Quantifying the Relationship of Bilateral Blood Flow in Glabrous Skin at Rest and During Sympathetic Perturbations

Sympathetic nervous system regulation of blood flow within glabrous skin occurs through control of vasoconstrictor tone, with vasodilation being a passive process. As bursts of sympathetic vasoconstrictor activity occur simultaneously at separate sites of the body, blood flow patterns should also be closely matched due to the direct connection between sympathetic nerves and peripheral microvessels. With sympathetic activity difficult and invasive to measure directly, the possibility of using blood conductance as an indirect measure seems promising. We investigated the relationship of bilateral blood conductance recordings of both middle fingers in ten (7M, 3F) healthy participants, while at rest and in response to perturbations known to elicit sympathetic activity. Cutaneous vascular conductance was measured from both middle fingers via laser Doppler flowmetry, while at rest in a thermoneutral room for 20 minutes and in response to 4 randomized sympathetic perturbations (2 breath holds and 2 cold stimuli) while centrally vasodilated via heating of the back. Correlation coefficients while at thermoneutral rest were high (0.80 ± 0.22) demonstrating a strong temporal relationship for blood conductance in both fingers. During the sympathetic perturbations, blood conductance in both fingers were more related during (0.93 ± 0.11) and post (0.87 ± 0.11) administration of the sympathetic perturbation than prior (0.67 ± 0.25) to the administration (p = 0.002). Taken together, these findings indicate that blood conductance patterns at separate sites of the body are significantly more related during vasoconstrictor activity and that blood conductance may have potential as a non-invasive measure of sympathetic activity

Short term sensory and vascular responses to physical agent modalities and exercise in healthy volunteers and patients with distal radius fracture.

Currently, there is weak evidence on the effectiveness of different rehabilitation regimens following distal radius fracture (DRF). This thesis evaluated sensory and vascular effects of exercise, thermal and ultrasound interventions that can be used in the mobilization phase (cast removal) after DRF. Methods This thesis includes 3 studies. The first study compared responses to Immersion in Cold water Evaluation (ICE) in the DRF and uninjured hands. Skin blood flow (Sbf), skin temperature (temp.) and sensory perception thresholds (sPT) at 2000Hz for A –beta fibres and at 5 Hz for C fibres were obtained before, immediately after ICE and 10 min later. The second study assessed Sbf, temp., and sPT before and after 3 conditions: control, 1 MHz continuous and 3 MHz pulsed US in healthy subjects. The third study assessed Sbf and sPT before and after 3 conditions: control, 5 min of high intensity and low intensity hand exercises in healthy subjects. Differences in these were analyzed using General Linear Models. Results In the DRF hand, Sbf increased (Mean Difference (MD) = -42.2 A.U.) immediately, at 1 min (MD= -35 A.U.), and 10 min after ICE (MD= -1 A.U.). There was a decrease in temp. for the index and little fingers immediately after ICE (MD=9. 9 & 9.1 o C) and these did not return to baseline by 10 min (MD= 4.4 & 4 o C). ICE had no effect on sPT at 5 Hz (p\u3e0.05). There was no difference between the DRF and uninjured hand on all measures(p\u3e0.05) except for the sPT at 2000Hz, which remained high on the DRF side for up to 10 min( MD= -1.8 m. A.). Both pulsed and continuous US caused small to moderate reductions in Sbf (MD= 2.8 A.U. & 3.9 A.U.), temp. (MD = 2.5 0 C & 1.1 0 C) and sPT at 5 Hz (MD=1.3 m. A. & 1 m. A.). US had no effect on sPT at 2000Hz (p\u3e0.05). Both type of exercises were insufficient to alter Sbf and sPT at 2000Hz and 5 Hz (p\u3e0.05). Conclusions Normal thermo-physiological responses were observed after ICE in both hands. A-beta fibres on the DRF side became less sensitive after ICE. Minor changes can occur in Sbf, temp., and sPT at 5 Hz following 3 to 5 min exposure to US in healthy subjects. Hand grip exercises had minimal impact on Sbf or sPT in healthy subjects. The changes seen with ICE and US are presumed to help with tissue healing and pain modulation which needs further investigation

