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UNCONSCIOUS PERCEPTION DURING ANAESTHESIA—COMMENT ON STATISTICS
BRITISH JOURNAL OF ANAESTHESIA
600
h and, as for other drugs, a gradual titration is required in order to normalize arterial pressure. In some patients, the effective infusion rate of labetalol is higher than 0.15 mg kg"1 h"1. This may be consistent with the findings of Fell, Chmielewski and Smith [2] who noted that plasma noradrenaline concentrations were increased during the late period after operation. Such a high degree of resting sympathetic drive may require an increase in the infused dose of the P-adrenergic blocking agent to block adrenergic receptors. This was probably the case in our study, in which neither bradycardia nor hypotension was observed. M. CHAUVIN
Boulogne REFERENCES 1. McNeil JJ, Louis WJ. Clinical pharmacokinetics of labetalol. Clinical Pharmacokinetics 1984; 9: 157. 2. Fell D, Chmielewski A, Smith G. Postoperative analgesia with controlled-release morphine sulphate: comparison with intramuscular morphine. British Medical Journal 1982; 285: 92-94.
UNCONSCIOUS PERCEPTION DURING ANAESTHESIA—COMMENT ON STATISTICS Sir,—Wilson and Spiegelhalter [1] criticize Bennett, Davis and Giannini [2] on their statistics. When comparing 9/11 with 9/21, they say P = 0.08, not 0.05 as Bennett claims. Two comments are needed: (1) If Dr Wilson is correct we are only 92% confident that this is a real difference, whereas by convention we need 95 % C. PRYS-ROBERTS confidence. Clearly, whichever figure is correct, we should Bristol draw the same conclusion—namely, that this interesting J. DAGNINO finding could well be genuine and needs verifying in a larger Santiago de Chile study. If the same percent results occurred with two samples of approx. 20, it would be highly significant by any test. REFERENCES (2) We all applaud Dr Wilson's plea for good statistics—it is 1. Chauvin M, Deriaz H, Viars P. Continuous i.v. infusion the only objective way to measure the strength of the evidence. of labetalol for postoperative hypertension. British Journal Unfortunately, he himself has used a version of Fisher's exact test, which many of us cannot accept. Apart from anything of Anaesthesia 1987; 59: 1250-1256. 2. Dagnino J, Prys-Roberts C. Assessment of p-adreno- else, in certain instances it can give impossible P values greater ceptor blockade during anesthesia in humans: use of than 1. This has been discussed in detail elsewhere [3]. The problem lies not in the maths, which is elementary, but isoproterenol dose-response curves. Anesthesia and Analin what we mean by probability. To judge this, a researchgesia 1985; 64: 305-311. 3. Prys-Roberts C, Dagnino J. Pharmacodynamic and worker is as well placed as a statistician (perhaps better, since kinetic profiles of beta-adrenoceptor antagonists ad- we have to act on our conclusions). The classical tail area idea ministered by continuous intravenous infusion. In: works perfectly for the t test, but it is never going to work for Stoeckel H, ed. Quantitation, Modelling and Control in Fisher's test. The statistical establishment seems unwilling to Anaesthesia. Stuttgart: Georg Thieme Verlag, 1985: get to grips with this problem. Anyone who cares about research and who has accepted the conventional versions 129-133. hitherto is referred to Cormack [3].
Sir,—We agree with Professor Prys-Roberts and Dr Dagnino that the rate of infusion of labetalol (0.2 mg kg"1 h"1) was too high. We calculated the infusion rate in order to obtain a steady state plasma concentration (C*) of 170 ng ml"1 on the basis of a clearance value of 20 ml kg"1 min"1 determined by previous pharmacokinetic studies after bolus i.v. injection [1]. In fact, the mean clearance value calculated in steady state conditions was lower than that used in our pharmacokinetic model and this explains why the measured 0 s was greater than the predicted one. In clinical practice, it is necessary to start the infusion at a slower rate—between 0.07 and 0.15 mg kg"1
R. S. CORMACK
Nonhwick Park REFERENCES 1. Wilson ME, Spiegelhalter D. Unconscious perception during anaesthesia. British Journal of Anaesthesia 1987; 59: 1333. 2. Bennett HL, Davis HS, Giannini JA. Non verbal response to intraoperative conversation. British Journal of Anaesthesia 1985; 57: 174-179. 3. Cormack RS. The meaning of probability in relation to Fisher's exact test. Metron 1986; 44: 1-30.
