Introduction
Ahlquist’s discovery in animal models of two distinct types of adrenergic receptors in 1948 set the foundation for the modern day critical care use of inotropic drugs. He named these receptors in relation to their activity as activators (alpha) or blockers (beta). His original work has been expanded exponentially by discovery of subtypes of the originally identified receptors as well as many other discrete types of vasoactive receptors. Though it was uniquely postulated that these vasoactive receptors respond only to sympathin (epinephrine), we now know that these G protein coupled receptors (GPCRs) are regulated by a variety of agonists and antagonists and play a key role in prevalence of sympathetic nervous system activity. In the cardiac ICU, these vasoactive receptors are stimulated with various natural and synthetic molecules, resulting in augmented cardiac output (CO), chronotropy and mean arterial pressure (MAP), and in some cases enhanced lusiotropy in the postsurgical cardiac setting. Norepinephrine, epinephrine, dopamine, dopexamine, dobutamine, milrinone, enoximone, levosimendan and phenylephrine are the most commonly encountered vasoactive agents in the intensive care unit. We will review the current evidence for the use of inotropic agents in the perioperative care of cardiac patients.
Alpha-1 Receptors
Furthering Ahlquist’s work, Piascik elucidated the mechanism of action of GPCRs. Upon agonist binding to the alpha-1 receptor (A1r), Gq protein stimulates the phospholipase C (PLC) system, which in its turn activates the 1,2-diacylglycerol (DAG) protein kinase C (PKC) pathway through hydrolysis. The consequence of this enzymatic process is an increased release of calcium from the sarcoplasmic reticulum (SR) and increased protein phosphorylation (Figure 15.1). The end result is vascular smooth muscle constriction. This leads to globally increased systemic vascular resistance (SVR). In the perioperative setting, A1r agonists are used to counter the decreased SVR seen with a variety of physiological and pathophysiological processes. The A1r does not undergo sensitisation, or internalisation, though at maximal supratherapeutic agonist doses, it could produce organ ischaemia or substantially increase SVR, which can be widely distributed in epicardial, renal, splanchnic, cerebral and pulmonary vascular beds.
Beta Receptors
B receptors (Br) are subtyped into B1, B2 and B3 variants and regulate inotropy and chronotropy as well as smooth muscle relaxation in various vascular beds. Their distribution is not uniform. Although B1r and B2r are both present in myocardium, thoracic aorta and carotid artery, and epigastric and pulmonary artery, B1 is the predominant receptor subtype in the myocardium. B1 agonism exerts its effect through the Gs GPCR pathway. This interaction in cardiac cells leads to calcium induced calcium release from the myocardial sarcoplasmic reticulum, thereby allowing increased actin-myosin cross linkages and an enhanced chronotropic and inotropic state.
In contrast to the action of beta agonists on cardiac cells, in smooth muscle, B2r stimulation leads to increased activity of cAMP dependent protein kinase, increased phosphorylation and activation of phospholamban, increased cellular calcium reuptake through the ryanodine receptors and, ultimately, vasodilation.
