RU2845323C1 - Method for pharmacological reversion of hypnotic action of central alpha-2-adrenoagonist dexmedetomidine - Google Patents

Abstract

FIELD: medical science.

SUBSTANCE: invention refers to medicine, namely to anaesthesiology, and can be used for pharmacological reversal of hypnotic action of central alpha-2-adrenoagonist dexmedetomidine. According to the declared method, the surgical operation is followed by stopping the dexmedetomidine infusion and introducing a hypnotic antagonist into the patient. After the dexmedetomidine infusion is stopped, the muscle tone is assessed by neuromuscular conduction monitoring TOF-Watch, a method for assessing hand muscle contraction in response to 4 consecutive electrical stimuli, if TOF index exceeds 25 %, galantamine 0.3-0.4 mg/kg is administered intravenously as an antagonist for decurarisation.

EFFECT: use of the invention enables reducing a risk of developing undesirable effects by reducing a rate of prolonged depression of consciousness following general anaesthesia, promotes better controllability of the anaesthesia with the use of intravenous hypnotics, improves patient’s anaesthesia.

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Description

The method relates to the field of medicine and can be used to restore consciousness after general anesthesia, when the hypnotic component is provided by the use of dexmedetomidine.

Sedation and anesthesia with the central alpha-2-agonist dexmedetomidine are widely used in modern medicine.

The introduction of this methodology into clinical practice will contribute to improving the quality and safety of anesthesia.

There is currently no effective way to manage the duration of sedation when using the intravenous anesthetic dexmedetomidine, unlike inhalation anesthetics, where stopping the inhalation leads to a rapid end of the hypnotic effect. In cases where the patient's awakening after general anesthesia is slow, the patient is transferred to the intensive care unit or recovery room, which leads to an increase in hospitalization and material costs.

A method similar to the reversal of the effect of a drug used in sedation and general anesthesia is known: reversal of the hypnotic effect of benzodiazepines using flumazenil. However, flumazenil is a selective blocker of benzodiazepine receptors, and these structures associated with the inhibitory chloride channel of the cell membrane are not involved in the mechanism of action of dexmedetomidine.

In our literature review, we found publications on the neuroprotective effect of galantamine in humans [Arias, Esperanza, Sonia Gallego-Sandín, Mércedes Villarroya, Antonio G. García and Manuela G. López. Unequal Neuroprotection Afforded by the Acetylcholinesterase Inhibitors Galantamine, Donepezil, and Rivastigmine in SH-SY5Y Neuroblastoma Cells: Role of Nicotinic Receptors. Journal of Pharmacology and Experimental Therapeutics 315 (2005): 1346–1353], but there is no mention of its use for reversal of general anesthesia. In addition, there are indications of the use of galantamine in the structure of treatment aimed at eliminating the effects of general anesthesia: Matveeva, O. B. Reversal of drug-induced sedation and general anesthesia: agonist-antagonist technique / O. B. Matveeva, V.M. Mizikov // Anesthesiology and reanimatology. - 2014. - Vol. 59, No. 5. - P. 37-41. But in this work, galantamine was only one of many drugs for eliminating the effects of anesthesia (and one of two anticholinesterase drugs), used in small doses as a drug for restoring muscle tone. The authors do not make any conclusions about the possible role of galantamine in restoring consciousness after general anesthesia.

