Inhalation Anesthetic Agents: Clinical Effects and Uses

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Inhalation anesthetic agents: Clinical effects and uses
Author: Stephen Robert Hays, MD, FAAP

Section Editor: Girish P Joshi, MB, BS, MD, FFARCSI
Deputy Editor: Nancy A Nussmeier, MD, FAHA
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2018. | This topic last updated: Sep 25, 2018.
INTRODUCTION — This topic will review the anesthetic and other clinical effects of inhalation anesthetics including the potent volatile agents
(sevoflurane, desflurane, isoflurane [and in some countries, halothane]) and one gas (nitrous oxide [N2O]), as well as uses of each agent to
induce and maintain general anesthesia. Properties of the inhalation anesthetics and techniques for their delivery via an anesthesia machine are
discussed separately. (See "Inhalation anesthetic agents: Properties and delivery" and "Anesthesia machines: Prevention, diagnosis, and
management of malfunctions".)
Clinical uses of intravenous agents to induce and maintain general anesthesia are reviewed in separate topics. (See "General anesthesia:
Intravenous induction agents" and "General anesthesia: Maintenance", section on 'Total intravenous anesthesia'.)
CLINICAL EFFECTS — Inhalation anesthetics produce sedation and general anesthesia as well as other clinical effects. Pharmacodynamic
parameters for each agent describe these effects (ie, what the drug does to the body).
Sedation and anesthesia
Continuum of effect: sedation to general anesthesia — Inhalation anesthetic agents demonstrate a dose-response effect, with
progressively higher doses providing progressively deeper levels of sedation and anesthesia (table 1). General anesthesia is a reversible state
that includes:
● Hypnosis (ie, loss of consciousness)
● Amnesia (ie, lack of recall)
● Analgesia (ie, pain relief)
● Akinesia (ie, immobility)
● Autonomic and sensory block
Inhalation agents are complete general anesthetic agents, in that they provide all of these components at clinically relevant concentrations.
MAC and MAC-awake values for inhalation agents — The minimum alveolar concentration (MAC) and MAC-awake values are measures of
inhalation anesthetic potency.
● MAC value – The MAC value is the concentration of an inhalation agent in the alveoli required to prevent movement in response to a
noxious stimulus in 50 percent of subjects after allowing sufficient time for uptake and redistribution of the inhalation agent to reach a steady
state (table 2) [1]. In human studies, the tested noxious stimulus is typically a skin incision. Thus, MAC is the effective dose (ED)50 for
absence of movement in response to surgical pain. Ablation of reflex arcs in the spinal cord involving sites of action that include the sensory
neurons of the dorsal root ganglion and motor afferent neurons is thought to be the primary mechanism for absence of movement, without
input from higher centers.
MAC values differ for each inhalation anesthetic agent (table 3). Only nitrous oxide (N2O) gas has a MAC value >100 (105 percent at
standard pressure and temperature). Thus, N2O has extremely low potency, and MAC cannot be achieved when N2O is delivered under
standard conditions.
● MAC-awake value – The MAC-awake (also termed MAC-aware) value is the concentration of an inhalation agent in the alveoli at which 50
percent of patients will not respond to a verbal or non-noxious tactile stimulus. Thus, MAC-awake is the ED50 for response to voice or light
touch and is thought to approximate the ED50 required for perceptive awareness and anesthetic recall. For each inhalation agent, MAC-
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awake values are approximately 40 percent of the standard MAC value required to tolerate surgical stimuli without movement. Suppression
of the brainstem and cortical centers involved in consciousness, in particular the reticular activating system, is thought to be the primary
mechanism responsible for absence of response to voice or light touch.
Influence of drug-drug interactions — The anesthetic effects of the different inhalation agents are additive. For example, if N2O is
administered at 0.5 MAC (approximately 50 percent N2O concentration) together with isoflurane administered at 0.5 MAC (approximately 0.6
percent isoflurane concentration), then the additive anesthetic effects should be approximately 1.0 MAC.
MAC for any inhalation anesthetic is decreased by concurrent administration of any intravenous (IV) anesthetic, sedative, and/or analgesic agent
(eg, sedative-hypnotics, benzodiazepines, opioids, lidocaine) [2].
When anesthetic drugs from different classes are combined, the effects are typically synergistic rather than merely additive [3]. Synergy is
particularly common when drugs acting primarily on gamma-aminobutyric acidA (GABAA) receptors (eg, volatile inhalation agents, propofol,
etomidate, benzodiazepines) are combined with drugs acting on other receptor types (eg, opioids).
MAC is decreased by acute alcohol use due to its sedative effects, or chronic use of amphetamines or alpha2 agonists, which may deplete central
nervous system (CNS) catecholamine levels (table 4). Conversely, MAC is increased by chronic alcohol use (likely due to enhanced hepatic
metabolism) and by recent use of either amphetamines, cocaine, or ephedrine since these agents may acutely increase CNS catecholamine
levels that enhance focused consciousness (table 4).
Influence of patient-related factors — MAC values are also influenced by patient age and coexisting conditions (table 4) [4]. Awareness of
such effects is important to avoid inadequate anesthesia or, conversely, anesthetic overdose.
Age — In general, MAC decreases incrementally with age, as shown in figures for isoflurane (figure 1), sevoflurane (figure 2), and
desflurane (figure 3). MAC is reduced at the extremes of age (eg, premature infants or patients >60 years old), although effects vary by agent. For
more soluble agents such as halothane (figure 4) and isoflurane (figure 5), MAC is reduced at birth, particularly in premature infants, rising until
around age six months before beginning to decrease with further aging. For newer less soluble agents such as sevoflurane (figure 6) and
desflurane (figure 4), and for N2O (figure 4), decreases in MAC not been demonstrated in young infants.
Other factors — MAC is markedly reduced in patients with severe comorbidities (eg, shock, anemia). Also, pregnancy decreases MAC.
Furthermore, hypothermia, hypothyroidism, hypercarbia, hypoxia, metabolic acidosis, and acute electrolyte abnormalities decrease MAC (table 4).
Conversely, hyperthermia, hyperthyroidism, anxiety, and other conditions associated with psychomotor activation increase MAC (table 4).
Other clinical effects
Skeletal and smooth muscle relaxation — All potent volatile inhalation anesthetics induce dose-dependent relaxation of both skeletal and
smooth muscle by inhibiting nicotinic acetylcholine receptors.
● Skeletal muscle relaxation – The volatile inhalation agents potentiate and reduce the required dose of a neuromuscular blocking agent
(NMBA). The degree of potentiation of NMBA effect depends upon the concentration of inhalation anesthetic administered, the duration of
exposure, and the specific agent. The degree to which each inhalation agent potentiates NMBA effects (from highest to lowest) is (see
"Clinical use of neuromuscular blocking agents in anesthesia", section on 'Drug interactions'):
desflurane > sevoflurane > isoflurane > halothane > N2O
The degree of skeletal muscle relaxation induced by administration of an inhalation agent alone may be insufficient for many procedures if
the surgeon requires profound muscle relaxation. Also, the degree of skeletal muscle relaxation may be insufficient to prevent patient
movement in response to all noxious surgical stimuli during light or moderate anesthetic depth. Thus, monitoring of the degree of
neuromuscular blockade is recommended to achieve adequate skeletal muscle relaxation when desired, as well to ensure complete reversal
when relaxation is no longer needed. (See "Monitoring neuromuscular blockade".)
● Smooth muscle relaxation – All volatile inhalation agents also induce smooth muscle relaxation, which may be beneficial in certain
situations. For example, uterine relaxation may be induced with administration of an inhalation anesthetic agent to facilitate extraction of
retained products of conception. Other clinical effects resulting from skeletal smooth muscle relaxation may be detrimental. For example,
gastrointestinal smooth muscle relaxation contributes to postoperative nausea, emesis, and ileus, while vesicoureteral smooth muscle
relaxation contributes to postoperative urinary retention.
Respiratory effects
Airway reflexes — Inhalation of volatile anesthetic agents can produce airway irritation and may precipitate coughing or laryngospasm
during induction of anesthesia, particularly with the more pungent agents (desflurane and isoflurane). This is more likely in patients who smoke or
have reactive airway disease (eg, asthma, chronic obstructive pulmonary disease [COPD], cystic fibrosis, α1-antitrypsin deficiency, chronic lung
disease of prematurity, or bronchopulmonary dysplasia [BPD]). The likelihood of airway complications, such as laryngospasm and bronchospasm,
due to inhalation agent pungency is (from most to least likely):
desflurane > isoflurane > halothane > sevoflurane > N2O
In particular, high concentrations (≥1.5 MAC) of desflurane are likely to cause airway irritation [5,6].
During Stage II, excitement and hyperstimulation exaggerate responses to laryngeal or pharyngeal stimuli (see 'Transient delirium and excitability'
below). These responses increase risk for laryngospasm or emesis. As transition to Stage III and deeper levels of anesthesia occurs, laryngeal
and pharyngeal airway reflexes are abolished, which facilitates laryngoscopy and intubation. However, risk for aspiration is present until the
airway has been secured. Hence, an inhalation anesthetic induction technique is typically avoided in patients with pre-existing risk factors for
aspiration.
Bronchial effects — The potent volatile inhalation anesthetic agents are bronchodilators, decrease airway responsiveness, and attenuate
bronchospasm. The bronchodilatory properties of the inhalation agents result from beta2 receptor stimulation, which results in an increase in
intracellular cyclic adenosine monophosphate, causing relaxation of bronchial smooth muscle [7]. In fact, volatile anesthetic agents may be used
for treatment of severe status asthmaticus. Sevoflurane has the most pronounced bronchodilatory properties of the available inhalation
anesthetics. Halothane was historically the agent of choice to prevent or treat bronchoconstriction, but it is no longer available in the United
States. Although desflurane directly relaxes airway smooth muscle at lower concentrations, higher concentrations (>1.5 MAC) may increase
airway resistance, particularly in patients who currently smoke [6,8-10]. (See "Anesthesia for adult patients with asthma", section on 'Inhalational
agents' and "Anesthesia for patients with chronic obstructive pulmonary disease", section on 'Maintenance: Choice of anesthetic agents and
techniques'.)
