Aldose reductase inhibitors: the end of an era or the need for different trial designs?

Despite numerous attempts over 16 years, the results of aldose reductase inhibitor (ARI) trials for the treatment of diabetic neuropathy have not proven efficacy. This paper reviews each of the ARI trials, examines confounding factors, and proposes a future course. The confounding factors considered are pharmacokinetics (ARI penetration of human nerve), length of trial (in terms of the natural history of diabetic neuropathy), trial endpoints (reversibility or slowing of progression), reproducibility of clinical measurements (in terms of power calculations), standardization and quality control of endpoints, and clinically meaningful differences in endpoints. We conclude that ARIs are most likely to have a beneficial effect in the management of diabetic distal symmetrical polyneuropathy and autonomic neuropathy but that the clinical role of ARIs is to slow the progression of diabetic neuropathy rather than to reverse it. Future trials should be designed with adequate statistical power, with consideration of the variability of the endpoint measurements for long enough duration, and with rigorous quality control to definitively confirm the utility of ARIs in the treatment of diabetic distal symmetrical polyneuropathy and autonomic neuropathy.

Cardiovascular autonomic nervous system tests: determination of normative values and effect of confounding variables.

OBJECTIVE: To determine normative values for heart rate variation to deep breathing (VAR) and Valsalva ratio (VAL) as well as the effect of various confounding variables on these measures using data from a large group of normal subjects collected from multiple centers. RESEARCH DESIGN AND METHODS: VAR and VAL were measured on 611 normal subjects, age range 9-79, from 63 centers and was analyzed at a single Autonomic Nervous System Reading Center. Using simple and stepwise logistic regression the effect of age, gender, height, weight, mean arterial blood pressure (MAP) and body mass index (BMI), on VAR and VAL was evaluated. RESULTS: The 95% normative values range (values at 2.5 to 97.5 percentile) for VAR (n = 580) was 12.8-103.5 (mean 49.7) and for VAL (n = 425) was 1.31-2.97 (mean 1.97). No gender effect was found for either VAR or VAL (p > 0.05). VAR correlated inversely with both age and MAP, while VAL correlated inversely with both age and BMI. Since age is the principal confounding variable for both VAR and VAL, normative values are also presented stratified by age. CONCLUSION: Normative values for VAR and VAL based on a large population sample are presented. However, the values presented may not be valid in patients with morbid obesity or malignant hypertension. These data are applicable for either individual patients or for use in multicenter research trials.

Clinical trials of diabetic neuropathy: past, present, and future.

This article reviews current knowledge of the etiology of diabetic neuropathy and the outcomes and limitations of previous trials and discusses future directions for the investigation of its prevention and treatment. Proposed mechanisms for the development of diabetic neuropathy have been widely studied. It has been shown that there is improvement of nerve function associated with some short-term clinical trials of treatments that address a number of possible etiologic pathways. Improvement of morphometry has also been demonstrated in some short-term clinical trials. However, with the exception of the Diabetes Control and Complications Trial (DCCT), long-term trials with adequate statistical power to evaluate clinical outcome endpoints have not been conducted. The changes in nerve function are similar in most of the clinical trials. For instance, in four clinical trials directed at separate mechanisms (improved glucose control, high myo-inositol diet, therapy with an aldose reductase inhibitor, and therapy with supplementary gamma-linolenic acid), a similar improvement in peroneal motor velocity of 1-2 m/s is observed. This implies that each of the proposed mechanisms contributes equally to the development of neuropathy or that there is some redundancy to their mechanisms. In addition to an etiologic approach, nonspecific neural stimulants, such as gangliosides and nerve growth factors, have also been investigated for the treatment of diabetic neuropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

A highly successful and novel model for treatment of chronic painful diabetic peripheral neuropathy.

