336 d CWKE. R. and Tt)(iwon. 1 iPeisona1 co~iimunicdiion.) WOOLCOCh. A I . BL4cKHUKlr. C. R. B . F R ~ E WM A NH.. . Z>LSTRn. W and SI'KIN(,.S. R 1 1 9 7 0 ~ Studies o1 chronic inon-tuberculous) lung direas? i n New Grr!nea p o p u l a r ~ ~ n aAmer . Rrr. r v y f l i r 102, 5 7 5 10 , A \ I ~ I R X ~ NH . R , .A\ai~loh.. J A and C o n s . J E I I Y ? ~ ) : Lung funcrion
2!.
value' t n healthy ch:ldrcn and adults from Highland and c o a j t n l a i m , of Papua \ c u Guinea: prediction nomogram? for forced e x p i r d l o i ~~ 0 1 ~ 1 1 1 2 and forced \ital capacity. Pupuo V Girinro n i i d I 17. I h 5
22
I I MCLXRMOTT.-34, MCDERMOTT. T I. and COLLIZI 41. M (19hXi 4 portable bellows spromerer and timing u n i t f o ~the m c a ~ ~ ~ r c i i i cofn l resplraton; tunction. M r d bwl E n p ~ g6 . 291 13. Miauk. F.. Sai \nr&z\. \,I J HYCTT.t . R t Y w L u h . J A . PI.ARI and COTIS.I E (19651 Automat(< measurement of lune function. I
27
?4
2, 9 3
Con\. J E . D%nB\.I. h 4 . E ~ u o o u P. C . H*I.L. .A hl.. h.IrDo\4in. 4 and S X L . ~ U ~hl. R SJ. (1972) lron~deficlencyanaemia 11s efleit on tlan,li.I iacior for the lung ( d ~ f f u s i n capacit?) p and v c r i l i l a t i o n and cardiac ficqucnc) d u i n g sub-maximal cxm.isc. Clrn S c ! . 42. 325 14 C n n \ J t , S%L\DIRS. hl. J , ADAM. J. E R . A W E R S J ~ .H R. and HALL.A hl (19?31: Lung function m coastal and Highland Neu Cruinennc comparxon M-irh Europeans. I k o r a i 28, 320 I S . CUTE,. I. E . ANUt.Km".i. 11. R and P&TRICK. 1 M 11974) Lung i l l n i t i o n and response to exercise in natiw N e w Ciuioenns role 01 gcnctic and environmental Sactois. Phil. T r u n ~ B. 268. 339 16. SIMON. G I 19?1). Pnociplec of chest X-ray dmgnosic. 3rd c4.. Buttcruurth. I3
25
28 29
.. T I I ~ M A4~ .J and KOSSTER. C. (1961) Thc recognilion heait dlseasr in tlic prcscncc of pulmonary dised>e.
Btii
Hrari J 26. 2 ? 3 . I S S,\\ERKIN. N Ci and E ~ ~ NDs . M D (1965): The sputum in bronchial arihnia pathognomonic patterns. .I Porh Hoi,r. 89, 535 19 FLETCHIR. C 2.1. PITO. R . S P t l Z F R . F. S. and Tl?lhFK. C M. 119701: .A follou up study of the naiural hirrory o f ohsrructiie bioiichitis I n Orie. N G M a n d Van dci Lendc. R. cd, . B w m l u r , . ~ I l l . Proceeding? of the Ihiid lntcrnatioiinl Sympuuum on Bronchitis. pp 103- I i6 Royal
V a n g o r ~ u m .A w n
30
1
?I
1
32.
1
B L R R O W \ . B.. FLrTrlil R C M HtqRt>. B E . J O N E S . N L and WOOTI 11 I .I. S. (19661 The e m p h y s c r n a t o u ~and bronchial type5 of chronic ariun), ob,tluctiun n climcuparhological stud? of pdfi~1113 i n Londun and Chlcdgo. Lancci 1, 830 THCRLHLCK. W hl.. I I t z U l R ~ O \ . J -2. M . FR,ASFR. R G and Bkils. D V-. I 1970) Chronic obstructirc lurip diaearc: a comparison hetaecn clmical. roentpenolupc. funclional and morpholngic crileiia in chronic bronchilir. emphyrem.!. asthma and bmnchiectasis. M e C H I R N I A K . N S. and CARL TO^. R. W. 119h61: Factor rcipirdlury iniuficiency in bronchiectasi5 .4mri J .+led 41. 562 BIR4TH. Ci , C A R O . I . MxLMbtRG. R. and obstiuction in pulmonary tuberculoris. CRorTn\. J and DOUGLAP. A. (1969): Edinburph. Blackwell Scisntitic Publicatiui A>. J. W. B and R I , ~ I 7 . U 11477) Rzspiral,,ry influence of early childhood I u w r rehpirator! a11 pollution and m o k i n g . B t u mi,d .I. 3, 1 Y 5 e Sate nf the cliionic bionchitic. a report of t h e ren year follow up in thc Canadian department of Veteran's a f i m i s cwoidinated study of chronic bronchitis. Am?, Kus tes),. D L 108, 1043 1 3 Department of Health. Education and Welfare (1971) The health consequcn'es oi bmoking. C.S. Ciorernmtnt Ynqtirg Officc. Washmg:on VaY nrR LEND€. R , DF KROO\. J P. M.. V 4 h nrR M r i ~ f K .G G T A M U ~ L IG~ GI... VisstK, B. F.. Dr VRir?. K and ORIE.\ C M ilY70). Possible indicator? of endogenous iactois in rhc d?vclopmenr of CNSI D I n One, N Ci M and Vlin der Lende. R eds.. Bion,hifrs I l i . pp 52-71 Royal Vdngorcum. Assen. LwAnlA F t (1967) Tropical eosinophilia-~a correlation of CII~ICBI. hirtoualhologic and lung function studie?. Dds ClwAr 52, 311 A w l n c o h . H K (1974) Thr cpidemiological and allergic featuics 01 asthma in thc New Guinea Highlands. Clcn Allerg\. 4, 171 C i n F r \ B E R G . M . MILNF.I. F and W A r T . .A (1 9 T I) Survcy of w o r k s e x p o 4 to dusts containing derivatiies 01 Bacillua iubtilia. Brir. med 1. 2. 629.
