Propofol Linearly Reduces the Vasoconstriction and Shivering Thresholds

Background: Skin temperature is best kept constant when determining response thresholds because both skin and core temperatures contribute to thermoregulatory control. In practice, however, it is difficult to evaluate both warm and cold thresholds while maintaining constant cutaneous temperature. A recent study shows that vasoconstriction and shivering thresholds are a linear function of skin and core temperatures, with skin contributing 20 plus/minus 6% and 19 plus/minus 8%, respectively. (Skin temperature has long been known to contribute [nearly equal] 10% to the control of sweating.) Using these relations, we were able to experimentally manipulate both skin and core temperatures, subsequently compensate for the changes in skin temperature, and finally report the results in terms of calculated core- temperature thresholds at a single designated skin temperature.

Methods: Five volunteers were each studied on 4 days: (1) control; (2) a target blood propofol concentration of 2 micro gram/ml; (3) a target concentration of 4 micro gram/ml; and (4) a target concentration of 8 micro gram/ml. On each day, we increased skin and core temperatures sufficiently to provoke sweating. Skin and core temperatures were subsequently reduced to elicit peripheral vasoconstriction and shivering. We mathematically compensated for changes in skin temperature by using the established linear cutaneous contributions to the control of sweating (10%) and to vasoconstriction and shivering (20%). From these calculated core-temperature thresholds (at a designated skin temperature of 35.7 degrees Celsius), the propofol concentration- response curves for the sweating, vasoconstriction, and shivering thresholds were analyzed using linear regression. We validated this new method by comparing the concentration-dependent effects of propofol with those obtained previously with an established model.

Results: The concentration-response slopes for sweating and vasoconstriction were virtually identical to those reported previously. Propofol significantly decreased the core temperature triggering vasoconstriction (slope = 0.6 plus/minus 0.1 degree Celsius *symbol* micro gram sup -1 *symbol* ml sup -1; r2 = 0.98 plus/minus 0.02) and shivering (slope = 0.7 plus/minus 0.1 degree Celsius *symbol* micro gram sup -1 *symbol* ml sup -1; r2 = 0.95 plus/minus 0.05). In contrast, increasing the blood propofol concentration increased the sweating threshold only slightly (slope = 0.1 plus/minus 0.1 degree Celsius *symbol* micro gram sup -1 *symbol* ml sup -1; r2 = 0.46 plus/minus 0.39).     

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).     

Isoflurane Produces Marked and Nonlinear Decreases in the Vasoconstriction and Shivering Thresholds

Background: Desflurane decreases the vasoconstriction and shivering thresholds disproportionately at high anesthetic concentrations. This result contrasts with the authors' previous report that isoflurane decreases the vasoconstriction threshold linearly. It is surprising that the basic shape of the concentration-response curve should differ with these two otherwise similar anesthetics. Therefore, the hypothesis that isoflurane produces a nonlinear reduction in the vasoconstriction threshold was tested. Because the effect of isoflurane on shivering remains unknown, the extent to which isoflurane reduces the shivering threshold also was determined.

Methods: Eight men volunteered to be studied on four randomly ordered days: (1) a target end-tidal isoflurane concentration of 0.55%, (2) a target concentration of 0.7%, (3) control (no anesthesia) and a target end-tidal concentration of 0.85%, and (4) a target end-tidal concentration of 1.0%. Volunteers were surface-cooled until peripheral vasoconstriction and shivering were observed. We arithmetically compensated for changes in skin temperature using the established linear cutaneous contributions to control for each response. From the calculated thresholds (core temperatures triggering responses at a designated skin temperature of 34 degrees C), the concentration-response relation was determined.

Results: Isoflurane administration produced a dose-dependent reduction in the vasoconstriction and shivering thresholds, decreasing each [nearly equal] 4.6 degrees C at an end-tidal concentration of 1%. Residual analysis indicated that the vasoconstriction and shivering thresholds were decreased in a nonlinear fashion during isoflurane administration. The vasoconstriction-to-shivering range was 1.5+/- 0.8 degree C without isoflurane, and did not change significantly during isoflurane administration.     

Increasing Mean Skin Temperature Linearly Reduces the Core- temperature Thresholds for Vasoconstriction and Shivering in Humans

Background: The contribution of mean skin temperature to the thresholds for sweating and active precapillary vasodilation has been evaluated in numerous human studies. In contrast, the contribution of skin temperature to the control of cold responses such as arteriovenous shunt vasoconstriction and shivering is less well established. Accordingly, the authors tested the hypothesis that mean skin and core temperatures are linearly related at the vasoconstriction and shivering thresholds in men. Because the relation between skin and core temperatures might vary by gender, the cutaneous contribution to thermoregulatory control also was determined in women.

