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 less than 20 mmHg.

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.

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 colorimetric 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 = 0.946, P less than 0.001), the two procedures estimate different glycosylated fractions. The colorimetric 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 colorimetric method, but not by column chromatography, are reproducible on hemolysates or packed erythrocytes on the subsequent determination of GHb by both methods. Determinations of GHb by the colorimetric method, but not by column chromatography, are reproducible on hemolysates or packed erythrocytes stored frozen for at least 5 mo. A unique advantage of the colorimetric procedure is the capability to estimate GHb levels when variant hemoglobins, including fetal and sickle hemoglobins, are present.

Outpatient management of uncomplicated lower-extremity infections in diabetic patients.

Most diabetic foot infections are believed to be caused by both aerobic and anaerobic bacteria and to require hospitalization and parenteral antimicrobial therapy. We prospectively evaluated diabetic patients with non-limb-threatening lower-extremity infections not yet treated with antibiotics. The patients were randomized to outpatient treatment with oral clindamycin hydrochloride or cephalexin for 2 weeks and evaluated every 3 to 7 days. In 56 assessable patients, curettage yielded a mean of 2.1 microorganisms. Aerobic gram-positive cocci were isolated in 50 cases (89%), and were the sole pathogen in 21 (42%) of these. Aerobic gram-negative bacilli and anaerobes were isolated in 20 (36%) and 7 (13%) cases, respectively, and almost always in polymicrobial infections. Fifty-one infections (91%) were eradicated, 42 (75%) after 2 weeks of treatment; only 5 (9%) were initially treatment failures, and 3 (5%) were subsequently cured with further outpatient oral antibiotic treatment. After a mean follow-up of 15 months, no further treatment was required in 43 (84%) of the cured patients. Previously untreated lower-extremity infections in diabetic patients are usually caused by aerobic gram-positive cocci, and generally respond well to outpatient management with oral antibiotic therapy.

Glycosylated hemoglobin and fasting plasma glucose in the assessment of outpatient glycemic control in NIDDM.

Interpreting measurements of fasting plasma glucose (FPG) and glycosylated hemoglobin (GHb) is subject to inherent limitations. The time course of change in GHb cannot be reliably specified in the individual patient, nor do single measurements of GHb convey any information regarding recent change or stability in glycemic control. To evaluate whether the clinical utility of these measurements may be extended, sequential measurements of FPG and GHb were examined from 16 outpatients with NIDDM followed over periods of 12 successive weeks or longer, including intervals following cessation of prior therapy or initiation of new hypoglycemic therapy with glipizide. In some individuals as well as groups of patients, changes in GHb followed patterns previously described by mean changes among groups of patients. Differing from those patterns, however, other individuals demonstrated prompt improvement in GHb following substantial improvement in FPG, confirming that patterns of change described from group means do not apply to all circumstances of changing glycemic control, though they may represent the most common. By using measurements of both FPG and GHb obtained on a single occasion to calculate a third parameter, called the glycosylated hemoglobin index (GHb-1), accurate information could be obtained regarding changes in glycemic control which occurred over intervals of 1-4 wk prior to the measurements. By this approach the utility of GHb measurements in the management of outpatients with NIDDM may be extended beyond retrospective description of the "average" prior metabolic control to include assessment of recent changes in glycemia, either deterioration or improvement.

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 to 80 amputations. Defining causal pathways that predispose to diabetic limb amputation suggests practical interventions that may be effective in preventing diabetic limb loss.

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.

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 greater than .05) with recent antibiotic treatment, age, race, or clinical duration of diabetes but was inversely correlated (P less than .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.

Insulin, pancreatic polypeptide, and glucagon antibodies in insulin-dependent diabetes mellitus.

To assess the possible value of the use of high-purity pork insulin (HPPI) in the United States, the serum insulin (I), pancreatic polypeptide (PP), glucagon (G), and somatostatin (SRIF) antibody binding characteristics have been determined in 90 conventional insulin-treated diabetic subjects and related to their degree of metabolic control, as assessed by glycosylated hemoglobin (HbA1) concentration. All diabetic subjects had antibodies to insulin, but there was no relationship between any of the antibody binding characteristics and HbA1 level: 47% possessed PP antibodies; mean +/- SEM HbA1 in these patients was 14.5 +/- 0.3%, identical to those without PP antibodies (14.5 +/- 0.4%); 10% had G binding antibodies with HbA1 levels of 14.6 +/- 0.8%, similar to those without G antibodies. No subject possessed SRIF antibodies. This lack of correlation between antibody characteristics and metabolic control makes it unlikely that, in the majority of patients, treatment with a less immunogenic insulin (HPPI) versus conventional insulin will result in improved diabetic control.

Comparative clinical reliability of fasting plasma glucose and glycosylated hemoglobin in non-insulin-dependent diabetes mellitus.

