Phil Ostrowski, Ehsan Ahmadnia, and Sussana Price
Nick Fletcher and Robert Crichton
Nick Fletcher and Robert Crichton
Hollmann D. Aya, Jeremy Cordingley, and Anthony Gordon
Susanna Price and Iain Parsons
Susanna Price, Andrew Constantine, and Sanjoy Bhattacharyya
Anthony Gordon and Robert Orme
β-Adrenergic agents are commonly used for cardiovascular support in critical care to increase cardiac output via β1-receptor-mediated inotropic and chronotropic effects to maintain adequate organ perfusion.
Non-cardiovascular indications for β2-agonists include bronchodilatation and uterine relaxation. Research is ongoing into the potential benefits of β2-agonists in reducing extravascular lung water in patients with acute respiratory distress syndrome (ARDS).
Effects of β-adrenergic agonists
Most β-adrenergic agonists in clinical use are active at more than one type of adrenergic receptor (β1, β2, β3, α1, and α2).
• Cardiac—β1 (and, to a much lesser degree, β2) effects include increased heart rate, increased conduction velocity throughout the heart, and increased rate of idioventricular pacemakers. All β-adrenergic agonists increase myocardial oxygen consumption and may precipitate myocardial ischaemia in susceptible patients (dobutamine is used to carry out myocardial stress testing). β-Agonists increase the incidence of cardiac arrhthymias.
• Βlood vessels—β2-agonists induce vasodilatation in coronary muscle, skeletal muscle, and pulmonary, splanchnic, and renal arterioles and arteries. α2-Agonists cause vasoconstriction in splanchnic, renal, and skin vessels, and, to a lesser degree, in coronary and pulmonary arterioles and arteries.
• Metabolic effects—β2-agonists cause increased glycogenolysis, gluconeogenesis in liver and skeletal muscle, increased potassium uptake in skeletal muscle, and increased lipolysis.
The clinical effects of a specific agent result from the sum of its actions at different receptors, and the profile of effects may change in a dose-dependent manner. In addition, effects may vary with alterations in intravascular volume.
As with vasoconstrictor drugs, it is important to optimize circulating volume before initiating β-agonist therapy. This may include the use of cardiac output monitoring.
The half-lives of all the β-agonists listed in this chapter are very short (a few minutes), with the exception of ephedrine. Caution should be used in patients already receiving monoamine oxidase inhibitors (MAOIs).
In some patients, particularly with sepsis, higher doses of β-agonists may be required to achieve the same clinical effects.
Adrenaline is a naturally occurring catecholamine produced in the adrenal medulla. It is a mixed α-, β1-, and β2-adrenergic agonist. At low doses, β2-mediated vasodilatation predominates, but at higher (non-physiological) doses increasing vasoconstriction occurs as a result of α1-adrenergic receptor agonism in the skin, mucosa, gastrointestinal tract, kidneys, and systemic veins.
Adrenaline is most commonly used as an inotrope in patients with low cardiac output, which does not improve in response to optimal fluid resuscitation and other inotropes.
Adrenaline infusion has been associated with increased arterial lactate concentration, metabolic acidosis, and worsening markers of splanchnic perfusion. As with all β-agonists, adrenaline increases the incidence of arrhythmias.
Adrenaline is given as an intravenous (IV) bolus during cardiac arrest because of its inotropic and vasoconstrictor action. While use of adrenaline is widely established in resuscitation algorithms, high-quality evidence supporting its efficacy remains limited. The effect of adrenaline on clinical outcomes in out-of-hospital cardiac arrest has been recently assessed in a multicentre clinical trial (PARAMEDIC-2) involving 8014 patients in the UK. At 30 days, 130 patients (3.2%) in the adrenaline group and 94 (2.4%) in the placebo group were alive (unadjusted odds ratio [OR] for survival 1.39; 95% confidence interval [CI] 1.06–1.82; P = 0.02). There was no evidence of a significant difference in the proportion of patients who survived until hospital discharge with a favourable neurological outcome (87 of 4007 patients [2.2%] versus 74 of 3994 patients [1.9%]; unadjusted OR 1.18; 95% CI 0.86–1.61). At the time of hospital discharge, severe neurological impairment had occurred in 39 of 126 (31.0%) of the survivors in the adrenaline group and in 16 of 90 (17.8%) of the placebo group. The author concluded that, in adults with out-of-hospital cardiac arrest, the use of adrenaline resulted in a significantly higher rate of 30-day survival than the use of placebo, but there was no significant difference in the rate of a favourable neurological outcome because more survivors had severe neurological impairment in the adrenaline group.
Adrenaline is the drug of choice for the management of anaphylactic shock because of both α1-mediated vasoconstriction and β2-mediated inhibition of mast cell release of inflammatory mediators, including histamine.
• Dose—IV bolus (during cardiac arrest, repeated every 3–5 min): 1 mg. Intramuscular (IM) (anaphylaxis): 0.5 mg. IV infusion: 0.01–1 µg/kg/min; usually started at a dose in the range of 0.02–0.05 µg/kg/min.
• Adverse effects: tachycardia, arrhythmias, vasoconstriction with potential organ dysfunction and necrosis, metabolic acidosis, hypokalaemia, increased blood glucose and lactate concentrations, increased metabolic rate.
Noradrenaline is a neurotransmitter found in sympathetic postganglionic nerve fibres and is a mixed β1- and α1-agonist. Infusion results in increased blood pressure and usually no change or an increase in cardiac output. Care must be taken to avoid using noradrenaline in hypovolaemic states, as cardiac output may decrease, impairing peripheral perfusion.
Noradrenaline is generally used to maintain adequate mean arterial pressure (MAP) following volume resuscitation and restoration of adequate cardiac output. In patients with cardiogenic shock, noradrenaline is therefore commonly used in combination with another β-agonist or phosphodiesterase (PDE)3 inhibitors.
• Dose: IV infusion: 0.01–1 µg/kg/min. Normal starting dose: 0.02–0.05 µg/kg/min.
• Adverse effects: vasoconstriction with potential organ dysfunction and necrosis, metabolic acidosis, and arrhythmias.
Isoprenaline is a synthetic agonist at β-receptors and has no significant α-adrenergic effects. Infusion results in increased heart rate and cardiac output, but decreased MAP because of β2-mediated vasodilatation. Its main use is as a chronotrope for the temporary management of bradycardias. It is also occasionally used as an inotrope in patients with pulmonary hypertension (PH) because of its pulmonary vasodilator effects.
• Dose: IV infusion: 0.5–10 µg/min.
• Adverse effects: tachycardia, arrhythmias.
Dopamine is the natural metabolic precursor of adrenaline and noradrenaline, and is an agonist at dopamine, α-, and β-receptors.
Effects vary according to infusion rate. At doses <3 µg/kg/min, dopamine receptor effects predominate, resulting in renal and splanchnic vasodilatation. Urine output may increase as a result of a proximal tubular diuretic effect. At doses of 3–10 µg/kg/min, β1-effects result in increased heart rate and contractility. At doses of 10–20 µg/kg/min, α1-receptor-mediated effects are more marked, leading to vasoconstriction.
Although dopamine has a natriuretic effect, addition of low-dose dopamine infusion to other cardiovascular support in critically ill patients does not improve renal function or decrease the requirement for acute renal replacement therapy.
In patients postcardiac surgery, use of dopamine is associated with an increased incidence of atrial fibrillation (AF).
• Dose: IV infusion: 1–10 µg/kg/min. Normal starting dose is 2–5 µg/kg/min.
• Adverse effects: tachycardia, arrhythmias, vasoconstriction, nausea, and vomiting.
Dobutamine is a synthetic agonist at mainly β1- but also β2- and α1-receptors. IV infusion causes increased heart rate and stroke volume, and vasodilatation. The effect on blood pressure is variable, and often concurrent noradrenaline infusion is required to prevent hypotension. It is used primarily for the management of low cardiac output, despite adequate fluid resuscitation, in patients with cardiogenic shock, usually post-myocardial infarction (MI) or following cardiac surgery. Dobutamine has been recommended to increase cardiac output, when required, in patients with septic shock.
• Dose: IV infusion: 0–20 µg/kg/min. Usual starting dose is 2–5 µg/kg/min, and it is rarely required to use >10 µg/kg/min.
• Adverse effects: tachycardia, arrhythmias, hypotension.
Dopexamine is a synthetic dopamine receptor and β2-receptor agonist. Dopexamine infusion causes increased heart rate, stroke volume, and systemic vasodilatation (including renal and splanchnic), resulting in increased cardiac output. Its inotropic effects are mild.
• Dose: IV infusion: 0.5–6 µg/kg/min.
• Adverse effects: tachycardia, hypotension.
Ephedrine is a direct α- and β-agonist, but also increases noradrenaline release from sympathetic nerves. Administration results in increased heart rate, cardiac output, and blood pressure. Although it is active if given orally, it is usually administered as an IV bolus. Tachyphylaxis occurs, making it unsuitable for IV infusion. Its main use is as treatment of temporary hypotension associated with epidural or spinal anaesthesia.
• Dose: IV bolus: 3–6 mg every 3 min, maximum 30 mg.
• Adverse effects: tachycardia, arrhythmias, central nervous system (CNS) stimulation.
Salbutamol is a selective β2-agonist primarily used for its bronchodilator effect. It is rarely used for cardiovascular support for patients with PH.
• Dose: IV infusion: 3–20 µg/min. Usual starting dose is 5 µg/min.
• Adverse effects: tachycardia, arrhythmias, hypokalaemia, hyperlactataemia.
Role of β-agonist drugs
High-risk surgical patient
A number of studies have reported improved survival of high-risk surgical patients when cardiac index or oxygen delivery is optimized to supranormal levels during the perioperative period using fluids and β-agonists. This does not appear to be agent-specific and has been reported in various studies using dobutamine, adrenaline, and dopexamine.
Low cardiac output is relatively common following cardiac surgery. Patients requiring a low degree of inotropic support are often managed with dopamine as this can usually be managed in level 2 critical care areas. For patients requiring more support, adrenaline, dobutamine, or a PDE3 inhibitor are commonly used.
Agents with combined inotropic and vasodilator properties such as dobutamine or PDE3 inhibitors are common choices. Tachycardia may limit doses of β-agonists. A subgroup analysis of the SOAP-II study compared noradrenaline and dopamine as first-line agents in patients presenting with cardiogenic shock, and found that dopamine is associated with significantly higher 28-day mortality. Low-dose adrenaline may be added if required, although the CardShock study noted that administration of adrenaline in cardiogenic shock was independently associated with increased 90-day mortality, as well as adverse cardiac and renal biomarker profiles, compared to other inotropic agents.
Noradrenaline is the first-line vasopressor in patients with septic shock. Dobutamine can be used in hypoperfusion refractory to fluid resuscitation if inotropic support is needed. Cardiovascular optimization needs to be carried out as early as possible to decrease the incidence of multiorgan failure. Dopamine has been shown to increase the risk of arrhythmia in septic shock and is not recommended as a first-line agent, but may be used in patients at low risk of arrhythmia. The SOAP-II study did not find a significant survival benefit for either noradrenaline or dopamine in septic shock.
PDEs are a family of enzymes that inactivate cyclic adenosine monophosphate (cAMP). PDE inhibitors increase cAMP levels, leading to increased contractility in myocardial cells and relaxation in smooth muscle. To date, 11 PDE subtypes have been identified in mammals, although only five subtypes have been found to have clinical relevance in humans. PDE inhibitors relevant to critical care will be discussed in this section and are classified into non-selective and selective inhibitors.
Non-selective PDE inhibitors
Theophylline and aminophylline (water-soluble complex of theophylline and ethylenediamine) act through non-specific PDE3 and 4 inhibition, resulting in increased intracellular cAMP levels. In addition, theophyllines are competitive antagonists of adenosine receptors. The main effects are increased heart rate, bronchodilatation, diuresis, and anti-inflammatory effects. Adverse effects include tachyarrythmias, tremor, electrolyte and glucose abnormalities, and nausea, vomiting, and diarrhoea.
The clinical utility of theophylline in the critical care setting is controversial. Meta-analyses have not found benefit for the use of IV theophylline for acute severe asthma. However, international consensus guidelines recommend its use as rescue therapy for asthma refractory to standard treatment.
No randomized controlled trials (RCTs) have demonstrated a benefit for theophylline in chronic obstructive pulmonary disease (COPD) patients suffering acute exacerbations. However, it may have a role in exacerbations refractory to standard therapy.
Small studies have shown increased diaphragmatic strength and mucociliary clearance in patients on intensive care units (ICUs). Owing to risk–benefit considerations, theophylline is not generally recommended for these indications in critically ill patients.
IV theophylline is administered as aminophylline slowly over 20 min; it is extremely irritant. The initial loading dose is 250–500 mg (5 mg/kg), followed by an infusion at 500 µg/kg/h. Extreme caution should be used in patients already on chronic theophylline therapy because of the risk of toxicity.
