General anesthesia: Intravenous induction agents

Author:: Brian Bravenec, MD
Section Editors:: Girish P Joshi, MB, BS, MD, FFARCSI; Ron M Walls, MD, FRCPC, FAAEM
Deputy Editor:: Nancy A Nussmeier, MD, FAHA

Literature review current through: Jan 2024.

This topic last updated: Oct 26, 2022.

INTRODUCTION — Propofol, etomidate, and ketamine are the intravenous (IV) sedative-hypnotic agents commonly used to induce general anesthesia (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.

Our overview of techniques for induction of general anesthesia with IV or inhalation anesthetics (or combinations of these agents) including the selection of specific agents is found in a separate topic. (See "Induction of general anesthesia: Overview".)

DOSING CONSIDERATIONS — All available sedative-hypnotic IV induction agents (eg, propofol, etomidate, ketamine, methohexital) 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 [1]. (See 'Adjuvant agents' below and "Induction of general anesthesia: Overview".)

●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 3). (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 [2]. A separate study by these investigators did not find any benefit of this combination in critically ill patients [3].

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 [4].

•Induction agents cannot be titrated to effect if rapid sequence induction and intubation is necessary. Reasonable doses of the selected agent(s) 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 may be administered to treat hemodynamic aberrations before induction or 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 acid_A (GABA_A) 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 [5].

●Antiemetic properties. Propofol is a good choice for patients at increased risk for postoperative nausea and vomiting [6]. (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 [7,8]. Propofol is useful for induction in patients with bronchospasm and asthma [8,9]. (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"):

•Anticonvulsant properties.

•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 [10].

●Suitability for patients with renal and/or hepatic insufficiency [11-17]. (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 [18-23]. 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 [20]. Severe hypotension may occur in patients who are hypovolemic or hemodynamically compromised, as well as in older patients [18]. (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 [24]. Propofol is typically coadministered with lidocaine and/or an opioid to minimize pain on injection [24-26] (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 [27]. 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 [28]. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Hypnotic induction agents' and "Management of food allergy: Avoidance", section on 'Lipid emulsions'.)

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 [1,29]. (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 [30]. 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) [31].

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 [11]. 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 [32,33].

Dosing — The induction dose of propofol for general anesthesia is 1 to 2.5 mg/kg (table 1) [34].

Dose-dependent hypotension is avoided by reducing the initial dose and titrating propofol in increments, particularly in the following circumstances:

●Older age (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 [35]. (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) [18,35].

●Coadministration of one or more adjuvant anesthetic agents acting on other receptor types because of synergistic effects [1,29].

ETOMIDATE — Etomidate is often selected for anesthetic induction in hemodynamically unstable patients because it causes minimal hemodynamic changes (table 1) [36]. It is an imidazole derivative that acts directly on the gamma-aminobutyric acid_A (GABA_A)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 [37]. 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 [37].

●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). 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 [38,39].

●Pain on injection occurring in up to 80 percent of patients, although typically less painful than propofol injection [38,40]. This is caused by venous irritation due to the low pH (6.9) of the 35 percent propylene glycol used in etomidate formulations [40]. 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 [38,41-44]. These jerking movements are due to subcortical disinhibition unrelated to cortical seizure activity [40]. Although coadministration of an opioid or benzodiazepine can attenuate myoclonus, these adjuvant agents are typically omitted in hemodynamically unstable patients [41-44]. (See 'Opioids' below and 'Midazolam' below.)

●Undesirable increases in BP, HR, and ICP that may occur during laryngoscopy and endotracheal intubation due to sympathetic stress responses. An opioid and/or lidocaine can be administered to attenuate these increases when appropriate (eg, elevated ICP, coronary artery disease, or aneurysm [cerebral or systemic] in a hemodynamically stable patient). (See 'Opioids' below and 'Lidocaine' below.)

●Mild increases in airway resistance [7].

●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 [45-54]. Cortisol plasma concentrations do not necessarily fall below the normal range, but may not appropriately rise in response to surgical stimulation after etomidate administration [52,53]. 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. Studies 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) [55]. 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 [56,57].

-One 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 [49].

•Emergency endotracheal intubation in critically ill patients:

-A 2015 systematic review of eight randomized trials concluded that etomidate was not associated with increased mortality compared with any other induction agent in critically ill patients (OR 1.17, 95% CI 0.86-1.60) [50].

-Another 2015 meta-analysis of randomized controlled trials and observational studies in critically ill patients diagnosed with sepsis noted that a single dose of etomidate did not increase mortality compared with those not receiving etomidate [58].

