Physicochemical Characteristics

Table 10-7. Physicochemical characterization of three benzodiazepines Diazepam Lorazepam Midazolam Molecular weight 284.7* 321.2* 362* (daltons)

pKa 3.3 (20°) 11.5 (20°) 6.2 (20°)* Water soluble No* Almost insoluble Yes† Lipid soluble Yes, highly Yes (relatively less Yes, highly lipophilic* lipophilic, however) lipophilic†

*Data from Moffet A: Clarke's Isolation and Identification of Drugs, 2nd ed. London, Pharmaceutical Press, 1986. †pH dependent: pH >4, lipid soluble; pH <4, water soluble.

Three benzodiazepine receptor agonists are commonly used in the practice of anesthesia in the United States: midazolam, diazepam , and lorazepam (Fig. 10-10 and Table 10-7). All these molecules are relatively small and lipid soluble at physiologic pH. Each milliliter of diazepam solution (5 mg) contains 0.4 mL propylene glycol, 0.1 mL alcohol, 0.015 mL benzyl alcohol, and sodium benzoate/benzoic acid in water for injection (pH 6.2 to 6.9). Lorazepam solution (2 or 4 mg/mL) contains 0.18 mL polyethylene glycol with 2% benzyl alcohol as a preservative. Midazolam solution contains 1 or 5 mg/mL midazolam plus 0.8% sodium chloride and 0.01% disodium edetate, with 1% benzyl alcohol used as a preservative. The pH is adjusted to 3 with hydrochloric acid and sodium hydroxide. Midazolam is the most lipid soluble of the three drugs in vivo,363 but because of its pH- dependent solubility, it is water soluble when formulated in a buffered acidic medium (pH 3.5). The imidazole ring of midazolam accounts for its stability in solution and rapid metabolism. The high lipophilicity of all three accounts for their rapid CNS effect, as well as their relatively large volumes of distribution.364 Metabolism page 335

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Table 10-8. Pharmacokinetic and pharmacodynamic comparison of midazolam and active metabolites*

EC50 EEG EC50 SVT Clearance VSS t½cl Midazolam 1.8 ng/mL 0.9 mg/mL 523 mL/min 60 L 98 min 1-Hydroxymidazolam 10.2 ng/mL 5.3 ng/mL 680 mL/min 69 L 69 min

*All values are significantly (P<.05) different between midazolam and 1-hydroxymidazolam. EC50, median effective concentration; EEG, peak electroencephalogram change; SVT, saccadic velocity (eye movement); t½ cl, clearance half-life; VSS, volume at steady state. From Mandema JW, Tuk B, van Steveninck AL, et al: Pharmacokinetic-pharmacodynamic modeling of the central nervous system effects of midazolam and its main metabolite 1- hydroxymidazolam in healthy volunteers. Clin Pharmacol Ther 51:715-728, 1992.

Biotransformation of the benzodiazepines occurs in the liver. The two principal pathways involve either hepatic microsomal oxidation (N-dealkylation or aliphatic hydroxylation) or glucuronide conjugation.352,365 The difference in the two pathways is significant because oxidation is susceptible to outside influences and can be impaired by certain population characteristics (e.g., old age), disease states (e.g., hepatic cirrhosis), or the coadministration of other drugs that can impair oxidizing capacity (e.g., cimetidine). Conjugation is less susceptible to these factors.352 Both midazolam and diazepam undergo oxidation reduction or phase I reactions in the liver.366 The fused imidazole ring of midazolam is oxidized rapidly by the liver, much more rapidly than the methylene group of the diazepine ring in other benzodiazepines. This rapid oxidation accounts for the greater hepatic clearance of midazolam than diazepam . Lorazepam is less affected by enzyme induction and some of the other factors known to alter the cytochrome P450 and other phase I enzymes. For example, inhibition of oxidative enzyme function by cimetidine impairs the clearance of diazepam ,367 but it has no effect on lorazepam .366 Age decreases and smoking increases the clearance of diazepam ,34 but neither has a significant effect on midazolam biotransformation.21 Habitual alcohol consumption increases the clearance of midazolam.368 Race, because of differences in the isoenzymes responsible for hydroxylation, produces genetic differences in drug metabolism.369 The high frequency of mutated alleles in Asians in the genes coding for CYP2C19 may explain the reduced hepatic biotransformation of diazepam .

