Maintenance of general anesthesia: Overview

INTRODUCTION — Immediately after induction of general anesthesia, additional agents are necessary to maintain the anesthetic state since most induction agents have a brief duration of action. This topic will discuss use of inhalation and intravenous (IV) agents during the maintenance phase of general anesthesia.

Induction of general anesthesia is discussed in separate topics. (See "Induction of general anesthesia: Overview" and "General anesthesia: Intravenous induction agents".)

Emergence from general anesthesia is also discussed separately. (See "Emergence from general anesthesia".)

ANESTHETIC GOALS

Overall goals — The overall goals of the maintenance phase of a general anesthetic are to maintain Stage III surgical anesthesia (ie, unconsciousness, amnesia, immobility, unresponsive to surgical stimulation (table 1)) at a safe anesthetic depth while also maintaining respiratory and hemodynamic stability. Standard monitors placed prior to induction of anesthesia are closely observed during anesthetic delivery in order to rapidly detect and correct hemodynamic, respiratory, or temperature derangements (see "Basic patient monitoring during anesthesia"). In addition, end-tidal inhalation anesthetic concentration (ETAC), raw or processed electroencephalography (EEG), or other specialized monitors are often used to estimate anesthetic depth to aid in avoiding awareness with recall, as discussed separately. (See "Accidental awareness during general anesthesia", section on 'Monitoring'.)

Other topics contain details regarding management of specific aspects of anesthesia during the maintenance phase:

●Maintenance of physiologic homeostasis including:

•Oxygenation and ventilation (see "Mechanical ventilation during anesthesia in adults")

•Hemodynamic stability (see "Hemodynamic management during anesthesia in adults")

•Temperature control (see "Perioperative temperature management")

●Prevention of awareness with recall (see "Accidental awareness during general anesthesia")

●Antinociception (analgesia) during increased intensity of the degree of noxious surgical stimulation (see "Perioperative uses of intravenous opioids in adults: General considerations")

●Muscle relaxation to facilitate surgery and/or prevent movement as necessary for certain surgical procedures (see "Clinical use of neuromuscular blocking agents in anesthesia")

Anesthetic depth — We individually titrate anesthetic agents to achieve an appropriate depth. We avoid excessive anesthetic depth and we avoid BP significantly lower than baseline values or frank hypotension, particularly in older patients and those at risk for development of perioperative neurocognitive disorders [1-3]. (See "Perioperative neurocognitive disorders in adults: Risk factors and mitigation strategies", section on 'Avoid excessive depth during general anesthesia'.)

An association has been noted between increasing anesthetic depth (gauged by processed EEG such as the bispectral index [BIS] monitor) and decreased postoperative survival in some observational studies; however, most studies did not report blood pressure (BP) data [4]. Yet low BP due to deep anesthesia has the strongest association with mortality in studies that did include BP data [5,6]. In a 2019 randomized study of more than 6600 patients >60 years old who were undergoing major surgery with a volatile inhalation anesthetic technique (see 'Inhalation anesthetic agents and techniques' below), lighter anesthesia targeting BIS values at 50 (median 47; range 44 to 51) was compared with deeper anesthesia targeting BIS values at 35 (median 39; range 36 to 42), while appropriate BP was maintained in all patients [7]. In patients maintained with lighter anesthesia, mean arterial BP was slightly higher (3.5 mmHg), while volatile anesthetic use was 30 percent lower (with a minimum alveolar concentration [MAC] of 0.62; range 0.52 to 0.73 versus a MAC of 0.88; range 0.74 to 1.04). One-year mortality was the same in both groups [7].

Also, neuromonitoring techniques such as processed EEG are often employed for patients at risk for awareness. (See "Accidental awareness during general anesthesia", section on 'Brain monitoring'.).

SELECTION OF MAINTENANCE TECHNIQUES — Maintenance of general anesthesia may be accomplished using a primary inhalation technique (see 'Inhalation anesthetic agents and techniques' below) or a primary intravenous (IV) technique (see 'Total intravenous anesthesia' below). A 2022 meta-analysis of randomized trials noted that choice of IV anesthesia with propofol versus inhalation anesthesia with sevoflurane did not affect mean inflammatory biomarker levels measured after various types of surgery (23 studies; 1611 participants) [8].

Combinations that include one or more sedative-hypnotic agents (eg, propofol or an inhalation anesthetic) and one or more analgesics (eg, an opioid or nonopioid analgesic agent), with or without use of a neuromuscular blocking agent (NMBA) are often employed to achieve "balanced" general anesthesia [9-12].

Ideal anesthetic maintenance agents have rapid onset of action, minimal cardiopulmonary or other side effects, and are cleared from the bloodstream quickly to ensure a rapid recovery. None of the available inhalation or IV anesthetic agents is ideal for all patients, and all have potential adverse side effects. Balanced (ie, multimodal) anesthetic techniques may increase the likelihood of achieving the desired goals (see 'Anesthetic goals' above), while using less of each drug than if it were administered alone by taking advantage of the synergism that occurs when anesthetic agents from different classes are combined [9-13]. However, the synergistic effects of such drug combinations may result in adverse effects such as hypotension or delayed emergence.

INHALATION ANESTHETIC AGENTS AND TECHNIQUES — All available volatile inhalation anesthetic agents (sevoflurane, desflurane, isoflurane, and in some countries halothane) may be used for complete maintenance of general anesthesia. An inhalation anesthetic technique may also include one gas (nitrous oxide [N₂O]) administered as a supplemental agent. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Maintenance of general anesthesia (all inhalation agents)'.)

