Tips from Other Journals
Three Treatment Regimens for Women with Hirsutism
Hirsutism results from increased androgen production or excessive androgen activity at the target level. The effect of androgens at the peripheral level depends on the metabolism of testosterone, the ability of free steroid fraction to cross the cell membrane and interaction with intracellular receptors. Pharmacologic treatment focuses on the androgen secretions or the target tissue. Cyproterone acetate has both central and peripheral activity when combined with ethinyl E2. Flutamide and finasteride are two other agents that have been used in the treatment of hirsutism. Fruzzetti and associates studied the safety and efficacy of each of these therapies to determine the best treatment regimen in patients with hirsutism.
The authors recruited 45 women with hirsutism who had no evidence of a secondary cause and had not received any hormonal therapy for six months. The women were randomly assigned to one of three treatment groups. The first treatment regimen was 25 mg of cyproterone acetate per day for the first 10 days of the menstrual cycle along with 20 µg of ethinyl E2 daily for 21 days. The second group received 250 mg of flutamide twice a day, and the third group received 5 mg of finasteride per day. One physician evaluated patients' hirsutism before initiating therapy, and liver function studies were performed to identify hormone levels at baseline and months 3, 6 and 12.
All three therapies significantly reduced hirsutism scores during the study with a similar percent decrease in scores among the groups. No significant side effects were reported in any of the groups, and no one dropped out of the study because of side effects.
Cyproterone acetate with ethinyl E2 has proved to be effective in reducing hirsutism. However, few trials looked at the safety and efficacy of flutamide and finasteride. This study demonstrated that these three agents were equally effective in reducing hirsutism scores, although they have different modes of activity. The authors conclude that all three agents can be used, with minimal side effects, in the treatment of hirsutism.
KARL MILLER, M.D.
Fruzzetti F, et al. Treatment of hirsuitism: comparisons between different antiandrogens with central and peripheral effects. Fert Steril March 1999;71:445-51.
Children With Pseudoseizures: Psychiatric Aspects and Outcomes
Pseudoseizures, sometimes known as psychogenic or hysterical seizures, resemble epileptic seizures but are not associated with abnormal cortical electrical discharges. This condition affects children as young as five years of age and is the underlying problem in up to 22 percent of adults who are referred to specialists for treatment of epilepsy. Sophisticated diagnostic testing, such as prolonged video electroencephalographic (EEG) monitoring, has helped differentiate pseudoseizures from true epilepsy. However, little is known about the psychiatric aspects and outcomes in children and adolescents with pseudoseizures. Wyllie and colleagues evaluated these factors in a retrospective review of pediatric and adolescent patients treated for pseudoseizures at the Cleveland Clinic Foundation between 1992 and 1996.
Children between nine and 18 years of age who had a diagnosis of pseudoseizures confirmed by ictal video EEG were eligible for the study. At the time of diagnosis, 70 percent of the patients were taking antiepileptic medication. However, these medications were discontinued in all patients before several days of testing with prolonged video EEG monitoring. During the monitoring period, each patient experienced at least one pseudoseizure that was described by the family and patients as "typical." EEG readings obtained during seizure activity were consistently normal, except in four children who had a previous and concurrent diagnosis of true epilepsy. After the diagnosis of pseudoseizure was confirmed, a pediatric neurologist immediately presented the results to the patients and family. Anticonvulsant medications were not resumed except in the four children with true epilepsy. All patients were also examined by a pediatric psychiatrist at this time to identify any underlying problems.
Thirty-four children with pseudoseizures were included in the study. Mean patient age was 14 years, and mean duration of pseudoseizures until video diagnosis was about 11 months. All patients had a diagnosis of conversion disorder according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. However, malingering, factitious disorder and factitious disorder by proxy were ruled out in all patients. Moderate to severe psychosocial stressors, such as severe family stress, sexual or physical abuse, and school failure, were identified in 31 patients. From this larger group, two principal subgroups were identified. Eleven patients had major mood disorders and, of these, seven had a history of sexual abuse. Eight patients experienced separation anxiety/school refusal but, in this group, psychosocial stressors were less severe. Patients in the latter subgroup also benefited from family counseling and, in some cases, medical therapy. However, in most patients, pseudoseizures tended to occur months or even years after a specific psychosocial stressor, such as physical or sexual abuse, or in the context of chronic family dysfunction.
Long-term follow-up was available for only 21 patients. Of these, 15 had had no seizures for nine to 55 months after the initial evaluation. These patients reported that the number of seizures gradually decreased until they were seizure-free, typically within two years. Two of the four children who had both epilepsy and pseudoseizures had no further recurrences but continued to take medication. Because of the small number of patients successfully contacted during follow-up, any analysis of outcomes would be inconclusive, although no clear trends were apparent between subgroups.
The authors conclude that all children and adolescents with suspected pseudoseizures should undergo video EEG and a detailed psychiatric evaluation. Most patients with pseudoseizures also have major mood disorders and severe psychosocial stressors. Specific stressors include parental divorce, death of a family member and sexual and physical abuse. Although it was not proved definitively in this study, the authors suggest that some children benefit from counseling or other mental health interventions, including medical therapy.
JEFFREY T. KIRCHNER, D.O.
Wyllie E, et al. Psychiatric features of children and adolescents with pseudoseizures. Arch Pediatr Adolesc Med March 1999;153:244-8.
The Medical Literature on Raloxifene for Osteoporosis
Raloxifene is an antiestrogen labeled for the prevention of osteoporosis in postmenopausal women. Because data on raloxifene are rapidly accumulating, Khovidhunkit and Shoback reviewed the literature published in the past 18 years on raloxifene.
Raloxifene has both estrogen-agonistic and estrogen-antagonistic properties: it acts as an estrogen antagonist on the uterus and breast, and as an estrogen agonist on bone and lipids. The term "selective estrogen receptor modulator" (SERM) has been coined to describe agents that interact with the estrogen receptor but have tissue-specific activities. SERMs compete with endogenous estrogens for binding to the receptor and may either activate or block estrogen activity.
Studies suggest that raloxifene inhibits bone loss by reducing bone resorption through the same mechanism as estrogen. It does not have an anabolic action on the skeleton. One study of postmenopausal women showed that raloxifene in a dosage of 60 mg per day for two years increased bone mineral density by 1.2 percent at the femoral neck and by 1.6 percent at the spine and total hip. Total-body bone mass had increased by 1.4 percent.
Raloxifene has been shown to have beneficial effects on lipid levels. A study of postmenopausal women demonstrated that 60 mg per day decreased the total cholesterol concentration by 6.4 percent and the LDL concentration by 10 to 12 percent. HDL cholesterol and triglycerides were unaffected.
No reports indicate that raloxifene exerts some of the other favorable cardiovascular effects of estrogen. For example, the agent has not been reported to reduce arterial vasoconstriction produced by regulation of the generation of nitric oxide and other vasoactive peptides, to improve insulin and glucose metabolism, or to improve hepatic cholesterol metabolism. No data support the idea that raloxifene can reduce cardiovascular events in humans.
Raloxifene was initially developed as a treatment for breast cancer but was found to be less effective than tamoxifen. Other SERMs seem to be more efficacious than raloxifene in controlling breast cancer cell growth. Two large trials are under way to evaluate whether raloxifene reduces the risk of breast cancer after two years of therapy in postmenopausal women.
Unlike estrogen and tamoxifen, raloxifene has no stimulatory effect on the uterus, suggesting that it may be associated with a lower risk for endometrial cancer. Long-term data to substantiate this effect are not available. This estrogen-antagonistic effect on the uterus is blunted in environments of high circulating estrogen, implying that raloxifene is unlikely to be useful in the treatment of estrogen-responsive diseases such as endometriosis and uterine leiomyoma.
Higher dosages of raloxifene have been found to result in a higher frequency of side effects, including fatigue, leg cramps and nausea. The most serious side effect is a threefold increase in the risk for venous thromboembolism, similar to that occurring with estrogen therapy.
The authors conclude that estrogen seems to be a better choice for prevention of osteoporosis in most postmenopausal women, especially in the early postmenopausal years, when the incidence of hot flushes is high, and bone loss is rapid.
RICHARD SADOVSKY, M.D.
Khovidhunkit W, Shoback DM. Clinical effects of raloxifene hydrochloride in women. Ann Intern Med March 2, 1999;130:431-9.
EDITOR'S NOTE: Raloxifene, a second-generation SERM, may be an alternative in patients who will not take hormone replacement therapy because of fear of breast cancer or in patients who have tried hormone replacement therapy but discontinued it because of associated breast tenderness or uterine bleeding. Patients currently doing well with estrogen replacement therapy who inquire about switching to raloxifene should be cautioned to wait until more data on raloxifene are available. The specific indication for raloxifene is to delay bone loss, not to treat postmenopausal symptoms or established osteoporosis. Other antiresorptive agents (estrogen, bisphosphonates) are more efficacious than raloxifene. Because the risk of venous thromboembolic events is increased with raloxifene, with the greatest risk occurring during the first four months of therapy, treatment should be discontinued 72 hours before and during periods of prolonged immobilization. Data are insufficient to make recommendations relative to patients with a history of breast cancer, but most experts believe that this agent is appropriate in postmenopausal women, especially those with an estrogen-positive tumor. Tamoxifen, however, remains a better adjuvant therapy for prevention of breast cancer recurrence.
--R.S.
Neonatal Jaundice: Does Human Milk or Type of Formula Matter?
The incidence of hyperbilirubinemia appears to be higher in breast-fed infants than in formula-fed infants. Temporary substitution with formula appears to hasten resolution of the jaundice, and this approach, though controversial, is recommended by the American Academy of Pediatrics. Gourley and colleagues attempted to determine if the specific type of formula (i.e., casein or whey) has an effect on neonatal jaundice.
