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The central control of shivering and non-shivering thermogenesis in the rat.

1. To test whether the preoptic area controls only non-shivering and the spinal cord only shivering thermogenesis, ten rats were chronically implanted with a preoptic and a spinal cord thermode each. The following were then studied: (a) the effect of propranolol (8 mg/kg.hr) on the metabolic response to cooling the preoptic area, and the spinal cord, (b) the effect of exogenous noradrenaline (0.5 mg/kg) on the metabolic response to cooling the preoptic area, and the spinal cord, and (c) the effect of warming the preoptic area on the metabolic response to cooling the spinal cord, and vice versa. 2. Administration of propranolol inhibited the metabolic response to cooling each of the thermosensitive areas, but the response to cooling the preoptic area was more strongly inhibited than that to cooling the spinal cord. 3. Administration of exogenous noradrenaline did not prevent the metabolic response to cooling either the preoptic area or the spinal cord. 4. Warming the spinal cord completely inhibited the metabolic response to cooling the preoptic area, and warming the preoptic area fully inhibited the metabolic response to cooling the spinal cord. 5. It is concluded that exogenous noradrenaline underestimates the capacity for non-shivering thermogenesis, and that both thermosensitive areas can control both forms of thermogenesis, but that the preoptic area threshold of non-shivering thermogenesis is probably lower than that of shivering, while the spinal cord threshold of shivering is probably lower than that of non-shivering thermogenesis.

Animals

The control of shivering and non-shivering thermogenesis in the rat.

1. The effect of intraperitoneal administration of propranolol (4, 8 and 12 mg/kg) on colonic temperature was studied in twelve rats during exposure to ambient temperatures of 30, 15 and 5 degrees C. 2. At 30 degrees C, propranolol had no effect on colonic temperature; at 15 and 5 degrees C, however, 4 mg propanolol/kg induced a fall in colonic temperature of about 0-8 degrees C, whereas 8 and 12 mg propanolol/kg induced a fall of about 1-5-2-0 degrees C. 3. Assuming that the temperature regulations system of the rat has a proportional controller and that the effect of propranolol was due to the blockade of non-shivering thermogenesis, the results are interpreted as showing that shivering is activated only when heat loss exceeds the capacity for non-shivering thermogenesis.

Animals

[Postoperative shivering: analysis of main associated factors].

This study was carried out in 75 female patients, ranked ASA 1 or 2, during recovery from balanced general anaesthesia. It aimed to find out the main determinants of postoperative shivering and its thermal effects. Skin and oesophageal temperature were recorded every ten minutes. Mean skin and body temperatures, and the intraoperative energy balance were calculated. There was no additional source of heating. Shivering was ranked from 0 to 2. Statistical analysis showed that the starting mean core and body temperatures were the only factors correlated with shivering and its intensity, whereas mean skin temperatures, age and opioid doses were not. Between 33.5 and 36.5 degrees C, there was a linear relationship between the oesophageal temperature at the end of anaesthesia and the incidence of shivering. A decrease of 1 degrees C in core temperature increased the probability of shivering by 33%. At 35.4 degrees C, 50% of patients shivered. There was a homogenous group of patients whose oesophageal temperature at the end of anaesthesia was between 35 and 36 degrees C. In this group, there was no significant difference between starting skin temperatures, whether the patient shivered or not. However, the core temperature of those within that group that did shiver returned to normal levels more quickly than in those that did not shiver. These data underlined the essential role played by core temperature at the end of anaesthesia in postoperative shivering and its intensity, as well as the heat producing value of shivering. It would therefore seem logical to prevent postoperative shivering by avoiding intraoperative hypothermia.

Adult

Alteration of shivering threshold in cold- and warm-adapted guinea pigs following intrahypothalamic injections of noradrenaline and of an adrenergic alpha-receptor blocking agent.

