In 1913, Sir James MacKenzie, physician in charge of the cardiac department at the London Hospital, defined cardiac failure as a condition in which ‘the heart is unable to maintain an efficient circulation when called upon to meet the efforts necessary to the daily life of the individual’. The causes of such circulatory failure in children include sepsis, primary myocardial disease such as myocarditis or cardiomyopathy producing end-stage failure with acute decompensation, and congenital cardiac disease. Children with congenitally malformed hearts suffering circulatory failure can present in the unoperated state, or in the early post-operative period after surgery, when the condition is usually recoverable. Myocardial performance in children with acute circulatory failure depends upon the underlying condition, and in some cases may change with time. The unifying feature for all children with acute circulatory failure is that the heart is unable to meet the circulatory demands of the tissues. Treatment, therefore, must be directed at restoring this critical balance.
Over the past decade, there have been important advances in the approach to the treatment of acute cardiac failure. Treatment has shifted away from a focus on myocardial contractility in favour of strategies which optimise systemic perfusion, protecting the myocardium through manipulation of afterload, control of the demand for oxygen, or in the extreme by providing complete myocardial rest.
The successful management of children with acute cardiac failure depends upon providing careful and individualised treatment, which begins with establishing the underlying cause, with subsequent tailoring of available treatments. In this chapter, I begin with a broad overview of the pathophysiology of circulatory failure in children. I then discuss the spectrum of available therapies for acute circulatory failure, focusing on pharmacological agents, and non-pharmacological treatments, considering both extracorporeal support and ventilation. The principles of good, basic intensive care, and the application of understanding of the complex circulatory physiology of children with cardiac disease, will complement all of the ensuing discussions, as these are prerequisites for successful therapy.
THE PATHOPHYSIOLOGY OF ACUTE CIRCULATORY FAILURE
Acute circulatory failure in children with cardiac disease can be classified into five broad categories, according to intrinsic cardiac function, global cardiac output, and overall balance of oxygen. These categories differ significantly in their manifestations, underlying causes, and subsequent therapeutic strategies, but share a common feature, which is the phenomenon of systemic hypoperfusion.
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Acute myocardial dysfunction with reduced cardiac output and increased afterload. Acute myocardial dysfunction with reduced systemic delivery of oxygen characterises the low cardiac output which complicates the post-operative course of around one in four children early after cardiopulmonary bypass. A fundamental feature of this is an elevated ventricular afterload, abnormal ventriculo-vascular interactions, as well as impaired systolic and/or diastolic function. This is the most commonly encountered cause of acute circulatory failure in children with cardiac disease.
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Preserved myocardial function with normal cardiac output but systemic hypoperfusion. Inadequate systemic delivery of oxygen can affect infants with a functionally univentricular heart and good ventricular contractility whose total cardiac output may be normal, but is maldistributed between the pulmonary and the systemic circulations. These infants are very dependent upon the maintenance of stable pulmonary and systemic vascular resistances, and even small changes in these can precipitate rapid circulatory failure and systemic hypoperfusion.
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Preserved systolic function with abnormalities of diastolic function. A proportion of patients with normal systolic function after surgical repair of tetralogy of Fallot, or conversion to the Fontan circulation, can develop a low cardiac output early after surgery which is secondary to diastolic dysfunction and inadequate flow of blood to the lungs. In these patients, treatment is directed at optimising diastolic function and cardiopulmonary interactions, while avoiding interventions which increase contractility.
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Residual anatomic lesions in post-operative patients. In a minority of patients after cardiac surgery, a low cardiac output state may be secondary to residual anatomic problems. In the absence of targeted investigations, these are often clinically indistinguishable from other causes of a low output, but are generally resistant to, or paradoxically may be worsened by, conventional medical interventions.
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Preserved myocardial function with normal or increased cardiac output. Inadequate systemic delivery of oxygen in the presence of normal myocardial function, reduced afterload, and normal or increased cardiac output, is an important, though unusual cause of acute circulatory failure. In this setting, despite a seemingly normal cardiac output, the total or regional demand for oxygen is excessively high. This occurs in children with sepsis, or the systemic inflammatory response syndrome. Deceptively, the prodrome of acute myocarditis may also present in this way, but this so-called honeymoon period generally precedes a rapid circulatory collapse.
The first four categories described above generally affect infants and children with congenitally malformed hearts who are undergoing cardiac surgery. We can surmise, therefore, that circulatory failure in many infants and children with heart disease is to an extent predictable. In these patients, therefore, medical management should routinely include proactive strategies which are targeted at the prevention of this phenomenon. If circulatory failure does occur, then this should prompt early investigation and subsequent therapeutic intervention with appropriate measures.