Sex-related differences in the microvascular function of pre-pubertal children

There is little research examining the effect of sex on skin blood flow (SkBF) in adults, and less in children. Sex-related differences in SkBF may help explain known thermoregulatory differences between males and females. The purpose of this study is to determine whether there are sex-related differences in the SkBF response to exercise, local heating, and acetylcholine (ACh). Additionally, the role of nitric oxide (NO) was examined. Laser-Doppler fluxmetry was used to assess forearm SkBF. Responses to exercise (30 min cycling, 60%O2max), local heating (44˚C), and ACh iontophoresis were assessed in 12 pre-pubertal boys (age=10.9 ±1.1y, O2max =1665 ± 282 ml·min-1) and 12 girls (age=11.1±1.2y, O2max =1537± 296 ml·min-1), with and without NO synthase inhibition, using Nω-nitro-L-arginine methyl ester (L-NAME) iontophoresis. Exercise-induced increase in SkBF was greater in boys compared with girls (528±290 and 374±192% of baseline, respectively, p=0.03). L-NAME blunted the SkBF response to exercise in boys and in girls (group-by-treatment interaction, p=.82). Local heating-induced SkBF was not significantly different between boys and girls (1445±900% and 1432±582%, respectively, p=.57). The ACh-induced SkBF was not different between the boys and girls, with no difference in the increase in SkBF (673±434% and 558±405%, respectively, p=.18). L-NAME blunted the SkBF response to ACh in boys and girls (group-by-treatment interaction, p=.19). These findings demonstrate that there are no differences between boys and girls in the responses to ACh and to local heating (44˚C). Additionally, the role of NO in the SkBF response appears similar in boys and girls both during exercise and ACh-mediated vasodilation. The greater SkBF response in the boys during exercise may be workload-related. Absolute and relative (%O2max) exercise intensity were not different between the two groups. Therefore, it is possible that the greater SkBF response in boys may be related to their greater workload relative to body mass (p=0.01). Additionally, sex-related factors (e.g., hormones) may interact with the exercise response or other vasodilators may be involved, resulting in the observed sex-related difference in the SkBF response to exercise

Wavelet analysis of laser Doppler microcirculatory signals: Current applications and limitations

Laser Doppler flowmetry (LDF) has long been considered a gold standard for non-invasive assessment of skin microvascular function. Due to the laser Doppler (LD) microcirculatory signal’s complex biological and physiological context, using spectral analysis is advisable to extract as many of the signal’s properties as feasible. Spectral analysis can be performed using either a classical Fourier transform (FT) technique, which has the disadvantage of not being able to localize a signal in time, or wavelet analysis (WA), which provides both the time and frequency localization of the inspected signal. So far, WA of LD microcirculatory signals has revealed five characteristic frequency intervals, ranging from 0.005 to 2 Hz, each of which being related to a specific physiological influence modulating skin microcirculatory response, providing for a more thorough analysis of the signals measured in healthy and diseased individuals. Even though WA is a valuable tool for analyzing and evaluating LDF-measured microcirculatory signals, limitations remain, resulting in a lack of analytical standardization. As a more accurate assessment of human skin microcirculation may better enhance the prognosis of diseases marked by microvascular dysfunction, searching for improvements to the WA method is crucial from the clinical point of view. Accordingly, we have summarized and discussed WA application and its limitations when evaluating LD microcirculatory signals, and presented insight into possible future improvements. We adopted a novel strategy when presenting the findings of recent studies using WA by focusing on frequency intervals to contrast the findings of the various studies undertaken thus far and highlight their disparities

Influence of upper limb ischaemia-reperfusion injury on the regulation of cutaneous blood flow during local thermal hyperaemia

