Drug therapy in persistent pulmonary hypertension of the newborn

Semin Neonatol 1997; 2:49-58

Drug therapy in persistent pulmonary hypertension of the newborn Duncan J. Macrae

Great Onno,d Street Hospital for Children, London UK

Key words: pulmonary hypertension, tolazoline, magnesium, prostacyclin, inhaled nitric oxide

The central pathophysiological feature of persistent pulmonary hypertension of the newborn (PPHN) is persistent constriction of the pulmonary vascular bed. Given this central feature, drugs which dilate the pulmonary circulation, that is lower pulmonary vascular resistance, have been recommended in the treatment of such infants. Intravenously administered vasodilators usually result in vasodilatation of both pulmonary and systemic vascular beds. Recent interest in the administration of drugs such as inhaled nitric oxide and inhaled prostacyclin directly to the lung appears to offer neonatologists clinically applicable selective pulmonary vasodilation. Clinical trials are needed to asses the role of these promising therapies with PPHN.

Persistent pulmonary hypertension of the newborn (PPHN) is characterized by a high pulmonary vascular resistance, resulting in right-to-left shunting of deoxygenated blood across the ductus arteriosus and foramen ovale. Although 'pulmonary hypoperfusion' had previously been recognized as a complication of neonatal respiratory distress [I], the first description of 'PFC syndrome----(persistence of the fetal circulation)' [2] recognized this pattern of shunting. Remarkably the report also recorded the potential of the vasodilator tolazoline, administered intravenously, to improve oxygenation by lowering pulmonary vascular resistance, and also the undesirable systemic hypotensive effect of that therapy. This paper reviews the principal drugs that have been used in the treatment of PPHN and recent developments in this field, whilst recognizing that clinical guidelines on the management of PPHN are still controversial [3].

Some fundamental considerations Pulmonary hypertension in the newborn infant has many potential causes. Numerous pulmonary and Correspondence: D. J. Macrae. Great Ormond Street tlospital for Children, London WC1N 3]'tt. UK (email: goshecmo~easynct.co.uk). 1084-2756/97/010049 + 10 S 12.00/00

cardiovascular diseases are associated with raised pulmonary vascular resistance. The syndrome first described by Gersony [2], that of 'PFC--persistent fetal circulation' was characterized by persistently elevated pulmonary vascular resistance in the absence of both focal lung disease and structural heart disease. The terms PFC and its successor PPHN have been used rather indiscriminately in babies with pulmonary hypertension and right-to-left shunting of blood associated with other conditions such as meconium aspiration, pneumonia, respiratory distress syndrome and congenital diaphragmatic hernia. Only those babies with pulmonary vasoconstriction and no other cardiopulmonary disease should be diagnosed as suffering from 'primary' PPHN. Babies with reactive pulmonary vasoconstriction associated with parenchymal lung disease are most accurately described as suffering from the parenchymal condition associated with 'second° ary' PPHN, laying appropriate emphasis on varying underlying pathophysiologies. It is extremely important to understand the pathophysiology of infants presenting with primary or secondary PPHN, as therapeutic interventions must be tailored to specific circumstances. As an example, a baby with pulmonary hypertension associated with the respiratory distress syndrome is likely to benefit © 1997 W.B. Saunders Company Ltd

D.J. Macrae

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more from the administration of surfactant and ventilatory measures to recruit lung volume than from specific measures to lower pulmonary vascular resistance (PVR). In contrast, a baby presenting with classical 'primary' PPHN with no parenchymal lung disease is most likely to benefit from the early introduction of a 'pulmonary' vasodiIator.

