# The Impact of Autonomic Dysreflexia on Blood Flow and  Skin Response in Individuals with Spinal Cord Injury

Authors: J. C. Ramella-Roman; J. M. Hidler
Journal: Advances in Optical Technologies
 (2008)

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## Abstract

Autonomic dysreflexia (AD) is an inappropriate response of the sympathetic nervous system that commonly occurs when individuals with spinal cord injury (SCI), at or above the sixth thoracic (T6) vertebra, are subjected to a noxious stimulus below the level of injury. An AD event can be put into motion by something as simple as an ingrown toenail or a full bladder, with symptoms ranging from headache, high blood pressure, and even stroke. We have characterized the onset of AD and resulting autonomic events in an individual with SCI using a fiberoptic-based probe. Two probes were located above and below the injury level, on the subjects forearm and thigh, respectively, and were connected to a dual channel spectrophotometer. Oxygen saturation was calculated using the reflectance spectra and an algorithm based on melanin and hemoglobin absorption. We noticed that during an AD event the amount of oxygen in the skin below the injury level dropped by as much as 40%, while above the injury level, skin oxygenation remained constant. In addition, we found that the level of skin perspiration below the level of injury increased significantly. We hypothesize that the combination of AD-related ischemia with pressure-related ischemia and increased perspiration places individuals with spinal cord injury level at T6 or above at an elevated risk for developing a pressure sore below the injury site.


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## Body

## 1. Introduction

Autonomic
dysreflexia (AD) is an inappropriate response of the sympathetic nervous system
in individuals with spinal cord injuries at or above the sixth thoracic
vertebra (T6). Some common symptoms of AD include
excessive sweating, pilomotor erection of skin hairs, headache, hypertension,
blurring of vision, and more rarely convulsion, loss of consciousness, cerebral
hemorrhage, and death [1]. An AD event is often induced by a noxious stimulus
below the level of injury, such as a full bladder, an ingrown nail, or a pressure
sore.The autonomic nervous system is responsible for
maintaining the body's homeostasis via the parasympathetic nervous system and
the sympathetic nervous system. These two systems have in most cases
complementary roles and exist in two different locations of the central nervous
system. In patients with T6 injuries or higher, the communication between the
parasympathetic nervous system and the sympathetic nervous system is
interrupted, so that the stimulation of one branch no longer corresponds to the
suppression of the other, resulting in the negative feedback loop of both
systems no longer working appropriately. A noxious
stimulus below T6 can cause a sympathetic response resulting in
vasoconstriction, headaches, pallor, and chills below the injury level.
Vasoconstriction produces a rise in blood pressure and consequent reflex
bradycardia through the baroreceptor reflex [1, 2]. Because of disruptions in
descending neural pathways, the parasympathetic nervous system is unable to
send or receive information regarding the status of the body below the injury
level, but tries to maintain the body's homeostasis by
slowing down the heart rate. As a result, above the injury level the patient
will experience a vagal response with vasodilation and bradycardia. An AD
episode can normally be stopped quickly by removing the painful stimulus that
triggered it; however, if no action is taken, the individual will experience
elevating levels of symptoms. AD has been the focus of many studies for its
