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Initiation and inhibition of shivering in the rat: interaction between peripheral and central factors.

1. Unanaesthetized, female white laboratory rats were subjected to almost square-wave changes in ambient temperature, from 20 degrees C to 35 degrees C, in a small climatic chamber. 2. Intracerebroventricular injections of serotonin and methysergide were made in shivering, unanaesthetized rats. 3. The integrated electromyogram of m. suprascapularis was recorded as a quantitative measure of shivering activity to monitor the effects of the above procedures. 4. Both warm transients and serotonin inhibited shivering, but methysergide blocked only the effect of serotonin.

Animals↗

Changes in the metabolism of the shivering hind leg of the young ox during several days of continuous cold exposure.

The effect of 4 days of continuous exposure to a cold environment on blood flow in, and oxygen and energy substrate uptake by the shivering hind leg has been studied in young steers. The animals shivered throughout the period of cold exposure and total oxygen consumption (total VO2) remained 40-50% greater than VO2 during thermoneutrality. Leg blood flow (leg Q) and oxygen uptake (leg VO2) increased two- and four-fold respectively on the first day of cold. Both had declined significantly by the final day, leg Q to a level 37% greater than, and leg VO2 to about double, pre-cold levels. The change in the relationships of leg Q and leg VO2 to total VO2 was examined by linear regression analysis, which suggested that the changing contribution of leg VO2 to total VO2 was entirely due to changes in leg Q, rather than in the arteriovenous difference in blood oxyhaemoglobin saturation across the leg. The net uptakes by the leg of free fatty acids (FFA), acetate, glucose and lactate all increased on the first day of cold. Both glucose and acetate uptakes were greater on day 4 than on day 1 in the cold, in spite of the lower leg VO2, but net uptakes of FFA and lactate were considerably lower. The decrease in net uptake of FFA is attributed mainly to an increase in the rate of lipolysis and release of FFA from fat depots in the leg, because of the associated progressive increase in the release of glycerol and oleic acid from the leg. The molar ratios of net carbohydrate substrate, acetate and FFA uptakes to leg VO2 are compared. The results suggest that tissues other than the leg muscles become increasingly important as sites of heat production, and that there are changes in the utilization of glucose, acetate and FFA by shivering muscle, during prolonged cold exposure.

Acetates↗

Age-related changes in oxygen and nutrient uptake by hindquarters in newborn pigs during cold-induced shivering.

Newborn pigs rely essentially on shivering thermogenesis in the cold. In order to understand the rapid postnatal enhancement of thermogenic capacities in piglets, the oxygen and nutrient uptake of hindquarters was measured in vivo in 1- (n = 6) and 5-day-old (n = 6) animals at thermal neutrality and during cold exposure. The hindquarters were considered to represent a skeletal muscle compartment. Indirect calorimetry and arterio-venous techniques were used. The cold challenge (23 C at 1 day old and 15 C at 5 days old for 90 min) induced a similar increase (+90 %) in regulatory heat production at both ages. Hindquarters blood flow was higher at 5 days than 1 day old at thermal neutrality (26 +/- 3 vs. 17 +/- 1 ml min-1 (100 g hindquarters)-1) and its increase in the cold was much more marked (+65 % at 5 days old vs. +25 % at 1 day old). Oxygen extraction by the hindquarters rose from 30-35 % at thermal neutrality to 65-70 % in the cold at both ages. The calculated contribution of skeletal muscle to total oxygen consumption averaged 34-40 % at thermal neutrality and 50-64 % in the cold and skeletal muscle was the major contributor to regulatory thermogenesis. Based on hindquarters glucose uptake and lactate release, carbohydrate appeared to be an important fuel for shivering. However, net uptake of fatty acids increased progressively during cold exposure at 5 days old. The enhancement in muscular blood supply and fatty acid utilization during shivering is probably related to the postnatal improvement in the thermoregulatory response of the piglet.

Aging↗

The influence of centrally applied noradrenaline on shivering and body temperature in the pigeon.

