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(1997) Cost effectiveness of administration of intravenous anesthetics for direct- current cardioversion by nonanesthesiologists. Am. J. Cariol. 79, 686–688. 46. Tung, R. T. and Bajaj, A. K. (1995) Safety of implantation of a cardioverter- defibrillator without general anesthesia in an electrophysiology laboratory. The American Journal of Cardiology 75(14), 908–912. 47. Rodeman, B. J. (1997) Conscious sedation during electrophysiology testing and radiofrequency catheter ablation. Critical Care Nursing Clinics of North America 9:3, 313–324. 48. Craney, J. M. and Gorman, L. N. (1997) Conscious sedation and implantable devices. Critical Care Nursing Clinics of North America 9:3, 325–334. 49. McGuire, B. M. (2001) Safety of endoscopy in patients with end-stage liver disease. Gastrointest. Endosc. Clinics of North America 11(1), 111–130. 50. Eige, S., Pritts, E. A., Palter, S. F., and Olive, D. L. (1999) Anesthesia for office endoscopy. Obstet. Gynecol. Clin. N. Am. 26(1), 99–108. 51. Iverson, R. E. (1999) Sedation and analgesia in ambulatory settings. Clinical Guidelines in Plast. Reconstr. Surg. 1559–1564. 52. Christian, M., Yeung, L., Williams, R., Lapinski, P., and Moy, R. (2000) Con- scious sedation in dermatologic surgery. Dermatology Surgery 26(10), 923–928. 53. Cohen, M. M., Doncan, P. G., and Tate, R. B. (1988) Does anesthesia contrib- ute to operative mortality? JAMA 260, 2859. Pharmacology of Sedative Agents 125 125 From: Contemporary Clinical Neuroscience: Sedation and Analgesia for Diagnostic and Therapeutic Procedures Edited by: S. Malviya, N. N. Naughton, and K. K. Tremper © Humana Press Inc., Totowa, NJ 6 Pharmacology of Sedative Agents Joseph D. Tobias, MD 1. INTRODUCTION Over the years, various pharmacologic agents have been developed to pro- vide sedation, anxiolysis, and amnesia. These agents have been used both as therapeutic agents (barbiturates to control intracranial pressure, propofol to treat refractory status epilepticus) and to provide sedation, anxiolysis, and amnesia in various clinical scenarios. In the setting of diagnostic and thera- peutic procedures, these agents usually are used to induce amnesia and to provide a motionless patient, which may be required to facilitate a procedure or achieve an accurate radiologic examination. When used during invasive and/or diagnostic procedures, although these agents provide amnesia, anxiolysis, and sedation, most—except for ketamine—possess limited intrin- sic analgesic properties and therefore are often combined with an opioid if analgesia is required (see Chapter 7). Although the majority of patients ex- perience few and mild cardiorespiratory effects, these agents can be potent respiratory depressants and may have adverse effects on cardiovascular func- tion. Therefore, these agents should be administered only by those who are well-acquainted with their use and pharmacologic properties and only in a controlled, monitored setting (see Chapter 8). This chapter reviews the more commonly used sedative agents, including propofol, ketamine, the barbitu- rates, the benzodiazepines, nitrous oxide, and chloral hydrate. 2. SPECIFIC AGENTS 2.1. Propofol Propofol is an intravenous (iv) anesthetic agent of the alkyl phenol group. Because of its insolubility in water, it is commercially available in an egg lecithin emulsion as a 1% (10 mg/mL) solution. Its chemical structure is distinct from that of the barbiturates and other commonly used anesthetic induction agents (1). Like the barbiturates, its mechanism of action involves 126 Tobias an interaction with the gamma-aminobutyric acid (GABA) receptor system; increasing the duration of time that the GABA molecule occupies the recep- tor. This results in increased chloride conductance across the cell membrane. Propofol is a sedative/amnestic agent and possesses no analgesic properties. Therefore, it should be combined with an opioid when analgesia is required. The anesthetic induction dose of propofol in healthy adults ranges from 1.5 to 3 mg/kg with recommended maintenance infusion rates of 50 to 200 mcg/kg/min, depending on the depth of sedation that is required. Following iv administration, propofol is rapidly cleared from the central compartment and undergoes hepatic metabolism to inactive water-soluble metabolites, which are then renally cleared. Propofol’s clearance rate exceeds that of hepatic