Congenital heart disease in relation to pulmonary hypertension in paediatric practice

PAEDIATRIC RESPIRATORY REVIEWS (2005) 6, 174–180

SERIES: PULMONARY VASCULAR DISEASE

Congenital heart disease in relation to pulmonary hypertension in paediatric practice Robert M.R. Tulloh Department of Congenital Heart Disease, Paul O’Gorman Building, Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol BS2 8BJ, UK KEYWORDS Congenital heart disease; Pulmonary hypertension; Magnetic resonance imaging; Pulmonary vascular disease; Endothelin antagonist; Phosphodiesterase inhibitor

Summary Pulmonary hypertension (PHT) is a well recognised feature of untreated congenital heart disease. This article will review the causes, known mechanisms, appropriate investigations and current therapies for PHT. The reader will understand the difference between PHT due to high pulmonary blood flow and PHT that is due to high pulmonary vascular resistance. The former is best treated by surgical or catheter intervention, whereas for the latter (Eisenmenger syndrome) only palliation is possible with medication or transplantation. Echocardiography and electrocardiography (ECG) should be performed in any child where there is a possibility of pulmonary hypertension, especially with long standing chronic lung disease and minor left to right shunt. Often these children may have dual pathology and their investigation and management may be a complex interaction between cardiac and respiratory therapists. New treatments and new techniques of assessment are now available and this may lead to improved recognition of PHT and prevention of long term disability as a result. ß 2005 Elsevier Ltd. All rights reserved.

INTRODUCTION

immediate neonatal period are chronic lung disease and a large left to right shunt secondary to a ventricular or atrioventricular septal defect (VSD or AVSD, respectively). Secondary PHT is now less common with the advent of early surgery, preventing pulmonary vascular disease. However, there is renewed interest in the subject now that there are widely available methods of assessment with echocardiography and also magnetic resonance imaging (MRI). In addition the possible use of oral medication has facilitated the therapy in these children. The aim of this article is to describe the aetiology, pathology and treatment of PHT in relation to congenital heart disease.

We have come a long way since Paul Wood described in 1958 the effects of high blood flow and high pressure on the pulmonary vascular bed.1 Since then cardiac catheterisation has become a widely used tool in the assessment of pulmonary vascular resistance (PVR) to determine suitability for cardiac surgery. The description of the histo-pathological changes in Eisenmenger syndrome2 have changed substantially from the time of Heath & Edwards,3 now being recognised as variable and not correlating well with catheterisation data4 or the clinical responses to medication.5 Pulmonary hypertension (PHT) is found in a wide variety of conditions affecting paediatric patients and an understanding of its aetiology and management is relevant to many paediatric disciplines including neonatology, pulmonology, cardiology and neurology. A diagnosis of primary or idiopathic PHT is very rare in childhood. Of the many secondary causes (Table 1),6 the commonest outside the 1526-0542/$ – see front matter ß 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2005.06.010

DEFINITION AND DIAGNOSIS A recent re-classification, by the World Health Organisation, of the causes of PHT has demonstrated the similarity between secondary PHT and idiopathic or primary PHT.7

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Table 1

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Causes of pulmonary hypertension in paediatrics.

Neonates

Persistent pulmonary hypertension (idiopathic) Respiratory distress syndrome & subsequent chronic lung disease Infection e.g. Streptococcus Structural disease e.g. congenital diaphragmatic hernia

Cardiac

Left to right shunt e.g. ASD, VSD, AVSD, PDA, AP window Transposition of the great arteries Obstructive lesions e.g. TAPVC, MS, HLHS, HOCM, DCM

Acquired

Chronic hypoxia e.g. cystic fibrosis, high altitude, interstitial disease Scoliosis, neuromuscular Airway obstruction e.g. tonsillar hypertrophy, tracheal stenosis, soft tissue Vasculitic

Idiopathic

Sporadic Familial

Abbreviations used: ASD, atrial septal defect; VSD, ventricular septal defect; AVSD, atrioventricular septal defect; PDA, persistent ductus arteriosus; AP, aorto-pulmonary; TAPVC, total anomalous pulmonary venous connection; MS, mitral stenosis; HLHS, hypoplastic left heart syndrome; HOCM, hypertrophic obstructive cardiomyopathy; DCM, dilated cardiomyopathy.

