The use and effectiveness of exercise for managing postural orthostatic tachycardia syndrome in young adults with joint hypermobility and related conditions: A scoping review.

PURPOSE: Postural Orthostatic Tachycardia Syndrome (POTS) is a form of dysautonomia. It may occur in isolation, but frequently co-exists in individuals with hypermobile variants of Ehlers-Danlos Syndrome (EDS) and related conditions (chronic fatigue syndrome [CFS] and fibromyalgia). Exercise is recommended for non-pharmacological POTS management but needs to be individualised. This scoping review explores the current literature on use and effectiveness of exercise-based management for POTS, with specific focus on individuals with joint hypermobility and related conditions who experience hypermobility, and/or pain, and/or fatigue. METHODS: A systematic search, to January 2023, of Medline, EMBASE, AMED, CINAHL and the Cochrane library was conducted. Studies that reported on adolescents and adults who had been diagnosed with POTS using standard criteria and underwent an exercise-based training intervention were included. RESULTS: Following full-text screening, 10 articles were identified (2 randomised control trials, 4 comparative studies and 4 case reports). One comparative study reported a small subset of participants with EDS and one case report included an individual diagnosed with CFS; the remainder investigated a wider POTS population. Overall, 3 months of endurance followed by resistance exercise, graduating from the horizontal-to-upright position reduced POTS symptoms and improved quality-of-life. CONCLUSION: The findings highlight a paucity of higher-level studies documenting exercise for POTS management in people with joint hypermobility and related conditions. Results from the wider POTS population demonstrate exercise is safe and effective. Large, well-designed clinical studies exploring exercise for POTS management adapting to meet the complex musculoskeletal and non-musculoskeletal features of symptomatic joint hypermobility are needed.

Interaction of large artery stiffness and baroreceptor function explored through multiple measurement techniques - a pilot study.

Baroreceptors, sensors that play a role in controlling arterial blood pressure (BP), are mechanical stretch receptors located in the aortic arch and carotid sinuses. Factors affecting the degree of stretch in the vessel wall with BP, such as increased arterial stiffness, may compromise baroreceptor sensitivity (BRS) to BP changes. Yet, evidence of this is scattered, as both baroreceptor sensitivity (BRS) and arterial stiffness are calculated variables with multiple methodological approaches. This pilot study (n=10) investigates the correlation of arterial stiffness and BRS using multiple BRS calculation techniques (spectral and sequence methodologies at aortic and finger sites) and arterial stiffness measurement [carotid-femoral pulse wave velocity (cfPWV), carotid compliance and distensibility]. BRS was assessed under resting BP conditions and during BP altered by maneuvers (0.1 Hz controlled breathing and leg ischemia). Magnitude of arterial stiffness - BRS correlation was positive for carotid distensibility and compliance, and negative for cfPWV, supporting the theory. A sample size of 100 participants (not rounded - exact figure by power calculation) would be required to confirm or reject all permutations of correlation between BRS by multiple calculation methods and large artery stiffness by PWV and compliance/distensibility measures.

Inspiratory muscle reflex control after incomplete cervical spinal cord injury.

