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The Differential Diagnosis of Joint Pain: Hemochromatosis
Hemochromatosis is the most common inherited metabolic condition in Western populations. An estimated 10 percent of persons of northern European descent carry the autosomal recessive gene, and one person in 250 is affected by the disease. The basic disorder of iron metabolism results in excessive absorption of iron and deposition in the tissues. Traditionally, hemochromatosis has been suspected only when the classic triad of cirrhosis, diabetes and skin pigmentation indicate advanced disease and irreversible tissue damage. McCurdie and Perry review the various presentations of hemochromatosis, particularly the potential savings through prevention of morbidity and mortality that is associated with early diagnosis.
Arthropathy occurs in approximately 64 percent of patients with hemochromatosis. Although joint pain was originally thought to be a late symptom of hemochromatosis, it is reported by 45 percent of patients at the time of diagnosis and may be the presenting complaint or the most severe presenting symptom in a majority of new cases. The typical patient is male (male-to-female ratio: 9:1), 40 to 60 years of age and likely to have a family history of hemochromatosis, cirrhosis or diabetes. The disease presents insidiously with symptoms such as lethargy, weakness, sleep disturbance or sexual problems. Patients with joint symptoms report arthralgias for an average of three years before diagnosis. Although any joint may be affected, the second and third metacarpophalangeal joints are characteristically stiff, painful and tender. Radiographs show small cysts and hooked osteophytes at the metacarpal heads. Patients may also present with early onset of osteoarthritis, especially in the hips, or with episodes of pseudogout. Pseudogout results from deposition of calcium pyrophosphate, usually in the wrists, knees, hips and symphisis pubis, and may occur in up to 72 percent of cases.
The authors advocate wider screening using family history, clinical signs of liver disease and diabetes, serum ferritin concentration, liver function tests, serum glucose concentration and radiography of symptomatic joints. The single most useful value is serum ferritin, which exceeds 1,000 ng per mL (1,000 µg per L) in patients with hemochromatosis, compared with normal adult values of up to 330 ng per mL (330 µg per L) in men and 120 ng per mL (120 µg per L) in women. First-degree relatives of patients with confirmed hemochromatosis should also undergo screening.
The treatment of hemochromatosis is regular venisection to deplete body iron stores. Weekly venisection may be required initially, but most patients require maintenance venisection only four to eight times per year. Once treatment is established, arthropathy improves in 30 percent of patients, worsens in 20 percent and is unchanged in the remainder. The development of diabetes and cirrhosis appears to be delayed or prevented, and the life expectancy of regularly treated patients is reported to be normal.
The authors report illustrative cases and urge consideration of hemochromatosis in the differential diagnosis of adults presenting with exercise-related or other joint pains. Early diagnosis can prevent the development of serious, irreversible complications.
ANNE D. WALLING, M.D.
McCurdie I, Perry JD. Haemochromatosis and exercise related joint pains. BMJ February 13, 1999;318:449-51.
Elevated Serum Creatinine Levels in Severe Hypothyroidism
The decreases in renal plasma flow and glomerular filtration rate (GFR) that accompany hypothyroidism are believed to be related to the generalized hypodynamic state of the circulatory system in hypothroidism. Elevation of serum creatinine levels is not generally mentioned as an abnormality that occurs in association with hypothyroidism, although reports of such an association exist. Kreisman and Hennessey evaluated serum creatinine levels in 24 consecutive patients with iatrogenically induced hypothyroidism in conjunction with treatment of thyroid carcinoma.
Serum creatinine concentrations and thyroid function tests were determined before, during and after the brief period of severe hypothyroidism, when no thyroid hormone was administered for the two weeks before administration of radioiodine. Severe acute hypothyroidism was defined as a thyroid-stimulating hormone value greater than 40 µU per mL (40 mIU per L); normal range: 0.3 to 5.0 µU per mL (0.3 to 5.0 mIU per L).
The creatinine level was increased in 26 of 29 episodes (90 percent) of hypothyroidism in a subgroup of 15 patients in whom creatinine values were obtained during the euthyroid state before induction of hypothyroidism. The mean hypothyroid creatinine values were significantly greater during hypothyroidism than during the euthyroid state. Creatinine values increased by 34.4 percent after induction of hypothyroidism.
Similarly, serum creatinine levels were significantly higher during hypothyroidism in a subgroup in which creatinine levels were determined both during hypothyroidism and after the return to euthyroidism. The mean hypothyroid creatinine value was significantly greater in 33 of the 36 episodes (92 percent). The mean hypothyroid value was 1.15 mg per dL (102 µmol per L), compared with 0.85 mg per dL (75 µmol per L) during the euthyroid state following the period of hypothyroidism. Serum creatinine values above the normal range occurred in six of the 36 hypothyroid episodes.
The rise in creatinine levels during hypothyroidism was not associated with abnormal creatine kinase levels or other evidence of hypothyroid myopathy or intrinsic renal disease. The findings demonstrated that very little time is required for the development of elevated serum creatinine levels during the hypothyroid state. The results argue against the previously held notion of a net unchanged creatinine value because of a balance between the decrease in renal clearance and a decrease in creatinine generation.
The authors conclude that the hypothyroid state is associated with a consistent elevation in the serum creatinine level, presumably related to a decrease in the GFR. The changes in serum creatinine levels develop rapidly and appear to be reversible. It may be clinically relevant to know of this association in that it could account for creatinine elevation in a patient with hypothyroidism. It should also alert the clinician to consider evaluation of thyroid function in a patient who has a modest serum creatinine elevation but whose thyroid status is unknown.
BARBARA APGAR, M.D., M.S.
Kreisman SH, Hennessey JV. Consistent reversible elevations of serum creatinine levels in severe hypothyroidism. Arch Intern Med January 11, 1999;159:79-82.
