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Lidocaine in experimental ventricular fibrillation : endotracheal vs intravenous use Brown, Linda Kathleen 1982

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LIDOCAINE IN EXPERIMENTAL VENTRICULAR FIBRILLATION: ENDOTRACHEAL vs INTRAVENOUS USE by LINDA KATHLEEN BROWN B.S.(Pharm.), The U n i v e r s i t y of B r i t i s h Columbia (1977) A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n THE FACULTY OF GRADUATE STUDIES D i v i s i o n of Pharmacology and Toxicology of the F a c u l t y of Pharmaceutical Sciences We accept t h i s t h e s i s as conforming to the re q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA APRIL 198 2 (c) Linda Kathleen Brown, 1982 In presenting t h i s thesis i n p a r t i a l f u l f i l m e n t of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library s h a l l make i t f r e e l y available for reference and study. I further agree that permission for extensive copying of t h i s thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. I t i s understood that copying or publication of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of The University of B r i t i s h Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 DE-6 (3/81) i i ABSTRACT The endotracheal (ET) route f o r the a d m i n i s t r a t i o n of se l e c t e d drugs has been proposed as an e f f e c t i v e a l t e r n a t e route of drug a d m i n i s t r a t i o n during emergency s i t u a t i o n s when an intravenous (IV) l i n e cannot be e s t a b l i s h e d . Lidocaine may be b e n e f i c i a l i n the treatment of v e n t r i c u l a r f i b r i l l a t i o n (VF) r e s u l t i n g from acute myocardial i n f a r c t i o n , although t h i s hypothesis has not been confirmed i n the l i t e r a t u r e . The e f f i c a c y of l i d o c a i n e i n the treatment of v e n t r i c u l a r f i b r i l -l a t i o n due to acute coronary a r t e r y l i g a t i o n was examined, as w e l l as the use of the endotracheal route as an a l t e r n a t i v e to IV i n j e c t i o n . Rabbits were anesthetized w i t h sodium p e n t o b a r b i t a l or halothane, intubated w i t h an endotracheal tube, and animals r e c e i v i n g p e n t o b a r b i t a l were mechanically r e s p i r e d . V e n t r i c u l a r f i b r i l l a t i o n was produced by o c c l u s i o n of the l e f t c i r c u m f l e x coronary a r t e r y , or by subsequent r e p e r f u s i o n of ischemic myocardium. Endotracheal a d m i n i s t r a t i o n of 2mg/Kg l i d o c a i n e (2mg/ml i n normal s a l i n e ) r e s u l t e d i n lower peak plasma l i d o c a i n e concentrations i n i t i a l l y compared w i t h IV i n j e c t i o n , but more sustained l e v e l s i n the the r a p e u t i c range f o r l i d o c a i n e (p<0.05). A d m i n i s t r a t i o n of l i d o c a i n e e i t h e r IV or ET during v e n t r i c u l a r f i b r i l l a t i o n r e s u l t e d i n a s i g n i f i c a n t increase (p<0.05) i n plasma l i d o c a i n e concentrations during the f i r s t minute compared wi t h c o n t r o l s . During v e n t r i c u l a r f i b r i l l a t i o n there was no s i g n i f i c a n t d i f f e r e n c e between plasma l i d o c a i n e l e v e l s f o l l o w i n g IV or ET a d m i n i s t r a t i o n . A d m i n i s t r a t i o n of l i d o c a i n e 2mg/Kg endotracheally ( i n normal s a l i n e ) during VF r e s u l t e d i n a s i g n i f i c a n t decrease i n the d u r a t i o n of f i b r i l l a t i o n compared wi t h untreated and normal s a l i n e c o n t r o l s (p <0.001). i v TABLE OF CONTENTS Page ABSTRACT i i LIST OF TABLES . ' v i LIST OF FIGURES v i i INTRODUCTION . 1. The Endotracheal Route f o r Lid o c a i n e A d m i n i s t r a t i o n 1 a) The Rat i o n a l e f o r Endotracheal Drug A d m i n i s t r a t i o n 1 b) Endotracheal Absorption of Drugs . 3 2. The A n t i f i b r i l l a t o r y E f f i c a c y of L i d o c a i n e . .. 11 a) Overview 11 b) Mechanisms of Arrhythmogenesis 13 c) E l e c t r o p h y s i o l o g i c a l E f f e c t s of Lidocaine i n Normal and Ischemic Myocardium 19 d) E f f e c t s of Lidocaine Seen C l i n i c a l l y 22 3. R a t i o n a l e and Purpose of the Present Study ........... 25 MATERIALS AND METHODS 1. Plasma Lidocaine L e v e l Studies ........... .... ........28 a) Animal Experiments .28 b) L i d o c a i n e Assay , 30 2. Coronary A r t e r y L i g a t i o n / V e n t r i c u l a r F i b r i l l a t i o n Studies .. . . . . . . ... . . . . . . , . , ,,.... . . . . 3 4 3. Analyses and S t a t i s t i c s 41 4. Drugs and Chemicals ............. ... ............ . . .... .42 RESULTS 1. Plasma Lidocaine L e v e l Studies ...................... 43 a) Endotracheal vs Intravenous L i d o c a i n e i n D i s t i l l e d Water During Halothane Anesthesia ............v.........43 b) The E f f e c t of P e n t o b a r b i t a l or Halothane Anesthesia on the Endotracheal Absorption of Lid o c a i n e i n D i s t i l l e d Water 43 V c) Plasma Lidocaine Levels F o l l o w i n g a ? e Endotracheal I n s t i l l a t i o n of Lidocaine i n E i t h e r D i s t i l l e d Water or Normal S a l i n e During P e n t o b a r b i t a l Anesthesia 4 9 d) Absorption of Lid o c a i n e F o l l o w i n g Endotracheal A d m i n i s t r a t i o n of Lidocaine i n Normal S a l i n e During Closed Chest C o n t r o l s , Open Chest C o n t r o l s , and V e n t r i c u l a r F i b r i l l a t i o n 56 e) Plasma Lidocaine Levels F o l l o w i n g Intravenous I n j e c t i o n of Lidocaine i n Normal S a l i n e During Open Chest Co n t r o l s and V e n t r i c u l a r F i b r i l l a t i o n 60 f) Plasma Lidocaine Levels F o l l o w i n g E i t h e r Intravenous I n j e c t i o n or Endotracheal I n s t i l l a t i o n of Lidocaine to Open Chest C o n t r o l s . . . . 6 4 g) Plasma Lidocaine Levels F o l l o w i n g Endotracheal I n s t i l l a t i o n or Intravenous I n j e c t i o n of Lidocaine During V e n t r i c u l a r F i b r i l l a t i o n • • • • ^9 h) Plasma Li d o c a i n e Levels F o l l o w i n g Endotracheal A d m i n i s t r a t i o n of Lido c a i n e 2mg/Kg i n D i s t i l l e d Water Followed by lmg/Kg Every F i v e Minutes 7 4 2. A n t i f i b r i l l a t o r y E f f i c a c y of Endotracheal Lidocaine 7 4 a) The E f f e c t of Endotracheal Lidocaine on Duration of V e n t r i c u l a r F i b r i l l a t i o n 7 4 b) Tendency f o r V e n t r i c u l a r F i b r i l l a t i o n : Three C l a s s i f i c a t i o n s ^0 c) Occlusion vs Reperfusion V e n t r i c u l a r F i b r i l l a t i o n 8 9 DISCUSSION , 9 6 REFERENCES. 10 8 v i LIST OF TABLES Table I. C a l c u l a t e d f i r s t - o r d e r r a t e constants and plasma h a l f - l i v e s f o r intravenous i n j e c t i o n and endotracheal i n s t i l l a t i o n of l i d o c a i n e i n d i s t i l l e d water , Page 48 Table I I . C a l c u l a t e d f i r s t - o r d e r r a t e constants and plasma h a l f - l i v e s f o r endotracheal i n s t i l l a t i o n of l i d o c a i n e i n d i s t i l l e d water and normal s a l i n e 57 Table I I I Table IV. Area under the curve, f r a c t i o n of dose absorbed and clearance of l i d o c a i n e f o l l o w i n g intravenous or endotracheal a d m i n i s t r a t i o n during e i t h e r v e n t r i c u l a r f i b r i l l a t i o n or open chest c o n t r o l s 6 3 Duration of v e n t r i c u l a r f i b r i l l a t i o n f o l l o w i n g endotracheal a d m i n i s t r a t i o n of l i d o c a i n e , normal s a l i n e , or no treatment , 78 Table V. Percent o c c l u s i o n of r i g h t v e n t r i c u l a r , l e f t v e n t r i c u l a r , and t o t a l v e n t r i c u l a r mass i n untreated c o n t r o l s , normal s a l i n e c o n t r o l s , and i n l i d o c a i n e -t r e a t e d animals . . . . , 79 Table VI. Table VII, Table V I I I , Table IX. Duration and frequency of v e n t r i c u l a r f i b r i l l a t i o n i n short v e n t r i c u l a r f i b r i l l a t i o n and long v e n t r i c u l a r f i b r i l l a t i o n c a t e g o r i e s , 8 1 Comparison of percent o c c l u s i o n of l e f t v e n t r i c u l a r , r i g h t v e n t r i c u l a r , and t o t a l v e n t r i c u l a r mass wi t h tendency to f i b r i l l a t e 87 Comparison of the incidence of v e n t r i c u l a r arrhythmias f o l l o w i n g ' coronary a r t e r y l i g a t i o n w i t h tendency to f i b r i l l a t e 88 Comparison of percent o c c l u s i o n of l e f t v e n t r i c u l a r , r i g h t v e n t r i c u l a r , and t o t a l v e n t r i c u l a r mass i n v e n t r i c u l a r f i b r i l l a t i o n o c c u r r i n g during an o c c l u s i o n or r e p e r f u s i o n phase 95 v i i LIST OF FIGURES Page Figure 1. P r i n c i p l e of homogeneous enzyme . . . 32 Figure 2. Schematic r e p r e s e n t a t i o n of the p o s i t i o n . . . 36 Figure 2a. C r o s s - s e c t i o n a l r e p r e s e n t a t i o n of the . . . 36 Figure 3. Plasma l i d o c a i n e l e v e l s f o l l o w i n g endotracheal i n s t i l l a t i o n or intravenous i n j e c t i o n of l i d o c a i n e i n d i s t i l l e d . . .45 Figure 4. Log plasma l i d o c a i n e c o n c e n t r a t i o n f o l l o w i n g endotracheal i n s t i l l a t i o n or intravenous i n j e c t i o n of l i d o c a i n e i n d i s t i l l e d water during halothane anesthesia .. , 47 Figure '5. Plasma l i d o c a i n e concentrations f o l l o w i n g endotracheal i n s t i l l a t i o n of l i d o c a i n e i n d i s t i l l e d water during e i t h e r halothane , 51 Figure 6. Plasma l i d o c a i n e concentrations f o l l o w i n g endotracheal i n s t i l l a t i o n of l i d o c a i n e i n ,- . . 53 Figure 7. Log plasma l i d o c a i n e c o n c e n t r a t i o n vs time f o l l o w i n g endotracheal i n s t i l l a t i o n of l i d o c a i n e i n e i t h e r normal s a l i n e or Figure 8. Plasma l i d o c a i n e l e v e l s f o l l o w i n g endo-t r a c h e a l a d m i n i s t r a t i o n of l i d o c a i n e i n normal s a l i n e during v e n t r i c u l a r f i b -r i l l a t i o n w i t h c a r d i a c massage, open chest . . ..59 Figure 9. Plasma l i d o c a i n e l e v e l s f o l l o w i n g i n t r a -venous i n j e c t i o n of l i d o c a i n e i n normal s a l i n e during v e n t r i c u l a r f i b r i l l a t i o n and Figure 10. Plasma l i d o c a i n e l e v e l s f o l l o w i n g endo-t r a c h e a l i n s t i l l a t i o n of l i d o c a i n e i n normal s a l i n e or intravenous i n j e c t i o n of 66 Figure 11. Log plasma l i d o c a i n e concentrations vs time f o l l o w i n g intravenous i n j e c t i o n of l i d o c a i n e i n normal s a l i n e or endotracheal i n s t i l l a t i o n of l i d o c a i n e i n normal s a l i n e ... 68 v i i i Page Figure 12. Plasma l i d o c a i n e l e v e l s observed f o l l o w i n g e i t h e r intravenous i n j e c t i o n of l i d o c a i n e i n normal s a l i n e or endotracheal i n s t i l l a t i o n of l i d o c a i n e i n normal s a l i n e during v e n t r i c u l a r f i b r i l l a t i o n w i t h c a r d i a c massage 71 Figure 13. Log plasma l i d o c a i n e concentrations vs time f o l l o w i n g e i t h e r intravenous i n j e c t i o n of l i d o c a i n e i n normal s a l i n e or endotracheal i n s t i l l a t i o n of l i d o c a i n e i n normal s a l i n e 7 3 Figure 14. Plasma l i d o c a i n e l e v e l s f o l l o w i n g endotracheal a d m i n i s t r a t i o n of a 'loading dose 1 followed by a 'maintenance dose 1 every 5 minutes 76 Figure 15. Blood pressure and ECG recordings during v e n t r i c u l a r f i b r i l l a t i o n w i t h manual heart massage 84 F i g u r e 16. Blood pressure and ECG recordings during a v e n t r i c u l a r f i b r i l l a t i o n episode which l a s t e d 25 seconds and terminated spontaneously 86 Figure 17. Comparison of blood pressure before and f o r 10 minutes a f t e r coronary a r t e r y l i g a t i o n i n animals i n which no v e n t r i c u l a r f i b r i l l a t i o n , short v e n t r i c u l a r f i b r i l l a t i o n or long v e n t r i c u l a r f i b r i l l a t i o n occurred 91 Figure 18. Changes i n heart r a t e f o l l o w i n g coronary a r t e r y o c c l u s i o n i n No VF, Short VF and Long VF experiments 93 i x ACKNOWLEDGEMENTS I would l i k e to express my g r a t i t u d e to Dr. Jack Diamond f o r h i s guidance and support, and f o r the opportunity to pursue t h i s p r o j e c t . I would e s p e c i a l l y l i k e to thank Pamela L i v i n g s t o n e , to whom I owe a great deal of thanks f o r her a s s i s t a n c e both i n the lab and i n the pr e p a r a t i o n of t h i s manuscript. My s i n c e r e g r a t i t u d e a l s o goes to Dr. David Hunt and Dr. Les V e r t e s i , without whose enthusiasm and encouragement t h i s p r o j e c t may never have been s t a r t e d . I would a l s o l i k e to thank Jo-anne Maxey, Evelyn Chu and Lynn P o l l o c k f o r t h e i r a s s i s t a n c e . This work was supported by the B r i t i s h Columbia Health Care Research Foundation and the B r i t i s h Columbia Heart Foundation, whose a s s i s t a n c e i s g r e a t l y appreciated. I would a l s o l i k e to express my a p p r e c i a t i o n to Syva Diagnostics L t d . f o r t h e i r t e c h n i c a l a s s i s t a n c e . 1 INTRODUCTION 1. The Endotracheal Route f o r Lidocaine A d m i n i s t r a t i o n a) The R a t i o n a l e f o r Endotracheal Drug A d m i n i s t r a t i o n Advanced p r e - h o s p i t a l care has expanded r a p i d l y throughout North America and Europe i n the past ten years (Cobb et a l , 1975; S c h a f f e r and Cobb, 1975). In B r i t i s h Columbia, Advanced L i f e Support (ALS) personnel have been p r o v i d i n g emergency p r e - h o s p i t a l care i n s e l e c t e d communities since 1975 ( V e r t e s i , 1978). On-site e v a l u a t i o n and treatment of many medical and s u r g i c a l emergencies are performed by h i g h l y t r a i n e d ambulance personnel, employees of the Emergency Health.Services Commission of B r i t i s h Columbia. These teams are able to e s t a b l i s h intravenous c a t h e t e r s , perform endotracheal i n t u b a t i o n , and administer d i r e c t - c u r r e n t countershock and s e l e c t e d drugs during c a r d i a c a r r e s t and other l i f e - t h r e a t e n i n g emergencies. The subject of drug a d m i n i s t r a t i o n v i a appropriate and e f f i c a c i o u s routes during these s i t u a t i o n s has only been addressed r e c e n t l y . A d m i n i s t r a t i o n of pharmacologic agents during c a r d i a c a r r e s t has most f r e q u e n t l y been accomplished v i a the p e r i p h e r a l intravenous (IV) route, s i n c e p e r i p h e r a l IV cannulas can u s u a l l y be r a p i d l y and s a f e l y e s t a b l i s h e d and provide d i r e c t access of the drug to the p a t i e n t ' s c i r c u l a t i o n (American Heart A s s o c i a t i o n , 1980). More r e c e n t l y , i t has been shown tha t during cardiopulmonary r e s u s i t a t i o n (CPR) i n humans, i n j e c t i o n of Cardio-Green dye v i a p e r i p h e r a l IV r e s u l t e d i n reduced a r t e r i a l concentrations and delayed appearance of peak 2 l e v e l s compared wi t h c e n t r a l i n j e c t i o n v i a the su b c l a v i a n v e i n (Kuhn e t a l , 1981). Other recent work i n dogs (Barsan e t a l , 1981) showed th a t c e n t r a l IV i n j e c t i o n of l i d o c a i n e during CPR r e s u l t e d i n higher peak l e v e l s of the drug than p e r i p h e r a l IV i n j e c t i o n . A delayed appearance of i n j e c t e d agents i n the c e n t r a l c i r c u l a t i o n during c a r d i a c a r r e s t may r e f l e c t slow venous r e t u r n and t h e r e f o r e may lead to a delayed response to the drug. This p a r t i c u l a r aspect of IV drug a d m i n i s t r a t i o n has not been e x t e n s i v e l y i n v e s t i g a t e d , and f u r t h e r work i n t h i s area i s necessary before c o n c l u s i v e statements may be made. At the present time, the p e r i p h e r a l IV route i s by f a r the most common route of drug a d m i n i s t r a t i o n both i n emergency p r e - h o s p i t a l care and i n the emergency room (American Heart Association,1980). The use of the p e r i p h e r a l IV route f o r drug a d m i n i s t r a t i o n may not always be p o s s i b l e during c a r d i a c a r r e s t . During CPR, intense p e r i p h e r a l v a s c u l a r c o n s t r i c t i o n r e s u l t s i n poor p e r i p h e r a l p e r f u s i o n , and i n s e r t i o n of an IV catheter may t e c h n i c a l l y be d i f f i c u l t or at times impossible (Greenberg, M. et a l , 1979 b). S t a t i s t i c s from the Advanced L i f e Support Program i n B r i t i s h Columbia (Emergency Health Services Academy, 1982) show that i n a s e r i e s of 1198 p a t i e n t s , 68% of IV l i n e s were e s t a b l i s h e d upon the f i r s t attempt, 87% a f t e r the second attempt, and 95% were s u c c e s s f u l f o l l o w i n g the t h i r d attempt. Since each a d d i t i o n a l attempt at s t a r t i n g an IV i s time consuming and s i n c e the r a p i d i t y w i t h which drug therapy i s i n s t i t u t e d i s c r i t i c a l , a l t e r n a t e routes of drug a d m i n i s t r a t i o n should be considered. 