N2O gas is not an airway irritant, but it is also not a bronchodilator, and has little effect on airway smooth muscle [7].
Ventilation — During induction and maintenance with inhalation anesthetic agents, spontaneous ventilation is relatively preserved in Stage
I, chaotic and unpredictable in Stage II, tachypneic with reduced tidal volume in Stage III, and abolished in Stage IV (figure 7). During Stages III
and IV, dose-dependent respiratory depressant effects of the inhalation agents progressively shift the respiratory carbon dioxide (CO2) response
curve to the right (blunting ventilatory response to hypercapnia), blunt the hypoxic ventilatory drive, and reverse hypoxic pulmonary
vasoconstriction (promoting perfusion of poorly ventilated lung, thereby increasing ventilation/perfusion ratio [V/Q] mismatch, which may result in
hypoxia).
Interventions to assist or control ventilation typically become necessary, depending on the stage of anesthetic depth and the patient's clinical
status.
Cardiovascular effects
● Potent volatile inhalation agents – The potent volatile anesthetics all induce myocardial depression with dose-dependent reductions in
blood pressure (BP) and cardiac output, although the mechanisms for decline in BP and the degree of myocardial depression differ among
agents (table 5) [2]. These effects may be beneficial in certain situations. For example, as anesthetic depth is increased with a volatile agent
during induction, sympathetic stress responses are beneficially blunted in anticipation of noxious stimuli caused by laryngoscopy and
endotracheal intubation (table 1).
Isoflurane, sevoflurane, and desflurane have primary vasodilatory properties, thereby reducing systemic vascular resistance (SVR) with
relatively little initial effect on cardiac inotropy. Isoflurane and desflurane tend to produce progressive tachycardia at progressively higher
concentrations, and tachycardia may be seen with sevoflurane at concentrations >1.0 MAC. In particular, desflurane may induce tachycardia
and hypertension due to its sympathomimetic properties, particularly with high or abruptly increased concentrations.
Halothane preserves SVR but is a negative inotrope. In progressively higher doses, halothane also has negative chronotropic properties and
may induce bradycardia or asystole, particularly in infants and young children who have relatively greater parasympathetic tone compared
with adults. Also, halothane sensitizes the myocardium to catecholamines more readily than all other inhalation agents, and is thus
associated with a higher incidence of ventricular and other dysrhythmias.
Although vascular, inotropic, and chronotropic effects of the potent volatile inhalation agents differ, at high concentrations that induce Stage
IV anesthetic depth (significantly above 1.0 MAC) each of these agents eventually induces cardiovascular collapse due to progressive
vasodilation, bradycardia, and negative inotropy. This is one manifestation of anesthetic overdose (ie, anesthetic depth that is "too deep")
(see 'Continuum of effect: sedation to general anesthesia' above).
● Nitrous oxide – N2O induces few hemodynamic changes in most patients, in part because delivery of concentrations higher than
approximately 0.75 MAC is not possible at standard ambient temperature and pressure. However, N2O may cause mild myocardial
depression and sympathetic nervous system stimulation, with mild increases in pulmonary vascular resistance. Although N2O has not been
associated with increased risk of cardiac complications after noncardiac surgery, it is typically avoided in patients with severe cardiomyopathy
or pulmonary hypertension [11-14].
Effects on cerebral physiology — Effects of inhalation and other anesthetic agents on cerebral physiology are summarized in the table (table
6).
● Potent volatile inhalation agents – The potent, halogenated inhalation anesthetics (sevoflurane, desflurane, isoflurane, halothane) are all
dose-dependent cerebral vasodilators. While they reduce cerebral metabolic rate (CMR), they can blunt cerebral autoregulation by
uncoupling cerebral blood flow (CBF) and metabolism, thereby increasing CBF and intracranial pressure (ICP). At MAC values <1 MAC, the
net effect is a modest decrease in CBF and responsiveness to CO2 is generally maintained. However, CBF increases more significantly at
concentrations >1 MAC. (See "Anesthesia for craniotomy", section on 'Potent inhalation agents'.)
● Nitrous oxide – N2O can increase CBF, CMR, and ICP, with generally preserved CO2 responsiveness. N2O-induced changes in cerebral
physiology are affected by ventilation and the administration of other anesthetic agents. (See "Anesthesia for craniotomy", section on 'Potent
inhalation agents'.)
Transient delirium and excitability — During the transition from sedation to general anesthesia occurring as a continuum of effect when
progressively higher doses of inhalation anesthetics are administered (eg, during inhalation induction of general anesthesia), patients initially pass
through Stage I, lasting from the onset of sedation until initial loss of consciousness (table 1) [15,16]. Patients then transiently pass through Stage
II, which is characterized by delirium, excitability, and an exaggerated response to any stimuli. This stage is likely to be more overt during
administration of inhalation anesthetic agents rather than IV agents. Various ocular, laryngeal, and musculoskeletal responses are manifestations
of Stage II (figure 7). During Stage II, patients are particularly prone to laryngospasm, emesis, and aspiration of gastric contents. Management of
these risks during Stage II involves maintenance of adequate ventilation, avoidance of unnecessary stimulation, and either rapid deepening of
anesthesia to reach Stage III (surgical anesthesia) (table 1), or termination of anesthetic administration if appropriate (eg, awakening the patient
after an unsuccessful endotracheal intubation attempt in order to perform an alternative technique such as awake flexible bronchoscopic
intubation).
Similar phenomena are evident during emergence from general anesthesia as the patient transitions from a deeper Stage III anesthetic state
through a transient phase with delirium and agitation (Stage II), before becoming aware and responsive to commands (Stage I). (See "Emergence
from general anesthesia", section on 'Agitation'.)
Postoperative nausea and vomiting — All inhalation agents are associated with increased risk for postoperative nausea and vomiting
(PONV) compared with IV anesthetic agents [14,17]. Similar to opioid agents, inhalation anesthetics stimulate the area postrema at the base of
the fourth ventricle in the medulla (part of the chemoreceptor trigger zone or emetogenic center), which triggers nausea and the vomiting reflex.
Notably, the emetogenic effects of inhaled anesthetics may be mitigated by prophylactic antiemetics [18].
N2O is associated with a modestly higher incidence of PONV compared with other inhalation anesthetics, although this may be mitigated if
standard antiemetic prophylactic measures are employed [11,19]. Prolonged administration may induce nausea and emesis based on mechanical
factors since N2O diffuses into bowel gas with resultant visceral distension [20]. (See "Postoperative nausea and vomiting", section on 'Anesthetic
factors'.)
Reactions with carbon dioxide absorbents — Carbon dioxide (CO2) absorbents are used in the circle breathing system of an anesthesia
machine to prevent hypercapnia caused by rebreathing of exhaled CO2. These absorbents contain strong bases (eg, calcium hydroxide, sodium
hydroxide [NaOH], potassium hydroxide [KOH], barium hydroxide, lithium hydroxide), which react with CO2 to form a carbonate. CO2 absorbents
also react with potent volatile anesthetic agents passing through them, particularly if the absorbent becomes desiccated. For this reason, the color
of the pH indicator of the CO2 absorbents is checked as part of the pre-use machine checkout to verify that the absorbent is not exhausted [21].
(See "Anesthesia machines: Prevention, diagnosis, and management of malfunctions", section on 'Carbon dioxide absorbent exhaustion or
toxicity'.)
Reactions between volatile anesthetic agents and CO2 absorbents that may result in adverse effects include:
● Formation of carbon monoxide – CO2 absorbents containing NaOH or KOH can induce production of carbon monoxide upon exposure to
halogenated volatile inhalation agents, with potential risk of carbon monoxide toxicity and significant carboxyhemoglobinemia. Absorbents
containing lithium hydroxide or barium hydroxide are not associated with carbon monoxide production although these CO2 absorbents are
more expensive. Desiccation of the absorbent, high absorbent temperature, high concentration of inhaled agent, or low fresh gas flow all
increase risk of carbon monoxide production.
Reactions of inhaled anesthetics with CO2 absorbents to induce carbon monoxide production (from most to least likely) may occur with:
desflurane > isoflurane > halothane = sevoflurane (Note that N2O does not induce carbon monoxide production)
● Formation of compound A – Sevoflurane interacts with the strong bases (NaOH, KOH) in some CO2 absorbents to produce compound A
(fluoromethyl-2,2-difluoro-1-[trifluoromethyl] vinyl ether). Compound A is nephrotoxic in rats. No study has demonstrated clinically significant
nephrotoxicity in humans even after prolonged administration of sevoflurane with low fresh gas flow rates, despite significant compound A
production. Nevertheless, the US Food and Drug Administration (FDA) recommends use of sevoflurane with fresh gas flow rates ≥1 L/min for
exposure less than one hour and ≥2 L/min for exposures more than one hour. Federal agencies in other countries have not made such
recommendations, nor have professional societies.
Neurotoxic effects in developing brain — Possible neurotoxic effects of inhalation agents on the developing brain are discussed separately.
(See "Neurotoxic effects of anesthetics on the developing brain".)
Teratogenic effects — Historically, there was significant concern regarding increased risk for pregnancy loss and association with congenital
malformations in the offspring of pregnant women chronically exposed to low levels of inhalation agents (eg, operating room nurses, surgeons,
anesthesiologists). Data are conflicting and the precise extent of risk, if any, is unclear [22]. However, these concerns resulted in requirements for
fastidious scavenging and appropriate venting of inhalation agents. This is an American Society of Anesthesiologists (ASA) recommendation [21],
as well as an Occupational Health and Safety Administration (OHSA) guideline [23].
Malignant hyperthermia (volatile inhalation agents) — All potent volatile inhalation anesthetic agents may induce malignant hyperthermia in
susceptible individuals. (See "Malignant hyperthermia: Clinical diagnosis and management of acute crisis", section on 'Triggering agents'.)
CLINICAL USES
Induction of general anesthesia
Inhalation induction (sevoflurane, halothane, nitrous oxide) — Primary inhalation induction is employed in the following situations:
● Pediatric patients – Induction with an inhalation agent is usually preferred by infants and young children because of their fear of needles
