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Common Questions About Low-Molecular-Weight Heparin
Venous thromboembolic disease is commonly encountered in family practice. Typically, patients are hospitalized and treated with intravenous unfractionated heparin and then converted to oral anticoagulant therapy with warfarin. Because of the inherent heterogeneous nature of "unfractionated" heparin, frequent adjustments in the dose of heparin need to be made to maintain optimal anticoagulation. Litin and associates present a summary of frequently asked questions regarding the use of low-molecular-weight heparin. Their discussion points include the following:
Unfractionated heparin is a mixture of polysaccharide chains with widely divergent molecular weights. Low-molecular-weight heparins are fragments of standard heparin molecules created by enzymatic or chemical depolymerization. Both forms of heparin have the same mechanism of action; namely, they exert an anticoagulation effect by activating antithrombin III. The advantage of low-molecular-weight heparin is that the anticoagulant response is unaffected by individual variation in plasma protein levels.
When the dosage is given on a weight-adjusted basis, the anticoagulant response is predictable. Therefore, laboratory monitoring is unnecessary in most patients. An exception is the patient with renal insufficiency who has a serum creatinine level higher than 2 mg per dL (180 µmol per L). The treatment effect of low-molecular-weight heparin has been shown to be identical to that of regular heparin. Even when administered in the hospital, low-molecular-weight heparin may offer an advantage with regard to ease of administration and less need for monitoring.
Three preparations of low-molecular-weight heparin are now available (ardeparin, dalteparin and enoxaparin), with no clear advantage to any one of the three. The cost of treatment may exceed $80 per day. Patients can be taught to self-administer the prefilled syringes and are instructed to do so twice a day. The injection is usually given subcutaneously on the anterior aspect of the abdomen.
Transition to warfarin follows a similar pattern, with an overlap of four to five days. Patients may remain ambulatory but should be advised to avoid prolonged periods of standing or sitting. Complications other than bleeding are infrequent; however, mild elevations of liver enzyme levels and mild hyperkalemia may occur.
The authors conclude that low-molecular-weight heparin offers a significant advantage to physicians who care for patients with venous thromboembolic disease, allowing a select group of patients to be treated safely and effectively as outpatients.
JIM NUOVO, M.D.
Litin SC, et al. Use of low-molecular-weight heparin in the treatment of venous thromboembolic disease: answers to frequently asked questions. Mayo Clin Proc June 1998;73: 545-51.
Effects of Postpartum Depression on Children
Non-psychotic major depression is estimated to occur in approximately 10 percent of mothers in the early weeks following delivery. Many new mothers appear to be vulnerable to depression in the first three months following pregnancy. Because this illness may result in disturbances of the cognitive and emotional development of the child, Cooper and Murray undertook a major review of postpartum depression.
Little biological basis has been identified for postpartum depression. The incidence may be increased in certain risk groups, including women with a history of depressive disorder, complications during delivery and certain other obstetric factors. Psychologic stressors consistently associated with postpartum depression include unemployment, marital conflict and lack of personal support from family and friends. The strongest association appears to be with previous depression. Attempts to develop predictive models for postpartum depression have achieved only modest sensitivity and specificity. In contrast, the condition may be reliably detected by self-reported scales such as the Edinburgh postnatal depression scale, which has been used in large-scale screening.
Postpartum depression may be initially overlooked by health care professionals but is usually a straightforward diagnosis. Several treatment strategies have been advocated, but few scientific studies have been conducted. No systematic evidence to validate the use of progesterone therapy has been found. One trial revealed a significant improvement in mood in patients who were treated with estrogen compared with placebo. Both fluoxetine and psychologic counseling were also found to be superior to placebo in a controlled trial, but more than one half of the patients declined to take antidepressant medication. Psychologic support has been found to be more effective than routine care in at least three published trials. Although few studies have examined the ways treatment affects the mother-infant relationship, evidence has shown that treatment significantly improves both the mother's mood and the quality of the mother-infant relationship. Children of depressed mothers have been shown to perform more poorly on cognitive tests at 18 months of age than did children of mothers who were not depressed.
The authors conclude that early detection of postpartum depression and early treatment by primary care physicians is important to lessen any disturbance in the relationship of the mother and child. Episodes of postpartum depression usually remit spontaneously two to six months after onset, but residual depressive symptoms may persist beyond one year. This effect was more marked in boys and, in other studies, persisted until five years of age.
ANNE D. WALLING, M.D.
Cooper PJ, Murray L. Postnatal depression. BMJ June 20, 1998;316:1884-6.
Multidrug-Resistant Pneumonia Among Nursing Home Residents
Infection by Streptococcus pneumoniae accounts for more deaths than any other vaccine-preventable bacterial infection. The case fatality rate from pneumococcal bacteremia approaches 40 percent in elderly patients. Of great concern in the United States is the growing number of drug-resistant strains of S. pneumoniae. Resistant strains have been identified in certain settings, such as day care centers, hospitals and a pediatric long-term care facility, but epidemics of drug-resistant pneumococcal disease have not been previously reported among adults. Nuorti and associates of the Centers for Disease Control and Prevention (CDC) report the findings of a two-week outbreak of multidrug-resistant S. pneumoniae serotype 23F infection among unvaccinated residents of a nursing home.
