Chapter 8 Intravenous Anesthetics Which Accounts for Their Rapid Onset of Action

Home , Emergence delirium, Fospropofol, Methohexital, Metomidate

Chapter INTRAVENOUS 8 ANESTHETICS Michael P. Bokoch and Helge Eilers

PROPOFOL Physicochemical Characteristics Pharmacokinetics Pharmacodynamics Intravenous nonopioid anesthetics have an important Clinical Uses role in modern anesthesia practice (Box 8.1).1-7 They are widely used to facilitate a rapid induction of gen- FOSPROPOFOL eral anesthesia and provide sedation during monitored Physicochemical Characteristics anesthesia care (MAC) and for patients in intensive care Pharmacokinetics settings (also see Chapter 41). With the introduction of Pharmacodynamics propofol, intravenous techniques are increasingly being Clinical Uses used for maintenance of anesthesia. However, similar to BARBITURATES inhaled anesthetics, the currently available intravenous Physicochemical Characteristics drugs do not produce only desirable effects (hypnosis, Pharmacokinetics amnesia, analgesia, immobility). Therefore, the concept Pharmacodynamics of “balanced anesthesia” evolved by using smaller doses Side Effects of multiple drugs rather than using larger doses with one Clinical Uses or two drugs. The fundamental drugs used with “balanced anesthesia” include inhaled anesthetics, sedative/hypnot- BENZODIAZEPINES ics, opioids, and neuromuscular blocking drugs (also see Physicochemical Characteristics Chapters 7, 9, and 11). Pharmacokinetics The intravenous anesthetics used for induction of gen- Pharmacodynamics eral anesthesia are lipophilic and preferentially partition Side Effects into highly perfused lipid-rich tissues (brain, spinal cord), Clinical Uses KETAMINE Physicochemical Characteristics Box 8.1 Drugs Classified as Intravenous Anesthetics Pharmacokinetics Isopropylphenols Pharmacodynamics Propofol Clinical Uses Fospropofol ETOMIDATE Barbiturates Physicochemical Characteristics Thiopental Methohexital Pharmacokinetics Benzodiazepines Pharmacodynamics Diazepam Clinical Uses Midazolam DEXMEDETOMIDINE Lorazepam Physicochemical Characteristics Remimazolam Phencyclidine Pharmacokinetics Ketamine Pharmacodynamics Carboxylated imidazole Clinical Uses Etomidate QUESTIONS OF THE DAY α2-Adrenergic agonist Dexmedetomidine

104 Downloaded for Wendy Nguyen ([email protected]) at University Of Minnesota - Twin Cities Campus from ClinicalKey.com by Elsevier on March 25, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Chapter 8 Intravenous Anesthetics which accounts for their rapid onset of action. Regardless groups of intravenous anesthetics (Fig. 8.1). It is insoluble of the extent and speed of their metabolism, termination in aqueous solutions and formulated as an emulsion con- of the effect of a single bolus dose is a result of redistri- taining 10% soybean oil, 2.25% glycerol, and 1.2% lecithin bution of the drug into less perfused and inactive tissues (the major component of the egg yolk phosphatide frac- such as skeletal muscles and fat. Thus, all drugs used for tion). Sterile technique is important because the available induction of anesthesia have a similar duration of action formulations support bacterial growth. Although either when administered as a single dose despite significant ethylenediaminetetraacetic acid (0.05 mg/mL), metabisul- differences in their metabolism. fite (0.25 mg/mL), or benzyl alcohol (1 mg/mL) is added to the emulsions by the different manufacturers as retardants of bacterial growth, solutions should be used as soon as PROPOFOL possible or at least within 12 hours after opening the propofol vial. The solutions appear milky white and slightly Propofol is the most frequently administered anesthetic viscous, their pH is approximately 7, and the propofol II drug for induction of anesthesia.2,3,6 In addition, propofol concentration is 1% (10 mg/mL). In some countries, a 2% is used during maintenance of anesthesia and is a com- formulation is available. Allergic reactions to propofol mon selection for sedation in the operating room as well are rare, and there is no evidence for cross-reactivity in as in the intensive care unit (ICU). Increasingly, propofol patients with immunoglobulin E confirmed allergy to egg, is also utilized for sedation and short-duration general soy, or peanut.8 The addition of metabisulfite in one of anesthesia in locations outside the operating room such the formulations is of concern for patients with reactive as interventional radiology suites and the emergency airways (asthma) or sulfite allergies. room (also see Chapter 38). Pharmacokinetics Physicochemical Characteristics Propofol is rapidly metabolized in the liver, and the result- Propofol (2,6-diisopropylphenol) is an alkylphenol with ing water-soluble compounds are presumed to be inac- hypnotic properties that is chemically distinct from other tive and excreted through the kidneys (Table 8.1). Plasma clearance is rapid and exceeds hepatic blood flow, thus indicating the importance of extrahepatic metabolism, CH(CH3)2 which has been confirmed during the anhepatic phase of liver transplantation. The lungs probably play a major role OH in this extrahepatic metabolism and likely account for the elimination of up to 30% of a bolus dose of propofol. The CH(CH3)2 rapid plasma clearance explains the more complete recovery from propofol with less “hangover” than observed with Fig. 8.1 Chemical structure of 2,6-diisopropylphenol (propofol). thiopental. As with other intravenous drugs, the effects of

Table 8.1 Pharmacokinetic Dataa for Intravenous Anesthetics

Induction Dose Duration of Protein Clearance (mL/ Drug (mg/kg IV) Action (min) Vdss (L/kg) T½α (min) Binding (%) kg/min) T½β (h) Propofol 1-2.5 3-8 2-10 2-4 97 20-30 4-23 Thiopental 3-5 5-10 2.5 2-4 83 3.4 11 Methohexital 1-1.5 4-7 2.2 5-6 73 11 4 Midazolam 0.1-0.3 15-20 1.1-1.7 7-15 94 6.4-11 1.7-2.6 Diazepam 0.3-0.6 15-30 0.7-1.7 10-15 98 0.2-0.5 20-50 Lorazepam 0.03-0.1 60-120 0.8-1.3 3-10 98 0.8-1.8 11-22 Ketamine 1-2 5-10 3.1 11-16 12 12-17 2-4 Etomidate 0.2-0.3 3-8 2.5-4.5 2-4 77 18-25 2.9-5.3 Dexmedetomidine N/A N/A 2-3 6 94 10-30 2-3 aData are for average adult patients. The duration of action reflects the duration after an average single IV dose. IV, Intravenous; N/A, not applicable; T½α, distribution half-time; T½β, elimination half-time; Vdss, volume of distribution at steady state.

