Biomedical subjects

Susan R Hopkins

Publications and source records attributed to Susan R Hopkins.

At least 19 recordsLinked to original sources

PubMed2007

Effect of acetazolamide on pulmonary and muscle gas exchange during normoxic and hypoxic exercise.

Acetazolamide (ACZ) is used to prevent acute mountain sickness at altitude. Because it could affect O2 transport in several different and potentially conflicting ways, we examined its effects on pulmonary and muscle gas exchange and acid-base status during cycle exercise at approximately 30, 50 and 90% VO2max in normoxia (F(IO2) = 0.2093) and acute hypoxia (F(IO2) = 0.125). In a double-blind, order-balanced, crossover design, six healthy, trained men (normoxic VO2max= 59 ml kg(-1) min(-1)) exercised at both F(IO2) values after ACZ (3 doses of 250 mg, 8 h apart) and placebo. One week later this protocol was repeated using the other drug (placebo or ACZ). We measured cardiac output (QT), leg blood flow (LBF), and muscle and pulmonary gas exchange, the latter using the multiple inert gas elimination technique. ACZ did not significantly affect VO2, QT, LBF or muscle gas exchange. As expected, ACZ led to lower arterial and venous blood [HCO3-], pH and lactate levels (P < 0.05), and increased ventilation (P < 0.05). In both normoxia and hypoxia, ACZ resulted in higher arterial P(O2) and saturation and a lower alveolar-arterial P(O2) difference (AaD(O2)) due to both less VA/Q mismatch and less diffusion limitation (P < 0.05). In summary, ACZ improved arterial oxygenation during exercise, due to both greater ventilation and more efficient pulmonary gas exchange. However, muscle gas exchange was unaffected.

Acetazolamide↗

PubMed2006

Advances in magnetic resonance imaging of lung physiology.

This review presents an overview of some recent magnetic resonance imaging (MRI) techniques for measuring aspects of local physiology in the lung. MRI is noninvasive, relatively high resolution, and does not expose subjects to ionizing radiation. Conventional MRI of the lung suffers from low signal intensity caused by the low proton density and the large degree of microscopic field inhomogeneity that degrades the magnetic resonance signal and interferes with image acquisition. However, in recent years, there have been rapid advances in both hardware and software design, allowing these difficulties to be minimized. This review focuses on some newer techniques that measure regional perfusion, ventilation, gas diffusion, ventilation-to-perfusion ratio, partial pressure of oxygen, and lung water. These techniques include contrast-enhanced and arterial spin-labeling techniques for measuring perfusion, hyperpolarized gas techniques for measuring regional ventilation, and apparent diffusion coefficient and multiecho and gradient echo techniques for measuring proton density and lung water. Some of the major advantages and disadvantages of each technique are discussed. In addition, some of the physiological issues associated with making measurements are discussed, along with strategies for understanding large and complex data sets.

Helium↗

PubMed2006

The effect of incomplete acetylene washout on cardiac output measurement using open circuit acetylene uptake.

The open circuit acetylene uptake method is a useful non-invasive means of measuring cardiac output. However, because of accumulation of inhaled acetylene in tissues, the cardiac output uptake is underestimated, if residual acetylene is not allowed to wash out completely in between measurements. We determined the effect of applying a correction factor that estimates mixed venous acetylene concentration from endtidal values to the calculation of cardiac output. This accounts for mixed venous acetylene present during measurements made before complete washout. Six healthy subjects performed steady-state exercise at approximately 30% and 60% of V(O2 max). Cardiac output measurements were made at each exercise intensity using the open circuit acetylene uptake method (inspired [acetylene] approximately 1%), with the first and last measurements having no detectible levels of acetylene in expired gas (reference measurement). Data were also obtained with immediate pre-measurement endtidal concentrations ranging from 3% to 15% of the inspired [acetylene], in random order in between. Oxygen consumption, carbon dioxide production and heart rate did not change significantly during testing at each exercise intensity. Reference cardiac output also did not change significantly and averaged 11.1+/-0.8 L/min at 30% of V(O2 max) and 16.5+/-2.0 L/min at 60% of V(O2 max). Uncorrected cardiac output measurements progressively underestimated cardiac output by 15% at the 3% of inspired endtidal [acetylene] and by over 50% at 15% [acetylene] (p<0.0001). However, when corrected for residual endtidal [acetylene], cardiac outputs were not significantly different from the reference measurements. The results of this study suggest that by accounting for residual endtidal acetylene in mixed venous blood, cardiac output can be accurately measured even when washout of acetylene is incomplete, allowing measurements as often as every 10-15 s.