The definition (mean pulmonary artery (PA) pressure >25 mmHg at rest or 30 mmHg with exercise)8 is not so useful in clinical practice as it tends to apply to adults rather than children. Also, we use echocardiography rather than cardiac catheterisation to undertake the initial screening and diagnosis so we need to use different diagnostic criteria. Some have used the presence of a high velocity regurgitant jet across the tricuspid valve (>2.8 m/s),8 but this does not take account of possible right ventricular outflow tract obstruction. Most paediatricians would accept that pulmonary hypertension is where: systolic pulmonary artery pressureðpPAÞ > 50% systemic pressure: This is usually derived from measuring the pressure drop across a regurgitant tricuspid valve or from the Doppler derived pressure drop across a known septal defect such as a VSD. If the systolic blood pressure is known, the systolic right ventricular (RV) pressure can be derived from the modified Bernouilli equation. For example, from a tricuspid regurgitant jet of V = 3.7 m/s, and assuming the right atrial pressure to be 5 mmHg, then:RV pressure ¼ 4 V2 þ RA ¼ ð4 x 3:72 Þ þ 5 ¼ 60 mmHg This is significantly high RV pressure and in the absence of any RV outflow tract obstruction, it clearly represents pulmonary hypertension.

Clinical examination Clinical signs of PHT are varied. In general, the smaller septal defects cause the loudest noises and it would be unlikely for a VSD with a thrill on examination to have pulmonary

hypertension. At birth, it is common to have cyanosis with hepatomegaly and a loud pulmonary second sound on auscultation. Often seen as a presentation of large septal defects, especially AVSD in Down’s syndrome, it may rapidly give way to heart failure as the PVR drops (pressure = resistance x flow). Before birth the PVR is higher than the systemic vascular resistance. Therefore ductal flow is towards the systemic circulation. Immediately after birth, it falls by 50% with the first breath and continues to fall for 3 months. This usually results in a fall in the pulmonary pressure. All children with a large VSD will have PHT from birth because the right and left ventricle pressures are equal. There is no left to right shunt until the PVR falls over the first few days of life. Therefore neonates with large VSDs will have no murmur on day 1 and will not be in heart failure until the end of the first week of life. In patients with congenital heart disease, pulmonary vascular resistance (high PVR) arises as a consequence of PHT. The former is a consequence of the latter when dealing with congenital heart disease. If left untreated, those children with a large post-tricuspid shunt may complain of breathlessness, particularly on exertion and there may be exercise-induced syncope. A chest radiograph may show pulmonary oligaemia, there may be RV hypertrophy on ECG and a low PaO2 on arterial blood gas measurement. Echocardiography can be used to measure the tricuspid regurgitant jet as above, thereby inferring systolic pulmonary artery pressure (pPA) and subsequent hypertension, provided there is no RV outflow tract obstruction or pulmonary stenosis. Pulmonary regurgitation can be used to determine the presence of diastolic PHT. Cardiac catheterisation, however, remains the diagnostic gold standard, as it allows accurate measurement of pulmonary artery pressure (pPA) and PVR. It also determines the degree of reversibility of PHT. Vasodilators such

176 as inhaled nitric oxide (NO)9 or prostacyclin10 (PGI2) can be used to reduce the PVR. This is particularly important in those with a left to right shunt to determine whether the pPA will fall post-operatively. To measure PVR in the cardiac catheter laboratory, accurate measurement of oxygen consumption (VO2) must be made using either a paramagnetic analyser (Deltatrac) or mass spectrometer. This should be performed in the presence of low/normal carbon dioxide and a fractional inspired oxygen concentration (FiO2) of approximately 0.35. The response to pulmonary vasodilators such as inhaled NO9 or PGI210 can then be assessed to determine suitability for surgery, or to arrive at a more accurate prognosis. Angiography can be dangerous, but an attempt should be made during catheterisation to exclude pulmonary artery branch stenosis or pulmonary vein stenosis,11 either of which may be difficult to exclude by echocardiography alone. (An alternative would be to undertake cardiac MRI or magnetic resonance angiography (MRA)). The stenosis may be amenable to surgical treatment or stent insertion at interventional cardiac catheterisation. Magnetic resonance imaging has added a significant further dimension to the investigation of PHT. Not only is it possible to determine pulmonary blood flow accurately, it is also possible to visualise detailed anatomy, much better than with conventional angiography.12 Indeed, newer techniques are now possible that are available to measure pulmonary artery compliance and which may supersede angiography, in terms of accuracy of prediction of response to surgery or to medication.13

