Sex Differences in Sympathetic Responses to Lower-Body Negative Pressure.

INTRODUCTION: Trauma-induced hemorrhage is a leading cause of death in prehospital settings. Experimental data demonstrate that females have a lower tolerance to simulated hemorrhage (i.e., central hypovolemia). However, the mechanism(s) underpinning these responses are unknown. Therefore, this study aimed to compare autonomic cardiovascular responses during central hypovolemia between the sexes. We hypothesized that females would have a lower tolerance and smaller increase in muscle sympathetic nerve activity (MSNA) to simulated hemorrhage. METHODS: Data from 17 females and 19 males, aged 19-45 yr, were retrospectively analyzed. Participants completed a progressive lower-body negative pressure (LBNP) protocol to presyncope to simulate hemorrhagic tolerance with continuous measures of MSNA and beat-to-beat hemodynamic variables. We compared responses at baseline, at two LBNP stages (-40 and -50 mmHg), and at immediately before presyncope. In addition, we compared responses at relative percentages (33%, 66%, and 100%) of hemorrhagic tolerance, calculated via the cumulative stress index (i.e., the sum of the product of time and pressure at each LBNP stage). RESULTS: Females had lower tolerance to central hypovolemia (female: 561 ± 309 vs male: 894 ± 304 min·mmHg [time·LBNP]; P = 0.003). At LBNP -40 and -50 mmHg, females had lower diastolic blood pressures (main effect of sex: P = 0.010). For the relative LBNP analysis, females exhibited lower MSNA burst frequency (main effect of sex: P = 0.016) accompanied by a lower total vascular conductance (sex: P = 0.028; main effect of sex). CONCLUSIONS: Females have a lower tolerance to central hypovolemia, which was accompanied by lower diastolic blood pressure at -40 and -50 mmHg LBNP. Notably, females had attenuated MSNA responses when assessed as relative LBNP tolerance time.

Burn size and environmental conditions modify thermoregulatory responses to exercise in burn survivors.

This project tested the hypothesis that burn survivors can perform mild/moderate-intensity exercise in temperate and hot environments without excessive elevations in core body temperature. Burn survivors with low (23 ± 5%TBSA; N = 11), moderate (40 ± 5%TBSA; N = 9), and high (60 ± 8%TBSA; N = 9) burn injuries performed 60 minutes of cycle ergometry exercise (72 ± 15 watts) in a 25°C and 23% relative humidity environment (ie, temperate) and in a 40°C and 21% relative humidity environment (ie, hot). Absolute gastrointestinal temperatures (TGI) and changes in TGI (ΔTGI) were obtained. Participants with an absolute TGI of >38.5°C and/or a ΔTGI of >1.5°C were categorized as being at risk for hyperthermia. For the temperate environment, exercise increased ΔTGI in all groups (low: 0.72 ± 0.21°C, moderate: 0.42 ± 0.22°C, and high: 0.77 ± 0.25°C; all P < .01 from pre-exercise baselines), resulting in similar absolute end-exercise TGI values (P = .19). Importantly, no participant was categorized as being at risk for hyperthermia, based upon the aforementioned criteria. For the hot environment, ΔTGI at the end of the exercise bout was greater for the high group when compared to the low group (P = .049). Notably, 33% of the moderate cohort and 56% of the high cohort reached or exceeded a core temperature of 38.5°C, while none in the low cohort exceeded this threshold. These data suggest that individuals with a substantial %TBSA burned can perform mild/moderate intensity exercise for 60 minutes in temperate environmental conditions without risk of excessive elevations in TGI. Conversely, the risk of excessive elevations in TGI during mild/moderate intensity exercise in a hot environment increases with the %TBSA burned.

Key Exercise Concepts in the Rehabilitation from Severe Burns.

This article presents information on the benefits of exercise in counteracting the detrimental effects of bed rest, and/or severe burns. Exercise is key for maintaining physical function, lean body mass, metabolic recovery, and psychosocial health after major burn injuries. The details of an exercise training program conducted in severely burned persons are presented, as well as information on the importance of proper regulation of body temperature during exercise or physical activity. The sections on exercise and thermoregulation are followed by a section on the role of exercise in scarring and contractures. Finally, gaps in the current knowledge of exercise, thermoregulation, and contractures are presented.

