UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

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

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
831-UBC_1982_A6_7 B76.pdf [ 4.93MB ]
Metadata
JSON: 831-1.0095537.json
JSON-LD: 831-1.0095537-ld.json
RDF/XML (Pretty): 831-1.0095537-rdf.xml
RDF/JSON: 831-1.0095537-rdf.json
Turtle: 831-1.0095537-turtle.txt
N-Triples: 831-1.0095537-rdf-ntriples.txt
Original Record: 831-1.0095537-source.json
Full Text
831-1.0095537-fulltext.txt
Citation
831-1.0095537.ris

Full Text

LIDOCAINE IN EXPERIMENTAL VENTRICULAR FIBRILLATION: ENDOTRACHEAL v s INTRAVENOUS USE by LINDA KATHLEEN BROWN B.S.(Pharm.), The U n i v e r s i t y o f 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 in THE FACULTY OF GRADUATE STUDIES D i v i s i o n o f Pharmacology and T o x i c o l o g y of the F a c u l t y of Pharmaceutical Sciences We a c c e p t t h i s t h e s i s as conforming to the r e q u i r e d standard  THE UNIVERSITY OF BRITISH COLUMBIA APRIL 198 2 (c)  L i n d a K a t h l e e n Brown, 1982  In p r e s e n t i n g  t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of  requirements f o r an advanced degree at the  the  University  o f B r i t i s h Columbia, I agree t h a t the L i b r a r y s h a l l make it  f r e e l y a v a i l a b l e f o r reference  and  study.  I  further  agree t h a t p e r m i s s i o n f o r e x t e n s i v e copying of t h i s t h e s i s f o r s c h o l a r l y purposes may department or by h i s o r her  be granted by the head o f representatives.  my  It is  understood t h a t copying or p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l gain  s h a l l not be allowed without my  permission.  Department of The  U n i v e r s i t y of B r i t i s h Columbia Main Mall Vancouver, Canada 1956  V6T  DE-6  (3/81)  1Y3  written  ii  ABSTRACT  The  e n d o t r a c h e a l (ET) r o u t e f o r t h e a d m i n i s t r a t i o n o f  s e 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 of drug a d m i n i s t r a t i o n intravenous  during  route  emergency s i t u a t i o n s when an  (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 t h e t r e a t m e n t o f 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 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 , a l t h o u g h t h i s h y p o t h e s i s has n o t been c o n f i r m e d i n t h e 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  fibril-  l a t i o n due t o a c u t e c o r o n a r y a r t e r y l i g a t i o n was examined, as w e l l as t h e use o f t h e e n d o t r a c h e a l r o u t e as an a l t e r n a t i v e t o IV i n j e c t i o n . R a b b i t s were a n e s t h e t i z e d  w i t h sodium  pentobarbital  or h a l o t h a n e , i n t u b a t e d  w i t h an e n d o t r a c h e a l t u b e , and a n i m a l s  receiving pentobarbital  were m e c h a n i c a l l y r e s p i r e d .  f i b r i l l a t i o n was produced by o c c l u s i o n o f t h e l e f t c o r o n a r y a r t e r y , o r by subsequent r e p e r f u s i o n  Ventricular circumflex  of ischemic  myocardium. Endotracheal administration  o f 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 lidocaine concentrations but more s u s t a i n e d (p<0.05).  i n i t i a l l y compared w i t h IV i n j e c t i o n ,  l e v e l s i n the therapeutic  Administration  range f o r l i d o c a i n e  o f l i d o c a i n e e i t h e r IV o r 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 resulted 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 c o n c e n t r a t i o n s minute compared w i t h c o n t r o l s .  during  During v e n t r i c u l a r  the f i r s t fibrillation  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 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 o r ET  administration.  A d m i n i s t r a t i o n o f l i d o c a i n e 2mg/Kg e n d o t r a c h e a l l y ( i n normal s a l i n e ) d u r i n g VF r e s u l t e d i n a s i g n i f i c a n t d e c r e a s e i n t h e d u r a t i o n o f f i b r i l l a t i o n compared w i t h u n t r e a t e d and normal s a l i n e c o n t r o l s (p <0.001).  iv TABLE OF CONTENTS Page ABSTRACT  i i  LIST OF TABLES  .  '  LIST OF FIGURES INTRODUCTION 1.  2.  3.  vi v i i  .  The E n d o t r a c h e a l Route f o r Lidocaine Administration a) The R a t i o n a l e f o r E n d o t r a c h e a l Drug A d m i n i s t r a t i o n b) E n d o t r a c h e a l A b s o r p t i o n o f Drugs 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 . .. a) Overview b) Mechanisms o f A r r h y t h m o g e n e s i s 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 o f L i d o c a i n e i n Normal and I s c h e m i c Myocardium d) E f f e c t s o f L i d o c a i n e Seen C l i n i c a l l y  1 1 .  3 11 11 13 19 22  R a t i o n a l e and Purpose o f t h e P r e s e n t Study ........... 25  MATERIALS AND METHODS 1.  Plasma L i d o c a i n e L e v e l S t u d i e s  ........... .... ........28  2. 3.  a) A n i m a l E x p e r i m e n t s .28 b) L i d o c a i n e Assay , 30 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 S t u d i e s .. . . . . . . ... . . . . . . , . , ,,.... . . . . 3 4 A n a l y s e s and S t a t i s t i c s 41  4.  Drugs and C h e m i c a l s ............. ... ............ . . .... .42  RESULTS 1.  Plasma L i d o c a i n e L e v e l S t u d i e s ...................... 43 a) E n d o t r a c h e a l v s I n t r a v e n o u s L i d o c a i n e i n D i s t i l l e d Water D u r i n g Halothane A n e s t h e s i a ............v.........43 b) The E f f e c t o f P e n t o b a r b i t a l o r Halothane A n e s t h e s i a on t h e Endotracheal Absorption of Lidocaine i n D i s t i l l e d Water 43  V  c) 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 of L i d o c a i n e i n E i t h e r D i s t i l l e d Water o r Normal S a l i n e D u r i n g P e n t o b a r b i t a l Anesthesia  2.  a  ?  e  4 9  d) A b s o r p t i o n o f L i d 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 L i d o c a i n e i n Normal S a l i n e D u r i n g 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 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 L i d o c a i n e L e v e l s 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 D u r i n g 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  60  f) 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 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 . . . . g) 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 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 h) 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/Kg i n D i s t i l l e d Water F o l l o w e d by lmg/Kg E v e r y F i v e M i n u t e 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 of Endotracheal Lidocaine a) The E f f e c t o f E n d o t r a c h e a l L i d o c a i n e on D u r a t i o n o f V e n t r i c u l a r F i b r i l l a t i o n 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 c) O c c l u s i o n v s R e p e r f u s i o n V e n t r i c u l a r Fibrillation  DISCUSSION REFERENCES.  ,  6 4  • • • • ^9  7 4  7 4  7 4  ^0 8 9  9 6  10 8  vi  LIST OF TABLES Page Table I .  Table I I .  Table I I I  T a b l e IV.  T a b l e V.  Table V I .  Table VII,  Table V I I I ,  Table IX.  Calculated f i r s t - o r d e r rate constants and plasma h a l f - l i v e s f o r i n t r a v e n o u s i n j e c t i o n and e n d o 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 d i s t i l l e d water ,  48  Calculated f i r s t - o r d e r rate constants and plasma h a l f - l i v e s f o r e n d o t r a c h e a l i n s t i l l a t i o n of lidocaine i n d i s t i l l e d water and normal s a l i n e  57  A r e a under t h e c u r v e , f r a c t i o n o f dose absorbed and c l e a r a n c e o f l i d o c a i n e following intravenous or endotracheal administration during either v e n t r i c u l a r f i b r i l l a t i o n o r open c h e s t c o n t r o l s  63  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 following endotracheal administration of l i d o c a i n e , normal s a l i n e , o r no treatment ,  78  Percent occlusion 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 u n t r e a t e d 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  D u r a t i o n and fibrillation fibrillation fibrillation  81  frequency of v e n t r i c u l a r i n short v e n t r i c u l a r and l o n g v e n t r i c u l a r categories ,  Comparison o f p e r c e n t o c c l u s i o n o f left ventricular, right ventricular, and t o t a l v e n t r i c u l a r mass w i t h tendency t o f i b r i l l a t e  87  Comparison 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 arrhythmias following' coronary artery l i g a t i o n w i t h tendency t o f i b r i l l a t e  88  Comparison o f p e r c e n t o c c l u s i o n o f left ventricular, right ventricular, and t o t a l v e n t r i c u l a r mass i n ventricular f i b r i l l a t i o n occurring 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 phase  95  vii  LIST OF FIGURES Page F i g u r e 1.  P r i n c i p l e o f homogeneous enzyme  F i g u r e 2.  Schematic r e p r e s e n t a t i o n o f t h e p o s i t i o n  F i g u r e 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  F i g u r e 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 lidocaine i n d i s t i l l e d  F i g u r e 4.  Figure  '5.  F i g u r e 6.  Log plasma l i d o c a i n e c o n c e n t r a t i o n following 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 d u r i n g h a l o t h a n e a n e s t h e s i a .. Plasma l i d o c a i n e c o n c e n t r a t i o n s 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 d u r i n g e i t h e r h a l o t h a n e Plasma l i d o c a i n e c o n c e n t r a t i o n s 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  F i g u r e 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 e n d o 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 e i t h e r normal s a l i n e o r  F i g u r e 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 endotracheal administration of lidocaine i n normal s a l i n e d u r 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 w i t h c a r d i a c massage, open c h e s t  F i g u r e 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 o f l i d o c a i n e i n normal s a l i n e d u r 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 and  F i g u r e 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 endot 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 o r i n t r a v e n o u s i n j e c t i o n o f  F i g u r e 11.  Log plasma l i d o c a i n e c o n c e n t r a t i o n s v s time f o l l o w i n g i n t r a v e n o u s i n j e c t i o n o f l i d o c a i n e i n normal s a l i n e o r e n d o t r a c h e a l i n s t i l l a t i o n o f l i d o c a i n e i n normal s a l i n e ...  . . . 32 . . . 36 . . . 36  . . .45  , 47  , 51  ,- . . 53  . . ..59  66  68  viii  Page F i g u r e 12.  F i g u r e 13.  F i g u r e 14.  Plasma l i d o c a i n e l e v e l s observed following e i t h e r intravenous i n j e c t i o n o f l i d o c a i n e i n normal s a l i n e 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 normal s a l i n e d u r 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 w i t h c a r d i a c massage  71  Log plasma l i d o c a i n e c o n c e n t r a t i o n s vs time f o l l o w i n g e i t h e r i n t r a v e n o u s i n j e c t i o n o f 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  73  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 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 a ' l o a d i n g d o s e f o l l o w e d by a 'maintenance d o s e every 5 minutes  76  B l o o d p r e s s u r e and ECG r e c o r d i n g s d u r 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 w i t h manual h e a r t massage  84  B l o o d p r e s s u r e and ECG r e c o r d i n g s d u r i n g a 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 which l a s t e d 25 seconds and t e r m i n a t e d spontaneously  86  Comparison o f b l o o d p r e s s u r e b e f o r e and f o r 10 minutes a f t e r c o r o n a r y a r t e r y l i g a t i o n i n a n i m a l s i n w h i c h 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  Changes i n h e a r t r a t e f o l l o w i n g c o r o n a r y a r t e r y o c c l u s i o n i n No VF, S h o r t VF and Long VF experiments  93  1  F i g u r e 15.  F i g u r e 16.  F i g u r e 17.  F i g u r e 18.  1  ix  ACKNOWLEDGEMENTS  I would l i k e t o e x p r e s s my g r a t i t u d e t o Dr. J a c k Diamond f o r h i s guidance and s u p p o r t , and f o r t h e o p p o r t u n i t y t o 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 t o thank Pamela L i v i n g s t o n e , t o whom I owe a g r e a t d e a l o f thanks f o r h e r a s s i s t a n c e  both  i n t h e l a b and i n t h e p r e p a r a t i o n o f t h i s m a n u s c r i p t . My s i n c e r e g r a t i t u d e a l s o goes t o Dr. D a v i d Hunt and Dr. Les V e r t e s i , w i t h o u t whose e n t h u s i a s m 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 t o thank Jo-anne Maxey, E v e l y n Chu and Lynn P o l l o c k f o r t h e i r  assistance.  T h i s work was s u p p o r t e d by t h e B r i t i s h Columbia H e a l t h Care Research F o u n d a t i o n and t h e B r i t i s h Columbia F o u n d a t i o n , 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 t o e x p r e s s my a p p r e c i a t i o n t o Syva D i a g n o s t i c s  Ltd. f o r their technical assistance.  Heart  1 INTRODUCTION  1.  a)  The  E n d o t r a c h e a l Route f o r L i d o c a i n e  Administration  The  R a t i o n a l e f o r E n d o t r a c h e a l 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 c a r e has expanded r a p i d l y t h r o u g h o u t N o r t h America and Europe i n the p a s t t e n y e a r s e t a l , 1975;  S c h a f f e r and Cobb, 1975).  Advanced L i f e Support (ALS)  In B r i t i s h Columbia,  p e r s o n n e l have been p r o v i d i n g  emergency p r e - h o s p i t a l c a r e i n s e l e c t e d communities s i n c e ( V e r t e s i , 1978). m e d i c a l and  On-site  (Cobb  e v a l u a t i o n and  1975  t r e a t m e n t of many  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 p e r s o n n e l ,  employees o f the Emergency  Commission of B r i t i s h Columbia. e s t a b l i s h intravenous and a d m i n i s t e r  These teams a r e a b l e  d i r e c t - c u r r e n t c o u n t e r s h o c k and  intubation,  s e l e c t e d drugs  l i f e - t h r e a t e n i n g emergencies.  s u b j e c t of drug a d m i n i s t r a t i o n v i a  and e f f i c a c i o u s r o u t e s d u r i n g these s i t u a t i o n s has addressed r e c e n t l y .  to  catheters, perform endotracheal  d u r i n g c a r d i a c a r r e s t and o t h e r The  Health.Services  appropriate o n l y been  A d m i n i s t r a t i o n o f p h a r m a c o l o g i c agents  d u r i n g 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 a c c o m p l i s h e d v i a the p e r i p h e r a l i n t r a v e n o u s  (IV) r o u t e , s i n c e p e r i p h e r a l IV  c a n n u l a s can u s u a l l y be r a p i d l y and  safely established  p r o v i d e d i r e c t a c c e s s of the drug t o the p a t i e n t ' s (American H e a r t A s s o c i a t i o n , 1980).  circulation  More r e c e n t l y , i t has  shown t h a t d u r i n g c a r d i o p u l m o n a r y r e s u s i t a t i o n (CPR) i n j e c t i o n of C a r d i o - G r e e n  and  been  i n humans,  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 c o n c e n t r a t i o n s  and d e l a y e d appearance of peak  2 l e v e l s compared w i t h c e n t r a l i n j e c t i o n v i a the s u b c l a v i a n v e i n (Kuhn e t a l , 1981). 1981)  Other r e c e n t work i n dogs (Barsan e t a l ,  showed t h a t c e n t r a l IV i n j e c t i o n o f l i d o c a i n e d u r i n g CPR  r e s u l t e d i n h i g h e r peak l e v e l s of the drug than p e r i p h e r a l IV injection. A d e l a y e d 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 d u r i n g c a r d i a c a r r e s t may and t h e r e f o r e may  r e f l e c t slow venous r e t u r n  l e a d t o a d e l a y e d response t o the drug.  This  p a r t i c u l a r a s p e c t o f 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 a r e a i s n e c e s s a r y b e f o r e c o n c l u s i v e s t a t e m e n t s may  be made.  A t the  p r e s e n t t i m e , the p e r i p h e r a l IV r o u t e i s by f a r t h e most common r o u t e o f 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 c a r e and i n the emergency room (American H e a r t A s s o c i a t i o n , 1 9 8 0 ) . The use of the p e r i p h e r a l IV r o u t e f o r drug a d m i n i s t r a t i o n may  n o t always be p o s s i b l e d u r i n g c a r d i a c a r r e s t .  During  CPR,  i n t e n s e 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 c a t h e t e r  may  t e c h n i c a l l y be d i f f i c u l t o r a t times i m p o s s i b l e (Greenberg, M. et  al,  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 H e a l t h S e r v i c e s Academy, 1982)  show  t h a t i n a s e r i e s o f 1198 p a t i e n t s , 68% o f 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 a t t e m p t , 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. a d d i t i o n a l attempt a t s t a r t i n g an the  S i n c e each  IV i s time consuming  and  since  r a p i d i t y w i t h which drug t h e r a p y 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 r o u t e s o f drug a d m i n i s t r a t i o n s h o u l d be c o n s i d e r e d .  3  Intravenous i n j e c t i o n v i a c e n t r a l catheter provide  a r e l i a b l e method o f drug d e l i v e r y d u r i n g  collapse.  could  cardiovascular  D u r i n g 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 I V c a n n u l a e i t h e r v i a t h e s u b c l a v i a n o r 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 a t times u n s a f e .  This  p r o c e d u r e i s a s s o c i a t e d w i t h a r i s k o f pneumothorax o r p e r f o r a t i o n of t h e c a r o t i d a r t e r y , and i s b e s t performed under w e l l - l i t controlled conditions Intracardiac administering  (American H e a r t A s s o c i a t i o n ,  1980).  (IC) i n j e c t i o n may a l s o be used f o r  drugs d u r i n g  c a r d i a c a r r e s t , however  this  t e c h n i q u e i s a s s o c i a t e d w i t h t h e r i s k o f pneumothorax, hemothorax,  p e r i c a r d i a l tamponade, m y o c a r d i a l l a c e r a t i o n and  c o r o n a r y 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  r o u t e f o r drug a d m i n i s t r a t i o n i s t h e r e f o r e advocated when no o t h e r methods a r e a v a i l a b l e o r a p p r o p r i a t e . The has  e n d o t r a c h e a l r o u t e f o r s e l e c t e d drug  administration  been proposed as an e f f e c t i v e a l t e r n a t e r o u t e 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 p r o l o n g e d a t t e m p t s t o s t a r t an IV may d e l a y d e f i n i t i v e t r e a t m e n t unnecessarily  (Redding e t a l , 1967; Elam, 1977; R o b e r t s e t a l , 1978;  Greenberg e t a l , 1979"; R o b e r t s e t 'al, 1 9 7 9 ; R o b e r t s e t a l , b a  1979  ).  E n d o t r a c h e a l 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 b e f o r e a t t e m p t i n g t o 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 o f drugs i f s a t i s f a c t o r y a b s o r p t i o n of drugs v i a t h a t r o u t e c o u l d be documented. b)  Endotracheal Absorption  o f Drugs  4  A b s o r p t i o n o f c e r t a i n drugs from t h e t r a c h e a , 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 e t a l , b 1967;  Elam, 1977; Greenberg e t 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 a t r o p i n e a r e c o n s i d e r e d t o be e s s e n t i a l drugs i n emergency c a r d i a c c a r e and i t has been p r o posed t h a t they may be e f f e c t i v e when a d m i n i s t e r e d v i a t h e endotracheal route  (Redding e t a l , 1967; Elam, 1977; R o b e r t s  e t a l , 1978; Greenberg e t a l , 1 9 7 9 ; Roberts e t a l , 1 9 7 9 ; a  a  Roberts e t a l , 1 9 7 9 ) . b  Roberts e t a l (1978, 1979 ) compared t h e b l o o d and p h a r m a c o l o g i c  levels  e f f e c t s o b t a i n e d when e p i n e p h r i n e was g i v e n by  e i t h e r the intravenous or endotracheal route i n anesthetized dogs.  E n d o t r a c h e a l 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  e p i n e p h r i n e d i l u t e d i n 5 ml normal s a l i n e i n t o an e n d o t r a c h e a l tube, o c c l u d i n g t h e end o f t h e tube f o r f i v e seconds t o p r e v e n t r e f l e x coughing  o f t h e s o l u t i o n , and then  performing R  f i v e q u i c k i n f l a t i o n s o f t h e 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  c o n c e n t r a t i o n s o f e p i n e p h r i n e were a c h i e v e d a t 15 seconds f o l l o w i n g both IV i n j e c t i o n and e n d o t r a c h e a l  (ET) i n s t i l l a t i o n ,  a l t h o u g h t h e peak l e v e l a c h i e v e d v i a t h e IV r o u t e was a p p r o x i m a t e l y t e n times t h a t a c h i e v e d w i t h t h e ET r o u t e .  