Theophylline undergoes hepatic metabolism, this is impaired in hepatic and cardiac failure. Plasma theophylline levels should be measured 4–6-hourly, aiming for a target concentration of 10–20 mg/l. Levels may be raised by smoking. Adverse effects may be seen in the therapeutic range and are more likely with theophylline levels >20 mg/l. Arrhythmias and convulsions may predate other signs of toxicity. An important side-effect of theophylline is hypokalaemia, the incidence of which is increased when it is used in combination with β-agonists.
Selective PDE inhibitors
PDE3 isoforms (A and B) are localized to numerous tissues, notably cardiac tissue, vascular smooth muscle, and platelets. PDE3 inhibitors cause increased intracellular calcium accumulation (via inhibition of cAMP breakdown), resulting in increased contractility in cardiac myocytes.
In addition, there is evidence that the rate of reuptake of calcium by sarcoplasmic reticulum of cardiac myocytes is increased with the use of PDE3 inhibitors, as this is also a cAMP-dependent activity. This enhanced diastolic relaxation (lusitropy) is particularly beneficial in patients with reduced left ventricular compliance.
The inhibition of PDE3 in vascular smooth muscle results in the potentiation of cyclic guanosine monophosphate (cGMP), causing vasodilatation. As a consequence, these agents result in reductions in systemic vascular resistance, pulmonary vascular resistance, and venous pressures.
There is some evidence for synergistic action between PDE3 inhibitors and β-agonists such as dobutamine in the setting of low cardiac output states. This effect has been well described in neonatal cardiac surgery.
PDE3 inhibitors may also be useful as first-line inotropic agents in patients who have either been on long-term β-blockers or who have a clinical indication for β-blockade in the setting of a low cardiac output state. Recent studies have detailed the long-term use of PDE3 inhibitors in class D heart failure as a bridge to left ventricular assist device or transplantation. Initial research for this indication revealed an increased rate of sudden death because of both ventricular tachycardias and bradycardias. Survival rates for this strategy have now significantly improved owing to the concomitant use of implantable cardioverter defibrillators. There is no evidence of increased mortality with PDE3 inhibitors used in the short term in the intensive care setting.
PDE3 inhibitors are commonly used in postsurgical cardiac intensive care patients with impaired left or right ventricular function and/or PH. There appears to be little clinical difference between agents in terms of effect. Because of the marked reduction in systemic vascular resistance, there is currently little role for these agents in patients with septic shock. As with all potent inodilators, caution should be exercised in their use in the presence of left ventricular outflow tract obstruction of any cause. There is currently little evidence to support the use of PDE3 inhibitors to treat diastolic dysfunction in clinical practice.
PDE3 inhibitors are usually given by IV infusion and it is important to consider that their half-lives are considerably longer than those of catecholamines. Dose reduction may be necessary in the presence of renal impairment and particularly in elderly patients. Acute tolerance does not appear to be a feature of these agents.
• Milrinone is administered IV as a loading dose of 50 µg/kg over 10 min (diluted), followed by infusion at a rate of 0.375–0.75 µg/kg/min. The loading dose is often omitted if hypotension is anticipated. It is usually continued for at least 12 h postcardiac surgery or for 48–72 h in congestive cardiac failure. It has a half-life of 30–60 min, but this may be significantly prolonged in patients with renal dysfunction. In this scenario, dose reduction is necessary to prevent severe vasodilatation.
• Milrinone has been studied extensively in cardiac surgical and heart failure patients. There is evidence that it facilitates weaning from cardiopulmonary bypass. In the cardiac intensive care setting, milrinone increases cardiac index without a marked increase in heart rate but at the expense of reduced systemic vascular resistance.
• In a comparison study with dobutamine, both drugs increased cardiac index significantly, but there was a greater achievement in MAP in patients receiving dobutamine. Milrinone had a slightly better safety profile, with the dobutamine group suffering a higher incidence of hypotension and new AF.
• Milrinone has been found to be as effective as 20 ppm nitric oxide in reducing pulmonary artery pressures in patients with PH. Because of this milrinone is increasingly utilized to avoid PH in bridging therapy for cardiac transplantation.
• Milrinone is generally preferred to other PDE3 inhibitors because of better PDE3 selectivity, its shorter half-life, and greater compatibility with other drugs administered by intravenous infusions.
• Enoximone causes an increase in cardiac index and reduction in systemic vascular resistance when compared with both placebo and dobutamine. As with milrinone, enoximone has been found to facilitate weaning from cardiopulmonary bypass.
• Enoximone is administered as a bolus of 0.5–1.5 mg/kg, followed by 0.5 mg/kg every 30 min until there is a satisfactory response, or to a maximum of 3 mg/kg. It has a half-life of 2 h.
• At the time of writing amrinone is no longer being manufactured or distributed. As the drug has not been discontinued for safety reasons it may become available again in the future.
• Amrinone has similar effects to the other PDE3 inhibitors.
• Impaired coagulation has been reported in some patients receiving amrinone owing to a reduction in platelet count and/or platelet function.
• Amrinone is administered as a loading dose of 0.75–1.5 mg/kg, followed by an infusion of 10 µg/kg/min. It has an elimination half-life of 3.5 h.
Chronic selective PDE4 inhibition has anti-inflammatory and immune-modulating functions for the respiratory mucosa in the setting of COPD. Improvements have been noted in forced expiratory volume in 1 s (FEV1) and exacerbation frequency; however, longer-term trials are in progress to assess the actual mortality outcome.
PDE5 inhibitors prevent the breakdown of cGMP in pulmonary vascular smooth muscle, increasing intracellular levels, resulting in vasorelaxation in the pulmonary vascular bed and, to a lesser extent, the systemic circulation. PDE5 receptors are also found in the lower oesophageal sphincter, visceral smooth muscle, and corpus cavernosum.
• Sildenafil is licensed for use in erectile dysfunction and PH.
• The dose is 12.5–50 mg three times a day orally, and an IV formulation is available. In the context of PH, the long-term use of sildenafil has been associated with improvements in right ventricular mass and functional status.
• In intensive care patients, it is often used as an adjunct to or step-down therapy from inhaled nitric oxide (iNO) in patients with severe PH, reducing rebound vasoconstriction. Systemic hypotension may occur.
• Recent evidence has suggested a role for sildenafil in the management of myocardial ischaemia reperfusion injury. Thus it may find clinical application in the management of cardiac arrest and myocardial stunning postcardiac surgery.
In critically ill patients, vasodilators may be indicated for treatment of systemic or PH, reduction of cardiac preload, or treatment of vasospasm in specific arterial systems.
Caution is required if administering vasodilators to patients with low fixed cardiac output, e.g. severe aortic stenosis, because of the risk of inducing severe hypotension.
Nitrates act directly on smooth muscle by release of NO from the parent molecule. Tolerance to nitrates can be reduced by the use of nitrate-free periods.
Glyceryl trinitrate (GTN) acts primarily on venous capacitance vessels, reducing venous return (preload). It has some arteriolar effect, decreasing afterload, and is a coronary vasodilator.
Onset of action is 2–5 min, with a half-life of 3 min. GTN undergoes hepatic and extrahepatic metabolism via red cells and vascular endothelium. Tachyphylaxis is common, with tolerance occurring within 24–48 h.
• Indications: congestive cardiac failure, cardiac ischaemia.
• Contraindications: aortic stenosis, hypertrophic obstructive cardiomyopathy, hypotension, tamponade, severe anaemia, hypertensive encephalopathy.
• Dose and route: available sublingually, orally, transdermally, and intravenously. Start IV infusion 10 µg/min and titrate by 10 µg/min to a maximum 200 µg/min.
Isosorbide mononitrate is an orally administered nitrate used for angina prophylaxis and treatment of heart failure.
Directly acting vasodilators
The main action of sodium nitroprusside (SNP) is relaxation of vascular smooth muscle in both arteries and veins that occurs via NO-stimulated increase in cGMP. At low doses, arterial vasodilatation predominates.
The hypotensive effect of SNP is seen within 1–2 min and may cause reflex tachycardia. Myocardial ischaemia can occur via a coronary steal syndrome.
Circulatory half-life is ~2 min. Nitroprusside metabolism can lead to methaemoglobin formation and metabolic acidosis. Specific therapy for overdose includes administration of sodium nitrite followed by sodium thiocyanate. Tachyphylaxis may occur.
• Indications: immediate reduction of blood pressure in hypertensive crises, acute congestive cardiac failure, and controlled hypotension intraoperatively.
• Contraindications: aortic coarctation, congenital optic atrophy, high-output cardiac failure, and severe B12 deficiency.
• Dose: start 0.3–0.5 µg/kg/min and titrate to maximum 8 µg/kg/min.
Hydralazine preferentially dilates arterioles via stimulation of cGMP. It is associated with reflex sympathetic activity, resulting in tachycardia. Hydralazine causes renin to be released by the juxtaglomerular apparatus, with subsequent angiotensin production, aldosterone release, and sodium retention; thus β-blockers or diuretics are often administered concurrently.
Onset of action is within 5–10 min IV, 20–30 min orally. The half-life is 2–4 h, but in patients with renal disease the half-life may increase up to 16 h.
• Indications: hypertension and hypertensive crisis.
• Contraindications: systemic lupus erythematosus, severe tachycardia, high-output heart failure, myocardial insufficiency caused by mechanical obstruction, and porphyria.
• Dose and route: orally, 10–25 mg two to four times a day for hypertension. Increase to 50–75 mg/6 h in cardiac failure. By slow IV injection, 5–10 mg, may be repeated after 20–30 min. By IV infusion, initially 200–300 µg/min, maintenance usually 50–150 µg/min.
Diazoxide is an arteriolar vasodilator and antihypertensive. It inhibits insulin release and hyperglycaemia may occur.
Onset of action is 5–10 min with duration of action of 4–12 h. Diazoxide is extensively protein-bound, partly hepatically metabolized, and partly excreted unchanged.
It is difficult to use to control blood pressure over short time periods because of its long half-life.
• Indications: hypertensive emergencies.
• Contraindications: ischaemic heart disease.
• Dose: by rapid IV injection, 1–3 mg/kg with a maximum single dose of 150 mg. Can be repeated after 5–15 min as required.
Calcium channel blockers have antianginal, antiarrhythmic, and vasodilatory effects. In cardiac muscle, calcium antagonism reduces myocardial contractility and cardiac output in a dose-dependent fashion. Impulse generation at the sinoatrial node and conduction via the atrioventricular node are calcium-dependent, and blockade decreases sinus node pacemaker rate and atrioventricular node conduction velocity.
There are three classes of calcium channel antagonists:
• Dihydropyridines (nifedipine, amlodipine, and nimodipine).
• Diphenylalkylamines (verapamil).
• Benzothiazepines (diltiazem).
Nifedipine is an arteriolar vasodilator. It can be administered orally, sublingually, or IV. Sublingual administration may cause rapid severe hypotension.
Onset of action is 2–5 min. It is hepatically metabolized with a plasma half-life of 4 h.
• Indications: angina, hypertension, Raynaud’s syndrome.
• Contraindications: aortic stenosis, porphyria, cardiogenic shock.
• Dose: 5–20 mg tds.
Peak plasma concentrations are reached within 1 h, orally or IV. Half-life is 1–2 h. Nimodipine undergoes hepatic metabolism; the dose should be halved in liver failure.
• Contraindications: severely raised intracranial pressure (ICP) in the context of subarachnoid haemorrhage.
• Dose: orally, 60 mg 4-hourly; IV, 500 µg–1 mg/h initially, increased to 2 mg/h as blood pressure tolerates.
Verapamil and diltiazem are used as antiarrythmic and antianginal agents and have limited vasodilatory actions. They should be used carefully in the presence of accessory conducting pathways, e.g. Wolf–Parkinson–White syndrome, as ventricular fibrillation may be precipitated.
α-Adrenergic receptor antagonists
Adrenergic receptors are subdivided into α1 and α2, and β1, β2, and β3 subtypes.
• α1-Receptors are responsible for vasoconstriction, gut smooth muscle relaxation, increased salivation, and gluconeogenesis.
• α2-Receptor agonists inhibit noradrenaline and acetylcholine release and stimulate platelet aggregation.
α-Blockade causes reduced systemic vascular resistance. There may be reflex sympathetic stimulation.
Phentolamine is a non-selective reversible competitive antagonist at both α1- and α2-receptors. Onset of activity is rapid, with duration of action of 10–15 min.
• Indications: phaeochromocytoma.
• Dose: 2–5 mg (IV), repeat as necessary.
Phenoxybenzamine is a non-selective irreversible α1- and α2-receptor antagonist. Noradrenaline reuptake is blocked, potentiating the action of β-agonists. Duration of action is 3–4 days.
• Indications: phaeochromocytoma.
• Dose: orally, initially 10 mg bd, increased to 1–2 mg/kg in divided doses; IV, 1 mg/kg daily, slow injection over 2 h daily.
Prazosin is a competitive α1-receptor antagonist.
• Indications: essential and renovascular hypertension, Raynaud’s disease, benign prostatic hypertrophy.
• Dose: initially 500 µg two or three times a day, increased to 20 mg/day in divided doses.
Doxazosin is also a competitive α1-receptor antagonist with a longer half-life than prazosin.
• Indications: essential hypertension, benign prostatic hypertrophy.
