Expert consensus in Guangdong province on the application of anticholinergic drugs before anesthesia (2021 edition)

Guangdong Province Expert Consensus on the Use of Anticholinergic Drugs Before Anesthesia (Edition 2021) [Editor's Note] This expert consensus was written by Professor Yao Weifeng under the guidance of the chairman and vice chairman of the 11th Committee of the Anesthesiology Branch of Guangdong Medical Association.
It was written with reference to the 2016 edition of "Expert Consensus on the Use of Anticholinergic Drugs Before Anesthesia" for reference by clinical anesthesiologists
.

 【Abstract】 Anticholinergic drugs have a long history of clinical application and were initially used in the treatment of respiratory diseases
.

At present, anticholinergic drugs are important preoperative drugs, and their preoperative application is an important measure to ensure the safe implementation of clinical anesthesia, and plays an important role in promoting rapid postoperative recovery of patients
.

At present, there are many types of anticholinergic drugs with different mechanisms of action.
Preoperative standardized and rational use of anticholinergic drugs can prevent the risks caused by anesthesia and surgical factors, ensure the safety of patients during the perioperative period, and improve the quality of anesthesia management during the perioperative period.

.

In order to further standardize the use of preoperative anticholinergic drugs, entrusted by the Anesthesiology Branch of the Guangdong Medical Association, this expert consensus invites anesthesia experts in related fields in the province, based on the latest research progress at home and abroad and expert consensus and guidelines, combined with surgical procedures in various centers.
Clinical practice experience of pre-application of anticholinergic drugs, from the application of anticholinergic drugs in clinical anesthesia and perioperative period, the selection and consideration of anticholinergic drugs before anesthesia, anticholinergic drugs The main points of preoperative application of anticholinergic drugs are described in terms of usage and dosage and precautions
.

Anesthesia and perioperative medicine are important support and guarantee for the development and progress of modern comfortable medical care
.

With the introduction of the concept of enhanced recovery after surgery (ERAS), anesthesiology not only needs to ensure the safety and effectiveness of clinical anesthesia, but also needs to maintain the balance of perioperative functions and the stability of the internal environment, so as to minimize anesthesia-related complications, Promote rapid postoperative recovery, improve long-term prognosis and quality of life in patients
.

 Pre-anesthesia evaluation and preparation is an important part of ensuring the safe implementation of clinical anesthesia.
Effective pre-operative evaluation can optimize pre-operative preparation and peri-operative management.
Appropriate pre-anaesthesia medication can relieve patient anxiety and help reduce intraoperative stress and anesthesia.
Surgery-related complications
.

Anticholinergic drugs, as one of the pre-anesthetic drugs, are mainly aimed at preventing adverse autonomic reflexes, sedating, relieving anxiety, increasing pain threshold, and reducing airway secretions
.

At present, the anticholinergic drugs used before anesthesia mainly include atropine, scopolamine, glycopyrronium bromide and penehyclidine hydrochloride
.

Since it acts on different muscarinic (M-type) choline receptor subtypes, there are differences in their pharmacological effects, indications and adverse reactions
.

Therefore, standardizing the selection and rational use of individualized preoperative anticholinergic drugs is an important part of preventing risks caused by anesthesia and surgical factors and ensuring the safety of patients during the perioperative period
.

1.
Application of anticholinergic drugs in clinical anesthesia Commonly used pre-anesthetic drugs include sedative-hypnotic drugs, narcotic analgesics, neuroleptic drugs, anticholinergic drugs, antihistamines, etc.
[1]
.

Appropriate pre-anaesthesia medication can stabilize the patient's mood, reduce the secretion of oropharyngeal, respiratory tract and gastric juice, reduce the risk of reflux aspiration, prevent autonomic reflexes that may be induced by tracheal intubation stimulation, increase pain threshold, and reduce invasive operations before anesthesia Pain and stress, reduce opioid dosage, and promote smooth induction of anesthesia
.

Among them, anticholinergic drugs are commonly used pre-anaesthesia drugs.
They can act on central and peripheral postganglionic cholinergic receptors to sedate, relieve tension of various smooth muscles, relax trachea and bronchi, inhibit glandular secretion, and prevent Laryngeal stimulation during intubation and intraoperative stretch-induced vagal reflex induced heart rate slowing, anti-bradycardia caused by a variety of anesthetics and other effects [2]
.

