[Pulmonary hypertension of the newborn--recent advances in the management and treatment].

Pulmonary hypertension of the newborn is a clinical syndrome with diverse etiology in which the transition from fetal circulation with high pulmonary vascular resistance to postnatal circulation with low pulmonary vascular resistance failed. The persistence of high pulmonary vascular pressure leads to right-left shunts and marked cyanosis. Despite of the advances in neonatology, the treatment of some forms of PPHN is often difficult and mortality rate remains high. In infants with PPHN appropriate interventions are critical to reverse hypoxemia, improve pulmonary and systemic perfusion and preserve end-organ function. Our understanding for management of PPHN has evaluated over decades. This review summarizes the current strategies for treatment of pulmonary hypertension of the newborn: general care, cardiovascular support, the advantages and limitations of different ventilatory strategies, oxygen therapy, extracorporal membrane oxygenation, and the evidence-based inhaled nitric oxide therapy. The balance between pulmonary vasoconstrictor and vasodilator mediators plays an important role for pulmonary vascular resistance. Recent studies are designed to develop evidence-based therapies for regulation of pulmonary vascular tone, safe medications for selective pulmonary vasodilatation effective for treatment of PPHN and other forms of pulmonary hypertension in the neonatal intensive care unit.

Persistent pulmonary hypertension of the newborn: pathogenesis, etiology, and management.

Persistent pulmonary hypertension of the newborn (PPHN) is characterized by severe hypoxemia shortly after birth, absence of cyanotic congenital heart disease, marked pulmonary hypertension, and vasoreactivity with extrapulmonary right-to-left shunting of blood across the ductus arteriosus and/or foramen ovale. In utero, a number of factors determine the normally high vascular resistance in the fetal pulmonary circulation, which results in a higher pulmonary compared with systemic vascular pressure. However, abnormal conditions may arise antenatally, during, or soon after birth resulting in the failure of the pulmonary vascular resistance to normally decrease as the circulation evolves from a fetal to a postnatal state. This results in cyanosis due to right-to-left shunting of blood across normally existing cardiovascular channels (foramen ovale or ductus arteriosus) secondary to high pulmonary versus systemic pressure. The diagnosis is made by characteristic lability in oxygenation of the infant, echocardiographic evidence of increased pulmonary pressure, with demonstrable shunts across the ductus arteriosus or foramen ovale, and the absence of cyanotic heart disease lesions. Management of the disease includes treatment of underlying causes, sedation and analgesia, maintenance of adequate systemic blood pressure, and ventilator and pharmacologic measures to increase pulmonary vasodilatation, decrease pulmonary vascular resistance, increase blood and tissue oxygenation, and normalize blood pH. Inhaled nitric oxide has been one of the latest measures to successfully treat PPHN and significantly reduce the need for extracorporeal membrane oxygenation.

Pulmonary hypertension in the newborn.

Pulmonary hypertension of the newborn occurs in 1.9 per 1000 live births and affected infants are hypoxaemic because of right-to-left shunts through the ductus arteriosus and foramen ovale. Pulmonary hypertension of the newborn may be primary, or secondary to a variety of conditions including intrapartum asphyxia, infection, pulmonary hypoplasia, congenital heart disease or drug therapy. It may occur in association with a normal number (maladaptation) or a decreased number of arteries (for example with pulmonary hypoplasia). Few strategies used in infants with pulmonary hypertension of the newborn have been subjected to rigorous evaluation. Inhaled nitric oxide has been shown to reduce the need for extracorporeal membrane oxygenation but not mortality, in term or near term born infants. Preliminary evidence suggests that other vasodilators given by the inhaled route may improve oxygenation and new vasodilators have become available; appropriately designed trials with long-term outcomes are required to test such therapies.

Clinically diagnosed nonocclusive mesenteric ischemia after cardiopulmonary bypass: retrospective study.

This retrospective study evaluates our experience with clinically diagnosed nonocclusive mesenteric ischemia after cardiopulmonary bypass. Twenty-three of 3,600 consecutive patients suffered from splanchnic malperfusion. Symptoms developed between day 2 and 6 postoperatively in 18 of 23 patients. Four of 23 patients had no abdominal symptoms. Laboratory evaluation revealed significantly higher serum lactate and creatine phosphokinase levels in the 18 symptomatic patients compared with those of a control group. Arteriography was performed in 20 cases and revealed nonocclusive splanchnic hypoperfusion. Risk factors for development of mesenteric ischemia include arrhythmias and low cardiac output. Patients with angiographically proven nonocclusive mesenteric ischemia were treated with intra-arterial bolus injection and subsequent intra-arterial infusion of tolazoline combined with heparin sodium. The overall mortality rate was 30% (7 of 23). Infusion therapy with tolazoline and heparin seems to be a successful treatment modality for clinically diagnosed mesenteric ischemia.

