a 17% decrease in systemic venous oxygen saturation, and a 46% increase in the ratio of mean pulmonary artery pressure to aortic pressure. Compared with children who had no significant increase in pulmonary artery pressure, children who experienced the development of prolonged pulmonary hypertension after inhaled nitric oxide therapy withdrawal had higher mean pulmonary artery pressure immediately before inhaled nitric oxide withdrawal (22 +/- 1 mm Hg versus 27 +/- 2 mm Hg; p = 0.04) and received inhaled nitric oxide for a longer duration (2 +/- 1 days versus 4 +/- 1 days; p = 0.01). Dipyridamole therapy attenuated the rise in pulmonary artery pressure and fall in systemic venous oxygen saturation in all six patients studied with rebound pulmonary hypertension after withdrawal of inhaled nitric oxide. CONCLUSION: We conclude that dipyridamole therapy acutely attenuates the adverse hemodynamic effects of rapid withdrawal of inhaled nitric oxide therapy. Children with higher pulmonary artery pressure and who are treated with inhaled nitric oxide for a longer duration may be at increased risk for adverse hemodynamic effects of inhaled nitric oxide therapy withdrawal. We speculate that dipyridamole therapy may sustain elevations of smooth muscle cyclic guanosine monophosphate induced by inhaled nitric oxide and that phosphodiesterase activity contributes to acute pulmonary hypertension after inhaled nitric oxide withdrawal.

Prolonged endothelin A receptor blockade attenuates chronic pulmonary hypertension in the ovine fetus.

Based on past studies of an experimental model of severe intrauterine pulmonary hypertension, we hypothesized that endothelin-1 (ET-1) contributes to high pulmonary vascular resistance (PVR), hypertensive lung structural changes, and right ventricular hypertrophy (RVH) caused by prolonged closure of the ductus arteriosus. To test this hypothesis, we studied the effects of BQ 123, a selective ET(A) receptor antagonist, after ligation of the ductus arteriosus in utero. In 19 late gestation fetal lambs (126+/-3 d; 147 d, term) we ligated the ductus arteriosus at surgery, and treated animals with either BQ 123 (1 mg/d) or vehicle (0.1% DMSO, HTN) in the pulmonary artery for 8 d. Chronic BQ 123 treatment attenuated the rise in mean pulmonary artery pressure (PAP) 8 d after ductus arteriosus ligation (78+/-2, HTN vs. 70+/-4 mmHg, BQ 123, P < 0.05). To study the effects of ET(A) blockade at birth, 15 animals were delivered by cesarean section and ventilated with 10% oxygen (O2), 100% O2 and inhaled nitric oxide (NO). Lambs treated with BQ 123 had lower PVR after delivery during ventilation with 10% O2, 100% O2, and inhaled NO (HTN vs. BQ 123, P < 0.05 for each intervention). Acute BQ 123 treatment (2 mg/30 min) lowered PVR in three HTN animals ventilated with 100% O2 and inhaled NO (P < 0.05). Chronic BQ 123 treatment prevented the development of RVH as determined by the ratio of the right ventricle/left ventricle + septum (0.79+/-0.03, HTN vs. 0.57+/-0.06, BQ 123, P < 0.05) and attenuated the increase in wall thickness of small pulmonary arteries (61+/-2, HTN vs. 50+/-2%, BQ 123, P < 0.05). In summary, chronic intrauterine ET(A) receptor blockade decreased PAP in utero, decreased RVH and distal muscularization of small pulmonary arteries, and increased the fall in PVR at delivery. We conclude that ET(A) receptor stimulation contributes to the pathogenesis and pathophysiology of experimental perinatal pulmonary hypertension.

Role of nitric oxide and cGMP system in regulation of ductus arteriosus tone in ovine fetus.

