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End-vessel reactivity and capillary clearance in diabetes mellitus
END-VESSEL CLEARANCE JOHN
REACTIVITY IN DIABETES F.
MULLANE,
PERIPHERAL VASCULAR DISEASE often occurs in patients with diabetes mellitus and may be associated with delayed wound healing or with skin ulceration, cellulitis, abscess, or gangrene. On histological examination the skin capillaries have endothelial proliferation [ 1, 31, Altered end-vessel clearance of waste products and increased reactivity to endogenous pressor substances may be important factors in the etiology of the diabetic’s delayed wound healing and susceptibility to infection. The response to intradermal saline and angiotensin has been studied in the diabetic patient to see if capillary clearance was prolonged and if end vessels were hyperreactive to a pressor substance. In addition, nondiawere with atherosclerosis betic patients studied because of the high incidence of atherosclerosis in diabetes mellitus [2, 51.
METHODS Patients included in this study were selected from 319 undergoing consecutive angiotensin skin tests performed on the medical, general surgical, and vascular surgical services. The patient groups selected for statistical analysis of the angiotensin skin test were: (1) diabetes From the Department of Surgery, State University of New York, Downstate Medical Center, Brooklyn, New York 11503. Submitted for publication July 14, 1969.
AND
M.D.,
CAPILLARY MELLITUS PH.D.
mellitus, (2) atherosclerosis, and (3) control. Control values were selected from elective surgical admissions. A patient was excluded from the control group if there was a family history or personal past history of diabetes mellitus, hypertension, and peripheral vascular disease. Atherosclerosis was determined on the basis of both an aortogram and peripheral vascular disease severe enough to warrant either amputation of an extremity or a bypass vascular graft. The criteria for the study were met in 126 of the 319 patients. Angiotensin amide from the same lot number was utilized throughout the study. Each patient received an intradermal injection of 0.1 cc. normal saline containing 0.1 pg. of angiotensin into the anterior surface of the forearm. In addition to having the angiotensin skin test, 43 of the 126 patients also received 0.1 cc. of normal saline intradermally. Both injections were given simultaneously into the same forearm, 6 cm. apart and parallel. A wheal with induration was noted in all persons with both saline and angiotensin. When first injected, angiotensin always gave an intense blanching, whereas, more often, the saline did not. The test doses were observed till there was complete disappearance of blanching and induration. During the first 4 hours, the forearms were checked a minimum of once every 20 minutes and thereafter, once every 30 minutes. 101
JOURNAL
OF
SURGICAL
Table 1.
RESEARCH
Number
Control Diabetic Atherosclerotic
10
NO.
2,
Skin Test
Angiotetin
Group
VOL.
50 65 11
Angiotensin Skin Test (minutes) 161 f 58 262 f 88 178 & 53
Group Comparison P
C vs. D
C vs. A
D vs. A
RESULTS
The average value and standard deviation for the angiotensin skin test in the study groups is presented in Table 1 together with statistical analysis for group comparison. The diabetic and atherosclerotic patients differed significantly from the controls. The atherosclerotic patient was less reactive than the diabetic. Although the mean values were significantly different, there was overlap in the values of all groups, The duration of the angiotensin amide skin test is compared with the intradermal injection of 0.1 cc. normal saline in Table 2. The control and diabetic patients reacted significantly longer to the intradermal angiotensin than to saline. The diabetic patient reacted longer to saline than did the control.
DISCUSSION
An increased susceptibility to infection and delayed wound healing in the diabetic may be due to an insulin lack [4] or to abnormalities of metabolic pathways. However, vascular perfusion and clearance factors are Table 2.
Group
Number
FEBRUARY
probably also of importance. Since the patient with diabetes mellitus in this study had a prolonged reactivity to intradermal angiotensin and delayed capillary clearance of saline, these end-vessel abnormalities may also promote infection and slow wound healing by reducing the perfusion of oxygen, nutrients, and antibiotics to the cells and by interfering with local capillary clearance of waste products. Prolonged reactivity to intradermal angiotensin in the diabetic patient was not related to the markedly increased incidence of atherosclerosis known to occur in the diabetic since there was a highly significant difference between the diabetic and nondiabetic atherosclerotic patient in reacting to the angiotensin skin test. Local capillary clearance may be a contributing factor to the increased reactivity to angiotensin since the diabetic patient took significantly longer than the control patient to remove the intradermal saline. The increased end-vessel reactivity of the diabetic patient could also be due to reduced number of capillaries, to altered electrolyte content of the vessel walls, or to altered metabolism of angiotensin. Endothelial proliferation of the skin vessels in the diabetic patient may have accounted for the prolonged clearance of saline.