and response to the pain of a needle stick [24]. (See "General anesthesia in neonates and children: Agents and techniques", section on
'Inhalation induction'.)
● Adult patients – Inhalation induction may be preferred in an adult if spontaneous breathing during induction is desired (eg, when intravenous
[IV] access cannot be obtained, or in patients with tracheal stenosis or an intraoral, pharyngeal, or mediastinal mass causing compression of
the airway). (See "Anesthesia for tracheal surgery", section on 'Induction' and "Anesthesia for patients with an anterior mediastinal mass",
section on 'Airway management during induction'.)
In general, adult patient satisfaction is lower after primary inhalation induction compared with IV induction, due to the unpleasant odor of the
gas [25] and a higher incidence of postoperative nausea and vomiting (PONV) [25-27]. However, development of nonpungent, nonirritant
volatile anesthetics with rapid onset, particularly sevoflurane, has made inhalation induction of anesthesia via facemask a more pleasant and
viable option (compared with older inhalation agents, particularly halothane) [26].
Inhalation induction of anesthesia requires a high concentration of a volatile anesthetic agent (see "Inhalation anesthetic agents: Properties and
delivery", section on 'Concentration effect'). However, the inspired concentration of a volatile anesthetic agent (eg, sevoflurane) should be
increased incrementally over 30 to 60 seconds during inhalation induction in order to avoid unpleasant pungency, airway irritation, and
laryngospasm or bronchospasm, which is more likely when high concentrations are rapidly introduced (see 'Airway reflexes' above and 'Bronchial
effects' above). Desflurane should not be used to induce anesthesia via facemask because it is the most pungent of the volatile anesthetics and
has the highest incidence of airway irritation (coughing, salivation, breath-holding, laryngospasm) and bronchospasm, particularly at high
concentrations (≥1.5 minimum alveolar concentration [MAC]) [5,28]. (See 'Disadvantages and adverse effects' below.)
Overpressurization of the anesthetic concentration or coadministration of nitrous oxide (N2O) speeds inhalation induction. (See "Inhalation
anesthetic agents: Properties and delivery", section on 'Overpressurization' and "Inhalation anesthetic agents: Properties and delivery", section on
'Second gas effect'.)
Since the time required to induce anesthesia with an inhalation technique is longer (usually requiring several minutes of ventilation), this
technique is not suitable for rapid sequence induction and intubation (RSII). (See "Rapid sequence induction and intubation (RSII) for
anesthesia".)
Use as a supplement (all inhalation agents) — Any of the inhalation agents may be employed as a component of anesthetic induction,
rather than as the primary induction agent. With this technique, initial loss of consciousness is achieved by administration of one or more IV
agents (see "General anesthesia: Intravenous induction agents"). Subsequently, an inhalation agent is administered to deepen anesthesia so that
airway reflexes and sympathetic stress responses will be beneficially blunted during laryngoscopy (see 'Airway reflexes' above and
'Cardiovascular effects' above). The potent volatile agents also induce a dose-dependent decrease in skeletal muscle tone, which improves
conditions for insertion of an endotracheal tube (ETT) or a supraglottic airway (SGA). (See 'Skeletal and smooth muscle relaxation' above.)
Maintenance of general anesthesia (all inhalation agents)
● Maintenance – All available volatile inhalation anesthetic agents (sevoflurane, desflurane, isoflurane, and in some countries halothane) may
be used for complete maintenance of general anesthesia. Dosing of an inhalation agent to maintain general anesthesia is determined by its
potency, reported as the MAC value (table 3) [4]. (See 'MAC and MAC-awake values for inhalation agents' above.)
MAC is decreased by concurrent administration of N2O or IV anesthetic agents such as sedative-hypnotics or opioids during maintenance of
general anesthesia (see 'Influence of drug-drug interactions' above and 'Influence of patient-related factors' above). Very commonly, a volatile
anesthetic agent is administered with or without N2O gas as a supplemental agent to maintain general anesthesia. Multiple medications are
utilized in such balanced techniques in order to provide a combination of hypnosis, amnesia, and analgesia, and may be supplemented with
a neuromuscular blocking agent (NMBA) if necessary to achieve complete immobility. (See "General anesthesia: Maintenance", section on
'Selection of maintenance agents'.)
● Emergence – As the surgical procedure nears completion, optimal timing for discontinuation of an inhalation agent must be planned to
prepare for an emergence from general anesthesia that is neither too early nor overly delayed. Timing for discontinuation depends on the
selected agent(s), doses employed, and duration of administration. Details are discussed in separate topics. (See "Emergence from general
anesthesia", section on 'Inhalation agents' and "Inhalation anesthetic agents: Properties and delivery", section on 'Clearance'.)
Procedural sedation (nitrous oxide) — N2O may be used during procedural sedation, most commonly in dental offices and other settings
outside the operating room (see "Office-based anesthesia", section on 'Selection of anesthetic agents: Goals'). N2O is also used as a self-
administered agent for management of pain during labor and delivery. (See "Pharmacologic management of pain during labor and delivery",
section on 'Nitrous oxide'.)
In these settings, specific advantages of the inhalation agent N2O include its availability, ease of delivery, and relative safety with usual
preservation of airway patency, spontaneous ventilation, and cardiovascular function, compared with use of various IV agents (eg, sedative-
hypnotics, anxiolytics, opioids, and other anesthetic adjuvant agents) (see 'Advantages' below). Disadvantages include inability to deliver
concentrations greater than approximately 75 percent MAC at standard clinical temperature and pressure. (See 'MAC and MAC-awake values for
inhalation agents' above and 'Disadvantages and adverse effects' below.)
In remote settings, lack of scavenging and appropriate venting is a potential disadvantage. Also, anesthesia care teams may not be available to
manage complications or provide a deeper level of anesthesia if necessary.
SPECIFIC INHALATION ANESTHETIC AGENTS
Potent volatile agents — All available potent volatile anesthetic agents are supplied as bottled liquids and are nonflammable (sevoflurane,
desflurane, isoflurane, halothane). Each is delivered via a specialized vaporizer mounted on the anesthesia machine. (See "Anesthesia
machines: Prevention, diagnosis, and management of malfunctions", section on 'Vaporizer malfunction'.)
There are advantages shared by all volatile inhalation anesthetic agents administered at a depth appropriate for Stage III surgical anesthesia
(table 1). These include bronchodilation, dose-dependent decrease in skeletal and smooth muscle tone, decreased cerebral metabolic rate
(CMR), and increased cerebral blood flow (CBF).
Effects shared by all volatile agents that may be disadvantageous include dose-dependent suppression of airway reflexes, respiratory depression,
and myocardial depression and vasodilation that may cause hypotension. Also, administration of any of the potent volatile agents is associated
with increased risk of nausea and emesis in the postoperative period, compared with most intravenous (IV) anesthetic alternatives [14,17].
Furthermore, all volatile agents have the potential to induce malignant hyperthermia in susceptible individuals. (See 'Other clinical effects' above.)
The available potent volatile agents differ in their specific advantages, disadvantages, and adverse effects, as described below.
Sevoflurane — Sevoflurane is supplied as a colorless bottled liquid that readily evaporates at standard temperature and pressure. It is
delivered via a vaporizer mounted on the anesthesia machine. Its properties are noted in the table (table 5).
Advantages
● Sweet-smelling, low pungency. Thus, sevoflurane is useful for inhalation induction.
● Low blood:gas partition coefficient, with consequent rapid uptake and induction of general anesthesia as well as rapid clearance and
emergence. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Blood:gas partition coefficient'.)
● Moderately high potency with a moderately low minimum alveolar concentration (MAC). (See 'MAC and MAC-awake values for inhalation
agents' above.)
● Lack of significant negative chronotropic or negative inotropic effects at concentrations near MAC, vasodilatory properties.
● Little effect on cerebral autoregulation across a range of concentrations [29]. (See 'Effects on cerebral physiology' above.)
Disadvantages and adverse effects
● High cost, particularly with use during longer procedures. Compared with other potent volatile anesthetic agents, expense is higher because
slightly higher fresh gas flows are employed (typically 1 to 2 L/minute of oxygen and/or air) to avoid formation of compound A. (See
'Reactions with carbon dioxide absorbents' above.)
● Theoretical risk of compound A-associated nephropathy. However, compound A is not generated by newer carbon dioxide absorbents. (See
'Reactions with carbon dioxide absorbents' above.)
● Possible increased risk of emergence delirium, particularly in children (table 7). (See "Emergence delirium and agitation in children", section
on 'Pathogenesis'.)
Typical uses — Overall, sevoflurane is the most commonly used potent volatile inhaled agent in developed countries.
● Induction – Sevoflurane is the most frequently used inhaled agent for induction of anesthesia (because of its minimal odor, lack of pungency,
and potent bronchodilatory characteristics [24-28,30,31]. Sevoflurane has many characteristics of the ideal induction agent, including
relatively rapid onset due to its low tissue and blood solubility. 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 delivered via a facemask [24,32,33].
● Maintenance – Sevoflurane is also frequently selected for maintenance of anesthesia because more rapid changes in anesthetic depth are
possible during painful interventions compared with more soluble agents such as isoflurane, and more rapid recovery occurs during
emergence after a short procedure. However, for procedures lasting longer than approximately two hours, emergence times are similar after
administration of sevoflurane or isoflurane because of their nearly identical fat solubilities, which allow similar accumulation in tissues during
prolonged administration. This is in contrast to desflurane, which is markedly less soluble in fat, accumulates less in tissues even after
prolonged administration, and is associated with more rapid emergence in most settings [34]. (See 'Advantages' below.)
Desflurane — Desflurane is supplied as a colorless bottled liquid that does not readily evaporate at standard temperature and pressure.
Desflurane is delivered by an electric heated vaporizer mounted on the anesthesia machine. Its properties are noted in the table (table 5).
Advantages
