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Prophylactic lidocaine in suspected acute myocardial infarction
CONCEPTS, COMPONENTS, AND CONFIGURATIONS
Prophylactic Lidocaine in Suspected Acute Myocardial Infarction Steven L. Goodman, MD* Joel M. Geiderman, MD* Ira J. Bernstein, MD, FACCt Evanston, Illinois
The incidence of serious ventricular arrhythmias following acute myocardial infarction is highest during the first few hours after injury, and thereafter declines. Several investigations into the prophylactic use of lidocaine to prevent the development of arrhythmias have shown that lidocaine, given in therapeutic doses, is effective in preventing ventricular fibrillation and in reducing early mortality. Lidocaine was found to be effective when given either by the intravenous or by the intramuscular routes. The recommended dosage is 100 mg given as an intravenous bolus followed by 2 to 4 mg/min as an infusion, which should be given by infusion pump. Another recommendation is to use two 100 mg boluses 20 minutes apart, along with the same infusion. We recommend that lidocaine be started as soon as possible in all patients suspected of having suffered an acute myocardial infarction. Goodman SL, Geiderman JM, Bernstein IJ: Prophylactic lidocaine in suspected acute myocardial infarction. JACEP 8:221224, June, 1979. /idocaine, myocardial infarction; cardiac arrest
INTRODUCTION The use of prophylactic lidocaine to prevent v e n t r i c u l a r a r r h y t h m i a s in pat i e n t s w i t h suspected m y o c a r d i a l infarction r e m a i n s controversial. This is imp o r t a n t to the e m e r g e n c y p h y s i c i a n who frequently performs the i n i t i a l evaluation and t r e a t m e n t of the p a t i e n t with suspected acute m y o c a r d i a l infarction. It is d u r i n g t h e c r i t i c a l p e r i o d of the i n i t i a l e v a l u a t i o n t h a t v e n t r i c u l a r arr h y t h m i a s are most likely to occur. 1 It is i m p o r t a n t for the e m e r g e n c y physician to be f a m i l i a r with lidocaine therapy, including pharmacology, risks and complications, a r g u m e n t s favoring its prophylactic use, and proposed m e t h o d of administration. PHARMACOLOGY
Lidocaine is a synthetic local anesthetic a g e n t first employed as an antiarr h y t h m i c medication in 1950 by Southworth 'et al. 2 S u b s e q u e n t studies have e s t a b l i s h e d lidocaine's effectiveness in c o m b a t t i n g v e n t r i c u l a r a r r h y t h m i a s . 3-6 A n i n t r a v e n o u s bolus of lidocaine is effective w i t h i n 30 seconds. W i t h i n 20 minFrom the Division of Emergency Medicine, Department of Surgery,* and the Department of Medicine,I- Evanston Hospital, Evanston, Illinois, and Northwestern University Medical School, Chicago, Illinois. Address for reprints: Joel M. Geiderman, MD, EvanstonHospital, Departmentof Surgery, Division of Emergency Medicine, 2650 Ridge Avenue, Evanston, Illinois 60201. 8:6 (June) 1979
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utes, h a l f of t h a t dose is cleared from the circulation, p r i m a r i l y by hepatic metabolism. 7 P l a s m a clearance is reduced in i n s t a n c e s of severe h e a r t f a i l u r e and/or liver disease, s Thus, p a t i e n t s in such clinical s i t u a t i o n s require a reduced dosage to avoid toxicity2 The m i n o r side effects of lidocaine a r e well known, and include n u m b n e s s , t i n g l i n g , and sleepiness. Serious toxic effects include c e n t r a l nervous system stimulation resulting in generalized convulsions. Profound v a s c u l a r collapse, secondary to h y p e r s e n s i t i v i t y , c a n also O c c u r . 10 C e r t a i n p r o p e r t i e s favor lidocaine's usage as a first line drug in the t r e a t m e n t of v e n t r i c u l a r a r r h y t h m i a in the face of acute myocardial infarction. L i d o c a i n e h a s little effect on myocardial contractility or peripheral v a s c u l a r resistance, and is not l i k e l y to contribute to the development of shock, s Because less t h a n 10% of the d r u g is e x c r e t e d b y t h e k i d n e y s , o l i g u r i a does not require a d j u s t m e n t of dosage, s A t t h e r a p e u t i c p l a s m a concentrations, lidocaine has only a m i n o r effect on the n o r m a l AV conduction system, s PREMONITORY ARRHYTHMIAS
The development of the coronary care u n i t d u r i n g the 1960s also saw the e s t a b l i s h m e n t of lidocaine as a n i m p o r t a n t a g e n t in controlling lifet h r e a t e n i n g a r r h y t h m i a s . In 1967, its use w a s proposed for the t r e a t ment of less serious ventricular r h y t h m disturbances, thought to be p r e m o n i t o r y to l i f e - t h r e a t e n i n g arr h y t h m i a s 2 ~ Lidocaine was recomm e n d e d ~ p r o p h y l a c t i c a l l y " for 1) premature ventricular contractions (PVCs) a t a frequency g r e a t e r t h a n 5/min; 2) ~R on T" phenomenon; 3) bigeminy; 4) multifocal PVCs, and 5) consecutive PVCs in runs of two in a row or more. More recently, investigators ~2-'4 have advocated the a d m i n i s t r a t i o n of l i d o c a i n e to p a t i e n t s who a r e suspected of h a v i n g s u s t a i n e d an acute m y o c a r d i a l infarction. W y m a n a n d H a m m e r s m i t h ~2 tested the hypothesis t h a t lidocaine would prevent vent r i c u l a r fibrillation and e a r l y d e a t h i f g i v e n prior to t h e occurrence of premonitory arrhythmias. They found t h a t w h e n a t h e r a p e u t i c dose of l i d o c a i n e was g i v e n to p a t i e n t s s u s t a i n i n g an acute m y o c a r d i a l infarction, it was h i g h l y effective in p r e v e n t i n g p r i m a r y v e n t r i c u l a r fibrillation. W i t h t h e r e g i m e n employed (which included the a d m i n i s t r a t i o n
INTRAVENOUS PROPHYLACTIC LIDOCAINE
significant difference with p < 0.002. Of t h e nine p a t i e n t s in t h e second group who e x p e r i e n c e d ventricular fibrillation, four did not have ~'warn. ing a r r h y t h m i a s " before the onset of t h e f i b r i l l a t i o n . P r e m o n i t o r y ar. r h y t h m i a s were registered in 59% of the p a t i e n t s in the control group who did not have v e n t r i c u l a r fibrillation. A l t h o u g h e i g h t of nine p a t i e n t s with p r i m a r y v e n t r i c u l a r fibrillation were resuscitated, t h e i r long-term surviv. al rate is not known. A recent study is addressed itself, in part, to t h e prognosis of cardiac a r r e s t complicating acute myocardial infarction. In myocardial infarction, w h i l e c a r d i a c a r r e s t occurred more commonly in patients who presented w i t h signs of h e a r t failure or previous h i s t o r y of myocardial infarction, every clinically .significant subgroup d i d e x p e r i e n c e c a r d i a c a r r e s t . Of g r e a t e r significance is t h a t cardiac a r r e s t w a s h i g h l y c o r r e l a t e d with d e a t h d u r i n g and after the hospital phase of acute myocardial infarction. In groups m a t c h e d according to the K i l l i p c l a s s i f i c a t i o n of h e a r t failure, is f i v e - y e a r s u r v i v a l was unif o r m l y lower a m o n g p a t i e n t s who e x p e r i e n c e d c a r d i a c a r r e s t during ~ hospitalization. If the cardiac arrest is the cause of this increased mortality, r a t h e r t h a n a m a r k e r of patients a t an increased risk of death, then its p r e v e n t i o n a s s u m e s g r e a t e r importance.
