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21: Nonopioid Intravenous Anesthetics
Cecil B. Drain; John M. Edwards, III
In current anesthesia practice, the use of intravenous (IV) nonopioid drugs is commonplace. IV anesthetics are grouped by primary pharmacologic action into nonopioid and opioid IV agents. The nonopioid agents are further grouped into barbiturates, nonbarbiturates, and sedatives. These drugs can be injected in a rapid IV manner for induction of anesthesia, or they can be used via continuous infusion pump for maintenance of anesthesia. Many of the nonopioid IV anesthetic drugs have stood the test of time. In fact, they are now being used more frequently in the postanesthesia care unit because they have less serious side effects than the opioid agents. The nonopioid IV anesthetic agents, because of their safety factors coupled with ease of use, have certainly found their place in the practice of anesthesia for enhancement of patient outcomes.
barbiturates; nonbarbiturates; nonopioid anesthetic agents; postanesthesia care unit; sedatives
Intravenous (IV) anesthetics are grouped by primary pharmacologic action into nonopioid and opioid IV agents. The nonopioid agents are further grouped into barbiturates, nonbarbiturates, and sedatives. These drugs can be injected in a rapid IV manner for induction of anesthesia, or they can be used via continuous infusion pump for maintenance of anesthesia. Many of the nonopioid IV anesthetic drugs have stood the test of time. In fact, they are now used more frequently in the postanesthesia care unit (PACU) because they have less serious side effects than the opioid agents. IV anesthetics have a wide range of use in the perioperative period. In current anesthesia practice, the use of IV drugs is commonplace. The time-tested use of the inhalation anesthetic agents has demonstrated that the agents possess some definite disadvantages. Because of the biotransformation hazards that have been reported with halogenated inhalation anesthetics, other techniques have been sought for general anesthesia. Because of their safety factors coupled with ease of use, the nonopioid IV anesthetic agents have certainly found their place in the practice of anesthesia for enhancement of patient outcomes.
Agonist A drug that has a specific receptor affinity that produces a predictable response.
Antagonist A drug that has the ability to block the effects of an agonist drug at the receptor site.
Anterograde Amnesia The inability to recall events that occur after the onset of amnesia.
Antianalgesic Administration of a drug that partially blocks the analgesic effects of other drugs that produce analgesia.
Antiemetic A drug that prevents or alleviates nausea and vomiting.
Cardiostimulatory Stimulation of the cardiovascular system.
Dissociative Anesthesia characterized by analgesia and amnesia without loss of respiratory function.
Esterases A chemical group that breaks down certain enzymes.
Extrapyramidal Effects of the structures outside the cerebrospinal pyramidal tracts of the brain associated with movement of the body.
Gamma-Aminobutyric Acid (GABA) An amino acid that functions as an inhibitory neurotransmitter in the brain and spinal cord.
Hypertriglyceridemia Type I hyperlipoproteinemia.
Neuroleptanalgesia A state of profound tranquilization with little or no depressant effect on the cortical centers.
Parenterally Treatment other than through the digestive system.
Resedation Sedation that recurs after clinical signs indicate that the sedation has ceased.
Retrograde Amnesia The inability to recall events that happened just before the onset of amnesia.
Sedatives Substances that have a calming effect.
Sympatholytic Antiadrenergic effects.
Sympathomimetic A pharmacologic agent that mimics the effects of stimulation of the sympathetic nervous system.
Thrombophlebitis Inflammation of a vein accompanied by the formation of a clot.
Torsades de Pointes (TdP) Potentially fatal heart arrhythmia.
Vagotonic Augmenting the parasympathetic activity by stimulating the vagus nerve.
Nonopioid drugs appear to interact with GABA in the brain. GABA is an inhibitory neurotransmitter, and activation of the GABA receptors by GABA on the postsynaptic membrane causes inhibition of the postsynaptic neuron. Barbiturates appear to bind to the GABA postsynaptic receptor with the net result of hyperpolarization of the postsynaptic neuron, inhibition of neuronal activity, and ultimately loss of consciousness. Conversely, etomidate (Amidate), which is a nonbarbiturate induction agent, probably antagonizes the muscarinic receptors in the central nervous system (CNS) and acts as an agonist to the opioid receptors, with the resultant action of these drugs being a loss of wakefulness.1
Sedatives, such as the benzodiazepines, bind to specific receptors in the limbic system. These benzodiazepine receptors use GABA as part of the neurotransmitter system. After the benzodiazepines have bound to the receptor, the action of GABA is enhanced, which leads to the hyperpolarized state and ultimately to inhibition of neuronal activity.2 The drug flumazenil is a specific benzodiazepine receptor antagonist. Consequently, after the administration of a benzodiazepine agonist, flumazenil can be administered. The resulting pharmacologic action of a benzodiazepine receptor antagonist on the benzodiazepine receptor is a reversal of the benzodiazepine agonist’s effects and neuronal activity resumes.