105 Downloaded for Wendy Nguyen ([email protected]) at University Of Minnesota - Twin Cities Campus from ClinicalKey.com by Elsevier on March 25, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Section II PHARMACOLOGY AND PHYSIOLOGY propofol are terminated by redistribution from the plasma effects such as twitching or spontaneous movement can and highly perfused compartments (such as brain) to poorly be observed during induction of anesthesia with propo- perfused compartments (such as skeletal muscle). A patient fol. Although these effects may resemble seizure activity, usually awakens within 8 to 10 minutes after an induction propofol is actually an anticonvulsant and may be safely dose of propofol, similar to the period of decline in plasma administered to patients with seizure disorders.6 Although concentration after a single bolus dose (Fig. 8.2).2,6 propofol may be toxic to developing neurons in ani- mals and cell culture, no human study has demonstrated Continuous Intravenous Infusion Propofol has two pharmacokinetic properties that make 8 it ideal for use as a continuous intravenous infusion: (1) Propofol 2.0 mg/kg rapid metabolism and efficient clearance from plasma, and 7 (2) slow redistribution from poorly perfused compartments 6 back into the central compartment. One way to characterize an anesthetic infusion is the “context-sensitive half-time,” 5 a parameter that describes the time needed for the plasma 4 Therapeutic levels of a drug to drop by 50% after stopping the infusion 3 range (Fig. 8.3).9,10 This time depends on the duration for which 2 an infusion has been run. The context-sensitive half-time of propofol is brief, even after a prolonged infusion, and 1 Plasma concentration ( µ g/mL) recovery remains relatively prompt. 0 0246810 12 14 16 18 20 Compartmental Model The kinetics of propofol (and other intravenous anesthet- Time (minutes) ics) after a single bolus and after continuous infusion is Fig. 8.2 Time course of the propofol plasma concentration after best described by a three-compartment model (also see a simulated single bolus injection of 2.0 mg/kg. The shape of this Chapter 4). These mathematical models have been used curve is similar for other induction drugs, although the slope and the as the basis for the development of systems for target- absolute concentrations are different. (From Vuyk J, Sitsen E, Reek- controlled infusions.11 ers M. Intravenous anesthetics. In: Miller RD, ed. Miller’s Anesthesia. 8th ed. Philadelphia: Elsevier; 2015: 821-863. (Original chapter: Reves JG, Glass PSA. Chapter 9, Nonbarbiturate intravenous anes- Pharmacodynamics thetics. In: Miller RD, ed. Miller’s Anesthesia. 3rd ed. New York, NY: Churchill Livingstone; 1990: 243-279.) The presumed mechanism of action of propofol is through potentiation of the chloride current mediated through the 12 γ-aminobutyric acid type A (GABAA) receptor complex. 150 Central Nervous System Diazepam Thiopental In the central nervous system (CNS), propofol primar- Midazolam ily acts as a hypnotic and does not have any analgesic Ketamine properties. It reduces the cerebral metabolic rate for oxy- 100 Propofol gen (CMRO2), which leads to decreased cerebral blood Etomidate flow (CBF) through preserved flow-metabolism cou- pling. This results in decreases in cerebral blood volume, 50 intracranial pressure (ICP), and intraocular pressure. The magnitude of these changes is comparable to those produced by thiopental. Although propofol can produce a desired decrease in ICP, the reduced CBF combined with 0 Context-sensitive half-time (minutes) the reduced mean arterial pressure caused by peripheral 0123 4 56789 vasodilation can critically compromise cerebral perfu- Infusion duration (hours) sion (also see Chapter 30). Propofol is probably neuroprotective during focal Fig. 8.3 Context-sensitive half-time for the most commonly ischemia to the same extent as thiopental or isoflurane. used intravenous anesthetics. Propofol, etomidate, and ketamine When administered in large doses, propofol produces have the smallest increase in context-sensitive half-times, with burst suppression in the electroencephalogram (EEG),13 prolonged infusions making these drugs more suitable for use as an end point that has been used for the administration continuous infusions. (From Vuyk J, Sitsen E, Reekers M. Intra- of intravenous anesthetics for neuroprotection dur- venous anesthetics. In: Miller RD, ed. Miller’s Anesthesia. 8th ed. Philadelphia:Elsevier; 2015:821-863.) ing neurosurgical procedures. Occasionally, excitatory

106 Downloaded for Wendy Nguyen ([email protected]) at University Of Minnesota - Twin Cities Campus from ClinicalKey.com by Elsevier on March 25, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Chapter 8 Intravenous Anesthetics long-term cognitive or memory problems in children who most effective and expedient means to reduce injection have received propofol anesthesia.14 pain is selecting an antecubital vein (larger, faster venous flow rate) for injection.20 Alternatively, if a hand vein Cardiovascular System is chosen, injecting a small dose of lidocaine (20 to 40 Propofol produces a larger decrease in systemic arterial mg intravenously [IV]) and applying proximal venous blood pressure than any other drug used for induction of occlusion for 15 to 60 seconds before injecting propofol anesthesia. Propofol causes profound vasodilation, whereas is similarly effective. Other helpful and expedient tech- its direct myocardial depressant effect is not clear. Vasodi- niques are premedication with a small dose of opioid,20 lation occurs in both the arterial and venous circulation pretreatment with larger doses of lidocaine (40 to 100 mg and leads to reductions in preload and afterload. The effect IV) without venous occlusion, and coadministration of is worse with rapid injection, and is more pronounced in lidocaine and propofol as an admixture.21 elderly patients, especially those with reduced intravas- cular fluid volume (also see Chapter 35). The degree of Induction and Maintenance of General Anesthesia II vasodilation may also be altered in patients with diabetes, Propofol (1 to 2.5 mg/kg IV) is the drug most com- hypertension, or obesity.15 Propofol markedly inhibits the monly administered for induction of general anesthesia. normal baroreflex response and produces only a small or no The dose should be decreased in the elderly, especially increase in heart rate, thus further exacerbating hypoten- those who have a reduced cardiovascular reserve, or after sion. Profound bradycardia and asystole after the admin- premedication with benzodiazepines or opioids. Children istration of propofol can occur in healthy adults despite generally require larger doses (2.5 to 3.5 mg/kg IV). Obese administration of prophylactic anticholinergic drugs.16 patients require a larger total dose compared with non- obese patients of similar height and age, but boluses for Respiratory System morbidly obese patients should be calculated per kilo- Propofol is a respiratory depressant and often produces gram of lean body weight rather than total body weight apnea following a dose used to induce anesthesia. A main- to avoid excess hypotension.22 Generally, titration of the tenance infusion of propofol decreases minute ventilation induction dose of propofol (i.e., rather than an arbitrary via reductions in tidal volume and respiratory rate, with bolus dose) helps prevent severe hemodynamic changes. the effect on tidal volume being more pronounced. The Propofol is also often used to maintain anesthesia as part ventilatory response to hypoxia and hypercapnia is also of a balanced regimen in combination with volatile anes- reduced. Propofol causes a more intense reduction in upper thetics, nitrous oxide, sedative-hypnotics, or opioids; or airway reflexes than does thiopental, which makes it well as part of a total intravenous anesthetic (TIVA) technique, suited for instrumentation of the airway, such as placement usually in combination with opioids. Some clinical tri- of a laryngeal mask airway. Propofol increases collaps- als suggest a reduction in postoperative pain scores and ibility of the upper airway by inhibiting genioglossus and opioid consumption for patients receiving propofol-based other muscles,17 and airway obstruction may occur with TIVA as compared with volatile anesthesia, but it is diffi- sedative doses or during emergence from propofol anes- cult to draw firm conclusions owing to small trial size and thesia. When compared with thiopental, propofol decreases significant patient heterogeneity.23 Therapeutic plasma the incidence of wheezing after induction of anesthesia and concentrations for maintenance of anesthesia normally tracheal intubation in healthy and asthmatic patients.18 range between 3 and 8 μg/mL (typically requiring a continuous infusion rate between 100 and 200 μg/kg/min) Other Effects when combined with nitrous oxide or opioids. Unlike many other anesthetics, propofol has antiemetic activity. Similar to thiopental and unlike volatile anes- Sedation thetics, propofol probably does not enhance neuromus- Propofol is a popular choice for sedation of mechani- cular blockade from neuromuscular blocking drugs. Yet, cally ventilated patients in the ICU (also see Chapter propofol often provides excellent clinical conditions for 41) and for sedation during procedures in or outside the endotracheal intubation without the use of neuromuscu- operating room. The required plasma concentration is 1 lar blocking drugs. Unexpected arrhythmias or electro- to 2 μg/mL, which normally requires a continuous infu- cardiogram changes occurring during propofol anesthesia sion rate between 25 and 75 μg/kg/min. Because of its should prompt laboratory evaluation for possible meta- pronounced respiratory depressant effect and its narrow bolic acidosis, rhabdomyolysis, or hyperkalemia (propofol therapeutic range, propofol should be administered only infusion syndrome).19 by individuals trained in airway management. Spon- taneous ventilation is usually preserved in children at quite rapid propofol infusion rates (200 to 250 g/kg/ Clinical Uses μ min), making it a good choice for pediatric procedures Pain from injection of propofol is a common complaint such as magnetic resonance imaging scans24 (also see that can lead to patient distress or dissatisfaction. The Chapter 34).

