Version July 2025
INTRODUCTION —
General anesthesia establishes a reversible state that includes:
●Hypnosis
●Amnesia
●Analgesia
●Akinesia
●Autonomic and sensory block
The goals for induction of general anesthesia are to rapidly, safely, and pleasantly produce these conditions while maintaining adequate oxygenation, ventilation, and hemodynamic stability. This topic provides an overview of anesthetic induction agents and techniques. Recommendations for specific types of surgical procedures and for patients with specific comorbidities are discussed in individual topics.
Intravenous (IV) agents commonly used to induce general anesthesia include propofol, etomidate, and ketamine (table 1), while adjuvant agents (eg, opioids, lidocaine, midazolam, and volatile anesthetics) are often used to supplement the effects of the primary sedative-hypnotic induction agent (table 2). This topic discusses advantages and beneficial effects, disadvantages and adverse effects, pharmacokinetics, dosing considerations, and typical uses of each of the sedative-hypnotic and adjuvant agents used to induce general anesthesia.
Inhalation anesthetics used during induction of general anesthesia are reviewed in separate topics. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Induction of general anesthesia' and "Inhalation anesthetic agents: Properties and delivery".)
Neuromuscular blocking agents are often used during induction of anesthesia, as discussed in a separate topic. (See "Clinical use of neuromuscular blocking agents in anesthesia".)
Airway management techniques used during induction of general anesthesia (eg, preoxygenation, airway management) are reviewed separately:
●(See "Preoxygenation and apneic oxygenation for airway management for anesthesia".)
●(See "Airway management for general anesthesia in adults".)
●(See "Rapid sequence induction and intubation (RSII) for anesthesia".)
●(See "Management of the anatomically difficult airway for general anesthesia in adults".)
SELECTION OF INDUCTION TECHNIQUE —
Induction of general anesthesia may be accomplished using primarily intravenous (IV) or primarily inhalation anesthetic agents.
Intravenous induction technique — Adult patients usually have IV access and typically prefer induction with IV anesthetic agents rather than an inhalation induction technique because:
●Unpleasant odor of anesthetic gases [1] - (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Induction of general anesthesia'.)
●Higher incidence of postoperative nausea and vomiting compared with use of IV agents such as propofol [1-3] - (See "Postoperative nausea and vomiting", section on 'Anesthetic factors'.)
●Longer induction time compared with IV induction. Several minutes of ventilation may be required. Thus, this technique is unsuitable for rapid sequence induction and intubation (RSI). (See "Rapid sequence induction and intubation (RSII) for anesthesia".)
Inhalation induction technique — An inhalation induction technique is often selected for younger pediatric patients or those with developmental delay to avoid fear of needles and responses to the pain of a needle stick [4]. Inhalation induction may also be the preferred method for adult patients when [5]:
●Maintenance of spontaneous ventilation is desirable during induction. Examples include patients with intraoral, pharyngeal, or mediastinal mass causing compression of the airway if an awake intubation technique is not feasible. (See "Anesthesia for patients with an anterior mediastinal mass", section on 'Airway management during induction'.)
●An in situ tracheostomy is present since unpleasant odor and irritation of the airway are not problematic.
●Intravenous (IV) access is difficult to obtain. However, IV access should be established immediately after induction so that common problems such as hypotension during induction can be treated.
Combinations of intravenous and inhalation agents — The ideal induction agent has a rapid onset of action, minimal cardiopulmonary or other side effects, and is cleared from the bloodstream quickly so that recovery is rapid. However, none of the available induction agents is ideal for all patients, and all have side effects. We typically administer combinations of agents from different pharmacologic classes during induction and/or maintenance of general anesthesia. This strategy minimizes the total dose of any one anesthetic agent, thereby reducing the incidence of undesirable side effects. Age and coexisting diseases affect selection and dosing of anesthetic induction and adjuvant agents. (See 'General considerations for dosing' below and "Inhalation anesthetic agents: Clinical effects and uses", section on 'Influence of patient-related factors'.)
One or more adjuvant intravenous (IV) agents are often administered during induction of general anesthesia to blunt the sympathetic stress response and cough reflex during laryngoscopy and intubation, minimize pain due to injection of irritating induction agents, and reduce the primary sedative-hypnotic dose. (See 'Adjuvant agents' below.)
An inhalation anesthetic agent, typically sevoflurane, is often added shortly after initial loss of consciousness is achieved using IV agents. Administration of inhalation anesthetic(s) deepens anesthesia and blunts airway reflexes and sympathetic stress responses during laryngoscopy. Potent volatile inhalation agents also induce a dose-dependent decrease in skeletal muscle tone, which improves conditions during insertion of either an endotracheal tube or supraglottic airway. However, concentrations of inhalation agents >1 MAC are avoided when combined with IV agents to minimize risk of hypotension. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Use as a supplement (all inhalation agents)'.)
Also, since a high fresh gas flow (FGF) rate (≥8 L/min) is used during mask ventilation, addition of an inhalation anesthetic generates high environmental emissions, as explained in a separate topic. (See "Environmental impact of perioperative care", section on 'Managing use of anesthetic inhalation agents'.)
GENERAL CONSIDERATIONS FOR DOSING —
All available sedative-hypnotic IV induction agents (eg, propofol, etomidate, ketamine, methohexital (table 1)) are capable of achieving adequate depth of general anesthesia. After IV injection, these induction agents have rapid onset due to their high lipid solubility allowing penetration of the blood-brain barrier, and the high proportion of the cardiac output (CO) that perfuses the brain (the effect site).
Typically, one or more adjuvant medications are also administered to achieve the desired initial depth of anesthesia and induction conditions (table 2 and table 3) [6]. (See 'Adjuvant agents' below.)
