Propofol

Propofol is one of the last introduced into clinical practice in / in anesthetics. It is an alkylphenol derivative (2,6-diisopropylphenol), prepared as a 1% emulsion containing 10% soybean oil, 2.25% glycerol and 1.2% egg phosphatide. Although propofol is not an ideal anesthetic, it has won the well-deserved recognition of anesthesiologists around the world due to its unique pharmacokinetic properties. Its wider use is limited only by high cost.

[1], [2], [3], [4], [5]

Propofol: a place in therapy

The search for the ideal anesthetic led to the creation of propofol. It is distinguished by the rapid and smooth onset of the hypnotic effect, the creation of optimal conditions for mask ventilation, laryngoscopy, and installation of a laryngeal airway. Propofol, unlike barbiturates, DB, ketamine, sodium oxybate, is administered only IV in the form of a bolus (preferably by titration) or infusion (dropping or infusion with a pump). As with other anesthetics, the choice of dosage and the rate of sleep after administration of propofol is influenced by factors such as the presence of premedication, the rate of administration, the elderly and senile age, the severity of the patient's condition, and the combination with other drugs. In children, the induction dose of propofol is higher than in adults, due to pharmacokinetic differences.

To maintain anesthesia, propofol is used as a basic hypnotic in combination with an inhalation or other intravenous anesthetic (TBBA). It is administered either bolus in small portions of 10-40 mg every few minutes depending on clinical needs, or infusion, which is certainly preferable because of the creation of a stable concentration of drugs in the blood and more convenience. The classical scheme for the introduction of the 1980s is 10-8-b mg / kg / h (after a bolus of 1 mg / kg infusion for 10 min at a rate of 10 mg / kg / h, the next 10 min is 8 mg / kg / h, in further, b mg / kg / h) is currently used less often because it does not allow rapid increase in the concentration of propofol in the blood, the bolus amount is not always easy to determine and, if necessary, reduce the depth of anesthesia by stopping the infusion; It is difficult to determine the appropriate time for its resumption.

Compared with other drugs for anesthesia, the pharmacokinetics of propofol is well modeled. This was a prerequisite for the practical implementation of the procedure for the infusion of propofol at the target concentration in the blood (ICP) by creating syringe perfusors with embedded microprocessors. Such a system relieves an anesthetist from complex arithmetical calculations to create the desired concentration of drugs in the blood (ie, the choice of infusion rates), allows for a wide range of rates of administration, visually demonstrates the effect of titration and orientates in the awakening period when discontinuing the infusion, combines ease of use and depth controllability anesthesia.

Propofol has proven itself in cardioanesthesiology due to intra- and postoperative hemodynamic stability, a reduction in the incidence of ischemic episodes. With operations on the brain, spine and spinal cord, the use of propofol allows, if necessary, to perform a wake-up test, which makes it an alternative to inhalation anesthesia.

Propofol is the first choice of drugs for providing anesthesia on an outpatient basis due to the rapidity of awakening, restoration of orientation and activation, characteristics comparable to those of the best representatives of inhalation anesthetics, as well as low probability of POT. The rapid restoration of the swallowing reflex promotes an earlier safe eating.

Another area of application in / in non-barbituric hypnotics is sedation during operations in conditions of regional anesthesia, with short-term medical and diagnostic manipulations, and in the ICU.

Propofol is considered one of the best drugs for sedation. Characteristic is the rapid achievement of the desired level of sedation by titration and rapid recovery of consciousness, even with long periods of infusion. It is also used for patient-controlled sedation, while having advantages over midazolam.

Propofol possesses good qualities of an induction agent, a controlled hypnotic at the stage of maintenance, and the best recovery characteristics after anesthesia. However, its use in patients with shortage of BCC and blood circulation depression is dangerous.

Mechanism of action and pharmacological effects

It is believed that propofol stimulates beta-subunits of the GABA-receptor, activating the chloride ion channels. In addition, it also inhibits NMDA receptors.

