Potentiation of the NO-cGMP pathway and blood flow responses during dynamic exercise in healthy humans.

PURPOSE: Previous work has shown nitric oxide (NO) contributes to ~15% of the hyperemic response to dynamic exercise in healthy humans. This NO-mediated vasodilation occurs, in part, via increases in intracellular cyclic guanosine monophosphate (cGMP), which is catabolized by phosphodiesterase. We sought to examine the effect of phosphodiesterase-5 (PDE-5) inhibition on forearm blood flow (FBF) responses to dynamic handgrip exercise in healthy humans and the role of NO. We hypothesized exercise hyperemia would be augmented by sildenafil citrate (SDF, PDE-5 inhibitor). We further hypothesized any effect of SDF on exercise hyperemia would be abolished with intra-arterial infusion of the NO synthase (NOS) inhibitor L-NG-monomethyl arginine (L-NMMA). METHODS: FBF (Doppler ultrasound) was assessed at rest and during 5 min of dynamic forearm handgrip exercise at 15% of maximal voluntary contraction under control (saline) conditions and during 3 experimental protocols: (1) oral SDF (n = 10), (2) intra-arterial L-NMMA (n = 20), (3) SDF and L-NMMA (n = 10). FBF responses to intra-arterial sodium nitroprusside (NTP, NO donor) were also assessed. RESULTS: FBF increased with exercise (p < 0.01). Intra-arterial infusion of L-NMMA resulted in a reduction in exercise hyperemia (17 ± 1 to 15 ± 1 mL/dL/min, p < 0.01). Although the hyperemic response to NTP was augmented by SDF (area under the curve: 41 ± 7 vs 61 ± 11 AU, p < 0.01), there was no effect of SDF on exercise hyperemia (p = 0.33). CONCLUSIONS: Despite improving NTP-mediated vasodilation, oral SDF failed to augment exercise hyperemia in young, healthy adults. These observations reflect a minor contribution of NO and the cGMP pathway during exercise hyperemia in healthy young humans.

Improved Ventilatory Efficiency with Locomotor Muscle Afferent Inhibition is Strongly Associated with Leg Composition in Heart Failure.

BACKGROUND: Skeletal muscle atrophy contributes to increased afferent feedback (group III and IV) and may influence ventilatory control (high VE/VCO2 slope) in heart failure (HF). OBJECTIVE: This study examined the influence of muscle mass on the change in VE/VCO2 with afferent neural block during exercise in HF. METHODS: 17 participants [9 HF (60±6 yrs) and 8 controls (CTL) (63±7 yrs, mean±SD)] completed 3 sessions. Session 1: dual energy x-ray absorptiometry and graded cycle exercise to volitional fatigue. Sessions 2 and 3: 5 min of constant-work cycle exercise (65% of peak power) randomized to lumbar intrathecal injection of fentanyl (afferent blockade) or placebo. Ventilation (VE) and gas exchange (oxygen consumption, VO2; carbon dioxide production, VCO2) were measured. RESULTS: Peak work and VO2 were lower in HF (p<0.05). Leg fat was greater in HF (34.4±3.0 and 26.3±1.8%) and leg muscle mass was lower in HF (63.0±2.8 and 70.4±1.8%, respectively, p<0.05). VE/VCO2 slope was reduced in HF during afferent blockade compared with CTL (-18.8±2.7 and -1.4±2.0%, respectively, p=0.02) and was positively associated with leg muscle mass (r2=0.58, p<0.01) and negatively associated with leg fat mass (r2=0.73, p<0.01) in HF only. CONCLUSIONS: HF patients with the highest fat mass and the least leg muscle mass had the greatest improvement in VE/VCO2 with afferent blockade with leg fat mass being the only predictor for the improvement in VE/VCO2 slope. Both leg muscle mass and fat mass are important contributors to ventilatory abnormalities and strongly associated to improvements in VE/VCO2 slope with locomotor afferent inhibition in HF.

Interactions between beta-2 adrenoceptor gene variation, cardiovascular control and dietary sodium in healthy young adults.