●Estimating dose – Fixed dosing regimens are not recommended. Initial doses of IV sedative-hypnotic and adjuvant agents are individualized. Factors affecting dosing include:
•Body weight – dosing is based on adjusted body weight, particularly in patients with obesity (table 4). (See "Anesthesia for the patient with obesity", section on 'Dosing anesthetic drugs'.)
•Known adverse effects (eg, hypotension, respiratory depression) of the induction agent.
•Individual patient variations in pharmacodynamics (ie, what the drug does to the patient) and pharmacokinetics (ie, what the patient does to the drug). For example, induction doses are reduced in patients with:
-Hemodynamic abnormalities due to hypovolemia, vasodilation, or myocardial dysfunction
-Impaired renal or hepatic function
-Advanced age and/or frailty (see "Anesthesia for the older adult", section on 'Selection and dosing of anesthetic agents')
-Compromised mental status (dementia, intoxication, metabolic derangements)
•Whether adjuvant drugs are coadministered – When agents from different classes are combined, the hypnotic effects are often synergistic rather than merely additive. For example, opioids allow dose reduction of the selected sedative-hypnotic agent. (See 'Adjuvant agents' below.)
•Whether a combination of sedative-hypnotic induction agents is used – We do not use combinations of sedative-hypnotic agents in our practice. Some clinicians do combine propofol with either ketamine or etomidate in an attempt to mitigate the hypotensive effects of propofol. However, evidence for advantages of such combinations is limited. One study in healthy patients (ASA physical status 1 or 2) found that a combination of propofol and ketamine improved hemodynamic stability [7]. A separate study by these investigators did not find any benefit of this combination in critically ill patients [8].
Also, the optimal dosing regimen for each component of the combination (ie, propofol and ketamine or etomidate) is unclear. There is significant heterogeneity among studies in dosing for each agent (eg, propofol, ketamine, etomidate), as well as whether an opioid or other adjunct agent was used during induction. Also, the influence of such combinations on adverse effects of the other sedative-hypnotic agent was not evaluated in most studies (eg, ketamine [psychotomimetic effects] or etomidate [adrenocortical suppression]).
●Titrating doses – Drug doses are typically titrated in increments, with a brief time between doses (eg, 30 seconds), unless a rapid sequence induction and intubation technique is selected. The following general principles are useful:
•Continually assess the state of consciousness (eg, responses to voice or tactile stimulation such as the lash reflex or placement of an oral airway) as well as heart rate (HR) and blood pressure (BP). While the time interval to maximum hypnotic effect is often longer than the titration interval, the onset of sedative/hypnotic effects is noticeable well before the peak effect. This should help avoid overdosing of the sedative-hypnotic.
•Although some clinicians attempt to use processed electroencephalogram (EEG) monitoring to assess anesthetic depth (eg, bispectral index [BIS] or entropy signal changes), there is a lag time of at least 30 seconds required for EEG signal processing. This lag between the patient's current state of consciousness and the displayed EEG value limits utility of this monitor during induction [9].
•Induction agents are administered at predetermined dosing during rapid sequence induction and intubation, rather than titrating the agents to effect. Reasonable doses of the selected agents are based on the patient's condition and planned coadministration of one or more adjuvant agents. If necessary, additional doses of the induction anesthetic, adjuvant agents, or vasoactive agents can be administered to treat hemodynamic aberrations immediately after successful intubation. (See 'Opioids' below.)
PROPOFOL —
Propofol is the most commonly used IV induction agent (table 1). Its primary mechanism of action is activation of the gamma-aminobutyric acidA (GABAA) receptor complex, the chief inhibitory neurotransmitter of the central nervous system. Propofol is also an antagonist of the N-methyl-D-aspartate (NMDA) receptor.
Advantages and beneficial effects — Advantages of propofol include (table 1):
●Rapid onset (30 to 45 seconds) and rapid recovery. The dose-dependent effect of propofol on pupillary diameter correlates with bispectral index (BIS) values [10].
●Antiemetic properties. Propofol is a good choice for patients at increased risk for postoperative nausea and vomiting [11]. (See "Postoperative nausea and vomiting".)
●Antipruritic properties. Propofol is a good choice for patients who will receive opioids, which often cause pruritus.
●Upper airway and bronchodilatory properties with decreased airway resistance [12-14]. Propofol is useful for induction in patients with bronchospasm and asthma [13,15]. (See "Anesthesia for adult patients with asthma", section on 'Anesthetic agents'.)
●Central nervous system effects that may be advantageous in patients with brain injury including (see "Anesthesia for patients with acute traumatic brain injury", section on 'Choice of anesthetic agents' and "Anesthesia for intracranial neurovascular procedures in adults"):
•Propofol has both proconvulsant and anticonvulsant properties [16], but has been used to effectively treat status epilepticus [14].
•Dose-dependent decreases in cerebral metabolic rate of oxygen consumption and consequent reduction in cerebral blood flow and intracranial pressure (ICP) are beneficial if mean arterial pressure and cerebral perfusion pressure are maintained [17].
●Suitability for patients with renal and/or hepatic insufficiency [18-24]. (See "Anesthesia for dialysis patients", section on 'Induction' and "Anesthesia for the patient with liver disease", section on 'Sedative hypnotics'.)
Disadvantages and adverse effects — Potential adverse effects of propofol include (table 1):
●Dose-dependent hypotension. This is due primarily to venous and arterial dilation, as well as decreased contractility [25-30]. Heart rate (HR) is minimally affected because the baroreceptor reflex is blunted. However, systolic blood pressure (BP) decreases to <90 mmHg in 16 percent of patients [27]. Severe hypotension may occur in patients who are hypovolemic or hemodynamically compromised, as well as in older patients [25]. (See 'Dosing' below.)