Dosing considerations — Dosing of each inhalation anesthetic agent is determined by its potency, reported as the minimum alveolar concentration (MAC) value (table 2), with 1 MAC being the concentration of an inhaled agent in the alveoli required to prevent movement in response to a surgical stimulus in 50 percent of patients (table 3). MAC values are influenced by patient age and coexisting diseases or conditions (table 4). (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'MAC and MAC-awake values for inhalation agents'.)

Titration of the potent inhalation anesthetic is necessary to maintain stage III surgical anesthesia with unconsciousness, amnesia, immobility, and absence of response to noxious stimulation. Doses of the volatile agent are decreased if N₂O is also inhaled and/or if intravenous (IV) anesthetic agent(s) are also administered [14]. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Influence of drug-drug interactions'.)

Volatile inhalation agents

Advantages and disadvantages — The potent volatile inhalation anesthetic agents share common advantages and disadvantages (see "Inhalation anesthetic agents: Clinical effects and uses", section on 'Clinical effects'):

●Advantages:

•Ease of administration.

•Reliable blockade of responses to sensory input such as painful stimuli [15].

•Bronchodilation.

•Dose-dependent decreases in skeletal and smooth muscle tone.

•Decreased cerebral metabolic rate (CMR).

•Increased cerebral blood flow (CBF).

•Ability to monitor end-tidal anesthetic concentration (ETAC) as an indicator of anesthetic depth; ETAC values of 0.8 to 1 MAC are typically adequate to prevent awareness with recall. (See "Accidental awareness during general anesthesia", section on 'End-tidal anesthetic concentration'.)

●Disadvantages:

•Dose-dependent suppression of airway reflexes.

•Dose-dependent respiratory depression.

•Dose-dependent myocardial depression and vasodilation that may cause hypotension.

•Increased risk of postoperative nausea and vomiting (PONV) compared with most IV anesthetic alternatives, unless prophylactic antiemetics are administered. (See "Postoperative nausea and vomiting", section on 'Anesthetic factors'.)

•Potential to induce malignant hyperthermia in susceptible individuals. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Other clinical effects'.)

Specific volatile inhalation agents — The available potent volatile agents differ in their specific advantages and adverse effects, which affects selection for the maintenance phase of general anesthesia. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Specific inhalation anesthetic agents'.)

Sevoflurane — Sevoflurane is often selected for maintenance of anesthesia during surgical procedures lasting less than two hours due to its low blood and tissue solubilities. Compared with older potent inhalation agents that have higher blood and tissue solubilities (eg, isoflurane), uptake during induction, changes in anesthetic depth during the maintenance phase of general anesthesia, and emergence are more rapid when sevoflurane is used. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Advantages'.)

A disadvantage for sevoflurane use as the primary maintenance agent during longer surgical procedures is cost, particularly when higher fresh gas flows (ie, >2 L/minute of oxygen and/or air) are employed to deliver it. Compared with isoflurane, there is little advantage for faster recovery after delivery of sevoflurane for more than two hours because the blood:fat partition coefficients of these agents are similar. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Disadvantages and adverse effects'.)

Further details regarding sevoflurane administration are discussed separately. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Sevoflurane'.)

Desflurane — Desflurane has the lowest blood and tissue solubility of the potent volatile inhalation agents, resulting in very rapid uptake and elimination with little accumulation in tissues. Thus, changes in anesthetic depth and recovery during emergence are rapid [16,17]. Use of desflurane is particularly advantageous in patients who are older, morbidly obese, or have sleep apnea [16-18]. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Advantages'.)

Similar to sevoflurane, a disadvantage of desflurane is its high cost during use as the primary maintenance agent for longer surgical procedures. Other disadvantages include pungency with a very high incidence of airway irritation (eg, coughing, salivation, breath-holding, laryngospasm), and sympathomimetic properties that result in tachycardia and hypertension, particularly if higher or abruptly increased concentrations are administered. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Disadvantages and adverse effects'.)

Further details regarding desflurane administration are discussed separately. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Desflurane'.)

Isoflurane — Isoflurane is commonly used as a primary agent to maintain general anesthesia during longer surgical cases. It is the more potent than sevoflurane or desflurane, inexpensive, and widely available. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Advantages'.)

Disadvantages of isoflurane compared with sevoflurane or desflurane include slower onset during induction and slower recovery due to higher blood and tissue solubility. Thus, emergence may be prolonged, particularly after a long duration of administration. Other disadvantages include pungency with potential airway irritation during induction and emergence. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Disadvantages and adverse effects'.)

Further details regarding isoflurane administration are discussed separately. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Isoflurane'.)

Halothane — Concern about hepatotoxicity has eliminated the use of halothane in North America; however it is still commonly used in some regions, particularly in pediatric patients.

Halothane has the slowest onset and recovery of any of the potent inhalation agents due to very high tissue and blood solubility. Emergence from anesthesia may be prolonged compared with other potent volatile agents. Other disadvantages include potential hepatotoxicity, as well as negative inotropy and chronotropy, and a high incidence of ventricular and other dysrhythmias. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Disadvantages and adverse effects'.)

Advantages include its very high potency and low cost. In addition, halothane is a bronchodilating agent with little airway irritability. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Advantages'.)

Further details regarding halothane administration are discussed separately. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Halothane'.)

Nitrous oxide gas — Nitrous oxide (N₂O) is a pressurized gas that is delivered via a flow meter on the anesthesia machine. N₂O gas is often selected as a supplemental agent during maintenance of general anesthesia with either an inhalation or IV anesthetic technique. Its use increases anesthetic depth, resulting in decreased dose requirements for coadministered anesthetic agents. In a review of the available evidence, the European Society of Anaesthesiologists Task Force on Nitrous Oxide concluded that a rational approach is targeted use of N₂O considering its risk/benefit ratio in any given patient, as with other anesthetic agents [19]. The authors routinely use N₂O in the absence of contraindications. However, N₂O cannot be used as a sole agent to maintain anesthesia because of its low potency (the MAC value is 104 percent). (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Typical uses'.)