The main mechanism of action of etomidate is probably related to the GABA system. In this case, alpha, gamma, beta1 and beta2 subunits of the GABAA receptor are particularly sensitive. The mechanism of sedative and hypnotic action of steroids is also associated with the modulation of GABA receptors.

Influence on the central nervous system

Propofol has no analgesic activity, and therefore is mainly seen as a hypnotic. In the absence of other drugs (opioids, relaxants), even at relatively high dosages, involuntary limb movements can be observed, especially with any traumatic stimulation. The concentration of propofol, in which 50% of patients do not react to the skin incision, is very high and is 16 μg / ml blood. For comparison: in the presence of 66% of the dinitrogen oxide, it decreases to 2.5 μg / ml, and with morphine premedication - up to 1.7 μg / ml.

Depending on the dose used, propofol causes sedation, amnesia and sleep. Sleeping occurs smoothly, without the stage of excitement. After awakening, patients tend to be satisfied with anesthesia, are complacent, sometimes report hallucinations and sexual dreams. By the ability to cause amnesia, propofol approaches midazolam and exceeds thiopental sodium.

Effects on cerebral blood flow

After administration of propofol in patients with normal intracranial pressure, it decreases by approximately 30%, a slight decrease in CPD (by 10%). In patients with increased intracranial pressure, its decrease is more pronounced (30-50%); Also, the decrease in CPD is more noticeable. To prevent the increase of these parameters during the intubation of the trachea, the introduction of opioids or an additional dose of propofol is necessary. Propofol does not alter autoregulation of cerebral vessels in response to changes in systemic blood pressure and the level of carbon dioxide. With the invariance of the main cerebral metabolic constants (glucose, lactate), PM02 decreases by an average of 35%.

[6], [7], [8]

Electroencephalographic picture

When propofol is used, the EEG is characterized by an initial increase in the rhythm, followed by a predominance of y and 9-wave activity. With a significant increase in the concentration of the drug in the blood (more than 8 μg / ml), the amplitude of the waves is markedly reduced, and suppressive flashes periodically appear. In general, changes in the EEG are similar to those with barbiturates.

The concentration of propofol in the blood, the ability to respond to stimuli and the presence of memories are well correlated with the BIS values. Propofol causes a decrease in the amplitude of early cortical responses and somewhat increases the latency of SSEP and MVP. The effect on propofol MVP is more pronounced than that of etomidate. Propofol causes a dose-dependent decrease in amplitude and an increase in the latency of mid-latent SVPs. It should be noted that it is one of those drugs, when using the information content of these options for processing signals of electrical activity of the brain during anesthesia is highest.

Information on the effect of propofol on convulsive and epileptiform EEG activity is largely contradictory. Various researchers attributed it to both anticonvulsant properties and, conversely, the ability to cause large epileptic seizures. In general, it should be recognized that the likelihood of convulsive activity against the background of the use of propofol is low, incl. In patients with epilepsy.

Many studies have confirmed the antiemetic properties of sub-hypnotic doses of propofol, incl. When carrying out chemotherapy. This distinguishes it from all used anesthetics. The mechanism of the antiemetic effect of propofol is not completely clear. There are data on the lack of its effect on B2-dopamine receptors and the non-involvement of this fat emulsion effect. Unlike other intravenous hypnotics (for example, thiopental sodium), propofol depresses the subcortical centers. There are suggestions that propofol changes the subcortical connections or directly depresses the vomiting center.

Of course, with multicomponent anesthesia, especially with the use of opioids, propofol's ability to prevent POT is reduced. Much is also determined by other risk factors for the occurrence of POTR (patient characteristics, type of surgical intervention). All other conditions being equal, the incidence of POND syndrome is significantly lower when using propofol as a basic hypnotic, but increasing the duration of propofol-opioid anesthesia levels this advantage over thiopental isoflurane anesthesia.

There are reports of weakening of pruritus in cholestasis and the use of opioids against the background of sub-hypnotic doses of propofol. Perhaps, this effect is associated with the ability of drugs to suppress the activity of the spinal cord.

