Roger E. Pecoraro

Pathways to diabetic limb amputation. Basis for prevention.

We defined the causal pathways responsible for 80 consecutive initial lower-extremity amputations to an extremity in diabetic patients at the Seattle Veterans Affairs Medical Center over a 30-mo interval from 1984 to 1987. Causal pathways, either unitary or composed of various combinations of seven potential causes (i.e., ischemia, infection, neuropathy, faulty wound healing, minor trauma, cutaneous ulceration, gangrene), were determined empirically after a synthesis by the investigators of various objective and subjective data. Estimates of the proportion of amputations that could be ascribed to each component cause were calculated. Twenty-three unique causal pathways to diabetic limb amputation were identified. Eight frequent constellations of component causes resulted in 73% of the amputations. Most pathways were composed of multiple causes, with only critical ischemia from acute arterial occlusions responsible for amputations as a singular cause. The causal sequence of minor trauma, cutaneous ulceration, and wound-healing failure applied to 72% of the amputations, often with the additional association of infection and gangrene. We specified precise criteria in the definition of causal pathway to permit estimation of the cumulative proportion of amputations due to various causes. Forty-six percent of the amputations were attributed to ischemia, 59% to infection, 61% to neuropathy, 81% to faulty wound healing, 84% to ulceration, 55% to gangrene, and 81% to initial minor trauma. An identifiable and potentially preventable pivotal event, in most cases an episode involving minor trauma that caused cutaneous injury, preceded 69 of 80 amputations. Defining causal pathways that predispose to diabetic limb amputation suggests practical interventions that may be effective in preventing diabetic limb loss.

Risk Factors for Amputation in Patients with Diabetes Mellitus: A Case-Control Study

OBJECTIVE To identify and quantify risk factors for lower extremity amputation in persons with diabetes mellitus. DESIGN Case-control study. SETTING A Veterans Affairs medical center. PATIENTS Eighty patients having amputation associated with diabetes and 236 diabetic controls without limb lesions were enrolled before surgery from the 21,167 inpatient care and outpatient surgical patients seen at the Seattle Veterans Affairs Medical Center during a 30-month period. MEASUREMENTS Selected vascular, neuropathic, environmental, health care, self care, nutritional, metabolic, lifestyle, and psychosocial risk factors were measured in all patients before surgery. RESULTS Statistically significant risk factors identified from analysis included insufficient mean below-knee and foot cutaneous circulation (odds ratio, 161; 95% CI, 55.1 to 469); ankle-arm blood pressure index less than 0.45 (odds ratio, 55.8; CI, 14.9 to 209); absence of lower leg vibratory perception (odds ratio, 15.5; CI, 8.3 to 28.7); low levels of high-density lipoprotein (HDL) subfraction 3 less than or equal to 0.7 mumol/L (odds ratio, 4.9; CI, 2.9 to 8.3); and no previous outpatient diabetes education (odds ratio, 3.2; CI, 1.6 to 6.6). A logistic regression analysis done to control for the potentially confounding effects of age; race; socioeconomic status; diabetes duration, type, and severity confirmed these findings and added a statistically significant interaction between foot transcutaneous oxygen tension and peripheral vascular disease history. Clinical interventions to alter these risk factors were identified, including aggressive treatment of infection, diabetes education, protective footwear, and preventive footcare. CONCLUSIONS Multiple risk factors exist along the continuum of conditions and events leading to lower extremity amputation in diabetes. Modification of certain risk factors by patients and health professionals may reduce the risk for amputation and thus decrease the human and dollar costs that accompany limb loss in this prevalent chronic disease.

The Independent Contributions of Diabetic Neuropathy and Vasculopathy in Foot Ulceration: How Great Are the Risks?

OBJECTIVE To describe the relative contributions of neurological and vascular abnormalities to the overall risk of diabetic foot ulceration. RESEARCH DESIGN AND METHODS A case-control study of diabetic veterans from the Seattle Veterans Affairs Medical Center was conducted using data collected from 46 patients with diabetic foot ulcers and 322 control subjects. Neuropathy was determined by vibratory, monofilament, and tendon reflex testing. Macro-vascular disease was measured by ankle-arm blood pressure index, and cutaneous perfusion was measured by transcutaneous oxygen tension (TcPO2) on the dorsal foot. A multi variate logistic regression model was used to adjust for confounding variables and to calculate the odds ratios (ORs) for each independent risk factor. RESULTS Three variables were significant independent predictors of foot ulceration: absence of Achilles tendon reflexes (adjusted OR 6.48, 95% confidence interval [CI] 2.37–18.06), insensate to the 5.07 monofilament (adjusted OR 18.42, 95% CI 3.83–88.47), and TcPO2 <30 mmHg (adjusted OR 57.87, 95% CI 5.08–658.96). Absent vibratory sensation and low ankle-arm blood pressure index were not significant independent risk factors. CONCLUSIONS Both neuropathy and vasculopathy are strong independent risk factors for the development of diabetic foot ulcers. In our model, the strongest risk factor is impaired cutaneous oxygenation. However, in the clinical setting, sensory examination with a 5.07 monofilament probably remains the single most practical measure of risk assessment.