Methods: In the first portion of the study, six men participated on 5 randomly ordered days, during which mean skin temperatures were maintained near 31, 34, 35, 36, and 37 degrees Celsius. Core hypothermia was induced by central venous infusion of cold lactated Ringer's solution sufficient to induce peripheral vasoconstriction and shivering. The core-temperature thresholds were then plotted against skin temperature and a linear regression fit to the values. The relative skin and core contributions to the control of each response were calculated from the slopes of the regression equations. In the second portion of the study, six women participated on three randomly ordered days, during which mean skin temperatures were maintained near 31, 35, and 37 degrees Celsius. At each designated skin temperature, core hypothermia sufficient to induce peripheral vasoconstriction and/or shivering was again induced by central venous infusion of cold lactated Ringer's solution. The cutaneous contributions to control of each response were then calculated from the skin- and core-temperature pairs at the vasoconstriction and shivering thresholds.

Results: There was a linear relation between mean skin and core temperatures at the response thresholds in the men: r = 0.90 plus/minus 0.06 for vasoconstriction and r = 0.94 plus/minus 0.07 for shivering. Skin temperature contributed 20 plus/minus 6% to vasoconstriction and 19 plus/minus 8% to shivering. Skin temperature in the women contributed to 18 plus/minus 4% to vasoconstriction and 18 plus/minus 7% to shivering, values not differing significantly from those in men. There was no apparent correlation between the cutaneous contributions to vasoconstriction and shivering in individual volunteers.     

The effect of Pyrogen Administration on Sweating and Vasoconstriction Thresholds during Desflurane Anesthesia

Background: General anesthetics increase the sweating-to-vasoconstriction interthreshold range (temperatures not triggering thermoregulatory defenses), whereas fever is believed to only increase the setpoint (target core temperature). However, no data characterize thresholds (temperatures triggering thermoregulatory defenses) during combined anesthesia and fever. Most likely, the combination produces an expanded interthreshold range around an elevated setpoint. The authors therefore tested the hypothesis that thermoregulatory response thresholds during the combination of fever and anesthesia are simply the linear combination of the thresholds resulting from each intervention alone.

Methods: The authors studied eight healthy male volunteers. Fever was induced on the appropriate days by intravenous injection of 30 IU/g human recombinant interleukin 2 (IL-2), followed 2 h later by an additional 70 IU/g. General anesthesia consisted of desflurane 0.6 minimum alveolar concentration (MAC). The volunteers were randomly assigned to the following groups: (1) control (no desflurane, no IL-2); (2) IL-2 alone; (3) desflurane alone; and (4) desflurane plus IL-2. During the fever plateau, volunteers were warmed until sweating was observed and then cooled to vasoconstriction. Sweating was evaluated from a ventilated capsule and vasoconstriction was quantified by volume plethysmography. The tympanic membrane temperatures triggering significant sweating and vasoconstriction identified the respective response thresholds. Data are presented as the mean +/- SD; P < 0.05 was considered significant.

Results: The interthreshold range was near 0.4[degree sign]C on both the control day and during IL-2 administration alone. On the IL-2 alone day, however, the interthreshold range was shifted to higher temperatures. The interthreshold range increased significantly during desflurane anesthesia to 1.9 +/- 0.6[degree sign]C. The interthreshold range during the combination of desflurane and IL-2 was 1.2 +/- 0.6[degree sign]C, which was significantly greater than on the control and IL-2 alone days. However, it was also significantly less than during desflurane alone.     

Relative Contribution of Skin and Core Temperatures to Vasoconstriction and Shivering Thresholds during Isoflurane Anesthesia

Background: Thermoregulatory control is based on both skin and core temperatures. Skin temperature contributes [approximate] 20% to control of vasoconstriction and shivering in unanesthetized humans. However, this value has been used to arithmetically compensate for the cutaneous contribution to thermoregulatory control during anesthesia-although there was little basis for assuming that the relation was unchanged by anesthesia. It even remains unknown whether the relation between skin and core temperatures remains linear during anesthesia. We therefore tested the hypothesis that mean skin temperature contributes [approximate] 20% to control of vasoconstriction and shivering, and that the contribution is linear during general anesthesia.

