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Use of Tamoxifen in Women with Early Breast Cancer
In patients with early breast cancer, all detectable cancer can be removed surgically from the breast or local lymph nodes. The threat of remaining micrometastases that might produce a clinically significant recurrence of the cancer several years after the original surgery has led to widespread use of tamoxifen. Although several studies indicate that tamoxifen improves survival and other outcome measures in some patients, the selection of appropriate patients and the duration of treatment remain unclear. The Early Breast Cancer Trialists' Collaborative Group used data from more than 36,000 women in 55 randomized trials to clarify the role of tamoxifen in the treatment of early breast cancer.
Information was sought on each woman participating in any randomized trial conducted since 1984, comparing treatment with tamoxifen with no treatment. The authors attempted to follow every woman until at least 1995. In the 55 trials, 36,689 women were followed for an average of 10 years. A total of 14,140 first recurrences of the cancer and 13,268 deaths were reported. The overall results showed significant reductions in mortality and recurrence in women who received tamoxifen. The proportional reductions in mortality for women who received tamoxifen for one, two and five years were 10, 15 and 22 percent, respectively. The corresponding rates of reduction in recurrence were 18, 25 and 42 percent. These benefits appeared substantially greater in women with estrogen-receptor (ER)positive tumors. In the 18,000 women with ERpositive tumors, the proportional reductions in mortality at one, two and five years of tamoxifen therapy were 14, 18 and 28 percent, respectively. The reduction was greater in women with ER++ tumors (36 percent) than in those with ER+ tumors (23 percent). The reductions in rate of recurrence in ERpositive women with one, two and five years of tamoxifen therapy were 21, 28 and 50 percent, respectively. These benefits appeared to be largely irrespective of age, menopausal status, use of chemotherapy or daily dosage of tamoxifen.
The high prevalence of ERpositive tumors in younger women and the longer duration of follow-up contributed to the conclusion that tamoxifen benefited younger women as well as those older than 50 years of age or of post-menopausal status.
In the 8,000 women with ERpoor tumors, the proportional reduction in mortality was about 6 percent and the reduction in recurrence was about 10 percent. The authors conclude that the benefits of tamoxifen in patients with ER-poor tumors are unclear and require further research.
Endometrial cancer was the only cause of death that increased significantly in women treated with tamoxifen. The 32 cases recorded are almost double the incidence of endometrial cancer after approximately two years of tamoxifen therapy. However, the relative rarity of endometrial cancer compared to breast cancer means that the reduction in recurrent or contralateral breast cancers more than balances the increase in endometrial cancer. No significant increase was detected in the incidence of colorectal cancer. Tamoxifen has been shown to reduce blood concentrations of low-density lipoprotein cholesterol by about 20 percent. The theoretic decrease in cardiovascular disease related to reduction in low-density lipoprotein that is induced by tamoxifen could not be verified from the study data.
The authors conclude that although much remains to be elucidated, some years of tamoxifen therapy substantially improve the 10-year survival rate in women with ERpositive early breast cancer.
ANNE D. WALLING, M.D.
Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet May 16, 1998;351:1451-67.
Invasive vs. Conservative Management of NonQ-Wave MI
Patients with nonQ-wave myocardial infarctions are generally thought to have an increased risk of early and late ischemic complications because of the presence of viable but jeopardized myocardial tissue within the zone of the initial infarction. To forestall these complications, patients are often aggressively managed, often with early coronary angiography. However, as a result of findings from several studies, the American College of CardiologyAmerican Heart Association guidelines on cardiac catheterization and myocardial infarction no longer advocate routine angiography in all patients with nonQ-wave infarctions. Despite this recommendation, early aggressive management is still practiced by many physicians. Boden and colleagues compared the outcomes following conservative and invasive management of patients with nonQ-wave infarctions.
This study is part of the Veterans Affairs NonQ-Wave Infarction Strategies in Hospital Trial. The 920 patients in the study were enrolled at 15 different sites. Nearly all of them (97 percent) were men; 462 were assigned to invasive management and 458 to conservative management. Eligibility criteria included evolving myocardial infarction, a creatine kinase MB isoenzyme level of no more than 1.5 times the upper limit of normal and no new abnormal Q waves on serial electrocardiography. Patients were excluded if they had a serious coexisting condition or ischemic complications such as resting ischemia or heart failure despite intensive medical therapy.
Patients were randomly assigned to conservative or invasive management within 24 to 72 hours after the onset of symptoms. Patients assigned to early invasive strategy underwent cardiac catheterization soon after randomization. Balloon angioplasty or, rarely, atherectomy was considered for significant single-vessel disease, and bypass surgery was recommended for multivessel disease. Patients designated to conservative management underwent radionuclide ventriculography to assess left ventricular function. In addition, a symptom-limited nuclear treadmill stress test was performed before these patients were discharged from the hospital.
During hospitalization, all of the patients received 325 mg of aspirin daily and long-acting diltiazem. Other drug therapies, including beta blockers, nitroglycerin, angiotensin converting enzyme inhibitors, heparin and thrombolytic therapy, were also used, if clinically indicated. The combined primary end point was death or nonfatal myocardial infarction during 12 months of follow-up.
A total of 152 cardiac events (138 patients, 72 nonfatal infarctions and 80 deaths) occurred in the invasive management group, compared with 139 cardiac events (123 patients, 80 nonfatal infarctions and 59 deaths) in the conservative management group. Follow-up lasted an average of 23 months. Overall, a 28 percent rate of cardiac events was documented during follow-up ranging from 12 to 44 months. The frequency of cardiac events was significantly higher in the invasive management group than in the conservative management group before hospital discharge and at one-month and one-year follow-up. In no subgroup was the invasive strategy associated with a better outcome.
There were no significant differences between the two groups in the use of medications. At hospital discharge, 89 percent were receiving aspirin, 55 percent were receiving a calcium channel blocker and 52 percent were receiving a beta blocker.
The authors conclude that in this population of moderate- to high-risk patients with nonQ-wave myocardial infarction, no clinical benefit was derived from early aggressive invasive treatment. In fact, this approach was associated with an increased risk of cardiac events and death during the first year after infarction. The authors advocate a conservative initial strategy based on an ischemia-guided approach.
JEFFREY T. KIRCHNER, D.O.
Boden WE, et al. Outcomes in patients with acute nonQ-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy. N Engl J Med June 18, 1998;338:1785-92.
Advantages of Venipuncture Over Heel Stick in Newborns
Blood samples in neonates are generally obtained by lancing the heel. Local anesthetics have not been shown to reduce the pain that accompanies this procedure. Larsson and colleagues conducted a randomized trial to determine if venipuncture of the dorsal aspect of the hand was more efficient and less painful than heel lancing.
A total of 120 healthy, full-term infants were included in the study and were randomly assigned to have a blood sample drawn by heel lancing with a large lancet or a small lancet or by venipuncture of the dorsum of the hand. The test area was warmed before the skin was punctured. For 60 seconds, blood was allowed to flow freely. If the proper sample amount had not been collected, squeezing or further skin puncture was done to ensure an adequate sample. The infants' facial reactions and crying were recorded and analyzed according to the Neonatal Facial Coding System, which uses a scoring range of zero to 600, with higher scores indicating more distress. The time needed to collect an adequate sample was also recorded.