The closest analogue (prototype) is a method of reversing the hypnotic effect of the highly selective alpha-2-adrenoreceptor agonist dexmedetomidine using a direct pharmacological antagonist - the central alpha-2-adrenoreceptor blocker atipamezole [Correa-Sales C., Rabin B.C., Maze M. A hypnotic response to dexmedetomidine, an alpha 2 agonist, is mediated in the locus coeruleus in rats. Anesthesiology. 1992 Jun; 76 (6): 948-52. doi: 10.1097/00000542-199206000-00013. PMID: 1350889]. The disadvantage of the prototype is that it can only be used in veterinary practice, and in human studies atipamezole caused negative side effects. There is data on another way to reverse the effects of dexmedetomidine - the use of cAMP [Correa-Sales C., Nacif-Coelho C., Reid K., Maze M. Inhibition of adenylate cyclase in the locus coeruleus mediates the hypnotic response to an alpha 2 agonist in the rat. J Pharmacol Exp Ther. 1992 Dec; 263 (3): 1046-9. PMID: 1361568], but this has nothing to do with the inhibition of acetylcholinesterase that we are talking about. There are published studies on the neuroprotective effect of galantamine in humans [Arias, Esperanza, Sonia Gallego-Sandín, Mércedes Villarroya, Antonio G. García and Manuela G. López. Unequal Neuroprotection Afforded by the Acetylcholinesterase Inhibitors Galantamine, Donepezil, and Rivastigmine in SH-SY5Y Neuroblastoma Cells: Role of Nicotinic Receptors. Journal of Pharmacology and Experimental Therapeutics 315 (2005): 1346-1353], but there is no discussion of its use for reversal of general anesthesia.

In our practice, we have noted that the use of galantamine (nivalin) for decurarization at a dose of 0.3-0.4 mg/kg of body weight against the background of the sedative or hypnotic effect of the central alpha-2-adrenergic agonist dexmedetomidine in the structure of anesthesia during various operations leads to a reversal of its hypnotic effect (restores consciousness), including according to objective control data using M-entropy monitoring or the qCON index (CONOX monitor).

Thus, we used the drug for the indication of restoring neuromuscular conductivity after the use of non-depolarizing relaxants, i.e. for decurarization, and the effect of reversal of the hypnotic component turned out to be a concomitant phenomenon. It is important to take into account that the instructions for the use of galantamine do not include such an indication as restoring consciousness after general anesthesia, therefore, for such an off-label prescription, a decision of the medical commission is organizationally necessary.

The following essential features common with the prototype have been identified for the claimed method: dexmedetomidine is used to provide the hypnotic component of anesthesia; at the end of anesthesia, a drug with antagonist properties is administered.

The technical problems that the present invention solves are increasing the controllability of general anesthesia, accelerating the patient's recovery of consciousness, and increasing his satisfaction with anesthesia due to rapid and complete awakening.

Technical problems are solved by a method of pharmacological reversal of the hypnotic action of the central alpha-2-adrenergic agonist dexmedetomidine, which consists in the fact that after a medical operation using dexmedetomidine as a sedative, the patient is administered an alpha-2-adrenergic receptor antagonist, with galantamine used as the antagonist, which is administered to the patient intravenously.

The technical results of the invention are the possibility of reversing the hypnotic component of general anesthesia, as well as reducing the risk of undesirable consequences of delayed awakening after anesthesia, such as drowsiness, difficulty in orientation, and hypodynamia.

The method is carried out as follows: the patient's weight is determined before anesthesia. On the day of the operation, immediately before it, the nurse anesthetist in the operating room inserts a peripheral venous catheter into the patient. Then, anesthesia is induced, then intravenous infusion of dexmedetomidine at a dose of 0.2-1.4 mcg/kg/h is used for maintenance to ensure the necessary depth of sedation, which is controlled using BIS monitoring, M-entropy monitoring, or the CONOX encephalographic algesimeter (qCON index). Upon completion of the operation, the dexmedetomidine infusion is stopped, muscle tone is assessed clinically by the appearance of signs of restoration of neuromuscular conduction and/or instrumentally using neuromuscular conduction monitoring, for example, TOF-Watch (a method for assessing hand muscle contraction in response to 4 consecutive electrical stimuli, expressed as a number of responses from 0 to 4, if there are 4 responses, the assessment is the ratio of the amplitude of the 4th response to the amplitude of the 1st as a percentage). If muscle relaxants were used during the operation, then after the appearance of clinical and instrumental signs of restoration of neuromuscular conduction (in particular, the TOF index is more than 25%), the patient is administered galantamine at a dose of 0.3-0.4 mg/kg for decurarization, which leads to restoration of neuromuscular conduction (clinically, as well as by the TOF index of 90% or more) and consciousness (clinically: awakening, the appearance of contact with the patient - and instrumentally using monitoring the depth of anesthesia (BIS (bispectral index), M-entropy, qCON index), after which the patient is transferred to the ward of the surgical or, if indicated, intensive care unit.

