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Prescribing in the community hospital : method of assessment and evaluation of modification strategies Jewesson, Peter John 1986

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PRESCRIBING IN THE COMMUNITY HOSPITAL: METHOD OF ASSESSMENT AND EVALUATION OF MODIFICATION STRATEGIES by PETER JOHN JEWESSON B.Sc. (Pharm), The U n i v e r a i t y o f B r i t i s h Columbia, 1978 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n THE FACULTY OF GRADUATE STUDIES ( F a c u l t y o f Pharmaceutical S c i e n c e s ) We accept t h i s t h e s i s as conforming t o the r e q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA A p r i l , 1986 & Peter John Jewesson, 1986 I n 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 o f t h e r e q u i r e m e n t s f o r an a d v a n c e d d e g r e e a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e t h a t t h e L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e a n d s t u d y . I f u r t h e r a g r e e 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 c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d by t h e h e a d o f my d e p a r t m e n t o r by h i s o r h e r r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . D e p a r t m e n t o f The U n i v e r s i t y o f B r i t i s h C o l u m b i a 2075 Wesbrook P l a c e V a n c o u v e r , Canada V6T 1W5 Dat e 79) i i ABSTRACT The need f o r t h e d e v e l o p m e n t o f a w e l l - c o n t r o l l e d m e t h o d o l o g i c a l s y s t e m t o e v a l u a t e t h e i m p a c t o f s t r a t e g i e s f o r m o d i f y i n g p r e s c r i b i n g b e h a v i o u r i n t h e community h o s p i t a l s e t t i n g i s e v i d e n t . E q u a l l y i m p o r t a n t i s t h e n eed t o d e s i g n i n t e r v e n t i o n p r o g r a m s w h i c h a r e b o t h p r a c t i c a l and e f f e c t i v e s t r a t e g i e s f o r m o d i f y i n g p r e s c r i b i n g b e h a v i o u r . To a c c o m p l i s h t h e s e o b j e c t i v e s a s t u d y was c o n d u c t e d t o d e t e r m i n e t h e r e l a t i v e i m p a c t o f t h r e e l e v e l s o f i n t e r v e n t i o n on p r e s c r i b i n g b e h a v i o u r . The i n t e r v e n t i o n s i n c l u d e d a c o n t r o l , a s t a n d a r d i n - h o s p i t a l n o n - f a c i l i t a t e d p e r s u a s i v e s t r a t e g y (pharmacy n e w s l e t t e r ) and a n o v e l m u l t i - c o m p o n e n t n o n - f a c i l i t a t e d p e r s u a s i v e s t r a t e g y (Drug Usage I n f o r m a t i o n (DUI) P r o g r a m ) . T h i s t h i r d l e v e l o f i n t e r v e n t i o n was d e s i g n e d t o m o d i f y p r e s c r i b i n g b e h a v i o u r i n a manner w h i c h was e f f e c t i v e , y e t p r a c t i c a l t o i m p l e m e n t . The f o u r - p a r t DUI P r ogram i n v o l v e d : 1) w r i t t e n announcement and h o s p i t a l e n d o r s e m e n t o f t h e p r o g r a m ; 2) d i s t r i b u t i o n o f an i n i t i a l r e p o r t c o n t a i n i n g t o p i c d r u g p r e s c r i b i n g p a t t e r n s and r e c o m m e n d a t i o n s f o r c h a n g e ; 3) d i s t r i b u t i o n o f a f o l l o w - u p r e p o r t i d e n t i f y i n g i m p r o v e m e n t s i n t o p i c p r e s c r i b i n g p a t t e r n s and r e i t e r a t i n g t h e c h ange r e c o m m e n d a t i o n s ; and 4) a m e d i c a l r o u n d s p r e s e n t a t i o n . Over t h e 2-month p e r i o d o f t h e DUI P rogram, e a c h p h y s i c i a n r e c e i v e d a p e r s o n a l i z e d l e t t e r a n n o u n c i n g t h e p rogram, i n i t i a l and f o l l o w - u p r e p o r t s and was i i i n o t i f i e d of the medical rounds p r e s e n t a t i o n . S i x d r u g - r e l a t e d t o p i c s i n v o l v i n g areas of p r e v i o u s l y i d e n t i f i e d suboptimal usage were s t u d i e d . These t o p i c s focused upon o p t i m i z a t i o n of dosage regimens f o r p r o p h y l a c t i c a n t i b i o t i c s , c e f a z o l i n , c i m e t i d i n e and gentamicin and serum drug l e v e l m o n itoring f o r t h e o p h y l l i n e and a n t i c o n v u l s a n t s . A p p r o p r i a t e n e s s of p r e s c r i b i n g behaviour f o r these t o p i c s was c a t e g o r i z e d a c c o r d i n g t o p r e - e s t a b l i s h e d e x p l i c i t p r ocess c r i t e r i a . T h i s was accomplished by a b l i n d e d review of h e a l t h r e c o r d s a t two s i m i l a r community h o s p i t a l s . Employing a d u p l i c a t e d Youden square experimental d e s i g n , each t o p i c i n each h o s p i t a l was randomly a l l o c a t e d t o one of the t h r e e i n t e r v e n t i o n l e v e l s . P a t t e r n s of p r e s c r i b i n g were then compared f o r p e r i o d s b e f o r e and a f t e r the i n t e r v e n t i o n s u s i n g a n a l y s i s of v a r i a n c e and c h i - s q u a r e s t a t i s t i c a l procedures. P o t e n t i a l i n t e r f e r i n g f a c t o r s i n c l u d i n g t e s t h o s p i t a l medical and pharmacy p u b l i c a t i o n s were monitored. P r e s c r i b i n g p a t t e r n s were s t a b l e f o r the s i x month p e r i o d p r i o r to the i n t e r v e n t i o n s . A comparison of the two component 3-month p e r i o d s d i d not i d e n t i f y any s p e c i f i c h o s p i t a l or t o p i c e f f e c t s . S i m i l a r l y , when comparing the 3-month p e r i o d s immediately before and a f t e r the i n t e r v e n t i o n s , no e f f e c t s a s s o c i a t e d with t o p i c s or h o s p i t a l s were e v i d e n t . However, i n t e r v e n t i o n e f f e c t s were apparent with the Drug Usage Information Program demonstrating an i v Improvement i n p r e s c r i b i n g p a t t e r n s g r e a t e r than both the pharmacy n e w s l e t t e r and c o n t r o l . No d i f f e r e n c e between the pharmacy n e w s l e t t e r i n t e r v e n t i o n and c o n t r o l was e v i d e n t . S i g n i f i c a n t improvement i n p r e s c r i b i n g p a t t e r n s was observed f o r t h r e e o f the f o u r t o p i c s addressed by the Drug Usage Information Program. These e f f e c t s p e r s i s t e d i n t o the second 3-month p e r i o d , however, some d i m i n u t i o n o f e f f e c t was apparent. No major extraneous i n f l u e n c e s t h a t might b i a s the changes i n p r e s c r i b i n g p a t t e r n s were i d e n t i f i e d . The study methodology developed p e r m i t t e d v a l i d assessment of the impact of m o d i f i c a t i o n s t r a t e g i e s on p r e s c r i b i n g behaviour i n the community h o s p i t a l . The r e s u l t s of t h i s study i n d i c a t e d t h a t d i s s e m i n a t i o n of drug i n f o r m a t i o n v i a standard h o s p i t a l pharmacy n e w s l e t t e r was i n e f f e c t i v e as a means of modifying p r e s c r i b i n g behaviour i n t h i s s e t t i n g . An a l t e r n a t i v e method i s the novel Drug Usage Information Program. T h i s program was both e f f e c t i v e and p r a c t i c a l t o implement. V TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS v LIST OF TABLES i x LIST OF FIGURES x LIST OF APPENDICES x i ACKNOWLEDGEMENTS x i i i DEDICATION x i v INTRODUCTION 1 A. DRUG PRESCRIBING IN HEALTH CARE 1 B. PRESCRIBING BEHAVIOUR : PHASES AND INFLUENCING 1 FACTORS 1. New drug adoption and p o s t - a d o p t i o n 2 p r e s c r i b i n g phases 2. F a c t o r s i n f l u e n c i n g p r e s c r i b i n g behaviour 4 C. PRESCRIBING BEHAVIOUR : MODIFICATION STRATEGIES 9 1. Re-educative s t r a t e g i e s 10 2. P e r s u a s i v e s t r a t e g i e s 11 3. Power s t r a t e g i e s 11 4. F a c i l i t a t i v e s t r a t e g i e s 12 5. R e l a t i v e e f f i c a c y of s t r a t e g i e s 13 6. A p p l i c a t i o n and combination of 13 s t r a t e g i e s D. MODIFICATION STRATEGIES : ASSESSMENT PROCEDURES 14 1. Process and outcome 14 2. Drug usage review (DUR) programs 15 v i E. MODIFICATION STRATEGIES : RESULTS OF PREVIOUS 17 RESEARCH F. SUMMARY 22 G. RESEARCH OBJECTIVE 22 METHODOLOGY 23 A. SUMMARY OF RESEARCH PLAN 23 B. INDEPENDENT VARIABLES 24 1. I n t e r v e n t i o n l e v e l s 24 1.1 C o n t r o l <I-1> 24 1.2 Standard h o s p i t a l pharmacy n e w s l e t t e r 25 <I-2> 1.3 Drug Usage Information Program 28 (1-3) 2. Drug usage t o p i c s 40 2.1 U t i l i z a t i o n p a t t e r n s 42 2.2 P i l o t drug usage reviews 42 2.3 Endorsements 42 2.4 D e s c r i p t i o n o f f i n a l t o p i c s 43 3. Te s t h o s p i t a l s i t e s 43 3.1 O p e r a t i o n a l c h a r a c t e r i s t i c s 46 3.2 P r e s c r i b e r s 46 3.3 P a t i e n t s 46 C. DATA COLLECTION PROCEDURES : DEPENDENT VARIABLE 47 1. P r e s c r i b i n g data 47 1.1 Case s e l e c t i o n 47 1.2 Data c o l l e c t i o n and p r o c e s s i n g 49 2. Extraneous f a c t o r s 50 D. DATA ANALYSIS AND PHASING 51 1. S t a t i s t i c a l a n a l y s i s 52 1.1 R e l a t i v e i n f l u e n c e of i n t e r v e n t i o n , 52 t o p i c and h o s p i t a l 1.2 R e l a t i v e i n f l u e n c e of the t h r e e 54 l e v e l s of i n t e r v e n t i o n 1.3 I n f l u e n c e of i n t e r v e n t i o n s on 54 s p e c i f i c t o p i c s v i i 2. Phasing 54 E. CONTROL TECHNIQUES 55 1. B l i n d i n g 55 1.1 P h y s i c i a n s 55 1.2 Pharmacists 57 1.3 I n v e s t i g a t o r 58 2. R e l i a b i l i t y 59 2.1 Health r e c o r d review 60 2.2 Data c o l l e c t i o n 61 3. Data e n t r y v e r i f i c a t i o n 62 4. Sample s i z e 62 5. Randomization 63 5.1 Treatment course s e l e c t i o n 63 5.2 I n t e r v e n t i o n a l l o c a t i o n 65 RESULTS 66 A. COMPARISON OF PRE-STUDY AND PRE-INTERVENTION 66 PERIODS B. COMPARISON OF PRE-INTERVENTION AND POST- 66 INTERVENTION PERIODS 1. R e l a t i v e i n f l u e n c e of i n t e r v e n t i o n , 66 t o p i c and h o s p i t a l 2. R e l a t i v e i n f l u e n c e of the thr e e 67 l e v e l s of i n t e r v e n t i o n 3. I n f l u e n c e o f i n t e r v e n t i o n s on s p e c i f i c 67 t o p i c s C. COMPARISON OF PRE-INTERVENTION AND POST- 67 STUDY PERIODS (1-3) D. COMPARISON OF POST-INTERVENTION AND POST- 67 STUDY PERIODS (1-3) E. EXTRANEOUS FACTORS 68 1. Medical rounds 68 v i i i 2. M edical n e w s l e t t e r s 68 3. Pharmacy i n s e r v i c e a and c l i n i c a l a c t i v i t i e s 68 4. Pharmacy n e w s l e t t e r s 69 DISCUSSION 70 A. METHODOLOGICAL SYSTEM 70 1. Measurement of behaviour changes 70 2. I n t e r n a l v a l i d i t y 71 3. E x t e r n a l v a l i d i t y 74 B. PRESCRIBING BEHAVIOUR MODIFICATION 75 1. S t a b i l i t y 75 2. Short term impact 76 2.1 C o n t r o l <I-1) 76 2.2 Standard h o s p i t a l pharmacy n e w s l e t t e r 77 <I-2> 2.3 Drug Usage Information Program 81 (1-3) 2.4 Comparison of i n t e r v e n t i o n s 84 2.4.1 E f f e c t i v e n e s s 84 2.4.2 Cost 85 3. Longer term impact (1-3) 87 4. E x t e r n a l v a l i d i t y 88 C. CONCLUSIONS AND RECOMMENDATIONS 89 REFERENCES 91 TABLES 102 FIGURES 110 APPENDICES 116 i x LIST OF TABLES Table Page I M o d i f i c a t i o n s t r a t e g i e s : impact on 102 p h y s i c i a n behaviour II C h a r a c t e r i s t i c s of the t e s t h o s p i t a l s 104 I I I C h a r a c t e r i s t i c s o f p r e s c r i b e r s a t the 105 t e s t h o s p i t a l s IV C h a r a c t e r i s t i c s o f p a t i e n t s d i s c h a r g e d 106 from t e s t h o s p i t a l s V Health r e c o r d review and data c o l l e c t i o n 107 VI P r e s c r i b i n g p a t t e r n s a c c o r d i n g t o p e r i o d 108 and l e v e l o f i n t e r v e n t i o n VII Changes i n p r e s c r i b i n g p a t t e r n s a c c o r d i n g t o i n t e r v e n t i o n , t o p i c and t e s t h o s p i t a l 109 X LIST OF FIGURES F i g u r e Page Changes i n p r e s c r i b i n g p a t t e r n s a c c o r d i n g 110 t o l e v e l o f i n t e r v e n t i o n Changes i n p r e s c r i b i n g p a t t e r n s a c c o r d i n g 111 t o t o p i c Changes i n p r e s c r i b i n g p a t t e r n s a c c o r d i n g 112 to t e s t h o s p i t a l Changes i n p r e s c r i b i n g p a t t e r n s : 1-1 113 i n t e r v e n t i o n Changes i n p r e s c r i b i n g p a t t e r n s : 1-2 114 i n t e r v e n t i o n Changes i n p r e s c r i b i n g p a t t e r n s : 1-3 115 i n t e r v e n t i o n x i LIST OF APPENDICES Appendix Page I P r o j e c t experimental design 116 II Pharmacy n e w s l e t t e r s d i s t r i b u t e d a t t e s t h o s p i t a l s 117 I I I I n t r o d u c t o r y l e t t e r d i s t r i b u t e d t o p h y s i c i a n s 130 IV Drug Usage Information Program i n i t i a l r e p o r t s d i s t r i b u t e d t o p h y s i c i a n s 132 V Drug Usage Information Program f o l l o w - u p r e p o r t s d i s t r i b u t e d t o p h y s i c i a n s 141 VI Medical rounds announcement d i s t r i b u t e d a t t e s t h o s p i t a l s 150 VII Drug u t i l i z a t i o n p a t t e r n s a t t e s t h o s p i t a l s 152 VI I I P i l o t drug usage reviews 154 IX T o p i c and c r i t e r i a endorsement from i n -dependent medical e x p e r t s 156 X C e f a z o l i n dosage schedules <T-1> 164 XI C i m e t i d i n e dosage i n g e r i a t r i c p a t i e n t s (T-2) 173 XII Gentamicin i n i t i a l e m p i r i c dosage <T-3) 183 XIII T h e o p h y l l i n e serum l e v e l m o n itoring <T-4> 192 XIV Systemic a n t i m i c r o b i a l p r o p h y l a x i s i n surgery <T-5) 198 XV XVI Admission serum drug l e v e l s <T-6) L e t t e r o f i n t r o d u c t i o n and i n t e n t sent t o p o t e n t i a l community h o s p i t a l t e s t s i t e s 208 214 x i i XVII Medical rounds conducted at t e s t 216 h o s p i t a l s d u r i n g p r o j e c t p e r i o d XVIII Medical and pharmacy n e w s l e t t e r t o p i c s 218 d u r i n g p r o j e c t p e r i o d x i i i ACKNOWLEDGEMENTS I want t o thank my mentor. Dr. Robin J . Ensom f o r h i s conti n u e d guidance i n t h i s endeavour. I am g r a t e f u l t o the members of my s u p e r v i s o r y committee i n c l u d i n g Dr. John M c N e i l l , Dr. Jack Diamond, Dr. David F i e l d i n g , Dr. Jake Hlynka, Dr. Marc L e v i n e , Dr. Gordon Page and Dr. John Ruedy. T h e i r c o n t r i b u t i o n s made t h i s r e s e a r c h p o s s i b l e . I a l s o acknowledge the e f f o r t s of Barbara Jewesson and the Health Records and Pharmacy Departments of the "Test H o s p i t a l s " f o r t h e i r p a t i e n c e and c o o p e r a t i o n throughout the many months of the p r o j e c t . F i n a l l y , I thank Health and Welfare Canada f o r t h e i r support of t h i s r e s e a r c h . x i v DEDICATION To my w i f e , my mother and f a m i l y and t o my f a t h e r who was unable t o see the completion of t h i s work. 1 INTRODUCTION A. DRUG PRESCRIBING IN HEALTH CARE Mounting evidence supports the c o n t e n t i o n of the World Health O r g a n i z a t i o n <1> t h a t drugs are not used t o t h e i r f u l l p o t e n t i a l a c c o r d i n g t o g e n e r a l l y accepted c r i t e r i a . There are numerous r e p o r t s of drug t h e r a p y - r e l a t e d problems i n the medical l i t e r a t u r e i n c l u d i n g : unnecessary therapy; use of q u e s t i o n a b l e drugs and drug regimens; poor drug therapy monitoring procedures; and the f r e q u e n t occurrence of p r e d i c t a b l e and a v o i d a b l e u n d e s i r e d drug e f f e c t s (2-9). These problems have been documented i n both the community and i n s t i t u t i o n a l p a t i e n t care s e t t i n g s . Adverse drug r e a c t i o n s have been r e p o r t e d to occur i n up to 18-30* of a l l h o s p i t a l i z e d p a t i e n t s (10-13). I n a p p r o p r i a t e drug usage can le a d t o i n c r e a s e s i n l e n g t h of h o s p i t a l s tay (14,15). T h e r e f o r e , the t h e r a p e u t i c and economic consequences of sub-optimal p r e s c r i b i n g are s i g n i f i c a n t . B. PRESCRIBING BEHAVIOUR : PHASES AND INFLUENCING FACTORS The environment i n which drug knowledge i s a c q u i r e d and t h a t i n which drugs are p r e s c r i b e d are both complicated and p o o r l y understood. In r e c e n t y e a r s , enormous advances have oc c u r r e d i n the realm of drug t h e r a p e u t i c s . As a r e s u l t the 2 p h y s i c i a n has been c o n f r o n t e d with the i n c r e a s i n g l y d i f f i c u l t t a sk of attempting t o keep a b r e a s t of the newest developments r e l a t e d t o drug usage i n the promotion o f h e a l t h . I t has only l a t e l y been r e c o g n i z e d t h a t the p r e s c r i b i n g o f drugs i s conducted w i t h i n a complex of medical, s o c i a l and marketing i n f l u e n c e s . Although r e s e a r c h haa been s u c c e s s f u l i n e l u c i d a t i n g s e v e r a l o f the f a c t o r s i n f l u e n c i n g t h i s process (16-20), much r e s e a r c h i s s t i l l e s s e n t i a l t o help us f u l l y understand t h i s process. 1. New drug adoption and pos t - a d o p t i o n p r e s c r i b i n g phases When c o n s i d e r i n g f a c t o r s i n f l u e n c i n g p r e s c r i b i n g behaviour we must f i r s t d i f f e r e n t i a t e two p r i n c i p a l phases of drug p r e s c r i b i n g . These are the adoption of a new drug and the p o s t - a d o p t i o n m o d i f i c a t i o n o f the p r e s c r i b i n g process f o r t h a t drug. The adoption phase has been d e s c r i b e d by M i l l e r (17) as a m u l t i p l e - s t e p process beginning with a p h y s i c i a n f i r s t e n c o u n t e r i n g a new drug and p r o g r e s s i n g t o the i n c o r p o r a t i o n o f t h a t drug i n t o h i s / h e r t h e r a p e u t i c armamentarium. F i v e stages a re i n h e r e n t t o the process of adoption i n c l u d i n g awareness, i n t e r e s t , e v a l u a t i o n , t r i a l and adopti o n . I n i t i a l awareness of a new drug may be f o l l o w e d by i n t e r e s t i n o b t a i n i n g f u r t h e r i n f o r m a t i o n . During the e v a l u a t i o n stage, i n f o r m a t i o n i s sought from c o l l e a g u e s and c o n s u l t a n t s . An e v a l u a t i o n i s made and the p h y s i c i a n decides whether t o p r e s c r i b e the drug or not. The p h y s i c i a n then 3 p r e s c r i b e s the drug f o r a l i m i t e d number of p a t i e n t s . I f the new drug does not meet e x p e c t a t i o n s , the p h y s i c i a n r e j e c t s or r e a s s e s s e s the drug. I f the drug meets most e x p e c t a t i o n s , the p h y s i c i a n w i l l l i k e l y proceed t o the adoption stage and p r e s c r i b e the drug r o u t i n e l y (17). F o l l o w i n g the process of adoption of the new drug i s the p o s t - a d o p t i o n phase d u r i n g which the p r e s c r i b i n g process e v o l v e s based on experience and new i n f o r m a t i o n . Changes which may occur d u r i n g t h i s phase i n c l u d e updating i n d i c a t i o n s f o r use, o p t i m i z i n g drug dosage a c c o r d i n g t o drug and p a t i e n t c h a r a c t e r i s t i c s and improving drug therapy monitoring procedures. The r e s u l t of t h i s p o s t - a d o p t i o n process i s a continued m o d i f i c a t i o n of the a p p l i c a t i o n of the drug t o p a t i e n t c a r e . M o d i f i c a t i o n s t o the p r e s c r i b i n g p rocess may occur f r e q u e n t l y f o r some drugs and not f o r o t h e r s . E v e n t u a l l y the drug may be d i s c o n t i n u e d i n favour of newer agents. S e v e r a l s t u d i e s have e v a l u a t e d the p o t e n t i a l i n f l u e n c e of v a r i o u s f a c t o r s on p r e s c r i b i n g behaviour. Three general approaches have been taken. These i n c l u d e q u e s t i o n i n g p h y s i c i a n s f o r t h e i r o p i n i o n s ( q u e s t i o n n a i r e s / i n t e r v i e w s ) , reviewing p r e s c r i b i n g frequency data to determine g e n e r a l u t i l i z a t i o n t r e n d s and r e v i e w i n g drug usage c h a r a c t e r i s t i c s t o e s t a b l i s h q u a l i t y of p r e s c r i b i n g . Opinion surveys are 4 very common, however, r e s u l t s may be b i a s e d and not n e c e s s a r i l y r e f l e c t a c t u a l p r e s c r i b i n g p a t t e r n s . V a r i a t i o n s i n approach can s i g n i f i c a n t l y a l t e r response outcome (20). I n t e r p r e t a t i o n s of these s u b j e c t i v e s t u d i e s thus must be made c a u t i o u s l y , however, they are u s e f u l i n e v a l u a t i n g the e f f e c t of f a c t o r s which cannot reasonably be c o n t r o l l e d . General u t i l i z a t i o n e v a l u a t i o n s t u d i e s are more o b j e c t i v e , yet cannot a s s e s s the e f f e c t of f a c t o r s on how a drug i s used. T h i s type o f study i s t h e r e f o r e more u s e f u l i n s t u d y i n g drug a d o p t i o n . Q u a l i t a t i v e drug usage s t u d i e s a s s e s s p r e s c r i b i n g a p p r o p r i a t e n e s s . However, d i s s o c i a t i o n o f the e f f e c t s of the i n d i v i d u a l i n f l u e n c i n g f a c t o r s and e l i m i n a t i o n o f c o n f u s i n g f a c t o r s can be d i f f i c u l t (20). These s t u d i e s r e l y h e a v i l y on s t a n d a r d i z e d methodologies which are e s s e n t i a l t o ensure v a l i d i t y and r e p r o d u c a b i l i t y of r e s u l t s (20). D i f f i c u l t i e s i n c o n d u cting t h i s type of study may account, i n p a r t , f o r the s m a l l number of r e p o r t s appearing i n the l i t e r a t u r e . 2. F a c t o r s i n f l u e n c i n g p r e s c r i b i n g behaviour S e v e r a l f a c t o r s appear t o have a s i g n i f i c a n t i n f l u e n c e on p r e s c r i b i n g behaviour. These are pharmaceutical r e p r e s e n t a t i v e s , c o l l e a g u e s , medical l i t e r a t u r e , e d u c a t i o n a l meetings and a v a r i e t y o f drug and p a t i e n t - s p e c i f i c v a r i a b l e s . Pharmaceutical r e p r e s e n t a t i v e s appear t o be a 5 " f i r s t s o u r c e " of i n f l u e n c e f o r new drug products (21-30). T h e i r r e l a t i v e i n f l u e n c e seems t o d e c l i n e aa the adoption p r o c e s s p r o g r e s s e s and d u r i n g the po s t - a d o p t i o n phase (31,32). Convenience and response t o i n f o r m a t i o n requests appear t o be f a v o u r a b l e r e p r e s e n t a t i v e a t t r i b u t e s , p a r t i c u l a r l y f o r the i s o l a t e d p r a c t i t i o n e r (19). Samples pro v i d e d by the pharmaceutical r e p r e s e n t a t i v e and d i r e c t m a i l a d v e r t i s i n g s e r v e t o augment the importance of t h i s source of i n i t i a l i n f o r m a t i o n (25,26,30). C o l l e a g u e s appear t o be an important " i n t e r m e d i a t e and f i n a l s o u r c e " of i n f o r m a t i o n d u r i n g the e v a l u a t i v e stage of the adoption phase. They a l s o tend t o be a c o n t i n u i n g source of i n f o r m a t i o n d u r i n g the post - a d o p t i o n phase (21,23-25,27,32). C o l l e a g u e s do not appear as important d u r i n g the e a r l i e r stages of adoption (24). Drug i n f o r m a t i o n and h o s p i t a l pharmacists a l s o appear t o be f r e q u e n t l y used aa sources of i n f o r m a t i o n d u r i n g the l a t e adoption and po s t - a d o p t i o n stages (33-36). Reference t e x t s are used e x t e n s i v e l y d u r i n g both the adoption and po s t - a d o p t i o n phases (19). Medical j o u r n a l s e x e r t an i n f l u e n c e on p r e s c r i b i n g behaviour through a r t i c l e s and a d v e r t i s i n g . J o u r n a l a r t i c l e s appear n e a r l y as important as pharmaceutical r e p r e s e n t a t i v e s i n the e a r l y awareness and i n t e r e s t s t a g e s of adop t i o n . J o u r n a l a r t i c l e s a l s o appear 6 n e a r l y aa important as c o l l e a g u e s d u r i n g the e v a l u a t i o n stage of a d o p t i o n . During t h i s stage they a c t as a " l e g i t i m i z i n g s o u r c e " o f i n f o r m a t i o n (24). J o u r n a l a r t i c l e s are a l s o important d u r i n g the p o s t - a d o p t i o n phase (32,37). J o u r n a l a d v e r t i s i n g and pharmaceutical company brochures a l s o appear to be important d u r i n g the e a r l y stages o f awareness and i n t e r e s t (22,24). These f a c t o r s do not appear t o be important d u r i n g the e v a l u a t i o n p r o c e s s , but seem t o have the g r e a t e s t impact a t the time of t r i a l o f the new drug. These f a c t o r s may a l s o have c o n s i d e r a b l e impact d u r i n g the c o n t i n u i n g p o s t - a d o p t i o n phase (32,38,39). E d u c a t i o n a l meetings appear t o be an important " f i r s t s o u r c e " of i n f o r m a t i o n about a drug, but appear t o have l i t t l e i n f l u e n c e d u r i n g the t r i a l and adoption s t a g e s (24,25). These meetings a l s o appear t o have an i n f l u e n c e on p r e s c r i b i n g m o d i f i c a t i o n d u r i n g the po s t - a d o p t i o n phase (24-26,31). Drug and p a t i e n t a t t r i b u t e s appear t o i n f l u e n c e adoption of a new drug (22-24,40). E a r l y s t u d i e s suggest t h a t pharmacological complexity, c o s t and pharmaceutical company r e p u t a t i o n appear t o i n f l u e n c e new drug adoption (22.24). T h e i r i n f l u e n c e d u r i n g the po s t - a d o p t i o n phase i s unknown. P a t i e n t demand and d i s e a s e c h a r a c t e r i s t i c s a l s o have a major I n f l u e n c e on new drug adoption (23). T h e i r i n f l u e n c e d u r i n g 7 the poat-adoption phase appears t o be v a r i a b l e (32,41,42). S e v e r a l f a c t o r s have been s t u d i e d with c o n f l i c t i n g r e s u l t s . These i n c l u d e medical s c h o o l attended, postgraduate t r a i n i n g , age, e x p e r i e n c e , p r a c t i c e l o c a t i o n and community pharmacists. P h y s i c i a n s g r a d u a t i n g from d i f f e r e n t medical s c h o o l s appear t o d i f f e r i n r a t e of new drug adoption and p o s t - a d o p t i o n phase p r e s c r i b i n g c h a r a c t e r i s t i c s (43-45), but the importance of t h i s f a c t o r may d i m i n i s h over time (46). T h i s apparent t i m e - r e l a t e d phenomenon may account, i n p a r t , f o r d i f f e r e n c e s i n f i n d i n g s r e p o r t e d (47). Other f a c t o r s i n c l u d i n g c h a r a c t e r i s t i c s of p r a c t i c e (42), s o c i a l f a c t o r s (23), and h o s p i t a l a f f i l i a t i o n (24,48) may become more s i g n i f i c a n t . P h y s i c i a n s with post-graduate t r a i n i n g appear t o adopt new drugs more r e a d i l y than those without (49). Although a t l e a s t t h r e e s t u d i e s have found t h a t p h y s i c i a n s with more post-graduate t r a i n i n g appear t o have improved drug understanding and p r e s c r i b e d u r i n g the p o s t - a d o p t i o n phase with g r e a t e r a p p r o p r i a t e n e s s (32,42,50,51), o t h e r s t u d i e s have demonstrated a r e v e r s e or l a c k of r e l a t i o n s h i p between p r e s c r i b i n g q u a l i t y and t r a i n i n g (47,52). Major d i f f e r e n c e s i n methodology e x i s t and may account f o r these i n c o n s i s t e n t f i n d i n g s . Those s t u d i e s demonstrating a r e l a t i o n s h i p between post-graduate t r a i n i n g and q u a l i t y of p r e s c r i b i n g were 8 undertaken with o p i n i o n surveys or u t i l i z a t i o n s t a t i s t i c s (32,42,50-52) while the study by H e l l i n g (47) i d e n t i f i e d a l a c k o f apparent r e l a t i o n s h i p u s i n g q u a l i t a t i v e drug usage e v a l u a t i o n approach. S e v e r a l i n v e s t i g a t o r s r e p o r t t h a t , when compared t o o l d e r p h y s i c i a n s , younger more r e c e n t graduates more r e a d i l y adopt a new drug (49) and tend t o co n t i n u e t o p r e s c r i b e more a p p r o p r i a t e l y (6,32,42,49,50,53,54). Conversely, other r e s e a r c h e r s have been unable t o f i n d a r e l a t i o n s h i p between age and experi e n c e and p r e s c r i b i n g behaviour (47,55). D i f f e r e n c e s i n methodology may a l s o be r e s p o n s i b l e f o r these r e s u l t s , although one study (54) found the r e l a t i o n s h i p depended upon the drug being e v a l u a t e d . T h i s suggests t h a t the r e l a t i o n s h i p between age and experience and r e s u l t i n g p r e s c r i b i n g behaviour i s drug-dependent. E a r l y p r e s c r i b i n g frequency s t u d i e s found d i f f e r e n c e s i n drug p r e s c r i b i n g a c c o r d i n g t o community s i z e (56,57). A more r e c e n t study (47) which examined q u a l i t y o f p r e s c r i b i n g r a t h e r than frequency of usage, however, found no such r e l a t i o n s h i p . Again, study methodologies v a r i e d con-s i d e r a b l y . S e v e r a l s t u d i e s (21,22,26,36) have found t h a t community pharmacists may not be an important source of i n f l u e n c e on 9 p r e s c r i b i n g behaviour. T h i s may be, i n part., due t o community pharmacists l a c k i n g drug i n f o r m a t i o n r e f e r e n c e s necessary t o accomplish t h i s r o l e (58). While these f a c t o r s p r o v i d e some c l u e s r e g a r d i n g the m u l t i t u d e o f sources of i n f l u e n c e on p r e s c r i b i n g behaviour, i t i s e v i d e n t t h a t f u r t h e r r e s e a r c h i s needed. The m a j o r i t y of those s t u d i e s undertaken have e v a l u a t e d i n f o r m a t i o n a l s ources i n the community s e t t i n g . A major p o r t i o n of t o t a l h e a l t h c a r e takes p l a c e i n the acute c a r e s e t t i n g . However, w e l l designed s t u d i e s on the i n f l u e n c e of the v a r i o u s i n f o r m a t i o n a l sources i n the h o s p i t a l are l a c k i n g . In p a r t i c u l a r , assessment of the i n f l u e n c e of f a c t o r s on p o s t - a d o p t i o n phase p r e s c r i b i n g behaviour has r e c e i v e d l i t t l e a t t e n t i o n . F i n a l l y , the i n t e r a c t i v e e f f e c t of these f a c t o r s must a l s o be examined more c l o s e l y t o a l l o w a b e t t e r understanding o f the r e l a t i o n s h i p of the p r o c e s s e s i n v o l v e d . T h i s , i n t u r n , would f a c i l i t a t e attempts t o modify p r e s c r i b i n g i n the h o s p i t a l s e t t i n g . C. PRESCRIBING BEHAVIOUR : MODIFICATION STRATEGIES Lear n i n g i s an i n t e r n a l p rocess r e s u l t i n g i n a change of behaviour (59). M o d i f i c a t i o n s t r a t e g i e s aimed a t drug usage are e x t e r n a l p rocesses intended t o a f f e c t l e a r n i n g and u l t i m a t e l y , p r e s c r i b i n g behaviour. An impact on p r e s c r i b i n g 10 behaviour through implementation o f such s t r a t e g i e s w i l l r e s u l t in changes in drug p r e s c r i b i n g p a t t e r n s . Zaltman and Duncan (60) have c l a s s i f i e d m o d i f i c a t i o n s t r a t e g i e s i n t o a system i n v o l v i n g f o u r d e s c r i p t o r s : 1) r e - e d u c a t i v e ; 2) p e r s u a s i v e ; 3) power; and 4) f a c i l i t -a t i v e . Re-educative, p e r s u a s i v e and power s t r a t e g i e s l i e on a continuum r e l a t i v e t o the degree of e x t e r n a l pressure e x e r t e d . F a c i l i t a t i v e s t r a t e g i e s a re employed t o enhance any of the other t h r e e . 1. Re-educative s t r a t e g i e s Re-education as opposed t o ed u c a t i o n i m p l i e s the u n l e a r n i n g and replacement of p r e v i o u s a t t i t u d e s or behaviours (60). These behaviours may have been f o r m a l l y l e a r n e d through medical s c h o o l t r a i n i n g or v i a the many i n f o r m a l sources o f i n f o r m a t i o n a v a i l a b l e t o the p h y s i c i a n . Re-educative s t r a t e g i e s are undertaken by p r e s e n t i n g unbiased f a c t u a l i n f o r m a t i o n t o j u s t i f y a change i n p r e s c r i b i n g behaviour. Medical l i t e r a t u r e (e.g. drug i n f o r m a t i o n n e w s l e t t e r s and j o u r n a l a r t i c l e s ) and some types o f c o n t i n u i n g e d u c a t i o n programs r e p r e s e n t examples of r e - e d u c a t i v e s t r a t e g i e s . 11 2. P e r s u a s i v e s t r a t e g i e s P e r s u a s i v e s t r a t e g i e s d i f f e r from r e - e d u c a t i v e s t r a t e g i e s i n t h a t changes are attempted p a r t i a l l y through b i a s i n the method by which the recommendations are p rovided (60). Less r e s e a r c h has been undertaken t o e v a l u a t e the impact of p e r s u a s i v e s t r a t e g i e s upon p r e s c r i b i n g behaviour. P e r s u a s i v e s t r a t e g i e s employ p r i n c i p l e s of r e a s o n i n g and inducement. Accuracy of the i n f o r m a t i o n g i v e n i s v a r i a b l e . To promote t h e i r p roducts, pharmaceutical d e t a i l i n g and j o u r n a l a d v e r t i s i n g employ p e r s u a s i v e t e c h n i q u e s . I n t e r p r o f e s s i o n a l communication a l s o r e f l e c t s p e r s u a s i v e t e c h n i q u e s . Medical p u b l i c a t i o n s f r e q u e n t l y employ p e r s u a s i v e s t r a t e g i e s by i d e n t i f y i n g r e s p e c t e d c l i n i c a l p r a c t i t i o n e r s (61). S i m i l a r l y , i n s t i t u t i o n s o f t e n d i s t r i b u t e in-house drug p r e s c r i b i n g g u i d e l i n e s endorsed by r e c o g n i z e d and r e s p e c t e d s p e c i a l i s t s (62,63). P e r s u a s i v e s t r a t e g i e s are designed to i n f l u e n c e f u t u r e p r e s c r i b i n g b e h a v i o u r - r e l a t e d d e c i s i o n s . 3. Power s t r a t e g i e s Power s t r a t e g i e s are used t o implement d e c i s i o n s . Power s t r a t e g i e s i n v o l v e c o e r c i o n t o o b t a i n compliance with recommendations (60). Power s t r a t e g i e s g e n e r a l l y do not i n v o l v e a c t i v e and w i l l i n g p a r t i c i p a t i o n of the t a r g e t group. The r e s u l t i n g low l e v e l of group commitment o f t e n r e s u l t s i n a need f o r continuous a p p l i c a t i o n of the s t r a t e g y to ensure 12 su c c e s s . H o s p i t a l drug f o r m u l a r i e s and some p r e s c r i b i n g r e s t r i c t i o n s r e f l e c t power s t r a t e g i e s . R e s t r i c t i o n s f r e q u e n t l y do not i n v o l v e any attempt t o e x p l a i n the problem f o r which the r e s t r i c t i o n s were developed t h e r e f o r e l e a r n i n g may p l a y a very minor r o l e i n t h i s form of i n t e r v e n t i o n . Power s t r a t e g i e s are f r e q u e n t l y employed when other s t r a t e g i e s have f a i l e d (60). 4. F a c i l i t a t i v e s t r a t e g i e s F a c i l i t a t i v e s t r a t e g i e s are used i n c o n j u n c t i o n with other s t r a t e g i e s (e.g. f a c i l i t a t e d p e r s u a s i v e s t r a t e g i e s ) . F a c i l i t a t i v e s t r a t e g i e s i n v o l v e the use of persons or groups t o a s s i s t i n the attempts t o change p r e s c r i b i n g behaviour (60). P e r s o n a l c o n t a c t between p h y s i c i a n s and peers or s p e c i a l i s t s (e.g. i n f e c t i o u s d i s e a s e c o n s u l t a n t s , c l i n i c a l p harmacists) p r o v i d e s f a c e - t o - f a c e d i a l o g u e and feedback which r e s u l t i n changes i n p r e s c r i b i n g behaviour. The pe r s o n a l nature o f t h i s approach promotes a commitment t o change. P h y s i c i a n s are accustomed t o r e q u e s t i n g c o n s u l t a t i o n s t h e r e f o r e t h i s form of i n t e r v e n t i o n i s u s u a l l y w e l l accepted. Success of these s t r a t e g i e s depends upon the p r e a c r i b e r ' a b e l i e f t h a t a need t o change p r e s c r i b i n g behaviour e x i s t s . P r e s c r i b i n g problems f o r which the magnitude and complexity o f change are s i g n i f i c a n t are best addressed by f a c i l i t a t i v e s t r a t e g i e s (60). 13 5. R e l a t i v e e f f i c a c y o f s t r a t e g i e s The e f f e c t i v e n e s s o f a m o d i f i c a t i o n s t r a t e g y i s dependent upon the nature of the p r e s c r i b i n g behaviour and the r e s i s t a n c e t o change (60). Short-term e f f i c a c y of the s t r a t e g i e s g e n e r a l l y r e f l e c t s the p r e s s u r e e x e r t e d . Power s t r a t e g i e s u s u a l l y have the g r e a t e s t immediate impact. Conversely, r e - e d u c a t i v e s t r a t e g i e s o f t e n r e q u i r e a p e r i o d of time be f o r e change i s observed. T h i s change may only be s h o r t - t e r m . Compared t o r e - e d u c a t i v e s t r a t e g i e s , p e r s u a s i v e s t r a t e g i e s can r e s u l t i n more immediate and s u s t a i n e d change. These s t r a t e g i e s are p a r t i c u l a r l y u s e f u l when r e s i s t a n c e t o change i s a n t i c i p a t e d (60>. 6. A p p l i c a t i o n and combination of s t r a t e g i e s Each l e v e l of s t r a t e g y may be best s u i t e d t o s p e c i f i c a p p l i c a t i o n s . Re-educative s t r a t e g i e s are i d e a l t o c r e a t e an i n i t i a l awareness of a drug d u r i n g the adoption phase. E v a l u a t i o n of the drug can be i n f l u e n c e d through p e r s u a s i v e t e c h n i q u e s . Changes i n a c t u a l p r e s c r i b i n g of the drug d u r i n g the a d o p t i o n and p o s t - a d o p t i o n phases may be i n f l u e n c e d by f a c i l i t a t e d or n o n - f a c i l i t a t e d p e r s u a s i v e and power s t r a t e g i e s . Combined or s e q u e n t i a l a p p l i c a t i o n of these s t r a t e g i e s may be a p p r o p r i a t e depending upon the nature of the behaviour t o be changed and the magnitude and r a t e of change d e s i r e d (64). 14 D. MODIFICATION STRATEGIES : ASSESSMENT PROCEDURES 1. Process and outcome The I n f l u e n c e of m o d i f i c a t i o n s t r a t e g i e s on p r e s c r i b i n g behaviour can be measured i n terms of impact on e i t h e r the p e r c e p t i o n s , process or product (outcome) of drug p r e s c r i b i n g . P e r c e p t i o n s of drug p r e s c r i b i n g do not n e c e s s a r i l y r e f l e c t a c t u a l p r e s c r i b i n g behaviour and should not be employed. Outcome or product r e f e r t o the u l t i m a t e e f f e c t s of the drug. T h i s i s o f t e n expressed i n terms of success or f a i l u r e of treatment and/or presence or absence of untoward e f f e c t s . Outcome more c l o s e l y r e f l e c t s q u a l i t y of p a t i e n t c a r e , however, s t u d i e s of t h i s nature are d i f f i c u l t t o conduct and i n t e r p r e t (65). Assessment of the q u a l i t y of medical care based upon the r e s u l t s of t h i s c a r e may be i n a p p r o p r i a t e s i n c e the r e s u l t of medical c a r e ( i . e . p a t i e n t outcome) depends not o n l y upon the medical treatments r e c e i v e d but a l s o upon s o c i a l , economic and demographic c h a r a c t e r i s t i c s of the p a t i e n t p o p u l a t i o n . E f f o r t s t o assess medical care q u a l i t y have g e n e r a l l y examined p h y s i c i a n performance. These process s t u d i e s r e l y on h e a l t h r e c o r d data and may a c t u a l l y r e s u l t i n a more c o n s e r v a t i v e e stimate of the adequacy of h e a l t h care than apparent through outcome assessment (66). Consequently, the p o s s i b l e d i s c r e p a n c y between outcome and process e v a l u a t i o n s 15 should be c o n s i d e r e d whenever r e s u l t s of p r o c e s s s t u d i e s are i n t e r p r e t e d (66). In s p i t e of these minor shortcomings, w e l l - d e s i g n e d p r o c e s s s t u d i e s p l a y a major r o l e i n the c u r r e n t e v a l u a t i o n of h e a l t h c a r e . D r u g - r e l a t e d p r o c e s s s t u d i e s t o a s s e s s m o d i f i c a t i o n s t r a t e g i e s u s u a l l y examine p r e s c r i b i n g performance as i t r e l a t e s t o f o u r s t e p s nested w i t h i n the s i x - s t e p drug use process d e s c r i b e d by Knapp and coworkers (67). These a r e : 1) d e t e r m i n a t i o n o f a need f o r the drug; 2) s e l e c t i o n of a s p e c i f i c drug product; 3) s e l e c t i o n of a regimen; and 4) monitoring the use of t h a t product. Although a l a r g e number of these s t u d i e s hsve been undertaken i n the p a s t , methodological shortcomings have f r e q u e n t l y made i t d i f f i c u l t t o e s t a b l i s h c o n c l u s i v e r e l a t i o n s h i p s between these s t r a t e g i e s and p r e s c r i b i n g behaviour (68,69). 