Female mice are protected from diabetes mellitus type 2 (DM2)-exacerbation of ischemic brain injury, concurrently expressing less soluble epoxide hydrolase (sEH), which degrades neuroprotective epoxyeicosatrienoates (EETs). We hypothesize that depleting EETs, via transgenic endothelial sEH overexpression, ablates protection of female brain against acute ischemic stroke. Nine-month-old female and male mice overexpressing human sEH in endothelium (Tie2hsEH) and WT littermates, with or without DM2, were subjected to 60-min middle cerebral artery occlusion. Plasma 14,15-EET concentration, brain capillary erythrocyte flux and infarct size at 24 h were measured. Tie2hsEH decreased 14,15-EET by 65% and 73%, capillary flux by 44% and 39%, and enlarged infarct size by 27% and 35% in DM2 and nondiabetic females, respectively. Tie2hsEH reduced male 14,15-EET by 39% only in nondiabetics, decreased capillary flux by 38% and 31% in DM2 and nondiabetics, respectively, without altering infarct size. DM2 did not alter 14,15-EET for either sex and had no effect on female capillary flux or infarct size. DM2 reduced capillary flux by 38% and 30%, and expanded infarct size by 33% and 32% in male Tie2hsEM and WT mice, respectively. EETs depletion by sEH overexpression overcomes intrinsic protection against acute microvascular and ischemic tissue injury in DM2 and nondiabetic adult/middle-aged females.

Purpose To inquire into clinical practices perceived to mitigate patients' intraoperative distress during awake craniotomies. Methods This mixed-methods study involved administration of Amsterdam Preoperative Anxiety and Information Scale and PTSD Checklist prior to the awake craniotomy to evaluate anxiety and information-seeking related to the procedure and symptoms of PTSD. Generalized Anxiety Disorder Scale and Depression Module of the Patient Health Questionnaire were administered before and after the procedure to evaluate generalized anxiety and depression. Patient interviews were conducted 2-weeks postprocedure and included a novel set of patient experience scales to assess patients' recollection of intraoperative pain, overall distress, anxiety, distress due to noise, perception of empowerment, perception of being well-prepared, overall satisfaction with anaesthesia management, and overall satisfaction with the procedure. Qualitative data were analysed using conventional content analysis. Results Participants (n = 14) had undergone an awake craniotomy for tissue resection due to primary brain tumours or medically-refractory focal epilepsy. Validated self-report questionnaires demonstrated reduced levels of generalized anxiety (pre mean = 8.66; SD = 6.41; post mean= 4.36; SD = 4.24) following the awake craniotomy. Postprocedure interviews revealed very high satisfaction with the awake craniotomy and anaesthesia management and minimal levels of intraoperative pain, anxiety, and distress. The most stressful aspects of the procedure included global recognition of medical diagnosis, anxiety provoked by unfamiliar sights, sounds, and sensations, a perception of a lack of information or misinformation, and long periods of immobility. Important factors in alleviating intraoperative distress included the medical team's ability to promote patient perceptions of control, establish compassionate relationships, address unfamiliar intraoperative sensations, and deliver effective anaesthesia management. Conclusion Compassion, communication, and patient perception of control were critical in mitigating intraoperative distress. Clinical practice recommendations with implications for all clinicians involved in patient care during awake craniotomies are provided. Use of these interventions and strategies to reduce distress are important to holistic patient care and patient experiences of care and may improve the likelihood of optimal brain mapping procedures to improve clinical outcomes during awake craniotomies.