Galantamine, a tertiary alkaloid that penetrates the blood-brain barrier and acts in the structures of the central nervous system, administered at a dose of 0.3-0.4 mg/kg of body weight, led to faster awakening compared to patients who were given neostigmine (a quaternary alkaloid) for decurarization. Thus, the average awakening time in patients who were given galantamine was 4.67 minutes versus 8.3 minutes in patients who did not receive it.

The photographs (Fig. 1 - 3) show graphs of the dynamics of the qCON index (anesthesia depth indicator - lower half of the display). The time at which galantamine was administered was 10:05. From 10:09, a clear increase in the qCON index to values corresponding to the restoration of consciousness is visible.

Thus, the described approach to anesthesia management reduces the risk of adverse events due to the fact that it reduces the frequency of cases of prolonged depression of consciousness after general anesthesia, promotes greater controllability of anesthesia using intravenous hypnotics, and improves patient satisfaction with anesthesia. It should be noted here that, unlike the intravenous hypnotic midazolam and its specific antagonist flumazenil, we propose to administer a universal antagonist in relation to all drugs used for general anesthesia.

It should be noted that many foreign anesthesia manuals describe in detail such a condition as central anticholinergic syndrome (CAS). This condition is characterized by the fact that the awakening of patients after general anesthesia differs from what is expected: some patients do not wake up for a long time, others wake up abruptly in a state of psychomotor agitation, and some patients experience generalized muscle tremors after anesthesia. The cause of this syndrome can be any drug used as a hypnotic, as well as many drugs used in the operating room as part of anesthesia. Thus, it is known that it can be caused by direct anticholinergics, inhalation and intravenous anesthetics, opioids (fentanyl, morphine), local anesthetics, barbiturates, benzodiazepines, H1- and H2-histamine blockers, neuroleptics. The most common causes of CAS include atropine, droperidol, volatile anesthetics, propofol, benzodiazepines, opiates, and ketamine, but dexmedetomidine is not on this list. Physostigmine and galantamine are known to be able to prevent or eliminate CAS that has already developed. We have shown the possibility of using galantamine to reverse the hypnotic component caused by alpha-2-adrenoreceptor agonists, which, given the above, allows us to consider acetycholinesterase inhibitors that penetrate the blood-brain barrier as universal drugs for reversing the hypnotic component of general anesthesia, as well as, subject to certain requirements, for reversing neuromuscular block. At the same time, acetylcholine deficiency in CNS synapses, given the identified antagonistic effect of galantamine in relation to dexmedetomidine, seems to be a universal mechanism for the development of general anesthesia.

The method proposed as an invention can be used in performing anesthesia during various types of operations.

Clinical examples of the method application:

Example 1

Patient M., 45 years old, 57 kg, ASA II. Concomitant pathology: hypertension stage I, obesity stage I (BMI 30), varicose veins of the lower extremities. Admitted for a planned operation - hysterectomy. The patient was admitted on the eve of the operation as planned in the evening, received phenazepam 0.5 mg as premedication.

Takes angiotensin antagonists and beta blockers.

The patient was taken to the operating room, where after induction of general anesthesia, dexmedetomidine infusion was started at a dose of 1.0 mcg/kg/h. Then, during anesthesia, the qCON index value of 40-60 was used as a guide, for which the dexmedetomidine infusion rate was changed in the range from 1.2 to 0.2 mcg/kg/h. In the last 30 min, the dose was 0.2 mcg/kg/min. No significant bradycardia or hypotension was recorded during the 2.5-hour operation. During anesthesia, rocuronium was administered once at a dose of 10 mg, fentanyl at 0.1 mg every 30 min to maintain muscle relaxation. Mechanical ventilation was performed in the protective normoventilation mode.