3 Intravenous i n j e c t i o n v i a c e n t r a l catheter could provide a r e l i a b l e method of drug d e l i v e r y during c a r d i o v a s c u l a r c o l l a p s e . During p r e - h o s p i t a l c a r d i a c a r r e s t , however, i n s e r t i o n of a c e n t r a l IV cannula e i t h e r v i a the su b c l a v i a n or e x t e r n a l j u g u l a r v e i n may a l s o be d i f f i c u l t , and at times unsafe. This procedure i s as s o c i a t e d w i t h a r i s k of pneumothorax or p e r f o r a t i o n of the c a r o t i d a r t e r y , and i s best performed under w e l l - l i t c o n t r o l l e d c o n d i t i o n s (American Heart A s s o c i a t i o n , 1980). I n t r a c a r d i a c (IC) i n j e c t i o n may a l s o be used f o r adm i n i s t e r i n g drugs during c a r d i a c a r r e s t , however t h i s technique i s a s s o c i a t e d w i t h the r i s k of pneumothorax, hemo-thorax, p e r i c a r d i a l tamponade, myocardial l a c e r a t i o n and coronary a r t e r y l a c e r a t i o n (Goldberg, 1974). The i n t r a c a r d i a c route f o r drug a d m i n i s t r a t i o n i s th e r e f o r e advocated when no other methods are a v a i l a b l e or appropriate. The endotracheal route f o r s e l e c t e d drug a d m i n i s t r a t i o n has been proposed as an e f f e c t i v e a l t e r n a t e route when a p e r i -p h e r a l IV l i n e cannot be q u i c k l y e s t a b l i s h e d and prolonged attempts to s t a r t an IV may delay d e f i n i t i v e treatment unneces-s a r i l y (Redding e t a l , 1967; Elam, 1977; Roberts e t a l , 1978; Greenberg e t a l , 1979"; Roberts e t 'al, 1979 a; Roberts et a l , b 1979 ). Endotracheal i n t u b a t i o n i s u s u a l l y performed r o u t i n e l y , even before attempting to e s t a b l i s h an IV l i n e , and would be a v a i l a b l e f o r a d m i n i s t r a t i o n of drugs i f s a t i s f a c t o r y absorption of drugs v i a t h a t route could be documented. b) Endotracheal Absorption of Drugs 4 Absorption of c e r t a i n drugs from the trachea, b r o n c h i , b r o n c h i o l e s , and a l v e o l i has been w e l l documented (Redding et a l , b 1967; Elam, 1977; Greenberg et a l , 1979 ). Epinephrine (adren-a l i n e ) , i s o p r o t e r e n o l , l i d o c a i n e and atropine are considered to be e s s e n t i a l drugs i n emergency c a r d i a c care and i t has been pro-posed t h a t they may be e f f e c t i v e when administered v i a the endotracheal route (Redding et a l , 1967; Elam, 1977; Roberts et a l , 1978; Greenberg et a l , 1979 a; Roberts e t a l , 1979 a; Roberts e t a l , 1979 b). Roberts et a l (1978, 1979 ) compared the blood l e v e l s and pharmacologic e f f e c t s obtained when epinephrine was given by e i t h e r the intravenous or endotracheal route i n anesthetized dogs. Endotracheal i n s t i l l a t i o n was performed by i n t r o d u c i n g epinephrine d i l u t e d i n 5 ml normal s a l i n e i n t o an endotracheal tube, o c c l u d i n g the end of the tube f o r f i v e seconds to prevent r e f l e x coughing of the s o l u t i o n , and then performing R f i v e quick i n f l a t i o n s of the lungs w i t h an Ambubag . Intravenous i n j e c t i o n s were performed i n t o a p e r i p h e r a l l e g v e i n . Maximum concentrations of epinephrine were achieved at 15 seconds f o l l o w i n g both IV i n j e c t i o n and endotracheal (ET) i n s t i l l a t i o n , although the peak l e v e l achieved v i a the IV route was approximately ten times t h a t achieved w i t h the ET route. The time course of epinephrine i n the blood f o l l o w i n g ET i n s t i l l a t i o n was found to d i f f e r from t h a t f o l l o w i n g IV i n j e c t i o n : at f i v e minutes f o l l o w i n g IV i n j e c t i o n , only 20% of the i n i t i a l c o n c e n t r a t i o n of epinephrine could be found, whereas w i t h the ET route at f i v e minutes, 80% of the i n i t i a l c o n c e n t r a t i o n remained. S i m i l a r r e s u l t s were obtained when the pharmacologic e f f e c t s of 5 epinephrine were compared when the drug was given by the two routes. These data suggest t h a t i n dogs, r a p i d absorption of epinephrine occurs from the lungs, trachea, and bro n c h i , f o l l o w -ing ET a d m i n i s t r a t i o n , and that the marked sustained e l e v a t i o n i n blood l e v e l s f o l l o w i n g ET i n s t i l l a t i o n may r e f l e c t some s o r t of depot, r e s e r v o i r , or sustained r e l e a s e mechanism. Roberts et a l (1979 ) have subsequently reported the s u c c e s s f u l use of endotracheal epinephrine i n two p a t i e n t s w i t h c a r d i o r e s p i r a t o r y c o l l a p s e . In 1967, Redding et aJL examined the e f f e c t i v e n e s s of epinephrine, given v i a d i f f e r e n t routes, i n r e v e r s i n g hypoxia-induced.cardiac a r r e s t i n dogs. The e f f e c t s of the drug were compared when i t was given by IV, intramuscular (IM), or i n t r a c a r d i a c (IC) i n j e c t i o n , or by endotracheal i n s t i l l a t i o n . Endotracheal i n s t i l l a t i o n was performed by g i v i n g epinephrine i n 1 mL and 10 mL d i s t i l l e d water, or i n 10 mL normal s a l i n e . The r e s u l t s i n d i c a t e t h a t epinephrine was e q u a l l y e f f e c t i v e i n r e s t o r i n g c i r c u l a t i o n when i n j e c t e d IV or when i n s t i l l e d v i a the ET route. The data f u r t h e r suggest that d e l i v e r y of the drug i s enhanced when i t i s d i l u t e d i n water as compared wi t h normal s a l i n e , s ince the mean time to r e t u r n of c i r c u l a t i o n f o l l o w i n g epinephrine i n water was s i g n i f i c a n t l y l e s s than f o l l o w i n g epinephrine i n s a l i n e . There was no d i f f e r e n c e between the time to r e t u r n of c i r c u l a t i o n or number of dogs responding to 1 mg epinephrine given IV or ET ( i n 10 mL d i s t i l l e d water). In 1977, Elam examined the intrapulmonary route f o r at r o p i n e , epinephrine, and l i d o c a i n e during hypoxia-induced 6 c a r d i a c a r r e s t i n dogs. His r e s u l t s i n d i c a t e t h a t intrapulmonary i n s t i l l a t i o n of the drugs through a catheter produced a more r a p i d and more sustained ECG response than IV a d m i n i s t r a t i o n v i a the femoral v e i n . Plasma l e v e l s of the drugs were not monitored, t h e r e f o r e t h e r a p e u t i c response, measured as ECG changes, was the only method used to determine onset and d u r a t i o n of a c t i o n by both routes. Absorption of l o c a l a n e s t h e t i c s from the trachea, b r o n c h i , b r o n c h i o l e s and lungs was documented as e a r l y as 1958, when Campbell and A d r i a n i reported s i g n i f i c a n t absorption producing blood l e v e l s comparable to those a t t a i n e d by intravenous i n j e c t i o n . The a n e s t h e t i c s s t u d i e d were t e t r a c a i n e , procaine, cocaine, and benzocaine. In c o n t r a s t to l a t e r work, they found th a t blood l e v e l s a t t a i n e d were a f u n c t i o n of t o t a l dose, and not of the c o n c e n t r a t i o n of s o l u t i o n used. They a l s o determined that absorption was more r a p i d from the trachea than from the pharynx, and higher peak l e v e l s were a t t a i n e d when the animals (dogs) were i n an u p r i g h t p o s i t i o n than i n the prone p o s i t i o n . This study was conducted to examine the p o s s i b i l i t y of systemic t o x i c i t y a r i s i n g from the c a r e l e s s or improper use of l o c a l a n e s t h e t i c s i n the upper r e s p i r a t o r y t r a c t . In 1961, Bromage and Robson i n v e s t i g a t e d the absorption of l i d o c a i n e i n t o the blood f o l l o w i n g IV, IM, e p i d u r a l , and endotracheal a d m i n i s t r a t i o n to anesthetized p a t i e n t s . I n t r a -venous l i d o c a i n e was given to seven p a t i e n t s as an i n f u s i o n (9.3 -100 mg/min) to a t o t a l dose of 9.7 -16.3 mg/Kg. Systemic t o x i c i t y was manifested by an acute drop i n blood pressure and decreased t i d a l volume. Convulsions followed these signs i f the i n f u s i o n was not terminated. L i d o c a i n e was a p p l i e d as a 4% spray 7 to the lar y n x and trachea p r i o r to endotracheal i n t u b a t i o n . Doses v a r i e d from 3.5 to 10.5 mg/Kg and were administered i n d i v i d e d amounts over 2^ -10 minutes. The r a t e of absorption v a r i e d w i d e l y , w i t h peak blood concentrations reached between 5-25 minutes a f t e r a d m i n i s t r a t i o n . The l a r g e v a r i a t i o n i n peak blood l e v e l s and r a t e s of absorption demonstrated may be due to v a r i a t i o n i n dosage, s i t e of a d m i n i s t r a t i o n , and d u r a t i o n of the a p p l i c a t i o n . As w i t h intravenous a d m i n i s t r a t i o n , i t seems l i k e l y t h a t r a p i d endo-t r a c h e a l a d m i n i s t r a t i o n of a bolus amount would produce a more r a p i d and higher peak blood l e v e l than i n t e r m i t t e n t spraying over a ten minute p e r i o d . Since t h i s i n v e s t i g a t i o n , many r e p o r t s have focused on the p o t e n t i a l t o x i c i t y of l i d o c a i n e when a p p l i e d t o p i c a l l y to mucous membranes, l a r y n x , trachea, b r o n c h i , and a l v e o l i . Most rep o r t s show prolonged and delayed absorption of l i d o c a i n e from the r e s p i r a t o r y t r a c t . Peak a r t e r i a l and venous plasma con-c e n t r a t i o n s of 3.2 jug/mL and 2.5 jug/mL r e s p e c t i v e l y have been demonstrated 2 - 5 minutes a f t e r 3 mg/Kg of a 10% s o l u t i o n was administered to the trachea and bronchi i n anesthetized p a t i e n t s (Pelton e t a l , 1970). Chu e t al_ (1975) demonstrated peak plasma l e v e l s of l i d o c a i n e i n venous blood 15 - 20 minutes f o l l o w i n g t o p i c a l anesthesia of the trachea using a s p e c i a l cannula to spray the s o l u t i o n . The average dose was 3.3 mg/Kg, and peak plasma l e v e l s were 2 5.6 rag/mL. The s o l u t i o n was sprayed i n t o the trachea p r i o r to i n t u b a t i o n of p a t i e n t s undergoing e l e c t i v e surgery. The mean time to peak plasma l e v e l was 15 - 20 minutes f o l l o w i n g ET a d m i n i s t r a t i o n and 2 minutes a f t e r IV i n j e c t i o n . 8 S i m i l a r r e s u l t s were reported using 2 mg/Kg sprayed onto the larynges and tracheas of anesthetized p a t i e n t s (Viegas and S t o e l t i n g , 1975). The authors reported peak plasma con-c e n t r a t i o n s of 1.7 - 0.2 jug/mL, 9 - 1 5 minutes a f t e r l i d o c a i n e a d m i n i s t r a t i o n . In p a t i e n t s who were intubated w i t h endotracheal tubes l u b r i c a t e d w i t h viscous l i d o c a i n e , peak plasma concentra-t i o n s were 2.4 - 0.3 ug/mL, 4 - 1 5 minutes a f t e r a d m i n i s t r a t i o n of the same dose of l i d o c a i n e . Curran e t a l (1975) a l s o noted delayed absorption of l i d o c a i n e from the larynx and trachea, and f u r t h e r determined that absorption from the l a r y n g e a l area i s decreased compared wit h absorption from the trachea. Peak plasma l e v e l s of 0.4 -2.5 ug/mL were obtained at 10 - 20 minutes from the l a r y n x , whereas peak l e v e l s of 1.9 - 8 pg/mL were reached at 5 - 15 minutes from the trachea. This f i n d i n g i s not unexpected due to the higher degree of v a s c u l a r i t y of the t r a c h e a l area compared to the l a r y n x . Uptake of l i d o c a i n e given v i a i n t e r m i t t e n t p o s i t i v e pressure breathing (IPPB) and u l t r a s o n i c n e b u l i z e r has been i n v e s t i g a t e d (Chinn e t a l , 1977). Plasma l e v e l s d i d not exceed 1.1 ug/mL although doses used were 280 mg v i a ultrasound and 400 mg v i a IPPB. S i m i l a r plasma l e v e l s were obtained using a metered dose a p p l i c a t o r (a f i n e spray) and using 50 mg or 100 mg only (Scott e t a l , 1976). They f u r t h e r reported that higher plasma l e v e l s were obtained when p a t i e n t s were paralyzed and v e n t i l a t e d , than when they had spontaneous r e s p i r a t i o n s . I t was f e l t t h a t a r t i f i c i a l v e n t i l a t i o n may f o r c e some of the drug deeper i n t o the pulmonary t r e e , whereas spontaneous r e s p i r a t i o n allows some of the 9 administered drug to be exhaled or coughed out. The slow uptake of l i d o c a i n e noted f o l l o w i n g adminis-t r a t i o n as a f i n e spray to the upper r e s p i r a t o r y t r a c t i s i n marked c o n t r a s t to the r a p i d ECG r e s u l t s obtained by Elam (1977) f o l l o w i n g i n s t i l l a t i o n of a s o l u t i o n v i a a ca t h e t e r i n t o the pulmonary area. The l a t t e r study demonstrates t h a t epinephrine, l i d o c a i n e , and a t r o p i n e may be e f f e c t i v e when given v i a the intrapulmonary route, and t h a t t h i s route may provide as r a p i d and more prolonged an e f f e c t i n c a r d i o r e s p i r a t o r y c o l l a p s e than the IV route. I t does not, however, examine the question of s u i t a b l e dosages and appropriate pharmacological responses. The o b j e c t i v e of cardiopulmonary r e s u s c i t a t i o n i s to r e s t o r e e f f e c t i v e pumping a c t i o n to the heart, and the use of ECG response alone as the primary c r i t e r i a f o r th e r a p e u t i c e f f e c t does not t o t a l l y answer t h i s question. I t appears that the use of l i d o c a i n e v i a the endotracheal route may be of b e n e f i t when an IV l i n e cannot be e s t a b l i s h e d . Although there i s considerable controversy i n the l i t e r a t u r e regarding the r a t e of absorption and amount absorbed, i t i s c l e a r that l i d o c a i n e i s absorbed from the l a r y n x , trachea, b r o n c h i , and lungs. There i s evidence to suggest that deep i n s t i l l a t i o n of l i d o c a i n e i n t o the lungs w i l l produce more r a p i d and higher peak plasma l e v e l s than t o p i c a l a p p l i c a t i o n to the l a r y n g e a l area. I t a l s o appears t h a t water may be a more appropriate v e h i c l e than normal s a l i n e , although t h i s should be confirmed. Due to the l a r g e v a r i a t i o n reported i n r a t e and extent of l i d o c a i n e a b s o r ption, i t i s necessary to f u r t h e r examine the plasma l e v e l s obtained when the drug i s given experimentally i n 10 a s i t u a t i o n analogous to t h a t encountered c l i n i c a l l y . In c a r d i a c a r r e s t , the hemodynamic status of the body d i f f e r s g r e a t l y from the normal s i t u a t i o n (Voorhees et a l , 1980). P e r i p h e r a l p e r f u s i o n i s o f t e n very poor, w i t h the m a j o r i t y of c i r c u l a t i n g blood volume i n the c e n t r a l c i r c u l a t i o n . I n s t i l l a t i o n of a drug i n t o the lungs may r e s u l t i n more r a p i d uptake i n t o the c e n t r a l c i r c u l a t i o n where i t s a c t i o n i s d e s i r e d , than intravenous i n j e c t i o n i n t o a p e r i p h e r a l v e i n . Due t o the p o t e n t i a l l y s e r i o u s adverse e f f e c t s which may occur when plasma l i d o c a i n e l e v e l s exceed 6 jag/ml (Bromage and Robson, 1961', Benowitz and M e i s t e r , 1978) , i t i s important to c l o s e l y determine the dosage necessary i n any given s i t u a t i o n . The pharmacokinetics of intravenous l i d o c a i n e have been a c c u r a t e l y determined (Benowitz and M e i s t e r , 1978), a l l o w i n g f o r safe and r a p i d a d m i n i s t r a t i o n of the drug v i a t h i s route. The same data i s necessary f o r the endotracheal route, i f the drug i s to be used e f f e c t i v e l y and s a f e l y i n t h i s manner. 11 2. The A n t i f i b r i l l a t o r y E f f i c a c y of Lidocaine a) Overview Acute myocardial i n f a r c t i o n (AMI) i s one of the lea d i n g causes of mo r b i d i t y and m o r t a l i t y i n Canada and the United States (Canadian Heart Foundation, 1980). By f a r the most dangerous consequence of myocardial ischemia i s the production of l e t h a l arrhythmias and sudden death. In 1980, acute myocardial i n f a r c t i o n r e s u l t e d i n death i n approximately 50,000 p a t i e n t s i n Canada alone (Canadian Heart Foundation, 1980). Of those p a t i e n t s s u f f e r i n g c a r d i o r e s p i r a t o r y a r r e s t , v e n t r i c u l a r f i b r i l l a t i o n i s the causa t i v e arrhythmia i n 50%-80% of cases, and e i t h e r a s y s t o l e , electromechanical d i s s o c i a t i o n , or severe bradycardia are the cause of the remainder ( V e r t e s i , 1978). Although prompt a n t i a r r h y t h m i c therapy may a b o l i s h arrhythmias and perhaps decrease the incidence of v e n t r i c u l a r f i b r i l l a t i o n ( Lie e t a l , 1974), many p a t i e n t s s t i l l develop VF e i t h e r p r i o r to a r r i v a l of advanced p r e - h o s p i t a l care personnel, p r i o r to a r r i v a l at h o s p i t a l , or before appropriate a n t i a r r h y t h m i c therapy has been i n s t i t u t e d . E l e c t r i c a l d e f i b r i l l a t i o n v i a d i r e c t - c u r r e n t counter-shock i s the treatment of choice to reverse v e n t r i c u l a r f i b r i l l a t i o n (American Heart A s s o c i a t i o n , 1980). This treatment i s not always s u c c e s s f u l , however, p a r t i c u l a r l y when VF has been e s t a b l i s h e d f o r a p e r i o d of time (Liberthson et. a_l, 1974; Eisenberg e t a l , 1980). Many drug p r o t o c o l s have been devised f o r r e s u s c i t a t i o n 12 from c a r d i a c a r r e s t . Drug therapy i n i . t i a . i l y evolved, e m p i r i c a l l y w i t h development of treatment regimens based on s c i e n t i f i c hypotheses and s u b j e c t i v e observations. Due to the d i f f i c u l t y i n performing c o n t r o l l e d human experiments during c a r d i a c a r r e s t , changes or advances i n drug therapy have come about p r i m a r i l y as a r e s u l t of animal experiments and s u b j e c t i v e o b servations, w i t h few c o n t r o l l e d human s t u d i e s . In the American Heart A s s o c i a t i o n ' s 'Standards and Guid e l i n e s f o r Cardiopulmonary R e s u s c i t a t i o n (CPR) and Emergency Cardiac Care (ECC) 1 (1980), l i d o c a i n e i s recommended as the drug of choice f o r the suppression of v e n t r i c u l a r e c t o p i c beats and v e n t r i c u l a r t a c h y c a r d i a . I t i s a l s o recommended i n the treatment of v e n t r i c u l a r f i b r i l l a t i o n unresponsive to e l e c t r i c a l d e f i b r i l l a t i o n alone. Since not a l l episodes of v e n t r i c u l a r f i b r i l l a t i o n can be s u c c e s s f u l l y terminated w i t h e l e c t r i c a l d e f i b r i l l a t i o n , and si n c e v e n t r i c u l a r f i b r i l l a t i o n continues to occur e i t h e r p r i o r to or de s p i t e i n s t i t u t i o n of appropriate therapy, c a r e f u l e v a l u a t i o n of cu r r e n t p r o t o c o l s and t h e i r e f f i c a c y i s mandatory. Although evidence suggests that l i d o c a i n e may be h e l p f u l i n ter m i n a t i n g 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 has not been c l e a r l y demonstrated i n c o n t r o l l e d c l i n i c a l t r i a l s . The f o l l o w i n g i s a survey of the l i t e r a t u r e regarding the known anti a r r h y t h m i c and e l e c t r o p h y s i o l o g i c a l p r o p e r t i e s of l i d o c a i n e , and the r a t i o n a l e f o r f u r t h e r experiments to document the extent of i t s a n t i f i b r i l l a t o r y e f f i c a c y i n v i v o . Although complex e l e c t r o p h y s i o l o g i c a l documentation of the e f f e c t s of l i d o c a i n e on the f i b r i l l a t i n g heart are beyond the scope of t h i s study, the f o l l o w i n g d i s c u s s i o n w i l l deal i n some depth w i t h mechanisms of arrhythmogenesis and the e l e c t r o -13 p h y s i o l o g i c a l a c t i o n s of l i d o c a i n e . These data w i l l be presented as support f o r the p o s s i b i l i t y that l i d o c a i n e may possess a n t i f i b r i l l a t o r y a c t i v i t y i n e s t a b l i s h e d v e n t r i c u