From population to neuron: exploring common mediators for metabolic problems and mental illnesses.

Major mental illnesses such as schizophrenia (SZ) and bipolar disorder (BP) frequently accompany metabolic conditions, but their relationship is still unclear, in particular at the mechanistic level. We implemented an approach of "from population to neuron", combining population-based epidemiological analysis with neurobiological experiments using cell and animal models based on a hypothesis built from the epidemiological study. We characterized high-quality population data, olfactory neuronal cells biopsied from patients with SZ or BP, and healthy subjects, as well as mice genetically modified for insulin signaling. We accessed the Danish Registry and observed (1) a higher incidence of diabetes in people with SZ or BP and (2) higher incidence of major mental illnesses in people with diabetes in the same large cohort. These epidemiological data suggest the existence of common pathophysiological mediators in both diabetes and major mental illnesses. We hypothesized that molecules associated with insulin resistance might be such common mediators, and then validated the hypothesis by using two independent sets of olfactory neuronal cells biopsied from patients and healthy controls. In the first set, we confirmed an enrichment of insulin signaling-associated molecules among the genes that were significantly different between SZ patients and controls in unbiased expression profiling data. In the second set, olfactory neuronal cells from SZ and BP patients who were not pre-diabetic or diabetic showed reduced IRS2 tyrosine phosphorylation upon insulin stimulation, indicative of insulin resistance. These cells also displayed an upregulation of IRS1 protein phosphorylation at serine-312 at baseline (without insulin stimulation), further supporting the concept of insulin resistance in olfactory neuronal cells from SZ patients. Finally, Irs2 knockout mice showed an aberrant response to amphetamine, which is also observed in some patients with major mental illnesses. The bi-directional relationships between major mental illnesses and diabetes suggest that there may be common pathophysiological mediators associated with insulin resistance underlying these mental and physical conditions.

Irs2 deficiency alters hippocampus-associated behaviors during young adulthood.

Type 2 diabetes mellitus (T2DM), characterized by hyperglycemia and insulin resistance, has been recognized as a risk factor for cognitive impairment and dementia, including Alzheimer's disease (AD). Insulin receptor substrate2 (IRS2) is a major component of the insulin/insulin-like growth factor-1 signaling pathway. Irs2 deletion leads to life-threatening T2DM, promoting premature death in male mice regardless of their genetic background. Here, we showed for the first time that young adult male mice lacking Irs2 on a C57BL/6J genetic background (Irs2-/-/6J) survived in different experimental environments and displayed hippocampus-associated behavioral alterations. Young adult male Irs2-/-/6J mice also exhibit aberrant alterations in energy and nutrient sensors, such as AMP-activated protein kinase (AMPK) and glucose transporter3 (GLUT3), and reduced core body temperature accompanied by abnormal change in the temperature sensor in the brain. These results suggest that Irs2 deficiency-induced impairments of brain energy metabolism and thermoregulation contribute to hippocampus-associated behavioral changes in young adult male mice.

Neonatal isolation augments social dominance by altering actin dynamics in the medial prefrontal cortex.

Social separation early in life can lead to the development of impaired interpersonal relationships and profound social disorders. However, the underlying cellular and molecular mechanisms involved are largely unknown. Here, we found that isolation of neonatal rats induced glucocorticoid-dependent social dominance over nonisolated control rats in juveniles from the same litter. Furthermore, neonatal isolation inactivated the actin-depolymerizing factor (ADF)/cofilin in the juvenile medial prefrontal cortex (mPFC). Isolation-induced inactivation of ADF/cofilin increased stable actin fractions at dendritic spines in the juvenile mPFC, decreasing glutamate synaptic AMPA receptors. Expression of constitutively active ADF/cofilin in the mPFC rescued the effect of isolation on social dominance. Thus, neonatal isolation affects spines in the mPFC by reducing actin dynamics, leading to altered social behavior later in life.

Epithelial Pten controls acute lung injury and fibrosis by regulating alveolar epithelial cell integrity.