The CDC investigation began in February 1996, after officials were notified that during a five-day period, three patients at a 100-bed nursing home in a rural community had been hospitalized because of pneumococcal bacteremia. Two of the patients died of rapidly progressive illness despite therapy with intravenous cefuroxime. Eleven of the 84 residents contracted pneumonia caused by the resistant strain, for an attack rate of 13 percent.
All isolates of S. pneumoniae were found to exhibit only intermediate sensitivity to penicillin and cefotaxime; the minimal inhibitory concentration was 1.0 µg per mL for both agents. The isolates were resistant to trimethoprim-sulfamethoxazole and erythromycin. They were susceptible only to vancomycin. The laboratory at the community hospital had not previously identified any resistant strains of S. pneumoniae since beginning routine screening of all isolates in 1995.
To evaluate the epidemiology of the outbreak, the investigators used swabs to obtain nasopharyngeal culture samples from all of the nursing home residents and employees. The resistant strain was identified in 17 (23 percent) of 74 residents and in two (3 percent) of 69 employees. One day after the investigation began, pneumococcal polysaccharide vaccine was administered to 71 unvaccinated residents, as well as 11 employees with chronic medical illnesses.
Because four additional cases of pneumonia occurred during the next three days, a seven-day course of oral penicillin or ofloxacin was initiated in all of the residents. Two employees who were colonized with the outbreak strain received combination chemoprophylaxis with rifampin and ofloxacin for one week. Results from testing of nasopharyngeal swabs after vaccination and chemoprophylaxis revealed colonization with the resistant strain in only three residents and in no employees. Five weeks later, only two residents were still colonized.
The patients who had pneumonia were similar to the other nursing home residents in mean age, race and sex. Multidrug-resistant S. pneumoniae serotype 23F was isolated from the blood of four patients and the respiratory tracts of three others. Three patients with bacteremia died. Only three (4 percent) of the 84 nursing home residents had received pneumococcal vaccination, although 60 (71 percent) residents had received influenza vaccination the previous fall.
The authors believe several factors contributed to this epidemic. Most of the nursing home residents had not received pneumococcal vaccination and thus were susceptible to S. pneumoniae. In addition, the prevalence of colonization with the virulent 23F strain was high (23 percent) in this population. (The reported rate of colonization with S. pneumoniae is usually less than 10 percent among adults.) The colonization and attack rates were higher among patients who were receiving antibiotics (or at the time nasopharyngeal samples were obtained, in residents who were not ill) when the illness developed. An association between recent antibiotic use and colonization or infection with drug-resistant S. pneumoniae has been reported in the literature.
The investigators believe the optimal strategy for controlling outbreaks of drug-resistant S. pneumoniae infection still needs to be determined. In the outbreak they investigated, administration of pneumococcal vaccine and, possibly, oral antibiotic chemoprohylaxis made a difference, as no additional cases of pneumonia developed after these interventions. In addition, the colonization rate decreased significantly.
JEFFREY T. KIRCHNER, D.O.
Nuorti JP, et al. An outbreak of multidrug-resistant pneumococcal pneumonia and bacteremia among unvaccinated nursing home residents. N Engl J Med June 25, 1998;338:1861-8.
EDITOR'S NOTE: This outbreak serves as a frightening wake-up call to physicians; drug-resistant S. pneumoniae is a growing problem that may have significant implications in the next several years. The current treatment guidelines for community-acquired pneumonia in adults, from the American College of Physicians and the Infectious Diseases Society of America, recommend a second- or third-generation cephalosporin, with or without erythromycin. Yet these antimicrobial agents would have failed as empiric therapy for the patients in this outbreak. Widespread use of the pneumococcal vaccine is obviously needed as well as a more judicious use of oral antibiotics.
J.K.
Exercise and Weight Training in Adolescents with Type 1 Diabetes
Recent studies of the effects of vigorous exercise on glycemic control in patients with type 1 diabetes (formerly known as insulin-dependent diabetes mellitus, or IDDM) have yielded conflicting results. Most of these studies, however, have evaluated aerobic exercise only, not weight training. To study the effects of weight training combined with aerobic exercise, Mosher and associates evaluated the impact of 12 weeks of such a regimen on cardiovascular fitness, muscle strength, glucose control and lipid profiles in adolescent males with type 1 diabetes.
The study included 11 males with well-controlled type 1 diabetes and 10 males without diabetes. The mean age of the males with diabetes was 17.2 years; males without diabetes had a mean age of 19.4 years. Before beginning the exercise program, each participant's endurance, strength, body weight and composition were determined, as well as blood glucose, glycosylated hemoglobin and lipid levels.