blood flow, suggesting an extrahepatic route of elimination. Propofol’s rapid clearance and metabolism account for its beneficial prop- erty of rapid awakening when the infusion is discontinued. There is no evi- dence to suggest altered clearance in patients with hepatic or renal dysfunction. Following its introduction into anesthesia practice, propofol’s pharmaco- dynamic profile—including a rapid onset, rapid recovery time, and lack of active metabolites—eventually led to its evaluation as an agent for intensive care unit (ICU) sedation (2,3), as well as for procedures outside of the oper- ating room. When compared with midazolam for sedation in adult ICU patients, propofol resulted in shorter recovery times, improved titration effi- ciency, reduced post-hypnotic obtundation, and more rapid weaning from mechanical ventilation (4). Lebovic et al. demonstrated the beneficial prop- erties of propofol for sedation during cardiac catheterization in children (5). Children received an initial dose of fentanyl (1 mcg/kg) followed by incre- mental bolus doses of propofol (0.5 mg/kg) until the appropriate level of sedation was achieved. Once an adequate level of sedation was achieved, a propofol infusion was started with the hourly rate equivalent to 3 times the induction dose. When compared with a group who received ketamine, the authors noted significantly less time to full recovery with propofol (24 ± 19 min vs 139 ± 87 min, p < 0.001). In addition to its favorable properties with regard to sedation and recovery times, propofol has beneficial effects on central nervous system (CNS) dynamics including a decreased cerebral metabolic rate for oxygen (CMRO 2 ), cerebral vasoconstriction, and lowering of intracranial pressure (ICP) (6). The latter effect is much the same as that seen with the barbiturates and etomidate. These CNS effects suggest that propofol may be an effective and beneficial agent for sedation in patients with altered intracranial compliance, provided that ventilation is monitored and controlled when necessary to prevent increases in P a CO 2 related to the respiratory depressant properties of propofol. Pharmacology of Sedative Agents 127 The preliminary laboratory and clinical experience with propofol have demonstrated its possible therapeutic role in regulating CNS dynamics and controlling ICP. Nimkoff et al. evaluated the effects of propofol, metho- hexital, and ketamine on cerebral perfusion pressure (CPP) and ICP in a feline model of cytotoxic and vasogenic cerebral edema (7). Vasogenic cerebral edema was induced by inflation of an intracranial balloon. Cyto- toxic cerebral edema was induced by an acute reduction in blood osmolarity using hemofiltration. Propofol lowered ICP and maintained CPP in vaso- genic cerebral edema, but had no effect in cytotoxic cerebral edema. The authors theorized that the loss of autoregulatory function with diffuse cyto- toxic edema uncoupled CMRO 2 from cerebral blood flow (CBF) and thereby eliminated propofol’s efficacy. Watts et al. evaluated the effects of propofol and hyperventilation on ICP and somatosensory evoked potentials (SEPs) in a rabbit model of intracra- nial hypertension (8). Following inflation of an intracranial balloon to increase the ICP to 26 ± 2 mmHg and produce a ≥ 50% reduction in SEPs, the animals were randomized to: group 1 (propofol followed by hyperventi- lation) or group 2 (hyperventilation followed by propofol). The ICP decrease was significantly greater in group 1 (final ICP: 12 ± 2 mmHg vs 16 ± 5 mmHg, p = 0.008). When comparing propofol with hyperventilation, propofol resulted in a greater ICP decrease: 16 ± 2 mmHg with propofol vs 21 ± 5 mmHg with hyperventilation, p = 0.007). When propofol was administered first, there was a significant increase in the amplitude of the SEPs. The mean arterial pressure (MAP) was maintained at baseline levels by the infusion of phe- nylephrine. More phenylephrine (p < 0.02) was required to maintain the MAP with propofol than with hyperventilation. Despite these encouraging animal studies, the review of the literature con- cerning propofol in humans provides somewhat contrasting results. Although several studies demonstrate a decrease in ICP, propofol’s cardiovascular effects with a lowering of the MAP can result in a decrease in the CPP. Without the maintenance of MAP, a decrease occurs in CPP that may lead to reflex cerebral vasodilation to