Acute Pancreatitis: Identifying Patients at Greatest Risk
Acute pancreatitis can cause death or morbidity in a significant number of cases. If the patients most vulnerable to poor outcomes could be detected early in the course of the disease, aggressive intervention could reduce morbidity and mortality rates. Talamini and colleagues assessed the effectiveness of a screening protocol based on chest radiographs and serum creatinine measurements that would allow high-risk patients with acute pancreatitis to be rapidly identified without the use of sophisticated diagnostic procedures.
Over 500 patients admitted to three Italian hospitals for treatment of acute pancreatitis were included in the study. The patients' ages ranged from 42 to 77 years, and just over one half of the patients were men. Necrotizing pancreatitis was diagnosed in 30.2 percent of the cases. Twenty patients died.
The rate of mortality correlated significantly with pleural effusions or pulmonary densities on chest radiography. Serum creatinine values greater than 2 mg per dL (177 µmol per L) were also significantly correlated with mortality. When both indicators were present, the mortality rate was 52.6 percent. The etiology of pancreatitis was only marginally associated with mortality. Idiopathic cases of pancreatitis were associated with mortality rates three times higher than those associated with biliary- or alcohol-associated cases. Logistic regression using multiple factors showed only serum creatinine level and abnormal chest radiograph to be factors associated with death. When either or both of these factors were positive, the sensitivity and specificity to predict mortality were 90 percent and 76 percent, respectively. These two factors also predicted necrotizing pancreatitis (sensitivity 60 percent and specificity 88 percent) and infected necrosis (sensitivity 73 percent and specificity 75 percent).
The authors conclude that this system of identifying patients at highest risk from acute pancreatitis compares favorably in accuracy to established scoring systems such as the Ranson, Glasgow and Hong Kong systems. The new system has the advantage of being very easy to use and requiring only two measures, both of which are likely to be available within a short time of onset of symptoms-- even in centers where sophisticated facilities are lacking.
ANNE D. WALLING, M.D.
Talamini G, et al. Serum creatinine and chest radiographs in the early assessment of acute pancreatitis. Am J Surg January 1999;177:7-14.
Preventing Recurrence of Depression in the Elderly
Depression is common in old age, affecting an estimated one in six elderly patients in medical practice and even more in nursing homes and hospitals. The risk of recurrence is higher if the first episode of depression occurs in old age. To study the effectiveness of measures to prevent recurrent depression in the elderly, Reynolds and colleagues conducted a randomized, placebo-controlled trial to compare the effects of nortriptyline, interpersonal psychotherapy and a combination of the two on the prevention of recurrence of major depression in the elderly.
The study included 107 patients who were 60 years of age or older and had been diagnosed as having unipolar major depression. This also had to be at least their second lifetime episode of major depression. The study patients were selected from a group of 180 patients who were enrolled in a study of the acute treatment of depression. The 107 patients continued their participation in the study during the maintenance therapy phase, after depression had been in remission for 16 weeks. There were 69 patients who were 60 to 69 years of age and 38 patients who were 70 years of age or older.
Patients enrolled in the maintenance phase of the study were randomized to one of four treatment groups: nortriptyline plus medication clinic visits (where symptoms and adverse effects were assessed); placebo plus medication clinic visits; monthly interpersonal psychotherapy sessions plus nortriptyline; or monthly psychotherapy sessions plus placebo. For those assigned to the placebo group, the active drug was tapered over a six-week period. Patients continued receiving their assigned therapy for three years or until recurrence of major depression developed. Psychotherapy consisted of 50-minute sessions with experienced psychotherapists.
Assessment of outcomes confirmed that older patients were more likely to have a recurrence of depression. In patients older than 70 years, recurrence developed during the three-year study in three of the nine patients (33 percent) who received nortriptyline and psychotherapy; in six of 11 patients (55 percent) who received nortriptyline and medication clinic visits; in five of eight patients (63 percent) who received placebo and psychotherapy; and in nine of 10 patients (90 percent) who received placebo and medication clinic visits.
In patients between 60 and 69 years of age, recurrence of depression developed in two of 16 patients (13 percent) who received nortriptyline and psychotherapy; in six of 17 patients (35 percent) who received nortriptyline and clinic visits; in 11 of 17 patients (65 percent) who received placebo and psychotherapy; and in 17 of 19 patients (89 percent) who received placebo and clinic visits.
The authors acknowledge that tricyclic antidepressants such as nortriptyline are often not prescribed for the elderly and that selective serotonin reuptake inhibitors (SSRIs) are favored over tricyclic antidepressants. Further studies are warranted to test the use of SSRIs for prevention of recurrence of major depression in the elderly. However, the long-term strategy of psychotherapy plus antidepressant medication (specifically, nortriptyline) may be a cost-effective and clinically effective method of intervention for preventing recurrence of depression in elderly patients.
GRACE BROOKE HUFFMAN, M.D.
Reynolds CF, et al. Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years. JAMA January 6, 1999;281:39-45.
Spouses of Demented Patients: Stress and Immunity
Elderly spouses who care for demented patients undergo substantial physical and psychologic stress. Several studies have documented increased morbidity in these spouses and have suggested a link to depressed immune function. Vedhara and colleagues studied the association between stress levels and immune function in caretakers of demented patients.
Fifty spousal caretakers of demented patients were recruited for the study and matched by age, sex and socioeconomic status with 67 control subjects. None of the study participants had a terminal illness and none was receiving drugs that could affect the immune system. All participants were assessed with the use of a battery of psychologic tests and all provided samples for estimation of cortisol and influenza IgG antibodies at baseline, three months and six months. At the six-month follow-up, trivalent influenza immunization was given to the study participants. Blood samples were taken to estimate IgG antibody response to each of the three vaccine components at seven, 14 and 28 days after immunization.
