Amiodarone supplants lidocaine in acls and cpr protocols
A m i o d a ro n e S u p p l a n t sL i d o c a i n e i n A C L S a n dC P R P ro t o c o l s
KEYWORDS Amiodarone Ventricular tachyarrhythmias Cardiac surgery
Amiodarone is an antiarrhythmic medication used to treat and prevent certain types ofserious, life-threatening ventricular arrhythmias. Amiodarone gained slow acceptanceoutside the specialized field of cardiac antiarrhythmic surgery because the side effectsare significant. Recent adoption of amiodarone in the ACLS (Advanced Cardiac LifeSupport) protocol has somewhat popularized this class of antiarrhythmics. Its use isslowly expanding in the acute medicine setting of anesthetics. This article summarizesthe use of amiodarone by anesthesiologists in the operating room and during cardio-pulmonary resuscitation (CPR).
In a population of 1000, the average annual occurrence of sudden cardiac death (SCD)is approximately 0.2%, but population-related frequency of cardiovascular disease indifferent areas of the country should be considered. There are approximately 400,000to 450,000 recorded occurrences of SCD in the United States, which accounts forabout 60% of all cardiovascular mortality in this country.Holter studies further indi-cate that approximately 85% percent of SCDs are caused by ventricular tachyarrhyth-mias, both pulseless ventricular tachycardia (VT) and ventricular fibrillation (VF).
VT is a critical condition that can lead to VF. VT is characterized as monomorphic
when waveforms are at a steady rate and amplitude, and polymorphic when theyare inconsistently variable. VF is another critical condition whereby the ventriclestremble rather than contract. VF waveforms are inconsistent in rate and amplitude,
a Department of Cardiothoracic and Vascular Anesthesia, San Raffaele Hospital, “Vita e Salute”University, Milan, Italyb Florida Gulf-to-Bay Anesthesiology, 1 Tampa General Circle, Suite A327, Tampa, FL 33606,USAc Department of Surgery/Anesthesiology, Florida Gulf-to-Bay Anesthesiology Associates &University of South Florida, 1 Tampa General Circle, Suite A327, Tampa, FL 33606, USA* Corresponding author. 1 Tampa General Circle, Suite A327, Tampa, FL 33606. E-mail address:
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often more than 300 beats per minute and more than 0.2 mV in amplitude. The irregularrate and amplitude indicates the inconsistent and hectic electrical activity andcontraction when the heart stops pumping. VF waveforms often weaken to asystolewithin 15 minutes.
In countries with prosperous resources, such as the United States and Europe,
cardiac arrest due to VT or VF is mostly caused by myocardial ischemia. As a conse-quence, major risk factors for SCD include those factors that can accelerate coro-nary artery disease. Other risk factors associated with SCD include age (typically45–75 years), male sex, and dilated cardiomyopathy.
Cardiac arrest due to VT or VF causes an interruption in oxygen supply that can lead
to critical ischemic damage to the organs. This condition is life-threatening, and leadsto death within minutes if untreated. The treatments for pulseless ventricular tachyar-rhythmias include use of defibrillation and antiarrhythmic drugs.
Cardiac action potentials are divided into fast-response action potential and slow-response action potential. Fast-response action potential, also known as nonpace-maker action potential, is found in nonnodal cardiomyocytes (atrial and ventricularmyocytes, and Purkinje tissue). This action potential type relies on fast sodiumchannels for depolarization. Slow-response action potentials, on the other hand,also known as pacemaker action potentials, are found in nodal tissue, whichconsists of sinoatrial and atrioventricular nodes, and depend on calcium channelsrather than sodium channels for depolarization
Cardiac action potentials, in general, use sodium and calcium channels for depo-
larization, and potassium channels for repolarization. In fast-response action poten-tial, phase 0 represents depolarization, whereby sodium channels open to enhancepositive membrane potential. Phase 1 is the initial repolarization, when potassiumchannels open and allow outward K1 current. There is, however, a slow increasein inward Ca21 current during this time, impeding the repolarization seen in phase2. This phase, however, lengthens the period of action potential, and is the onlyphase that shows a difference between cardiac action potentials and those of thenerves and skeletal muscle. Phase 3 is then the continuation of the repolarization,and phase 4 allows the action potential to return to resting membrane
Fig. 1. Cardiac action potential. (A) Fast-response action potential (atrial and ventricular my-ocytes, and Purkinje tissue). (B) Slow-response action potential (sinoatrial and atrioventric-ular nodes). ERP, effective refractory period; SA, sinoatrial.
