Intravenous Anesthetic Agents

Intravenous Anesthetic Agents

General Anesthesia

 

General anesthesia is a state of drug-induced unconsciousness. Other components of general anesthesia include amnesia, analgesia, immobility, and attenuation of autonomic responses to noxious stimuli.²⁵ Drugs used to induce general anesthesia should produce unconsciousness rapidly and smoothly while minimizing any cardiovascular changes. Table 9-2 lists additional desirable, as well as undesirable, characteristics of an IV induction agent. Although currently available IV induction agents possess many of the desirable characteristics, no agent is free of the undesirable effects. An IV induction agent is commonly administered for initiation of general anesthesia. Drugs commonly used for IV induction include ultrashort-acting barbiturates (thiopental, methohexital), etomidate, and propofol. The synthetic opioids (fentanyl, sufentanil, alfentanil, and remifentanil), benzodiazepines (primarily midazolam), and ketamine are less frequently used. Propofol can also be used to maintain general anesthesia, as drugs that do not accumulate during repeat or continuous dosing are ideal choices for maintenance therapy. When used at dosages lower than those necessary for unconsciousness, some of the IV anesthetic agents can be used to produce sedation for monitored anesthesia care or regional anesthesia, as well as in the medical procedure units and intensive care units (ICUs). Table 9-3 lists common clinical uses for IV anesthetic agents.

 

Table 9-2 Characteristics of an Intravenous Induction Agent

Desirable Characteristics Undesirable Characteristics Water soluble Histamine release Stable in solution Hypersensitivity reaction Small volume required for dose Local toxicity at injection site Rapid, smooth onset of action Pain on injection Predictable effect High therapeutic index Analgesic Amnestic Short duration to awakening Rapid full recovery Availability of reversal agent Adverse central nervous system effects Adverse cardiovascular effects Active metabolites

Table 9-3 Common Clinical Uses of IV Anesthetic Agents

Etomidate (Amidate) Midazolam (Versed) IV induction Anxiolysis Ketamine (Ketalar)a Amnesia Analgesia Sedation Sedation Propofol (Diprivan)a IV induction Sedation IM induction IV induction Methohexital (Brevital)a Maintenance of general anesthesia IV induction Thiopental Sedation IV induction aDose-dependent effects; sedation at lower doses, anesthesia at higher doses. IV, intravenous; IM, intramuscular.

 

Mechanisms of Action

Most IV anesthetic agents produce CNS depression by action on the γ-aminobutyric acid (GABA) benzodiazepine chloride ion channel receptor. GABA is the principal inhibitory neurotransmitter in the CNS. The barbiturates bind to a receptor site on the GABA-receptor complex, reducing the rate of dissociation of GABA from its receptor. This results in increased chloride conductance through the ion channel, nerve cell hyperpolarization, and inhibition of nerve impulse transmission. Barbiturates can directly activate the chloride channels by mimicking the action of GABA. Benzodiazepines also bind to this GABA-receptor complex and their subsequent potentiation of the inhibitory action of GABA is well described. At large doses, most of the benzodiazepine receptors will be occupied, and hypnosis (unconsciousness) will occur. The site of action of etomidate (Amidate) and propofol (Diprivan) is also at the GABA receptor, with etomidate augmenting GABA-gated chloride currents and propofol enhancing the activity of the GABA-activated chloride channel. Ketamine (Ketalar) acts at a different site than other induction agents. It produces dissociation between the cortex and the thalamus within the limbic system, resulting in a dissociative state; that is, the patient appears to be detached from his or her surroundings. Unlike anesthesia produced by other agents (e.g., propofol for induction followed by sevoflurane/nitrous oxide/oxygen for maintenance) where the patient's eyes are closed resembling normal sleep, a ketamine-anesthetized patient's eyes are often open and move from side to side. Ketamine also produces analgesia and amnesia in patients.²⁶

 

