Induction of general anesthesia: Overview

INTRODUCTION — General anesthesia establishes a reversible state that includes:

●Hypnosis

●Amnesia

●Analgesia

●Akinesia

●Autonomic and sensory block

The goals for induction of general anesthesia are to rapidly, safely, and pleasantly produce these conditions while maintaining adequate oxygenation, ventilation, and hemodynamic stability. This topic provides an overview of preinduction preparations and selection of anesthetic induction agents and techniques. Recommendations for specific types of surgical procedures and for patients with specific comorbidities are discussed in individual topics.

Specific intravenous (IV) and inhalation anesthetics and neuromuscular blocking agents used during induction of general anesthesia are reviewed in separate topics:

●IV induction and adjuvant agents (see "General anesthesia: Intravenous induction agents" and "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Induction')

●Inhalation agents (see "Inhalation anesthetic agents: Clinical effects and uses", section on 'Induction of general anesthesia' and "Inhalation anesthetic agents: Properties and delivery")

●Neuromuscular blocking agents (see "Clinical use of neuromuscular blocking agents in anesthesia")

Techniques used during induction of general anesthesia (eg, preoxygenation, airway management) are also reviewed separately:

●(See "Preoxygenation and apneic oxygenation for airway management for anesthesia".)

●(See "Airway management for induction of general anesthesia".)

●(See "Rapid sequence induction and intubation (RSII) for anesthesia".)

●(See "Management of the difficult airway for general anesthesia in adults".)

CONTINUUM OF SEDATION DURING ANESTHETIC INDUCTION — Anesthetic agents demonstrate a dose-response effect, with progressively higher doses providing progressively deeper levels of sedation and anesthesia. During induction of general anesthesia, sedation progresses as a continuum of effect rather than as a consecutive series of distinct states with clear transitions (table 1) [1].

Light/minimal sedation with anxiolysis and analgesia is a level in which responsiveness to voice, airway patency, spontaneous ventilation, and cardiovascular function are preserved. Moderate sedation, also termed conscious sedation, represents a deeper level of sedation and analgesia, in which the patient remains responsive to voice, has intact airway patency and spontaneous ventilation, but may have reduced blood pressure. Deep sedation is a state in which the patient no longer responds to voice, and may have compromised airway patency, ventilation, and cardiovascular function. However, movement in response to a noxious surgical stimulus still occurs. General anesthesia is an anesthetic depth at which the patient will not respond to voice or to noxious surgical stimuli.

As the patient progresses through deeper planes ("stages") of anesthesia, airway reflexes and patency, spontaneous ventilation, cardiovascular function, and muscle tone become increasingly depressed (figure 1). Patients may rapidly transition from one stage of anesthetic depth to the next. Thus, urgent interventions may become necessary to manage the airway or support respiratory and cardiovascular functions. For example, during "Stage 2," of general anesthesia (ie, the "reactive stage"), the patient is prone to laryngospasm requiring rapid intervention. During deeper states of general anesthesia, over-dosing of sedative/hypnotics may cause hypotension and cardiovascular collapse.

Some degree of resistance to changes in consciousness typically occurs during induction of general anesthesia such that a higher effect-site concentration of anesthetic agent may be necessary to achieve loss of consciousness compared with the concentration noted upon return of consciousness during emergence [2-4]. This phenomenon is termed hysteresis or "neural inertia." (See "Emergence from general anesthesia".)

PREPARATION FOR ANESTHETIC INDUCTION

Before patient arrival — Before patient arrival in the operating room (OR) or interventional suite, the following steps are necessary:

●Anesthesia machine checkout – The anesthesia machine checkout should be performed prior to the patient's arrival in the operating room (table 2) [5]. (See "Anesthesia machines: Prevention, diagnosis, and management of malfunctions".)

●Airway equipment preparation – Since all anesthetic induction agents and adjuvants may cause respiratory depression, preparations for advanced airway management are necessary. (See "Airway management for induction of general anesthesia", section on 'Preparation for induction of anesthesia'.)