Methods: Eight healthy male volunteers each participated on 3 separate days. On each day, they were anesthetized with 0.6 minimum alveolar concentrations of isoflurane. They then were assigned in random order to a mean skin temperature of 29, 31.5, or 34 [degree sign]C. Their cores were subsequently cooled by central-venous administration of fluid at [almost equal to] 3 [degree sign]C until vasoconstriction and shivering were detected. The relation between skin and core temperatures at the threshold for each response in each volunteer was determined by linear regression. The proportionality constant was then determined from the slope of this regression. These values were compared with those reported previously in similar but unanesthetized subjects.

Results: There was a linear relation between mean skin and core temperatures at the vasoconstriction and shivering thresholds in each volunteer: r2 = 0.98 +/- 0.02 for vasoconstriction, and 0.96 +/- 0.04 for shivering. The cutaneous contribution to thermoregulatory control, however, differed among the volunteers and was not necessarily the same for vasoconstriction and shivering in individual subjects. Overall, skin temperature contributed 21 +/- 8% to vasoconstriction, and 18 +/- 10% to shivering. These values did not differ significantly from those identified previously in unanesthetized volunteers: 20 +/- 6% and 19 +/- 8%, respectively.     

Cholesterol, But Not Cigarette Smoke, Decreases Rabbit Carotid Artery Relaxation

−3 molar norepinephrine (NE) while the experimental ring was contracted to 50% of maximum. Relaxation of the rings was achieved by adding incremental doses of acetylcholine. Our results showed that endothelial dysfunction, as measured by acetylcholine-mediated vasorelaxation, occurs in the rabbit carotid artery when exposed to high dietary cholesterol. Cigarette exposure alone in this particular vessel did not result in significant alteration in acetylcholine-mediated vasorelaxation.     

Dilution of Spinal Lidocaine Does Not Alter the Incidence of Transient Neurologic Symptoms

Background: Although it has been suggested that the dilution of 5% hyperbaric lidocaine before injection for spinal anesthesia may decrease the incidence of transient neurologic symptoms, previous studies have not noted a decreased incidence between 5% and 2% lidocaine. The aim of the current study was to determine whether the incidence of transient neurologic symptoms could be altered by further diluting spinal lidocaine from 2.0% to 0.5%.

Methods: One hundred nine patients with American Society of Anesthesiologist physical status 1 or 2 undergoing outpatient knee arthroscopy were randomized in a double-blind fashion to receive 50 mg hyperbaric spinal lidocaine as a 2.0%, 1.0%, or 0.5% concentration. On the third postoperative day, patients were contacted by a blinded investigator and questioned regarding the incidence of postoperative complications, including transient neurologic symptoms, defined as pain or dysthesia in one or both buttocks or legs occurring within 24 h of surgery.

Results: The incidence of transient neurologic symptoms did not differ among patients receiving 2.0% (incidence of 15.8%), 1.0% (incidence of 22.2%), and 0.5% (incidence of 17.1%) lidocaine (P = 0.756).     

Experimental Folate and Vitamin B12 Deficiency Does Not Alter Bone Quality in Rats

Hyperhomocysteinemia (HHCY) has been linked to fragility fractures and osteoporosis. Folate and vitamin B₁₂ deficiencies are among the main causes of HHCY. However, the impact of these vitamins on bone health has been poorly studied. This study analyzed the effect of folate and vitamin B₁₂ deficiency on bone in rats. We used two groups of rats: a control group (Co, n = 10) and a vitamin‐deficient group (VitDef, n = 10). VitDef animals were fed for 12 wk with a folate‐ and vitamin B₁₂–free diet. Co animals received an equicaloric control diet. Tissue and plasma concentrations of homocysteine (HCY), S‐adenosyl‐homocysteine (SAH), and S‐adenosyl‐methionine (SAM) were measured. Bone quality was assessed by biomechanical testing (maximum force of an axial compression test; F_max), histomorphometry (bone area/total area; B.Ar./T.Ar.], and the measurement of biochemical bone turnover markers (osteocalcin, collagen I C‐terminal cross‐laps [CTX]). VitDef animals developed significant HHCY (Co versus VitDef: 6.8 ± 2.7 versus 61.1 ± 12.8 μM, p < 0.001) that was accompanied by a high plasma concentration of SAH (Co versus VitDef: 24.1 ± 5.9 versus 86.4 ± 44.3 nM, p < 0.001). However, bone tissue concentrations of HCY, SAH, and SAM were similar in the two groups. Fmax, B.Ar./T.Ar., OC, and CTX did not differ between VitDef and Co animals, indicating that bone quality was not affected. Folate and vitamin B₁₂ deficiency induces distinct HHCY but has no effect on bone health in otherwise healthy adult rats. The unchanged HCY metabolism in bone is the most probable explanation for the missing effect of the vitamin‐free diet on bone.     