Ausr N / J bled (1975). 5 , pp 336 340 ~
~
~~
~~
~~
~
~
Extensive Drug Surveillance-A
~~
Pilot Study
D. C. Gerke*, E. Gail Easterbrookt, D. 6. Frewin: and T. I. Lee"" From the Departments of Human Physiology and Pharmacology, University of Adelaide and the Royal Adelaide HosDital
Summary: extensive drugsurveillance-A pilot study. D C G e r k e E G a i l Eaqterbrook D B Frewin and T I Lee Aust N Z J Med 1975 5, pp 336-340
The aim of this Extensive Drug Surveillance programme was to develop a system of drug monitoring suitable for detecting adverse
-
~
"Dental Surgeon Postgraduate Research Scholar University of Adelaide +Pharmacist Royal Adelaide Hospital :Senior Lecturer in P h a r m a d o g y University of Adelaide and Visiting Pharmacologist Royal Adelaide Hospital ""Chief Pharmacist Royal Adelaide Hospital Correspondence Dr D B Frewin Department of Human Physiology and Pharmacology University of Adelaide Adelaide South Australia 5001 Accepted for publication 4 February 1975
drug reactions in hospitalised patients. The monitored field was a general medical ward in the Royal Adelaide Hospital and monitoring was carried out for a period of one month (September 1974). A total of 85 patients (45 males and 40 females) were monitored and in 1 4 of them adverse reactions were noted. The overall incidence of such reactions was 16.5%. A greater intake of drugs was a significant finding in patients w h o experienced adverse reactions. Coupled with this was the observation that patients w h o stayed longer in hospital had a greater number of drugs administered to them. A third finding was the higher incidence of reactions in female patients.
The use of a drug monitoring system has largely been accepted as the most appropriate way of detecting adverse reactions to drugs in a monitored field.’ There has, however, been a diversity in the types of systems used. Gardner and Watson‘ described a pharmacist based monitoring system in a hospital which gave a yield of 10.5‘); adverse drug reactions. Seidl et reported an intensive hospital monitoring system with a detection rate of 13 6 9; probable reactions during hospitalisation, while MacDonald and MacKay“, using a system relying on physician reporting. showed only 1 n!o drug reactions in a monitored field. Koch-Weser et aL5, who used a spontaneous physician reporting system, registered a figure of approximately 4 for adverse reactions. The cxtensive drug surveillance (monitoring) system incorporates the more advantageous aspects of the above systems to provide a means of recording all adverse reactions as accurately as possible, but with perhaps greater ease, reliability and precision than with other systems. The purpose for establishing this drug surveillance programme was thrccfold :
(1) It was felt that the incidence of drug reactions occurring in the Royal Adelaide Hospital should be known. (2) Invaluable information about the adverse reactions caused by individual drugs would be compiled. Coupled with this, new drugs being administered within the hospital could be clinically assessed for efficacy, tolerance and toxicity from data collected by this monitoring system. (3) This surveillance programme has the potential for being a progressive monitoring system, thus allowing immediate feedback to the medical prescribers as to the possibility of adverse reactions occurring or, in fact. the occurrence of a reaction perhaps not detected by the prescriber. The programme therefore achieves the three objectives set out by the AMA Council on Drugs6 ; these serving : “(a) to alert physicians to the potential toxicity of new drugs, (b) as a reminder of the potential toxicity of drugs and chemicals in common use,
(c) as a reference for physicians investigating suspcctod reactions to drugs.” Methods
.Monitored Field For one month (September 1974) all male and female paticnts who were admittcd to a general medical ward in the Royal Adelaide Hospital entered the monitored field. Thcse patients werc monitored until they left the field either by transfer to another ward, discharge from thc hospital, or death. Monitoring was continued until discharge for those patients who remained in the ward aftcr the 30th of September. A new record was started if a patient was discharged and readmitted to thc ward within the initial month of surveillance. Drugs The definition of a drug was that used by the WHO’, i t . “A drug is dcfincd as any substance or product that is uscd or intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient.” Only drugs prescribed in the ward by attending medical officers were recorded. This ineant that doscs of laxativcs were sometimes not recorded, because they were usually given at the discretion of the nursing staff, and often there were no written records kept. Records of drugs given for radiological procedures were not maintained as this information was sometimes hard to retrieve. However, since all personnel who were involved in the management of these patients were aware of the drug surveillance programme. any adversc reactions which wcre thought to have resulted from either laxative therapy or from radiological agents would have been promptly reported Datu Collrccion Thc data was collectcd by thrce monitors (i.e. a pharmacist, a dentist and a clinical pharmacologist). These monitors visited the ward on a daily basis and rcviewed the mcdical record and drug charts of each patient. Relevant information from these source5 was transcribed on to special data acquisition forms. The role of thc monitor was to record accurately all specified data ( i t . “interesting” or “uninteresting” data was not omitted). Reactions and interactions were checked by the clinical pharmacologist. To guard against transcription errors at the time of initial data collection, the monitoring system’s record was re-checked against the hospital record after the patient had been discharged. Data, such as name, age, sex, hospital number, ward, date of admission, and diagnosis were recorded soon after admission of each patient. Previous drug reactions and allergics werc obtained from the patient’s medical history. Information about drug therapy was obtained by regular cxamination of the drug sheet for each patient. The drugs given, their route of administration, timing of treatment, dosage. total daily dose, and any change in treatment or dosage were recorded. The medical and nursing staff were questioncd regularly about the occurrence of events which may have constituted an adverse reaction to a drug. Constant surveillance of the medical progress records was carried out to observeany comments about adverse reactions, and the co-operation of the medical staff was solicited in notifying the monitors if such an event did occur. The data on one patient was excluded because or the fact that 65 of the 70 days spent in hospital were in an intensive care ward. away from the monitored field.
P,ohahi/itjbqfReocrion2~ "Definite: These are adverse reactions coiumonly known to occur with a clear-cut temporal association. positi\ e re-challenge test or laboratory confirmation. Probable: These are adverse reactions commonly knov,m to occur with a clear-cut temporal association and improvement on withdrawal of medicine. Possible: These are adverse reactions known to occur. The temporal relationship is less clear and other etiologies are also possible. Iloubtful: In this case some other cause of adverse reactions is judged more likely." S r r r r i t j . of K e i m u n
This was not classified and reactions were described on the basis of symptomatology produced in the patient. As more data accumulates. the classification of the severity of the reactions will become necessary.
