RU2523565C1 - Method for prevention of postoperative nausea and vomiting syndrome in gynaecological oncology - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method involves providing an anaesthetic support with using the preparations: midazolam, fentanyl, propofol by bolus injections and infusions, artificial pulmonary ventilation by gas mixture O₂:N₂O=1:2 inhalations. Postoperative nausea and vomiting are prevented by intravenous administration of ondansetron 8 mg and dexamethasone 8 mg at the stage of induction, and by intravenous administration of clonidine 0.0016±0.0002 mg/kg/h in infusions or 0.02-0.025 mg in bolus doses up to 0.0016±0.0002 mg/kg after intubation of the trachea within the first hour of operation with having blood pressure and heart rate controlled.

EFFECT: method is safe and high-effective for preventing postoperative nausea and vomiting.

1 ex

Description

The invention relates to medicine, namely to the use of anesthetics for the prevention of postoperative nausea and vomiting (POTD) in gynecological oncology practice.

At present, there is no ideal antiemetic whose preventive use would solve the problem of POTD, just as there is no ideal method of anesthesia and postoperative analgesia for patients at high risk of POTD. For this reason, the use of drug combinations and a multimodal approach to the prevention of POTD are becoming increasingly popular.

It is known that the frequency of POTR largely depends on the nature and location of the surgical intervention. Of particular importance is the problem of POTD in gynecological oncology, where the likelihood of developing these adverse events is very high and, according to a number of modern researchers, ranges from 27% to 70% (Fleming N.D. et al., 2011; Huh B.K. et al., 2010). Such high numbers are due to the frequent combination of reliable risk factors for POTD among this patient population. These include: female gender, non-smoking status, history of seasickness, perioperative use of opioid analgesics. Risk factors for developing POTD associated with the presence of cancer of the female genital area also include:

- an extensive volume of radical surgical interventions, including expanded lymphatic dissection, resection of the greater omentum, sometimes the adjacent sections of the intestine, bladder;

- Often prior to surgery chemoradiotherapy, contributing to the formation of adhesions, gastrointestinal mucositis;

- high reflexogenicity of the intervention zone associated with intense visceral autonomic innervation;

- psychoemotional stress, due to the awareness of patients about the existing cancer and the upcoming operation.

The above factors indicate the need to find new ways to prevent POTD among this patient population.

In recent scientific publications, two main directions of prevention and reduction of the frequency of POTD development are traced: the exclusion of anesthetics and analgesics with an emetogenic effect, and the use of antiemetics and their combinations as part of the anesthesiology manual.

It is known that the use of propofol and (or) midazolam instead of volatile anesthetics as hypnotic components of anesthesia helps to reduce the frequency of POTD.

- (Gauger P. O., Shanks A., Morris M., et al. Propofol decreases early postoperative nausea and vomiting in patients undergoing thyroid and parathyroid operations. World J Surg. 2008; 32 (7): 1525-34.)

In this study, patients were divided into 2 groups. In the study group, one of the components of anesthesia was propofol, in the control group it was excluded from the manual. The authors were able to show a decrease in the frequency of early POTD, but in later hours, patients suffered from POTD equally often in both groups. Similar results may be due to the fact that propofol is a short-acting drug and very briefly exerts its antiemetogenic effects in the early postoperative period.

- (Fujii Y., Itakura M. A prospective, randomized, double-blind, placebo-controlled study to assess the antiemetic effects of midazolam on postoperative nausea and vomiting in women undergoing laparoscopic gynecologic surgery. Clin Ther. 2010; 32 (9) : 1633-7).

In this study, a comparison was made between 3 groups: a placebo group and two study groups, in which patients received midazolam intravenously immediately after induction of anesthesia. Induction was carried out with propofol and fentanyl, maintenance of anesthesia with sevoflurane and fentanyl. The researchers showed a decrease in the frequency of POTD in the study groups compared with the placebo group. However, it should be noted that the frequency of POTR remained at the level of 27-30%, i.e. approximately every 3-4 patients suffered POTD. Probably, such a high frequency of POTR is due to the use of a volatile anesthetic sevoflurane instead of propofol to maintain anesthesia (Apfel S.S., Kranke P., Katz M.P., et al. Volatile anaesthetics may be the main cause of early but not delayed postoperative vomiting : a randomized controlled trial of factorial design. // Br J Anaesth. - 2002. - Vol.88. - Vol.659-68.) and refusal to use antiemetics for prophylactic purposes.

