Propofol

Propofol is one of the most recently introduced intravenous anesthetics into clinical practice. 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 earned well-deserved recognition from anesthesiologists around the world due to its unique pharmacokinetic properties. Its wider use is limited only by its high cost.

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Propofol: place in therapy

The search for an ideal anesthetic led to the creation of propofol. It is characterized by a rapid and smooth onset of hypnotic effect, creation of optimal conditions for mask ventilation, laryngoscopy, installation of a laryngeal airway. Unlike barbiturates, BD, ketamine, sodium oxybate, propofol is administered only intravenously as a bolus (preferably by titration) or infusion (drip or infusion using a pump). As with other anesthetics, the choice of dose and the speed of onset of sleep after the administration of propofol are affected by such factors as the presence of premedication, the rate of administration, old 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 inhalational or other intravenous anesthetic (IVAA). It is administered either as a bolus in small portions of 10-40 mg every few minutes depending on clinical needs, or as an infusion, which is certainly preferable due to the creation of a stable concentration of the drug in the blood and greater convenience. The classic regimen of administration of the 1980s 10-8-6 mg/kg/h (after a bolus of 1 mg/kg, infusion for 10 minutes at a rate of 10 mg/kg/h, the next 10 minutes - 8 mg/kg/h, then - 6 mg/kg/h) is currently used less often, since it does not allow for a rapid increase in the concentration of propofol in the blood, the bolus amount is not always easy to determine, and, if necessary, to 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 method of propofol infusion by target blood concentration (TBC) by creating syringe perfusors with built-in microprocessors. Such a system relieves the anesthesiologist from complex arithmetic calculations to create the desired concentration of the drug in the blood (i.e., choosing the infusion rates), allows a wide range of administration rates, clearly demonstrates the titration effect and guides in the timing of awakening when the infusion is stopped, combines ease of use and controllability of the depth of anesthesia.

Propofol has proven itself in cardiac anesthesiology due to intra- and postoperative hemodynamic stability, and a decrease in the frequency of ischemic episodes. In operations on the brain, spine, and spinal cord, the use of propofol allows, if necessary, to perform an awakening test, which makes it an alternative to inhalation anesthesia.

Propofol is the drug of first choice for providing anesthesia in outpatient settings 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 a low probability of PONV. Rapid restoration of the swallowing reflex contributes to earlier safe food intake.

Another area of application of intravenous non-barbiturate hypnotics is sedation during operations under regional anesthesia, during short-term therapeutic and diagnostic procedures, as well as in intensive care units.

Propofol is considered one of the best drugs for sedation purposes. It is characterized by 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, having advantages over midazolam.

Propofol has good properties as an induction agent, a controlled hypnotic during the maintenance phase, and the best recovery characteristics after anesthesia. However, its use in patients with BCC deficiency and circulatory depression is dangerous.

Mechanism of action and pharmacological effects

Propofol is thought to stimulate the beta subunit of the GABA receptor by activating 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, the alpha, gamma, beta1 and beta2 subunits of the GABA receptor are particularly sensitive. The mechanism of the sedative and hypnotic action of steroids is also associated with the modulation of GABA receptors.

Effect on the central nervous system

Propofol has no analgesic activity and is therefore primarily considered a hypnotic. In the absence of other drugs (opioids, muscle relaxants), even at relatively high doses, involuntary movements of the limbs may be observed, especially with any traumatic stimulation. The concentration of propofol at which 50% of patients show no reaction to a skin incision is very high and amounts to 16 μg/ml of blood. For comparison: in the presence of 66% dinitrogen oxide, it decreases to 2.5 μg/ml, and with premedication with morphine - to 1.7 μg/ml.

Depending on the dose used, propofol causes sedation, amnesia, and sleep. Falling asleep is gradual, without arousal. Upon awakening, patients usually feel satisfied with the anesthesia, are complacent, and sometimes report hallucinations and sexual dreams. In its ability to cause amnesia, propofol is close to midazolam and superior to sodium thiopental.

Effect on cerebral blood flow

After the introduction of propofol in patients with normal intracranial pressure, it decreases by approximately 30%, and CPP slightly decreases (by 10%). In patients with increased intracranial pressure, its decrease is more pronounced (30-50%); the decrease in CPP is also more noticeable. To prevent an increase in these parameters during tracheal intubation, opioids or an additional dose of propofol must be administered. Propofol does not change the autoregulation of cerebral vessels in response to changes in systemic blood pressure and carbon dioxide levels. With the main cerebral metabolic constants (glucose, lactate) unchanged, PM02 decreases by an average of 35%.