Results
Forty-five males and forty females were admitted to the ward during the period of surveillance. Two of the inales were discharged and latcr readinitted. This accounts for the discrepancy between the number of patients and the number of discharges. transfers or dcaths (Table 1). Fivc patients died during their hospital sojourn (Table 1). but none of these deaths were attributed to adverse reactions to drugs. There was a good match between the mean ages of the male arid female groups and also the mean duration of their stay in hospital. The principal diagnosis for each patient participating in the study is listed in Table 2. Four females and one male were admitted with a history of drug overdosage or abuse.
The breakdown of the various drugs which were administered to the patients is shown in Table 3. The mean number of routine drugs for inales WRS 5 . 3 and that for the females 4. The mean number of drugs on discharge was 3 . 9 (for males) and 2 . 8 (for females). The mean number of prescribers was 2 . 2 for the combined male and fcinale populations. The adverse reactions which were detected during the study are listed in Table 4. 111 mosi instances the suspected causative agents were either discontinued or decreased in dosage. However, in three patients the therapy remained unchanged despite the possibility that an adversc reaction was associated with it. The incidence of advcrsc drug reactions was 13.3",, (male) and 20"; (female), with an overall mean of 16.5% for the two sexes. The incidence of adverse reactions was thercforc greater in thc female group. When the drug intake of the patients was analysed in relation to the duration of their hospital stay, it was found that patients staying longer than 15.7 days (the mean) were administered inore drugs than those staying in hospital for less than this period ( P < 0.0005). It w a s also found that patients who developed adverse reactions had more drugs administered to them than those who did not ( P < 0.025). The population of patients suflering from inore than one reaction was also found t o have had more drugs ( P < 0.05) and ii longer stay ( P < 0.05) than the remainder of the patients who had only one adverse reaction.
TABLE 1 A comparison of male. female and group data
TABLE 2 Principal complaint on admiasion
Patient Male
Female -
Number of patients Number discharged Number tranrferred Number deaths Mean age (years) Range Medn jtay Iddys) Range
45* 40 4 3 63 2 25-95 16 1-54
40 33
5 2 61 5 21 94 15 2 4 51
Male
Total ( M dnd F)
_ _ _ ~
~
85 73 9
jt 62 4 21 95 15 7 1-54
* T w o male patients were admitted. discharged and readmitted during this study. The total number of admissions was therefore 87. t No deaths occurred due to drug reactions.
Female -
~~
Haema tological Cardiovascular Respiratory GIT GI! Hcpatic CNS Others
3 23
Total
45
6
3
15
I
38 14 6 1 4
9 4*
14 5
0
5 1
~
0 8* 3*
3* 1 3
Total
~
~~
40
85
* These figures includc thc five patients with a history of drug overdosage or abuse: three had GIT symptoms, one had respiratory symptoms and the other washypokalaernic.
330
DRUG SURVEILLANCE TECHNIQUFS Discussion
A total of 20 adverse drug reactions were detected in 14 patients during the period of this extensive drug surveillance programme which represents an incidence of 16.574 of drug reactions in the monitored population. This figure was obtained using the notation :
i:xs)
14 ,ncidence = No. of patients with adverse _ _ _ __drug _ _ - - ~reactions -- No. of patients exposed ~
loo
Our value for the incidence of reactions is greater than those reported by Gardner and Watson2 and Seidl el aL3 However, it must be noted that both those studies considered only definite and probable reactions, whereas our results included all categories of drug reaction. Several authors'. l 1 h ave concluded that the number of adverse reactions increases with the total number of drugs taken by individual patients. Our results support this conclusion. Our findings also indicate that the number of drugs administered to patients increases with the increased duration of their hospital stay, which is in agreement with the observations of Borda et d . I 2 Patients with severe or chronic illness are more likely to be hospitalised for longer periods of time and the influence of patient morbidity in relation to adverse drug reactions has to be taken into account. Diminished hepatic or renal function and associated altercd drug metabolism and excretion are some of the factors that must be considered. The administration of greater numbers of drugs ''5
to the severely ill m a y also lead to adverse reactions, either due to the agents themselves or due to drug interactions. An interesting finding to emerge from this study was the higher incidence of adverse reactions in the female group which is in keeping with the results of Hurwitz and Wade.' The female patients in our study received a mean total of 6 . 9 drugs as compared to a mean of 8 . 4 drugs in the males. The mean duration of hospital stay was not significantly different in the two groups. The reason for the female having a greater frequency of adverse reactions is therefore not explained on the basis of numbers of drugs taken. MacDonald and MacKay4 and Koch- Weser et L I I . ~ commented that adverse drug reactions were seldom recorded in the medical progress charts of each patient. To circumvent this problem in our study, the monitors regularly questioned the medical staff and patients in relation to adverse drug reactions and alterations
TABLE 4 Summary oiadverse reactions in male and iernalc patients
~~
Patient ~.~
~
Mean*
Koutincdrugs Statim d r u g s prndrugscaken p r n prescrihed ~
.
~~
Kange*
~~.
~~
IV d r u g s
-~
I 5.3 1.6 1-5
(2.4)
6-0 160 II 0 7 0 (8-0)
~
~~~~
8.4
Dischargedrugs
* Per paticnt. t Keprebents the
~~~
3 9
30wl
Mean ~
~~~~~
~~~~~
~
~~~~~~~
~~~~~~
Outcome' -
~ _ _..
Postural hypotension Possible Low plasma volume Doubtful
Decreased Stopped
6
Phenytoin
1 iolate. macrocytic anaemia Drowsy
Prohable
Decreased
14
DmLcpam
1 arterial 0,.2 1 respiration
Possible Probable
stopped Stopped
21
Predmsolone Co-trirnoxazole
GIT irritation I'hru4i lorail
24
Clonidine Morphine
Drowsy, dry mouth Vomiting
43
Fruacmide
Possible Possible Definite: Probable Definite? -~
Decreased Stopped Stopped Stopped Decreased
Probable
Stopped
Possible Definitet
Stopped Dccrcaacd ,Nor changed
~. __ _ __ _ - -. ~ ~~~
to
Hypokalaemia ~
~
~
~~
FEMAI.ES
Range
2
5
~
0.7 4 1-1 1.6
4 0 11-0
(2.21
(7-0)
5-4
IY 26
28
5-0
6.9
IY- 1
2.8
5-0
- .
