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A comparison of two conventional sedatives-diazepam and droperidol in combination with fentanyl in surgical.. Battrum-Mounts, Deborah E. 1985

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A COMPARISON OF TWO CONVENTIONAL SEDATIVES-DIAZEPAM  AND DROPERIDOL  COMBINATION WITH FENTANYL IN SURGICAL  IN PATIENTS  by D e b o r a h E.  Battrum-Mounts  B . S c , The U n i v e r s i t y o f T o r o n t o , 1975 D . D . S . , The U n i v e r s i t y o f T o r o n t o , 1 9 7 9  A T H E S I S SUBMITTED IN PARTIAL THE REQUIREMENTS  FULFILMENT OF  FOR THE DEGREE OF  MASTER OF SCIENCE  in THE  FACULTY OF GRADUATE STUDIES (Faculty of Dentistry)  We a c c e p t t h i s t h e s i s a s c o n f o r m i n g _ to^ t h e r e q u i r e d s t a n d a r d  THE  UNIVERSITY  OF B R I T I S H COLUMBIA  August, 0  D e b o r a h E.  1985  Battrum-Mounts  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 a t 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 f o r s c h o l a r l y purposes may department or by h i s or her  be granted by the head of representatives.  my  It i s  ^/understood t h a t copying or p u b l i c a t i o n of t h i s t h e s i s jfor f i n a n c i a l gain  s h a l l not be  allowed without my  permission.  Deborah E. Battrum  Department o f  r i p n t i s t r y  The U n i v e r s i t y of B r i t i s h Columbia 1956 Main Mall Vancouver, Canada V6T  Date  DE-6  /"i/jm  1Y3  Aug.  6.1985  written  i  ABSTRACT  One  hundred  patients  who w e r e t o  have c a t a r a c t  and i n t r a o c u l a r l e n s r e p l a c e m e n t c a r r i e d o u t w e r e one o f  two d r u g g r o u p s .  fentanyl nervous  anxiety.  cognizant  of  Patients,  others'  Experimental  Psychological Spielberger,  the  the  opionons,  nor of  central  and L u s h e n e ,  Gracely,  and s u r g e o n s  assignment of  d e s i g n was a b e t w e e n  Gorsuch  surgical  observes,  group  State-Trait  drug  Anxiety  Opinion  of  ratio  t h e a n a e s t h e t i c o u t c o m e was o b t a i n e d  from the  anaesthetist.  as a s e d a t i v e procedure fentanyl  to  local  anaesthetic  some d i f f e r e n c e s w e r e ' o u n d . combination provided  a n d had l i t t l e found  adjunct  if  any  the patients  Anaesthetists  rated  groups  and f o u n d  amount  of  recall  less the  for of  t h e r e was n o t  sedation they  opinion  this  type  found  The  of  the  diazepam/ procedure,  surgeons  diazepam/fentanyl  s e d a t i o n as e q u i v a l e n t  also  group. for  use  surgical  both  a s i g n i f i c a n t d i f f e r e n c e between  observed.  carrying  be s u c c e s s f u l f o r  intense overall  procedure.  r e s t l e s s i n the level of  Patients  a less  the  for  and  of  pain  ease of  surgeon,  to  design.  Inventory  from the  proved  were  treatment  p r o c e d u r e was o b t a i n e d  While both drug combinations  to  s i n g l e treatment  and t h e S e n s o r y / A f f e c t  Dubner and M c G r a t h .  to  droperidol/  following effects:  psychology  t e s t i n g c o n s i s t e d of  descriptors of  of  for  assigned  s y s t e m d e p r e s s i o n , c a r d i o v a s c u l a r d e p r e s s i o n and a b i l i t y  group.  out  randomly  p u r p o s e was t o c o m p a r e  and d i a z e p a m / f e n t a n y l  alleviate not  The  extraction  the  ii  TABLE OF ABBREVIATIONS  p.o.  per os  min.  minutes  mg.  mi 11i grams  C.N.S.  central  GABA  gamma a m i n o b u t y r i c  i . v.  intravenous  i .m.  intramuscular  G.I.S.  gastro  PAR  post anaesthetic  E.E.G. R.E.M.  '  nervous  system  intestinal  acid  system recovery  electro-encephalograph random e y e movement  iii TABLE OF CONTENTS Page Abstract  i  Table of Abbreviations  i i  Table of Contents  i i i  I  Introduction  1  II  Dental Sedatives-Prior to the Introduction of the Benzodiazepines  5  III  Benzodiazepines-General  IV  Specific Benzodiazepines and their Sedative Use in Dentistry  V  Pharmacology  " '^Applications of the Newer Benzodiazepines  12 20 34  VT  Conclusion  43  VTI  Neuroleptanalgesia  46  VIII  Fentanyl  IX  Introduction to the Experiment-Objectives  51  X  Rationale for Studying Surgical Cataract Patients, and for Drug Regimen  53  XI  Materials and Methods  54  XII  Assessment  60  XIII  Statistical Analysis  63  XIV  Results  64  XV  Discussion  80  XVT  Summary  85  XVII  Acknowledgement  87  XVIII  Appendices  88  XIX  Bibliography  94  XX  Statistics  98  ' 4 9  1  INTRODUCTION  Like other interaction  of three  on m a t u r a t i o n  phenomena  and s o c i a l  aversive  of dental  pointed out that  experiences.  efforts  treatment  than  d i d not attend  for financial  ultimately  surgical  dental  anxiety  available imagery  period of time, success. operator  (1).  phobias,  In 1 9 5 8 , Jam's  (2)  procedures  50% o f t h e p o p u l a t i o n because o f f e a r ,  rather  Hypnosis,  a reduction i n  cooperation bio-feedback  are presently and guided  h a v e b e e n u s e d by p s y c h o l o g i s t s f o r a c o n s i d e r a b l e f o r the treatment  o f other  learning intravenous  phobias with  considerable  sedation techniques, the  r e q u i r e s a c o n s i d e r a b l e amount o f t r a i n i n g i n h y p n o s i s a n d t e c h n i q u e s t o become s u c c e s s f u l  Also,  not every  However i f t h e time to  modeling  p r i o r to general  of obtaining  and an i n c r e a s e i n p a t i e n t  As w i t h  bio-feedback patient.  directly,  reasons ( 5 0 ) .  f o r some p a t i e n t s .  methods  may r e s u l t  p r i o r to dental patients  dependant  learning processes  through  results.  appointments  Non p h a r m a c o l o g i c a l m e t h o d s patient  through  through the  those  r e a s o n away d e n t a l  Hayden p o i n t e d o u t t h a t more t h a n  surveyed  fear develops  Learning  cannot  the fear o f patients  exceeded the f e a r o f general surgery.  developed  conditioning, or indirectly,  When v o l u n t a r y avoidance  dental  - those which are i n a t e ,  p r o c e s s e s , and those  from i n d i v i d u a l through  forms o f b e h a v i o r ,  patient  i s afforded,  t h e use o f i n t r a v e n o u s  in treating  c a n be h e l p e d w i t h certanly this  sedation.  the phobic  hypnosis.  i s a viable  alternative  2  anxiety  The  aim of  pharmacological  prone  dental  patient  attained  via  treatment normally  depression of  to  1960,  had been these  obtunded  the  with  to  first  the  the  terms e x i s t ,  in activity.  The  of  but  i s used i n a g r e a t e r  psychogenic  Obviously  the  anaesthesia.  encountered  i n the  necessity of  these  use o f  hypnosis.  chlordiazepoxide  and s e d a t i v e s .  on t h e  employed  drugs  definitions  may be c o n s i d e r e d t o  patient  be a  and w h i c h p r o d u c e s  A hypnotic  i s rendered  may be t h e  i n order to  of  relaxed.  fear  It  is  compound, (46).  used f o r  the  of  used as s e d a t i v e s  and  to  reduce  compound  a  free  same  for  sleep latency  physiological  previously  numerous  remaining comfortably  drugs  definitions  (LIBRIUM)  A number o f  conscious patient  interfere  themselves processes of  b e i n g somewhat  Since chlordiazepoxide, the  of  used b e n z o d i a z e p i n e ,  dose,  the  enabling  as g e n e r a l  a r e made n o t of  (CNS),  use o f s u c h p r o c e d u r e s  drugs which are not  nature  system  sedation  reflexes  d i s o r d e r s are often  that efforts  conscious  the  protective  pain c o n t r o l .  Anxiolytic  nervous  of  help  the  and d e p r e s s i o n w h i l e  a method  when u s e d t o  a state  maintaining  however a s e d a t i v e  not  except  central  yet  clinically  w h i c h has a c a l m i n g e f f e c t  and a n x i e t y  produce  introduction  used as h y p n o t i c s  reduction  the  be c a r r i e d o u t ,  Prior in  i s to  adjuncts,  there  drugs  T h e r e h a s been a g e n e r a l  with  hypnotics,  daytime  and t h e the  treatment  variability  human  liberally  has been a m a j o r  for shift  attaining  productivity.  leads to  the  interpreted. decrease  sedation  in  and  in presciption writing  to  3  other  members o f  a reduction widespread  the  in a c t i v i t y ,  Due  dental  treatment  dental  appointments  been e m p l o y e d t o  to the  due t o  Clinical  examples  have b e e n r e p o r t e d , (4).  benefit.  As w e l l ,  The most venous  or  if  the d e n t i s t  and r e l a x e d p a t i e n t of  sedation technique.  not  either  having  for  and t h u s  producing  the  could only  during  dental  drugs  have  appointment  death  due t o in  stress  good  r i s k w o u l d be a c o n s i d e r a b l e benefit  by h a v i n g a reflexes  sedation i n p a t i e n t s of  dentists  insecurity with  capable of  avoiding  dentist.  whose p r o t e c t i v e  majority  the  have been g e n e r a l l y  in this  produce  numerous  sudden and unexpected  reasons of  offices  (3)),  f e a r a n d make t h e  obtaining The  patients  p r i o r t o and  the population  a reduction  p r e c i s e method  techniques,  of  dental  levels,  even where p a t i e n t s  Obviously  cooperative  high anxiety  patient,  to  have t h e c a p a c i t y t o  h i g h numbers o f  (15%-20% o f  the  In a d d i t i o n  do s o more s e l e c t i v e l y t h a n  allay patients'  more a c c e p t a b l e t o  group.  benzodiazepines  CNS d e p r e s s i o n , y e t  barbiturates.  health  benzodiazepine  calm,  are  maintained.  i s by  use o r a l  intravenous  intra-  sedation techniques,  handling possible complications  effi ciently.  However, o r a l l y a d m i n i s t e r e d drugs as c o n s i s t a n t  in onset  and i n t e n s i t y  a d m i n i s t e r e d d r u g s as t h e r e blood plasma l e v e l s . be t i t r a t e d  t o meet  the  of effects  a r e numerous  By u s e o f  the  individual  are not as  as p r e d i c t a b l e intravenously  f a c t o r s which  intravenous needs o f  the  route  influence the  patients.  drugs  may  nor  4 At  present  t h e most  commonly u s e d d r u g s  sedation are benzodiazepines, is  a need t o  butyrophenones  compare t h e s e d i f f e r e n t  pharmacological t o make  recommendations  drug  regimen  for  dental  as t o  their  for  general  shortcomings  a r e m o s t commonly  and  For conventional for  Health  and the  in  from particular  used as  induction  and a d v a n t a g e s  known t o  study  those  the other  length  involved  two g r o u p s ;  in  with  their  benzo-  butyrophenones.  the  purposes of  drug treatment  Sciences at  pharmacological formulate  use o f  a n a e s t h e s i a , and have been s t u d i e d a t  u s e i t w o u l d be i n t e r e s t i n g t o diazepines  variations  on t h e p a t i e n t s ,  the appropriate  There  patients.  Since barbiturates agents  intravenous  or barbiturates.  drug regimes f o r  and p s y c h o l o g i c a l e f f e c t s  this  for  the  this  study  regimens University  i t was d e c i d e d t o  presently of  guidelines for  their  use i n  i n use a t t h e  British  and p s y c h o l o g i c a l v a r i a t i o n  compare  Columbia,  amongst  dentistry.  two  Centre for  patients,  and  to  5 A REVIEW OF LITERATURE  II  REGARDING SEDATIVE DRUGS PERTINANT TO DENTISTRY  - DENTAL S E D A T I V E S - P R I O R TO THE INTRODUCTION OF  P r i o r to the introduction barbiturates  w e r e t h e m o s t commonly  and a l l e v i a t i o n o f a n x i e t y . popularity,  BENZODIAZEPINES  of the benzodiazepines, used drugs  f o r purposes o f  Certain other non-barbiturates  e . g . ethchlorvynol,  rriu-probamate, c h l o r a l h y d r a t e  glutethimide,  the  paraldehyde,  sedation  h a d some ethinamid,  a n d some a n t i h i s t a m i n i c d r u g s w i t h  sedative  effects.  Chronologically, opium,  a l c o h o l , and t h e b e l l a d o n n a a l k a l o i d s t o w a r d  century.  Chloral  hydrate  and o r a l l y e f f e c t i v e minutes tages; gastric is  i t i s highly  sedatives with a fast hours.  onset o f a c t i o n  Chloral  hydrate  r e s u l t s i f taken without  is  narrow  is  planned.  h a s been h e l p f u l  i n the treatment  As t h e m a r g i n between  depression.  Even s m a l l  Internally  g a s t r i c o r duodenal  therapeutic  doses o f c h l o r a l hydrate  v a s o d i l a t i o n and h y p o t e n s i o n ,  Administration  o f s t a t u s e p i l e p t i c u s and  i t s h o u l d be a v o i d e d i n p a t i e n t s w h e r e  peripheral  (20-30)  h a s many d i s a d v a n -  food.  a b s o l u t e l y c o n t r a i n d i c a t e d t o those p a t i e n t s with  eclamptic seizures.  t h e end o f the 19th  i r r i t a t i n g t o t h e s k i n a n d mucous membranes a n d  i r r i t a t i o n often  It  "replaced"  (NOCTEC) a n d c h l o r a l b e t a i n e a r e i n e x p e n s i v e  and d u r a t i o n o f f o u r  ulcers.  is  t h e bromides and c h l o r a l hydrate  and t o x i c  general  dose  anaesthesia  may r e s u l t i n  a n d some d e g r e e o f m y o c a r d i a l  i t i s r a p i d l y converted to t r i c h l o r e t h a n o l  b e l i e v e d t o cause t h e c e n t r a l depressant  effects.  which  6  In  s p i t e o f t h e bad t a s t e t h e r e  sudden w i t h d r a w a l that is  after  c h r o n i c use r e s u l t s i n a s i m i l a r  c a u s e d by a l c o h o l w i t h d r a w a l  (8).  this  drug i n r e s t  used i n d e n t a l  have l a r g e l y t a k e n o v e r , homes,  syndrome  to  C o n s i d e r i n g these problems  d i f f i c u l t t o u n d e r s t a n d why i t i s s t i l l  While benzodiazepines of  i s an abuse p o t e n t i a l , and  there  sedation.  is still  c h r o n i c c a r e c e n t r e s a n d .some  it  some u s e  peadodontic  practices.  Paraldehyde, for  sedative  use f o r o v e r  effective with hydrate. The it  It  a p o l y m e r o f a c e t a l d e h y d e has been  l i v e r metabolism.  h a s some a b u s e p o t e n t i a l ,  Ethinamate  Because o f the s h o r t  reported in  both  but dental  to offer  chloral  In s p i t e o f t h e bad t a s t e patient  (VALMID), a u r e t h a n e ,  duration  sedative  acceptance i s poor  was i n t r o d u c e d t o t h e m a r k e t  o n s e t and s h o r t d u r a t i o n o f a c t i o n .  i t has had l i m i t e d p o p u l a r i t y  in dentistry.  Paradoxical  excitement  as a has been  i n c h i l d r e n a n d r a s h e s a n d g a s t r i c u p s e t a r e r e l a t i v e l y common a d u l t s and c h i l d r e n ( 8 ) . Ethchlorvynol  (PLACIDYL),  Because o f i t s r e l a t i v e l y f a s t 30 m i n u t e s a n d 4 - 6 h o u r s as  than  (8).  Taken o r a l l y i t has a f a s t  preoperative  i s i n e x p e n s i v e and o r a l l y  h a s a d i s a g r e e a b l e t a s t e a n d more t h a n 25% i s e x h a l e d .  balance undergoes  1954.  It  a r a p i d o n s e t and a l o n g e r d u r a t i o n  and t h e d r u g has l i t t l e  in  a century.  available  an o r a l  sedative  onset and d u r a t i o n  respectively),  in dentistry.  and has a n t i c o n v u l s a n t  a p p e a r e d on t h e m a r k e t  It  (approximately  i t h a s h a d some  popularity  has a wide m a r g i n o f  and muscle r e l a x a n t  i n 1954.  properties.  safety  However,  7 being a condensation product  of chloral hydrate,  s i m i l a r advantages  and d i s a d v a n t a g e s .  are:  dizziness,  after-teste,  facial  numbness.  Rarely,  there  and a t a x i a  reactions.  anticoagulant  response to dicoumerol  ethchlorvynol  i s absolutely  porphyria. is  Taken o r a l l y ,  considered to give  secobarbital  (DORIDEN)  similar in structure  associated with  acute a l l e r g i c  With prolonged  i n patients  have been r e p o r t e d , and  770 m i l l i g r a m s  sedative  are equivalent  i s somewhat  with  intermittent  (mg) e t h c h l o r v y n o l  r e s p o n s e t o t h a t o f 1 0 0 mg  i n 1955.  to methyprylon.  reactions, porphyria  Intravenously Acute  and b l o o d d y s c r a s i a s .  i t s absorption  central  depression occurs less  nervous  depressants.  Respiratory  barbiturates  b u t c i r c u l a t o r y d e p r e s s i o n may be more s e v e r e  and t h e a n t i - m u s c a r i n i c e f f e c t s  Meprobamate  Its f i r s t  and l a t e r as an a n x i o l y t i c .  Gastric pattern from  than with the i n overdose  p e r s i s t f o r hours.  There i s  (8).  (MILTOWN) i n t r o d u c e d i n 1 9 5 5 , r e c e i v e d  and l a y p o p u l a r i t y .  With-  s y s t e m (CNS)  frequently  no l o n g e r a n y r e a s o n t o recommend i t s u s e i n d e n t i s t r y  r e l a x i n g agent  is a  I t has been  i n t o x i c a t i o n may r e s u l t  o r from a combination w i t h o t h e r  rapid medical  It  t o those o f the b a r b i t u r a t e s .  erratic.  resembles that o f t h i o p e n t a l .  situations  commonly.  anticipated  u s e , p h y s i c a l a n d p s y c h i c d e p e n d e n c e may f o l l o w .  symptoms  overdose  also occur r e l a t i v e l y  was i n t r o d u c e d  piperadinedione  absorption  h y p o k i n e s i a and  contraindicated in patients  an e q u i v a l e n t  effects  Cases o f s u p p r e s s e d  approximately  exhibits  (6).  Glutethimide  drawal  The m o s t common s i d e  nausea and v o m i t i n g ,  M i l d hangover  are a l l e r g i c  i t therefore  both  u s e was a s a m u s c l e Clinical  t e s t i n g h a s shown  8  it  t o be l i t t l e  better  than a placebo a t suggested t h e r a p e u t i c  and l e s s  effective  than  sedative  effects.  I t may c a u s e w i d e s p r e a d C . N . S .  so u n e v e n l y , than  an i n t e r m e d i a t e  and i t i s n o t a g e n e r a l  the barbiturates  acting barbiturate  doses,  regarding  depression, yet  anaesthetic.  It  does  i s more s e l e c t i v e  i n the depression of spinal chord reflexes, being  selective only  for polysynaptic,  reflexes.  Although  it  t o be h y p e r a l g e s i c , when i t i s c o m b i n e d w i t h  analgesic  i s reported  compounds,  i t enhances the a n a l g e s i c e f f e c t .  plasma c o n c e n t r a t i o n in  the urine  is  6-17  peaks i n 1-3  unchanged.  hours.  Major  Little  impairment  The problems  the  bound.  abuse p o t e n t i a l  doses.  is high,  had been r e p o r t e d .  C.N.S.  excreted  Plasma T  n o t uncommon,  c o n t i n u e d use i n d e n t i s t r y  (8).  Though  overdose  is a relatively  i n the 60's, t h e r e  have  meprobamate.  marketing  Abrupt d i s c o n t i n u a t i o n a f t e r  t a k i n g t h e d r u g on a c h r o n i c b a s i s .  dose  depressant drugs w i l l  syndrome w h i c h i n c l u d e s a n x i e t y ,  and t h e r e  1/2  i s considerable  and w i t h i n a y e a r o f  considerably i n recent years,  benzodiazepines  is  its  H y p o t o n i a a l s o may  g a s t r i c d i s t u r b a n c e s and h a l l u c i n a t i o n s .  has dropped  patients  i s plasma p r o t e i n  when u s e d i n c o m b i n a t i o n w i t h  use r e s u l t s i n a w i t h d r a w a l  are s t i l l  Most o f t h e drug  o f l e a r n i n g and motor c o o r d i n a t i o n .  enhanced e f f e c t s  absorbed o r a l l y ,  In m u l t i p l e doses t h e r e  occur i n response to c l i n i c a l  tremors,  hours.  Well  problems which c o u l d a r i s e w i t h a s e d a t i v e  are d r o w s i n e s s and a t a x i a .  major  not monosynaptic  reports  chronic  insomnia,  popularity in hospitals  high s u i c i d e r i s k  Since the i n t r o d u c t i o n  is little  indication for i t s  in of  9  Hethagualone anticonvulsant, properties.  antispasmotic,  Antitussive  Tolerance  develops  effects.  In  is  (QUALUDE) a q u i n a z e - l i n e ,  absorbed  to  local  properties  in 2 hours,  are equivalent  causes f a t i g u e  hypnotic  doses i t  may c a u s e t r a n s i e n t  have been r e p o r t e d  somnambulism,  depressant  drugs.  methaqualone usual to  light  in dentistry,  Prior  to  and m a l o n i c a c i d ,  duration  of  its  though  it  dental  the  or years.  of  the  in fat.  for  in  peripheral  Excessive  it  a  belief  'high'  that the  similar  i t w o u l d be u n w i s e t o use as s u c h  other  without  gives effects  use  (5).  benzodiazepines,  the  barbiturates  Formed by a c o n d e n s a t i o n o f  on i t s own b a r b i t u r i c a c i d length alkyl  In  and  Residual  stem from the  Some f e e l  sedatives.  