Indications: congestive cardiac failure, cardiac ischaemia. Contraindications: aortic steno sis, hypertrophic obstructive cardiomyopathy (HOCM), hypoten- sion, tamponade, severe anemi a, hypertensive encepha- lopathy. Dose and route: available sublingually, orally, transder- mally and IV. Start IV infusion 10mcg/min and titrate by 10mcg/min to a maximum 200mcg/min . Diazoxide Diazoxide is an arteriolar vasodilator and antihypertensive. It inhibits insulin release, and hyperglycaemia may occur. Onset of action is 5 \200\22310min with duration of action of 4 \200\223 12h. Diazoxide is extensively protein bound, partly hepati- cally meta bolized and partly excreted unchanged. Dif \201 cult to use to control blood pressure over short time periods because of long half-life. \200 \200 \200 Isosorbide mononitrate (ISMN) ISMN is an orally administered nitrate used for angina prophy laxis and treatment of heart failure. Indications: hypertensive emergencies. Contraindications: ischaemic heart disease. Dose: by rapid IV injection, 1 \200\2233mg/kg with a maximum single dose of 150mg. Can be repeated after 5 \200\22315min as required. Isosorbide dinitrate (ISDN) ISDN has slower onset and is longer acting than GTN and can be administered sublingually, orally or by IV infusion. Calcium antagonists Calcium channel blockers have antianginal, antiarrythmic and vasodilato ry effects. In cardiac muscle, calcium antago- nism reduces myocardial contractility and ca rdiac output in a dose-dependent fashion. Impulse generation at the sinoatrial node and con duction via the atrioventricular node are calcium dependent, and blockade decreases sinus n ode pacemaker rate and atrioventricular node conduc- tion velocity. There are three classes of calcium channel antagonists: \200 Dihydropyridines (nifedipine, amlodipine, nimodipin e) \200 Diphenylalkylamines (verapamil) \200 Benzothiazepines (diltiazem) Directly acting vasodilators Sodium nitroprusside (SNP) The main action of SNP is relaxatio n of vascular smooth muscle in both arteries and veins that occurs via NO-stim- ulated incr ease in cGMP. At low doses, arterial vasodilata- tion predominates. The hypotensive effect of SNP is seen within 1 \200\2232 min and may cause re \202 ex tachycardia. Myocardial isc haemia can occur via a coronary steal syndrome. Circulatory half-life is 2min. Nitroprussi de metabolism can lead to methaemoglobin formation and metabolic aci- dosis. Speci \201 c therapy for overdose includes administra- tion of sodium nitrite followed by sodium thiocya nate. Tachyphylaxis may occur. \200 Nifedipine is an arteriolar vasodilator. It can be adminis- tered orally, sublingually or I V. Sublingual administration may cause rapid severe hypotension. Onset of action is 2 \200 \2235min. It is hepatically metabolized with a plasma half-life of 4h. \200 \200 Indications: immediate reduction of blood pressure in hypertensive crises, acute congestive cardiac failure, controlled hypotension intraoperatively. Contraindications: aortic coarct ation, congenital optic atrophy, high output cardiac failure, severe B12 de \201 - ciency. Dose: start 0.3 \200\2230.5/mcg/kg/min and titrate to maximum 8mcg/kg/min. Indications: angina, hypertension, Raynaud \200\231s syndrome. Contraindications: aortic st enosis, porphyria, cardiogenic shock. Dose: 5 \200\22320mg tds. Nimodipine has selective cerebral vasodilatory effects. It is indicated in the prevention a nd treatment of ischaemic neurological de \201 cit following subarachnoid hemorrhage. 171 CHAPTER 11.3 Vasodilators Peak plasma concentrations are reached within 1h, orally or IV. Half-life is 1 \200\2232h. Nimodipine undergoes hepatic metabolism; the dose should be halved in liver failure. \200 \200 Onset of action is 30 \200\22360min, peak action at 2 \200\2234h, and half- life is 8 \200 \22312h. 50% is excreted renally unchanged. \200 \200 \200 Indication: post-operative blood pressure control. Contraindication: (relative) depression. Dose: orally, 50 \200\223100mcg tds, increased to maximum 1.2mg/day; IV bolus, 10mcg repea ted until desired effect; IV infusion, 0.5 \200\2231.0mcg/kg/h. Contraindications: severely raised ICP. Dose: orally, 60mg 4 hourly; IV, 500mcg \200\2231mg /h initially, increased to 2mg/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 pathwaysm e.g. Wolf \200\223Parkinson \200\223White syn- drome, as VF may be precipitated. a-Adrenergic receptor antagonists Adrenergic receptors are subdivided into A1 and A2, and B1, B2 and B3 subtypes. \200 Methyldopa, an analog of L-dopa, causes decreased blood pressure by reduction in peripheral vascular resistance. It is hepatically metabolized and is renally excreted. Onset of actio n is 4 \200\2236h, half-life is 2h. Peak effect occurs at 3 \200\2236 h. Side effects inclu de sedation, lactation, extrapyramidal