The influence of pulmonary vascular pressures on lung diffusing capacity during incremental exercise in healthy aging.

Alveolar-capillary surface area for pulmonary gas exchange falls with aging, causing a reduction in lung diffusing capacity for carbon monoxide (DLCO). However, during exercise additional factors may influence DLCO, including pulmonary blood flow and pulmonary vascular pressures. First, we sought to determine the age-dependent effect of incremental exercise on pulmonary vascular pressures and DLCO. We also aimed to investigate the dependence of DLCO on pulmonary vascular pressures during exercise via sildenafil administration to reduce pulmonary smooth muscle tone. Nine younger (27 ± 4 years) and nine older (70 ± 3 years) healthy subjects performed seven 5-min exercise stages at rest, 0 (unloaded), 10, 15, 30, 50, and 70% of peak workload before and after sildenafil. DLCO, cardiac output (Q), and pulmonary artery and wedge pressure (mPAP and mPCWP; subset of participants) were collected at each stage. mPAP was higher (P = 0.029) and DLCO was lower (P = 0.009) throughout exercise in older adults; however, the rate of rise in mPAP and DLCO with increasing Q was not different. A reduction in pulmonary smooth muscle tone via sildenafil administration reduced mPAP, mPCWP, and the transpulmonary gradient (TPG = mPAP-mPCWP) in younger and older subjects (P < 0.001). DLCO was reduced following the reduction in mPAP and TPG, regardless of age (P < 0.001). In conclusion, older adults successfully adapt to age-dependent alterations in mPAP and DLCO. Furthermore, DLCO is dependent on pulmonary vascular pressures, likely to maintain adequate pulmonary capillary recruitment. The rise in pulmonary artery pressure with aging may be required to combat pulmonary vascular remodeling and maintain lung diffusing capacity, particularly during exercise.

External defibrillation failure due to antimicrobial incise drape.

Antimicrobial incise drapes adhere to a patient's skin during surgery in an attempt to reduce surgical infections. We describe a patient undergoing repeated aortic valve replacement who experienced sudden ventricular fibrillation before median sternotomy. External defibrillation was unsuccessful on multiple attempts using several defibrillators. On removal of the incise drape from the patient's chest, external defibrillation was immediately successful. Increased transthoracic impedance can be caused by multiple factors and may prevent defibrillation. To our knowledge, this is the first reported case of an antimicrobial incise drape preventing defibrillation. If external defibrillation, cardioversion, or pacing is indicated intraoperatively, we recommend prompt removal of the antimicrobial incise drapes before electrode placement if the drapes overlay the intended pad position. Since this case, our institutional practice has now changed to placement of 2 external adhesive defibrillator electrodes onto the patient's skin lateral to the surgical field before incise drape application to allow for defibrillation.

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.

Effects of respiratory muscle work on blood flow distribution during exercise in heart failure.

Heart failure (HF) patients have a reduced cardiac reserve and increased work of breathing. Increased locomotor muscle blood flow demand may result in competition between respiratory and locomotor vascular beds. We hypothesized that HF patients would demonstrate improved locomotor blood flow with respiratory muscle unloading during activity. Ten patients (ejection fraction = 31 +/- 3%) and 10 controls (CTL) underwent two cycling sessions (60% peak work). Session 1 (S1): 5 min of normal breathing (NB), 5 min respiratory muscle unloading with a ventilator, and 5 min of NB. Session 2 (S2): 5 min NB, 5 min of respiratory muscle loading with inspiratory resistance, and 5 min of NB. Measurements included: leg blood flow (LBF, thermodilution), cardiac output (Q), and oesophageal pressure (P(pl), index of pleural pressure). S1: P(pl) was reduced in both groups (HF: 73 +/- 8%; CTL: 60 +/- 13%, P < 0.01). HF: Q increased (9.6 +/- 0.4 vs. 11.3 +/- 0.8 l min(-1), P < 0.05) and LBF increased (4.8 +/- 0.8 vs. 7.3 +/- 1.1 l min(-1), P < 0.01); CTL: no changes in Q (14.7 +/- 1.0 vs. 14.8 +/- 1.6 l min(-1)) or LBF (10.9 +/- 1.8 vs. 10.3 +/- 1.7 l min(-1)). S2: P(pl) increased in both groups (HF: 172 +/- 16%, CTL: 220 +/- 40%, P < 0.01). HF: no change was observed in Q(10.0 +/- 0.4 vs. 10.3 +/- 0.8 l min(-1)) or LBF (5.0 +/- 0.6 vs. 4.7 +/- 0.5 l min(-1)); CTL: increased (15.4 +/- 1.4 vs. 16.9 +/- 1.5 l min(-1), P < 0.01) and LBF remained unchanged (10.7 +/- 1.5 vs. 10.3 +/- 1.8 l min(-1)). These data suggest HF patients preferentially steal blood flow from locomotor muscles to accommodate the work of breathing during activity. Further, HF patients are unable to vasoconstrict locomotor vascular beds beyond NB when presented with a respiratory load.