• Dose: initially 1 mg od titrated up to a maximum of 8 mg od.
Other α-receptor antagonists
Urapidil is an α1-receptor antagonist which also antagonizes central serotonin 5-HT1A receptors, and is commonly used in mainland Europe. It may be used in a chronic setting orally or acutely intravenously.
• Indications: essential hypertension, perioperative hypertension.
• Dose: orally, initially 30 mg twice-daily titrated to a maximum of 90 mg. IV infusion dosage initially 2 mg/min until adequate blood pressure control is reached, then 9–30 mg/h as a maintenance infusion.
Phenothiazines (chlorpromazine) and butyrophenones (haloperidol, droperidol) are competitive α-antagonists.
Mixed α- and β-antagonists
Labetalol is a competitive antagonist at both α1- and β-receptors, although β-blockade is predominant.
• Indications: hypertensive emergencies.
• Contraindications: sick sinus syndrome, second- and third-degree atrioventricular block, phaeochromocytoma, and Prinzmetal’s angina. The risk of bronchospasm should be appreciated prior to the use of peripherally acting β-blockade in the setting of asthma and COPD.
• Dose: orally, initially 100 mg twice a day, titrate to maximum 2.4 g/day in divided doses; IV bolus, 10–20 mg over 1 min, repeated every 5 min to maximum dose of 200 mg; IV infusion, 2 mg/min, increased as needed. Dose range 50–160 mg/h.
Carvedilol is a non-selective β-blocker with α1-antagonistic actions that cause vasodilatation. It is used in the treatment of hypertension and in congestive cardiac failure.
Centrally acting vasodilators
Clonidine is a centrally acting partial α2-agonist. There is a risk of rebound hypertension if stopped suddenly.
Onset of action is 30–60 min, peak action at 2–4 h, and half-life is 8–12 h. Fifty per cent is excreted renally unchanged.
• Indication: postoperative blood pressure control.
• Contraindication: (relative) depression.
• Dose: orally, 50–100 µg three times a day, increased to maximum 1.2 mg/day; IV bolus, 10 µg repeated until desired effect; IV infusion, 0.5–1.0 µg/kg/h.
Methyldopa, an analogue of levodopa, causes decreased blood pressure by reduction in peripheral vascular resistance. It is hepatically metabolized and renally excreted. Onset of action is 4–6 h, half-life is 2 h. Peak effect occurs at 3–6 h.
Side-effects include sedation, lactation, extrapyramidal signs and neuropsychiatric sequelae. Coombs test may become positive; may cause problems with cross-matching blood.
• Dose: orally, 250–300 mg two to three times a day, increase to maximum 3 g/day.
Angiotensin-converting enzyme inhibitors
Angiotensin-converting enzyme (ACE) inhibitors act by binding irreversibly to the angiotensin I binding site in the lung and preventing conversion to angiotensin II. Peripheral vascular resistance is decreased; cardiac output and heart rate are unchanged.
ACE inhibitors are used post-MI for their ventricular remodelling properties, and have been shown to improve long-term survival.
Oral administration is usual, although enalaprilat is available as an IV agent for use in patients who are unable to take oral therapy.
ACE inhibitors are renally excreted. Half-life is dependent on the preparation.
• Indications: hypertension, post-MI, cardiac failure, ischaemic heart disease.
• Contraindications: hyperkalaemia, acute renal dysfunction, renovascular disease, pregnancy, hereditary angio-oedema.
• Dose: There are several commonly used ACE inhibitors, dose is dependent upon preparation and in general should be up titrated as tolerated.
In critically ill patients, pulmonary vasodilators are used to prevent and treat acute right ventricular failure. In addition, inhaled pulmonary vasodilators are often used to improve oxygenation in patients with ARDS, although RCTs have not demonstrated improved survival.
PH in the critically ill
Vasodilators used in this setting include GTN, SNP, isoprenaline (see section on ‘β-Adrenergic agonists’), phentolamine, epoprostenol, and PDE inhibitors types 3 and 5 (see section on ‘Phosphodiesterase inhibitors’).
Vasodilators administered by inhalation are NO (see Chapter 11, section on ‘Nitric oxide’) and iloprost.
Chronic pulmonary vasodilator therapy
Treatment options have expanded over the past few years and now include oral agents, inhaled, and IV therapies.
• Prostanoids (epoprostenol [IV], iloprost [inhalation], treprostinil [SC], beraprost [oral]).
• Endothelin receptor antagonists (bosentan, ambrisentan, sitaxsentan).
Vasopressors are often used in intensive care to maintain cardiovascular stability. Although noradrenaline is the most commonly used, there are other agents that can also be used in particular clinical settings. Vasconstrictors have potentially serious adverse effects, such as myocardial, peripheral, and bowel ischaemia, as well as other less evident effects, such as immune modulation and bacterial stimulation. Vasopressin can be used to reduce the doses of catecholamines in the context of septic shock, but there is no evidence of improvement of clinical outcomes.
Classes of vasopressors
1. α1-Adrenergic receptor agonists: noradrenaline, metaraminol, phenylephrine, and ephedrine. α1-Agonists used primarily for their inotropic action (such as adrenaline and dopamine) are described in the section on ‘β-Adrenergic agonists’.
2. Vasopressin receptor agonists: vasopressin, terlipressin.
3. Nitric oxide synthase (NOS) inhibitors: l-NMMA (l-NG-monomethyl arginine), l-NAME (l-NG-nitro arginine methyl ester). In a clinical RCT, l-NMMA was found to increase mortality.
4. Guanylate cyclase inhibitors: methylene blue.
1. Vasodilation, such as that caused by sepsis and other systemic inflammation, spinal cord injury, vasodilator, and sedative drugs.
2. Cardiogenic shock, to maintain coronary perfusion pressure.
3. Maintenance of cerebral perfusion pressure (CPP) in brain-injured patients with raised ICP and as hypertensive treatment to prevent delayed cerebral ischaemia after subarachnoid haemorrhage.
Contraindications and cautions
1. Hypovolaemia, for which the primary treatment is fluid resuscitation, with or without a procedure to control haemorrhage. In practice, infusion of vasopressors at low doses may be required to maintain blood pressure whilst resuscitation is taking place.
2. Low cardiac output states: studies of noradrenaline have demonstrated that cardiac output may increase by 10–20%. Phenylephrine has been shown to increase cardiac output in septic shock, and vasopressin does not alter cardiac output. At low doses α1-agonists also cause venoconstriction, increasing the venous return and eventually cardiac output.
• Measurement of cardiac output and markers such as lactate, base deficit, and mixed or central venous oxygen saturation may be useful in assessing the effect of vasopressors.
• It is preferable to titrate vasopressors to the MAP rather than the systemic vascular resistance. MAP is measured directly and it is more clinically relevant.
Effects and side-effects
• Increased systolic and diastolic blood pressure, left ventricular stroke work, myocardial oxygen demand, and coronary perfusion pressure. Adrenaline may increase MAP in patients who do not respond adequately to other vasopressors owing to its greater inotropic activity.
• Venoconstriction and increased preload.
• Pulmonary vascular resistance may increase (e.g. noradrenaline) or decrease (e.g. vasopressin).
• Coronary artery dilation (e.g. noradrenaline) or constriction (e.g. vasopressin).
• Tachycardia, particularly with drugs which have significant β1-activity. (adrenaline, dopamine, ephedrine). Reflex bradycardia may occur with vasopressors that have little or no chronotropic activity (e.g. vasopressin). Noradrenaline usually causes little change in heart rate.
• All catecholamine vasopressors are potentially arrhythmogenic (particularly adrenaline and dopamine) and may cause myocardial ischaemia.
Effects on the splanchnic circulation
• Noradrenaline usually has little effect on splanchnic bloodflow, but a reduction in flow may occur, particularly if the patient is hypovolaemic. In combination with dobutamine, noradrenaline usually increases bloodflow to the gut.
• Dopamine increases mesenteric bloodflow.
• Adrenaline, phenylephrine, and vasopressin all decrease splanchnic bloodflow and may cause ischaemia, manifest as ileus, malabsorption, stress ulceration, or bowel infarction.
• Restoring blood pressure using vasopressors increases urine output and creatinine clearance in patients with volume-resuscitated septic shock. There are reports that this may be more marked with vasopressin infusion.
Effects on peripheral circulation
• Ischaemic extremities and skin lesions may occur with any vasopressor.
• Catecholamines cause increased total body oxygen consumption, increase in glucose production, peripheral insulin resistance and suppression of insulin release, leading to hyperglycaemia. They increase fatty acid and lactate production, and hepatic clearance of lactate can be impaired. Hyperlactataemia is especially common with adrenaline treatment.
Catecholamines stimulate bacterial growth by several mechanism, such as increasing bacterial iron uptake and stimulating gene expression.
Pharmacology of specific agents
α1-Receptors are present throughout the peripheral arterial and venous systems. Stimulation of the receptor leads to G-protein-mediated activation of phospholipase C and a cascade of intracellular signals leading to calcium-mediated vasoconstriction.
Noradrenaline is the amine neurotransmitter at postganglionic sympathetic nerve terminals and is an agonist at all adrenergic receptors. However, when exogenous noradrenaline is administered as an IV infusion, the α1 effects predominate.
• Dose: 0.01–1.5 µg/kg/min by IV infusion.
• Half-life: 2 min, leading to a steady-state plasma concentration within 10 min of starting or changing a constant rate of infusion.
• Metabolism: primarily in the liver, kidneys, brain, and lungs by monoamine oxidase (MAO) and catechol-o-methyltransferase (COMT) to inactive metabolites.
• Interactions: effects may be exaggerated and prolonged in patients taking MAOIs, even though this interaction is associated more often with indirect acting sympathomimetics.
Metaraminol is a synthetic amine with both direct and indirect sympathomimetic actions. The direct action is mainly on α1-receptors, although it has some β-receptor activity. The indirect action involves stimulation of the release of noradrenaline from nerve terminals.
• Use: short-term treatment of hypotension, e.g. in the initial resuscitation of the shocked patient, at the start of haemofiltration, and during anaesthesia for procedures on ICU.
• Dose: 0.2–1.0 mg by IV bolus.
Phenylephrine is a direct-acting synthetic sympathomimetic amine, with potent α1-agonist activity and no β-receptor activity.
• Dose: 50–100 µg by IV bolus, 0.5–8 µg/kg/min by IV infusion.
• Duration of action: 5–10 min.
• Metabolism: in the liver by MAO.
Ephedrine has both direct and indirect sympathomimetic actions.
• Dose: 3–6 mg by IV bolus.
• Duration of action: the elimination half-life is 4 h. However, the duration of clinical activity is often just a few minutes. This may be due to tachyphylaxis, as noradrenaline stores in nerve terminals become depleted. For the same reason, repeated boluses may be ineffective after the first 12–15 mg.
• Not metabolized by COMT or MAO. Some is metabolized in the liver, but 65% is excreted in the urine unchanged.
Vasopressin receptor agonists
Vasopressin is released from the posterior pituitary gland in response to increased plasma osmolality, decreased arterial blood pressure, or decreased intravascular volume.
It acts on three subtypes of vasopressin receptor:
• V1a receptors mediate vasoconstriction, both directly and by increasing vascular responsiveness to catecholamines.
• V2 receptors are found in the renal collecting ducts. Stimulation leads to increased water reabsorption.
• V1b (formerly V3) receptors are found mainly in the CNS, where they modulate secretion of adrenocorticotrophic hormone.
Arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), is an agonist at all vasopressin receptors.
• The plasma concentration of endogenous AVP usually increases in early septic shock but then a state of vasopressin deficiency develops. Infusion of vasopressin allows reduction or possibly even withdrawal of other vasopressors. At high doses complications, including cardiac arrest and regional ischaemia, become more likely. These limit its use as a sole vasopressor and it will often be used as an adjunctive therapy to spare noradrenaline use.
• Dose in septic shock: 0.01–0.06 U/min by IV infusion.
• Half-life: 6 min, duration of action 30–60 min.
• Metabolism: primarily in the liver and kidneys.
Terlipressin is a more selective V1 receptor agonist. Terlipressin has a longer duration of action than vasopressin, and can therefore be given by IV bolus. It is primarily used to treat variceal bleeding in a dose up to 2 mg IV four times daily. In septic shock, it can be used when AVP is not available.
• Dose in septic shock: initial bolus of 0.5 mg, repeated every 30 min to a maximum of 2 mg. Then 0.5–1 mg four times daily.
• Half-life: 6 h, duration of action 2–10 h.
Desmopressin is a synthetic selective V2 receptor agonist used to treat neurogenic diabetes insipidus and bleeding disorders. It is not used as a vasopressor.
Guanylate cyclase inhibitors
Methylthioninium chloride inhibits the activity of NOS as well as guanylate cyclase.
In small clinical trials in sepsis and postcardiac surgery, methylthioninium chloride had been shown to increase blood pressure and reduce conventional vasopressor use, but its effect on outcome is uncertain.
• Dose: an initial bolus of 1–2 mg/kg over 15–30 min then a continuous infusion of 0.25–1 mg/kg/h for 3 h to 3 days.