In healthy individuals, loading inspiratory muscles by brief inspiratory occlusion produces a short-latency inhibitory reflex (IR) in the electromyographic (EMG) activity of scalene and diaphragm muscles. This IR may play a protective role to prevent aspiration and airway collapse during sleep. In people with motor and sensory complete cervical spinal cord injury (cSCI), who were able to breathe independently, this IR was predominantly absent. Here, we investigated the reflex response to brief airway occlusion in 16 participants with sensory incomplete cSCI [American spinal injury association impairment scale (AIS) score B or C]. Surface EMG was recorded from scalene muscles and the lateral chest wall (overlying diaphragm). The airway occlusion evoked a small change in mouth pressure resembling a physiological occlusion. The short-latency IR was present in 10 (63%) sensory incomplete cSCI participants; significantly higher than the IR incidence observed in complete cSCI participants in our previous study (14%; P = 0.003). When present, mean IR latency across all muscles was 58 ms (range 29-79 ms), and mean rectified EMG amplitude decreased to 37% preocclusion levels. Participants without an IR had untreated severe obstructive sleep apnea (OSA), in contrast to those with an IR, who had either had no, mild, or treated OSA (P = 0.002). Insufficient power did not allow statistical comparison between IR presence or absence and participant clinical characteristics. In conclusion, spared sensory connections or intersegmental connections may be necessary to generate the IR. Future studies to establish whether IR presence is related to respiratory morbidity in the tetraplegic population are required.NEW & NOTEWORTHY Individuals with incomplete cSCI were tested for the presence of a short latency reflex inhibition of inspiratory muscles, by brief airway occlusion. The reflex was 4.5 times more prevalent in this group compared with those with complete cSCI and is similar to the incidence in able-bodied people. Participants without this reflex all had untreated severe OSA, in contrast to those with an IR, who either had no, mild, or treated OSA. This work reveals novel differences in the reflex control of inspiratory muscles across the cSCI population.

The prevalence and impact of orthostatic intolerance in young women across the hypermobility spectrum.

Orthostatic intolerance (OI) is frequently reported in young women with generalized hypermobility spectrum disorder (G-HSD) and hypermobile EDS (hEDS). However, it remains currently unclear whether OI is a comorbidity or fundamental part of the pathophysiology of G-HSD or hEDS. This study investigated the prevalence and impact of OI in young women across the hypermobility spectrum. Forty-five women (14-30 years, 15 controls, 15 G-HSD, and 15 hEDS) undertook a head-up tilt (HUT) and active stand test. Postural Orthostatic Tachycardia Syndrome (POTS) and Orthostatic Hypotension (OH) were assessed using age-related criteria. Autonomic dysfunction and quality-of-life questionnaires were also completed. The prevalence of POTS was higher in women with G-HSD than hEDS and control groups during HUT (43% vs. 7% and 7%, respectively, p < 0.05), but similar between groups during the active stand (47%, 27%, and 13% for G-HSD, hEDS, and control, respectively). No participants had OH. hEDS and G-HSD participants reported more severe orthostatic symptoms and poorer quality of life than controls. Although POTS was observed in hypermobile participants, there is no conclusive evidence that its prevalence differed between groups due to differences between the HUT and active stand assessments. Nevertheless, OI and broader autonomic dysfunction impacted on their quality of life.

Assessing breast lymphoedema following breast cancer treatment using indocyanine green lymphography.

PURPOSE: Breast lymphoedema is a largely unrecognised survivorship issue for women following breast cancer treatment. While a few objective methods have previously been applied to assess breast lymphoedema, none are capable of imaging breast lymphatics or identifying lymphatic morphological changes indicative of breast lymphoedema. The purpose of this study was to determine if indocyanine green (ICG) lymphography, a validated assessment technique in breast cancer-related lymphoedema), can visualise breast lymphatics and identify breast lymphoedema. Additionally, ICG lymphography was utilised to investigate lymphatic drainage pathways of the affected breast following breast-conserving therapy. METHODS: Twenty female participants (10 breast lymphoedema and 10 healthy controls) were recruited for this pilot study. All underwent a medical history, physical breast assessment, tissue dielectric constant measures of breast water content, and ICG lymphography. RESULTS: ICG lymphography identified lymphatic morphological changes in all breast lymphoedema participants (dermal backflow patterns = 10, collateral lymphatic drainage = 9) and none in the control group. The dominant lymphatic drainage pathway to the ipsilateral axilla was observed in all control participants but in only four breast lymphoedema participants. Collateral drainage pathways in the breast lymphoedema group were to: parasternal (6/10); contralateral axilla (4/10); intercostal (3/10); and clavicular (2/10) regions. CONCLUSION: These findings suggest ICG lymphography, through the identification of morphological lymphatic changes, is a potential qualitative objective assessment technique for breast lymphoedema. Furthermore, in this group of breast lymphoedema patients it identified changes to the normal drainage pathway of the breast. Understanding these changes will have implications for clinical management.