IV anesthesia began with barbiturate anesthesia. The long-acting barbiturates were introduced clinically in 1927, but thiopental in clinical anesthesia practice was not used until 1934. Barbiturate anesthesia had great popularity until the late 1990s; with the advent of propofol, thiopental is used in a very small percentage of the general anesthetics today.
Because of its historical significance, thiopental sodium (Pentothal) will be discussed at length. Today, this drug is rarely available in most hospitals and is used in rare instances. Probably the most profound explanation of why thiopental is not used is because of the excellent drug actions of propofol (Diprivan). Thiopental is most commonly injected IV to induce or sustain surgical anesthesia. It is usually used in conjunction with a potent inhalation anesthetic and nitrous oxide–oxygen combinations. The main reason for the use of other anesthetic agents with thiopental is that thiopental is a poor analgesic. For surgical procedures that are short and require minimal analgesia, thiopental and nitrous oxide–oxygen combinations can be used. This technique is commonly called the pent-nitrous technique. Thiopental is also used for (1) maintenance of light sleep during regional analgesia, (2) control of convulsions, and (3) rapidly quieting a patient who is too lightly anesthetized during a surgical procedure.
The mode of action of thiopental involves a phenomenon of redistribution. Thiopental has the ability to penetrate all tissues of the body without delay. Because the brain, as part of the vessel-rich group, is highly perfused, it receives approximately 10% of the administered IV dose within 40 seconds after injection. The patient usually becomes unconscious at this time. The thiopental then redistributes to relatively poorly perfused areas of the body. In the brain, the level of thiopental decreases to half its peak in 5 minutes and to one-tenth in 30 minutes. Recovery of consciousness usually occurs during this period. Recovery can be prolonged if the induction dose is excessive or if circulatory depression occurs to slow the redistribution phenomenon. Thiopental is metabolized in the body at a rate of 10% to 15% per hour.
Thiopental is a respiratory depressant.3 The chief effect is on the medullary and pontine respiratory centers. This depressant effect depends on the amount of thiopental administered, the rate at which it is injected, and the amount and type of premedication given to the patient. The response to carbon dioxide is depressed at all levels of anesthesia and abolished at deep levels of thiopental anesthesia; therefore, apnea can be an adverse outcome of high-dose thiopental.
Myocardial contractility is depressed and vascular resistance is increased after injection of thiopental. The result is that blood pressure is hardly affected, although it may be transiently reduced when the drug is first administered (when the vessel-rich group is highly saturated).
In addition to being nonexplosive, thiopental has the advantages of (1) rapid and pleasant induction, (2) reduction of postanesthetic excitement and vomiting, (3) quiet respiration, (4) absence of salivation, and (5) speedy recovery after small doses. The disadvantages of the drug are adverse respiratory actions including apnea, coughing, laryngospasm, and bronchospasm. Extravenous injection can result in tissue necrosis because of its highly alkaline pH (10.5–11).
Because thiopental can have an antianalgesic effect at low concentrations, some patients who have pain may be irrational, hyperactive, and restless during the initial recovery phase. The patient may exhibit some shivering related to lowered body temperature, which can result from a cold operating suite. Of concern to the perianesthesia nurse is the patient admitted with cold, clammy, and cyanotic skin. This effect occasionally occurs with thiopental and is caused, in part, by the peripheral vasoconstrictive action of the drug.
If the anesthesia time exceeds 1 hour or if the total dose of thiopental exceeds 1 g, patients may have a delayed awakening time because of the redistribution of thiopental. This phenomenon is particularly common in obese patients because the drug is highly fat soluble. At present, no antagonist exists for the barbiturates; therefore, airway management and monitoring of cardiovascular status are important.
Methohexital is an ultra–short-acting barbiturate IV anesthetic agent. It is usually indicated for short procedures in which rapid complete recovery of the patient is needed. Like thiopental, methohexital is rarely administered, primarily because of the excellent drug actions of propofol. Methohexital is approximately threefold more potent as thiopental, and the recovery time from anesthesia is extremely rapid (4–7 minutes) because the drug is redistributed from the CNS to the muscle and fat tissues, and a significant portion of the drug is metabolized in the liver.1 Consequently, the clearance of methohexital is approximately fourfold faster than that of thiopental. Methohexital causes about the same degree of cardiovascular and respiratory depression as thiopental. This drug can cause coughing and hiccups and, after injection, excitatory phenomena may appear such as tremor and involuntary muscle movements.
