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Anesth Analg 1999;88:103-108
© 1999 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MANAGEMENT

Changes in Rat Paw Perfusion After Experimental Mononeuropathy: Assessment by Laser Doppler Fluxmetry

Allen H. Hord, MD*,{dagger}, Donald D. Denson, PhD*, Michael J. Huerkamp, DVM{ddagger}, and John G. Seiler, III, MD{dagger}

Departments of *Anesthesiology and {dagger}Orthopaedics and {ddagger}Division of Animal Resources, Emory University School of Medicine, Atlanta, Georgia

Address correspondence and reprint requests to Allen H. Hord, MD, Department of Anesthesiology, Emory University School of Medicine, 1364 Clifton Rd. NE, Atlanta, GA 30322.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
This study was performed to determine the changes in perfusion that occur after chronic constriction injury (CCI). Male Sprague-Dawley rats weighing 275–300 g had loosely constricting ligatures placed around the left sciatic nerve. Paw withdrawal latency (PWL) to heat, skin temperature, and skin perfusion (laser Doppler) of the hind paws were measured before and for 30 days after CCI. PWL decreased significantly on the side of the CCI (maximum of 34% decrease on Postoperative Day [POD] 3), then returned to normal over a 20-day period. Skin temperature initially increased on the side of CCI, then decreased with respect to the control limb on PODs 20–30. Despite the initial increase in skin temperature on the side of CCI, skin perfusion significantly decreased immediately after CCI (maximum of 51% decrease on POD 6). The perfusion gradually returned to normal over 20 days. Because return to normal perfusion occurred while the skin temperature became colder than the control side, we conclude that there is no relationship between paw surface temperature and perfusion.

Implications: Our data suggest that loss of sympathetic tone in thermoregulatory arteriovenous anastomoses leads to decreased nutritional blood flow to the skin of the affected limb after chronic constriction injury, which is consistent with the findings reported in humans with reflex sympathetic dystrophy.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Blood flow alterations occur in patients with reflex sympathetic dystrophy (RSD) (1). Based on surface temperature measurements and scintigraphic assessment of regional perfusion, blood flow to the affected limb has been shown to increase temporarily, then decrease below normal (2). It is presumed that changes in sympathetic nervous system function cause these changes in skin temperature and perfusion in patients with RSD.

Using a model of chronic constriction injury (CCI), rats appear to develop signs common to causalgia and RSD, including postural changes, changes in skin and nail texture, and mechanical and thermal hyperalgesia (3). This neuropathic pain model has been used to investigate the pathological changes that occur in the injured nerve and the neurophysiologic changes that result from nerve injury. Few studies have focused on the changes in peripheral blood flow associated with the experimental neuropathy (4,5). In this animal model, temperature initially increases in the affected limb, then decreases below the temperature of the sham limb.

Because skin temperature and skin perfusion may not correlate, it is necessary to directly determine the effect of CCI on perfusion. We designed this study to establish the direction and duration of perfusion changes in the rat hind paw after CCI. In addition, we included a comparison group in which the hind limb was immobilized to determine whether decreased perfusion is caused by disuse of the limb.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study was approved by our animal care and use committee. Male Sprague-Dawley rats weighing 275–300 g were used. Rats were housed in clear plastic cages with solid floors and loose hardwood chip bedding and were allowed free access to food and water. The animals were acclimated to the environment and to the paw withdrawal testing procedure on three occasions before surgery. After three testing periods on different days, the rats underwent surgery or limb immobilization.

Twelve rats were anesthetized with 40 mg/kg intraperitoneal (IP) pentobarbital. Subsequent doses of pentobarbital 2–4 mg/kg were administered as necessary to maintain adequate anesthetic depth. After an adequate depth of anesthesia was verified by lack of response to tail pinch, surgery was performed to place four loosely constricting 4–0 chromic sutures around the left sciatic nerve, as previously described by Bennett and Xie (3). Identical surgery was then performed on the opposite (right) side, except that the ligatures were not placed (sham surgery).

