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Effects of graded compression on intraneural blood flow
ORIGINAL COMMUNICATIONS
Effects of graded compression on intraneural blood flow An in vivo study on rabbit tibial nerve Compression applied to a peripheral nerve may easily interfere with intraneural blood flow . In the present experimental study, a vital microscopic technique was lIsed to observe changes in intraneural microcirculation (intrafascicularly and extrafascicularly) wizen graded compression was applied to a rabbit's tibial nerve by a specially designed minicompression device. Interference with venular flow was observed already at a pressure of 20 to 30 mm Hg while arteriolar and intrafascicular capillary flow was impaired at about 40 to 50 mm Hg. At 60 to 80 mm Hg no blood flow could be observed in the nerve. Nerves observed 3 or 7 days after 2 hours of compression at 400 mm Hg showed no or vel)' slow stagnant blood flow within the previously compressed segment. It is concluded that acute compression of a nerve "Yay cause persistent impairment of intraneural microcirculation due to mechanical injury to blood vessels.
B. Rydevik, M.D., Ph.D ., G. Lundborg, M.D., Ph .D., and U. Bagge, M.D., Ph.D., Goteborg, Sweden
T
he maintenance of normal impulse propagation in a peripheral nerve depends on a continuous and adequate supply of oxygen, provided by the intraneural microcirculation. \, 2 Consequently, interference with intraneural blood flow may lead to impairment of nerve function, as demonstrated in experimental ischemia. 2 - 4 Compression of a peripheral nerve, which may occur in association with various clinical situations, can be expected to cause various degrees of occlusion of the intraneural blood vessels depending on the magnitude of the pressure applied. The role of ischemia in the pathophysiology of nerve compression lesions is still debated, however. Sunderland5 suggested that vascular occlusion and int\aneural microcirculatory impairment were of major importance for the development of functional disturbances in the carpal tunnel syndrome.
From the Laboratory of Experimental Biology, Department of Anatomy, and Division of Hand Surgery, Department of Orthopaedic Surgery I, Sahlgrens Hospital, University of Giiteborg, Giiteborg, Sweden. Supported by grants from the Swedish Medical Research Council (Projects Nos. 5188 and 663), the Faculty of Medicine at the University of Giiteborg , the Giiteborg Medical Society. and the Swedish Work Environment Fund. Received for publication April 30, 1979; revised April 23, 1980. Reprint requests: B. Rydevik, M.D., Laboratory of Experimental Biology, Department of Anatomy, University of Giiteborg, P. O. Box 33031, S-400 33 Giiteborg, Sweden.
0363-5023/811010003+ 10$01.00/0
Acute compression lesions of peripheral nerves, for example tourniquet paralysis, has been studied experimentally in several investigations. 6-9 It has been stated that the prolonged functional disorders seen in association with Saturday-night palsy and similar acute pressure lesions are based upon "mechanical effect of the applied pressure on the myelinated fibers and that ischemia due to compression of the intraneural blood vessels plays little if any part. "8 On the other hand, we have found in previous investigations that acute compression of rabbit peripheral nerve may lead to intraneural edema formation, indicating mechanical deformation and injury of the intraneural blood vessels. 2, \0 These findings suggest that there could be a considerable "vascular factor" in the pathophysiology of acute nerve compression lesions. When discussing the role of ischemia in the pathophysiology of nerve compression lesions, two different situations must be identified: the reaction of the intraneural microcirculation (1) during compression of a nerve and (2) after release of the pressure, that is, the late response of the vessels to the compression trauma. 11 We have not found any reports in the literature of studies on the intraneural blood flow in vivo during or after various degrees of controlled compression trauma. Thus, the ischemic factor does not seem to have been fully evaluated in these situations. The aim of the present experimental investigation was (1) to study intraneural blood flow in vivo during
© 1981 American Society for Surgery of the Hand
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Fig. 1. Compression device placed in the vital microscope. Compression cuffs are carefully placed around the tibial nerve and inflated with air of varying pressure, allowing effects of graded compression on intraneural blood flow to be studied.
graded, controlled compression of a peripheral nerve to determine critical pressure levels for interference with the intraneural microcirculation in the epineurium, perineurium, and endoneurium and (2) to study the recovery of the intraneural microcirculation in the compressed nerve segment following acute compression.
Material and methods Twenty-two adult rabbits of both sexes, weighing 2 to 2.5 kg were used. Anesthesia was induced by intramuscular injection of 2 mllkg body weight of Hypnorm (fluanison, 10 mg, and fentanyl, 0.2 mg/ml) and was maintained by additional doses of Hypnorm when necessary. Mean arterial blood pressure (MAP) was measured during the experiments by connecting an intraarterial catheter to a mercury manometer.
Impairment of intraneural microcirculation during compression (n = 15) Experimental model. The tibial nerve was used in this study. This nerve is multifascicular and can be easily exposed between the ankle and the knee. The nerve was surgically exposed by incisions through skin and fascia on both the lateral and medial side of the leg. The nerve was then mobilized from surrounding tissues over a 4 to 5 cm long distance by a careful atraumatic technique, using microsurgical instruments and a Zeiss OP MI operating microscope. A
piece of Plexiglas (5x lOx 15 mm), glued to a larger plate of Plexiglas, was then carefully inserted through the lateral skin incision between the muscle bellies. The piece of Plexiglas lay under the tibial nerve, functioning both as support for the nerve and as a light conductor in the microscope (Fig. 1). Compression of the nerve and simultaneous vital microscopic observation of the intraneural microcirculation of the compressed nerve segment required a transparent compression device. This was achieved by welding small cuffs of thin polyethylene film 12 and by placing one cuff beneath the nerve and another cuff above the nerve (Fig. 1). The cuffs were secured in place by a holder made of Plexiglas and brass, which was placed on top of, and connected to, the Plexiglas support under the nerve (Fig. 1). Both polyethylene cuffs were connected to a special pressure air system, * enabling inflation of the cuffs with air of desired, graded pressure as read on a manometer. The tibial nerve and the compression device were then transilluminated in a Leitz large vital microscope. 2 • 13 By this technique, intraneural blood flow could be observed in the nerve during compression. Control observations were made in the parts of the nerve located proximal and distal to the compressed nerve segment, which was 10 mm long. The animals were placed in insulating cushions to keep their body *AB Stille-Werner, Stockholm, Sweden.
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temperature constant. A heating lamp was placed over the experimental limb and adjusted to keep the local temperature close to the nerve 37° to 38° C, as measured by a thermistor. The nerve was kept moist with isotonic saline solution . Observations of the microcirculation were made by one person looking in the microscope while another person adjusted the pressure in the cuffs . The experiments were performed in such a way that the microscopist did not know the actual pressure level. The pressure was gradually elevated from zero, increasing stepwise 10 mm Hg each step, until the circulation had ceased completely in the compressed nerve segment , a procedure which generally required 3 to 4 minutes . At each pressure level the microscopist described the blood flow in various types of intraneural vessels according to the following criteria: No detectable impairment of intraneural blood flow + Slight impairment of intraneural blood flow velocity and/or minor reduction of vessel diameters + + Marked impairment of intraneural blood flow velocity and/or pronounced reduction of vessel diameters + + + Complete standstill in all intraneural blood vessels In this way the effects of graded compression on the quality of the intraneural microcirculation were determined concerning epineurial and perineurial venules and arterioles and endoneurial capillaries . A similar methodologic approach has been used in a previous study on the effects of stretching on intraneural blood flow .14 Observations were made both centrally and beneath the edges of the compression cuff. Photomicrographs were taken in all experiments; in some cases, the dynamics of the microcirculation during compression were also recorded on videotape to allow repeated, detailed analyses after the experiments . The pressure level giving complete circulatory standstill was maintained for 2 hours before release of pressure. Recirculation was then studied for about 30 minutes. Control of the accuracy of the compression device . It is important in experiments where the effects of graded compression on intraneural blood flow are studied, to establish a close correlation between the pressure read on the manometer and the pressure acting on the nerve. This was especially important in the present investigation where we studied and compared the microcirculation at pressure levels often separated by only 10 mm Hg. To test the accuracy of the transmission of pressure
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Fig. 2. Photomicrographs of the tibial nerve in vivo taken in the vital microscope before compression . A, The nerve fibers run diagonally (upper left to lower right comer). One red blood cell (RBC) is seen in an endoneurial capillary. In the upper left part of the picture there is a node of Ranvier INR) . B, Red blood cells are deformed when passing through endoneurial capillaries. One endothelial cell (Ee) is seen in the capillary wall. Arrows indicate direction of flow. (Scale = 1OILm.)