Rationale
Method of Administration
Because of the high prevalence of v e n t r i c u l a r a r r h y t h m i a s d u r i n g the first hour, and the lack of reliable premonitory electrical abnorm a l i t i e s , some 17 felt t h a t lidocaine should be given in every case of suspected m y o c a r d i a l infarction. Lie et a117 c o n d u c t e d a d o u b l e - b l i n d r a n domized study of 212 consecutive patients, u n d e r 70 y e a r s of age, admitted to the hospital w i t h i n six hours of onset of s y m p t o m s of acute myocard i a l i n f a r c t i o n . The p a t i e n t s w e r e a d m i t t e d to the study on the basis of a t y p i c a l h i s t o r y of chest p a i n and suspicious e l e c t r o c a r d i o g r a m (ECG) c h a n g e s . Two g r o u p s w e r e e s t a b lished c o m p a r a b l e in age, sex, site a n d size of i n f a r c t i o n . The r e s u l t s show t h a t in 107 p a t i e n t s who received a n i n t r a v e n o u s bolus of 100 m g lidocaine followed by a continuo u s i n f u s i o n a t 3 m g / m i n for 48 hours, none experienced v e n t r i c u l a r fibrillation. Of the r e m a i n i n g 105 pat i e n t s who received 5% glucose and water, nine experienced v e n t r i c u l a r f i b r i l l a t i o n . T h i s is a s t a t i s t i c a l l y
Prophylactic lidocaine started in the e m e r g e n c y d e p a r t m e n t should be given i n t r a v e n o u s l y . A therapeutic level of lidocaine (2 to 5 ~g/ml) s has been shown to be effectively achieved by a d m i n i s t e r i n g a loading dose of 100 rag, followed by an infusion at a rate of 2 to 4 m g / m i n 2 More recently, p h a r m a c o k i n e t i c s t u d i e s 19 have d e m o n s t r a t e d t h a t a m o r e steady p l a s m a level can be achieved by adm i n i s t e r i n g two bolus-doses of 100 rag, s e p a r a t e d by 20 m i n u t e s , along w i t h the s a m e infusion. This obviates the need to a d j u s t - t h e drip upward when the f i r s t bolus dose is cleared, a m a n e u v e r t h a t m i g h t result in toxicity once a s t e a d y state is achieved. To p r e v e n t t h e o c c u r r e n c e of lidocaine toxicity, an infusion pump may be used to control the rate.
of procainamide), the prevalence r a t e of p r i m a r y v e n t r i c u l a r f i b r i l l a t i o n dropped from 6.5% before a d m i n i s t r a t i o n of the protocol to 0.3% afterwards. An incidental finding was t h a t a significant n u m b e r of p a t i e n t s who experienced p r i m a r y v e n t r i c u l a r f i b r i l l a t i o n h a d no p r e m o n i t o r y r h y t h m disturbance. Seven out of 12 patients with primary ventricular f i b r i l l a t i o n h a d no such w a r n i n g . T h e s e f i n d i n g s , a n d others,~3,14 s u g g e s t e d t h a t a r r h y t h m i a s previo u s l y c o n s i d e r e d p r e m o n i t o r y were not a d e q u a t e c r i t e r i a for i n i t i a t i n g lidocaine t h e r a p y . A n t i a r r h y t h m i c t h e r a p y should be i n i t i a t e d w h e n l i f e - t h r e a t e n i n g ventricular arrhythmias are most l i k e l y to occur. The incidence of serious v e n t r i c u l a r a r r h y t h m i a s following an acute m y o c a r d i a l infarction is h i g h e s t d u r i n g the first few h o u r s after the coronary event and declines r a p i d l y t h e r e a f t e r . ' In excess of 40% of a l l d e a t h s from c o r o n a r y a t t a c k occur w i t h i n one hour of the onset of symptoms. 1 Among middle-aged men, 63% of d e a t h s following acute myocardial infarction occurred w i t h i n t h e first hour. ~5 V e n t r i c u l a r a r r h y t h m i a l e a d i n g to v e n t r i c u l a r f i b r i l l a t i o n is c o n s i d e r e d t h e m o s t common cause of e a r l y postmyocardial infarction death. TM
INTRAMUSCULAR PROPHYLACTIC LIDOCAINE • Rationale
Since p r o p h y l a c t i c a d m i n i s t r a tion of lidocaine by the intravenous !