Twelve additional rats were sedated with chloral hydrate 300 mg/kg IP, followed by 50–150 mg/kg IP as needed to abolish the righting reflex. The left lower limb was immobilized using adhesive tape to bind the limb against the trunk. Care was taken to place the limb in a position in which there was no strain on the hip or soft tissues. The right hind leg remained free. Food was placed inside the cage, and extra-length sipper straws for water bottles were used to ensure that the rats could have free access to food and water despite their impaired ability to rear. Perfusion testing was performed on postoperative days (PODs) 3 and 6. Tape was removed under chloral hydrate sedation before perfusion measurements and was replaced, when appropriate, while the animals were still sedated.

The animals were placed in a clear plastic cage with air holes on a glass testing table in which they could move freely (e.g., make postural adjustments), and left to acclimatize to the environment for 10 min. The device used for measurement of paw withdrawal tests consists of a radiant heat source (high-intensity projector lamp bulb) located below the glass floor and projected through a round aperture. A photoelectric cell detects light reflected off the paw and turns off the lamp and electronic clock when the paw is withdrawn.

Testing was performed 3 days before surgery or immobilization and every 2–3 days thereafter for 30 days. Five sets of tests were performed on each hind paw at each time of measurement. The first set of measurements on each hindpaw was discarded (as recommended by GJ Bennett; personal communication) because it has the highest variability.

Using the same 12 rats, testing of temperature and perfusion was performed after paw withdrawal latency (PWL) measurement. The animals were sedated with chloral hydrate 300 mg/kg IP initially, followed by 50–150 mg/kg IP, if necessary, until the righting reflex was abolished. When lightly sedated, the paw surface temperature was measured by using contact thermistors (Yellow Springs Instrument Co., Yellow Springs, OH) taped to the dorsal surfaces of both hind paws. When the animals were sedated enough to be placed supine, the laser Doppler probe (Perimed, Piscataway, NJ) was positioned on the mid-portion of the dorsal, lateral, hind paw so that it touched, but did not indent, the skin. A 10-s recording was taken. The procedure was performed a minimum of five times on each hind paw. In each animal, the four recordings with the highest average perfusion values were used to determine the mean for each limb.

Data are presented as mean ± SEM unless otherwise specified. Temperature measurements are expressed as the absolute differences between the CCI and control limbs. PWL and perfusion values for the CCI limb are expressed as a percentage of the corresponding value for the sham limb ([PWLL/PWLR] · 100). Differences between preoperative and postoperative times were assessed by using a one-way analysis of variance for repeated measures followed by a post hoc Scheffé's test for multiple comparisons. Intergroup comparisons for animals in the limb immobilization group and the corresponding control group were performed using a t-test for independent means. In all cases, a P value <0.05 was required for rejection of the null hypothesis.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Animals who underwent CCI all had signs of the development of the neuropathic pain syndrome postoperatively. The toes of the affected limb were held together with the foot everted. The limb was used for walking, but with an obvious limp. At rest, the foot was not placed in contact with the floor as frequently the control side. After thermal stimulation, the affected limb was held away from the floor for a longer period of time than the control side. Despite the mononeuropathy, animals continued to groom themselves normally and gain weight.

The PWL had been similar in both hind limbs before surgery. PWL values typically decreased slightly even on the sham side after surgery. Therefore, PWL values on the side of the CCI (left) are expressed as a percentage of the value on the sham (right) side ([PWLL/PWLR] · 100). PWL decreased significantly on the side of the CCI, with a maximal decrease of 34% on POD 3 compared with the sham side (Fig. 1). PWL on the side of CCI slowly returned to normal and was not significantly different from the sham side after POD 22.



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  		Figure 1. Surgical mononeuropathy (chronic constriction injury) results in reversible thermal hyperalgesia. Data are mean ± SEM for 12 animals. Paw withdrawal latencies (PWL) are expressed as the percent change in the operated limb compared with the sham limb, as described in Methods. PWL measurements were significantly lower (*P < 0.05) than the preoperative period at all postoperative measurement times up to Day 17, which demonstrates significant thermal hyperalgesia. PWL measurements on Days 24, 27, and 30 had returned to the preoperative control values.