SUMMARY Capillary clearance and end-vessel reactivity to pressor substances may be factors that could modify wound healing and the response to infection in diabetes mellitus. Angiotensin and saline were injected intradermally in control, diabetic, and atherosclerotic patients to evaluate this hypothesis. Capillary clearance of saline and end-vessel
Intradermal Angiotensin Angiotensin (minutes)
1970
and Saline
Saline
Avs. S (P)
Control Diabetic
12 31
189 +- 54 290 2 84
138 -+ 32 173 f 68
C vs. D
P
102
MULLANE:
reactivity to angiotensin were both prolonged in the diabetic patient when compared with the control and atherosclerotic patients. Reduced end-vessel perfusion and delayed capillary clearance could combine with the metabolic abnormalities of diabetes mellitus to facilitate the development of infection and to interfere with wound healing.
REFERENCES 1. Aaegenaes, O., and Moe, H. Lightmicroscopic study of skin capillaries Diabetes 10:253, 1961.
and electronof diabetics.
END-VESSEL
REACTIVITY
AND
CAPILLARY
CLEARASCE
2. Bell, E. T. Incidence of gangrene of the extremities in non-diabetic and diabetic persons, Arch. Path. (Chicago) 49:469, 1950. 3. Blumenthal, H. T., Hirata, Y., Owens, C. T., and Bems, A. W. A histo- and immunologic analysis of the small vessellesion of diabetes in the human and the rabbit. In Siperstein, M. D., Colwell, A. R., Sr., and Meyer, K. (Eds.), Small Blood Vessel Involvement in Diabetes Mel&s. Washington: Amer. Institute of Biological Sciences, 1964. P. 279. 4. Rosen, R. G., and Enquist, I. F. The healing wound in experimental diabetes. Surgery 50:525, 1961. 5. Waddell, W. R., and Field, R. A. Carbohydrate metabolism in atherosclerosis. Metabolism 9:800, 1960.
103
REACTIVITY IN DIABETES F.
MULLANE,
PERIPHERAL VASCULAR DISEASE often occurs in patients with diabetes mellitus and may be associated with delayed wound healing or with skin ulceration, cellulitis, abscess, or gangrene. On histological examination the skin capillaries have endothelial proliferation [ 1, 31, Altered end-vessel clearance of waste products and increased reactivity to endogenous pressor substances may be important factors in the etiology of the diabetic’s delayed wound healing and susceptibility to infection. The response to intradermal saline and angiotensin has been studied in the diabetic patient to see if capillary clearance was prolonged and if end vessels were hyperreactive to a pressor substance. In addition, nondiawere with atherosclerosis betic patients studied because of the high incidence of atherosclerosis in diabetes mellitus [2, 51.
METHODS Patients included in this study were selected from 319 undergoing consecutive angiotensin skin tests performed on the medical, general surgical, and vascular surgical services. The patient groups selected for statistical analysis of the angiotensin skin test were: (1) diabetes From the Department of Surgery, State University of New York, Downstate Medical Center, Brooklyn, New York 11503. Submitted for publication July 14, 1969.
AND
M.D.,
CAPILLARY MELLITUS PH.D.
mellitus, (2) atherosclerosis, and (3) control. Control values were selected from elective surgical admissions. A patient was excluded from the control group if there was a family history or personal past history of diabetes mellitus, hypertension, and peripheral vascular disease. Atherosclerosis was determined on the basis of both an aortogram and peripheral vascular disease severe enough to warrant either amputation of an extremity or a bypass vascular graft. The criteria for the study were met in 126 of the 319 patients. Angiotensin amide from the same lot number was utilized throughout the study. Each patient received an intradermal injection of 0.1 cc. normal saline containing 0.1 pg. of angiotensin into the anterior surface of the forearm. In addition to having the angiotensin skin test, 43 of the 126 patients also received 0.1 cc. of normal saline intradermally. Both injections were given simultaneously into the same forearm, 6 cm. apart and parallel. A wheal with induration was noted in all persons with both saline and angiotensin. When first injected, angiotensin always gave an intense blanching, whereas, more often, the saline did not. The test doses were observed till there was complete disappearance of blanching and induration. During the first 4 hours, the forearms were checked a minimum of once every 20 minutes and thereafter, once every 30 minutes. 101
JOURNAL
OF
SURGICAL
Table 1.