Use of vasopressors in specific situations
• Current guidelines recommend noradrenaline as the first-line vasopressor in septic shock.
• The target MAP of 65 mmHg may be adequate for most patients, depending on their premorbid blood pressure. Higher blood pressure targets lead to higher vasopressor use and more drug-related adverse effects.
• A clinical trial in patients with septic shock compared treatment with adrenaline versus the combination of noradrenaline and dobutamine. No significant difference was found in either mortality or serious adverse events.
• The VASST study showed no overall mortality benefit in patients with septic shock treated with vasopressin rather than noradrenaline alone.
Data from the VaNCS study suggests that vasopressin may reduce the incidence of acute kidney injury, the use of dialysis, and reduce the rates of AF in patients with vasoplegic shock after cardiac surgery.
Current international guidelines recommend adrenaline 1 mg by IV bolus as the first-line vasopressor/inotrope in cardiac arrest. Vasopressin may have a role in refractory ventricular fibrillation or out-of-hospital arrest in asystole.
Abstract: Arrhythmias are common in ICU patients, with AF predominating, particularly after cardiac surgery. All arrhythmias significantly prolong hospital stay, with ventricular arrhythmias increasing morbidity and mortality. Antiarrhythmic agents can be classified by their clinical or electrophysiological effect (Vaughan Williams classification). Despite significant side-effects amiodarone remains the most commonly used drug for tachyarrhythmias with multiple indications for use. Cardioversion is the treatment of choice in patients with haemodynamic instability secondary to a tachyarrhythmia. Whilst drugs for bradyarrhythmias can be used as temporizing measures, pacing remains the definitive treatment in unstable patients. Underlying causes for arrhythmias should always be considered. All antiarrhythmic medications are proarrhythmic and the relevant side-effects, cautions, and pharmacokinetics are discussed.
Introduction: Arrhythmias occur in 12–40% of ICU patients. AF is the commonest arrhythmia (10–65%), often following cardiac surgery.
All arrhythmias significantly prolong hospital stay. Ventricular arrhythmias are significantly associated with adverse neurological sequelae and increased mortality.
Antiarrhythmic agents are commonly classified according to their primary electrophysiological effect (Vaughan Williams classification; Table 12.1), although most agents have multiple modes of action. Many common antiarrhythmics are incompatible with the classification.
Table 12.1 Vaughan Williams classification
Na channel blockers
K channel blockers
Calcium channel blockers
Reproduced from The Journal of Clinical Pharmacology, 24, Williams E. M., A Classification of Antiarrhythmic Actions Reassessed After a Decade of New Drugs, pp. 129–147. Copyright (1984) permission of John Wiley and Sons.
Drugs for tachyarrhythmia
Mechanism of action: endogenous nucleoside with rapid onset and ultra-short duration of action. Acts via α1-receptors, depressing sinoatrial (SA) and atrioventricular (AV) nodal activity.
Use: diagnosis and treatment of cardiovascularly stable supraventricular tachycardia (SVT). Terminates AV node-dependent SVT. Unmasks flutter waves in atrial flutter (no effect on flutter circuit itself).
Dose: initial 6 mg followed by further 6 mg, if ineffective after 1–2 min give 12 mg. Administer as a fast IV bolus.
Pharmacokinetics: patients taking methylxanthines are less sensitive to adenosine (adenosine receptor antagonist activity). Conversely, dipyridamole can block adenosine transport back into the cell and enhance adenosine response.
Side-effects/cautions: bradycardia, asystole—although almost always transient. In awake patients commonly causes dyspnoea, apprehension, dizziness, headache. Caution in Wolf–Parkinson–White syndrome (WPW) where can precipitate ventricular fibrillation (VF). Avoid in acute myocardial ischaemia. Postcardiac transplant use 3 mg starting dose (increased sensitivity).
Mechanism of action: broad-spectrum class III antiarrhythmic agent that also demonstrates class I, II, and IV activity. Blocks sodium, potassium, and calcium channels in addition to α- and β-adrenoreceptors.
Use: 1) all haemodynamically stable tachyarrhythmias, including ventricular tachycardia (VT); 2) postoperative AF prevention; 3) rate control/cardioversion in established AF or atrial flutter. As effective as diltiazem when given intravenously for rate control of AF. Superior to lidocaine in cardiac arrest secondary to shock-resistant VF or VT.
Dose: initially IV 5 mg/kg (300 mg) over 30–60 min followed by 15 mg/kg over 23 h (maximum 1.2 g in 24 h). Dilute in glucose 5%. Maintenance by oral route. Following cardiac arrest 300 mg IV (if in VF/VT) with further 150 mg IV if required.
Pharmacokinetics/contraindications: delayed onset (6–8 h). Hepatic metabolism—substrate and inhibitor of cytochrome P450. No dose adjustment required in renal dialysis. IV administration may have less effect on the QRS and QT segments. Interacts with common transplant ICU immunosuppressants. Risk of prolonged QT with some antipsychotics, antifungals, and macrolide antibiotics. Risk of bradycardia in patients receiving novel hepatitis C medication.
Side-effects: can occur even in short-term use and persist or worsen on discontinuation owing to long half-life and extensive tissue distribution: hypotension (14–26%), torsades de pointes (TdP), bradycardia; nausea, vomiting, altered taste (25%); deranged liver function tests (LFTs) (4–25%); pulmonary fibrosis, pulmonary infiltrates (2–17%, possibly dose-related); thyroid biochemical abnormalities (30%); clinical hypothyroidism (2–10%), hyperthyroidism (2–10%).
Mechanism of action: class II antiarrhythmics acting by the reversible blockade of β1-cardiac adrenoreceptors.
Use: rate control in acute supraventricular tachycardias (commonly AF and atrial flutter), Post-operative AF prevention.
Contraindications/side-effects: caution in acute heart failure or asthma. Can cause hypotension, bradycardia, AV block.
Dose: IV 5 mg at rate of 1–2 mg per minute, repeated after 5 min if necessary, maximum 15 mg. To control arrhythmias on induction of anaesthesia 2 mg (maximum 10 mg).
Pharmacokinetics: peak effect is 20 min if used intravenously, 1–2 h oral.
Additional side-effects: possible increased risk of stroke if used preoperatively/intraoperatively compared with esmolol.
Mechanism of action: a β-blocker classified as a class III antiarrhythmic agent possessing additional class I activity.
Use: treatment/prevention of VT and SVT (including AF). Less effective than amiodarone in the prevention of VT, less effective than flecainide for conversion of AF. Has been used for the prevention of postoperative AF in cardiac surgery. Effective in preventing ventricular arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy.
Dose: 1–1.5 mg/kg over 20-min IV infusion. Orally 80–160 mg bd. Not used as an acute treatment.
Pharmacokinetics: reverse use dependence. Progressive QT prolongation as the heart rate slows. May be less effective at higher heart rates.
Additional side-effects: QT prolongation. Small risk of precipitating TdP, especially in the context of hypokalaemia.
Calcium channel blockers
Mechanism of action: class IV antiarrhythmics. Preferentially affect slow channels (SA and AV node—mediated by calcium) rather than sodium mediated fast channels (atria, ventricles, infra-nodal conduction). Slows phase 4 depolarisation, lengthens AV node refractory period.
Use: primarily used for the management of SVTs that use the AV node, particularly AVNRT. Less useful in AVRT (fast channel sodium influx mediated). Also rate control in AF, atrial flutter, and atrial tachycardia.
Pharmacokinetics: non-dihydropyridine calcium channel blockers (CCBs) exhibit use dependence (increase in blockade as the frequency of impulse generation and ventricular activation increases).
Side-effects/contraindications: all non-dihydropyridine CCBs diminish cardiac contractility and slow cardiac conduction. Avoid in bradycardic patients, second- and third-degree AV block, hypotension, and cardiogenic shock. Avoid in SVT secondary to an accessory pathway or wide complex tachycardia. Possible increase in early mortality following MI (nifedipine) due to alteration in electrophysiological myocardial properties. Possibly increase in gastrointestinal haemorrhage (non-dihydropyridine CCBs) in the elderly.
Additional use: multifocal atrial tachycardia.
Dose: initially 5–10 mg IV over 2–3 min. A further 5 mg every 20 min if no response (maximum 20 mg). Orally 40–120 mg tds.
Pharmacokinetics: peak effect IV 1–5 min.
Additional side-effects: hypotension (significant negative inotrope). Avoid IV use if recently treated with β-blockers (severe hypotension and asystole). Avoid in WPW as VT or VF may be precipitated.
Dose: initially 0.25 mg/kg IV over 2 min. If the response is inadequate, a second dose of 0.35 mg/kg over 2 min after 15 min or a continuous infusion of 10–15 mg/h.
Pharmacokinetics: peak IV effect 3 min.
Mechanism of action: cardiac glycoside, multiple mechanisms of action, including inhibition of Na-K-ATPase (slows AV node and pacemaker cell conduction) and increased efferent vagal activity.
Use: rate control in AF or atrial flutter if monotherapy with a β-blocker/CCB unsuccessful/inappropriate. No longer indicated as monotherapy for rate control in AF or AF prophylaxis for cardiac surgery/postoperative AF.
Dose: 10–15 μg/kg (usually 500 μg) IV over 30 min 6-hourly until effective (maximum 20 μg/kg). Oral 0.5-mg load, followed by 0.25 mg every 6 h repeated up to a maximum of 1.5 g. Loading doses should be halved in renal insufficiency, including in dialysis or low-weight patients.
Pharmacokinetics: relatively delayed onset of action (median time to ventricular rate control up to 6 h). Narrow therapeutic range. Caution in patients with renal insufficiency. Toxicity may precipitate any form of arrhythmia.
Side-effects/contraindications: junctional rhythm, asystole, heart block, ST depression, premature ventricular contractions, VT, VF (in WPW). Avoid in bradycardic patients. Exacerbated by hypokalaemia and hypomagnesaemia. Can increase myocardial oxygen demand; caution in MI, myocarditis. Also nausea, vomiting, diarrhoea; headache, confusion, xanthopsia; vesicant if extravasation occurs on IV administration; digoxin concentration can be affected in thyroid disease.
Treatment of toxicity: treatment of arrhythmias resulting from toxicity includes correction of electrolyte imbalance and digoxin antibodies. Temporary pacing may be required. DC cardioversion is controversial—ventricular arrhythmias may be precipitated.
Flecainide is a class Ic antiarrhythmic, exhibiting use dependence. Also inhibits ryanodine receptor 2 (RyR2), a major regulator of sarcoplasmic release of stored calcium ions. Commonly used orally as treatment or prophylaxis for AF. Can be used intravenously for resistant ventricular tachyarrythmias. Avoid in left ventricular dysfunction, sinus bradycardia or pre-excitation, or in the presence of, or suspected, coronary artery disease.
Lidocaine is a class Ib antiarrhythmic agent. Used only in the context of ventricular arrhythmias; currently second-line to amiodarone in VF/VT. Little effect on atrial and AV nodal tissue. Used in monomorphic VT but carries significant risk of degeneration to VF.
Magnesium sulfate has multiple effects: through acetylcholine, slowing SA node impulse formation and prolonging myocardial conduction, probably through stabilizing excitable membranes. Drug of choice in the treatment of TdP. Used in ventricular arrhythmias, particularly in the context of acute MI, biventricular failure, and in digoxin overdose. Dose: 5–10 mmol over 10–15 min IV. Can induce flushing, hypotension, and vasodilation. Avoid in neuromuscular disease. May accumulate in renal disease.
Drugs for bradyarrhythmia
Mechanism of action: an α- and β-adrenergic receptor agonist with varied effects depending on dose; utilized in bradycardia as a cardiac stimulator.
Use: asystolic arrest/pulseless electrical activity (may not improve survival-await further trials). Used as an infusion for symptomatic bradycardia unresponsive to pacing or atropine.
Pharmacokinetics: rapid onset with an IV half-life of <5 min.
Dose: 1 mg IV/intraosseous in cardiac arrest repeated every 3–5 min until return of spontaneous circulation. In symptomatic bradycardia IV infusion; 0.1–0.5 μg/kg/min titrated to effect.
Side-effects: proarrhythmic, can induce renal dysfunction and digital ischaemia in larger doses due to vasoconstriction. Can induce angina/chest pain.
Mechanism of action: acetylcholine blocker of parasympathetic receptors at multiple sites, enhances SA node automaticity.
Use: temporizing measure in sinus bradycardia. Ineffective in the management of higher degree block; limited effect on AV node.
Pharmacokinetics: rapid onset if given IV or IM with half-life of 2–3 h.
Dose: 0.5 mg every 3–5 min, not to exceed a total of 3 mg, doses <0.5 mg associated with transient bradycardia.
Side-effects/cautions: proarrhythmic (bradyarrhythmias and tachyarrhythmias). Significant cholinergic side-effects. Avoid in closed angle glaucoma. Ineffective in transplanted hearts (lack of vagal innervation).
Mechanism of action: both dopinergic and adrenergic agonist (dose-related activity).
Use: Heart block unresponsive to atropine or pacing. Any symptomatic bradycardia.
Pharmacokinetic: onset of action 5 min with half-life of 2 min.