Perioperative opioid requirements are decreased in hypoxic children living at altitude.

OBJECTIVES: To investigate the effect of altitude on perioperative opioid requirements in otherwise healthy children. AIM: To investigate whether children living and having surgery at high altitude received different doses of fentanyl than those living and having surgery at sea level. BACKGROUND: Recent studies in animals (Anesthesiology, 105, 2006 and 715) and children with obstructive sleep apnea (Anesthesiology, 105, 2006 and 665; Anesthesiology 100, 2004 and 806) suggest that analgesic effects of exogenous opioids are enhanced by hypoxia. However, the effects of hypoxia on perioperative narcotic requirements in otherwise healthy children have not been previously reported. METHODS/MATERIALS: We reviewed retrospectively the opioid requirements of pediatric patients who underwent cleft lip or palate surgery during Smile Network International mission trips to Cusco and Lima, Peru between 2007 and 2009. Patients who had surgery at high altitude were compared to those who had surgery at sea level. All patients received a standardized anesthetic with intravenous fentanyl as the only perioperative opioid. RESULTS: Hundred and two patients had surgery at 3399 m above sea level (masl) (Cusco) and 169 patients had surgery at 150 masl (Lima). Patients at high altitude had significantly lower baseline oxygen saturations (92 ± 4% vs 98 ± 3%; P < 0.001) and received 40% less opioid (1.2 ± 0.8 vs 2.0 ± 1.4 µg·kg(-1) per h; P < 0.001) compared to patients at sea level. CONCLUSIONS: Opioid administration was reduced in otherwise healthy children with altitude-induced chronic hypoxia when compared to non-hypoxic children undergoing similar operations under similar anesthetic regimens. Whether this difference is due to altitude or altitude-induced hypoxia, requires further study.

Adenosine receptor antagonist and augmented vasodilation during hypoxic exercise.

We tested the hypothesis that adenosine contributes to augmented skeletal muscle vasodilation during hypoxic exercise. In separate protocols, subjects performed incremental rhythmic forearm exercise (10% and 20% of maximum) during normoxia and normocapnic hypoxia (80% arterial O2 saturation). In protocol 1 (n = 8), subjects received an intra-arterial administration of saline (control) and aminophylline (adenosine receptor antagonist). In protocol 2 (n = 10), subjects received intra-arterial phentolamine (alpha-adrenoceptor antagonist) and combined phentolamine and aminophylline administration. Forearm vascular conductance (FVC; in ml x min(-1).100 mmHg(-1)) was calculated from forearm blood flow (in ml/min) and blood pressure (in mmHg). In protocol 1, the change in FVC (DeltaFVC; change from normoxic baseline) during hypoxic exercise with saline was 172 +/- 29 and 314 +/- 34 ml x min(-1) x 100 mmHg(-1) (10% and 20%, respectively). Aminophylline administration did not affect DeltaFVC during hypoxic exercise at 10% (190 +/- 29 ml x min(-1)x100 mmHg(-1), P = 0.4) or 20% (287 +/- 48 ml x min(-1) x 100 mmHg(-1), P = 0.3). In protocol 2, DeltaFVC due to hypoxic exercise with phentolamine infusion was 313 +/- 30 and 453 +/- 41 ml x min(-1) x 100 mmHg(-1) (10% and 20% respectively). DeltaFVC was similar at 10% (352 +/- 39 ml min(-1) x 100 mmHg(-1), P = 0.8) and 20% (528 +/- 45 ml x min(-1) x 100 mmHg(-1), P = 0.2) hypoxic exercise with combined phentolamine and aminophylline. In contrast, DeltaFVC to exogenous adenosine was reduced by aminophylline administration in both protocols (P < 0.05 for both). These observations suggest that adenosine receptor activation is not obligatory for the augmented hyperemia during hypoxic exercise in humans.

