Pharmacological characteristics of dexmedetomidine and its application in postoperative delirium in elderly patients

Postoperative delirium refers to the delirium that occurs in patients after undergoing surgical procedures. Its main characteristics are disturbances in consciousness levels and cognitive impairment, with large fluctuations in the condition and a relatively short course of illness. Dexmedetomidine (DEX) is a new type of sedative hypnotic drug that has the effects of inhibiting sympathetic nervous system, sedation, moderate analgesia, reducing anesthetic dosage, and reducing postoperative delirium.

In recent years, dexmedetomidine has been increasingly used in the prevention and treatment of postoperative delirium (POD) in elderly patients. This article summarizes and summarizes the pharmacological characteristics of dexmedetomidine and its related applications in postoperative delirium in elderly patients. Delirium is a common complication after major surgery. According to literature reports, the incidence of postoperative delirium in elderly patients over 65 years old is as high as 54.4%, significantly higher than severe postoperative complications such as myocardial infarction and respiratory failure.

The occurrence of postoperative delirium can have a series of adverse effects on patients, including prolonged stay in the ICU, increased hospitalization costs, increased incidence of perioperative complications, and long-term decline in cognitive function. Dexmedetomidine is a highly selective drug α 2-receptor agonists can act on the central and peripheral nervous systems respectively, exerting good anti anxiety, sedative hypnotic, moderate analgesic and other effects. They are widely used in clinical practice as sedative adjuvants for tracheal intubation in surgical patients, anesthesia maintenance, and mechanical ventilation in ICU patients.

Numerous literature has confirmed that dexmedetomidine has anti-inflammatory and neuroprotective effects, which can effectively alleviate cerebral ischemia-reperfusion injury and reduce the incidence of postoperative delirium. A recent study found that in a placebo-controlled study of dexmedetomidine and saline, the use of dexmedetomidine can reduce the incidence of postoperative delirium in elderly patients undergoing non cardiac surgery by 50% compared to the control group. This article summarizes a series of relevant information on the pharmacological characteristics of dexmedetomidine hydrochloride and its application in postoperative delirium in elderly patients, in order to provide more comprehensive guidance in clinical work.

1. Postoperative delirium

Postoperative delirium is a brain dysfunction caused by various factors, including advanced age, pre-operative cognitive impairment, comorbidities with other diseases, and traumatic stress, all of which can increase the incidence of postoperative delirium. Postoperative delirium mainly manifests as disturbance of consciousness level, attention deficit, and cognitive impairment. Its clinical manifestations have two distinct characteristics, namely acute onset and fluctuating course of disease. Acute onset refers to the sudden onset of symptoms within hours or days.

Fluctuations in the condition refer to symptoms that often appear, disappear, worsen or alleviate within 24 hours, with significant fluctuations and an intermediate period of wakefulness. The incidence of postoperative delirium in elderly patients is high, but clinical studies have shown that 40% of postoperative delirium can be prevented. For patients who have already experienced postoperative delirium, the principle of early detection and treatment should be adhered to, with the greatest effort to reduce the severity of delirium and shorten the duration of delirium occurrence. At present, there is no clear consensus on the pathogenesis of delirium. The widely studied and recognized theories include the inflammatory response theory, stress response theory, circadian rhythm theory, and cholinergic theory.

2. Pharmacological characteristics of dexmedetomidine

Dexmedetomidine, chemical name 4- [(1S) -1- (2,3-dimethylphenyl) ethyl] -1H-imidazole, is the right-handed enantiomer of medetomidine and is a commonly used high choice in clinical practice α 2 adrenergic receptor agonists have anti anxiety, sedative, hypnotic, and analgesic effects.

2.1 Effects on the central nervous system: The sedative and hypnotic effects of dexmedetomidine are manifested by its action on the brainstem locus coeruleus α 2 receptors produce physiological sleep responses. The analgesic effect of dexmedetomidine is achieved by acting on the locus coeruleus, spinal cord, and peripheral organs α Implemented through 2 receptors.

A study on brain tumor surgery showed that the sedative and analgesic effects of dexmedetomidine can reduce brain metabolic rate and cerebral blood flow in patients with brain tumors, lower intracranial pressure, facilitate early extubation after surgery, and also reduce the use of anesthetic and opioid drugs. In addition to conventional sedative, hypnotic, anti anxiety, and analgesic effects, dexmedetomidine also has certain neuroprotective effects on the brain (the mechanism of dexmedetomidine's neuroprotective effects will be elaborated in detail below).