Physiology and the treatment of PPHN Some fundamental observations are important in the drug management of PPHN. • Pulmonary arterial pressure is almost always suprasystemic in infants with PPHN. • The magnitude of right-to-left shunting across the ductus arteriosus is dependent on the ratio of PVR to SVR (systemic vascular resistance). Any vasodilator drug aimed at decreasing the degree of right-to-left shunt and improving oxygenation must lower the PVR:SVR ratio. • Right-to-left shunting also occurs at atrial level across the patent foramen ovale. The degree and direction of atrial shunt relates more to the relative compliance of the right and left ventricles, than the PVR:SVR ratio, although right ventricular compliance can be expected to increase as right ventricle pressures fall. Thus a disproportionate ischaemic injury to one or other ventricle can dramatically influence responses to specific vasodilators. • In all right-to-left shunt situations, final systemic oxygen saturation is a product of the relative volumes and oxygen saturations of pulmonary venous and systemic venous blood. For instance with no change in PVR:SVR ratio, and provided oxygen extraction remains unchanged, a measure which increases cardiac output will lead to a rise in systemic venous oxygen saturation and a rise in the resulting systemic arterial saturation. • Some babies present with severe pulmonary hypoplasia (as in congenital diaphragmatic hernia) or dysplasia as the principal cause of their pulmonary hypertension. The vast majority of these babies have in addition some degree of reversible pulmonary vasoconstriction, that is 'secondary PPHN'.

Physiologically based treatment options in PPHN Selective pulmonary vasodilators reduce the ratio of PVR to SVR, resulting in reduced shunting of

blood at the level of the ductus arteriosus, a consequent fall in venous admixture and rise in postductal oxygen saturations. Drugs which act as vasodilators of the pulmonary vascular bed are thought to be important in the management of PPHN, but other measures may be equally useful. Alveolar recruitment and increasing alveolar oxygen concentration lower PVR through abolition of hypoxic pulmonary vasoconstriction. In some babies with PPHN, exogenous surfactant will assist in recruiting and maintaining lung volume, improving oxygenation and thus lower PVR. Coronary, cerebral and systemic oxygen delivery must be maintained with appropriate use of inotropic drugs such as dopamine, dobutamine or adrenaline, and colloid or blood transfusion to optimize circulating blood volume and red cell mass. Acidosis is a potent cause of pulmonary vasoconstriction, and management of metabolic acidosis by measures to optimize cardiac output and oxygen delivery together with careful correction of any base deficit is recommended. Some authorities recommended that alkalinization in babies with PPHN be achieved through aggressive mechanical hyperventilation. The dangers of such ventilatory strategies, principally the high incidence of barotrauma and secondary lung injury are now widely recognized, and alternative strategies of 'permissive hypercapnia' involving metabolic but not respiratory alkalinization have been employed successfully. All of the measures outlined above have their place, but the drug treatment of PPHN must focus to a large extent on pharmacological agents which act to dilate the pulmonary vascular bed.

Intravenous vasodilators Given the critical nature of raised pulmonary vascular resistance in PPHN, it would seem that a potent pulmonary vasodilator would be essential in the treatment of this condition. The ideal pulmonary vasodilator would however act exclusively within the pulmonary vascular bed and would not cause systemic hypotension. A number of drugs have been used as vasodilators in PPHN, some of them very extensively, including tolazoline, prostacyclin, magnesium and inhaled nitric oxide. Other drugs including the nitrovasodilators glyceryl trinitrate and sodium nitroprusside and a variety of R-adrenergic blockers have also been used.

