Inhalation anesthetics

General anesthesia is defined as a drug-induced reversible depression of the central nervous system, resulting in the absence of the body's response to external stimuli.

The history of the use of inhalation anesthetics as general anesthetics began with the public demonstration of the first ether anesthesia in 1846. In the 1940s, dinitrogen oxide (Wells, 1844) and chloroform (Simpson, 1847) came into practice. These inhalation anesthetics were used until the mid-1950s.

In 1951, halothane was synthesized, which began to be used in anesthesiology practice in many countries, including Russia. Around the same time, methoxyflurane was obtained, but due to its too high solubility in blood and tissues, slow induction, prolonged elimination and nephrotoxicity, the drug currently has historical significance. The hepatotoxicity of halothane forced the search for new halogen-containing anesthetics to continue, which in the 1970s led to the creation of three drugs: enflurane, isoflurane and sevoflurane. The latter, despite its high cost, was widely used due to its low solubility in tissues and pleasant odor, good tolerability and rapid induction. And finally, the last drug of this group - desflurane was introduced into clinical practice in 1993. Desflurane has even lower tissue solubility than sevoflurane, and thus provides excellent control over the maintenance of anesthesia. When compared with other anesthetics of this group, desflurane has the fastest exit from anesthesia.

Quite recently, already at the end of the 20th century, a new gaseous anesthetic, xenon, entered into anesthesiological practice. This inert gas is a natural component of the heavy fraction of air (for every 1000 m3 of air there is 86 cm3 of xenon). Until recently, the use of xenon in medicine was limited to the field of clinical physiology. Radioactive isotopes 127Xe and 111Xe were used to diagnose diseases of the respiratory system, circulatory system, and organ blood flow. The narcotic properties of xenon were predicted (1941) and confirmed (1946) by N.V. Lazarev. The first use of xenon in a clinic dates back to 1951 (S. Cullen and E. Gross). In Russia, the use of xenon and its further study as an anesthetic is associated with the names of L.A. Buachidze, V.P. Smolnikov (1962), and later N.E. Burova. The monograph by N.E. Burova (jointly with V.N. Potapov and G.A. Makeev) “Xenon in Anesthesiology” (clinical and experimental study), published in 2000, is the first in world anesthesiological practice.

At present, inhalation anesthetics are used mainly during the period of anesthesia maintenance. For the purposes of induction of anesthesia, inhalation anesthetics are used only in children. Today, the anesthesiologist has two gaseous inhalation anesthetics in his arsenal - dinitrogen oxide and xenon and five liquid substances - halothane, isoflurane, enflurane, sevoflurane and desflurane. Cyclopropane, trichloroethylene, methoxyflurane and ether are not used in clinical practice in most countries. Diethyl ether is still used in some small hospitals of the Russian Federation. The proportion of various methods of general anesthesia in modern anesthesiology is up to 75% of the total number of anesthesia, the remaining 25% are various types of local anesthesia. Inhalation methods of general anesthesia dominate. IV methods of general anesthesia make up about 20-25%.

Inhalation anesthetics in modern anesthesiology are used not only as drugs for mononarcosis, but also as components of general balanced anesthesia. The idea itself - to use small doses of drugs that will potentiate each other and give an optimal clinical effect, was quite revolutionary in the era of mononarcosis. In fact, it was at this time that the principle of multicomponent modern anesthesia was implemented. Balanced anesthesia solved the main problem of that period - an overdose of a narcotic substance due to the lack of precise evaporators.

Dinitrogen oxide was used as the main anesthetic, barbiturates and scopolamine provided sedation, belladonna and opiates inhibited reflex activity, and opioids caused analgesia.

Today, for balanced anesthesia, along with dinitrogen oxide, xenon or other modern inhalation anesthetics are used, benzodiazepines have been replaced by barbiturates and scopolamine, old analgesics have given way to modern ones (fentanyl, sufentanil, remifentanil), new muscle relaxants have appeared that have a minimal effect on vital organs. Neurovegetative inhibition began to be carried out by neuroleptics and clonidine.

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Inhalation anesthetics: place in therapy

The era of mononarcosis using one or another inhalation anesthetic is becoming a thing of the past. Although this technique is still used in pediatric practice and in small-scale surgeries in adults. Multicomponent general anesthesia has dominated anesthesiology practice since the 1960s. The role of inhalation anesthetics is limited to achieving and maintaining the first component - turning off consciousness and maintaining the narcotic state during surgery. The depth of anesthesia should correspond to 1.3 MAC of the selected drug, taking into account all additional adjuvants that affect the MAC. The anesthesiologist should keep in mind that the inhalation component has a dose-dependent effect on other components of general anesthesia, such as analgesia, muscle relaxation, neurovegetative inhibition, etc.