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route has been shown 16 to reduce the inhospital incidence of v e n t r i c u l a r arrhythmia in acute myocardial infarction, it has been suggested 2°-22 that prophylaxis m i g h t also be effective i n t h e p r e h o s p i t a l p h a s e . A single i n t r a v e n o u s bolus of lidocaine maintains effective levels for only 10 to 20 m i n u t e s , 2~ and the use of a n infusion would be impractical for the p r e h o s p i t a l use p e r i o d . F o r t h i s reason, several studies have evaluated the use of i n t r a m u s c u l a r lidocaine. V a l e n t i n e et al 2° i n A u s t r a l i a conducted a d o u b l e - b l i n d s t u d y to test t h e h y p o t h e s i s t h a t a n intramuscular injection of 300 mg of lidocaine as a 10% solution into the deltoid muscle would p r e v e n t death for two hours after injection d u r i n g the p r e h o s p i t a l p h a s e of a c u t e myocardial infarction. A total of 249 patients w i t h either definite or possible infarction satisfied the authors' c r i t e r i a for e n t r y t o t h e s t u d y . Excluded were p a t i e n t s older t h a n 70 years, those with a h e a r t ~ralte less than 55/min, patients with a systolic blood pressure of less t h a n 90 m m Hg, and those with symptoms more than 12 hours in duration. Each patient received lidocaine or placebo injected i n t r a m u s c u l a r l y . D u r i n g the first two hours following injection, there were three deaths in 156 patients treated with lidocaine, while 8 of 113 placebo-treated patients died (p < 0.03). One s t u d y 21 of i n t r a m u s c u l a r lidocaine has shown a definite correlation b e t w e e n clinical r e s u l t s a n d the a c h i e v e m e n t of t h e r a p e u t i c lidocaine levels. Two h u n d r e d mg of lidocaine was given by i n t r a m u s c u lar injection to control v e n t r i c u l a r premature beats in 40 patients continuously monitored in a n i n t e n s i v e care u n i t . T h i r t y of 40 p a t i e n t s showed a good clinical response to the drug, with complete abolition of ventricular p r e m a t u r e beats. The majority demonstrated this response between 15 and 30 m i n u t e s following intramuscular injection. The clinical response correlated well with s e r u m COncentration of t h e d r u g , w h i c h achieved t h e r a p e u t i c levels at 15 minutes and peak levels at 30 m i n i utes in the majority of p a t i e n t s . . Liem et al ~2 recently presented an abstract in which they reported: a double blind study performed on 20 patients admitted with a diagnosis of acute m y o c a r d i a l i n f a r c t i o n a n d given 300 m g of lidocaine i n t r a m u s cularly. W h e n peripheral hypoperfuSlon was p r e s e n t on admission (de-
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fined as a blood pressure less t h a n 100 m m Hg a n d a cold, c l a m m y skin), a significantly lower level of p l a s m a lidocaine was achieved. They found this in five of six patients who developed v e n t r i c u l a r fibrillation. The a u t h o r s concluded t h a t the ineff e c t i v e n e s s of i n t r a m u s c u l a r lidoc a i n e i n j e c t i o n in p r e v e n t i n g vent r i c u l a r f i b r i l l a t i o n m a y be due to p e r i p h e r a l hypoperfusion t h a t prevents adequate plasma lidocaine levels from being reached.
Method of Administration Scott et a123 have suggested t h a t in order to obtain a rapid therapeutic blood level, an i n t r a v e n o u s bolus of 50 mg lidocaine be given prior to giving the intramuscular injection. They have shown t h a t this form of t h e r a p y will produce a m e a n plasma level of 2 pg/ml within two minutes. The p l a s m a level after 15 m i n u t e s was s i m i l a r to the level o b t a i n e d with i n t r a m u s c u l a r injection alone. Z e n e r et a116 have shown t h a t the rapid development of high therapeutic I~lood levels could be obtained by u s i n g higher doses of i n t r a m u s c u l a r lidocaine. They conducted a study in w h i c h 24 p a t i e n t s w i t h s u s p e c t e d a c u t e m y o c a r d i a l i n f a r c t i o n were given either a n intermediate dose, 4 mg/kg, or high dose, 6 mg/kg, of int r a m u s c u l a r lidocaine. A d m i n i s t r a tion of high dose lidocaine (average dose 450 mg) into the deltoid muscle provided both rapid development of h i g h t h e r a p e u t i c blood levels a n d persistence of those levels for over two hours.
SPECIAL CONSIDERATIONS P a t i e n t s with acute myocardial infarction and severe myocardial disease have been shown to absorb int r a m u s c u l a r lidocaine in a reliable m a n n e r . 21 The r e g i m e n is not reco m m e n d e d in the presence of shock because absorption may be erratic. 22 The i n t r a v e n o u s dose of l i d o c a i n e should be adjusted downward in the p r e s e n c e of s e v e r e h e a r t f a i l u r e and/or liver disease. A d v e r s e reactions to l i d o c a i n e a p p e a r to increase w i t h a d v a n c i n g age. In one study ~7 t h a t used lidocaine in a dosage of 3 mg/min, preceded by a n i n t r a v e n o u s bolus of 100 mg, there were minor side effects in 15% of the patients. These occurred i n 12 of 52 patients 60 years of age and older, while only four of 55 patients u n d e r age 60 experienced side effects. P r i m a r y ventricular fibrillation developed less frequently in pat i e n t s 60 years and older (one out of
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141 p a t i e n t s 69 years and older in one study). 17 These findings suggest t h a t t h e b e n e f i t s of p r o p h y l a c t i c lidocaine in the group over 69 years of age m a y not outweigh the risks of side effects. However, no physiologic basis exists to explain this observation, and it therefore r e m a i n s to be confirmed by a well controlled investigation. 24 C u r r e n t recommendations for p a t i e n t s 70 years or older call for a r e d u c t i o n of the l o a d i n g dose by 50% a n d for a n i n f u s i o n of 2 mg/ min. 24 Local infection and/or tissue necrosis at the site of injection of int r a m u s c u l a r l i d o c a i n e are not reported problems. I n t r a m u s c u l a r inj e c t i o n of lidocaine m a y r a i s e the serum creatine phosphokinase isoenzyme (CPK) level and may make enzyme confirmation of acute myocardial infarction difficult unless CPK isoenzymes are available. There is some controversy as to t h e a d v i s a b i l i t y of a d m i n i s t e r i n g lidocaine in the presence of bradyarr h y t h m i a . There is both experimental and c l i n i c a l evidence 2s t h a t slow h e a r t rates may be associated with a n increased frequency of v e n t r i c u l a r ectopic beats and a low fibrillation threshold. While most studies17, 2° to date have excluded patients with a h e a r t rate less t h a n 56 b e a t s / m i n , other investigators25 feel t h a t bradycardia, per se, is not a contraindication to the use of lidocaine if acute m y o c a r d i a l i n f a r c t i o n is suspected. They advise that these patients be g i v e n atropine in c o n j u n c t i o n with a d m i n i s t r a t i o n of lidocaine. In these studies, as the rate increased, vent r i c u l a r p r e m a t u r e beats tended to disappear, and the incidence of vent r i c u l a r f i b r i l l a t i o n decreased. No r e c o g n i z a b l e d i f f i c u l t i e s were encountered with such a drug regimen. In clinical usage, the occurrence of h y p o t e n s i o n as a r e s u l t of lidocaine t h e r a p y is rare. s There have been isolated reports s of lidocainei n d u c e d a r r h y t h m i a s i n c l u d i n g increased AV conduction abnormality, 1:1 conduction of a t r i a l flutter, as well as sinus arrest and AV block.