[9], [10], [11], [12], [13]

Influence on the cardiovascular system

During the induction of anesthesia, propofol causes vasodilation and myocardial depressions. Regardless of the presence of concomitant cardiovascular diseases, a significant reduction in blood pressure (systolic, diastolic, and mean) occurs in the background of administration of propofol, a decrease in the cardiac output volume (about 20%), cardiac index (by about 15%), OPSS (by 15-25%), the index of shock work of the left ventricle (IURLC) (approximately 30%). In patients with valvular heart disease, it reduces pre- and post-loading. Relaxation of smooth muscle fibers of arterioles and veins is due to depression of sympathetic vasoconstriction. Negative inotropic effect can be associated with a decrease in the level of intracellular calcium.

Hypotension can be more pronounced in patients with hypovolemia, left ventricular failure and in the elderly, and also directly depends on the administered dose and plasma concentration in plasma, the rate of administration, the presence of premedication and the simultaneous use of other drugs for co-induction. The peak concentration of propofol in the plasma after the bolus dose is significantly higher than with the infusion method of administration, so the decrease in blood pressure is more pronounced when the bolus dose is administered.

In response to direct laryngoscopy and intubation of the trachea, blood pressure increases, but the degree of this pressor reaction is less than when barbiturates are used. Propofol is the best in / in hypnotics, warning the hemodynamic response to the installation of the laryngeal mask. Immediately after the induction of anesthesia, the intraocular pressure decreases significantly (by 30-40%) and normalizes after intubation of the trachea.

It is characteristic that when propofol is used, oppression of the protective baroreflex occurs in response to hypotension. Propofol more significantly inhibits the activity of the sympathetic nervous system, rather than parasympathetic. It does not affect the conductivity and function of the sinus and atrioventricular nodes.

Rare cases of pronounced bradycardia and asystole after the use of propofol are described. It should be noted that these were healthy adult patients who underwent anticholinergic prophylaxis. The lethality associated with bradycardia is 1.4: 100 000 cases of propofol.

During the maintenance of anesthesia, blood pressure remains lower than the baseline by 20-30%. With the isolated use of propofol, the OPSS is reduced to 30% of the initial, while the VOC and SI do not change. Against the backdrop of combined application of dinitrogen oxide or opioids, on the contrary, reduced UOS and SI with a slight change in OPSS. Thus, the suppression of the sympathetic reflex response in response to hypotension persists. Propofol reduces coronary blood flow and myocardial oxygen consumption, while the delivery / consumption ratio remains unchanged.

Due to vasodilation, propofol suppresses the possibility of thermoregulation, which leads to hypothermia.

Influence on the respiratory system

After the administration of propofol, there is a pronounced decrease in DO and a short-term increase in BH. Propofol causes a respiratory arrest, the probability and duration of which depends on the dose, the rate of administration and the presence of premedication. Apnea after the introduction of an induction dose occurs in 25-35% of cases and can last more than 30 seconds. The duration of apnea is increased when opioids are added to the premedication or induction.

Propofol exerts a longer lasting effect on DO than on BH. Like other anesthetics, it causes a decrease in the response of the respiratory center to the level of carbon dioxide. But, unlike inhalation anesthetics, doubling the concentration of propofol in plasma does not lead to a further increase in PaCOa. As with barbiturates, PaO2 does not change significantly, but the ventilation response to hypoxia is inhibited. Propofol does not suppress hypoxic vasoconstriction in single-pulmonary ventilation. With prolonged infusion, incl. In sedative doses, DO and BH remain reduced.

Propofol has a certain bronchodilating effect, incl. In patients with COPD. But in this he is noticeably inferior to the halothane. Laryngospasm is unlikely.

Effects on the gastrointestinal tract and kidneys

Propofol does not significantly alter the motility of the gastrointestinal tract and the function of the liver. Reduction of hepatic blood flow is due to a decrease in systemic blood pressure. With prolonged infusion, it is possible to change the color of urine (green tint due to the presence of phenols) and its transparency (cloudiness due to uric acid crystals), but this does not change the function of the kidneys.