Dietary sodium affects function of the beta-2 adrenoceptor (ADRB2). We tested the hypothesis that haplotype variation in the ADRB2 gene would influence the cardiovascular and regional vasodilator responses to sympathoexcitatory manoeuvres following low, normal and high sodium diets, and ADRB2-mediated forearm vasodilation in the high sodium condition. Seventy-one healthy young adults were grouped by double homozygous haplotypes: Arg16+Gln27 (n = 31), the rare Gly16+Gln27 (n = 10) and Gly16+Glu27 (n = 30). Using a randomized cross-over design, subjects were studied following 5 days of controlled low, normal and high sodium with 1 month or longer between diets (and low hormone phase of the menstrual cycle). All three visits utilized ECG and finger plethysmography for haemodynamic measures, and the high sodium visit included a brachial arterial catheter for forearm vasodilator responses to isoprenaline with plethysmography. Lymphocytes were sampled for ex vivo analysis of ADRB2 density and binding conformation. We found a main effect of haplotype on ADRB2 density (P = 0.03) with the Gly16+Glu27 haplotype having the greatest density (low, normal, high sodium: 12.9 ± 0.9, 13.5 ± 0.9 and 13.6 ± 0.8 fmol mg(-1) protein, respectively) and Arg16+Gln27 having the least (9.3 ± 0.6, 10.1 ± 0.5 and 10.3 ± 0.6  fmol mg(-1) protein, respectively), but there were no sodium or haplotype effects on receptor binding conformation. In the mental stress trial, there was a main effect of haplotype on cardiac output (P = 0.04), as Arg16+Gln27 had the lowest responses. Handgrip and forearm vasodilation yielded no haplotype differences, and no correlations were present for ADRB2 density and haemodynamics. Our findings support cell-based evidence that ADRB2 haplotype influences ADRB2 protein expression independent of dietary sodium, yet the haemodynamic consequences appear modest in healthy humans.

The psychological and physiological effects of acute occupational stress in new anesthesiology residents: a pilot trial.

BACKGROUND: Occupational stress in resident physicians has profound implications for wellness, professionalism, and patient care. This observational pilot trial measured psychological and physiological stress biomarkers before, during, and after the start of anesthesia residency. METHODS: Eighteen physician interns scheduled to begin anesthesia residency were recruited for evaluation at three time points: baseline (collected remotely before residency in June 2013); first-month visit 1 (July); and follow-up visit 2 (residency months 3 to 5, September-November). Validated scales were used to measure stress, anxiety, resilience, and wellness at all three time points. During visits 1 and 2, the authors measured resting heart-rate variability, responses to laboratory mental stress (hemodynamic, catecholamine, cortisol, and interleukin-6), and chronic stress indices (C-reactive protein, 24-h ambulatory heart rate and blood pressure, 24-h urinary cortisol and catecholamines, overnight heart-rate variability). RESULTS: Thirteen interns agreed to participate (72% enrollment). There were seven men and six women, aged 27 to 33 yr. The mean ± SD of all study variables are reported. CONCLUSION: The novelty of this report is the prospective design in a defined cohort of residents newly exposed to the similar occupational stress of the operating environment. Because of the paucity of literature specific to the measures and stress conditions in this investigation, no data were available to generate a priori definition of primary outcomes and a data analytic plan. These findings will allow power analysis for future design of trials examining occupational stress and stress-reducing interventions. Given the importance of physician burnout in our country, the impact of chronic stress on resident wellness requires further study.

Outcomes after radical prostatectomy for cancer: a comparison between general anesthesia and epidural anesthesia with fentanyl analgesia: a matched cohort study.

BACKGROUND: The use of regional anesthesia for cancer surgery has been associated with improved oncologic outcomes. One of the proposed mechanisms is a reduction in the use of systemic opioids that may cause immunosuppression. We used a retrospective matched cohort design to compare long-term oncologic outcomes after prostatectomy for cancer performed under general anesthesia with systemic opioids or with epidural anesthesia with epidural fentanyl analgesia. Since epidural fentanyl is quickly reabsorbed systemically, we hypothesized that there would be no difference in long-term oncological outcomes between the 2 groups. METHODS: There were 486 men who underwent prostatectomy performed under epidural anesthesia between January 1, 1991, and January 31, 1996. They were 1:1 matched based on age (±5 years), surgical year (±1 year), and baseline prostate cancer pathology to patients who had general anesthesia with systemic opioids. Long-term cancer outcomes and all-cause mortality were examined. Analyses were performed using stratified proportional hazards regression models, with hazard ratios >1 indicating worse outcome for general anesthesia only compared with epidural anesthesia and fentanyl analgesia. RESULTS: After adjusting for positive surgical margins and adjuvant therapies, patients in the general anesthesia group were found not to be at increased risk of prostate cancer recurrence (hazard ratio [HR] = 0.79, 95% confidence interval [CI], 0.60-1.04], systemic tumor progression (HR = 0.92, 95% CI, 0.46-1.84), cancer-specific mortality (HR = 0.53, 95% CI, 0.18-1.58), or overall mortality (HR = 1.23, 95% CI 0.93-1.63) when compared with patients who received epidural anesthesia. CONCLUSIONS: Compared with general anesthesia with systemic opioids, epidural anesthesia and analgesia with fentanyl were not associated with improvement in oncologic outcomes in patients undergoing radical prostatectomy for cancer.