●Dose-dependent respiratory depression (decreases in respiratory rate, tidal volume, and ventilatory responses to hypoxia and hypercarbia) and apnea.
●Pain on injection occurring in approximately two-thirds of patients due to venous irritation caused by propofol itself rather than its lipid emulsion [31]. Propofol is typically coadministered with lidocaine and/or an opioid to minimize pain on injection [31-33] (see 'Lidocaine' below and 'Opioids' below). Also, administration into a larger vein may decrease discomfort.
●Contamination risk. Despite the addition of antimicrobials, propofol preparations support rapid bacterial growth due to the lipid emulsion containing egg lecithin, glycerol, and soybean oil. Fever, infection, sepsis, and death have been reported [34]. Risk is minimized by:
•Using an aseptic technique in drug preparation
•Avoiding multidose use from a single vial for more than one patient
•Discarding opened propofol after six hours
●Rare allergic reactions [35]. (See "Management of food allergy: Avoidance", section on 'Lipid emulsions' and "Perioperative anaphylaxis: Allergy evaluation and prevention of recurrent reactions".)
Drug-drug interactions — Coadministration of one or more adjuvant anesthetic agents acting on other receptor types, including opioids, benzodiazepines, and volatile anesthetics, may produce synergistic anesthetic effects as well as increase the potential for adverse effects (eg, hypotension). Thus, reduction of the propofol dose is prudent [6,36]. (See 'Adjuvant agents' below and 'Dosing' below.)
Pharmacokinetics — Propofol is highly lipid soluble with formulation in an aqueous emulsion containing egg phosphatide, soybean oil, and glycerol. Its onset of action is very rapid due to high lipid-solubility. The half-life of equilibration between plasma and effect site (the brain) is 1.5 to 2.6 minutes [37]. Duration of action is short (two to eight minutes), as propofol is rapidly redistributed from the brain into a very large volume of distribution in other tissues (3 to 12 L/kg) [38].
Most of the drug is conjugated in the liver and the resulting inactive metabolites are eliminated by the kidneys. Clearance of propofol is very rapid (20 to 30 mL/kg/minute), in excess of liver blood flow, suggesting extrahepatic metabolism [18]. Although propofol has a long terminal elimination half-life of 4 to 30 hours, actual plasma concentrations remain low throughout this time period after administration of a typical induction dose [39,40].
Dosing — The induction dose of propofol for general anesthesia is 1 to 2.5 mg/kg (table 1) [41].
Dose-dependent hypotension is avoided by reducing the initial dose and titrating propofol in increments, particularly in the following circumstances:
●Age >65 years (suggested dose is 1 to 1.5 mg/kg). Dose reduction is prudent due to changes in pharmacodynamics, as well as changes in clearance and central volume of distribution [42]. (See "Anesthesia for the older adult", section on 'Intravenous anesthetic and adjuvant agents'.)
●Hypovolemia (eg, sepsis, hemorrhage) or myocardial dysfunction (suggested dose is ≤1 mg/kg) [25,42].
●Coadministration of one or more adjuvant anesthetic agents acting on other receptor types because of synergistic effects [6,36].
ETOMIDATE —
Etomidate is often selected for anesthetic induction in hemodynamically unstable patients because it causes minimal hemodynamic changes (table 1) [43]. It is an imidazole derivative that acts directly on the gamma-aminobutyric acidA (GABAA) receptor complex to block neuroexcitation and produce anesthesia.
Advantages and beneficial effects — Advantages of etomidate include (table 1):
●Superior hemodynamic stability without vasodilation, myocardial depression, or decreases in sympathetic tone [44]. Blood pressure (BP), heart rate (HR), and cardiac output (CO) typically remain stable, but may increase if airway manipulation or pain causes sympathetic stimulation.
●The most favorable therapeutic index (ratio of median lethal dose [LD50] to median effective dose [EC50]) compared with other anesthetic induction agents [44].
●Rapid onset and recovery, similar to propofol.
●Central nervous system effects that may be advantageous, particularly in hemodynamically unstable patients with head injury or stroke, including dose-dependent decreases in cerebral metabolic rate of oxygen consumption and consequent reduction in cerebral blood flow and intracranial pressure (ICP) [14,16]. These effects are beneficial if mean arterial pressure and cerebral perfusion pressure are adequately maintained. (See "Anesthesia for patients with acute traumatic brain injury", section on 'Choice of anesthetic agents' and "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Head injury or stroke'.)
Disadvantages and adverse effects — Potential adverse effects of etomidate include (table 1):
●High incidence (approximately 30 percent) of postoperative nausea and vomiting [45,46].
●Pain on injection occurring in up to 80 percent of patients, although typically less painful than propofol injection [45,47]. This is caused by venous irritation due to the low pH (6.9) of the 35 percent propylene glycol used in etomidate formulations [47]. Pain is minimized or eliminated when etomidate is injected into a larger or central vein. Also, coadministration of lidocaine or an opioid may reduce pain, although these adjuvant agents are typically omitted in hemodynamically unstable patients. (See 'Lidocaine' below and 'Opioids' below.)
●Dose-related involuntary myoclonic movements, occurring in 50 to 80 percent of patients if etomidate is administered without any neuromuscular blocking agent [45,48-51]. These jerking movements are due to subcortical disinhibition unrelated to cortical seizure activity [47]. Although coadministration of an opioid or benzodiazepine can attenuate myoclonus, these adjuvant agents are typically omitted in hemodynamically unstable patients [48-51]. (See 'Opioids' below and 'Midazolam' below.)
