HEART RATE FAILURE

Profound bradycardia will reduce both cardiac output and mean arterial pressure if sympathetic tone is compromised. Inotropes will increase both rate and speed of conduction, in addition to augmenting peripheral venous return, thereby restoring cardiac output and mean arterial pressure.

Tachycardia is associated with decreased left coronary artery perfusion, due to reduction of diastolic time, during which coronary perfusion occurs. This may exacerbate myocardial ischaemia in patients with coronary artery disease, particularly if mean arterial pressure, specifically diastolic blood pressure, is compromised. Therefore, drugs that shorten diastolic time or compromise coronary perfusion should be used with caution in susceptible patients.

PRELOAD FAILURE

Loss of intravascular blood volume or extracellular fluid is the most common cause of inadequate ventricular preload. This is corrected with appropriate fluids to maintain and restore a euvolaemic state. Hypovolaemia must be recognised and treated as soon as possible, preferably before vasoactive therapy is used.

There are other determinants of ventricular preload and venous return. Factors such as loss of muscle tone, positive intrathoracic pressure, loss of atrial systole (atrial fibrillation) and ablation of sympathetic tone will also compromise preload by reducing venous return. Under these circumstances, volume replacement alone may be insufficient to maintain adequate preload and vasoactive therapy may be required to increase venous return.

MYOCARDIAL FAILURE

Myocardial or ‘pump’ failure may be divided into disorders of systolic ejection (systolic dysfunction) and diastolic filling (diastolic dysfunction).

Systolic dysfunction occurs as a result of reduced effective myocardial contractility. This may be due to primary myocardial factors such as ischaemia, infarction or cardiomyopathy. Myocardial depression of both right and left ventricular function may occur in severe sepsis or following prolonged infusions of catecholamines. Increased impedance to ventricular ejection (e.g. hypertensive states) or structural abnormalities (e.g. aortic stenosis or hypertrophic obstructive cardiomyopathy) may cause systolic dysfunction.

Diastolic dysfunction is characterised by reduced ventricular compliance or increased resistance to ventricular filling during diastole. It may be due to mechanical factors such as structural abnormalities of the ventricle (e.g. restrictive cardiomyopathy) or to impaired diastolic relaxation that occurs with myocardial ischaemia or severe sepsis. This results in elevated end-diastolic pressure and pulmonary venous congestion. Episodic or ‘flash’ pulmonary oedema is a common clinical sign of diastolic dysfunction.⁵ Tachycardias that shorten diastolic time may exacerbate diastolic failure. Diastolic dysfunction frequently accompanies systolic failure, in both acute and chronic cardiac failure, particularly in elderly patients.

In the presence of systolic dysfunction, adequate stroke volume may be maintained by an increase in left ventricular end-diastolic volume (the Frank–Starling relationship), provided diastolic function is optimal. However, if the loss of effective myocardial mass is critical, the ventricle will be unable to maintain an adequate stroke volume and cardiac output will fall. In this situation, systolic dysfunction usually requires treatment with inotropic agents in order to augment stroke volume, thereby increasing cardiac output and mean arterial pressure.

VASOREGULATORY FAILURE

Disruption or impairment of regulation of the peripheral vasculature may result in circulatory failure. This includes acute sympathetic denervation, such as high quadriplegia, epidural or total spinal anaesthesia (‘spinal’ shock); distributive failure such as anaphylaxis; or pathological ‘vasoplegia’ that occurs in severe sepsis.

These syndromes are characterised by reduced responsiveness of the peripheral circulation to endogenous or exogenous sympathetic stimulation. This results in pooling in the venous circulation due to the inability to provide a ‘stressed’ volume.⁴

Management of these conditions has traditionally focused on the arterial circulation with attempts to increase systemic vascular resistance, often regarded inaccurately as treatment of ‘afterload failure’. This is a misnomer as the problem is predominantly impaired venous return, compounded to a lesser extent by pathological arteriolar vasodilatation.⁶ Clearly, the effects of vasoregulatory failure will be exacerbated by concomitant hypovolaemia. Fluid loading to restore effective intravascular volume is essential.

Vasoactive agents may have a role in restoring vasoregulatory tone once adequate volume has been established.

