PROCEEDINGS OF THE B.P.S., 3rd-5th JANUARY, 1979 437P
due to the subjects themselves with that attributable to the investigators who perform and analyse the recordings. The subjects were healthy young adults; they did not smoke on the day of the experiment. All measurements were made in the post-absorptive state after the subjects had rested supine for at least 30 min. A minimum of three control recordings of ACG and STI were made as described (Burgess, Turner & Wadsworth, 1977; Denef, Popeye, 'de Geest & Kesteloot, 1975). Recordings of ACG and STI were made in 11 subjects on 2 separate days, and the variation in these measurements within and between subjects and days was determined. In 18 subjects, STI were, recorded after the administration of incremental doses of atropine given intravenously to produce a range of heart rates; ACG were recorded in 8 subjects under similar conditions. Regression analysis was used to derive the indices for QS2, left ventricular ejection time (LVET), pre-ejection period (PEP), PEP/LVET ratio and dA/dt/At max. In a separate study, two investigators made pairs of recordings of ACG and STI from 6 volunteers; the records were photocopied and the originals and copies were analysed independently by the two investigators. The relative contributions of subject, investigator, analyser, time and photocopying process to the variability of the measurements were assessed using analysis of variance. dA/dt/At max increased, and QS2 and LVET fell, as heart rate increased; PEP/LVET ratio fell only in female subjects. PEP in males and females, and PEP/LVET in males, showed no clear dependence on heart rate. Variation in the measured quantities due to the investigator, analyser, time and photocopying
Interlaboratory variability in determination of serum theophylline concentrations results of a quality control programme -
SUSAN BOOBIS Department of Clinical Pharmacology, St. Bartholomew's Hospital, London EClA 7BE
Theophylline preparations are frequently used in the treatment of asthma. The therapeutic range for serum theophylline is relatively low (56-112 gtmol/l; 10-20 ig/ml) and the achievement of adequate therapeutic response with minimum toxicity requires monitoring of serum theophylline levels. Many laboratories have
process was small compared with that attributable to the subject except in the case of PEP, where the analyser was responsible for 14.4% of the observed
variability. We conclude that: 1. dA/dt/At max requires correction for changes in heart rate. 2. The indices relating STI to heart rate in our studies differ substantially from those generally accepted and widely used (Weissler et al., 1968), perhaps due to important methodological differences. 3. The variability in measurement of ACG and STI which can be attributed to external factors, such as the investigator and analyser, is very low in comparison with the variability of the subjects being studied, with the possible exception of PEP.
References BURGESS, D.C., TURNER, P. & WADSWORTH, JANE
(1977). Cardiovascular responses to mianserin hydrochloride: a comparison with tricycic antidepressant drugs. Br. J. clin. Pharmac., 5, 2 1S-28S. COKKINOS, D.V., HEIMONAS, E.T., DEMOPOULOS, J.N., HARALAMBAKIS, A., TSARTSALIS, G., & GARDIKAS,
C.D. (1976). Influence of heart rate increase on uncorrected pre-ejection period/left ventricular ejection time (PEP/LVET) ratio in normal individuals. Br. Heart J., 38, 683-688. DENEF, B., POPEYE, R., DE GEEST, H. & KESTELOOT, H.
(1975). On the clinical value of calibrated displacement apexcardiography. Circulation, 5, 541-551. WEISSLER, A.M., HARRIS, W.S. & SCHOENFELD, C.D. (1968). Systolic time intervals in heart failure in man. Circulation, 37, 149.