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Antiemetic CH(CH3)2 Subanesthetic bolus doses of propofol or a subanes- O thetic infusion can be used to treat postoperative nau- OCH O PO– sea and vomiting (PONV) (10 to 20 mg IV, or 10 to 2 – 20 μg/kg/min as an infusion).25,26 Propofol TIVA, as O compared with volatile anesthetics, reduces PONV27 CH(CH3)2 but may not reduce unplanned admissions, postdis- Fig. 8.4 Structure of fospropofol. charge nausea and vomiting, or cost of anesthesia in the ambulatory setting.28 assay, and, therefore, reliable data on the kinetics are lacking.29 Six previously published studies were FOSPROPOFOL retracted in 2010.30

Propofol is the most commonly used intravenous anes- Pharmacodynamics thetic for induction and maintenance of anesthesia and probably also during MAC and conscious sedation. As The effect profile is similar to that of propofol. Given mentioned earlier, the lipid emulsion formulation of the kinetics previously described, fospropofol in theory propofol has several disadvantages including pain on should cause less hypotension31 and less respiratory injection, risk of bacterial contamination, and hypertri- depression than propofol. However, these benefits have glyceridemia with prolonged infusion. Intense research not yet been demonstrated in human studies. has therefore focused on finding alternative formulations or related drugs to address some of these problems. Fos- Clinical Uses propofol, a water-soluble prodrug of propofol, was devel- oped as an alternative and in 2008 was licensed by the Fospropofol is currently approved for sedation during Food and Drug Administration (FDA) as a sedating anes- MAC. Given as a bolus (6.5 mg/kg IV), onset of seda- thetic for use during MAC.29 tion is slower (4 to 8 min) and duration of action is longer (5 to 18 min) than an equivalent dose of propofol.32 Sedation can be maintained by redosing with 25% of Physicochemical Characteristics the initial bolus as needed. These dosing guidelines are Fospropofol, initially known under the name GPI 15715, is recommended only for patients weighing 60 to 90 kg, a water-soluble phosphate ester prodrug of propofol and and dose reduction by 25% is recommended for elderly is chemically described as 2,6-diisopropylphenoxymethyl patients (age > 65) or those with American Society of phosphate disodium salt (Fig. 8.4). It is metabolized by Anesthesiologists (ASA) physical classification III or IV. alkaline phosphatase in a reaction producing propofol, Common side effects of fospropofol include a perineal phosphate, and formaldehyde. Aldehyde dehydrogenase burning sensation and pruritus. in the liver and in erythrocytes rapidly metabolizes form- Small trials have demonstrated safety and efficacy of aldehyde to produce formate, which is further metabo- fospropofol for sedation during colonoscopy, bronchos- lized by 10-formyltetrahydrofolate dehydrogenase.29 The copy, and minor surgical procedures.32 Single studies available fospropofol formulation is a sterile, aqueous, have investigated fospropofol for TIVA during coronary colorless, and clear solution that is supplied in a single- artery bypass grafting33 and for ICU sedation of mechani- dose vial at a concentration of 35 mg/mL under the trade cally ventilated patients.34 Similar to propofol, airway name Lusedra. compromise remains a major concern. Hence, fospropofol should be administered only by personnel trained in airway management. Pharmacokinetics Because fospropofol is a prodrug that requires metabolism to form the active compound propofol, the BARBITURATES pharmacokinetics are complex. Onset and recovery are prolonged compared to propofol. Multicompart- Before the introduction of propofol, the intravenous anes- ment models with two compartments for fospropofol thetics most commonly used for induction of anesthesia and three for propofol have been used to describe the were barbiturates (thiopental, methohexital).2,4 kinetics. In theory, a fospropofol bolus should yield lower peak plasma levels and a delayed time-to-peak Physicochemical Characteristics compared with propofol. However, previous studies on pharmacokinetics/pharmacodynamics and tolerability Barbiturates are derived from barbituric acid (lacks hyp- of fospropofol were based on an inaccurate analytical notic properties) through substitutions at the N1, C2, and

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H O N S 1 62 Thiopental 53 CH3CH2 N 4 H CH3CH2CH2CH H O O N O CH3 1 62 Barbituric acid 53N 4 H H O N O 1 O 62 Methohexital 53 II H2C CH2CH2 N 4 CH3CH2C CCH CH3 O CH3

Fig. 8.5 Structure of barbituric acid and its derivatives.

C5 positions (Fig. 8.5). Based on their substitution at posi- other drugs that induce oxidative microsomal enzymes tion 2, barbiturates can be grouped into thiobarbiturates, (enzyme induction) enhances barbiturate metabolism. substituted with a sulfur (thiopental), or oxybarbiturates, Through stimulation of aminolevulinic acid synthetase, substituted with an oxygen (methohexital). Hypnotic, the production of porphyrins is increased. Therefore, sedative, and anticonvulsant effects, as well as lipid sol- barbiturates should not be administered to patients with ubility and onset time, are determined by the type and acute intermittent porphyria. position of substitution. Methohexital is cleared more rapidly by the liver than Thiopental and methohexital are formulated as sodium thiopental and thus has a shorter elimination half-time. salts mixed with anhydrous sodium carbonate. After This accounts for faster and more complete recovery reconstitution with water or normal saline, the solutions after methohexital administration. Although thiopen- (2.5% thiopental and 1% methohexital) are alkaline with tal is metabolized slowly and has a long elimination a pH higher than 10. Although this property prevents half-time, recovery after a single bolus administration bacterial growth and helps increase the shelf life of the is comparable to methohexital and propofol because it solution after reconstitution, it will lead to precipitation depends on redistribution to inactive tissue sites rather when mixed with acidic drug preparations such as neu- than metabolism (Fig. 8.6).35 However, even single-bolus romuscular blocking drugs. These precipitates can irre- induction doses of thiopental can, in some cases, lead to versibly block intravenous delivery lines if mixing occurs psychomotor impairment that lasts up to several hours. during administration. Furthermore, accidental injection If administered as repeated boluses or as a continuous into an artery or infiltration into paravenous tissue will infusion, especially when using larger doses to produce cause extreme pain and may lead to severe tissue injury. burst suppression on the EEG, recovery from the effects Several barbiturates, including thiopental and metho- of thiopental will be markedly prolonged because of the hexital, have optical isomers with different potencies. long context-sensitive half-time (see Fig. 8.3). However, the available formulations are racemic mix- tures, and their potencies reflect the summation of the Pharmacodynamics potencies of the individual isomers. The mechanism of action for the effect of barbiturates in the CNS presumably involves both enhancement of Pharmacokinetics inhibitory neurotransmission and inhibition of excitatory Barbiturates, except for phenobarbital, undergo hepatic transmission. Although the effects on inhibitory trans- metabolism most importantly by oxidation, but also by mission probably result from activation of the GABAA N-dealkylation, desulfuration, and destruction of the bar- receptor complex, the effects on excitatory transmission bituric acid ring structure. The resulting metabolites are are less well understood. The pentameric GABAA receptor inactive and excreted through urine and, after conjuga- can be composed of different combinations of subunits tion, through bile. In contrast, phenobarbital is mainly (see Benzodiazepines section), and the receptors may be eliminated unchanged via renal excretion. Chronic found both at synapses and at extrasynaptic sites.36 This administration of barbiturates or the administration of diversity of location and composition may explain why

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the EEG, and intravenous infusions may be useful in the 70 critical care setting to treat refractory status epilepticus Blood 60 Vessel-rich (typically third-line therapy after midazolam and propofol 40 Skeletal muscle have failed). An exception to this rule is methohexital, 50 Fat which activates epileptic foci, thus facilitating their iden- Metabolized tification during surgery targeted to ablate these sites. For 40 the same reason, methohexital is also a popular choice for anesthesia to facilitate electroconvulsive therapy (also see 30 Chapter 38).