A FRAMEWORK FOR THE MANAGEMENT OF ACUTE CIRCULATORY FAILURE IN CHILDREN
Acute cardiac failure in adults is often unexpected, whereas this condition is often predictable in many children with pre-existing cardiac disease. This unusual paradox presents a great opportunity for pre-emptive management in children who are undergoing surgery for congenitally malformed hearts, with the appropriate tailoring of postoperative management. Where anticipatory therapy is not possible, for example in acute myocarditis, or in circumstances where this does not prevent circulatory failure, then a proactive approach with early investigation, consideration of therapeutic targets, and appropriate intervention is recommended.
The Importance of Detailed Investigation
Although circulatory failure may be predictable in some settings, such as the post-operative period after cardiopulmonary bypass, it is unwise simply to accept its onset without considering early reinvestigation to guide therapy or to rule out a treatable cause. In children with circulatory instability early after cardiac surgery, echocardiography can immediately differentiate systolic and diastolic dysfunction, or may reveal an unexpected, acutely treatable cause such as a pericardial effusion. Similarly, detailed electrocardiography and atrial electrograms may demonstrate a treatable arrhythmia as the cause ( Fig. 14-1 ). Moreover, echocardiography or additional imaging with cardiac catheterisation or computerised tomographic angiography may confirm or exclude anatomic causes for circulatory failure, such as collateral circulations, residual intracardiac shunting, or obstruction in the pulmonary or systemic circulations ( Fig. 14-2 ).
Circulatory failure in post-operative cardiac patients can be due to different causes, which may be clinically indistinguishable, but which require very different treatments. Timely investigations, therefore, avoid the inappropriate use of therapies which may further exacerbate the underlying problem or its clinical manifestation. This is particularly relevant when circulatory failure is related to a tachyarrhythmia such as junctional ectopic tachycardia, an undiagnosed anatomic outflow obstruction or pure diastolic dysfunction. In these situations, which may all be clinically indistinguishable from systolic myocardial dysfunction, escalating inotropic therapy generally will further potentiate the haemodynamic instability. Having highlighted the importance of diagnosing or excluding treatable causes for circulatory failure, as part of a pragmatic approach to management, we must next focus upon current therapies for primary circulatory failure.
Therapeutic Targets
The basic premise for the management of acute circulatory failure is to restore the systemic balance of oxygen, by manipulating one or more of the following:
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Systolic function
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Diastolic function
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Preload
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Afterload
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Consumption of oxygen
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Cardiopulmonary interactions
This is most often achieved using one or more of the therapeutic tools listed below.
Therapeutic Tools
A variety of tools are available for the treatment of acute circulatory failure in children. Those which will be discussed in further detail are:
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Ventilation to optimise cardiopulmonary interactions
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Pharmacological agents to improve contractility and loading conditions
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Mechanical support, such as extracorporeal membrane oxygenation, or use of devices providing temporary ventricular assistance to optimise cardiac output while allowing myocardial rest.
In the remainder of this chapter, I will discuss how these essential haemodynamic tools can be applied to infants and children with circulatory failure in the intensive care unit.
THERAPIES FOR CIRCULATORY FAILURE IN CHILDREN
Ventilation
In this section, I discuss the application of one of our most basic haemodynamic tools, namely ventilation, in relation to children with cardiac disease. In addition to its primary function, which is to maintain gas exchange, ventilation is an important haemodynamic tool in children with cardiac disease, and should routinely be used to optimise the systemic perfusion. Cardiopulmonary interactions describe the interplay between spontaneous or mechanical ventilation and the cardiovascular system. These interactions differ greatly in health and disease, and unique interactions are present in children with congenitally malformed hearts.
The application of mechanical ventilation in children with circulatory failure requires an understanding of the underlying diagnosis and physiology, and of how cardiopulmonary interactions may therefore be tailored for an individual. Similar to inotropes, an approach which may benefit one patient may be highly detrimental to another, which highlights the importance of understanding the underlying pathophysiology.
Cardiopulmonary Interactions: Ventilation and the Cardiovascular System
The modern understanding of cardiopulmonary interactions has largely followed pioneering work from Cournand and his co-workers in the mid-1900s. 1 This group carried out a number of fundamental investigations, which addressed many aspects of the complex relationship between spontaneous and mechanical respiration and the cardiovascular system. They showed that, in the healthy circulation, the fall in intrathoracic pressure during spontaneous inspiration was associated with an increase in cardiac output secondary to increased right ventricular preload. Conversely, positive pressure ventilation produced a reduction in venous return and right heart filling, resulting in a small reduction in cardiac output which was proportional to the mean airway pressure ( Fig. 14-3 ).