Resting heart rate variability and exercise capacity in Type 1 diabetes.

People with type 1 diabetes (T1D) have lower exercise capacity (V̇O2max) than their age-matched nondiabetic counterparts (CON), which might be related to cardiac autonomic dysfunction. We examined whether Heart Rate Variability (HRV; indicator of cardiac autonomic modulation) was associated with exercise capacity in those with and without T1D. Twenty-three participants with uncomplicated T1D and 17 matched CON were recruited. Heart rate (HR; ECG), blood pressure (BP; finger photo-plethysmography), and respiratory rate (respiratory belt) were measured during baseline, paced-breathing and clinical autonomic reflex tests (CARTs); deep breathing, lying-to-stand, and Valsalva maneuver. Baseline and paced-breathing ECG were analyzed for HRV (frequency-domain). Exercise capacity was determined during an incremental cycle ergometer test while V̇O2, 12-lead ECG, and BP were measured. In uncomplicated T1D, resting HR was elevated and resting HRV metrics were reduced, indicative of altered cardiac parasympathetic modulation; this was generally undetected by the CARTs. However, BP and plasma catecholamines were not different between groups. In T1D, V̇O2max tended to be lower (P = 0.07) and HR reserve was lower (P < 0.01). Resting Total Power (TP) had stronger positive associations with V̇O2max (R2 ≥ 0.3) than all other traditional indicators such as age, resting HR, and self-reported exercise (R2 = 0.042-0.3) in both T1D and CON Alterations in cardiac autonomic modulation are an early manifestation of uncomplicated T1D. Total Power was associated with reduced exercise capacity regardless of group, and these associations were generally stronger than traditional indicators.

Influence of cerebral blood flow on central sleep apnea at high altitude.

STUDY OBJECTIVES: To further our understanding of central sleep apnea (CSA) at high altitude during acclimatization, we tested the hypothesis that pharmacologically altering cerebral blood flow (CBF) would alter the severity of CSA at high altitude. DESIGN: The study was a randomized, placebo-controlled single-blind study. SETTING: A field study at 5,050 m in Nepal. PATIENTS OR PARTICIPANTS: We studied 12 normal volunteers. INTERVENTIONS: Between days 5 to 10 at high altitude, CBF velocity (CBFv) was increased by intravenous (IV) acetazolamide (10 mg/kg) and reduced by oral indomethacin (100 mg). MEASUREMENTS AND RESULTS: Arterial blood gases, hypoxic and hypercapnic ventilatory responses, and CBFv and its reactivity to carbon dioxide were measured awake. Overnight polysomnography was performed. The central apnea-hypopnea index was elevated following administration of indomethacin (89.2 ± 43.7 to 112.5 ± 32.9 events/h; mean ± standard deviation; P < 0.05) and was reduced following IV acetazolamide (89.2 ± 43.7 to 47.1 ± 48.1 events/h; P < 0.001). Intravenous acetazolamide elevated CBFv at high altitude by 28% (95% confidence interval [CI]: 22-34%) but did not affect ventilatory responses. The elevation in CBFv was partly mediated via a selective rise in partial pressure of arterial carbon dioxide (PaCO2) (28 ± 4 to 31 ± 3 mm Hg) and an associated fall in pH (P < 0.01). Oral indomethacin reduced CBFv by 23% (95% CI: 16-30%), blunted CBFv reactivity, and increased the hypercapnic ventilatory response by 66% (95% CI: 30-102%) but had no effect on PaCO2 or pH. CONCLUSION: Our findings indicate an important role for cerebral blood flow regulation in the pathophysiology of central sleep apnea at high altitude.

The influence of tobacco smoking on the relationship between pressure and flow in the middle cerebral artery in humans.

