Anaesthesia, 1977, Volume 32, pages 240-246
Adiposity and the pharmacokinetics of halothane The effect of adiposity on the maintenance of and recovery from halothane anaesthesia
R. A. SARAIVA, J. N. LUNN, W. W. MAPLESON, B. A. WILLIS A N D J. M. FRANCE
Obesity is a common nutritional disorder in the developed countries. Fisher et al.' have recently reviewed the relevance of obesity to anaesthesia but they reported no quantitative pharmacokinetic studies. This study was designed to explore some of the effects of adiposity on the conduct of anaesthesia in a small surgical population. Method Fit, adult patients who were to be anaesthetized with nitrous oxide, oxygen and halothane, with endotracheal intubation and spontaneous respiration, for body-surface operations were interviewed pre-operatively. Thirty of them, whose hearing and mental ability were adequate for the purposes of the investigation, gave their informed consent to the protocol described below. Preliminaries
Skinfold thickness at specified sites was determined at a pre-operative visit by the technique of Tanner 8c Whitehouse2 using Harpenden calipers. These measurements were then used to estimate adiposity, as a percentage of body weight, according to the equations of Durnin & Womersley.3
At the same time a peripheral nerve stimulator was used to determine the minimum strength of stimulus which was necessary to cause a painful sensation on the skin of the forearm. The patient was told that this same stimulus would be reapplied during the recovery period in order to determine whether or not recovery from the anaesthetic had occurred. Anaesthetic technique
Pre-anaesthetic medication was given 1-14 hours pre-operatively and consisted of an appropriate dose of opiate and atropine. A sample of venous blood was taken for the determination4 of the blood-gas partition coefficient for halothane. Anaesthesia was induced with thiopentone (approximately 4 mglkg) and suxamethonium (30-40 mg) to facilitate endotracheal intubation. After ventilation with oxygen the larynx was sprayed with 4% lignocaine and a cuffed endotracheal tube inserted. When spontaneous ventilation recommenced a Magill attachment was used to administer approximately 3 % halothane, from a Fluotec Mark I11 vaporizer, in 4 litreslmin nitrous oxide and 2 litreslmin oxygen for 3 to 5 min, after which the halothane concentration
R. A. Saraiva, MD, MSc, Research Fellow, J. N. Lunn, MD, FFARCS, Senior Lecturer, W. W. Mapleson, DSc, FInstP, Professor of the Physics of Anaesthesia, B. A. Willis, PhD, Lecturer in the Physics of Anaesthesia and J. M. France, MB, FFARCS, Lecturer, Department of Anaesthetics, Welsh National School of Medicine, Cardiff. R. A. Saraiva is now at Divisao de Anestesiologia, Faculdade de Ciencias da Saude, Universidade de Brasilia, 70,000Brasilia-DF, Brasil, and J. M. France, at Maelor General Hospital, Wrexham. Requests for reprints to Dr J. N. Lunn.
Adiposity and the pharmacokinetics of halothane
241
kr ~~, , HALOTHANE ANALYSER
RECORDER
AIR
PUMP
Fig. 1. The apparatus.
was reduced to approximately 1% and maintained at that level throughout the operation. Observations
The vaporizer control was fitted with a position sensor so that its setting could be recorded continuously on a Servoscribe recorder. The halothane concentrations were measured with a Hook and Tucker ultra-violet halothane analyser and the ouput recorded continuously. Calibration of this analyser was checked with a Riken interferometer (Type 18). The arrangement for gas sampling is shown in Fig. 1. Inspired gas was sampled through a tube attached distal to the Magill reservoir bag. Gas which emerged from the expiratory valve was sampled after it had passed through the two mixing bags. The average flow rate of this gas is equal to the fresh-gas flow and not to the total ventilation; it is therefore referred to here as ‘mixed-spill’ gas rather than mixedexpired gas. End-expired gas was sampled from a tube close to the port of the expiratory duct valve. Because the response time of the Hook and Tucker analyser is too long to follow faithfully changes of concentrationat respiratory frequency, the fresh-gas flow was reduced to
2 litreslmin during each sampling period. Thus all the gas emerging through the expiratory valve was essentially of end-expiratory composition. Total expired ventilation was measured using a new Wright respirometer which was placed between the endotracheal tube and the duct valve. The ventilation was expressed in ml min-’ kg-’ body weight. Ventilation, fresh-gas flow and the three gas concentrations were recorded every 5 minutes throughout the administration of the anaesthetic. After the dressing had been applied to the surgical wound a further estimation of endexpired concentration of halothane was made and then the administration of halothane and nitrous oxide was discontinued. The times at which the patient reached a series of four defined levels of recovery were recorded. These were when the patient: (1) Responded to the intensity of stimulus, applied to the forearm by the peripheral nerve stimulator, determined preoperatively. (2) Obeyed commands, such as, ‘Put out your tongue’. (3) Answered a question, such as, ‘What is your name ?’ (4) Was well orientated in time and space,
(vE)
242
R.A. Saraiva et al.
that is, knew the day of the week and his whereabouts. Calculationsfrom observations
The rate of uptake of halothane is proportional, other things being equal, to the inspired concentration. Therefore, in order to minimise the effects of somewhat different concentrations in different patients, the measured rate of uptake was divided by the measured inspired concentration to obtain the rate of uptake per percent inspired concentration #ha]). At the moment of every measurement this was calculated from the formula: Vh.1
=
(F, -FD VF F1 x 100
where F, = fractional inspired concentration, & = fractional mixed-spill concentration, 0,= fresh-gas flowrate. The degree of equilibrium of the end-tidal concentration of halothane F E ' with the inspired concentration FI was calculated as FE'/FI, expressed as a percentage. The average for each of these calculated variables was taken for the period between 20 and 40 min after induction because, by that time, these variables were reasonably stable. This 20-min period is referred to below as the maintenance period.