Throughout the study, scores of emotional distress levels and cortisol levels were significantly higher for the caretakers than for the control subjects. At baseline, caretakers and control subjects did not differ in concentrations of antibodies to any of the influenza vaccine components. Following immunization, 26 of the control subjects (39 percent) had a positive response to at least one of the vaccine components, compared with only eight of the caretakers (16 percent). This difference was statistically significant. The vaccine contained three components, two of which had been included in the influenza vaccination offered in the previous year. The IgG response of caretakers to the new strain was significantly poorer than that of the control subjects, suggesting an association between chronic stress and poor immune function.
The authors conclude that elderly caretakers of demented spouses reported increased levels of distress and showed increased activation of the hypothalamic-pituitary-adrenal axis. One measurable outcome was poor antibody response to influenza vaccine, leaving caretakers more vulnerable to influenza infection despite immunization.
ANNE D. WALLING, M.D.
Vedhara K, et al. Chronic stress in elderly carers of demented patients and antibody response to influenza vaccination. Lancet February 20, 1999;353:627-31.
Summary of Data on Tamoxifen for Prevention of Breast Cancer
Approval of tamoxifen for use in women at increased risk of breast cancer was based on the results of a study reported in September 1998; the study followed 13,175 women for a mean of four years. Medical Letter consultants reviewed the current data on tamoxifen as a prophylactic agent for breast cancer.
Tamoxifen competes with estrogen to bind to estrogen receptors in the cell nucleus, thus altering gene transcription and protein synthesis, and inhibiting the growth of estrogen-dependent tumor cells. In some tissues, however, tamoxifen acts as an estrogen agonist, which relates to its effects on bone mineral density, lipid levels, the endometrium and clotting mechanisms.
The large-scale study of breast cancer prevention with tamoxifen (dosage of 20 mg per day) included women 35 years of age or older with at least one of the following risk factors for breast cancer: (1) an age of 60 years or greater; (2) a history of lobular breast cancer in situ; or (3) an estimated risk of breast cancer within five years that is greater than 1.66 percent. Of the 13,175 women in the study, 244 in the placebo group and 124 in the tamoxifen group developed breast cancer. In the subgroup of women over 60 years of age but otherwise at low risk, breast cancer developed in one of 297 women receiving placebo and in three of 284 women receiving tamoxifen.
Although smaller than the American study and utilizing different eligibility criteria, two European studies failed to demonstrate any effect of tamoxifen on the incidence of breast cancer. The findings from these two studies were also reported in 1998.
The incidence of endometrial cancer was higher in the women receiving tamoxifen. It developed in 18 women in the placebo group and 37 women in the tamoxifen group. All cancers occurring in the tamoxifen group were low grade and diagnosed at an early stage.
The incidence of myocardial infarction and fractures of the hip, spine or radius was similar in the two groups. Tamoxifen was associated with an increased incidence of deep venous thrombosis (35 versus 22 in placebo-treated patients), pulmonary embolism (18 versus six) and stroke (38 versus 24). The incidence of these disorders was increased in women over 50 years of age. Women receiving tamoxifen also had cataract formation more frequently (574 patients compared with 507 patients).
Currently, it is assumed that tamoxifen would need to be taken indefinitely to provide prophylaxis against breast cancer. The authors note that the long-term effects of tamoxifen on mortality are unknown. They estimate that the cost of 20 mg of tamoxifen per day for five years would be $6,000.
BARBARA APGAR, M.D., M.S.
Medical Letter consultants. Tamoxifen for prevention of breast cancer. Med Lett Drugs Ther January 1, 1999; 41(1043):1-2.
EDITOR'S NOTE: Tamoxifen belongs to a new class of drugs called selective estrogen reuptake modulators (SERMs). Clinical trials of a number of SERMs are currently under way. Although raloxifene is marketed for prevention of postmenopausal osteoporosis, it also has been reported to decrease the incidence of breast cancer. Unlike tamoxifen, however, raloxifene has not been associated with an increased risk of endometrial cancer. Nevertheless, clinical use of this agent for prevention of osteoporosis seems to be lagging behind marketing efforts. Symptoms of estrogen deficiency, specifically vasomotor instability, may be slowing clinical acceptance of this agent. Whether or not the physician endorses the use of traditional hormone replacement therapy, the long-term safety issues of hormone replacement therapy are clearer than those connected with the use of SERMs.
B.A.
Does Surgery Relieve the Symptoms of Varicose Veins?
Approximately 15 percent of men and 25 percent of women have visible varicose veins. Symptoms attributed to varicose veins include heaviness, swelling, aching, cramping and itching of the legs. Although the removal of varicose veins costs millions of dollars annually, little objective evidence validates the assumption that surgical therapies ameliorate these symptoms. Bradbury and colleagues used a community study in a city in Scotland to correlate factors such as age, sex and lower limb symptoms with the presence and severity of varicose veins.
They worked with general practitioners to study a representative sample of adults aged 18 to 64 years. The 1,566 study participants attended a special evening clinic or were visited at home by study personnel. Each participant completed an extensive questionnaire concerning the presence of symptoms. Participants were examined using standardized protocols and methods of recording varicosities and related findings. The mean age of the 867 women included in the study was 44.8 years, compared with a mean age of 45.8 years for the 699 men in the study.
Women were more likely than men to report symptoms, but for both sexes the prevalence of symptoms was strongly related to age. The age-adjusted prevalence of trunk varices was higher in men (39.7 percent) than in women (32.2 percent). The most common symptom reported in women was aching (53.8 percent); in men, the most common symptom was cramping (34.0 percent). No differences in symptoms were found between the right and left legs in any of the variables measured. The presence and severity of varices in men was statistically significant only with the symptom of itching. In women, statistically significant correlations were found between the severity of varices and the symptoms of heaviness, aching and itching. Clinically, the level of agreement between these symptoms and the severity of varices was too low to be useful in determining management. For example, in spite of statistically significant correlation, aching was reported by 45 percent of women without evidence of varices and by 63 percent of those with grade 2 or 3 varices.