Currently, in order to prevent POTD, along with anesthesia balanced from antiemetogenic positions, it is customary to use combinations of true antiemetics and adjuvant drugs, the antiemetic effect of which is not the main one.

The most common POTD prevention regimen today is a combination of 5HT3 receptor blockers and dexamethasone.

- (Gan TJ, Coop A, Philip BK. A randomized double-blind study of granisetrion plus dexamethasone versus ondansetron plus dexamathasone to prevent postoperative nausea and vomiting in patients undergoing abdominal hysterectomy. Anesth Analg. 2005; 101 (5): 1323-9 )

In the work, the antiemetogenic activity of granisetron and ondansetron was compared. Induction of anesthesia was carried out with propofol and fentanyl, and maintenance with fentanyl, isoflurane and nitrous oxide. 5HT3 receptor blockers were administered intravenously 15 minutes before tracheal intubation, dexamethasone immediately after intubation. The frequency of POTD in the first 24 hours after surgery in the granisetron-dexamethasone group was 56%, and in the ondansetron-dexamethasone group - 53%. The reason for such a high frequency of POTD in both groups could be the use of volatile anesthetics in the cancers of the anesthesiology.

- (Thomas R, Jones N. Prospective randomized, double-blind comparative study of dexamethasone, ondansetron, and ondansetron plus dexamethasone as prophylactic antiemetic therapy in patients undergoing day-case gynecological surgery. Br J Anaesth. 200; 87 (4): 588 -92).

This study was aimed at studying the antiemetic effect of the isolated use of the blocker of 5HT3 receptors of ondansetron, dexamethasone and their combination. Antiemetics were administered immediately after induction of anesthesia, which included propofol and fentanyl. Anesthesia was maintained with fentanyl, sevoflurane and nitrous oxide. The study showed the high efficiency of the combined use of ondansetron (4 mg) and dexamethasone (8 mg). The frequency of POTD in the first 24 hours after surgery was the lowest and amounted to 34.5%. However, this figure suggests that one in three patients had this unpleasant complication, the cause of which could be the use of volatile anesthetics to maintain anesthesia.

The authors of the proposed method for the prevention of POTD made their own assessment of the effectiveness of such a scheme with the exception of components that could potentially affect the increase in the frequency of complications among gynecological patients. At the induction stage, all patients received ondansetron and dexamethasone in similar doses - 4 mg and 8 mg, respectively. Instead of emetogenic volatile anesthetics, propofol and midazolam were used as a hypnotic component of anesthesia, which according to some authors have antiemetic properties (Gauger PG, Shanks A., Morris M., et al. Propofol decreased early postoperative nausea and vomiting in patients undergoing thyroid and parathyroid operations. World J Surg. 2008; 32 (7): 1525-34; Fujii Y., Itakura M. A prospective, randomized, double-blind, placebo-controlled study to assess the antiemetic effects of midazolam on postoperative nausea and vomiting in women undergoing laparoscopic gynecologic surgery. Clin Ther. 2010; 32 (9): 1633-7.). However, despite expectations, the POTR frequency was 32.6%, which cannot be considered satisfactory.

One of the effective combinations for the prevention of POTD is recognized by many researchers as a combination of 5HT3 receptor blockers and droperidol.

The results of a study by Sanchez-Ledesma MJ, Lopez-Olaondo L., Pueyo FJ, Carrascosa F., Ortega A. (A comparison of three antiemetic combinations for the prevention of postoperative nausea and vomiting // Anesth Analg. 2002; 95 (6) are known : 1590-1595.) In this work, we compared 3 groups. In the 1st group, at the stage of induction of anesthesia, an ontansetron antagonist of serotonin 5-HT3 receptors at a dose of 4 mg and droperidol 12.5 mg were injected intravenously, then, additional 12.5 mg droperidol was added 12 hours after the operation. In group 2, dexamethasone 8 mg and droperidol 12.5 mg at the stage of induction of anesthesia and an additional 1.25 mg of droperidol 12 hours after surgery. In group 3, ondansetron 4 mg and dexamethasone 8 mg only at the stage of induction of anesthesia. Maintenance of anesthesia was carried out by fentanyl, desflurane, nitrous oxide. The frequency of POTD in the 1st group was the smallest and amounted to 20%, in the 2nd group 60% and in the 3rd group 30%. These results indicate the need to use combined prophylaxis regimens, including true antiemetics, but also cannot be qualified as satisfactory.

