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. Esmolol Esmolol is an ultrashort-acting selective B1 antagonist that reduces heart rate. It is used to prevent tachycardia and hypertension in response to laryngoscopy, intubation an d other perioperative stimuli. Dose: 0.25 \200\2230.5mg/kg boluses followed by an infusion of 50 \200\223200mcg/kg/min. Transient hypotension can occur dur- ing loading dose. It is a vailable in 10ml (10mg/ml) vials for bolus administration and in ampoules containing 2.5g i n 10ml for continuous infusion. Pharmacokinetics: it is rapidly eliminated by red cell este - rases. Its distribution half-life is 2min and its elimination half-life is 9min. The side effects are therefore quickly reversible. Adverse effects 1 Hypotension 2 Severe bradycardia especially in combination with B- blockers 3 Reduces digoxin elimination and can precipitate digoxin toxicity. Diltiazem Diltiazem is a calcium channel antagonist belonging to the benzothiazepine group. It blocks the L-type calcium chan- nels similar to verapamil, but to a lesser extent. It r educes SVR, reduces the heart rate and contractility, but to a lesser extent than verapamil . It is thus less likely to com- promise the cardiac output. Pharmacokinetics: eliminated b y both hepatic metabolism (60%) and renal excretion (35%). Plasma elimination half- life is 3 \200\2235h. The active metabolite is desacetyldiltiazem. Dose: IV loading dose of 20mg o ver 2min. It may be repeated after 15min. Maintenance dose of 5 \200\22315mg/h infu- sion, depending on heart rate control. PO: 120 \200\223360mg/ day. Contraindications 1 Sinus bradycardia 2 Heart block 3 Cardiogenic shock 4 Overt heart failu re 5 Asthma. Propanolol Propranolol is a non-selective B1 and B2 antagonist. It decreases the heart rate , reduces myocardial contractility and suppresses renin release. Cardiac output and myocar- dial oxygen demand are reduced. Pharmacokinetics: it is highly lipid soluble and crosses t he blood \200\223brain barrier. It has a greater volume of distribution, and half-life is 4 \200\2236h. It is metabolized in the liver. Dose: administration of propranolol is titrat ed to desired effect, beginning with 0.5mg and progressing by 0.5mg increments every 3 \200 \2235min. It is administered at the rate of 1mg/min. Total dose is <10 mg. It is supplied a s 1mg/ml ampoule. Adverse effects 1 Hypotension 2 Bradycardia 3 Used with caution in combination with B-block ers and digoxin. Magnesium Magnesium is the second most abundant intracellular cat- ion. It stabilizes the e xcitable cell membrane. Dose: 5ml of 50% over 30min. May be repeated. Caution 1 Monitoring of serum magnesium levels is required. 2 It should be avoided in patie nts with renal insuf \201 ciency. 3 May cause AV nodal blockade. Adverse effects 1 Marked bradycardia 2 Bronchospasm 3 Congestive heart failure 4 Atrioventr icular heart block Digoxin Digoxin is a cardiac glycoside, C41H64O14, derived from leaves of the foxglove plan t. It increases the force of contraction 180 VG KULKARNI & S PRICE Pacemakers are coded using \201 ve letters and used as short- hand to designate pacing mo des. Chamber paced Chamber sensed Response Rate response Antitachycardia Indications for temporary cardiac pacing: 1 Sinus bradycardia/escape rhythm causing haemody namic O-none O-none O-none O-none O-none A-atrium A-atrium I-inhibit R-adapt P-ATP compromise V-ventricle V-ventricle T-triggered S-shock 2 Bridge to permanent pacing 3 Following cardiopulmonary bypass 4 During AMI: asystole, AV block 5. Bradycardia-dependent tachyarrhythmias D-dual D-dual D-dual D-dual S-single S-single due to increases in intracellular calcium concentra- tion resulting from inhibition of Na+/ K+ ATPase. It has vagotonic action on the AV node, so it is useful for rate control in SVT. Dose: IV loading of 0.25 \200\2230.5mg increments up to 1.0mg. Maintenance of 0.125 \200 \2230.250mg/day. Onset: gradual onset over 15 \200\22330min. Peak effect occurs 1 \200\2235 h after IV administration. Offset: it has a long half-life of 1.7 days. The main route of e limination is through the kidneys. Indications for permanent pacing: 1 AV heart block \200\224type II second degree or third d egree block 2 Bifascicular/trifascicular block 3 Sinus node dysfunction 4 Hypersensitive carotid sinus syndrome 5 Bradyarrhythmias following heart transplant 6 Prophylaxis for tachyarrhythmias \200\224with B-blockers \200\224 paroxysmal SVT, paroxysmal AF and long QT syndrome. Adapti ve rate pacing is used in patients with chronotropic incompetence. The heart rate is increa sed according to the physiological need. This need is detected by various methods: \200 \200 \200 Disadvantages 1 Long half-life 2 Low therapeutic index. 