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Impaired blood flow response following pressure load in diabetic patients with cardiac autonomic neuropathy
1003
Impaired Blood Flow Response Following Pressure Load in Diabetic Patients With Cardiac Autonomic Neuropathy Rob J. van Marum,
MD, Jan H. Meijer, PhD, Frits W. Bertelsmann,
ABSTRACT. van Marum RJ, Meijer JH, Bertelsmann PW, Ribbe MW. Impaired blood flow response following pressure load in diabetic patients with cardiac autonomic neuropathy. Arch Phys Med Rehabil 1997;78:1003-6. Objective: An impaired blood flow response is associated with an increased risk of developing decubitus ulcers. This study investigated whether diabetic patients with autonomic neuropathy show an impaired blood flow response following pressure load, compared with healthy controls. Design: Before-after trial. Setting: University hospital. Patients: Eighteen patients with type I diabetes and autonomic neuropathy, and 15 healthy volunteers. Results: The blood flow responsestarts with a latency period, followed by a temperature increase (described by the “time constant”). The blood flow response in both groups showed significant 0, < .Ol) differences. In diabetic patients, the latency time was 312 + 221sec, the time constant was 339 2 149sec, and the recovery time was 538 2 184sec. In controls, latency time was 83 2 47sec, time constant was 79 + 69sec, and recovery time was 162 2 103sec. The velocity of the blood flow response decreasedwith increasing duration of diabetes mellitus @ = .02). Conclusions: Diabetic patients with autonomic neuropathy show an impaired blood flow response after pressurerelief. This finding suggests that these patients have an increased risk of developing decubitus ulcers. 0 I997 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation
I
N EACH INDIVIDUAL, the impact of pressure load on tissues alters over time. This variation over time depends on factors such as local blood flow regulation.’ Meijer et al’.* studied the effects of pressure application on local blood flow in 109 nursing home aged patients and analyzed the relation between blood flow response and the development of decubitus ulcers. They found a significant relation between the velocity of blood flow recovery after a period of ischemia and the risk of developing decubitus ulcers. A slower recovery of blood flow was related to an increased risk of developing decubitus ulcers. Diabetes mellitus is a disorder in which disturbances of blood llow regulation frequently occur. Therefore, in clinical practice From the Deotimenr of General Practice. Nursine Home Medicine and Social Medicine. Vrij; Universiteit Amsterdam and N&g Home Waerthove. Sliedrecht (Dr. van Marum): Department of Medical Physics and 1nformaticskC.A.R. In\titutc. Vrije Lniversiteit Amsterdam (Dr. Meijer); Department of Neurology, Free University Hospital Amsterdam (Dr. Benelsmann): and Department of Genrrdl Practice. Nursine Home Medicine and Social Medicine. Vriie Universiteit Amsterdam (Dr. Ribge), The Netherlands. Submifted for puhhcation .Vovcmber lg. 1996. Accepted in revised form March
17. IW7. The authors have chosen not to select a disclosure statement. Reprint requests IO R. J. van Matum. MD, Department of General Practice, Nursing Home Medicine and Social Medicine, Vrije Universiteit. Van der Boechorststraat 7. IOXI BT. Amsterdam. The Netherlands. 0 1997 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation
0003-9’)‘)3/97/78fl9-4206$3.oo/o
MD, PhD, Miel W. Ribbe, MD, PhD
diabetes mellitus is often seen as an important risk factor for the development of decubitus ulcers.‘.“ However, evidence for this assumed relationship is circumstantial. In diabetic patients, autonomic dysfunction leads to an increased blood flow through arteriovenenous shunts and, subsequently, to a relatively impaired capillary flow, which increasesthe risk of ulcer development.’ Mein et al” found in a group of healthy patients who underwent minor surgery that blocking the sympathetic nerve system by spinal anesthesia resulted in a decreased recovery of local blood flow following pressure application. In several other studies,‘-13 a decreased vascular response following minor trauma, blood pressure fluctuation, or infusion of vasoactive agents was found in patients with type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus. In this study, we compared blood flow response in diabetic patients who had cardiac autonomic neuropathy, following local pressure application in the trochanter region, a region that is known as a high-risk area for decubitus ulcers, with blood flow response in a group of healthy volunteers. PATIENTS AND METHODS Patients There were 18 patients in the diabetic group, 12 men and 6 women with a mean age (+ SD) of 50 (2 10) years, a median age of 52 years, and a range of 33 to 65 years, who had type 1 diabetes mellitus and were registered as patients at a university hospital’s neurological department. The mean duration (t SD) of diabetes mellitus was 18 (+ 12) years. All patients suffered from cardiac autonomic neuropathy (expiration/inspiration [E/I] ratio [? SD], 1.06 [ + .03]) and showed symptoms of autonomic neuropathy (impotence, orthostatic hypotension, gastropareses, etc). None of the patients had decubitus or diabetic ulcers at the time of measurement and all were in good general health. Glycosylated hemoglobin (HbA,,) ranged from 4.7% to 9.6% (mean [? SD], 7.7% [? 1.41). In all patients, no other possible causesfor the existence of neuropathy other than diabetes mellitus existed (eg, alcohol abuse, malignancies, medication) and no signs were found of peripheral vascular disease (eg, claudicatio intermittens, peripheral necrosis, amputation, etc). All patients consented to participate in the study. The protocol was approved by the university hospital’s Ethical Review Board. Blood flow responses after pressure application in diabetic patients were compared with those of a control group of 15 healthy volunteers, 10 men and 5 women with a mean age (& SD) of 51 (2 11) years, a median age of 52 years, and a range of 34 to 66 years, who, at the time of the study, were not taking any medication. Sample size was calculated based on an (Y = .05 and p = .20. Method The existence of autonomic neuropathy was assessedon the basis of heart rate variations during deep breathing. Lying in a supine position, six deep expirations and inspirations were performed during the recording of a continuous electrocardiogram. The E/I ratio was expressedas the ratio of the mean value Arch
Phys Med
Rehabil
Vol78,
September
1997
1004
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IN DIABETIC
NEUROPATHY,
van
Marum
temperature increase following the Lt is described by the time constant (7-T).This time constant equals a temperature increase of 63.2% of the amplitude. The total recovery time is defined as the sum of the latency time and the time constant.