Dose: 5–10 μg/kg/min; titrate to effect.
Side-effects: anxiety, headache, proarrhythmic, avoid in any tachyarrhythmia, a vasopressor and vasoconstrictor with potential for tissue necrosis. Can induce angina/chest pain.
Mechanism of action: a β1- and β2-adrenoreceptor agonist. Isoprenaline has weakly positive inotropic effects but significant chronotropic effects. Also acts upon β2-adrenoreceptor stimulation in arteriolar smooth muscle, inducing vasodilation (overall decreases MAP).
Use: mild or transient episodes of heart block or as a bridge to pacemaker/temporary pacing/percutaneous pacing in serious episodes of heart block.
Pharmacokinetics: immediate onset IV with half-life of minutes.
Dose: IV infusion 2–10 μg/min titrated to effect.
Side-effects: proarrhythmic, angina, dizziness contraindicated in pre-existing tachyarrhythmia or in digoxin toxicity.
Inappropriate heart rates (tachycardia/bradycardia) as well as arrhythmia are associated with significant morbidity and mortality in the critically ill. Chronotropes (Greek: Χρόνος, ‘time’, and τρόπος, ‘turn’) are a group of drugs used acutely to prevent or control inappropriate heart rates (Table 12.2). Persistent or high-risk cases may require pacing.
Table 12.2 Effects of sympathetic adrenergic receptors
Smooth muscle contraction, vasoconstriction in skin, mucosa, and splanchnic circulation
Smooth muscle mixed effect, sympathetic attenuation, analgesia
Positive inotropy and chronotropy, platelet aggregation
Smooth muscle relaxation (vasodilation, bronchodilation)
Lipolysis, detrusor muscle relaxation
Natural catecholamine produced by the adrenal medulla.
Mechanism of action: direct α- and β-adrenergic receptor agonist. At low doses, β-effects and at higher doses α-effects predominate.
Pharmacokinetics: near immediate effect. Half-life ~2 min. Metabolized by COMT and MAO in the liver, kidney, and blood to vanillylmandelic acid and metadrenaline. Glucuronidated/sulphated and renally excreted.
Uses: 1) Cardiac arrest; 2) cardiogenic shock; 3) anaphylaxis; 4) bronchospasm.
Dose: cardiac arrest, 1 mg IV (10 ml of 1:10 000 solution), repeated every 3–5 min. Anaphylaxis, 500 μg IM (0.5 ml of 1:1000 solution) or 50 μg IV (0.5 ml of 1:10 000 solution), repeated as necessary.
Contraindications: no absolute contraindications. Caution in ischaemic heart disease.
Mechanism of action: direct β1- and β2-adrenergic receptor agonist. Causes positive inotropy and chronotropy, vasodilation, and unpredictable changes in systolic blood pressure (usually hypotension owing to reduced systemic vascular resistance).
Uses: interim measure in bradycardia with adverse features or risk of asystole, if unresponsive to atropine.
Pharmacokinetics: rapidly metabolized by COMT in the liver, then conjugated; however, up to 75% is unchanged. Renally excreted.
Dose: 5 μg/min IVI (0.02–0.2 μg/kg/min).
Adverse effects: arrhythmia, hypotension, coronary steal, unmasking pre-excitation.
Contraindications: AV block caused by digoxin.
Atropine (atropine sulfate)
Uncharged, tertiary amine ester. Diastereomeric mixture (L-hyoscyamine is active).
Mechanism of action: competitive muscarinic acetylcholine receptor antagonist. Crosses the blood–brain barrier. Results in vagolysis and tachycardia.
Uses: 1) Bradycardia; 2) organophosphate poisoning.
Pharmacokinetics: 50% protein bound. Half-life of 150 min. Hepatic hydrolysis. Renal elimination.
Dose: for bradycardia, 0.5 mg IV, repeated every 3–5 min. Maximum 3 mg.
Adverse effects: paradoxical bradycardia (doses <0.5 mg), tachycardia, central anticholinergic syndrome, constipation, mydriasis, urinary retention, sedation, amnesia, raised intraocular pressure.
Contraindications: gastrointestinal obstruction/atony, toxic megacolon. Caution in acute myocardial ischaemia and pyrexia. Ineffective in transplanted hearts.
Glycopyrronium bromide (glycopyrrolate)
Synthetic, charged, quaternary ammonium compound.
Mechanism of action: muscarinic receptor antagonist. Does not readily cross blood–brain barrier. Increases automaticity of SA node and atrial refractory period. Decreases AV node refractory period. Increases atrial contractility and global cardiac conduction velocity.
Uses: 1) Bradycardia; 2) neuromuscular blockade reversal.
Pharmacokinetics: minimally metabolized. 80% excreted renally, unchanged.
Dose: 0.2–0.4 mg IV, repeated if necessary.
Contraindications: gastrointestinal obstruction/atony, toxic megacolon, myasthenia gravis.
Polypeptide hormone released by pancreatic islet α-cells.
Mechanism of action: may increase intracellular Ca2+ in cardiac myocytes via adenylate cyclase and cAMP, causing positive inotropy and chronotropy.
Uses: bradycardia caused by β-blockers or CCBs.
Pharmacokinetics: half-life 10 min. Redistribution and proteolysis in liver, kidney, and blood.
Dose: 2–10 mg IV bolus in 5% glucose. Then 50 μg/kg/h IVI.
Adverse effects: hypersensitivity reactions, hypotension, hypokalaemia.
Methylxanthine derivative comprising 80% theophylline and 20% ethylene diamine (improves solubility).
Mechanism of action: non-selective PDE inhibitor, which increases cAMP. Demonstrates synergy with catecholamines by stimulating noradrenaline release.
Effects: positive inotropy and chronotropy, peripheral vasodilation, bronchodilation.
Uses: 1) Bradycardia; 2) acute life-threatening asthma.
Pharmacokinetics: demethylated and oxidized by cytochrome P450 (CYP450) enzymes. Caution with CYP450 inducers and inhibitors, especially macrolides. Narrow therapeutic index (10–20 mg/l). Renal elimination.
Dose: 5–7 mg/kg IV over 30 min then 0.5 mg/kg/h IVI (up to 1 mg/kg/h in smokers and those on cytochrome P450 (CYP450) inducers). Omit loading dose in those already taking regular theophylline.
Adverse effects: seizures, arrhythmia, hypertension, hypokalaemia.
Contraindications: dose adjustment in cardiac and hepatic impairment.
Ultra-short acting, selective β1-adrenergic receptor antagonist.
Uses: acute treatment of SVT, sinus tachycardia, or hypertension.
Pharmacokinetics: distribution half-life 2 min. Half-life 9 min. Hydrolysed by red blood cell esterases.
Dose: IV loading: 500 µg/kg over 1 min. Transient hypotension may occur. Maintenance: 50–200 µg/kg/min, IVI titrated by 25 µg/kg/min every 5 min.
Non-selective β-adrenergic receptor antagonist. Negatively inotropic and chronotropic, and suppresses renin release. Reduces cardiac output and myocardial oxygen demand. R-isomer prevents peripheral conversion of T4 to T3.
Uses: 1) hypertension; 2) sympathetic overactivation, including in thyrotoxic crisis and phaeochromocytoma (with α-blockade).
Pharmacokinetics: 95–100% absorption. High first pass metabolism. 90% plasma protein-bound. Crosses the blood–brain barrier and placenta. Half-life 4–6 h. Liver metabolism. Renal elimination.
Dose: 1 mg IV bolus, given over 1 min. Repeat as needed every 2 min. Maximum dose 10 mg.
Selective β1-adrenergic receptor antagonist. Effects similar to propranolol.
Uses: 1) Rate control in regular or irregular narrow complex tachycardia without adverse features; 2) rate control in stable, broad complex tachycardia where SVT with aberrancy is suspected.
Pharmacokinetics: peak IV effect in 20 min. Twenty per cent protein-bound. Half-life 3–7 h depending on pharmacogenetics (hepatic hydroxylation).
Dose: boluses of up to 5 mg IV at a rate of 1–2 mg/min. Repeat after 5 min if necessary, to a total dose of 10–15 mg. Intraoperatively, 2–4 mg IV at induction or to control arrhythmias during anaesthesia. Titrate in 2 mg boluses.
Adverse effects of β-blockers:
Bradycardia (via sinus slowing or AV block).
Congestive cardiac failure.
Worsening of obstructive airways disease, and bronchospasm.
Phenylalkylamine (class I) calcium channel antagonist.
Mechanism of action: use dependent blockade of voltage-sensitive slow (L-type) channels in the SA and AV nodes, reducing automaticity. Reduces contractility by reducing myocyte Ca2+ influx (plateau phase). Also vasodilatation.
Uses: 1) Acute rate control in AF as an alternative to β-blockers, e.g. in reactive, obstructive airways disease; 2) long-term rate control in AF, except when heart failure present; 3) rate control for AF in acute coronary syndrome without signs of heart failure.
Pharmacokinetics: peak IV effect 1–5 min. Half-life 3–7 h, prolonged with higher doses. Renal clearance.
Dose: initially 0.0375–0.15 mg/kg IV over 2 min. Further 5 mg every 20 min if no response. Maximum 20 mg. PO 40 mg b.d., 360 mg o.d. (extended release).
Adverse chronotropic effects: combined use with β-blockers may cause severe bradycardia. Reduces digoxin elimination and can precipitate digoxin toxicity.
Benzothiazepine (class III) calcium channel antagonist.
Mechanism of action: inhibits L-type calcium channels. Reduces contractility to a lesser degree than verapamil, therefore less likely to compromise cardiac output.
Uses: similar to verapamil. Preferred in the acute rate-control of AF as less negatively inotropic.
Pharmacokinetics: peak IV effect 3 min. Half-life 3–6 h. Clearance is 60% hepatic (via an active metabolite) and 40% renal.
Dose: PO 120–360 mg daily, in two or three divided doses. Equal doses of different modified release preparations may have differing clinical effects.
Adverse chronotropic effects: use with β-blockers may cause severe bradycardia.
cardiac glycoside (see section on ‘Antiarrhythmic agents’).
Uses: 1) Rate control in AF acutely, especially in decompensated heart failure, in place of β-blockers; 2) alternative long-term rate control in AF only in patients with left ventricular dysfunction and in sedentary/inactive patients.
Pharmacokinetics: gradual onset over 15–30 min, peak effect 1–5 h after IV administration. Half-life 1.7 days. Predominantly renally excreted.
Dose: IV loading 0.75–1 mg over at least 2 h. PO loading 0.75–1.5 mg in divided doses given over 24 h. Maintenance 125–250 μg daily.
Cautions/adverse chronotropic effects: reduced dose in renal impairment, ischaemia, and advanced age (e.g. 62.5 μg daily). IV to PO switching may require a dose increase by 20–33% to maintain plasma digoxin levels. Care needed to avoid toxicity.
class III antiarrhythmic
Mechanism of action: prolongs cardiac action potential and causes slowing of conduction via the SA and AV nodes.
Uses: rate control in regular narrow complex tachycardia without adverse features, particularly where other agents, e.g. β-blockers, are ineffective or contraindicated (decompensated cardiac failure, concomitant use of positive inotropic agents).
Dose: IV loading: 300 mg in 250 ml 5% glucose IV over 20–120 min, then 900 mg IVI over 24 h. Full IV loading requires 4.5–6 g, maximum rate 1.2 g per day. Administer centrally unless emergency. PO loading 200 mg tds for 1 week, then 200 mg bd for 1 week, followed by maintenance (usually 200 mg od).
Cautions/adverse effects: haemodynamic instability, QT prolongation, multiple drug interactions, thyroid dysfunction, pulmonary fibrosis, hepatitis.
Mechanism of action: decreases adrenal catecholamine release, antagonizes N-methyl-D-aspartate (NMDA) receptor, inhibits voltage-gated Ca2+ channel and Na+/K+ pump, and inhibits phospholipase Ca2+-mediated Ca2+ release.
Uses: 1) TdP; 2) other cardiac arrhythmias, especially with hypokalaemia. Also used in severe bronchospasm, and pre-eclampsia/eclampsia.
Dose: for arrhythmia, 2 g IV over 10–15 min.
Adverse effects: coma, confusion, arrhythmia, loss of deep tendon reflexes (may indicate toxicity), hypotension, muscle weakness, augmentation of neuromuscular blockade, and cardiac arrest (>12 mmol/l).
Contraindications: no absolute contraindications. Beware hypermagnesaemia.
This does not provide reliable ventricular stimulation. Use only when no other option is available. Alternatives (drugs/transvenous pacing) should be initiated as soon as possible.
Temporary transvenous pacing
This should be limited to cases where chronotropic drugs are insufficient or contraindicated. The time to permanent pacing or an alternative method of chronotropy should be as brief as possible.
Pacemakers are coded using five letters to designate pacing modes (Table 12.3).
Table 12.3 Code for pacemaker specifications
High-degree AV block without escape rhythm.
Life-threatening bradyarrhythmias, e.g. during percutaneous coronary intervention.
Rarely, in acute settings (acute MI, drug toxicity, concomitant systemic infection).