CONCLUSION P a t i e n t s seen in the emergency department with suspected acute myocardial infarction are at a risk of developing ventricular a r r h y t h m i a s . No r e l i a b l e p r e m o n i t o r y r h y t h m s exist t h a t predict all s u b s e q u e n t cases of ventricular fibrillation. Patients successfully resuscitated from v e n t r i c u l a r fibrillation m a y have decreased long-term survival as a re-
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sult of t h e episode. Thus, we advocate i n i t i a t i n g prophylactic a n t i a r r h y t h m i c t h e r a p y as soon as possible in p a t i e n t s w i t h s u s p e c t e d a c u t e myocardial infarction. L i d o c a i n e is w e l l s u i t e d as a p r o p h y l a c t i c agent and has been s h o w n to be effective. T h e recomm e n d e d dosages 9 are 100 m g g iv e n as an i n t r a v e n o u s bolus followed by 2 to 4 m g / m i n as an infusion, w h i c h should be g i v en by infusion pump. A n o t h e r r e c o m m e n d a t i o n 15,24 is to use two 100 mg boluses 20 m i n u t e s apart, along with the same infusion. A l t h o u g h lidocaine has not yet r e c e i v e d F e d e r a l Drug A d m i n i s t r a t i o n a p p r o v a l for p r o p h y l a c t i c int r a m u s c u l a r a d m i n i s t r a t i o n , studies 2° h a v e s h o wn t h a t t h e r a p e u t i c blood levels can be achieved by inject i o n into t h e deltoid muscle. Such a d m i n i s t r a t i o n is well suited for pat i e n t s strongly suspected of suffering an acute myocardial infarction first seen outside of the hospital setting. P a t i e n t s t h e n a r e at h i g h e s t r i s k of d e v e l o p i n g l i f e - t h r e a t e n i n g arr h y t h m i a s an d would b e n e f i t most from prophylaxis. It has been shown t h a t a single i n t r a m u s c u l a r dose m a y provide t h e r a p e u t i c blood levels for up to two hours after injection. Major toxicity resulting from overdosage includes central nervous s y s t e m s t i m u l a t i o n p r o g r e s s i n g to convulsions. H y p e r s e n s i t i v i t y reactions m a y also occur. ~ Minor toxic effects occur more frequently in older patients. Therefore, the loading dose and infusion rate must be reduced for p a t i e n t s 70 years or older. ~4 Dosage should also be adjusted in p a t i e n t s with severe congestive h e a r t f a il u r e or hepatic disease.
2. Southworth JL, McKusick JA, Pierce FC, et al: Ventricular-fibrillation precipitated by cardiac catheterization. J A M A 143:717, 1950.
15. Bainton CR, Peterson DR: Death~ from coronary heart disease in per~ fifty years of age and younger. N En~/~ Med 268:569-575, 1963. ~v
3. Weiss WA: Intravenous use of lidocaine for ventricular arrhythmias. Anesth A n a l g 39:369, 1960.
16. Zener JC, Kerber RE, Spivack AI) e~ al: Blood lidocaine levels and kinetics f~i~ lowing high dose intramuscular ad. ministration. C i r c u l a t i o n 47:984-986, 1973.
4. Lown B, Fakhro AM, Hood WB, et al: The coronary care unit: New perspectives and directions. J A M A 199:188-198, 1967. 5. Gianelly R, v o n d e r Groeben JO, Spivack AP, et al: Effect of lidocaine on ventricular arrhythmias in patients with coronary heart disease. N Eng~ J Med 277:1215-1219, 1967. 6. Chopra MP, Portal RW, Aber CP: Lignocaine therapy after acute myocardial infarction. B r Med J 1:213-216, 1969. 7. Goldfrank L, Osborn H: Lidocaine - uses and toxicity. H o s p i t a l P h y s i c i a n 14:26-32, 1978. 8. Rosen MR, Hoffman BF, Wit AL: Electrophysiology and pharmacology of cardiac arrhythmias. A m Heart J 89:526536, 1975. 9. Winkle RA, Glantz SA, Harrison DC: Pharmacologic therapy of ventricular arrhythmias. A m J Cardiol 36:629-649, 1975. 10. Harrison DC: Practical guidelines for the use of lidocaine. J A M A 233:12021204, 1975. 11. Lown B, Vassaux C, Hood WB, et aI: The coronary care unit. J A M A 199:156166, 1967.
17. Lie KI, Wellens HJ, Van Capelle l~J et al: Lidocaine in the prevention 0f primary ventricular fibrillation. N Engl d Med 291:1324-1326, 1974. 18. Conley MJ, McNeer JF, Lee KL, et al: Cardiac arrest complicating acute myocardial infarctions: Predictability and prognosis. A m J Cardiol 39:7-12, 1977. 19. Greenblatt DJ, Bolognini V, Koch. Weser J, et al: Pharmacokinetic approach to the clinical use of-lidocaine intrave. nously. J A M A 236:273-277, 1976. 20. Valentine PA, Frew JL, Mashford ML, et al: Lidocaine in the prevention of sudden death in the pre-hospital phase of acute infarction. N E n g l J M e d 291: 1327-1331, 1974. 21. Bernstein V, Bernstein M, Griffiths J, et al: Lidocaine intramuscularly in acute myocardial infarction. J A M A 219:1027, 1972. 22. Liem KL, Lie KI, Willebrands AF, et al: Mechanism of ineffectiveness of in. tramuscular lidocaine in preventing ven. tricular fibrillation. (Abstract), A m J Cardiol 41:408, 1978.
12. Wyman FG, Hammersmith L: Comprehensive treatment plan for the prevention of primary ventricular fibrillation in acute myocardial infarction. A m J Cardiol 35:661-667, 1974.
23. Scott DB, Gibson PJ, Vellani CW, et al: Plasma lidocaine levels after intravenous and intramuscular injection. Lancet 1:41, 1970. 24. Harrison DC: Should lidocaine be administered routinely to all patients after acute myocardial infarction. Circulation 58:581-583, 1978.
REFERENCES
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25. Pitt A, Lipp H, Anderson ST: Lidocaine given prophylactically to patients with acute myocardial infarction. Lancet 1:612-616, 1971.