BACKGROUND: Cigarette smoking is associated with an increased risk of stroke but the mechanism is unclear. The study examined whether acute and chronic cigarette smoking alters the dynamic relationship between blood pressure and cerebral blood flow. We hypothesised that acute and chronic smoking would result in a cerebral circulation that was less capable of buffering against dynamic fluctuations in blood pressure. Further, these changes would be accompanied by a reduction in baroreflex sensitivity, which is reduced after smoking (acute smoking). METHODS: We recruited 17 non-smokers and 15 habitual smokers (13 ± 5 pack years). Continuous measurements of mean cerebral blood flow velocity (transcranial Doppler ultrasound), blood pressure (finger photoplethysmography) and heart rate enabled transfer function analysis of the dynamic relationship between pressure and flow (gain, normalised gain, phase and coherence) and baroreflex sensitivity during supine rest before and after smoking a single cigarette (acute smoking). RESULTS: There were no between-group differences in gain, phase or coherence before acute smoking. However, both groups showed a reduction in gain and coherence, associated with a reduction in baroreflex sensitivity, and increase in phase after acute smoking. CONCLUSIONS: Contrary to our hypothesis, these findings suggest that in the face of a reduction in baroreflex sensitivity acute smoking may potentially improve the ability of the cerebral circulation to buffer against changes in blood pressure. However, chronic smoking did not alter the dynamic relationship between blood pressure and cerebral blood flow velocity. These results have implications on understanding mechanisms for attenuating stroke risk.

Cardiac baroreflex gain is frequency dependent: insights from repeated sit-to-stand maneuvers and the modified Oxford method.

Cardiac baroreflex gain is usually quantified as the reflex alteration in heart rate during changes in blood pressure without considering the effect of the rate of change in blood pressure on the estimated gain. This study sought to (i) characterize baroreflex gain as a function of blood pressure oscillation frequencies using a repeat sit-to-stand method and (ii) compare baroreflex gain values obtained using the sit-to-stand method against the modified Oxford method. Fifteen healthy individuals underwent the repeated sit-to-stand method in which blood pressure oscillations were driven at 0.03, 0.05, 0.07, and 0.1 Hz. Sixteen healthy participants underwent the sit-to-stand and modified Oxford methods to examine their agreement. Sit-to-stand baroreflex gain was highest at 0.05 Hz (8.8 ± 3.2 ms·mm Hg(-1)) and lowest at 0.1 Hz (5.8 ± 3.0 ms·mm Hg(-1)). Baroreflex gains at 0.03 Hz (7.7 ± 3.0 ms·mm Hg(-1)) and 0.07 Hz (7.5 ± 3.3 ms·mm Hg(-1)) were not different from the baroreflex gain at 0.05 Hz. There was moderate correlation between phenylephrine gain and sit-to-stand gain (r values ranged from 0.52 to 0.75; all frequencies, p < 0.05), but no correlation between sodium nitroprusside gain and sit-to-stand gain (r values ranged from -0.07 to 0.22; all p < 0.05). Bland-Altman analysis of phenylephrine gain and sit-to-stand gain showed poor agreement and a positive proportional bias. These results show that baroreflex gains derived from these 2 methods cannot be used interchangeably. Furthermore, cardiac baroreflex gain is frequency dependent between 0.03 Hz and 0.1 Hz, which challenges the conventional practice of summarizing baroreflex gain as a single number.

Worsening of central sleep apnea at high altitude--a role for cerebrovascular function.

Although periodic breathing during sleep at high altitude occurs almost universally, the likely mechanisms and independent effects of altitude and acclimatization have not been clearly reported. Data from 2005 demonstrated a significant relationship between decline in cerebral blood flow (CBF) at sleep onset and subsequent severity of central sleep apnea that night. We suspected that CBF would decline during partial acclimatization. We hypothesized therefore that reductions in CBF and its reactivity would worsen periodic breathing during sleep following partial acclimatization. Repeated measures of awake ventilatory and CBF responsiveness, arterial blood gases during wakefulness. and overnight polysomnography at sea level, upon arrival (days 2-4), and following partial acclimatization (days 12-15) to 5,050 m were made on 12 subjects. The apnea-hypopnea index (AHI) increased from to 77 ± 49 on days 2-4 to 116 ± 21 on days 12-15 (P = 0.01). The AHI upon initial arrival was associated with marked elevations in CBF (+28%, 68 ± 11 to 87 ± 17 cm/s; P < 0.05) and its reactivity to changes in PaCO2 [>90%, 2.0 ± 0.6 to 3.8 ± 1.5 cm·s(-1)·mmHg(-1) hypercapnia and 1.9 ± 0.4 to 4.1 ± 0.9 cm·s(-1)·mmHg(-1) for hypocapnia (P < 0.05)]. Over 10 days, the increases resolved and AHI worsened. During sleep at high altitude large oscillations in mean CBF velocity (CBFv) occurred, which were 35% higher initially (peak CBFv = 96 cm/s vs. peak CBFv = 71 cm/s) than at days 12-15. Our novel findings suggest that elevations in CBF and its reactivity to CO(2) upon initial ascent to high altitude may provide a protective effect on the development of periodic breathing during sleep (likely via moderating changes in central Pco2).