Efficacy and safety of tolazoline for treatment of severe hypoxemia in extremely preterm infants.

OBJECTIVE: To determine the efficacy of tolazoline as a rescue treatment for hypoxemia in preterm infants with respiratory distress syndrome. METHODS: Retrospective chart review on case series of infants weighing < 750 g at birth who received tolazoline during a severe hypoxemic episode while receiving maximal ventilator support for respiratory distress syndrome. A slow bolus infusion of low dose tolazoline (0.5 mg-2 mg/kg) mixed with plasmanate or normal saline (10 mL/kg) was administered. Outcome measures evaluated included an increase in PaO(2) > or =20 mm Hg from pretreatment value and an increase in oxygen saturation to > or =90%. RESULTS: Forty-three infants with a mean gestational age and birth weight of 24 weeks and 581 g, respectively, received tolazoline. All infants were mechanically ventilated and required a fraction of inspired oxygen of 1.0. Oxygenation improved in 72% (31/43) of infants with a tolazoline dose of 0.5 to 1.0 mg/kg. Of those who responded, PaO(2) values (mean +/- standard deviation) pretolazoline and posttolazoline were 32 +/- 7.5 mm Hg and 156 +/- 114.9 mm Hg, respectively. In all responders, oxygen saturation increased to > or =90% within 30 minutes of tolazoline administration. Improvement in pH, pCO(2), oxygenation index, and mean airway pressure was also noted. Among nonresponders, pH decreased and pCO(2) increased after tolazoline. Minimal change in blood pressure was noted in both responders and nonresponders. Heart rate decreased by 19 beats per minute among nonresponders compared with an increase of 3 beats per minute in those who responded to tolazoline. CONCLUSION: Tolazoline is an effective treatment of severe resistant hypoxemia in preterm infants who are already on vigorous ventilatory support.

Persistent pulmonary hypertension of the newborn: experience in a single institution.

Persistent pulmonary hypertension of the newborn (PPHN) remains one of the most challenging situations in the neonatal intensive care unit, and it is associated with high mortality and morbidity. The optimal treatment for PPHN is controversial. We report our 9-year experience in the management of PPHN through a retrospective review of 29 neonates with persistent pulmonary hypertension. The diagnosis of PPHN is made by echocardiography and/or preductal and postductal oxygen tension difference. The treatment modalities include supportive medical care, vasodilator therapy, mechanical ventilation and correction of underlying conditions. The wide diversity of etiologies of PPHN, the complications of vasodilator therapy, the management of assisted ventilation, the mortality and the morbidity are evaluated. There are 29 patients enrolled in this study, including 18 male and 11 female babies. Twenty-two patients (72%) are referred from other hospitals. The mean birth body weight is 2707 +/- 693 grams (range: 1450-4100 grams) and the mean gestational age is 37.1 +/- 3.1 weeks (range: 31-41 weeks). The underlying clinical conditions include meconium aspiration syndrome (n = 8), perinatal asphyxia (n = 7), respiratory distress syndrome (n = 5), sepsis and/or pneumonia (n = 4), congenital diaphragmatic hernia (n = 3) and idiopathic persistent fetal circulation (n = 2). In addition to supportive medical care and correction of underlying clinical conditions, most of the patients receive vasodilator therapy (Tolazoline) and nonhyperventilation respirator management. The overall mortality rate is 27.6% (8/29). The duration on ventilator therapy in the survival group (9.3 +/- 8.6 days) is not significantly different from in the mortality group (6.0 +/- 7.1 days) (p = 0.13). There is also no statistically significant difference between these two groups both in the maximal alveolar-arterial oxygen tension difference (594 +/- 53 mmHg and 613 +/- 37 mmHg, p = 0.145) and in the maximal oxygenation index (49.7 +/- 29.6 and 61.1 +/- 36.9, p = 0.172) before vasodilator therapy. However, twenty-four hours after treatment, these two parameters change significantly with the former changes to 426 +/- 198 mmHg and 643 +/- 7 mmHg, respectively (p < 0.001), and the latter changes to 21.6 +/- 15.8 and 82.3 +/- 54.8, respectively (p < 0.001). Skin rash, gastrointestinal hemorrhage, hypotension and hyponatremia are the most common complications of Tolazoline therapy. Eight patients have pulmonary complications including pneumothorax (n = 5) and pulmonary interstitial emphysema (n = 3). Two patients develop chronic lung disease. Three patients have neurodevelopmental handicap. In conclusion, we achieve a survival rate of nearly 75% in PPHN mainly with the administration of Tolazoline therapy and the nonhyperventilation respirator approach. Further well-controlled and multicenter studies with newer treatment modalities are crucial for the improvement of survival of PPHN in Taiwan.