The role of adrenergic receptors in the central thermoregulatory pathways controlling the shivering activity has been studied in groups of cold-adapted (CA), warm-adapted (WA) and newborn (NB) guinea pigs, which show quantitative differences in shivering threshold. In the CA and NB animals, which normally start to shiver at lower mean body temperature levels than the WA controls, microinjection of noradrenaline (1 mug in 1 mul) into the noradrenaline-sensitive area of the anterior hypothalamus elicited shivering at higher body temperatures at which normally only WA animals start to shiver. Similar injections into the hypothalamus of WA animals did not induce any further shift of the shivering threshold. Microinjections of the alpha-receptor blocking agent phentolamine into the same brain area shifted the shivering threshold in all groups of animals to lower body temperatures, the shift being proportional to the injected dose of phentolamine. The CA and NB animals required higher doses of phentolamine to produce a change in shivering threshold. It is concluded that adrenergic alpha receptors are involved in the central thermoregulatory mechanisms which adjust the thresholds for the thermoregulatory reactions.

Adaptation, Physiological

Relative intensity of muscular contraction during shivering.

The intensity of cold-induced shivering, quantified by surface electromyography (EMG) and then expressed as a function of the maximal myoelectrical activity (integrated EMG) obtained during a maximum voluntary contraction (MVC), was examined in this study in individuals classified by body fat. In addition, the relationship between shivering and metabolic rate (MR) and the relative contribution of various muscle groups to total heat production were studied. Ten seminude male volunteers, 5 LEAN (less than 11% body fat) and 5 NORM (greater than 15% body fat) were exposed to 10 degrees C air for 2 h. EMG of six muscle groups (pectoralis major, rectus abdominis, rectus femoris, gastrocnemius, biceps brachii, and brachioradialis) was measured and compared with the EMG of each muscle's MVC. A whole body index of shivering, determined from the mass-weighted intensity of shivering of each muscle group, was correlated with MR. After the initial few minutes of exposure, only the pectoralis major, rectus femoris, and biceps brachii continued to increase their intensity of shivering. Shivering intensity was higher in the central muscles, ranging from 5 to 16% of MVC compared with that in the peripheral muscles, which ranged from 1 to 4% of MVC. Shivering intensities were similar in the peripheral muscles for the LEAN and NORM groups, whereas differences occurred in the trunk muscles for the pectoralis major and rectus abdominis. The whole body index of shivering correlated significantly with each individual's increase in MR (r = 0.63-0.97).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

Urinary bladder/pulmonary artery temperature ratio of less than 1 and shivering in cardiac surgical patients.

BACKGROUND: Temperature gradients that normally exist between body areas may be altered as a result of heat generated by shivering. METHODS AND POPULATION: Two core thermal gradients between pulmonary artery and urinary bladder were compared with shivering in 37 coronary artery bypass graft patients. Pulmonary artery and urinary temperature were measured every 15 minutes, and shivering was evaluated electromyographically. RESULTS: Shivering developed in 28 patients (76%). With shivering the pulmonary artery/urinary bladder temperature ratio was less than 1 but in the nonshivering group was greater than 1. Correlation (r value) between pulmonary artery and urinary temperature ranged from 0.93 to 0.99. Rate pressure product was higher in the shivering group than in the nonshivering group. A pulmonary artery/urinary bladder temperature ratio of less than 1 was seen with shivering in this subset of patients. CONCLUSION: Pulmonary artery and urinary bladder temperatures are readily available clinically. The combination of a ratio of less than 1 and an increase in rate pressure product should be considered suggestive of shivering in coronary artery bypass graft patients.

Adult

Butorphanol for the relief of shivering associated with extradural anesthesia in parturients.

