0 1990 Raven Press, Ltd., New York

J Clin Gastroenterol 1990;12(2):145-7.

The Effect of Age on the Relative Potency of Midazolam and Diazepam for Sedation in Upper Gastrointestinal Endoscopy Susan G. Scholer, M.D., Daniel F. Schafer, M.D., and Jane F. Potter,

Diazepam and midazolam are considered safe and effective sedative agents for diagnostic procedures. However, there have been recent reports of deaths in older patients receiving midazolam for sedation. We examined the relative potency of diazepam compared with midazolam as a function of age in two large groups of patients receiving intravenous benzodiazepines for upper gastrointestinal endoscopy. While midazolam and diazepam are approximately equivalent before age 60, after age 60 the relative potency of midazolam compared with diazepam increases markedly. The rapid decline in dose necessary to sedate older patients with midazolam may explain deaths occurring in older patients who have received this drug. Until this problem receives definitive study, we advise that diazepam be preferred over midazolam for intravenous sedation in patients over 60. Key Words: Age-Midazolam-Diazepam-SedationEndoscopy.

M.D.

Benzodiazepines and their derivatives are extensively used as preoperative agents for surgical and diagnostic procedures. Diazepam has been used almost exclusively in all ages as a sedative before upper gastrointestinal endoscopy, but midazolam, an imidazobenzodiazepine, has been gaining favor because of its faster rate of onset and higher rate of amnesia (1). Recent reports, however, have associated this drug with preoperative deaths in older patients (2). Studies to determine the relative potency of midazolam compared with diazepam have almost universally used subjects from a broad age spectrum (1,3-5). In those analyses, the mean relative potency of midazolam for all ages is approximately twice that of diazepam. On the other hand, a study by Bell et al., examining doses of midazolam t o achieve sedation in 415 men undergoing upper endoscopy, found that the dose was at least as high as diazepam and that the dose declined substantially with age (6). This suggests that estimating relative potencies should take age into account. Failure to take age into account may produce recommendations that both undersedate the young and oversedate the old. We present data on 904 subjects to determine the dose of diazepam necessary to achieve sedation. Further, we compare our data to that of Bell et al. to determine the relative potencies of these drugs by 5-year intervals. Although in this study we compare data from two institutions, we have found no sing1e study using age stratification.

From the Section of Geriatrics and Gerontology, Department of Internal Medicine, University of Nebraska Medical Center (S.G.S., J.F.P.), and the Section of Gastroenterology, Department of Internal Medicine, Omaha Veterans Administration Hospital (D.F.S.), Omaha, Nebraska, U.S.A. Address correspondence and reprint requests to Dr. Susan G. Scholer at Section of Geriatrics and Gerontology, Department of Internal Medicine, University of Nebraska Medical Center, 42nd and Dewey, Omaha, Nebraska 68105, U.S.A. The results of this study were presented in poster form at the AGS-AFAR meeting May 14-16, 1987, New Orleans, Louisiana.

METHODS We retrospectively reviewed 1,125 upper gastrointestinal endoscopies performed at the Omaha Veterans Administration Medical Center from January of 1986 through July of 1987. All subjects were men with a mean

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age of 62.2 years (range of 25-93 years). Nine hundred and four valid cases remained for evaluation after exclusion of emergent procedures and cases with insufficient data. The procedures were performed by 10 staff gastroenterologists or fellows. All patients received Xylocaine throat spray and intravenous diazepam in 2-mg increments. All patients were sedated only to tolerance of the procedure. The mean dose and 95% confidence intervals of diazepam were calculated for 5-year age intervals. Linear regression of dose on age was performed by a standard procedure (7). Bell et al. (6) have published similar data in 794 patients (415 men and 379 women, ages 15-90 years) who received intravenous midazolam before upper gastrointestinal endoscopy. Midazolam was titrated to toleration of the procedure. Those data were reported as mean (*SD) of the dose of midazolam necessary to achieve sedation, by 5-year age intervals. The ratio of diazepam to midazolam for each 5-year age interval was calculated as a measure of the relative potency of these drugs in each age group. The higher the ratio, the greater the relative potency of midazolam for that age group.

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RESULTS Fig. 1 summarizes the results. In Fig. la, the dose of diazepam to achieve sedation is negatively correlated with age (p < 0.00001). The same relationship is seen with midazolam (Fig. Ib, p < 0.001) (6). Fig. Ic plots the ratio of diazepam to midazolam for the 5-year age intervals in Fig. l a and b. Before age 60, the ratio of drug to achieve sedation is relatively constant. After age 60, there is a dramatic rise in

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this ratio, showing that t h e amount of midazolam to

achieve sedation falls more rapidly compared with diazepam, i.e., the relative potency of midazolam increases progressively after age 60. n DISCUSSION Our data show that, in adult patients there is a steady decrease with age in the amount of intravenous diazepam necessary to achieve sedation. There are several possible mechanisms for this increased response to benzodiazepines in the elderly. Benzodiazepine receptors in the rodent and human central nervous system modulate the central action of benzodiazepines as part of a larger molecular complex containing receptors for GABA, a brain inhibitory neurotransmitter (8). Aging may change these receptors qualitatively or quantitatively, predisposing the aged patient to increased sedation from these drugs (9). Alternatively, pharmacokinetic changes that accompany aging may augment drug sensitivity by increasing the level of free drug at the receptor site and target organ (10). J Clin Gastroenterol, Vol. 12, No. 2,1990

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50 60 70 80 AGE (Years)

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FIG. 1. (a) Age dependence of diazepam dose required to perform upper endoscopy. Age of patients were calculated using date of birth and date of procedure. Means and standard deviations for diazepam dose were calculated for each 5-year interval of age. (b)Age dependence of midazolam dose required to perform upper endoscopy. Means and standard deviations for each 5-year interval were obtained from reference 6. Straight line is a calculated linear regression of the means. (c) Age dependence of the ratio for diazepamimidazolam doses required to perform upper endoscopy. Above age 60, subjects become progressively more sensitive to midazolam.