barbiturate  bound.  it  i s combined w i t h a l c o h o l o r  i s marketed  p a r t i c u l a r drug  Orally,  a r e common o c c u r r e n c e s .  abuse p o t e n t i a l ,  the marketing  different  Onset of  the  it  a s u l p h e r atom d e t e r m i n e s ,  of  solubility  when  drowsiness.  of  were t h e most p o p u l a r  absence of  l a s t months  i s an a p h r o d i s i a c w h i c h a l s o p r o v i d e s  In  Substitution  to  codeine.  behaviorial  depression.  paresthesias.  d r u g a b u s e seems t o  barbiturate-like  heroin.  this  Its  and  and o c c a s i o n a l l y d i z z i n e s s ,  and d r u g hangover  CNS d e p r e s s i o n i s p o t e n t i a t e d  antihistamine  those of  and becomes 7 0 - 9 0 % p l a s m a p r o t e i n  doses i t  dreaming,  to  anticonvulsant  causes myocardial  sedative  neuropathies  hypnotic,  a n a e s t h e t i c a n d weak  i t s depressant,  l a r g e doses i t  possesses  h a s no s e d a t i v e  c h a i n s , and t h e to  a great  effect.  presence  extent,  or  the onset  and  (6). effects  Thiopental,  brain rapidly causing C.N.S.  i s a l s o determined  which i s h i g h l y  lipid  d e p r e s s i o n and t h e n  by  its  soluble, is  urea  quickly  enters  10 distributed a short to other  to  the other  duration  Recovery  responsible for thiopental.  drug  action.  The  of  duration  degree of  effects.  In  i s predominant,  predominate.  result  secobarbital  it  of  i n the  the  i s reasonable  side chains at  of  b r a i n have  degree  unionized the  only  distributed  with  the  form of  ionized  inactive  replacement  C-5 a n d t h e  of  ionized  of  form.  sulpher with  removal  the  forms  t h a t the a l k a l i n i z a t i o n  the  been  is  than  a l s o has a b e a r i n g on  i n h i g h pH c o n d i t i o n s  i n the e x c r e t i o n  is  in  since metabolism  of a c t i o n to a greater  ionization  results  secobarbarbital  concentrations  M e t a b o l i s m i s a l s o e n h a n c e d by t h e the o x i d a t i o n  redistribution  l o w pH c o n d i t i o n s ,  while  Therefore  u r i n e would  peak  i s longer with  the  The  In c o n t r a s t ,  body t i s s u e s b e f o r e  reached.  duration  of  tissues.  o f methyl  oxygen, groups  a t N-3.  In inhibitory cortical  low doses b a r b i t u r a t e s  i n f l u e n c e of  activity.  intoxication. hypothalamus  An  reticular structures,  Clinically,  slowed,  and m e d u l l a r y  reflexes  respiratory  result  control.  resulting  uncontrolled  i s s i m i l a r to early i n depression of responsible for  In overdose  and d e a t h  in  of  situations,  results  ultimately  alcohol  the cardio-  respiration from  failure.  both m e t a b o l i c  Barbiturates  picture  centres which are  are absent  These drugs lead to  the  i n c r e a s e d dose w i l l  v a s c u l a r and r e s p i r a t o r y is  a c t by s e l e c t i v e r e m o v a l  will  have a h i g h abuse p o t e n t i a l and a d a p t i v e  cause the  tolerance,  i n d u c t i o n of  and  and c h r o n i c use  has  addiction.  hepatic microsomal  enzymes  11  responsible  for barbiturate  metabolism.  H o w e v e r t h e d r u g m u s t be  present f o r a s u f f i c i e n t time t o cause i n d u c t i o n . develops  to the adaptive  compensate  changes i n t h e nervous  f o r the drug e f f e c t s  exciteability.  Upon w i t h d r a w a l  Tolerance  system.  These  suffering  barbiturates  of barbituates  aggravate  an a b s t i n a n c e  acute attacks  from c o n g e n i t a l  porphyria.  Therapeutically  there  use o f b a r b i t u r a t e s ,  although  changes  by c a u s i n g a n i n c r e a s e i n n e u r o n a l  develops which i s s i m i l a r to that o c c u r r i n g with alcohol In a d d i t i o n ,  also  are s t i l l  their  several  syndrome  withdrawal.  in individuals  indications f o r the  i n d i c a t i o n s f o r use as day time  sedatives  and n i g h t  are s t i l l  used i n h o s p i t a l s f o r p r e m e d i c a t i o n p r i o r t o a n a e s t h e s i a ,  as  an a n t i c o n v u l s a n t  time s l e e p - i n d u c i n g agents  i n the treatment  a diagnostic a i d i n the practice of  Certain used w i t h oral  o f g r a n d mal e p i l e p s y ,  Hydroxyzine  h a s become p o p u l a r w i t h  or four  c a r r i e d o u t by t h e p a r e n t  well  prominant  have a l s o  paedodontic  practices.  It  hours,  it The  concentrations  so a d m i n i s t r a t i o n must be  i n advance.  (PHENERGAN)  sedative effects.  been  I t a l s o has a n t i e m e t i c and  i s d r o w s i n e s s , and peak p l a s m a  are not reached f o r three  Promethazine  effects  Due t o i t s w i d e m a r g i n o f s a f e t y  dentists with  m o s t common a d v e r s e e f f e c t  and as  (ATARAX), i s a v a i l a b l e f o r  and i n t r a m u s c u l a r a d m i n i s t r a t i o n . properties.  They  psychiatry.  sedatives with a n t i h i s t a m i n e  some s u c c e s s .  muscle r e l a x a n t  have d e c r e a s e d .  i s a powerful  antihistamine  i s a v a i l a b l e i n over  with  the counter  12  preparations,  and p a r e n t s o f t e n  their children. liable  A s i t i s a member o f t h e p h e n o t h i a z i n e  In d e n t i s t r y  potentiation  i s a problem w i t h  reduced dosage w i t h children,  this preparation.  I n a d d i t i o n , when u s e d w i t h  Since the c l i n i c a l  PHARMACOLOGY  i n t r o d u c t i o n of c h l o r d i a z e p o x i d e as  o v e r 2000 b e n z o d i a z e p i n e s  have been p r o d u c e d ,  been m a r k e t e d .  The t e r m b e n z o d i a z e p i n e  benzodiazepine,  as a l l C . N . S .  In p a r t i c u l a r , f o r t h o s e about  R-4.  Generally  in clinical  single  "Little  anxiolysis  group.  u s e , low e l e c t r o n density  exists  h a v e t h e same  qualitative  i n d u r a t i o n and q u a n t i t a t i v e  the pharmacological p r o f i l e o f any  different  from any o t h e r  i n approximately  the group,  : i . e . a l l produce  t h e same p r o p o r t i o n s "  possible to accentuate c e r t a i n e f f e c t s of  1-4  compound among t h e many now a v a i l a b l e t o t h e c l i n i c i a n ,  significantly  50 have  have t h e 5 a r y l  a l l benzodiazepines  evidance that  and about  refers to the 5, aryl  depressant types  and m e c h a n i s m s o f a c t i o n , b u t d i f f e r effects.  developed,  unexpectedly.  BENZODIAZEPINES-GENERAL  LIBRIUM,  Since  i t i s wise t o use a  s i n c e drug m e t a b o l i s m mechanisms a r e n o t f u l l y  d r u g o v e r d o s e may o c c u r  marketed  and m e p e r i d i n e .  this combination,  i t is  psychothera-  i t g a i n e d some p o p u l a r i t y when  (MEPERGAN), a c o m b i n a t i o n o f p r o m e t h a z i n e  Ill  group,  t o p r o d u c e s e r i o u s r e a c t i o n s when t a k e n w i t h o t h e r  peutic agents. as  use t h i s drug t o induce s l e e p i n  (7).  by a n a l y z i n g  is  sedation/  However,  i t is  the pharmacokinetics  e . g . t h o s e w i t h a l o n g T 1 / 2 c o u l d be u s e d w h e r e  prolonged e f f e c t s  such as daytime  a n x i o l y s i s a r e d e s i r a b l e , and t h o s e  13 with a short  T 1/2 u s e d w h e r e  short  term s e d a t i o n , o r hypnosis are  desired.  Ri  GENERAL BENZODIAZEPINE Theories  f o r binding sites  s u g g e s t e d by s e v e r a l stereospecific between of  STRUCTURE  people.  binding s i t e s ,  benzodiazepine suggested  theory  The a c t i v a t i o n  therapeutic  as an a m p l i f y i n g  Thus,  been  receptors  doses. acid  complex  of the benzodiazepine  c h a n g e i n t h e GABA r e c e p t o r  b y b l o c k i n g t h e a c t i o n s o f GABA m o d u l i n ; affinity.  have  a n d an e x c e l l e n t c o r r e l a t i o n h a s b e e n  r e c e p t o r - and c h l o r i d e i o n o p h o r e  (7).  i s that  t r i a d o f a gamma a m i n o b u t y r i c  produce a conformational  receptor  One c u r r e n t  b i n d i n g a f f i n i t i e s and average  a post-synaptic  affinity)  f o r the benzodiazepines  benzodiazepines  system which p o t e n t i a t e s  have shown  The e x i s t a n c e  (GABA)  receptor-  has been  receptor  would  (from low t o high  a p r o t e i n which  and t h e i r r e c e p t o r s  lowers  a r e viewed  GABA's i n h i b i t o r y e f f e c t s (8).  14  The w o r k o f  Squires et a l .  displaced  benzodiazepines  f r o m two  unable to  d i s t i n g u i s h between  and a n o t h e r  for  developed  for  an a n t a g o n i s t ,  benzodiazepines  yet  for  r e l a t e d to  with  little  of  the  same  theory  of  seems a r e a s o n a b l e o n e ,  to  the  different  s e d a t i v e and h y p n o t i c  are capable of anxiolysis,  depressant  different  developed  Ciba-Geigy  with  has  resemblance  These  also  to  observations  conformations  or  the  effects.  following central  muscle r e l a x a t i o n ,  of  epilespsy.  In  action exists.  neuromuscular  the  anaesthetics,  depressants.  The  however a t a g i v e n  the  Generally effects:  the case of  states  to  effects  the a t a x i c ,  the  muscle  sedation,  hypnosis,  activity  alprazolam,  intravenously  tolerance  benzodiazepines  in  the  a possible anti(i.v.)  in  v a s o d i l a t i o n , while i n high  low doses  result.  barbiturates,  a l c o h o l , other  benzodiazepines  benzodiazepines level  different  and a n t i c o n v u l s a n t  When g i v e n  b l o c k a d e may  Unlike  receptors for  p r o p e r t i e s more q u i c k l y t h a n does  d o s e s t h e r e may be m i l d c o r o n a r y  general  anticonvulsant  benzodiazepines  since tolerance develops  and a n t i - c o n v u l s a n t  treatment  theory  the  structural  was  receptor.  The  relaxant  Their  R o c h e Company  high receptor a f f i n i t y .  may be e x p l a i n e d by t h e e x i s t a n c e o f  diazepam  The  u s e a s an a n t a g o n i s t .  but w i t h  triazalopyradazine  whereas  a n x i o l y t i c and  sedative effects.  a compound w h i c h i s s t r u c t u r a l l y high receptor a f f i n i t y ,  binding s i t e s ,  t h e s e same two s i t e s .  s u g g e s t e d one b i n d i n g s i t e e x i s t e d effects,  ( 1 9 7 9 ) showed t h a t  act at  some members o f  are not all  sedatives general  levels of  the group  the  produce  and  neuronal neuraxis, more  15 effects for  than  others.  a l l members  level  although  of the neuraxis  indications  In any e f f e c t  the  cating doses,  result  profile  is similar  in selectivity at a particular  in variations  benzodiazepines,  f o r the c l i n i c a l  e . g . alprazolam  as an  (13).  on both  effects  patient  or i n a healthy  on t h e s e  patient  systems w i l l  the i n d i v i d u a l  Indirect  sedative/hypnotic  doses have  t h e c a r d i o v a s c u l a r and r e s p i r a t o r y  patient  be d i s c u s s e d w i t h  since  wili  the healthy  debilitated  pharmacological  some v a r i a t i o n  of the d i f f e r e n t  anti-depressant  if  The g e n e r a l  In  intoxi-  These e f f e c t s  will  drugs.  a c t i o n s on t h e g a s t r o i n t e s t i n a l  i t h a s b e e n shown t h a t  systems.  subjected to  vary.  little  in antianxiety  b e e n shown t o d e c r e a s e some g a s t r o i n t e s t i n a l  doses  t r a c t may o c c u r , benzodiazepines  disorders  in  have  nervous  patients.  PHARMACOKINETICS-ONSET AND DURATION  The numerous  pharmacokinetics  variables.  Administered  from t h e g a s t r o i n t e s t i n a l rate  of onset  system  of a c t i v i t y .  as i n t h e c a s e o f d i a z e p a m , bromazepam.  containing  (G.I.S.)  Absorption  absorption.  i s a major  of  absorption  determinant  of  as i n t h e case  by s l o w d i s i n t i g r a t i o n o f  i n the stomach.  by  o f some may be a s r a p i d a s 20 m i n .  and as s l o w as s i x hours  compounds  are determined  p e r os ( p . o . ) , t h e r a t e  E f f e c t s may be d e l a y e d  or the presence o f food aluminum  of the benzodiazepines  In a d d i t i o n ,  tablets,  the presence  i n t h e stomach reduces t h e r a t e  of  of  of  16  Given i n t r a m u s c u l a r l y  (i.m.),  the water  a r e more p r e d i c t a b l y a b s o r b e d t h a n n o n - w a t e r For  example,  lorazepam,  absorbed  i.m.,  surgical  procedures.  a water  and i s u s e d f o r  Given intravenously both  f o r water  and n o n - w a t e r  are w i t h i n minutes bind to with  the l i p i d  majority  a three  Generally,  the grey m a t t e r , vessel  rich  extent,  the  model the  is  organs,  anxiety  prior  the onset  i s most  predictable,  degree of  and v a r i a t i o n s All  model  For  i s proposed,  i s considered to  s u g g e s t e d model  d i s t r i b u t i o n determines  bromazepam a n d n i t r a z e p a m  but  resemble  s i n g l e dose d u r a t i o n  on  of  with  pharmacological  a subsequent  effects  (6).  surge  lipid  the  observed uptake  to  the white To a  matter, great  action.  diazepam,  circulation.  i s c o n s i d e r a b l e b i l i a r y s e c r e t i o n , f o l l o w e d hours  reabsorption,  onset  directly  for  m u s c l e , bone a n d f a t .  by e n t e r o h e p a t i c  in  the most  i s : a fast  there is a considerable e f f e c t  to  benzodiazepines  binding varies  p a r t i c u l a r drug.  plasma p r o t e i n s ,  predictably  of  s o l u b l e members,  The  benzodiazepines  benzodiazepines.  f o l l o w e d ' by a s l o w e r r e d i s t r i b u t i o n t o  Apparently  there  (i.v.),  compartment  a two c o m p a r t m e n t  drug p a t t e r n s .  treatment  f r o m one d r u g t o a n o t h e r .  s o l u b i l i t y of  soluble drugs,  soluble  soluble benzodiazepine the  human p l a s m a a l b u m i n .  soluble  Early later  i n plasma c o n c e n t r a t i o n  on, by and  17  METABOLISM AND ELIMINATION  U n l i k e most o t h e r the  benzodiazepines  Biotransformation and a c e t y l a t i o n place  phenyl  7-nitro  takes  conjugate.  medazepam  rapidly  the metabolite  Elderly slowly,  metabolites  with  therefore  appears  patients  takes  g l u c u r o n i d e being the major  have t r a c e amounts  are active  except  from t h e small  ring.  ring  metabolism  are the c h i e f conjugates  place i n the l i v e r ,  drug disappears  a t t h e benzo  Otherwise  --->, diazepam+oxazepam+.temazepam.  members t a k e s  and o n l y  Acetamides  a n d some t y p e s  Many n o n - c o n j u g a t e d  drugs,  p l a c e by n i t r o - r e d u c t i o n o f t h e benzo  o f the r e s u l t i n g amines.  compounds,  containing  are resistant to hydroxy!ation  at the 1 , 4 - d i a z e p i n e moiety,  resulting  o r benzo group  of  of the  sulfates.  i n themselves, e . g . Biotransformation  f o r flurazepam  f o r most  where t h e  intestine to the c i r c u l a t i o n  i n the urine.  metabolize  and e l i m i n a t e t h e drgus  t h e d r u g d o s e s h o u l d be a d j u s t e d  more  downwards  accordingly.  As a g r o u p  the benzodiazepines  enzyme s y n t h e s i s s i g n i f i c a n t l y . fluorazepam  are exceptions  ADVERSE  and these three  Others  diazepam and are capable o f  i n t h e group a r e n o t ( 6 ) .  EFFECTS At  adverse  Chlordiazepoxide,  however  i n d u c i n g t h e i r own m e t a b o l i s m .  do n o t i n d u c e m i c r o s o m a l  peak  effects  plasma c o n c e n t r a t i o n s ,  are: variations  t h e m o s t commonly  i n lightheadedness,  occuring  lassitude  18  i n c r e a s e d r e a c t i o n time t o s t i m u l i , psychomotor  functions.  a r e a l s o common. intensify  Confusion,  Alcohol  these e f f e c t s .  psychological  ataxia,  and i m p a i r e d mental and  amnesia, xerostomia,  and d y s a r t h r i a  or other  CNS d e p r e s s e n t s w i l l  p r o l o n g and  Although  uncommon,  a paradoxical  adverse  r e a c t i o n may o c c u r , t h e m e c h a n i s m o f w h i c h i s  unknown.  TOLERANCE Tolerance methaqualone  to benzodiazepines  and t h e b a r b i t u r a t e s ,  It  i s reasonable c l i n i c a l  in  some c a s e s ,  maintenance  of  the drug,  s i g n o f a need f o r i n c r e a s e d dose f o r  the b a r b i t u r a t e s ,  electroencephalographic  tolerance develops  (EEG) e f f e c t s .  Withdrawal  of  to benzodiazepines  c h r o n i c u s e h a s b e e n shown t o r e s u l t i n p o s s i b l e d e p r e s s i o n ,  anxiety  and a g i t a t i o n ,  dreams. return  p r a c t i c e to withdraw  effect.  As w i t h  after  and t o a l e s s e r extent t o a l c o h o l .  therapeutic  at the f i r s t  results i n cross-tolerance to  Less  often,  with  t h e accompaniment  o f abnormal  cases o f acute psychoses, d e l e r i u m ,  o f c o n v u l s i o n s have been  s l e e p and and t h e  reported.  EFFECTS ON S L E E P In t h e r a p e u t i c  hypnotic  doses t h e r e  l a t e n c y a n d an i n c r e a s e i n w a k e n i n g sleep are uniformly diazepam,  effected  flurazepam,  Not a l l s t a g e s  by a l l b e n z o d i a z e p i n e s .  and c h l o r d i a z e p o x i d e  sleep while  threshold.  i s a decrease i n sleep of  Oxazepam,  h a v e b e e n shown t o i n c r e a s e s t a g e 1  lorazepam,  nitrazepam  a n d temazepam  will  19  decrease t h i s  interval.  Stage  3 and 4 a r e d e c r e a s e d .  2 i s uniformly  A l l types  increased, while  stages  i n c r e a s e random e y e movement  (REM)  latency.  USE IN PREGNANCY  Because o f t h e r i s k o f t e r a t o g e n e s i s , benzodiazepines  i s n o t recommended  Benzodiazepines  have been used d u r i n g l a b o u r ,  hypothermia, Reportedly, withdrawal  DRUG  hypotonia,  benzodiazepines  i n the  that  d e p r e s s i o n may o c c u r . has r e s u l t e d i n a  may o c c u r .  Also,  elimination  have l i t t l e drugs,  there  doses i n  respiratory  effect,  respiratory  o f p e t i t mal e p i l e p s y . receptor antagonist  of  depression valproate  Valproate  When t a k e n  is in  such as  i s a d e l a y i n h e p a t i c m e t a b o l i s m and thus  of benzodiazepines,  benzodiazepines  therapeutic  t o cause p s y c h o t i c e p i s o d e s .  combination with a histamine (TAGAMET),  CNS d e p r e s s a n t s  i t i s p o s s i b l e f o r combinations  used f o r t r e a t m e n t  cimetidine  In normal  the aforementioned  and t h e b e n z o d i a z e p i n e s  system,  a l c o h o l and o t h e r  i n d i v i d u a l s benzodiazepines  a probability.  normally  d r u g i n t e r a c t i o n s may o c c u r when  a r e combined w i t h  b u t when c o m b i n e d w i t h  Where  the warnings  infant.  problems w i t h  drug p o t e n t i a t i o n  healthy  is  and m i l d r e s p i r a t o r y  with  pregnancy.  INTERACTIONS  Major  since  in the f i r s t trimester of  c a s e s o f c h r o n i c a b u s e by t h e m o t h e r syndrome  t h e use o f  r e s u l t i n g i n an enhanced  are metabolized  other  effect.  t h a n by t h e h e p a t i c  t h i s e l i m i n a t i o n problem i s not e x h i b i t e d .  20  IV  S P E C I F I C BENZODIAZEPINES  AND THEIR SEDATIVE USE IN  DENTISTRY  D i a z e p a m (VALIUM) was i n t r o d u c e d by t h e Roche company after  i t introduced  chlordiazepoxide  mainly  for i t s anti-anxiety  effect  w i t h minimal  mechanism.  (LIBRIUM).  effects.  D i a z e p a m was m a r k e t e d  T h e a i m was t o p r o d u c e a c a l m i n g  hypnosis and minimal  The p a t i e n t w o u l d s t i l l  reduction of the * f i g h t / f l i g h t '  be aware o f day t o d a y d a n g e r s ,  a n d be a b l e t o make t h e d e c i s i o n t o a v o i d t h e m ( 9 ) . was a l s o u s e d f o r i t s a n t i - c o n v u l s a n t The  anti-convulsant  phenobarbital will  effects  muscle r e l a x a n t meprobamate  and muscle r e l a x a n t  i n the reduction of generalized  anti-seizure  effect  effect  o c c u r s a t about  doses w i l l  In c l i n i c a l  With  intravenous  of  diazepam  doses, of  o n s e t and h a l f  vagal  life.  use i n r e p e t a t i v e  occur.  recognized  intravenous  doses, minor  administration  metabolites.  