Effects of acetazolamide on cerebrovascular function and breathing stability at 5050 m.

One of the many actions of the carbonic anhydrase inhibitor, acetazolamide (ACZ), is to accelerate acclimatisation and reduce periodic breathing during sleep. The mechanism(s) by which ACZ may improve breathing stability, especially at high altitude, remain unclear. We tested the hypothesis that acute I.V. ACZ would enhance cerebrovascular reactivity to CO2 at altitude, and thereby lower ventilatory drive and improve breathing stability during wakefulness. We measured arterial blood gases, minute ventilation (˙VE) and middle cerebral artery blood flow velocity (MCAv) before and 30 min following ACZ administration (I.V. 10 mg kg⁻¹) in 12 healthy participants at sea level and following partial acclimatisation to altitude (5050 m).Measures were made at rest and during changes in end-tidal PCO2 and PO2 (isocapnic hypoxia). At sea level, ACZ increased resting MCAv and its reactivity to both hypocapnia and hypercapnia (P < 0.05), and lowered resting VE, arterial O2 saturation (Sa,O2 ) and arterial PO2 (Pa,O2) (P < 0.05); arterial PCO2 (Pa,CO2 ) was unaltered (P > 0.05). At altitude, ACZ also increased resting MCAv and its reactivity to both hypocapnia and hypercapnia (resting MCAv and hypocapnia reactivity to a greater extent than at sea level). Moreover, ACZ at altitude elevated Pa,CO2 and again lowered resting Pa,O2 and Sa,O2 (P <0.05). Although the ˙VE sensitivity to hypercapnia or isocapnic hypoxia was unaltered following ACZ at both sea level and altitude (P > 0.05), breathing stability at altitude was improved (e.g. lower incidence of ventilatory oscillations and variability of tidal volume; P < 0.05). Our data indicate that I.V. ACZ elevates cerebrovascular reactivity and improves breathing stability at altitude, independent of changes in peripheral or central chemoreflex sensitivities. We speculate that Pa,CO2-mediated elevations in cerebral perfusion and an enhanced cerebrovascular reactivity may partly account for the improved breathing stability following ACZ at high altitude.

Influence of indomethacin on the ventilatory and cerebrovascular responsiveness to hypoxia.

Indomethacin (INDO) has the potential to be a useful tool to explore the influence of cerebral blood flow and its responses to CO(2) on ventilatory control. However, the effect of INDO on the cerebrovascular and ventilatory response to hypoxia remains unclear; therefore, we examined the effect of INDO on ventilatory and cerebrovascular sensitivity to hypoxia and hypercapnia. We measured end-tidal gases, ventilation (V(e)), and middle cerebral artery velocity (MCAv) before and 90 min following INDO (100 mg) in 12 healthy participants at rest and during hyperoxic hypercapnia and isocapnic hypoxia. Following INDO, resting VE and end-tidal gases were unaltered (P > 0.05), whilst MCAv was lowered by 25 ± 19% (P < 0.001). INDO ingestion reduced MCAv-CO(2) reactivity by 46 ± 29% (2.9 ± 0.9 vs. 1.7 ± 0.9 cm s(-1) mmHg(-1); P < 0.001) and enhanced the VE-CO(2) sensitivity by 0.5 ± 0.5 L min(-1) mmHg(-1) (1.9 ± 1.5 vs. 2.3 ± 1.6 L min(-1) mmHg(-1); P < 0.05). No changes were observed in either the MCAv or VE responsiveness to isocapnic hypoxia following INDO ingestion (P > 0.05). These findings indicate that INDO does not alter cerebrovascular and ventilatory responsiveness to hypoxia, indicating a preserved peripheral chemoreflex in response to this pharmacological agent.