cardiovascular effects [3], however, no study to date has evaluated its effect
on pressure sore formation. We believe that the circulatory dysfunction caused
by AD (hypoxia and ischemia) can negatively impact the health of the skin
contributing to the formation of skin ulcers.Skin hypoxia is often referred to as a one of the main
causes of skin damage [4, 5]. Several studies have shown that hypoxic wounds do
not heal as quickly as well oxygenated wounds [5], forcing an investigation on
the pathophysiological impact of hypoxia on healthy skin [6]. Previous studies
have shown that hypoxia leads to tissue angiogenesis, vascular leakage, and
consequently to skin deterioration [7]. A mediator in these alterations is the
vascular permeability factor [8] (VPF, also known as vascular endothelial
growth factor  (VEGF)). Steinbrech et al. [9] have shown a time-dependent change
in levels of VEGF and type II collagen under hypoxic condition. Levels of VEGF
mRNA in normal human dermal fibroblast increased by 140% after 6 hours of hypoxia. Likewise, collagen
mRNA expression increased by 170% after 24 hours of hypoxia. Finally Yamanaka and Ishikawa [5] showed that decreasing the oxygen tension to 2% increased mRNA of type I collagen from
cultured human skin. Recently Dalton et al. [6] have shown each of these
factors contribute to dermal failure and the formation of leg ulcers. Ischemia
is also a recognized risk factor in skin ulcer formation. Thorfinn et al. [10, 11] have shown that sitting on a hard surface reduces perfusion to a
biological zero.Several studies used reactive hyperemia [12–14]
as a way to measure perfusion response to load and skin stress. Herrman et al. [15] used a rat model to show that long-term ischemia (5 hours) due to
elevated surface pressure causes a persistent hyperemic response, suggesting a
compromise in the vasodilator mechanisms. In fact, persistent hyperemia is
considered stage I skin breakdown in the National Pressure Ulcer Advisory Panel
(NPUAP) definitions. In a related study by Thorfinn et al. [11], it was
found that through the use of laser doppler flowmetry (LDF), perfusion in the
skin over the ischial tuberosities of individuals with SCI after short and long
periods of loading was higher than in normal individuals although the initial
hyperemic response was significantly lower for SCI patients. Munstoe et al. [16, 17] have studied the role of ischemic-reperfusion injury in chronic wounds
and have pointed out that the related inflammatory mechanism caused by a
release of free radicals could lead to pressure ulcers. Finally, recent studies
[18] on animal models have shown that the onset of anoxia on an already
ischemic environment may cause a restructuring of the capillary bed with a
permanent increase in skin perfusion.
Stover et al. [19, 20] have shown that AD is a possible cause of
skin restructuring. In studying skin thickening in SCI patients with and
without AD symptoms it was shown that 80% of individuals with severe AD (grade 3)
developed skin thickening compared to the 22% of patients without AD symptoms. The reduction
of oxygenated flow coming from the femoral artery, characteristic of autonomic
dysreflexia, is likely to exacerbate the ischemic hypoxia due to pressure. AD
also causes increased perspiration that has been linked to skin ulcer formation
[21]. The goal of this study was to quantify blood flow rate, skin oxygenation
levels, the amount of skin perspiration, and other autonomically related events
during an episode of autonomic dysreflexia in an individual with spinal cord
injury. We hypothesize that during AD, the blood flow rate below the injury
level will drop significantly, translating into meaningful decreases in skin
oxygen levels. Additionally, we hypothesize that during AD, the amount of skin
perspiration will increase below the injury level.