Changes in drug distribution and clearance may alter plasma and brain concentration in older people, such that at a given time after a dose of benzodiazepine is administered, the measured plas-

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BENZODIAZEPINE DOSAGE A N D AGE ma level may be lower, higher, or the same as that of a young person (11,12). Midazolam is thought to be an effective and safe alternative to diazepam (13). Potency studies have demonstrated that midazolam is, alone, twice as potent as diazepam (1,3-5). In addition, the affinity of midazolam for the benzodiazepine receptor in the central nervous system is twice that of diazepam (14). Thus, the recommended dose of midazolam is less than diazepam. Bell et al. (6) examined the effect of age on the dose of midazolam necessary to achieve sedation in 794 subjects undergoing upper endoscopy (Fig. Ib). The results were similar to our data in that the dose required decreased throughout the adult age range. When the mean diazepam dose from our study was compared with the mean midazolam dose from Bell et al.’s data for the same 5-year age intervals, the ratio (mean dose of diazepam divided by mean dose of midazolam) increased dramatically after age 60 (Fig. lc). As age increases, relatively greater decreases in midazolam dosages are necessary compared with diazepam. The extreme potency of midazolam in old age is a likely explanation for the reported toxicity in older patients. Several limitations of our study need to be addressed. We did not consider factors that influence a subject’s sensitivity to benzodiazepines, such as cigarette smoking, alcohol use, or ingestion of other drugs. Nor did we address the mechanism for the apparent increase in sensitivity with age. Benzodiazepine pharmacokinetics are altered with aging (lo), and it is possible that the difference in the response of the older patient to a given dose of benzodiazepine was a result of a difference in plasma levels. We did not measure plasma levels. Finally, we compared data from our institution with that from a separate institution, where assessment of sedation may have been different. While institutional differences may have been significant, this would not alter the ratios of midazolam to diazepam as a function of age. Only systematic bias in the treatment of older subjects at one or both institutions would artifactually produce these results. Such an artifact might occur if older patients were systemically oversedated in our institution or systematically undersedated in the study of Bell et al. While possible, this is unlikely.

To date, the Food and Drug Administration has received 66 reports of deaths associated with respiratory or cardiac depression occurring primarily in elderly patients receiving intravenous midazolam for sedation (15). The use of centrally active agents in geriatric patients requires caution. Until a welldesigned, randomized study is conducted to examine the relative safety of these drugs in older patients, we feel that diazepam should remain the drug of choice in older patients requiring sedation for surgical and diagnostic procedures. REFERENCES 1. Whitwam JG, Al-Khudhairi D, McCloy RF. Comparison of midazolam and diazepam in doses of comparable potency during gastroscopy. Br J Anaesth 1983;55:773-7. 2. Food and Drug Administration. Warning reemphasized in midazolam labeling, Washington, DC: FDA Drug Bulletin, 1987;175. 3. Porro GB, Baroni S , Parente F, Lazzaron M. Midazolam vs. diazepam as premedication for upper gastrointestinal endoscopy: a randomized, double-blind, crossover study. Gastrointest Endosc 1988;34:252-4. 4. Cole SG, Brozinsky S , Isenberg JT. Midazolam, a new more potent benzodiazepine compared with diazepam: a randomized, double-blind study of preendoscopic sedatives. Gastrointest Endosc 1983;29:219-23. 5 . Lewis BS, Shlien RD, Wayne JD, Knight RJ, Aldoroty RA. Diazepam versus midazolam (versed) in outpatient colonoscopy: a double-blind, randomized study. Gastrointest Endosc 1989;35:334. 6 . Bell GD, Spickett GP, Reeve PA, Morden A, Logan RFA. Intravenous midazolam for upper gastrointestinal endoscopy: a study of 800 consecutive cases relating dose to age and sex of patient. Br J Clin Pharmacol 1987;23:241-3. 7. Jeanty P. Performing linear regression with 1-2-3. PC Magazine 1984;10:243-8. 8. Garrett KM, Tabakoff B. The development of type I and type I1 benzodiazepine receptors in the mouse cortex and cerebellum. Pharmacol Biochem Behav 1985;22:985-92. 9. Severson JA. Neurotransmitter receptors and aging. J A m Geriatr Soc 1984;32:247. 10. Greenblatt DJ, Divoll M, Abernathy DR, Ochs HR, Shader RI. Benzodiazepine Kinetics: Applications for therapeutics and pharmacogeriatrics. Drug Metab Rev 1983;14:251-92. 11. Cook PJ, Flanagan R , James IM. Diazepam tolerance: effect of age, regular sedation and alcohol. Br Med J 1984;289:3513. 12. Avram MJ, Fragen RJ, Caldwell NJ. Midazolam kinetics in women of two age groups. Clin Pharmacol Ther 1983;34: 505-8. 13. Lee MG, Hanna W, Harding H . Sedation for upper gastrointestinal endoscopy: a comparative study of midazolam and diazepam. Gastrointest Endosc 1988;35:824. 14. Mohler H, Okada T. Benzodiazepine receptor: demonstration in the central nervous system. Science 1977;198:849-51. 15. Munro I , ed. Midazolam-is antagonism justified? Lancet 1988;ii:14&2.

J Clin Gasrroenterol, Vol. 12, No. 2,1990

The effect of age on the relative potency of midazolam and diazepam for sedation in upper gastrointestinal endoscopy.

Diazepam and midazolam are considered safe and effective sedative agents for diagnostic procedures. However, there have been recent reports of deaths ...
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