P&T News: April/May 2001

Pharmacotherapy Changes in the ACLS Guidelines: Impact on UIHC Practitioners

Alan H. Mutnick, Pharm.D., FASHP
Peer Review Status: Internally Peer Reviewed by William Haynes, M.D., Associate Professor, Department of Internal Medicine

The American Heart Association recently published updated recommendations for life support, Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care, International Consensus on Science, also known as the International Guidelines 2000. Published in August 2000, these guidelines build upon the consensus recommendations of four previous national councils on cardiopulmonary resuscitation and emergency cardiac care. Of significant difference from previous guidelines, the 2000 Advanced Cardiac Life Support (ACLS) guidelines contain a rigorous review of evidence supporting drug use. A second unique feature of the new guidelines is that they include the consensus of international panels that examined the evidence supporting the use of a particular drug during resuscitation. Each recommendation is classified according to the strength of evidence supporting its use (Table 1).

Overview of Major Changes

Development of new therapies in the areas of acute coronary syndromes and stroke has prompted considerable changes in the guidelines. New evidence, or lack thereof, and newly approved medications have changed the pharmacology of resuscitation. Many changes in the ACLS guidelines include drugs that had been considered basic therapy for many years but were lacking data in the literature to support their efficacy. For example, arrhythmia management has been altered significantly; a number of new antiarrhythmic agents were added to the treatment algorithms, but lidocaine is no longer considered the agent of first choice because of the lack of evidence supporting its use.

Although numerous drugs were added in the 2000 guidelines, the majority of the agents are used for post-arrest hemodynamic support or correction of tachyarrhythmias. These agents should be available to cardiac and intensive care providers, but do not need to be routinely added to emergency carts and boxes. Amiodarone and vasopressin are the only cardiac agents that have been added to emergency drug trays at UIHC because of their addition to the ACLS guidelines. Although one drug is replacing lidocaine and the other is an alternative to epinephrine, both lidocaine and epinephrine remain in the emergency drug trays.

The information that follows provides an overview of some of the key changes recommended for ACLS in the International Guidelines 2000. The focus of the information is changes in drug therapy, categorized by type of condition. More detailed information can be found in the complete guideline document (Circulation 2000; 102:I1-I370).

Management of Arrhythmias

The revised ACLS guidelines state that an antiarrhythmic agent should be "considered" for patients in ventricular tachycardia (VT)/ventricular fibrillation (VF) who have not converted following three defibrillation attempts, administration of a vasopressor agent, and repeated defibrillation attempts. The recommendation is significantly different from earlier practice recommendations and is the result of the small amount of published evidence supporting use of an antiarrhythmic agent.

During the last decade, researchers have found that antiarrhythmic agents are often proarrhythmic and may generate VT/VF rather than preventing it. Only one agent, amiodarone, has this type of positive evidence; for that reason, it has been upgraded in the treatment of selected arrhythmias (Table 2).

Pulseless Ventricular Tachycardia and Ventricular Fibrillation
Patients with cardiac arrest most often present with ventricular fibrillation. Time correlates with loss of muscle and defibrillation is the key to survival (Class IIa-acceptable, standard of care). Electrical defibrillation wanes in value following the initial shock, with 75 percent of patients experiencing a return of spontaneous circulation (ROSC) after the first shock, and another 10 percent after the second shock. Drug therapy should be initiated after three defibrillation attempts.

Notable drug therapy changes recommended for management of VT/VF:

• Amiodarone (Class IIb -- acceptable but not recommended; weak supporting evidence) is a first-line antiarrhythmic agent before lidocaine (Class Indeterminate -- not recommended, not forbidden).
• Vasopressin (Class IIb) is an alternative pressor agent to epinephrine (Class Indeterminate). Although the studies are small, there is consistent, convincing evidence supporting vasopressin as an alternative first-line vasopressor to epinephrine, and there may be an associated lower adverse effect profile as compared to epinephrine.
• High-dose epinephrine should not be used routinely (Class Indeterminate). While there are numerous positive animal studies and case reports, little valid human evidence supports the benefit of it over placebo.
• Pediatric Advanced Life Support guidelines for VT/VF are consistent with the adult guidelines, except that epinephrine is the only recommended pressor agent. There are no data supporting the use of vasopressin in children with cardiac arrest, and the current guidelines do not recommend it. Additionally, amiodarone is recommended as a first-line antiarrhythmic agent, followed by lidocaine and magnesium in selected cases.