The effects of ventilation are not confined to its influences on the preload of the right heart. Positive pressure ventilation can also impede the emptying of the right heart through its effects on pulmonary vascular resistance, and may also reduce left ventricular afterload through a reduction in transmural left ventricular pressure. 2 These haemodynamic effects are, in practice, of minimal importance in the healthy individual. In the presence of circulatory failure, or in patients at risk for this, cardiopulmonary interactions become much more relevant in both the genesis of the problem, and in its treatment.
Cardiopulmonary Interactions in Children with Systolic Ventricular Dysfunction
In an historic study in 1973, it was shown that some adults with systolic ventricular dysfunction following open heart surgery responded to separation from positive pressure ventilation with an unexpected fall in cardiac output which was not associated with any disturbance in gas exchange. 3 Positive pressure ventilation reduces the work of breathing, filling of the right heart, and left ventricular transmural pressure, resulting in reduced left ventricular afterload. These cardiopulmonary interactions may be very desirable in patients with impaired systolic ventricular function, and are obviously lost on extubation from positive pressure ventilation. Similar haemodynamic effects also contribute to the improved early outcomes of adults presenting with acute, decompensated cardiac failure who are treated with non-invasive positive pressure ventilation. 4
Positive pressure ventilation should therefore routinely be considered as a form of haemodynamic support for young infants with systolic impairment early after cardiac surgical repair. Common post-operative examples where infants may benefit from the reduction in right ventricular preload, left ventricular afterload and work of breathing afforded by positive pressure ventilation include the arterial switch operation, reimplantation of an anomalous left coronary artery from the pulmonary trunk or relief of left ventricular obstruction. These infants, and others with significant cardiac dysfunction may also benefit from a period of continuous positive airways pressure as ongoing haemodynamic support following extubation. Children with acute myocardial dysfunction secondary to sepsis or myocarditis may similarly benefit from positive pressure ventilation, through either an endotracheal tube or via the non-invasive route.
Cardiopulmonary Interactions in Children with Abnormalities of Diastolic Function
Infants and children with diastolic impairment associated with congenital cardiac disease respond very differently to mechanical ventilation, and this highlights, once again, the importance of anticipating or diagnosing the problem, and tailoring therapy according to the underlying physiology. A low cardiac output in the presence of normal systolic ventricular function can complicate the early post-operative period of infants and children after surgery on the right heart, specifically after repair of tetralogy of Fallot, or establishment of the Fontan circulation. Although the anatomies of these entities are very different, their cardiopulmonary physiology in the early post-operative phase is in fact very similar.
The cardiac output of patients with the Fontan circulation is critically dependent upon the pulmonary vasculature. Consequently, the low cardiac output in these patients is most often related to inadequate flow of blood to the lungs, rather than problems with systolic ventricular function. In the absence of a subpulmonary ventricle, these patients depend upon the fall in intrathoracic pressure during spontaneous respiration in order to maintain flow to the lungs. Conversely, a positive intrathoracic pressure can impede or even reverse such flow. 5 Indeed, in his original description of his operation, Fontan observed the clinical improvement that accompanied extubation, and recommended that spontaneous respiration be established early after surgery. 6
A subgroup of patients early after repair of tetralogy of Fallot have a reduced cardiac output secondary to restrictive right ventricular physiology, and their cardiac output is very dependent upon diastolic forward flow to the pulmonary arteries. Of key importance for the intensive care of these patients, as for those with the Fontan circulation, is that their pulmonary flow is critically related to intrathoracic pressure. In children with restrictive physiology, increases in airway pressure reduce or completely obliterate the diastolic pulmonary flow, which is an important source of cardiac output. Conversely, by mimicking spontaneous respiration, negative pressure ventilation augments cardiac output. 7
Thus, children with the Fontan circulation, and a sub-group of patients early after repair of tetralogy of Fallot, share some fundamental, and quite unique cardiopulmonary interactions in the early post-operative period. In these patients, inappropriate ventilatory management using principles applied to children with systolic dysfunction could exacerbate clinical instability. The pre-emptive or early proactive circulatory management should include the use of low ventilatory pressures, and early extubation where possible.