from the cuffs to the nerve , the following experiments were perfonned. In five rabbits a 4 to 5 cm length segment of an abdominal vein (diameter 1 to 2 mm) was excised immediately postmortem. The vein was then placed in the compression device instead of the nerve, and one end was connected to a column of saline solution of known height, producing a flow of saline solution through the vein. The cuffs around the vein were then inflated with air until the flow of saline solution through the vein stopped due to compression of the vein . This procedure was done with various heights of the saline column. In all cases, the cuff pressure required to occlude the vein corresponded within ±5 mm Hg to the pressure generated by the saline column. This was taken as evidence of acceptable transmission of pressure from the cuffs to the nerve . Long-term effects of acute compression on intraneural blood flow (n = 7). The tibial nerves of
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Rydel'ik , Lundborg , and Bagge
The Journal of HAND SURGERY
Fig. 3. A to C. Effects of increasing cuff pressure on intraneural blood vessels as seen in the vital microscope. (Lower magnification than in Fig. 2.) A, Appearance of part of intraneural vascular bed before compression. Vessels seen are venules (V I and VJ located in the epineurium . Epineurial fat cells (Fe) are visible in upper left part. B, Effects of compression with cuff pressure 30 mm Hg. Note marked reduction of diameters of the two venules (VI and V2 ). At this pressure level, these vessels showed a slow, stagnant flow . C, Effects of compression at 60 mm Hg . The intraneural circulation in the compressed segment has now completely ceased. (Scale = 75ILm.)
these rabbits were exposed and compressed under aseptic conditions. The nerves were compressed at 400 mm Hg for 2 hours, which in this model is known to induce endoneurial edema at the edges of the compressed nerve segment. 10 After pressure release and
removal of the compression device, the skin was sutured . The animals were reanesthetized 3 or 7 days later, and the nerves were exposed and subjected to vital microscopy. The animals were also given an intravenous infusion of a solution of albumin labeled with
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Evans blue, which allows macroscopic visualization of the perfusion of intraneural vessels. Thus, vessels with intact circulation appear blue when the dye complex has perfused them.
Results Impairment of intraneural microcirculation during compression (n = 15) General findings. When the pressure in the compression cuffs was increased, the diameter of the nerve trunk gradually diminished, and the nerve became "pale." A detailed description of the blood flow characteristics at different pressure levels is given below, and the findings are also illustrated in Figs. 2 to 4. Control observations on intraneural microcirculation proximal and distal to the compressed segment did not reveal any blood flow changes at these levels. There were no detectable differences in intraneural blood flow between the central part of the compressed segment and beneath the edges of the cuffs when the nerve was compressed up to the pressure level inducing ischemia. The only distinct, specific effect seen at the edge zones was a displacement of epineural venules beneath the cuff edges toward the uncompressed parts of the nerve, a movement which occurred when the nerves were compressed at 20 to 30 mm Hg. The average mean arterial pressure was 78 mm Hg with a range of 65 to 100 mm Hg. o mm Hg. The application of cuffs around the nerve without inflation of air pressure caused no detectable impairment of intraneural microcirculation (Figs. 2, and 3, A ). However, in 2 of 15 nerves, a slight reduction of flow velocity was seen in some epineurial venules. 10 mm Hg. Compression at this pressure level induced slight impairment of flow velocity in epineurial venules in 5 out of 15 nerves. There were no detectable changes in flow velocity in any parts of the intraneural vascular bed for the remaining nerves. 20 mm Hg. At this pressure level, 13 of 15 nerves showed signs of impaired blood flow in epineurial venules, although the changes in flow velocity and vessel diameters were only slight in most cases. There was no impairment of blood flow in endoneurial capillaries or arterioles in epineurium and perineurium. 30 mm Hg. Compression of this magnitude induced impairment of blood flow and reduction of vessel diameters in venules in all nerves, and the changes were often pronounced (Fig. 3, B). Capillary flow in the endoneurium was mainly unaffected, although four of the nerves exhibited a slight reduction of flow velocity in these vessels. There were no detectable changes in arteriolar flow. 40 mm Hg. Complete standstill was induced in
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epineurial venules in 5 of 15 nerves, and the remaining nerves all showed marked reduction of epineurial venular flow. Endoneurial capillaries showed reduced flow in 12 of the 15 nerves, and some had marked flow reduction. Arteriolar flow was slightly reduced in eight nerves, but the remaining nerves showed normal flow. A striking finding at this pressure level was the appearance of "oscillations" of large arterioles, that is, heartbeat synchronous "contractions" and "dilatations" of the vessels. This phenomenon probably indicated that the cuff pressure was between the diastolic and the systolic blood pressure of these vessels. 50 mm Hg. Epineurial venules in most nerves were completely occluded. Those vessels still not completely blocked showed very slow, sluggish flow. There was also marked reduction of flow velocity in most endoneurial capillaries; in some nerves, there was no flow at all in these capillaries at this pressure level. High resolution objectives revealed that many of these capillaries still had preserved vessel lumina, as seen by the endothelial cell linings, although the capillaries were devoid of blood cells. Arteriolar flow was also reduced, and their "oscillations" were pronounced. 60 mm Hg. Epineurial venular blood flow was completely stopped in all nerves, the venules being totally occluded by the compression (Fig. 3, C). Endoneurial capillary flow was completely stopped in 11 of the 15 nerves. Arteriolar flow was completely stopped in nine nerves. In the remaining six nerves, only narrow lumina of these vessels were visible. 70 mm Hg. Circulation in venules, arterioles, and endoneurial capillaries was completely stopped in all nerves except in one, which showed slow, markedly reduced flow in arterioles and endoneurial capillaries. 80 mm Hg. All nerves had a completely stopped intraneural blood flow at this pressure level. In summary, the venular blood flow was already retarded at compression by 20 to 30 mm Hg cuff pressure. With increasing cuff pressure, intraneural blood flow was gradually decreased. A pressure of 60 mm Hg induced complete ischemia of the compressed segment in 9 of 15 nerves, and 70 mm Hg caused ischemia in all nerves but one, which was ischemic when compressed at 80 mm Hg. A summary of the findings in the 15 experiments is given in Fig. 4. Early recovery of blood flow. The cuff pressure inducing ischemia was maintained for 2 hours. Following release of pressure, the circulation was restored in all layers of the nerve within the first minute, but the blood flow was initially rather sluggish. There were no signs of thrombus formation, and there seemed to be only a slight increase in the number of white blood cells along the venular walls. However, the transparency of the
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The Journal of HAND SURGERY
Rydevik. Lundborg , and Bagge
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Fig. 4. Summary of the findings in all 15 experiments when the pressure in the cuffs was gradually increased from zero to the pressure which induced standstill. The procedure generally required 3 to 4 minutes. "Intraneural blood flow" reflects changes in flow velocity and vessel diameters. It is clearly demonstrated that the venular flow was first impaired. Capillary circulation in the endoneurium was not generally stopped until the feeding arterioles were occluded by the compression . Nine of the 15 nerves were completely ischemic when compressed at 60 mm Hg, and all but one were ischemic when the cuff pressure was 70 mm Hg.