2. Drug usage review (DUR) programs Q u a l i t y assurance i s the d e f i n i t i o n , measurement, e v a l u a t i o n , maintenance and improvement of s e r v i c e s p r o v i d e d (70,71). In the h o s p i t a l s e t t i n g , the c o l l e c t i v e a p p l i c a t i o n of these f i v e p r o c e s s e s has been a p p l i e d t o ensure the h e a l t h care system d e l i v e r s s e r v i c e s t h a t are a p p r o p r i a t e and e f f i c i e n t . Drug usage review (DUR) i s a form of q u a l i t y assurance 16 program which has been proposed f o r widespread and ongoing a p p l i c a t i o n i n the h o s p i t a l s e t t i n g (71,72). Simply s t a t e d , DUR i s a q u a l i t y assurance program f o r drug therapy (71). The primary g o a l of DUR i s t o "improve the q u a l i t y of p a t i e n t c a r e through the use of a p p r o p r i a t e drugs i n c o n d i t i o n s f o r which t h e i r use, based on sound and c u r r e n t medical judgement, i s i n d i c a t e d and a t a minimal c o s t c o n s i s t e n t with an a c c e p t a b l e q u a l i t y of c a r e " (73). To t h i s end, DUR can be used as a method of a s s e s s i n g the adequacy of present p r a c t i c e and e v a l u a t i n g the impact of m o d i f i c a t i o n s t r a t e g i e s aimed at improving p r e s c r i b i n g behaviour. Although c o n c e p t u a l l y d e f i n e d i n the l a t e 1960's, DUR has not been developed, r e f i n e d and adopted by h e a l t h care f a c i l i t i e s as r e a d i l y as other q u a l i t y assurance mechanisms (74). T h i s may be due, i n p a r t , t o a l a c k of c l e a r under-st a n d i n g of the concepts of a DUR program. Brodie and coworkers (74) d e s c r i b e DUR as being based upon f i v e components: 1) a u t h o r i t y - t o operate e f f e c t i v e l y , a drug usage program must g a i n l e g i t i m a c y 1 through endorsement by the r e c o g n i z e d a u t h o r i t i e s w i t h i n the f a c i l i t y ; 2) f a c i l i t y c h a r a c t e r i s t i c s - i n t e r p r e t a t i o n of p r e s c r i b i n g p a t t e r n s must i n c l u d e o p e r a t i o n a l and demographic c h a r a c t e r i s t i c s of the f a c i l i t y as these f a c t o r s w i l l i n f l u e n c e usage p a t t e r n s ; 3) p r o f i l e s o f drug usage - p r o f i l e s ( i . e . p a t i e n t h e a l t h r e c o r d s ) must be a v a i l a b l e t o allow assessment of 17 e x i s t i n g p a t t e r n s and the impact o f m o d i f i c a t i o n s t r a t e g i e s ; 4) c r i t e r i a and standards - o b j e c t i v e and e x p l i c i t c r i t e r i a t o d e f i n e a p p r o p r i a t e n e s s must be p r e - e s t a b l i s h e d t o allow u n p r e j u d i c e d comparison a g a i n s t e x i s t i n g treatment p r a c t i c e s ; and 5) e v a l u a t i o n scheme -e v a l u a t i o n of the impact of the review and m o d i f i c a t i o n s t r a t e g i e s must be weighed a g a i n s t the c o s t s of these procedures (74). S t u d i e s have e v a l u a t e d changes i n the q u a n t i t i e s of drugs p r e s c r i b e d without r e f e r e n c e t o the r a t i o n a l i t y of p r e s c r i b i n g (72,75). Other s t u d i e s have been conducted employing s u b j e c t i v e methods of a s s e s s i n g the impact of the m o d i f i c a t i o n procedures (75). O b j e c t i v e s t u d i e s employing o p e r a t i o n a l l y - d e f i n e d c r i t e r i a are needed t o ensure v a l i d and r e p r o d u c i b l e r e s u l t s . S t r i c t a p p l i c a t i o n of the DUR process i s r e q u i r e d (67,72). E. MODIFICATION STRATEGIES : RESULTS OF PREVIOUS RESEARCH S e v e r a l s t u d i e s have i n v e s t i g a t e d s t r a t e g i e s designed t o modify p h y s i c i a n behaviour i n both the community and i n s t i t u t i o n a l s e t t i n g s (Table I ) . Most s t r a t e g i e s aimed a t changing drug p r e s c r i b i n g behaviour i n the h o s p i t a l s e t t i n g have focused upon improvement i n the process of p r e s c r i b i n g . T h i s i m p l i e s m o d i f i c a t i o n of p r e s c r i b i n g behaviour dur i n g the 18 l a t t e r s t a g e s of adoption ( i . e . t r i a l and a d o p t i o n ) , and more f r e q u e n t l y , d u r i n g p o s t - a d o p t i o n phase. To be s u c c e s s f u l , i n t e r v e n t i o n programs must be both e f f e c t i v e and p r a c t i c a l t o implement. E f f e c t i v e n e s s should be determined i n terms of short-term impact and long-term t r e n d s . Although power s t r a t e g i e s have c o n s i d e r a b l e immediate e f f e c t s on p r e s c r i b i n g behaviour (79,103-112), these e f f e c t s tend t o p e r s i s t o n l y as long as c o n t r o l measures are c o n t i n u e d . Power s t r a t e g i e s may a l s o l e a d t o unexpected r e s u l t s such as u n d e s i r a b l e drug s u b s t i t u t i o n e f f e c t s (106). Such measures are l e s s accepted by h e a l t h p r o f e s s i o n a l s as an i n i t i a l approach t o drug p r e s c r i b i n g problems (129). Simple r e - e d u c a t i v e s t r a t e g i e s , by d e f i n i t i o n , a re not u s u a l l y e v a l u a t e d s i n c e s t u d i e s a s s e s s i n g the impact of i n t e r v e n t i o n s (e.g. n e w s l e t t e r s ) t y p i c a l l y i n v o l v e a p e r s u a s i v e component t o the i n f o r m a t i o n g i v e n . F a c i l i t a t e d p e r s u a s i v e s t r a t e g i e s have been shown to be e f f e c t i v e i n modifying p r e s c r i b i n g behaviour, y e t c o s t l y t o implement. I n t e r v e n t i o n examples i n c l u d e ongoing drug monitoring programs (undertaken by c l i n i c a l pharmacists, i n f e c t i o u s d i s e a s e c o n s u l t a n t s or other s p e c i a l i s t s ) (88-102) and f a c e - t o - f a c e academic d e t a i l i n g (87,128). Most h o s p i t a l s , p a r t i c u l a r l y community-based f a c i l i t i e s , do not have access t o these s p e c i a l i s t s , nor are the s i t e s capable of implementing s i m i l a r programs with e x i s t i n g r e s o u r c e s . 19 The most p r a c t i c a l type of i n t e r v e n t i o n programs to implement i n the h o s p i t a l s e t t i n g appear t o be those i n v o l v i n g n o n - f a c i l i t a t e d p e r s u a s i v e s t r a t e g i e s . These commonly i n v o l v e p r o v i s i o n of drug i n f o r m a t i o n , p r e s c r i b i n g feedback and g u i d e l i n e s through d i s s e m i n a t i o n of w r i t t e n m a t e r i a l (e.g. n e w s l e t t e r s and r e p o r t s ) or by group d i s c u s s i o n s (e.g. meetings and rounds). Although these s t r a t e g i e s are widely adopted by both community and t e a c h i n g h o s p i t a l s (62,76,78,86), these m o d i f i c a t i o n approaches have been undertaken with v a r i e d s u c c e s s . In a d d i t i o n , the e f f e c t i v e n e s s of these s t r a t e g i e s as r e p r e s e n t e d i n Table I may be b i a s e d by a tendency t o r e p o r t o n l y p o s i t i v e r e s u l t s . I n c o n s i s t e n t f i n d i n g s i n p r e v i o u s s t u d i e s are a major problem. In g e n e r a l , a p a u c i t y o f w e l 1 - c o n t r o l l e d t r i a l s e x i s t t o a s s e s s the impact of any m o d i f i c a t i o n s t r a t e g y on p r e s c r i b i n g behaviour. Most s t u d i e s have attempted t o examine t h i s r e l a t i o n s h i p u s i n g pre-experimental designs (e.g. one group p r e - p o s t / t e s t d e s i g n ) . These s t u d i e s t y p i c a l l y do not employ co n c u r r e n t c o n t r o l groups nor u t i l i z e r andomization and b l i n d i n g procedures t o minimize i n v e s t i g a t o r and s u b j e c t b i a s . The f i e l d study experimental approach used by a l l s t u d i e s a v o i d s the c r i t i c i s m of a r t i f i c i a l i t y of environment. However, the p o t e n t i a l i n f l u e n c e of extraneous v a r i a b l e s must be r e c o g n i z e d and 20 r e c o n c i l e d t o ensure i n t e r n a l v a l i d i t y o£ the study. C o n t r o l f o r the i n f l u e n c e o f these e x t e r n a l f a c t o r s i s u s u a l l y l a c k i n g . Most of the p r e v i o u s i n v e s t i g a t i o n s i n t o p r e s c r i b i n g behaviour m o d i f i c a t i o n s t r a t e g i e s have been conducted i n s i n g l e U.S. t e a c h i n g h o s p i t a l s . The p o r t a b i l i t y o f r e s u l t s t o other f a c i l i t i e s , p a r t i c u l a r l y Canadian community h o s p i t a l s , remains l a r g e l y undetermined. To reduce the p o t e n t i a l t h r e a t o f s i t e - r e l a t e d b i a s i n the assessment of a p a r t i c u l a r m o d i f i c a t i o n s t r a t e g y , experiments i n v o l v i n g two or more h o s p i t a l s are r e q u i r e d . Such i n v e s t i g a t i o n s undertaken i n the s e t t i n g of the community h o s p i t a l would have more a p p l i c a b i l i t y t o the o v e r a l l i n s t i t u t i o n a l h e a l t h care system i n Canada. The e f f e c t i v e n e s s of s i m i l a r m o d i f i c a t i o n s t r a t e g i e s has a l s o been shown t o vary a c c o r d i n g t o the nature of the drug t o p i c addressed (76-79). To adequately a s s e s s the impact of a p a r t i c u l a r m o d i f i c a t i o n s t r a t e g y , s e v e r a l independent drug t o p i c s should be addressed c o n c u r r e n t l y . T h i s would reduce the t h r e a t of t o p i c - r e l a t e d b i a s i n the e v a l u a t i o n o f t h a t s t r a t e g y . Of the s t u d i e s r e p o r t e d , those e v a l u a t i n g the impact of a p a r t i c u l a r i n t e r v e n t i o n program on p r e s c r i b i n g behaviour r e l a t i v e t o more than one t o p i c are r e l a t i v e l y uncommon (Table I ) . 21 I n t e r v e n t i o n programs are u s u a l l y c a t e g o r i z e d a c c o r d i n g t o the g e n e r a l approach taken (e.g. drug i n f o r m a t i o n b u l l e t i n s ) even though the format, content and system of d i s t r i b u t i o n o f the i n f o r m a t i o n i n h e r e n t t o each program i s o f t e n d r a m a t i c a l l y d i f f e r e n t . E d u c a t i o n a l and marketing p r i n c i p l e s a r e only r a r e l y r e p o r t e d as being i n c o r p o r a t e d i n t o the programs (128). A d e t a i l e d review of the m o d i f i c a t i o n procedures undertaken i s o f t e n u n a v a i l a b l e and i n t e r p r e t a t i o n o f r e s u l t s i s i m p o s s i b l e . In a d d i t i o n , few w e l l - c o n t r o l l e d s t u d i e s have c o n c u r r e n t l y examined the i n f l u e n c e o f more than one m o d i f i c a t i o n s t r a t e g y on p r e s c r i b i n g behaviour (124-128). Even more s c a r c e are s t u d i e s which have d i r e c t l y compared d i f f e r e n t m o d i f i c a t i o n s t r a t e g i e s on p r e s c r i b i n g behaviour r e l a t i v e t o m u l t i p l e drug t o p i c s (127,128). No r e p o r t s o f r e s e a r c h i n t o the comparative e v a l u a t i o n of m o d i f i c a t i o n s t r a t e g i e s on s e v e r a l drug t o p i c s i n more than one h o s p i t a l have been p u b l i s h e d . T h i s has r e s u l t e d i n attempts t o draw g l o b a l c o n c l u s i o n s r e g a r d i n g comparative s t r a t e g y e f f e c t i v e n e s s by c o n t r a s t i n g the r e s u l t s of i s o l a t e d , s i n g l e - i n t e r v e n t i o n s t u d i e s (130). T h i s p r o c e s s , coupled with a poor d e s c r i p t i o n of the i n t e r v e n t i o n procedures, makes the comparisons d i f f i c u l t and, more i m p o r t a n t l y , p o t e n t i a l l y i n v a l i d . 22 F. SUMMARY In summary, the need f o r the development of a w e l l - c o n t r o l l e d methodological system t o e v a l u a t e the r e l a t i o n s h i p between m o d i f i c a t i o n s t r a t e g i e s and p r e s c r i b i n g behaviour i n the h o s p i t a l s e t t i n g i s e v i d e n t . E q u a l l y important i s the need t o design i n t e r v e n t i o n programs which are both p r a c t i c a l and e f f e c t i v e s t r a t e g i e s f o r modifying p r e s c r i b i n g behaviour i n the community h o s p i t a l s e t t i n g . G. RESEARCH OBJECTIVE The main o b j e c t i v e of t h i s r e s e a r c h p r o j e c t was t o compare the e f f e c t i v e n e s s o f two n o n - f a c i l i t a t e d p e r s u a s i v e s t r a t e g i e s f o r modifying p r e s c r i b i n g behaviour i n the community h o s p i t a l . One s t r a t e g y r e p r e s e n t e d a present h o s p i t a l standard while the other r e p r e s e n t e d a novel approach designed t o improve the e f f i c a c y of t h i s s t r a t e g y c l a s s i f i c a t i o n . In order t o meet t h i s o b j e c t i v e , i t was f i r s t necessary t o develop a study methodology capable of e v a l u a t i n g the impact of m o d i f i c a t i o n s t r a t e g i e s on p r e s c r i b i n g behaviour i n the community h o s p i t a l s e t t i n g . 23 METHODOLOGY A. SUMMARY OF RESEARCH PLAN The i n t e n t o f the study was t o determine the r e l a t i v e impact o f t h r e e l e v e l s of i n t e r v e n t i o n (1-1, 1-2, 1-3) on p r e s c r i b i n g p a t t e r n s . S i x drug t o p i c s i n v o l v i n g sub-optimal usage were s t u d i e d ( T - l , T-2...T-6). These t o p i c s i n v o l v e d o p t i m i z a t i o n o f dosage regimens f o r p r o p h y l a c t i c a n t i b i o t i c s , c e f a z o l i n , c i m e t i d i n e and gentamicin and serum drug l e v e l m o n i t o r i n g f o r t h e o p h y l l i n e and a n t i c o n v u l s a n t s . P r e s c r i b i n g behaviour was c a t e g o r i z e d a c c o r d i n g t o whether or not p r e - e s t a b l i s h e d process c r i t e r i a were met f o r each e l i g i b l e p a t i e n t admission. T h i s was done by a n a l y z i n g data obtained r e t r o s p e c t i v e l y from h e a l t h r e c o r d s . P a t t e r n s of p r e s c r i b i n g behaviour were determined f o r each o f two t e s t h o s p i t a l s ( H - l , H-2). A d u p l i c a t e d Youden square experimental design was employed (131). Each t o p i c i n each h o s p i t a l was randomly a l l o c a t e d t o an i n t e r v e n t i o n l e v e l (Appendix I ) . P a t t e r n s of p r e s c r i b i n g were then compared f o r p e r i o d s b e f o r e and a f t e r the i n t e r v e n t i o n s . Changes i n p r e s c r i b i n g were eva l u a t e d r e l a t i v e t o : i n t e r v e n t i o n ; drug usage t o p i c ; and h o s p i t a l s i t e , u s i n g a n a l y s i s - o f - v a r i a n c e and chi-aquare s t a t i s t i c a l procedures. P o t e n t i a l i n t e r f e r i n g f a c t o r s were monitored to a s s i s t i n the j u s t i f i c a t i o n and e x p l a n a t i o n o f r e s u l t s . The study was conducted by two i n v e s t i g a t o r s . A b l i n d e d i n v e s t i g a t o r was r e s p o n s i b l e f o r data c o l l e c t i o n and 24 i n t e r v e n t i o n development, while an unblinded i n v e s t i g a t o r was r e s p o n s i b l e f o r i n t e r v e n t i o n implementation and a n a l y s i s . B. INDEPENDENT VARIABLES The p r o j e c t i n v o l v e d t h r e e independent v a r i a b l e s . These were: 1) i n t e r v e n t i o n ; 2) drug usage t o p i c ; and 3) t e s t h o s p i t a l s i t e . 1. I n t e r v e n t i o n L e v e l s Three l e v e l s o f i n t e r v e n t i o n were c o n c u r r e n t l y implemented i n an incomplete c r o s s o v e r f a s h i o n d u r i n g the i n t e r v e n t i o n p e r i o d (Appendix I ) . These were a c o n t r o l (1-1), a standard h o s p i t a l pharmacy n e w s l e t t e r (1-2) and a Drug Usage Information (DUI) Program (1-3). 1.1 C o n t r o l (1-1) C r i t e r i a A c o n t r o l l e v e l o f i n t e r v e n t i o n was i n c o r p o r a t e d i n t o the experimental design t o r e f l e c t p r e s c r i b i n g p a t t e r n s r e l a t i v e t o the t o p i c s i n the absence of any d i r e c t i n t e r v e n t i o n . T h i s l e v e l of i n t e r v e n t i o n provided t o p i c - s p e c i f i c assessment of the c o n s i s t e n c y o f p r e s c r i b i n g p a t t e r n s over the e n t i r e p r o j e c t p e r i o d . In a d d i t i o n t o t h i s c o n c u rrent c o n t r o l , the 6-month p e r i o d p r i o r t o a l l i n t e r v e n t i o n s served as a r e t r o s p e c t i v e c o n t r o l f o r the s i x t o p i c s . 25 Process No d i r e c t , attempts t o modify p r e s c r i b i n g behaviour were undertaken. However, the experimental d e s i g n r e q u i r e d t h a t a l l p h y s i c i a n s p a r t i c i p a t e i n each of the t h r e e l e v e l s of i n t e r v e n t i o n (two d i f f e r e n t t o p i c s a t each l e v e l ) . T h e r e f o r e , c o n t r o l groups were a l s o s u b j e c t e d t o 1-2 and 1-3 i n t e r v e n t i o n s r e l a t i v e t o other t o p i c s . 1.2 Standard h o s p i t a l pharmacy n e w s l e t t e r (1-2) C r i t e r i a A second l e v e l of i n t e r v e n t i o n was designed t o employ a n o n - f a c i l i t a t e d p e r s u a s i v e m o d i f i c a t i o n s t r a t e g y . T h i s i n t e r v e n t i o n was intended t o mimic a standard i n - h o s p i t a l method of d i s s e m i n a t i n g w r i t t e n drug p r e s c r i b i n g i n f o r m a t i o n . The i n t e r v e n t i o n i n c o r p o r a t e d recommendations which r e f l e c t e d p r e s c r i b i n g c r i t e r i a adopted f o r the s p e c i f i c t o p i c s . Process An e v a l u a t i o n of i n - h o s p i t a l m o d i f i c a t i o n s t r a t e g i e s e s t a b l i s h e d t h a t a standard method of d i s s e m i n a t i n g w r i t t e n drug p r e s c r i b i n g i n f o r m a t i o n a t the t e s t h o s p i t a l s was through pharmacy n e w s l e t t e r s . The p u b l i c a t i o n s c o n t a i n drug reviews, recommended treatment p r o t o c o l s and i n f o r m a t i o n a b s t r a c t e d from minutes of the Pharmacy & T h e r a p e u t i c s Committee. 26 Content and g e n e r a l format of t y p i c a l n e w s l e t t e r p u b l i c a t i o n s of t h i s nature were determined through a review o f 108 pharmacy n e w s l e t t e r s p u b l i s h e d between January 1982 and September 1984. These b u l l e t i n s were produced by the pharmacy departments of e i g h t B r i t i s h Columbia acute care h o s p i t a l s ( i n c l u d i n g the t e s t s i t e s ) and the B r i t i s h Columbia Drug & Poison Information Centre. Content and g e n e r a l format of the p r o j e c t n e w s l e t t e r s were designed t o resemble these p u b l i c a t i o n s . P r i o r t o d i s t r i b u t i o n , these 1-2 p u b l i c a t i o n s were reviewed and approved by the H o s p i t a l P r o j e c t Committee (see page 4 ). L i t e r a t u r e s u p p o r t i n g the p r e s c r i b i n g c r i t e r i a was p r o v i d e d t o the r e s p e c t i v e pharmacy departments. D e s c r i p t i o n Format The n e w s l e t t e r s were i d e n t i c a l i n appearance t o those r o u t i n e l y d i s t r i b u t e d a t the t e s t h o s p i t a l s . Two 3-page a r t i c l e s (one a r t i c l e per t o p i c ) were combined and p r i n t e d under the standard pharmacy n e w s l e t t e r masthead f o r each t e s t s i t e . Each p u b l i c a t i o n was dated, volume numbered and typed i n a manner which resembled p r e v i o u s p u b l i c a t i o n s a t the s i t e (Appendix I I ) . In keeping with p r e v i o u s pharmacy p u b l i c a t i o n s , no l i t e r a t u r e r e f e r e n c e s were p r o v i d e d , but were i d e n t i f i e d as " a v a i l a b l e from the pharmacy department upon re q u e s t " . 27 Content Each a r t i c l e c o n t a i n e d a g e n e r a l review o f the t o p i c drug(a) i n c l u d i n g pharmacokinetics, adverse e f f e c t s and drug c o a t s where a p p l i c a b l e . T h i s background i n f o r m a t i o n was designed t o j u s t i f y the p r e s c r i b i n g recommendations which f o l l o w e d . These recommendations r e f l e c t e d the p r e - e s t a b l i s h e d p r e s c r i b i n g c r i t e r i a (see page 4 >. These recommendations were i d e n t i c a l t o those employed f o r t o p i c s addressed by 1-3. No r e f e r e n c e was made t o any i n - h o s p i t a l e v a l u a t i o n of the t o p i c drug p r e s c r i b i n g . D i s t r i b u t i o n The pharmacy n e w s l e t t e r s were d i s t r i b u t e d by the pharmacy departments a t each t e s t h o s p i t a l . D i s t r i b u t i o n occured on the same day a t each s i t e and was conducted i n the u s u a l manner which i n c l u d e d the p r o v i s i o n of c o p i e s t o : 1. p h y s i c i a n ' s h o s p i t a l mailboxes 2. p h y s i c i a n ' s lounge area 3. medical departments 4. n u r s i n g u n i t s 5. n u r s i n g a d m i n i s t r a t i o n 6. h o s p i t a l a d m i n i s t r a t i o n 7. pharmacy s t a f f 8. pharmacy department f r o n t entrance No pharmacy n e w s l e t t e r s were d i s t r i b u t e d t o the other 28 t e s t s i t e or t o any other h o s p i t a l . 1.3 DUI Program <I-3> A t h i r d l e v e l of i n t e r v e n t i o n was designed t o employ a novel n o n - f a c i l i t a t e d p e r s u a s i v e s t r a t e g y . T h i s i n t e r v e n t i o n was intended t o modify p r e s c r i b i n g behaviour i n a manner which was e f f e c t i v e , y e t p r a c t i c a l t o implement. The i n t e r v e n t i o n i n v o l v e d both a w r i t t e n and group f a c e - t o - f a c e component and i n c o r p o r a t e d recommendations which r e f l e c t e d p r e s c r i b i n g c r i t e r i a adopted f o r the s p e c i f i c t o p i c s . The DUI Program was developed t o meet these o b j e c t i v e s . T h i s f o u r - p a r t program i n v o l v e d : 1) w r i t t e n announcement and endorsement of the DUI Program; 2) the d i s t r i b u t i o n of an i n i t i a l r e p o r t c o n t a i n i n g t o p i c drug p r e s c r i b i n g p a t t e r n s and recommendations f o r change; 3) the d i s t r i b u t i o n of a f o l l o w - u p r e p o r t i d e n t i f y i n g improvements i n t o p i c p r e s c r i b i n g p a t t e r n s and r e i t e r a t i n g the change recommend-a t i o n s ; and 4) a medical rounds p r e s e n t a t i o n . Over the 2-month p e r i o d of the DUI Program, each p h y s i c i a n r e c e i v e d the p e r s o n a l i z e d l e t t e r announcing the program, i n i t i a l and f o l l o w - u p r e p o r t s and was n o t i f i e d of the medical rounds p r e s e n t a t i o n . P a r t 1 - Announcement of the DUI Program C r i t e r i a The design of t h i s t h i r d l e v e l of i n t e r v e n t i o n 29 i n c o r p o r a t e d feedback of p r e s c r i b i n g p a t t e r n s t o p h y s i c i a n p a r t i c i p a n t s , t h e r e f o r e knowledge of an i n - h o a p i t a l study combined with a p o s s i b l e Hawthorne e f f e c t (132) was expected. Consequently, announcement of the DUI Program p r i o r t o d i s t r i b u t i o n o f the i n i t i a l r e p o r t s was con c e i v e d t o be an e f f e c t i v e method of us i n g a p o s s i b l e Hawthorne e f f e c t while r e d u c i n g p o t e n t i a l r e s i s t a n c e t o the recommendations. T h i s announcement was designed t o i d e n t i f y the program as a c o n f i d e n t i a l and a u t h o r i t a t i v e i n t e r n a l l y - s p o n s o r e d e f f o r t . In a d d i t i o n , the announcement served t o promote the e d u c a t i o n a l i n t e n t of the program and promote the a c t i v e and w i l l i n g p a r t i c i p a t i o n o f the p r e s c r i b e r s . P h y s i c i a n s were approached as p a r t i c i p a n t s o f an i n n o v a t i v e e d u c a t i o n a l program, not as m i s - p r e s c r i b e r s . Process A p e r s o n a l i z e d l e t t e r o f announcement was determined t o r e p r e s e n t the most e f f e c t i v e and p r a c t i c a l method of i n t r o d u c i n g the DUI Program t o a l l p h y s i c i a n s . Format and content of the l e t t e r was endorsed by the H o s p i t a l P r o j e c t Committee p r i o r t o d i s t r i b u t i o n . M a i l i n g l i s t s were generated f o r each h o s p i t a l which i n c l u d e d names and o f f i c e addresses of a l l p h y s i c i a n s s e l e c t e d f o r p a r t i c i p a t i o n i n the p r o j e c t (see page 47 > . 30 D e s c r i p t i o n Format I n t r o d u c t o r y l e t t e r s were p r i n t e d on a s i n g l e page of h o s p i t a l s t a t i o n e r y and each was p e r s o n a l i z e d by t y p i n g the p h y s i c i a n ' s name i n the heading of the l e t t e r . The l e t t e r s were co-signed by both the Chairman of the Pharmacy and T h e r a p e u t i c s Committee and the C h i e f of Medical S t a f f a t the r e s p e c t i v e t e s t h o s p i t a l s (Appendix I I I ) . Content I n t r o d u c t o r y l e t t e r s c o n t a i n e d i n f o r m a t i o n which i n t r o d u c e d the DUI program as an i n t e r n a l l y - o r g a n i z e d e d u c a t i o n a l program intended t o p r o v i d e u s e f u l drug i n f o r m a t i o n to the p h y s i c i a n s a t the t e s t h o s p i t a l . The l e t t e r s promoted the v a l i d i t y and r e a d a b i l i t y of the r e p o r t s t o be d i s t r i b u t e d d u r i n g the program. P h y s i c i a n s were urged to read the r e p o r t s immediately and keep them f o r f u t u r e r e f e r e n c e . Program endorsement by the Pharmacy and T h e r a p e u t i c s Committee and the Medical A d v i s o r y Committee was i d e n t i f i e d . Recommendation f o r such a program by the Canadian C o u n c i l on H o s p i t a l A c c r e d i t a t i o n was a l s o s t r e s s e d . F i n a l l y , the l e t t e r s emphasized the c o n f i d e n t i a l nature of the DUI Program and p r o v i d e d i n i t i a l n o t i c e of the medical rounds p r e s e n t a t i o n scheduled to conclude the program. D i s t r i b u t i o n L e t t e r s of announcement were mailed f i r s t - c l a s s t o 31 p h y s i c i a n s ' o f f i c e s on the f i r s t day of the DUI Program. T h i s o c c u r r e d 10 days a f t e r d i s t r i b u t i o n o f the pharmacy n e w s l e t t e r s (1-2). A l l m a i l i n g s were undertaken a t post o f f i c e s l o c a t e d i n the v i c i n i t y of the r e s p e c t i v e h o s p i t a l s t o minimize the r i s k of m i s d i r e c t e d m a i l i n g s and t o ensure c a n c e l l e d postage on the envelopes r e f l e c t e d l o c a l d i s t r i b u t i o n . I f a c u r r e n t o f f i c e address was u n a v a i l a b l e , the l e t t e r s were d i s t r i b u t e d t o p h y s i c i a n s by t h e i r t e s t h o s p i t a l mailboxes. P a r t 2 - DUI Program I n i t i a l Reports C r i t e r i a A novel method of d i s s e m i n a t i n g drug i n f o r m a t i o n which would have s i g n i f i c a n t impact upon p r e s c r i b i n g behaviour was i n c o r p o r a t e d i n t o the DUI Program. T h i s method of i n t e r v e n t i o n was designed t o c o n t a i n s e v e r a l f e a t u r e s which f o l l o w e d e d u c a t i o n a l and marketing p r i n c i p l e s f o r the m o d i f i c a t i o n of behaviour. The i n t e r v e n t i o n method was designed t o appear p r o f e s s i o n a l l y - d e v e l o p e d and a u t h o r i t a t i v e , yet e a s i l y comprehended, i n t e r e s t i n g and meaningful to the r e a d e r s . T h i s method of i n t e r v e n t i o n was a l s o designed t o be unique i n the t e s t h o s p i t a l s yet r e a d i l y accepted. Process C h a r a c t e r i s t i c s of s u c c e s s f u l i n t e r v e n t i o n programs i n v o l v i n g the d i s t r i b u t i o n of w r i t t e n m a t e r i a l were 1 32 e s t a b l i s h e d (59,60,133,134). Examples o f w r i t t e n I n t e r v e n t i o n m a t e r i a l were s o l i c i t e d from o t h e r educators. Format and content of the r e s u l t i n g r e p o r t s were endorsed by the H o s p i t a l P r o j e c t Committee p r i o r t o d i s t r i b u t i o n . D e s c r i p t i o n Format Two 2-page a r t i c l e s (one a r t i c l e per t o p i c ) were combined f o r each t e s t h o s p i t a l r e p o r t . P r o f e s s i o n a l appearance of the r e p o r t s was achieved by adopting a format resembling e x i s t i n g w e l l - d e s i g n e d i n f o r m a t i o n b u l l e t i n s t o which l o c a l p h y s i c i a n s were accustomed (Appendix I V ) . The r e p o r t s were s p e c i f i c a l l y designed so as not t o mimic pharmaceutical company brochures (12S). Each r e p o r t was b r i e f , i n f o r m a t i o n was c o n t a i n e d on two d o u b l e - s i d e d pages. An e y e c a t c h i n g , easy t o read b l a c k p r i n t on o f f - w h i t e heavy grade paper was s e l e c t e d . A two-color masthead and blue b o l d f a c e p r i n t t o h i g h l i g h t key concepts t o the reader was a l s o used. The r e p o r t s were not intended t o be simply read and d i s p o s e d of (135). Instead, p h y s i c a l a t t r i b u t e s o f the r e p o r t s were designed t o permit s t o r a g e i n a 3 - r i n g binder t o f a c i l i t a t e f u t u r e r e f e r e n c e . R e a d a b i l i t y was ensured by adopting an uncomplicated, l o g i c a l " format f o r the reader t o f o l l o w . Complex t a b l e s , f i g u r e s and terminology were avoided. Information was s u c c i n c t and p u b l i s h e d i n a columnar s t y l e with l a r g e , high 33 c o n t r a s t p r i n t t o improve l e g i b i l i t y . Vocabulary was d i r e c t , and e f f o r t s were made t o a v o i d being dogmatic. An attempt was a l s o made t o use a p o s i t i v e tone employing commonly a p p l i e d terms and a v o i d i n g ambiguity. The r e p o r t s were designed t o appeal t o both v e r b a l and v i s u a l t h i n k e r s . A summary box was i n c o r p o r a t e d t o summarize key concepts o f each a r t i c l e t o ensure e s s e n t i a l i n f o r m a t i o n and recommendations were pr o v i d e d t o "scanners" o f the r e p o r t s . I nformation and recommendations were t a b u l a t e d f o r b r e v i t y and t o help r e a d e r s p e r c e i v e meaningfulness o f m a t e r i a l . Key concepts were repeated and h i g h l i g h t e d i n blue b o l d f a c e p r i n t throughout the r e p o r t t o i n c r e a s e reader exposure t o these concepts. Repeat d i s t r i b u t i o n s o f the same r e p o r t i n c r e a s e d l i k e l i h o o d o f p r e s c r i b e r review o f m a t e r i a l . The h o s p i t a l a t which the p h y s i c i a n p r a c t i c e d and the nature o f the t o p i c was i d e n t i f i e d i n the h e a d l i n e r of each r e p o r t i n an e f f o r t t o i n c r e a s e reader i n t e r e s t . Reports were dated and a f o o t n o t e i n b o l d p r i n t a t the bottom of the f i r s t page was adopted t o a t t r a c t r e a d e r s t o the second t o p i c . A u t h o r i t a t i v e endorsement of the r e p o r t s was achieved by i d e n t i f y i n g i n bo l d p r i n t on the masthead of the r e p o r t t h a t the p u b l i c a t i o n was a j o i n t venture of the Medical A d v i s o r y Committee and Pharmacy and T h e r a p e u t i c s Committee. 34 Content The t h e r a p e u t i c s content of the r e p o r t s c o n s i s t e d o f : 1) a s u c c i n c t i n t r o d u c t i o n t o the t o p i c ; 2) r e s u l t s of the r e c e n t i n - h o s p i t a l drug usage study; 3) recommendations which i n c o r p o r a t e d the p r e s c r i b i n g c r i t e r i a ; and 4) s e l e c t r e f e r -ences to support the recommendations. The i n t r o d u c t i o n served t o j u s t i f y the recommendations which f o l l o w e d i n the r e p o r t . The drug usage study r e s u l t s were intended t o i d e n t i f y t o the r e a d e r s t h a t l e s s than optimal p r e s c r i b i n g was e v i d e n t i n the h o s p i t a l i n which they p r a c t i c e d . References served t o assure p h y s i c i a n s t h a t the r e p o r t content was drawn from the best a v a i l a b l e s t u d i e s and reviews i n the l i t e r a t u r e . D i s t r i b u t i o n Approximately ten days a f t e r d i s t r i b u t i o n of the announcement l e t t e r s , the r e p o r t s were mailed t o p h y s i c i a n s ' o f f i c e s a c c o r d i n g to the m a i l i n g l i s t s p r e v i o u s l y developed. The r e p o r t s were mailed f i r s t - c l a s s i n envelopes which i d e n t i f i e d the r e s p e c t i v e t e s t h o s p i t a l s . A second d i s t r i b u t i o n of these r e p o r t s was undertaken approximately two weeks l a t e r i n each h o s p i t a l . A copy of the r e p o r t was p l a c e d i n each p h y s i c i a n ' s h o s p i t a l mailbox and s e v e r a l c o p i e s were l e f t i n the p h y s i c i a n s ' h o s p i t a l 35 lounge. A few c o p i e s of the i n i t i a l r e p o r t s were provided to the pharmacy department. A copy of each r e p o r t was mailed t o the i n v e s t i g a t o r (c/o Health Records Department at each t e s t h o s p i t a l ) to confirm s u c c e s s f u l d i s t r i b u t i o n and estimate the r e q u i r e d d e l i v e r y time. P a r t 3 - DUI Program Follow-up Reports C r i t e r i a To maximize impact on p r e s c r i b i n g behaviour, a second e d i t i o n of the w r i t t e n i n t e r v e n t i o n m a t e r i a l was d i s t r i b u t e d as p a r t of the DUI Program. T h i s second episode was designed t o be an independent p u b l i c a t i o n of i n t e r e s t and b e n e f i t t o both r e a d e r s of the i n i t i a l r e p o r t and those who had f a i l e d t o do so. A l l f e a t u r e s i n h e r e n t t o the i n i t i a l r e p o r t s were i n c o r p o r a t e d . M o d i f i c a t i o n s t o a c t u a l p r e s c r i b i n g p a t t e r n s t a t i s t i c s (determined f o r the p e r i o d s i n c e the i n i t i a l r e p o r t ) were designed t o ensure e q u i v a l e n c y of r e p o r t c o n t e n t . T h i s i n t e r v e n t i o n s t r a t e g y u t i l i z e d the p r i n c i p l e s of r e p e t i t i o n , knowledge of response r e s u l t s and r e i n f o r c e m e n t and peer acceptance (59). Process Using the i n i t i a l r e p o r t s as a template, m o d i f i c a t i o n s were made t o i n c o r p o r a t e the p r i n c i p l e s o u t l i n e d and ensure the independent r e l e v a n c e of the f o l l o w - u p r e p o r t s . 36 D e s c r i p t i o n Format The f o l l o w - u p r e p o r t s were produced a c c o r d i n g t o the format g u i d e l i n e s i d e n t i f i e d f o r the i n i t i a l r e p o r t s . The r e p o r t s were p r i n t e d on d i f f e r e n t c o l o r e d paper from t h a t used f o r the f i r s t r e p o r t s (Appendix V). The order of the two t o p i c s was r e v e r s e d . These r e p o r t s were dated and the h e a d l i n e r f o r each t o p i c was mo d i f i e d t o r e f l e c t t h a t r e s u l t s of a fo l l o w - u p study were e n c l o s e d . Content R e p e t i t i o n was achieved by a d d r e s s i n g the same two t o p i c s and d e s i g n i n g the t h e r a p e u t i c s content of the fo l l o w - u p r e p o r t s t o be s i m i l a r t o the i n i t i a l r e p o r t s . Although minor m o d i f i c a t i o n s t o the wording and approach t o the m a t e r i a l were made, the recommendations which r e f l e c t e d p r e s c r i b i n g c r i t e r i a were i d e n t i c a l to the i n i t i a l r e p o r t s . Feedback r e g a r d i n g p r e s c r i b e r response t o the f i r s t r e p o r t was p r o v i d e d by i n c o r p o r a t i n g s t a t i s t i c s i n d i c a t i n g an improvement i n p r e s c r i b i n g p a t t e r n s r e l a t i v e t o the i n i t i a l drug usage study. P o s i t i v e changes i n p r e s c r i b i n g p a t t e r n s were emphasized as was the need f o r f u r t h e r improvements. Peer acceptance was i d e n t i f i e d by emphasizing the improvement i n p r e s c r i b i n g behaviour which r e f l e c t e d a gen e r a l acceptance 37 o f the standards proposed. D i s t r i b u t i o n S i x weeks a f t e r the primary m a i l i n g o f the i n i t i a l r e p o r t , the f o l l o w - u p r e p o r t s were mailed t o p h y s i c i a n s ' o f f i c e s i n an i d e n t i c a l f a s h i o n as employed p r e v i o u s l y . A second d i s t r i b u t i o n o f these r e p o r t s was a l s o undertaken a t the r e s p e c t i v e t e s t h o s p i t a l s on the day of the medical rounds p r e s e n t a t i o n . A copy of the r e p o r t was p l a c e d i n each p h y s i c i a n ' s mailbox and s e v e r a l c o p i e s were l e f t i n the p h y s i c i a n s ' lounge. In a d d i t i o n , c o p i e s o f the i n i t i a l and f o l l o w - u p r e p o r t s were d i s t r i b u t e d a t the medical rounds p r e s e n t a t i o n . The d i s t r i b u t i o n process was again monitored by having a copy of each f o l l o w - u p r e p o r t mailed t o the i n v e s t i g a t o r at the r e s p e c t i v e h o s p i t a l h e a l t h r e c o r d s departments. P a r t 4 - Medical Rounds P r e s e n t a t i o n s C r i t e r i a To conclude the DUI Program, a p r a c t i c a l form of a f a c e - t o - f a c e s t r a t e g y was i n c o r p o r a t e d i n t o the DUI Program. T h i s method of i n t e r v e n t i o n was designed t o complement the w r i t t e n i n t e r v e n t i o n methods by p r o v i d i n g a forum f o r d i r e c t p h y s i c i a n c o n t a c t which would al l o w f o r 2-way d i s c u s s i o n and feedback and would a s s i s t i n engendering a commitment to 38 change p r e s c r i b i n g behaviour. Proceaa An e v a l u a t i o n of i n - h o s p i t a l i n f o r m a t i o n programs e s t a b l i s h e d t h a t r e g u l a r l y scheduled medical rounds were a standard and p r a c t i c a l method of d i s s e m i n a t i n g drug i n f o r m a t i o n u s i n g a f a c e - t o - f a c e s t r a t e g y . Approval f o r the use of t h i s method of i n t e r v e n t i o n was o b t a i n e d from the H o s p i t a l P r o j e c t Committee. Scheduling arrangements were made with those i n d i v i d u a l s r e s p o n s i b l e f o r s c h e d u l i n g medical rounds at each t e s t s i t e . In an e f f o r t t o maximize gen e r a l attendance, announcement of the medical rounds p r e s e n t a t i o n s were prov i d e d t o each p h y s i c i a n v i a the announcement l e t t e r and v i a a n o t i c e i n s e r t e d i n the o f f i c e m a i l i n g of the f o l l o w - u p r e p o r t s (Appendix V I ) . In a d d i t i o n , announcement of the p r e s e n t a t i o n was p r o v i d e d through r e g u l a r channels a t each t e s t h o s p i t a l (monthly seminar t o p i c n o t i c e s ) . F i n a l l y , c o p i e s of the n o t i c e s were d i s t r i b u t e d t o a l l p h y s i c i a n mailboxes i n each h o s p i t a l ten days p r i o r t o the events. D e s c r i p t i o n Format The p r e s e n t a t i o n s were given by the unblinded i n v e s t i g a t o r . The speaker was i n t r o d u c e d as a l o c a l expert 39 i n p harmacokinetics and a c o - i n v e s t i g a t o r i n a c u r r e n t drug therapy e v a l u a t i o n p r o j e c t a t a l o c a l t e a c h i n g h o s p i t a l . No r e f e r e n c e t o any p e r s o n a l involvement with the DUI program was made. The p r e s e n t a t i o n a t each h o s p i t a l was 40 minutes long and an equal p o r t i o n of time was devoted t o each of the two t o p i c s . S l i d e s of t a b l e s and change recommendations e x t r a c t e d d i r e c t l y from the r e p o r t s were i n c o r p o r a t e d i n t o the p r e s e n t a t i o n produced t o p r o v i d e v i s u a l r e i n f o r c e m e n t . Content S p e c i f i c content o f the p r e s e n t a t i o n s was designed t o ensure e q u i v a l e n c y o f i n f o r m a t i o n f o r each of the two t o p i c s presented a t each t e s t s i t e . The t o p i c s were i n t r o d u c e d i n such a manner as t o j u s t i f y the recommendations. Drug usage p a t t e r n s i d e n t i f i e d i n the f i r s t r e p o r t s were d i s c u s s e d . Improvements i n drug usage subsequent t o the f i r s t r e p o r t were emphasized as was the need f o r f u r t h e r change. The p r e s e n t a t i o n s concluded with q u e s t i o n p e r i o d s to address any q u e s t i o n s or concerns r e g a r d i n g recommendations being made. The p r e s e n t a t i o n s and q u e s t i o n p e r i o d s were d i s c r e t e l y taped t o a s s i s t i n e v a l u a t i o n of the p r e s e n t a t i o n and i d e n t i f i c a t i o n of p o t e n t i a l p r e s c r i b e r problems. Attendance The p r e s e n t a t i o n s were attended by approximately 5% of p h y s i c i a n s a t H-l and 8% of p h y s i c i a n s a t H-2. 40 2. Drug usage t o p i c s C r i t e r i a Drug usage t o p i c s were i d e n t i f i e d and s t u d i e s conducted to allow measurement of the impact of the i n t e r v e n t i o n s . T o p i c s were s e l e c t e d baaed upon the f o l l o w i n g c r i t e r i a : 1 ) drug(s) are a v a i l a b l e on gen e r a l formulary at each t e s t h o s p i t a l ; 2) drug(s) are a n t i c i p a t e d t o be a v a i l a b l e f o r the d u r a t i o n of the p r o j e c t ; 3) drug(s) are f r e q u e n t l y p r e s c r i b e d a t each t e s t h o s p i t a l t o p r o v i d e minimum sample s i z e as r e q u i r e d f o r s t a t i s t i c a l a n a l y s i s (see page 6 >; 4) drug(s) should possess r e c o g n i z e d t h e r a p e u t i c v a l u e ; 5) drug(s) are c o s t l y (based upon u n i t c o s t or r a t e o f use) or have a re c o g n i z e d p o t e n t i a l f o r d o s e - r e l a t e d adverse r e a c t i o n s ; 6> drug(s) have a known p o t e n t i a l f o r i n a p p r o p r i a t e p r e s c r i b i n g based upon p r e v i o u s s t u d i e s ; 7) e x p l i c i t q u a n t i t a t i v e process c r i t e r i a can be e s t a b l i s h e d f o r the a p p r o p r i a t e p r e s c r i b i n g of the drug(s) based upon l i t e r a t u r e ; 8) c r i t e r i a f o r a p p r o p r i a t e drug(s) usage endorsed by h o s p i t a l p r o j e c t committee and 41 independent expert medical users; 9) p r e - i n t e r v e n t i o n p a t t e r n s of drug(s) usage sho u l d r e f l e c t p r e s c r i b i n g c o n t r a r y t o the p r e - e s t a b l i s h e d c r i t e r i a i n a t l e a s t 50ss of treatment courses; 10) improvements i n drug usage should be o b t a i n a b l e ; 11) drug(s) should be o l d e r and e s t a b l i s h e d t o minimize e x t e r n a l i n f l u e n c e s (e.g. pharmaceutical r e p r e s e n t a t i v e " d e t a i l i n g " , medical j o u r n a l a r t i c l e s ) ; and 12) drug(s) should have a low p r o b a b i l i t y of becoming the t a r g e t of in-house extraneous i n f l u e n c e s other than the study i n t e r v e n t i o n s . A l l t o p i c s were designed to p r i m a r i l y i n v o l v e e v a l u a t i o n of p r e s c r i b i n g process m o d i f i c a t i o n s d u r i n g the p o s t - a d o p t i v e phase. O p t i m i z a t i o n of drug regimen and drug monitoring procedures were focused upon r a t h e r than assessment of drug c h o i c e . T o p i c c r i t e r i a were n o n - c o n t r o v e r s i a l and e a s i l y a t t a i n a b l e t o enhance the impact of the i n t e r v e n t i o n s . Process I d e n t i f i c a t i o n of s u i t a b l e t o p i c s was undertaken i n t h r e e s t a g e s : 1) e v a l u a t i o n of drug u t i l i z a t i o n p a t t e r n s ; 2) p i l o t drug usage s t u d i e s ; and 3) endorsement of f i n a l 42 t o p i c s . 2.1 U t i l i z a t i o n p a t t e r n s U t i l i z a t i o n p a t t e r n s were determined by a review of a random sample o f a v a i l a b l e h e a l t h r e c o r d s f o r acute care p a t i e n t s admitted d u r i n g the pre-study p e r i o d (Appendix V I I ) . Drugs p r e s c r i b e d f r e q u e n t l y enough t o p r o v i d e a s u f f i c i e n t number of treatment courses t o r e f l e c t p r e s c r i b i n g t r e n d s were s e l e c t e d f o r f u r t h e r d e t a i l e d review. 