Results Twelve men and eighteen women were studied. Table 1 lists the mean, minimum and maximum values of all the parameters and variables. Some measurements could not be made on all patients; therefore some patients had to be omitted from the various analyses below. On the average the women were more obese (36.3% adiposity) than the men (19.7%). Ventilation, age, and partition coefficient A, as well as adiposity, may affect the pharmacokinetics of halothane. Their simultaneous effects were separated by means of multipleregression analysis, the results of which are given in Table 2. Each regression coefficient (b) shows how the dependent variable (rate of uptake or approach to equilibrium) changes when one independent variable (adiposity, ventilation, age or A) changes, having allowed for the effects of concomitant changes in the other three variables. The corresponding values of P indicate that two of these regression coefficients are statistically significant. For instance, in the presence of an increase of adiposity of 1 % of body weight with no change in the other three independent variables, the rate of uptake can be expected to increase by 0.375 ml min-' %-' (P = 00019). On the other hand, for each 1 year increase in age, rate of uptake can be expected to decrease by 0.258 ml min-' %-' dp = 0.006).
Table 1. Means and ranges of the measured variables Mean
Min
Max
n
42.9 67.8 163.2 29.6 56.8 12.1 93.0 2.64 0.54 63.8 10.0 14.7 18.7 22.8
15 46.5 145.0 12.2 48.0 3.7 54.0 2.07 0-35 13 2 3 6 9
70 97.5 183.0 44.6 73.0 19.3 188.0 3.19 0.75 165 22 25 32 46
30 30 30 30 24 24 24 24 21 21 21 21 21 21
* Average values for 'maintenance' (i.e. from 20 to 40 min after induction). t End-tidal concentration of halothane at the end of the administration. $ Duration of administration. 5 Times to the four levels of recovery.
Adiposity and the pharmacokinetics of halothane
243
Table 2. Multiple regression analyses*-Maintenance (19 patients) Adiposity
Age (years)
VE
(%)
(ml min-’ kg-’)
0.375 0.0019
0.054 0.09
-0.258
0.073 0.09
0.145 0.20
Rate of uptake of halothane, 6,,, (ml min-’ % - l )
b P
Degree of equilibrium, FE’IFI (%I
b
-0.178
P
020
At 0.844 0.8
0.006
-7.61 0.12
* These regression coefficients differ from those given in a preliminary report of this work’
because in that report adiposity was estimated from equations6 based on measurements in young subjects only. Blood-gas partition coefficient. Table 3. Multiple regression analyses*-Recovery (21 patients)
Recovery time (min) TI
Adiposity
Duration (min)
Final F d (%I
Age (years)
b 0.148
0,044 0.16
20.6 0.06
-0‘136 0.2
0,046 0.14
35.9
-0.167 0.12
0.031 0.9
P 0.06
0.084 0.03
31.7 0.017
-0.258 0.045
4.56 03
b 0.475 P 0.015
0122 0.014
42.1 0.0 I 2
-0.328 0.04
3.96 0.6
(%I
P 0.23
Tz
b 0.181
P 014 Ts T4
b 0.281
0.003
L -1.31 0.7
* See footnote to Table 2. Table 3 shows corresponding figures for the dependence of the four recovery times (T 1-l-4) on adiposity, duration of administration, endtidal concentration at the conclusion of the administration, (final FE’), age and 1. Ventilation is not included here because it was not measured during recovery. (The 21 patients on which the table is based do not include all the 19 in Table 2.)
Discussion Maintenance Rate of uptake. The multiple-regression analysis in Table 2 shows that the increase in rate of uptake with adiposity is statistically significant (P = 0.0019). This can presumably be attributed, not to the additional storage capacity of the extra fat, but to the extra blood flow to it.’ This is because blood which perfuses fat is virtually cleared of halothane throughout
the maintenance periods and therefore the greater the blood flow to the fat the more the uptake of h a l ~ t h a n e Table .~ 2 also shows that rate of uptake decreases with increasing age and this relationship is also highly significant (P = 0.006). This could be because cardiac output decreases as age increases.’O An increase in rate of uptake with increasing ventilation is to be expected although the increase here does not reach statisticalsignificance(P = 0.09). The effect of L is completely non-significant (P = 0.8);this is discussed below. Degree of equilibrium. The directions in which FE’/FI changed with the different variables (Table 2) were those to be expected theoretically, although none of the changes was significant. For instance, when ventilation is large, the supply of anaesthetic to the lungs is increased and so a greater end-tidal concentration is to be expected: the regression coefficient, b, is positive (Table 2). In old age, cardiac output
244
R.A. Saraiva et al.
is less and therefore the rate of removal of anaesthetic from the lungs is less, so that, again, a greater end-tidal concentration is to be expected: again, b is positive. In fat subjects, there is increased blood flow to fat and hence increased removal of anaesthetic and therefore a decreased end-tidal concentration is to be expected: b is negative. Finally, when 1 is large, it is to be expected that the rate of removal will be greater and the end-tidal concentration less. In our results b is indeed negative and is more nearly significant (P = 0.12) than was the increase in rate of uptake with 1 mentioned above (P= 0.8).