20 Cardiovascular System Administered dose (%) Administration of barbiturates for induction of anesthesia 10 typically produces modest decreases in systemic arterial blood pressure that are smaller than those produced by 0 propofol. This decrease in systemic arterial blood pressure 1310 30 100300 is principally due to peripheral vasodilation and reflects Time (min) barbiturate-induced depression of the medullary vaso- motor center and decreased sympathetic nervous system Fig. 8.6 After rapid intravenous injection of thiopental, the per- outflow from the CNS. Although barbiturates blunt the centage of the administered dose remaining in blood (brown line) baroreceptor reflex, compensatory increases in heart rate rapidly decreases as the drug moves from blood to highly perfused vessel-rich tissues (blue line), especially the brain. Subse- limit the magnitude and duration of hypotension. More- quently, thiopental is redistributed to skeletal muscles (red line) over, dilation of peripheral capacitance vessels leads to and, to a lesser extent, to fat (pink line). Ultimately, most of the pooling of blood and decreased venous return, thus result- administered dose of thiopental undergoes metabolism (green ing in reduced cardiac output and systemic arterial blood line). (From Saidman LJ. Uptake, distribution, and elimination of pressure. Indeed, exaggerated decreases in blood pressure barbiturates. In Eger EI, ed. Anesthetic Uptake and Action. Balti- are likely to follow the administration of barbiturates to more: Williams & Wilkins; 1974:264-284, used with permis- patients with hypovolemia, cardiac tamponade, cardiomy- sion.) opathy, coronary artery disease, or cardiac valvular disease because these groups are less able to compensate for the effects of peripheral vasodilation. Hemodynamic effects are several different types of GABAA-mediated currents are also more pronounced with larger doses and rapid injec- found in the CNS (fast versus slow, phasic versus tonic). tion. The negative inotropic effects of barbiturates, which Different intravenous anesthetics may have some selec- are readily demonstrated in isolated heart preparations, are 37 tivity for certain types of GABAA receptors. usually masked in vivo by baroreceptor reflex-mediated responses. Central Nervous System Barbiturates produce dose-dependent CNS depression Respiratory System ranging from sedation to general anesthesia when admin- Barbiturates are respiratory depressants and lead to istered in induction doses.4 They do not have analgesic decreased minute ventilation via smaller tidal volumes properties and may even reduce the pain threshold, and and respiratory rates. Anesthetic induction doses of thio- thus could be classified as anti-analgesics. Barbiturates are pental and methohexital typically induce transient apnea, potent cerebral vasoconstrictors and produce predictable which is more pronounced in the presence of other respi- decreases in CBF, cerebral blood volume, and ICP. As a ratory depressants. Barbiturates also decrease the ventila- result, they decrease CMRO2 in a dose-dependent manner tory responses to hypercapnia and hypoxia. Resumption up to the point where the EEG becomes a flat line. The of spontaneous breathing after an anesthetic induction ability of barbiturates to decrease ICP and CMRO2 makes dose of a barbiturate is characterized by a slow breathing these drugs useful in the management of patients with rate and decreased tidal volume. Suppression of laryngeal space-occupying intracranial lesions38 (also see Chapter 30). reflexes and cough reflexes is not as profound as after Furthermore, they may provide neuroprotection from propofol administration, which makes barbiturates an focal cerebral ischemia (stroke, surgical retraction, tem- inferior choice for airway instrumentation in the absence porary clips during aneurysm surgery) but probably not of neuromuscular blocking drugs. Furthermore, stimula- from global cerebral ischemia (cardiac arrest). Yet, the use tion of the upper airway or trachea (secretions, laryngeal of barbiturates to lower ICP after traumatic brain injury mask airway, direct laryngoscopy, tracheal intubation) cannot be justified, as the associated hypotension may during inadequate depression of airway reflexes may compromise cerebral perfusion pressure and worsen out- result in laryngospasm or bronchospasm. This phenom- comes.39 Most barbiturates decrease electrical activity on enon is not unique to barbiturates but is true in general

110 Downloaded for Wendy Nguyen ([email protected]) at University Of Minnesota - Twin Cities Campus from ClinicalKey.com by Elsevier on March 25, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Chapter 8 Intravenous Anesthetics when the dose of anesthetic is inadequate to suppress the After administering a barbiturate, it is common to give suc- airway reflexes. cinylcholine or a nondepolarizing neuromuscular blocking drug to produce skeletal muscle relaxation and facilitate tracheal intubation. In some situations, the anesthesia pro- Side Effects vider may choose a “rapid-sequence induction” of anes- Accidental intra-arterial injection of barbiturates thesia, typically when a patient is at increased risk for results in excruciating pain and intense vasoconstric- aspiration of gastric contents. The classic drug regimen tion, often leading to severe tissue injury involving for rapid-sequence induction is a barbiturate, usually thio- gangrene.4 Aggressive therapy is directed at reversing pental, followed by succinylcholine in rapid succession. the vasoconstriction to maintain perfusion and reduce Important advantages of this technique are avoidance of the drug concentration by dilution. One approach to bag-mask ventilation and early tracheal intubation with a treatment is blockade of the sympathetic nervous sys- cuffed tube. Although thiopental was the traditional drug tem in the involved extremity (stellate ganglion block). used for rapid-sequence induction, propofol is currently the II Barbiturate crystal formation probably results in the more frequent choice. occlusion of distal, small-diameter arterioles. Crystal For patients who are not at increased risk of aspirating formation in veins is less hazardous because of the gastric contents, intravenous barbiturates may be used ever-increasing diameter of veins. Accidental subcuta- to initiate a gradual induction. Small doses of thiopental neous injection (extravasation) of barbiturates results (0.5 to 1.0 mg/kg IV) may improve patient acceptance of a in local tissue irritation, thus emphasizing the impor- face mask and negate any unpleasant memory of pungent tance of using dilute concentrations (2.5% thiopen- volatile anesthetics. The induction can then be completed tal, 1% methohexital). If extravasation occurs, some by delivering an inhaled agent such as sevoflurane. This recommend local injection of the tissues with 0.5% type of slow induction helps titrate the anesthetic effect lidocaine (5 to 10 mL) in an attempt to dilute the bar- more carefully and avoids exaggerated hemodynamic biturate concentration. responses. A gradual induction can also be accomplished Life-threatening allergic reactions to barbiturates are by careful titration of intravenous anesthetics alone, rare, with an estimated occurrence of 1 in 30,000 patients. but propofol is probably a more logical choice for this However, barbiturate-induced histamine release is occa- application because it has a shorter context-sensitive sionally seen. half-time (see Fig. 8.3).10 Rectal administration of a barbiturate such as methohexital (20 to 30 mg/kg) may be used to facilitate induction of anesthesia in mentally chal- Clinical Uses lenged and uncooperative pediatric patients. The principal clinical uses of barbiturates are rapid intravenous induction of anesthesia, treatment of increased Neuroprotection (Also See Chapter 30) ICP, or to provide neuroprotection from focal cerebral When used for neuroprotection, barbiturates have tradi- ischemia.4 A continuous intravenous infusion of a bar- tionally been titrated to achieve an isoelectric EEG, an biturate such as thiopental is rarely used to maintain end point that indicates maximal reduction of CMRO2. anesthesia because of its long context-sensitive half-time More recent data demonstrating equal protection after and prolonged recovery period (see Fig. 8.3).10 Prolonged smaller doses have challenged this practice.4 One risk of infusions to achieve “barbiturate coma” for neuroprotec- using high-dose barbiturate therapy to decrease ICP or to tion may cause immune suppression, hypo- and hyperka- provide protection against focal cerebral ischemia (car- lemia, and hypothermia.38 diopulmonary bypass, carotid endarterectomy, thoracic aneurysm resection) is the associated hypotension, which Induction of Anesthesia can critically reduce cerebral perfusion pressure and may Administration of thiopental (3 to 5 mg/kg IV) or metho- require the administration of vasoconstrictors to main- hexital (1 to 1.5 mg/kg IV) produces unconsciousness in tain systemic arterial blood pressure. In a large registry of less than 30 seconds. Patients may experience a garlic or patients undergoing repair of acute type A aortic dissec- onion taste during induction of anesthesia. When used as tion, there was no benefit from barbiturates for prevent- an anesthetic for electroconvulsive therapy, methohexital ing permanent neurologic dysfunction,42 and these drugs may allow for longer seizure duration when compared are unlikely to be of benefit during cardiac surgery. with propofol.41 With the introduction of sugammadex as a reversal drug for rocuronium neuromuscular blockade, methohexital plus rocuronium may become a more BENZODIAZEPINES common anesthetic cocktail for electroconvulsive therapy (also see Chapter 11). Benzodiazepines commonly used in the perioperative period The utility of barbiturates can be illustrated by describ- include diazepam, midazolam, and lorazepam, as well ing several different techniques for anesthesia induction. as the selective benzodiazepine antagonist flumazenil.1,5