signs and neuropsychiatric sequelae. Coombs test may become positive; may cause problems with X-matching blood. \200 Dose: orally, 250 \200\223300mg bd/tds, increase to maximum 3g/day. A1 receptors are responsible for vasoconstriction, gut smooth muscle relaxation, increased salivation and glu- coneogenesis. A2 receptor agonists inhibit noradrenaline and acetyl- ch oline release and stimulate platelet aggregation. Angiotensin inhibitors Angiotensin-converting enzyme (ACE) inhibitors ACE inhibitors act by binding irreversibly to the angiotensin I binding site in the lung and preventing conversi on to angi- otensin II. Peripheral vascular resistance is decreased; car- diac output and h eart rate are unchanged. ACE inhibitors are used post-MI for their ventricular remodeling p roperties, 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 tak e oral therapy. ACE inhibitors are renally excreted. Half-life is dependent on the preparat ion. \200 A-Blockade causes reduced systemic vascular resistance. There may be re \202 ex sympatheti c stimulation. Phentolamine is a non-selective reversible competitive antagonist at both A1 and A2 receptors Onset of activity is rapid, with duration of action of 10 \200\22315min. \200 \200 Phenoxybenzamine is a non-selective irreversible A1 and A2 receptor antagonis t. Noradrenaline re-uptake is blocked, potentiating the action of B agonists. Duration of a ction is 3 \200\2234 days. \200 \200 Indications: phaeochromocytoma. Dose: 2 \200\2235mg (IV), repeat as necessary Indications: phaeochromocytoma. Dose: orally, initially 10mg bd, increased to 1 \200\2232mg /kg in divided doses; IV, 1mg/kg daily, slow injection over 2h daily. Indications: hypertension, post-MI, cardiac failure, ischae- mic heart disease. Contraindic ations: hyperkalaemia, acute renal dysfunc- tion, renovascular disease, pregnancy, heredita ry angioedema. Dose: captopril 12.5 \200\22350mg 8 hourly. Onset of action 20 \200\22330min , duration of activity 4h. Peak effect 90min post-dose. May cause profound hypotension in c ritically ill; usual to start with test dose of 6.25mg. Prazosin is a competitive A1 receptor antagonist. \200 Indications: essential and renovascular hypertension, Raynaud \200\231s disease, benign pro static hypertrophy. Dose: initially 500mcg bd/tds at night, increased to 20mg/ day in divid ed doses. Pulmonary vasodilators In critically ill patients, pulmonary vasodilators are used to preve nt and treat acute RV failure. In addition, inhaled pul- monary vasodilators are often used to improve oxygena- tion in patients with ARDS, although RCTs have not demonstrated improv ed survival. Other a receptor antagonists Phenothiazines (chlorpromazine) and butyrophe- nones (haloperi dol, droperidol) are competitive A antago- nists. Mized a and b antagonists Labetolol is a competitive antagonist at both A1 and B receptors, although B-blockade is predominant. \200 \200 Pulmonary hypertension in the critically ill Vasodilators used in this setting include GTN, SNP, isopre- naline (Chapter 11.1), phentolamine, prostacyclin, and PDE inhibitors types 3 and 5 (see Chapter 11.2). Vasodilators administered by inhalation are NO (Chapter 10.2) an d iloprost. Indications: hypertensive emergencies. Dose: orally, initially 100mg bd, titrate to maximum 2.4g/ day in divided doses; IV bolus, 10 \200\22320mg over 1min, repeated every 5min to ma ximum dose of 200mg; IV infusion, 2mg/min, increased as needed. Dose range 50 \200\223 160m g/h. Chronic pulmonary vasodilator therapy Treatment options have expanded over the last few yea rs and now include oral agents, inhaled and IV therapies. \200 Carvedilol is a non-selective B-blocker with A1 antagonistic actions that cause vasodilatat ion. It is used in the treatment of hypertension and in congestive cardiac failure. Prostanoids (epoprostenol (IV), iloprost (inhalation), treprostanil (SC), beraprost (oral)) . Endothelin receptor antagonists (bosentan, ambrisentan, sitaxentan). Centrally acting vasodilators Clonidine is a centrally acting partial A2 agonist. There is a risk of rebound hypertension if stopped suddenly. 172 A BRAME & J CORDINGLEY Further reading Bersten AD, Soni N, eds., Oh \200\231s intensive care manual, 5th edition, Katzung BG. Basic and clinical pharmacology, 6th edn. Appleton & Lange, 1995. LaRaia A, Waxman A. Pulmonary arterial hypertension: evaluation Butterworth-Heinemann, 2003. and management, South Med J 2007; 100: 393 \200\2239. Galie N, Manes A, Branzi A. Prostanoids for pulmonary hyperten- www.merck.com The Merck Manual, 18th edn. Merck & Co, sion, Am J Respir Med 2003; 2: 123 \200\22337. 2006 \200\2232007. Joint Formulary Committee. British National Formulary. 