The authors conclude that the presence of symptoms alone cannot be used to reliably select patients for surgical treatment of varicosities. Lower limb symptoms are very prevalent in adults, irrespective of the presence of varices, and may not be improved by surgery.
ANNE D. WALLING, M.D.
Bradbury A, et al. What are the symptoms of varicose veins? Edinburgh vein study cross sectional population survey. BMJ February 6, 1999:318:353-6.
EDITOR'S NOTE: It is good to see research being conducted on common but unglamorous conditions such as varicose veins; however, the findings from this study raise several issues. The study finds that very large numbers of adults, especially women, have nonspecific leg symptoms about which we understand little and for which we have no therapies based on pathophysiology or clinical trials. This study confirms that some patients have extensive and severe varicosities yet remain asymptomatic; it also throws doubt on the etiology of symptoms commonly attributed to varicosities. The conclusion from this very large and well-conducted study is that surgery for varicose veins may have cosmetic benefits but little or no effect on symptoms. Many health maintenance organizations require well-documented symptoms attributed to varicose veins in addition to poor results from nonsurgical treatments before covering the costs of surgery or sclerosing therapy. Will the results of this study lead to the re-classification of all varicose vein surgery into the "cosmetic" group?
A.D.W.
Orlistat for Weight Control and Risk Factor Reduction
Achieving sustained weight loss is difficult for obese patients, even those who follow a diet and exercise program. Because obesity is associated with an increased risk of morbidity and mortality, a need for a new and effective therapeutic treatment exists. Orlistat is a gastrointestinal (GI) lipase inhibitor that prevents GI uptake of about 30 percent of consumed fat. Davidson and colleagues conducted a randomized, double-blind, placebo-controlled study to test the hypothesis that patients who are treated with orlistat combined with dietary intervention would lose more weight and be better able to maintain the weight loss than patients treated with placebo plus diet. They also studied the effectiveness of orlistat in the reduction of risk factors, such as cardiovascular risk, hypertension and insulin resistance, in obese patients.
The trial included adults whose body mass index was between 30 and 43 kg per m2 and who had not had a weight loss of more than 4 kg (8 lb, 13 oz) in the previous three months. Patients with significant medical or psychiatric problems and patients who used medications that could alter lipid levels or appetite were excluded. Initially, a medical history was taken for all patients. They also had a physical examination, an electrocardiogram and a wide range of laboratory tests. During the four-week lead-in period patients followed a diet that allowed each one a calculated amount of energy per day based on each patient's estimated daily energy requirement. Patients were also given placebo capsules during this time to determine compliance.
At the end of the four-week period, patients were classified into either the group that lost less than 2 kg (4 lb, 6 oz) or the group that lost at least 2 kg. Those who had a treatment compliance of 75 percent or more were then randomized to receive either placebo or 120 mg of orlistat three times per day, along with the low-calorie diet. After one year of treatment, patients who had been taking orlistat and had compliance rates of at least 70 percent were randomized to receive either placebo, or 60 or 120 mg of orlistat three times per day for another year. The patients who had taken placebo continued to use placebo. Patients began a maintenance diet during the second year of the study to prevent or diminish weight regain rather than to continue weight loss. Body weight, the primary outcome measured, was assessed frequently throughout the two-year study period.
Of the 892 patients who were initially enrolled in the lead-in, 880 completed at least one follow-up measurement. There were 591 patients who completed one year of the study, and 403 who completed both years, for a two-year completion rate of 45 percent. Reasons for withdrawal were similar among all groups. The four-week lead-in low-calorie diet led to a weight loss of about 2.3 kg (5 lb, 1 oz) per participant. Subsequently, patients in the orlistat group lost more weight than patients in the placebo group. By the end of the first year, 65.7 percent of patients in the orlistat group had lost more than 5 percent of their initial body weight compared with only 43.6 percent of patients in the placebo group. More than 10 percent of initial body weight was lost by 38.9 percent of patients taking orlistat compared with only 24.8 percent of patients taking placebo. Patients treated with 120 mg of orlistat during the second year had significantly less weight regain than those whose dosage of orlistat was halved and those taking placebo. Two years of taking 120 mg of orlistat led to a 7.6 percent (± 0.9 percent) weight loss. Those who took placebo for two years lost only 4.5 percent (± 0.9 percent) of their initial body weight by the end of the study.
Risk factor reduction was also examined. Patients taking 120 mg of orlistat had a significant reduction in systolic and diastolic blood pressures between weeks zero and 52 of treatment compared with the placebo group. Total cholesterol levels also decreased in the orlistat group, while they rose in the placebo group. This finding was independent of weight loss. The orlistat group had more GI side effects, but generally these were self-limited and only moderate in intensity.
The authors conclude that orlistat, when taken for two years and combined with a hypocaloric diet, can assist obese patients with weight loss and may reduce some obesity-related risk factors.
GRACE BROOKE HUFFMAN, M.D.
Davidson MH, et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat. A randomized controlled trial. JAMA January 20, 1999; 281:235-42.
Is Revaccination with the Pneumococcal Vaccine Safe?
Revaccination with the pneumococcal vaccine is recommended after five years for patients older than 65 who were initially vaccinated before age 65 and for patients age 64 or younger who are immunocompromised. To study the safety of revaccination, Jackson and colleagues compared reactions after first vaccination with those experienced after revaccination among 1,400 patients.
The reactions in 901 patients who received their first vaccination were compared with those in 513 patients who received a second vaccination at least five years after the first one. Patients ranged from 50 to 74 years of age and were excluded if they had reported any significant adverse events following their first pneumococcal vaccination. Each patient kept a diary to record temperature twice daily for the week following the injection. Adverse reactions, including erythema and induration, were recorded for 13 days after the vaccination.
No serious adverse events occurred in any of the patients. Patients who received a second pneumococcal vaccination experienced significantly more injection site reactions than did those who were vaccinated for the first time. Soreness of the arm was reported by 74 percent of the revaccinated group and by 57 percent of the group receiving a first vaccination (relative risk: 1.3).