Introduction to Anesthesia

The issue of induction of anesthesia today, one might say, has been resolved in favor of intravenous anesthetics with subsequent transition to an inhalation component for the purpose of maintaining anesthesia. The basis of such a decision is, of course, the patient's comfort and speed of induction. However, it should be borne in mind that at the transition stage from induction of anesthesia to the maintenance period there are several pitfalls associated with the inadequacy of anesthesia and, as a result, the body's reaction to the endotracheal tube or skin incision. This is often observed when the anesthesiologist uses ultra-short-acting barbiturates or hypnotics devoid of analgesic properties for induction of anesthesia and does not have time to saturate the body with an inhalation anesthetic or a strong analgesic (fentanyl). The hyperdynamic reaction of blood circulation accompanying this condition can be extremely dangerous in elderly patients. Preliminary administration of muscle relaxants makes the patient's violent response invisible. However, the monitors show a "vegetative storm" in the cardiovascular system. It is during this period that patients often awaken with all the negative consequences of this condition, especially if the operation has already begun.

There are several options for preventing the activation of consciousness and smooth achievement of the maintenance period. This is timely saturation of the body with inhalation anesthetics, allowing to achieve MAC or better EDC5 by the end of the action of the intravenous introductory agent. Another option may be a combination of inhalation anesthetics (dinitrogen oxide + isoflurane, sevoflurane or xenon).

A good effect is observed with a combination of benzodiazepines with ketamine, dinitrogen oxide with ketamine. The anesthesiologist's confidence is given by additional administration of fentanyl and muscle relaxants. Combined methods are widely used, when inhalation agents are combined with intravenous. Finally, the use of strong inhalation anesthetics sevoflurane and desflurane, which have low solubility in blood, allows for rapid achievement of narcotic concentrations even before the induction anesthetic ceases to act.

Mechanism of action and pharmacological effects

Despite the fact that about 150 years have passed since the first ether anesthesia was administered, the mechanisms of the narcotic action of inhalation anesthetics are not completely clear. Existing theories (coagulation, lipoid, surface tension, adsorption), proposed in the late 19th and early 20th centuries, could not reveal the complex mechanism of general anesthesia. In the same way, the theory of water microcrystals of two-time Nobel laureate L. Pauling did not answer all the questions. According to the latter, the development of the narcotic state is explained by the property of general anesthetics to form peculiar crystals in the aqueous phase of tissues, which create an obstacle to the movement of cations through the cell membrane and thereby block the process of depolarization and the formation of the action potential. In subsequent years, studies appeared that showed that not all anesthetics have the property of forming crystals, and those that do, form crystals in concentrations exceeding clinical ones. In 1906, the English physiologist C. Sherrington suggested that general anesthetics exert their specific action mainly through synapses, exerting an inhibitory effect on synaptic excitation transmission. However, the mechanism of suppression of neuronal excitability and inhibition of synaptic excitation transmission under the influence of anesthetics has not been fully elucidated. According to some scientists, anesthetic molecules form a kind of cloak on the neuron membrane, which hinders the passage of ions through it and thereby prevents the process of membrane depolarization. According to other researchers, anesthetics change the functions of the cation "channels" of cell membranes. It is obvious that different anesthetics have different effects on the main functional links of synapses. Some of them inhibit excitation transmission mainly at the level of nerve fiber terminals, while others reduce the sensitivity of membrane receptors to the mediator or inhibit its formation. The predominant effect of general anesthetics in the zone of interneuronal contacts can be confirmed by the antinociceptive system of the body, which in the modern sense is a set of mechanisms that regulate pain sensitivity and have an inhibitory effect on nociceptive impulses in general.

The concept of changes in the physiological lability of neurons and especially synapses under the influence of narcotic substances allowed us to come closer to understanding that at any given moment of general anesthesia, the degree of inhibition of the function of various parts of the brain is not the same. This understanding was confirmed by the fact that, along with the cerebral cortex, the function of the reticular formation was most susceptible to the inhibitory effect of narcotic substances, which was the prerequisite for the development of the "reticular theory of anesthesia." This theory was confirmed by data that the destruction of certain areas of the reticular formation caused a state close to drug-induced sleep or anesthesia. Today, the idea has formed that the effect of general anesthetics is the result of inhibition of reflex processes at the level of the reticular substance of the brain. In this case, its ascending activating influence is eliminated, which leads to deafferentation of the higher parts of the central nervous system. Despite the popularity of the "reticular theory of anesthesia," it cannot be recognized as universal.