Statistical Analysis
Fig 1. Typical skin temperature response curves following pressure relief. The pressure stimulis is applied at To and removed after 10 minutes at T,. Temperature changes are registered at steps of 0.1%. After pressure relief, there is a latency period (Lt) during which no temperature changes occur, followed by a period during which skin temperature increases [time constant: 7). Lt and r together form the total recovery time. The top curve shows the blood flow response of a 29-year-old healthy man, with a typical rapid increase of skin temperature, including reactive hyperemia. The bottom curve shows the response of a 42-yearold woman with diabetic autonomic neuropathy, in whom the blood flow response is delayed.
of the longest RR intervals during each expiration and the mean of the shortest RR intervals during each inspiration. The existence of autonomic neuropathy was assumed when the E/I ratio was less than or equal to the 5th percentile limit for age-related normal ranges.14 Although the E/I ratio reflects parasympathetic cardiac functioning, based on the duration of diabetes mellitus, one may assume a mixed sympathetic/parasympathetic neuropathy.15 For the determination of blood flow response following pressure application, we used the pressure-time-temperature (PTT) method described by Meijer et al.’ With this noninvasive method, a change in skin temperature in response to a pressure load on the trochanter major can be measured. During the pressure load, skin temperature decreases, whereas it increases again after the pressure load is removed. In a reproducibility test no significant (p > .05) differences were found between repeated measurements.’ In this study, a pressure load of lOOkPa was applied for 10 minutes to an area of lcm’ of the trochanter region of subjects lying on their side. A temperature sensoP at the same site was used to measure skin temperature simultaneously (accuracy of
Arch
Phys
Med Rehabil
Vol78,
September
1997
Since temperature measurements stopped 10 minutes after removing the pressure load, it was not possible to calculate the actual latency time, time constant, and total recovery time in cases where the latency time was longer than 600 seconds. For the purposes of statistical analysis, we arbitrarily assigned a latency time and total recovery time of 600 seconds in those cases and used a nonparametric test (Mann Whitney) to determine the significance of the differences between the latency time, time constant, and total recovery time between the groups. The Jonckheere-Terpstra Test, exact versionb was used to determine a trend between the number of years the patient was known to have diabetes mellitus and the blood flow response. The same test was used to investigate the relation between the extent of autonomic neuropathy (E/I ratio) or the glycemic control (HbA,,) and the velocity of the blood flow response. All tests were two sided. For each test, p < .05 was considered significant. All results are expressed as means (2 SD).
RESULTS In 6 of the 18 diabetic patients, latency time was longer than 600 seconds, so no recovery response was measured. In the group of controls every subject had a latency time (or total recovery time) less than 600 seconds. The time constant was known in 12 diabetic patients and all controls. No significant difference in skin temperature between patients and controls was found before the pressure application (table 1). A significant difference between the diabetic patients and the controls was found for latency time, time constant, and total recovery time. A significant difference was also found between the duration of diabetes mellitus and the velocity of recovery of the blood flow (p = .02); the velocity of the blood flow response decreased with increasing duration of diabetes mellitus. No relation was found between the extent of autonomic neuropathy (E/I ratio) or the glycemic control (HbAr,) and the velocity of the blood flow response.