RISK FACTORS FOR DEVELOPING PHT Left to right shunt The main factors for developing PHT are the size of the shunt and the pressure of blood in the pulmonary artery.14 It seems likely that the degree of shunt causes more stretch in the pulmonary artery and hence increased injury to the endothelium and pulmonary arterial smooth muscle cells. However, it is clear that the type of cardiac defect and the oxygen saturation of the blood in the pulmonary artery are also important. For example, rarely does an atrial septal defect (ASD) cause pulmonary vascular disease. Indeed, there is evidence that the presence of symptoms in infants with secundum ASD suggests the possibility of pulmonary vascular disease from other causes, such as idiopathic PHT, chronic lung disease or pulmonary vein stenosis.15 However, 50% of large VSD cause pulmonary vascular disease by 2 years of age and most infants with transposition of the great arteries and VSD are inoperable by the age of 9 months.16

Transposition of the great arteries This condition seems to obey few of the rules of cardiovascular physiology. Transposition with a VSD will cause

R. M. R. TULLOH pulmonary vascular disease with alarming rapidity17 but this seems reasonable in the face of high pulmonary artery pressure and flow. However, it is less clear why some children with transposition and an intact ventricular septum (and hence with low pulmonary artery pressure) should also fall prey to severe pulmonary vascular disease, even if the arterial switch operation is carried out at a reasonably early age.18

Pulmonary venous hypertension There are many causes of this condition. In the older child with mitral valve stenosis there can be severe PHT which is reversible once the mitral valve has been repaired. The same is often true of the child with dilated cardiomyopathy, who may have systemic levels of PHT secondary to grossly elevated left atrial pressure over a number of years. However, in these children it is not clear how long and how high a pressure is damaging such that a straightforward cardiac transplantation becomes a much more difficult heart and lung transplantation (M. Burch, pers. comm.). The situation is very different in those with pulmonary vein obstruction, usually due to pulmonary vein stenosis, perhaps after repair of total anomalous pulmonary venous connection. This will cause severe PHT at any age, including the newborn period.19 It is notoriously difficult to treat, with few units claiming successful surgery or interventional catheterisation.20 The veins are very reactive and there is a high incidence of pulmonary hypertensive crises in the immediate post-operative period. These are recognised as episodes of sudden and severe rise in the PVR, often presenting as a fall in the systemic oxygen saturations, followed by a bradycardia and perilous falls in cardiac output. These can be lethal, but are less common now that definitive cardiac surgery is performed at a younger age for children with left to right shunt.

PATHOLOGICAL CHANGES AND GENETICS Despite differences in causation, there are many similarities in the histo-pathological changes in the pulmonary vasculature independent of the presence of idiopathic PHT or PHT secondary to congenital heart disease. The first change observed is an extension of muscle into peripheral, normally non-muscular arteries.21 Electron microscopic examination confirms that this is due to differentiation of precursor cells into mature smooth muscle cells.22 Medial hypertrophy then occurs in normally muscular arteries, both due to hypertrophy and hyperplasia of existing smooth muscle cells together with an increase in extracellular matrix. Gradually there is a loss of arterial density, due to impaired growth and loss of arterioles. Later still, there are dilation complexes, with plexogenic lesions and fibrinoid necrosis.4

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Endothelial cells become very abnormal in response to high pressure and high flow, with deep twisted ridges, misshapen cells and an increase in microfilament density along with fragmentation of elastin fibres.23 Abnormal flow leads to production of elastases, which in turn release biologically active mitogens such as fibroblast growth factor (FGF-2) and transforming growth factor (TGF-b). An increase in the glycoproteins tenascin and fibronectin, which amplify proliferative responses and smooth muscle cell migration, lead to hypertrophy of the media of the arterial wall.24,25 There are now many recognised genetic abnormalities in children and families with idiopathic PHT. Approximately 8% of these patients have a familial history of the disease and mutations in the 2q33 3-cM locus, the bone morphogenetic protein receptor-2 (BMPR-2) have been identified and linked to familial PHT.26 Currently, there is little evidence that secondary PHT is linked to a gene in the same fashion, but much work is progressing on the subject and the situation may change in time.27