Forearm vasodilator responses to a ß-adrenergic receptor agonist in premenopausal and postmenopausal women.

Beta-adrenergic vasodilator responses may be blunted in humans who are at an increased risk for hypertension. Because menopause is associated with an increase in blood pressure, we tested the hypothesis that forearm blood flow responses to the ß-adrenergic receptor agonist isoproterenol are blunted in older, postmenopausal women compared to young, premenopausal women. We used venous occlusion plethysmography to measure forearm blood flow in young premenopausal (26 ± 1 years; n = 13) and postmenopausal (61 ± 2 years; n = 12) women. Forearm blood flow and mean arterial pressure were measured at baseline and during isoproterenol infusion at 1.0, 3.0, 6.0, and 12.0 ng/100 mL tissue/min. The two groups did not differ in body mass index or mean arterial pressure. Baseline forearm blood flow was similar between young and postmenopausal women (3.7 ± 0.5 vs. 2.9 ± 0.4 mL/100 mL tissue/min, respectively; P > 0.05). At the lowest dose of isoproterenol, forearm blood flow vasodilator responses were lower in postmenopausal women compared with young women (5.8 ± 0.4 vs. 7.4 ± 0.3 mL/100 mL tissue/min, respectively; P < 0.05). Thereafter, forearm blood flow remained similar between the groups for the remaining isoproterenol doses. In conclusion, ß-adrenergic receptor-mediated forearm vasodilator responses are blunted in healthy, older postmenopausal women at lower but not higher doses of isoproterenol. This suggests that in aging women, ß-adrenergic receptor-mediated vasodilator responses may be blunted at a moderate level of stimulation while maximum receptor responses are preserved.

Effect of ß2-adrenergic receptor polymorphisms on epinephrine and exercise-stimulated lipolysis in humans.

The ß2-adrenergic system is an important regulator of human adipose tissue lipolysis. Polymorphisms that result in amino acid substitutions in the ß2-adrenergic receptor have been reported to alter lipolysis. We hypothesized that variations in the amino acid at position 16 of the ß2-adrenergic receptor would result in different lipolytic responses to intravenous epinephrine and exercise. 17 volunteers homozygous for glycine at position 16 (Gly/Gly, nine female) and 16 volunteers homozygous for arginine at position 16 (Arg/Arg, eight female) of the ß2-adrenergic receptor participated in this study. On one study day participants received infusions of epinephrine at submaximal (5 ng kg(-1) min(-1)) and maximal (40 ng kg(-1) min(-1)) lipolytic doses. The other study day volunteers bicycled for 90 min at 50-60% of maximum oxygen consumption (VO2max). [9,10-(3)H] Palmitate was infused both days to measure free fatty acid - palmitate kinetics. Oxygen consumption was measured using indirect calorimetry. Palmitate release rates in response to epinephrine and exercise were not different in the Gly/Gly and Arg/Arg participants. The only statistically significant difference we observed was a lesser ΔVO2 in Arg/Arg volunteers in response to the submaximal epinephrine infusion. The polymorphisms resulting in Arg/Arg and Gly/Gly at position 16 of the ß2-adrenergic receptor do not result in clinically meaningful differences in lipolysis responses to epinephrine or submaximal exercise.

Cyclo-oxygenase-2 inhibition and endothelium-dependent vasodilation in younger vs. older healthy adults.