Acetylene↗

PubMed2006

Steep head-down tilt has persisting effects on the distribution of pulmonary blood flow.

Head-down tilt has been shown to increase lung water content in animals and alter the distribution of ventilation in humans; however, its effects on the distribution of pulmonary blood flow in humans are unknown. We hypothesized that head-down tilt would increase the heterogeneity of pulmonary blood flow in humans, an effect analogous to the changes seen in the distribution of ventilation, by increasing capillary hydrostatic pressure and fluid efflux in the lung. To test this, we evaluated changes in the distribution of pulmonary blood flow in seven normal subjects before and after 1 h of 30 degrees head-down tilt using the magnetic resonance imaging technique of arterial spin labeling. Data were acquired in triplicate before tilt and at 10-min intervals for 1 h after tilt. Pulmonary blood flow heterogeneity was quantified by the relative dispersion (standard deviation/mean) of signal intensity for all voxels within the right lung. Relative dispersion was significantly increased by 29% after tilt and remained elevated during the 1 h of measurements after tilt (0.84 +/- 0.06 pretilt, 1.09 +/- 0.09 calculated for all time points posttilt, P < 0.05). We speculate that the mechanism most likely responsible for our findings is that increased pulmonary capillary pressures and fluid efflux in the lung resulting from head-down tilt alters regional blood flow distribution.

Adult↗

PubMed2006

Exercise induced arterial hypoxemia: the role of ventilation-perfusion inequality and pulmonary diffusion limitation.

Many apparently healthy individuals experience pulmonary gas exchange limitations during exercise, and the term "exercise induced arterial hypoxemia" (EIAH) has been used to describe the increase in alveolar-arterial difference for oxygen (AaDO2), which combined with a minimal alveolar hyperventilatory response, results in a reduction in arterial PO2. Despite more than two decades of research, the mechanisms of pulmonary gas exchange limitations during exercise are still debated. Using data in 166 healthy normal subjects collated from several previously published studies it can be shown that approximately 20% of the variation in PaO2 between individuals can be explained on the basis of variations in alveolar ventilation, whereas variations in AaDO2 explain approximately 80%. Using multiple inert gas data the relative contributions of ventilation-perfusion ("VA/Q") inequality and diffusion limitation to the AaDO2 can be assessed. During maximal exercise, both in individuals with minimal (AaDO2 < 20 Torr, x = 13 +/- 5, means +/- SD, n = 35) and moderate to severe (AaDO2= 25-40 Torr, x = 33 +/- 6, n = 20) gas exchange limitations, VA/Q inequality is an important contributor to the AaDO2. However, in subjects with minimal gas exchange impairment, VA/Q inequality accounts for virtually all of the AaDO2 (12 +/- 6 Torr), whereas in subjects with moderate to severe gas exchange impairment it accounts for less than 50% of the AaDO2 (15 +/- 6 Torr). Using this framework, the difficulties associated with unraveling the mechanisms of pulmonary gas exchange limitations during exercise are explored, and current data discussed.

Diffusion↗

PubMed2005

Heterogeneous pulmonary blood flow in response to hypoxia: a risk factor for high altitude pulmonary edema?