Propofol is a rapid-acting nonbarbiturate induction agent. It is administered IV as a 1% solution and is the most popular IV anesthetic in use. The dose for induction is 2 to 2.5 mg/kg.4 However, the dose should be reduced in elderly patients and those with cardiac disease or hypovolemia. In addition, propofol in combination with midazolam acts synergistically. In fact, the dose of propofol can be reduced by 50% when it is administered in combination with midazolam. When propofol is used as the sole induction agent, it is usually administered over 15 seconds and produces unconsciousness within approximately 30 seconds. Emergence from this drug is more rapid than emergence from thiopental or methohexital because propofol has a half-life of 2 to 9 minutes.5 Therefore, the duration of anesthesia after a single induction dose is 3 to 8 minutes, depending on the dose of the propofol. A major advantage of this drug is its ability to allow the patient a rapid return to consciousness with minimal residual CNS effects. Moreover, the drug’s low incidence rate of nausea and vomiting is of particular importance to perianesthesia nursing care. In fact, propofol may possess antiemetic properties.
Propofol decreases the cerebral perfusion pressure, cerebral blood flow, and intracranial pressure. It produces a reduction in the blood pressure similar in magnitude to or greater than thiopental in comparable doses. The decrease in blood pressure is also accompanied by a reduction in cardiac output or systemic vascular resistance. This reduction in blood pressure is more pronounced in elderly patients and patients with compromised left ventricular function. As opposed to the reduction in blood pressure, the pulse usually remains unchanged after the administration of propofol because of a sympatholytic or vagotonic effect of the drug. As a result, bradycardia can be assessed after injection of propofol in some patients. In this instance, an anticholinergic drug such as atropine or glycopyrrolate (Robinul) can be administered to reverse the bradycardia.
Propofol has a profound depressant effect on both the rate and depth of ventilation. In fact, after the induction dose is administered, apnea normally occurs. The incidence rate of apnea is greater after propofol than after thiopental and may approach 100%. Consequently, if propofol is administered in the PACU, the perianesthesia nurse should be prepared to support the patient’s ventilation and, if necessary, intubate the patient6 (see Chapter 30).
Clinically, this drug is useful for IV induction of anesthesia, especially for outpatient surgery.7 Propofol is also an excellent choice for procedures that require a short period of unconsciousness such as cardioversion and electroconvulsive therapy. In addition, propofol can be used for sedation during local standby procedures. This drug does not interfere with or alter the effects of succinylcholine because it has such a rapid plasma clearance. Costi et al.7 found that transition to propofol at the end of sevoflurane anesthesia reduced the incidence of emergence agitation in children and improved the quality of emergence. Propofol can be used during surgery in a continuous IV infusion, and the patients still emerge from anesthesia in a rapid manner without any CNS depression. This drug can be used in the PACU as a continuous infusion, and the level of sedation can be adjusted by titration to effect.6 The typical infusion rates for sedation with propofol are between 25 and 100 mcg/kg/min.
With administration within 12 hours of IV sedation, propofol is characterized by a more rapid recovery from its sedative effects than midazolam. When propofol is discontinued, extubation can be performed in a short time; propofol is cleared rapidly because of redistribution to fatty tissue and hepatic metabolism to inactive metabolites.8
Long-term or high-dose infusions can result in hypertriglyceridemia, which is usually associated with elevated levels of pancreatic enzymes and possibly with pancreatitis. After long infusions, plasma concentrations of propofol gradually increase unless the infusion rate is decreased over time. Current data seem to indicate that the recovery from propofol is less rapid after 12 hours of IV sedation. Propofol is contraindicated in patients sensitive to soybean oil, egg lecithin, or glycerol.7
When a patient has received propofol for induction or even via continuous infusion, the perianesthesia nursing care should be based mainly on the other drugs used during surgery. Because propofol is so rapid and has no cumulative effects, the pharmacologic effects are normally dissipated within 8 to 10 minutes. Consequently, the patient usually arrives in the PACU awake and in pain; therefore, analgesics should be titrated to effect. Titration is recommended in the immediate postoperative period because propofol and opioid analgesics can have a synergistic effect.
Propofol is a major component used in modern clinical anesthesia practice such as when the total intravenous anesthesia (TIVA) technique is used. It offers many advantages and few disadvantages. More specifically, propofol has one major advantage over all the other IV induction agents—early awakening. It can be used in the PACU if indicated. Consult individual state boards of nursing for any requirements regarding nursing management of the patient receiving propofol. The major concern for the postanesthesia care of the patient who has received this drug is the level of postoperative pain. The nursing assessment and appropriate interventions for pain are the most important aspects of care for the patient who has received this drug.6
Etomidate (Amidate), a derivative of imidazole, is a short-acting IV hypnotic synthesized in the 1960s by the laboratories of Janssen Pharmaceutica (Beerse, Belgium). It is not related chemically to the commonly used hypnotic agents. This drug is a mere hypnotic and does not possess any analgesic actions. Etomidate is safe for administration to patients because it has a high therapeutic index. Metabolism of this drug is accomplished by hydrolysis in the liver and by plasma esterases, with the final metabolite being pharmacologically inactive. The cardiovascular effects of etomidate are minimal; when the drug is injected in therapeutic doses, only a small blood pressure decrease and a slight heart rate increase may be observed. Etomidate causes a minimal reduction in the cardiac index and the peripheral resistance. This drug does not seem to produce arrhythmias, which is why etomidate is used in place of propofol as an induction agent for patients with cardiac dysfunction. Respiratory effects include a dose-related reduction in the tidal volume and respiratory frequency, which can lead to apnea.1 Laryngospasm, cough, and hiccups can occur during injection of this drug; however, the severity of these clinical phenomena can be reduced with an opiate premedication.