DISCUSSION The response of local blood flow regulation to pressure application is a complex matter. In physiological situations, tissue damage or a short period of ischemia leads to reactive hyperemia, a quick response from the local capillary system, as a result of local vasodilatation in this capillary vascular system. This vasodilatation is strongly determined by the vasodilatating substance nitric oxide (NO), a substance produced by the endothelium. In endothelium dysfunction, NO production is decreased.16-‘* Local autoregulation is known to be impaired in type 1 diabetes.8-‘0.‘2 Vasoregulation is not determined by local autoregulation alone; autonomic nervous regulation also plays Table 1: Results (Mean Patients With Autonomic
f SD) of the PIT Measurements of Diabetic Neuropathy and Healthy Volunteers (n = 33) Diabetic Patients With Autonomic Neuropathy IN = 18)
Initial skin temperature Latency time (set) Time constant (set) Recovery time (set)
32.7 312 339 538
2 2 -c 5
0.6 221 149 (n = 12) 184
Controls (N = 151
33.4 a3 79 162
2 k 5 2
1.9 47 69 103
Significance
p=
.15
p < .Ol p i .Ol p < .Ol
BLOOD
FLOW
RESPONSE
IN DlABETlC
an important role. Decreased functioning of the sympathetic nervous system leads to increased shunting through arteriovenous anastomoses. The consequences of this increase in anastomotic flow may include an increase in tissue temperature and metabolic demand. It may predispose the patient to edema formation, with a subsequent increase in tissue pressure, resulting in a relative impairment of capillary flow. Impaired vasomotion resulting from neuropathy may also decrease tissue perfusionr Although most ulcers in diabetic patients occur in the feet or ankle region, in our study all measurements were done on the trochanteric region, because the FIT method has only been validated for the trochanteric region. Furthermore, measuring at the trochanteric region makes it possible to compare the results of this study with the results of other studies in which the PIT method is used. Since all patients suffered from a proven and distinct cardiac autonomic neuropathy, we may safely assume that autonomic innervation of the trochanteric region was also impaired, although no regional test was done for the assessment of neuropathy. The results of our measurements show that diabetic patients with autonomic neuropathy show a signihcantly delayed (latency) and slower (time constant) blood flow response after relief of a pressure load. Since Mein et al” used the same PTT method in their study concerning the blood flow response after a blockade of the sympathetic nerve system. it is interesting to compare the results of their study with ours. They found that a blockade of the sympathetic nerve system, using spinal anesthesia, resulted in a delayed and slower blood flow response (mean 1~ SD] latency time, I07 [ 2 531 set; time constant, I95 [ 2 I 121 set; and total recovery time. 300 [Z 1461 sec).h These figures show that diabetic patients with autonomic neuropathy have a considerably slower and more delayed blood flow response than rclatively healthy subjects during spinal anesthesia. Therefore, we conclude that the impaired blood flow response in diabetic patients with autonomic neuropathy is not exclusively determined by deterioration in sympathetic functioning. This conclusion is supported by the study of Steel et al.“’ They found, using plethysmography, that all diabetic patients had a significantly slower blood how response compared with healthy controls. The blood flow response of diabetic patients with autonomic neuropathy. however, was considerably slower than that of diabetic patients without neuropathy. Also, other studies have found impaired blood How responses in nonneuropathic patients with type I diabetes mcllitusx ‘(‘.” It is plausible to suggest that in addition to decreased functioning of the sympathetic nerve system. a decreased functioning of the cndothelium must also be of importance in the pathophysiology of an impaired blood flow response. Earlier research showed that a decreased relaxation of diabetic arteries is connected with an increased production of free radicals.“’ The release of these free radicals, accumulated during the ischemic period, has a damaging cffcct during reperfusion on the endothelium (reflow-paradox), which leads to decreased vasoactivity.“.” This phenomenon could account for the slow time constant of diabetic patients. The delayed latency (sometimes longer than IO minutes) found in our diabetic patients shows a similarity with the socalled “no-retlow phenomenon.” which was described earlier in connection with ischemia-rcpcrfusion conditions.“,“’ This “no-rellow phenomenon” that occurs after a period of ischemia is thought to result from swelling of the capillary cndothelium, impairment of microvascular blood fluidity, and a consecutive increase in hydraulic resistance. Based on this assumption, we conclude that the diminished blood flow response in diabetic autonomic neuropathy probably results mainly from damage to
NEUROPATHY,
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Marum