The conditioning program consisted of 45 minutes of aerobic exercise and weight training three times a week for 12 weeks. The patients with diabetes consumed an evening meal supplemented by 5 to 10 g of complex carbohydrates two hours before their exercise sessions.
During the training sessions, only one patient with diabetes had a hypoglycemic episode. By the end of the 12-week training period, the patients with diabetes had gained lean body mass (3.5 percent) and decreased body fat by 5.2 percent. Cardiorespiratory endurance improved by 10.5 percent and 12.0 percent in the diabetes and control groups, respectively. Glycosylated hemoglobin levels in the group with diabetes fell by 0.96 percent, even though control was good before the study began. Total cholesterol levels decreased in the persons with diabetes, although not significantly. Both groups showed significantly increased high-density lipoprotein cholesterol levels and significantly decreased low-density lipoprotein cholesterol levels.
The authors conclude that the aerobic and weight training program improved muscle strength, cardiorespiratory endurance and lean body mass in the males with diabetes. It also led to improved lipid profiles and glycosylated hemoglobin levels in these patients, even though this group of adolescents had well-controlled type 1 diabetes. The improved cardiovascular fitness and endurance could reduce their risk of early coronary artery disease as well.
KARL MILLER, M.D.
Mosher PE, et al. Aerobic circuit exercise training: effect on adolescents with well-controlled insulin-dependent diabetes mellitus. Arch Phys Med Rehabil June 1998; 79:652-7.
Menorrhagia: Thermal Balloon or Rollerball Ablation?
Because menorrhagia is the underlying reason for more than one third of the hysterectomies performed annually in the United States, the development of alternative treatments is very important. Hysteroscopic rollerball endometrial ablation has been shown to have a clinical efficacy comparable to that of hysterectomy, but the technique requires considerable training and is most successful when combined with weeks of preoperative therapy to reduce the thickness of the endometrial lining. Rollerball ablation also carries a small but finite risk of hemorrhage, uterine perforation and complications of anesthesia. The thermal uterine balloon system is believed to provide comparable efficacy with less need for preoperative treatment, general anesthesia or extensive operator training. Meyer and colleagues compared the rollerball ablation technique with the thermal balloon technique.
Fourteen investigative centers in North America enrolled 275 women who had menorrhagia resistant to medical therapy and were considered good candidates for endometrial ablation. The patients were between 29 and 51 years of age (mean age: 40 years) and reported, on average, a 10-year history of menorrhagia. All of the study participants had received normal results on Papanicolaou smears and endometrial biopsies within the previous six months. Each woman's uterine cavity was anatomically normal. The presence of menorrhagia was documented, and patients provided subjective information about their symptoms and the effect the symptoms had on their normal daily activities. The patients were randomly assigned to treatment with either thermal balloon or rollerball ablation. No endometrial pretreatments were used. Types of anesthesia and analgesia were not controlled in the study. Patients were discharged the same day the procedure was performed and contacted by telephone within 24 hours. At one week and at three, six and 12 months following ablation, patients were examined, and symptoms and menstrual charts assessed.
The procedures were performed on 255 women. After 12 months, complete evaluation data were available for 239 participants. The two groups were comparable before the study in all important variables, including symptoms and hemoglobin levels. General anesthesia was given to 84 percent of those treated with rollerball ablation, compared with 53 percent of those undergoing thermal balloon ablation. The procedure was completed in less than 30 minutes in 71 percent of patients treated with thermal balloon ablation, but the same was true for only 28.6 percent of those in the rollerball treatment group. No complications were noted in those treated with the thermal balloon technique, but one case of uterine perforation, two cases of fluid overload and one case of cervical lacerations occurred in patients treated with rollerball ablation. Postoperative complications, mostly local infections, occurred in four patients in the thermal balloon treatment group and three in the rollerball treatment group. Over 80 percent of patients in both groups reported a return to normal bleeding or less bleeding 12 months after the procedure. The number of women with anemia was reduced in both groups by over 60 percent. Over 85 percent of all patients indicated that they were "highly satisfied" with the results of the procedure.
The authors conclude that uterine thermal balloon endometrial ablation is as efficacious as rollerball ablation and may have advantages in safety and related factors. Both procedures provide effective treatment for menorrhagia in selected patients.
ANNE D. WALLING, M.D.
Meyer WR, et al. Thermal balloon and rollerball ablation to treat menorrhagia: a multicenter comparison. Obstet Gynecol July 1998;92:98-103.
Fenofibrate for Treatment of Hypertriglyceridemia
Clofibrate and gemfibrozil are fibrates that increase lipoprotein lipase activity and triglyceride clearance, thus shifting the subgroup pattern of low-density lipoprotein (LDL) cholesterol to one that is less atherogenic. These effects appear to directly modify expression of several genes involved in lipoprotein metabolism; they also decrease hepatic secretion of very-low-density lipoprotein (VLDL) cholesterol and release of fatty acids from adipose tissue. This reduction of VLDL leads to decreased transfer of cholesterol from high-density lipoprotein (HDL) to VLDL, thus increasing serum HDL levels. Medical Letter consultants reviewed micronized fenofibrate, which was recently labeled for this purpose by the U.S. Food and Drug Administration, to determine if it offers any advantage over currently available fibrates.