Antiarrhythmic drugs have different effects on action potentials, and are classifiedbased on their mechanism of action. Many proposals have been made in classifyingthe antiarrhythmic drugs, but Vaughan Williams’ classification seems to be the mostused.There are 4 classes in Vaughan Williams’ classification, which are shown in
Class I antiarrhythmics act as sodium channel blockers. These antiarrhythmics attachto and block sodium channels accountable for rapid depolarization in fast-responsecardiac action potentials. The faster the depolarization of a cell, the faster adjacentcells would be depolarized, causing a faster regeneration and conduction of actionpotentials between the cells. Blocking sodium channels would decrease the actionpotential conduction velocity, and this action is helpful in repressing irregular conduc-tion that can cause tachycardias.
Table 1Vaughan Williams classification for antiarrhythmic drugs
Moderate Na1 channel blocking effect with conduction impairment
Marked Na1 channel blocking effect with significant
Depressed automaticity and conduction in slow-response cells
Impair calcium release to reduce contractility
Potassium channel blockade lengthens refractoriness by delaying recovery
Most agents are not purely potassium blockers and have properties of other classes
AMIODARONE, BRETYLIUM, AZIMILIDE, DOFETILIDE, IBUTILIDE
Predominantly blocks calcium entry in slow-response
Stimulation of adenosine receptor results in opening
of potassium channels with predominant effect ofhyperpolarization; This will depress automaticity inSA nodal cells and conduction in AV nodal cells
Minimal effect of shortening repolarization
Abbreviations: AV, atrioventricular; SA, sinoatrial.
Class I is further broken down to subclasses A, B, and C. These subclasses are
based on the drugs’ ability to alter action potential duration (APD) and effective refrac-tory period (ERP). ERP is also known as absolute refractory period, and indicates theperiod in which, with an action potential already started, a new action potential cannotbe started until the cell returns to resting membrane potential. Increasing ordecreasing APD or ERP can increase or decrease arrhythmias based on the causeof the condition. Class IA increases APD and ERP, whereas class IB decreasesAPD and ERP, and IC has no effect on APD and ERP. Class IA drugs are classifiedas moderate sodium channel blockers, whereas IB drugs are weak and IC drugsare strong. Class IA drugs are used to treat atrial fibrillation, flutter, and supraventric-ular and ventricular tachyarrhythmias. Class IB drugs are used to treat ventriculartachyarrhythmias. Class IC drugs are used to treat life-threatening supraventricularand ventricular tachyarrhythmias.
Class II drugs are known as b-blockers. b-Blockers attach to b-adrenoceptors incardiac nodal tissue, the conducting system, and contracting myocytes to block cate-cholamines (noradrenaline and adrenaline) from binding to the adrenoceptors. b-Blockers are further divided into b1-blockers and b2-blockers. The heart has both
b-adrenoceptors, but b1 predominate in number and function. b-Receptors bindnorepinephrine released from sympathetic adrenergic nerves, as well as norepineph-rine and epinephrine in the blood.
b-Blockers can reduce sympathetic influences that usually stimulate chronotropy
(heart rate), inotropy (contractility), dromotropy (electrical conduction), and lusitropy(relaxation). Therefore, b-blockers would enable a reduction in heart rate, contractility,conduction velocity, and relaxation rate. b-Blockers are used to treat hypertension,angina, myocardial infarction, arrhythmias, and heart failure, and have been proposedas protective strategy to prevent perioperative cardiac events in patients undergoingmajor surgery.