A confirmation of the foregoing is the data of a study in which clonidine was used as a monoprophylaxis of POTD (Oddby-Muhrbeck E., Eksborg S., Bergendahl HT, et al. Effects of clonidine on postoperative nausea and vomiting in breast cancer surgery. Anesthesiology 2002; 96. ( 5): 1109-14). In order to simplify the protocol and obtain the significance of differences in the study, no antiemetogenic anesthesia regimens were used and antiemetics were not prescribed for prophylactic purposes. At the induction step, clonidine (2 μg / kg) was administered intravenously together with fentanyl and propofol. Anesthesia was maintained by sevoflurane, nitrous oxide and fentanyl. A comparison was made with a placebo group. In the POTD control group, 20 out of 30 patients (66.7%) suffered., In the clonidine group, 11 out of 30 patients (36.7%). The results showed a statistically significant decrease in the frequency of POTD, which confirmed the antiemetogenic properties of clonidine, but it still remained at high numbers.

The claimed invention is directed to solving the problem of reducing the risk of developing POTD in patients with gynecological oncology profile. The problem is solved by applying the optimal intraoperative regimen, including the use of a combination of ondansetron, clonidine and dexamethasone with antiemetogenic components of anesthesia.

Using in clinical practice the proposed method allows to achieve several technical (therapeutic) results:

- reducing the likelihood of developing POTD,

- reduction of intraoperative need for drugs for anesthesia used for hypnotic purpose,

- reduction of intraoperative and postoperative need for opioid analgesics,

- the possibility of early extubation and ensuring a safe and comfortable course of the early postoperative period.

These therapeutic results in the implementation of the invention are achieved due to the fact that, as in the known method, anesthetic administration is carried out using drugs: midazolam, fentanyl, propofol bolus and mechanical ventilation with a gas mixture of O ₂ : N ₂ O = 1: 2 inhalation.

A feature of the proposed method is that the prevention of POTD is carried out by intravenous administration of ondansetron - 8 mg and dexamethasone - 8 mg on ethane induction and intravenous administration of clonidine infusion 0.0016 ± 0.0002 mg / kg / h or bolus at 0.02- 0.025 mg to a maximum dose of 0.0016 ± 0.0002 mg / kg after tracheal intubation in the first hour of surgery under continuous monitoring of blood pressure and heart rate.

The invention consists in the following.

When performing advanced cancer interventions on female genital organs, the risk of developing POTD is extremely high. The developed POTD syndrome can cause not only patient discomfort, but also lead to serious complications such as aspiration of vomit, asphyxia, hemodynamic disturbances, divergence of sutures of the surgical wound, bleeding, dehydration and electrolyte imbalance.

The inventors have developed a method for the prevention of POTD in high-risk patients through the intraoperative use of a combination of clonidine, 5-HT ₃ antagonist (ondansetron) and dexamethasone. This combination showed a significant decrease in the frequency of POTD syndrome.

The antiemetic mechanism of action of ondansetron is based on direct blockade of the central 5-HT3 receptors of the chemotactic zone of the vomiting center. The mechanism of action of dexamethasone on the vomiting center is not exactly known. There is evidence that glucocorticosteroids regulate the concentration of neurotransmitters, receptor density, signal transmission and neural configuration. Similar effects can indirectly affect the transmission of stimulatory signals to the vomiting center (Katzung B.G. Basic & Clinical Pharmacology. Stamford, Connecticut. Appleton & Lange. L998).

Clonidine leads to presynaptic activation of peripheral α ₂ -adrenoreceptors, helps to reduce the release of norepinephrine into the bloodstream, respectively slowing down the rate of transmission of a nerve impulse to central adrenoreceptors. The physiological equivalent of this reaction is the suppression of feelings of nausea and vomiting. In addition, clonidine also has hypnotic and antinociceptive effects. The results of the studies conducted by the authors confirm the beneficial effect of clonidine on the course of anesthesia. In particular, there was a decrease in the intraoperative and postoperative need for opioid analgesics, which provided earlier awakening and extubation of patients.

In the claimed method, clonidine was administered only after induction of anesthesia and stabilization of hemodynamic parameters, since in weakened cancer patients it can cause depression of the cardiovascular system. Since clonidine was used only intraoperatively, the authors determined doses of the drug that are safe for cancer patients.

Thus, the combined use of several drugs with antiemetogenic properties provides a synergistic effect of the achieved therapeutic results.

The method is as follows.