3 Interindividual variations in the rapeutic and toxic serum activity-based sensors QT-based sensors minute ventilation sensors levels and dosages. Adverse effects 1 Can precipitate any arrhythmia. 2 Loss of appetite, nausea, vomiting and diarrhea 3 Blurred vision, visual disturbances, confusion, drowsi- ness, dizziness, nightma res, agitation and/or depression Overdrive pacing and cardioversion \200\223defibrillation are methods used to stop tachyarr hythmias. Modern pacemak- ers can be incorporated with an ICD (internal cardiover- tor \200 \223de \201 brillator). 4 Acute psychosis, delirium, amnesia. Further reading Ali-Melkkila T, Kaila T, Antila K, et al. Effects of glycopyrrolate and atr opine on heart rate variability. Acta Anaesthesiol Scand 1991; 35: 436 \200\22341. Amiodarone Amiodarone is a class III antiarrhythmic agent. It blocks potassium channels, an d is an A and B receptor non-com- petitive antagonist. Pharmacokinetics: has very high lipi d solubility resulting in marked tissue accumulation. It is metabolized hepatically and the elimination half-life is 20 \200\223100 days. Dose: loading dose of 300mg (5mg/kg) over 30 \200\22360min. Maintenance: 900mg (15mg/kg) over 23h. Carruthers SG, McCall B, Cordell BA, et al. Relationships between heart rate and PR interva l during physiological and pharmaco- logical interventions. Br J Clin Pharmacol 1987; 23: 2 59 \200\22365. Clemo HF, Wood MA, Gilligan DM, et al. Intravenous amiodarone for acute heart rate control in the critically ill patients with atrial tachyarrhythmias. Am J Cardiol 1998; 81: 594 \200\2238. Gray RJ, Bateman TM, Czer LS, et al. Esmolol: a new ultrashort-act- ing beta-adrenergic blo cking agent for rapid control of heart rate in postoperative supraventricular tachyarrhythm ias. J Am Coll Cardiol 1985; 5: 1451 \200\2236. Adverse effects 1 Haemodynamic instability due to myocardial depression Hays JV, Gilman JK, Rubal BJ. Effect of magnesium sulfate on ventricular rate control in at rial \201 brillation. Ann Emerg Med 1994; 24: 61 \200\2234. and A blockade. 2 Prolongation of QT interval 3 Multiple drug interactions 4 Long-term: hypo/hyperthyroidis m, corneal deposits, Joradaens L, Trouerbach J, Calle P, et al. Conversion of atrial \201 brilla- tion to sinu s rhythm and rate control by digoxin in comparison to placebo. Eur Heart J 1997; 18: 643 \200\2238. hepatitis, pulmonary \201 brosis and photosensitivity. Miller MR, Kim N, Goodman SN, et al. The evidence regarding the drugs used for ventricular rate control. J Fam Pract 2000; 49: 47 \200\22359. Electrical methods Electrical pacing of the heart is a reliable method of rate support. Pac ing can be either temporary or permanent. Resuscitation Council UK. Advanced life support provider manual, 5th edn. Resuscitation Council UK. Advantages 1 Immediate effect 2 Reliable 3 Ability to synchronize atrial and biventricular contractions 4 Reduced risk of untoward effects and proarrhythmia 5 Ability to incorporate cardiovertor-de \201 brillator. This page intentionally left blank 182 S WADDY Antianginal agents increasing myocardial contractility without necessarily overcoming existing B-blockade of c oronary vasodilatation to the same extent may worsen ischaemia. Abrupt withdrawal can preci pitate acute hypertensive crises, crescendo angina and heart failure. Beware the unexplaine d post-operative crisis following accidental omission! Antianginal agents are of key importance to the critical care physician. Patients may devel op ischaemia and require treatment while under our care and, with increasing num- bers of p atients with significant co-morbidities, many patients are taking these agents when they be come sick and require intensive care Pathophysiology Unstable angina or acute coronary syndrome and stable angina have different pathophysiology and treatment. The best way to prevent angina in a critically ill patient with stable angina is to ensure they are well oxygenated, that their blood pressure (especi ally the diastolic and therefore coronary perfusion) is well maintained and that tachycardi a is prevented. Antianginal agents should be used with great caution in patients who are un stable as you will block many of the receptors you might well be trying to stimulate in a f ew hours time to maintain that blood pressure. B-Blockers These are \201 rst-line antiang inal agents in stable patients. Think about this as you pile in adrenergic drugs to a patie nt with a past history of angina. They have negative inotropic and negative chronotropic ac tions and limit myocardial oxygen demand. They are also effective antihypertensives. These combined actions reduce LV wall tension and thus further improve blood supply and