2.2 Effects on the respiratory system: Dexmedetomidine has a mild effect on the respiratory system while exerting sedative and hypnotic effects. This sedative and hypnotic effect is similar to physiological sleep, and the ventilation changes are also similar to normal sleep, so there is less respiratory depression. In an experiment comparing the blood concentrations of remifentanil and dexmedetomidine in vivo, the blood concentration of dexmedetomidine reached 2.4 μ G/L, no respiratory inhibitory effect of dexmedetomidine has been observed. However, dexmedetomidine can cause airway obstruction by relaxing the tension of the pharyngeal muscles, and close observation is still necessary in clinical medication to avoid adverse events.

2.3 Effects on the cardiovascular system: The effects of dexmedetomidine on the cardiovascular system are mainly manifested in slowed heart rate and decreased systemic vascular resistance, leading to reduced cardiac output and hypotension. The effect of dexmedetomidine on blood pressure can manifest as a bidirectional effect, with low concentrations of dexmedetomidine reducing blood pressure and high concentrations of dexmedetomidine increasing hypertension.

The most common adverse reactions of dexmedetomidine are the occurrence of cardiovascular adverse events, mainly including hypotension and bradycardia. The main reason is that dexmedetomidine stimulates the heart α 2 receptors inhibit the sympathetic nervous system, leading to reflexive bradycardia and the occurrence of hypotension. For adverse events such as hypotension and bradycardia caused by dexmedetomidine, treatment methods mainly include slowing down or stopping drug infusion, accelerating fluid replacement, raising the lower limbs, and using vasopressor drugs (such as atropine and glucuronium bromide). In addition, research has found that dexmedetomidine also has a certain protective effect on ischemic myocardium after coronary blood flow occlusion.

3. The application and shortcomings of traditional drugs in postoperative delirium in elderly patients

3.1 Antipsychotic drugs: Previous studies have found that low-dose haloperidol can reduce the incidence of postoperative delirium in elderly patients in the ICU. With the development of diagnostic technology and multi center, large-scale research, in recent years, research results have shown that haloperidol cannot reduce the incidence of delirium in critically ill elderly patients, nor can it improve the short-term survival rate of elderly patients who have already experienced postoperative delirium. Haloperidol has adverse reactions to the central nervous system and cardiovascular system during use, such as extravertebral system reactions, QT interval prolongation, arrhythmia, hypotension, etc. Therefore, it is not recommended in clinical practice to use this type of drug as a routine medication for preventing delirium.

3.2 Cholinesterase inhibitors: Although multiple studies have shown a correlation between cholinergic deficiency and delirium, multiple studies have shown that cholinesterase inhibitors have no effect on preventing postoperative delirium in elderly patients. At present, the use of cholinesterase inhibitors in clinical practice is not advocated for the prevention and treatment of postoperative delirium in elderly patients.

3.3 Benzodiazepine drugs: For delirium caused by alcohol withdrawal or benzodiazepine drug withdrawal, this drug can be used. For ordinary delirium patients or high-risk delirium patients who do not have alcohol withdrawal or benzodiazepine drug withdrawal, the use of this drug can increase the risk of delirium. Therefore, it is not recommended to use this type of medication for routine treatment of delirium.

4. Application and advantages of dexmedetomidine in postoperative delirium in elderly patients

4.1 Brain Neuroprotection: As a new type of sedative and hypnotic drug, dexmedetomidine is increasingly being used in clinical practice. Hoffman et al. found for the first time in animal experiments that dexmedetomidine has a neuroprotective effect on the brain, which can be α 2-Adrenergic antagonist atemizole reverses. A randomized double-blind placebo-controlled trial by Su et al. found that prophylactic use of low-dose dexmedetomidine (0-1 per hour) μ G/kg can effectively reduce the incidence of delirium in elderly ICU patients 7 days after surgery.