Rituximab, Anti-CD20, Induces In Vivo Cytokine Release But Does Not Impair Ex Vivo T-Cell Responses

Pre-formed HLA antibodies (Ab), reported as panel-reactive antibody (PRA), prolong transplant waiting time. We hypothesized that rituximab (RIT) could reduce PRA via B-cell depletion. As part of a Phase I study of single RIT dose, we studied in vivo and ex vivo effects on T-cell immune responses. Nine subjects (n = 3) were treated at 50, 150, and 375 mg/m(2). Serum interleukin-1alpha (IL-1alpha), IL-6, IL-12, tumor necrosis factor beta (TNF-beta), and interferon-gamma (IFN-gamma) were measured by enzyme-linked immunosorbent assay (ELISA). T-cell function was monitored with T-cell proliferation assays. IL-6 levels rose in eight patients (7.15 +/- 4.38 pg/mL to 86.22 +/- 77.08, p = 0.021). The high-dose group had detectable TNF-betapost rituximab infusion (874.7 +/- 1466.5 pg/mL). There was no decline in T-cell proliferation in response to phytohemagglutinin or allogeneic lymphocyte stimuli. Stimulation indices in the presence of both concentrations of tetanus toxoid rose significantly at 4 weeks.     

Nefopam, a Nonsedative Benzoxazocine Analgesic, Selectively Reduces the Shivering Threshold in Unanesthetized Subjects

Background: The analgesic nefopam does not compromise ventilation, is minimally sedating, and is effective as a treatment for postoperative shivering. The authors evaluated the effects of nefopam on the major thermoregulatory responses in humans: sweating, vasoconstriction, and shivering.

Methods: Nine volunteers were studied on three randomly assigned days: (1) control (saline), (2) nefopam at a target plasma concentration of 35 ng/ml (low dose), and (3) nefopam at a target concentration of 70 ng/ml (high dose, approximately 20 mg total). Each day, skin and core temperatures were increased to provoke sweating and then reduced to elicit peripheral vasoconstriction and shivering. The authors determined the thresholds (triggering core temperature at a designated skin temperature of 34[degrees]C) by mathematically compensating for changes in skin temperature using the established linear cutaneous contributions to control of each response.

Results: Nefopam did not significantly modify the slopes for sweating (0.0 +/- 4.9[degrees]C [middle dot] [mu]g-1 [middle dot] ml; r2 = 0.73 +/- 0.32) or vasoconstriction (-3.6 +/- 5.0[degrees]C [middle dot] [mu]g-1 [middle dot] ml; r2 = -0.47 +/- 0.41). In contrast, nefopam significantly reduced the slope of shivering (-16.8 +/- 9.3[degrees]C [middle dot] [mu]g-1 [middle dot] ml; r2 = 0.92 +/- 0.06). Therefore, high-dose nefopam reduced the shivering threshold by 0.9 +/- 0.4[degrees]C (P < 0.001) without any discernible effect on the sweating or vasoconstriction thresholds.     

Interleukin-18 Affects Local Cytokine Expression But Does Not Impact on the Development of Kidney Allograft Rejection

Interleukin-18 is predominantly a macrophage-derived cytokine with a key role in inflammation and cell-mediated immunity. Having previously demonstrated IL-18 upregulation in a rat model of kidney rejection, here we examined IL-18 in a fully MHC-mismatched murine model of acute kidney rejection using IL-18-deficient recipients (IL-18-/-) and animals administered neutralizing IL-18 binding protein (IL-18BP). Gene expression of IL-18 and its receptor were significantly upregulated in allografts compared to isografts, as was the cellular infiltrate (T cells and macrophages) (p < 0.001). Allografts developed kidney dysfunction (p < 0.05) and tubulitis (p < 0.01) not observed in controls. There was a significant reduction in gene expression of IL-18 downstream pro-inflammatory molecules (iNOS, TNFalpha and IFNgamma) in IL-18-/- recipients (p < 0.01), and IL-18BP-treated animals. The CD4+ infiltrate and IL-4 mRNA expression was greater in the IL-18-/- recipients than wild-type (WT) allografts and IL-18BP-treated animals (p < 0.05), suggesting a Th2-bias which was supported by IFNgamma and IL-4 ELISPOT data and an increased eosinophil accumulation (p < 0.001). Neither IL-18 deficiency nor neutralization prevented renal dysfunction or tubulitis. This study demonstrates increased production of IL-18 in murine kidney allograft rejection and provides evidence that IL-18-induced pathways of inflammation are active. However, neither IL-18 deficiency nor neutralization was protective against the development of allograft rejection.     