●Drug preparation – Routinely administered anesthetic drugs should be prepared. Drugs for treatment of common complications and emergencies should be immediately available. These include but are not limited to:

•A sedative/hypnotic, most commonly propofol; etomidate or ketamine can be selected for hemodynamically unstable patients. (See "General anesthesia: Intravenous induction agents".)

•A neuromuscular blocking agent (NMBA), either a nondepolarizing agent (eg, rocuronium, vecuronium) or a depolarizing agent (succinylcholine). (See "Clinical use of neuromuscular blocking agents in anesthesia".)

•A vasopressor, most commonly phenylephrine. Alternatives include ephedrine or dilute norepinephrine as appropriate (table 3).

•An anticholinergic (atropine or glycopyrrolate).

After patient arrival — After patient arrival in the OR, the following steps are completed:

●Monitoring – In addition to continuous personal observation provided by the anesthesia provider, the patient should be connected to standard American Society of Anesthesiologists (ASA) monitors before induction of general anesthesia [6]. Standard monitors include but are not limited to: electrocardiogram (ECG), pulse oximetry, blood pressure (BP), and temperature monitors, as well as an oxygen (O₂) analyzer and a continuous end-tidal carbon dioxide (ETCO₂) analyzer (eg, capnography, capnometry, or mass spectroscopy) in the patient breathing system (table 4). Preinduction measurements are obtained to ensure proper functioning of the monitors and to establish the patient's baseline values. (See "Basic patient monitoring during anesthesia".)

●Intravenous access – Virtually all adult patients have at least one peripheral venous or other vascular access catheter placed before induction. Catheters should be checked to ensure that they are patent. Intravenous (IV) fluids and equipment to obtain additional venous access should be immediately available. (See "Peripheral venous access in adults".)

●Preprocedure checklist – An appropriate preprocedure checklist should be completed; an example is provided in the table (table 5). (See "Patient safety in the operating room", section on 'Timeouts, briefing, and debriefing'.)

Immediately before induction

●Positioning for induction – Before induction of anesthesia, the patient's head is positioned in the sniffing position for optimal airway management (atlanto-occipital extension with head elevation of 3 to 7 cm) [7], supported so that the neck is flexed and the head extended (assuming an absence of cervical spine pathology). If not contraindicated, the head of the bed is elevated 20 to 30 degrees. (See "Airway management for induction of general anesthesia", section on 'Patient positioning'.)

●Preoxygenation (denitrogenation) – Before administration of any anesthetic induction or adjuvant agents, the patient is preoxygenated (denitrogenated) with 100 percent O₂ to increase O₂ reserve, thereby providing additional time to secure the airway [8,9]. (See "Airway management for induction of general anesthesia", section on 'Preoxygenation'.)

SELECTION OF INDUCTION TECHNIQUE — Induction of general anesthesia may be accomplished using primarily intravenous (IV) or primarily inhalation anesthetic agents. Most adults prefer induction primarily with IV agents. (See "General anesthesia: Intravenous induction agents" and "Inhalation anesthetic agents: Clinical effects and uses", section on 'Induction of general anesthesia'.)

Notably, adults may be less satisfied with a primary inhalation induction technique compared with IV induction due to the unpleasant odor of anesthetic gases [10], as well as a higher incidence of postoperative nausea and vomiting compared with use of IV agents such as propofol (see "Postoperative nausea and vomiting", section on 'Anesthetic factors') [10-12]. Furthermore, inhalation induction time is longer compared with IV induction. Several minutes of ventilation may be required. Thus, this technique is unsuitable for rapid sequence induction and intubation (RSII). (See "Rapid sequence induction and intubation (RSII) for anesthesia".)

The ideal induction agent has a rapid onset of action, minimal cardiopulmonary or other side effects, and is cleared from the bloodstream quickly so that recovery is rapid. However, none of the available induction agents is ideal for all patients, and all have side effects. We typically administer combinations of agents from different pharmacologic classes during induction and/or maintenance of general anesthesia. This strategy minimizes the total dose of any one anesthetic agent, thereby reducing the incidence of undesirable side effects. Age and coexisting diseases affect selection and dosing of anesthetic induction and adjuvant agents. (See "General anesthesia: Intravenous induction agents", section on 'Dosing considerations' and "Inhalation anesthetic agents: Clinical effects and uses", section on 'Influence of patient-related factors'.)