Drug therapy in PPHN

Tolazoline Tolazoline, administered intravenously, has been the vasodilator most widely used to treat babies with PPHN. Its use in this role is serendipitous, stemming from its apposition to Gersony's original report of 'PFC syndrome' [2], rather than from controlled studies of its efficacy, kinetics or safety. Tolazoline has a number of pharmacological actions. It acts as a vasodilator both through its mild antagonism of R~ adrenergic receptors, and its histamine-like effect mediated either through activity at the histaminergic H z receptor [4] or by causing histamine release [5, 6]. In vitro, histamine produces vascular smooth muscle relaxation through the endothelial-dependent nitric oxideguanylate cyclase pathway. However, in a recently published study, Curtis et al. [7] showed that in a fetal lamb model of pulmonary hypertension, tolazoline induced vasodilatation independent of nitric oxide production. Tolazoline lowers pulmonary vascular resistance raised by hypoxia [4, 8] and in newborns with PPHN [9]. In an early study of neonates with refractory hypoxic respiratory failure, response to tolazoline, defined as an increase in Pao 2 of 20mmHg, was not found to correlate with survival. The use of tolazoline is associated with a number of potentially serious adverse effects including systemic hypotension and gastric ulceration and haemorrhage [2, 6--12]. The reported incidence of systemic hypotension lies between 2 and 67%, the result of the nonselective vasodilating activity of the drug. Gastric ulceration and haemorrhage also occur, consistent with tolazoline's histamine-like effects on gastric secretion [10-12]. Other adverse effects reported in babies receiving tolazoline such as seizures, renal failure and thrombocytopenia are more a reflection of the severity of their hypoxaemic condition than specific effects of the drug itself. High concentrations of tolazoline have been noted to have a negative inotropic effect in animal preparations. Tolazoline adminstration has usually been performed with a loading dose of I - 2 mg/kg followed by 1-2 mg/kg per hour. Whilst the pulmonary vasodilator effects of tolazoline are dose related, adverse effects are favoured by high dose regimes. Monin et al [56] demonstrated that a 0.5 mg/kg loading dose followed by 0.5 mg/kg per hour maintenance dose was effective in achieving adequate plasma concentrations. Ward [13] made

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similar lower dose recommendations, suggesting that an infusion rate of 0.28 mg/kg per hour be used after a loading dose of I mg/kg. Ward also documented accumulation of tolazoline, a drug which is mainly eliminated by renal excretion, in neonates with impaired renal function [13], and suggested that tolazoline dosage should be reduced if urine output falls below I ml/kg per hour.

Prostacyclin Prostacyclin is a ubiquitous endothelial-derived vasodilator. It plays a role in maintaining normal vascular tone, and plays a prominent role in the transitional circulation. Prostacyclin has been extensively used as a pulmonary and as a systemic vasodilator. Prostacyclin also inhibits platelet aggregation, and is used as an anticoagulant in extracorporeal circuits. Prostacyclin acts by activating adenylate cyclase via a prostacyclin receptor. Cyclic AMP activates protein kinase A, leading to effects which include reduction in free intracellular calcium in the smooth muscle cell and consequent vasorelaxation. Prostacyclin is rapidly hydrolysed in aqueous solutions, and has a biological half-life of 2-3 minutes. Prostacyclin also stimulates nitric oxide release from the endothelium [14]. Usually administered intravenously at doses of 5-20 mg/kg per minute, prostacyclin is a non-selective vasodilator, that is it should be anticipated that prostacyclin will lower SVR and PVR simultaneously. Prostacyclin has been shown to lower pulmonary vascular resistance in hypoxic newborn lambs [15] and a number of reports of its use in clinical studies have been published [16, 17]. Although effective in some babies, prostacyclin has proved ineffective or hazardous in others, with reported adverse effects including systemic hypotension, myocardial infarction [18] and extended bleeding times.

Magnesium At high serum concentrations, magnesium is a potent vasodilator, muscle relaxant and sedative. Elevation of intracellular ionized calcium is central to the occurrence of vasoconstriction. Magnesium, a physiological calcium antagonist, reduces or abolishes calcium-controlled vasoconstriction [19-21]. Magnesium may also act as a vasodilator through effects on the production, release, metabolism or