1. Noradrenaline (NA) was injected in a volume of 1.0 mul. through chronically implanted cannula into the hypothalamus of the unanaesthetized pigeon.2. In doses of 1-15 mug NA caused complete inhibition of shivering of dose-dependent duration. Histological mapping of the brain showed that NA was exerting its inhibitor action in the region above the optic chiasma bordering on the posterior hypothalamus and the anterior preoptic nucleus.3. At low ambient temperature, the NA induced inhibition of the cold tremor caused a fall of core temperature which lasted as long as shivering was inhibited. Shivering induced by local cooling of the spinal cord, and by the combined cooling of the skin and the spinal cord, was likewise inhibited by the cerebral application of NA. There was no evidence of an adjustment of the temperature set-point by NA.4. A rapid rise in skin temperature of the unfeathered feet, whenever NA was injected indicated a reduction in peripheral vasomotor tone.

Animals↗

The relationship between ventilation and oxygen consumption in man is the same during both moderate exercise and shivering.

1. Four naïve subjects clothed in protective suits were immersed up to the neck in water on twenty-two occasions, the minimum skin temperature was 20 degrees C and the average skin temperature 26 degrees C. Subjects at first rested, initially demonstrating an increase in thermal muscular tone which did not lead to perceptible limb movements. Later, while resting, visible shivering with small unco-ordinated limb movements supervened. The subjects then exercised while still immersed by stationary cycling. 2. Steady-state minute oxygen consumption (VO2) and minute ventilation (VE) were measured on 152 occasions by timed collection of expired air. 3. The first collection was made at least 5 min after initial immersion. Hyperventilation due to recent immersion in cold water was not demonstrated. 4. The same linear relationship between VE and VO2 was demonstrated whether the increased oxygen consumption was due to shivering alone or to a combination of shivering and exercise. 5. VE was matched to VO2 in spite of an increase in the work of breathing as well as any ventilation-perfusion mismatching as a consequence of head-out water immersion. 6. Minute ventilation was not influenced by the large co-ordinated limb movements which only occurred during exercise. These results reinforce previous findings which have shown that in conscious man VE can be closely matched to VO2 below the anaerobic threshold despite large variations in the type and intensity of limb movements. 7. When VO2 is increased by thermal muscular tone VE is increased in direct proportion in a situation when the limbs are not perceptibly moving at all.

Adult↗

Shivering thermogenesis during acute hypercapnia.

The effects of acute hypercapnia on human thermoregulation during cold exposure were investigated by immersion of eight male subjects to the neck in a 15 degrees C water bath until their core temperatures dropped to 35 degrees C or until 1 h of immersion had elapsed. Air was inspired throughout each experiment, with the exception of a 15-min period commencing with the attainment of an esophageal temperature (Tes) of 36.5 degrees C, during which subjects inspired a gas mixture containing 4% CO2, 20% O2, and 76% N2. Oxygen uptake (VO2, L.min-1), inspired minute ventilation (Vi, L.min-1), esophageal temperature (Tes, degrees C), rectal temperature (Tre, degrees C), mean unweighted skin temperature (Tsk, degrees C), mean heat flux (Q, W.m-2), and electromyographic activity (EMG, mV) of the trapezius and masseter muscles were recorded continuously. VO2 and integrated EMG activity (IEMG) were used as the primary indicators of shivering thermogenesis. Shivering EMG was attenuated immediately following the switch of the inhaled gas mixture from air to 4% CO2. For both the masseter and trapezius muscles the IEMG was significantly suppressed (p < 0.05) during the hypercapnic period. The IEMG values preceding the switch to the hypercapnic mixture were 15% greater than those during the CO2 period. Similarly, IEMG values in the post-CO2 period were 55% greater than during the CO2 period. It is concluded that acute periods of hypercapnia during cold exposure may result in transient suppression of shivering tremor, but this does not appear to affect thermal balance, as reflected in the absence of any significant effect on Tes.

Acute Disease↗

Propranolol and pyrogen effects of shivering and nonshivering thermogenesis in rats.

