inhalational anesthetics
Inhalation anesthetics include nitrous oxide (the oldest of all anesthetics) and several halogenated agents: desflurane (halogenated with fluorine only; halogenation increases potency and is essential to ensure nonflammability), halothane (halogenated with fluorine, chlorine and bromo), isoflurane (halogenated with fluorine and chlorine) and sevoflurane (halogenated with fluorine only). Halothane was the first extremely successful fluorinated inhalational anesthetic and quickly replaced all other strong inhalational anesthetics. Efforts to develop other halogenated anesthetics with more ideal inhalational anesthetic properties than halothane led to the introduction of isoflurane, desflurane, and sevoflurane.
Inhalational anesthetics act on many receptors (eg, GABAA, glycine, acetylcholine, serotonin, NMDA) in a way that could plausibly explain the anesthesia. It is not yet clear which receptors mediate anesthesia.
Characteristics of the ideal inhalational anesthetic include adequate potency, low blood and tissue solubility, resistance to physical and metabolic degradation, protective effects, and absence of damage to vital tissues. Physical and metabolic degradation can create compounds that cause injury. Other ideal characteristics include the absence of a tendency to cause convulsions, respiratory irritation, and circulatory stimulation; little or no impact on the ozone layer; and low acquisition costs. Cost considerations are discussed in detail in Chernin's article in this supplement.
The ideal anesthetic produces anesthesia while allowing the use of a high concentration of oxygen. The minimum alveolar concentration (MAC) of an anesthetic in an atmosphere that suppresses movement in response to a noxious stimulus in 50% of subjects provides the standard definition of inhalational anesthetic potency. In patients 30 to 60 years of age, the MAC values for halothane, isoflurane, sevoflurane, and desflurane are 0.75%, 1.15%, 1.85%, and 6.0%, respectively, at one atmosphere, suggesting that all are effective and can be administered with a high concentration of oxygen.[4,5]In contrast, the MAC for nitrous oxide is 104% in one atmosphere and must be declared in a pressurized chamber for safety reasons.
The solubility of an anesthetic in blood is quantified as the blood:gas partition coefficient, which is the ratio of the concentration of an anesthetic in the blood phase to the concentration of the anesthetic in the gas phase when the anesthetic is in equilibrium between the two phases For example, if the concentration of an anesthetic in arterial blood is 3% and the concentration in the lungs is 6%, the partition coefficient would be 0.5. A low blood:gas partition coefficient reflects a low affinity of the blood for the anesthetic, a desirable property as it provides more precise control over the anesthetic state and faster recovery from anesthesia. Blood:gas partition coefficients for inhalational anesthetics range from approximately 0.45 for nitrous oxide and desflurane and 0.65 for sevoflurane, to 1.4 for isoflurane and 2.4 for halothane (Table 1). .
Likewise, the tissue:gas partition coefficient is the ratio between the concentration of an anesthetic in a tissue and the concentration of the anesthetic in the gas phase when the anesthetic is in equilibrium between the two phases. A low tissue:gas partition coefficient reflects poor tissue solubility. The tissue:gas partition coefficients for nitrous oxide in brain and fat are lower than the values for strong inhalational anesthetics (Table 1), indicating that their solubility in tissues is low. The solubilities of desflurane and nitrous oxide in lean tissue are similar, but the solubility of desflurane in fat is ten times greater. The tissue solubility of desflurane is approximately half that of sevoflurane; Sevoflurane has half the solubility of isoflurane; and isoflurane has half the solubility of halothane.
Differences in the solubility of inhalational anesthetics in blood and tissue have important implications for patient recovery from anesthesia. We anticipated that recovery from desflurane anesthesia would be faster than recovery from sevoflurane anesthesia, and recovery from sevoflurane anesthesia would be faster than recovery from isoflurane anesthesia. Several reports support this prediction.[36,37,38,39]In a randomized multicenter study of 246 adults undergoing short outpatient procedures, patients receiving sevoflurane were oriented significantly earlier and were able to get up without nausea or dizziness than patients receiving isoflurane, which is more soluble.[36]However, there were no significant differences between the two treatment groups in time to discharge from the PACU.
In a randomized study of 50 adults undergoing short elective orofacial procedures, patients receiving desflurane were oriented an average of 6 minutes earlier and discharged from the PACU 19 minutes earlier than patients receiving the more soluble isoflurane.[37]The differences were significant.