OBJECTIVE: To investigate why, in spite of a vast variety of treatment agents, the alleviation of pain in patients with diabetic neuropathy is difficult. Previous studies have not used a treatment algorithm based on anatomic site and neuropathophysiological source of the neuropathic pain. RESEARCH DESIGN AND METHODS: A model that categorizes the types of pain into three groups (superficial, deep, and muscular) was applied in 75 diabetic patients with chronic (> 12 mo) painful distal symmetrical polyneuropathy in a controlled case series. Twenty-two patients were untreated and 53 patients were treated with imipramine +/- mexiletine for deep pain, capsaicin for superficial pain, and stretching exercises and metaxalone +/- piroxican for muscular pain. Each type of pain was scored separately on a scale of 0 (none) to 19 (worst), and the total of all three types was used as an index of overall pain. Ability to sleep through the night was scored by a scale of 1 (never) to 5 (always). RESULTS: No significant differences were observed in initial pain scores, sleep scores, demographics, biochemistries, or physical findings between the two groups. After 3 mo a significant improvement in scores was noted in the treated but not the untreated patients. In addition, a significant difference was found in the change of scores between the treated and untreated patients: total pain (-18 +/- 2 vs. 0 +/- 2), deep pain (-7 +/- 1 vs. 0 +/- 1), superficial pain (-5 +/- 1 vs. 0 +/- 1), muscular pain (-6 +/- 1 vs. 0 +/- 1), and sleep (1.2 +/- 0.2 vs. 0.2 +/- 0.2), all P < 0.0001. In treated patients 21% became pain-free (total pain < 2), 66% had improvement (decrease in total pain > 5, but not total elimination of painful symptoms), and 13% were considered treatment failures (a decrease in total pain of < or = 5). This compares with 0 (P < 0.02), 10 (P < 0.0001), and 90% (P < 0.0001), respectively, in the untreated patients. CONCLUSIONS: This study presents a new rationale and hypothesis for the successful treatment of chronic painful diabetic peripheral neuropathy. It uniquely bases the treatment algorithm on the types and sources of the pain.

Morphologic, biochemical, and molecular evidence of apoptosis during the reperfusion phase after brief periods of renal ischemia.

A multiparametric analysis to demonstrate that even brief periods of arterial clamping can initiate extensive cell loss in a rat kidney through the process of apoptosis during the 48-hour period after reperfusion was performed. Microscopic examination of rat renal tissues subject to a 5-, 30-, or 45-minute period of complete ischemia showed the presence of apoptotic bodies both within and occasionally between renal tubules, appearing as early 12 hours after reperfusion, and increasing in numbers at 24 hours. Furthermore, DNA extracted from such reperfused renal tissue demonstrated the appearance of a distinct "ladder" pattern of DNA fragments after electrophoresis in agarose gels, a phenomenon commonly associated with cells undergoing apoptosis and in contrast to the predominant smear pattern obtained after electrophoresis of DNA extracted from necrotic renal tissue. Finally, messenger RNA (mRNA) encoding sulfated glycoprotein-2, a gene product previously identified to apoptotic renal cells, was found to be highly expressed in the 30-minute arterial clamped rat kidney after 24 hours of reperfusion, but was not detectable in mRNA extracted from renal tissue after 24 hours chronic infarction. This study demonstrates that a combination of morphologic, biochemical, and molecular markers can be used to distinguish predominant modes of cell death in varying forms of tissue injury. Application of these analytical techniques to renal vascular injury has distinguished that brief periods of complete ischemia initiates a form of cell death (apoptosis) during a subsequent reperfusion phase that is drastically different from cellular necrosis induced by prolonged severe ischemia.

Use of residual volume as a marker for enteral feeding intolerance: prospective blinded comparison with physical examination and radiographic findings.