Class III drugs are known as potassium channel blockers and comprise amiodarone. Class III drugs bind and block the potassium channels used for repolarization, thusslowing down the repolarization process. By delaying repolarization, APD and effec-tive ERP would increase. Drugs that help increase ERP are effective in suppressingtachyarrhythmias caused by reentry mechanisms. Potassium channel blockers areused to treat supraventricular and ventricular arrhythmias, life-threatening arrhyth-mias, and atrial fibrillation and flutter.
Class IV drugs are known as calcium channel blockers. These drugs bind to L-typecalcium channels on vascular smooth muscle, cardiac myocytes, and cardiac nodaltissue. These channels regulate calcium entry into myocytes that stimulate smoothmuscle and cardiac myocyte contractions. Calcium entry block enables calciumchannel blockers to cause vasodilation, and decrease contractility, heart rate, andconduction velocity. Calcium channel blockers are administered for hypertension,angina, and arrhythmia therapies.
Procainamide and bretylium historically had an important clinical presence in ACLSand PALS (Pediatric Advanced Life Support), but today amiodarone is consideredthe drug of choice in cardiac arrest. Lidocaine continues to be an important drug,but is considered more as a local anesthetic than as an antiarrhythmic.
Even though amiodarone was discovered in 1962, it was not put into use until 1967. Amiodarone was primarily used as an antianginal drug. In 1969, it was promoted tobe used more specifically as an antiarrhythmic drug. The use of amiodarone as an anti-arrhythmic to treat supraventricular and ventricular arrhythmias occurred primarily inFrance, South America, and the Scandinavian countries. By the mid-1980s, intravenousamiodarone was commonly used in Europe. In 1985, amiodarone gained approval bythe US Food and Drug Administration (FDA). However, as harmful effects arose repeat-edly, amiodarone was no longer viewed as an ideal antiarrhythmic.By the mid-1990s,amiodarone was being used as “reserve antiarrhythmic” when other antiarrhythmicagents failed. By the start of the millennium, amiodarone regained its position as theideal antiarrhythmic in treating VT and VF, as suggested in the ACLS
Amiodarone, also known as Pacerone or Cordarone, is an antiarrhythmic agent thatacts by reducing heart rate when it is too fast, such as in VF, tachycardia, atrial fibril-lation, and atrial flutter. Amiodarone is categorized in Vaughan Williams Class III,where its properties include inhibiting potassium channels, protracting action potentialduration and ERP, and averting recurring arrhythmias. Even though amiodarone isclassified as Class III, it does also have effects seen in Class I, II, and IV; however,the main mechanism of action is not yet known.
Acute arrhythmias are usually treated with a pump-infusion system to deliver
constant intravenous dose of amiodarone, whereas patients with chronic arrhythmiasand children may receive an oral administration as amiodarone hydrochloride.
Amiodarone molecule composition consists of 37.3% iodine in weight Due
to this iodine composition, amiodarone is known to cause many adverse effects con-cerning thyroidal complications when administered chronically.
Amiodarone can be advantageous in stabilizing monomorphic and polymorphic VT,
and other tachycardias. Metabolism of amiodarone is rather intricate. Intravenously,amiodarone’s half-life is short just as the distribution is large, and the redistributiongoes to the fat, liver, heart, and brain. Redistribution is slow, approximately a fewhours or days, while amiodarone stays in the serum for about 12 to 24 hours. As
Fig. 2. Chemical structure of amiodarone.
amiodarone is metabolized via the liver, it evolves to become desethylamiodarone,a Vaughan Williams Class III
Amiodarone has numerous side effects. Most individuals administered amiodarone ona chronic basis will experience at least one side effect.