l a r f i b r i l l a t i o n . b) Mechanisms of Arrhythmogenesis Several models have been developed to study under-l y i n g mechanisms i n v o l v e d i n the e l e c t r o p h y s i o l o g i c a l events accompanying acute myocardial i n f a r c t i o n (Wit and Friedman, 1975). Arrhythmia production and sudden death as a r e s u l t of o c c l u s i o n of a coronary a r t e r y have been c l e a r l y demonstrated i n animal experiments where acute s u r g i c a l o c c l u s i o n of a coronary a r t e r y has r e s u l t e d i n e l e c t r o p h y s i o l o g i c sequelae which are s i m i l a r to those reported i n man during acute myocardial i n f a r c t i o n . Many p a t i e n t s i n whom sudden death has occurred, however, show no s i g n i f i c a n t degree of o c c l u s i o n of coronary blood flow (Bashe et a_l, 1975). Temporary spasm of a coronary a r t e r y has been demonstrated c l i n i c a l l y i n man, and may be a f a c t o r i n sudden death i n p a t i e n t s i n whom no s i g n i f i c a n t degree of coronary a r t e r y o c c l u s i o n can l a t e r be found ( O l i v a and B r e c k i n r i d g e , 1977). Coronary a r t e r i a l spasm was seen i n 40% of myocardial i n f a r c t i o n s due to coronary a r t e r y disease. Spasm was of t e n seen to be superimposed on an a t h e r o s c l e r o t i c o b s t r u c t i o n already present. R e l i e f of the spasm r e s u l t e d i n r e t u r n of patency of the a r t e r y i n some p a t i e n t s . In order to mimic the c l i n i c a l s i t u a t i o n , animal models have been developed i n which temporary o c c l u s i o n of a coronary a r t e r y i s followed by r e p e r f u s i o n . Both o c c l u s i o n 14 and r e p e r f u s i o n of coronary a r t e r i a l blood flow have been shown to be h i g h l y arrhythmogenic i n many animal s p e c i e s , i n c l u d i n g dogs, c a t s , and r a t s ( B a t t l e e t a l , 1974; A x e l r o d e t a l , 1975; E l - S h e r i f e t a l , 1975; L e v i t e s e t a l , 1975; Kane e t a l , 1979; K a p l i n s k y e t a l , 1979; Murdock e t a l , 19 80; K a p l i n s k y e t a l , 1981). O c c l u s i o n of the l e f t a n t e r i o r descending coronary a r t e r y i n dogs has c o n s i s t e n t l y r e s u l t e d i n the p r o d u c t i o n of v e n t r i c u l a r arrhythmias w i t h i n a few minutes of o c c l u s i o n (Axelrod e t a l , 1975; E l - S h e r i f e t a l , 1975; L e v i t e s e t a l , 1975; K a p l i n s k y e t a l , 1979; Murdock e t a l , 1980; K a p l i n s k y e t al', 1981) . These arrhythmias u s u a l l y peak i n frequency w i t h i n about 4 - 8 minutes and then abate. Spontaneous v e n t r i c u l a r f i b r i l l a t i o n has been r e p o r t e d i n 65% of animals f o l l o w i n g t h i s o c c l u s i o n procedure (Fujimoto e t a l , 1981), although the frequency w i t h which t h i s event o c c u r r e d i n other s t u d i e s v a r i e d g r e a t l y from l%- 4 0 % ( B a t t l e e t a_l, 1974; K a p l i n s k y e t a l , 1979; K a p l i n s k y e t a l , 1981; Ouyang et a l , 1981) . R e p e r f u s i o n of ischemic myocardium i n the dog has a l s o been shown to be h i g h l y arrhythmogenic, r e s u l t i n g i n the p r o d u c t i o n of v e n t r i c u l a r arrhythmias immediately upon r e l e a s e of the l i g a t u r e ( L e v i t e s e t a l , 1975; Murdock e t a_l, 1980) and subsequent v e n t r i c u l a r f i b r i l l a t i o n i n up to 60%-65% of animals ( B a t t l e e t a_l, 1974; K a p l i n s k y e t a_l, 1981). P r o d u c t i o n of arrhythmias upon o c c l u s i o n and r e l e a s e has a l s o been demonstrated i n the c a t (Corr e t a l , 1978; Penkoske e t a l , 1978) w i t h an o v e r a l l m o r t a l i t y due to v e n t r i c u l a r f i b r i l l a t i o n of 29% f o l l o w i n g o c c l u s i o n and 25% f o l l o w i n g r e p e r f u s i o n . 15 Occlusion and r e p e r f u s i o n arrhythmias have been noted to have d i s t i n c t i v e c h a r a c t e r i s t i c s w i t h respect to onset, frequency and d u r a t i o n . Arrhythmias due to coronary a r t e r y o c c l u s i o n have been noted to develop g r a d u a l l y , peak w i t h i n 4 - 8 minutes and then abate i n about 10 - 12 minutes (Corr et a l , 1978; Penkoske et a l , 1978; Murdock et a l , 1980). Some i n v e s t i g a t o r s have noted a second phase of arrhythmias which occurs from 12 - 30 minutes f o l l o w i n g l i g a t i o n (Kaplinsky et a l , 1979) although other s t u d i e s in, cats using o c c l u s i o n periods of the same d u r a t i o n have not noted t h i s (Corr et a_l, 1978; Penkoske e t a l , 1978). Reperfusion arrhythmias, however, have been shown to occur almost immediately upon r e l e a s e of the l i g a t u r e or w i t h i n one minute of r e l e a s e , and abate r a p i d l y w i t h i n the f o l l o w i n g 1 - 2 minutes ( B a t t l e et aJL, 1974; Axelrod et a l , 1975; Penkoske e t a l , 1978; Murdock et a l , 1980). Kaplinsky et a l (1981), however, a l s o demonstrated a second phase of arrhythmias o c c u r r i n g w i t h i n 2 - 7 minutes a f t e r r e p e r f u s i o n . Mechanisms r e s p o n s i b l e f o r the production of a r r h y t h -mias upon o c c l u s i o n or r e p e r f u s i o n of a coronary a r t e r y are thought to be complex and i n v o l v e many f a c t o r s . The c o n t r i b u t i o n of neurohormonal, biochemical and e l e c t r o -p h y s i o l o g i c a l f a c t o r s have yet to be completely defined. In general though, i t i s f e l t t h a t arrhythmias can occur v i a two d i f f e r e n t e l e c t r o p h y s i o l o g i c a l processes, r e - e n t r y and enhanced a u t o m a t i c i t y (Han, 1969). Re-entry i s proposed to occur when an e l e c t r i c a l impulse i s blocked along one pathway, t r a v e l s along an a l t e r n a t e route, and then e v e n t u a l l y r e - e x c i t e s more proximal t i s s u e by t r a v e l l i n g i n a retrograde f a s h i o n along the 16 o r i g i n a l b l o c k e d r o u t e . T h i s may occur as a r e s u l t of a r e d u c t i o n i n conduction v e l o c i t y i n one segment of myocardium r e l a t i v e to another, or by d i f f e r e n c e s i n r e f r a c t o r y p e r i o d s i n a d j a c e n t t i s s u e . Enhanced a u t o m a t i c i t y or spontaneous d e p o l a r i z a t i o n may occur as a r e s u l t of an i n c r e a s e i n slope of phase 4 d i a s t o l i c d e p o l a r i z a t i o n ( i n c a r d i a c t i s s u e with those i n t r i n s i c p r o p e r t i e s ) , an i n c r e a s e ( l e s s negative) i n the maximum d i a s t o l i c p o t e n t i a l a t the end of r e p o l a r i z a t i o n , or a decrease (more negative) i n the e l e c t r i c a l t h r e s h o l d f o r a c t i o n p o t e n t i a l development. These concepts have been r e c e n t l y reviewed by s e v e r a l authors (Wit and Friedman, 1975; Ribner e t a_l, 1979; Vera and Mason, 1981). Acute o c c l u s i o n of a coronary a r t e r y has been shown to r e s u l t i n a r e d u c t i o n i n 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 r e s h o l d which p a r a l l e l e d appearance of v e n t r i c u l a r arrhythmias and s u s c e p t i b i l i t y to both spontaneous and e l e c t r i c a l l y - i n d u c e d v e n t r i c u l a r f i b r i l l a t i o n ( B a t t l e e t a l , 1974; A x e l r o d e t a l , 1975; Corbalan e t a l , 1976). Both conduction delay and a decrease i n r e f r a c t o r y p e r i o d have been shown to occur w i t h i n ischemic myocardial t i s s u e f o l l o w i n g coronary a r t e r y o c c l u s i o n ( L e v i t e s e t a l , 1975; Penkoske e t a l , 1978; K a p l i n s k y e t a l , 1979; Murdock et a l , 1980). These changes d i d not occur i n non-ischemic myocardial t i s s u e . Marked f r a c t i o n a t i o n of e l e c t r i c a l a c t i v i t y as recorded by e p i c a r d i a l and s u b e p i c a r d i a l e l e c t r o d e s has a l s o been observed and c o i n c i d e s with i n c r e a s e d arrhythmia frequency. The f r a c t i o n a t i o n of e l e c t r i c a l a c t i v i t y r e f l e c t s non-homogeneous d e p o l a r i z a t i o n of myocardial c e l l s , probably 17 from slow conducting t i s s u e ( E l - S h e r i f e t a_l, 1975; K a p l i n s k y e t a l , 1979; Murdock e t a l , 1980). Demonstration of f r a c t i o n a t i o n of e l e c t r i c a l a c t i v i t y , c o n d u c t i o n delay and a decrease i n r e f r a c t o r y p e r i o d i n ischemic m y o c a r d i a l t i s s u e have l e d most i n v e s t i g a t o r s to promote r e -e n t r y as the most l i k e l y mechanism f o r arrhythmia p r o d u c t i o n f o l l o w i n g coronary a r t e r y o c c l u s i o n . Re-entry has been demonstrated c l i n i c a l l y i n man i n the genesis of s u p r a v e n t r i c u l a r t a c h y c a r d i a (Goldreyer and Bigger, 1971) and v e n t r i c u l a r f i b r i l l a t i o n (Josephson e t a l , 1978). The evidence f o r a mechanism f o r arrhythmias f o l l o w i n g coronary a r t e r y r e p e r f u s i o n i s not so c l e a r . 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 r e s h o l d decreases w i t h i n approximately 3 minutes f o l l o w i n g o c c l u s i o n of a coronary a r t e r y i n most animal models ( B a t t l e e t a l , 1974; A x e l r o d e t a l , 1975; Corbalan e t a l , 1976). T h i s t h r e s h o l d r e t u r n s to normal i n approximately 10 minutes. Upon r e p e r f u s i o n , the t h r e s h o l d f o r v e n t r i c u l a r f i b r i l l a t i o n has been shown to drop almost immediately to l e v e l s seen f o l l o w i n g o c c l u s i o n , and t h i s r e d u c t i o n i s of b r i e f d u r a t i o n . K a p l i n s k y e t a l (1981) r e p o r t e d the a s s o c i a t i o n of immediate r e p e r f u s i o n arrhythmias w i t h the reappearance of nonhomogeneous, fragmented e l e c t r i c a l a c t i v i t y . These c o n d i t i o n s c o u l d p r o v i d e c o n d i t i o n s s u i t a b l e f o r r e - e n t r y . They a l s o noted a delayed p e r i o d of arrhythmias beyond the time when conduction a b n o r m a l i t i e s had r e t u r n e d to c o n t r o l l e v e l s , and a s s o c i a t e d t h i s w i t h augmented a u t o m a t i c i t y . Augmented a u t o m a t i c i t y demonstrated by o v e r d r i v e s u p p r e s s i o n and enhanced i d i o -v e n t r i c u l a r r a t e s has been suggested by Penkoske et. a_l (1978) 18 as a p o s s i b l e mechanism of arrhythmia p r o d u c t i o n d u r i n g r e -p e r f u s i o n . In a d d i t i o n , l o c a l i z e d areas of depressed conduction v e l o c i t y e x i s t , i n d i c a t i n g heterogeneous recov e r y a f t e r r e p e r f u s i o n . I t i s p o s s i b l e t h a t K a p l i n s k y (1981) and co-workers were ab l e to d e f i n e more c l e a r l y d u r i n g r e p e r f u s i o n a temporal sequence of r e - e n t r y f o l l o w e d c l o s e l y by augmented a u t o m a t i c i t y . Re-entry as a mechanism f o r r e p e r f u s i o n arrhythmias has a l s o been proposed by Murdock e t a l (1980), who demonstrated nonhomogeneous re c o v e r y of conduction which c o i n c i d e d w i t h a r e t u r n of arrhythmias. The r o l e of humoral and b i o c h e m i c a l parameters on arrhythmogenesis may be very complex. A d r e n e r g i c i n f l u e n c e s d u r i n g induced m y o c a r d i a l ischemia have been observed, i n c l u d i n g enhanced sympathetic a f f e r e n t d i s c h a r g e (Brown, 1967). Both phentolamine and p r o p r a n o l o l have been shown to reduce the 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 r e s h o l d changes which occur d u r i n g coronary a r t e r y o c c l u s i o n (Corbalan e t a_l, 1976) . These e f f e c t s were not seen f o l l o w i n g r e p e r f u s i o n , suggesting t h a t a d r e n e r g i c mechanisms may not be as s i g n i f i c a n t a t t h a t time. R e g i o n a l c y c l i c AMP l e v e l s have been measured and compared wi t h l o c a l e l e c t r o p h y s i o l o g i c a c t i v i t y f o l l o w i n g coronary a r t e r y o c c l u s i o n (Corr e t a l , 1978). A l t e r a t i o n s i n i n t r a m y o c a r d i a l conduction time c o r r e l a t e d w e l l w i t h onset of arrhythmias. Coronary o c c l u s i o n a l s o r e s u l t e d i n an i n c r e a s e i n cAMP l e v e l s i n ischemic t i s s u e which was maximal a t 15 minutes and p a r a l l e l e d an i n c r e a s e i n arrhythmias. C y c l i c AMP was a l s o e l e v a t e d i n the normal myocardium f o l l o w i n g o c c l u s i o n , but to a s i g n i f i c a n t l y lower extent than i n ischemic 19 t i s s u e . Spontaneous v e n t r i c u l a r f i b r i l l a t i o n was s i g n i f i c a n t l y c o r r e l a t e d w i t h e l e v a t e d cAMP l e v e l s . Pretreatment w i t h p r o p r a n o l o l caused a s i g n i f i c a n t r e d u c t i o n i n cAMP l e v e l s and a lower i n c i d e n c e of arrhythmias and v e n t r i c u l a r f i b r i l l a t i o n . I ncreased washout of met a b o l i c waste products r e s u l t i n g from impaired blood flow and a l t e r e d c e l l u l a r p e r m e a b i l i t y have a l s o been proposed as mechanisms f o r a r r h y t h -mogenesis d u r i n g coronary a r t e r y r e p e r f u s i o n . I t has been observed t h a t p r o l o n g a t i o n of o c c l u s i o n time r e s u l t s i n an i n c r e a s e d i n c i d e n c e of induced v e n t r i c u l a r f i b r i l l a t i o n upon r e p e r f u s i o n (Corbalan e t a l , 1976). I t i s p o s s i b l e t h a t there may be a minimum o c c l u s i o n time r e q u i r e d f o r some of these b i o c h e m i c a l a l t e r a t i o n s to occur. Increased 'washout' o f potassium and l a c t a t e from ischemic myocardium has been r e p o r t e d d u r i n g r e p e r f u s i o n (Lang e t a l , 1974). These metabolic products may be r e l e a s e d due to d i s r u p t i o n of c e l l u l a r membrane i n t e g r i t y and may c o n t r i b u t e t o l o c a l i z e d e l e c t r o p h y s i o l o g i c a l changes i n the myocardium. c) E l e c t r o p h y s i o l o g i c a l E f f e c t s of L i d o c a i n e i n Normal  and Ischemic Myocardium L i d o c a i n e has been shown to f u r t h e r slow conduction v e l o c i t y i n ischemic c a r d i a c t i s s u e without e f f e c t on normal t i s s u e (Kupersmith, 1979). Since conduction i n ischemic myocardium i s a l r e a d y slowed, thereby p r o v i d i n g a mechanism f o r r e - e n t r y , f u r t h e r slowing of impulses i n t h i s r e g i o n may r e s u l t i n b i d i r e c t i o n a l b l o c k and t e r m i n a t i o n of r e - e n t r y . L a z z a r a 20 e t a l (1978) o b s e r v e d t h a t l i d o c a i n e c o n s i s t e n t l y reduced c o n d u c t i o n i n i s o l a t e d i s c h e m i c c a r d i a c c e l l s , and t h a t t h i s change i n c o n d u c t i o n c o i n c i d e d w i t h t h e d i s a p p e a r a n c e o f abnormal spontaneous b e a t s . T h i s i m p a i r e d c o n d u c t i o n was t o t a l l y e x t i n g u i s h e d by l i d o c a i n e as w e l l as by t e t r o d o t o x i n . They c o n c l u d e d t h a t a r r h y t h m i a s may r e s u l t from d e p r e s s i o n of t h e f a s t sodium c h a n n e l s i n i s c h e m i c c e l l s r e s u l t i n g i n slowed c o n d u c t i o n . Membrane r e s p o n s i v e n e s s ( u p s t r o k e v e l o c i t y o f phase 0 i n r e l a t i o n t o r e s t i n g membrane p o t e n t i a l ) was a l s o i m p a i r e d i n i s c h e m i c c e l l s and was f u r t h e r r e d u c e d by l i d o c a i n e . T h i s may a l s o c o n t r i b u t e t o the o b s e r v a t i o n t h a t l i d o c a i n e e x t i n g u i s h e s c o n d u c t i o n i n i s c h e m i c c e l l s w hich p r e v i o u s l y e x h i b i t e d d e l a y e d c o n d u c t i o n and r e - e n t r y . The e f f e c t s o f l i d o c a i n e i n a b o l i s h i n g a l r e a d y d e p r e s s e d f a s t r e s p o n s e s have a l s o been r e p o r t e d by Brennan e t a l (1975). A n o t h e r mechanism by w h i c h l i d o c a i n e may e x e r t i t s a n t i a r r h y t h m i c e f f e c t s i s t h r o u g h a l t e r a t i o n s i n r e f r a c t o r y p e r i o d . L i d o c a i n e has been shown t o p r o l o n g th e e f f e c t i v e r e f r a c t o r y p e r i o d (ERP) i n i s c h e m i c c a r d i a c t i s s u e w i t h o u t s i g n i f i c a n t l y c h a n g i n g a c t i o n p o t e n t i a l d u r a t i o n (APD) ( K u p e rsmith, 1979). The e f f e c t s seen i n normal t i s s u e were a d e c r e a s e i n APD b u t no e f f e c t on ERP. The o v e r a l l r e s u l t , t h e r e f o r e , was a d e c r e a s e i n the r a t i o o f APD/ERP t o a p p r o x i m a t e l y 1.0 i n t h e i s c h e m i c zone, w i t h a s m a l l e r r e ^ d u c t i o n o c c u r r i n g i n the normal zone. T h i s change i n r e f r a c t o r i n e s s i n t i s s u e known t o g e n e r a t e a r r h y t h m i a s may a l s o e x p l a i n some o f the a n t i a r r h y t h m i c p r o p e r t i e s o f l i d o c a i n e . A u t o m a t i c i t y has been shown t o be a l t e r e d by l i d o c a i n e t h r o u g h a r e t a r d a t i o n o f spontaneous phase 4 d e p o l a r i z a t i o n 21 (Bigger and Mandel, 1970; Rosen e t a_l, 1973) without r e d u c i n g the r e s t i n g membrane p o t e n t i a l (Lazzara e t a l , 1975). Han and c o l l e a g u e s (1974) demonstrated the a b i l i t y of l i d o c a i n e to suppress e c t o p i c beats due to enhanced a u t o m a t i c i t y and r e -e n t r y f o l l o w i n g m y ocardial ischemia i n the dog. The r e d u c t i o n i n 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 r e s h o l d (VFT) accompanying coronary a r t e r y o c c l u s i o n has been shown to be a b o l i s h e d by l i d o c a i n e (Spear e t a l , 1972; Borer e t a l , 1976). A d m i n i s t r a t i o n of l i d o c a i n e i n these s t u d i e s was,also a s s o c i a t e d w i t h a r e d u c t i o n i n the i n c i d e n c e of spontaneous v e n t r i c u l a r f i b r i l l a t i o n . The p o s s i b i l i t y t h a t l i d o c a i n e may a f f e c t VFT d u r i n g m y o c a r d i a l ischemia has a l s o been i n v e s t i g a t e d by Kramer and coworkers (1981), who found no d i f f e r e n c e i n t h r e s h o l d v a l u e s between c o n t r o l and l i d o c a i n e - t r e a t e d groups. The d i s c r e p a n c i e s between r e s u l t s may be due to d i f f e r e n c e s i n stimulus frequency and i n t e n s i t y used to determine VFT. Pre-treatment w i t h l i d o c a i n e has been shown to be e f f e c t i v e i n r e d u c i n g the i n c i d e n c e of arrhythmias and v e n t r i c u l a r f i b r i