RATIONALE: Injury to alveolar epithelial cells (AECs) and to their repair process is integral to the pathogenesis of acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF). The mechanisms regulating the integrity of AECs and their intrinsic regulators remain unclear. Pten is a tumor suppressor, and its function in epithelial cells during organ fibrosis is unknown. OBJECTIVES: To determine the role of epithelial Pten in ALI and lung fibrosis. METHODS: Bronchioalveolar epithelium-specific Pten-deleted SP-C-rtTA/(tetO)(7)-Cre/Pten(Δ/Δ) (SOPten(Δ/Δ)) mice were studied by structural, biochemical, and physiologic analyses and compared with wild-type mice. Further mechanistic studies were performed in vivo, in vitro, and on samples from patients with IPF. MEASUREMENTS AND MAIN RESULTS: SOPten(Δ/Δ) mice demonstrated exacerbated alveolar flooding and subsequent augmented lung scarring with enhanced disassembly of tight junctions (TJs) of AECs and degradation of basement membranes. The induction of dominant negative PTEN gene in lung epithelial cells led to augmented transforming growth factor-1-induced disruptions of TJs. Epithelial-derived myofibroblasts were increased in the epithelium-specific Pten-deficient mice. The lungs of bleomycin-treated SOPten(Δ/Δ) mice showed increased pAkt, pS6K, Snail, and matrix metalloproteinase expressions and decreased claudin-4, E-cadherin, and laminin-ß1 expressions. Akt inactivation definitively saved SOPten(Δ/Δ) mice through amelioration of ALI and retention of AEC integrity. We detected a reduction of PTEN expression and AKT hyperactivation in the AECs of human IPF lungs. CONCLUSIONS: Our results highlight epithelial Pten as a crucial gatekeeper controlling ALI and lung fibrosis by modulating AEC integrity, and the Pten/PI3K/Akt pathway as a potential therapeutic target in these intractable diseases.

Effects of high-fat diet on nutrient metabolism and cognitive functions in young APPKINL-G-F/NL-G-F mice.

AIM: Type 2 diabetes mellitus (T2DM) is an increased risk factor for Alzheimer's disease (AD); however, the relationship between the 2 conditions is controversial. High-fat diet (HFD) causes cognitive impairment with/without Aß accumulation in middle-aged or aged transgenic (Tg) and knock-in (KI) AD mouse models, except for metabolic disorders, which commonly occur in all mice types. Alternatively, whether HFD in early life has an impact on nutrient metabolism and neurological phenotypes in young AD mouse models is not known. In the present study, we examined the effects of HFD on young APPKINL-G-F/NL-G-F mice, one of the novel KI-AD mouse models. METHODS: The mice were categorized by diet into 2 experimental groups, normal diet (ND) and HFD. Four-week-old wild-type (WT) and APPKINL-G-F/NL-G-F mice were fed ND or HFD for 9 weeks. Both types of mice on ND and HFD were examined during young adulthood. RESULTS: HFD caused T2DM-related metabolic disturbances in both young WT and APPKINL-G-F/NL-G-F mice, whereas impaired thermoregulation and shortage of alternative energy sources specifically occurred in young APPKINL-G-F/NL-G-F mice. However, HFD had no impact on the cognitive function, Aß levels, and phosphorylation of hippocampal insulin receptor substrate 1 (IRS1) at all the 3 Ser sites in both types of mice. CONCLUSION: HFD is effective in causing metabolic disturbances in young WT and APPKINL-G-F/NL-G-F mice but is ineffective in inducing neurological disorders in both types of mice, suggesting that the aging effects, along with long-term HFD, facilitate neurological alterations.

Involvement of insulin receptor substrates in cognitive impairment and Alzheimer's disease.