The most serious reaction caused by amiodarone is interstitial lung disease. Risk
factors include high cumulative dose, more than 400 mg per day, duration over 2months, age, and preexisting pulmonary disease. Common practice is to avoid usingthe agent if possible in individuals with decreased lung function. The most specific testof pulmonary toxicity due to amiodarone is a dramatic reduction in gas exchange,measurable by a decreased diffusion capacity of carbon monoxide on pulmonaryfunction testing.
Thyroxine and amiodarone have similar structures. Due to the iodine content of the
agent, abnormalities in thyroid function are common. Both underactivity and overac-tivity of the thyroid may occur while on amiodarone treatment. Measurement of freethyroxine (FT4) alone may be unreliable in detecting these problems, so thyroid-stimulating hormone (TSH) should also be checked every 6 months.
Corneal microdeposits (corneal verticillata, also called vortex keratopathy) are
almost universally present (>90%) in individuals taking amiodarone for at least6 months. These deposits typically do not cause any symptoms. Optic neuropathyoccurs in 1% to 2% of people and is not dose dependent. Bilateral optic disk swellingand mild and reversible visual field defects can also occur.
Long-term administration of amiodarone is associated with a blue-gray discolor-
ation of the skin, more commonly seen in individuals with lighter skin tones. The discol-oration may revert on cessation of the drug. However, the skin color may not returncompletely to
The most common adverse effect of intravenous amiodarone is This
complication may possibly be associated with the infusion rate. Hypotension can betreated with vasopressor drugs, positive inotropic agents, and volume expansion ther-apies, or reduction of the infusion rate.
While amiodarone is known for its tachycardia treatments, it has proarrhythmic
effects as well, such as bradycardia, asystole, and torsade de pointes. However, in clin-ical practice it might be difficult to differentiate between an insufficient dose of amiodar-one and actual proarrhythmic effects. If the arrhythmias persist even with a higher doseand the patient is hemodynamically unstable, the drug should be ceased as soon aspossible. QT interval analysis can help in reaching this decision. The problem is quitecomplex, as amiodarone can increase the QT interval while not inducing torsade depointes, and can cause polymorphic VT while not stretching the QT interval.
Before its popularity evolved in the United States after its approval from the FDA, lido-caine was used to treat arrhythmias. Amiodarone and lidocaine are often used for CPRin cardiac arrest. Before amiodarone had been included in the ACLS algorithm, lido-caine was listed as the primary drug of choice to treat VF or VT (VF/VT). In 2000, asthe guidelines in ACLS made some changes using an evidence-based approach,amiodarone was approved as the primary drug of choice in the ACLS tachycardiaalgorithm. After amiodarone’s approval, some studies were also performed showingits effectiveness in preliminary The 2005 revision of the ACLS guide-lines also mentions amiodarone as the preferred antiarrhythmic drug of choice based
on trials. ACLS guidelines now indicate that amiodarone must be the first antiar-rhythmic administered to treat VF/VT; and only after attempts at using amiodaroneare ineffective can lidocaine and procainamide be
TRIALS REGARDING AMIODARONE IN SUSTAINED VENTRICULARTACHYARRHYTHMIAS AND CARDIAC ARREST
Even though lidocaine had been used to treat VF/VT for many years, there was lack ofevidence for its usefulness over other drugs. Compared with other antiarrhythmics,more controlled data can be found for amiodarone. Based on comparison trials whereinit was tested with other antiarrhythmics, amiodarone has been shown to enhancesurvival to hospital admission; however, a benefit in survival to hospital dischargehas not yet been
Levine and investigated the response to intravenous amiodarone in a
prospective, double-blinded, randomized study of 273 patients with life-threateningventricular arrhythmias causing systolic blood pressure to decrease to below80 mm Hg with clinical signs and symptoms of shock. All patients included wererefractory to lidocaine, procainamide, and bretylium, and were randomized to receive1 of 3 doses of amiodarone: 525, 1050, or 2100 mg over 24 hours. The primary endpoint was to determine the proportion of patients who survived with no furtherepisodes of hemodynamically instable VT. Secondary end points were survival duringthe first 24 hours, successful therapy, additional boluses of intravenous amiodarone,and proarrhythmic effect.
