Circulatory Changes at Birth

During the transition from intrauterine to extrauterine life, major circulatory changes occur which have important implications for the clinical care of the newborn.^1,2 At birth in the normal newborn, the low-resistance placenta is eliminated from the circulation, resulting in an immediate increase in systemic vascular resistance (SVR). The pulmonary vascular resistance (PVR) falls when the lungs become responsible for gas exchange, and the fetal channels, foramen ovale, and arterial duct become redundant and close. In addition to altered hemodynamics in babies born with congenital heart disease, some babies with structurally normal hearts have a persistent right-to-left shunt after birth due to failure of the transition from fetal to postnatal circulation. Babies with this circulatory pattern, which is characterized by failure of the PVR to fall, have persistent pulmonary hypertension of the newborn (PPHN).³ PPHN is one of the two principal causes of nonpulmonary cyanosis in the neonate, the other being cyanotic congenital heart disease.

The right ventricle (RV) and left ventricle (LV) contribute equally to fetal cardiac output. At birth, the LV becomes responsible for the systemic circulation, characterized by its high vascular resistance. The PVR falls suddenly at birth to approximately 50% of fetal levels to facilitate the required increase in pulmonary blood flow. It continues to fall to adult values during the first 6 to 8 weeks of life as the smooth muscle layer in the media of the pulmonary arterioles progressively thins out. The LV progressively adapts to its high-pressure role by rapid myocardial growth, in contrast to the RV, which regresses to its low-pressure subpulmonary role. The presence of congenital heart defects can profoundly alter these adaptive processes (see later).

Physiology of the Neonatal Myocardium

The neonatal myocardium is functionally immature.⁴ Age-dependent changes in intrinsic function and integration with a maturing circulation determines its response to insults such as hypoxia and ischemia.⁵

The myocardium matures in the postnatal period by increasing the number, volume, and conformation of its myocytes. The cell membrane (sarcolemma) develops the T-tubular system, which facilitates rapid conduction of the action potential to the center of the cell, and the arrangement of myofibrils gradually becomes more uniform, improving its contractile function. In parallel with these structural changes, myocellular metabolism matures. Proper contractile function of the cardiac myocyte depends on an efficient excitation-contraction process, which is activated by the binding of calcium to troponin C. In the adult heart, calcium release from the sarcoplasmic reticulum (SR) is the predominant source of calcium for troponin C activation. In contrast in the neonate, activation relies substantially on calcium influx through the L-type calcium channels. Optimal function of the neonatal myocardium is therefore exquisitely dependent on maintenance of normal extracellular calcium concentrations. Other elements of myocyte function are age dependent, such as the sarcoplasmic reticulum calcium-ATPase (SERCA) which is present in reduced quantities in the immature heart. This results in relatively inefficient calcium re-uptake and therefore slower diastolic relaxation of the neonatal compared to the adult myocyte and is at least in part responsible for the prominence of diastolic dysfunction in the failing neonatal myocardium.

Healthy infants have higher plasma concentrations of catecholamines and higher-density cardiac sympathetic innervation than older children and adults. This may partly explain the reduced ability of neonates to increase cardiac output in response to endogenous or exogenous catecholamines. Children in heart failure also have higher plasma catecholamine concentrations⁶ but reduced densities of β-adrenergic receptors compared to age-matched controls.⁷ The effects of this are similar to those seen with exogenous agonist-induced desensitization. Children with severe heart failure show evidence of uncoupling of β₁-adrenergic receptors from the enzyme adenylcyclase⁷ and other maladaptive responses that result in reduced response to receptor agonists. In addition to heart failure, chronic hypoxia, such as is seen in cyanotic congenital heart disease, induces activation of the sympathetic nervous system, with resultant adrenergic receptor desensitization. Developmental aspects of myocardial support have recently been reviewed.⁸ The characteristics of the neonatal ventricle are listed in Table 84-1.

TABLE84-1 Characteristics of the Neonatal Ventricle

Congestive Heart Failure

Although the basic pathophysiologic mechanisms of heart failure have age-independent common mechanisms, the presentation and management of heart failure changes with age. The overwhelming cause of heart failure in the first year of life is congenital heart disease, usually with an intracardiac left-to-right shunt or a ventricular obstructive lesion (Table 84-2). By contrast, the primary abnormality in adult heart failure is usually left ventricular dysfunction. Heart failure in adults is often gradual in onset; the neonate has little functional reserve, resulting in rapid decompensation and an emergent presentation.