depressive  With t h e r a p e u t i c  doses  of  i n b l o o d p r e s s u r e and normal  acetylcholine, serotonin,  stimulation  A  the presence o f a c t i v e  a r e i n s i g n i f i c a n t changes  responses t o a d r e n a l i n e ,  i n plasma w i t h i n one  I n p r a c t i c e , t h e many v a r i a b l e s  on b l o o d p r e s s u r e have been n o t e d . there  peak  8-10 hours a f t e r  due t o d r u g r e d i s t r i b u t i o n a n d / o r  and c e n t r a l  i n that  o f diazepam a r e s u p e r i o r t o those  claims single oral  p r e v i o u s l y mentioned w i l l  diazepam  effects.  t h e s i g n i f i c a n t CNS d e p r e s s i o n c a u s e d b y  hour and r a p i d l y d e c l i n e o v e r 2 - 3 h o u r s .  effects  diazepam  (6).  Roche  rebound  seizures,  doses o f p h e n o b a r b i t a l .  properties  Later,  h a v e b e e n shown t o be s u p e r i o r t o t h o s e  reduce s e i z u r e s without  equivalent  shortly  carotid occlusion  21  CLINICAL  INDICATIONS  Being the f i r s t intravenously  in dentistry  rapid popularity reflexes will  with  procedure.  i s 15-45 minutes, will  Usually  This  exhibit  they r e c a l l  dentistry,  or periodontal  surgery  less  procedures  traumatic  when s e d a t i v e e f f e c t s  Clinically,  healthy  amount w i l l  adult  patients  doses  gained  protective  the r e a l i z a t i o n  that  i n i t s e l f a l l a y much a n x i e t y .  The  adult with  only  patient  after  intravenous  a mean o f a b o u t  30 m i n u t e s .  the l a t t e r  surgical  removal  i n patients  o f impacted t e e t h ,  crown and b r i d g e p r o c e d u r e s .  c o u l d be l e f t  f o r t h e end o f t h e  apical The  appointment  are diminishing.  t h e dosage used f o r t h e p a t i e n t (the V e r r i l l  sign),  vary from p a t i e n t  i s that  required  and a s l u r r i n g o f s p e e c h .  to patient,  b u t i n most  1 2 . 5 mg a d m i n i s t e r e d i n t r a v e n o u s l y  is sufficient.  LOCAL COMPLICATIONS  C o n s i d e r a b l e r e s e a r c h has been d e v o t e d thrombophlebitis. slowly  into  It  they  parts of the procedure.  c o u l d be p a r t i c u l a r l y u s e f u l  and l e n g t h y  produce marked p t o s i s exact  i n sedative  diazepam  a c e r t a i n degree o f amnesia r e g a r d i n g t h e  amnesic e f f e c t  r e q u i r i n g quadrant  administered  purposes,  F o r many p a t i e n t s ,  o f a c t i o n i n the average  Most p a t i e n t s  The  since  n o t be " p u t t o s l e e p " , w i l l  administration  anaesthetic  for anti-anxiety  dentists  are not obtunded.  duration  to  non-general  to the incidence of  h a s b e e n f o u n d t h a t when t h e d r u g  the veins of the ante-cubital  fossa there  i s injected  i s a decreased  22  risk of  of thrombophlebitis  the hand.  when c o m p a r e d t o i n j e c t i o n i n t o  In a d d i t i o n ,  use o f t h e i . v . d r i p  t e c h n i q u e when  t h e v e i n s o f t h e d o r s u m o f t h e hand h a s p r o v e n thrombophlebitis  over  Other l o c a l inadvertant  direct injection of  Properi .v.technique  injection  and knowledge  effective  in  hematoma,  avoiding  p h l e b i t i s , and  (at the ante-cubital  of local  injecting  diazepam.  complications include:  brachial artery  t h e dorsum  fossa)  anatomy i s i m p o r t a n t  (48).  in  a v o i d i n g these s e q u e l a e .  SYSTEMIC  COMPLICATIONS  In o r d e r t o a v o i d is  important.  Society  Suitable  patients  of Anaesthesiology  When t r e a t i n g  patients  systemic complications, patient  (ASA I ) ,  taking other  cardiovascular abnormalities alternative  methods  the manufacturer  before  on w e i g h t  numerous  the American  (ASA I I )  CNS a c t i n g d r u g s ,  categories.  o r those  with  abberations, (24,38).  dose f o r c h i l d r e n o v e r  and degree o f e x c i t e m e n t .  s u g g e s t s g i v i n g 2 - 5 mg p . o .  the  Shortly  and c e r t a i n  and t h o s e w i t h mental  intravenous  p r i o r t o the appointment minutes  f i t into  o f s e d a t i o n s h o u l d be s o u g h t  A suggested 2 - 1 0 mg d e p e n d i n g  generally  selection  before  two y e a r s  is  Alternatively,  r e t i r i n g the  night  and 5 - 1 0 m g , t a k e n on an empty s t o m a c h , 45  appointment.  after  diazepam  became a v a i l a b l e f o r u s e i n  papers appeared d i s c u s s i n g  the advantages  dentistry,  and d i s a d v a n t a g e s  -  of  i t s intravenous  use.  It  by i t s e l f a n d i n h e a l t h y for  conscious sedation  during oral studies  surgical  2  3  h a s b e e n shown t h a t  patients,  (10)."  i s not the only major  The o c c u r r e n c e o f c a r d i a c  p r o c e d u r e s has been d e m o n s t r a t e d  on c a r d i a c f u n c t i o n .  "no i n c i d e n c e o f v a s o v a g a l  In t h e i r s t u d y ,  or frank  syncopal  w h e r e a s two s u b j e c t s d u r i n g t h e c o n t r o l b r a d y c a r d i a and h y p o t e n s i o n  They a l s o d e m o n s t r a t e d  anxiety,  indication arrhythmias  by c o n d u c t i n g  H i l l m a n and M c F a l l reaction, with  10 m i n u t e s a f t e r  transient  intravenous  anaesthesia administration  c o n s i s t a n t l y l o w e r serum  i n sedated versus placebo treated  (10)".  17-hydrocorticosteroid  patients;  consistantly  l o w e r s y s t o l i c and d i a s t o l i c b l o o d p r e s s u r e s and a s t a b i l i z a t i o n respiration  i n sedated p a t i e n t s over  The level  with  surgical of  authors  patients.  the f o l l o w i n g reasoning.  A patient  about  t o undergo a  p r o c e d u r e i s bound t o e x p e r i e n c e some p s y c h o l o g i c a l m a n i f e s t i o n s  stress.  The a u t o n o m i c  nervous  s y s t e m comes i n t o p l a y w i t h  o f the sympathetic nervous  response.  Assuming the p a t i e n t  the parasympathetic loss  of  e x p l a i n the s i g n i f i c a n c e o f the drop i n s t e r o i d  activation  the  placebo  showed  sedation,  experience displayed  i n the f i r s t  p l a c e b o i n j e c t i o n and d u r i n g l o c a l  levels,  "preoperative  nervous  system,  parasympathetic i n t h e extreme  nervous  If  or  flight1  i s going to stay f o r the procedure,  system w i l l  continue to s t r i v e to  of e q u i l i b r i u m with the sympathetic  s i n c e gained dominance.  i . e . the ' f i g h t  the  vasovagal  nervous  retrieve  s y s t e m , which has  syncope o c c u r s , then the  s y s t e m has s u d d e n l y a c h i e v e d dominance.  c i r c u m s t a n c e may c a u s e d e a t h  (11).  This,  S i n c e p a t i e n t s who  had b e e n s e d a t e d d i s p l a y e d c o n s i s t a n t l y l o w e r c o r t i c o s t e r o i d l e v e l s a n d  24 l o w e r s y s t o l i c and d i a s t o l i c b l o o d p r e s s u r e s t h a n d i d patients,  T a g g a r d and H e d w o r t h y - W h i t e l y p r o p o s e t h a t t h e  e q u i l i b r i u m between in  the  t h e two n e r v o u s  sedated p a t i e n t .  which the is  patient  with  the  the  almost to  remains c o o p e r a t i v e ,  i s less ideal  the  of  study  intravenous  local  extraction.  response to  Goldstein,  point of  Dionne e t  d i a z e p a m and t h e  anaesthetic  in patients  S p e c i f i c a l l y t h e y were  psychological,  a l . , observed  i n c l u s i o n of undergoing  interested  plasma c a t e c h o l a m i n e ,  Cortisol  t h i r d molar e x t r a c t i o n s .  Whereas  third  i n the  significant  is  norepinephrine  change  i n c l u s i o n of  noted.  suggested  changes  The  the  that,  responsible for  diazepam without However  in a significant  nervous  the  sympathetic  nervous  They c o n c l u d e d t h a t  s y s t e m r e s p o n s e by  sympathetic  nervous  the  diazepam  system  c i r c u l a t o r y changes which o c c u r d u r i n g  the  system  i n s y s t o l i c p r e s s u r e and h e a r t  the  of  e p i n e p h r i n e would account f o r  response noted.  reductions  more t h a n j u s t the  of  p a r t i c i p a t i o n of  sympathetic  accompanying  patients,  and c a r d i a c o u t p u t w i t h i n m i n u t e s  direct effect  The  result  in  norepinephrine  rate or s y s t o l i c pressure.  e p i n e p h r i n e was shown t o  i n producing the  e l i m i n a t i o n of  indicate  heart  i n plasma e p i n e p h r i n e  injection.  without  i n the  non-sedated  molar  circulatory,  and l i p i d plasma  the  epinephrine  response i n sedated p a t i e n t s  increase  yet  anterograde  a b o l i s h e d the  the  in  sleeping,  i n the  increase  occur  a s one  i n c r e a s e d 60% d u r i n g s u r g e r y  the  of  l i k e l y to  state  and has an  loss  experience.  In a n o t h e r effects  systems  They p r o p o s e d  i s sedated,  easily aroused,  amnesic  unsedated  rate,  is  stress  25  situations Regarding  (12).  This  i s i n agreement  reported  This  that the elevated  would suggest  nonsedated  patients  sympathetic  neural  of local  significantly less  norepinephrine  activity  (12)."  For e t h i c a l  than the e f f e c t s  a n d s i n c e e v a l u a t i o n was made a t t h r e e  the  anaesthetic.  increase i n  reasons,  since the considerably spinephrine,  hours p o s t o p e r a t i v e l y ,  the  i n pain decided to  have been t r e a t e d w i t h o u t  local  surgery.  responses i n the  anaesthetic with  not wishing to leave t h e i r patients  group which would  during  epinephrine are of  of local  study.  "the pre-  anxiety  r e s u l t e d from an a n x i e t y - p r o d u c e d  anaesthetic without  shorter duration  authors,  the aforementioned  the psychological responses of the p a t i e n t s ,  medicated patients  effects  with  omit  s e d a t i o n and w i t h an  epinephrine  free  Therefore conclusions  epinephrine  e f f e c t s were based on s e d a t e d p a t i e n t s  regarding  only.  SHORT ACTING VERSUS LONG ACTING BENZODIAZEPINES  Whereas years  as t h e s e d a t i v e  development appeared  agent  o f numerous  has h e l d a prominant of choice, further  competitors.  Several  f o r t h e i n d i c a t i o n s and uses o f drugs  systematic in  diazepam  review of the benzodiazepines,  1980 s u g g e s t e d t h a t seven f a c t o r s  use i n t h e r a p y  (13).  p o s i t i o n f o r many r e s e a r c h has l e a d t o t h e  guidelines  have  i n the group.  the B r i t i s h Medical  i n s h o u l d be c o n s i d e r e d  In a Journal before  26  This to the  following  agents',  on t h e  of  2.  l o n g term e f f i c a c y  3.  residual effects  4.  p o s s i b l e dependence  5.  withdrawal  6.  e v a l u a t i o n of the pharmacological g e n e r a l p r a c t i c e and  7.  use i n the  The  committee  and  insomnia  of  therapy  daytime  sedation)  syndrome  exceeds  implications  10 h o u r s )  diazepam,  'short-acting  function,  properties  of  the  short-acting  properties  of  the  long-acting  rapid excretion  the  i n the  renal  accumulation  be a d v a n t a g e o u s  individual  term treatment  of  anxiety  of  drugs  as a n x i o l y t i c s  and h y p n o t i c s  p r i n c i p l e s (14).  drugs,  short-acting  short  of  impaired  over  the  group.  i n the  be u s e d i n t r e a t m e n t  and l a c k o f  group would  e f f i c a c y of  the drugs  agents'  temazepam.  i n t h e e l d e r l y and i n t h o s e w i t h  the  on  'long-acting  e.g.  and medazepam a n d  and  or hepatic  drugs  (particularly  drew a d i s t i n c t i o n between  lorazepam,  t h a t any o f  indications  elderly  chlordiazepoxide  Regarding  in a l l  symptoms  ( w h e r e p l a s m a T 1/2  pharmacological  attention  factors:  Particularly  the  M e d i c i n e s drew  anxiety  triazolam,  found  Review  1.  chlorazepate, e.g.  Committee  It  was n o t  dysmennorrhoea,  committee  group would  and i n s o m n i a . i s not  the  be  A rigid  based on  recommended depression,  effective division  sound that  these  tension  27  headaches,  psychotic i l l n e s s ,  children.  Indications  spasm,  symptomatic  for  o r i n the  the  treatment  use o f  anxiety  l o n g - a c t i n g agent"  of  or insomnia  were f o r  alcohol withdrawal,  night  in  muscular terrors,  and  somnambulism.  C o n s i d e r a b l e d i s c u s s i o n h a s b e e n r a i s e d on t h e of  the  benzodiazepines  treatment the  of  insomnia.  view that  (including loss  there  The  benzodiazepines)  of  use.  demonstrated  A loss  The  could  efficacy in anti-anxiety  conclusion of  will  This  i s not  not o c c u r .  tremor,  on t h e  half  be a s s h o r t  l i g h t of  'return'  treatment  study  addiction  symptoms including  after  the p a r t i c u l a r drug i n v o l v e d ,  of  as i s t h e c a s e w i t h  as i s the case w i t h it  (15).  (13) potential  abrupt  reportedly  do o c c u r . latency  short-acting  long-acting  benzodiazepines.  as i t would appear the p r e v i o u s drug  and i t s  drugs,  i s p o s s i b l e t o s e e why a p h y s i c i a n  and s h o u l d t h e r e f o r e  anxiety  are  anxiety,  life  t h e s e symptoms,  of  symptoms  also  these problems  is little  say t h a t  show  was  there  nausea and v o m i t i n g  would r e p r e s c r i b e the d r u g ,  the  to  Indeed  a s 24 h o u r s ,  had b e e n a p p r o p r i a t e  there  hold  hypnotics,  studies  ataxia,  and as l o n g as t h r e e d a y s , In  patients with  the  o v e r a few weeks/  the B r i t i s h Medical Journal  d e s p i t e media r e p o r t s  apprehension, Depending  sleep latency,  in  (FDA-USA)  t h ° l o n g term use o f  s i n c e most s l e e p l a b o r a t o r y  prescriptions for  benzodiazepines.  withdrawal  support  when t h e s e d r u g s w e r e u s e d c h r o n i c a l l y , y e t  continued repeat  stated that  to  reduction of of  a few months  Food and Drug A d m i n i s t r a t i o n  is l i t t l e  of e f f i c a c y i n the  months  to  when u s e d o v e r a p e r i o d o f  effectiveness  regimen  be c o n t i n u e d i n o r d e r t o  manifestations.  avoid  28  LONG-ACTING  BENZODIAZEPINES  Chlordiazepoxide treatment half  (LIBRIUM) i s p r e s e n t l y used f o r  and a l c o h o l w i t h d r a w a l  as potent  has a h a l f  a n d i s c o n s i d e r e d t o be a p p r o x i m a t e l y  a s e d a t i v e as diazepam.  life  o f 12-28 h o u r s ,  While chlordiazepoxide  l i v e r disease i s relevant  metabolites:  desmethylchlordiazepoxide,  of  The l a t t e r  5-15 hours.  not well  b e c a u s e o f i t s numerous demoxepam,  desmethyldiazepam  Desmethyldiazepam  reportedly  has a h a l f  l i v e r disease.  i t i s usually given  Unlike  diazepam,  anaesthetic adjunct available for oral  About 1/3 as p o t e n t  I t s u s e f u l n e s s as an  has n o t been d e m o n s t r a t e d administration  i n the treatment  and does  i t h a s n o t b e e n shown t o r e a c t w i t h t h e  since i t i s only  (17).  Another l o n g - a c t i n g agent,  to  and a l c o h o l  i n d o s e s o f 3 0 - 6 0 mg f o r a n t i -  drug c i m e t i d i n e , nor with d i s u l f i r a m .  indicated  i t  should not  I t does n o t have a c t i v e m e t a b o l i t e s  not accumulate i n p a t i e n t s w i t h  anxiety.  of  route.  treatment.  as d i a z e p a m ,  life  W h i l e a b s o r p t i o n i s good o r a l l y ,  Oxazepam (SERAX) i s a l s o u s e d f o r a n t i a n x i e t y withdrawal  life  absorbed i n t r a m u s c u l a r l y and c h l o r d i a z e p o x i d e  be g i v e n by t h a t  active  i s m a r k e t e d a s (SERAX) and has a h a l f  e l i m i n a t i o n o f up t o 120 h o u r s . is  itself  the p o s s i b i l i t y of accumulation i n the  patient with  and o x a z e p a m .  antianxiety  of anxiety  chlorazepate  (TRANXENE)  and a l c o h o l w i t h d r a w a l .  is Due  r a p i d d e c a r b o x y l a t i o n o f t h e compound i n t h e s t o m a c h , t h e d r u g  29  is  absorbed as desmethyldiazepam.  in  30-60 minutes,  metabolite effects ation  the e f f e c t s  Because c h l o r a z e p a t e  a r e l i k e l y due i n s t e a d t o t h i s  w h i c h has a plasma h a l f  i n c r e a s e over  life  two t o t h r e e  reaction with alcohol  levels  o f about  peak  active  50-120 hours  since  days o f c o n t i n u e d u s e . The p o t e n t i -  appears  t o be c o n s i d e r a b l e .  The e f f e c t s  of motor impairment  seem p a r t i c u l a r l y s e v e r e a n d l a s t f o r d a y s .  therefore  use i n  of l i t t l e  It i s  dentistry.  SHORT-ACTING AGENTS  Some o f t h e more common s h o r t - a c t i n g a g e n t s lorazepam,  temazepam,  triazolam,  and h a l a z e p a m .  by t h e d r u g c o m p a n i e s h a v e e m p h a s i z e d agents.  However r e s e a r c h c o n t i n u e s  applicable  t h a n was o r i g i n a l l y  of anxiety  as an a d j u n c t as p o t e n t  only.  to general  a sedative  and has d e m o n s t r a t e d  Marketing  some e f f e c t s  of  t o show them t o be more  strategies these widely  thought.  Lorazepam (ATIVAN), treatment  only  i n use a r e  was i n i t i a l l y  In r e c e n t y e a r s  anaesthesia.  as diazepam,  introduced f o r the i t has r i s e n i n  C o n s i d e r e d t o be a b o u t  i t h a s no a c t i v e  no a c c u m u l a t i o n i n p a t i e n t s  The W y e t h C o . p r e s e n t l y m a r k e t s  popularity  the drug  i n three  1.  tablets  for oral  2.  tablets  for sublingual  3.  i n suspension f o r intramuscular or administration.  five  times  metabolities,  with  liver  forms  disease.  for administration:  administration a d m i n i s t r a t i o n and intravenous  30  When a d m i n i s t e r e d tration  achieved  intramuscular an h o u r . (18).  administration. it  than  introduction  preparation gually  takes  lorazepam,  and p r e d i c t a b l e the  i s claimed to  Orally,  For  sublingually,  of  would  provides  be e q u i v a l e n t The  about  peak  agents,  analgesies,  and  Due walls  of  effects,  effects  to  less  be 1 2 - 1 5  This  contrasts  with  somewhat  since waiting is  Properly  usually  not  atropine  diazepam  peak  rapid  However s i n c e  pain of  an  with  sulphate,  diazepam.  to  diazepam,  the  the  the  i.m.  sublin-  injection.  general narcotic  practical  15 m i n u t e s  prior  feasible  i n most  onset  Because of  this,  relatively  of  antianxiety  is administration  the  use i n local  office  procedure.  within  long onset  intravenous  on  be  surgical/dental  peak e f f e c t s  dental  the  pain  and i n t r a m u s c u l a r l y  to administering general  incidence of  Clinical  anticipated  The  irritates  h a s b e e n shown t o  which provides  intravenously. its  lorazepam  (19).  intravenously  prior  limits  diluted,  and p h l e b i t i s ,  than w i t h  minutes  when g i v e n  lorazepam  reach the  lorazepam  be c o m p a t a b l e  i n s o l u b i l i t y in water,  than w i t h  longer  must  minutes  its  when a d m i n i s t e r e d  considerably  the  about  antiemetics.  thrombophlebitis  consistantly  to  a v a i l a b i l i t y of  without  via  occurs in  i s f a r more  as a d m i n i s t e r i n g  muscle r e l a x a n t s ,  blood v e s s e l s .  injection,  the  concen-  that achieved  and c h l o r d i a z e p o x i d e .  L o r a z e p a m h a s been shown t o anaesthetic  plasma  concentration  tablets,  seem r e d u n d a n t ,  equivalent  to  intramuscularly  diazepam  sublingual  peak  an h o u r and a h a l f  absorption for  the  2-3  of dentistry  anaesthetic  situations.  In  31  teaching s i t u a t i o n s , or  i n some s u r g i c a l  t h i r d molar e x t r a c t i o n s ,  Interestingly, used l a r g e d o s e s .  Due t o  the  is  time.  d i f f i c u l t to  manufacturer  This  lorazepam  i s more f e a s i b l e .  most r e s e a r c h w i t h  intravenous  prolonged recovery  time,  t h a t a d m i n i s t r a t i o n be up t o recovery  use o f  s i t u a t i o n s such as m u l t i p l e  two h o u r s p r i o r t o  lorazepam  Wyeth h a s  surgery,  admits that only  for  to  upper ends o f  recovery  2 - 4 mg i v ,  tested.  A danger e x i s t s w i t h the form s i n c e o p e r a t o r s  administration of  accustomed to the f a s t onset of  s u f f i c i e n t time to assess the e f f e c t s  administer additional  drug.  Since the  lack of  could  instead  the drug i n diazepam  of  to administer a d d i t i o n a l  Regarding the  the amnesic e f f e c t s of  higher therapeutic  recall  doses,  e n t e r i n g the s u r g i c a l  o r e n t e r i n g the  declines  for  i n about  20% o f  it  about  two m i n u t e s 30 m i n u t e s .  