Background: Type 2 diabetes (DM2) exacerbates stroke injury, reduces efficacy of endovascular therapy, and worsens long-term functional outcome. Sex differences exist in stroke incidence, response to therapy, poststroke microvascular dysfunction, and functional recovery. In this study, we tested the hypotheses that poor outcome after stroke in the setting of DM2 is linked to impaired microvascular tissue reperfusion and that male and female DM2 mice exhibit different microvascular reperfusion response after transient middle cerebral artery occlusion (MCAO). Methods: Transient MCAO was induced for 60 minutes using an intraluminal filament in young adult DM2 and nondiabetic control male and female mice. Capillary flux in deep cortical layers was assessed using optical coherence tomography–based optical microangiography (OMAG), and associated regional brain infarct size was evaluated by hematoxylin and eosin staining. Results: Compared to baseline, MCAO reduced absolute capillary red blood cell flux by 84% at 24 hours post-MCAO in male DM2 ( P <0.001) but not male control mice. When normalized to pre-MCAO baseline, red blood cell flux 24 hours after stroke was 64% lower in male DM2 mice than male nondiabetic controls ( P <0.01). In females, MCAO decreased capillary flux by 48% at 24 hours post-MCAO compared with baseline in DM2 ( P <0.05) but not in control mice. Red blood cell flux of female DM2 mice did not differ from that of nondiabetic controls either before or 24 hours after MCAO. Furthermore, normalized capillary flux 24 hours after MCAO failed to differ between female DM2 mice and nondiabetic controls. Concomitantly, male but not female DM2 mice experienced 25% larger infarct in caudate-putamen versus respective nondiabetic controls ( P <0.05). Conclusions: DM2 impairs capillary perfusion and exacerbates ischemic deep brain injury in male but not female young adult mice. Premenopausal females appear to be protected against DM2-related capillary dysfunction and brain injury.

No current treatments target microvascular reperfusion after stroke, which can contribute to poor outcomes even after successful clot retrieval. The G protein–coupled receptor GPR39 is expressed in brain peri-capillary pericytes, and has been implicated in microvascular regulation, but its role in stroke is unknown. We tested the hypothesis that GPR39 plays a protective role after stroke, in part due to preservation of microvascular perfusion. We generated GPR39 knockout (KO) mice and tested whether GPR39 gene deletion worsens capillary blood flow and exacerbates brain injury and functional deficit after focal cerebral ischemia. Stroke was induced in male and female GPR39 KO and WT littermates by 60-min middle cerebral artery occlusion (MCAO). Microvascular perfusion was assessed via capillary red blood cell (RBC) flux in deep cortical layers in vivo using optical microangiography (OMAG). Brain injury was assessed by measuring infarct size by 2,3,5-triphenyltetrazolium chloride staining at 24 h or brain atrophy at 3 weeks after ischemia. Pole and cylinder behavior tests were conducted to assess neurological function deficit at 1 and 3 weeks post-stroke. Male but not female GPR39 KO mice exhibited larger infarcts and lower capillary RBC flux than WT controls after stroke. Male GPR39 KO mice also exhibited worse neurologic deficit at 1 week post-stroke, though functional deficit disappeared in both groups by 3 weeks. GPR39 deletion worsens brain injury, microvascular perfusion, and neurological function after experimental stroke. Results indicate that GPR39 plays a sex-dependent role in re-establishing microvascular flow and limiting ischemic brain damage after stroke.

Soluble epoxide hydrolase (sEH) is abundant in the brain, is upregulated in type 2 diabetes mellitus (DM2), and is possible mediator of ischemic injury via the breakdown of neuroprotective epoxyeicosatrienoic acids (EETs). Prophylactic, pre-ischemic sEH blockade with 4-[[trans-4-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]cyclohexyl]oxy]-benzoic acid (tAUCB) reduces stroke-induced infarct in normal and diabetic mice, with larger neuroprotection in DM2. The present study tested whether benefit occurs in normal and DM2 mice if tAUCB is administered after stroke onset. We performed 60 min middle cerebral artery occlusion in young adult male C57BL mice divided into four groups: normal or DM2, with t-AUCB 2 mg/kg or vehicle 30 min before reperfusion. Endpoints were (1) cerebral blood flow (CBF) by laser Doppler, and (2) brain infarct at 24 h. In nondiabetic mice, t-AUCB reduced infarct size by 30% compared to vehicle-treated mice in the cortex (31.4 ± 4 vs. 43.8 ± 3 (SEM)%, respectively) and 26% in the whole hemisphere (26.3 ± 3 vs. 35.2 ± 2%, both p < 0.05). In contrast, in DM2 mice, tAUCB failed to ameliorate either cortical or hemispheric injury. No differences were seen in CBF. We conclude that tAUCB administered after ischemic stroke onset exerts brain protection in nondiabetic but not DM2 mice, that the neuroprotection appears independent of changes in gross CBF, and that DM2-induced hyperglycemia abolishes t-AUCB-mediated neuroprotection after stroke onset.

