Chapter 6 Intravenous Anesthetics
1. Name some examples of intravenous anesthetics. What are the potential clinical uses of intravenous anesthetics?
Propofol
2. What type of chemical structure is propofol?
3. What is the mechanism of action of propofol?
4. How is propofol cleared from the plasma?
5. What degree of metabolism does propofol undergo? How should the dose of propofol be altered when administered to patients with liver dysfunction?
6. What is the context-sensitive half-time of propofol relative to other intravenous anesthetics? What is the effect-site equilibration time of propofol relative to other intravenous anesthetics?
7. How does the emergence from a propofol anesthetic or propofol induction differ from the emergence seen with the other induction agents?
8. How does propofol affect the cardiovascular system?
9. How does propofol affect ventilation?
10. How does propofol affect the central nervous system?
11. How does propofol affect the seizure threshold?
12. What is the relationship between propofol and nausea and vomiting?
13. How is propofol administered for sedation?
14. How is propofol administered for maintenance anesthesia?
15. How can the pain associated with the intravenous injection of propofol be attenuated?
16. Why is asepsis important when handling propofol?
17. Which patients may be at risk for a life-threatening allergic reaction to propofol?
Barbiturates
21. Name some of the barbiturates. From what chemical compound are they derived?
22. What is the mechanism of action of barbiturates?
23. How are barbiturates cleared from the plasma?
24. What degree of metabolism do barbiturates undergo?
25. What is the context-sensitive half-time of barbiturates relative to other intravenous anesthetics? What is the effect-site equilibration time of barbiturates relative to other intravenous anesthetics?
26. How do methohexital and thiopental compare with regard to induction doses, duration of action, and clinical utility?
27. How do barbiturates affect the arterial blood pressure?
28. How do barbiturates affect the heart rate?
29. How do barbiturates affect ventilation?
30. How do barbiturates affect laryngeal and cough reflexes?
31. How do barbiturates affect the central nervous system? How do barbiturates affect an electroencephalogram?
32. How should thiopental be administered and dosed for cerebral protection in patients with persistently elevated intracranial pressures?
33. What are the various routes and methods for the administration of barbiturates in clinical anesthesia practice?
34. What are some potential adverse complications of the injection of thiopental?
35. What is the risk of a life-threatening allergic reaction to barbiturates?
Benzodiazepines
36. Name some of the commonly used benzodiazepines. What are some of the clinical effects and properties of benzodiazepines that make them useful in anesthesia practice?
37. What is the mechanism of action of benzodiazepines?
38. Where are benzodiazepine receptors located?
39. How does midazolam compare with diazepam with regard to its affinity for the benzodiazepine receptor?
40. How does water-soluble midazolam cross the blood-brain barrier to gain access to the central nervous system?
41. What is the effect-site equilibration time of benzodiazepines relative to other intravenous anesthetics? How do the context-sensitive half-times of the benzodiazepines compare?
42. How do benzodiazepines affect the cardiovascular system?
43. How do benzodiazepines affect ventilation?
44. How do benzodiazepines affect the central nervous system?
45. What are some clinical uses of benzodiazepines in anesthesia practice?
46. How do midazolam and diazepam compare with regard to time of onset and degree of amnesia when administered for sedation?
47. What are some advantages and disadvantages of benzodiazepines for use as induction agents?
48. How can the effects of benzodiazepines be reversed?
49. What organic solvent is used to dissolve diazepam into solution? What are some of the effects of this solvent?
Ketamine
51. What chemical compound is ketamine a derivative of? What is its mechanism of action?
52. How do patients appear clinically after an induction dose of ketamine?
53. What is the mechanism by which the effects of ketamine are terminated?
54. What are the induction doses for intravenous and intramuscular routes of administration of ketamine? What is the time of onset for the effect of ketamine subsequent to its administration?
55. How does ketamine affect the cardiovascular system?
56. How does ketamine affect ventilation?
57. How does ketamine affect skeletal muscle tone? How does this affect the upper airway?
58. How does ketamine affect the central nervous system?
59. What does the emergence delirium associated with ketamine refer to? What is the incidence? How can it be prevented?
60. What are some common clinical uses of ketamine?
61. What can the repeated administration of ketamine lead to? How is it manifest clinically?
Etomidate
63. What type of structure is etomidate? What is its mechanism of action?
64. How is etomidate cleared from the plasma?
65. What degree of metabolism does etomidate undergo?
66. What is the context-sensitive half-time of etomidate relative to other intravenous anesthetics? What is the effect-site equilibration time of etomidate relative to other intravenous anesthetics?