Aggressive systematic treatment for central retinal artery occlusion.

PURPOSE: To report the efficacy of an aggressive systematic regimen for the treatment of acute nonarteritic central retinal artery occlusion (CRAO). METHODS: Eleven patients who had unilateral CRAO with symptoms of fewer than 48 hours' duration were treated with an aggressive stepwise systematic regimen until retinal circulation improved or until all the treatment steps were performed. Five patients with unilateral CRAO and symptoms of fewer than 48 hours' duration were treated in the same institution in an arbitrary nonsystematic manner. The therapeutic steps of the aggressive treatment included ocular massage, sublingual isosorbide dinitrate, intravenous acetazolamide, intravenous mannitol or oral glycerol, anterior chamber paracentesis, intravenous methylprednisolone followed by streptokinase, and retrobulbar tolazoline. After each step, retinal flow was evaluated by three-mirror contact lens. The nonsystematic treatment was arbitrary and included one or several of the above. Visual acuity and complete eye examination data were recorded before and after treatment. RESULTS: Visual acuity and retinal arterial supply were improved in eight (73%) of the 11 patients treated in the stepwise systematic manner. All eight patients in whom visual acuity improved had symptoms for fewer than 12 hours, and the presumed cause was either platelet-derived or cholesterol embolus from atheroma or the patients had glaucoma. Patients in whom visual acuity did not improve had CRAO that was attributed to calcified emboli or primary antiphospholipid antibody syndrome and had symptoms more than 12 hours before treatment. Visual acuity did not improve in all five patients with the nonsystematic treatment regardless of the presumed cause or duration of the occlusion. The success of the treatment in the systematic treatment group was statistically significantly better compared with the outcome of the nonsystematic treated group (Fischer exact test, P = .01). CONCLUSIONS: In the treatment of CRAO, an aggressive systematic regimen including medical and mechanical means may reestablish retinal circulation and improve visual outcome. The cause of arterial occlusion, the nature of occlusive emboli, and the duration of retinal ischemia may determine the visual outcome, but a larger series is warranted to verify the effectiveness of the treatment and the prognostic factors.

Cerebral blood flow during treatment for pulmonary hypertension.

AIM: To determine if the haemodynamics of systemic and cerebral circulation are changed during treatment for persistent pulmonary hypertension of the newborn (PPHN). METHODS: Fifteen term newborn piglets with hypoxia induced pulmonary hypertension were randomly assigned either tolazoline infusion (Tz), hyperventilation alkalosis(HAT), and inhaled nitric oxide (iNO). Mean pulmonary arterial pressure (PAP), mean systemic arterial pressure (SAP), and cerebral blood flow volume (CBF) were measured. RESULTS: During hypoxic breathing, PAP increased significantly in all groups. After treatment PAP decreased significantly in all groups, but no significant difference was observed between groups. SAP decreased significantly only in the Tz group, and CBF reduced significantly only in the HAT group. On the other hand, iNO did not change SAP or CBF. CONCLUSION: Inhaled NO might be ideal for the resolution of pulmonary hypertension.

Limb-threatening lower extremity ischemia successfully treated with intra-arterial infusion--case reports.

The authors present two patients with acute arterial vasospasm of the lower extremities causing marked ischemia. One patient had a history of Raynaud's disease, the second had been taking Cafergot for migraine headaches. Both patients's were given a test dose of intra-arterial tolazoline (50 mg). The patient with Raynaud's disease demonstrated marked improvement diffusely and was successfully treated with overnight infusion of papaverine. The second patient, taking Cafergot, demonstrated no angiographic response to tolazoline. It was speculated that the arteries of this patient were thrombosed. The patient was successfully treated with urokinase and remained free of pain at the 15-month follow-up.