The metabolites of benzodiazepines can be important. Diazepam forms two active metabolites, oxazepam and desmethyldiazepam, both of which add to and prolong the drug's effects. Midazolam is biotransformed to hydroxymidazolams, which have activity and, when given over a longer time, can accumulate.370 However, these metabolites are rapidly conjugated and excreted in urine. 1-Hydroxymidazolam has an estimated clinical potency that is 20% to 30% that of midazolam.35 It is excreted largely by the kidneys and can cause profound sedation in patients with renal impairment.36 The primary hydroxymetabolite is cleared more rapidly35 than midazolam in healthy patients (Table 10-8). Thus, the metabolites are less potent and normally cleared more rapidly than midazolam, so they are of little concern in patients with normal hepatic and renal function. Lorazepam has five metabolites, but the principal one is conjugated to glucuronide. This metabolite is inactive, water soluble, and rapidly excreted by the kidney. Pharmacokinetics

Add to lightbox Figure 10-11 Simulated time course of plasma levels of midazolam after an induction dose of 0.2 mg/kg. Plasma levels required for hypnosis and amnesia during surgery are 100 to 200 ng/mL, with awakening usually occurring at levels lower than 50 ng/mL.

The three benzodiazepines used in anesthesia are classified as short (midazolam), intermediate (lorazepam ), and long lasting (diazepam ), according to their metabolism and plasma clearance (see Table 10-1).21,37 The plasma disappearance curves of all the benzodiazepines can be fitted to a two- or three-compartment model. Protein binding and volumes of distribution are not importantly different among these three benzodiazepines, but their clearance is significantly different. The clearance rate of midazolam ranges from 6 to 11 mL/kg/min, whereas clearance of lorazepam is 0.8 to 1.8 mL/kg/min and that of diazepam is 0.2 to 0.5 mL/kg/min.21 Because of these differences in clearance, the drugs have predictably different plasma disappearance curves (Figs. 10-11 to 10-13). They also have different context-sensitive half-times (see Fig. 10-3). Although the termination of action of these drugs is primarily a result of redistribution of the drug from the CNS to other tissues after use in anesthesia, after daily (long-term) repeated administration or after prolonged continuous infusion, midazolam blood levels will decrease more rapidly than blood levels of the other drugs because of its greater hepatic clearance. Thus, patients given continuous infusions of midazolam or repeated boluses over days should awaken faster than those given diazepam or lorazepam .

Add to lightbox Figure 10-12 Simulated time course of plasma levels of diazepam after an induction dose of 0.5 mg/kg. Plasma levels required for hypnosis and amnesia during surgery are 0.6 to 1.0 µg/mL, with awakening usually occurring at levels lower than 0.5 µg/mL.

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Add to lightbox Figure 10-13 Simulated time course of plasma levels of lorazepam after an induction dose of 0.1 mg/kg. Plasma levels required for hypnosis and amnesia during surgery are between 50 and 150 ng/mL, with awakening usually occurring at levels lower than 50 ng/mL.

Factors known to influence the pharmacokinetics of benzodiazepines are age, gender, race, enzyme induction, and hepatic and renal disease. Diazepam is sensitive to some of these factors, particularly age. Increasing age tends to reduce the clearance of diazepam 38 significantly and the clearance of midazolam to a lesser degree.39 Lorazepam is resistant to the effects of age, gender, and renal disease on pharmacokinetics. These drugs are all affected by obesity. The volume of distribution is increased as drug goes from plasma into adipose tissue. Although clearance is not altered, elimination half-lives are prolonged because of delayed return of the drug to plasma in obese persons.39 In general, sensitivity to benzodiazepines in some groups, such as the elderly, is greater despite relatively modest pharmacokinetic effects; thus, factors other than pharmacokinetics must be considered when these drugs are used. Pharmacology All benzodiazepines have hypnotic, sedative, anxiolytic, amnesic, anticonvulsant, and centrally produced muscle relaxant properties. The drugs differ in their potency and efficacy with regard to each of the pharmacodynamic actions. The chemical structure of each drug dictates its particular physicochemical properties and pharmacokinetics, as well as its receptor binding characteristics. Binding of benzodiazepines to their respective receptors is of high affinity and is stereospecific and saturable; the order of receptor affinity (and thus potency) of the three agonists is lorazepam > midazolam > diazepam . Midazolam is approximately 3 to 6 times40 and lorazepam 5 to 10 times as potent as diazepam .