Sixty full-term neonates were enrolled in the three-week study. They were divided into three groups, with 20 infants each receiving human milk, whey-predominant formula (Enfamil) and a casein-hydrolysate formula (Nutramigen). The formula groups were assigned randomly. Fourteen infants (seven of the breast-fed infants, two Enfamil-fed infants and five Nutramigen-fed infants) were withdrawn from the study before its completion.
All three types of feedings were initiated within 60 minutes of birth and offered on demand every one to three hours. Infants who received alternative feedings or required phototherapy were excluded from the study. The degree of jaundice was assessed daily by a transcutaneous "jaundice index" for the first seven days of life and every two to three days for the subsequent two weeks. The jaundice index has been shown to correlate highly with serum bilirubin concentrations.
Transcutaneous jaundice indexes were significantly higher throughout the study in the breast-fed infants. The jaundice index was significantly higher in the human milk group than in the Enfamil group on days 13 to 19, in the Enfamil group than in the Nutramigen group on days 6 to 16 and in the human milk group than in the Nutramigen group on days 3 to 20.
The authors conclude that jaundice levels are lower in infants fed hydrolyzed casein formula than in infants fed a whey-based formula. They suggest that a possible explanation for this difference is that Nutramigen has been shown to contain an inhibitor of b-glucuronidase, a chemical believed to enhance absorption of intestinal bilirubin, leading to higher serum levels. Further studies are needed to clarify this issue. The findings suggest that infants who develop breast milk jaundice benefit from a casein-based formula such as Nutramigen for a short period while the jaundice is resolving.
JEFFREY T. KIRCHNER, D.O.
Gourley GR, et al. Neonatal jaundice and diet. Arch Pediatr Adolesc Med February 1999;153:184-8.
Vaccinations and Other Health Care Measures for Foreign Travel
Taking precautions to avoid contaminated food and water, and receiving necessary vaccinations can minimize health risks when traveling to underdeveloped regions of the world. Rizvon and associates review the common issues and preventive measures for international travel.
The authors advise travelers to seek health care advice about foreign travel four to six weeks before departure. Health-related documents to take along on the trip include an updated vaccination certificate, a list of medications and a copy of any other important medical information, such as an electrocardiogram for patients with cardiac disease. In addition to a standard first-aid kit, which should include medications such as analgesics, antihistamines and motion sickness agents, prepackaged oral rehydrant solutions can be taken along to treat dehydration if travelers' diarrhea occurs. Health advice regarding food and water precautions and accessibility of health care abroad are essential. Patients should be advised to learn what their health insurance will cover. Coverage that includes evacuation insurance may be important.
Vaccination Recommendations for Foreign Travel
Disease
Vaccine dosing schedule
Comments*
Booster interval
Hepatitis A Adults: Havrix, 1,440 El U IM; Vaqta, 50 units IM Inactivated Havrix contains 2 phenoxyethanol as a preservative. With both vaccines, the most common side effects are mild and usually disappear within 1 to 2 days. Adults: 6 to 12 months Immune globulin: 0.02 mL per kg IM for <3-month stay; 0.06 mL per kg IM for >3-month stay Avoid concurrent live vaccines. Repeat every 5 months Hepatitis B Engerix B, accelerated: 3 doses at zero, 30 and 60 days; standard: 3 doses at zero, 1 and 6 months Teenagers may not need vaccination since hepatitis B vaccination is included in the childhood immunization program. Accelerated: 12 months
Standard: UnknownYellow fever 0.5 mL SC at least 10 days before travel Live attenuated virus; avoid in pregnancy, in patients with severe egg allergy and immunosuppressed patients. Repeat every 10 years Typhoid fever Oral: 1 capsule every other day, 4 doses Live attenuated strain ty21a strain; avoid in patients with acute febrile or gastrointestinal illness. 5 years Injectable: ViCPS vaccine, 1 dose Contains phenol; use with caution in patients with thrombocytopenia, coagulopathy, pregnancy (category C) and immunocompromised state. 2 years IM inactivated (heat-phenol) injectable: 2 doses, 4 weeks apart Reactions such as fever, myalgias and soreness at injection site are more common than with the single-dose ViCPS vaccine. 3 years Poliomyelitis Unvaccinated: 3 doses IM or SC, 1 month apart; completed vaccination: 1 booster dose Enhanced-potency inactivated poliovirus vaccine preferred in pregnancy (category C); avoid in patients with hypersensitivity to neomycin, streptomycin or polymixin B. -- Cholera 2 doses IM or SC, 1 or more weeks apart 50 percent efficacy; give at least 3 weeks after yellow fever vaccine. 6 months Meningococcal meningitis 1 dose SC Needed for travel to Saudi Arabia. None, but 3 years later in high-risk groups
IM=intramuscularly; SC=subcutaneously.
*--Allergic reactions related to the vaccine component can occur. History of allergic reactions to vaccines should be evaluated before vaccination.
Reprinted with permission from Rizvon MK, Qazi S, Ward LA. International travel and vaccinations. West J Med 1999;170:97-103.
Prophylaxis against malaria is important for travel to Mexico and Central America. Chloroquine, in a dosage of 500 mg once weekly, can be taken for malaria prophylaxis. Prophylaxis should begin one week before travel and continue for four weeks after return. Mefloquine, in a dosage of 250 mg once a week, can be used in patients who are traveling to areas of chloroquine-resistant disease. Doxycycline, in a dosage of 100 mg once daily, can be used as an alternative in patients who cannot take mefloquine. Mefloquine should be avoided in patients with a seizure disorder and in patients taking drugs that delay cardiac conduction.
Use of an insect repellent that contains 25 to 30 percent deet (N,N-diethyl-3-methylbenzamide) can reduce the risk of acquiring malaria. Children, however, should use deet in a concentration of 10 percent or less. While it cannot be applied to skin, permethrin on clothing may help reduce exposure to mosquito bites.
The accompanying table summarizes vaccination recommendations for foreign travel. Hepatitis A vaccine, given in two doses, provides long-term protection, while immune globulin can be given for short-term protection. Yellow fever vaccine may be a consideration for travelers to tropical Africa or South America. Typhoid fever vaccine is available in both oral and injectable forms. Adhering to the precautions for avoiding contaminated food and water may also reduce the risk of exposure to typhoid. The cholera vaccine is rarely used in preparation for foreign travel. The risk of cholera in American travelers who follow food and water precautions is low, and the vaccine is only 50 percent effective. Vaccinations for meningococcal meningitis, Japanese B encephalitis, rabies, tick-borne encephalitis and anthrax are available for travelers visiting endemic areas. Other immunizations should include hepatitis B, poliovirus, measles-mumps-rubella (MMR), diphtheria and tetanus.
RICHARD SADOVSKY, M.D.
Rizvon MK, et al. International travel and vaccinations. West J Med February 1999;170:97-103.
Nocturnal Asthma Controlled With Long-Acting Beta Agonist
Patients with nocturnal asthma who are clinically stable have decreased cognitive performance during the day and poorer sleep quality than their healthy counterparts. Asthma management focuses on minimizing the impact of symptoms on daily functioning and overall well-being. Nighttime symptoms traditionally have been treated with multiple medications. Recently, a newer long-acting beta agonist, salmeterol, has been used to reduce both nocturnal and daytime asthma symptoms. Lockey and colleagues evaluated the effectiveness of salmeterol in controlling nocturnal symptoms in patients with moderate persistent asthma. Safety evaluations were also conducted to correlate with overall measurements of quality of life.
Patients with an established diagnosis of asthma who had nighttime symptoms on at least six of 14 days during the baseline screening period were enrolled in this multi-center, randomized, placebo-controlled study. Exclusion criteria included pregnancy or lactation, serious medical illness, history of immunotherapy and current use of oral or inhaled beta-adrenergic agonists. Patients who met the study criteria were randomized to receive two puffs daily of either salmeterol or a placebo. Albuterol was used for breakthrough symptoms, and its use was recorded. Patients returned for follow-up visits every four weeks. At each visit, peak expiratory flow, patient diaries of symptoms and nighttime awakenings, and records of supplemental albuterol use were recorded. In addition, the Asthma Quality of Life Questionnaire (AQLQ) was administered at baseline and at each follow-up visit. The safety of the drug was evaluated on the basis of physical examination, vital signs, number of exacerbations and reports of adverse events.
A total 474 patients were enrolled in the study, with 240 in the salmeterol group and 234 in the placebo group. At baseline, study characteristics, including AQLQ scores, pulmonary function measurements and the incidence of steroid or theophylline use, were similar between groups. However, after the first four weeks and every four weeks thereafter, patients in the salmeterol group reported a better quality of life, improved peak expiratory flow measurements, reduced nighttime awakening and fewer daytime symptoms compared with patients receiving placebo. Salmeterol was well tolerated, with no clinical differences in examination findings and vital signs between groups.
The authors conclude that salmeterol is a safe, effective agent for treating nocturnal asthma. Salmeterol improved peak expiratory flow, quality of life scores and other pulmonary functions as well. In addition to the improvement in nighttime symptoms, patients reported an improved ability to carry on with their daily activities without fear of an exacerbation and with minimal side effects.
KARL MILLER, M.D.
Lockey RF, et al. Nocturnal asthma. Effect of salmeterol on quality of life and clinical outcomes. Chest March 1999; 115:666-73.