maintain CBF, which may result in an in- crease in ICP and negate the decrease in ICP induced by propofol. Herregods et al. evaluated the effects of a propofol bolus (2 mg/kg administered over 90 s) on ICP and MAP in six adults with an ICP greater than 25 mmHg following traumatic brain injury (9). The mean ICP decreased from 25 ± 3 to 11 ± 4 mmHg (p < 0.05). However, there was a decrease in the MAP and consequently a decrease in the CPP from 92 ± 8 mmHg to a low of 50 ± 7 mmHg. The CPP was less than 50 mmHg in four of six patients. No vasoconstrictor agent was administered to maintain the MAP. 128 Tobias Similar results were obtained by Pinaud et al. during their evaluation of the effects of propofol on CBF, ICP, CPP, and cerebral arteriovenous oxy- gen content difference in 10 adults with traumatic brain injury (10). Although propofol decreased ICP (11.3 ± 2.6 to 9.2 ± 2.5 mmHg, p < 0.001), there was also a decrease in MAP, which resulted in an overall decrease in CPP from 82 ± 14 to 59 ± 7 mmHg, p < 0.01. Other investigators in patients with traumatic brain injury (11) or during cerebral aneurysm surgery (12) have noted similar effects of propofol on ICP and MAP with an overall lowering of CPP caused by the greater decrease in MAP than ICP. Farling et al. reported their experience with propofol for sedation in 10 adult patients with closed head injuries (13). Propofol was administered as a continuous infusion of 2–4 mg/kg/h for 24 h. Additional therapy for increased ICP included mannitol and hyperventilation. The mean rate of propofol infu- sion was 2.88 mg/kg/h. There was a statistically significant decrease in the mean ICP of 2.1 mmHg from baseline achieved at 2 h following the start of the propofol infusion. No decrease in MAP was noted. The CPP increased during the 24-h study period, and the difference was statistically significant at the 24-h point (CPP increase of 9.8 mmHg, p = 0.028). The authors con- cluded that propofol was a suitable agent for sedation in head-injury patients who required mechanical ventilation. Spitzfadden et al. reported their experience with the use of propofol to pro- vide sedation and control ICP in two adolescents (14). Dopamine was used to maintain MAP and CPP. Propofol resulted in adequate sedation and control of ICP. When compared with barbiturates, the usual time-honored therapy for pharmacologic control of ICP, the authors suggested that a significant advan- tage of propofol was a much more rapid awakening. The latter effect may be most evident following prolonged (>48 h) administration of barbiturates. Further study will be required to fully evaluate the role of propofol in controlling ICP. With control of MAP, the initial clinical and laboratory evidence suggests that propofol can be used to decrease CMRO 2 , CBF, and ICP. Additional benefits of propofol in patients with altered intracranial compliance include maintenance of CBF autoregulation in response to changes in MAP and P a CO 2 as well as preliminary evidence that suggests a possible protective effect of propofol during periods of cerebral hypoperfu- sion and ischemia (15,16). These latter effects are similar to those reported with the use of barbiturates (17). It is postulated that the neuroprotective effects may result from alterations in CMRO 2 or propofol’s antioxidant prop- erties related to its phenol ring structure. Following its increased use both in and outside of the operating room, certain adverse effects have been reported with propofol (Table 1). Propo- Pharmacology of Sedative Agents 129 fol’s cardiovascular effects are similar to those of the barbiturates, including an overall lowering of the MAP related to both peripheral vasodilation and negative inotropic properties (18). Propofol also alters the baroreflex responses, thereby resulting in a smaller increase in heart rate for a given decrease in blood pressure. These cardiovascular effects are especially pronounced fol- lowing bolus administration. Although generally well-tolerated by patients with adequate cardiovascular function, these effects may result in detrimen- tal physiologic effects in patients with compromised cardiovascular func- tion. Tritapepe et al. have demonstrated that the administration of calcium chloride (10 mg/kg) prevented the deleterious cardiovascular effects of propofol during anesthetic induction in patients undergoing coronary artery bypass grafting (19). In