Implantation: right ventricular free wall perforation causing cardiac tamponade (may manifest following wire removal).
Pacing lead: displacement, change of capture threshold, malfunction, accidental extraction.
External pacemaker: loss of power.
Limited mobility: venous thromboembolism, infection.
Permanent pacing in bradycardia:
Consider when a transient or reversible cause is excluded.
Major indications (class I evidence):
Persistent or intermittent, symptomatic sinus node disease with syncope.
Persistent or intermittent type II second-degree or third-degree AV block ± symptoms.
Unexplained syncope and bifascicular BBB if high-risk features on ILR monitoring or at EPS.
Postcardiac surgery or transcatheter aortic valve implantation patients with high-degree AV block or sinus node dysfunction.
Heart transplant patients with sinus node dysfunction.
Other indications (class IIa evidence):
Carotid sinus syncope (dominant cardioinhibitory carotid sinus syndrome and recurrent unpredictable syncope).
Second-degree type I AV block with symptoms, or high-risk at EPS.
Recurrent/severe reflex syncope with dominant cardioinhibition in older patients, with either a. spontaneous asystolic pauses (extrinsic/functional) or b. CI-CSS on testing.
Syncope and asymptomatic sinus bradycardia, with a prolonged corrected SNRT on EPS.
Heart transplant patients with chronotropic incompetence.
For patients at an increased risk of sudden cardiac death, e.g. low ejection fraction, requiring permanent pacing, consider referral for cardiac resynchronization therapy ± defibrillator, or a pacemaker with internal cardioverter defibrillator function.
Unstable angina or acute coronary syndrome and stable angina have different pathophysiology and treatment. The best way to prevent angina in critically ill patients with stable angina is to ensure they are well oxygenated, that their blood pressure (especially the diastolic and therefore coronary perfusion) is well maintained and that tachycardia is prevented. Antianginal agents should be used with great caution in patients who are unstable as you will block many of the receptors you might well be trying to stimulate in a few hours’ time to maintain that blood pressure.
These are first-line antianginal agents in stable patients. This needs to be considered when using adrenergic agents for cardiovascular support. β-Blockers have negative inotropic and negative chronotropic actions and limit myocardial oxygen demand. They are also effective antihypertensives. These combined actions reduce left ventricular wall tension and thus further improve blood supply and oxygen delivery to the myocardium. By preferentially prolonging diastole they further increase coronary perfusion. They have been extensively investigated for preoptimization of high-risk surgical patients and are recommended by the American Heart Association for continuation in patients already taking these drugs and for initiation in high-risk patients undergoing vascular and high-risk surgery as long as they are started at least a week in advance of surgery and carefully titrated to heart rate and blood pressure.
Other beneficial actions
β-Blockers inhibit platelet aggregation, reduce the risk of ventricular arrhythmias in acute ischaemia, slow conduction, and have actions on cardiac remodelling that make them beneficial in chronic heart failure.
Cardiac and circulatory adverse actions
Heart failure: because of inhibition of the sympathetic drive, β-blockers carry the risk of worsening left ventricular dysfunction acutely. In the setting of critical illness, this is a significant concern; it occurs in <6% of patients who are stable before initiation of β-blockade. However, cardioselective β-blockers are a key component of the long-term management of left ventricular dysfunction, where they are introduced slowly and cautiously in stable patients.
Cardiac conduction abnormalities: β-blockers should be avoided in patients with sick sinus syndrome and there is a risk of precipitating heart block in those with conduction abnormalities. This can be exacerbated by drug interactions (e.g. CCBs, digoxin).
Peripheral vascular disease: symptomatic worsening has been observed in those with severe arterial disease, and most surgeons will prefer to stop them in the context of peripheral vascular surgery; however, this is probably overstated and the evidence is poor.
Inhibition of coronary vasodilatation: this is overcome by the beneficial effects of β-blockade on myocardial oxygen demand in stable patients. In the critically ill patient with acute circulatory insufficiency this may become clinically significant, especially as diastolic blood pressure falls. The relative potency of pressors at β1- and β2-receptors in increasing myocardial contractility without necessarily overcoming existing β-blockade of coronary vasodilatation to the same extent could in theory worsen ischaemia.
Abrupt withdrawal can precipitate acute hypertensive crises, crescendo angina, and heart failure. Beware the unexplained postoperative crisis following accidental omission!
Extracirculatory adverse actions
Bronchoconstriction is worsened by β-blockade, especially with non-selective agents and high doses of selective agents.
Hyperkalaemia: catecholamines cause uptake of potassium into cells and β-blockers inhibit this—it is rarely of clinical relevance.
Hypoglycaemia is worsened and recovery slowed in those on β-blockers. The symptoms of hypoglycaemia, sweating, tachycardia, and anxiety, are masked by β-blockade. These effects are less or absent if cardioselective agents are used.
Pharmacokinetics and drug specifics
The intensivist must be aware of the metabolism and elimination of common drugs. Atenolol is excreted 50% in the faeces and 50% in the urine, mostly as unchanged drug; there is ~10% liver metabolism and the half-life is 6–9 h in healthy individuals; accumulation in renal failure is common and presents frequently to acute medicine. Metoprolol (also bisoprolol, propranolol, and oxprenolol) is extensively metabolized in the liver by the CYP2D6 enzyme complex. The half-life is bimodally distributed in the population and is either ~3 h or 8 h (hence some patients need tds administration and others bd). The hepatic metabolism makes this drug particularly useful in the critical care patient. Carvedilol is hepatically metabolized, but one metabolite is 13 times more potent at β-blockade and is then excreted in the faeces. Sotalol is entirely excreted unchanged in the urine; this drug also has class III antiarrhythmic activity at higher doses (>80 mg bd) and can cause significant QT interval prolongation. Labetalol is hepatically metabolized and also has α-blocking activity; it is frequently used for control of blood pressure in subarachnoid haemorrhage as there is no cerebral vasodilatation, and is easily titrated; it also has a role in management of phaeochromocytoma, but should not be relied on as the only source of α-antagonism. Esmolol is degraded by red cell esterases, with a half-life of 9 min; it is used for acute hypertension and supraventricular arrhythmias and not for angina. Esmolol might have an important role in critically ill patients with severe sepsis and has shown a mortality benefit in one randomized study, probably by protecting the heart by partly blocking the β-activity of high doses of noradrenaline, and therefore reducing heart rate.
Patients with β-blocker overdose will present with hypotension and bradycardia. The PR interval may be prolonged and QRS complexes may be broadened. Hypoglycaemia and mild hyperkalaemia may be noted (if accumulation has resulted in renal failure this may be marked).
Treatment should be according to ABC principles; specific therapy includes atropine (0.5 mg IV repeated every 5 min to 3 mg), glucagon 5 mg IV bolus (increases intracellular cAMP and therefore calcium independently from β-adrenoreceptors) repeated if no response after 5 min and followed by infusion of 1–5 mg/h. Calcium (10 ml of 10% calcium chloride centrally or 30 ml of 10% calcium gluconate peripherally); insulin and glucose have also been used in β-blocker overdose, titrating up to 50 IU in 50 g glucose over 1 h. Catecholamines will often be necessary, but may result in myocardial ischaemia. PDE inhibitors are attractive as the increase in cAMP will be independent of β-blockade. Other therapies that can be added in desperation include sodium bicarbonate for arrhythmia, magnesium (especially if QT prolonged with sotalol), aminophylline, transvenous pacing, aortic balloon pump, haemodialysis, and even methylthioninium chloride to inhibit NO production and increase vascular tone.
These drugs are frequently used for angina and blood pressure control in patients who cannot tolerate β-blockade. There are two pharmacological (and functional) groups. The dihydropyridines (e.g. nifedipine, amlodipine, felodipine) reduce afterload and cause coronary vasodilatation, whereas the non-dihydropyridines (diltiazem, verapamil) are also rate-controlling. Systematic analysis does not show any benefit for these drugs in preventing MI or mortality; therefore, β-blockers remain first line unless contraindicated. In the recovering critically ill, amlodipine has become commonly used as an antihypertensive owing to its lack of effect on heart rate and conduction, and avoidance of β-blockade ‘in case’ the patient deteriorates and requires catecholamine support; there is, however, no evidence that this is any safer than cautious β-blockade with an appropriate agent.
Pharmacokinetics and drug specifics
Amlodipine is hepatically metabolized, has a peak effect at 6–12 h, and an elimination half-life of 30–50 h if hepatic function is normal. Diltiazem has a half-life of 4 h and is hepatically metabolized, but has active metabolites and these are partially excreted in the urine. Nifedipine is hepatically metabolized to inactive metabolites; the half-life is 2–5 h, but slow release preparations are usually used and these must not be crushed for nasogastric tube administration; its use is best avoided in critically ill patients. Verapamil is hepatically metabolized; its use in the critically ill is best avoided owing to the risk of heart failure.
Patients with CCB overdose will be hypotensive and may or may not be bradycardic depending on the agent. An ABC approach is taken, plus specific therapy with calcium (10 ml of 10% calcium chloride, repeated as necessary or followed by infusion at 0.5 mEq calcium/kg/h). Glucagon can also be used. Vasopressors (noradrenaline) may be necessary and also PDE inhibitors (only once vasopressors are initiated and can be titrated to counter hypotension). Insulin and glucose treatment has been used successfully. Transvenous pacing and aortic balloon pump may be necessary.
These are used for their arterial and venous dilatation, reducing preload and afterload and myocardial work. GTN infusion (50 mg in 50 ml titrated from 1 to 15 ml/h) provides rapid relief of unstable angina. Rapid reversibility makes GTN useful in critically ill patients for angina, heart failure, and hypertensive crises. Prolonged administration (>24 h) results in tolerance to the nitrate and reduced efficacy. Headache and tachycardia are common side-effects and nitrates should be avoided in those with right ventricular infarction and hypertrophic obstructive cardiomyopathies and in intracerebral haemorrhage. Prolonged administration of IV nitrates can result in methaemoglobinaemia and possibly resistance to heparin. Look for transdermal nitrate patches in hypotensive obtunded patients with a past history of ischaemic heart disease and remove (especially before defibrillation). Sublingual nitrates are normally avoided in critically ill patients owing to the unpredictable degree of hypotension.
Other antianginal drugs
Opiates provide important symptomatic relief and should always be used to ameliorate the sympathetic drive in acute ischaemia. They do not provide outcome benefit.
Potassium channel sensitizers such as nicorandil have an arterial and venous vasodilatory action but may also have a role in ischaemic preconditioning and myocardial protection. Its use in the critically ill patient remains experimental.
Ranolazine is a fatty acid oxidase inhibitor that prevents calcium overload in myocytes by inhibiting the late inward sodium current and reducing sodium–calcium exchange. Its antiangina action does not cause bradycardia or hypotension. Intensivists should be aware that it causes prolongation of the QT interval.
Ivabradine has a specific action on the sinus node pacemaker current via the f-channel, the hyperpolarization-activated cyclic nucleotide gated channels, reducing heart rate. Its use in those intolerant of β-blockade is increasing both in treating refractory angina and heart failure, especially in those failing to slow adequately with the maximum tolerated dose of β-blockade. By definition, it is only of use if the patient is in sinus rhythm.
Platelets interact with a range of clotting factors, endothelial surfaces, and tissue components, as well as with each other to form a blood clot. Most of the time they are inactive, awaiting stimulation, until there is vessel injury, when they are appropriately activated to form a component of the blood clot plugging the gap. There are a variety of situations where there is inappropriate activation or where we do things to the patient that result in undesirable platelet activation. There are a series of drugs that can be used to prevent this. Figure 12.1 shows sites of action of the key antiplatelet drugs.
If you have to stop antiplatelet therapy (or gastrointestinal absorption is unreliable) in anyone who has had a coronary stent in the past year, especially the past 3 months, then discuss their management with your cardiology team immediately as there is a significant risk of in-stent thrombosis.
Combination therapy of aspirin plus P2Y12 (adenosine diphosphate [ADP]) receptor blockers is a very potent anticoagulation combination. Because huge numbers of patients are on these drugs do not be complacent about the degree of platelet inhibition that is sometimes achieved before you undertake invasive procedures.
Aspirin acts by irreversibly acetylating cyclo-oxygenase type 1 (COX-1) found in platelets. This is achieved at low doses (usually 75 mg daily) and prevents COX-1 from producing prostaglandin H2, which would otherwise be used in production of thromboxane A2, which is stored in platelets and acts as a local amplifier of platelet activation.
Coronary disease: aspirin is used in stable coronary disease for primary and secondary prevention and in unstable disease for treatment of MI.
The second International Study on Infarct Survival (ISIS-2) demonstrated that 160 mg aspirin daily reduced 5-week mortality by 23% in acute ST elevation myocardial infarction (STEMI). This was the same as the reduction achieved by streptokinase (25%) and, used together, an odds reduction of 42% is achieved (from 13.2% to 8.0% mortality). Aspirin is an important therapy!
Cerebrovascular disease: aspirin is also used for secondary prevention of cerebrovascular disease, giving ~25% odds reduction in a meta-analysis of 195 trials.