l l a t i o n f o l l o w i n g coronary a r t e r y l i g a t i o n i n r a t s (Kane e t aJL, 1979) . I t has a l s o been shown to e l e v a t e VFT and a f f o r d p r o t e c t i o n a g a i n s t ouabain-induced arrhythmias i n i s o l a t e d r a b b i t and guinea p i g h e a r t s ( A l m o t r e f i and Baker, 1980; A l m o t r e f i and Baker, 1981). Boudoulas and coworkers (1978 a) have found t h a t l i d o c a i n e e x e r t e d a p r o t e c t i v e e f f e c t on canine ischemic myocardium. F o l l o w i n g coronary a r t e r y o c c l u s i o n , ST-segment e l e v a t i o n commonly seen d u r i n g ischemia was reduced by l i d o c a i n e , and coronary s i n u s CPK was shown to i n c r e a s e i n the c o n t r o l 22 group more than i n the l i d o c a i n e - t r e a t e d group. They p o s t u l a t e d t h a t t h i s p r o t e c t i o n may r e s u l t from the negative i n o t r o p i c e f f e c t of l i d o c a i n e . Boudoulas et a l (1978 b) have a l s o reported t h a t l i d o c a i n e decreased ischemic i n j u r y and n e c r o s i s f o l l o w i n g coronary o c c l u s i o n . Pretreatment w i t h l i d o c a i n e 10 minutes p r i o r to a 40 minute coronary a r t e r y o c c l u s i o n ( i n dogs) has been shown to r e s u l t i n a t h r e e - f o l d r e d u c t i o n i n i n f a r c t s i z e , a r e d u c t i o n i n v e n t r i c u l a r arrhythmias upon o c c l u s i o n and r e l e a s e , decreased r a t e of r i s e of l e f t v e n t r i c u l a r developed pressure and increased l e f t v e n t r i c u l a r e n d - d i a s t o l i c pressure (Nasser et a l , 1980). Coronary a r t e r y o c c l u s i o n was a s s o c i a t e d w i t h decreased m i t o c h o n d r i a l r e s p i r a t i o n i n the center of i n f a r c t e d t i s s u e which was not a l t e r e d by l i d o c a i n e therapy. Since r e g i o n a l myocardial blood flow was lowest i n the l i d o c a i n e - t r e a t e d groups, the authors proposed th a t l i d o c a i n e d i d not exert i t s e f f e c t s through negative i n o t r o p i c mechanisms but r a t h e r through p r e s e r v a t i o n of myocardial c e l l membrane i n t e g r i t y . In an u n c o n t r o l l e d study, Carden and Steinhaus (1956) reported s u c c e s s f u l r e s u s c i t a t i o n from v e n t r i c u l a r f i b r i l l a t i o n i n 21 of 23 dogs f o l l o w i n g i n t r a v e n t r i c u l a r a d m i n i s t r a t i o n of l i d o c a i n e . L i d ocaine dosage was 15mg/Kg and response was seen i n a mean time of 7 minutes (range 2 - 2 7 minutes). d) E f f e c t s of Lidocaine Seen C l i n i c a l l y L i d o c aine was f i r s t synthesized i n Sweden i n 194 3 and was used f o r many years as a l o c a l a n e s t h e t i c agent. In 1950, Southworth e t a l reported the s u c c e s s f u l use of l i d o c a i n e 23 to reverse v e n t r i c u l a r f i b r i l l a t i o n which r e s u l t e d from c a r d i a c c a t h e t e r i z a t i o n . In 1967, Lown proposed the concept t h a t premature v e n t r i c u l a r c o n t r a c t i o n s (PVCs) were warning arrhythmias which would u l t i m a t e l y lead to v e n t r i c u l a r f i b r i l l a t i o n or v e n t r i c u l a r t a c h y c a r d i a . Suppression of these e c t o p i c beats w i t h a n t i -arrhythmic therapy was t h e r e f o r e presumed to be a l o g i c a l step i n the prevention of the more se r i o u s subsequent arrhythmias. The terms 'warning arrhythmias 1 or 'premonitory arrhythmias 1 g e n e r a l l y r e f e r r e d to frequent v e n t r i c u l a r e c t o p i c beats or PVGs (greater than 5/minute), m u l t i f o c a l or p a i r e d e c t o p i c s , and those o c c u r r i n g on or near the preceeding T wave. Lidocaine has been demonstrated to be very e f f e c t i v e i n t e r m i n a t i n g v e n t r i c u l a r t a c h y c a r d i a and i n a b o l i s h i n g or reducing the number and frequency of PVCs when plasma l e v e l s of 1.5 - 5.5 /ig/mL are obtained ( G i a n e l l y et a l , 1967; J e w i t t et a l , 1968; Spracklen et a l , 1968). L i d o c a i n e , t h e r e f o r e , has been used r o u t i n e l y to suppress v e n t r i c u l a r e c t o p i c beats during the acute phase of myocardial i n f a r c t i o n and presumably to prevent VF or v e n t r i c u l a r tachy-c a r d i a . Plasma l i d o c a i n e l e v e l s greater than 6 jug/mL may be a s s o c i a t e d w i t h t o x i c i t y , such as muscular i r r i t a b i l i t y , convul-s i o n s , myocardial depression , and coma:(Gianelly et a l , 1967; Benowitz and M e i s t e r , 1978). More r e c e n t l y , the concept t h a t VF i s preceeded by warning arrhythmias, and t h a t a n t i a r r h y t h m i c therapy at t h a t time w i l l prevent VF i n those p a t i e n t s , has been questioned. I t has been observed t h a t 25%-40% of p a t i e n t s d i d not e x h i b i t warning arrhythmias p r i o r to VF, and t h a t premonitory arrhythmias occur 24 as f r e q u e n t l y i n p a t i e n t s who do not develop VF as i n those p a t i e n t s who do (Lie et a l , 1975; Ribner e t a l , 1979). Furthermore, many 'warning arrhythmias' may go un-detected during r o u t i n e s u r v e i l l a n c e i n a coronary care u n i t , r e s u l t i n g i n delayed a n t i a r r h y t h m i c therapy (Lown e_t a l , 1975) . A t t e n t i o n has since been focused on the concept of prop h y l a x i s a g a i n s t VF i n a l l p a t i e n t s w i t h acute myocardial i n f a r c t i o n . L i d ocaine p r o p h y l a x i s has rec e i v e d considerable a t t e n t i o n i n the l i t e r a t u r e . L i e e t a l , (1974), i n a do u b l e - b l i n d , randomized t r i a l i n a s e r i e s of 212 consecutive p a t i e n t s , assessed the e f f i c a c y of l i d o c a i n e i n preventing VF i n acute myocardial i n f a r c t i o n . Their f i n d i n g s i n d i c a t e t h a t l i d o c a i n e i n the dosage given was h i g h l y e f f e c t i v e (p< 0.002) i n preventing VF. These f i n d i n g s were supported by other workers (Valentine et a l , 1974; Wyman and Hammersmith, 1974; S z e p l a k i e t a l , 1976). Although prompt treatment w i t h a n t i a r r h y t h m i c drugs may decrease the incidence of VF, many p a t i e n t s s t i l l develop VF e i t h e r p r i o r to a r r i v a l of a p r e - h o s p i t a l advanced l i f e support u n i t (ALS), p r i o r to a r r i v a l a t h o s p i t a l , or before d e f i n i t i v e a n t i a r r h y t h m i c drug therapy has been i n s t i t u t e d . E l e c t r i c a l d e f i b r i l l a t i o n v i a d i r e c t - c u r r e n t countershock i s the treatment of choice to reverse the f i b r i l l a t i o n , but t h i s i s not always s u c c e s s f u l . In a s e r i e s of 301 p a t i e n t s t r e a t e d by the ALS rescue squad from the'Miami F i r e Department, only 199 could be d e f i b -r i l l a t e d d e s p i te the use of conventional c a r d i a c a r r e s t drug t h e r ^ apy. Furthermore, of those d e f i b r i l l a t e d , approximately 40% had recurrence of VF. Approximately 50% of those d e f i b r i l l a t e d died p r i o r to a r r i v a l a t h o s p i t a l (Liberthson e t a l , 1974). Eisenberg 25 et a l (1980) reported t h a t i n 36 cases of o u t - o f - h o s p i t a l v e n t r i c u l a r f i b r i l l a t i o n , 27 p a t i e n t s remained i n v e n t r i c u l a r f i b r i l l a t i o n a f t e r the f i r s t d e f i b r i l l a t i o n attempt. Both epinephrine and l i d o c a i n e are c u r r e n t l y used i n ca r d i a c a r r e s t p r o t o c o l s i n the management of v e n t r i c u l a r f i b r i l l a t i o n (American Heart A s s o c i a t i o n , 1980; Redding, 1977). The question as to whether l i d o c a i n e i s u s e f u l i n r e s t o r i n g e f f e c t i v e c a r d i a c c o n t r a c t i o n s from VF i s not c l e a r . A review of the ; l i t e r a t u r e , .revealed. no c o n t r o l l e d s t u d i e s i n the use of l i d o c a i n e alone i n the management of VF. Nevertheless, i t has been the concept i n c a r d i a c a r r e s t drug therapy t h a t l i d o c a i n e and/or epinephrine be used i n the treatment of VF unresponsive to d e f i b r i l l a t i o n , s ince w i t h h o l d i n g drugs i n t h i s s i t u a t i o n w i l l c e r t a i n l y not be of value. 3. Rationale and Purpose of the Present Study S t a t i s t i c s from the Vancouver Advanced L i f e Support Program i n d i c a t e t h a t approximately 13% of p a t i e n t s t r e a t e d i n the p r e - h o s p i t a l s e t t i n g f a i l t o have an IV l i n e e s t a b l i s h e d a f t e r two attempts (Emergency Health Services Academy, 1982). These p a t i e n t s , t h e r e f o r e , cannot r e c e i v e adequate drug therapy u n t i l the IV l i n e i s i n pla c e , unless a l t e r n a t e routes of drug a d m i n i s t r a t i o n are a v a i l a b l e . I t i s p o s s i b l e that l i d o c a i n e may be e f f e c t i v e when administered i n the form of a s o l u t i o n v i a an endotracheal tube. The r a t e and extent of absorption need to be determined during both normal c a r d i o v a s c u l a r s t a t u s and v e n t r i c u l a r f i b r i l l a t i o n . L idocaine i s c u r r e n t l y i n widespread use i n the 26 treatment and prevention of v e n t r i c u l a r f i b r i l l a t i o n and ta c h y c a r d i a . Considerable e f f o r t has been d i r e c t e d towards prevention of these arrhythmias, and i t appears t h a t l i d o c a i n e may be e f f e c t i v e when given p r i o r t o the onset of VF. Lidocaine appears to be e f f e c t i v e i n the treatment of v e n t r i c u l a r tachy-c a r d i a . Prevention of VF i s of v i t a l concern during the i n i t i a l stages of acute myocardial i n f a r c t i o n . However, s i g n i f i c a n t numbers of p a t i e n t s are i n VF when seen by an emergency ALS crew, or develop VF before any d e f i n i t i v e treatment i s i n s t i t u t e d . D e f i b r i l l a t i o n and c o r r e c t i o n of acid-base balance are of primary concern i n t h i s s i t u a t i o n . I t appears th a t d e s p i t e the use of e l e c t r i c a l d e f i b r i l l a t i o n , approximately 1/3 -' 1/2 of p a t i e n t s are not able to be d e f i b r i l l a t e d s u c c e s s f u l l y . Evidence i n the l i t e r a t u r e suggests th a t l i d o c a i n e may a b o l i s h v e n t r i c u l a r arrhythmias by e l i m i n a t i n g r e - e n t r a n t pathways and by reducing augmented a u t o m a t i c i t y . I t i s th e r e f o r e p o s s i b l e t h a t l i d o c a i n e may a s s i s t e l e c t r i c a l d e f i b r i l l a t i o n i n te r m i n a t i n g v e n t r i c u l a r f i b r i l l a t i o n . The value of l i d o c a i n e i n the te r m i n a t i o n of ongoing VF has not been e s t a b l i s h e d . Although epinephrine and l i d o c a i n e are used i n t h i s s i t u a t i o n , the e f f i c a c y of e i t h e r agent has not been demonstrated c o n c l u s i v e l y i n c o n t r o l l e d c l i n i c a l t r i a l s . I t appears th a t the e f f i c a c y of l i d o c a i n e i n the treatment of v e n t r i c u l a r f i b r i l l a t i o n due to acute myocardial i n f a r c t i o n i s a question which has yet to be answered. I t i s the aim of t h i s study to i n v e s t i g a t e the e f f i c a c y of l i d o c a i n e when administered v i a an endotracheal tube during experimentally-induced v e n t r i c u l a r f i b r i l l a t i o n . Onset, peak 27 and d u r a t i o n of plasma l i d o c a i n e l e v e l s w i l l be examined f o l l o w i n g both endotracheal and intravenous a d m i n i s t r a t i o n i n a r a b b i t model. 28 MATERIALS AND METHODS 1. Plasma Lidocaine Level Studies a) Animal Experiments White New Zealand r a b b i t s of e i t h e r sex weighing 2.0 -3.5 Kg. were anesthetized w i t h e i t h e r halothane v i a i n h a l a t i o n or intravenous sodium p e n t o b a r b i t a l . Halothane was administered i n i t i a l l y i n a conc e n t r a t i o n of approximately 4%. When deep pai n r e f l e x e s were absent the r a b b i t s were intubated o r a l l y w i t h a M a g i l l type endotracheal tube ( s i z e 3.0 - 4.0 I.D., N a t i o n a l Catheter Corp.) using a Welch A l l y n laryngescope and p e d i a t r i c s i z e M i l l e r blade ( s i z e 01). Anesthesia was maintained w i t h 1.0 -1.5% halothane and r a b b i t s were allowed to breathe spontaneously. Halothane c o n c e n t r a t i o n was regulated using two flowmeters (Roger Gilmont Instruments I n c . ) . One flowmeter d e l i v e r e d 95% 0 2/5% C0 2 while the other passed 0 2/C0 2 through a chamber c o n t a i n i n g halothane l i q u i d . P e n t o b a r b i t a l (30 - 60 mg/Kg) was i n j e c t e d v i a the marginal ear v e i n using a 21 gauge b u t t e r f l y i n f u s i o n s et (Abbott Venisystems) kept patent using normal s a l i n e w i t h heparin (5 u n i t s / m l ) . Supplemental p e n t o b a r b i t a l was o c c a s i o n a l l y r e q u i r e d during long experiments. P e n t o b a r b i t a l - a n e s t h e t i z e d r a b b i t s were placed i n a supine p o s i t i o n on an operating t r a y and an endotracheal tube was placed v i a tracheotomy i n the same a n t e r o - p o s t e r i o r 29 p o s i t i o n as would be achieved v i a o r a l intubation. The rabbits were respired at a rate of 26 per minute and t i d a l volume of 25 - 35 ml ( C F . Palmer Respirator). A r t e r i a l blood pressure (BP) was recorded from the carotid artery using a Gould Statham P23Db phys i o l o g i c a l pressure transducer. A three-way stopcock was attached to the carotid artery cannula for sampling of a r t e r i a l blood for plasma lidocaine determinations. Lead II of a three-lead electrocardiogram (ECG) was monitored using Grass needle electrodes. Both ECG and blood pressure were recorded continuously on a Grass Instruments 2-Channel Polygraph. Rectal temperature was monitored with a Yellow Springs Instruments Model 47 scanning telethermometer and temperature was maintained between 37°C - 39°C using an infrared heating lamp. Normal rabbit body temperature i s 39.4°C (Kaplan, 1979). For endotracheal lidocaine studies a solution of lidocaine 2 mg/ml in either d i s t i l l e d water or normal saline was i n s t i l l e d d i r e c t l y into the endotracheal tube, followed by four quick lung i n f l a t i o n s using a pe d i a t r i c Laerdal bag. Unless otherwise stated, the dosage used for a l l experiments was 2 mg/kg lidocaine HC1. Following i n s t i l l a t i o n of the solution the endotracheal tube was either reconnected to the respirator or the rabbit was allowed to resume spontaneous respirations, depending on the anesthetic used. For intravenous experiments, either a 2 mg/ml solution of lidocaine in d i s t i l l e d water was injected within f i v e 30 seconds into the rabbit marginal ear vein or a 20 rug/ml solution of lidocaine in normal saline was injected into a d i s t a l hind leg vein at the same rate. The leg vein was isolated s u r g i c a l l y and cannulated with polyethylene tubing (PE - 90). Following i n j e c t i o n of either lidocaine solution the tubing was flushed with 0.25 ml normal saline. Following either endotracheal i n s t i l l a t i o n or intravenous i n j e c t i o n of lidocaine, 0.5 ml a r t e r i a l blood samples were withdrawn from the caroti d artery cannula at 15 seconds, 30 seconds, 1 minute, 2, 3, 4, 10, 20 and 30 minutes. Samples were placed in 1.5 ml polypropylene microcentrifuge tubes (VWR S c i e n t i f i c Inc.) containing approximately 1.5 mg disodium EDTA per tube. The samples were centrifuged in an Eppendorf microcentrifuge for one minute at 8000 x g, and the plasma was stored in a re f r i g e r a t o r (4-6°C) for future lidocaine assay. Unless otherwise stated, plasma lidocaine l e v e l studies were performed in animals in which no further surgical procedures had been performed. "Open Chest" and "Ventricular F i b r i l l a t i o n " s u r g i c a l procedures are described in section II and were employed for some studies where indicated, b) LIDOCAINE ASSAY Plasma samples were assayed for lidocaine within seven days of the experiment using EMIT enzyme immunossay marketed by Syva Diagnostics Ltd., Montreal (Pape et a l , 1978; Rubenstein, 1978) (Figure 1). Preliminary studies were conducted in the lab to ascertain that s t a b i l i t y of the samples 31 Figure 1 P r i n c i p l e of homogeneous enzyme immunoassay. When the enzyme-ligand conjugate i s complexed to the antibody ( l e f t ) , the enzyme substrate . i s excluded from the a c t i v e s i t e and enzyme a c t i v i t y i s reduced. The presence of l i g a n d r e l e a s e s a p o r t i o n of the enzyme conjugate, which i s then a c t i v e ( r i g h t ) . Copyright 1978 Syva Diagnostics L t d . , Montreal (with permission) 32 33 over t h i s time period lay within +5% of samples assayed immediately following experiments. Equipment used for the assay procedure consisted of a G i l f o r d Stasar III spectrophotometer, a Syva Model 1500 Pip e t t e r - D i l u t e r , a Syva CP-5000 Microprocessor, Emit -cad Lidocaine Assay K i t s , Emit -cad Lidocaine Control, and 1.5 ml disposable autoanalyzer cups (conical bottoms). Each Emit assay k i t consisted of Antibody/Substrate Reagent A, Enzyme Reagent B, six lidocaine c a l i b r a t o r s containing O, 1.0, 2.0, 3.0, 5.0 and 12.0 Aig/ml lidocaine, and 0.055M t r i s - H C l buffer solution (pH 7.9). A l l solutions were prepared prior to use with the addition of d i s t i l l e d water. Reconstituted Antibody/Reagent A contained a standardized preparation of immunized sheep gamma globulin, glucose-6-phosphate and NAD, monoethylglycinexylidide (MEGX) and preservative in 0.055M t r i s HC1 buffer at pH 5.0. Reconstituted Enzyme Reagent B contained glucose-6-phosphate dehydrogenase - l a b e l l e d lidocaine and preservatives in 0.55M t r i s HC1 buffer at pH 7.9. A standard curve was run at the sta r t of each assay. Standard procedure for either c a l i b r a t o r s or unknown samples was as follows: The p i p e t t e r - d i l u t e r was programmed to withdraw 50 u l of lidocaine sample (unknown or c a l i b r a t o r ) , Antibody/Substrate Reagent A, or Enzyme Reagent B and dispense i t with 250 pi t r i s HC1 buffer solution into an autoanalyzer cup. I n i t a l l y two s e r i a l d i l u t i o n s of 34 unknown or c a l i b r a t o r were performed, followed by the a d d i t i o n of 1:5 d i l u t i o n s of Reagent A and then Reagent B to the second l i d o c a i n e d i l u t i o n . The r e a c t i o n mixture was a s p i r a t e d immediately i n t o the spectrophotometer flow c e l l , a c t i v a t i n g the microprocessor to time and record absorbance measurements a t 15 and 45 seconds a f t e r a s p i r a t i o n (expressed as a change i n absorbance over 30 seconds,A A). D u p l i c a t e absorbance measurements were made on the 0 ug/ml c a l i b r a t o r (AAQ) and the d i f f e r e n c e ( A A - A A Q ) between t h i s reading and the reading f o r the other c a l i b r a t o r s (AA) was determined by the microprocessor i n order to p l o t a standard curve. C a l i b r a t i o n of the standard curve was checked w i t h a known l i d o c a i n e c o n c e n t r a t i o n (4ug/ml). The absorbance measurements of unknown samples were used i n the same manner ( A A - A A Q ) to determine concentrations by use of the standard curve. D u p l i c a t e l i d o c a i n e determinations were made on each plasma sample. Plasma l i d o c a i n e l e v e l s greater than 13ug/ml (outside assay l i m i t s ) were determined by performing an a d d i t i o n a l 1:5 d i l u t i o n of the plasma sample p r i o r to a d d i t i o n of Reagents A & B. 2. Coronary A r t e r y L i g a t i o n / V e n t r i c u l a r F i b r i l l a t i o n Studies White New Zealand r a b b i t s weighing 2.0-3.5 Kg were anesthetized w i t h intravenous p e n t o b a r b i t a l and prepared as 35 Figure 2 Schematic r e p r e s e n t a t i o n of the p o s i t i o n of the suture placed around the l e f t c i r c u m f l e x coronary a r t e r y . Figure 2.a C r o s s - s e c t i o n a l r e p r e s e n t a t i o n of placement of the l i g a t i n g suture before and a f t e r l i g a t i o n was secured. 