High gastric residual volumes (RVs) are a frequent cause for cessation of total enteral nutrition (TEN). This study was designed to determine the RV that indicates intolerance or inadequate gastric emptying and to compare the RV findings in a blinded fashion with those findings obtained on physical examination and radiography. Twenty healthy normal volunteers (HNV), 8 stable patients with gastrostomy tubes (GTP), and 10 critically ill patients (CIP) were evaluated prospectively for 8 hours while receiving TEN. No subjects were clearly intolerant (ie, vomiting, aspiration). Of the total RVs recorded, 13.1% were greater than or equal to 150 mL in the CIP group, whereas only 2.4% of the RVs were greater than or equal to 150 mL in the HNV group. None of the RVs in the GTP group were greater than or equal to 150 mL. Objective scores on physical examination failed to correlate with RV (p = .397), as did objective scores on radiography (p = .742). However, objective scores on physical examination were significantly related to scores on radiography (p = .016). Abnormal physical examination findings were found in 4 out of 11 patients (GTP + CIP) with RVs less than 100 mL and in 6 out of 7 with RVs greater than or equal to 100 mL. Abnormal radiographic results were found in 6 out of 11 patients with RVs less than 100 mL, in 7 out of 7 patients with RVs greater than or equal to 100 mL, and in 4 out of 20 HNVs. There was no difference in RVs obtained from the supine or right lateral decubitus positions.(ABSTRACT TRUNCATED AT 250 WORDS)

Creative fund-raising for nursing homes. An additional revenue source in tough economic times.

Nursing home administrators and sponsors should look to fund-raising as a way to increase their facilities' revenues. The board should first appoint a development coordinator and a special board to be responsible for the fund-raising program. The nursing home can reach potential contributors by regularly sending printed material to specially selected persons from its mailing list. The staff must know the procedures to follow when someone wants to make a donation (e.g., to whom the check should be made payable). To generate interest and to motivate contributors, the fund-raising board should identify specific needs for which the contributions will be solicited. A computer program can help keep track of to whom acknowledgements must be sent. Options for a fund-raising program include memorial and honor gifts, gifts in kind, grants and special gifts, special events, deferred gifts, educational programs, and membership clubs.

Diabetic autonomic neuropathy--Part I. Autonomic nervous system data analysis by a computerized central unit in a multicenter trial.

To determine the feasibility of utilizing a central, computerized unit to analyze autonomic nervous system function tests for a 10-year, multicenter, clinical trial, the Autonomic Nervous System Reading Center was established. The Reading Center selected and standardized testing methods, designed the testing protocol, developed testing equipment, computerized data analysis, and instituted measures to monitor data quality. Three cardiovascular testing methods, RR-variation, Valsalva maneuver, and postural testing, were selected because each is a simple, non-invasive, quantitative, sensitive, and reproducible test. Furthermore, a hierarchy of sensitivity has been established with these cardiovascular autonomic nervous system measurements: RR-variation, Valsalva maneuver, and finally postural testing. Confounding variables were minimized by prescribing eligibility criteria. Testing equipment, designed to record time between RR intervals in a form easily read into a computer, has been in 21 clinics for three years and a total of 54 technicians have been trained. Over 85 percent of the autonomic nervous system tests performed have been usable at initial testing. A central reading center is an efficient and necessary means of collecting and analyzing data for a multicenter clinical trial.

Diabetic autonomic neuropathy--Part II. Coefficient of variation of RR-variation and Valsalva maneuver tests.

To confirm the reliability and validity of cardiovascular autonomic nervous system tests, RR-variation and Valsalva maneuver, coefficient of variation for triplicate tests was calculated. The testing data were collected from patients participating in the Statil Neuropathy Trial. Triplicate testing was done within a three-week period at three different time points: baseline, 12 months, and 18 months. BMDP Statistical Software was used in the analysis. There is no significant difference between the coefficients of variation between clinics for either RR-variation or Valsalva maneuver tests. The coefficient of variation of pooled data was not significantly different from the coefficient of variation of individual clinics. Furthermore, there was no evidence that there was a significant worsening of coefficient of variation with time. Thus, RR-variation and Valsalva maneuver provide reliable and reproducible results that do not vary in consistency over time.

