Takehiko Ikeda

Meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold

Background: Meperidine administration is a more effective treatment for shivering than equianalgesic doses of other opioids. However, it remains unknown whether meperidine also profoundly impairs other thermoregulatory responses, such as sweating or vasoconstriction. Proportional inhibition of vasoconstriction and shivering suggests that the drug acts much like alfentanil and anesthetics but possesses greater thermoregulatory than analgesic potency. In contrast, disproportionate inhibition would imply a special antishivering mechanism. Accordingly, the authors tested the hypothesis that meperidine administration produces a far greater concentration‐dependent reduction in the shivering than vasoconstriction threshold. Methods: Nine volunteers were each studied on three days: 1) control (no opioid); 2) a target total plasma meperidine concentration of 0.6 micro gram/ml (40 mg/h); and 3) a target concentration of 1.8 micro gram/ml (120 mg/h). Each day, skin and core temperatures were increased to provoke sweating and then subsequently reduced to elicit vasoconstriction and shivering. Core‐temperature thresholds (at a designated skin temperature of 34 degrees Celsius) were computed using established linear cutaneous contributions to control sweating (10%) and vasoconstriction and shivering (20%). The dose‐dependent effects of unbound meperidine on thermoregulatory response thresholds was then determined using linear regression. Results are presented as means +/‐ SDs. Results: The unbound meperidine fraction was [nearly equal] 35%. Meperidine administration slightly increased the sweating threshold (0.5 +/‐ 0.8 degrees Celsius [center dot] micro gram sup ‐1 [center dot] ml; r2 = 0.51 +/‐ 0.37) and markedly decreased the vasoconstriction threshold (‐3.3 +/‐ 1.5 degrees Celsius [center dot] micro gram sup ‐1 [center dot] ml; r sup 2 = 0.92 +/‐ 0.08). However, meperidine reduced the shivering threshold nearly twice as much as the vasoconstriction threshold (‐6.1 +/‐ 3.0 degrees Celsius [center dot] micro gram sup ‐1 [center dot] ml; r2 = 0.97 +/‐ 0.05; P = 0.001). Conclusions: The special antishivering efficacy of meperidine results at least in part from an uncharacteristically large reduction in the shivering threshold rather than from exaggerated generalized thermoregulatory inhibition. This pattern of thermoregulatory impairment differs from that produced by alfentanil, clonidine, propofol, and the volatile anesthetics, all which reduce the vasoconstriction and shivering thresholds comparably.

Comparison of the Effect-site keOs of Propofol for Blood Pressure and EEG Bispectral Index in Elderly and Younger Patients

BACKGROUND Drug effect lags behind the blood concentration. The goal of this investigation was to determine the time course of plasma concentration and the effects of propofol demonstrated by electroencephalogram or blood pressure changes and to compare them between elderly and young or middle-aged patients. METHODS A target-controlled infusion was used to rapidly attain and maintain four sequentially increasing, randomly selected plasma propofol concentrations from 1 to 12 microg/ml in 41 patients aged 20-85 yr. The target concentration was maintained for about 30 min. Bispectral index (BIS), spectral edge frequency, and systolic blood pressure (SBP) were used as measures of propofol effect. Because the time courses of these measures following the started drug infusion showed an exponential pattern, the first-order rate constant for equilibration of the effect site with the plasma concentration (k(eO)) was estimated by fitting a monoexponential model to the effect versus time data resulting from the pseudo-steady-state propofol plasma concentration profile. RESULTS The half-times for the plasma-effect-site equilibration for BIS were 2.31, 2.30, 2.29, and 2.37 min in patients aged 20-39, 40-59, 60-69, and 70-85 yr, respectively (n = 10 or 11 each). The half-times for SBP were 5.68, 5.92, 8.87, and 10.22 min in the respective age groups. All were significantly longer than for BIS (P < 0.05). The propofol concentration at half of the maximal decrease of SBP was significantly greater (P < 0.05) in the elderly than in the younger patients. CONCLUSIONS The effect of propofol on BIS occurs more rapidly than its effect on SBP. Age has no effect on the rate of BIS reduction with increasing propofol concentration, whereas with increasing age, SBP decreases to a greater degree but more slowly.