[14], [15], [16], [17], [18]

Effect on the endocrine response

Propofol does not significantly affect the production of cortisol, aldosterone, renin, as well as the response to changes in the concentration of ACTH.

[19], [20], [21], [22], [23], [24],

Effect on neuromuscular transmission

Like thiopental sodium, propofol does not affect neuromuscular transmission, blocked by muscle relaxants. It does not cause muscle tension, suppresses pharyngeal reflexes, which provides good conditions for the installation of a laryngeal mask and intubation of the trachea after the administration of propofol alone. However, this increases the likelihood of aspiration in patients at risk of vomiting and regurgitation.

[25], [26], [27], [28], [29]

Other effects

Propofol has antioxidant properties similar to vitamin E. This effect may be partially related to the phenolic structure of the drug. Propofol phenolic radicals have a retarding effect on the processes of lipid peroxidation. Propofol limits the flow of calcium ions into cells, thereby providing a protective effect against calcium-induced cell apoptosis.

Sodium oxybate has pronounced systemic antihypoxic, radioprotective properties, increases resistance to acidosis and hypothermia. The drug is effective for local hypoxia, in particular with retinal hypoxia. After the introduction, actively enters into the metabolism of the cell, therefore called the metabolic hypnotics.

Propofol does not cause malignant hyperthermia. The use of propofol and etomidate in patients with hereditary porphyria is safe.

Tolerance and dependence

Tolerance to propofol may occur with repeated anesthesia or a multi-day infusion for the purpose of sedation. There are reports of the development of propofol addiction.

Pharmacokinetics

Propofol is administered IV, which allows you to quickly reach high concentrations in the blood. Its extremely high solubility in fats determines the rapid penetration of drugs into the brain and the achievement of equilibrium concentrations. The onset of action corresponds to one circle of circulation of the forearm - the brain. After the induction dose, the peak effect occurs approximately in 90 seconds, the anesthesia lasts 5-10 minutes.

The duration of the effect of most IV hypnotics depends largely on the dose administered and is determined by the rate of redistribution from the brain and blood to other tissues. The pharmacokinetics of propofol with different doses are described using a two- or three-sector (three-chamber) model, regardless of the size of the bolus administered. Using a two-chamber model, the initial T1 / 2 propofol in the distribution phase is from 2 to 8 minutes, T1 / 2 to the elimination phase from 1 to 3 hours. The three-sector kinetic model is represented by a three-exponential equation and includes primary rapid distribution, slow redistribution, cross- given the inevitable cumulation of drugs. T1 / 2 propofol in the initial rapid phase of the distribution varies from 1 to 8 min, in the slow phase of the distribution - 30-70 min, and in the elimination phase varies from 4 to 23 hours. This longer T1 / 2 in the elimination phase more accurately reflects the slow return of medication from mildly perfused tissues to the central sector for subsequent elimination. But this does not affect the speed of awakening. With prolonged infusion, it is important to consider the context-sensitive T1 / 2 drug.

The volume of distribution of propofol immediately after injection is not very high and is approximately 20-40 liters, but in the equilibrium state it increases and ranges from 150 to 700 liters in healthy volunteers, and in the elderly it can reach 1,900 liters. Drugs are characterized by high clearance from the central sector and a slow return from badly perfused tissues back. The main metabolism occurs in the liver, where propofol forms water-soluble inactive metabolites (glucuronide and sulfate). In unchanged form with feces, up to 2% is excreted, in the urine - less than 1% of the drug. Propofol is characterized by a high overall clearance (1.5-2.2 l / min), exceeding the hepatic blood flow, which indicates extrahepatic pathways of metabolism (possibly through the lungs).

Thus, the early end of the hypnotic effect of propofol is due to the rapid distribution of large pharmacologically inactive tissues and an intensive metabolism that outstrips its slow entry back into the central sector.