There were 50 infants in the venipuncture group, 50 in the small lancet group and 20 in the large lancet group. An additional 11 neonates were included in a sham heel stick group. Distress was measured 15 seconds after the first skin puncture. Infants in the venipuncture group had a median score of 247, which was significantly lower than scores in the lancet groups. During manipulation to obtain the blood sample, infants in the venipuncture group again showed significantly less discomfort than did infants in the lancet groups. No differences in distress were found between the sham heel stick group and the venipuncture group during manipulation to obtain the blood sample. Most infants (86 percent) in the venipuncture group required only one puncture to obtain an adequate sample, compared with only 40 percent of the large lancet group and 19 percent of the small lancet group. Venipuncture took significantly less time to provide an adequate sample (median: 191 seconds) compared with the large lancet (median: 279 seconds) and the small lancet (median: 419 seconds).
The authors conclude that venipuncture in the dorsum of a neonate's hand is less painful and more effective than lancing the infant's heel with either a small or a large lancet.
GRACE BROOKE HUFFMAN, M.D.
Larsson BA, et al. Venipuncture is more effective and less painful than heel lancing for blood tests in neonates. Pediatrics May 1998;101:882-6.
Adherence to Guidelines for Treating Acute Gastroenteritis
In 1996, the American Academy of Pediatrics (AAP) revised guidelines for the management of acute gastroenteritis in children. Oral rehydration solution, even in the presence of vomiting, is the cornerstone of treatment. Recent evidence in the literature indicates that unrestricted diets are not ill-advised in the presence of mild diarrhea, and there is no need to avoid lactose. Shamir and colleagues analyzed results from a multiple-choice questionnaire given to Israeli physicians to examine their knowledge and their implementation of the revised AAP guidelines.
The 17-item questionnaire consisted of three parts: demographic information, knowledge about the management of acute gastroenteritis in infants and children, and information about the pediatrician's own treatment practices.
Eighty-seven pediatricians completed the questionnaire. Overall, they were aware of 73 percent of the current AAP recommendations about treatment of acute gastroenteritis in children, but actually followed only 60 percent of the guidelines' recommendations in their practices. Most of the physicians (83 percent) knew that oral rehydration solutions should be used for dehydration in patients with acute gastroenteritis, but only 69 percent knew that these solutions were useful for both mild and moderate dehydration. Almost all of the physicians surveyed (93 percent) knew that oral rehydration solution was better than other clear liquids for the management of acute gastroenteritis, and 86 percent knew it could be used even if the patient was vomiting. However, although the current AAP guidelines recommend continuing full-strength feeds in an infant with acute gastroenteritis, 67 percent of those surveyed did not recommend this practice. The so-called BRAT (banana, rice, apple and toast) diet was recommended by 83 percent of pediatricians, even though this diet has a low calorie content. Fifty-five percent of pediatricians believe that milk products should be avoided.
The authors conclude that awareness of the revised AAP guidelines for management of acute gastroenteritis has not translated to following the guidelines in clinical practice. Further education about the guidelines is needed.
GRACE BROOKE HUFFMAN, M.D.
Shamir R, et al. Management of acute gastroenteritis in children in Israel. Pediatrics May 1998;101:892-4.
Lung Cancer in Candidates for Lung-Volume Reduction Surgery
Lung-volume reduction surgery for severe pulmonary emphysema is an effective means of reducing dyspnea and improving pulmonary function. Preoperative evaluation of potential candidates may include computed tomography (CT), which may reveal unsuspected primary lung tumors. Rozenshtein and associates report their experience in patients with unsuspected lung cancer undergoing preoperative CT examination before lung-volume reduction surgery for severe emphysema.
A total of 148 patients with severe pulmonary emphysema who underwent lung-volume reduction surgery between September 1994 and March 1996 were included in the study. Preoperative chest CT revealed 18 pulmonary nodules suspicious of lung cancer in 17 (11 percent) of the 148 patients. At the time of lung reduction surgery, an attempt was made to excise all suspected lung cancers detected at CT. Sixteen of the tumors were resected.
Nine of the 16 resected nodules proved to be non-small cell carcinoma. The remaining seven nodules were benign. Histologic subtypes of the malignant nodules included adenocarcinoma and squamous cell carcinoma. Eight of the nine lung cancers were stage I. All of the carcinomas were peripheral, and their maximum diameters ranged from 1.0 to 3.8 cm (mean diameter: 2.1 cm). Only one patient with lung cancer had an accompanying aortopulmonary lymph node, measuring 1.5 cm on CT. Four patients underwent mediastinal lymph node biopsy, and no metastases were found.
The 5 percent frequency of stage I lung cancer in these patients with severe emphysema is higher than that reported in previous studies. The mean age (65 years) of the patients in the present study is comparable to that of patients in whom lung cancer is detected. The authors note that detection of lung cancer with CT in patients with severe emphysema in this study is about 10-fold higher than the detection rate of breast cancer on screening mammography.
The authors recommend preoperative CT examination in candidates for lung-volume reduction surgery. Increased use of this operation may lead to increased detection of early lung cancer in patients with severe emphysema.
BARBARA APGAR, M.D., M.S.
Rozenshtein A, et al. Incidental lung carcinoma detected at CT in patients selected for lung volume reduction surgery to treat severe pulmonary emphysema. Radiology May 1998;207:487-90.
Antisocial Personality and Substance Abuse
Antisocial behavior is predictive of adolescent and adult involvement in substance abuse. In addition, conduct disorder during adolescence is a strong prognostic indicator for antisocial personality disorder and psychoactive substance abuse in adulthood. Myers and associates prospectively studied a group of adolescents who met the criteria for conduct disorder to evaluate factors associated with progression to adult antisocial personality disorder in the context of models of antisocial behavior.
A total of 146 adolescents who were recruited from inpatient substance abuse treatment programs completed interviews during the course of treatment and four years after treatment ended. Eighty-four of the participants, of whom 71 percent were males, met the criteria in the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) for antisocial personality disorder. The subjects with antisocial personality disorder had significantly greater rates of drug use but not alcohol use during the three months before treatment.
Onset of conduct disorder behavior at 10 years of age or earlier, a greater diversity of conduct disorder behavior and heavier drug use before admission were the most reliable predictors of antisocial behavior diagnosis. The group with antisocial personality disorder reported more frequent problems in school or work related to alcohol and drug use. The subjects in the antisocial personality disorder group had significantly higher rates of alcohol use at the four-year interview than those without antisocial disorder. The antisocial personality disorder group had an incidence of problems with a spouse or partner related to alcohol or drug use that was five times higher than that of the group without antisocial disorder.