The  time c o u r s e o f e p i n e p h r i n e i n t h e b l o o d f o l l o w i n g ET i n s t i l l a t i o n was found t o 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 : a t f i v e minutes f o l l o w i n g IV i n j e c t i o n , o n l y 20% o f t h e i n i t i a l c o n c e n t r a t i o n o f e p i n e p h r i n e c o u l d be found, whereas w i t h t h e ET route a t f i v e minutes,  80% o f t h e 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 o b t a i n e d when t h e p h a r m a c o l o g i c  effects of  5  e p i n e p h r i n e were compared when t h e drug was g i v e n by t h e two routes. These d a t a suggest t h a t i n dogs, r a p i d a b s o r p t i o n o f e p i n e p h r i n e o c c u r s from t h e l u n g s , t r a c h e a , and b r o 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 t h a t t h e marked s u s t a i n e d e l e v a t i o n  i n b l o o d 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 , o r s u s t a i n e d r e l e a s e mechanism.  Roberts  e t a l (1979 ) have s u b s e q u e n t l y r e p o r t e d t h e s u c c e s s f u l use o f e n d o t r a c h e a l e p i n e p h r i n e 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 collapse. In 1967, Redding e t aJL examined t h e e f f e c t i v e n e s s o f epinephrine, given v i a d i f f e r e n t routes, i n reversing hypoxiai n d u c e d . c a r d i a c a r r e s t i n dogs.  The e f f e c t s o f t h e drug were  compared when i t was g i v e n by I V , i n t r a m u s c u l a r (IM), o r intracardiac  (IC) i n j e c t i o n , o r by e n d o t r a c h e a l  instillation.  E n d o t r a c h e a l 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, o r 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 e p i n e p h r i n e 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 o r when i n s t i l l e d v i a t h e ET r o u t e .  The d a t a f u r t h e r suggest  that  d e l i v e r y o f t h e drug i s enhanced when i t i s d i l u t e d i n water as compared w i t h normal s a l i n e , s i n c e t h e mean time t o r e t u r n o f c i r c u l a t i o n f o l l o w i n g e p i n e p h r i n e 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 e p i n e p h r i n e i n s a l i n e .  There was no  d i f f e r e n c e between t h e time t o r e t u r n o f c i r c u l a t i o n o r number o f dogs r e s p o n d i n g distilled  t o 1 mg e p i n e p h r i n e g i v e n IV o r ET ( i n 10 mL  water). In  1977, Elam examined t h e i n t r a p u l m o n a r y r o u t e f o r  a t r o p i n e , e p i n e p h r i n e , and l i d o c a i n e d u r i n g  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 t h r o u g h a c a t h e t e r produced a more r a p i d and more s u s t a i n e d ECG the f e m o r a l v e i n .  response than IV a d m i n i s t r a t i o n v i a  Plasma l e v e l s of the drugs were not m o n i t o r e d ,  t h e r e f o r e t h e r a p e u t i c r e s p o n s e , measured as ECG  changes,  was  the o n l y method used t o determine o n s e t and d u r a t i o n of a c t i o n by b o t h r o u t e s . A b s o r p t i o n o f l o c a l a n e s t h e t i c s from the 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  when Campbell and A d r i a n i r e p o r t e d s i g n i f i c a n t producing  trachea,  absorption  b l o o d l e v e l s comparable t o those a t t a i n e d by  injection.  The  1958,  intravenous  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 , p r o c a i n e ,  c o c a i n e , and b e n z o c a i n e .  I n c o n t r a s t t o l a t e r work, they  found  t h a t b l o o d 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 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. a b s o r p t i o n was  They a l s o determined t h a t  more r a p i d from the t r a c h e a than from the pharynx,  and h i g h e r peak l e v e l s were a t t a i n e d when the animals i n an u p r i g h t p o s i t i o n t h a n i n the prone p o s i t i o n . was  not  (dogs) were  This  conducted t o examine the p o s s i b i l i t y of s y s t e m i c  study  toxicity  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 . I n 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 b l o o d 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 .  venous l i d o c a i n e was  g i v e n t o seven p a t i e n t s as an i n f u s i o n (9.3 -  100 mg/min) t o a t o t a l dose of 9.7 t o x i c i t y was  manifested  d e c r e a s e d t i d a l volume. i n f u s i o n was  Intra-  -16.3  mg/Kg.  Systemic  by an acute drop i n b l o o d p r e s s u r e Convulsions  not t e r m i n a t e d .  and  f o l l o w e d t h e s e s i g n s i f the  L i d o c a i n e was  a p p l i e d as a 4%  spray  7  t o t h e l a r y n x and t r a c h e a p r i o r t o e n d o t r a c h e a l  intubation.  Doses v a r i e d from 3.5 t o 10.5 mg/Kg and were a d m i n i s t e r e d i n d i v i d e d amounts over 2^-10 m i n u t e s .  The r a t e o f a b s o r p t i o n  w i d e l y , w i t h peak b l o o d c o n c e n t r a t i o n s  varied  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 b l o o d  l e v e l s and r a t e s o f  a b s o r p t i o n demonstrated may be due t o 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 o f t h e a p p l i c a t i o n . intravenous  As w i t h  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 o f a b o l u s amount would produce a more r a p i d and h i g h e r peak b l o o d  l e v e l than i n t e r m i t t e n t spraying  over a t e n minute p e r i o d . S i n c e 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 f o c u s e d on t h e p o t e n t i a l t o x i c i t y o f 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 t o mucous membranes, l a r y n x , t r a c h e a , b r o n c h i , and a l v e o l i .  Most  r e p o r t s show p r o l o n g e d and d e l a y e d a b s o r p t i o n o f 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 o f a 10% s o l u t i o n was administered  t o t h e t r a c h e a and b r o n c h i  i n anesthetized  patients  ( P e l t o n e t a l , 1970). Chu  e t al_ (1975) demonstrated peak plasma l e v e l s o f  l i d o c a i n e i n venous b l o o d  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 t o spray the  solution.  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 t h e t r a c h e a  p r i o r t o i n t u b a t i o n o f p a t i e n t s undergoing e l e c t i v e s u r g e r y .  The  mean time t o 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 r e p o r t e d u s i n g 2 mg/Kg  sprayed  onto t h e l a r y n g e s and t r a c h e a s o f a n e s t h e t i z e d p a t i e n t s and S t o e l t i n g , 1975).  The a u t h o r s  (Viegas  r e p o r t e d peak plasma con-  c e n t r a t i o n s o f 1.7 - 0.2 jug/mL, 9 - 1 5 minutes a f t e r l i d o c a i n e administration.  I n p a t i e n t s who were i n t u b a t e d w i t h  tubes l u b r i c a t e d w i t h v i s c o u s l i d o c a i n e , peak plasma  endotracheal 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 t h e same dose o f l i d o c a i n e . C u r r a n e t a l (1975) a l s o noted d e l a y e d a b s o r p t i o n o f l i d o c a i n e from t h e l a r y n x and t r a c h e a , and f u r t h e r d e t e r m i n e d t h a t a b s o r p t i o n from t h e l a r y n g e a l a r e a i s d e c r e a s e d compared w i t h a b s o r p t i o n from t h e t r a c h e a .  Peak plasma l e v e l s o f 0.4 -  2.5 ug/mL were o b t a i n e d a t 10 - 20 minutes from t h e l a r y n x , whereas peak l e v e l s o f 1.9 - 8 pg/mL were reached a t 5 - 15 minutes from t h e t r a c h e a .  T h i s f i n d i n g i s n o t unexpected due t o  the h i g h e r degree o f v a s c u l a r i t y o f t h e t r a c h e a l area compared t o the l a r y n x . Uptake o f l i d o c a i n e g i v e n 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 investigated  (IPPB) and u l t r a s o n i c n e b u l i z e r has been  (Chinn e t a l , 1977).  Plasma l e v e l s d i d n o t exceed  1.1 ug/mL a l t h o u g h doses used were 280 mg v i a u l t r a s o u n d and 400 mg v i a IPPB. S i m i l a r plasma l e v e l s were o b t a i n e d u s i n g a metered dose a p p l i c a t o r (a f i n e spray) and u s i n g 50 mg o r 100 mg o n l y ( S c o t t e t a l , 1976).  They f u r t h e r r e p o r t e d t h a t h i g h e r plasma  l e v e l s were o b t a i n e d when p a t i e n t s were p a r a l y z e d 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 o f t h e drug deeper i n t o t h e pulmonary t r e e , whereas spontaneous r e s p i r a t i o n a l l o w s some o f t h e  9  a d m i n i s t e r e d drug t o be e x h a l e d o r coughed o u t . The  slow uptake o f 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 t o 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 t o t h e r a p i d ECG r e s u l t s o b t a i n e d by Elam (1977) following i n s t i l l a t i o n of a solution v i a a catheter into the pulmonary a r e a .  The l a t t e r study demonstrates t h a t e p i n e p h r i n e ,  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 g i v e n v i a t h e i n t r a p u l m o n a r y r o u t e , and t h a t t h i s r o u t e may p r o v i d e as r a p i d and more p r o l o n g e d 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 r o u t e .  I t does n o t , however, examine t h e q u e s t i o n o f  s u i t a b l e dosages and a p p r o p r i a t e p h a r m a c o l o g i c a l r e s p o n s e s . o b j e c t i v e of cardiopulmonary  The  resuscitation i s to restore  e f f e c t i v e pumping a c t i o n t o t h e h e a r t , and t h e use o f ECG response  a l o n e as t h e p r i m a r y c r i t e r i a f o r t h e r a p e u t i c e f f e c t  does n o t t o t a l l y answer t h i s q u e s t i o n . I t appears t h a t t h e use o f l i d o c a i n e v i a t h e e n d o t r a c h e a l r o u t e may be o f b e n e f i t when an IV l i n e cannot be established.  Although there i s considerable controversy i n the  l i t e r a t u r e r e g a r d i n g t h e r a t e o f a b s o r p t i o n and amount i t i s c l e a r t h a t l i d o c a i n e i s absorbed b r o n c h i , and l u n g s .  absorbed,  from t h e l a r y n x , t r a c h e a ,  There i s e v i d e n c e t o suggest t h a t deep  i n s t i l l a t i o n o f l i d o c a i n e i n t o t h e lungs w i l l produce more r a p i d and h i g h e r 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 t o t h e laryngeal area.  I t a l s o appears t h a t water may be a more  a p p r o p r i a t e v e h i c l e than normal s a l i n e , a l t h o u g h t h i s s h o u l d be confirmed. Due t o t h e l a r g e v a r i a t i o n r e p o r t e d i n r a t e and e x t e n t o f l i d o c a i n e a b s o r p t i o n , i t i s n e c e s s a r y t o f u r t h e r examine t h e plasma l e v e l s o b t a i n e d when the drug i s g i v e n e x p e r i m e n t a l l y i n  10 a s i t u a t i o n analogous t o t h a t encountered c l i n i c a l l y .  In cardiac  a r r e s t , the hemodynamic s t a t u s o f 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 e t a l , 1980).  Peripheral  p e r f u s i o n i s o f t e n v e r y p o o r , w i t h the m a j o r i t y o f c i r c u l a t i n g b l o o d volume i n the c e n t r a l c i r c u l a t i o n . i n t o the l u n g s may  Instillation  o f a drug  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 i n t r a v e n o u s injection into a peripheral vein. Due t o t h e p o t e n t i a l l y s e r i o u s a d v e r s e e f f e c t s w h i c h may  o c c u r 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 i m p o r t a n t to c l o s e l y determine the dosage n e c e s s a r y i n any g i v e n s i t u a t i o n . The p h a r m a c o k i n e t i c s o f i n t r a v e n o u s 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 s a f e and  r a p i d a d m i n i s t r a t i o n o f the drug v i a t h i s r o u t e .  The same d a t a  i s n e c e s s a r y f o r the e n d o t r a c h e a l r o u t e , i f the drug i s t o 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 o f L i d o c a i n e  a)  Overview  Acute m y o c a r d i a l i n f a r c t i o n  (AMI) i s one o f t h e l e a d i n g  causes o f m o r b i d i t y and m o r t a l i t y i n Canada and t h e U n i t e d States  (Canadian Heart F o u n d a t i o n , 1980).  By f a r t h e most  dangerous consequence o f m y o c a r d i a l i s c h e m i a i s t h e p r o d u c t i o n of  l e t h a l a r r h y t h m i a s and sudden d e a t h .  I n 1980, 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 r e s u l t e d i n death i n a p p r o x i m a t e l y 50,000 p a t i e n t s i n Canada a l o n e  (Canadian Heart F o u n d a t i o n , 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 t h e c a u s a t i v e a r r h y t h m i a i n 50%-80% o f c a s e s , and e i t h e r a s y s t o l e , e l e c t r o m e c h a n i c a l d i s s o c i a t i o n , o r severe b r a d y c a r d i a a r e t h e cause o f t h e remainder  (Vertesi,  1978).  A l t h o u g h prompt a n t i a r r h y t h m i c t h e r a p y may a b o l i s h a r r h y t h m i a s and perhaps decrease 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 fibrillation  ( L i e 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 t o a r r i v a l o f advanced p r e - h o s p i t a l c a r e p e r s o n n e l , 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 antiarrhythmic t h e r a p y 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 t h e t r e a t m e n t o f c h o i c e t o r e v e r s e v e n t r i c u l a r fibrillation  (American H e a r t A s s o c i a t i o n , 1980).  This  treatment  i s n o t 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 o f time Eisenberg e t a l ,  ( L i b e r t h s o n et. a_l, 1974;  1980).  Many drug p r o t o c o l s have been d e v i s e d 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  arrest.  Drug t h e r a p y i n i . t i a . i l y e v o l v e d , e m p i r i c a l l y  w i t h development o f t r e a t m e n t 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 t o t h e d i f f i c u l t y  i n p e r f o r m i n g c o n t r o l l e d human e x p e r i m e n t s d u r i n g  cardiac  a r r e s t , changes o r advances i n drug t h e r a p y have come about p r i m a r i l y as a r e s u l t o f a n i m a l e x p e r i m e n t s observations, with  few c o n t r o l l e d human s t u d i e s .  I n t h e American H e a r t A s s o c i a t i o n ' s Guidelines  and s u b j e c t i v e  f o r Cardiopulmonary R e s u s c i t a t i o n  Emergency C a r d i a c Care (ECC)  1  'Standards and (CPR) and  (1980), l i d o c a i n e i s recommended  as t h e d r u g o f c h o i c e f o r t h e s u p p r e s s i o n o f v e n t r i c u l a r b e a t s and v e n t r i c u l a r t a c h y c a r d i a .  ectopic  I t i s a l s o recommended i n t h e  treatment o f v e n t r i c u l a r f i b r i l l a t i o n unresponsive t o 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 c a n be s u c c e s s f u l l y t e r m i n a t e d w i t h  electrical  d e f i b r i l l a t i o n , and 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 to occur e i t h e r p r i o r t o o r despite therapy, c a r e f u l evaluation e f f i c a c y i s mandatory.  continues  i n s t i t u t i o n of appropriate  of current protocols  and t h e i r  A l t h o u g h e v i d e n c e suggests t h a t  may be h e l p f u l i n t e r m i n a t i n g  ventricular f i b r i l l a t i o n ,  lidocaine this  has  n o t 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  The  f o l l o w i n g i s a s u r v e y o f t h e l i t e r a t u r e r e g a r d i n g t h e known  antiarrhythmic and  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  trials.  of lidocaine,  t h e r a t i o n a l e f o r f u r t h e r e x p e r i m e n t s t o document t h e e x t e n t  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 . A l t h o u g h complex e l e c t r o p h y s i o l o g i c a l documentation o f the e f f e c t s o f l i d o c a i n e on t h e f i b r i l l a t i n g h e a r t a r e beyond t h e scope o f t h i s s t u d y , t h e f o l l o w i n g d i s c u s s i o n w i l l d e a l i n some depth w i t h mechanisms o f a r r h y t h m o g e n e s i s and t h e e l e c t r o -  13 p h y s i o l o g i c a l actions of l i d o c a i n e .  These d a t a w i l l be p r e s e n t e d  as s u p p o r t f o r t h e 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 possess antifibrillatory  b)  a c t i v i t y i n established ventricular f i b r i l l a t i o n .  Mechanisms o f A r r h y t h m o g e n e s i s  S e v e r a l models have been developed t o s t u d y underl y i n g mechanisms i n v o l v e d i n t h e e l e c t r o p h y s i o l o g i c a l events accompanying 1975).  acute myocardial i n f a r c t i o n  (Wit and Friedman,  A r r h y t h m i a p r o d u c t i o n and sudden death as a r e s u l t o f  o c c l u s i o n o f a c o r o n a r y a r t e r y have been c l e a r l y  demonstrated  i n a n i m a l e x p e r i m e n t s where a c u t e s u r g i c a l o c c l u s i o n o f a c o r o n a r y 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 a r e s i m i l a r t o those r e p o r t e d myocardial i n f a r c t i o n .  i n man d u r i n g  acute  Many p a t i e n t s i n whom sudden death  has o c c u r r e d , however, show no s i g n i f i c a n t degree o f o c c l u s i o n of c o r o n a r y b l o o d  flow  (Bashe e t a_l, 1975).  Temporary spasm  of a c o r o n a r y 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 o f c o r o n a r y 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). was  Coronary a r t e r i a l spasm  seen i n 40% o f m y o c a r d i a l i n f a r c t i o n s due t o c o r o n a r y  artery disease.  Spasm was o f t e n seen t o be superimposed on an  a t h e r o s c l e r o t i c obstruction already present.  R e l i e f o f the  spasm r e s u l t e d i n r e t u r n o f p a t e n c y o f t h e a r t e r y i n some patients. I n o r d e r t o mimic t h e 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 o f a c o r o n a r y a r t e r y i s f o l l o w e d by r e p e r f u s i o n .  Both o c c l u s i o n  14  and  reperfusion  shown t o be including et  of  coronary a r t e r i a l  highly  arrhythmogenic  dogs, c a t s ,  a l , 1975;  i n dogs has  (Axelrod  et  of  Levites  e t a l , 1979;  et  Axelrod  al,  1975;  Murdock e t a l , 19 80;  .  ventricular  anterior  a few  descending  production  minutes of  occlusion  Levites  Murdock e t a l , 1980;  T h e s e a r r h y t h m i a s u s u a l l y peak i n m i n u t e s and  this  occlusion  has  then abate.  been r e p o r t e d  procedure  greatly  from  e t a l , 1979;  l%-40%  Kaplinsky  of  et a l ,  Kaplinsky frequency  Spontaneous i n 65%  of  animals  (Fujimoto e t a l , 1981),  frequency with which t h i s  varied  coronary  i n the  E l - S h e r i f e t a l , 1975;  fibrillation  a l t h o u g h the  Kaplinsky  left  e t a l , 1979;  about 4 - 8  following  the  consistently resulted  e t a l , 1975;  al', 1981)  studies  ( B a t t l e e t a l , 1974;  arrhythmias within  Kaplinsky  within  species,  e t a l , 1981).  ventricular  1975;  f l o w have b e e n  i n many a n i m a l  a l , 1975;  Kaplinsky  Occlusion artery  rats  E l - S h e r i f et  Kane e t a l , 1979; Kaplinsky  and  blood  event occurred  ( B a t t l e e t a_l,  e t a l , 1981;  in  other  1974;  Ouyang e t a l ,  1981) . Reperfusion of a l s o b e e n shown t o be production of  the  i s c h e m i c myocardium  highly  ( L e v i t e s e t a l , 1975;  subsequent v e n t r i c u l a r f i b r i l l a t i o n animals of  ( B a t t l e e t a_l, 1974;  1978) of  29%  w i t h an  i n the  cat  (Corr  and  occlusion  and  immediately  i n up  release  due 25%  upon  to  60%-65%  e t a_l, 1 9 8 1 ) .  e t a l , 1978;  overall mortality  following  has  has  also  the  release  Murdock e t a_l, 1980)  Kaplinsky  a r r h y t h m i a s upon o c c l u s i o n  demonstrated  dog  arrhythmogenic, r e s u l t i n g i n  of v e n t r i c u l a r arrhythmias  ligature  i n the  and  of Production  been  Penkoske e t a l ,  to v e n t r i c u l a r following  fibrillation  reperfusion.  15  O c c l u s i o n and  r e p e r f u s i o n a r r h y t h m i a s have been noted  t o 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 r e s p e c t t o o n s e t , f r e q u e n c y and d u r a t i o n .  A r r h y t h m i a s due  to coronary a r t e r y  o c c l u s i o n have been noted t o d e v e l o p g r a d u a l l y , peak w i t h i n 4-8  minutes and  e t a l , 1978;  then abate i n about 10 - 12 minutes  Penkoske e t a l , 1978;  (Corr  Murdock e t a l , 1980).  Some  i n v e s t i g a t o r s have noted a second phase of a r r h y t h m i a s w h i c h o c c u r s from 12 - 30 minutes f o l l o w i n g l i g a t i o n 1979)  (Kaplinsky et a l ,  although other studies in, cats using o c c l u s i o n periods  the same d u r a t i o n have not noted t h i s  of  (Corr e t a_l, 1978;  Penkoske e t a l , 1978). Reperfusion  arrhythmias,  however, have been shown t o  o c c u r a l m o s t i m m e d i a t e l y 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 following 1 - 2 1975;  minutes ( B a t t l e e t aJL, 1974;  Penkoske e t a l , 1978;  the  Axelrod et a l ,  Murdock e t a l , 1980).  