A sizable local reaction, defined as 10.2 cm of redness, developed in 11 percent of the revaccinated group, compared with 3 percent of the group receiving the vaccine for the first time.
The authors conclude that local reaction is significantly more likely in patients who are revaccinated at least five years after the initial pneumococcal vaccination. However, the redness, swelling and pain are self-limited and do not constitute a reason to not recommend revaccination at the appropriate interval.
GRACE BROOKE HUFFMAN, M.D.
Jackson LA, et al. Safety of revaccination with pneumococcal polysaccharide vaccine. JAMA January 20, 1999;281:243-8.
Determining Capacity to Provide Informed Consent toTreatment
Studies have shown that assessment of a patient's capacity to provide informed consent is likely to be biased if the physician relies on a general impression of the patient's ability to understand the information. Mental status tests, such as the standardized Mini-Mental Status Examination (MMSE), are sometimes used to assess the patient's capacity to consent to treatment. Etchells and associates compared the reliability of three methods of evaluating the patient's capacity to provide informed consent: the standardized MMSE, a specifically designed semistructured capacity assessment and a capacity assessment conducted by experts in this type of evaluation.
Areas and Suggested Questions for Performing the Aid to Capacity Evaluation (ACE)
The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.
Adapted with permission from Etchells E, Darzins P, Silberfeld M, Singer PA, McKenny J, Naglie G, et al. Assessment of patient capacity to consent to treatment. J Gen Intern Med 1999;14:27-34.The study included 100 patients who, at the time of entry into the study, were facing nonemergent decisions about treatment and were either refusing treatment or consenting to treatment but were not clearly capable of making an informed decision. Patients who were clearly capable to make an informed decision and were consenting to treatment were excluded from the study.
The authors developed a semistructured instrument, called the Aid to Capacity Evaluation (ACE), that prompts inquiry into seven relevant areas (see the accompanying table). After each area is assessed, the clinician decides whether the patient is "definitely incapable," "probably incapable," "probably capable" or "definitely capable." Medical residents and senior medical students administered the ACE assessment.
In addition to the ACE, the standardized MMSE was performed, as well as an assessment of capacity by two independent experts. The results of these three measures were compared, and likelihood ratios (LR) were calculated for the ACE and the MMSE.
The expert evaluations revealed that 37 percent of the 100 patients were not capable of making an informed consent to treatment. If the ACE result was "definitely incapable," the probability of incapacity was 92 percent (LR: 20). If the ACE result was "definitely capable," the probability of incapacity dropped to 3 percent (LR: 0.05). If the ACE result was "probably incapable" or "probably capable," the chance that a patient would be improperly classified according to the ACE was increased.
When a patient had a standardized MMSE score of zero to 16, the probability of incapacity was 89 percent (LR: 15), whereas a standardized MMSE score of 24 to 30 decreased the probability of incapacity to 3 percent (LR: 0.05). When an ACE result of "probably incapable" or "definitely incapable" was combined with a standardized MMSE score of zero to 16, the probability of incapacity increased to 96 percent (LR: 40). Similarly, when the ACE result showed that the patient was "probably capable" or "definitely capable" and the MMSE score was 24 to 30, the patient had only a 3 percent probability of incapacity (LR: 0.05).
The authors conclude that a specific instrument to assess capacity, such as the one they developed, can closely agree with an assessment made by an expert and can be administered by medical students, residents or physicians. The combination of the MMSE and a method of assessment like the ACE may provide information about a patient's capacity to consent to treatment.
GRACE BROOKE HUFFMAN, M.D.
Etchells E, et al. Assessment of patient capacity to consent to treatment. J Gen Intern Med January 1999;14:27-34.
Analysis of Patients' Perspectives on Quality Care at the End of Life
Knowing what most patients consider to be quality care at the end of life can be useful when discussing the subject of end-of-life care with patients and family members. To determine which issues are important to patients, Singer and colleagues conducted in-depth interviews of patients to identify which elements of end-of life care are most important to them.
The 126 patients in the study were from three groups: 48 patients on renal dialysis, 40 patients with human immunodeficiency virus (HIV) infection and 38 patients who were residents at a long-term care facility. The subject of end-of-life care was approached initially by asking the participants open-ended questions to elicit information about their views on advance care planning and other issues related to end-of-life care. The interviews proceeded until no new concepts about end-of-life care emerged. The interviews were analyzed qualitatively to classify issues that emerged in the interviews into various categories, or domains.
Domains for Quality Care at the End of Life: Elements Identified in Four Reports
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Reprinted with permission from Singer PA, Martin DK, Kelmer M. Quality end-of-life care: patients' perspectives. JAMA 1999;281;163-8.
Five major domains relating to quality end-of-life care were extracted. The five most prevalent concepts mentioned by the participants were the following: (1) receiving adequate pain/symptom management; (2) avoiding prolongation of dying; (3) having a sense of control; (4) relieving the burden to loved ones; and (5) strengthening relationships with loved ones.
Of these five domains, avoidance of prolonged dying was the one most frequently mentioned, with 77 (61.1 percent) of the 126 participants expressing a concern about "lingering" and "being kept alive" after they no longer could enjoy their lives. Three of the five domains--achieving a sense of control during dying, relieving the burden that dying would pose on loved ones and strengthening relationships with loved ones during the dying experience--were mentioned by a similar number of participants, 48 (38.1 percent) in the first two groups and 49 (38.9 percent) in the third group. The fifth most common domain--receiving adequate pain and symptom control--was cited by 28 (22.5 percent) patients. The sixth most common category was mentioned by less than 5 percent of patients.
The authors conclude that the five domains identified in their study may serve as a conceptual foundation for improving the quality of care at the end of life. When the authors compared the end-of-life issues raised by the patients in their study with those identified in other studies, they found some differences in content. See the accompanying table for a summary of the domains of quality end-of-life care identifed in other studies and in the current study. The authors note that the descriptions of quality end-of-life care obtained from the patients in their study are more straightforward, more specific and simpler than those derived from expert models.