Those in the antisocial personality disorder group were four times more likely to report needing professional help for emotional problems overall but not for problems unrelated to alcohol or drug use. This group also experienced more serious depression and anxiety when substance abuse was concurrent. The adolescents with antisocial personality disorder were significantly more likely to have legal problems, to have been arrested or to have spent time in jail, especially when the antisocial behavior was associated with substance abuse.
These results are consistent with theoretic models of the persistence of antisocial behavior and emphasize the importance of early, severe deviant behavior as a predictor of adult antisocial behavior. In addition, abuse of alcohol and drugs appears to support progression of antisocial pathology in adolescents. Heavier involvement with substance abuse may limit options for engaging in more socially acceptable activities. Among the subjects with antisocial personality disorder and substance abuse, overall functioning was poorer, suggesting that alcohol and drug abuse may be closely involved in the progression of antisocial pathology among adolescents with a history of substance abuse. The results would also indicate that difficulties continue because of lack of remediation or improvement in daily functioning.
The authors conclude that antisocial behavior has little likelihood of regressing after the critical period during which many cognitive and interpersonal skills are typically acquired and refined. This study has important clinical implications. Careful assessment of the extent of conduct disorder behavior and identification of behavior that occurs before and independent of substance abuse may serve to identify persons who may be at risk of persisting in antisocial behavior. These persons should receive more targeted interventions to reduce violent and criminal offenses among serious juvenile offenders. Although the functioning achieved through treatment may be less than optimal, it may be adequate to prevent serious deviant behavior.
BARBARA APGAR, M.D., M.S.
Myers, MG, et al. Progression from conduct disorder to antisocial personality disorder following treatment for adolescent substance abuse. Am J Psychiatry 1998;155: 479-85.
EDITOR'S NOTE: The increase in published reports of violence committed by adolescents shows that clinicians must pay special attention to antisocial pathology among their adolescent patients. The combination of drugs and alcohol may cause these adolescents to engage in more violent acts as adults. Careful assessment of conduct disorder should be a part of every adolescent health maintenance examination.
B.A.
Classification System for Stratification of Stroke Risk
Most strokes are thought to be related to atherosclerosis of the large cerebral arteries or small vessel disease related to systemic hypertension. In approximately 30 percent of patients who have had a stroke, a potential cardioembolic source can be identified. High-risk cardiac groups include patients with rheumatic mitral stenosis, atrial fibrillation, acute anterior myocardial infarction, global cardiomyopathy and prosthetic valves. Additional cardiac abnormalities associated with stroke that are identified primarily by echocardiography include patent foramen ovale and atrial septal defect, atrial septal aneurysm, mitral valve prolapse, aortic atherosclerosis and mobile atheroma, left atrial spontaneous echo contrast, and mitral valve strands. O'Brien and associates developed a risk classification system based on the presence or absence of abnormalities found on transesophageal echocardiography to stratify risk in stroke patients without a cardiac source of embolism on clinical examination.
Forty stroke patients without any of the commonly accepted risk factors for cardiac source of stroke were included in the study. Demographic data and medical history were obtained, and a directed physical examination was performed at the time patients underwent transesophageal echocardiography. Patients were considered to be at high risk if any cardiac risk factors were identified on echocardiography. Patients were followed for an average of 14 months to check on treatment and the occurrence of other cardiovascular events.
The presence or absence of abnormalities on transesophageal echocardiography was a predictor of cardiovascular survival (cardiac and stroke) in the study participants. Patients identified as being low risk by echocardiography had a higher rate of survival (92 percent) compared with high-risk patients (78 percent) during the study period.
The data also suggest an association between individual echocardiographic findings, such as left ventricular hypertrophy and the presence of aortic atherosclerotic plaque with recurrent cerebral infarction. Left atrial enlargement and intra-atrial spontaneous contrast were associated with stroke death. Typically, the highest yield of transesophageal echocardiography in the setting of stroke is in patients younger than 45 years. Despite a mean age of 67 years, 60 percent of the patients in the present study had a potential cardiac etiology for the stroke.
This study also provides evidence that transesophageal echocardiography may be useful even in patients with a conventionally accepted stroke mechanism to identify an additional cardiac risk factor. For example, the finding of mobile aortic debris in a patient with carotid disease who is also a suboptimal surgical candidate may lead to medical management.
The authors conclude that the results of the study support the hypothesis that a subgroup of patients with aortic atherosclerosis and spontaneous echo contrast is at high risk for stroke or cardiac death. In addition, left atrial enlargement and left ventricular hypertrophy represent risk factors for death and recurrent fatal and nonfatal stroke, respectively. Transesophageal echocardiography also appears to be useful in stroke patients with a low clinical suspicion of a cardiac source of embolism, both for the diagnosis of a potential stroke cause and for prognosis after stroke.
RICHARD SADOVSKY, M.D.
O'Brien PJ, et al. Usefulness of transesophageal echocardiography in predicting mortality and morbidity in stroke patients without clinically known cardiac sources of embolus. Am J Cardiol May 1, 1998;81:114451.
Sodium Restricted Diets: Necessary in Hypertension?
Findings from recent large population studies have provided conflicting information about the advantages of lowering sodium in the treatment of patients with hypertension. Graudal and colleagues reviewed the literature to determine the effects of dietary sodium restriction on systolic and diastolic blood pressures, and renin, aldosterone and lipid levels.
The authors conducted a Medline search for randomized studies of sodium intake and hypertension. Studies were included if they evaluated at least one of the following effect parameters: body weight, amount of sodium reduction, systolic and diastolic blood pressure before and after the intervention, and renin, aldosterone and lipid levels before and after the intervention.
The search yielded 58 studies including hypertensive patients and 56 studies including normotensive patients. These studies were integrated into two separate meta-analyses. In the hypertensive patients, a mean reduction in sodium intake of 118 mEq per L (118 mmol per L) per day led to decreases of 3.9 mm Hg and 1.9 mm Hg in systolic and diastolic blood pressures, respectively. In the normotensive patients, a mean reduction in sodium intake of 160 mEq per L (160 mmol per L) per day led to decreases of 1.2 mm Hg and 0.26 mm Hg in systolic and diastolic blood pressures, respectively. Renin and aldosterone levels increased significantly in patients with reduced sodium intake. Lipid levels were adversely affected in patients who undertook short-term high reductions in sodium intake. It is not known if these effects are clinically significant.
The authors conclude that the effects of sodium reduction on blood pressure in normotensive patients do not support a general recommendation for a sodium-restricted diet in this population. Sodium reduction may be recommended as an adjunctive treatment in patients with hypertension. However, studies evaluating hard end points (i.e., myocardial infarction, stroke and death) instead of those assessing substitute end points, such as blood pressure, are necessary before the usefulness of sodium-restricted diets can be truly judged.
GRACE BROOKE HUFFMAN, M.D.
Graudal NA, et al. Effects of sodium restriction on blood pressure, renin, aldosterone, catecholamines, cholesterols and triglyceride. A meta-analysis. JAMA May 6, 1998;279:1383-91.
Role of Vaccination in the Prevention of Hepatitis A
Hepatitis A causes one of the most common infectious diseases in the world and may produce clinical conditions ranging from asymptomatic infection to acute liver failure. Koff reviews the role of immunization in the prevention of this disease.