The micronized form of fenofibrate is more rapidly and completely absorbed than the standard formulation, which is available outside the United States. A 67-mg micronized capsule of fenofibrate is the bioequivalent of a 100-mg, non-micronized tablet. Taking the drug with food increases the rate of absorption, and plasma concentration reaches a peak in six to eight hours. Fenofibrate has a half-life of approximately 20 hours and is metabolized in the liver and excreted mainly in the urine.
Few studies have been published regarding the micronized form of fenofibrate. Comparative studies in patients with hypercholesterolemia and hypertriglyceridemia have demonstrated that micronized fenofibrate, in a dosage of 200 mg daily, decreased LDL cholesterol levels slightly less than did a dosage of 20 mg of simvastatin or pravastatin daily, but it had a significantly greater effect on triglyceride levels. The decrease in triglyceride levels was about 30 to 50 percent, with slightly greater increases (1 to 34 percent) in HDL cholesterol levels. In one randomized study, atorvastatin (in a dosage of 10 or 20 mg daily) was less effective than non-micronized fenofibrate (in a dosage of 100 mg three times daily) in lowering triglyceride levels or in raising HDL cholesterol levels. Atorvastatin was, however, more effective in lowering LDL cholesterol levels. Although few study comparisons of gemfibrozil and fenofibrate have been conducted, fenofibrate appears to have more favorable effects on the lowering of LDL cholesterol levels.
No data are available on the effects of fenofibrate on morbidity and mortality from coronary heart disease. Although randomized trials with other fibrates have shown slower progression to coronary atherosclerosis and a decrease in the incidence of coronary events, there was no effect on the total mortality rate. Although clofibrate reduced the number of coronary events, the total mortality rate was increased because of an increase in malignant and gastrointestinal disease.
The most commonly reported adverse effects of micronized fenofibrate are rash and gastrointestinal symptoms. Increases in serum creatinine concentrations have been reported and, as with other fibrates, cholelithiasis, hepatitis and myositis can also occur. All fibrates, including micronized fenofibrate, potentiate the effects of oral anticoagulant medications. It is unclear if fenofibrate increases the risk of rhabdomyolysis when taken concurrently with a statin drug. If micronized fenofibrate is used with cholestyramine or colestipol, it should be taken one hour before or four to six hours after the resin. Fenofibrate may also increase the nephrotoxicity of cyclosporin.
Micronized fenofibrate is available in 67-mg capsules. The manufacturer recommends an initial dosage of 67 mg, taken once daily with a meal, increasing at four- to eight-week intervals (if necessary) to a maximum dosage of 201 mg daily. The drug should not be used in patients with hepatic or severe renal impairment. The authors conclude that once-daily doses of micronized fenofibrate lower elevated serum triglyceride concentrations, raise serum HDL cholesterol levels and improve LDL cholesterol levels. Based on currently available data, fenofibrate appears to be more convenient than gemfibrozil and may have more favorable effects on LDL cholesterol levels.
BARBARA APGAR, M.D., M.S.
Medical Letter consultants. Fenofibrate for hypertriglyceridemia. Med Letter Drugs Ther July 3, 1998;40(1030):68-9.
Atherosclerosis and Cardiac Risk Factors in Young Persons
The relationship between atherosclerosis and coronary heart disease is complex. Long-term studies in adults have determined that the progression of atherosclerosis is related to the presence of specific risk factors that reinforce each other over time if not treated. Autopsy data from adults have also demonstrated a relationship between coronary artery disease and cardiovascular risk factors, including cigarette smoking and high cholesterol levels. Berenson and colleagues report the findings from the Bogalusa Heart Study, which examined the influence of multiple cardiovascular risk factors on the extent of atherosclerosis in young people.
The Bogalusa Heart Study followed patients (65 percent white and 35 percent black) from birth to 38 years of age. To date, the researchers have collected data on approximately 14,000 people. The authors examined autopsy data from 204 study participants who had died from various causes, mostly trauma, between 1978 and 1996. Before their deaths, information had been obtained on body mass index, cigarette smoking status, blood pressure, and total cholesterol, triglyceride, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol levels.
At autopsy, the coronary arteries and the aorta were sectioned longitudinally to permit evaluation of the extent of lipid deposition on the intimal surface, including the presence of fatty streaks and raised fibrous plaques. The lesions were examined and graded visually by three pathologists who were unaware of the risk-factor status of the deceased person. The extent of atherosclerosis was expressed as the mean of the values assigned to the vessels by the three pathologists.