According to the patient's condition and the characteristics of surgical anesthesia, the targeted and individualized selection of appropriate anticholinergic drugs is beneficial to reduce anesthesia and surgical complications, increase the perioperative safety of patients, and promote early postoperative recovery of patients
.

 2 The application of anticholinergic drugs in the perioperative period 2.
1 Pharmacological effects The receptors that can specifically bind to acetylcholine (ACh) are called cholinergic receptors (acetylcholine receptors), which can be divided into M type and nicotinic type ( N type) receptors
.

According to pharmacological classification, M receptors are divided into five subtypes, M1 to M5 [3], the central subtypes are mainly M1, M2, M4, and M5, and the peripheral nerves are mainly M1, M2, and M3 subtypes
.

M-type receptors are mainly distributed on the effector cell membranes innervated by postganglionic cholinergic nerve fibers.
When ACh binds to M-type receptors, it can produce a series of excitatory effects on parasympathetic nerve endings, including inhibiting cardiac activity and slowing heart rate.
The contraction of bronchial smooth muscle causes airway spasm, the contraction of gastrointestinal smooth muscle induces gastrointestinal colic, the contraction of bladder detrusor muscle promotes urination, and the secretion of digestive glands and sweat glands is promoted
.

The distribution and function of M-type receptor subtypes are of great clinical significance, and the anticholinergic drugs used before anesthesia are all M-type receptor blockers, which mainly act on M1, M2, and M3-type receptors.
The distribution and physiological functions of M-type receptor subtypes are summarized in Table 1
.

The pharmacological effects after M-type receptor blockade are opposite to those after agonism
.

2.
2 The influence of commonly used anticholinergic drugs on anesthesia At present, commonly used anticholinergic drugs (M receptor antagonists) before anesthesia include atropine, scopolamine, glycopyrronium bromide and penehyclidine hydrochloride
.

According to the selectivity of drugs to M receptor subtypes, they can be divided into non-selective and selective M receptor antagonists
.

Atropine and scopolamine can non-selectively block various subtypes of M receptors, glycopyrronium bromide is a selective M3 receptor antagonist, and penehyclidine hydrochloride can selectively act on M1 and M3 receptors.
Not sensitive to M2 receptors
.

The pharmacological effects and research progress of these anticholinergic drugs are described below
.

2.
2.
1 Atropine Atropine is the most commonly used M receptor antagonist in clinical practice
.

The application of 0.
3-0.
5 mg before anesthesia can show that oropharyngeal and airway secretions are significantly reduced, which is conducive to the exposure of oropharyngeal intubation and prevention of secretion aspiration
.

Atropine has a strong effect on cardiac M2 receptors.
In small doses (0.
2-0.
3 mg), it blocks the M1 receptors on the presynaptic membrane of parasympathetic ganglia, promotes the release of ACh, and increases the heart rate in a short time.
Slightly slow down
.

Increasing the dose of atropine (0.
4-0.
6 mg) can block M2 receptors in the sinus node of the heart and inhibit severe sinus bradycardia, atrioventricular block, and even sinus bradycardia caused by vagal hyperreflexia.
Asystole, etc.
, increase the heart rate, so the atropine test is often used to assist in the diagnosis of sick sinus syndrome; at the same time, atropine has a dose-dependent excitation or inhibition of the central nervous system
.

Clinically, atropine can reduce the excitability of various smooth muscles, and is suitable for gastrointestinal endoscopy, gastrointestinal colic, bladder irritation, and compound morphine for biliary colic and renal colic
.

Atropine can inhibit cervical reticular nerve fibers and epinephrine (or norepinephrine) excitatory effect on the cervix and make the cervix relax, reflex to strengthen uterine contractions, and promote the progress of labor [4]
.

Atropine can dilate peripheral blood vessels, flushing and burning reactions may occur due to facial vasodilation, but it does not affect blood pressure
.

In addition, atropine can be used for anti-infective toxic shock and rescue of organophosphate poisoning
.