● Very low blood:gas partition coefficient, with consequent very rapid uptake and induction of general anesthesia, as well as very rapid
clearance and emergence. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Blood:gas partition coefficient'.)
● Very low oil:gas partition coefficient with consequent minimal uptake into adipose tissue. Due to its absence of accumulation in tissues
because of its low solubility in oil, desflurane is particularly advantageous for patients who are morbidly obese or have sleep apnea [35-37].
(See "Inhalation anesthetic agents: Properties and delivery", section on 'Oil:gas partition coefficient'.)
● Undergoes the least metabolism of all potent volatile agents. (See "Inhalation anesthetic agents: Properties and delivery", section on
'Metabolism'.)
● Compared with sevoflurane, an advantage for desflurane is safety during use with low fresh gas flows in the breathing circuit. (See
'Sevoflurane' above.).
● Very high pungency. Desflurane is the most pungent of the volatile anesthetics.
● Marked airway irritation (eg, coughing, salivation, breath-holding, laryngospasm), particularly with administration at concentrations ≥1.5 MAC,
due to high pungency. (See 'Airway reflexes' above.)
● A high incidence of coughing during emergence compared with sevoflurane [5,28,36,37]. (See "Emergence from general anesthesia", section
on 'Airway or respiratory problems'.)
● For these reasons, desflurane is not suitable for inhalation induction of anesthesia (see 'Inhalation induction (sevoflurane, halothane, nitrous
oxide)' above) [5,28]. Also, desflurane is not ideal for patients who smoke or have asthma or have reactive airway disease (eg, asthma,
chronic obstructive pulmonary disease [COPD], cystic fibrosis, α1-antitrypsin deficiency, chronic lung disease of prematurity, or
bronchopulmonary dysplasia [BPD]). Although desflurane at lower concentrations (<1.5 MAC) has been used during maintenance of
anesthesia for patients at risk for bronchospasm, higher concentrations may increase airway resistance [6,8-10]. (See "Anesthesia for adult
patients with asthma", section on 'Inhalational agents' and "Anesthesia for patients with chronic obstructive pulmonary disease", section on
'Maintenance: Choice of anesthetic agents and techniques'.)
● Tachycardia and hypertension due to sympathomimetic properties, particularly with administration of high or abruptly increased inspired
concentrations [38]. With continued administration, hypertension tends to resolve at steady state, although tachycardia may persist. These
properties also limit use of desflurane as a primary agent for induction of general anesthesia, since any inhalation agent must be rapidly
increased to produce a high enough concentration to induce unconsciousness in a previously awake patient.
● Since tachycardia may persist, desflurane is not ideal for patients with significant ischemic heart disease, hypertrophic obstructive
cardiomyopathy, aortic or mitral stenosis, or other patients for whom tachycardia is undesirable. If desflurane is used during maintenance of
anesthesia for such patients, high concentrations and rapid increases in concentration are avoided. (See "Anesthesia for noncardiac surgery
in patients with ischemic heart disease", section on 'Prevention of ischemia'.)
● Very high cost, particularly during long procedures.
● Need for a specialized electric heated vaporizer.
● Low potency with high MAC.
Typical uses — Desflurane is frequently selected for maintenance of anesthesia, particularly during short procedures, because very rapid
changes in anesthetic depth are possible during painful interventions, and very rapid recovery occurs during emergence. Due to ease of titration,
rapidity of recovery, and minimal residual effects, desflurane is particularly advantageous for older patients and those who are morbidly obese or
have sleep apnea [36,37].
Isoflurane — Isoflurane is supplied as a colorless bottled liquid that readily evaporates at standard temperature and pressure. It is delivered
via a vaporizer mounted on the anesthesia machine. Its properties are noted in the table (table 5).
Advantages
● High potency with low MAC.
● Very low cost, particularly with use during long procedures.
● Little effect on cerebral autoregulation at concentrations <1 MAC [39,40].
● High pungency, which limits its utility as a primary agent for inhalation induction of anesthesia.
● Moderately high blood:gas partition coefficient, with consequent slow uptake and induction of general anesthesia, compared with sevoflurane
or desflurane. This further limits use of isoflurane during induction (except as a supplemental agent). (See 'Use as a supplement (all
inhalation agents)' above.)
● High solubility in fat, associated with prolonged emergence particularly after prolonged procedures because of accumulation in tissues. This
property limits its use in procedures of short duration.
● Positive chronotropy with associated tachycardia that may be clinically significant when tachycardia is undesirable (eg, ischemic heart
disease). (See "Anesthesia for noncardiac surgery in patients with ischemic heart disease", section on 'Prevention of ischemia'.)
● Mild negative inotropy, vasodilatory properties.
Typical uses
● Maintenance – Isoflurane is frequently selected for maintenance of anesthesia, particularly if the anticipated duration of the procedure is long,
because it is inexpensive, widely available, and the most potent of the volatile anesthetics. Its unpleasant pungency limits its utility as a
primary inhalation agent during induction, although it may be employed as a supplemental agent after administration of IV induction agents in
order to deepen and maintain anesthesia.
As with sevoflurane, isoflurane has high solubility in fat and is associated with prolonged emergence particularly after prolonged procedures
because of accumulation in tissues. Thus, timing for discontinuation of isoflurane must be carefully planned as the surgical procedure is
nearing completion. (See "Emergence from general anesthesia", section on 'Discontinue anesthetic agents'.)
Halothane — Halothane is supplied as a bottled liquid that readily evaporates at standard temperature and pressure. It is delivered via a
vaporizer mounted on the anesthesia machine. Properties of halothane are noted in the table (table 5).
Stability of halothane is maintained with the addition of 0.01 percent thymol, which may accumulate in the vaporizer to eventually impart a yellow
color to the remaining liquid. Development of such discoloration indicates that the halothane vaporizer should be drained and cleaned.
Advantages
● Sweet-smelling gas with only moderate pungency. Thus, halothane is often used for inhalation induction in resource-poor countries where it
remains available.
● Very low cost.
● Wide availability.
● Very high potency with very low MAC.
● Very high solubility in blood, tissue, and oil, with consequent very slow uptake and induction of general anesthesia, as well as very slow
clearance and emergence. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Blood:gas partition coefficient' and
"Inhalation anesthetic agents: Properties and delivery", section on 'Brain:blood partition coefficient' and "Inhalation anesthetic agents:
Properties and delivery", section on 'Oil:gas partition coefficient'.)
● Negative inotropy and significant negative chronotropy, even if administered at relatively low concentrations. At high concentrations,
halothane may induce severe bradycardia or asystole.
● High incidence of ventricular and other dysrhythmias due to sensitization of the myocardium to catecholamines.
● Undergoes greater hepatic metabolism than all other inhalation agents, with associated risks for both cytotoxic and autoimmune
hepatotoxicity and halothane hepatitis. (See "Halothane hepatitis".)
Typical uses — Halothane is no longer commercially available in North America due to its adverse effects (particularly the possibility of
halothane hepatitis), and the development of newer inhalation agents that have replaced it, in particular sevoflurane. However, halothane is still
widely used for both induction and maintenance of general anesthesia in many countries with limited resources due to its low cost and wide
availability.
Nitrous oxide gas — Nitrous oxide (N2O) gas is supplied as a pressurized gas in equilibrium with its liquid phase that is delivered via a flow
meter on the anesthesia machine. (See "Anesthesia machines: Prevention, diagnosis, and management of malfunctions", section on
'Compressed gas flowmeter malfunction'.)
Advantages
● Slightly sweet-smelling gas, with no pungency and no potential for airway irritation. Thus, N2O is useful for inhalation induction.
● Very low blood:gas partition coefficient, with consequent very rapid rate of rise of its alveolar concentration and onset of anesthetic effect.
Changes in anesthetic depth during maintenance are also very rapid. Furthermore, addition of N2O near the end of surgery may speed
recovery from anesthesia, particularly if a volatile agent with a high blood:gas partition coefficient is being administered (eg, isoflurane,
halothane). In one study, addition of N2O during the last 30 minutes of an isoflurane-based anesthetic reduced the time to extubation by
approximately two minutes (2.0 minutes, 95% CI 0.6-3.4), as well as reducing time to eye opening, following commands, and being oriented
[41]. Presumably, faster recovery occurred because the anesthesia provider could reduce the administered concentration of isoflurane, as
well as taking advantage of the "second-gas" effect of N2O, as noted in the next bullet. (See "Inhalation anesthetic agents: Properties and
delivery", section on 'Blood:gas partition coefficient' and 'Disadvantages and adverse effects' below.)
● Increases speed of anesthetic onset and offset when coadministered with any potent volatile inhalation agent, compared with administration
of the potent agent alone. This is due to a phenomenon termed the "second gas" effect. Notably, second gas effects with N2O are more
pronounced with more soluble volatile anesthetics (eg, isoflurane, halothane). (See "Inhalation anesthetic agents: Properties and delivery",
section on 'Second gas effect'.)
● Analgesic and anxiolytic properties, which typically decrease requirements for the primary inhalation agent and/or for IV anesthetic agents.
(See 'Influence of drug-drug interactions' above.)
● Reduced likelihood of postoperative opioid-induced hyperalgesia and potentially reduced incidence of chronic postsurgical pain [42,43].
Results of the Enhanced Neuro Imaging Genetics through Meta-Analysis (ENIGMA) multicenter study of N2O as a component of balanced
general anesthesia suggested a decreased incidence of chronic pain in patients receiving N2O [14].
● Negligible hemodynamic effects.
● Undergoes no significant biotransformation.
● Low cost.
● Very low potency and consequent inability to deliver concentrations greater than approximately 0.75 MAC at standard clinical temperature
and pressure. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Oil:gas partition coefficient'.)
● Association with a modestly higher incidence of postoperative nausea and vomiting (PONV) compared with other inhalation anesthetic
