[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.

One- to three-year outcome for 14 neonatal survivors of extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation, using venoarterial or venovenous perfusion, is a safe and effective procedure in the term of near-term infant with life-threatening respiratory failure. Without extracorporeal membrane oxygenation, due to the severity of their disease, these children are at high risk for neurologic damage, chronic lung disease, and death. Because survival is not expected without extracorporeal membrane oxygenation therapy, there is no corresponding control group to which these survivors may be compared. In this report, we reviewed the outcome at 1 to 3 years in the first 14 survivors of extracorporeal membrane oxygenation treated at our institution. Seven of 14 neonatal extracorporeal membrane oxygenation survivors (50%) were normal or near normal at between 1 and 3 years of age. Ten (71%) had normal mental ability. We conclude that in neonates with high mortality risk from respiratory failure, near-normal growth and development can be expected in the majority who survive with extracorporeal membrane oxygenation treatment.

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.

Developmental follow-up of hyperventilated neonates: preliminary observations.

A group of 13 newborn infants greater than 37 weeks' gestation were selected to be hyperventilated because of severe hypoxemia refractory to conventional mechanical ventilation, ie, failure to maintain PaO2 greater than 50 torr with an FIO2 of 1.0, despite PaCO2 less than or equal to 40 torr and pH greater than or equal to 7.40. Eleven survived; nine were available for follow-up evaluations. As a group, the nine infants were exposed to a PaCO2 less than or equal to 20 torr for 51.8 +/- 11.8 (mean +/- SEM) hours, to PaCO2 less than or equal to 15 torr for 11.8 +/- 3.3 hours, to a pH greater than 7.50 for 64.4 +/- 18.6 hours, and to a pH greater than or equal to 7.60 for 6.1 +/- 2.9 hours. One infant was lost to follow-up after a normal assessment at nine months. the other eight infants (seven AGA, one markedly SGA) were at least 1 1/4 years old at the time of evaluation. The seven AGA infants had a normal developmental quotient (mean 110 [range 96-130] by Stanford-Binet or Bayley assessment); the one SGA infant had a Bayley score of 89. All eight had normal neurologic examinations. These preliminary findings are reassuring with respect to neurologic and developmental outcome following prolonged hyperventilation.

Management of infants with severe respiratory failure and persistence of the fetal circulation, without hyperventilation.

The successful management of 15 infants suffering from persistence of fetal pulmonary circulation and in severe respiratory failure is presented. The treatment regimen focused on minimizing barotrauma. Infants were intubated nasotracheally and ventilated with intermittent mandatory ventilation. Peak inspiratory pressures were determined by the clinical assessment of chest excursion. Ventilator settings and fractional inspiratory oxygen (FiO2) were selected to maintain a PaO2 between 50 and 70 mm Hg; PaCO2 was not a controlling parameter and was allowed to increase as high as 60 mm Hg. Hyperventilation and muscle relaxants were not used. High ventilator rate was used in ten infants who required high inspiratory pressure to maintain chest excursion, with a favorable response in five. Tolazoline was given to 14 infants of whom ten showed an improvement in oxygenation; dopamine was given to three infants who were oliguric. All infants survived, and only one infant developed chronic lung disease which was defined by the infant's need for supplemental oxygen beyond 30 days of life.

Endotracheal administration of tolazoline in hypoxia-induced pulmonary hypertension.

STUDY OBJECTIVE: To compare the pulmonary and systemic vascular responses to intravenously (IV) and endotracheally (ET) administered tolazoline (Tz) in newborn lambs with hypoxia-induced pulmonary hypertension. DESIGN: Randomized, controlled study design. METHODS: Twenty lambs, 2 to 7 days of age, were anesthetized, intubated, and surgically catheterized for continuous physiologic monitoring and cardiac output measurements using radiolabeled microspheres. After a postoperative stabilization period, the lambs were ventilated with a hypoxic gas mixture which was titrated to increase mean pulmonary artery pressure (MPAP) 30% to 50% above baseline. Each animal was randomly assigned to receive either IV-Tz (2 mg/kg), ET-Tz (4 mg/kg), or ET-saline (Sal, control group). RESULTS: ET-Tz significantly (P < .05) reduced MPAP, PVRI (pulmonary vascular resistance index), MPAP/mean artery pressure (MAP) and PVRI/systemic vascular resistance index (SVRI), but not SVRI. IV-Tz lowered (P < .05) MPAP, PVRI, and PVRI/SVRI but also produced significant reductions in MAP and SVRI while only transiently decreasing MPAP/MAP: MPAP/MAP and PVRI/SVRI ratios were consistently lower in the ET-Tz animals than either the IV-Tz or ET-Sal animals. CONCLUSIONS: Our results suggest that ET-Tz produced a more selective pulmonary vascular response than IV-Tz and may warrant further investigation for potential clinical applications.