Type 2 diabetes-associated with impaired insulin/insulin-like growth factor-1 (IGF1) signaling (IIS)-is a risk factor for cognitive impairment and dementia including Alzheimer's disease (AD). The insulin receptor substrate (IRS) proteins are major components of IIS, which transmit upstream signals via the insulin receptor and/or IGF1 receptor to multiple intracellular signaling pathways, including AKT/protein kinase B and extracellular-signal-regulated kinase cascades. Of the four IRS proteins in mammals, IRS1 and IRS2 play key roles in regulating growth and survival, metabolism, and aging. Meanwhile, the roles of IRS1 and IRS2 in the central nervous system with respect to cognitive abilities remain to be clarified. In contrast to IRS2 in peripheral tissues, inactivation of neural IRS2 exerts beneficial effects, resulting in the reduction of amyloid ß accumulation and premature mortality in AD mouse models. On the other hand, the increased phosphorylation of IRS1 at several serine sites is observed in the brains from patients with AD and animal models of AD or cognitive impairment induced by type 2 diabetes. However, these serine sites are also activated in a mouse model of type 2 diabetes, in which the diabetes drug metformin improves memory impairment. Because IRS1 and IRS2 signaling pathways are regulated through complex mechanisms including positive and negative feedback loops, whether the elevated phosphorylation of IRS1 at specific serine sites found in AD brains is a primary response to cognitive dysfunction remains unknown. Here, we examine the associations between IRS1/IRS2-mediated signaling in the central nervous system and cognitive decline.

Serine Phosphorylation of IRS1 Correlates with Aß-Unrelated Memory Deficits and Elevation in Aß Level Prior to the Onset of Memory Decline in AD.

The biological effects of insulin signaling are regulated by the phosphorylation of insulin receptor substrate 1 (IRS1) at serine (Ser) residues. In the brain, phosphorylation of IRS1 at specific Ser sites increases in patients with Alzheimer's disease (AD) and its animal models. However, whether the activation of Ser sites on neural IRS1 is related to any type of memory decline remains unclear. Here, we show the modifications of IRS1 through its phosphorylation at etiology-specific Ser sites in various animal models of memory decline, such as diabetic, aged, and amyloid precursor protein (APP) knock-in NL-G-F (APPKINL-G-F) mice. Substantial phosphorylation of IRS1 at specific Ser sites occurs in type 2 diabetes- or age-related memory deficits independently of amyloid-ß (Aß). Furthermore, we present the first evidence that, in APPKINL-G-F mice showing Aß42 elevation, the increased phosphorylation of IRS1 at multiple Ser sites occurs without memory impairment. Our findings suggest that the phosphorylation of IRS1 at specific Ser sites is a potential marker of Aß-unrelated memory deficits caused by type 2 diabetes and aging; however, in Aß-related memory decline, the modifications of IRS1 may be a marker of early detection of Aß42 elevation prior to the onset of memory decline in AD.

Metformin treatment ameliorates diabetes-associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1.

Age-related reduction in adult hippocampal neurogenesis is correlated with cognitive impairment. Diabetes is a chronic systemic disease that negatively affects adult neural stem cells and memory functions in the hippocampus. Despite growing concern regarding the potential role of diabetic drugs in neural abnormalities, their effects on progressive deterioration of neurogenesis and cognitive functions remain unknown. Here, we show that the combination of aging and diabetes in mice causes a marked decrease in hippocampal neurogenesis along with memory impairment and elevated neuroinflammation. Prolonged treatment with metformin, a biguanide antidiabetic medication, promotes cell proliferation and neuronal differentiation and inhibits aging- and diabetes-associated microglial activation, which is related to homeostatic neurogenesis, leading to enhanced hippocampal neurogenesis in middle-aged diabetic mice. Although chronic therapy with metformin fails to achieve recovery from hyperglycemia, a key feature of diabetes in middle-aged diabetic mice, it improves hippocampal-dependent spatial memory functions accompanied by increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), atypical protein kinase C ζ (aPKC ζ), and insulin receptor substrate 1 (IRS1) at selective serine residues in the hippocampus. Our findings suggest that signaling networks acting through long-term metformin-stimulated phosphorylation of AMPK, aPKC ζ/λ, and IRS1 serine sites contribute to neuroprotective effects on hippocampal neurogenesis and cognitive function independent of a hypoglycemic effect.

Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes.

