Sevoflurane is currently the only inhalational anesthetic with advantageous properties in relation to other properties, namely, the absence of an irritating effect on the respiratory tract and a low blood/gas distribution coefficient [1, 2]. The absence of a strong odor and rapid induction of anesthesia, without additional injections, makes sevoflurane an ideal drug for mask induction of anesthesia in children [3]. Currently, two methods of induction of anesthesia using sevoflurane are used [4]. The first method is stepwise induction, which involves gradually increasing the concentration of sevoflurane in the breathing circuit. This technique is accompanied by an increase in the induction time of anesthesia, which requires physical restraint of the child during anesthesia. The second method is bolus induction of anesthesia. It should be noted that bolus induction with sevoflurane using the VIMA (Volatile Induction and Maintenance Anesthesia) technique is more common and popular in pediatric anesthesiology [5]. The essence of this technique is to give the patient sevoflurane in a high concentration (6-8%), which ensures rapid falling asleep within 20-30 seconds.
However, the VIMA technique also has its drawbacks, such as patient agitation during induction of anesthesia, the development of bradycardia and the occurrence of post-anesthesia agitation upon awakening. The stage of excitation is characterized by the appearance after loss of consciousness of motor reactions that require holding the patient, and occurs in 60-90% of children during induction of anesthesia with sevoflurane [6]. During the arousal stage, pulmonary ventilation may decrease due to simultaneous contraction of the trunk and neck muscles, which increases the risk of developing hypoxia and hypercapnia. A number of authors [7, 8] believe that the cause of tonic-clonic motor activity during induction of anesthesia is epileptiform cortical activity that develops when using sevoflurane.
The development of bradycardia is associated with the specific effect of sevoflurane on the autonomic nervous system, namely with the suppression of its parasympathetic component at the beginning of induction, which leads to a temporary increase in the effect of the sympathetic component on the heart. The consequence of this is short-term tachycardia; subsequently, as anesthesia deepens, sympathetic-adrenal activity decreases, which leads to the development of bradycardia [9]. In addition to its effect on the autonomic nervous system, sevoflurane is also characterized by a direct inhibitory effect on the sinus node [10, 11]. Severe bradycardia can be life-threatening [12].
Post-anesthesia agitation is a specific phenomenon that occurs in children and is accompanied by motor agitation, lack of contact with the child, disorientation and crying [13-16]. This condition can last from several minutes to 1 hour and goes away on its own, but requires monitoring of the child, prolongs the child’s recovery time after anesthesia and leads to concern for parents [17]. The incidence of agitation varies from 10 to 67% [18]. Data from recent studies show that the frequency of post-anesthesia agitation in children when using sevoflurane and desflurane is approximately the same and amounts to 25% [19].
The hypothesis of our study was to use the phenomenon of preconditioning at the induction stage of anesthesia to prevent the negative effects of sevoflurane anesthesia. In recent years, the phenomenon of preconditioning with sevoflurane has been widely studied, and the cardioprotective and neuroprotective effects of this inhalational anesthetic are discussed [5, 20]. We hypothesized that to achieve a preconditioning effect, induction of anesthesia with sevoflurane should consist of two boluses. The first inhalation bolus of sevoflurane in high concentration (6%) should ensure not only a rapid loss of consciousness, but also preconditioning of the child’s body. The second bolus of sevoflurane is performed to achieve the required depth of anesthesia, install a laryngeal mask and transfer to artificial ventilation (ALM).
The purpose of the study was to compare the effect of the traditional VIMA (Volatile Induction and Maintenance Anesthesia) technique and the new VIMA technique with double bolus sevoflurane induction on the incidence of agitation, bradycardia and agitation in children.