Arterial baroreflex control of heart rate during exercise in postural tachycardia syndrome.

Patients with postural tachycardia syndrome (POTS) have excessive tachycardia without hypotension during orthostasis as well as exercise. We tested the hypothesis that excessive tachycardia during exercise in POTS is not related to abnormal baroreflex control of heart rate (HR). Patients (n = 13) and healthy controls (n = 10) performed graded cycle exercise at 25, 50, and 75 W in both supine and upright positions while arterial pressure (arterial catheter) and HR (ECG) were measured. Baroreflex sensitivity of HR was assessed by bolus intravenous infusion of phenylephrine at each workload. In both positions, HR was higher in the patients than the controls during exercise. Supine baroreflex sensitivity (HR/systolic pressure) in POTS patients was -1.3 +/- 0.1 beats.min(-1).mmHg(-1) at rest and decreased to -0.6 +/- 0.1 beats.min(-1).mmHg(-1) during 75-W exercise, neither significantly different from the controls (P > 0.6). In the upright position, baroreflex sensitivity in POTS patients at rest (-1.4 +/- 0.1 beats.min(-1).mmHg(-1)) was higher than the controls (-1.0 +/- 0.1 beats.min(-1).mmHg(-1)) (P < 0.05), and it decreased to -0.1 +/- 0.04 beats.min(-1).mmHg(-1) during 75-W exercise, lower than the controls (-0.3 +/- 0.09 beats.min(-1).mmHg(-1)) (P < 0.05). The reduced arterial baroreflex sensitivity of HR during upright exercise was accompanied by greater fluctuations in systolic and pulse pressure in the patients than in the controls with 56 and 90% higher coefficient of variations, respectively (P < 0.01). However, when baroreflex control of HR was corrected for differences in HR, it was similar between the patients and controls during upright exercise. These results suggest that the tachycardia during exercise in POTS was not due to abnormal baroreflex control of HR.

Reduced stroke volume during exercise in postural tachycardia syndrome.

Postural tachycardia syndrome (POTS) is characterized by excessive tachycardia without hypotension during orthostasis. Most POTS patients also report exercise intolerance. To assess cardiovascular regulation during exercise in POTS, patients (n = 13) and healthy controls (n = 10) performed graded cycle exercise at 25, 50, and 75 W in both supine and upright positions while arterial pressure (arterial catheter), heart rate (HR; measured by ECG), and cardiac output (open-circuit acetylene breathing) were measured. In both positions, mean arterial pressure, cardiac output, and total peripheral resistance at rest and during exercise were similar in patients and controls (P > 0.05). However, supine stroke volume (SV) tended to be lower in the patients than controls at rest (99 +/- 5 vs. 110 +/- 9 ml) and during 75-W exercise (97 +/- 5 vs. 111 +/- 7 ml) (P = 0.07), and HR was higher in the patients than controls at rest (76 +/- 3 vs. 62 +/- 4 beats/min) and during 75-W exercise (127 +/- 3 vs. 114 +/- 5 beats/min) (both P < 0.01). Upright SV was significantly lower in the patients than controls at rest (57 +/- 3 vs. 81 +/- 6 ml) and during 75-W exercise (70 +/- 4 vs. 94 +/- 6 ml) (both P < 0.01), and HR was much higher in the patients than controls at rest (103 +/- 3 vs. 81 +/- 4 beats/min) and during 75-W exercise (164 +/- 3 vs. 131 +/- 7 beats/min) (both P < 0.001). The change (upright - supine) in SV was inversely correlated with the change in HR for all participants at rest (R(2) = 0.32), at 25 W (R(2) = 0.49), 50 W (R(2) = 0.60), and 75 W (R(2) = 0.32) (P < 0.01). These results suggest that greater elevation in HR in POTS patients during exercise, especially while upright, was secondary to reduced SV and associated with exercise intolerance.

Cerebrovascular reactivity to hypercapnia is unimpaired in breath-hold divers.