The RNA virus responsible for hepatitis A is a small, non-enveloped, spherical particle that is thermostable and acid-resistant. The liver is the only target organ, but little is understood about the minimum infective dose, gastrointestinal transport mechanisms or receptors in the liver that facilitate infection. Virus replication takes place exclusively in infected hepatocytes, and viral particles then pass through the biliary system into the intestine to continue the cycle of fecal-oral infection in another host. Hepatitis A virus is excreted in the feces for up to two weeks before symptoms appear, reaching a peak at the onset of symptoms and continuing for at least another week. Viral shedding declines rapidly but may continue for several months in a few persons. The average incubation period is 30 days (range: 15 to 50 days). About one third of the U.S. population has serologic evidence of previous infection, but this rate is declining, presumably as a result of improved hygiene. Person-to-person transmission within the household is the most common mode of infection, but community outbreaks also occur because of contamination of water or food.
Patients with hepatitis A infection may have any combination of gastrointestinal and systemic complaints such as fever, malaise, weakness, anorexia, arthralgias, myalgia and flu-like symptoms. Jaundice with dark urine, pruritus and hepatic tenderness may occur. Serum aminotransferase levels are usually elevated, and IgM antibody is detectable for three to six months after infection. Bilirubin concentrations are elevated in patients with jaundice. Most patients recover spontaneously with symptomatic treatment and complete abstinence from alcohol. Patients rarely develop relapsing hepatitis, cholestatic hepatitis or acute liver failure requiring transplantation.
The traditional preventive measure for hepatitis A infection is passive immunization with immunoglobulin containing IgG antibody to hepatitis A virus. This measure is still recommended for children younger than two years and for postexposure prophylaxis of household contacts of infected persons. Immunoglobulin may not be effective if given more than two weeks after exposure; protection lasts for no more than six months. Live attenuated hepatitis A vaccines are being developed in China, and several inactivated vaccines are available in Europe and the United States. These inactivated vaccines produce antibody levels comparable to those achieved following natural infection and approximately 15 times those attained by passive immunization. Studies indicate that most recipients seroconvert, with the exception of very young children, who may have a blunted response because of maternal antibodies. Projections indicate immunity from hepatitis A virus lasts for at least 10 years after two doses of vaccine.
The author concludes that education and immunization are vital to controlling hepatitis A infection. Travelers should be vaccinated for hepatitis A virus two weeks before travel to endemic areas. Immunoglobulin may also be administered at the time of vaccination, at a separate site, if travel is to occur in less than two weeks. Vaccination is also recommended for persons who are at high risk of fecal-oral spread because of sexual practices or poor hygiene, and for persons whose professions put them at high risk--sewage workers, health and child care workers, and veterinary surgeons. In developed countries, good hygiene is likely to be a major factor in controlling hepatitis A. In developing countries, universal vaccination in childhood is the optimal strategy and may become possible when vaccines for hepatitis A are made available in a combined form with other "routine" immunizations.
ANNE D. WALLING, M.D.
Koff RS. Hepatitis A. Lancet May 30, 1998;341:1643-9.
Factors Increasing Hemorrhage Risk in Warfarin Users
Warfarin is frequently prescribed although major hemorrhage is a serious side effect. McMahan and associates conducted a retrospective cohort study to determine the incidence of major hemorrhage among patients on warfarin therapy and to identify patient characteristics that would predict those at risk of hemorrhage.
The authors used a pharmacy database to identify patients at a Veterans Affairs Medical Center who had been given prescriptions for warfarin. Patients were included in the study if warfarin therapy had been started while the subject was an inpatient and was to continue for more than 10 days. Medical records were reviewed to collect baseline information on history of stroke, atrial fibrillation, gastrointestinal bleeding, a low hematocrit level, an elevated creatinine level and acute myocardial infarction. Demographic information and information about warfarin dosage and other medications prescribed at discharge were also recorded. The primary outcome variable that was assessed was major hemorrhage, using a standard definition that included survival, amount of blood lost and consequences of bleeding.
A total of 579 patients were included in the study. Of these, 565 were available for follow-up at the end of the study period. In the latter group, 40 patients had major hemorrhages and one patient died. The gastrointestinal tract was the most common site of major hemorrhage (63 percent), followed by the urinary tract (28 percent), the musculoskeletal system (15 percent), the nasopharynx (13 percent) and the lungs (8 percent). Some patients had more than one site of hemorrhage. Patients receiving both warfarin and aspirin therapy did not have an increased risk of bleeding.
The authors conclude that there are three independent predictors of major hemorrhage in patients taking warfarin--alcohol abuse, chronic renal insufficiency and a history of gastrointestinal bleeding--but that the decision to initiate warfarin therapy should continue to be made on the basis of individual risks and benefits in patients who are otherwise candidates for anticoagulant therapy.
GRACE BROOKE HUFFMAN, M.D.
McMahan DA, et al. Risk of major hemorrhage for outpatients treated with warfarin. J Gen Intern Med May 1998;13:311-6.
Readability of Consent Forms for Surgical and Other Procedures
The amount of information in consent forms for surgical and other procedures varies among hospitals, as does the process for presenting the form to patients scheduled for a procedure. The consent form may be presented to the patient by a physician, a nurse or even nonmedical personnel. The readability of consent forms also varies. Hopper and colleagues evaluated the quality, including the readability, of consent forms used in U.S. hospitals.
Letters requesting a copy of each institution's surgical and procedure consent form were sent to a random selection of 2,194 hospitals. A total of 681 responses were received, of which 616 provided a copy of the form used at the hospital. The consent forms were analyzed for readability by means of the RightWriter 4.0 computer software program. This program evaluates readability according to eight criteria: a readability index, a strength index, a descriptive index, a jargon index, sentence structure recommendations, words to review, a word frequency list and the number of words per sentence. To ensure accuracy, two investigators also separately evaluated the overall content of each form and looked for the inclusion of such information as the name of the patient, the name of the procedure and the physician who would be performing the procedure, the name of the person providing consent, the benefits and risks of the procedure, alternatives to the procedure, and contraindications to and complications of anesthesia.
Most of the consent forms required at least a high school education level to be understood. The mean grade level readability score was 12.6 years. Only 29 forms could be understood by persons reading below the eighth-grade level. The number of words in the forms varied from a low of 58 to a high of 4,217. The strength index of the forms was very low, averaging 0.2 for all states and regions (a well-written document would have a score of at least 0.5 out of 1.0).
While most of the forms included general descriptions of the procedure and its benefits, risks and alternatives, only a small number of them included specific details. For example, only 6.2 percent listed the benefits of the specific procedure, and only 5.4 percent listed alternatives. Most (87.4 percent) of the forms asked permission for anesthesia, but only 47.7 percent included mention of the additional risks of anesthesia. The specific risks of anesthesia were described in only 14.9 percent of the forms. Only 50.9 percent of the forms specifically stated that the patient understood the procedure, and only 27.1 percent stated that the patient's questions had been answered. The physician's signature was required on only 43.2 percent of the forms.
