Labetalol Labetalol is a selective A1- and non-selective B-adrenergic receptor blocker. Its differential effects on A:B receptors are 1:3 after oral administration and 1:7 after IV a dministra- tion, respectively. The drug can be given IV as a 20 \200\22380mg mini-bolus inj ection (q 10min) or 2 \200\2234mg/min infusion. Labetalol produces a prompt and controlled reduction in Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure-lowering drugs o n central aortic pressure and clinical outcomes: principal results of the Conduit Artery Fu nction Evaluation (CAFE) study. Circulation 2006; 113: 1213 \200\22325. Williams B, Poulter NR, Brown MJ, et al. Guidelines for manage- ment of hypertension: repor t of the fourth working party of the British Hypertension Society, 2004-BHS IV. J Hum Hyper tens 2004; 18: 139 \200\22385. 288 T PRABHAHAR & S PRICE Tachyarrhythmias Excessive rapidity in the action of the heart, usually de \201 ned as a heart rate >100bpm , and associated with increased incidence of major cardiac events and length of ICU stay. T achyarrhythmias may arise from the atria or the ventricles. Management principles \200 Generally, as for AF \200 Digoxin may convert to AF (rate co ntrol easier) \200 Overdrive atrial pacing may be used to cardiovert (suc- cess rate of a pproximately <50%) Atrial \201 brillation (AF) Characterized by uncoordinated atrial activation. Main fea- t ures are described in Table 18,2,1. Multi-focal atrial tachycardia Multi-focal atrial tachycardia is an irregular cardiac rhyth m caused by at least 2 different sites of competing atrial activ- ity with the sinus node. The main features are described in Table 18.2.1. Management principles \200 \200 Correction/removal of potential cause(s) Restoration of sinus rhythm if possible (chemical/ electri- cal cardioversion) Prevention/exclusion of intracardiac thrombus (TOE) Rate contro l (amiodarone/B-blocker/calcium channel blockade) where cardioversion is not possible Antic oagulation may be required and should be tailored to the individual patient situation Management principles \200 Frequently transient. May spontaneously convert to sinus rhythm, AF or atrial \202 utter Treat any precipitating cause Antiarrhythmics (B-blockers, magnesium or verapamil) may be u sed Electrical cardioversion is not generally effective \200 \200 Prophylaxis and maintenance of sinus rhythm \200 Pre-excitation syndromes Characterized by intermittent tachycardia (narrow or broad complex ) associated with an accessory AV connec- tion where a re-entry circuit between atria and v entricles occurs. Includes the Wolf \200\223Parkinson \200\223White (WPW) syn- drome. Note that pre-excitation (delta wave) is seen in only 3/1000 ECGs. Risk of post-cardiothoracic surgery AF is reduced by amiodarone, B-blockade or dltiazem. Di goxin should not be used. In post-operative AF, rhythm control should be the initial option . If antiarrhythmics are required to maintain sinus rhythm, B-blockade/amiodarone may be co nsidered Management principles \200 \200 Atrial \202 utter Atrial flutter is the expression of rapid and regular atrial excitation . The main features are described in Table 18.2.1. AF is potentially life-threatening (may degenerate to VF) In 50% of patients with WPW, card iac arrest is the \201 rst manifestation Adenosine should be avoided Table 18.2.1 Rhythm Substrate ECG features Incidence Risk factors 4 \200\2235% general ICU; 25 \200\223 40% cardiac ICU Age, diabetes, hypertension, structural and ischaemic heart disease, cardiac failure, chang es in intravascular volume, increased sympathetic activity, inotropic agents, intracardiac lines, electrolyte imbalance, lung disease, SIRS, hyperthyroidism Absent P waves; \201 brillatory waves and irregular ventricular response (intact AV condu ction) AF Following 4 \200\2236 re-entry circuit wavelets in the atria near anatomical/ functional ba rriers 5.2% general ICU As AF, plus pericarditis AFl Multiple re-entrant/ ectopic atrial waves Regular \200\230saw-tooth \200\231 atrial de \202 exion waves best seen in leads II, III and aVF COPD, hypoxaemia, PE, congestive heart failure and electrolyte imbalance. 0.05 \200\2230.32% in-patients. ICU incidence not known \200\224probably underdiagnosed Atrial rate >100bpm and >3 morphologically distinct P waves. P \200\223P intervals are irre gular and there is an isoelectric baseline between P waves MAT ?Triggered activity due to intracellular calcium overload or delayed \200\230afterdepolari zation \200\231 41% general ICU Cardiac disease, electrolyte imbalance, hypoxaemia, acidaemia, drugs Wide QRS complexes (>140ms), negative precordial, independent atrial activity, capture and fusion beats VT Originates from one or more ventricular ectopic foci, rate >100bpm Not known Risk factors: drugs electrolyte imbalance, subarachnoid hemorrhage, QTc prolongation and in secticide poisoning Characteristic paroxysms of 5 \200\22320 beats at heart rate >200bpm and alternating electr ical axis in 10 \200\22312 beats TdP Cycles of alternating electrical polarity with electrical axis rotating around the baseline . AF = atrial \201 brillation; A \202 , atrial \202 utter; MAT = multi-focal atrial tach ycardia; VT = ventricular tachycardia; TdP = Torsade de pointes. 