1. Premedication in the ward 2 hours before surgery intramuscularly: diazepam 0.15 ± 0.03 mg / kg, clemastine 0.045 ± 0.095 mg / kg;

2. Premedication in the ward 30 minutes before surgery intramuscularly: diazepam 0.15 ± 0.03 mg / kg, atropine 0.01 mg / kg;

3. Preoxegination for 2-3 minutes in the operating room through the face mask;

4. Induction of anesthesia intravenously: midazolam 0.08 ± 0.02 mg / kg, fentanyl 0.0022 ± 0.0003 mg / kg, propofol 0.48 ± 0.2 mg / kg;

5. Intra-suspension myopelgia: rocuronium bromide 0.67 ± 0.16 mg / kg;

6. Intubation of the trachea;

7. PREVENTION PROTECTION:

- at the stage of induction of an on-chain suspension of ondazetroi 8 mg, dexamethasone 8 mg;

- after tracheal intubation in the first hour of the operation under the control of blood pressure and heart rate, intravenously infusion or bolus of 0.02-0.025 mg clonidine to 0.0016 ± 0.0002 mg / kg;

8. Maintenance of anesthesia: fentanyl 0.0024 ± 0.0007 mg / kg / h in a tricuspid bolus, propofol 1.3 ± 0.45 mg / kg / h intravenously infusion, respiration with a mixture of N ₂ O / O ₂ = 2: 1;

9. Maintenance of myoplegia: rocuronium bromide 0.32 ± 0.13 mg / kg / h;

10. Extubation of the trachea after complete restoration of muscle tone and consciousness in the wake-up chamber, oxygenation through nasal respiratory catheters for 1 hour with a flow of O ₂ 3-5 3-5 l / min.

In accordance with the inventive method, more than 50 patients (mean age 46.7 ± 12.3 years) were treated at the Institute, who successfully performed oncological operations on the organs of the female genitalia, large in volume and trauma. Under conditions of total intravenous anesthesia (midazolam, propofol, fentanyl) with mechanical ventilation gas mixture O ₂ : N ₂ O = 1: 2, extended surgical interventions were performed for patients with malignant neoplasms of the female genital sphere of the II-III stage. Most patients had a physical status of ASA I-II. The duration of surgical interventions averaged 3.2 ± 1.0 hours, blood loss 13.2 ± 12.6 ml / kg. Intraoperatively, standard monitoring of hemodynamics (blood pressure, Ps, SaO ₂ , ECG), anesthesia level (AIP), neuromuscular conduction (TOF watch) was carried out. In the postoperative period, the intensity of POTD and pain was assessed using a visual analogue scale (VAS). VAS patients (0-100 points) were asked to determine the presence and severity of nausea and pain in the evening and morning after surgery. Calling for vomiting, vomiting, the intensity of nausea above 60 points according to YOUR, the patient's independent demand for medication for nausea was regarded as a POTD incident. POTD incidents were recorded within 24 hours after surgery. Statistical processing of data was carried out using the program Statistica 6.0 for Windows (StatSoft Inc., USA), the reliability of the difference in relative values was estimated using χ ² , the significance of differences among the absolute values was determined using the Mann-Whitpy U-test. The difference in values was considered significant at p <0.05.

Execution examples

1. Patient B. Age 53 years, body weight 103 kg. Department of Oncogynecology FSBI «MNIII named after P.A. Herzen »Ministry of Health of the Russian Federation Diagnosis: Ovarian cancer of the 16th stage T _1b N _x M ₀ Concomitant diseases: hypertension II Art. History: POTD syndrome after cholecystectomy, does not smoke. Physical Status ASA II. Operation - hysterectomy with appendages, resection of the greater omentum.

1. Premedication in the ward 2 hours before surgery intramuscularly: diazepam 10 mg, clemastip 2 mg.

2. Premedication in the ward 30 minutes before surgery intramuscularly: diazepam 10 mg, atropine 1 mg.

3. Preoxegination for 2-3 minutes in the operating room through the face mask.

4. Induction of anesthesia intravenously: midazolam 10 mg, fentanyl 0.2 mg, propofol 50 mg.

5. Myopelgia intravenously: rocuronium bromide 60 mg.

6. Intubation of the trachea with a Portex tube No. 8, mechanical ventilation apparatus Drager Fabius, under the control of the gas composition of capillary blood.

7. PREV prophylaxis: at the induction stage, intravenous ondansetron 8 mg, dexamethasop 8 mg; after tracheal intubation in the first hour of surgery under the control of blood pressure and heart rate intravenously bolus clonidine at 0.025 mg to 0.15 mg.