Chronology and Determinants of Tissue Repair in Diabetic Lower-Extremity Ulcers

The natural history of tissue repair and the critical determinants of faulty healing of diabetic ulcers remain obscure despite recent advances in our knowledge of the cellular physiology of normal cutaneous healing. To characterize the chronology and identify important factors affecting healing, we applied an objective method to quantify the rate of wound healing of full-thickness lower-extremity ulcers in 46 diabetic outpatients who received local wound care under a standardized clinical protocol. The initial ulcer healing rate, eventual status of tissue repair, and definitive clinical outcome were not significantly associated with age; diabetes type, duration, or treatment; level or change in glycosylated hemoglobin; current smoking; presence of sensory neuropathy; ulcer location or class; initial infection; or frequency of recurrent infections. However, direct measures of local cutaneous perfusion, estimated by periwound measurements of transcutaneous O2 tension (TcPo2) and transcutaneous CO2 tension (TcPco2), were significantly associated with the initial rate of tissue repair (P = 0.003 and 0.005, respectively). The strong prediction of early healing by these parameters of local skin perfusion was independent from the effects of segmental Doppler arterial blood pressure at the dorsalis pedis, although eventual ulcer reepithelialization was significantly related to foot blood pressure and periwound TcPo2 and TcPco2. We conclude that periwound cutaneous perfusion is the critical physiological determinant of diabetic ulcer healing, indicating a 39-fold increased risk of early healing failure when the average periwound TcPo2 is <20 mmHg.

Comparison of a Colorimetric Assay for Glycosylated Hemoglobin with Ion-exchange Chromatography

Because levels of glycosylated hemoglobin (GHb) are increased in diabetes and reflect the previous metabolic control, clinicians and clinical investigators are finding increasing applications for measurements of GHb in diabetic patients. We report the characterization of a colorimetrie assay procedure for GHb and compare its performance with that of a commonly used assay by ion-exchange chromatography. Although results of GHb determination by both methods correlate highly (r = 0.943, P < 0.001), the two procedures estimate different glycosylated fractions. The colorimetrie procedure is nonstoichiometric, requiring careful standardization of assay conditions, including the concentration of total hemoglobin in the assayed aliquot, to achieve precision and permit comparison of results. We characterized the effect of storage of hemolysates or packed erythrocytes on the subsequent determination of GHb by both methods. Determinations of GHb by the colorimetrie method, but not by column chromatography, are reproducible on hemoly-sates or packed erythrocytes stored frozen for at least 5 mo. A unique advantage of the colorimetrie procedure is the capability to estimate GHb levels when variant hemoglobins, including fetal and sickle hemoglobins, are present.

The Health and Functional Status of Veterans With Diabetes

OBJECTIVE To determine the extent of functional impairment among veterans with diabetes and investigate whether such functional impairment is associated with measures of glycemic control, sensory neuropathy, lower extremity macrovascular disease, or other comorbid conditions. RESEARCH DESIGN AND METHODS A 20-item general health survey (SF-20) developed by the Medical Outcomes Study (MOS) Group, was administered to 577 subjects participating in a prospective study of risk factors for diabetic foot ulceration. Measures of glycemic control and neurovascular disease included GHb, sensory lower extremity neuropathy assessed by aesthesiometry, and segmental lower extremity doppler blood pressures. RESULTS Veterans with diabetes have major decreases in all domains of functional status; 87% were in poor health in terms of physical functioning and 86% in terms of health perceptions. Those with advancing age, symptoms of neuropathy and claudication, and a medical history of complications associated with diabetes had significantly more impairment of health status than those without. GHb values did not correlate with functional status measures. Subjects with neuropathy had statistically significant functional impairment. Subjects with vasculopathy had only two significantly low health status measures. CONCLUSIONS In summary, the findings from this survey reveal that veterans with diabetes have low functional status scores. The presence of symptoms and complications accounts for only part of the impairments experienced by this group.