The mechanism of action of benzodiazepines is reasonably well understood.371-373 The interaction of ligands with the benzodiazepine receptor represents one of the few examples in which the complex systems of biochemistry, molecular pharmacology, genetic mutations, and clinical behavioral patterns can be explained. More is understood about the mechanism of action of benzodiazepines than about the mechanism of many other general anesthetics. Through recent genetic studies the GABAA subtypes have been found to mediate the different effects (amnesic, anticonvulsant, anxiolytic, and sleep).373 Sedation, anterograde amnesia, 373 and anticonvulsant properties are mediated through α1-receptors, and anxiolysis and 373 muscle relaxation are mediated by the α2 GABAA receptor. Drug effect is a function of the blood level. By using plasma concentration data and pharmacokinetic simulations, it has been estimated that a benzodiazepine receptor occupancy rate of less than 20% may be sufficient to produce the anxiolytic effect, sedation is observed with 30% to 50% receptor occupancy, and unconsciousness requires 60% or higher occupation of benzodiazepine agonist receptors.374

Add to lightbox Figure 10-14 Model of the γ-aminobutyric acid (GABA)-benzodiazepine receptor complex. Current data suggest a pentameric protein composed of α-, β-, and γ-subunits; the proposed arrangement of subunits is arbitrary. There are two sites for GABA binding (on the β-subunits) and a single site for benzodiazepine (BDZ) binding (depicted on the γ2- subunit). Homology between the GABAα receptor and the nicotinic acetylcholine receptor suggests that the chloride ion channel is formed by contributions from each subunit. (Redrawn with modification from Zorumski CF, Isenberg KE: Insights into the structure and function of GABA-benzodiazepine receptors: Ion channels and psychiatry. Am J Psychiatry 148:162, 1991.)

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page 338 It is agreed that benzodiazepines exert their general effects by occupying the benzodiazepine receptor that modulates GABA, the major inhibitory neurotransmitter in the brain. GABA- adrenergic neurotransmission counterbalances the influence of excitatory neurotransmitters. Benzodiazepine receptors are found in highest density in the olfactory bulb, cerebral cortex, cerebellum, hippocampus, substantia nigra, and inferior colliculus, but lower densities are found in the striatum, lower portion of the brainstem, and spinal cord. Although there are two GABA receptors, the benzodiazepine receptor is part of the GABAA receptor complex on the subsynaptic membrane of the effector neuron. This receptor complex is made up of three protein subunits-α, β, and γ-arranged as a pentameric glycoprotein complex (Fig. 10-14). These proteins contain the various ligand binding sites of the GABAA receptor, such as the benzodiazepine, GABA, and barbiturate binding sites. The benzodiazepine binding site is 375,376 located on the γ2-subunit, and the β-subunit is thought to contain the binding site for GABA. With activation of the GABAA receptor, gating of the channel for chloride ions is triggered. The cell becomes hyperpolarized and therefore resistant to neuronal excitation. It is now postulated that the hypnotic effects of benzodiazepines are mediated by alterations in the potential-dependent calcium ion flux.375 The degree of modulation of GABA receptor function has a built-in limitation, which explains the relatively high degree of safety with benzodiazepines.

Add to lightbox Figure 10-15 Spectrum of the intrinsic activities of benzodiazepine receptor ligands, which range from agonists to inverse agonists. Structures of agonist, partial agonist, antagonist, partial inverse agonist, and inverse agonist compounds are shown. Intrinsic activity is greatest among agonists and is least among inverse agonists. Intrinsic activities are schematically indicated as positive by a plus sign and as negative by a minus sign, with 0 indicating a lack of intrinsic activity. (Redrawn with modification from Mohler H, Richards JG: The benzodiazepine receptor: A pharmacological control element of brain function. Eur J Anaesthesiol Suppl 2:15-24, 1988.) A fascinating and therapeutically significant discovery regarding the benzodiazepine receptor is that the pharmacologic spectrum of ligands includes three different types or classes371 that have been termed agonists, antagonists, and inverse agonists (Fig. 10-15), names that connote their actions. Agonists (e.g., midazolam) alter the conformation of the GABAA receptor complex so that binding affinity for GABA is increased, with resultant opening of the chloride channel. Agonists and antagonists bind to a common (or at least overlapping) area of the receptor by forming differing reversible bonds with the receptor.377 The well-known effects of an agonist then occur (anxiolysis, hypnosis, and anticonvulsant action). Antagonists (e.g., flumazenil ) occupy the benzodiazepine receptor, but they produce no activity and therefore block the actions of both agonists and inverse agonists. Inverse agonists reduce the efficiency of GABA-adrenergic synaptic transmission, and because GABA is inhibitory, the result of decreased GABA is CNS stimulation. The potency of the ligand is dictated by its affinity for the benzodiazepine receptor and the duration of effect by the rate of clearance of the drug from the receptor.