High altitude pulmonary edema (HAPE) is a rapidly reversible hydrostatic edema that occurs in individuals who travel to high altitude. The difficulties associated with making physiologic measurements in humans who are ill or at high altitude, along with the idiosyncratic nature of the disease and lack of appropriate animal models, has meant that our understanding of the mechanism of HAPE is incomplete, despite considerable effort. Bronchoalveolar lavage studies at altitude in HAPE-susceptible subjects have shown that mechanical stress-related damage to the pulmonary blood gas barrier likely precedes the development of edema. Although HAPE-susceptible individuals have increased pulmonary arterial pressure in hypoxia, how this high pressure is transmitted to the capillaries has been uncertain. Using functional magnetic resonance imaging of pulmonary blood flow, we have been able to show that regional pulmonary blood flow in HAPE-susceptible subjects becomes more heterogeneous when they are exposed to normobaric hypoxia. This is not observed in individuals who have not had HAPE, providing novel data supporting earlier suggestions by Hultgren that uneven hypoxic pulmonary vasoconstriction is an important feature of those who develop HAPE. This brief review discusses how uneven hypoxic pulmonary vasoconstriction increases regional pulmonary capillary pressure leading to stress failure of pulmonary capillaries and HAPE. We hypothesize that, in addition to the well-documented increase in pulmonary vascular pressure in HAPE-susceptible individuals, increased perfusion heterogeneity in hypoxia results in lung regions that are vulnerable to increased mechanical stress.

Altitude Sickness↗

PubMed2005

The lung at maximal exercise: insights from comparative physiology.

Horses are bred selectively for aerobic performance and have extraordinarily high maximal oxygen consumption, approximately double the mass-specific value for human athletes. Pulmonary limitations to exercise performance are well described in these animals, including exercise-induced arterial hypoxemia and exercise-induced pulmonary hemorrhage. In human athletes, pulmonary limitations are recognized increasingly as affecting athletic performance. Potential pulmonary limitations during maximal exercise are compared in human and equine athletes.

Exercise↗

PubMed2004

Pulmonary blood flow heterogeneity during hypoxia and high-altitude pulmonary edema.

Uneven hypoxic pulmonary vasoconstriction has been proposed to expose parts of the pulmonary capillary bed to high pressure and vascular injury in high-altitude pulmonary edema (HAPE). We hypothesized that subjects with a history of HAPE would demonstrate increased heterogeneity of pulmonary blood flow during hypoxia. A functional magnetic resonance imaging technique (arterial spin labeling) was used to quantify spatial pulmonary blood flow heterogeneity in three subject groups: (1) HAPE-susceptible (n = 5), individuals with a history of physician-documented HAPE; (2) HAPE-resistant (n = 6), individuals with repeated high-altitude exposure without illness; and (3) unselected (n = 6), individuals with a minimal history of altitude exposure. Data were collected in normoxia and after 5, 10, 20, and 30 minutes of normobaric hypoxia FI(O(2)) = 0.125. Relative dispersion (SD/mean) of the signal intensity was used as an index of perfusion heterogeneity. Oxygen saturation was not different between groups during hypoxia. Relative dispersion was not different between groups (HAPE-susceptible 0.94 +/- 0.05, HAPE-resistant 0.94 +/- 0.05, unselected 0.87 +/- 0.06; means +/- SEM) during normoxia, but it was increased by hypoxia in HAPE-susceptible (to 1.10 +/- 0.05 after 30 minutes, p < 0.0001) but not in HAPE-resistant (0.91 +/- 0.05) or unselected subjects (0.87 +/- 0.05). HAPE-susceptible individuals have increased pulmonary blood flow heterogeneity in acute hypoxia, consistent with uneven hypoxic pulmonary vasoconstriction.

Adult↗

PubMed2004

Increased hypoxic ventilatory response during 8 weeks at 3800 m altitude.

Acclimatization to chronic hypoxia (CH) increases ventilation (V(I)) and the isocapnic hypoxic ventilatory response (HVR) over 2-14 days but hypoxic desensitization blunts the HVR after years of CH. We tested for hypoxic desensitization during the first 2 months of CH by studying five normal subjects at sea level (SL) and for 8 weeks at 3800 m (CH, PI(O(2)) approximately 90 Torr). We measured the isocapnic HVR (Delta V(I)/Delta Sa(O(2)) and tested for hypoxic ventilatory decline (HVD) by stepping Sa(O(2)) to 80% after 14 min at 90%. The HVR increased significantly after 2 days and remained significantly elevated for 8 weeks of CH. HVD was similar at SL and during 8 weeks of CH. Hence, hypoxic desensitization of the HVR does not occur after only 8 weeks of hypoxia and the increased HVR during this time does not involve changes in HVD.