The present research was developed to investigate the effects of acute upper limb ischaemia- reperfusion (I-R) on neurovascular and endothelial control of the cutaneous micro-circulation in the forearm and finger by evaluating its influence on the magnitude and kinetics of the vasodilatory response to local skin heating. Study 1 investigated between-day reliability of the local heating response in non-glabrous and glabrous index finger skin. Study 2 investigated the effects of I-R on the local heating response in non-glabrous and glabrous skin of the index finger. Study 3 investigated within- and between-day reliability of the local heating response in non-glabrous forearm skin. Study 4 investigated the effects of I-R on the local heating response in non-glabrous forearm skin, as well as the contribution of sensory nerves in mediating the magnitude and kinetics of this response. When data were normalized for blood pressure and expressed as cutaneous vascular conductance (CVC) reliability was generally comparable across all skin sites. In non-glabrous skin reliability was superior when CVC was normalized to maximum heating. At all skin sites, normalizing CVC to baseline produced poor results. Vasodilatory onset time and time to initial peak during local heating produced moderate to good reliability for all skin sites in Studies 1 and 3. In the finger, I-R did not influence the magnitude of the local heating response for the initial peak or plateau phases in either skin type. However, I-R did cause a ~23% delay in vasodilatory onset time and a ~16% delay in time to initial peak in non-glabrous skin. In the forearm, I-R attenuated the initial peak and plateau phases by ~31% and ~34%, respectively. Vasodilatory onset time was also delayed by 34% post-ischaemia. The contribution of sensory nerves in mediating the initial peak and vasodilatory onset time were significantly reduced post-ischaemia, while sensory nerves did not influence the plateau. It is concluded that upper limb I-R impairs the local heating response in non-glabrous forearm and index finger skin. A combination of cutaneous sensory nerve impairment and reduced nitric oxide bioavailability appear to be responsible for attenuating the vasodilatory response to local skin heating under these conditions

Evaluating local skin heating as an early detection method for small-fiber neuropathy in women with breast cancer receiving paclitaxel (Taxol®)

Indiana University-Purdue University Indianapolis (IUPUI)The purpose of this prospective, observational study was to determine if a technique used to detect early signs of small-fiber neuropathy (local skin heating) could detect signs of small-fiber taxane-induced peripheral neuropathy (TIPN) in breast cancer survivors (BCS) during the first 6 weeks of Taxol®. Aims of the study were to compare the mean size of (1) axon reflexes and (2) axon flares (both markers of small fiber nerve function) in BCS receiving Taxol® to the size of reflexes/flares in healthy female controls (HCs). A third aim was to determine whether the size of axon reflexes/flares correlated with (a) overall TIPN severity and (b) severity of individual signs/symptoms of TIPN during early Taxol®. Data for the study was collected from nine BCS and 20 HCs (N = 29). All BCS had first-time, non-metastatic cancer and received weekly or bi-weekly Taxol®. Data was collected at 3 time-points: Time 1 (day 0, before Taxol®), Time 2 (day 14), and Time 3 (day 42). Axon reflexes and flares were generated using a validated 40-minute skin heating protocol. Axon reflexes were measured using laser Doppler Flowmetry. Axon flares were measured using full-field laser perfusion imaging. TIPN was measured using the 5-item Short Form of the Total Neuropathy Score (Reduced Version). Results identified potential signs of small-fiber TIPN in BCS after 6 weeks of Taxol®. Contrary to expectation, axon reflexes were larger for BCS at Time 3 than HCs, suggesting that Taxol® may be associated with an increase in small-fiber nerve function like that seen in pre-clinical studies. Clinical signs/symptoms of TIPN were not significantly correlated with axon reflexes or axon flares at the same time point. Analyses of axon flare size were confounded by issues with the data. These results add to the growing body of evidence showing that Taxol® affects small-diameter sensory nerves and provides the first evidence in humans that changes in small-fiber nerve function may be detectable after just 6 weeks of Taxol® therapy. Studies in larger samples are needed to validate these findings

Examining the roles of core and local temperature on forearm skin blood flow

The interaction between local and reflexive control of skin blood flow (SkBF) is unclear. This thesis isolated the roles of rectal (Tre) and local (Tloc) temperature on forearm SkBF regulation at normal and elevated body temperatures, and to investigate the interaction between local and reflexive SkBF control. While either normothermic (Tre ~37.0°C) or hyperthermic (∆Tre +1.1°C), SkBF was assessed on the dorsal aspect of each forearm in 10 participants while Tloc was manipulated in an A-B-A-B fashion between neutral (33.0°C) and hot (38.5°C). Finally, local heating to 44°C was performed to elicit maximal SkBF. Data are presented as a percentage of maximal cutaneous vascular conductance (CVC), calculated as laser-Doppler flux divided by mean arterial pressure. Tloc manipulations performed during normothermia had significantly greater effects on CVC than during hyperthermia. The decreased modification to SkBF from the Tloc changes during hyperthermia suggests that strong reflexive vasodilation attenuates local SkBF control mechanisms