Management of Pulseless Electrical Activity (PEA) and Asystole
The updated guidelines have no changes in the pharmacotherapy for either PEA or asystole. Epinephrine remains the drug of choice, followed by atropine. Epinephrine should be administered as 1 mg IV every 3 to 5 minutes (Class Indeterminate) followed by atropine 1 mg IV every 3 to 5 minutes. An added suggestion in management is the need to search for identifiable reversible causes -- the 5 Hs and 5 Ts which involve medications or require pharmacologic intervention [i.e., hydrogen ion (acidosis), hyperkalemia, hypokalemia (drug overdose or accidental ingestion), and thrombosis (coronary or pulmonary)].

The administration of sodium bicarbonate is appropriate in the following conditions: known, pre-existing hyperkalemia (Class I); known, pre-existing, bicarbonate-responsive acidosis; tricyclic antidepressant overdose; or urine alkalinization in aspirin or other drug overdose situation (Class IIa); and intubated and ventilated patients with long arrest interval, or return of circulation after a long arrest interval (Class IIb).

Management of Bradycardia

Two points should be considered regarding the management of bradycardia:

1. Transcutaneous pacing is the intervention of choice for symptomatic bradycardia (Class I).
2. Lidocaine could be lethal in treating a combination of third degree heart block and ventricular escape rhythm.

Atropine remains the drug of choice (1 mg every 3 to 5 minutes, up to a total of 0.03 to 0.04 mg/kg). Low dose dopamine (2 to 5 mcg/kg/min) can be added and titrated to 20 mcg/kg/min if bradycardia is associated with low blood pressure. Epinephrine may be added if symptoms are severe.

Management of Tachycardia
In light of the proarrhythmic potential of most antiarrhythmic agents, the Guidelines 2000 attempts to limit exposure to them and makes the following general recommendations:

• A specific rhythm diagnosis should occur before implementing therapy.
• Determine if the patient is "stable or unstable;" if the patient is experiencing symptoms, prepare for immediate cardioversion.
• Do not overuse adenosine to distinguish between a wide-complex tachycardia and a presumed stable ventricular tachycardia (SVT) with aberrancy.
• Identify patients with diminished cardiac function (ejection fraction < 40 percent or signs of congestive heart failure) and treat them cautiously with antiarrhythmic agents.
• Never use more than one antiarrhythmic agent unless absolutely necessary. If the selected antiarrhythmic agent fails, institute electrical cardioversion.

  Atrial Fibrillation and Atrial Flutter
  Decision points, which are key for therapy of atrial fibrillation and atrial flutter, include the status of heart function, the length of the arrhythmia, consideration of Wolff-Parkinson-White syndrome, and whether the goal is to control rate or convert rhythm.

  • In a patient with preserved heart function, the following agents can be used to control the rate: beta-adrenergic blockers (Class I), calcium channel blockers (Class I), and digitalis (Class IIb).
  • The recommended agents for management of patients who also have congestive heart failure are amiodarone (Class IIb), digitalis (Class IIb), and diltiazem (Class IIb).
  • When atrial fibrillation or atrial flutter is present for over 48 hours, the patient should receive anticoagulation for three weeks before and four weeks after conversion.
  • If atrial fibrillation or atrial flutter is present for less than three weeks and the patient has normal heart function, then one of several antiarrhythmic agents can be used: amiodarone (Class IIa), ibutilide (Class IIa), flecainide (Class IIa), or propafenone (Class IIa).
  • If the patient has impaired heart function, then direct current cardioversion or amiodarone (Class IIb) is recommended.

  Paroxysmal Supraventricular Tachycardia (PSVT) Management
  If there are no contraindications, vagal stimulation or adenosine should be used to initially terminate PSVT.

  • If the patient has preserved left ventricle (LV) function, then treatment could include an AV nodal blocking agent such as a calcium channel blocker (verapamil or diltiazem, Class I), beta-adrenergic blocker (Class I), or digoxin (Class IIb).
  • If the AV nodal blocking agent is ineffective, then electrical cardioversion should be considered.
  • If the patient fails the AV nodal blocking agent or electrical cardioversion, and the PSVT persists or recurs, then an antiarrhythmic agent may be started: amiodarone (Class IIa), flecainide (Class IIa), procainamide (Class IIa), propafenone (Class IIa), or sotalol (Class IIa).