Carrasco et al. found that compared to haloperidol, dexmedetomidine can shorten the stay time and reduce the incidence of delirium in patients without mechanical ventilation in the ICU. At present, there are many studies on the protective mechanism of dexmedetomidine on the brain nerves. A large number of literature has confirmed that dexmedetomidine mainly exerts neuroprotective effects on the brain by inhibiting sympathetic nervous activity, reducing catecholamine concentration, inhibiting glutamate release, and regulating cell apoptosis.

4.1.1 Inhibition of sympathetic nervous system activity: reducing catecholamine concentration: Dexmedetomidine can both inhibit the activity of the sympathetic nervous system and directly act on the cell bodies and dendrites of monoamine neurons in the brain α 2 receptors reduce the release of catecholamines from norepinephrine nerve endings. Dexmedetomidine can reduce the release of inflammatory factors and cytokines in endotoxin induced shock rats by inhibiting the sympathetic nervous system and reducing stress responses in the body. Dexmedetomidine can alleviate vascular spasm caused by subarachnoid hemorrhage in rabbits by inhibiting the release of catecholamines in brain tissue, and has a protective effect on brain injury.

4.1.2 Balanced calcium ion concentration: Inhibition of glutamate release: Ischemia and hypoxia can cause the release of excitatory amino acids (such as glutamate) in the brain. High concentrations of glutamate can cause excessive excitation of N-methyl-D-aspartate receptors in neurons, leading to calcium ion influx and activation of calcium dependent proteases, causing cytoskeletal damage and free radical damage. Dexmedetomidine can activate the presynaptic membrane α 2-AR, inhibits N-type voltage-gated calcium channels and directly inhibits calcium ion influx; At the same time, it can also open outward potassium channels, depolarize the presynaptic membrane, indirectly inhibit calcium ion influx, and thus inhibit the release of glutamate.

4.1.3 Regulation of cell apoptosis: Cell apoptosis is an active programmed death of multicellular organisms controlled by multiple genes, mainly involving caspase-1, caspase-3, etc. A detached experiment found that dexmedetomidine can inhibit the expression of caspase-3, prevent its impact on long-term neurocognitive function, and alleviate ischemia-reperfusion injury in rat lungs.

4.2 Reducing Anesthetic Dosage: Dexmetomidine is often used as an anesthetic adjunct in clinical practice, and has a synergistic effect with inhaled anesthetics, propofol, midazolam, and opioids. When used together, it can reduce the dosage of other anesthetic drugs. According to literature reports, inhalation anesthetics such as sevoflurane and isoflurane can increase the permeability of the blood-brain barrier (BBB), thereby promoting the occurrence and progression of postoperative delirium.

Dexmedetomidine activates the central nervous system α 2 receptors can improve the dysfunction of the hypothalamic pituitary adrenal axis (HPA), weaken stress response, and alleviate damage to the sensory and motor systems after sevoflurane anesthesia.

4.3 Maintaining hemodynamic stability: Elderly patients, especially those with concomitant diseases such as hypertension and coronary heart disease, should pay attention to maintaining hemodynamic stability during surgery to avoid drastic fluctuations in blood pressure. In craniotomy surgery, strong pain stimulation can activate the sympathetic nervous system, causing a significant increase in blood pressure and intracranial pressure. Sanders et al.'s research has shown that administering dexmedetomidine to general anesthesia patients undergoing intracranial tumor resection can reduce severe hemodynamic fluctuations during craniotomy, scalp dissection, and other procedures, as well as reduce the dosage of antihypertensive drugs.

5. Recommended method and dosage of dexmedetomidine for postoperative delirium in elderly patients

Both intraoperative adjuvant sedation and postoperative ICU sedation with dexmedetomidine have been shown to reduce the incidence of postoperative delirium in elderly patients and shorten the duration of postoperative delirium. The European Union has approved dexmedetomidine for sedation in adult patients. The most common adverse reaction of infusion of dexmedetomidine is the occurrence of cardiovascular events, mainly including hypotension and bradycardia. In clinical use, close attention should be paid to the occurrence of hypotension and bradycardia in patients. Although such situations have a low incidence in clinical practice, they should still be taken seriously and prevented to avoid inducing cardiac arrest. Elderly people often experience a decrease in renal function. When using dexmedetomidine, which is mainly excreted through the kidneys, a slow injection load of 0.5 should be considered for timing μ G/kg, infusion for more than 10 minutes, or no load is used for prevention.