Injection of bacterial endotoxin (Piromen) into unanesthetized rats elicited increases in shivering and nonshivering thermogenesis as well as in colonic temperature. In animals exposed to 24-25 degrees C, treatment with propranolol (a beta-adrenergic antagonist) markedly diminished the pyrogen-induced increases in oxygen consumption (heat production) and colonic temperature with little change occurring in shivering activity. In contrast, in rats exposed to mild cold (17-18 degrees C), propranolol did not significantly alter the magnitude of the pyrogen-evoked thermogenesis. Rather in these animals, shivering tended to increase when nonshivering thermogenesis was blocked. These data are interpreted as reflecting differential effects of pyrogen on the pathways controlling the two modes of heat production in the rat.

Animals↗

Brainstem control of shivering in the cat. II. Facilitation.

Regions containing areas and pathways mediating heat gain responses in the mesencephalon and upper pons and in the medulla were studied using topical microinjection of a local anesthetic. These facilitatory areas and pathways were compared in the decerebrated and intact cats. In lower pontine preparations shivering was abolished by bilateral injections of procaine into the lateral medullary reticular formation. Injections into the same areas in the intact anesthetized cat resulted in the cessation of shivering. These effects on facilitatory areas are reversible and can be repeated in the same preparation several times. Permanent effects were obtained by electrolytic lesions or by the local microinjections of 1% osmic acid. In summary it shown, by means of microinjection of local anesthetic, that the pathways mediating shivering in the intact and lower pontine cats are located in the same area in lateral reticular formation of pons and medulla.

Animals↗

Synchrony between breathing and shivering in three muscles of bantam hens exposed to cold eggs.

Unrestrained, incubating bantam hens (Gallus domesticus) were exposed to cold, water-perfused eggs to induce shivering. Mean rectified electromyogram (EMG activity) was recorded from the iliotibialis, gastrocnemius, and pectoralis muscles, together with breathing and O2 consumption. EMG activity in all three muscles varied in synchrony with breathing, as confirmed by spectral analysis. The highest shivering intensity occurred during end expiration. This synchrony was also present when respiratory frequency was increased by hypercapnic/hypoxic stimuli and tended to improve with increasing respiratory frequency and tidal volume. The absolute modulation of shivering intensity remained relatively constant with increasing average intensity, indicating that breathing-modulated motor units are activated first. In the less active pectoralis muscle, all activity was modulated. Modulation is probably not restricted to one type of muscle fiber because it occurs in both predominantly red hindquarter muscles and the white pectoralis muscle. It is tentatively suggested that respiratory drive-related influence from the brain stem has a synchronizing effect on spinal cord activity. A bursting activity pattern may be more favorable for muscle circulation than a tonic discharge pattern.

Animals↗

Thermal insulation and shivering threshold in Greek sponge divers.

Sublingual temperature (Tor), average skin temperature (Tsk), and skin heat flow (Hsk) were determined in a field study for six Greek sponge divers and seven nondiving controls during head-out immersions at water temperature of 21 degrees C. Wetsuits kept Tsk at 22-28 degrees C for 1-3 h until Tor fell to 36.5-35.5 degrees C and violent shivering [metabolic rate (M) = 100-150 W . m-2] ended the test. At a steady Tsk, immediately before shivering, overall tissue insulation (It), calculated as (Tor--Tsk)/Hsk, was linearly related to mean subcutaneous fat thickness (MFT) in both groups without statistical difference between them. The onset of shivering, as detected by a sharp increase of M, occurred at the same Tor for a Tsk of about 26 degrees C, and the relationship of M vs. Tor (i.e., metabolic sensitivity) was the same for both groups. Contrary to other groups accustomed to diving in cold water, the use of a wetsuit for a long time has evidently prevented cold adaptation in these divers.

Adipose Tissue↗

Synchronized slow-amplitude modulations in the electromyograms of shivering muscles.