AIM: A major feature of endothelial dysfunction is reduced endothelium-dependent vasodilation, which in ageing may be due to decreased production of endothelial prostacyclin, or nitric oxide (NO), or both. METHOD: We tested this hypothesis in 12 younger (age 18-38 years, six women) and 12 older healthy adults (age 55-73 years, six post-menopausal women). Endothelium-dependent vasodilation was assessed by the forearm vascular conductance (FVC) response to intra-arterial acetylcholine (ACh) (0.5, 1.0, 2.0, 4.0 µg dl(-1) forearm tissue min(-1) ) before and 90 min after inhibition of the enzyme cyclo-oxygenase-2 (COX-2) with oral celecoxib (400 mg), followed by the addition of endothelial NO synthase inhibition with intra-arterial N(G) -monomethyl-l arginine acetate (L-NMMA). RESULTS: Ageing was associated with a significantly reduced FVC response to ACh (P = 0.009, age-by-dose interaction; highest dose FVC ± SEM in ageing: 11.2 ± 1.4 vs. younger: 17.7 ± 2.4 units, P = 0.02). Celecoxib did not reduce resting FVC or the responses to ACh in any group. L-NMMA significantly reduced resting FVC and the responses to ACh in all groups, and absolute FVC values following L-NMMA were similar between groups. CONCLUSION: In healthy normotensive younger and older adults, there is minimal contribution of prostacyclin to ACh-mediated vasodilation, yet the NO component of vasodilation is reduced with ageing. In the clinical context, these findings suggest that acute administration of medications that inhibit prostacyclin (i.e. COX-2 inhibitors) evoke modest vascular consequences in healthy persons. Additional studies are necessary to test whether chronic use of COX-2 medications reduces endothelium dependent vasodilation in older persons with or without cardiovascular risk factors.

Postoperative acute respiratory distress syndrome in patients with previous exposure to bleomycin.

OBJECTIVE: To determine the incidence and risk factors for postoperative acute respiratory distress syndrome (ARDS) in a large cohort of bleomycin-exposed patients undergoing surgery with general endotracheal anesthesia. PATIENTS AND METHODS: From a Mayo Clinic cancer registry, we identified patients who had received systemic bleomycin and then underwent a major surgical procedure that required more than 1 hour of general anesthesia from January 1, 2000, through August 30, 2012. Heart, lung, and liver transplantations were excluded. Postoperative ARDS (within 7 days after surgery) was defined according to the Berlin criteria. RESULTS: We identified 316 patients who underwent 541 major surgical procedures. Only 7 patients met the criteria for postoperative ARDS; all were white men, and 6 were current or former smokers. On univariate analysis, we observed an increased risk of postoperative ARDS in patients who were current or former smokers. Furthermore, significantly greater crystalloid and colloid administration was found in patients with postoperative ARDS. We also observed a trend toward longer surgical duration and red blood cell transfusion in patients with postoperative ARDS, although this finding was not significant. Intraoperative fraction of inspired oxygen was not associated with postoperative ARDS. In bleomycin-exposed patients, the incidence of postoperative ARDS after major surgery with general anesthesia is approximately 1.3% (95% CI, 0.6%-2.6%). For first major procedures after bleomycin therapy, the incidence is 1.9% (95% CI, 0.9%-4.1%). CONCLUSION: The risk of postoperative ARDS in patients exposed to systemic bleomycin appears to be lower than expected. Smoking status may be an important factor that modifies the risk of postoperative ARDS in these patients.

Dietary sodium influences the effect of mental stress on heart rate variability: a randomized trial in healthy adults.

BACKGROUND: Dietary sodium influences intermediate physiological traits in healthy adults independent of changes in blood pressure. The purpose of this study was to test the hypothesis that dietary sodium affects cardiac autonomic modulation during mental stress. METHOD: In a prospective, randomized cross-over design separated by 1 month between diets, 70 normotensive healthy young adults (F/M: 44/26, aged 18-38 years) consumed a 5-day low (10 mmol/day), normal (150 mmol), and high (400 mmol) sodium diet followed by heart rate variability (HRV) recordings at rest and during 5-min computerized mental arithmetic. Women were studied in the low hormone phase of the menstrual cycle following each diet. RESULTS: Diet did not affect resting blood pressure, but heart rate (HR) (mean ± SE) was 66 ± 1, 64 ± 1, and 63 ± 1 bpm in low, normal, and high sodium conditions, respectively (analysis of variance P = 0.02). For HRV, there was a main effect of sodium on resting SD of normalized RR intervals (SDNN), square root of the mean squared difference of successive normalized RR intervals (RMSSD), high frequency, low-frequency normalized units (LFnu), and high-frequency normalized units (HFnu) (P < 0.01 for all). The response to low sodium was most marked and consistent with sympathetic activation and reduced vagal activity, with increased LFnu and decreased SDNN, RMSSD, and HFnu compared to both normal and high sodium conditions (P ≤0.05 for all). Dietary sodium-by-mental stress interactions were significant for mean NN, RMSSD, high-frequency power, LFnu, and low frequency/high frequency ratio (P < 0.05 for all). The interactions signify that sodium restriction evoked an increase in resting sympathetic activity and reduced vagal activity to the extent that mental stress caused modest additional disruptions in autonomic balance. Conversely, normal and high sodium evoked a reduction in resting sympathetic activity and incremental increase in resting vagal activity, which were disrupted to a greater extent during mental stress compared to low sodium. CONCLUSION: We conclude that autonomic control of HRV at rest and during mental stress is altered by dietary sodium in healthy normotensive young adult men and women.