INTRAVENOUS ANESTHETIC INDUCTION

Patient selection — Adult patients usually have intravenous (IV) access and typically prefer induction with IV agents.

Techniques and anesthetic agents

Induction with endotracheal intubation — Selection and dosing of sedative-hypnotic and adjuvant agents are determined by patient-specific factors, including age and comorbidities. (See "General anesthesia: Intravenous induction agents", section on 'Dosing considerations'.)

●Intravenous sedative-hypnotic agent – During IV induction with planned endotracheal intubation, a primary IV sedative-hypnotic induction agent is typically administered (table 6). (See "General anesthesia: Intravenous induction agents".)

●Intravenous adjuvant agents – One or more adjuvant IV agents (eg, short-acting opioid, lidocaine, midazolam (table 7)) are also typically administered during induction to blunt the sympathetic stress response and cough reflex during laryngoscopy and intubation, minimize pain due to injection of the anesthetic induction agents, and supplement effects of the primary sedative-hypnotic anesthetic and reduce their dose. As an example, a reasonable combination of adjuvant agents is fentanyl 25 to 100 mcg, followed by lidocaine 50 to 100 mg, with both administered immediately prior to induction when either propofol or etomidate is selected for the sedative-hypnotic induction agent. We start with the lower end of these dose ranges in patients with conditions such as advanced age and/or frailty; hemodynamic abnormalities caused by persistent bleeding or other factors resulting in hypovolemia, vasodilation, or myocardial dysfunction; or impaired renal or hepatic function. (See "General anesthesia: Intravenous induction agents", section on 'Adjuvant agents' and "General anesthesia: Intravenous induction agents", section on 'Dosing considerations'.)

However, scant evidence is available to support use of any particular combination of agents. Notably, coadministration of agents acting on different receptor types may produce synergistic anesthetic effects. Thus, avoiding use of multiple agents or reducing doses may be prudent in older patients or those with significant comorbidities, particularly impaired renal and/or hepatic function. Adjuvant agents are typically avoided altogether in patients with actual or potential hemodynamic instability.

●Neuromuscular blocking agent – A neuromuscular blocking agent (NMBA) is usually administered before endotracheal intubation (table 8). (See 'Neuromuscular blocking agents' below and "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Endotracheal intubation'.)

●Addition of an inhalation agent – Inhalation anesthetic agent(s) are often added shortly after initial loss of consciousness is achieved using IV agents. Administration of inhalation anesthetic(s) deepens anesthesia and blunts airway reflexes and sympathetic stress responses during laryngoscopy. Potent volatile inhalation agents also induce a dose-dependent decrease in skeletal muscle tone, which improves conditions during insertion of either an endotracheal tube or supraglottic airway. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Use as a supplement (all inhalation agents)'.)

Induction with supraglottic airway placement — During IV induction with planned insertion of a supraglottic airway (SGA) such as a laryngeal mask airway (LMA), an adequate depth is necessary to avoid coughing, gagging, breath-holding, laryngospasm, or bronchospasm. (See "Supraglottic devices (including laryngeal mask airways) for airway management for anesthesia in adults", section on 'Placement technique'.)

Similar to induction with planned endotracheal intubation (see 'Induction with endotracheal intubation' above), lidocaine is typically administered before the selected primary IV sedative-hypnotic induction agent [13]. (See "General anesthesia: Intravenous induction agents".)

However, opioids may be avoided or minimized during the induction sequence if spontaneous ventilation is planned after SGA insertion to avoid a period of apnea due to opioid-induced respiratory depression. (See "Supraglottic devices (including laryngeal mask airways) for airway management for anesthesia in adults", section on 'Choice of mode of ventilation'.)

If difficulties are encountered with SGA placement or initial ventilation, additional doses of the selected sedative-hypnotic agent can be administered. Alternatively, intubation with an endotracheal tube can be performed. (See "Supraglottic devices (including laryngeal mask airways) for airway management for anesthesia in adults", section on 'Troubleshooting'.)