The pharmacokinetics of propofol are influenced by factors such as age, gender, concomitant diseases, body weight, and shared drugs. In elderly patients, the volume of the central chamber and the clearance of propofol are lower than in adults. In children, on the contrary, the volume of the central chamber is greater (by 50%), and the clearance is higher (by 25%) when calculated for body weight. Thus, in elderly patients, doses of propofol should be reduced, and in children - increased. Although it should be noted that the data on the change in induction doses of propofol in the elderly are not as convincing as in the case of benzodiazepines. In women, the volume of distribution and clearance is higher, although T1 / 2 does not differ from that of men. With liver diseases, the volume of the central chamber and the volume of propofol distribution increase, while T1 / 2 is slightly elongated, and the clearance is not changed. By lowering the hepatic blood flow, propofol can slow down its own clearance. But more importantly, its effect on the own redistribution between tissues by reducing CB. It should be taken into account that when using the IR apparatus, the volume of the central chamber increases, and hence the required initial dose of the preparation.

The effect of opioids on propofol kinetics is largely contradictory and individual. There is evidence that a single bolus of fentanyl does not alter the pharmacokinetics of propofol. According to other data, fentanyl may reduce the volume of distribution and total clearance of propofol, and also reduce the consumption of propofol by the lungs.

The time to reduce the concentration of propofol twice after an 8-hour infusion is less than 40 minutes. And since clinically used infusion rates for waking usually require a decrease in the concentration of propofol by less than 50% of the concentrations necessary to maintain anesthesia or sedation, recovery of consciousness occurs quickly even after prolonged infusion. Thus, along with etomidate propofol is better than other hypnotics suitable for prolonged infusion for the purpose of anesthesia or sedation.

Contraindications

Absolute contraindication to the use of propofol is the intolerance of this drug or its components. Relative contraindication is hypovolemia of different genesis, expressed coronary and cerebral atherosclerosis, states in which undesirably reducing the CPD. Propofol is not recommended for use during pregnancy and for anesthesia in obstetrics (except abortion).

Propofol is not used for anesthesia in children under 3 years of age and for sedation in the ICU in children of all ages. Continues to study his involvement in several lethal outcomes of this age category. The use of a new dosage form propofol, containing a mixture of long and medium chain triglycerides, is allowed starting from the month of the child's life. The use of etomidate is contraindicated in patients with adrenal insufficiency. Due to the inhibition of the production of corticosteroids and mineralocorticoids, it is contraindicated for prolonged sedation in the ICU. It is considered inexpedient to use etomidate in patients with high risk of POT.

[30], [31]

Tolerance and side effects

Propofol and etomidate are usually well tolerated by patients. However, in many cases, patients experience weakness and weakness for some time after anesthesia with etomidate. Most of the undesirable effects of propofol are associated with overdose and initial hypovolemia.

Pain when administered

Propofol and pregnenolone cause moderate soreness.

With the administration of propofol, the pain is less than with the administration of etomidate, but more than with the administration of thiopental sodium. Pain is reduced with the use of veins of larger diameter, preliminary introduction (for 20-30 seconds) of 1% lidocaine, other local anesthetics (prilokain, procaine) or high-speed opioids (alfentanil, remifentanill). It is possible to mix propofol with lidocaine (0.1 mg / kg). A somewhat lesser effect is the preliminary (per 1 h) application of the propofol cream containing 2.5% lidocaine and 2.5% prilocaine to the zone of presumed administration. A decrease in pain with the preliminary administration of 10 mg of labetalol or 20 mg of ketamine is shown. Thrombophlebitis occurs rarely (<1%). Attempts to create a non-lipid solvent for propofol have so far been unsuccessful due to the high frequency of thrombophlebitis caused by the solvent (up to 93%). Paravasal administration of drugs causes erythema, which passes without treatment. Accidental intra-arterial administration of propofol is accompanied by severe soreness, but does not lead to damage to the endothelium of the vessel.

Inhibition of respiration

When using propofol, apnea occurs at the same frequency as after barbiturates, but more often lasts more than 30 seconds, especially when combined with opioids.