PHYSIOLOGICAL

Agonists bind to populations of adrenergic receptors, largely divided into α and β subgroups. Further subgroups of α- (α_1A, α_1B, α_2A, α_2B, α_2C) and β-receptors (β₁, β₂, β₃) have been identified.⁷

Signal transduction from agonist–receptor occupation to the effector cell is modulated by conformational changes in G proteins associated with these receptors. Under the additional influence of second messengers such as nitric oxide, endothelin and eicosanoids, these conformational changes promote the release of calcium from intracellular stores and increase membrane calcium permeability. Subsequent phosphorylation of substrate proteins via protein kinases act as third messengers to trigger a cascade of events which lead to specific cardiovascular effects.

β-Receptor occupancy predominantly activates adenyl cyclase to increase the conversion of adenosine triphosphate to cAMP. α-Receptor occupancy acts independently of cAMP by activation of phospholipase C which increases inositol phosphates (IP₃ and IP₄) and diacyl glycerol.

This complex agonist–receptor–effector relationship is responsible for homeostatic mechanisms such as physiological responses to stress and autoregulation.

PATHOPHYSIOLOGICAL

The activity and function of this system is dynamic and may be markedly influenced by pathological states. This mayresult in qualitative changes in the agonist–receptor–effector organ relationship (desensitisation) where receptors no longer respond to physiological or pharmacological sympathetic stimulation to the same extent. Quantitative changes such as reduced receptor density, receptor sequestration and enzymatic uncoupling (downregulation) may also result in impaired responses.⁸

CARDIOVASCULAR

The cardiovascular effects of the catecholamines under physiological conditions are shown in Table 82.3.

Table 82.3 Cardiovascular effect of catecholamines

Noradrenaline, adrenaline and dopamine all tend to increase stroke volume, cardiac output and mean arterial pressure, with little change in heart rate and a low incidence of dysrhythmias. The effects on the peripheral vasculature are similar, with all agents increasing venous return without significant changes in calculated systemic vascular resistance.

Isoprenaline increases cardiac output predominantly by increasing heart rate and by moderate inotropy. This occurs without a significant change in blood pressure due to predominant β₂-receptor induced veno- and vasodilatation.

The profile of dobutamine is similar to isoprenaline, although increases in heart rate are not as pronounced. Both of these agents may decrease mean arterial pressure, particularly in hypovolaemic patients, due to reduced venous return caused by venodilatation. The adverse effects of dobutamine and isoprenaline on heart rate and mean arterial pressure may compromise patients with ischaemic heart disease. However, the vasodilatory effects of dobutamine may be useful in selected patients with predominant systolic heart failure as a means of reducing afterload.

In the failing myocardium, particularly in patients with cardiac failure following cardiopulmonary bypass or septic shock, endogenous stores of noradrenaline are markedly reduced.⁹ Furthermore, there may be significant desensitisation and downregulation of cardiac β-receptors. In these situations, α₁– and α₂-receptors have an important role in maintaining inotropy and peripheral vasoresponsiveness.¹⁰ This may be expressed clinically as ‘tolerance’ or tachyphylaxis to catecholamines, particularly with predominantly β-agonists such as dobutamine. This phenomenon may explain the requirement for high doses of catecholamines in refractory shock states. Consequently, the role of β-agonists in patients with severe myocardial failure has been questioned.

Catecholamines have a significant effect on the venous circulation. These drugs primarily restore or maintain ‘stressed volumes’ of the capacitance vessels under pathological conditions, thereby maintaining or increasing cardiac output and mean arterial pressure. This is important in ‘vasoplegic’ states such as septic shock.¹¹

In clinically used doses, intravenously administered catecholamines have minimal direct vasoconstrictive effects on conducting arterial vessels. Consequently, derived indices such as systemic vascular resistance do not reliably reflect the effect of catecholamines on the peripheral vasculature.

The development of peripheral gangrene in refractory septic shock has been attributed to catecholamine-induced vasoconstriction. There is little evidence to support this as the development of tissue gangrene in these situations primarily occurs as a consequence of intravascular thrombosis caused by sepsis-mediated coagulopathy.