INHALATION ANESTHETIC INDUCTION — Properties, mechanisms of action, and delivery of inhalation agents are discussed separately (table 9). (See "Inhalation anesthetic agents: Properties and delivery".)

Patient selection — An inhalation induction technique is often selected for younger pediatric patients or those with developmental delay to avoid fear of needles and responses to the pain of a needle stick [14]. Inhalation induction may also be the preferred method for adult patients when:

●Maintenance of spontaneous ventilation is desirable during induction. Examples include patients with intraoral, pharyngeal, or mediastinal mass causing compression of the airway if an awake intubation technique is not feasible.

●An in situ tracheostomy is present since unpleasant odor and irritation of the airway are not problematic.

●Intravenous (IV) access is difficult to obtain. However, IV access should be established immediately after induction so that common problems such as hypotension during induction can be treated.

Techniques and specific inhalation agents — Inhalation induction of anesthesia requires a high concentration of a volatile anesthetic agent, with or without nitrous oxide (N₂O). Development of non-pungent, nonirritant volatile anesthetics that have rapid onset (eg, sevoflurane) has made inhalation induction of anesthesia via facemask less irritating and viable option compared with induction using older inhalation agents [11].

Modified administration techniques can be used to facilitate the speed of anesthetic induction. For example, the breathing circuit may be primed with a high sevoflurane concentration (eg, 8 percent) plus N₂O. Then the patient is instructed to take a vital capacity breath (defined as a complete expiration followed by a complete inspiration), followed by a period of apnea with inflated lungs (ie, "breath-holding") [15]. Typically this single breath technique achieves the 2 percent alveolar sevoflurane concentration required to tolerate painful interventions such as surgical incision [16]. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Technique-related considerations'.)

Potent volatile agents — Advantages shared by all potent volatile anesthetic agents during induction of general anesthesia include excellent bronchodilation, dose-dependent decrease in skeletal muscle tone, and decrease in cerebral metabolic rate of oxygen consumption (CMRO₂). Disadvantages of these agents include respiratory depression, systemic vasodilation, and decreased blood pressure (BP), adverse effects which are dose-dependent. In rare instances, all potent volatile agents can precipitate malignant hyperthermia. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Other clinical effects'.)

●Sevoflurane – Sevoflurane has many characteristics of the ideal induction agent, and is the most commonly used potent volatile inhaled agent for this purpose. It has minimal odor, lacks pungency, and has potent bronchodilating characteristics [10-12,14,17-19]. Furthermore, sevoflurane has relatively rapid onset due to its low tissue and blood solubilities, which also result in rapid clearance from the bloodstream and rapid recovery. The time to loss of consciousness may be as little as 60 seconds if a high concentration of sevoflurane (eg, 4 to 8 percent) is briefly delivered via a facemask [14,15,20]. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Sevoflurane' and "Inhalation anesthetic agents: Clinical effects and uses", section on 'Induction of general anesthesia'.)

●Isoflurane – Isoflurane is the most potent of the volatile anesthetics but is not ideal for use as the sole induction agent because of its relative pungency and slow onset (and recovery) compared with sevoflurane. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Isoflurane'.)

●Halothane – Halothane is a sweet-smelling gas with only moderate pungency. However, halothane is no longer commercially available in North America due to adverse effects (particularly the possibility of halothane hepatitis). Also, halothane has the slowest onset compared with all other potent inhalation agents during induction of anesthesia because of its high tissue and blood solubility. Other disadvantages include significant myocardial depression at higher doses and risk of arrhythmias due to sensitization of the myocardium to catecholamines (either endogenous or exogenously administered epinephrine or norepinephrine). For these reasons, newer inhalation agents such as sevoflurane have been developed to replace halothane. However, halothane is still used in many countries with limited resources for both induction and maintenance of general anesthesia due to its low cost and wide availability. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Halothane'.)

●Desflurane – Desflurane is generally not used during induction of anesthesia via facemask. It is the most pungent of the volatile anesthetics and has the highest incidence of airway irritation (coughing, salivation, breath-holding, laryngospasm), particularly at high concentrations [17,21]. Also, desflurane can cause sympathetic stimulation, tachycardia, and hypertension when administered in high or abruptly increased inspired concentrations. Since any inhalation agent must be rapidly increased to produce a high concentration during induction of general anesthesia in an awake patient, these properties limit use of desflurane during induction. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Desflurane'.)