The authors draw several conclusions from their study. Significant variability exists in both readability and content of consent forms included in the study. Moreover, the majority of consent forms require at least a 12th-grade reading level and are too complex for the average person to fully understand. The authors attribute at least some of the complexity to medicolegal concerns. The authors hope the findings of their study will encourage hospitals to develop readable consent forms that are appropriate for most patients' reading levels.
JEFFREY T. KIRCHNER, D.O.
Hopper KD, et al. The readability of currently used surgical/procedure consent forms in the United States. Surgery May 1998;123:496-503.
Idiopathic Thrombocytopenic Purpura Diagnosis in Children
Idiopathic thrombocytopenic purpura is a relatively common pediatric disorder. It tends to follow a self-limited course, but treatment with gamma globulin or corticosteroids is often instituted to prevent bleeding complications. It has been standard practice to perform a bone marrow aspiration to rule out leukemia as part of the initial work-up of a child with an abnormally low platelet count. Several older studies questioned the need for this procedure but did not provide convincing evidence because of small sample size or methodology. Calpin and associates performed a retrospective study to determine whether any diagnoses of leukemia were discovered in a large series of bone marrow aspiration samples that were collected from children diagnosed with acute idiopathic thrombocytopenic purpura who had typical hematologic features of this disease.
The reports of all bone marrow aspirations performed at the Hospital for Sick Children in Toronto from January 1, 1984, until May 31, 1996, were reviewed. This cohort included both inpatient and outpatient reports on bone marrow aspirations that were performed to confirm a provisional diagnosis of idiopathic thrombocytopenic purpura. The peripheral blood smear and complete blood count performed nearest to the time of the bone marrow aspiration were also reviewed to see if the patient had typical features of idiopathic thrombocytopenic purpura. "Typical features" included a normal hemoglobin, a normal total white blood cell and neutrophil count, and a platelet count of less than 50,000 3 103 per µL (50,000 3 109 per L). The researchers then analyzed the outcomes of all bone marrow aspirations performed in children to confirm idiopathic thrombocytopenic purpura with typical laboratory features to see if any other diagnosis was found. In a similar fashion, the final diagnoses of all children who underwent bone marrow aspiration to confirm idiopathic thrombocytopenic purpura but who had abnormal laboratory features were also obtained.
During the time reviewed, 7,612 bone marrow aspirations were performed. Of these, 484 (6.4 percent) were performed to confirm a provisional diagnosis of idiopathic thrombocytopenic purpura. During the same 12-year period, 672 children were admitted to the institution with a primary diagnosis of acute idiopathic thrombocytopenic purpura. The study estimate indicated that 72 percent of children with idiopathic thrombocytopenic purpura underwent a bone marrow aspiration. Among 332 children with a platelet count of less than 50,000 3 103 per µL (50,000 3 109 per L) but otherwise normal or typical hematologic parameters, no cases of leukemia were diagnosed. In the group of 135 children with atypical hematologic features for idiopathic thrombocytopenic purpura, three children were diagnosed with leukemia. All three of these children had at least two atypical hematologic values in the complete blood cell count, and all had a clinical presentation not consistent with idiopathic thrombocytopenic purpura. Eight additional children in the group with atypical laboratory results were found to have aplastic anemia. The authors conclude that in children who present with thrombocytopenia and otherwise typical hematologic features of idiopathic thrombocytopenia--platelet count less than 50,000 3 103 per µL (50,000 3 10> per L) with a normal hemoglobin, white blood cell count and neutrophil count--the risk of missing a diagnosis of leukemia is less than 1 percent. They also cite the significant cost of this procedure ($700 to $800) and associated morbidity, including pain, bleeding and infection.
JEFFREY T. KIRCHNER, D.O.
Calpin C, et al. Is bone marrow aspiration needed in acute childhood idiopathic thrombocytopenic purpura to rule out leukemia? Arch Pediatr Adolesc Med April 1998;152:345-7.
Effects of Hypertension in Black Pregnant Women
Preterm birth occurs in approximately 18 percent of live births to black mothers and is reported to be increasing in incidence. Black infants have a risk of mortality two times higher than white infants. Much of this difference is attributed to the higher rate of preterm delivery, but little is understood about the factors that can result in preterm birth. Samadi and Mayberry conducted a case-control study to assess the effects of chronic hypertension preceding pregnancy and pregnancy-induced hypertension on preterm delivery in black mothers.
National hospital discharge records between 1988 and 1993 were used to identify black mothers with spontaneous preterm births. Among the 2,347 study patients who had preterm deliveries and the 23,857 control subjects who had full-term deliveries, 547 (2.1 percent) were identified as having chronic hypertension before pregnancy, and 1,144 women (4.4 percent) met criteria for pregnancy-induced hypertension.
The risk of preterm delivery was almost doubled in women with either chronic (odds ratio: 1.8) or pregnancy-induced (odds ratio: 1.6) hypertension. The risk was particularly high in mothers with pregnancy-aggravated hypertension. After adjusting for confounding factors, these mothers were found to have four times the risk of preterm delivery as normotensive mothers. Other significant conditions such as poor fetal growth, antepartum hemorrhage and placental separation were more prevalent in mothers of preterm infants than in control subjects. The increased risk of preterm birth in hypertensive women was significant after adjustment for these factors plus age, marital status and insurance type.
The authors stress the contribution of hypertensive conditions to preterm birth. Because chronic hypertension is 2.5 times more common in black women than in white women, significantly more black women enter pregnancy at risk of premature birth. Black women with pregnancy-aggravated hypertension are at particularly high risk of premature delivery. Consequently, infants born to these women are at increased risk of morbidity and mortality. Although much more information regarding the relationship between maternal hypertension and preterm birth remains to be elucidated, monitoring and controlling risk factors for preterm delivery in black patients with hypertension has the potential to reduce infant mortality and morbidity.
ANNE D. WALLING, M.D.
Samadi AR, Mayberry RM. Maternal hypertension and spontaneous preterm births among black women. Obstet Gynecol June 1998;91:899-904.
Cost Comparison of Enoxaparin vs. Unfractionated Heparin
A 16 percent reduction in the 14-day incidence of death, myocardial infarction or recurrent angina was reported with the use of enoxaparin as compared with unfractionated heparin in the Efficacy and Safety of Subcutaneous Enoxaparin in NonQ wave Coronary Events (ESSENCE) study. Mark and associates conducted a prospective, detailed economic analysis of the study findings.
Hospital billing data were available for 655 of the 936 patients in the ESSENCE study. During initial enrollment in the study, fewer major medical resources were used in the patients receiving enoxaparin compared with those receiving heparin. The greatest effect was a 5 percent absolute reduction in the use of coronary angioplasty. Trends for diagnostic catheterization and coronary bypass surgery favored enoxaparin but were not statistically significant. The duration of stay in the intensive care unit and the total length of hospitalization were shorter in patients receiving enoxaparin than in those receiving heparin, but the difference was not statistically significant.