nerve soon decreased, indicating that the nerve had become edematous. Late effects of acute compression on intraneural blood flow (n = 7). In four of the seven nerves, vital microscopy revealed a complete standstill in all intraneural blood vessels in the previously compressed nerve segment 3 and 7 days after the acute compression at 400 mm Hg for 2 hours . This was further visualized by making intravenous infusion of an Evans bluealbumin solution, which lead to a rapid blue staining of the intraneural blood vessels proximal and distal to the compressed nerve segment, indicating that there was circulation in these vessels at the time of analysis. In the compressed nerve segment, however, there was no perfusion of Evans blue-albumin in intraneural blood vessels, as seen in the operating microscope (Fig. 5) . There was a slow, stagnant flow in epineurial arterioles and venules in the remaining three nerves, but endoneurial capillaries were mainly out of function. Epineurial vessels were of abnormal appearance; they were coiled and looked like the newly formed vessels in a granulation tissue. In these cases the nerve was also strictly adherent to the surrounding tissues. Intrave-
nously infused Evans blue-albumin was detected in epineurial vessels both in the uncompressed parts and in the compressed segment of these nerves. Discussion Impairment of intraneural blood flow during compression. When the pressure in the cuffs was gradually increased, the first signs of impairment of intraneural microcirculation appeared in epineurial venules when cuff pressure was 20 to 30 mm Hg (Figs . 3, Band 4) . At this pressure level, which according to our experimental procedure was maintained for a short time, there were little or no minor retrograde effects on capillary circulation in the fascicles. Prolonged compression at this low pressure magnitude may, however, cause retardation or stasis of capillary circulation due to general impairment of venular flow or occlusion of venular vessels, as proposed by Sunderland 5 with regard to the pathophysiology of the carpal tunnel syndrome. Microangiographic techniques applied to animal and human nerves 2 , 15 have demonstrated that small venules draining the blood from individual fascicles often join to form a large vein in the epineurium . If
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such a vein is occluded due to prolonged compression, this might cause retrograde stasis and impairment of capillary circulation in several fascicles. Impaired capillary circulation caused by prolonged venular stasis may also induce hypoxic injury of the endoneurial capillary endothelium, resulting in increased capillary permeability and subsequent endoneurial edema formation. 2 Such edema might acutely affect nerve function by altering the ionic balance in the endoneurium and by increasing the endoneurial pressure. 2 Long-standing epineurial or endoneurial edema may be invaded by fibroblasts and transferred into intraneural fibrotic scar tissue. When the pressure in the compression cuffs was raised to 60 to 80 mm Hg, the circulation in the endoneurial capillaries and also in the feeding arterioles was stopped, that is, the compressed nerve segment became ischemic (Figs. 3, C and 4). This finding corresponds well with results reported by Bentley and Schlappl on their dyeperfusion experiments, where they found that compression of cat sciatic nerve at 60 to 65 mm Hg, stopped the circulation in at least the superficial vessels of the compressed nerve segment. The capillary perfusion pressure in various vascular beds of experimental animals such as rabbits, cats, and dogs has been demonstrated to be about 25 to 30 mm Hg.16-18 Studies of the microcirculation in the rabbit tracheal mucosa during cuff compression show that complete circulatory standstill usually occurs at cuff pressures of about 35 mm Hg.12 If this is accurate, why is it necessary to apply 60 to 80 mm Hg pressure on a nerve to stop the circulation of endoneurial capillaries? We believe that at least two mechanisms may work to increase the resistance of intraneural microvessels toward external compression. One must first consider the general microscopic anatomy of the nerve trunk, especially its connective tissue components. The nerve fascicles are embedded in epineurial connective tissue, and this connective tissue packing may protect the nerve fascicles from external compression. 11 Moreover, the endoneurial space of each fascicle is surrounded by the perineurial sheath, which is a very strong structure that can resist various kinds of trauma such as compression, 10 prolonged ischemia,19 and dissection trauma inflicted by internal neurolysis. 20 If the perineurium is split, however, the nerve fibers herniate through the opening, and a phenomenon known as "perineurial window" results. 21 If a fascicle is transversely severed, the nerve fibers bulge out at the cut end causing "mushrooming" to occur. These phenomena indicate that the endoneurial tissues are normally under elevated pressure, which has, in fact, been
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recently confirmed by direct measurements of endoneurial fluid pressure. 22-24 It has been demonstrated in these studies that the endoneurial fluid pressure levels in normal rat sciatic nerves range from 0.4 to 2.9 mm Hg22 and from O. 15 to 2.2 mm Hg. 24 On the other hand, the interstitial fluid pressure in other tissues (subcutaneous and muscle) has been shown to be negative: -2 ± 2 mm Hg,18 -6 to -8 mm Hg,25 and -4.7 ± 0.8 mm Hg.26 Thus, if we assume that the interstitial fluid pressure outside the perineurium is negative, there may be an outwardly directed net pressure gradient over the perineurium in the order of about 5 mrn Hg. This relative elevation of the endoneurial fluid pressure in normal nerves is maintained by the perineurium and will probably give the fascicles some mechanical "stiffness," thus serving to protect intrafascicularly located capillaries and nerve fibers from external compression. The second factor, which we believe is of decisive importance, is the characteristic intrinsic microvascular anatomy of the nerve. Along the entire nerve trunk, there are usually a few large epineurial arterioles which branch rather abruptly into the endoneurial capillary networks. Our observations show that complete impairment of endoneurial capillary circulation did not occur until those large arterioles were occluded. Thus, it seems that the presence of such large arterioles in the nerve functions to maintain a high vascular perfusion pressure in a compressed nerve segment even at compression pressures which, in other tissues without such large arterioles, would have caused complete ischemia.12. 27 Pressure levels ranging from about 10 to 80 mm Hg, and in some situations even higher, have been recorded experimentally in the human carpal tunnel 28- 30 and in the ulnar nerve in the cubital tunnel. 31 Therefore, it seems justified to assume that the intraneural circulatory changes demonstrated in this study during compression up to 80 mm Hg may be of pathophysiologic significance in human entrapment neuropathies. Early recovery of intraneural blood flow. When the cuff pressure was released after 2 hours of compression at 60 to 80 mm Hg, the intraneural circulation was restored within 1 minute. This finding is in agreement with observations made in other studies on recirculation after peripheral nerve ischemia2. 32 and after ischemia of hamster cheek pouch.27 The nerve soon became edematous, however, as indicated by a markedly decreased transparency in the vital microscope. The epineurial vessels are more susceptible to compression trauma than the endoneurial vessels and respond easily to increased permeability.lo The edema
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The Journal of HAND SURGERY
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Fig. 5. Tibial nerve, 7 days after compression by 400 mm Hg for 2 hours. Animal had received an intravenous injection of Evans blue-albumin just prior to reexposure of the nerve. This dye then perfused all vessels. except those not having any flow of blood . In this nerve, the Evans bluealbumin had penetrated the vessels proximal and distal to the compressed nerve segment, but not the vessels in this zone. This finding indicates that there was no blood flow in the previously compressed nerve segment. In the schematic drawing, arrows indicate edges of the compressed nerve segment, the length of which was 10 mm. Gray color indicates the parts of the nerve which had been perfused by Evans blue dye. *Indicates nerve, **is tendon , and ***is muscle.