The electromyograms (EMG) of shivering human subjects exposed to 0 degrees C air in an environmental chamber were analyzed to detect slow-amplitude modulations (SAMs, less than 1 Hz) in the EMGs of widely separated muscles and to study the relationship of these SAMs to respiration rate and skin temperature. Distinct amplitude modulations were observed in the raw EMGs during shivering. The peaks in EMG activity occurred simultaneously in the majority of the monitored muscles in all subjects. Pearson correlations between the average rectified EMGs of 93% of the muscles were significant (P less than 0.05). Visual analysis of the EMG and respiration signals indicated that the peaks in muscular activity occurred 6-12 times/min, whereas respiration ranged from 10 to 23 cycles/min. For all subjects respiration was at a higher frequency than amplitude modulation in the EMG. Comparison of EMG records with expiratory flow rate traces in shivering subjects indicated no one-to-one correlation between the occurrence of respiration and EMG amplitude modulations. Respiratory flow rate and average rectified EMG showed significant correlation in only 33% of the cases. In addition, skin temperature changes could not be correlated with the SAMS.

Adult↗

Shivering and cardiorespiratory responses during normocapnic hypoxia in the pigeon.

To study the inhibitory effect of hypoxia on the cold defense mechanism, pigeons were exposed at low ambient temperature (5 degrees C) to various inhaled gas mixtures: normoxia [0.21 fractional concentration of O2 (FIO2)], hypoxia (0.07 FIO2), and normocapnic hypoxia (0.07 FIO2 + 0.045 FICO2). Electromyographic (EMG) activity indicative of shivering thermogenesis was inhibited during hypoxia, and body temperature (Tre) fell by 0.09 degrees C/min. Respiratory frequency (f) and minute ventilation (VE) increased by 143 and 135%, respectively, compared with normoxia, but tidal volume (VT) was not changed. PO2, PCO2, and O2 contents in the arterial and mixed venous blood were decreased and pH was enhanced. During normocapnic hypoxia, shivering EMG was present at approximately 50% of the normoxic intensity; Tre fell by only 0.04 degrees C/min. Arterial and mixed venous PCO2 and pH were the same as during normoxia, but VE increased by 430% because of twofold increases in both f and VT. During normocapnic hypoxia, arterial PO2 and O2 content were higher than during hypoxia alone. We conclude that the persistence of shivering during normocapnic hypoxia is due to maintenance of critical levels of arterial PO2 and O2 content.

Animals↗

The influence of epidural pethidine on shivering during lower segment caesarean section under epidural anaesthesia.

A prospective study of 94 patients undergoing elective lower segment caesarean section under epidural anaesthesia was performed in order to determine the incidence of shivering and the influence of epidural pethidine. Epidural anaesthesia was established with bupivacaine 0.5% with adrenaline, with or without additional lignocaine 2% with adrenaline, to total 20-25 ml. With the injection of epidural local anaesthesia an extra 5 ml of solution was administered into the epidural space--pethidine 25 mg preservative-free, in normal saline, or normal saline alone. Patient, administering anaesthetist and observer were blinded to the nature of the test substance. Shivering was assessed by an independent observer and subsequently rated by the patient. Other side-effects also recorded were nausea, vomiting, pruritus and drowsiness. The incidence of shivering was 36% in the control (saline) group and 11% in the pethidine group. The difference was highly significant (P less than 0.01). There was no significant difference in the incidence of maternal nausea, vomiting, drowsiness or pruritus, or neonatal Apgar scores. Cord blood samples were assayed for pethidine, revealing low or absent pethidine concentrations.

Adult↗

Single-dose parenteral pharmacological interventions for the prevention of postoperative shivering: a quantitative systematic review of randomized controlled trials.