8:6 (June) 1979
Prophylactic Lidocaine in Suspected Acute Myocardial Infarction Steven L. Goodman, MD* Joel M. Geiderman, MD* Ira J. Bernstein, MD, FACCt Evanston, Illinois
The incidence of serious ventricular arrhythmias following acute myocardial infarction is highest during the first few hours after injury, and thereafter declines. Several investigations into the prophylactic use of lidocaine to prevent the development of arrhythmias have shown that lidocaine, given in therapeutic doses, is effective in preventing ventricular fibrillation and in reducing early mortality. Lidocaine was found to be effective when given either by the intravenous or by the intramuscular routes. The recommended dosage is 100 mg given as an intravenous bolus followed by 2 to 4 mg/min as an infusion, which should be given by infusion pump. Another recommendation is to use two 100 mg boluses 20 minutes apart, along with the same infusion. We recommend that lidocaine be started as soon as possible in all patients suspected of having suffered an acute myocardial infarction. Goodman SL, Geiderman JM, Bernstein IJ: Prophylactic lidocaine in suspected acute myocardial infarction. JACEP 8:221224, June, 1979. /idocaine, myocardial infarction; cardiac arrest
INTRODUCTION The use of prophylactic lidocaine to prevent v e n t r i c u l a r a r r h y t h m i a s in pat i e n t s w i t h suspected m y o c a r d i a l infarction r e m a i n s controversial. This is imp o r t a n t to the e m e r g e n c y p h y s i c i a n who frequently performs the i n i t i a l evaluation and t r e a t m e n t of the p a t i e n t with suspected acute m y o c a r d i a l infarction. It is d u r i n g t h e c r i t i c a l p e r i o d of the i n i t i a l e v a l u a t i o n t h a t v e n t r i c u l a r arr h y t h m i a s are most likely to occur. 1 It is i m p o r t a n t for the e m e r g e n c y physician to be f a m i l i a r with lidocaine therapy, including pharmacology, risks and complications, a r g u m e n t s favoring its prophylactic use, and proposed m e t h o d of administration. PHARMACOLOGY
Lidocaine is a synthetic local anesthetic a g e n t first employed as an antiarr h y t h m i c medication in 1950 by Southworth 'et al. 2 S u b s e q u e n t studies have e s t a b l i s h e d lidocaine's effectiveness in c o m b a t t i n g v e n t r i c u l a r a r r h y t h m i a s . 3-6 A n i n t r a v e n o u s bolus of lidocaine is effective w i t h i n 30 seconds. W i t h i n 20 minFrom the Division of Emergency Medicine, Department of Surgery,* and the Department of Medicine,I- Evanston Hospital, Evanston, Illinois, and Northwestern University Medical School, Chicago, Illinois. Address for reprints: Joel M. Geiderman, MD, EvanstonHospital, Departmentof Surgery, Division of Emergency Medicine, 2650 Ridge Avenue, Evanston, Illinois 60201. 8:6 (June) 1979
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utes, h a l f of t h a t dose is cleared from the circulation, p r i m a r i l y by hepatic metabolism. 7 P l a s m a clearance is reduced in i n s t a n c e s of severe h e a r t f a i l u r e and/or liver disease, s Thus, p a t i e n t s in such clinical s i t u a t i o n s require a reduced dosage to avoid toxicity2 The m i n o r side effects of lidocaine a r e well known, and include n u m b n e s s , t i n g l i n g , and sleepiness. Serious toxic effects include c e n t r a l nervous system stimulation resulting in generalized convulsions. Profound v a s c u l a r collapse, secondary to h y p e r s e n s i t i v i t y , c a n also O c c u r . 10 C e r t a i n p r o p e r t i e s favor lidocaine's usage as a first line drug in the t r e a t m e n t of v e n t r i c u l a r a r r h y t h m i a in the face of acute myocardial infarction. L i d o c a i n e h a s little effect on myocardial contractility or peripheral v a s c u l a r resistance, and is not l i k e l y to contribute to the development of shock, s Because less t h a n 10% of the d r u g is e x c r e t e d b y t h e k i d n e y s , o l i g u r i a does not require a d j u s t m e n t of dosage, s A t t h e r a p e u t i c p l a s m a concentrations, lidocaine has only a m i n o r effect on the n o r m a l AV conduction system, s PREMONITORY ARRHYTHMIAS
The development of the coronary care u n i t d u r i n g the 1960s also saw the e s t a b l i s h m e n t of lidocaine as a n i m p o r t a n t a g e n t in controlling lifet h r e a t e n i n g a r r h y t h m i a s . In 1967, its use w a s proposed for the t r e a t ment of less serious ventricular r h y t h m disturbances, thought to be p r e m o n i t o r y to l i f e - t h r e a t e n i n g arr h y t h m i a s 2 ~ Lidocaine was recomm e n d e d ~ p r o p h y l a c t i c a l l y " for 1) premature ventricular contractions (PVCs) a t a frequency g r e a t e r t h a n 5/min; 2) ~R on T" phenomenon; 3) bigeminy; 4) multifocal PVCs, and 5) consecutive PVCs in runs of two in a row or more. More recently, investigators ~2-'4 have advocated the a d m i n i s t r a t i o n of l i d o c a i n e to p a t i e n t s who a r e suspected of h a v i n g s u s t a i n e d an acute m y o c a r d i a l infarction. W y m a n a n d H a m m e r s m i t h ~2 tested the hypothesis t h a t lidocaine would prevent vent r i c u l a r fibrillation and e a r l y d e a t h i f g i v e n prior to t h e occurrence of premonitory arrhythmias. They found t h a t w h e n a t h e r a p e u t i c dose of l i d o c a i n e was g i v e n to p a t i e n t s s u s t a i n i n g an acute m y o c a r d i a l infarction, it was h i g h l y effective in p r e v e n t i n g p r i m a r y v e n t r i c u l a r fibrillation. W i t h t h e r e g i m e n employed (which included the a d m i n i s t r a t i o n
INTRAVENOUS PROPHYLACTIC LIDOCAINE
significant difference with p < 0.002. Of t h e nine p a t i e n t s in t h e second group who e x p e r i e n c e d ventricular fibrillation, four did not have ~'warn. ing a r r h y t h m i a s " before the onset of t h e f i b r i l l a t i o n . P r e m o n i t o r y ar. r h y t h m i a s were registered in 59% of the p a t i e n t s in the control group who did not have v e n t r i c u l a r fibrillation. A l t h o u g h e i g h t of nine p a t i e n t s with p r i m a r y v e n t r i c u l a r fibrillation were resuscitated, t h e i r long-term surviv. al rate is not known. A recent study is addressed itself, in part, to t h e prognosis of cardiac a r r e s t complicating acute myocardial infarction. In myocardial infarction, w h i l e c a r d i a c a r r e s t occurred more commonly in patients who presented w i t h signs of h e a r t failure or previous h i s t o r y of myocardial infarction, every clinically .significant subgroup d i d e x p e r i e n c e c a r d i a c a r r e s t . Of g r e a t e r significance is t h a t cardiac a r r e s t w a s h i g h l y c o r r e l a t e d with d e a t h d u r i n g and after the hospital phase of acute myocardial infarction. In groups m a t c h e d according to the K i l l i p c l a s s i f i c a t i o n of h e a r t failure, is f i v e - y e a r s u r v i v a l was unif o r m l y lower a m o n g p a t i e n t s who e x p e r i e n c e d c a r d i a c a r r e s t during ~ hospitalization. If the cardiac arrest is the cause of this increased mortality, r a t h e r t h a n a m a r k e r of patients a t an increased risk of death, then its p r e v e n t i o n a s s u m e s g r e a t e r importance.