The molecular link between obesity and beta cell failure that causes diabetes is difficult to establish. Here we show that a conditional knockout of insulin receptor substrate 2 (Irs2) in mouse pancreas beta cells and parts of the brain--including the hypothalamus--increased appetite, lean and fat body mass, linear growth, and insulin resistance that progressed to diabetes. Diabetes resolved when the mice were between 6 and 10 months of age: functional beta cells expressing Irs2 repopulated the pancreas, restoring sufficient beta cell function to compensate for insulin resistance in the obese mice. Thus, Irs2 signaling promotes regeneration of adult beta cells and central control of nutrient homeostasis, which can prevent obesity and diabetes in mice.

A comparison of ondansetron with promethazine for treating postoperative nausea and vomiting in patients who received prophylaxis with ondansetron: a retrospective database analysis.

BACKGROUND: There are little data on the efficacy of antiemetics for treating postoperative nausea and vomiting (PONV) in patients who received prior PONV prophylaxis. METHODS: In this retrospective database analysis, we compared the efficacy of ondansetron with that of promethazine for treating PONV in adults receiving general anesthesia who failed ondansetron prophylaxis. RESULTS: Three thousand sixty-two patients received ondansetron and 752 received promethazine after failure of ondansetron prophylaxis. The complete response (no PONV and no further rescue) was 68% after administration of promethazine and 50% after ondansetron administration (P < 0.0001). There was no difference in complete response between 6.25 mg and higher doses of promethazine. CONCLUSIONS: Promethazine was significantly more effective than ondansetron for treating PONV after failed ondansetron prophylaxis. Promethazine 6.25 mg was as effective as higher doses.

Social isolation suppresses actin dynamics and synaptic plasticity through ADF/cofilin inactivation in the developing rat barrel cortex.

Exposure to a stressful environment early in life can cause psychiatric disorders by disrupting circuit formation. Actin plays central roles in regulating neuronal structure and protein trafficking. We have recently reported that neonatal isolation inactivated ADF/cofilin, the actin depolymerizing factor, resulted in a reduced actin dynamics at spines and an attenuation of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor delivery in the juvenile rat medial prefrontal cortex (mPFC), leading to altered social behaviours. Here, we investigated the impact of neonatal social isolation in the developing rat barrel cortex. Similar to the mPFC study, we detected an increase in stable actin fraction in spines and this resulted in a decreased synaptic AMPA receptor delivery. Thus, we conclude that early life social isolation affects multiple cortical areas with common molecular changes.

Postoperative nausea and vomiting following inpatient surgeries in a teaching hospital: a retrospective database analysis.

OBJECTIVE: To report the incidence of postoperative nausea and vomiting (PONV), to describe the use of anti-emetics both for the prophylaxis and treatment of PONV, and to assess resource utilization and duration of post-anesthesia care unit (PACU) stay. RESEARCH DESIGN AND METHODS: We retrieved data from the Duke Anesthesia Peri-operative database. We included adult patients, who underwent inpatient surgery under general anesthesia with inhaled agents between January 2004 and February 2005, and had two or more risk factors for PONV documented preoperatively (female, previous history of PONV or motion sickness, non-smoker or use of postoperative opioid). Data on the use of prophylactic anti-emetics, the incidence of PONV, nausea scores, pain scores, and the use of rescue anti-emetics in PACU and in the period between PACU discharge and 24 h after surgery were recorded. Resource utilization and cost assessment was performed from the perspective of the hospital and included length and direct cost of PACU stay, as well as the acquisition costs of rescue anti-emetics in PACU. Descriptive statistics were used to summarize the demographic characteristics of patients. For group comparisons, data were analyzed with the t-test for continuous data, and the Chi-square test for categorical data. Multiple linear regression models were used to evaluate the association between PONV and PACU length of stay adjusting for confounding factors. RESULTS: A total of 3641 patients were included in the analysis. Of those, 2869 (79%) received prophylactic anti-emetics. In the PACU, nausea and vomiting were reported in 16% and 3% of the patients, respectively. Rescue anti-emetics were given to 26% of all patients. The incidence of vomiting was significantly less in patients who received PONV prophylaxis (p = 0.03). In multiple linear regression models, the duration of PACU stay was longer by a mean of 25 min in patients who experienced PONV or received rescue anti-emetics in PACU (p < 0.0001) despite the fact that the duration of surgery was shorter by a mean of 24 min in this group of patients (p < 0.0001). Following PACU discharge, 40% of patients reported nausea, vomiting or needed rescue anti-emetics. PONV was associated with significantly increased resource utilization and costs of PACU stay (p < 0.0001). Emesis was associated with greater incremental cost (138 US dollars) than nausea (85 US dollars), mainly from the longer duration of PACU stay. CONCLUSIONS: PONV remain a significant problem postoperatively and often persists beyond PACU discharge. The presence of PONV is associated with increased length of PACU stay and greater resource utilization and costs.