Acclimatization↗

PubMed2004

Does gender affect human pulmonary gas exchange during exercise?

Women may experience greater pulmonary gas exchange impairment during exercise than men. To test this we used the multiple inert gas elimination technique to study eight women and seven men matched for age, height and (O(2) max) ( approximately 48 ml x kg(-1) min(-1)) during normoxic and hypoxic (inspired P(O(2))= 95 Torr) cycle exercise. Resting lung function was similar between the sexes, except for a lower carbon monoxide diffusing capacity (DL(CO)) in women (P < 0.05). Arterial P(O(2)),P(CO(2)) and alveolar-arterial O(2) difference (A-aD(O(2))) were not significantly different in men and women. Despite a lower diffusing capacity for O(2) (DL(O(2))) in women, the ratio DL(O(2))/beta (which estimates pulmonary end-capillary diffusion equilibrium) was similar between men and women and estimates of diffusion limitation during hypoxic exercise were not different between the sexes. Ventilation-perfusion inequality (described by the second moment of the perfusion distribution, logSD increased during both normoxic and hypoxic exercise. Surprisingly, logSD values were slightly lower for women under all conditions (P < 0.05), but this did not significantly affect gas exchange. These data indicate that these active women, despite a lower DL(CO) and DL(O(2)), do not experience greater exercise-induced abnormalities in gas exchange than men matched for age, height, aerobic capacity and lung size. Possibly fitness level and lung size are more important in determining whether or not pulmonary gas exchange impairment occurs during exercise than sex per se.

Adult↗

PubMed2004

Gender and pulmonary gas exchange during exercise.

Relative to body size, women have a lower diffusing capacity for carbon monoxide, smaller airway diameter, and smaller lung volumes than men. The effect that these differences have on gas exchange during exercise is incompletely understood. Women may have a larger alveolar-arterial PO(2) difference that may be compensated for, in part, by increased alveolar ventilation.

Exercise↗

PubMed2004

Functional magnetic resonance imaging of the lung: a physiological perspective.

Functional lung imaging has the potential to offer many new insights into mechanisms of pulmonary disease. While the physiologist has access to a number of techniques to evaluate lung function, such as multiple inert gas elimination technique or the injection of microspheres, these techniques have significant disadvantages, including lack of spatial information or low spatial resolution and, in the case of microspheres, an inability to make measurements in humans. The functional imaging techniques based on magnetic resonance (MR), computed tomography (CT), or positron emission tomography (PET) hold substantial promise. In this article, specific issues related to the MR evaluation of pulmonary blood flow, including quantification of heterogeneity, reliability, and validity of the technique, are discussed to highlight some of the important physiologic issues that affect functional imaging. Additional physiologic considerations include the anatomic partitioning of blood flow, and the effects of posture, breath holding, and exercise. The relationships between these many factors and the collection of regional pulmonary perfusion data are explored.

Animals↗

PubMed2004

Comparative physiology of lung complexity: implications for gas exchange.

Lungs evolved to increase diffusing capacity by compartmentalizing and reducing the size of individual gas exchange units. This increased the potential for gas exchange limitations from ventilation-perfusion heterogeneity. However, comparative studies on reptiles, birds, and mammals show that heterogeneity is independent of lung complexity.

Animals↗

PubMed2003

Beta-adrenergic or parasympathetic inhibition, heart rate and cardiac output during normoxic and acute hypoxic exercise in humans.