-A subsequently published randomized trial compared induction with etomidate versus ketamine in 801 critically ill patients did note lower survival on day 7 in the etomidate group (77.3 versus 85.1 percent), but no difference by day 28 (64.1 versus 66.8 percent) [59].

•Emergency endotracheal intubation in patients with septic shock:

-A 2012 meta-analysis of randomized controlled trials and observational studies in patients with frank septic shock suggests that use of etomidate may increase risk for development of adrenal insufficiency and mortality [60]. Thus, we usually select ketamine rather than etomidate in patients with septic shock. (See "Intraoperative management of shock in adults", section on 'Septic shock'.)

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 in most settings. 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 [61]. (See "Glucocorticoid therapy in septic shock in adults".)

In an individual patient 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.

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 [1]. (See 'Adjuvant agents' below and 'Dosing' below.)

Pharmacokinetics — Etomidate has a rapid onset, similar to propofol [62]. The half-life of equilibration between plasma and effect site (the brain) is 1.6 minutes [63]. 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 [62-64].

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) [65]. 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 [1]. (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) [66-68]. 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 [69]. 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) [70]. 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 [71].

Advantages and beneficial effects — Advantages of ketamine include (table 1) [72]:

●Increases in BP, HR, and CO in most patients due to increased sympathetic tone [66-68], and reduced vasodilation due to inhibition of production of vascular nitric oxide [73]. 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 [74,75]. (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 [67,76].

●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 [77-80]. (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) [72]:

●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 [81-83]:

-Ischemic heart disease due to potential for imbalance between myocardial oxygen supply and demand [84]. (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 [85].

•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) [86]. 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 [87-89]. Prior administration of a benzodiazepine may minimize these effects [90].

•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 [91]. However, some clinical studies suggest that ketamine does not significantly interfere with cerebral metabolism [81,92,93].

•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 [94].

●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 [85]. (See "Anesthesia for patients 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) [95]. (See "Anesthesia for patients with substance use disorder or acute intoxication", section on 'Amphetamines and similar agents' and "Anesthesia for patients 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 [1]. 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) [96]. Volume of distribution of ketamine is approximately 3 L/kg [97,98]. Duration of action is 10 to 20 minutes because ketamine has several active metabolites after hepatic metabolism [89,99]. 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 [97,98].

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 [97-99]. Peak plasma concentrations occur after 15 to 30 minutes and are similar to concentrations after IV administration of 2 mg/kg [100]. Due to variable absorption from muscle tissue, clinical duration of action may be significantly longer after IM administration compared with IV administration [100].

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'.)

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 acid_A (GABA_A) 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 [101].

●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 [102]. Thus, methohexital is contraindicated in patients with porphyria, as are other barbiturates.

●Rare anaphylactic reactions. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Hypnotic induction agents'.)

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.)

ADJUVANT AGENTS — One or more adjuvant 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). (See "Induction of general anesthesia: Overview", section on 'Techniques and anesthetic agents'.)

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 [103].

•Attenuation of the stress responses to laryngoscopy and intubation that would otherwise result in tachycardia and hypertension [104-106].

•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 [25,26,107-110]. Notably, optimal pain reduction may be achieved with lidocaine alone or a combination of lidocaine plus an opioid [109]. (See 'Lidocaine' below.)

•Supplementation of sedation, which reduces dose requirements for the sedative-hypnotic induction agent by 40 to 70 percent [111-115].

●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: Overview", 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 4). To avoid adverse effects, dose reduction is prudent for older adults, those with hemodynamic instability, or if other anesthetic or adjuvant agents 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 4). (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 [116-125].

•Decreased incidence of bronchospasm due to reduced airway responsiveness to noxious stimuli and to drugs that cause bronchospasm, despite an increase in airway tone [126-128]. (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 [129]. A meta-analysis noted that addition of lidocaine to propofol before injection also reduces pain [26]. Lidocaine is typically more effective than an opioid for mitigation of injection pain because of its local anesthetic effect [24-26,107-110,129].

●Potential adverse 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.

•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 acid_A (GABA_A) receptor, thereby inhibiting neurotransmission [130].

●Advantages before and during induction – Dose-dependent potentially beneficial properties include [131]:

•Anxiolysis

•Amnesia

•Anticonvulsant properties

•Supplementation of sedation, which reduces dose requirements for the sedative-hypnotic induction agent [113].

●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 [131].

•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) [131,132].

•Postoperative amnesia, prolonged drowsiness, and cognitive dysfunction, particularly in older patients [133,134]. 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 [134]. (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 [135,136],

•Occasional unpredictable paradoxical reactions (eg, irritability, aggressiveness, delirium) [137,138].