It must be acknowledged that much has been done in this area. However, there are still questions that have no reliable answers.

Minimum alveolar concentration

The term "minimum alveolar concentration" (MAC) was introduced in 1965 by Eger et al. as a standard for the potency (strength, power) of anesthetics. This is the MAC of inhalation anesthetics that prevents motor activity in 50% of subjects who are given a pain stimulus. The MAC for each anesthetic is not a static value and may vary depending on the patient's age, ambient temperature, interaction with other drugs, the presence of alcohol, etc.

For example, the introduction of narcotic analgesics and sedatives reduces MAC. Conceptually, a parallel can be drawn between MAC and the average effective dose (ED50), just as ED95 (absence of movement in response to a pain stimulus in 95% of patients) is equivalent to 1.3 MAC.

Minimum alveolar concentration of inhalation anesthetics

• Dinitrogen oxide - 105
• Xenon - 71
• Hapotane - 0.75
• Enflurane - 1.7
• Isoflurane - 1.2
• Sevoflurane - 2
• Desflurane - 6

To achieve MAC = 1, hyperbaric conditions are required.

Addition of 70% dinitrogen oxide, or nitrous oxide (N20), to enflurane reduces the MAC of the latter from 1.7 to 0.6, to halothane - from 0.77 to 0.29, to isoflurane - from 1.15 to 0.50, to sevoflurane - from 1.71 to 0.66, to desflurane - from 6.0 to 2.83. In addition to the causes listed above, MAC is reduced by metabolic acidosis, hypoxia, hypotension, a2-agonists, hypothermia, hyponatremia, hypoosmolarity, pregnancy, alcohol, ketamine, opioids, muscle relaxants, barbiturates, benzodiazepines, anemia, etc.

The following factors do not affect MAC: duration of anesthesia, hypo- and hypercarbia within the range of PaCO2 = 21-95 mm Hg, metabolic alkalosis, hyperoxia, arterial hypertension, hyperkalemia, hyperosmolarity, propranolol, isoproterenol, naloxone, aminophylline, etc.

Effect on the central nervous system

Inhalation anesthetics cause very significant changes at the level of the central nervous system: loss of consciousness, electrophysiological disturbances, changes in cerebral hemodynamics (cerebral blood flow, oxygen consumption by the brain, cerebrospinal fluid pressure, etc.).

When inhaling inhalation anesthetics, the relationship between cerebral blood flow and cerebral oxygen consumption is disrupted with increasing doses. It is important to keep in mind that this effect is observed when cerebral vascular autoregulation is intact against the background of normal intracranial arterial pressure (BP) (50-150 mm Hg). Increased cerebral vasodilation with subsequent increase in cerebral blood flow leads to a decrease in cerebral oxygen consumption. This effect decreases or disappears with a decrease in BP.

Each strong inhalation anesthetic reduces the metabolism of brain tissue, causes vasodilation of cerebral vessels, increases the pressure of cerebrospinal fluid and cerebral blood volume. Dinitrogen oxide moderately increases the general and regional cerebral blood flow, so there is no significant increase in intracranial pressure. Xenon also does not increase intracranial pressure, but compared to 70% dinitrogen oxide, it almost doubles the speed of cerebral blood flow. Restoration of previous parameters occurs immediately after the gas supply is stopped.

In the waking state, cerebral blood flow is clearly correlated with the brain's oxygen consumption. If the consumption decreases, cerebral blood flow also decreases. Isoflurane can maintain this correlation better than other anesthetics. The increase in cerebral blood flow by anesthetics tends to gradually normalize to the initial level. In particular, after induction anesthesia with halothane, cerebral blood flow normalizes within 2 hours.

Inhalational anesthetics have a significant effect on the volume of cerebrospinal fluid, influencing both its production and its reabsorption. Thus, while enflurane increases the production of cerebrospinal fluid, isoflurane has virtually no effect on either production or reabsorption. Halothane decreases the rate of cerebrospinal fluid production but increases resistance to reabsorption. In the presence of moderate hypocapnia, isoflurane is less likely to cause a dangerous increase in spinal pressure compared to halothane and enflurane.

Inhalation anesthetics have a significant effect on the electroencephalogram (EEG). With an increase in the concentration of anesthetics, the frequency of bioelectric waves decreases and their voltage increases. At very high concentrations of anesthetics, zones of electrical silence can be observed. Xenon, like other anesthetics, in a concentration of 70-75% causes depression of alpha and beta activity, reduces the frequency of EEG oscillations to 8-10 Hz. Inhalation of 33% xenon for 5 minutes to diagnose the state of cerebral blood flow causes a number of neurological disorders: euphoria, dizziness, breath holding, nausea, numbness, numbness, heaviness in the head. The decrease in the amplitude of alpha and beta waves observed at this time is transient, and the EEG is restored after the xenon supply is stopped. According to N.E. Burov et al. (2000), no negative effects of xenon on brain structures or metabolism were observed. Unlike other inhalation anesthetics, enflurane can cause high-amplitude repeated sharp-edged wave activity. This activity can be neutralized by decreasing the dose of enflurane or increasing PaCOa.