The Effects of Meperidine and Sufentanil on the Shivering Threshold in Postoperative Patients

Background: Meperidine (pethidine) reportedly treats postoperative shivering better than equianalgesic doses of other [micro sign]-receptor agonists. The authors' first goal was to develop a method to accurately determine postoperative shivering threshold, and then to determine the extent to which meperidine and sufentanil inhibit postoperative shivering.

Methods: A computer-controlled infusion was started before operation in 30 patients, with target plasma concentrations of 0.15, 0.30, or 0.60 [micro sign]g/ml meperidine or 0.1, 0.15, or 0.2 ng/ml sufentanil targeted; patients were randomly assigned to each drug and concentration. The infusion was continued throughout surgery and recovery. Anesthesia was maintained with nitrous oxide and isoflurane. Core temperatures were [almost equal to] 34 [degree sign]C by the end of surgery. The compensated core temperature at which visible shivering and a 20% decrease in steady-state oxygen consumption was recorded identified the shivering threshold. A blood sample for opioid concentration was obtained from each patient at this time. The ability of each opioid to reduce the shivering threshold was evaluated using linear regression.

Results: End-tidal isoflurane concentrations were <0.2% in each group at the time of extubation, and shivering occurred [almost equal to] 1 h later. Meperidine linearly decreased the shivering threshold: threshold ([degree sign]C) = -2.8 [middle dot] [meperidine ([micro sign]g/ml)] + 36.2; r2 = 0.64, P = 0.0005. Sufentanil also linearly decreased the shivering threshold: threshold ([degree sign]C) = -7.8 [middle dot] [sufentanil (ng/ml)] + 36.9; r (2) = 0.46, P = 0.02.     

Alfentanil Blocks Reflex Pupillary Dilation in Response to Noxious Stimulation But Does Not Diminish the Light Reflex

Background: Estimation of the micro-agonist opioid effect in anesthetized and paralyzed patients is often imprecise and can be obscured by concomitant administration of drugs that affect the sympathetic nervous system, such as beta-adrenergic blocking agents. As an alternative to hemodynamic measures of opioid effect, the authors tested the hypothesis that the pupillary light reflex or pupillary reflex dilation correlated with alfentanil concentrations during isoflurane anesthesia.

Methods: Six volunteers were anesthetized on 4 days with 0.8% isoflurane. Alfentanil was administered intravenously to target total plasma concentrations of 0, 25, 50, and 100 ng/ml. A 5-s tetanic electrical stimulus was applied to the skin. Pupil size and the pupillary light reflex were recorded before and after alfentanil administration, and before and for 8 min after the stimulus.

Results: Alfentanil exponentially impaired reflex pupillary dilation, decreasing the maximum response amplitude from 5 mm at 0 ng/ml, to 2.3 mm at 25 ng/ml, to 1.0 mm at 50 ng/ml, and finally to 0.2 mm at 100 ng/ml. In contrast, only the highest concentration of alfentanil depressed the dilation of the pupil in the first 2 s after the stimulus. Alfentanil administration had no effect on the pupillary light reflex.     

The Addition of 7.5% Glucose Does Not Alter the Neurotoxicity of 5% Lidocaine Administered Intrathecally in the Rat

Background: Recent reports of major and minor neurologic sequelae after spinal anesthesia have generated concern regarding the safety of some currently used intrathecal agents. The role of glucose, if any, in neurotoxic injury associated with spinal anesthesia is not known. The current experiments sought to determine whether the presence of 7.5% glucose alters the neurotoxicity of intrathecally administered 5% lidocaine.

Methods: Two experiments were performed. First, 48 rats were implanted with an intrathecal catheter and randomly divided into eight equal groups. Each animal received a single intrathecal infusion of 5% lidocaine (groups P1-P4) or 5% lidocaine with 7.5% glucose (G1-G4) for 0.5, 1, 2, or 4 h at a rate of 1 micro liter/min. Sensory function was assessed using the tail-flick test; a deficit was defined as a complete lack of response to the heat stimulus at the proximal, mid or distal portion of the tail persisting 4 days after the infusion. In the second experiment, 60 rats were randomly divided into two groups to receive a 1-h intrathecal infusion of 5% lidocaine or 5% lidocaine with 7.5% glucose. Animals were evaluated for increase in the latency of the tail-flick reflex 4 days after infusion.

Results: In the first experiment, the two lidocaine solutions produced similar dose-dependent loss of sensory function. In the second experiment, the two solutions induced similar alterations in tail-flick latency.