induced by compression at 60 to 80 mm Hg for 2 hours was probably restricted to the epineurium,lo failing to reach the nerve fibers in the endoneurium due to the barrier function of the perineurial sheath . 1o • 3:1, 34 Late effects of high level compression on intraneural blood flow. Considering the rapidly reversible effects of low-pressure compression on intraneural blood flow, we tested to determine whether highpressure compression might have any persistent effects on intraneural circulation . In previous experiments, we found that direct compression of a nerve at 400 mm Hg
for 2 hours is followed by rapid restoration of intraneural blood flow when the pressure was released. However, the compression trauma had induced intraneural vascular injury with edema formation in the endoneurium at the edges of the compressed nerve segment. 10 In the present investigation, we have demonstrated that acute compression of this magnitude may, in addition, lead to late impairment of intraneural circulation (Fig . 5) . The mechanism behind this phenomenon may be twofold: (1) it is obvious that direct mechanical injury of intraneural blood vessels may
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cause endothelial injury with subsequent thrombous formation and (2) it is possible that the posttraumatic endoneurial edema may increase the endoneurial pressure, possibly leading to collapse of endoneurial capillaries. Posttraumatic impairment of intraneural blood flow caused by thrombi and/or collapse of endoneuria I capillaries will lead to a "secondary" ischemia after pressure release, which should further contribute to the neural lesion. It is widely recognized that nerve fibers may respond to acute compression trauma with subsequent functional deterioration due to segmental demyelination or degeneration with the degree of injury depending on the magnitude of the trauma. 6.35, 3 6 We want to emphasize, on the basis of the findings in the present study, that the intraneural microvessels may also respond to compression injury with prolonged impairment of the microcirculation in the compressed nerve segment. Such a mechanism is likely to contribute to the functional disorders often seen after acute nerve compression.
REFERENCES 1. Bentley FH, Schlapp W: The effects of pressure on conduction in peripheral nerve . J Physiol (Lond) 102:72-82, 1943 2. Lundborg G: Ischemic nerve injury. Experimental studies on intraneural microvascular pathophysiology and nerve function in a limb subjected to temporary circulatory arrest. Scand J Plast Reconstr Surg [Suppl 6], 1970 3. Gerard RW: The response of nerve to oxygen lack . Am J Physiol 92:498-541, 1930 4. Lehmann JE: The effect of asphyxia on mammalian A nerve fibers. Am J Physiol 119: 111 -20, 1937 5. Sunderland S: The nerve lesion in the carpal tunnel syndrome. J Neurol Neurosurg Psychiatry 39:615-26, 1976 6. Ochoa J, Fowler TJ, Gilliatt RW: Anatomical changes in peripheral nerves compressed by a pneumatic tourniquet. J Anat 113:433-55 , 1972 7. Fowler RJ, Danta G, Gilliatt, RW: Recovery of nerve conduction after a pneumatic tourniquet. Observations on the hind-limb of the baboon . J Neurol Neurosurg Psychiatry 35:638-47, 1972 8. Rudge P, Ochoa 1, Gilliatt RW : Acute peripheral nerve compression in the baboon. J Neurol Sci 23:403-20, 1974 9. Williams IR, Gilliatt RW, Jefferson D: Limb ischaemia and acute nerve compression . Electroencephalogr Clin Neurophysiol 43:592, 1977 10. Rydevik B, Lundborg G: Permeability of intraneural microvessels and perineurium following acute , graded experimental nerve compression . Scand J Plast Reconstr Surg 11: 179-87, 1977 II . Sunderland S: Nerves and nerve injuries. ed 2. Edinburgh, 1978, E & S Livingstone , Ltd . 12. Stenqvist 0, Bagge U: Cuff pressure and microvascular
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occlusion in the tracheal mucosa. An intravital microscopic study in the rabbit. Acta Otolaryngol 88: 451-4, 1979 13. Lundborg G, Branemark P-I : Microvascular structure and function of peripheral nerves. Vital microscopic studies of the tibial nerve in the rabbit. Adv Microcirc 1:66-88, 1968 14 . Lundborg G , Rydevik B: Effects of stretching the tibial nerve of the rabbit. J Bone Joint Surg [Br] 55:390-401, 1973 15 . Lundborg G: The intrinsic vascularization of human peripheral nerves-Structural and functional aspects. J HAND SURG 4:35-41, 1979 16. Wiederhielm CA, Woodburg JW , Kirk S, Rushmer RF: Pulsatile pressures in the microcirculation of frog's mesentery. Am J Physiol 207 : 173-6, 1964 17 . Fronek K, Zweifach BW: Microvascular pressure distribution in skeletal muscle and the effect of vasodilation. Am J Physiol 228:791-6 , 1975 18. Hargens AR, Akeson WH , Mubarak SJ, Owen CA , Evans KL, Garetto LP, Gonsalves MR, Schmidt DA: Fluid balance within the canine anterolateral compartment and its relationship to compartment syndromes. J Bone Joint Surg [ Am] 60:499-505, 1978 19 . Lundborg G, Nordborg C, Rydevik B, Olsson Y: The effect of ischemia on the permeability of the perineurium to protein tracers in rabbit tibial nerve. Acta Neurol Scand 49:287-94, 1973 20. Rydevik B, Lundborg G , Nordborg C: Intraneural tissue reactions induced by internal neurolysis. Scand J Plast Reconstr Surg 10:3-8, 1976 21. Spencer PS, Raine CS, Prineas JW: The perineurial window-A new model of focal demyelination and remyelination. Brain Res 96:323-31, 1975 22 . Low P, Marchand G, Know F, Dyck PJ: Measurement of endoneurial fluid pressure with polyethylene matrix capsules. Brain Res 122:373-7,1977 23. Low PA, Dyck P1: Increased endoneurial fluid pressure in experimental lead neuropathy . Science 269:427-8, 1977 24 . Powell HC , Myers RR, Zweifach BW, Lampert PW: Endoneurial pressure in hexachlorophene neuropathy . Acta Neuropathol (Beri) 41 : 139-44, 1978. 25. Guyton AC, Granger HJ, Taylor AE: Interstitial fluid pressure. Physiol Rev 51:527-63 , 1971 26. Chen HI, Granger HJ, Taylor AE: Interaction of capillary interstitial and lymphatic forces in the canine hindpaw. Circ Res 29:245-54, 1976 27. Romanus M, Stenqvist 0, Haljamiie H, Seifert F: Pressure induced ischemia. l. An intravital microscopic study in hamster cheek pouch of microvascular reactions during and after ischemia . Eur Surg Res 9:444-59, 1977 28 . Brain RW, Wright AD , Wilkinson M: Spontaneous compression of both median nerves in the carpal tunnel. Lancet 1:277-82, 1947 29. Tanzer RC: The carpal tunnel syndrome. J Bone Joint Surg [Am] 41:626-34, 1959
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30. Smith EM, Sonstegard DA , Anderson WH: Carpal tunnel syndrome: Contribution of flexor tendons. Arch Phys Med Rehabil 58:379-85, 1977 31 . Pechan J, Julis I: The pressure measurement in the ulnar nerve . A contribution to the pathophysiology of the cubital tunnel syndrome . J Biomech 8:75-9, 1975 32. Lundborg G: Structure and function of the intraneural microvessels as related to trauma, edema formation and nerve function. J Bone Joint Surg [Am] 57:938-48, 1975 33. Olsson Y, Kristensson K, Klatzo I: Permeability of blood vessels and connective tissue sheaths in the peripheral
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nervous system to exogenous proteins. Acta Neuropathol (Berl) Suppl 5:61-9 , 1971 34 . S6derfeldt B, Olsson Y, Kristensson K: The perineurium as a diffusion barrier to protein tracers in human peripheral nerve . Acta Neuropathol (Berl) 25 : 120-6, 1973 35 . Denny-Brown D, Brenner C: Paralysis of nerve induced by direct pressure and by tourniquet. Arch Neurol Psych 51 : 1-26,1944 36. Rydevik B, Nordborg C: Changes in nerve function and nerve fiber structure induced by acute, graded compression . J Neurol Neurosurg Psychiatry (in press)
NOTICE: Effective March I, 1981, all correspondence for the JOURNAL OF HAND SURGERY should be sent to: Adrian E. Flatt , M.D., Department of Surgery, Norwalk Hospital, Norwalk, CT 06856
Effects of graded compression on intraneural blood flow An in vivo study on rabbit tibial nerve Compression applied to a peripheral nerve may easily interfere with intraneural blood flow . In the present experimental study, a vital microscopic technique was lIsed to observe changes in intraneural microcirculation (intrafascicularly and extrafascicularly) wizen graded compression was applied to a rabbit's tibial nerve by a specially designed minicompression device. Interference with venular flow was observed already at a pressure of 20 to 30 mm Hg while arteriolar and intrafascicular capillary flow was impaired at about 40 to 50 mm Hg. At 60 to 80 mm Hg no blood flow could be observed in the nerve. Nerves observed 3 or 7 days after 2 hours of compression at 400 mm Hg showed no or vel)' slow stagnant blood flow within the previously compressed segment. It is concluded that acute compression of a nerve "Yay cause persistent impairment of intraneural microcirculation due to mechanical injury to blood vessels.