Of the 273 included patients, 110 (40%) survived within 24 hours without hypoten-
sive ventricular tachyarrhythmia with amiodarone as a single antiarrhythmic. Thenumber of supplemental doses of intravenous amiodarone was significantly greaterin the 525-mg group than in the 2100-mg group (P 5 .0043). However, there was noclear dose-response correlation observed with respect to successful rate or mortality. This study concluded that amiodarone is a relatively safe therapy for hypotensiveventricular tachyarrhythmias.
In another randomized, double-blinded study,amiodarone was compared with
a placebo, polysorbate 80, a diluent for amiodarone, in 504 adults with nontrau-matic prehospital cardiac arrest with VF or pulseless VT who had not been resus-citated after 3 precordial shocks. Of these patients, 246 were randomized toreceive 300 mg of intravenous amiodarone (only a single dose) while 258 receivedplacebo. The primary end point was admission to the hospital with a spontaneouslyperfusing rhythm. Secondary end points were adverse effects, the number of pre-cordial shocks required after the study drug, the total duration of CPR, and theneed for additional drugs. Eighty-eight percent of the patients had VF and 7%had pulseless VT. There was no significant difference between the two groupsin the mean duration of the resuscitative efforts, the number of shocks, or theproportion of patients requiring additional antiarrhythmics. More patients receivingamiodarone had hypotension (59% vs 48%, P 5 .04) or bradycardia (41% vs25%, P 5 .004). The patients in the amiodarone group were more likely to surviveto be admitted to the hospital (44% vs 34%, P 5 .03). This trial showed that theadministration of amiodarone resulted in a higher rate of survival to hospitaladmission in patients with prehospital cardiac arrest due to refractory ventriculartachyarrhythmias.
Another studycompared amiodarone and lidocaine in adult patients with preho-
spital VF, resistant to 3 shocks, intravenous epinephrine, and a further shock. In total347 patients were enrolled; 180 were randomized to receive amiodarone (5 mg/kg
estimated body weight) while 167 received lidocaine (1.5 mg/kg). The primary endpoint was survival to admission to the hospital. Secondary end points included survivalto discharge from the hospital and adverse events. After treatment with amiodarone,22.8% of patients survived to hospital admission, as compared with 12.0% of patientstreated with lidocaine (P 5 .009). Among the 41 patients who survived to hospitaladmission after receiving amiodarone, 9 survived to hospital discharge (5% of theentire group), as compared with 5 of the 20 initial survivors in the lidocaine group(3% of the entire group) (P 5 .34). The investigators concluded that if an antiarrhythmicdrug is to be considered in patients with shock-resistant VF, intravenous amiodaroneshould be the drug of choice, due to higher rates of survival to hospital admission inpatients receiving amiodarone as compared with lidocaine.
Pollak and conducted a retrospective study in which charts of 347
patients who underwent cardiac resuscitation were studied to determine whetherthe use of amiodarone improved survival in the case of in-hospital cardiac arrest. The end points were survival of resuscitation effort to return of spontaneous circula-tion, and survival to discharge.
Pulseless VT or VF were present in 95 patients. Clinical uptake of amiodarone
was limited; only 36 patients received amiodarone while 59 patients received otherantiarrhythmics. In the 36 patients receiving amiodarone, survival of resuscitationwas 67% vs 83% in the 59 patients receiving other drugs. Survival to dischargewas 36.1% and 55.9% in the two groups, respectively. This study concludedthat use of amiodarone was less than 50% and that no clinically observablesurvival benefit could be documented in in-hospital cardiac arrest. Possible expla-nations for the difference between this experience and that found in out-of-hospital resuscitation trials include differing patient populations and operatorbias during resuscitation.