Long-term administration of benzodiazepines produces tolerance, which is defined as a decrease in efficacy of the drug over time.378 Although the mechanism of chronic tolerance is not fully understood, it appears that long-term exposure to benzodiazepines causes decreased receptor binding and function (i.e., downregulation of the benzodiazepine-GABAA receptor complex). This decrease would explain the increased dose requirements of benzodiazepines for anesthesia in patients who take them on a long-term basis. Interestingly, it appears that after the cessation of long-term use of benzodiazepines, the receptor complex becomes upregulated,378 which could mean an increased susceptibility to benzodiazepines during a period after recent use. page 338

page 339 The onset and duration of action of a bolus intravenous dose of a benzodiazepine depend on the lipid solubility of the drug, a finding that probably explains the differences in onset and duration of action of the three benzodiazepines used in clinical practice in the United States. Midazolam and diazepam have a more rapid onset of action (usually within 30 to 60 seconds) than lorazepam does (60 to 120 seconds). The half-life of equilibrium between the plasma concentration and the EEG effect of midazolam is approximately 2 to 3 minutes and is not affected by age.379 This half-life is about two times longer than that of diazepam , but when compared with diazepam , midazolam has sixfold greater intrinsic potency.40 Similar data for other benzodiazepines are not available. Like onset, the duration of effect is also related to lipid solubility and the blood level.380 The more rapid redistribution of midazolam and diazepam than that of lorazepam (presumably because of the lower lipid solubility than that of lorazepam )363 accounts for the shorter duration of their actions.

Effects on the Central Nervous System (see Chapter 21)

The benzodiazepines reduce CMRO2 and CBF in a dose-related manner. Midazolam and diazepam maintain a relatively normal ratio of CBF to CMRO2. In healthy human volunteers, midazolam, 0.15 mg/kg, induces sleep and reduces CBF by 34% despite a slight increase in 381 382 PaCO2 from 34 to 39 mm Hg. Brown and colleagues studied EEG tracings after 10 mg intravenous midazolam and showed the appearance of rhythmic beta activity at 22 Hz within 15 to 30 seconds of administration in healthy volunteers. Within 60 seconds, a second beta rhythm occurred at 15 Hz. Alpha rhythm started to reappear at 30 minutes; however, after 60 minutes, resistant rhythmic beta activity was noted at 15- to 20-µV amplitude. The EEG changes were similar to the EEG effects with diazepam and were not typical of light sleep, although the patients were clinically asleep. The best method of monitoring depth with midazolam is use of the EEG BIS index.383

Midazolam, diazepam , and lorazepam all increase the seizure initiation threshold of local anesthetics and lower the mortality rate in mice exposed to lethal doses of local anesthetics.384 Midazolam and diazepam induce a dose-related protective effect against cerebral hypoxia, which was demonstrated by extension of mouse survival time when mice were placed in 5% oxygen. The protection afforded by midazolam is superior to that of diazepam but less than that of pentobarbital.384 Antiemetic effects are not a prominent action of the benzodiazepines.

Effects on the Respiratory System Benzodiazepines, like most intravenous anesthetics, produce dose-related central respiratory system depression. The respiratory depression may be greater with midazolam than with diazepam and lorazepam , although comparative studies of the three do not exist. Lorazepam (2.5 mg intravenously [IV]) produces a similar, but shorter-lasting decrease in tidal volume and minute ventilation than diazepam (10 mg IV) does in patients with lung disease.385 The peak decrease in minute ventilation after midazolam (0.15 mg/kg) is almost identical to that produced in healthy patients given diazepam (0.3 mg/kg), as determined by carbon dioxide response data.386 The slopes of the ventilatory response curves to carbon dioxide are flatter than normal (control) but not shifted to the right, as with opioids. Judging from the plasma level and steepness of the dose-response effect on PaCO2 curves (Fig. 10- 16),387 midazolam is about five to nine times as potent as diazepam . The peak onset of ventilatory depression with midazolam (0.13 to 0.2 mg/kg) is rapid (about 3 minutes), and significant depression remains for about 60 to 120 minutes.348,388 The rate of midazolam administration affects the time of onset of peak ventilatory depression; the faster the drug is given, the more quickly this peak depression occurs.388 The respiratory depression associated with midazolam is more pronounced and of longer duration in patients with chronic obstructive pulmonary disease, and the duration of ventilatory depression is longer with midazolam (0.19 mg/kg) than with thiopental (3.3 mg/kg).348 Lorazepam (0.05 mg/kg) alone does not depress the carbon dioxide response, but when lorazepam is combined with meperidine, predictable respiratory depression occurs.389 It is probable that benzodiazepines and opioids produce additive or supra-additive (synergistic) respiratory depression, even though they act at different receptors.