●Mild increases in airway resistance [12].
●Transient acute adrenal insufficiency. Following a single induction dose of etomidate, reversible inhibition of 11-beta-hydroxylase (which converts 11-deoxycortisol to cortisol) causes adrenocortical suppression lasting <24 hours in both healthy and critically ill patients [52-61]. Cortisol plasma concentrations do not necessarily fall below the normal range, but may not appropriately rise in response to surgical stimulation after etomidate administration [59,60]. Although the clinical significance of this transient inhibition of cortisol biosynthesis is uncertain, the preponderance of evidence suggests that etomidate is not harmful if used as a single dose to induce anesthesia in relatively healthy patients.
However, in patients with suspected adrenal insufficiency (eg, those receiving chronic glucocorticoid therapy) but without evidence of septic shock, the risk of further cortisol suppression caused by etomidate is balanced against risk of hemodynamic instability caused by induction with other agents. Notably, we do not administer multiple bolus doses or infusions of etomidate.
Studies in specific settings include the following:
•Noncardiac surgery – A retrospective study in patients undergoing noncardiac surgery reported a higher 30-day mortality in 2144 patients receiving etomidate for induction compared with 5233 propensity-matched patients receiving propofol (odds ratio [OR] 2.5, 98% CI 1.9-3.4) [62]. Important confounding covariates in this study include frequent selection of etomidate for induction in patients who are critically ill.
•Cardiac surgery – Retrospective studies in patients undergoing cardiac surgery have not noted increased mortality after use of etomidate for anesthetic induction compared with other induction agents [63,64]. Similarly, a prospective study in patients undergoing coronary artery bypass grafting noted no differences in mortality, perioperative vasopressor requirements, time to extubation, or length of intensive care unit stay after use of etomidate compared with propofol for induction [56].
•Endotracheal intubation in critically ill patients – In a 2024 observational study that included 1,689,945 critically ill patients, nearly half (738,855) received etomidate for endotracheal intubation to establish mechanical ventilation [65]. The investigators established 22,273 matched pairs who received either etomidate or ketamine. Patients receiving etomidate had a higher mortality compared with those who received ketamine (21.6 versus 18.7 percent; adjusted OR 1.28, 95% CI 1.21-1.34), a finding that was independent of subsequent treatment with corticosteroids. Similarly, a 2023 meta-analysis that included 11 trials with 2704 critically ill patients noted that use of etomidate for induction was associated with increased mortality (319/1359 [23 percent] versus 267/1345 [20 percent]; risk ratio [RR] 1.16. 95% CI 1.01-1.33) [66]. A 2015 meta-analysis that included 16 observational studies and two randomized trials in 5552 critically ill patients diagnosed with sepsis noted that a single dose of etomidate did not increase mortality compared with those not receiving etomidate [67]. Thus, for critically ill patients, we usually select ketamine rather than etomidate. (See "Intraoperative management of shock in adults", section on 'Induction'.)
Furthermore, if etomidate is used in a septic patient who subsequently develops refractory hypotension, we administer a stress dose of a glucocorticoid (eg, IV hydrocortisone 100 mg or dexamethasone 4 mg). However, we do not administer prophylactic glucocorticoids to most patients. In one retrospective study that included 582 patients who received intraoperative steroids after anesthetic induction with etomidate (typically dexamethasone at a median dose of 6 mg), mortality was not different from that of 1023 propensity-matched patients who received etomidate but no steroids [68]. (See "Corticosteroid therapy for refractory septic shock in adults".)
Drug-drug interactions — Coadministration of one or more adjuvant anesthetic agents acting on other receptor types (eg, opioids, benzodiazepines, volatile anesthetics) may produce synergistic anesthetic effects [6]. (See 'Adjuvant agents' below and 'Dosing' below.)
Pharmacokinetics — Etomidate has a rapid onset, similar to propofol [69]. The half-life of equilibration between plasma and effect site (the brain) is 1.6 minutes [70]. Duration of action is short (3 to 12 minutes) due to rapid redistribution from the brain to other tissues. The volume of distribution is 2.5 to 4.5 L/kg [69-71].
The main route of metabolism is ester hydrolysis in the liver resulting in pharmacologically inactive metabolites. Clearance of etomidate is high (18 to 25 mL/kg/minute). Terminal elimination half-life is three to five hours.
Dosing — The induction dose of etomidate for general anesthesia is 0.15 to 0.3 mg/kg (table 1) [72]. To minimize inhibition of cortisol biosynthesis, repeated bolus doses of etomidate are usually avoided. (See 'Disadvantages and adverse effects' above.)
Although the dose of etomidate is not typically adjusted to avoid hemodynamic side effects, it is prudent to reduce the initial dose to 0.1 to 0.15 mg/kg in patients with hemodynamic instability, particularly in those with severe hypotension or shock. Also, dose may also be adjusted if adjuvant anesthetic agents are administered during induction [6]. (See "Intraoperative management of shock in adults", section on 'Induction' and 'Adjuvant agents' below.)
KETAMINE —
Ketamine may be selected to induce anesthesia in a hypotensive patient as it typically increases blood pressure (BP), heart rate (HR), and cardiac output (CO) by increasing sympathetic tone (table 1) [73-75]. The primary mechanism of action is noncompetitive antagonism of glutamate at the N-methyl-D-aspartate (NMDA) receptor-cation channel complex, causing neuroinhibition and anesthesia [76]. Also, ketamine excites opioid receptors within the insular cortex, putamen, and thalamus, thereby producing analgesia.