At the 30-day follow-up, the differences between the two groups in resource use were equivalent to those seen at baseline or increased slightly in favor of enoxaparin. Reductions in the use of diagnostic catheterization (57 percent versus 63 percent for heparin) and coronary angioplasty (18 percent versus 22 percent for heparin) with enoxaparin were accompanied by a reduction in length of stay in the intensive care unit. The 30-day rehospitalization rate was 14 percent in the enoxaparin group and 16 percent in the heparin group.
While enoxaparin therapy costs almost twice as much as heparin therapy ($155 versus $80), the differences in resource consumption produced a $600 savings in hospital costs and a $237 savings in physician fees in the enoxaparin group. The total medical cost for the initial hospitalization was $11,857 for the enoxaparin group and $12,620 for the heparin group, resulting in a $763 savings with enoxaparin therapy. At the end of 30 days, the trends in cost figures that favored enoxaparin were all statistically significant. The total cumulative savings associated with enoxaparin at 30 days was $1,172.
The authors conclude that enoxaparin is among a select group of therapies that improves important clinical outcomes and reduces net treatment costs relative to traditional therapy. The most substantial reduction in resource use with enoxaparin was decreased use of coronary angioplasty, a consequence of the reduction in recurrent ischemic events.
BARBARA APGAR, M.D., M.S.
Mark DB, et al. Economic assessment of low-molecular-weight heparin (enoxaparin) versus unfractionated heparin in acute coronary syndrome patients: results from the ESSENCE randomized trial. Circulation May 5, 1998;97:1702-7.
Effects of Lowering Average or Below-Average Cholesterol
It has been demonstrated that there is a continuous association between cholesterol levels and the risk of myocardial infarction or death from coronary heart disease. Studies have documented that for middle-aged persons, each 0.6 mmol per L drop in total cholesterol confers about 30 percent less risk of coronary heart disease across a wide range of cholesterol levels. Cholesterol lowering has also been shown to reduce the risk of initial and recurrent coronary heart disease in patients with elevated cholesterol levels. MacMahon and associates of the LIPID Trial Research Group conducted a randomized, double-blind trial to evaluate the effects of cholesterol lowering on carotid atherosclerosis among patients with a history of myocardial infarction or unstable angina and average or below average levels of total cholesterol (from 154 to 270 mg per dL [4 to 7 mmol per L]).
A total of 522 patients were randomized to treatment with a low-fat diet plus pravastatin (40 mg daily) or with a low-fat diet plus placebo. The mean age of participants at the time of enrollment was 61 years. Before randomization and again after two and four years, ultrasound scans of the right common carotid artery were performed. The choice of this vessel as the primary end point in the trial was based on studies demonstrating the histologic validity of such ultrasound measurements. Total cholesterol was measured at the initial visit and at annual visits thereafter. Additional lipid studies were also performed three years after randomization. The primary study outcome was the change from baseline in carotid wall thickness after two and four years of follow-up. Follow-up data were available from 88 percent of study participants after two years and from 77 percent after four years.
Over the four-year study period, total cholesterol was reduced by an average of 38.6 mg per dL (1.0 mmol per L) in the pravastatin group compared with the placebo group. In addition, during the first three years of follow-up, low-density-lipoprotein (LDL) cholesterol, apolipoprotein B and total triglyceride levels were reduced by an average of 34.7 mg per dL (0.9 mmol per L), 1.93 mg per dL (0.05 mmol per L) and 11.2 mg per dL (0.29 mmol per L), respectively, in the pravastatin group compared with the placebo group. Over the same interval, apolipoprotein A1 and high-density-lipoprotein (HDL) cholesterol levels increased by 2.31 mg per dL (0.06 mmol per L) in the group receiving pravastatin and by 1.93 mg per dL (0.05 mmol per L) in the group receiving placebo.
After two years of follow-up, the mean carotid wall thickness increased by 0.039 mm in the placebo group and was essentially unchanged in the pravastatin group. After four years of follow-up, the mean carotid wall thickness had increased by a total of 0.048 mm in the placebo group and declined by 0.014 mm in the pravastatin group. Overall, after two years, there was a 0.049-mm difference in carotid wall thickness between the groups and after four years, a 0.062-mm difference between the groups. The ratio of lumen-to-wall thickness increased by 5 percent after two years and by 8 percent after four years in patients receiving pravastatin compared with those receiving placebo.
The results of this study demonstrate that treatment with the HMG CoA reductase inhibitor pravastatin reduced the development of carotid atherosclerosis among patients with a history of coronary heart disease and average to below-average cholesterol levels. Treatment with pravastatin reduced total cholesterol levels by 19 percent, LDL cholesterol levels by 27 percent, apolipoprotein B levels by 19 percent and total triglyceride levels by 13 percent. Conversely, apolipoprotein A1 and HDL cholesterol levels both increased by about 5 percent. There was no detectable carotid wall thickening over four years of follow-up among patients receiving pravastatin.
The authors conclude that cholesterol-lowering agents can reduce the risk of clinical sequelae of atherosclerotic disease in not only a large proportion of the at-risk population but also those patients with average or below-average cholesterol levels. These findings combined with results from previous trials suggest that such treatment might also be expected to reduce the risk of ischemic stroke.
BARBARA APGAR, M.D., M.S.
MacMahon S, et al. Effects of lowering average or below-average cholesterol levels on the progression of carotid atherosclerosis. Results of the LIPID Atherosclerosis Substudy. Circulation May 1998;97:1784-90.
Risks and Benefits of Surgery for Carotid Endarterectomy
The role of surgery in symptomatic carotid stenosis is controversial. Long-term benefits, particularly the prevention of stroke, may not outweigh the risks of surgery. There is also uncertainty regarding the medical treatment of carotid stenosis, the role of comorbidities and difficulties in defining the degree of stenosis, significant subgroups of patients and the experience/skill of individual surgeons. In the largest randomized clinical trial to date, the European Carotid Surgery Trial compared the outcome of early surgical intervention with delaying surgery as long as possible after an ischemic event attributable to carotid artery stenosis.
Patients were eligible for the study if within the previous six months they had experienced an event suspicious for carotid ischemia not resulting in serious permanent disability. All patients underwent contrast angiography of the symptomatic artery. The percentage of stenosis in the symptomatic artery was estimated by a single researcher for all patients. Patients were then randomly allocated to either the surgical treatment group or the control group. All patients received optimal medical treatment as determined by their physician. This included advice about the risk factors of smoking, treatment of hypertension and antiplatelet medication. Patients were followed at four and 12 months during the first year and then annually until the end of 1995. The mean duration of follow-up was 6.1 years.
The two groups had some small baseline differences: the surgical group had a slightly higher prevalence of both hypertension and ischemic heart disease. However, these differences were unlikely to have been clinically relevant. There was a nonsignificant tendency for patients in the control group to be treated more aggressively with antiplatelet and lipid-lowering drugs during the follow-up period.