Local radiant heating increases subcutaneous oxygen tension

BACKGROUND We evaluated a novel bandage that incorporates a thermostatically controlled radiant heater. We first determined optimal bandage temperature, based on increases in subcutaneous oxygen tension, a measure correlating well with resistance to infection and wound strength. We then tested the hypothesis that prolonged radiant heating would increase collagen deposition in experimental thigh wounds. METHODS The experimental bandages were positioned on the anterior thigh of 8 volunteers, and heated for 2 hours at 38 degrees C, 42 degrees C, or 46 degrees C, in a random order. Subcutaneous oxygen tension under the bandage was recorded from an electrode positioned within a subcutaneous tonometer. We studied 10 volunteers in the second protocol. For 1 week, the experimental bandage was continuously applied to one thigh, and heated to 38 degrees C using a 2-hour on/off cycle. On the alternate week, a standard gauze bandage was applied to the contralateral thigh. Treatment order was randomly assigned. Wound collagen deposition under each bandage was evaluated with subcutaneous polytetrafluoroethylene tubes, which were removed and assayed for hydroxyproline on the eighth day. Data are presented as means +/- SDs. RESULTS Skin temperature during heating ranged from 36 degrees C to 37.5 degrees C. Oxygen tension increased approximately 50% during heating, but the increase was comparable at the three tested temperatures. Even after heating was discontinued, subcutaneous oxygen tension remained elevated for the remaining 3 study hours. Collagen deposition after 1 week of active heating was 3.4 +/- 1.0 microg/ cm. After 1 week of control treatment, collagen deposition was 3.2 +/- 1.1 microg/cm (P = not significant). CONCLUSIONS Our data suggest that radiant heating at 38 degrees C significantly increases subcutaneous oxygen tension, and presumably resistance to infection. However, prolonged heating at this temperature does not increase wound collagen deposition.

Induction of anesthesia with ketamine reduces the magnitude of redistribution hypothermia.

Hypothermia after induction of general anesthesia results largely from core-to-peripheral redistribution of body heat. Both central inhibition of tonic thermoregulatory vasoconstriction in arteriovenous shunts and anesthetic-induced arteriolar and venous dilation contribute to this redistribution. Ketamine, unique among anesthetics, increases peripheral arteriolar resistance; in contrast, propofol causes profound venodilation that other anesthetics do not. We therefore tested the hypothesis that induction of anesthesia with ketamine causes less core hypothermia than induction with propofol. Twenty patients undergoing elective surgery were randomly assigned to anesthetic induction with either 1.5 mg/kg ketamine (n = 10) or 2.5 mg/kg propofol (n = 10). Anesthesia in both groups was subsequently maintained with sevoflurane and 60% nitrous oxide in oxygen. Forearm minus finger, skin-temperature gradients <0°C were considered indicative of significant arteriovenous shunt vasodilation. Ketamine did not cause vasodilation just after induction, whereas propofol rapidly induced vasodilation. Core temperatures in the patients given ketamine remained significantly greater than those in the patients induced with propofol. These data suggest that maintaining vasoconstriction during induction of anesthesia reduces the magnitude of redistribution hypothermia.

Optimal propofol plasma concentration during upper gastrointestinal endoscopy in young, middle-aged, and elderly patients.