Shivering is a frequent complication in the postoperative period. The relative efficacy of pharmacological interventions to prevent this phenomenon is not well understood. We performed a systematic search for full reports of randomized comparisons of prophylactic, parenteral, single-dose antishivering interventions with inactive control (placebo or no treatment). Variable doses were converted to fixed doses. Dichotomous data on the absence of shivering were analyzed by using relative benefit (RB) and number needed to treat (NNT) with 95% confidence intervals (CI). Data from 27 trials (1348 adults received an antishivering intervention; 931 were controls) were analyzed. The average incidence of shivering in controls was extremely frequent (52%). Clonidine 65-300 microg (1078 patients), meperidine 12.5-35 mg (250 patients), tramadol 35-220 mg (250 patients), and nefopam 6.5-11 mg (204 patients) were tested in at least 3 trials each. All were more effective than control. For clonidine, meperidine, and nefopam, there was some weak evidence of dose responsiveness. For small-dose clonidine (65-110 microg), the RB compared with control was 1.32 (95% CI, 1.16-1.51); for medium-dose clonidine (140-150 microg), the RB was 1.83 (95% CI, 1.47-2.27); and for large-dose clonidine (220-300 microg), the RB was 1.52 (95% CI, 1.30-1.78). For all clonidine regimens combined, the RB was 1.58 (95% CI, 1.43-1.74), with an NNT of 3.7. For all meperidine regimens combined, the RB was 1.67 (95% CI, 1.37-2.03), with an NNT of 3. For all tramadol regimens combined, the RB was 1.93 (95% CI, 1.56-2.39), with an NNT of 2.2. For all nefopam regimens combined, the RB was 2.62 (95% CI, 2.02-3.40), with an NNT of 1.7. Methylphenidate, midazolam, dolasetron, ondansetron, physostigmine, urapidil, and flumazenil were tested in no more than 3 trials each, with a limited number of patients.

Clonidine↗

Independent risk factors for postoperative shivering.

Postoperative shivering (PAS) is uncomfortable for patients and potentially risky. In this observational trial we sought to identify independent risk factors for PAS after general anesthesia. Potential risk factors for PAS were recorded in 1340 consecutive patients. Signs of shivering, peripheral and core temperature, and thermal comfort were recorded in the postanesthetic care unit. The data were split into an evaluation data set (n = 1000) and a validation data set (n = 340). The first was used to identify independent risk factors for PAS and to formulate a risk score using backward-elimination logistic regression analysis. The proposed model was subsequently tested for its discrimination and calibration properties using receiver operating characteristic (ROC)-curve analysis and linear correlation between the predicted and the actual incidences of PAS in the validation group. The incidence of PAS was 11.6%. There were three major risk factors: young age, endoprosthetic surgery, and core hypothermia, with age being the most important. The risk score derived from this analysis had a reasonable discriminating power, with an area under the ROC-curve of 0.69 (95% confidence interval, 0.60-0.78; P < 0.0001). Furthermore the equation of the calibration curve (y = 0.69x + 6; R2= 0.82; P < 0.05) indicated a good and statistically significant agreement between predicted and actual PAS incidence. Postoperative shivering can be predicted with acceptable accuracy using the four risk factors identified in the present study. The presented model may serve as a clinical tool to help clinicians to rationally administer prophylactic antishivering drugs.

Adult↗

Does shivering thermogenesis enhance the individual's ability to maintain rectal temperature during immersion in cold water?

Shivering thermogenesis may enable individuals to maintain rectal temperature during acute cold exposure. This data analysis revisited this hypothesis and compared previously published data with unpublished data from our laboratory on those subjects that were terminated from cold water immersion early because of a reduction in rectal temperature (T(re)) - 35 degrees C. T(re), mean skin temperature (T(sk)), and oxygen uptake (VO2) were recorded at 5, 30, 60, and 90 min of immersion and were used to calculate 3delta readings for each exposure, that is, deltaT(30) minus T5, T60 minus T(30), and T(90) minus T(60). Single group t-tests were used to examine differences in deltaT(re), deltaT(sk), and deltaVO2 between the published data (PD) group and the individual subjects who were terminated early (TE) at each of three water temperatures (18 degrees C, 22 degrees C, 26 degrees C). For deltaVO2 the TE subjects were dichotomized by fatness (low percent fat, 8%-12%; or high percent fat, 18%-22%) to account for the VO2 differences between these groups (i.e., fatness) during cold water immersion. deltaT(re) was significantly (p < 0.05) decreased in TE subjects compared with PD subjects at all timepoints for 18 degrees C and 26 degrees C. At 22 degrees C, the TE subject exhibited a significantly greater (p < 0.05) decrease in deltaT(re) than the PD group at 90 min of immersion only. No significant (p > 0.05) differences in deltaT(sk) between the PD and TE groups were detected for any of the exposure temperatures over all time points. No difference (p > 0.05) between PD subjects and TE subjects for deltaVO2 was exhibited at any time point at any temperature. It appears that with respect to the TE group, elevations in VO2 were comparable to the PD group, but the TE group was unable to maintain T(re) during cold water immersion. In conclusion, from these data it appears that shivering thermogenesis does in part enhance the individual's ability to maintain T(re); however, as evidenced in the TE group, it also appears that the alterations in shivering thermogenesis for certain individuals may not be great enough to offset heat loss.