67. How does etomidate affect the cardiovascular system?
68. How does etomidate affect ventilation?
69. How does etomidate affect the central nervous system?
70. How does etomidate affect the seizure threshold?
71. What are the endocrine effects of etomidate?
72. What are some potential negative effects associated with the administration of etomidate?
Dexmedetomidine
73. What type of structure is dexmedetomidine?
74. What is the mechanism of action for dexmedetomidine?
75. What are some common clinical uses for dexmedetomidine?
76. What are the typical doses for dexmedetomidine when used as infusion in the operating room?
77. How does dexmedetomidine affect the cardiovascular system?
78. How does dexmedetomidine affect the respiratory system?
79. What are the effects of dexmedetomidine on cerebral blood flow?
Answers*
1. Examples of intravenous anesthetics include the barbiturates, benzodiazepines, opioids, etomidate, propofol, ketamine, and dexmedetomidine. These drugs can be used as induction agents or, in combination with other anesthetics, for the maintenance of anesthesia. (100)
Propofol
2. Propofol is a lipid-soluble isopropyl phenol formulated as an emulsion. The current formulation consists of 1% propofol, soybean oil, glycerol, and purified egg phosphatide. (100, Figure 9-1)
3. The mechanism by which propofol exerts its effects is not fully understood, but it appears to be in part via the gamma-aminobutyric acid (GABA) activated chloride ion channel. Evidence suggests that propofol may interact with the GABA receptor and maintain it in an activated state for a prolonged period, thereby resulting in greater inhibitory effects on synaptic transmission. Propofol also inhibits the NMDA subtype of the glutamate receptor, which may contribute to its CNS effects. (101)
4. Propofol is cleared rapidly from the plasma through both redistribution to inactive tissue sites and rapid metabolism by the liver. (100-101)
5. Propofol is extensively metabolized by the liver to inactive, water-soluble metabolites, which are then excreted in the urine. Less than 1% of propofol administered is excreted unchanged in the urine. The metabolism of propofol is extremely rapid. Patients with liver dysfunction appear to rapidly metabolize propofol as well, lending some proof that extrahepatic sites of metabolism exist. This has been further supported by evidence of metabolism during the anhepatic phase of liver transplantation. (100)
6. The context-sensitive half-time refers to the time required to pass for the concentration of a particular drug to reach 50% of its peak plasma concentration after the discontinuation of its administration as a continuous intravenous infusion for a given duration. The context-sensitive half-time of a drug depends mostly on the drug’s lipid solubility and clearance mechanisms. The continuous infusion of propofol rarely results in cumulative drug effects. After the continuous administration of propofol for several days for sedation in the intensive care unit the discontinuation of the infusion resulted in the rapid recovery to consciousness. The lack of cumulative effects of propofol illustrates that the context-sensitive half-time of propofol is short. The effect-site equilibration time refers to the interval of time required between the time that a specific plasma concentration of the drug is achieved and a specific effect of the drug can be measured. The effect-site equilibration time reflects the time necessary for the circulation to deliver the drug to its site of action, such as the brain. The rapid administration of an induction dose of propofol results in unconsciousness in less than 30 seconds, illustrating its rapid effect-site equilibration time. (100-101, Figure 9-3)
7. After the administration of propofol, patients experience a rapid return to consciousness with minimal residual central nervous system effects. Patients who are to undergo brief procedures or outpatient surgical patients may especially benefit from the rapid wake-up associated with propofol anesthesia. Propofol also tends to result in the patient awakening with a general state of well-being and mild euphoria. Patient excitement has also been observed. Hallucinations and sexual fantasies have been reported to have occurred in association with the administration of propofol. (101)
8. The administration of an induction dose of propofol results in a profound decrease in systolic blood pressure greater than any other induction agent. This effect of propofol appears to be primarily due to vasodilation, which is dose dependent. Unlike the barbiturates, the heart rate is usually unchanged with the administration of propofol. Propofol may selectively decrease sympathetic nervous system activity more than parasympathetic nervous system activity. In fact, propofol inhibits the normal baroreceptor reflex such that profound bradycardia and asystole have occurred in healthy adults after its administration. (102)
9. The administration of an induction dose of propofol (1.5 to 2.5 mg/kg) almost always results in apnea through a dose-dependent depression of ventilation in a manner similar to, but more prolonged than, that of thiopental. The apnea that results appears to last for 30 seconds or greater and is followed by a return of ventilation that is characterized by rapid, shallow breathing such that the minute ventilation is significantly decreased for up to 4 minutes. Propofol causes a greater reduction in airway reflexes than any other induction agent, making it a better choice as the sole agent for instrumentation of the airway. (102)
10. The administration of propofol results in decreases in intracranial pressure, cerebral blood flow, and cerebral metabolic oxygen requirements in a dose-dependent manner. In patients with an elevated intracranial pressure, the administration of propofol, however, may be accompanied by undesirable decreases in the cerebral perfusion pressure. (101-102)