TABLE84-2 Common Causes of Heart Failure in Childhood

The clinical features⁹ of heart failure in infants are listed in Table 84-3. A prominent sign of cardiac failure in infancy is difficulty in feeding secondary to increased respiratory rate and effort. This equates to exertional dyspnea in the older child or adult. Failure to thrive results and leads to the classic “wizened” appearance. Although hepatomegaly is a common sign of heart failure in infants (resulting from an increase in total circulating volume and hepatic venous congestion), peripheral edema, ascites, and pericardial or pleural effusions are much less commonly seen than in adults. One relatively common feature of severe heart failure in infancy is the occurrence of compression of the bronchial tree—particularly the left mainstem or lower lobe bronchus—secondary to extrinsic compression by an enlarged left atrium or pulmonary artery. This can cause airway obstruction and associated lobar collapse, or localized hyperinflation due to distal air-trapping. Long-standing extrinsic compression may rarely cause tracheobronchomalacia, resulting in long-term respiratory difficulties even after resolution of heart failure.

TABLE84-3 Clinical Features of Heart Failure in Infants

Cyanosis

Cyanosis is the visible manifestation of greater than 5 g/dL of reduced deoxygenated hemoglobin in cutaneous blood vessels, and is a prominent feature in many types of congenital heart disease. Peripheral cyanosis results from high oxygen extraction ratios across the tissue vascular bed, reflecting low tissue blood flow or high tissue oxygen demand. Central cyanosis results from desaturation of arterial blood, which may be due to pulmonary disease or right-to-left shunting of deoxygenated systemic venous blood in association with a congenital heart defect. Pulmonary and cardiac causes of central cyanosis can usually be differentiated by allowing the child to breathe 100% oxygen (a “hyperoxic test”), which will result in a substantial improvement in oxygen saturation the case of cyanosis of pulmonary origin but have little effect on the child with cyanosis due to right-to-left shunt.¹⁰ During administration of 100% oxygen, arterial oxygen tensions (PaO₂) above 160 mm Hg are highly suggestive of a noncardiac diagnosis, and a PaO₂ over 250 mm Hg excludes it. Occasionally, differential cyanosis is seen where one or both of the upper limbs are normally saturated and the lower limbs cyanosed. The cause is deoxygenated blood traversing the arterial duct to enter the aorta distal to the origin of one or both subclavian arteries and supplying the lower limbs, while oxygenated blood from the left ventricle predominantly supplies the upper limbs.

Chronic hypoxemia induces the twin physiologic responses of erythropoiesis, resulting in polycythemia and an increase in blood volume in a compensatory attempt to maintain oxygen-carrying capacity. However, as hemoglobin concentrations rise, blood viscosity increases and ultimately leads to sluggish flow in the peripheral circulation, cellular aggregation, and the occurrence of thrombotic lesions. Polycythemic patients are at high risk of thrombotic complications in situations of increased fluid loss (e.g., intercurrent diarrheal illness) or inadequate fluid intake (e.g., preoperative fasting). In addition to polycythemia, most children with chronic cyanosis develop finger clubbing, the result of an increased number of capillaries laid down in the vascular beds of the fingers and toes. Rare but important complications of severe cyanosis arise primarily from hypoxemia and polycythemia and include cerebral and pulmonary thrombosis and cerebral abscess.

Pulmonary Vasculature and Pulmonary Hypertension

The pulmonary vascular bed is of central importance to the manifestations of congenital heart disease from the first hours of life. Pulmonary vascular resistance usually falls dramatically in response to aeration of the lungs with the first breaths. Thereafter, the smooth muscle of the pulmonary vascular bed thins gradually during the first months of life, with associated fall in PVR to adult values by approximately 2 months of age. In infants with congenital heart lesions where an intracardiac communication between the systemic and pulmonary circulations is present, such as a ventricular septal defect (VSD), the fall in PVR encourages flow into the low-resistance pulmonary vascular bed, and a left-to-right shunt develops. In response to the increased flow and subsequent shear stress this induces, progressive structural changes occur in the pulmonary arteries and arterioles. Initially these changes consist of accelerated extension of muscle to the distal “non-muscular” pulmonary arteries and medial muscular hypertrophy in the proximal muscular arteries. Later changes involve gradual hypertrophy of the arterial intima, with deposition of collagen and elastin leading to gradual luminal obstruction and eventual occlusion. Associated with this is the development of plexiform lesions, the histologic hallmark of pulmonary vascular disease. Mild pulmonary vascular changes are of little significance to the cardiac intensivist; however, children with more extensive medial muscular hypertrophy of the pulmonary arteries are at risk of labile pulmonary hypertension (PHT) in the postoperative period (see later). The extent of pulmonary hypertensive changes frequently determine the feasibility of surgical options. Children with established fixed high PVR are unsuitable for corrective surgery, as surgical separation of the two circulations in the face of fixed high PVR will result in immediate right ventricular failure. Smaller elevations in PVR determine operability in the single-ventricle Fontan circulation (discussed later). Calculation of PVR and the response to varying vasodilators can be achieved following a pulmonary reversibility study in the cardiac catheter laboratory.^11–13