 2.
2.
2 Scopolamine Scopolamine is a belladonna alkaloid.
As a non-selective M-type receptor antagonist, it has peripheral antimuscarinic effects and central sedative, antiemetic, and amnestic effects
.

Scopolamine has stronger respiratory stimulatory effects, anti-motion sickness and anti-paralysis effects, and inhibition of glandular secretion than atropine, but weaker effects on the heart, gastrointestinal tract and bronchial smooth muscle than atropine
.

Although its half-life in plasma is short, its dose-dependent adverse reactions (especially hallucinations, dizziness and drowsiness, etc.
) or excessive excitement and restlessness caused by higher doses need to be paid attention to in clinical work [5]
.

Scopolamine is safe and effective as first-line monotherapy or in combination with other drugs in the treatment of postoperative nausea and vomiting (PONV) in adults [6-7]
.

In addition, the effect of scopolamine to dredge the pulmonary microcirculation is conducive to stabilizing the vital signs of patients with new coronary pneumonia [8]
.

 2.
2.
3 Glycopyrronium bromide Glycopyrronium bromide is a long-acting quaternary ammonium cholinergic receptor antagonist, which has strong inhibition of gastric secretion and regulation of gastrointestinal peristalsis, and is mainly used for the treatment of chronic gastritis, gastric and duodenal ulcers
.

Glycopyrrolate has a stronger anti-salivary effect than atropine, but has no central anticholinergic activity.
Intravenous or intramuscular injection can be used for pre-anesthetic administration to inhibit glandular and salivary secretion
.

An RCT trial showed that compared with atropine, glycopyrronium bromide can also be used safely to prevent neostigmine-induced heart rate slowing, and glycopyrronium bromide is more beneficial to maintain stable heart rate in patients, but may increase the rate of surgery.
risk of urinary retention [9]
.

In addition, because glycopyrronium bromide has high selectivity for choline M3 receptors and can specifically bind to and inhibit the M3 receptors on bronchial smooth muscle, it is currently mainly developed as a powder spray for the treatment of COPD
.

Some authors have proposed that glycopyrronium bromide powder in the treatment of asthma and COPD, in addition to bronchodilator effect, also has anti-inflammatory effect [10]
.

2.
2.
4 Penehyclidine Hydrochloride Penehyclidine Hydrochloride can selectively act on M1 and M3 receptors, but has a weaker effect on M2 receptors[11], and retains its physiological function of negative feedback regulating the release of acetylcholine.
Therefore, the impact on heart rate is small
.

The use of penehyclidine hydrochloride in the perioperative period can selectively act on the M1 and M3 receptors in the airway and lung tissue, which can effectively inhibit glandular secretion, relax airway smooth muscle, reduce the elastic resistance of the lung, and increase the lung compliance.
Thereby improving intraoperative pulmonary ventilation and oxygenation, and reducing postoperative complications such as pulmonary infection and atelectasis[12-13]
.

Because penehyclidine hydrochloride does not act on cardiac M2 receptors, it can effectively avoid the increased heart rate and myocardial oxygen consumption caused by preoperative anticholinergic drugs, so it is often used in some special patients (such as severe hypertension, unstable blood pressure, etc.
).
angina pectoris, hyperthyroidism, etc.
) before surgery
.

Penehyclidine hydrochloride maintains long-term efficacy and has few adverse reactions.
It inhibits the vagus nerve and relaxes visceral smooth muscle, so it is often used in gastrointestinal endoscopy, hysteroscopy and other operations [14]
.

Penehyclidine hydrochloride can prevent vagal hyperreflexia in the perioperative period, and administration of penehyclidine hydrochloride (dose 10 μg/kg, maximum 0.
5 mg) immediately after induction of anesthesia can significantly reduce the incidence of intraoperative oculocardiac reflex in patients with strabismus surgery.
The incidence of PONV does not affect the postoperative resuscitation of patients [15]
.

Neurons in the central cholinergic system of elderly patients degenerate, ACh esterase, ACh transferase and ACh receptors are decreased accordingly, and the sensitivity to cholinergic drugs is enhanced
.