Hyperglycemia worsens stroke, yet rigorous glycemic control does not improve neurologic outcome. An alternative is to target downstream molecular mediators triggered by hyperglycemia. Soluble epoxide hydrolase (sEH) is a potential mediator of ischemic injury via its metabolism of neuroprotective epoxyeicosatrienoic acids (EETs). We previously demonstrated that sEH mRNA is overexpressed in type 1 diabetic (T1D) mice, and specific sEH blockade protects the brain from the deleterious effect of T1D on stroke. We tested the hypothesis that type 2 diabetes (T2D) exacerbates injury following middle cerebral artery occlusion (MCAO) in part by up-regulating expression of EPHX2 (gene encoding for sEH) and decreasing brain concentrations of neuroprotective EETs. T2D was produced by combined high-fat diet, nicotinamide and streptozotocin in male C57BL/6J mice. T2D and control mice were treated with vehicle or the sEH inhibitor trans-4-[4-(3-Adamantan-1-yl-ureido) -cyclohexyloxy]-benzoic acid (t-AUCB; 1mg/kg, i.p., 7 days), then subjected to 60-min MCAO. Compared to normal chow-fed mice, high fat diet-fed mice exhibited a 1.7 fold upregulation of EPHX2 mRNA in brain (p<0.05, n=7). T2D mice had increased blood glucose levels compared to control mice before, during and after MCAO (p<0.001, n=4-5). Relative laser-Doppler perfusion of the MCA territory after reperfusion was decreased in T2D mice compared to controls (p<0.05, n= 4-5). Vehicle-treated T2D mice sustained larger cortical infarcts than vehicle-treated control mice (p<0.05, n=5-7). t-AUCB decreased fasting glucose levels at baseline and throughout ischemia (p<0.001, n=4-5) and improved cortical perfusion after MCAO (p<0.001, n=4-5) in T2D mice. In line with these improvements, t-AUCB significantly reduced infarct size in T2D mice (p<0.05 vs. T2D vehicle, n= 5-7). We conclude that increasing EETs bioavailability via sEH inhibition improves stroke outcome in T2D in part by improving glycemic status and improving post-ischemic reperfusion in the ischemic territory.

Inhibition of soluble epoxide hydrolase (sEH) is a potential target of therapy for ischemic injury. sEH metabolizes neuroprotective epoxyeicosatrienoic acids (EETs). We recently demonstrated that sEH inhibition reduces infarct size after middle cerebral artery occlusion (MCAO) in type 1 diabetic mice. We hypothesized that inhibition of sEH would protect against ischemic injury in type 2 diabetic mice. Type 2 diabetes was produced by combined high-fat diet, nicotinamide and streptozotocin in male mice. Diabetic and control mice were treated with vehicle or the sEH inhibitor t-AUCB then subjected to 60-min MCAO. Compared to chow-fed mice, high fat diet-fed mice exhibited an upregulation of sEH mRNA and protein in brain, but no differences in brain EETs levels were observed between groups. Type 2 diabetic mice had increased blood glucose levels at baseline and throughout ischemia, decreased laser-Doppler perfusion of the MCA territory after reperfusion, and sustained larger cortical infarcts compared to control mice. t-AUCB decreased fasting glucose levels at baseline and throughout ischemia, improved cortical perfusion after MCAO and significantly reduced infarct size in diabetic mice. We conclude that sEH inhibition, as a preventative treatment, improves glycemic status, post-ischemic reperfusion in the ischemic territory, and stroke outcome in type 2 diabetic mice.