289 CHAPTER 18.2 Tachyarrhythmias causes, IV magnesium. Consider overdrive pacing or iso- proterenol Early consultation with an electrophysiologist is advised for the ICU patient with a pre-ex citation syndrome Electrical cardioversion should be used in emergency Key points \200 Ventricular tachycardia Characterized by a regular broad-complex tachycardia. The main feat ures are described in Table 18.2.1. Treatment of all tachyarrhythmias on the ICU should include correction/removal of potential causes. Restoration of sinus rhythm is the main goal. Where standard pharmacological or el ectrical therapy fails, expert advice should be sought from an electro- physiologist as spe cialist intervention may be required. \200 Management principles \200 \200 In all cases: correction/removal of potential cause(s) Non-sustained VT with haemodynamic c ompromise: consider lignocaine/amiodarone infusion or ventricular pacing Sustained VT with no haemodynamic compromise: ligno- caine/amiodarone and, if no myocardial ischaemia, con- s ider procainamide. If drug treatment fails, cardioversion Sustained VT with haemodynamic co mpromise: cardio- version Polymorphic VT with normal QT interval: may be associ- ated with myocardial ischaemia; therefore, electrical car- dioversion is recommended with a plan for revascularization where possible Torsade de pointes: the main features described in Table 1 8.2.1. In addition to correction/removal of potential Further reading Blomstrom-Lundqvist C, Scheinman MM, Aliot EM, et al. ACC/ AHA/ESC guidelin es for the management of patients with supraventricular arrythmias. J Am Coll Cardiol 2003; 42: 1493 \200\223531. Grant AO. Recent advances in the treatment of arrhythmias. Circ J 2003; 67: 651 \200\2235. National Collaborating Center for Chronic Conditions. Atrial \201 bril- lation; national clinical guideline for management in primary and secondary care. London: Royal College of P hysicians, 2006. Trappe HJ, Brandt B, Weismuller P, et al. Arrhythmias in the inten- sive care patient. Curr Opin Crit Care 2003; 9: 345 \200\22355. Trohman RG. Supraventricular tachycardia: Implication for the intensivist. Crit Care Med 2000; 28 (Suppl.): N129 \200\22335. 290 A IGUCHI & S PRICE Bradyarrhythmias A slow ventricular rate, usually de \201 ned as <60bpm, but may be absolute (<40bpm) or re lative (excessively slow for the patient \200\231s clinical status). Bradyarrhythmias are d ue to either sinus node dysfunction or AV conduction distur- bances. in anterior MI may result from large infarct size, LV dysfunction or conduction abnormaliti es. It is associated with poor prognosis. First degree (PR interval >0.2s): does not normal ly require intervention. Second degree (Mobitz type I, Wenckebach): progressive lengthening of PR interval until failed conduction. Second degree (Mobitz type II): constant PR interv al with intermittent failure of conduction. Third degree (complete heart block): independen t atrial and ventricular activity. Causes of bradyarrhythmia These are divided into intrinsic (degeneration, acquired cardiac disease including cardiac surgery, in \201 ltrative dis- eases, congenital heart disease, infection) and extrinsic (neurological, pharmacological, endocrine, electrolyte dis- turba nce, hypothermia). Bradyarrhythmia is common in intensive care settings. It is usually tran sient and often related to extrinsic factors such as drugs and airway manip- ulation. Facto rs which increase the likelihood of arrhythmia in ICU include: 1 Pre-existing cardiac disea se 2 Treatment with antiarrhythmics 3 Recent macrovascular event 4 Microvascular disease ca using ischaemia 5 Altered acid \200\223base balance 6 High CO2 7 Abnormal electrolyte balan ce 8 Endogenous catecholamines (pain, anxiety) 9 Exogenous catecholamines (inotropes) 10 Su ction/bronchoscopy/airway maneuvers 11 Deep anesthesia/sedation 12 Anesthesia drugs (muscle relaxants, regional) Risk of progression to high grade AV block The risk of progression to high grade AV block a nd to asys- tole need to be assessed in all patients with AV conduction disturbances. Where indicated, back-up pacing should be considered: \200 First degree and Morbitz type I second degree AV block \200\224low risk Morbitz type I seco nd degree AV block with wide QRS \200\224high risk especially in the context of anterior MI Morbitz type II second degree AV block with wide QRS or associated with anterior MI \200 \224high risk Speci \201 c conditions Infective endocarditis (IE) Development of new AV block