addition to the negative inotropic properties, central vagal tone may be augmented, leading to bradycardia (20) or asystole when combined with other medications known to alter cardiac chronotropic function (fentanyl, succinylcholine) (21). Although the relative bradycardia is generally con- sidered a beneficial effect in patients at risk for myocardial ischemia, it may be detrimental in patients with fixed stroke volumes whose cardiac output is heart-rate-dependent. Unusual neurologic manifestations including opisthotonic posturing, myoclonic movements (especially in children), and seizure-like activity have Table 1 Adverse Effects Reported with Propofol Hypotension Negative inotropic effects Vasodilation Bradycardia, asystole Neurologic sequelae Opisthotonic posturing Seizure-like activity Myoclonus Respiratory depression, apnea Anaphylactoid reactions Metabolic acidosis and cardiac failure (with prolonged administration in the pediatric population) Pain on injection Bacterial contamination of solution Hyperlipidemia Hypercarbia 130 Tobias been reported with propofol administration (22–25). Although some of the initial reports suggested actual seizure activity, these concerns have most likely been overemphasized, since no electroencephalographic evidence of seizure activity has been documented during the abnormal movements seen with propofol administration. Additionally, propofol is considered a valu- able agent in the treatment of patients with refractory status epilepticus that is unresponsive to conventional therapy (26). Although many studies have examined the cardiovascular effects of propofol, the respiratory-depressant effects of propofol should not be over- looked. Although propofol has become a popular agent for deep sedation in the spontaneously breathing patient, reports demonstrate a relatively high incidence of respiratory effects including hypoventilation, upper airway obstruction, and apnea (27). As with any sedative agent, some degree of hypoventilation is likely to occur in all patients breathing spontaneously. These effects may be detrimental related to the alterations in P a CO 2 and its obvious deleterious effects on CBF, ICP, and CPP. Despite these potential deleterious effects on respiratory function, recent laboratory and clinical studies suggest that propofol may be advantageous when instrumenting the airway of patients with reactive airway disease. In an animal model, Chih- Chung et al. demonstrated that propofol attenuates carbachol-induced air- way constriction (28). The mechanism involves a decrease in intracellular inositol phosphate accumulation, thereby limiting intracellular calcium availability. The latter results from a decrease in calcium release from intra- cellular stores as well as a decrease in transmembrane movement. In children, a significant issue with the prolonged use of propofol—such as ongoing sedation in the pediatric ICU setting—are reports of unexplained metabolic acidosis, brady-dysrhythmias, and fatal cardiac failure (29,30). The initial report of Parke et al. published in 1992 included five children with respiratory infections and respiratory failure who received prolonged propofol infusions, although in higher than usual doses (up to 13.6 mg/kg/h). Other anecdotal reports subsequently appeared, followed by a review by Bray examining the reports from the medical literature of 18 children with suspected propofol infusion syndrome (31). Risk factors for the syndrome identified by Bray included propofol administration for more than 48 h or doses greater than 4 mg/kg/h. However, several children received doses greater than 4 mg/kg/h for longer than 48 h, suggesting that factors other than dose and duration are necessary for development of the syndrome. Other associated factors included age; 13 of the 18 patients were 4 yr of age or younger, and only 1 of 18 was more than 10 yr of age. Since the review of Bray et al, the syndrome has been reported in a 17-yr-old patient (32). As suggested by the initial report of Parke et al., there may be an association of [...]