Although this drug causes some pain at the site of injection, it does not appear to cause a release of histamine. Spontaneous involuntary movements and tremor have been observed after the injection of etomidate. These involuntary movements can be reduced with an opiate premedication. Etomidate reduces both intracranial and intraocular pressure and is therefore considered safe for use in patients with intracranial pathologic conditions. This short-acting hypnotic is particularly well suited for the induction of neuroleptanalgesia and inhalation anesthesia. The induction dose ranges from 0.2 to 0.3 mg/kg, which produces sleep in 20 to 45 seconds after injection; the patient wakes within 7 to 15 minutes after induction.2
Research has shown that etomidate inhibits steroid synthesis, and patients who receive etomidate via continuous infusion have marked adrenocortical suppression for as long as 4 days.1 Even when etomidate is administered as a single dose, adrenal function is suppressed for 5 to 8 hours. Consequently, after the administration of etomidate, a decrease is seen in cortisol, 17-alpha-hydroxyprogesterone, aldosterone, and corticosterone levels. Therefore, etomidate is administered only to selected patients and is no longer administered via continuous IV infusion.1,5
Benzodiazepines, which are sedatives, have enhanced the anesthetic outcomes of the surgical patient. They depress the limbic system without causing cortical depression. More specifically, they interact with the inhibitory neurotransmitter GABA and thus result in reduced orientation (hypnotic effect), retrograde amnesia, anxiolysis, and relaxing of the skeletal muscle.1,2 Opiates and barbiturates enhance the hypnotic action of benzodiazepines.
Midazolam has become a popular drug in anesthesia practice and in the perianesthesia care of surgical patients. Midazolam can be used for premedication, cardioversion, endoscopic procedures, and induction of anesthesia and as an intraoperative adjunct for inhalation anesthesia. It also is an excellent agent for sedation during regional anesthetic techniques. The principal action of midazolam is on the benzodiazepine receptors in the CNS, particularly on the limbic system, which results in a reduction in anxiety and profound anterograde amnesia. This drug also has excellent hypnotic, anticonvulsant, and muscle relaxant properties.
The water-soluble midazolam may offer some advantages over diazepam. It causes depression of the CNS by inducing sedation, drowsiness, and finally sleep with increasing doses. Midazolam is three to four times as potent as diazepam, has a shorter duration of action, and has a lesser incidence rate of injection pain and postinjection phlebitis and thrombosis. More specifically, this drug has a rapid onset of action, peak in action between 10 and 30 minutes, and duration of action between 1 and 4 hours. Midazolam administered at a dose of 0.2 mg/kg produces a decrease in blood pressure, increase in heart rate, and reduction in systemic vascular resistance. Midazolam should be used with caution in patients with myocardial ischemia and those with chronic obstructive pulmonary disease.9 Postoperative patients who have a substantial amount of hypovolemia should be not administered midazolam. In addition, midazolam does not affect intracranial pressure.4,10 Consequently, this drug can be used safely in neurosurgical patients in addition to patients with intracranial pathophysiology.
This drug can be administered in the PACU; therefore, the perianesthesia nurse must monitor the patient for respiratory depression after injection because midazolam causes a dose-dependent respiratory depression. Given that every patient in the PACU has received a plethora of depressant drugs during surgery, midazolam can be potentiated easily when administered in the PACU. Because of this potentiation factor, any dose of midazolam administered in the PACU should be considered effective enough to cause profound respiratory depression. Therefore, oxygen and resuscitative equipment must be immediately available, and a person skilled in maintaining a patent airway and supporting ventilation should be present.11 Extra care also should be observed in patients with limited pulmonary reserve and in the elderly and debilitated with reduction of the dosage of midazolam by 25% to 30%.2
Midazolam can be given via continuous infusion for patients who need sustained sedation.8 However, midazolam has a pH-dependent diazepine ring; at physiologic pH, the ring can close and cause CNS penetration. In addition, its metabolites are partially active, all of which make midazolam not the drug of choice for long-term sedation. Midazolam is sometimes used in the treatment of critically ill patients who are agitated. The guidelines for use can be found in Box 21.1.
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