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receptor sites of the vasodilator prostaglandins such as PGI2. Magnesium has been used for many years as a treatment of pregnancy-associated severe hypertension [22] during which serum magnesium concentrations of 2-3.5 mmol/1 are required. As magnesium ions cross the placenta promptly, the effects of such concentrations on the neonate have failed to demonstrate any substantial adverse effects [23]. High serum magnesium concentrations have been shown to reduce hypoxia-induced pulmonary hypertension in animals [24]. In a subsequent clinical study, Abu-Osba [25] treated 9 neonates with severe PPHN with intravenous magnesium sulphate heptahydrate given as a bolus dose over 20--30 minutes followed by an infusion at 20--50 mg/kg per hour. This regime raised serum magnesium levels substantially and resulted in gradual improvements in oxygenation over the first 6 hours of magnesium treatment, presumably due to pulmonary vasodilatation. Postductal Pao 2 rose from 4.66 -4- 1.80 kPa (mean 4- SD) at baseline to 12.04-1-7.07 kPa after 6 hours of magnesium treatment. Systemic hypotension was noted, with a reduction in systemic pressure from 54.2 4- 13.6 mmHg at baseline to 47 -4- 15.1 mmHg after 2 hours of magnesium treatment. Of the 9 infants treated, two failed to respond and died. One baby died 7 days after magnesium was discontinued. Others have followed Abu-Osba in reporting small uncontrolled studies of the use of magnesium in term [26] and preterm babies [27] with PHNN. A carefully conducted animal study into the vasodilating effects of magnesium sulphate in pulmonary hypertensive piglets [28] demonstrated clearly that vasodilatation induced by magnesium was non-selective, and cautioned against its use as a 'pulmonary' vasodilator in PPHN.

Inhaled vasodilators Nitric oxide In 1987 Palmer and colleagues [29] published their landmark paper in Nah~re, identifying nitric oxide (NO) (or an NO-containing substance) as the molecule responsible for the biological activity of endothelial-derived relaxing factor (EDRF). In addition to its endothelial functions including modulation of vascular tone and decreasing platelet and neutrophil adherence, it is now recognized that NO is a ubiquitous biological mediator with

D.J. Macrae

important roles in, among others, the immune and nervous systems. Endogenous nitric oxide and the pulmonary endothelium

Nitric oxide is synthesized from the amino acid I.-arginine by nitric oxide synthases of which there are 3 types, an endothelial type (eNOS, type iiiNOS), a neuronal type and a macrophage (inducible) type. The eNOS is found in all vascular endothelium, the heart (endocardium and myocardium) and platelets (see Fig. 1). NO produced in the endothelial cell diffuses into adjacent vascular smooth muscle, acting as a messenger molecule, stimulating the enzyme soluble guanylate cycIase leading to the conversion of guanylate triphosphate (GTP)to cyclic guanylate monophosphate (cGMP) a n d subsequently lowering intracellular calcium. The exact mechanisms by which cGMP produces vasodilatation have not been characterized, but may involve activation of calcium-gated K + channels. NO may also have a direct (noncGMP mediated) effect. Once produced, endothelial cGMP is inactivated by hydrolysis to 5-GMP by activity of the GMP-specific enzyme Type-5 phosphodiesterase (PDES). Nitrovasodilators such as sodium nitroprusside and the organic nitrates mimic the effects of endogenous nitric oxide as they act as prodrugs, forming nitric oxide in smooth muscle cells. Clinical studies suggest that eNOS has a role in controlling pulmonary vascular tone in normal children and adults. NO production by eNOS is controlled by a number of factors including shear stress, pulsatile flow and acute hypoxia. Nitric oxide is released continuously in many vascular beds and seems to have a role in maintaining basal vascular tone. Hypoxia decreases pulmonary endothelial NO production and may contribute to hypoxic pulmonary vasoconstriction. eNOS activity has been shown to be impaired in a number of pulmonary hypertensive states. Celermajer and colleagues [30] demonstrated that inhibitors of NOS induce pulmonary vasoconstriction, and that the response to endothelialdependent vasodilators but not NO donors are impaired in children with pulmonary vascular disease [30] implying impaired NO production through endothelial damage. Giaid and Saleh [3I] have recently demonstrated reduced NOS expression in the lungs of patients with pulmonary hypertension.