Issues in intensive care
Gastrointestinal bleeding is a major side-effect of aspirin. This risk should be put in perspective. In a meta-analysis of 22 randomized trials of aspirin therapy, the increased risk of major bleeding from aspirin was 70%, but this translates to an absolute annual increase of only 0.13% in stable patients (769 patients need to be treated with aspirin to cause one major bleed). Clearly these absolute risks will be greater in the intensive care population. A past history of gastrointestinal bleeding should not prevent the administration of aspirin acutely in STEMI; in other situations you need to make an assessment of the relative risk–benefit balance.
Bronchospasm is seen in up to 10% of new users.
Perioperative: in general, aspirin should not be suspended for operations as this significantly increases the risk of perioperative coronary events, unless bleeding would be catastrophic, e.g. intracranial and spinal surgery.
Reversal of aspirin: requires platelet transfusion.
Dipyridamole inhibits adenosine deaminase and PDE, resulting in accumulation of adenosine and cAMP. It is used as a second-line agent in stroke prevention in conjunction with aspirin or in those intolerant of aspirin. It is also used in cardiac stress testing owing to its vasodilatory action. There are few reports of overdose, but hypotension and MI are reported. Dipyridamole has a half-life of 10 h; more rapid reversal requires platelet transfusion.
P2Y12 receptor blockers
Clopidogrel, ticlopidine (withdrawn because of poor safety profile once clopidogrel was established), and prasugrel are metabolized to active metabolites which bind irreversibly to P2Y12 and block binding of ADP on the platelet surface and interrupt platelet activation.
Ticagrelor is a cyclopentyltriazolopyrimidine that reversibly binds P2Y12 receptor. This might make it a good choice in the ICU.
When clopidogrel was the only drug available this was easy; now, with numerous trials comparing to placebos and comparing to each other and different hospitals interpreting guidance differently the decision on which agent is used has become less clear. The key advantages of the newer drugs is their more rapid onset of action (clopidogrel takes 6 h to achieve 20–30% platelet inhibition whereas prasugrel achieves >20% in 30 min) and less variability in the degree of platelet inhibition (around 20–25% of the population are relatively clopidogrel-resistant), hence their popularity in urgent stenting. Needless to say, the more reliably effective drugs also cause more reliable bleeding.
Acute coronary syndrome
Clopidogrel is a key drug in the management of unstable angina and non-ST elevation MI (NSTEMI), and studies have demonstrated a reduction in vascular events when clopidogrel is added to aspirin therapy for up to 12 months (MI reduced from 6.7% to 5.2% in the CURE study at 1 year). There is an increase in bleeding and individual patient risks should be considered when starting this treatment (major bleeding increased from 2.7% to 3.7% in CURE). Clopidogrel is frequently used as first-line therapy in patients intolerant of or allergic to aspirin.
Clopidogrel reduced the relative risk of in-stent thrombosis by 26.9% at 1 year (absolute reduction of 3%) following percutaneous coronary intervention (PCI) in the CREDO study (the control group was given clopidogrel for 3 months post-PCI and both groups continued aspirin). Evidence suggests that pretreatment with thienopyridines further reduces in-stent thrombosis provided the loading dose (300 mg clopidogrel) is at least 6 h before the procedure (it may be possible to improve the outcomes when loading in advance is impossible by giving a larger loading dose, 600 mg). Prasugrel and ticagrelor are now both much more commonly used peri-stenting.
Clopidogrel and proton pump inhibitors (PPIs) interact by PPIs inhibiting CYP2C19, which is required to convert clopidogrel to its active metabolites; while the effect of this clinically has been subject to much debate (genetic variation is probably very important here) it is best to avoid PPIs if at all possible. Prasugrel and ticagrelor use different CYPs so do not suffer the PPI effect.
Issues in intensive care
Cardiothoracics: there is evidence that clopidogrel therapy may significantly increase bleeding postoperatively, incidence of return to theatre, and transfusion requirements in cardiothoracic surgery. If possible it should be suspended at least 5 days before bypass surgery. This effect is mitigated if clopidogrel is started at least 4 h postoperatively in those with low drain outputs, where there may be an outcome benefit to starting clopidogrel. An assessment on an individual patient basis and the likelihood of the patient having an unstable coronary event during drug suspension should be made.
Non-cardiac surgery and medical patients: there are very few data. Individual assessment of coronary risk versus bleeding risk should be made. If the patient has had coronary stent implantation within 1 month (bare metal stents) or 3 months (coated or drug-eluting stents), then only severe or life-threatening bleeding should prompt cessation of clopidogrel as the risk of stent occlusion is significant.
Perioperative: platelet transfusion should only be used in the context of overt haemorrhage and not pre-emptively even if a decision to stop clopidogrel is made preoperatively (neurosurgery may be an exception).
There are only two reported cases of clopidogrel overdose: one without symptoms and one developing pulmonary haemorrhage and haemothorax.
Reversal: requires platelet transfusion. Talk to the haematologists.
GpIIb/IIIa receptor antagonists
There are two classes of agent:
• Antibody to the receptor (abciximab).
• Small molecule inhibitors (tirofiban®; and eptifibatide®).
These agents act by blocking the GpIIb/IIIa receptor on the platelet surface. This receptor binds fibrin so is key to creating the meshwork of fibrin and activated platelets that forms the platelet plug of a clot.
Abciximab has complex pharmacokinetics, but the key point is that the molecule takes days to clear from the plasma completely, and clinically platelet function takes ~48 h to recover from cessation of an infusion. Recovery of platelet function is much more rapid from the small molecule inhibitors (within a few hours).
Abciximab can cause a unique form of thrombocytopenia, occurring between 30 min and 24 h of administration, that results in a profound drop in platelets, believed to be because of the presence of ‘preformed’ antibodies to ‘hidden’ epitopes on platelets. Confusingly, pseudothrombocytopenia can also be seen, but this recovers within 4 h, and different platelet counts are seen with different anticoagulants in the sampling tube, e.g. ethylenediamine tetra-acetic acid versus citrate. Both these are much less common with tirofiban or eptifibatide.
STEMI: should not be used in STEMI unless used prior to angiography and primary angioplasty ± stent. They are used in the context of failed thrombolysis or reinfarction whilst awaiting transfer for rescue PCI.
NSTEMI: meta-analysis shows that, if the serum troponin is elevated concurrently with additional high-risk factors and if PCI is planned, there is mortality and MI benefit to using these drugs, and this benefit is still seen with concurrent clopidogrel therapy. However, since the introduction of newer P2Y12 antagonists, the routine use of bivalirudin or fondaparinux, and very short time to angiography, the use of glycoprotein inhibitors is reducing. However, in intensive care we will still have patients who are bridging to coronary artery bypass graft or whose gastrointestinal tract is not absorbing oral P2Y12 inhibitors reliably, where these drugs still very much have a place.
Bleeding risk: is elevated, especially with concurrent use of other agents. All the GpIIb/IIIa inhibitors require dose adjustment in patients with renal failure, and use with caution in the elderly and with weight adjustment in smaller patients.
Reversal: platelet transfusion, but tirofiban and eptifibatide reverse within a few hours anyway.
Epoprostenol (prostacyclin, PGI2®)
This is used in intensive care as a method of anticoagulation for extracorporeal circuits. It acts by stimulating adenylate cyclase and increasing cAMP levels, which inhibits platelet activation. It is useful for its very rapid reversibility within a few minutes of stopping the infusion (half-life is 6 min). Its use is limited by cost and profound vasodilatation (it is also used for pulmonary vasodilatation in idiopathic PH). The introduction of citrate-based anticoagulation for external circuits will make the use of epoprostenol very rare, if not obsolete.
Summary of indications
• Primary prevention in high-risk patients (coronary and cerebrovascular).
• Secondary prevention all patients.
• Precoronary and postcoronary stenting.
• Second-line therapy in high-risk coronary disease in combination with aspirin.
• Precoronary and postcoronary stenting.
• Alternative to aspirin in those intolerant.
Diuretics are frequently used in the critically ill, although the rationale for their use is not always logical.
The most common reasons are for reduction of tissue or pulmonary oedema, to promote urine output for oliguric states, to control ascites, and occasionally to change blood acid–base balance to help weaning, such as with acetazolamide.
Tissue oedema, pulmonary oedema, and ascites
Tissue oedema is the accumulation of fluid in the interstitial space. It results in circulating hydrostatic forces overwhelming the protective safety factors described by Guyton. These relate lymphatic flow, interstitial oncotic pressure, and capillary hydrostatic pressure, assuming normal endothelial permeability in a given tissue. In health, tissues have remarkably different capillary permeabilities from each other. For example, brain has non-fenestrated capillaries, while muscle, subcutaneous tissue, intestines, kidneys, and liver are progressively more permeable. The variability between these components explains why it is considerably easier to develop skin oedema than pulmonary oedema for a given hypervolaemic state.
In the critically ill, the tendency for greater capillary permeability with systemic inflammatory states exacerbates the tendency to oedema. Tissue and pulmonary leakiness result in oedema with modest capillary hydrostatic pressure rises.
Pulmonary oedema may be hydrostatic, as it is with iatrogenic circulating hypervolaemia. This is more likely in those with unheralded cardiac dysfunction and uncommon in fluid-deficient septic or haemorrhagic patients. It also follows the hypervolaemic state associated with the hyperaldosteronism of cardiac dysfunction or the mechanical perturbation associated with valvular incompetence or pericardial constriction. Equally, a significant reduction in cardiac performance through abnormal rhythms or deteriorating contractility may acutely or insidiously precipitate pulmonary oedema through left atrial pressure rises.
Ascites is a hallmark of patients with severe cirrhosis. Mechanical obstruction by slow portal vein flow or thrombosis results in peritoneal cavity fluid accumulation. This is the result of hepatic sinusoidal outflow obstruction due to fibrosis. Continuing fluid accumulation is halted by the dynamic balance between peritoneal hydrostatic pressure and the forces of transudation. Reduction of the former by aspiration leads to a rapid reaccumulation of ascites. Those with cirrhosis also retain sodium, which promotes ascites and peripheral oedema. Two theories for salt retention have been proposed, although both result in increased aldosterone activity
The first is underfill theory, which suggests that splanchnic pooling and peripheral vasodilatation reduce the effective intravascular volume and stimulate secondary sodium retention.
The second, overflow theory, suggests primary sodium retention through intrahepatic hypertension and an ill-defined hepatorenal reflex. The latter stimulates renal sympathetics, which promote sodium retention.
The decompensated cirrhotic patient is characterized by vasodilatation, arteriovenous fistulae, and fluid and albumin loss through ascites, which all lead to reduced effective intravascular volume. The latter stimulates compensatory secondary sodium retention, oliguria, and impaired water excretion.
Appropriateness of diuretics for oedema
While diuretics may be an appropriate treatment for patients with hydrostatic pulmonary oedema secondary to circulating hypervolaemia, they are less appropriate for the hyperpermeable pulmonary congestion or oedema of inflammatory states.
Where oedema is largely driven by sodium retention and hyperaldosteronism, diuretics are appropriate and of value, although control of the driving mechanism, such as myocardial dysfunction, is likely to be more successful for oedema control.
Diuretic therapy for hyperpermeability, pulmonary oedema of chest infection, or aspiration pneumonitis may modestly improve oxygenation, particularly if there is alveolar rather than interstitial oedema; however, the improvement is short-lived because defective permeability is not resolved. Large oxygenation improvement suggests a significant hydrostatic component
Diuretic therapy to achieve negative balance may in hyperpermeability states result in circulating hypovolaemia, renal dysfunction, a fall in cardiac output, and greater inotrope need, which are associated with poor outcomes. However, several meta-analyses of the current evidence suggest that negative fluid balance is associated with better clinical outcomes without significant cardiovascular complications.
In critical illness, increased capillary permeability is common. Oedema formation, particularly in subcutaneous and muscle tissue where the safety factors are not as well developed, is expected. Increased capillary permeability will result in a total positive fluid balance together with intravascular hypovolaemia. Therapeutic efforts should be targeted to stop the underlying cause of the inflammatory process and avoid unnecessary administration of fluids. Fluid administration should be targeted to maintain end-organ perfusion rather than prespecified haemodynamic values.
It is notable that in the recovery phase of systemic inflammation, when permeability tends back to normal, spontaneous diuresis occurs without haemodynamic perturbations.
Indications for diuretic therapy
• Hydrostatic pulmonary oedema.
• Congestive cardiac failure.
• Cerebral oedema.
• Hyperaldosteronism-mediated oedema, nephrosis, cirrhosis, cor pulmonale.
• Peripheral oedema to reduce capillary leakage.
• Change arterial blood chemistry to aid weaning.
Commonly used diuretics in the critically ill
This is a weak diuretic that produces a sustained daily diuresis by inhibiting sodium uptake in the cortical thick ascending limb of the loop of Henlé and in early distal tubules. It has to gain tubular access by glomerular filtration to be active. It is used for long-term hypertension management and uncommonly used in the acute phase of critical illness.
Metolazone is a powerful thiazide given in doses 5–10 mg twice-daily, but is only available in oral preparations. It can provide significant diuresis when loop diuretics are becoming ineffective. It can be used for resistant peripheral oedema and in the critically ill can help provide a diuresis in those with non-oliguric chronic renal failure.