Pharmacologic Support

β-Adrenergic Agonists

Clinical and experimental studies have demonstrated marked age-related differences in the hemodynamic response to inotropic therapy. Although some of the observed differences may be accounted for by differences in drug pharmacokinetics, the variable maturation of the sympathetic nervous system, its receptors, and the cardiac myocytes mitigate against the recommendation of narrow specific dose ranges for the use of catecholamines in neonates and children.⁸

In clinical pediatric practice, adrenergic agonists are titrated to hemodynamic effect much as they are in adults (Table 84-4). When systolic ventricular function is impaired, low-dose epinephrine is commonly used as the first-line inotrope, although dobutamine and dopamine still have their advocates. Dopamine was formerly preeminent but is now less favored because of its noncardiac adverse effects.¹⁸ Additional agents should be administered according to assessment of response, judged clinically and from available hemodynamic monitoring. Higher-dose epinephrine, norepinephrine, or vasopressin can be used in refractory circulatory failure, particularly if vasodilation is present, such as occurs occasionally after cardiopulmonary bypass in children.^19,20 Isoproterenol is a nonspecific β-adrenergic agonist whose principal cardiovascular effects are vasodilation and increasing heart rate. The drug is rarely used in intensive care except as a chronotropic agent where heart rate is critically low and cardiac pacing not yet established. Caution is needed when higher-dose catecholamine support is used in the neonate, as these can induce a rise in ventricular end-diastolic pressure (EDP) in a ventricle already developmentally noncompliant. Catecholamine-induced myocardial necrosis has been identified in neonatal animal models.^21,22

TABLE84-4 Vasoactive Agents in Children

Pulmonary Vasodilators and Other Strategies to Prevent and Treat Pulmonary Hypertension¹¹

Oxygen alone is a potent dilator of the pulmonary vascular bed, with both alveolar oxygen concentration and systemic oxygen saturation having a favorable influence. Pulmonary vascular resistance is also influenced by lung volume, being raised at both low and very high lung volumes. Avoiding atelectasis, alveolar hypoxia, and pulmonary arteriolar hypoxia are simple strategies to minimize PVR and pulmonary artery pressure. Historically, most IV drugs used to treat PHT had nonselective effects, dilating both the pulmonary and systemic vascular beds. Tolazoline, prostaglandin E1, and prostacyclin are among many agents which have been used as pulmonary vasodilators. Prostacyclin is a short-acting vasodilator which acts via increasing levels of the intracellular messenger, cAMP, which has been widely used in the treatment of primary PHT in children.⁵² The pulmonary effects of such nonselective agents are frequently limited by their nonspecific action leading to clinically important systemic hypotension. In contrast, nitrates, sodium nitroprusside, and indeed nitric oxide act via the activation of guanylate cyclase and hence increase cellular levels of cyclic guanosine monophosphate (cGMP) which is then inactivated by PDE5.

Elevation of PVR is seen in all children following cardiopulmonary bypass (CPB),²⁶ with reactive postoperative pulmonary hypertensive episodes typically occurring in children following correction of left-to-right shunt lesions or in those with preoperative pulmonary venous hypertension.⁵³ These crises are particularly associated with long CPB durations and late presentation for surgery. In the current era, early corrective surgery has dramatically reduced the numbers of infants in whom PHT is a major perioperative issue. Postoperative PHT is still seen in neonates and infants in association with lesions such as obstructed total anomalous pulmonary venous drainage, truncus arteriosus, and mitral valve replacement for congenital mitral stenosis. Children with lesser elevations in PVR may also benefit from pulmonary vasodilatation, including children with predominant RV dysfunction, for instance following cardiac transplantation⁵⁴ and in Fontan circulations and relatively high PVR.⁵⁵ General measures associated with the prevention and treatment of PHT should be considered before deploying specific pulmonary vasodilators (see Table 84-5). In patients at high risk of PHT following cardiac surgery, left ventricular filling can be maintained by right-to-left shunting through a small, surgically created atrial septal defect (ASD). Right-to-left shunt acts as a safety valve, and while some systemic desaturation occurs, LV filling and hence cardiac output are maintained.

