Acta anaesth. scand. 1978, 22, 303-313
Individual Variation in Response to Thiopental J0RGEN H. CHRISTENSEN and FREDERIK ANDREASEN Department of Anaesthesiology, Aarhus Kommunehospital and Institute of Pharmacology, University of Aarhus, Aarhus, Denmark
The anaesthetic records of 540 patients operated on during a 3-week period were studied. The purpose was to elucidate the influence of age, sex, concentration of haemoglobin, creatinine concentration in serum, heart disease, and the premedication given on the size of the induction dose of thiopental. A statistically significant fall in dose with advancing age was seen after the age of 60 and the significance increased when a weight-related dose was used for the calculations. A 6% difference, indicating a lower induction dose in women, was not statistically significant. When premedication with scopolamine and morphine had been used, significantly less thiopental was needed to induce anaesthesia than after atropine, diazepam and pethidine. When both sexes were considered, no correlation was found between haemoglobin concentration and induction dose of thiopental, but in two groups of women, weak negative correlations between these two variables were found. Thirty-seven patients on long-term treatment with digoxin and a diuretic required significantly less thiopental than 37 patients, otherwise comparable, not receiving this medication. About 60% of the dose used in 21 patients who were to have operations on their limbs was needed in 21 patients who were to be operated for valvular heart disease. Eleven patients with moderately elevated serum creatinine (average 2.1 1.0 mg/100 ml) required 11% (not statistically significant) less than 11 patients with normal serum creatinine (1.1 k 0.2 mg/ 100 ml). A considerable individual variation still exists for patients who are comparable with respect to all factors known to influence sensitivity to thiopental.
Received 22 August, accepted for publication 30 September 1977
For many years it has been known that the dosage of thiopental needed during operations shows considerable individual variation. The influence of diseases (SHIDEMAN et al. 1949, DUNDEE& RICHARDS 19543, other drugs (DUNDEE & GRAY1951), racial factors (SCOTT1953), body weight, sex and age (DUNDEE1954) have been the subject of publications. For all these studies, differences in the accumulation of the drug and in the nature of the operations performed could influence dosage. The same is true of the concomitant use of other drugs during the anaesthesia. Over the past 25 years, anaesthesiological techniques, as well as surgical procedures, have undergone developments which make it possible to operate on increasingly older
patients presenting a higher and higher risk. Also the population during that period may have changed with respect to tolerance to anaesthetic agents. Since the publication of the well-known studies by BRODIEet al. (1952) in dogs, and by PRICEet al. (1959) in humans on the disposition of thiopental, advances in technology have made it more possible to follow and describe the fate of drugs in the organism (BISCHOFF& DEDRICK1968 and BREIMER 1974). The intravenous administration of thiopental to induce anaesthesia offers one of the rare clinical situations where an immediate correlation between dose and effect can be studied. For these reasons, we decided to reevaluate the problems concerning the varia-
304
J. H . CHRISTENSEN AND F. ANDREASEN
tions in the individual response to thiopental by combined pharmacodynamic and pharmacokinetic investigations. The present study was carried out as a first approach to determine the magnitude of the problem in clinical work today. The results were obtained by a planned investigation utilizing the standard daily procedure and the anaesthesiologists were not particularly informed about the study. The purpose was to investigate whether the size of the induction dose of thiopental was influenced by: 1) Age, 2) Sex, 3) The level of the haemoglobin concentration, 4) Creatinine concentration in serum above the upper normal level, 5) A condition making long-term therapy with digoxin and a diuretic necessary, and 6) The premedication given.
In this way, information was also obtained about individual variations between patients, who were comparable with respect to all factors known to influence sensitivity to thiopenta1. MATERIALS AND METHODS Anaesthetic records of patients operated in Aarhus Kommunehospital, were studied. Starting from May 11, 1976, the number of records fulfilling the criteria described below reached the target of 500 by June 5, 1976. Records of operations performed with extracorporal circulation from May 1 I to October 31, 1976, were included in the study. We excluded records from neurosurgical operations and operations not planned the preceding day. The following information was transferred from the anaesthetic record to a standard sheet: age, sex, body weight, haemoglobin, and for patients above the age of 50, serum creatinine, EGG and chest X-ray. The clinical diagnosis, the name of the operation performed and all information concerning preoperative medication were registered on the standard sheet, and so were the drug used, the dose and the time when the premedication was given, and finally the induction dose of thiopental (which is defined below). Patients for whom one or more of these details were not available were excluded, and so were patients to whom the premedication was given at a time different from that described in the standard procedure.