Isquemia intestinal por bajo flujo esplácnico / Low flow splachnic intestinal ischemia

El déficit circulatorio de este cuadro se ubica en la microcirculación intestinal por fallo de bomba, shock o uso de digital. Dolor abdominal repentino, distensión, enterorragia y los antecedentes llevan a la sospecha clínica y al diagnóstico. El tratamiento es en principio médico, con el esquema de Boley (Tolazolina y Papaverina), controlado por arteriografía; si no cede, el intestino necrótico debe ser removido quirúrgicamente. Material y Método: Se consideran 22 casos. Todos consultaron por dolor abdominal repentino, distensión y enterorragia. Sólo 3 carecían de antecedentes, los 19 restantes provenían de UTI, U.C., o tenían tratamiento con digital. Se utilizó el análisis univariable de variables cualitativas. Resultados: Se operaron 18 (81,8 por ciento), falleciendo sin operar 4 (18 por ciento). La mortalidad global fue de 15 (68,1 por ciento). Siete (31,8 por ciento) tuvieron buena evolución, ellos presentaron sólo lesiones de intestino delgado.

Acute effect of oral prostacyclin and inhaled nitric oxide on pulmonary hypertension in children.

The hemodynamic effects of acute oral administration of a newly-developed prostacyclin analogue (beraprost sodium; 1-2 micrograms/kg), inhaled nitric oxide (NO; 20 ppm) and tolazoline hydrochloride (1 mg/kg) were measured in 17 children (mean age 1 year and 9 months) with pulmonary hypertension complicating congenital heart disease or primary pulmonary hypertension. Beraprost, NO and tolazoline achieved approximately equivalent reductions in pulmonary vascular resistance (20%, 26% and 18%, p < 0.05), but the greatest percentage decrease of pulmonary to systemic resistance ratio was obtained after administration of NO (33%, p < 0.05). Furthermore, combined administration of beraprost and NO produced the maximum effect of pulmonary vasodilation without adverse effects (49%). Beraprost appears to be an effective and available substitute for NO and tolazoline in screening for pulmonary vasodilator responsiveness. The combined use of beraprost and NO may provide an alternative treatment for pulmonary hypertension in children without serious complications.

Endotracheal tolazoline administration in neonates with persistent pulmonary hypertension.

OBJECTIVES: Our purpose was to study the effectiveness of endotracheal tolazoline (ET-Tz) in the treatment of neonatal persistent pulmonary hypertension (PPHN). STUDY DESIGN: ET-Tz was administered to 12 neonates with a clinical diagnosis of PPHN. The gestational age ranged from 25 to 42 weeks, and the birth weights from 850 to 3612 gm. The dose of tolazoline ranged from 1 to 2.5 mg/kg. RESULTS: There was a significant increase (p < 0.005) in the mean levels of oxygen saturation and the arterial oxygen tension, and a significant decrease (p < 0.005) in the oxygenation index, between the pretolazoline and the posttolazoline groups, but arterial carbon dioxide tension did not change. After the initial analysis, the groups were subdivided into preterm and term subgroups, because we secondarily observed that the average changes from predose to postdose levels in the above parameters were significantly different (p < 0.001) in the two subgroups by Student's paired t test. CONCLUSIONS: The data indicate that ET-Tz is effective in improving oxygenation in neonates with PPHN, particularly sick preterm infants. The endotracheal route is preferred because it is devoid of significant side effects (e.g., hypotension and flushing). A randomized, controlled, double-blinded, multicenter trial for the use of ET-Tz in PPHN is warranted.

Use of tolazoline to counteract vasospasm in peripheral arterial catheters in neonates.

Arterial access for blood sampling and continuous blood pressure monitoring is the cornerstone of modern neonatal intensive care. Although umbilical arterial catheters have traditionally been utilized for arterial access, they are associated with potentially devastating complications. Consequently, there has been an increase in the use of peripheral arterial catheters. Unfortunately, these catheters have a limited useful lifespan secondary to vasospasm, intimal damage and/or thrombus formation. In this report, we describe the use of tolazoline (0.02 to 0.2 mg/kg/h) to counteract local arterial vasospasm in five critically ill neonates, where arterial access was vital for care but difficult to maintain.

Spasms of the hepatic artery following percutaneous transluminal angioplasty and tolazoline administration in a liver transplant patient.

Vascular complications after liver transplantation include occlusion or stenosis near the sites of anastomosis in the hepatic artery, portal vein, and vena cava. Balloon angioplasty of these stenoses carries little risk and is a useful procedure for the treatment of these problems. Here we describe the case of a liver transplant patient who underwent balloon angioplasty for stenosis of the hepatic artery and who developed spasms of the hepatic artery which were aggravated following intraarterial administration of Tolazoline.