patients  after This  treated with  be  especially at patients  the e n t i r e procedure  Compared w i t h  and  overdose.  lorazepam,  has been found t h a t  theatre,  recovery area.  amnesia peaks about  d r u g r e s u l t i n g i n an  this  clinical  r e s p o n s e c o u l d mask i t s e l f a s l a c k o f e f f i c a c y t h e o p e r a t o r may tempted  of  could  lorazepam  immediate  it  have  time  t h e d o s e was a l s o r e d u c e d , e . g .  0 . 5 m g s h o u l d be  as  The  recommended d o s e s  be c o n s i d e r a b l y r e d u c e d i f  to wait  minimize  two h o u r s r e c o v e r y t i m e .  been c o n s i s t a n t l y s t u d i e d , and t h e y b e l i e v e t h a t  fail  suggested  a l s o would p r e s e n t a problem i n d e n t i s t r y  hold a patient  has  diazepam  not  itself  i.v.,patient  a d m i n i s t r a t i o n and h a s b e e n shown t o  do  steadily  be t h e  diazepam versus 80-90%  case of  32  patients  treated with  lorazepam  c o u l d be a c o n s i d e r a b l e  benefit  of  alone.  the dental  procedure  (20). if  Lorazepam,1 i k e diazepam patients, the  respiratory  tions the  has l i t t l e  least  other  system.  two  bound,  plasma p r o t e i n  Due t o advisable to  c o u l d be c o n f i n e d t o  its  the  d o s e s r e a c h peak p l a s m a  lorazepam  first  The  Its  potentiation  only absolute  than  known  h y p e r s e n s i t i v i t i e s to other  acute narrow angle glaucoma,  seems t o  effects  long onset  be somewhat  less  concentrahour,  since  at  W h i l e 85% i s  with  a  narcotic analgesics i t  contraindications for  scopolamine, are  and i n p a t i e n t s  with  are s i m i l a r to  lorazepam,  than with  with  in patients a primary  with  depressive  gravis.  those occuring with  t i m e when t a k e n o r a l l y ,  is  combination  in patients  benzodiazepines,  pronounced  glucuronide  effect.  d i s o r d e r o r p s y c h o s i s , and i n t h o s e w i t h m y a s t h e n i a  Adverse  or  d o s e s i n one  main m e t a b o l i t e ,  or accumulation  i n combination with  recall  does n o t a p p r e c i a b l y d i s p l a c e most  bound d r u g s . central  20 m i n u t e s .  recall  healthy  on t h e c a r d i o v a s c u l a r  h o u r s and s u b l i n g u a l  other  the  the  doses i n  r e d u c e d r u g d o s e s when n a r c o t i c s a r e u s e d i n  lorazepam.  Because of  lack of  r o u t e may h a v e c o n s i d e r a b l e u s e i n d e n t i s t r y  h a s no d e m o n s t r a b l e  with  to  additional  in therapeutic  While oral  50% i s a b s o r b e d w i t h i n  plasma p r o t e i n  it  appreciable effect  i n one and a h a l f  sublingual  The  the abuse  diazepam.  diazepam. potential  TABLE 1 (17)  GENERIC NAME  DIAZEPAM  FLURAZEPAM  LORAZEPAM  OXAZEPAM  TRIAZOLAM  TRADE NAME  VALIUM  DALMANE  ATIVAN  SERAX  HALCION  PRESENT USES  -anticonvulsant "hyPnotic  -antianxiety - a l c o h o l withdrawal  -muscle r e l a x a n t  - a n a e s t h e t i c adjunct  -antianxiety -alcohol  -hypnotic  withdrawal  -antianxiety PATHWAY OF METABOLISM  CATEGORY OF ELIMINATION  -oxidation  oxidation  conjugation  conjugation  oxidation  -long  -long  -short  -short  -ultra-short  -diazepam (24-28)  -desalkylflurazepam  -lorazepam(9-25)  -oxazepam (5-15)  - t r i a z o l a m (2-3)  HALF-LIFE T 1/2 PARENT & METABOLITES (HOURS)  -desmethyldiazepam (50-120) -temazepam  (9.5-12.5)  -oxazepam (5-15)  (47-100)  34  V  A P P L I C A T I O N OF NEWER BENZODIAZEPINES  The  recent  administration recall of  i n t r o d u c t i o n o f lorazepam t a b l e t s  h a s b e e n shown t o " p r o d u c e a c l i n i c a l l y  the p e r i o d before that  (21)".  the operation  lorazepam  Gale,  useful  impairs retrieval  Galloon  i m p a i r m e n t o f memory recall  input  lack  memories  recall  i n contrast  by c a u s i n g  on t h e c o n s o l i d a t i o n p r o c e s s by a f f e c t i n g  and r e c o g n i t i o n e q u a l l y .  This  a m n e s i c e f f e c t was a l s o  demonstrated  t o be more p r o f o u n d when l o r a z e p a m was a d m i n i s t e r e d  sublingually  than  follows not than  available.  A suitable explanation  Since absorption  intramuscular route,  a painful for  i n t r a m u s c u l a r l y a l t h o u g h a b s o r p t i o n by b o t h  similar patterns.  of  and P o r t e r  of information  d i a z e p a m w h i c h h a s b e e n shown i n s t e a d t o a f f e c t  both  for sublingual  f o r t h o s e p a t i e n t s who m i g h t o t h e r w i s e h a v e u n p l e a s a n t  demonstrated to  FOR DENTAL USE  routes  f o r t h i s phenomena i s  i s s l i g h t l y more r a p i d by s u b l i n g u a l  t h e added advantage  of not administering  i n j e c t i o n w o u l d seem t o i n d i c a t e l i t t l e  i n t r a m u s c u l a r use i n d e n t i s t r y ,  i f any i n d i c a t i o n  e x c e p t on a h o s p i t a l  out-patient  basis.  Another benzodiazepine  w h i c h has demonstrated  a b s o r p t i o n when a d m i n i s t e r e d i n t r a m u s c u l a r l y i s (ROHYPNOL).  predictable  flunitrazepam  I t may a l s o be a d m i n i s t e r e d i . v . o r p . o . N e v e r t h e l e s s ,  c o m p a r e d w i t h o t h e r more commonly  u s e d members o f t h e g r o u p ,  f l u n i t r a z e p a m was f o u n d t o be s u p e r i o r i n s e v e r a l a s p e c t s . associated with children  less  post-operative  flunitrazepam  vomiting than diazepam.  h a s b e e n shown t o p r e v e n t  oral I t was In  fasciculations  when  35  c a u s e d by s u x a m e t h o n i u m more e f f e c t i v e l y t h a n d i a z e p a m regard to  sedation in equipotent  induction.  be s u p e r i o r ,  demonstrated  with  with diazepam, in equipotent a b o u t 85% o f  (23).  the p a t i e n t s  at a l l .  The  water  Ataxia  with  flunitrazepam  walls.  t o diazepam patient  will  It  for  intravenous  start  remember t h e l o c a l  l a t e r most p a t i e n t s immediately a f t e r  compared  administration, of  the  procedure  anaesthetic  25% h a d  could not  recovered remember  t h e p r o c e d u r e was  arm p a i n a n d t h r o m b o p h l e b i t i s was (23).  This  i s considered to  the  somewhat  and i t s l e s s  need an e s c o r t i n e i t h e r  the high incidence of numerous  less  be due t o  irritating effect  is a viable  the  on  alternative  sedation purposes i n d e n t i s t r y .  use o f d i a z e p a m ,  attempt to c o n t r o l  the  T h i r t y mintues a f t e r ,  flunitrazepam  intravenous  Regarding the  via intravenous  would appear f l u n i t r a z e p a m  still  diazepam.  flunitrazepam.  incidence of  s o l u b i l i t y of  vessel  could not  to  Regarding  f l u n i t r a z e p a m was  Forty minutes a f t e r  a n d one week  more p r o n o u n c e d w i t h  frequent  soluble drug,  for either drug.  procedures  situation.  l o r a z e p a m and  soluble benzodiazepine,  a non-water  i n each group,  to  i n c i d e n c e o f h e a d a c h e was  flunitrazepam over  does  prior  found  R e g a r d i n g a n x i o l y s i s , d i a z e p a m was shown  a reduction i n the  A water  injection  in patients  u s i n g h i g h e r doses i n a s i m i l a r  adverse e f f e c t s ,  With  o r a l d o s e s , f l u n i t r a z e p a m was  t o be s u p e r i o r t o d i a z e p a m a n d f l u r a z e p a m anaesthetic  (22).  The  case.  t h r o m b o t i c phenomena  with  s t u d i e s h a v e b e e n made  or e l i m i n a t e the problem (24).  Until  recently  in the  36  drug has o n l y glycol  been a v a i l a b l e o n l y  diazepam  i n such s o l v e n t s as propylene  i s insoluble i n water.  Propylene  g l y c o l has  b e e n shown t o p r o d u c e m o t o r i n c o o r d i n a t i o n , d e p r e s s i o n o f m o s t reflexes  and a t a x i a  developed  (25).  i n the 1970's.  A new s o l v e n t  for lipid  s o l u b l e d r u g s was  The a c t i v e s u b s t a n c e was d i s s o l v e d i n s o y a  bean o i l and t h e n e m u l s i f i e d i n w a t e r .  I n 1981 K a b i V i t r u m  t h e d i a z e p a m e m u l s i o n (DIAZEMULS TM) i n t h e U n i t e d pharmacokinetic  and pharmacodynamic  t o have a h i g h e r m a r g i n o f s a f e t y  Kingdom.  s t u d i e s showed t h i s  than  an a q u e o u s  introduced Comparative  diazepam  preparation  of  w h i l e plasma c o n c e n t r a t i o n s and e l i m i n a t i o n k i n e t i c s f o r both similar. of  adverse e f f e c t s  feature of  The m a j o r  of this  d i f f e r e n c e s were such as p a i n ,  formulation  and t h r o m b o p h l e b i t i s .  in that  (VALIUM).  T h e t i s s u e a l s o seems t o r e t u r n  under c i r c u m s t a n c e s o f e x t r a v a s a t i o n  diazepam.  This  with  s t u d y was c a r r i e d o u t u s i n g v e i n s  as i t i s h i g h l y  l i k e l y t o have t h r o m b o t i c  a d m i n i s t r a t i o n o f (VALIUM) t h r o u g h  Clinically, it  t h e t i s s u e changes d i f f e r  infusion from  (VALIUM). The widespread  does n o t o c c u r , and p a i n on i n j e c t i o n i s l e s s w i t h  than w i t h quickly  An i n t e r e s t i n g  i s not raised s i g n i f i c a n t l y a t the i n j e c t i o n s i t e ,  bruising  diazepam,  decreased incidence  seen under s i m i l a r c i r c u m s t a n c e s w i t h diazepam  tissue  fossa,  the g r e a t l y  emulsion  were  has been s e e n t o o c c u r on a c c i d e n t a l  the s o l u t i o n extravenously,  those  synaptic  (DIAZEMULS)  t o normal  (DIAZEMULS)  more than  with  i n the a n t i - c u b i t a l phenomena  occur  during  a v e i n i n t h e dorsum o f t h e hand ( 4 8 ) .  because o f the decreased v i s c o s i t y o f  i s n e c e s s a r y t o i n j e c t more s l o w l y ,  (DIAZEMULS),  as t h e s o l u t i o n e n t e r s  the vein  37  with  considerably less  r e s i s t a n c e than  W h i l e one o f t h e m a j o r the problem o f thrombophlebotic  (VALIUM)  (25)  problems o f i . v . diazepam, phenomena,  h a s c e n t r e d upon t h e u s e o f w a t e r  soluble  much r e c e n t  sequlae than diazepam  a p p r o a c h has been t o s t u d y  a "short  avoid the incidence of local  while proving prolonged  successful i n the l a t t e r  recovery  desireable,  time.  r e c o n s t r u c t i o n where a p p o i n t m e n t s w o u l d be a v i a b l e a l t e r n a t i v e appears  t i t r a t i o n would  be o f u t m o s t  Another water (HYPNOVAL) soluble  i t s shorter duration  Chemically, in  increasing recovery  factor,  flunitrazepam  of teeth  for full  may l a s t s e v e r a l  a sedative  structure,  time,  Unfortunatley,  longer duration  has a  of effects  is  mouth  hours,  then  Intravenously as diazepam,  soluble benzodiazepine,  this  flunitrazepam so c a r e f u l  midazolam  i s receiving considerable attention.  benzodiazepines,  Another  importance.  Like  O f p e r h a p s more i n t e r e s t  o f a c t i o n and s h o r t e r  recovery  when c o m p a r e d t o d i a z e p a m ,  a r e an i m i d a z o l e  ring substitution,  maleate  the other  t h i s a l s o shows e x c e l l e n t l o c a l  when i n j e c t i o n i n t r a v e n o u s l y . is  (VALIUM).  (28)."  to diazepam.  t o be 15 t i m e s a s p o t e n t  (ROHYPNOL) h a s shown  effects  In c a s e s where  e . g . i n the preparation  research  a c t i n g d r u g w h i c h c a n be r e i n j e c t e d  i n measured increments as r e q u i r e d , w i t h o u t and s t i l l  of  benzodiazepines.  As was m e n t i o n e d e a r l i e r , f l u n i t r a z e p a m incidence of local  has been  and t h e i n t r o d u c t i o n  (DIAZEMULS) h a s shown t o be a v i a b l e a l t e r n a t i v e ,  less  (27).  water  tolerance in  dentistry,  time.  the s a l i e n t  differences  i n midazolam,  38  which accounts f o r i t s increased water substitution it  solubility.  A  fluoride  i s responsible f o r the increased potency.  i s buffered  In s o l u t i o n ,  t o a pH o f 3 . 3 t o m a i n t a i n t h e b e n z o d i a z e p i n e  i n t h e open p o s i t i o n  ring  (29).  DIAGRAMME 2  Diazepam  Midazolam  is still  Because of the a c i d i c  Midazolam  largely  i n the experimental  pH o f m i d a z o l a m  solutions, alkaline  s h o u l d n o t be a d m i n i s t e r e d c o n c o m i t a n t l y . water  soluble,  (VALIUM)  the burning  i s not present  Biotransformation takes  place i n the l i v e r .  none o f w h i c h a r e a c t i v e . the  'second peak'  effect  Since midazolam  sensation experienced with  during  intravenous  of midazolam,  noted w i t h  solutions is  diazepam  injection.  first  Three m e t a b o l i t e s Midazolam  stage.  hydroxy!ation,  have been  therefore diazepam,  by  fails  to  identified, exhibit  because o f i t s l a c k  39  of a c t i v e metabolites half  life  and e n t e r o h e p a t i c  of midazolam  i s i n the  diazepam which i s over  24 h o u r s .  94% p l a s m a p r o t e i n  bound,  the  range  volume o f  has been d e m o n s t r a t e d .  i n d u c t i o n times range  to  determine  the  it  was f o u n d  that there  safety this  between margin  in clinical  Generally  i s a common d o s e - r e s p o n s e  situation.  96% o f  and m i d a z o l a m  patients  would  anterograde  amnesia  of  its  High  prove  useful  is effective  In  single intravenous i n the  drug  This  two m i n u t e s ,  doses,  would account  speaking,  tests  dose-response  for  for  its  benzodiazepines  treatment  of  i n producing these.  anxious  In one  a n d 57% a t 43  study  minutes.  i s s u p e r i o r t o diazepam and l o r a z e p a m ,  for  (31).  in patients  with  r a p i d a c t i o n and modest e f f e c t s  a potential  problem w i t h  to diazepam,  ischemic heart on haemodynamic  i n d u c t i o n d o s e s may r e s u l t i n t r a n s i e n t  hypotension,  hypoglycemic  general  two m i n u t e s .  Having s i m i l a r c a r d i o v a s c u l a r e f f e c t s possibly  great  nor of  induction of  are d e s i r a b l e i n the  showed a m n e s i a a t  indicate i t  the  difference  use.  patients,  approximately  anticoagulants  f r o m one t o  10 mg a n d 15 mg.  Amnesic e f f e c t s  This  for  sleep after  was l i t t l e  doses o f  is  to  safety.  anaesthesia,  effects  plasma  as compared  d i s t r i b u t i o n i s so  oral  In s t u d i e s u s i n g m i d a z o l a m  of  The  Both these q u a l i t i e s i n d i c a t e the  s h o u l d have a wide m a r g i n o f  duration  1.7-2.4 hours,  While midazolam  t h a t no s i g n i f i c a n t d i s p l a c e m e n t o f agents  c i r c u l a t i o n (30).  disease  may  "because  parameters"  hypotension.  hypovolemic  it  patients  The may  be  (29).  40  related  to  the p o o l i n g of  blood i n the  When u s e d as a g e n e r a l episodes of episodes the  apnea o c c u r but  anaesthetic  these are not  are s i g n i f i c a n t l y s h o r t e r than  use o f  thiopental  the  produced a f a s t e r first  irritation,  hour o f  hydroxyzine  atropine,  was f o u n d  dose r e l a t e d .  those  transient  However s u c h  known t o t a k e  premedicants,  and  place  with  hydroxyzine  concluded  o n s e t and s u p e r i o r a n x i o l y t i c  treatment.  and w i d e r p a t i e n t  than w i t h  induction agent,  w h i c h compared midazolam  (ATARAX) a s i n t r a m u s c u l a r s e d a t i v e midazolam  bed.  (29).  Another study,  over  splanchnic vascular  (32).  More a m n e s i c e f f e c t s ,  that effects  less  a c c e p t a n c e was r e p o r t e d w i t h The  a d d i t i o n of  t o enhance the  sedative  hyoscine,  but  local  midazolam not  c a p a b i l i t i e s of  both  drugs.  It water  would appear  s o l u b i l i t y , short  systemic e f f e c t s , sedative  half  may i n t h e  have  lives,  l a b e l l e d midazolam,  acting agents. hydroxylation blood.  future  the c o n t i n u i n g e f f o r t  their elimination half  (33)  life,  that  midazolam w i t h  and low i n c i d e n c e o f become an i m p o r t a n t  its  increased  local  and  drug f o r  dental  treatment.  In to  therefore,  Their to  the  pathways  highly  c l a s s i f y these drugs  Greenblatt,  triazolam,  Di v o l 1,  according  Abernathy  and b r o t i z o l a m  of metabolism involve  a glucuronide,  While with  to  as  et  al.  ultra-short  oxidation  and  a n d no a c t i v e s u b s t a n c e s r e m a i n i n  lipid  s o l u b l e d r u g s s u c h as d i a z e p a m ,  the half  41  life  of  e l i m i n a t i o n may be a l m o s t  a c t i o n due t o t h e a c t i n g agents termination  drug  tablets  it  duration  the  lack of short  (HALCION),  the treatment  of  duration  insomnia.  of  the  habituation  day a f t e r  of  insomniacs'  other  reasonable to  believe that  would  minimal to  the  peak  after lack of  hepatic  the  flunitrazepam  effects  in  better  induction,  than  i n i n s o m n i a c s h a s shown t h a t occur over  and p s y c h o m o t o r  h a s shown t h e  period  performances  insomnia.  It  i n the anxiety  prone  patient,  and  effects  seen w i t h  i n 1-2 hours  Greenblatt  Elimination  al  feel  this  capacity i n e l d e r l y i n d i v i d u a l s together (33).  This  i n the  In t h e e l d e r l y an et  would m a n i f e s t  have  longer-acting agents,  When t a k e n o r a l l y t r i a z o l a m  hours. (33).  the  due  reaches  healthy  exagerated  i s due t o a  with  when  seems  sedative effects  active metabolites.  no  least residual effects  used f o r  low end o f  a t w e l v e month  dose  o c c u r s i n 2-4  in mg  hypnotic  normally  be  drugs.  usual  blood flow  the  i s believed to  the  r e s p o n s e has been n o t e d . oxidizing  short  i n 0 . 2 5 mg o r 0 . 5  is little  cognitive  benzodiazepines  plasma c o n c e n t r a t i o n  individual  of  non-insomniac.  triazolam  using triazolam  that  i t s hypnotic  orally  Triazolam  or tolerance  compared w i t h  produce  tissues, in  a c t i o n i n t h e s e new  be s u p e r i o r t o  i n the  Long t e r m use o f  Monitoring  of  Administered  sleep.  placebo i n these e f f e c t s  (34).  the duration  as r e d i s t r i b u t i o n i n  active metabolites  h a s b e e n shown t o  for  peripheral  has been used m a i n l y f o r  and q u a l i t y  tendancy  to  action.  is this  responsible for Triazolam  rapid r e d i s t r i b u t i o n to  e l i m i n a t i o n may be a s i m p o r t a n t  of  It  inconsequential  reduced  reduced  as an i n c r e a s e i n  systemic  42  availability increase  and s u b s e q u e n t l y  an i n c r e a s e i n h a l f - l i f e .  i n s y s t e m i c a v a i l a b i l i t y h a s b e e n n o t e d when t a k e n  with cimetidine or i s o n i a z i d . hepatic disease, availability  it  present  p o s s i b i l i t y of  the  for  '  using the  day-time  often  than  p r i o r to  with  only  for  sedative  triazolam  the  w o u l d seem t o  bio-  the  treatment  half  life  effect  sedative  and l a c k  and  explore  of  anxiolytic  patients'  lack  a c t i n g agents  the  night  sleep.  the  treatment.  For night  The  (36).  prior  to  The  p r i o r to  should  an  less  elective  dental  dental  triazolam  conclusion  e f f e c t s w e r e more  the nervous  of  procedures.  i n h o s p i t a l when g i v e n  or a placebo  lorazepam.  triazolam  be s u i t a b l e  and t h e  had r e d u c e d s l e e p l a t e n c y a n d w o r k  flurazepam  than with  the a d m i n i s t r a t i o n of  for  use p r i o r to d e n t a l  that patients  surgery,  those taking  improved  other  w o u l d be i n t e r e s t i n g t o  sedation, these u l t r a - s h o r t  d r a w n was t h a t a s i n g l e d o s e t a k e n operation  or  combination  patient.  has been d e m o n s t r a t e d night  shortened  It  in  an  extraction.  Considering the non-accumulating e f f e c t s ,  be a c c e p t a b l e d r u g s  the  form.  while u t i l i z i n g the  the dental  c a r r i e d over  It  cirrhosis  an i n c r e a s e i n  drug has been m a r k e t e d  i n the o r a l  accumulation property, effects  with  incomplete f i r s t - p a s s hepatic  i n s o m n i a and o n l y  the  In p a t i e n t s  i s reasonable to expect  due t o  At of  Similarly  pronounced  patient treatment  43  VI  CONCLUSION  The the  patient  ideal  to  dental  sleep yet  maintain protective extent with Obviously is  still  sedative then,  reflexes.  