Standardprocedure of induction A 2.5% solution of thiopental is injected through a vein on the back of the hand until the ciliary reflex disappears. The first dose of 200-250 mg is given over 2025 s. After that, repeated doses of 25-50 mg are injected over 1-2 s every 15 s. Before each injection the patient is examined to determine whether the ciliary reflex is present or absent. I n severely ill cardiac patients, the speed of injection is reduced according to the judgement of the anaesthesiologist. Using this procedure all patients in the present study were induced within 4 min. All constituents of the total dose thus found necessary to abolish the ciliary reflex - and sufficient to make intubation possible - are written on the anaesthetic record and in the following this dose is referred to as the “induction dose.” Thus no oxygen, anaesthetic gas, assisted ventilation or any additional drug is given to the patient before the full induction dose has been given and its effect has been assessed. Standardpremedication scopolamine, Two types were used: (1) Morphine subcutaneously 16 4 h before the induction (10 mg 0.4 mg scopolamine, reduced to 50% morphine after the age of 56 and to 25% after the age of 70). (2) Pethidine (0.8-1 .O mg/kg body weight) diazepam 5 mg atropine 0.5 mg, intramuscularly 4-1 h before the induction.
+
+
+
+
Calculations The statistical significance of the differences between groups of individuals was tested by the two-tailed t-test. The relationship between induction doses and haemoglobin concentrations was evaluated by calculations of Pearson’s coefficient of correlation.
RESULTS Figure 1 shows the relationship between age and induction dose of thiopental for 540 patients who were included in the study according to the criteria described above. The lower curve shows the number of mg actually given to induce anaesthesia, while the upper curve shows the dose in mg/kg body weight. Both curves reach a maximum between 20 and 30 years of age, and for both curves the decrease from this age interval to the age interval between 40-50 years is statistically significant; but while the P-value is between 0.02 and 0.05 for the lower curve, it is between 0.001 and 0.01 for the upper curve. Also, as indicated on the curves, the statistical significance of the decrease in
305
INDIVIDUAL VARIATION I N RESPONSE TO THIOPENTAL
F 2
4
400
4 t
Z
y1
L
300 Fig. 1. The relationship between age and induction dose of thiopental for 540 patients. The lower curve shows the average number of mg given to the patients in each age group. I n the upper curve the doses are weight related. For both curves there is a statistically significant fall in the dose from 20-30 to 40-50 years (0.02< P
Individual Variation in Response to Thiopental J0RGEN H. CHRISTENSEN and FREDERIK ANDREASEN Department of Anaesthesiology, Aarhus Kommunehospital and Institute of Pharmacology, University of Aarhus, Aarhus, Denmark
The anaesthetic records of 540 patients operated on during a 3-week period were studied. The purpose was to elucidate the influence of age, sex, concentration of haemoglobin, creatinine concentration in serum, heart disease, and the premedication given on the size of the induction dose of thiopental. A statistically significant fall in dose with advancing age was seen after the age of 60 and the significance increased when a weight-related dose was used for the calculations. A 6% difference, indicating a lower induction dose in women, was not statistically significant. When premedication with scopolamine and morphine had been used, significantly less thiopental was needed to induce anaesthesia than after atropine, diazepam and pethidine. When both sexes were considered, no correlation was found between haemoglobin concentration and induction dose of thiopental, but in two groups of women, weak negative correlations between these two variables were found. Thirty-seven patients on long-term treatment with digoxin and a diuretic required significantly less thiopental than 37 patients, otherwise comparable, not receiving this medication. About 60% of the dose used in 21 patients who were to have operations on their limbs was needed in 21 patients who were to be operated for valvular heart disease. Eleven patients with moderately elevated serum creatinine (average 2.1 1.0 mg/100 ml) required 11% (not statistically significant) less than 11 patients with normal serum creatinine (1.1 k 0.2 mg/ 100 ml). A considerable individual variation still exists for patients who are comparable with respect to all factors known to influence sensitivity to thiopental.