  If LV function is impaired, the therapeutic options are limited because numerous agents should be avoided. In this case, digoxin (Class IIb), amiodarone (Class IIb), or diltiazem (Class IIb) should be considered, whereas cardioversion should be avoided.

  SVT Management
  The primary decision point for this algorithm is the determination as to whether the patient has monomorphic VT or polymorphic VT. Additionally, left ventricular status is determined, and for polymorphic VT, the QT baseline interval is established.

  • For stable monomorphic VT, treatment with IV procainamide, IV amiodarone, or IV beta-adrenergic blockers is recommended. This is a shift from previous recommendations where lidocaine was recommended, followed by procainamide and bretylium.
  • If the patient has LV impairment, amiodarone or lidocaine should be considered, followed by synchronized cardioversion.

  Polymorphic VT has varying QRS morphology and is often associated with ischemic heart events, electrolyte abnormalities, or toxic conditions. Torsades de pointes is an example of a polymorphic VT, and like other tachycardias, it frequently terminates, but will recur and is often unstable. An initial assessment of the cause of the SVT should be completed. Medications known to prolong the QT interval should be discontinued, and electrolyte imbalances should be corrected. Though not rigorously evaluated in randomized clinical trials, several options for prolonged baseline QT intervals (suggestive of torsades) exist:

  • IV magnesium (Class Indeterminate) for torsades; other polymorphic VT will not respond.
  • Temporary atrial or ventricular pacing, "overdrive pacing" (Class Indeterminate).
  • If no contraindications exist, isoproterenol (Class Indeterminate and not routinely available due to international shortages) can be administered to accelerate heart rate while temporary pacing is initiated.
  • Beta-adrenergic blockers may be used as adjunct therapy to pacing.
  • Lidocaine (Class Indeterminate) may be used.

Treatment to Optimize Cardiac Output and Blood Pressure
As epinephrine and vasopressin have been previously discussed, the following brief section describes several changes in the 2000 Guidelines for patients in the post-arrest period.

• Dopamine is still recommended for use during resuscitation efforts, particularly for patients with hypotension secondary to symptomatic bradycardia or after ROSC. Doses of 5 to 20 mcg/kg/min are recommended.
• Recent studies have reported that low-dose (2 to 4 mcg/kg/min) dopamine's increase in urine output does not correlate with an improvement in renal glomerular filtration rate; therefore, dopamine has been removed as a recommended modality in patients who present with acute oliguric renal failure.
• Milrinone is a newly added inotropic agent within the 2000 Guidelines. It acts similarly to amrinone, as a phosphodiesterase III inhibitor, and possesses inotropic as well as vasodilatory properties. It is used in severe heart failure or cardiogenic shock that has not been responsive to standard therapy.

Summary

The International Guidelines 2000 are comprehensive and well researched. They represent the first opportunity to develop standards of practice which are evidence-based, and they begin to remove older, established therapies which have become standards of care without clear evidence that there is a patient benefit. The intention of this article is to provide a brief synopsis of the updated guidelines as well as information about recent additions to and deletions from the emergency drug trays provided throughout UIHC. If additional information is warranted, please contact the Drug Information Center at 6-2600.

Amiodarone Practice Pearls The recommended dose of amiodarone is 300 mg IV push. Amiodarone adheres to plastic surfaces, so it cannot be made in IV bags; use glass. If an IV infusion of amiodarone is needed, call Pharmacy as soon as possible so it can be prepared in glass. Amiodarone is available as 150 mg in 3 ml glass ampules; the contents of two ampules should be drawn up in a plastic syringe just prior to administration. Amiodarone MUST be diluted with 20 ml of dextrose 5% in water immediately prior to administration because it can cause severe thrombophlebitis when given in a peripheral vein. Amiodarone is compatible with dextrose or normal saline, and the 300 mg bolus does not require a central line. Defibrillation should be continued during preparation of the drug. The ARREST study averaged five shocks prior to amiodarone administration and four following administration. If arrhythmia recurs, a second dose of 150 mg may be given (maximum 2.2 grams over 24 hours). If amiodarone is administered as a maintenance dose, it is incompatible with plastic, as well as several other cardiovascular drugs and will require a dedicated line. Three ampules of amiodarone (150 mg/3 ml ampule) have been added to each emergency drug tray at UIHC.