Rationale
Method of Administration
Because of the high prevalence of v e n t r i c u l a r a r r h y t h m i a s d u r i n g the first hour, and the lack of reliable premonitory electrical abnorm a l i t i e s , some 17 felt t h a t lidocaine should be given in every case of suspected m y o c a r d i a l infarction. Lie et a117 c o n d u c t e d a d o u b l e - b l i n d r a n domized study of 212 consecutive patients, u n d e r 70 y e a r s of age, admitted to the hospital w i t h i n six hours of onset of s y m p t o m s of acute myocard i a l i n f a r c t i o n . The p a t i e n t s w e r e a d m i t t e d to the study on the basis of a t y p i c a l h i s t o r y of chest p a i n and suspicious e l e c t r o c a r d i o g r a m (ECG) c h a n g e s . Two g r o u p s w e r e e s t a b lished c o m p a r a b l e in age, sex, site a n d size of i n f a r c t i o n . The r e s u l t s show t h a t in 107 p a t i e n t s who received a n i n t r a v e n o u s bolus of 100 m g lidocaine followed by a continuo u s i n f u s i o n a t 3 m g / m i n for 48 hours, none experienced v e n t r i c u l a r fibrillation. Of the r e m a i n i n g 105 pat i e n t s who received 5% glucose and water, nine experienced v e n t r i c u l a r f i b r i l l a t i o n . T h i s is a s t a t i s t i c a l l y
Prophylactic lidocaine started in the e m e r g e n c y d e p a r t m e n t should be given i n t r a v e n o u s l y . A therapeutic level of lidocaine (2 to 5 ~g/ml) s has been shown to be effectively achieved by a d m i n i s t e r i n g a loading dose of 100 rag, followed by an infusion at a rate of 2 to 4 m g / m i n 2 More recently, p h a r m a c o k i n e t i c s t u d i e s 19 have d e m o n s t r a t e d t h a t a m o r e steady p l a s m a level can be achieved by adm i n i s t e r i n g two bolus-doses of 100 rag, s e p a r a t e d by 20 m i n u t e s , along w i t h the s a m e infusion. This obviates the need to a d j u s t - t h e drip upward when the f i r s t bolus dose is cleared, a m a n e u v e r t h a t m i g h t result in toxicity once a s t e a d y state is achieved. To p r e v e n t t h e o c c u r r e n c e of lidocaine toxicity, an infusion pump may be used to control the rate.
of procainamide), the prevalence r a t e of p r i m a r y v e n t r i c u l a r f i b r i l l a t i o n dropped from 6.5% before a d m i n i s t r a t i o n of the protocol to 0.3% afterwards. An incidental finding was t h a t a significant n u m b e r of p a t i e n t s who experienced p r i m a r y v e n t r i c u l a r f i b r i l l a t i o n h a d no p r e m o n i t o r y r h y t h m disturbance. Seven out of 12 patients with primary ventricular f i b r i l l a t i o n h a d no such w a r n i n g . T h e s e f i n d i n g s , a n d others,~3,14 s u g g e s t e d t h a t a r r h y t h m i a s previo u s l y c o n s i d e r e d p r e m o n i t o r y were not a d e q u a t e c r i t e r i a for i n i t i a t i n g lidocaine t h e r a p y . A n t i a r r h y t h m i c t h e r a p y should be i n i t i a t e d w h e n l i f e - t h r e a t e n i n g ventricular arrhythmias are most l i k e l y to occur. The incidence of serious v e n t r i c u l a r a r r h y t h m i a s following an acute m y o c a r d i a l infarction is h i g h e s t d u r i n g the first few h o u r s after the coronary event and declines r a p i d l y t h e r e a f t e r . ' In excess of 40% of a l l d e a t h s from c o r o n a r y a t t a c k occur w i t h i n one hour of the onset of symptoms. 1 Among middle-aged men, 63% of d e a t h s following acute myocardial infarction occurred w i t h i n t h e first hour. ~5 V e n t r i c u l a r a r r h y t h m i a l e a d i n g to v e n t r i c u l a r f i b r i l l a t i o n is c o n s i d e r e d t h e m o s t common cause of e a r l y postmyocardial infarction death. TM
INTRAMUSCULAR PROPHYLACTIC LIDOCAINE • Rationale
Since p r o p h y l a c t i c a d m i n i s t r a tion of lidocaine by the intravenous !