BACKGROUND Suitable propofol plasma concentrations during gastroscopy have not been determined for suppressing somatic and hemodynamic responses in different age groups. METHODS Propofol sedation at target plasma concentrations from 0.5 to 4.0 microgram/ml were performed randomly in three groups of patients (23 per group) who were undergoing elective outpatient gastroscopy: ages 17-49 yr (group 1), 50-69 yr (group 2), and 70-89 yr (group 3). Plasma propofol concentration in which 50% of patients do not respond to these different stimuli were determined by logistic regression: verbal command (Cp50ls), somatic response to gastroscopy (Cp50endo), and gag response to gastroscopy (Cp50gag). Hemodynamic responses were also investigated in the different age groups. RESULTS Cp50ls concentrations were 2.23 microgram/ml (group 1), 1.75 microgram/ml (group 2), and 1.40 microgram/ml (group 3). The Cp50endo values in groups 1 and 2 were 2.87 and 2.34 microgram/ml, respectively, which were significantly higher than their respective Cp50ls values. Cp50endo value in group 3 was 1.64 microgram/ml, which was close to its Cp50ls value. Because of a high degree of interpatient variability, Cp50gag could not be defined. Systolic blood pressure response decreased with increasing propofol concentrations. CONCLUSIONS The authors determined the propofol concentration necessary for gastroscopy and showed that increasing age reduces it. Propofol concentration that suppresses somatic response induces loss of consciousness in almost all young patients.

Influence of Thermoregulatory Vasomotion and Ambient Temperature Variation on the Accuracy of Core-temperature Estimates by Cutaneous Liquid-crystal Thermometers

Background Recently, liquid crystal skin‐surface thermometers have become popular for intraoperative temperature monitoring. Three situations during which cutaneous liquid‐crystal thermometry may poorly estimate core temperature were monitored: (1) anesthetic induction with consequent core‐to‐peripheral redistribution of body heat, (2) thermoregulatory vasomotion associated with sweating (precapillary dilation) and shivering (minimal capillary flow), and (3) ambient temperature variation over the clinical range from 18–26 degrees Celsius. Methods The core‐to‐forehead and core‐to‐neck temperature difference was measured using liquid‐crystal thermometers having an [nearly equal] 2 degrees Celsius offset. Differences exceeding 0.5 degrees Celsius (a 1 degree Celsius temperature range) were a priori deemed potentially clinically important. Seven volunteers participated in each protocol. First, core‐to‐peripheral redistribution of body heat was produced by inducing propofol/desflurane anesthesia; anesthesia was then maintained for 1 h with desflurane. Second, vasodilation was produced by warming unanesthetized volunteers sufficiently to produce sweating; intense vasoconstriction was similarly produced by cooling the volunteers sufficiently to produce shivering. Third, a canopy was positioned to enclose the head, neck, and upper chest of unanesthetized volunteers. Air within the canopy was randomly set to 18, 20, 22, 24, and 26 degrees Celsius. Results Redistribution of body heat accompanying induction of anesthesia had little effect on the core‐to‐forehead skin temperature difference. However, the core‐to‐neck skin temperature gradient decreased [nearly equal] 0.6 degrees Celsius in the hour after induction of anesthesia. Vasomotion associated with shivering and mild sweating altered the core‐to‐skin temperature difference only a few tenths of a degree centigrade. The absolute value of the core‐to‐forehead temperature difference exceeded 0.5 degrees Celsius during [nearly equal] 35% of the measurements, but the difference rarely exceeded 1 degree Celsius. The core‐to‐neck temperature difference typically exceeded 0.5 degrees Celsius and frequently exceeded 1 degree Celsius. Each 1 degree Celsius increase in ambient temperature decreased the core‐to‐forehead and core‐to‐neck skin temperature differences by less than 0.2 degree Celsius. Conclusions Forehead skin temperatures were better than neck skin temperature at estimating core temperature. Core‐to‐neck temperature differences frequently exceeded 1 degree Celsius (a 2 degrees Celsius range), whereas two thirds of the core‐to‐forehead differences were within 0.5 degrees Celsius. The core‐to‐skin temperature differences were, however, only slightly altered by inducing anesthesia, vasomotor action, and typical intraoperative changes in ambient temperature.

Investigation of effective anesthesia induction doses using a wide range of infusion rates with undiluted and diluted propofol.