Nitrous oxide gas — N₂O is a sweet-smelling gas without pungency or potential for airway irritation. N₂O increases speed of anesthetic onset if coadministered with any potent volatile inhalation agent, compared with administration of the potent agent alone, due to a phenomenon termed the "second gas" effect. Thus, it is often used as an adjuvant agent during inhalation induction of general anesthesia. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Second gas effect' and "Inhalation anesthetic agents: Clinical effects and uses", section on 'Nitrous oxide'.)

Notably, N₂O is avoided during induction in certain patients, including those with pre-existing bowel distention, increased middle ear pressure, pneumothorax, pneumoperitoneum, pneumocephalus, intraocular gas, or venous air embolism [22-24]. Further gaseous distension of such spaces during administration of N₂O has potentially significant adverse consequences (eg, nausea with emesis, tension pneumothorax, increased intracranial pressure, vision loss, expansion of entrapped intravascular air). Also, N₂O is typically avoided during induction in patients with cardiomyopathy and/or pulmonary hypertension because it causes mild myocardial depression and mild sympathetic nervous system stimulation that may increase pulmonary vascular resistance. (See "Inhalation anesthetic agents: Clinical effects and uses", section on 'Disadvantages and adverse effects'.)

NEUROMUSCULAR BLOCKING AGENTS

●For endotracheal intubation – During induction of general anesthesia, a neuromuscular blocking agent (NMBA) is usually administered to facilitate laryngoscopy and intubation if endotracheal intubation is planned (table 8). (See "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Endotracheal intubation'.)

The choice of NMBA should be based on the desired speed of onset, reversibility, patient comorbidities, and anticipated difficulty of airway intubation. If rapid sequence intubation and induction is desired, either succinylcholine (SCh; 1 to 1.5 mg/kg) or rocuronium (1.2 mg/kg) is typically selected. If a relatively large dose of rocuronium is used to achieve swift onset of optimal intubating conditions, the neuromuscular blocking effect may be rapidly terminated by administering sugammadex 16 mg/kg [25,26]. (See "Rapid sequence induction and intubation (RSII) for anesthesia", section on 'Neuromuscular blocking agents (NMBAs)' and "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Sugammadex'.)

Nondepolarizing NMBAs administered in usual doses (eg, rocuronium 0.6 mg/kg, vecuronium, cisatracurium, atracurium, and pancuronium) have a slower onset than SCh but are often selected for elective intubation to avoid the side effects of SCh if the patient does not need RSII and does not have a potentially difficult airway (table 8).

●For supraglottic airway insertion – Occasionally, a small dose of an NMBA is employed to facilitate supraglottic airway (SGA) placement by preventing coughing and other airway responses. (See 'Induction with supraglottic airway placement' above.)

VASOPRESSOR AGENTS — Vasopressor agents may be administered to treat hypotension during induction of general anesthesia. Typical choices of agents are (table 3) (see "Intraoperative use of vasoactive agents", section on 'Vasopressor and positive inotropic agents'):

●Phenylephrine, a pure alpha₁-adrenergic agonist that causes both arterial and venous vasoconstriction. Administration of phenylephrine 40 to 100 mcg IV bolus increases blood pressure (BP). Doses may be repeated if necessary.

●Ephedrine, an alpha and beta receptor adrenergic agonist that causes release of endogenous norepinephrine stores. Administration of ephedrine 5 to 10 mg IV bolus increases both BP and heart rate (HR). Doses may be repeated if necessary.

Occasionally, continuous infusion of a phenylephrine or a more potent vasopressor (eg, norepinephrine) may be necessary to maintain hemodynamic stability during and immediately after induction of general anesthesia.

CLINICAL CASE EXAMPLES — Patient-specific or procedure-specific considerations may affect selection of anesthetic induction techniques and agents. The following clinical examples are discussed in detail in separate topics:

●Hemodynamically unstable patient – In a patient with actual or potential hemodynamic instability (eg due to hypovolemia, vasodilation, or severe myocardial dysfunction) (see "Intraoperative management of shock in adults"), we typically select etomidate (0.2 to 0.4 mg/kg) or ketamine (0.5 to 2 mg/kg) to induce general anesthesia [27].