Managing First Trimester Spontaneous Abortion
Spontaneous abortion in the first trimester occurs in up to 20 percent of recognized pregnancies. However, the actual prevalence may be even higher, as many women are treated outside of a hospital setting or are unaware of the pregnancy. For the past 50 years, surgical evacuation by dilatation and curettage (D&C) has been the primary treatment of spontaneous abortion. This procedure is generally considered safe, but complications such as infection, bleeding, uterine perforation and decreased fertility occur in up to 10 percent of women. Recent studies have questioned the need for routine D&C, suggesting that expectant or medical management might be more appropriate. Geyman and colleagues performed a pooled quantitative literature evaluation to compare the outcomes of medical, surgical and expectant management of first trimester spontaneous abortions.
The literature search included MEDLINE citations on spontaneous abortion from 1966 to 1998, along with additional studies listed in the Cochrane database and in Best Evidence. Inclusion criteria consisted of all large studies that evaluated the outcomes of the three approaches to treatment of spontaneous abortion during the first 13 weeks of pregnancy. Studies that included any other type of abortion, had fewer than 15 patients and included significant medical complications or evidence of ectopic pregnancy were excluded. A meta-analysis of the data was planned but deemed impossible because of the lack of randomized controlled trials in the databases on this topic. Vaginal bleeding of less than three weeks, products of conception fully expelled by two weeks and absence of complications were considered successful outcomes of treatment.
Thirty-one studies were retrieved from the literature search. Of these, 18 met the inclusion criteria, including nine studies that evaluated expectant management, three that evaluated medical treatment with misoprostol or prostaglandin, and 10 that evaluated surgical treatment. Expectant management had an overall success rate of 92.5 percent, compared with 93.6 percent for surgical management. The number of pooled patients for these approaches was 545 and 1,408, respectively. The three studies that evaluated the outcomes of medical management included only 198 patients and had an overall success rate of 51.5 percent.
The authors conclude that expectant management of first trimester spontaneous abortion is safe and effective. Monitoring serial chorionic gonadotropin levels or examining the uterus with transvaginal sonography should be considered in select patients to rule out ectopic pregnancy. Surgical treatment is indicated if the patient has persistent brisk vaginal bleeding, infection or unacceptable pain, or if the gestational age of the fetus is greater than 13 weeks. For more information, see the accompanying figure detailing specific approaches to management of spontaneous abortion. Further studies, particularly randomized controlled trials, are needed to clarify the parameters and indications for expectant management of spontaneous abortion.
JEFFREY T. KIRCHNER, D.O.
Geyman JP, et al. Expectant, medical, or surgical treatment of spontaneous abortion in first trimester of pregnancy? A pooled quantitative literature evaluation. J Am Board Fam Pract January-February 1999;12:55-64.
Spontaneous Abortion in the First Trimester
Patient has spontaneous inevitable or incomplete abortion in first trimester Initial evaluation:
Vital signs
Pelvic examination
Transvaginal sonography usefulAfebrile
Stable vital signs
Uterus "empty" by transvaginal sonography or product of conception <50 mm (anteroposterior diameter)No excess bleeding or pain 
No
D&C (consider manual
vacuum aspiration)
Outpatient follow-up
CounselingYes Offer expectant treatment Outpatient follow-up
Consider serial hCGs
Counseling
Rising or persistent hCGs?
Yes
Further work-up
Rule out ectopic pregnancyFIGURE. Approach to management of spontaneous inevitable or incomplete abortion in the first trimester. (hCG=human chorionic gonadotropin; D&C=dilatation and curettage) Adapted with permission from Geyman JP, et al. Expectant, medical, or surgical treatment of spontaneous abortion in first trimester of pregnancy? A pooled quantitative literature evaluation. J Am Board Fam Pract 1999;12:62.
Comparison of Carvedilol and Metoprolol in Stable Angina
Carvedilol is a competitive antagonist of beta1, beta2 and alpha1 adrenoreceptors and, unlike other beta blockers, it is a powerful antioxidant, inhibiting cytotoxicity from oxygen radicals. In addition to its cardioprotective properties, carvedilol also has been found to have a mild beneficial effect on lipid levels in hypertensive patients with dyslipidemia. Van der Does and associates investigated the safety of higher dosages of carvedilol in patients with angina who did not adequately respond to lower dosages and compared the effects of carvedilol with those of metoprolol.
All 367 patients in the double-blind, randomized, multicenter study had exertional angina that improved with short-acting nitrates or rest. Coronary artery disease had been documented by angiography, a positive stress test or a previous myocardial infarction. Ergometric exercise testing was done before randomization and after each treatment period. Exercise test variables were symptom-limited total exercise time, time to onset of anginal pain and time to onset of 1-mm ST-segment depression.
Patients were initially randomized to receive 25 mg of carvedilol twice daily or 50 mg of metoprolol twice daily for four weeks. After four weeks of therapy at the low dosages, carvedilol and metoprolol dosages were increased if the total exercise time after the low-dose therapy was less than one minute. In this phase of the study, the carvedilol dosage was increased to 50 mg twice daily and the metoprolol dosage was increased to 100 mg twice daily. These dosages were continued for an additional eight weeks, after which ergometric exercise testing was again performed.
Both groups had a reduction in ST-segment depression of approximately 40 percent; reductions in heart rate and systolic blood pressure were also similar. Compared with metoprolol, carvedilol was found to improve the time to 1-mm ST-segment depression. The difference in this effect was statistically significant.
The occurrence of adverse events was similar between groups and ranged in severity from episodes of bradycardia, supraventricular tachycardia, dyspnea with sweating and wheezing, and atrial fibrillation, to less serious events such as dizziness, bronchitis, headache, back pain and gastroenteritis. Adverse events were more common among patients over 65 years of age.
The authors conclude that both treatment regimens produced clinically important improvements in exercise-induced angina. Carvedilol appeared to exert a somewhat greater anti-ischemic effect, as indicated by the variable time to 1-mm ST-segment depression. Since the response to the two drugs was equivalent with respect to beta blockade, it is thought that the vasodilatory and antioxidative effects of carvedilol may contribute to its beneficial influence on myocardial ischemia.
RICHARD SADOVSKY, M.D.
Van der Does R, et al. Comparison of safety and efficacy of carvedilol and metoprolol in stable angina pectoris. Am J Cardiol March 1, 1999;83:643-9.
Do Three Indicators Correlate with Severity of Asthma?
Classifying the severity of asthma may be a conundrum for physicians and patients alike. Most classification systems incorporate many variables, including poor symptom control, medication type and dosage, and objective measurements of lung function. In 1991, the National Asthma Education Program (NAEP) published criteria for mild, moderate and severe asthma that included the frequency of symptoms, objectively measured pulmonary function and the frequency of corticosteroid use. However, given the highly variable nature of asthma, this system was considered imperfect. Gauging the severity of asthma according to self-reports of the frequency and severity of symptoms is appealing, but these reports typically reflect current levels of control or compliance with treatment. Osborne and associates compared the NAEP criteria with physician-assessed severity measures to determine which more accurately identified asthma severity.
All patients in a regional HMO population who had either been hospitalized in the previous two years or had taken medication in the previous year for asthma were eligible for the study. Patients were evaluated clinically by spirometry and completed a questionnaire about their respiratory symptoms and medications. Patients were asked whether they had experienced wheezing, coughing or shortness of breath at any time within the previous four weeks and whether they had experienced these symptoms at night. Three scaled indexes, based on the NAEP criteria, were developed to classify asthma severity. In addition, the medical records of all patients were reviewed by two pulmonologists who collected data on the frequency of asthma exacerbations and assessed the asthma severity.
Of the 914 patients eligible for the study, 193 patients met the criteria for enrollment. Overall, 107 patients were classified as having moderate or severe asthma when the physician-assessed severity rating scale was used. When the NAEP criteria were applied to this group, only 53 percent of these patients were classified as having either moderate or severe asthma. Of particular concern as a result of this comparison were the patients who were classified as having mild asthma but actually had severe asthma and vice versa. The frequency of use of corticosteroids and spirometry results correlated with the physician assessment of asthma severity. However, there was no correlation between level of current symptoms and the physician assessment, even when nighttime symptoms were included in the assessment.
The authors conclude that while symptoms are a key patient concern and an important focus of asthma management, they do not correlate with asthma severity. Rather, symptoms better measure control and compliance with medication. As protocols and practice guidelines for asthma management evolve, they must not rely heavily on asthma symptoms. Physician judgment continues to be a more reliable measure of asthma severity.
KARL MILLER, M.D.
Osborne ML, et al. Lack of correlation of symptoms with specialist-assessed long-term asthma severity. Chest January 1999;115:85-91.
Which Treatment Is Best for Urinary Stress Incontinence?
Urinary stress incontinence, a condition characterized by involuntary loss of urine during coughing, sneezing or physical activity, may affect up to one third of women. Incontinence is socially embarrassing, often causing women to avoid social situations and limit regular physical exercise. Various therapies have been recommended, including pelvic floor exercises, surgery, electrical stimulation and use of weighted vaginal cones. However, data comparing the effectiveness of these modalities with no intervention are conflicting and inconclusive. Bo and colleagues evaluated the effectiveness of pelvic floor exercises, electrical stimulation and vaginal cone therapy compared with no treatment in women with stress incontinence.
Women eligible for this randomized controlled trial in Great Britain were either recruited by local advertising or were on a waiting list for surgical treatment. Baseline assessment included a urogynecologic history, uroflowmetry, cystometry, pad test and urinalysis. Inclusion criteria consisted of a history of genuine stress incontinence and more than 4 g of urine leakage on pad testing. Women with significant health problems, including urinary tract infection, were not eligible for the study. After stratification by severity of leakage on pad testing, patients were randomized into three treatment groups and a control group that received no treatment. Patients were taught about the anatomy of the pelvis and lower urinary tract, and were taught how to contract the muscles of the pelvic floor. In addition, patients were told that all treatments were expected to be equally effective, so they should follow only one protocol during the study period. Women in the pelvic muscle training group were asked to perform eight to 12 high-intensity contractions three times daily at home, along with weekly group training sessions with a physical therapist. Women in the electric stimulation group were treated 30 minutes a day following a standardized protocol. Women in the weighted vaginal cones group were asked to retain one of three weights for 20 minutes daily. Follow-up examinations were conducted every month for the six-month study period.