## 2. Material and Methods

Our preliminary
measurements were made on an individual with a T6 level injury classified as
ASIA A on the American Spinal Injury Association sensory and motor impairment
scale. As such, this individual had no sensation or volitional movement below
the T6 injury level. Five different diagnostic modalities were measured: blood
pressure, lower limb temperature, femoral artery blood flow velocity, pulse
oximetry in the right thumb and right toe, and oxygen saturation in the forearm
skin (above injury level), and thigh skin (below injury level). Measurements
were first taken from the subject15 minutes after the subject emptied his bladder.
The subject then began consuming water, slowly filling his bladder. The test
was interrupted when the subject acknowledged persistent symptoms of AD
resulting from a full bladder, while his blood pressure remained under 150/100 mm Hg. All measurements were conducted in 5 minutes intervals apart from skin oxygenation
that was measured automatically every 30 seconds. Systolic and diastolic pressures were
measured with an electronic blood pressure measuring device (Jobar
International, China). A thermocouple attached to the patients left leg
measured surface temperature. The femoral artery blood velocity was measured
with an ultrasound probe (HP Sonos 2000, Palo Alto CA). Measurement of oxygen
saturation on the patients thumb and toe
were done with a portable pulse oximeter (Digit, Smiths Medical, Waukesha, Wis,
USA). Finally, skin oxygenation was measured spectroscopically.Our spectroscopic technique measures local oxygen
saturationStO2 in the skin microcirculation and differs from
pulse oximetry which measures oxygen saturation in arterial blood only. Our
experimental apparatus consisted of two custom-made optical probes constructed
with two optical fibers (Figure 1), and a dual channel spectrophotometer (Ocean
Optics, Dunedin, Fla, USA).Figure 1
Measurement location
of the fiber optic probe used in the skin oxygen saturation measurements. The
fiber optics were enclosed in a black Delrin case with a fiber to fiber
separation of2.2 mm, both fibers were 0.6 mm in diameter.Fiber diameter and separation were chosen in order to
obtain a shallow probing depth (<1.5 mm). This ensured correct measurement of
superficial skin. Two0.6 mm diameter multimode fibers (Ocean Optics,
Dunedin, Fla, USA) were positioned at 2.2 mm center to center and were supported by a
Delrin casing. One fiber was used as the light source and was attached to a
tungsten halogen lamp (Ocean Optics, Dunedin, Fla, USA); the second fiber was
used as a detector and was connected to one channel of the spectrophotometer
(Ocean Optics, Dunedin, Fla, USA). Finally the device was tested on a
custom-made reflectance standard described by Moffitt et al. [22].
Similar probes have been used recently to measure tumor oxygenation in vivo
[23], as well as optical properties of scattering biological tissues [24, 25], and are ideal for measurements where the penetration depth is low. The probing
depth of our system was assessed with the aid of Monte Carlo simulations of
light propagation into skin. Figure 2 shows the results of a simulation
conducted with 3 million photons.Figure 2
Monte Carlo simulation of light propagation in tissue. The different contours represent the
number of photons reaching different depths (bin). In the insert, a pictorial
description of our approach, every time a photon reaches a particular location
the bin values are increased (+1). The graphs shows
that photons will reach depths as far as1.2 mm and still be able to return to the
collection fiber. An averaging filter (20×20 pixels in size) was used to smooth the figure
and to generate legible contours; the general trend shown in the graph did not
change with the addition of the filter.Skin was represented  by two layers of
different optical properties. The top most layer represented the epidermis and
was 60μm in thickness (μa=35cm−1,μs=450cm−1,
and g=0.78 at 540 nm); the second layer, representing the
dermis, was semiinfinite (μa=5cm−1,μs=450cm−1, and g=0.81 at 540 nm); the skin optical properties for
each layer were from [26] by van Gemert et al. The Monte Carlo program
followed the general structure of MCML [27] and was able to handle layers but
did not consider Fresnel reflections at the interfaces. Photons were launched
by a source fiber 600μm in diameter, NA  =  0.39, and collected by an
identical detector fiber at 0.22 mm distance from the source. The propagation
media was divided in square bins 10μm×10μm in size, initially all the bins were set to a
zero value. Only the trajectories of the photons leaving the source fiber and
reaching the detector fiber were tracked. Each time a photon reached a location
in the media the value of the corresponding bin was increased by one fold (see
insert in Figure 2).Moore et al. [28] have measured dermis thickness
using ultrasound both for able-bodied individuals as well as individuals with
systemic sclerosis showing no significant difference among the two populations,
dermis thickness in the right thigh was 1.379±0.217 mm for controls and 0.8±0.13 mm in the upper arm. In light of these
measurements and looking at Figure 2, we can note that the photons traveling from
the source to the collector fiber reached depths as far as 1.5 mm, spanning the full length of a normal
epidermis and dermis [26, 28]. From this simple simulation we can assume that
the probe design is suitable to measure superficial skin hemodynamics.


### 2.1. Phantom Measurements

Calibration of
the fiber optic probe was accomplished with an optical phantom, whose optical
properties had been characterized as described in the paper by Moffitt et al. [22]. From the calibrated optical properties, and using Farrells equation [29],
we calculated the total reflectance captured by a fiber optic layout with 2.2 mm center-to-center fiber separation (thin line). Finally, we experimentally
measured the standard reflectance using the fiber probe and spectrometer as
discussed in the previous section. The fiber tip/phantom interface was matched
using a water droplet, and a 99% Spectralon reflectance standard was used to
normalize the experimental results, both experimental and calibrated values are
shown in Figure 3.Figure 3
Calibration of the fiber optic probe. The solid symbols represent the values obtained
experimentally with the fiber probe and the Ocean Optics spectrometer. The
dashes represent the calculated reflectance for a set of experimentally measured
optical properties. The optical properties of the standard had a larger margin
of uncertainty at lower wavelengths as shown by the large standard deviation.
The experimental results and theoretical findings were both normalized by the
550 nm reflectance.