awakeyiz also decreases with increasing age, even though this has not been explicitly demonstrated.12 Therefore, since any variation in terminal end-tidal concentration has been allowed for in the multiple regression, it might be expected that old people would take longer to reach their presumably lower MAC awake and therefore that recovery time would be increased in old age. The only mechanism which we can think of to explain our results is as follows. The reduced cardiac output in the older patients would have produced less saturation of the lean tissues during maintenance and this may have led to a quicker fall in Table 4. Correlation coefficients(19 patients)
Recovery It should be remembered that 70% NnO was administered to all our patients; this was discontinued at the same moment as the halothane. The results (Table 3) and the following discussion therefore refer to recovery from halothane in 70% N20. All four recovery times increase with adiposity and the rate of increase becomes progressively greater with the successive recovery times. Similarly, P progressively decreases but only reaches significance at the fourth level of recovery. Similar progressive, or nearly-progressive, trends can be seen in the effects of duration of administration and final end-tidal concentration (both positive, as would be expected) and of age (negative). The probabilities for all three of these variables are comparable to, or more significant than, those for adiposity. The effects of 1 are completely non-significant at each level of recovery although there is a nearly progressive trend of slope (from negative to positive) with level of recovery. The decrease in recovery time with increasing age, which is significant at levels 3 and 4, is puzzling. Old people tend to have lower cardiac outputs but, since ventilation was not measured during recovery, and since it was spontaneous, it must be presumed that the older patients also had lower alveolar ventilation. The combined effect of these two factors would be a delay in washout and a tendency for recovery time to increase with age. Likewise, the minimum alveolar concentration for surgical anaesthesia (MAC) decreases with increasing age so that it is likely that 'MAC
1 Adiposity
0, Age
-0.25 -
0.62** -0.15
-
025 -0.49* 0.34
* P< 0.05; ** P< 0.01. alveolar and brain concentration during recovery, despite the contrary tendencies just mentioned. The multiple regressions in Tables 2 and 3 reveal the separate effects of the various independent variables (adiposity, age, etc.) during maintenance and recovery. However, in any population of patients the independent variables are likely to be correlated with one another to some degree, in which case the overall effect on the dependent variables (rate of uptake etc.) will be the algebraic sum of the separate effects of the independent variables. The correlation coefficients are given in Table 4 from which it is evident that, for instance, fat patients in our sample of the surgical population tended to be old (r = 0.62). Consequently, the increased uptake to be expected from the increased adiposity of a typical fat patient (b = 0.375, Table 2) would be counteracted to some extent by the decreased uptake to be expected from his increased age (b = -0.258). In addition, there would be other small effects arising from the correlation between adiposity and ventilation and 1. The combined effect of the simultaneous variations in the four independent variables
Adiposity and the pharmacokinetics of halothane in our sample of patients is revealed by a simple, single regression of rate of uptake on adiposity. This showed a reduced and non-significant effect (b = 0.138, P = 0.18). . The interpretation of the difference between the results of the multiple and single regressions can be illustrated by considering two imaginary situations. In the first the adiposity of patients is known but nothing else! Then, if two patients, one with 15% adiposity and the other with 45%, were to be drawn at random from our sample they would be likely to differ in age, ventilation and t in such a way that the slope of the single regression (b = 0.138) would be best for estimating the difference in rate of uptake between the two patients: (45-15)x0.138 = 4.1 ml min-’ 7i-l. In the second situation, suppose that ample information is available about two other patients and that this shows that they also have 15% and 45% adiposity but are identical in every other respect. Then the slope of the multiple regression (b = 0.375) would be best, leading to a likely difference in rate of uptake of (45-15) ~ 0 . 3 7 5= 11.2 ml min-’ % - l . Similar considerations apply to the effecfs on the approach to equilibrium but here the interactions of the separate effects of the independent variables and their correlations with adiposity are such that the single regression of Fe’/F, on adiposity (b = -0.169, P = 0.20) is very little different from the multiple (b = -0.178, P = 0.20). In the case of recovery, the single regressions show slightly less dependence on adiposity with slightly less significance at all four levels: b = 0.09, 0.16, 0.20, 0.36; P = 0.4, 0.17, 0.13, 0.04. Clinical implications
The results of the multiple regressions reveal, within the limitations of the present data, the fundamental, independent effects of the various factors which may influence the dependent variables (rate of uptake, FE’/F,and recovery times). The results of the single regressions, on the other hand, reveal the pharmacokinetic differences between fat patients and thin patients in the present sample, without making any allowances for concomitant differences in any of the factors, such as age and ventilation, which also influence rate of uptake, etc. Thus, amongst our patients, the fat ones did
245
not have a significantly greater rate of uptake than the thin ones (single regression); but it can be calculated from the data of Tables 1 and 2 that fat, young patients (say 45% adiposity) would have about three times the rate of uptake of thin, young patients (say 15% adiposity). Therefore, if a totally-closed anaesthetic system were in use, it would be necessary to have about three times as much halothane supplied to the system to maintain the same depth of anaesthesia. When a non-rebreathing or semi-closed anaesthetic system is in use, the anaesthetist has direct control of the inspired concentration of halothane and therefore it is the effect of adiposity on the relationship between end-tidal and inspired concentration which must be considered. Since neither the multiple (Table 2) nor the single regression was significant it is unlikely that any effect of adiposity on depth of anaesthesia or anaesthetic requirements would be detectable clinically. It can be calculated from the data in Tables 1 and 3 that, under the conditions of these anaesthetics, recovery to the fourth level would take nearly half an hour in a patient with 45% adiposity but little more than a quarter of a n hour in one with 15%. Thus the practice of some anaesthetists of discontinuing halothane somewhat earlier in obese patients seems justified. The effect of duration of administration is relatively small: about 7 min increase in recovery time to level 4 for each hour increase in duration. However, it is necessary to remember that it has been shown theoreticallys that recovery time is more sensitive to duration of administration of halothane when that administration exceeds about 2 hours. The effect of terminal end-tidal concentration is such that, if it were about 1 %, as compared with the 0 5 % in this study, this might delay recovery to the fourth level by about 20 min. The effect of age on recovery to the fourth level amounts to about 3 min decrease per decade increase in age. Summary
Thirty fit patients (15-70 years, 46-98 kg) undergoing body-surface operations were selected to include a wide range of adiposity (1245% of total body weight estimated from
246
R.A. Saraiva et al.