the endothelium and, to a lesser extent, from dysfunctioning of the autonomic nerve system. Unfortunately, we did not have detailed information on the vascular condition of the trochanteric region of the patients. Since it is known that diabetic patients sustain regional atherosclerotic vascular disease rather than uniformly systemic lesions, the area tested may not have been involved equally in all patients, and this may partly account for the variations in blood flow response among the patients. Diabetes mellitus can lead to an increased vascular resistance as a result of specific changes in the capillary wall, hemodynamic change (increased permeability), and blood changes (increased blood viscosity, increased rigidity of erythrocytes). These factors may also contribute to delayed blood flow response.‘5 This study also shows that the blood Bow response decreases with an increased duration of diabetes mellitus. Diabetes mellitus leads to increasing damage to the anatomic structures essential for vasoregulation. In a study among aged somatic nursing home patients, a significant relation was found between the velocity of blood flow response following pressure relief and the risk of developing decubitus ulcers in a period of 4 weeks after the measurements. A decreased velocity of the response corresponded with an increased risk of decubitus ulcers.‘.’ Rccause blood flow response is independent of age, it is reasonable to assume that although the mean age of the subjects in that study was higher than the mean age of the diabetic patients in our study, diabetic patients with autonomic neuropathy have an increased risk of developing decubitus ~lccts.‘~ Our findings also suggest that this risk of developing decubitus ulcers increases with the duration of diabetes mellitus. References
I. Meijer JH. Schut GL, Ribhe M, Goovaens HG. Nieuwenhuys R. Rculen JPH, et al. Method for the measurement of susceptibility to decubitus ulcers formation. Med Biol En8 Comput 1989:27:502-6. 2. Meijer JH, Germs PH. Schneider H, Ribbe MW. Susceptibility to decubitus ulcer formation. Arch Phys Mcd Rchabil 1994;75:31823. 3. Gosnell DJ. Pressure sore risk assessment. Part II. Analysis of risk factors. Decubitus 1989;2:40-3. 4. Centraal Begeleidingsorgaan voor de Intercollegiate Toetsing Herziening consensus decubitus. Utrecht. The Netherlands: Centraal Begeleidingsorgaan voor de lntercollegiale Toetsing; 1992. 5. Flynn MD, Tooke JE. Diabetic neuropathy and the microcirculation. Diabet Med 1995; I2:298-30 I. 6. Mcin CJ, Wagemans MFM. Faes TJC, Meijer JH, Ribbe MW. Stein temperature response to a pressure load: studies in subjects hefore and during spinal anesthesia. Arch Phys Med Rehabil 1995;76:243Ii. 7. Jaap AJ. Hammersley MS, Shore AC, Tookc JE. Reduced microvascular hyperaemia in subjects at risk of developing type 2 (noninsulin-dependent) diabetes meltitus. Diahetologia 1994:37:214-6. 8. Rayman G. Williams SA, Spencer PD. Smaje LH, Wise PH. Tooke JE. Impaired microvascular hyperacmic response to minor skin trauma in type I diabetes. BMJ lOX6;292: 129.5-8. 9. Fans 1. Vagn Nielsen H, Hendriksen 0, Parving HH, Lassen NA. Impaired autoregulation of blood flow in skeletal muscle and suhcutaneous tissue in long term type I (insulin-dependent) diabetic patients with microangiopathie. Diabetologia 1983:25:486-X. 10. Kasuup J, Norgaard T, Parving HH, Hendriksen 0. Lassen NA. Impaired autoregulation of blood flow in subcutaneous tissue ot long term type I (insulin-dependent) diabetic patients with microangiopathy: an index of ancriolar dysfunction. Diahetologia 198.5128: 71 l-7. I I. Katz MA. McNeil1 G. Defective vastdilatation response to exercise in cutaneous precapillary vessels in diabetic humans. Diabetes 1987; 36: 1386-96.
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12. Railton R, Newman P, Hislop J, Harrower ADB. Reduced transcutaneous oxygen tension and impaired vascular response in type 1 (insulin-dependent) diabetes. Diabetologia 1983;25:340-2. 13. McVeigh GE, Brennan GM, Johnston GD, McDermott BJ, McGrath LT, Henry WR, et al. Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1992;35:771-6. 14. Sundkvist G, Almer LO, Lilja B. Respiratory influence on heart rate in diabetes mellitus. BMJ 1979;1(6168):924-5. 15. Tooke JE, Ostergren, Lins PE, Fagrell B. Skin microvascular blood flow control in long duration diabetics with and without complications. Diabet Res 1987;5:189-92. 16. Marin J, Sanchez-Ferrer CF. Role of endothelium-formed nitric oxide on vascular responses. Gen Pharmacol 1990;21:575-87. 17. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993;329:2002-12. 18. Wennmalm A. Endothelial nitric oxide and cardiovascular disease. J Intern Med 1994;235:317-27. 19. Steel M, Nolan C, Nankervis A, Kiers L, Kilpatrick C, Lichtenstein M, et al. Forearm arterial vascular responsiveness in insulin-dependent diabetic subjects. Diabet Res Clin Pratt 1993;21:127-36. 20. Diederich D, Skopec J, Diederich A, Dai FX. Endothelial dysfunction in mesentetic resistance arteries of diabetic rats: role of free radicals. Am J Physiol 1994;266: 1153-61.
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21. Menger MD, Pelikan S, Steiner D, Messmer K. Microvascular ischaemia-reperfusion injury in striated muscle: significance of “reflow paradox.” Am J Physiol 1992;263:Hl901-6. 22. Traystman RJ, Kirsch JR, Koehler RC. Oxygen radical mechanisms of brain injury following ischaemia and reperfusion. J Appl Physiol 1991;7l:Pll85-95. 23. Menger MD, Steiner D, Messmer K. Microvascular ischaemia-reperfusion injury in striated muscle: significance of “no reflow.” Am J Physiol 1992;263:Hl892-900. 24. Jerome SN, Kong L, Korthuis RJ. Microvascular dysfunction in postischemic skeletal muscle. J Invest Surg 1994;7:3-16. 25. Tooke JE. The microcirculation in diabetes. Diabet Med 1987;4: 189-96. 26. Xakellis GC, Frantz RA, Arteaga M, Meletiou S. Dermal blood flow response to constant pressure in healthy older and younger subjects. J Gerontol 1993;48:M6-9.