11. The effects of propofol on the seizure threshold are controversial. The administration of propofol has resulted in seizures and opisthotonos and has been used to facilitate the mapping of seizure foci. Propofol has also been used to treat seizures. High doses of propofol can result in burst suppression on the electroencephalogram. Excitatory effects that cause muscle twitching are not uncommon, but do not indicate seizure activity. (102)
12. Propofol appears to have a significant antiemetic effect, given the low incidence of nausea and vomiting in patients who have received a propofol anesthetic. In addition, propofol administered in subhypnotic doses of 10 to 15 mg has successfully treated both postoperative nausea and vomiting and nausea in patients receiving chemotherapy. (102)
13. Propofol may be administered for sedation through a continuous intravenous infusion at a rate of 25 to 75 μg/kg/min. At these doses, propofol will provide sedation and amnesia without hypnosis. Because of the pronounced respiratory depressant effect, propofol, even for sedation, should only be administered by individuals trained in airway management. (102)
14. Propofol may be administered for maintenance anesthesia through a continuous intravenous infusion at a rate of 100 to 200 μg/kg/min. The clinician may use signs of light anesthesia such as hypertension, tachycardia, diaphoresis, or skeletal muscle movement as indicators for the need to increase the infusion rate of propofol. For procedures lasting more than 2 hours, the use of propofol for maintenance anesthesia may not be cost effective. (102)
15. The injection of propofol intravenously can cause pain in awake patients. The pain can be attenuated by using large veins for its administration, or with the prior administration of lidocaine at the injection site. Alternatively, lidocaine may be mixed with the propofol for simultaneous infusion. (102)
16. Asepsis is important when handling propofol because the solvent for propofol, a lipid emulsion containing soybean oil, glycerol, and lecithin, provides for a favorable culture medium for bacterial growth. Ethylenediaminetetraacetic acid, metabisulfate, or benzyl alcohol is added to the propofol formulation in an attempt to suppress bacterial growth. (100)
17. Patients at risk for a life-threatening allergic reaction to propofol are those with a history of atopy or allergy to other drugs that also contain a phenyl nucleus or isopropyl group. Anaphylactoid reactions to the propofol itself and separate from the lipid emulsion have been reported. (100)
Fospropofol
18. Fospropofol is a water-soluble phosphate ester prodrug of propofol. It is metabolized by alkaline phosphatase in a reaction that produces propofol and also phosphate and formaldehyde, which is then further metabolized. (103, Figure 9-4)
19. Fospropofol is water-soluble and comes in an aqueous, sterile preparation. It can be injected without the need for a lipid emulsion, thereby reducing the risk for contamination. (103)
20. In the United States, fospropofol is currently approved for sedation during monitored anesthesia care. (103)
Barbiturates
21. Thiopental is the most commonly used barbiturate in the practice of anesthesia. Other barbiturates include pentobarbital, thiamylal, and methohexital. The barbiturate compounds are a derivative of barbituric acid. Structural alterations of two of the carbon atoms of barbituric acid result in the barbiturates used in clinical practice. Historically, the barbiturates had been classified as short-acting or long-acting agents. This method of classification is no longer used because of the erroneous implication that the duration of action is predictable for a given agent. (103, Figure 9-5)
22. The mechanism of action of barbiturates is based on their ability to enhance and mimic the action of the neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system. GABA is the main inhibitory neurotransmitter in the central nervous system. Barbiturates bind to the GABA receptor and increase the duration of activity of the GABA receptor, such that the chloride ion influx into the cells is prolonged. The chloride ion hyperpolarizes the cell and inhibits postsynaptic neurons. At higher concentrations, the chloride ion channel may be stimulated by the barbiturate alone even in the absence of GABA. (104)
23. Barbiturates are cleared from the plasma primarily through its rapid redistribution to inactive tissue sites after its administration as a bolus. (103-104, Figure 9-6)
24. Barbiturates are eliminated from the body through hepatic metabolism. Less than 1% of the drug is excreted unchanged by the kidneys. (103-104)
25. Barbiturates are most often used for the intravenous induction of general anesthesia. Maximal brain uptake and onset of effect takes place within 30 seconds after the rapid intravenous injection of a barbiturate. Rapid awakening follows the administration of an induction dose of a barbiturate secondary to the rapid redistribution of these drugs. This accounts for the short effect-site equilibration time for these agents. The duration of action of a barbiturate after its intravenous injection is dictated by its redistribution from the plasma to inactive sites. Large or repeated doses of the lipid-soluble barbiturates can result in saturation of the inactive sites. This may lead to the accumulation of a drug and to prolonged effects of the usually short-acting drugs. The context-sensitive half-time of barbiturates is thus prolonged. (103-104, Figure 9-3)
26. The induction dose of methohexital is 1 to 1.5 mg/kg intravenously, whereas the induction dose of thiopental is 3 to 5 mg/kg IV. Methohexital undergoes greater hepatic metabolism than thiopental, resulting in a shorter duration of action and more rapid awakening. Based on the shorter duration of action of methohexital, it is sometimes chosen over thiopental for the induction of anesthesia for patients undergoing outpatient procedures when rapid awakening is desired. An example of a procedure in which methohexital is frequently chosen for the induction of anesthesia is electroconvulsive shock therapy. This is not only due to the short duration of action of methohexital, but also to its epileptogenic property. (105-106)