11 0
. .__.. . ~ ~
Probability
Uethyldopa Bendrolluaridc
35 38
-~~ ..-
-
~
~~
Reaction
~
~~~~~
Totalt
~
kernales -~~~~
.~~~ ~~
~~
~ . - ..~ ~ ....
mug
Trimeprannc
Nurnhcr of dift'erent d r u g s administered
~~
M4LbS ...
2
TABLE 3
Males
~-__
~
total n u m b e r of drugs administered t o the patient. Adjustment has been made if any ovcrlap in the IV, routine, stattm a n d pm schedules exists. IV = intravenous; prn = pro re nata
39
Nalidixic acid Sorbide nitrate
Urticaria1 rash Headacbe
Fruscmidc Chlororhiazide Colchicine Frusemide lmipramine Colchicine Frusemtde Yrusemide
Gout Prcapilalzd diabetes Diarrhoea Gout Constipation Diarrhoea Gout Postural hypotension 2' to hypokalacmia
* The drug WAS
Possible Probable Definitet Possible Prubablz Detinrtd Possible
Stoppcd Decreased
Nor changed Decreased Nor changed Decreased
stopped, decreased in dosage or continued unchanged. and kboratory conlirmatiun was obtained. Re-challenge u ' a ~not instituted 1 No re-challenge. Strong icrnporal asaucmimn. Symptoms completely disappcarcd wlien drug was withdrawn. Drowsines.; and dry mouth aic the inubt commonly reportcd side efiects in patients on clonidine therapy.
t A clear cut temporal association
340
GERKE ET A L .
of drug therapy. Although this was a timeconsuming practice, it ensured a more reliable feedback of information. A history of drug taking prior to admission to hospital was obtained from some patients. However, an accurate drug-history was often not obtained due to a number of factors (e.g. patient morbidity, inability to remember drug names, and the fact that analgesics and laxatives were often not considered by the patient as being drugs). Although the number ofpatients in the present study was small, the information derived from it proved to be valuable. However, extension
VOL.
5
NO.
4
of such a programme is desirable, and, with expansion, further data on the number of reactions occurring with individual drugs and the characteristics of susceptible patients could be compiled. The most valuable attribute of the programme is that it has the potential to act as a progressive monitoring system, with immediate feedback to the prescribing medical practitioners, and would therefore assist in averting iatrogenic disease. Acknowledgements
The co-operation of the medical and nursing staff who assisted with this study is gratefully acknowlcdgcd. We thank Mrs. L. L. Kingston for secretarial assislance.
References I . Report of a WHO Meeting (1969). lnternational drug monitoring. 'Thc role of the hospital. Wid Hith Org. trchn. Rep. Ser (1969). 425, 5. 2. GARDNER. P. and WATSON, L J (1970): Adverse drug reactions A pharmacist based monitoring system. Clin Pharmurui. Ther. 11. 802 3. StlDL, L. G.. THORNTO\, G. F., S M I T HJ,. W. and CI CI.1, L. E (1966). Studies on the epidemiology of adverse drug reactions 111. Reachons in patieqts on a general medical sewice. Bid1. Johris N o p k . f l o p . 119, 299. 4. MACDONALD, M . G. and MACKAY,B. R. (19641: Adverse drug rractmni Experience of Mary Fletcher Hospital dunng 1962, J Amer. nted. Ass. 190, 1071. 5 . KO~H-WESER, J., SIDEL, V. W., SWEtT, R. H., K A N A R ~ K P.. and EAT"&. A. E. (1969): Factors determining physician reporting of adverse drug reactions. New, Engl. J . Med. 280, 20. 6. A M A Council on Drugs (IY64). Registry ot adberw reactions. J. Amer med. ASS. 188, 374.
Aust N Z
J Med (1975). 5, pp 340 347 - -~
7. Report vf a WHO Meeting (1966): Principles for pre-clinical testing of drug safety. Wld Hlth Org. rechn. Rep. Ser. (1966), 341, 7. 8. SElDr. L. G.. THORYTON. G F. and CI I F t , L. E. (1965): Eptdemio1ogic;il studies of adverse drug reactions. Amer. J . p h i . Ilirh 55, 1170 9 HLRWITZ.N. and WADF, 0. L (1969). lntcnsive hospital monitoring 01adverse reactions to drugs, Brir. med. . I1, 531. 10. SCHIMMFL, E M. (1964). The hazards o l hospitalimtion. Am!. inicrn
Med. 60. 100. I I . SMITH,J. W., S ~ I D LL. ci. and CLUFI.L E 11966): Studics on ths cpidsmlology ofadvcrse drug reactions. V. Clinical factors influencing susceptibility. Ann. inrem. Wed. 65, 629 12. BOKDA,I . JICK, H.. Si.os1, D ., DihAN, 8.. G I L M A \ ,8 . and C I ~ A L M I K I . T.(IY67): Studies of drug usage i n five Boston hospitals. J . A m r r . ncrd ASJ. 202, 506
~~~
~
-~~~~~
CASE REPORT
Diarrhoea and Colitis Associated with Antibiotic Treatment A Report of 16 cases G. E. Gibson', R. Rowland? and R. Hecker:
From the Gastroenterology Unit, Royal Adelaide Hospital and The Institute of Medical and Veterinary Science, Adelaide "Visiting G a s t r o e n t e r o l o g i s t , Royal A d e l a i d e Hospital t S e n i o r H i s t o p a t h o l o g i s t , T h e I n s t i t u t e of M e d i c a l and V e t e r i n a r y
Science :Director,
G a s t r o e n t e r o l o g y Unit, R o y a l A d e l a i d e H o s p i t a l
Correspondence Dr. R Rowland. Senior H i s t o p a t h o l o g i s t , T h e Institute of Medical a n d V e t e r i n a r y Science Box 14, Rundle S t r e e t Post O f f i c e , A d e l a i d e , South Australia 5000 Accepted for publication: 18 F e b r u a r y . 1975
Summary: Diarrhoea and colitis associated with antibiotic treatment. G E Gibson, R Rowland and R Hecker, Aust. N.Z. J. Med., 1975, 5, pp. 340-347
Sixteen cases of colitis developing within twenty-one days of antibiotic therapy are reported. There was a wide range of disease severity. Lincomycin and Clindamycin were implicated in twelve. The colitis was of t w o pathological patterns, pseudomembranous
2!.
