Mechanism of perioperative chills and preventive and control measures Constant body temperature is an important factor to ensure the physiological and metabolic stability of the body. During the perioperative period, due to the inhibition of thermoregulation by anesthetics and the lack of proper insulation measures for patients, patients are often accompanied by varying degrees of decreased body temperature, which even leads to the occurrence of chills. Chills not only increase intraocular pressure and intracranial pressure, but also increase oxygen consumption and CO2 production by 2~3 times, and this increase in metabolism is extremely detrimental to patients with intrapulmonary shunts, fixed cardiac output and reduced respiratory reserve. Therefore, effective prevention and control of perioperative chills is one of the key measures in anesthesia management. The possible mechanisms of perioperative chills and the pharmacological effects of different anti-chills are reviewed in this paper as follows. Wang Xuejun, Department of Anesthesia, Qinghai Red Cross Hospital 1 Mechanism of occurrence The exact mechanism of occurrence of chills is still unclear. There is evidence that insulation and input of warm fluids are not effective in preventing the occurrence of chills. Most scholars believe that postoperative chills are a thermoregulatory phenomenon, a physiological response to the decrease in central body temperature after anesthesia.1 Causes of chills after intradural block The incidence of chills after intradural block is as high as 60%. The possible mechanism is: because some sympathetic nerves are blocked due to endotracheal anesthesia, the blood vessels in the blocked area cannot compensate for the contraction, and the body’s response to cold is weakened, so the body temperature is rapidly distributed from the central chamber to the peripheral chamber by conduction, and the body temperature in the central chamber then decreases, because the motor nerve block can reduce muscle movement and tension and reduce heat production, and the rise of skin temperature in the blocked area gives the regulatory system 1.2 Causes of chills due to general anesthesia Chills often occur in hypothermic patients when they awaken from general anesthesia. The mechanism may be that the anesthetic inhibits the thermoregulatory system, so that the threshold of chills decreases, and the threshold of chills returns to normal during the disappearance of anesthesia, which makes the difference between the hypothermic state of the body and the body temperature threshold that is now close to normal, and therefore leads to the occurrence of chills. However, it is worthwhile to further investigate the phenomenon that chills often do not occur in the severely hypothermic state, while chills often occur in patients with near normal body temperature.1.3 Other Studies have found that 50% of patients have a deep body temperature of 38.4°C. Therefore, it is believed that the stimulation of surgery can lead to an upward shift of the temperature tuning point, resulting in the occurrence of chills and an increase in body temperature. In addition, infection, pulmonary atelectasis, thermogenic substances released from trauma, body surface disinfection, surgical field exposure, heat dissipation exceeding metabolic heat production and intraoperative input of large amounts of cryogenic fluids, and low room temperature can lead to the occurrence of chills. 2 Pharmacological regulation of chills Studies have demonstrated that monoamines, choline-like substances, cations, endogenous peptides and ***A receptor antagonists can act on the thermoregulatory system and participate in the regulation of body temperature 2.1 Pharmacological basis of biogenic amines In 1963, Feldberg and Myers first discovered that the balance between norepinephrine and 5-HT in the preoptic area of the hypothalamus determines the level of the thermoregulation point. It was demonstrated that injection of epinephrine and other amine neuromediators into the ventricles of the cat produced corresponding thermoregulatory effects. Injections of 5-HT can lead to chills and vasoconstriction with an increase in deep body temperature; conversely, injections of norepinephrine and epinephrine can lower body temperature and antagonize the temperature-raising effects of 5-HT; injections of dopamine at doses similar to norepinephrine into the hypothalamus of conscious monkeys can produce effects similar to those of norepinephrine, but with relatively mild cooling. The mechanism of action is to inhibit synaptic uptake of 5-HT, norepinephrine, and dopamine, with only a mild lowering effect on normal body temperature. The mechanism of action is similar to that of Nefopam, i.e., it inhibits the uptake of 5-HT, norepinephrine and epinephrine, promotes the release of 5-HT, and effectively acts on central α2-adrenergic receptors. Although it was found to have varying degrees of opioid effects, its effects were not reversed by Naloxane, which was also found to only partially reverse the anti-chilling effects of tramadol in studies in volunteers. (2) α2 adrenergic receptor agonists These drugs act mainly on k+ channels, which increase k+ inward flow and put nerve cells in a hyperpolarized state, slowing nerve impulse transmission channels and leading to a decrease in the sensitivity of the temperature center to body temperature. In addition, it can also block Ca2+ inward flow, so that Ca2+ stays on the surface of the cell, which has the effect of stabilizing the cell membrane and reducing the impulse pathway in the thermoregulatory center. Its representative drug is Colotin. (3) Anti-hypertensive drug Ketanserin is an α1 receptor antagonist, mainly antagonizing 5-HT and α1 adrenergic receptors, and also having different degrees of agonistic effects on central presynaptic α2 adrenergic receptors, with only a weak anti-chilling effect. (4) 5-HT3 receptor antagonist is a class of anti-emetic drugs, whose representative is Endansidone. Studies have shown that Endansidone 8mg sedation can effectively inhibit the occurrence of postoperative chills without cardiovascular side effects, and there is no interaction with morphine, diazepam and sodium thiopental. Since its intravenous injection produces the maximum effect at 1.5h, with a half-life of 3h, it is recommended to be used preoperatively for the best effect. Gresilon is another highly selective 5-HT3 receptor antagonist, and 3 mg of gresilon slowly administered by sedation can effectively prevent the occurrence of postoperative chills, and the possible mechanism is the inhibition of body temperature regulation at the hypothalamic level.2.2 Pharmacological basis of cholinergic drugs