### 2.2. Analysis of Spectral Data

Two different
algorithms yielding similar results were used to model the reflectance spectra
acquired with the spectrophotometer. The first algorithm is described by
Kollias and Baqer [25] and uses the curve of absorbance of skin, which is
simply the logarithm of the ratio of the skin diffused reflectance to a
reflectance standard (Spectralon standard 99% reflectance). The total absorbance curve of
skin is corrected for melanin absorption by subtracting its contribution from
the general data. Skin pigmentation is approximated as the slope of a fitted
straight line between the values of absorbance at 620 nm and 720 nm, the
absorbance curve of melanin decreasing monotonically between 600 nm and 750 nm.
Oxygen saturation is calculated by using tabulated absorption curves of
oxygenated and deoxygenated hemoglobin to fit the experimental data in the
range 550 nm to 580 nm. In this range both curves exhibit local maxima [30].The second algorithm used to model reflectance spectra
is based on the Farrells equation and
has been used by Bargo et al. [23, 24]. Tabulated skin chromophores
spectra [30, 31] are used to model the skin absorption μa and reduced scattering coefficient μs'.
The model considers the effect of the absorption of oxygenated hemoglobin μaoxy,
deoxygenated hemoglobin μadeoxy,
water μawater,
and melanin μamelanin.
The scattering coefficient of skin is modeled as a combination of Mie (M) and
Rayleigh (R) scatterers [32]:(1)M=4.59103nm−0.913[cm−1],R=1.741012nm−4[cm−1],μs′=a(M+R)[cm−1]. The total absorption in the skin is given
by(2)μa=B(StO2μaoxy+(1−StO2μadeoxy))+Wμawater[cm−1]. The calculated optical coefficients μa and μs' are used in combination with fiber separation
and interface index of reflection in the Farrells equation to
calculate total reflectance (RFarrel) from skin in the range of wavelengths of
interest (500–700 nm). The impact of melanin is finally added to the model
using a simple Beer-Lambert law as shown below:(3)TotalR=Ce−NμaMelanin2LepidermisRFarrel, where μamelanin=6.61011nm−3.33 [32] and the photon trajectory in and out of
the epidermis is taken into account by multiplying the epidermis thickness by 2. For these models we considered the epidermis to be 60μm in thickness. A least square mechanism is
finally used to fit the theoretical results to the experimental data, fitting
parameters are oxygen saturation (StO2), water content (W), blood fraction (B), scattering fraction (a), and melanin fraction (N). A wavelength-independent parameter C is used to account for the effect of fiber
collection efficiency [24]. This method has the advantage of obtaining
information not only for oxygen saturation, but also for the skin components
previously mentioned. These parameters can then be used to assess the quality
and stability of the model. A typical least square fit obtained with this model
is shown in Figure 4.Figure 4
Normalized
data (filled circles) and corresponding least square fit (line) obtained with
the model by Bargo et al. Values ofStO2 for this particular fit were 0.58, the
fraction of water was 0.65, and the blood volume fraction was 0.0009.Both models yield similar results showing a decrease
of oxygen saturation in the skin below the injury level at the onset of AD.
Although the general temporal trend was identical for both algorithms, the
numerical values ofStO2 were at times different, up to 10%.
This difference can be minimized by changing the starting parameters of Bargo's
algorithm. In this paper we will show the StO2 results obtained with the algorithm by Kollias et al.


## 2.1. Phantom Measurements

Calibration of
the fiber optic probe was accomplished with an optical phantom, whose optical
properties had been characterized as described in the paper by Moffitt et al. [22]. From the calibrated optical properties, and using Farrells equation [29],
we calculated the total reflectance captured by a fiber optic layout with 2.2 mm center-to-center fiber separation (thin line). Finally, we experimentally
measured the standard reflectance using the fiber probe and spectrometer as
discussed in the previous section. The fiber tip/phantom interface was matched
using a water droplet, and a 99% Spectralon reflectance standard was used to
normalize the experimental results, both experimental and calibrated values are
shown in Figure 3.Figure 3
Calibration of the fiber optic probe. The solid symbols represent the values obtained
experimentally with the fiber probe and the Ocean Optics spectrometer. The
dashes represent the calculated reflectance for a set of experimentally measured
optical properties. The optical properties of the standard had a larger margin
of uncertainty at lower wavelengths as shown by the large standard deviation.
The experimental results and theoretical findings were both normalized by the
550 nm reflectance.