Therefore, the application of penehyclidine hydrochloride in elderly patients should consider its impact on postoperative cognitive function, and individualized treatment should be adopted
.

Preoperative administration of penehyclidine hydrochloride or scoline did not increase the incidence of postoperative cognitive dysfunction (POCD) and postoperative delirium (POD)[16].
0.
75mg, can effectively play a role and reduce the incidence of POCD [17]
.

In addition, penehyclidine hydrochloride has organ protection, can reduce ischemia-reperfusion injury in the heart, lung, brain, kidney, and intestine, as well as improve acute kidney injury, acute lung injury, chronic obstructive pulmonary disease, sepsis And septic shock, sepsis, etc.
[18-22]
.

Penehyclidine hydrochloride after cardiopulmonary resuscitation can effectively improve cerebral perfusion pressure, reduce intracranial pressure, reduce brain tissue edema and inflammation, and improve neurological function [23]
.

 3 Selection and consideration of anticholinergic drugs before anesthesia 3.
1 Respiratory system For patients with severe pulmonary insufficiency, brain injury coma, respiratory depression or partial airway obstruction, scopolamine and other drugs with sedative and hypnotic effects should be avoided
.

For patients with respiratory tract infection, large amount of sputum, and massive hemoptysis, if the inflammation is not effectively controlled, and the sputum and blood are not completely coughed up, anticholinergic drugs should be used cautiously, otherwise, the sputum will be thick and difficult to discharge, and even the lower respiratory tract will be blocked
.

 3.
2 In patients with coronary heart disease such as circulatory system hypertension and unstable angina pectoris, in order to avoid increasing myocardial oxygen consumption and load, it is necessary to prevent further increase in heart rate and blood pressure before anesthesia and in the induction process.
Atropine should be used with caution, and scopolamine or hydrochloric acid should be used instead.
Penehyclidine, combined with sedative drugs to relieve tension and anxiety in patients
.

Bradycardia (<50 beats/min) in patients with non-sick sinus syndrome, more common in patients with severe liver disease, is due to vagal hyperactivity caused by increased jaundice, routine use of atropine is required before anesthesia, and the dose can be increased to 0.
8~ 1mg; for cholecystectomy, etc.
, atropine can be added in time to prevent the gallbladder reflex caused by gallbladder traction
.

3.
3 Central nervous system Patients with increased intracranial pressure, traumatic brain injury, and early hepatic encephalopathy are extremely sensitive to sedative drugs, and conventional doses may lead to delayed recovery after surgery
.

Therefore, sedative-hypnotics such as scopolamine should be avoided except in cases with preoperative agitation, delirium, mental agitation or epilepsy
.

In acute craniocerebral injury, when the intracranial pressure increases sharply, and the patient has changes in various vital signs such as blood pressure, slow heartbeat and pulse, respiratory rhythm disorder, and elevated body temperature (Cushing's reaction), do not blindly use atropine.
Relieve intracranial hypertension
.

Vagal hyperreflexia (carotid sinus reflex) may occur during carotid endarterectomy.
Anticholinergic drugs can be used preventively before surgery, and heart rate should be closely monitored during surgery
.

 3.
4 In patients with endocrine system hyperthyroidism, if the basal metabolic rate and heart rate cannot be effectively controlled before surgery, larger doses of sedative drugs should be used, atropine should be avoided, and scopolamine or penehyclidine hydrochloride can be used instead
.

3.
5 Eye diseases Eye surgery, especially in children with strabismus correction, may cause reflex bradycardia and even cardiac arrest (oculocardiac reflex) during the operation.
Routine use of atropine is required before surgery for prevention, which can be increased to 0.
 5 ~ 2mg (child/adult)
.

In narrow-angle glaucoma, the use of atropine is absolutely contraindicated without the use of miotic drugs, because the latter can contract the ciliary muscle and further increase intraocular pressure
.