Effect on the cardiovascular system

All strong inhalational anesthetics depress the cardiovascular system, but their hemodynamic effects vary. The clinical manifestation of cardiovascular depression is hypotension. In particular, with halothane, this effect is mainly due to a decrease in myocardial contractility and the frequency of its contractions with a minimal decrease in total vascular resistance. Enflurane both causes depression of myocardial contractility and reduces total peripheral resistance. Unlike halothane and enflurane, the effect of isoflurane and desflurane is mainly due to a decrease in vascular resistance and is dose-dependent. With an increase in the concentration of anesthetics to 2 MAC, BP can decrease by 50%.

A negative chronotropic effect is characteristic of halothane, whereas enflurane more often causes tachycardia.

The data of experimental studies by Skovster al., 1977, showed that isoflurane suppresses both vagal and sympathetic functions, but due to the fact that vagal structures are suppressed to a greater extent, an increase in heart rate is observed. It should be noted that the positive chronotropic effect is more often observed in young subjects, and in patients over 40 years of age its severity decreases.

Cardiac output is reduced primarily by a decrease in stroke volume with halothane and enflurane and to a lesser extent with isoflurane.

Halothane has the least effect on the heart rhythm. Desflurane causes the most pronounced tachycardia. Since blood pressure and cardiac output either decrease or remain stable, cardiac work and myocardial oxygen consumption decrease by 10-15%.

Dinitrogen oxide has variable effects on hemodynamics. In patients with heart disease, dinitrogen oxide, especially in combination with opioid analgesics, causes hypotension and a decrease in cardiac output. This does not occur in young subjects with a normally functioning cardiovascular system, where activation of the sympathoadrenal system neutralizes the depressant effect of dinitrogen oxide on the myocardium.

The effect of dinitrogen oxide on the pulmonary circulation is also variable. In patients with elevated pulmonary artery pressure, the addition of dinitrogen oxide may further increase it. It is interesting to note that the decrease in pulmonary vascular resistance with isoflurane is less than the decrease in systemic vascular resistance. Sevoflurane affects hemodynamics to a lesser extent than isoflurane and desflurane. According to the literature, xenon has a beneficial effect on the cardiovascular system. A tendency to bradycardia and some increase in blood pressure are noted.

Anesthetics have a direct effect on hepatic circulation and on vascular resistance in the liver. In particular, while isoflurane causes vasodilation of the hepatic vessels, halothane does not. Both reduce total hepatic blood flow, but oxygen demand is lower with isoflurane anesthesia.

The addition of dinitrogen oxide to halothane further reduces splanchnic blood flow, and isoflurane may prevent renal and splanchnic vasoconstriction associated with somatic or visceral nerve stimulation.

Effect on heart rhythm

Cardiac arrhythmias may be observed in more than 60% of patients under inhalation anesthesia and surgery. Enflurane, isoflurane, desflurane, sevoflurane, dinitrogen oxide and xenon are less likely to cause rhythm disturbances than halothane. Arrhythmias associated with hyperadrenalineemia are more pronounced in adults under halothane anesthesia than in children. Hypercarbia contributes to arrhythmias.

Atrioventricular nodal rhythm is often observed during inhalation of almost all anesthetics, perhaps with the exception of xenon. This is especially pronounced during anesthesia with enflurane and dinitrogen oxide.

Coronary autoregulation provides an equilibrium between coronary blood flow and myocardial oxygen demand. In patients with ischemic heart disease (IHD), coronary blood flow does not decrease under isoflurane anesthesia, despite a decrease in systemic blood pressure. If hypotension is caused by isoflurane, then in the presence of experimental coronary artery stenosis in dogs, severe myocardial ischemia occurs. If hypotension can be prevented, isoflurane does not cause steal syndrome.

At the same time, dinitrogen oxide added to a strong inhalation anesthetic can disrupt the distribution of coronary blood flow.

Renal blood flow does not change under general inhalation anesthesia. This is facilitated by autoregulation, which reduces the total peripheral resistance of the renal vessels if systemic blood pressure decreases. The rate of glomerular filtration decreases due to the decrease in blood pressure, and, as a result, urine production decreases. When blood pressure is restored, everything returns to the original level.