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route has been shown 16 to reduce the inhospital incidence of v e n t r i c u l a r arrhythmia in acute myocardial infarction, it has been suggested 2°-22 that prophylaxis m i g h t also be effective i n t h e p r e h o s p i t a l p h a s e . A single i n t r a v e n o u s bolus of lidocaine maintains effective levels for only 10 to 20 m i n u t e s , 2~ and the use of a n infusion would be impractical for the p r e h o s p i t a l use p e r i o d . F o r t h i s reason, several studies have evaluated the use of i n t r a m u s c u l a r lidocaine. V a l e n t i n e et al 2° i n A u s t r a l i a conducted a d o u b l e - b l i n d s t u d y to test t h e h y p o t h e s i s t h a t a n intramuscular injection of 300 mg of lidocaine as a 10% solution into the deltoid muscle would p r e v e n t death for two hours after injection d u r i n g the p r e h o s p i t a l p h a s e of a c u t e myocardial infarction. A total of 249 patients w i t h either definite or possible infarction satisfied the authors' c r i t e r i a for e n t r y t o t h e s t u d y . Excluded were p a t i e n t s older t h a n 70 years, those with a h e a r t ~ralte less than 55/min, patients with a systolic blood pressure of less t h a n 90 m m Hg, and those with symptoms more than 12 hours in duration. Each patient received lidocaine or placebo injected i n t r a m u s c u l a r l y . D u r i n g the first two hours following injection, there were three deaths in 156 patients treated with lidocaine, while 8 of 113 placebo-treated patients died (p < 0.03). One s t u d y 21 of i n t r a m u s c u l a r lidocaine has shown a definite correlation b e t w e e n clinical r e s u l t s a n d the a c h i e v e m e n t of t h e r a p e u t i c lidocaine levels. Two h u n d r e d mg of lidocaine was given by i n t r a m u s c u lar injection to control v e n t r i c u l a r premature beats in 40 patients continuously monitored in a n i n t e n s i v e care u n i t . T h i r t y of 40 p a t i e n t s showed a good clinical response to the drug, with complete abolition of ventricular p r e m a t u r e beats. The majority demonstrated this response between 15 and 30 m i n u t e s following intramuscular injection. The clinical response correlated well with s e r u m COncentration of t h e d r u g , w h i c h achieved t h e r a p e u t i c levels at 15 minutes and peak levels at 30 m i n i utes in the majority of p a t i e n t s . . Liem et al ~2 recently presented an abstract in which they reported: a double blind study performed on 20 patients admitted with a diagnosis of acute m y o c a r d i a l i n f a r c t i o n a n d given 300 m g of lidocaine i n t r a m u s cularly. W h e n peripheral hypoperfuSlon was p r e s e n t on admission (de-
8;6 (June) 1979
fined as a blood pressure less t h a n 100 m m Hg a n d a cold, c l a m m y skin), a significantly lower level of p l a s m a lidocaine was achieved. They found this in five of six patients who developed v e n t r i c u l a r fibrillation. The a u t h o r s concluded t h a t the ineff e c t i v e n e s s of i n t r a m u s c u l a r lidoc a i n e i n j e c t i o n in p r e v e n t i n g vent r i c u l a r f i b r i l l a t i o n m a y be due to p e r i p h e r a l hypoperfusion t h a t prevents adequate plasma lidocaine levels from being reached.
Method of Administration Scott et a123 have suggested t h a t in order to obtain a rapid therapeutic blood level, an i n t r a v e n o u s bolus of 50 mg lidocaine be given prior to giving the intramuscular injection. They have shown t h a t this form of t h e r a p y will produce a m e a n plasma level of 2 pg/ml within two minutes. The p l a s m a level after 15 m i n u t e s was s i m i l a r to the level o b t a i n e d with i n t r a m u s c u l a r injection alone. Z e n e r et a116 have shown t h a t the rapid development of high therapeutic I~lood levels could be obtained by u s i n g higher doses of i n t r a m u s c u l a r lidocaine. They conducted a study in w h i c h 24 p a t i e n t s w i t h s u s p e c t e d a c u t e m y o c a r d i a l i n f a r c t i o n were given either a n intermediate dose, 4 mg/kg, or high dose, 6 mg/kg, of int r a m u s c u l a r lidocaine. A d m i n i s t r a tion of high dose lidocaine (average dose 450 mg) into the deltoid muscle provided both rapid development of h i g h t h e r a p e u t i c blood levels a n d persistence of those levels for over two hours.
SPECIAL CONSIDERATIONS P a t i e n t s with acute myocardial infarction and severe myocardial disease have been shown to absorb int r a m u s c u l a r lidocaine in a reliable m a n n e r . 21 The r e g i m e n is not reco m m e n d e d in the presence of shock because absorption may be erratic. 22 The i n t r a v e n o u s dose of l i d o c a i n e should be adjusted downward in the p r e s e n c e of s e v e r e h e a r t f a i l u r e and/or liver disease. A d v e r s e reactions to l i d o c a i n e a p p e a r to increase w i t h a d v a n c i n g age. In one study ~7 t h a t used lidocaine in a dosage of 3 mg/min, preceded by a n i n t r a v e n o u s bolus of 100 mg, there were minor side effects in 15% of the patients. These occurred i n 12 of 52 patients 60 years of age and older, while only four of 55 patients u n d e r age 60 experienced side effects. P r i m a r y ventricular fibrillation developed less frequently in pat i e n t s 60 years and older (one out of
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141 p a t i e n t s 69 years and older in one study). 17 These findings suggest t h a t t h e b e n e f i t s of p r o p h y l a c t i c lidocaine in the group over 69 years of age m a y not outweigh the risks of side effects. However, no physiologic basis exists to explain this observation, and it therefore r e m a i n s to be confirmed by a well controlled investigation. 24 C u r r e n t recommendations for p a t i e n t s 70 years or older call for a r e d u c t i o n of the l o a d i n g dose by 50% a n d for a n i n f u s i o n of 2 mg/ min. 24 Local infection and/or tissue necrosis at the site of injection of int r a m u s c u l a r l i d o c a i n e are not reported problems. I n t r a m u s c u l a r inj e c t i o n of lidocaine m a y r a i s e the serum creatine phosphokinase isoenzyme (CPK) level and may make enzyme confirmation of acute myocardial infarction difficult unless CPK isoenzymes are available. There is some controversy as to t h e a d v i s a b i l i t y of a d m i n i s t e r i n g lidocaine in the presence of bradyarr h y t h m i a . There is both experimental and c l i n i c a l evidence 2s t h a t slow h e a r t rates may be associated with a n increased frequency of v e n t r i c u l a r ectopic beats and a low fibrillation threshold. While most studies17, 2° to date have excluded patients with a h e a r t rate less t h a n 56 b e a t s / m i n , other investigators25 feel t h a t bradycardia, per se, is not a contraindication to the use of lidocaine if acute m y o c a r d i a l i n f a r c t i o n is suspected. They advise that these patients be g i v e n atropine in c o n j u n c t i o n with a d m i n i s t r a t i o n of lidocaine. In these studies, as the rate increased, vent r i c u l a r p r e m a t u r e beats tended to disappear, and the incidence of vent r i c u l a r f i b r i l l a t i o n decreased. No r e c o g n i z a b l e d i f f i c u l t i e s were encountered with such a drug regimen. In clinical usage, the occurrence of h y p o t e n s i o n as a r e s u l t of lidocaine t h e r a p y is rare. s There have been isolated reports s of lidocainei n d u c e d a r r h y t h m i a s i n c l u d i n g increased AV conduction abnormality, 1:1 conduction of a t r i a l flutter, as well as sinus arrest and AV block.