●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 "Anesthetic management for enhanced recovery after major noncardiac surgery (ERAS)", section on 'Medications administered in the preoperative period'.)

Remimazolam — Remimazolam is an ultra-short-acting benzodiazepine that is approved by the US Food and Drug Administration (FDA) for induction and maintenance of sedation in adults undergoing procedures lasting ≤30 minutes [139], and in Japan for use as a general anesthetic [140,141]. Although data describing safety and efficacy of remimazolam for induction of anesthesia are scant, this agent may prove useful to avoid the adverse effects of longer-acting benzodiazepines such as midazolam [142-145]. (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 'Dosing considerations' 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 change blood pressure (BP), heart rate (HR), or cardiac output (CO).

-Disadvantages and adverse effects – Transient acute adrenal insufficiency, higher incidence of postoperative nausea and vomiting, pain on injection, involuntary myoclonic movements, mild increases in airway resistance, and absence of analgesic effect.

-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.

Hendrickx JF, Eger EI 2nd, Sonner JM, Shafer SL. Is synergy the rule? A review of anesthetic interactions producing hypnosis and immobility. Anesth Analg 2008; 107:494.
Smischney NJ, Beach ML, Loftus RW, et al. Ketamine/propofol admixture (ketofol) is associated with improved hemodynamics as an induction agent: a randomized, controlled trial. J Trauma Acute Care Surg 2012; 73:94.
Smischney NJ, Nicholson WT, Brown DR, et al. Ketamine/propofol admixture vs etomidate for intubation in the critically ill: KEEP PACE Randomized clinical trial. J Trauma Acute Care Surg 2019; 87:883.
Bowdle TA. Can we prevent recall during anesthesia?. In: Evidence-Based Practice of Anesthesiology, 3rd ed, Fleisher L (Ed), Elsevier, Philadelphia 2013.
Sabourdin N, Meniolle F, Chemam S, et al. Effect of Different Concentrations of Propofol Used as a Sole Anesthetic on Pupillary Diameter: A Randomized Trial. Anesth Analg 2020; 131:510.
Gan TJ, Belani KG, Bergese S, et al. Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting. Anesth Analg 2020; 131:411.
Eames WO, Rooke GA, Wu RS, Bishop MJ. Comparison of the effects of etomidate, propofol, and thiopental on respiratory resistance after tracheal intubation. Anesthesiology 1996; 84:1307.
Conti G, Ferretti A, Tellan G, et al. Propofol induces bronchodilation in a patient mechanically ventilated for status asthmaticus. Intensive Care Med 1993; 19:305.
Pizov R, Brown RH, Weiss YS, et al. Wheezing during induction of general anesthesia in patients with and without asthma. A randomized, blinded trial. Anesthesiology 1995; 82:1111.
Pinaud M, Lelausque JN, Chetanneau A, et al. Effects of propofol on cerebral hemodynamics and metabolism in patients with brain trauma. Anesthesiology 1990; 73:404.
Shafer SL. Advances in propofol pharmacokinetics and pharmacodynamics. J Clin Anesth 1993; 5:14S.
Gray PA, Park GR, Cockshott ID, et al. Propofol metabolism in man during the anhepatic and reperfusion phases of liver transplantation. Xenobiotica 1992; 22:105.
Smith I, White PF, Nathanson M, Gouldson R. Propofol. An update on its clinical use. Anesthesiology 1994; 81:1005.
Takizawa D, Hiraoka H, Nakamura K, et al. Propofol concentrations during the anhepatic phase of living-related donor liver transplantation. Clin Pharmacol Ther 2004; 76:648.
Takizawa D, Hiraoka H, Goto F, et al. Human kidneys play an important role in the elimination of propofol. Anesthesiology 2005; 102:327.
Kuipers JA, Boer F, Olieman W, et al. First-pass lung uptake and pulmonary clearance of propofol: assessment with a recirculatory indocyanine green pharmacokinetic model. Anesthesiology 1999; 91:1780.
Reekers M, Boer F, Vuyk J. Basic concepts of recirculatory pharmacokinetic modelling. Adv Exp Med Biol 2003; 523:19.
Shafer SL. Shock values. Anesthesiology 2004; 101:567.