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Electroencephalographic picture

When using propofol, the EEG is characterized by an initial increase in the os-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 decreases noticeably, and bursts of suppression appear periodically. In general, the changes in the EEG are similar to those with the use of barbiturates.

The concentration of propofol in the blood, the ability to respond to stimuli, and the presence of memories correlate well with the BIS values. Propofol causes a decrease in the amplitude of early cortical responses and slightly increases the latency of SSEPs and MEPs. The effect of propofol on MEPs is more pronounced than that of etomidate. Propofol causes a dose-dependent decrease in the amplitude and an increase in the latency of mid-latency SEPs. It should be noted that it is one of those drugs that provide the highest information content of the above-mentioned options for processing signals of electrical activity of the brain during anesthesia.

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

Many studies have confirmed the antiemetic properties of subhypnotic doses of propofol, including during chemotherapy. This distinguishes it from all other anesthetics used. The mechanism of the antiemetic action of propofol is not entirely clear. There is evidence of its lack of effect on B2-dopamine receptors and the non-involvement of fat emulsion in this effect. Unlike other intravenous hypnotics (e.g., sodium thiopental), propofol depresses subcortical centers. There are suggestions that propofol changes subcortical connections or directly depresses the vomiting center.

Of course, with multicomponent anesthesia, especially with the use of opioids, the ability of propofol to prevent PONV is reduced. Much is also determined by other risk factors for the occurrence of PONV (the characteristics of the patient himself, the type of surgical intervention). All other things being equal, the incidence of PONV syndrome is significantly lower when using propofol as a basic hypnotic, but an increase in the duration of propofol-opioid anesthesia levels out its stated advantage over thiopental-isoflurane anesthesia.

There are reports of a decrease in pruritus in cholestasis and when using opioids against the background of the introduction of subhypnotic doses of propofol. This effect is possibly associated with the ability of the drug to suppress spinal cord activity.

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Effect on the cardiovascular system

During induction of anesthesia, propofol causes vasodilation and myocardial depression. Regardless of the presence of concomitant cardiovascular diseases, propofol administration causes a significant decrease in blood pressure (systolic, diastolic, and mean), a decrease in stroke volume (SV) (by about 20%), cardiac index (CI) (by about 15%), total peripheral vascular resistance (TPVR) (by 15-25%), and left ventricular stroke work index (LVSI) (by about 30%). In patients with valvular heart disease, it reduces both pre- and afterload. Relaxation of smooth muscle fibers of arterioles and veins occurs due to inhibition of sympathetic vasoconstriction. The negative inotropic effect may be associated with a decrease in intracellular calcium levels.

Hypotension may be more pronounced in patients with hypovolemia, left ventricular failure and in the elderly, and directly depends on the administered dose and the concentration of the drug in the plasma, the rate of administration, the presence of premedication and the simultaneous use of other drugs for coinduction. The peak concentration of propofol in the plasma after a bolus dose is significantly higher than with the infusion method of administration, therefore the decrease in blood pressure is more pronounced with a bolus administration of the calculated dose.

In response to direct laryngoscopy and tracheal intubation, there is an increase in blood pressure, but the degree of this pressor reaction is less than with barbiturates. Propofol is the best intravenous hypnotic, preventing the hemodynamic response to the installation of a laryngeal mask. Immediately after the induction of anesthesia, intraocular pressure decreases significantly (by 30-40%) and normalizes after tracheal intubation.

It is characteristic that when using propofol, the protective baroreflex is suppressed in response to hypotension. Propofol suppresses the activity of the sympathetic nervous system more significantly than the parasympathetic one. It does not affect the conductivity and function of the sinus and atrioventricular nodes.

Rare cases of severe bradycardia and asystole have been reported following propofol administration. It should be noted that these were healthy adult patients receiving anticholinergic prophylaxis. The bradycardia-related mortality rate is 1.4:100,000 cases of propofol administration.

During maintenance of anesthesia, BP remains reduced by 20-30% compared to the initial level. With isolated use of propofol, OPSS decreases to 30% of the initial level, and SOS and CI do not change. With the combined use of dinitrogen oxide or opioids, on the contrary, SOS and CI decrease with an insignificant change in OPSS. Thus, the suppression of the sympathetic reflex reaction in response to hypotension is preserved. Propofol reduces coronary blood flow and myocardial oxygen consumption, while the delivery/consumption ratio remains unchanged.