Because accurate determination of glycosylated hemoglobin (GHb) is difficult and relatively expensive in comparison with the modest cost and ready availability for tests of fasting plasma glucose (FPG), we examined the reliability of repeated measurements of FPG and GHb in typical diabetic outpatients taken in the usual clinical setting. We determined FPG and GHb concurrently on three separate occasions spanning 4 wk in 41 patients with non-insulin-dependent diabetes mellitus (NIDDM) and, for contrast, 5 with insulin-dependent diabetes mellitus (IDDM). Most of the NIDDM subjects were obese, with initial FPG levels ranging from 93 to 355 mg/dl. The reliability of each test was estimated by calculating two measures: the intraclass correlation coefficient (rho I) and the coefficient of variation (CV) for the repeated test values. For NIDDM patients treated with diet or oral hypoglycemic agents (OHA), rho I for FPG, log(FPG), and GHb were very similar. For insulin-treated NIDDM patients, rho I for FPG was somewhat lower than the coefficient in other treatment groups, and the reliability of FPG by this measure did not match the reliability of GHb within the limits of statistical significance. By analyzing the CV of test values repeated within subject, the reliability of FPG did not differ from GHb in any of the NIDDM treatment groups. Although patients were recruited sequentially to minimize sample selection bias, caution must be exercised in the interpretation of the statistical analyses of reliability with either rho I or CV due to limitations imposed by small sample size.(ABSTRACT TRUNCATED AT 250 WORDS)

NIDDM and prevalence of nasal Staphylococcus aureus colonization. San Luis Valley Diabetes Study.

Previous studies of hospitalized and ambulatory patients have found a higher prevalence of Staphylococcus aureus nasal colonization in diabetic than nondiabetic subjects. We examined this association in a geographically based study among 551 residents of the San Luis Valley of Colorado and found no statistically significant increase in the relative risk of nasal S. aureus colonization in 188 non-insulin-dependent diabetic (NIDDM) versus 363 nondiabetic subjects (relative risk 1.3, 95% confidence limits 0.9-1.8). Adjustment for confounding by age, sex, ethnicity, county of residence, and frequency of hospitalizations or physician visits in the previous year did not affect the results. Among the diabetic subjects, S. aureus colonization was not associated with type of treatment for diabetes, level of glucose control, clinical duration of diabetes, or frequency of hospitalizations or physician visits in the previous year. In this population-based study, diabetes mellitus did not increase S. aureus nasal colonization, suggesting that factors other than diabetes mellitus may have caused the higher colonization rate found in previous clinic-based studies.

Ascorbic acid metabolism in diabetes mellitus.

Competition for membrane transport between glucose and ascorbic acid (AA) has been shown in vitro in human lymphocytes, granulocytes, and fibroblasts. Therefore, we examined the effects of acute administration of i.v. glucose on AA levels in mononuclear (MNL) and polymorphonuclear leukocytes (PMN) and on leukocyte chemotaxis. Plasma glucose and AA, MNL AA, PMN AA, and chemotaxis by MNL and PMN were measured before and after i.v. glucose in fasted normal male volunteers. A decline in AA occurred in PMN as well as MNL, but decreases in AA induced acutely by transient hyperglycemia were not associated with changes in chemotaxis. However, under conditions of prolonged hyperglycemia maintained by a glucose clamp technique, significant changes (p less than 0.01) in chemotaxis by both PMN and MNL were observed after 210 and 240 min, with changes in chemotaxis to several chemoattractants significantly correlated with decreases in intracellular AA after 240 min (p less than 0.05). These results are consistent with the hypothesis that chronic hyperglycemia may be associated with intracellular deficits of leukocyte AA, an impaired acute inflammatory response, and altered susceptibility to infection and faulty wound repair in patients with diabetes.

The diabetic foot. Soft tissue and bone infection.

Diabetic patients, as a consequence of various neurologic, vascular, and metabolic perturbations, are at high risk for developing infections of the soft tissue and bones of the feet. The microbial etiology of soft tissue in infections is best determined by cultures of a tissue curetting or aspiration, rather than a swab. Aerobic gram-positive cocci are the major pathogens in diabetic foot infections; these may be the sole isolate(s) in acute uncomplicated infections, but they are usually accompanied by aerobic gram-negative bacilli or anaerobes in chronic or previously treated infections. Carefully selected patients with mild infections can be treated as outpatients with oral antibiotics, but others require hospitalization and broad-spectrum parenteral antibiotics. Bone infections are frequently diagnosed on the basis of roentgenographs and nuclear medicine scans, but these methods are often inaccurate, and bone cultures should be obtained whenever possible.

Definitions and guidelines for assessment of wounds and evaluation of healing.

BACKGROUND: Chronic wounds represent a worldwide problem. For laboratory and clinical research to adequately address this problem, a common language needs to exist. OBSERVATION: This language should include a system of wound classification, a lexicon of wound descriptors, and a description of the processes that are likely to affect wound healing and wound healing end points. CONCLUSIONS: The report that follows defines wound, acute wound, chronic wound, healing and forms of healing, wound assessment, wound extent, wound burden, and wound severity. The utility of these definitions is demonstrated as they relate to the healing of a skin wound, but these definitions are broadly applicable to all wounds.

Validity and reliability of a self-administered health history questionnaire.