2.2 P i l o t drug usage reviews Drugs meeting t o p i c c r i t e r i a and minimum sample s i z e requirements were i d e n t i f i e d . C r i t e r i a d e s c r i b i n g a p p r o p r i a t e p r e s c r i b i n g were then developed. Fourteen p i l o t drug usage s t u d i e s were then conducted t o i d e n t i f y usage p a t t e r n s and determine the most s u i t a b l e t o p i c s f o r use i n the p r o j e c t . Treatment courses were s e l e c t e d from those p a t i e n t admissions reviewed d u r i n g the u t i l i z a t i o n study and from h e a l t h r e c o r d s f o r other p a t i e n t s d i s c h a r g e d d u r i n g the same p e r i o d . P i l o t drugs, proposed c r i t e r i a and r a t i o n a l e f o r t o p i c e x c l u s i o n are l i s t e d i n Appendix V I I I . 2.3 Endorsements Endorsement of t o p i c s and p r e s c r i b i n g c r i t e r i a were obtained from f o u r independent medical e x p e r t s (Appendix I X ) . These i n d i v i d u a l s were l o c a l c l i n i c i a n s with acknowledged e x p e r t i s e i n the p r e s c r i b i n g o f the t o p i c d r u g ( s ) . A l l 43 t o p i c s and p r e s c r i b i n g c r i t e r i a were a l s o endorsed by the H o s p i t a l P r o j e c t Committee. 2.4 D e s c r i p t i o n of f i n a l t o p i c s S i x t o p i c s were chosen f o r the purposes of the p r o j e c t . T - l i n v o l v e d frequency of a d m i n i s t r a t i o n of c e f a z o l i n . T-2 i n v o l v e d r e n a l f u n c t i o n m o nitoring and dosage adjustment of c i m e t i d i n e i n g e r i a t r i c p a t i e n t s . T-3 focused upon d e t e r m i n a t i o n of i n i t i a l gentamicin dosage based upon age group and weight. T-4 i n v o l v e d serum t h e o p h y l l i n e l e v e l m o n i toring i n p a t i e n t s with acute r e s p i r a t o r y problems. T-5 focused upon the t i m i n g of the i n i t i a l p r o p h y l a c t i c a n t i m i c r o b i a l dose f o r s u r g e r y . F i n a l l y , T-6 i n v o l v e d serum t h e o p h y l l i n e and a n t i c o n v u l s a n t l e v e l s on admission f o r p a t i e n t s with acute b r o n c h o s p a s t i c or s e i z u r e d i s o r d e r s . A d e t a i l e d d e s c r i p t i o n of each t o p i c ( i n c l u d i n g c r i t e r i a to e v a l u a t e p r e s c r i b i n g ) i s p r o v i d e d i n Appendices X - XV. 3. T e s t h o s p i t a l s i t e s C r i t e r i a The s e l e c t i o n of t e s t h o s p i t a l s was designed t o ensure f a v o u r a b l e s i t e c h a r a c t e r i s t i c s and e q u i v a l e n c y a c r o s s s i t e s . T h i s i n v o l v e d e v a l u a t i o n of the a t t r i b u t e s of i n d i v i d u a l p o t e n t i a l t e s t s i t e s and the s i m i l a r i t y a c r o s s a l l p o t e n t i a l t e s t s i t e s . S e l e c t i o n of the most i d e a l t e s t s i t e s f o l l o w e d . P o t e n t i a l t e s t s i t e s were r e q u i r e d to meet the f o l l o w i n g c r i t e r i a : 1) each h o s p i t a l must be a community-based ge n e r a l acute c a r e f a c i l i t y ; 2) each h o s p i t a l must not be a c t i v e l y i n v o l v e d i n f o rmal u n i v e r s i t y - b a s e d t e a c h i n g program; 3) each h o s p i t a l must be i n c l o s e p r o x i m i t y to Vancouver t o f a c i l i t a t e r o u t i n e data c o l l e c t i o n ; and 4) each h o s p i t a l must be w i l l i n g t o p a r t i c i p a t e i n the p r o j e c t . S i m i l a r i t y of these i n d i v i d u a l t e s t s i t e s r e q u i subsequent e v a l u a t i o n a c c o r d i n g t o the f o l l o w i n g c r i t e r i a : 1) t e s t h o s p i t a l s should be g e o g r a p h i c a l l y s e p a r a t e d t o minimize a c t i v e medical s t a f f d u p l i c a t i o n ; 2) t e s t h o s p i t a l s should be of s i m i l a r f a c i l i t y s i z e and nature of medical and pharmacy s e r v i c e s p r o v i d e d ; 3) t e s t h o s p i t a l s should have s i m i l a r o p e r a t i o n a l c h a r a c t e r i s t i c s ( i n c l u d i n g t o t a l acute c a r e admissions, mean l e n g t h of s t a y ) ; 4) t e s t h o s p i t a l s should serve a p a t i e n t p o p u l a t i o n l a r g e enough to p r o v i d e s u f f i c i e n t treatment courses f o r review; 5) t e s t h o s p i t a l s should have s i m i l a r medical s t a f f demographics ( i n c l u d i n g t o t a l , percent 45 a c t i v e , year and p l a c e of g r a d u a t i o n and year o f r e g i s t r a t i o n , and medical s p e c i a l t y ) ; and 6) t e s t h o s p i t a l s have s i m i l a r p a t i e n t demographics ( i n c l u d i n g sex and age d i s t r i b u t i o n ) . Process L e t t e r s of i n t r o d u c t i o n and i n t e n t (Appendix XVI) were then sent t o the medical a d m i n i s t r a t i v e heads a t s i x community h o s p i t a l s l o c a t e d i n southern B r i t i s h Columbia. Subsequent meetings with these i n d i v i d u a l s , the C h i e f s of Medical S t a f f , Chairmen o f the Pharmacy & T h e r a p e u t i c s Committees, D i r e c t o r s of Pharmacy and Health Records Departments ( r e f e r r e d t o as the " H o s p i t a l P r o j e c t Committees") were undertaken. Two h o s p i t a l s f e l t t h a t c u r r e n t medical/pharmacy r e l a t i o n s h i p s would not support such a p r o j e c t and d i d not wish t o p s r t i c i p a t e a t the present time. Two o t h e r h o s p i t a l s were eager t o p a r t i c i p a t e but unique medical s e r v i c e s p r o v i d e d by these s i t e s made them l e s s than i d e a l c a n d i d a t e s due t o a l a c k of e q u i v a l e n c y with other s i t e s . The remaining two h o s p i t a l s were e n r o l l e d i n the p r o j e c t . At each h o s p i t a l , the Pharmacy and T h e r a p e u t i c s Committees and Medical A d v i s o r y / E x e c u t i v e Committees were then a p p r i s e d of the g e n e r a l nature of the p r o j e c t and t h e i r f u l l support f o r the p r o j e c t was o b t a i n e d . 46 D e s c r i p t i o n 3.1 O p e r a t i o n a l C h a r a c t e r i s t i c s Both h o s p i t a l s are government-funded g e n e r a l acute care community h o s p i t a l s . These s i t e s <H-1 and H-2) are two of the l a r g e s t community h o s p i t a l s i n B r i t i s h Columbia with t o t a l bed numbers (acute and extended care) of 637 and 602, r e s p e c t i v e l y . The h o s p i t a l s are l o c a t e d approximately 10 k i l o m e t r e s from each other and p r o v i d e h e a l t h c a r e s e r v i c e s f o r independent p o p u l a t i o n s of 138,000 and 170,000 people. O p e r a t i o n a l c h a r a c t e r i s t i c s o f the two h o s p i t a l s are p rovided i n Table I I . 3.2 P r e a c r i b e r s A l l p h y s i c i a n s and d e n t i s t s with p r e s c r i b i n g p r i v i l e g e s a t e i t h e r h o s p i t a l were p o t e n t i a l p a r t i c i p a n t s i n the p r o j e c t . C h a r a c t e r i s t i c s of those p h y s i c i a n s meeting s e l e c t i o n c r i t e r i a (see page 4 7 ) f o r m a i l i n g l i s t i n c l u s i o n are p r o v i d e d i n Table I I I . 3.3 P a t i e n t s A l l p a t i e n t s admitted to e i t h e r of the two h o s p i t a l s were p o t e n t i a l p r o j e c t p a r t i c i p a n t s . C h a r a c t e r i s t i c s of the acute c a r e p a t i e n t p o p u l a t i o n served by each of the h o s p i t a l s are p r o v i d e d i n Table IV. These data r e p r e s e n t f i s c a l p e r i o d s immediately p r i o r t o the i n i t i a l phase of the 47 p r o j e c t . C. DATA COLLECTION PROCEDURES - DEPENDENT VARIABLE 1 P r e s c r i b i n g data 1.1 Case s e l e c t i o n C r i t e r i a A l l p a t i e n t s d i s c h a r g e d from an acute admission a t the t e s t h o s p i t a l s were e l i g i b l e f o r i n c l u s i o n . A p a t i e n t s t a y was i n c l u d e d i f : 1) a t a r g e t drug was p r e s c r i b e d ; 2) a l l a s s o c i a t e d t o p i c i n c l u s i o n c r i t e r i a were met (Appendices X-XV); and 3) the p a t i e n t stay was randomized i n t o the study ( a c c o r d i n g t o process d e s c r i b e d on page 63 ). P a t i e n t s were excluded i f the p r e s c r i b i n g p h y s i c i a n : 1) was a member of the H o s p i t a l P r o j e c t Committee (see page 46 ); 2) had ad m i t t i n g p r i v i l e g e s a t both t e s t h o s p i t a l s ; 3) was not on medical s t a f f d u r i n g the pre-study or p r e - i n t e r v e n t i o n p e r i o d s ; or 4) was not a c t i v e or d i d not have locum p r e s c r i b i n g p r i v i l e g e s a t the time of the i n t e r v e n t i o n s . I n d i v i d u a l h e a l t h r e c o r d s are maintained by the Health Records Departments f o r a l l i n p a t i e n t s i n accordance with standards developed by the Canadian C o u n c i l On H o s p i t a l A c c r e d i t a t i o n (136). P a t i e n t admissions were i d e n t i f i e d v i a a review of d a i l y or monthly p a t i e n t d i s c h a r g e census. Each p a t i e n t was 48 i d e n t i f i e d by name and a p a t i e n t number which was maintained f o r a l l subsequent admissions. Using the p a t i e n t number, h e a l t h r e c o r d s for- acute c a r e p a t i e n t s were l o c a t e d and the a p p r o p r i a t e p a t i e n t admission was reviewed by the b l i n d e d i n v e s t i g a t o r t o e s t a b l i s h whether a t a r g e t drug had been p r e s c r i b e d and whether some or a l l t o p i c c r i t e r i a were met. In the event a h e a l t h r e c o r d was i n i t i a l l y u n a v a i l a b l e f o r review, t h i s p rocess was repeated u n t i l the h e a l t h r e c o r d was l o c a t e d and a review of the p a t i e n t admission c o u l d be accomplished. A l l h e a l t h r e c o r d review was undertaken by the one b l i n d e d i n v e s t i g a t o r . A d i s c h a r g e l i s t coding system was developed t o f a c i l i t a t e i d e n t i f i c a t i o n of p a t i e n t admissions which met some or a l l c r i t e r i a f o r t o p i c i n c l u s i o n . These codes were entered by the b l i n d e d i n v e s t i g a t o r onto c o p i e s of the d i s c h a r g e l i s t s t o al l o w f o r f u r t h e r p a t i e n t i d e n t i f i c a t i o n and sampling i f r e q u i r e d . D e s c r i p t i o n H e a l t h r e c o r d s of p a t i e n t s d i s c h a r g e d between May 1, 1984 and J u l y 22, 1985 were reviewed. Health r e c o r d s l o c a t e d and reviewed and'those u n a v a i l a b l e a t completion of the study are i d e n t i f i e d i n Table V. 49 1.2 Data C o l l e c t i o n and P r o c e s s i n g C r i t e r i a Data c o l l e c t i o n waa designed t o a s s i s t i n the d e t e r m i n a t i o n of whether p r e s c r i b i n g c r i t e r i a were being met. For each treatment course s e l e c t e d f o r t o p i c i n c l u s i o n , measurements were made of those v a r i a b l e s i d e n t i f i e d as necessary t o e s t a b l i s h whether c r i t e r i a were met. I d e n t i f i c a t i o n of the date of p a t i e n t admission and t a r g e t drug(s) p r e s c r i b i n g , s i t e of admission and code i d e n t i f i c a t i o n of the p r e s c r i b i n g p h y s i c i a n was a l s o undertaken. Data c o l l e c t i o n was designed t o be accomplished i n a manner which p r o v i d e d an e f f i c i e n t and convenient instrument f o r d a i l y use, and p r o v i d e d the computer e n t r y o p e r a t o r s with numeric data i n an e a s i l y f o l l o w e d format t o minimize e n t r y e r r o r s <137). Process A l l p r e s c r i b i n g data were obtained from the p a t i e n t h e a l t h r e c o r d u s i n g a manual a u d i t process f o r h e a l t h r e c o r d review (138). For every p a t i e n t admission, the h e a l t h r e c o r d c o n t a i n e d i d e n t i f i c a t i o n of p a t i e n t , a d m i t t i n g d i a g n o s i s , h i s t o r y of p a t i e n t , r e p o r t of p h y s i c a l examinations, d i a g n o s t i c and t h e r a p e u t i c o r d e r s ( i n c l u d i n g p r e s c r i p t i o n s ) , o b s e r v a t i o n s , and r e p o r t s of a c t i o n s and f i n d i n g s ( i n c l u d i n g l a b o r a t o r y r e p o r t s ) . 50 When s e l e c t e d f o r t o p i c i n c l u s i o n , a l l necessary data f o r a p a r t i c u l a r treatment course were manually entered onto m o d i f i e d 80-column F o r t r a n coding forms. Where a p p l i c a b l e , q u a l i t a t i v e i n f o r m a t i o n (e.g. sex and admission d i a g n o s i s ) were coded i n t o numeric form t o f a c i l i t a t e convenience of c o l l e c t i o n and data e n t r y . A l l data c o l l e c t i o n was undertaken by the same i n v e s t i g a t o r a l s o r e s p o n s i b l e f o r h e a l t h r e c o r d review. The number of treatment courses sampled i s shown i n Table V. S p e c i f i c data e x t r a c t e d a c c o r d i n g t o t o p i c are i d e n t i f i e d i n Appendices X-XV. 2. Extraneous f a c t o r s C r i t e r i a A s u r v e i l l a n c e system was designed t o monitor f o r m a l i z e d i n - h o s p i t a l drug i n f o r m a t i o n a c t i v i t i e s and i d e n t i f y p o t e n t i a l sources of confounding i n f l u e n c e on p r e s c r i b i n g p a t t e r n s . Process A l l medical rounds p r e s e n t a t i o n s scheduled d u r i n g the p r o j e c t were i d e n t i f i e d . Where p o s s i b l e , these were attended by the b l i n d e d i n v e s t i g a t o r t o e s t a b l i s h the p o t e n t i a l extent of i n f l u e n c e . Copies of a l l medical b u l l e t i n s produced d u r i n g the p r o j e c t were o b t a i n e d . Formal c l i n i c a l pharmacy a c t i v i t i e s d u r i n g the p r o j e c t were reviewed with the D i r e c t o r s of Pharmacy a f t e r completion of data c o l l e c t i o n . Copies of a l l pharmacy b u l l e t i n s produced d u r i n g the p r o j e c t were o b t a i n e d . Throughout the p r o j e c t , H o s p i t a l P r o j e c t Committee members were requested to c o n t a c t the unblinded i n v e s t i g a t o r i f any programs or a c t i v i t i e s were planned which might i n t e r f e r e with the p r o j e c t . D e s c r i p t i o n T o p i c s of medical rounds and a l l medical and pharmacy n e w s l e t t e r s or b u l l e t i n s d i s t r i b u t e d d u r i n g the p r o j e c t are i d e n t i f i e d i n Appendices XVII and XVIII. D. DATA ANALYSIS AND PHASING The r e s t r i c t i o n i n the a v a i l a b i l i t y of s i m i l a r h o s p i t a l s coupled with a d e s i r e t o examine t h r e e l e v e l s of i n t e r v e n t i o n ( i n c l u d i n g a c o n t r o l ) and m u l t i p l e drug-usage t o p i c s r e q u i r e d the use of a d u p l i c a t e d incomplete L a t i n square (Youden Square) experimental d e s i g n . T h i s design i s c o n s t r u c t e d by a rearrangement of balanced incomplete b l o c k s . I t possesses the c h a r a c t e r i s t i c double c o n t r o l of the l a t i n square without the r e s t r i c t i o n t h a t the number of r e p l i c a t e s must equal the number of treatments. Every treatment appears twice i n a column ( r e p l i c a t i o n ) and every p a i r of treatments appears 52 tog e t h e r an equal number of times (131). 1. S t a t i s t i c a l A n a l y s i s C r i t e r i a The e f f e c t s of the i n t e r v e n t i o n s on p r e s c r i b i n g behaviour were analyzed u s i n g a t h r e e - l e v e l s t a t i s t i c a l approach. Changes i n p r e s c r i b i n g p a t t e r n s were ev a l u a t e d a c c o r d i n g t o : 1> the i n f l u e n c e of h o s p i t a l s , t o p i c s and i n t e r v e n t i o n s ; 2) the r e l a t i v e i n f l u e n c e of the t h r e e i n t e r -v e n t i o n l e v e l s ; and 3) the i n f l u e n c e of the i n t e r v e n t i o n s on s p e c i f i c t o p i c s ( i n c l u d i n g long-term e f f e c t s ) . Process and D e s c r i p t i o n P r e s c r i b i n g data f o r the s t u d i e s were grouped by p e r i o d and h o s p i t a l a c c o r d i n g t o p r e s c r i p t i o n or admission date depending upon the t o p i c . 1.1 R e l a t i v e i n f l u e n c e o f i n t e r v e n t i o n , t o p i c and h o s p i t a l For each of the 12 i n t e r v e n t i o n , t o p i c and h o s p i t a l combinations, raw p r o p o r t i o n a l "treatment courses meeting t o p i c c r i t e r i a " data f o r 3-month p e r i o d s were transformed i n t o p e r c e n t d i f f e r e n c e v a l u e s (pre-study versus p r e - i n t e r v e n t i o n , p r e - i n t e r v e n t i o n versus p o s t - i n t e r v e n t i o n > . A standard a n a l y s i s - o f - v a r i a n c e (ANOVA) was then undertaken t o e s t a b l i s h the i n f l u e n c e of t o p i c s and h o s p i t a l s on changes i n p r e s c r i b i n g p a t t e r n s d u r i n g the p e r i o d b e f o r e i n t e r v e n t i o n s . 53 Due t o the imbalance o f the incomplete c r o s s o v e r study d e s i g n , a m o d i f i e d ANOVA was undertaken t o e v a l u a t e p r e / p o s t i n t e r v e n t i o n changes. Standard e r r o r s were determined f o r the p r o p o r t i o n a l d a t a . These were baaed upon the sum of r e l a t i v e l y l a r g e samples from the two 3-month p e r i o d s , t h e r e f o r e assumed t o be exact with a normal d i s t r i b u t i o n . Standard e r r o r v a l u e s v a r i e d from 4.90* t o 8.88* ( l e s s than a f a c t o r of two), thus the i n d i v i d u a l v a l u e s were r e p l a c e d by a common val u e "v" where V=[average (standard e r r o r 2 ) ] l / 2 = 7.59*. In the ANOVA model, the t r u e value of the e f f e c t e quals o v e r a l l e f f e c t p l u s the e f f e c t s of t o p i c , h o s p i t a l , i n t e r v e n t i o n and any i n t e r a c t i o n e f f e c t s . However, the experimental d e s i g n o f t h i s p r o j e c t does not all o w f o r assessment o f i n d i v i d u a l i n t e r a c t i v e e f f e c t s . T h e r e f o r e a " l a c k of f i t " e f f e c t was s u b s t i t u t e d . T h i s e f f e c t was a l s o assumed t o be random, i d e n t i c a l and normally d i s t r i b u t e d . T h i s was confirmed by a normal p r o b a b i l i t y p l o t o f r e s i d u a l s which demonstrated no obvious s y s t e m a t i c departure from a s t r a i g h t l i n e . A n a l y s i s t o determine the magnitude of the lack of f i t r e v e a l e d no r e a l evidence t o suggest t h a t t h i s was s i g n i f i c a n t (SS Error/v2=5.40, p>0.15), t h e r e f o r e a n a l y s i s proceeded under the assumption t h a t i n t e r a c t i o n e f f e c t s was minimal. Source of e f f e c t r e l a t i v e t o h o s p i t a l , t o p i c and i n t e r v e n t i o n were then assessed. 54 1.2 R e l a t i v e i n f l u e n c e of the t h r e e l e v e l s of i n t e r v e n t i o n Using the same m o d i f i e d ANOVA procedure d e s c r i b e d above, the r e l a t i v e impact of each of the t h r e e l e v e l s of I n t e r v e n t i o n was determined. 1.3 I n f l u e n c e of i n t e r v e n t i o n s on s p e c i f i c t o p i c s To determine the e f f e c t s of the i n t e r v e n t i o n s on s p e c i f i c t o p i c s , p r o p o r t i o n a l data were compared using Y a t e s ' - c o r r e c t e d t w o - t a i l e d c h i - s q u a r e a n a l y s i s . G r a p h i c a l r e p r e s e n t a t i o n was a l s o employed to t r e n d s of t o p i c drug usage over the e n t i r e p r o j e c t S i g n i f i c a n c e f o r a l l s t a t i s t i c a l procedures was p < 0.05. 2. Phasing C r i t e r i a Examination of changes i n p r e s c r i b i n g p a t t e r n s r e q u i r e d the d e s i g n a t i o n of time p e r i o d s which were: 1> of s u f f i c i e n t l e n g t h t o a l l o w f o r s t a t i s t i c a l e v a l u a t i o n of a s u f f i c i e n t number of treatment courses; 2) s u c c i n c t enough t o permit d e t e c t i o n of temporary e f f e c t s ; and 3) designed t o ensure t h a t any immediate e f f e c t s of the i n t e r v e n t i o n s would be d e t e c t e d . Process and D e s c r i p t i o n U t i l i z a t i o n s t a t i s t i c s obtained d u r i n g the p i l o t s t u d i e s examine p e r i o d . s e t at 55 and minimum sample s i z e data (see page 62) were used to e s t i m a t e the d u r a t i o n of each p e r i o d . Based upon these parameters, 3-month p e r i o d s were determined be s t capable of d e t e c t i n g changes i n p r e s c r i b i n g p a t t e r n s . These p r e - i n t e r v e n t i o n and p o s t - i n t e r v e n t i o n p e r i o d s were scheduled t o commence on the day p r i o r t o and f o l l o w i n g the i n t e r v e n t i o n p e r i o d s . To f a c i l i t a t e e v a l u a t i o n of longer-term impacts of the i n t e r v e n t i o n s , data were a l s o c o l l e c t e d f o r an a d d i t i o n a l 3-month p e r i o d p r i o r t o the p r e - i n t e r v e n t i o n p e r i o d ( t h i s was denoted the pre-study p e r i o d ) and f o r a 3-month p e r i o d a f t e r the p o s t - i n t e r v e n t i o n p e r i o d ( t h i s was denoted the post-study p e r i o d ) . E. CONTROL TECHNIQUES 1. B l i n d i n g B l i n d i n g of study p h y s i c i a n s , pharmacists and one i n v e s t i g a t o r was undertaken. 1.1 P h y s i c i a n s C r i t e r i a D i f f e r e n t l e v e l s of b l i n d i n g of the p h y s i c i a n p a r t i c i p a n t s was t o occur over t h r e e s u c c e s s i v e stages of the study: 1) d u r i n g the pre-study and p r e - i n t e r v e n t i o n p e r i o d s ; 2) a f t e r the d i s t r i b u t i o n of the DUI Program 56 announcement, l e t t e r and p r i o r t o d i s t r i b u t i o n o f the i n i t i a l DUI Program r e p o r t ; and 3> a f t e r d i s t r i b u t i o n o f the i n i t i a l DUI Program r e p o r t . At each stage , a d i f f e r e n t l e v e l of b l i n d i n g would a r i s e as a consequence of the key i n f o r m a t i o n g i v e n t o the p h y s i c i a n p a r t i c i p a n t s . P h y s i c i a n s p a r t i c i p a t i n g i n the H o s p i t a l P r o j e c t Committee were r e q u i r e d t o be f a m i l i a r with most as p e c t s of the p r o j e c t . However, b l i n d i n g of the members of the Medical A d v i s o r y Committee or Pharmacy and T h e r a p e u t i c s Committee to the s i x t o p i c s was designed t o minimize the number of f u r t h e r p h y s i c i a n e x c l u s i o n s . With the e x c e p t i o n o f these committees, a t no time were p h y s i c i a n p a r t i c i p a n t s informed of the u l t i m a t e o b j e c t i v e o f the p r o j e c t nor were they a p p r i s e d o f the u n i v e r s i t y involvement. Process B l i n d i n g of p h y s i c i a n p a r t i c i p a n t s was assured d u r i n g the p r o j e c t design and pre-study and p r e - i n t e r v e n t i o n p e r i o d s . During these p e r i o d s the g e n e r a l nature and i n t e n t of the p r o j e c t was known onl y t o the H o s p i t a l P r o j e c t Committee and t o the c u r r e n t members of the Pharmacy & T h e r a p e u t i c s Committee and the Medical A d v i s o r y Committee a t each h o s p i t a l . During the i n t e r v e n t i o n p e r i o d , p h y s i c i a n s were informed t h a t an in-house study of drug usage was being conducted. 57 T h i s r e s u l t e d from d i s t r i b u t i o n of the l e t t e r announcing the DUI Program. However, no d e s c r i p t i o n o f the t o p i c s were pr o v i d e d i n the l e t t e r . Only a f t e r d i s t r i b u t i o n of the i n i t i a l DUI Program r e p o r t s d i d p h y s i c i a n s become aware of the two t o p i c s s e l e c t e d f o r t h e i r h o s p i t a l . During the e n t i r e p r o j e c t , o n l y the members of the H o s p i t a l P r o j e c t Committee were a p p r i s e d o f the nature of a l l s i x t o p i c s . 1.2. Pharmacists C r i t e r i a B l i n d i n g o f pharmacists t o the e x i s t e n c e of the p r o j e c t and the involvement of the u n i v e r s i t y was designed t o minimize p o t e n t i a l extraneous i n f l u e n c e on p r e s c r i b i n g p a t t e r n s . Complete b l i n d i n g was assured d u r i n g the pre-study and p r e - i n t e r v e n t i o n p e r i o d s . During the i n t e r v e n t i o n p e r i o d , pharmacists became aware of the g e n e r a l nature of the t o p i c s addressed by the pharmacy n e w s l e t t e r and the DUI Program r e p o r t s i n t h e i r h o s p i t a l . Process During the p r e - i n t e r v e n t i o n p e r i o d , no pharmacists were informed of the p r o j e c t . Immediately p r i o r t o the i n t e r v e n t i o n p e r i o d , s t a f f pharmacists a t each h o s p i t a l were a p p r i s e d o f the nature and i n t e n t of the p r o j e c t . The pharmacy b u l l e t i n s were pr o v i d e d t o the pharmacists on the day of d i s t r i b u t i o n . As w e l l , pharmacists r e c e i v e d c o p i e s of the DUI Program i n i t i a l r e p o r t . B l i n d i n g t o the remaining 58 two t o p i c s was s u s t a i n e d throughout the p r o j e c t . 1.3. I n v e s t i g a t o r C r i t e r i a A double b l i n d d e s i g n was employed t o minimize r e s e a r c h e r b i a s on response v a r i a b l e measurement. To accomplish t h i s , b l i n d i n g was r e q u i r e d d u r i n g the f o l l o w i n g procedures: 1) h e a l t h r e c o r d review; 2) data c o l l e c t i o n ; 3) r e l i a b i l i t y t e s t i n g ; 4) data a n a l y s i s ; and 5) i n t e r v e n t i o n development. Process The b l i n d e d i n v e s t i g a t o r (unaware which t o p i c s were s e l e c t e d f o r each l e v e l of i n t e r v e n t i o n a t each h o s p i t a l ) was i n v o l v e d i n a l l the procedures d e s c r i b e d above. The same b l i n d e d i n v e s t i g a t o r was r e s p o n s i b l e f o r d e v e l o p i n g the format and content of the i n t e r v e n t i o n programs. To ensure b l i n d i n g was maintained, e d u c a t i o n a l m a t e r i a l was developed f o r each p o s s i b l e combination of h o s p i t a l , i n t e r v e n t i o n and t o p i c . To t h i s end, s i x pharmacy b u l l e t i n s , 12 i n i t i a l DUI Program r e p o r t s and 12 follow-up r e p o r t s were developed. Using a randomization process d e s c r i b e d l a t e r , an u nblinded i n v e s t i g a t o r .subsequently matched the a p p r o p r i a t e i n t e r v e n t i o n m a t e r i a l f o r each randomly a l l o c a t e d combination and e l i m i n a t e d the remaining m a t e r i a l . F i n a l p r o d u c t i o n and d i s t r i b u t i o n of the m a t e r i a l 59 was a l s o undertaken without the b l i n d e d i n v e s t i g a t o r being aware of the a l l o c a t i o n . The b l i n d e d i n v e s t i g a t o r r e s p o n s i b l e f o r data c o l l e c t i o n d i d not c o n t a c t any medical or pharmacy personnel d u r i n g the i n t e r v e n t i o n or p o s t - i n t e r v e n t i o n p e r i o d s o f the p r o j e c t . No w r i t t e n i n t e r v e n t i o n m a t e r i a l was d i s t r i b u t e d t o the h e a l t h r e c o r d s department. With the e x c e p t i o n o f the head, employees of t h i s department were unaware of the s p e c i f i c nature of the p r o j e c t f o r i t s d u r a t i o n . A l l p r o j e c t - r e l a t e d q u e r i e s were requested t o be d i r e c t e d towards the unblinded i n v e s t i g a t o r . 2. R e l i a b i l i t y C r i t e r i a H e a l t h r e c o r d review and data c o l l e c t i o n f o r p a t i e n t admissions p r i o r t o and f o l l o w i n g the i n t e r v e n t i o n s was designed: 1) t o occur i n a manner which reduced any t i m e - r e l a t e d changes i n the procedure; 2) to minimize i n t e r - o b s e r v e r v a r i a t i o n ; and 3) t o ensure any v a r i a t i o n would be non-systematic. Process and D e s c r i p t i o n Health r e c o r d review and data c o l l e c t i o n f o r the p r e - i n t e r v e n t i o n and p o s t - i n t e r v e n t i o n p e r i o d s o c c u r r e d c o n c u r r e n t l y . A l l procedures were undertaken by the same b l i n d e d i n v e s t i g a t o r . T h i s i n v e s t i g a t o r was experienced i n 60 the h e a l t h r e c o r d a u d i t process (80,139,140). C l e a r o p e r a t i o n a l d e f i n i t i o n s o f i n c l u s i o n c r i t e r i a were developed. These were a p p l i e d e q u a l l y a t each h o s p i t a l . In a d d i t i o n , most v a r i a b l e s f o r which data were c o l l e c t e d were q u a n t i t a t i v e i n nature t o minimize i n t e r p r e t a t i o n . Two procedures were designed t o e s t a b l i s h the r e l i a -b i l i t y o f : 1) the h e a l t h r e c o r d review process ( h e a l t h r e c o r d l o c a t i o n and review f o r t a r g e t drug usage); and 2) the data c o l l e c t i o n p r o c e s s . 2.1 Health r e c o r d review In the f i r s t procedure, 100 p r e v i o u s l y reviewed p a t i e n t admissions (50 from each h o s p i t a l ) were s e l e c t e d from the d i s c h a r g e l i s t s v i a a s y s t e m a t i c sampling method which provided a balanced r e p r e s e n t a t i o n a c r o s s the e n t i r e p r o j e c t p e r i o d . A r e c o r d of p a t i e n t numbers, presence/absence of t a r g e t d r u g ( s ) , i n c l u s i o n c r i t e r i a and randomization s t a t u s were rec o r d e d by the unblinded i n v e s t i g a t o r . From t h i s l i s t , p a t i e n t numbers and d i s c h a r g e dates were then p r o v i d e d t o the b l i n d e d i n v e s t i g a t o r who subsequently l o c a t e d the h e a l t h r e c o r d s and reviewed the p a t i e n t admission i n q u e s t i o n . R e s u l t s of the second review were then compared t o the o r i g i n a l . N i n e t y - t h r e e h e a l t h r e c o r d s (H-l - 48, H-2 - 45) were a v a i l a b l e f o r review. The t o t a l number of t o p i c drug(s) i d e n t i f i e d f o r each pass a t H-l was 66 and 68 while at H-2 61 each pass i d e n t i f i e d a t o t a l o f 73 drugs. Ten v a r i a t i o n s (7*) i n the i d e n t i f i c a t i o n o f t o p i c drugs (presence/absence) o c c u r r e d . 2.2 Data c o l l e c t i o n In the second procedure, a f u r t h e r 45 h e a l t h r e c o r d s from each h o s p i t a l c o n t a i n i n g p r e v i o u s l y i d e n t i f i e d t a r g e t drug treatment courses (approximately 14 per t o p i c ) were s e l e c t e d v i a a s y s t e m a t i c sampling method which provided r e p r e s e n t a t i o n a c r o s s the e n t i r e 15-month p r o j e c t p e r i o d . T h i s was accomplished u s i n g the computer database t o i d e n t i f y treatment c o u r s e s , p a t i e n t numbers, d i s c h a r g e dates and t o p i c number were recorded by the unblinded i n v e s t i g a t o r . T h i s l i s t was pr o v i d e d t o the b l i n d e d i n v e s t i g a t o r who subsequently l o c a t e d the h e a l t h r e c o r d s and c o l l e c t e d treatment course data u s i n g the i d e n t i c a l data c o l l e c t i o n form adopted p r e v i o u s l y . Treatment course v a r i a b l e s were d e f i n e d as " e s s e n t i a l " i f the v a r i a b l e was used t o determine i f c r i t e r i a were met. Twenty-nine e s s e n t i a l v a r i a b l e s were i d e n t i f i e d f o r the s i x s t u d i e s . R e s u l t s of the second data c o l l e c t i o n were then compared t o the o r i g i n a l . E i g h t y - f o u r h e a l t h r e c o r d s ( H - l - 43, H-2 - 41) were a v a i l a b l e f o r review a t the time of the procedure. Data were c o l l e c t e d f o r a t o t a l of 404 v a r i a b l e e n t r i e s (one e n t r y / e s s e n t i a l v a r i a b l e / t r e a t m e n t c o u r s e / t o p i c ) . Twenty-two v a r i a t i o n s i n measurements were i d e n t i f i e d (5.4JO. None of 62 these measurement v a r i a t i o n s would have a l t e r e d c a t e g o r i z a t i o n o f the treatment courses i n v o l v e d . Nine v a r i a t i o n s were due t o ambiguity of measurement (e.g. weight was a v a i l a b l e from more than one s o u r c e ) , e i g h t v a r i a t i o n s were due t o r e c o r d i n g wrong v a l u e s and f i v e v a r i a t i o n s were due t o s u b j e c t i v i t y of measurement (e.g. p r e s c r i p t i o n not dated t h e r e f o r e e s t i m a t e d ) . 3. Data e n t r y v e r i f i c a t i o n Completed data c o l l e c t i o n forms were reviewed by the b l i n d e d i n v e s t i g a t o r f o r obvious e r r o r s and omissions and t r a n s f e r r e d i n t o computerized database by data p r o c e s s o r s a t the U n i v e r s i t y o f B r i t i s h Columbia. A double-entry procedure was then employed t o v e r i f y a l l data f i l e s . T h i s was accomplished by i n i t i a l data e n t r y by an o p e r a t o r f o l l o w e d by r e - e n t r y o f same data by a second o p e r a t o r while u s i n g a v e r i f y mode which i d e n t i f i e s d i s c r e p a n c i e s i n the data e n t e r e d . Where d i s c r e p a n c i e s were e v i d e n t , the F o r t r a n data c o l l e c t i o n sheet was reviewed t o determine the proper e n t r y and necessary m o d i f i c a t i o n s made. 4. Sample s i z e C r i t e r i a Minimum sample s i z e approximation was undertaken t o estimate the minimum sample s i z e r e q u i r e d f o r comparison of t o p i c - s p e c i f i c p r e s c r i b i n g p a t t e r n s p r i o r t o and f o l l o w i n g an i n t e r v e n t i o n program a t one t e s t h o s p i t a l . 63 Process and D e s c r i p t i o n Alpha (Type I e r r o r ) was s e t a t 0.05 and beta (Type II e r r o r ) was s e t a t 0.20 (power was t h e r e f o r e s e t a t 0.80) f o r a t w o - t a i l e d t e s t . Based upon average p r o p o r t i o n s of p r e - i n t e r v e n t i o n treatment courses meeting c r i t e r i a (approximately 50?s), estimated impact of i n t e r v e n t i o n l e v e l (20* improvement with 1-2), an estimated sample s i z e of 100 treatment courses per t o p i c was determined (141). 5. Randomization Randomization was designed t o occur a t two l e v e l s : 1) treatment course s e l e c t i o n ; and 2) a l l o c a t i o n of i n t e r -v e n t i o n l e v e l t o each t o p i c and h o s p i t a l combination (Appendix I ) . 5.1 Treatment course s e l e c t i o n C r i t e r i a Treatment course s e l e c t i o n was designed t o p r o v i d e an unbiased sample i n order to r e f l e c t p o p u l a t i o n p r e s c r i b i n g p a t t e r n s p r i o r t o and f o l l o w i n g the i n t e r v e n t i o n s . Process and D e s c r i p t i o n Based upon p r e v i o u s l y determined u t i l i z a t i o n s t a t i s t i c s and the estimated sample s i z e r e q u i r e d , a case s e l e c t i o n r a t e was determined f o r each t o p i c . For t o p i c s T-2, T-3, T-4 and T-6, a l l treatment courses meeting i n c l u s i o n c r i t e r i a were s u b j e c t e d t o data c o l l e c t i o n . In the remaining t o p i c s , a 64 r e l a t i v e excess of cases e x i s t e d . T h e r e f o r e , cases were randomly s e l e c t e d f o r i n c l u s i o n or e x c l u s i o n a c c o r d i n g t o the pre-determined case s e l e c t i o n r a t e . For t o p i c T - l , o n l y 50* of treatment courses meeting i n c l u s i o n c r i t e r i a were randomly s e l e c t e d f o r the purposes of data c o l l e c t i o n . There were two e x c e p t i o n s . For a 7-week p e r i o d d u r i n g the p r e - i n t e r v e n t i o n p e r i o d a t H-l and the e n t i r e 13-week p r e - i n t e r v e n t i o n p e r i o d a t H-2, 24* and 44* case s e l e c t i o n r a t e s were employed, r e s p e c t i v e l y . These r a t e s r e f l e c t e d the pre-determined minimal y i e l d s estimated necessary t o p r o v i d e s u f f i c i e n t sample s i z e s . These r a t e s were employed duri n g i n i t i a l data c o l l e c t i o n but were l a t e r m o d ified t o ensure s u f f i c i e n t sample s i z e . The second e x c e p t i o n was a 14-week p e r i o d d u r i n g the i n t e r v e n t i o n and p o s t - i n t e r v e n t i o n p e r i o d s a t both t e s t h o s p i t a l s i n which a l l treatment courses meeting i n c l u s i o n c r i t e r i a were s u b j e c t e d to data c o l l e c t i o n . These case s e l e c t i o n r a t e s were employed du r i n g i n i t i a l data c o l l e c t i o n , but were l a t e r i n c r e a s e d f o r the sake of h e a l t h r e c o r d review convenience. For t o p i c T-5, onl y 50* of treatment courses meeting i n c l u s i o n c r i t e r i a were randomly s e l e c t e d f o r the purposes of data c o l l e c t i o n . There was one e x c e p t i o n . For a 7-week p e r i o d d u r i n g the p r e - i n t e r v e n t i o n p e r i o d a t H-l and the e n t i r e p r e - i n t e r v e n t i o n p e r i o d a t H-2, onl y 25* and 30* case s e l e c t i o n r a t e s were employed, r e s p e c t i v e l y . Lower y i e l d s 65 d u r i n g the p r e - i n t e r v e n t i o n p e r i o d are f o r the same reasons as i d e n t i f i e d f o r T - l . The f i n a l number of treatment courses s e l e c t e d f o r each t o p i c i n each h o s p i t a l i s presented i n Table V. 5.2 I n t e r v e n t i o n a l l o c a t i o n C r i t e r i a The random a l l o c a t i o n of each l e v e l of i n t e r v e n t i o n t o a s p e c i f i c study t o p i c and h o s p i t a l was designed to minimize p o t e n t i a l i n v e s t i g a t o r b i a s . P rocess and D e s c r i p t i o n A two-by-six matrix (Appendix I) was designed which r e f l e c t e d the d e s i r e d combinations of h o s p i t a l and i n t e r v e n t i o n l e v e l . Each t o p i c was then randomly a l l o c a t e d t o one of the s i x i d e n t i f i e r s ( i . e . T - l , T-2,...T-6). The pharmacy randomly order of appearance of the each t o p i c i n the n e w s l e t t e r s and i n i t i a l DUI Program r e p o r t was a l s o determined and r e v e r s e d i n the f o l l o w - u p r e p o r t s . 66 RESULTS P r o p o r t i o n a l data r e f l e c t i n g p r e s c r i b i n g p a t t e r n s are prov i d e d i n Table VI. A l l p r e s c r i b i n g data i s grouped a c c o r d i n g t o the study p e r i o d i n which the event o c c u r r e d . Grouped p r e s c r i b i n g data (expressed as mean percentage of treatment courses meeting t o p i c c r i t e r i a ) f o r each l e v e l of i n t e r v e n t i o n are d e p i c t e d i n F i g u r e 1. S i m i l a r l y , grouped p r e s c r i b i n g data f o r each t o p i c and f o r each h o s p i t a l are shown i n F i g u r e s 2 and 3, r e s p e c t i v e l y . F i n a l l y , p r e s c r i b i n g data f o r each l e v e l o f i n t e r v e n t i o n are shown i n F i g u r e s 4, 5 and 6. A. COMPARISON OF PRE-STUDY AND PRE-INTERVENTION PERIODS Changes i n p r e s c r i b i n g p a t t e r n s between these two 3-month p e r i o d s were not a s s o c i a t e d with any s p e c i f i c h o s p i t a l (ANOVA, p>0.20) or t o p i c (ANOVA, p>0.20) e f f e c t s . B. COMPARISON OF PRE-INTERVENTION AND POST-INTERVENTION PERIODS 1. R e l a t i v e i n f l u e n c e o f i n t e r v e n t i o n , t o p i c and h o s p i t a l The r e l a t i v e e f f e c t s of the i n t e r v e n t i o n s , t o p i c s and h o s p i t a l s on changes i n p r e s c r i b i n g p a t t e r n s between these two 3-month p e r i o d s are presented i n Table V I I . While i n t e r v e n t i o n e f f e c t s were apparent, no e f f e c t s a s s o c i a t e d 67 h o s p i t a l s were e v i d e n t . 2. R e l a t i v e i n f l u e n c e of l e v e l s o f i n t e r v e n t i o n S i g n i f i c a n t d i f f e r e n c e s between 1-3 and 1-1 (ANOVA, p<0.005) and between 1-3 and 1-2 (ANOVA, p<0.0001) were demonstrated. No d i f f e r e n c e between 1-2 and 1-1 was apparent (ANOVA, p>0.20). 3. I n f l u e n c e of i n t e r v e n t i o n s on s p e c i f i c t o p i c s A s i g n i f i c a n t improvement i n p r e s c r i b i n g p a t t e r n s was found f o r t h r e e of the f o u r t o p i c s i n the 1-3 group. These were T-3 (Chi-square, p<0.0005), T-5 (Chi-square, p<0.0001) and T-6 (Chi-square, p<0.01). No other s i g n i f i c a n t changes were i d e n t i f i e d . C. COMPARISON OF PRE-INTERVENTION AND POST-STUDY PERIODS (1-3) A s i g n i f i c a n t improvement i n p r e s c r i b i n g p a t t e r n s was found f o r t h r e e of the f o u r t o p i c s i n the 1-3 group. These were T-3 (Chi-square, p<0.05), T-5 (Chi-square, p<0.05) and T-6 (Chi-square, p<0.005). Although a p o s i t i v e t r e n d was i d e n t i f i e d , no s i g n i f i c a n t d i f f e r e n c e i n p r e s c r i b i n g p a t t e r n s was found f o r T-4 (Chi-square, p>0.05). D. COMPARISON OF POST-INTERVENTION AND POST-STUDY PERIODS (1-3) While a decrease i n percent c r i t e r i a met was apparent 68 f o r T-3 and T-5, t h i s was onl y s i g n i f i c a n t f o r T-5 (Chi-square, p<0.05>. No s i g n i f i c a n t change i n p r e s c r i b i n g p a t t e r n s were e v i d e n t f o r T-3 (Chi-square, p>0.05>, T-4 (Chi-square, p>0.20> and T-6 (Chi-square, p>0.20). E. EXTRANEOUS FACTORS 1. Medical rounds Two medical rounds were conducted d u r i n g the p r o j e c t which focused upon t h e r a p e u t i c s i s s u e s r e l a t e d t o the study t o p i c s (Appendix XVII). However, content o f these events was independent of t o p i c c r i t e r i a . 2. Medical n e w s l e t t e r s No extraneous medical n e w s l e t t e r s were d i s t r i b u t e d a t H-l d u r i n g the p r o j e c t . Two n e w s l e t t e r s were d i s t r i b u t e d a t H-2. However, these c o n t a i n e d no i n f o r m a t i o n s p e c i f i c t o the t o p i c s (Appendix X V I I I ) . 3. Pharmacy i n s e r v i c e s and c l i n i c a l a c t i v i t i e s No formal p a r t i c i p a t i o n by pharmacists i n any medical education program took p l a c e d u r i n g the p r o j e c t . Monthly c l i n i c a l a c t i v i t y r e p o r t s i d e n t i f i e d no d i r e c t pharmacist involvement r e l a t i v e t o any t o p i c . No new c l i n i c a l programs were implemented nor were any changes made i n type of drugs and/or p a t i e n t s r o u t i n e l y monitored by the pharmacy department. 69 4. Pharmacy n e w s l e t t e r s N e i t h e r pharmacy department a t the t e s t h o s p i t a l s d i s t r i b u t e d extraneous n e w s l e t t e r s which contained i n f o r m a t i o n s p e c i f i c t o the t o p i c s (Appendix X V I I I ) . 