Due to vasodilation, propofol suppresses the ability to thermoregulate, which leads to hypothermia.

Effect on the respiratory system

After the introduction of propofol, there is a marked decrease in VO and a short-term increase in RR. Propofol causes respiratory arrest, the probability and duration of which depend on the dose, 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 increases with the addition of opioids to the premedication or induction.

Propofol has a longer lasting effect on RV than on RR. Like other anesthetics, it causes a decrease in the respiratory center response to carbon dioxide levels. However, unlike inhalation anesthetics, doubling the plasma propofol concentration does not lead to a further increase in PaCOa. As with barbiturates, PaO2 does not change significantly, but the ventilatory response to hypoxia is suppressed. Propofol does not suppress hypoxic vasoconstriction during one-lung ventilation. With prolonged infusion, including sedative doses, RV and RR remain reduced.

Propofol has some bronchodilating effect, including in patients with COPD. But in this it is significantly inferior to halothane. Laryngospasm is unlikely.

Effects on the gastrointestinal tract and kidneys

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

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Effect on endocrine response

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

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Effect on neuromuscular transmission

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

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Other effects

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

Sodium oxybate has pronounced systemic antihypoxic, radioprotective properties, increases resistance to acidosis and hypothermia. The drug is effective in local hypoxia, in particular in retinal hypoxia. After administration, it actively enters into cell metabolism, therefore it is called a metabolic hypnotic.

Propofol does not provoke 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 multi-day infusion for sedation. There have been reports of propofol dependence.

Pharmacokinetics

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

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

The volume of distribution of propofol immediately after injection is not very high and is approximately 20-40 l, but at steady state it increases and fluctuates from 150 to 700 l in healthy volunteers, and in the elderly it can reach 1900 l. The drugs are characterized by high clearance from the central sector and slow return from poorly perfused tissues back. The main metabolism occurs in the liver, where propofol forms water-soluble inactive metabolites (glucuronide and sulfate). Up to 2% of the drug is excreted unchanged in feces, and less than 1% in urine. Propofol is characterized by high total clearance (1.5-2.2 l/min), exceeding the hepatic blood flow, which indicates extrahepatic metabolic pathways (possibly through the lungs).

Thus, the early termination of the hypnotic effect of propofol is due to the rapid distribution into a large volume of pharmacologically inactive tissues and intensive metabolism, which outpaces its slow return to the central sector.

The pharmacokinetics of propofol are affected by factors such as age, gender, concomitant diseases, body weight, and concomitant medications. In elderly patients, the central chamber volume and clearance of propofol are lower than in adults. In children, on the contrary, the central chamber volume is larger (by 50%), and the clearance is higher (by 25%) when calculated for body weight. Thus, propofol doses should be reduced in elderly patients and increased in children. Although it should be noted that the data on changes in induction doses of propofol in the elderly are not as convincing as in the case of benzodiazepines. In women, the values of distribution volume and clearance are higher, although T1/2 does not differ from that in men. In liver diseases, the central chamber volume and distribution volume of propofol increase, while T1/2 is slightly prolonged, and clearance does not change. By reducing hepatic blood flow, propofol can slow its own clearance. But more important is its effect on its own redistribution between tissues by reducing SV. It should be taken into account that when using the IR device, the volume of the central chamber increases, and therefore the required initial dose of the drug.

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

The time it takes for propofol concentrations to halve after an 8-hour infusion is less than 40 minutes. And since clinically used infusion rates typically require propofol concentrations to be reduced to less than 50% of those needed to maintain anesthesia or sedation, recovery of consciousness is rapid even after prolonged infusions. Thus, along with etomidate, propofol is better suited than other hypnotics for prolonged infusion for anesthesia or sedation.

Contraindications

An absolute contraindication to the use of propofol is intolerance to this drug or its components. A relative contraindication is hypovolemia of various origins, severe coronary and cerebral atherosclerosis, conditions in which a decrease in CPP is undesirable. Propofol is not recommended for use during pregnancy and for anesthesia in obstetrics (except for termination of pregnancy).