or bundle branch block in IE implies an aortic root abscess, usually in the non-coro- nary cusp. This complication is associated with signi \201 cant risk of abrupt development of high grade AV block, and immediate temporary pacing wire insertion is indicated. The case should be di scussed with cardiologists and car- diac surgeons. Sinus node dysfunction (sick sinus syndrome: \200 \200 1:600 patients >65yrs. Multiple ECG manifestations including: sinus bradycardia, sinus arre st, sinoatrial block, tachy-brady syndrome, AF. Most common manifestation in the ICU is exc essive bradycardia upon treatment of tachyarrhythmia. Sinus node dysfunction post-anterior MI is relatively common (5 \200\22330%). Often associated with concomitant AV node block. T reatment is usually not required unless associated with cardiac failure, hypotension or con tinu- ing myocardial ischaemia. In tachy-brady syndrome, pharmacological intervention to co ntrol the ventricular rate during tachycardia by blocking AV conduction with B-blockers, ca lcium chan- nel blockers or digitalis may not be possible without pac- ing due to sinus nod e depression. Lyme disease AV block is the most common manifestation of myocarditis in this condition. An tibiotic treatment usually resolves the AV block, but temporary pacing may be required. Clinical approach Although the clinical approach to the ICU patient with bradycardia does n ot differ from that in the non-ICU set- ting, the thresholds at which intervention may be i ndicated differ, and have to be tailored to each individual patient. Principles of manageme nt include exclusion/removal of potential causes, assessment of the haemodynamic impact of the bradycardia and special investigations, whilst rapidly assessing full clinical status o f the patients. Further princi- ples of management are outlined below: 1 Immediate interven tion may not be required if the Atrioventricular conduction disturbance \200 \200 Abnormalities arise in the AV node or the bundle of His. Multiple ECG manifestations includ ing: \201 rst/second/third degree AV block, bundle branch block, fascicular block. Narrow QRS implies block in the AV node; wide QRS implies infranodal block. Most common cause foc al injury (MI), but may result from right heart catheter-related trauma. Where seen in conj unction with aortic endocarditis, may indicate aortic root abscess with risk of progression to high grade AV block. Myocardial ischaemia should be excluded with develop- ment of new bundle branch block. Budle branch block patient is haemodynamically stable. 2 Correct electrolytes and ensure adequacy of oxygena- tion and ventilation. This should be carried out simulta- neously with other treatment if haemodynamically compromised. Serum p otassium should be maintained at >4.5mmol/l in patients with cardiac disease or post-car- d iac surgery (excluding post-cardiac transplantation). 3 Treat all reversible ischaemia. AMI must be considered as a cause of bradyarrhythmia and managed appropriately. 4 If rate is s low and the patient is haemodynamically com- promised then consider pacing. Indications for pacing are discussed below. CHAPTER 18.3 Bradyarrhythmias 291 Pharmacotherapy Intermittent sinus node dysfunction may respond to a small dose of atropine , but the response is unpredictable. With prolonged bradyarrhythmia and severe, aggravating ven- tricular irritability not responding to atropine or isoprena- line, temporary pacing should be considered. The following drugs are used to treat bradyarrhythmia: causes. Although a change in drug therapy should be con- sidered for drug-induced bradyarrh ythmia, pacing may be an acceptable approach if no agent with equivalent ef \201 cacy is a vailable. Atrial pacing is preferred in the patients with sinus node dysfunction as it redu ces the incidence of AF, pacemaker syndrome and thromboembolism. Indications for pacing in general ICU: 1 Symptomatic sinus bradycardia (SBP <80) unresponsi ve Glycopyrrolate Class: muscarininc anticholinergic agent. Synthetic quater- nary amine with no central effect. Indications: treatment of bradycardia, antisialogogue. Dose: 200 \200 \223600mcg IV bolus. Peak effect occurs 3min after IV injection. Interaction: none Adverse effect: dry mouth, inability to sweat, fever. to drug therapy 2 Morbitz type II second degree AV block 3 Third degree AV block 4 Bilateral bundle branch block (alternating bundle branch block or right bundle branch block with alternating left a nterior fasicular block/left posterior 5 Newly acquired or age-indeterminate bifasicular block with \201 rst degree AV block. 6 Newly acquired AV block or bundle branch block in IE Atropine Class: muscarininc anticholinergic agent. Naturally occur- ring tertiary amine whi ch penetrates blood \200\223brain barrier Indications: Treatment of bradycardia when associ ated with haemodynamic compromise or ventricular ectopy Dose: 0.02mg/kg. Repeat in 5min if required. 