27. The administration of barbiturates typically results in a decrease in arterial blood pressure by 10 to 20 mm Hg. This decrease in blood pressure primarily results from peripheral vasodilation. The vasodilation that accompanies the administration of barbiturates is due to a combination of depression of the vasomotor center in the medulla and a decrease in sympathetic nervous system outflow from the central nervous system. Exaggerated blood pressure decreases may be seen in patients who are hypertensive, whether or not they are being treated by antihypertensives. The administration of barbiturates should also be undertaken with caution in patients who are dependent on the preload to the heart to maintain cardiac output, as in patients with ischemic heart disease, pericardial tamponade, congestive heart failure, heart block, or hypovolemia. (105)
28. The administration of barbiturates results in an increase in heart rate. This increase in heart rate is thought to be due to a baroreceptor-mediated reflex response to the decrease in blood pressure caused by the administration of the barbiturate. The increase in heart rate may increase myocardial oxygen requirements during a time when significant decreases in blood pressure may decrease coronary artery blood flow as well. Given this, the administration of a barbiturate to patients with ischemic heart disease must be done with extreme caution. Although the administration of barbiturates typically results in an increase in heart rate, the cardiac output may be decreased. This is in part due to the direct myocardial contractile depression that results from the administration of barbiturates. The effect of a decrease in cardiac output by barbiturates is not of such significance that it is frequently seen clinically, however. (105)
29. Barbiturates depress ventilation centrally by depressing the medullary ventilatory centers. This is manifest clinically as a decreased responsiveness to the ventilatory stimulatory effects of carbon dioxide. Depending on the dose administered, the patient will have a slow breathing rate and small tidal volumes to the extent that apnea follows. Typically, after an induction dose of barbiturate transient apnea will result and require controlled ventilation of the lungs. When spontaneous ventilation is resumed, it is again characterized by a slow breathing rate and small tidal volumes. (105)
30. Induction doses of thiopental alone do not reliably depress laryngeal and cough reflexes. Stimulation of the upper airway, as with the placement of an oral airway or an endotracheal tube, can result in laryngospasm or bronchospasm. It is therefore recommended that adequate suppression of these reflexes be obtained before instrumenting the airway. This can be accomplished with increased doses of a barbiturate, by the administration of a neuromuscular blocking drug, or by the addition of another preoperative medicine, such as opioids, to augment the anesthetic effects of thiopental during stimulation of the upper airway. (105)
31. Barbiturates are potent cerebral vasoconstrictors. This results in a decrease in cerebral blood flow, a decrease in cerebral blood volume, a decrease in intracranial pressure, and a decrease in cerebral metabolic oxygen requirements. Barbiturates are also thought to depress the reticular activating system, which is believed to be important in maintaining wakefulness. Thiopental produces a dose-dependent depression of the electroencephalogram. A flat electroencephalogram may be maintained with a continuous infusion of thiopental. Methohexital is the only barbiturate that does not decrease electrical activity on an electroencephalogram. In fact, methohexital activates epileptic foci and is often used intraoperatively to identify epileptic foci during the surgical ablation of these foci. The effects of barbiturates on the central nervous system indicate that barbiturates are useful for patients in whom elevated intracranial pressures are a concern. Examples of patients who may benefit from the administration of a barbiturate as an induction agent or as maintenance anesthesia include patients with intracranial space-occupying lesions or patients who have suffered head trauma. (105)
32. In patients with persistently elevated intracranial pressures, barbiturates may be administered intravenously in high doses to decrease the intracranial pressure. Care must be taken to avoid decreases in mean arterial pressure that would compromise the cerebral perfusion pressure under these conditions. To ascertain the optimal dose of barbiturate administered for these patients, an electroencephalogram can be obtained. The dose of barbiturate can be titrated to a flat-line electroencephalogram. When the electroencephalogram is isoelectric there is no further depression of cerebral metabolism or of cerebral metabolic oxygen requirements with increasing doses of barbiturate. This allows the clinician to administer the dose of barbiturate that provides the maximal benefit with minimal adverse effects. Barbiturates may offer some cerebral protection for patients with regional cerebral ischemia. Patients with global cerebral ischemia, such as from cardiac arrest, are not thought to derive any protection from the administration of barbiturates. (105-106)