## 2.2. Analysis of Spectral Data

Two different
algorithms yielding similar results were used to model the reflectance spectra
acquired with the spectrophotometer. The first algorithm is described by
Kollias and Baqer [25] and uses the curve of absorbance of skin, which is
simply the logarithm of the ratio of the skin diffused reflectance to a
reflectance standard (Spectralon standard 99% reflectance). The total absorbance curve of
skin is corrected for melanin absorption by subtracting its contribution from
the general data. Skin pigmentation is approximated as the slope of a fitted
straight line between the values of absorbance at 620 nm and 720 nm, the
absorbance curve of melanin decreasing monotonically between 600 nm and 750 nm.
Oxygen saturation is calculated by using tabulated absorption curves of
oxygenated and deoxygenated hemoglobin to fit the experimental data in the
range 550 nm to 580 nm. In this range both curves exhibit local maxima [30].The second algorithm used to model reflectance spectra
is based on the Farrells equation and
has been used by Bargo et al. [23, 24]. Tabulated skin chromophores
spectra [30, 31] are used to model the skin absorption μa and reduced scattering coefficient μs'.
The model considers the effect of the absorption of oxygenated hemoglobin μaoxy,
deoxygenated hemoglobin μadeoxy,
water μawater,
and melanin μamelanin.
The scattering coefficient of skin is modeled as a combination of Mie (M) and
Rayleigh (R) scatterers [32]:(1)M=4.59103nm−0.913[cm−1],R=1.741012nm−4[cm−1],μs′=a(M+R)[cm−1]. The total absorption in the skin is given
by(2)μa=B(StO2μaoxy+(1−StO2μadeoxy))+Wμawater[cm−1]. The calculated optical coefficients μa and μs' are used in combination with fiber separation
and interface index of reflection in the Farrells equation to
calculate total reflectance (RFarrel) from skin in the range of wavelengths of
interest (500–700 nm). The impact of melanin is finally added to the model
using a simple Beer-Lambert law as shown below:(3)TotalR=Ce−NμaMelanin2LepidermisRFarrel, where μamelanin=6.61011nm−3.33 [32] and the photon trajectory in and out of
the epidermis is taken into account by multiplying the epidermis thickness by 2. For these models we considered the epidermis to be 60μm in thickness. A least square mechanism is
finally used to fit the theoretical results to the experimental data, fitting
parameters are oxygen saturation (StO2), water content (W), blood fraction (B), scattering fraction (a), and melanin fraction (N). A wavelength-independent parameter C is used to account for the effect of fiber
collection efficiency [24]. This method has the advantage of obtaining
information not only for oxygen saturation, but also for the skin components
previously mentioned. These parameters can then be used to assess the quality
and stability of the model. A typical least square fit obtained with this model
is shown in Figure 4.Figure 4
Normalized
data (filled circles) and corresponding least square fit (line) obtained with
the model by Bargo et al. Values ofStO2 for this particular fit were 0.58, the
fraction of water was 0.65, and the blood volume fraction was 0.0009.Both models yield similar results showing a decrease
of oxygen saturation in the skin below the injury level at the onset of AD.
Although the general temporal trend was identical for both algorithms, the
numerical values ofStO2 were at times different, up to 10%.
This difference can be minimized by changing the starting parameters of Bargo's
algorithm. In this paper we will show the StO2 results obtained with the algorithm by Kollias et al.