STUDY OBJECTIVE: To assess the efficacy of butorphanol for the relief of shivering following the epidural administration of 2% lidocaine. DESIGN: Randomized, double-blind study. SETTING: Labor and delivery department of a university-affiliated hospital inpatient facility. PATIENTS: Sixty-one healthy labor patients. INTERVENTIONS: Patients who had sustained shivering associated with lidocaine epidural anesthesia were given normal saline or butorphanol 1 mg. Patients were observed for 20 minutes following the administration of a study solution. MEASUREMENTS AND MAIN RESULTS: Shivering ceased within a mean time of 12.9 +/- 3.8 minutes in approximately 81% of the patients who received epidural butorphanol (p < 0.01), while 3% of the patients in the placebo group had no shivering following the administration of epidural saline. No sedation or changes in fetal heart rate were associated with epidural butorphanol. CONCLUSIONS: Epidural butorphanol is effective in the treatment of postepidural shivering associated with epidural lidocaine. Epidural agonist opioids have been reported to be efficacious in the management of postepidural shivering. This study demonstrated that a partial agonist opioid also is effective in the treatment of postepidural shivering.

Adult

[Intramuscular meperidine for the prevention of shivering in spinal anesthesia].

Intravenous meperidine 25mg has been employed effectively to treat shivering following regional anesthesia and general anesthesia. The study was designed to evaluate the effectiveness of intramuscular meperidine for the prevention of shivering in spinal anesthesia. The series consisted of 60 patients who were divided into 2 groups with 30 patients in each, undergoing lower abdominal or lower extremity surgery. All patients were given diazepam 0.1mg/kg i.v. for anxiolysis when they came to the operating room. In a double blind and randomized fashion, patients in the study (meperidine) group received meperidine 25mg IM (= 0.5ml). In the control group 0.9% N/S 0.5ml IM was given instead. All patients received spinal anesthesia 15 minutes later. Measurement of the levels of sensory loss to pinprick was made. The ambient temperature and the rectal temperature were continuously monitored to evaluate the effect of the change in body temperature on shivering during operation. The degree and the occurrence of shivering were carefully evaluated and recorded by a blind-trust observer. There was no significant difference in maximal analgesic level, ambient temperature and change of rectal temperature during operation between the groups. Shivering occurred in 17 patients (56.7%) in the saline group with an onset time of 7.9 +/- 2.5min following spinal anesthesia. In the meperidine group, shivering occurred only in 3 patients (10%) with an onset time of 54 +/- 29.5min after spinal anesthesia. There was a significantly lower incidence of shivering in the meperidine group than in the saline group (p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Abdomen

The dysmyelinating mouse mutations shiverer (shi) and myelin deficient (shimld).

Shiverer (shi/shi) is an autosomal recessive mouse mutation that produces a shivering phenotype in affected mice. A shivering gait can be seen from a few weeks after birth until their early death, which occurs between 50 and 100 days. The central nervous system of the mutant mouse is hypomyelinated but the peripheral nervous system appears normal. The myelin of the CNS, wherever present, is not well compacted and lacks the major dense line. Myelin basic protein (MBP), which is associated with the major dense line, is absent, and this is due to a deletion of the major part of the gene encoding MBP. Transgenic shiverer mice that have integrated and express the wild-type mouse MBP transgene no longer shiver and have normal life spans. Conversely, normal mice that have integrated an antisense MBP transgene, shiver. Myelin deficient shimld/shimld is allelic to shiverer (shi/shi) but the mutant mouse is less severely affected. Although MBP is present in the CNS, it is low in quantity and is not developmentally regulated. The gene encoding MBP has been both duplicated and inverted. Transgenic shimld/shimld mice with the wild-type MBP transgene have normal phenotypes.

Animals

Comparison of meperidine and pancuronium for the treatment of shivering after cardiac surgery.