Acute hypoxia increases heart rate (HR) and cardiac output (Qt) at a given oxygen consumption (VO2) during submaximal exercise. It is widely believed that the underlying mechanism involves increased sympathetic activation and circulating catecholamines acting on cardiac beta receptors. Recent evidence indicating a continued role for parasympathetic modulation of HR during moderate exercise suggests that increased parasympathetic withdrawal plays a part in the increase in HR and Qt during hypoxic exercise. To test this, we separately blocked the beta-sympathetic and parasympathetic arms of the autonomic nervous system (ANS) in six healthy subjects (five male, one female; mean +/- S.E.M. age = 31.7+/-1.6 years, normoxic maximal VO2 (VO2,max)=3.1+/-0.3 l min(-1)) during exercise in conditions of normoxia and acute hypoxia (inspired oxygen fraction=0.125) to VO2,max. Data were collected on different days under the following conditions: (1)control, (2) after 8.0 mg propranolol i.v. and (3) after 0.8 mg glycopyrrolate i.v. Qt was measured using open-circuit acetylene uptake. Hypoxia increased venous [adrenaline] and [noradrenaline] but not [dopamine] at a given VO2 (P<0.05, P<0.01 and P=0.2, respectively). HR/VO2 and Qt/VO2 increased during hypoxia in all three conditions (P<0.05). Unexpectedly, the effects of hypoxia on HR and Qt were not significantly different from control with either beta-sympathetic or parasympathetic inhibition. These data suggest that although acute exposure to hypoxia increases circulating [catecholamines], the effects of hypoxia on HR and Qt do not necessarily require intact cardiac muscarinic and beta receptors. It may be that cardiac alpha receptors play a primary role in elevating HR and Qt during hypoxic exercise, or perhaps offer an alternative mechanism when other ANS pathways are blocked.

Adrenergic beta-Antagonists↗

PubMed2003

Persistence of the lactate paradox over 8 weeks at 3,800 m.

The arterial blood lactate [La] response to exercise increases in acute hypoxia, but returns to near the normoxic (sea level, SL) response after 2 to 5 weeks of altitude acclimatization. Recently, it has been suggested that this gradual return to the SL response in [La], known as the lactate paradox (LP), unexpectedly disappears after 8 to 9 weeks at altitude. We tested this idea by recording the [La] response to exercise every 2 weeks over 8 weeks at altitude. Five normal, fit SL-residents were studied at SL and 3,800 m (Pbar = 485 torr) in both normoxia (PIO2 = 150 torr) and hypoxia (PIO2 = 91 torr approximately air at 3,800 m). Arterial [La] and blood gas values were determined at rest and during cycle exercise at the same absolute workloads (0, 25, 50, 75, 90, and 100% of initial SL-VO2Max) and exercise duration (4, 4, 4, 2, 1.5, and 0.75 min, respectively) at each time point. [La] curves were elevated in acute hypoxia at SL (p < 0.01) and at 3,800 m fell progressively toward the SL-normoxic curve (p < 0.01). On the same days, [La] responses in acute normoxia showed essentially no changes over time and were similar to initial SL normoxic responses. We also measured arterial catecholamine levels at each load and found a close relationship to [La] over time, supporting a role for adrenergic influence on [La]. In summary, extending the time at this altitude to 8 weeks produced no evidence for reversal of the LP, consistent with prior data obtained over shorter periods of altitude residence.

Acclimatization↗

PubMed2003

A pig model of high altitude pulmonary edema.

High altitude pulmonary edema (HAPE) affects unacclimatized individuals ascending rapidly to high altitude. The pathogenesis of HAPE is not fully elucidated, and many investigative techniques that could provide valuable information are not suitable for use in humans; thus, an animal model is desirable. Rabbits, sheep, dogs, and ferrets have been shown not to consistently develop HAPE, and studies in rats are limited by the animal's small size and inconsistent response. Pigs develop a marked pulmonary vasoconstrictive response to hypoxia, and preliminary studies of HAPE in pigs have been promising. To determine the suitability of pigs as an animal model of HAPE, we exposed six subadult (20 to 25 kg) pigs to normobaric hypoxia (10% oxygen) for 48 hr. One week before, and immediately after exposure to hypoxia, under anesthesia, arterial blood gases were obtained and bronchoalveolar lavage (BAL) and chest x-ray were performed. Hypoxia increased alveolar-arterial pressure difference for oxygen from 22 +/- 9 to 38 +/- 5 torr, p < 0.01) and red cell (from 12.3 +/- 5.9 to 27.4 +/- 5.3 cells x 10(5)/mL(-1), p < 0.001) and white cell (from 1.59 +/- 0.90 to 7.88 +/- 3.36 cells x 10(5)/mL(-1), p < 0.05) concentrations in BAL in all animals. Total BAL protein concentration increased by 64% and fractional albumin by 38% (both p < 0.05) posthypoxia. One animal had evidence of pulmonary edema on X ray. Some pigs develop findings consistent with early HAPE when exposed to normobaric hypoxia. Increasing the duration of hypoxic exposure or exercising the animals in hypoxia may better model the disease process observed in humans with clinically significant HAPE.