Aging enhances autonomic support of blood pressure in women.

The autonomic nervous system plays a central role in both acute and chronic blood pressure regulation in humans. The activity of the sympathetic branch of the autonomic nervous system is positively associated with peripheral resistance, an important determinant of mean arterial pressure in men. In contrast, there is no association between sympathetic nerve activity and peripheral resistance in women before menopause, yet a positive association after menopause. We hypothesized that autonomic support of blood pressure is higher after menopause in women. We examined the effect of ganglionic blockade on arterial blood pressure and how this relates to baseline muscle sympathetic nerve activity in 12 young (25±1 years) and 12 older postmenopausal (61±2 years) women. The women were studied before and during autonomic blockade using trimethaphan camsylate. At baseline, muscle sympathetic nerve activity burst frequency and burst incidence were higher in the older women (33±3 versus 15±1 bursts/min; 57±5 versus 25±2 bursts/100 heartbeats, respectively; P<0.05). Muscle sympathetic nerve activity bursts were abolished by trimethaphan within minutes. Older women had a greater decrease in mean arterial pressure (-29±2 versus -9±2 mm Hg; P<0.01) and total peripheral resistance (-10±1 versus -5±1 mm Hg/L per minute; P<0.01) during trimethaphan. Baseline muscle sympathetic nerve activity was associated with the decrease in mean arterial pressure during trimethaphan (r=-0.74; P<0.05). In summary, our results suggest that autonomic support of blood pressure is greater in older women compared with young women and that elevated sympathetic nerve activity in older women contributes importantly to the increased incidence of hypertension after menopause.

Influence of locomotor muscle afferent inhibition on the ventilatory response to exercise in heart failure.

NEW FINDINGS: What is the central question of this study? Patients with heart failure often develop ventilatory abnormalities at rest and during exercise, but the mechanisms underlying these abnormalities remain unclear. This study investigated the influence of inhibiting afferent neural feedback from locomotor muscles on the ventilatory response during exercise in heart failure patients. What is the main finding and its importance? Our results suggest that inhibiting afferent feedback from locomotor muscle via intrathecal opioid administration significantly reduces the ventilatory response to exercise in heart failure patients. Patients with heart failure (HF) develop ventilatory abnormalities at rest and during exercise, but the mechanism(s) underlying these abnormalities remain unclear. We examined whether the inhibition of afferent neural feedback from locomotor muscles during exercise reduces exercise ventilation in HF patients. In a randomized, placebo-controlled design, nine HF patients (age, 60 ± 2 years; ejection fraction, 27 ± 2%; New York Heart Association class 2 ± 1) and nine control subjects (age, 63 ± 2 years) underwent constant-work submaximal cycling (65% peak power) with intrathecal fentanyl (impairing the cephalad projection of opioid receptor-sensitive afferents) or sham injection. The hypercapnic ventilatory response was measured to determine whether cephalad migration of fentanyl occurred. There were no differences in hypercapnic ventilatory response within or between groups in either condition. Despite a lack of change in ventilation, tidal volume or respiratory rate, HF patients had a mild increase in arterial carbon dioxide (P(aCO(2)) and a decrease in oxygen (P(aO(2)); P < 0.05 for both) at rest. The control subjects demonstrated no change in P(aCO(2)), P(aO(2)), ventilation, tidal volume or respiratory rate at rest. In response to fentanyl during exercise, HF patients had a reduction in ventilation (63 ± 6 versus 44 ± 3 l min(-1), P < 0.05) due to a lower respiratory rate (30 ± 1 versus 26 ± 2 breaths min(-1), P < 0.05). The reduced ventilation resulted in lower P aO 2 (97.6 ± 2.5 versus 79.5 ± 3.0 mmHg, P < 0.05) and increased P(aCO(2)) (37.3 ± 0.9 versus 43.5 ± 1.1 mmHg, P < 0.05), with significant improvement in ventilatory efficiency (reduction in the ventilatory equivalent for carbon dioxide; P < 0.05 for all). The control subjects had no change in ventilation or measures of arterial blood gases. These data suggest that inhibition of afferent feedback from locomotor muscle significantly reduces the ventilatory response to exercise in HF patients.