agents, although this may be mitigated if antiemetic prophylactic measures are employed [11,19]. Diffusion into bowel gas with associated
visceral distension may increase risk of PONV, particularly after prolonged use. However, not all studies have noted increased risk of PONV
with short-term administration of N2O, even if no prophylactic antiemetic agents were administered [41]. (See "Postoperative nausea and
vomiting", section on 'Anesthetic factors'.)
● Diffuses into any air-filled cavity to displace nitrogen. 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 [2,11,19].
Further gaseous distension of such spaces has potentially significant adverse consequences (eg, nausea with emesis, tension
pneumothorax, increased intracranial pressure (ICP), vision loss, expansion of entrapped intravascular air).
● Possible increased incidence of postoperative atelectasis in patients with pre-existing poor pulmonary function. In one systematic review,
patients undergoing N2O-based techniques had an increased incidence of atelectasis (odds ratio [OR] 1.57, 95% CI 1.18-2.10), but there
were no effects on mortality, pneumonia, or other adverse postoperative outcomes [11]. Thus, the clinical relevance of this finding is unclear.
● Potential for transient diffusion hypoxia with discontinuation of N2O at low inspired oxygen concentrations. Upon discontinuation, bulk transfer
of N2O gas into the alveolus displaces oxygen and decreases alveolar oxygen concentration, potentially inducing desaturation. Such
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'.)
● Potential for fire hazard. Although not itself flammable, N2O supports combustion and a potential fire hazard exists (particularly in
combination with bowel gas). (See "Fire safety in the operating room", section on 'Nitrous oxide'.)
● Mild myocardial depression and sympathetic nervous system stimulation, with mildly increased pulmonary vascular resistance. Although N2O
is typically avoided in patients with severe cardiomyopathy and pulmonary hypertension, it has not been associated with increased risk of
cardiac complications after noncardiac surgery [11-14].
● N2O should be avoided in patients with disorders of B12, folate, or methionine synthesis or metabolism.
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N2O inactivates vitamin B12. In patients who have pre-existing vitamin B12 deficiency, this may result in neurotoxicity with sensory
neuropathy, myelopathy, and encephalopathy. Recovery may be slow and incomplete even after treatment with vitamin B12.
Vitamin B12 is an essential cofactor for methylenetetrahydrofolate reductase (MTHFR; ie, methionine synthetase), an enzyme critical in both
folate (vitamin B9) and homocysteine/methionine pathways. N2O-induced oxidation of vitamin B12 inhibits methionine synthetase activity [2],
thereby impairing synthesis of both tetrahydrofolate and methionine. Reduced tetrahydrofolate synthesis impairs purine and thymidine
synthesis and may cause immunosuppression [44]. Reduced methionine synthesis and associated increased levels of homocysteine also
theoretically increase risk for thrombosis and may lead to endothelial dysfunction [45].
● Some potential for abuse because of its analgesic, anxiolytic, and euphoric properties.
● Association with teratogenic effects in animal models, although this has not been demonstrated in humans. However, adequacy of
scavenging should be ensured during use in operating rooms or other settings near potentially pregnant health care workers [46,47]. (See
'Teratogenic effects' above.)
Typical uses
● Induction – N2O gas is commonly used as an adjuvant agent during inhalation induction of general anesthesia. Due to its very low solubility
in blood, the rate of rise of its alveolar concentration occurs very rapidly during inhalation induction. Since N2O has low potency it is rarely
used as the sole anesthetic agent (MAC value is 104 percent); however, it is commonly coadministered with a potent volatile inhalation agent
because its "second gas" effect hastens the onset of anesthesia and increases in anesthetic depth [11]. (See "Inhalation anesthetic agents:
Properties and delivery", section on 'Second gas effect'.)
● Maintenance – N2O gas is also commonly used during maintenance of general anesthesia as an adjuvant to a volatile anesthetic and/or IV
anesthetic agents because it is widely available and inexpensive. Administration of N2O increases anesthetic depth, resulting in decreased
dosing of other anesthetic agents. However, N2O cannot be used as a sole agent to maintain anesthesia because of its low potency (MAC
value is 104 percent) [11].
● Procedural sedation — N2O may be used during procedural sedation or as a self-administered agent for management of pain during labor
and delivery.
N2O use is always avoided in patients with pre-existing bowel distention, increased middle ear pressure, pneumothorax, pneumoperitoneum,
pneumocephalus, intraocular gas, or venous air embolism [2,11,19]. Also, N2O is typically avoided in patients with cardiomyopathy and pulmonary
hypertension because it causes mild myocardial depression and sympathetic nervous system stimulation with increases in pulmonary vascular
resistance. Furthermore, N2O use is generally avoided in patients with vitamin B12 deficiency or those with other MTHFR deficiencies.
SUMMARY AND RECOMMENDATIONS
● The primary clinical effect of inhalation anesthetic agents is dose-dependent sedation progressing to complete general anesthesia with
hypnosis, amnesia, analgesia, akinesia, and autonomic and sensory block (table 1 and table 8). (See 'Continuum of effect: sedation to
general anesthesia' above.)
● The minimum alveolar concentration (MAC) value is the concentration of an inhalation agent in the alveoli required to prevent movement in
response to a noxious stimulus in 50 percent of subjects, while the MAC-awake (also termed MAC-aware) value is the concentration of an
inhalation agent in the alveoli at which 50 percent of patients will not respond to a verbal or non-noxious tactile stimulus (table 2). These
values are measures of inhalation anesthetic potency. (See 'MAC and MAC-awake values for inhalation agents' above.)
● Inhalation agents may be used as primary agents to induce general anesthesia (sevoflurane or halothane with or without nitrous oxide [N2O])
or as supplemental agents to induce or maintain anesthesia (all inhalation agents). N2O is occasionally used during procedural sedation or
as a self-administered agent for management of pain during labor and delivery. (See 'Clinical uses' above.)
● Clinical effects shared by all volatile inhalation anesthetics administered at a depth appropriate for Stage III surgical anesthesia include dose-
dependent decrease in skeletal and smooth muscle tone (including bronchial and uterine relaxation), suppression of airway reflexes,
respiratory depression, myocardial depression with decreased blood pressure, and decreased cerebral metabolic rate with increased
cerebral blood flow. (See 'Skeletal and smooth muscle relaxation' above and 'Respiratory effects' above and 'Cardiovascular effects' above
and 'Effects on cerebral physiology' above.)
● All inhalation agents are associated with transient delirium and exaggerated responses to stimuli during Stage II as anesthesia is being
induced (Stage II (table 1 and figure 7)), with increased risk of laryngospasm, emesis, and aspiration of gastric contents. Also, all inhalation
agents are associated with increased risk of nausea and emesis in the postoperative period (compared with IV alternatives). All have
possible neurotoxic and teratogenic effects. Malignant hyperthermia can be induced in susceptible individuals. (See 'Other clinical effects'
above.)
● The potent volatile agents differ in their specific advantages, disadvantages, and adverse effects, as described above (see 'Potent volatile
agents' above):
• Sevoflurane (See 'Sevoflurane' above.)
• Desflurane (See 'Desflurane' above.)
• Isoflurane (See 'Isoflurane' above.)
• Halothane (See 'Halothane' above.)
● N2O has specific advantages, disadvantages, and adverse effects that differ from the potent volatile agents. (See 'Nitrous oxide gas' above.)
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6. Nyktari V, Papaioannou A, Volakakis N, et al. Respiratory resistance during anaesthesia with isoflurane, sevoflurane, and desflurane: a
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Gas Mixture for Anaesthesia (ENIGMA)-II Trial. Anesthesiology 2015; 123:1267.
14. Myles PS, Leslie K, Chan MT, et al. The safety of addition of nitrous oxide to general anaesthesia in at-risk patients having major non-
cardiac surgery (ENIGMA-II): a randomised, single-blind trial. Lancet 2014; 384:1446.
15. Hewer CL. THE STAGES AND SIGNS OF GENERAL ANAESTHESIA. Br Med J 1937; 2:274.
16. Guelrud AE. Inhalation anesthesia: A fundamental guide, 2nd ed, The Macmillan Company, New York 1951.
17. Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J
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18. Schaefer MS, Kranke P, Weibel S, et al. Total intravenous anaesthesia versus single-drug pharmacological antiemetic prophylaxis in adults:
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20. Fernández-Guisasola J, Gómez-Arnau JI, Cabrera Y, del Valle SG. Association between nitrous oxide and the incidence of postoperative
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Topic 114826 Version 12.0
GRAPHICS
Stages of anesthetic depth
Stage I Analgesia state: Patient is conscious and rational, with decreased perception of pain.
Stage II Delirium stage: Patient is unconscious; body responds reflexively; irregular breathing pattern with breathholding.
Stage III Surgical anesthesia: Increasing degrees of muscle relaxation; unable to protect airway.
Stage IV Medullary depression: There is depression of cardiovascular and respiratory centers.
Adapted from: Hewer CL. The stages and signs of general anesthesia. Br Med J 1937; 2:274.
Graphic 107796 Version 2.0
Definition of minimum alveolar concentration (MAC) values
MAC level Effect
0.3 MAC MAC awake (MAC value below this will allow the patient to become conscious)
1 MAC End-tidal concentration of anesthetic agent necessary to prevent movement in response to a surgical stimulus in 50% of
patients
1.5 MAC MAC value where 90% of patients will not move in response to a surgical stimulus
2.0 MAC MAC-BAR (MAC value required to block autonomic responses to a surgical stimulus in 50% of patients)
MAC: minimum alveolar concentration; a value of 1.0 MAC is the concentration of an inhalation anesthetic agent in the alveoli required to prevent movement
to a surgical stimulus in 50% of patients.
Minimum alveolar concentration (MAC) values for inhalation agents: 1 MAC
Inhalation anesthetic agent Minimum alveolar concentration (MAC) value (1 MAC)*
Nitrous oxide 104
Desflurane 6.6
Sevoflurane 1.8
Isoflurane 1.17
Halothane 0.75
The minimum alveolar concentration (MAC) value is the concentration of an inhalation anesthetic agent in the lung alveoli required to prevent
movement in response to a surgical stimulus in 50% of patients.
* These MAC values are for a 40-year-old person.
Factors that influence minimum alveolar concentration (MAC) values of inhalation anesthetic agents
Factors that increase MAC Factors that decrease MAC
Chronic alcohol use Acute alcohol use