Baroreflex sensitivity following acute upper-body exercise in the cold among stable coronary artery disease patients.

Background: A cold environment and exercise separately affect the autonomic nervous system (ANS), baroreflex sensitivity (BRS), and blood pressure variability (BPV) but their combined effects on post-exercise recovery are not known. Our cross-over trial examined these responses following upper-body static and dynamic exercise performed in a cold and neutral environment in patients with coronary artery disease (CAD). Methods: 20 patients with stable coronary artery disease performed both graded static (10%-30% of maximal voluntary contraction) and dynamic (light, moderate and high perceived intensity) upper-body exercise at -15°C and +22°C for 30 min. Electrocardiogram and continuous blood pressure were measured to compute post-exercise (10 and 30 min after exercise) spectral powers of heart rate (HR), blood pressure variability and BRS at low (0.04-0.15 Hz) and high (0.15-0.4 Hz) frequencies. Results: Static upper-body exercise performed in a cold environment increased post-exercise high frequency (HF) spectral power of heart rate (HF RR) (p < 0.001) and reduced heart rate (p = 0.001) and low-to-high frequency (LF/HF) ratio (p = 0.006) more than in a neutral environment. In addition, post-exercise mean BRS (p = 0.015) and high frequency BRS (p = 0.041) increased more following static exercise in the cold than in a neutral environment. Dynamic upper-body exercise performed in a cold environment reduced post-exercise HF BRS (p = 0.019) and systolic blood pressure (p = 0.003). Conclusion: Static upper-body exercise in the cold increased post-exercise BRS and overall vagal activity but without reduced systolic blood pressure. Dynamic upper-body exercise in the cold reduced post-exercise vagal BRS but did not affect the other parameters. The influence of cold exposure on post-exercise autonomic and cardiovascular responses following static upper-body exercise require further studies. This information helps understanding why persons with cardiovascular diseases are vulnerable to low environmental temperature. ClinicalTrials.gov: NCT02855905 (04/08/2016).

Aging Increases Enterocyte Damage during a 3-Hour Exposure to Very Hot and Dry Heat: A Preliminary Study.

Profound heat stress can damage the gastrointestinal barrier, leading to microbial translocation from the gut and subsequent systemic inflammation. Despite the greater vulnerability of older people to heat wave-related morbidity and mortality, it is unknown if age modulates gastrointestinal barrier damage and inflammation during heat stress. Therefore, the aim of this study was to determine if aging impacted enterocyte damage and systemic inflammatory responses to a 3-h exposure to very hot and dry (47 °C, 15% humidity) heat with accompanying activities of daily living (intermittent activity at 3 METS). Data from 16 young (age 21 to 39 years) and 16 older (age 65 to 76 years) humans were used to address this aim. In each group, log-transformed plasma concentrations of intestinal fatty acid binding protein (I-FABPlog), interleukin-8 (IL-8log), and tissue factor (TFlog) were assessed as indices of enterocyte damage, systemic inflammation, and blood coagulation, respectively, before and after the 3-h heat exposure. In the younger cohort, I-FABPlog concentration did not increase from pre to post heat exposure (p = 0.264, d = 0.20), although it was elevated in the older group (p = 0.014, d = 0.67). The magnitude of the increase in I-FABPlog was greater in the older participants (p = 0.084, d = 0.55). Across all participants, there was no correlation between the change in core temperature and the change in IFABPlog. There was no change in IL-8log in the younger group (p = 0.193, d = 0.23) following heat exposure, but we observed a decrease in IL-8log in the older group (p = 0.047, d = 0.48). TFlog decreased in the younger group (p = 0.071, d = 0.41), but did not change in the older group (p = 0.193, d = 0.15). Our data indicate that I-FABPlog concentration (an index of enterocyte damage) is increased in older humans during a 3-h extreme heat exposure. Future studies should determine whether this marker reflects increased gastrointestinal barrier permeability in older individuals during heat exposure.

Age alters the thermoregulatory responses to extreme heat exposure with accompanying activities of daily living.