Pharmacogenetic workup of perioperative serotonin syndrome.

Serotonin syndrome is gaining attention in perioperative and chronic pain settings due to the growing prevalence of multimodal therapies that increase serotonin levels and thereby heighten patient risk. A patient's genetic make-up may further increase the risk of serotonin syndrome. A case of serotonin syndrome on emergence after general anesthesia is presented. A subsequent cytochrome P4502D6 genetic test result suggested a potential alteration in metabolism. For this patient, who was taking combination antidepressant medications and receiving common perioperative medicines, additive pharmacodynamic effects converged with a pharmacogenetic predisposition, resulting in serotonin syndrome.

Sex differences in salt sensitivity to nitric oxide dependent vasodilation in healthy young adults.

Dietary sodium and blood pressure regulation differs between normotensive men and women, an effect which may involve endothelial production of nitric oxide (NO). Therefore, we tested the hypothesis that differences in the NO component of endothelium-dependent vasodilation between low and high dietary sodium intake depend on sex. For 5 days prior to study, healthy adults consumed a controlled low-sodium diet (10 mmol/day, n = 30, mean age ± SE: 30 ± 1 yr, 16 men) or high-sodium diet (400 mmol/day, n = 36, age 23 ± 1 yr, 13 men). Forearm blood flow (FBF, plethysmography) responses to brachial artery administration of acetylcholine (ACh, 4 µg·100 ml tissue(-1)·min(-1)) were measured before and after endothelial NO synthase inhibition with N(G)-monomethyl-l-arginine (l-NMMA, 50 mg bolus + 1 mg/min infusion). The NO component of endothelium-dependent dilation was calculated as the response to ACh before and after l-NMMA accounting for changes in baseline FBF: [(FBF ACh - FBF baseline) - (FBF ACh(L-NMMA) - FBF baseline(L-NMMA))]. This value was 5.7 ± 1.3 and 2.5 ± 0.8 ml·100 ml forearm tissue(-1)·min(-1) for the low- and high-sodium diets, respectively (main effect of sodium, P = 0.019). The sodium effect was larger for the men, with values of 7.9 ± 2.0 and 2.2 ± 1.4 for men vs. 3.1 ± 1.3 and 2.7 ± 1.0 ml·100 ml forearm tissue(-1)·min(-1) for the women (P = 0.034, sex-by-sodium interaction). We conclude that the NO component of endothelium-dependent vasodilation is altered by dietary sodium intake based on sex, suggesting that endothelial NO production is sensitive to dietary sodium in healthy young men but not women.

Endoscopic transthoracic limited sympathotomy for palmar-plantar hyperhidrosis: outcomes and complications during a 10-year period.

OBJECTIVE: To review surgical results of endoscopic transthoracic limited sympathotomy for palmar-plantar hyperhidrosis during the past decade. PATIENTS AND METHODS: We retrospectively reviewed 155 consecutive patients who underwent surgery from June 30, 2000, through December 31, 2009, for medically refractory palmar-plantar hyperhidrosis using a technique of T1-T2 sympathotomy disconnection, designed for successful palmar response and minimization of complications. RESULTS: Of the 155 patients, 44 (28.4%) were male, and 111 (71.6%) were female; operative times averaged 38 minutes. No patient experienced Horner syndrome, intercostal neuralgia, or pneumothorax. The only surgical complication was hemothorax in 2 patients (1.3%); in 1 patient, it occurred immediately postoperatively and in the other patient, 10 days postoperatively; treatment in both patients was successful. All 155 patients had successful (warm and dry) palmar responses at discharge. Long-term follow-up (>3 months; mean, 40.2 months) was obtained for 148 patients (95.5%) with the following responses to surgery: 96.6% of patients experienced successful control of palmar sweating; 69.2% of patients experienced decreased axillary sweating; and 39.8% of patients experienced decreased plantar sweating. At follow-up, 5 patients had palmar sweating (3 patients, <3 months; 1 patient, 10-12 months; 1 patient, 16-18 months). Compensatory hyperhidrosis did not occur in 47 patients (31.7%); it was mild in 92 patients (62.2%), moderate in 7 patients (4.7%), and severe in 2 patients (1.3%). CONCLUSION: In this series, a small-diameter uniportal approach has eliminated intercostal neuralgia. Selecting a T1-T2 sympathotomy yields an excellent palmar response, with a very low severe compensatory hyperhidrosis complication rate. The low failure rate was noted during 18 months of follow-up and suggests that longer follow-up is necessary in these patients.