Background: The influence of infusion rate on the induction dose–response relation has not been investigated over a wide range of infusion rates. In this study, the authors defined the effect of different propofol infusion rates on the times and doses necessary to reach clinical induction of anesthesia. Methods: The subjects of the study were 250 patients classified as American Society of Anesthesiologists physical status I or II aged 25–55 yr. For induction with undiluted propofol, 180 patients were allocated randomly to one of two groups of 90 patients each (A and B). Each group was further divided into nine subgroups (10 patients each) that were administered propofol infusion at rates of 10, 15, 20, 30, 40, 60, 100, 200, and 300 mg · kg−1 · h−1. The remaining 70 patients (group C) were allocated randomly into seven subgroups (10 patients each), and these groups were induced with diluted propofol (0.5 mg/ml) at the rates of 10, 15, 30, 60, 100, 200, and 300 mg · kg−1 · h−1. Group B was given crystalloid at the same infusion rates as group C via a catheter in the opposite arm. Induction time, induction dose, plasma arterial propofol concentration at loss of consciousness, and percentage decrease of systolic blood pressure were measured. A previously reported three-compartment model with an effect-site rate constant for propofol of 0.456/min was used to predict the induction time and dose at each infusion rate. Results: The differences between predicted induction time and dose and the observed time and dose could be explained by factoring in the lag time from infusion site to central compartment (lag timecirculation) and the amount of propofol in transit during this time (residual dosecirculation). Residual dosecirculation and lag timecirculation correlated with infusion time from 20 to 60 s for undiluted and from 0 to 40 s for diluted propofol. At the infusion rates greater than 80 mg · kg−1 · h−1, rapid circulation because of incomplete mixing in the central compartment decreased the excess induction time and dose. The use of diluted propofol significantly attenuated the decrease in systolic blood pressure provoked by the residual dosecirculation. Conclusions: Induction dose and time are dependent on infusion rate in a complex manner, and residual dosecirculation was a factor in overdose and hemodynamic depression. Hypotension during induction was attenuated by diluted propofol.

Less Core hypothermia when anesthesia is induced with inhaled sevoflurane than with intravenous propofol

UNLABELLED Hypothermia after the induction of anesthesia results initially from core-to-peripheral redistribution of body heat. Sevoflurane and propofol both inhibit central thermoregulatory control, thus causing vasodilation. Propofol differs from sevoflurane in producing substantial peripheral vasodilation. This vasodilation is likely to facilitate core-to-peripheral redistribution of heat. Once heat is dissipated from the core, it cannot be recovered. We therefore tested the hypothesis that the induction of anesthesia with i.v. propofol causes more core hypothermia than induction with inhaled sevoflurane. We studied patients undergoing minor oral surgery randomly assigned to anesthetic induction with either 2.5 mg/kg propofol (n = 10) or inhalation of 5% sevoflurane (n = 10). Anesthesia in both groups was subsequently maintained with sevoflurane and 60% nitrous oxide in oxygen. Calf minus toe skin temperature gradients <0 degrees C were considered indicative of significant vasodilation. Ambient temperature and end-tidal concentrations of maintenance sevoflurane were comparable in each group. Patients in both groups were vasodilated throughout most of the surgery. Nonetheless, core temperatures in patients who received propofol were significantly lower than those in patients who received inhaled sevoflurane. These data support our hypothesis that even a brief period of vasodilation causes substantial redistribution hypothermia that persists throughout surgery. IMPLICATIONS Core temperatures in patients who received i.v. propofol were consistently lower than those in patients who received inhaled sevoflurane, although anesthesia was subsequently maintained with sevoflurane in nitrous oxide in both groups. This suggests that even a brief period of propofol-induced vasodilation during anesthetic induction causes substantial redistribution hypothermia that persists throughout surgery.