8. Maintenance of anesthesia: fentanyl 0.0024 mg / kg / h IV bolus, propofol 1.52 mg / kg / h intravenously infusion, respiration with a mixture of N ₂ O / O ₂ = 2: 1.

9. Maintenance of myoplegia: rocuronium bromide 0.1 mg / kg / h.

10. Extubation of the trachea after complete restoration of muscle tone and consciousness in the wake-up chamber, oxygenation through nasal respiratory catheters for 1 hour with a flow of O ₂ 3-5 3-5 l / min.

The duration of the operation is 2 hours 40 minutes. The course of anesthesia is stable, oxygenation and gas exchange are adequate. HELL 168-122 / 107-90 mmHg Heart rate 81-53 bpm. PO _2kap 61-91 mmHg, RSO _2kap 35-30 mmHg, BE _cap from -0.9 to -0.5. Blood loss 300 ml, diuresis 300 ml, intravenous infusion 2200 ml. The postoperative period was uneventful, without complications. There was no nausea or vomiting throughout the postoperative period.

2. Patient M. Age 28 years, body weight 68 kg. Department of Oncogypecology Federal State Budgetary Institution Scientific Research Institute named after P.A. Herzen »Ministry of Health of the Russian Federation. Diagnosis: Cervical cancer of stage 161 T _1b1 N ₀ M ₀ . History: POTD syndrome after abdominal trachelectomy. Physical status of ASA I. Operation - extended hysterectomy with fallopian tubes, ovarian transposition.

1. Premedication on board 2 hours before surgery intramuscularly: diazepam 10 mg, clemastine 2 mg.

2. Premedication in the ward 30 minutes before surgery intramuscularly: diazepam 10 mg, atropine 0.7 mg.

3. Preoxegination for 2-3 minutes in the operating room through the face mask.

4. Induction of intravenous anesthesia: midazolam 7.5 mg, fentanyl 0.15 mg, propofol 30 mg.

5. Intravenous myopelgia: rocuronium bromide 50 mg.

6. Intubation of the trachea with a Portex tube No. 7.5, mechanical ventilation apparatus Drager Fabius, under the control of the gas composition of capillary blood.

7. PREV prophylaxis: at the induction stage, intravenous ondansetron 8 mg, dexamethasone 8 mg; after tracheal intubation in the first hour of surgery under the control of blood pressure and heart rate, intravenously infusion of clonidine at a rate of 0.0015 mg / kg / hour.

8. Maintenance of anesthesia: fentanyl 0.0023 mg / kg / h intravenously bolus, propofol 2.1 mg / kg / h intravenously infusion, respiration with a mixture of N ₂ O / O ₂ = 2: 1.

9. Maintenance of myoplegia: rocuronium bromide 0.51 mg / kg / h.

10. Extubation of the trachea after complete restoration of muscle tone and consciousness in the wake-up chamber, oxygenation through nasal respiratory catheters for 1 hour with a flow of O ₂ 3-5 3-5 l / min.

The duration of the operation is 2 hours 45 minutes. The course of anesthesia is stable, oxygenation and gas exchange are adequate. HELL 128-98 / 77-52 mm Hg Heart rate 87-55 beats / min. PO _2kap 128-90 mmHg, RSO _2kap 36-34 mmHg, BE _cap from 0.7 to -1.2. Blood loss 300 ml, diuresis 200 ml, intravenous infusion of 2800 ml. The postoperative period was uneventful, without complications. There was no nausea or vomiting throughout the postoperative period.

The developed method made it possible to increase the comfort and safety of the early postoperative period in patients with gynecological oncology profile with a high risk of developing POTD by reducing the frequency of POTD to 14.6%.

Claims (1)

A method for the prevention of postoperative nausea and vomiting syndrome in oncogynecology, including performing anesthetic administration with the help of drugs: midazolam, fentapil, propofol bolus and infusion, mechanical ventilation gas mixture O ₂ : N ₂ O = 1: 2 inhalation, characterized in that the prevention of POTD is carried out by intravenous administration of ondansetron - 8 mg and dexamethasopa - 8 mg at the stage of induction and intravenous administration of clonidine infusion 0.0016 ± 0.0002 mg / kg / h or bolus 0.02-0.025 mg to 0.0016 ± 0.0002 mg / kg after tracheal intubation in the first hour of surgery under control of blood pressure and heart rate.