 3.
6 Autonomic nervous activity Certain anesthesia and surgical operations can induce abnormal activity of the autonomic nervous system, such as anesthesia laryngoscope placement, endotracheal intubation, endotracheal suction, surgical support of laryngoscope to expose the glottis, and artificial abortion surgery to dilate the cervix.
Operations such as internal hemorrhoidectomy and dilation of the anus can cause active vagal reflexes and even cardiac arrest.
Sufficient anticholinergic drugs should be used to prevent them.
Spinal anesthesia inhibits the sympathetic nerve, and an excessively high level of anesthesia inhibits the cardiac acceleration nerve, and the vagus nerve is relatively Hyperthyroidism should be balanced with an appropriate amount of anticholinergic drugs
.

 3.
7 Others Diethyl ether, ketamine, and sodium oxybate are likely to cause a sharp increase in respiratory secretions, exuberant glandular secretion in children, and some oropharyngeal surgeries should routinely use anticholinergic drugs
.

The muscle relaxant pancuronium bromide can easily cause tachycardia, so scopolamine or penehyclidine hydrochloride should be used; succinylcholine can easily cause bradycardia, so atropine should be used
.

 4 Dosage and precautions of anticholinergic drugs 4.
1 Dosage and adverse reactions of anticholinergic drugs Anticholinergic drugs are generally used 15-30 min before induction of anesthesia, and the specific dosage is shown in Table 2 [24]
.

4.
2 Precautions for the use of anticholinergic drugs 4.
2.
1 Atropine (1) Those who cannot tolerate other belladonna alkaloids are also intolerant to atropine
.

(2) Elderly male patients should be alert to the occurrence of adverse reactions such as dysuria and constipation
.

(3) Use with caution: severe heart disease, brain damage, severe hypertension, hyperthyroidism, reflux esophagitis, ulcerative colitis, occult glaucoma and other diseases, as well as pregnant and lactating women
.

(4) Contraindicated in: patients with high fever, glaucoma and prostatic hypertrophy
.

(5) Drug incompatibility: Minimize the use of magnesium or calcium-containing antacids, carbonic anhydrase inhibitors, sodium bicarbonate, citrate, amantadine, phenothiazine, other anticholinergics, primidone The compatibility of drugs such as procainamide, tricyclic antidepressants, etc.
, can prolong the action time of atropine and increase the toxic and side effects
.

4.
2.
2 Scopolamine (1) Contraindicated in: severe heart disease, glaucoma, prostatic hypertrophy, gastrointestinal stenosis or obstruction, gastroesophageal reflux disease, ulcerative colitis
.

(2) Use with caution: acute heart failure, unstable angina pectoris, hypertensive emergency, severe tachycardia caused by high fever or hyperthyroidism, liver and kidney insufficiency, as well as infants, the elderly, pregnant women and lactating patients
.

(3) Overdose can be rescued with barbiturates or chloral hydrate, or counteracted with cholinergic drugs such as neostigmine
.

(4) Drug Interactions: It cannot be used in combination with antidepressant, psychiatric and Parkinson's disease drugs
.

4.
2.
3 Glycopyrronium bromide (1) It should be used with caution in patients with urinary retention, unstable ischemic cardiomyopathy, left ventricular failure, previous history of myocardial infarction, arrhythmia, and QT prolongation syndrome
.

(2) Contraindicated in: patients with allergy to this product, pyloric obstruction, glaucoma or prostatic hypertrophy
.

(3) Drug interactions: It should not be used in combination with other long-acting M-type receptor antagonists; Cimetidine can prolong the renal metabolism of glycopyrronium bromide, and caution should be used in combination
.

4.
2.
4 Penehyclidine hydrochloride (1) Synergistic effect of drugs: when used in combination with other anticholinergic drugs, there is a synergistic effect, and the dosage should be reduced as appropriate
.

 (2) The number and function of central cholinergic receptors in elderly patients are decreased, and the dose should be reduced as appropriate
.

(3) Prostatic hypertrophy, high fever, pregnant women and lactating women should be used with caution
.

(4) It should be used with caution in patients with severe pulmonary infection with less sputum, thick sputum, and sputum that is difficult to expectorate
.

(5) This product has no obvious effect on the heart rate.
If the heart rate is not lower than the normal value, there is no need to use atropine
.

(6) The elimination half-life of the drug is long, the single dose should not be too large, and the medication interval should not be too short
.

(7) Contraindicated in patients with glaucoma
.