Supplemental perioperative fluid administration increases tissue oxygen pressure.

BACKGROUND: Wound infections are common and serious surgical complications. Wound perfusion delivers oxygen, inflammatory cells, growth factors, and cytokines to injured tissues. Hypoperfused regions experience low oxygen tensions that do not support adequate oxidative killing or wound healing. Clinicians may fail to recognize clinically important hypovolemia because hemodynamic stability and urine output are maintained after peripheral perfusion is compromised. We tested the hypothesis that supplemental fluid administration during and after elective colon resection increases tissue perfusion and tissue oxygen pressure. METHODS: Fifty-six patients undergoing colon resection were randomly assigned to conservative (8 mL x kg(-1) x h(-1), n = 26) or aggressive (16 to 18 mL x kg(-1) x h(-1), n = 30) fluid management. Anesthetic technique was standardized. We used 60% nitrous oxide in 40% oxygen. During surgery and postanesthetic recovery, subcutaneous oxygen tension (P(sq)O(2)) was measured by using a polarographic sensor implanted subcutaneously into 1 upper arm. Capillary blood flow was evaluated postoperatively with a thermal diffusion system. Data were analyzed with 2-tailed t tests; P value less than.05 was considered statistically significant. RESULTS: Hemodynamic and renal responses were similar in the groups. Intraoperative tissue oxygen tension was significantly greater in patients given supplemental fluid: 81 +/- 26 vs 67 +/- 18 mm Hg, P =.03. Postoperative P(sq)O(2) (77 +/- 26 vs 59 +/- 15 mm Hg, P =.009) and capillary blood flow (69 +/- 12 vs 53 +/- 12, P <.001) were also greater in the supplemental fluid patients. CONCLUSIONS: Supplemental perioperative fluid administration significantly increases tissue perfusion and tissue oxygen partial pressure. Optimizing tissue perfusion will require providing more fluid than indicated by normal clinical criteria or use of invasive monitoring to guide treatment. The actual effect of supplemental fluid administration on incidence of wound infection requires further investigation.

Insulin-like signaling, nutrient homeostasis, and life span.

Insulin-like signaling is critical for nutrient homeostasis, growth and survival. However, work with lower metazoans-Caenorhabditis elegans and Drosophila-shows that reduced insulin-like signaling extends life span. In addition, reduced insulin signaling in higher animals-rodents and humans-causes glucose intolerance and hyperinsulinemia that progresses to diabetes and shortens the life span of affected individuals. Hyperinsulinemia usually develops to maintain glucose homeostasis and prevent the progression toward life-threatening type 2 diabetes; however, increased circulating insulin may have negative effects on the brain that promote age-related disease. We discuss the possibility that the brain is the site where reduced insulin-like signaling can consistently extend mammalian life span-just as reduced insulin-like signaling extends the life span of lower metazoans.

Brain IRS2 signaling coordinates life span and nutrient homeostasis.

Reduced insulin-like signaling extends the life span of Caenorhabditis elegans and Drosophila. Here, we show that, in mice, less insulin receptor substrate-2 (Irs2) signaling throughout the body or just in the brain extended life span up to 18%. At 22 months of age, brain-specific Irs2 knockout mice were overweight, hyperinsulinemic, and glucose intolerant; however, compared with control mice, they were more active and displayed greater glucose oxidation, and during meals they displayed stable superoxide dismutase-2 concentrations in the hypothalamus. Thus, less Irs2 signaling in aging brains can promote healthy metabolism, attenuate meal-induced oxidative stress, and extend the life span of overweight and insulin-resistant mice.