Pharmacokinetics

The onset and duration of effect are the most important pharmacokinetic properties of IV anesthetic agents when used for induction of anesthesia. In general, the commonly used IV induction agents have a rapid onset of action and short clinical duration, with the short clinical duration resulting from redistribution of the drug from the brain to other tissue sites (e.g., muscle, fat). Using the barbiturates as an example, thiopental and methohexital undergo maximal brain uptake within 30 seconds of injection as a result of their high lipophilicity and high rate of blood flow to the brain. This is followed by a decline over the next 5 minutes to half of the initial peak brain concentration, predominately through drug redistribution. As a result, patients awaken in <10 minutes after a single induction dose of thiopental, despite a half-life of approximately 11 hours. Because cumulative effects can be seen after repeat or continuous dosing of barbiturates due to fat deposition and storage, these drugs make poor choices for maintenance of general anesthesia. The degree to which metabolism plays a role in the clinical duration of IV induction agents is variable; rapid metabolism can be a significant factor in the relatively shorter duration to full recovery of propofol.²⁶ Table 9-4 compares the pharmacokinetic properties of IV anesthetic agents.^26,27,28

Table 9-4 Pharmacokinetic Comparison of Common Intravenous Anesthetic Agents

Drug Half-Life (hours) Onset (seconds) Clinical Duration (minutes)a Hangover Effectb Etomidate (Amidate) 2–5 ≤30 3–12 + Ketamine (Ketalar) 1–3 30–60 10–20 ++ – +++c Methohexital (Brevital) 4 ≤30 5–10 + Midazolam (Versed) 1–4 30–90 10–20 +++d Propofol (Diprivan) 0.5–7 ≤45 5–10 0 – + Thiopental (Pentothal) 11 ≤30 5–10 ++ aTime from injection of agent to return to conscious state. bResidual psychomotor impairment after awakening. cWhen ketamine is administered as the induction agent (e.g., 5–10 mg/kg IM). dWhen midazolam is administered as the induction agent (e.g., 0.15 mg/kg IV). Adapted from references 26, 27, 28.

 

Adverse and Beneficial Effects

IV anesthetic agents can produce a variety of adverse and beneficial effects other than loss of consciousness (e.g., cardiovascular depression or stimulation, pain on injection, nausea and vomiting, respiratory depression or stimulation, CNS cerebroprotection or excitation, adrenocorticoid suppression). Table 9-5 compares the relative significance of these effects among available agents.^26,27,28 The most troublesome are usually cardiovascular effects or CNS excitation reactions. Contribution to postoperative nausea and vomiting (PONV) and “hangover” can be significant and may delay full recovery and patient discharge from the PACU. This is of particular concern in the ambulatory surgery setting because the patient will be discharged home. CNS effects can include hiccups, myoclonus, seizure activity, euphoria, hallucinations, and emergence delirium. The cerebroprotective effect produced by barbiturates, etomidate, and propofol results from a reduction in cerebral blood flow secondary to cerebral vasoconstriction. As a result, cerebral metabolic rate, cerebral blood flow, and intracranial pressure are reduced.^26,27,28 This effect is useful if these drugs are available in therapeutic concentrations at a time of potential cerebral ischemia. Thiopental, for example, has been given during deep hypothermic circulatory arrest to minimize the possibility of ischemic events.

Table 9-5 Adverse Effects and Costs of Intravenous Induction Agents

Adverse Effect Etomidate (Amidate) Ketamine (Ketalar) Methohexital (Brevital) Midazolam (Versed) Propofol (Diprivan) Thiopental (Pentothal) Adrenocorticoid suppression +a – – – – – Cerebral protection + – + + + + Cardiovascular depression – – ++ + ++ ++ Emergence delirium or euphoria – ++ – – + – Myoclonus +++ + ++ – + + Nausea/vomiting +++ ++ ++ + – ++ Pain on injection ++ – + – ++ + Respiratory depression ++ – ++ +/++ ++ ++ Relative cost ++ ++ +++ + + +++ aNot shown to be clinically significant in single dose. + to ++++, likelihood of adverse effect relative to other agents (or increasing cost for cost comparison); –, no effect. Adapted from references 26, 27, 28.