CONCLUSION P a t i e n t s seen in the emergency department with suspected acute myocardial infarction are at a risk of developing ventricular a r r h y t h m i a s . No r e l i a b l e p r e m o n i t o r y r h y t h m s exist t h a t predict all s u b s e q u e n t cases of ventricular fibrillation. Patients successfully resuscitated from v e n t r i c u l a r fibrillation m a y have decreased long-term survival as a re-
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sult of t h e episode. Thus, we advocate i n i t i a t i n g prophylactic a n t i a r r h y t h m i c t h e r a p y as soon as possible in p a t i e n t s w i t h s u s p e c t e d a c u t e myocardial infarction. L i d o c a i n e is w e l l s u i t e d as a p r o p h y l a c t i c agent and has been s h o w n to be effective. T h e recomm e n d e d dosages 9 are 100 m g g iv e n as an i n t r a v e n o u s bolus followed by 2 to 4 m g / m i n as an infusion, w h i c h should be g i v en by infusion pump. A n o t h e r r e c o m m e n d a t i o n 15,24 is to use two 100 mg boluses 20 m i n u t e s apart, along with the same infusion. A l t h o u g h lidocaine has not yet r e c e i v e d F e d e r a l Drug A d m i n i s t r a t i o n a p p r o v a l for p r o p h y l a c t i c int r a m u s c u l a r a d m i n i s t r a t i o n , studies 2° h a v e s h o wn t h a t t h e r a p e u t i c blood levels can be achieved by inject i o n into t h e deltoid muscle. Such a d m i n i s t r a t i o n is well suited for pat i e n t s strongly suspected of suffering an acute myocardial infarction first seen outside of the hospital setting. P a t i e n t s t h e n a r e at h i g h e s t r i s k of d e v e l o p i n g l i f e - t h r e a t e n i n g arr h y t h m i a s an d would b e n e f i t most from prophylaxis. It has been shown t h a t a single i n t r a m u s c u l a r dose m a y provide t h e r a p e u t i c blood levels for up to two hours after injection. Major toxicity resulting from overdosage includes central nervous s y s t e m s t i m u l a t i o n p r o g r e s s i n g to convulsions. H y p e r s e n s i t i v i t y reactions m a y also occur. ~ Minor toxic effects occur more frequently in older patients. Therefore, the loading dose and infusion rate must be reduced for p a t i e n t s 70 years or older. ~4 Dosage should also be adjusted in p a t i e n t s with severe congestive h e a r t f a il u r e or hepatic disease.
2. Southworth JL, McKusick JA, Pierce FC, et al: Ventricular-fibrillation precipitated by cardiac catheterization. J A M A 143:717, 1950.
15. Bainton CR, Peterson DR: Death~ from coronary heart disease in per~ fifty years of age and younger. N En~/~ Med 268:569-575, 1963. ~v
3. Weiss WA: Intravenous use of lidocaine for ventricular arrhythmias. Anesth A n a l g 39:369, 1960.
16. Zener JC, Kerber RE, Spivack AI) e~ al: Blood lidocaine levels and kinetics f~i~ lowing high dose intramuscular ad. ministration. C i r c u l a t i o n 47:984-986, 1973.
4. Lown B, Fakhro AM, Hood WB, et al: The coronary care unit: New perspectives and directions. J A M A 199:188-198, 1967. 5. Gianelly R, v o n d e r Groeben JO, Spivack AP, et al: Effect of lidocaine on ventricular arrhythmias in patients with coronary heart disease. N Eng~ J Med 277:1215-1219, 1967. 6. Chopra MP, Portal RW, Aber CP: Lignocaine therapy after acute myocardial infarction. B r Med J 1:213-216, 1969. 7. Goldfrank L, Osborn H: Lidocaine - uses and toxicity. H o s p i t a l P h y s i c i a n 14:26-32, 1978. 8. Rosen MR, Hoffman BF, Wit AL: Electrophysiology and pharmacology of cardiac arrhythmias. A m Heart J 89:526536, 1975. 9. Winkle RA, Glantz SA, Harrison DC: Pharmacologic therapy of ventricular arrhythmias. A m J Cardiol 36:629-649, 1975. 10. Harrison DC: Practical guidelines for the use of lidocaine. J A M A 233:12021204, 1975. 11. Lown B, Vassaux C, Hood WB, et aI: The coronary care unit. J A M A 199:156166, 1967.
17. Lie KI, Wellens HJ, Van Capelle l~J et al: Lidocaine in the prevention 0f primary ventricular fibrillation. N Engl d Med 291:1324-1326, 1974. 18. Conley MJ, McNeer JF, Lee KL, et al: Cardiac arrest complicating acute myocardial infarctions: Predictability and prognosis. A m J Cardiol 39:7-12, 1977. 19. Greenblatt DJ, Bolognini V, Koch. Weser J, et al: Pharmacokinetic approach to the clinical use of-lidocaine intrave. nously. J A M A 236:273-277, 1976. 20. Valentine PA, Frew JL, Mashford ML, et al: Lidocaine in the prevention of sudden death in the pre-hospital phase of acute infarction. N E n g l J M e d 291: 1327-1331, 1974. 21. Bernstein V, Bernstein M, Griffiths J, et al: Lidocaine intramuscularly in acute myocardial infarction. J A M A 219:1027, 1972. 22. Liem KL, Lie KI, Willebrands AF, et al: Mechanism of ineffectiveness of in. tramuscular lidocaine in preventing ven. tricular fibrillation. (Abstract), A m J Cardiol 41:408, 1978.
12. Wyman FG, Hammersmith L: Comprehensive treatment plan for the prevention of primary ventricular fibrillation in acute myocardial infarction. A m J Cardiol 35:661-667, 1974.
23. Scott DB, Gibson PJ, Vellani CW, et al: Plasma lidocaine levels after intravenous and intramuscular injection. Lancet 1:41, 1970. 24. Harrison DC: Should lidocaine be administered routinely to all patients after acute myocardial infarction. Circulation 58:581-583, 1978.
REFERENCES
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1. Adjey AAJ, Geddes IS, Webb SW, et al: The acute phase of myocardial infarction. Lancet 1:501-504, 1971.
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