Thermoregulatory Vasoconstriction Does Not Impede Core Warming during Cutaneous Heating

Background: Although forced-air warming rapidly increases intraoperative core temperatures, it is reportedly ineffective postoperatively. A major difference between these two periods is that arteriovenous shunts are usually dilated during surgery, whereas vasoconstriction is uniform in hypothermic postoperative patients. Vasoconstriction may decrease efficacy of warming because its major physiologic purposes are to reduce cutaneous heat transfer and restrict heat transfer between the two thermal compartments. Accordingly, we tested the hypothesis that thermoregulatory vasoconstriction decreases cutaneous transfer of applied heat and restricts peripheral-to-core flow of heat, thereby delaying and reducing the increase in core temperature.

Methods: Eight healthy male volunteers anesthetized with propofol and isoflurane were studied. Volunteers were allowed to cool passively until core temperature reached 33 degrees C. On one randomly assigned day, the isoflurane concentration was reduced, to provoke thermoregulatory arteriovenous shunt vasoconstriction; on the other study day, a sufficient amount of isoflurane was administered to prevent vasoconstriction. On each day, forced-air warming was then applied for 2 h. Peripheral (arm and leg) tissue heat contents were determined from 19 intramuscular needle thermocouples, 10 skin temperatures, and "deep" foot temperature. Core (trunk and head) heat content was determined from core temperature, assuming a uniform compartmental distribution. Time-dependent changes in peripheral and core tissue heat contents were evaluated using linear regression. Differences between the vasoconstriction and vasodilation study days, and between the peripheral and core compartments, were evaluated using two-tailed, paired t tests. Data are presented as means +/-SD; P < 0.01 was considered statistically significant.

Results: Cutaneous heat transfer was similar during vasoconstriction and vasodilation. Forced-air warming increased peripheral tissue heat content comparably when the volunteers were vasodilated and vasoconstricted: 48+/-7 versus 53+/-10 kcal/h. Core compartment tissue heat content increased similarly when the volunteers were vasodilated and vasoconstricted: 51+/-8 versus 44+/- 11 kcal/h. Combining the two study days, the increase in peripheral and core heat contents did not differ significantly: 51+/-8 versus 48 +/-10 kcal/h, respectively. Core temperature increased at essentially the same rate when the volunteers remained vasodilated (1.3 degrees C/h) as when they were vasoconstricted (1.2 degrees Celsius/h).     

Thermoregulatory Thresholds for Vasoconstriction in Patients Anesthetized with Various 1-Minimum Alveolar Concentration Combinations of Xenon, Nitrous Oxide, and Isoflurane

Background: Nitrous oxide limits intraoperative hypothermia because the vasoconstriction threshold with nitrous oxide is higher than with equi-minimum alveolar concentrations of sevoflurane or isoflurane, presumably because of its stimulating actions on the sympathetic nervous system. Xenon, in contrast, does not cause sympathetic activation. Therefore, the authors tested the hypothesis that the vasoconstriction threshold during xenon-isoflurane anesthesia is less than during nitrous oxide-isoflurane anesthesia or isoflurane alone.

Methods: Fifteen patients each were randomly assigned to one of three 1-minimum alveolar concentration anesthetic regimens: (1) xenon, 43% (0.6 minimum alveolar concentration) and isoflurane, 0.5% (0.4 minimum alveolar concentration); (2) nitrous oxide, 63% (0.6 minimum alveolar concentration) and isoflurane 0.5%; or (3) isoflurane, 1.2%. Ambient temperature was maintained near 23[degrees]C and the patients were not actively warmed. Thermoregulatory vasoconstriction was evaluated using forearm-minus-fingertip skin temperature gradients. A gradient exceeding 0[degrees]C indicated significant vasoconstriction. The core-temperature threshold that would have been observed if skin had been maintained at 33[degrees]C was calculated from mean skin and distal esophageal temperatures at the time of vasoconstriction.

Results: The patients' demographic variables, preinduction core temperatures, ambient operating room temperatures, and fluid balance were comparable among the three groups. Heart rates were significantly less during xenon anesthesia than with nitrous oxide. The calculated vasoconstriction threshold was lowest with xenon (34.6 +/- 0.8[degrees]C, mean +/- SD), intermediate with isoflurane alone (35.1 +/- 0.6[degrees]C), and highest with nitrous oxide (35.7 +/- 0.6[degrees]C). Each of the thresholds differed significantly.     