Propofol is not used for anesthesia in children under 3 years of age and for sedation in the ICU in children of all ages, as its involvement in several fatal outcomes in this age group is still being studied. The use of a new dosage form of propofol containing a mixture of long- and medium-chain triglycerides is permitted starting from the age of one month. The use of etomidate is contraindicated in patients with adrenal insufficiency. Due to the suppression of corticosteroid and mineralocorticoid production, it is contraindicated for long-term sedation in the ICU. It is considered inappropriate to use etomidate in patients with a high risk of PONV.

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Tolerability and side effects

Propofol and etomidate are generally well tolerated by patients. However, in many cases, patients feel weak and fatigued for some time after anesthesia with etomidate. Most adverse effects of propofol are related to overdose and initial hypovolemia.

Pain when inserted

Propofol and pregnenolone cause moderate pain.

With propofol administration, the pain is less than with etomidate, but more than with sodium thiopental. Pain is reduced by using larger-diameter veins, preliminary administration (20-30 sec) of 1% lidocaine, other local anesthetics (prilocaine, procaine) or fast-acting opioids (alfentanil, remifentanil). Mixing propofol with lidocaine (0.1 mg/kg) is possible. A somewhat lesser effect is achieved by preliminary (1 hour) application of a cream containing 2.5% lidocaine and 2.5% prilocaine to the area of the intended propofol administration. Pain is reduced by preliminary administration of 10 mg labetalol or 20 mg ketamine. Thrombophlebitis is rare (< 1%). Attempts to create a non-lipid solvent for propofol have so far been unsuccessful due to the high incidence of thrombophlebitis caused by the solvent (up to 93%). Paravasal administration of the drug causes erythema, which resolves without treatment. Accidental intra-arterial administration of propofol is accompanied by severe pain, but does not result in damage to the vascular endothelium.

Respiratory depression

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

Hemodynamic shifts

During induction of anesthesia with propofol, the greatest clinical significance is the decrease in blood pressure, the degree of which is higher in patients with hypovolemia, in the elderly, and with the combined administration of opioids. Moreover, subsequent laryngoscopy and intubation do not cause such a pronounced hyperdynamic response as during induction with barbiturates. Hypotension is prevented and eliminated by infusion load. In case of ineffectiveness of prophylaxis of vagotonic effects with anticholinergic drugs, it is necessary to use sympathomimetics such as isoproterenol or epinephrine. During prolonged sedation with propofol in children in the intensive care unit, the development of metabolic acidosis, "lipid plasma", refractory bradycardia with progressive heart failure, in some cases resulting in death, has been described.

Allergic reactions

Although no changes in immunoglobulin, complement, or histamine levels were detected after propofol administration, the drug can cause anaphylactoid reactions in the form of flushing, hypotension, and bronchospasm. The incidence of such reactions is reported to be less than 1:250,000. The likelihood of anaphylaxis is higher in patients with a history of allergic reactions, including those to muscle relaxants. The phenolic core and diisopropyl side chain of propofol, rather than the fat emulsion, are responsible for allergic reactions. Anaphylaxis during first use is possible in patients sensitized to the diisopropyl radical, which is present in some dermatological drugs (finalgon, zinerit). The phenolic core is also part of the structure of many drugs. Propofol is not contraindicated in patients with egg white allergy, since it is realized through the albumin fraction.

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Postoperative Nausea and Vomiting Syndrome

Propofol is rarely associated with the provocation of PONV. Instead, it is considered by many researchers to be a hypnotic with antiemetic properties.

Awakening reactions

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

Impact on immunity

Propofol does not alter the chemotaxis of polymorphonuclear leukocytes, but inhibits phagocytosis, particularly with respect to Staphylococcus aureus and Escherichia coli. In addition, the fatty environment created by the solvent promotes rapid growth of pathogenic microflora if aseptic precautions are not observed. These circumstances make propofol potentially responsible for systemic infections with prolonged administration.

Other effects

Propofol has no clinically significant effect on hemostasis and fibrinolysis, although in vitro platelet aggregation is reduced by fat emulsion.

Interaction

Propofol is most often used as a hypnotic in combination with other drugs for anesthesia (other intravenous anesthetics, opioids, inhalation anesthetics, muscle relaxants, auxiliary 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 much greater clinical significance.