GRACE BROOKE HUFFMAN, M.D.
Singer PA, et al. Quality end-of-life care: patients' perspectives. JAMA January 13, 1999;281:163-8.
Review of Parkinson's Disease and Available Treatments
For every 100,000 people, 150 have Parkinson's disease, and 20 new cases are diagnosed each year. In addition to substantial morbidity and mortality, this disorder has significant costs such as medical care and drug treatment, and loss of earnings. A review by Schapira emphasizes the heterogeneity of the condition and the importance of selecting therapies specific to the needs and tolerances of each patient.
The cause of Parkinson's disease is loss of dopaminergic neurons in the substantia nigra of the midbrain. By the time the classic symptoms of bradykinesia, rigidity and resting tremor become apparent, as much as 70 to 80 percent of the dopaminergic neurons may already have died. It is now apparent that Parkinson's disease can result from any condition that attacks the dopaminergic neurons and is best conceptualized as a syndrome with multiple potential causes. Epidemiologic studies and studies of families with specific subtypes of Parkinson's disease indicate a genetic component, probably linked to aberrations on chromosomes 2, 4 and 6. The only environmental toxin currently linked to Parkinson's disease is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), but various pesticides and herbicides are suspected of contributing to development of the disease.
Current therapy for Parkinson's disease aims to balance amelioration of symptoms with the long-term side effects of medications. Levodopa, enhanced by combination with a dopa decarboxylase inhibitor, is the most common medication in current use; however, its usefulness is limited by motor complications. After five years of treatment, approximately one half of patients treated with levodopa experience dyskinesias and fluctuations in symptom control. Some neurologists recommend initial therapy with a dopamine agonist, beginning with low dosages and initially adding domperidone to relieve nausea and other side effects. The newer dopamine agonists have fewer side effects and may control symptoms for up to four years in a substantial proportion of patients, allowing levodopa to be reserved for more advanced disease with more significant symptoms. Use of selegiline prolongs the action of dopamine and delays the need for additional therapy for about nine months to one year. Recently, concerns have been raised about the safety of selegiline. Other treatments, such as antimuscarinic agents and amantadine, are being used as alternatives to dopamine-related drugs but have significant side effects. Newer drugs include catechol O-methyltransferase (COMT) inhibitors, but there is a risk of hepatotoxicity with these agents. Drugs in development based on biochemical pathways include dopamine reuptake inhibitors and adenosine antagonists.
Two new lines of research focus on neurons rather than biochemical pathways. At least part of the action of current drugs such as selegiline may consist of "neuroprotection" through influence on apoptotic pathways. Studies of cyclosporin A and its derivatives may lead to such drugs, but these will need to be highly selective to avoid adverse effects on the immune system. Other areas of research concern antioxidants, drugs that reduce glutamate neurotoxicity and agents that modulate immune and inflammatory systems only in the relevant areas of the brain.
Surgical treatments are being developed for use in selected patients. Pallidotomy can benefit patients with significant dyskinesias, bradykinesia and rigidity. Tremor may be improved by thalamotomy and by deep brain stimulation of the globus pallidus or the subthalamic nucleus. Experimental fetal nigral implants have improved symptoms in selected patients.
ANNE D. WALLING, M.D.
Schapira AH. Parkinson's disease. BMJ January 30, 1999; 318:311-4.
Hypodermoclysis: A Cure for Moderate Dehydration
The technique of hypodermoclysis, or subcutaneous infusion, was largely abandoned in the 1950s, mainly because complications such as pain, sepsis and shock were often linked to practical errors. Ferry and associates review the advantages and disadvantages of this technique and offer practical guidelines for its use in older patients.
Hypodermoclysis is a simple procedure that may be used in cases of mild or moderate dehydration. It may also be used for the infusion of an amino acid solution for the short-term prevention of malnutrition. Studies have shown that fluids administered subcutaneously are well absorbed; in fact, they are absorbed as well as fluids that are given intravenously. Another advantage of hypodermoclysis is that regulations governing intravenous (IV) line use in a long-term care facility do not pertain to the use of hypodermoclysis. Septicemia and thrombosis are avoided with hypodermoclysis, and the risk of hypervolemia is lower when compared with IV therapy. The patient also has more freedom of movement because of the recommended infusion sites (see accompanying table).
Indications and Contraindications of Hypodermoclysis
Indications Infusion of saline/glucosaline solutions to prevent or to treat mild dehydration Inadequate oral fluid intake because of age-related reduced thirst with fever and anorexia Difficulty in swallowing fluids Uncooperative, agitated, confused or demented patients Transient or mild hyperthermia Fluid loss higher than normal because of diarrhea, vomiting or diuretic treatment Dependence, difficulty with access to fluids and foods Impossibility of increasing oral fluid intake or instigating tube feeding Peripheral veins difficult to puncture Infusion of amino acid solution to limit malnutrition Insufficient short-term food intake Enteral nutrition undesirable in view of confusion or digestive contraindications, e.g., vomiting or fecal compaction Enteral or parenteral nutrition technically impossible Infusion of saline/glucosaline solutions during end-of-life stage Maintaining ease of contact with family and caregivers by avoiding dehydration-related confusion Analgesics and anxiolytics infused subcutaneously with fluids Contraindications Emergency situations: collapse, shock, severe electrolytic disturbance or major dehydration (serum Na >150 mmol per L, osmolality >300 mmol per kg, BUN/creatinine ratio >25) Evident hypocoagulation (whether spontaneous or therapeutic) Severe heart disorders (relative contraindication)
BUN=blood urea nitrogen.
Adapted with permission from Ferry M, Dardaine V, Constans T. Subcutaneous infusion or hypodermoclysis: a practical approach. J Am Geriatr Soc 1999;47:93-5.