70 DISCUSSION T h i a study r e p r e s e n t s a l a r g e - s c a l e randomized c o n t r o l l e d experiment t o e v a l u a t e a s t a n d a r d i n - h o s p i t a l n o n - f a c i l i t a t e d p e r s u a s i v e s t r a t e g y as compared t o a novel n o n - f a c i l i t a t e d p e r s u a s i v e s t r a t e g y designed t o modify p r e s c r i b i n g behaviour i n the community h o s p i t a l s e t t i n g . A study methodology was developed t o permit v a l i d assessment of the m o d i f i c a t i o n s t r a t e g i e s through a review of p r e s c r i b i n g p a t t e r n s . The r e s u l t s of t h i s study i n d i c a t e t h a t d i s s e m i n a t i o n of drug i n f o r m a t i o n v i a h o s p i t a l pharmacy n e w s l e t t e r s was i n e f f e c t i v e . C o nversely, the DUI Program was both an e f f e c t i v e and p r a c t i c a l method of improving drug usage by modifying p h y s i c i a n behaviour. A. METHODOLOGICAL SYSTEM 1. Measurement of behaviour changes T h i s study methodology was designed t o e v a l u a t e group p r e s c r i b i n g p a t t e r n s i n community h o s p i t a l s . These p r e s c r i b i n g p a t t e r n s were intended t o r e f l e c t changes i n p r e s c r i b i n g behaviour r e s u l t i n g from the m o d i f i c a t i o n s t r a t e g i e s . The study was q u a l i t a t i v e , e v a l u a t i n g the r a t i o n a l i t y of drug p r e s c r i b i n g , p a r t i c u l a r l y as i t r e l a t e s t o the p o s t - a d o p t i o n phase. P h y s i c i a n performance was measured by a s s e s s i n g a c t u a l p r e s c r i b i n g data and comparing these t o p r e - e s t a b l i s h e d c r i t e r i a . Consequently, t h i s type 71 of e v a l u a t i o n measured the enactment of the p h y s i c i a n s ' d r u g - r e l a t e d p e r c e p t i o n s and decision-making p r o c e s s e s . As opposed t o drug i n d i c a t i o n s and c h o i c e , the t o p i c s chosen r e f l e c t e d the f i n a l two s t e p s i n the process of p r e s c r i b i n g , namely s e l e c t i o n of a regimen and procedures f o r monitoring the use of the drug. 2. I n t e r n a l v a l i d i t y S e v e r a l f e a t u r e s were i n c o r p o r a t e d i n t o the design of the study methodology t o maximize i n t e r n a l v a l i d i t y (142). An incomplete c r o s s o v e r experimental d e s i g n was used i n t h i s study. Although a complete c r o s s o v e r d e s i g n (eg. 3 l e v e l s of i n t e r v e n t i o n d i r e c t e d a t 3 t o p i c s i n 3 h o s p i t a l s ) may have been more s u i t a b l e , a t h i r d h o s p i t a l s i t e of s i m i l a r s e l e c t i o n c h a r a c t e r i s t i c s was u n a v a i l a b l e . Rather than i n v o l v e a t h i r d h o s p i t a l with d i s s i m i l a r f e a t u r e s which may have a f f e c t e d the outcome of the m o d i f i c a t i o n s t r a t e g i e s , the experimental design was m o d i f i e d t o accommodate the a v a i l a b l e t e s t f a c i l i t i e s . The p r e - p o s t design of the study was adopted t o p r o v i d e r e t r o s p e c t i v e c o n t r o l groups. T h i s p e r m i t t e d e v a l u a t i o n of p r e s c r i b i n g t r e n d s r e l a t i v e t o a l l t o p i c s f o r a 6 month p e r i o d b e f o r e the i n t e r v e n t i o n s o c c u r r e d . No s i t e - r e l a t e d d i f f e r e n c e s were found with r e s p e c t t o changes i n p r e s c r i b i n g p a t t e r n s . T h e r e f o r e , the c o n c u r r e n t c o n t r o l s (1-1) a t each 72 h o s p i t a l p r o v i d e d a v a l i d assessment of c o n t i n u i n g p r e s c r i b i n g p a t t e r n s i n the absence of d i r e c t attempts t o modify p h y s i c i a n behaviour. These groups counteracted t h r e a t s t o i n t e r n a l v a l i d i t y caused by h i s t o r y , maturation and m o r t a l i t y (142). Randomization of treatment course sampling and i n t e r v e n t i o n a l l o c a t i o n c o n t r o l l e d f o r the p o t e n t i a l t h r e a t of s e l e c t i o n . S t a n d a r d i z e d h e a l t h r e c o r d review and data c o l l e c t i o n procedures were used c o n s i s t e n t l y throughout the study t o c o n t r o l f o r p o s s i b l e measurement i n c o n s i s t e n c i e s . P r e - e s t a b l i s h e d e x p l i c i t c r i t e r i a f o r treatment course s e l e c t i o n and c a t e g o r i z a t i o n a l s o c o n t r o l l e d f o r t h i s f a c t o r . The procedures were performed under c o n d i t i o n s which minimized p o s s i b l e i n f l u e n c e t o the r e s u l t s o f the p r o j e c t . T h i s was accomplished by m a i n t a i n i n g p h y s i c i a n b l i n d i n g t o a l l data c o l l e c t i o n a c t i v i t i e s i n the Health Records Department. Although informed of the DUI Program, p h y s i c i a n s were b l i n d e d t o the e x i s t e n c e of the o v e r a l l study and the nature of those t o p i c s not addressed by the t h i r d i n t e r v e n t i o n l e v e l . T h i s c o n t r o l l e d f o r p h y s i c i a n b i a s r e l a t i v e t o any pr e - c o n c e i v e d n o t i o n s r e g a r d i n g the study. I n v e s t i g a t o r b i a s was a l s o minimized by e n s u r i n g the data c o l l e c t i o n was undertaken without being aware of the a l l o c a t i o n of i n t e r v e n t i o n t o each t o p i c i n the t e s t h o s p i t a l s . 73 S i x independent d r u g - r e l a t e d t o p i c s were s t u d i e d . Some s i m i l a r i t y o f t o p i c drugs and c r i t e r i a may have r e s u l t e d i n an event i n t e r n a l t o the conduct of the study which a l t e r e d the c o n d i t i o n s f o r the c o n t r o l group i n H-2 i n ways other than intended. T o p i c s T-4 and T-6 con t a i n e d recommendations f o r t h e o p h y l l i n e serum l e v e l s a t times r e l a t i v e t o onset of therapy. Vague serum l e v e l o r d e r s by p h y s i c i a n s <T-6) are common p l a c e and o f t e n l e a v e the c l i n i c a l d e c i s i o n of proper sampling t i m i n g t o the ward c l e r k s and ph l e b o t o m i s t s , u n l e s s the p h y s i c i a n v e r b a l l y c l a r i f i e s the w r i t t e n order (143). In a s s o c i a t i o n with a t h e o p h y l l i n e treatment course (T-6), t h i s type of order may have r e s u l t e d i n serum l e v e l s being drawn a f t e r i n i t i a t i o n of therapy i n s t e a d o f p r i o r as recommended by the DUI Program a t H-2. T h i s would r e s u l t i n c a t e g o r i z a t i o n as i n a p p r o p r i a t e f o r t h i s t o p i c . I f the treatment course a l s o met T-4 i n c l u s i o n c r i t e r i a , the r e s u l t i n g l a t e t h e o p h y l l i n e serum l e v e l would r e s u l t i n c a t e g o r i z a t i o n as a p p r o p r i a t e f o r T-4. T h i s " s p i l l - o v e r " would cause an i n c r e a s e i n the number of treatment courses meeting c r i t e r i a as demonstrated by the c o n t r o l group a t H-2. Another p o s s i b l e e x p l a n a t i o n f o r t h i s o b s e r v a t i o n r e l a t e s to the medical rounds gi v e n a t t h i s h o s p i t a l . Although T-6 c r i t e r i a and recommendations were d i s c u s s e d d u r i n g the DUI Program, H-2 p h y s i c i a n s i n attendance were a l s o i n t e r e s t e d i n t h e o p h y l l i n e l e v e l s d u r i n g therapy. The speaker chose to address these q u e s t i o n s and t h i s may have a l s o i n f l u e n c e d p r e s c r i b i n g behaviour r e l a t i v e t o T-4. 74 The dependent, v a r i a b l e of t h i s study was the process of drug p r e s c r i b i n g as r e f l e c t e d by the h e a l t h r e c o r d . Measurement of t h i s v a r i a b l e p r o v i d e d a v a l i d and r e l i a b l e e s t i m a t i o n of the u l t i m a t e t a r g e t of the m o d i f i c a t i o n s t r a t e g i e s , namely p h y s i c i a n behaviour. Although p h y s i c i a n performance was being assessed, t h i s r e l a t e s t o p a t i e n t outcome and may a c t u a l l y p r o v i d e a more meaningful i n t e r p r e t a t i o n o f the q u a l i t y of the h e a l t h care p r o c e s s . 3. E x t e r n a l v a l i d i t y The study methodology was s u c c e s s f u l i n meeting the s t a t e d o b j e c t i v e s under s p e c i f i c experimental c o n d i t i o n s . Use of t h i s methodology to assess o t h e r m o d i f i c a t i o n s t r a t e g i e s , drug t o p i c s and h o s p i t a l s i t e s i s dependent upon a c h i e v i n g s i m i l a r c o n d i t i o n s . In c o n s i d e r i n g a p p l i c a t i o n of t h i s methodology t o other i n t e r v e n t i o n s , sample s i z e must be determined with r e f e r e n c e to the p r e - i n t e r v e n t i o n p r e s c r i b i n g p a t t e r n s and the a n t i c i p a t e d magnitude of change i n response t o the i n t e r v e n t i o n s . A procedure f o r t h i s has been d e s c r i b e d i n the methodology s e c t i o n of t h i s r e p o r t . The drug t o p i c s were s e l e c t e d a c c o r d i n g t o c e r t a i n c h a r a c t e r i s t i c s . T o p i c s focused upon f r e q u e n t l y p r e s c r i b e d drugs a s s o c i a t e d with a high p r o p o r t i o n of treatment courses 75 not meeting p r e - e s t a b l i s h e d c r i t e r i a . Other t o p i c s c o u l d be assessed by t h i s method so long aa a s u f f i c i e n t sample was a v a i l a b l e . Frequency of drug use and p r e - i n t e r v e n t i o n p r e s c r i b i n g p a t t e r n s must be c o n s i d e r e d . The study was undertaken i n l a r g e , a c c r e d i t e d community h o s p i t a l s . These s i t e s were s e l e c t e d based upon a s i m i l a r i t y of p a t i e n t , p r e s c r i b e r and drug usage c h a r a c t e r i s t i c s . Test s i t e s r e q u i r e d a high admission r a t e of p a t i e n t s from a l l age groups and a s t a b l e group of q u a l i t a t i v e l y s i m i l a r p r e s c r i b e r s . Thus, e x t r a p o l a t i o n to other h o s p i t a l s i t e s can o n l y be made i f these s i t e s possess s i m i l a r o p e r a t i o n a l c h a r a c t e r i s t i c s . A p p l i c a t i o n of t h i s methodology to s m a l l e r h o s p i t a l s or t e a c h i n g h o s p i t a l s with l e s s s t a b l e p h y s i c i a n p o p u l a t i o n s may not be p o s s i b l e . B. PRESCRIBING BEHAVIOUR MODIFICATION 1. S t a b i l i t y Some p r e s c r i b i n g p a t t e r n f l u c t u a t i o n was observed d u r i n g the 6-month p e r i o d b e f o r e i n t e r v e n t i o n s . However, when p a t t e r n s from the two c o n s e c u t i v e 3-month phases duri n g t h i s p e r i o d were compared, no s i g n i f i c a n t changes i n p r e s c r i b i n g were a s s o c i a t e d with e i t h e r h o s p i t a l s i t e or t o p i c . Although the b a s e l i n e q u a l i t y of p r e s c r i b i n g (as assessed by percentage c r i t e r i a met) d i f f e r e d from s i t e t o s i t e and from t o p i c to t o p i c , no s y s t e m a t i c v a r i a t i o n was observed ( F i g u r e s 76 2 and 3 ) . T h i s f i n d i n g supports the h y p o t h e s i s t h a t low l e v e l s of e x t e r n a l i n f l u e n c e on the t o p i c s e x i s t e d p r i o r to the i n t e r v e n t i o n s . 2. Short term impact ' Changes i n p r e s c r i b i n g p a t t e r n s between the 3-month p e r i o d s b e f o r e and a f t e r the i n t e r v e n t i o n s were e v i d e n t . Although these p r e s c r i b i n g changes were apparent a c r o s s the two h o s p i t a l s , no d i f f e r e n c e i n the nature of t h i s change was observed. T h e r e f o r e , h o s p i t a l - s p e c i f i c e f f e c t s on p r e s c r i b i n g p a t t e r n changes were l a c k i n g ( F i g u r e 3 ) . S i m i l a r l y , p r e s c r i b i n g changes i n a l l s i x t o p i c s were e v i d e n t , however, no d i f f e r e n c e i n the nature of t h i s change was observed. Consequently, t o p i c - s p e c i f i c e f f e c t s on p r e s c r i b i n g p a t t e r n changes were a l s o l a c k i n g ( F i g u r e 2 ) . When e v a l u a t i n g the e f f e c t s of the i n t e r v e n t i o n s , i t was apparent t h a t a change i n p r e s c r i b i n g had occ u r r e d and t h a t t h e r e was a d i f f e r e n c e i n the magnitude of change a c c o r d i n g to the l e v e l of i n t e r v e n t i o n a p p l i e d ( F i g u r e 1>. S p e c i f i c a l l y , the DUI Program had r e s u l t e d i n s i g n i f i c a n t improvement i n p r e s c r i b i n g behaviour, while the pharmacy n e w s l e t t e r s were e q u i v a l e n t t o the c o n t r o l groups i n t h a t t h e r e was a l a c k of demonstrated e f f e c t . 2.1 C o n t r o l (1-1) P h y s i c i a n s served as t h e i r own c o n t r o l s r e l a t i v e t o two t o p i c s . S i n c e p h y s i c i a n s were a l s o s u b j e c t e d t o the other 77 i n t e r v e n t i o n s , the c o n c u r r e n t c o n t r o l group allowed e v a l u a t i o n of the impact of the DUI Program and the pharmacy n e w s l e t t e r s on the c o n t r o l t o p i c s . As expected, the pharmacy n e w s l e t t e r and DUI Program r e p o r t s and rounds had no impact on the c o n t r o l t o p i c s . I t was a l s o apparent t h a t the DUI Program announcement l e t t e r lacked any independent e f f e c t on p r e s c r i b i n g behaviour. C o n t r o l group p r e s c r i b i n g p a t t e r n s remained s t a b l e a f t e r d i s t r i b u t i o n of the l e t t e r . T h i s was a l s o expected as p h y s i c i a n s were only aware of two t o p i c s being i n v e s t i g a t e d a t t h e i r h o s p i t a l and t h e r e f o r e were u n l i k e l y to change ge n e r a l p r e s c r i b i n g h a b i t s i n response to the announcement l e t t e r . 2.2 Standard h o s p i t a l pharmacy n e w s l e t t e r (1-2) The d i s t r i b u t i o n of a pharmacy n e w s l e t t e r a l s o had no apparent impact on p r e s c r i b i n g behaviour. T h i s c o n c l u s i o n i s based upon a f a i l u r e t o i d e n t i f y any change i n the p r o p o r t i o n of treatment courses meeting c r i t e r i a a f t e r the i n t e r v e n t i o n was implemented. The i n a b i l i t y of a standard pharmacy n e w s l e t t e r t o modify p r e s c r i b i n g behaviour has been observed p r e v i o u s l y (76,79). However, other r e s e a r c h e r s have shown t h a t c e r t a i n types of t h i s m o d i f i c a t i o n s t r a t e g y may have short-term impact (81,82). The p o s s i b l e reasons f o r d i f f e r e n c e s i n f i n d i n g s have been mentioned b r i e f l y i n the i n t r o d u c t i o n of t h i s r e p o r t . 78 C h a r a c t e r i s t i c s of the i n t e r v e n t i o n procedures, p a r t i c i p a n t s , s e t t i n g and r e s e a r c h d e s i g n may account f o r these i n c o n s i s t e n c i e s . S e v e r a l s t u d i e s have e v a l u a t e d the impact of pharmacy b u l l e t i n s , however, although s i m i l a r l y l a b e l l e d , the i n t e r v e n t i o n procedures and t o p i c s are o f t e n d i f f e r e n t . S i m i l a r t o the 1-2 i n t e r v e n t i o n , i n e f f e c t i v e p u b l i c a t i o n s have been produced i n a monograph form (76,79), while other e f f e c t i v e p u b l i c a t i o n s resemble r e p o r t s d i s t r i b u t e d d u r i n g the DUI Program (78,82). T o p i c s have ranged from s p e c i f i c drugs (76,80) to broad drug c l a s s e s (78,79). C r i t e r i a f o r usage have focused upon c h o i c e , as w e l l as s e l e c t i o n of regimen (77,78,82). S u c c e s s f u l m o d i f i c a t i o n s t r a t e g i e s g e n e r a l l y appear t o be those which address more s p e c i f i c drug t o p i c s , i n c o r p o r a t e feedback of p r e s c r i b i n g p a t t e r n s and apply simple, e a s i l y adopted change recommendations. I n t e r v e n t i o n programs are not conducted i n a vacuum. E f f i c a c y of these measures i s dependent upon the a d m i n i s t r a t o r s of the program, the messengers, where the program i s l o c a t e d and other s i t u a t i o n a l f a c t o r s (127,128). Program impact i s a l s o dependent upon p a r t i c i p a n t - i n t e r -v e n t i o n i n t e r a c t i o n s . O v e r l o o k i n g p a r t i c i p a n t c h a r a c t e r -i s t i c s can r e s u l t i n mistakenly c o n c l u d i n g t h a t outcomes of these s t r a t e g i e s are u n p r e d i c t a b l e . Recognizing the p o t e n t i a l h e t e r o g e n e i t y of the p r e s c r i b e r p o p u l a t i o n a t which a program i s aimed can not only a s s i s t i n the a n a l y s i s of the i n f l u e n c e of such e f f o r t s , but a l s o p r o v i d e h e l p f u l s t r u c t u r e 79 t o p l a n f u t u r e m o d i f i c a t i o n s t r a t e g i e s . In t h i s study, i n t e r v e n t i o n - s p e c i f i c f a c t o r s can be i d e n t i f i e d which may have accounted f o r the l a c k of e f f e c t of the standard i n t e r v e n t i o n method employed. The pharmacy n e w s l e t t e r was a t r a d i t i o n a l p u b l i c a t i o n i n both t e s t h o s p i t a l s . No endorsement by a u t h o r i t i e s other than the pharmacy department was r o u t i n e l y p r o v i d e d . The n e w s l e t t e r s were i d e n t i c a l i n format t o p r e v i o u s p u b l i c a t i o n s . S i n c e the p u b l i c a t i o n s were produced i n - h o s p i t a l u s i n g a v a i l a b l e f a c i l i t i e s , appearance was l e s s p r o f e s s i o n a l . Content was lengthy and c o n t a i n e d s e v e r a l concepts i n a d d i t i o n to the one c e n t r a l t o the t o p i c . S i n c e t h e r e was no attempt t o a l t e r t y p i c a l format and content c h a r a c t e r i s t i c s , p h y s i c i a n s were not expected t o respond any d i f f e r e n t l y t o t h i s p u b l i c a t i o n than to p r e v i o u s n e w s l e t t e r s . Two t o p i c s r e p o r t e d i n the n e w s l e t t e r s were s u c c e s s f u l l y addressed by the DUI Program. T h e r e f o r e , l a c k of impact of these p u b l i c a t i o n s does not appear to be due to p h y s i c i a n r e s i s t a n c e t o the change recommendations. They may, however, have been a g a i n s t adoption of these recommendations without support of a u t h o r i t y b o d i e s , peers and the l i t e r a t u r e . D i s t r i b u t i o n of the n e w s l e t t e r s o c c u r r e d by usual means. To t h i s end, only one episode o f d i s t r i b u t i o n was undertaken. In a d d i t i o n , only those p h y s i c i a n s with h o s p i t a l mailboxes p e r s o n a l l y r e c e i v e d the p u b l i c a t i o n s . S i n c e t h i s represented approximately t w o - t h i r d s of p r e s c r i b e r s , l a c k of access to 80 the n e w s l e t t e r i s another f a c t o r which may have caused i t s f a i l u r e . Avorn (128) a l s o found t h a t i n e f f e c t i v e n e s s of w r i t t e n i n t e r v e n t i o n s can occur i n p a r t due t o the f a c t t h a t many p h y s i c i a n s do not see the m a t e r i a l a t a l l . D i s t r i b u t i o n t o a l l ward n u r s i n g s t a t i o n s , medical and a d m i n i s t r a t i v e departments was a l s o accomplished, however, t h i s a p p a r e n t l y d i d not have any impact on the success o f the i n t e r v e n t i o n . C o n f l i c t i n g r e s u l t s may a l s o be due t o d i f f e r e n c e s i n re s e a r c h d e s i g n . An a b b r e v i a t e d t i m e - s e r i e s design (2-week p e r i o d s ) used by B e r b a t i s (82) was capable of d i s c e r n i n g the short-term impact of t h e i r p u b l i c a t i o n s on p r e s c r i b i n g behaviour. Roberts (76) used a 20-week pre/post grouped data approach t o a n a l y s i s and t h i s may have d i l u t e d any short-term impact which may have o c c u r r e d . T h i s , i n t u r n , would l e a d t o the p o t e n t i a l l y erroneous c o n c l u s i o n t h a t such p u b l i c a t i o n s were i n e f f e c t i v e . The present study ev a l u a t e d changes i n p r e s c r i b i n g behaviour by comparing two 3-month p e r i o d s b e f o r e and immediately a f t e r the d i s t r i b u t i o n o f the pharmacy n e w s l e t t e r . T h i s i n t e r v a l was chosen to p r o v i d e a s u f f i c i e n t number of treatment courses t o permit d e t e c t i o n of a 20* change i n p r e s c r i b i n g p a t t e r n s . While i n s e n s i t i v e t o s m a l l e r or temporary changes, t h i s study methodology was designed to ev a l u a t e an e s t i m a t i o n of r e l e v a n t i n t e r v e n t i o n program impact on p r e s c r i b i n g behaviour. 81 2.3. DUI Program (1-3) The DUI Program was e f f e c t i v e i n modifying p r e s c r i b i n g behaviour. T h i s c o n c l u s i o n i s based upon the o b s e r v a t i o n t h a t s i g n i f i c a n t changes i n the p r o p o r t i o n of treatment courses meeting c r i t e r i a o c c u r r e d upon completion of the i n t e r v e n t i o n program. The DUI Program was intended as an e d u c a t i o n a l package. The package was designed t o p r o v i d e maximum impact on p r e s c r i b i n g behaviour while remaining p r a c t i c a l t o implement. To ensure a d i s c e r n a b l e d i f f e r e n c e i n impact between the DUI Program and pharmacy n e w s l e t t e r s , the 2-month DUI Program con t a i n e d s e v e r a l components i n c l u d i n g an i n t r o d u c t o r y l e t t e r , i n i t i a l and f o l l o w - u p r e p o r t s and a medical rounds p r e s e n t a t i o n . The study design d i d not permit e v a l u a t i o n of any one component t o assess i t s r e l a t i v e c o n t r i b u t i o n t o the o v e r a l l impact of the program. Instead, the impact of the e n t i r e package was assessed immediately a f t e r completion. The Hawthorne e f f e c t (132) was a p o s s i b l e i n f l u e n c i n g f a c t o r i n h e r e n t t o t h i s m o d i f i c a t i o n s t r a t e g y . The announcement l e t t e r , r e p o r t s and rounds p r e s e n t a t i o n s a l e r t e d p h y s i c i a n s t o the f a c t t h a t an i n t e r n a l study was being conducted r e l a t i v e t o two t o p i c s . S i m i l a r t o Avorn (128), the h o s p i t a l approached the p r e s c r i b e r s as p a r t i c i p a n t s of an i n n n o v a t i v e e d u c a t i o n a l program r a t h e r than as m i s p r e s c r i b e r s . Consequently, the c o n t r i b u t i o n of the 82 Hawthorne e f f e c t t o the impact o f the o v e r a l l program may have been o n l y been minor. The e f f e c t o f the announcement l e t t e r alone appeared t o be n e g l i g i b l e , but the combined e f f e c t o f the l e t t e r and the remaining components of the DUI program cannot be assessed i n t h i s study. D i s s e m i n a t i o n o f p r e s c r i b i n g p a t t e r n feedback and change recommendations v i a w r i t t e n r e p o r t s has been undertaken p r e v i o u s l y with r e l a t i v e success (80-82,86). Comparison with the r e s u l t s o f the present study i s d i f f i c u l t , however, as the DUI Program r e p o r t s were onl y a p a r t of the o v e r a l l m o d i f i c a t i o n s t r a t e g y and because many a t t r i b u t e s of the r e p o r t s themselves were unique t o t h i s study. Format .and content of i n i t i a l and fo l l o w - u p r e p o r t s were designed t o i n c r e a s e the l i k e l i h o o d t h a t the r e p o r t s would be read and the change recommendations adopted by the p r e s c r i b e r s to whom they were s e n t . S e v e r a l d i s t r i b u t i o n s over a 2-month p e r i o d i n c r e a s e d the l i k e l i h o o d of a v a i l a b i l i t y a t the teachab l e moment. The i n f o r m a t i o n c o n t a i n e d i n the r e p o r t s was a l s o designed t o i n c r e a s e the l i k e l i h o o d of p e r c e p t i o n s by readers of a demonstrated need t o change p r e s c r i b i n g behaviour. Information was provided i n a c l e a r , p o s i t i v e p r e s e n t a t i o n t o minimize r e s i s t a n c e t o change and a l t e r n a t i v e behaviour was pro v i d e d t o r e p l a c e the behaviour being e l i m i n a t e d . The medical rounds were conducted t o f a c i l i t a t e change by p r o v i d i n g f a c e - t o - f a c e i n t e r a c t i o n with an expert i n the 83 use o f the t o p i c drugs. Such p r e s e n t a t i o n s a re common to many i n t e r v e n t i o n programs alone or i n c o n j u n c t i o n with other s t r a t e g i e s (Table 1). S i m i l a r t o w r i t t e n p u b l i c a t i o n s , the impact o f t h i s form of i n t e r v e n t i o n i s dependent upon s e v e r a l f a c t o r s i n c l u d i n g program content, p a r t i c i p a n t c h a r a c t e r i s t i c s (and atte n d a n c e ) , s e t t i n g and e v a l u a t i o n t e c h n i q u e s . V a r i a t i o n i n these f a c t o r s can l e a d t o d i f f e r e n t impacts on p r e s c r i b i n g behaviour. The format and content of the study p r e s e n t a t i o n s were i d e n t i c a l a t each h o s p i t a l and designed t o review and supplement the i n f o r m a t i o n p r o v i d e d i n the p r e v i o u s l y d i s t r i b u t e d r e p o r t s . Although a p p a r e n t l y w e l l - d e s i g n e d , the p r e s e n t a t i o n s may have had only a minor c o n t r i b u t i o n t o the o v e r a l l impact of the program. Attendance was t y p i c a l f o r the medical rounds a t the h o s p i t a l s but re p r e s e n t e d l e s s than 10* of a l l p r e s c r i b e r s . S i n c e no attempt was made t o i d e n t i f y the attendees (to maintain c o n f i d e n t i a l i t y ) , we cannot assess whether these i n d i v i d u a l s were among the major p r e s c r i b e r s of the t o p i c drugs or not. An a l t e r n a t i v e t o t h i s s i n g l e group s e s s i o n may have been m u l t i p l e seminars t o i n c r e a s e the l i k e l i h o o d of exposure t o the recommendations. However, the p r a c t i c a l i t y o f r e p e a t i n t e r v e n t i o n s o f t h i s nature i n the community h o s p i t a l s e t t i n g i s q u e s t i o n a b l e and f o r t h i s reason not attempted i n t h i s study. The o v e r a l l impact o f the DUI Program was a do u b l i n g of the number of sampled treatment courses meeting c r i t e r i a 84 d u r i n g the f i r s t t h r e e months. In s p i t e of t h i s dramatic improvement, on l y about 50* of a l l treatment courses were judged a p p r o p r i a t e . T h i s f i n d i n g suggests t h a t the program may be v a l u a b l e only as an i n i t i a l approach t o problems i n h o s p i t a l drug usage and other measures may be necessary to e f f e c t f u r t h e r change. 2.4 Comparison of i n t e r v e n t i o n s 2.4.1 E f f e c t i v e n e s s The f e a t u r e s of the i n t e r v e n t i o n s which were p o s t u l a t e d to have l e a d to t h e i r e f f e c t i v e n e s s or l a c k of e f f e c t i v e n e s s have been i d e n t i f i e d . S e v e r a l d i f f e r e n c e s between the two i n t e r v e n t i o n s were apparent and these are p o s t u l a t e d to have lead t o the d i s s i m i l a r impact on p r e s c r i b i n g behaviour observed. These d i f f e r e n c e s i n c l u d e d : 1> v a r i a t i o n i n the a d m i n i s t r a t o r s and support groups r e l a t i v e t o each i n t e r v e n t i o n ( i . e . the pharmacy department versus the Pharmacy and T h e r a p e u t i c s Committee and Medical A d v i s o r y Committee); 2) v a r i a t i o n i n the format i n which the drug p r e s c r i b i n g i n f o r m a t i o n was p r o v i d e d to p h y s i c i a n s ( i . e . a standard pharmacy n e w s l e t t e r versus a p r o f e s s i o n a l l y - p r o d u c e d r e p o r t ) ; 3) v a r i a t i o n i n the s p e c i f i c content of the i n f o r m a t i o n p r o v i d e d ( i . e . g e n e r a l p r e s c r i b i n g i n f o r m a t i o n versus s p e c i f i c i n f o r m a t i o n and a c t u a l i n - h o s p i t a l p r e s c r i b i n g p a t t e r n feedback combined with e a s i l y adopted change recommendations); and 4) v a r i a t i o n i n the s p e c i f i c a t t r i b u t e s of the d i s t r i b u t i o n a l process ( s i n g l e episode 85 i n - h o s p i t a l d i s t r i b u t i o n o£ n e w s l e t t e r s versus repeated episodes of i n - h o s p i t a l and e x t e r n a l m a i l i n g of l e t t e r s and r e p o r t s ) . 2.4.2 Cost The e f f e c t i v e n e s s of any i n t e r v e n t i o n program must, i n p a r t , be e v a l u a t e d i n terms of the c o s t s of implementation. Programs d i r e c t e d a t drug p r e s c r i b i n g which are e f f e c t i v e y e t expensive t o conduct (eg. some types of f a c i l i t a t i v e s t r a t e g y programs) have l i m i t e d a p p l i c a b i l i t y u n l e s s s i g n i f i c a n t c o s t s a v i n g s can be demonstrated t o j u s t i f y t h e i r undertaking. Cost s a v i n g s can be expressed e i t h e r i n terms of e f f e c t s on the process of h e a l t h care (eg. i n c r e a s e d frequency of s e l e c t i o n of regimen of c h o i c e ) or through e f f e c t s on outcome of h e a l t h c a r e (eg. decreased m o r b i d i t y , r a t e of r e - h o s p i t a l i z a t i o n and e x p e n d i t u r e s f o r h e a l t h care among a p a t i e n t p o p u l a t i o n ) ( 1 4 4 ) . A s i g n i f i c a n t amount of time, e f f o r t and expense i s c u r r e n t l y devoted to the continued p r o d u c t i o n of pharmacy n e w s l e t t e r s . However, t h i s study i n d i c a t e s t h a t t h i s c o s t cannot be j u s t i f i e d i n terms of impact on the process (and outcome) of h e a l t h c a r e . S e v e r a l authors have advocated a l t e r n a t i v e i n t e r v e n t i o n programs (eg. f a c i l i t a t i v e s t r a t e g i e s ) which are e f f e c t i v e , yet appear c o s t l y i n terms of manpower and r e s o u r c e s . Most 86 o£ these educators have f a i l e d t o i d e n t i f y the c o s t of t h e i r programs. Without t h i s v i t a l i n f o r m a t i o n , the f e a s i b i l i t y of adopting the proposed measures to o p t i m i z e p r e s c r i b i n g behaviour cannot be adequately assessed and the p r a c t i c a l v a l u e of such r e s e a r c h may be c o n s i d e r e d q u e s t i o n a b l e (145,146). The DUI Program conducted d u r i n g t h i s study was designed t o u t i l i z e e x i s t i n g community h o s p i t a l f a c i l i t i e s and manpower. The estimated " s t a r t - u p " c o s t of the program was l e s s than $3.00 per p h y s i c i a n t o p i c . The m a j o r i t y of t h i s c o s t was r e l a t e d t o p u b l i c a t i o n and d i s t r i b u t i o n of the r e p o r t s , an expense which would be reduced with s u c c e s s i v e episodes (144). T h i s c o s t i s e a s i l y j u s t i f i e d i f the t o p i c s addressed i n v o l v e d s a v i n g s i n drug purchasing expenditures al o n e . The drug usage review process necessary to p r o v i d e p r e s c r i b i n g p a t t e r n feedback f o r the DUI Program was and should c o n t i n u e to be undertaken as a c o - o p e r a t i v e venture of the medical and pharmaceutical d i s c i p l i n e s i n the h o s p i t a l . The h e a l t h r e c o r d review and data c o l l e c t i o n procedures used i n t h i s study, however, were of g r e a t e r magnitude and complexity than necessary t o maintain the DUI Program f o r the purposes of p r o v i d i n g p r e s c r i b i n g feedback. A s m a l l e r sampling of treatment courses t o estimate p r e s c r i b i n g p a t t e r n s and the impact of the program would be adequate. 87 The procedures can be conducted by e x i s t i n g h o s p i t a l pharmacists (as p a r t of t h e i r c l i n i c a l a c t i v i t i e s ) and h e a l t h r e c o r d p e r s o n n e l . Medical a d v i s o r y committees and Pharmacy and T h e r a p e u t i c s committees e x i s t i n a l l a c c r e d i t e d community h o s p i t a l s and these a u t h o r i t i e s p r o v i d e the necessary support f o r t h i s type of q u a l i t y assurance program. 3. Longer term impact (1-3) Short term e f f e c t s may d i f f e r g r e a t l y from long term e f f e c t s (20). T h i s study e v a l u a t e d impact of the m o d i f i c a t i o n s t r a t e g i e s over a 3-month p e r i o d f o l l o w i n g completion of the i n t e r v e n t i o n s . To p r o v i d e i n s i g h t i n t o the continued d u r a t i o n of impact r e l a t i v e t o these i n t e r v e n t i o n s , data were a l s o c o l l e c t e d f o r a f u r t h e r 3-month post-study p e r i o d immediately f o l l o w i n g the 3-month p o s t - i n t e r v e n t i o n phase. Only those t o p i c s addressed by the DUI Program showed a s i g n i f i c a n t change i n p r e s c r i b i n g p a t t e r n s . P r e s c r i b i n g p a t t e r n s f o r T-4 i n H-l were more a p p r o p r i a t e than the other t o p i c s and continued to improve i n the post-study phase. However, these improvements were not confirmed by s t a t i s t i c a l a n a l y s i s . T h i s was, i n p a r t , due to the r e l a t i v e l y high l e v e l of a p p r o p r i a t e p r e s c r i b i n g b e f o r e the program was implemented. While T-3, T-5 and T-6 continued t o demonstrate b e t t e r p r e s c r i b i n g p a t t e r n s i n the post-study phase (as compared to the p r e - i n t e r v e n t i o n phase), a d e c l i n e i n impact s s was e v i d e n t . T h i s d i m i n u t i o n i n e f f e c t was most e v i d e n t f o r T-5 s u g g e s t i n g t h a t the continued e f f e c t i v e n e s s o f the OUI Program may be topic-dependent. T o p i c s such as p r o p h y l a c t i c a n t i m i c r o b i a l p r e s c r i b i n g may r e q u i r e f o l l o w - u p programs t o s u s t a i n a measurable impact on behaviour. 4. E x t e r n a l v a l i d i t y Although the s p e c i f i c f i n d i n g s and c o n c l u s i o n s of t h i s study should be l i m i t e d t o the i n t e r v e n t i o n s , t o p i c s and h o s p i t a l s which were e v a l u a t e d , some g e n e r a l i z a t i o n s can be made. The m o d i f i c a t i o n s t r a t e g i e s e v a l u a t e d i n t h i s study i n v o l v e d procedures which are r e p r e s e n t a t i v e o f the l e v e l s of i n t e r v e n t i o n which can and do occur i n the community h o s p i t a l s e t t i n g . T h e r e f o r e , the g e n e r a l i z a t i o n of r e s u l t s r e l a t i v e to s t r a t e g i e s should be v a l i d . P r e s c r i b i n g behaviour r e l a t i v e t o s i x d r u g - r e l a t e d t o p i c s was e v a l u a t e d . Although the t o p i c s were chosen to r e p r e s e n t s i m i l a r a s p e c t s of the p r e s c r i b i n g p r o c e s s , these t o p i c s v a r i e d a c c o r d i n g t o the drugs i n v o l v e d , the nature of the c r i t e r i a a p p l i e d , and both the number and s p e c i a l t y of p r e s c r i b e r s i n v o l v e d . T h i s v a r i a t i o n a l s o i n c r e a s e s the extent t o which the f i n d i n g s of the study can be e x t r a p o l a t e d t o other t o p i c s . 89 E x t e r n a l v a l i d i t y of t h i s r e s e a r c h was opti m i z e d by conducting the experiment i n the s e t t i n g o f the l a r g e community h o s p i t a l . E v a l u a t i o n was not c o n f i n e d t o a s i n g l e s i t e . T h i s i n c r e a s e s the exte n t t o which the f i n d i n g s of t h i s study can be g e n e r a l i z e d t o other h o s p i t a l s . C. CONCLUSIONS AND RECOMMENDATIONS A study methodology was developed t o permit v a l i d assessment o f the impact of m o d i f i c a t i o n s t r a t e g i e s on p r e s c r i b i n g behaviour i n the community h o s p i t a l . The r e s u l t s of t h i s study i n d i c a t e t h a t standard d i s s e m i n a t i o n o f drug i n f o r m a t i o n v i a h o s p i t a l pharmacy n e w s l e t t e r s i n the format p r e s e n t l y employed may be i n e f f e c t i v e . In view o f these r e s u l t s , h o s p i t a l Pharmacy and T h e r a p e u t i c s Committees should r e - e v a l u a t e continued use of t h i s form of i n t e r v e n t i o n . An a l t e r n a t i v e method of modifying p r e s c r i b i n g d e c i s i o n s i s the novel DUI Program. T h i s p r a c t i c a l program r e p r e s e n t s an i n i t i a l approach t o o p t i m i z i n g drug usage through m o d i f i c a t i o n o f p h y s i c i a n behaviour i n the community h o s p i t a l . 