Recovery from minor gynecologic procedures was compared in 60 women receiving desflurane or sevoflurane.[28]Time to orientation was 5 minutes shorter and time to discharge 0.5 hours earlier in the desflurane group than in the sevoflurane group. Differences between treatment groups were significant. Differences between inhalational anesthetics in orientation time and discharge time may result in savings when PACU staff operate in shorter times. However, they may not affect settings where policies and procedures require an extended stay in the PACU.
Differences between inhalational anesthetics may be even more important after prolonged anesthesia due to increased accumulation of anesthetic in tissues. Recovery from prolonged anesthesia (approximately five hours) was compared with desflurane or isoflurane in 30 patients.[39]As predicted by differences in solubility, the time it took the patient to open their eyes was significantly shorter with desflurane than with isoflurane (12 minutes vs. 24 minutes). PACU discharge time was also significantly shorter with desflurane (46 minutes) than with isoflurane (81 minutes). These differences exceed those observed in the study comparing the two anesthetics in patients undergoing the brief elective orofacial procedures described above.
To minimize waste and reduce costs, strong inhalational anesthetics are delivered in an absorption loop system that contains sorbents that remove carbon dioxide and allow the inhalational anesthetic to be rebreathed. The absorbents are composed of dibasic bases (calcium hydroxide, barium hydroxide) and monobasic bases (sodium hydroxide, potassium hydroxide) plus 15% water. Calcium hydroxide makes up most absorbents, such as soda lime (Sodasorb®) o Baralyme®. Bases can degrade strong inhalation anesthetics. The degradation products may depend on whether the absorbent is wet or desiccated (it can dry out when the absorbent is exposed to high rates of fresh gas input for a long time) and the type of anesthetic inhaled. Some degradation products are cause for concern. For example, wet and dry pads degrade sevoflurane to Compound A, a nephrotoxin in animals and possibly humans. Dry pads can break down all inhalational anesthetics into carbon monoxide (mostly desflurane)[40]; This problem does not occur with wet pads. These dangers are indicated in the package insert.
In a laboratory model, decomposition of sevoflurane by dried absorbent produced high temperatures (an exothermic reaction), carbon monoxide, explosion, and fire.[41]Several clinical cases of fire have been reported. Therefore, the sevoflurane product label includes a warning that extremely rare cases of spontaneous fires in the breathing circuit of the anesthesia machine have been reported during the use of sevoflurane in conjunction with a dry carbon dioxide absorbent.[42]The problem has not been reported with other strong inhalation anesthetics. Halothane does not degrade to compound A, but does degrade to a parallel unsaturated nephrotoxic compound. However, it is not made in the amounts that Compound A is made; therefore, the risk of nephrotoxicity is reduced.[43]
Compound A nephrotoxicity has been demonstrated in animals exposed to high concentrations of Compound A, although it is uncommon in humans.[44]However, the product label for sevoflurane includes a warning that sevoflurane administration may be for more than two MAC hours (eg, one CAM for two hours or two MAC for one hour) and at gas flow rates fresh less than 2 L/min associated with proteinuria. and glycosuria.[42]Therefore, exposure to sevoflurane for more than two MAC hours at flow rates of 12 L/min should be avoided to minimize exposure to Compound A, and the use of fresh gas flow rates less than 1 L/min is not recommended.[42]These flow rate limitations make administration of sevoflurane less cost-effective than it could be, as low fresh gas flow rates preserve anesthetic.
The products of the metabolism of inhalational anesthetics can cause tissue damage. The nature of the lesion depends on the level of metabolism and the nature of the metabolites. In the past, metabolic degradation of anesthetics was a major problem (eg, chloroform degradation causes liver damage), but with the powerful inhalational anesthetics in use today, this is a relatively rare problem.[44]
Desflurane, halothane, and isoflurane are metabolized to trifluoroacetate, which can cause hepatotoxicity through an immunological mechanism involving trifluoroacetyl hapten formation and an autoimmune response.[44]The incidence of liver damage depends on the extent of metabolism, with the highest rates associated with halothane and much lower rates with isoflurane and desflurane (Table 2). In fact, only one case of injury attributed to desflurane has been reported, despite the fact that desflurane has been administered to tens of millions of patients.[45]
Approximately 5% of an inhaled dose of sevoflurane is metabolized to inorganic fluoride and hexafluoroisopropanol.[44]Sevoflurane is not associated with hepatotoxicity.