Pharmacological properties of the drug Sevoflurane
Inhalation anesthetic agent. Inhalation use causes a rapid loss of consciousness, which quickly recovers after cessation of anesthesia. Induction of anesthesia is accompanied by minimal arousal and signs of irritation of the upper respiratory tract and does not cause excessive secretion in the tracheobronchial tree and stimulation of the central nervous system. Causes dose-dependent suppression of respiratory function and a decrease in blood pressure. The threshold level of sevoflurane, which causes the development of arrhythmias under the influence of epinephrine, is comparable to that of isoflurane and exceeds the threshold level of halothane. Sevoflurane has a minimal effect on intracranial pressure and does not cause an increase in renal or liver failure. Does not affect the concentration function of the kidneys even with prolonged general anesthesia (up to about 9 hours). The low solubility of sevoflurane in the blood ensures a rapid increase in alveolar concentration when administered under general anesthesia and a rapid decrease after cessation of inhalation. The ratio of alveolar concentration and concentration in the inhaled mixture in the accumulation phase 30 minutes after inhalation of sevoflurane is 0.85. During the elimination phase, the alveolar concentration ratio after 5 minutes is 0.15. Less than 5% of the absorbed dose is metabolized by cytochrome P450 (GYP 2E1) to hexafluoroisopropanol, releasing inorganic fluorine and carbon dioxide (or carbon dioxide alone). The resulting hexafluoroisopropanol is quickly conjugated with glucuronic acid and excreted in the urine. Sevoflurane is the only fluorinated volatile general anesthetic that is not metabolized to trifluoroacetic acid. The concentration of fluoride ions depends on the duration of general anesthesia, the concentration of sevoflurane administered and the composition of the mixture. Barbiturates do not cause defluoridation of sevoflurane.
Discussion
In light of recent publications examining the phenomenon of sevoflurane preconditioning, it can be assumed that the use of sevoflurane preconditioning during the first bolus phase of induction may be rational in terms of minimizing complications of inhalational anesthesia. Preconditioning is a term that arose to describe the phenomenon of metabolic adaptation of the body or its individual organs (myocardium, brain, etc.) to a damaging factor, the preliminary short-term exposure of which can increase the resistance of the body’s cells to subsequent stress. Preconditioning is a kind of “training” of the body, triggering endogenous mechanisms of adaptation to the action of a damaging factor [21].
Studies that studied epileptiform activity of the brain during induction of anesthesia with sevoflurane, which is associated with the development of the excitation stage [8], showed that the first peaks of epileptiform activity on the electroencephalogram appear 70 s from the start of bolus induction. As the authors note, the exhaled sevoflurane concentration by this time reaches 3.5%.
We used a double bolus induction technique, in which the first bolus was short-lived, averaging no more than 30–40 s, and the sevoflurane concentration in exhaled air rarely exceeded 3%. Thus, it can be assumed that the concentration of sevoflurane in the brain did not reach the threshold level required for the development of epileptiform activity. Perhaps this led to a statistically significantly lower frequency of the excitement stage in children of the 2nd group.
The phenomenon of myocardial preconditioning, in our opinion, can also explain the almost 8 times lower incidence of bradycardia during induction of anesthesia in children of group 2. It was the first short-term bolus of sevoflurane that provided anesthetic preconditioning of the myocardium, since the second bolus and the observed increase in the concentration of anesthetic on exhalation from 0.2-0.3 to 2.5% no longer led to a decrease in heart rate. On the contrary, heart rate increased by an average of 10-15 beats/min and remained at this level throughout anesthesia. Theoretically, we believe that using this technique of induction of anesthesia, the development of bradycardia can be completely avoided. However, the technical difficulty may lie in the fact that to prevent bradycardia, the fastest possible decrease in the concentration of sevoflurane in the body after the first bolus is required (from 3 to 0.3% in exhaled air), and this requires providing hyperventilation through auxiliary ventilation, which is not always possible .
The minimal frequency in children of group 2 of the phenomenon of post-anesthesia agitation, which has much in common with the stage of excitation [15], can be explained by the effect of preconditioning and, as a consequence, possible neuroprotection.
The technique we developed for double bolus induction of anesthesia is economically more profitable, since the supply of sevoflurane at high flows before installation of the laryngeal mask and transfer to mechanical ventilation continues for 1.5-2 minutes (the first bolus - 30 s, the second - 1-1, 5 minutes). With the traditional technique, the delivery of sevoflurane at high flows lasts up to 4-6 minutes.