33. There are various routes and methods for the administration of barbiturates in clinical anesthesia practice. For instance, the rapid intravenous administration of a bolus of barbiturate is indicated for a rapid sequence induction of anesthesia. The bolus of barbiturate should be immediately followed by the administration of succinylcholine or a nondepolarizing neuromuscular blocking drug to produce skeletal muscle paralysis and facilitate tracheal intubation under these conditions. Alternatively, small doses of intravenous thiopental, in the range of 0.5 to 1 mg/kg, may be administered to adult patients who have difficulty accepting the application of an anesthesia mask and/or the inhalation of a volatile anesthetic. The rectal administration of the barbiturate methohexital can be used to facilitate the induction of anesthesia in young or uncooperative patients. (106)
34. Potential adverse complications of the injection of thiopental may result from accidental intraarterial, subcutaneous, and even appropriate venous administration of thiopental. The accidental intraarterial injection of barbiturates results in excruciating pain and intense vasoconstriction that can last for hours. It is believed that barbiturate crystal formation in the blood causes the occlusion of distant small diameter arteries and arterioles. There are several treatment modalities for this potential problem, including the intraarterial injection of papaverine and/or lidocaine, sympathetic nervous system blockade by stellate ganglion block of the involved upper extremity, and the administration of heparin to prevent thrombosis. Despite aggressive therapy, gangrene of the extremity often results. The accidental subcutaneous injection of barbiturates results in local tissue irritation. The irritation may proceed to pain, edema, erythema, or even tissue necrosis, depending on the volume and concentration injected. It has been recommended that 5 to 10 ml of 0.5% lidocaine be injected locally when the subcutaneous injection of thiopental occurs in an attempt to dilute the barbiturate. Venous thrombosis has been seen after the intravenous administration of thiopental. It is presumed that the thrombosis results from the deposition of barbiturate crystals in the vein. The crystallization of barbiturates is more likely to occur when the pH of the blood is too low to keep the alkaline barbiturate in solution. (105)
35. Life-threatening allergic reactions to barbiturates are rare. The risk has been estimated to be 1 in 30,000. (105)
Benzodiazepines
36. Benzodiazepines that are commonly used in the perioperative period include midazolam, diazepam, and lorazepam. The most common effects of benzodiazepines are their anxiolytic and sedative effects. When administered at higher doses, benzodiazepines may also produce unconsciousness. Other properties of benzodiazepines include anterograde amnesia, a lack of retrograde amnesia, minimal cardiopulmonary depression, anticonvulsant activity, and relative safety when taken in overdose. Clinical uses of benzodiazepines include their use for preoperative medication, for intravenous sedation, for the intravenous induction of anesthesia, and for the suppression of seizure activity. In addition to the intravenous route of administration, benzodiazepines can be administered via intramuscular, intranasal, and sublingual routes. (106, Figure 9-7)
37. Benzodiazepines exert their effects through their actions on the gamma-aminobutyric acid (GABA) receptor. When GABA receptors are stimulated by the inhibitory neurotransmitter GABA, a chloride ion channel opens, allowing chloride ions to flow into the cell. This results in hyperpolarization of the neuron and a resistance of the neuron to subsequent depolarization. Benzodiazepines enhance the effect of GABA by binding to subunits of the GABA receptor and maintaining the chloride channel open for a longer period of time. (107, Figure 9-8)
38. Benzodiazepine receptors are located primarily on postsynaptic nerve endings in the central nervous system. The greatest density of benzodiazepine receptors is in the cerebral cortex. The distribution of benzodiazepine receptors is consistent with the minimal cardiopulmonary effects of these drugs. (107)
39. Midazolam has almost two times the affinity for benzodiazepine receptors than does diazepam, which is consistent with its greater potency. (107)
40. Midazolam is a hydrophilic drug. When midazolam is exposed to the pH of the blood it undergoes a change in its structure and becomes highly lipid soluble. This change in structure allows it to cross the blood-brain barrier and gain access to the central nervous system. (106-107)
41. Benzodiazepines are highly lipid-soluble drugs. This allows them to gain rapid entrance into the central nervous system by crossing the blood-brain barrier, where they are able to exert their effects. Thus the effect-site equilibration time of benzodiazepines is short, although it is slower than propofol or thiopental. The duration of action of benzodiazepines is dependent on the redistribution of the drug from the brain to inactive tissue sites. A continuous infusion or repeated boluses can result in saturation of the inactive tissue sites and a prolongation of the drug effect, particularly for the benzodiazepines that have active metabolites. For instance, diazepam undergoes hepatic metabolism to active metabolites, whereas midazolam has no active metabolites. The context-sensitive half-times for diazepam and lorazepam are prolonged when compared with that of midazolam. (107)
42. Induction doses of midazolam may lead to decreases in systemic blood pressure that are greater than those seen with the induction dose of diazepam. This effect of midazolam may be particularly pronounced in patients who are hypovolemic. The decrease in systemic blood pressure is believed to be due to decreases in systemic vascular resistance. (67, 107-108)
43. In general, benzodiazepines alone produce dose-dependent ventilatory depressant effects. Transient apnea may occur with the rapid administration of induction doses of midazolam, particularly if an opioid has been used for premedication. (108)