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Benzodiazepines are unique among intravenous anesthet- midazolam is selectively metabolized by hepatic cytochrome ics in that their action can readily be terminated by admin- P450 3A4 to a single dominant metabolite, 1-hydroxymid- istration of their selective antagonist flumazenil. Their azolam. Whereas 1-hydroxymidazolam has sedative effects most desired effects are anxiolysis and anterograde amne- similar to the parent compound, it undergoes rapid gluc- sia, which are extremely useful for premedication. uronidation and clearance.2 This metabolite does not cause significant sedation in patients with normal hepatic and renal function unless midazolam is given as a prolonged infusion. Physicochemical Characteristics Furthermore, the short duration of action of a single dose The chemical structure of the benzodiazepines contains of midazolam is due to its lipid solubility and rapid redis- a benzene ring fused to a seven-member diazepine ring, tribution as prevously described. Despite its prompt passage hence their name (Fig. 8.7). The three benzodiazepines into the brain, midazolam is considered to have a slower commonly used in the perioperative setting are all highly effect-site equilibration time than propofol and thiopental. lipophilic, with midazolam having the highest lipid solu- In this regard, intravenous doses of midazolam should be bility. All three drugs are highly protein bound, mainly to sufficiently spaced to permit the peak clinical effect to be serum albumin. Although they are used as parenteral for- recognized before a repeat dose is considered. mulations, all three drugs are absorbed after oral admin- The elimination half-time of diazepam greatly exceeds istration. Other possible routes of administration include that of midazolam, thus explaining why the CNS effects intramuscular, intranasal, and sublingual. Exposure of of diazepam are prolonged, especially in elderly patients. the acidic midazolam preparation to the physiologic pH Of the three commonly used intravenous benzodiaze- of blood causes a change in the ring structure that ren- pines, midazolam has the shortest context-sensitive half- ders the drug more lipid soluble, thus speeding its passage time, making it the most suitable for continuous infusion across the blood-brain barrier and its onset of action. (see Fig. 8.6).10 Recently, a new ultrashort-acting benzodiazepine named remimazolam (CNS-7056) has entered clinical tri- Pharmacokinetics als. Remimazolam contains a carboxylic ester group that is The highly lipid-soluble benzodiazepines rapidly enter the rapidly hydrolyzed by tissue esterases, analogous to remi- CNS, which accounts for their rapid onset of action, fol- fentanil (also see Chapter 9).32 As compared to midazolam, lowed by redistribution to inactive tissue sites and sub- remimazolam has a smaller volume of distribution, faster sequent termination of the drug effect (see Table 8.1). clearance, and clearance independent of body weight.43 Metabolism of benzodiazepines occurs in the liver through The metabolite of remimazolam has extremely low GABAA microsomal oxidation (N-dealkylation and aliphatic hydrox- affinity (>400 times lower than CNS-7056) and is unlikely ylation) and glucuronide conjugation. Microsomal oxida- to yield clinically relevant sedation. The kinetic properties tion, the primary pathway for metabolism of midazolam of remimazolam make it a promising intravenous anes- and diazepam, is more susceptible to external factors such thetic drug that may yield less prolonged sedation com- as age, diseases (hepatic cirrhosis), and the administration pared with midazolam, particularly in patients with liver of other drugs that modulate the efficiency of the enzyme disease or those taking cytochrome P450–inhibiting drugs. systems. Lorazepam is one of few benzodiazepines that does not undergo oxidative metabolism and is excreted after a Pharmacodynamics single-step conjugation to glucuronic acid. Diazepam undergoes hepatic metabolism to active Benzodiazepines work through activation of the GABAA metabolites (desmethyldiazepam and oxazepam) that may receptor complex and enhancement of GABA-mediated contribute to the prolonged effects of this drug. By contrast, chloride currents, thereby leading to hyperpolarization

CH3 N H3C N O O COOC2H5 N N N N OH CI N CI N CI N F N

F CI O CH3

Midazolam Lorazepam Diazepam Flumazenil

Fig. 8.7 Chemical structure of the most commonly used benzodiazepines and their antagonist flumazenil.

112 Downloaded for Wendy Nguyen ([email protected]) at University Of Minnesota - Twin Cities Campus from ClinicalKey.com by Elsevier on March 25, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Chapter 8 Intravenous Anesthetics of neurons and reduced excitability (Fig. 8.8).44 There Safety Profile are specific binding sites for benzodiazepines on GABAA Benzodiazepines have a very favorable side effect pro- receptors, thus explaining why they were initially termed file. When administered alone, these drugs cause only “benzodiazepine receptors.” Consistent with its greater minimal depression of ventilation and the cardiovascular potency, midazolam has an affinity for GABAA receptors system, making them relatively safe even in larger doses. that is approximately twice that of diazepam. Furthermore, the CNS effects can be reversed by the selec- GABAA receptors that are responsive to benzodiaz- tive benzodiazepine antagonist, flumazenil, thus adding epines occur almost exclusively on postsynaptic nerve to the safety margin. endings in the CNS, with the greatest density found in the cerebral cortex. The anatomic distribution of Central Nervous System (Also See Chapter 30) GABAA receptors (restricted to the CNS) is consistent Like propofol and barbiturates, benzodiazepines decrease with the minimal effects of benzodiazepines outside CMRO2 and CBF, but to a lesser extent. In contrast to the CNS. Indeed, the magnitude of depression of ven- propofol and thiopental, midazolam is unable to produce II tilation and the development of hypotension after the an isoelectric EEG, thus emphasizing that there is a ceil- administration of benzodiazepines are lower than that ing effect on reduction of CMRO2 by benzodiazepines. observed when barbiturates are used for induction of Patients with decreased intracranial compliance demon- anesthesia (Table 8.2). strate little or no change in ICP after the administration of midazolam. Benzodiazepines have not been shown to Spectrum of Effects possess neuroprotective properties. They are potent anti- The wide spectrum of effects of benzodiazepines is convulsants for the treatment of status epilepticus, alco- similar for all drugs in this class, although potencies hol withdrawal, and local anesthetic-induced seizures. for individual effects may vary between drugs.5 The most important effects of benzodiazepines are their Cardiovascular System sedative-hypnotic action and their amnestic properties When used for induction of anesthesia, midazolam pro- (anterograde, but not retrograde, amnesia).45 In addi- duces a larger decrease in arterial blood pressure than tion, benzodiazepines function as anticonvulsants and diazepam. These changes are most likely due to peripheral are used to treat seizures. These effects are mediated vasodilation inasmuch as cardiac output is not changed. through the α-subunits of the GABA receptor, whereas Midazolam-induced hypotension is more likely in hypo- anxiolysis and muscle relaxation are mediated through volemic patients. the γ-subunits. The site of action for muscle relaxation is in the spinal cord, and this effect requires much Respiratory System larger doses. Benzodiazepines produce minimal depression of ventilation, although transient apnea may follow rapid intravenous administration of midazolam for induction of anesthesia, especially in the presence of opioid premedi- – – Cl Cl cation. Benzodiazepines decrease the ventilatory response Benzo to carbon dioxide, but this effect is not usually significant β α α β if they are administered alone. More severe respiratory depression can occur when benzodiazepines are adminis- γ tered together with opioids.1,46

Side Effects Allergic reactions to benzodiazepines are extremely rare to nonexistent. Pain during intravenous injection and subsequent thrombophlebitis are most pronounced with diazepam and reflect the poor water solubility of this benzodiazepine. It is the organic solvent, propylene glycol, required to dissolve diazepam that is most likely responsible for pain during intramuscular or intravenous Fig. 8.8 Schematic depiction of the γ-aminobutyric acid (GABA) type A receptor forming a chloride ion channel. Benzodiazepines administration, as well as for the unpredictable absorp- (Benzo) attach selectively at the interface of α- and γ- subunits and tion after intramuscular injection. Midazolam is more are presumed to facilitate the action of the inhibitory neurotrans- water soluble (but only at low pH), thus obviating the mitter GABA. (From Mohler H, Richards JG. The benzodiazepine need for an organic solvent and decreasing the likelihood receptor: a pharmacological control element of brain function. Eur J of exaggerated pain or erratic absorption after intramus- Anesthesiol Suppl. 1988;2:15-24, used with permission.) cular injection or pain during intravenous administration.