Use of the drug Sevoflurane
During general anesthesia, it is necessary to know the concentration of sevoflurane coming from the vaporizer. To do this, you can use a vaporizer specifically calibrated for sevoflurane. Introduction to general anesthesia: the dose is selected individually and titrated until the desired effect is achieved, taking into account the age and condition of the patient. After inhalation of sevoflurane, a short-acting barbiturate or other drug may be administered to induce general anesthesia intravenously. For administration of general anesthesia, sevoflurane can be used in oxygen or in a mixture of oxygen and nitric oxide. Before surgery, inhaled sevoflurane at concentrations up to 8% usually provides induction of general anesthesia in less than 2 minutes in both adults and children. Maintenance general anesthesia: The required level of general anesthesia can be maintained by inhaling sevoflurane at a concentration of 0.5–3% with or without nitric oxide. The minimum alveolar concentration is the concentration at which 50% of patients have no motor activity in response to a single irritation (skin incision). Minimum alveolar concentration values for adults and children, taking into account age: from 0 to 1 month (term newborns) sevoflurane in oxygen - 3.3%, from 1 to 6 months - 3%, from 6 months to 3 years - 2.8% , in a mixture (65% nitric oxide and 35% oxygen) - 2%; from 3 to 12 years - sevoflurane in oxygen - 2.5%; 25 years - sevoflurane in oxygen - 2.6%, in a mixture (65% nitric oxide and 35% oxygen) - 1.4%; 40 years - 2.1 and 1.1%, respectively; 60 years - 1.7 and 0.9%; 80 years - 1.4 and 0.7%. The minimum alveolar concentration of sevoflurane decreases with age and with the addition of nitric oxide.
Material and methods
For this study, approval was received from the ethics committee of the Tver State Medical University. The study was retrospective and prospective. The retrospective study included 210 children (group 1) aged 3 to 6 years who underwent dental treatment under inhalation anesthesia with sevoflurane (traditional VIMA technique). The prospective study included 90 children (group 2) of the same age who underwent dental treatment using the new VIMA technique, using double bolus induction with sevoflurane. The somatic status of the children in the groups did not differ and amounted to class I-III according to the ASA (American Society of Anesthesiologists) classification. There were no differences between groups in gender composition. All children received anesthesia in the morning, on an empty stomach. The last intake of fluid was allowed no later than 2 hours before anesthesia. Premedication was not used in children.
When treating children of group 1, the traditional VIMA induction technique was used. Its essence was that the anesthesia machine circuit was pre-filled with a gas-narcotic mixture consisting of 60% nitrous oxide (N2O) (3 l/min), 40% oxygen (O2) (2 l/min) and 6% sevoflurane. Then the child was allowed to breathe through a face mask with this gas-narcotic mixture. After loss of consciousness, the sevoflurane concentration was reduced to 4%, and the child continued to breathe this mixture for 5-6 minutes until the required depth of anesthesia was achieved, a laryngeal mask was installed, and he was transferred to mechanical ventilation.
The difference between double bolus induction of anesthesia and the traditional technique was that after the first bolus of 6% sevoflurane in a flow of O2 and N2O 2 and 3 l/min, respectively, leading to the child falling asleep, the anesthetic supply was stopped. The anesthesia machine circuit was purged with 100% O2. The child continued to breathe through the anesthesia machine circuit for 3-4 minutes at the same flows of O2 and N2O, while the concentration of sevoflurane in the exhaled air decreased from 3 to 0.3-0.2%. When hypoventilation developed, auxiliary mask ventilation was used. The second bolus of sevoflurane, with the evaporator fully open and the previous O2 and N2O supply flows, began from the moment the heart rate stopped decreasing and the heart rate began to increase by 2-3 beats per minute. The duration of the repeated bolus was 1-1.5 minutes. This time is enough to achieve the required level of anesthesia, install a laryngeal mask and transfer the child to mechanical ventilation.
Maintenance of anesthesia in children of the study groups was the same and consisted of sevoflurane (2-2.5%) in a gas narcotic mixture flow of 1.5 l/min (O2 - 0.6 l/min, N2O - 0.9 l/min). We used a Fabius Plus anesthesia machine (Dräger, Germany) with a Scio Four Oxi plus gas analyzer and an Infinity Vista XL monitor. The duration of anesthesia in children of both groups was the same and amounted to 95±10 minutes. In all children, volumetric ventilation was used in the normoventilation mode: the level of carbon dioxide at the end of expiration (etCO2) was 35-40 mm Hg. Monitoring during anesthesia included the following indicators: heart rate, blood pressure, blood oxygen saturation level (SpO2), etCO2, inspiratory and expiratory concentrations of O2, N2O and sevoflurane, tidal volume (Vt, Tidal Volume), body temperature, and electrocardiography results .
Statistical processing was carried out using IBM SPSS Statistics v software. 21, data presented as M ± m
(
M
- mean,
m
- standard error of the mean), 95% confidence interval (CI).
The normality of group distribution was assessed using the Kolmogorov-Smirnov test, the statistical significance of the difference between groups was assessed using the t
-test for independent samples;
statistical significance was determined at a p
<0.05.