Nitric oxide is an endogenous endothelial-derived vasodilator and a gas at room temperature. If added to inhaled gas mixtures in children with reactive PHT, it induces selective pulmonary vasodilation.⁵⁶ It is distributed to ventilated alveoli, from where it diffuses into the adjacent pulmonary arteriolar smooth muscle. Inhaled nitric oxide (iNO) has been shown in randomized controlled trials to be effective and safe therapy in neonates with PPHN. Although the evidence for outcome benefit is limited to one randomized controlled study,⁵⁷ there is a substantial body of evidence to show that iNO is effective in pediatric cardiac patients, including those with acute postoperative PHT following congenital heart surgery^58,59 and following pediatric heart transplantation. Inhaled nitric oxide can also be used in preoperative assessment of patients with PHT.^13,60

Other candidate selective pulmonary vasodilators undergoing investigation in children include inhaled prostacyclin⁶¹; the PDE5 inhibitor, sildenafil^62–64; and bosentan, an endothelin-1 receptor blocker.^65–67

Mechanical Circulatory Support

Extracorporeal membrane oxygenation (ECMO) is a mature technology which has been used to support over 27,000 neonates with respiratory failure, in whom survival rates of 70% to 80% are expected. Its use in this indication is supported by randomized controlled trials that demonstrate good short- and medium-term outcomes.⁶⁸ ECMO and ventricular assist devices (VADs) have subsequently been used to provide temporary circulatory support in children with intractable circulatory failure (see Chapter 93). Indications for mechanical circulatory support include selected children with problems including severe ventricular failure, refractory arrhythmias, and cardiac arrest.^69,70 The aim of mechanical circulatory support in such circumstances is to provide optimal cardiac output while resting the heart, awaiting its recovery, or to achieve survival by successful support of the child to cardiac transplantation. Single-center series⁷¹ and collaborative registry figures of ECMO⁷² or VAD for acute postoperative indications report similar figures for survival to hospital discharge (~40%) in children who (it is assumed) would not have survived without mechanical support. Rapid-deployment ECMO has recently been reported as an effective intervention for the management of cardiac arrest in the pediatric cardiac ICU and cardiac catheter laboratory.⁷³ Hospital survival figures for CPR-ECMO seem encouraging,⁷⁴ but long-term neurodevelopmental follow-up studies are urgently needed before such strategies can be recommended unequivocally.^75,76

Presentation

Most children present with signs and symptoms of heart failure including dyspnea, upper abdominal discomfort, nausea, and vomiting. Abdominal symptoms are often misdiagnosed as indicative of gastroenteritis, although the astute clinician will note the absence of diarrhea. It is presumed that these abdominal symptoms result from hepatic congestion and gut edema as a result of right heart failure or ischemia (from splanchnic vasoconstriction). A history of an antecedent flulike illness is strongly suggestive of a diagnosis of myocarditis. Some children with myocarditis follow a fulminant course typified by rapid onset of cardiogenic shock.^81,82

The chest x-ray in acutely presenting cardiomyopathies typically shows cardiomegaly and pulmonary venous congestion. An echocardiogram will reveal left atrial and ventricular dilatation and impaired systolic and diastolic function and often mitral or tricuspid regurgitation. Electrocardiographic (ECG) features are mostly nonspecific and include ST and T-wave changes and arrhythmias. The presence of Q waves may indicate anomalous origin of the left coronary artery from pulmonary artery (ALCAPA). If ALCAPA cannot be unequivocally excluded by echocardiography, coronary angiography must be undertaken.

As cardiomyopathies result from a variety of acquired or inherited disorders, the differentiation of secondary (and possibly treatable) causes of dilated cardiomyopathy from the idiopathic form of the disease is of the greatest importance. Endomyocardial biopsies can be obtained to assist in the diagnosis of myocarditis and other specific myocardial diseases.