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Impaired Blood Flow Response Following Pressure Load in Diabetic Patients With Cardiac Autonomic Neuropathy Rob J. van Marum,
MD, Jan H. Meijer, PhD, Frits W. Bertelsmann,
ABSTRACT. van Marum RJ, Meijer JH, Bertelsmann PW, Ribbe MW. Impaired blood flow response following pressure load in diabetic patients with cardiac autonomic neuropathy. Arch Phys Med Rehabil 1997;78:1003-6. Objective: An impaired blood flow response is associated with an increased risk of developing decubitus ulcers. This study investigated whether diabetic patients with autonomic neuropathy show an impaired blood flow response following pressure load, compared with healthy controls. Design: Before-after trial. Setting: University hospital. Patients: Eighteen patients with type I diabetes and autonomic neuropathy, and 15 healthy volunteers. Results: The blood flow responsestarts with a latency period, followed by a temperature increase (described by the “time constant”). The blood flow response in both groups showed significant 0, < .Ol) differences. In diabetic patients, the latency time was 312 + 221sec, the time constant was 339 2 149sec, and the recovery time was 538 2 184sec. In controls, latency time was 83 2 47sec, time constant was 79 + 69sec, and recovery time was 162 2 103sec. The velocity of the blood flow response decreasedwith increasing duration of diabetes mellitus @ = .02). Conclusions: Diabetic patients with autonomic neuropathy show an impaired blood flow response after pressurerelief. This finding suggests that these patients have an increased risk of developing decubitus ulcers. 0 I997 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation
I
N EACH INDIVIDUAL, the impact of pressure load on tissues alters over time. This variation over time depends on factors such as local blood flow regulation.’ Meijer et al’.* studied the effects of pressure application on local blood flow in 109 nursing home aged patients and analyzed the relation between blood flow response and the development of decubitus ulcers. They found a significant relation between the velocity of blood flow recovery after a period of ischemia and the risk of developing decubitus ulcers. A slower recovery of blood flow was related to an increased risk of developing decubitus ulcers. Diabetes mellitus is a disorder in which disturbances of blood llow regulation frequently occur. Therefore, in clinical practice From the Deotimenr of General Practice. Nursine Home Medicine and Social Medicine. Vrij; Universiteit Amsterdam and N&g Home Waerthove. Sliedrecht (Dr. van Marum): Department of Medical Physics and 1nformaticskC.A.R. In\titutc. Vrije Lniversiteit Amsterdam (Dr. Meijer); Department of Neurology, Free University Hospital Amsterdam (Dr. Benelsmann): and Department of Genrrdl Practice. Nursine Home Medicine and Social Medicine. Vriie Universiteit Amsterdam (Dr. Ribge), The Netherlands. Submifted for puhhcation .Vovcmber lg. 1996. Accepted in revised form March
17. IW7. The authors have chosen not to select a disclosure statement. Reprint requests IO R. J. van Matum. MD, Department of General Practice, Nursing Home Medicine and Social Medicine, Vrije Universiteit. Van der Boechorststraat 7. IOXI BT. Amsterdam. The Netherlands. 0 1997 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation
0003-9’)‘)3/97/78fl9-4206$3.oo/o
MD, PhD, Miel W. Ribbe, MD, PhD
diabetes mellitus is often seen as an important risk factor for the development of decubitus ulcers.‘.“ However, evidence for this assumed relationship is circumstantial. In diabetic patients, autonomic dysfunction leads to an increased blood flow through arteriovenenous shunts and, subsequently, to a relatively impaired capillary flow, which increasesthe risk of ulcer development.’ Mein et al” found in a group of healthy patients who underwent minor surgery that blocking the sympathetic nerve system by spinal anesthesia resulted in a decreased recovery of local blood flow following pressure application. In several other studies,‘-13 a decreased vascular response following minor trauma, blood pressure fluctuation, or infusion of vasoactive agents was found in patients with type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus. In this study, we compared blood flow response in diabetic patients who had cardiac autonomic neuropathy, following local pressure application in the trochanter region, a region that is known as a high-risk area for decubitus ulcers, with blood flow response in a group of healthy volunteers. PATIENTS AND METHODS Patients There were 18 patients in the diabetic group, 12 men and 6 women with a mean age (+ SD) of 50 (2 10) years, a median age of 52 years, and a range of 33 to 65 years, who had type 1 diabetes mellitus and were registered as patients at a university hospital’s neurological department. The mean duration (t SD) of diabetes mellitus was 18 (+ 12) years. All patients suffered from cardiac autonomic neuropathy (expiration/inspiration [E/I] ratio [? SD], 1.06 [ + .03]) and showed symptoms of autonomic neuropathy (impotence, orthostatic hypotension, gastropareses, etc). None of the patients had decubitus or diabetic ulcers at the time of measurement and all were in good general health. Glycosylated hemoglobin (HbA,,) ranged from 4.7% to 9.6% (mean [? SD], 7.7% [? 1.41). In all patients, no other possible causesfor the existence of neuropathy other than diabetes mellitus existed (eg, alcohol abuse, malignancies, medication) and no signs were found of peripheral vascular disease (eg, claudicatio intermittens, peripheral necrosis, amputation, etc). All patients consented to participate in the study. The protocol was approved by the university hospital’s Ethical Review Board. Blood flow responses after pressure application in diabetic patients were compared with those of a control group of 15 healthy volunteers, 10 men and 5 women with a mean age (& SD) of 51 (2 11) years, a median age of 52 years, and a range of 34 to 66 years, who, at the time of the study, were not taking any medication. Sample size was calculated based on an (Y = .05 and p = .20. Method The existence of autonomic neuropathy was assessedon the basis of heart rate variations during deep breathing. Lying in a supine position, six deep expirations and inspirations were performed during the recording of a continuous electrocardiogram. The E/I ratio was expressedas the ratio of the mean value Arch
Phys Med
Rehabil
Vol78,
September
1997
1004
BLOOD
FLOW
RESPONSE
IN DIABETIC
NEUROPATHY,
van
Marum
temperature increase following the Lt is described by the time constant (7-T).This time constant equals a temperature increase of 63.2% of the amplitude. The total recovery time is defined as the sum of the latency time and the time constant.