Infancy (highest MAC at 6 months) Older age
Hypernatremia Hyponatremia
Hyperthermia Hypothermia
Amphetamines Anemia (Hgb <5 g/dL)
Cocaine Hypercarbia
Ephedrine Hypoxia
Metabolic acidosis
Pregnancy
Nitrous oxide
Opioids
Benzodiazepines
Propofol
Alpha 2 agonists
Intravenous lidocaine
Factors that increase or decrease the minimum alveolar concentration (MAC) value, defined as the concentration of an inhalation anesthetic
agent in the alveoli required to prevent movement in response to a surgical stimulus in 50 percent of patients.
MAC: minimum alveolar concentration; Hgb: hemoglobin.
Adapted from:
1. McKay RE. Inhaled anesthetics. In: Basics of Anesthesia, 6th ed, Miller RD, Pardo, Jr., MC (Eds), Elsevier, Philadelphia 2011.
2. Bartunek AE, Minimum alveolar concentration. In: Faust's Anesthesiology Review, 4th ed, Murray MJ, Harrison BA, Mueller JT, et al (Eds), Elsevier,
Philadelphia 2015.
3. Miller's Anesthesia, 8th ed, Miller RD, Cohen NH, Eriksson LI, et al (Eds), Elsevier, Philadelphia 2015.
Minimum alveolar concentration (MAC) chart for isoflurane
MAC is the minimum alveolar concentration of an inhalation anesthetic agent that prevents 50% of
patients from moving in response to a surgical stimulus.
MAC: minimum alveolar concentration; N 2 O: nitrous oxide.
Originally published in: Nickalls RW, Mapleson WW. Age-related iso-MAC charts for isoflurane, sevoflurane and
desflurane in man. Br J Anaesth 2003; 91:170. Reproduced with permission from Dick Nickalls, MBBS, BSc, PhD,
FRCA. Copyright © 2003 RWD Nickalls.
Minimum alveolar concentration (MAC) chart for sevoflurane
Iso-MAC chart for sevoflurane (age ≥1 year). The vertical shifts for the nitrous oxide 50 and 67% scales
are 0.86 and 1.16, respectively.
Minimum alveolar concentration (MAC) chart for desflurane
Iso-MAC chart for deslurane (age ≥1 year). The vertical shifts for the nitrous oxide 50 and 67% scales
are 3.25 and 4.22, respectively.
Effect of age on minimum alveolar concentration
Comparison of fitted lines with published values. Solid lines = fitted values, from 1 to 80 years, for each
anesthetic as a whole, based on data for age >1 year; dashed lines = extrapolation to age 0. The bias and extra
scatter of published values about these extrapolations draw attention to their invalidity. A 10 times expanded
time scale has been used for ages >1 year to separate the many published values in that age range. The circles
are used for alternate anesthetics. Five agents are omitted to avoid cluttering the diagram: for each agent, only
a single estimate of MAC was available and the fitted line necessarily went through that value.
MAC: minimum alveolar concentration.
Reproduced from: Mapleson WW. Effect of age on MAC in humans: a meta-analysis. Br J Anaesth 1996; 76:179.
Illustration used with the permission of Elsevier Inc. All rights reserved.
Changes in MAC with age
MAC is the minimum alveolar concentration of an inhalation anesthetic agent that prevents
50% of patients from moving in response to a surgical stimulus. MAC is lowest in the
extreme elderly: data are for ages 5 to 95 years.
MAC: minimum alveolar concentration.
Data from:
1. Cameron CB, Robinson S, Gregory GA. The minimum alveolar concentration of Isoflurane in
children. Anesth Analg 1984; 63:418.
2. Stevens WC, Dolan WM, Gibbons RT, et al. Minimum alveolar concentrations (MAC) of
isoflurane with and without nitrous oxide in patients of various ages. Anesthesiology 1975;
42:197.
From: LeDez KM, Lerman J. The minimum alveolar concentration (MAC) of isoflurane in preterm
neonates. Anesthesiology 1987; 67:301. Copyright © 1987 American Society of Anesthesiologists.
Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material
is prohibited.
Age-related changes in sevoflurane MAC in neonates and children
The mean (± standard deviation) end-tidal concentration of sevoflurane in oxygen for each of the six age groups
from neonates to older children up to 12 years of age. The data for MAC at 30 years of age were obtained from
Scheller, et al [1]. MAC is the minimal alveolar concentration of an inhalation agent required to prevent movement in
response to a noxious stimulus in 50 percent of subjects.
MAC: minimal alveolar concentration.
Reference:
1. Scheller MS, Saidman LJ, Partridge BL. MAC of sevoflurane in humans and the New Zealand white rabbit. Can J Anaesth
1988; 35:153.
From: Lerman J, Sikich N, Kleinman S, Yentis S. The pharmacology of sevoflurane in infants and children. Anesthesiology 1994;
80:814. Copyright © 1994 American Society of Anesthesiologists. Reproduced with permission from Wolters Kluwer Health.
Unauthorized reproduction of this material is prohibited.
Signs indicating stages of anesthesia
Modified from: Gillespie NA. The signs of anesthesia. Anesth Analg 1943; 22:275. Copyright © 1943 International Anesthesia Research Society. Reproduced with
permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited.
Inhalation anesthetic agents
Generic name Nitrous oxide Halothane Isoflurane Sevoflurane Desflurane
Brand name N/A Fluothane Forane Ultane Suprane
Chemical formula N2O C 2 HBrClF 3 C 3 H 2 ClF 5 O C4H3F7O C3H2F6O
Odor Slightly sweet Sweet Sweet Sweet Sweet
Color Colorless Colorless Colorless Colorless Colorless
Pungency None Moderate High Low Very high
Solubility:blood:gas Very low: 0.46 Very high: 2.40 Moderately high: Low: 0.65 Very low: 0.45
partition coefficient 1.40
Redistribution:brain:blood 1.1 1.9 1.6 1.7 1.3