Add to lightbox Figure 10-16 A, Increase in PaCO2 from baseline versus plasma concentration after three intravenous bolus doses of diazepam (0.15 mg/kg) given at 20-minute intervals. B, Increase in PaCO2 from baseline versus the midazolam plasma concentration after three intravenous bolus doses of midazolam (0.05 mg/kg) given at 20-minute intervals. The solid line represents a best-fit model of the data from the three injections. Mean values are represented as plus or minus standard error of the mean. (Redrawn from Sunzel M, Paalzow L, Berggren L, Eriksson I: Respiratory and cardiovascular effects in relation to plasma levels of midazolam and diazepam . Br J Clin Pharmacol 25:561-569, 1988.)

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page 340 Apnea occurs with the benzodiazepines. The incidence of apnea after induction of anesthesia with thiopental or midazolam is similar. Apnea occurred in 20% of 1130 patients given midazolam for induction and 27% of 580 patients given thiopental in clinical trials with midazolam.359 Apnea is related to the dose of the benzodiazepine and is more likely to occur in the presence of opioids. Old age, debilitating disease, and other respiratory depressant drugs probably also increase the incidence and degree of respiratory depression and apnea with benzodiazepines.

Effects on the Cardiovascular System Used alone, the benzodiazepines have modest hemodynamic effects. The hemodynamic changes reported with anesthetic induction doses of diazepam , midazolam, and lorazepam are shown in Table 10-2. These values represent the peak hemodynamic effect in the first 10 minutes after administration and are derived from studies of both healthy subjects and patients with ischemic and valvular heart disease.169,170,184,331,390 The predominant hemodynamic change is a slight reduction in arterial blood pressure that results from a decrease in systemic vascular resistance. The mechanism by which benzodiazepines maintain relatively stable hemodynamics involves the preservation of homeostatic reflex mechanisms,341 but some evidence indicates that the baroreflex is impaired by both midazolam and diazepam .391 Midazolam causes a slightly greater decrease in arterial blood pressure than the other benzodiazepines do, but the hypotensive effect is minimal and about the same as seen with thiopental.185 Despite the hypotension, midazolam, even in doses as high as 0.2 mg/kg, is safe and effective for induction of anesthesia even in patients with severe aortic stenosis. The hemodynamic effects of midazolam and diazepam are dose related: the higher the plasma level, the greater the decrease in systemic blood pressure387; however, there is a plateau plasma drug effect above which little change in arterial blood pressure occurs. The plateau plasma level for midazolam is 100 ng/mL, and that for diazepam is about 900 ng/mL.387 Heart rate, ventricular filling pressure, and cardiac output are maintained after induction of anesthesia with the benzodiazepines. In patients with elevated left ventricular filling pressure, diazepam and midazolam produce a "nitroglycerin- like" effect by lowering the filling pressure and increasing cardiac output.

The stresses of endotracheal intubation and surgery are not blocked by midazolam.169 Thus, adjuvant anesthetics, usually opioids, are often combined with benzodiazepines. The combination of benzodiazepines with opioids and nitrous oxide has been investigated in patients with ischemic and valvular heart disease.184,392-394 Whereas the addition of nitrous oxide to midazolam (0.2 mg/kg) and diazepam (0.5 mg/kg) has trivial hemodynamic consequences, the combination of benzodiazepines with opioids does have a supra-additive effect.395 Combinations of diazepam with fentanyl or sufentanil, midazolam with fentanyl392 or sufentanil,394 and lorazepam with fentanyl or sufentanil393 all produce greater decreases in systemic blood pressure than each drug does alone. Presumably, combinations of benzodiazepines with remifentanil will do the same. The mechanism for this synergistic hemodynamic effect is not completely understood, but it is probably related to a reduction in sympathetic tone when the drugs are given together.396 There is evidence that diazepam and midazolam decrease catecholamines,391 a finding consistent with this hypothesis. Uses Intravenous Sedation

Table 10-9. Uses and doses of intravenous benzodiazepines Midazolam Diazepam Lorazepam Induction 0.05-0.15 mg/kg 0.3-0.5 mg/kg 0.1 mg/kg Maintenance 0.05 mg/kg prn 0.1 mg/kg prn 0.02 mg/kg prn 1.0 µg/kg/min Sedation* 0.5-1.0 mg repeated 2 mg repeated 0.25 mg repeated 0.07 mg/kg IM

*Incremental doses are given until the desired degree of sedation is obtained. prn, as required to keep the patient hypnotic and amnestic.