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.     

Fructose Administration Increases Intraoperative Core Temperature by Augmenting Both Metabolic Rate and the Vasoconstriction Threshold

Background: The authors tested the hypothesis that intravenous fructose ameliorates intraoperative hypothermia both by increasing metabolic rate and the vasoconstriction threshold (triggering core temperature).

Methods: Forty patients scheduled to undergo open abdominal surgery were divided into two equal groups and randomly assigned to intravenous fructose infusion (0.5 g [middle dot] kg-1 [middle dot] h-1 for 4 h, starting 3 h before induction of anesthesia and continuing for 4 h) or an equal volume of saline. Each treatment group was subdivided: Esophageal core temperature, thermoregulatory vasoconstriction, and plasma concentrations were determined in half, and oxygen consumption was determined in the remainder. Patients were monitored for 3 h after induction of anesthesia.

Results: Patient characteristics, anesthetic management, and circulatory data were similar in the four groups. Mean final core temperature (3 h after induction of anesthesia) was 35.7[degrees] +/- 0.4[degrees]C (mean +/- SD) in the fructose group and 35.1[degrees] +/- 0.4[degrees]C in the saline group (P = 0.001). The vasoconstriction threshold was greater in the fructose group (36.2[degrees] +/- 0.3[degrees]C) than in the saline group (35.6[degrees] +/- 0.3[degrees]C; P < 0.001). Oxygen consumption immediately before anesthesia induction in the fructose group (214 +/- 18 ml/min) was significantly greater than in the saline group (181 +/- 8 ml/min; P < 0.001). Oxygen consumption was 4.0 l greater in the fructose patients during 3 h of anesthesia; the predicted difference in mean body temperature based only on the difference in metabolic rates was thus only 0.4[degrees]C. Epinephrine, norepinephrine, and angiotensin II concentrations and plasma renin activity were similar in each treatment group.     

Vasoconstriction and vasodilation in erectile physiology

Recent studies have demonstrated that vasoconstriction in the erectile vasculature of the penis is mediated in part by RhoA/Rho-kinase signaling. However, this constrictor activity must be overcome to permit the vasodilation essential for erection. We hypothesize that the primary action of nitric oxide and other agents that cause penile erection is inhibition of the RhoA/Rho-kinase pathway, thereby allowing vasodilation and erection. This hypothesis, as well as experiments using hypogonadal and hypertensive animal models, are discussed in terms of the potential clinical value of Rho-kinase inhibitors for the treatment of erectile dysfunction.     

Thermoregulatory abnormalities of the foot

Thermoregulatory abnormalities are well known but poorly understood phenomena. Pathologic alterations of microvascular blood flow occur in a variety of diseases of the foot, and often cause severe functional impairment. The structure, function, and methods for testing thermoregulatory abnormalities are reviewed. Pathologic manifestations of abnormal thermoregulation are also discussed.     

Thermoregulatory defect in rats during anesthesia

Male rats of the Fischer 344, Sprague-Dawley, Brattleboro, and Wistar strains, balb/C mice, and Hartley guinea pigs were divided into 2 treatment groups. One group drank tap water while the other group drank water containing 1 mg/ml of phenobarbital. Animals were exposed to sevoflurane, enflurane, methoxyflurane, isoflurane, or halothane in a closed chamber. In some of the experiments, soda lime was included and in other the chamber was heated to 39 degrees C with a water blanket. Eighty-six percent (43/50) of Fischer 344 rats treated with phenobarbital and esposed to either sevoflurane or enflurane, in the presence of either soda lime or exogenous heat, died within a few hours after exposure. Fischer 344 rats and rats of other strains drinking phenobarbital water and exposed to methoxyflurane were affected, but to a lesser degree. Rats drinking ordinary tap water and phenobarbital-treated rats not exposed to either soda lime or exogenous heat were unaffected. Guinea pigs and mice also were unaffected. We postulate that the toxic response represents a species-specific thermoregulatory defect, precipitated by heat and occurring in rats treated with phenobarbital in combination with sevoflurane, endlurane, or methoxyflurane.     