●Advantages – Advantages of N₂O include [19,20] (see "Inhalation anesthetic agents: Clinical effects and uses", section on 'Advantages'):

•Rapid onset and offset due to its very low blood solubility. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Partition coefficients and potency'.)

•During the maintenance phase of general anesthesia, coadministration of N₂O with any potent volatile inhalation agent allows more rapid changes in anesthetic depth due to a phenomenon termed the "second gas" effect. Similarly, speed of induction and emergence are increased with coadministration of N₂O due to dilution of the alveolar concentration of the volatile anesthetic. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Second gas effect'.)

•Analgesic properties.

•Anxiolytic properties.

•Minimal hemodynamic effects.

•Cheap and wide availability.

●Disadvantages – Disadvantages include:

•Potential for diffusion into any air-filled cavity, displacing nitrogen gas. Thus, administration is avoided in patients with possible pre-existing bowel distention, increased middle ear pressure, pneumothorax, pneumoperitoneum, pneumocephalus, intraocular gas, or venous air embolism. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Disadvantages and adverse effects'.)

•Although visceral distension may slightly increase risk of PONV, particularly if no antiemetic prophylactic measures are employed, this does not preclude its use in patients without contraindications [19]. (See "Postoperative nausea and vomiting", section on 'Anesthetic factors'.)

•Potential for transient diffusion hypoxia if N₂O is discontinued at a low inspired oxygen concentration. In this circumstance, bulk transfer of N₂O gas into the alveolus displaces oxygen, thereby decreasing alveolar oxygen concentration and potentially inducing desaturation. Diffusion hypoxia may be prevented by delivery of high inspired oxygen concentration for several minutes before and after discontinuing N₂O. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Second gas effect'.)

Reevaluation of available evidence suggests that the perceived drawbacks of N₂O (eg, nausea, vomiting, bowel distension) have been exaggerated or misdirected. We do not specifically avoid N₂O unless there is a contraindication for its use [19]. Further details regarding N₂O administration are discussed separately. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Nitrous oxide'.)

INTRAVENOUS ANESTHETIC AGENTS AND TECHNIQUES

General considerations — Appropriate doses of intravenous (IV) anesthetic agents are titrated to maintain stage III surgical anesthesia with unconsciousness, amnesia, immobility, and absence of response to noxious stimulation, similar to considerations for inhalation anesthetic agents. (See 'Anesthetic goals' above and 'Dosing considerations' above.)

When IV anesthetic drugs from different classes are combined, the hypnotic effects are often synergistic rather than merely additive, requiring dose reductions for each agent. Synergy is particularly common when drugs acting primarily on gamma-aminobutyric acid_A (GABA_A) receptors (eg, propofol) are combined with drugs acting on other receptor types (eg, opioids, alpha₂ agonists such as dexmedetomidine) [9]. Similarly, doses of IV agents should be reduced when an inhalation agent such as nitrous oxide (N₂O) or a potent volatile anesthetic agent is coadministered. (See "General anesthesia: Intravenous induction agents", section on 'Dosing considerations' and "Inhalation anesthetic agents: Clinical effects and uses", section on 'Influence of drug-drug interactions'.)

Total intravenous anesthesia — Total intravenous anesthesia (TIVA) employs a sedative-hypnotic anesthetic (typically propofol) and an analgesic component (typically an opioid agent). Adjuncts such as dexmedetomidine, ketamine, or lidocaine infusions may be used for patient-specific or procedure-specific reasons to replace or minimize the total propofol and/or total opioid doses [21]. Overall, these adjunct agents have limited benefits and specific potential adverse effects, as noted below.

Guidelines for the safe practice of TIVA were jointly published in 2019 by the Association of Anaesthetists, the Society for Intravenous Anesthesia in Great Britain [22]. These include:

●Infusion doses of the IV agents are adjusted based on age, frailty, and comorbid medical conditions. Typically, a low initial infusion setting (eg, of propofol) is adjusted by making small incremental increases.

●Drug and fluid lines should be as close to the patient as possible to minimize dead space. Whenever possible, the IV catheter of central venous catheter through which the infusion is being delivered should be visible throughout the anesthetic care.

●Guidelines for use of IV infusion pumps, including smart pumps, syringe pumps, and target-controlled infusion (TCI) devices are discussed separately:

•(See "Intravenous infusion devices for perioperative use", section on 'Smart pumps'.)

•(See "Intravenous infusion devices for perioperative use", section on 'Syringe pumps'.)

•(See "Intravenous infusion devices for perioperative use", section on 'Target-controlled infusion systems'.)

●Concerns include the possibility of awareness during anesthesia (see "Accidental awareness during general anesthesia", section on 'Brain monitoring'), or, conversely, excessive anesthetic depth with delayed recovery (see "Perioperative neurocognitive disorders in adults: Risk factors and mitigation strategies", section on 'Avoid excessive depth during general anesthesia'). For this reason, raw or processed electroencephalography (EEG) monitoring (eg, the bispectral index [BIS]) or other neuromonitoring techniques are often used to aid intraoperative dosing (table 5) [22-24].

●Indications and advantages – A TIVA technique is selected in the following circumstances:

•Patients requiring general anesthesia if there are absolute contraindications (eg, history of malignant hyperthermia) (see "Malignant hyperthermia: Diagnosis and management of acute crisis", section on 'MH triggers') or relative contraindications (eg, high risk for postoperative nausea and vomiting [PONV]) (see "Postoperative nausea and vomiting", section on 'Anesthetic factors') for administration of volatile agents.

