ANOTHER LOOK AT ACUTE TOLERANCE TO THIOPENTONE

Transcription

1 Br. J. Anaesth. (1980), 52, 1005 ANOTHER LOOK AT ACUTE TOLERANCE TO THIOPENTONE W. TONER, P. J. HOWARD, W. A. W. MCGOWAN AND J. W. DUNDEE SUMMARY The phenomenon of "acute tolerance" to thiopentone was re-examined in 82 subjects with induction doses of 2-15 mgkg~'. There was a strong positive correlation between the venous plasma thiopentone concentrations on recovery from anaesthesia and the induction dose, expressed as either mg kg"' or mg m~ 2. Recovery time was proportionately shorter with larger doses, being directly related to log, 0 of the plasma concentration at awakening. There is great individual variation in the response to thiopentone, including the dose required to induce anaesthesia and the plasma concentration at which patients recover consciousness. The work of Brodie (1952) clarified the latter; each of four subjects was infused with two different doses and it was seen (table I) that the plasma concentration at TABLE I. Plasma concentrations at wakening in four subjects each infused with two doses of thiopentone. From Brodie (7952). Subject V M G N Plasma concn Dose at wakening (ing kg" ') (ugmt 1 ) Thiopentone recovery was greater when the larger dose of drug was given. These doses are outside the range used today, but Dundee, Price and Dripps (1956) described a phenomenon which they called "acute tolerance" to thiopentone. In 16 subjects given single doses of thiopentone ranging from 2 to 12 mg kg"' they found that patients receiving the larger doses awakened at a greater arterialized W. TONER, B.SC.; P. J. HOWARD, F.S.A.L.T., F.I.S.T.; W. A. W. McGOWAN, M.D., F.F.A.R.C.S.; J. W. DUNDEE, M.D., PH.D., F.F.A.R.C.S., MJt.c.p.; Department of Anaesthetics, The Queen's University of Belfast, Northern Ireland /80/ venous plasma concentration of the drug than those given smaller doses. With the availability of modern and less timeconsuming analytical techniques (Toner et al., 1979) a further, more comprehensive examination of the phenomenon of acute tolerance was undertaken in 82 unselected, unpremedicated adults. The dose of thiopentone ranged from 2 to 15 mg kg" 1 and venous blood was used for analysis. The findings of this study have been summarized by Dundee (1980) and Dundee and others (1980). METHODS Doses were allocated at random and injected rapidly over 2-5 s. The time was noted from injection to recovery (open eyes on command). In some patients the thiopentone was given well in advance of operation, the time to recovery was noted and anaesthesia was reinduced with nitrous oxide in oxygen and a further small dose of barbiturate. With larger doses a short operation was carried out during nitrous oxide in oxygen anaesthesia, but nitrous oxide was discontinued immediately and recovery usually took a further 3-5 min. Immediately on waking a venous blood sample (for thiopentone analysis) was drawn from the arm opposite to that used for injection. Plasma thiopentone concentration was estimated using an Anachem High Performance Liquid Chromatograph fitted with a fixed wavelength ultra-violet light detector (254 nm) with sensitivity set at A reverse phase (15 cm x 0.3 cm i.d.) spherisorb 10 ODS column and a mobile phase of methanol-water 50 : 50 at a pressure of 7000 kpa was used (Toner et al., 1979). In presenting the data, the dose of thiopentone is expressed as mg kg"' except infigure 2. Student's Macmillan Publishers Ltd 1980

2 1006 BRITISH JOURNAL OF ANAESTHESIA r-test and linear regression analyses were used as required. RESULTS Eighty-two patients were studied. The relationship between the plasma thiopentone concentration at awakening and the dose administered (mgkg" 1 ) is shown in figure 1. There was a 32 / r Dose (mg rrr 2 ) 155" 500 FIG. 2. Relationship between dose of thiopentone (mg m 2 and venous plasma concentration at wakening ( ig ml" '). 30» T Dose (mgkg" 1 ) FIG. 1. Relationship between dose of thiopentone (mg kg" 1 ) and venous plasma concentration at wakening (ng ml"'). positive linear relationship between these two factors (r = 0.694). With the dose expressed as mg m~ 2, a similar relationship was shown with a correlation value of r = (fig. 2). Hereafter, the dose will be expressed as mg kg"'. Figure 3 groups the doses of thiopentone and table II shows the significance of the difference of average plasma concentrations in the thiopentone groups. Table II also shows average times to wakening and the significance of difference between groups. 1! r? < a Dose range (mgkg- 1 ) FIG. 3. Data as for figure 1 divided into six groups. = Individual patients; = mean of groups; O = patients who did not go to sleep. In the group receiving less than 3.5 mgkg" 1, seven patients did not go to sleep, but samples TABLE II. Grouped data on average plasma thiopentone concentrations at wakening, and average recovery times in each group, tseven patients did not sleep; *one patient did not sleep Dose (mgkg" 1 ) n Average plasma thiopentone concn at wakening (ugml-'lsem) P Average time to wakening (min±sem).p < t 15* ± ± ± ± ± ±2.0 <0.5 <0.1 <0.2 n«^. K/.J < ± ± ± ± ± <rc\ OS < «r 0 0 ^. U. V <.u.l,n i <0,5

