Steven A. Romero

Control of cerebral blood velocity with furosemide-induced hypovolemia and upright tilt

The purpose of this study was to test the hypothesis that exacerbated reductions of cerebral blood velocity (CBV) during upright tilt with dehydration are associated with impaired cerebrovascular control. Nine healthy men were tilted head-up (HUT) to 70° for 10 min on two occasions separated by 7 days under euhydration (EUH) and dehydration (DEH; 40 mg of furosemide and water restriction) conditions. Beat-by-beat arterial pressures and CBV were measured during a 5-min supine baseline and during the first (T1) and last (T2) 5 min of HUT. Cerebral autoregulation and arterial baroreflex sensitivity were assessed in the frequency domain with cross-spectral techniques. DEH reduced plasma volume by 10% (P = 0.008) and supine mean CBV (CBV(mean)) by 11% (P = 0.002). Mean arterial pressure (MAP), stroke volume, and baroreflex sensitivity decreased during HUT (P ≤ 0.002), but absolute reductions were similar between hydration conditions, with the exception of stroke volume, which was lower at T1 during DEH than EUH (P = 0.04). CBV(mean) during DEH was lower (7 cm/s) over the course of the entire 10 min of HUT (P ≤ 0.004) than during EUH. Low-frequency oscillations (0.07-0.2 Hz) of MAP and CBV(mean) and MAP-CBV(mean) coherence were higher during DEH than EUH at T1 (P ≤ 0.02), but not at T2. Our results suggest that increased coherence between arterial pressure and CBV with the combination of DEH and HUT are indicative of altered cerebrovascular control. Increased CBV oscillations with DEH may reflect acute protective mechanisms to ensure adequate cerebral perfusion under conditions of reduced central blood volume.

Acute limb heating improves macro- and microvascular dilator function in the leg of aged humans

Local heating of an extremity increases blood flow and vascular shear stress throughout the arterial tree. Local heating acutely improves macrovascular dilator function in the upper limbs of young healthy adults through a shear stress-dependent mechanism but has no such effect in the lower limbs of this age group. The effect of acute limb heating on dilator function within the atherosclerotic prone vasculature of the lower limbs of aged adults is unknown. Therefore, the purpose of this study was to test the hypothesis that acute lower limb heating improves macro- and microvascular dilator function within the leg vasculature of aged adults. Nine young and nine aged adults immersed their lower limbs at a depth of ~33 cm into a heated (~42°C) circulated water bath for 45 min. Before and 30 min after heating, macro (flow-mediated dilation)- and microvascular (reactive hyperemia) dilator functions were assessed in the lower limb, following 5 min of arterial occlusion, via Doppler ultrasound. Compared with preheat, macrovascular dilator function was unchanged following heating in young adults (P = 0.6) but was improved in aged adults (P = 0.04). Similarly, microvascular dilator function, as assessed by peak reactive hyperemia, was unchanged following heating in young adults (P = 0.1) but was improved in aged adults (P < 0.01). Taken together, these data suggest that acute lower limb heating improves both macro- and microvascular dilator function in an age dependent manner. NEW & NOTEWORTHY We demonstrate that lower limb heating acutely improves macro- and microvascular dilator function within the atherosclerotic prone vasculature of the leg in aged adults. These findings provide evidence for a potential therapeutic use of chronic lower limb heating to improve vascular health in primary aging and various disease conditions.

Combat stress or hemorrhage? Evidence for a decision-assist algorithm for remote triage.

INTRODUCTION In the setting of remote military triage, when physical access to the patient is not possible, traditional physiological measurements available to a combat medic may not differentiate between a wounded soldier and an active soldier. We tested the hypothesis that changes in high-frequency R-R interval spectral power (RRI HF) and pulse pressure (PP) would differ between progressive central hypovolemia (simulated hemorrhage) and exercise to evaluate their potential for remotely distinguishing active from bleeding soldiers. The RRI HF and PP were used because of their ability to track central hypovolemia. METHODS There were 12 (8 female/4 male) healthy, normotensive, nonsmoking subjects (age 27 +/- 2 yr; height 169 +/- 3 cm; weight 68 +/- 5 kg) who were exposed to progressive lower body negative pressure (LBNP) and a supine cycle ergometer protocol. ECG and blood pressure were measured continuously. Exercise workloads were determined by matching the heart rate (HR) responses to each LBNP level. Data were analyzed in time and frequency domains. RESULTS HR increased from 67 +/- 3 bpm at rest to 101 +/- 4 bpm by -60 mmHg LBNP and was matched within 5% during exercise. By the final stage, RRI HF decreased by a similar magnitude during both LBNP (-78 +/- 7%) and exercise (-85 +/- 6%). PP decreased by 30 +/- 4% with LBNP compared with an increase of 20 +/- 6% during exercise. CONCLUSION Monitoring PP in combination with RRI HF would distinguish a bleeding from an active soldier. Technologies that incorporate telemetry to track these derived vital signs would provide a combat medic with remote decision support to assess soldier status on the battlefield.