53rd edn. London: British Medical As sociation and Royal Pharmaceutical Society of Great Britain, 2007. This page intentionally left blank 174 T PALFREMAN & J CORDINGLEY Vasopressors Re \202 ex bradycardia may occur with vasopressors that have little or no chronotropic act ivity. Norepinephrine usually causes either no change or a small decrease in heart rate. Al l vasopressors are potentially arrhythmogenic (partic- ularly epinephrine and dopamine) and may cause myo- cardial ischaemia. There are few good quality clinical trials to guide use in speci \201 c clinical situation s. Classes of vasopressors 1 A1-Adrenergic receptor agonists: norepinephrine, meta- raminol, p henylephrine and ephedrine. A1 Agonists, used primarily for their inotropic action, includi ng adrenaline and dopamine, are described in Chapter 11.1. Effects on the splanchnic circulation \200 Norepinephrine usually has little effect on splanchnic blood \202 ow, but a reduction in \202 ow may occur, particu- larly if the patient is hypovolaemic. In combination with dob utamine, norepinephrine usually increases blood \202 ow to the gut. Dopamine increases me senteric blood \202 ow. Epinephrine, phenylephrine and vasopressin all decrease splanchni c blood \202 ow and may cause clinically important ischaemia, manifest as ileus, malabsor ption, stress ulcera- tion or bowel infarction. 2 Vasopressin receptor agonists: vasopressin, terlipressin. 3 Nitric oxide synthase (NOS) i nhibitors: L-NMMA, L-NAME. In a clinical RCT, L-NMMA was found to increase mortality 4 Guanylate cyclase inhibitors: methylene blue. \200 Corticosteroids may be used as an adjunct to vasopressors in septic shock, and are consider ed in Chapter 27.9. Indications 1 Vasodilation, such as that caused by SIRS, spinal cord Effects on renal function \200 injury, vasodilator and sedative drugs. 2 Cardiogenic shock, to improve coronary perfusion pres- sure (second-line treatment after an intra-aortic balloon pump). Norepinephrine increases urine output and creatinine clearance in patients with volume-resu scitated septic shock, used alone or when combined with dobutamine. Similar improvements ha ve been noted with vasopressin and phenylephrine. 3 Maintenance of CPP in brain-injured patients with rai- sed ICP. 4 Cardiopulmonary resuscitation. Effects on the skin \200 Contraindications and cautions 1 Hypovolaemia, for which the primary treatment is \202 ui d resuscitation, with or without a procedure to control hemorrhage. In reality, bolus doses of vasopressors may be required to defend blood pressure whilst resuscita- tion is taking place. Ischaemic extremities and skin lesions may occur with any vasopressor, but particularly wit h vasopressin. Metabolic effects \200 Adrenaline causes increased glucose production and suppression of insulin release, leading to hyperglycaemia. Hepatic clearance of lactate is impaired, and therefore lactate is a les s useful marker of tissue perfusion. 2 Low cardiac output states: studies of norepinephrine have demonstrated that cardiac outpu t may increase by 10 \200\22320%. Phenylephrine has been shown to increase car- diac output in septic shock, and vasopressin either decreases or does not alter cardiac output. \200 Pharmacology of speci \201 c agents 1-Adrenoceptor agonists A1 Receptors are present thr oughout the peripheral arte- rial and venous systems. Stimulation of the receptor leads to G-protein-mediated activation of phospholipase C, and a cascade of intracellular signals le ading to calcium-medi- ated vasoconstriction. Norepinephrine is the amine neurotransmitter at post-gan- glionic sympathetic nerve terminals, and is an agonist at all adrenergic recep tors. However, when exogenous nore- pinephrine is administered as an IV infusion the A1 eff ects predominate. \200 \200 A fall in cardiac output is less likely if the patient has been adequately \202 uid resus citated. Measurement of cardiac output and markers such as lactate, base de \201 cit and m ixed or central venous oxy- gen saturation may be invaluable in assessing the effect of vas opressors. It may seem logical to titrate vasopressors to the sys- temic vascular resistanc e (SVR). However,it is prefer- able to titrate vasopressors to the MAP that is clinically r elevant and measured directly. Dose: 0.01 \200\2231.5 mcg/kg/min by IV infusion Half-life: 2min, leading to a steady-state plasma concen- tration within 10min of starting or changing a constant rate infusion. Meta bolism: primarily in the liver, kidneys, brain and lungs by monoamine oxidase (MAO) and cat echol-o- methyltransferase (COMT), to inactive metabolites. Interactions: effects may be ex aggerated and prolonged in patients taking MAOIs, even though this interaction is asso- cia ted more often with indirect acting sympathomimetics. Metaraminol is a synthetic amine with both direct and indi- rect sympathomimetic actions. The direct action is mainly on A1 rece ptors, although it has some B receptor