•Patients undergoing surgical procedures with neuromonitoring (eg, spine surgery) because use of a sedative hypnotic (eg, propofol) and an opioid agent has less effect on evoked potentials than potent volatile inhalation agents or N₂O. In particular, motor evoked potentials (MEPs) are very sensitive to inhalation agents, while somatosensory-evoked potentials (SSEPs) are moderately affected. However, propofol causes a dose-dependent decrease in EEG amplitude and frequency, ultimately producing burst suppression and electrical silence at high doses. (See "Neuromonitoring in surgery and anesthesia", section on 'Anesthetic effects on neuromonitoring' and "Neuromonitoring in surgery and anesthesia", section on 'Maintenance of anesthesia'.)

●Disadvantages – Potential disadvantages of TIVA include the following:

•Blood concentrations (and therefore effect site concentration) of IV anesthetic agents are not easily obtained. This contrasts with inhalation anesthetics, for which the exhaled end-tidal anesthetic concentration (ETAC) of each agent can be continuously monitored, allowing real-time dose adjustments of anesthetic depth. Although processed or unprocessed EEG indices or other neuromonitoring techniques are often used to titrate anesthetic agents during TIVA, such indices do not reliably confirm that patients are not aware. However, a 2017 meta-analysis concluded that use of processed EEG (eg, BIS) monitoring to guide TCI of propofol dosing allows better maintenance of the target anesthetic depth compared with manual control based on standard monitoring [23]. (See "Accidental awareness during general anesthesia", section on 'Total intravenous anesthesia' and "Accidental awareness during general anesthesia", section on 'Brain monitoring'.)

•TIVA is associated with dose-dependent suppression of airway reflexes and respiratory depression, similar to potent volatile inhalation agents.

•TIVA is also associated with dose-dependent vasodilation and myocardial depression that may cause hypotension, similar to potent volatile inhalation agents.  

•When the limb containing the IV catheter is tucked at the patient's side table or not continuously visible due to surgical draping, unrecognized IV infiltration and extravasation of a continuous IV infusion into the tissue of a tucked limb can occur, resulting in compartment syndrome. Also, unrecognized disconnection of the IV tubing from the catheter may result in failure to administer the intended medication. (See "Intravenous infusion devices for perioperative use", section on 'Extravasation of a continuous infusion'.)

•Possible errors in IV drug delivery via infusion devices include syringe pump or "smart" pump setting errors that may go undetected (eg, wrong rate, wrong dose, wrong concentration, wrong medication), failure to deliver the intended agent, overriding soft limits with consequent overdosing, or underdosing with possible awareness. (See "Intravenous infusion devices for perioperative use", section on 'Risks for medication errors' and "Intravenous infusion devices for perioperative use", section on 'Smart pumps'.)

•TIVA anesthetic techniques are typically more costly than inhalation techniques, depending on which specific IV agents are selected [25,26]. Target-controlled infusion (TCI) systems are not currently approved in the United States for clinical use during TIVA techniques. (See "Intravenous infusion devices for perioperative use", section on 'Target-controlled infusion systems'.)

Specific intravenous agents

Sedative-hypnotic agent: Propofol — Propofol is usually selected as the sedative-hypnotic component to maintain general anesthesia during a TIVA technique.

●Dosing – Propofol is typically administered as a continuous infusion using a syringe pump or a smart pump that requires operator programming. Although not available in the United States, closed-loop TCI systems are used in some countries for delivery of propofol during a TIVA technique. However, intersubject variability (eg, obesity, underweight status) in pharmacokinetic and pharmacodynamic parameters used in models to calculate the drug concentration of propofol at the effect site has limited utility of TCI systems. (See "Intravenous infusion devices for perioperative use" and "Intravenous infusion devices for perioperative use", section on 'Target-controlled infusion systems'.)

The typical dose range for propofol is 75 to 150 mcg/kg per minute in younger and healthier patients who can tolerate these higher doses. Propofol dosing is reduced by factors such as older age, hypovolemia, vasodilation, myocardial dysfunction, and coadministration of other agents, as discussed separately. (See "General anesthesia: Intravenous induction agents", section on 'Dosing considerations'.)

Ideally, propofol dosing is titrated using EEG-based neuromonitoring, although other technology has been used in some centers (eg, isolated forearm technique) (see "Accidental awareness during general anesthesia", section on 'Brain monitoring'). The infusion rate is titrated to the patient's responses to noxious surgical stimulation when such monitoring technology is not available. In some countries, TCI systems are used to predict the propofol concentration in the plasma and at the effect site (ie, the brain); however, TCI systems are not available in the United States [23,27]. (See "Intravenous infusion devices for perioperative use", section on 'Target-controlled infusion systems'.)

●Advantages and potential adverse effects – Advantages of propofol include rapid onset and recovery (figure 1), and antiemetic, anticonvulsant, antipruritic, and bronchodilatory properties. It is suitable for patients with renal and/or hepatic insufficiency (see "General anesthesia: Intravenous induction agents", section on 'Advantages and beneficial effects'). When used as the sedative-hypnotic component of a TIVA technique during maintenance of general anesthesia, propofol may also have beneficial antioxidant, anti-inflammatory, and immunomodulatory effects [28].

Clinically significant adverse side effects of propofol are minimal, particularly when titrated to desired depth. However, hypotension can occur at higher doses in susceptible patients, primarily due to venous and arterial dilation. Dose-dependent respiratory depression is also a known side effect. (See "General anesthesia: Intravenous induction agents", section on 'Disadvantages and adverse effects'.)

Benzodiazepine: remimazolam — Remimazolam is a novel benzodiazepine developed in Japan for use as an induction and maintenance anesthetic agent. Remimazolam is ultra-short acting and it is metabolized by non-specific tissue esterases [29]. In bolus dose it is cleared three times as quickly as midazolam [30].