Dobutamine
Dobutamine is a synthetic Br (B1, B2) agonist, which entered clinical use in 1978 as a promising replacement for dopamine in the treatment of acute decompensated heart failure. It has a 3:1 B1:B2 agonist activity and a trivial alpha-1 effect. Dobutamine is used in clinical practice for the treatment of acute decompensated heart failure in a dose dependent fashion, usually starting with an infusion of 2–3 μg/kg/min and rapidly uptitrated to a therapeutic dose of 7.5–15 μg/kg/min. It increases CO, stroke volume and coronary perfusion with minimal pulmonary vascular effect. Furthermore it has moderate chronotropy as it improves the atrioventricular (AV) conduction. Tachycardia has been reported to be more significant compared to use of milrinone, hence overall oxygen (O2) consumption may be increased with its use. Dobutamine has a mean plasma half-life of 2–3 minutes titratable, though after a 72 hour infusion, many patients become resistant to dobutamine, due to tachyphylaxis, with resultant rebound hypertension on discontinuation probably due to beta receptor downregulation and internalisation. Dobutamine has been shown to increase myocardial oxygen consumption, as well as malignant ventricular arrhythmias, at any dose. Even though dobutamine improves cardiac output, it has not been shown to optimise regional O2 delivery to ischaemic vascular beds that need O2 the most. A recent randomised controlled trial comparing norepinephrine-dobutamine to epinephrine in patients with acute non-ischaemic cardiogenic shock requiring inotropic support found no difference in overall metabolic and objective parameters (O2 delivery and renal perfusion) between the two groups. Thus, in patients with non-ischaemic HF requiring inotropic support, dobutamine may be the better agent compared to epinephrine given the tendency of epinephrine to aggravate lactic acidosis and, conversely, its lower effectiveness in an acidotic milieu. Though dobutamine infusions are frequently used as pharmacological therapy for bridge to cardiac transplantation or for long-term management of heart failure in patients not eligible for transplant, eosinophilic hypersensitivity reactions have been reported. The relationship between dobutamine and eosinophilia appears to be related to dose of dobutamine and duration of treatment, eventually resulting in eosinophilic myocarditis with unfortunate further decompensation of the patient’s underlying cardiac disease. It is well documented that chronic infusions of dobutamine are associated with higher risk for mortality.
Norepinephrine (NE)
The primary endogenous neurotransmitter in humans, norepinephrine, has a more profound effect at A1r than at B1r and B2r at clinically relevant doses. Extensive research has been done focusing on the effects of NE in the setting of sepsis, and in clinical practice it has a profound vasoconstrictive effect with less heart rate variability when compared to dopamine and epinephrine. This finding, along with the decreased mortality associated with NE as compared to other vasoactive medications, makes it the gold standard choice in the setting of septic shock. In the cardiac ICU it is used to increase systolic and diastolic pressures and therefore coronary perfusion pressure, in a variety of vasoplegic states, thus giving it a favourable cardiac profile compared to dopamine and phenylephrine. It appears that the overall effect of NE on CO is determined through the interplay of systemic vascular resistance, heart rate and stroke volume variation (SVV). Patients with a SVV greater than 8.4% are likely to increase their CO in response to NE, while those with a SVV less than 8.4% are likely to decrease their cardiac output in the same setting. Prolonged infusions of NE may have direct toxic effects on cardiac myocytes, though this has only been demonstrated in animal models.
Epinephrine (Epi)
Epinephrine has a dose dependent affinity for A1r, B1r and B2r. At low doses, it acts primarily on B1r, increasing chronotropy, inotropy and lusitropy. As the dose is increased, a profound A1r effect is noted. Epi acts to increase coronary blood flow at low doses by increasing the relative time the myocardium is in diastole. At higher doses, it acts by increasing diastolic and therefore coronary perfusion pressure. Epi also acts to increase blood flow to the pulmonary vasculature through alpha-1 mediated pulmonary vasoconstriction, and dilates bronchioles through B2 mediated smooth muscle dilation. Levy et al. compared Epi to combination norepinephrine-dobutamine in cardiogenic shock patients without acute coronary syndrome and found that although Epi is as effective as norepinephrine-dobutamine at achieving haemodynamic goals, it was also associated with increased rates of lactic acidosis, tachycardia, arrhythmias and worsened perfusion to gastric mucosa. Furthermore, use of Epi in treatment of myocardial depression and low cardiac output syndrome may be associated with more adverse effects on the end-organ function such as kidneys in the postoperative period.
Isoproterenol
Isoproterenol is a purely synthetic B1 and B2 receptor agonist at clinical doses. While the B1 effects in cardiac cells lead to increased inotropic and chronotropic states, the increased cAMP in smooth muscles of the respiratory bronchioles and vasculature leads to bronchodilation with an increase in lung compliance and decrease in SVR respectively. Isoproterenol is used in the EP laboratory to induce AV nodal re-entrant tachycardias, as well as to initiate Wolff–Parkinson–White (WPW) syndrome re-entry and to chemically pace patients in third degree heart block, a property that is very useful in heart transplants particularly at the time of separation from CPB. Experimentally, isoproterenol is used to induce acute myocardial infarctions and HF due to the myocardial ischaemia it induces during long infusions.