Nitrous oxide is not subject to any metabolism. However, it inactivates methionine synthase, a B vitamin12dependent enzyme essential for the production of DNA.[47]Nitrous oxide can cause tissue damage by inactivating methionine synthase, but this problem is rare and probably occurs only in patients with vitamin B deficiency or long-term exposure to nitrous oxide. The lesion affects the blood-forming elements or the central nervous system.[48,49]
Hypoxic preconditioning is a phenomenon in which a brief period of hypoxia protects vital tissues from a subsequent prolonged period of hypoxia. Similarly, brief administration of inhalational anesthetics before, during, or after experimentally induced myocardial hypoxia reduces the extent of tissue damage (ie, infarct size) caused by hypoxia in animals.[50]The protective effect of strong inhalational anesthetics varies; infarct size may be significantly smaller with desflurane, halothane, or isoflurane than in the control group, with the difference in infarct size between the sevoflurane and control groups being less.[50]The size of the infarct is smaller with desflurane.
Whether differences in protective efficacy observed in animals translate into differences in humans was investigated in a controlled study in 45 high-risk patients (ie, older than 70 years with three-vessel coronary disease and ejection fraction less than 50%). ) undergoing coronary artery surgery. bypass graft surgery and randomized to receive propofol, desflurane, or sevoflurane.[51]The percentage of patients with abnormal postoperative levels of troponin I, proteins that reflect myocardial cell damage, was significantly higher in the propofol group than in the desflurane or sevoflurane groups, but the percentages in the desflurane and sevoflurane groups were not. differed.
Therefore, effective inhalational anesthetics protect vital tissues. No differences in the protective effect of the various agents in animals have been observed in humans.
Seizures and agitation have been reported in patients (mainly children and young adults) receiving sevoflurane.[42,52]Desflurane, halothane, isoflurane, and nitrous oxide are not associated with seizures. In a study of 41 adult women undergoing gynecologic surgery, intraoperative epileptiform discharges on electroencephalogram and postoperative agitation were treated with i.v. Inhaled propofol or sevoflurane to maintain anesthesia.[53]Intraoperative epileptiform activity occurred in 31% of patients who received sevoflurane and in none of the patients who received propofol. Restlessness one hour after surgery was reported by 31% in the sevoflurane group and 12% in the propofol group, a significant difference. Sevoflurane is more likely to cause seizures in patients at baseline risk of seizures.
Inhalation anesthetics vary in their acridity (an acrid agent is characterized by a pungent or acrid taste or odor) and their tendency to irritate the respiratory tract. In a double-blind study, 81 patients who did not receive premedication were randomized to inhale two MACs of desflurane (12%), isoflurane (2.3%), or sevoflurane (4%) over 60 seconds of an anesthetic mask breathing circuit.[54]Twenty (74%) of the 27 patients who received desflurane and 11 (41%) of the 27 patients who received isoflurane reported respiratory tract irritation (coughing and verbal protest or forced removal of the mask). One patient receiving sevoflurane coughed but completed the study. Differences between treatment groups were significant.
Due to its low acuity and low risk of respiratory irritation, sevoflurane is currently the most popular anesthetic in North America for inhalation induction. On the other hand, desflurane is avoided for induction due to its great acrimony and high risk of respiratory irritation. The label for desflurane advises that it should not be used for mask induction in pediatric patients due to the high incidence of moderate to severe laryngospasm, cough, breath-holding, increased secretion, and oxyhemoglobin hyposaturation.[46]Desaturation episodes seen in children (particularly preschool-age children) have not been seen in adults. Pediatric airways are likely to be more sensitive than adult airways.[55]
Airway irritation is absent when one MAC of desflurane, isoflurane, or sevoflurane is used instead of two MACs.[56]A threshold for airway irritation can be identified experimentally by increasing the concentration of the inhaled anesthetic until a concentration that causes airway irritation is reached. This limit is one MAC (6%) for desflurane and one and a half MACs (1.8%) for isoflurane.[56]There is no limit for halothane or sevoflurane because they do not cause respiratory irritation at any concentration.
Opioids significantly reduce the potential for airway irritation from inhalation anesthetics. In a randomized study of 180 adults who received inhaled desflurane for anesthetic induction, the frequency of cough in patients treated with low-dose opioid agonist fentanyl 1 µg/kg (5%) or morphine 0.1 mg/kg (8%) than in an IV saline solution (25%).[57]
The lack of airway irritation by anesthetics at concentrations below one MAC has important clinical implications. Many anesthetics are administered via a laryngeal mask (LM) airway, and airway irritation can interfere with the use of this technique. However, studies show that during maintenance of anesthesia through LMA, the occurrence of coughing or other manifestations of irritation does not differ between anesthetics.[58,59,60]
Potent inhalational anesthetics differ minimally in their effects on the circulation in steady-state anesthesia. In 12 healthy male subjects who received CAM of one and a half quarters of desflurane or sevoflurane for eight hours in an experimental (ie, non-surgical) setting, heart rate and mean arterial pressure differed from controls with both anesthetics, but not they did it. distinguish between the two anesthetics.[61]
The heart rate response to induction with inhaled desflurane or sevoflurane was compared in 21 healthy young volunteers who received successively higher (mean MAC, one MAC, and one and a half MAC) dial (vaporizer) concentrations of desflurane (3%, 6% and 9%) or sevoflurane (1%, 2% and 3%, respectively).[62]The rapid transition from one MAC to one and a half MAC transiently increased heart rate and blood pressure in the desflurane group and slightly decreased heart rate and blood pressure in the sevoflurane group.