Adult↗

Effects of exercise and intermittent cold exposure on shivering and nonshivering thermogenesis in rats.

The effects of both exercise training and intermittent cold acclimation on heat production (shivering and nonshivering thermogenesis (NST)) in rats were studied. Warm-acclimated rats (housed at 24 degrees C, WA) and intermittently cold-acclimated rats (exposed daily to -5 degrees C for 2 h, CA) were forced to run (25 m.min-1 for 1 h) every day (WA-T and CA-T). WA and CA left sedentary (WA-S and CA-S) served as controls. Norepinephrine (NE)-induced thermogenic capacity assessed from the increment of oxygen consumption (VO2) and colonic temperature (Tc) were measured 4 weeks after commencing acclimation and exercise training. The thermogenic capacity was greater in CA than in WA. However, in WA, WA-T responded to NE less than WA-S, whereas the response of CA-T and CA-S did not differ. Wet weight of interscapular brown adipose tissue (IBAT) and its protein (and dry matter--regarded to be highly representative of protein) content were larger in CA than in WA. Respective sedentary and exercised groups of rats had similar IBAT protein (and dry matter) content although tissue weight was lighter in WA-T than in WA-S. Lipid content of IBAT was also larger in CA than in WA. IBAT of WA-T had less lipid compared to that of WA-S while no difference was seen between CA-S and CA-T. Shivering activity during acute cold (4 degrees C) exposure was less in CA compared to WA and there was no difference between respective groups of exercised and sedentary rats. Propranolol, a blocker of NE-dependent NST, eliminated the difference in shivering among these four groups. When exposed to severe cold (-10 or -20 degrees C), the fall in Tc of rats fasted for 18 h was greater in WA than in CA. CA-T showed a greater decrease in Tc than CA-S during -20 degrees C exposure while it did not differ during -10 degrees C exposure. On the other hand, Tc of WA-T and WA-S did not differ significantly during either cold exposure period. These results suggest that exercise training in rats housed at 24 degrees C suppresses NE-dependent NST whereas another nonshivering thermogenic mechanism (NE-independent) may compensate this suppression. However, NE-dependent NST of WA-S and WA-T did not parallel protein (dry matter) content of IBAT; no difference existed in IBAT protein between these two groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Acclimatization↗

Effect of amino acid solutions on intraoperative hypothermia and postoperative shivering. Comparison of two anesthetic regimens.

BACKGROUND: Intraoperative hypothermia is a major adverse effect of general anesthesia. The different anesthetics may influence thermoregulation differently. Proteins or amino acids have been postulated to stimulate heat production. The purpose of this study is to compare the effects of intraoperative administration of amino acid solutions on intraoperative hypothermia and postoperative shivering in two different anesthetic regimens. METHODS: Forty ASA I-III craniotomy patients were assigned to four groups of 10 patients in a randomized prospective study, as follows: ISO - isoflurane-based anesthesia; PRO - propofol-based anesthesia; ISO + AA - Isoflurane-based anesthesia with supplementation of amino acid infusion; PRO + AA - Isoflurane-based anesthesia with supplementation of amino acid infusion. Hemodynamic parameters, esophageal temperature and postoperative shivering scores were recorded. RESULTS: Core temperatures were higher during emergence in amino acid-treated propofol group, compared with the other groups. The core temperature decreased significantly in three groups throughout the operation, except the in amino acid-treated propofol group. The shivering intensity was less in the amino acid-treated groups. CONCLUSION: The anesthetic method may influence the thermic effect of amino acids under general anesthesia. Propofol anesthesia has more thermogenic effect than isoflurane when combined with amino acid solutions.

Amino Acids↗