value' t n healthy ch:ldrcn and adults from Highland and c o a j t n l a i m , of Papua \ c u Guinea: prediction nomogram? for forced e x p i r d l o i ~~ 0 1 ~ 1 1 1 2 and forced \ital capacity. Pupuo V Girinro n i i d I 17. I h 5
22
I I MCLXRMOTT.-34, MCDERMOTT. T I. and COLLIZI 41. M (19hXi 4 portable bellows spromerer and timing u n i t f o ~the m c a ~ ~ ~ r c i i i cofn l resplraton; tunction. M r d bwl E n p ~ g6 . 291 13. Miauk. F.. Sai \nr&z\. \,I J HYCTT.t . R t Y w L u h . J A . PI.ARI and COTIS.I E (19651 Automat(< measurement of lune function. I
27
?4
2, 9 3
Con\. J E . D%nB\.I. h 4 . E ~ u o o u P. C . H*I.L. .A hl.. h.IrDo\4in. 4 and S X L . ~ U ~hl. R SJ. (1972) lron~deficlencyanaemia 11s efleit on tlan,li.I iacior for the lung ( d ~ f f u s i n capacit?) p and v c r i l i l a t i o n and cardiac ficqucnc) d u i n g sub-maximal cxm.isc. Clrn S c ! . 42. 325 14 C n n \ J t , S%L\DIRS. hl. J , ADAM. J. E R . A W E R S J ~ .H R. and HALL.A hl (19?31: Lung function m coastal and Highland Neu Cruinennc comparxon M-irh Europeans. I k o r a i 28, 320 I S . CUTE,. I. E . ANUt.Km".i. 11. R and P&TRICK. 1 M 11974) Lung i l l n i t i o n and response to exercise in natiw N e w Ciuioenns role 01 gcnctic and environmental Sactois. Phil. T r u n ~ B. 268. 339 16. SIMON. G I 19?1). Pnociplec of chest X-ray dmgnosic. 3rd c4.. Buttcruurth. I3
25
28 29
.. T I I ~ M A4~ .J and KOSSTER. C. (1961) Thc recognilion heait dlseasr in tlic prcscncc of pulmonary dised>e.
Btii
Hrari J 26. 2 ? 3 . I S S,\\ERKIN. N Ci and E ~ ~ NDs . M D (1965): The sputum in bronchial arihnia pathognomonic patterns. .I Porh Hoi,r. 89, 535 19 FLETCHIR. C 2.1. PITO. R . S P t l Z F R . F. S. and Tl?lhFK. C M. 119701: .A follou up study of the naiural hirrory o f ohsrructiie bioiichitis I n Orie. N G M a n d Van dci Lendc. R. cd, . B w m l u r , . ~ I l l . Proceeding? of the Ihiid lntcrnatioiinl Sympuuum on Bronchitis. pp 103- I i6 Royal
V a n g o r ~ u m .A w n
30
1
?I
1
32.
1
B L R R O W \ . B.. FLrTrlil R C M HtqRt>. B E . J O N E S . N L and WOOTI 11 I .I. S. (19661 The e m p h y s c r n a t o u ~and bronchial type5 of chronic ariun), ob,tluctiun n climcuparhological stud? of pdfi~1113 i n Londun and Chlcdgo. Lancci 1, 830 THCRLHLCK. W hl.. I I t z U l R ~ O \ . J -2. M . FR,ASFR. R G and Bkils. D V-. I 1970) Chronic obstructirc lurip diaearc: a comparison hetaecn clmical. roentpenolupc. funclional and morpholngic crileiia in chronic bronchilir. emphyrem.!. asthma and bmnchiectasis. M e C H I R N I A K . N S. and CARL TO^. R. W. 119h61: Factor rcipirdlury iniuficiency in bronchiectasi5 .4mri J .+led 41. 562 BIR4TH. Ci , C A R O . I . MxLMbtRG. R. and obstiuction in pulmonary tuberculoris. CRorTn\. J and DOUGLAP. A. (1969): Edinburph. Blackwell Scisntitic Publicatiui A>. J. W. B and R I , ~ I 7 . U 11477) Rzspiral,,ry influence of early childhood I u w r rehpirator! a11 pollution and m o k i n g . B t u mi,d .I. 3, 1 Y 5 e Sate nf the cliionic bionchitic. a report of t h e ren year follow up in thc Canadian department of Veteran's a f i m i s cwoidinated study of chronic bronchitis. Am?, Kus tes),. D L 108, 1043 1 3 Department of Health. Education and Welfare (1971) The health consequcn'es oi bmoking. C.S. Ciorernmtnt Ynqtirg Officc. Washmg:on VaY nrR LEND€. R , DF KROO\. J P. M.. V 4 h nrR M r i ~ f K .G G T A M U ~ L IG~ GI... VisstK, B. F.. Dr VRir?. K and ORIE.\ C M ilY70). Possible indicator? of endogenous iactois in rhc d?vclopmenr of CNSI D I n One, N Ci M and Vlin der Lende. R eds.. Bion,hifrs I l i . pp 52-71 Royal Vdngorcum. Assen. LwAnlA F t (1967) Tropical eosinophilia-~a correlation of CII~ICBI. hirtoualhologic and lung function studie?. Dds ClwAr 52, 311 A w l n c o h . H K (1974) Thr cpidemiological and allergic featuics 01 asthma in thc New Guinea Highlands. Clcn Allerg\. 4, 171 C i n F r \ B E R G . M . MILNF.I. F and W A r T . .A (1 9 T I) Survcy of w o r k s e x p o 4 to dusts containing derivatiies 01 Bacillua iubtilia. Brir. med 1. 2. 629.