Although endogenous nitric oxide (NO) modulates basal tone in the fetal pulmonary and systemic circulations, little is known about its role in regulating ductus arteriosus (DA) tone. Immunostaining of DA tissue from late-gestation fetal lambs demonstrated strong staining for endothelial NO synthase (eNOS) in DA endothelium. To study the physiological role of the NO and guanosine 3',5'-cyclic monophosphate (cGMP) system in the DA in vivo, we measured the hemodynamic effects of NG-nitro-L-arginine (L-NNA; 30 mg), a NOS inhibitor, methylene blue (40 mg), a guanylate cyclase inhibitor, and indomethacin (0.8 mg), a cyclooxygenase inhibitor, in 10 chronically prepared late-gestation fetal lambs. L-NNA increased main pulmonary artery (MPA) and aortic pressures (P < 0.05 vs. baseline) but did not change the pressure gradient between the MPA and the aorta. L-NNA caused a small decrease in DA flow and a slight rise in resistance across the DA. Methylene blue increased both MPA pressure and the pressure gradient between the MPA and the aorta from 0.3 +/- 0.2 (baseline) to 7.0 +/- 2.7 mmHg (P < 0.05). Indomethacin increased both MPA pressure and the pressure gradient between the MPA and the aorta from 1.1 +/- 0.4 (baseline) to 6.3 +/- 1.5 mmHg (P < 0.05) after 40 min. Indomethacin decreased DA flow and increased DA resistance. We conclude that eNOS is in fetal DA endothelial cells and that NOS inhibition causes constriction of the DA in vivo. DA constriction after NOS inhibition is minimal, especially in comparison with cyclooxygenase inhibition. Methylene blue also constricts the DA, suggesting that guanylate cyclase activity contributes to DA relaxation. We speculate that, although the NO and cGMP system modulates DA tone, prostaglandins may play a greater role.

Chronic intrauterine pulmonary hypertension alters endothelin receptor activity in the ovine fetal lung.

Although endothelin (ET) contributes to the regulation of pulmonary vascular tone in the normal fetus, little is known about its role in pulmonary hypertension in the perinatal period. To examine the role of the ETB receptor in the normal ovine fetal lung, we studied the hemodynamic effects of ET-3 (a selective ETB receptor agonist) before and after RES-701 (a selective ETB receptor antagonist). RES-701 (10 mu g/min for 10 min) did not change basal pulmonary tone and blocked pulmonary vasodilation to ET-3 (500 ng/min for 10 min). To examine the effects of experimental perinatal pulmonary hypertension on activity of the ETA and ETB receptors, we studied the hemodynamic effects of ET-3, ET-1 (a nonselective ETA and ETB receptor agonist), and BQ 123 (a selective ETA receptor antagonist) in 12 chronically prepared late gestation fetal lambs after partial ligation of the ductus arteriosus. Serial changes in the pulmonary vascular effects of these agents were measured early (1-3 d) and late (7-10 d) after partial ductus arteriosus ligation. Left lung total pulmonary resistance in the normal late-gestation fetus was 0.62 +/- 0.01 mm Hg/ml/min (n = 4). After partial ductus arteriosus ligation, total pulmonary resistance increased to 1.2 +/- 0.3 (early; p < 0.05 versus normal), and progressively rose to 1.9 +/- 0.2 mm Hg/ml/min (late; p < 0.05 versus early). Intrapulmonary infusion of ET-3 (500 ng/min for 10 min) increased pulmonary blood flow from 94 +/- 11 to 183 +/- 17 mL/min in the normal fetus, but had no effect during late pulmonary hypertension. Infusions of ET-1 (50 ng/min for 30 min) caused transient pulmonary vasodilation followed by vasoconstriction during early pulmonary hypertension. During late pulmonary hypertension, however, infusion of ET-1 caused predominantly vasoconstriction. Pulmonary vasodilation to BQ 123 (100 mu g/min for 10 min) was greater during late than early pulmonary hypertension (43 versus 21%; p < 0.05). After 10 d of ductus arteriosus ligation, immunoreactive ET-1 content in whole lung tissue was 3-fold higher in hypertensive (n = 7) than control (n = 10) lungs (p < 0.05). We conclude that the ETB receptor contributes little to regulation of basal vascular tone in the normal ovine fetal lung and that chronic intrauterine pulmonary hypertension causes the loss of ETB-mediated vasodilation, progressive ETA-mediated vasoconstriction, and increased lung ET-1 content. We speculate that diminished ETB receptor-mediated vasodilation in combination with enhanced ETA receptor-mediated vasoconstriction and increased ET-1 production contributes to high pulmonary vascular resistance in perinatal pulmonary hypertension.

Dipyridamole, a cGMP phosphodiesterase inhibitor, causes pulmonary vasodilation in the ovine fetus.