 
Skin temperature on the side of the CCI initially increased (maximum 0.88°C on POD 10) compared with the sham side, then decreased (maximum -1.01°C on POD 22) compared with the sham limb. There were large interindividual variations in paw temperature, but the group average showed statistically significant differences between PODs 10–15 and PODs 22–30 (Fig. 2). There had been no difference in perfusion values between sides before CCI. Despite the initial increase in skin temperature on the side of CCI, skin perfusion significantly decreased immediately after CCI (maximum of 51% on POD 6). The perfusion gradually returned to normal over 22 days and remained normal throughout the remainder of the postoperative period (Fig. 3).



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  		Figure 2. Surgical mononeuropathy (chronic constriction injury) results in significant temperature changes in the affected limb. Data are mean ± SEM for eight animals. Skin temperature on the side of the chronic constriction injury initially increased on Postoperative Days (PODs) 10, 13, and 15, with the maximal increase occurring on POD 10 (0.88°C) compared with the sham side. Skin temperatures then decreased on PODs 20–30, with the maximal decrease occurring on POD 22 (maximum -1.01°C) compared with the sham limb. There were large interindividual variations in paw temperature, but the group average showed statistically significant differences between PODs 10, 13, and 15 (#) and PODs 20–30 (*)(P < 0.05).

 


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  		Figure 3. Surgical mononeuropathy (chronic constriction injury) results in a reversible decrease in peripheral perfusion. Data are mean ± SEM for 12 animals. Perfusion changes are expressed as the percent change in the operated limb compared with the sham limb, as described in Methods. Perfusion was significantly lower (*P < 0.05) than the preoperative period at all postoperative measurement times up to Day 20, which demonstrates a parallel response compared with the time course of thermal hyperalgesia (Fig. 1). Peripheral perfusion had returned to control by Postoperative Day 22 and remained unchanged for the duration of the experimental period, which demonstrates the reversibility of the effects of chronic constriction injury on perfusion.

 
Animals tolerated immobilization of the hind limb without complications, except for skin irritation from the tape. After 3 days of complete immobilization, there was no decrease in perfusion of the treated limb compared with the control limb (perfusion = 106% of control side) (Fig. 4). There was no change in perfusion in the limb compared with its preoperative value (P = 0.862). However, there was a statistically significant difference between animals with immobilized limbs and those with CCI (P < 0.005). After 6 days of immobilization, perfusion decreased by 52% and was not statistically different from those animals who had CCI (P = 0.149). Perfusion was significantly different from preoperative control (P < 0.005).



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  		Figure 4. Perfusion changes associated with surgical mononeuropathy (chronic constriction injury) are not caused by disuse. Data are presented as mean ± SEM for 12 animals in each group. Perfusion changes are expressed as the percent change in the operated limb compared with the sham limb, as described in Methods. Perfusion was significantly lower (*P < 0.003) for the chronic constriction injury group on Postoperative Day 3 compared with the group in which the limb had been experimentally immobilized. By Postoperative Day 6, perfusion had decreased in the experimental immobilization group and was not significantly different from that in the chronic constriction injury group.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
All rats developed a neuropathic pain syndrome. Thermal hyperalgesia to radiant heat was present until POD 20. These changes in PWL parallel those described by Bennett and Xie (3). Wakisaka et al. (5) have shown that, after CCI, there is an abnormally large difference in temperature between the sham and CCI hind paws. There were large interindividual variations, but the group average showed statistically significant trends. Temperatures were initially hotter on the side of the CCI, but, with time, they became abnormally cold. Similarly, we found that the skin temperature of the paw on the affected side initially increased. After 18 days, the skin temperature of the CCI limb decreased below that of the sham limb and was significantly lower than temperatures on PODs 10–15. Decrease in perfusion occurred within 3 days after CCI and gradually returned to normal by POD 22. Decreases in PWL paralleled decreases in perfusion. During the same time period, the temperature was increased, which indicates no relationship between skin temperature and skin perfusion after CCI.