Ausr N / J bled (1975). 5 , pp 336 340 ~
~
~~
~~
~~
~
~
Extensive Drug Surveillance-A
~~
Pilot Study
D. C. Gerke*, E. Gail Easterbrookt, D. 6. Frewin: and T. I. Lee"" From the Departments of Human Physiology and Pharmacology, University of Adelaide and the Royal Adelaide HosDital
Summary: extensive drugsurveillance-A pilot study. D C G e r k e E G a i l Eaqterbrook D B Frewin and T I Lee Aust N Z J Med 1975 5, pp 336-340
The aim of this Extensive Drug Surveillance programme was to develop a system of drug monitoring suitable for detecting adverse
-
~
"Dental Surgeon Postgraduate Research Scholar University of Adelaide +Pharmacist Royal Adelaide Hospital :Senior Lecturer in P h a r m a d o g y University of Adelaide and Visiting Pharmacologist Royal Adelaide Hospital ""Chief Pharmacist Royal Adelaide Hospital Correspondence Dr D B Frewin Department of Human Physiology and Pharmacology University of Adelaide Adelaide South Australia 5001 Accepted for publication 4 February 1975
drug reactions in hospitalised patients. The monitored field was a general medical ward in the Royal Adelaide Hospital and monitoring was carried out for a period of one month (September 1974). A total of 85 patients (45 males and 40 females) were monitored and in 1 4 of them adverse reactions were noted. The overall incidence of such reactions was 16.5%. A greater intake of drugs was a significant finding in patients w h o experienced adverse reactions. Coupled with this was the observation that patients w h o stayed longer in hospital had a greater number of drugs administered to them. A third finding was the higher incidence of reactions in female patients.
The use of a drug monitoring system has largely been accepted as the most appropriate way of detecting adverse reactions to drugs in a monitored field.’ There has, however, been a diversity in the types of systems used. Gardner and Watson‘ described a pharmacist based monitoring system in a hospital which gave a yield of 10.5‘); adverse drug reactions. Seidl et reported an intensive hospital monitoring system with a detection rate of 13 6 9; probable reactions during hospitalisation, while MacDonald and MacKay“, using a system relying on physician reporting. showed only 1 n!o drug reactions in a monitored field. Koch-Weser et aL5, who used a spontaneous physician reporting system, registered a figure of approximately 4 for adverse reactions. The cxtensive drug surveillance (monitoring) system incorporates the more advantageous aspects of the above systems to provide a means of recording all adverse reactions as accurately as possible, but with perhaps greater ease, reliability and precision than with other systems. The purpose for establishing this drug surveillance programme was thrccfold :
(1) It was felt that the incidence of drug reactions occurring in the Royal Adelaide Hospital should be known. (2) Invaluable information about the adverse reactions caused by individual drugs would be compiled. Coupled with this, new drugs being administered within the hospital could be clinically assessed for efficacy, tolerance and toxicity from data collected by this monitoring system. (3) This surveillance programme has the potential for being a progressive monitoring system, thus allowing immediate feedback to the medical prescribers as to the possibility of adverse reactions occurring or, in fact. the occurrence of a reaction perhaps not detected by the prescriber. The programme therefore achieves the three objectives set out by the AMA Council on Drugs6 ; these serving : “(a) to alert physicians to the potential toxicity of new drugs, (b) as a reminder of the potential toxicity of drugs and chemicals in common use,
(c) as a reference for physicians investigating suspcctod reactions to drugs.” Methods
.Monitored Field For one month (September 1974) all male and female paticnts who were admittcd to a general medical ward in the Royal Adelaide Hospital entered the monitored field. Thcse patients werc monitored until they left the field either by transfer to another ward, discharge from thc hospital, or death. Monitoring was continued until discharge for those patients who remained in the ward aftcr the 30th of September. A new record was started if a patient was discharged and readmitted to thc ward within the initial month of surveillance. Drugs The definition of a drug was that used by the WHO’, i t . “A drug is dcfincd as any substance or product that is uscd or intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient.” Only drugs prescribed in the ward by attending medical officers were recorded. This ineant that doscs of laxativcs were sometimes not recorded, because they were usually given at the discretion of the nursing staff, and often there were no written records kept. Records of drugs given for radiological procedures were not maintained as this information was sometimes hard to retrieve. However, since all personnel who were involved in the management of these patients were aware of the drug surveillance programme. any adversc reactions which wcre thought to have resulted from either laxative therapy or from radiological agents would have been promptly reported Datu Collrccion Thc data was collectcd by thrce monitors (i.e. a pharmacist, a dentist and a clinical pharmacologist). These monitors visited the ward on a daily basis and rcviewed the mcdical record and drug charts of each patient. Relevant information from these source5 was transcribed on to special data acquisition forms. The role of thc monitor was to record accurately all specified data ( i t . “interesting” or “uninteresting” data was not omitted). Reactions and interactions were checked by the clinical pharmacologist. To guard against transcription errors at the time of initial data collection, the monitoring system’s record was re-checked against the hospital record after the patient had been discharged. Data, such as name, age, sex, hospital number, ward, date of admission, and diagnosis were recorded soon after admission of each patient. Previous drug reactions and allergics werc obtained from the patient’s medical history. Information about drug therapy was obtained by regular cxamination of the drug sheet for each patient. The drugs given, their route of administration, timing of treatment, dosage. total daily dose, and any change in treatment or dosage were recorded. The medical and nursing staff were questioncd regularly about the occurrence of events which may have constituted an adverse reaction to a drug. Constant surveillance of the medical progress records was carried out to observeany comments about adverse reactions, and the co-operation of the medical staff was solicited in notifying the monitors if such an event did occur. The data on one patient was excluded because or the fact that 65 of the 70 days spent in hospital were in an intensive care ward. away from the monitored field.
P,ohahi/itjbqfReocrion2~ "Definite: These are adverse reactions coiumonly known to occur with a clear-cut temporal association. positi\ e re-challenge test or laboratory confirmation. Probable: These are adverse reactions commonly knov,m to occur with a clear-cut temporal association and improvement on withdrawal of medicine. Possible: These are adverse reactions known to occur. The temporal relationship is less clear and other etiologies are also possible. Iloubtful: In this case some other cause of adverse reactions is judged more likely." S r r r r i t j . of K e i m u n
This was not classified and reactions were described on the basis of symptomatology produced in the patient. As more data accumulates. the classification of the severity of the reactions will become necessary.