Cardiopulmonary Interactions in the Functionally Univentricular Circulation
Ventilation is a very simple, and fundamental tool which can, and should, be used to manipulate the perfusion of young infants with a functionally univentricular circulation. Similar principles can be applied to infants with hypoplastic left heart syndrome and its variants before or after surgery, to infants with a common arterial trunk in the pre-operative setting, and to neonates early after a systemic-to-pulmonary shunt. The maintenance of a stable pulmonary resistance is key to the early optimisation of these infants, and this is greatly influenced by ventilation. Seemingly minor increases in pulmonary blood flow secondary to alkalosis, or excess inspired oxygen, can compromise systemic flow. A time of particularly high risk is immediately after birth, when there may be a temptation to resuscitate these infants with oxygen, or hyperventilation. Even minimal periods of supplemental oxygen can be highly detrimental to these infants, and can precipitate metabolic acidosis, shock and circulatory collapse. This is an important factor which differentiates the resuscitation of infants with a prenatal diagnosis, from those without, in whom supplemental oxygen is more likely to be administered. The outcome of these infants is in part associated with their worst acid-base state, which is critically related to ventilatory management, and is influenced by the timing of diagnosis. 8
In infants with a functionally univentricular circulation who are haemodynamically unstable in the pre-operative period, conservative levels of positive pressure ventilation can be used to control pulmonary flow. Ventilation using high airway pressures, or slow rates, is no longer used deliberately to induce respiratory acidosis and pulmonary vasoconstriction, as acidosis is not advantageous to these infants. Instead, mechanical ventilation stabilises the pulmonary resistance, and in turn this helps to optimise the systemic perfusion.
The use of supplemental nitrogen or carbon dioxide, delivered with the ventilatory gases, to augment the systemic perfusion before or after Norwood-type operations, has also been investigated. There is limited data which suggest that, while the addition of nitrogen to achieve an inspired oxygen fraction of around 0.17 lowers the systemic arterial saturations, it also reduces the mixed venous saturation and cerebral delivery of oxygen. In contrast, the addition of 3% carbon dioxide to the ventilatory circuit improves mixed venous saturation and cerebral saturation without changing the systemic arterial saturation, suggesting that this manoeuvre does improve the systemic delivery of oxygen in high risk infants. 9,10
Summary of Ventilation as a Haemodynamic Tool
Children with cardiac disease have complex, and varied, cardiopulmonary interactions, which depend upon the underlying diagnosis, type of surgery, and associated myocardial function. Ventilation should routinely be tailored to manipulate haemodynamic performance, and may often be of more benefit to the child than pharmacotherapy ( Table 14-1 ).
| SPONTANEOUS RESPIRATION | POSITIVE PRESSURE VENTILATION/CPAP | ||||
|---|---|---|---|---|---|
| Nature of Cardiac Failure | Key Considerations | Cardiopulmonary Features | Haemodynamic Effect | Cardiopulmonary Features | Haemodynamic Effect |
|
|
|
|
|
|
| Post-op tetralogy of Fallot |
|
| Improved cardiac output |
| Reduced cardiac output |
| Post-op Fontan |
| Increased preload | Improved pulmonary flow and cardiac output |
| Reduced cardiac output |
| Duct-dependent systemic flow |
| Respiratory alkalosis and oversaturation often associated with low pulmonary vascular resistance | May result in excessive pulmonary flow, reduced systemic perfusion | Better control of pulmonary flow, pH, and pulmonary resistance | Improved systemic cardiac output |
Cardiovascular Drugs
In recent years, the approach to pharmacological therapy for acute circulatory failure has moved away from the historical premise that the default target for treatment should be myocardial contractility. A better understanding of the pathophysiology and haemodynamic manifestations of circulatory failure in children has resulted in a shift away from therapy using pure inotropes to measures which also focus on the peripheral vasculature, and the interactions between the periphery and the myocardium. Current approaches are aimed at optimising afterload and manipulating contractility with careful, not excessive, inotropic therapy, while avoiding any unwanted increases in vascular resistance or myocardial oxygen consumption.
Drug therapies for acute circulatory failure are generally categorised according to their pharmacological actions, and also by their physiological effects. The classes of drugs most commonly used to treat acute circulatory failure in children are catecholamines and phosphodiesterase inhibitors. More recently, a number of newer drugs which influence cardiovascular function through very different mechanisms including sensitisation to calcium, and neurohormonal effects, have also become available for clinical use. The physiological effects of drugs used to treat cardiac failure are inotropic, vasodilator or a combination of the two, the so-called inodilator effect.
Special Considerations in Children
When approaching pharmacological treatment of cardiac failure in infants and children, it is important first to consider some unique factors affecting children, which influence the choice of therapy in specific situations.