Thermoregulatory management for mild therapeutic hypothermia

Mild therapeutic hypothermia is an important neuroprotective concept after out-of-hospital cardiac arrest^{[*37] and [*97]} and improves outcome after pediatric ischemic hypoxic encephalopathy.⁴⁸ Many studies are currently ongoing to determine additional evidence-based indications for mild therapeutic hypothermia.This article presented numerous possibilities and methods for the induction and maintenance of therapeutic hypothermia. There are several feasible, efficient and affordable options to implement mild therapeutic hypothermia in any intensive care setting – neither financial restraints nor infrastructural issues should therefore be reasons not to provide patients adequate neuroprotective treatment.In summary, a recommendation for any specific cooling method or any particular sedation regimen is not possible yet – more evidence and further clinical studies are needed to establish optimized hypothermia treatment procedures.

Conflict of interest

Dr. Oliver Kimberger: No conflict of interest.Dr. Andrea Kurz: No conflict of interest.

• For a fast induction and efficient maintenance of mild therapeutic hypothermia shivering and vasoconstriction thresholds have to be lowered.

• Apart from general anaesthetics meperidine, dexmedetomidine, nefopam, buspirone and skin warming lower thermoregulatory thresholds.

• With a well balanced combination of different anti-shivering drugs mild therapeutic hypothermia can be induced and maintained in awake patients, e.g. to allow neurological monitoring.

• Accurate measurement of core temperature during mild therapeutic hypothermia is very important. Pulmonary artery, oesophagus, nasopharynx, bladder or tympanic temperature should be used for core temperature measurement.

• During hypothermia the half-life of all drugs is notably prolonged, and dosing has to be adjusted accordingly.

• There are many efficient cooling methods commercially available, an evidence-based recommendation for any specific method has yet to be established.

• Research is warranted on new drugs lowering the shivering threshold without concomitant sedation and respiratory toxicity.

• Further large clinical trials are necessary to explore additional indications for mild therapeutic hypothermia.

Thermoregulatory vasoconstriction decreases cutaneous heat loss

To determine the extent to which thermoregulatory vasoconstriction decreases heat loss to the environment, we measured regional heat flux, average skin temperature, and tympanic membrane temperature before and after thermoregulatory vasoconstriction in five minimally clothed volunteers maintained in a 30.8 +/- 0.1 degrees C environment. Thermoregulatory vasoconstriction was induced by central venous infusion of cooled fluid. Peripheral cutaneous blood flow was evaluated with venous-occlusion volume plethysmography and skin-surface temperature gradients. Laser Doppler flowmetry was used to measure vasoconstriction in centrally located skin. This model mimics the common clinical situation in which patients in a warm environment are centrally cooled by administration of cold intravenous fluids or by lavage of internal cavities with cold fluids. Tympanic membrane temperature decreased 1.5 +/- 0.3 degrees C in the first 15 min after the cold fluid infusion was started and remained approximately 1 degrees C below control values during the rest of the study. Average skin-surface temperature decreased slowly to approximately 0.7 degrees C below control. Flow in capillaries of centrally distributed skin, determined with laser Doppler flowmetry, decreased only approximately 40%. Total heat flux, and flux from the arms and legs decreased approximately 25% (15.5 +/- 0.3 W). Heat loss from the trunk and head decreased only 17%, whereas, loss from the hands and feet (10.5% of the body surface area) decreased approximately 50%. All measured values decreased significantly following vasoconstriction (P less than 0.01). Therefore, thermoregulatory vasoconstriction in a thermoneutral environment appears to decrease cutaneous loss of metabolic heat approximately 25%.     

Thermoregulatory control after upper extremity replantation

Four patients with complete forearm amputations between the wrist and elbow were analyzed prospectively to determine the interrelationships of thermoregulation to pain, cold intolerance, arterial integrity, venous competence, motor nerve recovery, sensory nerve recovery, and time. Patients were examined at 6 weeks, 3 months, 6 months, 1 year, and 2 years after replantation. Vasomotor regulatory capacity was assessed by isolated cold-stress testing. Pain had diminished in all patients by 6 months to 1 year, regardless of other factors. Cold tolerance and normal thermoregulatory response, as indicated by cold-stress test performances, were temporally related to attainment of two-point sensory discrimination (p less than 0.05), or to motor nerve recovery (p less than 0.05), or to both.     