The disadvantages of this therapy are that no more than 1.5 L of fluid may be administered at a single perfusion site, and there is a brief delay before the fluid reaches the intravascular space. One side effect that was reported occasionally several decades ago was vascular collapse, related to the infusion of large quantities of solutions without electrolytes. This effect is prevented by adding 2 to 4 g of sodium chloride to the glucose solution (either 2.5 percent or 5 percent). Another possible solution is isotonic saline (sodium chloride, 0.9 percent). Potassium is not essential but may be added to either of these solutions.
Hypodermoclysis is accomplished with the use of a 21- to 25-gauge butterfly needle attached to the fluid via a single tube with a flow visualization chamber. After strict local asepsis, the needle is introduced at a 45-degree angle into the tissue beneath the skin of the thigh (anterior, lateral or medial aspect), the abdominal wall, the subclavicular regions of the thorax or the back (inter- or subscapular areas). The fluid may be infused as fast as 125 mL per hour (for up to eight hours) or even up to 250 mL per hour (for up to four hours). The infusion site must be changed after administration of 1.5 L of fluid. Although infusion of an amino acid solution may be effective when nutritional status must be supported, this technique does not replace tube feedings or parenteral nutrition regimens.
The authors conclude that hypodermoclysis is a simple and effective method of treating mild to moderate dehydration in elderly patients. Since hospitalization may be avoided with the use of this technique, the patient may also benefit psychologically and financially.
GRACE BROOKE HUFFMAN, M.D.
Ferry M, et al. Subcutaneous infusion or hypodermoclysis: a practical approach. J Am Geriatr Soc January 1999; 47:93-5.
Use of Buccal Midazolam in Childhood Seizures
Prolonged seizures can cause significant morbidity and mortality in children. If seizures last longer than five minutes, status epilepticus is likely to occur, with potentially serious consequences. Prompt, effective treatment at home or school could improve outcomes and possibly prevent hospital admission, but the treatment must be provided in a form suitable for administration by parents, teachers or caretakers. Many caretakers report that the use of rectal diazepam is unacceptable or inconvenient. In addition, there is some concern that rectal administration could contribute to allegations of sexual abuse. Liquid medications absorbed directly through the buccal mucosa may provide an alternative to rectal diazepam. Scott and colleagues compared the effectiveness of rectal diazepam with that of buccal liquid midazolam in children with continuous seizures of more than five minutes' duration.
Students living in a residential school for patients with severe disability were included in the study. The midazolam was administered by squirting 2 mL (10 mg) of liquid medication into the side of the mouth using a syringe. When a seizure lasted more than three minutes, treatment was selected by drawing a card to establish randomization. The selected treatment (rectal diazepam or buccal midazolam) was administered unless the jaws were too tightly clenched to administer the liquid midazolam. In these cases, rectal diazepam was administered, but the seizure episode was not included in the study. If the seizure continued for 10 minutes after administration of the study medication, additional therapies were used.
Buccal midazolam was used in 40 episodes and rectal diazepam in 39 episodes of seizure during the study. The treated patients did not differ in age, sex, type of seizure or seizure frequency. Although more patients responded to buccal midazolam (30 of 40 episodes, or 75 percent, compared with 23 of 39 episodes, or 59 percent) and the median time from the administration of medication until termination of the seizure was shorter (six minutes for midazolam compared with eight minutes for diazepam), these differences were not statistically significant. No clinically significant differences in blood pressure, oxygen saturation or other variables were detected between the treatment groups.
The authors conclude that buccal midazolam is effective in the acute treatment of seizures. They report that placing the syringe between the teeth and cheek was readily accomplished even in patients undergoing tonic seizures, and staff members found the administration of small quantities of midazolam easy. They discuss the advantages of the buccal route of administration, especially in adolescents and older children, and conclude that the buccal route may become the preferred method of administration of anti-seizure medications, particularly for seizure events occurring in the community.
ANNE D. WALLING, M.D.
Scott RC, et al. Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet February 20, 1999; 353:623-6.
Do Plant and Pesticide Allergens Have a Place in Patch Testing?
Plant and pesticide allergens are known to cause contact dermatitis but are not used routinely in patch testing. Mark and associates investigated the role of plant and pesticide allergens in contact dermatitis by performing patch tests of these allergens in 26 patients who were suspected of having photodermatitis or airborne allergic contact dermatitis.
Patch and photopatch tests were performed according to the guidelines of the North American Contact Dermatitis Group. Duplicate sets of photoallergens were applied to the back to allow evaluation of the subject's response to patch tests and photopatch tests with ultraviolet B, ultraviolet A and visible light. The responses to ultraviolet light and visible light were quantified on the second day. The patches on the nonirradiated sites were uncovered after 48 hours. The dermal responses were quantified at 48 hours and 96 hours for both the nonirradiated and irradiated sites.
Responses were graded on a scale from 1+ (erythema, infiltration, possibly papules) to 3+ (bullae and ulcers). If the reactions on the patch and photopatch test sites were equivalent, the tests were interpreted as signifying allergic contact dermatitis. If a positive reaction was greater on the photopatch site than on the patch site, both allergic contact dermatitis and photoallergic contact dermatitis were considered to be present. A negative response on patch testing but a positive response on photopatch testing was interpreted as photoallergic contact dermatitis.
Of 26 patients, 12 (46 percent) had positive reactions to patch testing with the plant and pesticide allergens. In five patients, the reactions indicated allergic contact dermatitis; in another five, they indicated photoallergic contact dermatitis; and in two, they indicated both types of contact dermatitis. The allergic contact dermatitis reactions were to dandelion and tansy, and to the pesticides folpet and captafol. The photodermatitis reactions were to the same pesticides. In addition, three of the photoallergic reactions were to sunscreens, six were to fragrances and three were to antibacterial agents.