●Dosing – As a component of TIVA general anesthesia, maintenance doses of remimazolam are approximately 1 mg/kg per hour [31].  

●Advantages and potential adverse effects – Remimazolam has faster clearance than midazolam [30]. Although data are scant, its safety profile and side effects (eg, respiratory depression, hypotension, bradycardia) are similar to propofol [31,32]. However, some case reports of anaphylaxis have been published [33-35]. Although remimazolam is licensed in the United States, clinical use will likely be limited pending further studies.

Analgesic component: Opioid agents — An opioid is usually selected to provide the analgesic component of a TIVA technique.

●Dosing – In general, we use the lowest dose of opioid for the shortest period of time necessary, while ensuring provision of adequate analgesia [36-38].

Protocols for enhanced recovery after surgery (ERAS) emphasize limiting the dose of perioperative opioids because of potential adverse effects in the postoperative period (see below). Multimodal opioid-sparing strategies in such protocols include administration of nonopioid analgesics such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase (COX)-2 specific inhibitors, and adjuvant agents with analgesic properties (eg, dexamethasone, ketamine), as well as use of nonpharmacologic analgesic techniques such as regional blocks. Further discussion is found in other topics:

•(See "Anesthetic management for enhanced recovery after major noncardiac surgery (ERAS)", section on 'Pain prophylaxis' and "Anesthetic management for enhanced recovery after major noncardiac surgery (ERAS)", section on 'Management of pain'.)

•(See "Approach to the management of acute pain in adults", section on 'Creating a plan for analgesia'.)

Some clinicians advocate "opioid-free" anesthesia, whereby multimodal nonopioid analgesic agents and techniques are used rather than administering any intraoperative (or postoperative) opioid. However, data are insufficient to recommend patient-specific or procedure-specific indications for such complete opioid avoidance [13,39-42]. In an individual patient, it remains essential to ensure effective intraoperative and postoperative analgesia if opioids are minimized or avoided [36,37,43]. (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Opioid-free and opioid-sparing anesthetic techniques' and 'Adjuvant agents' below.)

●Advantages and potential adverse effects – Benefits of opioids include effective analgesia, reduced requirements for other IV and inhalation anesthetic agents, attenuation of autonomic responses to noxious stimuli, and blunting of cough and gag reflexes during airway manipulation. (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'.)

Potential adverse effects of opioids during and after general anesthesia include (see "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Prevention and management of adverse opioid effects'):

•Intraoperative period – Exacerbation of adverse effects of other anesthetic agents (eg, propofol, inhalation anesthetics) including hypotension and respiratory depression may occur. Other potential adverse effects include bradycardia, chest wall and skeletal muscle rigidity, and delayed emergence.

•Postoperative period – Nausea and vomiting, delirium, pruritus, urinary retention, and potential for acute tolerance and opioid-induced hyperalgesia may occur in the postoperative period.  

●Selection of an opioid agent – Selection of a specific opioid and dosing considerations depend on procedure-specific factors (eg, degree of analgesia required, planned duration of surgery), patient-specific factors (eg, age, comorbidities, tolerance to opioids), the desired speed of onset and offset, and whether other analgesic agents are coadministered. (See "Perioperative uses of intravenous opioids: Specific agents".)

•Continuous infusion during a TIVA anesthetic technique – Remifentanil is often selected for continuous infusion during a TIVA technique, particularly during shorter procedures when the intensity of noxious surgical stimulation is expected to vary considerably. When coadministered with propofol, dose-dependent analgesic effects of remifentanil reduce somatic movement and autonomic nervous system (figure 2), and these effects are more marked for painful stimuli than for nonpainful stimuli such as calling the patient's name [15]. However, when coadministered with sevoflurane, these effects diminish with higher remifentanil concentrations (eg, >2 ng/mL predicted effect site concentration, which is approximately equivalent to a continuous infusion of remifentanil at 0.1 ng/kg per minute) (figure 2) [15].  

Sufentanil may be selected as an alternative opioid infusion for longer TIVA anesthetics due to its lower cost.

•Bolus dosing – A short-acting opioid such as fentanyl is typically selected for bolus dosing during a TIVA anesthetic technique or to provide supplemental analgesia during general anesthesia.

•Intraoperative dosing to provide postoperative analgesia – A long-acting opioid (eg, morphine or hydromorphone) is typically selected, and administered approximately 20 to 30 minutes before emergence from general anesthesia if significant postoperative pain is anticipated.

Agent-specific uses, dosing, advantages, disadvantages, drug-drug interactions, and pharmacokinetics for opioids employed during general anesthesia are described separately (table 6 and figure 3 and figure 4 and figure 5):

•Remifentanil (see "Perioperative uses of intravenous opioids: Specific agents", section on 'Remifentanil')

•Fentanyl (see "Perioperative uses of intravenous opioids: Specific agents", section on 'Fentanyl')

•Sufentanil (see "Perioperative uses of intravenous opioids: Specific agents", section on 'Sufentanil')

•Alfentanil (see "Perioperative uses of intravenous opioids: Specific agents", section on 'Alfentanil')

•Hydromorphone (see "Perioperative uses of intravenous opioids: Specific agents", section on 'Hydromorphone')

•Morphine (see "Perioperative uses of intravenous opioids: Specific agents", section on 'Morphine')

Adjuvant agents — Infusions of other adjuvant agents (eg, dexmedetomidine, ketamine, lidocaine (figure 1)) may be used to reduce or replace propofol as the sedative-hypnotic component or an opioid as the analgesic component of a TIVA technique. Addition of such adjuvant agents results in synergistic rather than merely additive effects [9-11]. However, data are scant regarding specific combinations of anesthetic agents; thus, limited knowledge exists regarding potential clinical benefits and adverse effects of such combinations. Dose reduction of all administered agents is appropriate when these synergistic effects result in undesirable decreases in blood pressure.