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page 341 Benzodiazepines are used for sedation as preoperative premedication, intraoperatively during regional or local anesthesia, and postoperatively. The anxiolysis, amnesia, and elevation of the local anesthetic seizure threshold are desirable benzodiazepine actions. The dose of drugs should be titrated for this use; end points of titration are adequate sedation or dysarthria (Table 10-9). The onset of action is more rapid with midazolam, with a peak effect usually reached within 2 to 3 minutes of administration; the time to peak effect is slightly longer with diazepam and is still longer with lorazepam . The duration of action of these drugs depends primarily on the dose used. Although the onset is more rapid with midazolam than with diazepam after bolus administration, recovery is similar,397 probably because both drugs have similar early plasma decay (redistribution) patterns (see Figs. 10-11 and 10-12). With lorazepam , sedation and particularly amnesia are slower in onset398 and are longer lasting than with the other two benzodiazepines.370,399,400 A disparity in the level of sedation versus the presence of amnesia (patients seem conscious and reasonably coherent, yet they are amnesic for events and instructions) is often seen with all three benzodiazepines. Lorazepam is particularly unpredictable with regard to the duration of amnesia, and such unpredictability is undesirable in patients who wish or need to have recall in the immediate postoperative period.398 The degree of sedation and reliable amnesia, as well as preservation of respiratory and hemodynamic function, are better overall with benzodiazepines than with other sedative-hypnotic drugs used for conscious sedation. When midazolam is compared with propofol for sedation, the two are generally similar except that emergence or wake-up is more rapid with propofol . Propofol requires closer medical supervision because of its respiratory depression.401,402 Despite the wide safety margin with benzodiazepines, respiratory function must be monitored when these drugs are used for sedation to prevent undesirable degrees of respiratory depression. There may be a slight synergistic action between midazolam and spinal anesthesia with respect to ventilation.403 Thus, the use of midazolam for sedation during regional and epidural anesthesia requires vigilance with regard to respiratory function, just as when these drugs are given with opioids. Sedation for longer periods, for example, in the ICU, is accomplished with benzodiazepines. Prolonged infusion will result in accumulation of drug and, in the case of midazolam, significant concentration of the active metabolite. Reviews have pointed out concerns as well as advantages of benzodiazepine sedation.370,404-407 The chief advantages are amnesia and hemodynamic stability, and the disadvantage with respect to propofol is the sometimes longer dissipation of effects when infusions are terminated. Superiority of one drug over the other has not been established; both agents should always be titrated downward to maintain sedation as required. Dosing should not be fixed; instead, it should be reduced over time to avoid the accumulation of parent or metabolites during prolonged infusion.

Oral Sedation For many years diazepam was given orally for preoperative sedation. It is still used in 5- to 15-mg doses in adults for this purpose. More recently, an oral formulation of midazolam has been used primarily for oral premedication in pediatric patients. The dose is 0.5 mg/kg, and one preparation is from the Roche parenteral formulation of 0.5 mg/mL (Roche Laboratories, Inc., Nutley, NJ) mixed with 10 mg/kg oral acetaminophen (McNeil-PPC, Inc., Fort Washington, PA).408 Other preparations have been developed, such as strawberry-flavored glucose (pH 4.5) prepared by the pharmacy that is stable for 8 weeks.409 The 0.5-mg/kg oral dose is rapid acting; it provides reliable amnesia within 10 minutes and effectively sedates children for induction of anesthesia.408

Induction and Maintenance of Anesthesia

Add to lightbox Figure 10-17 Simulated quantal concentration-response curves generated by the parameterized pharmacodynamic model for midazolam. (Redrawn from Jacobs JR, Reves JG, Marty J, et al: Aging increases pharmacodynamic sensitivity to the hypnotic effects of midazolam. Anesth Analg 80:143-148, 1995.)

Midazolam is the benzodiazepine of choice for induction of anesthesia. Although both diazepam and lorazepam have been used for induction of general anesthesia, the faster onset and lack of venous complications make midazolam better suited for this use. With midazolam, induction of anesthesia is defined as unresponsiveness to command and loss of the eyelash reflex. When midazolam is used in appropriate doses (see Table 10-9), induction occurs less rapidly than with thiopental,359 but the amnesia is more reliable. Numerous factors influence the rapidity of action of midazolam and the other benzodiazepines when used for induction of general anesthesia, including the dose, speed of injection, degree of premedication, age, American Society of Anesthesiologists (ASA) physical status, and concurrent anesthetic drugs.359,410 In a well-premedicated, healthy patient, midazolam (0.2 mg/kg given in 5 to 15 seconds) will induce anesthesia in 28 seconds, whereas with diazepam (0.5 mg/kg given in 5 to 15 seconds), induction occurs in 39 seconds.169 Elderly patients require lower doses of midazolam than younger patients do (Fig. 10-17).411,412 Patients older than 55 years and those with ASA physical status higher than class III require a 20% or greater reduction in the induction dose of midazolam.359 The usual induction dose of midazolam in premedicated patients is between 0.05 and 0.15 mg/kg. When midazolam is used with other anesthetic drugs (coinduction), a synergistic interaction occurs,382,413,414 and the induction dose is less than 0.1 mg/kg (Fig. 10-18). Synergy is seen when midazolam is used with opioids or other hypnotics such as thiopental and propofol .