Alterations in cerebral blood flow and cerebrovascular reactivity during 14 days at 5050 m.

Brain blood flow increases during the first week of living at high altitude. We do not understand completely what causes the increase or how the factors that regulate brain blood flow are affected by the high-altitude environment. Our results show that the balance of oxygen (O(2)) and carbon dioxide (CO(2)) pressures in arterial blood explains 40% of the change in brain blood flow upon arrival at high altitude (5050 m). We also show that blood vessels in the brain respond to increases and decreases in CO(2) differently at high altitude compared to sea level, and that this can affect breathing responses as well. These results help us to better understand the regulation of brain blood flow at high altitude and are also relevant to diseases that are accompanied by reductions in the pressure of oxygen in the blood.

Initial orthostatic hypotension at high altitude.

There are several reports on syncope occurring following standing at high altitude (HA), yet description of the detailed physiological responses to standing at HA are lacking. We examined the hypothesis that appropriate physiological adjustments to upright posture would be compromised at HA (5050 m). Ten healthy volunteers stood up rapidly from supine rest, for 3 min, at sea level and at 5050 m. Beat-to-beat mean arterial blood pressure (MAP, Finometer), middle cerebral artery blood velocity (MCAv, Transcranial Doppler), end-tidal PCO(2) and PO(2), and heart rate (ECG) were recorded continuously. After 14 days at HA, baseline MAP and MCAv were not different to sea level, although HR was elevated. Neither the magnitude of initial (<15 s) responses to standing, nor the time course of initial recovery differed at HA compared with sea level (p > 0.05). By 3 min of standing, MAP was restored to supine values both at sea level (-3 +/- 12 mmHg) and HA (4 +/- 10 mmHg), although there was more complete recovery of HR at sea level (+13 +/- 10 b.min(-1), p = 0.02 vs. + 23 +/- 10 b.min(-1), p = 0.01). Reduced MCAv at 3 min was comparable at sea level and altitude (both -16%). These data indicate that initial cardiovascular and cerebrovascular responses to standing are unaltered when partially acclimatized to HA.

Influence of indomethacin on ventilatory and cerebrovascular responsiveness to CO2 and breathing stability: the influence of PCO2 gradients.

Indomethacin (INDO), a reversible cyclooxygenase inhibitor, is a useful tool for assessing the role of cerebrovascular reactivity on ventilatory control. Despite this, the effect of INDO on breathing stability during wakefulness has yet to be examined. Although the effect of reductions in cerebrovascular CO(2) reactivity on ventilatory CO(2) sensitivity is likely dependent upon the method used, no studies have compared the effect of INDO on steady-state and modified rebreathing estimates of ventilatory CO(2) sensitivity. The latter method includes the influence of PCO(2) gradients and cerebral perfusion, whereas the former does not. We examined the hypothesis that INDO-induced reduction in cerebrovascular CO(2) reactivity would 1) cause unstable breathing in conscious humans and 2) increase ventilatory CO(2) sensitivity during the steady-state method but not during rebreathing methods. We measured arterial blood gases, ventilation (VE), and middle cerebral artery velocity (MCAv) before and 90 min following INDO ingestion (100 mg) or placebo in 12 healthy participants. There were no changes in resting arterial blood gases or Ve following either intervention. INDO increased the magnitude of Ve variability (index of breathing stability) during spontaneous air breathing (+4.3 +/- 5.2 Deltal/min, P = 0.01) and reduced MCAv (-25 +/- 19%, P < 0.01) and MCAv-CO(2) reactivity during steady-state (-47 +/- 27%, P < 0.01) and rebreathing (-32 +/- 25%, P < 0.01). The Ve-CO(2) sensitivity during the steady-state method was increased with INDO (+0.5 +/- 0.5 l x min(-1) x mmHg(-1), P < 0.01), while no changes were observed during rebreathing (P > 0.05). These data indicate that the net effect of INDO on ventilatory control is an enhanced ventilatory loop gain resulting in increased breathing instability. Our findings also highlight important methodological and physiological considerations when assessing the effect of INDO on ventilatory CO(2) sensitivity, whereby the effect of INDO-induced reduction of cerebrovascular CO(2) reactivity on ventilatory CO(2) sensitivity is unmasked with the rebreathing method.