3 ANOTHER LOOK AT ACUTE TOLERANCE TO THIOPENTONE were taken between 1 and 2 min after injection; this also applies to one patient in the group receiving 3.5^5.5 mg kg" 1. These concentrations were less than those of the patients who went to sleep (P<0.1). Although averages of plasma concentrations and wakening times between consecutive groups were not significantly different (table II), a highly significant (P<0.02) difference was found between alternate groups. There was a less marked correlation (r = 0.56) between the dose of thiopentone and time to recovery. However, using the grouping of doses shown in figure 3, a very good correlation (r = 0.98) between log10 average plasma thiopentone concentration on wakening and the average recovery time was obtained (fig. 4). r-oae 5 10 Average time to recovery 1007 compared favourably with r = in the 82 patients. One may question the validity of venous concentrations of thiopentone, but generally the blood was sampled 4-5 min after induction and by that time the difference between arterial and venous concentration should be negligible. This study further substantiates the view that plasma thiopentone concentration is a poor guide to the depth of anaesthesia; the findings regarding concentrations at recovery support those of the previous study by Dundee, Price and Dripps (1956) and that by Brand and others (1961) who found no correlation between plasma thiopentone concentrations and the "depth" of anaesthesia as judged by the electroencephalogram. The medico-legal implications of this finding are obvious. Serial plasma concentrations may be a guide to the depth of anaesthesia and to the speed of recovery, but isolated concentrations are meaningless. 15 FIG. 4. Relationship between log 10, average plasma thiopentone concentrations at wakening (ng ml ~') and average time to wakening (min) concns at recovery (yn ml"11 FIG. 5. Scatter of venous thiopentone concentrations at wakening. Figure 5 shows the distribution of plasma concentrations of thiopentone at the time of recovery A comparison of figures 1 and 2 suggests that there in these 82 patients. Undoubtedly the pheno2 is little advantage in using mg m~ as a means of menon of "acute tolerance" is a major factor in this expressing the dose of thiopentone rather than the scatter., l more commonly used mg kg". REFERENCES This paper does not elucidate the mechanism of Brand, L., Mazria, V. D. B., Poznak, A. V., Burns, J. J., and the phenomenon of acute tolerance. The present Mark, U C. (1961). Lack of correlation between electrostudy confirms the relationship found in the smalencephalographic effects and plasma concentrations of ler series of Dundee, Price and Dripps (1956). thiopentone. Br. J. Anaenh., 33, 92. Although the correlation coefficient in the earlier Brodie, B. B. (1952). Physiological disposition and chemical fates of thiobarbiturates in the body. Fed. Proc., 11, 632. data was 0.74, based on only 16 patients, this DISCUSSION

4 1008 BRITISH JOURNAL OF ANAESTHESIA Dundee, J. W. (1980). Some factors influencing plasma thiopentone concentrations at waking. Br. J. Anaesth., 52, 101P. McGowan, W. A. W., Toner, W., and Howard, P. J. (1980). Plasma thiopentone levels on recovery. Irish J. Med. Sci., 148, 238. Price, H. L., and Dripps, R. D. (1956). Acute tolerance to thiopentone in man. Br. J. Anaesth., 28, 344. Toner, W., Howard, P. J., Dundee, J. W., and Mcllroy, P. D. A. (1979). Estimation of plasma thiopentone. The use of high performance liquid chromatogtaphy and an ether extraction. Anaesthesia, 34, 657. EXAMEN COMPLEMENTAIRE DE L'ACCOUTUMANCE AIGUE AU THIOPENTONE RESUME On a a nouveau examine le phenomcne de raccoutumance aigue au thiopentone sur 82 sujets, en utilisant dcs doses d'induction de 2-15 mg kg"'. On a constate unc forte correlation positive entre les concentrations de thiopentone dans le plasma veineux au moment de la reprise de conscience, apres l'anesthesie, et la dose d'induction, exprimeesoit en mg kg" 1 soitcnmg m" 2. Le temps necessairc a la reprise de corisdence a etc proportionnellemcnt plus court avec les doses les plus impotantes, celui-ci etant directemcnt relic au log 10 de la concentration dans le plasma au moment du reveil. EINE WEITERE BETRACHTUNG DER AKUTEN TOLERANZ FUR THIOPENTON ZUSAMMBNFASSUNG Das Phanomen der akuten Toleranz auf Thiopenton wurde bei 82 Personen mit Narkosedoscn von 2-15 mg kg" 1 neu untersucht. Es besteht eine starke positive Verbindung zwischen den vcndsen Plasma-Thiopentonkonzentrationen nach Aufwachen aus der Narkose und der Narkosedosis, ausgedruckt entweder in mg kg "' oder in mg m " 2. Die Erholungszeit war proportional kurzer mit grdsseren Dosen und stand in direktem Zusammenhang zu log 10 der Plasmakonzentration beim Erwachen. UN NUEVO EXAMEN DE LA TOLERANCIA AGUDA A LA TIOPENTONA SUMARIO El fenomeno de "tolerancia aguda" a la tiopentona se volvio a frnminar en 82 pacicntes mediantc dosis dc induccion de 2 15 mg kg" '. Tuvo lugar unafuertecorrelacionpositivaentre las concentraciones de tiopentona en el plasma venoso al recuperarse dc la anestesia y la dosis de induccion, exprcsada bien en mg kg" ' o en mg m" 2. El tiempo de recuperacion fue proporcionalmente mas corto para las mayores dosis, viniendo relacionado directamentc al log, 0 de la concentracion de plasma al momento de despertar.