Essentially all persons studied had fatty streaks in the aorta. The prevalence of fatty streaks in the coronary arteries was 50 percent in persons from two to 15 years of age and 85 percent in persons from 21 to 39 years of age. The prevalence of raised fibrous plaque lesions in the aorta increased with age, reaching 60 percent in persons 26 to 39 years of age. The prevalence of raised plaques in the coronary vessels was 8 percent in persons from two to 15 years of age and 69 percent in persons from 26 to 39 years of age. With both types of lesions, there was a trend toward involvement of an increasing percentage of the intimal surface with increasing age.
In correlating the extent of vascular lesions with antemortem risk factors, study results showed a positive and significant association with body mass index, systolic blood pressure (except for fibrous plaques in the aorta), diastolic blood pressure (except for fibrous plaques in the coronary arteries), total cholesterol, LDL cholesterol and serum triglyceride levels. Persons with a known history of cigarette smoking did not have a greater prevalence of coronary or aortic lesions compared with persons who did not smoke. However, smokers did have a greater mean percentage of intimal surface area involvement for both coronary vessels and the aorta. Collectively, the extent of fatty-streak lesions in coronary arteries was 8.5 times greater in persons with three or four risk factors, and the extent of fibrous plaques in the arteries was 12 times as great, compared with persons with no identifiable risk factors.
The authors conclude that the extent of coronary and aortic lesions in children and young adults significantly correlates with the presence of cardiovascular risk factors, including body mass index, systolic blood pressure, serum LDL cholesterol level, triglyceride concentration and cigarette smoking. They believe their data support the Framingham Study, which determined that multiple cardiac risk factors have a synergistic effect on morbidity and mortality from cardiovascular disease. In addition, cigarette smoking appears to adversely affect the extent of coronary disease in persons with other risk factors.
JEFFREY T. KIRCHNER, D.O.
Berenson GS, et al. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. N Engl J Med June 4, 1998;338:1650-6.
EDITOR'S NOTE: Data from the Bogalusa Heart Study certainly suggest that known risk factors for coronary disease begin to have an effect in early adulthood and possibly even in childhood. This suggestion is in keeping with an earlier report (the "PDAY" study) that found an association between atherosclerotic lesions in adolescents and smoking and high cholesterol levels. Data from the Bogalusa Study bring up the question of screening and intervention for cardiac disease in young adults and children. There still is no evidence that early intervention, such as treating hypertension in younger patients, is efficacious in the long run. Cholesterol screening and medical treatment of hyperlipidemia in children remain controversial interventions and are not practiced by the majority of clinicians. However, interventions such as counseling against tobacco use and encouraging healthy dietary habits and exercise appear to be reasonable and potentially effective ways to reduce the future risk of heart disease.
J.K.
Clinical Behavior Problems in Children with Nocturnal Enuresis
While some studies of primary nocturnal enuresis suggest that it is a symptom of an underlying psychiatric or behavior problem, others suggest that it is a discrete entity requiring only treatment of the bedwetting itself. Friman and colleagues performed a study to evaluate whether a relationship exists between nocturnal enuresis and clinically significant comorbid behavior problems.
Data were collected from three groups: children with nocturnal enuresis who were referred for a behavioral evaluation; children with problem behavior and no enuresis who were referred for a behavioral evaluation (clinical sample); and children without enuresis who were not referred for a behavioral evaluation (nonclinical sample).
Children in the enuresis group were referred to one of two pediatric behavioral clinics, had failed to attain nocturnal continence for any six-month period and had been bedwetting at least once a week before referral. The clinical group was selected from 429 children who were referred to the same two pediatric clinics. The third group was randomly selected from a standardization group of 614 children who were seen at an outpatient pediatric clinic for minor illnesses or well-child care. Each group contained 92 children (62 boys and 30 girls) matched for age and sex. Children ranged in age from five to 13 years (mean age: 7.8 years).
The Eyberg Child Behavior Inventory (ECBI), a standardized parent-report scale that represents 36 common childhood behaviors, was used to assess each child. This instrument yields a problem intensity score and a problem number score, and has been well documented as an assessment tool for childhood behavior characteristics.
Children referred because of behavior problems (the clinical group) were found to have mean problem number and problem intensity scores significantly higher than those of the enuresis and the nonclinical groups. The authors also calculated the number of problem intensity and problem number scores that fell above the clinical cutoffs. At least one ECBI score above the clinical cutoff was present in 38 (61 percent) of the 62 boys and in 18 (60 percent) of the 30 girls in the clinical group. In contrast, 24 boys (39 percent) and five girls (17 percent) with enuresis had at least one ECBI score above the clinical cutoff. In the nonclinical group, 12 boys (19 percent) and four girls (13 percent) had such scores.
The authors conclude that children with primary nocturnal enuresis do not have significant behavioral comorbidity. They believe nocturnal enuresis is a discrete biobehavioral entity that can be managed by the pediatrician or family physician. Unless the child's clinical presentation is unusual, referral for a mental health evaluation is not necessary.
JEFFREY T. KIRCHNER, D.O.
Friman PC, et al. Do children with primary nocturnal enuresis have clinically significant behavior problems? Arch Pediatr Adolesc Med June 1998;152:537-9.