partition coefficient
Potency:oil:gas partition Very low: 1.4 Very high: 224.0 High: 97.0 Moderately high: Low: 18.7
coefficient 42.0
Minimum alveolar 105.0% 0.8% 1.2% 2.0% 6.0%

concentration
(MAC) = ED 50 for
response to surgery
MAC-awake/MAC-aware 68.0% 0.4% 0.5% 0.6% 2.5%

= ED 50 for response to
voice/touch
Blood pressure effect Negligible Dose-dependent Dose-dependent Dose-dependent Dose-dependent

hypotension hypotension hypotension hypotension
Vascular effect Negligible Negligible Vasodilation Vasodilation Initial

vasoconstriction,
later vasodilation
Inotropic effect Negligible Negative Slightly negative Slightly negative Initial positive, later
negative
Chronotropic effect Negligible Bradycardia Tachycardia Tachycardia >1 MAC Tachycardia
How supplied Pressurized bottled Bottled liquid Bottled liquid Bottled liquid Bottled liquid
gas
How delivered Flowmeter Vaporizer Vaporizer Vaporizer Electric heated

vaporizer
Fire risk Supports combustion Non-flammable Non-flammable Non-flammable Non-flammable
Notes Nausea/emesis Nausea/emesis; Nausea/emesis; Nausea/emesis; Nausea/emesis;

bradycardia/asystole; potentially significant inhalational induction airway irritation;
inhalational tachycardia initial
induction; no longer sympathomimetic
used in US
N/A: not applicable.
The effects of anesthetic agents on cerebral physiology
Cerebral
Anesthetic agents CMRO 2 CBF ICP
autoregulation
Nitrous oxide ↑↑ ↑↑↑ ↑↑ No change
Sevoflurane ↓ ↑↑ ↑ No change
Isoflurane ↓↓ ↑ ↑ No change
Desflurane ↓ ↑↑↑ ↑↑ No change
Propofol, thiopental, and ↓↓↓ ↓↓↓ ↓↓ No change

etomidate
Benzodiazepines ↓ ↓↓ ↓ No change
Ketamine ↑↑ Unknown Unknown No change
Dexmedetomidine ↓↓ ↓ No change ↓
Opioids ↑ ↓↓ ↓ No change
For further details, refer to the UpToDate topic on anesthesia for craniotomy.
CMRO 2 : cerebral metabolic rate of oxygen; CBF: cerebral blood flow; ICP: intracranial pressure.
Factors that may or may not be associated with emergence delirium
Factors that predispose to ED
Age: Most frequent between two and six years [1]
Anesthetics: Sevoflurane ≈ desflurane ≈ isoflurane >> TIVA > halothane [2-6]
Preoperative mental state: Increased anxiety, temperament* [7,8]
Factors that do not predispose to ED
Rapid emergence [9]
Deep anesthesia (bispectral index <45.5) [10,11]
Preoperative anxiety* [12,13]
The factors that have been associated with a greater probability of developing ED are shown in the top portion of this table; those that have
been found to not be associated with development of ED are shown in the bottom portion. Administration of sevoflurane, desflurane, and
isoflurane confer approximately equivalent risk, and greater risk than TIVA. ED is least likely after halothane anesthesia.
ED: emergence delirium; TIVA: total intravenous anesthesia.