Hemodynamic changes

With the induction of anesthesia with propofol, the greatest clinical benefit is a decrease in blood pressure, which is higher in patients with hypovolemia, in the elderly, and in the combined administration of opioids. And the subsequent laryngoscopy and intubation do not cause such a pronounced hyperdynamic response, as induction by barbiturates. Hypotension is prevented and eliminated by an infusion load. In the case of ineffective prevention of vagotonic effects with anticholinergic drugs, it is necessary to use sympathomimetics such as isoproterenol or epinephrine. When prolonged sedation with propofol in children in the ICU is described the development of metabolic acidosis, "lipid plasma", refractory bradycardia with progressive heart failure, which in some cases ended in a fatal outcome.

Allergic reactions

Although after the administration of propofol, changes in immunoglobulin, complement and histamine levels were not detected, drugs can cause anaphylactoid reactions in the form of reddening of the skin, hypotension and bronchospasm. It is reported that the frequency of such reactions is less than 1: 250 000. The probability of anaphylaxis is higher in patients with allergic reactions in the anamnesis, incl. On muscle relaxants. Responsible for allergic reactions are not the fatty emulsion, but the phenolic core and the diisopropyl side chain of propofol. Anaphylaxis on first use is possible in patients sensitized to diisopropyl radical, which is present in some dermatological drugs (finalgon, zinerit). The phenol core is also part of the structure of many drugs. Propofol is not contraindicated in patients with an allergy to egg white, because it is realized through the albumin fraction.

[32], [33], [34]

Postoperative nausea and vomiting syndrome

Propofol is rarely associated with provocation of POT. On the contrary, many researchers consider it to be a hypnotic with antiemetic properties.

Reaction of awakening

With anesthesia with propofol, awakening occurs most rapidly, with a clear orientation, a clear restoration of consciousness and mental functions. In rare cases, excitation, neurological and mental disorders, asthenia are possible.

Influence on immunity

Propofol does not change chemotaxis of polymorphonuclear leukocytes, but suppresses phagocytosis, in particular, with respect to Staphylococcus aureus and Escherichia coli. In addition, the fatty medium created by the solvent promotes the rapid growth of pathogenic microflora when the aseptic rules are not observed. These circumstances make propofol potentially responsible for systemic infections with prolonged administration.

Other effects

Propofol does not have a clinically significant effect on hemostasis and fibrinolysis, although in in vitro experiments platelet aggregation decreases under the action of a fat emulsion.

Interaction

Propofol is most often used as a hypnotic in combination with other drugs for anesthesia (other intravenous anesthetics, opioids, inhalational anesthetics, muscle relaxants, ancillary drugs). Pharmacokinetic interactions between anesthetics can occur due to changes in distribution and clearance caused by hemodynamic shifts, changes in protein binding or metabolism due to activation or inhibition of enzymes. But pharmacodynamic interactions of anesthetics are of far greater clinical importance.

The recommended calculated doses are reduced in patients with premedication, with co-induction. The combination with ketamine allows to avoid the inherent propofol depression of hemodynamics and neutralizes its negative hemodynamic influences. Coinduction with midazolam also reduces the amount of propofol administered, which reduces the oppressive effect of propofol on hemodynamics and does not slow the awakening period. The combination of propofol with DB prevents possible spontaneous muscular activity. When propofol with thiopental sodium or DB is used, synergy is observed with respect to sedative, hypnotic and amnestic effects. However, apparently, it is undesirable to share propofol with drugs that have a similar effect on hemodynamics (barbiturates).

The use of dinitrogen oxide and isoflurane also reduces the consumption of propofol. For example, against the background of inhalation mixture with 60% dinitrogen oxide EC50 propofol decreases from 14.3 to 3.85 mkg / ml. This is important from an economic point of view, but it deprives TWVA of its main advantages. The need for propofol at the induction stage also reduces esmolol.