Older adults are at greater risk for heat-related morbidity and mortality, due in part to age-related reductions in heat dissipating capabilities. Previous studies investigating the impact of age on responses to heat stress used approaches that lack activities of daily living and therefore may not accurately depict the thermal/physiological strain that would occur during actual heatwaves. We sought to compare the responses of young (18-39 yr) and older (≥65 yr) adults exposed to two extreme heat simulations. Healthy young (n = 20) and older (n = 20) participants underwent two 3-h extreme heat exposures on different days: 1) DRY (47°C and 15% humidity) and 2) HUMID (41°C and 40% humidity). To mimic heat generation comparable with activities of daily living, participants performed 5-min bouts of light physical activity dispersed throughout the heat exposure. Measurements included core and skin temperatures, heart rate, blood pressure, local and whole body sweat rate, forearm blood flow, and perceptual responses. Δ core temperature (Young: 0.68 ± 0.27°C vs. Older: 1.37 ± 0.42°C; P < 0.001) and ending core temperature (Young: 37.81 ± 0.26°C vs. Older: 38.15 ± 0.43°C; P = 0.005) were greater in the older cohort during the DRY condition. Δ core temperature (Young: 0.58 ± 0.25°C vs. Older: 1.02 ± 0.32°C; P < 0.001), but not ending core temperature (Young: 37.67 ± 0.34°C vs. Older: 37.83 ± 0.35°C; P = 0.151), was higher in the older cohort during the HUMID condition. We demonstrated that older adults have diminished thermoregulatory responses to heat stress with accompanying activities of daily living. These findings corroborate previous reports and confirm epidemiological data showing that older adults are at a greater risk for hyperthermia.NEW & NOTEWORTHY Using an experimental model of extreme heat exposure that incorporates brief periods of light physical activity to simulate activities of daily living, the extent of thermal strain reported herein more accurately represents what would occur during actual heatwave conditions. Despite matching metabolic heat generation and environmental conditions, we show that older adults have augmented core temperature responses, likely due to age-related reductions in heat dissipating mechanisms.

Attrition of Well-Healed Burn Survivors to a 6-Month Community-Based Exercise Program: A Retrospective Evaluation.

The purpose of this study was to evaluate whether burn survivors have lower adherence compared to non-burned control individuals during a 6-month community-based exercise program. In burn survivors, we sought to answer if there was a relation between the size of the burn injury and dropout frequency. Fifty-two burn survivors and 15 non-burned controls (n = 67) were recruited for a 6-month community-based (ie, non-supervised), progressive, exercise training program. During the exercise program, 27% (ie, 4 of the 15 enrolled) of the non-burned individuals dropped out of the study, while 37% (ie, 19 of the 52) of the burn survivors dropped out from the study. There was no difference in the percentage of individuals who dropped out between groups (P = .552). There was no difference in size of the burn injury, expressed as percent body surface area burned (%BSA) between the burn survivors that dropped out versus those who completed the exercise regimen (P = .951). We did not observe a relation between %BSA burned and dropouts (log odds = -0.15-0.01(%BSA), B = -0.01, SE = 0.015, P = .541). There was no effect of %BSA burned on the probability of dropout [Exp (B) = 0.991, 95% CI (0.961, 1.020)] and there were no differences in the percentage of individuals who dropped out of the study based on %BSA burned (χ2(1) = 0.44, P = .51). These data demonstrate that burn survivors have similar exercise adherence relative to a non-burned group and the extent of a burn injury does not affect exercise program adherence.

Inhibiting regional sweat evaporation modifies the ventilatory response to exercise: interactions between core and skin temperature.

In humans, elevated body temperatures can markedly increase the ventilatory response to exercise. However, the impact of changing the effective body surface area (BSA) for sweat evaporation (BSAeff) on such responses is unclear. Ten healthy adults (9 males, 1 female) performed eight exercise trials cycling at 6 W/kg of metabolic heat production for 60 min. Four conditions were used where BSAeff corresponded to 100%, 80%, 60%, and 40% of BSA using vapor-impermeable material. Four trials (one at each BSAeff) were performed at 25°C air temperature, and four trials (one at each BSAeff) at 40°C air temperature, each with 20% humidity. The slope of the relation between minute ventilation and carbon dioxide elimination (V̇E/V̇co2 slope) assessed the ventilatory response. At 25°C, the V̇E/V̇co2 slope was elevated by 1.9 and 2.6 units when decreasing BSAeff from 100 to 80 and to 40% (P = 0.033 and 0.004, respectively). At 40°C, V̇E/V̇co2 slope was elevated by 3.3 and 4.7 units, when decreasing BSAeff from 100 to 60 and to 40% (P = 0.016 and P < 0.001, respectively). Linear regression analyses using group average data from each condition demonstrated that end-exercise mean body temperature (integration of core and mean skin temperature) was better associated with the end-exercise ventilatory response, compared with core temperature alone. Overall, we show that impeding regional sweat evaporation increases the ventilatory response to exercise in temperate and hot environmental conditions, and the effect is mediated primarily by increases in mean body temperature.NEW & NOTEWORTHY Exercise in the heat increases the slope of the relation between minute ventilation and carbon dioxide elimination (V̇E/V̇co2 slope) in young healthy adults. An indispensable role for skin temperature in modulating the ventilatory response to exercise is noted, contradicting common belief that internal/core temperature acts independently as a controller of ventilation during hyperthermia.