measurements of skinfold thickness). They were anaesthetized with halothane and 70% NzO in O1. From measurements of total ventilation (ml min-‘ kg-’) and of halothane concentrations in inspired (F,) end-tidal (Fe‘) and ‘mixed-spill’ (F;) gases, the following parameters were calculated for 5-min intervals from 20 to 40 min after induction: the rate of uptake of halothane per percent inspired concentration (fih.1 ml min-’ %-l) and the degree of equilibrium achieved with the inspired concentration, calculated as FE’/FIexpressed as a percentage. Multiple-regression analysis of the results for 19 patients, taking account of the effects of body fat, ventilation, age, and the blood-gas partition coefficient 1 of halothane for the individual patient, showed that VhSIh.1 increased with adiposity (b = 0.375, P = 0~0019),and with ventilation (b = 0.054, P = 0.09) but decreased with increasing age (b = -0.258, P = 0.006). The time intervals between the end of the anaesthetic and the achievement of four defined levels of recovery (response to painful stimulus, obedience to a simple command, response to a question, orientation in time and space), were recorded. Multiple-regression analysis showed that recovery time increased with adiposity, duration of administration and endtidal concentration at the end of the administration, and decreased with increasing age. All four effects were statistically non-significant at the first levels of recovery but all increased at the later levels and all eventually became significant.
Key words PHARMACOKINETICS ;recovery, adipasity. ANAESTHETICS, VOLATILE; halothane.
Acknowledgments It is a pleasure to thank Professors W.W. Mushin and M.D.A. Vickers for their advice.
The manner of assessing recovery is the result of unpublished work by Dr D.N. Davies, now at St Andrew’s Hospital, Billericay, Essex, when he was in this Department.
References 1. FISHER, A., WATERHOUSE, T.D. & ADAMS,A.P. (1975) Obesity: its relation to Anaesthesia. Anaesthesia, 30, 633. 2. TANNER,J.M. & WHITEHOUSE, R.H. (1962)
Standards for subcutaneous fat in British children. Percentiles for thickness of skinfolds over triceps and below scapula. British Medical Journal, i, 446. 3. DURNIN,J.V.G.A. & WOMERSLEY, J. (1974) Body fat assessed from total body density and its estimation from skinfold thickness: measurements on 481 men and women aged from 16 to 72 years. British Journal of Nutrition, 32, 17. 4. STEWARD, A., MAPLESON, W.W. & ALLOTT,P.R. (1972) A comparison of in uiuo and in uitro partition coefficients for halothane in the rabbit. British Journal of Anaesthesia, 44, 650. R.A., LUNN,J.N., MAPLESON, W.W., 5. SARAIVA, WILLIS,B.A. & FRANCE,J.M. (1975) The effect of obesity on the uptake of halothane during maintenance of anaesthesia. British Journal of Anaesthesia, 47, 1023. 6. SLOAN, A.W. & WEIR,J.B.DEV. (1970) Nomograms ‘ for prediction of body density and total body fat from skin-fold measurements. Journal of Applied Physiology, 28, 221. G.T. & DEUTSCH, S. (1967) Measurement 7. LESSER, of adipose tissue blood flow and perfusion in man by uptake of 85Kr. Journal of Applied Physiology, 23, 621. 8 . MAPLESON, W.W. (1962) Quantitative prediction of anesthetic concentrations. In: Uptake and distribution of anesthetic agents (Ed. by E. M. Papper & R. J. Kitz), p. 104. McGraw-Hill, New York. 9. SARAIVA, R.A. (1974) On nutritional factors in the pharmacokinetics of anaesthetics with special reference to obesity. M.Sc. Thesis, University of Wales. 10. BRANDFONBRENER, M., LANDOWNE, M. & SHOCK, N.W. (1955) Changes in cardiac output with age. Circulation, 12, 557. 11. GREGORY, G.A., EGER,E.I. XI & MUNSON,E.S. (1969) The relationship between age and halothane requirement in man. Anesthesiology, 30, 488. 12. STOELTING, R.K., LONGNECKER, D.E. & EGER, E.I. I1 (1970) Minimum alveolar concentrations in man on awakening from methoxyflurane, halothane, ether and fluroxene anesthesia: MAC awake. Anesthesiology, 3 3 , 5 .