CONTROL OF PULMONARY VASCULAR RESISTANCE To understand the management of PHT, it is important to have a basic knowledge of the factors involved in PVR control. Although there is some understanding of how relaxation of pulmonary vascular smooth muscle is mediated at the cellular level (Fig. 1), the exact mechanisms by which oxygen, carbon dioxide and pH actually control PVR are poorly understood. There are a number of different pathways by which control of the PVR is effected (Fig. 2). The NO pathway appears to be less effective in the presence of PHT. High levels of cyclic guanosine monophosphate (cGMP) are present in patients with PHT, suggesting that there is an increased level of endogenous NO which is reversing the effect of vasoconstricting factors on the pulmonary vasculature.28,29 There is also evidence for increased amounts of endothelin 1 in response to high flow and pressure.30 The levels of many other factors, such as atrial natriuretic peptide and thromboxanes, have been shown to be abnormal in PHT. It seems likely that all of these will prove to be of value in providing a route for a pharmacological attack on the abnormal vasoconstriction in the pulmonary vasculature in PHT.

PREVENTION AND TREATMENT OF PHT The most important advance in the prevention of morbidity and mortality for children with congenital heart disease and high pulmonary artery pressure and flow, is to operate early in order to prevent the development of pulmonary vascular disease.17 Historically, the measured PVR had to be less than

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Figure 1 The Nitric Oxide (NO) Pathway. Nitric oxide synthase (NOS) promotes the formation of NO in the vascular endothelium from L-arginine and oxygen in a calcium-dependent process. A number of cofactors are involved including magnesium sulphate (Mg2SO4), nicotinamide adenine dinucleotide phosphate (NADPH) and tetrahydrobiopterin. NO diffuses into vascular smooth muscle cells where it acts on guanylate cyclase (GC) to promote formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). This promotes the uptake of calcium by the sarcoplasmic reticulum (SR), leading to relaxation. G, G-kinase; pk, pyruvate kinase; ACh, acetylcholine.

7 U.m2 but this is changing with improved intensive care facilities and the use of NO and other pulmonary vasodilators postoperatively. Certainly, the incidence of PHT postoperatively is much less than 20 years ago.31 It is essential to remember that the basic care of the patient in the intensive care unit is still most important with good attention to adequate ventilation, chest physiotherapy and antibiotics as appropriate. Establishment of good airway mechanics to optimise ventilation is essential to maintain pPA at a low level. Maintenance of a low mean airway pressure, if necessary by high frequency oscillation, keeping pH at the upper limit of the normal range, maintaining good oxygenation and running the CO2 low (paCO2 3–3.5 kPa) will all help to keep the pPA within the normal range, or to reduce it if it is raised. Under these conditions, the effectiveness of pulmonary vasodilators will be markedly increased. In addition, the judicious use of sedation with fentanyl, which has additional sympatholytic activity and clonidine, should act prophylactically against pulmonary hypertensive crises.32 As the cardiac output increases, so does recruitment of small resistance pulmonary arteries. The resulting increase in total cross-sectional area of pulmonary blood flow reduces the PVR. It is important, however, to use inotropes which do not cause pulmonary vasoconstriction. The previous tendency to use dopamine led to inappropriate a activity and pulmonary vasoconstriction. It is preferable to use inodilators since they improve myocardial oxygen supply and cause pulmonary vasodilation. Examples are the

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Figure 2 ETb.