Furosemide is a powerful short-acting agent very commonly used either to improve pulmonary function consequent to cardiac failure or less effectively to ‘dry out lungs’ in those with pulmonary congestion or oedema related to systemic or localized pulmonary inflammation.
Furosemide is also used to accelerate oedema clearance in those in the recovery phase of critical illness. Infusions can be effective in low doses, starting in diuretic-naive kidneys from 1 mg/h.
It acts by enzymatic inhibition of cortical and medullary thick ascending loop of Henlé Na+ K+ 2Cl– cotransporter. This tubular cell brush border-sited enzyme facilitates the movement of sodium into the tubular cell; sodium is then is pumped out of the cell into the interstitium by energy-dependent Na+ K+ ATPase. Consequently, furosemide reduces tubular energy requirements.
Like thiazides, furosemide increases delivery of sodium- and chloride-rich filtrate to distal tubular potassium and hydrogen ion-secreting sites. The diuretic-driven plasma volume contraction causes an increase in aldosterone secretion, which promotes sodium exchange for K+ and H+ ions at these sites. The loss of chloride and the cation exchanges result in hypokalaemia and a mild metabolic alkalosis. Magnesium losses are also substantial.
A further consequence of large quantities of chloride and sodium reaching distal tubules is stimulation of the juxtaglomerular apparatus, which results in renin- and adenosine-mediated afferent glomerular arteriolar vasoconstriction.
This is available only as an oral preparation; it is a competitive antagonist of aldosterone with a linear diuretic response in doses between 25 and 100 mg. It has a long duration of action and its active elements are spironolactone and its metabolite canrenone. It is commonly combined with loop diuretics for its synergistic diuretic effect while sparing potassium losses. Its main use is to control hyperaldosteronism-driven oedematous states, typically cardiac, cirrhotic, or nephrotic. It has been shown to reduce mortality associated with severe cardiac failure (ejection fractions <35%).
Amiloride also acts at the collecting tubule, but prevents sodium uptake by the sodium pump and not by aldosterone inhibition.
Carbonic anhydrase inhibitors
This is available as either IV or oral preparations: 250–500 mg 6-hourly is a modestly effective diuretic. By inhibition of carbonic anhydrase in the proximal tubule it facilitates bicarbonate and sodium loss. The resulting high sodium tubular content leads to greater potassium–sodium exchanges in the distal collecting tubules and results in hypokalaemia.
Consequently, acetazolamide is one of the few causes of hypokalaemic, hyperchloraemic metabolic acidosis.
Acetazolamide can be used to provide a mild hyperchloraemic metabolic acidosis to correct metabolic alkalosis that is impeding weaning. Typically patients receiving loop diuretics develop a mild metabolic alkalosis (chloride and K+ losses). They may also have a secondary metabolic alkalosis that accompanies hypercarbia of hypoventilation. Such patients have apnoeic episodes during attempts at weaning if the pH >7.45.
Impaired weaning can be managed with a few days’ course of acetazolamide until pH is mildly acidotic. It should be noted that cerebrospinal fluid pH might take a further 48 h to correct; therefore, apnoea episodes on a ventilator may continue. Potassium and magnesium losses will be large, and plasma concentrations should be kept at the high end of the normal range.
The diuretic effect of acetazolamide tends to tail off after a few days.
Mannitol is commonly used as pulse therapy to reduce cerebral oedema and improve ICP control. It does not cross the blood–brain barrier and provides an osmotic gradient for cerebral cellular and extracellular water movement to the vascular space. Theoretically it would be expected that mannitol is more effective for management of cytotoxic cerebral oedema (white and grey matter cellular swelling due to ischaemia) than vasogenic (capillary permeability, interstitial) oedema, which affects mainly white matter.
Mannitol promotes diuresis by gaining access to the renal tubule. It has a molecular weight of 182 Da and is readily filtered. It inhibits sodium and water uptake in all parts of the tubule by its osmotic effect.
Hypovolaemia and renal impairment may follow continuous aggressive therapy (>6 pulses/day) in the absence of urine loss replenishment.
Levosimendan is a relatively new type of inotropic agent, differing significantly from conventional catecholamines in its mechanism of action and physiological effects. Introduced into clinical practice in 2000, it is referred to as an inodilator owing to its combined effects of positive inotropy and vasodilatation. It also possesses a number of other properties that account for some of its clinical effects. Although originally licensed and extensively investigated for the treatment of acute decompensated heart failure (ADHF), levosimendan may also be indicated in the management of other low cardiac output states such as cardiogenic shock complicating acute coronary syndrome and during cardiac surgery. It has also been evaluated as a therapy in sepsis.
Mechanisms of action
Levosimendan has three main actions—inotropy, vasodilatation, and cardioprotection. These are summarized in Figure 12.2.
Levosimendan exerts its inotropic effects by increasing the sensitivity of cardiac troponin C (cTnC) to calcium. It binds to calcium-saturated cTnC in systole, stabilizing the binding of calcium to cTnC, thereby increasing the force of contraction without increasing intracellular calcium concentrations or myocardial oxygen consumption. In addition, and in contrast to conventional catecholamines, levosimendan also improves diastolic function, an effect that may in part be due to cAMP or ATP-dependent potassium (K) channel activation. Levosimendan also inhibits PDE3 but the contribution of this property to the positive inotropic effect is unclear. Documented cardiac effects include dose-dependent increases in stroke volume and cardiac output, with reductions in pulmonary artery wedge pressure and peripheral vascular resistance along with a fall in systemic blood pressure due to vasodilatation.
In vascular smooth muscle levosimendan activates ATP-dependent K channels, resulting in vasodilatation in the pulmonary, coronary, and peripheral arterial circulations and in the portal venous circulation. It is likely that this is responsible for some of the benefits seen in other organ functions.
Levosimendan has been shown to have specific cardioprotective properties. It enhances NO release, leading to increased coronary bloodflow and reduced myocardial oxygen demand. However, the opening of mitochondrial ATP-dependent K channels is thought to be critical for both the short- and longer-term cardioprotective effects, including a reduction in infarct size, that have been demonstrated experimentally. Clinically this may be relevant in patients undergoing PCI and cardiac surgery.
Other non-inotropic beneficial effects from levosimendan have been shown, including anti-inflammatory—reduced levels of proinflammatory cytokines, e.g. tumour necrosis factor-α, interleukin-6 in patients with ADHF, and antiapoptotic and antioxidative effects.
Levosimendan has been shown in clinical studies to have a number of effects on other organs. These include:
Renal—increased GFR in patients with ADHF and postcardiac surgery.
Hepatic—increased portal venous flow and hepatic perfusion.
Respiratory—improved right ventricular function in patients with ARDS; increased diaphragmatic contractility.
CNS—limited evidence suggests a possible neuroprotective role.
Levosimendan is usually administered as an intravenous infusion at a rate of 0.05–0.2 μg/kg/min for 24 h. A loading dose of 6–12 μg/kg is suggested but carries a risk of hypotension and tachyarrhythmias and therefore may be best avoided in critically ill patients. When used in haemodynamically unstable patients, coadministration of a vasopressor is frequently needed and it is important to ensure that patients are adequately volume-loaded to minimize the risk of hypotension. Close observation, including invasive monitoring, is recommended. Levosimendan has a half-life of around 1–1.5 h but is converted in the small intestine to an active metabolite, OR-1896. OR-1896 has an elimination half-life of around 80 h, which explains the prolonged haemodynamic effect, which can last for up to 10 days; elimination is prolonged in the presence of significant renal or hepatic dysfunction.
Adverse effects and contraindications
Levosimendan has a good safety profile. The main adverse effects of levosimendan are hypotension and cardiac arrhythmias. Other common adverse effects include hypokalaemia, headache, insomnia, and gastrointestinal effects, e.g. nausea and diarrhoea. Postmarketing data between 2000 and 2010 reported a serious adverse event rate of 0.2%; hypotension occurred in 0.03% and arrhythmias in 0.02%. Levosimendan is contraindicated in patients with severe hypotension and tachycardia, severe renal and liver impairment, a history of TdP, and known mechanical obstruction of left ventricular inflow and outflow.
Use in clinical practice
Levosimendan has been extensively investigated as a therapy for ADHF in a number of large-scale trials. It has been widely shown to improve haemodynamics and symptoms in the short term along with reductions in brain natriuretic peptide, but a consistent benefit on mortality has not been seen. In the 2016 European Society of Cardiology guideline for the diagnosis and management of heart failure, levosimendan was only weakly recommended (class IIb) for the treatment of hypotension secondary to β-adrenoreceptor blockade; the authors concluded that levosimendan was not suitable in patients with hypotension unless coadministered with another inotrope or vasopressor. The use of levosimendan in ADHF therefore remains controversial.
Acute coronary syndromes
Traditional inotropic agents, often combined with mechanical support such as an intra-aortic balloon pump, are the mainstays of treatment of cardiogenic shock complicating acute coronary syndrome. There is some evidence to suggest that levosimendan may be of benefit in acute heart failure complicating acute coronary syndrome; in the placebo-controlled RUSSLAN trial, which recruited 504 patients with heart failure within 5 days of an acute MI, there was improved survival at 14 days with levosimendan, which remained at 180 days. Other smaller trials have also shown benefits with improvements in left ventricular systolic and diastolic function. In the context of cardiogenic shock, levosimendan was superior to enoximone, with a survival benefit at 30 days in a study of 32 patients. Improvements in cardiac index have been demonstrated in other trials, although patient numbers are generally small. An expert review published in 2016 concluded that levosimendan at a dose of 0.05–0.1 µg/kg/min for 24 h should be a treatment of choice for cardiogenic shock in combination with noradrenaline to counter the vasodilatation. The group also concluded that levosimendan should be considered for patients with hypotension (systolic blood pressure <110 mmHg) and clinical signs of heart failure.
Cardiac surgery causes profound effects, including sympathetic activation and inflammation that can lead to organ dysfunction. In particular, the presence of a low cardiac output state during the perioperative period is associated with significantly increased risk of complications and death. Inotropic support is often needed perioperatively to improve ventricular function, but conventional catecholamines may have important adverse effects. Levosimendan has been evaluated in a variety of cardiac surgical interventions, including on- and off-pump surgery, bypass grafting, and valve surgery, although not in large-scale trials. A recent consensus opinion concluded there is evidence to suggest that levosimendan improves haemodynamics in both the pulmonary and systemic circulations with subsequent benefits on renal and hepatic function, and reductions in ICU and hospital length of stay. Levosimendan may be particularly effective in supporting the right ventricle. However, the results from two multicentre randomized double-blind placebo-controlled trials have recently been presented. In the 849-patient LEVO-CTS trial, the use of prophylactic levosimendan commenced prior to surgery in patients with an ejection fraction of <35% did not reduce a four-component end-point of mortality, the use of renal replacement therapy or mechanical circulatory support, and perioperative MI. The CHEETAH study investigated whether the use of levosimendan reduced mortality in patients with perioperative cardiovascular dysfunction after cardiac surgery; the trial was stopped early after recruiting 506 patients due to futility. Thus the routine use of levosimendan in these patient groups cannot be recommended.
Myocardial dysfunction is a well-recognized complication of sepsis and echocardiographic studies suggest it may be present in up to 60% of patients. The mechanism of septic myocardial dysfunction is thought to include altered calcium trafficking and reduced sensitivity of troponin to calcium, which makes levosimendan an attractive therapy for this condition. An initial RCT published in 2005 comparing levosimendan 0.2 μg/kg/min to dobutamine 5 μg/kg/min in 28 patients with echocardiographically proven myocardial dysfunction showed significant reductions in arterial lactate, left ventricular stroke work index, and pulmonary artery pressure, along with improved creatinine clearance. A meta-analysis published in 2015 included seven studies with a total of 248 patients and found a significant reduction in mortality in those treated with levosimendan compared with controls (odds ratio 0.78, 95% confidence interval 0.63–0.98).
The largest trial to date of levosimendan in sepsis was the LeoPARDS trial (Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis), a randomized, placebo-controlled trial in 516 with septic shock across 34 adult ICUs in the UK. Given the pleiotropic effects of levosimendan all patients with septic shock were included, not just those with confirmed myocardial dysfunction. Patients were randomized to receive a 24-h infusion of levosimendan 0.05–0.2 μg/kg/min or placebo in addition to standard care. There was no improvement in organ dysfunction or in any of the prespecified subgroups, including those with the lowest cardiac output, in patients who received levosimendan. MAP was lower in the levosimendan group in the first 24 h with higher noradrenaline use in this group. In the levosimendan-treated group, heart rates were higher, there was a higher rate of supraventricular arrhythmias, and patients required a longer period of mechanical ventilation. These findings do not support the routine use of levosimendan in patients with sepsis, although whether it still has a role for those with proven myocardial dysfunction and extremely low cardiac output remains unclear.
Multiple choice questions and further reading
Interactive multiple choice questions to test your knowledge on this chapter and additional further reading can be found in Appendix Chapter 12 Multiple choice questions and further reading