Hyperglycemia-induced Intracellular Depletion of Ascorbic Acid in Human Mononuclear Leukocytes

It has recently been reported that glucose and its analogues inhibit in vitro ascorbic acid transport across the cell membrane of polymorphonuclear leukocytes and fibroblasts. We have studied the effect of in vivo hyperglycemia on the intracellular ascorbic acid level of mononuclear leukocytes in normal and diabetic human subjects. Administration of an intravenous glucose load resulted in a prompt decrease of mononuclear leukocyte ascorbic acid level in the normal subjects. The rate of its decline correlated closely with the rate of change of plasma glucose. Among the NIDDM subjects in the fasting state, the plasma glucose was high and the leukocyte ascorbic acid level was low when compared with that of the normal subjects. The decrease in the leukocyte ascorbic acid level during disposition of the i.v. glucose load was not statistically significant in the diabetics. The hyperglycemia-induced intracellular depletion of ascorbic acid could be clinically important and requires further evaluation.

Factors Affecting Staphylococcal Colonization Among NIDDM Outpatients

Because colonization with Staphylococcus aureus probably predisposes to staphylococcal infections, we examined several factors that may be associated with staphylococcal carriage in outpatients with non-insulin-dependent diabetes mellitus and in nondiabetic controls. Nose and skin carrier rates for 59 diabetic patients were significantly greater (30.5%) than for 44 controls (11.4%) (P = .02), but rates did not differ significantly between diabetic patients who injected insulin (31.0%) and those who did not (30.0%). Among the diabetic patients, staphylococcal colonization was not significantly correlated (P > .05) with recent antibiotic treatment, age, race, or clinical duration of diabetes but was inversely correlated (P < .03) with glycemic control, as measured by fasting plasma glucose and glycosylated hemoglobin levels. Hospitalization in the previous year was also associated with staphylococcal colonization, and it was significantly more common among the diabetic patients than the controls; however, this did not account for the increased colonization rates observed. Our results in a well-characterized population confirm an increased rate of staphylococcal colonization among diabetic as compared with nondiabetic outpatients but demonstrate that neither injections of insulin nor various pertinent demographic factors explain this finding.

Relationship of patient request fulfillment to compliance, glycemic control, and other health care outcomes in insulin-dependent diabetes

Patients’ perceptions of the extent to which their health care needs have been met may affect compliance with prescribed health behaviors and related health outcomes. The authors examined the relationships of “patient request fulfillment” to patient compliance, glycemic control, and several other health care outcomes in 51 adult outpatients with insulin-dependent diabetes mellitus. On average, patients retrospectively cited 4.5 long-term requests, of which over three-fourths were fulfilled. Fulfillment of these requests was significantly associated with patient satisfaction, perceived health status, fewer insulin reactions, and greater insulin injection time reliability (p<0.05), but not with several other measures of compliance. Higher patient request fulfillment at single visits was correlated, as hypothesized, with subsequent reduction in glycosylated hemoglobin, but this association was not statistically significant. These results suggest that patient request fulfillment is associated with several aspects of health behavior and health status in adults with insulin-dependent diabetes. Further studies are needed to confirm these observations and determine whether strategies to enhance patient request fulfillment can enhance health care outcomes.

Variations in patient compliance with common long-term drugs

An indirect measure of adherence to drug regimens was developed from pharmacy records of prescription refills. This measure was validated by demonstrations of significant relationships between compliance with hydrochlorothiazide and propranolol and expected physiologic effects of these drugs (decreased blood pressures and decreased pulse rates, respectively). The measure was used to survey compliance with 20 common drugs prescribed to 419 outpatients for long-term administration on regular schedules. Eight of the study drugs showed very low levels of compliance, suggesting “take-as-needed” (PRN) use, in spite of medical record, pharmacy record, and label instructions for regular administration. For the whole survey population, 12 truly “non-PRN” drugs showed a considerable gradient in mean compliance rates, ranging from digoxin (76.6 per cent) to hydralazine (50.4 per cent). Within-patient differences in mean compliance with different drugs were shown (e.g., hydrochlorothiazide 61.2 per cent versus potassium chloride 41.2 per cent mean compliance, p < 0.001). Correlations between compliance rates with different drugs in a single regimen were sometimes strikingly low. We conclude that 1) chart and prescription directions for regular administration are not sufficient to identify “non-PRN” drugs in compliance studies; 2) when compliance is an outcome measure in health care trials, drug mix is an important confounding variable; 3) in outpatient clinical settings, it may be appropriate to be inherently more suspicious of noncompliance with some drugs than others; and 4) patients may comply at different rates with individual drug components of a single regimen.