Awakening after benzodiazepine anesthesia is a result of redistribution of drug from the brain to other less well perfused tissues. Emergence (defined as orientation to time and place) of young, healthy volunteers who have received 10 mg of intravenous midazolam occurs in about 15 minutes,382 and after an induction dose of 0.15 mg/kg, it occurs in about 17 minutes.29 Emergence time is related to the dose of midazolam, as well as the dose of adjuvant anesthetic drugs.359 Emergence from midazolam (0.32 mg/kg)/fentanyl anesthesia is about 10 minutes longer than that from thiopental (4.75 mg/kg)/fentanyl anesthesia330 and is more prolonged than with propofol .30 This difference accounts for some anesthesiologists' preference for propofol induction for short operations. page 341

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Add to lightbox Figure 10-18 Vertical axes all represent drug dose in milligrams per kilogram. On the right, median effective dose (ED50) isobolograms for the hypnotic interactions among midazolam, alfentanil, and propofol are shown. The dotted lines are additive effect lines; note that all combinations fall within the line representing synergism or supra-additive effect. On the left, a triple interaction is depicted. The shaded area represents an additive plane passing through three single-drug ED50 points (small open circles). The largest closed circle (with arrows) is the ED50 point for the triple combination. The smaller closed circles are ED50 points for the binary combinations. R ratios on all graphs represent the interaction (1.0 indicates an additive effect) of the various drug combinations. Note that the combination of midazolam and alfentanil produces the greatest synergism, but the combination of all three is also synergistic. P values denote the significance of the additive effects. (Redrawn with modification from Vinik HR, Bradley EL Jr, Kissin I: Triple anesthetic combination: Propofol- midazolam-alfentanil. Anesth Analg 76:S450, 1993.)

Benzodiazepines lack analgesic properties and must be used with other anesthetic drugs to provide sufficient analgesia; however, as maintenance anesthetic drugs during general anesthesia, benzodiazepines provide hypnosis and amnesia. Double-blind studies comparing midazolam and thiopental as the hypnotic component of balanced anesthesia330,415 have shown that midazolam is superior for this use because of better amnesia and a smoother hemodynamic course. Opioid requirements are less with midazolam. Midazolam (0.6 mg/kg) lowers the MAC of halothane by 30%416 and presumably has a similar effect on other inhaled anesthetics. The question of an optimal redosing scheme after induction when midazolam is used as a maintenance hypnotic component of general anesthesia has not been answered. The amnesic period after an anesthetic dose is about 1 to 2 hours. Infusions of midazolam have been used to ensure a constant and appropriate depth of anesthesia.416 Experience indicates that a plasma level of more than 50 ng/mL when used with adjuvant opioids (e.g., fentanyl) or inhaled anesthetics (e.g., nitrous oxide, volatile anesthetics), or with both, is achieved with a bolus loading dose of 0.05 to 0.15 mg/kg and a continuous infusion of 0.25 to 1 µg/kg/min.413 This dose is sufficient to keep the patient asleep and amnesic but arousable at the end of surgery. Lower infusion doses may be required in some patients and with certain opioids. Midazolam, as well as diazepam and lorazepam , will accumulate in the blood with repeated bolus administration or with continuous infusion, just as most intravenous anesthetics do on repeated injection. If the benzodiazepines do accumulate with repeated administration, prolonged arousal time can be anticipated. This concern is less of a problem with midazolam than with diazepam and lorazepam because of the shorter context-sensitive half-time and greater clearance of midazolam.

UPDATE Date Added: 20 August 2004 Gail A. Van Norman, MD, Clinical Associate Professor, Anesthesiology, Affiliate Associate Professor, Dept of Biomedical History and Ethics, University of Washington, Seattle, Washington Intrathecal midazolam

Efforts to improve intrathecal (IT) treatment of oncologic, perioperative and labor pain have lead to the study of a number of pharmacologic agents as both primary and adjunct therapies, including opiates, a-blockers, N-type calcium channel blockers, and GABA receptor agonists. Recent reports have focused on the potential role of IT midazolam as an adjunct to IT opiate analgesia.