Initially, patients with RSD have a warm limb that has increased total perfusion (2). The limb eventually becomes cool, pale, or cyanotic and has normal or decreased total flow and skin temperature (2,6). It has been suggested that the decrease in temperature is a result of increased sympathetic tone. However, Wakisaka et al. (5) have shown in rats that sympathetic innervation of the hindpaw with CCI actually diminishes over time, even while the temperature is decreasing. Using histofluorescent staining of catecholamines, the authors showed gradual loss of norepinephrine-containing sympathetic efferents on the side of the CCI. The decrease was noted by POD 5 and was marked by PODs 10–14. By Day 30 after CCI, there was near complete loss of catecholamines. Correlation with skin temperature before the rats were killed showed no relationship between skin temperature and norepinephrine content. Given the results of these experiments, the changes in skin temperatures seen in the rat are not explained by changes in sympathetic innervation. This could be due to receptor hypersensitization in the presence of circulating catecholamines. Although this postulate has not been proven, there is increased extraction of systemic catecholamines in the venous effluent from limbs with RSD compared with the unaffected side when levels of catecholamines are measured in the venous effluent of each limb (7).

It is possible that the chloral hydrate used for sedation decreases perfusion, but hypnotic doses (300 mg/kg) have minimal effects on the cardiovascular system and baroreceptor reflexes in the rat (8). Larger doses may lead to a dose-dependent decrease in heart rate, myocardial contractility, respiratory rate, tidal volume, and blood pressure. Because it is impossible to use the laser Doppler in the awake rat, a hypnotic must be used for the measurement of perfusion. {alpha}2-agonists. N-methyl-D-aspartate receptor antagonists, such as xylazine and ketamine, were avoided because they may have altered the development of the neuropathic pain syndrome (9). Pentobarbital has been used for anesthesia in this model and does not seem to prevent the development of the neuropathic pain syndrome. However, because pentobarbital may significantly decrease blood pressure, chloral hydrate was chosen for sedation in the present study because it provides cardiovascular stability in rats that is superior to other sedatives and is not known to interact with {alpha}-receptors. Although the administration of chloral hydrate may have caused a slight generalized decrease in perfusion, we do not believe that it would change the relationship between the treated and sham limbs. This is supported by the fact that the normal equality of perfusion between limbs was not altered in preoperative control measurements or on POD 3 after immobilization, despite the use of chloral hydrate.

Laser Doppler fluxmetry (LDF) measures perfusion by directing a laser light through the skin. Stationary tissue reflects the light without a change in frequency. Moving cells, especially red blood cells, cause a Doppler shift in frequency of the reflected light. Perfusion in the tissues is proportional to the amount of light reflected to the probe that has undergone a shift in frequency. The depth of penetration of the laser determines the depth of the blood vessels in which perfusion is measured. The optical properties of the skin and the distance of separation between the optical fibers that send and receive the laser determine the depth of penetration (10). A probe with a fiber separation of 0.3 mm has a maximal sensitivity at a depth of 0.8 mm in the human finger (11). We used a probe with a fiber separation of 0.25 mm, which should have even less penetration. The specific optical properties of the rat hind paw are unknown but would be predicted to demonstrate less laser penetration because of the highly cornified nature of the skin of the rat paw (10). Therefore, the device used in this study likely has maximal sensitivity at a depth <0.8 mm (12).