3mg is needed for complete vagal blockade in adult Interaction: none Adverse effe cts: dry mouth, inhibition of sweating, dif \201 culty swallowing, hallucination, blurred vision Contraindication: glaucoma Indications for pacing in AMI A degree of AV block occurs in 12 \200\22325% of AMI, commonl y associated with inferoposterior MI causing AV nodal ischae- mia with RV impairment. The s inus and AV nodes are rela- tively resistant to permanent injury by infarction, and normal function should recover over time. However, per- manent damage occurs more readily to the b undle of His. Anterior MI often cause AV nodal block in the bundle of His, and it can progr ess suddenly to complete heart block. Therefore, even transient complete AV block in the Hi s \200\223 Purkinje system due to infarction justi \201 es the insertion of a pacemaker. 1 AV block post-anterior MI associated with cardiac fail- ure, hypotension or continuing myo cardial ischaemia 2 First degree AV block and bundle branch block associ- Isoprenaline Class: short-acting synthetic catecholamine with pure B- adrenergic-stimulatin g properties (B1>B2) Indications: in emergencies to increase heart rate in brady- cardia or in heart block Dose: 0 \200\22310mcg/min Interactions: none Adverse effects: reduction in diastolic blood pressure, head- ache, tremor, palpitations, arrhythmia and sweating ated with anterior MI 3 Newly acquired bifasicular block associated with ante- rior MI 4 Alternating bundle branch block with anterior MI Indications for pacing after cardiac surgery AV block is one signi \201 cant complication of cardiac surgery particularly post-valve replacement and in surgery for con- genital hear t disease (1 \200\2233%). Epicardial wires are inserted perioperatively for the management of arrhythmias (brady- cardia, nodal/junctional arrhythmia, AV block) associated with haemo dynamic compromise, and those who are at high risk of post-operative arrhythmia. Adrenaline Class: B- and A-adrenergic receptor agonist Indication: asystole, inotropic ther apy, anaphylactic reaction, acute severe asthma Dose: for bradyarrhythmia 5 \200\22310mcg I V bolus via central vein. Followed if necessary by infusion 0.01 \200\2230.2mcg/kg/min Inte raction: exaggerated pressor and tachycardiac response with other sympathomimetics Adverse effects: tachycardia, hypertension, vasoconstriction, arrhythma, hyperglycaemia, thrombophr ebitis/necrosis if given via peripheral vein Further reading European Society of Intensive Care Medicine. Patient-centered Acute Care Tr aining (PACT) arrhythmia module, www.esicm. org. Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002 guideline update for implanta tion of cardiac pacemakers and antiarrhythmia devices: summary article: a report of the Ame rican College of Cardiology/American Heart Association Task Force on Practice Guidelines (A CC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). Circulation 2002: 106: 214 5 \200\22361. Pacing Pacing is a de \201 nitive life-saving treatment for bradyarrhyth- mia. Various mod es of pacing are available, including: mechanical, transcutaneous, transvenous, transoesoph a- geal and transthoracic. Clinical judgment is required for symptomatic bradyarrhythmia se condary to extrinsic Mangrum JM, DiMarco JP. The evaluation and management of bradycardia. N Engl J Med 2000; 342: 703 \200\2239. 292 D TARDITI & S HOLLENBERG Myocardial infarction: diagnosis Acute coronary syndromes (ACS) are differentiated into three categories: unstable angina (U A), non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocar dial infarction (STEMI). All share a com- mon pathophysiology: plaque rupture with subseque nt platelet activation, adhesion and aggregation, thrombin generation and ultimately thromb us formation. Classi \201 cation by ECG provides a useful framework for management and tre atment of ACS, as those with STEMI bene \201 t from early reperfusion therapy (pharmacolog ical or mechanical), vs those patients with NSTEMI or UA for whom catheter-based therapy re quires risk strati \201 cation. Due to increased sensitivity of new troponin assays, a joi nt ACC/ESC committee proposed the following de \201 nition of an acute, evolving or recent MI: Typical rise and gradual fall (troponin) or rapid rise and fall (CK-MB) of biochemical markers of myocar- dial necrosis with at least one of the following: \200 \200 ECG The \201 ndings on ECG will depend on the duration of symp- toms, size of myocardium affected, and location and extent of ischaemia/infarction. An initially normal ECG does not exclude ischaemia or even acute infarction. If the initial ECG is normal and symptoms pers ist, it should be repeated at 5 \200\22310min intervals. The \201 rst ECG changes with to tal coronary occlusion will usually be peaked T waves in the anatomic area of the