Prognosis

Recent studies have reported 5-year survival rates in childhood cardiomyopathy of between 64% and 84%, although the impact of cardiac transplantation on survival rates is not clear in all studies. In contrast to myocarditis, sudden death is uncommon in children with other forms of dilated cardiomyopathy. Children with cardiomyopathies who fail to respond to conservative treatment, and especially those with ongoing requirement for IV inotropic support, ventilatory support, or mechanical circulatory support and children with recurrent arrhythmias are candidates for early cardiac transplantation.⁸³ Late recovery of ventricular function is, however, possible.⁸⁴ The prognosis for cardiomyopathy due to myocarditis in children appears to differ from adults, with survival of up to 80% among children who reach the hospital alive.^85,86 Many children who survive the acute phase go on to recover normal cardiac function—in marked contrast to adults, in whom mortality rates of 20% at 1 year increased to 56% at 5 years.⁸⁰

ICU Management of Dilated Cardiomyopathy and Myocarditis

In children presenting with acute heart failure, hypotension, or cardiogenic shock, β-adrenergic agonists may improve systolic ventricular function. PDE3 inhibitors such as milrinone are of hemodynamic benefit in acute heart failure, although large trials in adult heart failure have failed to show clear benefit from chronic administration.⁸⁷ While metoprolol and carvedilol may be of benefit in chronic heart failure,^29,39,40 they should be avoided in hemodynamically unstable children. Nasal or mask continuous positive airway pressure (CPAP) has been shown to result in symptomatic improvement both by unloading of respiratory muscles and lowering of LV afterload as a consequence of raising intrathoracic pressure.⁸⁸ Children in severe heart failure have high SVRs and no ventricular reserve. Great care is therefore needed if sedative agents are administered to facilitate tracheal intubation or ICU procedures. Agents with the least effects on the cardiovascular system should be chosen and allowance made for slow circulatory times when titrating sedative doses.

The use of mechanical circulatory support with ECMO or ventricular-assist systems can be life saving in children with myocarditis or cardiomyopathy who develop cardiogenic shock.^89,90 A high proportion of children who receive mechanical support for fulminant myocarditis will recover ventricular function. Those who do not may be bridged to cardiac transplantation. Clearly, survival with a recovered native ventricle is a better outcome for a child than survival via cardiac transplantation. A multicenter series⁸⁶ documented a median time to return of ventricular function of 9 days in those who survived without transplantation. The absolute time limits for recovery of native ventricular function have not been established, although pragmatic decisions on whether or not to proceed to cardiac transplantation should probably be made if cardiac recovery has not occurred after 10 to 14 days of support.⁹¹

Lesions with Predominant Left-To-Right Shunt

Ventricular septal defect is the archetypal lesion associated with left-to-right shunting of blood. VSDs may occur in isolation or in association with other cardiac anomalies. Ventricular output will follow the path of least resistance, resulting in blood shunting across the defect and into the lungs, as the PVR is lower than the SVR. The magnitude of the shunt, usually expressed as the ratio of pulmonary blood flow to systemic blood flow (Qp : Qs), depends on the size of the VSD and the level of the PVR. Small-diameter defects offer resistance at the level of the ventricular septum, limiting flow from the left to right ventricle and maintaining a pressure gradient between the two chambers. Larger-diameter defects are unrestrictive, with no pressure gradient between the two ventricles, and in this situation, flow is solely dependent on the ratio of PVR to SVR. Small, restrictive VSDs rarely result in symptoms in infancy, typically presenting when a cardiac murmur is detected as an incidental finding. Infants with larger unrestrictive VSDs gradually develop congestive cardiac failure due to the increase in pulmonary blood flow which occurs as the developmental fall in PVR falls in the first weeks of life.⁹⁷ Thus the consequences of a moderate or large unrestrictive VSD are increased pulmonary blood flow (high Qp : Qs) and extra volume work demanded of the left ventricle. The volume overload of the LV results in LV enlargement and failure. If large left-to-right shunts are left untreated, PVR gradually rises. Although the initial rise is the result of pulmonary arteriolar muscular hypertrophy which is reversible, irreversible pulmonary vascular obstructive disease⁹⁸ eventually ensues and may result in the onset of right-to-left shunt (Eisenmenger syndrome). For this reason, steps must be taken in all children with congenital heart lesions and raised pulmonary blood flow to correct the lesion or protect the lungs by either a corrective procedure or a palliative procedure such as pulmonary artery banding before severe pulmonary vascular changes develop. With the exception of isolated atrial septal defects, most left-to-right shunt lesions which require surgical intervention present in the first year of life, with heart failure and associated development of PHT. The principal lesions are described next.

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