Maturational Influences
The neonatal myocardium differs significantly from the more mature heart in its innervation, and contractile reserve. The neonatal heart is less densely supplied with sympathetic nerve terminals than older infants and adults, which results in reduced myocardial effects, and less re-uptake of catecholamines. This latter factor may also predispose to the cardiotoxicity of catecholamines which has been described in the neonatal myocardium. 11 The newborn myocardium is, conversely, more sensitive to changes in intracellular calcium such that agents which act upon this may be of greater utility.
The Pulmonary Vasculature
Pulmonary hypertension, or lability of the pulmonary vascular resistance, is commonly encountered in newborns and infants with cardiac disease, and changes in pulmonary vascular tone can play a role in the genesis of circulatory failure in some patients. Patients at increased risk of pulmonary hypertension include those with structural heart disease resulting in excessive pulmonary blood flow, pulmonary venous hypertension or a functionally univentricular circulation. Pulmonary vascular instability can be further compounded in the newborn transitional circulation, and by cardiac surgery and cardiopulmonary bypass which disturbs the balance between endogenous pulmonary vasodilators and constrictors. 12,13
Complex Circulations
Careful control of vascular tone is a pre-requisite for the circulatory management of patients with more complex congenitally malformed hearts, in particular those with a functionally univentricular heart. In these patients, acute changes in pulmonary or systemic vascular resistance can immediately impact on the systemic delivery of oxygen, and can rapidly precipitate acute circulatory failure. In these patients, stable pulmonary vascular resistance, and an appropriately dilated systemic vasculature is highly desirable. 14,15
The presence of severe congenital cardiac disease can also impact on the responsiveness of the heart to exogenous agents. Sympathetic dysregulation is most marked in newborns and young infants with cyanotic or critical acyanotic cardiac disease. In these infants, a reduced density of β-adrenoreceptors is associated with elevated endogenous levels of noradrenaline and a partial uncoupling of the receptor to adenylate cyclase. As a result the myocardium is less responsive to β-adrenergic stimulation. 16
Catecholamines
Adrenaline, noradrenaline and dopamine are endogenous neurotransmitters that play a central role in the physiological response to physiological stressors including hypoxia, hypotension, hypovolaemia, acidosis, temperature, and pain. Exogenous catecholamines are commonly administered to infants and children with circulatory failure, or to those who are at risk for this.
Catecholamine Receptors
Catecholamines produce their clinical effects through their interaction with post-synaptic α- and β-adrenergic receptors, and dopaminergic receptors, which are located on the myocardium, and on the peripheral vasculature. The α 1 -, α 2 -, and β-adrenoreceptors were originally characterised by Ahlquist in 1948. Each is known to have at least three sub-types. The physiological effects of catecholamine receptor stimulation are produced through alterations in intracellular ionised calcium.
Physiological Effects of Individual Receptor Stimulation
Stimulation of α 1 -receptors leads to increased influx of calcium to the post-synaptic effector cell, resulting in peripheral vasoconstriction; α 2 – and β-adrenergic agonists bind to their respective G-protein coupled adrenoreceptors, and activate adenylate cyclase which increases intracellular cyclic-adenosine monophosphate. This produces increased contractility, heart rate, and vasodilation. Dopamine receptors are located on tissues and the peripheral vasculature. They are classified into two categories according to their structure and actions. These receptors are generally referred to as dopamine 1 -like, specifically dopamine 1 and dopamine 5, subtypes, and dopamine 2 -like, comprising dopamine 2 , 3 , and dopamine 4 subtypes. 17–19 Stimulation of dopamine receptors results in vasorelaxation through two potential mechanisms. Stimulation of dopamine 1 -like receptors reduces the sensitivity of the post-synaptic cell to intracellular calcium. 20 Stimulation of dopamine 2 -like receptors, in contrast, inhibits release of noradrenaline from the nerve terminal. 21
Pattern of Receptor Stimulation by Individual Catecholamines
Adrenaline
Adrenaline is an α- and β-agonist, which at lower doses theoretically produces predominantly β-effects, such as increased heart rate and contractility, with some reduction in peripheral resistance, and an increase in cardiac output. At higher doses, adrenaline stimulates α-receptors and increases vascular resistance, with a concomitant increase in myocardial demand for oxygen. Although the effects are in theory dose-related, in practice the degree of relative β- versus α-effects in response to adrenaline is unpredictable, and systemic vasoconstriction is common.
Noradrenaline
Noradrenaline predominantly stimulates α-receptors, resulting in systemic vasoconstriction, without directly influencing cardiac output. This may be desirable in the presence of excessive vasodilation, but can potentially worsen the cardiovascular performance in patients with elevated ventricular afterload and borderline ventricular function.