Scheffer GJ, Ten Voorde BJ, Karemaker JM, et al. Effects of thiopentone, etomidate and propofol on beat-to-beat cardiovascular signals in man. Anaesthesia 1993; 48:849.
Hug CC Jr, McLeskey CH, Nahrwold ML, et al. Hemodynamic effects of propofol: data from over 25,000 patients. Anesth Analg 1993; 77:S21.
Bein B, Renner J, Caliebe D, et al. Sevoflurane but not propofol preserves myocardial function during minimally invasive direct coronary artery bypass surgery. Anesth Analg 2005; 100:610.
Ebert TJ. Sympathetic and hemodynamic effects of moderate and deep sedation with propofol in humans. Anesthesiology 2005; 103:20.
Masuda T, Tomiyama Y, Kitahata H, et al. Propofol inhibits volume-sensitive chloride channels in human coronary artery smooth muscle cells. Anesth Analg 2003; 97:657.
Euasobhon P, Dej-Arkom S, Siriussawakul A, et al. Lidocaine for reducing propofol-induced pain on induction of anaesthesia in adults. Cochrane Database Syst Rev 2016; 2:CD007874.
Picard P, Tramèr MR. Prevention of pain on injection with propofol: a quantitative systematic review. Anesth Analg 2000; 90:963.
Jalota L, Kalira V, George E, et al. Prevention of pain on injection of propofol: systematic review and meta-analysis. BMJ 2011; 342:d1110.
Muller AE, Huisman I, Roos PJ, et al. Outbreak of severe sepsis due to contaminated propofol: lessons to learn. J Hosp Infect 2010; 76:225.
Asserhøj LL, Mosbech H, Krøigaard M, Garvey LH. No evidence for contraindications to the use of propofol in adults allergic to egg, soy or peanut†. Br J Anaesth 2016; 116:77.
Vinik HR, Bradley EL Jr, Kissin I. Triple anesthetic combination: propofol-midazolam-alfentanil. Anesth Analg 1994; 78:354.
Absalom AR, Mani V, De Smet T, Struys MM. Pharmacokinetic models for propofol--defining and illuminating the devil in the detail. Br J Anaesth 2009; 103:26.
Khan KS, Hayes I, Buggy DJ. Pharmacology of anaesthetic agents I: intravenous induction agents. Contin Educ Anaesth Crit Care Pain 2014; 14:100.
Hughes MA, Glass PS, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology 1992; 76:334.
Shafer SL, Stanski DR. Improving the clinical utility of anesthetic drug pharmacokinetics. Anesthesiology 1992; 76:327.
Drug insert for propofol: FDA-approved dose http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019627s046lbl.pdf (Accessed on April 26, 2016).
Kirkpatrick T, Cockshott ID, Douglas EJ, Nimmo WS. Pharmacokinetics of propofol (diprivan) in elderly patients. Br J Anaesth 1988; 60:146.
Das S, Forrest K, Howell S. General anaesthesia in elderly patients with cardiovascular disorders: choice of anaesthetic agent. Drugs Aging 2010; 27:265.
Forman SA. Clinical and molecular pharmacology of etomidate. Anesthesiology 2011; 114:695.
Holdcroft A, Morgan M, Whitwam JG, Lumley J. Effect of dose and premedication on induction complications with etomidate. Br J Anaesth 1976; 48:199.
Fruergaard K, Jenstrup M, Schierbeck J, Wiberg-Jørgensen F. Total intravenous anaesthesia with propofol or etomidate. Eur J Anaesthesiol 1991; 8:385.
Paul F. White and Matthew R. Eng. Intravenous Anesthetics. In: Clinical Anesthesia, Seventh, Paul G. Barash (Ed), Lippincott Williams & Wilkins, Philadelphia 2013. p.478-500.
Hüter L, Schreiber T, Gugel M, Schwarzkopf K. Low-dose intravenous midazolam reduces etomidate-induced myoclonus: a prospective, randomized study in patients undergoing elective cardioversion. Anesth Analg 2007; 105:1298.
Hueter L, Schwarzkopf K, Simon M, et al. Pretreatment with sufentanil reduces myoclonus after etomidate. Acta Anaesthesiol Scand 2003; 47:482.
Stockham RJ, Stanley TH, Pace NL, et al. Fentanyl pretreatment modifies anaesthetic induction with etomidate. Anaesth Intensive Care 1988; 16:171.
Schwarzkopf KR, Hueter L, Simon M, Fritz HG. Midazolam pretreatment reduces etomidate-induced myoclonic movements. Anaesth Intensive Care 2003; 31:18.
Cohan P, Wang C, McArthur DL, et al. Acute secondary adrenal insufficiency after traumatic brain injury: a prospective study. Crit Care Med 2005; 33:2358.