Results
Forty-five males and forty females were admitted to the ward during the period of surveillance. Two of the inales were discharged and latcr readinitted. This accounts for the discrepancy between the number of patients and the number of discharges. transfers or dcaths (Table 1). Fivc patients died during their hospital sojourn (Table 1). but none of these deaths were attributed to adverse reactions to drugs. There was a good match between the mean ages of the male arid female groups and also the mean duration of their stay in hospital. The principal diagnosis for each patient participating in the study is listed in Table 2. Four females and one male were admitted with a history of drug overdosage or abuse.
The breakdown of the various drugs which were administered to the patients is shown in Table 3. The mean number of routine drugs for inales WRS 5 . 3 and that for the females 4. The mean number of drugs on discharge was 3 . 9 (for males) and 2 . 8 (for females). The mean number of prescribers was 2 . 2 for the combined male and fcinale populations. The adverse reactions which were detected during the study are listed in Table 4. 111 mosi instances the suspected causative agents were either discontinued or decreased in dosage. However, in three patients the therapy remained unchanged despite the possibility that an adversc reaction was associated with it. The incidence of advcrsc drug reactions was 13.3",, (male) and 20"; (female), with an overall mean of 16.5% for the two sexes. The incidence of adverse reactions was thercforc greater in thc female group. When the drug intake of the patients was analysed in relation to the duration of their hospital stay, it was found that patients staying longer than 15.7 days (the mean) were administered inore drugs than those staying in hospital for less than this period ( P < 0.0005). It w a s also found that patients who developed adverse reactions had more drugs administered to them than those who did not ( P < 0.025). The population of patients suflering from inore than one reaction was also found t o have had more drugs ( P < 0.05) and ii longer stay ( P < 0.05) than the remainder of the patients who had only one adverse reaction.
TABLE 1 A comparison of male. female and group data
TABLE 2 Principal complaint on admiasion
Patient Male
Female -
Number of patients Number discharged Number tranrferred Number deaths Mean age (years) Range Medn jtay Iddys) Range
45* 40 4 3 63 2 25-95 16 1-54
40 33
5 2 61 5 21 94 15 2 4 51
Male
Total ( M dnd F)
_ _ _ ~
~
85 73 9
jt 62 4 21 95 15 7 1-54
* T w o male patients were admitted. discharged and readmitted during this study. The total number of admissions was therefore 87. t No deaths occurred due to drug reactions.
Female -
~~
Haema tological Cardiovascular Respiratory GIT GI! Hcpatic CNS Others
3 23
Total
45
6
3
15
I
38 14 6 1 4
9 4*
14 5
0
5 1
~
0 8* 3*
3* 1 3
Total
~
~~
40
85
* These figures includc thc five patients with a history of drug overdosage or abuse: three had GIT symptoms, one had respiratory symptoms and the other washypokalaernic.
330
DRUG SURVEILLANCE TECHNIQUFS Discussion
A total of 20 adverse drug reactions were detected in 14 patients during the period of this extensive drug surveillance programme which represents an incidence of 16.574 of drug reactions in the monitored population. This figure was obtained using the notation :
i:xs)
14 ,ncidence = No. of patients with adverse _ _ _ __drug _ _ - - ~reactions -- No. of patients exposed ~
loo
Our value for the incidence of reactions is greater than those reported by Gardner and Watson2 and Seidl el aL3 However, it must be noted that both those studies considered only definite and probable reactions, whereas our results included all categories of drug reaction. Several authors'. l 1 h ave concluded that the number of adverse reactions increases with the total number of drugs taken by individual patients. Our results support this conclusion. Our findings also indicate that the number of drugs administered to patients increases with the increased duration of their hospital stay, which is in agreement with the observations of Borda et d . I 2 Patients with severe or chronic illness are more likely to be hospitalised for longer periods of time and the influence of patient morbidity in relation to adverse drug reactions has to be taken into account. Diminished hepatic or renal function and associated altercd drug metabolism and excretion are some of the factors that must be considered. The administration of greater numbers of drugs ''5
to the severely ill m a y also lead to adverse reactions, either due to the agents themselves or due to drug interactions. An interesting finding to emerge from this study was the higher incidence of adverse reactions in the female group which is in keeping with the results of Hurwitz and Wade.' The female patients in our study received a mean total of 6 . 9 drugs as compared to a mean of 8 . 4 drugs in the males. The mean duration of hospital stay was not significantly different in the two groups. The reason for the female having a greater frequency of adverse reactions is therefore not explained on the basis of numbers of drugs taken. MacDonald and MacKay4 and Koch- Weser et L I I . ~ commented that adverse drug reactions were seldom recorded in the medical progress charts of each patient. To circumvent this problem in our study, the monitors regularly questioned the medical staff and patients in relation to adverse drug reactions and alterations
TABLE 4 Summary oiadverse reactions in male and iernalc patients
~~
Patient ~.~
~
Mean*
Koutincdrugs Statim d r u g s prndrugscaken p r n prescrihed ~
.
~~
Kange*
~~.
~~
IV d r u g s
-~
I 5.3 1.6 1-5
(2.4)
6-0 160 II 0 7 0 (8-0)
~
~~~~
8.4
Dischargedrugs
* Per paticnt. t Keprebents the
~~~
3 9
30wl
Mean ~
~~~~~
~~~~~
~
~~~~~~~
~~~~~~
Outcome' -
~ _ _..
Postural hypotension Possible Low plasma volume Doubtful
Decreased Stopped
6
Phenytoin
1 iolate. macrocytic anaemia Drowsy
Prohable
Decreased
14
DmLcpam
1 arterial 0,.2 1 respiration
Possible Probable
stopped Stopped
21
Predmsolone Co-trirnoxazole
GIT irritation I'hru4i lorail
24
Clonidine Morphine
Drowsy, dry mouth Vomiting
43
Fruacmide
Possible Possible Definite: Probable Definite? -~
Decreased Stopped Stopped Stopped Decreased
Probable
Stopped
Possible Definitet
Stopped Dccrcaacd ,Nor changed
~. __ _ __ _ - -. ~ ~~~
to
Hypokalaemia ~
~
~
~~
FEMAI.ES
Range
2
5
~
0.7 4 1-1 1.6
4 0 11-0
(2.21
(7-0)
5-4
IY 26
28
5-0
6.9
IY- 1
2.8
5-0
- .