44. Benzodiazepines decrease cerebral blood flow and cerebral metabolic oxygen requirements in a dose-dependent manner, but there is a ceiling to this effect. This makes benzodiazepines safe for use in patients with intracranial space-occupying lesions, although the administration of benzodiazepines to patients with intracerebral pathologic processes may make subsequent neurologic evaluation of the patient difficult secondary to the potentially prolonged effects of these drugs. Benzodiazepines also have anticonvulsant effects that are thought to occur through the enhancement of the inhibitory effects of the neurotransmitter GABA acid in the central nervous system. Benzodiazepines have been shown to increase the seizure threshold or treat seizures due to local anesthetic toxicity, alcohol withdrawal, and epilepsy. The dose of diazepam used to treat seizures is 0.1 mg/kg intravenously. An isoelectric electroencephalogram is not able to be achieved with the administration of benzodiazepines. (107-108)
45. Clinical uses of benzodiazepines in anesthesia practice include preoperative medication, intravenous sedation, the intravenous induction of anesthesia, and the suppression of seizure activity. (109)
46. When administered for sedation, midazolam has a more rapid onset and produces a greater degree of amnesia than diazepam. The slow onset and greater duration of action of lorazepam limits its usefulness as a preoperative medication. All benzodiazepines may have prolonged and more pronounced sedative effects in the elderly. (109)
47. The intravenous induction doses of midazolam and diazepam are 0.1 to 0.2 mg/kg and 0.2 to 0.3 mg/kg, respectively. The time of onset of midazolam is anywhere between 30 and 80 seconds, depending on the dose and premedication. The time of onset of midazolam is more rapid than the time of onset of diazepam, making it the benzodiazepine of choice for the induction of anesthesia. The speed of onset of both these agents can be facilitated by the prior administration of opioids. Benzodiazepines are advantageous over barbiturates for the induction of anesthesia only because of their potentially lesser circulatory effects and greater reliability for the production of amnesia. A disadvantage of benzodiazepines for the induction of anesthesia is their lack of analgesic properties. Additional medicines would need to be administered to blunt the cardiovascular and laryngeal responses to direct laryngoscopy. The major disadvantage of benzodiazepines for the induction of anesthesia is delayed awakening, which limits the usefulness of benzodiazepines for this purpose. Midazolam is the shortest-acting of the benzodiazepines and therefore the most appropriate choice of benzodiazepine for the induction of anesthesia. Even so, awakening after a single induction dose of midazolam in healthy volunteers takes more than 15 minutes. Diazepam and lorazepam require even greater periods of time before awakening after an induction dose, precluding their use as anesthesia induction agents. (108-109)
48. The effects of benzodiazepines can be reversed by a specific antagonist drug, flumazenil. Flumazenil is a competitive antagonist that binds to the benzodiazepine receptor but has little intrinsic activity. Flumazenil should be titrated to effect by administering 0.2 mg intravenously every 60 seconds up to a total dose of 1 to 3 mg. Flumazenil binds tightly to the benzodiazepine receptor but is cleared rapidly from the plasma. This results in a short duration of action of only about 20 minutes. The short duration of action of flumazenil requires that the patient be closely monitored for resedation after a dose of flumazenil is administered to reverse the effects of a benzodiazepine. Alternatively, an infusion of flumazenil may be started and titrated to the desired effect to maintain a constant plasma level of this reversal agent. (109)
49. Propylene glycol is an organic solvent used to dissolve lipid soluble diazepam into solution. Propylene glycol is likely responsible for the unpredictable absorption of diazepam when administered intramuscularly. It is also responsible for the pain and possible subsequent thrombophlebitis experienced by patients on the intravenous injection of diazepam. (109)
50. Allergic reactions to benzodiazepines are extremely rare. (109)
Ketamine
51. Ketamine is a derivative of phencyclidine. The administration of ketamine produces unconsciousness and analgesia that is dose related. The exact mechanism by which ketamine exerts its effects is unknown. Ketamine occupies some μ-opioid receptors in the brain and spinal cord, which may partially explain its analgesic effects. Ketamine also binds to the NMDA receptor, which is believed to mediate the general anesthetic actions of ketamine. Other receptors that ketamine interacts with include monoaminergic receptors, muscarinic receptors, and calcium ion channels. Functionally, ketamine is believed to cause selective depression of the projections from the thalamus to the limbic system and cortex. The anesthesia derived from the administration of ketamine has thus been termed a dissociative anesthesia. There have not been any drugs isolated that are able to antagonize the effects of ketamine. (109-110, Figure 9-9)
52. After an induction dose of ketamine the patient appears to be in a cataleptic state. The appearance of the patient may be characterized as eyes remaining open with a slow nystagmic gaze; the maintenance of cough, swallow, and corneal reflexes; moderate dilation of the pupils; lacrimation; salivation; and an increase in skeletal muscle tone, with apparently coordinated but purposeless movements of the extremities. Induction doses of ketamine provide an intense analgesia and amnesia in patients despite the patient appearing as if he or she may be awake. (109)