Dexmedetomidine — Dexmedetomidine is a highly selective alpha₂ agonist acting on receptors in the brain and spinal cord. Dexmedetomidine is not routinely used as an adjunct to reduce dosing of sedative-hypnotic and opioid agents during maintenance of general anesthesia. Its use as a sedative in intraoperative interventions and intensive care unit are discussed in separate topics. (See "Monitored anesthesia care in adults", section on 'Dexmedetomidine' and "Pain control in the critically ill adult patient", section on 'Dexmedetomidine'.)

●Dosing – Data are limited regarding optimal dosing during coadministration of dexmedetomidine with hypnotic intravenous or potent inhalation anesthetic agents. It is typically administered as a continuous infusion at 0.1 to 0.3 mcg/kg per hour, although higher doses up to 0.8 mcg/kg per hour are sometimes used. Dosing should be reduced in patients with hepatic insufficiency since dexmedetomidine is heavily protein-bound; thus, its elimination half-life may be prolonged [44]. Also, dosing is reduced in patients with reduced hepatic blood flow such as those with low cardiac output, and in older adults due to age-related decline in hepatic mass and function [45,46] (see "Anesthesia for the older adult", section on 'Intravenous anesthetic and adjuvant agents'). Clearance of dexmedetomidine is not affected by fat mass in obese patients; thus, weight-based dosing may result in higher than necessary plasma concentrations [47].

●Advantages – Advantages of dexmedetomidine include its analgesic, sedative, anxiolytic, antiemetic, and sympatholytic properties [48]. In particular, the analgesic effects of dexmedetomidine result in opioid-sparing effects [49,50]. In a randomized trial in 90 patients, a single intraoperative bolus dose of dexmedetomidine 0.5 mcg/kg reduced remifentanil-induced hyperalgesia [51]. Also, dexmedetomidine reduces requirements for propofol or potent inhalation anesthetics in a synergistic fashion; however, the degree of synergism remains unknown [9,52]. However, data regarding the overall efficacy and clinical significance of dexmedetomidine-induced decreases in postoperative pain and opioid requirements are inconsistent [53-55].

In a 2020 meta-analysis, administration of dexmedetomidine during the perioperative period was associated with less postoperative nausea and vomiting (PONV) [56]. However, this study has significant limitations because the use of routine PONV prophylaxis was not considered, thus questioning the clinical utility of the conclusions.

Some studies suggest that intraoperative administration of dexmedetomidine ameliorates or reduces the incidence of agitated emergence delirium [57-59] or postoperative delirium [60]. However, data are not consistent [61,62]. (See "Perioperative neurocognitive disorders in adults: Risk factors and mitigation strategies", section on 'Intravenous agents associated with lower risk'.)

●Disadvantages and adverse effects – Adverse effects of dexmedetomidine include the potential to cause hypotension and/or bradycardia due to its sympatholytic effects, particularly if coadministered with other agents that also cause these effects (eg, propofol or inhalation agents) [52,63]. In one randomized trial in 80 patients undergoing laparoscopic surgery, addition of a continuous infusion of dexmedetomidine to a continuous infusion of propofol administered via a closed-loop anesthesia delivery system (see "Intravenous infusion devices for perioperative use", section on 'Target-controlled infusion systems') resulted in consistent reduction of propofol requirements [52]. However, in this study, addition of dexmedetomidine increased the incidence of significant bradycardia (9 versus 41 percent) and hypotension (6 versus 26 percent), and increased time to emergence and degree of sedation in the early postoperative period. In another randomized trial in 312 patients, those receiving balanced opioid-free anesthesia with a dexmedetomidine infusion at 0.4 to 1.4 mcg/kg per hour had a higher incidence of hypoxemia and severe bradycardia, as well as delayed extubation and prolonged stay in the postanesthesia care unit (PACU), compared with those receiving an infusion of the short-acting opioid remifentanil at 0.1 to 0.25 mcg/kg per minute [61]. Other studies have demonstrated similar adverse effects of dexmedetomidine infusion used as an adjunct agent for maintenance of anesthesia [24,63-66].

Assessment of dexmedetomidine-induced level of sedation is difficult [67]. Also, dexmedetomidine has a variable context-sensitive half-time that depends on the duration of a continuous infusion (eg, four minutes after infusion for 10 minutes; 250 minutes after infusion for eight hours). This leads to difficulty in decisions regarding optimal timing for discontinuation of dexmedetomidine in order to prepare for emergence from general anesthesia. (See "Emergence from general anesthesia", section on 'Discontinue anesthetic agents'.)

Furthermore, resolution occurs gradually after discontinuation of dexmedetomidine. Thus, relative overdosing, respiratory depression, hemodynamic depression of heart rate and blood pressure, residual sedation, and delayed recovery may persist in the early postoperative period, particularly after coadministration of dexmedetomidine with a sedative-hypnotic or opioid [52,64]. (See "Monitored anesthesia care in adults", section on 'Dexmedetomidine'.)

Ketamine — Ketamine is an N-methyl-d-aspartate receptor antagonist that produces dissociative anesthesia (profound analgesia while appearing disconnected from surroundings) [68].

●Dosing – Dosing during a TIVA technique begins with an IV bolus of 0.25 to 0.35 mg/kg, followed by infusion of less than 1 mg/kg per hour. There is no role for a single dose of ketamine during the maintenance phase of anesthesia.