oxygen de livery to the myocardium. By preferentially prolonging diastole they fur- ther increase cor onary perfusion. They have been exten- sively investigated for pre-optimization of high ris k surgical patients and are recommended by the American Heart Association for continuation in patients already taking these drugs and for initiation in high risk (and possibly interm ediate risk) patients undergoing vascular and high risk surgery. Extracirculatory adverse actions Bronchoconstriction is worsened by B-blockade, espe- ciall y with non-selective agents, and high doses of selective agents. Hyperkalaemia: catecholami nes cause uptake of potas- sium into cells and B-blockers inhibit this, it is rarely of cli nical relevance. Hypoglycaemia is worsened and recovery slowed in those on B-blockers. The symptoms of hypoglycaemia, sweating, tachycardia, anxiety are masked by B-blockade. These e ffects are less or absent if cardioselective agents are used. Pharmacokinetics and drug speci \201 cs The intensivist must be aware of the metabolism an d elim- ination of common drugs. Atenolol is excreted 50% in the feces and 50% in the urine , mostly as unchanged drug; there is 10% liver metabolism and the half-life is 6 \200\2239 h in healthy individuals; accumulation in renal failure is common and presents frequently t o acute medicine. Metoprolol (also bisoprolol, propranolol, oxprenolol) is extensively meta bolized in the liver by the CYP2D6 enzyme complex. The half-life is bimodally distributed i n the population and is either 3h or 8h (hence some patients need tds adminis- tration and others bd). The hepatic metabolism makes this drug particularly useful in the recovering c ritical care patient. Carvedilol is hepatically metabolized, but one metabolite is 13 times more potent at B-blockade and is then excreted in the feces. Sotalol is entirely excreted unchanged in the urine; this drug also has class III antiarrhythmic activity at higher dose s (>80mg bd). Labetalol is hepatically metabolized, and also has A-block- ing activity. Esm olol is degraded by red cell esterases, with a half-life of 9min; it is used for acute hype rtension and supraventricular arrhythmias, and not for angina. Other bene \201 cial actions B-Blockers inhibit platelet aggregation, reduce the risk of v entricular arrhythmias in acute ischaemia, slow conduc- tion and have actions on cardiac re modeling that make them bene \201 cial in chronic heart failure. Cardiac and circulatory adverse actions Heart failure: due to inhibition of the sympathetic drive, B-blockers carry the risk of worsening LV dysfunction. In the setting of critical i llness, this is a signi \201 cant concern; it occurs in <6% of patients who are stable bef ore initiation of B-blockade. Cardiac conduction abnormalities: B-blockers should be avoide d in patients with sick sinus syndrome, and there is a risk of precipitating heart block in those with conduc- tion abnormalities. This can be exacerbated by drug inter- actions (e.g . calcium channel blockers, digoxin). Peripheral vascular disease: symptomatic worsening ha s been observed in those with severe arterial disease, and most surgeons will prefer to sto p them in the context of peripheral vascular surgery, however this is probably over- stated and the evidence is poor. Inhibition of coronary vasodilatation: is overcome by the bene \201 cial effects of B-blockade on myocardial oxygen demand in stable patients. In the crit ically ill patient with acute circulatory insuf \201 ciency this may become clinically sig ni \201 cant, especially as diastolic blood pressure falls. The relative potency of presso rs at B1 and B2 receptors in b -Blocker overdose These patients will present with hypotension and brady- cardia. The PR interval may be prolonged, and QRS com- plexes may be broadened. Hypoglycaemia and mild hyp erkalaemia may be noted (if accumulation has resulted in renal failure this may be marked). Treatment should be according to ABC principles (see Chapter 25.1); speci \201 c therapy includes atropine (0.5mg IV repeated every 5min to 3mg), glucagon 5mg IV bolus (increases i ntracellular cAMP and therefore calcium inde- pendently from B adrenoreceptors) repeated if no response after 5min and followed by infusion of 1 \200\2235mg/h. Calcium (10ml of 10% c alcium chloride centrally or 30ml of 10% calcium gluconate peripherally). Insulin and glu- cose have also been used in B-blocker overdose titrating up to 50U in 50g glucose over 1h. Catecholamines will often be necessary, but may result in myocardial ischaemia for the reas ons postulated above. PDE inhibitors are attractive as the increase in cAMP will be indepen dent of B-blockade. Other therapies that can be added in