Effect on the respiratory system

All inhalation anesthetics have a depressant effect on respiration. As the dose increases, breathing becomes shallow and frequent, the inhalation volume decreases, and the carbon dioxide tension in the blood increases. However, not all anesthetics increase the respiration rate. Thus, isoflurane can increase the respiration rate only in the presence of dinitrogen oxide. Xenon also slows down respiration. Upon reaching 70-80% concentration, respiration slows down to 12-14 per minute. It should be borne in mind that xenon is the heaviest gas of all inhalation anesthetics and has a density coefficient of 5.86 g/l. In this regard, the addition of narcotic analgesics during xenon anesthesia, when the patient breathes independently, is not indicated. According to Tusiewicz et al., 1977, the efficiency of respiration is 40% provided by the intercostal muscles and 60% by the diaphragm. Inhalation anesthetics have a dose-dependent depressant effect on the muscles mentioned, which increases significantly when combined with narcotic analgesics or drugs with a central muscle relaxant effect. With inhalation anesthesia, especially when the concentration of the anesthetic is high enough, apnea may occur. Moreover, the difference between the MAC and the dose causing apnea varies among anesthetics. The smallest is that of enflurane. Inhalation anesthetics have a unidirectional effect on the tone of the airways - they reduce airway resistance due to bronchodilation. This effect is expressed to a greater extent in halothane than in isoflurane, enflurane and sevoflurane. Therefore, it can be concluded that all inhalation anesthetics are effective in patients with bronchial asthma. However, their effect is due not to blocking the release of histamine, but to preventing the bronchoconstrictor effect of the latter. It should also be remembered that inhalation anesthetics inhibit mucociliary activity to some extent, which, together with such negative factors as the presence of an endotracheal tube and inhalation of dry gases, creates conditions for the development of postoperative bronchopulmonary complications.

Effect on liver function

Due to the relatively high (15-20%) metabolism of halothane in the liver, the opinion about the possibility of a hepatotoxic effect of the latter has always existed. And although isolated cases of liver damage were described in the literature, this danger did exist. Therefore, the synthesis of subsequent inhalation anesthetics had the main goal of reducing the hepatic metabolism of new halogen-containing inhalation anesthetics and reducing the hepatotoxic and nephrotoxic effects to a minimum. And if the percentage of metabolization of methoxyflurane is 40-50%, and halothane is 15-20%, then for sevoflurane it is 3%, enflurane - 2%, isoflurane - 0.2% and desflurane - 0.02%. The data presented indicate that desflurane does not have a hepatotoxic effect, for isoflurane it is only theoretically possible, and for enflurane and sevoflurane it is extremely low. Out of a million sevoflurane anesthesias performed in Japan, only two cases of liver injury have been reported.

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Effect on blood

Inhalation anesthetics affect hematopoiesis, cellular elements, and coagulation. In particular, the teratogenic and myelosuppressive effects of dinitrogen oxide are well known. Long-term exposure to dinitrogen oxide causes anemia due to inhibition of the enzyme methionine synthetase, which is involved in the metabolism of vitamin B12. Megaloblastic changes in the bone marrow have been detected even after 105 minutes of inhalation of clinical concentrations of dinitrogen oxide in severely ill patients.

There are indications that inhalational anesthetics affect platelets and thereby promote bleeding either by affecting vascular smooth muscle or by affecting platelet function. There is evidence that halothane reduces their ability to aggregate. A moderate increase in bleeding has been noted with halothane anesthesia. This phenomenon was absent with inhalation of isoflurane and enflurane.

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Effect on the neuromuscular system

It has long been known that inhalation anesthetics potentiate the action of muscle relaxants, although the mechanism of this effect is unclear. In particular, it has been found that isoflurane potentiates succinylcholine block to a greater extent than halothane. At the same time, it has been noted that inhalation anesthetics cause a greater degree of potentiation of non-depolarizing muscle relaxants. A certain difference is observed between the effects of inhalation anesthetics. For example, isoflurane and enflurane potentiate neuromuscular blockade of greater duration than halothane and sevoflurane.

Impact on the endocrine system

During anesthesia, glucose levels increase either due to decreased insulin secretion or due to a decrease in the ability of peripheral tissues to utilize glucose.

Of all the inhalation anesthetics, sevoflurane maintains glucose concentration at the initial level, and therefore sevoflurane is recommended for use in patients with diabetes.

The assumption that inhalation anesthetics and opioids cause secretion of antidiuretic hormone was not confirmed by more precise research methods. It was found that a significant release of antidiuretic hormone is part of the stress response to surgical stimulation. Inhalation anesthetics also have little effect on the level of renin and serotonin. At the same time, it was found that halothane significantly reduces the level of testosterone in the blood.