Hypochloremic metabolic alkalosis following tolazoline-induced gastric hypersecretion.

Gastric hypersecretion following administration of tolazoline resulted in severe hypochloremic alkalosis in an infant with persistent fetal circulation. An initial bolus injection of 2 mg/kg was followed by an infusion of 5 mg/kg/hr for 24 hours. The infusion was then maintained at 2 mg/kg/hr for the next four days. Volume of gastric secretions exceeded 25 ml/kg/24 hr. Weaning from tolazoline and replacement of chloride and potassium corrected the metabolic alkalosis.

Pulmonary artery catheter placement with two-dimensional echocardiographic guidance: a technique applicable in critically ill neonates.

In nine critically ill neonates with persistent fetal circulation, femoral venous catheters were inserted at the bedside to initiate treatment and provide venous access. After femoral vein puncture or cutdown, a 5-F sheath was placed in the inferior vena cava through the femoral vein. With use of two-dimensional echocardiographic guidance, a 5-F balloon angiographic catheter was advanced through the inferior vena cava into the right atrium and subsequently manipulated through the tricuspid valve and into the main pulmonary artery. No major complications were attributable to the procedure. When performed by a pediatric cardiologist, this technique is as safe as umbilical catheter placement.

Use of tolazoline in newborn infants with diaphragmatic hernia and severe cardiopulmonary disease. A preliminary report.

Two newborn infants with congenital diaphragmatic hernia, one of whom died, had significant improvement in arterial oxygen tension (Pao2) after intravenous administration of tolazoline (Priscoline) (1 to 2 mg. per kilogram). In both infants, systemic hypotension developed within minutes of administration of the drug and required pharmacologic and hemodynamic intervention. The response to tolazoline was more dramatic in the infant who survived, and his oxygen requirements were significantly reduced after the use of this drug. The infant who died also had a significant response to tolazoline. Tolazoline appears to be an important pharmacologic agent for use in the postoperative care of infants with diaphragmatic hernia and associated hypoxemia and acidosis.

Radionuclide scintiphotography in defining postoperative pulmonary vasoconstriction. Succesful results after tolazoline administration in a four-month-old infant with congenital heart disease.

99mTechnetium macroaggregated albumin has successfully been used to define severe postoperative pulmonary vasoconstriction in a four-month-old boy with D-transposition of the great vessels who had undergone a Blalock-Hanlon surgical atrial septectomy. Radionuclide imaging documented clinically suspected pulmonary vasoconstriction and led to the successful use of tolazoline (Priscoline) to reverse the vasoconstriction with improved pulmonary blood flow patterns.

Treatment of experimental frostbite with intra-arterial sympathetic blocking drugs.

A number of experimental and clinical studies have shown that early regional surgical sympathectomy decreases tissue loss following frostbite, presumably by relieving vasospasm and increasing blood flow. This study was performed to determine if a decrease in tissue loss following a standard cold injury could be obtained following a regional "medical sympathectomy" achieved by the intra-arterial administration of sympathetic blocking drugs. A standard cold injury was produced in rabbits and the animals were divided into nine treatment groups. Various treatment modalities were evaluated, including rapid rewarming, intra-arterial reserpine and tolazoline, and intravenous low molecular weight dextran. In the slowly rewarmed animals, the usual clinic situation, the regional intra-arterial administration of reserpine and tolazoline significantly reduced tissue loss, equalling the results obtained in the rapidly rewarmed group. These results indicate that the early achievement of a regional "medical sympathectomy" may be of benefit in reducing tissue loss following frostbite in patients, especially in those in whom rapid rewarming cannot be performed.

Congenital diaphragmatic hernia: pathophysiology and pharmacologic support.

The incidence of death from congenital diaphragmatic hernia appears to be unchanged in recent years despite advances in resuscitation, transport, and ventilatory support. Bilateral lung hypoplasia and abnormal pulmonary vascular reactivity as developmental consequences of the defect appear to play a major role in the continued high mortality rate. Recent advances in pharmacologic support have further elucidated the mechanisms of ventilatory failure in these patients and may represent means of improving survival in the future.