myo- card ium in jeopardy followed within minutes by ST-seg- ment elevation. The diagnosis of STEMI i s de \201 ned by \211 1mm of ST eleva- tion in two anatomically contiguous leads, new or presum- ably new left bundle branch block (LBBB), or true posterior MI. The \201 nding of LBBB in the setting of possible ACS is a common cause for delay in reperfusion or treatmen t due to concern regarding diagnosis and risk of therapy. This is an ideal situation for di rect referral to cardiac catheteriza- tion when merited. True posterior infarction is sugge sted by marked ST-seg- ment depression con \201 ned to leads V1 \200\223V4 and accompa- ni ed by tall R waves in the right precordial leads and upright T waves. Ischaemic symptoms ECG changes indicative of ischaemia (ST-segment eleva- tion or depressio n) Development of pathological Q waves on the ECG Coronary artery intervention (e.g. angiop lasty) \200 Localization of ischaemia/infarction \200 \200 \200 \200 Clinical approach Signs and symptoms The symptoms of angina are described as (1) substernal chest discomfort with characteristic quality and duration that is (2) provoked by exertion or emotional stress and (3) relieved by rest or nitroglycerin. Angina is classi \201 ed a s typical (all 3) or atypical. While typical angina raises the probability of coronary arte ry disease (CAD), symptoms not characteristic of typical angina (i.e. sharp stabbing pain o r pain reproducible by palpation) do not exclude ACS. At least 1/5 of MIs are clinically un recognized because of atyp- ical symptoms. In one study, 7% of patients with pain fully rep roduced with palpation were found to have ACS. In patients with a history of CAD, assess if chest discom- fort is similar to prior episodes of angina. I and aVL \200\224high lateral V5 and V6 \200\224lateral II, III, aVF \200\224inferior V1, V2, V3, V4 \200\224anterior-septal Patients with inferior STEMI and haemodynamic compro- mise should be assessed with a right precordial V4R lead to detect ST-segment elevation ( \211 1mm) and an echocardio- gram to s creen for RV infarction. Biochemical cardiac markers Biochemical cardiac markers of injury should be measured in all patients who present with chest pain consistent with ACS, for both the diagnosis of myocar dial necrosis and the estimation of prognosis. There is a quantitative relationship between the level of marker elevation and the risk for adverse outcome. CK-MB begins to appear 4 \200\2238h after onset of infarction and peaks at 12 \200\22324h, with return to baseline a t 2-4 days. Levels may be elevated in patients with severe skeletal muscle damage. Cardiac troponins (I and T) have greater sensitiv- ity and speci \201 city than CK-MB. Both convey prognostic information beyond that supplied by the ECG, clinical char- acteristics at pres entation and predischarge exercise test. Although troponins accurately identify myocardial necro- sis, necrosis may not necessarily be secondary to athero- sclerotic CAD. Physical examination The bedside examination is important for excluding alter- native diagn oses such as aortic dissection or pericarditis, as well as diagnosing certain complications . \200 \200 \200 Distended neck veins \200\224elevated RV diastolic pressure Pulmonary crackles \200\224elev ated LV \201 lling pressure Holosystolic murmur at apex \200\224mitral regurgitation from papillary muscle dysfunction Holosystolic murmur at left lower sternal border \200\224acut e ventricular septal defect due to septal rupture History \200 \200 \200 \200 \200 \200 \200 \200 \200 Important caveats Women present more often than men with atypical chest pain and symptoms. Diabetic patients may have atypical symptoms or none at all due to autonomic dysfunction. E lderly persons may have atypical presentations such as generalized weakness, stroke, syncop e or a change in men- tal status. Traditional risk factors for CAD are only weakly predicti ve of acute ischaemia, and are less important than symptoms, ECG and cardiac biomarkers. Assess cardiac risk factors for CAD History of CAD/coronary intervention/CABG History of pe ripheral arterial disease Diabetes Hypertension Hyperlipidaemia Smoking Family history of p remature CAD Prior stroke/transient ischaemic attack (TIA) 293 CHAPTER 18.4 Myocardial infarction: diagnosis Echocardiography Echocardiography can be very useful in patients with sus- pected ACS, part icularly those with equivocal ECG \201 nd- ings. The presence of a regional wall motion a bnormality is highly suggestive of acute ischaemia, and its absence sug- gests that a large ischaemic territory is not present. Echocardiographic \201 ndings can also sometimes sug gest alternative diagnoses. Echocardiography provides a good measure of overall LV performa nce, allows for evaluation of valvular structure and function, and can identify areas of ak inesis and thinning suggestive of previous