## 3. Results

Typical results
obtained with the spectrophotometer and the fiber-optic probes over the
experimental test session are shown in Figure5. Two measurements were taken
simultaneously on the subjects forearm and
thigh using a dual channel spectrophotometer. AD causes a dilation of the
vessel above the injury level and a constriction of the vessels below it. The
purpose of this test was to show the effect of vessel constriction on the skin
surface. Values of skin oxygenation (StO2) were constant at the beginning of the
measurement for the first 15 minutes. However, as the subject started
experiencing AD, oxygen saturation decreased quickly. Similar trends are observed in other diagnostic modalities (Figure 6).Figure 5
The effect of AD on the skin of an individual with complete SCI. The measurement on the
forearm albeit noisy is stable around (StO2~52%), while the measurement on the thigh
decreases over time going from 52% down to ~37%.Figure 6
Measured modalities during an AD event, the lines 2nd order fits to the data.The temperature in the subjects lower
extremities decreased from33∘C to 31.2∘C over the course of the experiment, while
femoral artery systolic velocity dropped from ~110 cm/sec to ~40 cm/sec. Interestingly, the pulse rate
progressively slowed during the AD event, however we did not notice a
significant increase in blood pressure as cited by the literature [21]. During
the measurement the test subject described an increase in perspiration, and
indeed an independent observation was made that the skin was noticeably moist
to the touch; this is an important finding since humidity is considered a risk
factor in the formation of skin ulcer, surprisingly analysis conducted with
Bargo's model did not show any change in skin water content. Finally the pulse
oximetry measurements on the thumb and toe remained constant at a 97%(±1%) level (not shown in graph). It is worth noting
that while oxygen values in the main vessels remained constant, insufficient
blood and oxygen reached the skin capillaries, possibly due to the
vasoconstriction below T6.During the entire experiment, we carefully monitored
the well-being of the test subject, specifically the subjects systolic and
diastolic blood pressure levels, as well as the subjects discomfort
level. The first identification of AD symptoms came from the individual 15
minutes into the test; the test was interrupted at the patients request after
45 minutes.Relieving the noxious stimulus by draining the bladder
had an immediate impact on the AD symptoms, as shown in Figure7. The release
events are clearly observed in the oxygen saturation curve following an AD
event. During AD oxygen content in the skin decreased to 22%.
Interestingly, a second AD event occurred caused by a re-filling of the bladder
due to the large quantity of water consumed. During this second, less serious
episode of AD, oxygen content in the skin decreased to 42%,
which immediately recovered after the bladder was drained for a second time.
Oxygen saturation values increased dramatically in a very brief time interval
after the bladder was drained, surpassing normal values. This is indicative of
a rush of oxygenated blood to the superficial capillary bed possibly causing
reperfusion injury [17].Figure 7
Two sequential
AD events as detected by a SCI individual. At stimulus release oxygen
saturation increases and overshoots to values above the norm. The patient
relieved himself twice during this test at about100 minutes and 140 minutes from the start of the test. Lines were
manually drawn to pinpoint the AD events.


## 4. Conclusions

Autonomic dysreflexia is a fairly common event for
people with spinal cord injury at or above the T6 level. Unfortunately, few SCI
individuals or clinicians are aware of the potential consequences of its
symptoms. The long-term effects of AD have not been explored to their full
extent. One study [19] has shown that patients experiencing high levels of AD
develop skin thickening, and since AD influences the circulatory system it is
very possible that the skin capillary bed is also impacted. In this study we
have demonstrated a quantitative method to measure the effect of AD on the skin
oxygenation. Oxygen saturation is reduced to 40% of its original value and skin temperature is
reduced of 2 to 3 degrees Centigrade possibly due to a decreased skin
perfusion.It is interesting to note that measurements of pulse
oximetry in the thumb and toe of the test subject did not show any change with
the onset of AD contrary to what was measured with the fiber probe. Pulse oximetry
is a technique that measures arterial oxygenation by relying on its pulsatile
nature, [33]. It is commonly accepted that the signal in pulse oximetry derives
from the arterioles in the junction of dermis and hypodermis [34], this
junction can be as deep as 2 mm in the skin and it is beyond the probing depth
capability of our fiber optics (Figure 2). The signal measured in this paper
comes from the non-pulsatile capillary blood flow in the dermis and
papillary-plexus, part of the DC signal that is eliminated in pulse oximetry.
Since the oxygen saturation values measured with the pulse oximeter did not
change during AD, we can deduce that we are measuring a local reduction in
blood flow and oxygen in lieu of a systemic physiological event. The real origin
of the measured signal would be better understood with a combination of
reflectance spectroscopy and laser Doppler (LD) monitoring. An independent
measurement of perfusion such as the one offered by the LD would clarify the
impact on the signal due to a decrease in blood volume in the capillary bed as
opposed to a reduction of the oxyhemoglobin molecules. Future work will be
directed to such a study. Finally we want to recognize that much work remains
to be done in generalizing these findings to a larger sample group, and our
measurements are to be considered preliminary, but nevertheless the effect of
AD on the circulatory system has been well documented [2–4], and a clear
consequence of vasoconstriction is a peripheral decrease in perfusion, which
ultimately points to skin deperfusion and deoxygenation.



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*Source: 797214-2008-08-26.xml*