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Am J Hosp Pharm 1983;40:2080. Table I. Modification strategies : Impact on physician behaviour Raf Intervention Topic S i t e s * * Impact** # # Type* # Drug(s) # Type I. N o n - f a c i l i t a t e d persuasive strategies 76 1 newsletter 1 cephalosporins 1 hospital Ct> -77 1 newsletter 1 drug groups 1 o f f i c e ( i ) • SS 1 newsletter 2 t e t r a c y c l i n e 1 o f f i c e (!) • chloramphenicol 78 1 newsletter 5 drug groups 1 hospital <c> • 79 1 newsletter 6 drug groups 1 hospital (t> -SO 1 w. feedback 1 c e f o x i t i n 1 hospital <t> 81 1 w. feedback 1 a n t i b i o t i c s 1 hospital (t) * 82 1 w. feedback 1 analgesics 1 hospital <t> 83 1 w. feedback & seminar 1 aminoglycosides 1 hospital Ct> 62 1 v. feedback fi guidelines 1 a n t i b i o t i c s 1 hoapltal <t> 84 1 v. feedback fi guidelines 1 a n t i b i o t i c s 1 hospital <c> 85 1 v. feedback & seminar fi newsletter 1 gentaalcln 1 ho s p i t a l <t> • 86 1 w. feedback & v. feedback 1 a n t i b i o t i c s 1 ho s p i t a l <g> * 87 1 academic 2 a n t i b i o t i c 1 o f f i c e (i> • d e t a i l i n g groups I I . F a c i l i t a t e d persuasive s t r a t e g i e s 88 1 rx. , monitor 1 c e f a z o l i n 1 hospital <t> -89 1 rx. . monitor 1 a n t i b i o t i c s 1 ho s p i t a l <t> 90 1 rx. . monitor 1 prn drugs 1 hospital <1> 91 1 rx. . monitor 1 antipsychotics 1 hospital (p) 92 1 rx. . monitor 1 a n t i b i o t i c s 1 hospital <c> 93 1 rx. . monitor 1 analgesic/ 1 ho s p i t a l (1) • antinflammatory 63 1 rx. . monitor 1 a n t i b i o t i c s 1 h o s p i t s l <t> • fi md. monitor 94 1 rx. monitor 1 a n t i b i o t i c s 1 hospital <c> • fi md. monitor 95 1 guidelines 1 s n t i b i o t i c s 1 hospital tt) fi md. monitor 96 1 rx. , monitor 1 TPN so l u t i o n 2 hospital <t> fi newsletter & c h e c k l i s t fi seminar 97 1 rx. . monitor 1 drug l e v e l s 1 h o s p i t s l <t> • fi newsletter 6 semlnsr 98 1 rx. . monitor 1 gentamicin 1 hospital <t> • fi newsletter 99 1 rx. . monitor 1 cephalosporins 1 hospital <t> • & newsletter 100 1 rx. . monitor 1 c e f a z o l i n 1 hospital <t> fi seminar 101 1 rx, . monitor 1 digoxin 1 hospital <1> * b seminsr 102 1 rx, . monitor 13 drug groups 1 h o s p i t s l Cc) & newsletter & seminar I I I . Power st r a t e g i e s 103 1 j u s t i f l c a t i o n 1 cephalosporins 1 hospital <c> 104 1 j u s t i f i c a t i o n 1 s n t i b i o t i c s 1 hospital <c> * 105 1 approval 1 cefotaxime 1 hospital (t) -79 1 form, r e s t r i c t 1 analgesic 1 hospital <t> * 106 1 form, r e s t r i c t 1 propoxyphene 1 hospital <t> • 107 1 form, r e s t r i c t 1 a n t i b i o t i c s 1 hospital <c> • 108 1 j u s t i f i c a t i o n fi auto, stop 1 a n t i b i o t i c s 1 h o s p i t s l <t> * 109 1 j u s t i f i c a t i o n fi auto, stop 1 a n t i b i o t i c s 1 hospital <t> 110 1 j u s t i f l e s t i o n fi md. monitor 1 s n t i b i o t i c s 1 hospital Ct) 111 1 form, r e s t r i c t & auto, stop 1 a n t i b i o t i c s 1 hospital <c> * 112 1 approval 2 sedatives 1 hospital <c> fi j u s t i f i c a t i o n cephalosporins Tabla I. Modification Strategies : Impact on physician behaviour (contlnuad) Raf Intervention • • Type* Topic # Drug(a) S i t e s * * • Typa Impact' IV. Othar strategy coabinatlona 113 1 v. f e e d b a c k t ( u l n a r & c h a c k l l a t 114 1 v. f e e d b a c k C. j u a t l f i c a t l o n 115 1 a p p r o v a l £ a a a l n a r 116 1 v. f e e d b a c k C. a a a l n a r 6 a u t o , a t o p 117 1 f o r * , r e a t r l c t 6 a u t o , a t o p & n e w s l e t t e r 1 a a l n o g l y c o a l d e a 1 h o a p l t a l <c> 1 d r u g g r o u p 1 1 a n t l b i o t i c a 1 1 a n t l b i o t i c a 1 1 a n t i h i s t a m i n e * 1 o f f i c e (1) h o a p l t a l (t> h o a p l t a l (c> o f f i c e (1) V. C o a p a r l a o n o f a t r a t e g l e s 118 119 120 121 122 123 124 125 126 127 c o n t r o l a a a l n a r c o n t r o l r e m i n d e r c o n t r o l a e n i n a r c o n t r o l a a a l n a r c o n t r o l r x . a o n l t o r & a a a l n a r c o n t r o l r x . m o n i t o r £> aeminar c o n t r o l . md. m o n i t o r & aeminar f i n a n c i a l c o n t r o l r x / a d a o n l t o r a p p r o v a l aeminar w.feedback r e m i n d e r n e w s l e t t e r r x . academic d e t a i l i n g md. academic d e t a i l i n g c o n t r o l w. f e e d b a c k r x . academic d e t a i l i n g 1 a n t i h y p e r -t e n s i v e s 1 a l l d r u g s 1 a n t l b i o t i c a 1 l a b t e a t 2 a n t i p a c h o t l c a a n t l c o n v u l a a n t a 2 a l l d r u g s a n t l b i o t i c a 1 l a b t e a t a c a f a z o l l n l a b t e a t a a n t i b i o t i c g r o ups propoxyphene v a s o d i l a t o r a c e p h a l e x i n 1 h o a p l t a l <t> 1 o f f i c e <c> 2 h o a p l t a l ( t ) 2 h o a p l t a l <t> 2 h o a p l t a l «p> 2 h o a p l t a l <t> 1 h o a p l t a l <t> 1 h o a p l t a l <t> h o a p l t a l (t> h o a p l t a l Cc> o f f i c e (i> o f f i c e «i> n e w a l e t t e r - p u b l i c a t i o n c o n t a i n i n g p r e s c r i b i n g recommendations w, v. f e e d b a c k - w r i t t e n o r v e r b a l f e e d b a c k o f p r e v i o u a p h y s i c i a n performance ( s u r v e y ) aeminar - e d u c a t i o n a l meeting w i t h o u t f e e d b a c k o f p r e v i o u a p e r f o r m a n c e g u i d e l i n e s - l n - h o u s e g u i d e l i n e s f o r d r u g usage academic d e t a i l i n g - f a c e - t o - f a c e i n t e r a c t i o n w i t h p h y a i c l a n rx.md. m o n i t o r i n g - p h a r a a c l a t o r p h y a i c l a n m o n i t o r i n g o f performance j u s t i f i c a t i o n - w r i t t e n j u s t i f i c a t i o n f o r p r e a c r i b l n g drug r e q u i r e d a p p r o v a l - a p p r o v a l n e c e a s a r y t o p r e s c r i b e drug f o r m , r e a t r l c t - f o r m u l a r y r e s t r i c t i o n drug a u t o , a t o p - a u t o a a t l c a t o p on q u a n t i t y o f drug d l a p e n s e d c h e c k l i s t - non-mandatory c h a c k l l a t on c h a r t t o d i r e c t d r u g p r e s c r i b i n g r e m i n d e r - manual/computer g e n e r a t e d r e m i n d e r n o t i c e ' h o s p i t a l ( t ) - t e a c h i n g <c> - community <p) - p a y c h l a t r i c (g) - group o f a f f i l i a t e d (1) - l o n g term c a r e o f f i c e <i> - i n d i v i d u a l <c> - c l i n i c i m p l i e s an.Impact on p h y s i c i a n b e h a v i o u r demonstrated - I m p l i e s no impact obaerved ./- i m p l i e s e q u i v o c a l impact 104 Table I I . C h a r a c t e r i s t i c s of the t e s t h o s p i t a l s F a c t o r H o s p i t a l (*)* H - l H Beds S e r v i c e Medical/Surgery 53 43 P e d i a t r i c s 6 6 Ma t e r n i t y 5 4 I n t e n s i v e / C a r d i a c Care 2 2 P s y c h i a t r y 0 3 Extended C a r e / R e h a b i l i t a t i o n 34 42 Acute c a r e d i s c h a r g e s S e r v i c e Medicine 30 21 Ob s t e t r i c s / G y n e c o l o g y 29 34 Surgery 11 12 Orthopedics 10 10 P e d i a t r i c s 8 9 Urology 6 4 0ther*« 6 10 Performance i n d i c a t o r s O p e r a t i v e procedures 38 40 C o n s u l t a t i o n s 40 49 Emergency admissions 50 46 Deaths 4 2 * from P r o f e s s i o n a l A c t i v i t y Study CPAS) and Health Medical Records I n s t i t u t e (HMRI) medical s t a t i s t i c s f o r the f i s c a l p e r i o d A p r i l 1983-March 1984 ** i n c l u d e s p s y c h i a t r y , d e n t i s t r y , o t o r h i n o l a r y n g o l o g y and ophthalmology 105 Tab l e I I I . C h a r a c t e r i s t i c s o f p r e s c r i b e r s a t the t e s t h o s p i t a l s F a c t o r H o s p i t a l H - l H - 2 T o t a l p r e s c r i b e r s * 203 264 H o s p i t a l s t a t u s (Ji) A c t i v e 45 64 A s s o c i a t e 12 8 V i s i t i n g / L o c u m 27 19 C o u r t e s y / C o n s u l t i n g 16 10 P r a c t i c e (*) General p r a c t i c e 55 50 S p e c i a l i t y 45 50 Medicine 60 51 Surgery 40 49 Graduation L o c a t i o n U.B.C. 26 22 Canada** 43 35 Fo r e i g n 31 43 Mean year (sd) 64(11) 67(10) Mean r e g i s t r a t i o n year (sd) 68(11) 72(9) To p i c p r e s c r i b e r s (*) « * « T - l 28 25 T - 2 34 33 T - 3 26 24 T - 4 26 32 T - 5 10 11 T - 6 25 26 H o s p i t a l mailbox (*) 62 72 * meeting p r o j e c t i n c l u s i o n c r i t e r i a ** excludes U.B.C. » » » p r o p o r t i o n o f t e s t h o s p i t a l f o r p r e s c r i b i n g t o p i c drugs p r e s c r i b e r s r e s p o n s i b l e T a b l e IV. C h a r a c t e r i s t i c s o f p a t i e n t s d i s c h a r g e d from t e a t h o s p i t a l s F a c t o r T o t a l acute c a r e d i s c h a r g e s * Male (*) Age d i s t r i b u t i o n (% t o t a l ) 0 - 1 4 years 15 - 64 years over 64 years Mean l e n g t h o f s t a y (days) 0 - 14 years 15 - 64 years over 64 years T o t a l H o s p i t a l H - l H - 2 14,603 17,859 42 41 18.6 53.7 27.7 26.7 55.8 17.5 4.9 5.8 13.1 7.7 3.7 7.9 13.1 7.7 * from P r o f e s s i o n a l A c t i v i t y Study (PAS) and Health Medical Records I n s t i t u t e (HMRI) medical s t a t i s t i c s f o r f i s c a l p e r i o d A p r i l 1983 t o March 1984 107 Tabl e V. H e a l t h r e c o r d review and data c o l l e c t i o n F a c t o r H o s p i t a l H - l H - 2 T o t a l T o t a l h e a l t h r e c o r d s 18,161 21,630 39,811 reviewed* He a l t h r e c o r d s u n a v a i l a b l e 42 53 95 f o r review Treatment courses analysed T - 1 674 497 1,171 T - 2 269 288 557 T - 3 226 420 646 T - 4 324 474 798 T - 5 395 308 703 T - 6 311 353 664 T o t a l 2,199 2,340 4,539 acute c a r e p a t i e n t s o n l y 108 Table VI. P r e s c r i b i n g p a t t e r n s a c c o r d i n g t o p e r i o d and l e v e l o f i n t e r v e n t i o n Hosp. T o p i c Pre-Study P r o p o r t i o n o f treatment courses meeting t o p i c c r i t e r i a Pre-I n t e r . P e r i o d I n t e r -v e n t i o n P ost-I n t e r . Post-Study 1-1 1 1 2 2 1 6 2 4 34/117 19/103 12/77 14/85 32/56 36/75 33/60 36/64 T o t a l 114/325 102/332 53/179 11/49 37/54 56/107 157/389 37/182 7/53 40/62 75/136 159/433 22/93 13/47 24/56 41/72 100/268 1-2 1 1 2 2 2 3 1 5 T o t a l 38/74 15/56 38/126 40/89 131/345 29/67 15/51 16/80 23/53 83/251 2/5 1/3 2/6 3/6 8/20 30/62 21/64 52/178 34/89 137/393 29/61 8/52 36/107 22/71 95/291 1-3 1 1 2 2 4 5 3 6 T o t a l 37/76 13/90 23/90 8/60 81/316 40/75 9/69 15/83 19/71 83/298 39/57 19/66 21/78 36/80 115/281 47/69 36/76 41/86 42/85 166/316 34/47 27/94 27/83 32/57 120/281 109 Table V I I . Changes i n p r e s c r i b i n g p a t t e r n s a c c o r d i n g t o i n t e r v e n t i o n , t o p i c and t e s t h o s p i t a l F a c t o r Group Change i n * Degree of P va l u e * * c r i t e r i a met freedom I n t e r v e n t i o n 2 <0.0001 I - 1 5.1 1 - 2 3.2 1 - 3 25.4 Top i c 5 >0.20 T - 1 5.6 T - 2 7.3 T - 3 16.5 T - 4 13.5 T - 5 14.6 T - 6 9.6 H o s p i t a l 1 >0.20 H - l 9.4 H - 2 13.0 * Net change i n unweighted mean % c r i t e r i a met (comparison of p r e - i n t e r v e n t i o n p e r i o d versus post-i n t e r v e n t i o n p e r i o d ) " ' c a l c u l a t e d by ANOVA as d e s c r i b e d i n t e x t 110 100 90 80 70 h- 60 111 DC LU I-50 40 DC O 30 20 10 - 6 PRE-STUDY PERIOD PRE-INTERVENTION PERIOD POST-INTERVENTION PERIOD 1-1 1-2 1-3 POST-STUDY PERIOD - 3 + 3 + 6 TIME (months) F i g u r e 1. Changes i n p r e s c r i b i n g p a t t e r n s a c c o r d i n g t o l e v e l of i n t e r v e n t i o n . ^ P o i n t s r e p r e s e n t the percent of cases f o r which c r i t e r i a have been met i n the p e r i o d i d e n t i f i e d f o r the group designated by the symbol. I l l 100 90 80 70 111 OC LU I— DC O 60 50 40 30-20 10 PRE-STUDY PERIOD PRE-IMTERVENTKDN PERIOD • T - 1 A T - 2 • T - 3 O T-4 A T - 5 • T - 6 • — - — ° ^ a \\\ POST- POST-; INTERVENTION STUDY PERIOD PERIOD - 6 •3 +3 TIME (months) + 6 F i g u r e 2. Changes i n p r e s c r i b i n g p a t t e r n s a c c o r d i n g t o t o p i c P o i n t s r e p r e s e n t the percent o f cases f o r which c r i t e r i a have been met i n the p e r i o d i d e n t i f i e d f o r the group designated by the symbol. 112 100 90 80 ~ 70 60 50 40 30-20 10 - 6 PRE-STUDY PERIOD PRE-INTER VENTION PERIOD • H -1 • H - 2 r I POST- : POST-I INTERVENTION i STUDY : PERIOD : PERIOD 3 +3 TIME (months) + 6 F i g u r e 3. Changes i n p r e s c r i b i n g p a t t e r n s a c c o r d i n g t o h o s p i t a l P o i n t s r e p r e s e n t the percent of cases f o r which c r i t e r i a have been met i n the p e r i o d i d e n t i f i e d f o r the group desi g n a t e d by the symbol. 113 100 00 80 70 60 50-40 30 20 10 *• -! D ' PRE -STUDY PERIOD PRE- | INTERVENTION ! PERIOD i - 6 POST-INTERVENTION PERIOD • T-1 H-1 • T - 2 H-2 O T - 4 H-2 • T - 6 H-1 POST-STUDY PERIOD 3 +3 TIME (months) + 6 F i g u r e 4. Changes i n p r e s c r i b i n g p a t t e r n s : 1-1 i n t e r v e n t i o n P o i n t s r e p r e s e n t the percent of cases f o r which c r i t e r i a have been met i n the p e r i o d i d e n t i f i e d f o r the group designated by the symbol. 114 100 90 80 70 60 50 40 30 20 10 - 6 PRE-STUDY PERIOD PRE-IMTERVENTION PERIOD POST-INTERVENTION PERIOD • T-1 H-2 • T-2 H-1 • T - 3 H-1 A T-5 H-2 POST-STUDY PERIOD - 3 +3 T I M E ( m o n t h s ) + 6 F i g u r e 5. Changes i n p r e s c r i b i n g p a t t e r n s : 1-2 i n t e r v e n t i o n P o i n t s r e p r e s e n t the percent of cases f o r which c r i t e r i a have been met i n the p e r i o d i d e n t i f i e d f o r the group desi g n a t e d by the symbol. 115 111 O C H I I-oc o 100 00 8 0 7 0 -6 0 50 4 0 3 0 20 • 10 PRE-STUDY PERIOD PRE-INTERVENTION PERIOD POST-BMTERVENTION PERIOD • T-3 H-2 O T-4 H-1 A T-5 H-1 • T-6 H-2 POST-STUDY PERIOD - 6 - 3 + 3 + 6 T I M E ( m o n t h s ) F i g u r e 6. Changes i n p r e s c r i b i n g p a t t e r n s : 1-3 i n t e r v e n t i o n P o i n t s r e p r e s e n t the percent o£ esses f o r which c r i t e r i a have been met i n the p e r i o d i d e n t i f i e d f o r the group desi g n a t e d by the symbol. 116 Appendix I. P r o j e c t experimental d e s i g n * T o p i c H o s p i t a l H-l H-2 T - 1 T - 2 T - 3 T - 4 T - 5 T - 6 1 - 1 1 - 3 * d u p l i c a t e d Youden square d e s i g n (131) (random a l l o c a t i o n ) 117 Appendix I I . Pharmacy n e w s l e t t e r s d i s t r i b u t e d t o p h y s i c i a n s ( s i t e i d e n t i f i c a t i o n removed and n e w s l e t t e r photo-reduced) -2 and T-3 H-l VOLUME NO. 17 ILLUSTRATION 4 November, 19S4 CIMETIDINE: A REVIEW Clmetldlne (Tagamet** and others) 1$ a histamine h^-receptor antagonist widely used In the treatment of peptic ulcer disease and pathological hypersecretory states such as Zoll Inger-Ell Ison syndrome. Clmetldlne has also attained a prominent role In the treatment of upper gastrointestinal bleeding and the prevention of aspiration pneumonitis and stress ulceration in the critically 111 patient. Adverse Effects Since Its release In Great Britain (1976), Canada and the United States (1977), clmetldlne has received Immediate acceptance and extensive use owing to Its efficacy and apparent lack of adverse effects. In spite of this seemingly low Incidence of side effects, several reports of serious toxicity have appeared 1n the literature over the last several years (Table 1). In particular, elderly patients, patients with Impaired renal function and patients with liver disease appear quite susceptible to the dose-related C N S effects of clmetldlne which range from mental confusion and delirium to hallucinations and coma. Table 1. Adverse Effects Reported with Clmetldlne Use Central nervous** confusion system delirium dizziness drowsiness slurred speech depression encephal opathles hallucinations coma Cardiovascular* Endocrine Gastrointestinal severe bradycardia hypotension hyperglycemia hyperosmolar nonketotic coma gynecomastia decreased libido and Impotence liver enzyme elevation diarrhea pancreatitis paralytic Ileus perforation of ulcers upon withdrawal H e m a t o l o g i c a g r a n u l o c y t o s i s p a n c y t o p e n i a t h r o m b o c y t o p e n i a D e r m a t o l o g l c p s o r i a s i s g i a n t u r t i c a r i a S t e v e n s - J o h n s o n s y n d r o m e • r e l a t e d t o r a p i d IV a d m i n i s t r a t i o n • • r e l a t e d t o a d v a n c e d a g e , I m p a i r e d r e n a l f u n c t i o n , l i v e r d i s e a s e and I V d o s i n g P h a r m a c o k i n e t i c s C i m e t l d l n e 1s p r i m a r i l y a b s o r b e d In t h e s m a l l I n t e s t i n e w i t h a r e p o r t e d b i o a v a i l a b i l i t y o f 6 0 t o 8 6 % . I n a h e a l t h y a d u l t w i t h o u t r e n a l o r h e p a t i c d i s e a s e , t h e s e r u m h a l f - l i f e 1s a p p r o x i m a t e l y 2 h o u r s , w i t h a v o l u m e o f d i s t r i b u t i o n a b o u t 80% o f body w e i g h t ( a v e r a g e 57 L ) . C i m e t l d l n e 1s p r i m a r i l y e x c r e t e d I n t h e u r i n e v i a g l o m e r u l a r f i l t r a t i o n a n d t u b u l a r s e c r e t i o n w i t h a p p r o x i m a t e l y 70% a p p e a r i n g u n c h a n g e d . The l i v e r m e t a b o l i z e s a p p r o x i m a t e l y 20% o f t h e p a r e n t d r u g t o a s u l f o x i d e d e r i v a t i v e . The r e m a i n i n g 10% I s f o u n d In t h e f e c e s . A p r i m a r y f a c t o r c o n t r i b u t i n g t o a l t e r e d c i m e t l d l n e k i n e t i c s 1s r e n a l i m p a i r m e n t . R e n a l d y s f u n c t i o n s i g n i f i c a n t l y r e d u c e s c i m e t l d l n e c l e a r a n c e f r o m t h e b o d y . The v o l u m e o f d i s t r i b u t i o n o f t h e d r u g 1s a l s o r e d u c e d In r e n a l i m p a i r m e n t l e a d i n g t o e l e v a t e d s e r u m c i m e t i d i n e l e v e l s . I n a d d i t i o n , a r e d u c t i o n i n t h e n o n - r e n a l c l e a r a n c e o f c i m e t i d i n e has b e e n d e m o n s t r a t e d 1n t h e u r e m i c p a t i e n t s u g g e s t i n g a d e c r e a s e i n c i m e t i d i n e m e t a b o l i s m In s e v e r e r e n a l f a i l u r e . H e p a t i c I m p a i r m e n t has a l s o b e e n I m p l i c a t e d In a l t e r i n g c i m e t i d i n e p h a r m a c o k i n e t i c s . E l i m i n a t i o n o f t h e d r u g 1s r e d u c e d a n d t h e h a l f - H f e o f t h e d r u g I s e x t e n d e d i n t h e p r e s e n c e o f l i v e r f a i l u r e . H e p a t i c d i s e a s e a l s o a p p e a r s t o I n c r e a s e t h e p e r m e a b i l i t y o f t h e b l o o d b r a i n b a r r i e r t o c i m e t i d i n e and may p r e d i s p o s e t h e p a t i e n t t o CNS t o x i c i t i e s . A g e - R e l a t e d P h a r m a c o k i n e t i c C h a n g e s An i n c r e a s i n g p r o p o r t i o n o f t h e e l d e r l y p o p u l a t i o n a r e r e c e i v i n g c i m e t i d i n e f o r e x t e n d e d p e r i o d s , e s p e c i a l l y when s u r g i c a l I n t e r v e n t i o n i s n o t a p p r o p r i a t e . Numerous s t u d i e s have e x a m i n e d t h e p h a r m a c o k i n e t i c s o f c i m e t i d i n e i n t h e e l d e r l y p a t i e n t . R e n a l c l e a r a n c e o f c i m e t i d i n e i s r e d u c e d i n t h e g e r i a t r i c p a t i e n t due t o an a g e - r e l a t e d d e c r e a s e i n k i d n e y f u n c t i o n . I f a g e - i n d e p e n d e n t r e n a l I m p a i r m e n t I s a l s o e v i d e n t , 1 t w i l l f u r t h e r r e d u c e c l e a r a n c e o f c i m e t i d i n e I n t h e e l d e r l y p a t i e n t . H e p a t i c c l e a r a n c e o f c i m e t i d i n e I s a l s o d e c r e a s e d 1n t h e g e r i a t r i c p a t i e n t . The c a p a c i t y o f t h e l i v e r t o c l e a r d r u g s by m e t a b o l i s m d e c r e a s e s w i t h a g e , a n d b l o o d f l o w t o t h e l i v e r d e c l i n e s w i t h h e p a t i c e x t r a c t i o n o f d r u g s o f t e n b e i n g r e d u c e d . 120 - 3 -Total plasma clearance of clmetldlne Is highly age-correlated, decreasing by half between the ages of 30 and 65 years. This is almost entirely due to a reduction In the renal clearance of the drug with advancing age. Although less significant, hepatic disease also appears to depress total systemic clearance necessitating a reduction in dosage to avoid dose-related side effects. The volume of distribution of clmetldlne Is Inversely correlated to age. This can be explained by the loss of body fat associated with age since clmetldlne distributes mainly Into muscle tissue with negligible distribution Into fat. From these observations, 1t can be Inferred that clmetldlne blood concentrations will be higher In the elderly population than 1n younger adults receiving the same daily dose. Therefore, on pharmacokinetic grounds, these Individuals should receive a lower dose than the younger patient. In addition, older patients tend to have reduced gastric add production which tend to decrease dosage requirements. > Recommended Dosages The usual recommended dose for the treatment of duodenal and non-malignant gastric ulcers, gastroesophageal reflux disease and upper gastrointestinal hemorrhage in the young health adult 1s 1200 mg per day. This can be administered as 600 mg twice daily, at breakfast and bedtime or 300 mg four times a day, with meals and at bedtime. The manufacturer recommends prophylaxis of stress ulceration with 300 mg Intravenously every 6 hours, or more frequently to maintain gastric pH above 4. For prophylaxis of recurrent duodenal ulcer, the usual dosage of clmetldlne Is 400 mg at bedtime. Prophylactic treatment with higher dosages or more frequent administration does not increase efficacy. Dosage regimen modifications have been devised to account for the age-related decline In the capacity of the kidneys to excrete clmetldlne. Kidney function should be routinely monitored for any elderly patient (over 60 years of age) receiving clmetldlne. In the hospital setting, renal function should probably be established during each admission. To determine the kidney function of an elderly patient, an Initial blood urea nitrogen (BUN) determination is recommended. If the BUN 1s reported as less than 20 mg/dL, renal function Is probably adequate and the patient will generally tolerate a full dosage of cimetidine. If, however, the BUN exceeds 20 mg/dL, this may be evidence of renal Impairment and a serum creatinine (SCr) should be determined to better establish the extent of the reduction 1n kidney function. Table 2 provides guidelines for cimetidine dosage reductions In the elderly based upon age, weight and renal function (as reflected by serum creatinine). These have been derived from literature recommendations and estimations of creatinine clearance employing the Cockcroft Gault formula. The guidelines apply to the non-prophylactic use of clmetldlne. Most authorities also recommend that patients with concurrent liver Impairment be closely monitored for adverse effects since these Individuals are further predisposed to dose-related toxiticies. 121 - 4 -Table 2. Serum Creatinine Values for Recommended Cimetldlne Dosage Reduction to 900 mg/day* Age (yr) 60 - 74 75 - 90 Weight (kg) £ 6 0 > 1.2 > 0.9 » 60 > 1.6 > 1.3 •further reductions In dosage should be undertaken 1f serum creatinine values are significantly higher than those appearing in table. GENTAMICIN AND TOBRAMYCIN: A REVIEW Although a number of extended-spectrum beta lactam antibiotics have recently been Introduced commercially, the aminoglycosides remain extremely Important agents for the prevention and treatment of infections. Gentamicin (Garamydn®) and tobramycin (Nebcin*), probably the most frequently used aminoglycoside antibiotics, are effective 1n the prevention and treatment of infections caused by susceptible gram-negative bacteria. The pharmacokinetics of these drugs has received more attention over the past several years than any other antibiotics currently available which has resulted in the development of more precise dosing guidelines. Microbiological Activity In general, gentamicin and tobramycin are active against many aerobic gram-negative bacteria and some aerobic gram-positive bacteria. Tobramycin 1s usually more effective against Pseudomonas aeruginosa and slightly less effective against Serratia than gentamicin. Both antibiotics are Ineffective against fungi, viruses and most anaerobic bacteria. Pharmacokinetics The pharmacokinetics of aminoglycosides varies widely amongst patients, even those who have a normal serum creatinine. This Interpatlent variation 1s apparent for all aminoglycosides. Since gentamicin and tobramycin are not metabolized and are excreted unchanged 1n the urine primarily by glomerular filtration, plasma concentrations are higher and elimination half-lives are longer In patients with Impaired renal function. In Infants, aminoglycoside half-Hves are inversely proportional to birth weight and gestational age. This probably reflects renal maturity. Many factors can effect the disposition and elimination of aminoglycosides in the body. Age has a significant effect on elimination of these antibiotics. Half-lives are shorter In children and longer In the elderly. This Is probably due to variation In cardiac output, glomerular filtration rate, and renal blood flow. Aminoglycosides are distributed primarily Into extracellular fluid space. "Volume of distribution" (Vd), a term used to describe the volume Into which a drug distributes, 1s affected by many physiologic and pathologic states. The volume of distribution of gentamicln and tobramycin determines the size of dose needed to achieve a desired serum concentration. Average Vd for these antibiotics Is approximately 0.25 L/kg. Dehydration reduces this volume which subsequently reduces dosing requirements. Patients with CHF, ascites, peritonitis, severe burns, gram-negative sepsis or Immediately postpartum will have expanded volumes necessitating larger doses to reach therapeutic serum levels. Desired Peak/Trough Serum Concentrations Improved treatment response has been associated with obtaining therapeutic serum concentrations of aminoglycosides early 1n therapy. Nephro- and ototoxicity can be minimized 1f these concentrations are maintained within a specific range throughout the treatment course. Several factors should be considered when selecting desired peak (post-Infusion) and trough (pre-infusion) concentrations for a specific patient. These factors Include the clinical condition of the patient, site(s) of Infection and relative sensitivity of the suspected or Isolated pathogen(s). Peak serum concentrations should range between 5 and 8 vg/ml for patients with soft-tissue Infections or less severe gram-negative Infections. In patients with more severe gram-negative sepsis or gram-negative pneumonias, the peak serum concentrations should range between 8 and 10 vg/ml. The trough concentrations for gentamldn and tobramycin should be less than 2.0 ug/ml. These suggested values for peaks and troughs are guidelines which may need to be modified for specific patients. Dosing Recommendations Manufacturers of gentamicln and tobramycin recommend an Initial dose of 1 mg/kg of body weight repeated every 8 hours for the treatment/prevention of systemic Infections 1n adults with normal renal function. It has been demonstrated, however, that initial doses of this magnitude will frequently produce peak serum concentrations of less than 4 mcg/ml. Studies have shown that therapeutic serum concentrations 1n septic patients may only be achievable by starting with a regimen of 5 mg/kg/day in three divided doses. These results have been repeatedly supported by studies Involving gynecologic patients, patients with pneumonia and patients with other serious Infections In which dosages of aminoglycosides required to obtain therapeutic serum concentrations were higher than those estimated by conventional methods. Numerous nomograms and methods have also been devised to aid In the adjustment of aminoglycoside dosages according to renal function. These aids may decrease the potential risk of toxicity associated with excessive dosing but have also been shown to lead to underdosing in many patients. In addition, many of the predictive methods available are cumbersome and c o m p l i c a t e d to use thus Baking them I m p r a c t i c a l f o r r o u t i n e c l i n i c a l appl I c a t l o n . A s i m p l e dosage c a l c u l a t i o n based upon body weight remains as the s i n g l e most a c c u r a t e and p r a c t i c a l method of I n i t i a t i n g a gentamicin o r tobramycin treatment regimen. Based upon a volume of d i s t r i b u t i o n o f 0 . 2 5 L/kg In the a d u l t , a dose o f 1 . 5 mg/kg can be expected to r a i s e the serum c o n c e n t r a t i o n by 6 v g / m l . T h i s 1s w i t h i n the normal t h e r a p e u t i c range f o r most I n f e c t i o n s . T a b l e 1 r e p r e s e n t s the a m i n o g l y c o s i d e dosage recommendations f o r the treatment or p r e v e n t i o n of systemic I n f e c t i o n s . S m a l l e r doses are recommended f o r the treatment of uncomplicated u r i n a r y t r a c t i n f e c t i o n s . Most a u t h o r i t i e s agree t h a t w i t h the use of these o r any o t h e r p r e d i c t i v e dosage methods, serum c o n c e n t r a t i o n d e t e r m i n a t i o n s should be undertaken when a v a i l a b l e and a p p r o p r i a t e dosage adjustments made to ensure t h e r a p e u t i c c o n c e n t r a t i o n s e a r l y 1n t h e r a p y . T a b l e 1 RECOMMENDED INITIAL GENTAMICIN AND TOBRAMYCIN DOSAGE REGIMENS Age Dose I n t e r v a l * * (mg/kg TBW) (hours) A d u l t s * 1 .5 8 and c h i l d r e n > 10 y r 5-10 y r s 2 . 0 8 1 week - 5 y r s 2 . 5 8 < 1 week 2 . 5 12 ( f u l l term) • A d u l t doses should be rounded to the n e a r e s t m u l t i p l e of 10 mg ( e g . 95 mg c a l c u l a t e d - 100 mg p r e s c r i b e d ) " • P a t i e n t s w i t h Impaired renal f u n c t i o n w i l l l i k e l y r e q u i r e an adjustment In the dosage I n t e r v a l s i n c e the r a t e of e l i m i n a t i o n of these drugs w i l l be r e d u c e d . T h i s adjustment should be based upon serum l e v e l s . References a v a i l a b l e from the pharmacy department upon r e q u e s t . 124 T o p i c s T - l and T - 5 H o s p i t a l H-2 Volume IV ILLUSTRATION III November 1984 A REVIEW OF THE FIRST GENERATION CEPHALOSPORINS: FOCUS ON CEFAZOLIN m AM Since their Introduction In the early 1970'a, cefazolin (Ancef* and Kefzol*) and other "fi r s t generation" cephalosporins including cephalothln (Keflin*) have had resounding commercial success. This Is in part because, unlike most available penicillins, they combine In a •ingle drug, activity against staphylococci and gram-negative bacteria. These properties make cephalosporins valuable for empiric therapy, mixed infections and for surgical prophylaxis. When compared with cephalothln, cefazolin Is essentially equivalent In terms of therapeutic effectiveness, microbiological activity and toxicity. The important differences between these two older generation cephalosporins, however, Is In their pharmacokinetic properties. Microbiological Activity Cefazolin has a broad spectrum of bactericidal activity. Cram-positive cocci, with the exception of enterococcl and methlclllin-reslstant staphylococci are quite susceptible to cefazolin. Among the gram-negative enteric b a c i l l i : Escherichia c o l l , Klebsiella pneumoniae, Proteus m l r a b l l i 6 , Salmonella species, and Shigella species are regularly susceptible to cefazolin. This drug Is only moderately Inhibitory to Haemophilus Influenzae and weakly active against Bacteroldes f r a g l l l 6 . Many strains of enterococcl and staphylococci exhibit enhanced susceptibility to a combination of cefazolin and aminoglycosides. Cefazolin is Inactive against fungi and viruses. Pharmacokinetics Cefazolin is not appreciably absorbed from the CI tract and must be administered parenterally. The only oral cephalosporin available at this hospital Is cephalexin (Keflex* and Ceporex*). Following IV and IM administration, peak cefazolin serum concentrations are attained within 5 minutes and 1-2 hours, respectively. The serum half-life of cefazolin is 69-132 minutes in adults with normal renal function. This compares to half-lives of only 30-72 minutes for cephalothln, cephalexin and cefoxitin and 24-84 minutes for penicillin, amplclllln and carbenlclllln. Because cefazolin Is eliminated from the body primarily by renal excretion through passive filtration and active secretion, there is an Increase in both serum half-life and peak levels In patients with impaired kidney function. Half-lives of 7 hours have been reported in adults with creatinine clearance of approximately 25 ml/minute and up to 57 hours in adults with creatinine clearances of less than 5 ml/minute. Cefazolin Is frequently compared with and considered equivalent to cephalothln. THL6 drug does not, however, possess similar pharmacokinetic properties to cephalothln. Comparative pharmacologic studies ID Adults have demonstrated that cefazolin achieves peak serum levels about four times higher than cephalothln (30-42 vg/ml versus 7-12 vg/ml after • 500 mg IM dose), has a lower rate of elimination through the kidneys (resulting in a longer half-life), undergoes somewhat higher protein binding In serum (85Z versus 65Z) and possesses a smaller volume of distribution when cephalothln. (Hflng to these pharmacokinetic properties, cefazolin can usually be administered roughly half as often and in half the amount as cephalothln. Adverse Reactions The most common adverse reactions observed with cefazolin are similar to those associated with cephalothln and other cephalosporins and penicillins. These reactions are generally olid and Include rash, drug fever, positive direct and indirect Coombs' test results and transient elevation of some serum enzymes. IV administration can cause thrombophletvlis. Compared to cephalothln, cefazolin can be given Intramuscularly with less discomfort. Although all cephalosporins have been shown to induce renal tubular cell damage when given to laboratory animals In high doses, clinical evidence of renal impairment with cefazolin has not been reported with doses as high as 12 gram/day. Because of similarity in structure of penicillins and cephalosporins, patients allergic to penicillin may theoretically show cross-reactivity when administered cefazolin. In fact, clinically evident allergic reactions to cephalosporins occur Infrequently (approximately 52) in patients with known penicillin hypersensitivity. However, patients with a history of immediate reaction to penicillin should not receive cefazolin. Conversely, a history of a delayed allergic reaction does not preclude the use of this drug. Dosage , Administration and Cost The recommended intravenous or intramuscular dose varies with the type and severity of Infection. Most authorities recommend adult regimens outlined in Table 1 on the next page. 126 - 3 -Table 1. Recommended cefazolin dosage regimen* Indication Dose (ng) Interval (hr) Mild 250-1000 8-12 Infections Moderate 500 8 Infections Severe 1000 8 Infections Very severe 2000 8 infections Surgical 500-1000 8 prophylaxis •dosage reduction required for patients with Impaired renal function. Cefazolin is available in 500 ng and 1 gram vials for reconstitutlon. Drug cost of 10 days therapy is approximately $87.00 (based upon a dosage regimen of 3 grams cefazolin per day). 127 - 4 -ANTIMICROBIAL PROPHYLAXIS IN SURGERY Antimicrobial drugs are administered to about one-third of all hospitalized patients. Approximately sixty percent of these drugs will be given to surgical service patients and one-half of these patients will receive the drug6 for prophylaxis purposes. Prophylaxis Implies the use of antimicrobials to prevent surgical infection where none exists at the time of surgery. A solid base of both experimental and clinical evidence exists to define criteria and principles guiding an effective use of antimicrobials in various surgical procedures. Rational use of prophylactic antimicrobials has reduced septic complications, duration of post-operative care, the need for intensive care nursing and mortality (Table 1). Prophylaxis is generally used only In patients at high risk of surgical infection or if consequences of post-operative infection are life-threatening and where risks associated with the use of such drugs Is acceptable to both the patient and the hospital environment. In certain clinical situations, including operations on the large bowel, vaginal hysterectomy, bone and joint operations, and premature rupture of the membranes, surgical prophylaxis has been shown to reduce the rate of post-operative Infection. In other categories of 6 u r g i c a l treatment, controversy s t i l l exists regarding the value of prophylaxis. Table 1. Advantages and disadvantages of antimicrobial prophylaxis in surgery Advantages Reduction of: wound infections anastomotic healing problems po6t-operative mortality post-operative hospital stay need for intensive care cost of non-prophylatic antimicrobials cost of hospital care Extention of surgical treatment to high risk groups Disadvantages toxic reactions allergic manifestations bacterial resistance superinfections delay in diagnosis of infectious complications microbiological disturbances unnecessary exposure to antimicrobials The most Important determinant In post-operative infections Is the presence of bacteria In the surgical field at the time of wound closure. Delayed post-operative Initiation of a prophylactic antimicrobial appears to allow time for physiological changes to occur at the wound surface which Interfere with diffusion of the drug so that the antimicrobial does not reach the bacteria In sufficient concentration. Antimicrobials can therefore only be expected to exert a limited effect after that period. 128 - 5 -Systemic Antimicrobial Administration Successful use of prophylactic antimicrobials Is dependent on an appropriate choice of agent, administration at the correct time and by the optimal route. Antimicrobials should be administered in dosages appropriate for the likely pathogens associated with the surgical procedures. Systemic distribution of an antimicrobial can be achieved by the oral and rectal route In addition to parenteral administration. However, greater predictability results from intravenous administration of the drug. When systemic prophylactic antimicrobials are employed, they should be given only for the Immediate perl-operative period to allow for adequate tissue distribution during the surgical procedure and for a short time post-operatively. Chemoprophylaxis should be commenced Immediately prior to an operation. Administration should be timed to ensure that peak serum levels coincide as nearly as possible with the period of bacterial contamination. When administered Intravenously, this can be accomplished during the Initiation of anesthesia or during the operative procedure. When administered intramuscularly, the f i r 6 t dose can be given on the ward shortly before the scheduled procedure since peak serum levels usually occur 1-2 hours after administration. The optimal duration of prophylaxis Is at present unknown. Available Information indicates that continuation of administration beyond the recovery room does not contribute to the prevention of wound infection in clean contaminated cases. Most authorities recommend limiting antimicrobial administration to the f i r s t 24 to 48 hours after surgery. Adherence to this practice will probably reduce the number of drug reactions and Infusion set-related infections, diminish to some degree the rate of emergence of resistant microorganisms and save not only the cost of unused drugs but also the significant costs of procuring, storing, dispensing and administration of such drugs. Table 2 represents approximate hospital costs of antimicrobials frequently used for prophylaxlc purposes. These drug costs are based upon usual adult doses for a 48 hour duration of therapy. 129 - 6 -Table 2. Cost comparison of parenteral antimicrobials routinely employed  for prophylaxis Agent Regimen Cost of therapy Ampiclllln 1 g Q6H 9.00 2 g Q4H 27.00 Cefazolin 500 mg Q8H 9.00 1 g Q8H 18.00 Cefoxitin 1 g Q6H 63.00 2 g Q6H 125.00 Clindamycin 300 mg Q6H 35.00 600 mg Q6H 70.00 Cloxaclllin 1 g Q6H 8.00 2 g Q4H 23.00 Gentamicin 80 mg Q8H 12.00 Metronidazole 500 mg Q8H 70.00 Penicillin G 2 MU Q4H 5.00 4 MU Q4H 10.00 Tobramycin 80 mg Q8H 26.00 References available from the pharmacy department upon request. 130 Appendix I I I . I n t r o d u c t o r y l e t t e r s d i s t r i b u t e d t o p h y s i c i a n s ( s i t e i d e n t i f i c a t i o n removed and l e t t e r photo-reduced) November 9, 1984. Re : A Drug Usage I n f o r m a t i o n P r o g r a m a t H o s p i t a l T h i s l e t t e r i s i n t e n d e d t o i n t r o d u c e a Pr o g r a m t o be c o n d u c t e d a t Drug Usage I n f o r m a t i o n H o s p i t a l . O v er t h e n e x t two mont h s , e d u c a t i o n a l b u l l e t i n s c o n t a i n i n g c o n c i s e , a u t h o r i t a t i v e and r e a d a b l e d r u g I n f o r m a t i o n and t h e r e s u l t s o f r e c e n t l y c o n d u c t e d d r u g u s a g e s t u d i e s a t t h i s h o s p i t a l w i l l be d i s t r i b u t e d t o y o u . T h e s e d r u g u s a g e s t u d i e s h a v e b e e n u n d e r t a k e n i n a manner w h i c h e n s u r e s c o m p l e t e c o n f i d e n t i a l i t y o f b o t h t h e p r e s c r i b e r and p a t i e n t . The aim o f t h i s p r o g r a m i s t o p r o v i d e y o u and y o u r f e l l o w p h y s i c i a n s w i t h i m p o r t a n t u p - t o - d a t e d r u g i n f o r m a t i o n e s s e n t i a l t o good c l i n i c a l p r a c t i c e . T he p r o g r a m 1s a c o o p e r a t i v e v e n t u r e o f t h e M e d i c a l A d v i s o r y C o m m i t t e e and t h e P h armacy ft T h e r a p e u t i c s C o m m i t t e e . T h i s p r o c e s s has b e e n recommended by t h e C a n a d i a n C o u n c i l on H o s p i t a l A c c r e d i t a t i o n as p a r t o f t h e p r o f e s s i o n a l c a r e e v a l u a t i o n p r o c e d u r e . The e d u c a t i o n a l b u l l e t i n s w i l l be s e n t t o y o u r h o s p i t a l m a i l b o x and t o y o u r o f f i c e t o e n s u r e y o u ha v e a c c e s s t o t h e d r u g i n f o r m a t i o n p r o v i d e d . We u r g e y o u r e a d t o t h e s e b u l l e t i n s as soon as t h e y a r r i v e and keep them f o r f u t u r e r e f e r e n c e . T o c o m p l e t e t h i s p r o g r a m , a d r u g I n f o r m a t i o n s e m i n a r w i l l be s c h e d u l e d a t ^^B^smat^AWSiMM H o s p i t a l 1n e a r l y J a n u a r y . We h a v e c a r e f u l l y d e s i g n e d t h i s Drug Usage I n f o r m a t i o n P r o g r a m t o be p e r t i n e n t t o i m p o r t a n t d r u g I s s u e s . We a r e c o n f i d e n t t h e p r o g r a m w i l l be o f v a l u e t o y o u i n y o u r p r a c t i c e . C h a i r m a n P h a r m a c y ft T h e r a p e u t i c s C o m m i t t e e C h i e f o f M e d i c a l S t a f f Appendix IV. DUI Program I n i t i a l reports d i s t r i b u t e d to physicians <site I d e n t i f i c a t i o n removed and reports photo-reduced) 133 T o p i c s T-4 and T-5 H o s p i t a l H - l DRUG USAGE INFORMATION PROGRAM Published as a Joint venture of U i e Medical Advisory Committee and the Pharmacy ft Therapeutics Committee NOVEMBER/DECEMBER 1984 Theophylline Serum Levels at The routine availability of serum theophylline levels hag made the optimal use of theophylline products a reality. Benefit and risk with theophylline have been demonstrated to relate directly to serum theophylline concentration. In adults and children, levels below 10 mcg/mL do not give optimal bronchodilator effect, and substantial toxicity may occur in the presence of levels above 20 mcg/mL.1 Theophylline levels and therapeutic/toxic response* Serum Level Response (mcg/mL) 0- 5 6-10 10-20 20-35 > 35 Sub-therapeutic Sub-optimal Optimal Minor adverse effect* (significant toxicity io susceptible patients) Cardiac arrhythmias and seizures •therapeutic/toxic levels are lower in neonates Many factors alter adult dosing requirements to achieve therapeutic levels of theophylline including age, smoking, cardiac or hepatic disease and con-current administration of interacting drugs (cime-tidine, erythromycin).* Children also show a wide variation in their rate of theophylline metabolism and in genera] need larger comparative doses relative to body weight.*-* Serum theophylline measurement is therefore essential to obtain opti-mal acute and chronic management of broncho-spastic disorders in both the adult and pediatric patient while minimising the risk of toxicities. Serum levels are particularly important in pa-tients receiving TV aminophylhne therapy because of the potential for rapid changes in serum drug SUMMARY 1. Serum theophylline levels correlate well with therapeutic efficacy (10-20 mcg/mL) and toxicity (greater than 20 mcg/niL). Use of these levels provides an objective basis for dosage adjust-ment of theophylline-containinp pn-parations (aminophvlline, Theodm . Choledyl5, Palaron* and others 2. A study at this hospital revealv th;.t less than 507< of all patients rfcecivin-theophylline-containing preparations for acute bronchospastic complaints were monitored with serum theophyl-line levels. 3. Serum theophylline levels should be monitored during the acute manage-ment of bronchospastic patients. Levels drawn 24 - 48 hours following in hospital initiation or change? it. theophylline dosage provide useful information regarding the need fo: further dosage adjustments. levels and frequent dosage adjustments associated with this form of treatment Furthermore, patients receiving TV therapy are usually acutely ill and metabolic rates may rapidly change.* The variability of theophylline dosage require-ments and the strong relationship between serum levels and clinical effects mandate that drug concentrations be used to monitor the potential risks and benefits of theophylline therapy. Surgical Antimicrobial Prophylaxis a t L ^ ^ B ^ ^ ^ - page 3 t ySBJSBRB^y - Drag Usage IaformatioB November/Deeenber 1984 DRUG USAGE STUDY Health records of adult and pediatric patients admitted between April and October 1984 were scanned to identify individuals who received a theophylline-containing product during their stay. Patients admitted for an unrelated disorder who simply continued pre-admission oral therapy were excluded as were patients receiving less than 48 hours of therapy while in hospital. Serum concentration data must be interpreted together with the patient's current clinical status, response, and timing of serum levels relative to the initial and last dose. A level obtained 24 - 48 hours after in hospital initiation of therapy or change in dosage provides the most useful information on which to base further dosage adjustments.1 Dosage adjustments are indicated if levels exceed 20 mcg/mL or are less than 10 mcg/mL and control is not optimal. Randomly selected treatment courses were then reviewed for 60 patients. Data regarding serum level monitoring was specifically sought. Serum theophylline levels were undertaken in less than 50% of adults and 40% of pediatrics receiving theophylline in hospital. Levels ranged from 3.4 to 44.2 mcg/mL. Over 60% of these levels were outside of the normal therapeutic range. This confirms the variability in dosage requirements and therefore the need for serum theophylline monitoring. Serum theophylline level monitoring Serum Level (mcg/mL) Adults and children over 1? yr. undetermined <10 10-20 >20 Children under 17 yr. undetermined <10 10-20 >20 Incidence (%) 55 15 15 15 64 22 14 0 Guidelines for determining serum theophylline levels Route of Time since Sample time relative Administration initiation or dosage change <hr> Intravenous Oral 24 - 48 24 - 48 to time of dose unimportant immediately prior (trough) Levels drawn 24-48 hours following in hospital initiation or changes in theophylline dosage provide useful information to determine the need for further dosage adjustments. References 1. Van Dellen RG. Theophylline. Practical application of new knowledge. Mayo Clin Proc 1979; 54:733-745. 2. Hendeles L, Weinberger M, Johnson G. Monitoring serum theophylline levels. Clin Pharmacokin 1978; 3:294-312. 3. Price J. Asthma in children: treatment. Br Med J 1964: 288:1895-97. 4. Zaske DE. Miller KW, Strem EL, et al. Oral aminophyUine therapy. Increased dosage requirements in children. JAMA 1977; 237:1453-1455. 