Statistical Analysis
Fig 1. Typical skin temperature response curves following pressure relief. The pressure stimulis is applied at To and removed after 10 minutes at T,. Temperature changes are registered at steps of 0.1%. After pressure relief, there is a latency period (Lt) during which no temperature changes occur, followed by a period during which skin temperature increases [time constant: 7). Lt and r together form the total recovery time. The top curve shows the blood flow response of a 29-year-old healthy man, with a typical rapid increase of skin temperature, including reactive hyperemia. The bottom curve shows the response of a 42-yearold woman with diabetic autonomic neuropathy, in whom the blood flow response is delayed.
of the longest RR intervals during each expiration and the mean of the shortest RR intervals during each inspiration. The existence of autonomic neuropathy was assumed when the E/I ratio was less than or equal to the 5th percentile limit for age-related normal ranges.14 Although the E/I ratio reflects parasympathetic cardiac functioning, based on the duration of diabetes mellitus, one may assume a mixed sympathetic/parasympathetic neuropathy.15 For the determination of blood flow response following pressure application, we used the pressure-time-temperature (PTT) method described by Meijer et al.’ With this noninvasive method, a change in skin temperature in response to a pressure load on the trochanter major can be measured. During the pressure load, skin temperature decreases, whereas it increases again after the pressure load is removed. In a reproducibility test no significant (p > .05) differences were found between repeated measurements.’ In this study, a pressure load of lOOkPa was applied for 10 minutes to an area of lcm’ of the trochanter region of subjects lying on their side. A temperature sensoP at the same site was used to measure skin temperature simultaneously (accuracy of
Arch
Phys
Med Rehabil
Vol78,
September
1997
Since temperature measurements stopped 10 minutes after removing the pressure load, it was not possible to calculate the actual latency time, time constant, and total recovery time in cases where the latency time was longer than 600 seconds. For the purposes of statistical analysis, we arbitrarily assigned a latency time and total recovery time of 600 seconds in those cases and used a nonparametric test (Mann Whitney) to determine the significance of the differences between the latency time, time constant, and total recovery time between the groups. The Jonckheere-Terpstra Test, exact versionb was used to determine a trend between the number of years the patient was known to have diabetes mellitus and the blood flow response. The same test was used to investigate the relation between the extent of autonomic neuropathy (E/I ratio) or the glycemic control (HbA,,) and the velocity of the blood flow response. All tests were two sided. For each test, p < .05 was considered significant. All results are expressed as means (2 SD).
RESULTS In 6 of the 18 diabetic patients, latency time was longer than 600 seconds, so no recovery response was measured. In the group of controls every subject had a latency time (or total recovery time) less than 600 seconds. The time constant was known in 12 diabetic patients and all controls. No significant difference in skin temperature between patients and controls was found before the pressure application (table 1). A significant difference between the diabetic patients and the controls was found for latency time, time constant, and total recovery time. A significant difference was also found between the duration of diabetes mellitus and the velocity of recovery of the blood flow (p = .02); the velocity of the blood flow response decreased with increasing duration of diabetes mellitus. No relation was found between the extent of autonomic neuropathy (E/I ratio) or the glycemic control (HbAr,) and the velocity of the blood flow response.