ideal  It  has y e t  will  may be s e e n t h e r e f o r e ,  the appointment  that  benzodiazepine  Less  the  benzodiazepines  the b a r b i t u r a t e s . and t h e  Motor  respect, problem.  the  benzodiazepines  Even i n t h e  previously  overall  not in  to the  the  likely  is  than  a n d c o n t i n u e s t o be a p r o b l e m .  In  i n s e d a t i v e doses demonstrate  the  barbiturates  the  with  employed this least  benzodiaze-  as s e d a t i v e s s i n c e t h e  benzo-  to produce r e s p i r a t o r y d e p r e s s i o n . This  patient with chronic lung disease. benzodiazepine  b r e a t h i n g due t o h y p o x i c d r i v e  Pharmacokinetically,  barbiturates  both the drug  be i n t e r p r e t e d a s a r e c o m m e n d a t i o n t h a t o n e u s e  may be i n d i c a t i o n s f o r  popular  effects  benzodiazepines  r e s p i r a t o r y compromised p a t i e n t  pines are superior to diazepines are less  i s seen w i t h  impairment v a r i e s with  individual patient,  offer  patients.  receptor s p e c i f i c i t y ,  'drug hangover'  over.  impairment  a r e g e n e r a l l y more p r e d i c t a b l e t h a n when s e d a t i v e s u c h a s are used.  will  great  is  s i n c e long term  benefits over  a g e n t s when t r e a t i n g a n x i o u s  Due t o  i n t e r f e r e t o any  put  employed.  t h e d e n t i s t a c o n s i d e r a b l e number o f sedative  not  t o be f o u n d ,  a f a c t o r w i t h any drug  It  almost  l e a v e him a r o u s a b l e , c o o p e r a t i v e and  day t o day a c t i v i t i e s a f t e r  the  i s one w h i c h w i l l  n o t due t o  t h e most u s e f u l  benzodiazepines  However, w i t h c a u t i o n ,  s e d a t i v e use e . g .  sedative  is  when t h e  there patient  hypercarbia. in dentistry  i s one  with  44  rapid onset.  Oral  diazepam and s u b l i n g u a l l o r a z e p a m ,  o n s e t o f 20 m i n u t e s a r e q u i t e a c c e p t a b l e i n t h e d e n t a l Diazepam f o r m u l a t i o n s , 3-4 m i n u t e s , still  are also presently accepted.  o f (DIAZEMULS)  thrombotic  i n turn  as a l t e r n a t i v e s  i n dental  long term e f f e c t s o f the s e d a t i v e ,  which  i n spite of  producing  i s metabolized  are metabolized  a benzodiazepine  which i s  t o compounds w i t h  of older patients  It treatment  i n the short term.  be f o r s h o r t  term u s e .  (TRANXENE) s h o u l d be a v o i d e d residual is  motor  lives.  since  and i n those w i t h  benzodiazepines  tolerance should not occur i n dental should only  of  i t does liver  effects,  doses.  i s accepted that  of anxiety  both  long half  d i s e a s e where most s e d a t i v e s t e n d t o p r o d u c e e x a g g e r a t e d i n recommended  For  t o diazepam and oxazepam,  i n m i n i m i z i n g long term e f f e c t s  not a l t e r the treatment  fewer  sedation i s to minimize the  t o n u m e r o u s a c t i v e a g e n t s s h o u l d be a v o i d e d .  Lorazepam i s e f f e c t i v e  even  good  (VALIUM).  Since a major goal  e x a m p l e medazepam  of  H o w e v e r (V AL IUM) i . v . i s  i n North America,  and (ATIVAN)  phenomena t h a n  biotransformed  practice.  a d m i n i s t e r e d i n t r a v e n o u s l y w i t h an o n s e t  by f a r t h e m o s t p o p u l a r  reports  b o t h w i t h an  impairment,  It  follows that  treatment Drugs  in dentistry  are e f f e c t i v e  drug  since these  of  agents  such as c h l o r a z e p a t e since there  i s considerable  due t o t h e a c t i v e m e t a b o l i t e s .  i n d i c a t e d i n the long term treatment  i n the  anxiety.  I t s use  45  Regarding s o l u b l e agents effective fewer  for  local  a dental  such as f l u n i t r a z e p a m sedation of  should not  office after  the  with  investigated  for  p r i o r to  surgery,  and t o  water  than  be  produce  There i s a s l i g h t l y  sedated patients  greater  with  i n i t s use as  s h o u l d be e s c o r t e d  from  appointment.  i t s lack of  enterhepatic c i r c u l a t i o n , lack  s e c o n d peak e f f e c t ,  use i n d e n t i s t r y ,  appear to  newer  a n d m i d a z o l a m h a v e b e e n shown t o  ataxia with flunitrazepam  a c t i v e m e t a b o l i t e s and l a c k o f  to date  benzodiazepines;  be a m a j o r d e t e r r i n g f a c t o r  sedative since a l l  Midazolam, of  patients  post-operative  This  the dental  use o f  c o m p l i c a t i o n s than diazepam.  incidence of diazepam.  intravenous  but  its qualities  has y e t  to  be  demonstrated  i n d i c a t e i t w o u l d be a g o o d c a n d i d a t e f o r  dental  use.  While dental i n a number o f w a y s . methods, the  the p a t i e n t  benzodiazepine  contraindicates  f e a r may be e x t r e m e l y If  anxiety  common,  it  c a n be r e d u c e d  c a n n o t be a l l a y e d by n o n - p h a r m a c o l o g i c a l  may be t r e a t e d w i t h a n x i o l y t i c a g e n t s  group,  the use o f  unless the p a t i e n t s ' these  drugs.  medical  usually  history  of  46  NEUROLEPTANALGESIA  HISTORY -  In 1 9 4 9 , t h e c o n c e p t o f an a n a e s t h e t i c  which blocked the cerebral responses This  normally  was a c h i e v e d  and m e p e r i d i n e .  cortical,  activated  some e n d o c r i n e ,  by s u r g e r y  He l a t e r a d d e d a b u t y r o p h e n o n e ,  his patients  characterized  by a n a l g e s i a , a b s e n c e o f c l i n i c a l l y  during It  reflexes,  as a n e u r o l e p t i c  a mental  anaesthetic  state  o f detachment  disinterest  recommended  i n the environment,  cooperative,  activity  cardiovascular  (44).  properties.  drugs  procedures. patients  anaesthesia  d i s p l a y o f emotion  tend  or dysarthria  being  procedures.  initiative,  and a  t o be e a s i l y a r o u s e d a n d  a n d seem t o h a v e i n t e l l e c t u a l  incoordination,  i n healthy  i t  patients  cause a s t r i k i n g l a c k o f  little  Subjects  in  of surgical  regional  drug,  Clinically  and i n d i f f e r e n c e  reflexes  doses d u r i n g  range o f a f f e c t .  no a t a x i a ,  of  It i s  motor  and a n t i e m e t i c  i n d u c t i o n and m a i n t e n a n c e  In m a n , n e u r o l e p t i c  limited  maintenance  i s a l s o used f o r i t s s e d a t i v e  with  s t a t e he  (INAPSINE)  does n o t cause l o s s o f p r o t e c t i v e  treated  droperidol,,  apparent  a n d a m n e s i a i n some b u t n o t a l l p a t i e n t s  While c l a s s i f i e d  produces  usually  became known a s n e u r o l e p t a n a l g e s i a .  and s u p p r e s s i o n o f a u t o n o m i c  droperidol  chlorpromazine,  The c l i n i c a l  achieved with  DROPERIDOL -  by L a b o r i t ( 4 3 ) .  of promethazine,  and a n o p i o i d a n a l g e s i c s u c h a s f e n t a n y l .  stability,  and autonomic  was p r o p o s e d  by t h e a d m i n i s t r a t i o n  technique  functions  (6).  intact;  there  is  47  Chemically, Pharmacologically, a-adrenergic  the  in addition  actions.  It  In  a-adrenergic  r a p i d changes  While effects  are  adverse  renal,  demonstrated  rare.  The  heart  (49).  ventilation  during the  and r e a l  anaesthetic  required  for  onset  three  ten minutes,  of  clinical  and d u r a t i o n  Since droperidol  is usually  is  about 20-30 m i n u t e s ,  additional  indicated.  signs for  d o s e s may m a n i f e s t  and s i n c e f e n t a n y l  Clinical  themselves  an i n c r e a s e i n s y m p a t h e t i c diaphoresis  to  hypotension,  other  have not  Depressed assisted The  need o f  two  of  and l i m b movements.  an i n c r e a s e d b l o o d  Because of  additive  or  usually  to  four  for shorter fentanyl  supplemental  as an i n c r e a s e d p u l s e r a t e  activity),  time  short,  fentanyl  increments  and  been  has a r e l a t i v e l y  the  cardiac  epinephrine,  is usually  combined w i t h  duration  usually  vasodilatation.  relatively  action  on  considerable  i s necessary.  procedures,  are  a  may be p r o f o u n d .  anaesthetic of  any a f f e c t  p o s s i b i l i t y , and  signs of  if  avoided.  effects  procedures  has  depressants.  i n moderate  sensitized  effects  it  and  may be o b s e r v e d ,  or hepatic  Respiratory  is a predictable  hours.  i s not  haematological  profound  s h o u l d be  bradycardia  CNS  patients,  may r e s u l t  in posture  transient  other  has l i t t l e  o c c u r due t o  respiration  to  anti-fibrillatory  hypovolemic  blocking effect  derivative.  inducing neurolepsis,  circumstances, droperidol  c a r d i o v a s c u l a r system.  therefore  to  a l s o enhances  drop i n blood pressure w i l l Its  i s a butyrophenone  blocking, anti-emetic,  anticonvulsant Under normal  droperidol  (marking pressure, potentiating  48  effects  i t i s recommended t h a t  used i n c o m b i n a t i o n w i t h agents  t h e u s u a l d o s e s be r e d u c e d by 50% when  barbiturates,  (46).  After  bolus  intravenous  t a c h y c a r d i a may o c c u r .  This  i n j e c t i o n , h y p o t e n s i o n and  i s o f s h o r t d u r a t i o n a n d may be a v o i d e d  by s l o w a d m i n i s t r a t i o n o f t h e d r u g . have r e p o r t e d Dental since  narcotics or anti-psychotic  having a ' b i g tongue'  patients  s h o u l d be l e s s  they u s u a l l y expect  p r o c e d u r e s where r e g i o n a l  ADVERSE REACTIONS extrapyramidal  A small  percentage of  and d i f f i c u l t y  titration,  thic  occur only  i n about  specific oxygen,  antidote,  r e s t l e s s n e s s and e x c i t e m e n t . the extrapyramidal  1% o f t h e p a t i e n t s . the treatment  This  syndrome  With  careful  reactions, or oversedation  Since droperidol  o f overdose  is chiefly  h a s no  supportive; extrapyramidal  recommends a d o s e o f 2 . 5 - 5 . 0 mg be g i v e n  i n t r a v e n o u s l y as an a d j u n c t  to regional anaesthesia.  doses f o r d e b i l i t a t e d or e l d e r l y p a t i e n t s  benefits  are derived with  for  the c l i n i c i a n  both  and a k a t h i s i a , an  a n a n t i - p a r k i n s o n i a n d r u g may be i n d i c a t e d ( 4 9 ) .  The m a n u f a c t u r e r  in  occurring  r e s t o r a t i o n o f f l u i d l e v e l s , and i n t h e c a s e o f  symptoms,  dental  anaesthesia i s customary.  I n a d d i t i o n t o t h e uncommonly  syndrome,  effects  t o encounter these problems a f t e r  effects of oculogyria, dystonia,  o f unusual  swallowing.  l i k e l y to complain of these  e m e r g e n c e s y n d r o m e may o c c u r o n r a r e o c c a s i o n s . consists  patients  Reductions  are indicated.  the combination of droperidol  and p a t i e n t ,  there  i s a potential  While  and f e n t a n y l p r o b l e m when  49  this  combination  duration  i s u s e d on a n o u t p a t i e n t  basis.  o f a c t i o n o f 24 h o u r s o f d r o p e r i d o l  action of fentanyl  there  c o u l d be d i s m i s s e d o n l y "tranquilizer" be s u f f e r i n g  effect  t o have t h e a n a l g e s i c e f f e c t  remain,  from mental  i . e . the patient  agitation  i s properly monitored,  from P a r k i n s o n ' s  and t h e s h o r t d u r a t i o n  of  i s a d i s t i n c t p o s s i b i l i t y that the patient wear o f f and t h e  c o u l d appear  calm y e t  and r e s t l e s s n e s s ( 4 5 ) .  When j u d i c i o u s l y u s e d d r o p e r i d o l patient  Due t o t h e p o s s i b l e  i s a safe drug,  i s not hypovolemic,  provided the  and i s n o t s u f f e r i n g  disease.  FENTANYL-(SUBLIMAZE)  Fentanyl  citrate  i s a synthetic  anaesthetic actions s i m i l a r to morphine, While i t i s considered a 'short' to  i t s analgesic effects;  considerably effects, shows  fentanyl  little  changes  longer  (45).  a n d some s e d a t i v e  acting narcotic,  i t respiratory  this  depressant  less  than other  with  properties.  term  refers  e f f e c t s may l a s t  W h i l e most n a r c o t i c s d e m o n s t r a t e  shows t h i s  effect  narcotic analgesic  opioids.  emetic  Fentanyl  on t h e c a r d i o v a s c u l a r s y s t e m and o n l y  minor  i n p u l s e and b l o o d p r e s s u r e have been n o t e d ( 4 6 ) .  Interestingly, demonstrated  after  t h e a d d i t i o n o f 10 mg d i a z e p a m ,  a s i g n i f i c a n t decrease i n stroke  and b l o o d p r e s s u r e ,  and an i n c r e a s e i n c e n t r a l  volume, venous  several cardiac  patients output  pressure (46).  50  Chemically, as m e p e r i d i n e , Though a l l  fentanyl  alphaprodine,  drugs  in this  they a l l demonstrate  i s grouped w i t h  a n i l e r i d i n e and  group d i f f e r  the  n a r c o t i c s such  diphenoxylate.  s t r u c t u r a l l y from  s i m i l a r pharmacological e f f e c t s  morphine,  to  morphine.  Fentanyl Diagram  from  (6).  Pharmacologically, and p r o d u c e s e f f e c t s  are s i m i l a r to morphine clinical  symptoms  fentanyl  c h i e f l y on t h e  a s a n a l g e s i a and r e s p i r a t o r y  of  but  protein  than average binding.  response to  the  binds to  CNS.  less  the o p i o i d  Clinically  depression.  Absorption  often  therapeutic  and  doses.  effects onset Therefore  demonstrate  and d e c r e a s e d  T h e s e phenomena may a c c o u n t f o r 'average'  manifests  redistribution.  Older patients  plasma c o n c e n t r a t i o n s ,  this  receptors,  Gastro-intestinal  pronounced.  i s r a p i d , as i s drug  plasma l e v e l s decrease r a p i d l y . higher  j  plasma  an i n c r e a s e d  51  INTRODUCTION TO THE STUDY  In c o n s i d e r a t i o n o f t h e a f o r e m e n t i o n e d and b u t y r o p h o n o n e s , combination with + fentanyl,  i t was r e a s o n a b l e t o s t u d y  fentanyl.  and d r o p e r i d o l  choice of these s p e c i f i c group were many; in for at  intravenous surgical  the University  and a p p r o x i m a t e l y the patients these drugs  in  such  in  + fentanyl,  drugs  were c h o s e n .  Reasons  as b e i n g r e p r e s e n t a t i v e and d r o p e r i d o l  diazepam  and both drugs  o f t h e drug  are readily  available  equal  Care  surgical  basis  Unit.  u s e t h e s e drugs on a r e g u l a r  f r e q u e n c y when p r o v i d i n g  undergoing  sedatives  a r e used on a r e g u l a r  o f B r i t i s h Columbia Acute  anaesthetists  f o r the  sedative  services  procedures at t h i s centre.  Each  i s u s u a l l y combined w i t h a n a r c o t i c such as f e n t a n y l  procedures.  In  dentistry,  diazepam  be be i n t e r e s t i n g t o s t u d y pharmacological  i s often  aspects o f diazepam  drug combinations  used f o r s e d a t i o n .  the anaesthetic,  a d r u g w h i c h i s n o t commonly these  these drugs  s o l u t i o n s , both a r e employed as c o n v e n t i o n a l  procedures,  of  benzodiazepines  S p e c i f i c a l l y the combinations  both diazepam  In a d d i t i o n ,  for  drugs,  It  would  p s y c h o l o g i c a l , and  i n r e l a t i o n to those of  used i n d e n t i s t r y ,  a r e s u i t a b l e f o r use i n  droperidol,  and see i f t h e use o f dentistry.  52  O B J E C T I V E S OF THE STUDY  To c o m p a r e t w o c o n v e n t i o n a l and D r o p e r i d o l / F e n t a n y l ,  sedative combinations;  i n patients  underoing c a t a r a c t  and i n t r a o c u l a r l e n s r e p l a c e m e n t f o r t h e f o l l o w i n g  1.  CNS  operatively  Diazepam/Fentanyl extraction  effects.  DEPRESSION - t o o b s e r v e a n d c o m p a r e t h e d e p r e s s i o n i n t r a and p o s t - o p e r a t i v e l y  and check f o r major d i f f e r e n c e s i n  magnitude.  2.  CVS EFFECTS  and h y p o t e n s i o n ,  - to observe p a t i e n t s  intra-operatively  f o r occurrence of  and i m m e d i a t e l y  bradycardia  post-operatively  and c o m p a r e d i f f e r e n c e s i n o c c u r r e n c e .  3.  A L L E V I A T I O N OF ANXIETY  - t o note  regimens i n the r e l i e f o f the p a t i e n t s ' side-effects  4.  i n h e r e n t d i f f e r e n c e s i n the drug anxiety,  5.  adverse  i f any.  TO ASSESS SURGEON AND ANAESTHETIST  between  and note  OPINIONS  - f o r any p r e f e r e n c e  t h e two c o m b i n a t i o n s .  TO ASSESS FOR PSYCHOMOTOR IMPAIRMENT - t o a s s e s s  combination l e f t  the patient  if  either  impaired c o n s i d e r a b l y longer than d i d the  other.  6. for of  TO E S T A B L I S H A UNIFORM PROTOCOL the j u d i c i o u s treatment  of dental  for assessing  out-patients  d r u g s a s t h e y become a v a i l a b l e f o r c l i n i c a l u s e .  sedative  methods  f o r t h e f u t u r e use  53  RATIONALE FOR STUDYING EYE  PATIENTS  Due t o t h e s i g n i f i c a n t numbers o f p a t i e n t s cataract extraction Sciences  Centre,  treated with  at the U n i v e r s i t y  different  regional  drug  being treated  o f B r i t i s h Columbia  Health  regimens f o r these p a t i e n t s  a n a e s t h e s i a and c o n s c i o u s s e d a t i o n  for  being  techniques  c a n be c o m p a r e d .  These p a t i e n t s that  both  need s u r g i c a l  are s i m i l a r to dental  a general  anaesthetic,  basis.  Considering the uniformity to the r e l a t i v e l y  cataract extraction surgical for  patients,  the following  patients  in  p r o c e d u r e s w h i c h u s u a l l y may be t r e a t e d  without  the access  surgical  a n d b o t h may be t r e a t e d of the operating  small  out-patient  c o n d i t i o n s , and  l a r g e numbers o f p a t i e n t s  as compared t o r e l a t i v e l y  on a n  undergoing  numbers  i t was d e c i d e d t o u s e c a t a r a c t p a t i e n t s  of  dental  as s u b j e c t s  experiment.  RATIONALE FOR THE DRUG REGIMEN  Since the drugs of c h o i c e i n North America today f o r use as s e d a t i v e  adjuncts  are benzodiazepines narcotics, intravenous  to regional  anaesthesia/analgesia i n surgery  o r butyrophenones  and s i n c e a t t h i s use i n Canada,  time few benzodiazepines  acting  are licenced  for  i t was c o n s i d e r e d r e a s o n a b l e t o s t u d y t h e  t w o m o s t commonly u s e d c o m b i n a t i o n s diazepam/fentanyl  i n combination with short  i n use a t t h i s c e n t r e .  (VALIUM/SUBLIMAZE) and d r o p e r i d o l / f e n t a n y l  These a r e  54  (INAPSINE/SUBLIMAZE).  While both o f these combinations as a d j u n c t s  to anaesthesia with  p r o c e d u r e s where there  are s t i l l  where  regional  numerous  patients  oral  procedures;  procedures  treated with"general  such as p e r i o d o n t a l ,  ophthalmologic  anaesthetic  and u r o l o g i c a l p r o c e d u r e s ,  procedures  :  anaesthetics suffice.  e n d o d o n t i c and such as c a t a r a c t  and c e r t a i n  a r e s u i t a b l e f o r non g e n e r a l  methods.  METHODS AND MATERIALS  The  and t h e A c u t e  -  acceptance of t h i s experimental  from the U n i v e r s i t y  Care H o s p i t a l  Experimentation  approached t o e x p l a i n the experiment  Three s e n i o r undergraduate t o do t h e p s y c h o l o g i c a l t e s t i n g  Patients  protocol  was o b t a i n e d  o f B r i t i s h C o l u m b i a Human E x p e r i m e n t a t i o n  The O p h t h a l m o l o g y A n a e s t h e s i a  time  surgical  i s not a requirement,  and i n t r a o c u l a r l e n s r e p l a c e m e n t ;  gynecological  short  a n a e s t h e s i a and s e d a t i v e a d j u n c t would dental  extraction  undergoing  intense muscle r e l a x a t i o n  Specifically, surgical  patients  have p r o v e n s u c c e s s f u l  undergoing  Committee  and N u r s i n g  Psychology  (Appendix 1 ) .  Department  and t o seek t h e i r  Committee,  were  cooperation.  students  offered  their  involved.  cataract extraction  r e p l a c e m e n t were approached t o r e q u e s t  their  and i n t r a o c u l a r  p a r t i c i p a t i o n i n the  lens  55  study. sign  T h o s e who a g r e e d w e r e g i v e n ( A p p e n d i x 2J_.  point  during the  subsequent  informed consent documentation  P a t i e n t s were p e r m i t t e d t o  study  if  leave the study at  t h e y s o w i s h e d w i t h no e f f e c t  on  their  Design -  Experimentally  a between g r o u p ,  single  treatment  d e s i g n where p a t i e n t ,  p s y c h o l o g i s t , o p h t h a l m o l o g i s t and n u r s i n g  were n o t  t h e d r u g g r o u p a s s i g n m e n t was c h o s e n .  