den Brinker M, Joosten KF, Liem O, et al. Adrenal insufficiency in meningococcal sepsis: bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality. J Clin Endocrinol Metab 2005; 90:5110.
Jackson WL Jr. Should we use etomidate as an induction agent for endotracheal intubation in patients with septic shock?: a critical appraisal. Chest 2005; 127:1031.
Schenarts CL, Burton JH, Riker RR. Adrenocortical dysfunction following etomidate induction in emergency department patients. Acad Emerg Med 2001; 8:1.
Basciani RM, Rindlisbacher A, Begert E, et al. Anaesthetic induction with etomidate in cardiac surgery: A randomised controlled trial. Eur J Anaesthesiol 2016; 33:417.
Bruder EA, Ball IM, Ridi S, et al. Single induction dose of etomidate versus other induction agents for endotracheal intubation in critically ill patients. Cochrane Database Syst Rev 2015; 1:CD010225.
Absalom A, Pledger D, Kong A. Adrenocortical function in critically ill patients 24 h after a single dose of etomidate. Anaesthesia 1999; 54:861.
Fragen RJ, Weiss HW, Molteni A. The effect of propofol on adrenocortical steroidogenesis: a comparative study with etomidate and thiopental. Anesthesiology 1987; 66:839.
Jameson P, Desborough JP, Bryant AE, Hall GM. The effect of cortisol suppression on interleukin-6 and white blood cell responses to surgery. Acta Anaesthesiol Scand 1997; 41:304.
Malerba G, Romano-Girard F, Cravoisy A, et al. Risk factors of relative adrenocortical deficiency in intensive care patients needing mechanical ventilation. Intensive Care Med 2005; 31:388.
Komatsu R, You J, Mascha EJ, et al. Anesthetic induction with etomidate, rather than propofol, is associated with increased 30-day mortality and cardiovascular morbidity after noncardiac surgery. Anesth Analg 2013; 117:1329.
Heinrich S, Schmidt J, Ackermann A, et al. Comparison of clinical outcome variables in patients with and without etomidate-facilitated anesthesia induction ahead of major cardiac surgery: a retrospective analysis. Crit Care 2014; 18:R150.
Wagner CE, Bick JS, Johnson D, et al. Etomidate use and postoperative outcomes among cardiac surgery patients. Anesthesiology 2014; 120:579.
Gu WJ, Wang F, Tang L, Liu JC. Single-dose etomidate does not increase mortality in patients with sepsis: a systematic review and meta-analysis of randomized controlled trials and observational studies. Chest 2015; 147:335.
Matchett G, Gasanova I, Riccio CA, et al. Etomidate versus ketamine for emergency endotracheal intubation: a randomized clinical trial. Intensive Care Med 2022; 48:78.
Chan CM, Mitchell AL, Shorr AF. Etomidate is associated with mortality and adrenal insufficiency in sepsis: a meta-analysis*. Crit Care Med 2012; 40:2945.
Komatsu R, You J, Rajan S, et al. Steroid administration after anaesthetic induction with etomidate does not reduce in-hospital mortality or cardiovascular morbidity after non-cardiac surgery. Br J Anaesth 2018; 120:501.
Bergen JM, Smith DC. A review of etomidate for rapid sequence intubation in the emergency department. J Emerg Med 1997; 15:221.
Kaneda K, Yamashita S, Woo S, Han TH. Population pharmacokinetics and pharmacodynamics of brief etomidate infusion in healthy volunteers. J Clin Pharmacol 2011; 51:482.
Van Hamme MJ, Ghoneim MM, Ambre JJ. Pharmacokinetics of etomidate, a new intravenous anesthetic. Anesthesiology 1978; 49:274.
Perouansky M, Hemmings HC. Intravenous anaesthetic agents. In: Foundations of Anesthesia, 2nd ed, Hemmings HC, Hopkins PM (Eds), Elsevier, Philadelphia 2006. p.295.
Gray LD, Morris C. The principles and conduct of anaesthesia for emergency surgery. Anaesthesia 2013; 68 Suppl 1:14.
Morris C, Perris A, Klein J, Mahoney P. Anaesthesia in haemodynamically compromised emergency patients: does ketamine represent the best choice of induction agent? Anaesthesia 2009; 64:532.
Pandit JJ. Intravenous anaesthetic agents. Anaesthesia and Intensive Care Medicine 2007; 9:154.
Rogers R, Wise RG, Painter DJ, et al. An investigation to dissociate the analgesic and anesthetic properties of ketamine using functional magnetic resonance imaging. Anesthesiology 2004; 100:292.