 

Agent Selection

The selection of an IV anesthetic agent should be determined based on patient characteristics, circumstances associated with surgery, and cost. Patient characteristics may include history of PONV, allergy profile, psychiatric history, or cardiovascular status. Circumstances associated with surgery that could influence the choice of IV anesthetic include the postoperative admission status (inpatient vs. outpatient), placement of an IV line, duration of surgery, and extubation status at the end of the procedure. The cost of induction agents varies, with older agents (e.g., thiopental, methohexital) priced higher per single induction dose than newer agents (e.g., etomidate, propofol).

 

Propofol Use in Ambulatory Surgery: Antiemetic Effect and Full Recovery Characteristics

4. K.T., a 19-year-old girl, ASA-I, is admitted to the ambulatory surgery center for strabismus surgery to correct misalignment of her extraocular muscles. She is otherwise healthy, and all laboratory values obtained before surgery are within normal limits. The duration of K.T.'s surgery is anticipated to be approximately 90 minutes. Which IV induction agent should be used?

 

Propofol (Diprivan) is a good choice here for several reasons. Strabismus surgery is considered highly emetogenic because operative manipulation of extraocular muscles triggers the release of dopamine, serotonin, and acetylcholine (Ach) in the chemoreceptor trigger zone (CTZ) through the oculoemetic reflex.²⁹ Therefore, precautions should be taken to reduce the possibility of nausea and vomiting postoperatively. Propofol produces the lowest incidence of PONV when compared with other IV induction agents and the volatile inhalation agents; it has even been associated with a direct antiemetic effect.³⁰ This effect does not preclude the need for prophylactic antiemetic therapy, but may contribute to the avoidance of emesis in K.T. Furthermore, ambulatory surgery demands rapid, full recovery from general anesthesia. Propofol, etomidate, and methohexital produce less of a hangover than other IV induction agents. Propofol, in particular, is associated with a more rapid recovery of psychomotor function and a patient-perceived superior quality of recovery.²⁸ Propofol also offers advantages for maintenance of anesthesia in this case, and it does not accumulate when administered as a continuous infusion.

 

Etomidate Use in Cardiovascular Disease

5. L.M., a 73-year-old man, ASA-IV, is in need of repair of an abdominal aortic aneurysm. During a preoperative evaluation a few days before surgery, his blood pressure (BP) was 160/102 mmHg, and his medical records revealed hypertension that was poorly controlled by hydrochlorothiazide 25 mg daily and metoprolol XL (Toprol) 100 mg daily. He also has angina that occasionally requires treatment with SL nitroglycerin. An exercise stress test showed electrocardiogram changes at a moderate exercise load. Two days before the elective aneurysm repair was scheduled, L.M. presented to the emergency department (ED) with a 4-hour history of severe back pain. His surgeon believes that there is a high likelihood that the aneurysm is leaking or expanding and schedules surgery immediately. What is the best plan for L.M.'s anesthetic induction and maintenance?

L.M. has significant cardiovascular disease, and care should be taken to minimize any cardiovascular depression, tachycardia, or hypertension during induction and maintenance of anesthesia. Of the currently available induction agents, etomidate has the most stable cardiovascular profile²⁸ and is associated with minimal cardiovascular depression. Opioids generally produce minimal cardiovascular effects and could potentially be used for induction. Thiopental, propofol, and ketamine can cause hemodynamic changes and are best avoided in L.M. Etomidate would be an excellent choice for induction, followed by isoflurane (with low-dose opioids) to maintain anesthesia. Although opioid-based anesthetics provide cardiovascular stability, the doses required to maintain anesthesia can prolong the duration of respiratory depression, which might necessitate postoperative mechanical ventilation.