Prognosis of Acute Renal Failure in the Elderly Patient
When determining whether to offer a certain treatment, some physicians may consider a patient's age group rather than the individual patient. There is an assumption that many treatments are less likely to benefit patients of advanced age. Pascual and colleagues conducted a longitudinal study to determine if advancing age should be used as a discriminating factor in treating acute renal failure in patients 80 years of age or older.
Adult patients who were treated for acute renal failure at one of 13 hospitals during a nine-month period were included in the study. Demographic information, etiology of the acute renal failure, medications, serum creatinine levels, need for dialysis and mortality rates were recorded. Patients were included in the study if they had previously normal renal function and a rise of serum creatinine to more than 2.0 mg per dL (177 mmol per L) plus one of the following conditions: normal serum creatinine level at admission; elevated serum creatinine level at admission with at least 50 percent recovery by discharge; elevation of serum creatinine level at admission without evidence of chronic renal failure; or mild chronic renal failure (baseline serum creatinine level of greater than 3.0 mg per dL [265 mmol per L] with a sudden rise in serum creatinine).
The study population included 103 patients who were 80 years or older, 256 patients between 65 and 79 years of age, and 389 patients who were younger than 65 years. The most likely cause of the acute renal failure was defined in each case. In patients 80 years of age or older, acute tubular necrosis accounted for 39 percent of the cases of acute renal failure versus 30 percent related to prerenal causes and 20 percent related to obstructive causes. Acute renal failure was preceded by a prerenal cause with similar frequency in each of the three groups. The changes in serum creatinine were similar in all three age groups. Diuretic use was also similar among the three groups. Patients who were very elderly were less likely to have hemodialysis prescribed than were patients in the 65- to 79-year-old age group. A stratified analysis showed that age was not significantly related to mortality in any of the three groups. When the more serious cause of acute renal failure, acute tubular necrosis, was considered alone, the risk of dying was again not higher in the older patients. Poor prognosis was associated with sustained hypotension and the need for dialysis, but not with oliguria.
Although the incidence of acute renal failure is higher in very elderly patients, the clinical course and mortality rates were not different when compared with younger cohorts. The authors conclude that age alone should not be used in determining if patients with acute renal failure should receive certain treatments, such as dialysis.
GRACE BROOKE HUFFMAN, M.D.
Pascual J, et al. Causes and prognosis of acute renal failure in the very old. J Am Geriatr Soc June 1998;46:721-5.
Depression in Men Before and After the Birth of a Child
Many studies have evaluated depression among women during and after pregnancy, but information is limited on the impact of the birth of a child in men. Deater-Deckard and colleagues studied the prevalence of depressive symptoms in men before and after the birth of a child and any relationship between depression and family structure.
Male partners of 6,667 women who gave birth during the nine-month study period completed two surveys that assessed depressive symptoms. The first survey was performed when the pregnancy was at 18 weeks of gestation, and the other was conducted eight weeks after the birth of the infant. The content of the surveys covered depression measures, life events, social support, qualities of the partnership and basic demographic information. The mothers completed similar surveys.
The men were categorized according to four family structures: traditional families, with both parents residing in the home and all children biologically related to both partners; stepfather families, with both parents living in the home along with the father's stepchildren, with or without biological children of the couple; stepmother families, with both parents living in the home along with the mother's stepchildren, with or without biological children of the couple; and single-mother families, with the mother not living with the child's father.
The survey revealed that 2.9 percent of the men in a traditional family had depression scores of more than 12 when their partners were at 18 weeks of gestation, and 3.0 percent had such scores eight weeks after delivery. In contrast, in stepfather families, 6.8 percent of the men had depression scores of more than 12, both at 18 weeks of gestation and eight weeks postpartum. In stepmother families, 10.3 percent of the men had depression scores of more than 12 during the pregnancy, and 7.3 had such scores eight weeks after the birth of the child. In single-mother families, 11.5 percent of the men had depression scores of more than 12 at the 18-week survey, but this rate fell to 5.1 percent eight weeks after delivery.
The higher levels of depressive symptoms in the men who were stepfathers were found to correlate with higher rates of depression among the partners, less education, more life events, less social support, smaller social networks and more aggression within their relationships. The level of the women's depressive symptoms was the strongest correlate of the men's depressive symptoms.
The authors conclude that men in stepfamilies and men who are partners of single mothers are more likely than men from traditional families to have depressive symptoms before and after the birth of a child. The authors point out that their data did not provide diagnostic information for the participants. Thus, these findings may not be generalizable to studies that used more precise measures of depression in men. Nevertheless, the findings suggest that men in stepfamilies may be at increased risk of depression compared with men in traditional families, and this risk is closely linked to their partners' depressive symptoms.
KARL MILLER, M.D.
Deater-Deckard K, et al. Family structure and depressive symptoms in men preceding and following the birth of a child. Am J Psychiatry June 1998;155:818-23.