infarction. Echo is also the proce- dure of choi ce for rapid identi \201 cation of complications of MI. European Society of Cardiology http://www.escardio.org/knowledge/guidelines/ GRACE ACS Risk Management Tools http://www.outcomes-umassmed.org/grace/acs_ risk/acs_risk.swf Jaffe AS, Babuin L, Apple FS. Biomarkers in acute cardiac disease: The present and the future. J Am Coll Cardiol 2006; 48: 1 \200\22311. Thygesen K, Alpert JS, White HD, et al. Universal de \201 nition of myo- cardial infarction. Circulation 2007; 116: 2634 \200\22353. Rothwell PM, Coull AJ, Silver LE, et al. Population-based study of event-rate, incidence, c ase fatality, and mortality for all acute vas- cular events in all arterial territories (Ox ford Vascular Study). Lancet 2005; 366: 1773 \200\22383. Thygesen K, Alpert JS, White DH; on behalf of the Joint ESC/ACCF/ AHA/WHF Task Force for th e Redefinition of Myocardial Infarction. Universal de \201 nition of myocardial infarction . Eur Heart J 2007; 28: 2525 \200\22338. Further reading Dzau VJ, Antman EM, Black HR, et al. The cardiovascular disease continuum v alidated: clinical evidence of improved patient outcomes: Part I: Pathophysiology and clini cal trial evidence (risk factors through stable coronary artery disease). Circulation 2006; 114: 2850 \200\22370. Wang K, Asinger RW, Marriott HJ. ST-segment elevation in condi- tions other than acute myoc ardial infarction. N Engl J Med 2003; 349: 2128 \200\22335. 294 D TARDITI & S HOLLENBERG NSTEMI General principles Risk strati \201 cation It is essential to identify those patients at h ighest risk for future cardiac events who may bene \201 t from a more aggres- sive or inva sive therapeutic approach. Factors predicting high risk: \200 \200 \200 \200 Anticoagulation Heparin The rationale for use of both heparin and ASA is 2-fold: they inter fere with thrombin formation at different sites, and rebound after heparin discontinuation can be blunted by ASA. LMWH is preferred by many physicians because of a lower incidence of HIT, ease of administration without need for monitoring, and a lesser degree of plate- let activation. UFH should be given by bolus (60U/kg IV, maximum 5000U) and infusion (12U/kg/h , maximum 1000U/h) adjusted to maintain aPTT between 50 and 70s. Presence and extent of ST-segment depression Elevated cardiac biomarkers Haemodynamic insta bility Persistent chest pain despite appropriate medical ther- apy TIMI rsk score The TIMI risk score predicts outcome in patients with UA or NSTEMI from 7 va riables on presentation: \200 \200 Direct thrombin inhibitors (DTIs) DTIs, which include bivalirudin, lepirudin and hirudin, a re another alternative to UFH. Bivalirudin compared with UFH has shown signi \201 cantly l ess bleeding the ACUITY and REPLACE-2 trials, with similar outcomes in terms of ischae- mic events. Age \211 65yrs Presence of at least three risk factors for CAD (hyper- tension, diabetes, dyslipidaemia, smoking or positive fam- ily history of early MI) Prior coronary stenosis \211 50% Presence of ST-segment deviation on admission ECG At least two anginal episodes in prior 24h Elevated serum cardiac biomarkers Use of aspirin in prior 7 days Antianginals Nitrates Sublingual GTN is administered to patients presenting with chest pain , followed by IV GTN for hypertension, heart failure or if chest pain persists after three sublingual GTN tablets. Caution must be observed in severe RV infarction, severe aortic ste nosis or patients who have taken PDE inhibitors for erectile dysfunction within the previou s 24h. \200 \200 \200 \200 Patients are considered to be low risk (score of 0 \200\2232), inter- mediate risk (3 \200 \2234) or high risk (5 \200\2237). The composite end- point of all-cause mortality, MI and severe recurrent ischaemia at 14 days varies according to the number of TIMI risk factors ( score of 0 or 1, 4.7% vs score of 6 or 7, 40.9%). b-Blockers Multiple controlled trials have demonstrated the ef \201 cacy of B-blockers in AMI. Although no randomized trials spe- ci \201 cally address B-blockers in UA and NSTEMI, they are recommended. Initial medical therapy Antiplatelet therapy Aspirin All patients should receive 162 \200 \223325mg of uncoated aspirin (ASA) as soon as possible after onset of symptoms. The \201 rst tablet should be chewed to establish high blood levels rapidly. Further medical therapy Lipid-lowering therapy (statins) A mortality bene \201 t of atorva statin 80mg daily was demon- strated in the PROVE-IT TIMI 22 and MIRACL trials. Initial int ensive statin therapy, rather than gradual uptitration, is recommended due to the suggestio n of bene \201 t in the \201 rst 30 days in the PROVE-IT TIMI 22 trial. Clopidogrel Clopidogrel can replace ASA in intolerant patients, and leads to signi \201 ca nt bene \201 ts in NSTEMI when given in addi- tion to ASA. Standard dosing regimen from th e CURE