36 37 described in section 1. The chest was opened with a medial i n c i s i o n through the sternum and retractors were used to enlarge the chest opening. The thymus gland was either p a r t i a l l y removed or clamped to the chest wall to provide clear v i s u a l i z a t i o n of the heart. The pericardium was opened medially and attached to the chest wall with 4-0 s i l k suture (Ethicon, Inc.) i f necessary, to provide a cradle for the heart. Using 4-0 s i l k black braided cardiovascular sutures (Ethicon, Inc.) a t i e was placed in the apex of the l e f t v e n t r i c l e to a s s i s t in manipulation of the heart. The l e f t circumflex branch of the l e f t coronary artery was vi s u a l i z e d by l i f t i n g the l e f t a t r i a l appendage with forceps and rotating the heart s l i g h t l y to the righ t . A cardiovascular 4-0 s i l k suture was then placed through the myocardium and around the artery as diagrammed in Figures 2 and 2a. The suture ends were passed through a piece of polyethylene tubing for later use i n clamping off the artery. When possible, the suture was placed proximal to d i v i s i o n of the circumflex artery into two branches. When the ligature was i n place the heart was allowed to recover for at least 10 - 20 minutes or u n t i l blood pressure and ECG returned to pre-thoracotomy l e v e l s . Ligation of the artery was accomplished by p u l l i n g both ends of the suture through the tubing and clamping t i g h t l y with hemostatic forceps (Figure 2a). Occlusion of the artery could be vi s u a l i z e d by blanching of part of the l e f t v e n t i c l e , often the apex and posterior wall, and was usually accompanied by a drop i n a r t e r i a l blood pressure. 38 Occulsion of the artery was maintained for 15 minutes at which time the ligature was loosened and a 5 minute reperfusion phase allowed to occur. At the end of the reperfusion phase the ligature was resecured. A maximum of three cycles of occlusion (15 minutes) and reperfusion (5 minutes) were performed. Ventricular f i b r i l l a t i o n occurred during both occlusion and reperfusion phases, although i t did not occur i n every experiment. Each experiment f e l l into one of three d i s t i n c t categories depending on the frequency and length of f i b r i l l a t i o n : 1. No ventricular f i b r i l l a t i o n : The heart did not f i b r i l l a t e at any time during the experiment. 2. Short ventricular f i b r i l l a t i o n : Ventricular f i b r i l l a t i o n persisted for less than 2 minutes and terminated spontaneously (mean 0.6 minutes, range 0.2 - 1.8 minutes). 3. Long ventricular f i b r i l l a t i o n : Ventricular f i b r i l l a t i o n persisted longer than 2 minutes (mean 9.7 minutes, range 6.3 - 12.5 minutes). This group was used for both plasma lidocaine l e v e l studies during ventricular f i b r i l l a t i o n and lidocaine e f f i c a c y studies. Blood pressure, ECG and frequency of arrhythmias were monitored at various times, for comparison of these parameters with tendency to f i b r i l l a t e in the three categories. When ventricular f i b r i l l a t i o n did occur the heart was 39 allowed to f i b r i l l a t e for 15 seconds with no intervention. Manual pumping of the heart would then be started to maintain mean a r t e r i a l blood pressure between 25-50 mmHg. A r t i f i c i a l c i r c u l a t i o n would be continued for 2 minutes of ventricular f i b r i l l a t i o n unless the heart started to beat again on i t s own. If conversion to spontaneous cardiac rhythm occurred within t h i s two minute period, the arrhythmia would be included in a "short ventricular f i b r i l l a t i o n " category and the experiment continued in the appropriate occlusion/reperfusion cycle. When ventricular f i b r i l l a t i o n occurred during an occlusion phase the ligature was kept secured for the duration of the f i b r i l l a t i o n and i f i t occurred during reperfusion the t i e was l e f t loose. Further episodes of ventricular f i b r i l l a t i o n would be managed in the same manner depending on their duration. Plasma lidocaine l e v e l studies during ventricular f i b r i l l a t i o n were i n s t i t u t e d when f i b r i l l a t i o n had proceeded for at least two minutes. Lidocaine was administered either endotracheally or intravenously and carotid artery blood samples were drawn at appropriate times as detailed i n section 1. C i r c u l a t i o n was maintained by means of cardiac massage u n t i l the onset of spontaneous cardiac rhythm. Plasma lidocaine l e v e l studies in sham-operated open chest controls were treated in the same manner but with the l i g a t i o n l e f t unsecured and no cardiac massage necessary. Lidocaine e f f i c a c y studies were performed only when 40 ventricular f i b r i l l a t i o n had persisted for 2 minutes. After 2 minutes of ventricular f i b r i l l a t i o n either 2 mg/kg lidocaine (2 mg/ml i n normal saline) or l ml/kg normal saline was administered endotracheally in a blind, randomized fashion. Cardiac massage was maintained u n t i l the return of spontaneous cardiac rhythm or for the duration of the experiment. Untreated control experiments were performed in the same manner except no treatment was given at 2 minutes of ventricular f i b r i l l a t i o n . If spontaneous c i r c u l a t i o n resumed within ten minutes after administration of either lidocaine, s a l i n e , or no treatment, a r t i f i c i a l c i r c u l a t i o n was stopped and blood pressure and ECG were recorded. Subsequent cardiovascular status was monitored for 30 minutes. If ventricular f i b r i l l a t i o n persisted, at 10 minutes following administration of lidocaine, normal saline or no treament, e l e c t r i c a l d e f i b r i l l a t i o n was attempted (0.5 joules) to a maximum of 2 d e f i b r i l l a t i o n attempts (Mennen-Greatback Electr o n i c s Inc. DC D e f i b r i l l a t o r ) . If d e f i b r i l l a t i o n was successful the cardiovascular status was monitored for 30 minutes as above. At the end of each experiment, the heart was removed and perfused with 20ml normal saline on a modified Langendorf-type apparatus. With the l i g a t i o n secured, the heart was then perfused slowly with 20ml Methyl Green B i o l o g i c a l Stain (0.5 mg/ml) to delineate the occluded areas of the myocardium. Occluded areas were excised, weighed and expressed as percent wet weight of l e f t v e n t r i c u l a r , right ventricular and t o t a l ventricular mass. 4 1 3. Analyses and S t a t i s t i c s Plasma l i d o c a i n e values were c a l c u l a t e d by the Syva CP 5 000 microprocessor i n r e l a t i o n to a standard curve f o r l i d o c a i n e . Samples were assayed i n d u p l i c a t e and the mean value entered as one data p o i n t . A l l values were p l o t t e d as the mean + standard e r r o r of the mean (S.E.M.) f o r the i n d i c a t e d number of experiments. The Student's t - t e s t f o r unpaired data was used to determine s t a t i s t i c a l s i g n i f i c a n c e between treatment groups. Data were considered to be s i g n i f i c a n t l y d i f f e r e n t at p<0.05 f o r a 2 - t a i l e d t e s t . F i r s t - o r d e r r a t e constants f o r e l i m i n a t i o n (fi) were determined from the slope of the back-extrapolated e l i m i n a t i o n p o r t i o n of the l o g c o n c e n t r a t i o n vs time curve. Absorption-d i s t r i b u t i o n (endotracheal) and d i s t r i b u t i o n (intravenous) r a t e constants (<<) were c a l c u l a t e d from the slope of the l i n e c a l c u l a t e d by the method of r e s i d u a l s . Slope, y - i n t e r c e p t , and c o r r e l a t i o n c o e f f i c i e n t (r) were determined using l o g l i n e a r l e a s t squares r e g r e s s i o n a n a l y s i s . C a l c u l a t i o n of the area under the curve f o r the f i r s t ten minutes f o l l o w i n g drug a d m i n i s t r a t i o n (AUC^Q) was done by the t r a p e z o i d a l r u l e method. F r a c t i o n of an endotracheal dose absorbed i n ten minutes (f^g) was c a l c u l a t e d by the formula AUC 1 Q (ET) f i o = — AUC,n (IV) 42 Clearance of l i d o c a i n e i n ten minutes (CI^Q) was c a l c u l a t e d using the formula. C l 1 0 f^Q x dose AUC 1 ( ) These parameters are not true values since they assess c o n d i t i o n s during the f i r s t ten minute of each experiment only. The c a l c u l a t e d values should t h e r e f o r e be i n t e r p r e t e d c a u t i o u s l y , 4. Drugs and Chemicals Disodium ethylenediamine t e t r a a c e t i c a c i d (Disodium EDTA or EDTA) - Sigma Chemical Co. Halothane (Fluothane ) - Ayerst L a b o r a t o r i e s . Lidocaine HC1 - Dottbonapace Co., I t a l y , and I.M.S. L t d . , Montreal. P e n t o b a r b i t a l sodium - B.D.H. Chemical Co. RESULTS 1. Plasma Lidocaine L e v e l Studies a) Endotracheal vs Intravenous Lidocaine i n D i s t i l l e d  Water During Halothane Anesthesia Figure 3 shows a r t e r i a l plasma l i d o c a i n e l e v e l s obtained f o l l o w i n g e i t h e r endotracheal i n s t i l l a t i o n or intravenous i n j e c t i o n of 2mg/Kg l i d o c a i n e (2mg/ml i n d i s t i l l e d water). The experiments were performed under halothane anesthesia and i n j e c t i o n was made v i a the marginal ear v e i n . A d m i n i s t r a t i o n of l i d o c a i n e endotracheally r e s u l t e d i n s i g n i f i c a n t l y higher plasma concentrations at 15 seconds and 1 minute although there was no s i g n i f i c a n t d i f f e r e n c e at or f o l l o w i n g the 2 minute p o i n t . A semi-logarithmic p l o t of plasma l i d o c a i n e con-c e n t r a t i o n vs time i s shown i n Figure 4. Foll o w i n g both i n t r a -venous i n j e c t i o n and endotracheal i n s t i l l a t i o n , l i d o c a i n e was shown to e x h i b i t f i r s t - o r d e r pharmacokinetic behavior. C a l c u l a t e d r a t e constants and h a l f - l i v e s f o r d i s t r i b u t i o n and e l i m i n a t i o n are summarized i n Table I . The combined ab s o r p t i o n -d i s t r i b u t i o n r a t e constant (=* ) f o r endotracheal l i d o c a i n e had a c a l c u l a t e d value approximately 70% t h a t of intravenous i n j e c t i o n . E l i m i n a t i o n r a t e constants (y^) were s i m i l a r f o r both routes. b) The E f f e c t of P e n t o b a r b i t a l or Halothane Anesthesia on  the Endotracheal Absorption of Lidocaine i n D i s t i l l e d Water 44 Figure 3 Plasma l i d o c a i n e l e v e l s vs time f o l l o w i n g endotracheal (ET) i n s t i l l a t i o n or intravenous (IV) i n j e c t i o n of 2mg/Kg l i d o c a i n e (2mg/ml i n d i s t i l l e d water) during halothane anesthesia. Numbers of experiments are i n d i c a t e d . A l l p o i n t s represent mean plasma l e v e l s - S.E.M. of the number of experiments i n d i c a t e d . s i g n i f i c a n t l y g r eater than IV at p<0.05. 46 Figure 4 Log plasma l i d o c a i n e concentrations vs time f o l l o w i n g endotracheal (ET) i n s t i l l a t i o n or intravenous (IV) i n j e c t i o n of 2mg/Kg l i d o c a i n e (2mg/ml i n d i s t i l l e d water) during halothane anesthesia. A l l p o i n t s represent mean plasma concentrations of the number of experiments i n d i c a t e d . * s i g n i f i c a n t l y greater than IV at p<0.05. Log plasma l idocaine (ug/ml) 3 II 48 Table 1 C a l c u l a t e d f i r s t - o r d e r a b s o r p t i o n - d i s t r i b u t i o n K E T ) / d i s t r i b u t i o n (?S|'IV) , and e l i m i n a t i o n {ft) r a t e constants and plasma h a l f - l i v e s f o r intravenous i n j e c t i o n and endotracheal i n s t i l l a t i o n of 2mg/Kg l i d o c a i n e (2mg/ml) i n d i s t i l l e d water. Route of A d m i n i s t r a t i o n Lidocaine Lidocaine 2mg/kg IV 2mg/kg ET . -1 n „^ . -1 1.77 mm 1.23 mm (r=-0.9789) (r=-0.9973) -2 -1 2.03 x 10 min 1.99 x 1 0 ~ 2 m i n _ 1 (r=-0.9906) th (<?0 0.347 min 0.563 min th (jS) 32.7 min 34.8 min a - data c a l c u l a t e d from Figure 4. 49 Figure 5 shows plasma l i d o c a i n e concentrations observed f o l l o w i n g endotracheal i n s t i l l a t i o n of l i d o c a i n e 2mg/ml i n d i s t i l l e d water during e i t h e r halothane or p e n t o b a r b i t a l anesthesia. Animals anesthetized w i t h halothane were allowed to breathe spontaneously w h i l e those anesthetized w i t h p e n t o b a r b i t a l were mechanically r e s p i r e d . Mean plasma l i d o c a i n e concentrations were greater at a l l time p o i n t s during halothane anesthesia, although the d i f f e r e n c e s were not s t a t i s t i c a l l y s i g n i f i c a n t . c) Plasma Lidocaine Levels F o l l o w i n g Endotracheal I n s t i l l a t i o n of Lidocaine i n E i t h e r D i s t i l l e d Water  or Normal S a l i n e During P e n t o b a r b i t a l Anesthesia Figure 6 shows the e f f e c t of using e i t h e r normal s a l i n e or d i s t i l l e d water as the v e h i c l e f o r l i d o c a i n e a d m i n i s t r a t i o n on l i d o c a i n e absorption v i a the endotracheal route. The dosage was 2mg/kg f o r both groups. A d m i n i s t r a t i o n of l i d o c a i n e 2mg/ml i n d i s t i l l e d water r e s u l t e d i n i n i t i a l plasma l i d o c a i n e con-c e n t r a t i o n s which were greater than those observed f o l l o w i n g a d m i n i s t r a t i o n of l i d o c a i n e 2mg/ml i n normal s a l i n e . This d i f f e r e n c e was s t a t i s t i c a l l y s i g n i f i c a n t (p< .05) at only 30 seconds a f t e r l i d o c a i n e a d m i n i s t r a t i o n . A f t e r 2 minutes, higher plasma l i d o c a i n e concentrations were observed when l i d o c a i n e was administered i n normal s a l i n e than when d i s t i l l e d water was used as the v e h i c l e . These d i f f e r e n c e s were not s t a t i s t i c a l l y s i g n i f i c a n t . F igure 7 represents a semi-logarithmic p l o t of plasma l i d o c a i n e c o n c e n t r a t i o n vs time f o l l o w i n g endotracheal 50 Figure 5 Plasma l i d o c a i n e concentrations vs time f o l l o w i n g endotracheal i n s t i l l a t i o n of 2mg/Kg l i d o c a i n e (2mg/ml i n d i s t i l l e d water) during e i t h e r halothane or p e n t o b a r b i t a l anesthesia. Numbers of experiments are i n d i c a t e d and a l l p o i n t s represent mean plasma l e v e l s - S.E.M. There was no s i g n i f i c a n t d i f f e r e n c e (p<0.05) between the two groups. 51 52 Figure 6 Plasma l i d o c a i n e concentrations vs time f o l l o w i n g endotracheal i n s t i l l a t i o n of 2mg/Kg l i d o c a i n e (2mg/ml) i n e i t h e r normal s a l i n e or d i s t i l l e d water. A l l animals were anesthetized w i t h p e n t o b a r b i t a l . Numbers of experiments are i n d i c a t e d and a l l p o i n t s represent mean plasma l e v e l s - S.E.M. s i g n i f i c a n t l y g r eater than normal s a l i n e at p< 0.05. 53 5 4 Figure 7 Log plasma l i d o c a i n e c o n c e n t r a t i o n vs time f o l l o w i n g endotracheal i n s t i l l a t i o n of 2mg/Kg l i d o c a i n e (2mg/ml) i n e i t h e r normal s a l i n e or d i s t i l l e d water. A l l animals were anesthetized w i t h p e n t o b a r b i t a l . A l l p o i n t s represent mean plasma l e v e l s - S.E.M. of the number of experiments i n d i c a t e d . 55 E \ CO 3 1.0 CD .9 C .8 CO OC .7 T3 .6 ma .5 00 ca Q. .4 C30 Lo .3 o • Normal Saline • Water 10 15 T ime (min) 20 25 56 a d m i n i s t r a t i o n of l i d o c a i n e i n e i t h e r normal s a l i n e or d i s t i l l e d water. This p l o t shows a r a p i d a b s o r p t i o n - d i s t r i b u t i o n phase f o r l i d o c a i n e i n d i s t i l l e d water which i s l o g l i n e a r , a l l o w i n g c a l -c u l a t i o n of a f i r s t - o r d e r a b s o r p t i o n - d i s t r i b u t i o n r a t e constant i n normal s a l i n e curve i s not log l i n e a r during e i t h e r the absorp-t i o n - d i s t r i b u t i o n or e l i m i n a t i o n phases up to 30 minutes, there-f o r e a best estimate of these r a t e constants was obtained. This was done by (a) assuming t h a t e l i m i n a t i o n of l i d o c a i n e a f t e r admin-i s t r a t i o n i n normal s a l i n e occurred i n a manner p a r a l l e l w i t h i t s e l i m i n a t i o n f o l l o w i n g a d m i n i s t r a t i o n i n d i s t i l l e d water, and (b) c a l c u l a t i n g the a b s o r p t i o n - d i s t r i b u t i o n r a t e constant from t h i s p a r a l l e l l i n e . d) Absorption of Lidocaine F o l l o w i n g Endotracheal A d m i n i s t r a t i o n of Lidocaine i n Normal S a l i n e During  Closed Chest C o n t r o l s , Open Chest Controls and  V e n t r i c u l a r F i b r i l l a t i o n Figure 8 shows the time course of plasma l i d o c a i n e l e v e l s f o l l o w i n g endotracheal a d m i n i s t r a t i o n of l i d o c a i n e 2mg/ml i n normal s a l i n e i n c l o s e d chest c o n t r o l s , open chest c o n t r o l s and open chest animals during v e n t r i c u l a r f i b r i l l a t i o n . A l l animals were an e s t h e t i z e d w i t h p e n t o b a r b i t a l . A d m i n i s t r a t i o n of l i d o c a i n e e n d o t r a c h e a l l y to sham-operated open chest c o n t r o l s r e s u l t e d i n s l i g h t l y higher plasma l i d o c a i n e concentrations over the f i r s t three minutes than a d m i n i s t r a t i o n to c l o s e d chest c o n t r o l s , although the d i f f e r e n c e was not s i g n i f i c a n t . When l i d o c a i n e i n normal s a l i n e was administered endo t r a c h e a l l y during v e n t r i c u l a r f i b r i l l a t i o n w i t h c a r d i a c (.es<) and e l i m i n a t i o n r a t e constant The l i d o c a i n e 57 Table I I C a l c u l a t e d f i r s t - o r d e r a b s o r p t i o n - d i s t r i b u t i o n ( o ( E T ) and e l i m i n a t i o n (/3) r a t e constants and plasma h a l f - l i v e s f o r endotracheal i n s t i l l a t i o n of 2mg/Kg l i d o c a i n e (2mg/ml) i n normal s a l i n e and d i s t i l l e d water. V e h i c l e of A d m i n i s t r a t i o n Lidocaine 2mg/ml i n D i s t i l l e d Water Lidocaine 2mg/ml i n Normal S a l i n e 0.741 m i n - 1 0.786 m i n - 1 -2 -1 2.53 x 10 min -2 -1 2.65 x 10 min th ( o i ) 0.935 min 0.882 min th (f3 ) 27.4 min 26.2 min a - data c a l c u l a t e d from Figure 7. 