21 Nonopioid intravenous anesthetics
Intravenous anesthetics are grouped by primary pharmacologic action into nonopioid and opioid intravenous agents. The nonopioid agents are further grouped into the barbiturates, nonbarbiturates, and sedatives. These drugs can be injected in a rapid intravenous fashion for induction of anesthesia, or they can be used via continuous infusion pump for maintenance of anesthesia. Many of the nonopioid intravenous anesthetic drugs have stood the test of time. In fact, they are now being used more frequently in the postanesthesia care unit (PACU) because the less serious side effects than the opioid agents. Intravenous anesthetics have a wide range of use in the perioperative period. In current anesthesia practice, the use of intravenous 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 the halogenated inhalation anesthetics, other techniques have been sought for general anesthesia. Because of their safety factors coupled with ease of use, the nonopioid intravenous anesthetic agents have certainly found their place in the practice of anesthesia for enhancement of patient outcomes.
The nonopioid drugs appear to interact with gamma-aminobutyric acid (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. The barbiturates appear to bind to the GABA postsynaptic receptor, with the net result of hyperpolarization of the postsynaptic neuron and 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.1 The resultant action of these drugs is a loss of wakefulness.
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 pharmacologic actions on the benzodiazepine receptor are reversed, and neuronal activity resumes.
Intravenous anesthesia began with barbiturate anesthesia. The long-acting barbiturates were introduced clinically in 1927, but Tovell and Lundy did not begin to use thiopental in clinical anesthesia practice until 1934. Since then, barbiturate anesthesia had great popularity until the late 1990s; with the advent of propofol, thiopental is used in approximately 5% of the general anesthetics today.
Because of its historical significance, thiopental sodium (Pentothal) will be discussed in 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 intravenously 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: (1) for maintenance of light sleep during regional analgesia; (2) for control of convulsions; and (3) for 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 intravenous 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 was 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 is 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 to 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 intravenous 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 (Diprivan). Methohexital is approximately threefold more potent as thiopental, and the recovery time from anesthesia is extremely rapid (4 to 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 does thiopental. This drug can cause coughing and hiccups and, after injection, excitatory phenomena may appear, such as tremor and involuntary muscle movements.
Propofol (Diprivan) is a rapid-acting nonbarbiturate induction agent. It is administered intravenously as a 1% solution and is the most popular intravenous anesthetic in use. The dose for induction is 2 to 2.5 mg/kg.4 The dose should be reduced in elderly patients and in patients 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 minutes5; 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 in 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 intravenous induction of anesthesia, especially for outpatient surgery.7 The drug 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. Propofol can be used during surgery in a continuous intravenous infusion, and the patients still emerge from anesthesia in a rapid fashion 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 intravenous 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.
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 intravenous sedation. Propofol is contraindicated in patients who are sensitive to soybean oil, egg lecithin, or glycerol and is not recommended for PACU or intensive care unit (ICU) administration in children because of the possibility of emergence agitation.8
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 that were used during surgery, because propofol is so rapid and has no cumulative effects; its 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. It offers many advantages and few disadvantages. More specifically, propofol has one major advantage over all the other intravenous induction agents: early awakening. It can be used in the PACU if indicated. The major concern for the perianesthesia 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 of the patient who has received this drug.6
Etomidate (Amidate), which is a derivative of imidazole, is a short-acting intravenous hypnotic that was 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 therefore is 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.
Research has shown that etomidate inhibits steroid synthesis and that 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 intravenous infusion.1,5
The 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 the 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, a peak in action between 10 and 30 minutes, and a duration of action between 1 and 4 hours. Midazolam administered at a dose of 0.2 mg/kg produces a decrease in blood pressure, an increase in heart rate, and a reduction in systemic vascular resistance. Midazolam should be used with caution in patients with myocardial ischemia and in those with chronic obstructive pulmonary disease.9 Postoperative patients who have a substantial amount of hypovolemia should not receive 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 PACU11; therefore the postanesthesia 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. 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%.
Midazolam can be given via continuous infusion for patients who need sustained sedation.7 However, midazolam has a pH-dependent diazepine ring; at physiologic pH, the ring can close, causing 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.