Unlike other anesthetic induction agents, ketamine is structurally similar to phencyclidine and produces dissociative anesthesia (profound analgesia while appearing disconnected from surroundings) [77]. The term "dissociative," is also used to describe the electroencephalographic (EEG) effects of ketamine because EEG activity in the hippocampus is dissociated from that in the thalamo-neocortical system. An association between the dissociative and analgesic effects of ketamine is likely [78].
Advantages and beneficial effects — Advantages of ketamine include (table 1) [79]:
●Increases in BP, HR, and CO in most patients due to increased sympathetic tone [73-75], and reduced vasodilation due to inhibition of production of vascular nitric oxide [80]. However, these increases in BP and CO do not occur if presynaptic catecholamine stores have been depleted.
●Bronchodilatory properties. Thus, ketamine is useful in patients with bronchospasm and/or asthma, particularly if emergency intubation for severe bronchospasm is necessary [81-85]. (See "Anesthesia for adult patients with asthma", section on 'Anesthetic agents'.)
●Maintenance of airway reflexes and respiratory drive. Thus, ketamine is useful when maintenance of spontaneous respiration is desirable [74,86].
●Profound analgesic properties, even in sub-hypnotic doses. Thus, administration of an opioid adjuvant agent is unnecessary during anesthetic induction (see 'Opioids' below). Also, intraoperative administration of ketamine reduces postoperative opioid consumption in patients with chronic pain, opioid tolerance, or hyperalgesia [87-90]. (See "Nonopioid pharmacotherapy for acute pain in adults", section on 'Ketamine'.)
●Suitability for patients with renal and/or hepatic insufficiency without dose adjustments. (See 'Dosing' below.)
●Rapid onset and recovery after IV administration, similar to propofol.
●Alternative routes of administration when necessary. Intramuscular (IM) injection is used in rare cases when IV access is impractical or inadvertently lost during induction (eg, in a severely agitated patient). Oral or rectal administration is also feasible for children.
Disadvantages and adverse effects — Ketamine has the following potential adverse effects (table 1) [79]:
●Cardiovascular effects
•Although ketamine's unique ability to stimulate catecholamine receptors may be beneficial in hypotensive patients, the resulting increases in BP, HR, contractility, and pulmonary arterial pressure (PAP) may be detrimental in selected patient groups [91-93]:
-Ischemic heart disease due to potential for imbalance between myocardial oxygen supply and demand [94]. (See "Anesthesia for noncardiac surgery in patients with ischemic heart disease", section on 'Induction'.)
-Hypertension due to further undesirable increases in BP. (See "Anesthesia for patients with hypertension".)
-Pulmonary hypertension or right heart dysfunction due to further increases in PAP. (See "Anesthesia for noncardiac surgery in patients with pulmonary hypertension or right heart failure", section on 'Induction and maintenance of general anesthesia'.)
-Cocaine use (known or suspected), as ketamine may potentiate the cardiovascular toxicity of cocaine leading to myocardial ischemia, arrhythmias, and pulmonary hypertension [95].
-Acute hemorrhage especially intracranial hemorrhage where a further rise in blood pressure could increase ICP or cause more rapid blood loss.
•Intrinsic mild myocardial depressant properties that are normally overcome by increased sympathetic tone, but may become apparent if catecholamine reserves are depleted (eg, patients with shock due to severe sepsis, hypovolemia, or cardiogenic causes; patients chronically using cocaine) [96]. Since myocardial depressant effects are dose-related, induction doses are reduced in any patient with profound hypotension (mean arterial pressure <50 mmHg) or shock. (See 'Dosing' below.)
●Neurologic effects
•Psychotomimetic effects that include hallucinations, nightmares, and vivid dreams occurring during and shortly after emergence from anesthesia [97-99]. Prior administration of a benzodiazepine may minimize these effects [100].
•Double vision; blurry vision.
•Sympathomimetic effects that increase cerebral blood flow and intracranial pressure (ICP) in spontaneously breathing patients. (See "Anesthesia for craniotomy in adults", section on 'Induction of anesthesia' and "Anesthesia for patients with acute traumatic brain injury", section on 'Choice of anesthetic agents'.)
•Possible increased cerebral metabolism with increased sympathetic stimulation [101]. However, some clinical studies suggest that ketamine does not significantly interfere with cerebral metabolism [91,102,103].
•Unique EEG effects that may result in misinterpretation of processed EEG values (eg, the bispectral index [BIS]). (See "Neuromonitoring in surgery and anesthesia", section on 'Intravenous agents'.)
•Patients with cognitive dysfunction as it might exacerbate this in the postoperative period [104].
●Airway effects
•Increased salivation and upper airway secretions.
•Minimal attenuation of airway reflexes.
Drug-drug interactions
●Potentiation of the cardiovascular toxicity of cocaine that may lead to myocardial ischemia, arrhythmias, and pulmonary hypertension [95]. (See "Anesthetic considerations for adults with substance use disorder or acute intoxication", section on 'Cocaine'.)
●Additive effects with chronically administered medications that have noradrenergic effects (eg, amphetamines, norepinephrine reuptake inhibitors such as tricyclic antidepressants) [105]. (See "Anesthetic considerations for adults with substance use disorder or acute intoxication", section on 'Amphetamines and similar agents' and "Anesthetic considerations for adults with substance use disorder or acute intoxication", section on 'Hallucinogens and dissociative drugs'.)
●Synergistic anesthetic effects if coadministered with a volatile inhalation anesthetic agent during induction. Thus, the induction dose of ketamine may be reduced [6]. However, no dose reduction is necessary when ketamine is coadministered with other IV adjuvant agents. (See 'Adjuvant agents' below and 'Dosing' below.)
