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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.

Hemorrhage is a leading cause of battlefield and civilian trauma deaths. Several pain medications, including fentanyl, are recommended for use in the prehospital (i.e., field setting) for a hemorrhaging solider. However, it is unknown whether fentanyl impairs arterial blood pressure (BP) regulation, which would compromise hemorrhagic tolerance. Thus, the purpose of this study was to test the hypothesis that an analgesic dose of fentanyl impairs hemorrhagic tolerance in conscious humans. Twenty-eight volunteers (13 females) participated in this double-blinded, randomized, placebo-controlled trial. We conducted a presyncopal limited progressive lower body negative pressure test (LBNP; a validated model to simulate hemorrhage) following intravenous administration of fentanyl (75 µg) or placebo (saline). We quantified tolerance as a cumulative stress index (mmHg·min), which was compared between trials using a paired, two-tailed t test. We also compared muscle sympathetic nerve activity (MSNA; microneurography) and beat-to-beat BP (photoplethysmography) during the LBNP test using a mixed effects model [time (LBNP stage) × trial]. LBNP tolerance was not different between trials (fentanyl: 647 ± 386 vs. placebo: 676 ± 295 mmHg·min, P = 0.61, Cohen's d = 0.08). Increases in MSNA burst frequency (time: P < 0.01, trial: P = 0.29, interaction: P = 0.94) and reductions in mean BP (time: P < 0.01, trial: P = 0.50, interaction: P = 0.16) during LBNP were not different between trials. These data, the first to be obtained in conscious humans, demonstrate that administration of an analgesic dose of fentanyl does not alter MSNA or BP during profound central hypovolemia, nor does it impair tolerance to this simulated hemorrhagic insult.

Posttraumatic stress disorder (PTSD) is more prevalent in women and associated with greater risk of major forms of cardiovascular disease, but physiological mechanisms underlying this association remain unknown. We hypothesized that abnormal sympathetic responses to sympathoexcitatory stimuli might predispose PTSD patients to a greater risk of cardiovascular disease. We examined changes in integrated muscle sympathetic nerve activity (MSNA) burst and multiunit action potential (AP) recruitment patterns as well as hemodynamic responses during cold pressor test (CPT) in 14 women with PTSD and 14 healthy control subjects. Data were collected during 1-min baseline, 2-min CPT, and 3-min recovery. At baseline, blood pressure (BP) was not different between groups; however, heart rate and sympathetic neural activity were greater in women with PTSD [MSNA burst frequency (BF): 27 ± 13 vs. 18 ± 14 bursts/min ( P = 0.04); AP frequency: 272 ± 152 vs. 174 ± 146 spikes/min ( P = 0.03)]. In response to CPT, BP responses exhibited a significant group × time interaction ( P = 0.01) highlighted by a significant diastolic BP main group effect ( P = 0.048) despite the finding that increases in integrated MSNA burst responses were not different between groups ( P > 0.05). However, compared with control subjects, AP firing frequency (group × time interaction P = 0.0001, group P = 0.02) and AP per burst (group × time interaction P = 0.03, group P = 0.03) were augmented in women with PTSD. Collectively, women with PTSD exhibited a greater pressor response and an exaggerated sympathetic neural recruitment pattern during sympathoexcitatory stimuli that may, in part, explain the propensity toward developing hypertension and cardiovascular disease later in life. NEW & NOTEWORTHY The novel findings of the present study are that women with posttraumatic stress disorder (PTSD) have an augmented pressor response to the sympathoexcitatory stimulus of a cold pressor test (CPT) compared with healthy control subjects. Although integrated muscle sympathetic nerve activity burst responses were not significantly different between groups, total sympathetic action potential discharge in response to the CPT was markedly elevated in women with PTSD exhibiting increased firing of low-threshold axons as well as the recruitment of latent subpopulations of larger-sized axons that are otherwise silent at baseline. Aberrant autonomic circulatory control in response to sympathoexcitatory stimulus may in part explain the propensity toward developing hypertension and cardiovascular disease in this population.