B. Rydevik, M.D., Ph.D ., G. Lundborg, M.D., Ph .D., and U. Bagge, M.D., Ph.D., Goteborg, Sweden
T
he maintenance of normal impulse propagation in a peripheral nerve depends on a continuous and adequate supply of oxygen, provided by the intraneural microcirculation. \, 2 Consequently, interference with intraneural blood flow may lead to impairment of nerve function, as demonstrated in experimental ischemia. 2 - 4 Compression of a peripheral nerve, which may occur in association with various clinical situations, can be expected to cause various degrees of occlusion of the intraneural blood vessels depending on the magnitude of the pressure applied. The role of ischemia in the pathophysiology of nerve compression lesions is still debated, however. Sunderland5 suggested that vascular occlusion and int\aneural microcirculatory impairment were of major importance for the development of functional disturbances in the carpal tunnel syndrome.
From the Laboratory of Experimental Biology, Department of Anatomy, and Division of Hand Surgery, Department of Orthopaedic Surgery I, Sahlgrens Hospital, University of Giiteborg, Giiteborg, Sweden. Supported by grants from the Swedish Medical Research Council (Projects Nos. 5188 and 663), the Faculty of Medicine at the University of Giiteborg , the Giiteborg Medical Society. and the Swedish Work Environment Fund. Received for publication April 30, 1979; revised April 23, 1980. Reprint requests: B. Rydevik, M.D., Laboratory of Experimental Biology, Department of Anatomy, University of Giiteborg, P. O. Box 33031, S-400 33 Giiteborg, Sweden.
0363-5023/811010003+ 10$01.00/0
Acute compression lesions of peripheral nerves, for example tourniquet paralysis, has been studied experimentally in several investigations. 6-9 It has been stated that the prolonged functional disorders seen in association with Saturday-night palsy and similar acute pressure lesions are based upon "mechanical effect of the applied pressure on the myelinated fibers and that ischemia due to compression of the intraneural blood vessels plays little if any part. "8 On the other hand, we have found in previous investigations that acute compression of rabbit peripheral nerve may lead to intraneural edema formation, indicating mechanical deformation and injury of the intraneural blood vessels. 2, \0 These findings suggest that there could be a considerable "vascular factor" in the pathophysiology of acute nerve compression lesions. When discussing the role of ischemia in the pathophysiology of nerve compression lesions, two different situations must be identified: the reaction of the intraneural microcirculation (1) during compression of a nerve and (2) after release of the pressure, that is, the late response of the vessels to the compression trauma. 11 We have not found any reports in the literature of studies on the intraneural blood flow in vivo during or after various degrees of controlled compression trauma. Thus, the ischemic factor does not seem to have been fully evaluated in these situations. The aim of the present experimental investigation was (1) to study intraneural blood flow in vivo during
© 1981 American Society for Surgery of the Hand
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Fig. 1. Compression device placed in the vital microscope. Compression cuffs are carefully placed around the tibial nerve and inflated with air of varying pressure, allowing effects of graded compression on intraneural blood flow to be studied.
graded, controlled compression of a peripheral nerve to determine critical pressure levels for interference with the intraneural microcirculation in the epineurium, perineurium, and endoneurium and (2) to study the recovery of the intraneural microcirculation in the compressed nerve segment following acute compression.
Material and methods Twenty-two adult rabbits of both sexes, weighing 2 to 2.5 kg were used. Anesthesia was induced by intramuscular injection of 2 mllkg body weight of Hypnorm (fluanison, 10 mg, and fentanyl, 0.2 mg/ml) and was maintained by additional doses of Hypnorm when necessary. Mean arterial blood pressure (MAP) was measured during the experiments by connecting an intraarterial catheter to a mercury manometer.
Impairment of intraneural microcirculation during compression (n = 15) Experimental model. The tibial nerve was used in this study. This nerve is multifascicular and can be easily exposed between the ankle and the knee. The nerve was surgically exposed by incisions through skin and fascia on both the lateral and medial side of the leg. The nerve was then mobilized from surrounding tissues over a 4 to 5 cm long distance by a careful atraumatic technique, using microsurgical instruments and a Zeiss OP MI operating microscope. A
piece of Plexiglas (5x lOx 15 mm), glued to a larger plate of Plexiglas, was then carefully inserted through the lateral skin incision between the muscle bellies. The piece of Plexiglas lay under the tibial nerve, functioning both as support for the nerve and as a light conductor in the microscope (Fig. 1). Compression of the nerve and simultaneous vital microscopic observation of the intraneural microcirculation of the compressed nerve segment required a transparent compression device. This was achieved by welding small cuffs of thin polyethylene film 12 and by placing one cuff beneath the nerve and another cuff above the nerve (Fig. 1). The cuffs were secured in place by a holder made of Plexiglas and brass, which was placed on top of, and connected to, the Plexiglas support under the nerve (Fig. 1). Both polyethylene cuffs were connected to a special pressure air system, * enabling inflation of the cuffs with air of desired, graded pressure as read on a manometer. The tibial nerve and the compression device were then transilluminated in a Leitz large vital microscope. 2 • 13 By this technique, intraneural blood flow could be observed in the nerve during compression. Control observations were made in the parts of the nerve located proximal and distal to the compressed nerve segment, which was 10 mm long. The animals were placed in insulating cushions to keep their body *AB Stille-Werner, Stockholm, Sweden.
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temperature constant. A heating lamp was placed over the experimental limb and adjusted to keep the local temperature close to the nerve 37° to 38° C, as measured by a thermistor. The nerve was kept moist with isotonic saline solution . Observations of the microcirculation were made by one person looking in the microscope while another person adjusted the pressure in the cuffs . The experiments were performed in such a way that the microscopist did not know the actual pressure level. The pressure was gradually elevated from zero, increasing stepwise 10 mm Hg each step, until the circulation had ceased completely in the compressed nerve segment , a procedure which generally required 3 to 4 minutes . At each pressure level the microscopist described the blood flow in various types of intraneural vessels according to the following criteria: No detectable impairment of intraneural blood flow + Slight impairment of intraneural blood flow velocity and/or minor reduction of vessel diameters + + Marked impairment of intraneural blood flow velocity and/or pronounced reduction of vessel diameters + + + Complete standstill in all intraneural blood vessels In this way the effects of graded compression on the quality of the intraneural microcirculation were determined concerning epineurial and perineurial venules and arterioles and endoneurial capillaries . A similar methodologic approach has been used in a previous study on the effects of stretching on intraneural blood flow .14 Observations were made both centrally and beneath the edges of the compression cuff. Photomicrographs were taken in all experiments; in some cases, the dynamics of the microcirculation during compression were also recorded on videotape to allow repeated, detailed analyses after the experiments . The pressure level giving complete circulatory standstill was maintained for 2 hours before release of pressure. Recirculation was then studied for about 30 minutes. Control of the accuracy of the compression device . It is important in experiments where the effects of graded compression on intraneural blood flow are studied, to establish a close correlation between the pressure read on the manometer and the pressure acting on the nerve. This was especially important in the present investigation where we studied and compared the microcirculation at pressure levels often separated by only 10 mm Hg. To test the accuracy of the transmission of pressure
Graded compression
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Fig. 2. Photomicrographs of the tibial nerve in vivo taken in the vital microscope before compression . A, The nerve fibers run diagonally (upper left to lower right comer). One red blood cell (RBC) is seen in an endoneurial capillary. In the upper left part of the picture there is a node of Ranvier INR) . B, Red blood cells are deformed when passing through endoneurial capillaries. One endothelial cell (Ee) is seen in the capillary wall. Arrows indicate direction of flow. (Scale = 1OILm.)