Hyperglycemia worsens stroke, yet rigorous glycemic control does not improve neurologic outcome. An alternative is to target downstream molecular mediator(s) triggered by hyperglycemia but independent of prevailing glycemia. Soluble epoxide hydrolase (sEH) is a potential mediator of injury via its metabolism of neuroprotective epoxyeicosatrienoic acids (EETs). We tested whether hyperglycemia exacerbates cerebral injury by upregulating sEH and decreasing brain EET levels. Type 1 diabetes mellitus was modeled by streptozotocin (STZ; 50 mg/kg per day intraperitoneally, 5 days) in male mice. At 4 weeks, STZ-treated and control mice underwent 45-minute middle cerebral artery occlusion (MCAO) with or without sEH blockade by trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB; 1 mg/kg intraperitoneally daily for 6 days before MCAO). The STZ-treated mice had increased sEH mRNA expression in cerebral vessels and decreased EET concentrations in brain. There was no difference in cortical perfusion between groups. The STZ-treated mice sustained larger brain infarct than controls. Pretreatment with t-AUCB eliminated the difference in infarct size and EETs concentration between STZ-treated mice and controls, without altering glycemia. We conclude that type 1 diabetes mellitus upregulates sEH mRNA and decreases concentrations of neuroprotective EETs within the brain, leading to worse stroke outcome. The data indicate that sEH antagonism may be beneficial in the setting of hyperglycemic stroke.

Lactic acidosis occurs during orthotopic liver transplantation (OLT), especially during the anhepatic and early postreperfusion phases. Dichloroacetate (DCA) inhibits pyruvate dehydrogenase kinase-1, indirectly activating mitochondrial pyruvate dehydrogenase. This, in turn, markedly reduces systemic lactate production and, to a lesser extent, increases hepatic lactate uptake. The result is moderation of lactic acidosis in many clinical conditions. This study evaluated the efficacy of DCA in controlling lactic acidosis during OLT and improving perioperative outcome from OLT. After informed consent, 250 patients for OLT received either intraoperative DCA or placebo. DCA (40 mg/kg intravenously) or placebo was administered after anesthesia induction and repeated 4 hours later. Intraoperative measures were arterial blood gases, lactate, and Na+ and utilization of blood products, CaCl2, and NaHCO3. Outcome measures were time to tracheal extubation, intensive care unit length of stay, hospital length of stay, requirement for postoperative plasma transfusion, retransplantation, and perioperative mortality. DCA reduced the arterial lactic acid concentration by an average of 44% (1.8 mmol L-1, P < 0.001), stabilized the acid-base balance, and reduced NaHCO3 administration by 80% (P < 0.001). Postoperatively, DCA-treated patients required 50% less postoperative plasma transfusion (2 versus 4 units, respectively, P = 0.016), but the incidence of transfusion was similar in both groups (62% versus 60%, P = 0.381). DCA did not alter time to extubation, intensive care unit length of stay, or hospital length of stay. In conclusion, DCA attenuated lactic acidosis during OLT, stabilizing the intraoperative acid-base balance and decreasing NaHCO3 use. DCA decreased postoperative plasma transfusion requirement but otherwise had no measurable effect on perioperative outcome parameters.

Purpose of review Common definitions for workplace generations are the silent generation (born 1925–1945), the baby boomer generation (1946–1962), generation X (1963–1981), and generation Y (1982–2000). Distinct motivational and value perceptions stereotype generations. This review defines the characteristics of workplace generations today and provides insight into how differences influence the workplace environment. Recent findings Senior faculty members are mostly boomers, whereas residents and junior faculty members tend to belong to generation X. Medical students and incoming interns are from generation Y. When compared with boomers, generation X is more savvy with technology, more independent, less loyal to the institution, and seeks balance between work and lifestyle. The 80-h resident working week restriction has reinforced differences between older and younger physicians. Generation Y exhibits traits that are similar to those of generation X. Their increased interest in anesthesiology may reflect, in part, their assumption that it affords better control of lifestyle. Summary Understanding, improved communication strategies, mentorship, and flexibility in methods employed to achieve common goals are most likely to capture the interest and cooperation of members of generation X and possibly Y. Future studies should test effects of particular interventions on outcome in terms of recruitment and performance milestones.