Kaplinsky  e t a l (1981), however, a l s o demonstrated a second phase of arrhythmias occurring 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 p r o d u c t i o n  of a r r h y t h -  mias upon o c c l u s i o n o r r e p e r f u s i o n of a c o r o n a r y a r t e r y are thought t o be complex and  i n v o l v e many f a c t o r s .  c o n t r i b u t i o n of neurohormonal, b i o c h e m i c a l  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 y e t t o be c o m p l e t e l y general  defined.  In  though, i t i s f e l t t h a t a r r h y t h m i a s can o c c u r v i a  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, automaticity  (Han,  1969).  r e - e n t r y and  two  enhanced  R e - e n t r y i s proposed t o o c c u r when  an e l e c t r i c a l i m p u l s e i s b l o c k e d a l o n g an a l t e r n a t e r o u t e , and proximal  The  a l o n g one  pathway, t r a v e l s  then e v e n t u a l l y r e - e x c i t e s more  t i s s u e by t r a v e l l i n g i n a r e t r o g r a d e  fashion along  the  16  original  blocked route.  reduction  T h i s may  i n conduction v e l o c i t y  relative  to another,  adjacent  tissue.  o r by  occur  as a r e s u l t  i n one  differences  segment o f  o c c u r as a r e s u l t  diastolic  o f an  depolarization  properties),  an  negative)  i n the e l e c t r i c a l  development. several Vera  (Wit and  and Mason,  1975;  1975;  o c c l u s i o n of a coronary  which p a r a l l e l e d  ventricular  Both  1975;  to both  artery  has  coronary  The  and  electrically-induced Axelrod et a l ,  a decrease  artery  occlusion  in refractory myocardial  (Levites et a l ,  K a p l i n s k y e t a l , 1979;  These changes d i d not occur  in  Murdock  non-ischemic  Marked f r a c t i o n a t i o n o f e l e c t r i c a l  epicardial  a l s o been observed frequency.  b e e n shown t o  arrhythmias  ( B a t t l e e t a l , 1974;  c o n d u c t i o n d e l a y and  tissue.  as r e c o r d e d by  by  f i b r i l l a t i o n threshold  s p o n t a n e o u s and  P e n k o s k e e t a l , 1978;  myocardial  potential  e t a l , 1976).  following  e t a l , 1980).  (more  e t a_l, 1979;  p e r i o d h a v e b e e n shown t o o c c u r w i t h i n i s c h e m i c tissue  diastolic  reviewed  Ribner  appearance of v e n t r i c u l a r  fibrillation  Corbalan  or a decrease  have b e e n r e c e n t l y  Friedman,  intrinsic  i n t h e maximum  threshold for action  i n a reduction i n ventricular  susceptibility  those  1981).  Acute result  of r e p o l a r i z a t i o n ,  These concepts  authors  depolarization  tissue with  increase (less negative)  a t t h e end  periods i n  i n c r e a s e i n s l o p e o f phase 4  (in cardiac  potential  a  myocardium  in refractory  Enhanced a u t o m a t i c i t y or spontaneous may  of  and  and  subepicardial  coincides with  activity  e l e c t r o d e s has  increased arrhythmia  f r a c t i o n a t i o n of e l e c t r i c a l  non-homogeneous d e p o l a r i z a t i o n o f m y o c a r d i a l  activity cells,  reflects probably  17  from slow c o n d u c t i n g et  a l , 1979;  tissue  conduction delay  entry  as  and  i n refractory period  mechanism f o r a r r h y t h m i a  coronary artery  genesis  Bigger,  electrical  activity,  in  ischemic  t i s s u e have l e d most i n v e s t i g a t o r s t o promote  R e - e n t r y has the  f r a c t i o n a t i o n of  a decrease  t h e most l i k e l y  following  Kaplinsky  Murdock e t a l , 1 9 8 0 ) .  Demonstration of  myocardial  ( E l - S h e r i f e t a_l, 1975;  of  1971)  production  occlusion.  been demonstrated c l i n i c a l l y  supraventricular and  re-  tachycardia  ventricular fibrillation  i n man  (Goldreyer  in  and  (Josephson e t a l ,  1978). The  evidence  f o r a mechanism f o r a r r h y t h m i a s  coronary artery reperfusion fibrillation  threshold  following o c c l u s i o n of ( B a t t l e e t a l , 1974; This  threshold  has  the  so  clear.  decreases within  approximately  e t a l , 1975;  Kaplinsky  et a l  reperfusion  to normal i n approximately threshold  conditions period  of  and  this  for ventricular  reduction  (1981) r e p o r t e d  arrhythmias with  fragmented e l e c t r i c a l  the  the  activity.  suitable for re-entry. a r r h y t h m i a s beyond the  abnormalities  had  returned  ventricular  overdrive  rates  has  to  10  minutes.  fibrillation  l e v e l s seen  i s of b r i e f  a s s o c i a t i o n of  reappearance of  duration. immediate  nonhomogeneous,  These c o n d i t i o n s  could  They a l s o n o t e d a  provide  delayed  t i m e when c o n d u c t i o n  to c o n t r o l l e v e l s ,  t h i s w i t h augmented a u t o m a t i c i t y . d e m o n s t r a t e d by  3 minutes  C o r b a l a n e t a l , 1976).  b e e n shown t o d r o p a l m o s t i m m e d i a t e l y  following occlusion,  Ventricular  a c o r o n a r y a r t e r y i n most a n i m a l m o d e l s  Axelrod  returns  Upon r e p e r f u s i o n ,  i s not  following  Augmented  suppression  and  b e e n s u g g e s t e d by  and  associated  automaticity  enhanced  idio-  P e n k o s k e et. a_l (1978)  18  as a p o s s i b l e mechanism o f a r r h y t h m i a perfusion. velocity  In a d d i t i o n ,  exist,  reperfusion.  localized  indicating  production during re-  areas of depressed  heterogeneous  I t i s possible that Kaplinsky  w o r k e r s were a b l e t o d e f i n e more c l e a r l y a temporal  recovery  conduction  after  (1981) and  co-  during reperfusion  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  automaticity. Re-entry has  as a mechanism f o r r e p e r f u s i o n a r r h y t h m i a s  a l s o been proposed  by Murdock e t a l  (1980),  who  demonstrated  nonhomogeneous r e c o v e r y o f c o n d u c t i o n w h i c h c o i n c i d e d w i t h return of  arrhythmias. The  role  arrhythmogenesis during  induced  enhanced  o f h u m o r a l and  may  be  sympathetic  ventricular  artery  were n o t  seen  t h r e s h o l d changes which o c c u r  o c c l u s i o n ( C o r b a l a n e t a_l, 1976) .  n o t be  compared w i t h  local  artery  as  significant  c y c l i c AMP  of  arrhythmias.  in  cAMP l e v e l s  i n ischemic  paralleled  also  occlusion,  Coronary  an  time  Both the during  These  effects  that adrenergic  time.  have b e e n m e a s u r e d  and  activity following  o c c l u s i o n (Corr e t a l , 1978).  intramyocardial conduction  was  at that  electrophysiologic  in  AMP  levels  including  (Brown, 1967).  p r o p r a n o l o l have b e e n shown t o r e d u c e  Regional  m i n u t e s and  discharge  following reperfusion, suggesting  mechanisms may  on  Adrenergic influences  i s c h e m i a have b e e n o b s e r v e d ,  afferent  fibrillation  coronary  biochemical parameters  v e r y complex.  myocardial  p h e n t o l a m i n e and  coronary  a  Alterations  correlated w e l l with  occlusion also  resulted  t i s s u e w h i c h was  onset  i n an  maximal a t  increase i n arrhythmias.  increase 15  Cyclic  e l e v a t e d i n the normal myocardium f o l l o w i n g  but  to a s i g n i f i c a n t l y  lower  extent  than  i n ischemic  19  tissue.  Spontaneous v e n t r i c u l a r f i b r i l l a t i o n  correlated with propranolol a lower  elevated  levels.  caused a s i g n i f i c a n t  incidence  of arrhythmias  Increased resulting  cAMP  blood  reduction  i n cAMP  and v e n t r i c u l a r  flow  significantly  Pretreatment  washout o f m e t a b o l i c  from impaired  was  with l e v e l s and  fibrillation.  waste  products  and a l t e r e d  cellular  p e r m e a b i l i t y h a v e a l s o b e e n p r o p o s e d a s mechanisms f o r a r r h y t h mogenesis d u r i n g observed  coronary  that prolongation  increased  incidence  reperfusion  artery reperfusion.  o f o c c l u s i o n time r e s u l t s  o f induced  (Corbalan  e t a l , 1976).  I t i s possible that  myocardium has been r e p o r t e d These m e t a b o l i c  to disruption of c e l l u l a r  contribute  there  these  'washout' o f p o t a s s i u m and l a c t a t e f r o m  (Lang e t a l , 1 9 7 4 ) . due  f o r some o f  upon  a l t e r a t i o n s to occur.  Increased ischemic  i n an  ventricular fibrillation  may be a minimum o c c l u s i o n t i m e r e q u i r e d biochemical  I t has been  to localized  during  reperfusion  products  membrane  may be r e l e a s e d  integrity  and may  e l e c t r o p h y s i o l o g i c a l changes i n t h e  myocardium.  c)  Electrophysiological Effects of Lidocaine and  Ischemic  Lidocaine velocity tissue  (Kupersmith,  myocardium re-entry, in  Myocardium  h a s b e e n shown t o f u r t h e r s l o w  i n ischemic  c a r d i a c t i s s u e without 1979).  i s already  block  Since  effect  conduction  slowed, thereby  f u r t h e r slowing  bidirectional  i n Normal  o f impulses  and t e r m i n a t i o n  conduction on n o r m a l  i n ischemic  p r o v i d i n g a mechanism f o r i n this  r e g i o n may  of re-entry.  result  Lazzara  20  et a l  (1978) o b s e r v e d t h a t  lidocaine  consistently  reduced  conduction i n i s o l a t e d ischemic cardiac  cells,  change i n c o n d u c t i o n c o i n c i d e d  disappearance  abnormal spontaneous beats. e x t i n g u i s h e d by concluded that  lidocaine  with  the  and  that  this  of  T h i s i m p a i r e d c o n d u c t i o n was  as w e l l as by  a r r h y t h m i a s may  tetrodotoxin.  totally  They  r e s u l t from d e p r e s s i o n of  the  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 conduction.  Membrane r e s p o n s i v e n e s s  (upstroke v e l o c i t y  p h a s e 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 ) impaired i n ischemic c e l l s T h i s may  also  contribute  and  was  t o the  further  r e d u c e d by  observation that  extinguishes conduction i n ischemic c e l l s which exhibited  d e l a y e d c o n d u c t i o n and  lidocaine  in abolishing  a l s o b e e n r e p o r t e d by  period.  Brennan e t a l  The  period  previously effects  w h i c h l i d o c a i n e may  i n ischemic cardiac  exert i t s refractory effective  tissue  s i g n i f i c a n t l y changing a c t i o n p o t e n t i a l duration  d e c r e a s e i n APD therefore,  was  but  The no  e f f e c t on  a decrease i n the  ERP.  The  r a t i o o f APD/ERP  i s c h e m i c zone, w i t h  duction occurring  i n the  normal zone.  some o f  (APD)  overall  i n the  explain  without  e f f e c t s seen i n n o r m a l t i s s u e were  a p p r o x i m a t e l y 1.0  refractoriness  of  (1975).  b e e n shown t o p r o l o n g t h e  (ERP)  ( K u p e r s m i t h , 1979).  lidocaine.  lidocaine  e f f e c t s i s through a l t e r a t i o n s i n  L i d o c a i n e has  refractory  re-entry.  also  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 n o t h e r m e c h a n i s m by antiarrhythmic  was  of  result, to  a smaller  re^  T h i s change i n  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 the  antiarrhythmic  Automaticity through a r e t a r d a t i o n  has of  a  properties  b e e n shown t o be  spontaneous phase 4  of  also  lidocaine.  a l t e r e d by  lidocaine  depolarization  21 (Bigger the  and  Mandel,  1970;  Rosen e t a_l, 1973)  r e s t i n g membrane p o t e n t i a l  colleagues  (1974) d e m o n s t r a t e d  suppress e c t o p i c entry  (Lazzara  following The  b e a t s due  accompanying c o r o n a r y a r t e r y  t o be  abolished  1976).  associated  The  i n the  that  and  i n reducing  the  1979)  r a b b i t and  A l m o t r e f i and  exerted  myocardium. elevation and  of  shown  Borer et a l , was,also  spontaneous  coronary  sinus  be  in groups.  to determine  b e e n shown t o  arrhythmias  be  and  artery  ligation  arrhythmias  (Almotrefi  in  VFT.  a l s o b e e n shown t o e l e v a t e  and  in VFT  in  Baker,  1981).  coworkers  coronary  seen d u r i n g was  by  to d i f f e r e n c e s  ouabain-induced  a protective  CPK  due  coronary  guinea p i g hearts  Following  commonly  I t has  Baker,  VFT  lidocaine-treated  of  following  against  affect  difference  l i d o c a i n e has  incidence  .  B o u d o u l a s and lidocaine  f o u n d no  i n t e n s i t y used  fibrillation  afford protection  1980;  re-  threshold  a l s o been i n v e s t i g a t e d  between r e s u l t s may  f r e q u e n c y and  (Kane e t aJL,  isolated  to  and  been  a l , 1972;  incidence  v a l u e s b e t w e e n c o n t r o l and  ventricular rats  has  l i d o c a i n e may  (1981), who  Pre-treatment with effective  and  dog.  occlusion  (Spear e t  i s c h e m i a has  coworkers  discrepancies  stimulus  lidocaine  l i d o c a i n e i n these studies  possibility  myocardial  Kramer and  i n the  Han  fibrillation.  The  threshold  of  with a reduction  ventricular  during  lidocaine  Administration  of  in ventricular fibrillation  (VFT)  by  ability  ischemia  reducing  e t a l , 1975).  to enhanced a u t o m a t i c i t y  myocardial  reduction  the  without  (1978 ) have f o u n d t h a t a  e f f e c t on  canine  ischemic  artery occlusion, i s c h e m i a was  shown t o  increase  ST-segment  r e d u c e d by i n the  lidocaine,  control  22 group more than i n the t h a t t h i s p r o t e c t i o n may of l i d o c a i n e .  lidocaine-treated  They  Boudoulas e t a l (1978 ) have a l s o r e p o r t e d necrosis  following  occlusion. l i d o c a i n e 10 minutes p r i o r t o a  40 minute c o r o n a r y a r t e r y o c c l u s i o n r e s u l t i n a three-fold reduction  ( i n dogs) has  been shown t o  i n i n f a r c t s i z e , a reduction  v e n t r i c u l a r a r r h y t h m i a s upon o c c l u s i o n  and  release,  increased  in  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 p r e s s u r e  and  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 p r e s s u r e (Nasser e t a l ,  Coronary a r t e r y o c c l u s i o n was  mitochondrial was  effect  that  b  Pretreatment with  1980).  postulated  r e s u l t from the n e g a t i v e i n o t r o p i c  l i d o c a i n e d e c r e a s e d i s c h e m i c i n j u r y and coronary  group.  associated  with  decreased  r e s p i r a t i o n i n the c e n t e r o f i n f a r c t e d t i s s u e which  not a l t e r e d by l i d o c a i n e t h e r a p y .  b l o o d f l o w was  l o w e s t i n the  Since regional  lidocaine-treated  groups,  myocardial the  a u t h o r s proposed t h a t l i d o c a i n e d i d not e x e r t i t s e f f e c t s through n e g a t i v e i n o t r o p i c mechanisms but r a t h e r preservation  through  o f m y o c a r d i a l c e l l membrane i n t e g r i t y .  I n an u n c o n t r o l l e d reported successful  s t u d y , Carden and  Steinhaus  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  (1956)  fibrillation  i n 21 o f 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 lidocaine.  L i d o c a i n e dosage was  15mg/Kg and  i n a mean time o f 7 minutes (range 2 - 2 7  d)  1950,  was  seen  minutes).  E f f e c t s of L i d o c a i n e Seen C l i n i c a l l y  L i d o c a i n e was and  response was  of  f i r s t s y n t h e s i z e d i n Sweden i n 194 3  used f o r many y e a r s as a l o c a l a n e s t h e t i c  Southworth e t a l r e p o r t e d the s u c c e s s f u l  use  agent. of  In  lidocaine  23 to  r e v e r s e 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  catheterization. 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 a r r h y t h m i a s  which  would u l t i m a t e l y l e a d 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 o r v e n t r i c u l a r tachycardia.  S u p p r e s s i o n o f these e c t o p i c b e a t s w i t h a n t i -  a r r h y t h m i c t h e r a p y was  t h e r e f o r e presumed t o be a l o g i c a l  step  i n the p r e v e n t i o n o f t h e more s e r i o u s subsequent a r r h y t h m i a s . The terms 'warning a r r h y t h m i a s  1  o r 'premonitory a r r h y t h m i a s  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 ( g r e a t e r than 5/minute), m u l t i f o c a l o r 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 o r near t h e p r e c e e d i n g T wave. has been demonstrated  Lidocaine  t o be v e r y 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 o r r e d u c i n g the number and f r e q u e n c y o f PVCs when plasma l e v e l s o f 1.5 obtained  ( G i a n e l l y e t a l , 1967;  - 5.5 /ig/mL are  J e w i t t e t 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 t o  suppress  v e n t r i c u l a r e c t o p i c b e a t s d u r i n g the acute phase o f m y o c a r d i a l i n f a r c t i o n and presumably t o p r e v e n t VF o r v e n t r i c u l a r t a c h y cardia.  Plasma l i d o c a i n e l e v e l s g r e a t e r than 6 jug/mL may  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  be  i r r i t a b i l i t y , convul-  s i o n s , m y o c a r d i a l d e p r e s s i o n , and c o m a : ( G i a n e l l y e t 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 a r r h y t h m i a s , and t h a t a n t i a r r h y t h m i c t h e r a p y a t t h a t time w i l l p r e v e n t VF i n t h o s e p a t i e n t s , has been q u e s t i o n e d . been observed t h a t 25%-40% o f p a t i e n t s d i d not e x h i b i t  I t has warning  a r r h y t h m i a s p r i o r t o VF, and t h a t p r e m o n i t o r y a r r h y t h m i a s  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 n o t d e v e l o p VF as i n those p a t i e n t s who do ( L i e e t a l , 1975; R i b n e r e t a l , 1979). F u r t h e r m o r e , many 'warning a r r h y t h m i a s '  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 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  care  unit,  (Lown e_t a l , 1975) .  A t t e n t i o n has s i n c e been f o c u s e d on t h e concept o f p r o p 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 a c u t e infarction.  L i d o c a i n e p r o p h y l a x i s has r e c e i v e d  myocardial  considerable  a t t e n t i o n i n the l i t e r a t u r e . Lie  e t a l , (1974), i n a d o u b l e - b l i n d , randomized  i n a s e r i e s o f 212 c o n s e c u t i v e p a t i e n t s , a s s e s s e d l i d o c a i n e i n p r e v e n t i n g VF i n acute m y o c a r d i a l  trial  the e f f i c a c y of  infarction.  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 t h e dosage g i v e n was h i g h l y effective  (p< 0.002) i n p r e v e n t i n g VF.  These f i n d i n g s were  supported  by o t h e r workers ( V a l e n t i n e e t a l , 1974; Wyman and  Hammersmith, 1974; S z e p l a k i e t a l , 1976). Although  prompt t r e a t m e n t  w i t h a n t i a r r h y t h m i c drugs  may d e c r e a s e t h e i n c i d e n c e o f 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 t o a r r i v a l o f a p r e - h o s p i t a l advanced l i f e unit  (ALS), p r i o r t o a r r i v a l a t h o s p i t a l , o r b e f o r e  a n t i a r r h y t h m i c drug t h e r a p y has been i n s t i t u t e d .  support  definitive  Electrical  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 c h o i c e t o r e v e r s e t h e f i b r i l l a t i o n , b u t t h i s i s n o t always successful.  I n a s e r i e s o f 301 p a t i e n t s t r e a t e d by t h e ALS r e s c u e  squad from the'Miami F i r e Department, o n l y 199 c o u l d be d e f i b r i l l a t e d d e s p i t e t h e use o f c o n v e n t i o n a l c a r d i a c a r r e s t drug t h e r ^ apy.  F u r t h e r m o r e , o f those d e f i b r i l l a t e d , a p p r o x i m a t e l y  r e c u r r e n c e o f VF.  Approximately  40% had  50% o f those d e f i b r i l l a t e d d i e d  p r i o r t o a r r i v a l a t h o s p i t a l ( L i b e r t h s o n e t a l , 1974).  Eisenberg  25 e t a l (1980) r e p o r t e d t h a t i n 36 c a s e s o f o u t - o f - h o s p i t a l ventricular 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 t h e f i r s t d e f i b r i l l a t i o n attempt. Both e p i n e p h r i n e  and l i d o c a i n e a r e c u r r e n t l y used i n  c a r d i a c a r r e s t p r o t o c o l s i n t h e management o f v e n t r i c u l a r fibrillation  (American H e a r t A s s o c i a t i o n , 1980; Redding, 1977).  The  as t o 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  question  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 n o t c l e a r . the ; l i t e r a t u r e , .revealed.  A review of  no c o n t r o l l e d s t u d i e s i n t h e use o f  l i d o c a i n e a l o n e i n t h e management o f VF.  Nevertheless,  i t has  been t h e concept i n c a r d i a c a r r e s t drug t h e r a p y t h a t l i d o c a i n e and/or e p i n e p h r i n e  be used i n t h e t r e a t m e n t o f VF u n r e s p o n s i v e  to d e f i b r i l l a t i o n , since withholding  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 n o t be o f v a l u e .  