53. The redistribution of highly lipid-soluble ketamine to inactive tissue sites allows for rapid awakening after the administration of a bolus of ketamine. Ketamine undergoes extensive hepatic metabolism to norketamine for its elimination. Norketamine has between 20% and 30% of the potency of ketamine and may contribute to some of the delayed effects of ketamine when administered as a continuous infusion. (110)
54. For the induction of anesthesia, the intravenous dose of ketamine is 1 to 2 mg/kg, whereas the intramuscular dose is 5 to 10 mg/kg. The induction of anesthesia after intravenous administration is achieved within 60 seconds. The induction of anesthesia after intramuscular administration is achieved within 2 to 4 minutes. Return of consciousness after an intravenous induction dose of ketamine usually requires 10 to 20 minutes, whereas full orientation may take 60 to 90 minutes. Ketamine may also be administered orally or rectally. (110-111)
55. The administration of ketamine results in an increase in systemic blood pressure, pulmonary artery blood pressure, heart rate, and cardiac output. The systemic blood pressure may increase by 20 to 40 mm Hg over the first 5 minutes after induction doses of ketamine are administered. The rise in blood pressure is often sustained for over 10 minutes. The degree of hemodynamic change elicited by the administration of ketamine is not influenced by the dose of ketamine that is administered, but it can be blunted by the prior administration of barbiturates, benzodiazepines, or opioids. These cardiovascular effects of ketamine are most likely mediated centrally through the activation of the sympathetic nervous system and the direct stimulation of sympathetic nervous system outflow. Endogenous norepinephrine release has been found to accompany the administration of ketamine. This property of ketamine may make it useful as an induction agent in hypovolemic patients in whom hemodynamic support is beneficial. Conversely, patients with a history of myocardial ischemia may be adversely affected by the increases in myocardial oxygen demand induced by the administration of ketamine, making ketamine a poor choice for an induction agent in this patient population. Of note, the cardiovascular stimulatory effects of ketamine may not be as pronounced and may even be absent in patients who are catecholamine depleted. In catecholamine-depleted patients, such as the trauma patient, the administration of ketamine may actually lead to myocardial depression and a decrease in systemic blood pressure. (110)
56. The administration of ketamine can result in a transient depression of ventilation, even apnea with large doses, but the resting PaCO2 is typically unaltered in these patients. Ketamine relaxes bronchial smooth muscle, resulting in bronchodilation. This effect of ketamine is most likely mediated by its sympathomimetic effects and may make it useful as an induction agent in patients with bronchial asthma. The administration of ketamine also induces an increase in airway secretions. When ketamine is used as an induction agent, the administration of an antisialagogue preoperatively may be useful in decreasing the amount of airway secretions. (110)
57. Ketamine preserves and may even increase skeletal muscle tone. Patients have varying degrees of purposeful skeletal muscle movement and hypertonus after an induction dose of ketamine. The preservation of skeletal muscle tone results in maintenance of a patent upper airway and the preservation of cough and swallow reflexes. Despite this, airway protection by these reflexes against regurgitation or vomiting cannot be assumed. (110)
58. Ketamine has excitatory effects on the central nervous system such that there are increases in cerebral metabolism, cerebral blood flow, intracranial pressure, and cerebral metabolic oxygen requirements associated with its administration. These excitatory effects of ketamine are reflected by the development of theta wave activity on the electroencephalogram when ketamine is administered. Because of the central nervous system excitatory effects of ketamine, it is not recommended as an induction agent in patients with space-occupying intracranial lesions or after head trauma in whom increases in the intracranial pressure can be detrimental. (110)
59. The emergence after the administration of ketamine has been associated with a delirium, often referred to as an emergence delirium. The severity of the emergence delirium varies. The emergence of delirium manifests as vivid dreaming, visual and auditory illusions, and a sense of floating outside the body. These sensations are often associated with confusion, excitement, and fear, and are unpleasant to the patient. The emergence of delirium typically occurs in the first hour after emergence and persists for 1 to 3 hours. The incidence of emergence delirium with ketamine administration has been estimated to be up to 30%, and it is more likely to occur when ketamine is used as the sole anesthetic agent. The risk of emergence delirium can be decreased with the preoperative or postinduction administration of benzodiazepines. (110)
60. Some common clinical uses of ketamine include its administration for the induction of anesthesia in hypovolemic patients, its intramuscular injection for the induction of anesthesia in children or in developmentally disabled patients who are difficult to manage, and for dressing changes and debridement procedures in burn patients. Small doses of ketamine may be titrated for its analgesic effects. (110-111)
61. The repeated administration of ketamine may result in the development of a tolerance to the analgesic effects of ketamine. Clinically, this would manifest as an increase in the dose of ketamine required with each subsequent anesthetic to provide sufficient analgesic effects. An example in which this situation may arise is in burn patients who are being administered ketamine while undergoing recurrent dressing changes. (110)
Etomidate
63. Etomidate is an imidazole derivative. The mechanism by which etomidate exerts its effects is not completely understood. It appears that etomidate acts in part through agonist effects at the GABA receptor. (111, Figure 9-10)