Data were collected on 107 of the 122 women who met the inclusion criteria. Demographic information and clinical findings were similar across groups at baseline. After six months, women in all treatment groups showed some increase in strength of the pelvic floor muscles, whereas women in the control group showed no significant improvement. Those in the muscle training group showed the greatest improvement in muscle strength and the greatest reduction in leakage on the pad test compared with women in the other two treatment groups. In addition, muscle training had no adverse effects, while discomfort and motivation difficulties were reported with the other modalities. At the end of the study, 14 women in the muscle training group, three in the electrical stimulation group, two in the vaginal cones group and one in the control group reported that their symptoms had resolved.
The authors conclude that pelvic floor exercises provided the most effective and acceptable therapy for genuine stress incontinence. They recommend that exercise should be promoted as the first line of therapy for this problem.
ANNE D. WALLING, M.D.
Bo K, et al. Single blind, randomized controlled trial of pelvic floor exercises, electrical stimulation, vaginal cones, and no treatment in management of genuine stress incontinence in women. BMJ February 20, 1999;318:487-93.
Repeat Vasectomy Reversal Effective After Prior Failures
With over 500,000 procedures performed annually, vasectomy is one of the most common surgical procedures in the United States. Although it is largely considered a permanent procedure, a few patients request a reversal. Microsurgical reversals have proved to be highly successful; however, up to 30 percent of reversals fail to reestablish sperm ejaculate. Hernandez and Sabanegh studied the success rate of vasectomy reversals after one or more failed attempts.
The authors reviewed the cases of 41 men who underwent vasectomy reversal again after one or more attempts at reversal had failed. The same surgeon performed these microsurgical reversal procedures. The data reviewed included date of vasectomy and first reversal attempt, history of prior conception with current partner, history of female infertility factors and smoking status. Semen analysis was performed three months after the procedure and quarterly for up to one year. Both patient and partner were interviewed during follow-up to determine postprocedure pregnancy rates. The mean follow-up period was eight months.
Thirty-eight of the men had undergone one prior reversal attempt and three had undergone two prior procedures. The mean age of the men was 39. A mean of 10.6 years had elapsed between the original vasectomy and the study procedure. Seventy-three percent of the men required vasoepididymostomy on at least one side during the reversal procedure, whereas only 4 percent of men undergoing initial reversal required vasoepididymostomy.
The postprocedure patency rate was 79 percent, with a pregnancy rate of 31 percent. The mean total motile sperm count after the procedure was 38 million. The only factor predictive of future conception was prior conception with the same partner; 80 percent of these men initiated a pregnancy, compared with 17 percent of men who had not previously conceived with their partner.
Even in experienced hands, vasectomy reversal may fail. Microsurgery after a failed vasectomy reversal can restore patency levels at rates consistent with those for the original procedure. The pregnancy rate was slightly lower than that for other studies, but the authors attributed this to the short length of follow-up. The authors conclude that microsurgical reversal of vasectomies after one or more failed attempts is associated with high patency rates and moderate pregnancy rates.
KARL MILLER, M.D.
Hernandez J, Sabanegh ES. Repeat vasectomy reversal after initial failure: overall results and predictors of success. J Urology April 1999;161:1153-6.
Community-Acquired Pneumonia: New Guidelines
The combination of community-acquired pneumonia (CAP) and influenza ranks as the sixth leading cause of death in the United States. The crude rate of these two conditions has increased by almost 60 percent in the past 15 years, making CAP a rapidly growing health risk, particularly among the elderly. Most cases of CAP are caused by Streptococcus pneumoniae, with an expanding list of other etiologic agents, including Haemophilus influenzae and Chlamydia pneumoniae. Unfortunately, an etiologic agent is never identified in up to 60 percent of patients with CAP. If no pathogen is identified, the diagnosis must be made on the basis of clinical criteria alone, none of which is definitive. In the past, the American Thoracic Society (ATS) and the Infectious Disease Society of America (IDSA) established evaluation and treatment guidelines for patients with CAP. Recently, however, IDSA proposed new guidelines based on the changing pattern of etiologic agents in an effort to streamline patient evaluation and identification of the associated etiologic agent. Bernstein summarizes these recommendations.
The new IDSA guidelines emphasize identification of the pathogen responsible for CAP. The new algorithm begins with obtaining a thorough history, including identification of symptoms consistent with CAP, such as a cough, fever and a prior history of pneumonia. Additional risk factors, including a history of viral infections, immunosuppression, neutropenia and pulmonary edema, also need to be identified at this time. The next step is obtaining a chest radiograph to establish the diagnosis and provide a baseline to assess trends in the patient's condition. Additional diagnostic studies include Gram stain and culture of sputum, a complete blood count including differential and a comprehensive metabolic profile. Severely ill patients should also be tested for tuberculosis and Legionella disease.
Guidelines for empiric treatment of CAP continue to evolve. IDSA now recommends macrolides, doxycycline or fluoroquinolones for primary therapy, as each of these agents is effective against the primary pathogen and many others. Therapy for patients with severe pneumonia should include fluoroquinolones, erythromycin or azithromycin, supplemented with cefotaxime, ceftriaxone or a beta-lactam/beta-lactamase inhibitor. Hospitalized patients can usually be switched from intravenous to oral therapy within three days. The total course of treatment in patients with CAP caused by Streptococcus pneumoniae should be seven to 14 days or until the patient has been afebrile for 72 hours. In patients with atypical pathogens, treatment should continue for 10 to 21 days.
The author concludes that the new IDSA guidelines cover all aspects of patient management. Greater emphasis is placed on obtaining a thorough history and a comprehensive battery of diagnostic tests, particularly sputum cultures, to guide therapy. Recommendations for antibiotic therapy include specific agents that have been proved effective against a variety of pathogens. The new IDSA guidelines are currently being integrated with revised guidelines from ATS to establish a single set of recommendations for the evaluation and treatment of CAP.
KARL MILLER, M.D.
Bernstein JM. Treatment of community-acquired pneumonia. IDSA guidelines. Chest March 1999;115:9S-13S.
How Parents Make the Decision About Circumcision
Routine circumcision remains a commonly performed but controversial surgical procedure. Possible benefits include a decreased risk of urinary tract infections, fewer sexually transmitted diseases and a lower incidence of penile cancer. In 1989, the American Academy of Pediatrics modified its position on routine circumcision, changing from opposition to stating that parents should be told about the risks and benefits of the procedure and that informed consent should be obtained. Few parents are aware of the medical debate over circumcision, and most make their decision based on concerns of appearance and hygiene. Tiemstra surveyed parents to determine how they made their decision about circumcision and if their physician influenced this decision. The time at which parents discussed the procedure was also noted.
Questionnaires were distributed to parents of all male infants six months of age or younger who presented to one of two family practice clinics for a well-child visit over a period of six months. The 13-item questionnaire included eight questions about their decision-making process and the timing of the decision; three questions about the location of prenatal care and their religious tradition; and two questions in check-list form that cited reasons for or against circumcision.
Fifty-five surveys were distributed, but only 52 were completed. The health plans of the parents varied, as did the principal provider of prenatal care. Forty-four (80 percent) of the infants had been circumcised. Forty-three parents made their decision either before or during the pregnancy--before discussing it with their physician or midwife. Of these, only four parents discussed their decision with a physician before delivery. When asked about the information given by their physician, more than 80 percent of the parents indicated that the physician was neutral about the procedure, 13 percent said circumcision was recommended and 4 percent were advised against the procedure. When asked if their discussion changed their minds, 83 percent said no. However, among those who did change their minds, more than one half selected circumcision. Seven of eight parents in the latter group reported having a neutral discussion about the procedure, and in only one instance was circumcision chosen after it was recommended.
Circumcision was most commonly done at birth for reasons of hygiene, convenience, other "medical" reasons and a history of the father being circumcised. Religion was not a significant factor. The most common reasons for not doing the procedure were related to the belief that it is not necessary, that it is painful and that the father was not circumcised.
The author concludes that most parents decide about circumcision before they discuss it with their physician and that the physician's opinions do not significantly affect their decision. Social reasons, such as hygiene and convenience, remain more important for parents than the medical indications for circumcision. Physicians who wish to influence this decision might consider discussing circumcision at the preconception visit.
JEFFREY T. KIRCHNER, D.O.
Tiemstra JD. Factors affecting the circumcision decision. J Am Board Fam Pract January-February 1999;12:16-20.
Combination Therapy to Improve Control of COPD
Chronic obstructive pulmonary disease (COPD) is characterized by air flow obstructions that result from bronchitis or emphysema. Exacerbations of the disease are common, resulting in additional costs and increased utilization of health care resources. Therapy with bronchodilators, such as ipratropium and albuterol, can often reverse the airway hyperreactivity associated with COPD. The combination of these two agents has been shown to provide greater bronchodilation than each agent alone. However, little is known about the effect of this combination on costs and utilization of health care resources. Friedman and associates conducted a post-hoc review of two double-blinded, randomized prospective trials on the safety and efficacy of these two agents when used alone or in combination to evaluate the pharmacoeconomic effects of each regimen.