Hypercapnic cerebrovascular reactivity is decreased in obstructive sleep apnoea and congestive heart disease perhaps as a result of repeated apnoeas. To test the hypothesis that repeated apnoeas blunt cerebrovascular reactivity to hypercapnia, we studied breath hold divers and determined cerebrovascular reactivity by measuring changes in middle cerebral artery velocity (MCAV, cm s(-1)) per mmHg change in end-tidal partial pressure of CO2(PET,CO2 ) in response to two hyperoxic hypercapnia rebreathing manoeuvres (modified Read protocol) in elite breath-hold divers (BHD, n=7) and non-divers (ND, n=7). In addition, ventilation and central (beat-to-beat stroke volume measurement with Modelflow technique) haemodynamics were determined. Ventilatory responses to hypercapnia were blunted in BHD versus ND largely due to lower breathing frequency. Cerebrovascular reactivity did not differ between groups (3.7 +/- 1.4 versus 3.4 +/- 1.3% mmHg(-1) in BHD and ND, respectively; P=0.90) and the same was found for cerebral vascular resistance and MCAV recovery to baseline after termination of the CO2 challenge. Cardiovascular parameters were not changed significantly during rebreathing in either group, except for a small increase in mean arterial pressure for both groups. Our findings indicate that the regulation of the cerebral circulation in response to hypercapnia is intact in elite breath-hold divers, potentially as a protective mechanism against the chronic intermittent cerebral hypoxia and/or hypercapnia that occurs during breath-hold diving. These data also suggest that factors other than repeated apnoeas contribute to the blunting of cerebrovascular reactivity in conditions like sleep apnoea.

Excessive heart rate response to orthostatic stress in postural tachycardia syndrome is not caused by anxiety.

Postural tachycardia syndrome (POTS) is characterized by excessive increases in heart rate (HR) without hypotension during orthostasis. The relationship between the tachycardia and anxiety is uncertain. Therefore, we tested whether the HR response to orthostatic stress in POTS is primarily related to psychological factors. POTS patients (n = 14) and healthy controls (n = 10) underwent graded venous pooling with lower body negative pressure (LBNP) to -40 mmHg while wearing deflated antishock trousers. "Sham" venous pooling was performed by 1) trouser inflation to 5 mmHg during LBNP and 2) vacuum pump activation without LBNP. HR responses to mental stress were also measured in both groups, and a questionnaire was used to measure psychological parameters. During LBNP, HR in POTS patients increased 39 +/- 5 beats/min vs. 19 +/- 3 beats/min in control subjects at -40 mmHg (P < 0.01). LBNP with trouser inflation markedly blunted the HR responses in the patients (9 +/- 2 beats/min) and controls (2 +/- 1 beats/min), and there was no HR increase during vacuum application without LBNP in either group. HR responses during mental stress were not different in the patients and controls (18 +/- 2 vs. 19 +/- 1 beats/min; P > 0.6). Anxiety, somatic vigilance, and catastrophic cognitions were significantly higher in the patients (P < 0.05), but they were not related to the HR responses during LBNP or mental stress (P > 0.1). These results suggest that the HR response to orthostatic stress in POTS patients is not caused by anxiety but that it is a physiological response that maintains arterial pressure during venous pooling.

Influence of beta2-adrenergic receptor genotype on airway function during exercise in healthy adults.

BACKGROUND: In humans, beta(2)-adrenergic receptors (beta(2)ARs) influence airway tone. There are known functional polymorphisms of the beta(2)AR, such as substitution of glycine for arginine at codon 16. We sought to determine if this variation in genotype differentially influences airway function during exercise. METHODS: Healthy subjects without asthma who were either homozygous for Arg16 (n = 16; mean age, 29 +/- 2 years [+/- SD]; mean maximum oxygen uptake [Vo(2)], 32 +/- 2 mL/kg/min) or the Gly16 allele (n = 26; mean age, 30 +/- 1 years; mean maximum Vo(2), 33 +/- 1 mL/kg/min) participated in the study. Baseline testing included spirometry and maximal symptom-limited exercise. On a separate day, an arterial cannula was placed to measure catecholamine levels. Subjects then performed exercise at two work levels (40% and 75% of peak work) for 9 min each and performed spirometry at 3-min intervals for assessment of airway function. RESULTS: There were no statistically significant differences between groups in maximum Vo(2) or baseline spirometry (p > 0.05). With both light and heavy exercise, the groups had similar increases in the forced expiratory flow at 50% of vital capacity (FEF(50)). FEF(50) increased by 14 +/- 4% and 15 +/- 3% in arginine and glycine groups, respectively, by end exercise (p > 0.05). During recovery (5 min and 10 min after), the Gly16 homozygotes demonstrated persistent bronchodilation (10 min after FEF(50) = + 7 +/- 2% over pre-exercise) while the Arg16 subjects had a rapid return to baseline (10 min after FEF(50) = - 3 +/- 3%, p = 0.007 between groups). No differences were observed in the catecholamine responses between genotypes, although the increase in epinephrine in the arginine group tended to be higher (p = 0.07). CONCLUSIONS: These data suggest that the Arg16Gly polymorphism of the beta(2)AR does not influence airway function during short-duration low- and high-intensity exercise. However, during recovery, the Arg16 genotype is associated with a reduced bronchodilation, possibly due to increased catecholamine desensitization.