Congenital posterolateral diaphragmatic hernia: new dimensions in management.

A retrospective analysis of 93 consecutive children with congenital posterolateral diaphragmatic hernia (CDH) was performed to determine outcome, ability to predict the development of persistent fetal circulation (PFC) requiring pharmacologic or extracorporeal membrane oxygenation (ECMO), and whether drugs or ECMO have improved survival. No patient died who was more than 24 hours of age at operation. Of 66 (71%) infants who were younger than 24 hours, 38 (58%) died. Preoperative and postoperative alveolar-arterial oxygen differences (AaDo2) did not consistently predict survival or death. Pharmacologic management of PFC in 30 patients resulted in a temporary improvement in 13 (43%). Survival was attributable to drugs in only seven (23%). ECMO was used in eight patients, all of whom had failed to improve with pharmacologic therapy and had a 100% predicted mortality rate based on the Neonatal Pulmonary Insufficiency Index. All eight had temporary improvement, while five (62%) completely cleared the PFC and four (50%) survived. Significant complications occurred in six patients. Earlier and more reliable methods of predicting high-risk infants are needed. Pharmacologic manipulation of PFC associated with CDH did not significantly improve survival. ECMO may prove to be a useful means of supporting these infants until more effective ventilatory and pharmacologic methods become available.

Mesenteric and peripheral vascular ischemia secondary to ergotism.

At the present time ergotism is due primarily to excessive use or abuse of ergot preparations for migraine headaches. The diagnosis may be made with the evidence of vascular ischemia in the presence of a history of migraines and its treatment with this drug. The therapy for the vasospasm is directed chiefly at the discontinuation of the ergot preparation, with further treatment aimed at the relief of symptoms or prevention of complications. A case is presented of lower extremity ischemia with impending gangrene of both feet in a patient with a history of chronic schizophrenia. Arteriograms revealed symmetrical vasospasm in the lower extremities as well as spasm of the superior mesenteric artery and its intestinal branches. This is believed to be the first documented case of mesenteric vasospasm due to ergotism. Treatment was instituted with low molecular weight dextran, tolazoline, and reserpine with rapid and complete resolution. Caution is advised in the use of ergot preparations in neuropsychiatric disorders.

Selective intra-arterial tolazoline infusion in peripheral arterial trauma.

Intra-arterial tolazoline has been used as an adjunct for angiographers and has been investigated for application in certain peripheral vascular disorders secondary to its potent activity as a vasodilator. We have had experience with three cases in which severe peripheral arterial trauma had resulted in nonviable extremities in spite of both orthopedic manipulation and vascular reconstruction. Continuous infusions of intra-arterial tolazoline were begun with marked improvement in blood flow in all extremities and resultant viability in all three within 48 hours. All three of these extremities, although severely traumatized, had one patent vessel distal to the popliteal trifurcation which was patent and which insured at least some flow to the distal extremity. Canine experiments were performed which demonstrated that intra-arterial tolazoline increased distal limb blood flow but did not moderate muscle surface hydrogen ion increase. These experiments confirm that the most important effect of the drug is in opening of precapillary arteriovenous shunts in the skin which increase total blood flow in medium and large size blood vessels in the injured limb. Major systemic effects of the drug were not observed when used in these specified concentrations and when monitored carefully by nursing personnel. We therefore feel that infusion of tolazoline can be used in specified cases of peripheral arterial trauma when both orthopedic and vascular reconstruction have not restored adequate blood flow to the traumatized extremity.

Effect of intra-arterial vasodilators on blood flow in ischemic dog colon.

The vasodilators papaverine hydrochloride, tolazoline hydrochloride, and isoproterenol hydrochloride were infused into the superior mesenteric artery (SMA) of dogs in which an ischemic Thiry-Vella colon loop had been formed. The washout of an intra-arterial injection of xenon Xe 133 to the normal and ischemic colon segments was used to measure bowel wall blood flow. Tolazoline and papaverine significantly increased the washout of 133Xe, but isoproterenol did not. Papaverine increased SMA flow. Neither of these two drugs altered the systemic blood pressure or pulse. However, isoproterenol augmented the SMA flow and pulse by factors of 1.8 and 1.5, respectively. These results support the favorable clinical reports that have found papaverine and tolazoline of use in the treatment of nonocclusive bowel ischemia.

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.

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.

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.