Dopamine
Dopamine is the immediate in vivo precursor to norepinephrine. The actions of dopamine are mediated by five distinct GPCRs (D1–D5). These receptors are found in various densities on the surface of cells in the nervous system, pulmonary artery, splanchnic circulation and renal tubules. Dopamine-1 receptors (DA1) are found in the proximal convoluted tubules, ascending loop of Henle and collecting ducts. DA2 receptors are mainly located in the renal vascular endothelium. These receptors couple to Gs which peripherally increases cAMP, causing vasodilation. At low dose infusions up to 3 μg/kg/min, dopamine stimulates DA1 predominantly and results in vasodilation by increasing the intracellular cAMP (and therefore lowering calcium influx) at the level of vascular endothelium in renal, mesenteric beds. In the kidneys, dopamine inhibits the NaCl cotransporter at the distal convoluted tubule causing diuresis. Despite improving renal blood flow, dopamine has not been shown to improve glomerular filtration rate. At the level of myocardium DA1–DA4 receptors are found mainly in atria. At escalating doses (3–10 μg/kg/min) dopamine binds to these receptors as well as B1r and causes both chronotropy and inotropy, although it is not quite clear whether these effects are indirect (via presynaptic NE release) or by direct B1r stimulation. At doses higher than 10 μg/kg/min, dopamine binds to A1r causing peripheral vasoconstriction. A trial comparing dopamine to NE in patients with diagnosis of shock found that among the subset of patients with cardiogenic shock, the rate of death was significantly higher in the group treated with dopamine than in the group treated with NE.
Figure 15.1 β1 receptor: AC adenylyl cyclase, cAMP cyclic adenosine monophosphate, PDE phosphodiesterase, PKA phosphokinase A, SR sarcoplasmic reticulum, TnC troponin C. Please refer to the text for detailed explanation.
Milrinone
While most of the vasoactive medications used in the cardiac ICU directly exert their effects on GPCRs, milrinone, a bipyridine PDE-3 inhibitor, utilises a novel mechanism, and is therefore not subject to receptor phosphorylation, internalisation of deactivation, and thus does not demonstrate the need for therapeutic dose escalation due to tachyphylaxis. Milrinone exerts its inotropic effect by inhibiting the conversion of cAMP to AMP, which causes smooth muscle relaxation in peripheral vasodilation, while in cardiac cells increased cAMP causes increased lusitropy and inotropy (Figure 15.2). Due to its lack of receptor internalisation and downregulation, like direct B2r, milrinone can be used in a beta receptor depleted state, such as stage D heart failure awaiting heart transplant. Milrinone has been shown to improve diastolic dysfunction and increases flow in coronary artery bypass grafts after cardiopulmonary bypass, however this effect is not demonstrable if milrinone is given prior to initiation of cardiopulmonary bypass. On the other hand if milrinone is administered in inhaled fashion prior to initiation of CPB it is beneficial in the first 24 hours postoperatively in cardiac patients with pulmonary hypertension. The clinical effect of long-term administration of milrinone in ambulatory patients was evaluated by Packer who found an excessive mortality rate in the milrinone treated group. Milrinone home infusion may be an alternative in stage 1B patients awaiting OHT, although the presence of ICD is advisable given the possibility of ventricular tachycardia. Milrinone may also be combined with beta-blockers in stage D heart failure, although large scale studies still need to be designed to evaluate outcomes in these patients. A 2012 meta-analysis of milrinone treatment in adult cardiac surgery suggests that milrinone is associated with a significantly increased risk of dying when compared with other drugs (mainly levosimendan). Even though OPTIME-CHF investigation showed that milrinone infusion in CHF exacerbation does not improve the mortality, it demonstrated that it may have a positive impact on renal functions when secondary outcomes were analysed. However, the full extent of this effect would have to be evaluated further.