cognizant  of  d o u b l e - b l i n d d e s i g n was a c h i e v e d by a l l o w i n g o n l y t h e assigned to the p a t i e n t cooperation  ethical  i n not  nature of for  individual practical  t a l k i n g to the other the  treatment  a n a e s t h e t i s t s to patients  of  -  A n a l y s i s of  One  All  members.  of  their  Due t o  i t would not  to which drug  the drugs  have been treatment  have  in  the  been  the which  d a t a l a t e r showed a n a b s e n c e their  had t h e a b i l i t y t o c o m m u n i c a t e w e l l  p a t i e n t s were randomly  of  knowledge.  Rl=50 o r  p a t i e n t s were 45 y e a r s o r o l d e r , male i n E n g l i s h and d i d  Measurement  r e g a r d i n g random a s s i g n m e n t by s e x t o the  and a s k i n g  hundred p a t i e n t s were a s s i g n e d t o groups  have s e r i o u s h e a r i n g i m p a i r m e n t s .  that  anaesthetists  N e i t h e r would i t  viscosities  staff  This  would have i m m e d i a t e l y a l e r t e d t h e a n a e s t h e t i s t t o  by r a n d o m a s s i g n m e n t . female,  staff  have been unaware  by t h e a n a e s t h e t i s t s i n s p i t e o f  Sample  protocol  the p a t i e n t s  had b e e n a s s i g n e d .  d r u g had b e e n a s s i g n e d . bias  the experimental  s i n c e the d i f f e r e n t  experiment  any  treatment.  Experimental  delicate  to  for  different  a s s i g n e d by s e x .  systematic  drug groups All  or  not bias  showed  patients  c a t a r a c t e x t r a c t i o n and i n t r a o c u l a r l e n s r e p l a c e m e n t i n a t  R2=50  needed  l e a s t one  eye.  56  Exclusions - Before random assignment, as noted from the medical h i s t o r y , a l l patients being treated f o r insomnia, anxiety neuroses, depression, or f o r chronic pain were excluded from the study. Patients with myasthenia g r a v i s , Parkinson's Disease o r with a l l e r g i e s to the drugs being tested were eliminated from the study.  Drug Treatment -Rl=Fentanyl + Droperidol -R2=Fentanyl + Diazepam  TREATMENT SETTING - A l l patients were admitted as i n - p a t i e n t s to the Acute Care Centre a t the U n i v e r s i t y o f B r i t i s h Columbia H o s p i t a l .  VARIATION OF TREATMENT FROM NORMAL - A l l patients were treated as patients are normally treated a t t h i s centre.  Patients were not given  anything by mouth f o r a t l e a s t s i x hours pre-operatively. No premedication (sedatives) was administered.  TESTING METHODOLOGY - The psychology students administered the pre-operative  state portion ( i n order t o e s t a b l i s h the base-line f o r  anxiety) of the State T r a i t Anxiety Inventory STAI ( 3 9 ) (Appendix 3 ) i n the patient's room on the ward the evening p r i o r to the surgery. In the case o f ten 'day-surgery' p a t i e n t s , the patients were administered the state portion of the STAI i n the day-surgery holding room. None o f the patients was tested i n the ante-room to the operating room.  Neither the patient nor the psychology student was cognizant  of the patient assignment t o drug group Rl or R 2 .  57  Patients  were brought  minutes  before  s u r g e r y was t o  status,  and s u r g i c a l  to  the operating  begin,  preparation.  for  room a p p r o x i m a t e l y  v e r i c a t i o n of  When t h e p a t i e n t  room he was t r a n s f e r r e d  assistance of  the  dorsum o f  left  hand o r t h e  l e f t wrist with  a n d an i n t r a v e n o u s  solution of  0 . 9 % s a l i n e was b e g u n .  the of  the  intravenous dextrose  the  nurses.  l i n e had  The  intravenous  This  were at yet  titrated  able to  of  B r i t i s h Columbia Health  r e s p o n d t o commands,  and h a v i n g  administered the  block  partial  and " O ' B r i a n "  bupivicaine  1.5%,  c h o i c e depended interactions  have been d e m o n s t r a t e d the  draped  1  the  Jelco-intracath  the #22'  In a few c a s e s a  solution  a saline solution  flow of  An a d d i t i o n a l  hole  the eye.  toe,  of  when  protective  the  surgeon.  when e i t h e r o f  holding.  calm,  intact.  (retro-bulbar anaesthetic  these  was  The  No s i g n i f i c a n t  Patients  drug  anaesthetics  All were  patients then  c u s t o m a r y manner a t  physical contact with  i.e.  epinephrine.  being tested.  i n the  sedation  reflexes  anaesthetic The  patient  Patients  conscious  p l a s t i c d r a p e was p l a c e d o v e r  The o n l y  the  Sciences Centre,  block).  o x y g e n by m a s k .  f r o m head t o  on w h e t h e r  both without  drug combinations  centre.  hand  local  nerve  or l i d o c a i n e 2.0%,  received a constant  anaesthetist  facial  on t h e p r e f e r e n c e o f  combined w i t h  for  depending  according to acceptable standards  University  surgically  a  or diazepam/fentanyl.  The o p h t h a l m o l o g i s t  is  table with  empty.  receive droperidol/fentanyl  the  into  l i n e was e s t a b l i s h e d i n  was c h a n g e d t o  S e d a t i o n was a d m i n i s t e r e d , was t o  the s u r g i c a l  been e s t a b l i s h e d on t h e w a r d w i t h  5.0% s o l u t i o n .  bag was  to  physical  was b r o u g h t  the o p e r a t i n g  20  this  the face w i t h  t h e p a t i e n t was  a by  58  All minutes. draping  patients  The b l o o d p r e s s u r e c u f f and remained t h e r e  electrocardiograph left  were m o n i t o r e d  and r i g h t  shoulder  concurrently with  l e a d II  and ground  blood  The monitoring  i f necessary,  surgery  of v i t a l  A Honeywell  was a t t a c h e d  t o each p a t i e n t  leads.  to convert  procedure  increments  was begun a n d d u r i n g  there  because o f p a t i e n t  was p a i n f u l  of fentanyl  attempt to give surgical either the  Cefalozin  patient  were a d m i n i s t e r e d .  sodium  70 y e a r s the  local  (ANCEF),  had p e n i c i l l i n  post-operative of age.  sedatives  via  for.  Neither  was a s a p r o p h y l a c t i c  tested.  patient contact.  that  either  additional  I n no c a s e was t h e r e a n y  or Gentamicin  o f these drugs  the  restlessness, or  was a n x i o u s ,  anaesthetic.  i n patients  than  verbal  stimulation,  related allergies.  infections  being  E+M  anaesthetic  other  was l i t t l e  The l a s t p a r t  consisted of the subconjunctival  cephalosporin a n t i b i o t i c , of  that time,  movement,  or the patient  additional  procedure  to a general  h o w e v e r t h i s was n o t c a l l e d  because o f s i g n s o f i n c r e a s i n g sympathetic the  to  P u l s e was m o n i t o r e d  s i g n s and o c c a s i o n a l l y r e a s s u r i n g t h e  i t became o b v i o u s  arm p r i o r  the procedure.  t h a t t h e s u r g e r y was p r o c e e d i n g w e l l , If  ten  pressure.  In a l l c a s e s t h e a b i l i t y was a v a i l a b l e  signs every  was p l a c e d o n t h e r i g h t  during  running  for vital  of the  administration  Sulfate  of  (GARAMYCIN),  The i n d i c a t i o n f o r  if  this  t o reduce the i n c i d e n c e  at high r i s k ,  e . g . those  reacts s i g n i f i c a n t l y  with  over  59  The  drapes were  the a s s i s t a n c e of recovery  (PAR).  the  II  was m o n i t o r e d ,  of  time  about  t h e n u r s e s and o r d e r l i e s t o p o s t  showed no s i g n s o f  i n PAR,  along with  until  suitable for  The p o r t i o n of  anaesthetic  having  respiratory distress.  b l o o d p r e s s u r e and p u l s e f o r  r e t u r n i n g to the ward.  arrival  the  the a n a e s t h e t i s t considered the p a t i e n t  an h o u r and a h a l f .  by m o u t h a f t e r  with  T h e r e t h e o x y g e n by mask was u s u a l l y d i s c o n t i n u e d  if  status  patient  removed a n d t h e p a t i e n t was t r a n s f e r r e d  at  The  duration to  be  of  I n m o s t c a s e s t h i s t i m e was  p a t i e n t s were p e r m i t t e d t o  have  fluids  PAR.  psychology student  t h e STAI a p p r o x i m a t e l y  some v a r i a t i o n due t o t h e  Lead  returned to a d m i n i s t e r the five  s t a n d a r d ward  state/trait  hours post o p e r a t i v e l y routines.  with  60  ASSESSMENT  1 -  PSYCHOLOGICAL  The surgery. except the  patients  The s t a t e  w e r e a d m i n i s t e r e d t h e STAI t h e e v e n i n g  p o r t i o n was r e p e a t e d  i n t h e c a s e o f two p a t i e n t s  surgical  p r o c e d u r e and t h e y were t e s t e d j u s t  provided  patients  hours  by t h e a u t h o r s  normalized,  f o r general medical  to  post-operatively  who w e r e d i s m i s s e d t w o h o u r s  Raw s c o r e s w e r e t a b u l a t e d , date  five  prior  after  p r i o r to being dismissed.  and compared t o t h e surgical  (GMS)  (39).  Post-operatively  the Sensory/Affect  was a p p l i e d by t h e same p s y c h o l o g y  student  Pain testing  scale  (40)  who h a d a d m i n i s t e r e d t h e  STAI.  Examples o f t h e q u e s t i o n a i r e s  f o r (39) and (40) a r e  ( A p p e n d i x 3) and ( A p p e n d i x 4 ) .  2 -  ANAESTHETIC  Trends were a n a l y s e d .  f o r b l o o d p r e s s u r e and p u l s e changes f o r both Any o c c u r r e n c e o f r e s p i r a t o r y o b s t r u c t i o n  o r d e p r e s s i o n was m o n i t o r e d return  to the ward.  until  the patient  groups  (stridor)  was deemed h e a l t h y  to  61  Mean d o s e s a n d s t a n d a r d d e v i a t i o n f o r d r u g g r o u p s analysed.  Opinions  o f degree o f s e d a t i o n o f t h e p a t i e n t  s u r g e r y w e r e made a c c o r d i n g t o t h e s c a l e o f B e r g g r e n ,  during the  Erriksson  and d r u g g r o u p s w e r e a n a l y s e d f o r d i f f e r e n c e s i n s e d a t i o n Anaesthetist  ratings of the o v e r a l l  scaled according to the d i f f e r e n t anaesthesia procedure, days t o d i f f e r e n t anaesthetists  were  produced.  p r o c e d u r e were a l s o a n a l y s e d and  drug groups.  In keeping  with  t h e a n a e s t h e t i s t s were r o t a t e d on d i f f e r e n t  surgeons and t h e i r p a t i e n t s .  to patients  in different  Assignment  drug groups  i s shown  of below.  An a t t e m p t was made t o h a v e t h e a n a e s t h e t i s t s do a p p r o x i m a t e l y t h e i r case load i n each drug  Anaesthetists  half  group.  Droperidol/Fentanyl  4  A B C D E F G H  (41),  9 6  3  4 5 6  0  Diazepam/Fentanyl  3 12 7 2 7 7 7 2  OVERALL OPINION OF THE SEDATION OF THE PATIENT  0- u n a b l e t o p r o c e e d w i t h t h e s u r g e r y d u e t o t h e l a c k o f s e d a t i o n 1 - awake b u t c o o p e r a t i v e 2 - drowsy b u t responds r e a d i l y t o s t i m u l i 3- a s l e e p b e t w e e n r e c o r d i n g s o f bp a n d p u l s e 4- asleep - but aroused with d i f f i c u l t y 5 - r e a c t i o n t o p a i n f u l s t i m u l i , b u t no v e r b a l c o n t a c t  62  ANAESTHETIST  0 - unable  OPINION OF THE PROCEDURE  t o proceed as p l a n n e d  1 - sedation just additional 2 -  good  3 -  excellent  sufficient,  were t i t r a t e d  drowsy,  the endpoint  r e s t l e s s , required  of sedation,  to stimuli  and m a i n t a i n i n g  3 - SURGICAL ASSESSMENT of the overall  a c c o r d i n g t o drug  OVERALL 0 -  t h e a b i l i t y t o answer  3 -  excellent  pressure questions.  (APPENDIX 5 )  p r o c e d u r e and t h e o p i n i o n s were  analysed  unable t o proceed as planned  good  being  the ease o f  EASE OF PERFORMANCE OF SURGERY  2 -  patient  T h e s u r g e o n was a s k e d t o r a t e  group.  1 - able to proceed with  of  sedation of  such as blood  THE ANAESTHETIC RECORD USED FOR EACH PATIENT -  performance  numerous  the majority  a n a e s t h e t i c a l l y to endpoint  but responding w e l l  measurements,  patient  increments  Regarding (67%)  (poor)  some d i f f i c u l t y  (fair)  63  STATISTICAL ANALYSIS FOR S U R G I C A L , A N A E S T H E T I C , AND PSYCHOLOGICAL DATA Hotelling's  The  T - S q u a r e A n a l y s i s , a n o m n i b u s m u l t i v a r i a t e a n a l y s i s was  carried out.  Subsequent  2-way B y s t r a t a  t e s t i n g u s i n g c h i - s q u a r e , a n d ANOVA ( o r  ANOVAS) w e r e c a r r i e d o u t w h e r e t h e m u t i v a r i a t e  results  were s i g n i f i c a n t .  PSYCHOLOGICAL-STATE TRAIT ANXIETY INVENTORY N o r m a t i v e d a t a h a v e been r e p o r t e d by t h e a u t h o r s and s u r g i c a l it  patients.  (STAI)  -  f o r general medical  The i n f o r m a t i o n p r o v i d e d by t h e a u t h o r s  made  p o s s i b l e t o compare s c o r e s o b t a i n e d i n t h i s s e l e c t e d e x p e r i m e n t a l  group.  Raw s c o r e s o n t a i n e d i n t h i s e x p e r i m e n t w e r e n o r m a l i z e d a n d  c o m p a r e d by d r u g g r o u p .  The e x p e r i m e n t a l  s c o r e s w e r e c o m p a r e d by  t a k i n g t h e means a n d s t a n d a r d d e v i a t i o n s f o r t h e d i f f e r e n t  drug  g r o u p s a n d c o m p a r i n g them t o t h o s e s u p p l i e d by t h e a u t h o r s .  SENSORY/AFFECT RATIO DESCRIPTORS - The p a t i e n t s '  description  o f e a c h d e s c r i p t o r was g r a p h e d by g r o u p i n g t h e d a t a a n d p l o t t i n g i t . The mean r a n k  v e r s u s r a t i o d e s c r i p t o r magnitudes were a l s o  ANAESTHETIC - O p i n i o n s  o f t h e a n a e s t h e t i s t s were  by ANOVA t e c h n i q u e and t h e n s c o r e s w e r e g r a p h e d .  plotted. analysed  The c h i - s q u a r e  test  was u s e d f o r d r u g g r o u p c o m p a r i s o n s f o r t h i s s e d a t i o n o p i n i o n a n d f o r the o p i n i o n regarding the o v e r a l l ease o f performance o f the procedure.  SURGICAL - S u r g e o n s o p i n i o n s w e r e a n a l y z e d by ANOVA t e c h n i q u e t h e n t h e o p i n i o n s were t a b u l a t e d and g r a p h e d . a p p l i e d f o r drug comparisons.  C h i - s q u a r e t e s t was  64  RESULTS  One  hundred cases were completed, however any that did not  f o l l o w the standardized  anaesthetic, s u r g i c a l or psychological format  e s t a b l i s h e d at the outset were not included i n the data a n a l y s i s . Those cases include two patients who  had o r i g i n a l l y agreed to p a r t i -  cipate i n the study but requested a general anaesthetic at the time of surgery as they did not want to know "what was  going on." Three  p a t i e n t s were treated with general anaesthetics at the request of the anaesthetist due to the p a t i e n t s ' previous h i s t o r y of epilepsy. Although these patients had been s t a b i l i z e d f o r two years without a s e i z u r e , the use of general  anaesthetic i s understandable considering  the d e l i c a t e nature of the procedure. out under microscopic  Cataract e x t r a c t i o n i s c a r r i e d  conditions and any unexpected movement by the  p a t i e n t could have disastrous consequences.  Five other patients  had  agreed to p a r t i c i p a t e . However upon psychological t e s t i n g i t was believed the p a t i e n t s ' had some misunderstanding of the questions the p a t i e n t s ' r e s u l t s were thus excluded. p a r t i c i p a t e but a f t e r surgery was  Two  and  patients agreed to  completed f e l t too t i r e d to  answer any questions and d i d not wish to continue.  Each of these  two patients was  Four patients  from a d i f f e r e n t treatment group.  were dismissed p r i o r to completion of the psychological t e s t i n g . I t was  f e l t psychological post-operative  ment s e t t i n g would introduce e r r o r . diazepam/fentanyl group and 37  t e s t i n g outside the t r e a t -  A t o t a l of 47  patients from the  patients from the d r o p e r i d o l /  fentanyl group had t h e i r r e s u l t s analysed.  While the dropout rate  65  for  droperidol/fentanyl  fentanyl  g r o u p was g r e a t e r  than the diazepam/  g r o u p t h i s d i f f e r e n c e i n r a t e may be d u e t o i n h e r e n t  differences  i n t h e drug combination o r t o chance d i f f e r e n c e s i n t h e groups random  sampling.  PSYCHOLOGICAL RESULTS - A d m i n i s t r a t i o n o f t h e STAI the p a t i e n t data the  despite  data obtained i n t h i s  indicated  that  study c o r r e l a t e d well with the  from t h e general medical s u r g i c a l  patient  (GMS) d a t a f o r w h i c h  norms w e r e e s t a b l i s h e d ( 3 9 ) .  ANXIETY--TRAIT MEAN  ANXIETY-STATE  (PRE-OP)  SD  MEAN  SD  GMS  41.33  12.55  42.68  13.76  EXPERIMENT RESULTS  42.26  10.49  42.27  10.10  A c o m p a r i s o n o f t h e means a n d s t a n d a r d d e v i a t i o n s o b t a i n e d experiment patients  c o r r e l a t e s well with those f o r general medical  of Spielburger et a l .  Therefore,  was f o u n d t h a t  surgical  using a two-tailed  ANOVA w i t h a £ . 0 1 , s i n c e n> 2 5 , a n d t h e C e n t r a l it  in this  Limit  Theorum h o l d s ,  t h e r e was n o t a s i g n i f i c a n t d i f f e r e n c e i n s c o r e s  f o r GMS p a t i e n t s a n d e x p e r i m e n t a l trait,  and t h e a n x i e t y  socres  f o r post-op  patients  state pre-op.  GMS p a t i e n t s .  f o r s c o r e s on t h e  anxiety-  S p i e l b u r g e r e t a l do n o t  By t h e s e s t a n d a r d s ,  offer  the experimental  66  p a t i e n t s w e r e c o n s i d e r e d t o be t y p i c a l conditions of anxiety  in their overall  f o r both s t a t e and t r a i t  state/trait  testing.  A 2 - w a y B y s t r a t a ANOVA was c a r r i e d o u t b e t w e e n d r u g versus  pre-operative  groups  a n d p o s t - o p e r a t i v e n o r m a l i z e d s c o r e s on t h e s t a t e  portion  of the STAI,  p ^.01.  A s i g n i f i c a n t d i f f e r e n c e was f o u n d i n t h i s  respect  f o r both drugs over t i m e , w i t h both groups demonstrating  immediate p o s t - o p e r a t i v e a n x i e t y  - than p r e - o p e r a t i v e a n x i e t y .  lower This  is  consistant with the findings of Spielburger et a l .  An ANOVA was c a r r i e d o t t o t e s t  f o r between drug v a r i a b i l i t y  versus w i t h i n s u b j e c t v a r i a b i l i t y f o r both p r e - o p e r a t i v e and p o s t operative  s c o r e s on t h e STAI i n o r d e r t o d e t e r m i n e i f t h e r e was some  difference  over time.  For pre-op  found w i t h p £ . 0 2 , and F=5.5304. statistics over time  However i n p o s t - o p  r e s u l t s i n p _<.09 a n d F - 2 . 7 8 5 0 .  amount.  For both drug groups,  only s l i g h t l y post-operatively. Auerbach  This  s c o r e s ANOVA  Thus some c h a n g e i n s c o r e s  r e s u l t e d , depending on t h e drug t r e a t m e n t ,  considerable  of  s c o r e s a s i g n i f i c a n t d i f f e r e n c e was  though n o t a  state anxiety  increased  i s consistant with the findings  ( 4 2 ) , who e l a b o r a t e d on t h e f i n d i n g s o f S p i e l b u r g e r ' s S T A I  i n e v a l u a t i n g t h e e f f e c t s o f s u r g e r y - i n d u c e d s t r e s s on a n x i e t y  and t h e  relationship  to t h i s  stress.  between p r e - o p  s t a t e and post-op  s t a t e adjustment  67  ANXIETY-TRAIT MEAN  ANXIETY-STATE  SD  MEAN  SD  MEAN  pre-operative  SD  post-operative  DRUG GROUP Drop/Fent 44.91  10.18  44.34  10.07  46.12  8.71  39.60  10.80  40.19  10.14  42.46  10.00  Diaz/Fent  In found  s p i t e o f random a s s i g n m e n t t h e r e was a s i g n i f i c a n t d i f f e r e n c e  in trait  anxiety  droperidol/fentanyl reported take trait  scores f o r patients  patients  between  scoring s l i g h t l y higher.  this difference  into consideration.  s t a t i s t i c s showing t h e diazepam/fentanyl  lower than similar  drug g r o u p s , w i t h the  the droperidol/fentanyl  patients  The s t a t i s t i c s  Consistent with the  patients  the state  t o have  scored  scores y i e l d e d  findings. While both  use i n t h i s  d r u g c o m b i n a t i o n s p r o v e d t o be g o o d s e d a t i v e s  procedure,  some s u b t l e d i f f e r e n c e s w e r e  Regarding the scores o f the p a t i e n t s Descriptors,  i t was f o u n d t h a t  maximum s e n s a t i o n e x t r e m e describe  the e f f e c t i v e  fentanyl  patients  noted.  Sensory/Affect  a l t h o u g h p a t i e n t s may h a v e f o u n d t h e  o r c o n s i d e r a b l e , they  q u a l i t i e s t h e same.  (44%),  on t h e  for  d i d not n e c e s s a r i l y  Of t h e d r o p e r i d o l /  a n d (30%) o f d i a z e p a m / f e n t a n y l  patients  d e s c r i b e d t h e s e n s a t i o n a t t h e most i n t e n s e time d u r i n g s u r g e r y as 9 o r g r e a t e r on t h e s c a l e o f G r a c e l e y ,  Dubner and McGrath  (graph  1).  68  GRAPH 1 PATIENTS'  OPINION - SENSORY  DESCRIPTORS  GROUP DATA SENSORY  69  Analysis  of  these data  u s i n g c h i - s q u a r e t e c h n i q u e , a t a <_.01  t h e r e was a s i g n i f i c a n t number o f intense or greater other words,  a s i g n i f i c a n t number o f  with  the  values  o p i n i o n amongst  opinions of in  the  of  patients  to  (44%)  patients (49%)  uncomfortable  t h e e x p e r i e n c e was q u i t e  this  the choices offered  t h e o t h e r eye the  When  s e n s o r y and both drug  plotted,  affective  combinations,  t h e r e was a l s o a drug group.  range,  both  patients  'done' i n the  (graph 2 ) .  g r o u p was  The m o s t group  common  was  less  Many o f f e r e d  p l e a s a n t and t h a t i n the  difference  w h i l e t h e m o s t common o p i n i o n  i n the diazepam/fentanyl  that  None o f  c o m b i n a t i o n was u s e d ,  i n the droperidol/fentanyl  any o f  have  scale,  in different  than  to  opinion  t h e y w o u l d be  same manner i f  droperidol/fentanyl  the  i t were  group  happy  necessary.  volunteered  comment.  Analysis  of  d a t a by H o t e l l i n g ' s  was no s i g n i f i c a n t b i a s , groups  regarding  In  1A).  patients  annoying  as  procedure  group g e n e r a l l y r a n k i n g l o w e r f o r  Regarding the a f f e c t i v e of  for  show a g e n e r a l i z e d i n c r e a s e f o r  (Graph  rated the  c o m b i n a t i o n was u s e d .  v e r s u s mean r a n k  diazepam/fentanyl  descriptors  patients  droperidol/fentanyl  t h a n when t h e d i a z e p a m / f e n t a n y l r a t i o magnitude  r a t i n g the procedure  d e p e n d i n g on w h i c h d r u g c o m b i n a t i o n was u s e d .  as more i n t e n s e when t h e  descriptors  patients  showed  sex.  F(10,64)=l.5944,  T-Square t e s t  shoed  p < J 2 8 6 between  there  drug  70  GRAPH 2 PATIENT'S  OPINION-AFFECT  DESCRIPTORS  :0UPED DATA AFFECT S C A L E  a'  Ul  My/A  a  m ////A  3-5 AFFECT UNITS U77X DIAZEPAM /TENTANYL  71  SURGICAL RESULTS - The s u r g e o n s  rated  (89%) o f t h e p r o c e d u r e s a s  e x c e l l e n t o r good r e g a r d i n g e a s e o f p e r f o r m a n c e stated  i n t h e methods  the group opinions  s e c t i o n , t h e surgeons were n o t c o g n i z a n t  to which the p a t i e n t s a r e shown  of the surgery.  had been a s s i g n e d .  Composites  As of of  below.  SURGEON OPINION  0  1  DROP/FENT  0 ( 0 %)  3 ( 8 %)  13 (35%)  21  (57%)  DIAZ/FENT  1 (2 %)  4 ( 8 %)  5 (11%)  37  (79%)  I t was f o u n d nions  that  was s i g n i f i c a n t l y b e t t e r  the  surgeon  upheld t h i s  this  of surgery  (Graph 3 ) .  at p £.001.  than d r o p e r i d o l / f e n t a n y l  procedure at t h i s  result  3  t h e r e was a s i g n i f i c a n t d i f f e r e n c e  o f ease o f performance  undergoing  2  for  i n the surgeons'  Diazepam/Fentanyl patients  f a c i l i t y from the p o i n t  Multivariate  F (10,64)=7.257,  of view  a n a l y s i s f o r ungrouped p £.001.  opi-  data  of  72  GRAPH  3  S U R G E O N OPINION ATI  z < a  till  O £ ••i a s  llll  I*"  li> -I  _  I  1  ZZ)  DROPZRiDOL/FENTANTY'L  OPiNiOrJ SCALE  isS  DIAZ EPAM/FENTANYL  73  ANAESTHETIC RESULTS  In surgery, normal  -  keeping with e t h i c a l  practices necessary i n conducting  the a n a e s t h e t i s t s conducted the sedation i n keeping  hospital  p r o c e d u r e s and a n a e s t h e s i a p r a c t i c e s .  the p a t i e n t s were t i t r a t e d  this  c o o p e r a t i v e y e t awake  In o r d e r t o t i t r a t e  a drug to a p a t i e n t ' s  r e a c t i o n s must be made.  manufacturers  recommendations,  of  need,  c o n s i d e r a t i o n s as t o t h e a g e , p h y s i c a l s t a t u s , and  p o s s i b l e drug  full  patient.  r e a s o n i t was d e c i d e d t h a t a f i x e d d o s e r e g i m e n was n o t  indicated. numerous  Therefore,  to safe l e v e l s o f sedation i n keeping  w i t h t h e s u r g e o n ' s need f o r a c a l m , For  with  In k e e p i n g w i t h  t h e drug doses were  reduced  t h e r a p e u t i c d o s e s when c o m b i n e d w i t h f e n t a n y l .  d o s e s f o r e a c h d r u g when c o m b i n e d w i t h  Recommended Experimental  dose dose  fentanyl  the drug from  Comparison a r e shown  below.  Diazepam  Droperidol  Fentanyl  5 . 0 - 1 0 . 0 mg  2.3-5.0  50-100 yg  5.4mg 5 0 2 . 4  -  mg  53ug SD28  1.7mg 5 0 . 8  6 6 u g SD57  I t may be s e e n t h a t when p a t i e n t s w e r e t i t r a t e d t o s e d a t e d levels  that  t h e mean d r u g d o s e s u s e d w e r e w i t h i n t h e m a n u f a c t u r e r s '  recommendations. droperidol  S i g n i f i c a n t l y more f e n t a n y l  than w i t h  increments o f fentanyl  diazepam,  was u s e d when c o m b i n e d  F(10,64)=7.257,  p^.0001. Additional  w e r e more commonly g i v e n when d r o p e r i d o l was  u s e d t h a n when d i a z e p a m was u s e d .  with  74  SCORE - O v e r a l l 0  1  sedation  2  (from  p.61)  3  4  5  DRUG TREATMENT (%)  (%)  (%)  (%)  (%)  Droperidol/Fentanyl  0  11  (30)  25 ( 6 8 )  1  (2)_  0  0  Diazepam/Fentanyl  0  10  (22)  34 ( 7 2 )  1  (2)  1 (2)  1  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 overall drug to  sedation achieved during the procedure  groups  (67%) w e r e  cooperative  and a n x i e t y  category.  free,  the patient  anaesthetist  2, only  in  as t o  both  according  the majority  of  patients  (26%) w e r e s e d a t e d t o t h e awake  As i t i s t h e i n t e n t i o n o f c o n s c i o u s  patients  t h e drowsy  with  reflexes  stage.  intact,  i s t o s e d a t e on t h e ' l i g h t '  a p p e a r e d t o be a p o w e r f u l  cooperative  (6%) o f t h e  drapes  patients  (the patient  f o r the eye) the obvious  c o n t a c t was v i a a n a e s t h e t i s t - p a t i e n t  yet  Considering the d i f f i c u l t y  due t o t h e s u r g i c a l  completely covered except  this  i . e . patients  that  i t i s s i g n i f i c a n t that only  s e d a t e d beyond  viewing  While i t i s apparent  sedated to category  sedation to maintain  were  drug groups  a p p e a r e d t o have b e e n s e d a t e d t o t h e same l e v e l  t h e above s c a l e .  but  between  side.  hand h o l d i n g .  is  preference  The o n l y  of  f o r the  physical  F o r many  patients  and p o s i t i v e a i d d u r i n g t h e procedure.  (2)  75  Results  f o r the anaesthetist  rating of the overall  procedure a r e : ( f r o m p . 62)  ANAESTHETIST OPINION  DRUG TREATMENT  0  K*).  2(.«)  DROPERIDOL/FENTANYL  0  5(14%)  10 (27%)  DIAZEPAM/FENTANYL  1  7(15%)  5  3(«) 22 (59%) 34  (11%)  (74%)  30 -\  ^  1  20  15 -}  5-4  ^»f  r  -  -r c  «.« »a * i  ^1  1771 DROP ESI CXJL/FENTANVl.  x  OPINION SCALE  p * - * * •"  DiAZ EPAM/ FENTANYL  76 Chi-square a n a l y s i s at g r e a t e r number o f i n the  ct £  .01 s h o w e d t h e r e was a s i g n i f i c a n t l y  c a s e s r a t e d a s good o r e x c e l l e n t f o r  diazepam/fentanyl  group than  the  it  drug  others'  S y s t e m a t i c e r r o r c a n be r u l e d o u t  c a s e s by e a c h a n a e s t h e t i s t was e v e n l y  since  of  the  distributed  between  groups.  Regarding  hemodynamic/respiratory With both drug group  cases.  This  consequences  i s not for  As t h e  the  drug a d m i n i s t r a t i o n , i n  any p a t i e n t s  (PVC's)  i n e i t h e r drug group.  group e x h i b i t e d premature  approximately  Signs of increases by t h e  T h e r e w e r e no r e c u r r e n c e s o f  increased sympathetic  in pulse rate,  doses o f  drug i n j e c t i o n .  the diazepam/fentanyl  group.  This  terminated  r e s p o n s e , such as discomfort  increments of  a n a e s t h e t i c were g i v e n .  c a s e was r e s p i r a t o r y d i s t r e s s n o t e d .  cardiac  these episodes.  r e s t l e s s n e s s , and e x p r e s s i o n s o f  local  in  ventricular  P V C ' s were  p a t i e n t w e r e t r e a t e d by g i v i n g a d d i t i o n a l  No a d d i t i o n a l  blood  most  f r e q u e n c y was i n c r e a s i n g o v e r t h e n e x t two m i n u t e s ,  a minute.  in  One p a t i e n t  f i v e minutes a f t e r  l i d o c a i n e was a d m i n i s t e r e d , a n d t h e e p i s o d e s o f within  experiment;  an u n e x p e c t e d o c c u r r e n c e a n d t h e r e w e r e no s e r i o u s  droperidol/fentanyl  contractions  results of  combinations a t r a n s i e n t f a l l  p r e s s u r e was n o t e d s h o r t l y a f t e r  the  aware o f e a c h  group.  i s u n l i k e l y that observer bias entered i n t o the opinions  anaesthetists.  number o f  data,  i n the d r o p e r i d o l / f e n t a n y l  S i n c e t h e e i g h t a n a e s t h e t i s t s were n o t opinions  grouped  In o n l y  fentanyl. one  occurred in a patient  He was t r e m b l i n g s e v e r e l y upon  from  arrival  77  at  post  anaesthetic  breathing Humidified corrected.  The  trends  different  for  recovery  approximately  (PAR)  and had c o n s i d e r a b l e  ten minutes  after  arrival  o x y g e n by mask was a d m i n i s t e r e d a n d t h e  at  b l o o d p r e s s u r e and p u l s e r a t e s  treatment  g r o u p s a r e shown  self  patient.  patients  i n the  two  below:  Droperidol/ Fentanyl Pulse  for  PAR.  condition  T h e r e w e r e no r e c u r r i n g e p i s o d e s f o r t h i s  of  difficulty  Diazepam/ Fentanyl  BP  Pulse  BP  remained constant  53%  53%  63%  46%  0%  3%  2%  6%  32%  21%  22%  26%  3%  5%  0%  11%  transient increase transient decrease general increase general  F o r b o t h d r u g c o m b i n a t i o n s t h e t e n d a n c y was f o r t h e p u l s e decrease 12% 18% 13% 11% r a t e a n d b l o o d p r e s s u r e t o r e m a i n c o n s t a n t , o r show o n l y a t r a n s i e n t decrease.  78  ADDITIONAL PATIENT COMMENTS -  As t h e e x p e r i m e n t  proceeded,  r e g a r d i n g t h e p r o c e d u r e were n o t e d . from the d r o p e r i d o l / f e n t a n y l irritated  group  i n PAR,yet outwardly  description  a n y u n s o l i c i t e d comments  S p e c i f i c a l l y , four  patients  commented t h e y h a d f e l t  had appeared c a l m .  f r o m one p a t i e n t was t h a t he f e l t  The  quite  best  a s i f he was t r y i n g  t o e s c a p e b u t d i d n o t know w h y , n o r was he a b l e t o e x p r e s s h i s anxiety. but  He commented t h i s  f e e l i n g d i d n o t come on  he n o t i c e d i t b e g i n n i n g t o w a r d  c o n t i n u i n g f o r some h o u r s diazepam/fentanyl  Six  t h e end o f t h e procedure and  afterward.  None o f t h e p a t i e n t s  g r o u p made s i m i l a r  other  patients  the end o f the procedure. droperidol/fentanyl  group.  commented t h e y f e l t  Five of these patients  routine  procedures of t h i s  practice for surgical  procedure additional the  from the s t a r t  as o n l y  from the  (GARAMYCIN), a  nature.  PROCEDURE  o f the a d m i n i s t r a t i o n o f the drug  t o a maximum o f 90 m i n u t e s  i n PAR.  at  range o f a n a e s t h e t i c times o c c u r e d , r a n g i n g from a  minimum o f 20 m i n u t e s  patient  were  or gentamicin  REQUIRED FOR PERFORMANCE OF THE SURGICAL  intravenously,  the 'needles'  They were r e f e r r i n g t o t h e i n j e c t i o n (ANCEF)  A wide  from the  comments.  subconjuntivally of cefalozin  TIME  immediately  to the a r r i v a l  Where t h e a n a e s t h e t i s t s m o s t o f t e n fair,  the procedures took over  increments o f fentanyl  longer the procedure,  t h e more  rated the o v e r a l l  an h o u r ,  had been a d m i n i s t e r e d . restless  o f the  the patient  and Generally  tended  to  79  become. narrow  This  w o u l d be an e x p e c t e d  and h a r d ,  the drapes  t h e i r maximum s e d a t i v e anaesthetic effect  For significant especially  result,  totally  cover the p a t i e n t ,  e f f e c t s over  20-30 minutes,  difference  in patients'  scores,  F(10,12)=7.8358,p_<.0007.  f o r both  t i m e was l e s s  found  no s i g n i f i c a n t d i f f e r e n c e  mean a n a e s t h e t i c was 4 8 m i n u t e s ,  scores i n both drug  t h a n 45 m i n u t e s ,  lasted less  time  for patients  lose  local  progressed.  t h e r e was a sensory and  both  s c o r e d much l o w e r  when  surgeons and a n a e s t h e t i s t s  i n opinion f o r the o v e r a l l than  is  combinations,  While the p a t i e n t s  total  when t h e p r o c e d u r e  t h a n 45 m i n u t e s  the drugs  and t h e  would a l s o d e c r e a s e as the procedure  a n a e s t h e t i c time l e s s  affect  as t h e o p e r a t i n g t a b l e  or greater  procedure  t h a n 45 m i n u t e s .  i n the droperidol/fentanyl  and f o r t h e d i a z e p a m / f e n t a n y l  g r o u p was 37  The group  minutes.  80  DISCUSSION  Psychological their  l e v e l s of  pre-operative  anxiety  t e s t i n g showed t h e p a t i e n t s for  general  and p o s t - o p e r a t i v e  While both  drug combinations  procedure,  patients  tended to  droperidol/fentanyl affect,  have The  the  patient  droperidol possible, the  these  the  Regarding group  choices offered. the o t h e r eye  if  it  simply could not  in opinion  However i t  all  patients,  i s due  or that  i s not  procedure  happy  to  necessary.  s t o r a g e may be r e s p o n s i b l e  not  remember,  the  of  rated the  became  out.  if  opinion  Many w e r e  to  the  it  for  and  is  fact  t h e d i f f e r e n c e was  p o s s i b l e to  both  surgical  p r o c e d u r e more i n t e n s e  diazepam/fentanyl  for  the  S i n c e d i a z e p a m has an a m n e s i c e f f e c t ,  difference  drug i t s e l f .  prove  either  due  of  possibilities.  the  thus  the  d i a z e p a m on memory  response.  that  opinion of  for  repeated, of  Surgical  at  the  carried  t o be s u c c e s s f u l f o r  h a s a l s o , b u t o n l y on s o m e ,  patient the  in the  any o f  procedure  strong effect  this  to  than  find  in  patients with  as t o t h e t e s t s  c o m b i n a t i o n was u s e d .  many p a t i e n t s  as b e i n g l e s s  medical s u r g i c a l  anxiety  proved  were t y p i c a l  opinion  showed t h e r e  diazepam/fentanyl  for  this  surgical  good v e r s u s e x c e l l e n t s t a n d a r d .  the the  difference ease o f  It titrated  the  i n degree of  performance  of  was a s i g n i f i c a n t l y procedure,  Numerous  sedation noted the  i s i n t e r e s t i n g to note  surgical  that  better  when  rated  possibilities  exist  i n the p a t i e n t  and  procedure.  w h i l e the  anaesthetists  a n a e s t h e t i c doses so p a t i e n t s would remain c o n s c i o u s  81  yet  cooperative,  group were w e l l  t h e doses a d m i n i s t e r e d to p a t i e n t s  i n the droperidol  b e l o w t h e recommended d o s e o f t h e m a n u f a c t u r e r ;  however  t h e d o s e s f o r t h e d i a z e p a m g r o u p w e r e w i t h i n t h e recommended d o s e o f the manufacturer.  Other than wanting  to avoid possible  depression or excessive sedative e f f e c t s , complications with  both d r o p e r i d o l  since these are p o s s i b l e  and diazepam,  all  t h e a n a e s t h e t i s t s was t h a t t h e m a n u f a c t u r e r  too  high.  the opinion  droperidol  popular  several years ago.  r e l a t i v e t o t h e amount o f f e n t a n y l  amongst  recommended d o s e was  One d r u g c o m b i n a t i o n o f d r o p e r i d o l a n d f e n t a n y l  INNOVAR h a d become q u i t e of  respiratory  called  H o w e v e r t h e amount  present  i n the drug  r a t i o was s u c h t h a t o n e h a d t o a d m i n i s t e r a c o n s i d e r a b l e amount o f t h e drug t o o b t a i n patients  the benefit of the fentanyl.  The r e s u l t was t h a t t h e  r e c e i v e d t o o much d r o p e r i d o l , a n d a d v e r s e e f f e c t s o f d r o p e r i d o l  were o b s e r v e d r e l a t i v e l y o f t e n , extrapyramidal  symptoms,  commonly u s e d i n m a j o r  i . e . respiratory depression,  and e x c e s s i v e s e d a t i o n .  INNOVAR i s n o t  c e n t r e s now, y e t t h e c o m b i n a t i o n i s p o p u l a r ,  when t h e a n a e s t h e t i s t c o m b i n e s t h e two d r u g s h i m s e l f . sacrifice  i n dosage t o m i n i m i z e  sedative effect. sedative effects  with  complications also decreases the  The t h e r a p e u t i c  remained c o n s t a n t ,  decreases.  for droperidol  regarding  diazepam.  b o t h d r u g s c a u s e d hemodynamic c h a n g e s i n k e e p i n g  drug manufacturer warnings.  pressure  index  i s narrower than t h a t o f  As e x p e c t e d ,  Perhaps t h e  though  Generally  p u l s e r a t e and b l o o d  some p a t i e n t s  None o f t h e c h a n g e s was s i g n i f i c a n t .  showed  transient  82  T h e r e was a s i g n i f i c a n t d i f f e r e n c e b e t w e e n c o m b i n a t i o n s as t o t h e procedure,  p^.008.  48 m i n u t e s , both  The  and f o r  the  as t i m e  for  effective  was 37 m i n u t e s . by  the considered  during the procedure increased i n  t h e p r o c e d u r e e x c e e d e d 45 m i n u t e s ,  and found  be c o n s i d e r a b l y g r e a t e r a s  severity the  well.  T h e r e was no s i g n i f i c a n t d i f f e r e n c e i n t h e amount depression observed i n t r a - o p e r a t i v e l y nor p o s t - o p e r a t i v e l y . b o t h d r u g s w e r e c o n s i d e r e d t o be c l i n i c a l l y e q u i v a l e n t  Due t o t h e age o f do n o t  gain f u l l  v i s i o n immediately a f t e r  difficult  to evaluate  could not  be o b t a i n e d .  kept  i n PAR  p r i o r to  psychomotor Judging  to  sit  the ward.  remained about frail  were  and d r i n k  kept about  two  hours.  aspect.  patients was  When  w e r e d i s m i s s e d t h e same d a y ,  to  patients  be t h e  the d r u g .  Interestingly,  were  d i d not appear  f l u i d s , t h e y were  regardless of  Therefore  time p a t i e n t s  T h o s e who w e r e p h y s i c a l l y w e l l  a n h o u r i n PAR  received droperidol  surgery.  there  s i g n i f i c a n t f a c t o r h e r e seemed t o  condition.  diazepam/fentanyl  the ward,  it  CNS.  as a r e l i a b l e b a s e - l i n e  two d r u g c o m b i n a t i o n s .  up u n s u p p o r t e d  The  age a n d g e n e r a l  the  the procedure,  impairment,  of  in this  and t h e f a c t t h a t  f r o m t h e amount o f  returning to  be a d i f f e r e n c e b e t w e e n were a b l e t o  the p a t i e n t s  was  Although  and s u r g e o n s i n t h i s a s p e c t , t h e p a t i e n t s  q u a l i t i e s to  the  average time f o r d r o p e r i d o l / f e n t a n y l  diazepam/fentanyl  sensation f e l t  group  t i m e needed t o c a r r y o u t  c o m b i n a t i o n s were c o n s i d e r e d e q u a l l y e f f e c t i v e  anaesthetists that  amount o f  drug  returned patient's usually  T h o s e who  no p a t i e n t s who while five  of  p a t i e n t s were d i s m i s s e d w i t h i n a few hours o f  were had  the the  83  Regarding the e s t a b l i s h m e n t of a uniform p r o t o c o l use o f  intravenous  complications, and s u r g i c a l methods  sedative procedures, c o n s i d e r i n g the  good p a t i e n t  handling of  a c c e p t a n c e , and u n i f o r m i t y  the procedure,  i s a good o u t l i n e f o r  duration  in-patient  surgical  the  of  a water  effects.  Not day,  the  diazepam,  amnesic e f f e c t s and t h e  midazolam,  due t o  local  have l e s s are  surgery.  sufficiently  of  the  patient  thus  or  the  short  use  s h o r t o n s e t and available in  of  duration  Canada. following  be s i m i l a r t o t h o s e  of  diazepam are m i s s i n g w i t h  the s u r g e r y ,  The m a j o r p r o b l e m i s t o  so t h e  outlined in  solubility.  c o u l d have a r i s e n r e g a r d i n g t h e d e p t h o f the  anaesthetic  r e s i d u a l drowsiness the  reported to  Due t o t h e d e l i c a t e n a t u r e  out  with  i r r i t a n t effects of  i t s water  of  t o d i a z e p a m m i g h t be t h e  U n f o r t u n a t l e y t h i s drug i s not y e t patient  of  the  procedures.  