In the group undergoing immediate surgery, 669 patients (37 percent) died or experienced a major stroke during the follow-up period. The risk of stroke or death was highest within 30 days of surgery. Of the 1,745 patients assigned to the surgery group, the risk of non-fatal major stroke or death within 30 days of surgery was 7 percent. In the control group, 442 patients (36.5 percent) died or experienced a major stroke during the follow-up period. The risk of major stroke was clearly related to the age of the patient and to the severity of carotid stenosis, but only during the first two to three years following randomization. The authors compiled survival curves to estimate the balance of benefit and harm at different ages and with different degrees of carotid stenosis. These models show that in general the advantages of surgery at three years outweighed the risks only when stenosis was greater than 80 percent of the diameter of the artery. The cutoff points for benefit varied with the age and sex of the patient. In general, men benefited slightly more from surgery than did women.
The authors conclude that decisions about endarterectomy must be based on factors such as patient characteristics (age and sex) and the physician's surgical expertise, but, in general, the balance of risk and benefit does not favor surgery when less than approximately 80 percent of the artery is occluded following a symptomatic episode of carotid ischemia.
ANNE D. WALLING, M.D.
European Carotid Surgery Trialists' Collaborative Group. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet May 9, 1998;351: 1379-87.
EDITOR'S NOTE: Applying the results of this study to one's practice is challenging in two respects. First, the results are not quite as clear-cut as described above. The survival diagrams illustrate large zones of "no clear result" and delineate hazard or benefit from surgery by the age of the patient and the degree of stenosis. For a 70-year-old man, the zone of "no clear hazard or benefit" starts around stenosis of 20 percent and extends to approximately 80 percent. For women, clinical decisions may be somewhat easier, as the corresponding area of uncertainty extends from about 70 to 90 percent. In perhaps the majority of patients, however, there can be no confidence that surgery will prevent the very serious consequences of cerebral ischemia. Although we are accustomed to making clinical decisions based on incomplete information, the second challenge--balancing the instinct to actively intervene to help a patient at risk of stroke with the need for objectivity and prudence in decision-making--appears particularly vexing in this situation.
A.D.W.
Comparison of Techniques for Saphenous Vein Harvesting
Patients undergoing coronary artery bypass grafting frequently complain more about postoperative discomfort from the site of leg vein harvesting than about their sternotomy wound. The traditional method of harvesting the greater saphenous vein, a groin-to-ankle incision, involves the longest incision used in surgical practice and may cause minor complications in up to 31 percent of patients. Major complications are believed to be rare, but the morbidity and costs of minor complications from vein harvesting comprise an area of surgical practice that requires further study. Horvath and colleagues used a prospective, nonrandomized, case-matched study that compared two new, less invasive techniques of harvesting the saphenous vein that were designed to minimize trauma and complications.
During a 10-month period, 60 patients underwent saphenous vein harvest using either the bridge technique or the endoscopic saphenous vein harvest technique. Patients undergoing emergency coronary artery bypass graft or additional cardiac procedures, and those with active infections, uncontrolled diabetes or lower extremity arterial or venous ulcerations were not included in the study. Patients were assigned to one of the two techniques by case matching. All vein harvesting was done by two physician assistants. Data on wound healing and complications were obtained two and eight weeks after surgery.
The bridge technique requires approximately four incisions in the thigh and four to five incisions in the lower leg to harvest the complete vein, leaving "bridges" of intact skin and tissue. Endoscopic saphenous vein harvesting uses a subcutaneous dissecting instrument that is guided videoscopically along the anterior surface of the vein. This technique requires an incision from 3 to 4 cm in length at selected sites and allows larger branches to be clipped or coagulated before vein removal.
The two groups of patients were well matched, although more patients in the endoscopic group suffered from peripheral vascular disease. The 29 patients who underwent harvesting using the bridge technique had an average of 5.0 incisions, and the 31 patients who underwent endoscopic vein harvesting had an average of 2.3 incisions. Although the number and total length of incisions were significantly less in the patients undergoing the endoscopic technique, the length of vein harvested was significantly longer. The total time from incision to closure, including the time for preparation of the vein, was significantly shorter with the endoscopic technique. Minor wound complications occurred in 10 patients (32 percent) who underwent endoscopic harvesting and one patient (3 percent) who underwent the bridge procedure. Most complications using the endoscopic technique were minor hematomas and, when these were excluded, the complication rate was 13 percent. The complication rate decreased during the study period. This decrease was attributed to improved staff education and experience. None of the complications prolonged the hospital stay or led to readmission. The two groups of patients had similar lengths of hospital stay and time to postoperative ambulation.
The authors conclude that saphenous vein harvesting using the endoscopic technique allows for harvesting of long segments of vein, utilizes shorter and fewer incisions, and requires less time than the bridge technique. The greater incidence of minor complications can be diminished through staff education and experience.
ANNE D. WALLING, M.D.
Horvath KD, et al. Operative outcomes of minimally invasive saphenous vein harvest. Am J Surg May 1998;175:391-5.
Use of Topical Cyproterone Acetate for Women with Acne
Because the sebaceous gland is sensitive to androgens, there has been interest in developing a topical antiandrogen. Cyproterone acetate is a potent steroidal antiandrogen with progestational activity that has been used in combination with estrogen to treat women with hyperandrogenization. Cyproterone acetate competes with dihydrotestosterone for androgen receptors. Gruber and associates compared the effectiveness of topical cyproterone acetate with oral medication consisting of 0.035 mg of ethinyl estradiol and 2 mg of cyproterone acetate in women with acne.
Forty women were randomized to undergo treatment with 0.035 mg of oral ethinyl estradiol and 2 mg of cyproterone acetate, topical 20-mg cyproterone acetate lotion or placebo. The patients were assessed monthly for three months. Acne severity, lesion counts and determinations of serum cyproterone concentrations were graded clinically. Response to therapy was measured by calculating the difference between baseline measurements and measurements after three months of therapy. None of the patients received any systemic therapy for six weeks before the study began.
During the assessment period, both oral and topical cyproterone acetate were found to be significantly more effective than placebo in reducing mean facial acne grades and lesion counts. No significant differences were observed between the oral and topical cyproterone therapy groups.
After three months of topical cyproterone acetate application, lesion counts had decreased from a mean of 35.9 to a mean of 9.1. Serum cyproterone acetate concentrations were below the detection limit of 28 pg per mL before the treatment but increased to values between 119 and 311 pg per mL after topical cyproterone treatment. No adverse effects occurred in any of the groups during treatment.
Results of this study suggest that although well-established hormonal and nonhormonal treatments of acne are numerous, a topical agent can be efficacious without having adverse effects. Although other therapies such as spironolactone, flutamide, progesterone and gonadotropin-releasing agonists have been used to treat androgen symptoms in women, these medications may cause systemic side effects. Previous studies using topical cyproterone acetate have been unsuccessful because of inability to deliver the active substance to the target cell. This disadvantage was overcome by using a liposome lotion as the carrier for the active drug. Serum cyproterone acetate levels were 10 times lower after topical application than after oral use, but with a similar clinical response.
The authors conclude that topical cyproterone acetate is as effective as oral cyproterone acetate used in combination with ethinyl estradiol. This formulation represents a suitable alternative or additional topical treatment for women with acne.