11 0
. .__.. . ~ ~
Probability
Uethyldopa Bendrolluaridc
35 38
-~~ ..-
-
~
~~
Reaction
~
~~~~~
Totalt
~
kernales -~~~~
.~~~ ~~
~~
~ . - ..~ ~ ....
mug
Trimeprannc
Nurnhcr of dift'erent d r u g s administered
~~
M4LbS ...
2
TABLE 3
Males
~-__
~
total n u m b e r of drugs administered t o the patient. Adjustment has been made if any ovcrlap in the IV, routine, stattm a n d pm schedules exists. IV = intravenous; prn = pro re nata
39
Nalidixic acid Sorbide nitrate
Urticaria1 rash Headacbe
Fruscmidc Chlororhiazide Colchicine Frusemide lmipramine Colchicine Frusemtde Yrusemide
Gout Prcapilalzd diabetes Diarrhoea Gout Constipation Diarrhoea Gout Postural hypotension 2' to hypokalacmia
* The drug WAS
Possible Probable Definitet Possible Prubablz Detinrtd Possible
Stoppcd Decreased
Nor changed Decreased Nor changed Decreased
stopped, decreased in dosage or continued unchanged. and kboratory conlirmatiun was obtained. Re-challenge u ' a ~not instituted 1 No re-challenge. Strong icrnporal asaucmimn. Symptoms completely disappcarcd wlien drug was withdrawn. Drowsines.; and dry mouth aic the inubt commonly reportcd side efiects in patients on clonidine therapy.
t A clear cut temporal association
340
GERKE ET A L .
of drug therapy. Although this was a timeconsuming practice, it ensured a more reliable feedback of information. A history of drug taking prior to admission to hospital was obtained from some patients. However, an accurate drug-history was often not obtained due to a number of factors (e.g. patient morbidity, inability to remember drug names, and the fact that analgesics and laxatives were often not considered by the patient as being drugs). Although the number ofpatients in the present study was small, the information derived from it proved to be valuable. However, extension
VOL.
5
NO.
4
of such a programme is desirable, and, with expansion, further data on the number of reactions occurring with individual drugs and the characteristics of susceptible patients could be compiled. The most valuable attribute of the programme is that it has the potential to act as a progressive monitoring system, with immediate feedback to the prescribing medical practitioners, and would therefore assist in averting iatrogenic disease. Acknowledgements
The co-operation of the medical and nursing staff who assisted with this study is gratefully acknowlcdgcd. We thank Mrs. L. L. Kingston for secretarial assislance.
References I . Report of a WHO Meeting (1969). lnternational drug monitoring. 'Thc role of the hospital. Wid Hith Org. trchn. Rep. Ser (1969). 425, 5. 2. GARDNER. P. and WATSON, L J (1970): Adverse drug reactions A pharmacist based monitoring system. Clin Pharmurui. Ther. 11. 802 3. StlDL, L. G.. THORNTO\, G. F., S M I T HJ,. W. and CI CI.1, L. E (1966). Studies on the epidemiology of adverse drug reactions 111. Reachons in patieqts on a general medical sewice. Bid1. Johris N o p k . f l o p . 119, 299. 4. MACDONALD, M . G. and MACKAY,B. R. (19641: Adverse drug rractmni Experience of Mary Fletcher Hospital dunng 1962, J Amer. nted. Ass. 190, 1071. 5 . KO~H-WESER, J., SIDEL, V. W., SWEtT, R. H., K A N A R ~ K P.. and EAT"&. A. E. (1969): Factors determining physician reporting of adverse drug reactions. New, Engl. J . Med. 280, 20. 6. A M A Council on Drugs (IY64). Registry ot adberw reactions. J. Amer med. ASS. 188, 374.
Aust N Z
J Med (1975). 5, pp 340 347 - -~
7. Report vf a WHO Meeting (1966): Principles for pre-clinical testing of drug safety. Wld Hlth Org. rechn. Rep. Ser. (1966), 341, 7. 8. SElDr. L. G.. THORYTON. G F. and CI I F t , L. E. (1965): Eptdemio1ogic;il studies of adverse drug reactions. Amer. J . p h i . Ilirh 55, 1170 9 HLRWITZ.N. and WADF, 0. L (1969). lntcnsive hospital monitoring 01adverse reactions to drugs, Brir. med. . I1, 531. 10. SCHIMMFL, E M. (1964). The hazards o l hospitalimtion. Am!. inicrn
Med. 60. 100. I I . SMITH,J. W., S ~ I D LL. ci. and CLUFI.L E 11966): Studics on ths cpidsmlology ofadvcrse drug reactions. V. Clinical factors influencing susceptibility. Ann. inrem. Wed. 65, 629 12. BOKDA,I . JICK, H.. Si.os1, D ., DihAN, 8.. G I L M A \ ,8 . and C I ~ A L M I K I . T.(IY67): Studies of drug usage i n five Boston hospitals. J . A m r r . ncrd ASJ. 202, 506
~~~
~
-~~~~~
CASE REPORT
Diarrhoea and Colitis Associated with Antibiotic Treatment A Report of 16 cases G. E. Gibson', R. Rowland? and R. Hecker:
From the Gastroenterology Unit, Royal Adelaide Hospital and The Institute of Medical and Veterinary Science, Adelaide "Visiting G a s t r o e n t e r o l o g i s t , Royal A d e l a i d e Hospital t S e n i o r H i s t o p a t h o l o g i s t , T h e I n s t i t u t e of M e d i c a l and V e t e r i n a r y
Science :Director,
G a s t r o e n t e r o l o g y Unit, R o y a l A d e l a i d e H o s p i t a l
Correspondence Dr. R Rowland. Senior H i s t o p a t h o l o g i s t , T h e Institute of Medical a n d V e t e r i n a r y Science Box 14, Rundle S t r e e t Post O f f i c e , A d e l a i d e , South Australia 5000 Accepted for publication: 18 F e b r u a r y . 1975
Summary: Diarrhoea and colitis associated with antibiotic treatment. G E Gibson, R Rowland and R Hecker, Aust. N.Z. J. Med., 1975, 5, pp. 340-347
Sixteen cases of colitis developing within twenty-one days of antibiotic therapy are reported. There was a wide range of disease severity. Lincomycin and Clindamycin were implicated in twelve. The colitis was of t w o pathological patterns, pseudomembranous