Although no direct effect of cholinergic drugs was found in the preoptic area/hypothalamus of cats, rats, and other animals, M- and N-type cholinergic drugs injected into the monkey hypothalamus resulted in vasoconstriction, chills, and elevated body temperature responses. Injection of atropine or nicotine into the ventricles of rabbits inhibited chills and lowered body temperature. Therefore, both receptor subtypes may be involved in the regulation of body temperature. Therapeutic agents Toxaprine, dulcolax and colestipol are representative drugs. Toxopamine is a traditional, low-selective central cholinesterase inhibitor whose analgesic effect is mainly mediated by central cholinergic M receptors. Tracheal injection of cholinesterase antagonists produces analgesic effects mainly through M receptors and, to a lesser extent, μ and α receptors. However, no experiments have yet shown that they produce anticholinergic effects via the same receptor mechanism. Recent studies have demonstrated that atropine can also mildly increase the threshold of vasoconstriction and chills, and has a mild anti-chill effect.2.3 Pharmacological basis of peptide drugs There are a large number of peptides in the brain, especially in the hypothalamus. These peptides can be divided into three categories according to their effects on nerve impulses: (1) local application of thyrotropin-releasing hormone can reduce the excitation of heat-sensitive nerves in the preoptic area/hypothalamus and activate cold-sensitive nerves, thus causing hyperthermia; (2) application of angiotensin II and morphine can inhibit heat-sensitive nerves and cold-sensitive nerves, respectively; (3) Bombesin and neuropressin have inhibitory effects on impulse conduction of both types of nerve fibers. (3) Bombesin and neuropressin have inhibitory effects on impulse transmission in both types of nerve fibers. The effects of opioid peptides on body temperature are related to the type of animal, drug dose, ambient temperature and controlled temperature. For example, small doses of Met-cerebrosides and β-endocerebrosides injected into the ventricles resulted in increased body temperature, but larger doses of cerebrosides and endocerebrosides injected into the ventricles resulted in decreased body temperature (probably as a result of their reduced metabolic thermogenesis). Therapeutic use μ-agonists (including morphine, fentanyl and alfentanil) have some therapeutic effect on postoperative chills. In addition, epidural injections of lidocaine and fentanyl may also reduce the occurrence of chills. Epidural injection of sufentanil produces a dose-dependent decrease in body temperature and the onset of chills. Pethidine is a potent anti-chill drug with an anti-chill effect twice as large as the anti-vasoconstriction effect. It agonizes not only μ receptors but also κ receptors and has varying degrees of effect on a variety of non-opioid receptors. For example, analgesic doses of dulcolax can effectively inhibit the reuptake of 5-HT (but dulcolax in combination with monoamine oxidase inhibitors can lead to central 5-HT accumulation and potentially fatal hyperthermia) and inhibit the reuptake of central and nerve terminal norepinephrine, and this effect is not blocked by naloxone, so it is not regulated by opioid receptors. In addition, it agonizes α2-adrenergic receptors; exerts a non-competitive antagonistic effect on ***A receptors in the murine spinal cord; and exerts a competitive antagonistic effect on M receptors. The unique anti-chilling effect of dulcolax may be the result of the combined modulation of these different types of receptors.2.4 Cationic substances Ca2+ and Na+ have opposite effects on the regulation of body temperature. If a large dose of Ca2+ is injected into the dorsal hypothalamus, it leads to a decrease in body temperature, while an injection of a large dose of Na+ leads to an increase in body temperature. Within the organism, the ratio of these two ions may be involved in regulating the level of the thermoregulatory point. When the peripheral temperature changes, can quickly lead to changes in the ratio of these two ions, inducing the temperature center to shift up or down the regulatory point, so that increased heat production or increased heat loss but the exact process of change to be studied. 2.5 ***A receptor antagonists (1) magnesium sulfate is ***A receptor antagonist, recently found that it can also antagonize the occurrence of chills. (2) Diphenhydramine has both M and ***A receptor antagonistic effect, which can be used for perioperative pain relief and can effectively prevent the occurrence of chills. (3) Ketamine is a competitive ***A antagonist and can also be used to treat postoperative chills, but it should be used with caution because it also has the effects of anesthesia, blocking ammonia uptake, and κ-receptor excitation. 2.6 Stimulants (1) Ritalin is another effective antichillic drug. The mechanism of its excitatory effect is to act on the presynaptic sites of dopamine, norepinephrine and 5-HT nerve fibers, blocking the reuptake of these neurotransmitters. Its activation of the spinal cord and the upstream arousal system may be the main mechanism of action for its anti-chill effect, but no substrate has been identified for its action. (2) Morpholinone is a weak stimulant, which mainly excites the respiratory center. It can also be used to treat postoperative chills, but its mechanism of action is not yet known. In addition, after halothane anesthesia, the application of morpholinone also has a hypnotic effect. 2.7 Other (1) general anesthetic hypnotic Doxapram is a new type of general anesthetic hypnotic, and the study proved that 0.5 mg-kg-1 doxapram slow sedation can effectively treat the occurrence of postoperative chills after general anesthesia, and there is no significant effect on blood pressure and heart rate. (2) Dexamethasone, an amino acid, can also reduce the incidence of chills to varying degrees. In conclusion, no specific anatomical structure or physiological or pharmacological site of action has been identified to determine the chilling response. It is possible that the neurological, endocrine and motor systems jointly regulate the process of the onset and development of chills. Therefore, it is recommended that all patients should be insulated except for patients requiring intraoperative hypothermia for the protection of important organs such as the heart and brain and spinal injuries. Various anti-chilling drugs can antagonize chills to different degrees through different mechanisms of action. Clinically, different anti-chilling drugs can be selected according to the type of anesthesia and surgery and the degree of chills of patients.