What we talk about when we talk with medical students.

In this article, we review how we interact with medical students in our efforts to teach blood pressure regulation and systemic cardiovascular control along with related elements of respiratory and exercise physiology. Rather than provide a detailed lecture with key facts, we attempted to outline our approach to teaching integrative cardiovascular physiology to medical students, which includes five major themes. First, focus on questions versus answers and facts. We believe that this offers both the learner and teacher a number of advantages. Second, avoid teaching dogma in the name of clarity (i.e., heavy focus on teaching "facts" that have not yet been fully investigated). This is especially important because of the way knowledge evolves over time. Third, include laboratory-based experiences in human integrative physiology. Fourth, provide students with intellectual frameworks versus a list of "facts" to serve as a platform for question generation. Finally, focus on the role of integration and regulatory redundancy in physiology and the idea that physiology is a narrative that can help. In this article, we discuss the philosophy behind the themes outlined above and argue that questions, and not answers, are where the action is for both research and education.

Autonomic function following endoscopic thoracic sympathotomy for hyperhidrosis.

PURPOSE: Primary palmar-plantar hyperhidrosis is the condition of excessive sweating of the hands and feet. For severe and medically refractory cases, endoscopic thoracic sympathotomy (ETS) is a bilateral ganglion-sparing disconnection between the stellate and T2 ganglion in an effort to minimize compensatory hyperhidrosis. The purpose of this study was to determine the effect of ETS on cardiac autonomic function. METHODS: Participants in this study were 22 otherwise healthy hyperhidrosis patients with 17 returning 1-12 months after surgery. Heart rate (HR) and blood pressure were collected at rest and during sequential nitroprusside/phenylephrine infusion (modified Oxford). To determine change in cardiac autonomic function, heart rate variability indices of RMSSD, LF and HF (log, nu) power were calculated. Sequential baroreflex sensitivity was also calculated. RESULTS: After surgery, resting HR on standardized ECG tended to be lower and reached significance during the modified Oxford baseline (p < 0.001). HRV changed significantly between assessments with an increase in HF (nu) and decrease in LF (nu) and LF (log) spectral ranges (p < 0.05), while the increase in RMSSD was marginally significant (p < 0.06). Compared with matched controls, HRV indices were significantly different before surgery, but similar after surgery. No change was detected in resting sequential baroreflex sensitivity, baroslope obtained by modified Oxford or QTc interval. CONCLUSIONS: We conclude that ETS changes cardiac autonomic modulation of HR to levels similar to controls. Despite the minimally destructive nature of ETS, effects on HRV are consistent with previously reported post-sympathectomy blunting of exaggerated sympathetic control associated with hyperhidrosis. No significant changes in the baroreflex indices suggest that ETS did not significantly affect blood pressure regulation.

Hemodynamics following endoscopic thoracic sympathotomy for palmar hyperhidrosis.

PURPOSE: We studied patients with palmar hyperhidrosis before and after endoscopic thoracic sympathotomy (ETS) to determine the effect of chronic sympathetic denervation on (1) forearm blood flow (FBF) response to mental stress and (2) exercise tolerance. METHODS AND RESULTS: Twenty-two healthy patients were evaluated before ETS, and 17 returned after surgery (11 F; 19-32 years). We measured heart rate (HR; 12 lead), blood pressure, and FBF (plethysmography, ml dl(-1) min(-1)). Supine HR tended to decrease after ETS (69 ± 10 vs. 66 ± 6, p = 0.2). Mental stress FBF was recorded during baseline, 3-min Stroop color word test, and 2-min recovery. Mental stress responses were unaffected by ETS. However, during post-mental stress recovery period, ETS resulted in a significant elevation in FBF (2 ± 1 vs. 3 ± 1), FVC (3 ± 1 vs. 4 ± 2), and a decrease in FVR (52 ± 22 vs. 32 ± 16, p < 0.01 for all). ETS resulted in a reduction in pre-exercise seated baseline HR (94 ± 2.5 beats/min preoperatively vs. 84 ± 4.3 beats/min postoperatively, p < 0.05), maximal HR response to cycle exercise, and exercise systolic blood pressure (172 ± 5.2 mmHg pre-op vs. 158 ± 5.9 mmHg post-op, p < 0.05) but not mean or diastolic pressure. VO(2)max and exercise duration determined by cycle ergometry was unchanged. CONCLUSIONS: Functional evidence of upper limb denervation is observed during the FBF recovery period from mental stress and hemodynamic alterations associated with upright cycle exercise. However, the sustained exercise capacity suggests modest clinical consequences.

beta2-Adrenoceptor gene variation and systemic vasodilatation during ganglionic blockade.