The microcirculation of the skin has been studied extensively in humans. The outer layer of skin (0.2–2 mm) has its own circulation, the cutaneous plexus, which supplies nutritional blood flow to the skin (13,14). This layer is thermally passive in the transfer of heat from the body to the environment. Thermoregulatory blood flow occurs below this surface layer and accounts for 90% of total cutaneous blood flow (15). Arteriovenous anastomoses (AVAs), which are partially controlled by sympathetic innervation, dilate to promote core heat loss (16,17). In humans, blockade of sympathetic nerves or receptors alone does not lead to complete dilation of AVAs, which indicates that there is also active nonsympathetic control of AVAs (16,17). Because the laser Doppler has maximal sensitivity at a depth of <0.8 mm, it measures nutritional blood flow and part of the AVA flow in the rat hind paw. The exact proportion of nutritional and AVA blood flow measured in this tissue is unknown (17,18). Clinically, a probe with fiber separation of 0.3 mm measures skin capillary blood flow in the human finger, not thermoregulatory flow through AVAs (12). In our study, the skin temperature increase in the early postoperative period indicates an increase in thermoregulatory AVA flow while our laser Doppler measure of perfusion decreased. If the laser Doppler was partly measuring AVA flow, then nutritional blood flow in the skin actually decreased more than our measurements indicated.

Digital temperatures and LDF measures of blood flow parallel each other in normal humans (19). However, decreased nutritional blood flow despite increased total limb blood flow has been observed in patients with RSD (20). Decreased nutritional blood flow does not correlate with skin temperature, which is a function of AVA flow (21). Rosen et al. (20) have shown that patients with RSD have decreased skin blood flow and loss of normal autoregulation during dependency and in response to contralateral cooling. They found no relationship between skin temperature and skin blood flow using LDF and video-photometric capillaroscopy. Nutritional capillary blood flow is dependent on the degree of constriction of the subpapillary arteriolar plexus and the downstream venous pressure. Both of these factors may be influenced by increased sympathetic stimulation, which constricts both arterioles and veins of the extremity. Precapillary arterioles respond to local increases in PCO2 or decreases in PO2 by dilating to increase nutrient flow (22,23). AVAs seem to be largely controlled by sympathetic nerves. Sympathetic stimulation causes constriction of AVAs, forcing blood through capillaries with high resistance to flow. Withdrawal of sympathetic stimulation opens AVAs, shunting blood into a low-resistance venous plexus in which heat exchange occurs more efficiently. Increased paw temperature in our animals with CCI is consistent with withdrawal of sympathetic tone, presumably caused by sciatic nerve injury. This finding is consistent with the loss of catecholamine-containing nerve endings in animals after CCI (5). However, the reason for decreased nutritional flow is less clear. It could be due to shunting of arterial blood through AVAs and away from superficial capillaries. Even capillaries that are fully dilated due to both metabolic factors and withdrawal of sympathetic stimulation would have 1000 times more resistance to flow than large AVAs (24). Restoration of sympathetic tone to AVAs through development of receptor hypersensitization could then restore nutritional blood flow.

Our data suggest that perfusion was significantly decreased in the early postoperative period, a finding that we considered could be related to decreased use of the limb (25). Therefore, we completely immobilized a hind paw in a series of rats to investigate the relationship between immobilization and perfusion. Even with complete immobilization, there was no decrease in perfusion of the limb after 3 days, although a decrease in perfusion was seen after 6 days. These findings are not consistent with the rats with CCI, in which perfusion decreased within 3 days. The decrease in perfusion in the rats with CCI occurred even while the limb was being used frequently, albeit less than the sham side. Our findings of increased skin temperature in rats with CCI are consistent with those of Greyson and Tepperman (25), who found radionuclide evidence of increased total limb blood flow in patients with disuse and RSD versus decreased blood flow in patients with disuse alone.

In summary, although paw skin temperature initially increased after CCI, then decreased, perfusion decreased immediately and returned to normal over time. These findings help to explain the discrepancy between skin temperature and catecholamine staining reported by Wakisaka et al. (5). The decrease in perfusion probably represents decreased nutritional blood flow to the skin despite an initial increase in thermoregulatory blood flow in deeper tissues presumably caused by loss of sympathetic tone in AVAs. Similar findings have been reported in humans with RSD. The cause for decreased nutritional blood flow in this experimental neuropathy requires further investigation.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication September 23, 1998.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press