Brain Death Impairs Pancreatic Microcirculation

Brain death (BD) influences the quality of donor grafts in transplantation. To evaluate the impact of BD on pancreas grafts, we investigated the influence of BD on the microcirculation and histology of the pancreas in a rat model of explosive BD. A group of Wistar rats (n=7), rendered brain dead by inflating an intracranially inserted Fogarty catheter was compared with controls (CO) using intravital epifluorescence-microscopy over 4 h after BD induction; functional capillary density (FCD), leukocyte adherence (AL) in post-capillary venules, histology and pancreatic enzymes were investigated. Four hours after BD, FCD decreased (333 +/- 11 vs. baseline 444 cm/cm2 +/- 5 SEM; p<0.01) and showed lower values than CO (388 +/- 9 p<0.01). In BD, AL was increased (628 cells/mm2 +/- 110 SEM vs. baseline 123 +/- 32, and vs. CO 180 +/- 33; p<0.001). BD caused increased histological damage (CO 1.6 score-points +/- 0.7 SD vs. BD 8.3 +/- 7.1; p<0.05). Amylase was higher in BD (p<0.05) but did not reach pathological values. We show for the first time that BD causes relevant changes in pancreatic microcirculation, histology and leukocyte endothelial interaction which might have a serious impact on the function of grafts. New strategies for preventing this damage are therefore highly desirable in order to improve the outcome of pancreas transplantation.     

Calcium Channel Blockade in Rats with Cyclosporine-Induced Vasoconstriction

Calcium channel blockade has been found to attenuate nephrotoxicity of cyclosporine. However, it is not known whether intrarenal vasoconstriction caused by cyclosporine is totally mediated by vascular smooth muscle calcium influx. To study the protective effects of two calcium blockers on cyclosporine-induced intrarenal vasoconstriction and renal microvascular blood flow, hydronephrotic rat kidneys were suspended in an environmentally controlled tissue bath. Renal microvessel diameters and microvascular blood flow were determined by in vivo videomicroscopy and Doppler velocimetry. Calcium channel blockade was achieved by adding verapamil hydrochloride (5.6 ± 10-⁵ M) or diltiazem hydrochloride (2.8 × 10-⁵ M) to the tissue bath, which respectively resulted in a 15 ± 2% and 16 ± 3% interlobular arteriolar dilation, a 13 ± 3% and 12 ± 2% afferent arteriolar dilation, and a 60 ± 8% and 46 ± 14% increase in interlobular blood flow. When cyclosporine (1.7 × 10-³ M) was added to the tissue bath, there was a constriction of the interlobular arterioles to 4 ± 3% below baseline in rats receiving verapamil and 9 ± 3% below baseline in rats receiving diltiazem. Microvascular blood flow was reduced by the addition of cyclosporine to 3 ± 4% above original baseline values in the verapamil group and 22 ± 6% below baseline in the diltiazem group. Afferent arterioles were similarly constricted by cyclosporine. The results indicate that calcium blockade causes preglomerular vasodilation and protects the microvascular blood flow induced by cyclosporine. Since verapamil or diltiazem did not prevent arteriolar constriction as observed when cyclosporine was added, it was concluded that the mechanism of acute cyclosporine-induced vasoconstriction is not solely mediated by vascular smooth muscle calcium influx through potential dependent channels.     

Thermoregulatory response to intraoperative head-down tilt.

Thermoregulation interacts with cardiovascular regulation within the central nervous system. We therefore evaluated the effects of head-down tilt on intraoperative thermal and cardiovascular regulation. Thirty-two patients undergoing lower-abdominal surgery were randomly assigned to the 1) supine, 2) 15 degrees -20 degrees head-down tilt, 3) leg-up, or 4) combination of leg-up and head-down tilt position. Core temperature and forearm minus fingertip skin-temperature gradients (an index of peripheral vasoconstriction) were monitored for 3 h after the induction of combined general and lumbar epidural anesthesia. We also determined cardiac output and central-venous and esophageal pressures. Neither right atrial transmural pressure nor cardiac index was altered in the Head-Down Tilt group, but both increased significantly in the Leg-Up groups. The vasoconstriction threshold was reduced in both leg-up positions but was not significantly decreased by head-down tilt. Final core temperatures were 35.2 degrees C +/- 0.2 degrees C (mean +/- SEM) in the Supine group, 35.0 degrees C +/- 0.2 degrees C in the Head-Down Tilt group, 34.2 degrees C +/- 0.2 degrees C in the Leg-Up group (P < 0.05 compared with supine), and 34.3 degrees C +/- 0.2 degrees C when leg-up and head-down tilt were combined (P < 0.05 compared with supine). These results confirm that elevating the legs increases right atrial transmural pressure, reduces the vasoconstriction threshold, and aggravates intraoperative hypothermia. Surprisingly, maintaining a head-down tilt did not increase right atrial pressure. IMPLICATIONS: Intraoperative hypothermia is exaggerated when patients are maintained in the leg-up position because the vasoconstriction threshold is reduced. However, head-down tilt (Trendelenburg position) does not reduce the vasoconstriction threshold or aggravate hypothermia. The head-down tilt position thus does not require special perioperative thermal precautions or management unless the leg-up position is used simultaneously.     