5. George RB. Some recent advances in the management of asthma. Arch Intern Med 1982; 142:933-35. Less than 50% of all theophylline treatment courses were associated with serum level assessment. A significant portion of those serum levels determined were outside of the normal therapeutic range for theophylline. The varia-tion in measured levels confirms the clinical usefulness of monitoring this parameter. RECOMMENDATIONS Serum theophylline levels are a useful clinical tool to help avoid toxicity and optimize therapy in bronchospastic patients.'-6 135 fArof D u p Information November/December 1984 8 Surgical Antimicrobial Prophylaxis Prophylactic antimicrobial use has been demon-strated to reduce the incidence of infectious complications associated with certain surgical pro-cedures. Antimicrobial prophylaxis in surgery is effective in the prevention of surgical infection only where no infection exists prior to the procedure.1'* Successful use of prophylactic antimicrobials is dependent on several factors including the timing of the initial dose relative to the surgical procedure. The critical period when infection may be sup-pressed by antimicrobials begins the moment bacteria gain access to the tissue and is over within 2 - 3 hours.* Delayed initiation of prophylaxis allows time for physiological changes to occur at the wound surface which interfere with diffusion of the drug reducing its ability to reach bacteria in sufficient concentration. Antimicrobials can only be expected to exert a limited effect after this period.14 Factors determining the effectiveness of antimicrobial prophylaxis in surgery Type of surgical procedure Choice of antimicrobial drug Dosage and route of administration Timing of initial dose Duration of peri-operative administration SUMMARY 1. The effectiveness of prophylactic anti-microbials is enhanced by administra-tion of the initial dose immediately prior to the surgical procedure. 2 . A study at this hospital reveals that more than 5 0 % of prophylactic anti-microbials were initiated after wound closure. 3. Antimicrobial prophylaxis should be commenced immediately prior to a surgical procedure. This ensures opti-mal antibacterial activity at the time of potential bacterial contamination. Practical guidelines are provided. procedure in the absence of suggestions of an infectious process according to standard guide-lines.' Therefore, prophylaxis was defined as situ-ations in which the antimicrobial was used to prevent infection when no evidence of infection was evident at the initiation of therapy. Sixty randomly selected patients who had re-ceived antimicrobial prophylaxis were further reviewed. Data regarding timing of the initial dose of antimicrobial prophylaxis was specifically sought. The most important determinant of post-op-erative infections is the presence of bacteria in the surgical field at the time of wound closure. Antimicrobials provide maximum suppression of infection when they are administered before bacteria gain access to tissue.* DRUG USAGE STUDY Health records of patients admitted between April and October, 1984 were scanned to identify indi-viduals administered an antimicrobial drug. Anti-microbial usage was then classified as prophylactic when initiated within 12 hours of a surgical Timing of initial antimicrobial dose Timing Pre-operative Intra-operative Post-operative Incidence (%) 12 27 61 Only about 107c of prophylactic courses were initiated prior to commencement of a surgical procedure. More than 509e of courses were initiated after closure, usually in the recovery room. 4 pflS^EiBBS^ - Drag Usage iBformatka Novsmber/Deoenbar M M RECOMMENDATIONS Antimicrobial administration should be timed to ensure peak serum levels wfl] coincide with the period of potential bacterial contamination. TV Administration Intravenous administration should occur during initiation of anaesthesia. This provides peak blood levels at the commencement of the surgical procedure. IM Administration Intramuscular administration should occur on the ward shortly before the scheduled procedure as peak serum levels of roost antimicrobials occurs 1 -2 hours after IM injection of the drug. Duration of Prophylactic Course Available information indicates that continuation of drug administration beyond the recovery room does not contribute to the prevention of wound infection. Current recommendations suggest limiting anti-microbial administration to the first 24 - 48 hours after completion of surgery. >*» Intravenous administration commenced during induction of anaesthesia appears to be the most certain way to ensure an adequate concentration of an antimicrobial drug at the time the tissues are exposed to bacterial contamination. References 1. Hojer H. Antimicrobial prophylaxis in abdominal surgery 1982; 10 (Suppl):101-15. 2. Shapiro M, Townsend TR, Rosner B and Kass EH. Use of antimicrobial drugs in general hospitals. Patterns of pro-phylaxis. N Engl J Med 1979; 301:351-355. 3. Burke JF. The effective period of preventive antibiotic action in experimental incisions and dermal lesions. Surgery 1961; 50:161-66. 4. Polk HC, Lopei-Mayor JF. Postoperative wound infection: a prospective study of determinant factors and prevention. Surgery 1969; 66:97-103. 5. Davidson A1G. Clark G, Smith G. Post-operative wound infection: a computer analysis. Br J Surg 1971; 58:333-37. 137 T o p i c s T-6 and T-3 H o s p i t a l H-2 DRUG USAGE INFORMATION PROGRAM Published as a joint venture of the Medical Advisory Committee and the Pharmacy A Therapeutics Committee NOVEMBER/DECEMBER 1984 Admission Serum Drug Levels at Although acute management of the patient with an acute bronchospastic or seizure disorder is the first priority, it is important to remember that serum drug level measurements provide invaluable assistance in assessing the effectiveness of therapy aimed at preventing such problems. Specifically, admission serum levels are useful in determining if inadequate dosage or compliance was partially responsible for the acute exacerbation.' •* Admission levels and interpretation for some commonly monitored drugs S c r u m Levels (mcg/mL) Tbeopbyuuie Phenytotn F b e n o b a r M U ] <10 <10 <15 Imerpreutk» Ipvctigmtkm Sub- Underdosing optimal Compliance problems Drug interactions 15-40 Optimal Need for adjunctive therapy >40 Potentially Overdosage toxic Compliance problems Drug interactions Blood sampling for baseline drug level measurements prior to commencing in hospital drug therapy can provide valuable informa-tion for the chronic management of the patient with an acute bronchospastic or seizure dis-order. 10-20 >20 10-20 >20 S U M M A R Y 1. Admission serum drug levels will pro-vide valuable information for the chronic management of patients ad-mitted for acute bronchospastic or seizure disorders with known or sus-pected use of medications for which serum drug level monitoring is avail-able (theophylline, phenytoin, pheno-barbital and others). 2. A study at this hospital reveals that 607< of patients admitted with aruie bronchospastic or seizure disorders were previously taking medications for which serum drug level monitoring is available. In less than 209; of these cases were admission serum levels undertaken to estimate drug concen-trations at the time of the exacerbation. 3. Blood sampling for admission serum drug level measurements should be undertaken for all patients admitted for an acute bronchospastic or seizure disorder with known or suspected use of medications for which serum drug level monitoring is available. Proper assessment of serum levels at the time of exacerbation requires that sampling occur as soon as possible and before administration of the monitored drug in hospital. Gentamicin at |- page 3 S f^ BSLall^ SEa^ ED' DRU* U u p Information November/December 1964 DRUG USAGE STUDY Health records of patients admitted between April and October 1984 were scanned to identify indivi-duals admitted with an acute bronchospastic or seizure disorder. Further review was then under-taken to identify 60 of those patients who received a measurable drug prior to and during that admission. Data regarding admission serum drug level moni-toring was specifically sought. 60% of patients admitted with bronchospastic or seizure disorders had been taking medications for which serum drug level monitoring is available. Only 11% of patients had admission serum drug levels undertaken prior to the administration of the same drug. Those admission serum drug levels reported were frequently below the normal thera-peutic range suggesting underdosing or compliance problems. Where serum levels are determined to be below or above the normal therapeutic range at the time of the exacerbation, investigation to establish a cause is warranted. Where serum levels are with-in the normal therapeutic range, adjunctive therapeutic measures may be indicated to mini-mize or prevent further occurrences.'-* Blood sampling for admission serum drug level measurements should be undertaken for all patients admitted with an acute broncho-spastic or seizure disorder and taking medi-cations for which serum drug level measure-ment is available. To allow for assessment of serum levels at the time of exacerbation, sampling must occur as soon as possible after admission and before administratior of the monitored drug in hospital. Admission serum drug level monitoring of some commonly monitored drugs Serum Level Incidence (mcg/mL) (%) Theophylline not determined 88 less than 10 9 10-20 3 Aaticonvulaanta not determined 100 References 1. Richens A, Warrington S. When should plasma drug levels be monitored? Drugs 1979; 17:488-500. 2. Kurt H. Penry JK. Usefulness of blood levels of antiepileptic drugs. Arch Neurol 1974; 31:283-88. 3. Eadie MJ. Plasma level monitoring of anticonvulsants. Clin Pharmacokin 1976; 1:52-66. 4. Van DeUen RG. Theophylline. Practical application of new knowledge. Mayo Clin Proc J979; 54:733-45. Admission blood sampling for the purposes of determining serum drug levels at the time of exacerbation was undertaken in less than 207V of patients admitted with drug-managed bronchospastic or seizure disorders. RECOMMENDATIONS Admission serum drug levels provide valuable information for the management of the patient with an uncontrolled bronchospastic or seizure disorder known to be taking medications for which serum drug level measurements are available. To allow for assessment of serum levels at the time of exacerba-tion, sampling must occur as soon as possible after admission and prior to the administration of the monitored drug in hospital.1 Admission drug level results are not usually available to contribute to the acute management of the patient (eg. when deciding whether to administer a drug loading dose). However, this information will be valuable to assist in making decisions regarding the continuing management of the patient. - Drug Usage Information November/December 1964 S Gentamicin at The effectiveness of gentamicin is associated with peak serum concentrations. Higher patient re-sponse rates are achieved with gentamicin when therapeutic peak concentrations are obtained early in therapy.1 Similar observations have been made for tobramycin. Initiating a gentamicin treatment course with a standard 60-80 mg dose is likely to result in under-dosing in many adult patients.' Therapeutic serum concentrations for the treatment or prevention of systemic gram-negative infections can best be achieved by starting a regimen of 1.5 mg/kg/dose for the majority of adult patients .*-« Pediatric patients have greater milligram per kilogram dosage requirements than adults. Specific pediatric recom-mendations are related to the child's age and weight.5 Therapeutic peak serum gentamicin levels and dosages in adults* Indication Lower urinary tract infection Systemic infection Pneumonia and bum sepsis Peak Serum Drug Level (mcg/mL) N/A Dosage Per Interval (mg/kg) 1.0 6-7 7-9 1.5 2.0 •based upon an average adult volume of distribution of 0.25 L/kg To avoid underdosing, initial dosages based upon body weight and age group represent an accurate, practical and safe method of initiating effective gentamicin therapy. SUMMARY 1. Initial gentamicin dosage calculation:, should be individualized based unor. weight and age group to maximize tht ability to achieve therapeutic peal; serum concentrations. 2 . A study at this hospital reveals that 907c of adults received standard initial gentamicin dosages of 6 0 or 80 mg/ dose rather than dosages individu-alized by patient weight. In fact, ap-proximately 707c of initial regimens were lower than the recommended dosage of 1.5 mg/kg/dose. Available serum levels also suggest underdosing. Pediatric dosages were also frequently found to be less than recommended. 3. Initial gentamicin dosages should be based upon body weight and age group. Most adults will require 80 -1 4 0 mg/dose to obtain therapeutic peak serum levels. Currently recom-mended initial dosage regimen guide-lines for all age groups are provided. DRUG USAGE STUDY Health records of adult and pediatric patients admitted between April and October 1984 were scanned to identify individuals administered genta-micin. Patients receiving this agent for uncompli-cated urinary tract infections were excluded. Randomly selected treatment courses were then reviewed for 60 of the identified patients. Data regarding initial dosage regimens and serum gentamicin level determinations were specifically Bought. 90% of all adult patients were administered standard doses of 60 - 80 mg as an initial dosage regimen. Serum levels were rarely undertaken during initial therapy. When available, the majority of peak serum levels were less than 5 mcg/mL. 4 - Drag Usage Information Novenber/Dexcaaber 1984 Although more pediatric and neonatal patients received initial per interval gentamicin dosages within 20% of those currently recommended, a larger proportion were underdosed by more than 40%. Similarity of initial gentamicin dosages to recommended dosages % Recommended Dosage Adults and children >10 yr. <60 60 - 60 80 - 120 Children <10 yr. and neonates <60 60 • 80 80 • 120 >120 Incidence (%) 38 36 26 44 13 37 6 Approximately 70% of initial gentamicin dosages in all age groups were equivalent to less than 80% of the recommended milligram per kilogram dose. RECOMMENDATIONS Therapeutic failures with gentamicin have been attributed to inadequate peak concentrations which frequently occur with the use of standard 60 to 80 mg doses in adults and smaller than recommended dosages in pediatrics. Optimal therapy with gen-tamicin is determined by the appropriateness of the initial dosage chosen and the proper monitoring of efficacy and toxicity during therapy.' Initial amino-glycoside dosages should be based upon body weight and age group. Currently recommended initial dosage regimen guidelines for all age groups are provided. Adult doses should be rounded to the nearest 10 mg increment. Therapeutic response Serum concentrations of gentamicin are represen-tative of tissue levels throughout the body. The guidelines provided are designed to provide recom-mended peak and trough gentamicin concentrations of 5 - 7 mcg/mL and less than 2 mcg/mL, respectively Higher peak levels are usually required for patients with gram-negative pulmonary infections or life-threatening infections, while lower levels for patients with uncomplicated urinary tract infections. Dosage adjustments B b o u l d be based upon peak/trough serum concentration determinations. Avoiding drug toxicity Gentamicin can cause ototoxicity and nephro-toxicity. Serum creatinine should be measured within 4 days of initiating gentamicin. Discontinu-ation of therapy or extension of dosing intervals is indicated if serum creatinine rises by more than 50% from pre-therapy values or increases by more than 0.5 mg/dL. The use of this or other predictive dosage methods should be followed, where possible, with serum concentration determinations and dosage adjust-ments to ensure therapeutic serum concentrations early in treatment. Interval extensions are also indicated if trough levels exceed 2 mcg/mL. Guidelines for initial gentamicin dosage regimens Age group Adults and children > 10 yr 5-10 yr 1 wk - 5 yr < 1 wk (full term) Dosage* (mg/kg/doee) 1.5 2.0 2.5 2.5 Interval*1 (hr) 8 8 12 •smaller dosages are required for the treatment of uncompli-cated urinary tract infections **patients with impaired renal function will likely require an adjustment of dosage interval Initial gentamicin dosages should be bast upon body weight and age group. Aduhs vi: frequently require dosages of 80-140 \r.z pc dosage interval to obtain therapeutic se; i r levels early in therapy. Pediatric dosagvs nv_~i also be calculated from the patient's wei,.i : while considering this age group. References 1. Ackerman BH, Bailie GR, Zaske DE. Aminoglycoside therapy Improving patient response and safety. Postgrad Med J 1984; 75:177-85. 2. Siber GR, Ecbeverria P. Smith AL, et al. Pharmacokinetics of gentamicin in children and adults. J Infect Dis 1975; 132:637-651. 3. Summer WR, Michael JR, Lipsky JJ. Initial aminoglycoside levels in the critically Ol. Crit Care Med 1983; 11:948-50. 4. Wilkowske CJ, Hermans PE. General principles of anti-microbial therapy. Mayo Clin Proc 1983; 58:6-13. 5. Riff L, Schauf V. Use of aminoglycosides in the neonate. Seminars in Perinatology 1982; 6:155-65. Appendix V. DUI Program f o l l o w - u p r e p o r t s d i s t r i b u t e d p h y s i c i a n s ( s i t e i d e n t i f i c a t i o n removed and r e p o r t s photo-reduced) T o p i c s T -5 and T-4 H o s p i t a l H-l DRUG USAGE INFORMATION PROGRAM Published as a joint venture of the Medical Advisory Committee and the Pharmacy ft Therapeutics Committee JANUARY 1985 Surgical Antimicrobial Prophylaxis: Results of a Follow-up Study Antimicrobial prophylaxis use has been shown to reduce the rate of postoperative infection associated with certain surgical procedures. The use of anti-microbial prophylaxis in surgery is effective in the prevention of surgical infection only in the absence of infection prior to the procedure.1-1 Successful use of prophylactic antimicrobials is dependent on several factors. Equally important to the actual choice of drug is the timing of the initial dose relative to the surgical procedure. To achieve m a - i i m n m effect, an antimicrobial must be given before contamination of tissues with bacteria. Within two to three hours after contamination, damage to tissues will occur and infection will be established. Initiating an antimicrobial at this time can no longer be considered prophylaxis.' Delayed initiation of prophylaxis also allows time for physiological changes to occur at the wound surface which interfere with diffusion of the drug. This reduces its ability to reach bacteria in sufficient concentrations. Antimicrobials can only be expected to exert a limited effect after this period.'-4 Factors determining the effectiveness of antimicrobial prophylaxis in surgery Type of surgical procedure and patient Choice of antimicrobial drug Dosage and route of administration Timing of initial dose Duration of peri-operative administration To achieve maximum effect, prophylactic antimicrobials must be given before contami-nation of tissues with bacteria,' SUMMARY 1. Prophylactic antimicrobial efficacy is enhanced by administration of the initial dose immediately prior to the surgical procedure. 2. A follow-up study at this hospital reveals a 60% increase in the frequency of prophylactic antimicrobial courses initiated pre- or intra-operatively during the second review period. Even so, approximately 40% of patients were not adequately covered at the time of the operation. 3. Prophylaxis should be commenced immediately prior to a surgical pro-cedure. Intravenous administration commenced during induction of anaes-thesia appears to be the most certain way to ensure an adequate concentra-tion of an antimicrobial drug at the time the tissues are exposed to bacterial contamination. FOLLOW-UP DRUG USAGE STUDY A second chart review was undertaken to identify changes in patterns of antimicrobial prophylaxis since publication of the results of the first review in the first Drug Usage Information report in November 1984. Health records of patients admitted during December 1984 (2nd Review Period) were scanned to identify individuals administered an antimicrobial drug. Antimicrobial usage was then classified as prophyl-actic when initiated within 12 hours of a surgical procedure in the absence of suggestions of an infectious process according to standard guide-Theophylline Serum Levels: Results of a Follow-up Study - page 3 ft ffR^§S^IX39~ Tyro? Usage Information January MSB lines*Therefore, prophylaxis was defined as situa-tions in which the antimicrobial was used to prevent infection when no evidence of infection was evident at the initiation of therapy. Twenty-five randomly selected patients who had received antimicrobial prophylaxis were further reviewed. Data regarding timing of the initial dose of antimicrobial prophylaxis was specifically sought Tuning of initial antimicrobial dose Timing Incidence (%) 1st Review Period 2nd Review Period Pre-operative 12 26 Intra-operative 27 36 Poat-operative 61 38 A 6 0 % increase in the frequency of prophylac-tic courses initiated pre- or intra-operatively was observed during the second review period. Even so, approximately 407c of surgical pa-tients were not adequately covered at the time of the operation. References 1. Hojer H. Antimicrobial prophylaxis in abdominal surgery 1982; 10 (Suppl):101-15. 2. Shapiro M, Towns end TR, Rosner B, Kass EH. Use of antimicrobial drugs in general hospitals. Patterns of pro-phylaxis. N Engl J Med 1979; 301:351-355. 3. Burke JF. The effective period of preventive antibiotic action in experimental incisions and dermal lesions. Surgerv 1961; 50:161-68. 4. Polk HC, Lopex-Mayar JF: Postoperative wound infection: a prospective study of determinant factors and prevention. Surgery 1969; 66:97-103. 6. Davidson AIG, Clark G, Smith G. Post-operative wound infection: a computer analysis. Br J Surg 1971; 58:333-37. RECOMMENDATIONS Antimicrobial administration should be timed to ensure peak serum levels will coincide with the period of potential bacterial contamination. IV Administration Intravenous administration should occur during initiation of anaesthesia. This provides peak blood levels at the commencement of the surgical procedure. Dd Administration Intramuscular administration should occur on the ward shortly before the scheduled procedure as peak serum levels of most antimicrobials occur 1 • 2 hours after IM injection of the drug. Duration of Prophylactic Course Available information indicates that continued administration beyond the recovery room does not contribute to the prevention of wound infection. Current recommendations suggest limiting anti-microbial administration to the first 24 - 48 hours after completion of surgery.'•*•» Intravenous administration commenced during Induction of anaesthesia appears to be the most certain way to ensure an adequate concentration of an antimicrobial drug at the time the tissues are exposed to bacterial contamination. 144 - Drag VuLge Information January I960 S Theophylline Serum Levels: Results of a Follow-up Study Therapeutic efficacy and toxicity with theophylline have been demonstrated to relate directly to serum theophylline concentrations. In both adults and children, levels below 10 mcg/mL do not give optimal bronchodilator effect, and substantial toxi-city may occur in the presence of levels above 20 mcg/mL.* No one dosage for maintenance therapy can be recommended for all patients. Serum levels will vary markedly in patients receiving similar theo-phylline dosages. Adult dosing requirements to achieve therapeutic levels of theophylline are affected by many factors including age, Bmoking, cardiac or hepatic disease and concurrent admi-nistration of interacting drugs (cimetidine, ery-thromycin).1 Children show a wide variation in their rate of theophylline metabolism and in general need larger doses relative to body weight.*4 Serum theophylline measurement is therefore essential to obtain optimal acute and chronic management of bronchospastic disorders while minimizing the risk of toxicities. Serum theophylline levels are particularly important in patients receiving IV aminophylline therapy because of the potential for dramatic changes in serum drug levels and frequent dosage adjustments associated with this form of treatment. Further-more, patients receiving IV therapy are usually acutely ill and metabolic rates may rapidly change.* Theophylline levels and therapeutic/toxic response* Serum Level Response (mcg/mL) 0- 5 5-10 10-20 20-35 >35 Sub-therapeutic Sub-optimal Optimal Minor adverse effects (significant toxicity in susceptible patients) Cardiac arrhythmias and seizures "therapeutic/toxic levels are lower in neonates Large inter-patient variation in theophylline dosage requirements and the strong relation-ship between serum levels and clinical effects mandate that drug concentrations be used to monitor the potential risks and benefits of theophylline therapy. SUMMARY 1. Serum theophylline levels correlate well with therapeutic efficacy (10 • 20 mcg/mL) and toxicity (greater than 20 mcg/mL). Serum levels provide an objective basis for dosage adjustment of theophylline-containing prepara-tions (aminophylline, Theodurx, Cho-ledyl®, Palaron® and others). 2. A follow-up study at this hospital reveals a 60% increase in the frequency of theophylline serum levels during the second review period. Even so, approximately 30% of patients receiv-ing theophylline-containing prepara-tions for acute bronchospastic com-plaints were not monitored with serum theophylline levels. 3. Serum theophylline levels should be monitored during the acute manage-ment of bronchospastic patients. Levels drawn 24 - 48 hours following in hospital initiation or changes in theophylline dosage provide useful information regarding the need for further dosage adjustments. FOLLOW-UP DRUG USAGE STUDY A second chart review was undertaken to identify changes in the frequency of theophylline serum levels since publication of the results of the first review in the first Drug Usage Information report in November 1984. Health records of adult and pediatric patients admitted during December 1984 (2nd Review Period) were scanned to identify individuals who received a theophylline-containing product during their stay. Patients admitted for an unrelated disorder who simply continued pre-admission oral therapy were excluded as were patients receiving less than 48 hours of therapy while in hospital. Randomly selected treatment courses were then reviewed for 25 patients. Data regarding serum level monitoring was specifically sought. Drug Utsfe Information January ISSS A 60% increase in the frequency of serum theo-phylline levels was observed during the second review period Compared to the first review period, a more narrow range of serum levels was observed. Levels varied from 5.1 to 15.6 mcg/mL. No levels exceeded the normal therapeutic range, however, over 50% of the reported levels were below this range. This re-confirms the variability in dosage requirements and therefore the need for serum theophylline monitoring to optimize therapy. Serum theophylline level monitoring Serum Level (mcg/mL) Adult* and children over 17 yr. undetermined <10 10-20 >20 Children under 17 yr. undetermined <10 10-20 >20 Incidence (%) 1st Review Period tad I n i r » 65 15 15 15 64 22 14 0 28 42 30 0 42 19 39 0 A 60% increase in the frequency of serum theophylline levels was observed during the second review period. More than 707c of all theophylline treatment courses were associ-ated with serum level assessment. A signifi-cant portion of those serum levels determined were below the normal therapeutic range for theophylline. The variation in measured levels confirms the clinical usefulness of monitoring this parameter. Guidelines for determining serum theophylline levels Route of Administration Intravenous Oral lime since initiation or dosage change Car) 24-48 24-48* Sample time relative to time of doae unimportant immediately prior (trough) Levels drawn 24-48 hours following in hospital initiation or changes in theophylline dosage provide useful information to determine the need for further dosage adjustments. References 1. Van DeUen RG. Theophylline. Practical application of new knowledge. Mayo Clin Proc 1979; 54:733-745. 2. Hendeles L, Weinberger M , Johnson G. Monitoring serum theophylline levels. Clin Pharmacokin 1978; 3:294-312. 3. Price J . Asthma in children: treatment. Br Med J 1984: 288:1895-97. 4. Zaske DE, Miller KW, Strem EL, et al. Oral aminophylline therapy. Increased dosage requirements in children. JAMA 1977; 237:1453-1455. 5. George RB. Some recent advances in the management of asthma. Arch Intern Med 1982; 142:933-35. RECOMMENDATIONS Serum theophylline levels represent a useful clinical tool to assist in avoiding toxicity while optimizing bronchodilator therapy." Serum theophylline concentration data must be interpreted together with the patient's current clinical status, response, and tuning of serum levels relative to the initial and last dose. A level obtained 24 - 48 hours after in hospital initiation of therapy or change in dosage provides the most useful information on which to base further dosage adjustments.1 Dosage adjustments are indicated if levels exceed 20 mcg/mL or are less than 10 mcg/mL and control is not optimal. T o p i c s T-3 and T-6 H o s p i t a l H-2 D R U G U S A G E I N F O R M A T I O N P R O G R A M Published as a joint venture of the Medical Advisory Committee and the Pharmacy *V Therapeutic* Committee JANUARY 1985 Gentamicin Prescribing: Results of a Follow-up Study A relationship between peak serum gentamicin concentrations and success of therapy has been clearly established.1 Therapeutic failures with gen-tamicin have been attributed to inadequate peak (and trough) serum levels. Low levels such as these frequently occur with dosage regimens recom-mended by the manufacturer. Initiating a gentamicin treatment course with a standard 60 - 80 mg dosage is likely to result in underdosing in many adult patients. Numerous studies have demonstrated that dosages needed to attain therapeutic serum concentrations are fre-quently higher than conventional doses. Despite the use of higher doses, patients rarely show evidence of ototoxicity or nephrotoxicity.1 Therapeutic serum concentrations for the treat-ment or prevention of systemic gram-negative infections can best be achieved by starting a regimen of 1.5 mg/kg/dose for the majority of adult patients.*" Pediatric patients have greater milligram per kilogram dosage requirements than adults. Specific pediatric recommendations are related to the child's age and weight.* Therapeutic peak serum gentamicin levels and dosages in adults* Indication Lower urinary tract infection Systemic infection Pneumonia and burn aepais Peak Serum Drug Level (mcg/mL) N/A 6- 7 7- 9 Doaage Per Interval (mg/kg) 1.0 IA 2.0 SUMMARY 1. Initial gentamicin dosages should be individualized based upon body weight and age group to maximize the ability to achieve therapeutic peak serum concentrations. 2. A follow-up study at this hospital reveals a 79% increase in the frequency of initial gentamicin dosages within 20% of the recommended mg/kg dose during the second review period. Even so, a significant proportion of initial adult dosages continued to be signifi-cantly lower than recommended. Available serum levels also suggest underdosing. 3. Initial gentamicin dosages should be based upon body weight and age group. Most adults will require 80 • 140 mg per dosage interval to obtain therapeutic peak serum levels. Cur-rently recommended initial dosage regimen guidelines for all age groups are provided. 'baaed upon an average aduh volume of distribution of 0.25 L/kg To avoid underdosing, initial gentamicin dosages based upon body weight and age group represent an accurate, practical and safe method of initiating effective therapy. FOLLOW-UP DRUG USAGE STUDY A second chart review was undertaken to identify changes in patterns of gentamicin prescribing since publication of the results of the first review in the first Drug Usage Information Program report in Admission Serum Drug Levels: Results of a Follow-up Study - page 3 • Drag Usage lafbrmaiioB Jaauary 1886 November 1984. Health records of adult and pediatric patients admitted during December 1984 (2nd Review Period) were scanned to identify individuals administered gentamicin. Patients re-ceiving this agent for uncomplicated urinary tract infections were excluded Randomly selected treat-ment courses were then reviewed for 25 of the identified patients. Data regarding initial dosage regimens and serum gentamicin level determinations were specifically sought. At least 90% of all adult patients continued to receive standard doses of 60-80 mg as an initial dosage regimen. The small number of pediatric and neonatal patients reviewed all received initial per interval gentamicin dosages within 20% of those currently recommended during the second review period. Comparison of initial gentamicin dosages to recommended dosages laeideae* <%) 1st Review Period 2nd Review Adults and Children >10 yr. <60 60 - 80 80-120 Children <10 yr. and neonates <60 60 - 80 80 - 120 >120 26 44 13 37 6 16 38 46 0 0 100 0 A 79% increase in the frequency of initial gentamicin dosages within 20% of the recom-mended mg/kg dose was observed during the second review period. Even so, approximately 507c of initial dosages were below these limits. RECOMMENDATIONS Therapeutic failures with gentamicin have been attributed to inadequate peak concentrations which frequently occur with the use of standard 60 to 80 mg doses in adults and smaller than recommended dosages in pediatrics. Optimal therapy with genta-micin is determined by the appropriateness of the initial dosage chosen and the proper monitoring of efficacy and toxicity during therapy.1 Initial genta-micin dosages should be based upon body weight and age group. Therapeutic response Serum concentrations of gentamicin are represent-ative of tissue levels throughout the body. The guidelines provided are designed to provide recom-mended peak and trough gentamicin concentra-tions of 5 - 7 mcg/mL and less than 2 mcg/mL, respectively. Higher peak levels are usually required for patients with gram-negative pulmonary infec-tions or life-threatening infections, while lower levels for patients with uncomplicated lower urinary tract infections. Dosage adjustments should be based upon peak/trough serum concentration determinations. Avoiding drug toxicity Gentamicin can cause ototoxicity and nephrotoxicity. Serum creatinine should be measured within 4 days of initiating gentamicin. Discontinuation of therapy or extension of dosing intervals is indicated if serum creatinine rises by more than 50% from pre-therapy values or increases by more than 0.5 mg/dL. Serum gentamicin levels with subsequent dosage adjustments can help the clinician minimize the risk of toxicity while assuring treatment success. Inter-val extensions are indicated if trough levels exceed 2 mcg/mL. Guidelines for initial gentamicin dosage regimens Age group Adults and children > 10 yr. 6 - 10 yr. I wk. - 5 yr. <1 wk. (full term) Dosage* (mg/kg/doae) 1.S 2.0 2.6 2.5 Interval** (hr) 8 8 12 •smaller dosages are required for the treatment of uncompli-cated urinary tract infections. Adult doses should be rounded to the nearest 10 mg increment **patient£ with impaired renal function will likely require an adjustment of dosage interval. Initial gentamicin dosages should be indivi-dualized according to body weight and age group. Adults will frequently require dosages of 80 - 140 mg per dosage interval to obtain therapeutic serum levels. Pediatric and neo-natal patients require a greater mg/kg dose to achieve similar levels. References 1. Ackerman BH, Bailie GR, Zaske DE. Aminoglycoside therapy. Improving patient response and safety. Postgrad Med J 1984; 75:17745. 2. Siber GR, Echeverria P, Smith AL, et al Pharmacokinetics of gentamicin in children and adults. J Infect Dis 1975; 132*37-651. 3. Summer WR, Michael JR. LipBky JJ. Initial aminoglycoside levels in the critically 01. Crit Care Med 1983; 11:948-50. 4. Wilkowske CJ, Hermans PE. General principles of anti-microbial therapy. Mayo Clin Proc 1983; 58.-6-13. 6. Riff L, Schauf V. Use of aminoglycosides in the neonate. Seminars in Perinatology 1982; 6:155-65. 148 JKff^Saj^-*-'11-»»Jfr- Drug l'tt|! ImformmtJot. January 1S86 S Admission Serum Drug Levels: Results of a Follow-up Study During the initial hospital management of a patient with an acute bronchospastic or seizure disorder, baseline serum drug level measurements provide invaluable assistance in assessing the effectiveness of therapy aimed at preventing such problems. Specifically, admission blood sampling for theo-phylline or anticonvulsant levels is useful for determining whether inadequate dosage or comp-liance was partially responsible for the acute exacerbation in patients known or suspected to be taking these medications.1-4 Admission levels and interpretation for some commonly monitored drugs Sema Leveb (mef/aoL) TbeopbyUioe PbeDyloizi Interpretation I n v e y t i g i t w i <10 10-20 >20 <10 <15 Sub-optimal 10-20 15-40 Optimal Underdosing Compliance problems Drug interactions Need for adjunctive therapy >20 >40 Potentially Overdosage toxic Compliance problems Drug interactions Blood sampling for baseline drug level measurements prior to commencing in hospi-tal theophylline or anticonvulsant drug therapy will provide valuable information for the chronic management of the patient with an acute bronchospastic or seizure disorder. FOLLOW-UP DRUG USAGE STUDY A second chart review was undertaken to identify changes in the frequency of admission serum levels since the publication of the results of the first SUMMARY 1. Admission serum drug levels provide useful information for the chronic management of patients admitted for acute bronchospastic or seizure dis-orders who are known or suspected to take medications for which serum drug level monitoring is available (theophylline, phenytoin, phenobarbe-tal and others). 2. A follow-up study at this hospital reveals a 90% increase in the fre-quency of admission blood sampling to establish serum drug levels at the time of exacerbation during the second review period. Even so, baseline serum levels were not requested in over 75% of patients known or sus-pected to be taking the monitored drugs prior to admission. 3. Blood sampling for admission serum drug level measurements should be undertaken for all patients admitted for an acute bronchospastic or seizure disorder with known or suspected use of medications for which serum drug level monitoring is available. Serum level requests should specify that blood sampling occur soon after admission and PRIOR TO administration of the monitored drug in hospital. review in the first Drug Usage Information Program report in November 1984. Health records of patients admitted during December 1984 were scanned to identify individuals admitted with an acute bronchospastic or seizure disorder. Further review was then undertaken to identify 20 of those patients who received a measurable drug prior to and during that admission. Data regarding admission serum drug level monitoring was specifically sought. 1 4 f ^ t o a f e j e g j j ^ ^ g a - D T M Usage Iafbmuuh, JamurylSU Admission serum drug level monitoring of some commonly monitored drugs Senun Level Incidence {%) (mCC/mL) 1« ««vtow PmhoS tad B»rir> Parted Theophylline not determined 88 77 l eu than 10 9 17 10-20 S 6 Anticonvulsants* not determined 100 0 leas than NTH 0 0 within NTH 0 100 NTR - normal therapeutic range * 1 patient only Serum drug levels were frequently requested con-current with the initial drug administration order without specifying the need to draw levels before the drug is given- This resulted in blood sampling soon after (instead of prior to) initiation of the monitored drug. The resulting serum level inform-ation did not accurately reflect the admission serum drug level and was too early after commencement of in hospital therapy to reflect steady-state levels on the current regimen. A 90% increase in the frequency of admission blood sampling to establish serum drug levels at the time of exacerbation was observed during the second review period. Even so, baseline blood sampling occurred in less than 25% of patients admitted with bronchospastic or seizure disorders known or suspected to be taking a drug for which serum drug level measurement is available. RECOMMENDATIONS Admission serum drug levels provide valuable information for the management of the patient with an uncontrolled bronchospastic or seizure disorder known or suspected to be taking medications (eg. theophylline, phenytoin, pbenobarbital) for which serum drug level measurement is available. To allow for assessment of serum levels at the time of exacerbation, blood sampling must occur as soon as possible after admission and PRIOR TO the administration of the monitored drug in hospital.' Admission drug level results are not usually avail-able to contribute to the acute management of the patient (eg. when deciding whether to administer a drug loading dose). However, this information will be valuable to assist in making decisions regarding the continuing management of the patient Where serum levels are determined to be below or above the normal therapeutic range at the time of the exacerbation, investigation to establish a cause is warranted. Where serum levels are within the normal therapeutic range, adjunctive therapeutic measures may be indicated to minimize or prevent further occurrences.^ * Blood sampling for admission serum drug level measurements should be undertaken for all patients admitted with an acute broncho-spastic or seizure disorder and taking medica-tions for which serum drug level measurement is available. To allow for assessment of serum levels at the time of exacerbation, serum level requests should specify that blood sampling occur as soon as possible after admission and prior to administration of the monitored drug(8) in hospital. References 1. Richens A, Warrington S. When should plasma drug levels be monitored? Drugs 1979; 17:488-500. 2. Kutt H, Penry JK Usefulness of blood levels of antiepileptic drugs. Arch Neurol 1974; 31:283-88. 3. Eadie MJ. Plasma level monitoring of anticonvulsants. Clin Pharmacokin 1976; 1:52-66. 4. Van Dellen RG. Tbeophylline. Practical application of new knowledge. Mayo Clin Proc 1979; 54:733-45. 