3.  R a t i o n a l e and Purpose o f t h e P r e s e n t Study  S t a t i s t i c s from t h e Vancouver Advanced L i f e  Support  Program i n d i c a t e t h a t a p p r o x i m a t e l y 13% o f 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 a t t e m p t s (Emergency H e a l t h  S e r v i c e s 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 d r u g t h e r a p y u n t i l t h e IV l i n e i s i n p l a c e , u n l e s s a l t e r n a t e r o u t e s o f drug administration are a v a i l a b l e . I t i s p o s s i b l e 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 administered The  i n t h e form o f a s o l u t i o n v i a an e n d o t r a c h e a l  r a t e and e x t e n t o f a b s o r p t i o n  need t o be d e t e r m i n e d  tube.  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 . Lidocaine  i s c u r r e n t l y i n w i d e s p r e a d use i n t h e  26  t r e a t m e n t and p r e v e n t i o n o f v e n t r i c u l a r f i b r i l l a t i o n and tachycardia.  C o n s i d e r a b l e e f f o r t has been d i r e c t e d  towards  p r e v e n t i o n o f t h e s e a r r h y t h m i a s , and i t appears t h a t  lidocaine  may be e f f e c t i v e when g i v e n p r i o r t o t h e o n s e t o f VF.  Lidocaine  appears t o be e f f e c t i v e i n t h e t r e a t m e n t o f v e n t r i c u l a r t a c h y cardia. P r e v e n t i o n o f VF i s o f v i t a l c o n c e r n d u r i n g t h e i n i t i a l stages o f 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 o f p a t i e n t s a r e i n VF when seen by an emergency ALS crew, o r d e v e l o p VF b e f o r e any d e f i n i t i v e t r e a t m e n t 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 o f a c i d - b a s e b a l a n c e a r e o f primary concern i n t h i s s i t u a t i o n . use  I t appears t h a t d e s p i t e t h e  o f e l e c t r i c a l d e f i b r i l l a t i o n , a p p r o x i m a t e l y 1/3 -' 1/2 o f  p a t i e n t s a r e n o t a b l e t o 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 . i n t h e l i t e r a t u r e s u g g e s t s t h a t l i d o c a i n e may a b o l i s h  Evidence  ventricular  a r r h y t h m i a s by e l i m i n a t i n g r e - e n t r a n t pathways and by r e d u c i n g augmented a u t o m a t i c i t y .  I t i s therefore  possible  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 t e r m i n a t i n g  that  lidocaine  ventricular  fibrillation. The  value of l i d o c a i n e i n the termination  VF has n o t been e s t a b l i s h e d .  o f ongoing  A l t h o u g h e p i n e p h r i n e 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 , t h e e f f i c a c y o f e i t h e r agent has n o t been demonstrated c o n c l u s i v e l y  i n controlled c l i n i c a l  trials.  It  appears t h a t t h e e f f i c a c y o f l i d o c a i n e i n t h e t r e a t m e n t o f 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 i s a q u e s t i o n which has y e t t o be answered. I t i s t h e aim o f t h i s study t o i n v e s t i g a t e t h e e f f i c a c y of l i d o c a i n e when a d m i n i s t e r e d v i a an e n d o t r a c h e a l tube d u r i n g 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 o f 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 b o t h e n d o t r a c h e a l and i n t r a v e n o u s 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 L i d o c a i n e L e v e l S t u d i e s  a)  A n i m a l Experiments White New Zealand  r a b b i t s o f e i t h e r sex w e i g h i n g 2.0 -  3.5 Kg. were a n e s t h e t i z e d w i t h e i t h e r h a l o t h a n e or i n t r a v e n o u s  v i a inhalation  sodium p e n t o b a r b i t a l .  Halothane was a d m i n i s t e r e d concentration o f approximately  4%.  initially in a When deep p a i n r e f l e x e s  were absent t h e r a b b i t s were i n t u b a t e d o r a l l y w i t h a M a g i l l type e n d o t r a c h e a l  tube ( s i z e 3.0 - 4.0 I.D., N a t i o n a l  Corp.) u s i n g a Welch A l l y n l a r y n g e s c o p e M i l l e r blade 1.5% h a l o t h a n e  ( s i z e 01).  and p e d i a t r i c  A n e s t h e s i a was m a i n t a i n e d  Catheter size  w i t h 1.0 -  and r a b b i t s were a l l o w e d t o breathe  spontaneously.  Halothane c o n c e n t r a t i o n was r e g u l a t e d u s i n g two  f l o w m e t e r s (Roger G i l m o n t I n s t r u m e n t s I n c . ) .  One flowmeter  d e l i v e r e d 95% 0 / 5 % C 0 w h i l e t h e o t h e r passed 0 / C 0 2  2  2  t h r o u g h a chamber c o n t a i n i n g h a l o t h a n e Pentobarbital  2  liquid.  (30 - 60 mg/Kg) was i n j e c t e d v i a t h e  m a r g i n a l e a r v e i n u s i n g a 21 gauge b u t t e r f l y i n f u s i o n s e t (Abbott Venisystems) k e p t p a t e n t u s i n g 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 required 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 p l a c e d i n a supine p o s i t i o n on an o p e r a t i n g t r a y and an e n d o t r a c h e a l tube was p l a c e d v i a tracheotomy i n t h e 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 i n t u b a t i o n .  The r a b b i t s  were r e s p i r e d a t a r a t e of 26 per minute and t i d a l volume of 25 - 35 ml ( C F . Palmer R e s p i r a t o r ) . A r t e r i a l blood p r e s s u r e  (BP) was recorded from the  c a r o t i d a r t e r y using a Gould Statham P23Db p h y s i o l o g i c a l pressure transducer.  A three-way stopcock was attached to the  c a r o t i d a r t e r y cannula f o r sampling plasma l i d o c a i n e d e t e r m i n a t i o n s . electrocardiogram electrodes.  I I of a t h r e e - l e a d using Grass  needle  Both ECG and blood pressure were recorded Instruments  R e c t a l temperature  was  Lead  (ECG) was monitored  c o n t i n u o u s l y on a Grass  Instruments  of a r t e r i a l blood f o r  2-Channel Polygraph.  was monitored  with a Yellow  Model 47 scanning telethermometer  maintained  heating lamp.  Springs  and temperature  between 37°C - 39°C using an i n f r a r e d Normal r a b b i t body temperature  i s 39.4°C  (Kaplan, 1979). For e n d o t r a c h e a l l i d o c a i n e s t u d i e s a s o l u t i o n of l i d o c a i n e 2 mg/ml i n e i t h e r d i s t i l l e d was  instilled  directly  water or normal s a l i n e  i n t o the endotracheal tube, followed by  four quick lung i n f l a t i o n s using a p e d i a t r i c L a e r d a l bag. Unless otherwise s t a t e d , the dosage used f o r a l l experiments was  2 mg/kg l i d o c a i n e HC1.  Following i n s t i l l a t i o n  of the  s o l u t i o n the e n d o t r a c h e a l tube was e i t h e r reconnected  to the  r e s p i r a t o r or the r a b b i t was allowed to resume spontaneous r e s p i r a t i o n s , depending on the a n e s t h e t i c used. For intravenous experiments, of  lidocaine i n d i s t i l l e d  e i t h e r a 2 mg/ml s o l u t i o n  water was i n j e c t e d w i t h i n f i v e  30  seconds i n t o the r a b b i t marginal ear v e i n or a 20 rug/ml s o l u t i o n of l i d o c a i n e i n normal s a l i n e was i n j e c t e d i n t o a distal  hind  l e g v e i n at the same r a t e .  The l e g v e i n  was  i s o l a t e d s u r g i c a l l y and cannulated with p o l y e t h y l e n e tubing - 90). tubing  Following  (PE  i n j e c t i o n of e i t h e r l i d o c a i n e s o l u t i o n the  was f l u s h e d with 0.25 ml normal s a l i n e . Following  e i t h e r e n d o t r a c h e a l 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 , 0.5 ml a r t e r i a l  blood  samples were withdrawn from the c a r o t i d a r t e r y cannula at 15 seconds, 30 seconds, 1 minute, 2, 3, 4, 10, 20 and 30 minutes. Samples were p l a c e d microcentrifuge  i n 1.5 ml p o l y p r o p y l e n e  tubes (VWR S c i e n t i f i c  Inc.) c o n t a i n i n g  approximately 1.5 mg disodium EDTA per tube. The  samples were c e n t r i f u g e d  microcentrifuge stored  i n an Eppendorf  f o r one minute a t 8000 x g, and the plasma was  i n a r e f r i g e r a t o r (4-6°C) f o r f u t u r e  l i d o c a i n e assay.  U n l e s s otherwise s t a t e d , plasma l i d o c a i n e  level  s t u d i e s were performed i n animals i n which no f u r t h e r procedures had been performed. Fibrillation" and  "Open Chest" and " V e n t r i c u l a r  s u r g i c a l procedures are d e s c r i b e d  were employed f o r some s t u d i e s where b)  surgical  i n s e c t i o n II  indicated,  LIDOCAINE ASSAY Plasma samples were assayed f o r l i d o c a i n e w i t h i n  seven  days of the experiment using EMIT  enzyme immunossay marketed  by Syva D i a g n o s t i c s  (Pape e t a l , 1978;  L t d . , Montreal  Rubenstein, 1978) (Figure  1).  Preliminary  conducted i n the l a b to a s c e r t a i n  s t u d i e s were  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 o f homogeneous enzyme immunoassay. When t h e enzyme-ligand  c o n j u g a t e i s complexed  t o t h e a n t i b o d y ( l e f t ) , t h e enzyme s u b s t r a t e . i s e x c l u d e d from t h e a c t i v e s i t e and enzyme activity  i s reduced.  The presence o f l i g a n d  r e l e a s e s a p o r t i o n o f t h e enzyme c o n j u g a t e , which i s then a c t i v e  (right).  C o p y r i g h t 1978 Syva D i a g n o s t i c s L t d . , M o n t r e a l (with permission)  32  33  over t h i s time p e r i o d l a y w i t h i n +5% immediately f o l l o w i n g  of samples  assayed  experiments.  Equipment used f o r the assay procedure c o n s i s t e d of a G i l f o r d S t a s a r I I I spectrophotometer, a Syva Model  1500  P i p e t t e r - D i l u t e r , a Syva CP-5000 M i c r o p r o c e s s o r , Emit -cad L i d o c a i n e Assay K i t s , Emit -cad L i d o c a i n e C o n t r o l , and 1.5 d i s p o s a b l e autoanalyzer cups Each Emit  ml  ( c o n i c a l bottoms).  assay k i t c o n s i s t e d of A n t i b o d y / S u b s t r a t e  Reagent A, Enzyme Reagent B, s i x l i d o c a i n e c a l i b r a t o r s c o n t a i n i n g O, 1.0,  2.0,  3.0,  5.0  0.055M t r i s - H C l b u f f e r s o l u t i o n prepared p r i o r  and 12.0 Aig/ml l i d o c a i n e , (pH 7.9).  and  A l l s o l u t i o n s were  to use with the a d d i t i o n of d i s t i l l e d  water.  R e c o n s t i t u t e d Antibody/Reagent A c o n t a i n e d a s t a n d a r d i z e d p r e p a r a t i o n of immunized sheep gamma g l o b u l i n , glucose-6-phosphate and NAD,  m o n o e t h y l g l y c i n e x y l i d i d e (MEGX)  and p r e s e r v a t i v e i n 0.055M t r i s HC1 R e c o n s t i t u t e d Enzyme Reagent dehydrogenase t r i s HC1  b u f f e r at pH  5.0.  B c o n t a i n e d glucose-6-phosphate  - l a b e l l e d l i d o c a i n e and p r e s e r v a t i v e s i n 0.55M  b u f f e r at pH  7.9.  A standard curve was  run at the s t a r t of each assay.  Standard procedure f o r e i t h e r c a l i b r a t o r s or unknown was  samples  as f o l l o w s : The p i p e t t e r - d i l u t e r was programmed to withdraw of  l i d o c a i n e sample  (unknown or c a l i b r a t o r ) ,  Antibody/Substrate Reagent A, or Enzyme Reagent dispense i t with 250 pi an autoanalyzer cup.  50 u l  t r i s HC1  Initally  buffer solution  two s e r i a l  B and into  d i l u t i o n s of  34  unknown o r c a l i b r a t o r were performed,  f o l l o w e d by t h e  a d d i t i o n o f 1:5 d i l u t i o n s o f Reagent A and then Reagent B t o t h e 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 m i x t u r e was a s p i r a t e d i m m e d i a t e l y i n t o t h e spectrophotometer  flow c e l l , a c t i v a t i n g the  m i c r o p r o c e s s o r t o time and r e c o r d absorbance measurements a t 15 and 45 seconds a f t e r aspiration  (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 t h e 0 ug/ml c a l i b r a t o r  (AA ) Q  and t h e d i f f e r e n c e  (AA-AA ) Q  between  t h i s r e a d i n g and t h e r e a d i n g f o r t h e o t h e r c a l i b r a t o r s determined curve.  ( A A ) was  by t h e m i c r o p r o c e s s o r i n o r d e r t o p l o t a s t a n d a r d  C a l i b r a t i o n o f t h e s t a n d a r d c u r v e 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 o f unknown samples were used i n t h e same manner (AA-AA ) Q  curve.  t o determine c o n c e n t r a t i o n s by use o f t h e s t a n d a r d D u p l i c a t e l i d o c a i n e d e t e r m i n a t i o n s were made on each  plasma sample. Plasma l i d o c a i n e l e v e l s g r e a t e r than 13ug/ml ( o u t s i d e assay l i m i t s ) were determined  by p e r f o r m i n g an a d d i t i o n a l 1:5  d i l u t i o n o f t h e plasma sample p r i o r t o a d d i t i o n o f 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  Fibrillation  Studies  White New Zealand r a b b i t s w e i g h i n g 2.0-3.5 Kg were a n e s t h e t i z e d w i t h i n t r a v e n o u s p e n t o b a r b i t a l and p r e p a r e d 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  s u t u r e p l a c e d around the l e f t c i r c u m f l e x c o r o n a r y artery.  F i g u r e 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 s u t u r e b e f o r e and a f t e r l i g a t i o n secured.  was  36  37  d e s c r i b e d i n s e c t i o n 1.  The chest was opened with a medial  i n c i s i o n through the sternum and r e t r a c t o r s were used t o enlarge the chest opening.  The thymus gland was e i t h e r  p a r t i a l l y removed or clamped to the chest w a l l to p r o v i d e v i s u a l i z a t i o n of the h e a r t .  The p e r i c a r d i u m was opened  m e d i a l l y and attached to the chest w a l l with 4-0 s i l k ( E t h i c o n , Inc.) Using  i f necessary, 4-0 s i l k  ( E t h i c o n , Inc.)  black b r a i d e d c a r d i o v a s c u l a r sutures  a t i e was p l a c e d i n the apex of the l e f t of the h e a r t .  c i r c u m f l e x branch of the l e f t coronary  The l e f t  a r t e r y was v i s u a l i z e d by  the l e f t a t r i a l appendage with f o r c e p s and r o t a t i n g the  heart s l i g h t l y was  suture  to provide a c r a d l e f o r the h e a r t .  v e n t r i c l e to a s s i s t i n manipulation  lifting  clear  to the r i g h t .  A c a r d i o v a s c u l a r 4-0 s i l k  suture  then p l a c e d through the myocardium and around the a r t e r y as  diagrammed i n F i g u r e s 2 and 2a. through a p i e c e of p o l y e t h y l e n e  The suture ends were passed tubing f o r l a t e r use i n  clamping  o f f the a r t e r y .  When p o s s i b l e , the suture was p l a c e d  proximal  to d i v i s i o n of the c i r c u m f l e x a r t e r y i n t o two branches. When the l i g a t u r e was i n p l a c e the h e a r t was allowed  to  recover  f o r a t l e a s t 10 - 20 minutes or u n t i l blood  and ECG returned to pre-thoracotomy l e v e l s . a r t e r y was accomplished  L i g a t i o n of the  by p u l l i n g both ends of the suture  through the tubing and clamping (Figure 2a).  pressure  t i g h t l y with hemostatic  forceps  O c c l u s i o n of the a r t e r y c o u l d be v i s u a l i z e d by  blanching of p a r t of the l e f t v e n t i c l e , o f t e n the apex and p o s t e r i o r w a l l , and was u s u a l l y accompanied by a drop i n a r t e r i a l blood  pressure.  38  O c c u l s i o n of the a r t e r y was maintained f o r 15 minutes at which time the l i g a t u r e was loosened and a 5 minute r e p e r f u s i o n phase allowed to occur.  A t the end of the  r e p e r f u s i o n phase the l i g a t u r e was r e s e c u r e d . three c y c l e s of o c c l u s i o n minutes)  were  (15 minutes)  A maximum of  and r e p e r f u s i o n (5  performed.  Ventricular  fibrillation  o c c u r r e d during both  o c c l u s i o n and r e p e r f u s i o n phases, although i t d i d not occur i n every experiment.  Each experiment  d i s t i n c t c a t e g o r i e s depending  fell  i n t o one of three  on the frequency and l e n g t h o f  fibrillation: 1.  No v e n t r i c u l a r f i b r i l l a t i o n : fibrillate  2.  The heart d i d not  at any time d u r i n g the experiment.  Short v e n t r i c u l a r f i b r i l l a t i o n : fibrillation  Ventricular  p e r s i s t e d f o r l e s s than 2 minutes and  terminated spontaneously  (mean 0.6 minutes,  range 0.2  - 1.8 minutes). 3.  Long v e n t r i c u l a r fibrillation minutes,  fibrillation:  Ventricular  p e r s i s t e d longer than 2 minutes  range  6.3 - 12.5 minutes).  (mean 9.7  T h i s group was  used f o r both plasma l i d o c a i n e l e v e l s t u d i e s during ventricular  fibrillation  and l i d o c a i n e  efficacy  studies. Blood p r e s s u r e , ECG and frequency of arrhythmias were monitored at v a r i o u s times, f o r comparison with tendency  to f i b r i l l a t e  of these  parameters  i n the three c a t e g o r i e s .  When 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 occur the h e a r t was  39  allowed  to f i b r i l l a t e  f o r 15 seconds with no i n t e r v e n t i o n .  Manual pumping of the heart would then be s t a r t e d to maintain mean a r t e r i a l blood pressure  between 25-50 mmHg.  c i r c u l a t i o n would be continued fibrillation own.  Artificial  f o r 2 minutes of v e n t r i c u l a r  unless the heart s t a r t e d to beat again on i t s  I f conversion  to spontaneous c a r d i a c rhythm o c c u r r e d  w i t h i n t h i s two minute p e r i o d , the arrhythmia i n a "short v e n t r i c u l a r f i b r i l l a t i o n " experiment continued  would be i n c l u d e d  category and the  i n the a p p r o p r i a t e o c c l u s i o n / r e p e r f u s i o n  cycle. When v e n t r i c u l a r  fibrillation  occurred during an  o c c l u s i o n phase the l i g a t u r e was kept secured of  the f i b r i l l a t i o n  t i e was l e f t  f o r the d u r a t i o n  and i f i t occurred during r e p e r f u s i o n the  loose.  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  would be  managed i n the same manner depending on t h e i r d u r a t i o n . Plasma l i d o c a i n e l e v e l s t u d i e s during fibrillation for  were i n s t i t u t e d when f i b r i l l a t i o n  a t l e a s t two minutes.  ventricular had proceeded  L i d o c a i n e was administered  either  e n d o t r a c h e a l l y or i n t r a v e n o u s l y and c a r o t i d a r t e r y blood samples were drawn a t a p p r o p r i a t e times as d e t a i l e d 1.  C i r c u l a t i o n was maintained  i n section  by means of c a r d i a c massage  u n t i l the onset of spontaneous c a r d i a c rhythm.  Plasma  l i d o c a i n e l e v e l s t u d i e s i n sham-operated open chest c o n t r o l s were t r e a t e d i n the same manner but with the l i g a t i o n unsecured and no c a r d i a c massage  left  necessary.  L i d o c a i n e e f f i c a c y s t u d i e s were performed only when  40  ventricular f i b r i l l a t i o n minutes of v e n t r i c u l a r  had p e r s i s t e d f o r 2 minutes.  fibrillation  either  After 2  2 mg/kg l i d o c a i n e (2  mg/ml i n normal s a l i n e ) or l ml/kg normal s a l i n e was administered e n d o t r a c h e a l l y i n a b l i n d , randomized  fashion.  C a r d i a c massage was maintained u n t i l the r e t u r n o f spontaneous c a r d i a c rhythm or f o r the d u r a t i o n of the experiment. Untreated c o n t r o l experiments were performed i n the same manner except no treatment was g i v e n a t 2 minutes of v e n t r i c u l a r fibrillation. If  spontaneous c i r c u l a t i o n resumed w i t h i n t e n minutes  a f t e r a d m i n i s t r a t i o n of e i t h e r l i d o c a i n e , 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 p r e s s u r e and ECG were recorded.  Subsequent  s t a t u s was monitored f o r 30 minutes. fibrillation of  cardiovascular  I f ventricular  p e r s i s t e d , a t 10 minutes f o l l o w i n g  administration  l i d o c a i n e , normal s a l i n e 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 j o u l e s ) to a maximum o f 2  d e f i b r i l l a t i o n attempts (Mennen-Greatback Defibrillator).  E l e c t r o n i c s Inc. DC  I f d e f i b r i l l a t i o n was s u c c e s s f u l the  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 as above. At  the end of each experiment, the heart was removed  and p e r f u s e d with 20ml normal s a l i n e on a m o d i f i e d Langendorf-type apparatus.  With the l i g a t i o n secured, the  h e a r t was then p e r f u s e d slowly with 20ml Methyl Green B i o l o g i c a l Stain  (0.5 mg/ml) to d e l i n e a t e the occluded areas of  the  Occluded areas were e x c i s e d , weighed and  myocardium.  expressed as percent wet weight of l e f t v e n t r i c u l a r , 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.  right  41  3.  A n a l y s e s and S t a t i s t i c s  Plasma l i d o c a i n e v a l u e s were c a l c u l a t e d by t h e Syva CP 5 000 m i c r o p r o c e s s o r i n r e l a t i o n t o a s t a n d a r d c u r v e f o r lidocaine.  Samples were assayed i n d u p l i c a t e and t h e mean  v a l u e e n t e r e d as one d a t a p o i n t .  