*Conflicting data, further studies required
References:
1. Aono J, Ueda W, Mamiya K, Takimoto E, Manabe M. Greater incidence of delirium during recovery from sevoflurane anesthesia in preschool boys.
2. Beksow A, Westrin P. Sevoflurane causes more postoperative agitation in children than does halothane. Acta Anaesth Scand 1999; 43:536.
3. Meyer RR, Munster P, Werner C, Brambrink AM. Isoflurane is associated with a similar incidence of emergence agitation/delirium as sevoflurane in
young children – a randomized controlled study. Paediatr Anaesth 2007; 17:56.
4. Hasani A, Ozgen S, Baftiu N. Emergence agitation in children after propofol versus halothane anesthesia. Med Sci Monit 2009; 15:CR302.
5. Chandler JR, Myers D, Mehta D, et al. Emergence delirium in children: a randomized trial to compare total intravenous anesthesia with propofol and
remifentanil to inhalational sevoflurane anesthesia. Paediatr Anaesth 2013; 23:309.
6. Costi D, Cyna AM, Ahmed S, et al. Effects of sevoflurane versus other general anaesthesia on emergence agitation in children. Cochrane Database
Syst Rev 2014; 12:CD007084.
7. Aono J, Mamiya K, Manabe M. Preoperative anxiety is associated with a high incidence of problematic behavior on emergence after halothane
anesthesia in boys. Acta Anaesthiol Scand 1999; 43:542.
8. Kain ZN, Caldwell-Andrews AA, Maranets I, et al. Preoperative anxiety and emergence delirium and postoperative maladaptive behaviors. Anesth
Analg 2004; 99:1648.
9. Cohen IT, Finkel JC, Hannallah RS, et al. Rapid emergence does not explain agitation following sevoflurane anaesthesia in infants and children: a
comparison with propofol. Paediatr Anaesth 2003; 13:63.
10. Faulk DJ, Twite MD, Zuk J, et al. Hypnotic depth and the incidence of emergence agitation and negative postoperative behavioral changes. Paediatr
Anaesth 2010; 20:72.
11. Frederick HJ, Wofford K, Dear GL, Schulman SR. A randomized controlled trial to determine the effect of depth of anesthesia on emergence agitation
in children. Anesth Analg 2016; 122:1141.
12. Berghmans JM, Poley M, Weber F, et al. Does the child behavior checklist predict levels of preoperative anxiety at anesthetic induction and
postoperative emergence delirium? A prospective cohort study. Minerva Anestesiol 2015; 81:145.
13. Joo J, Lee Sm Lee Y. Emergence delirium is related to the invasiveness of strabismus surgery in preschool-age children. J Internat Med Res 2014;
42:1311.
Continuum of sedation/analgesia/anesthesia
Moderate
Minimal sedation sedation/analgesia Deep
General anesthesia ◊
(anxiolysis)* (conscious sedation/analgesia Δ
sedation) ¶
Responsiveness Normal response to verbal Purposeful § response to Purposeful § response after Unarousable, even with
stimulation verbal or tactile stimulation repeated or painful painful stimulus
stimulation
Airway Unaffected No intervention required Intervention may be Intervention often required

required
Spontaneous ventilation Unaffected Adequate May be inadequate Frequently inadequate
Cardiovascular function Unaffected Usually maintained Usually maintained May be impaired
Because sedation is a continuum, it is not always possible to predict how an individual patient will respond. Hence, practitioners intending to
produce a given level of sedation should be able to rescue patients whose level of sedation becomes deeper than initially intended. Individuals
administering moderate sedation/analgesia (conscious sedation) should be able to rescue patients who enter a state of deep
sedation/analgesia, while those administering deep sedation/analgesia should be able to rescue patients who enter a state of general
anesthesia.
* A drug-induced state during which patients respond normally to verbal commands. Although cognitive function and coordination may be impaired,
ventilatory and cardiovascular functions are unaffected.
¶ A drug-induced depression of consciousness during which patients respond purposefully § to verbal commands, either alone or accompanied by light tactile
stimulation. No interventions are required to maintain a patient airway, and spontaneous ventilation is adequate. Cardiovascular function is usually
maintained.
Δ A drug-induced depression of consciousness during which patients cannot be easily aroused but respond purposefully § following repeated or painful
stimulation. The ability to independently maintain ventilatory function may be impaired. Patients may require assistance in maintaining a patient airway, and
spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained.
◊ A drug-induced loss of consciousness during which patients are not arousable, even by painful stimulation. The ability to independently maintain
ventilatory function is often impaired. Patients often require assistance in maintaining a patient airway, and positive pressure ventilation may be required
because of depressed spontaneous ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired.
§ Reflex withdrawal from a painful stimulus is not considered a purposeful response.
From: American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Practice guidelines for sedation and analgesia
by non-anesthesiologists. Anesthesiology 2002; 96:1004. Copyright © 2002 American Society of Anesthesiologists. Reproduced with permission from
Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited.
Contributor Disclosures
Stephen Robert Hays, MD, FAAP Nothing to disclose Girish P Joshi, MB, BS, MD, FFARCSI Speaker's Bureau: Mallinckrodt
Pharmaceuticals [pain management (intravenous acetaminophen)]; Baxter [anesthesia (desflurane)]. Consultant/Advisory Boards: Pacira
Pharmaceuticals [pain management (bupivacaine); Merck [anesthesia (sugammadex)]. Nancy A Nussmeier, MD, FAHA Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-
level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is
required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

Inhalation Anesthetic Agents: Clinical Effects and Uses

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Inhalation anesthetic agents: Clinical effects and uses - UpToDate 11/14/18, 12(44 AM

Official reprint from UpToDate®

Inhalation anesthetic agents: Clinical effects and uses

Author: Stephen Robert Hays, MD, FAAP

Sedation and anesthesia

● Hypnosis (ie, loss of consciousness)

● Amnesia (ie, lack of recall)

● Analgesia (ie, pain relief)

● Akinesia (ie, immobility)

● Autonomic and sensory block

Other clinical effects

desflurane > sevoflurane > isoflurane > halothane > N2O

desflurane > isoflurane > halothane > sevoflurane > N2O

(see 'Continuum of effect: sedation to general anesthesia' above).

Induction of general anesthesia

Maintenance of general anesthesia (all inhalation agents)

SPECIFIC INHALATION ANESTHETIC AGENTS

● Sweet-smelling, low pungency. Thus, sevoflurane is useful for inhalation induction.

Disadvantages and adverse effects

Disadvantages and adverse effects

● Very high cost, particularly during long procedures.

● Need for a specialized electric heated vaporizer.

● Low potency with high MAC.

● High potency with low MAC.

● Very low cost, particularly with use during long procedures.

● Little effect on cerebral autoregulation at concentrations <1 MAC [39,40].

Disadvantages and adverse effects

● Mild negative inotropy, vasodilatory properties.

● Very low cost.

● Very high potency with very low MAC.

Disadvantages and adverse effects

● Negligible hemodynamic effects.

● Undergoes no significant biotransformation.

Disadvantages and adverse effects

SUMMARY AND RECOMMENDATIONS

• Sevoflurane (See 'Sevoflurane' above.)

• Desflurane (See 'Desflurane' above.)

• Isoflurane (See 'Isoflurane' above.)

• Halothane (See 'Halothane' above.)

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 114826 Version 12.0

Stages of anesthetic depth

Stage IV Medullary depression: There is depression of cardiovascular and respiratory centers.

Graphic 107796 Version 2.0

Definition of minimum alveolar concentration (MAC) values

MAC level Effect

Graphic 109424 Version 2.0

Minimum alveolar concentration (MAC) values for inhalation agents: 1 MAC

Inhalation anesthetic agent Minimum alveolar concentration (MAC) value (1 MAC)*

Nitrous oxide 104

* These MAC values are for a 40-year-old person.

Graphic 109494 Version 2.0

Factors that increase MAC Factors that decrease MAC

Chronic alcohol use Acute alcohol use

MAC: minimum alveolar concentration; Hgb: hemoglobin.

Graphic 109495 Version 2.0

Minimum alveolar concentration (MAC) chart for isoflurane

MAC: minimum alveolar concentration; N 2 O: nitrous oxide.

Graphic 113991 Version 1.0

Minimum alveolar concentration (MAC) chart for sevoflurane

MAC: minimum alveolar concentration; N 2 O: nitrous oxide.

Graphic 117701 Version 1.0

Minimum alveolar concentration (MAC) chart for desflurane

MAC: minimum alveolar concentration; N 2 O: nitrous oxide.