SPAK-Knockout Mice Manifest Gitelman Syndrome and Impaired Vasoconstriction

Polymorphisms in the gene encoding sterile 20/SPS1-related proline/alanine-rich kinase (SPAK) associate with hypertension susceptibility in humans. SPAK interacts with WNK kinases to regulate the Na⁺-K⁺-2Cl⁻ and Na⁺-Cl⁻ co-transporters [collectively, N(K)CC]. Mutations in WNK1/4 and N(K)CC can cause changes in BP and dyskalemia in humans, but the physiologic role of SPAK in vivo is unknown. We generated and analyzed SPAK-null mice by targeting disruption of exons 9 and 10 of SPAK. Compared with SPAK^+/+ littermates, SPAK^+/− mice exhibited hypotension without significant electrolyte abnormalities, and SPAK^−/− mice not only exhibited hypotension but also recapitulated Gitelman syndrome with hypokalemia, hypomagnesemia, and hypocalciuria. In the kidney tissues of SPAK^−/− mice, the expression of total and phosphorylated (p-)NCC was markedly decreased, but that of p-OSR1, total NKCC2, and p-NKCC2 was significantly increased. We observed a blunted response to thiazide but normal response to furosemide in SPAK^−/− mice. In aortic tissues, total NKCC1 expression was increased but p-NKCC1 was decreased in SPAK-deficient mice. Both SPAK^+/− and SPAK^−/− mice had impaired responses to the selective α₁-adrenergic agonist phenylephrine and the NKCC1 inhibitor bumetanide, suggesting that impaired aortic contractility may contribute to the hypotension of SPAK-null mice. In summary, SPAK-null mice have defects of NCC in the kidneys and NKCC1 in the blood vessels, leading to hypotension through renal salt wasting and vasodilation. SPAK may be a promising target for antihypertensive therapy.Sterile 20/SPS1-related proline/alanine-rich kinase (SPAK)^1,2 and oxidative stress-responsive kinase 1 (OSR1)³ are serine/threonine kinases that share high homology in both their N-terminal catalytic and C-terminal regulatory domains and are widely distributed in the brain, pancreas, heart and kidney.^2–5 SPAK and OSR1 are downstream substrates of WNK [With-No-Lysine (K)] 1 and 4 kinases and upstream regulators of the cation-chloride co-transporters (Na⁺-K⁺-2Cl⁻ co-transporter [NKCC] 1 and 2 and Na⁺-Cl⁻ co-transporter [NCC]).^6–9 Specifically, phosphorylation and activation of SPAK and OSR1 by WNK1/4 can in turn phosphorylate and activate NCC/NKCC1.^10,11Gene mutations of the NCC in the distal convoluted tubules (DCTs) and NKCC2 in the thick ascending limb of the loop of Henle (TAL) cause autosomal recessive Gitelman syndrome (GS)¹² and Bartter syndrome (BS),¹³ respectively. These congenital renal tubular disorders are characterized by renal salt-losing hypotension, secondary hyperreninemia and hyperaldosteronism, and hypokalemic metabolic alkalosis; however, mutations in the WNK1 and WNK4 genes cause autosomal dominant pseudohypoaldosteronism type II (PHAII) featuring the mirror image of GS,^14,15 with salt-sensitive hypertension, low plasma renin activity and inappropriately high plasma aldosterone level, and hyperkalemic metabolic acidosis. A recent human study also showed that genetic variations in the intron regions of STK39, the gene encoding SPAK, could enhance its expression and increase susceptibility to hypertension.¹⁶ These findings suggest that SPAK and OSR1 play important roles in BP and renal tubular electrolyte regulation.We previously found that phosphor (p-) but not total SPAK and OSR1 were increased along with increased total and p-NCC expression in kidneys of WNK4^D561A/+ knock-in mice, recapitulating human PHAII.¹⁷ Conversely, a WNK4 hypomorphic mouse (by targeting disruption of exon 7 whereby the PHAII-causing mutations are clustered) clearly showed hypotension and decreased expression of p-SPAK/OSR1 and p-NCC.¹⁸ These and other previous findings further reiterate the importance of the WNK4-SPAK/OSR1-NCC pathway in the pathogenesis of PHAII.Because SPAK and OSR1 share high homology in both their catalytic and regulatory domains and their expression in tissues often overlaps, it is crucial to tease apart the role of each kinase. The generation and analysis of individual SPAK- or OSR1-deficient mice may provide better platforms to study this issue. For this purpose, we generated SPAK- and OSR1-null mice by disrupting exons 9 and 10 of the Stk39 (SPAK) and Oxsr1 (OSR1) genes, respectively. Homozygous OSR1-null mice died in utero as in the recently reported OSR1 gene–trapped mice.¹⁹ We therefore analyzed the SPAK (Stk39)-null mice to investigate its role in the kidneys and blood vessels. Results to be reported indicate that SPAK^−/− mice exhibited not only hypotension but the phenotype of GS.     