Corssen G, Domino EF. Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesth Analg 1966; 45:29.
Olofsen E, Kamp J, Henthorn TK, et al. Ketamine Psychedelic and Antinociceptive Effects Are Connected. Anesthesiology 2022; 136:792.
Kung J, Meisner RC, Berg S, Ellis DB. Ketamine: A review of an established yet often underappreciated medication. APSF Newsletter 2020; June issue:64.
Chen RM, Chen TL, Lin YL, et al. Ketamine reduces nitric oxide biosynthesis in human umbilical vein endothelial cells by down-regulating endothelial nitric oxide synthase expression and intracellular calcium levels. Crit Care Med 2005; 33:1044.
Corssen G, Gutierrez J, Reves JG, Huber FC Jr. Ketamine in the anesthetic management of asthmatic patients. Anesth Analg 1972; 51:588.
Denmark TK, Crane HA, Brown L. Ketamine to avoid mechanical ventilation in severe pediatric asthma. J Emerg Med 2006; 30:163.
Eikermann M, Grosse-Sundrup M, Zaremba S, et al. Ketamine activates breathing and abolishes the coupling between loss of consciousness and upper airway dilator muscle dysfunction. Anesthesiology 2012; 116:35.
Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev 2006; :CD004603.
Loftus RW, Yeager MP, Clark JA, et al. Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology 2010; 113:639.
McGuinness SK, Wasiak J, Cleland H, et al. A systematic review of ketamine as an analgesic agent in adult burn injuries. Pain Med 2011; 12:1551.
Joly V, Richebe P, Guignard B, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology 2005; 103:147.
Långsjö JW, Kaisti KK, Aalto S, et al. Effects of subanesthetic doses of ketamine on regional cerebral blood flow, oxygen consumption, and blood volume in humans. Anesthesiology 2003; 99:614.
Hanouz JL, Persehaye E, Zhu L, et al. The inotropic and lusitropic effects of ketamine in isolated human atrial myocardium: the effect of adrenoceptor blockade. Anesth Analg 2004; 99:1689.
Hanouz JL, Zhu L, Persehaye E, et al. Ketamine preconditions isolated human right atrial myocardium: roles of adenosine triphosphate-sensitive potassium channels and adrenoceptors. Anesthesiology 2005; 102:1190.
Gooding JM, Dimick AR, Tavakoli M, Corssen G. A physiologic analysis of cardiopulmonary responses to ketamine anesthesia in noncardiac patients. Anesth Analg 1977; 56:813.
Cheng DC. The drug addicted patient. Can J Anaesth 1997; 44:R101.
Weiskopf RB, Bogetz MS, Roizen MF, Reid IA. Cardiovascular and metabolic sequelae of inducing anesthesia with ketamine or thiopental in hypovolemic swine. Anesthesiology 1984; 60:214.
Bowdle TA, Radant AD, Cowley DS, et al. Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state plasma concentrations. Anesthesiology 1998; 88:82.
Kleinloog D, Uit den Boogaard A, Dahan A, et al. Optimizing the glutamatergic challenge model for psychosis, using S+ -ketamine to induce psychomimetic symptoms in healthy volunteers. J Psychopharmacol 2015; 29:401.
Kamp J, Olofsen E, Henthorn TK, et al. Ketamine Pharmacokinetics. Anesthesiology 2020; 133:1192.
Grace RF. The effect of variable-dose diazepam on dreaming and emergence phenomena in 400 cases of ketamine-fentanyl anaesthesia. Anaesthesia 2003; 58:904.
Gardner AE, Dannemiller FJ, Dean D. Intracranial cerebrospinal fluid pressure in man during ketamine anesthesia. Anesth Analg 1972; 51:741.
Långsjö JW, Salmi E, Kaisti KK, et al. Effects of subanesthetic ketamine on regional cerebral glucose metabolism in humans. Anesthesiology 2004; 100:1065.
Hudetz JA, Pagel PS. Neuroprotection by ketamine: a review of the experimental and clinical evidence. J Cardiothorac Vasc Anesth 2010; 24:131.
Barreto Chang OL, Kreuzer M, Morgen DF, et al. Ketamine-Associated Intraoperative Electroencephalographic Signatures of Elderly Patients With and Without Preoperative Cognitive Impairment. Anesth Analg 2022; 135:683.
Kudoh A, Takahira Y, Katagai H, Takazawa T. Small-dose ketamine improves the postoperative state of depressed patients. Anesth Analg 2002; 95:114.