trial is a 300mg loading dose followed by a maintenance daily dose of 75mg; higher l oading doses are under investigation. One issue with clopidogrel is signi \201 cantly incr eased bleed- ing rates in those persons who undergo emergent or urgent coronary artery bypa ss surgery in <5 days. Renin \200\223angiotensin \200\223aldosterone inhibition ACE inhibitors/ARBs Oral ACE inhib itors should be administered within the \201 rst 24h of MI onset in patients with an ante rior STEMI, heart failure or LVEF \211 40%. This class of drugs reduces mortality in patie nts with MI as demonstrated in ISIS-4 (captopril) and GISSI-3 (lisinopril). These drugs sho uld not be adminis- tered IV in the 1st 24h or in patients with hypotension (SBP <100mm Hg) . ARBs (valsartan and candesartan) are generally reserved for patients intolerant of ACE in hibitors. ARBs were as effective as ACE inhibitors in the immediate post-MI setting in the VALIANT study, but the combination of the two demonstrated an increased incidence of advers e effects without improving survival. Glycoprotein IIB/IIIA Inhibitors These should be given to any patients in whom PCI is plann ed. For those not undergoing PCI, they should be reserved for those at high risk for cardia c events such as a TIMI score \211 4, elevated serum troponin, continuing ischaemia, sympt oms of heart failure, impaired systolic function, sustained ventricular tachycardia or haem odynamic instability. There are three glycoprotein IIB/IIIA inhibitors: tiro \201 ban, ept i \201 batide and abciximab. The infusion should be started on presentation and continued for 48 \200\22372h or until PCI is performed. Abciximab is bene \201 cial in PCI, but was not effective as medical therapy for NSTEMI in the GUSTO IV trial. Epti \201 batide and ti ro \201 ban have been shown to be effective in patients with high risk features not underg oing PCI, and can also be used in patients undergoing PCI. Aldosterone antagonists Eplerenone, an aldosterone antagonist, when given to patients an LV EF \211 40%, and symptomatic heart failure or diabetes along with ACE inhibitors and stand ard therapy in the EPHESUS trial, reduced mortality signi \201 cantly at 30 days (3.2 vs 4 .6% with standard care). 295 CHAPTER 18.5 NSTEMI Early invasive vs conservative therapy Cardiac catheterization may be undertaken in patient s pre- senting with symptoms suggestive of unstable coronary syndromes for one of several r easons: to assist with risk strati \201 cation, as a prelude to revascularization and to e xclude signi \201 cant epicardial coronary stenosis as a cause of symptoms when the diagno sis is uncertain. An early invasive approach has now been compared with a conservative appr oach in several prospective studies. Two earlier trials, the TIMI IIIb study and the VANQWI SH trial, both performed before use of coronary stenting and plate- let glycoprotein IIb/II Ia inhibitors was widespread, were negative. More recently, several trials, including a sub study of FRISC II, TACTICS TIMI-18 and RITA-3 found a signi \201 - cant reduction in the c ombined end-point of death, MI or recurrent angina with invasive management. The most recen t comparison, the ICTUS study, found no difference in a composite of death, MI or rehospita lization for angina at 1yr between a group assigned to early invasive manage- ment and anot her assigned to selectively invasive manage- ment. As >40% of patients in the selectively i nvasive group were revascularized in the \201 rst month, this trial probably argues not s o much against an early invasive strategy as for selection of those patients most likely to benefit. Alternatively (or in parallel), improved adjunctive antiplate- let, antithrombin and lipid-lowering therapy may have nar- rowed the difference between strategies. Further reading ACC guidelines UA/NSTEMI http://content.onlinejacc. org/cgi/reprint/50/7/e1 Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guide- lines for the management of pa tients with unstable angina/ non-ST-elevation myocardial infarction \200\224executive summa ry. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction). Circulation 2007; 1 16: 803 \200\22377. Bavry AA, Kumbhani DJ, Rassi AN, et al. Bene \201 t of early invasive therapy in acute cor onary syndromes: a meta-analysis of contemporary randomized clinical trials. J Am Coll Card iol 2006; 48: 1319 \200\22325. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus mod- erate lipid lowering with s tatins after acute coronary syndromes. N Engl J Med 2004; 350: 1495 \200\223504. Dzau VJ, Antman EM, Black HR, et al. The cardiovascular disease continuum validated: clinic al evidence of improved patient out- comes. Part II: clinical trial evidence (acute coronar y syndromes through renal disease) and future directions. Circulation 2006; 114: 2871 \200 \22391. The TIMI Study Group http://www.timi.org Yusuf S, Zhao F, Mehta SR, et al. Effects of clopi dogrel in addition to aspirin in patients with acute coronary syndromes without st-segment elevation. N Engl J Med 2001; 345: 494 \200\223502. 