Plasma hyperosmolality attenuates skin sympathetic nerve activity during passive heat stress in humans

Plasma hyperosmolality delays the onset for sweat production and cutaneous vasodilatation during heat stress in humans; however, the mechanism by which hyperosmolality exerts this effect remains unknown. This study examined if plasma hyperosmolality exerts a central and/or peripheral modulation of thermoregulatory function in humans. The main findings are that plasma hyperosmolality delays the increase in skin sympathetic nerve activity during whole‐body passive heat stress in humans. In contrast, local intradermal infusion of hyperosmotic saline did not affect sweating or cutaneous vasodilatation. These results suggest that plasma hyperosmolality delays the onset threshold for sweating and cutaneous vasodilatation by inhibiting efferent thermoregulatory activity in humans.

Evidence of a broad histamine footprint on the human exercise transcriptome

Histamine is a primordial signalling molecule, capable of activating cells in an autocrine or paracrine fashion via specific cell surface receptors, in a variety of pathways that probably predate its more recent role in innate and adaptive immunity. Although histamine is normally associated with pathological conditions or allergic and anaphylactic reactions, it may contribute beneficially to the normal changes that occur within skeletal muscle during the recovery from exercise. We show that the human response to exercise includes an altered expression of thousands of protein‐coding genes, and much of this response appears to be driven by histamine. Histamine may be an important molecular transducer contributing to many of the adaptations that accompany chronic exercise training.

Healthy aging does not compromise the augmentation of cardiac function during heat stress

During heat stress, stroke volume is maintained in young adults despite reductions in cardiac filling pressures. This is achieved by a general augmentation of cardiac function, highlighted by a left and upward shift of the Frank-Starling relation. In contrast, healthy aged adults are unable to maintain stroke volume during heat stress. We hypothesized that this would be associated with a lack of shift in the Frank-Starling relation. Frank-Starling relations were examined in 11 aged [69 ± 4 (SD) yr, 4 men/7 women] and 12 young (26 ± 5 yr, 6 men/6 women) adults during normothermic and heat stress (1.5°C increase in core temperature) conditions. During heat stress, increases in cardiac output were attenuated in aged adults (+2.5 ± 0.3 (95% CI) vs. young: +4.5 ± 0.5 l/min, P < 0.01) because of an attenuated chronotropic response (+30 ± 4 vs. young: +42 ± 5 beats/min, P < 0.01). In contrast to our hypothesis, a leftward shift of the Frank-Starling relation maintained stroke volume during heat stress in aged adults (76 ± 8 vs. normothermic: 74 ± 8 ml, P = 0.38) despite reductions in cardiac filling pressure (6.6 ± 1.0 vs. normothermic: 8.9 ± 1.1 mmHg, P < 0.01). In a subset of participants, volume loading was used to return cardiac filling pressure during heat stress to normothermic values, which resulted in a greater stroke volume for a given cardiac filling pressure in both groups. These results demonstrate that the Frank-Starling relation shifts during heat stress in healthy young and aged adults, thereby preserving stroke volume despite reductions in cardiac filling pressures.

Cardiac and Thermal Strain of Elderly Adults Exposed to Extreme Heat and Humidity With and Without Electric Fan Use

Cardiac and Thermal Strain of Elderly Adults Exposed to Extreme Heat and Humidity With and Without Electric Fan Use Heat-related morbidity and mortality are important health challenges posed by global climate change.1 Electric fans provide a low-cost and accessible cooling intervention, although their effectiveness remains debatable. Due to theoretical risks of accelerated heat gain and dehydration, fan use is discouraged above ambient temperatures of approximately 35°C.2 However, empirical data to support or refute their use during heat wave conditions are sparse.3 Fan use delays elevations in heart rate and core temperature of young adults exposed to 42°C.4 However, it remains unknown if fans are effective in vulnerable populations, such as the elderly who display altered cardiovascular and thermoregulatory responses during heat exposure.5 We hypothesized that fan use would delay elevations in heart rate and core temperature of elderly adults exposed to extreme heat and humidity.

Mast cell degranulation and de novo histamine formation contribute to sustained post-exercise vasodilation in humans.