Adiposity and the pharmacokinetics of halothane The effect of adiposity on the maintenance of and recovery from halothane anaesthesia
R. A. SARAIVA, J. N. LUNN, W. W. MAPLESON, B. A. WILLIS A N D J. M. FRANCE
Obesity is a common nutritional disorder in the developed countries. Fisher et al.' have recently reviewed the relevance of obesity to anaesthesia but they reported no quantitative pharmacokinetic studies. This study was designed to explore some of the effects of adiposity on the conduct of anaesthesia in a small surgical population. Method Fit, adult patients who were to be anaesthetized with nitrous oxide, oxygen and halothane, with endotracheal intubation and spontaneous respiration, for body-surface operations were interviewed pre-operatively. Thirty of them, whose hearing and mental ability were adequate for the purposes of the investigation, gave their informed consent to the protocol described below. Preliminaries
Skinfold thickness at specified sites was determined at a pre-operative visit by the technique of Tanner 8c Whitehouse2 using Harpenden calipers. These measurements were then used to estimate adiposity, as a percentage of body weight, according to the equations of Durnin & Womersley.3
At the same time a peripheral nerve stimulator was used to determine the minimum strength of stimulus which was necessary to cause a painful sensation on the skin of the forearm. The patient was told that this same stimulus would be reapplied during the recovery period in order to determine whether or not recovery from the anaesthetic had occurred. Anaesthetic technique
Pre-anaesthetic medication was given 1-14 hours pre-operatively and consisted of an appropriate dose of opiate and atropine. A sample of venous blood was taken for the determination4 of the blood-gas partition coefficient for halothane. Anaesthesia was induced with thiopentone (approximately 4 mglkg) and suxamethonium (30-40 mg) to facilitate endotracheal intubation. After ventilation with oxygen the larynx was sprayed with 4% lignocaine and a cuffed endotracheal tube inserted. When spontaneous ventilation recommenced a Magill attachment was used to administer approximately 3 % halothane, from a Fluotec Mark I11 vaporizer, in 4 litreslmin nitrous oxide and 2 litreslmin oxygen for 3 to 5 min, after which the halothane concentration
R. A. Saraiva, MD, MSc, Research Fellow, J. N. Lunn, MD, FFARCS, Senior Lecturer, W. W. Mapleson, DSc, FInstP, Professor of the Physics of Anaesthesia, B. A. Willis, PhD, Lecturer in the Physics of Anaesthesia and J. M. France, MB, FFARCS, Lecturer, Department of Anaesthetics, Welsh National School of Medicine, Cardiff. R. A. Saraiva is now at Divisao de Anestesiologia, Faculdade de Ciencias da Saude, Universidade de Brasilia, 70,000Brasilia-DF, Brasil, and J. M. France, at Maelor General Hospital, Wrexham. Requests for reprints to Dr J. N. Lunn.
Adiposity and the pharmacokinetics of halothane
241
kr ~~, , HALOTHANE ANALYSER
RECORDER
AIR
PUMP
Fig. 1. The apparatus.
was reduced to approximately 1% and maintained at that level throughout the operation. Observations
The vaporizer control was fitted with a position sensor so that its setting could be recorded continuously on a Servoscribe recorder. The halothane concentrations were measured with a Hook and Tucker ultra-violet halothane analyser and the ouput recorded continuously. Calibration of this analyser was checked with a Riken interferometer (Type 18). The arrangement for gas sampling is shown in Fig. 1. Inspired gas was sampled through a tube attached distal to the Magill reservoir bag. Gas which emerged from the expiratory valve was sampled after it had passed through the two mixing bags. The average flow rate of this gas is equal to the fresh-gas flow and not to the total ventilation; it is therefore referred to here as ‘mixed-spill’ gas rather than mixedexpired gas. End-expired gas was sampled from a tube close to the port of the expiratory duct valve. Because the response time of the Hook and Tucker analyser is too long to follow faithfully changes of concentrationat respiratory frequency, the fresh-gas flow was reduced to
2 litreslmin during each sampling period. Thus all the gas emerging through the expiratory valve was essentially of end-expiratory composition. Total expired ventilation was measured using a new Wright respirometer which was placed between the endotracheal tube and the duct valve. The ventilation was expressed in ml min-’ kg-’ body weight. Ventilation, fresh-gas flow and the three gas concentrations were recorded every 5 minutes throughout the administration of the anaesthetic. After the dressing had been applied to the surgical wound a further estimation of endexpired concentration of halothane was made and then the administration of halothane and nitrous oxide was discontinued. The times at which the patient reached a series of four defined levels of recovery were recorded. These were when the patient: (1) Responded to the intensity of stimulus, applied to the forearm by the peripheral nerve stimulator, determined preoperatively. (2) Obeyed commands, such as, ‘Put out your tongue’. (3) Answered a question, such as, ‘What is your name ?’ (4) Was well orientated in time and space,
(vE)
242
R.A. Saraiva et al.
that is, knew the day of the week and his whereabouts. Calculationsfrom observations
The rate of uptake of halothane is proportional, other things being equal, to the inspired concentration. Therefore, in order to minimise the effects of somewhat different concentrations in different patients, the measured rate of uptake was divided by the measured inspired concentration to obtain the rate of uptake per percent inspired concentration #ha]). At the moment of every measurement this was calculated from the formula: Vh.1
=
(F, -FD VF F1 x 100
where F, = fractional inspired concentration, & = fractional mixed-spill concentration, 0,= fresh-gas flowrate. The degree of equilibrium of the end-tidal concentration of halothane F E ' with the inspired concentration FI was calculated as FE'/FI, expressed as a percentage. The average for each of these calculated variables was taken for the period between 20 and 40 min after induction because, by that time, these variables were reasonably stable. This 20-min period is referred to below as the maintenance period.