BACKGROUND:The purpose of this study was to test the equivalence of efficacy and compare the safety of the 6% hydroxyethyl starches (HES) Voluven (HES 130/0.4; Fresenius Kabi, Bad Homburg, Germany) and hetastarch (HES 670/0.75 in saline) for intravascular volume replacement therapy during major orthopedic surgery.METHODS:In a prospective, controlled, randomized, double-blind, multicenter trial of patients undergoing major orthopedic surgery, 49 patients were treated with HES 130/0.4 and 51 patients were treated with hetastarch. Infusion of colloids was guided by central venous and arterial blood pressures. The primary efficacy endpoint was the volume of colloid solution infused; the primary safety endpoints were calculated total erythrocyte loss, the nadir factor VIII activity, and the nadir von Willebrand factor concentration within 2 h of completion of surgery.RESULTS:The total volume of colloid solution required for intraoperative volume replacement did not differ between HES 130/0.4 and hetastarch (1,613+/-778 [SD] ml for HES 130/0.4 and 1,584+/-958 ml for hetastarch). The nadir factor VIII activity within 2 h of the end of surgery was lower for hetastarch than for HES 130/0.4 (P=0.0499); for those who received greater than 1,000 ml colloid, the nadir factor VIII activity and von Willebrand factor concentration within 2 h of end of surgery were lower for hetastarch than for HES 130/0.4 (P=0.0487 and P=0.008, respectively).CONCLUSION:Voluven (HES 130/0.4) and hetastarch are equally efficacious plasma volume substitutes; however, HES 130/0.4 has a lesser effect on coagulation.

Supported in part by PHS Grants DK-19525 and 5 M01 RR000334, and a Clinical Scientist Research Award from the International Anesthesia Research Society.

Dichloroacetate (DCA) has been used as an experimental treatment for lactic acidosis because it lowers plasma lactic acid concentration. Three potential mechanisms could underlie the hypolactatemic action of DCA, but the dominant mechanism in vivo remains unclear. This study tested whether DCA-induced hypolactatemia occurs via decreased lactate production, increased lactate clearance, or decreased rate of glycolysis in healthy humans and in patients with end-stage cirrhosis. Cirrhosis is associated with decreased hepatic pyruvate dehydrogenase (PDH) content. Six healthy volunteers and 7 cirrhotic patients received a primed, constant infusion of 1-13C-pyruvate and 15N-alanine for 5 hours. DCA (35 mg/kg intravenously) was administered at 2 hours. Plasma isotopic enrichment was measured by gas chromatography/mass spectrometry (GC/MS), and exhaled CO2 enrichment by isotope ratio mass spectrometry. Pyruvate and alanine production rates (Ra) were determined by isotope dilution, and pyruvate oxidation calculated as 13CO2 production from 13C-pyruvate. Ra lactate was calculated as the difference between Ra pyruvate and its disposal by oxidation to CO2 and conversion to alanine. Baseline plasma lactate kinetics in cirrhotic patients did not differ from controls. DCA decreased lactate concentration in both groups by approximately 53%. DCA decreased glycolysis (Ra pyruvate) by 24%, increased the fraction of pyruvate oxidized to CO2 by 26%, and decreased pyruvate transamination to alanine by 25%. DCA also inhibited lactate production by 85%, but decreased plasma lactate clearance by 60% in both groups. DCA reduces plasma lactic acid concentration by inhibiting production, via stimulating pyruvate oxidation and inhibiting glycolysis, rather than increasing clearance. In addition, end-stage cirrhosis does not alter either the mechanism or the magnitude of the metabolic response to DCA.