In humans, acute aerobic exercise elicits a sustained postexercise vasodilation within previously active skeletal muscle. This response is dependent on activation of histamine H1 and H2 receptors, but the source of intramuscular histamine remains unclear. We tested the hypothesis that interstitial histamine in skeletal muscle would be increased with exercise and would be dependent on de novo formation via the inducible enzyme histidine decarboxylase and/or mast cell degranulation. Subjects performed 1 h of unilateral dynamic knee-extension exercise or sham (seated rest). We measured the interstitial histamine concentration and local blood flow (ethanol washout) via skeletal muscle microdialysis of the vastus lateralis. In some probes, we infused either α-fluoromethylhistidine hydrochloride (α-FMH), a potent inhibitor of histidine decarboxylase, or histamine H1/H2-receptor blockers. We also measured interstitial tryptase concentrations, a biomarker of mast cell degranulation. Compared with preexercise, histamine was increased after exercise by a change (Δ) of 4.2 ± 1.8 ng/ml (P < 0.05), but not when α-FMH was administered (Δ-0.3 ± 1.3 ng/ml, P = 0.9). Likewise, local blood flow after exercise was reduced to preexercise levels by both α-FMH and H1/H2 blockade. In addition, tryptase was elevated during exercise by Δ6.8 ± 1.1 ng/ml (P < 0.05). Taken together, these data suggest that interstitial histamine in skeletal muscle increases with exercise and results from both de novo formation and mast cell degranulation. This suggests that exercise produces an anaphylactoid signal, which affects recovery, and may influence skeletal muscle blood flow during exercise.NEW & NOTEWORTHY Blood flow to previously active skeletal muscle remains elevated following an acute bout of aerobic exercise and is dependent on activation of histamine H1 and H2 receptors. The intramuscular source of histamine that drives this response to exercise has not been identified. Using intramuscular microdialysis in exercising humans, we show both mast cell degranulation and formation of histamine by histidine decarboxylase contributes to the histamine-mediated vasodilation that occurs following a bout of aerobic exercise.

A single dose of histamine-receptor antagonists before downhill running alters markers of muscle damage and delayed-onset muscle soreness

Histamine contributes to elevations in skeletal muscle blood flow following exercise, which raises the possibility that histamine is an important mediator of the inflammatory response to exercise. We examined the influence of antihistamines on postexercise blood flow, inflammation, muscle damage, and delayed-onset muscle soreness (DOMS) in a model of moderate exercise-induced muscle damage. Subjects consumed either a combination of fexofenadine and ranitidine (blockade, n = 12) or nothing (control, n = 12) before 45 min of downhill running (-10% grade). Blood flow to the leg was measured before and throughout 120 min of exercise recovery. Markers of inflammation, muscle damage, and DOMS were obtained before and at 0, 6, 12, 24, 48, and 72 h postexercise. At 60 min postexercise, blood flow was reduced ~29% with blockade compared with control (P < 0.05). Markers of inflammation were elevated after exercise (TNF-ɑ, IL-6), but did not differ between control and blockade. Creatine kinase concentrations peaked 12 h after exercise, and the overall response was greater with blockade (18.3 ± 3.2 kU·l-1·h-1) compared with control (11.6 ± 2.0 kU·l-1·h-1; P < 0.05). Reductions in muscle strength in control (-19.3 ± 4.3% at 24 h) were greater than blockade (-7.8 ± 4.8%; P < 0.05) and corresponded with greater perceptions of pain/discomfort in control compared with blockade. In conclusion, histamine-receptor blockade reduced postexercise blood flow, had no effect on the pattern of inflammatory markers, increased serum creatine kinase concentrations, attenuated muscle strength loss, and reduced pain perception following muscle-damaging exercise.NEW & NOTEWORTHY Histamine appears to be intimately involved with skeletal muscle during and following exercise. Blocking histamines actions during muscle-damaging exercise, via common over-the-counter antihistamines, resulted in increased serum creatine kinase, an indirect marker of muscle damage. Paradoxically, blocking histamines actions attenuated muscle strength loss and reduced perceptions of muscle pain for 72 h following muscle-damaging exercise. These results indicate that exercise-induced histamine release may have a broad impact on protecting muscle from exercise-induced damage.

Hemodynamic Stability to Surface Warming and Cooling During Sustained and Continuous Simulated Hemorrhage in Humans.

ABSTRACT One in 10 deaths worldwide is caused by traumatic injury, and 30% to 40% of those trauma-related deaths are due to hemorrhage. Currently, warming a bleeding victim is the standard of care due to the adverse effects of combined hemorrhage and hypothermia on survival. We tested the hypothesis that heating is detrimental to the maintenance of arterial pressure and cerebral perfusion during hemorrhage, while cooling is beneficial to victims who are otherwise normothermic. Twenty-one men (31 ± 9 y) were examined under two separate protocols designed to produce central hypovolemia similar to hemorrhage. Following 15 min of supine rest, 10 min of 30 mm Hg of lower body negative pressure (LBNP) was applied. On separate randomized days, subjects were then exposed to skin surface cooling (COOL), warming (WARM), or remained thermoneutral (NEUT), while LBNP continued. Subjects remained in these thermal conditions for either 40 min of 30 mm Hg LBNP (N = 9), or underwent a continuous LBNP ramp until hemodynamic decompensation (N = 12). Arterial blood pressure during LBNP was dependent on the thermal perturbation as blood pressure was greater during COOL (P >0.001) relative to NEUT and WARM for both protocols. Middle cerebral artery blood velocity decreased (P <0.001) from baseline throughout sustained and continuous LBNP, but the magnitude of reduction did not differ between thermal conditions. Contrary to our hypothesis, WARM did not reduce cerebral blood velocity or LBNP tolerance relative to COOL and NEUT in normothermic individuals. While COOL increased blood pressure, cerebral perfusion and time to presyncope were not different relative to NEUT or WARM during sustained or continuous LBNP. Warming an otherwise normothermic hemorrhaging victim is not detrimental to hemodynamic stability, nor is this stability improved with cooling.