150 Appendix VI. Medical rounds announcement d i s t r i b u t e d a t t e s t h o s p i t a l s ( s i t e i d e n t i f i c a t i o n removed) 151 • •• GRAND ROUNDS ••* T O P I C : Drug Usage Information Program CUEST SPEAKER : Dr. Robin Ensom Asst. Professor and D i v i s i o n Chairman Faculty of Pharmaceutical Sclaneaa U n i v e r s i t y of B r i t i s h Columbia Dr. E n i o i i s a c o - d i r e c t o r of th« Drug Measurement S e r v i c e and the p r i n c i p l e i n v e s t i g a t o r of the B.C. Health Car* Foundation funded Drug Therapy E v a l u a t i o n Unit at S t . Paul's Hoap l t a l i n Vancouver T I M E AND P L A C E : January 9, 1985 0900 hrs Conference Room 152 Appendix V I I . Drug u t i l i z a t i o n p a t t e r n s a t t e s t h o s p i t a l s H o s p i t a l * H - l H Drug c l a s s / % as % % drug Discharges Drug C l a s s Discharges Drug Class A n a l g e s i c s 80 Tylenol#3 33 F r o s s t 292 23 codeine 9 propoxyphene 3 acetaminophen 11 morphine 29 meperidine 50 pentazocine 6 Tylenol#2 1 asa 3 F i o r i n a l 1 a n i l e r i d i n e 0 other 2 S e d a t i v e / Hypnotics 71 oxazepam 35 diazepam 18 c h l o r a l hydrate 13 s e c o b a r b i t a l 17 methylprylon 9 T u i n a l 5 lorazepam 1 A n t i b i o t i c s 38 a m p i c i l l i n 17 c e f a z o l i n 14 c e p h a l e x i n 15 p e n / c l o x a c i l l i n 6 erythromycin 2 t e t r a c y c l i n e 2 a m o x i c i l l i n 1 c e f o x i t i n 1 gent/tobramycin 4 c l i n d a m y c i n 2 bactrim 3 metronidazole 1 74 19 43 31 13 5 4 5 5 4 2 2 1 6 17 12 17 11 8 29 44 32 4 6 4 1 1 1 2 4 3 1 0 0 O i l 1 0 0 56 36 36 53 18 6 9 13 6 9 17 16 24 9 0 0 5 O 0 1 4 6 34 25 9 20 21 8 17 22 4 9 9 3 7 3 3 7 3 1 2 1 4 9 1 4 9 6 3 7 3 2 4 4 3 7 1 2 4 153 Appendix V I I . continued H o s p i t a l " H - l H - 2 Drug c l a s s / % % % % drug Discharges Drug C l a s s Discharges Drug C l a s s Antinauseants diphenhydramine promethazine/ p r o c h l o r p e r a z i n perphenazine and ot h e r s L a x a t i v e s Magnolax Colace/Senokot Metamucil S e l e c t e d drugs c i m e t i d i n e d i g o x i n furosemide o r a l potassium h e p a r i n t h e o p h y l l i n e phenytoin b e t a - b l o c k e r s v a s o d i l a t o r s n o n s t e r o i d a l a n t i - i n f l a m m a t o r y * random s e l e c t i o n of a v a i l a b l e h e a l t h r e c o r d s from H-l (N=212) and H-2 CN=186> «"approximately 4% of d i s c h a r g e d p a t i e n t s r e c e i v i n g drug r e q u i r e d to achieve minimum sample s i z e 44 11 68 17 34 25 56 41 10 15 17 7 4 61 25 24 11 9 4 46 38 16 7 21 13 4 5 7 5 10 11 4 10 6 8 8 4 7 2 11 12 5 154 Appendix V I I I . P i l o t drug usage reviews Drug T o p i c (n*> / process e v a l u a t e d Proposed c r i t e r i a R a t i o n a l e f o r e x c l u s i o n C e f a z o l i n (74) frequency of a d m i n i s t r a t i o n Oxaxepam (105) dosage schedule dose every 8 hours or longer v a r i a b l e as r e q u i r e d T - l c r i t e r i a not f u l l y accepted frequency of misuse low D i g o x i n (75) r e n a l f u n c t i o n and e l e c t r o l y t e m onitoring dosage A m p i c i l l i n (70) c u l t u r e and s e n s i t i v i t y Heparin (9) monitoring T h e o p h y l l i n e m o n i t o r i n g parameters serum c r e a t i n i n e c a l c i u m and magnesium l e v e l s determine by age, weight and serum c r e a t i n i n e a c c o r d i n g t o formula p r i o r t o s t a r t of therapy f r e q u e n t PTT, p l a t e l e t and hemoglobin l e v e l s serum t h e o p h y l l i n e l e v e l d u r i n g acute use c r i t e r i a not f u l l y accepted h e a l t h r e c o r d incomplete and c r i t e r i a not f u l l y accepted c r i t e r i a not f u l l y accepted frequency of use low T-4 A n t i m i c r o b i a l p r o p h y l a x i s (81) schedule i n i t i a t e p r i o r t o procedure T-5 155 Appendix V I I I . continued Drug T o p i c (n*> / process e v a l u a t e d A n a l g e s i c s (68) dosage schedule P r o p r a n o l o l (10) dosage schedule Gentamicin (32) i n i t i a l dosage Serum Drug L e v e l s (109) pre-drug therapy A n t i d i a r r h e a l s (27) dosage Proposed c r i t e r i a R a t i o n a l e f o r e x c l u s i o n frequency of dosing frequency of to r e f l e c t d u r a t i o n misuse low of a c t i v i t y dose every 8-12 hours f o r hyper-t e n s i o n determine by formula a c c o r d i n g t o age and weight determine measurable drug l e v e l p r i o r t o s t a r t of therapy frequency of use and misuse low T-3 T-6 dose a c c o r d i n g t o low s i g n i f i c a n c e recommended regimen problem - low impact a n t i -c i p a t e d C i m e t i d i n e (83) r e n a l f u n c t i o n m o n itoring and dosage BUN and serum T-2 c r e a t i n i n e determine dose by age, weight and SCr A n t a c i d s (11) dosage dose a c c o r d i n g t o low s i g n i f i c a n c e recommended regimen problem - low impact a n t i -c i p a t e d * h e a l t h r e c o r d s reviewed 156 Appendix IX. T o p i c and c r i t e r i a endorsement from independent medical e x p e r t s THE UNIVERSITY OF BRITISH COLUMBIA " D E P A R T M E N T O F M E D I C I N E _- --_ V A N C O U V E R , B.C., C A N A D A j ' " • ^ 1 M g ..... V .V:;" 157 D I V I S I O N O F I N F E C T I O U S D I S E A S E VANCOUVER GENERAL HOSPITAL _ ACUTE CARE HOSPITAL-ST. PAUL'S HOSPITAL SHAUGHNESSY HOSPITAL Dr. Peter Jewesson Faculty of Pharmaceutical Sciences U.B.C. Campus 2146 East Mall Vancouver, B.C. VST 1W5 Dear Peter: I have reviewed your study proposal, "Drug Usage Review Study Topic Number 1 -Cefazolin: Optomization of Prescribed Drug Regimen." The following comments are offered: 1. The study rationale is well supported and the study is definitely worthwhile. 2. I am a bit concerned of the rather rigid approach that all prescriptions with intervals shorter than eight hours are automatically considered inappropriate without due consideration of the nature and severity of illness. Since your objective is not to assess appropriateness but rather to determine if prescription behaviour can be altered by some form of intervention, it is not necessary to take such a rigid stand regarding the "appropriateness" of the prescriptions. Why not simply state that the standard regimens for consideration will be up to 2 grams every eight hours and leave it at that. During the pre-intervention assessment, the frequency of variation from the established standards can be assessed. One does not have to state that this variation is necessarily "inappropriate." During the intervention phase, the appropriate dosage intervals can be emphasized and the post-intervention phase can be directly compared with the pre-intervention usage pattern to see if prescription habit has been changed at all and to prove that the significant change is indeed due to the intervention procedures. 3. It is not entirely correct to describe the study as a retrospective study. It appears that the first half of the study is retrospective while the second half is prospective in nature. 4. You indicate under 5.2 that a comparison wHl be made between phase 1 patterns of drug usage and patterns demonstrated by "control" and "experimental" groups. However, the nature of this control group was never described in the methods. I believe the inclusion of a concurrent control group would be extremely important in order to prove that any change is indeed due to the intervention and not due to other unrelated factors. Although it would be ideal to have a control and experimental group within the same hospital setting, this may not always be feasible. An alternative approach would be to monitor two hospitals in exactly the same manner, except that intervention measures were carried out in only one of the two hospitals. It would be July 3, 1984 164 Appendix X: C e f a z o l i n dosage schedules ( T - l ) A. D e f i n i t i o n of Problem C e f a z o l i n i s r o u t i n e l y being p r e s c r i b e d f o r a d m i n i s t r a t i o n a t dosage i n t e r v a l s of s i x hours or l e s s . For the treatment or p r e v e n t i o n of most i n f e c t i o n s , c e f a z o l i n can be a d m i n i s t e r e d at e i g h t hour i n t e r v a l s or l o n g e r . B. Background A n t i b i o t i c s are p r e s c r i b e d more o f t e n than any other c l a s s of t h e r a p e u t i c agents (1,2). A n t i b i o t i c s t h e r e f o r e consume a l a r g e p o r t i o n of the h o s p i t a l pharmacy's drug budget. Of the c u r r e n t l y a v a i l a b l e a n t i b i o t i c s , the c e p h a l o s p o r i n s are f r e q u e n t l y the most widely employed agents i n the h o s p i t a l s e t t i n g (3>. T h i s i s p r i m a r i l y due t o t h e i r broad spectrum of a c t i v i t y and r e l a t i v e l y low i n c i d e n c e of s e r i o u s s i d e e f f e c t s . C e p h a l o s p o r i n s are a l s o among the most c o s t l y a n t i b i o t i c s a c c o u n t i n g f o r 20* t o 53x of the drug budget (4-6). C e f a z o l i n , i n p a r t i c u l a r , r e p r e s e n t s one of the l a r g e s t a n t i b i o t i c e x p e n d i t u r e s . The suboptimal use of c e f a z o l i n can have a s i g n i f i c a n t impact on h o s p i t a l c o s t s . Recent r e p o r t s on c e f a z o l i n usage suggest t h a t e x c e s s i v e dosages are f r e q u e n t l y being used ' i n the treatment and p r e v e n t i o n of i n f e c t i o u s d i s e a s e s (5,7-10) In these s t u d i e s , c o u r s e s examined regimens. l e s s than 10* of f o l l o w e d l i t e r a t u r e 165 c e f a z o l i n treatment recommended dosage Pharmacokinetic Comparisons When compared with other f i r s t and second g e n e r a t i o n c e p h a l o s p o r i n s , the pharmacokinetic p r o p e r t i e s o f c e f a z o l i n are unique. The serum h a l f l i f e o f c e f a z o l i n i a 69 - 132 minutes i n a d u l t s with normal r e n a l f u n c t i o n . T h i s i s compared with o n l y 30-60 minutes f o r c e p h a l o t h l n , 41-65 minutes f o r c e f o x i t i n , and 27-126 minutes f o r cefamandole (11-15). When adm i n i s t e r e d i n equal recommended dosages t o he a l t h y v o l u n t e e r s , the c o n c e n t r a t i o n of c e f a z o l i n i n serum i s approximately f o u r times as hig h as t h a t achieved by c e p h a l o t h l n , another f i r s t g e n e r a t i o n c e p h a l o s p o r i n (12). In a d d i t i o n , high blood l e v e l s p e r s i s t e d f o r g r e a t e r than 8 hours with c e f a z o l i n as compared t o about 2 hours f o r c e p h a l o t h l n (12,16). When compared t o a n t i b i o t i c s t h a t a re recommended t o be ad m i n i s t e r e d every s i x hours, c e f a z o l i n has a serum h a l f - l i f e a pproximately twice as long r e s u l t i n g i n more s u s t a i n e d blood l e v e l s (Table 1>. C e f a z o l i n a l s o p r o v i d e s c o m p a r a t i v e l y high peak blood l e v e l s . F i n a l l y , t h i s a n t i b i o t i c possesses e x c e l l e n t t i s s u e p e n e t r a t i o n i n c l u d i n g bone, p l e u r a l f l u i d and b i l e (11-19). The high serum p r o t e i n b i n d i n g o f t h i s 166 agent, does not s i g n i f i c a n t l y reduce e x t r a v a s c u l a r pene-t r a t i o n <19>. Table I . Comparative serum h a l f - l i v e s and dosage i n t e r v a l s of some formulary a n t i b i o t i c s * A n t i b i o t i c Serum Dosage H a l f - l i f e I n t e r v a l <hr) <hr) C l o x a c i l l i n 0.4-0.9 6 P e n i c i l l i n G 0.5-0.7 6 Cep h a l e x i n 0.5-1.0 6 C e f o x i t i n 0.7-1.0 6-8 Erythromycin 1.0-1.5 6 A m o x i c i l l i n 0.7-1.4 8 CEFAZOLIN 1.2-2.2 8 Gentamicin 1.5-2.5 8 • i n p a t i e n t s with normal r e n a l f u n c t i o n These pharmacokinetic p r o p e r t i e s permit c e f a z o l i n t o be ad m i n i s t e r e d l e s s f r e q u e n t l y a t i n t e r v a l s o f 8 hours or longer without l o s s o f c l i n i c a l e f f e c t i v e n e s s . 167 Dosage Recommendations Recommended c e f a z o l i n dosage recommendations have been p r o v i d e d by I n f e c t i o u s d i s e a s e s p e c i a l i s t s , drug companies and o t h e r s (7-11,18,20-22). Package i n s e r t s from the two manufacturers of t h i s product recommend t h a t the u s u a l dosage o f c e f a z o l i n f o r m i l d g r a m - p o s i t i v e i n f e c t i o n s i s 250mg t o 500mg every 8 hours. In acute uncomplicated u r i n a r y t r a c t i n f e c t i o n s , a dosage of 500mg every 8 hours, t o 1 gram every 12 hours i s recommended. Usual dosage f o r pneumococcal pneumonia i s 500mg every 12 hours and i n moderate t o severe i n f e c t i o n s , the u s u a l a d u l t dosage i s SOOmg t o 1 gram every 6 t o 8 hours (21,22). Recommendations are a l s o p r o v i d e d t o reduce the t o t a l d a i l y dosage i n the presence of r e n a l impairment. Although t h e r e i s g e n e r a l agreement with moat of these recommendations, other independent sources suggest t h a t dosing on a 6 h o u r l y b a s i s i s e x c e s s i v e and would recommend t h a t the a d m i n i s t r a t i o n of c e f a z o l i n every 8 t o 12 hours (or g r e a t e r depending upon r e n a l f u n c t i o n ) , e i t h e r im or i v , should be adequate c l i n i c a l l y (7-11,18,20). S e v e r a l other f a c t o r s must be c o n s i d e r e d when i n i t i a t i n g a c e f a z o l i n treatment c o u r s e . The nature and s e v e r i t y of the i n f e c t i o n must be e s t a b l i s h e d based upon the c h a r a c t e r i s t i c s of the p a t i e n t (age, presence of immunocomprimising d i s e a s e or t h e r a p y ) , the i n f e c t i o u s p rocess (extent and l o c a t i o n of i n f e c t i o n , n e c e s s i t y f o r s u r g i c a l drainage) and the 168 s u s c e p t i b i l i t y of the I n f e c t i n g o r g a n i s m ( s ) . Where r e n a l Impairment i a e v i d e n t , dosage r e d u c t i o n s o f c e f a z o l i n are recommended (20). I f l a r g e r t o t a l d a i l y dosages are d e s i r e d , t h i s can be accomplished by i n c r e a s i n g the s i z e of the i n d i v i d u a l dose w h i l e m a i n t a i n i n g a frequency of every 8 hours. Cost Savings Resources are s c a r c e . When the frequency of a d m i n i s t r a t i o n of c e f a z o l i n i s reduced, the h o s p i t a l r e a l i z e s c o s t s a v i n g s i n terms of drug product e x p e n d i t u r e s , IV equipment and p r e p a r a t i o n c o s t s , and expenses r e l a t e d t o i n f u s i o n set-up and m o n i t o r i n g . Less f r e q u e n t a d m i n i s t r a t i o n of the drug can a l s o be t h e o r e t i c a l l y expected t o improve p a t i e n t c a r e by f u r t h e r r e d u c i n g the r i s k of i n t r o d u c i n g i n f e c t i o n v i a in t r a v e n o u s s e t co n t a m i n a t i o n . T h i s would be accomplished by minimizing the number of drug r e c o n s t i t u t i o n s and mlnibag p r e p a r a t i o n s which are o f t e n undertaken i n n o n s t e r i l e environments by n u r s i n g p e r s o n n e l . Less f r e q u e n t a d m i n i s t r a t i o n of drug may a l s o reduce the i n c i d e n c e of adverse sequalae r e l a t e d t o e x c e s s i v e dosage p r e s c r i b i n g i n r e n a l f a i l u r e , p r o v i d e d t o t a l d a i l y dose i s reduced. 169 C. Development of the Drug Usage Review P r o t o c o l 1 . Study p o p u l a t i o n The study p o p u l a t i o n i n c l u d e d a l l acute c a r e p a t i e n t s admitted t o the t e s t h o s p i t a l s d u r i n g the p r o j e c t p e r i o d . The f i r s t treatment course per p a t i e n t admission f o r which c e f a z o l i n was p r e s c r i b e d and a d m i n i s t e r e d a t a s p e c i f i e d i n t e r v a l was e l i g i b l e f o r study i n c l u s i o n . A treatment course was d e f i n e d as a regimen of drug a d m i n i s t r a t i o n with no i n t e r v a l between c o n s e c u t i v e doses exceeding 24 hours. 2. C r i t e r i a f o r Drug Usage Review In order t o a p p r o p r i a t e l y p r e s c r i b e c e f a z o l i n , the i n i t i a l order f o r each treatment course had to s p e c i f y a dosage i n t e r v a l of e i g h t hours or l o n g e r . 3. Endorsement of C r i t e r i a C r i t e r i a f o r drug usage review were endorsed by the H o s p i t a l P r o j e c t Committee and an independent medical expert user p r i o r t o the study. 4. Sampling Procedure When atudy i n c l u s i o n requirements were met, treatment courses were randomly s e l e c t e d f o r sampling and data c o l l e c t i o n . T h i s was accomplished u s i n g random sampling procedures d e s c r i b e d In the r e p o r t methodology. 5. Information C o l l e c t e d I n formation was c o l l e c t e d f o r each treatment course i n c l u d i n g : 1. p a t i e n t number 2. admission date 3. age 4. sex 5. d u r a t i o n of atay 6. p r e s c r i p t i o n date 7. i n i t i a l dosage regimen p r e s c r i b e d (dose and frequency) 8. t o t a l doses a d m i n i s t e r e d d u r i n g treatment course a t s p e c i f i e d frequency 9. p r e s c r i b i n g p h y s i c i a n 171 References 1. Hendeles L . Need f o r " c o u n t e r - d e t a i l i n g " a n t i b i o t i c s . Am J Hosp Pharm 1976;33:918-924. 2 . Simmons HE, S t o l l e y PO. T h i s i s medical progress? Trends and consequences of a n t i b i o t i c use i n the United S t a t e s . JAMA 1974;227:1023-1028. 3. Kennedy DL, Forbes MB, Baum C, Jones JK. A n t i b i o t i c use i n U.S. h o s p i t a l s i n 1981. Am J Hosp Pharm 1983;40:797-801. 4. Kunin CM, Tupasi T, C r a i g WA. Use of a n t i b i o t i c s : a b r i e f e x p o s i t i o n of the problems and some t e n t a t i v e s o l u t i o n s . Ann I n t e r n Med 1973;79:555-560. 5. Sohn CA, Wolter HA, McSweeney GW. E f f e c t i v e n e s s of a c e p h a l o s p o r i n e d u c a t i o n program : a pharmacy educ a t i o n program. Drug I n t e l l C l i n Pharm 1980;14:272-277. 6. Jewesson PJ, Ho R, Jang Q, Watts G, Chow AW. A u d i t i n g a n t i b i o t i c use i n a t e a c h i n g h o s p i t a l : f o c u s on c e f o x i t i n . Can Med Assoc J 1983; 128:1075-1078. 7. Suzuki NT, Pelham LD. Cost b e n e f i t of pharmacist concurrent m o n i t o r i n g of c e f a z o l i n p r e s c r i b i n g . Am J Hosp Pharm 1983;40:1187-91. 8. Noel MW, Paxinos J . C e p h a l o s p o r i n s : Use review and c o s t a n a l y s i s . Am J Hosp Pharm 1978;35:933-935. 9. Katz E, Schlamowitz S. Savings achieved through c e p h a l o s p o r i n s u r v e i l l a n c e . Am J Hosp Pharm 1978;35:1521-1523. 10. Ma MY, G o l d s t e i n EJC, Meyer RD. E f f e c t o f c o n t r o l programs on c e f a z o l i n p r e s c r i b i n g i n a t e a c h i n g h o s p i t a l . Am J Hosp Pharm 1979;36:1055-1058. 11. N i g h t i n g a l e CH, Greene DS, Q u i n t i l i a n i R. Pharmacokinetics and c l i n i c a l use of c e p h a l o s p o r i n a n t i b i o t i c s . J Pharm S c i 1975;64:1899-1927. 12. K i r b y MM, Regamey C. Pharmacokinetics of c e f a z o l i n compared with f o u r o t h e r c e p h a l o s p o r i n s . J I n f e c t D is 1973;128 <Suppl>:S341-S346. 13. Gilman AG, Goodman LS, Gilman A. The pha r m a c o l o g i c a l b a s i s of t h e r a p e u t i c s . MacMillan P u b l i s h i n g Co. Inc.: New York,NY, 1980:1961-1963. 172 14. McEvoy GK (ed) . Drug i n f o r m a t i o n '84. American h o s p i t a l f o r m u l a r y s e r v i c e . American S o c i e t y of H o s p i t a l Pharmacists: Bethesda, MD, 1984. 15. Q u i n t i l i a n i R, N i g h t i n g a l e CH. C e f a z o l i n . Ann I n t e r n Med 1978;89:650-56. 16. R i e s K, L e v i s o n ME, Kaye D. C l i n i c a l and i n v i t r o e v a l u a t i o n of c e f a z o l i n , a new c e p h a l o s p o r i n a n t i b i o t i c . A n t imicrob Agents Chemother 1973;3:163-174. 17. M o e l l e r i n g RC J r , Swartz MN. Drug therapy: The newer c e p h a l o s p o r i n s . N Engl J Med 1976;294:24-28. 18. Wang RIH, Garthwaite SM. The c l i n i c a l pharmacology of a n t i b i o t i c s . P a r t IV. c e p h a l o s p o r i n s . Drug Ther 1976;6:103-106,111-113. 19. Pe t e r s o n LR, Gerding DN. I n f l u e n c e of p r o t e i n b i n d i n g of a n t i b i o t i c s on serum pharmacokinetics and e x t r a v a s c u l o r p e n e t r a t i o n : c l i n i c a l l y u s e f u l concepts. Rev I n f e c t Dis 1980;2:340-48. 20. Bennett WM, Aronoff GR, Morrison G, Golper TA, P u l l i a m J , Wolfson M, S i n g e r I. Drug p r e s c r i b i n g i n r e n a l f a i l u r e : d osing g u i d e l i n e s f o r a d u l t s . Am J Kidney Dis 1983;3:155-193. 21. Anon. Ancef^ (package i n s e r t ) . Smith, K l i n e and French Canada L t d . : Montreal, Quebec, (undated). 22. Anon. K e f z o l R (package i n s e r t ) . E l i L i l l y fi. Co.: I n d i a n a p o l i s , Ind., 1976. 173 Appendix XI. C i m e t i d i n e dosage In g e r i a t r i c p a t l e n t a <T-2) A. D e f i n i t i o n o f Problem C i m e t i d i n e I s r o u t i n e l y being p r e s c r i b e d f o r g e r i a t r i c p a t i e n t s i n s t a n d a r d t h e r a p e u t i c dosea . These i n d i v i d u a l s may r e q u i r e reduced doses o f c i m e t i d i n e due t o a d i m i n i s h e d drug c l e a r a n c e , s m a l l e r volume o f d i s t r i b u t i o n and other p h y s i o l o g i c a l f a c t o r s which l e a d t o i n c r e a s e d blood l e v e l s of the drug. A reduced d a i l y doae can h e l p minimize the o c c u r r e n c e o f some concentration-dependent adverse sequelae without comprimising t h e r a p e u t i c e f f e c t . B. Background C i m e t i d i n e (Tagamet^) i s a s p e c i f i c H 2 - r e c e p t o r a n t a g o n i s t . T h i s drug has been shown t o s p e c i f i c a l l y prevent g a s t r i c a c i d s e c r e t i o n f o l l o w i n g s t i m u l a t i o n with h i s t a m i n e , p e n t a g a s t r i n , c a f f e i n e and food (1,2). I t i s a weak base, h i g h l y w a t e r - s o l u b l e and t o t a l s ystemic c l e a r a n c e i s mainly determined by r e n a l c l e a r a n c e . Adverse r e a c t i o n r e p o r t s r e l a t e d t o c i m e t i d i n e d u r i n g i t s I n v e s t i g a t i o n a l and immediate post-marketing p e r i o d were minimal. However, subsequent r e p o r t s i n d i c a t e t h a t e l d e r l y p a t l e n t a , p a t i e n t s with comprimised r e n a l f u n c t i o n and p a t i e n t s with l i v e r impairment are s u s c e p t i b l e t o c i m e t i d i n e t o x i c i t i e s , e s p e c i a l l y c e n t r a l nervous system s i d e e f f e c t s i n c l u d i n g 174 mental c o n f u s i o n , h a l l u c i n a t i o n s , d i o r i e n t a t i o n and d e p r e s s i o n . These adverse e f f e c t s appear t o be d o s e - r e l a t e d , are seen when standard dosages are employed and are u s u a l l y r e v e r s i b l e upon r e d u c t i o n or d i s c o n t i n u a t i o n o f the drug ( 3 ) . Recent r e p o r t s on c i m e t i d i n e usage have suggested t h a t p a t i e n t s may be r e c e i v i n g an i n a p p r o p r i a t e l y high d a i l y dosage of c i m e t i d i n e a c c o r d i n g t o r e n a l f u n c t i o n . Many of the r e p o r t s on p o s s i b l e c o m p l i c a t i o n s of c i m e t i d i n e have i n v o l v e d the use of standard doses (4-8). H a l l and coworkers (9) found t h a t 84*< of a l l p a t i e n t s r e c e i v i n g c i m e t i d i n e s t a r t e d with the recommended dosage of 300mg f o u r times d a i l y . Subsequent dosage adjustments f o r a g e - r e l a t e d r e d u c t i o n i n r e n a l f u n c t i o n o c c u r r e d i n only 46*< of p a t i e n t s . C o n v e r s e l y , i n onl y 41* of dosage adjustments was t h e r e documentation or an i n d i c a t i o n of the reason f o r the change. An unpublished r e p o r t from S t . Paul' s H o s p i t a l (10) conf i r m s t h i s f i n d i n g with approximately 28?« of treatment courses a s s o c i a t e d with i n a p p r o p r i a t e regimens based upon r e n a l f u n c t i o n . Pharmacokinetic C o n s i d e r a t i o n s S e v e r a l pharmacokinetic and pharmacodynamic a l t e r a t i o n s are observed i n the e l d e r l y which reduce dosage requirements i n t h i s p o p u l a t i o n . The volume of d i s t r i b u t i o n of c i m e t i d i n e i s i n v e r s e l y c o r r e l a t e d t o age (11). T h i s can be explained 175 by the l o s s o f l e a n body mass a s s o c i a t e d with age s i n c e c i m e t i d i n e mainly d i s t r i b u t e s i n t o muscle t i s s u e with n e g l i g a b l e d i s t r i b u t i o n i n t o f a t . In a d d i t i o n , t o t a l plasma c l e a r a n c e o f c i m e t i d i n e i s a l s o h i g h l y a g e - c o r r e l a t e d , d e c r e a s i n g by h a l f between the ages of 30 and 65 years (12). T h i s i s almost e n t i r e l y due t o a r e d u c t i o n i n the r e n a l c l e a r a n c e o f the drug with advancing age. Although l e s s s i g n i f i c a n t , h e p a t i c d i s e a s e may a l s o depress t o t a l systemic c l e a r a n c e n e c e s s i t a t i n g a r e d u c t i o n i n dosage t o av o i d d o s e - r e l a t e d a i d e e f f e c t s . From these o b s e r v a t i o n s , i t can be i n f e r r e d t h a t c i m e t i d i n e blood c o n c e n t r a t i o n s w i l l be highe r i n the e l d e r l y p o p u l a t i o n than i n younger a d u l t s r e c e i v i n g the same d a i l y dose. T h e r e f o r e , on pharmacokinetic grounds, these i n d i v i d u a l s should r e c e i v e a lower dose than the younger p a t i e n t . In a d d i t i o n , o l d e r p a t i e n t s tend t o have reduced g a s t r i c a c i d p r o d u c t i o n which may decrease dosage requirements (13). Dosage Recommendations Dosage regimens have been proposed t o account f o r age and r e n a l impairment. R i t s c h e l and coworkers (14) recommend t h a t p a t i e n t s aged between 65 and 75 years o f age should r e c e i v e a c i m e t i d i n e d a i l y dosage of onl y 600mg, p a t i e n t s above 75 years 400mg, and p a t i e n t s above 85 years only 200mg d a i l y . Larsson and a s s o c i a t e s (15) a l s o suggest t h a t " i n most p a t i e n t s over 65 years of age should r e c e i v e a dosage 176 r e d u c t i o n , even I f apparent serum c r e a t i n i n e i s normal". P a t i e n t s with d e c l i n i n g r e n a l f u n c t i o n should r e c e i v e doses based upon c r e a t i n i n e c l e a r a n c e ( C c r ) . C l e a r a n c e s o f 15 - 35 nl/min r e q u i r e a dosage o f 200mg BID, 15 - 30 ml/min r e q u i r e 200mg TID and 30-75 ml/min r e q u i r e a dosage of 200mg QID (15). These dosage adjustments are s i m i l a r t o those proposed by two oth e r s t u d i e s (16,17). Luk (16) proposes a dosage regimen of 300mg Q6H i n p a t i e n t s with Ccr of g r e a t e r than 40ml/min, 300mg QSH with Ccr of 20 - 40ml/min and 300mg Q12H i n p a t i e n t s with Ccr of l e s s than 20ml/min. In p a t i e n t s with " s e v e r l y impaired r e n a l f u n c t i o n " , the manufacturer recommends a c i m e t i d i n e dosage of 300mg every 12 hours on l y (10). No s p e c i f i c d e f i n i t i o n o f " s e v e r l y i m p a i r e d " i a pro v i d e d however. The p o t e n t i a l b e n e f i t s of redu c i n g the d a i l y dosage of c i m e t i d i n e are s e v e r a l . P a t i e n t c a r e may be improved by re d u c i n g the p o t e n t i a l f o r d o s e - r e l a t e d adverse e f f e c t s , and a r e d u c t i o n o f h o s p i t a l c o s t s r e l a t e d t o unnecessary drug e x p e n d i t u r e s and n u r s i n g time devoted t o drug a d m i n i s t r a t i o n i s f e a s i b l e . C. Development of the Drug Usage Review P r o t o c o l 1. Study p o p u l a t i o n The study p o p u l a t i o n i n c l u d e d a l l acute care p a t i e n t s aged 60 years o r o l d e r admitted t o the t e a t h o s p i t a l s d u r i n g the p r o j e c t p e r i o d . The f i r s t treatment course per p a t i e n t admission f o r which c i m e t i d i n e was p r e s c r i b e d and ad m i n i s t e r e d was e l i g i b l e f o r study i n c l u s i o n . A treatment course was d e f i n e d as a regimen o f drug a d m i n i s t r a t i o n with no i n t e r v a l between c o n s e c u t i v e doaes exceeding 24 hours. S e l e c t i o n t o exclude those p a t i e n t s r e c e i v i n g i n i t i a l p r o p h y l a c t i c c i m e t i d i n e treatment courses was undertaken. P r o p h y l a x i s was d e f i n e d as d a i l y doses o f 400 mg or l e s s a t bedtime or p r e - o p e r a t i v e l y . A l s o excluded were p a t i e n t s f o r whom no weight was r e p o r t e d i n the h e a l t h r e c o r d ( c u r r e n t or p r i o r admission) and p a t i e n t s f o r whom l a b o r a t o r y t e s t s t o a s s e s s r e n a l f u n c t i o n (blood urea n i t r o g e n (BUN) and serum c r e a t i n i n e (SCr)) were ordered by the p h y s i c i a n d u r i n g the c u r r e n t admission but were not r e p o r t e d i n the h e a l t h r e c o r d . 2. C r i t e r i a f o r Drug Usage Review In order t o a p p r o p r i a t e l y p r e s c r i b e c i m e t i d i n e , the f o l l o w i n g f o l l o w i n g process had t o be f o l l o w e d : 2.1 Estimate r e n a l f u n c t i o n . A BUN determin-178 a t i o n had t o be o b t a i n e d f o r each p a t i e n t admiaaion. 2.2 I f the r e p o r t e d BUN was l e s s than or e q u i v a l e n t t o 20mg/100ml, a standar d d a l l y dose of 1200mg of c i m e t i d i n e was c o n s i d e r e d a p p r o p r i a t e . I f the r e p o r t e d BUN exceeded 20 mg/lOOml, an e v a l u a t i o n of serum c r e a t i n i n e CSCr) had to be obtained d u r i n g t h a t p a t i e n t admission t o b e t t e r e stimate r e n a l f u n c t i o n . 2.3 Based upon the r e p o r t e d SCr, a reduced d a i l y dose of 900 mg d a i l y or l e s s was r e q u i r e d i f the f o l l o w i n g c o n d i t i o n s are met* : Weight (kg) Age <yr) 6 0 - 7 5 > 76 <= 60 SCr>1.2 SCr>0.9 > 60 SCr>1.6 SCr>1.3 * these g u i d e l i n e s were developed u s i n g the C o c k c r o f t - G a u l t equation <19) to estimate c r i t i c a l serum c r e a t i n i n e values f o r c r e a t i n i n e c l e a r a n c e s o f approximately 40 ml/minute. I f serum c r e a t i n i n e i s l e s s than c r i t i c a l v a l u e s shown, a standard d a i l y dose of 1200mg of c i m e t i d i n e was c o n s i d e r e d a p p r o p r i a t e . A l l assessments Involved the f i n a l dose of c i m e t i d i n e r e c e i v e d while i n h o s p i t a l . When the f i n a l d a i l y dosage equaled 400 mg or l e s s , p r o p h y l a x i s was assumed and the treatment course was deemed a p p r o p r i a t e . Endorsement of C r i t e r i a C r i t e r i a f o r drug usage review were endorsed by the H o s p i t a l P r o j e c t Committee and an independent medical expert user p r i o r t o the study. Sampling Procedure When study i n c l u s i o n requirements were met, data was c o l l e c t e d f o r a l l treatment courses i d e n t i f i e d . I n f o r m a t i o n C o l l e c t e d Information was c o l l e c t e d f o r each treatment course i n c l u d i n g : 1. p a t i e n t number 2. admission date 3. age 4. sex 5. weight 6. d u r a t i o n of s t a y 7. p r e s c r i p t i o n date fi. i n i t i a l dosage regimen (dose/frequency) 9. f i n a l dosage regimen (dose/frequency) 10. therapy s t a t u s d u r i n g s t a y (continued/stopped> 11. i n i t i a l BUN (value r e p o r t e d p r i o r t o i n i t i a l p r e s c r i p t i o n date or f i r s t value r e p o r t e d a f t e r t h i s date i f u n a v a i l a b l e ) 12. i n i t i a l SCr (value r e p o r t e d p r i o r t o i n i t i a l p r e s c r i p t i o n date or f i r s t v a l u e r e p o r t e d a f t e r t h i s date i f u n a v a i l a b l e ) 13. f i n a l BUN ( l a s t v a l u e r e p o r t e d w h i l e a c t i v e ) 14. f i n a l SCr ( l a s t v alue r e p o r t e d while a c t i v e ) l a i R eferences 1. Henn RM, Isenberg J I , Maxwell V e t a l . I n h i b i t i o n o f g a s t r i c a c i d s e c r e t i o n u l c e r . N Engl J Med 1975;298:3715. 2. Burland WL, Duncan WAM, H e l l e l b o T e t a l . Pharmacologic e v a l u a t i o n o f c i m e t i d i n e . A new his t a m i n e H2-receptor a n t a g o n i s t i n h e a l t h l y man. Br J Pharmacol 1975;2:481-6. 3. Sawyer D, Conner CS, S c a l l e y R. C i m e t i d i n e : Adverse r e a c t i o n s and acute t o x i c i t y . Am J Hosp Pharm 1981;38:188-97. 4. McMillen MA, Ambis D, S i e g e l JH. C i m e t i d i n e and mental c o n f u s i o n . N Engl J Med 1978;298:284-285. 5. Agarwal SK. C i m e t i d i n e and v i s u a l h a l l u c i n a t i o n s . JAMA 1978;240:214. 6. Vickey TR. C i m e t i d i n e r e a c t i o n . Drug I n t e l l C l i n Pharm 1978;12:242. 7. M o g e l n i c k i SR, Wall J L , F i n l a y s o n DC. Physostigmine r e v e r s a l o f c i m e t i d i n e - i n d u c e d mental c o n f u s i o n . JAMA 1979;241:826. 8. Schentag J J , C a l l e r i G, Rose JQ, Cerr a FB, DeGlopper E, Bernhard H. Pharmacokinetic and c l i n i c a l s t u d i e s i n p a t i e n t s with c i m e t i d i n e - a s s o c i a t e d mental c o n f u s i o n . Lancet 1979;1:177-181. 9. H a l l KW, Behun M, Irvine-Meek J , Otten N. Use of c i m e t i d i n e i n h o s p i t a l p a t i e n t s . Can Med Assoc J 1981;124:1579-1585. 10. B e a r d s e l l A. Intravenous c i m e t i d i n e : assessment of i n i t i a l dosage regimens. ( H o s p i t a l Pharmacy Residency P r o j e c t ) S t . Paul's H o s p i t a l : Vancouver,1983. 11. R e d o l f i A, B o r g o g e l l i E, Lodola E. Blood l e v e l o f c i m e t i d i n e i n r e l a t i o n t o age. Eur J C l i n Pharmacol 1979;15:257-261. 12. Somogyi A, Gugler R. C l i n i c a l pharmacokinetics o f c i m e t i d i n e . C l i n Pharmacokin 1983;8:463-495. 13. Bender AD. E f f e c t of age on i n t e s t i n a l a b s o r p t i o n : i m p l i c a t i o n s f o r drug a b s o r p t i o n i n the e l d e r l y . J Am G e r i a t r Soc 1968;16:1331-1339. 14. R i t s c h e l WA. C i m e t i d i n e dosage regimen f o r p a t i e n t s with r e n a l f a i l u r e and g e r i a t r i c p a t i e n t s . Eur J C l i n Pharmacol 1982;23:501-4. 182 15. Larsaon R, Norlander B, Bodemar G, Walan A. Stea d y - s t a t e k i n e t i c s and dosage requirements of c i m e t i d i n e i n r e n a l f a i l u r e . C l i n Pharmacokinet 1981;6:316-25. 16. Luk GD, Luk WJ, Hendrix TR. C i m e t i d i n e and impaired r e n a l f u n c t i o n . Ann I n t e r n Med 1979;90:991-2. 17. B j a e l d a g e r PAL, Jensen JB, Laraen NE, Hvldberg EF. E l i m i n a t i o n o f o r a l c i m e t i d i n e i n c h r o n i c r e n a l f a i l u r e and d u r i n g h e m o d i a l y s i s . Br J C l i n Pharmacol 1980;9:585-92. 18. Anon. Tagamet" (package i n s e r t ) . Smith, K l i n e and French Canada L t d . : Quebec, 1984. 19. C o c k c r o f t DW, G a u l t MH. P r e d i c t i o n of c r e a t i n i n e c l e a r a n c e from serum c r e a t i n i n e . Nephon 1976;16:31-41. 183 Appendix X I I . Gentamicin i n i t i a l e m p i r i c dosage <T-3> A. D e f i n i t i o n o f Problem I n i t i a l a minoglycosides dosages are r o u t i n e l y p r e s c r i b e d f o r a d u l t and p e d i a t r i c p a t i e n t s without r e f e r e n c e t o body weight. P a t i e n t s should r e c e i v e aminoglycosides i n dosages which account f o r both t h e i r age group and d i f f e r e n c e s i n body weight t o ensure t h e r a p e u t i c serum l e v e l s o f the drugs are a c h i e v e d . B. Background The e f f e c t i v e n e s s o f aminoglycosides i s a s s o c i a t e d with serum c o n c e n t r a t i o n s a t t a i n e d d u r i n g therapy <l-4). Higher p a t i e n t response r a t e s are achieved when t h e r a p e u t i c peak serum c o n c e n t r a t i o n s are obt a i n e d e a r l y i n therapy ( 1 ) . S u c c e s s f u l therapy has a l s o been a s s o c i a t e d with maintenance of adequate trough c o n c e n t r a t i o n s ( 2 ) . I n i t i a t i n g a gentamicin treatment course with a standard 60mg t o 80mg dose i s l i k e l y t o r e s u l t i n underdosing i n many a d u l t p a t i e n t s . Recommended t h e r a p e u t i c serum c o n c e n t r a t i o n s f o r the treatment or p r e v e n t i o n of v a r i o u s i n f e c t i o n s a re shown i n Table 1. 184 Table I. T h e r a p e u t i c peak serum gentamicin l e v e l s and dosages i n a d u l t s * I n d i c a t i o n Peak Serum Dosage Drug L e v e l Per I n t e r v a l (ug/ml) (mg/kg) u r i n a r y n/a 1.0 t r a c t i n f e c t i o n s y s t e m i c 5-7 1.5 i n f e c t i o n pneumonia 7-9 2.0 and burn s e p s i s Dosing Recommendations Package i n s e r t s f o r gentamicin and tobramycin recommend an i n i t i a l dose of 1 mg/kg of body weight repeated every 8 hours i n a d u l t p a t i e n t s with normal r e n a l f u n c t i o n (6,7). I t has been demonstrated, however, t h a t i n i t i a l doses of t h i s magnitude w i l l f r e q u e n t l y produce peak serum c o n c e n t r a t i o n s of l e s s than 4 mcg/ml ( 8 ) . Other s t u d i e s support t h i s f i n d i n g (9-12). Noone and a s s o c i a t e s (1) demonstrated t h a t 185 t h e r a p e u t i c serum l e v e l a of gentamicin i n s e p t i c p a t i e n t s c o u l d o n l y be achieved by s t a r t i n g with a regimen of 5mg/kg/day i n t h r e e d i v i d e d doses. Zaske (9) r e p o r t e d t h a t 38* of p a t i e n t s with normal serum c r e a t i n i n e r e q u i r e d d a i l y dosages h i g h e r than the recommended regimen of 3 t o 5mg/kg to a c h i e v e t h e r a p e u t i c serum l e v e l s and o n l y 20* of these p a t i e n t s r e q u i r e d dosages of l e s s than 3mg/kg. A r e c e n t r e p o r t by Summer and coworkers (10) showed t h a t 59* of c r i t i c a l l y i l l p a t i e n t s had i n i t i a l blood aminoglycoside c o n c e n t r a t i o n s below the recommended peak l e v e l of 5 ug/ml, when given r e l a t i v e l y l a r g e IV doses of 2mg/kg body weight. Zaske (11) a l s o r e p o r t e d wide i n t e r p a t i e n t v a r i a t i o n s i n 249 gynecology p a t i e n t s r e q u i r i n g dosage regimens ra n g i n g from 1.9 t o 14.0 mg/kg/day t o a c hieve t h e r a p e u t i c a l l y e f f e c t i v e serum l e v e l s . F i n a l l y , a study by C i p o l l e and co-workers (12) showed t h a t dosages of tobramycin r e q u i r e d t o o b t a i n t h e r a p e u t i c serum c o n c e n t r a t i o n s f o r the treatment of pneumonia were high e r than those estimated by c o n v e n t i o n a l methods. Numerous nomograms and methods have been de v i s e d to a i d i n the adjustment of dosage a c c o r d i n g t o r e n a l f u n c t i o n . These a i d s may decrease the p o t e n t i a l r i s k of t o x i c i t y a s s o c i a t e d with e x c e s s i v e aminoglycoside but may a l s o l e a d to underdosing i n some p a t i e n t s (13). Most a u t h o r i t i e s agree t h a t the use of any p r e d i c t i v e dosage methods should be f o l l o w e d with serum c o n c e n t r a t i o n d e t e r m i n a t i o n s and dosage 186 adjustment, t o ensure t h e r a p e u t i c c o n c e n t r a t i o n s e a r l y i n therapy. S i n c e many methods are i m p r a c t i c a l f o r c l i n i c a l use, a simple dosage c a l c u l a t i o n based upon age group and body weight f o l l o w e d by serum l e v e l s r e p r e s e n t s the s i m p l e s t and most e f f e c t i v e method of a p p r o p r i a t e l y dosing a m i n o g l y c o s i d e s . Such a system would f a c i l i t a t e the need t o ach i e v e adequate e a r l y aminoglycoaide l e v e l s p a r t i c u l a r l y i n p a t i e n t s with s e r i o u s i n f e c t i o n s . To t h i s end, an i n i t i a l dose of 1.7mg/kg of gentamicin/tobramycin t o be used i n a d u l t s u n t i l i n d i v i d u a l i z e d dosage recommendations are a v a i l a b l e has been recommended by s e v e r a l authors t o achieve d e a i r e d peak c o n c e n t r a t i o n s of 6 to 10 ug/ml (1,14-16). Other a u t h o r i t i e s recommend an aminoglycoside dose of 1.5mg/kg every 8 hours f o r p a t i e n t s > 10 yea r s , 2.0mg/kg every 8 hours f o r p a t i e n t s 5 years - 10 yea r s , 2.5mg/kg every 8 hours f o r p a t i e n t s 1 week - 5 years and 2.5mg/kg every 12 hours f o r p a t i e n t s l e s s than one week of age ( f u l l term)(17-21). C. Development of the Drug Usage Review P r o t o c o l 1. Study p o p u l a t i o n The study p o p u l a t i o n i n c l u d e d a l l acute care p a t i e n t s admitted t o the t e s t h o s p i t a l s d u r i n g the p r o j e c t p e r i o d . The f i r s t treatment course per p a t i e n t admission f o r which gentamicin was p r e s c r i b e d and a d m i n i s t e r e d was e l i g i b l e f o r study i n c l u s i o n . A treatment course was d e f i n e d as a regimen of drug a d m i n i s t r a t i o n w i t h no i n t e r v a l between c o n s e c u t i v e doses exceeding 24 hours. S e l e c t i o n t o exclude those p a t i e n t s r e c e i v i n g g entamicin f o r uncomplicated lower u r i n a r y t r a c t i n f e c t i o n s was undertaken. A l s o excluded were p a t i e n t s f o r whom a reco r d e d weight or h e i g h t was u n a v a i l a b l e ( c u r r e n t admission or p r i o r a d m i s s i o n ) . C r i t e r i a f o r Drug Usage Review In order t o a p p r o p r i a t e l y p r e s c r i b e gentamicin, the f o l l o w i n g process had t o be f o l l o w e d : 2.1 The i n i t i a l dosage of gentamicin was based upon age group and a c t u a l body weight a c c o r d i n g t o the g u i d e l i n e s : Age group Dosage* (yr) (mg/kg/dose) A d u l t s and 1.5 (1.3-1.7) >10 yr o l d 5-10 yr 2.0 (1.75-2.25) 1 week- 2.5 (2.25-2.75) 5 yr < 1 week 2.5 (2.25-2.75) •a c c e p t a b l e d e v i a t i o n (15*) from c r i t e r i a i s shown i n b r a c k e t s Endorsement o f C r i t e r i a C r i t e r i a f o r drug usage review were endorsed by the H o s p i t a l P r o j e c t Committee and an Independent medical expert uaer p r i o r t o the atudy. Sampling Procedure When atudy i n c l u s i o n requirements were met, data was c o l l e c t e d f o r a l l treatment courses i d e n t i f i e d . I nformation C o l l e c t e d Information was c o l l e c t e d f o r each treatment course i n c l u d i n g : 1. p a t i e n t number 2. admission date 3. age 4. sex 5. t o t a l body weight 6. h e i g h t ' 7. d u r a t i o n of s t a y 8. p r e s c r i p t i o n date 9. i n i t i a l maintenance dosage regimen 10. serum l e v e l s drawn ( i n i t i a l regimen) 189 11. t o t a l doaea g i v e n ( I n i t i a l regimen) 12. p r e s c r i b i n g p h y s i c i a n 190 References 1. Noone P, Parsons TMC, P a t t i s o n JR, Slack RCB, G a r f i e l d - D a v i e s D. E x p e r i e n c e i n m o n i t o r i n g gentamicin therapy during treatment of s e r i o u s gram-negative s e p s i s . Br Med J 1974;11477-481. 2. Anderson ET, Young LS, Hewitt WL. Simultaneous a n t i b i o t i c l e v e l s i n "breakthrough" gram-negative rod b a c t e r i a . Am J Med 1976;611493-497. 