●Advantages – Ketamine has anesthetic and excellent analgesic effects that reduce requirements for other anesthetic agents (eg, propofol, potent inhalation anesthetics). It is often used in opioid-tolerant patients undergoing major surgical procedures, particularly when regional analgesic techniques are not possible [69]. Ketamine maintains airway reflexes and respiratory drive, which is advantageous in patients who are breathing spontaneously, and also has excellent bronchodilatory properties. (See "General anesthesia: Intravenous induction agents", section on 'Advantages and beneficial effects'.)

In cases when neuromonitoring is necessary, a ketamine infusion may be used as an adjuvant agent because it beneficially augments motor evoked potential (MEP) and somatosensory evoked potential (SSEP) amplitudes [70,71]. (See "Neuromonitoring in surgery and anesthesia", section on 'Intravenous agents'.)

●Disadvantages and adverse effects – Ketamine increases sympathetic tone with typical increases in blood pressure, heart rate, and cardiac output, which may be beneficial in patients with hemodynamic instability, but may be detrimental in patients with ischemic heart disease or systemic hypertension. Furthermore, these sympathomimetic effects increase pulmonary artery pressure and intracranial pressure, effects which may be detrimental in patients with pulmonary hypertension or elevated intracranial pressure (ICP). (See "General anesthesia: Intravenous induction agents", section on 'Disadvantages and adverse effects'.)

Other potential adverse effects of ketamine include psychotomimetic effects that may cause hallucinations, nightmares, and vivid dreams during and shortly after emergence from anesthesia. Even single low doses of ketamine used for induction of anesthesia (0.5 mg to 1 mg/kg) can induce such negative experiences [72]. Thus, ketamine is typically reserved for opioid-tolerant patients who are undergoing painful surgery in order to avoid or limit opioid dosing [69]. (See "Delayed emergence and emergence delirium in adults", section on 'Evaluation and treatment'.)

Lidocaine — Lidocaine is a local anesthetic agent that is often used during IV induction of general anesthesia to suppress airway reflexes, reduce the pain of injection of other induction agents, and supplement their anesthetic effects. Lidocaine infusion is occasionally used during maintenance of general anesthesia as a component of a multimodal analgesia technique. (See "General anesthesia: Intravenous induction agents", section on 'Lidocaine'.)

●Dosing – When used during the maintenance phase, lidocaine is administered as a 1 to 1.5 mg/kg bolus, followed by continuous infusion of 1 to 1.5 mg/kg per hour (or 2 mg/minute in some studies) [73-75]. Notably, calculated doses should be based on lean or adjusted body weight, rather than on actual body weight (calculator 1 and calculator 2) [75].

●Advantages – Some studies have reported that infusion of lidocaine reduces opioid and sedative-hypnotic requirements and improves postoperative pain control after open or laparoscopic abdominal surgery, particularly if regional anesthetic techniques cannot be employed, and lidocaine may also improve pain control and reduce airway reactivity in patients undergoing head and neck procedures [73-76].

However, the overall role of lidocaine infusion as an analgesic adjunct is questionable. A 2018 meta-analysis concluded that lidocaine infusion does not have any beneficial effects on postoperative pain scores, opioid consumption, opioid-related adverse effects, or gastrointestinal recovery compared with placebo or no treatment [77].

●Disadvantages and adverse effects – Few studies have assessed adverse effects of administering a continuous IV infusion of lidocaine [77]. However, the risk of local anesthesia systemic toxicity (LAST) may rarely occur due to inadvertent boluses of IV lidocaine or accidental infusion pump programming errors, and is potentially life-threatening [78]. Also, lidocaine has the potential to cause hypotension [79,80].

NEUROMUSCULAR BLOCKING AGENTS

General considerations — A neuromuscular blocking agent (NMBA) may be employed to improve surgical conditions in selected cases.

Two classes of NMBAs exist: depolarizing (succinylcholine [SCh]) and nondepolarizing agents (eg, rocuronium, vecuronium, pancuronium, atracurium, cisatracurium, mivacurium) (table 7). All nondepolarizing NMBAs have a slower onset and longer duration than SCh. A nondepolarizing NMBA is typically selected during the maintenance phase unless the surgical procedure is expected to last only a few minutes. (See "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Classification of neuromuscular blocking agents'.)

Intraoperative monitoring of the intensity of neuromuscular blockade is necessary throughout the maintenance phase of general anesthesia when a NMBA is administered [81-83]. (See "Monitoring neuromuscular blockade".)

Advantages and disadvantages

●Advantages:

•Muscle relaxation in the surgical field and/or complete absence of movement facilitates safety and technical performance in many surgical procedures, and may allow lower insufflation pressures during laparoscopy. (See "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Facilitation of surgery'.)

•Use of an NMBA may reduce total administered doses of anesthetic agents. (See "Accidental awareness during general anesthesia", section on 'Neuromuscular blockade'.)

●Disadvantages:

•Risk of awareness is potentially increased since use of an NMBA may reduce the total administered doses of anesthetic agents, particularly when complete paralysis eliminates all purposeful movement. (See "Accidental awareness during general anesthesia", section on 'Neuromuscular blockade'.)

•Residual neuromuscular block after administration of NMBAs is an important risk factor for anesthesia-related morbidity and mortality. Strategies to avoid residual block are discussed in detail in a separate topic. (See "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Avoidance of residual neuromuscular blockade'.)

•NMBAs, particularly rocuronium and SCh, have a relatively high incidence of anaphylaxis compared with other agents employed during general anesthesia. Anaphylaxis is more common in some countries (eg, Australia, New Zealand, France, and Norway), possibly due to immunologic cross-reactivity with pholcodine (an over-the-counter cough suppressant available in those countries). (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Neuromuscular-blocking agents'.)