Both studies included patients with an established diagnosis of COPD, characterized by stable, moderately severe air flow obstruction and use of two or more pulmonary agents to control their symptoms. Physical examination, laboratory studies and electrocardiography (ECG) were performed at entry and at the end of the study. Following a two-week baseline, patients were randomized to receive ipratropium, albuterol, or a combination of the two agents. Pulmonary function tests were performed on days 1, 29, 57 and 85 in all groups at 15-minute intervals for the first hour, then hourly for eight hours. Data on utilization of health care resources, including the number and severity of exacerbations, the number and length of hospital stays resulting from exacerbations, and the number of patient days of increased doses or additional medications needed were collected as well.
The combination of ipratropium and albuterol significantly improved peak forced expiratory volume when compared with each agent independently. Patients taking albuterol alone had more exacerbations of COPD, more hospitalization days and increased use of additional medication than patients treated with ipratropium alone or ipratropium in combination with albuterol. As a result, the total cost of care was higher in this group, despite the fact that albuterol costs less than the other agents. Patients who received ipratropium alone or in combination with albuterol experienced fewer exacerbations, had fewer hospital stays and took fewer additional medications.
The authors conclude that the combination regimen should be considered early in the management of moderate or severe COPD, as it provides superior bronchodilation and is associated with fewer exacerbations than albuterol or ipratropium alone. Fewer exacerbations improves the quality of life and significantly reduces the cost of health care for these patients.
KARL MILLER, M.D.
Freidman M, et al. Pharmacoeconomic evaluation of a combination of ipratropium plus albuterol compared with ipratropium alone and albuterol alone in COPD. Chest March 1999;115:635-41.
Oral and Insulin Antidiabetic Regimens in Type 2 Diabetes
The United Kingdom Prospective Diabetes Study (UKPDS) revealed that use of metformin in patients with type 2 diabetes was associated with more favorable outcomes with respect to the development of diabetes-related end points, all-cause mortality and stroke. However, the UKPDS did not investigate how patients who have poorly controlled glucose levels while receiving oral agents should be treated with insulin. Yki-Järvinen and associates compared four antidiabetic regimens to evaluate their effects on glucose control, weight gain and hypoglycemic episodes in patients with type 2 diabetes (formerly known as noninsulin-dependent diabetes) inadequately controlled with sulfonylureas alone.
The one-year study comprised 96 patients randomized into four treatment groups. All patients in each group received intermediate-acting human isophane insulin, 100 IU per mL at 9 p.m., with the dose adjusted according to home glucose monitoring. In addition to the bedtime insulin, the four treatment groups received as follows: group 1, glyburide, one 3.5-mg tablet before breakfast and two 3.5-mg tablets before dinner, plus metformin placebo; group 2, metformin, two 500-mg tablets before breakfast and two 500-mg tablets before dinner, plus glyburide placebo; group 3, glyburide and metformin together, taken in the same dosages as those used in the previously described groups; and group 4, no oral therapy and a second injection of insulin before breakfast. Patients with severe cardiovascular disease or microvascular disease, and patients who had previously received insulin therapy were excluded from the study.
Patients were instructed to increase their insulin dose by 4 IU per day if the fasting glucose level exceeded 144 mg per dL (8 mmol per L) on three consecutive measurements and by 2 IU per day if the fasting glucose level exceeded 108 mg per dL (6 mmol per L) on three consecutive measurements. While the initial bedtime doses of insulin were similar in the four groups, they varied among groups after 12 months of treatment. Specifically, the bedtime insulin dosage averaged 24 IU per day in patients receiving glyburide, 36 IU per day in those receiving metformin, 20 IU per day in those receiving both oral drugs and 24 IU per day in those receiving insulin both in the morning and at bedtime.
Unlike patients in the other three treatment groups, patients receiving metformin and bedtime insulin had a progressive decrease in the hemoglobin A1c level. After one year, the hemoglobin A1c level in the metformin group averaged 7.2 percent. The frequency of hypoglycemic episodes in this group was also significantly lower than in the other three groups. During the 12 months of therapy, the mean number of symptomatic hypoglycemic episodes per patient was 1.8 in patients receiving metformin plus bedtime insulin, compared with 3.4 hypoglycemic episodes in the glyburide group, 3.3 episodes in the group receiving both oral drugs and 3.9 episodes in the group receiving two doses of insulin.
With respect to weight gain on the different regimens, patients who took metformin plus bedtime insulin did not gain weight during the one-year study. In contrast, weight gain averaged 3.9 kg (8.6 lb) in patients receiving glyburide plus bedtime insulin, 3.6 kg (7.9 lb) in patients receiving bedtime insulin and the two oral drugs, and 4.6 kg (10.1 lb) in patients taking morning and bedtime insulin.
The authors conclude that the combination of bedtime insulin and metformin prevented weight gain during insulin therapy and resulted in the best overall glycemic control. The authors suggest the improved glycemic control occurring in all of the treatment groups is likely to be the result of teaching patients to adjust their insulin dosage on the basis of home glucose monitoring.
In an accompanying editorial, Nathan notes that the pathophysiology of type 2 diabetes--insulin resistance compounded by falling insulin secretion--can be treated in many ways. Insulin resistance can be decreased with diet, weight loss, exercise or medications, while insulin levels can be increased with agents that increase endogenous insulin secretion or with insulin injections. Nathan states that the 20-year UKPDS, partly because of its design, did not provide clear answers about which therapies are most advantageous. While the current study showed that the combination of bedtime insulin and metformin resulted in lower hemoglobin A1c levels, less weight gain and fewer episodes of hypoglycemia, it remains to be shown whether this combination would avert the worsening metabolic control that occurs over time in patients with type 2 diabetes. In addition, it is not known whether the added expense of such a combination is worth its weight-sparing effect. The UKPDS showed that modest weight gain does not diminish the decrease in microvascular complications that accompanies improved control of diabetes and may not be such a dangerous effect of treatment. However, Nathan concludes that the current study provides yet more support for the idea that intensive therapy goals can be achieved in patients with type 2 diabetes.
RICHARD SADOVSKY, M.D.
Yki-Järvinen H, et al. Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med March 2, 1999;130:389-96, and Nathan DM. Treating type 2 diabetes with respect [Editorial]. Ann Intern Med March 2, 1999;130: 440-1.
Can RSV Infection Be Prevented in At-Risk Infants and Children?
Palivizumab has recently been labeled by the U.S. Food and Drug Administration for prevention of respiratory syncytial virus (RSV) in high-risk infants and children. RSV is the most common cause of bronchiolitis and pneumonia in young children, with almost all infants affected at least once by two years of age. RSV usually causes a mild upper respiratory infection in otherwise healthy children, but hospitalization is common in premature infants and children with chronic immune deficiency, congenital heart disease and chronic lung disease.
No vaccine is currently available for RSV. Monthly intravenous injections of a hyperimmune globulin preparation decrease the incidence of RSV hospitalization in at-risk infants and children. However, its use is somewhat limited because of the inconvenience of monthly injections, concerns about use of a live attenuated vaccine and unexpected increases in adverse events in some children. Medical Letter consultants reviewed the available data on palivizumab.
A total of 1,500 premature infants and chronically ill children were given monthly intramuscular injections of palivizumab for five months at the start of the RSV season in a randomized, placebo-controlled study. Hospitalization was necessary in 4.8 percent of the patients in the treatment group and in 10.6 percent of the patients receiving placebo. The rate of hospitalization was also lower in both healthy premature infants and children with chronic lung disease taking palivizumab. Side effects were limited to increases in aminotransferase activity in the treatment group. The mortality rate was 1 percent or less in both groups.
The authors conclude that palivizumab significantly decreases the incidence of hospitalization for treatment of RSV in premature infants and in some young children with chronic lung disease but is a relatively expensive medication. The American Academy of Pediatrics has published detailed recommendations for use of palivizumab based on age, gestational age and the presence and severity of chronic lung disease or congenital heart disease. Although palivizumab appears to be relatively safe in selected children, the cost may be prohibitive.
BARBARA APGAR, M.D., M.S.
Medical Letter consultants. Palivizumab (Synagis) for prevention of RSV infection. Med Lett Drugs Ther January 1, 1999;41(1043):3-4.
Are Calcium Channel Blockers Safe in Diabetic Hypertension?
The leading cause of death among patients with diabetes is cardiovascular disease. Many diabetic patients also have hypertension. Calcium channel blockers have been shown to be effective for treating both hypertension and ischemic heart disease, as well as for preventing renal complications in patients with diabetes. Evidence suggests, however, that the dihydropyridine class of calcium channel blockers may actually provoke myocardial infarction in patients with coronary artery disease. To evaluate this, Tuomilehto and other investigators from the Systolic Hypertension in Europe (Syst-Eur) trial performed a post-hoc analysis of their data to determine the effect of nitrendipine, a calcium channel blocker, on long-term outcomes in diabetic and nondiabetic patients with hypertension.
Patients eligible for the trial had to be at least 60 years old and have a systolic blood pressure of 160 to 219 mm Hg and a diastolic pressure of less than 95 mm Hg. Diabetic patients were included only if their blood sugar levels were under good control. The patients were randomly assigned in a double-blind fashion to receive either nitrendipine or placebo. The dosage of the study medication was titrated to attain a systolic pressure of less than 150 mm Hg. If necessary, enalapril was added as a second-line drug and hydrochlorothiazide as a third-line drug for further blood pressure control. The end points that were evaluated included stroke, acute myocardial infarction, congestive heart failure and sudden death.
A total of 4,695 patients were randomized into the study, 492 of whom had diabetes. In the diabetic patients at randomization, the mean systolic blood pressure was 175 mm Hg, and the mean diastolic pressure was 86 mm Hg. The numbers were essentially the same in the nondiabetic patients. Approximately 66 percent of all patients were women, and 7 percent were smokers. The median duration of follow-up was two years. The overall antihypertensive treatments during this time were similar for both diabetic and nondiabetic patients.