Atrial fibrillation (AF) is an important and frequent complication after cardiac surgery,occurring in almost one-third of patients undergoing coronary artery bypass graftingand in up to 44% of patients undergoing a valvular procedure. Heart failure, hypoten-sion, increased risk of stroke, need for anticoagulation, increased length of stay in thehospital, and long-term mortality are some of the various potential consequences ofpostoperative AF.
Postoperative AF was found to be significantly reduced in a double-blinded
in which 124 patients were randomized to receive either oral amiodarone(64 patients) or placebo (60 patients) for a minimum of 7 days before elective cardiacsurgery with cardiopulmonary bypass. Amiodarone dose was 600 mg/d for 7 days,then 200 mg/d until discharge from the hospital. The incidence of postoperativeAF was 25% (16 patients) in the amiodarone group and 53% (25 patients) in thegroup receiving placebo (P 5 .003). Patients in the amiodarone group were hospital-ized for significantly fewer days than those in placebo group (6.5 Æ 2.6 vs 7.9 Æ 4.3days, P 5 .04), and total hospitalization costs were also significantly less in the amio-darone group (P 5 .03). No difference was found in the occurrence of postoperativecomplications between the two groups.
The safety of short-term amiodarone therapy with fentanyl-containing anesthesia
was investigated in a randomized, double-blinded, placebo-controlled trial of cardiacsurgical patients with fentanyl-isoflurane anesthesia.There were 84 patientsenrolled: 45 patients received amiodarone (3.4 g over 5 days or 2.2 g over 24 hours)while 39 received placebo. The primary end point was to compare the incidence of
hemodynamic instability, defined as: net increase in fluid balance during surgery ofmore than 2 L, use of more than10 mg/kg/min dopamine, other vasopressive cate-cholamines, and need for a phosphodiesterase inhibitor or intra-aortic balloonpump. There were no significant differences between the two groups in any indicatorfor hemodynamic instability.
Although valvular surgery poses a greater risk for AF, most studies in cardiac
surgery have been performed in patients undergoing coronary revascularization. Inseveral of these protocols, the preoperative loading regimen was administered orally;however, this approach is currently impractical because most patients undergoingelective cardiac surgery are admitted the night before the procedure. Beaulieu andrandomized 120 patients to receive either amiodarone (intravenousloading dose after the induction of anesthesia followed by a 2-day perfusion) orplacebo to compare the occurrence of postoperative AF. Postoperative AF occurredmore frequently in patients who received amiodarone (59.3% vs 40.0% in the controlgroup, P 5 .035). Four preoperative factors were found to be associated with a higherrisk of postoperative AF: older age (P 5 .0003), recent myocardial infarction (P 5 .026),preoperative angina (P 5 .0326), and use of calcium channel blockers (P 5 .0078). Thisstudy showed that intravenous amiodarone administered in the perioperative perioddid not reduce the burden of postoperative AF in valvular surgery.
Amiodarone use during anesthesia for noncardiac procedures has not been
described specifically, if not for patients requiring continuous antiarrhythmic therapy.
Amiodarone is an antiarrhythmic drug that is useful to treat AF and perioperativetachyarrhythmias in cardiac surgery, and is the drug of choice for the treatment ofout-of-hospital cardiac arrest as indicated in the ACLS protocol. Despite the prom-ising results obtained in these settings, data about the use of amiodarone in noncar-diac procedures are still lacking, and further studies are necessary to assess whetheramiodarone can be advantageous.
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Virtual screening of HIV-1 protease inhibitorsidentify the potential binding sites of the inhibitors byagainst human cytomegalovirus protease usinggenerating a grid box that is big enough to cover theentire surface of the protein. The protein-inhibitorcomplexes derived from the first ranked docking solutionin the preliminary docking procedure were consequentlysolvated in a TIP3-water shell, a
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