It has been noted that inhalation anesthetics during induction have a greater effect on the release of hormones (adrenocorticotropic, cortisol, catecholamines) than drugs for intravenous anesthesia.

Halothane increases catecholamine levels to a greater extent than enflurane. Since halothane increases the sensitivity of the heart to adrenaline and promotes arrhythmias, the use of enflurane, isoflurane, and sevoflurane is more indicated for the removal of pheochromocytoma.

Effect on the uterus and fetus

Inhalational anesthetics cause myometrium relaxation and thereby increase perinatal blood loss. Compared with dinitrogen oxide anesthesia in combination with opioids, blood loss after halothane, enflurane and isoflurane anesthesia is significantly higher. However, the use of small doses of 0.5% halothane, 1% enflurane and 0.75% isoflurane as an adjunct to dinitrogen oxide and oxygen anesthesia, on the one hand, prevents awakening on the operating table, on the other hand, does not significantly affect blood loss.

Inhalational anesthetics cross the placenta and affect the fetus. In particular, 1 MAC of halothane causes fetal hypotension even with minimal maternal hypotension and tachycardia. However, this fetal hypotension is accompanied by a decrease in peripheral resistance, and as a result, peripheral blood flow remains at a sufficient level. However, isoflurane is safer for the fetus.

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Pharmacokinetics

Direct delivery of a gaseous or vaporous anesthetic to the patient's lungs promotes rapid diffusion of the drug from the pulmonary alveoli into the arterial blood and its further distribution throughout the vital organs, creating a certain concentration of the drug in them. The severity of the effect ultimately depends on achieving a therapeutic concentration of the inhalation anesthetic in the brain. Since the latter is an exceptionally well-perfused organ, the partial pressure of the inhalation agent in the blood and brain equalizes fairly quickly. The exchange of the inhalation anesthetic through the alveolar membrane is very effective, so the partial pressure of the inhalation agent in the blood circulating through the pulmonary circulation is very close to that found in the alveolar gas. Thus, the partial pressure of the inhalation anesthetic in the brain tissues differs little from the alveolar partial pressure of the same agent. The reason why the patient does not fall asleep immediately after the start of inhalation and does not wake up immediately after its termination is mainly the solubility of the inhalation anesthetic in the blood. The penetration of the drug into the site of its action can be represented in the form of the following stages:

• evaporation and entry into the airways;
• crossing the alveolar membrane and entering the blood;
• transition from the blood through the tissue membrane into the cells of the brain and other organs and tissues.

The rate of entry of an inhalation anesthetic from the alveoli into the blood depends not only on the solubility of the anesthetic in the blood, but also on the alveolar blood flow and the difference in partial pressures of the alveolar gas and venous blood. Before reaching the narcotic concentration, the inhalation agent goes the following way: alveolar gas -> blood -> brain -> muscles -> fat, i.e. from well-vascularized organs and tissues to poorly vascularized tissues.

The higher the blood/gas ratio, the higher the solubility of the inhalation anesthetic (Table 2.2). In particular, it is obvious that if halothane has a blood/gas solubility ratio of 2.54, and desflurane has a ratio of 0.42, then the rate of onset of induction of anesthesia for desflurane is 6 times higher than for halothane. If we compare the latter with methoxyflurane, which has a blood/gas ratio of 12, it becomes clear why methoxyflurane is not suitable for induction of anesthesia.

The amount of anesthetic that undergoes hepatic metabolism is significantly less than that exhaled through the lungs. The percentage of metabolized methoxyflurane is 40-50%, halothane - 15-20%, sevoflurane - 3%, enflurane - 2%, isoflurane - 0.2%, and desflurane - 0.02%. Diffusion of anesthetics through the skin is minimal.

When the anesthetic supply is stopped, its elimination begins according to the principle opposite to induction. The lower the anesthetic solubility coefficient in the blood and tissues, the faster the awakening. Rapid elimination of the anesthetic is facilitated by a high oxygen flow and, accordingly, high alveolar ventilation. The elimination of dinitrogen oxide and xenon occurs so quickly that diffusion hypoxia may occur. The latter can be prevented by inhalation of 100% oxygen for 8-10 minutes under control of the percentage of the anesthetic in the blown air. Of course, the speed of awakening depends on the duration of the anesthetic use.