Herd DW, Anderson BJ, Keene NA, Holford NH. Investigating the pharmacodynamics of ketamine in children. Paediatr Anaesth 2008; 18:36.
White PF, Schüttler J, Shafer A, et al. Comparative pharmacology of the ketamine isomers. Studies in volunteers. Br J Anaesth 1985; 57:197.
Clements JA, Nimmo WS. Pharmacokinetics and analgesic effect of ketamine in man. Br J Anaesth 1981; 53:27.
Cohen ML, Trevor AJ. On the cerebral accumulation of ketamine and the relationship between metabolism of the drug and its pharmacological effects. J Pharmacol Exp Ther 1974; 189:351.
Grant IS, Nimmo WS, McNicol LR, Clements JA. Ketamine disposition in children and adults. Br J Anaesth 1983; 55:1107.
Taylor C, Stoelting VK. Methohexital sodium - a new ultrashort acting barbiturate. Anesthesiology 1960; 21:29.
Harrison GG, Meissner PN, Hift RJ. Anaesthesia for the porphyric patient. Anaesthesia 1993; 48:417.
Kelly HE, Shaw GM, Brett CN, et al. The effect of titrated fentanyl on suppressed cough reflex in healthy adult volunteers. Anaesthesia 2016; 71:529.
Chung KS, Sinatra RS, Halevy JD, et al. A comparison of fentanyl, esmolol, and their combination for blunting the haemodynamic responses during rapid-sequence induction. Can J Anaesth 1992; 39:774.
Cork RC, Weiss JL, Hameroff SR, Bentley J. Fentanyl preloading for rapid-sequence induction of anesthesia. Anesth Analg 1984; 63:60.
Dahlgren N, Messeter K. Treatment of stress response to laryngoscopy and intubation with fentanyl. Anaesthesia 1981; 36:1022.
El-Radaideh KM. [Effect of pretreatment with lidocaine, intravenous paracetamol and lidocaine-fentanyl on propofol injection pain. Comparative study. Rev Bras Anestesiol 2007; 57:32.
Prabhakar H, Singh GP, Ali Z, et al. Pharmacological and non-pharmacological interventions for reducing rocuronium bromide induced pain on injection in children and adults. Cochrane Database Syst Rev 2016; 2:CD009346.
Aouad MT, Siddik-Sayyid SM, Al-Alami AA, Baraka AS. Multimodal analgesia to prevent propofol-induced pain: pretreatment with remifentanil and lidocaine versus remifentanil or lidocaine alone. Anesth Analg 2007; 104:1540.
Rahman Al-Refai A, Al-Mujadi H, Petrova Ivanova M, et al. Prevention of pain on injection of propofol: a comparison of remifentanil with alfentanil in children. Minerva Anestesiol 2007; 73:219.
Kazama T, Ikeda K, Morita K. The pharmacodynamic interaction between propofol and fentanyl with respect to the suppression of somatic or hemodynamic responses to skin incision, peritoneum incision, and abdominal wall retraction. Anesthesiology 1998; 89:894.
Smith C, McEwan AI, Jhaveri R, et al. The interaction of fentanyl on the Cp50 of propofol for loss of consciousness and skin incision. Anesthesiology 1994; 81:820.
Short TG, Plummer JL, Chui PT. Hypnotic and anaesthetic interactions between midazolam, propofol and alfentanil. Br J Anaesth 1992; 69:162.
Kazama T, Ikeda K, Morita K. Reduction by fentanyl of the Cp50 values of propofol and hemodynamic responses to various noxious stimuli. Anesthesiology 1997; 87:213.
Van Aken H, Meinshausen E, Prien T, et al. The influence of fentanyl and tracheal intubation on the hemodynamic effects of anesthesia induction with propofol/N2O in humans. Anesthesiology 1988; 68:157.
STEINHAUS JE, GASKIN L. A study of intravenous lidocaine as a suppressant of cough reflex. Anesthesiology 1963; 24:285.
Aouad MT, Sayyid SS, Zalaket MI, Baraka AS. Intravenous lidocaine as adjuvant to sevoflurane anesthesia for endotracheal intubation in children. Anesth Analg 2003; 96:1325.
Davidson JA, Gillespie JA. Tracheal intubation after induction of anaesthesia with propofol, alfentanil and i.v. lignocaine. Br J Anaesth 1993; 70:163.
Jakobsen CJ, Ahlburg P, Holdgård HO, et al. Comparison of intravenous and topical lidocaine as a suppressant of coughing after bronchoscopy during general anesthesia. Acta Anaesthesiol Scand 1991; 35:238.
Lin CS, Sun WZ, Chan WH, et al. Intravenous lidocaine and ephedrine, but not propofol, suppress fentanyl-induced cough. Can J Anaesth 2004; 51:654.