Influence of high altitude on cerebrovascular and ventilatory responsiveness to CO2.

An altered acid-base balance following ascent to high altitude has been well established. Such changes in pH buffering could potentially account for the observed increase in ventilatory CO(2) sensitivity at high altitude. Likewise, if [H(+)] is the main determinant of cerebrovascular tone, then an alteration in pH buffering may also enhance the cerebral blood flow (CBF) responsiveness to CO(2) (termed cerebrovascular CO(2) reactivity). However, the effect altered acid-base balance associated with high altitude ascent on cerebrovascular and ventilatory responsiveness to CO(2) remains unclear. We measured ventilation , middle cerebral artery velocity (MCAv; index of CBF) and arterial blood gases at sea level and following ascent to 5050 m in 17 healthy participants during modified hyperoxic rebreathing. At 5050 m, resting , MCAv and pH were higher (P < 0.01), while bicarbonate concentration and partial pressures of arterial O(2) and CO(2) were lower (P < 0.01) compared to sea level. Ascent to 5050 m also increased the hypercapnic MCAv CO(2) reactivity (2.9 +/- 1.1 vs. 4.8 +/- 1.4% mmHg(1); P < 0.01) and CO(2) sensitivity (3.6 +/- 2.3 vs. 5.1 +/- 1.7 l min(1) mmHg(1); P < 0.01). Likewise, the hypocapnic MCAv CO(2) reactivity was increased at 5050 m (4.2 +/- 1.0 vs. 2.0 +/- 0.6% mmHg(1); P < 0.01). The hypercapnic MCAv CO(2) reactivity correlated with resting pH at high altitude (R(2) = 0.4; P < 0.01) while the central chemoreflex threshold correlated with bicarbonate concentration (R(2) = 0.7; P < 0.01). These findings indicate that (1) ascent to high altitude increases the ventilatory CO(2) sensitivity and elevates the cerebrovascular responsiveness to hypercapnia and hypocapnia, and (2) alterations in cerebrovascular CO(2) reactivity and central chemoreflex may be partly attributed to an acid-base balance associated with high altitude ascent. Collectively, our findings provide new insights into the influence of high altitude on cerebrovascular function and highlight the potential role of alterations in acid-base balance in the regulation in CBF and ventilatory control.

Clinical screening of autonomic dysfunction in multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) can affect the autonomic nervous system. Although exercise may be beneficial for people with MS, those with autonomic dysfunction may have altered heart rate responses to exercise. We investigated the hypothesis that the pattern of increase in heart rate on commencement of a simple cycle test would be different in those participants with MS who had been shown to have autonomic dysfunction on laboratory testing compared with both control participants and MS participants not exhibiting autonomic involvement. METHOD: A controlled cohort study with a volunteer sample of 31 adults with MS (26 women, 5 men) with a mean age of 46 +/- 8.00 years (32-60 years), a median Expanded Disability Severity Scale of 3 (1-6) and a mean duration since diagnosis of 10.3 years (0.1-39 years). Thirty-one age-matched, non-disabled, sedentary but healthy adults (26 women, 5 men) with a mean age of 45 +/- 9.5 years (24-57) comprised the control group. Autonomic function was evaluated using continuous heart rate and blood pressure responses to rhythmical deep breathing, the Valsalva manoeuvre, passive postural change and a simple cycle test. RESULTS: There were no significant differences in age, height or weight (p < 0.05) between the two groups or on any of the autonomic test results (p < 0.05). Five participants with MS (16%) had abnormal autonomic function on laboratory testing, two of whom demonstrated an abnormal heart rate response to the cycle test. CONCLUSIONS: It is suggested that physiotherapists monitor the heart rate response to a dynamic exercise test in people with MS prior to prescribing an exercise programme to ensure patients' safety. Should the response appear delayed or attenuated, referral for more formal autonomic laboratory testing is recommended.