Fundamental Principles and Clinical Practice of Anaesthesia P. Hutton, G.M. Cooper, F.M. James III, J.F. Butterworth IV, eds. London, United Kingdom: Martin Dunitz, 2002. ISBN 1-899066- 57-8. 1072 pp., $135.00. This new anesthesia textbook is edited by four prominent academic anesthesiologists, two each from the United Kingdom and the United States, and is targeted at individuals in the first 2 years of anesthesia training. The book is bigger and more comprehensive than the typical introductory textbooks used in medical school, yet more concise than the definitive textbooks used in the United States as either reference material or preparation for the board examinations for the American Board of Anesthesiology. Including the four editors, each of whom contributed extensively to the book, there are 53 contributing authors. Many, but not all, chapter authors hail from the home institutions of the editors, the University of Birmingham in the United Kingdom and Wake Forest University in the United States. The book is divided into 87 chapters, each of which is subdivided in the table of contents into succinct topics occupying a page or less, which facilitates quickly finding an area of interest. Chapters are copiously illustrated with tables, graphs, and/or photographs to supplement the text. Appended at the end of each chapter there is a deliberately brief list of further reading material for more in-depth review. The chapters, in turn, are organized into four sections: Basic Anesthesia Practice, which covers principles of general anesthesia, airway management, and regional anesthesia; Integrated Basic Science, which presents the fundamental biological principles underlying the specialty; The Presenting Patient, which highlights anesthetic implications of comorbidity; and Special Subjects, which discusses essential procedures performed by the practicing anesthesiologist, considerations outside of the operating room, and assorted other topics. The complete index at the end of the book complements the excellent table of contents to allow fast referral to a subject matter of interest. The first section seamlessly overviews fundamental aspects of anesthesia care from the preoperative visit, anesthesia equipment and monitoring, considerations in airway management, patient positioning, and basic issues associated with the induction, maintenance, and emergence from general anesthesia. The chapters on anesthesia equipment, which include color photographs, are especially good. Regional anesthesia, while by no means handled exhaustively, is reasonably complete in the common techniques of neuraxial anesthesia, brachial plexus blockade, and Bier block. A limitation is that local anesthetics widely used in the United States (e.g. mepivicaine and chorprocaine) are not mentioned, probably because their use in the United Kingdom is limited or nonexistent. Another limitation is that tables listing local anes-thetic alternativesand doses for spinal and epidural anesthesia, which would be important for the junior trainee, are missing. The chapter on surgical requirements for anesthesia was adequate for simple procedures but did not address issues associated with craniotomy, thoracotomy with or without one-lung ventilation, or cardiopulmonary bypass. The section on basic science, in particular, is new and attractive because of its strong and relatively in-depth presentation. It is by far the largest section, accounting for 482 pages divided among 23 chapters. In this way it differs most from the approach of U.S. elementary textbooks that integrate the basic science into the practice of anesthesiology. It is not clear why the chapters on “Properties of the Endothelium,” “G Proteins,” “Cellular Aging,” and “Nitric Oxide” are separated from the rest of the basic science topics and placed in the last section. However, it is easy to track down these subjects using either the table of contents or the index at the end of the book. The material is clearly presented and will be understandable for all anesthesia trainees. Organization of the third section centers on the pathology that a patient brings to the operating room. A chapter each is dedicated to considerations for pediatric patients, elderly patients, and patients with pregnancy, obesity, abnormal EKG, coronary artery disease, valvular heart disease, anemia, pulmonary disease, diabetes mellitus, other endocrine dysfunctions, jaundice, arthritis, renal dysfunction, infection, neurological disease, and acute abdomen. This type of mental organization is especially helpful in assessing patients and the type of risks associated with their comorbidities, regardless of the planned surgery. Difficulties encountered with the book are the transatlantic vocabulary and the lack of chapters dealing with more complex surgical operations. Examples of the former are words such as “suxamethonium” versus “succinylcholine,” “lignocaine” versus “lidocaine,” “trolley” versus “gurney,” and “fridge” versus “refrigerator.” U.S. trainees without an interface with a British-experienced anesthesiologist may have trouble deciphering these terms. While it is understandable that comprehensive anesthesia considerations for a given surgical procedure are not among the topics presented, it is common for U.S. trainees to encounter more complex cases such as a craniotomy, thoracotomy, or cardiopulmonary bypass by the time of their second year of training. Therefore, it would be necessary for U.S. anesthesia residents to consult another textbook to attain adequate insight for the conduct of anesthesia during these procedures. There was no mention of the special concerns of providing anesthesia care in the MRI suite, which is an environment to which trainees will be exposed and would have been valuable in the last section. On the other hand, the emphasis and organization of the book is ideal for anesthesia trainees in the United Kingdom, for whom a 2-year training period culminates in a basic science-laden Primary FRCA examination. This hurdle must be overcome before one can graduate to more complex anesthesia training. Clearly the Primary FRCA syllabus was in mind when the book was planned, as it comprehensively covers the syllabus and would need only minor supplementation from other texts. There is no doubt that this book will prove to be immensely useful and popular with new U.K. anesthesia trainees. In summary, this is an excellent new book that we wholeheartedly recommend for U.K. trainees working toward the Primary FRCA examination. It would serve as an enjoyable and useful addition for their U.S. counterparts, but will not supplant more established texts. It should certainly have a place in every departmental library.