Downloaded from http://bja.oxfordjournals.org/ at McMaster University Library on June 28, 2015
CONTINUOUS I.V. INFUSION OF LABETALOL FOR POSTOPERATIVE HYPERTENSION Sir,—Drs Chauvin, Deriaz and Viars [1] presented an interesting study of labetalol as a means of suppressing postoperative hypertension. Their study concentrated on the haemodynamic effects of a loading dose of labetalol 1.5 mg kg"1, followed by an infusion of 0.2 mg kg"1 h"1, but also provided data on plasma concentrations from which the clearance of the drug can be deduced. In their introduction and discussion, they imply that Dagnino and Prys-Roberts [2] published pharmacodynamic and pharmacokinetic data on infusions of labetalol. We wish to correct any misinterpretation of this statement. In that paper, we applied isoprenaline dose-response curves as a means of quantifying the pharmacodynamic effects of a number of beta-adrenoceptor antagonists, including labetalol administered by i.v. infusion. In a separate study [3], we described the fuller relationship between the pharmacokinetic and dynamic effects of infusions of labetalol, relating the degree of beta-receptor blockade (as determined by the chronotropic dose of isoprenaline CD25) to the plasma concentration of the drug, rather than simply to the infusion rate. As part of this latter study we determined the clearance of labetalol after 24 and 48 h of infusion at a constant rate. We found the median value to be 11 ml kg"1 min"1 (range 5.8-24.7), a value very similar to that quoted by Chauvin and his colleagues. We found that an infusion of labetalol 0.15 mgkg"1 h"1 caused sufficient hypotension to decrease urine output in a number of our patients in the intensive care unit. For this reason, we would caution against use of the dose recommended by Chauvin and his colleagues (0.2 mg kg"1 h"1) for more than the 5.5 h for which they studied their patients.
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600
h and, as for other drugs, a gradual titration is required in order to normalize arterial pressure. In some patients, the effective infusion rate of labetalol is higher than 0.15 mg kg"1 h"1. This may be consistent with the findings of Fell, Chmielewski and Smith [2] who noted that plasma noradrenaline concentrations were increased during the late period after operation. Such a high degree of resting sympathetic drive may require an increase in the infused dose of the P-adrenergic blocking agent to block adrenergic receptors. This was probably the case in our study, in which neither bradycardia nor hypotension was observed. M. CHAUVIN
Boulogne REFERENCES 1. McNeil JJ, Louis WJ. Clinical pharmacokinetics of labetalol. Clinical Pharmacokinetics 1984; 9: 157. 2. Fell D, Chmielewski A, Smith G. Postoperative analgesia with controlled-release morphine sulphate: comparison with intramuscular morphine. British Medical Journal 1982; 285: 92-94.