●Need for rapid sequence induction and endotracheal intubation – In a patient with high risk for pulmonary aspiration, rapid sequence induction and intubation (RSII) is typically selected to minimize the time the patient is sedated with an unprotected airway. A single rapid bolus of the sedative-hypnotic agent is immediately followed by administration of the neuromuscular blocking agent (NMBA). Underdosing either the sedative-hypnotic or the NMBA may result in laryngospasm if intubation is not successful on first attempt or patient recall. Notably additional adjuvant agents (eg, opioids, lidocaine, midazolam) are usually minimized or avoided for a RSII technique. (See "Rapid sequence induction and intubation (RSII) for anesthesia".)

In some patients with very high risk for aspiration, awake intubation is performed rather than RSII, particularly if a potentially difficult airway is anticipated. (See "Management of the difficult airway for general anesthesia in adults", section on 'Awake intubation'.)

●Older patient – In general, doses of intravenous and inhalation induction agents should be reduced in an older adult. (See "Anesthesia for the older adult", section on 'Selection and dosing of anesthetic agents'.)

●Patients with specific comorbidities:

•Heart disease – (See "Anesthesia for noncardiac surgery in patients with ischemic heart disease", section on 'Induction' and "Intraoperative management for noncardiac surgery in patients with heart failure", section on 'Induction'.)

•End stage renal disease – (See "Anesthesia for dialysis patients", section on 'Induction'.)

•Brain tumor or head injury – (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'.)

•Eye injury – (See "Anesthesia for emergency eye surgery", section on 'Choice of induction and adjuvant anesthetic agents'.)

SUMMARY AND RECOMMENDATIONS

●Definition of general anesthesia – General anesthesia is a reversible state that includes hypnosis, amnesia, analgesia, akinesia, and autonomic and sensory block such that the patient will not respond to voice or to noxious surgical stimuli. During induction of general anesthesia, sedation progresses as a continuum of effect rather than as a consecutive series of distinct states with clear transitions (figure 1 and table 1). (See 'Continuum of sedation during anesthetic induction' above.)

●Preparations for induction

•Before patient arrival – Anesthesia machine checkout procedure (table 2), preparation for advanced airway management, and preparation of routinely administered drugs. (See 'Before patient arrival' above.)

•After patient arrival – Connection of standard American Society of Anesthesiologists (ASA) monitors, establishment of intravenous (IV) access, completion of preprocedure checklist (table 5). (See 'After patient arrival' above.)

•Immediately before induction – Head positioning in the sniffing position, preoxygenation using 100 percent oxygen. (See 'Immediately before induction' above.)

●Intravenous anesthetic induction – Most adults prefer induction with IV agents. Combinations of agents from different pharmacologic classes are typically administered to minimize dose of each anesthetic agent (see 'Intravenous anesthetic induction' above):

•Sedative-hypnotic agent (eg, propofol, etomidate, ketamine) (table 6)

•Adjuvant agent(s) (eg, short-acting opioid, lidocaine, midazolam) (table 7)

•Neuromuscular blocking agent (NMBA) if endotracheal intubation is planned or to facilitate supraglottic airway placement (table 8) (see 'Neuromuscular blocking agents' above)

•Inhalation anesthetic agent(s), often added shortly after achieving initial loss of consciousness

●Inhalation anesthetic induction – Inhalation induction is often preferred by children due to fear of needles, and may be selected for adults when spontaneous breathing during induction is desirable. Agents include the potent volatile anesthetics (eg, isoflurane, sevoflurane, desflurane) and the gas nitrous oxide (table 9). (See 'Inhalation anesthetic induction' above.)

●Use of vasopressor agents – Phenylephrine or ephedrine may be administered if necessary to treat hypotension. (See 'Vasopressor agents' above.)

●Patient-specific and procedure-specific considerations – (See 'Clinical case examples' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Liza M Weavind, MBBCh, FCCM, MMHC, who contributed to an earlier version of this topic review.