Inhalation Anesthetic Agents - Clinical Effects and Uses - UpToDate

05/10/2018 Inhalation anesthetic agents: Clinical effects and uses - UpToDate
Author: Stephen Robert Hays, MD, FAAP
Section Editor: Girish P Joshi, MB, BS, MD, FFARCSI
Deputy Editor: Nancy A Nussmeier, MD, FAHA
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 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
doseresponse 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 MACawake values for inhalation agents — The minimum alveolar concentration (MAC) and
MACawake 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
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potency, and MAC cannot be achieved when N2O is delivered under standard conditions.
● MACawake value – The MACawake (also termed MACaware) value is the concentration of an
inhalation agent in the alveoli at which 50 percent of patients will not respond to a verbal or nonnoxious
tactile stimulus. Thus, MACawake 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, MACawake 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 drugdrug 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, sedativehypnotics, 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 gammaaminobutyric
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 patientrelated 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, α1antitrypsin 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 preexisting 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 [6,810]. (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, dosedependent
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 dosedependent 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 [1114].
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 dosedependent 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.
N2Oinduced 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 preuse 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 (fluoromethyl2,2difluoro1[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) [2527]. 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, breathholding, 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 MACawake 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 drugdrug interactions'
above and 'Influence of patientrelated 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 "Officebased anesthesia", section on
'Selection of anesthetic agents: Goals'). N2O is also used as a selfadministered 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, sedativehypnotics, 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 MACawake 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, dosedependent 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 dosedependent 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
● Sweetsmelling, 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
MACawake 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 Aassociated 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 [2428,30,31].
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 [3537]. (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, breathholding, 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, α1antitrypsin 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 [6,810]. (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.)
https://www.uptodate.com/contents/inhalation-anesthetic-agents-clinical-effects-and-uses?search=anesthetics&source=search_result&selectedTitle=3~150&us… 10/17
● 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
● Sweetsmelling gas with only moderate pungency. Thus, halothane is often used for inhalation induction
in resourcepoor 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 sweetsmelling 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 isofluranebased
anesthetic reduced the time to extubation by approximately two minutes (2.0 minutes, 95% CI 0.63.4),
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 "secondgas" 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 drugdrug interactions' above.)
● Reduced likelihood of postoperative opioidinduced 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 shortterm administration of N2O, even if no prophylactic antiemetic agents were
administered [41]. (See "Postoperative nausea and vomiting", section on 'Anesthetic factors'.)
● Diffuses into any airfilled cavity to displace nitrogen. Thus, administration is avoided in patients with
possible preexisting 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 preexisting poor pulmonary
function. In one systematic review, patients undergoing N2Obased techniques had an increased
incidence of atelectasis (odds ratio [OR] 1.57, 95% CI 1.182.10), 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 [1114].
● N2O should be avoided in patients with disorders of B12, folate, or methionine synthesis or metabolism.
N2O inactivates vitamin B12. In patients who have preexisting 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 selfadministered agent for
management of pain during labor and delivery.
N2O use is always avoided in patients with preexisting 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 dosedependent 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 MACawake (also termed MACaware) value is the concentration of an inhalation agent in the alveoli
at which 50 percent of patients will not respond to a verbal or nonnoxious tactile stimulus (table 2).
These values are measures of inhalation anesthetic potency. (See 'MAC and MACawake 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 dosedependent 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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