Thermal management of the patient: where does the patient lose and/or gain temperature?

PURPOSE OF REVIEW: Anesthesia inhibits normal thermoregulatory control, leading to perioperative hypothermia or allowing therapeutic hypothermia. During the last decade many studies have shown the effects of anesthesia on thermoregulation. As a consequence many active warming and cooling devices are available to manipulate patients' core temperature. This review focuses on new findings in the field of temperature management. RECENT FINDINGS: Thermal management of patients has improved tremendously in recent years. Many outcome studies have shown adverse effects of perioperative hypothermia, as well as beneficial effects of therapeutic hypothermia after out-of-hospital cardiac arrest and brain trauma. However, inducing hypothermia is limited by physiologic thermoregulatory responses. Small reductions in core temperature lead to vasoconstriction and shivering, effectively hindering hypothermia. Thus prevention of vasoconstriction and shivering have become major goals during induction of therapeutic hypothermia. All anesthetics, opioids and sedatives lower the vasoconstriction and shivering threshold, thus allowing hypothermia. However, these drugs have side effects, such as respiratory depression, sedation and nausea. Several drugs, alone or in combination, lower the shivering threshold while causing minimal or no side effects. SUMMARY: Anesthesia affects thermoregulatory control and leads to perioperative hypothermia. The prevention of perioperative hypothermia improves patient's outcome. Therapeutic hypothermia can be induced and also improves outcome in certain conditions.

Supplemental intravenous crystalloid administration does not reduce the risk of surgical wound infection.

Wound perfusion and oxygenation are important determinants of the development of postoperative wound infections. Supplemental fluid administration significantly increases tissue oxygenation in surrogate wounds in the subcutaneous tissue of the upper arm in perioperative surgical patients. We tested the hypothesis that supplemental fluid administration during and after elective colon resections decreases the incidence of postoperative wound infections. Patients undergoing open colon resection were randomly assigned to small-volume (n = 124, 8 mL.kg(-1).h(-1)) or large-volume (n = 129, 16-18 mL.kg(-1).h(-1)) fluid management. Our major outcomes were two distinct criteria for diagnosis of surgical wound infections: 1) purulent exudate combined with a culture positive for pathogenic bacteria, and 2) Center for Disease Control criteria for diagnosis of surgical wound infections. All wound infections diagnosed using either criterion by a blinded observer in the 15 days after surgery were considered in the analysis. Wound healing was evaluated with the ASEPSIS scoring system. Of the patients given small fluid administration, 14 had surgical wound infections; 11 given large fluid therapy had infections, P = 0.46. ASEPSIS wound-healing scores were similar in both groups: 7 +/- 16 (small volume) versus 8 +/- 14 (large volume), P = 0.70. Our results suggest that supplemental hydration in the range tested does not impact wound infection rate.

Malignant hyperthermia.

Malignant hyperthermia (MH) is an uncommon, life-threatening, acute pharmacogenetic disorder of the skeletal muscle cell. It manifests in susceptible individuals as a hypermetabolic response on exposure to halogenated volatile anaesthetics and depolarizing muscle relaxants. There may also be a relationship between susceptibility to MH, heat stroke and exercise-induced rhabdomyolysis. The pathophysiology of the crisis involves an uncontrolled release of cytoplasmic free calcium from the sarcoplasmic reticulum leading to activation of energy-producing biochemical pathways. Organ system failure and rhabdomyolysis may occur as a result of high fever, hyperkalaemia and acidosis. The ryanodine receptor, the calcium-release channel of the sarcoplasmic reticulum, is the primary locus for malignant hypothermia susceptibility. Multiple mutations in the gene for the ryanodine receptor protein are causative. Other genes may also be involved. A classical fulminant crisis presents with a rising end-tidal carbon dioxide, skeletal muscle rigidity, tachycardia, hyperthermia and acidosis. Mortality may be as high as 70% if the syndrome is not recognized and treated. Immediate discontinuation of triggering agents, oxygenation, and correction of acidosis and electrolyte abnormalities, cooling and dantrolene are essential for treatment of the syndrome. Thanks to clinical and research investigations, widespread education and the introduction of dantrolene sodium, the mortality from MH is less than 5%. This chapter provides an overview and an update of MH.