Vasopressin Practice Pearls Vasopressin is recommended as a single, one-time dose of 40 units IV. Vasopressin has a longer half-life (10 to 20 minutes) compared to epinephrine, and therefore, requires less frequent administration than epinephrine. Due to the lack of data or experience, a second dose of vasopressin is considered Class Indeterminate. Although there is little evidence to support what to do if a patient does not respond to vasopressin, the ACLS experts agree that reinstituting epinephrine 10-20 minutes after vasopressin would appear appropriate. Vasopressin is available in 20 units/ml ampules at a UIHC. Two ampules of vasopressin have been added to each emergency drug tray at UIHC.

Additions to /Deletions from Emergency Drug Tray (Effective February 5, 2001)

Items added to Emergency Drug Tray Amiodarone injection 150 mg/3ml ampule x 3 ampules Vasopressin injection 20 units/ml x 2 vials Adenosine injection 6 mg vials x 5 vials Esmolol injection 10 ml/ml, 10 ml vials x 2 vials

Items removed from Emergency Drug Tray Propranolol injection 1mg/ml, 1 ml ampule Isoproterenol injection 1:5000 injection (discontinued by manufacturer) Bretylium injection 50mg/ml, 10 ml vials (discontinued by manufacturer) Epinephrine injection with cardiac needle 1mg/10 ml (1:10,000) Edrophonium injection (Tensilon) 10 mg/1 ml

Emergency Drug Tray Contents Map.

References:

1. Circulation 2000; 102:I1-I370.
2. JAMA 1974; 227:833-68.
3. JAMA 1980; 244:453-509.
4. JAMA 1992; 268:2212-302.
5. JAMA 1986; 255:2905-89.
6. N Engl J Med 1999; 341:871-8.
7. Ann Intern Med 1996; 124:1061-4.
8. Lancet 1997; 1997:535-7.

Table 1: Classification of Recommendations
CLASS	LEVEL OF EVIDENCE	COMMENTS
I Definitely recommended	Excellent	Interventions are always acceptable, proven safe, and definitely useful.
IIa Acceptable and useful	Good to very good	Interventions are acceptable, safe, and useful. Intervention of choice. Standard of care.
IIb Acceptable and useful	Fair to good	Interventions are acceptable, safe, and useful. Optional or alternative interventions. Within the standard of care.
Indeterminate Promising, evidence lacking, immature	xx	Interventions can still be used, but the quality and quantity of research falls short of supporting a final class decision.
III May be harmful; no benefit documented	Unacceptable	Intervention should not be used because evidence of benefit is lacking or studies suggest or confirm harm.

Table 2. Recommendations for the Use of Antiarrhythmics (Guidelines 2000)
ANTIARRHYTHMIC	CLASSIFICATION	COMMENTS
Amiodarone	IIb	ARREST study showed significant increase in live admissions as compared to placebo; for VF/pulseless VT.
Amiodarone	IIa	In stable monomorphic and polymorphic ventricular tachycardia.
Bretylium	IIb	Dropped from ventricular fibrillation treatment algorithm (VF/pulseless VT algorithm) due to inability to obtain raw materials to produce it.
Lidocaine	Indeterminate	Lack of studies in humans demonstrating its effectiveness for shock-resistant VF. Previous studies revealed no significant increase in survival.
Magnesium	IIb	Only indicated when a patient has hypomagnesemia or the patient has torsades de pointes and hypomagnesemia. Routine use in patients post MI is no longer recommended.
Procainamide	IIb	Indicated for intermittent or recurrent VF/VT; however, requires long infusion time, and there is a lack of clinical studies or reliable retrospective studies to support its use during cardiac arrest.

Portions of the manuscript were adapted from previous work done by Dr. Karen E. Koch, Pharm.D., Director of Clinical Research, North Mississippi Health Services, in the Pharmacotherapy Bulletin for Novation Supply Company, January, 2001.