The recommended calculated doses are reduced in patients with premedication, with coinduction. Combination with ketamine allows to avoid the inherent hemodynamic depression of propofol and neutralizes its negative hemodynamic effects. Coinduction with midazolam also reduces the amount of propofol administered, which reduces the depressing effect of propofol on hemodynamics and does not slow down the awakening period. The combination of propofol with BD prevents possible spontaneous muscle activity. When using propofol with sodium thiopental or BD, synergism is observed in relation to sedative, hypnotic and amnestic effects. However, it is apparently undesirable to use propofol together with drugs that have a similar effect on hemodynamics (barbiturates).

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

Potent opioids of the fentanyl group (sufentanil, remifentanil) when used together reduce both the distribution and clearance of propofol. This requires their careful combination in patients with BCC deficiency due to the risk of severe hypotension and bradycardia. For the same reasons, the possibilities of combined use of propofol and vegetostabilizing drugs (clonidine, droperidol) are limited. When using suxamethonium during induction, the vagotonic effect of propofol must be taken into account. Synergism of opioids and propofol allows for a reduction in the amount of propofol administered, which does not worsen the parameters of recovery from anesthesia in the case of short-term interventions. With continued infusion, awakening occurs faster with remifentanil than with a combination of propofol with alfentanil, sufentanil or fentanyl. This allows the use of relatively lower propofol infusion rates and higher remifentanil rates.

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 enzymatic system.

Cautions

Despite the obvious individual advantages and relative safety of non-barbiturate sedative-hypnotic drugs, the following factors must be taken into account:

• age. To ensure adequate anesthesia in elderly patients, a lower concentration of propofol in the blood is required (by 25-50%). In children, induction and maintenance doses of propofol based on body weight should be higher than in adults;
• duration of the intervention. The unique pharmacokinetic properties of propofol allow it to be used as a hypnotic component to maintain prolonged anesthesia with a low risk of prolonged depression of consciousness. However, drug accumulation does occur to a certain extent. This explains the need to reduce the infusion rate as the duration of the intervention increases. The use of propofol for prolonged sedation in patients in the intensive care unit requires periodic monitoring of blood lipid levels;
• concomitant cardiovascular diseases. Use of propofol in patients with cardiovascular and debilitating diseases requires caution due to its depressant effect on hemodynamics. Compensatory increase in heart rate may not occur due to some vagotonic activity of propofol. The degree of hemodynamic depression during propofol administration can be reduced by preliminary hydration, slow administration by titration. Propofol should not be used in patients in shock and in cases of suspected massive blood loss. Propofol should be used with caution in children during strabismus correction surgery due to the likelihood of increased oculocardial reflex;
• concomitant respiratory diseases do not have a significant effect on the propofol dosing regimen. Bronchial asthma is not a contraindication to the use of propofol, but serves as an indication for the use of ketamine;
• concomitant liver diseases. Although no changes in propofol pharmacokinetics are observed in liver cirrhosis, recovery after its use in such patients is slower. Chronic alcohol dependence does not always require increased doses of propofol. Chronic alcoholism causes only minor changes in propofol pharmacokinetics, but recovery may also be somewhat slower;
• concomitant renal diseases do not significantly alter the pharmacokinetics and dosing regimen of propofol;
• pain relief during labor, effect on the fetus, GHB is harmless to the fetus, does not inhibit the contractility of the uterus, facilitates the opening of its cervix, and therefore can be used for pain relief during 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 labor. It can be used to terminate pregnancy in the first trimester. The safety of the drug for newborns during breastfeeding is unknown;
• intracranial pathology. In general, propofol has won the sympathy of neuroanesthesiologists due to its controllability, cerebroprotective properties, and the possibility of neurophysiological monitoring during operations. Its use in the treatment of Parkinsonism is not recommended, since it can distort the effectiveness of stereotactic surgery;
• Risk of contamination. The use of propofol, especially during long surgeries or for sedation (over 8-12 hours), is associated with a risk of infection, since intralipid (propofol lipid solvent) is a favorable environment for the growth of microorganism cultures. The most common pathogens are Staphylococcus epidermidis and Staphylococcus aureus, Candida albicans fungi, less common growth of Pseudomonas aeruginosa, Klebsiella and mixed flora. Therefore, strict adherence to aseptic rules is necessary. It is unacceptable to store drugs in open ampoules or syringes, as well as multiple use of syringes. Every 12 hours it is necessary to change infusion systems and three-way taps. With strict adherence to these requirements, the frequency of contamination from the use of propofol is low.

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