Dopexamine
Dopexamine is a dopamine analogue that has activity at DA1, DA2, B1r and B2r. It has more significant B2r activity than B1r and hence, along with DA receptors, activation leads to cerebral, coronary and renal vasodilation and increased perfusion. Despite its particular vasodilatory property, in certain vascular beds it is considered an inotrope. Animal studies initially demonstrated that dopexamine may have immunomodulatory effect (B2 interaction), notably decreased lactataemia and cytokine release in animal models of endotoxaemia. This effect has not been duplicated in clinical observations. Dopexamine was compared to dobutamine in a randomised double blind, cross-over fashion, in a paediatric population undergoing cardiac surgery for non-complex congenital correction, for separation from CPB and mitigating myocardial stunning. Both agents had a similar increase in CI. Obviously patients treated with dopexamine had lower systemic vascular resistance (SVR).
Calcium Sensitisers
In normal cardiac cells, tropomyosin and troponin C (TnC) inhibit the binding of thick to thin filaments. TnC, in the presence of calcium released from the sarcoplasmic reticulum, causes a conformational change in the troponin-tropomyosin complex, allowing extensive thick and thin filament interaction and thereby myocardial contraction (Figure 15.2). Once calcium diffuses off its binding site on TnC, tropomyosin again returns to its resting position, blocking the thick and thin filament contractile apparatus. Under typical physiological conditions, a large cardiac contractile reserve exists. Experimental and in vivo models have demonstrated that increasing calcium concentration in the sarcoplasmic reticulum leads to increased binding of TnC and, therefore, increased heart rate and inotropic state. It was this contractile reserve that led to the development of calcium sensitising agents that either increase the affinity of TnC for calcium or act directly on the thick and thin filaments to allow interaction with little endogenous calcium required. Two drugs that act to increase the affinity of TnC for calcium are currently available outside the USA, pimobendan and levosimendan.
Pimobendan is an oral agent that exerts its inotropic effect through calcium sensitising as well c-AMP dependent pathway. It has only been studied in the EPOCH study in a randomised double blind fashion, which demonstrated a non-statistically significant decrease in sudden cardiac death, hospitalisation for HF, and death from HF in the pimobendan treatment group. This study also found significantly decreased adverse cardiac events in the treatment group.
Levosimendan, which has a similar mechanism of action to pimobendan, has been shown not only to improve inotropy as well as lusitropy, but also to cause vasodilation by activating ATP dependent K channels on the smooth muscles. Levosimendan has been demonstrated to increase SV and CI by 28% and 39% respectively, while marginally increasing heart rate and meanwhile decreasing the left and right filling pressures and systemic arterial pressures when compared to placebo in a double blind RCT. The LIDO trial, which compared levosimendan to dobutamine, demonstrated that levosimendan exerted superior haemodynamic effects and in secondary and post hoc analyses was associated with a lower risk of death after 31 and 180 days. In addition, the second Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy (REVIVE II) study showed that patients with ADHF who received levosimendan in addition to standard therapy were more likely to show clinical improvement and less likely to deteriorate than patients on standard therapy alone. However, there was no significant change in 90 day mortality and there were more adverse side effects (tachyarrhythmia and hypotension) in the levosimendan group. As the previous studies had only compared levosimendan to placebo, the SURVIVE trial compared levosimendan to dobutamine in a double blind RCT in patients requiring inotropic support for ADHF and found that despite an initial reduction in plasma B-type natriuretic peptide level in patients in the levosimendan group compared with patients in the dobutamine group, levosimendan did not significantly reduce all-cause mortality at 180 days or affect any secondary clinical outcomes. Like milrinone, levosimendan used in combination with a beta adrenergic antagonist may have beneficial effects in patients with cardiogenic shock who exhibit tachycardia in response to inotropic agents.