Dopamine
Dopamine was identified as an endogenous neurotransmitter in 1958, 22 and was subsequently shown to have pressor effects, 23,24 and direct cardiac effects. 25 Dopamine stimulates α, β, and dopamine receptors, and produces an array of physiological responses with vasodilation secondary to dopaminergic stimulation, and α- and β-adrenergic stimulation at higher doses. The theoretical dose-related spectrum of effects led to the labels of renal and cardiac doses being applied for lower and higher doses, respectively. This concept is now obsolete, as there is no evidence to support such specific dose-selective actions. 26 Thus, the physiological effects seen when dopamine is administered are increases in contractility, heart rate, and vascular tone, with little if any convincing evidence of systemic vasodilation.
Dobutamine
Dobutamine was originally developed as a selectively inotropic catecholamine for adults with circulatory failure. 27 The drug has primarily β-adrenergic effects, with increased contractility and peripheral vasodilation, accompanied by a modest increase in heart rate. 28 It also improves myocardial flow, which balances adverse effects on consumption of oxygen brought about by the chronotropic response. 29
Caveats with the Administration of Catecholamines
The clinical response to catecholamines is often less clear-cut or predictable than might be hoped. This is, in part, related to the highly variable dose-response relationship which has already been described. It is also due to the intrinsic property of most agents to produce multiple physiological effects, and due to unique factors present in children.
Unpredictable Pattern of Catecholamine Receptor Stimulation
Catecholamines have multiple physiological effects, and the overall efficacy of a single agent relies on any undesirable effects being counter-balanced by beneficial effects. For example, if the chronotropic response to adrenaline or dopamine, which may result in increased myocardial consumption of oxygen, to adrenaline or dopamine is not met with an appropriate increase in myocardial flow, then myocardial ischaemia may result. Moreover, a single catecholamine may stimulate more than one receptor, which could produce exactly opposing effects. For example, exogenous dopamine may concomitantly produce α-mediated vasoconstriction and dopaminergic vasodilation. A desired effect can also prove detrimental if endogenous cardiovascular compensation is not achieved. The administration of noradrenaline can produce peripheral vasoconstriction. The resulting increase in ventricular afterload may need to be met by an increase in contractility, and if this cannot be achieved through endogenous compensation, the net result is worsening of the cardiac output.
Factors Related to the Patient
Downregulation of catecholamine receptors due to elevated endogenous levels is well-recognised in critically ill infants and children with cardiac disease. Specific circumstances include patients who have received exogenous catecholamines for prolonged periods, those with cardiac disease and overwhelming circulatory failure, and children who have recently undergone cardiopulmonary bypass. 30,31
Clinical Application of Catecholamines in Children
Despite the factors which are listed above, catecholamines remain the first line therapy for acute circulatory failure in children. This is undoubtedly related to familiarity with these drugs and our ability to work around aspects of their inherent unpredictability, features which are somewhat off-set by their rapid onset of action and short half-life. 32,33 In addition catecholamines are widely available and relatively cheap.
Clinical Trials Comparing Effects of Catecholamines
A number of randomised studies in adults have suggested that, as a single agent, dobutamine is superior to dopamine in its haemodynamic effects in post-cardiac surgical patients, 34 after major surgery, 35 and in the setting of septic shock. 36 There are few clinical trials comparing the haemodynamic effects of catecholamines in paediatric cardiac intensive care, and none which focus on objective outcome measures. In children with cardiac disease, it is extremely important to consider not only cardiac output as a marker of the haemodynamic efficacy of a catecholamine, but equally to consider its influence on other vascular beds. While dopamine and dobutamine both improve the global cardiac output in infants and children after cardiac surgery, 37,38 dopamine, and not dobutamine, increases pulmonary vascular resistance in these patients. 39 In a model of right ventricular injury and pulmonary hypertension, dopamine, dobutamine and adrenaline all produced similar improvements in right ventricular function. Dobutamine and adrenaline, but not dopamine, reduced the pulmonary vascular impedance, and adrenaline was the only agent which improved overall pulmonary vascular and right ventricular coupling. 40
Adrenaline
Adrenaline is generally administered as an inotropic agent in patients with poor myocardial function, for example early after cardiac surgery. Even at the lowest doses, systemic vasoconstriction may complicate the administration of adrenaline, and this can exacerbate the elevated ventricular afterload which is characteristically common in the early post-operative period. In order to overcome unwanted systemic vasoconstriction, consideration should be given to the concomitant, and careful, addition of a short-acting intravenous nitro-vasodilator.