A self-administered, health history questionnaire devised for routine use in a general medical clinic is completed without the assistance of clinic personnel and used, unedited, by the providers. The reliability and validity of the responses of 23 patients to this questionnaire were tested statistically. In our setting, more than 90 percent of the patients referred for care are capable of completing the questionnaire. The 23 patients averaged 32 minutes to complete the questionnaire. An average of 34 minutes of encounter time is required to obtain the same historical data by interview. Test-retest reliability of patients' responses to the questionnaire was 90 percent. More than 92 percent of the patients' written responses to health history items agreed with the data obtained in a blinded fashion by internists in the traditional interview. The questionnaire accurately obtains items of history frequently missing from the recorded ambulabory care data base, and in some instances obtains items of history more effectively than the interviewing physician. The study results showed a low incidence of false positive (1.8 percent) and false negative (2.8 percent) responses to questionnaire items.

Foot ulceration and infections in elderly diabetics.

Foot lesions occur commonly among patients with diabetes, particularly the elderly and those with sensory neuropathy. Because of serious or recurrent infections and impaired healing processes, initially trivial lesions may progress to chronic nonhealing wounds, gangrene, or untreatable infections that can lead to limb amputation. Strategies to prevent amputation depend on understanding the multifactorial nature of diabetic foot disease; providing effective ongoing preventive care, including patient education; and prompt and aggressive treatment of foot lesions when they occur. The approach to treatment of infections depends on many factors, including the severity of the soft tissue infection, whether or not underlying bone or joints are involved, the types of infecting organisms, the patient's social situation, and his other medical problems. Proper diagnostic studies followed by appropriate antimicrobial therapy and local wound care can usually lead to resolution of these potentially serious infections.

Treatment of lower respiratory infections in outpatients with ofloxacin compared with erythromycin.

To assess the safety and efficacy of a ten-day oral course of ofloxacin (400 mg 12 hourly) as compared with erythromycin (400 mg every 6 hours) for treatment of lower respiratory tract infections, fifty-two adult outpatients with pulmonary infiltrates (pneumonia) or with a cough and purulent sputum (bronchitis) were evaluated. Expectorated sputum specimens were Gram-stained and cultured, and antibody titres to Mycoplasma pneumoniae, Legionella pneumophilia, and in most cases Chlamydia pneumoniae were measured on acute and convalescent serum samples. Patients were evaluated clinically, microbiologically and radiographically three to five days after concluding therapy; the incidence of adverse reactions was monitored throughout the study period. The ofloxacin group (N = 25) was comprised of nineteen patients with pneumonia and six patients with bronchitis. The erythromycin group (N = 27) was comprised of thirteen patients with pneumonia and fourteen patients with bronchitis. All fifty-two patients were either clinically improved or cured after therapy. Microbiological cure was documented in all fourteen cases (27%) in which causative pathogens were identified. Clinical cure was achieved with ofloxacin in 68% of patients with pneumonia and in 83% of patients with bronchitis, while clinical cure with erythromycin was achieved in 46% of patients with pneumonia and 54% of patients with bronchitis. Adverse reactions (mostly mild gastrointestinal or central nervous system symptoms) were reported by eight patients receiving ofloxacin and four patients receiving erythromycin. While the types of adverse effects were similar, ofloxacin showed a trend toward a higher rate of cure than erythromycin. Ofloxacin is a promising new antibiotic for the treatment of acute lower respiratory infections.

Paradoxical transcutaneous oxygen response to cutaneous warming on the plantar foot surface: a caution for interpretation of plantar foot TcPO2 measurements.

We examined the effect of cutaneous warming on the transcutaneous oxygen measurement (TcPO2) at standard locations below the knee, on the dorsal foot, on the plantar right great toe, and on the plantar surface under the second metatarsal head of 656 diabetic and 16 nondiabetic subjects. All subjects underwent a directed medical history, physical examination, and neurovascular lower extremity evaluation and assessment of autonomic neuropathy. Associations between autonomic neuropathy and TcPO2 were tested using two-way analysis of variance and multiple linear regression. An unexpected, statistically significant fall in TcPO2 occurred with cutaneous warming from 37 degrees C to 44 degrees C on the plantar great toe surface that did not differ by presence of autonomic neuropathy, or the presence of diabetes (mean change: -8.82 mmHG, 95% confidence interval [CI]: -7.70 to -9.93). The TcPO2 measured at the plantar metatarsal head site also fell with cutaneous warming from 37 degrees C to 44 degrees C (mean change: -9.67 mmHG, 95% CI: -7.75 to -11.59). As expected, the TcPO2 increased with cutaneous warming from 37 degrees C to 44 degrees C on the dorsal foot site (mean rise:= 35.61 mmHg, 95% CI: 34.18 to 37.04). The mean TcPO2 at any site did not differ by presence of autonomic neuropathy at either 37 degrees C or 44 degrees C. We conclude that cutaneous warming leads to a paradoxical fall in TcPO2 on the plantar foot surface that does not depend on the presence of autonomic neuropathy or diabetes. Caution in interpretation of ambient versus warmed plantar TcPO2 values is recommended.

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.