Shivering after cardiac surgery can produce adverse haemodynamic and metabolic sequelae. In this study, the metabolic effects of shivering and the efficacy of treatment with meperidine or pancuronium were studied, using a metabolic cart, in 61 patients who had undergone cardiac surgery. The patients received premedication with morphine, perphenazine and diazepam or lorazepam, and were anaesthetised with fentanyl or sufentanil and diazepam. Muscle relaxation was achieved with pancuronium. Patients were monitored with a radial arterial line, pulmonary artery catheter and oesophageal and urinary bladder temperature probes. Rewarming to an oesophageal temperature of 38 degrees C was achieved before the termination of CPB and was maintained for a minimum of 15 min reperfusion time. Every 15 min after surgery, the patients' temperature at three sites (pulmonary artery, oesophagus, bladder) and shivering scores were monitored. Hourly measurements were made of haemodynamic variables (MAP, PAOP, CVP, SVR, PVR, CI), carbon dioxide production, oxygen consumption and respiratory quotient. If the patient shivered, the measurements were recorded prior to drug treatment and repeated 30 min later following randomization to either: meperidine 0.25 mg.kg-1 (Group 1), meperidine 0.5 mg.kg-1 (Group 2) or pancuronium 0.06 mg.kg-1 intravenously (Group 3). Thirty-two patients shivered and mean VO2 and VCO2 values were greater in the shivering group than in the nonshivering patients (VO2 334.8 +/- 17.6 vs. 240.5 +/- 8.8 ml.min-1; VCO2 238.8 +/- 17.2 vs 199.2 +/- 8.4 ml.min-1, P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance

Thermogenesis induced by inhibition of shivering during cold exposure in exercise-trained rats.

The present investigation was conducted to examine the role of nonshivering and shivering thermogenesis caused by cold exposure in exercise-trained rats. Wistar rats were divided into warm-acclimated (WA), exercise-trained (ET) and cold-acclimated (CA) groups. The trachea was cannulated and a ventilator was connected under light anesthesia and in the supine position. Shivering, oxygen consumption, colonic temperature, blood glucose, and free-fatty acids were measured at 25 degrees C and then at 0 degrees C room temperatures. D-tubocurarine chloride (curare, 0.04 mg/100 g body weight, ip) was given to inhibit muscular activity. Cold-induced oxygen consumption in the ET and WA groups did not decrease when shivering was inhibited, whereas it increased in the CA. The magnitude just after shivering onset for the ET and CA groups as significantly greater than for the WA group. Colonic temperature at the onset of shivering was significantly higher in the WA group than in the ET and the CA groups. The blood glucose concentration during cold exposure and curarization was elevated in the ET group, and did not change in the CA or WA groups. The present results suggest that endurance training at a thermoneutral environment increases cold-induced thermogenic capacity in rats, which may be attributed to preferential carbohydrate utilization.

Acclimatization

[Effect of halothane on the peripheral cutaneous vasoconstriction and shivering induced by internal body cooling in rabbits].

Although suppression of thermoregulatory mechanisms by anesthetics is generally assumed, the extent to which thermoregulatory responses are active during general anesthesia is not known. To evaluate the effect of anesthetics on thermoregulation, we investigated the threshold body core temperatures to induce peripheral cutaneous vasoconstriction and shivering in spontaneously breathing rabbits. Rabbits are anesthetized with halothane at 0.05, 0.2 and 0.4 MAC (minimum alveolar concentration). Internal whole body cooling was performed by perfusing the cool water through an intestinal U-shaped thermode placed in the colon. Core (esophagus) and peripheral (ear) temperatures were measured with thermistors. The esophageal temperatures at the beginning of peripheral cutaneous vasoconstriction and shivering induced by internal whole body cooling were determined. Peripheral cutaneous vasoconstriction was not significantly affected by halothane. However, the incidence of shivering was significantly decreased by halothane dose-dependently. Threshold of shivering (37.3 +/- 0.8 degrees C) was significantly lower than that of peripheral cutaneous vasoconstriction (38.9 +/- 1.1 degrees C). We conclude that the halothane can exert an influence on shivering.

Animals

[Shivering during recovery after cardiac surgery under extracorporeal circulation. Inconveniences and methods of prevention].