RESEARCH
Number
Control Diabetic Atherosclerotic
10
NO.
2,
Skin Test
Angiotetin
Group
VOL.
50 65 11
Angiotensin Skin Test (minutes) 161 f 58 262 f 88 178 & 53
Group Comparison P
C vs. D
C vs. A
D vs. A
RESULTS
The average value and standard deviation for the angiotensin skin test in the study groups is presented in Table 1 together with statistical analysis for group comparison. The diabetic and atherosclerotic patients differed significantly from the controls. The atherosclerotic patient was less reactive than the diabetic. Although the mean values were significantly different, there was overlap in the values of all groups, The duration of the angiotensin amide skin test is compared with the intradermal injection of 0.1 cc. normal saline in Table 2. The control and diabetic patients reacted significantly longer to the intradermal angiotensin than to saline. The diabetic patient reacted longer to saline than did the control.
DISCUSSION
An increased susceptibility to infection and delayed wound healing in the diabetic may be due to an insulin lack [4] or to abnormalities of metabolic pathways. However, vascular perfusion and clearance factors are Table 2.
Group
Number
FEBRUARY
probably also of importance. Since the patient with diabetes mellitus in this study had a prolonged reactivity to intradermal angiotensin and delayed capillary clearance of saline, these end-vessel abnormalities may also promote infection and slow wound healing by reducing the perfusion of oxygen, nutrients, and antibiotics to the cells and by interfering with local capillary clearance of waste products. Prolonged reactivity to intradermal angiotensin in the diabetic patient was not related to the markedly increased incidence of atherosclerosis known to occur in the diabetic since there was a highly significant difference between the diabetic and nondiabetic atherosclerotic patient in reacting to the angiotensin skin test. Local capillary clearance may be a contributing factor to the increased reactivity to angiotensin since the diabetic patient took significantly longer than the control patient to remove the intradermal saline. The increased end-vessel reactivity of the diabetic patient could also be due to reduced number of capillaries, to altered electrolyte content of the vessel walls, or to altered metabolism of angiotensin. Endothelial proliferation of the skin vessels in the diabetic patient may have accounted for the prolonged clearance of saline.
SUMMARY Capillary clearance and end-vessel reactivity to pressor substances may be factors that could modify wound healing and the response to infection in diabetes mellitus. Angiotensin and saline were injected intradermally in control, diabetic, and atherosclerotic patients to evaluate this hypothesis. Capillary clearance of saline and end-vessel
Intradermal Angiotensin Angiotensin (minutes)
1970
and Saline
Saline
Avs. S (P)
Control Diabetic
12 31
189 +- 54 290 2 84
138 -+ 32 173 f 68
C vs. D
P
102
MULLANE:
reactivity to angiotensin were both prolonged in the diabetic patient when compared with the control and atherosclerotic patients. Reduced end-vessel perfusion and delayed capillary clearance could combine with the metabolic abnormalities of diabetes mellitus to facilitate the development of infection and to interfere with wound healing.
REFERENCES 1. Aaegenaes, O., and Moe, H. Lightmicroscopic study of skin capillaries Diabetes 10:253, 1961.
and electronof diabetics.
END-VESSEL
REACTIVITY
AND
CAPILLARY
CLEARASCE
2. Bell, E. T. Incidence of gangrene of the extremities in non-diabetic and diabetic persons, Arch. Path. (Chicago) 49:469, 1950. 3. Blumenthal, H. T., Hirata, Y., Owens, C. T., and Bems, A. W. A histo- and immunologic analysis of the small vessellesion of diabetes in the human and the rabbit. In Siperstein, M. D., Colwell, A. R., Sr., and Meyer, K. (Eds.), Small Blood Vessel Involvement in Diabetes Mel&s. Washington: Amer. Institute of Biological Sciences, 1964. P. 279. 4. Rosen, R. G., and Enquist, I. F. The healing wound in experimental diabetes. Surgery 50:525, 1961. 5. Waddell, W. R., and Field, R. A. Carbohydrate metabolism in atherosclerosis. Metabolism 9:800, 1960.
103