DISCUSSION The response of local blood flow regulation to pressure application is a complex matter. In physiological situations, tissue damage or a short period of ischemia leads to reactive hyperemia, a quick response from the local capillary system, as a result of local vasodilatation in this capillary vascular system. This vasodilatation is strongly determined by the vasodilatating substance nitric oxide (NO), a substance produced by the endothelium. In endothelium dysfunction, NO production is decreased.16-‘* Local autoregulation is known to be impaired in type 1 diabetes.8-‘0.‘2 Vasoregulation is not determined by local autoregulation alone; autonomic nervous regulation also plays Table 1: Results (Mean Patients With Autonomic
f SD) of the PIT Measurements of Diabetic Neuropathy and Healthy Volunteers (n = 33) Diabetic Patients With Autonomic Neuropathy IN = 18)
Initial skin temperature Latency time (set) Time constant (set) Recovery time (set)
32.7 312 339 538
2 2 -c 5
0.6 221 149 (n = 12) 184
Controls (N = 151
33.4 a3 79 162
2 k 5 2
1.9 47 69 103
Significance
p=
.15
p < .Ol p i .Ol p < .Ol
BLOOD
FLOW
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an important role. Decreased functioning of the sympathetic nervous system leads to increased shunting through arteriovenous anastomoses. The consequences of this increase in anastomotic flow may include an increase in tissue temperature and metabolic demand. It may predispose the patient to edema formation, with a subsequent increase in tissue pressure, resulting in a relative impairment of capillary flow. Impaired vasomotion resulting from neuropathy may also decrease tissue perfusionr Although most ulcers in diabetic patients occur in the feet or ankle region, in our study all measurements were done on the trochanteric region, because the FIT method has only been validated for the trochanteric region. Furthermore, measuring at the trochanteric region makes it possible to compare the results of this study with the results of other studies in which the PIT method is used. Since all patients suffered from a proven and distinct cardiac autonomic neuropathy, we may safely assume that autonomic innervation of the trochanteric region was also impaired, although no regional test was done for the assessment of neuropathy. The results of our measurements show that diabetic patients with autonomic neuropathy show a signihcantly delayed (latency) and slower (time constant) blood flow response after relief of a pressure load. Since Mein et al” used the same PTT method in their study concerning the blood flow response after a blockade of the sympathetic nerve system. it is interesting to compare the results of their study with ours. They found that a blockade of the sympathetic nerve system, using spinal anesthesia, resulted in a delayed and slower blood flow response (mean 1~ SD] latency time, I07 [ 2 531 set; time constant, I95 [ 2 I 121 set; and total recovery time. 300 [Z 1461 sec).h These figures show that diabetic patients with autonomic neuropathy have a considerably slower and more delayed blood flow response than rclatively healthy subjects during spinal anesthesia. Therefore, we conclude that the impaired blood flow response in diabetic patients with autonomic neuropathy is not exclusively determined by deterioration in sympathetic functioning. This conclusion is supported by the study of Steel et al.“’ They found, using plethysmography, that all diabetic patients had a significantly slower blood how response compared with healthy controls. The blood flow response of diabetic patients with autonomic neuropathy. however, was considerably slower than that of diabetic patients without neuropathy. Also, other studies have found impaired blood How responses in nonneuropathic patients with type I diabetes mcllitusx ‘(‘.” It is plausible to suggest that in addition to decreased functioning of the sympathetic nerve system. a decreased functioning of the cndothelium must also be of importance in the pathophysiology of an impaired blood flow response. Earlier research showed that a decreased relaxation of diabetic arteries is connected with an increased production of free radicals.“’ The release of these free radicals, accumulated during the ischemic period, has a damaging cffcct during reperfusion on the endothelium (reflow-paradox), which leads to decreased vasoactivity.“.” This phenomenon could account for the slow time constant of diabetic patients. The delayed latency (sometimes longer than IO minutes) found in our diabetic patients shows a similarity with the socalled “no-retlow phenomenon.” which was described earlier in connection with ischemia-rcpcrfusion conditions.“,“’ This “no-rellow phenomenon” that occurs after a period of ischemia is thought to result from swelling of the capillary cndothelium, impairment of microvascular blood fluidity, and a consecutive increase in hydraulic resistance. Based on this assumption, we conclude that the diminished blood flow response in diabetic autonomic neuropathy probably results mainly from damage to