Effects of combined inhibition of ATP-sensitive potassium channels, nitric oxide, and prostaglandins on hyperemia during moderate exercise.

ATP-sensitive potassium (KATP) channels have been suggested to contribute to coronary and skeletal muscle vasodilation during exercise, either alone or interacting in a parallel or redundant process with nitric oxide (NO), prostaglandins (PGs), and adenosine. We tested the hypothesis that KATP channels, alone or in combination with NO and PGs, regulate exercise hyperemia in forearm muscle. Eighteen healthy young adults performed 20 min of moderate dynamic forearm exercise, with forearm blood flow (FBF) measured via Doppler ultrasound. After steady-state FBF was achieved for 5 min (saline control), the KATP inhibitor glibenclamide (Glib) was infused into the brachial artery for 5 min (10 microg.dl(-1).min(-1)), followed by saline infusion during the final 10 min of exercise (n = 9). Exercise increased FBF from 71 +/- 11 to 239 +/- 24 ml/min, and FBF was not altered by 5 min of Glib. Systemic plasma Glib levels were above the therapeutic range, and Glib increased insulin levels by approximately 50%, whereas blood glucose was unchanged (88 +/- 2 vs. 90 +/- 2 mg/dl). In nine additional subjects, Glib was followed by combined infusion of NG-nitro-L-arginine methyl ester (L-NAME) plus ketorolac (to inhibit NO and PGs, respectively). As above, Glib had no effect on FBF but addition of L-NAME + ketorolac (i.e., triple blockade) reduced FBF by approximately 15% below steady-state exercise levels in seven of nine subjects. Interestingly, triple blockade in two subjects caused FBF to transiently and dramatically decrease. This was followed by an acute recovery of flow above steady-state exercise values. We conclude 1) opening of KATP channels is not obligatory for forearm exercise hyperemia, and 2) triple blockade of NO, PGs, and KATP channels does not reduce hyperemia more than the inhibition of NO and PGs in most subjects. However, some subjects are sensitive to triple blockade, but they are able to restore FBF acutely during exercise. Future studies are required to determine the nature of these compensatory mechanisms in the affected individuals.

Arg16Gly polymorphism of the beta2-adrenergic receptor is associated with differences in cardiovascular function at rest and during exercise in humans.

In humans, subjects homozygous for arginine (ArgArg) at codon 16 of the beta2-adrenergic receptor (beta2AR) have been shown to have greater agonist-mediated desensitization than subjects homozygous for glycine (GlyGly). We sought to determine if this substitution differentially influenced cardiovascular function during short duration (9 min) low and high intensity exercise (40 and 75% of peak work). Healthy Caucasian ArgArg (n = 16), GlyGly (n = 31) and ArgGly (n = 17) subjects matched for age, sex and peak oxygen uptake were studied. There were no differences in adrenaline (ADR) at rest or with heavy exercise, but the ArgArg group had lower ADR with light exercise (P = 0.04). Resting heart rate (HR) was higher in ArgArg (P < 0.01), while cardiac output (Q), stroke volume (SV), and mean arterial pressure (MAP) were lower than the other groups (HR = 86+/-2, 78+/-2, 80+/-1 beats min(-1); Q = 5.7+/-0.81, 6.1+/-0.18, 6.7+/-0.22 l min(-1); SV = 68+/-3, 82+/-3, 89+/-4 ml beat(-1); MAP = 92+/-1, 103+/-2, 98+/-1 mmHg-- for ArgArg, ArgGly and GlyGly, respectively, means +/-s.e.m., P < 0.01), however, no differences were observed in systemic vascular resistance (SVR). With low intensity exercise and high intensity exercise the ArgArg group continued to have a lower , SV and MAP compared to the other groups (P < 0.05), with no differences observed in SVR. During recovery, the ArgArg subjects continued to have a lower MAP but there were no differences in HR, , or SVR. These data suggest that subjects homozygous for Arg at codon 16 of the beta2AR have reduced and MAP at rest that persist during exercise with no evidence for differential changes over the course of exercise despite large changes in catecholamines. This may suggest possible genotype-related differences in baseline receptor function or density which causes phenotypic differences at rest that are sustained during short-term exercise.