... of etomidate and thiopental anesthesia for cardioversion J Cardiothor Vasc Anes 5, 56 3 5 65 74 Canessa, R., Lema, G., Urzua, J., et al (1991) Anesthesia for elective cardioversion: a comparison of four anesthetic agents J Cardiothor Vasc Anes 5, 56 6 5 68 75 McDowall, R H., Scher, C S., and Barst, S M (19 95) Total intravenous anesthesia for children undergoing brief diagnostic or therapeutic procedures. .. used agents for sedation It was originally synthesized in 1832 and introduced into clinical practice in 1869 by Liebreich For street and recreational use, chloral hydrate is the ingredient combined with alcohol in mixtures known as “knockout drops” and “Mickey Finns.” It is available as capsules ( 250 mg, 50 0 mg), syrup ( 250 mg /5 mL and 50 0 mg /5 mL), and suppositories (3 25 mg, 50 0 mg, and 650 mg) Chloral... sterile saline to solutions of 1–2 .5% Induction doses vary based on the potency of the agent Methohexital is the most potent (2. 5 3 times that of thiopental) and thiopental is the least potent Induction doses are also higher in neonates and infants Anesthetic induction doses for thiopental vary from 3 5 mg/kg in healthy adults, 5 6 mg/kg in children, and 6–8 mg/kg in neonates and infants The barbiturates... 34 0–3 42 23 Saunders, P R I and Harris, M N E (1992) Opisthotonic posturing and other unusual neurological sequelae after outpatient anesthesia Anaesthesia 47, 55 2 5 57 Pharmacology of Sedative Agents 149 24 Collier, C and Kelly, K (1991) Propofol and convulsions—The evidence mounts Anaesthesiol Intensive Care 19, 57 3 5 75 25 Finley, G A., MacManus, B., Sampson, S E., Fernandez, C V., and Retallick, I (1993)... ketamine and morphine Anesthesiology 66, 15 3–1 56 54 Lanning, C F., Harmel, M H (19 75) Ketamine anesthesia Annu Rev Med 26, 13 7–1 41 55 Taylor, P A and Towey, R M (1971) Depression of laryngeal reflexes during ketamine administration Br Med J 2, 68 8–6 89 56 Shapiro, H M., Wyte, S R., and Harris, A B (1972) Ketamine anesthesia in patients with intracranial pathology Br J Anaesth 44, 120 0–1 204 57 Gardner,... flow and metabolism in rabbits Stroke 18, 44 5 4 44 60 White, P F., Way, W L., and Trevor, A J (1982) Ketamine—its pharmacology and therapeutic uses Anesthesiology 56 , 11 9–1 36 61 Weksler, N., Ovadia, L., Muati, G., and Stav, A (1993) Nasal ketamine for paediatric premedication Can J Anaesth 40, 11 9–1 21 62 Qureshi, F A., Mellis, P T., and McFadden, M A (19 95) Efficacy of oral ketamine for providing sedation. .. Nitrous oxide Infusion range/comments 2 5 1 00 mcg/kg/min 1 0–3 0 mcg/kg/min No infusion because of potential for adrenal suppression 2 .5 mg/kg — 1–3 mg/kg 1–4 mg/kg/h 0.0 5 0 .1 mg/kg 1 5 mcg/kg/min; larger doses needed for non-parenteral routs (see Table 4) 8 0–1 00 mg/kg Oral administration only, limited data regarding adult dose, limit maximum dose to 2.0 grams 3 0–7 0% via inhalation route *These dosing... Pentobarbital for sedation during mechanical ventilation in the Pediatric ICU patient J Intens Care Med 15, 11 5 1 20 85 Holst, J J (1962) Use of nitrous oxide-oxygen analgesia in dentistry Int Dent J 12, 4 7 5 1 86 Griffin, G C., Campbell, V D., and Joni, R (1981) Nitrous oxide-oxygen sedation for minor surgery: experience in a pediatric setting JAMA 2 45, 241 1–2 414 87 Litman, R S., Berkowitz, R J., and Ward,... ketamine and the rapid recovery with propofol This combination can be used for brief invasive procedures or for ICU sedation For these purposes, ketamine can be added to the propofol solution to produce a mixture containing 3 5 mg/ mL ketamine and 10 mg/mL propofol For brief procedures, incremental doses of 0.1 mL/kg can be administered, resulting in the delivery of 0. 3–0 .5 mg/kg of ketamine and 1 mg/kg... thiopental, and etomidate, but was prolonged with midazolam The information concerning the use of etomidate for sedation in children is more limited McDowall et al compared etomidate, propofol, and ketamine for sedation during procedures in pediatric oncology patients ( 75) Ketamine was associated with vomiting (14.6%), agitation ( 15% ), and tachycardia (19 .5% ) Etomidate was associated with vomiting (9.9%) and . conscious sedation for bronchoscopy. Chest 1 15( 5), 143 7–1 440. 20. Matot, I. and Kramer, M. R. (2000) Sedation in outpatient bronchoscopy. Respir. Med. 94, 114 5 1 153 . 21. Landrum, L. (1997) Conscious sedation. Changing patterns of sedation use for routine out- patient diagnostic gastroscopy between 1989 and 1998. Aliment. Pharmacol. Ther. 15, 21 7–2 20. 25. Zuccaro, G. (2000) Sedation and sedationless endoscopy 23, 53 1 5 35. 13. Prakash, U. B. S., Offord, K. P., and Stubbs, S. E. (1991) Bronchoscopy in North America: The ACCP survey. Chest 100, 166 8–1 6 75. 14. Poi, P. J. H., Chuah, S. Y., Srinivas, P., and