Among 109 subjects who had undergone cardiac surgery under ECC, the authors recorded 50 (45 p. 100) who suffered from shivering during the coming round period. Comparing the series of patients who shivered, with that of the subjects who did not shiver, the authors demonstrate in the first case, an increase in cellular metabolism, the cardiac index, heart rate, central venous pressure and cardiac work. They subsequently note the apprearance of mixed acidosis and an increase in the lactate-pyruvate ratio. Certain patients, in whom the cardiac output did not keep up with the metabolic demand considerably increased the arterio-venous oxygen difference. Blood loss is increased as well as coagulation time showing a more intense heparin rebound. The study of the drugs used during anesthesia showed that the patients who had received chlorprotixene, as the neuroleptic, a neuroleptic with adrenolytic properties, had a very decreased frequency of shivering in comparison with those who had received droperidol. The placing of the patient at the end of the intervention on a heating mattress, combined with the administration of chlorprotixene during anesthesia, prevented the appearance of shivering.

Adult

Chimeric and molecular genetic analysis of myelin-deficient (shiverer and mld) mutant mice.

The shiverer and myelin-deficient (mld) mutants are two allelic mutations. Both are characterized by hypomyelination in the CNS and deficient expression of the MBP gene. Chimeric analysis of the pathogenesis of shiverer showed that shiverer mutation acts intrinsic to the oligodendrocyte, which is the only cell type expressing the MBP gene in the CNS. Molecular genetic studies by several groups demonstrated that shiverer is a deletion mutation in the MBP gene. Consequently, no MBP is produced in the shiverer mutant. In mld, however, partial expression of the MBP gene was observed. Interestingly, MBP was expressed in a mosaic fashion in the CNS of mld mice. Molecular genetic studies revealed that the mld mutant has duplicated MBP genes in tandem on a distal part (E2-4) of chromosome 18q. The reduced expression was based on the level of mRNA. A large portion is inverted in the upstream copy, and an intact copy is located downstream. We showed in mld mutants that antisense RNA corresponding to the inverted segment is transcribed, and it forms RNA duplex, with the RNA transcribed from the normal gene located downstream.

Animals

Regulation of myelin basic protein gene transcription in normal and shiverer mutant mice.

We describe the measurement of myelin basic protein gene transcription rate, and of the accumulation of both mature mRNA and total transcripts from the myelin basic protein gene in brains from mice of wild-type and homozygous shiverer genotypes at several ages spanning postnatal development. In wild-type brains the accumulation of total transcripts as well as mature mRNA, and the transcription rate, all follow the same general pattern of rising sharply from a low level at birth to a peak at 20 days, and continuing at a somewhat reduced level into adulthood. Thus a major factor in the developmental regulation of myelin basic protein expression is the control of transcription rate. The shiverer mutation consists of a deletion of the 3' end of the myelin basic protein gene which completely prevents production of mature mRNA and protein, and results in severe dysmyelination and a trembling behavior. In shiverer brains, the transcription rates for the intact 5' end of the gene follow closely those seen in wild-type animals up to the age at which maximal myelination normally occurs. Total myelin basic protein transcripts follow a similar profile but at less than 5% the level seen in wild-type, and, as expected, no mature mRNA is detected. Thus the shiverer deletion does not remove information required for efficient, developmentally regulated transcription, and the low level of myelin basic protein gene transcripts in this mutant must be a result of their reduced stability. A higher than normal myelin basic protein gene transcription rate in older shiverer animals raises interesting questions regarding the regulatory mechanisms controlling myelinogenesis.

Animals

Acute mild cold exposure with shivering reduces 24 h glucose levels in individuals with type 2 diabetes but not prediabetes.