activity. The indirect action involves stimulation o f the release of norepinephrine from nerve terminals. Effects and sideeffects Cardiovascular effects \200 Increased systolic and diastolic blood pressure, LV stroke work, myocardial oxygen demand a nd coronary per- fusion pressure. Epinephrine may increase MAP in patients who do not respo nd adequately to other vaso- pressors, due to its greater inotropic activity. Venoconstrict ion and increased preload. Pulmonary vascular resistance may increase (e.g. nore- pinephrin e) or decrease (e.g. vasopressin). Coronary artery dilation (e.g. norepinephrine) or con- s triction (e.g. vasopressin). Tachycardia, particularly with drugs which have signi \201 - cant B1 activity, e.g. epinephrine, dopamine, ephedrine. \200 175 CHAPTER 11.4 Vasopressors Use: short-term treatment of hypotension, e.g. in the initial resuscitation of the shocked patient, at the start of haemo- \201 ltration, during anesthesia for procedures on ITU. D ose: 0.2 \200\2231.0mg by IV bolus. In vasoplegic shock caused by cardiopulmonary bypass, one trial has shown a reduction in mo rtality and duration of shock with methylene blue compared to conventional vasopressors. \200 Dose: an initial bolus of 1 \200\2232mg/kg over 15 \200\22330min then a continuous infusion of 0.25 \200\2231mg/kg/h for 3h to 3 days. Phenylephrine is a direct acting synthetic sympathomimetic amine, with potent A1 agonist ac tivity and no B receptor activity. \200 Use of vasopressors in speci \201 c situations Septic shock \200 Dose: 50 \200\223100mcg by IV bolus, 0.5 \200\2238mcg/kg/min by IV infusion. Duration of ac tion: 5 \200\22310min. Metabolism: in the liver by MAO. Current guidelines recommend either dopamine or norepinephrine as the \201 rst-line vasop ressor in septic shock. An observational study demonstrated increased mortality in patients treated with dopamine rather than other catecholamines. The target MAP of 65mm Hg may be a dequate for most patients, depending on their pre-morbid blood pres- sure. A recent trial i n patients with septic shock compared treatment with adrenaline vs the combination of nore- pinephrine and dobutamine. No signi \201 cant difference was found in either mortality or serious adverse events. Phenylephrine by IV infusion may be useful when tachy- cardia limi ts treatment with norepinephrine, and adrena- line. Initial reports of the VASST study show no overall mor- tality bene \201 t in patients with septic shock treated with vasopressin rather than norepinephrine alone. \200 Ephedrine has both direct and indirect sympathomimetic actions. \200 \200 Dose: 3 \200\2236mg by IV bolus. Duration of action: the elimination half-life is 4h. Howev er, the duration of clinical activity is often just a few minutes. This may be due to tachy phylaxis, as nore- pinephrine stores in nerve terminals become depleted. For the same reaso n, repeated boluses may be ineffec- tive after the \201 rst 12 \200\22315mg. Not metaboli zed by COMT or MAO. Some is metabolized in the liver, but 65% is excreted in the urine unch anged. Vasopressin receptor agonists Vasopressin is released from the posterior pituitary gland in response to increased plasma osmolality, decreased arte- rial blood pressure or decreased intravascular volume. It acts on three subtypes of vasopressin receptor: \200 Cardiac arrest \200 Current international guidelines recommend epinephrine 1mg by IV bolus as the \201 rst-li ne vasopressor in cardiac arrest. Vasopressin may have a role in refractory ventricu- lar \201 brillation or out-of-hospital arrest in asystole. V1 receptors mediate vasoconstriction, both directly and by increasing vascular responsiven ess to catecholamines. V2 receptors are found in the renal collecting ducts. Stimulation le ads to increased water reabsorption. V3 receptors are found mainly in the CNS system, where they modulate secretion of adrenocorticotrophic hor- mone (ACTH). Brain injury \200 There are no good trials comparing different vasopres- sors for augmentation of CPP. Howeve r, it is common practice to use norepinephrine or dopamine to maintain a CPP of 60 \200\223 70mm Hg. Arginine vasopressin (AVP) also known as antidiuretic hor- mone (ADH). It is an agonist at V1, V2 and V3 receptors. \200 The plasma concentration of endogenous AVP usually increases in early septic shock. In more prolonged shock, a state of vasopressin de \201 ciency develops. Infusion of vasopressin may allow reduction or withdrawal of other vasopressors. At doses >0.05U/min complications including cardiac arrest and regional ischaemia become more likely. These limit its use, an d mean that it cannot generally be titrated as a sole vasopressor. Dose in septic shock: 0. 