UNCONSCIOUS PERCEPTION DURING ANAESTHESIA—COMMENT ON STATISTICS Sir,—Wilson and Spiegelhalter [1] criticize Bennett, Davis and Giannini [2] on their statistics. When comparing 9/11 with 9/21, they say P = 0.08, not 0.05 as Bennett claims. Two comments are needed: (1) If Dr Wilson is correct we are only 92% confident that this is a real difference, whereas by convention we need 95 % C. PRYS-ROBERTS confidence. Clearly, whichever figure is correct, we should Bristol draw the same conclusion—namely, that this interesting J. DAGNINO finding could well be genuine and needs verifying in a larger Santiago de Chile study. If the same percent results occurred with two samples of approx. 20, it would be highly significant by any test. REFERENCES (2) We all applaud Dr Wilson's plea for good statistics—it is 1. Chauvin M, Deriaz H, Viars P. Continuous i.v. infusion the only objective way to measure the strength of the evidence. of labetalol for postoperative hypertension. British Journal Unfortunately, he himself has used a version of Fisher's exact test, which many of us cannot accept. Apart from anything of Anaesthesia 1987; 59: 1250-1256. 2. Dagnino J, Prys-Roberts C. Assessment of p-adreno- else, in certain instances it can give impossible P values greater ceptor blockade during anesthesia in humans: use of than 1. This has been discussed in detail elsewhere [3]. The problem lies not in the maths, which is elementary, but isoproterenol dose-response curves. Anesthesia and Analin what we mean by probability. To judge this, a researchgesia 1985; 64: 305-311. 3. Prys-Roberts C, Dagnino J. Pharmacodynamic and worker is as well placed as a statistician (perhaps better, since kinetic profiles of beta-adrenoceptor antagonists ad- we have to act on our conclusions). The classical tail area idea ministered by continuous intravenous infusion. In: works perfectly for the t test, but it is never going to work for Stoeckel H, ed. Quantitation, Modelling and Control in Fisher's test. The statistical establishment seems unwilling to Anaesthesia. Stuttgart: Georg Thieme Verlag, 1985: get to grips with this problem. Anyone who cares about research and who has accepted the conventional versions 129-133. hitherto is referred to Cormack [3].
Sir,—We agree with Professor Prys-Roberts and Dr Dagnino that the rate of infusion of labetalol (0.2 mg kg"1 h"1) was too high. We calculated the infusion rate in order to obtain a steady state plasma concentration (C*) of 170 ng ml"1 on the basis of a clearance value of 20 ml kg"1 min"1 determined by previous pharmacokinetic studies after bolus i.v. injection [1]. In fact, the mean clearance value calculated in steady state conditions was lower than that used in our pharmacokinetic model and this explains why the measured 0 s was greater than the predicted one. In clinical practice, it is necessary to start the infusion at a slower rate—between 0.07 and 0.15 mg kg"1
R. S. CORMACK
Nonhwick Park REFERENCES 1. Wilson ME, Spiegelhalter D. Unconscious perception during anaesthesia. British Journal of Anaesthesia 1987; 59: 1333. 2. Bennett HL, Davis HS, Giannini JA. Non verbal response to intraoperative conversation. British Journal of Anaesthesia 1985; 57: 174-179. 3. Cormack RS. The meaning of probability in relation to Fisher's exact test. Metron 1986; 44: 1-30.
Downloaded from http://bja.oxfordjournals.org/ at McMaster University Library on June 28, 2015
CONTINUOUS I.V. INFUSION OF LABETALOL FOR POSTOPERATIVE HYPERTENSION Sir,—Drs Chauvin, Deriaz and Viars [1] presented an interesting study of labetalol as a means of suppressing postoperative hypertension. Their study concentrated on the haemodynamic effects of a loading dose of labetalol 1.5 mg kg"1, followed by an infusion of 0.2 mg kg"1 h"1, but also provided data on plasma concentrations from which the clearance of the drug can be deduced. In their introduction and discussion, they imply that Dagnino and Prys-Roberts [2] published pharmacodynamic and pharmacokinetic data on infusions of labetalol. We wish to correct any misinterpretation of this statement. In that paper, we applied isoprenaline dose-response curves as a means of quantifying the pharmacodynamic effects of a number of beta-adrenoceptor antagonists, including labetalol administered by i.v. infusion. In a separate study [3], we described the fuller relationship between the pharmacokinetic and dynamic effects of infusions of labetalol, relating the degree of beta-receptor blockade (as determined by the chronotropic dose of isoprenaline CD25) to the plasma concentration of the drug, rather than simply to the infusion rate. As part of this latter study we determined the clearance of labetalol after 24 and 48 h of infusion at a constant rate. We found the median value to be 11 ml kg"1 min"1 (range 5.8-24.7), a value very similar to that quoted by Chauvin and his colleagues. We found that an infusion of labetalol 0.15 mgkg"1 h"1 caused sufficient hypotension to decrease urine output in a number of our patients in the intensive care unit. For this reason, we would caution against use of the dose recommended by Chauvin and his colleagues (0.2 mg kg"1 h"1) for more than the 5.5 h for which they studied their patients.
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