DRUGS ADDED TO STOCK

EPTIFIBATIDE
Injection: 20 mg/10 ml, 75 mg/100 ml, 200 mg/100 ml
Eptifibatide (Integrilin® - COR) is indicated for the treatment of patients with acute coronary syndrome (unstable angina or non-Q-wave MI) who are to be managed medically or those who are undergoing percutaneous coronary interventions. It is also indicated for use during percutaneous coronary intervention in patients not presenting with acute coronary syndrome.

Note: The prescribing of eptifibatide is restricted to Cardiology Attending Staff Physicians and Fellows.

LEVOCARNITINE
Injection: 1 gm
Levocarnitine (Carnitor® - Sigma-Tau) is indicated for the acute and chronic treatment of patients with an inborn error of metabolism which results in secondary carnitine deficiency and for the prevention and treatment of carnitine deficiency in patients with end-stage renal disease who are undergoing dialysis. IV therapy is required during a metabolic crisis.

NATEGLINIDE
Tablets: 60 mg, 120 mg
Nateglinide (Starlix® - Novartis) is an oral antidiabetic agent which is indicated as monotherapy in patients with Type 2 diabetes whose hyperglycemia cannot be adequately controlled with diet and exercise and who have not been chronically treated with other antidiabetic agents. It is also indicated for use with metformin for patients who are not adequately controlled with metformin alone.

PEGINTERFERON ALFA-2B
Injection: 100 mcg, 160 mcg, 240 mcg, and 300 mcg
Peginterferon alfa-2b (PEG-Intron® - Schering) is indicated as monotherapy for the treatment of chronic hepatitis C in adult patients not previously treated with interferon alpha who have compensated liver disease. It is dosed once weekly, while regular interferon alfa-2b is dosed three times weekly.

TACROLIMUS
Ointment: 0.03%, 0.1%
Tacrolimus (Protopic® - Fujisawa) is indicated for the short-term or intermittent long-term treatment of moderate to sever atopic dermatitis in patients who are refractory to, or intolerant of, or in whom conventional (e.g., corticosteroids, phototherapy) treatments are inadvisable.

ZIPRASIDONE
Capsules: 30 mg, 40 mg, 60 mg, and 80 mg
Ziprasidone (Geodon® - Pfizer) is an atypical antipsychotic agent that is indicated for the treatment of schizophrenia.

Note: Clinical trials indicate that QTc prolongation may occur during ziprasidone therapy. Because of this risk, ziprasidone should not be used with other drugs that prolong the QTc interval (e.g., quinidine, dofetilide, pimozide, sotalol, moxifloxacin). The use of ziprasidone is also contraindicated in patients with a known history of QTc prolongation, recent acute MI, or with uncompensated heart failure. Ziprasidone should be used with caution in patients who are at risk for significant electrolyte disturbances (e.g., introduction of diuretic therapy). The initial prescription order for ziprasidone is restricted to prescribing by Psychiatry and Neurology staff.

ADDITIONAL ACTIONS

BECLOMETHASONE DIPROPIONATE ORAL INHALER
The QVAR® brand of beclomethasone dipropionate oral inhaler was added to stock. These inhalers do not contain chlorofluorocarbons (CFC) as propellants.

BUSULFAN INJECTION
A 60 mg/10 ml injection (Busulfex®) was added to stock.

FLUTICASONE WITH SALMETEROL ORAL INHALER
This combination product (Advair®) has been added to stock.

FOLLITROPIN BETA INJECTION
The Follistim® brand has been added to stock.

METHYLPHENIDATE SUSTAINED-RELEASE TABLET
A 54 mg strength (Concerta®) has been added to stock.

PANCRELIPASE CAPSULE
This product with lipase 12,000 unit, protease 39,000 unit and amylase 39,000 unit strength (Ultrase MT-12®) has been added to stock.

DRUGS DELETED FROM STOCK

GLYCERIN (OPHTHALGAN®) OPHTHALMIC SOLUTION
Discontinued by the manufacturer.

RAPACURONIUM (RAPLON®) INJECTION
Withdrawn from the market due to adverse effects. Succinylcholine and other neuromuscular blocking agents are available.

THEOPHYLLINE 300 mg SUSTAINED-RELEASE CAPSULES (SLO-BID® GYROCAP)
Discontinued by the manufacturer. Other strengths are available.

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