01 \200\2230.04U/min by IV infusion. Dose in cardiac arrest: 40U IV bolus Half-life: 6min, duration of action 30 \200\22360min. Metabolism: primarily in the liver and kidneys Further reading Annane D, Vignon P, Renault A, et al. Norepinephrine plus dobuta- mine vers us epinephrine alone for management of septic shock : a randomized trial. Lancet 2007; 370: 676 \200\22384. Beale RJ, Hollenberg SM, Vincent JL, et al. Vasopressor and inotropic support in septic sho ck: and evidence-based review. Crit Care Med 2004; 32: S455 \200\22365. Faber P, Ronald A, Millar BW. Methylthioninium chloride: pharma- cology and clinical applic ations with special emphasis on nitric oxide mediated vasodilatory shock during cardiopulmo nary bypass. Anesthesia 2005; 60: 575 \200\22387. \200 \200 \200 Hollenberg SM, Ahrens TS, Annane D, et al. Practice parameters for hemodynamic support of s epsis in adult patients. Crit Care Med 2004; 32: 1928 \200\22348. Terlipressin is a selective V1 receptor agonist. Terlipressin has a longer duration of acti on than vasopressin, and can there- fore be give by IV bolus. It is primarily used to treat variceal bleeding in a dose of 2mg IV four times daily. In refractory septic shock, can be used when AVP not available. \200 LeDoux D, Astiz ME, Carpati CM, et al. Effects of perfusion pressure on tissue perfusion in septic shock. Crit Care Med 2000; 28: 2729 \200\223 32. Levin RL, Degrange MA, Bruno GF, et al. Methylene blue reduces mortality and morbidity in v asoplegic patients after cardiac sur- gery. Ann Thoracic Surg 2004; 77: 496 \200\2239. Dose in septic shock: initial bolus of 0.5mg, repeated every 30min to a maximum of 2mg. The n 0.5 \200\2231mg four times daily. Half-life: 6h, duration of action 2 \200\22310h. Mullner M, Urbanek B, Havel C, et al. Vasopressors for shock. Cochrane Database Syst Rev 2004; (3): CD003709. Russell JA. Vasopressin in septic shock. Crit Care Med 2007; 35: Desmopressin is a synthetic selective V2 receptor agonist, used to treat neurogenic diabete s insipidus and bleeding disorders. It is not used as a vasopressor. S609 \200\22315. Sakr Y, Reinhart K, Vincent JL, et al. Does dopamine administration in shock in \202 uence outcome? Results of the sepsis occurrence in acutely ill patients (SOAP) study. Crit Care Med 2006; 43: 589 \200\22397. Guanylate cyclase inhibitors Methylene blue inhibits the activity of NOS as well as guan- y late cyclase. 176 MH LANE & S PRICE Antiarrhythmic agents include treatment of torsade de pointes and arrhythmias secondary to drug toxicity, in part icular digoxin toxicity. Arrhythmias represent disturbances in normal sinus rhythm, occurring as a result of disorde red impulse forma- tion or conduction, or action potential disorders. Arrhythmias are commo n in intensive care patientsm and have been shown to prolong ICU stay, with a trend towards increased mortality. Atrial arrhythmias, in particular AF, predominate in post-surgical pa tients especially following cardiac and thoracic surgery. In contrast, ventricular arrhythm ias are more common in the mixed ICU patient population. Antiarrhythmic agents are traditio nally classi \201 ed according to their primary electrophysiological effect in the Vaughn Williams classi \201 cation (Table 11.5.1). Although many agents have multiple modes of ac tion and do not \201 t easily into any one class, other classi \201 cation systems have proved com- plex and are not routinely used. Other commonly used drugs such as adenosine an d digoxin are not included in this classi \201 cation. Commonly used antiarrhythmic agents Verapamil Competitive calcium channel blocker (class IV antiarrhyth- mic agent). Use: treatment of SVT, AF and atrial \202 utter. Dose: initiall y 5 \200\22310mg IV over 2 \200\2233 min. A further 5mg every 20min if no response (maximum 20mg). Orally 40 \200\223120mg tds. As effective as adenosine in terminating SVT, but pote ntial for hypotension as has signi \201 cant negative inotropic effects. Use with caution in patients with poor ventricular function. Avoid IV use if recently treated with B-blocker s as may result in severe hypotension and asystole. Avoid in Wolff \200\223 Parkinson-White as VT or VF may be precipitated. Adenosine Endogenous nucleoside with rapid onset and ultrashort duration of action. Termina tion of SVT mediated via A1 receptors, depressing SA and AV nodal activity. Use: diagnosis and treatment of cardiovascularly stable SVT. Dose: initial 3mg followed by further 6mg the n 12mg after 1 \200\2232min if not effective. Administer as a fast IV bolus. As effective a s verapamil in terminating SVT, but associated with increased incidence of minor side effec ts including dyspnoea, chest discomfort and facial \202 ushing. Table 11.5.1 Vaughn Williams classi \201 cation Class Action Drugs Class I Na channel blockers Ia ADP prolonged Procainamide Ib ADP shortened Lignocaine Ic ADP unchanged Flecanide Propafenone B-Blockers Class II