After two years, systolic and diastolic blood pressures in the diabetic patients in the active treatment and placebo groups differed by 8.6 and 3.9 mm Hg, respectively. In the nondiabetic patients, these differences were 10.3 mm Hg systolic and 4.5 mm Hg diastolic. After adjusting for age, sex, smoking status and previous history of cardiovascular complications, the researchers found that the active-treatment group of diabetic patients had a 55 percent reduction in overall mortality, a 69 percent reduction in all cardiovascular events, a 76 percent reduction in cardiovascular mortality and a 73 percent reduction in fatal and nonfatal strokes. Nondiabetic patients who received hypertensive treatment had a 26 percent reduction in all cardiovascular events and a 38 percent reduction in fatal and nonfatal strokes. Collectively, the effect of active treatment on overall mortality and mortality associated with cardiovascular events was greater in the patients with diabetes than in patients without that disease.
The authors conclude that active treatment of systolic hypertension effectively reduces cardiovascular events, mortality associated with these events, and strokes. The benefits are even greater in patients who have diabetes. Furthermore, the authors believe this study shows that calcium channel blockers are a safe and effective therapy in patients with cardiovascular disease.
JEFFREY T. KIRCHNER, D.O.
Tuomilehto J, et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med March 4, 1999;340:677-84.
Guidelines for Managing Chronic Renal Failure
It is estimated that 3 million Americans will have chronic renal failure by the year 2008. Diabetes and hypertension account for two thirds of persons with chronic renal failure. Other high-risk patients include those with chronic glomerulonephritis or a family history of renal disease. High-risk patients should be screened with quarterly blood pressure measurements, and annual urinalysis, serum creatinine and 24-hour urinary microalbumin measurements. McCarthy reviewed the literature on managing chronic renal failure and developed a helpful mnemonic, "BEANS," to help physicians remember the steps that should be taken in at-risk patients to slow the progression of renal disease.
Blood Pressure Control. Blood pressure should be reduced to 130/85 mm Hg in patients with renal disease. The blood pressure should be no more than 125/80 mm Hg in patients who have more than 3 g per day of protein in their urine. Angiotensin-converting enzyme inhibitors are the preferred antihypertensive therapy in patients without hyperkalemia and serum creatinine levels of less than 3 mg per dL (265 mmol per L). Nondihydropyridine calcium channel blockers may also help to slow the progression of kidney disease.
Erythropoietin. Patients with chronic anemia related to renal failure should be treated when their hemoglobin level reaches 10 g per dL (100 g per L), with a hematocrit less than 30 percent, to improve function and cardiac problems. Treatment includes 200 mg per day of elemental iron and 1 mg per day of folic acid. If this treatment does not raise the hemoglobin level to 10 g per dL, patients should be treated with 40 to 60 U per kg of subcutaneous erythropoietin one or two times per week. This dosage should be increased 25 percent if the targeted hemoglobin level is not reached in four weeks. Some patients have a rapid response to erythropoietin; therefore, renal function must be monitored monthly, and iron studies must be checked quarterly to detect hypertension and hyperkalemia.
Access for Long-Term Dialysis. Placement of long-term hemodialysis access when the serum creatinine level reaches 4 mg per dL (350 mmol per L) and the glomerular filtration rate is less than 20 mL per min improves survival and decreases hospitalization and complication rates. Furthermore, it increases the chance that the patient will be a candidate for peritoneal or home dialysis.
Nutritional Care. The need to obtain optimal nutrition in the anorexic patient must be balanced with the need to restrict protein, sodium, potassium and phosphorus intake. Poor outcomes are associated with an albumin level less than 3 g per dL (30 g per L). Patients who are 5 to 10 percent below ideal body weight, who eat less than 30 kcal per kg per day or who spontaneously eat less than 0.8 g per kg per day are at risk of muscle wasting. Once patients are on dialysis, their protein restriction can be liberalized to 1 to 2 g per kg per day. Bicarbonate should be supplemented when the serum bicarbonate level is below 20 mEq per L. Patients should receive vitamin B and folic acid supplements, and water-soluble vitamins. Supplements with vitamin A, vitamin D2 and vitamin C should not be given. Phosphorus levels should be maintained at 3.5 to 5 mg per dL (1.13 to 1.61 mmol per L) with dietary restriction and phosphate-binding calcium salts at meal times.
Specialist Referral. Guidelines for referral include a glomerular filtration rate less than 30 mL per min per 1.73 m2 (serum creatinine level of 3 mg per dL) or an anticipated need for dialysis within a year. A patient who is a candidate for a renal transplant should also be referred.
CLARISSA C. KRIPKE, M.D.
Medical Editing FellowMcCarthy JT. A practical approach to the management of patients with chronic renal failure. Mayo Clin Proc March 1999;74:269-73.
Risk of Mural Thrombus After a Brief Period of Atrial Fibrillation
The term "stunning" is used to describe the mechanical dysfunction of the left atrium that occurs after conversion of atrial fibrillation to sinus rhythm. This phenomenon has been implicated in the development of embolic events after cardioversion of atrial fibrillation. Studies have shown that electric remodeling can occur in only seven minutes of atrial fibrillation and can be sufficient to promote subsequent episodes of atrial fibrillation. Whether stunning develops after a brief episode of atrial fibrillation is unknown. Sparks and colleagues studied the effect of a brief duration of atrial fibrillation on the mechanical function of the left atrium and the left atrial appendage in patients with underlying structural heart disease. The authors also attempted to determine the risk of embolic events.
The study included 24 patients with significant structural heart disease, including a low ejection fraction and an increased atrial diameter. These patients were undergoing implantation of a ventricular implantable cardioverter defibrillator when the study was performed. Transesophageal echocardiography was used to evaluate the left atrium and the atrial appendage before, during and after the induction of atrial fibrillation.
Left atrial function and left atrial appendage function were assessed at six junctures: (1) when the heart was in sinus rhythm one minute before induction of atrial fibrillation; (2) after induction of atrial fibrillation at one minute; (3) after induction of atrial fibrillation at 10 minutes; (4) immediately after reversion of atrial fibrillation to sinus rhythm; (5) when the heart was in sinus rhythm five minutes after reversion; and (6) when the heart was in sinus rhythm 10 minutes after reversion of atrial fibrillation. The arrhythmia continued for 15 minutes, at which time it was allowed to resolve spontaneously. If spontaneous resolution did not occur by 20 minutes, a sinus rhythm was re-established electrically. Spontaneous echo contrast was evaluated at the six time points.
During atrial fibrillation, changes in velocities within the left atrium and the atrial appendage were observed, but velocities returned to baseline immediately after converting to sinus rhythm. No significant change in left atrial function was seen immediately after the termination of atrial fibrillation.
The authors conclude that a 15- to 20-minute period of atrial fibrillation is not associated with left atrial stunning, even in patients with underlying heart disease. The findings suggest that patients with short runs of atrial fibrillation that spontaneously convert to sinus rhythm do not require anticoagulation therapy to reduce the risk of embolic stroke.
KARL MILLER, M.D.
Sparks PB, et al. Left atrial mechanical function after brief duration atrial fibrillation. J Am Coll Cardiol February 1999;33:342-9.
Does Two Weeks of Bed Rest Bring About Relief from Sciatica?
Few studies support the recommendation that bed rest be instituted for the treatment of low back pain and sciatica. Nonetheless, many patients and physicians seem to favor this form of therapy, especially in the acute period. Vroomen and colleagues performed a randomized, controlled, blinded trial to evaluate the efficacy of bed rest in the treatment of sciatica.
The 183 patients entering the study presented to their primary physicians with back pain that radiated into the leg. Excluded were persons who had previously undergone spinal surgery, were involved with workers' compensation claims or had severe coexisting disease. History, physical examination and magnetic resonance imaging (MRI) of the lumbar spine were obtained. Patients who did not have strong clinical evidence of sciatica or were found to have an indication, such as cauda equina syndrome, for immediate surgery were excluded.
Patients were randomized to bed rest or watchful waiting for two weeks. Patients treated with bed rest were instructed to stay in a supine or lateral recumbent position as much as possible. They were only allowed to get out of bed to go to the bathroom and to bathe. Patients in the control group were allowed to perform routine activities but were asked to refrain from any activities that caused significant strain to their backs. The two groups were demographically similar with respect to clinical findings.
Patients kept diaries of their functional status and the number of hours they spent in bed each day. A visual analog scale was used for self-reports of the degree of pain. Patients were allowed to take 1,000 mg of acetaminophen three times a day, supplemented by 10 to 40 mg of codeine six times a day or 500 mg of naprosyn three times a day. Follow-up office visits to assess pain and functional status were made at two and 12 weeks. A home visit was made during the third week. The investigators who did the assessments did not know the patients' treatment status.
At the two- and 12-week evaluations, no significant differences were noted between the two groups with regard to the patients' and the examiners' assessment of improvement. At two weeks, 37 percent of the bed-rest group and 35 percent of the control group reported "great improvement" in symptoms. Overall, 70 percent of the bed-rest group reported some degree of improvement at two weeks, compared with 65 percent of the control group. At 12 weeks, 87 percent of the patients in each group reported improvement. The investigators' assessment of improvement at two weeks was 73 percent for the bed-rest group and 65 percent for the control group. At 12 weeks, the investigators' assessments were 86 percent improvement for the bed-rest group and 89 percent improvement for the control group. Diary entries revealed that the bed-rest group spent an average of 21 hours daily in bed, compared with 10 hours for the control group.
Regarding secondary outcomes, the median number of missed days of work was the same for both groups, as was the percentage of patients who went on to have surgery (17 percent in the bed-rest group and 19 percent in the control group). The rate of acetaminophen use was the same for both groups. The control group, however, reported using heat on an average of five occasions compared with twice for the bed-rest patients.