Postanesthetic vasoconstriction slows peripheral-to-core transfer of cutaneous heat, thereby isolating the core thermal compartment

Forced-air warming during anesthesia increases core temperature comparably with and without thermoregulatory vasoconstriction. In contrast, postoperative forced-air warming may be no more effective than passive insulation. Nonthermoregulatory anesthesia-induced vasodilation may thus influence heat transfer. We compared postanesthetic core rewarming rates in volunteers given cotton blankets or forced air. Additionally, we compared increases in peripheral and core heat contents in the postanesthetic period with data previously acquired during anesthesia to determine how much vasomotion alters intercompartmental heat transfer. Six men were anesthetized and cooled passively until their core temperatures reached 34 [degree sign] C. Anesthesia was then discontinued, and shivering was prevented by giving meperidine. On one day, the volunteers were covered with warmed blankets for 2 h; on the other, volunteers were warmed with forced air. Peripheral tissue heat contents were determined from intramuscular and skin thermocouples. Predicted changes in core temperature were calculated assuming that increases in body heat content were evenly distributed. Predicted changes were thus those that would be expected if vasomotor activity did not impair peripheral-to-core transfer of applied heat. These results were compared with those obtained previously in a similar study of anesthetized volunteers. Body heat content increased 159 +/- 35 kcal (mean +/- SD) more during forced-air than during blanket warming (P < 0.001). Both peripheral and core temperatures increased significantly faster during active warming: 3.3 +/- 0.7[degree sign]C and 1.1 +/- 0.4[degree sign]C, respectively. Nonetheless, predicted core temperature increase during forced-air warming exceeded the actual temperature increase by 0.8 +/- 0.3[degree sign]C (P < 0.001). Vasoconstriction thus isolated core tissues from heat applied to the periphery, with the result that core heat content increased 32 +/- 12 kcal less than expected after 2 h of forced-air warming (P < 0.001). In contrast, predicted and actual core temperatures differed only slightly in the anesthetized volunteers previously studied. In contrast to four previous studies, our results indicate that forced-air warming increases core temperature faster than warm blankets. Postanesthetic vasoconstriction nonetheless impeded peripheral-to-core heat transfer, with the result that core temperatures in the two groups differed less than might be expected based on systemic heat balance estimates. Implications: Comparing intercompartmental heat flow in our previous and current studies suggests that anesthetic-induced vasodilation influences intercompartmental heat transfer and distribution of body heat more than thermoregulatory shunt vasomotion. (Anesth Analg 1997;85:899-906)

Meperidine and alfentanil do not reduce the gain or maximum intensity of shivering.

Background Thermoregulatory shivering can be characterized by its threshold (triggering core temperature), gain (incremental intensity increase with further core temperature deviation), and maximum intensity. Meperidine (a combined micro‐ and kappa‐agonist) treats shivering better than equianalgesic doses of pure micro‐opioid agonists. Meperidines special antishivering action is mediated, at least in part, by a disproportionate decrease in the shivering threshold. That is, meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold, whereas alfentanil (a pure micro‐agonist) decreases the vasoconstriction and shivering thresholds comparably. However, reductions in the gain or maximum shivering intensity might also contribute to the clinical efficacy of meperidine. Accordingly, we tested the hypothesis that meperidine reduces the gain and maximum intensity of shivering much more than alfentanil does. Methods Ten volunteers were each studied on three separate days: (1) control (no drug); (2) a target total plasma meperidine concentration of 1.2 micro gram/ml; and (3) a target plasma alfentanil concentration of 0.2 micro gram/ml. Skin temperatures were maintained near 31 [degree sign] Celsius, and core temperatures were decreased by central‐venous infusion of cold lactated Ringers solution until maximum shivering intensity was observed. Shivering was evaluated using oxygen consumption and electromyography. A sustained increase in oxygen consumption identified the shivering threshold. The gain of shivering was calculated as the slope of the oxygen consumption versus core temperature regression, and as the slope of electromyographic intensity versus core temperature regression. Results Meperidine and alfentanil administration significantly decreased the shivering thresholds. However, neither meperidine nor alfentanil reduced the gain of shivering, as determined by either oxygen consumption or electromyography. Opioid administration also failed to significantly decrease the maximum intensity of shivering. Conclusions The authors could not confirm the hypothesis that meperidine reduces the gain or maximum intensity of shivering more than alfentanil does. These results suggest that meperidines special antishivering effect is primarily mediated by a disproportionate reduction in the shivering threshold.