AIMS/HYPOTHESIS: Repeated cold exposure with shivering has been proposed as a potential strategy to enhance glucose metabolism by increasing energy expenditure and substrate utilisation. However, acute effects/benefits of cold-induced shivering on glucose homeostasis in metabolically compromised individuals are unknown. Here, we aimed to determine whether cold exposure at two different intensities improves 24 h glucose homeostasis in individuals with prediabetes and type 2 diabetes. METHODS: In a randomised crossover trial conducted in the South Limburg/Maastricht region of the Netherlands, men and postmenopausal women with prediabetes (n=12) and stable type 2 diabetes (n=12), aged 40-75 years, body mass index &#x2265;27 and &#x2264;35 kg/m2, non-smoking and sedentary, underwent two whole-body cold exposure sessions using a water-perfused suit. Session order was randomised using an online randomisation tool (randomizer.org); participants were masked to the cold exposure intensity received, but investigators were not. Sessions were designed to elicit ~1.5-fold (mild, 15&#xb0;C) and ~2.5-fold (moderate, 4&#xb0;C) increases in resting metabolic rate (RMR). Continuous glucose monitoring assessed interstitial glucose concentrations over 24 h periods before and after each intervention, with controlled diet and activity. Shivering was confirmed via indirect calorimetry and electromyography. RESULTS: In both study groups and periods, RMR increased significantly vs baseline (p<0.001 for all). In prediabetes, the increase in the final 1 h of cold was 1.53&#xa0;&#xd7;&#xa0;RMR in mild and 1.94&#xa0;&#xd7;&#xa0;RMR in moderate cold. In type 2 diabetes, the increase was 1.57&#xa0;&#xd7;&#xa0;RMR and 2.09&#xa0;&#xd7;&#xa0;RMR in the final 1 h of mild and moderate cold, respectively. In prediabetes, neither mild nor moderate cold exposure altered mean 24 h glucose levels. In contrast, after mild cold exposure the type 2 diabetes group exhibited a significant reduction in mean 24 h glucose levels (-0.6&#xa0;&#xb1;&#xa0;0.5 mmol/l, p=0.003) and fasting glucose (-0.6&#xa0;&#xb1;&#xa0;0.8 mmol/l, p=0.019), as well as an increase in time in normal range (+8.8&#xa0;&#xb1;&#xa0;10.3%, p=0.013) and reduced time in hyperglycaemia (-10.9&#xa0;&#xb1;&#xa0;12.9%, p=0.014). Moderate cold did not significantly affect any of the glucose outcomes in type 2 diabetes. Baseline fasting glucose, age and ALT levels were predictors of the glucose-lowering response, suggesting greater benefits in individuals who have higher baseline glucose levels, are younger and/or have more optimal liver health, i.e. lower ALT. CONCLUSIONS/INTERPRETATION: Acute mild cold exposure with shivering reduced 24 h glucose levels in individuals with type 2 diabetes. No changes were observed in prediabetes. The observed effects appear to depend on baseline metabolic status rather than acute substrate utilisation during cold exposure. These findings support the potential of cold exposure as an adjunct non-pharmacological therapy for type 2 diabetes, although further mechanistic studies and validation in larger cohorts are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT05576025 FUNDING: Dutch Organisation for Knowledge and Innovation in Health, Healthcare and Well-being (ZonMw): 09120012010062.

Humans

Catecholaminergic alpha-receptors and shivering in the rat.

1. A rise or a fall in systemic blood pressure brought about by the I.V. infusion of peripherally acting drugs (adenosine, noradrenaline or methoxamine) inhibited shivering in the cold-exposed rat. 2. Since the injection of commonly used doses of noradrenaline (0.05-0.10 mumole) into a lateral cerebral ventricle of a rat was usually accompanied by a rise in blood pressure special precautious were required to determine whether noradrenaline had a specific central effect on shivering. 3. Small doses of noradrenaline (0.02-0.03 mumole) or clonidine (0.01 mumole) which had no effect on blood pressure when injected into a lateral cerebral ventricle still inhibited shivering in the cold-exposed rat and this effect was prevented by phentolamine. 4. It is concluded that noradrenaline can inhibit the cold sensor-shivering pathway in its central course by an action on alpha-receptors.

Adenosine