The authors conclude that bed rest is not more effective than watchful waiting in patients with sciatica-type symptoms related to lumbosacral injury. This finding is in keeping with the findings of at least three other previously published studies
JEFFREY T. KIRCHNER, D.O.
Vroomen PC, et al. Lack of effectiveness of bed rest for sciatica. N Engl J Med February 11, 1999; 340:418-23.
Quality-of-Life Scores After Laparoscopic Antireflux Surgery
While gastroesophageal reflux disease (GERD) can usually be improved with medical therapy and lifestyle alterations, such lifestyle changes as dietary modification, sleeping with the head of the bed elevated and not eating late in the day may have a negative effect on the patient's quality of life. Trus and associates evaluated the effects of laparoscopic antireflux surgery on quality of life in patients with severe GERD.
Patients in the study underwent evaluation for possible surgery to correct GERD. The mean age of the 345 patients was 49 ± 14 years, and most of them underwent surgery for typical reflux symptoms, such as heartburn, regurgitation and dysphagia. The mean duration of GERD was eight years.
The generic (not disease-specific) medical outcome study questionnaire was used to evaluate quality-of-life measures. This 36-item form measures health concepts such as physical function, pain, general health perception, vitality, social function, mental health and well-being. A total of 289 patients completed a preoperative questionnaire, 223 completed a postoperative questionnaire, 181 completed both preoperative and postoperative questionnaires, and 50 completed the questionnaire one year after laparoscopic antireflux surgery.
The scores for each of eight quality-of-life measures showed significant improvement after antireflux surgery. The scores remained significantly improved for at least one year, indicating that surgery relieved reflux symptoms without negatively affecting quality of life.
The authors conclude that laparoscopic antireflux surgery is an effective treatment in patients with GERD. The findings suggest that it may be more effective than medical therapy in improving quality-of-life measures.
RICHARD SADOVSKY, M.D.
Trus TL, et al. Improvement in quality of life measures after laparoscopic antireflux surgery. Ann Surg March 1999;229:331-6.
EDITOR'S NOTE: Laparoscopic fundoplication has made it less invasive to operate on patients with GERD. Studies of laparoscopic antireflux surgery suggest that the typical symptoms of heartburn and regurgitation are relieved at a higher rate than the atypical symptoms associated with pulmonary, pharyngolaryngeal and epigastric syndromes. Good response to a preoperative trial of omeprazole or histamine H2- receptor blockers was reported to be significantly associated with a better surgical outcome and greater relief of atypical symptoms. Manometric findings were not found to predict relief of atypical symptoms after surgery.
--R.S.
Bupropion With or Without Patches for Smoking Cessation
Of the 20 million Americans who try to quit smoking each year, only about 6 percent continue to abstain from cigarettes in the long term. The availability of nicotine replacements in a patch or gum has helped, but only about 20 percent of persons who use these methods are successful. The observation that a depressed affect correlated with nicotine dependence led to the use of antidepressant therapies to help people quit smoking. Jorenby and colleagues compared bupropion, a nicotine patch, a combination of those two agents, and placebo to determine their efficacy in helping people stop smoking cigarettes.
The study enrolled 893 patients who were at least 18 years of age and smoked at least 15 cigarettes per day. Persons were excluded for a variety of reasons, including cardiac, pulmonary or renal disease, seizure disorder, major depression, pregnancy, use of nicotine replacement in the previous six months or previous use of bupropion. Baseline data included serum cotinine and exhaled carbon dioxide levels, results of depression and nicotine dependence measures. The primary outcome to be assessed was the rate of abstinence at six and 12 months of follow-up. Secondary outcomes included weight gain, withdrawal symptoms and Beck Depression Inventory scores.
The subjects were randomly assigned to receive placebo, a nicotine patch, bupropion or both nicotine patch and bupropion. The length of the trial was nine weeks, with a one-week lead-in period and an assigned quit date on day 8. The bupropion patients received two 150-mg tablets daily, and all other persons received placebo tablets. The nicotine patch groups applied a 21-mg patch on day 8 and continued this daily for eight weeks, followed by a 14-mg patch in the eighth week and a 7-mg patch in the ninth week. All other participants were given placebo patches. Additional supports included weekly counseling sessions and telephone follow-up. Smoking cessation was self-reported but expired carbon monoxide was measured weekly during the nine-week treatment period. Further clinic follow-up and relapse-prevention counseling was done at weeks 10, 12, 26 and 52.
The subjects (58.8 percent female, 41.2 percent male) had smoked an average of 26 cigarettes per day for a mean of 26 years. Of the 893 initial subjects, 311 did not complete the study; however, of these, 134 participated in the follow-up assessments. Persons from the placebo groups had the highest rate of discontinuing treatment (48.8 percent) compared with those who received the combined treatment (28.6 percent). At week 4 of the trial, 48 percent of the nicotine patch group, 60.2 percent of the bupropion group and 66.5 percent of those receiving both therapies were abstinent. The number of persons not smoking at six months was 18.8 percent in the placebo group, 21.3 percent in the nicotine patch group, 34.8 percent in the bupropion group and 38.8 percent in the group receiving the combined therapy. By month 12, 15.6 percent of the placebo group, 16.4 percent of the nicotine patch group, 30.3 percent of the bupropion group and 35.5 percent of the combination-treatment group were not smoking.
At the start of the trial, mean weight was comparable among the groups. By week 7 of the study, persons in the placebo group had gained the most weight, 2.1 kg (4.6 lb) compared with the combination-therapy group, who had the lowest average weight gain, 1.1 kg (2.4 lb). Insomnia was the most common adverse event, reported by 48 percent of the combined-therapy group, 42 percent of the bupropion group, 30 percent of the nicotine patch group and 20 percent of the placebo participants. Another finding of note was that all participants had Beck Depression Scores within the normal range at the onset of the study, and none of the treatments affected follow-up depression scores.
The authors conclude that the use of sustained-release bupropion, with or without a nicotine patch, is significantly more effective for long-term smoking cessation than the use of a nicotine patch alone. The other interesting observation derived from this study was that the use of dual placebos produced a 15.6 percent cessation rate, which is comparable to the 16.4 percent cessation rate achieved by patients who used a nicotine patch.
JEFFREY T. KIRCHNER, D.O.
Jorenby DE, et al. A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med March 4, 1999;340:685-91.
ACE Inhibitors and Mortality Following Myocardial Infarction
Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce the incidence of sudden cardiac death and nonfatal subsequent infarctions following myocardial infarction (MI). These agents attenuate left ventricular dilation, resulting in less ventricular enlargement. ACE inhibitors have also been shown to decrease the likelihood of malignant ventricular arrhythmias. Domanski and colleagues reviewed the literature from 1978 to 1997 in an attempt to confirm the benefit of ACE inhibitors in reducing mortality after MI.
A MEDLINE search for all randomized trials of ACE inhibitor use in post-myocardial infarction for January 1978 through August 1997 was conducted for meta-analysis. Inclusion criteria consisted of randomized comparisons of ACE inhibitor and placebo treatment of acute MIs within 14 days after the event, studies that were conducted for a period of six weeks or longer with a blinded follow-up of six weeks or longer, and studies that reported the total, cardiovascular and sudden cardiac death mortalities.
Sudden cardiac death was defined as "sudden unexpected collapse without documentation of arrhythmia or collapse due to intractable ventricular tachycardia/fibrillation."
Fifteen studies, with a total of 15,104 patients, met the inclusion criteria. Of the 2,054 cardiovascular deaths identified, 900 were considered sudden cardiac deaths. Meta-analysis of the data from these studies revealed that the incidence of cardiovascular or sudden cardiac death was lower in patients taking ACE inhibitors than in those taking placebo. Study duration and the use of other agents, such as aspirin, beta-adrenergic blocking agents and calcium channel blockers, were not included in the meta-analysis, since they had only a small treatment effect.
The authors conclude that ACE inhibitor therapy reduces the overall incidence of cardiovascular death following acute MI. The use of ACE inhibitors also reduces sudden cardiac deaths by 20 percent, which is a significant reduction. However, the exact mechanism for this reduction has not been definitively established.
KARL MILLER, M.D.
Domanski MJ, et al. Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction. A meta-analysis of randomized clinical trials. J Am Coll Cardiol March 1999; 33:598-604.
Angioplasty and Stent Placement in Multiple-Vessel Disease
Patients with multiple-vessel coronary artery disease were once considered poor candidates for angioplasty because of the high incidence of re-stenosis. Before the widespread use of stents with angioplasty, surgical intervention with coronary artery bypass grafting (CABG) resulted in better clinical outcomes for these patients. Kornowski and associates evaluated the clinical outcomes of patients with multiple-vessel disease treated with angioplasty, including stent placement when indicated, compared with patients who had single-vessel disease treated in a similar manner.
A consecutive series of 2,339 patients treated with stents at a cardiology research center between 1994 and 1997 were enrolled in the study. Patients were grouped according to whether single-vessel or multiple-vessel disease (two or more lesions) was present. All patients underwent electrocardiography before and after surgery, and blood samples were obtained every eight hours postoperatively to measure creatine kinase MB (CK-MB) enzyme levels. Clinical outcomes at one year were assessed by telephone interviews, and any late clinical events were documented.
Basic demographic information was similar between groups, although patients in the single-vessel group were more likely to have had angioplasty and CABG and a recent history of myocardial infarction. The indications and types of stents used were similar between groups, as were the lesion configurations and measurements. Overall, success rates after the procedure, major in-hospital complication rates, and other potential early postoperative complications were the same between groups. Of note, however, was the increased incidence of CK-MB "leak" in the multiple-vessel group. Long-term follow-up revealed no differences in mortality rates or in the number of revascularization procedures between groups, and the event-free survival curves were the same.