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the endothelium and, to a lesser extent, from dysfunctioning of the autonomic nerve system. Unfortunately, we did not have detailed information on the vascular condition of the trochanteric region of the patients. Since it is known that diabetic patients sustain regional atherosclerotic vascular disease rather than uniformly systemic lesions, the area tested may not have been involved equally in all patients, and this may partly account for the variations in blood flow response among the patients. Diabetes mellitus can lead to an increased vascular resistance as a result of specific changes in the capillary wall, hemodynamic change (increased permeability), and blood changes (increased blood viscosity, increased rigidity of erythrocytes). These factors may also contribute to delayed blood flow response.‘5 This study also shows that the blood Bow response decreases with an increased duration of diabetes mellitus. Diabetes mellitus leads to increasing damage to the anatomic structures essential for vasoregulation. In a study among aged somatic nursing home patients, a significant relation was found between the velocity of blood flow response following pressure relief and the risk of developing decubitus ulcers in a period of 4 weeks after the measurements. A decreased velocity of the response corresponded with an increased risk of decubitus ulcers.‘.’ Rccause blood flow response is independent of age, it is reasonable to assume that although the mean age of the subjects in that study was higher than the mean age of the diabetic patients in our study, diabetic patients with autonomic neuropathy have an increased risk of developing decubitus ~lccts.‘~ Our findings also suggest that this risk of developing decubitus ulcers increases with the duration of diabetes mellitus. References
I. Meijer JH. Schut GL, Ribhe M, Goovaens HG. Nieuwenhuys R. Rculen JPH, et al. Method for the measurement of susceptibility to decubitus ulcers formation. Med Biol En8 Comput 1989:27:502-6. 2. Meijer JH, Germs PH. Schneider H, Ribbe MW. Susceptibility to decubitus ulcer formation. Arch Phys Mcd Rchabil 1994;75:31823. 3. Gosnell DJ. Pressure sore risk assessment. Part II. Analysis of risk factors. Decubitus 1989;2:40-3. 4. Centraal Begeleidingsorgaan voor de Intercollegiate Toetsing Herziening consensus decubitus. Utrecht. The Netherlands: Centraal Begeleidingsorgaan voor de lntercollegiale Toetsing; 1992. 5. Flynn MD, Tooke JE. Diabetic neuropathy and the microcirculation. Diabet Med 1995; I2:298-30 I. 6. Mcin CJ, Wagemans MFM. Faes TJC, Meijer JH, Ribbe MW. Stein temperature response to a pressure load: studies in subjects hefore and during spinal anesthesia. Arch Phys Med Rehabil 1995;76:243Ii. 7. Jaap AJ. Hammersley MS, Shore AC, Tookc JE. Reduced microvascular hyperaemia in subjects at risk of developing type 2 (noninsulin-dependent) diabetes meltitus. Diahetologia 1994:37:214-6. 8. Rayman G. Williams SA, Spencer PD. Smaje LH, Wise PH. Tooke JE. Impaired microvascular hyperacmic response to minor skin trauma in type I diabetes. BMJ lOX6;292: 129.5-8. 9. Fans 1. Vagn Nielsen H, Hendriksen 0, Parving HH, Lassen NA. Impaired autoregulation of blood flow in skeletal muscle and suhcutaneous tissue in long term type I (insulin-dependent) diabetic patients with microangiopathie. Diabetologia 1983:25:486-X. 10. Kasuup J, Norgaard T, Parving HH, Hendriksen 0. Lassen NA. Impaired autoregulation of blood flow in subcutaneous tissue ot long term type I (insulin-dependent) diabetic patients with microangiopathy: an index of ancriolar dysfunction. Diahetologia 198.5128: 71 l-7. I I. Katz MA. McNeil1 G. Defective vastdilatation response to exercise in cutaneous precapillary vessels in diabetic humans. Diabetes 1987; 36: 1386-96.
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12. Railton R, Newman P, Hislop J, Harrower ADB. Reduced transcutaneous oxygen tension and impaired vascular response in type 1 (insulin-dependent) diabetes. Diabetologia 1983;25:340-2. 13. McVeigh GE, Brennan GM, Johnston GD, McDermott BJ, McGrath LT, Henry WR, et al. Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1992;35:771-6. 14. Sundkvist G, Almer LO, Lilja B. Respiratory influence on heart rate in diabetes mellitus. BMJ 1979;1(6168):924-5. 15. Tooke JE, Ostergren, Lins PE, Fagrell B. Skin microvascular blood flow control in long duration diabetics with and without complications. Diabet Res 1987;5:189-92. 16. Marin J, Sanchez-Ferrer CF. Role of endothelium-formed nitric oxide on vascular responses. Gen Pharmacol 1990;21:575-87. 17. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993;329:2002-12. 18. Wennmalm A. Endothelial nitric oxide and cardiovascular disease. J Intern Med 1994;235:317-27. 19. Steel M, Nolan C, Nankervis A, Kiers L, Kilpatrick C, Lichtenstein M, et al. Forearm arterial vascular responsiveness in insulin-dependent diabetic subjects. Diabet Res Clin Pratt 1993;21:127-36. 20. Diederich D, Skopec J, Diederich A, Dai FX. Endothelial dysfunction in mesentetic resistance arteries of diabetic rats: role of free radicals. Am J Physiol 1994;266: 1153-61.
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21. Menger MD, Pelikan S, Steiner D, Messmer K. Microvascular ischaemia-reperfusion injury in striated muscle: significance of “reflow paradox.” Am J Physiol 1992;263:Hl901-6. 22. Traystman RJ, Kirsch JR, Koehler RC. Oxygen radical mechanisms of brain injury following ischaemia and reperfusion. J Appl Physiol 1991;7l:Pll85-95. 23. Menger MD, Steiner D, Messmer K. Microvascular ischaemia-reperfusion injury in striated muscle: significance of “no reflow.” Am J Physiol 1992;263:Hl892-900. 24. Jerome SN, Kong L, Korthuis RJ. Microvascular dysfunction in postischemic skeletal muscle. J Invest Surg 1994;7:3-16. 25. Tooke JE. The microcirculation in diabetes. Diabet Med 1987;4: 189-96. 26. Xakellis GC, Frantz RA, Arteaga M, Meletiou S. Dermal blood flow response to constant pressure in healthy older and younger subjects. J Gerontol 1993;48:M6-9.
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