Specific neuromuscular blocking agents — Selection of a specific NMBA is based on the planned duration of the surgical procedure, presence of severe renal or hepatic dysfunction, the NMBA that was administered during anesthetic induction, whether the surgical procedure requires peripheral nerve stimulation or motor-evoked potential (MEP) monitoring, and availability and cost of each agent within an individual institution or country (table 7).

Further details regarding use of NMBAs are discussed separately. (See "Clinical use of neuromuscular blocking agents in anesthesia".)

TRANSITION TO THE EMERGENCE PHASE — Emergence is the return of consciousness after discontinuing administration of anesthetic and adjuvant agents at the end of the surgical procedure. Most patients transition smoothly from a surgical anesthetic state (Stage III) to an awake state (Stage I) (table 1). Preparations for emergence are discussed in a separate topic. (See "Emergence from general anesthesia", section on 'Preparations for emergence'.)

SUMMARY AND RECOMMENDATIONS

●Goals – Overall goals during the maintenance phase of a general anesthetic include maintaining Stage III surgical anesthesia (ie, unconsciousness, amnesia, immobility, and unresponsiveness to surgical stimulation (table 1)) at a safe anesthetic depth, while also maintaining respiratory and hemodynamic stability. (See 'Anesthetic goals' above.)

●Techniques – Maintenance of general anesthesia may be accomplished by employing a primary inhalation technique, a primary intravenous (IV) technique, or a combination of inhalation and IV agents. Coadministration of agents from different classes takes advantage of their synergistic effects, increasing the likelihood of achieving the desired anesthetic goals while using less of each drug than if it were administered alone. (See 'Selection of maintenance techniques' above.)

●Inhalation anesthetic agents

•Potent volatile inhalation agents – Specific advantages, disadvantages, and adverse effects differ among these agents, as described separately:

-Sevoflurane (see "Inhalation anesthetic agents: Clinical effects and uses", section on 'Sevoflurane')

-Desflurane (see "Inhalation anesthetic agents: Clinical effects and uses", section on 'Desflurane')

-Isoflurane (see "Inhalation anesthetic agents: Clinical effects and uses", section on 'Isoflurane')

-Halothane (see "Inhalation anesthetic agents: Clinical effects and uses", section on 'Halothane')

-Dosing considerations – Dose titration of potent volatile inhalation agents is necessary to maintain stage III surgical anesthesia. Each inhalation anesthetic agent's potency is reported as a minimum alveolar concentration (MAC) value (table 3 and table 2), which is influenced by patient age and coexisting diseases or conditions (table 4). Dosing is decreased with concomitant administration of nitrous oxide (N₂O) and/or if IV anesthetic agents. (See 'Volatile inhalation agents' above.)

-Advantages – General advantages of the potent volatile inhalation agents (eg, sevoflurane, desflurane, isoflurane, halothane) include ease of titration, dose-dependent decreases in skeletal muscle tone, cerebral metabolic rate, and bronchodilation (except desflurane), and ability to use end-tidal anesthetic concentration (ETAC) values to titrate anesthetic depth. ETAC values of 0.8 to 1 MAC are typically adequate to prevent awareness with recall.

-Disadvantages – General disadvantages include dose-dependent systemic vasodilation (with decreased blood pressure) and respiratory depression, and increased risk of postoperative nausea and vomiting (PONV) compared with most IV anesthetic alternatives, unless prophylactic antiemetics are administered. The volatile inhalation anesthetics also have the potential to precipitate malignant hyperthermia. (See 'Volatile inhalation agents' above.)

●Nitrous oxide – Nitrous oxide (N₂O) is a pressurized anesthetic gas delivered via a flow meter on the anesthesia machine. We routinely use N₂O unless there is a contraindication. Advantages include rapid onset and offset of anesthetic effect that allows decreased dosing of other anesthetic agents, as well as analgesia and anxiolysis. N₂O is always avoided in patients with pre-existing bowel distention, increased middle ear pressure, pneumothorax, pneumoperitoneum, pneumocephalus, intraocular gas, or venous air embolism. (See 'Nitrous oxide gas' above.)

●Total intravenous anesthesia (TIVA) – TIVA employs an IV sedative-hypnotic anesthetic (typically propofol) and an analgesic agent (typically an opioid). (See 'Total intravenous anesthesia' above.)

•Propofol – Propofol is most commonly selected as the sedative-hypnotic component of a TIVA technique because of its rapid onset and recovery; beneficial antiemetic, bronchodilatory, and anticonvulsant properties; and relatively benign adverse side effects. Propofol is infused at 75 to 150 mcg/kg per minute, with titration according to individual requirements, the degree of noxious surgical stimulation, and coadministration of other anesthetic agents. (See 'Sedative-hypnotic agent: Propofol' above.)

•Opioids – An opioid is most commonly employed as the analgesic component of a TIVA technique. Potential adverse effects include exacerbation of hypotensive effects of propofol, respiratory depression, bradycardia, PONV, ileus, constipation, delirium, pruritus, and potential for acute tolerance. Choice of a specific opioid is dependent upon patient- and procedure-specific factors (table 6).

•Other adjuvant agents – Infusions of other IV agents (eg, dexmedetomidine, ketamine, lidocaine) may be used for patient-specific or procedure-specific reasons to reduce or replace propofol as the sedative-hypnotic component or an opioid as the analgesic component of a TIVA technique. Overall, these adjunct agents have limited benefits and specific potential adverse effects, as noted above. (See 'Adjuvant agents' above.)

●Neuromuscular blocking agents (NMBAs) – A nondepolarizing NMBA is typically employed if profound muscle relaxation in the surgical field and/or absence of movement are necessary (table 7). Disadvantages of neuromuscular blockade include intraoperative elimination of purposeful movement as a sign of awareness, and the potential for residual postoperative neuromuscular weakness, which may lead to respiratory complications. (See 'Neuromuscular blocking 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.