58 Figure 8 Plasma l i d o c a i n e l e v e l s vs time f o l l o w i n g endotracheal a d m i n i s t r a t i o n of 2mg/Kg l i d o c a i n e (2mg/ml i n normal s a l i n e ) during v e n t r i c u l a r f i b r i l l a t i o n w i t h c a r d i a c massage, open chest (sham-operated) c o n t r o l s and clo s e d chest c o n t r o l s . A l l animals were anesthetized w i t h p e n t o b a r b i t a l . A l l p o i n t s represent mean plasma l e v e l s + S.E.M. of the number of experiments i n d i c a t e d . * s i g n i f i c a n t l y g reater than open chest c o n t r o l s a t p < 0.05. 59 22\ 20-18-16 t * ET • Vent r i cu la r f ib r i l la t ion o O p e n chest contro l • C l o s e d chest control g 1^ C O O TJ -12 " 101 n = 5 0 -0 T T Time (min) 8 10 60 massage, a marked increase i n plasma l i d o c a i n e c o n c e n t r a t i o n was observed over a l l time p o i n t s . The increase was s i g n i f i c a n t (p< 0 . 0 5 ) at 1 5 seconds, 3 0 seconds and 1 minute post-a d m i n i s t r a t i o n . C a l c u l a t e d area under the curve to 1 0 minutes (AUC l r i), x u i f r a c t i o n of dose absorbed i n 1 0 minutes ( f ± n ) and clearance of l i d o c a i n e over the i n i t i a l 1 0 minutes (Cl^g) are reported i n Table I I I . A U C ^ Q was increased during v e n t r i c u l a r f i b r i l l a t i o n and C I ^ Q was decreased. Amount of l i d o c a i n e absorbed was 7 1 % and 72% i n c o n t r o l s and v e n t r i c u l a r f i b r i l l a t i o n , r e s p e c t i v e l y . e) Plasma Lidocaine Levels F o l l o w i n g Intravenous I n j e c t i o n  of L idocaine i n Normal S a l i n e During Open Chest Controls and V e n t r i c u l a r F i b r i l l a t i o n F i gure 9 shows plasma l i d o c a i n e l e v e l s observed f o l l o w i n g intravenous i n j e c t i o n of l i d o c a i n e 20mg/ml i n normal s a l i n e during v e n t r i c u l a r f i b r i l l a t i o n w i t h c a r d i a c massage or to open chest (sham-operated) c o n t r o l s . I n j e c t i o n was made v i a d i s t a l h i n d l e g v e i n and animals were anesthetized w i t h p e n t o b a r b i t a l . Plasma l i d o c a i n e l e v e l s were greater a t a l l times during v e n t r i c u l a r f i b r i l l a t i o n although t h i s was s i g n i f i c a n t (p< 0.05) only a t one minute. Table I I I shows area under the curve to 10 minutes ( A U C ^ Q ) , f r a c t i o n of the dose absorbed i n 10 minutes ( f ± n ) and clearance of l i d o c a i n e i n the i n i t i a l 10 minutes (Cl^g) f o r open chest c o n t r o l s and v e n t r i c u l a r f i b r i l l a t i o n , A U C ^ w a s increased during v e n t r i c u l a r f i b r i l l a t i o n and C l , _ was decreased. 61 Figure 9 Plasma l i d o c a i n e l e v e l s vs time f o l l o w i n g intravenous i n j e c t i o n of 2mg/Kg l i d o c a i n e (20mg/ml i n normal s a l i n e ) during v e n t r i c u l a r f i b r i l l a t i o n and open chest c o n t r o l s . A l l animals were ane s t h e t i z e d w i t h p e n t o b a r b i t a l and i n j e c t i o n was made v i a a d i s t a l h i n d l e g v e i n . A l l p o i n t s represent mean plasma l e v e l s + S.E.M. of the number of experiments i n d i c a t e d . * s i g n i f i c a n t l y greater than open chest c o n t r o l s at p < 0.05. 62 63 Table I I I Area under the curve (A U C ^ Q), f r a c t i o n of dose absorbed ( f ^ ) and c l e a r a n c e ( C l ^ ) of l i d o c a i n e d u r i n g f i r s t 10 minutes a b f o l l o w i n g intravenous or en d o t r a c h e a l a d m i n i s t r a t i o n to e i t h e r v e n t r i c u l a r f i b r i l l a t i o n or open che s t c o n t r o l s . L i d o c a i n e 2mg/kg IV L i d o c a i n e 2mg/kg ET Normal VF Normal VF 25.8 65.8 18.22 47.25 1.0 1.0 0.71 0.72 186 87 218 88 a L i d o c a i n e 20mg/ml i n normal s a l i n e i n t o d i s t a l h i n d l e g v e i n b L i d o c a i n e 2mg/ml i n normal s a l i n e A U C jug, mm. u u 1 0 V ml ; f10 C l , _ (ml/min) 64 f) Plasma Lidocaine L e v e l s F o l l o w i n g E i t h e r Intravenous  I n j e c t i o n or Endotracheal I n s t i l l a t i o n of Lidocaine to  Open Chest Con t r o l s Plasma l i d o c a i n e l e v e l s observed f o l l o w i n g endotracheal (ET) i n s t i l l a t i o n of l i d o c a i n e 2mg/ml i n normal s a l i n e , or intravenous (IV) i n j e c t i o n of l i d o c a i n e 20mg/ml i n normal s a l i n e , are shown i n Figure 10. Figure 11 shows a semi-logarithmic p l o t of t h i s data. These comparisons were obtained by r e -arranging data from s e c t i o n s (d) and (e). The dosage of l i d o c a i n e used was 2mg/kg f o r both routes. A l l animals were anesthetized w i t h p e n t o b a r b i t a l and i n j e c t i o n was made v i a a d i s t a l h i n d l e g v e i n . I n j e c t i o n of l i d o c a i n e r e s u l t e d i n peak plasma l e v e l s at 15 and 30 seconds which were s i g n i f i c a n t l y greater (p<0.05) than those obtained f o l l o w i n g endotracheal i n s t i l l a t i o n . These l e v e l s decreased r a p i d l y , however, and a t 2 minutes, the plasma l e v e l s f o l l o w i n g endotracheal a d m i n i s t r a t i o n were s i g n i f i c a n t l y greater than those obtained from intravenous i n j e c t i o n (p<.0.05). There were no s i g n i f i c a n t d i f f e r e n c e s between plasma l e v e l s a t any other time p o i n t s . C a l c u l a t e d area under the curve, f r a c t i o n of dose absorbed and clearance i n the f i r s t 10 minutes are compared i n Table I I I . Area under the curve was smaller during endotracheal a d m i n i s t r a t i o n than during intravenous i n j e c t i o n and the f r a c t i o n of the dose absorbed endotracheally was 71%. Clearance of l i d o c a i n e i n the f i r s t 10 minutes was only s l i g h t l y l a r g e r f o l l o w i n g endotracheal a d m i n i s t r a t i o n than f o l l o w i n g IV i n j e c t i o n . 65 Figure 10 Plasma l i d o c a i n e l e v e l s vs time f o l l o w i n g endotracheal i n s t i l l a t i o n of 2mg/Kg l i d o c a i n e (2mg/ml i n normal s a l i n e ) or intravenous i n j e c t i o n of l i d o c a i n e (20mg/ml i n normal s a l i n e ) . Animals were ane s t h e t i z e d w i t h p e n t o b a r b i t a l and were open chest (sham-operated) c o n t r o l s . I n j e c t i o n was made v i a a d i s t a l h i n d l e g v e i n . A l l values represent mean plasma l e v e l s + S.E.M. of the number of experiments i n d i c a t e d . * s i g n i f i c a n t l y greater than endotracheal a t p<0.05. ** s i g n i f i c a n t l y g r eater than intravenous a t p < 0.05. 66 67 Figure l l Log plasma l i d o c a i n e concentrations vs time f o l l o w i n g intravenous (IV) i n j e c t i o n of 2mg/Kg l i d o c a i n e (20mg/ml i n normal s a l i n e ) or endotracheal (ET) i n s t i l l a t i o n of 2mg/Kg l i d o c a i n e (2mg/ml i n normal s a l i n e ) . Animals were open chest (sham-operated) c o n t r o l s and were ane s t h e t i z e d w i t h p e n t o b a r b i t a l . I n j e c t i o n was made v i a a d i s t a l h i n d l e g v e i n . Numbers of experiments are i n d i c a t e d and a l l values represent mean plasma l e v e l s . * s i g n i f i c a n t l y greater than ET at p< 0.05. .**• s i g n i f i c a n t l y greater than IV at p< 0.05. o CJ1 Log plasma lidocaine (ug/ml) o co o 3 ll cn 3 II 4*. I f f • -4 — m < H 69 g) Plasma Lidocaine Levels F o l l o w i n g Endotracheal I n s t i l l a t i o n or Intravenous I n j e c t i o n of Lidocaine  During V e n t r i c u l a r F i b r i l l a t i o n F igure 12 shows plasma l i d o c a i n e l e v e l s observed during v e n t r i c u l a r f i b r i l l a t i o n w i t h c a r d i a c massage f o l l o w i n g e i t h e r endotracheal i n s t i l l a t i o n of l i d o c a i n e 2mg/ml i n normal s a l i n e or intravenous i n j e c t i o n of l i d o c a i n e 20mg/ml i n normal s a l i n e . Figure 13 shows a semi-logarithmic p l o t of t h i s data. The dosage used i n a l l cases was 2mg/Kg and IV i n j e c t i o n was made v i a a d i s t a l h i n d l e g v e i n . A l l animals were anesthetized w i t h p e n t o b a r b i t a l . These comparisons were obtained by re-arranging data from s e c t i o n s (d) and (e). Although intravenous i n j e c t i o n r e s u l t e d i n higher plasma l i d o c a i n e l e v e l s over a l l time p o i n t s , the d i f f e r e n c e s were not s t a t i s t i c a l l y s i g n i f i c a n t . When only experiments i n which spontaneous conversion to normal sinus rhythm occurred were considered, the d i f f e r e n c e s between the intravenous and endotracheal routes were l a r g e r . (Three out of four animals administered l i d o c a i n e v i a the intravenous route converted from v e n t r i c u l a r f i b r i l l a t i o n to normal sinus rhythm i n a mean time of 1.4 - 0.1 minutes). Conversion to normal sinus rhythm occurred i n a l l animals administered l i d o c a i n e v i a the endotracheal route i n a time of 1.4 - 0.4 minutes post a d m i n i s t r a t i o n . A separate curve demonstrating plasma l i d o c a i n e l e v e l s from those animals which d i d show conversion f o l l o w i n g intravenous l i d o c a i n e i s shown i n Figure 12. The d i s t r i b u t i o n phase of l i d o c a i n e f o l l o w i n g IV i n j e c t i o n was shortened when conversion to spontaneous c a r d i a c 70 Figure 12 Plasma l i d o c a i n e l e v e l s vs time f o l l o w i n g e i t h e r intravenous i n j e c t i o n of 2mg/Kg l i d o c a i n e (20mg/ml i n normal s a l i n e ) or endotracheal i n s t i l l a t i o n of 2mg/Kg l i d o c a i n e (2mg/ml i n normal s a l i n e ) during v e n t r i c u l a r f i b r i l l a t i o n w i t h c a r d i a c massage. A l s o shown i s data from only those intravenous experiments i n which spontaneous conversion to normal sinus rhythm occurred. Animals were anesthetized w i t h p e n t o b a r b i t a l . A l l p o i n t s represent mean plasma l e v e l s + S.E.M. of the number of experiments i n d i c a t e d . Intravenous i n j e c t i o n was accomplished v i a a d i s t a l h i n d l e g v e i n . 71 72 Figure 13 Log plasma l i d o c a i n e concentrations vs time f o l l o w i n g e i t h e r intravenous (IV) i n j e c t i o n of 2mg/kg l i d o c a i n e (20mg/ml i n normal s a l i n e ) or endotracheal (ET) i n s t i l l a t i o n of 2mg/kg l i d o c a i n e (2mg/ml i n normal s a l i n e ) . Intravenous i n j e c t i o n was made v i a d i s t a l h i n d l e g v e i n and animals were anesthetized w i t h p e n t o b a r b i t a l . A l s o shown i s data from only those intravenous experiments i n which spontaneous conversion to normal sinus rhythm occurred. A l l values represent mean plasma l e v e l s of the number of experiments shown. '. ; Log plasma lidocaine (ug/ml) ro co ^ cn O) co C O Q ro o co o cn o o • o • m H < < CO 13 74 output occurred. Comparison of area under the curve (A U C ^ Q), f r a c t i o n of dose absorbed (f^g) a n d clearance i n 10 minutes (Cl^g) are shown f o r intravenous and endotracheal l i d o c a i n e during v e n t r i -c u l a r f i b r i l l a t i o n i n Table I I I . V e n t r i c u l a r f i b r i l l a t i o n i ncreased A U C ^ Q p r o p o r t i o n a t e l y both intravenous.and endotracheal l i d o c a i n e and C l ^ n was the same f o r both routes. h) Plasma Lidocaine Levels F o l l o w i n g Endotracheal  A d m i n i s t r a t i o n of Lidocaine 2mg/Kg i n D i s t i l l e d  Water Followed by lmg/Kg Every F i v e Minutes Figure 14 shows plasma l i d o c a i n e concentrations observed f o l l o w i n g a "loading dose" of 2mg/Kg l i d o c a i n e e n dotracheally i n d i s t i l l e d water and a "maintenance dose" of lmg/Kg endo t r a c h e a l l y every f i v e minutes. The s o l u t i o n strength was 2mg/ml and the a n e s t h e t i c used was p e n t o b a r b i t a l . A d m i n i s t r a t i o n of "maintenance doses" every f i v e minutes r e s u l t e d i n accumulation of both peak and trough plasma l e v e l s over the 20 minute p e r i o d . Trough concentrations had accumulated s i g n i f i c a n t l y by 20 minutes (p^.0.05). 2. A n t i f i b r i l l a t o r y E f f i c a c y of Endotracheal Lidocaine a) The E f f e c t of Endotracheal Lidocaine on Duration of V e n t r i c u l a r F i b r i l l a t i o n Table IV shows the length of time v e n t r i c u l a r f i b r i l -l a t i o n p e r s i s t e d f o l l o w i n g endotracheal i n s t i l l a t i o n of 2mg/Kg 75 Figure 14 Plasma l i d o c a i n e l e v e l s vs t i m e " f o l l o w i n g ^endotracheal a d m i n i s t r a t i o n of a 2mg/kg "loading dose" followed by a lmg/kg "maintenance dose" every 5 minutes. The s o l u t i o n used was l i d o c a i n e 2mg/ml i n d i s t i l l e d water and animals were anesthetized w i t h p e n t o b a r b i t a l . Values are the mean plasma l e v e l s - S.E.M. of three experiments. * s i g n i f i c a n t l y greater than trough l e v e l a t 5 minutes (p<0.05). I Plasma Lidocaine (ug/ml) ro 4^ q> co -"• 01 CO o 7 II CO i H 3 3 5" i no O / I 9L 77 l i d o c a i n e (2mg/ml i n normal s a l i n e ) , lml/Kg normal s a l i n e , or no treatment. In a l l cases, the hearts were manually pumped as described i n the methods. A d m i n i s t r a t i o n of l i d o c a i n e 2 minutes a f t e r the s t a r t of v e n t r i c u l a r f i b r i l l a t i o n s i g n i f i c a n t l y reduced the d u r a t i o n of f i b r i l l a t i o n compared to e i t h e r untreated or normal s a l i n e c o n t r o l s (p <0.001). There was no s i g n i f i c a n t d i f f e r e n c e i n the d u r a t i o n of VF between untreated and normal s a l i n e c o n t r o l s . The e f f e c t of l i d o c a i n e on VF was s i g n i f i c a n t r e g a r d l e s s of whether the f i b r i l l a t i o n occurred during an o c c l u s i o n or r e p e r f u s i o n phase. Table V shows percent o c c l u s i o n of l e f t , r i g h t and t o t a l v e n t r i c u l a r mass i n the untreated c o n t r o l s , normal s a l i n e c o n t r o l s , and l i d o c a i n e - t r e a t e d group. There was no s i g n i f i c a n t d i f f e r e n c e i n percent o c c l u s i o n between any of the treatment groups. VThen p o s s i b l e , c a r d i o v a s c u l a r s t a t u s was monitored f o r 30 minutes a f t e r conversion to spontaneous c a r d i a c rhythm i n normal s a l i n e c o n t r o l s and l i d o c a i n e - t r e a t e d animals. Of the s i x animals r e c e i v i n g l i d o c a i n e , a l l resumed spontaneous rhythm w i t h i n 1.2 minutes of r e c e i v i n g the drug (mean 0.7 - 0.1 minute). Three of those animals survived to 3 0 minutes post-conversion with adequate blood pressure and ECG. Two animals survived l e s s than 10 minutes, wi t h inadequate c a r d i a c output (electro-mechanical d i s s o c i a t i o n ) as the cause of death. One animal was terminated at 10 minutes with adequate BP and ECG ( p r i o r to i n s t i t u t i o n of the 30 minute p r o t o c o l ) . In the normal s a l i n e c o n t r o l group, three animals had 78 Table IV Duration of v e n t r i c u l a r f i b r i l l a t i o n f o l l o w i n g ET a d m i n i s t r a t i o n of l i d o c a i n e (2mg/Kg) i n normal s a l i n e , normal s a l i n e (l:ml/Kg) or no treatment (minutes). V e n t r i c u l a r f i b r i l l a t i o n p e r s i s t e d f o r 2 minutes p r i o r to i n i t i a t i o n of p r o t o c o l . Numbers of experiments are i n d i c a t e d i n parentheses. Untreated Normal S a l i n e Untreated & Lidocaine C o n t r o l s C o n t r o l s Normal S a l i n e 2mg/Kg (Iml/Kg) Controls Combined Occlusion 8.4 - 1.1 (n=3) 10.0 (n=l) 8.8 - 0.8 (n=4) + * 0.7 - 0.1 (n=3.) c + + Reperfusion 6.3 - 1.2 7.2 - 1.1 (n=2) (n=4) 6.9 - 0 (n=6) + * 0.8 - 0.2 (n=3) T o t a l 7.6 - 0.9 (n=5) 7.8 - 1.0 (n=5) 7.7 - 0.6 (n=10) + * 0.7 - 0.1 (n=6) * s i g n i f i c a n t l y shorter than untreated c o n t r o l s , normal s a l i n e c o n t r o l s or both a t p ( 0.001. a - times c o r r e c t e d (-2'min) to a l l o w f o r 2 minutes of v e n t r i c u l a r f i b r i l l a t i o n p r i o r to a d m i n i s t r a t i o n of l i d o c a i n e or normal s a l i n e . b - experiments where v e n t r i c u l a r f i b r i l l a t i o n occurred during 15 minute o c c l u s i o n phase, c - experiments where v e n t r i c u l a r f i b r i l l a t i o n occurred during 5 minute r e p e r f u s i o n phase. 79 Table V Percent o c c l u s i o n 3 of r i g h t v e n t r i c u l a r , l e f t v e n t r i c u l a r and t o t a l v e n t r i c u l a r mass i n untreated c o n t r o l s , normal s a l i n e b c c o n t r o l s and l i d o c a i n e - t r e a t e d group . Untreated & Lidocaine Percent Untreated Normal S a l i n e Normal S a l i n e 2mg/Kg ET n , Contr o l s C o n t r o l s Controls i n o c c l u s i o n ( n = 5 ) (1ml/Kg) Combined Normal S a l i n e (n=5) (n=10) (n=6) Right 5 . 9 1 3 . 9 6.8 i 3.2 6.4 - 2.4 7.8 - 3.2 V e n t r i c l e L e f t 46.1 - 2.9 40.4 - 2.4 43.3 - 2.0 44.6 - 5.6 V e n t r i c l e T o t a l 3 6 > Q + 3 _ 3 3 1 > 3 + 2 > Q 3 3 > 6 + 2 > Q 3 5 > 4 + 4 > 9 V e n t r i c l e a - no s i g n i f i c a n t d i f f e r e n c e i n percent o c c l u s i o n between any of the groups. b - normal s a l i n e lml/Kg endotracheally. c - 2mg/Kg l i d o c a i n e (2mg/ml i n normal s a l i n e ) endotracheally. 