After the last suture, dexmedetomidine was switched off. TOF 31%. The patient was given galantamine - 20 mg (0.35 mg/kg). The patient woke up within 2 minutes, and was extubated after another 1 minute. According to the Aldrete scale, the score was 10, and she was transferred to a specialized department.

Example 2

Patient A., 38 years old, 97 kg, BMI 29.1. ASA III. Planned referral for thoracoscopic removal of a left lung mass. Concomitant diseases: hypertension stage II, ischemic heart disease, PICS (AMI 2021); duodenal ulcer, outside of exacerbation. Chronic pancreatitis, outside of exacerbation. Basic therapy: antihypertensive, rhythm-reducing, antiplatelet agents, gastroprotective.

Premedication: 0.5 mg phenazepam. Standard general anesthesia induction: 0.1 mg fentanyl, 2 mg/kg body weight propofol, and 0.6 mg/kg body weight rocuronium. Then, dexmedetomidine infusion was started at a dose of 0.7 mcg/kg/h. During anesthesia, the qCON index value of 40-60 was used as a guide, for which the dexmedetomidine infusion rate was changed in the range from 1.4 to 0.3 mcg/kg/h. In the last 10 minutes, the dose was 0.3 mcg/kg/min. No significant hypotension was recorded during the 3-hour operation; there was an episode of hemodynamically insignificant bradycardia of 47/min. During anesthesia, rocuronium was administered once at 10 mg, fentanyl at 0.1 mg every 30 min to maintain muscle relaxation. Mechanical ventilation was performed in the protective normoventilation mode.

After the last suture, dexmedetomidine was switched off. TOF 25%. The patient was given galantamine - 40 mg (0.4 mg/kg). The patient woke up within 5 minutes, and was extubated after another 2 minutes. According to the Aldrete scale, the score was 9, and he was transferred to a specialized department.

Example 3 without the use of galantamine

Patient I., 77 years old, 81 kg, ASA II. Concomitant diseases: type 2 diabetes. Bronchial asthma.

Premedication: phenazepam 0.5 mg. Anesthesia was maintained by dexmedetomidine infusion at a dose of 1.0 μg/kg/h. During anesthesia, the qCON index value of 40-60 was used as a guide, for which the dexmedetomidine infusion rate was changed in the range from 1.2 to 0.2 μg/kg/h. In the last 30 minutes, the dose was 0.2 μg/kg/min. No significant hypotension was recorded during the 4.5-hour operation, the minimum heart rate was 44/min without hemodynamic effects. Fentanyl was administered once at 0.1 mg after 2 hours due to an episode of heart rate increase to 80/min, blood pressure to 130/72 mm Hg. Mechanical ventilation was performed in the protective normoventilation mode.

At the end of the operation, dexmedetomidine was switched off, spontaneous recovery of consciousness was expected. After 17 minutes, the patient opened his eyes, 2 minutes after that he was fully available for contact, vital functions were compensated. According to the Aldrete scale, the assessment was 9, he was transferred to the intensive care unit for observation in the next 24 hours, taking into account his age and the duration of the operation.

The proposed method was used during anesthesia in 47 patients. The results of objective control of sedation and comparison of awakening time with spontaneous awakening after anesthesia with dexmedetomidine confirm the effectiveness of galantamine for reversing the hypnotic component of anesthesia, which is important for its optimization.

Claims (2)

1. A method for pharmacologically reversing the hypnotic action of the central alpha-2-adrenergic agonist dexmedetomidine, which consists in the fact that after performing a surgical operation, the dexmedetomidine infusion is stopped, then the patient is administered a hypnotic antagonist, characterized in that after stopping the dexmedetomidine infusion, muscle tone is assessed using TOF-Watch neuromuscular conductivity monitoring - a method for assessing hand muscle contraction in response to 4 consecutive electrical stimuli, if the TOF index is more than 25%, the patient is administered galantamine intravenously as an antagonist for decurarization at a dose of 0.3-0.4 mg/kg. 2. The method according to item 1, characterized in that a CONOX anesthesia depth monitor is used as a tool for monitoring the severity of the hypnotic effect of the anesthetic.