Human cerebral arteriovenous vasoactive exchange during alterations in arterial blood gases.

Cerebral blood flow (CBF) is highly regulated by changes in arterial Pco(2) and arterial Po(2). Evidence from animal studies indicates that various vasoactive factors, including release of norepinephrine, endothelin, adrenomedullin, C-natriuretic peptide (CNP), and nitric oxide (NO), may play a role in arterial blood gas-induced alterations in CBF. For the first time, we directly quantified exchange of these vasoactive factors across the human brain. Using the Fick principle and transcranial Doppler ultrasonography, we measured CBF in 12 healthy humans at rest and during hypercapnia (4 and 8% CO(2)), hypocapnia (voluntary hyperventilation), and hypoxia (12 and 10% O(2)). At each level, blood was sampled simultaneously from the internal jugular vein and radial artery. With the exception of CNP and NO, the simultaneous quantification of norepinephrine, endothelin, or adrenomedullin showed no cerebral uptake or release during changes in arterial blood gases. Hypercapnia, but not hypocapnia, increased CBF and caused a net cerebral release of nitrite (a marker of NO), which was reflected by an increase in the venous-arterial difference for nitrite: 57 +/- 18 and 150 +/- 36 micromol/l at 4% and 8% CO(2), respectively (both P < 0.05). Release of cerebral CNP was also observed during changes in CO(2) (hypercapnia vs. hypocapnia, P < 0.05). During hypoxia, there was a net cerebral uptake of nitrite, which was reflected by a decreased venous-arterial difference for nitrite: -96 +/- 14 micromol/l at 10% O(2) (P < 0.05). These data indicate that there is a differential exchange of NO across the brain during hypercapnia and hypoxia and that CNP may play a complementary role in CO(2)-induced CBF changes.

Prenatal nicotine exposure increases apnoea and reduces nicotinic potentiation of hypoglossal inspiratory output in mice.

We examined the effects of in utero nicotine exposure on postnatal development of breathing pattern and ventilatory responses to hypoxia (7.4 % O2) using whole-body plethysmography in mice at postnatal day 0 (P0), P3, P9, P19 and P42. Nicotine delayed early postnatal changes in breathing pattern. During normoxia, control and nicotine-exposed P0 mice exhibited a high frequency of apnoea (f(A)) which declined by P3 in control animals (from 6.7 +/- 0.7 to 2.2 +/- 0.7 min(-1)) but persisted in P3 nicotine-exposed animals (5.4 +/- 1.3 min(-1)). Hypoxia induced a rapid and sustained reduction in f(A) except in P0 nicotine-exposed animals where it fell initially and then increased throughout the hypoxic period. During recovery, f(A) increased above control levels in both groups at P0. By P3 this increase was reduced in control but persisted in nicotine-exposed animals. To examine the origin of differences in respiratory behaviour, we compared the activity of hypoglossal (XII) nerves and motoneurons in medullary slice preparations. The frequency and variability of the respiratory rhythm and the envelope of inspiratory activity in XII nerves and motoneurons were indistinguishable between control and nicotine-exposed animals. Activation of postsynaptic nicotine receptors caused an inward current in XII motoneurons that potentiated XII nerve burst amplitude by 25 +/- 5 % in control but only 14 +/- 3 % in nicotine-exposed animals. Increased apnoea following nicotine exposure does not appear to reflect changes in basal activity of rhythm or pattern-generating networks, but may result, in part, from reduced nicotinic modulation of XII motoneurons.