Pharmacokinetics
●IV administration – Ketamine has a rapid onset (approximately one minute) [106]. Volume of distribution of ketamine is approximately 3 L/kg [107,108]. Duration of action is 10 to 20 minutes because ketamine has several active metabolites after hepatic metabolism [99,109]. Norketamine, the primary metabolite, has significant pharmacodynamic effects similar to those of ketamine, but with one-tenth to one-third of ketamine's potency. Thus, norketamine contributes to total time until return of consciousness after an induction dose (9 to 20 minutes), and also contributes to analgesic effects, which last longer than the anesthetic effects [107,108].
Clearance of ketamine is similar to liver blood flow (15 to 20 mL/kg/minute). Neither renal nor moderate hepatic dysfunction has a clinically significant effect on ketamine clearance. The terminal elimination half-life is two to three hours.
●IM administration – Onset of action after IM administration is approximately 15 to 30 minutes, which is much slower than onset after IV induction [107-109]. Peak plasma concentrations occur after 15 to 30 minutes and are similar to concentrations after IV administration of 2 mg/kg [110]. Due to variable absorption from muscle tissue, clinical duration of action may be significantly longer after IM administration compared with IV administration [110].
Dosing — The IV induction dose of ketamine for general anesthesia is 1 to 2 mg/kg IV (table 1). The IM induction dose is 4 to 6 mg/kg.
Ketamine dosing is not usually adjusted to avoid hemodynamic side effects (see 'Advantages and beneficial effects' above). Also, dose reduction is unnecessary when ketamine is coadministered with other IV adjuvant agents since these agents have only additive or infra-additive (antagonistic) effects when combined with ketamine, rather than synergistic effects (see 'Adjuvant agents' below). However, a lower initial dose of 0.5 to 1 mg/kg is prudent for patients with severe hypotension or shock since catecholamine reserves may be depleted. (See "Intraoperative management of shock in adults", section on 'Induction'.)
BARBITURATES
Methohexital — Methohexital is an oxybarbiturate sedative-hypnotic induction agent that activates seizure foci; thus, it is ideal for patients undergoing electroconvulsive therapy (ECT) (table 1). (See "Technique for performing electroconvulsive therapy (ECT) in adults", section on 'Anesthesia technique'.)
Similar to propofol, barbiturates such as methohexital facilitate inhibitory neurotransmission by enhancing gamma-aminobutyric acidA (GABAA) receptor function and direct activation of chloride channels, thereby mimicking the action of GABA. Methohexital also inhibits excitatory neurotransmission via glutamate and nicotinic acetylcholine receptors.
Advantages and beneficial effects — The unique ability of methohexital to activate seizure foci is ideal for ECT procedures.
Disadvantages and adverse effects — Methohexital has the following potential adverse effects (table 1):
●The activation of seizure foci is a disadvantage in patients with seizure disorder.
●Dose-dependent decreases in blood pressure (BP) due to venodilation and decreased myocardial contractility result in reflex increases in heart rate (HR) because baroreceptor reflexes remain intact. Although reductions in BP after methohexital administration are typically less than after propofol administration (see 'Disadvantages and adverse effects' above), we titrate the induction dose in patients likely to develop hypotension (eg, older patients), and in those who may develop imbalances in myocardial oxygen supply versus demand. (See "Anesthesia for the older adult", section on 'Cardiovascular system' and "Anesthesia for noncardiac surgery in patients with ischemic heart disease", section on 'Prevention of ischemia'.)
●Dose-dependent respiratory depression with decreases in respiratory rate, tidal volume, and ventilatory response to hypoxia and hypercarbia that may lead to apnea.
●Pain on injection occurring in up to 60 percent of patients [111].
●Involuntary myoclonic movements (similar to etomidate (see 'Disadvantages and adverse effects' above)), as well as hiccups.
●Exacerbation of acute intermittent porphyria, which occurs due to induction of hepatic enzymes involved in heme biosynthesis [112]. Thus, methohexital is contraindicated in patients with porphyria, as are other barbiturates.
●Rare anaphylactic reactions. (See "Perioperative anaphylaxis: Allergy evaluation and prevention of recurrent reactions".)
Drug-drug interactions — Coadministration of one or more adjuvant anesthetic agents acting on other receptor types (eg, opioids, benzodiazepines, volatile anesthetics) may produce synergistic anesthetic effects. Thus, reduction of the methohexital dose is prudent. (See 'Adjuvant agents' below and 'Dosing' below.)
Pharmacokinetics — Methohexital has a rapid onset (10 to 30 seconds), and a duration of action lasting 5 to 10 minutes. Volume of distribution is approximately 2 L/kg. Metabolism occurs in the liver and clearance is somewhat lower than other sedative-hypnotic induction agents. The elimination half-life is approximately four hours.
Dosing — The induction dose of methohexital is 1 to 1.5 mg/kg. To avoid dose-dependent hypotension, we administer a dose at the lower end of this range, titrated in increments, in patients who are older or have medical comorbidities, and when supplemental adjuvant anesthetic agents are coadministered. (See 'Adjuvant agents' below.)
Thiopental — With the introduction of propofol, thiopental use for induction of general anesthesia has declined.
Disadvantages and adverse effects — Thiopental use is limited by:
●Lack of availability in some countries
●Potentially prolonged sedative effect
●Higher incidence of nausea and vomiting compared to other widely available agents
●Possible development of tolerance
●Exacerbation of acute intermittent porphyria, similar to methohexital
Pharmacokinetics — The elimination half-life of thiopental is approximately nine hours, but can be as long as 26 hours, particularly if repeated doses are administered, resulting in lingering sedative effects.