R. M. R. TULLOH

Summary of mechanisms to increase or decrease pulmonary vasoconstriction. GTP, cGMP, PDE III, PDE V, AMP, ATP, ETa,

nitrates such as sodium nitroprusside (SNP), the phosphodiesterase inhibitors such as enoximone, amrinone and milrinone, or even dobutamine, which acts primarily via b receptors. If there is then the need for additional pharmacological agents, NO would be the next drug of choice.33 This has the advantage of being administered by an inhalation route and the dose is easily altered. A typical child with postoperative PHT will only need to be maintained on low dose NO at about 5–10 parts per million. Further agents to work on the NO pathway include sildenafil, a phosphodiesterase V inhibitor.34 Working well on endogenous NO, it also enhances exogenous NO allowing transfer from the intensive care,35 or weaning from high levels of inspired NO. Sildenafil has marked downregulatory responses, meaning that it is less useful as a long term single agent medication, but its use is still being evaluated.36 There are now a range of other medications. The dual endothelin receptor antagonist Bosentan has shown promising results in children with primary PHT37 and also seems to be safe in adults with Eisenmenger syndrome38 but its use in paediatric patients with congenital heart disease and high pulmonary blood flow has yet to be evaluated. In addition, there are newer endothelin receptor (ET-A) antagonists that are being assessed. Prostacyclin (PGI2) has a different mechanism of action, acting directly on the smooth muscle cell and causing a reduction in PVR by means of an increase in cyclic AMP.39 Its effects are additive to those of NO and it can be useful when NO has failed or resistance to NO has occurred. Since there is tolerance to exogenous NO by means of a negative feedback on NO production, PGI2 can be useful during weaning from NO in a similar fashion.40

Since the use of inhaled NO has become more widespread, the need for extracorporeal membrane oxygenation (ECMO) as a rescue treatment for severe pulmonary hypertension has diminished.41 It may still be required if the above measures fail, especially if there is severe PHT exacerbated by respiratory disease, in the presence of severe congenital cardiac disease which requires urgent operation.

Postoperative Pulmonary Hypertension Some children undergo cardiac surgery with little or no complication but discharge echocardiography reveals ongoing PHT. These children will often die young, possibly much earlier than if they had not undergone repair. It is possible that some have underlying primary PHT and that the repair of the cardiac disease has accelerated their demise. However, some may be controlled or even successfully treated by aggressive attention to good airway mechanics, night-time oxygen and even supplemental medication in the postoperative period. There is evidence that those with a good long term outcome will have normal pPA at 1 year post-operatively.17

MANAGEMENT OF CHRONIC PULMONARY HYPERTENSION The British Cardiac Society has recently published guidelines for the management of longstanding pulmonary hypertension in adults and children.8 This document emphasises the need for such patients to be managed in specialist units with experience in investigation and provision of complex forms of treatment. Choice of therapy is based on the findings of vasodilator testing at cardiac catheterisation and

PULMONARY HYPERTENSION IN PAEDIATRIC PRACTICE

includes oral vasodilator therapy with calcium antagonists (such as nifedipine or diltiazem),42 or intravenous prostacyclin.43 All patients should be anticoagulated, ideally with warfarin, and many respond to domiciliary nocturnal oxygen.44 In patients who suffer recurrent syncope, atrial septostomy may be of benefit.45 Patients whose disease is severely symptomatic and progressive despite optimal medical treatment should be considered for lung or heart/ lung transplantation. However, in contrast to the survival for those with primary PHT, which is only about 3 years (without medication), the survival with Eisenmenger syndrome is much longer.14 Finally, although it is not possible to reverse the fixed elevated PVR associated with large untreated left to right shunts, it is hoped that there may be a mechanism found to reverse the damage caused by PHT in congenital heart disease to allow affected children to undergo successful corrective surgery.

PRACTICE POINTS
Primary pulmonary hypertension (PHT) is rare and often genetic in origin.
Secondary PHT is common and most often due to left to right shunt or chronic lung disease. Large ventricular (VSD) or atrioventricular septal defect (AVSD) should be corrected before 4 months of age to prevent pulmonary vascular disease.
Investigation is multifaceted and should be undertaken by a team with cardiac and respiratory facilities.
Echocardiography provides the mainstay of diagnostic tools for PHT.
Cardiac catheterisation is the gold standard for measuring pulmonary vascular resistance, with measured oxygen consumption.
New therapies with oral endothelin antagonists or phosphodiesterase inhibitors are proving promising for the treatment of established pulmonary vascular disease.

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