Arg16/Gly beta2-adrenergic receptor polymorphism alters the cardiac output response to isometric exercise.

Normotensive adults homozygous for glycine (Gly) of the Arg16/Gly beta2-adrenergic-receptor polymorphism have 1) greater forearm beta2-receptor mediated vasodilation and 2) a higher heart rate (HR) response to isometric handgrip than arginine (Arg) homozygotes. To test the hypothesis that the higher HR response in Gly16 subjects serves to maintain the pressor response [increased cardiac output (CO)] in the setting of augmented peripheral vasodilation to endogenous catecholamines, we measured continuous HR (ECG), arterial pressure (Finapres), and CO (transthoracic echocardiography) during isometric, 40% submaximal handgrip to fatigue in healthy subjects homozygous for Gly (n = 30; mean age +/- SE: 30 +/- 1.2, 13 women) and Arg (n = 17, age 30 +/- 1.6, 11 women). Resting data were similar between groups. Handgrip produced similar increases in arterial pressure and venous norepinephrine and epinephrine concentrations; however, HR increased more in the Gly group (60.1 +/- 4.3% increase from baseline vs. 45.5 +/- 3.9%, P = 0.03), and this caused CO to be higher (Gly: 7.6 +/- 0.3 l/m vs. Arg: 6.5 +/- 0.3 l/m, P = 0.03), whereas the decrease in systemic vascular resistance in the Gly group did not reach significance (P = 0.09). We conclude that Gly16 homozygotes generate a higher CO to maintain the pressor response to handgrip. The influence of polymorphic variants in the beta2-adrenergic receptor gene on the cardiovascular response to sympathoexcitation may have important implications in the development of hypertension and heart failure.

A restrospective perspective.

Venous occlusion plethysmography is a simple but elegant technique that has contributed to almost every major area of vascular biology in humans. The general principles of plethysmography were appreciated by the late 1800s, and the application of these principles to measure limb blood flow occurred in the early 1900s. Plethysmography has been instrumental in studying the role of the autonomic nervous system in regulating limb blood flow in humans and important in studying the vasodilator responses to exercise, reactive hyperemia, body heating, and mental stress. It has also been the technique of choice to study how human blood vessels respond to a variety of exogenously administered vasodilators and vasoconstrictors, especially those that act on various autonomic and adrenergic receptors. In recent years, plethysmography has been exploited to study the role of the vascular endothelium in health and disease. Venous occlusion plethysmography is likely to continue to play an important role as investigators seek to understand the physiological significance of newly identified vasoactive factors and how genetic polymorphisms affect the cardiovascular system in humans.

Agonist-dependent variablity of contributions of nitric oxide and prostaglandins in human skeletal muscle.