Drugtherapy in PPHN

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riD)

Alveolus~-I']'D

NO

f

~ ~L-arginine-"~

0 2 ~ ~

I~D J

Endothelial cell k,. L-citrulline

HO

f " ~

NO J

Smooth muscle cell

Guanylateeyclase Pulmonary capillary

fibre "" relaxation '~" [

~

J Vasodilatati0n l

Figure 1. Schematicrepresentation of the role of exogenous NO in lowering pulmonary vascularresistance. NO plays an important role in the control of the pulmonary circulation in the perinatal period. At birth endogenous NO production contributes to the fall in PVR [32]. It has been demonstrated in animals that inhibitors of eNOS prevent the postnatal fall in PVR, and a lower synthetic rate for NO has been reported in babies with PPHN [33]. This may be due to deficiency of the arginine substrate for the NOS enzyme [34]. It is therefore likely that defective NO production or control plays a role in the pathophysiology of persistent pulmonary hypertension of the newborn and it is reasonable to hypothesize that making good the nitric oxide deficiency in the lung might be beneficial. Exogenous nitric oxide as a pulmonary vasodilator

Nitric oxide, a colourless sweet smelling gas at room temperature and pressure, is a free radical with a half life of seconds. Exogenous inhaled NO diffuses from alveoli to pulmonary vascular smooth muscle and produces vasodilatation by the same mechanism as endothelial-derived NO. Excess NO diffuses into the blood stream where it is rapidly inactivated by avid binding to haemoglobin and subsequent metabolism to nitrates and nitrites, thereby limiting its action to the pulmonary vascular bed (Fig. 1). The critical distinction between inhaled nitric oxide and intravenous vasodilators, that it is a selective dilator of the pulmonary vascular bed,

has been clearly demonstrated in animal models [35-37]. Higgenbottam and colleagues (personal communication) reported the first human application of inhaled NO, in a comparative study of its systemic and pulmonary dilating effects in a group of adult patients with primary pulmonary hypertension. In this study, 40 ppm inhaled NO but not prostacyclin, produced selective pulmonary vasodilatation. Frostell and colleagues [38] subsequently demonstrated that inhaled NO reverses hypoxia-induced pulmonary vasoconstriction in human volunteers but has no effect on basal pulmonary vascular tone indicating that under normal circumstances the pulmonary circulation is maximally dilated. Because inhaled NO is delivered to ventilated areas of the lung, its vasodilatory effects improve ventilation-perfusion matching, reducing intrapulmonary shunting of mixed venous blood. The vasodilatory effects of inhaled NO have been reported at concentrations ranging from less than I to 80 ppm. At higher concentrations (I00300 ppm), inhaled NO has been reported to produce bronchodilatation. Inhaled NO may also reduce adhesion and aggregation of platelets and lessen neutrophil activation in the injured lung. The non-vasodilator effects of NO may modify disease processes favourably in babies with PPHN. Leakage of albumin into the alveolar space after lung injury may be reduced. Platelet and leukocyte adhesion, which are believed to

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contribute to acute lung injury, are believed to be reduced or inhibited. Chemistry and biochemistry of nitric oxide

NO is one of the three oxides of nitrogen, the others being N O 2 and N20. NO is a free radical which itself is relatively unreactive. It is a common environmental pollutant produced by combustion including the burning of fossil fuels, which in the presence of oxygen is converted to nitrogen dioxide. Nitric oxide is believed to be a relatively harmless constituent of cigarette smoke which contains 400--1000 ppm [34]. Supplies of nitric oxide are presented in pressurized cylinders diluted with nitrogen, to a final cylinder NO concentration ranging from several hundred to 1000 ppm. Nitrogen dioxide is present in concentrated nitric oxide cylinders, and the concentration of NO 2 increases slowly with time. The cylinder shelf life of an NO cylinder is typically stated as 2 years, based on maintaining a decrease in NO concentration of less than 1% and NO 2 concentration not increasing beyond 2%. Toxicity

Whilst NO is not without the potential to induce adverse effects, inhalation of a relatively low concentration of NO (up to 100 ppm) has been shown to be without adverse effects in a number of animal models. An occupational exposure limit for NO in the USA is set at 25 ppm. A number of potential problems may however occur as a result of NO inhalation. Formation of methaemoglobin