Side effects of the drug Sevoflurane
During use - depression of cardiac and respiratory function (dose-dependent), nausea, vomiting, increased cough, decreased or increased blood pressure, agitation, drowsiness (after recovery from general anesthesia), chills, bradycardia, tachycardia, dizziness, increased salivation, apnea after intubation , laryngospasm, fever. Rarely - postoperative hepatitis; in children receiving sevoflurane for induction of general anesthesia - dystonia (the connection with the use of sevoflurane has not been established). After use: rarely: convulsions, malignant hyperthermia and allergic reactions (rash, urticaria, itching, bronchospasm, anaphylactic or anaphylactoid reactions), mood changes, transient hyperglycemia and leukocytosis. During and after general anesthesia - a transient increase in inorganic fluoride in the blood serum, an increase in the activity of liver transaminases.
Special instructions for the use of Sevoflurane
Sevoflurane should only be used by persons experienced in general anesthesia. It is necessary to have equipment for airway management, mechanical ventilation, oxygen therapy and resuscitation at the ready. Because patients usually recover quickly from general anesthesia with sevoflurane, they may require postoperative analgesia earlier. Susceptible patients may develop a state of skeletal muscle hypermetabolism, resulting in an increase in their oxygen demand and the development of a malignant hyperthermia syndrome, the first sign of which is hypercapnia, and its clinical symptoms may include muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias and/or instability HELL. Some of these nonspecific symptoms may also appear during early general anesthesia, acute hypoxia, hypercapnia, and hypovolemia. Treatment of malignant hyperthermia: drug withdrawal, intravenous administration of dantrolene and supportive symptomatic therapy. Renal failure may develop later, so diuresis should be monitored and maintained if possible. The level of general anesthesia can change easily and quickly, so only specially calibrated vaporizers should be used to deliver sevoflurane. As general anesthesia deepens, there is an increasing decrease in blood pressure and depression of respiratory function. When general anesthesia is maintained, increasing sevoflurane concentrations causes a dose-dependent decrease in blood pressure. An excessive decrease in blood pressure may be associated with the depth of general anesthesia; in such cases it can be increased by reducing the concentration of sevoflurane supplied. In persons with coronary artery disease, it is necessary to maintain stable hemodynamics to avoid myocardial ischemia. When patients emerge from general anesthesia, they should be carefully monitored before being transported to the ward. Since increased effects of muscle relaxants are observed several minutes after the start of sevoflurane inhalation, reducing the dose of muscle relaxants during induction of general anesthesia may lead to delayed tracheal intubation or inadequate muscle relaxation. During endotracheal intubation, dosages of non-depolarizing muscle relaxants should not be reduced; While maintaining general anesthesia, additional doses of muscle relaxants are administered based on the response to nerve stimulation. During neurosurgical interventions where there is a threat of increased intracranial pressure, sevoflurane should be used with caution in combination with measures aimed at reducing intracranial pressure, such as hyperventilation. The safety of sevoflurane for mothers and newborns has been established when used for general anesthesia for caesarean section. Inorganic fluoride concentrations usually reach a maximum within 2 hours after sevoflurane is stopped and return to preoperative levels within 48 hours (the increase in fluoride concentrations is not accompanied by renal dysfunction). For some time after general anesthesia, it is necessary to refrain from driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.
Sevoflurane, liquid for inhalation anesthesia
Sevoflurane should only be administered by persons who are trained in general anesthesia. It is mandatory to have equipment to maintain airway patency, perform artificial ventilation, provide oxygen and restore blood circulation.
The concentration of sevoflurane supplied from the evaporator must be accurately known. Because volatile anesthetics have different physical properties, only vaporizers specifically calibrated for the use of sevoflurane should be used.
The use of general anesthesia should be individualized based on the patient's response to anesthesia. As the depth of anesthesia increases, the degree of hypotension and respiratory depression increases.
There are reports that previous use of halogenated hydrocarbon anesthetics, especially if the interval between use was less than 3 months, may increase the potential risk of developing liver damage.
There have been isolated reports of QT prolongation, very rarely associated with torsade de pointes (TdP), which has been fatal in exceptional cases. Sevoflurane should be used with caution in patients prone to this condition.
In patients with mitochondrial disorders, general anesthesia, incl. sevoflurane should be used with caution.