 

Methohexital for Electroconvulsive Therapy

6. T.B., a 33-year-old woman, ASA-I, will undergo an electroconvulsive therapy (ECT) procedure for treatment of her severe, medication-resistant depression. T.B. is scheduled to go home within 1 to 2 hours after the procedure, which will be performed under general anesthesia. What IV induction agent should be used?

ECT procedures are an important method of treatment of severe and medication-resistant depression, mania, and other serious psychiatric conditions. During the ECT procedure, an electrical current is applied to the brain, resulting in an electroencephalographic (EEG) spike and wave activity, a generalized motor seizure, and acute cardiovascular response. For an optimal therapeutic (antidepressant) response, T.B.'s seizure activity should last from 25 to 50 seconds. General anesthesia is administered to ensure amnesia, prevent bodily injury from the seizure, and control the hemodynamic changes. When selecting an IV induction agent, its effect on EEG seizure activity, its ability to blunt the hemodynamic response to ECT, and its recovery profile (e.g., short time to discharge, nonemetogenic) are important considerations. Because most IV induction agents have anticonvulsant properties, small doses must be used to allow adequate seizure duration. Methohexital is considered the gold standard. Propofol, in smaller doses, can also be used. Combining a short-acting opioid such as remifentanil with propofol will allow a small dose of propofol to be used and the seizure duration to be prolonged. Although etomidate does not adversely affect the seizure duration, the hemodynamic response to ECT is accentuated because etomidate is cardiovascularly stable and cannot blunt the cardiovascular response to ECT. In addition, it can cause nausea and vomiting, resulting in delayed recovery. Midazolam reduces seizure activity, and ketamine increases the risk of delayed recovery by producing nausea and ataxia.^31,32 Therefore, methohexital, in a dose of 0.75 to 1 mg/kg IV, can be administered because it will not affect the seizure duration or prolong T.B.'s recovery time. Alternatively, a small dose of propofol (0.75 mg/kg) and remifentanil (up to 1 mcg/kg) are also appropriate.

 

Ketamine Use in Pediatrics

7. R.L., a 4-year-old boy, ASA-II, is scheduled for a painful debridement and dressing change that is anticipated to take approximately 15 minutes. He is brought to the procedure room near the OR along with his parents and is in distress over parting from them. He currently has no IV line in place. How could sedation and analgesia be provided to R.L.?

Ideally, analgesia should be provided without the need to start an IV and, for children with a high level of separation anxiety, in the presence of a parent. Although ketamine can be given intramuscularly, administration by this route is painful and not optimal. However, it might be preferable to starting an IV in R.L. for a short, painful procedure. At relatively low doses (3 or 4 mg/kg IM), ketamine produces analgesia and a compliant patient who is not heavily sedated. Intubation is unnecessary because ketamine causes little or no respiratory depression. Ketamine, however, can produce a dissociative stare and nystagmus, random movements of the head and extremities, and tonic/clonic movements. R.L.'s parents should be informed about these potential effects. An anticholinergic drug (e.g., glycopyrrolate) can be given along with ketamine to counteract its sialagogue effect. Ketamine use has expanded to EDs because of the quality of sedation and analgesia and the short duration of action (<30 minutes) associated with this drug. Appropriate guidelines for use of ketamine in this setting should be followed.³³

 

Delirium and hallucinations are unusual adverse effects of ketamine that occur in 10% to 30% of patients on awakening from anesthesia. Emergence reactions (e.g., dreaming, illusions, sense of floating out of body) vary in severity; occur within hours of awakening from anesthesia; and occur more often in adults, females, frequent dreamers, patients with personality disorders, and patients receiving high doses of ketamine (>2 mg/kg) by rapid IV administration. These reactions can be attenuated by prophylactic administration of benzodiazepines.^28,33 R.L. is at very low risk for an emergence reaction based on age, gender, dose, and route of ketamine administration; therefore, benzodiazepines are not needed in R.L.

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