A l l v a l u e s were p l o t t e d as  the mean + s t a n d a r d e r r o r o f t h e mean (S.E.M.) f o r t h e i n d i c a t e d number o f e x p e r i m e n t s . The S t u d e n t ' s t - t e s t f o r u n p a i r e d d a t a was used t o determine  statistical  s i g n i f i c a n c e between t r e a t m e n t  groups.  Data were c o n s i d e r e d t o be s i g n i f i c a n t l y d i f f e r e n t a t p<0.05 for  a 2-tailed test. F i r s t - o r d e r rate constants f o r e l i m i n a t i o n  determined  (fi) were  from t h e s l o p e o f t h e b a c k - e x t r a p o l a t e d e l i m i n a t i o n  p o r t i o n o f t h e l o g c o n c e n t r a t i o n v s time c u r v e . distribution  Absorption-  ( e n d o t r a c h e a l ) and d i s t r i b u t i o n ( i n t r a v e n o u s ) r a t e  c o n s t a n t s (<<) were c a l c u l a t e d from t h e s l o p e o f t h e l i n e c a l c u l a t e d by t h e method o f r e s i d u a l s .  S l o p e , 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 l e a s t squares r e g r e s s i o n  using l o g l i n e a r  analysis.  C a l c u l a t i o n o f t h e a r e a under t h e c u r v e f o r t h e f i r s t t e n m i n u t e s 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  t h e t r a p e z o i d a l r u l e method. F r a c t i o n o f an e n d o t r a c h e a l dose absorbed minutes ( f ^ g ) was c a l c u l a t e d by t h e f o r m u l a AUC f  io  =  1Q  (ET)  — AUC, (IV) n  i n ten  42  C l e a r a n c e o f l i d o c a i n e i n t e n minutes  (CI^Q)  was  c a l c u l a t e d u s i n g t h e formula. f^Q x dose C l  10 AUC  1()  These parameters a r e n o t t r u e v a l u e s s i n c e they c o n d i t i o n s d u r i n g t h e f i r s t t e n minute o f each experiment  assess only.  The c a l c u l a t e d v a l u e s s h o u l d 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 e t h y l e n e d i a m i n e  tetraacetic acid  (Disodium EDTA o r  EDTA) - Sigma Chemical Co. Halothane (Fluothane ) - A y e r s t L a b o r a t o r i e s . L i d o c a i n e 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 L i d o c a i n e L e v e l S t u d i e s  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 D u r i n g Halothane A n e s t h e s i a  F i g u r e 3 shows a r t e r i a l plasma l i d o c a i n e  levels  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 o f 2mg/Kg l i d o c a i n e experiments  (2mg/ml i n d i s t i l l e d w a t e r ) .  The  were performed under h a l o t h a n e a n e s t h e s i a and  i n j e c t i o n was made v i a t h e m a r g i n a l e a r v e i n .  Administrationof  l i d o c a i n e e n d o t r a c h e a l l y r e s u l t e d i n s i g n i f i c a n t l y h i g h e r plasma c o n c e n t r a t i o n s a t 15 seconds and 1 minute a l t h o u g h 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 a t o r f o l l o w i n g t h e 2 minute p o i n t . A s e m i - l o g a r i t h m i c p l o t o f plasma l i d o c a i n e c e n t r a t i o n v s time i s shown i n F i g u r e 4.  con-  F o l l o w i n g both  intra-  venous i n j e c t i o n and e n d o t r a c h e a l i n s t i l l a t i o n , l i d o c a i n e was shown t o e x h i b i t f i r s t - o r d e r p h a r m a c o k i n e t i c  behavior.  C a l c u l a t e d r a t e c o n s t a n t s 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 a r e summarized i n T a b l e I . The combined 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 c o n s t a n t (=* ) f o r e n d o t r a c h e a l l i d o c a i n e had a c a l c u l a t e d v a l u e a p p r o x i m a t e l y 70% t h a t o f i n t r a v e n o u s i n j e c t i o n . E l i m i n a t i o n r a t e c o n s t a n t s (y^) were s i m i l a r f o r b o t h r o u t e s .  b)  The E f f e c t o f P e n t o b a r b i t a l o r Halothane A n e s t h e s i a on the E n d o t r a c h e a l A b s o r p t i o n o f L i d o c a i n e 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 v s 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 o f 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) d u r i n g h a l o t h a n e  anesthesia.  Numbers o f e x p e r i m e n t s a r e i n d i c a t e d .  A l l points  r e p r e s e n t mean plasma l e v e l s - S.E.M. o f t h e number o f e x p e r i m e n t s i n d i c a t e d .  s i g n i f i c a n t l y g r e a t e r than IV a t p < 0 . 0 5 .  46 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 s v s time following endotracheal intravenous  (ET) i n s t i l l a t i o n o r  (IV) i n j e c t i o n o f 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) d u r i n g anesthesia.  halothane  A l l p o i n t s r e p r e s e n t mean plasma  c o n c e n t r a t i o n s o f t h e number o f e x p e r i m e n t s indicated.  *  s i g n i f i c a n t l y g r e a t e r than IV a t p < 0 . 0 5 .  Log  plasma  3 II  lidocaine  (ug/ml)  48  Table 1  Calculated distribution  first-order absorption-distribution K ( ' ) , and e l i m i n a t i o n {ft) r a t e ?S|  IV  and plasma h a l f - l i v e s f o r i n t r a v e n o u s endotracheal in  E  T  )/  constants  i n j e c t i o n and  i n s t i l l a t i o n o f 2mg/Kg l i d o c a i n e (2mg/ml)  d i s t i l l e d water.  Route o f A d m i n i s t r a t i o n  2mg/kg IV  Lidocaine 2mg/kg ET  . -1 1.77 mm (r=-0.9789)  „^ . -1 1.23 mm (r=-0.9973)  2.03 x 10 -2min -1 (r=-0.9906)  1.99 x 1 0 ~ m i n  Lidocaine  n  2  th (<?0  0.347 min  0.563 min  th (jS)  32.7 min  34.8 min  a - d a t a c a l c u l a t e d from F i g u r e 4.  _ 1  49  F i g u r e 5 shows plasma l i d o c a i n e c o n c e n t r a t i o n s observed f o l l o w i n g endotracheal  i n s t i l l a t i o n o f l i d o c a i n e 2mg/ml  i n d i s t i l l e d water d u r i n g e i t h e r h a l o t h a n e anesthesia. to breathe  or p e n t o b a r b i t a l  Animals a n e s t h e t i z e d w i t h halothane spontaneously  were a l l o w e d  w h i l e those a n 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 were m e c h a n i c a l l y  respired.  Mean plasma l i d o c a i n e  c o n c e n t r a t i o n s were g r e a t e r a t a l l time p o i n t s d u r i n g anesthesia, although  halothane  t h e d i f f e r e n c e s were n o t s t a t i s t i c a l l y  significant.  c)  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 Instillation  Endotracheal  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 D u r i n g P e n t o b a r b i t a l A n e s t h e s i a  F i g u r e 6 shows t h e e f f e c t o f u s i n g 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 t h e 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 a b s o r p t i o n v i a t h e e n d o t r a c h e a l was 2mg/kg f o r b o t h groups.  route.  The dosage  A d m i n i s t r a t i o n o f 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 conc e n t r a t i o n s w h i c h were g r e a t e r 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 o f l i d o c a i n e 2mg/ml i n normal s a l i n e . d i f f e r e n c e was s t a t i s t i c a l l y  significant  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 .  This  (p< .05) a t o n l y 30 A f t e r 2 minutes, higher  plasma l i d o c a i n e c o n c e n t r a t i o n s 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 t h e v e h i c l e .  These d i f f e r e n c e s were n o t s t a t i s t i c a l l y  significant. F i g u r e 7 r e p r e s e n t s a s e m i - l o g a r i t h m i c p l o t o f plasma l i d o c a i n e c o n c e n t r a t i o n v s time f o l l o w i n g e n d o t r a c h e a l  50 Figure 5  Plasma l i d o c a i n e c o n c e n t r a t i o n s v s 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 anesthesia.  or pentobarbital  Numbers o f e x p e r i m e n t s a r e  i n d i c a t e d and a l l p o i n t s r e p r e s e n t 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 c o n c e n t r a t i o n 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 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 a n 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 . Numbers o f e x p e r i m e n t s a r e i n d i c a t e d and a l l p o i n t s r e p r e s e n t 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 e a t e r than normal s a l i n e a t p< 0.05.  53  54  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 v s time f o l l o w i n g endotracheal lidocaine  instillation  o f 2mg/Kg  (2mg/ml) i n e i t h e r normal s a l i n e o r  d i s t i l l e d water.  A l l animals were a n e s t h e t i z e d  with pentobarbital.  A l l p o i n t s r e p r e s e n t mean  plasma l e v e l s - S.E.M. o f t h e number o f experiments i n d i c a t e d .  55  • Normal Saline • Water  E \  CO 3  T3  .6  ma  OC  CD C CO  1.0 .9 .8 .7  .5  00 ca Q.  .4  Lo  C30  .3  o  10  15 T ime (min)  20  25  56  administration water.  o f l i d o c a i n e i n e i t h e r normal s a l i n e o r  distilled  T h i s 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 w h i c h i s l o g l i n e a r , a l l o w i n g 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 (. ) and es<  e l i m i n a t i o n rate constant  constant  The  i n normal s a l i n e c u r v e i s not l o g l i n e a r d u r i n g  cal-  lidocaine  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 t o 30 m i n u t e s , f o r e a b e s t e s t i m a t e o f t h e s e r a t e c o n s t a n t s was was  done by  there-  obtained.  This  (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 o c c u r r e d i n a manner p a r a l l e l w i t h i t s elimination following administration  i n d i s t i l l e d w a t e r , 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 c o n s t a n t from t h i s parallel d)  line. A b s o r p t i o n of L i d o c a i n e Administration  of Lidocaine  C l o s e d Chest C o n t r o l s , Ventricular Figure  Following  Endotracheal  i n Normal S a l i n e D u r i n g  Open Chest C o n t r o l s  and  Fibrillation  8 shows the time c o u r s e of plasma l i d o c a i n e  l e v e l s following endotracheal administration  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 c h e s t c o n t r o l s , open c h e s t c o n t r o l s open c h e s t a n i m a l s d u r i n g were a n e s t h e t i z e d endotracheally  ventricular f i b r i l l a t i o n .  with pentobarbital.  Administration  t h r e e minutes than a d m i n i s t r a t i o n a l t h o u g h the d i f f e r e n c e was  of  lidocaine  not  over the  first  to c l o s e d chest c o n t r o l s , significant.  When l i d o c a i n e i n normal s a l i n e was endotracheally  A l l animals  t o sham-operated open c h e s t 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 h i g h e r plasma l i d o c a i n e c o n c e n t r a t i o n s  administered  during v e n t r i c u l a r f i b r i l l a t i o n with  and  cardiac  57  Table I I C a l c u l a t e d  first-order  ( o ( ) and e l i m i n a t i o n E T  absorption-distribution (/3) r a t e c o n s t a n t s and  plasma h a l f - l i v e s f o r e n d o t r a c h e a l  instillation  o f 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.  Vehicle of Administration Lidocaine 2mg/ml i n D i s t i l l e d Water 0.741 2.53 th ( o i ) th  (f3 )  min  Lidocaine 2mg/ml i n Normal S a l i n e 0.786 m i n  - 1  -2 -1 x 10 min  2.65  27.4  26.2  min  a - d a t a c a l c u l a t e d from F i g u r e  -2 -1 x 10 min  0.882 min  0.935 min  7.  - 1  min  58  Figure 8  Plasma l i d o c a i n e l e v e l s v s time f o l l o w i n g e n d o t r a c h e a l administration  o f 2mg/Kg l i d o c a i n e  (2mg/ml i n  normal s a l i n e ) d u r 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 c a r d i a c massage, open c h e s t  (sham-operated)  c o n t r o l s and c l o s e d c h e s t c o n t r o l s . were a n e s t h e t i z e d  with  with pentobarbital.  A l l animals A l l points  r e p r e s e n t mean plasma l e v e l s + S.E.M. o f t h e number o f e x p e r i m e n t s i n d i c a t e d .  *  s i g n i f i c a n t l y greater a t p < 0.05.  t h a n open c h e s t c o n t r o l s  59  22\  20ET  t*  18• Ventricular o Open  16  • Closed  g  fibrillation  chest chest  control control  1^  n=5 C  12  O O  TJ "  101  00  8  T  Time  T  (min)  10  60 massage, a marked i n c r e a s e 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 o b s e r v e d over a l l time p o i n t s . (p< 0 . 0 5 )  The  i n c r e a s e was  a t 1 5 seconds, 3 0 seconds and  was  significant  1 minute p o s t -  administration . C a l c u l a t e d a r e a under the c u r v e t o 1 0 minutes  (AUC ), lri  xu  f r a c t i o n of dose absorbed i n 1 0 minutes  (f  ± n  i  ) and c l e a r a n c e of  l i d o c a i n e over the i n i t i a l 1 0 minutes (Cl^g) a r e r e p o r t e d i n Table I I I . and C I ^ Q and  AUC^Q  was  was  increased during v e n t r i c u l a r  decreased.  fibrillation 71%  Amount o f l i d o c a i n e absorbed was  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 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 v e n o u s  Injection  of L i d o c a i n e i n Normal S a l i n e D u r i n g 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  F i g u r e 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 i n t r a v e n o u s 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 d u r 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 w i t h c a r d i a c massage or to open c h e s t  (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 a n i m a l s were a n e s t h e t i z e d w i t h pentobarbital.  Plasma l i d o c a i n e l e v e l s were g r e a t e r 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 (p< 0.05)  o n l y a t one  t h i s was  significant  minute.  T a b l e I I I shows a r e a under the curve to 10 minutes (AUC^Q),  f r a c t i o n o f the dose absorbed i n 10 minutes ( f  ± n  ) and  c l e a r a n c e o f 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 c h e s t 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 d u r 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 and C l , _ was  increased  decreased.  61  Figure 9  Plasma l i d o c a i n e l e v e l s v s time f o l l o w i n g i n j e c t i o n o f 2mg/Kg l i d o c a i n e  intravenous  (20mg/ml i n normal  s a l i n e ) d u r 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 and open chest controls.  A l l a n i m a l s were  with pentobarbital  anesthetized  and i n j e c t i o n was made v i a a  d i s t a l hindleg vein.  A l l p o i n t s r e p r e s e n t mean  plasma l e v e l s + S.E.M. o f t h e number o f e x p e r i m e n t s indicated.  *  s i g n i f i c a n t l y greater a t p < 0.05.  t h a n open c h e s t c o n t r o l s  62  63  Table I I I  Area u n d e r t h e c u r v e and  clearance  following  a  or endotracheal  fibrillation  f  U C u u  10  V  jug, mm. ml ;  10  Cl,_  (ml/min)  b  first  10 m i n u t e s  administration to either  o r open c h e s t c o n t r o l s .  Lidocaine  A  o f dose a b s o r b e d ( f ^ )  ( C l ^ )of l i d o c a i n e during  intravenous  ventricular  (AUC^Q), f r a c t i o n  2mg/kg IV  Lidocaine  2mg/kg ET  Normal  VF  25.8  65.8  18.22  47.25  1.0  1.0  0.71  0.72  186  87  a  Lidocaine  20mg/ml i n n o r m a l s a l i n e  b  Lidocaine  2mg/ml i n n o r m a l  saline  Normal  218  into d i s t a l  VF  88  hindleg  vein  64  f)  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 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 t o Open Chest C o n t r o l s  Plasma l i d o c a i n e l e v e l s observed  following  endotracheal  (ET) i n s t i l l a t i o n o f l i d o c a i n e 2mg/ml i n normal s a l i n e , o r intravenous  (IV) i n j e c t i o n o f l i d o c a i n e 20mg/ml i n normal s a l i n e ,  are shown i n F i g u r e 10. p l o t of t h i s data.  F i g u r e 11 shows a s e m i - l o g a r i t h m i c  These comparisons were o b t a i n e d by r e -  a r r a n g i n g d a t a from s e c t i o n s (d) and ( e ) .  The dosage o f  l i d o c a i n e used was 2mg/kg f o r b o t h r o u t e s . A l l a n i m a l s were a n 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 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 a t 15 and 30 seconds which were s i g n i f i c a n t l y g r e a t e r (p<0.05) than those following endotracheal  instillation.  These l e v e l s decreased minutes,  obtained  r a p i d l y , however, and a t 2  t h e plasma l e v e l s f o l l o w i n g 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  were s i g n i f i c a n t l y g r e a t e r than those o b t a i n e d from i n t r a v e n o u s injection  (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 o t h e r time p o i n t s . C a l c u l a t e d a r e a under t h e c u r v e , f r a c t i o n o f dose absorbed  and c l e a r a n c e i n t h e f i r s t 10 minutes a r e compared i n  T a b l e I I I . Area under t h e c u r v e was s m a l l e r d u r i n g  endotracheal  a d m i n i s t r a t i o n than d u r i n g i n t r a v e n o u s i n j e c t i o n and t h e f r a c t i o n o f t h e dose absorbed  e n d o t r a c h e a l l y was 71%. C l e a r a n c e o f  l i d o c a i n e i n t h e f i r s t 10 minutes was o n l y s l i g h t l y  larger  f o l l o w i n g 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 than f o l l o w i n g IV injection.  65  F i g u r e 10  Plasma l i d o c a i n e l e v e l s v s time f o l l o w i n g i n s t i l l a t i o n o f 2mg/Kg l i d o c a i n e  endotracheal  (2mg/ml i n normal  s a l i n e ) o r i n t r a v e n o u s i n j e c t i o n o f l i d o c a i n e (20mg/ml i n normal s a l i n e ) .  Animals were a n 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 and were open c h e s t controls. vein.  (sham-operated)  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  A l l v a l u e s r e p r e s e n t mean plasma l e v e l s  + S.E.M. o f t h e number o f experiments  *  indicated.  s i g n i f i c a n t l y g r e a t e r than e n d o t r a c h e a l a t p<0.05.  ** s i g n i f i c a n t l y g r e a t e r than i n t r a v e n o u s a t p < 0.05.  66  67  Figure l l  Log plasma l i d o c a i n e c o n c e n t r a t i o n s v s time following intravenous lidocaine  (IV) i n j e c t i o n o f 2mg/Kg  (20mg/ml i n normal s a l i n e ) o r e n d o t r a c h e a l  (ET) i n s t i l l a t i o n o f 2mg/Kg l i d o c a i n e normal s a l i n e ) .  (2mg/ml i n  Animals were open c h e s t  (sham-operated)  c o n t r o l s and were a n 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 . 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 o f experiments  a r e i n d i c a t e d and a l l v a l u e s  r e p r e s e n t mean plasma  levels.  *  s i g n i f i c a n t l y g r e a t e r than ET a t p< 0.05.  .**• s i g n i f i c a n t l y g r e a t e r than IV a t p< 0.05.  Log  o  plasma  lidocaine  (ug/ml)  co o  o  CJ1  3 3 ll  II  4*.  cn  I f f •  — <  -4  m H  69  g)  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 E n d o t r a c h e a l Instillation  or Intravenous  During V e n t r i c u l a r  I n j e c t i o n of Lidocaine  Fibrillation  F i g u r e 12 shows plasma l i d o c a i n e l e v e l s observed 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  during  either  e n d o t r a c h e a l i n s t i l l a t i o n o f l i d o c a i n e 2mg/ml i n normal s a l i n e o r i n t r a v e n o u s i n j e c t i o n o f l i d o c a i n e 20mg/ml i n normal s a l i n e . F i g u r e 13 shows a s e m i - l o g a r i t h m i c p l o t o f t h i s d a t a .  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 hindleg vein. pentobarbital.  A l l animals were a n e s t h e t i z e d w i t h  These comparisons were o b t a i n e d by r e - a r r a n g i n g  d a t a 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 , t h e d i f f e r e n c e s were n o t s t a t i s t i c a l l y  significant.  When o n l y experiments  i n which spontaneous c o n v e r s i o n  to normal s i n u s rhythm o c c u r r e d were c o n s i d e r e d , t h e d i f f e r e n c e s between t h e i n t r a v e n o u s and e n d o t r a c h e a l r o u t e s were l a r g e r . (Three o u t o f f o u r a n i m a l s a d m i n i s t e r e d l i d o c a i n e v i a t h e i n t r a v e n o u s r o u t e c o n v e r t e d 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 s i n u s rhythm i n a mean time o f 1.4 - 0.1 m i n u t e s ) . C o n v e r s i o n t o normal s i n u s rhythm o c c u r r e d i n a l l a n i m a l s a d m i n i s t e r e d l i d o c a i n e v i a t h e e n d o t r a c h e a l r o u t e i n a time o f 1.4 - 0.4 minutes p o s t a d m i n i s t r a t i o n . A s e p a r a t e demonstrating did  curve  plasma l i d o c a i n e l e v e l s from those a n i m a l s which  show c o n v e r s i o n f o l l o w i n g i n t r a v e n o u s l i d o c a i n e i s shown i n  F i g u r e 12.  The d i s t r i b u t i o n phase o f 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 s h o r t e n e d when c o n v e r s i o n t o spontaneous c a r d i a c  70  F i g u r e 12  Plasma l i d o c a i n e l e v e l s v s 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 o f 2mg/Kg l i d o c a i n e (20mg/ml  i n normal s a l i n e ) o r e n d o t r a c h e a l  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 ) d u r 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 w i t h c a r d i a c massage. shown i s d a t a from o n l y those  intravenous  Also  experiments  i n which spontaneous c o n v e r s i o n t o normal s i n u s rhythm o c c u r r e d . pentobarbital.  