Noradrenaline
Noradrenaline should be used carefully as a single agent in cardiac intensive care, as it generally increases the systemic vascular resistance without any compensatory enhancement of cardiovascular performance. It may, therefore, exacerbate a low cardiac output in patients with minimal myocardial reserve and borderline ventricular function. When used in low doses, nonetheless, it is useful for patients with circulatory failure secondary to a post-operative systemic inflammatory response. Noradrenaline can be used either alone, or in combination with careful inotropic support, to improve pulmonary perfusion in patients where this is critically reduced, or coronary arterial perfusion in patients with diastolic run-off. Examples are patients with a borderline cardiac output but good ventricular function after conversion to the Fontan circulation, young infants after construction of a systemic-to-pulmonary arterial shunt, or infants with a critically obstructed pulmonary circulation prior to any surgical relief.
Dopamine
The systemic and pulmonary vasoconstriction which often accompanies the administration of dopamine somewhat negates its desirable inotropic effects, and renders the agent less useful as a single agent for infants and children with circulatory failure. This can, in part, be mitigated by combining dopamine with a systemic vasodilator. Dopamine, nonetheless, is uncommonly used in paediatric cardiac intensive care.
Dobutamine
Dobutamine is arguably the most commonly used single agent for the treatment of acute circulatory failure in all age groups. The appeal of dobutamine as a single agent arises from the combination of its inotropic effects with systemic and coronary vasodilation, which unlike other catecholamines co-exist at a single dose. These properties underpin its popularity in infants and children weaning from cardiopulmonary bypass, and in the initial treatment of primary myocardial failure.
Phosphodiesterase Inhibitors
These agents are classed as inodilators, being agents with both inotropic and vasodilator properties.
The Biology of Phosphodiesterase Inhibitors
Phosphodiesterase inhibitors are derivatives of bypridine. They prevent the intracellular hydrolysis of 3’5’ cyclic adenosine monophosphate by the enzyme phosphodiesterase III, which is plentiful in the myocardium and vascular smooth muscle cells. There are three such inhibitors, namely amrinone, enoximone, and milrinone. Their pharmacological effects are mediated through an increase in intracellular cyclic adenosine monophosphate, which has been shown to result in peripheral and coronary vasodilation, increased myocardial contractility, and improved myocardial relaxation. 41–43 In theory, therefore, they are inodilators with additional lusitropic, or diastolic relaxant, effects.
Milrinone
Milrinone is the phosphodiesterase inhibitor which is most widely used at present. It improves cardiovascular performance through systemic vasodilation, and has additional pulmonary vasodilator properties, which may be particularly desirable in young infants at risk of post-operative pulmonary hypertension. 44 It is now very frequently used in paediatric cardiac intensive care as a short-term infusion, and its most common use is in the early period after cardiopulmonary bypass, where its prophylactic use has been shown to prevent the onset of a low cardiac output in patients already receiving intravenous catecholamines. 45
Most clinicians readily refer to milrinone as an inodilator . There is no question that milrinone is a potent vasodilator. It is unclear whether the clinical improvement, or maintenance, of haemodynamic stability in children receiving milrinone may simply be through a reduction in afterload alone, or whether this is also attributable to its inotropic and lusitropic properties. In order to investigate this, a comparison of the haemodynamic effects of milrinone with a pure vasodilator would be necessary.
Pharmacology of Milrinone
Milrinone has a more complex pharmacokinetic profile than catecholamines. It has a slower onset of action, a much longer half-life, around 3 hours, and is excreted unchanged by the kidney. In order to achieve its maximum efficacy in a timely manner, milrinone must be administered as a loading dose followed by a continuous infusion. The dose administered should be adjusted according to both age, and renal function. 46,47 The clinical effects are generally evident for between 6 and 24 hours after discontinuing the infusion, and this important observation should influence the timing of initiating oral vasodilator therapy.
Caveats with Administration
An important consideration when administering milrinone is that the vasodilation, and the reduction in filling pressures which accompany its initial use may be substantial. This is particularly significant following cardiopulmonary bypass and ultrafiltration, when the patient is often hypovolaemic. To this end, a bolus of colloid should be available to militate against this effect during the early phase of administration. In general, its overall beneficial effects outweigh this temporary and avoidable phenomenon.
A more important consideration with all phosphodiesterase inhibitors is the confidence with which a vasodilator with a long duration of action can, or should, be administered to a given patient. For example, the use of milrinone as the first-line agent in patients with any potential for fixed cardiac outlet obstruction would not be recommended, as the fall in preload and afterload may impair subsequent systemic and/or pulmonary perfusion. In these circumstances, the initial use of a vasodilator with a short half-life, such as a nitro-vasodilator, would be advisable in order to ascertain whether vasodilation will be tolerated.