296 D TARDITI & S HOLLENBERG STEMI In conjunction with \201 brinolytic therapy, IV B-blockers reduce the incidence of subseq uent non-fatal re-infarction and recurrent ischaemia. A key to prevention of recurrent isch aemia is judicious but aggressive titration of B-block- ade to achieve both heart rate and blood pressure control (heart rate \211 60 beats/min and blood pressure \211 120/80. B-Bl ockers should not be administered acutely to patients with sigini \201 cant bradycardia, S BP <100mm Hg, moderate \200\223 severe heart failure, AV block or reactive airway disease/ active wheezing. Many of these patients will tolerate B-blockers when started later. Import ant update regarding IV b-bockers: Based on results of the COMMIT-CCS2 trial, it seems rea- sonable to defer IV B-blockers in patients who are haemo- dynamically compromised, as mort ality may be increased in such patients. Risk strati \201 cation \200\224before reperfusion Risk strati \201 cation in STEMI can b e based on initial history, physical examination, ECG and CXR. High risk features include a dvanced age, low blood pressure, tachycardia, heart failure and anterior MI. Killip class ( I = no congestive heart failure, II = rales, S3, congestion on CXR, III pulmo- nary oedema, IV cardiogenic shock) can be used for clinical strati \201 cation. A TIMI risk score for STEMI includes 8 predictors: \200 Age \211 75 years \200\2243 points; 65 \200\22374 year s \200\2242 points \200 History of diabetes, hypertension or angina \200\2241 point \200 Systolic blood pressure <100mm Hg \200\2243 points \200 Heart rate >100 beats/min \200 \2242 points \200 Killip class II \200\223IV \200\2242 points \200 Weight <76kg \200 \2241 point \200 Anterior ST elevation or LBBB \200\2241 point \200 Time to reperfusion therapy >4h \200\2241 point Reperfusion therapy Rapid reperfusion is the most important objective in treatment of patie nts with STEMI. A decision must be made as soon as possible regarding primary PCI vs throm- bolysis. While door to balloon time is the standard of care measurement, with a goal door to needle time (thrombol- ysis) <30min, and goal door to balloon (primary PCI) <90min, the decision should be make by assessing time and risk. Reperfusion therapy, particularly \201 brinolytics, is most effec- tive when instituted with the first 3h. Unfortunately, pat ients with STEMI present at a mean of 3 \200\2234h after symp- tom onset. In addition, achi eving prompt reperfusion when transfer to another hospital is required is challenging. In t he NRMI 4 registry, only 5.3% of patients transferred for pri- mary PCI had a door to ballo on time \211 90min. All patients with cardiogenic shock or Killip class \211 3 should rec eive primary PCI. In addition, patients with contraindi- cations to fibrinolysis should be reperfused with PCI. Absolute contraindications to fibrinolysis in STEMI include: \200 \200 The TIMI risk score for STEMI has been validated in pre- dicting in-hospital mortality. The re is a continuous relation- ship between the score and 30 day and 1yr mortality regardless of reperfusion strategy. The location of the MI in STEMI by ECG can predict out- comes. Th e greater the number of leads with ST elevation, lack of ST resolution at 90 \200\223180min after thrombolysis, presence of Q waves, or anterior compared with inferior infarcts. Therapy Initial management The initial goals when the diagnosis of STEMI is made include: \200 \200 \200 Relief of ischaemic pain Assessment of haemodynamic state Initiation of reperfusion therapy (primary PCI or throm- bolysis) Antithrombotic therapy to prevent rethrombosis or subtotal stenosis at the site of ruptured plaque Any prior intracranial hemorrhage (ICH) Known structural cerebral vascular lesion (e.g. AV mal- formation) Known malignant intracranial neoplasm Ischaemic stroke within 3 months EXCE PT acute ischae- mic stroke within 3h Suspected aortic dissection Active bleeding or bleedi ng diathesis (excluding men- ses) Signi \201 cant closed-head or facial trauma within 3 mo nths In the emergency department, initial management includes oxygen, ASA, B-blockers, analgesia , GTN, and anticoagula- tion with heparin. \200 Acute therapy Reperfusion therapy should be accomplished with either primary PCI or thrombo lysis as discussed below. Antiplatelet therapy should include ASA, clopidogrel and, in pati ents undergoing PCI, glycoprotein IIb/IIIa inhibitors (tiro \201 ban, epti \201 batide or abciximab). IV GTN should be used in patients with heart failure, hypertension or persiste nt chest pain after three sublingual GTN tablets. B-Blockers should be administered to all patients without contraindications who experience STEMI. \200 