Six Months of Exercise Training Improves Ventilatory Responses during Exercise in Adults with Well-Healed Burn Injuries.

INTRODUCTION: Pulmonary function is lower after a severe burn injury, which could influence ventilatory responses during exercise. It is unclear whether exercise training improves pulmonary function or ventilatory responses during exercise in adults with well-healed burn injuries. Therefore, we tested the hypothesis that exercise training improves pulmonary function and ventilatory responses during exercise in adults with well-healed burn injuries. METHODS: Thirty-nine adults (28 with well-healed burn injuries and 11 non-burn-injured controls) completed 6 months of unsupervised, progressive exercise training including endurance, resistance, and high-intensity interval components. Before and after exercise training, we performed comprehensive pulmonary function testing and measured ventilatory responses during cycling exercise. We compared variables using two-way ANOVA (group-time; i.e., preexercise/postexercise training (repeated factor)). RESULTS: Exercise training did not increase percent predicted spirometry, lung diffusing capacity, or airway resistance measures (time: P ≥ 0.14 for all variables). However, exercise training reduced minute ventilation ( V̇E ; time: P ≤ 0.05 for 50 and 75 W) and the ventilatory equivalent for oxygen ( V̇E /V̇O 2 ; time: P < 0.001 for 75 W) during fixed-load exercise for both groups. The ventilatory equivalent for carbon dioxide ( V̇E /V̇CO 2 ) during exercise at 75 W was reduced after exercise training (time: P = 0.04). The percentage of age-predicted maximum heart rate at the ventilatory threshold was lower in adults with well-healed burn injuries before ( P = 0.002), but not after ( P = 0.22), exercise training. Lastly, exercise training increased V̇E and reduced V̇E /V̇O 2 during maximal exercise (time: P = 0.005 for both variables). CONCLUSIONS: These novel findings demonstrate that exercise training can improve ventilatory responses during exercise in adults with well-healed burn injuries.

Cardiac remodeling in well-healed burn survivors after 6 months of unsupervised progressive exercise training.

Aerobic exercise is important in the rehabilitation of individuals with prior burn injuries, but no studies have examined whether adult burn survivors demonstrate cardiac remodeling to long-term aerobic exercise training. In this study, we tested the hypothesis that 6 months of progressive exercise training improves cardiac magnetic resonance imaging-based measures of cardiac structure and function in well-healed burn survivors. Secondary analyses explored relations between burn surface area and changes in cardiac structure in the cohort of burn survivors. V̇o2peak assessments and cardiac magnetic resonance imaging were performed at baseline and following 6 months of progressive exercise training from 19 well-healed burn survivors and 10 nonburned control participants. V̇o2peak increased following 6 months of training in both groups (Control: Δ5.5 ± 5.8 mL/kg/min; Burn Survivors: Δ3.2 ± 3.6 mL/kg/min, main effect of training, P < 0.001). Left ventricle (LV) mass (Control: Δ1.7 ± 3.1 g/m2; Burn survivors: Δ1.8 ± 2.7 g/m2), stroke volume (Control: Δ5.8 ± 5.2 mL/m2; Burn Survivors: Δ2.8 ± 4.2 mL/m2), and ejection fraction (Control: Δ2.4 ± 4.0%; Burn Survivors: Δ2.2 ± 4.3%) similarly increased following 6 months of exercise training in both cohorts (main effect of training P < 0.05 for all indexes). LV end-diastolic volume increased in the control group (Δ6.5 ± 4.5 mL/m2) but not in the cohort of burn survivors (Δ1.9 ± 2.7 mL/m2, interaction, P = 0.040). Multiple linear regression analyses revealed that burn surface area had little to no effect on changes in ventricular mass or end-diastolic volumes in response to exercise training. Our findings provide initial evidence of physiological cardiac remodeling, which is not impacted by burn size, in response to exercise training in individuals with well-healed burn injuries.NEW & NOTEWORTHY Aerobic exercise is important in the rehabilitation of individuals with prior burn injuries, but no studies have examined whether adult burn survivors demonstrate cardiac remodeling to long-term aerobic exercise training. In this study, we tested the hypothesis that 6 months of progressive exercise training would improve cardiac magnetic resonance imaging-based measures of cardiac structure and function in well-healed burn survivors. Our findings highlight the ability of exercise training to modify cardiac structure and function in well-healed burn survivors and nonburned sedentary controls alike.