Dosing — Doses for induction of anesthesia are 3 to 4 mg/kg, administered in two to four incremental doses.
ADJUVANT AGENTS —
One or more adjuvant intravenous (IV) agents are often administered during induction of general anesthesia to blunt the sympathetic stress response and cough reflex during laryngoscopy and intubation, minimize pain due to injection of irritating induction agents, and reduce the primary sedative-hypnotic dose. The most common selections are a short-acting opioid, lidocaine, or a benzodiazepine such as midazolam or remimazolam (table 2).
Coadministration of agents acting on different receptor types may produce synergistic anesthetic effects. Thus, reducing doses is prudent in older patients or those with significant comorbidities, particularly impaired renal and/or hepatic function. In patients with hemodynamic instability, administration of adjuvant agents is typically avoided.
Opioids — Short-acting opioids are the most commonly used adjuvant agents during induction of general anesthesia (table 2). (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Opioid use as an adjuvant agent'.)
●Advantages during induction (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'.)
•Suppression of airway reflexes that result in coughing and/or bronchospasm during laryngoscopy and endotracheal intubation [113].
•Attenuation of the stress responses to laryngoscopy and intubation that would otherwise result in tachycardia and hypertension [114-116].
•Reduction of pain caused by IV injection of propofol, etomidate, methohexital, or some muscle relaxants, if administered approximately one minute before injection of the irritating agent [32,33,117-120]. Optimal pain reduction may be achieved with lidocaine alone or a combination of lidocaine plus an opioid [119]. (See 'Lidocaine' below.)
•Supplementation of sedation, which reduces dose requirements for the sedative-hypnotic induction agent by 40 to 70 percent [121-125].
●Potential adverse effects (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Prevention and management of adverse opioid effects'.)
•Exacerbation of hypotension induced by administration of sedative-hypnotic agents such as propofol, which may be mitigated by dose reduction of the sedative-hypnotic.
•Bradycardia
•Dose-dependent respiratory depression and/or apnea, a side effect of all commonly used opioids. If laryngeal mask airway insertion with subsequent spontaneous ventilation is planned, some clinicians omit opioid administration during the induction sequence to avoid a period of postinduction apnea.
•Postoperative adverse effects such as nausea and vomiting, ileus, constipation, urinary retention, pruritus, delirium, acute tolerance, or hyperalgesia in the postoperative period are more likely if large or additional opioid doses are administered during the maintenance phase of general anesthesia. (See "Maintenance of general anesthesia", section on 'Analgesic component: Opioid agents'.)
●Dosing
•Routine induction with endotracheal intubation - Typical doses for each of the opioids that may be used during routine induction of anesthesia are noted in the tables (table 3). To avoid adverse effects, dose reduction is prudent for older adults, those with hemodynamic instability, or if other anesthetic or adjuvant agents (particularly benzodiazepines) are coadministered.
•Remifentanil intubation technique - When remifentanil is used for rapid sequence induction and intubation, an induction dose of propofol is typically administered first, followed by remifentanil 3 to 5 mcg/kg together with ephedrine 10 mg (table 3). (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Remifentanil intubation technique' and "Rapid sequence induction and intubation (RSII) for anesthesia", section on 'Remifentanil intubation'.)
Lidocaine — Lidocaine is often administered during induction of general anesthesia (table 2). It is a class 1B anti-arrhythmic agent that works by reversibly binding sodium ion channels and holding them open with a net effect of preventing depolarization.
●Advantages during induction
•During inhalation induction of general anesthesia - Suppression of the cough reflex and laryngospasm during laryngoscopy and intubation [126-135].
•Decreased incidence of bronchospasm due to reduced airway responsiveness to noxious stimuli and to drugs that cause bronchospasm, despite an increase in airway tone [136-138]. (See "Anesthesia for adult patients with asthma", section on 'Induction of anesthesia'.)
•Reduction of pain caused by IV injection of propofol, etomidate, methohexital, or some muscle relaxants when administered into the same vein at a low dose approximately one minute before injection of the irritating agent [139]. A meta-analysis noted that addition of lidocaine to propofol before injection also reduces pain [33]. Lidocaine is typically more effective than an opioid for mitigation of injection pain because of its local anesthetic effect [31-33,117-120,139].
●Potential adverse effects
•Possibility of lidocaine-induced ventricular rate increases in patients with atrial fibrillation or flutter at doses >50 mg.
●Dosing – Dose is based on the indication:
•Reduction of pain on injection due to propofol or another agent – 30 to 40 mg is administered into the same vein.
•Attenuation of airway responses to laryngoscopy and endotracheal intubation – 1 to 1.5 mg/kg is administered as a bolus. However, dose is reduced to 0.5 to 1 mg/kg in older patients, and is usually eliminated or reduced to ≤0.5 mg/kg in patients with hemodynamic instability.
Benzodiazepines
Midazolam — Some clinicians administer midazolam as an anxiolytic shortly before or after transport into the operating room (table 2). The primary mechanism of action is activation of the gamma-aminobutyric acidA (GABAA) receptor, thereby inhibiting neurotransmission [140].
●Advantages before and during induction – Dose-dependent potentially beneficial properties include [141]:
•Anxiolysis
•Amnesia
•Anticonvulsant properties
•Supplementation of sedation, which reduces dose requirements for the sedative-hypnotic induction agent [123].
●Potential adverse effects – Dose-dependent potential adverse effects include:
•Mild systemic vasodilation and decreased cardiac output (CO), with consequent decrease in blood pressure (BP). This may be pronounced in patients with preexisting hypovolemia or vasodilation [141].