Withdrawal period

Recovery from anesthesia in modern anesthesiology is quite predictable if the anesthesiologist has sufficient knowledge of the clinical pharmacology of the drugs used. The rate of recovery depends on a number of factors: the drug dose, its pharmacokinetics, patient age, duration of anesthesia, blood loss, amount of transfused oncotic and osmotic solutions, patient and ambient temperature, etc. In particular, the difference in the rate of recovery when using desflurane and sevoflurane is 2 times faster than when using isoflurane and halothane. The latter drugs also have an advantage over ether and methoxyflurane. And yet, the most controllable inhalation anesthetics act longer than some intravenous anesthetics, such as propofol, and patients wake up within 10-20 minutes after the inhalation anesthetic is stopped. Of course, all drugs that were administered during anesthesia should be taken into account.

Maintenance of anesthesia

Anesthesia can be maintained using only an inhalation anesthetic. However, many anesthesiologists still prefer to add adjuvants to the inhalation agent, in particular analgesics, muscle relaxants, hypotensive agents, cardiotonics, etc. Having in their arsenal inhalation anesthetics with different properties, the anesthesiologist can choose an agent with the desired properties and use not only its narcotic properties, but also, for example, the hypotensive or bronchodilatory effect of the anesthetic. In neurosurgery, for example, preference is given to isoflurane, which maintains the dependence of the caliber of cerebral vessels on carbon dioxide tension, reduces oxygen consumption by the brain, and has a beneficial effect on the dynamics of the cerebrospinal fluid, reducing its pressure. It should be borne in mind that during the period of anesthesia maintenance, inhalation anesthetics are able to prolong the effect of non-depolarizing muscle relaxants. In particular, with enflurane anesthesia, the potentiation of the muscle relaxant effect of vecuronium is much stronger than with isoflurane and halothane. Therefore, the doses of muscle relaxants should be reduced in advance if strong inhalation anesthetics are used.

Contraindications

A common contraindication for all inhalation anesthetics is the absence of specific technical means for precise dosing of the corresponding anesthetic (dosimeters, evaporators). A relative contraindication for many anesthetics is severe hypovolemia, the possibility of malignant hyperthermia and intracranial hypertension. Otherwise, contraindications depend on the properties of inhalation and gaseous anesthetics.

Dinitrogen oxide and xenon have high diffusion capacity. The risk of filling closed cavities with gases limits their use in patients with closed pneumothorax, air embolism, acute intestinal obstruction, during neurosurgical operations (pneumocephalus), plastic surgery on the eardrum, etc. Diffusion of these anesthetics into the cuff of the endotracheal tube increases the pressure in it and can cause ischemia of the tracheal mucosa. It is not recommended to use dinitrogen oxide in the postperfusion period and during operations in patients with heart defects with compromised hemodynamics due to the cardiodepressant effect in this category of patients.

Dinitrogen oxide is also not indicated in patients with pulmonary hypertension, since it increases pulmonary vascular resistance. Dinitrogen oxide should not be used in pregnant women to avoid a teratogenic effect.

A contraindication for the use of xenon is the need to use hyperoxic mixtures (cardiac and pulmonary surgery).

For all other (except isoflurane) anesthetics, conditions associated with increased intracranial pressure are contraindications. Severe hypovolemia is a contraindication to the use of isoflurane, sevoflurane, desflurane, and enflurane due to their vasodilatory effect. Halothane, sevoflurane, desflurane, and enflurane are contraindicated if there is a risk of developing malignant hyperthermia.

Halothane causes myocardial depression, which limits its use in patients with severe heart disease. Halothane should not be used in patients with unexplained liver dysfunction.

Kidney disease and epilepsy are additional contraindications for enflurane.

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Tolerability and side effects

Dinitrogen oxide, by irreversibly oxidizing the cobalt atom in vitamin Bi2, inhibits the activity of B12-dependent enzymes such as methionine synthetase, necessary for the formation of myelin, and thymidine synthetase, necessary for DNA synthesis. In addition, long-term exposure to dinitrogen oxide causes bone marrow depression (megaloblastic anemia) and even neurological deficit (peripheral neuropathy and funicular myelosis).

Since halothane is oxidized in the liver to its main metabolites, trifluoroacetic acid and bromide, postoperative liver dysfunctions are possible. Although halothane hepatitis is rare (1 case per 35,000 halothane anesthesias), the anesthesiologist should be aware of this.

It has been established that immune mechanisms play an important role in the hepatotoxic effect of halothane (eosinophilia, rash). Under the influence of trifluoroacetic acid, liver microsomal proteins play the role of a trigger antigen that initiates an autoimmune reaction.

Side effects of isoflurane include moderate beta-adrenergic stimulation, increased blood flow in skeletal muscles, decreased total peripheral vascular resistance (TPVR) and blood pressure (D.E. Morgan and M.S. Mikhail, 1998). Isoflurane also has a depressant effect on respiration, to a somewhat greater extent than other inhalation anesthetics. Isoflurane reduces hepatic blood flow and diuresis.