Results Twelve men and eighteen women were studied. Table 1 lists the mean, minimum and maximum values of all the parameters and variables. Some measurements could not be made on all patients; therefore some patients had to be omitted from the various analyses below. On the average the women were more obese (36.3% adiposity) than the men (19.7%). Ventilation, age, and partition coefficient A, as well as adiposity, may affect the pharmacokinetics of halothane. Their simultaneous effects were separated by means of multipleregression analysis, the results of which are given in Table 2. Each regression coefficient (b) shows how the dependent variable (rate of uptake or approach to equilibrium) changes when one independent variable (adiposity, ventilation, age or A) changes, having allowed for the effects of concomitant changes in the other three variables. The corresponding values of P indicate that two of these regression coefficients are statistically significant. For instance, in the presence of an increase of adiposity of 1 % of body weight with no change in the other three independent variables, the rate of uptake can be expected to increase by 0.375 ml min-' %-' (P = 00019). On the other hand, for each 1 year increase in age, rate of uptake can be expected to decrease by 0.258 ml min-' %-' dp = 0.006).
Table 1. Means and ranges of the measured variables Mean
Min
Max
n
42.9 67.8 163.2 29.6 56.8 12.1 93.0 2.64 0.54 63.8 10.0 14.7 18.7 22.8
15 46.5 145.0 12.2 48.0 3.7 54.0 2.07 0-35 13 2 3 6 9
70 97.5 183.0 44.6 73.0 19.3 188.0 3.19 0.75 165 22 25 32 46
30 30 30 30 24 24 24 24 21 21 21 21 21 21
* Average values for 'maintenance' (i.e. from 20 to 40 min after induction). t End-tidal concentration of halothane at the end of the administration. $ Duration of administration. 5 Times to the four levels of recovery.
Adiposity and the pharmacokinetics of halothane
243
Table 2. Multiple regression analyses*-Maintenance (19 patients) Adiposity
Age (years)
VE
(%)
(ml min-’ kg-’)
0.375 0.0019
0.054 0.09
-0.258
0.073 0.09
0.145 0.20
Rate of uptake of halothane, 6,,, (ml min-’ % - l )
b P
Degree of equilibrium, FE’IFI (%I
b
-0.178
P
020
At 0.844 0.8
0.006
-7.61 0.12
* These regression coefficients differ from those given in a preliminary report of this work’
because in that report adiposity was estimated from equations6 based on measurements in young subjects only. Blood-gas partition coefficient. Table 3. Multiple regression analyses*-Recovery (21 patients)
Recovery time (min) TI
Adiposity
Duration (min)
Final F d (%I
Age (years)
b 0.148
0,044 0.16
20.6 0.06
-0‘136 0.2
0,046 0.14
35.9
-0.167 0.12
0.031 0.9
P 0.06
0.084 0.03
31.7 0.017
-0.258 0.045
4.56 03
b 0.475 P 0.015
0122 0.014
42.1 0.0 I 2
-0.328 0.04
3.96 0.6
(%I
P 0.23
Tz
b 0.181
P 014 Ts T4
b 0.281
0.003
L -1.31 0.7
* See footnote to Table 2. Table 3 shows corresponding figures for the dependence of the four recovery times (T 1-l-4) on adiposity, duration of administration, endtidal concentration at the conclusion of the administration, (final FE’), age and 1. Ventilation is not included here because it was not measured during recovery. (The 21 patients on which the table is based do not include all the 19 in Table 2.)
Discussion Maintenance Rate of uptake. The multiple-regression analysis in Table 2 shows that the increase in rate of uptake with adiposity is statistically significant (P = 0.0019). This can presumably be attributed, not to the additional storage capacity of the extra fat, but to the extra blood flow to it.’ This is because blood which perfuses fat is virtually cleared of halothane throughout
the maintenance periods and therefore the greater the blood flow to the fat the more the uptake of h a l ~ t h a n e Table .~ 2 also shows that rate of uptake decreases with increasing age and this relationship is also highly significant (P = 0.006). This could be because cardiac output decreases as age increases.’O An increase in rate of uptake with increasing ventilation is to be expected although the increase here does not reach statisticalsignificance(P = 0.09). The effect of L is completely non-significant (P = 0.8);this is discussed below. Degree of equilibrium. The directions in which FE’/FI changed with the different variables (Table 2) were those to be expected theoretically, although none of the changes was significant. For instance, when ventilation is large, the supply of anaesthetic to the lungs is increased and so a greater end-tidal concentration is to be expected: the regression coefficient, b, is positive (Table 2). In old age, cardiac output
244
R.A. Saraiva et al.
is less and therefore the rate of removal of anaesthetic from the lungs is less, so that, again, a greater end-tidal concentration is to be expected: again, b is positive. In fat subjects, there is increased blood flow to fat and hence increased removal of anaesthetic and therefore a decreased end-tidal concentration is to be expected: b is negative. Finally, when 1 is large, it is to be expected that the rate of removal will be greater and the end-tidal concentration less. In our results b is indeed negative and is more nearly significant (P = 0.12) than was the increase in rate of uptake with 1 mentioned above (P= 0.8).