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Table 8.2 Summary of the Pharmacodynamic Effects of Commonly Used Intravenous Anesthetics

Dose/Effect Propofol Thiopental Midazolam Ketamine Etomidate Dexmedetomidine Dose for induction of 1.5-2.5 3-5 0.1-0.3 1-2 0.2-0.3 anesthesia (mg/kg IV) Systemic blood pressure Decreased Decreased Unchanged to Increased * Unchanged to Decreased † decreased decreased Heart rate Unchanged to Increased Unchanged Increased Unchanged to Decreased decreased increased

Systemic vascular Decreased Decreased Unchanged to Increased Unchanged to Decreased † resistance decreased decreased Ventilation Decreased Decreased Unchanged Unchanged Unchanged to Unchanged to decreased decreased Respiratory rate Decreased Decreased Unchanged to Unchanged Unchanged to Unchanged decreased decreased Response to carbon Decreased Decreased Decreased Unchanged Decreased Unchanged dioxide Cerebral blood flow Decreased Decreased Decreased Increased to Decreased Decreased unchanged Cerebral metabolic Decreased Decreased Decreased Increased to Decreased Unchanged requirements for oxygen unchanged Intracranial pressure Decreased Decreased Unchanged Increased to Decreased Unchanged unchanged Anticonvulsant Yes Yes Yes Yes? No No Anxiolysis No No Yes No No Yes? Analgesia No No No Yes No Yes? Emergence delirium No? No No Yes No May reduce Nausea and vomiting Decreased Unchanged Decreased Unchanged Increased Unchanged Adrenocortical suppression No No Yes? No Yes No Pain on injection Yes No No No No No

*May cause direct myocardial depression and hypotension in critically ill or catecholamine-depleted patients. †Bolus injection may increase systemic vascular resistance and blood pressure. IV, Intravenous.

Clinical Uses for preoperative medication. Midazolam (1 to 2 mg IV) Benzodiazepines are used for (1) preoperative medica- is effective for premedication, sedation during regional tion, (2) intravenous sedation, (3) intravenous induction anesthesia, and brief therapeutic procedures.5,47 Addition of anesthesia, and (4) suppression of seizure activity. The of midazolam to propofol sedation for colonoscopy may slow onset and prolonged duration of action of lorazepam improve operating conditions without slowing recovery limit its usefulness for preoperative medication or induc- time or worsening cognitive impairment at discharge.48 tion of anesthesia, especially when rapid and sustained When compared with diazepam, midazolam produces awakening at the end of surgery is desirable. Flumazenil a more rapid onset, with more intense amnesia and less (8 to 15 μg/kg IV) may be useful for treating patients expe- postoperative sedation. Many patients who receive preop- riencing delayed awakening, but its duration of action is erative midazolam do not recall the operating room, and brief (about 20 minutes) and resedation may occur. some have no memory of the preoperative holding area.49 Both anesthesia providers and surgeons should be aware Preoperative Medication and Sedation (Also See Chapter 13) of this fact when providing information to patients and The amnestic, anxiolytic, and sedative effects of ben- families prior to surgery. Although awareness during anes- zodiazepines are the basis for the use of these drugs thesia is rare (also see Chapter 47), benzodiazepines seem

114 Downloaded for Wendy Nguyen ([email protected]) at University Of Minnesota - Twin Cities Campus from ClinicalKey.com by Elsevier on March 25, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Chapter 8 Intravenous Anesthetics to be superior to ketamine and barbiturates for prevention 50 of recall. Midazolam is commonly used for oral premedi- O cation of children. For example, 0.5 mg/kg administered orally 30 minutes before induction of anesthesia provides CI reliable sedation and anxiolysis in children without pro- NHCH3 ducing delayed awakening.51 Midazolam also lowers the incidence of PONV.52 Despite these possible benefits, the Fig. 8.9 Chemical structure of ketamine. routine use of premedication with benzodiazepines for elective surgery may not improve patient experience.53 The synergistic effects between benzodiazepines and KETAMINE other drugs, especially opioids and propofol, facilitate better sedation and analgesia. However, the combination Ketamine, a phencyclidine derivative that received FDA of these drugs also exacerbates respiratory depression approval for clinical use in 1970, is different from most II and may lead to airway obstruction or apnea.46 These other intravenous anesthetics in that it produces sig- drugs may also increase the risk for aspiration of gastric nificant analgesia.2,3 The characteristic cataleptic state contents by impairing pharyngeal function and the coor- observed after an induction dose of ketamine is known dination between breathing and swallowing.54 Benzodi- as “dissociative anesthesia,” wherein the patient’s eyes azepine effects, as well as synergy with other respiratory remain open with a slow nystagmic gaze (cataleptic state). depressants, are more pronounced in the elderly (also see Chapter 35) so smaller doses and careful titration may Physicochemical Characteristics be necessary. Caution is advised when using benzodiazepines for sedation of critically ill, mechanically ventilated Ketamine is a partially water-soluble and highly lipid- patients, as this drug class has been linked to longer dura- soluble derivative of phencyclidine (Fig. 8.9). It is between tion of ICU stay and increased delirium compared with 5 and 10 times more lipid soluble than thiopental. Of the alternative regimens (propofol or dexmedetomidine).55,56 two stereoisomers the S(+) form is more potent than the R(−) isomer. Only the racemic mixture of ketamine (10, Induction of Anesthesia 50, 100 mg/mL) is available in the United States. Although rarely used for this purpose, general anesthesia After its initial introduction, ketamine was for a time can be induced by the administration of midazolam (0.1 established as a safe anesthetic. However, the popularity to 0.3 mg/kg IV). The onset of unconsciousness, however, of ketamine has since declined, and its unpleasant psy- is slower than after the administration of thiopental, pro- chomimetic side effects have limited its use in anesthesia. pofol, or etomidate. Onset of unconsciousness is facili- Still, the unique features of ketamine (potent analgesia tated when a small dose of opioid (fentanyl, 50 to 100 μg with minimal respiratory depression) make it a very valu- IV) is injected 1 to 3 minutes before midazolam is admin- able alternative in certain settings. More recently it has istered. Despite the possible production of lesser circula- become popular as an adjunct administered at subanal- tory effects, it is unlikely that the use of midazolam or gesic doses to limit or reverse opioid tolerance and in the diazepam for induction of anesthesia offers any advan- treatment of major depression.58,59 tages over barbiturates or propofol. Delayed awakening is a potential disadvantage after an induction dose of a Pharmacokinetics benzodiazepine. The high lipid solubility of ketamine ensures a rapid onset Suppression of Seizure Activity of effect. Like other intravenous induction drugs, the effect The efficacy of benzodiazepines as anticonvulsants of a single bolus injection is terminated by redistribution owes to their ability to enhance the inhibitory effects to inactive tissue sites. Metabolism occurs primarily in the of GABA, particularly in the limbic system. Indeed, liver and involves N-demethylation by the cytochrome diazepam (0.1 mg/kg IV) is often effective in abolish- P-450 system. Norketamine, the primary active metabolite, ing seizure activity produced by local anesthetics or is less potent (one third to one fifth the potency of ket- alcohol withdrawal. Lorazepam (0.1 mg/kg IV) is the amine) and is subsequently hydroxylated and conjugated intravenous benzodiazepine of choice for status epi- into water-soluble inactive metabolites that are excreted in lepticus. Diazepam (0.2 mg/kg IV) may also be used. urine. Ketamine is the only intravenous anesthetic that has For prehospital treatment of status epilepticus, intra- low protein binding (12%) (see Table 8.1). muscular (IM) administration of midazolam (10 mg IM for patients > 40 kg; 5 mg IM for patients 13 to 40 Pharmacodynamics kg) is effective, can be performed more rapidly than intravenous therapy, and may decrease the need for The mechanism of action of ketamine is complex, but the hospitalization.57 major anesthetic effect is produced through inhibition of