A n i m a l s were a n e s t h e t i z e d w i t h A l l p o i n t s r e p r e s e n t mean plasma  l e v e l s + S.E.M. o f t h e number o f e x p e r i m e n t s indicated. via  Intravenous  i n j e c t i o n was  a d i s t a l hindleg vein.  accomplished  71  72  F i g u r e 13  Log plasma l i d o c a i n e c o n c e n t r a t i o n s vs time following e i t h e r intravenous 2mg/kg l i d o c a i n e endotracheal  (IV) i n j e c t i o n o f  (20mg/ml i n normal s a l i n e ) o r  (ET) i n s t i l l a t i o n o f 2mg/kg  (2mg/ml i n normal s a l i n e ) .  Intravenous  lidocaine injection  was made v i a d i s t a l h i n d l e g v e i n and a n i m a l s were a n 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 l s o shown i s d a t a from o n l y those i n t r a v e n o u s experiments  i n which  spontaneous c o n v e r s i o n t o normal s i n u s rhythm occurred.  A l l v a l u e s r e p r e s e n t mean plasma l e v e l s  o f t h e number o f experiments  shown. '.  ;  Log  plasma  ro  lidocaine  co ^ cn O) co  (ug/ml) COQ  ro o  co o  cn  o o  • o • m H <  <  CO  13  74 output occurred. Comparison o f a r e a under t h e c u r v e of dose absorbed  (f^g)  a  n  (AUC^Q),  fraction  d c l e a r a n c e i n 10 minutes (Cl^g) a r e  shown f o r i n t r a v e n o u s and e n d o t r a c h e a l l i d o c a i n e d u r 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 i n Table I I I . increased  AUC^Q  Ventricular  fibrillation  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 ^ was t h e same f o r b o t h r o u t e s . n  h)  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 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 o f L i d o c a i n e 2mg/Kg i n D i s t i l l e d Water F o l l o w e d by lmg/Kg E v e r y F i v e M i n u t e s  F i g u r e 14 shows plasma l i d o c a i n e c o n c e n t r a t i o n s observed f o l l o w i n g a " l o a d i n g dose" o f 2mg/Kg l i d o c a i n e e n d o t r a c h e a l l y i n d i s t i l l e d water and a "maintenance dose" o f lmg/Kg e n d o t r a c h e a l l y e v e r y f i v e m i n u t e s .  The s o l u t i o n  s t r e n g t h was 2mg/ml and t h e 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 o f "maintenance doses" e v e r y f i v e minutes r e s u l t e d i n a c c u m u l a t i o n o f b o t h peak and t r o u g h plasma l e v e l s over t h e 20 minute p e r i o d .  Trough c o n c e n t r a t i o n s had accumulated  s i g n i f i c a n t l y by 20 minutes  2.  (p^.0.05).  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 o f E n d o t r a c h e a l L i d o c a i n e on D u r a t i o n o f Ventricular  Fibrillation  Table IV shows t h e l e n g t h o f time v e n t r i c u l a r  fibril-  l a t i o n p e r s i s t e d f o l l o w i n g e n d o t r a c h e a l i n s t i l l a t i o n o f 2mg/Kg  75  F i g u r e 14  Plasma l i d o c a i n e l e v e l s v s 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 o f a 2mg/kg " l o a d i n g dose" f o l l o w e d by a lmg/kg "maintenance dose" e v e r y 5 m i n u t e s . 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 a n i m a l s were a n 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 . V a l u e s a r e t h e mean plasma l e v e l s - S.E.M. o f t h r e e experiments.  *  s i g n i f i c a n t l y g r e a t e r than trough l e v e l a t 5 minutes  (p<0.05).  I  Plasma Lidocaine (ug/ml) ro  4^  q>  co  -"•  7  II CO  i  i  H  3 3  5"  01  / I  no O  CO  o  9L  77 lidocaine  (2mg/ml i n normal s a l i n e ) , l m l / K g normal s a l i n e , or  treatment.  no  I n a l l c a s e s , the h e a r t s were m a n u a l l y pumped as  d e s c r i b e d i n the methods. Administration  of l i d o c a i n e 2 minutes a f t e r the  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  start  duration  of f i b r i l l a t i o n compared t o e i t h e r u n t r e a t e d or normal s a l i n e controls  (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  VF between u n t r e a t e d and l i d o c a i n e on VF was  i n the d u r a t i o n  normal s a l i n e c o n t r o l s .  s i g n i f i c a n t regardless  f i b r i l l a t i o n o c c u r r e d d u r i n g an o c c l u s i o n T a b l e V shows p e r c e n t o c c l u s i o n  The  of whether  of  e f f e c t of the  or r e p e r f u s i o n of l e f t , r i g h t  phase. and  t o t a l v e n t r i c u l a r mass i n the u n t r e a t e d c o n t r o l s , normal s a l i n e c o n t r o l s , and difference  lidocaine-treated  group.  There was  i n p e r c e n t o c c l u s i o n between any  of the  no s i g n i f i c a n t 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  30 minutes a f t e r c o n v e r s i o n t o spontaneous c a r d i a c normal s a l i n e c o n t r o l s and  lidocaine-treated  monitored f o r rhythm i n  animals.  Of the  six  a n i m a l s 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  m i n u t e s of r e c e i v i n g the drug (mean 0.7  Three of those a n i m a l s s u r v i v e d  animals survived  minute).  to 3 0 minutes p o s t - c o n v e r s i o n  w i t h adequate b l o o d p r e s s u r e and Two  - 0.1  ECG.  l e s s than 10 m i n u t e s , w i 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 d e a t h .  One  a n i m a l was  t e r m i n a t e d a t 10 minutes  w i t h adequate BP and  ECG  ( p r i o r t o i n s t i t u t i o n of the 30 minute  protocol). I n the normal s a l i n e c o n t r o l group, t h r e e a n i m a l s  had  78  T a b l e IV 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 of l i d o c a i n e  f o l l o w i n g ET  administration  (2mg/Kg) i n normal s a l i n e , normal s a l i n e (l ml/Kg) or :  no t r e a t m e n t ( m i n u t e s ) .  Ventricular f i b r i l l a t i o n persisted  2 minutes p r i o r t o i n i t i a t i o n of p r o t o c o l .  for  Numbers of  e x p e r i m e n t s are i n d i c a t e d i n p a r e n t h e s e s .  Untreated Controls  Normal S a l i n e Controls (Iml/Kg)  Occlusion  8.4  - 1.1 (n=3)  Reperfusionc  6.3  -+ 1.2 (n=2)  7.2  Total  7.6  - 0.9 (n=5)  7.8  *  s i g n i f i c a n t l y shorter  Untreated & Normal S a l i n e Controls Combined  Lidocaine 2mg/Kg  8.8  - 0.8 (n=4)  0.7  + * - 0.1 (n=3.)  -+ 1.1 (n=4)  6.9  - 0 (n=6)  0.8  + * - 0.2 (n=3)  - 1.0 (n=5)  7.7  - 0.6 (n=10)  0.7  + * - 0.1 (n=6)  10.0 (n=l)  than u n t r e a t e d c o n t r o l s , normal s a l i n e  c o n t r o l s o r b o t h a t p ( 0.001. a - times c o r r e c t e d  (-2'min) t o 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  saline. b - e x p e r i m e n t s where 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 e d 15 minute o c c l u s i o n  phase,  c - e x p e r i m e n t s where 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 e d 5 minute r e p e r f u s i o n  during  phase.  during  79  Table V Percent o c c l u s i o n  o f 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  3  t o t a l v e n t r i c u l a r mass i n u n t r e a t e d  c o n t r o l s , normal s a l i n e  c o n t r o l s b and l i d o c a i n e - t r e a t e d group c.  Lidocaine 2mg/Kg ET in Normal S a l i n e (n=6)  Untreated Controls  Right Ventricle  5.913.9  6.8 i 3.2  6.4 - 2.4  7.8 - 3.2  46.1 - 2.9  40.4 - 2.4  43.3 - 2.0  44.6 - 5.6  n  L  e  f  t  ( n = 5 )  Normal S a l i n e Controls (1ml/Kg) (n=5)  Untreated & Normal S a l i n e Controls Combined (n=10)  Percent , occlusion  Ventricle Total Ventricle  3 6 > Q  + _ 3  3  3 1 > 3  +  2 > Q  3 3 > 6  +  2 > Q  3 5 > 4  +  4 > 9  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 p e r c e n t o c c l u s i o n between any o f t h e 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 c o n v e r s i o n t o "normal s i n u s rhythm" and two 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 w a t t - s e c o n d s , DC  animals  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  a n i m a l s s u r v i v e d a f u r t h e r 30 minutes w i t h adequate b l o o d p r e s s u r e and ECG,  and one was  cardiovascular  b)  t e r m i n a t e d a t 5 minutes w i t h a c c e p t a b l e  status.  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  Classifications  All of  c o r o n a r y a r t e r y l i g a t i o n experiments f e l l i n t o  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  Long V e n t r i c u l a r F i b r i l l a t i o n Fibrillation  (Long VF) o r No  one  (Short VF),  Ventricular  (No V F ) ( a s r e p o r t e d i n methods).  All  c o n t r o l experiments i n which v e n t r i c u l a r  fibrillation  o c c u r r e d 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 r e s p e c t t o d u r a t i o n of  ventricular f i b r i l l a t i o n  fibrillation  (Table V I ) .  l a s t e d f o r l e s s than two minutes  minute, range 0.18-1.83 m i n u t e s , n=10) (Long V F ) , f i b r i l l a t i o n (mean 9.5  - 0.07,  which f i b r i l l a t e d 6.5 minutes  I n one g r o u p , ( S h o r t V F ) , (mean 0.56  -  0.7  and i n the o t h e r group,  l a s t e d f o r a p p r o x i m a t e l y 10  range 6.5-12.5 m i n u t e s , n=16).  minutes  A l l hearts  f o r l o n g e r than two minutes d i d so f o r a t l e a s t  ( u n l e s s 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  lidocaine efficacy  experiments.  A l s o shown i n T a b l e VI are t h e number o f  fibrillation  e p i s o d e s per a n i m a l i n the S h o r t and Long VF c a t e g o r i e s . was a tendency  f o r m u l t i p l e e p i s o d e s of f i b r i l l a t i o n  the S h o r t VF c a t e g o r y . phase o f the e x p e r i m e n t .  There  to occur i n  Many of t h e s e 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 I n a l l a n i m a l s s t u d i e d , o n l y one Long VF  8  1  Table VI D u r a t i o n and f r e q u e n c y o f v e n t r i c u l a r ventricular  fibrillation  fibrillation  i n short  and l o n g v e n t r i c u l a r  fibrillation  Number o f VF Episodes  Duration Mean - S.E. (min)  categories.  Number of Animals  VF Frequency (#per experiment)  o f VF Range (min)  S h o r t VF: Occlusion  Reperfusion  9  7  3  1 3  Total  1  1 . 3  0  .  6  2  -  0  .  1  8  0  .  1  7  -  1  .  8  3  4  2 4  6 . 0  0  .  5  4  ±  0  .  0  8  0  .  1  7  -  1  .  8  3  1  3 3  3 . 0  0  .  5  6  -  0  .  0  7  0  .  1  7  -  1  .  8  3  1  .  0  -  1  .  0  8  .  8  -  1  2  .  5  8  .  9  ±  0  .  9  6  .  5  -  1  1  .  5  9  .  7  ±  o  .  7  6  .  5  -  1  2  .  5  Long V F : Occlusion  4  4  1 . 0  Reperfusion  6  6  1 . 0  Total  1  0  1  0  . 1 . 0  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 p h a s e ,  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,  1  82 e p i s o d e o c c u r r e d per experiment  a l t h o u g h one a n i m a l 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 g u r e 15 shows t y p i c a l ECG  fibrillation.  and b l o o d p r e s s u r e t r a c i n g s  o b t a i n e d d u r 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 w i t h open-chest manual h e a r t massage.  A mean s y s t o l i c BP o f 50mm Hg was  w i t h t h i s method and massage was i m a t e l y 130 compressions  performed  per minute.  i n c r e a s e d t o lOmm/sec and massage was ECG  a t a r a t e of  approx-  When t h e c h a r t speed  was  t e m p o r a r i l y stopped,  the  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 b l o o d p r e s s u r e  t r a c i n g demonstrates t r a c i n g was for  usually obtained  the absence o f c a r d i a c o u t p u t .  This  t a k e n from an experiment where f i b r i l l a t i o n  lasted  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  endotracheally. F i g u r e 16 shows t y p i c a l ECG during a s h o r t f i b r i l l a t i o n episode  and BP t r a c i n g s o b t a i n e d ( l e s s than 2 m i n u t e s ) .  Shown a r e the p e r i o d o f 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. T a b l e V I I shows p e r c e n t o c c l u s i o n o f 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, S h o r t VF and Long VF categories.  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 o c c l u d e d  areas between the S h o r t VF, Long VF and No VF  groups.  The 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 i n the No group, o r p r i o r 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  VF  i n the S h o r t 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 p e r c e n t o f h e a r t s which d i d not demonstrated protocol.  fibrillate  v e n t r i c u l a r a r r h y t h m i a s d u r i n g the e x p e r i m e n t a l  The i n c i d e n c e o f a r r h y t h m i a s was  greater p r i o r to  s h o r t o r l o n g f i b r i l l a t i o n e p i s o d e s , 90% and 75%  respectively.  Where m u l t i p l e s h o r t 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 d u r i n g one  83  F i g u r e 15  Blood p r e s s u r e and ECG r e c o r d i n g 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 w i t h manual h e a r t massage.  The c h a r t speed was i n c r e a s e d t o  lOmm/sec from lOmm/min every minute t o 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 l a c k of c a r d i a c  output.  84  1  min  85  F i g u r e 16  B l o o d p r e s s u r e and ECG r e c o r d i n g s d u r i n g a 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 which l a s t e d 25 seconds and terminated  spontaneously.  The t r a c i n g was r u n a t  a c h a r t speed o f lOmm/second e x c e p t f o r t h e a r e a indicated  by t h e d a r k b a r t o t h e r i g h t o f t h e  t r a c i n g , where  the  c h a r t speed was lOrnm/minute.  86  5  sec  87  Table  VII  Comparison ventricle  of and  percent occlusion  of  total  mass w i t h  ventricular  left  ventricle,  right  tendency  to  fibrillate.  % Area  % Right Ventricle  No  Ventricular  Fibrillation  Short  >  g  +  ^  8  % Left Ventricle  3  6  >  4  +  4  >  1  % Total Ventricle  2  ^  Q  +  3  >  4  3  Ventricular  Fibrillation  Long  3  Occluded  . „ +  4.8  1 3  Ventricular  6  >  g  N  -  _  »  1.9  +  R  46.7  4  3  >  g  +  »  +  ->  R  R  4.6  -  2  >  3  +  N  36.0  3  4  >  3  -  A •,  4.1  +  Fibrillation  a  - Ventricular during  the  fibrillation  d i d not  occur  a t any  experiment.  b  - Ventricular  fibrillation  lasted  for less  c  - Ventricular  fibrillation  lasted  longer than  Includes treated  time  a l l animals with  in control  lidocaine.  groups  than  and  2  2  minutes.  minutes.  group  88  Table  VIII  Comparison following  of the incidence coronary  artery  of ventricular  ligation  with  arrhythmias  tendency  to  fibrillate.  Number o f Animals  No  Number o f Animals with Ventricular Arrhythmias  % with Arrhythmias  Ventricular  Fibrillation  Short  3  Ventricular  Fibrillation  Long  Ventricular c Fibrillation  a  - ventricular during  b  - VF  lasted  only  c  - VF in  the  prior  lasted control  ^2  ^  759. 0  f i b r i l l a t i o n d i d not occur  a t any  time  experiment.  f o r less  than  to f i r s t  longer groups  2 minutes.  Arrhythmias  reported  fibrillation.  than  2 minutes.  and group  Includes a l l animals  treated  with  lidocaine.  89 experiment,  o n l y the time p r i o r t o the f i r s t f i b r i l l a t i o n  was  noted f o r a r r h y t h m i a s . F i g u r e s 17 and 18 compare the changes i n b l o o d  pressure  and h e a r t r a t e w h i c h o c c u r r e d d u r i n g the f i r s t t e n minutes a f t e r c o r o n a r y a r t e r y o c c l u s i o n i n the No VF, S h o r t VF and Long VF categories. In a l l t h r e e groups,  the l a r g e s t drop i n b l o o d  pressure  o c c u r r e d d u r i n g the f i r s t two minutes a f t e r o c c l u s i o n o f the artery  ( F i g u r e 1 7 ) , a f t e r w h i c h b l o o d p r e s s u r e appeared t o  stabilize.  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 b l o o d  pressure  between the t h r e e groups a t any time p o i n t s . H e a r t r a t e was  shown t o d e c l i n e f o l l o w i n g  a r t e r y l i g a t i o n i n animals i n w h i c h v e n t r i c u l a r occurred  ( F i g u r e 18).  There was  coronary  fibrillation  no a p p r e c i a b l e change i n h e a r t  r a t e i n a n i m a l s 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 o c c u r . The  l a r g e s t change i n h e a r t r a t e o c c u r r e d over the f i r s t  minutes o f o c c l u s i o n i n the Long VF c a t e g o r y .  There was  two 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 h e a r t r a t e a t t e n minutes between a n i m a l s where no f i b r i l l a t i o n o r l o n g  fibrillation  occurred.  c)  O c c l u s i o n vs R e p e r f u s i o n V e n t r i c u l a r  Fibrillation  T a b l e IX shows the p e r c e n t o c c l u s i o n of l e f t , r i g h t , t o t a l v e n t r i c u l a r mass i n experiments fibrillation  and  where v e n t r i c u l a r  ( l o n g e r t h a n two minutes) o c c u r r e d 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 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  o c c l u d e d areas were performed w i t h the l i g a t u r e s s e c u r e d i n a l l  90  F i g u r e 17  Comparison o f b l o o d p r e s s u r e b e f o r e and f o r 10 minutes a f t e r c o r o n a r y a r t e r y l i g a t i o n i n a n i m a l s i n which no v e n t r i c u l a r short ventricular f i b r i l l a t i o n minutes), or long v e n t r i c u l a r occurred  fibrillation, ( l e s s than 2 fibrillation  ( l o n g e r than 2 m i n u t e s ) .  Values  shown a r e mean s y s t o l i c and d i a s t o l i c p r e s s u r e s f o r t h e number o f a n i m a l s i n d i c a t e d . no s i g n i f i c a n t d i f f e r e n c e  There was  i n blood pressure  between the t h r e e groups a t any time point,'..;  91  No VF  = Short VF  Long VF  92  F i g u r e 18  Changes i n h e a r t r a t e f o l l o w i n g c o r o n a r y a r t e r y o c c l u s i o n i n No VF, S h o r t VF ( l e s s t h a n 2 m i n u t e s ) , and Long VF ( g r e a t e r  than 2 minutes) e x p e r i m e n t s .  V a l u e s e x p r e s s e d a r e mean h e a r t r a t e - S.E.M. o f t h e number o f e x p e r i m e n t s  *  indicated.  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  e x p e r i m e n t s , as d e s c r i b e d i n t h e 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 p r e l i g a t i o n , p o s t - l i g a t i o n o r p r e - f i b r i l l a t i o n b l o o d p r e s s u r e s and h e a r t r a t e s between a n i m a l s where VF o c c u r r e d d u r i n g 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 o u t o f seven animals where VF ( l o n g e r than two minutes) o c c u r r e d d u r i n g o c c l u s i o n , and i n seven o u t o f n i n e a n i m a l s where i t occurred during reperfusion. v e n t r i c u l a r a r r h y t h m i a s preceeded  D u r i n g S h o r t VF  experiments,  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 a n i m a l s where i t o c c u r r e d d u r i n g o c c l u s i o n and i n two o u t o f t h r e e where i t 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.  95  T a b l e IX Comparison right  of percent  v e n t r i c l e and t o t a l  ventricular an  occlusion  fibrillation  occlusion  (mean  i  ventricle,  v e n t r i c u l a r mass i n (>2 m i n ) o c c u r r i n g  or reperfusion  % Area Occluded  of left  Phase  during  period.  Where VF  Occurred  S.E.M.) Reperfusion  Occlusion Phase*  o, *o  Right  o. "o  Left  o, o  Total  a  - no s i g n i f i c a n t  8.4 - 3.3  Ventricle  Ventricle  Ventricle  reperfusion  Phase  3  5.7  - 2.1  - 3.7  45.6  - 2.6  42.3  36.1  - 2.7  32.8-  difference  0  3.2  between o c c l u s i o n and  groups.  b  - VF o c c u r r e d  during  occlusion  phase.  c  - VF o c c u r r e d  during  reperfusion  phase.  96  DISCUSSION  The p r e s e n t study i n d i c a t e s t h a t l i d o c a i n e i s r a p i d l y and e x t e n s i v e l y absorbed  f o l l o w i n g a d m i n i s t r a t i o n v i a an endo-  t r a c h e a l tube i n the r a b b i t . those of Elam was  noted  These data are i n agreement w i t h  (1977) where a prompt ECG  i n hypoxia-induced Others  response  have p r e v i o u s l y r e p o r t e d s i m i l a r r e s u l t s u s i n g  Elam, 1977;  plasma l e v e l s  lidocaine  c a r d i a c a r r e s t i n dogs.  ET e p i n e p h r i n e , where r a p i d but prolonged e t a l , 1967;  to ET  Roberts  responses  e t a l , 1978)  (Roberts e t a l , 1979a) were  and  (Redding  sustained  observed.  R e s u l t s of the p r e s e n t study showed lower peak plasma l e v e l s f o l l o w i n g ET l i d o c a i n e when compared to IV  (Figures 10 &  11), but slower d e c l i n e i n plasma l e v e l s , so t h a t a t two the ET plasma l e v e l was  s i g n i f i c a n t l y g r e a t e r than the IV  T h i s delayed a b s o r p t i o n may  be due  drug i n the a l v e o l i , as suggested for epinephrine.  