Impact of the Insoluble Gas Concentration on Measured Stroke Volume at Rest and Submaximal Exercise Using the Innocor Device.

INTRODUCTION: The Innocor® device uses an insoluble gas (SF 6 ) to estimate lung volume and the rate of disappearance of a soluble gas (nitrous oxide) to measure pulmonary blood flow (PBF), which approximates cardiac output assuming no shunt. We sought to identify error in the measurement of the insoluble gas in an effort to reduce variation in Innocor® measurement. METHODS: We enrolled 28 participants from the Dallas Heart Study (mean age, 63 yr; 57% men; 43% White). Stroke volume was measured at rest and at submaximal (20 and 40 W) exercise using both echocardiography (Philips iE33) and the Innocor® device. We defined a priori peak and equilibrium SF 6 measurement errors as greater or less than 20% of the mean observed value. Three Innocor measurements were obtained at rest ( n = 27) for a total of 81 measurements. Of these, 22% had SF 6 measurements that fell outside of the a priori range. RESULTS: Resting Innocor® stroke volume measures with peak SF 6 measured above a priori range (>0.12%) was associated with larger stroke volumes compared with stroke volume measures without peak SF 6 error (101.4 [26.8] vs 64.9 [8.7] mL; P = 0.006) and overestimated stroke volume when compared with stroke volume by echo (101.4 [26.8] vs 59.9 [16.3] mL; P = 0.017). A similar pattern was observed at submaximal exercise. In contrast, there was no consistent association between variation in equilibrium SF 6 concentrations and measured stroke volume. CONCLUSIONS: Variability in peak SF 6 concentration is common while using the Innocor® device and results in overestimated stroke volume. These findings have implications for research protocols using this device.

Evidence for Chronotropic Incompetence in Well-healed Burn Survivors.

Due to various pathophysiological responses associated with a severe burn injury, we hypothesized that burn survivors exhibit chronotropic incompetence. To test this hypothesis, a graded peak oxygen consumption (V̇O2peak) test was performed in 94 adults (34 nonburned, 31 burn survivors with 14-35% body surface area grafted, and 29 burn survivors with >35% body surface area grafted). The threshold of 35% body surface area grafted was determined by receiver operating characteristic (ROC) curve analysis. Peak exercise heart rates (HRmax) were compared against age-predicted HRmax within each group. The proportion of individuals not meeting their age-predicted HRmax (within 5 b/min) were compared between groups. Age-predicted HRmax was not different from measured HRmax in the nonburned and moderate burn groups (P = .09 and .22, respectively). However, measured HRmax was 10 ± 6 b/min lower than the age-predicted HRmax in those with a large burn injury (P < .001). While 56 and 65% of individuals in the nonburned and moderate burn group achieved a measured HRmax within 5 b/min or greater of age-predicted HRmax, only 21% of those in the large burn group met this criterion (P < .001). These data provide preliminary evidence of chronotropic incompetence in individuals with severe burn injury covering >35% body surface area.

Altered cardiac ß1 responsiveness in hyperthermic older adults.