The authors believe the number of positive reactions in this study can be attributed in part to the inclusion of plant and pesticide allergens in the allergic testing series. They conclude that plant and pesticide allergens should be incorporated into the routine evaluation of photosensitive patients. Contact allergy to dandelion is an important factor in patients with summer exacerbation of dermatitis. Besides environmental exposure to plant and pesticide allergens, the increasingly common use of herbal remedies that contain plant products offers an additional method of exposure to plant allergens. The authors report that four of the 12 study patients with positive responses would not have been given the correct diagnosis if plant and pesticide allergens had been omitted from the testing panel.
BARBARA APGAR, M.D., M.S.
Mark KA, et al. Allergic contact and photoallergic contact dermatitis to plant and pesticide allergens. Arch Dermatol January 1999;135:67-70.
Preventing Complications in Patients with Type 2 Diabetes
Although microvascular complications such as retinopathy, nephropathy and neuropathy cause significant morbidity and mortality, preventive efforts in type 2 diabetes (formerly known as noninsulin-dependent diabetes) have concentrated on prevention of heart disease, stroke and other macrovascular events. Gæde and colleagues investigated the ability of intensive behavior and pharmacologic therapy to slow progression of microvascular complications in high-risk patients with type 2 diabetes as evidenced by microalbuminuria.
Study subjects were recruited from a Danish diabetes clinic. All of the patients met World Health Organization diagnostic criteria for type 2 diabetes, and microalbuminuria was identified by at least four of six urine samples. Patients were randomly assigned to either standard treatment following the recommendations of the Danish Medical Association or to intensive management that incorporated behavior modification and stepwise pharmacologic therapy designed to maximize glucose control and compliance.
All participants received individualized dietary advice. Patients in the intensive-intervention group were counseled to stop smoking and to participate in 30 minutes of light to moderate exercise three to five times per week. Regardless of blood pressure, intensive-intervention patients received an angiotensin-converting enzyme (ACE) inhibitor in a dosage equivalent to 50 mg of captopril twice daily. These patients also received 250 mg of vitamin C and 100 mg of vitamin E, with the intake increased fivefold for those who continued to smoke. Patients with a history of cardiovascular disease were given 150 mg of aspirin daily.
If the hemoglobin A1C (HbA1C) level could not be suitably maintained by diet alone after a three-month trial, hypoglycemic agents were added to the therapeutic regimen, and the dosage was titrated to obtain glycemic control. If combinations of maximum dosages of oral agents failed to bring HbA1C levels within the acceptable range, insulin therapy was substituted for oral hypoglycemic agents. If blood pressure was not adequately controlled by ACE inhibitors, stepwise therapy introducing other agents was used until control was obtained. Statin drugs were used to reduce elevated cholesterol levels, and fibrates were used to reduce elevated triglyceride levels.
In the intensive-therapy group, 73 of 80 randomized patients completed approximately four years of follow-up, compared with 76 of 80 patients assigned to standard therapy. Nephropathy developed in eight patients in the intensive-intervention group, compared with 19 of the usual-care patients. Progression of retinopathy was documented in 19 of the intensive-care patients and in 33 of those treated routinely. Eight of the intensively treated patients and 22 of those in the standard-therapy group had progression of autonomic neuropathy.
The authors conclude that intensive multifactorial intervention may be sustained over several years and may significantly slow progression of the microvascular complications of type 2 diabetes.
ANNE D. WALLING, M.D.
Gæde P, et al. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet February 20, 1999;353:617-22.
Should Patients with CAD Risk Take Antioxidants?
Helping patients lower their risk of coronary artery disease remains an important task for family physicians. Typically, the focus has been on the reduction of risk factors by controlling plasma lipid levels, blood pressure and weight. However, recent advances in the understanding of atherosclerosis have suggested that dietary antioxidants may play a role in preventing primary or secondary coronary artery disease. Specifically, antioxidants may inhibit proatherogenic and prothrombotic events in the coronary arterial wall. Writing for the Nutrition Committee of the American Heart Association, Tribble reviewed the literature to define the potential role of antioxidants in the prevention of coronary artery disease.
Sources of Antioxidants
The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication. Antioxidants derived from dietary sources, including vitamins C and E, and beta-carotene, have received the greatest attention with regard to prevention of coronary artery disease. Many food sources contain antioxidants (see the accompanying table). Foods that contain a-tocopherol (vitamin E) and beta-carotene are of particular interest, as both of these substances are carried within low-density lipoproteins. Also of interest is the role of selenium, copper, zinc and manganese, as these trace elements are believed to act as antioxidants as well.
The American Heart Association evaluated the results of large cohort studies and primary and secondary prevention trials. Large observational studies have shown that consumption of antioxidant-rich foods or supplements reduces the risk of coronary artery disease. The largest of these cohort studies is the Nurses' Health Study, in which 85,000 participants were followed for approximately eight years. The risk of coronary disease was lowest among women with the highest intake of vitamin E. None of the studies reviewed found a link between disease risk and consumption of vitamin C. Even though observational studies support a relationship between disease risk and consumption of dietary antioxidants, evidence from randomized trials on primary prevention is lacking. However, results from secondary prevention trials have been more supportive. For example, the Cambridge Heart Antioxidant Study showed that the risk of myocardial infarction was reduced up to 77 percent in patients who took high dosages of vitamin E.
The author concludes that, given the current evidence, patients should be advised to follow a balanced diet consistent with the dietary guidelines of the American Heart Association, with emphasis on antioxidant-rich fruits, vegetables and whole grains. Diet alone may not provide the levels of vitamin E associated with a lower risk of coronary disease, but the absence of data from randomized trials precludes establishing a general recommendation for vitamin E supplementation.
JIM NUOVO, M.D.
Tribble DL. Antioxidant consumption and risk of coronary heart disease: emphasis on vitamin C, vitamin E, and beta-carotene. A statement for healthcare professionals from the American Heart Association. Circulation February 1999;99:591-95.
Copyright © 1999 by the American Academy of Family Physicians.
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