115 Downloaded for Wendy Nguyen ([email protected]) at University Of Minnesota - Twin Cities Campus from ClinicalKey.com by Elsevier on March 25, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Section II PHARMACOLOGY AND PHYSIOLOGY the N-methyl-d-aspartate (NMDA) receptor complex.60 If gases remain stable. Transient hypoventilation and, ketamine is administered as the sole anesthetic, amnesia in rare cases, a short period of apnea can follow rapid is not as complete as with the administration of a benzo- administration of large intravenous doses for induction diazepine. Reflexes are often preserved, but it cannot be of anesthesia. The ability to protect the upper airway in assumed that patients are able to protect their upper air- the presence of ketamine cannot be assumed despite the way. The eyes remain open, and the pupils are moderately presence of active airway reflexes. Especially in children, dilated with a nystagmic gaze. Frequently, lacrimation the risk for laryngospasm because of increased salivation and salivation are increased, and premedication with an is increased and can be reduced by premedication with an anticholinergic drug may be indicated to limit this effect anticholinergic drug. Ketamine relaxes bronchial smooth (see Table 8.2). muscles and may be helpful in patients with reactive airways and in the management of patients experiencing Emergence Reactions bronchoconstriction. The unpleasant emergence reactions after ketamine administration are the main factor limiting its use. Such Clinical Uses reactions may include vivid colorful dreams, hallucina- tions, out-of-body experiences, and increased and dis- The unpleasant emergence reactions after the adminis- torted visual, tactile, and auditory sensitivity. These tration of ketamine have restricted its use as a general reactions can be associated with fear and confusion. A anesthetic.62 Nevertheless, ketamine’s unique properties, euphoric state may also be induced, which explains the including profound analgesia, stimulation of the sym- potential for abuse of the drug. Children usually have a pathetic nervous system, bronchodilation, and minimal lesser incidence of severe emergence reactions. Admin- respiratory depression, make it an important alterna- istration of a benzodiazepine in combination with ket- tive to the other intravenous anesthetics and a desirable amine may help limit the unpleasant emergence reactions adjunct in many cases. Moreover, ketamine can be admin- and also increase amnesia. istered by multiple routes (intravenous, intramuscular, oral, rectal, epidural), thus making it a useful option for Central Nervous System (Also See Chapter 30) premedication in mentally challenged and uncooperative In contrast to other intravenous anesthetics, ketamine is a pediatric patients (also see Chapter 34). cerebral vasodilator that increases CBF as well as CMRO2. Thus, ketamine is usually avoided in patients with intra- Induction and Maintenance of Anesthesia cranial disease, especially increased ICP. Nevertheless, Induction of anesthesia can be achieved with ketamine, 1 the undesirable effects on CBF may be blunted by con- to 2 mg/kg IV or 4 to 6 mg/kg IM. Though not commonly trolled ventilation and the maintenance of normocap- used for maintenance of anesthesia, the short context- nia.61 Despite the potential to produce myoclonic activity, sensitive half-time makes ketamine a consideration for ketamine is considered an anticonvulsant and may be this purpose (see Fig. 8.3).10 For example, general anes- considered for treatment of status epilepticus when more thesia can be achieved with the infusion of ketamine, 15 conventional drugs are ineffective. to 45 μg/kg/min, plus 50% to 70% nitrous oxide or by ketamine alone, 30 to 90 μg/kg/min. Cardiovascular System Ketamine can produce significant, but transient increases Analgesia in systemic arterial blood pressure, heart rate, and car- Small bolus doses of ketamine (0.2 to 0.8 mg/kg IV) may diac output, presumably by centrally mediated sympa- be useful during regional anesthesia when additional thetic stimulation. These effects, which are associated analgesia is needed (e.g., cesarean section under neur- with increased cardiac work and myocardial oxygen con- axial anesthesia with an insufficient regional block). sumption, are not always desirable and can be blunted by Ketamine provides effective analgesia without compro- coadministration of benzodiazepines, opioids, or inhaled mise of the airway. An infusion of a subanalgesic dose anesthetics. Though more controversial, ketamine is a of ketamine (3 to 5 μg/kg/min) during general anesthe- direct myocardial depressant. This property is usually sia and in the early postoperative period may be use- masked by its stimulation of the sympathetic nervous sys- ful to produce analgesia or reduce opioid tolerance and tem, but it may become apparent in critically ill patients opioid-induced hyperalgesia,63 although not all stud- with limited ability to increase their sympathetic nervous ies examining the use of ketamine as an adjunct show system activity. the desired improvement in pain scores and recovery.64 Because of the presence of NMDA receptors on periph- Respiratory System eral nociceptors, local and topical application of ket- Ketamine does not produce significant respiratory amine appears to be a reasonable approach that might depression. When used as a single drug, the respiratory allow achievement of higher local tissue concentrations response to hypercapnia is preserved and arterial blood in an attempt to avoid undesired CNS effects. However,

116 Downloaded for Wendy Nguyen ([email protected]) at University Of Minnesota - Twin Cities Campus from ClinicalKey.com by Elsevier on March 25, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Chapter 8 Intravenous Anesthetics convincing evidence from controlled trials is lacking the dose, with each 0.1 mg/kg providing about 100 sec- and so far support for this modality mainly comes from onds of unconsciousness. Because of its minimal effects case reports.65 on hemodynamics and short context-sensitive half-time, larger doses, repeated boluses, or continuous infusions Treatment of Major Depression can safely be administered (see Fig. 8.3).10 Etomidate, Ketamine has recently received increasing attention as a like most other intravenous anesthetics, is highly pro- therapeutic option for treatment-resistant major depression. tein bound (77%), primarily to albumin. Development of A single intravenous infusion of ketamine (0.5 mg/kg over novel short-acting etomidate derivatives (e.g., ABP-700) 40 minutes) was shown to be superior to midazolam for is under way with the goal of finding an analog with reduction of depressive symptoms in less than 24 hours.66 limited adrenal side effects.67 With optimization of dose, timing, and frequency of treat- ments, ketamine may prove useful for maintenance of Pharmacodynamics antidepressant effects in treatment-resistant patients.59 II Etomidate has GABA-like effects and seems to primarily act through potentiation of GABAA-mediated chloride ETOMIDATE currents, like most other intravenous anesthetics.7

Etomidate is an intravenous anesthetic with hypnotic but Central Nervous System (Also See Chapter 30) not analgesic properties and with minimal hemodynamic Etomidate is a potent cerebral vasoconstrictor, as reflected effects.2,3,7 The pharmacokinetics of etomidate make it by decreases in CBF and ICP. These effects of etomidate suitable for use as a continuous infusion, but it is not are similar to those produced by comparable doses of widely used mainly because of its endocrine side effects. thiopental. Despite its reduction of CMRO2, etomidate failed to show neuroprotective properties in animal studies, and human studies are lacking. Excitatory spikes on Physicochemical Characteristics the EEG are more frequent after etomidate than from Etomidate is a carboxylated imidazole derivative that has thiopental. Similar to methohexital, etomidate may acti- two optical isomers (Fig. 8.10). The available preparation vate seizure foci, manifested as fast activity on the EEG. contains only the active D(+) isomer, which has hypnotic In addition, spontaneous movements characterized as properties. The drug is poorly soluble in water and is myoclonus occur in more than 50% of patients receiving therefore supplied as a 2 mg/mL solution in 35% propyl- etomidate, and this myoclonic activity may be associated ene glycol. The solution has a pH of 6.9 and thus does not with seizure-like activity on the EEG. cause problems with precipitation like thiopental does. Cardiovascular System A characteristic and desired feature of induction of anes- Pharmacokinetics thesia with etomidate is cardiovascular stability after An induction dose of etomidate produces rapid onset of bolus injection.7 Arterial blood pressure decreases are anesthesia, and recovery depends on redistribution to modest or absent and principally reflect decreases in inactive tissue sites (comparable to thiopental and propo- systemic vascular resistance. Any hypotensive effects fol). Metabolism is primarily hepatic by ester hydrolysis of etomidate are probably exaggerated in the presence to inactive metabolites, which are then excreted in urine of hypovolemia. Etomidate produces minimal changes (78%) and bile (22%). Less than 3% of an administered in heart rate and cardiac output. The depressive effects dose of etomidate is excreted unchanged in the urine. of etomidate on myocardial contractility are minimal at Clearance of etomidate is about five times that for thio- concentrations used for induction of anesthesia. pental, as reflected by a shorter elimination half-time (see Table 8.1). The duration of action is linearly related to Respiratory System The depressant effects of etomidate on ventilation are less pronounced than those of barbiturates, although O N apnea may occasionally follow rapid intravenous injec-

CH3 CH2 OC tion. Depression of ventilation may be exaggerated when N etomidate is combined with inhaled anesthetics or opioids. CH CH 3 Endocrine System Etomidate causes adrenocortical suppression by producing a dose-dependent inhibition of 11β-hydroxylase, an enzyme necessary for the conversion of cholesterol to Fig. 8.10 Chemical structure of etomidate. cortisol (Fig. 8.11).68 This suppression lasts at least 4 to 8