Compared with younger adults, passive heating induced increases in cardiac output are attenuated by ∼50% in older adults. This attenuated response may be associated with older individuals' inability to maintain stroke volume through ionotropic mechanisms and/or through altered chronotropic mechanisms. The purpose of this study was to identify the interactive effect of age and hyperthermia on cardiac responsiveness to dobutamine-induced cardiac stimulation. Eleven young (26 ± 4 yr) and 8 older (68 ± 5 yr) participants underwent a normothermic and a hyperthermic (baseline core temperature +1.2°C) trial on the same day. In both thermal conditions, after baseline measurements, intravenous dobutamine was administered for 12 min at 5 µg/kg/min, followed by 12 min at 15 µg/kg/min. Primary measurements included echocardiography-based assessments of cardiac function, gastrointestinal and skin temperatures, heart rate, and mean arterial pressure. Heart rate responses to dobutamine were similar between groups in both thermal conditions (P > 0.05). The peak systolic mitral annular velocity (S'), i.e., an index of left ventricular longitudinal systolic function, was similar between groups for both thermal conditions at baseline. While normothermic, the increase in S' between groups was similar with dobutamine administration. However, while hyperthermic, the increase in S' was attenuated in the older participants with dobutamine (P < 0.001). Healthy, older individuals show attenuated inotropic, but maintained chronotropic responsiveness to dobutamine administration during hyperthermia. These data suggest that older individuals have a reduced capacity to increase cardiomyocyte contractility, estimated by changes in S', via ß1-adrenergic mechanisms while hyperthermic.

Six months of unsupervised exercise training lowers blood pressure during moderate, but not vigorous, aerobic exercise in adults with well-healed burn injuries.

Exercise training reduces cardiovascular disease risk, partly due to arterial blood pressure (BP) lowering at rest and during fixed-load exercise. However, it is unclear whether exercise training can reduce BP at rest and during exercise in adults with well-healed burn injuries. Therefore, the purpose of this investigation was to test the hypothesis that 6 mo of unsupervised exercise training reduces BP at rest and during lower-body cycle ergometry in adults with well-healed burn injuries. Thirty-nine adults (28 with well-healed burn injuries and 11 controls) completed 6 mo of unsupervised, progressive exercise training including endurance, resistance, and high-intensity interval components. Before and after exercise training, we measured BP at rest, during fixed-load submaximal exercise (50 and 75 W), during fixed-intensity submaximal exercise (40% and 70% of V̇o2peak), and during maximal exercise on a lower-body cycle ergometer. We compared cardiovascular variables using two-way ANOVA (group × pre/postexercise training [repeated factor]). Adults with well-healed burn injuries had higher diastolic BP at rest (P = 0.04), which was unchanged by exercise training (P = 0.26). Exercise training reduced systolic, mean, and diastolic BP during fixed-load cycling exercise at 75 W in adults with well-healed burn injuries (P ≤ 0.03 for all), but not controls (P ≥ 0.67 for all). Exercise training also reduced mean and diastolic BP during exercise at 40% (P ≤ 0.02 for both), but not at 70% (P ≥ 0.18 for both), of V̇o2peak. These data suggest that a 6-mo unsupervised exercise training program lowers BP during moderate, but not vigorous, aerobic exercise in adults with well-healed burn injuries.NEW & NOTEWORTHY Adults with well-healed burn injuries have greater cardiovascular disease morbidity and all-cause mortality compared with nonburn-injured adults. We found that exercise training reduced blood pressure (BP) during fixed-load cycling at 75 W and during moderate, but not vigorous, intensity cycling exercise in adults with well-healed burn injuries. These data suggest that 6 mo of unsupervised exercise training provides some degree of cardioprotection by reducing BP responses during submaximal exercise in well-healed burn-injured adults.

Human temperature regulation under heat stress in health, disease, and injury.

The human body constantly exchanges heat with the environment. Temperature regulation is a homeostatic feedback control system that ensures deep body temperature is maintained within narrow limits despite wide variations in environmental conditions and activity-related elevations in metabolic heat production. Extensive research has been performed to study the physiological regulation of deep body temperature. This review focuses on healthy and disordered human temperature regulation during heat stress. Central to this discussion is the notion that various morphological features, intrinsic factors, diseases, and injuries independently and interactively influence deep body temperature during exercise and/or exposure to hot ambient temperatures. The first sections review fundamental aspects of the human heat stress response, including the biophysical principles governing heat balance and the autonomic control of heat loss thermoeffectors. Next, we discuss the effects of different intrinsic factors (morphology, heat adaptation, biological sex, and age), diseases (neurological, cardiovascular, metabolic, and genetic), and injuries (spinal cord injury, deep burns, and heat stroke), with emphasis on the mechanisms by which these factors enhance or disturb the regulation of deep body temperature during heat stress. We conclude with key unanswered questions in this field of research.