64. The induction dose of etomidate is 0.3 mg/kg. The administration of etomidate in induction doses results in unconsciousness in less than 30 seconds. The duration of action of etomidate after an induction dose is very short, owing to its rapid clearance from the plasma through redistribution to inactive tissue sites. (111)
65. Etomidate rapidly undergoes nearly complete ester hydrolysis to pharmacologically inactive metabolites by the liver, with less than 3% of the drug being excreted in the urine unchanged. (111)
66. Like thiopental and propofol, etomidate is highly lipid soluble, which allows it to quickly cross the blood-brain barrier to exert its effects. This accounts for the short effect-site equilibration time for these agents. The context-sensitive half-time of etomidate may be prolonged if repeated or continuous doses of the drug result in saturation of the inactive sites. It is less likely than thiopental to accumulate and have prolonged effects, however. (111, Figure 9-3)
67. The administration of etomidate provides cardiovascular stability in that induction doses of etomidate result in minimal changes in heart rate, mean arterial pressure, central venous pressure, stroke volume, or cardiac index. Minimal decreases in blood pressure may result from the administration of etomidate to hypovolemic patients. The cardiovascular stability associated with etomidate sets it apart from the other induction agents and is the basis for its usefulness as an induction agent in patients with limited cardiac reserve. When etomidate is administered to these patients, it is important to realize that it does not have any analgesic effects. Supplemental agents need to be administered in conjunction with etomidate to blunt the stimulatory effects of direct laryngoscopy. (111)
68. The administration of etomidate alone appears to result in less depressant effects on ventilation than propofol or thiopental. The effects of etomidate on ventilation may be augmented when administered in combination with other anesthetics or opioids. (111)
69. The administration of etomidate results in decreases in cerebral blood flow, intracranial pressure, and cerebral metabolic oxygen requirements. Etomidate has similar effects as barbiturates on the electroencephalogram as well, such that etomidate may be titrated to an isoelectric electroencephalogram to maximally decrease cerebral metabolic oxygen requirements. (111)
70. The administration of etomidate has been shown to increase the activity of seizure foci on an electroencephalogram. Etomidate is similar to methohexital in this regard. Its effects can be used intraoperatively to facilitate intraoperative mapping of seizure foci for surgical ablation. (111)
71. The administration of etomidate is associated with the suppression of adrenocortical function. The suppression of adrenocortical function may last for up to 4 to 8 hours after the induction dose of etomidate has been administered. The concern regarding this suppression of adrenocortical function is the potential for the adrenal cortex to be unresponsive to adrenocorticotropic hormone. Should the adrenal cortex be unresponsive to adrenocorticotropic hormone, desirable protective responses against the stresses that accompany the perioperative period may be prevented. No adverse outcomes have been shown to have occurred secondary to short-term adrenocortical suppression associated with the administration of etomidate, however. (111-112, Figure 9-11)
72. Potential negative effects associated with the administration of etomidate include pain during intravenous injection, superficial thrombophlebitis, involuntary myoclonic movements, and an increased incidence of postoperative nausea and vomiting. (111-112)
Dexmedetomidine
73. Dexmedetomidine, the active S-enantiomer of medetomidine, is an imidazole. It is also a selective α2-adrenergic agonist. (112)
74. Dexmedetomidine is a highly selective α2-adrenergic agonist and exerts its effects through activation of α2 receptors in the central nervous system. The analgesic effects originate at the level of the spinal cord, and its hypnotic effects likely originate through receptor sites in the locus ceruleus. (113)
75. Some common clinical uses for dexmedetomidine include infusion as an adjunct during general anesthesia in the operating room, sedation for procedures, sedation for airway management (i.e., fiber-poptic intubation), and sedation of intubated patients in the intensive care unit. (113)
76. When administered during general anesthesia, dexmedetomidine (0.5- to 1-μg/kg loading dose over a period of 10 to 15 minutes, followed by an infusion of 0.2 to 0.7 μg/kg/hr) decreases the dose requirements for inhaled and injected anesthetics. (113)
77. Dexmedetomidine infusion decreases systemic blood pressure by moderate decreases in heart rate and systemic vascular resistance. Bradycardia associated with dexmedetomidine infusion may sometimes require treatment. Severe bradycardia, heart block, and asystole have been described. A bolus injection may produce transient increases in systemic blood pressure and pronounced decreases in heart rate, an effect that is probably mediated through activation of peripheral α2-adrenergic receptors. (113)
78. Dexmedetomidine has only minor effects on the respiratory system when compared with other intravenous anesthetics. These effects include small decreases in tidal volume without much change in the respiratory rate. The ventilatory response to carbon dioxide is unchanged. Upper airway obstruction as a result of sedation is possible and may be augmented when dexmedetomidine is combined with other sedative-hypnotics. (113)
79. Dexmedetomidine likely leads to a decrease in cerebral blood flow without significant changes in intracranial pressure and cerebral metabolic oxygen requirements. (113)