The effects of aging and how they alter care.

Geriatrics, which is still a young medical specialty, is only just beginning to discover how the elderly react to illness and treatment. One of the discoveries is that the elderly do not always respond or show symptoms in the same way as a younger patient. Some basic understanding of the effects of aging on a person can lead to useful strategies in meeting the elderly's needs. A lack of understanding about changes in the elderly's sense organs probably causes the most frustration in the relationship between the elderly patient and the care provider. The ability to see diminishes in approximately 20 percent of the elderly. Approximately one third experience a hearing loss. The elderly have a decreased number of taste buds, especially those affecting sweet and salty tastes. Their ability to perceive pain, pressure, and temperature may decrease as well. The healthcare professional should be aware of the difference in the geriatric data base from that at other life stages and should look for clues that the elderly patient is suffering from diminished senses.

Ministry forges a special bond between a parish and a hospital.

What happens when a parish and a hospital join forces to help meet the physical, social, and spiritual needs of patients? The patients benefit, the hospital benefits, and the parish benefits. A Twining Ministry has expanded patient care at Mercy Hospital in Urbana, Il, where people from St. Matthew's parish in neighboring Champaign volunteer at the hospital. The parish and the hospital teamed up for this effort when Sr. Myra Lambert, SSCM, working in the Pastoral care Department at Mercy, set out to develop closer ties with Catholic parishes in the community. Meanwhile, St. Matthew's was looking for ways parishioners could get involved in a ministry that extended beyond parish boundaries. The hospital chose the 25-bed rehabilitation unit as the focal point of the ministry. St. Matthew's recruited volunteers; Mercy trained them. About 50 volunteers are currently involved in the ongoing program. They assist by helping plan and carry out a variety of activities inside and outside the hospital. They visit patients and provide temporary homes for patients' families; they offer transportation, make phone calls, and do mailings for support groups. They also help with meals, write and read letters, take patients for walks, and transport them to other service areas in the hospital.

Creating a quality assurance program for long-term care.

A system approach to quality assurance in long-term care facilities considers residents' total environment and all aspects of their livers--physical, social, psychological, spiritual, and intellectual. This approach lends a holistic perspective to quality assurance, expanding it from a "numbers game" to an integral part of the facility's philosophy. In developing measurement criteria for a quality assurance program, staff should not overlook systems, procedures, and reporting mechanisms already in place that may provide useful data. Some of these systems include risk management activities, continuing education programs, compliance reports, clinical affiliations, performance reviews, and peer review and administrative audits. Residents and their families are key sources of information about the quality of care. In addition to surveying these groups, long-term care facilities also should involve their resident councils in the quality assurance process.

Assessing retirement needs of women religious.

Religious institutes must plan to meet the financial needs of their retired members and must consider the environment, living arrangements, and quality of life after retirement. Recently ServantCor, a Catholic human services system based in Kankakee, IL, helped two institutes of religious women plan a more comprehensive retirement program by developing a model for them to assess their retirement needs. The model was based on information from eight sources: The institute's current practice. Projected demographic data on number of retired sisters and number of infirmary beds that would be needed over the next two decades. Questionnaires on all the sisters' perceptions of retirement. Interviews with selected sisters concerning issues covered in the questionnaires. Site visits to residences for retired sisters. Geriatric services available in the area where the largest number of retired sisters lived. Retirement programs for other religious institutes in the area. The adequacy of the institute's financial resources. At one institute, focus groups with older laypersons also were held to determine ministry possibilities in the area. Six months after the studies' completion, the provincials of the two institutes said that it helped them in planning to meet the sisters' future infirmary needs. They cited an increased awareness of the need for a holistic approach to retirement. The provincial at one institute said that members' attitude toward the infirmary had improved. At the other institute, they obtained a broader perspective on ministry possibilities to the elderly in the area.