Hand Cutaneous Perfusion Dynamics in Plastic Surgery: A Feasibility Study of Hand Cutaneous Microcirculation During Standard Practices in Plastic Surgery Using Laser Doppler Flowmetry

Introduction Upper limb injuries are common, accounting for a significant proportion of unplanned visits to hospital services in the UK. The severity of such injuries varies significantly. In its most severe form, substantial injuries require immediate specialist input and subsequent long-term rehabilitation. Poor management can result in loss of function and disability, leading to loss of productivities and independence. Elevation of the limb is a routine practice following an injury to the limbs, as it is thought to be able to reduce oedema secondary to inflammation and venous pooling through gravity. However, it has been suggested that elevation may reduce local blood flow in selected situations due to increased hydrostatic pressure created by limb elevation. There appears to be no census to the ideal duration and position of limb elevation. The evidence of ideal duration and position of elevation remains sparse. Laser Doppler Flowmetry (LDF) is a non-invasive, probe-based perfusion monitoring technique which has been used in many clinical and research settings unrelated to hand surgery. This feasibility study aims to determine whether LDF can be used for research of hand cutaneous perfusion dynamics in common hand surgery practices such as limb elevation. Methods The PeriFlux 5000 LDF system was used to investigate how cutaneous perfusion alters according to the different hand locations in healthy participants. From this initial hand mapping experiment, an optimal point of measurement was found. This point was used for the subsequent elevation experiment where the cutaneous perfusion level was measured as the participants place their arm and forearm into five different positions of varying degrees of elevation. Results Laterality and hand dominance status does not influence the level of cutaneous circulation on the hand. There are significant differences in the level of circulation between the volar and dorsal aspect of the hand, as well as between digital and hand measurements. Cutaneous perfusion levels do not alter significantly between different digits provided the same locations are measured. Elevation of the limb leads to a reduction of cutaneous perfusion in a degree dependent manner. Discussion This study appears to be the first mapping study of cutaneous perfusion of the hand with LDF to date. Further insight into upper limb perfusion dynamics is gained from the elevation study. This feasibility study has found that LDF is well tolerated by participants and provides objective measurements of cutaneous perfusion. Further research would be helpful to further our understanding and further optimise outcomes in patients with upper limb conditions

Non-invasive techniques for predicting soft tissue during pressure induced ishaemia.

PhDSoft tissue breakdown occurs in association with biochemical changes that can be attributed to a reduction in blood and lymph flow to a localised tissue area in response to applied pressure. The resulting ischaemia can lead to a reduction in available oxygen and accumulation of waste products. Tissue breakdown leading to the development of pressure sores afflicts patients who are already debilitated, although not all patients appear to be equally susceptible. Measurement of sweat biochemistry and blood gas tensions may reflect the biochemical process in the underlying tissues and provide a simple and non-invasive method of investigating the status of soft tissues. The potential of specific sweat metabolites to act as markers of soft tissue status during and following loading has been investigated at a clinically relevant site in healthy volunteers, and in two clinically relevant patient groups. A range of validation procedures were undertaken and a series of parameters derived to investigate the temporal profile of sweat biochemistry, and identify various modes of gas tension response. Investigations at the loaded sacrum of healthy individuals showed a statistically significant increase in sweat lactate, urea, urate and chloride concentrations which were dependent upon the level of externally applied pressure. Mean increases of between 10%-60% were demonstrated for sweat metabolite concentrations at the loaded site compared to the control site for applied pressures in the range 40-120 mmHg. Similar increases were demonstrated in sweat collected from highly loaded tissue areas within the stump socket of lower limb amputees. A threshold value for P02 tension was identified, amounting to a 60% reduction from the unloaded value, which was associated with elevated tissue carbon dioxide levels as well as increased sweat metabolite concentrations in the loaded phase. This finding may provide a useful predictor of soft tissue status during prolonged loading. No pessimist ever discovered the secrets of the stars, or sailed to an uncharted land, or opened a new heaven to the human spirit. Helen Adam