They observed  of e p i n e p h r i n e than we  observed  minutes level.  to a depot or r e s e r v o i r of by Roberts  e t a l (1978; 1979a)  even more prolonged  ET a b s o r p t i o n  w i t h l i d o c a i n e , perhaps due  to  l o c a l v a s o c o n s t r i c t i o n of lung v a s c u l a t u r e through s t i m u l a t i o n of  c * - r e c e p t o r s by  epinephrine.  R e s u l t s o b t a i n e d i n e a r l y experiments are perhaps somewhat m i s l e a d i n g .  Using IV i n j e c t i o n as a  standard, the p e r c e n t of l i d o c a i n e absorbed was  c a l c u l a t e d t o be 132%  the curve.  v i a the ET  route  based on measurement of the area under  These data are c l a r i f i e d  p e r c e n t of the ET dose absorbed be approximately  (Figures 3 & 4)  i n F i g u r e s 10 & 12 where  over ten minutes was  70% of an IV dose.  shown t o  I t i s possible that greater  97  and more prolonged plasma l e v e l s were seen w i t h the ET r o u t e than w i t h the IV r o u t e due t o the i n i t i a l method used t o a d m i n i s t e r the IV i n j e c t i o n . in  L i d o c a i n e was i n j e c t e d as a 2mg/ml s o l u t i o n  a dosage o f 2mg/Kg v i a the m a r g i n a l ear v e i n .  T h i s volume  (lml/Kg) may p a r a l l e l a r e l a t i v e l y l a r g e volume i n j e c t i o n i n man, approximately 50 - 100ml based on comparison blood volume. distribute  of t o t a l  When g i v e n r a p i d l y a volume of t h i s s i z e may  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 na  s m a l l e r peak plasma l e v e l than seen f o l l o w i n g a s m a l l volume IV b o l u s i n j e c t i o n .  Furthermore,  due t o the time r e q u i r e d t o  i n j e c t a r e l a t i v e l y l a r g e volume, the t r u e peak plasma l e v e l probably occurred p r i o r 15  to t a k i n g the f i r s t  lidocaine  sample a t  seconds. Delayed a b s o r p t i o n o f ET l i d o c a i n e was r e f l e c t e d  ina  f i r s t - o r d e r r a t e c o n s t a n t (O<ET) which was approximately 70% o f the v a l u e c a l c u l a t e d f o r the TV r o u t e .  I t should be noted  that  0( ,j. i n t h i s case i s a r e f l e c t i o n o f both a b s o r p t i o n and E  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. is  complete,  hence ^ j y i  n  F o l l o w i n g IV i n j e c t i o n a b s o r p t i o n  t h i s case i s a t r u e r e f l e c t i o n o f the  d i s t r i b u t i o n of l i d o c a i n e i n t h i s model. E l i m i n a t i o n r a t e c o n s t a n t s (/9) f o r the two r o u t e s o f a d m i n i s t r a t i o n were found t o be s i m i l a r  (Figure 4, Table I ) .  T h i s suggests t h a t a b s o r p t i o n v i a the ET r o u t e was v i r t u a l l y complete w i t h i n approximately t e n minutes. distribution,,distribution,  Absorption -  and e l i m i n a t i o n h a l f - l i v e s were  extremely s h o r t i n t h i s model, due t o r a p i d c i r c u l a t i o n in  the r a b b i t .  times  T h i s accounts i n p a r t f o r the l a r g e standard  e r r o r s o b t a i n e d d u r i n g the f i r s t  15 - 30 seconds o f sampling  98  i n most  experiments. S p o n t a n e o u s o r a r t i f i c i a l v e n t i l a t i o n h a d no  significant  e f f e c t on plasma  instillation  although during  p l a s m a l e v e l s were g e n e r a l l y  l e v e l s were n o t e d  may  spontaneous r e s p i r a t i o n seen.  This  i n v e n t i l a t i o n methods a n d d r u g  i nFigure  although  there  Absorption  6  was a s i g n i f i c a n t  of distilled  and P h i p p s ,  difference only  water from t h e a l v e o l i than a b s o r p t i o n  compared Data  1946) .  a t 30 s e c o n d s .  h a s b e e n shown t o  o f normal  saline  As shown b y R e d d i n g e t a_l (1967)  may  be p r o l o n g e d when n o r m a l s a l i n e i s t h e  theduration  a-', c h a n g e i n t h e e f f i c a c y o f t h e d r u g .  o f e f f e c t o f the drug vehicle,  without  F o r these r e a s o n s , and  p o t e n t i a l f o r n o r m a l s a l i n e t o b e a more p h y s i o l o g i c medium  than d i s t i l l e d saline  water,  1968)  i t was d e c i d e d  for further endotracheal Lidocaine  is  i n distilled  s u g g e s t a s i m i l a r phenomenon f o r l i d o c a i n e ,  c o n f i r m e d by these data,  the  administration  onset o f a c t i o n  and  the  and v e n t i l a t e d .  ( R e d d i n g e t a_l, 1967) .  i n normal s a l i n e  occur a t a f a s t e r rate (Courtice  lidocaine  of epinephrine  w a t e r h a s b e e n shown t o have a s h o r t e r with administration  to the  discrepancy.  Endotracheal administration  shown  plasma  i n p a t i e n t s who were p a r a l y z e d  account f o r t h i s  higher  i si ncontrast  e t a l (1976), where h i g h e r  r e p o r t by S c o t t  Differences  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  and t h e r e f o r e  lipid  t o use l i d o c a i n e i n normal  studies.  i s a n o i l s o l u b l e compound  (Merck  Index,  has t h e p o t e n t i a l t o d i f f u s e w e l l  across  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 t h e r e  n o t 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 o r  normal s a l i n e . , Calculated  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 ) a r e rough e s t i m a t e s a t b e s t due t o t h e l a c k o f 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 p r o l o n g e d  a b s o r p t i o n - d i s t r i b u t i o n phase when t h e 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 The  fashion.  s m a l l 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 o c c u r r e d upon opening t h e c h e s t c a v i t y  ( F i g u r e 8)  i s presumably due t o changes produced i n i n t r a t h o r a c i c p r e s s u r e by t h i s p r o c e d u r e . Of i n t e r e s t i s t h e l a 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 I t may be p o s t u l a t e d accompany c a r d i a c  (Figures  8 & 9).  t h a t t h e c i r c u l a t o r y changes which  arrest  (with c a r d i a c massage) c o u l d r e s u l t i n  a p r o l o n g e d d i s t r i b u t i o n phase and confinement o f adequate c i r c u l a t i n g blood flow t o the c e n t r a l c i r c u l a t i o n .  T h i s may  have produced t h e a b n o r m a l l y h i g h 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 l o n g e r p e r i o d o f 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 a r e r e f l e c t e d i n t h e d e c r e a s e d t e n - minute c l e a r a n c e s (Cl^g) c a l c u l a t e d d u r i n g v e n t r i c u l a r fibrillation  (Table I I I ) .  B a r s a n e t a l (1981) a l s o r e p o r t e d peak plasma l i d o c a i n e l e v e l s which were e l e v a t e d 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 i n dogs r e c e i v i n g CPR d u r i n g c a r d i a c  w e l l i n t o t h e t o x i c range o r c e n t r a l venous i n j e c t i o n arrest.  emphasize t h e need f o r s i m i l a r c l i n i c a l current  cardiac  These o b s e r v a t i o n s  studies  i n man, s i n c e  a r r e s t dosage regimens may indeed produce  drug l e v e l s w h i c h a r e h i g h e r t h a n one would o t h e r w i s e assume. I n f a c t , an assumption i s o f t e n made d u r i n g c a r d i a c therapy that lack of c l i n i c a l  a r r e s t drug  response may be due i n p a r t t o  100  poor c i r c u l a t i n g l e v e l s of the d r u g ' i n q u e s t i o n ; doses may  then be  additional  given.  Ventricular f i b r i l l a t i o n  ( w i t h 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 route  endotracheal  (Table I I I ) d u r i n g the f i r s t t e n minutes a f t e r drug  administration.  Based on t h i s o b s e r v a t i o n ,  p l u s the f a c t t h a t  d u r 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 peak plasma l i d o c a i n e l e v e l s were o b s e r v e d 30 seconds a f t e r a d m i n i s t r a t i o n o f the drug,  one  c o u l d assume t h a t adequate c i r c u l a t i o n t o the l u n g s i s m a i n t a i n e d in this condition. The  'depot' e f f e c t f o l l o w i n g e n d o t r a c h e a l  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  ( F i g u r e s 12 & 13). was  p r o l o n g e d and  T h i s may via  Compared w i t h IV i n j e c t i o n ,  distribution  i n i t i a l peak plasma l e v e l s were not as  have some t h e r a p e u t i c advantage s i n c e  t h i s r o u t e may  administration  high.  administration  a v o i d i n i t i a l t o x i c l e v e l s and p r o l o n g  time i n the t h e r a p e u t i c  the  range.  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 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 and  s t e a d y a c c u m u l a t i o n of b o t h peak  t r o u g h plasma l i d o c a i n e l e v e l s ( F i g u r e 14).  I t may  be  assumed from t h i s t h a t i f s m a l l e r doses had been g i v e n more f r e q u e n t l y , a pseudo 'steady s t a t e  1  been a c h i e v e d w i t h i n the t h e r a p e u t i c  plasma l e v e l c o u l d have range.  A f t e r b o t h 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 o c c u r r e d  in a parallel  S i n c e 70% of the o r i g i n a l ET dose had been absorbed by  fashion. 10  m i n u t e s , 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 m e t a b o l i s m or s t o r a g e  c o u l d a c c o u n t f o r the r e m a i n i n g 30% of the dose.  P o s t e t a l (1978) has demonstrated a c c u m u l a t i o n 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 o f a c c u m u l a t i o n o f l i d o -  caine i n lung t i s s u e i s not c l e a r a t t h i s time, although l i d o c a i n e e n d o t r a c h e a l s p r a y has been used f o r t o p i c a l a n e s t h e s i a for  many y e a r s w i t h o u t e v i d e n c e o f l u n g t o x i c i t y .  Endotracheal a d m i n i s t r a t i o n of lidocaine during p r o l o n g 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 had a profound e f f e c t on r e d u c i n g t h e d u r a t i o n o f t h e a r r h y t h m i a r e g a r d l e s s o f 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 o r r e p e r f u s i o n o f t h e coronary a r t e r y  (Table I V ) .  Without e x c e p 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 r e v e r t e d t o an o r g a n i z e d c a r d i a c rhythm w i t h i n 1.2 minutes o f 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 m i n . ) . T h i s i s i n c o n t r a s t t o 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 m i n . ) . mean d u r a t i o n o f 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  The  experiments  i s , i n f a c t , a r t i f i c i a l l y s h o r t e n e d s i n c e most a r r h y t h m i a s were t e r m i n a t e d a t t e n minutes w i t h e l e c t r i c a l  defibrillation  i f spontaneous c o n v e r s i o n t o an o r g a n i z e d h e a r t b e a t had n o t occurred. Comparison o f p e r c e n t v e n t r i c u l a r mass t o which f l o w was o c c l u d e d was  blood  (Table V) shows t h a t t h e response t o l i d o c a i n e  n o t b i a s e d i n any way by s m a l l e r o c c l u d e d zones i n t h o s e  animals. No f u r t h e r e p i s o d e s o f v e n t r i c u l a r  fibrillation  o c c u r r e d i n any a n i m a l s a f t e r c o n v e r s i o n t o 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 a n i m a l s appeared t o be r e l a t i v e l y a r r h y t h m i a - f r e e once an o r g a n i z e d h e a r t beat had begun. In most a n i m a l models o f c o r o n a r y o c c l u s i o n i n t h e  102  literature,  there  susceptibility it  appeared  occurred  was  to  that  within  perfusion  appear  to  be  ventricular occlusion -  ten  or  two  periods  fibrillation. induced  fifteen  fibrillation  definite  In  this  fibrillation  model,  always  minutes  of  o c c l u s i o n , and  almost  as  soon  occurred  as  the  re-  ligature  released. Since  reported shock  a  conclusion  trial  of  sodium  to  two  as  were  ordered  by  sodium  bicarbonate),  drug.  The  remaining hospital  authors  or  used,between A  criticism,  number  given  during  state  the  any  mean  the  two  no  one  in this  attempt  to  details  are  given  Patients  not  (epinephrine,  of  this  lOOmg  upon  study  IV  bolus  group  from at  and  the  It  i s not  randomized;  physician  with  patients had  p a t i e n t s were to  s t i l l  sequence  do  by  The the  was not  the  Other with  respect  cardiac  other  attempt.  selected  to  rhythms.  in fibrillation  e x h i b i t e d any  resuscitation  respect  other  of  hospital.  subsequent  preceding  the  authors  initiation  any  the  patients  lidocaine  the  l i d o c a i n e a d m i n i s t r a t i o n and  during  of  at  open  of  to  hospital  chloride,  antiarrhythmic  are  time  the  calcium  arrival  the  at  further  difference in  attempt,  arrival  s t a t e d whether  intravenous  no  are  arrival  not  counter-  difference i n percent  resuscitation  time  hospital  plus  with  has  groups.  aspects Only  -  (1981)  lidocaine plus  significant  resuscitation which  either  fibrillation  no  however.  of  f u r t h e r therapy  was  of  -  Harrison  countershocks  physicians  reported  there  study,  fibrillation.  given  in ventricular and  this  l i d o c a i n e i n out  electrical  bicarbonate  therapy  drugs  of  refractory ventricular  responding  not  of  upon  cardiac study  rhythms was  ordering  lidocaine administration.  The  103 a u t h o r s were u n a b l e t o determine t h e c r i t e r i a used i n these cases f o r t h e use o f l i d o c a i n e .  T h i s r e p o r t does, however,  address t h e q u e s t i o n o f a n t i a r r h y t h m i c therapy o f 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 , and r a i s e s some v e r y a p p r o p r i a t e concerns w i t h regard t o c u r r e n t F i r s t l y , appropriateness be a s s e s s e d ,  therapy.  o f a l l agents used  should  w i t h r e s p e c t t o b o t h immediate response and l o n g -  term s u r v i v a l o f p a t i e n t s .  S e c o n d l y , dosages o f drugs c u r r e n t l y  used s h o u l d be examined f o r b o t h e f f i c a c y and t o x i c i t y .  As  shown i n t h e c u r r e n t s t u d y , plasma l e v e l s o f l i d o c a i n e d u r i n g c a r d i a c a r r e s t may i n f a c t be much h i g h e r i n i t i a l l y than o f t e n presumed.  S i n c e t h e c i r c u l a t i o n time i n a s m a l l a n i m a l 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 o f man, a d i r e c t p a r a l l e l cannot be drawn w i t h r e s p e c t t o r a t e and e x t e n t o f appearance of l i d o c a i n e i n t h e b l o o d d u r i n g 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 cardiac a r r e s t  has r e c e n t l y been e v a l u a t e d by Nowak e t a l (1981).  They r e p o r t e d  g r e a t e r 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 p l a c e b o  (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  o t h e r drug t h e r a p y was a d m i n i s t e r e d a c c o r d i n g t o American H e a r t Association  (1980) g u i d e l i n e s .  Of note i s t h e f a c t t h a t  l i d o c a i n e was used more f r e q u e n t l y i n t h e group who r e c e i v e d 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 t h e p l a c e b o group. (or  These t r e n d s may have p r e d i s p o s e d  patients to increased  decreased) s u r v i v a l . L i d o c a i n e has a l s o " 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 t h e management o f o u t - o f - h o s p i t a l v e n t r i c u l a r fibrillation  (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% o f p a t i e n t s had  104 c o n v e r t e d t o an o r g a n i z e d rhythm i n b o t h groups, whereas f o l l o w ing  either lidocaine  (lOOmg) o r b r e t y l i u m (500mg) i n t r a v e n o u s l y  p l u s an.average o f 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% o f 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 c o n v e r t e d t o an o r g a n i z e d rhythm.  The p e r c e n t o f  p a t i e n t s i n t h e 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 s u b s e q u e n t l y d i s c h a r g e d 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 t o t h e number d i s c h a r g e d home i n H a r r i s o n ' s (1981) s t u d y (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 o f l i d o c a i n e as an a d j u n c t t o t h e management o f v e n t r i c u l a r f i b r i l l a t i o n needs t o be performed.  C e r t a i n l y t h e d a t a from t h e p r e s e n t 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 , a t l e a s t i n t h e model used.  I t was n o t p o s s i b l e  i n t h i s a n i m a l model t o a s s e s s o n l y f i b r i l l a t i o n  episodes  r e f r a c t o r y t o 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 h e a r t s were easily defibrillated electrically.  I t t h e r e f o r e became  n e c e s s a r y t o a s s e s s t h e e f f i c a c y o f l i d o c a i n e as a c h e m i c a l d e f i b r i l l a t o r a l o n e , and n o t as an a d j u n c t t o e l e c t r i c a l defibrillation. The t h r e e c l i n i c a l  s t u d i e s mentioned  herein are the  f i r s t r e p o r t e d attempts t o d i r e c t l y address t h e i s s u e o f a n t 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 refractory ventricular f i b r i l l a t i o n .  F u r t h e r work i n t h i s  a r e a i s d e f i n i t e l y r e q u i r e d b e f o r e d e c i s i o n s c o n c e r n i n g t h e most a p p r o p r i a t e a g e n t s , dosages and r o u t e s o f a d m i n i s t r a t i o n can be made. In  t h e a n i m a l model used i n t h i s s t u d y , c e r t a i n t r e n d s  were observed c o n c e r n i n g d u r a t i o n o f v e n t r i c u l a r  fibrillation.  105  It  was  noted  animals (Table  i n which VII).  ventricular between  appeared  of  VF  that  efficacy  Other  ventricular would  could  once  animal,  have  is  these  short  conduction  larger  trend  occluded  such  as the  (40-45%)  area  rabbit  of  and  area  to  ischemic maintenance  obvious  these  possibly such  lidocaine  the areas  their  fibrillation  of short  fibrillation was  o f damaged less  t o produce  since  to that  time.  trends i n  study  episodes  during  episode  were  prior  where t h e  designs  trends.  r e p e r f u s i o n than  necessary  the  two d i s t i n c t  since  patterns  fibrillation  that  often occurred  reveal  arrhythmias  o f time  two m i n u t e s ,  fibrillation  that  two d i s t i n c t  f o r at least  ventricular  during  possible  a  o u t on animals  fibrillation,  long  large  not reported  an e p i s o d e a  statistically  be c a r r i e d  defibrillation  Short  and  heart  I t became  only  not necessarily  frequently  animal  left  occluded  I t i s interesting  t o t h e amount  had p e r s i s t e d  authors  a  p r e l i m i n a r y experiments,  respect  study  spontaneous  with  occluded  pathways.  (Table V I ) .  arrhythmia  hearts  of  mass  i s required f o r the production  with  persisted  small  i s not  often i n  had been  respectively),  to fibrillate.  During developed  groups  more  i n percent  ventricular  and p=0.128  a relatively  ventricle  re-entrant  VF  to occur  o f myocardium  of total  i n which  i n a  perhaps  area  and Long  (p=0.104  appeared  the difference  and p e r c e n t  likely  speculate  left  a certain  to exist  more  heart  fibrillation  Although  t h e No  significant  were  that  able  occurred  occlusion  (Table V I ) ,  had o c c u r r e d  unlikely  myocardium to sustain  a prolonged  more  i n an  to occur.  I t  generating the abnormal  episode  of  106  ventricular  fibrillation.  As reperfusion this  study  of to  ventricular This  was  develop  over  differences occlusion  In  acute  in  man  fibrillation  a  into  clinical  efficacy  between  same  summary,  route  arrest.  These  study  be  of reperfusion.  of  remains  undergoing  data  that  that  may  fibrillation  ventricular  due  fibrillation  plus  drug  in relation  may  whether  given  levels  The  achieved before  intravenous  lend be  lidocaine  lidocaine  r e q u i r e d , however,  route  long  IX).  findings  fibrillation  simply  a  of  to  unclear.  indicates  drawn.  to  finally  Areas  defibrillation  these  tended  other  phases.  Since  electrical  which  No  studies suggest  f o r administration of  endotracheal  lidocaine  two  (Table  infarction.  situation  choice  in  i n terminating ventricular  studies are  of  often resulting  occlusion,  groups  episode  significance  can  after  the  i n both  these  in ventricular  conclusions  in  fibrillation.  e n d o t r a c h e a l l y s i n c e plasma  Futher  the  minutes  fibrillation  This  or  the  found  minute  was  occlusion arrhythmias  ventricular  were noted  literature,  myocardium  w i t h i n one  period of  myocardial  the  i n the  h i g h l y arrhythmogenic,  i s managed w i t h  therapy, the  be  effective  to  trials  previously ischemic  were  ventricular  be  i n other  i n contrast to  degenerating  may  reported  an  administration, should  drugs  support  to  have  are  any  route  intravenously comparable.  