therefore established assay procedures for theophylline. Twenty laboratories, in the United Kingdom, Europe and Australia, took part in a pilot study to assess interlaboratory variability in determining serum theophylline concentrations. Each laboratory received two samples of pooled patient serum containing theophylline each month, and was asked to report their results and method to us. Data obtained over a period of 5 months were collated, enabling certain conclusions to be drawn. Of the twenty laboratories in the scheme, fifteen returned at least one set of results during this time. Two laboratories dropped out because of difficulties with method, and three laboratories returned no results. The laboratories returning results used the
438P
PROCEEDINGS OF THE B.P.S., 3rd-5th JANUARY, 1979
following assays: gas-liquid chromatography (GLC), high-pressure liquid chromatography (HPLC), EMIT enzyme immunoassay (Syva Corporation), thin-layer chromatography (TLC) and ultraviolet spectrometry. A monthly 'performance index' was devised, based on the number of standard deviations of each result from the group mean. A laboratory whose result came within + 0.5 of one standard deviation from the mean scored 1, the best 'performance index', while Table 1 'Performance index' patterns for a 'good' (A) and a 'poor' (B) laboratory, each using the EMIT system
Laboratory Month
A
B
May June July August
3.5 2.5 1.5 2.5 2
6 4.5 6.5 5.5
September
8
The current use of narcotic analgesics in hospital practice K. CHAN School of Pharmacy, Liverpool Polytechnic, Liverpool L3 3AF
This present study presents a survey, based on the analysis of records in the 'Controlled Drugs' register (The Misuse of Drugs Regulations, 1973), on the
laboratories whose results differed from the group mean by 5 or more standard deviations scored 10, a very poor 'performance index'. Table 1 shows the records of a 'good' laboratory and of a 'poor' one. The performance of the various assay methods was also assessed in this way. Overall, HPLC was consistently best, with an index of 2, while EMIT and ultraviolet spectrometry, with an index of 3.5, were poorest. This study, although only on a small scale, has revealed large differences in the values reported by various laboratories for the same samples, and of the fifteen laboratories returning results, at least one has had a consistently poor performance throughout. It is clear that the results produced by such laboratories could often have led to incorrect drug dosage adjustments being made had the samples come from real patients. The measurement of serum theophylline concentrations may be more misleading than helpful if good internal and external quality control is not employed, and the results of this pilot scheme highlight the need for much greater attention to the accuracy of assay techniques for theophylline.
current use of narcotics in three teaching hospitals and one non-teaching hospital in the Mersey Region. Results have revealed a certain pattern in the use of these drugs in hospital practice, similar to those obtained from a previous survey in the West Midland
Region (Chan, Mitchard & Trueman, 1976). Over the 5-year period (1972 to 1976) teaching hospital A used nearly 1.5 times more narcotics than the non-teaching hospital (73,608 and 49,448 doses; 105,6 and 98.8 doses per bed, respectively). The most popular narcotic was the synthetic analogue, pethidine, in both hospitals (Table 1). Over the 3-year
Table 1 Rank order of narcotic used in teaching hospital A and non-teaching hospital (% of 5-year total, 1972-1976)
Teaching hospitalA (73608 doses) Preparation
Rank 2 3 4 5 6 7 8 9
Pethidine Morphine Diamorphine Phenoperidine Fentanyl Papaveretum Dihydrocodeine Methadone Piritramide
44.5 22.9 22.4 5.4 2.3 1.8 0.6
due to the subjects themselves with that attributable to the investigators who perform and analyse the recordings. The subjects were healthy young adults; they did not smoke on the day of the experiment. All measurements were made in the post-absorptive state after the subjects had rested supine for at least 30 min. A minimum of three control recordings of ACG and STI were made as described (Burgess, Turner & Wadsworth, 1977; Denef, Popeye, 'de Geest & Kesteloot, 1975). Recordings of ACG and STI were made in 11 subjects on 2 separate days, and the variation in these measurements within and between subjects and days was determined. In 18 subjects, STI were, recorded after the administration of incremental doses of atropine given intravenously to produce a range of heart rates; ACG were recorded in 8 subjects under similar conditions. Regression analysis was used to derive the indices for QS2, left ventricular ejection time (LVET), pre-ejection period (PEP), PEP/LVET ratio and dA/dt/At max. In a separate study, two investigators made pairs of recordings of ACG and STI from 6 volunteers; the records were photocopied and the originals and copies were analysed independently by the two investigators. The relative contributions of subject, investigator, analyser, time and photocopying process to the variability of the measurements were assessed using analysis of variance. dA/dt/At max increased, and QS2 and LVET fell, as heart rate increased; PEP/LVET ratio fell only in female subjects. PEP in males and females, and PEP/LVET in males, showed no clear dependence on heart rate. Variation in the measured quantities due to the investigator, analyser, time and photocopying
Interlaboratory variability in determination of serum theophylline concentrations results of a quality control programme -
SUSAN BOOBIS Department of Clinical Pharmacology, St. Bartholomew's Hospital, London EClA 7BE
Theophylline preparations are frequently used in the treatment of asthma. The therapeutic range for serum theophylline is relatively low (56-112 gtmol/l; 10-20 ig/ml) and the achievement of adequate therapeutic response with minimum toxicity requires monitoring of serum theophylline levels. Many laboratories have
process was small compared with that attributable to the subject except in the case of PEP, where the analyser was responsible for 14.4% of the observed
variability. We conclude that: 1. dA/dt/At max requires correction for changes in heart rate. 2. The indices relating STI to heart rate in our studies differ substantially from those generally accepted and widely used (Weissler et al., 1968), perhaps due to important methodological differences. 3. The variability in measurement of ACG and STI which can be attributed to external factors, such as the investigator and analyser, is very low in comparison with the variability of the subjects being studied, with the possible exception of PEP.