Low-dose morphine reduces pain perception and blood pressure, but not muscle sympathetic outflow, responses during the cold pressor test.

Our knowledge about how low-dose (analgesic) morphine affects autonomic cardiovascular regulation is primarily limited to animal experiments. Notably, it is unknown if low-dose morphine affects human autonomic cardiovascular responses during painful stimuli in conscious humans. Therefore, we tested the hypothesis that low-dose morphine reduces perceived pain and subsequent sympathetic and cardiovascular responses in humans during an experimental noxious stimulus. Twenty-nine participants (14 females/15 males; 29 ± 6 yr; 26 ± 4 kg·m-2, means ± SD) completed this randomized, crossover, placebo-controlled trial during two laboratory visits. During each visit, participants completed a cold pressor test (CPT; hand in ∼0.4°C ice bath for 2 min) before and ∼35 min after drug/placebo administration (5 mg iv morphine or saline). We compared pain perception (100 mm visual analog scale), muscle sympathetic nerve activity (MSNA; microneurography; 14 paired recordings), and beat-to-beat blood pressure (BP; photoplethysmography) between trials (at both pre- and postdrug/placebo time points) using paired, two-tailed t tests. Before drug/placebo infusion, perceived pain (P = 0.92), ΔMSNA burst frequency (n = 14, P = 0.21), and Δmean BP (P = 0.39) during the CPT were not different between trials. After the drug/placebo infusion, morphine versus placebo attenuated perceived pain (morphine: 43 ± 20 vs. placebo: 57 ± 24 mm, P < 0.001) and Δmean BP (morphine: 10 ± 7 vs. placebo: 13 ± 8 mmHg, P = 0.003), but not ΔMSNA burst frequency (morphine: 10 ± 11 vs. placebo: 13 ± 11 bursts·min-1, P = 0.12), during the CPT. Reductions in pain perception and Δmean BP were only weakly related (r = 0.34, P = 0.07; postmorphine CPT minus postplacebo CPT). These data provide valuable information regarding how low-dose morphine affects autonomic cardiovascular responses during an experimental painful stimulus.NEW & NOTEWORTHY In this randomized, crossover, placebo-controlled trial, we found that low-dose morphine administration reduced pain perception and blood pressure responses during the cold pressor test via attenuated increases in heart rate and cardiac output. We also determined that muscle sympathetic outflow responses during the cold pressor test seem to be unaffected by low-dose morphine administration. Finally, our exploratory analysis suggests that biological sex does not influence morphine-induced antinociception in healthy adults.

Adults with well-healed burn injuries have lower pulmonary function values decades after injury.

Sub-acute (e.g., inhalation injury) and/or acute insults sustained during a severe burn injury impairs pulmonary function. However, previous work has not fully characterized pulmonary function in adults with well-healed burn injuries decades after an injury. Therefore, we tested the hypothesis that adults with well-healed burn injuries have lower pulmonary function years after recovery. Our cohort of adults with well-healed burn-injuries (n = 41) had a lower forced expiratory volume in one second (Burn: 93 ± 16 vs. Control: 103 ± 10%predicted, mean ± SD; d = 0.60, p = 0.04), lower maximal voluntary ventilation (Burn: 84 [71-97] vs. Control: 105 [94-122] %predicted, median [IQR]; d = 0.84, p < 0.01), and a higher specific airway resistance (Burn: 235 ± 80 vs. Control: 179 ± 40%predicted, mean ± SD; d = 0.66, p = 0.02) than non-burned control participants (n = 12). No variables were meaningfully influenced by having a previous inhalation injury (d ≤ 0.44, p ≥ 0.19; 13 of 41 had an inhalation injury), the size of the body surface area burned (R2  ≤ 0.06, p ≥ 0.15; range of 15%-88% body surface area burned), or the time since the burn injury (R2  ≤ 0.04, p ≥ 0.22; range of 2-50 years post-injury). These data suggest that adults with well-healed burn injuries have lower pulmonary function decades after injury. Therefore, future research should examine rehabilitation strategies that could improve pulmonary function among adults with well-healed burn injuries.

Low-dose morphine reduces tolerance to central hypovolemia in healthy adults without affecting muscle sympathetic outflow.