Lumbar Support for Prevention of Occupational Back Injury
A frequent cause of disability in the workplace is low back injury. Strategies to reduce the incidence of low back injury in the workplace include education and the use of lumbar supports. Van Poppel and associates conducted a randomized trial to determine if education and used lumbar supports reduced the number of back pain episodes reported by a group of airline cargo workers.
A total of 312 persons were included in the six-month study and were randomly assigned to one of four groups: group 1 used lumbar supports and received education about proper lifting techniques; group 2 received education but used no lumbar supports; group 3 used lumbar supports but did not receive education; and group 4 had no intervention. The type of lumbar support used by study participants had hook-and-loop fasteners, flexible stays and an anchor belt but no shoulder straps. Education consisted of three sessions on lifting techniques, for a total of five hours. The third session included individual on-the-job instruction. Demographic information, history of back pain and presence of low back pain were assessed at baseline. Occurrence of low back pain and use of sick leave for back pain were assessed monthly during the study, as was compliance with wearing the lumbar support.
There were no significant differences in age, history of back problems or amount of sick leave taken because of back problems among the groups at baseline. More than one half of the workers (60 percent) expected the lumbar supports to reduce low back pain, and 69 percent thought that the lifting education would be useful. After the education sessions, 11 percent of the workers said they followed proper lifting techniques as taught, 73 percent said they lifted as taught some of the time, and 11 percent said they never followed the lifting techniques. Only 43 percent of the workers reported wearing lumbar supports more than one half of the time. About one half of the study subjects thought the supports were too restrictive, uncomfortable or too hot. On the other hand, about one half of the participants also reported that the lumbar support was easy to use and was supportive of the back.
In workers who had no history of low back pain, the use of interventions did not significantly reduce the number of sick days used because of back pain. In those who reported a history of low back pain at baseline, there was a slight decrease in the number of sick days taken because of back pain in the group using lumbar support.
The authors conclude that the use of lumbar support, lumbar support plus education or education alone did not prevent back pain. Further research is needed to determine the effectiveness of lumbar supports in workers who have a history of low back pain. In an accompanying editorial, Dillingham concurs that further research is needed to determine if the use of lumbar supports can reduce disability, costs and loss of productivity attributed to back injury in the workplace.
GRACE BROOKE HUFFMAN, M.D.
Van Poppel MN, et al. Lumbar supports and education for the prevention of low back pain in industry. A randomized controlled trial. JAMA June 10, 1998;279:1789-94, and Dillingham TR. Lumbar supports for prevention of low back pain in the workplace [Editorial]. JAMA June 10, 1998;279:1826-8.
Itraconazole Oral Solution for Oropharyngeal Candidiasis
Oropharyngeal candidiasis is the most frequently occurring opportunistic infection in persons infected with human immunodeficiency virus (HIV). There tends to be high relapse rates with first-line therapies such as topical clotrimazole or nystatin, and systemic azole therapy (ketoconazole, fluconazole or itraconazole) is usually required. However, a marked increase has been seen in the number of fluconazole-resistant cases. Some small studies have found that itraconazole suspension is effective in patients with oral candidiasis. Phillips and colleagues performed a randomized double-blind study to compare the safety and efficacy of itraconazole oral solution with fluconazole capsules for the treatment of oropharyngeal candidiasis in patients with acquired immunodeficiency syndrome.
Patients enrolled in the study included HIV-infected adults who were at least 19 years old, had CD4 lymphocyte counts of less than 400 per mm3 (400 3 106 per L) and pseudomembranous oropharyngeal candidiasis documented by mycologic culture. Patients were excluded if they had taken any oral azole within the past two weeks, had esophageal involvement of disease, alanine or aspartate aminotransferase levels greater than five times the upper limit of normal or a creatinine clearance less than 50 mL per minute (0.84 mL per s). Patients were randomized to receive either fluconazole capsules (100 mg daily for 14 days) or itraconazole oral solution (either 100 mg daily for 14 days or 100 mg twice daily for seven days).
The patients were evaluated on the eighth and 15th days of treatment and again at one week and two weeks during follow-up. Clinical assessment was quantified with a scoring system that included the severity of signs and symptoms as well as the extent of the lesions. Responses were classified as complete, markedly improved, moderately improved, unchanged or deteriorated. Mycologic assessment was performed by microscopy (KOH, Gram stain or methylene blue stain) and culture. To assess safety and adverse events, hematologic and biochemical laboratory tests were performed 24 hours before enrollment, as well as on days 8 and 15 of treatment and at the end of the two-week follow-up period.