Extracorporeal membrane oxygenation with veno-venous bypass and apneic oxygenation for treatment of severe neonatal respiratory failure.

Seven newborn infants with life-threatening respiratory failure were treated with veno-venous (V-V) extracorporeal lung support and apneic oxygenation after maximal ventilatory and pharmacological treatment failed. Diagnosis were meconium aspiration syndrome in 3 cases, respiratory distress syndrome in 2, sepsis in 1, congenital diaphragmatic hernia in 1. Before ECMO 6 infants received tolazoline, 4 surfactant, 3 high frequency ventilation, 1 prostaglandin E, 1 epoprostenol, 2 nitric oxide. Newborns were highly hypoxemic at admission and all but one underwent rescue cannulation. V-V bypass was performed with a single lumen single cannula and tidal flow was generated by an alternating clamp using a non-occlusive roller pump. The mean duration of bypass was 162.4 +/- 162.3 hours and infants were extubated 94.5 +/- 74.8 hours after decannulation. Five newborns survived and two died. Growth and neurologic development of the older children is normal. The extracorporeal lung support with V-V bypass associated with apneic oxygenation was effective in reversing severe neonatal respiratory failure unresponsive to maximal ventilatory and pharmacological support. An early referral, prior to meeting ECMO criteria, is important in order to avoid hypoxic complications preceding ECMO.

Pulmonary hypertension in respiratory distress syndrome.

Pulmonary hypertension was associated with nonresponse to surfactant in six premature infants with respiratory distress syndrome. The diagnosis was suspected on the basis of a discrepancy between the X-ray findings and the severity of the clinical status as reflected by hypoxia despite maximal ventilatory support. The diagnosis of pulmonary hypertension was made by pre- and postductal oxygen saturation differences or by echodoppler cardiography, showing suprasystemic right ventricular pressures or right to left shunts through a patent foramen ovale or the ductus arteriosus. The response to surfactant was quantified by the arterial/alveolar (a/A) ratio difference before and 1 hr after therapy ("delta a/A ratio"); the delta a/A ratio was 0 +/- 0.01, which indicates a nonresponse. A single dose of 1 mg/kg tolazoline was administrated and the response assessed by a/A difference. A delta a/A ratio of 0.11 +/- 0.11 (range 0.02-0.32) represented a dramatic response and enabled oxygenation in these severely ill infants. No significant side effects were observed. We conclude that pulmonary hypertension may be an important and reversible condition in certain cases of respiratory distress syndrome and has to be considered in infants who do not respond to surfactant.

Current management of congenital diaphragmatic hernia.

Infants born with congenital diaphragmatic hernia have a high mortality which is essentially due to the associated lung hypoplasia. However, there have been several recent innovations, both in the surgical approach and in techniques of neonatal intensive care, which have improved the outlook for some of these critically ill infants.

The role of alpha-adrenergic mechanisms within the area postrema in dopamine-induced emesis.

Intracerebroventricular injection of dopamine (0.5-4.0 mg) produced dose-dependent and short-lasting emesis (1-8 min) in cats, which was abolished after ablation of the area postrema. Relatively selective alpha 2-adrenoceptor antagonists (yohimbine and idazoxan) and a mixed alpha 1- and alpha 2-adrenoceptor antagonist (tolazoline), but not a non-selective alpha 1-adrenoceptor antagonist (prazosin), injected intracerebroventricularly inhibited the emesis induced by intracerebroventricular dopamine. However, dopamine receptor antagonists (chlorpromazine, droperidol, spiperone, domperidone, triflupromazine, sulpiride and metoclopramide), an antimuscarinic drug (atropine), a ganglionic blocking agent (mecamylamine), an opioid receptor antagonist (naloxone) and a 5-HT receptor antagonist (methysergide), all injected intracerebroventricularly, had no significant effect on emesis evoked by intracerebroventricular dopamine. The emetic response to intracerebroventricular dopamine was attenuated in cats pretreated with intracerebroventricular reserpine, 6-hydroxydopamine, alpha-methyl-p-tyrosine and hemicholinium-3. It is postulated that dopamine-induced emesis is mediated through the release of noradrenaline acting at alpha 2-adrenoceptors and that it depends on the integrity of monoaminergic and possibly cholinergic structures within the area postrema. It appears, therefore, that the emetic effect of intracerebroventricular dopamine is mediated by adrenergic rather than dopaminergic mechanisms in the area postrema, at least in the cat.