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).     

Hypoxic Pulmonary Vasoconstriction in Man: Effects of Hyperventilation

The pulmonary vasoconstriction response to hypoxia was studied in eight anaesthetized supine subjects. One lung was made hypoxic while the other was ventilated with 100% oxygen. This was achieved by separating the tidal gas-distribution to the lungs by means of a double-lumen tracheal catheter. The hypoxic pulmonary vasoconstriction (HPV) response was estimated from the blood flow diversion away from the hypoxic lung. Blood flow distribution between the lungs was calculated from the regional expired carbon dioxide production, assuming regional carbon dioxide production to be proportional to blood flow. The subjects were studied during six different conditions. Firstly, when ventilated with 100% oxygen to both lungs at a PaCO2 of about 6 kPa. Secondly, with 100% oxygen to the left lung and 5% oxygen in nitrogen to the right (test) lung. The ratio between carbon dioxide output from right and left lung was calculated. These measurements were repeated during two states of hyperventilation (PaCO2 of about 4.5 kPa and 3.5 kPa, respectively) with and without hypoxia (conditions 3-6). During normoventilation, blood flow distribution between the lungs was equal. During hypoxia, blood flow distribution to the hypoxic lung decreased by 35% of the pre-hypoxic value. Furthermore, a decrease in arterial oxygen tension from 51.5 +/- 4.5 to 11.5 +/- 2.1 kPa was observed. During excessive hyperventilation (PaCO2 3.2 +/- 0.2 kPa), blood flow distribution to the hypoxic right lung decreased by only 10% of its pre-hypoxic value. A further decrease in arterial oxygen tension to 8.5 +/- 1.8 kPa was observed. This decrease in PaO2 was possibly due to an increased venous admixture caused by an abolished HPV response. It is concluded that hyperventilation counteracts hypoxic pulmonary vasoconstriction in man.     

Does Dopamine Suppress Stress-Induced Intestinal and Renal Vasoconstriction?

Dopamine interference with intestinal and renal sympathetic reflex vasoconstrictor responses was studied in cats anaesthetized with diazepam, fentanyl and nitrous oxide. Vasoconstriction was induced by electric stimulation of the hypothalamic defence-alarm area and by stimulation of somatic and visceral afferents. In addition, intestinal vasoconstriction was elicited by direct stimulation of postganglionic sympathetic efferent nerves. In the intestine, dopamine administration (7.5 microgram X kg-1 X min-1) was not associated with an attenuation of the investigated sympathetic vasoconstrictor responses, although dopamine per se decreased intestinal vascular resistance by 36 +/- 4%. Due to this dopamine-induced background vasodilation, the intestinal blood flow level during stimulation procedures and concomitant dopamine infusion was higher than during similar stimulations prior to dopamine (for defence-alarm area stimulation 45 +/- 16%, for afferent nerve stimulation 79 +/- 22% and for efferent postganglionic nerve stimulation 66 +/- 16%). In the kidney, dopamine per se had only minor effects on vascular resistance and on changes in vascular tone elicited by the stimulation procedures. The renal blood flow level in response to the stimulation procedures was not significantly affected by dopamine. In conclusion, dopamine may contribute to a sustained intestinal blood flow level when administered during supervening stress-related sympathetic activation.