In 12 healthy male subjects randomly selected to receive both induction anesthetics on separate occasions, the effect of rapid increases in desflurane and isoflurane concentrations on heart rate and blood pressure was compared.[63]Both desflurane and isoflurane caused transient increases in heart rate and blood pressure at concentrations near or above the MAC, with the increase being greater for desflurane than for isoflurane. Thus, inhalational anesthetics differ in their circulatory-stimulating effects during anesthetic induction, but usually only limited differences are seen during maintenance of anaesthesia.
Weiskopf and colleges[64]also observed a transient increase in heart rate and blood pressure in healthy subjects when the end-tidal desflurane concentration was increased rapidly (eg, over one minute) from 4% to 8%. The response of blood pressure to heart rate was greater when the increase in end-expiratory concentration was faster. The investigators also evaluated the effect of two different doses of fentanyl (1.5 µg/kg and 4.5 µg/kg) and found a dose-dependent reduction in heart rate response to desflurane.[64]Therefore, when desflurane is used for anesthetic induction, circulatory stimulation can be minimized by gradually increasing the concentration, limiting the concentration increase (ie, not exceeding the threshold for circulatory stimulation), and using fentanyl as a premedication. The desflurane product label advises against the use of desflurane as a sole agent for the induction of anesthesia in patients with coronary artery disease or in any patient in whom an increase in heart rate or blood pressure is not desired.[46]
Compounds with a chlorine or bromine moiety (eg, halothane, isoflurane, chlorofluorocarbons) can deplete the atmospheric ozone layer, causing ultraviolet radiation to reach Earth. This is of potential but limited importance for halothane and isoflurane, and essentially irrelevant for desflurane and sevoflurane (both lack chlorine and bromine residues).[Sixty-five]The greenhouse effect (avoiding infrared energy loss) is only an issue with nitrous oxide (and trivial compared to other sources like fertilizers).
Its high MAC (ie, low potency) limits the utility of nitrous oxide compared to the more potent halogenated inhalational anesthetics. Although halothane shares some of the characteristics of the ideal inhaled anesthetic (eg, high potency and lack of respiratory irritation, circulatory stimulation, and seizures), its increased solubility and risk of hepatotoxicity limit its current use. Choosing between sevoflurane, isoflurane, and desflurane involves weighing the pros and cons of each agent. All three agents have sufficient potency and a protective effect on vital tissues and can decompose to carbon monoxide in the presence of a dry carbon dioxide absorbent.
Sevoflurane has moderate solubility in blood and tissues and does not cause respiratory irritation, circulatory stimulation, or hepatotoxicity. It is especially useful for inducing anesthesia and is environmentally friendly (ie it does not deplete the ozone layer). However, sevoflurane may be associated with nephrotoxicity from physical degradation of Compound A, seizures, and postoperative agitation. There is a risk of explosion and fire in the breathing circuit of the anesthesia machine when sevoflurane is used with a dry carbon dioxide absorbent. Sevoflurane has a high initial cost, and the flow rate restrictions required to minimize exposure to Compound A add to the cost of using sevoflurane.
Isoflurane has a relatively high solubility in blood and tissues and is associated with an intermediate risk of respiratory irritation (between sevoflurane and desflurane), circulatory stimulation, and hepatotoxicity. It does not cause seizures. Isoflurane has minimal impact on the ozone layer and has a much lower initial cost than sevoflurane and desflurane.
Compared to sevoflurane and isoflurane, desflurane has lower solubility in blood and tissues (meaning it allows for faster recovery). It is associated with essentially no risk of hepatotoxicity. It may also protect vital tissues to a greater extent, although research in humans is needed to determine if there are differences in protection between anesthetics. Desflurane is not associated with seizures and is environmentally friendly. However, desflurane is associated with a higher risk of respiratory irritation and circulatory stimulation than other active substances. It is similar in cost to sevoflurane.