The relative contributions of endothelium-dependent dilators [nitric oxide (NO), prostaglandins (PGs), and endothelium-derived hyperpolarizing factor (EDHF)] in human limbs are poorly understood. We tested the hypothesis that relative contributions of NO and PGs differ between endothelial agonists acetylcholine (ACh; 1, 2, and 4 microg.dl(-1).min(-1)) and bradykinin (BK; 6.25, 25, and 50 ng.dl(-1).min(-1)). We measured forearm blood flow (FBF) using venous occlusion plethysmography in 50 healthy volunteers (27 +/- 1 yr) in response to brachial artery infusion of ACh or BK in the absence and presence of inhibitors of NO synthase [NOS; with NG-monomethyl-L-arginine (L-NMMA)] and cyclooxygenase (COX; with ketorolac). Furthermore, we tested the idea that the NOS + COX-independent dilation (in the presence of L-NMMA + ketorolac, presumably EDHF) could be inhibited by exogenous NO administration, as reported in animal studies. FBF increased approximately 10-fold in the ACh control; L-NMMA reduced baseline FBF and ACh dilation, whereas addition of ketorolac had no further effect. Ketorolac alone did not alter ACh dilation, but addition of L-NMMA reduced ACh dilation significantly. For BK infusion, FBF increased approximately 10-fold in the control condition; L-NMMA tended to reduce BK dilation (P < 0.1), and addition of ketorolac significantly reduced BK dilation. Similar to ACh, ketorolac alone did not alter BK dilation, but addition of L-NMMA reduced BK dilation. To test the idea that NO can inhibit the NOS + COX-independent portion of dilation, we infused a dose of sodium nitroprusside (NO-clamp technique) during ACh or BK that restored the reduction in baseline blood flow due to L-NMMA. Regardless of treatment order, the NO clamp restored baseline FBF but did not reduce the NOS + COX-independent dilation to ACh or BK. We conclude that the contribution of NO and PGs differs between ACh and BK, with ACh being more dependent on NO and BK being mostly dependent on a NOS + COX-independent mechanism (EDHF) in healthy young adults. The NOS + COX-independent dilation does not appear sensitive to feedback inhibition from NO in the human forearm.

A comparison of peripheral skin blood flow and temperature during endoscopic thoracic sympathotomy.

The assessment of sympathetic denervation to the upper extremities during surgery for hyperhidrosis is essential in predicting postoperative outcome, particularly for endoscopic thoracic chain sympathotomy, a recently described, minimally destructive technique that minimizes postoperative compensatory hyperhidrosis. To test the hypothesis that skin blood flow (SkBF; laser Doppler flowmetry) provides a faster and more reliable indication of denervation than temperature (temp), we prospectively compared palmar SkBF and fingertip temp in 10 patients undergoing endoscopic thoracic chain sympathotomy for essential hyperhidrosis. From baseline to peak values, palmar SkBF (mean +/- SEM) increased 273.3 +/- 24.7 arbitrary units and 252.4 +/- 30.1 arbitrary units, whereas temp increased 0.9 degrees C +/- 0.3 degrees C and 1.5 degrees C +/- 0.6 degrees C on the right and left, respectively. Upon effective sympathotomy of the right thoracic chain, the time to peak SkBF was 43 +/- 13 s, whereas the time to peak temp was 277 +/- 53 s (P <0.001). On the left, the time to peak SkBF was 81 +/- 14 s, and time to peak temp was 305 +/- 34 s (P <0.001). All patients considered the sympathotomy successful. We conclude that laser Doppler SkBF is superior to temp in temporal resolution for assessment of denervation during sympathotomy and that it provides a superior qualitative and quantitative adjunct to monitoring denervation.

Is physician anesthesia cost-effective?

UNLABELLED: One of the most controversial issues in anesthesia is whether nonmedically directed nurse anesthetists are relatively more cost-effective than anesthesiologists in the provision of anesthesia care. We electronically surveyed anesthesia practices throughout the United States to estimate the range in anesthesia professional costs from the payer perspective. Using this survey data on anesthesia reimbursement and published outcomes studies, we developed an ad hoc model to estimate the cost-effectiveness of physician-directed anesthesia relative to a nonmedically directed nurse anesthetist model of care from the payer perspective. Cost-effectiveness ratios were defined as the ratio of incremental costs associated with physician anesthesia relative to the estimated incremental life expectancy gains with this model of care (i.e., dollars per year of life saved [US dollars /YLS]). Reference case results suggest that physician anesthesia is cost saving with an estimated incremental cost-effectiveness ratio of -US dollars 2601/YLS for a younger privately insured patient and an estimated cost-effectiveness ratio of -US dollars 4410/YLS for an elderly Medicare insured patient. Cost-effectiveness ratios ranged from -US dollars 4410 to US dollars 38778/YLS in univariate and multivariate sensitivity analyses across payer types. Results were most sensitive to assumed differences in reimbursement (commercial conversion factors) and to mortality rate assumptions by provider type. This analysis offers economic evidence in support of the physician anesthesia model of care. IMPLICATIONS: Recent outcome studies suggest improved patient outcomes when physicians medically direct nurse anesthetists versus anesthesia care delivered with nonmedically directed nurses. The relative cost-effectiveness of this practice model is, however, unknown. This economic analysis suggests that outcome gains with physician anesthesia may be obtained at cost savings or, under conservative assumptions, at a cost deemed reasonable by society.