Nitric oxide binds avidly to haem containing proteins, with an association rate constant approximately 300 greater than for oxygen, leading to the formation of metHb. It is this association which neutralizes the excess inhaled NO and ensures that its effects remain localized in the lung. Methaemoglobin can accumulate under certain conditions, and must be measured regularly during administration of inhaled NO to prevent accumulation of metHb to levels which significantly reduce oxygen carrying capacity of blood. Activity of the enzyme responsible for further metabolism of metHb, methaemoglobin reductase, may be decreased in the newborn period and therefore

D.J. Macrae

neonates may be at particular risk of developing methaemoglobinaemia during inhaled NO administration. In babies with normal or high total Hb concentrations, metHb levels of less than 5% are clinically insignificant. We recommend measuring metHb levels before and 1 hour after commencing inhaled NO, and thereafter every 8 hours. If metHb levels between 5-7% are detected, inhaled NO dosage should be reduced and the metHb measurement repeated. If levels of metHb do not fall, rise further or if very high levels (greater than 7%) are detected, we again consider dose reduction or cessation of inhaled NO delivery, and possibly treatment with methylene blue (lmg/kg i.v.). Formation of nitrogen dioxide

In the gas phase NO reacts with oxygen to form nitrogen dioxide (NO 2) (see equations I-3). The rate reaction is a third order process that occurs in proportion to the concentration of both oxygen and NO [39]. Thus any prolonged contact with oxygen in clinical delivery will promote production of NO 2. 2NO+O2~2NO 2

(I)

NO + O2--~NO 3

(2)

NO 3 + N O ~ 2 N O 2

(3)

It is clear from both animal and human studies that toxic effects can be seen following exposure to NO 2 levels of I7 ppm for 72 hours [40] to 25 ppm for 30 minutes [4I]. Exposure to concentrations as low as 2.3 ppm NO 2 for 5 hours results in detectable changes in alveolar permeability and reduces antioxidant defences [42]. Long-term follow-up studies of patients who have received inhaled NO are required to document any delayed toxic effects. Free radical reactions

NO reacts with the superoxide anion to form the reactive species peroxynitrite, and further reaction leads to hydroxyl radical (OH) formation. Hydroxyl radicals are known to have the potential to damage lipid membranes and produce cell injury. It is not known to what extent other cell structures including DNA may be injured by reactive nitric oxide metabolites. If DNA damage were shown to occur, then carcinogenesis could follow. However inhaled NO may also scavenge more reactive free radical species in acute lung injury [43]. The balance

Drug therapy in PPHN

between its potentially beneficial antioxidant and harmful pro-oxidant effects are not known. Increased bleeding time

A study in adult volunteers has demonstrated a slight prolongation of bleeding time associated with inhalation of NO. So far, reports in neonates have not highlighted any excess morbidity during inhaled NO therapy attributable to bleeding [44]. It would however be sensible not to administer inhaled NO to babies with bleeding disorders or existing bleeding complication such as an intraventricular haemorrhage. Health and safety

The US National Institute for Occupational Safety and Health have published limits for occupational exposure to NO and NO 2 [45]. They suggest a 'permitted exposure limit' of 5 ppm for NO z and 25 ppm for NO, and 'recommended exposure limits' of I ppm ceiling for NO 2 and 25 ppm (10 hour time-weighted average) for NO. The environmental concentrations of NO and NO 2 to which healthcare workers are exposed through current medical applications are negligible when NO is administered via a ventilator circuit in an intensive care unit. Nevertheless, it seems prudent to recommend disposal of exhaust ventilator gases via a scavenging or absorptive system to minimize low level exposure. In units using inhaled NO, procedures must be established to detect slow leaks of concentrated NO from stock cylinders and manage situations such as cylinder changes in such a way as to prevent accidental release of concentrated NO. Inhaled NO in P P H N

In 1992 two reports appeared in the same issue of the Lancet describing the use of inhaled NO in neonates with severe respiratory failure. Roberts et al [46] reported that NO 80 ppm for 30 minutes acutely improved oxygenation in six neonates but that improvement was sustained in only one infant once inhaled NO was withdrawn. Kinsella et al [47] recorded similar acute responses to inhaled NO 20 ppm given for 4 hours to nine infants, and documented sustained responses in six babies who subsequently received inhaled NO 6 ppm for 24 hours. Finer et al [48] conducted a dose-response study of inhaled NO in 23 hypoxic near-term infants.