Esmolol Digoxin A cardiac glycoside with multiple mechanisms of action including inhibition of Na-K -ATPase (which results in slowed AV node and pacemaker cell conduction) and increased effer ent vagal activity. Use: rate control in AF and atrial \202 utter if monotherapy with a B -blocker or calcium channel blocker unsuccessful. Dose: 10 \200\22315mcg/kg (usually 500mcg ) IV over 30min 6 hourly until effective (max 20mcg/kg). Digoxin has a narrow therapeutic r ange, and side effects are common, exacerbated by hypokalaemia and hypomag- nesaemia. Toxic ity may precipitate any form of arrhythmia, most commonly junctional bradycardia, bigeminy and heart block. Treatment of arrhythmias resulting from toxicity includes correction of el ectrolyte imbalance and digoxin antibodies. Temporary pacing may be required. The use of DC CV remains controversial as severe ventricular arrhyth- mias may be precipitated. Digoxin i s no longer indicated as montherapy for rate con- trol in AF and has no role in AF prophyla xis for cardiac surgery or in the treatment of post-operative AF. Metoprolol Class III K channel blockers Amiodorone Sotalol Class IV Ca channel blockers Verapamil Diltiazem Clinical classi \201 cation It is more useful clinically to divide antiarrhythmic agents a ccording to their use in the treatment of tachyarrhyth- mias. \200 Supraventricular tachycardias (SVTs) \200 \200 \200 \200 Ventricular tachycardias ( VTs) \200 Lignocaine Both SVTs and VTs \200 Amiodorone \200 Procainamide \200 Sotal ol \200 Flecanide Verapmil Adenosine B-Blockers Digoxin b -Blockers A group of drugs which act by the reversible blockade of B1 cardiac adrenorecep tors (class II). B-Blockers are used for rate control in acute SVT including AF and atrial \202 utter. Longer acting B-blockers are the treatment of choice for rhythm control in pe rsistent AF and rate control in permanent AF and symptomatic parox- ysmal AF. B-Blockers ar e also indicated for AF prophylaxis post-cardiac surgery. It is important to note that most have a narrow therapeu- tic index and all are potentially proarrhythmic. In the majority of patients with haemodynamic instability second- ary to an arrhythmia, the initial treatment of choice will be direct current cardioversion (DCCV). E xceptions to this 177 CHAPTER 11.5 Antiarrhythmic agents Esmolol Use: rate control in acute SVT in theater and on ICU. Dose: 0.25mg/kg IV bolus or 5 0 \200\223150mcg/kg/min infusion. Esmolol has a rapid onset (<2min) and offset (<20min) of action and is available for IV use only. Hypotension and bradycardia may occur, but side ef fects are limited due to the short duration of action. Dose: 1 \200\2231.5mg/kg over 20min IV infusion. Orally 80 \200\223160mg bd. Not commonly u sed as an acute treatment given need for slow IV infusion administration. There is a small risk of precipitating torsades de pointes especially with hypokalaemia. Bradycardia and hyp otension may be a problem in patients with poor LV function. Lignocaine A class Ib antiarrhythmic agent. Use: essentially limited to patients with susta ined polymor- phic VT associated with myocardial ischaemia unrespon- sive to procainamide o r amiodorne. Dose: initial bolus of 1mg/kg IV followed by an infusion. Lignocaine is no lon ger recommended in the ALS algorithm for the treatment of ventricular tachyarrhythmias. Amiodorone A broad-spectrum class III antiarrhythmic agent that also demonstrates class I, II and IV activity. Use: multiple uses in almost all arrhythmias, especially when other ant iarrhythmics have proved ineffective or are con- traindicated. It can be used for rate cont rol or cardiover- sion in AF and atrial \202 utter, as AF prophylaxis post-cardiac surger y, in haemodynamically stable VT and SVT, and in cardiac arrest with persistent VT or VF. I t should be used as \201 rst-line treatment for pharmacological cardioversion in persiste nt AF with structural heart disease and for non-life- threatening cardiovascularly unstable AF if delay in DCCV. Dose: initially IV 5mg/kg (300mg) over 30 \200\22360min followed by 1 5mg/kg over 23h (maximum 1.2g in 24h). Dilute in dex- trose 5%. Further maintenance is usua lly by oral route. Following cardiac arrest 300mg IV. Although bradycardia and hypotension can occur after bolus injection, amiodorone tends to be a cardiovascularly stable drug with low proarrhythmic potential. Hypothyroidism and thyrotoxicosis are common side effects and can present within 48h of treatment. Thyrotoxicosis can be refractory to treatment, with a mio- dorone therapy needing to be withdrawn to gain control. Several patterns of amiodorone -induced pulmonary toxic- ity have been reported. Of particular concern in ICU patients is a reported incidence of ARDS in 10 \200\22350% of patients treated with amiodorone. Magnesium Although not classed as