Hemorrhage is a leading cause of preventable battlefield and civilian trauma deaths. Low-dose (i.e., an analgesic dose) morphine is recommended for use in the prehospital (i.e., field) setting. Morphine administration reduces hemorrhagic tolerance in rodents. However, it is unknown whether morphine impairs autonomic cardiovascular regulation and consequently reduces hemorrhagic tolerance in humans. Thus, the purpose of this study was to test the hypothesis that low-dose morphine reduces hemorrhagic tolerance in conscious humans. Thirty adults (15 women/15 men; 29 ± 6 yr; 26 ± 4 kg·m-2, means ± SD) completed this randomized, crossover, double-blinded, placebo-controlled trial. One minute after intravenous administration of morphine (5 mg) or placebo (saline), we used a presyncopal limited progressive lower-body negative pressure (LBNP) protocol to determine hemorrhagic tolerance. Hemorrhagic tolerance was quantified as a cumulative stress index (mmHg·min), which was compared between trials using a Wilcoxon matched-pairs signed-rank test. We also compared muscle sympathetic nerve activity (MSNA; microneurography) and beat-to-beat blood pressure (photoplethysmography) during the LBNP test using mixed-effects analyses [time (LBNP stage) × trial]. Median LBNP tolerance was lower during morphine trials (placebo: 692 [473-997] vs. morphine: 385 [251-728] mmHg·min, P < 0.001, CI: -394 to -128). Systolic blood pressure was 8 mmHg lower during moderate central hypovolemia during morphine trials (post hoc P = 0.02; time: P < 0.001, trial: P = 0.13, interaction: P = 0.006). MSNA burst frequency responses were not different between trials (time: P < 0.001, trial: P = 0.80, interaction: P = 0.51). These data demonstrate that low-dose morphine reduces hemorrhagic tolerance in conscious humans. Thus, morphine is not an ideal analgesic for a hemorrhaging individual in the prehospital setting.NEW & NOTEWORTHY In this randomized, crossover, placebo-controlled trial, we found that tolerance to simulated hemorrhage was lower after low-dose morphine administration. Such reductions in hemorrhagic tolerance were observed without differences in MSNA burst frequency responses between morphine and placebo trials. These data, the first to be obtained in conscious humans, demonstrate that low-dose morphine reduces hemorrhagic tolerance. Thus, morphine is not an ideal analgesic for a hemorrhaging individual in the prehospital setting.

Low-dose fentanyl reduces pain perception, muscle sympathetic nerve activity responses, and blood pressure responses during the cold pressor test.

Our knowledge about how low-dose (analgesic) fentanyl affects autonomic cardiovascular regulation is primarily limited to animal experiments. Notably, it is unknown if low-dose fentanyl influences human autonomic cardiovascular responses during painful stimuli in humans. Therefore, we tested the hypothesis that low-dose fentanyl reduces perceived pain and subsequent sympathetic and cardiovascular responses in humans during an experimental noxious stimulus. Twenty-three adults (10 females/13 males; 27 ± 7 yr; 26 ± 3 kg·m-2, means ± SD) completed this randomized, crossover, placebo-controlled trial during two laboratory visits. During each visit, participants completed a cold pressor test (CPT; hand in ∼0.4°C ice bath for 2 min) before and 5 min after drug/placebo administration (75 µg fentanyl or saline). We compared pain perception (100-mm visual analog scale), muscle sympathetic nerve activity (MSNA; microneurography, 11 paired recordings), and beat-to-beat blood pressure (BP; photoplethysmography) between trials (at both pre- and postdrug/placebo timepoints) using paired, two-tailed t tests. Before drug/placebo administration, perceived pain (P = 0.8287), ΔMSNA burst frequency (P = 0.7587), and Δmean BP (P = 0.8649) during the CPT were not different between trials. After the drug/placebo administration, fentanyl attenuated perceived pain (36 vs. 66 mm, P < 0.0001), ΔMSNA burst frequency (9 vs. 17 bursts/min, P = 0.0054), and Δmean BP (7 vs. 13 mmHg, P = 0.0174) during the CPT compared with placebo. Fentanyl-induced reductions in pain perception and Δmean BP were moderately related (r = 0.40, P = 0.0641). These data provide valuable information regarding how low-dose fentanyl reduces autonomic cardiovascular responses during an experimental painful stimulus.