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Overall 13 infants responded with increases in Pao 2 greater than 10% or 10 mmHg. Doses were administered in random order, and no differences were seen in responses for any doses between 5 and 80 ppm. It would be naive to expect inhaled NO to be universally effective in PPHN and similar conditions. Goldman et al [49] evaluated inhaled NO 20 ppm in a group of 25 severely hypoxic term neonates and identified four patterns of response. Two neonates did not respond. Nine neonates although responding well initially, failed within 24 hours to sustain that response. Eleven babies responded well initially and sustained that response and were weaned from inhaled NO. A final group of three infants responded to inhaled NO administration but continued to require high doses for prolonged periods of time to maintain oxygenation. All three of these latter babies died. Lung histology revealed pulmonary hypoplasia and dysplasia. The lungs were poorly aIveolarized and an increase in the amount of connective tissue was noted throughout the lungs. A recent review from Abman and Kinsella [50] highlights the many possible causes of 'nonresponse' to inhaled nitric oxide. These authors stress the importance of ensuring lung inflation with adequate alveolar recruitment prior to administration of inhaled NO. In the presence of significant alveolar underrecruitmenL inhaled NO may lower PVR to some extent, but substantial intrapulmonary shunting and hence hypoxaemia persist. Even in the presence of raised PVR and severe hypoxaemia due to right-to-left shunting and in the absence of atelectasis, a sustained clinical improvement may not be achieved with inhaled NO. We have seen two infants with severe hypoxaemia and PPHN secondary to severe perinatal asphyxia, in whom a trial of inhaled NO induced systemic hypotension. Subsequently echocardiographic examination revealed the cause to be severe left ventricular dysfunction with relative sparing of right ventricular function. In these infants, the systemic circulation was dependent on blood shunting right-to-left across the arterial duct. Therefore administration of inhaled NO immediately induced systemic hypotension, in proportion to a decrease in ductal shunt. The decrease in PVR and increased return of blood to the pulmonary veins are also likely to worsen pulmonary oedema in babies presenting with obstructed total anomalous pulmonary venous return, congenital mitral

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D.J. Macrae

stenosis and other situations where pulmonary oedema occurs due to pulmonary venous hypertension. An echocardiographic evaluation ought to be obtained to exclude major cardiovascular anomalies in such infants. It seems to be clear from acute studies that administration of inhaled NO leads to measurable physiological improvement in many babies with PPHN. However randomized controlled clinical trials are required to ascertain whether inhaled NO improves clinical outcomes. Several such studies are underway in the US, Canada and Europe. Early indications from a joint US-Canadian study are encouraging [51]. In addition to proof of clinical benefit, the toxicology of inhaled NO has not been adequately evaluated in neonates and confirmation of its safety will be required before it can be recommended as a drug for widespread clinical use. Once established on inhaled NO, it appears that endogenous NO production is suppressed and this may explain the clinical observation of dependency on inhaled NO during clinical use. The occurrence of dependency during therapy may render a baby unable to be transported within or between hospitals, as may be necessary if the baby reaches ECMO criteria, unless inhaled NO is administered during transfer.

Administration NO has yet to be licensed in any country as a drug, but is available widely in many countries including those of Europe, North America and Australasia as a gas produced to 'medical' levels of purity and is administered to patients under a number of exemptions related to investigative protocols or 'compassionate use'. It is important for users of inhaled NO to be aware that it is not approved as a drug in the treatment of PPHN, and that neither short-term efficacy nor longer-term freedom from toxicity are confirmed. Any system for delivery of nitric oxide to a patient's lungs must • •

Deliver NO at known concentration Minimize the mixing time of NO oxygen, to minimize NO 2 production.

with

Workers in the field have tended to deliver NO either by accurate gas flow meters into a main gas stream, or by using gas blender systems. Our group investigated a system of delivering NO to a continuous ventilator (Babylog 8000) via a low range flow meter [52]. The maximum NO 2 gener-

ated with 80ppm NO in 21% oxygen was 1.3 ppm, but in 80% oxygen the same concentration of NO resulted in an NO 2 concentration of 5.1 ppm.