an antiarrhythmic agent, magne- sium is often used in the treatment of ventricular arrhyth- mias. Use: drug of choice in the treatment of torsade de pointes. Also used for polymorphic VT, particularly in the setting of acute MI and in digo xin overdose. May be used as an adjunct for rate control in AF. Dose: 5 \200\22310mmol over 10 \200\22315min IV. Key points \200 DCCV is the treatment of choice in patients with haemodynamic instability secondary to a ta chyarrhyth- mia. Correct underlying electrolyte imbalances. All antiarrhythmic drugs are po tentially proarrhythmic. \200 Further reading Blomstr m-Lundqvist C, Scheinman MM, Aliot EM, et al. ACC/ AHA/ESC guideli nes for the management of patients with supra- ventircular arrhythmias executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Prac tice Guidelines, and the European Society of Cardiology Committee for Practice Guidelines ( Writing Committee to Develop Guidelines for the Management of Patients with Supraventricula r Arrhythmias). J Am Coll Cardiol 2003; 42: 1493 \200\223531. Procainamide A class Ia antiarrythmic agent. Use: \201 rst-line treatment of sustained mo nomorphic VT in stable patients. Also used for repetitive zoomorphic VT. It can also be use d in the treatment of SVT. Dose: 100mg by slow IV infusion not exceeding 50mg/min. Repeated every 5min up to a maximum of 1g. Can be given orally, 50mg/kg daily in divided doses. The use of procainamide has been limited by a number of cardiac and non-cardiac side effects. Rapid administration may result in hypotension, reduced cardiac output, prolon- gation of t he Q-T interval and torsades de pointes. Chronic use may cause a lupus-like syndrome in up to 20% of patients. Holdgate A, Foo A. Adenosine versus intravenous calcium channel antagonists for the treatme nt of supraventricular tachycardia in adults. Cochrane Database Syst Rev 2006; (4): CD00515 4. National Clinical Guideline for the Management of Atrial Fibrillation. NICE Guideline 36. 2006. Reinelt P, Karth GD, Gepert A, et al. Incidence and type of cardiac arrhythmias in critical ly ill patients: a single center experience in a medical \200\223cardiological ICU. Intensi ve Care Med 2001; 27: 1466 \200\22373. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2 006 guide- lines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death executive summary: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines, and the European Society of C ardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for th e Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol 2006; 48: 1064 \200\223108. Sotalol A B-blocker classi \201 ed as a class III antiarrhythmic agent possessing addition al class I activity. Use: has been used to treat both ventricular and supraven- tricular ar rhythmias, although recently limited to treatment of ventricular arrhythmias. May be useful in repetitive poly- morphic VT. Recommended for the prevention of post- operative AF in ca rdiac surgery. 178 VG KULKARNI & S PRICE Chronotropes Adrenaline Adrenaline is a natural catecholamine produced by the adre- nal medulla. It is d irect agonist at A1-, A2-, B1and B2-adrener- gic receptors. At doses <0.03mcg/kg/min B rece ptors are preferentially activated. At higher doses, even A receptors are activated. Heart rate and contractility are increased at all doses. At low doses, SVR decreases, but increas es at higher doses due to A-mediated vasoconstriction. Pharmacokinetics: rapidly taken up b y neurons and tissues, and metaboliaed by MAO and COMT. Administration: IV, SC, via ETT and IM. Dose: 0.5 \200\2231.0mg bolus for resuscitation. 0.02 \200\2230.2mcg/kg/ min for both inotropic and chronotropic effects. Availability: epinephrine is available in vials at conc entra- tions of 1:1000 and 1:10 000m and pre- \201 lled syringes at a concentration of 1:1 0 000. A 1:100 000 concentration is available for pediatric use. Chronotropes (from the Greek khronos, meaning time) are drugs that alter the heart rate. Po sitive chronotropes: 1 B1 agonists: isoprenaline, dobutamine, adrenaline. 2 Antimuscarinic agents: atropine, glycopyrrolate. 3 Glucagon 4 Triiodothyronine(T3) Negative chronotropes: 1 B1 antagonists: propranolol, esmolol, metoprolol 2 Calcium channel antagonists: verapamil , diltiazem. 