80 spontaneous conversion to "normal sinus rhythm" and two animals were e l e c t r i c a l l y d e f i b r i l l a t e d (0.5 watt-seconds, DC counter-shock) 10 minutes a f t e r normal s a l i n e a d m i n i s t r a t i o n . Four animals survived a f u r t h e r 30 minutes w i t h adequate blood pressure and ECG, and one was terminated at 5 minutes w i t h acceptable c a r d i o v a s c u l a r s t a t u s . b) Tendency f o r V e n t r i c u l a r F i b r i l l a t i o n : Three  C l a s s i f i c a t i o n s A l l coronary a r t e r y l i g a t i o n experiments f e l l i n t o one of three c a t e g o r i e s : Short V e n t r i c u l a r F i b r i l l a t i o n (Short VF), Long V e n t r i c u l a r F i b r i l l a t i o n (Long VF) or No V e n t r i c u l a r F i b r i l l a t i o n (No VF)(as reported i n methods). A l l c o n t r o l experiments i n which v e n t r i c u l a r f i b r i l l a t i o n occurred f e l l i n t o two d i s t i n c t c a t e g o r i e s w i t h respect to d u r a t i o n of v e n t r i c u l a r f i b r i l l a t i o n (Table V I ) . In one group,(Short VF), f i b r i l l a t i o n l a s t e d f o r l e s s than two minutes (mean 0.56 - 0.7 minute, range 0.18-1.83 minutes, n=10) and i n the other group, (Long VF), f i b r i l l a t i o n l a s t e d f o r approximately 10 minutes (mean 9.5 - 0.07, range 6.5-12.5 minutes, n=16). A l l hearts which f i b r i l l a t e d f o r longer than two minutes d i d so f o r a t l e a s t 6.5 minutes (unless t r e a t e d w i t h l i d o c a i n e ) and were used i n the l i d o c a i n e e f f i c a c y experiments. A l s o shown i n Table VI are the number of f i b r i l l a t i o n episodes per animal i n the Short and Long VF c a t e g o r i e s . There was a tendency f o r m u l t i p l e episodes of f i b r i l l a t i o n to occur i n the Short VF category. Many of these occurred during a r e p e r f u s i o n phase of the experiment. In a l l animals s t u d i e d , only one Long VF 8 1 Table VI Du r a t i o n and frequency of v e n t r i c u l a r f i b r i l l a t i o n i n s h o r t v e n t r i c u l a r f i b r i l l a t i o n and long v e n t r i c u l a r f i b r i l l a t i o n c a t e g o r i e s . Number of Number of VF VF Dur a t i o n of VF Frequency Mean Range Animals Episodes (#per - S.E. experiment) (min) (min) Short VF: O c c l u s i o n 3 7 R e p e r f u s i o n 1 3 4 T o t a l 1 1 9 2 4 3 3 1 . 3 0 . 6 2 - 0 . 1 8 0 . 1 7 - 1 . 8 3 6 . 0 0 . 5 4 ± 0 . 0 8 0 . 1 7 - 1 . 8 3 3 . 0 0 . 5 6 - 0 . 0 7 0 . 1 7 - 1 . 8 3 Long VF: O c c l u s i o n 4 4 1 . 0 1 1 . 0 - 1 . 0 8 . 8 - 1 2 . 5 R e p e r f u s i o n 6 6 1 . 0 8 . 9 ± 0 . 9 6 . 5 - 1 1 . 5 T o t a l 1 0 1 0 . 1 . 0 9 . 7 ± o . 7 6 . 5 - 1 2 . 5 a - VF o c c u r r e d d u r i n g an o c c l u s i o n phase, b - VF o c c u r r e d d u r i n g a r e p e r f u s i o n phase, 82 episode occurred per experiment although one animal had m u l t i p l e short f i b r i l l a t i o n s p r i o r to e s t a b l i s h i n g a long f i b r i l l a t i o n . F igure 15 shows t y p i c a l ECG and blood pressure t r a c i n g s obtained during v e n t r i c u l a r f i b r i l l a t i o n w i t h open-chest manual heart massage. A mean s y s t o l i c BP of 50mm Hg was u s u a l l y obtained w i t h t h i s method and massage was performed at a r a t e of approx-imately 130 compressions per minute. When the chart speed was increased to lOmm/sec and massage was temporarily stopped, the ECG t r a c i n g s show v e n t r i c u l a r f i b r i l l a t i o n and the blood pressure t r a c i n g demonstrates the absence of c a r d i a c output. This t r a c i n g was taken from an experiment where f i b r i l l a t i o n l a s t e d f o r 10 minutes a f t e r a d m i n i s t r a t i o n of lml/Kg normal s a l i n e e n d o t r a c h e a l l y . Figure 16 shows t y p i c a l ECG and BP t r a c i n g s obtained during a short f i b r i l l a t i o n episode ( l e s s than 2 minutes). Shown are the p e r i o d of f i b r i l l a t i o n f o l l o w e d by spontaneous conversion to a r e g u l a r heart beat. Table VII shows percent o c c l u s i o n of l e f t , r i g h t and t o t a l v e n t r i c u l a r mass i n the No VF, Short VF and Long VF c a t e g o r i e s . There was no s i g n i f i c a n t d i f f e r e n c e i n occluded areas between the Short VF, Long VF and No VF groups. The incidence of v e n t r i c u l a r arrhythmias i n the No VF group, or p r i o r to v e n t r i c u l a r f i b r i l l a t i o n i n the Short VF and Long VF groups i s shown i n Table V I I I , F i f t y - s e v e n percent of hearts which d i d not f i b r i l l a t e demonstrated v e n t r i c u l a r arrhythmias during the experimental p r o t o c o l . The incidence of arrhythmias was greater p r i o r to short or long f i b r i l l a t i o n episodes, 90% and 75% r e s p e c t i v e l y . Where m u l t i p l e short f i b r i l l a t i o n episodes occurred during one 83 Figure 15 Blood pressure and ECG recordings during v e n t r i c u l a r f i b r i l l a t i o n w i t h manual heart massage. The ch a r t speed was increased to lOmm/sec from lOmm/min every minute to demonstrate v e n t r i c u l a r f i b r i l l a t i o n and lack of c a r d i a c output. 84 1 m i n 85 Figure 16 Blood pressure and ECG recordings during a v e n t r i c u l a r f i b r i l l a t i o n episode which l a s t e d 25 seconds and terminated spontaneously. The t r a c i n g was run a t a c h a r t speed of lOmm/second except f o r the area i n d i c a t e d by the dark bar to the r i g h t of the t r a c i n g , where the ch a r t speed was lOrnm/minute. 86 5 sec 87 T a b l e V I I C o m p a r i s o n o f p e r c e n t o c c l u s i o n o f l e f t v e n t r i c l e , r i g h t v e n t r i c l e and t o t a l v e n t r i c u l a r mass w i t h t e n d e n c y t o f i b r i l l a t e . % A r e a O c c l u d e d % R i g h t % L e f t % T o t a l V e n t r i c l e V e n t r i c l e V e n t r i c l e No V e n t r i c u l a r 3 > g + ^ 8 3 6 > 4 + 4 > 1 2 Q ^ + 3 > 4 F i b r i l l a t i o n 3 S h o r t V e n t r i c u l a r . „ + N _ » R + » R ->R N + A •, 4.8 - 1.9 46.7 - 4.6 36.0 - 4 .1 F i b r i l l a t i o n 1 3 L o n g V e n t r i c u l a r 6 > g + 4 3 > g + 2 > 3 3 4 > 3 + F i b r i l l a t i o n a - V e n t r i c u l a r f i b r i l l a t i o n d i d n o t o c c u r a t any t i m e d u r i n g t h e e x p e r i m e n t . b - V e n t r i c u l a r f i b r i l l a t i o n l a s t e d f o r l e s s t h a n 2 m i n u t e s . c - V e n t r i c u l a r f i b r i l l a t i o n l a s t e d l o n g e r t h a n 2 m i n u t e s . I n c l u d e s a l l a n i m a l s i n c o n t r o l g r o u p s and g r o u p t r e a t e d w i t h l i d o c a i n e . 88 T a b l e V I I I C o m p a r i s o n o f t h e i n c i d e n c e o f v e n t r i c u l a r a r r h y t h m i a s f o l l o w i n g c o r o n a r y a r t e r y l i g a t i o n w i t h t e n d e n c y t o f i b r i l l a t e . Number o f Number o f A n i m a l s w i t h % w i t h A n i m a l s V e n t r i c u l a r A r r h y t h m i a s A r r h y t h m i a s No V e n t r i c u l a r F i b r i l l a t i o n 3 S h o r t V e n t r i c u l a r F i b r i l l a t i o n L o n g V e n t r i c u l a r ^ ^ 2 759. c 0 F i b r i l l a t i o n a - v e n t r i c u l a r f i b r i l l a t i o n d i d n o t o c c u r a t any t i m e d u r i n g t h e e x p e r i m e n t . b - VF l a s t e d f o r l e s s t h a n 2 m i n u t e s . A r r h y t h m i a s r e p o r t e d o n l y p r i o r t o f i r s t f i b r i l l a t i o n . c - VF l a s t e d l o n g e r t h a n 2 m i n u t e s . I n c l u d e s a l l a n i m a l s i n c o n t r o l g r o u p s and g r o u p t r e a t e d w i t h l i d o c a i n e . 89 experiment, only the time p r i o r to the f i r s t f i b r i l l a t i o n was noted f o r arrhythmias. Figures 17 and 18 compare the changes i n blood pressure and heart r a t e which occurred during the f i r s t ten minutes a f t e r coronary a r t e r y o c c l u s i o n i n the No VF, Short VF and Long VF c a t e g o r i e s . In a l l three groups, the l a r g e s t drop i n blood pressure occurred during the f i r s t two minutes a f t e r o c c l u s i o n of the a r t e r y (Figure 17), a f t e r which blood pressure appeared to s t a b i l i z e . There was no s i g n i f i c a n t d i f f e r e n c e i n blood pressure between the three groups a t any time p o i n t s . Heart r a t e was shown to d e c l i n e f o l l o w i n g coronary a r t e r y l i g a t i o n i n animals i n which v e n t r i c u l a r f i b r i l l a t i o n occurred (Figure 18). There was no appreciable change i n heart r a t e i n animals i n which v e n t r i c u l a r f i b r i l l a t i o n d i d not occur. The l a r g e s t change i n heart r a t e occurred over the f i r s t two minutes of o c c l u s i o n i n the Long VF category. There was a s i g n i f i c a n t d i f f e r e n c e (p<0.05) i n heart r a t e at ten minutes between animals where no f i b r i l l a t i o n or long f i b r i l l a t i o n occurred. c) Occlusion vs Reperfusion V e n t r i c u l a r F i b r i l l a t i o n Table IX shows the percent o c c l u s i o n of l e f t , r i g h t , and t o t a l v e n t r i c u l a r mass i n experiments where v e n t r i c u l a r f i b r i l l a t i o n (longer than two minutes) occurred during an o c c l u -s i o n or r e p e r f u s i o n phase. There were no s i g n i f i c a n t d i f f e r e n c e s i n these measurements between the two groups. Measurements of the occluded areas were performed w i t h the l i g a t u r e s secured i n a l l 90 Figure 17 Comparison of blood pressure before and f o r 10 minutes a f t e r coronary a r t e r y l i g a t i o n i n animals i n which no v e n t r i c u l a r f i b r i l l a t i o n , s hort v e n t r i c u l a r f i b r i l l a t i o n ( l e s s than 2 minutes), or long v e n t r i c u l a r f i b r i l l a t i o n occurred (longer than 2 minutes). Values shown are mean s y s t o l i c and d i a s t o l i c pressures f o r the number of animals i n d i c a t e d . There was no s i g n i f i c a n t d i f f e r e n c e i n blood pressure between the three groups a t any time point,'..; 91 No VF = Short VF Long VF 92 Figure 18 Changes i n heart r a t e f o l l o w i n g coronary a r t e r y o c c l u s i o n i n No VF, Short VF ( l e s s than 2 minutes), and Long VF (greater than 2 minutes) experiments. Values expressed are mean heart r a t e - S.E.M. of the number of experiments i n d i c a t e d . * s i g n i f i c a n t l y l e s s than no v e n t r i c u l a r f i b r i l l a t i o n a t p<.0.05. • No VF A Short VF • Long VF Pre-ligation 2 min 5min Post- ligation 10 min 94 experiments, as described i n the methods. There were no s i g n i f i c a n t d i f f e r e n c e s i n pre-l i g a t i o n , p o s t - l i g a t i o n or p r e - f i b r i l l a t i o n blood pressures and heart r a t e s between animals where VF occurred during o c c l u s i o n or r e p e r f u s i o n phases. V e n t r i c u l a r arrhythmias occurred p r i o r to VF i n f i v e out of seven animals where VF (longer than two minutes) occurred during o c c l u s i o n , and i n seven out of nine animals where i t occurred during r e p e r f u s i o n . During Short VF experiments, v e n t r i c u l a r arrhythmias preceeded the f i r s t f i b r i l l a t i o n episode i n a l l seven animals where i t occurred during o c c l u s i o n and i n two out of three where i t occurred during a r e p e r f u s i o n phase. 95 T a b l e IX C o m p a r i s o n o f p e r c e n t o c c l u s i o n o f l e f t v e n t r i c l e , r i g h t v e n t r i c l e and t o t a l v e n t r i c u l a r mass i n v e n t r i c u l a r f i b r i l l a t i o n (>2 min) o c c u r r i n g d u r i n g an o c c l u s i o n o r r e p e r f u s i o n p e r i o d . % A r e a O c c l u d e d (mean i S.E.M.) Phase Where VF O c c u r r e d O c c l u s i o n Phase* 3 R e p e r f u s i o n P h a s e 0 o, *o R i g h t V e n t r i c l e 8.4 - 3.3 5.7 - 2.1 o. "o L e f t V e n t r i c l e 45.6 - 2.6 42.3 - 3.7 o, o T o t a l V e n t r i c l e 36.1 - 2.7 3 2 . 8 - 3.2 a - no s i g n i f i c a n t d i f f e r e n c e between o c c l u s i o n and r e p e r f u s i o n g r o u p s . b - VF o c c u r r e d d u r i n g o c c l u s i o n p h a s e . c - VF o c c u r r e d d u r i n g r e p e r f u s i o n p h a s e . 96 DISCUSSION The present study indicates that lidocaine i s rapi d l y and extensively absorbed following administration v i a an endo-tracheal tube i n the rabbit. These data are i n agreement with those of Elam (1977) where a prompt ECG response to ET lidocaine was noted i n hypoxia-induced cardiac arrest i n dogs. Others have previously reported similar r e s u l t s using ET epinephrine, where rapid but prolonged responses (Redding et a l , 1967; Elam, 1977; Roberts et a l , 1978) and sustained plasma l e v e l s (Roberts et a l , 1979a) were observed. Results of the present study showed lower peak plasma level s following ET lidocaine when compared to IV (Figures 10 & 11), but slower decline i n plasma l e v e l s , so that at two minutes the ET plasma l e v e l was s i g n i f i c a n t l y greater than the IV l e v e l . This delayed absorption may be due to a depot or reservoir of drug i n the a l v e o l i , as suggested by Roberts et a l (1978; 1979a) for epinephrine. They observed even more prolonged ET absorption of epinephrine than we observed with lidocaine, perhaps due to l o c a l vasoconstriction of lung vasculature through stimulation of c *-receptors by epinephrine. Results obtained i n early experiments (Figures 3 & 4) are perhaps somewhat misleading. Using IV i n j e c t i o n as a standard, the percent of lidocaine absorbed v i a the ET route was calculated to be 132% based on measurement of the area under the curve. These data are c l a r i f i e d i n Figures 10 & 12 where percent of the ET dose absorbed over ten minutes was shown to be approximately 70% of an IV dose. I t i s possible that greater 97 and more prolonged plasma leve l s were seen with the ET route than with the IV route due to the i n i t i a l method used to administer the IV i n j e c t i o n . Lidocaine was injected as a 2mg/ml solution i n a dosage of 2mg/Kg v i a the marginal ear vein. This volume (lml/Kg) may p a r a l l e l a r e l a t i v e l y large volume i n j e c t i o n i n man, approximately 50 - 100ml based on comparison of t o t a l blood volume. When given rapid l y a volume of t h i s size may di s t r i b u t e r a p i d l y throughout the c i r c u l a t i o n , r e s u l t i n g i n a smaller peak plasma l e v e l than seen following a small volume IV bolus i n j e c t i o n . Furthermore, due to the time required to i n j e c t a r e l a t i v e l y large volume, the true peak plasma lidocaine l e v e l probably occurred p r i o r to taking the f i r s t sample at 15 seconds. Delayed absorption of ET lidocaine was r e f l e c t e d i n a f i r s t - o r d e r rate constant (O<ET) which was approximately 70% of the value calculated for the TV route. I t should be noted that 0(E,j. i n t h i s case i s a r e f l e c t i o n of both absorption and d i s t r i b u t i o n which were not separated, and i s not a pure d i s t r i b u t i o n rate constant. Following IV i n j e c t i o n absorption i s complete, hence ^ j y i n t h i s case i s a true r e f l e c t i o n of the d i s t r i b u t i o n of lidocaine i n t h i s model. Elimination rate constants (/9) for the two routes of administration were found to be simi l a r (Figure 4, Table I ) . This suggests that absorption v i a the ET route was v i r t u a l l y complete within approximately ten minutes. Absorption -d i s t r i b u t i o n , , d i s t r i b u t i o n , and elimination h a l f - l i v e s were extremely short i n thi s model, due to rapid c i r c u l a t i o n times i n the rabbit. This accounts i n part for the large standard errors obtained during the f i r s t 15 - 30 seconds of sampling 98 i n most experiments. Spontaneous or a r t i f i c i a l v e n t i l a t i o n had no s i g n i f i c a n t e f f e c t on plasma l i d o c a i n e l e v e l s f o l l o w i n g ET i n s t i l l a t i o n although d u r i n g spontaneous r e s p i r a t i o n h i g h e r plasma l e v e l s were g e n e r a l l y seen. T h i s i s i n c o n t r a s t to the r e p o r t by S c o t t e t a l (1976), where high e r plasma l i d o c a i n e l e v e l s were noted i n p a t i e n t s who were p a r a l y z e d and v e n t i l a t e d . D i f f e r e n c e s i n v e n t i l a t i o n methods and drug a d m i n i s t r a t i o n may account f o r t h i s d i s c r e p a n c y . E n d o t r a c h e a l a d m i n i s t r a t i o n of epi n e p h r i n e i n d i s t i l l e d water has been shown to have a s h o r t e r onset of a c t i o n compared wit h a d m i n i s t r a t i o n i n normal s a l i n e (Redding e t a_l, 1967) . Data shown i n F i g u r e 6 suggest a s i m i l a r phenomenon f o r l i d o c a i n e , although there was a s i g n i f i c a n t d i f f e r e n c e o n l y a t 30 seconds. A b s o r p t i o n o f d i s t i l l e d water from the a l v e o l i has been shown to occur a t a f a s t e r r a t e than a b s o r p t i o n of normal s a l i n e ( C o u r t i c e and Phipps, 1946) . As shown by Redding e t a_l (1967) and confirmed by these data, the d u r a t i o n of e f f e c t of the drug may be prolonged when normal s a l i n e i s the v e h i c l e , without a-', change i n the e f f i c a c y of the drug. For these reasons, and the p o t e n t i a l f o r normal s a l i n e t o be a more p h y s i o l o g i c medium than d i s t i l l e d water, i t was decid e d to use l i d o c a i n e i n normal s a l i n e f o r f u r t h e r e n d o t r a c h e a l s t u d i e s . L i d o c a i n e i s an o i l s o l u b l e compound (Merck Index, 1968) and t h e r e f o r e has the p o t e n t i a l to d i f f u s e w e l l across the l i p i d a l v e o l a r membrane. T h i s may p a r t l y e x p l a i n why there i s not a l a r g e d i f f e r e n c e between i t s a b s o r p t i o n i n water or normal s a l i n e . , C a l c u l a t e d pharmacokinetic parameters f o r ET l i d o c a i n e 99 i n normal s a l i n e and d i s t i l l e d water (Table I I ) are rough estimates at best due to the lack of time p o i n t s beyond 30 minutes. They do, however, i l l u s t r a t e a s l i g h t l y prolonged absorption - d i s t r i b u t i o n phase when the assumption i s made that f i n a l e l i m i n a t i o n should occur i n a p a r a l l e l f a s h i o n . The small e l e v a t i o n i n ET l i d o c a i n e l e v e l s above c o n t r o l s which occurred upon opening the chest c a v i t y (Figure 8) i s presumably due to changes produced i n i n t r a t h o r a c i c pressure by t h i s procedure. Of i n t e r e s t i s the la r g e e l e v a t i o n i n plasma l i d o c a i n e l e v e l s observed during v e n t r i c u l a r f i b r i l l a t i o n (Figures 8 & 9). I t may be po s t u l a t e d t h a t the c i r c u l a t o r y changes which accompany c a r d i a c a r r e s t (with c a r d i a c massage) could r e s u l t i n a prolonged d i s t r i b u t i o n phase and confinement of adequate c i r c u l a t i n g blood flow to the c e n t r a l c i r c u l a t i o n . This may have produced the abnormally high plasma l i d o c a i n e l e v e l s which p e r s i s t e d f o r a longer pe r i o d of time than i n c o n t r o l s . These changes i n drug d