awakeyiz also decreases with increasing age, even though this has not been explicitly demonstrated.12 Therefore, since any variation in terminal end-tidal concentration has been allowed for in the multiple regression, it might be expected that old people would take longer to reach their presumably lower MAC awake and therefore that recovery time would be increased in old age. The only mechanism which we can think of to explain our results is as follows. The reduced cardiac output in the older patients would have produced less saturation of the lean tissues during maintenance and this may have led to a quicker fall in Table 4. Correlation coefficients(19 patients)
Recovery It should be remembered that 70% NnO was administered to all our patients; this was discontinued at the same moment as the halothane. The results (Table 3) and the following discussion therefore refer to recovery from halothane in 70% N20. All four recovery times increase with adiposity and the rate of increase becomes progressively greater with the successive recovery times. Similarly, P progressively decreases but only reaches significance at the fourth level of recovery. Similar progressive, or nearly-progressive, trends can be seen in the effects of duration of administration and final end-tidal concentration (both positive, as would be expected) and of age (negative). The probabilities for all three of these variables are comparable to, or more significant than, those for adiposity. The effects of 1 are completely non-significant at each level of recovery although there is a nearly progressive trend of slope (from negative to positive) with level of recovery. The decrease in recovery time with increasing age, which is significant at levels 3 and 4, is puzzling. Old people tend to have lower cardiac outputs but, since ventilation was not measured during recovery, and since it was spontaneous, it must be presumed that the older patients also had lower alveolar ventilation. The combined effect of these two factors would be a delay in washout and a tendency for recovery time to increase with age. Likewise, the minimum alveolar concentration for surgical anaesthesia (MAC) decreases with increasing age so that it is likely that 'MAC
1 Adiposity
0, Age
-0.25 -
0.62** -0.15
-
025 -0.49* 0.34
* P< 0.05; ** P< 0.01. alveolar and brain concentration during recovery, despite the contrary tendencies just mentioned. The multiple regressions in Tables 2 and 3 reveal the separate effects of the various independent variables (adiposity, age, etc.) during maintenance and recovery. However, in any population of patients the independent variables are likely to be correlated with one another to some degree, in which case the overall effect on the dependent variables (rate of uptake etc.) will be the algebraic sum of the separate effects of the independent variables. The correlation coefficients are given in Table 4 from which it is evident that, for instance, fat patients in our sample of the surgical population tended to be old (r = 0.62). Consequently, the increased uptake to be expected from the increased adiposity of a typical fat patient (b = 0.375, Table 2) would be counteracted to some extent by the decreased uptake to be expected from his increased age (b = -0.258). In addition, there would be other small effects arising from the correlation between adiposity and ventilation and 1. The combined effect of the simultaneous variations in the four independent variables
Adiposity and the pharmacokinetics of halothane in our sample of patients is revealed by a simple, single regression of rate of uptake on adiposity. This showed a reduced and non-significant effect (b = 0.138, P = 0.18). . The interpretation of the difference between the results of the multiple and single regressions can be illustrated by considering two imaginary situations. In the first the adiposity of patients is known but nothing else! Then, if two patients, one with 15% adiposity and the other with 45%, were to be drawn at random from our sample they would be likely to differ in age, ventilation and t in such a way that the slope of the single regression (b = 0.138) would be best for estimating the difference in rate of uptake between the two patients: (45-15)x0.138 = 4.1 ml min-’ 7i-l. In the second situation, suppose that ample information is available about two other patients and that this shows that they also have 15% and 45% adiposity but are identical in every other respect. Then the slope of the multiple regression (b = 0.375) would be best, leading to a likely difference in rate of uptake of (45-15) ~ 0 . 3 7 5= 11.2 ml min-’ % - l . Similar considerations apply to the effecfs on the approach to equilibrium but here the interactions of the separate effects of the independent variables and their correlations with adiposity are such that the single regression of Fe’/F, on adiposity (b = -0.169, P = 0.20) is very little different from the multiple (b = -0.178, P = 0.20). In the case of recovery, the single regressions show slightly less dependence on adiposity with slightly less significance at all four levels: b = 0.09, 0.16, 0.20, 0.36; P = 0.4, 0.17, 0.13, 0.04. Clinical implications
The results of the multiple regressions reveal, within the limitations of the present data, the fundamental, independent effects of the various factors which may influence the dependent variables (rate of uptake, FE’/F,and recovery times). The results of the single regressions, on the other hand, reveal the pharmacokinetic differences between fat patients and thin patients in the present sample, without making any allowances for concomitant differences in any of the factors, such as age and ventilation, which also influence rate of uptake, etc. Thus, amongst our patients, the fat ones did
245
not have a significantly greater rate of uptake than the thin ones (single regression); but it can be calculated from the data of Tables 1 and 2 that fat, young patients (say 45% adiposity) would have about three times the rate of uptake of thin, young patients (say 15% adiposity). Therefore, if a totally-closed anaesthetic system were in use, it would be necessary to have about three times as much halothane supplied to the system to maintain the same depth of anaesthesia. When a non-rebreathing or semi-closed anaesthetic system is in use, the anaesthetist has direct control of the inspired concentration of halothane and therefore it is the effect of adiposity on the relationship between end-tidal and inspired concentration which must be considered. Since neither the multiple (Table 2) nor the single regression was significant it is unlikely that any effect of adiposity on depth of anaesthesia or anaesthetic requirements would be detectable clinically. It can be calculated from the data in Tables 1 and 3 that, under the conditions of these anaesthetics, recovery to the fourth level would take nearly half an hour in a patient with 45% adiposity but little more than a quarter of a n hour in one with 15%. Thus the practice of some anaesthetists of discontinuing halothane somewhat earlier in obese patients seems justified. The effect of duration of administration is relatively small: about 7 min increase in recovery time to level 4 for each hour increase in duration. However, it is necessary to remember that it has been shown theoreticallys that recovery time is more sensitive to duration of administration of halothane when that administration exceeds about 2 hours. The effect of terminal end-tidal concentration is such that, if it were about 1 %, as compared with the 0 5 % in this study, this might delay recovery to the fourth level by about 20 min. The effect of age on recovery to the fourth level amounts to about 3 min decrease per decade increase in age. Summary
Thirty fit patients (15-70 years, 46-98 kg) undergoing body-surface operations were selected to include a wide range of adiposity (1245% of total body weight estimated from
246
R.A. Saraiva et al.