from the cuffs to the nerve , the following experiments were perfonned. In five rabbits a 4 to 5 cm length segment of an abdominal vein (diameter 1 to 2 mm) was excised immediately postmortem. The vein was then placed in the compression device instead of the nerve, and one end was connected to a column of saline solution of known height, producing a flow of saline solution through the vein. The cuffs around the vein were then inflated with air until the flow of saline solution through the vein stopped due to compression of the vein . This procedure was done with various heights of the saline column. In all cases, the cuff pressure required to occlude the vein corresponded within ±5 mm Hg to the pressure generated by the saline column. This was taken as evidence of acceptable transmission of pressure from the cuffs to the nerve . Long-term effects of acute compression on intraneural blood flow (n = 7). The tibial nerves of
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The Journal of HAND SURGERY
Fig. 3. A to C. Effects of increasing cuff pressure on intraneural blood vessels as seen in the vital microscope. (Lower magnification than in Fig. 2.) A, Appearance of part of intraneural vascular bed before compression. Vessels seen are venules (V I and VJ located in the epineurium . Epineurial fat cells (Fe) are visible in upper left part. B, Effects of compression with cuff pressure 30 mm Hg. Note marked reduction of diameters of the two venules (VI and V2 ). At this pressure level, these vessels showed a slow, stagnant flow . C, Effects of compression at 60 mm Hg . The intraneural circulation in the compressed segment has now completely ceased. (Scale = 75ILm.)
these rabbits were exposed and compressed under aseptic conditions. The nerves were compressed at 400 mm Hg for 2 hours, which in this model is known to induce endoneurial edema at the edges of the compressed nerve segment. 10 After pressure release and
removal of the compression device, the skin was sutured . The animals were reanesthetized 3 or 7 days later, and the nerves were exposed and subjected to vital microscopy. The animals were also given an intravenous infusion of a solution of albumin labeled with
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Evans blue, which allows macroscopic visualization of the perfusion of intraneural vessels. Thus, vessels with intact circulation appear blue when the dye complex has perfused them.
Results Impairment of intraneural microcirculation during compression (n = 15) General findings. When the pressure in the compression cuffs was increased, the diameter of the nerve trunk gradually diminished, and the nerve became "pale." A detailed description of the blood flow characteristics at different pressure levels is given below, and the findings are also illustrated in Figs. 2 to 4. Control observations on intraneural microcirculation proximal and distal to the compressed segment did not reveal any blood flow changes at these levels. There were no detectable differences in intraneural blood flow between the central part of the compressed segment and beneath the edges of the cuffs when the nerve was compressed up to the pressure level inducing ischemia. The only distinct, specific effect seen at the edge zones was a displacement of epineural venules beneath the cuff edges toward the uncompressed parts of the nerve, a movement which occurred when the nerves were compressed at 20 to 30 mm Hg. The average mean arterial pressure was 78 mm Hg with a range of 65 to 100 mm Hg. o mm Hg. The application of cuffs around the nerve without inflation of air pressure caused no detectable impairment of intraneural microcirculation (Figs. 2, and 3, A ). However, in 2 of 15 nerves, a slight reduction of flow velocity was seen in some epineurial venules. 10 mm Hg. Compression at this pressure level induced slight impairment of flow velocity in epineurial venules in 5 out of 15 nerves. There were no detectable changes in flow velocity in any parts of the intraneural vascular bed for the remaining nerves. 20 mm Hg. At this pressure level, 13 of 15 nerves showed signs of impaired blood flow in epineurial venules, although the changes in flow velocity and vessel diameters were only slight in most cases. There was no impairment of blood flow in endoneurial capillaries or arterioles in epineurium and perineurium. 30 mm Hg. Compression of this magnitude induced impairment of blood flow and reduction of vessel diameters in venules in all nerves, and the changes were often pronounced (Fig. 3, B). Capillary flow in the endoneurium was mainly unaffected, although four of the nerves exhibited a slight reduction of flow velocity in these vessels. There were no detectable changes in arteriolar flow. 40 mm Hg. Complete standstill was induced in
Graded compression
7
epineurial venules in 5 of 15 nerves, and the remaining nerves all showed marked reduction of epineurial venular flow. Endoneurial capillaries showed reduced flow in 12 of the 15 nerves, and some had marked flow reduction. Arteriolar flow was slightly reduced in eight nerves, but the remaining nerves showed normal flow. A striking finding at this pressure level was the appearance of "oscillations" of large arterioles, that is, heartbeat synchronous "contractions" and "dilatations" of the vessels. This phenomenon probably indicated that the cuff pressure was between the diastolic and the systolic blood pressure of these vessels. 50 mm Hg. Epineurial venules in most nerves were completely occluded. Those vessels still not completely blocked showed very slow, sluggish flow. There was also marked reduction of flow velocity in most endoneurial capillaries; in some nerves, there was no flow at all in these capillaries at this pressure level. High resolution objectives revealed that many of these capillaries still had preserved vessel lumina, as seen by the endothelial cell linings, although the capillaries were devoid of blood cells. Arteriolar flow was also reduced, and their "oscillations" were pronounced. 60 mm Hg. Epineurial venular blood flow was completely stopped in all nerves, the venules being totally occluded by the compression (Fig. 3, C). Endoneurial capillary flow was completely stopped in 11 of the 15 nerves. Arteriolar flow was completely stopped in nine nerves. In the remaining six nerves, only narrow lumina of these vessels were visible. 70 mm Hg. Circulation in venules, arterioles, and endoneurial capillaries was completely stopped in all nerves except in one, which showed slow, markedly reduced flow in arterioles and endoneurial capillaries. 80 mm Hg. All nerves had a completely stopped intraneural blood flow at this pressure level. In summary, the venular blood flow was already retarded at compression by 20 to 30 mm Hg cuff pressure. With increasing cuff pressure, intraneural blood flow was gradually decreased. A pressure of 60 mm Hg induced complete ischemia of the compressed segment in 9 of 15 nerves, and 70 mm Hg caused ischemia in all nerves but one, which was ischemic when compressed at 80 mm Hg. A summary of the findings in the 15 experiments is given in Fig. 4. Early recovery of blood flow. The cuff pressure inducing ischemia was maintained for 2 hours. Following release of pressure, the circulation was restored in all layers of the nerve within the first minute, but the blood flow was initially rather sluggish. There were no signs of thrombus formation, and there seemed to be only a slight increase in the number of white blood cells along the venular walls. However, the transparency of the
8
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Rydevik. Lundborg , and Bagge
Intraneural blood flow
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Fig. 4. Summary of the findings in all 15 experiments when the pressure in the cuffs was gradually increased from zero to the pressure which induced standstill. The procedure generally required 3 to 4 minutes. "Intraneural blood flow" reflects changes in flow velocity and vessel diameters. It is clearly demonstrated that the venular flow was first impaired. Capillary circulation in the endoneurium was not generally stopped until the feeding arterioles were occluded by the compression . Nine of the 15 nerves were completely ischemic when compressed at 60 mm Hg, and all but one were ischemic when the cuff pressure was 70 mm Hg.