Regional infusions of beta(2)-adrenoceptor (ADRB2) agonist have generally shown that individuals homozygous for Gly16 produces greater vasodilatation than those homozygous for Arg16. Systemic infusions have shown an opposite effect on systemic vascular resistance (SVR), possibly confounded by baroreflexes or interactions between single nucleotide polymorphism (SNP) positions 16 and 27. We tested the hypothesis that ADRB2 gene variation would influence the SVR response to ADRB2 agonist terbutaline (Terb) during ganglionic blockade. Forty healthy young adults were recruited according to the double homozygous haplotypes: Arg16 + Gln27 (n = 13), the rare Gly16 + Gln27 (n = 6), and Gly16 + Glu27 (n = 21). Arterial pressure was measured by brachial arterial catheter, and cardiac output by acetylene breathing. Lymphocytes were sampled for ex vivo analysis of ADRB2 density and binding conformation. Following baroreflex ablation with trimethaphan (3-7 mg min(1)), continuous phenylephrine was titrated to restore blood pressure to baseline. Terb was infused i.v. at 33 and 67 ng kg(1) min(1) for 15 min/dose. There was partial evidence to suggest a main effect of haplotype on the change in SVR (P = 0.06). For SNP position 16, the highest dose of Terb produced lower SVR in Gly16 (mean +/- s.e.m.: 7.5 +/- 0.4) vs. Arg16 (8.9 +/- 0.7 units; P = 0.03). Lymphocyte ADRB2 binding conformation was similar but receptor density was greater in Gly16 vs. Arg16 (P = 0.05). We conclude that during ganglionic blockade, the SVR response to systemic ADRB2 agonist is suggestive of augmented ADRB2 function in Gly16 + Glu27 homozygotes, with greater influence from Gly16, providing further evidence that ADRB2 gene variation influences vasodilatation.

Roles of nitric oxide synthase and cyclooxygenase in leg vasodilation and oxygen consumption during prolonged low-intensity exercise in untrained humans.

The vasodilator signals regulating muscle blood flow during exercise are unclear. We tested the hypothesis that in young adults leg muscle vasodilation during steady-state exercise would be reduced independently by sequential pharmacological inhibition of nitric oxide synthase (NOS) and cyclooxygenase (COX) with NG-nitro-L-arginine methyl ester (L-NAME) and ketorolac, respectively. We tested a second hypothesis that NOS and COX inhibition would increase leg oxygen consumption (VO2) based on the reported inhibition of mitochondrial respiration by nitric oxide. In 13 young adults, we measured heart rate (ECG), blood pressure (femoral venous and arterial catheters), blood gases, and venous oxygen saturation (indwelling femoral venous oximeter) during prolonged (25 min) steady-state dynamic knee extension exercise (60 kick/min, 19 W). Leg blood flow (LBF) was determined by Doppler ultrasound of the femoral artery. Whole body VO2 was measured, and leg VO2 was calculated from blood gases and LBF. Resting intra-arterial infusions of acetylcholine (ACh) and nitroprusside (NTP) tested inhibitor efficacy. Leg vascular conductance (LVC) to ACh was reduced up to 53±4% by L-NAME+ketorolac infusion, and the LVC responses to NTP were unaltered. Exercise increased LVC from 4±1 to 33.1±2 ml.min(-1).mmHg(-1) and tended to decrease after L-NAME infusion (31±2 ml.min(-1).mmHg(-1), P=0.09). With subsequent administration of ketorolac LVC decreased to 29.6±2 ml.min(-1).mmHg(-1) (P=0.02; n=9). While exercise continued, LVC returned to control values (33±2 ml.min(-1).mmHg(-1)) within 3 min, suggesting involvement of additional vasodilator mechanisms. In four additional subjects, LVC tended to decrease with L-NAME infusion alone (P=0.08) but did not demonstrate the transient recovery. Whole body and leg VO2 increased with exercise but were not altered by L-NAME or L-NAME+ketorolac. These data indicate a modest role for NOS- and COX-mediated vasodilation in the leg of exercising humans during prolonged steady-state exercise, which can be restored acutely. Furthermore, NOS and COX do not appear to influence muscle VO2 in untrained healthy young adults.