117 Downloaded for Wendy Nguyen ([email protected]) at University Of Minnesota - Twin Cities Campus from ClinicalKey.com by Elsevier on March 25, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Section II PHARMACOLOGY AND PHYSIOLOGY hours after a single induction dose of etomidate, and rela- that etomidate increases mortality after a single dose for tive adrenal insufficiency may last up to 24 to 48 hours.69 intubation of septic patients.73-75 Etomidate remains a This property has generated great controversy over the useful hypnotic for electroconvulsive therapy as it pro- safety of etomidate for intubation of critically ill patients vides a longer seizure duration than propofol or metho- and as an induction drug for general anesthesia.70 hexital (also see Chapter 38).76

Clinical Uses DEXMEDETOMIDINE Etomidate is an alternative to propofol and barbiturates for the rapid intravenous induction of anesthesia, espe- Dexmedetomidine is a highly selective α2-adrenergic ago- 77 cially in patients with compromised myocardial contrac- nist. Recognition of the usefulness of α2-agonists was tility, coronary artery disease, or severe aortic stenosis.71,72 based on the observation that patients receiving chronic After a standard induction dose (0.2 to 0.3 mg/kg IV), the clonidine therapy have decreased anesthetic require- onset of unconsciousness is comparable to that achieved ments. The effects of dexmedetomidine can be reversed by thiopental and propofol. There is a frequent incidence with α2-antagonist drugs. of pain during intravenous injection of etomidate, which may be followed by venous irritation. Involuntary myo- Physicochemical Characteristics clonic movements are common but may be masked by the concomitant administration of neuromuscular block- Dexmedetomidine is the active S-enantiomer of medeto- ing drugs. Awakening after a single intravenous dose of midine, a highly selective α2-adrenergic agonist and etomidate is rapid, with little evidence of any residual imidazole derivative that is used in veterinary medicine. depressant effects. Etomidate does not produce analgesia, Dexmedetomidine is water soluble and available as a par- and PONV may be more common than after the admin- enteral formulation (Fig. 8.12). istration of thiopental or propofol. The principal limiting factor in the clinical use of etomidate for induction of Pharmacokinetics anesthesia is its ability to transiently depress adrenocortical function.68 Theoretically, this suppression may be Dexmedetomidine undergoes rapid hepatic metabolism either desirable if it reduces neurohormonal stresses dur- involving conjugation, N-methylation, and hydroxyl- ing surgery and anesthesia, or undesirable if it prevents ation. Metabolites are excreted through urine and bile. useful protective responses against perioperative stresses. Clearance is high, and the elimination half-time is short Recent meta-analyses have challenged earlier findings (see Table 8.1). However, there is a significant increase in the context-sensitive half-time from 4 minutes after a 10-minute infusion to 250 minutes after an 8-hour 40 infusion. Etomidate Thiopental Pharmacodynamics 30 Dexmedetomidine produces its effects through activation of CNS α2-receptors. 20 Central Nervous System Hypnosis presumably results from stimulation of α2- receptors in the locus ceruleus, and the analgesic effect 10 originates at the level of the spinal cord. The sedative

Plasma cortisol ( µ g/100 mL) effect produced by dexmedetomidine has a different quality than that of other intravenous anesthetics in 0 that it more resembles a physiologic sleep state through 04812162024 Hours N H CH3 Fig. 8.11 Etomidate, but not thiopental, is associated with de- NH creases in the plasma concentrations of cortisol. p < 0.005 ver- CH3 H3C sus thiopental, mean ± SD (standard deviation). (From Fragen RT, Shanks CA, Molteni A, et al. Effects of etomidate on hormonal responses to surgical stress. Anesthesiology. 1984;61:652-656,

used with permission.) Fig. 8.12 Chemical structure of dexmedetomidine.

118 Downloaded for Wendy Nguyen ([email protected]) at University Of Minnesota - Twin Cities Campus from ClinicalKey.com by Elsevier on March 25, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Chapter 8 Intravenous Anesthetics activation of endogenous sleep pathways. Dexmedetomi- Although there is no evidence of benefit to mortal- dine decreases CBF without significant changes in ICP ity risk, dexmedetomidine may reduce the duration of 85 and CMRO2 (see Table 8.2). Tolerance and dependence can mechanical ventilation, shorten length of ICU stay, develop. Although changes in the EEG do occur, spikes and improve sleep quality.86 In the operating room, dex from seizure foci are not suppressed making dexme- medetomidine may be used as an adjunct to general detomidine a useful drug for epilepsy surgery.78 Evoked anesthesia or to provide sedation during regional anes- potentials monitored during spine surgery are not sup- thesia or awake fiberoptic tracheal intubation.87 When pressed at usual infusion doses.79 administered during general anesthesia, dexmedetomidine (0.5- to 1-μg/kg IV initial dose over a period of 10 Cardiovascular System to 15 minutes, followed by an infusion of 0.2 to 0.7 μg/ Dexmedetomidine infusion produces moderate decreases kg/h) decreases the dose requirements for inhaled and in heart rate and systemic vascular resistance and, con- intravenous anesthetics. Awakening and the transition to sequently, decreases in systemic arterial blood pressure. the postoperative setting may benefit from dexmedeto- II A bolus injection may produce transient increases in sys- midine-produced sedative and analgesic effects with- temic arterial blood pressure and pronounced decreases out respiratory depression. Dexmedetomidine seems to in heart rate, an effect that is probably due to vasocon- decrease perioperative opioid consumption and improve 88 striction mediated by peripheral α2-adrenergic receptors. pain scores, but analgesic benefit has not been shown Clinically useful initial doses (0.5 to 1 μg/kg IV over in all settings.89 10 minutes) increase systemic vascular resistance and Dexmedetomidine has been used extensively in chil- mean arterial pressure, but probably do not significantly dren and has demonstrated efficacy in this population.90 increase pulmonary vascular resistance.80 Bradycardia Specifically, it may be beneficial for prevention of emergence or hypotension associated with dexmedetomidine infu- delirium after pediatric anesthesia91 (also see Chapter 34). sion may require treatment. Increasing age and decreased At the other extreme of age, dexmedetomidine may be baseline arterial blood pressure (mean arterial pressure superior to propofol for reducing delirium in elderly patients < 70 mm Hg) are risk factors for hemodynamic insta- requiring sedation after cardiac or noncardiac surgery92,93 bility during dexmedetomidine infusion.81 Heart block, (also see Chapter 35). severe bradycardia, or asystole may result from unop- posed vagal stimulation. The response to anticholinergic drugs is unchanged. When used as an adjunct to general QUESTIONS OF THE DAY anesthesia, dexmedetomidine reduces plasma catecholamine levels and may attenuate heart rate increases dur- 1. What are the expected cardiovascular and respiratory ing emergence.82,83 effects of propofol? What techniques can reduce injection pain with propofol? Respiratory System 2. What are the risks of high-dose barbiturate therapy The effects of dexmedetomidine on the respiratory sys- to decrease intracranial pressure (ICP) or provide tem are a small to moderate decrease in tidal volume and neuroprotection? minimal change in the respiratory rate. The ventilatory 3. What are the respiratory effects of benzodiazepines response to carbon dioxide is minimally impaired, but the when administered alone and when administered response to hypoxia seems reduced to a similar degree concurrently with opioids? How do benzodiazepines as propofol.84 Although the respiratory effects are mild, impact pharyngeal function? upper airway obstruction as a result of sedation is possi- 4. How do the central nervous system (CNS) effects of ble. In addition, dexmedetomidine has a synergistic seda- ketamine differ from that of propofol or barbiturates? tive effect when combined with other sedative-hypnotics. What are the potential benefits of ketamine as an analgesic drug? 5. What are the effects of dexmedetomidine on tidal Clinical Uses volume and respiratory rate? What are the expected Dexmedetomidine is principally used for the short- cardiovascular effects of dexmedetomidine infusion? term sedation of tracheally intubated and mechani- What cardiovascular effects may be evident after a cally ventilated patients in an intensive care setting.77 bolus injection of dexmedetomidine?

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