nerve soon decreased, indicating that the nerve had become edematous. Late effects of acute compression on intraneural blood flow (n = 7). In four of the seven nerves, vital microscopy revealed a complete standstill in all intraneural blood vessels in the previously compressed nerve segment 3 and 7 days after the acute compression at 400 mm Hg for 2 hours . This was further visualized by making intravenous infusion of an Evans bluealbumin solution, which lead to a rapid blue staining of the intraneural blood vessels proximal and distal to the compressed nerve segment, indicating that there was circulation in these vessels at the time of analysis. In the compressed nerve segment, however, there was no perfusion of Evans blue-albumin in intraneural blood vessels, as seen in the operating microscope (Fig. 5) . There was a slow, stagnant flow in epineurial arterioles and venules in the remaining three nerves, but endoneurial capillaries were mainly out of function. Epineurial vessels were of abnormal appearance; they were coiled and looked like the newly formed vessels in a granulation tissue. In these cases the nerve was also strictly adherent to the surrounding tissues. Intrave-
nously infused Evans blue-albumin was detected in epineurial vessels both in the uncompressed parts and in the compressed segment of these nerves. Discussion Impairment of intraneural blood flow during compression. When the pressure in the cuffs was gradually increased, the first signs of impairment of intraneural microcirculation appeared in epineurial venules when cuff pressure was 20 to 30 mm Hg (Figs . 3, Band 4) . At this pressure level, which according to our experimental procedure was maintained for a short time, there were little or no minor retrograde effects on capillary circulation in the fascicles. Prolonged compression at this low pressure magnitude may, however, cause retardation or stasis of capillary circulation due to general impairment of venular flow or occlusion of venular vessels, as proposed by Sunderland 5 with regard to the pathophysiology of the carpal tunnel syndrome. Microangiographic techniques applied to animal and human nerves 2 , 15 have demonstrated that small venules draining the blood from individual fascicles often join to form a large vein in the epineurium . If
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such a vein is occluded due to prolonged compression, this might cause retrograde stasis and impairment of capillary circulation in several fascicles. Impaired capillary circulation caused by prolonged venular stasis may also induce hypoxic injury of the endoneurial capillary endothelium, resulting in increased capillary permeability and subsequent endoneurial edema formation. 2 Such edema might acutely affect nerve function by altering the ionic balance in the endoneurium and by increasing the endoneurial pressure. 2 Long-standing epineurial or endoneurial edema may be invaded by fibroblasts and transferred into intraneural fibrotic scar tissue. When the pressure in the compression cuffs was raised to 60 to 80 mm Hg, the circulation in the endoneurial capillaries and also in the feeding arterioles was stopped, that is, the compressed nerve segment became ischemic (Figs. 3, C and 4). This finding corresponds well with results reported by Bentley and Schlappl on their dyeperfusion experiments, where they found that compression of cat sciatic nerve at 60 to 65 mm Hg, stopped the circulation in at least the superficial vessels of the compressed nerve segment. The capillary perfusion pressure in various vascular beds of experimental animals such as rabbits, cats, and dogs has been demonstrated to be about 25 to 30 mm Hg.16-18 Studies of the microcirculation in the rabbit tracheal mucosa during cuff compression show that complete circulatory standstill usually occurs at cuff pressures of about 35 mm Hg.12 If this is accurate, why is it necessary to apply 60 to 80 mm Hg pressure on a nerve to stop the circulation of endoneurial capillaries? We believe that at least two mechanisms may work to increase the resistance of intraneural microvessels toward external compression. One must first consider the general microscopic anatomy of the nerve trunk, especially its connective tissue components. The nerve fascicles are embedded in epineurial connective tissue, and this connective tissue packing may protect the nerve fascicles from external compression. 11 Moreover, the endoneurial space of each fascicle is surrounded by the perineurial sheath, which is a very strong structure that can resist various kinds of trauma such as compression, 10 prolonged ischemia,19 and dissection trauma inflicted by internal neurolysis. 20 If the perineurium is split, however, the nerve fibers herniate through the opening, and a phenomenon known as "perineurial window" results. 21 If a fascicle is transversely severed, the nerve fibers bulge out at the cut end causing "mushrooming" to occur. These phenomena indicate that the endoneurial tissues are normally under elevated pressure, which has, in fact, been
Graded compression
9
recently confirmed by direct measurements of endoneurial fluid pressure. 22-24 It has been demonstrated in these studies that the endoneurial fluid pressure levels in normal rat sciatic nerves range from 0.4 to 2.9 mm Hg22 and from O. 15 to 2.2 mm Hg. 24 On the other hand, the interstitial fluid pressure in other tissues (subcutaneous and muscle) has been shown to be negative: -2 ± 2 mm Hg,18 -6 to -8 mm Hg,25 and -4.7 ± 0.8 mm Hg.26 Thus, if we assume that the interstitial fluid pressure outside the perineurium is negative, there may be an outwardly directed net pressure gradient over the perineurium in the order of about 5 mrn Hg. This relative elevation of the endoneurial fluid pressure in normal nerves is maintained by the perineurium and will probably give the fascicles some mechanical "stiffness," thus serving to protect intrafascicularly located capillaries and nerve fibers from external compression. The second factor, which we believe is of decisive importance, is the characteristic intrinsic microvascular anatomy of the nerve. Along the entire nerve trunk, there are usually a few large epineurial arterioles which branch rather abruptly into the endoneurial capillary networks. Our observations show that complete impairment of endoneurial capillary circulation did not occur until those large arterioles were occluded. Thus, it seems that the presence of such large arterioles in the nerve functions to maintain a high vascular perfusion pressure in a compressed nerve segment even at compression pressures which, in other tissues without such large arterioles, would have caused complete ischemia.12. 27 Pressure levels ranging from about 10 to 80 mm Hg, and in some situations even higher, have been recorded experimentally in the human carpal tunnel 28- 30 and in the ulnar nerve in the cubital tunnel. 31 Therefore, it seems justified to assume that the intraneural circulatory changes demonstrated in this study during compression up to 80 mm Hg may be of pathophysiologic significance in human entrapment neuropathies. Early recovery of intraneural blood flow. When the cuff pressure was released after 2 hours of compression at 60 to 80 mm Hg, the intraneural circulation was restored within 1 minute. This finding is in agreement with observations made in other studies on recirculation after peripheral nerve ischemia2. 32 and after ischemia of hamster cheek pouch.27 The nerve soon became edematous, however, as indicated by a markedly decreased transparency in the vital microscope. The epineurial vessels are more susceptible to compression trauma than the endoneurial vessels and respond easily to increased permeability.lo The edema
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The Journal of HAND SURGERY
:.:.:.................................. .