Altitude Sickness↗

PubMed2002

Human autonomic activity and its response to acute oxygen supplement after high altitude acclimatization.

It is well established that after acclimatization at high altitude, many sympathetic pathways are hyperactive yet heart rate (HR) remains unchanged. In this study, we attempted to determine if this unchanged heart rate is due to compensatory mechanisms such as changes in parasympathetic activity or levels of receptors for autonomic neurotransmitters. We also examined the role played by hypoxia in these autonomic adaptations to high altitude. Three experiments were carried out on five healthy lowlanders both at sea level (SL) and after 2 weeks of acclimatization at 3800 m (Post-Ac) with: (a) placebo (control); (b) acute beta-adrenergic receptor blockade by propranolol (PRO), or (c) acute parasympathetic receptor blockade by glycopyrrolate (GLY). Compared with SL control values, post-Ac venous norepinephrine (NE) and dopamine increased by 96% (p < 0.001) and 55% (p < 0.05), but epinephrine and HR did not change. PRO resulted in a smaller decrease in HR (bpm) Post-Ac than at SL (15 +/- 6 vs. 21 +/- 6, p < 0.05), while GLY caused a greater increase in HR Post-Ac than at SL (59 +/- 8 vs. 45 +/- 6, p < 0.05). Breathing oxygen at SL concentration while at altitude did not decrease NE, or alter the effect of PRO on HR, but reduced the chronotropic effect of GLY by 14% (p < 0.05). These results suggest that after acclimatization to altitude, increased parasympathetic neurotransmitter release and decreased beta-adenoreceptor activity account for the unchanged HR despite enhanced sympathetic activity. Acute oxygen replacement rapidly counteracted the parasympathetic, but not sympathetic hyperactivity that occurs at high altitude.

Acclimatization↗

PubMed2002

Role of the autonomic nervous system in the reduced maximal cardiac output at altitude.

After acclimatization to high altitude, maximal exercise cardiac output (QT) is reduced. Possible contributing factors include 1) blood volume depletion, 2) increased blood viscosity, 3) myocardial hypoxia, 4) altered autonomic nervous system (ANS) function affecting maximal heart rate (HR), and 5) reduced flow demand from reduced muscle work capability. We tested the role of the ANS reduction of HR in this phenomenon in five normal subjects by separately blocking the sympathetic and parasympathetic arms of the ANS during maximal exercise after 2-wk acclimatization at 3,800 m to alter maximal HR. We used intravenous doses of 8.0 mg of propranolol and 0.8 mg of glycopyrrolate, respectively. At altitude, peak HR was 170 +/- 6 beats/min, reduced from 186 +/- 3 beats/min (P = 0.012) at sea level. Propranolol further reduced peak HR to 139 +/- 2 beats/min (P = 0.001), whereas glycopyrrolate increased peak HR to sea level values, 184 +/- 3 beats/min, confirming adequate dosing with each drug. In contrast, peak O(2) consumption, work rate, and QT were similar at altitude under all drug treatments [peak QT = 16.2 +/- 1.2 (control), 15.5 +/- 1.3 (propranolol), and 16.2 +/- 1.1 l/min (glycopyrrolate)]. All QT results at altitude were lower than those at sea level (20.0 +/- 1.8 l/min in air). Therefore, this study suggests that, whereas the ANS may affect HR at altitude, peak QT is unaffected by ANS blockade. We conclude that the effect of altered ANS function on HR is not the cause of the reduced maximal QT at altitude.

Acclimatization↗