During maintenance of anesthesia, increasing the concentration of sevoflurane leads to a dose-dependent decrease in blood pressure. Excessive reduction in blood pressure may be related to the depth of anesthesia, and in such cases it can be corrected by reducing the inhaled concentration of sevoflurane. As with any anesthetic agent, it is important to maintain hemodynamic stability in patients with coronary artery disease to prevent myocardial ischemia.
Arousal from anesthesia should be carefully assessed before removing the patient from the recovery room.
Restoration of consciousness after the use of sevoflurane usually occurs within a few minutes; the effect on intellectual abilities after anesthesia has not been studied. As with other anesthetics, slight changes in mood may be observed over the next 2-3 days after anesthesia.
Liver.
Very rare cases of mild, moderate and severe postoperative liver dysfunction or hepatitis with or without jaundice have been reported with the use of sevoflurane in patients with underlying liver disease or with drugs known to cause liver dysfunction.
Malignant hyperthermia.
In susceptible individuals, potent inhaled anesthetics can initiate a musculoskeletal hypermetabolic state, resulting in increased oxygen demand and a clinical syndrome known as malignant hyperthermia. One case of malignant hyperthermia was reported in clinical studies. This syndrome manifests as hypercapnia and may include nonspecific signs such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmia, and/or unstable blood pressure (some of these symptoms may also occur with superficial anesthesia, acute hypoxia, hypercapnia, and hypovolemia). Treatment includes discontinuation of initiating agents (eg, sevoflurane), intravenous dantrolene sodium, and supportive care. Later, renal failure may develop, so diuresis must be monitored and maintained.
Perioperative hyperkalemia.
The use of inhalational anesthetics is associated with rare cases of increased plasma potassium levels, which can manifest as arrhythmias; there have been cases of death in children in the postoperative period. Patients with latent or overt neuromuscular diseases, especially Duchenne neuromuscular dystrophy, are particularly susceptible. In most of these cases, succinylcholine was used simultaneously. These patients also experienced a significant increase in plasma CPK levels, and in some cases, myoglobinuria.
Although these manifestations are similar to malignant hyperthermia, no patients had signs or symptoms of muscle rigidity or a hypermetabolic state. Early and intensive correction of hyperkalemia and treatment of arrhythmias, followed by screening for latent neuromuscular diseases, is recommended.
Patients with renal failure.
Due to the small number of patients with renal impairment studied (baseline serum creatinine level greater than 133 µmol/L (1.5 mg/dL)), the safety of Sevoflurane in this group has not been fully established.
Neurosurgery:
Sevoflurane should be prescribed with caution to patients at risk of increased intracranial pressure and measures aimed at reducing intracranial pressure should be used.
Cramps.
Rare cases of seizures have been reported with the use of sevoflurane. The use of sevoflurane has been associated with the occurrence of seizures in young adults (<21 years of age) as well as in older adults, regardless of the presence of risk factors for seizure susceptibility. It is necessary to conduct a clinical assessment of patients before using sevoflurane if there is a risk of seizures. The use of an electroencephalogram helps optimize the dose of sevoflurane and prevent the development of seizures in patients with a predisposition to their occurrence.
Replacement of dried CO2 absorbents.
When sevoflurane is used with overdried CO2 sorbents, rare cases of excessive overheating and/or spontaneous combustion in anesthesia machines have been described. Replacement of CO2 absorbents that have dried out must be carried out before using Sevoflurane to prevent exothermic reactions that increase the degradation of Sevoflurane. When the CO2 sorbent dries, the color of the indicator does not always change. Therefore, the absence of changes in the color of the indicator cannot be considered confirmation of adequate hydration. CO2 sorbents must be changed regularly, regardless of the color of the indicator.
Drug interactions Sevoflurane
the safety and effectiveness of sevoflurane has been confirmed when used simultaneously with various drugs that are often used in surgical practice: drugs affecting the function of the central nervous system and autonomic nervous system, muscle relaxants, antimicrobial drugs, including aminoglycosides, hormones and their synthetic derivatives, blood products and cardiovascular vascular agents, including epinephrine. Sevoflurane can be used with barbiturates, benzodiazepines and opioid analgesics. Sevoflurane enhances the effect of pancuronium bromide, vecuronium bromide and atracurium besilate (dose adjustment required). Benzodiazepines and opioid analgesics reduce the minimum alveolar concentration of sevoflurane. The minimum alveolar concentration of sevoflurane is reduced by concomitant use of nitric oxide.