5 fir. J. Anaesth. (1980), 52, 1009 COMPARATIVE STUDY OF THE CLINICAL EFFECTS OF TOFIZOPAM, NITRAZEPAM AND PLACEBO AS ORAL PREMEDICATION A. PAKKANEN, J. KANTO, L. KANGAS AND M. MANSDCKA SUMMARY In a double-blind randomized study 47 patients received tofizopam 100 mg orally the night before operation, and 100 mg on the morning of operation; 49 patients received nitrazepam 5 mg and 50 patient J received placebo. On average the nitrazepam group slept better and were better sedated than the tofizopam or placebo groups. Compared with placebo or nitrazepam, tofizopam decreased the excitement of the patients. The effect of tofizopam on apprehension and excitement was ugnificantly better than those of placebo or nitrazepam. Nitrazepam, but not tofizopam, significantly decreased the induction requirements of thiopentone. In this study we have compared the clinical effects of tofizopam with those of nitrazepam and a placebo. Nitrazepam, a 7-nitrobenzodiazepine, has prominent sedative and hypnotic effects; it also has anxiolytic, muscle-relaxing, anticonvulsant and amnesic properties, all of which are beneficial when it is used as an oral premedicant (Dundee and Haslett, 1970; Kangas, Kanto and Mansikka, 1977). Tofizopam is a relatively new benzodiazepine derivative (l-(3,4-dimethoxy-phenyl)- 4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine), with a distinct anxiolytic effect. However, it differs from other benzodiazepines in having, apparently, no sedative properties (Petocz and Kosoczky, 1975; Varady, Bolla and Sebo, 1975). PATIENTS AND METHODS In this double-blind study three groups of patients received, in random order, tofizopam 100 mg (two tablets of Grandaxin, test preparation, Farmos Group Ltd, Turku, Finland, each containing tofizopam 50 mg) (group 1, n = 47), nitrazepam 5 mg (one tablet of Somitran, Medipolar, Oulu, Finland, and one placebo tablet) (group 2, n = 49) or two placebo tablets (group 3, n = 50), orally at 9 p.m. on the night before operation and at 7 a.m. on the following morning. Mean ages, weights and ANTTI PAKKANEN, M.D.; JUSSI KANTO, M.D.; MAIJA MANSIKKA, M.D.; Department of Anacsthesiology, Turku University Central Hospital, Turku 52, Finland. LAURI KANGAS, M.SC., Research Center, Farmos Group Ltd, Turku 10, Finland /80/ heights of the patients were 42.6 ± 13.6 (SD) yr, kg and 165.6±7.9cm in group 1; 39.7 ± 14.9 yr, 67.6 ±10.2 kg and cm in group 2; yr, kg and ±8.2 cm in group 3. The patients were in good general health (ASA class 1, except for one patient in group 3 and two patients in group 1 and 2 who were ASA class 2). About half of each group were gynaecological inpatients and the other half e.n.t. inpatients (males and females in equal numbers; there were no significant differences between the three groups in this respect). The subjective and objective assessments before operation (carried out by M.M. in gynaecological patients and A.P. in e.n.t. patients) were recorded in the operating room, as suggested by Dundee, Moore and Nicholl (1962) with minor modifications as presented in our earlier studies (Kangas, Kanto and Mansikka, 1977; Kanto et al., 1979, 1980; Mansikka et al., 1979; Mansikka, Kangas and Kanto, 1980). The mean time interval between the second dose of the drug and the assessment was 2.74±1.38 (SD) h in group 1, 2.90 ± 1.62 h in group 2 and 2.65 ± 1.34 h in group 3. Thiopentone was given as an i.v. induction agent until loss of the eyelid reflex, the dose (mgkg" 1 ) being recorded in order to test the sedation produced by the three different premedicants. The statistical analyses of the results were carried out with )j 2 -test and Student's t test. RESULTS Patients in the nitrazepam group slept significantly better and were more sedated than those in the Macmillan Publishers Ltd 1980