i s t r i b u t i o n are r e f l e c t e d i n the decreased ten - minute clearances (Cl^g) c a l c u l a t e d during v e n t r i c u l a r f i b r i l l a t i o n (Table I I I ) . Barsan et a l (1981) a l s o reported peak plasma l i d o c a i n e l e v e l s which were elevated w e l l i n t o the t o x i c range f o l l o w i n g e i t h e r p e r i p h e r a l venous or c e n t r a l venous i n j e c t i o n i n dogs r e c e i v i n g CPR during c a r d i a c a r r e s t . These observations emphasize the need f o r s i m i l a r c l i n i c a l s t u d i e s i n man, since c u r r e n t c a r d i a c a r r e s t dosage regimens may indeed produce drug l e v e l s which are higher than one would otherwise assume. In f a c t , an assumption i s o f t e n made during c a r d i a c a r r e s t drug therapy th a t lack of c l i n i c a l response may be due i n pa r t to 100 poor c i r c u l a t i n g l e v e l s of the drug'in question; a d d i t i o n a l doses may then be given. V e n t r i c u l a r f i b r i l l a t i o n (with c a r d i a c massage) d i d not a l t e r the amount of l i d o c a i n e absorbed v i a the endotracheal route (Table I I I ) during the f i r s t ten minutes a f t e r drug a d m i n i s t r a t i o n . Based on t h i s o bservation, plus the f a c t that during v e n t r i c u l a r f i b r i l l a t i o n peak plasma l i d o c a i n e l e v e l s were observed 30 seconds a f t e r a d m i n i s t r a t i o n of the drug, one could assume t h a t adequate c i r c u l a t i o n to the lungs i s maintained i n t h i s c o n d i t i o n . The 'depot' e f f e c t f o l l o w i n g endotracheal a d m i n i s t r a t i o n of l i d o c a i n e was a l s o observed during v e n t r i c u l a r f i b r i l l a t i o n (Figures 12 & 13). Compared w i t h IV i n j e c t i o n , d i s t r i b u t i o n was prolonged and i n i t i a l peak plasma l e v e l s were not as high. This may have some th e r a p e u t i c advantage si n c e a d m i n i s t r a t i o n v i a t h i s route may avoid i n i t i a l t o x i c l e v e l s and prolong the time i n the t h e r a p e u t i c range. Endotracheal a d m i n i s t r a t i o n of l i d o c a i n e every f i v e minutes r e s u l t e d i n slow and steady accumulation of both peak and trough plasma l i d o c a i n e l e v e l s (Figure 14). I t may be assumed from t h i s t h a t i f smaller doses had been given more f r e q u e n t l y , a pseudo 'steady s t a t e 1 plasma l e v e l could have been achieved w i t h i n the t h e r a p e u t i c range. A f t e r both IV and ET a d m i n i s t r a t i o n of l i d o c a i n e the f i n a l e l i m i n a t i o n (/S) phase occurred i n a p a r a l l e l f a s h i o n . Since 70% of the o r i g i n a l ET dose had been absorbed by 10 minutes, one might p o s t u l a t e t h a t e x t r a - h e p a t i c metabolism or storage could account f o r the remaining 30% of the dose. Post et a l (1978) has demonstrated accumulation of l i d o c a i n e i n 101 perfused r a t lungs. The s i g n i f i c a n c e of accumulation of l i d o -caine i n lung t i s s u e i s not c l e a r at t h i s time, although l i d o c a i n e endotracheal spray has been used f o r t o p i c a l anesthesia f o r many years without evidence of lung t o x i c i t y . Endotracheal a d m i n i s t r a t i o n of l i d o c a i n e during prolonged v e n t r i c u l a r f i b r i l l a t i o n had a profound e f f e c t on reducing the d u r a t i o n of the arrhythmia r e g a r d l e s s of whether f i b r i l l a t i o n r e s u l t e d from o c c l u s i o n or r e p e r f u s i o n of the coronary a r t e r y (Table I V ) . Without exception, v e n t r i c u l a r f i b r i l l a t i o n r e v e r t e d to an organized c a r d i a c rhythm w i t h i n 1.2 minutes of l i d o c a i n e a d m i n i s t r a t i o n (mean 0.7 + 0.1 min.). This i s i n c o n t r a s t to c o n t r o l experiments where f i b r i l l a t i o n p e r s i s t e d f o r 6.5 - 12.5 minutes (mean 7.7 + 0.6 min.). The mean d u r a t i o n of v e n t r i c u l a r f i b r i l l a t i o n i n c o n t r o l experiments i s , i n f a c t , a r t i f i c i a l l y shortened s i n c e most arrhythmias were terminated at ten minutes w i t h e l e c t r i c a l d e f i b r i l l a t i o n i f spontaneous conversion to an organized heart beat had not occurred. Comparison of percent v e n t r i c u l a r mass to which blood flow was occluded (Table V) shows th a t the response to l i d o c a i n e was not biased i n any way by smaller occluded zones i n those animals. No f u r t h e r episodes of v e n t r i c u l a r f i b r i l l a t i o n occurred i n any animals a f t e r conversion to r e g u l a r c a r d i a c rhythm ( i n the l i d o c a i n e e f f i c a c y s t u d i e s ) . Even non l i d o c a i n e -t r e a t e d animals appeared to be r e l a t i v e l y arrhythmia - f r e e once an organized heart beat had begun. In most animal models of coronary o c c l u s i o n i n the 102 l i t e r a t u r e , t h e r e a p p e a r t o be two d e f i n i t e p e r i o d s o f s u s c e p t i b i l i t y t o v e n t r i c u l a r f i b r i l l a t i o n . I n t h i s m o d e l , i t a p p e a r e d t h a t o c c l u s i o n - i n d u c e d f i b r i l l a t i o n a l w a y s o c c u r r e d w i t h i n t e n o r f i f t e e n m i n u t e s o f o c c l u s i o n , and r e -p e r f u s i o n f i b r i l l a t i o n o c c u r r e d a l m o s t as s o o n as t h e l i g a t u r e was r e l e a s e d . S i n c e c o n c l u s i o n o f t h i s s t u d y , H a r r i s o n (1981) has r e p o r t e d a t r i a l o f l i d o c a i n e i n o u t - o f - h o s p i t a l c o u n t e r -s h o c k r e f r a c t o 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 . P a t i e n t s n o t r e s p o n d i n g t o two e l e c t r i c a l c o u n t e r s h o c k s p l u s i n t r a v e n o u s s o d i u m b i c a r b o n a t e were g i v e n e i t h e r l i d o c a i n e p l u s f u r t h e r t h e r a p y as o r d e r e d by p h y s i c i a n s ( e p i n e p h r i n e , c a l c i u m c h l o r i d e , s o d i u m b i c a r b o n a t e ) , o r f u r t h e r t h e r a p y w i t h no a n t i a r r h y t h m i c d r u g . The a u t h o r s r e p o r t e d no d i f f e r e n c e i n p e r c e n t o f p a t i e n t s r e m a i n i n g i n v e n t r i c u l a r f i b r i l l a t i o n upon a r r i v a l a t t h e h o s p i t a l and t h e r e was no s i g n i f i c a n t d i f f e r e n c e i n o t h e r d r u g s u s e d , b e t w e e n t h e two g r o u p s . A number o f a s p e c t s o f t h i s s t u d y a r e open t o c r i t i c i s m , however. O n l y one lOOmg IV b o l u s o f l i d o c a i n e was g i v e n d u r i n g any r e s u s c i t a t i o n a t t e m p t , and t h e a u t h o r s do n o t s t a t e t h e mean t i m e i n t h i s g r o u p f r o m i n i t i a t i o n o f t h e r e s u s c i t a t i o n a t t e m p t t o a r r i v a l a t t h e h o s p i t a l . O t h e r d e t a i l s w h i c h a r e n o t g i v e n a r e t h e t i m e s e q u e n c e w i t h r e s p e c t t o l i d o c a i n e a d m i n i s t r a t i o n and any s u b s e q u e n t c a r d i a c r h y t h m s . I t i s n o t s t a t e d w h e t h e r p a t i e n t s s t i l l i n f i b r i l l a t i o n upon a r r i v a l a t t h e h o s p i t a l had e x h i b i t e d any o t h e r c a r d i a c r h y t h m s d u r i n g t h e p r e c e d i n g r e s u s c i t a t i o n a t t e m p t . The s t u d y was n o t r a n d o m i z e d ; p a t i e n t s were s e l e c t e d by t h e o r d e r i n g p h y s i c i a n w i t h r e s p e c t t o l i d o c a i n e a d m i n i s t r a t i o n . The 103 authors were unable to determine the c r i t e r i a used i n these cases f o r the use of l i d o c a i n e . This r e p o r t does, however, address the question of ant i a r r h y t h m i c therapy of countershock -r e f r a c t o 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 , and r a i s e s some very appropriate concerns w i t h regard to current therapy. F i r s t l y , appropriateness of a l l agents used should be assessed, w i t h respect to both immediate response and long-term s u r v i v a l of p a t i e n t s . Secondly, dosages of drugs c u r r e n t l y used should be examined f o r both e f f i c a c y and t o x i c i t y . As shown i n the current study, plasma l e v e l s of l i d o c a i n e during c a r d i a c a r r e s t may i n f a c t be much higher i n i t i a l l y than o f t e n presumed. Since the c i r c u l a t i o n time i n a small animal such as a r a b b i t d i f f e r s g r e a t l y from t h a t of man, a d i r e c t p a r a l l e l cannot be drawn w i t h respect to r a t e and extent of appearance of l i d o c a i n e i n the blood during c a r d i a c a r r e s t . B r e t y l i u m therapy i n the treatment of c a r d i a c a r r e s t has r e c e n t l y been evaluated by Nowak e t a l (1981). They reported greater s u r v i v a l i n p a t i e n t s r e c e i v i n g b r e t y l i u m (39%) than those r e c e i v i n g placebo (9%) f o r v e n t r i c u l a r f i b r i l l a t i o n . A l l other drug therapy was administered according to American Heart A s s o c i a t i o n (1980) g u i d e l i n e s . Of note i s the f a c t that l i d o c a i n e was used more f r e q u e n t l y i n the group who received b r e t y l i u m , and i s o p r o t e r e n o l was used more o f t e n i n the placebo group. These trends may have predisposed p a t i e n t s to increased (or decreased) s u r v i v a l . L i d o c a i n e has also" been compared r e c e n t l y w i t h b r e t y l i u m i n the management of out - of - h o s p i t a l v e n t r i c u l a r f i b r i l l a t i o n (Haynes e t 'al', 1981) . A f t e r one e l e c t r i c a l d e f i b r i l l a t i o n attempt, approximately 24% of p a t i e n t s had 104 converted to an organized rhythm i n both groups, whereas f o l l o w -ing e i t h e r l i d o c a i n e (lOOmg) or b r e t y l i u m (500mg) i n t r a v e n o u s l y plus an.average of 1.6 a d d i t i o n a l d e f i b r i l l a t o r y shocks, 89% of p a t i e n t s r e c e i v i n g b r e t y l i u m and 9 3% of p a t i e n t s r e c e i v i n g l i d o c a i n e had converted to an organized rhythm. The percent of p a t i e n t s i n the l i d o c a i n e and b r e t y l i u m - t r e a t e d groups who were subsequently discharged home was 26% and 34% r e s p e c t i v e l y , which i s somewhat i n c o n t r a s t to the number discharged home i n Harrison's (1981) study (2-11%). I t appears t h a t f u r t h e r e v a l u a t i o n of l i d o c a i n e as an adjunct to the management of v e n t r i c u l a r f i b r i l l a t i o n needs to be performed. C e r t a i n l y the data from the present study i n d i c a t e t h a t l i d o c a i n e may posess some a n t i f i b r i l l a t o r y e f f i c a c y , at l e a s t i n the model used. I t was not p o s s i b l e i n t h i s animal model to assess only f i b r i l l a t i o n episodes r e f r a c t o r y to e l e c t r i c a l d e f i b r i l l a t i o n s i n c e a l l hearts were e a s i l y d e f i b r i l l a t e d e l e c t r i c a l l y . I t th e r e f o r e became necessary to assess the e f f i c a c y of l i d o c a i n e as a chemical d e f i b r i l l a t o r alone, and not as an adjunct to e l e c t r i c a l d e f i b r i l l a t i o n . The three c l i n i c a l s t u d i e s mentioned h e r e i n are the f i r s t reported attempts to d i r e c t l y address the i s s u e of ant i a r r h y t h m i c therapy i n the treatment of d e f i b r i l l a t i o n -r e f r a c t o 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 . Further work i n t h i s area i s d e f i n i t e l y r e q u i r e d before d e c i s i o n s concerning the most appropriate agents, dosages and routes of a d m i n i s t r a t i o n can be made. In the animal model used i n t h i s study, c e r t a i n trends were observed concerning d u r a t i o n of v e n t r i c u l a r f i b r i l l a t i o n . 1 0 5 I t was n o t e d t h a t f i b r i l l a t i o n a p p e a r e d t o o c c u r more o f t e n i n a n i m a l s i n w h i c h a c e r t a i n a r e a o f m y o c a r d i u m had b e e n o c c l u d e d ( T a b l e V I I ) . A l t h o u g h t h e d i f f e r e n c e i n p e r c e n t o f l e f t v e n t r i c u l a r and p e r c e n t o f t o t a l v e n t r i c u l a r mass o c c l u d e d between t h e No VF and Long VF g r o u p s i s n o t s t a t i s t i c a l l y s i g n i f i c a n t ( p = 0 . 1 0 4 and p = 0 . 1 2 8 r e s p e c t i v e l y ) , a t r e n d a p p e a r e d t o e x i s t i n w h i c h h e a r t s w i t h a l a r g e r o c c l u d e d a r e a were more l i k e l y t o f i b r i l l a t e . I t i s i n t e r e s t i n g t o s p e c u l a t e t h a t i n a s m a l l a n i m a l h e a r t s u c h a s t h e r a b b i t h e a r t p e r h a p s a r e l a t i v e l y l a r g e a r e a ( 4 0 - 4 5 % ) o f i s c h e m i c l e f t v e n t r i c l e i s r e q u i r e d f o r t h e p r o d u c t i o n and m a i n t e n a n c e o f r e - e n t r a n t p a t h w a y s . D u r i n g p r e l i m i n a r y e x p e r i m e n t s , two d i s t i n c t p a t t e r n s d e v e l o p e d w i t h r e s p e c t t o t h e amount o f t i m e f i b r i l l a t i o n p e r s i s t e d ( T a b l e V I ) . I t became o b v i o u s t h a t t h e l i d o c a i n e e f f i c a c y s t u d y c o u l d o n l y be c a r r i e d o u t on a n i m a l s where t h e a r r h y t h m i a had p e r s i s t e d f o r a t l e a s t two m i n u t e s , s i n c e s p o n t a n e o u s d e f i b r i l l a t i o n o f t e n o c c u r r e d p r i o r t o t h a t t i m e . O t h e r a u t h o r s have n o t r e p o r t e d t h e s e two d i s t i n c t t r e n d s i n v e n t r i c u l a r f i b r i l l a t i o n , p o s s i b l y s i n c e t h e i r s t u d y d e s i g n s w o u l d n o t n e c e s s a r i l y r e v e a l s u c h t r e n d s . S h o r t v e n t r i c u l a r f i b r i l l a t i o n e p i s o d e s o c c u r r e d more f r e q u e n t l y d u r i n g r e p e r f u s i o n t h a n d u r i n g o c c l u s i o n ( T a b l e V I ) , and o n c e an e p i s o d e o f s h o r t f i b r i l l a t i o n had o c c u r r e d i n an a n i m a l , a l o n g f i b r i l l a t i o n e p i s o d e was u n l i k e l y t o o c c u r . I t i s p o s s i b l e t h a t t h e a r e a s o f damaged my o c a r d i u m g e n e r a t i n g t h e s e s h o r t a r r h y t h m i a s were l e s s a b l e t o s u s t a i n t h e a b n o r m a l c o n d u c t i o n n e c e s s a r y t o p r o d u c e a p r o l o n g e d e p i s o d e o f 106 v e n t r i c u l a r f i b r i l l a t i o n . As r e p o r t e d i n o t h e r t r i a l s i n t h e l i t e r a t u r e , r e p e r f u s i o n o f p r e v i o u s l y i s c h e m i c m y o c a r d i u m was f o u n d i n t h i s s t u d y t o be h i g h l y a r r h y t h m o g e n i c , o f t e n r e s u l t i n g i n v e n t r i c u l a r f i b r i l l a t i o n w i t h i n one m i n u t e o f r e p e r f u s i o n . T h i s was i n c o n t r a s t t o o c c l u s i o n a r r h y t h m i a s w h i c h t e n d e d t o d e v e l o p o v e r a p e r i o d o f m i n u t e s a f t e r o c c l u s i o n , f i n a l l y d e g e n e r a t i n g i n t o v e n t r i c u l a r f i b r i l l a t i o n . No o t h e r d i f f e r e n c e s were n o t e d between t h e two p h a s e s . A r e a s o f o c c l u s i o n were t h e same i n b o t h g r o u p s u n d e r g o i n g a l o n g v e n t r i c u l a r f i b r i l l a t i o n e p i s o d e ( T a b l e I X ) . I n summary, t h e s e s t u d i e s s u g g e s t t h a t l i d o c a i n e may be e f f e c t i v e i n t e r m i n a t i n g v e n t r i c u l a r f i b r i l l a t i o n due t o 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 . S i n c e v e n t r i c u l a r f i b r i l l a t i o n i n man i s managed w i t h e l e c t r i c a l d e f i b r i l l a t i o n p l u s d r u g t h e r a p y , t h e s i g n i f i c a n c e o f t h e s e f i n d i n g s i n r e l a t i o n t o t h e c l i n i c a l s i t u a t i o n r e m a i n s u n c l e a r . T h i s s t u d y i n d i c a t e s t h a t l i d o c a i n e may have s i m i l a r e f f i c a c y i n v e n t r i c u l a r f i b r i l l a t i o n w h e t h e r g i v e n i n t r a v e n o u s l y o r e n d o t r a c h e a l l y s i n c e p l a s m a l e v e l s a c h i e v e d a r e c o m p a r a b l e . F u t h e r s t u d i e s a r e r e q u i r e d , however, b e f o r e any d e f i n i t i v e c o n c l u s i o n s c a n be drawn. The i n t r a v e n o u s r o u t e i s s t i l l t h e r o u t e o f c h o i c e f o r a d m i n i s t r a t i o n o f d r u g s d u r i n g c a r d i a c a r r e s t . T h e s e d a t a s i m p l y l e n d s u p p o r t t o t h e h y p o t h e s i s t h a t t h e e n d o t r a c h e a l r o u t e may be a n e f f e c t i v e a l t e r n a t e r o u t e f o r l i d o c a i n e a d m i n i s t r a t i o n , s h o u l d a c c e s s t o an I V l i n e be d e l a y e d . 107 CONCLUSIONS 1. In the r a b b i t , l i d o c a i n e i s absorbed as r a p i d l y f o l l o w i n g endotracheal a d m i n i s t r a t i o n as f o l l o w i n g intravenous i n j e c t i o n , w i t h approximately 70% of an endotracheal dose absorbed over 10 minutes. 2. F o l l o w i n g endotracheal a d m i n i s t r a t i o n lower peak plasma l i d o c a i n e . l e v e l s and s l i g h t l y prolonged d i s t r i b u t i o n were observed compared w i t h p e r i p h e r a l intravenous i n j e c t i o n . 3. F o l l o w i n g both intravenous and endotracheal a d m i n i s t r a t i o n during v e n t r i c u l a r f i b r i l l a t i o n , peak plasma l i d o c a i n e l e v e l s are greater and i n i t i a l d i s t r i b u t i o n i s prolonged, compared w i t h c o n t r o l s . 4. A d m i n i s t r a t i o n of l i d o c a i n e e ndotracheally during p e r s i s t e n t v e n t r i c u l a r f i b r i l l a t i o n due to acute coronary a r t e r y l i g a t i o n s i g n i f i c a n t l y shortens the d u r a t i o n of f i b r i l l a t i o n . 108 REFERENCES: A l m o t r e f i , A.A. and Baker, J.B.E, 1980, The A n t i f i b r i l l a t o r y Potency of A p r i n d i n e , M e x i l e t i n e , Tocainide and Lignocaine Compared on Langendorff-Perfused Hearts of Rabbits and Guinea-Pigs. J . Pharm. Pharmacol. 3_2, 746-750. A l m o t r e f i , A.A. and Baker, J.B.E, 1981. A n t i f i b r i l l a t o r y E f f i c a c y of Encainide, L o r c a i n i d e and ORG 6001 Compared w i t h Lignocaine i n I s o l a t e d Hearts of Rabbits and Guinea-Pigs. Br. J . Pharmacol. 73, 373-377. American Heart A s s o c i a t i o n . 1980. Standards and G u i d e l i n e s f o r Cardiopulmonary R e s u s c i t a t i o n (CPR) and Emergency Cardiac Care (ECC). 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