3 Digoxin 4 Amiodarone 5 Magnesium (high dose IV) Isoprenaline Isoprenaline is a synthetic catecholamine and acts as a B1 and B2 agonist. The re are no A effects. Because of this, it increases heart rate, contractility and cardiac ou tput. Systemic and pulmonary vascular resistance is decreased. Half-life: 2min. Pharmacokin etics: 60% is excreted unchanged and the remaining is conjugated in the liver or metabolize d by MAO and COMT. Dose: IV 0.02 \200\2230.5mcg/kg/min. It can be administered safely throu gh a peripheral line. Atropine Atropine is a tertiary amine consisting of tropic acid and tropine. The levorotato ry form is active, but is commer- cially available as the racemic mixture. It antagonizes a ce- tylcholine at muscarinic receptors, resulting in vagolysis and tachycardia. Atropine is included in the bradyarrhyth- mia and asystole resuscitation algorithms. Dose: IV bolus of 0.4 \200\2231.0 mg in adults up to 3mg. In chil- dren, use 20mcg/kg (minimum 0.1mg and max imum 0.4mg, may be repeated). Pharmacokinetics: the heart rate effects are seen within seco nds of IV administration and last up to 15 \200\22330min. If given IM, PO or SC, offset occ urs in 4h. The drug is mini- mally metabolized and undergoes renal elimination. Indications 1 Bradycardia unresponsive to atropine, when electrical pacing is not available. 2 Use as a temporary therapy in AV block either to reduce the block or to increase rate of idioventricular foci. Adverse effects 1 Tachycardia 2 Bradycardia at low doses 3 Sedation 4 Central anticholinerg ic syndrome at higher doses 5 Urinary retention 6 Increases intraocular pressure in narrow- angle glaucoma. Contraindications 1 Do not use in resuscitation of asystole because isopren- aline-induced vasodilatation results in reduced carotid and coronary blood \202 ow. Adverse effects 1 Hypotension 2 Proarrhythmogenic 3 Coronary steal 4 Tachycardia 5 May unma sk pre-excitation in patients with an accessory Glycopyrrolate Glycopyrrolate is a synthetic quaternary amine containing mandelic acid. It does not cross the blood \200\223brain barrier and is devoid of central effects. It causes less tachycardia when compared with atropine. Its use is in mild bradycar- dia and to count er muscarinic effects of neostigmine. Atropine remains the drug of choice in life-threateni ng bradyarrhythmias. Dose: IV bolus of 0.1 \200\2230.2mg repeated every 2 \200\2233min. Use 5 \200\22310mcg/kg in children. conduction pathway. Dobutamine Dobutamine is a synthetic catecholamine distributed as a racemic mixture. Dobuta mine is a direct B1 agonist, with limited B2 and A effects, and has no A2 or dopaminergic a ctivity. It increases the heart rate, contractility, cardiac output and decreases both SVR and pulmonary vascular resistance (PVR). The blood pressure either increases or remains unc hanged. Half-life: 2min. Pharmacokinetics: It is metabolized by COMT and conjuga- tion in t he liver. It produces an active metabolite. Dose: 2 \200\22320mcg/kg/min. It is supplied in 20ml vials contain- ing 250mg. It is diluted at least up to 50ml in 5% dextrose before inf usion. Glucagon Glucagon is a peptide hormone produced by the A cells of the pancreas. It increase s intracellular cAMP, acting via a speci \201 c receptor. It increases heart rate, contrac tility, atrio- ventricular conduction and cardiac output. This effect is seen even in the p resence of B-blockade. Pharmacokinetics: termination of action is by redistribution and pro teolysis in liver, kidney and plasma. Duration of action is 20 \200\22330min. 179 CHAPTER 11.6 Chronotropes Dose: 1 \200\2235 mg IV slowly; 0.5 \200\2232.0 mg IM/SC. It is infused at 25 \200\22375mcg /min. 5 Withdrawal syndrome following discontinuation. 6 Raynaud \200\231s phenomenon. Adverse effects 1 Hyperglycaemia 2 Hypokalaemia 3 Nausea and vomiting 4 Tachycardia 5 Aller gic reactions. Metoprolol Metoprolol is a selective B1 antagonist. Mechanism of action and effects are sim ilar to propranolol. Dose: by IV injection, up to 5mg at rate of 1 \200\2232mg/min, repeate d after 5min if necessary, up to a total dose of 10 \200\223 15mg. Triiodothyronine (T3) T3 and thyroxine are thyroid hormones, of which T3 is the active form . It enters the cell and acts via receptors on the nucleus and mitochondria. It stimulates gene transcription and accelerates oxidative phosphorylation. T3 increases heart rate and c ontractility. Dose: IV 0.4mcg/kg as bolus followed by 0.4mcg/kg infused over 6h. It is rare ly used to increase the heart rate alone. It may be of use post-bypass when conventional th erapies have failed, but is not recommended routinely. One has to be careful not to induce cardiac ischaemia. Verapamil Verapamil is a calcium channel antagonist belonging to the phenylalkylamine group . It preferentially binds to L-type calcium channels in its depolarized inactivated state ( use- dependent blockade). These channels are present in both the myocardial and vascular sm ooth muscle cells. Verapamil causes vasodilatation, reduces the heart rate andcontrac- tili ty, and may cause hypotension. Pharmacokinetics: elimination occurs by hepatic metabo- lism and the plasma half-life is 3 \200\22310h. Dose: IV loading dose of 5 \200\22310mg. Dose m ay be repeated after 30min. Maintenance: 5 \200\22315mg/h. PO: 40 \200\22380 mg 3 \200\2234 times a day. Pediatric doses: 75 \200\223200mcg/kg IV.