measurements of skinfold thickness). They were anaesthetized with halothane and 70% NzO in O1. From measurements of total ventilation (ml min-‘ kg-’) and of halothane concentrations in inspired (F,) end-tidal (Fe‘) and ‘mixed-spill’ (F;) gases, the following parameters were calculated for 5-min intervals from 20 to 40 min after induction: the rate of uptake of halothane per percent inspired concentration (fih.1 ml min-’ %-l) and the degree of equilibrium achieved with the inspired concentration, calculated as FE’/FIexpressed as a percentage. Multiple-regression analysis of the results for 19 patients, taking account of the effects of body fat, ventilation, age, and the blood-gas partition coefficient 1 of halothane for the individual patient, showed that VhSIh.1 increased with adiposity (b = 0.375, P = 0~0019),and with ventilation (b = 0.054, P = 0.09) but decreased with increasing age (b = -0.258, P = 0.006). The time intervals between the end of the anaesthetic and the achievement of four defined levels of recovery (response to painful stimulus, obedience to a simple command, response to a question, orientation in time and space), were recorded. Multiple-regression analysis showed that recovery time increased with adiposity, duration of administration and endtidal concentration at the end of the administration, and decreased with increasing age. All four effects were statistically non-significant at the first levels of recovery but all increased at the later levels and all eventually became significant.
Key words PHARMACOKINETICS ;recovery, adipasity. ANAESTHETICS, VOLATILE; halothane.
Acknowledgments It is a pleasure to thank Professors W.W. Mushin and M.D.A. Vickers for their advice.
The manner of assessing recovery is the result of unpublished work by Dr D.N. Davies, now at St Andrew’s Hospital, Billericay, Essex, when he was in this Department.
References 1. FISHER, A., WATERHOUSE, T.D. & ADAMS,A.P. (1975) Obesity: its relation to Anaesthesia. Anaesthesia, 30, 633. 2. TANNER,J.M. & WHITEHOUSE, R.H. (1962)
Standards for subcutaneous fat in British children. Percentiles for thickness of skinfolds over triceps and below scapula. British Medical Journal, i, 446. 3. DURNIN,J.V.G.A. & WOMERSLEY, J. (1974) Body fat assessed from total body density and its estimation from skinfold thickness: measurements on 481 men and women aged from 16 to 72 years. British Journal of Nutrition, 32, 17. 4. STEWARD, A., MAPLESON, W.W. & ALLOTT,P.R. (1972) A comparison of in uiuo and in uitro partition coefficients for halothane in the rabbit. British Journal of Anaesthesia, 44, 650. R.A., LUNN,J.N., MAPLESON, W.W., 5. SARAIVA, WILLIS,B.A. & FRANCE,J.M. (1975) The effect of obesity on the uptake of halothane during maintenance of anaesthesia. British Journal of Anaesthesia, 47, 1023. 6. SLOAN, A.W. & WEIR,J.B.DEV. (1970) Nomograms ‘ for prediction of body density and total body fat from skin-fold measurements. Journal of Applied Physiology, 28, 221. G.T. & DEUTSCH, S. (1967) Measurement 7. LESSER, of adipose tissue blood flow and perfusion in man by uptake of 85Kr. Journal of Applied Physiology, 23, 621. 8 . MAPLESON, W.W. (1962) Quantitative prediction of anesthetic concentrations. In: Uptake and distribution of anesthetic agents (Ed. by E. M. Papper & R. J. Kitz), p. 104. McGraw-Hill, New York. 9. SARAIVA, R.A. (1974) On nutritional factors in the pharmacokinetics of anaesthetics with special reference to obesity. M.Sc. Thesis, University of Wales. 10. BRANDFONBRENER, M., LANDOWNE, M. & SHOCK, N.W. (1955) Changes in cardiac output with age. Circulation, 12, 557. 11. GREGORY, G.A., EGER,E.I. XI & MUNSON,E.S. (1969) The relationship between age and halothane requirement in man. Anesthesiology, 30, 488. 12. STOELTING, R.K., LONGNECKER, D.E. & EGER, E.I. I1 (1970) Minimum alveolar concentrations in man on awakening from methoxyflurane, halothane, ether and fluroxene anesthesia: MAC awake. Anesthesiology, 3 3 , 5 .