Multiple sclerosis (MS), a progressive neurological disease, can lead to impairments in the autonomic control of cardiovascular function. We tested the hypothesis that individuals with relapsing-remitting MS (n = 10; 7 females, 3 males; 13 ± 4 yr from diagnosis) exhibit impaired carotid baroreflex control of blood pressure and heart rate compared with sex, age, and body weight-matched healthy individuals (CON: n = 10; 7 females, 3 males). At rest, 5-s trials of neck pressure (NP; +40 Torr) and neck suction (NS; -60 Torr) were applied to simulate carotid hypotension and hypertension, respectively, while mean arterial pressure (MAP; finger photoplethysmography), heart rate (HR), cardiac output (CO; Modelflow), and total vascular conductance (TVC) were continuously measured. In response to NP, there was a blunted increase in peak MAP responses (MS: 5 ± 2 mmHg) in individuals with MS compared with healthy controls (CON: 9 ± 3 mmHg; P = 0.005), whereas peak HR responses were not different between groups. At the peak MAP response to NP, individuals with MS demonstrated an attenuated decrease in TVC (MS, -10 ± 4% baseline vs. CON, -15 ± 4% baseline, P = 0.012), whereas changes in CO were similar between groups. Following NS, all cardiovascular responses (i.e., nadir MAP and HR and percent changes in CO and TVC) were not different between MS and CON groups. These data suggest that individuals with MS have impaired carotid baroreflex control of blood pressure via a blunted vascular conductance response resulting in a diminished ability to increase MAP in response to a hypotensive challenge., (Copyright © 2016 the American Physiological Society.)

Objective: To determine whether on-scene BP is associated with early neurological deterioration (END) in patients with spontaneous intracerebral haemorrhage (SICH)., Methods: This retrospective cohort study enrolled consecutive ambulance-transported adult SICH patients treated at our emergency department (ED) from January 2007 through December 2012. END was defined as a ≥2-point decrease in GCS within 24 h of ED arrival. The exact relationship between on-scene BP and END was assessed using multiple logistic regression analyses for adjusting age, gender, Charlson Index, aspirin use, smoking, elapsed time, consciousness level on ED arrival, haematoma size, intraventricular extension, midline shift and infratentorial ICH. We further calculated the -2 log-likelihood decrease for each regression model incorporated with the BP values measured at different times to compare model fitness., Results: After adjusting for the covariates, on-scene systolic BP (by 10 mm Hg incremental: OR = 1.126, 95% CI 1.015 to 1.265), diastolic BP (by 10 mm Hg incremental: OR=1.146, 95% CI 1.019 to 1.303) and mean arterial pressure (MAP) (by 10 mm Hg incremental: OR=1.225, 95% CI 1.057 to 1.443) were significantly associated with END; adding on-scene MAP into the regression model yielded the highest model fitness increase. Adding on-scene BPs into the regression model yielded higher model fitness increase than adding ED and admission BPs., Conclusions: Few on-scene BP indices were associated with neuroworsening within 24 h after ED arrival in non-comatose SICH patients. Compared with BP measured on ED arrival or admission, on-scene BP had a stronger correlation with END., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: We aim to investigate prognostic effects of carotid strain (CS) and strain rate (CSR) in hypertension. Methods: We prospectively recruited 120 patients being treated for hypertension (65.8 ± 11.8 years, 58% male) in this observational study. Peak circumferential CS and peak CSR after ejection were identified using two‐dimensional speckle tracking ultrasound. Major cardiovascular events were any admission for stroke, acute coronary syndrome, and heart failure. Results: After a mean follow‐up period of 63.6 ± 14.5 months, 14 (12%) patients had cardiovascular events. Age (75.3 ± 9.2 vs 64.6 ± 11.6 years; p = 0.001), systolic blood pressure (131.8 ± 15.5 vs 143.1 ± 16.6 mm Hg; p = 0.021), diastolic blood pressure (74.6 ±11.4 vs 82.1 ± 12.2 mm Hg; p = 0.039), use of diuretics (71 vs 92%; p = 0.014), carotid CS (2.17 ± 1.02 vs 3.28 ± 1.14 %; p = 0.001), and CSR (.28 ±.17 vs.51 ±.18 1/s; p < 0.001) were significantly different between the patients who did and did not reach the end‐points. Multivariate Cox regression analysis controlling for age, systolic blood pressure, diastolic blood pressure, and use of diuretics showed that CS (HR.425, 95%CI.223–.811, p = 0.009) and CSR (HR.001, 95%CI.000–.072, p = 0.001) were independent predictors for cardiovascular events. Conclusion: In conclusions, decreased CS and CSR were associated with cardiovascular events in hypertension. [ABSTRACT FROM AUTHOR]