Insulin regulates glucose and potassium metabolism by acting differently upon peripheral tissues (e.g., skeletal muscle) and the splanchnic bed, including the liver. Liver disease is accompanied by "insulin resistance" of glucose metabolism, whereby glucose intolerance occurs despite relatively increased plasma insulin concentration. However, it is unknown whether insulin resistance extends to potassium metabolism. Further, it is uncertain whether the hyperglycemia and alterations of plasma potassium concentration observed during liver transplantation result from changes in circulating insulin concentration, altered sensitivity to insulin, or both, as the diseased liver is removed and replaced with a graft organ. The present study evaluated the role of the liver in maximal insulin responsiveness of whole-body glucose and potassium metabolism, using a hyperinsulinemic clamp technique, to identify the mechanism(s) underlying post-reperfusion hyperglycemia and intraoperative hyperkalemia. Two protocols were employed: in protocol 1 (n = 10), no exogenous insulin was administered. In protocol 2 (n = 10), an intravenous insulin bolus (666 mU . kg-1) was administered after anesthesia induction, followed by an infusion at 500 mU.m-2.min-1, which continued until 3 hours after portal vein unclamping. Plasma concentrations of glucose and potassium were regulated by glucose and potassium chloride infusion (euglycemic eukalemic clamp). Insulin-stimulated exogenous glucose and potassium uptakes were determined in protocol 2 before skin incision and during the dissection, anhepatic, and neohepatic stages. In both protocols, serial measurements of hemodynamic arterial blood gases, glucose, free fatty acids, potassium, insulin, and glucagon concentrations were made. Without insulin (protocol 1), progressive hyperglycemia peaked after portal vein unclamping (post-reperfusion hyperglycemia), with no concomitant decrease in plasma insulin concentration. Intraoperative plasma potassium concentration did not change. Insulin infusion (protocol 2) produced a stable hyperinsulinemia (approximately 2000 microU/mL). Hyperinsulinemia did not eliminate post-reperfusion hyperglycemia. Insulin-stimulated glucose uptake, in mg . kg-1 . min-1, was 8.10 +/- 0.78 (mean +/- SE) before skin incision, 7.62 +/- 0.82 during the hepatic dissection, 4.40 +/- 0.75 during the anhepatic stage, and 4.06 +/- 0.74 at 3 hours after portal vein unclamping. Insulin-stimulated potassium uptake, in mEq . kg-1 . hr-1, was 0.24 +/- 0.02 before skin incision, 0.21 +/- 0.04 during hepatic dissection, 0.07 +/- 0.02 during the anhepatic stage, and 0.21 +/- 0.04 and 0.19 +/- 0.05 at 30 minutes and 3 hours, respectively, after portal vein unclamping. We conclude that post-reperfusion hyperglycemia is not due to inadequate insulin stimulation. Liver disease-induced insulin resistance of glucose metabolism is exacerbated by hepatectomy and is not reversed during the intraoperative neohepatic stage. Liver disease does not impair maximal insulin-stimulated potassium uptake. The liver, even with end-stage disease, accounts for approximately 70% of insulin-stimulated potassium uptake.