•Respiratory depression, particularly if an opioid is concurrently administered. Minute ventilation and the ventilatory response to carbon dioxide decrease, and apnea may occur with higher doses (≥0.15 mg/kg) [141,142].
•Postoperative amnesia, prolonged drowsiness, and cognitive dysfunction, particularly in older patients [143,144]. Also, in a retrospective study of nearly three million patients undergoing total knee or hip arthroplasty, risk of in-hospital falls was increased if midazolam was administered in the perioperative period [144]. (See "Perioperative neurocognitive disorders in adults: Risk factors and mitigation strategies", section on 'Intravenous agents associated with higher risk'.)
•Pharyngeal dysfunction and discoordinated breathing and swallowing [145,146].
•Occasional unpredictable paradoxical reactions (eg, irritability, aggressiveness, delirium) [147,148].
●Dosing – For anxious adults, a midazolam dose of 1 to 2 mg may be administered to alleviate anxiety. However, we avoid routine administration of benzodiazepine for premedication or during anesthetic induction, which is consistent with most protocols for enhanced recovery after surgery. (See "Overview of enhanced recovery after major noncardiac surgery (ERAS)", section on 'Preoperative medications'.)
Remimazolam — Remimazolam is an ultra-short-acting benzodiazepine that is approved by the US Food and Drug Administration (FDA) for sedation in adults undergoing procedures lasting ≤30 minutes [149] (see "Monitored anesthesia care in adults", section on 'Remimazolam'), and approved in Japan for use as a general anesthetic [150,151]. Although data describing safety and efficacy of remimazolam for induction of anesthesia are scant, this agent may prove useful to avoid adverse effects of longer-acting benzodiazepines such as midazolam [152-155]. (See 'Midazolam' above.)
SUMMARY AND RECOMMENDATIONS
●Dosing considerations – Initial doses of intravenous (IV) sedative-hypnotic and adjuvant agents are individualized. Factors affecting dosing include adjusted body weight and other patient factors, dose-dependent adverse effects (eg, hypotension), and planned coadministration of adjuvant drugs. Supplemental doses are titrated if necessary. (See 'General considerations for dosing' above.)
●Sedative-hypnotic induction agents – Propofol, etomidate, and ketamine are the IV sedative-hypnotic agents commonly used to induce general anesthesia (table 1).
•Propofol (See 'Propofol' above.)
-Uses and advantages – Propofol is selected for most hemodynamically stable patients because of its rapid onset and offset and beneficial antiemetic, antipruritic, bronchodilatory, and anticonvulsant properties.
-Disadvantages and adverse effects – Dose-dependent hypotension and respiratory depression, pain on injection, and contamination risks.
-Dosing considerations – Induction dose is 1 to 2.5 mg/kg, but doses are reduced and titrated for some patients (eg, older age, hypovolemia, myocardial dysfunction) or circumstance (eg, coadministration of adjuvant anesthetic agents).
•Etomidate (See 'Etomidate' above.)
-Uses and advantages – Etomidate is often selected for patients with hemodynamic instability because it does not generally adversely affect blood pressure (BP), heart rate (HR), or cardiac output (CO).
-Disadvantages and adverse effects – Transient acute adrenal insufficiency. For this reason, we usually select ketamine rather than etomidate in critically ill patients with septic shock. Etomidate also has a higher incidence of postoperative nausea and vomiting, pain on injection, involuntary myoclonic movements, mild increases in airway resistance, and absence of analgesic effect compared with other induction agents.
-Dosing considerations – Induction dose is 0.15 to 0.3 mg/kg. To minimize inhibition of cortisol biosynthesis, repeated bolus doses are avoided.
•Ketamine (See 'Ketamine' above.)
-Uses and advantages – Ketamine may be selected for patients with impending or actual hypotension because administration typically increases BP, HR, and CO. Other advantages of ketamine include bronchodilation, profound analgesic properties, maintenance of airway reflexes and respiratory drive, and either IV or intramuscular (IM) routes of administration.
-Disadvantages and adverse effects – Increases in BP and HR as well as increases in pulmonary artery pressure (PAP) that may be detrimental in patients with ischemic heart disease or systemic or pulmonary hypertension, increases in cerebral blood flow and intracranial pressure (ICP), and a high incidence of psychotomimetic effects.
-Dosing considerations – IV induction dose is 1 to 2 mg/kg IV. IM induction dose is 4 to 6 mg/kg.
•Methohexital (See 'Methohexital' above.)
-Uses and advantages – Methohexital is used almost exclusively as an induction agent for patients undergoing ECT procedures because it activates seizure foci.
-Disadvantages and adverse effects – Activation of seizure foci is a disadvantage in patients with seizure disorder. Other adverse effects include dose-dependent BP decreases and respiratory depression, pain on injection, involuntary myoclonic movements, hiccups, exacerbation of acute intermittent porphyria, and rare anaphylactic reactions.
-Dosing considerations – Induction dose is 1 to 1.5 mg/kg.
●Adjuvant agents – One or more adjuvant IV agents (eg, short-acting opioid, lidocaine, or benzodiazepine [midazolam or remimazolam] (table 2)) are often administered during induction to blunt the sympathetic stress response and cough reflex during laryngoscopy and intubation, minimize pain due to injection of irritating anesthetic induction agents, and supplement effects of the selected sedative-hypnotic agent to allow dose reduction. (See 'Adjuvant agents' above.)
ACKNOWLEDGMENTS —
The UpToDate editorial staff acknowledges Liza M Weavind, MBBCh, FCCM, MMHC, and Adam King, MD, who contributed to an earlier version of this topic review.