Endogenous nitric oxide (NO) modulates fetal pulmonary vascular tone by stimulating guanosine 3',5'-cyclic monophosphate (cGMP) production in vascular smooth muscle. Because cGMP is hydrolyzed and inactivated by phosphodiesterase enzymes, we evaluated the hemodynamic effects of two cGMP-specific phosphodiesterase (PDE5) inhibitors, dipyridamole and zaprinast, in the near-term chronically prepared ovine fetus. Brief (10 min) intrapulmonary infusions of dipyridamole caused dose-dependent increases in left pulmonary artery flow and decreases in left pulmonary arterial resistance that persisted for > 40 min after termination of the infusion. Prolonged (2 h) infusions of dipyridamole caused sustained pulmonary vasodilation throughout the infusion period. To compare the hemodynamic effects of dipyridamole with the PDE5 antagonist zaprinast, we studied the responses to equimolar doses of both agents in four fetuses. Zaprinast caused dose-dependent pulmonary vasodilation that was equivalent to that noted with equimolar doses of dipyridamole. To determine whether adenosine is involved with dipyridamole-induced pulmonary vasodilation, we compared the hemodynamic response to dipyridamole before and after administration of the potent adenosine receptor (P1) antagonist 8-phenyltheophylline (8-PT). Pretreatment with 8-PT markedly attenuated adenosine-induced pulmonary vasodilation but had no effect on the hemodynamic response to dipyridamole. We conclude that cGMP-specific phosphodiesterase activity is important in regulating fetal pulmonary vascular tone. In addition, dipyridamole administration causes dose-dependent pulmonary vasodilation that is equivalent to zaprinast and not primarily due to its effects on adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of nitric oxide, endothelin, and prostaglandins in the transition of the pulmonary circulation.

This review emphasizes the importance of three endothelial-derived products in regulating fetal and transitional pulmonary vascular tone. Although the pathophysiologic events that culminate in PPHN are poorly understood, it is likely that endothelial cell dysfunction, with an alteration in the normal "balance" of endothelial-derived mediators, is a contributing factor. In addition to the three vasoactive mediators described herein, several other neurohumoral agents influence fetal and transitional pulmonary vascular tone. In addition, structural changes in the pulmonary circulation, with abnormal proliferation of smooth muscle and extracellular matrix components, also contribute to failure of normal postnatal adaptation. Continued research is necessary to better define the complex interactions that result in the normal transition from the fetal to the postnatal state. Continued advances in the understanding of the normal transition will allow a more rational approach to management of the failed transition reflected in the disease state, PPHN.

Estimation of liquid-vapor critical loci for CO2-solvent mixtures using a peak-shape method.

Critical-mixture curves for 13 CO2-solvent binary mixtures were estimated using the peak-shape method. Mixture critical points were determined within 1 degrees C and 1 atm. The results for CO2-toluene and CO2-methanol were compared to previously reported data from high-pressure view cell studies. No more than a 3% difference was observed in the data generated by the two different techniques. A few abnormalities encountered while using the peak-shape method are also discussed.

Direct percutaneous transluminal coronary angioplasty for patients with exclusions from thrombolysis.

Direct percutaneous transluminal coronary angioplasty (PTCA) is a recognized alternative to intravenous thrombolytic therapy for early acute myocardial infarction (AMI). Fewer than one half of patients with AMI are candidates for thrombolytic therapy. We reviewed the records of 251 patients with the discharge diagnosis of AMI to determine the number of patients ineligible for thrombolysis who might be treatable with reperfusion methods other than intravenous thrombolysis. Forty percent of the patients (n = 101) were first seen within 6 hours and 51% (n = 128) were first seen within 12 hours of symptom onset. One third of the patients (n = 83) had no clear symptom at the time of initial examination. Exclusion criteria for intravenous thrombolysis were present in 187 of 251 patients (75%). Exclusion criteria for thrombolytic therapy included ECG ineligibility (n = 133), chest pain for more than 6 hours (n = 67), and age over 75 years (n = 64), comprising 79% of all exclusions. Of those first seen within 6 hours of symptom onset, 43 of 101 patients (43%) had an ineligible ECG, and 13 of 101 (13%) had age over 75 as exclusion criteria for thrombolysis. Forty-eight of 251 patients (19%) received intravenous thrombolysis. After early coronary angiography, intracoronary thrombolysis, direct PTCA, and emergency coronary artery bypass grafting were used in an additional 30 patients. The use of other forms of reperfusion therapy increased the number of patients treated early to 70 of 251 (28%) (p = 0.03). The use of a variety of forms of reperfusion therapy substantially increases the number of patients treated early compared with sole use of intravenous thrombolysis.(ABSTRACT TRUNCATED AT 250 WORDS)