soluble benzodiazepine  o n l y would the  lack  handling of out-patient  An i n t e r e s t i n g a l t e r n a t i v e midazolam,  the protocol  for  procedure w i l l  c e r t a i n problems  sedation necessary to sedate the  be p a i n l e s s y e t  carry  patient  not  over-sedate  r i s k i n g respiratory depression or other  adverse  effects.  W h i l e some m i g h t a d v o c a t e have c r e a t e d t h e p r o b l e m i n t h a t in  some b u t n o t  some p a t i e n t s .  all patients, The  a f i x e d dose regimen, t h i s  t h e d o s e may h a v e b e e n  sufficient  o r m i g h t have p r o d u c e d o v e r  added f a c t t h a t most o f  would  sedation  t h e p a t i e n t s were  a n d d e b i l i t a t e d a l s o w o u l d be a c o n t r a i n d i c a t i o n f o r a f i x e d  in  elderly dose,  84 since  these p a t i e n t s  in  different  is  to  titrate  a l l metabolize  magnitudes. the  patient  The  drugs at d i f f e r e n t  best technique,  to a safe l e v e l  rates,  and  albeit a subjective  given uniform q u a l i t i e s .  react one,  85  SUMMARY The diazepam, for  the  comparison of  two c o n v e n t i o n a l  when c o m b i n e d w i t h  administration of  of  sedation of  the  patients  cataract extraction  judiciously drug  proved to  be s u c c e s s f u l  t h a t was n e e d e d f o r  few c o m p l i c a t i o n s were n o t e d  and  protocol  outlined.  for  the  providing  surgical  systemically for  procedure  When  used  either  combination.  combinations procedure. their  regarding surgeons' Diazepam/fentanyl  anxiety  fentanyl  between  t h e two  drug  o p i n i o n o f ease o f c a r r y i n g out  proved  superiod to  the  droperidol/fentanyl  opinion.  The of  A safe  and i n t r a - o c u l a r l e n s r e p l a c e m e n t .  A s i g n i f i c a n t d i f f e r e n c e was f o u n d  in  droperidol  was c a r r i e d o u t .  t h e s e d r u g c o m b i n a t i o n s was  Both combinations the  fentanyl  sedatives  patients  between  group  procedure  to  a l s o f o u n d t h e r e was a d i f f e r e n c e  t h e two  drug groups.  Patients  found  both  s e n s o r y and a f f e c t i v e  be l e s s  than  d i d the p a t i e n t s  i n the  in  diazepam/  q u a l i t i e s of  i n the  alleviation  the  droperidol/fentanyl  group.  For 45 m i n u t e s Since the and b o t h  both  drug groups,  when t h e a n a e s t h e t i c t i m e  t h e p r o c e d u r e was r a t e d more s e v e r e by p a t i e n t a n a e s t h e t i c outcome  the  combination  patient  and t h e  s u p e r i o r to  the  for  b o t h p r o c e d u r e s was  surgeon  found the  droperidol/fentanyl  exceeded indicators.  equivalent,  diazepam/fentanyl combination,  the  use  86  of  diazepam  or another  benzodiazepine  such s u r g i c a l procedures. extrapyramidal use whenever  effects possible.  with  s h o u l d be u s e d when p o s s i b l e  In a d d i t i o n ,  the  benzodiazepines  lack of  the  i s another  for  possibility reason f o r  of  their  87  ACKNOWLEDGEMENT  To t h e f o l l o w i n g p e o p l e for  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 h e i r a s s i s t a n c e and a d v i c e f o r t h i s t h e s i s : Dr.  David  Donaldson  -  Dentistry  Dr.  J o h n H. M c N e i l l  -  Pharmacy  Dr.  Kenneth  -  Psychology  Dr.  Bruce B l a s b e r g  -  Dentistry  Craig  F o r a d v i c e a n d a s s i s t a n c e d u r i n g t h e s t u d y a t t h e UBC A c u t e Care  Centre Dr.  B e r n a r d MacLeod  -  Dr.  Hugo S u t t o n  -  Ophthalmology  L i s a Mowatt  -  Psychology  Nick  -  Psychology  -  Psychology  Rizzo  Colleen  Grimshaw  and t h e A n a e s t h e t i s t s , participated For for  Ophthalmologists  a n d t h e i r p a t i e n t s who  i n the study. assistance i n c a r r y i n g out the s t a t i s t i c a l  t e s t s , and  composing the computer g r a p h i c s : Lyla For  Yip  -  Dentistry  g r a n t i n g me a c c e s s t o t h e i r o f f i c e s on n u m e r o u s o c c a s i o n s .  Rosalind Tobias  -  Dentistry  Judith  -  Dentistry  -  Pharmacy  For  W i l l cox  typing the t h e s i s  Celine  Gunawardene  and t o t h e F a c u l t y for  Anaesthesia  of Dentistry,  offering the opportunity  University of British  Columbia,  t o c a r r y o u t the program o f s t u d i e s  THANK YOU  89  APPENDIX 2  The patient  f o l l o w i n g i s representative of  the approach to  r e q u e s t i n g he o r s h e p a r t i c i p a t e i n t h e  the  experiment.  We a r e c u r r e n t l y c o n d u c t i n g a s t u d y t o c o m p a r e two o f t h e d r u g s we u s e f o r p a t i e n t s who a r e h a v i n g e y e p r o c e d u r e s s u c h a s y o u r s . Only n o r m a l p r o c e d u r e s w i l l be f o l l o w e d . We a r e a s k i n g p a t i e n t s t o a n s w e r some q u e s t i o n s a b o u t how t h e y f e e l b e f o r e t h e p r o c e d u r e , a n d t h e n some o t h e r q u e s t i o n s when t h e p r o c e d u r e i s f i n i s h e d . This w i l l t a k e a b o u t 1 0 - 1 5 m i n u t e s o f y o u r t i m e . You a r e n o t u n d e r a n y d e l i g a t i o n t o p a r t i c i p a t e , and i f y o u a g r e e t o p a r t i c i p a t e and l a t e r c h a n g e y o u r m i n d t h a t w i l l be f i n e . I t w i l l n o t e f f e c t t h e p r o c e d u r e o r y o u r t r e a t m e n t i n any way. I h a v e a c o n s e n t f o r m I am g o i n g t o r e a d t o y o u a n d i f y o u a r e w i l l i n g t o p a r t i c i p a t e then I w i l l ask you to s i g n . Do y o u h a v e any q u e s t i o n s ?  Patient I, study.  #  agree to p a r t i c i p a t e i n  this  I u n d e r s t a n d t h e t r e a t m e n t w i l l n o t v a r y f r o m any normal p r o c e d u r e s which are u s u a l l y followed f o r p a t i e n t s undergoing c a t a r a c t removal. I u n d e r s t a n d t h e p u r p o s e i s t o compare t h e e f f e c t s o f d r u g s used i n p a t i e n t s undergoing c a t a r a c t r e m o v a l . I u n d e r s t a n d t h o s e who A n a e s t h e s i o l o g i s t , the me t h e q u e s t i o n s b e f o r e appear anywhere e x c e p t Time i n v o l v e d t o total.  normally  w i l l be i n v o l v e d i n t h e s t u d y a r e m y s e l f , t h e o p h t h a l m o l o g i s t , a n d an o b s e r v e r who w i l l a s k and a f t e r t h e s u r g e r y . My name w i l l n o t a s n o r m a l l y i t w o u l d a p p e a r on m e d i c a l r e c o r d s .  answer the q u e s t i o n s w i l l  be a b o u t  10-15  minutes  I u n d e r s t a n d I may r e f u s e t o e n t e r t h e s t u d y o r w i t h d r a w f r o m i t a n y t i m e i f I s o c h o o s e w i t h o u t i t e f f e c t i n g my t r e a t m e n t i n any  Patient Witness Date  Signature  in  at way.  90 APPENDIX - 3-STATE SELF-EVALUATION QUESTIONNAIRE  Developed by C. D. Spielberger, R. L. Gorsuch and R. Lushene STAI F O R M  X-1  NAME  DATE  DIRECTIONS: A number of statements which people have used to describe themselves are given below. Read each statement and then blacken in the appropriate circle to the right of the statement to indicate how you feel right now, that is, at this moment. There are no right or wrong answers. Do not spend too much time on any one statement but give the answer  | >  2 S  S § C jjj  <  s  F  5  $  8  ©  ®  ®  ®  2. I feel secure  ©  ®  ®  ®  3. I am tense  ©  ®  ®  ®  4. I am regretful  ©  ®  ®  ®  5. I feel at ease  ©  ®  ®  ®  6. I feel upset  ©  ®  ®  ®  7. I am presently worrying over possible misfortunes  ©  ®  ®  ®  8. I feel rested  ©  ®  ®  ®  9. I feel anxious  ©  ®  ®  ®  ©  ®  ®  ®  11. I feel self-confident  ®  ®  ®  ®  12. I feel nervous  ©  .®  ®  ®  13. I am jittery  ©  ®  ®  ®  14. I feel "high strung"  ©  ®  ®  ®  15. I am relaxed  ©  ©  ®  ®  16. I feel content  ©  ®  ®  ®  17. I am worried  ®  ®  ®  ®  18. I feel over-excited and "rattled"  ®  ®  ®  ®  19. I feel joyful  ®  ®  ®  ®  20. I feel pleasant  ®  ®  ®  ®  which seems to describe your present feelings best. 1. I feel calm  :  10. I feel comfortable  :  < E •<  91 APPENDIX - 3 TRAIT SELF-EVALUATION  QUESTIONNAIRE  S T A I F O R M X-2  NAME  :  DATE  D I R E C T I O N S : A number of statements which people have used to describe themselves are given below. Read each statement and then blacken in the appropriate circle to the right of the statement to indicate how you generally feel. There are no right or wrong answers. Do not spend too much time on any one statement but give the answer which seems to describe how you generally feel.  :  g z 5 E  S § 3 S 2  c 3 z  t o § * > 2  21. I feel pleasant  ©  ®  ®  ®  22. I tire quickly  ©  ®  ®  ®  ©  ®  ®  ®  24. I wish I could be as happy as others seem to be  ©  ®  ®  ®  25. I am losing out on things because I can't make up my mind soon enough....  ©  ®  ®  ®  26. I feel rested  ®  ®  ®  ®  27. I am "calm, cool, and collected"  ©  ®  ®  ®  28. I feel that difficulties are piling up so that I cannot overcome them  ©  ®  ®  ®  29. I worry too much over something that really doesn't matter  ©  ®  ®  ®  30. I am happy  ©  ®  ®  ®  ©  ®  ®  ®  ©  ®  ®  ®  33. I feel secure  ©  ®  ®  ®  34. I try to avoid facing a crisis or difficulty  ©  ®  ®  ®  ©  ®  ®  ©  36. I am content  ©  ®  ®  ®  37. Some unimportant thought runs through my mind and bothers me  ©  ®  ®  ®  38. I take disappointments so keenly that I can't put them out of my mind ....  ©  ®  ®  ®  39. I am a steady person  ©  ®  ®  ®  ©  ®  ®  ®  23. I feel like crying  .'.  ^  '.  :  31. I am inclined to take things hard 32. I lack self-confidence  35. I feel blue  .„,...-  :  40. I get in a state of tension or turmoil as I think over my recent concerns and interests  92 APPENDIX 4  9-1  am g o i n g t o  have j u s t the  had.  ask you  some q u e s t i o n s  about  When t h e s u r g e r y was t a k i n g  s e n s a t i o n you  felt  at  the most  intense  the eye s u r g e r y  that  p l a c e how w o u l d y o u  you  describe  time?  0 0 - E x t r e m e l y weak 01- Faint 0 2 - V e r y weak 03- Verv-jnild 04- M i l d 0 5 - Very moderate 0 6 - S l i g h t l y moderate 07- Moderate 08- Barely strong 09- Clear cut 10- S l i g h t l y i n t e n s e 11- S t r o n g 12- Intense 13- Very i n t e n s e 14- E x t r e m e l y i n t e n s e  10-1  am g o i n g t o  general.  a s k y o u how y o u w o u l d  Which o f  the  s u r g e r y you  000102030405060708091011121314-  Distracting Annoying l)ncomfortable Unpleasant Irritating Upsetting Distressing Miserable Frightful Dreadful Horrible Agonizing Intolerable Unbearable Excruciating  the f o l l o w i n g  have j u s t  had?  rate  the o v e r a l l  best describes your  surgery  feelings  for  in  93 UBC  HEALTH SCIENCES CENTRE  HOSPITAL  APPENDIX 5  ANAESTHESIA RECORD PREOPERATIVE  ANAESTHETIST OPERATION SURGEON ANAESTHETIC MANAGEMENT  200  TIME !  180  i  I I I  160 140 120 100  I  *  80 60 40 20  POSTOPERATIVE  I  I  94 BIBLIOGRAPHY  1.  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F u r t h e r Communication C u r r e n t T h e r a p e u t i c R e s e a r c h , V o l . 2 8 , #1, J u l y 1980.  97  39.  S t a t e T r a i t A n x i e t y Inventory (STAI) Manual, S p i e l b u r g e r C D . , Gorsuch R . L . , Lushene R . E . , Psychologist Press  1970  40.  R a t i o S c a l e s o f S e n s o r y and A f f e c t i v e V e r b a l P a i n D e s c r i p t o r s , G r a c e l y R . H . , M c G r a t h P . , D u b n e r R . , PAIN 5 ( 1 9 7 8 ) 5 - 1 8 .  41.  L.  42.  S.M.  43.  H.  L a b o r i t , P . H u g y e n a r d : P r a t i q u e , de L - H i b e r n o t h e r a p i e in Chirurgie et in Medicine. P a r i s , Masson e t c i e , 1954.  44.  J.  B o v i l l , P. S e b e l , T. S t a n l e y . Opioid Analgesics in Anaesthesia: W i t h S p e c i a l R e f e r e n c e t o T h e i r Use i n C a r d i o v a s c u l a r A n a e s t h e s i a , A n a e s t h e s i o l o g y 6 1 : 7 3 2 , 1984.  45.  J.  E d m o n d s - S e a l , C. P r y s - R o e r t s : P h a r m a c o l o g y o f D r u g s i n Neuroleptanalgesia. B r . J . Anaes (46) 2 8 8 - 2 9 3 , 1974.  46.  S t a n l e y T . H . , W e b s t e r L . R . , : A n a e s t h e t i c R e q u i r e m e n t s and C a r d i o v a s c u l a r E f f e c t s o f F e n t a n y l - O x y g e n and Fentanyl-DiazepamOxygen A n a e s t h e s i a i n M a n . A n a e s t h e s i a a n d A n a l g e s i a 5 7 : 4 1 1 - 4 1 6 , 1978.  47.  Bennett C . R . , C o n s c i o u s S e d a t i o n : An A l t e r n a t i v e J . D e n t R e s t 63 ( 6 ) : 8 3 2 - 8 3 3 J u n e , 1984.  48.  Donaldson D., Gibson G . , Local Complica i o n s w i t h Intravenous D i a z e p a m J . C a n a d i a n D e n t a l A s s o c i a t i o n #7: 3 3 7 - 3 4 1 , 1979.  49.  Compendium o f P h a r m a c e u t i c a l s a n d S p e c i a l t i e s C a n a d i a n P h a r m a c e u t i c a l A s s o c i a t i o n , 1984 p . 3 0 2 .  50.  Hayden, I. c h a p t e r II i n S e d a t i o n , Locan and G e n e r a l D e n t i s t r y . Lea and F e b i g e r , 1980.  B e r g g r e n , I. E r i k s o n , P. M o l l e n h o l t . Sedation for Fibreoptic Gastroscopy: A Comparative Study o f Midazolam and Diazepam B r . J . A n a e s t h . 1983 A p r ; 5 5 ( 4 ) : 2 8 9 - 9 6 . Aurebach. T r a i t - S t a t e A n x i e t y and Adjustment J o u r n a l o f C o n s u l t i n g and C l i n i c a l P s y c h o l o g y , #2, 2 6 4 - 2 7 1 .  to Surgery, 1973, V o l . 4 0 ,  to General  Anaesthesia  Anaesthesia  in  98  <TSOUARE V A R - V 4 - V 1 3 S T R A T - V 1 - . 1 H O T E L L l N G ' S T-SOUARE T-SOUAREEOUALITY  18.187  D-SOUARE-  N  .98412  OF STRATUM M E A N S : MEANS  VARIABLE 4 . PRE 5 . POST 6 . TRAIT 7.SENS 8.AFF 9.OPIN 10.SED 11. TIME 12. T0TF 13 . T O  2>  DF-  10.  64  F-  1.5944  SIG-  .1286  FOR SEX  M 3 9 . 152 44.394 42.242 6.0909 1 .4545 2.6364 2.5152 38.333 43.485 .27576 "33"  -1  F 43.071 43.905 45.119 7.8333 2.7619 2.5714 2.5000 45.000 59.286 .29048 42  -1  <TSOUARE V A R - 4 - 1 3 S T R A T - V 1 1 : ( 2 0 . 4 5 ) . ( 4 6 , 9 0 ) > H O T E L L l N G ' S T-SOUARE <1> T I M E : ( 2 0 , 4 5 ) <2> T I M E : ( 4 6 , 9 0 ) T-SOUAREEQUALITY  137.13  D-SOUARE-  OF STRATUM M E A N S : MEANS  VARIABLE 4.PRE 5.POST 6.TRAIT 7.SENS 8.AFF 9.0PIN 10.SED 11.TIME 12.T0TF 13.TD  N <STOP>  <1> 38.143 39.952 41.905 6.8095 1.1429 2.6190 2.2857 29.524 40.O0O .28571 21  75.094 DF-  10.  FOR T I M E  -1  12 „  <2> 48.000 44.500 49.OO0 8.50O0 6.0000 2.5000 2.5000 90.000 65.000 .15000 2  -1  F-  7.8358  SIG-  .0007  )  99  <ANOVA V A R - 4 - 5 S T R A T - V 3 : 1 . 2 UNIVARIATE 1-WAY ANOVA  ANALYSIS  OF  VARIANCE  OF  COMBIN-1.-2.1;ALLPAIRS  4 . V 4  N-  75  OUT  OF  SOURCE  DF  BETWEEN WITHIN  1 73  418.67 5526.3  418.67 75.703  TOTAL  74  5945.0  (RANDOM  ETA-  .2654  V3  ETA-SQR-  N  S U M OF  .0704  MEAN  SORS  (VAR  MEAN  COMP-  VARIANCE  75  SOR  F-STATISTIC  EFFECTS  34  43.941  74.784  8.6478  (2)  41  39.195  76.461  8.7442  GRAND  75  41.347  80.338  8.9631  MULTIPLE COMPARISON PREDICTED F-STAT SIGNIF  - 3 4 . 4 4 9  1.OOOO  PAIRWISE STRATA  (1)  4.7461  UNIVARIATE  OF  1-WAY  5.5304  .0214  3.3622  ANOVA  VARIANCE  OF  5 . V 5  7*5 O U T  1  248.20  248.20  6505.7 6753.9  8 9 .1 2 0 (RANDOM  .0367  SORS  OF  73 74 ETA-SOR-  S U M OF  N »  BETWEEN WITHIN TOTAL  V3  (VAR  MEAN  COMP-  75  SOR  MEAN  (1)  34  46.118  75.925  8.7135  (2)  41  42.463  100.00  10.000  GRAND  75  44. 120  91.269  9.5535  OBSERVED  MULTIPLE PREDICTED  STD  VARIANCE  COMPARISON F-STAT  F-STATISTIC 2.7850 EFFECTS  4.2793  N  CONTRAST  10.86)  SCHEFFE ALLOWANCES LEV-.9000  DF  .1917  AMONG-  SCHEFFE ALLOWANCES LEV=.9O00  SOURCE  ETA-  STATISTICS)  .OOOO  MULTIPLE COMPARISON DIFF F-STAT SIGNIF  (2)  ANALYSIS  130.73  */.VAR  .0214  DEV  (1)  CONTRAST OBSERVED  SIGNIF  5.5304  9.2260  STD  LEVELS-.9>  SIGNIF  SIGNIF .0994  STATISTICS)  %VAR AMONG- 4 . 5 8 )  DEV  SCHEFFE  ALLOWANCES  LEV-.9000  100  <ANOVA VAR-4-5 STRAT-V3:1.2 UNIVARIATE 1-WAY ANOVA  ANALYSIS  OF  VARIANCE  OF  SOURCE  DF  BETWEEN WITHIN TOTAL  1 73 74  ETA-  .2654  V3  ETA - S O R "  N  COMBIN"1,-2.1;ALLPAIRS  4.V4  N-  SUM OF  75  SORS  MEAN  75  SOR  F-STATISTIC  418.67  COMP-  VARIANCE  EFFECTS  34  43.941  74 . 7 8 4  8.6478  41  39.195  76.461  8.7442  GRAND  75  41.347  80.338  8.9631  -34  MULTIPLE COMPARISON PREDICTED F-STAT SIGNIF  .449  1.OOOO  PAIRWISE STRATA  130.73  STATISTICS) 10.86)  DEV  (1) (2)  CONTRAST OBSERVED  .0214  '/.VAR AMONG*  9.2260  STD  SIGNIF  5.5304  75.703 (RANDOM  5945.0 (VAR  OF  MEAN  418.67 5526.3  .0704  OUT  LEVELS-.9>  SCHEFFE ALLOWANCES LEV-.9000  .0000  MULTIPLE COMPARISON DIFF F-STAT SIGNIF  SCHEFFE ALLOWANCES LEV-.9000  (1) (2)  4.7461  UNIVARIATE  ANALYSIS  OF  1-WAY  5.5304  TOTAL .1917  V3  5 . V 5  N-  1  248.20  73 74  6505.7 6753.9  BETWEEN  -  OF  75  DF SUM OF SORS  WITHIN  3.3622  ANOVA  VARIANCE  SOURCE  ETA  .0214  ETA-SQR"  .0367  N  MEAN  OUT  OF  75  MEAN SOR 248.20  (VAR COMP=  4.2793  STD  VARIANCE  46.118  75.925  8.7135  42.463  100.OO  10.000  GRAND  75  4 4 . 1 2 0  91.269  9.5535  9  MULTIPLE  COMPARISON F-STAT  SIGNIF  V.VAR AMONG"  DEV  34  PREDICTED  .0994  (RANDOM EFFECTS STATISTICS)  41  OBSERVED  2.7850  89.120  (1) (2)  CONTRAST  F-STATISTIC SIGNIF  SCHEFFE  ALLOWANCES  LEV-.90O0  4 . 5 8 )  101  (1) (2)  34  4 6 . 2 3 5  43.882  6.6244  41  41.878  41.110  6.4  GRAND  75  4 3 . 8 5 3  46.559  6.8234  UNIVARIATE  ANALYSIS  OF  1-WAY  ANOVA  VARIANCE  SOURCE  117  OF  DF  BETWEEN  7.V7  SUM  N «  OF  7 5 OUT  SORS  MEAN  OF SOR  1  25.413  25.413  WITHIN  73  1205.3  16.510  TOTAL  74  1230.7  (RANDOM  ETA-  .1437  V3  ETA-SOR-  .0206  (VAR  COMP»  F-STATISTIC  EFFECTS  .23948  MEAN  (1) (2)  34  7 . 7 0 5 9  17.365  41  6.5366  15.805  4 . 1672 3.9755  GRAND  75  7 . 0 6 6 7  16.631  4.0781  ANALYSIS  OF  1-WAY  OF  SOURCE  DF  BETWEEN  1 73 74  TOTAL ETA-  .2457  V3  ETA-SOR-  8 . V 8  SUM OF  NSORS  27.610 , 4 2 9 . 7 8 457.39 .0604  7 5 OUT MEAN  SOR  F-STATISTIC  COMP-  .58435  STD  6.6747 5.2378  2.5835  GRAND  75  2.1867  6.1809  2.4861  BETWEEN WITHIN TOTAL  •/.VAR  .0336  STATISTICS) AMONG-  9 . 0 3 )  DEV  2.8529 1.6341  SOURCE  VARIANCE  EFFECTS  34 41  OF  1.43)  SIGNIF  4.6897  (1) (2)  ANALYSIS  AMONG-  75  27.610 5.8874 (RANDOM  ,  (VAR  OF  MEAN  1-WAY  STATISTICS)  DEV  N  UNIVARIATE  •/.VAR  .2187  ANOVA  VARIANCE  WITHIN  STD  SIGNIF  1.5392  N  UNIVARIATE  VARIANCE  75  2.2886  ANOVA  VARIANCE  OF  DF  9 . V 9  SUM  OF  NSORS  75  OUT MEAN  OF SOR  .62195  .62195  73  31.378  .42984  74  32.0O0  (RANDOM  1  75 F-STATISTIC 1.4469 EFFECTS  SIGNIF .2329  STATISTICS)  102 ETA-  .1394 ETA-SOR- .0194 (VAR COMP- .51681 -2 N  V3  MEAN  VARIANCE  STD DEV  (D  (2)  34 41  2.5000 2.6829  .43939 .42195  .66287 .64958  GRAND  75  2.60OO  .43243  .65760  UNIVARIATE  1-WAY ANOVA  ANALYSIS OF VARIANCE OF 10.V10  Between within  1 73 74  TOTAL  .0446  N- 75 OUT OF- 75  DF SUM OF SORS  •SOURCE  ETA-  .80956 -1 40.666 40.747  ETA-SOR- .0020  MEAN SOR  (VAR COMP- -.12808 -1  MEAN  (1) (2)  34 41  2.4706 2.5366  .49911 .60488  .70648 .77774  GRAND  75  2.5067  .55063  .74204  UNIVARIATE  VARIANCE  DF SUM OF SORS  BETWEEN WT THIN TOTAL  1 73 74  V3  STD DEV  N- 75' OUT OF 75  SOURCE  .3043  2255.2 22100. 24355.  ETA-SOR" .0926  MEAN SOR  F-STATISTIC SIGNIF  2255:2 7.4493 .0079 302.73 (RANDOM EFFECTS STATISTICS)  (VAR COMP- 52.522  N  MEAN  (D  (2)  34 41  48.088 37.073  389.42 231.22  19.734 15.206  GRAND  75  42.067  329. 12  18.142  UNIVARIATE  '/.VAR AMONG- -0.  1-WAY ANOVA  ANALYSIS OF VARIANCE OF 11.V11  ETA-  F-STATISTIC SIGNIF  .B0956 -1 .14533 .7041 .55706 (RANDOM EFFECTS STATISTICS)  N  V3  ?.VAR AMONG- 1.19  VARIANCE  STD DEV  1-WAY ANOVA  ANALYSIS O F VARIANCE O F 12.V12  N- 75 OUT OF 75  '/.VAR AMONG- 14.78)  103  SOURCE  DF SUM OF SORS  BETWEEN WITHIN  1 73  4390.5 85626.  4390.5 1173.0  TOTAL  74  90017.  (RANDOM EFFECTS STATISTICS)  ETA" .2208 V3  ETA-SQR" .0488 N  MEAN  (ll)-i, (2)  34 41  60.735 45.366  GRAND  75  52.333  UNIVARIATE 1-WAY  MEAN SOR  F-STATISTIC SIGNIF '  (VAR COMP» 86.556 VARIANCE  -  3.7431  .0569  %VAR AMONG" 6.87)  STD DEV  1724.4 717.99  4 1.526 26.795  1216.4  34.878  ANOVA  ANALYSIS OF VARIANCE OF 13.V13  N" 75 OUT OF 75  SOURCE  DF SUM OF SORS  BETWEEN WITHIN  1 73  296.50 264.96  296.50 3.6295  TOTAL  74  561.45  (RANDOM EFFECTS STATISTICS)  ETA- .7267 V3  ETA-SQR" .5281  MEAN SOR  (VAR COMP- 7.8784  N  MEAN  VARIANCE  STD DEV  (1) (2)  34 41  1.6279 5.6220  .65351 6.0848  .80840 2.4667  GRANO  75  3.8113  7.5872  2.7545  F-STATISTIC SIGNIF 81.690  .OOOO  V.VAR AMONG- 68.46)  

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