3. Zaake DE, Bootman JL, Solem LB, e t a l . Increased burn p a t i e n t s u r v i v a l with i n d i v i d u a l i z e d dosages of g e n t a m i c i n . Surgery 1982;91:142-149. 4. Moore RD, Smith CR, Lietman PS. The a s s o c i a t i o n of aminoglycoside plasma l e v e l s with m o r t a l i t y i n p a t i e n t s with gram - n e g a t i v e bacteremia. J I n f e c t D i s 1984;149:443-445. 5. C i p o l l e RJ, S e l f e r t RD, Zaske DE, e t a l . H o s p i t a l a c q u i r e d gram-negative pneumonias : response r a t e and dosage requirements with i n d i v i d u a l i z e d tobramycin therapy. Ther Drug Monitor 1980;2:359-363. 6. E l i L i l l y Canada Inc. Nebcin** (package i n s e r t ) . E l i L i l l y Canada Inc.: O n t a r i o , 1982. 7. S c h e r i n g Canada Inc. Garamycin (package i n s e r t ) . S c h e r i n q Canada Inc.: Quebec, (undated). 8. Dahlgren JG, Anderson ET, Hewitt WL. Gentamicin blood l e v e l s : a guide to n e p h r o t o x i c i t y . A n timicrob Agents Chemother 1975;8:58-62. 9. Zaske DE, C i p o l l e RJ, R o t s c h a f e r JC, Solem LD, Mosier NR, S t r a t e RG. Gentamicin pharmacokinetics i n 1,640 p a t i e n t s : method f o r c o n t r o l of serum c o n c e n t r a t i o n s . Antimicrob Agents Chemother 1982;21:407-411. 10. Summer WR, Michael JR, L i p s k y J J . I n i t i a l aminoglycoside l e v e l s i n the c r i t i c a l l y i l l . C r i t Care Med 1983;11:948-950. 11. Zaske DE, C i p o l l e RJ, S t r a t e RG, Dickes WF. Increased gentamicin dosage requirements : r a p i d e l i m i n a t i o n i n 249 gynecology p a t i e n t s . Am J Obstet Gynecol 1981;139:896. 12. C i p o l l e RJ, S e l f e r t RD, Zaske DE, e t a l . H o s p i t a l acquired gram-negative pneumonias : response r a t e and dosage requirements with i n d i v i d u a l i z e d tobramycin therapy. Ther Drug Monitor 1980;2:359-363. 191 13. Leaar TS, Rotachafer JC, Strand LM, Solem LD, Zaske DE. Gentamicin d o s i n g e r r o r s with f o u r commonly used nomograms. JAMA 1982;248:1190-93. 14. Moore RA, Tonnies FE. Aminoglycoside d o s i n g s e r v i c e provided by b a c c a l a u r e a t e - l e v e l pharmacists. Am J Hosp Pharm 1984;41:98-105. 15. Barza M, S c h e i f e RT. Drug therapy reviews : a n t i m i c r o b i a l spectrum, pharmacology and t h e r a p e u t i c use of a n t i b i o t i c s P a r t 4 : a m i n o g l y c o s i d e s . Am J Hosp Pharm 1977;34:723-737. 16. S i b e r GR, e t a l . Pharmacokinetics of gentamicin i n c h i l d r e n and a d u l t s . J I n f e c t D i s 1975;132:637-651. 17. Ackerman BH, B a i l i e GR, Zaske DE. Aminoglycoside therapy. Improving p a t i e n t response and s a f e t y . Postgrad Med 1984;75:177-185. 18. McCracken GH, e t a l . Pharmacologic e v a l u a t i o n o f gentamicin i n newborn i n f a n t s . J I n f e c t D i s 1971;124S:S214-S223. 19. E c h e v e r r i a P, e t a l . Age-dependent dose response t o gentamicin. J P e d i a t r i c s 1975;87:805-808. 20. Kaplan JM, e t a l . C l i n i c a l pharmacology of tobramycin i n newborns. Am J Dis C h i l d 1978;125:656-660. 21. Zenk KE, Miwa L, Cohen JL, Waffarn F, Huxtable RF. E f f e c t of body weight on gentamicin pharmacokinetics i n neonates. C l i n Pharm 1984;3:170-3. 192 Appendix X I I I . T h e o p h y l l i n e serum l e v e l m o n i t o r i n g <T-4> A. D e f i n i t i o n o f Problem T h e o p h y l l i n e i s r o u t i n e l y being p r e s c r i b e d without the accompaniment of serum l e v e l s t o a i d i n mo n i t o r i n g therapy. Serum t h e o p h y l l i n e l e v e l s should be undertaken f o r a l l p a t i e n t s with acute r e s p i r a t o r y problems t o o p t i m i z e therapy and a s s i s t i n the avoidance of d o s e - r e l a t e d adverse sequalae. B. Background In 1982, t h e o p h y l l i n e was the t w e l f t h most common drug p r e s c r i b e d i n the United S t a t e s <1>. T h e o p h y l l i n e i s a l s o one of the most common causes of i a t r o g e n i c c o m p l i c a t i o n s i n the h o s p i t a l s e t t i n g ( 2 ) . F o r t u n a t e l y , the r o u t i n e a v a i l a b i l i t y of serum t h e o p h y l l i n e c o n c e n t r a t i o n s has made s a f e t h e o p h y l l i n e use a r e a l i t y . T h e o p h y l l i n e i s a p o t e n t i a l l y t o x i c drug, e s p e c i a l l y when giv e n p a r e n t e r a l l y . B e n e f i t and r i s k have been demonstrated t o be r e l a t e d d i r e c t l y t o serum t h e o p h y l l i n e c o n c e n t r a t i o n s <2-4>. 193 Serum T h e o p h y l l i n e Response C o n c e n t r a t i o n s <ug/ml> 5-10 l e s s than optimal 10-20 optimal 20-35 g e n e r a l l y minor adverse e f f e c t s > 35 p o t e n t i a l f o r c a r d i a c arrhythmias s e i z u r e s & death There i s no one dosage f o r maintenance therapy of t h e o p h y l l i n e t h a t can be recommended f o r a l l p a t i e n t s . T h i s i s due t o the wide v a r i a b i l i t y i n t h e o p h y l l i n e pharmacokinetics (2-5). Dosage g u i d e l i n e s based upon body weight should be c o n s i d e r e d approximations on l y as the wide i n t e r - and i n t r a - i n d i v i d u a l v a r i a t i o n i n t h e o p h y l l i n e c l e a r a n c e makes t h e i r i n d i a c r i m i n a n t a p p l i c a t i o n hazardous (4,6-9). Many f a c t o r s a l t e r dosing requirements to achieve t h e r a p e u t i c l e v e l s of t h e o p h y l l i n e i n c l u d i n g age, smoking, c a r d i a c or h e p a t i c d i s e a s e and concurrent a d m i n i s t r a t i o n of drugs i n c l u d i n g c i m e t i d i n e and e rythromycin. Serum t h e o p h y l l i n e l e v e l s are t h e r e f o r e e s s e n t i a l f o r the optimal acute and c h r o n i c management of b r o n c h o s p a s t i c d i s o r d e r s i n both the a d u l t and p e d i a t r i c p o p u l a t i o n s . Serum t h e o p h y l l i n e l e v e l s are p a r t i c u l a r l y important i n p a t i e n t s r e c e i v i n g p a r e n t e r a l a m i n o p h y l l i n e therapy because 194 of the p o t e n t i a l f o r dramatic changes i n serum l e v e l s and f r e q u e n t dosage adjustments a s s o c i a t e d with t h i s form of treatment. Furthermore, p a t i e n t s r e c e i v i n g intravenous therapy a r e u s u a l l y a c u t e l y 111 end m e t a b o l i c r a t e s may change r a p i d l y i n t h i s p o p u l a t i o n . C. Development of the Drug Usage Review P r o t o c o l 1. Study p o p u l a t i o n The study p o p u l a t i o n i n c l u d e d a l l acute care p a t i e n t s d i s c h a r g e d from the t e s t h o s p i t a l s d u r i n g the p r o j e c t p e r i o d . The f i r s t treatment course per p a t i e n t admission f o r which t h e o p h y l l i n e was p r e s c r i b e d and a d m i n i s t e r e d was e l i g i b l e f o r study i n c l u s i o n . A treatment course was d e f i n e d as a regimen of drug a d m i n i s t r a t i o n with no i n t e r v a l between c o n s e c u t i v e doses exceeding 24 hours. P a t i e n t s admitted f o r non-bronchospastic complaints who c o n t i n u e d pre-admission use of o r a l (or i n t r a v e n o u s i f t e m p o r a r i l y o r a l l y i n t o l e r a n t ) t h e o p h y l l i n e d u r i n g h o s p i t a l i z a t i o n without documented i n h o s p i t a l evidence of bronchospasm were excluded. In a d d i t i o n , p a t i e n t s who r e c e i v e d l e s s than 48 hours of t h e o p h y l l i n e therapy while i n h o s p i t a l were excluded. 195 2. C r i t e r i a f o r Drug Usage Review To a p p r o p r i a t e l y p r e s c r i b e t h e o p h y l l i n e , each treatment course had t o be a s s o c i a t e d with a p h y s i c i a n r e q uest f o r a serum t h e o p h y l l i n e c o n c e n t r a t i o n . T h i s serum l e v e l was t o be drawn d u r i n g t h e o p h y l l i n e therapy. Where serum t h e o p h y l l i n e l e v e l s were requested but no r e s u l t s were r e p o r t e d i n the h e a l t h r e c o r d , the treatment course was s t i l l c o n s i d e r e d a c c e p t a b l e . 3. Endorsement of C r i t e r i a C r i t e r i a f o r drug usage review were endorsed by the H o s p i t a l P r o j e c t Committee and an independent medical expert user p r i o r t o the study. 4. Sampling Procedure When study i n c l u s i o n requirements were met, data was c o l l e c t e d f o r a l l treatment courses i d e n t i f i e d . I n f o r m a t i o n C o l l e c t e d Information was c o l l e c t e d f o r each treatment course i n c l u d i n g : 1. p a t i e n t number 2. admission date 3. age 4. sex 5. weight 6. d u r a t i o n of stay 7. i n i t i a l maintenance dosage p r e s c r i b e d and r e c e i v e d 8. d u r a t i o n of i n t r a v e n o u s t h e o p h y l l i n e therapy 8. d u r a t i o n of o r a l t h e o p h y l l i n e therapy 10. i n i t i a l serum l e v e l r e p o r t e d d u r i n g i n t r a v e n o u s therapy 11. i n i t i a l serum l e v e l r e p o r t e d d u r i n g o r a l therapy 197 References 1 . Baujn C, Kennedy DL, Forbes MB, Jones JK. Drug use and ex p e n d i t u r e s i n 1982. JAMA 1985;253:382-386. 2. O g i l v i e RI. C l i n i c a l p harmacokinetics of t h e o p h y l l i n e . C l i n Pharmacokinet 1978;3:267-293. 3. Hendelea L. Weinberger M, Johnson G. M o n i t o r i n g serum t h e o p h y l l i n e l e v e l s . C l i n Pharmacokinet 1978;3:294-312. 4. Jusko WJ, Gardner MJ, Mangione A, e t a l . F a c t o r s a f f e c t i n g t h e o p h y l l i n e c l e a r a n c e s : age, tobacco, marijuana, c i r r h o s i s , c o n g e s t i v e h e a r t f a i l u r e , o b e s i t y , o r a l c o n t r a c e p t i v e s , b enzodiazepines, b a r b i t u r a t e s and e t h a n o l . J Pharm S c i 1979;68:1358-1366. 5. Van D e l l e n RG. T h e o p h y l l i n e . P r a c t i c a l a p p l i c a t i o n o f new knowledge. Mayo C l i n Proc 1979;54:733-745. 6. Jackson J E , Powell JR, Wandell M, e t a l . C i m e t i d i n e decreases t h e o p h y l l i n e c l e a r a n c e . Am Rev R e s p i r D i s 1981;123:615-617. 7. S t a i b AH, Schuppan D, L i s s n e r R, e t a l . Pharmacokinetics and metabolism of t h e o p h y l l i n e i n p a t i e n t s with l i v e r d i s e a s e s . Int J C l i n Pharmacol, Ther and Tox 1980;18:500-502. 8. Zarowitz BJM, S z e f l e r SJ, Lasezkay GM. E f f e c t o f erythromycin base on t h e o p h y l l i n e k i n e t i c s . C l i n Pharmacol Ther 1981;29:601-605. 9. Vicuna N, McNay JL, Ludden TM, e t a l . Impaired t h e o p h y l l i n e c l e a r a n c e i n p a t i e n t s with cor pulmonale. Br J C l i n Pharmacol 1979;7:33-37. 198 Appendix XIV. Systemic a n t i m i c r o b i a l p r o p h y l a x i s i n surgery (T-5) A. D e f i n i t i o n o f Problem Systemic p r o p h y l a c t i c a n t i m i c r o b i a l s a re being r o u t i n e l y i n i t i a t e d a f t e r s u r g i c a l wound c l o s u r e . A n t i m i c r o b i a l p r o p h y l a x i s should be commenced immediately p r i o r t o i n i t i a t i o n o f a s u r g i c a l procedure t o ensure optimal a n t i b a c t e r i a l a c t i v i t y a t the time o f p o t e n t i a l b a c t e r i a l c o n t a m i n a t i o n . B. Background A n t i m i c r o b i a l p r o p h y l a x i s r e f e r s t o the a d m i n i s t r a t i o n of these agents t o p a t i e n t s without evidence of e s t a b l i s h e d i n f e c t i o n . The o b j e c t i v e of s u r g i c a l p r o p h y l a x i s i s t o reduce subsequent p o s t - o p e r a t i v e i n f e c t i o u s c o m p l i c a t i o n s . A s o l i d base of both experimental and c l i n i c a l evidence e x i s t s t o show t h a t systemic a n t i b i o t i c s given p r e - o p e r a t i v e l y s i g n i f i c a n t l y decrease the i n c i d e n c e of wound i n f e c t i o n s i n c e r t a i n s u r g i c a l procedures (1-4). T h i s has allowed f o r the d e f i n i t i o n of c r i t e r i a and p r i n c i p l e s g u i d i n g an e f f e c t i v e use of a n t i m i c r o b i a l s i n v a r i o u s s u r g i c a l procedures (5-14). P r o p h y l a x i s i s only recommended i n p a t i e n t s a t high r i s k o f s u r g i c a l i n f e c t i o n or i f consequences of p o s t - o p e r a t i v e 199 I n f e c t i o n a re l i f e - t h r e a t e n i n g and where r i s k s a s s o c i a t e d w i t h the use of such drugs i s a c c e p t a b l e t o both the p a t i e n t and the h o s p i t a l environment (&>. S u c c e s s f u l use of p r o p h y l a c t i c a n t i m i c r o b i a l s i a dependent upon s e v e r a l f a c t o r s . A n t i m i c r o b i a l s should be ad m i n i s t e r e d p a r e n t e r a l l y or v i a oth e r r o u t e s demonstrated t o be e f f e c t i v e and i n s u f f i c i e n t dosages t o i n h i b i t the l i k e l y pathogens a s s o c i a t e d with the s u r g i c a l procedure <9>. P a r e n t e r a l a n t i m i c r o b i a l s should be i n i t i a t e d w i t h i n one hour of the commencement of the procedure. T h i s t i m i n g r e s u l t s i n t h e r a p e u t i c drug l e v e l s i n the wound and r e l a t e d t i s s u e s d u r i n g the procedure but does not promote the development of b a c t e r i a l r e s i s t a n c e . A l t e r n a t i v e l y , some ex p e r t s even suggest two t o t h r e e doses immediately p r i o r t o the procedure p r o v i d e d no doses are give n p o s t - o p e r a t i v e l y (2,10). The c r i t i c a l p e r i o d when i n f e c t i o n may suppressed by a n t i m i c r o b i a l s begins the moment b a c t e r i a gain access t o the t i s s u e and i s u s u a l l y over w i t h i n 2 t o 3 hours <1,2>. Delayed i n i t i a t i o n of p r o p h y l a x i s a l l o w s time f o r p h y s i o l o g i c a l changes t o occur a t the wound s u r f a c e which i n t e r f e r e with d i f f u s i o n of the drug so t h a t the a n t i m i c r o b i a l may not reach the b a c t e r i a a t a s u f f i c i e n t c o n c e n t r a t i o n (1,2). A n t i m i c r o b i a l s can only be expected to e x e r t a l i m i t e d e f f e c t a f t e r t h a t p e r i o d . 200 F a c t o r s determining e f f e c t i v e n e s s o f a n t i m i c r o b i a l p r o p h y l a x i s i n surgery Types o f s u r g i c a l procedures Choice o f a n t i m i c r o b i a l drugs Dosage and r o u t e of a d m i n i s t r a t i o n Timing of i n i t i a l dose D u r a t i o n of p e r i - o p e r a t i v e a d m i n i s t r a t i o n Chemoprophylaxis should t h e r e f o r e be commenced i m m e d i a t e l y . p r i o r to an o p e r a t i o n . A d m i n i s t r a t i o n should be timed t o ensure t h a t peak serum l e v e l s c o i n c i d e as n e a r l y as p o s s i b l e with the p e r i o d of b a c t e r i a l c o n t a m i n a t i o n . When adm i n i s t e r e d i n t r a v e n o u s l y , t h i s can c o n v e n i e n t l y be accomplished i n the a n a e s t h e t i c room. Intramuscular i n j e c t i o n s , on the other hand, may be a d m i n i s t e r e d on the ward s h o r t l y b e f o r e the p a t i e n t i s brought t o the o p e r a t i n g room. C. Development of the Drug Usage Review P r o t o c o l 1. Study p o p u l a t i o n The study p o p u l a t i o n i n c l u d e d a l l acute care p a t i e n t a d i s c h a r g e d from the t e s t h o s p i t a l s during the p r o j e c t p e r i o d . The f i r s t s u r g i c a l treatment course per p a t i e n t admission f o r which a t a r g e t 201 a n t i m i c r o b i a l drug (below) woe p r e s c r i b e d and ad m i n i s t e r e d was e l i g i b l e f o r study i n c l u s i o n . T a r g e t A n t i m i c r o b i a l Drugs Reviewed* A m p i c i l l i n A m o x i c i l l i n C e f a z o l i n C e f o x i t i n Cephalexin Clindamycin C l o x a c i l l i n Gentamicin Metronidazole P e n i c i l l i n Tobramycin 'formulary drugs a v a i l a b l e f o r use and commonly employed f o r p r o p h y l a x i s . Target drugs excluded a l l o r a l bowel p r e p a r a t i o n s (eg. o r a l neomycin, erythromycin) and drugs u n l i k e l y t o be employed f o r s u r g i c a l p r o p h y l a x i s (eg. u r i n a r y a n t i s e p t i c s ) . S e l e c t i o n was undertaken t o i n c l u d e o n l y those treatment c o u r s e s : 1) i n i t i a t e d w i t h i n 12 hours p r i o r t o the commencement of a n a e s t h e s i a r e l a t e d t o the i n i t i a l s u r g i c a l procedure; and 2) l e s s than 12 hours a f t e r t e r m i n a t i o n of a n a e s t h e s i a f o r t h a t same procedure. Using p r e - e s t a b l i s h e d g u i d e l i n e s (15), f u r t h e r s e l e c t i o n t o i n c l u d e o n l y those treatment courses i n i t i a t e d i n the absence of evidence of i n f e c t i o n was undertaken. S p e c i f i c a l l y , absence of i n f e c t i o n was c o n s i d e r e d i f , a t the time o f the i n i t i a l dose (and f o r 24 hours p r i o r t o and a f t e r t h a t dose) the f o l l o w i n g c o n d i t i o n s were met: 1) p a t i e n t was a f e b r i l e ; 2) white blood c e l l count was w i t h i n normal range with no " l e f t s h i f t " ; 3) no notes i n h e a l t h r e c o r d suggested p o s s i b i l i t i t y of i n f e c t e d l e s i o n of the s k i n , c h e s t , abdomen, or g e n i t o u r i n a r y t r a c t ; 4) no i n d i c a t i o n i n the o p e r a t i v e r e c o r d t h a t i n f e c t i o n was present (eg. pus or abscess) or t h a t contamination had occured d u r i n g the procedure; and 5) no m i c r o b i o l o g i c a l r e p o r t s ( i e . c u l t u r e and s e n s i t i v i t y t e s t i n g ) were requested and/or r e p o r t e d d u r i n g the 24 hour p e r i o d surrounding the procedure (15). C r i t e r i a f o r Drug Usage Review In order t o a p p r o p r i a t e l y p r e s c r i b e a n t i m i c r o b i a l s f o r s u r g i c a l p r o p h y l a x i s , the i n i t i a l dose f o r each treatment course had to be 203 a d m i n i s t e r e d p r i o r t o the commencement of the o p e r a t i v e procedure. 3. Endorsement of C r i t e r i a C r i t e r i a f o r drug usage review were endorsed by the H o s p i t a l P r o j e c t Committee and an independent medical expert user p r i o r t o the study. 4. Sampling Procedure When study s c r e e n i n g requirements were met, treatment courses were randomly s e l e c t e d f o r f u r t h e r s e l e c t i o n e v a l u a t i o n and data c o l l e c t i o n . T h i s was accomplished u s i n g random sampling procedures d e s c r i b e d i n the r e p o r t methodology. 5. Information C o l l e c t e d Information was c o l l e c t e d f o r each treatment course i n c l u d i n g : 1. p a t i e n t number 2. admission date 3. age 4. sex 5. d u r a t i o n of s t a y a n t i m i c r o b i a l p r e s c r i p t i o n date a n t i m i c r o b i a l drugs time a n a e s t h e t i c commenced time s u r g i c a l procedure commenced time a n a e s t h e t i c terminated time i n i t i a l dose of a n t i m i c r o b i a l ( a ) a d m i n i s t e r e d * * d u r a t i o n of p o s t - o p e r a t i v e a n t i m i c r o b i a l treatment course*** s t a t u s of s u r g i c a l procedure ( e l e c t i v e , n o n - e l e c t i v e (semi-urgent), n o n - e l e c t i v e (urgent)) p r e s c r i b i n g p h y s i c i a n * * i f more than one a n t i m i c r o b i a l i n i t i a l l y a d m i n i s t e r e d pre- or p o s t - o p e r a t i v e l y , average time of a d m i n i s t r a t i o n documented u n l e s s g r e a t e r than two hours between times of i n i t i a l drug a d m i n i s t r a t i o n i n which case time of f i r s t dose documented. I f two or more drugs i n i t i a l l y a d m i n i s t e r e d i n t r a - o p e r a t i v e l y , time of f i r s t dose documented. ** * o n l y those drugs i n i t i a t e d p r o p h y l a c t i c purposes. Any other i n i t i a t e d p o s t - o p e r a t i v e l y and f o r drugs a f t e r i n i t i a t i o n o f primary druga were excluded. 206 References 1. Burke J F . The e f f e c t i v e p e r i o d o f p r e v e n t i v e a n t i b i o t i c a c t i o n i n experimental i n c i s i o n s and dermal l e s i o n s . Surgery 1961;50:161-168. 2. Polk HC J r , Lopez-Mayor J F . P o s t o p e r a t i v e wound i n f e c t i o n : A p r o s p e c t i v e study o f determinant f a c t o r s and p r e v e n t i o n . Surgery 1969;66:97-103. 3. C l a r k JS, Condon RE, B a r t l e t t JG e t a l . P r e - o p e r a t i v e o r a l a n t i b i o t i c s reduce s e p t i c c o m p l i c a t i o n s o f c o l o n o p e r a t i o n s : r e s u l t s o f p r o s p e c t i v e , randomized, d o u b l e - b l i n d c l i n i c a l study. Ann Surg 1977;186:250-259. 4. Strachan CJS, Black J , Powis SJA, e t a l . P r o p h y l a c t i c use of c e f a z o l i n a g a i n s t wound s e p s i s a f t e r cholecystectomy. Br Med J 1977;174:1254-1256. 5. Duff P, Park RC. A n t i b i o t i c p r o p h y l a x i s i n v a g i n a l h y s t e r -ectomy : review. Obstet Gynecol 1980;55<Suppl):193S-201S. 6. Hojer H. A n t i m i c r o b i a l p r o p h y l a x i s i n abdominal s u r g e r y . J Anti m i c r o b Chemother 1982;10CSupppl>:101-115. 7. Ke i g h l e y MRB, Burdon DW. A n t i m i c r o b i a l p r o p h y l a x i s i n sur g e r y . Kent, England: Pitman Medical P u b l i s h i n g Co L t d . , 1979. 8. Davidson AIG, Smith G, Smylie HG. A b a c t e r i o l o g i c a l atudy of the immediate environment of a s u r g i c a l wound. Br J Surg 1971;58:326-333. 9. Burnakis TG. S u r g i c a l a n t i m i c r o b i a l p r o p h y l a x i s : p r i n c i p l e s and g u i d e l i n e s . Pharmacotherapy 1984;4:248-271. 10. Stone HH, Hooper CA, Kolb LD, Gehereber CE, Dawkins E J . A n t i b i o t i c p r o p h y l a x i s i n g a s t r i c , b i l i a r y and c o l o n i c s u r g e r y . Ann Surg 1976:184:443-450. 11. Wittmann DH. P r o p h y l a x i s i n gen e r a l s u r g e r y . I n f e c t Surg 1983;1:825-829. 12. Polk BF. A n t i m i c r o b i a l p r o p h y l a x i s t o prevent mixed b a c t e r i a l i n f e c t i o n . J An t i m i c r o b Chemother 1981;8<Suppl D):115-129. 207 13. Ledger WJ, Gee C, Lewis Wp. G u i d e l i n e s f o r a n t i b i o t i c p r o p h y l a x i s i n gynecology. Am J Obstet Gynecol 1975;121:1038-1045. 14. Todd JC. Wound i n f e c t i o n : e t i o l o g y , p r e v e n t i o n and management. Surg C l i n North Am 1968;48:787-798. 15. Veterans A d m i n i s t r a t i o n Ad Hoc I n t e r d i s c i p l i n a r y Advisory Committee on A n t i m i c r o b i a l Drug Usage : P r o p h y l a x i s i n su r g e r y . JAMA 1977;237:1003-1008. 208 Appendix XV. Admission serum drug l e v e l s (T-6) A. D e f i n i t i o n o f Problem Admission serum drug l e v e l s a re not r o u t i n e l y being u t i l i z e d t o a s s e s s pre-admission drug therapy i n s p e c i f i c p a t i e n t s . Admission serum drug l e v e l s p r o v i d e u s e f u l i n f o r m a t i o n f o r the c h r o n i c management of p a t i e n t s admitted f o r acute b r o n c h o s p a s t i c or s e i z u r e d i s o r d e r s who are known or suspected t o take medications f o r which serum drug l e v e l m o nitoring i s a v a i l a b l e ( t h e o p h y l l i n e , phenytoin, p h e n o b a r b i t a l and other a n t i c o n v u l s a n t s ) . Serum l e v e l r e q u e s t s should s p e c i f y t h a t blood sampling occur soon a f t e r admission and p r i o r t o a d m i n i s t r a t i o n of the monitored drugs i n h o s p i t a l . B. Background During the i n i t i a l h o s p i t a l management of a p a t i e n t with an acute b r o n c h o s p a s t i c or s e i z u r e d i s o r d e r , b a s e l i n e serum drug l e v e l measurements p r o v i d e i n v a l u a b l e a s s i s t a n c e i n a s s e s s i n g the e f f e c t i v e n e s s of therapy aimed a t p r e v e n t i n g such problems. S p e c i f i c a l l y , admission blood sampling f o r t h e o p h y l l i n e or a n t i c o n v u l s a n t l e v e l s i s u s e f u l f o r determining whether inadequate dosage or compliance was p a r t i a l l y r e s p o n s i b l e f o r the acute e x a c e r b a t i o n i n p a t i e n t s known or suspected t o be t a k i n g these medications ( 1 - 5 ) . 209 Blood sampling f o r b a s e l i n e drug l e v e l measurements p r i o r t o commencing i n - h o s p i t a l t h e o p h y l l i n e or a n t i c o n v u l s a n t drug therapy p r o v i d e s v a l u a b l e i n f o r m a t i o n f o r the c h r o n i c management of the p a t i e n t with an acute b r o n c h o s p a s t i c or s e i z u r e d i s o r d e r . C. Development of the Drug Usage Review P r o t o c o l 1. Study p o p u l a t i o n The study p o p u l a t i o n i n c l u d e d a l l acute c a r e p a t i e n t s admitted t o the t e s t h o s p i t a l s d u r i n g the p r o j e c t p e r i o d . Each p a t i e n t admission with an ad m i t t i n g d i a g n o s i s of an acute b r o n c h o s p a s t i c or s e i z u r e d i s o r d e r was e l i g i b l e f o r study i n c l u s i o n . B r o n c h o s p a s t i c d i s o r d e r s i n c l u d e d asthma, cho n i c o b s t r u c t i v e pulmonary d i s e a s e , emphysema or b r o n c h i o l i t i s . S e i z u r e d i s o r d e r s i n c l u d e d f e b r i l e s e i z u r e s and s e i z u r e s r e l a t e d t o a l c o h o l withdrawal. F u r t h e r s e l e c t i o n t o i n c l u d e only p a t i e n t s known or suspected t o be r e c e i v i n g measurable t a r g e t drugs (below) p r i o r t o admission and as w e l l as r e c e i v i n g the same drugs d u r i n g h o s p i t a l i z a t i o n was undertaken. F i n a l l y , p a t i e n t s with serum l e v e l s obtained w i t h i n 24 hours p r i o r t o admission were excluded as f u r t h e r serum l e v e l s were presumed unnecessary. Measurable Target Drugs * T h e o p h y l l i n e Phenytoin P h e n o b a r b i t a l Carbamazepine V a l p r o i c A c i d Primidone *serum l e v e l measurements a v a i l a b l e a t t e s t h o s p i t a l s C r i t e r i a f o r Drug Usage Review In order to a p p r o p r i a t e l y p r e s c r i b e t h e o p h y l l i n e and a n t i c o n v u l s a n t s , blood sampling f o r admission serum drug l e v e l measurements had to be requested f o r a l l p a t i e n t s admitted with an acute b r o n c h o s p a s t i c or s e i z u r e d i s o r d e r and t a k i n g one or more drugs f o r which serum l e v e l measurments are a v a i l a b l e . Where a p h y s i c i a n order d i d not s p e c i f y the time of blood sampling r e l a t i v e t o the f i r s t dose of the t a r g e t d r u g ( s ) , sampling time had t o r e f l e c t blood c o l l e c t i o n p r i o r t o i n i t i a t i o n of therapy. 211 3. Endorsement of C r i t e r i a C r i t e r i a f o r drug usage review were endorsed by the H o s p i t a l P r o j e c t Committee and an independent medical expert user p r i o r t o the study. 4. Sampling Procedure When study i n c l u s i o n requirements were met, data was c o l l e c t e d f o r a l l treatment courses i d e n t i f i e d . 5. Information C o l l e c t e d Information was c o l l e c t e d f o r each treatment course i n c l u d i n g : 1. p a t i e n t number 2. admission date 3. age 4. sex 5. d u r a t i o n of stay 6. a d m i t t i n g d i a g n o s i s 7. pre-admission t a r g e t drugs 212 8. nature of serum l e v e l r e q u e st ( p r i o r t o therapy, u n s p e c i f i e d or o t h e r ) * 9. time of blood sampling f o r i n i t i a l serum l e v e l 10. serum drug l e v e l ( s ) 11. time of a d m i n i s t r a t i o n of f i r s t dose of t a r g e t drug(s) 12. a d m i t t i n g p h y s i c i a n 13. p h y s i c i a n r e s p o n s i b l e f o r p r e s c r i b i n g t a r g e t drugs * i f pre-drug serum l e v e l were requested by the p h y s i c i a n but blood sampling time was not documented and no l e v e l was r e p o r t e d i n the h e a l t h r e c o r d , the treatment course was deemed a c c e p t a b l e u n l e s s the p h y s i c i a n n e g l e c t e d t o s t a t e t h a t blood sampling was to occur p r i o r to i n - h o s p i t a l therapy with the t a r g e t d r u g ( a ) . I f two or more pre-admission t a r g e t drugs were used p r i o r t o admission and the p h y s i c i a n requested serum l e v e l s f o r at l e a s t one drug, the treatment course waa deemed a c c e p t a b l e . 213 References 1. Richens A, Warrington S. When should plasma drug l e v e l s be monitored? Drugs 1979;17:488-500. 2. Kutt H, Penry JK. U s e f u l n e s s of blood l e v e l s o f a n t i e p i l e p t i c drugs. Arch Neurol 1974;31:283-88. 3. Eadie MJ. Plasma l e v e l m o n itoring of a n t i c o n v u l s a n t s . C l i n Pharmacokin 1976;1:52-66. 4. Van D e l l e n RG. T h e o p h y l l i n e . P r a c t i c a l a p p l i c a t i o n of new knowledge. Mayo C l i n Proc 1979;54:733-45. 5. Guernsey BG, Ingrim NB, Hokanson JA e t review of t h e o p h y l l i n e assays : sampling Drug I n t e l l C l i n Pharm 1984;18:906-12. a l . A u t i l i z a t i o n p a t t e r n s and use. 214 Appendix XVI. L e t t e r of i n t r o d u c t i o n and i n t e n t s ent t o p o t e n t i a l community h o s p i t a l t e s t s i t e s Dear Dr. 215 We ire presently undertaking a Major research project entitled, "The Development of a Methodological System to Evaluate the Comparative Impact and Longevity of Various Educative Strategies Designed to Opti-mize Drug Usage*. This project Is a continuation of my wort In drug use review 1n acute care settings, and is intended to serve as • thesis project for rry Ph.D. student, Hr. Peter Jewesson. The project Involves the examination of Institutional therapeutic drug usage. As you are aware, therapeutic agents are frequently not used optimally. The literature contains many reports of sub-optimal drug usage and attentpts to modify prescribing practices. The goals of this particular project are to: 1) design a methodological system capable of evaluating the compara-tive efficacy of various educational approaches designed to modify drug usage; 2) demonstrate, through application, the Impact of these educational strategies, and 3) compare these with respect to efficacy, longevity of benefit and Indirect benefit through dissemination. A double blind crossover multiple time series experimental design with concurrent and retrospective controls wi l l be employed. Subjects wi l l Include a l l general practitioners and patients meeting Inclusion c r i -teria at three similar geographically separated community hospitals. Studies Involving three Identified drug therapy problems (see attached) w i l l be conducted 1n two phases. Phase I (12 months) represents a pre-intervention control period. Phase II (12 months), a post-Intervention period for each study. Three types of educational Interaction w i l l be Implemented between these phases. Including c r i t i c a l (providing feed-back regarding Institutional patterns of drug usage), non-critical (providing educational material regarding optimal drug usage), and no Intervention (control). Educational material wi l l be distributed to meet this end. A review of the present state of knowledge Indicates the lack of well controlled studies of this nature. The development of a system as out-lined above Is essential to the evaluation of education In the optimi-zation of drug use. Those Institutions directly participating In the project can expect to benefit from anticipated Improvements In drug usage related to the Individual studies. Your Hospital meets the Inclusion criteria as a potential experimental site for this project. Participation of the Institution would Involve agreement to allow access to patient medical records (discharged patients only) for on-site examination for the duration of the study and permission to distribute educational material to those general practitioners Identified as meeting study crit e r i a . Information obtained about the research participants (both general practitioners and patients) during the course of the Investigation w i l l remain confidential throughout and after Its completion. No Informa-tion which specifically Identifies Individuals or institutions and pre-scribing patterns thereof will be made available to any individuals or groups (Including the other experimental sites) outside of the Immediate Investigators. No effort will be made to specifically Iden-t i f y individual physicians (except for the purposes of educational material distribution) or their prescribing habits. Instead, these participants will be randomly allocated to either a 'control* or "treatment" group and the prescribing patterns of the group as a whole w i l l be examined. The proposed schedule for this project is Uovember 1983 through April 1985. The nature of the design of this project required blinding of the sub-jects Involved. To accomplish this, 1t 1s necessary to keep a l l infor-mation regarding this project confidential. The Investigators would appreciate your cooperation 1n this respect, regardless of the decision as to participation. Ue look forward to the opportunity to meet with you In the near future to determine your Interests. If any questions should arise In the meantime, please do not hesitate to c a l l . Sincerely, Robin J. Enson, Pharm. D. Assistant Professor Faculty of Pharmaceutical Sciences University of British Columbia 216 Appendix XVII. Medical rounds conducted a t t e s t h o s p i t a l s d u r i n g p r o j e c t p e r i o d Date H o s p i t a l H - l H 1984 May J u n e / J u l y / August September October No r e c o r d o f any rounds conducted No rounds conducted C l i n i c a l g e n e t i c s Concepts i n treatment of asthma* O r t h o t i c s Newborn r e s u s c i t a t i o n Thrombocytopenia M i t r a l v a l v e s t e n o s i s New a n t i b i o t i c s C a r d i o l o g y case p r e s e n t a t i o n New concepts i n c a r d i o -t h o r a c i c s u rgery A n o r e c t a l problems Formulary a d d i t i o n s Insomnia e v a l u a t i o n and treatment M o r t a l i t y review P a t i e n t e d u c a t i o n i n the MD o f f i c e Vaccine R e i t e r syndrome Nuclear medicine N u t r i t i o n and e n t e r a l f e e d i n g I n f a n t n u t r i t i o n Death rounds IHD management Nervous system trauma O b s t e t r i c case review Advance i n pneumonia N u t r i t i o n a l support G a s t r o e n t e r o l o g y update P e d i a t r i c d i a b e t e s Needle biopsy C l i n i c a l d e p r e s s i o n P e d i a t r i c case O s t e o p o r o s i s Voice d i s o r d e r s November AIDS Rhythm d i s t u r b a n c e s Thrombocytopenia S o f t t i s s u e i n j u r y F r a c t u r e d i s l o c a t i o n s F a c i a l p a r a l y s i s Coronary r i s k f a c t o r s 217 Appendix XVI I I . Medical and pharmacy n e w s l e t t e r t o p i c s d u r i n g p r o j e c t p e r i o d Date 1984 May June H o s p i t a l H - l No n e w s l e t t e r s T y l e n o l e l i x i r Formulary changes O r a l potassium July/August Benzodiazepine review September/ October November December 1985 January/ February March April/May June No n e w s l e t t e r s P r o j e c t n e w s l e t t e r Formulary changes No n e w s l e t t e r s Imferon g u i d e l i n e s C e p h a l o s p o r i n a v a i l a b i l i t y Formulary changes No n e w s l e t t e r s No n e w s l e t t e r s H - 2 No n e w s l e t t e r No n e w s l e t t e r s No n e w s l e t t e r s Formulary changes Transderm V F l a g y l i n r e n a l f a i l u r e Naprosyn S u p p o s i t o r i e s P r o j e c t n e w s l e t t e r No n e w s l e t t e r s No n e w s l e t t e r s No n e w s l e t t e r s Drug dosing i n r e n a l f a i l u r e * Formulary changes* Imferon g u i d e l i n e s ASA Formulary changes* T h i r d g e n e r a t i o n c e p h a l o s p o r i n s J u l y No n e w s l e t t e r s No n e w s l e t t e r s * medical n e w s l e t t e r t o p i c s 218 Appendix XVII. continued Date H o s p i t a l H - l H - 2 December J u v e n i l e a r t h r i t i s Ear inflammation Dermatology X-ray q u i z Pulmonary embolus Diseases o f b r e a s t 1985 January A d u l t t r a n s p l a n t program Blood l i p i d s i n hy p e r t e n s i o n Shoulder p a i n Vacuum i n o b s t e t r i c s Diabetes i n pregnancy Blood l i p i d s i n hy p e r t e n s i o n Hypertension therapy Adolescent p s y c h i a t r y M i t r a l v a l v e s t e n o s i s February March A p r i l Heparin therapy B r e a s t carcinoma O s t e o a r t h r i t i s G a s t r o e n t e r o l o g y advances Scuba d i v i n g medicine Ocular d i a b e t e s Anemia therapy. Hematuria Neurosurgery update Death rounds Lower s t e r n a l p a i n Benzodiazepine update New a n t i - a r r h y t h m i c s Headache Adolescent h e a l t h O s t e o a r t h r i t i s Drug assays * Caseroom c o m p l i c a t i o n s P e r i p h e r a l v a s c u l a r i n s u f f i c i e n c y R e t r o v i r u s e s S k i n tumours May June/July L i p i d s and c o n t r a c e p t i o n C l i n i c a l pathology conf erence Rheumatoid d i s e a s e Thrombophlebitis Oxygen therapy Sexual c h i l d abuse Ob/Gyn case rounds F e t a l m o nitoring F i b e r g l a s s rounds M u l t i p l e myeloma P e d i a t r i c opthamology D i a b e t i c management Recurrent headache Ear i n f e c t i o n X-rays and f i l m s * d i s c u s s e d i n t e x t J e w e s s o n P J , R e m i c k RA. I n f l u e n c e o f b l o o d c o l l e c t i o n t u b e s o n t r i -c y c l i c a n t i d e p r e s s a n t a s s a y s . J o u r n a l o f C l i n i c a l P c y c h o p h a r m a c o l o g y 1 9 8 6 ; 6 : 5 1 - 2 . J e w e s s o n P J , E n s o m R J . I n f l u e n c e o f b o d y f a t o n t h e v o l u m e o f d i s t r i -b u t i o n o f t h e o p h y l l i n e . T h e r a p e u t i c D r u g M o n i t o r i n g 1 9 8 5 ; 7 : 1 9 7 - 2 0 1 . J e w e s s o n P J , R e m i c k RA. S e r u m l e v e l m o n i t o r i n g o f t r i c y c l i c a n t i -d e p r e s s a n t t h e r a p y . B r i t i s h C o l u m b i a M e d i c a l J o u r n a l 1 9 8 5 ; 2 7 : 6 3 9 - 6 4 0 . J e w e s s o n P J , B a c h a n d R, Chow AW. E v a l u a t i o n o f p a r e n t e r a l m e t r o n i d a z o l e i n a n a c u t e c a r e t e a c h i n g h o s p i t a l . C a n a d i a n M e d i c a l A s s o c i a t i o n J o u r n a l 1 9 8 5 ; 1 3 2 : 7 8 5 - 7 8 9 . J e w e s s o n P J , Chow AW. T h e p h a r m a c o k i n e t i c s a n d u s e o f a n t i m i c r o b i a l d r u g s d u r i n g p r e g n a n c y . I n ; I n f e c t i o n s a n d R e p r o d u c t i v e H e a l t h ( V o l u m e 7 ) ; E n c y c l o p e d i a o f R e p r o d u c t i v e H e a l t h : HTP P r e s s o f E n g l a n d 1 9 8 4 : L a n c a s t e r , E n g l a n d , 1 9 8 4 . E n s o m R J , J e w e s s o n P J . I n f l u e n c e o f a h o s p i t a l p h a r m a c y r e s i d e n c y o n c a r e e r a d v a n c e m e n t a n d s a t i s f a c t i o n . C a n a d i a n J o u r n a l o f H o s p i t a l P h a r m a c y 1 9 8 5 ; 2 : 5 - 9 . J e w e s s o n P J , Chow AW. D e a l i n g w i t h t h e m i s u s e o f a n t i b i o t i c s i n t h e h o s p i t a l . C a n a d i a n M e d i c a l A s s o c i a t i o n J o u r n a l 1 9 8 3 ; 1 2 8 : 1 0 6 1 - 2 J e w e s s o n P J , Chow AW. A u d i t i n g a n t i b i o t i c u s e i n a t e a c h i n g h o s p i t a l : f o c u s o n c e f o x i t i n . C a n a d i a n M e d i c a l A s s o c i a t i o n J o u r n a l 1 9 8 3 ; 1 2 8 : 1 0 7 5 - 7 8 B a c h a n d R, J e w e s s o n P J . H a n d l i n g o f new a n t i n e o p l a s t i c a g e n t s : who d o we p r o t e c t ? C a n a d i a n J o u r n a l o f H o s p i t a l P h a r m a c y 1 9 8 2 ; 3 5 : 1 6 6 Chow AW, J e w e s s o n P J . P h a r m a c o k i n e t i c s u n d s a f e t y o f a n t i m i c r o b i a l a g e n t s d u r i n g p r e g n a n c y . R e v i e w s o f I n f e c t i o u s D i s e a s e s 1 9 8 5 ; 7 : 2 8 7 - 3 1 3 . M e l i k i a n DM, J e w e s s o n P J . C h r o n i c o b s t r u c t i v e p u l m o n a r y d i s e a s e ( C O P D ) : e m p h y s e m a / b r o n c h i t i s . C a n a d i a n C o n f e r e n c e o n C o n t i n u i n g E d u c a t i o n i n P h a r m a c y 1 9 7 9 ; 2 : 3 - 1 8 . J e w e s s o n P J , Chow AW. S u f e t y o f a n t i m i c r o b i a l a g e n t s d u r i n g p r e g n a n c y . T h e M e d i c a l l e t t e r 1 9 8 5 : 2 7 ; 9 3 - 9 5 ( o n r e q u e s t b y e d i t o r s ) E n s o m R J , J e w e s s o n P J , H l y n k a J N , R u o d y J , K e n n e d y J . A r e v i e w o f p a r e n t e r a l c i m e t i d i n e p r e s c r i b i n g i n n m a j o r t e a c h i n g h o s p i t a l . C a n a d i a n J o u r n a l o f H o s p i t a l P h a r m a c y ( a c c e p t e d f o r p u b l i c a t i o n i n 1 9 8 5 ) . B a c h a n d KL, J u w o c c o n l-'J , uhow AW . L>«..vi: 1 o p u e n t , a j u p j t c t t i u i i c u d a p p r a i s a l o f a r e s e r v e d a n t i m i c r o b i a l d r u g p r o g r a m a t a m a j o r t e a c h i n g h o s p i t a l . J o u r n a l o f t h e A m e r i c a n M e d i c a l A s s o c i a t i o n 1 9 8 5 ( s u b m i t t e d f o r p u b l i c a t i o n ) . E n s o m R J , J e w e s s o n P J , M i y a t a M, H l y n k a J N , R u e d y J , K e n n e d y J . T h e o p h y l l i n e d o s i n g : E f f o r t s t o i m p r o v e p r e s c r i b i n g p r a c t i c e s . J o u r n a l o f E m e r g e n c y M e d i c i n e 1,985 ( s u b m i t t e d f o r p u b l i c a t i o n ) . C how AW, J e w e s s o n P J . U s e a n d s a f e t y o f a n t i m i c r o b i a l a g e n t s d u r i n g p r e g n a n c y . A n n a l s o f I n t e r n a l M e d i c i n e 1 9 8 6 ( s u b m i t t e d f o r p u b l i c a t i o n ) . AWARDS AND R E C O G N I T I O N N a t i o n a l H e a l t h a n d W e l f a r e C a n a d a P h . D . F e l l o w s h i p A w a r d , N a t i o n a l H e a l t h a n d W e l f a r e C a n a d a , 1 9 8 3 - 1 9 8 5 N a t i o n a l H e a l t h a n d W e l f a r e C a n a d a M . S c . F e l l o w s h i p A w a r d , N a t i o n a l H e a l t h a n d W e l f a r e C a n a d a , 1 9 8 2 - 1 9 8 3 C a n a d i a n F o u n d a t i o n f o r t h e A d v a n c e m e n t o f P h a r m a c y , P r o f e s s i o n a l P r a c t i c e F e l l o w s h i p , 1 9 8 1 H.C. L e P a t o u r e l F e l l o w s h i p i n H o s p i t a l P h a r m a c y , F a c u l t y o f P h a r m a c e u t i c a l S c i e n c e s , U n i v e r s i t y o f B r i t i s h C o l u m b i a , 1 9 7 8 Sam a n d J a c k B a s s B u r s a r y , U n i v e r s i t y o f B r i t i s h C o l u m b i a , 1 9 7 7 P a s t P r e s i d e n t A w a r d , C a n a d i a n S o c i e t y o f H o s p i t a l P h a r m a c i s t s , 1 9 8 0 -1 9 8 1 

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