Sevoflurane is degraded by soda lime, which is used to fill the absorber of the anesthesia-respiratory apparatus. The concentration of the final product "A" increases if sevoflurane comes into contact with dry soda lime in a closed circuit at low gas flow. The risk of developing tubular necrosis of the kidneys increases significantly.

The toxic effect of a particular inhalation anesthetic depends on the percentage of drug metabolism: the higher it is, the worse and more toxic the drug is.

Side effects of enflurane include inhibition of myocardial contractility, decreased blood pressure and oxygen consumption, increased heart rate (HR) and total peripheral vascular resistance (TPVR). In addition, enflurane sensitizes the myocardium to catecholamines, which should be kept in mind and epinephrine at a dose of 4.5 mcg/kg should not be used. Other side effects include respiratory depression when administering 1 MAC of the drug - pCO2 during spontaneous breathing increases to 60 mm Hg. Hyperventilation should not be used to eliminate intracranial hypertension caused by enflurane, especially if a high concentration of the drug is administered, since an epileptiform seizure may develop.

Side effects of xenon anesthesia are observed in people who are addicted to alcohol. In the initial period of anesthesia, they experience pronounced psychomotor activity, which is leveled by the introduction of sedatives. In addition, the development of diffusion hypoxia syndrome is possible due to the rapid elimination of xenon and its filling of the alveolar space. To prevent this phenomenon, it is necessary to ventilate the patient's lungs with oxygen for 4-5 minutes after turning off the xenon.

At clinical doses, halothane may cause myocardial depression, especially in patients with cardiovascular disease.

Interaction

During the period of maintaining anesthesia, inhalation anesthetics are able to prolong the action of non-depolarizing muscle relaxants, significantly reducing their consumption.

Due to its weak anesthetic properties, dinitrogen oxide is usually used in combination with other inhalation anesthetics. This combination allows to reduce the concentration of the second anesthetic in the respiratory mixture. Combinations of dinitrogen oxide with halothane, isoflurane, ether, and cyclopropane are widely known and popular. To enhance the analgesic effect, dinitrogen oxide is combined with fentanyl and other anesthetics. An anesthesiologist should be aware of another phenomenon, when the use of a high concentration of one gas (for example, dinitrogen oxide) facilitates an increase in the alveolar concentration of another anesthetic (for example, halothane). This phenomenon is called the secondary gas effect. In this case, ventilation (especially gas flow in the trachea) and the concentration of the anesthetic at the alveolar level increase.

Since many anesthesiologists use combined methods of inhalation anesthesia, when vaporous drugs are combined with dinitrogen oxide, it is important to know the hemodynamic effects of these combinations.

In particular, when dinitrogen oxide is added to halothane, cardiac output decreases, and in response, the sympathoadrenal system is activated, leading to an increase in vascular resistance and an increase in blood pressure. When dinitrogen oxide is added to enflurane, a small or insignificant decrease in blood pressure and cardiac output occurs. Dinitrogen oxide in combination with isoflurane or desflurane at the MAC level of anesthetics leads to a slight increase in blood pressure, associated mainly with an increase in total peripheral vascular resistance.

Dinitrogen oxide in combination with isoflurane significantly increases coronary blood flow against the background of a significant decrease in oxygen consumption. This indicates a violation of the mechanism of autoregulation of coronary blood flow. A similar picture is observed when dinitrogen oxide is added to enflurane.

Halothane, when combined with beta-blockers and calcium antagonists, increases myocardial depression. Caution is required when combining monoamine oxidase (MAO) inhibitors and tricyclic antidepressants with halothane due to the development of unstable blood pressure and arrhythmias. Combining halothane with aminophylline is dangerous due to the development of severe ventricular arrhythmias.

Isoflurane combines well with dinitrogen oxide and analgesics (fentanyl, remifentanil). Sevoflurane combines well with analgesics. It does not sensitize the myocardium to the arrhythmogenic effect of catecholamines. When interacting with soda lime (a CO2 absorber), sevoflurane decomposes to form a nephrotoxic metabolite (an A-olefin compound). This compound accumulates at high temperatures of respiratory gases (low-flow anesthesia), and therefore it is not recommended to use a fresh gas flow of less than 2 liters per minute.

Unlike some other drugs, desflurane does not cause myocardial sensitization to the arrhythmogenic effect of catecholamines (epinephrine can be used up to 4.5 mcg/kg).

Xenon also interacts well with analgesics, muscle relaxants, neuroleptics, sedatives and inhalation anesthetics. The above agents potentiate the action of the latter.