Thoracic epidural anesthesia increases tissue oxygenation during major abdominal surgery.

UNLABELLED: Intraoperative surgical stress may markedly increase adrenergic nerve activity and plasma catecholamine concentrations, which causes peripheral vasoconstriction and decreased tissue oxygen partial pressure possibly leading to tissue hypoxia. Tissue hypoxia is associated with an increased incidence of surgical wound infections. Thoracic epidural anesthesia blocks afferent neural stimuli and inhibits efferent sympathetic outflow in response to painful stimuli. Consequently, we tested the hypothesis that supplemental thoracic epidural anesthesia during major abdominal surgery improves tissue perfusion and subcutaneous oxygen tension. Thirty patients were randomly assigned to two groups: general (n = 15) or combined general and epidural anesthesia (n = 15). Anesthesia technique and fluid management were standardized. Subcutaneous tissue oxygen tension was measured continuously in the upper arm with a Clark type electrode. Data were compared with unpaired, two-tailed t-tests, Wilcoxon's ranked sum test, or repeated-measures analysis of variance and Scheffé F tests as appropriate; P < 0.05 was considered statistically significant. After 60 min, intraoperative tissue oxygen tension was significantly larger during combined anesthesia than during general anesthesia (54.3 +/- 7.4 mm Hg versus 42.1 +/- 8.6 mm Hg; P = 0.0002). Subcutaneous tissue oxygen tension remained significantly higher in the combined general/epidural anesthesia group throughout the observation period. Hemodynamic responses and global oxygen variables were similar in the groups. Thoracic epidural anesthesia improved intraoperative tissue oxygen tension outside the area of the epidural block. Thus, our results give evidence that supplemental neural nociceptive block blunts generalized vasoconstriction caused by surgical stress and adrenergic responses. IMPLICATIONS: Thoracic epidural anesthesia blunts the decrease of subcutaneous tissue oxygen tension caused by surgical stress and adrenergic vasoconstriction during major abdominal surgery. Consequently, combined general and epidural anesthesia helps to provide sufficient tissue oxygenation.

Effects of a circulating-water garment and forced-air warming on body heat content and core temperature.

BACKGROUND: Forced-air warming is sometimes unable to maintain perioperative normothermia. Therefore, the authors compared heat transfer, regional heat distribution, and core rewarming of forced-air warming with a novel circulating-water garment. METHODS: Nine volunteers were each evaluated on two randomly ordered study days. They were anesthetized and cooled to a core temperature near 34 degrees C. The volunteers were subsequently warmed for 2.5 h with either a circulating-water garment or a forced-air cover. Overall, heat balance was determined from the difference between cutaneous heat loss (thermal flux transducers) and metabolic heat production (oxygen consumption). Average arm and leg (peripheral) tissue temperatures were determined from 18 intramuscular needle thermocouples, 15 skin thermal flux transducers, and "deep" hand and foot thermometers. RESULTS: Heat production (approximately 60 kcal/h) and loss (approximately 45 kcal/h) were similar with each treatment before warming. The increases in heat transfer across anterior portions of the skin surface were similar with each warming system (approximately 65 kcal/h). Forced-air warming had no effect on posterior heat transfer, whereas circulating-water transferred 21+/-9 kcal/h through the posterior skin surface after a half hour of warming. Over 2.5 h, circulating water thus increased body heat content 56% more than forced air. Core temperatures thus increased faster than with circulating water than forced air, especially during the first hour, with the result that core temperature was 1.1 degrees +/- 0.7 degrees C greater after 2.5 h (P < 0.001). Peripheral tissue heat content increased twice as much as core heat content with each device, but the core-to-peripheral tissue temperature gradient remained positive throughout the study. CONCLUSIONS: The circulating-water system transferred more heat than forced air, with the difference resulting largely from posterior heating. Circulating water rewarmed patients 0.4 degrees C/h faster than forced air. A substantial peripheral-to-core tissue temperature gradient with each device indicated that peripheral tissues insulated the core, thus slowing heat transfer.