Monitoring It is essential to know the concentrations of both NO and NO 2 delivered to patients, both to optimize treatment and minimize toxicity. Environmental monitoring may also be required. Two types of detector are available, chemiluminescent and electrochemical. Chemiluminescence analysers are large, costly and relatively noisy but have an excellent sensitivity for all nitrogen oxides down to the 'parts per billion' range and have a rapid response time. Accurate calibration is necessary. These devices underestimate the concentration of NO in oxygen enriched environments (by I0-I5%) due to the chemical phenomena known as quenching. Electrochemical devices are smaller, silent and less expensive than chemiluminescence devices. They are however less sensitive, with a detection threshold of approximately 0.5 parts per million. The fuel cell sensors of these devices are very sensitive to both humidity and pressure and must be well protected in breathing circuits if accurate readings are to be obtained. The sensor depends on a chemical reaction taking place, which gradually uses up supplies of electrolyte within the sensor. Sensors therefore have a concentrationtime weighted lifespan, and can be exhausted extremely quickly if accidentally left in contact with concentrated nitric oxide. All types of NO and NO 2 analyser require calibration before use.

Aerosol delivery of vasodilators It is clear from the preceding discussion that pulmonary selectivity among vasodilators has been difficult to achieve since there are in fact no known vasodilators which selectively dilate any part of the circulation to which they have access. Nitric oxide is only selective because it is delivered directly to the lung as a gas and is inactivated by its fortuitous affinity to Hb. The concept of selectivity by route of adminstration has recently seen 'old' drugs revisited, with reports of direct delivery to the lung of prostacyclin [53] and tolazoline [54, 55]. In theory, if the drug were delivered selectively to ventilated

Drug therapy in PPHN

alveoli in babies with PPHN, PVR would be lowered and right-to-left shunt abolished as with inhaled N O . Whether it then went on to cause systemic effects would depend on characteristics of the individual drug. Prostacyclin hydrolyses spontaneously with a half life of 2 - 3 minutes to an inactive metabolite, and it is possible that it may be hydrolysed sufficiently rapidly for it to cause negligible systemic effect. This is not likely to be the case with tolazoline, a drug with a half life of several hours. Direct delivery of tolazoline to the lung will ensure high local concentrations and possibly promote both rapid and potent initial effect, but ultimately the drug will pass into the systemic circulation unchanged whereupon it will exert its familiar non-selective effects. Nebulized drugs also have their drawbacks, especially in small babies. Apart from the possibility of systemic absorption, airway resistance can increase during nebulization, leading to a rise in Paco 2 and fall in pH. In babies with P P H N this would be poorly tolerated. The same proof of efficacy would be required of any drug delivered directly to the lung b y nebulization or other means as is required of inhaled N O , that is there should be a significant beneficial effect on outcome detected in randomized controlled trials.

Summary There is no unequivocal evidence in the published literature supporting improved outcome in P P H N associated with the use of any of the commonly used intravenous vasodilators. N e w e r drug therapies for PPHN, such as inhaled N O and other locally administered agents require assessment in randomized controlled trials. If beneficial effects on outcome of P P H N are demonstrated, the results of such trials will provide useful evidence from which updated clinical guidelines for the drug management of P P H N can be developed. References

1 Chu J, Clements J, Cotton E et al. The pulmonary hypoperfusion syndrome. Pediatrics 1965; 3.5: 733-742. 2 Gersony W, Duc GH, Sinclair J. 'PFC' syndrome (persistence of the fetal circulation). Circulation (Supplement Ill) 1969; 40: 87. 3 Sahni R, Wung J-T, James S. Controversies in management of persistent pulmonary hypertension of the newborn. Pediatrics 1994; 94: 307-309.

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