The powerful opioids of the fentanyl group (sufentanil, remifentanil), when combined, reduce both the distribution and clearance of propofol. This requires careful combination of them in patients with BCC deficiency because of the danger of severe hypotension and bradycardia. For the same reasons, the combined use of propofol and vegetotabilizing drugs (clonidine, droperidol) is limited. When using suxamethonium during induction, it is necessary to take into account the vagotonic effect of propofol. The synergism of opioids and propofol allows to reduce the amount of propofol administered, which, with short interventions, does not worsen the recovery parameters after anesthesia. With continued infusion, awakening occurs faster with remifentanil than with propofol combined with alfentanil, sufentanil or fentanyl. This allows the use of relatively lower infusion rates of propofol and higher rates of remifentanil.

Propofol, depending on the dose, inhibits the activity of cytochrome P450, which can reduce the rate of biotransformation and enhance the effects of drugs metabolized with the participation of this enzyme system.

Caveats

Despite the obvious separate advantages and relative safety of non-barbituric sedative-hypnotic drugs, it is necessary to consider the following factors:

• age. To ensure adequate anesthesia, elderly patients require a lower concentration of propofol in the blood (by 25-50%). In children, induction and maintenance dosages of propofol, based on body weight, should be higher than in adults;
• duration of intervention. The unique pharmacokinetic characteristics of propofol make it possible to use it as a hypnotic component to maintain long-term anesthesia with little risk of prolonged depression of consciousness. But to a certain extent, the accumulation of drugs still occurs. This explains the need to reduce the infusion rate as the intervention time is extended. The use of propofol for prolonged sedation in patients in the ICU requires periodic monitoring of blood lipid levels;
• concomitant cardiovascular diseases. The use of propofol in patients with cardiovascular and debilitating diseases requires caution in connection with its depressing effect on hemodynamics. Compensatory frequency of heart rate may not be due to some vagotonic activity of propofol. Reducing the degree of oppression of hemodynamics with the administration of propofol can be pre-hydration, slow administration by titration. Do not use propofol in patients in a state of shock and with presumed massive blood loss. Caution should be used propofol in children during surgery for the correction of strabismus in connection with the likelihood of strengthening the oculocardial reflex;
• concomitant diseases of the respiratory system do not have a significant effect on the dosage regimen of propofol. Bronchial asthma is not a contraindication to the use of propofol, but serves as an indication for the use of ketamine;
• concomitant liver disease. Despite the fact that cirrhosis of the liver does not show changes in the pharmacokinetics of propofol, recovery after its use in such patients is slower. Chronic alcohol dependence does not always require increased dosages of propofol. Chronic alcoholism causes only minor changes in the pharmacokinetics of propofol, but recovery may also be somewhat delayed;
• Concomitant kidney disease does not significantly alter the pharmacokinetics and dosage regimen of propofol;
• anesthesia in childbirth, the effect on the fetus, GHB is harmless to the fetus, does not depress the uterine contractility, facilitates the opening of its cervix, so it can be used to anesthetize labor. Propofol reduces the basal tone of the uterus and its contractility, penetrates the placental barrier and can cause fetal depression. Therefore, it should not be used during pregnancy and anesthesia during childbirth. It can be used to terminate pregnancy in the first trimester. Safety of drugs for newborns with breastfeeding is unknown;
• intracranial pathology. In general, propofol has won the sympathy of neuroanesthesiologists due to its manageability, cerebroprotective properties, the possibility of neurophysiological monitoring during operations. It is not recommended its use in the treatment of Parkinsonism, t. It can distort the effectiveness of stereotactic surgery;
• danger of contamination. The use of propofol, especially for prolonged operations or for sedation (more than 8-12 hours), is associated with a risk of infection, since intralipid (fatty propofol solvent) is a favorable medium for the growth of cultures of microorganisms. The most frequent pathogens are epidermal and staphylococcus aureus, fungi of Candida albicans, less often the growth of Pseudomonas aeruginosa, Klebsiella and mixed flora. Therefore, strict compliance with asepsis rules is necessary. It is inadmissible to store drugs in open ampoules or in syringes, as well as repeated use of syringes. Every 12 hours, the system needs to be changed for infusion and three-way valves. With strict adherence to these requirements, the frequency of contamination from the use of propofol is low.

[35], [36], [37]