While IT midazolam shows promise as an adjunct to IT anesthesia and to IT fentanyl labor analgesia, toxicity studies of IT midazolam have been contradictory in several key aspects, and clinical studies have proven to be ethically controversial, due to patient safety considerations.

Midazolam acts to enhance the activity of GABA via its action at the BZ binding site of a subunit of the GABAA receptor. The receptor is a chloride-ionophor that stabilizes transmembrane potential when activated, resulting in decreased excitability in neurons. In afferent neurons, modest depolarizations after GABA binding cause paradoxical reduction in neuron transmitter release, and consequent presynaptic inhibition. BZ subunits appear in dorsal root ganglia and spinal neurons, and tend to suppress afferent evoked excitation in the substantial gelatinosa and motor horn, and appear to exert an inhibitory effect on spinal sensory and motor excitability.

Animal studies using IT midazolam have been reported since the early 1980s, with contradictory results. Early dog studies demonstrated the anticipated afferent inhibition, without effects on resting arterial blood pressure. IT midazolam was demonstrated to have an antispacticity effect in cats. Antinociceptive responses were also shown in rats, rabbits and sheep. Safety studies, however, yielded some disturbing results, with both rat and rabbit studies showing direct neurotoxicity from lumbar and intracisternal midazolam that was more pronounced than lidocaine, and were in contrast with both ketamine and bupivacaine, which showed no histopathologic effects. A recent study of chronic IT infusions of midazolam in sheep and pigs demonstrated no obvious clinical neurotoxicity, but did show consistent histopathologic changes in neuronal tissue that were attributed to inflammation from the spinal catheter. However, it should be pointed out that midazolam was delivered in a preservative-free formulation, as continuous infusion, and not as a single bolus dose.

Eighteen peer-reviewed studies of IT midazolam in human subjects have appeared in the literature, including relatively small patient groups who have received IT midazolam in both bolus and continuous infusion form. Two recent clinical studies suggest a positive effect of IT midazolam when given as an adjunct to intrathecal anesthesia and as an adjunct to IT fentanyl labor analgesia. However, several points should be noted: 1) only six studies represented controlled trials, 2) the typical positive benefits have included an antispacticity effect, increased duration of motor and sensory block, increased time to first analgesia request, and decrease of postoperative analgesic requirements, all without a reported increase in hypotension, bradycardia, nausea and vomiting, 3) the neurotoxicity of IT midazolam in humans poorly studied and understood, and 4) although midazolam is nearly always administered as an adjunct to other IT medication, to date no studies have been done in animal models to delineate the potential adverse interactions between intrathecally- administered midazolam and other drugs. In addition, in the United States, commercially available midazolam is the sulfate preparation, not suitable for IT administration.

Clinical use of IT midazolam awaits further study to more clearly outline human toxicity and examine the effects of drug interactions during IT use, as well as the development of an appropriately formulated, stabilized and purified preparation that is safe for intrathecal injection.

1. Cousins M and Miller R. Intrathecal midazolam: an ethical editorial dilemma. Anesth Analg. 2004. 98:1507-8 Medline Similar articles 2. Johansen MJ, et al. Safety of continuous intrathecal midazolam infusion in the sheep model. Anesth Analg 2004. 98:1528-35 Medline Similar articles 3. Tucker A, et al. Intrathecal midazolam I; a cohort study investigating safety. Anesth Analg. 2004 98:1512-20 Medline Similar articles 4. Tucker A, et al. Intrathecal midazolam II: combination with intrathecal fentanyl for labor pain. Anesth Analg. 2004. 98:1521-7 Medline Similar articles 5. Yaksh TL, and Allen JW. The use of intrathecal midazolam in humans: a case study of process. Anesth Analg. 2004. 98:1536-45 Medline Similar articles 6. Yaksh TL, and Allen JW. Preclinical insights into the implementation of intrathecal midazolam: a cautionary tale. Anesth Analg. 2004. 98:1509-11 Medline Similar articles Side Effects and Contraindications Benzodiazepines are remarkably safe drugs. They have a relatively high margin of safety, especially when compared with barbiturates. They are also free of allergenic effects and do not suppress the adrenal gland.414 The most significant problem with midazolam is respiratory depression. The major side effects of lorazepam and diazepam , in addition to respiratory depression, are venous irritation and thrombophlebitis, problems related to aqueous insolubility and the requisite solvents.359 When used as sedatives or for induction and maintenance of anesthesia, benzodiazepines can produce an undesirable degree or a prolonged interval of postoperative amnesia, sedation, and rarely, respiratory depression. These residual effects can be reversed with flumazenil .