Key points: Low dose ketamine is a leading medication used to provide analgesia in pre‐hospital and hospital settings. Low dose ketamine is increasingly used off‐label to treat conditions such as depression.In animals, ketamine stimulates the sympathetic nervous system and increases blood pressure, but these physiological consequences have not been studied in conscious humans.Our data suggest that low dose ketamine administration blunts pain perception and reduces blood pressure, but not muscle sympathetic nerve activity burst frequency, responses during a cold pressor test in healthy humans.These mechanistic, physiological results inform risk‐benefit analysis for clinicians administering low dose ketamine in humans. Low dose ketamine is an effective analgesic medication. However, our knowledge of the effects of ketamine on autonomic cardiovascular regulation is primarily limited to animal experiments. Notably, it is unknown if low dose ketamine influences autonomic cardiovascular responses during painful stimuli in humans. We tested the hypothesis that low dose ketamine blunts perceived pain, and blunts subsequent sympathetic and cardiovascular responses during an experimental noxious stimulus. Twenty‐two adults (10F/12M; 27 ± 6 years; 26 ± 3 kg m−2, mean ± SD) completed this randomized, crossover, placebo‐controlled trial during two laboratory visits. During each visit, participants completed cold pressor tests (CPT; hand in ∼0.4°C ice bath for 2 min) pre‐ and 5 min post‐drug administration (20 mg ketamine or saline). We compared pain perception (100 mm visual analogue scale), muscle sympathetic nerve activity (MSNA; microneurography, 12 paired recordings), and beat‐to‐beat blood pressure (BP; photoplethysmography) during the pre‐ and post‐drug CPTs separately using paired, two‐tailed t tests. For the pre‐drug CPT, perceived pain (P = 0.4378), MSNA burst frequency responses (P = 0.7375), and mean BP responses (P = 0.6457) were not different between trials. For the post‐drug CPT, ketamine compared to placebo administration attenuated perceived pain (P < 0.0001) and mean BP responses (P = 0.0047), but did not attenuate MSNA burst frequency responses (P = 0.3662). Finally, during the post‐drug CPT, there was a moderate relation between cardiac output and BP responses after placebo administration (r = 0.53, P = 0.0121), but this relation was effectively absent after ketamine administration (r = −0.12, P = 0.5885). These data suggest that low dose ketamine administration attenuates perceived pain and pressor, but not MSNA burst frequency, responses during a CPT. Key points: Low dose ketamine is a leading medication used to provide analgesia in pre‐hospital and hospital settings. Low dose ketamine is increasingly used off‐label to treat conditions such as depression.In animals, ketamine stimulates the sympathetic nervous system and increases blood pressure, but these physiological consequences have not been studied in conscious humans.Our data suggest that low dose ketamine administration blunts pain perception and reduces blood pressure, but not muscle sympathetic nerve activity burst frequency, responses during a cold pressor test in healthy humans.These mechanistic, physiological results inform risk‐benefit analysis for clinicians administering low dose ketamine in humans. [ABSTRACT FROM AUTHOR]

Key points: Haemorrhage is the leading cause of battlefield and civilian trauma deaths. Given that a haemorrhagic injury on the battlefield is almost always associated with pain, it is paramount that the administered pain medication does not disrupt the physiological mechanisms that are beneficial in defending against the haemorrhagic insult.Current guidelines from the US Army's Committee on Tactical Combat Casualty Care (CoTCCC) for the selection of pain medications administered to a haemorrhaging soldier are based upon limited scientific evidence, with the clear majority of supporting studies being conducted on anaesthetized animals. Specifically, the influence of low‐dose ketamine, one of three analgesics employed in the pre‐hospital setting by the US Army, on haemorrhagic tolerance in humans is unknown.For the first time in conscious males and females, the findings of the present study demonstrate that the administration of an analgesic dose of ketamine does not compromise tolerance to a simulated haemorrhagic insult.Increases in muscle sympathetic nerve activity during progressive lower‐body negative pressure were not different between trials. Despite the lack of differences for muscle sympathetic nerve activity responses, mean blood pressure and heart rate were higher during moderate hypovolemia after ketamine vs. placebo administration. Haemorrhage is the leading cause of battlefield and civilian trauma deaths. For a haemorrhaging soldier, there are several pain medications (e.g. ketamine) recommended for use in the prehospital, field setting. However, the data to support these recommendations are primarily limited to studies in animals. Therefore, it is unknown whether ketamine adversely affects physiological mechanisms responsible for maintenance of arterial blood pressure (BP) during haemorrhage in humans. In humans, ketamine has been demonstrated to raise resting BP, although it has not been studied with the concomitant central hypovolemia that occurs during haemorrhage. Thus, the present study aimed to test the hypothesis that ketamine does not impair haemorrhagic tolerance in humans. Thirty volunteers (15 females) participated in this double‐blinded, randomized, placebo‐controlled trial. A pre‐syncopal limited progressive lower‐body negative pressure (LBNP; a validated model for simulating haemorrhage) test was conducted following the administration of ketamine (20 mg) or placebo (saline). Tolerance was quantified as a cumulative stress index and compared between trials using a paired, two‐tailed t test. We compared muscle sympathetic nerve activity (MSNA; microneurography), beat‐to‐beat BP (photoplethysmography) and heart rate (electrocardiogram) responses during the LBNP test using a mixed effects model (time [LBNP stage] × drug). Tolerance to the LBNP test was not different between trials (Ketamine: 635 ± 391 vs. Placebo: 652 ± 360 mmHg‧min, p = 0.77). Increases in MSNA burst frequency (time: P < 0.01, trial: p = 0.27, interaction: p = 0.39) during LBNP stages were no different between trials. Despite the lack of differences for MSNA responses, mean BP (time: P < 0.01, trial: P < 0.01, interaction: p = 0.01) and heart rate (time: P < 0.01, trial: P < 0.01, interaction: P < 0.01) were higher during moderate hypovolemia after ketamine vs. placebo administration (P < 0.05 for all, post hoc), but not at the end of LBNP. These data, which are the first to be obtained in conscious humans, demonstrate that the administration of low‐dose ketamine does not impair tolerance to simulated haemorrhage or mechanisms responsible for maintenance of BP. Key points: Haemorrhage is the leading cause of battlefield and civilian trauma deaths. Given that a haemorrhagic injury on the battlefield is almost always associated with pain, it is paramount that the administered pain medication does not disrupt the physiological mechanisms that are beneficial in defending against the haemorrhagic insult.Current guidelines from the US Army's Committee on Tactical Combat Casualty Care (CoTCCC) for the selection of pain medications administered to a haemorrhaging soldier are based upon limited scientific evidence, with the clear majority of supporting studies being conducted on anaesthetized animals. Specifically, the influence of low‐dose ketamine, one of three analgesics employed in the pre‐hospital setting by the US Army, on haemorrhagic tolerance in humans is unknown.For the first time in conscious males and females, the findings of the present study demonstrate that the administration of an analgesic dose of ketamine does not compromise tolerance to a simulated haemorrhagic insult.Increases in muscle sympathetic nerve activity during progressive lower‐body negative pressure were not different between trials. Despite the lack of differences for muscle sympathetic nerve activity responses, mean blood pressure and heart rate were higher during moderate hypovolemia after ketamine vs. placebo administration. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Does dietary nitrate supplementation with beetroot juice attenuate thermoregulatory and cardiovascular strain in older adults during severe heat stress?What is the main finding and its importance?A 7‐day nitrate supplementation regimen lowered resting mean arterial pressure in thermoneutral conditions. During heat stress, core and mean skin temperatures, vasodilatory responses, sweat loss, heart rate and left ventricular function were unchanged, and mean arterial pressure was only transiently reduced, post‐supplementation. These data suggest nitrate supplementation with beetroot juice does not mitigate thermoregulatory or cardiovascular strain in heat‐stressed older individuals. This study tested the hypothesis that dietary nitrate supplementation with concentrated beetroot juice attenuates thermoregulatory and cardiovascular strain in older individuals during environmental heat stress. Nine healthy older individuals (six females, three males; aged 67 ± 5 years) were exposed to 42.5 ± 0.1°C and 34.0 ± 0.5% relative humidity conditions for 120 min before (CON) and after 7 days of dietary nitrate supplementation with concentrated beetroot juice (BRJ; 280 ml, ∼16.8 mmol of nitrate daily). Core and skin temperatures, body mass changes (indicative of whole‐body sweat loss), skin blood flow and cutaneous vascular conductance, forearm blood flow and vascular conductance, heart rate, arterial blood pressures and indices of cardiac function were measured. The 7‐day beetroot juice regimen increased plasma nitrate/nitrite levels from 27.4 ± 15.2 to 477.0 ± 102.5 μmol l−1 (P < 0.01) and lowered resting mean arterial pressure from 90 ± 7 to 83 ± 10 mmHg at baseline under thermoneutral conditions (P = 0.02). However, during subsequent heat stress, no differences in core and skin temperatures, skin blood flow and vascular conductance, forearm blood flow and vascular conductance, whole‐body sweat loss, heart rate, and echocardiographic indices of systolic function and diastolic filling were evident following nitrate supplementation (all P > 0.05). Mean arterial pressure was lower in BRJ vs. CON during heat stress (treatment‐by‐time interaction: P = 0.02). Overall, these findings suggest that dietary nitrate supplementation with concentrated beetroot juice does not attenuate thermoregulatory or cardiovascular strain in older individuals exposed to severe ambient heat stress. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS), a progressive neurological disease, can result in autonomic dysfunction. Impairments in the autonomic control of cardiovascular and thermoregulatory function during exercise have been observed in MS. Attenuated elevations in blood pressure during exercise in MS patients can negatively impact blood flow to skeletal muscle. Diminished sweating during exercise may impair heat dissipation likely limiting the exercise intensity that can be performed before detrimental core temperatures are reached. Further understanding the physiologic mechanisms of autonomic dysfunction during exercise in MS may lead to the development of novel therapeutic strategies targeted at improving quality of life in individuals with this disease. [ABSTRACT FROM AUTHOR]