definitive is still  during the  the  cardiac  hypothesis  effective  alternate  access  an  to  similar  IV  line  that  route be  for  delayed.  107  CONCLUSIONS  1.  I n t h e 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 following 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 i n t r a v e n o u s i n j e c t i o n , w i t h a p p r o x i m a t e l y 70% o f an e n d o t r a c h e a l dose absorbed over 10 m i n u t e s .  2.  F o l l o w i n g 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 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 p r o l o n g e d 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 i n t r a v e n o u s i n j e c t i o n .  3.  F o l l o w i n g b o t h i n t r a v e n o u s and e n d o t r a c h e a l administration during ventricular  fibrillation,  peak plasma l i d o c a i n e l e v e l s a r e g r e a t e r and i n i t i a l d i s t r i b u t i o n i s p r o l o n g e d , compared with controls. 4.  Administration of lidocaine endotracheally during persistent ventricular due t o a c u t e c o r o n a r y a r t e r y  fibrillation ligation  s i g n i f i c a n t l y shortens the d u r a t i o n of fibrillation.  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 o f A p r i n d i n e , M e x i l e t i n e , T o c a i n i d e and L i g n o c a i n e Compared on L a n g e n d o r f f - P e r f u s e d H e a r t s o f R a b b i t s and G u i n e a - P i g s . J . Pharm. Pharmacol. 3_2, 746-750. A l m o t r e f i , A.A. and Baker, J.B.E, 1981. Antifibrillatory E f f i c a c y of E n c a i n i d e , L o r c a i n i d e and ORG 6001 Compared w i t h L i g n o c a i n e i n I s o l a t e d H e a r t s o f R a b b i t s and G u i n e a - P i g s . B r . 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 C a r d i a c Care (ECC). J.A.M.A. 244, 453-509. A x e l r o d , P., V e r r i e r , R. and Lown, B. 1975. V u l n e r a b i l i t y to V e n t r i c u l a r F i b r i l l a t i o n D u r i n g Acute Coronary A r t e r i a l O c c l u s i o n and R e l e a s e . Am. J . C a r d i o l . 3_6, 776-782. Barsan, W.G., Levy, R.C. and Weir, H. 1981. Lidocaine Levels D u r i n g CPR: D i f f e r e n c e s A f t e r P e r i p h e r a l Venous, C e n t r a l Venous, and I n t r a c a r d i a c I n j e c t i o n s . Ann. Emerg. Med. 10, 73-78. Bashe, W.J., Baba, N., K e l l e r , M.D., Geer, J.C. and Anthony, J.R. 1975. P a t h o l o g y of A t h e r o s c l e r o t i c H e a r t D i s e a s e i n Sudden Death. I I . The S i g n i f i c a n c e of M y o c a r d i a l I n f a r c t i o n . C i r c u l a t i o n . 51-52(Suppl I I I ) , 111-63-69. B a t t l e , W.E., N a i n i , S., A v i t a l l , B. , B r i l l a , A.H., Banas, J.S. B e t e , J.M. and L e v i n e , H.J. 1974. D i s t i n c t i v e Time Course of V e n t r i c u l a r V u l n e r a b i l i t y t o F i b r i l l a t i o n D u r i n g and A f t e r R e l e a s e o f Coronary L i g a t i o n . Am. J . C a r d i o l . 34, 42-47. Benowitz, N.L. and M e i s t e r , W. 1978. C l i n i c a l Pharmacokinetics of L i g n o c a i n e - C l i n . Pharmacokinet. 3_, 177-201. B i g g e r , J.T. and Mandel, W.J. 1970. E f f e c t o f L i d o c a i n e on the 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 V e n t r i c u l a r Muscle and P u r k i n j e F i b e r s . J . C l i n . I n v e s t . 4_9_, 63-77. B o r e r , J.S., H a r r i s o n , L.A., Kent, K.M., Levy, R., G o l d s t e i n , R.E. and E p s t e i n , S.E. 1976. B e n e f i c i a l E f f e c t o f L i d o c a i n e on V e n t r i c u l a r E l e c t r i c a l S t a b i l i t y and Spontaneous V e n t r i c u l a r F i b r i l l a t i o n During Experimental Myocardial I n f a r c t i o n . Am. J . C a r d i o l . 37_, 860-861. Boudoulas, H., Karayannacos, P.E., L e w i s , R.P., Kakos, G.S., K i l m a n , J.W. and Vasko, J.S. 1978a. P o t e n t i a l E f f e c t o f L i d o c a i n e on Ischemic M y o c a r d i a l I n j u r y . E x p e r i m e n t a l and C l i n i c a l O b s e r v a t i o n s . J . Surg. Res. 2_4_, 469-476.  109  Boudoulas, H., Karayannacos,• P .E., L e w i s , R,P., Kakos, G. S. , K i l m a n , J.W. and Vasko, J,S. 1978b. I n f l u e n c e o f L i d o c a i n e on Ischemic M y o c a r d i a l I n j u r y . E u r . J . C a r d i o l . 1_, 91-104. Brennan, F . J . , W i t , A.L. and C r a n e f i e l d , P.F. 1975, 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 o f L i d o c a i n e on Depressed C a r d i a c Fibers (Abstr.). C i r c u l a t i o n . 51-52(Suppl I I ) , 11-85. Bromage, P.R. and Robson, J.G. 1961. C o n c e n t r a t i o n s o f L i g n o caine i n the Blood a f t e r Intravenous, Intramuscular, E p i d u r a l and 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 . A n a e s t h e s i a . 16, 461-478. Brown, A.M. 1967. E x c i t a t i o n o f A f f e r e n t C a r d i a c Sympathetic Nerve F i b e r s D u r i n g M y o c a r d i a l Ischaemia. J . Physiol. (Lond.). 190^, 35-53. Campbell, D. and A d r i a n i , J . 1958. A b s o r p t i o n o f L o c a l A n e s t h e t i c s . J.A.M.A. 168, 873-877. Canadian Heart F o u n d a t i o n . 1980. F a c t s and F i g u r e s . Heart F o u n d a t i o n ( P u b l i s h e r s ) .  Canadian  Carden, N.L. and S t e i n h a u s , J.E. 1956. L i d o c a i n e i n C a r d i a c 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 . C i r c . Res. 4, 680-683. C h i n n , W.M., Z a v a l a , D.C. and Ambre, J . 1977. Plasma L e v e l s of Lidocaine Following Nebulized Aerosol A d m i n i s t r a t i o n . Chest. 71, 346-348. Chu, S.S., Rah, K.H., Brannan, M.D. and Cohen, J . L . 1975. Plasma C o n c e n t r a t i o n o f L i d o c a i n e a f t e r E n d o t r a c h e a l Spray. Anesth. A n a l g . , C u r r . Res. 54, 438-441. Cobb, L.A., Baum, R.S., A l v a r e z , H. and S c h a f f e r , W.A. 1975. R e s u s c i t a t i o n from 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 : Four Years F o l l o w - u p . C i r c u l a t i o n . 51-51(Suppl I I I ) , 223228. C o r b a l a n , R., V e r r i e r , R.L. and Lown, B. 1976. D i f f e r i n g Mechanisms f o r V e n t r i c u l a r V u l n e r a b i l i t y D u r i n g Coronary A r t e r y O c c l u s i o n and R e l e a s e . Am. Heart J . 9_2, 223-230. C o r r , P.B., W i t k o w s k i , F.X. and S o b e l , B.E. 1978. Mechanisms C o n t r i b u t i n g t o M a l i g n a n t Dysrhythmias Induced by Ischemia i n t h e C a t . J . C l i n . I n v e s t . 63^, 109-119. C o u r t i c e , F.C. and P h i p p s , P . J . 1946. The A b s o r p t i o n o f F l u i d s From t h e Lungs. J . P h y s i o l . 105, 186-190. C u r r a n , J . , H a m i l t o n , C. and T a y l o r , T. 1975. T o p i c a l A n a l g e s i a B e f o r e T r a c h e a l I n t u b a t i o n . A n a e s t h e s i a . 30, 765-768.  110 E i s e n b e r g , M.S., Copass, M.K., H a l l s t r o m , A.P., B l a k e , B., Bergner, L., S h o r t , F.A. and Cobb, L.A. 1980. Treatment o f O u t - o f - H o s p i t a l C a r d i a c A r r e s t s w i t h Rapid D e f i b r i l l a t i o n by Emergency M e d i c a l T e c h n i c i a n s . N. E n g l . J . Med. 302, 1379-1383. Elam, J.O. 1977. The I n t r a p u l m o n a r y Route f o r CPR Drugs. Advances i n Cardiopulmonary R e s u s c i t a t i o n . S a f e r , P. S p r i n g e r - V e r l a g , New York, 132-137.  In (Ed.)  E l - S h e r i f , N., S c h e r l a g , B.J. and L a z z a r a , R. 1975. Electrode Catheter Recordings During Malignant V e n t r i c u l a r Arrhythmia F o l l o w i n g E x p e r i m e n t a l Acute M y o c a r d i a l I s c h e m i a : Evidence For Re-entry due t o C o n d u c t i o n Delay and B l o c k i n Ischemic Myocardium. C i r c u l a t i o n . 5_1, 1003-1014. Emergency H e a l t h S e r v i c e s Academy. (K. S u t h e r l a n d ) .  1982.  F u j i m o t o , T., Hamamoto, H., P e t e r , T. R e l a t i o n Between Conduction Delay F i b r i l l a t i o n : C h a r a c t e r i s t i c s of Impulses D u r i n g A c u t e M y o c a r d i a l 48, 287-294.  P e r s o n a l Communication  and Mandel, W.J. 1981. and V e n t r i c u l a r C o n d u c t i o n o f Premature Ischemia. Am. J . C a r d i o l .  G i a n e l l y , R., von der Groeben, J.O., S p i v a c k , A.P. and H a r r i s o n , D.C. 1967. E f f e c t o f L i d o c a i n e on V e n t r i c u l a r A r r h y t h m i a s i n P a t i e n t s w i t h Coronary Heart D i s e a s e . N. E n g l . J . Med. 277, 1215-1219. Goldberg, A. 1974. 290, 381-385.  Cardiopulmonary  Arrest.  N Engl. J.  Med.  G o l d r e y e r , B.N. and B i g g e r , J . T . J r . 19 71. S i t e o f Reentry i n Paroxysmal 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 i n Man. Circulation 43_, 15-26. Greenberg, M.I., R o b e r t s , J.R., K r u s z , J.C. and B a s k i n , S.I. 1979a. E n d o t r a c h e a l E p i n e p h r i n e i n a Canine A n a p h y l a c t i c Shock Model. Ann. Emerg. Med. (J.A.C.E.P.) 8, 500-503. Greenberg, M.I., R o b e r t s , J.R., B a s k i n , S.I. and Wagner, D.K. 1979b. The Use o f E n d o t r a c h e a l M e d i c a t i o n f o r C a r d i a c A r r e s t . T o p i c s i n Emergency M e d i c i n e . 1, 29-40. Han,  J . 1969. Mechanisms o f V e n t r i c u l a r A r r h y t h m i a s A s s o c i a t e d w i t h M y o c a r d i a l I n f a r c t i o n . Am. J . C a r d i o l . 2_4, 800-813.  Han,  J . , G o e l , B.G., Yoon, M.S. and Rogers, R. 1974. E f f e c t of Procainamide and L i d o c a i n e on V e n t r i c u l a r A u t o m a t i c i t y and Reentry D u r i n g A c u t e Coronary O c c l u s i o n . Am. J . C a r d i o l . 34, 171-178.  H a r r i s o n , E.E. 1981. L i d o c a i n e i n P r e h o s p i t a l Countershock Refractory Ventricular F i b r i l l a t i o n . Ann. Emerg. Med. 10, 420-423.  Ill  Haynes, R.E., Chirm, T.L. , Copass, M.K. and Cobb, L.A. 1981. Comparison o f B r e t y l i u m T o s y l a t e and L i d o c a i n e i n Management o f 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 : A Randomized T r i a l . Am. J . C a r d i o l . 48_, 353-356. J e w i t t , D.E., K i s h o n , Y. and Thomas, M. 1968. L i g n o c a i n e i n the Management o f A r r h y t h m i a s A f t e r Acute M y o c a r d i a l I n f a r c t i o n . Lancet. 1, 266-270. Josephson, M.E., H o r o w i t z , L.N. and F a r s h i d i , A. 1978. Continuous L o c a l E l e c t r i c a l A c t i v i t y . A Mechanism o f R e c u r r e n t V e n t r i c u l a r T a c h y c a r d i a . C i r c u l a t i o n . 5_7, 659-665. Kane, K., McDonald, F. and P a r r a t t , J.R. 1979. Coronary A r t e r y L i g a t i o n i n A n a e s t h e t i z e d Rats a a Model f o r the Assessment o f A n t i d y s r h y t h m i c A c t i v i t y : The E f f e c t s o f L i g n o c a i n e , P r o p r a n o l o l and ORG 6001. Proceedings o f the B.P.S. A p r i l 4-6. 463-464P. K a p l a n , H. and Timmons, E. ( E d s . ) . 1979. The R a b b i t : A Model f o r the P r i n c i p l e s o f Mammalian P h y s i o l o g y and Surgery. Academic P r e s s , New York. K a p l i n s k y , E., Ogawa, S., B a l k e , C.W. and D r e i f u s , L.S. 1979. Two P e r i o d s o f E a r l y V e n t r i c u l a r A r r h y t h m i a i n the Canine 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 Model. C i r c u l a t i o n . 6_0, 397-403. K a p l i n s k y , E., Ogawa, S., M i c h e l s o n , E.L. and D r e i f u s , L.S. 1981. I n s t a n t a n e o u s and Delayed V e n t r i c u l a r A r r h y t h m i a s A f t e r R e p e r f u s i o n o f A c u t e l y Ischemic Myocardium: E v i d e n c e f o r M u l t i p l e Mechanisms. C i r c u l a t i o n . 6J3_, 333-340. Kramer, B., G u l k e r , H., and Meesmann, W. 1981. The E f f e c t s o f L i d o c a i n e on 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 and Primary 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 Acute Experimental Coronary O c c l u s i o n . B a s i c Res. C a r d i o l . 29-43. Kuhn, G.J., W h i t e , B.C., Swetnam, R.E., Mumey, J.F., Rydesky, T i n t i n a l l i , J.E., Krome, R.L. and Hoehner, P.J. 1981. P e r i p h e r a l vs C e n t r a l C i r c u l a t i o n Times D u r i n g CPR: A P i l o t Study. Ann. Emerg. Med. 10_, 417-419.  M.F.,  K u p e r s m i t h , J . 1979. E l e c t r o p h y s i o l o g i c a l and A n t i a r r h y t h m i c E f f e c t s o f L i d o c a i n e i n Canine A c u t e M y o c a r d i a l Ischemia. Am. H e a r t . J . 9_7, 360-365. Lang, T.W., Corday, E., G o l d , H., Meerbaum, S., Rubino, S., C o s t a n t i n i , C., H i r o s e , S., Osher, J . and Rosen, V. 1974. Consequences o f R e p e r f u s i o n A f t e r Coronary O c c l u s i o n : E f f e c t s on Hemodynamic and R e g i o n a l M y o c a r d i a l M e t a b o l i c F u n c t i o n . Am. J . C a r d i o l . 3_3/ 69-81. L a z z a r a , R., E l - S h e r i f , N., B e f e l e r , B. and S c h e r l a g , B.J. L i d o c a i n e A c t i o n on Depressed C a r d i a c C e l l s ( A b s t r . ) . C i r c u l a t i o n . 51-52(Suppl I I ) , 11-85.  1975.  112  L a z z a r a , R., Hope, R.R., E l - S h e r i f , N. and S c h e r l a g , B . J . 1 9 7 8 . E f f e c t s o f L i d o c a i n e on Hypoxic and Ischemic C a r d i a c C e l l s . Am. J . C a r d i o l . 4 1 , 8 7 2 - 8 7 9 . L e v i t e s , R., Banka, V. and H e l f a n t , R.H. 1 9 7 5 . E l e c t r o p h y s i o l o g i c E f f e c t s o f Coronary O c c l u s i o n and R e p e r f u s i o n : O b s e r v a t i o n s o f D i s p e r s i o n o f R e f r a c t o r i n e s s and V e n t r i c u l a r Automaticity. Circulation. 5_2, 7 6 0 - 7 6 5 . L i b e r t h s o n , R.R., N a g e l , E.L., Hirschman, J.C. and N u s s e n f e l d , S.R. 1 9 7 4 . P r e h o s p i t a l E l e c t r i c a l D e f i b r i l l a t i o n . N. E n g l . J . Med. 2 9 1 , 3 1 7 - 3 2 1 . L i e , K . I . , W e l l e n s , H.J., van C a p e l l e , F . J . and D u r r e r , D. 1974. Lidocaine i n the Prevention o f Primary V e n t r i c u l a r Fibrillation. N. E n g l . J . Med. 291, 1324-1326. Lown, B., F a k h r o , A.M., Hood, W.B.Jr., and Thorn, G.W. 1967. The Coronary Care U n i t : New P e r s p e c t i v e s and D i r e c t i o n s . J.A.M.A. 199, 188-198. Lown, B., C a l v e r t , A.F., A r m i n g t o n , R. and Ryan, M. 1975. M o n i t o r i n g F o r S e r i o u s A r r h y t h m i a s and High R i s k o f Sudden Death. C i r c u l a t i o n . 51-52(Suppl I I I ) , I I I - 1 8 9 - 1 9 8 . Merck Index, The. 1968. Merck & Co. I n c . , Rahway, New J e r s e y . S t e c h e r , P. (Ed.). 8 t h Ed. Murdock, D.K., Loeb, J.M., E u l e r , D.E. and R a n d a l l , W.C. 1980. E l e c t r o p h y s i o l o g y o f Coronary R e p e r f u s i o n : A Mechanism f o r Reperfusion Arrhythmias. Circulation. 6_1/ 175-182. N a s s e r , F.N., W a l l s , J.T., Edwards, W.D. and H a r r i s o n , C E . 1980. L i d o c a i n e - Induced R e d u c t i o n i n S i z e o f E x p e r i m e n t a l M y o c a r d i a l I n f a r c t i o n . Am. J . C a r d i o l . 4_6, 967-975. Nowak, R.M., Bodnar, T.J., Dronen, S., Gentzkow, G. and T o m l a n o v i c h , M.C. 1981. B r e t y l i u m T o s y l a t e as I n i t i a l Treatment f o r Cardiopulmonary A r r e s t : Randomized Comparison With Placebo. Ann. Emerg. Med. 10, 404-407. O l i v a , P.B. and B r e c k i n r i d g e , J.C. 1977. A r t e r i o g r a p h i c E v i d e n c e o f Coronary A r t e r i a l Spasm i n A c u t e M y o c a r d i a l Infarction. Circulation. 5_6, 366-374. Ouyang, P., B r i n k e r , J.A., B u l k l e y , B.H., J u g d u t t , B . I . and Varghese, P.J. 1981. Ischemic V e n t r i c u l a r F i b r i l l a t i o n : The Importance o f B e i n g Spontaneous. Am. J . C a r d i o l . 48, 455-459. Pape, B.E., W h i t i n g , R., P a r k e r , K.M. and M i t r a , R. 1978. Enzyme Immunoassay and G a s - L i q u i d Chromatography Compared f o r D e t e r m i n a t i o n o f L i d o c a i n e i n Serum. C l i n . Chem. 24., 2020-2022.  113  P e l t o n , D.A., Daly, M., Cooper, P.D. and Conn, A.W. 1970. Plasma L i d o c a i n e C o n c e n t r a t i o n s F o l l o w i n g T o p i c a l A e r o s o l A p p l i c a t i o n t o the Trachea and B r o n c h i . Can. Anaesth. Soc. J . 17, 250-253. Penkoske, P.A., Sobel, B.E. and C o r r , P.B. 1978. D i s p a r a t e E l e c t r o p h y s i o l o g i c a l A l t e r a t i o n s Accompanying Dysrhythmia Due t o Coronary O c c l u s i o n and R e p e r f u s i o n i n t h e Cat. C i r c u l a t i o n . 5_8, 1023-1035. Post, C , Andersson, R.G.G., R o r f e l d t , A. and N i l s s o n , E. 1978. T r a n s p o r t and B i n d i n g o f L i d o c a i n e by Lung S l i c e s and Perfused Lung of Rats. A c t a Pharmacologica e t Toxicologica. 4_3, 156-163. Redding, J.S., Asuncion, J.S. and Pearson, J.W. 1967. E f f e c t i v e Routes o f Drug A d m i n i s t r a t i o n During C a r d i a c A r r e s t . Anesth. Analg., C u r r . Res. 4_6, 253-258. Ribner, H., I s a a c s , E. and Frishman, W. 1979. L i d o c a i n e P r o p h y l a x i s A g a i n 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 n Acute Myocardial I n f a r c t i o n . Prog. C a r d i o v a s c . D i s . 21, 287-313. Roberts, J.R., Greenberg, M.I., Knaub, M. and Baskin, S.I. 1978. Comparison o f the Pharmacological E f f e c t s o f E p i n e p h r i n e Administered by the Intravenous and E n d o t r a c h e a l Routes. Ann. Emerg. Med. (J.A.C.E.P.) . ]_, 260-264. Roberts, J.R., Greenberg, M.I., Knaub, M.A., Kendrick, Z.V. and Baskin, S.I. 1979a. Blood L e v e l s F o l l o w i n g Intravenous and E n d o t r a c h e a l E p i n e p h r i n e A d m i n i s t r a t i o n . Ann. Emerg. Med. (J.A.C.E.P.). 8, 53-56. Roberts, J.R., Greenberg, M.I. and Baskin, S.I. 1979b. Endotracheal Epinephrine 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 . Ann. Emerg. Med. (J.A.C.E.P.). 13, 515-519. Rosen, M.R., Merker, C., and Pippenger, C.E. 1973. E f f e c t s of C l i n i c a l l y Relevant Plasma L i d o c a i n e C o n c e n t r a t i o n s on E l e c t r o p h y s i o l o g i c P r o p e r t i e s o f Canine P u r k i n j e F i b e r s . (Abstr.). C i r c u l a t i o n . 47-48(Suppl I V ) , 209. Rubenstein, K.E. 19 78. Homogeneous Enzyme Immunoassay Today. Scand. J . Immunol. 8^(Suppl 7), 57-62. S c h a f f e r , W.A. and Cobb, L.A. 1975. Recurrent V e n t r i c u l a r F i b r i l l a t i o n and Modes o f Death i n S u r v i v o r s o f Out-ofHospital Ventricular F i b r i l l a t i o n . N. E n g l . J . Med. 293, 260-262. S c o t t , D.B., L i t t l e w o o d , B.G., Covino, B.G. and Drummond, G.B. 1976. Plasma L i g n o c a i n e C o n c e n t r a t i o n s F o l l o w i n g E n d o t r a c h e a l Spraying With a n . A e r o s o l . In C l i n i c a l T o x i c o l o g y . Duncan, W.A. (Ed.). E x c e r p t a Medica, Amsterdam. 417, 255-257.  114 Spear, J . , Moore, E.N. and G e r s t e n b l i t h , G. 1972. E f f e c t of L i d o c a i n e on 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 i n the Dog D u r i n g A c u t e Ischemia and Premature V e n t r i c u l a r C o n t r a c t i o n s . C i r c u l a t i o n . £6, 65-73. S p r a c k l e n , F.H.N., K i m e r l i n g , J . J . , Besterman, E.M.M. and L i t c h f i e l d , J.W. 1968. Use o f L i g n o c a i n e i n Treatment o f Cardiac Arrhythmias. B r . Med. J . 1, 89-91. S z e p l a k i , S., S z i l a i g y i , A., H a r s a n y i , A., S z e p l a k i , Z., Mate, K. and K u l c s a r , M. 1976. Lidocaine Prophylaxis i n Prei n f a r c t i o n A n g i n a and i n the R e a c t i v e Stage o f M y o c a r d i a l . Infarction. Agressologie. 17, 245-250. V a l e n t i n e , P.A., Frew, J.L., M a s h f o r d , M.L. and Sloman, J.G. 1974. L i d o c a i n e i n the P r e v e n t i o n of Sudden Death i n the P r e - H o s p i t a l Phase o f Acute I n f a r c t i o n . N. E n g l . J . Med. 291, 1327-1331. V e r a , Z. and Mason, D.T. 19 81. Reentry V e r s u s A u t o m a t i c i t y : Role i n T a c h y a r r h y t h m i a G e n e s i s and A n t i a r r h y t h m i c Therapy. Am. H e a r t . J . 1981. 101, 329-338. V e r t e s i , L. 1978. The Paramedic Ambulance: A Canadian Experience. Can. Med. A s s o c . J . 119, 25-28. V i e g a s , 0. and S t o e l t i n g , R.K. 1975. Lidocaine i n A r t e r i a l Blood a f t e r Laryngotracheal A d m i n i s t r a t i o n . Anesthesiology 43, 491-493. Voorhees, W.D., Babbs, C F . and T a c k e r , W.A.Jr. 1980. Regional B l o o d Flow D u r i n g C a r d i o p u l m o n a r y R e s u s c i t a t i o n i n Dogs. C r i t . Care Med. 8, 134-136. W i t , A.L. and Friedman, P.L. 1975. Basis for Ventricular A r r h y t h m i a s Accompanying M y o c a r d i a l I n f a r c t i o n . Arch. I n t e r n . Med. 135, 459-472. Wyman, M.G. and Hammersmith, L. 1974. Comprehensive Treatment P l a n f o r the P r e v e n t i o n o f P r i m a r y V e n t r i c u l a r F i b r i l l a t i o n i n Acute M y o c a r d i a l I n f a r c t i o n . Am. J . C a r d i o l . 33, 661-667. —  

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
http://iiif.library.ubc.ca/presentation/dsp.831.1-0095537/manifest

Comment

Related Items