Received 22 August, accepted for publication 30 September 1977
For many years it has been known that the dosage of thiopental needed during operations shows considerable individual variation. The influence of diseases (SHIDEMAN et al. 1949, DUNDEE& RICHARDS 19543, other drugs (DUNDEE & GRAY1951), racial factors (SCOTT1953), body weight, sex and age (DUNDEE1954) have been the subject of publications. For all these studies, differences in the accumulation of the drug and in the nature of the operations performed could influence dosage. The same is true of the concomitant use of other drugs during the anaesthesia. Over the past 25 years, anaesthesiological techniques, as well as surgical procedures, have undergone developments which make it possible to operate on increasingly older
patients presenting a higher and higher risk. Also the population during that period may have changed with respect to tolerance to anaesthetic agents. Since the publication of the well-known studies by BRODIEet al. (1952) in dogs, and by PRICEet al. (1959) in humans on the disposition of thiopental, advances in technology have made it more possible to follow and describe the fate of drugs in the organism (BISCHOFF& DEDRICK1968 and BREIMER 1974). The intravenous administration of thiopental to induce anaesthesia offers one of the rare clinical situations where an immediate correlation between dose and effect can be studied. For these reasons, we decided to reevaluate the problems concerning the varia-
304
J. H . CHRISTENSEN AND F. ANDREASEN
tions in the individual response to thiopental by combined pharmacodynamic and pharmacokinetic investigations. The present study was carried out as a first approach to determine the magnitude of the problem in clinical work today. The results were obtained by a planned investigation utilizing the standard daily procedure and the anaesthesiologists were not particularly informed about the study. The purpose was to investigate whether the size of the induction dose of thiopental was influenced by: 1) Age, 2) Sex, 3) The level of the haemoglobin concentration, 4) Creatinine concentration in serum above the upper normal level, 5) A condition making long-term therapy with digoxin and a diuretic necessary, and 6) The premedication given.
In this way, information was also obtained about individual variations between patients, who were comparable with respect to all factors known to influence sensitivity to thiopenta1. MATERIALS AND METHODS Anaesthetic records of patients operated in Aarhus Kommunehospital, were studied. Starting from May 11, 1976, the number of records fulfilling the criteria described below reached the target of 500 by June 5, 1976. Records of operations performed with extracorporal circulation from May 1 I to October 31, 1976, were included in the study. We excluded records from neurosurgical operations and operations not planned the preceding day. The following information was transferred from the anaesthetic record to a standard sheet: age, sex, body weight, haemoglobin, and for patients above the age of 50, serum creatinine, EGG and chest X-ray. The clinical diagnosis, the name of the operation performed and all information concerning preoperative medication were registered on the standard sheet, and so were the drug used, the dose and the time when the premedication was given, and finally the induction dose of thiopental (which is defined below). Patients for whom one or more of these details were not available were excluded, and so were patients to whom the premedication was given at a time different from that described in the standard procedure.
Standardprocedure of induction A 2.5% solution of thiopental is injected through a vein on the back of the hand until the ciliary reflex disappears. The first dose of 200-250 mg is given over 2025 s. After that, repeated doses of 25-50 mg are injected over 1-2 s every 15 s. Before each injection the patient is examined to determine whether the ciliary reflex is present or absent. I n severely ill cardiac patients, the speed of injection is reduced according to the judgement of the anaesthesiologist. Using this procedure all patients in the present study were induced within 4 min. All constituents of the total dose thus found necessary to abolish the ciliary reflex - and sufficient to make intubation possible - are written on the anaesthetic record and in the following this dose is referred to as the “induction dose.” Thus no oxygen, anaesthetic gas, assisted ventilation or any additional drug is given to the patient before the full induction dose has been given and its effect has been assessed. Standardpremedication scopolamine, Two types were used: (1) Morphine subcutaneously 16 4 h before the induction (10 mg 0.4 mg scopolamine, reduced to 50% morphine after the age of 56 and to 25% after the age of 70). (2) Pethidine (0.8-1 .O mg/kg body weight) diazepam 5 mg atropine 0.5 mg, intramuscularly 4-1 h before the induction.
+
+
+
+
Calculations The statistical significance of the differences between groups of individuals was tested by the two-tailed t-test. The relationship between induction doses and haemoglobin concentrations was evaluated by calculations of Pearson’s coefficient of correlation.
RESULTS Figure 1 shows the relationship between age and induction dose of thiopental for 540 patients who were included in the study according to the criteria described above. The lower curve shows the number of mg actually given to induce anaesthesia, while the upper curve shows the dose in mg/kg body weight. Both curves reach a maximum between 20 and 30 years of age, and for both curves the decrease from this age interval to the age interval between 40-50 years is statistically significant; but while the P-value is between 0.02 and 0.05 for the lower curve, it is between 0.001 and 0.01 for the upper curve. Also, as indicated on the curves, the statistical significance of the decrease in
305
INDIVIDUAL VARIATION I N RESPONSE TO THIOPENTAL
F 2
4
400
4 t
Z
y1
L
300 Fig. 1. The relationship between age and induction dose of thiopental for 540 patients. The lower curve shows the average number of mg given to the patients in each age group. I n the upper curve the doses are weight related. For both curves there is a statistically significant fall in the dose from 20-30 to 40-50 years (0.02< P