Nishino T, Hiraga K, Sugimori K. Effects of i.v. lignocaine on airway reflexes elicited by irritation of the tracheal mucosa in humans anaesthetized with enflurane. Br J Anaesth 1990; 64:682.
Pandey CK, Raza M, Ranjan R, et al. Intravenous lidocaine suppresses fentanyl-induced coughing: a double-blind, prospective, randomized placebo-controlled study. Anesth Analg 2004; 99:1696.
Pandey CK, Raza M, Ranjan R, et al. Intravenous lidocaine 0.5 mg.kg-1 effectively suppresses fentanyl-induced cough. Can J Anaesth 2005; 52:172.
Warner LO, Balch DR, Davidson PJ. Is intravenous lidocaine an effective adjuvant for endotracheal intubation in children undergoing induction of anesthesia with halothane-nitrous oxide? J Clin Anesth 1997; 9:270.
Yukioka H, Hayashi M, Terai T, Fujimori M. Intravenous lidocaine as a suppressant of coughing during tracheal intubation in elderly patients. Anesth Analg 1993; 77:309.
Adamzik M, Groeben H, Farahani R, et al. Intravenous lidocaine after tracheal intubation mitigates bronchoconstriction in patients with asthma. Anesth Analg 2007; 104:168.
Chang HY, Togias A, Brown RH. The effects of systemic lidocaine on airway tone and pulmonary function in asthmatic subjects. Anesth Analg 2007; 104:1109.
Maslow AD, Regan MM, Israel E, et al. Inhaled albuterol, but not intravenous lidocaine, protects against intubation-induced bronchoconstriction in asthma. Anesthesiology 2000; 93:1198.
Xing J, Liang L, Zhou S, et al. Intravenous Lidocaine Alleviates the Pain of Propofol Injection by Local Anesthetic and Central Analgesic Effects. Pain Med 2018; 19:598.
Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand 2008; 118:69.
Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ. Midazolam: pharmacology and uses. Anesthesiology 1985; 62:310.
Forster A, Gardaz JP, Suter PM, Gemperle M. Respiratory depression by midazolam and diazepam. Anesthesiology 1980; 53:494.
Rogers JF, Morrison AL, Nafziger AN, et al. Flumazenil reduces midazolam-induced cognitive impairment without altering pharmacokinetics. Clin Pharmacol Ther 2002; 72:711.
Athanassoglou V, Cozowicz C, Zhong H, et al. Association of perioperative midazolam use and complications: a population-based analysis. Reg Anesth Pain Med 2022; 47:228.
Hårdemark Cedborg AI, Sundman E, Bodén K, et al. Effects of morphine and midazolam on pharyngeal function, airway protection, and coordination of breathing and swallowing in healthy adults. Anesthesiology 2015; 122:1253.
Petroianni A, Ceccarelli D, Conti V, Terzano C. Aspiration pneumonia. Pathophysiological aspects, prevention and management. A review. Panminerva Med 2006; 48:231.
Mancuso CE, Tanzi MG, Gabay M. Paradoxical reactions to benzodiazepines: literature review and treatment options. Pharmacotherapy 2004; 24:1177.
Lepousé C, Lautner CA, Liu L, et al. Emergence delirium in adults in the post-anaesthesia care unit. Br J Anaesth 2006; 96:747.
Remimazolam (Byfavo) for short-term procedural sedation. Med Lett Drugs Ther 2022; 64:26.
Masui K. Remimazolam besilate, a benzodiazepine, has been approved for general anesthesia!! J Anesth 2020; 34:479.
Keam SJ. Remimazolam: First Approval. Drugs 2020; 80:625.
Hirata N, Hayamizu K, Yamakage M. How to administer remimazolam for anesthesia induction. J Anesth 2020; 34:962.
Dai G, Pei L, Duan F, et al. Safety and efficacy of remimazolam compared with propofol in induction of general anesthesia. Minerva Anestesiol 2021; 87:1073.
Doi M, Morita K, Takeda J, et al. Efficacy and safety of remimazolam versus propofol for general anesthesia: a multicenter, single-blind, randomized, parallel-group, phase IIb/III trial. J Anesth 2020; 34:543.
Zhou J, Leonowens C, Ivaturi VD, et al. Population pharmacokinetic/pharmacodynamic modeling for remimazolam in the induction and maintenance of general anesthesia in healthy subjects and in surgical subjects. J Clin Anesth 2020; 66:109899.

Topic 94533 Version 29.0

خرید پکیج

General anesthesia: Intravenous induction agents

References