A total of 194 patients completed the trial. Baseline characteristics, including sex, mean age and average CD4 cell counts (approximately 150 per mm3 [150 3 106 per mL]), were essentially the same for all three groups. An acceptable clinical response viewed as complete or markedly improved was achieved in 90 percent of the patients receiving fluconazole; 90 percent of the patients receiving itraconazole once daily, and 82 percent of the patients receiving itraconazole twice daily. At day 14 of treatment, cultures were negative in 53 percent of the patients receiving fluconazole, 57 percent of the patients receiving itraconazole once daily and 44 percent of the patients receiving itraconazole twice daily. The clinical relapse rates within 18 days after treatment were 34 percent in the group receiving fluconazole, 35 percent in the group receiving itraconazole once daily and 37 percent in the group receiving itraconazole twice daily. There was no difference in adverse events among the three treatment groups. Gastrointestinal problems were the most commonly reported adverse events. There were no consistent changes in biochemical or hematologic parameters, although patients in each of the three groups had abnormalities at baseline. The frequency of abnormalities was considered to be reflective of the underlying disease.
The authors conclude that itraconazole oral solution at a dosage of 100 mg once daily for 14 days or 100 mg twice daily for seven days is an effective treatment for oropharyngeal candidiasis. The longer course of itraconazole treatment appears to be therapeutically equivalent to the fluconazole regimen of 100 mg once daily for 14 days.
JEFFREY T. KIRCHNER, D.O.
Phillips P, et al. A double-blind comparison of itraconazole oral solution and fluconazole capsules for the treatment of oropharyngeal candidiasis in patients with AIDS. Clin Infect Dis June 1998;26:1368-73.
Home Use of Rectal Diazepam Gel for Repetitive Seizures
Some patients with epilepsy are affected by acute repetitive, or serial, seizures that last several minutes or hours and do not follow the pattern of their usual seizures. Benzodiazepines are the drugs of choice for the treatment of acute repetitive seizures. They are safe and they work quickly. However, oral administration is often difficult in a patient who is actively convulsing. Dreifuss and colleagues performed a randomized, double-blind, parallel-group, placebo-controlled study to assess the safety and efficacy of at-home administration of rectal diazepam gel for acute repetitive seizures. The high lipid solubility of this form of diazepam allows for rapid absorption and penetration into the central nervous system.
The study included 91 patients aged two to 60 years who had had at least four episodes of repetitive seizures during the preceding year and at least one such episode in the previous three months. All patients had followed a stable antiepileptic regimen for at least four weeks before the beginning of the study. Patients were ineligible for the study if they were receiving long-term drug therapy other than anticonvulsants, had a phenobarbital level higher than 30 mg per L (130 µmol per L) or were receiving long-term benzodiazepine therapy.
Caregivers were taught how to identify repetitive seizures, administer diazepam rectally, and monitor and record respirations, skin color, seizure activity and adverse events. When acute repetitive seizures occurred, the caregiver telephoned a nurse, who maintained constant contact. The caregiver reported on the patient's condition so the nurse could intervene if problems developed.
Rectal diazepam gel was administered in dosages of 0.5 mg per kg for children two to five years of age, 0.3 mg per kg for children six to 11 years of age and 0.2 mg per kg for children 12 years of age and older and for adults. A second dose was given four hours after the first and, in adults, a third dose was given eight hours after the second dose. The period of observation and data recording by caregivers began immediately after the first dose and continued for 12 hours in children and for 24 hours in adults.
Diazepam gel was found to be significantly more effective than placebo in reducing seizure frequency in both adults and children. This difference was noted as early as 30 minutes after the initial dose and continued throughout the observation period. The caregiver's global assessment of the treatment outcome was significantly higher for children receiving diazepam than for children receiving placebo, but no significant difference was observed in this outcome variable for adults in either group. None of the patients who received diazepam required emergency room treatment.
Adverse events were reported more commonly in the diazepam group (46.7 percent) than in the placebo group (30.4 percent), but the difference was not significant. The most commonly reported adverse effect in the patients receiving diazepam was somnolence (15 patients). No instances of respiratory difficulty occurred.
The authors conclude that rectal diazepam gel is safe and effective for acute repetitive seizures and can be administered by caregivers who know how to monitor the person's response. In an accompanying editorial, Vining states that the cost of rectal diazepam gel in the Baltimore area is about $70 to $90 for a 10-mg dose, compared with approximately $6 for a 10-mg vial of parenteral diazepam solution. Nevertheless, she states, the gel form has advantages. It is stable at room temperature, packaged in the specific dose prescribed for the patient and can be easily administered. She notes that diazepam gel would be useful, for example, when patients are traveling and a parenteral solution cannot be refrigerated. It also would be "a reassuring safety net" for patients who are prone to status epilepticus and who travel or live far from a hospital. However, she cautions that this formulation should not be used to prevent recurrent febrile seizures, and physicians should be careful that the fear of seizures does not lead to overprescribing of this drug.
JEFFREY T. KIRCHNER, D.O.
Dreifuss FE, et al. A comparison of rectal diazepam gel and placebo for acute repetitive seizures. N Engl J Med June 25, 1998;338:1869-75, and Vining EP. Gaining a perspective on childhood seizures [Editorial]. N Engl J Med June 25, 1998;338:1916-8.
"Tips from Other Journals" are written by the medical editors of American Family Physician.
Copyright © 1998 by the American Academy of Family Physicians.
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