The authors conclude that angioplasty with stent placement may be a viable alternative to CABG in treating selected patients with multiple vessel coronary artery disease, primarily those with two-vessel disease. Success rates and both short- and long-term outcomes are similar in patients with either type of vessel disease.
KARL MILLER, M.D.
Kornowski R, et al. Procedural results and late clinical outcomes following multivessel coronary stenting. J Am Coll Cardiol February 1999;33:420-6.
Montelukast vs. Beclomethasone for Control of Persistent Asthma
Inhaled corticosteroids, such as beclomethasone, are the medications most commonly used to control asthma, but problems with compliance limit their effectiveness, especially in children and elderly patients. Leukotriene receptor antagonists are now considered to be alternative first-line controller medications. The oral leukotriene receptor antagonist montelukast has demonstrated efficacy in both adults and children, and is well tolerated. Malmstrom and associates compared oral montelukast, inhaled beclomethasone and placebo in patients with chronic asthma who required the daily use of a controller medication.
The 12-week study included 895 patients 15 to 85 years of age who required at least a single daily puff of an as-needed, short-acting inhaled beta agonist. Eligibility criteria also included a forced expiratory volume in one second (FEV1) of 50 to 85 percent of the predicted value, and an increase of at least 15 percent in the absolute FEV1 after inhalation of a beta agonist.
Patients were randomized to receive one of three treatments: (1) montelukast, 10 mg in the evening, (2) inhaled beclomethasone, 200 µg twice daily or (3) placebo. The study design included a two-week placebo run-in period, a 12-week double-blind treatment period and a three-week double-blind placebo washout period. Withdrawal from therapy was evaluated by switching a subset of patients who received active treatment to placebo in a blinded manner. If severe episodes of asthma developed, patients were treated with oral steroids; patients who had more than two worsening episodes were dropped from the study.
Spirometry was performed at each visit, and participants completed questionnaires about daytime asthma symptoms and nocturnal awakening. They also kept a diary of morning and evening peak expiratory flow rates and daily use of as-needed salbutamol.
Compared with placebo, both montelukast and beclomethasone provided significant benefit with respect to FEV1, daytime symptom scores, as-needed beta agonist use, morning and evening peak expiratory flow rates and nocturnal awakenings. FEV1 improved 13.1 percent with inhaled beclomethasone, compared with an improvement of 7.4 percent with oral montelukast. Beclomethasone had a larger mean effect than montelukast. The reduction in asthma attacks was similar in the beclomethasone and montelukast groups, and both active treatment groups showed significantly reduced eosinophil counts. Clinical adverse events were similar in all three groups.
The authors conclude that oral montelukast and inhaled beclomethasone provide similar protection against worsening episodes of asthma. Both are generally well tolerated. Although there was similar compliance in all groups in this study, data suggest that oral therapy is associated with greater adherence.
In an accompanying editorial, Smith points out that the response to inhaled corticosteroids, the gold standard treatment, may be 70 to 80 percent. It is not clear whether this is due to noncompliance, a lack of effect, poor delivery to the lungs or a combination of these factors. Smith also compared the positive and negative attributes of inhaled corticosteroids and leukotreine receptor antagonists (see the accompanying table). It remains impossible to predict an individual patient's responsiveness to one treatment or the other, and the place for leukotriene receptor antagonists in the treatment of asthma is not yet well defined. Nevertheless, Smith believes that leukotriene receptor antagonists may be a good first choice in patients with mild persistent asthma (symptoms occurring less than daily) based on the safety and oral bioavailability of this class of drugs. In patients with moderate persistent asthma (symptoms occurring daily), inhaled corticosteroids may be a better first choice because of the higher likelihood that they will be effective. In patients with severe persistent asthma (continuous symptoms), the addition of antileukotrienes to treatment with corticosteroids (inhaled and oral) and long-acting beta agonists may be beneficial.
RICHARD SADOVSKY, M.D.
Malmstrom K, et al. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. Ann Intern Med March 16, 1999;130:487-95, and Smith LJ. Newer asthma therapies [Editorial]. Ann Intern Med March 16, 1999;130:531-2.
Attributes of Leukotriene Receptor Antagonists and Inhaled Corticosteroids Agent
Positive attributes
Negative attributes
Leukotriene
receptor
antagonistsOral bioavailability
Easy to administer
Few side effects (with short-term use)
Effective in patients who cannot tolerate aspirin
Reach distal airways and lung parenchymaInhibit only a single mediator
Limited clinical experience
Unknown long-term toxicity
Effective in only 50 to 70% of patients
Systemic delivery and availabilityInhaled
corticosteroidsDirect deilvery to the airways
Broad anti-inflammatory action
Minimal systemic availability
Effective in >70% of patients
Well-defined toxicityDifficult-to-use delivery system
Local toxicity (such as thrush and dysphonia)
Systemic toxicity with higher dosages (such as osteoporosis, cataracts and skin bruising)
Reprinted with permission from Smith LJ. New asthma therapies [Editorial]. Ann Intern Med 1999;130:531-2.Biliary Symptoms and Predictors of Common Bile Duct Stones
Common bile duct stones complicate cholelithiasis in 10 to 15 percent of cases. Most authorities believe ductal stones should be removed because of possible complications, including cholangitis and acute pancreatitis. The ability to predict the presence or absence of bile duct stones would be helpful in the management of these patients. Because of new diagnostic and therapeutic approaches, such as endoscopic retrograde cholangiopancreatography (ERCP), endoscopic ultrasonography and laparoscopic surgery, Prat and associates conducted a study to identify predictors of common bile duct stones in patients with biliary symptoms.
The 880 patients in the prospective study had been referred for endoscopic ultrasonography for the evaluation of common bile duct stones. This procedure is considered the gold standard for the diagnosis of common bile duct stones. The prevalence of choledocholithiasis in the study population was 18.8 percent (166 of 880 patients). In patients under age 70, the prevalence of choledocholithiasis was 14 percent; in patients over 70, the prevalence was 32 percent.
Data analyses revealed that independent predictive variables for the presence of choledocholithiasis in patients younger than 70 years were an elevated (more than seven times normal) g-glutamyl transferase (GGT) level, a pathologic gallbladder and an abnormal common bile duct (dilated or with an intraluminal hyperechoic image on transabdominal ultrasound). In patients older than 70 years, independent predictors were elevated GGT, fever and a "suspect" common bile duct.
The authors conclude that screening of patients at risk for choledocholithiasis can be done using the three predictive criteria according to the patient's age. In patients undergoing cholecystectomy, two predictors (common bile duct size and GGT level) may be useful for screening.
RICHARD SADOVSKY, M.D.
Prat F, et al. Prediction of common bile duct stones by noninvasive tests. Ann Surg March 1999;229:362-8.
Oral vs. Intravenous Ciprofloxacin for Severe Urinary Tract Infection
Combination therapy, such as ampicillin plus gentamicin, and single-drug therapy, such as a third-generation cephalosporin, a broad-spectrum beta-lactam agent or a fluoroquinolone, are frequently used empirically to treat severe urinary tract infections (UTIs). This approach, however, is generally not based on clinical trials that have identified the choice of antibacterial agents. In addition, the recommendation of parenteral therapy for severe UTIs is based on the unproven assumption that oral therapy is inadequate for bacteremic UTIs. Mombelli and associates performed a prospective, randomized study to compare oral and intravenous ciprofloxacin in the initial empiric treatment of serious pyelonephritis or complicated UTIs, including cases of suspected bacteremia.
A total of 141 patients with complicated UTIs were randomized to receive intravenous ciprofloxacin, 200 mg every 12 hours, or oral ciprofloxacin, 500 mg every 12 hours. Seventy-two patients were in the oral therapy group and 69 were in the intravenous therapy group. Intravenous ciprofloxacin was administered for a minimum of 72 hours or at least until the patient was afebrile for 24 hours. Patients receiving intravenous therapy were then switched to oral therapy. The patient's response to the initial treatment was evaluated in terms of suppression of growth of the causative organisms on the third to fifth days of therapy and of relief of fever and UTI symptoms. Treatment failure was defined as the need to change to a different empiric therapy before the results of susceptibility testing were available. A change in therapy was deemed necessary if fever and chills persisted or signs of sepsis developed.
The two treatment groups were comparable with respect to the type of UTI, the signs and symptoms, the results of susceptibility testing and the frequency of bacteremia. Fever and symptoms abated rapidly in most patients, without a significant difference between the two groups. Among patients with pyelonephritis, fever lasted significantly longer in those who had bacteremia compared with those who did not have bacteremia. However, no difference was found in the mean duration of fever. Fever lasted for a mean of 1.7 days in those who received oral therapy and 1.9 days in those who received intravenous therapy.
Rates of microbiologic failure (3 percent with oral therapy and 2 percent with intravenous therapy) were low, as were rates of unsatisfactory clinical response (4 percent and 3 percent in the oral and intravenous groups, respectively). None of the patients required a change of antibiotic therapy because of clinical deterioration during the initial empiric treatment. However, microbiologic or clinical failure occurred in seven patients. In addition, initial therapy had to be changed in five patients in the oral therapy group and in three patients in the intravenous therapy group because of isolation of enterococci or other resistant strains. The occurrence of adverse effects was extremely low with oral or intravenous ciprofloxacin.
The authors conclude that oral ciprofloxacin is as effective as intravenous ciprofloxacin in the initial empiric treatment of severe UTIs, including bacteremic forms, provided that severe sepsis, obstruction or foci of renal suppuration are not present. Alt