References BURGESS, D.C., TURNER, P. & WADSWORTH, JANE
(1977). Cardiovascular responses to mianserin hydrochloride: a comparison with tricycic antidepressant drugs. Br. J. clin. Pharmac., 5, 2 1S-28S. COKKINOS, D.V., HEIMONAS, E.T., DEMOPOULOS, J.N., HARALAMBAKIS, A., TSARTSALIS, G., & GARDIKAS,
C.D. (1976). Influence of heart rate increase on uncorrected pre-ejection period/left ventricular ejection time (PEP/LVET) ratio in normal individuals. Br. Heart J., 38, 683-688. DENEF, B., POPEYE, R., DE GEEST, H. & KESTELOOT, H.
(1975). On the clinical value of calibrated displacement apexcardiography. Circulation, 5, 541-551. WEISSLER, A.M., HARRIS, W.S. & SCHOENFELD, C.D. (1968). Systolic time intervals in heart failure in man. Circulation, 37, 149.
therefore established assay procedures for theophylline. Twenty laboratories, in the United Kingdom, Europe and Australia, took part in a pilot study to assess interlaboratory variability in determining serum theophylline concentrations. Each laboratory received two samples of pooled patient serum containing theophylline each month, and was asked to report their results and method to us. Data obtained over a period of 5 months were collated, enabling certain conclusions to be drawn. Of the twenty laboratories in the scheme, fifteen returned at least one set of results during this time. Two laboratories dropped out because of difficulties with method, and three laboratories returned no results. The laboratories returning results used the
438P
PROCEEDINGS OF THE B.P.S., 3rd-5th JANUARY, 1979
following assays: gas-liquid chromatography (GLC), high-pressure liquid chromatography (HPLC), EMIT enzyme immunoassay (Syva Corporation), thin-layer chromatography (TLC) and ultraviolet spectrometry. A monthly 'performance index' was devised, based on the number of standard deviations of each result from the group mean. A laboratory whose result came within + 0.5 of one standard deviation from the mean scored 1, the best 'performance index', while Table 1 'Performance index' patterns for a 'good' (A) and a 'poor' (B) laboratory, each using the EMIT system
Laboratory Month
A
B
May June July August
3.5 2.5 1.5 2.5 2
6 4.5 6.5 5.5
September
8
The current use of narcotic analgesics in hospital practice K. CHAN School of Pharmacy, Liverpool Polytechnic, Liverpool L3 3AF
This present study presents a survey, based on the analysis of records in the 'Controlled Drugs' register (The Misuse of Drugs Regulations, 1973), on the
laboratories whose results differed from the group mean by 5 or more standard deviations scored 10, a very poor 'performance index'. Table 1 shows the records of a 'good' laboratory and of a 'poor' one. The performance of the various assay methods was also assessed in this way. Overall, HPLC was consistently best, with an index of 2, while EMIT and ultraviolet spectrometry, with an index of 3.5, were poorest. This study, although only on a small scale, has revealed large differences in the values reported by various laboratories for the same samples, and of the fifteen laboratories returning results, at least one has had a consistently poor performance throughout. It is clear that the results produced by such laboratories could often have led to incorrect drug dosage adjustments being made had the samples come from real patients. The measurement of serum theophylline concentrations may be more misleading than helpful if good internal and external quality control is not employed, and the results of this pilot scheme highlight the need for much greater attention to the accuracy of assay techniques for theophylline.
current use of narcotics in three teaching hospitals and one non-teaching hospital in the Mersey Region. Results have revealed a certain pattern in the use of these drugs in hospital practice, similar to those obtained from a previous survey in the West Midland
Region (Chan, Mitchard & Trueman, 1976). Over the 5-year period (1972 to 1976) teaching hospital A used nearly 1.5 times more narcotics than the non-teaching hospital (73,608 and 49,448 doses; 105,6 and 98.8 doses per bed, respectively). The most popular narcotic was the synthetic analogue, pethidine, in both hospitals (Table 1). Over the 3-year
Table 1 Rank order of narcotic used in teaching hospital A and non-teaching hospital (% of 5-year total, 1972-1976)
Teaching hospitalA (73608 doses) Preparation
Rank 2 3 4 5 6 7 8 9
Pethidine Morphine Diamorphine Phenoperidine Fentanyl Papaveretum Dihydrocodeine Methadone Piritramide
44.5 22.9 22.4 5.4 2.3 1.8 0.6