Fig. 5. Tibial nerve, 7 days after compression by 400 mm Hg for 2 hours. Animal had received an intravenous injection of Evans blue-albumin just prior to reexposure of the nerve. This dye then perfused all vessels. except those not having any flow of blood . In this nerve, the Evans bluealbumin had penetrated the vessels proximal and distal to the compressed nerve segment, but not the vessels in this zone. This finding indicates that there was no blood flow in the previously compressed nerve segment. In the schematic drawing, arrows indicate edges of the compressed nerve segment, the length of which was 10 mm. Gray color indicates the parts of the nerve which had been perfused by Evans blue dye. *Indicates nerve, **is tendon , and ***is muscle.
induced by compression at 60 to 80 mm Hg for 2 hours was probably restricted to the epineurium,lo failing to reach the nerve fibers in the endoneurium due to the barrier function of the perineurial sheath . 1o • 3:1, 34 Late effects of high level compression on intraneural blood flow. Considering the rapidly reversible effects of low-pressure compression on intraneural blood flow, we tested to determine whether highpressure compression might have any persistent effects on intraneural circulation . In previous experiments, we found that direct compression of a nerve at 400 mm Hg
for 2 hours is followed by rapid restoration of intraneural blood flow when the pressure was released. However, the compression trauma had induced intraneural vascular injury with edema formation in the endoneurium at the edges of the compressed nerve segment. 10 In the present investigation, we have demonstrated that acute compression of this magnitude may, in addition, lead to late impairment of intraneural circulation (Fig . 5) . The mechanism behind this phenomenon may be twofold: (1) it is obvious that direct mechanical injury of intraneural blood vessels may
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cause endothelial injury with subsequent thrombous formation and (2) it is possible that the posttraumatic endoneurial edema may increase the endoneurial pressure, possibly leading to collapse of endoneurial capillaries. Posttraumatic impairment of intraneural blood flow caused by thrombi and/or collapse of endoneuria I capillaries will lead to a "secondary" ischemia after pressure release, which should further contribute to the neural lesion. It is widely recognized that nerve fibers may respond to acute compression trauma with subsequent functional deterioration due to segmental demyelination or degeneration with the degree of injury depending on the magnitude of the trauma. 6.35, 3 6 We want to emphasize, on the basis of the findings in the present study, that the intraneural microvessels may also respond to compression injury with prolonged impairment of the microcirculation in the compressed nerve segment. Such a mechanism is likely to contribute to the functional disorders often seen after acute nerve compression.
REFERENCES 1. Bentley FH, Schlapp W: The effects of pressure on conduction in peripheral nerve . J Physiol (Lond) 102:72-82, 1943 2. Lundborg G: Ischemic nerve injury. Experimental studies on intraneural microvascular pathophysiology and nerve function in a limb subjected to temporary circulatory arrest. Scand J Plast Reconstr Surg [Suppl 6], 1970 3. Gerard RW: The response of nerve to oxygen lack . Am J Physiol 92:498-541, 1930 4. Lehmann JE: The effect of asphyxia on mammalian A nerve fibers. Am J Physiol 119: 111 -20, 1937 5. Sunderland S: The nerve lesion in the carpal tunnel syndrome. J Neurol Neurosurg Psychiatry 39:615-26, 1976 6. Ochoa J, Fowler TJ, Gilliatt RW: Anatomical changes in peripheral nerves compressed by a pneumatic tourniquet. J Anat 113:433-55 , 1972 7. Fowler RJ, Danta G, Gilliatt, RW: Recovery of nerve conduction after a pneumatic tourniquet. Observations on the hind-limb of the baboon . J Neurol Neurosurg Psychiatry 35:638-47, 1972 8. Rudge P, Ochoa 1, Gilliatt RW : Acute peripheral nerve compression in the baboon. J Neurol Sci 23:403-20, 1974 9. Williams IR, Gilliatt RW, Jefferson D: Limb ischaemia and acute nerve compression . Electroencephalogr Clin Neurophysiol 43:592, 1977 10. Rydevik B, Lundborg G: Permeability of intraneural microvessels and perineurium following acute , graded experimental nerve compression . Scand J Plast Reconstr Surg 11: 179-87, 1977 II . Sunderland S: Nerves and nerve injuries. ed 2. Edinburgh, 1978, E & S Livingstone , Ltd . 12. Stenqvist 0, Bagge U: Cuff pressure and microvascular
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occlusion in the tracheal mucosa. An intravital microscopic study in the rabbit. Acta Otolaryngol 88: 451-4, 1979 13. Lundborg G, Branemark P-I : Microvascular structure and function of peripheral nerves. Vital microscopic studies of the tibial nerve in the rabbit. Adv Microcirc 1:66-88, 1968 14 . Lundborg G , Rydevik B: Effects of stretching the tibial nerve of the rabbit. J Bone Joint Surg [Br] 55:390-401, 1973 15 . Lundborg G: The intrinsic vascularization of human peripheral nerves-Structural and functional aspects. J HAND SURG 4:35-41, 1979 16. Wiederhielm CA, Woodburg JW , Kirk S, Rushmer RF: Pulsatile pressures in the microcirculation of frog's mesentery. Am J Physiol 207 : 173-6, 1964 17 . Fronek K, Zweifach BW: Microvascular pressure distribution in skeletal muscle and the effect of vasodilation. Am J Physiol 228:791-6 , 1975 18. Hargens AR, Akeson WH , Mubarak SJ, Owen CA , Evans KL, Garetto LP, Gonsalves MR, Schmidt DA: Fluid balance within the canine anterolateral compartment and its relationship to compartment syndromes. J Bone Joint Surg [ Am] 60:499-505, 1978 19 . Lundborg G, Nordborg C, Rydevik B, Olsson Y: The effect of ischemia on the permeability of the perineurium to protein tracers in rabbit tibial nerve. Acta Neurol Scand 49:287-94, 1973 20. Rydevik B, Lundborg G , Nordborg C: Intraneural tissue reactions induced by internal neurolysis. Scand J Plast Reconstr Surg 10:3-8, 1976 21. Spencer PS, Raine CS, Prineas JW: The perineurial window-A new model of focal demyelination and remyelination. Brain Res 96:323-31, 1975 22 . Low P, Marchand G, Know F, Dyck PJ: Measurement of endoneurial fluid pressure with polyethylene matrix capsules. Brain Res 122:373-7,1977 23. Low PA, Dyck P1: Increased endoneurial fluid pressure in experimental lead neuropathy . Science 269:427-8, 1977 24 . Powell HC , Myers RR, Zweifach BW, Lampert PW: Endoneurial pressure in hexachlorophene neuropathy . Acta Neuropathol (Beri) 41 : 139-44, 1978. 25. Guyton AC, Granger HJ, Taylor AE: Interstitial fluid pressure. Physiol Rev 51:527-63 , 1971 26. Chen HI, Granger HJ, Taylor AE: Interaction of capillary interstitial and lymphatic forces in the canine hindpaw. Circ Res 29:245-54, 1976 27. Romanus M, Stenqvist 0, Haljamiie H, Seifert F: Pressure induced ischemia. l. An intravital microscopic study in hamster cheek pouch of microvascular reactions during and after ischemia . Eur Surg Res 9:444-59, 1977 28 . Brain RW, Wright AD , Wilkinson M: Spontaneous compression of both median nerves in the carpal tunnel. Lancet 1:277-82, 1947 29. Tanzer RC: The carpal tunnel syndrome. J Bone Joint Surg [Am] 41:626-34, 1959
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30. Smith EM, Sonstegard DA , Anderson WH: Carpal tunnel syndrome: Contribution of flexor tendons. Arch Phys Med Rehabil 58:379-85, 1977 31 . Pechan J, Julis I: The pressure measurement in the ulnar nerve . A contribution to the pathophysiology of the cubital tunnel syndrome . J Biomech 8:75-9, 1975 32. Lundborg G: Structure and function of the intraneural microvessels as related to trauma, edema formation and nerve function. J Bone Joint Surg [Am] 57:938-48, 1975 33. Olsson Y, Kristensson K, Klatzo I: Permeability of blood vessels and connective tissue sheaths in the peripheral
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NOTICE: Effective March I, 1981, all correspondence for the JOURNAL OF HAND SURGERY should be sent to: Adrian E. Flatt , M.D., Department of Surgery, Norwalk Hospital, Norwalk, CT 06856