Clinical Uses of Milrinone
Milrinone is a useful agent for infants and children who have, or who are at risk of developing acute cardiac failure secondary to ventricular dysfunction, for example children immediately after cardiac surgery in whom there is no obstruction to the ventricular outlets. In this setting, milrinone can be used as a single agent, or as an adjunct to an inotropic catecholamine. Milrinone may also be useful in children who are at additional risk of developing circulatory failure secondary to post-operative pulmonary hypertension, for example after closure of a large intracardiac shunt, or after early neonatal reparative surgery. Additional clinical uses include patients with severe myocardial dysfunction which is unrelated to cardiac surgery, for example children with an acute decompensation of chronic cardiac failure.
Newer Vasoactive Agents
Sensitisers to Calcium
The role of calcium in cardiovascular regulation has been alluded to in this chapter and elsewhere. It is clear that the majority of cardiotonic drugs exert their haemodynamic effects either directly or indirectly through their influence on intracellular calcium. Most inotropes increase contractility through changing concentrations of ionised calcium within the cytoplasm or sarcoplasmic reticulum of the cardiomyocyte. An additional mechanism of action of cardiovascular agents has recently been established, which is to increase the sensitivity of the contractile apparatus to calcium without altering its total intracellular concentration. 48 Levosimendan was the first such agent to enter clinical practice, and has gained great popularity in the treatment of adults with circulatory failure.
Biology of Levosimendan
Levosimendan increases myocardial contractility through sensitisation to calcium. Levosimendan also produces coronary and peripheral vasodilation by opening the adenosine triphosphate–dependent potassium channels within the mitochondria of vascular smooth muscle. 49 Levosimendan, therefore, has very different molecular actions to those of all the drugs so far discussed, and all of these properties would make it a very appealing drug as the primary, adjunctive, or secondary therapy for children with acute circulatory failure.
Levosimendan has been widely investigated in a number of models of cardiovascular dysfunction, and is known to improve global haemodynamics and left and right ventricular systolic function, without increasing the myocardial demand for oxygen. Its effects, however, are not confined to myocardial contractility, and the agent also has been shown to optimise right and left ventriculo-vascular coupling, along with systemic and pulmonary vascular resistances, in laboratory models of myocardial injury. 50,51
Pharmacology and Administration of Levosimendan
The concept of treating acute circulatory failure with long-acting vasoactive drugs has already been introduced. Levosimendan has much longer duration of clinical effects than milrinone, and its pharmacokinetics have dictated its unusual dosing regime. It has at least two active metabolites, which both have prolonged effects. 52 The current recommended dose regime for levosimendan in adults is for a bolus dose to be followed by an infusion for 24 hours. Thus, a single infusion of levosimendan produces haemodynamic effects which last for between 4 and 7 days. The unique pharmacokinetics of levosimendan result in the potential for its use in a cyclic manner, or potentially rotating with intermittent catecholamine administration.
Clinical Application of Levosimendan
Levosimendan has been widely investigated in adults with acute decompensated cardiac failure, and early experience suggested improved survival in these patients when compared with dobutamine. 53 This observation, however, was not borne out in the more recent SURVIVE study. 54 Levosimendan has also been shown to improve right ventricular performance in patients with acute lung injury, 55 and regional perfusion in patients with septic myocardial dysfunction. 56 In combination with dobutamine, levosimendan appears to have superior haemodynamic effects, and improves early outcome compared with milrinone in high risk adults after cardiac surgery. 57
Levosimendan would appear to be a very appealing agent for use in infants and children requiring continued cardiovascular support, in whom prolonged treatment with catecholamines is likely to be met with tachyphylaxis. In these patients, the administration of a single dose of levosimendan should enable the discontinuation of catecholamines, with their reintroduction several days later, by which time receptor-responsiveness is likely to have been regained. This approach has been shown to improve survival when compared with a single dose of catecholamine in adults with severe cardiac failure. 58
Levosimendan in Children
The experience with levosimendan in children is currently very limited. We have recently reported improved ejection fraction and reduced catecholamine requirements in children with severe cardiac failure who were given levosimendan ( Fig. 14-4 ). 59 Its role in children early after cardiac surgery has not been established, though the agent shows great promise in this area. In a laboratory comparison of levosimendan and milrinone in a model of infant cardiac surgery, we have recently shown that the two agents have equivalent effects on afterload and ventricular-vascular coupling, but levosimendan has superior effects on contractility. 51 The drug, therefore, is an inodilator which shows great potential for infants and children with cardiac failure, but which warrants much more detailed investigation in this population.