BARBARA APGAR, M.D., M.S.
Gruber DM, et al. Topical cyproterone acetate treatment in women with acne. Arch Dermatol April 1998;134:459-63.
Safety of Stereotactic Brain Biopsy for Intracranial Lesions
Stereotactic biopsy is an invasive technique that allows the physician to accurately localize and sample lesions within the brain, but is considered by some physicians to have significant morbidity and mortality rates with a high risk of sampling error. Initially performed freehand in the 1970s using computed tomographic (CT) scans as a guide, the technique changed after the development of the rigid head frame in the early 1980s. Guided by CT scan or by magnetic resonance imaging (MRI), the procedure is indicated when the pathology of the brain lesion is unknown or when future treatment decisions depend on the histologic nature of the lesion. Stereotactic biopsy can safely sample lesions deep within the brain, those in the eloquent cortex and those that are surgically unresectable. The technique is also indicated for use in patients who are too ill to undergo general anesthesia. Hall reports the results of stereotactic biopsies performed from February 1991 to December 1996 at the University of Minnesota Hospital and Clinic, Minneapolis.
A total of 134 stereotactic biopsies performed in 122 patients were reviewed. The patients participating in the study ranged from three to 83 years of age, with a mean age of 41 years. The medical and surgical records of all patients were analyzed to determine age, gender, location of lesion, frozen-section diagnosis, permanent pathologic diagnosis, diagnostic yield of the procedure and associated morbidity and mortality.
The majority of biopsies were performed using local anesthesia (1 percent lidocaine) and intravenous sedation. After a stereotactic headframe was placed on the patient, CT or MRI was used to determine the biopsy target coordinates. MRI was preferred for brainstem lesions. During the procedure, a tissue sample was routinely sent for frozen section or, if infection with acquired immunodeficiency syndrome was suspected, either a touch or a smear preparation of a tissue specimen was obtained. After the biopsy, patients were observed overnight for any neurologic deterioration and were usually discharged the following morning.
Eighty-five lesions (63 percent) were biopsied with CT guidance and 49 lesions (37 percent) with MRI guidance. General anesthesia was used for biopsy of 28 lesions; seven of these were in children. The most frequently biopsied lesions were malignant brain tumors (62 lesions), followed by benign tumors (24 lesions) and neurologic disorders (23 lesions). Seven of the lesions biopsied did not demonstrate an intraoperative diagnosis; four of these were also found to be nondiagnostic on permanent pathology. Reasons for diagnostic failure included close proximity of the lesion to the cerebrospinal fluid pathways, inability to obtain diagnostic tissue despite multiple passes or inability of the needle to penetrate the mass.
Following biopsy, one patient who had a pontine anaplastic astrocytoma experienced temporary hemiparesis related to edema. A second patient sustained a fatal hemorrhage after a vascular pineal region mass was biopsied.
The author concludes that stereotactic brain biopsy is an extremely safe and effective procedure for determining the pathology of intracranial lesions. In this case series, the diagnostic yield was 96 percent, the morbidity rate was 0.7 percent and the mortality rate was 0.7 percent. A comparison of 7,471 similar procedures performed at other institutions yielded similar results: diagnostic yield of 91 percent, morbidity rate of 3.5 percent and mortality rate of 0.7 percent.
JEFFREY T. KIRCHNER, D.O.
Hall WA. The safety and efficacy of stereotactic biopsy for intracranial lesions. Cancer May 1, 1998;82:1749-55.
Antibiotics for Permanent Pacemaker Implantation
Infection is a serious, potentially fatal complication after permanent pacemaker implantation. Because septicemia and endocarditis have been described in patients receiving permanent pacemakers, many physicians routinely prescribe antibiotic prophylaxis at the time of implantation to prevent infectious complications. At present, however, no evidence shows that this strategy is beneficial. To elucidate the effectiveness of antibiotic prophylaxis in reducing infection rates, Da Costa and associates performed a meta-analysis of all available randomized trials.
A total of seven trials met the inclusion criteria; these studies represented the only pertinent data available on antibiotic prophylaxis at the time of pacemaker implantation. A total of 2,023 patients with established permanent pacemaker implantation were included in the studies. Of these patients, 1,011 received systemic antibiotic prophylaxis, and 1,012 did not. There was no difference in the proportion of patients with preexisting disorders likely to predispose them to infection, such as diabetes, malignancy or recent surgery. All procedures were performed in the operating room, and the skin was assiduously disinfected before surgery. In two of the studies, end-point events were a repeat operation for complications from infection, a repeat operation because of signs of inflammation around the pacemaker pocket, fever or septicemia, and abscess or the presence of pus in the generator pocket. Follow-up duration ranged from one month to four years. The delay to infection ranged from five to 356 days.
The incidence of end-point events in the control groups ranged from zero to 12 percent. The meta-analysis suggested a consistent protective effect of antibiotic pretreatment. Antibiotic administration at the time of pacemaker insertion significantly reduced the risk of pacemaker infection. Most commonly, wound infection, inflammation and skin erosion were reduced or prevented. There is some remaining uncertainty about whether antibiotics prevent septicemia or endocarditis. The recommendation that the risk of infection is best reduced when antibiotics were administered two hours before insertion was followed by six of the seven studies included in the meta-analysis.
The authors conclude that systemic antibiotic prophylaxis administered at the time of pacemaker insertion significantly reduces the incidence of infectious complications. In addition to reducing complications, antibiotic prophylaxis can provide cost savings. Results of this meta-analysis support the use of prophylactic antibiotics at the time of pacemaker insertion to prevent short-term pocket infections, skin erosion or septicemia. Their efficacy with regard to late septicemia or endocarditis is unknown.
BARBARA APGAR, M.D., M.S.
Da Costa A, et al. Antibiotic prophylaxis for permanent pacemaker implantation. A meta-analysis. Circulation May 1998;97:1796-801.
Interpretation of Head CTs to Determine Stroke Treatment
The treatment of acute stroke now includes recombinant tissue plasminogen activator (TPA), approved for use in select patients within three hours of acute ischemic stroke. The presence of intracranial blood on computed tomographic (CT) scan of the head excludes patients from this therapy. It is generally advised that patients with an increased risk of hemorrhage (such as those with sulcal effacement, mass effect or edema) not receive recombinant TPA. Schriger and associates evaluated physician accuracy in interpreting cranial CT scans to determine eligibility for thrombolytic therapy in patients with acute stroke.
The authors of the study and a neuroradiologist reviewed all cranial CT scans performed at a university teaching hospital during a one-year period and selected head CTs that showed parenchymal hemorrhage, early infarction, calcification and old infarction. Using a consensus process, they classified each scan that demonstrated acute infarction as easy, intermediate or difficult to interpret, and each scan that demonstrated hemorrhage as easy or difficult to interpret.
Physicians participating in the study were asked to assume that each scan was of a patient who arrived at the hospital within hours after the onset of a neurologic deficit. Each physician was asked to decide if the patient was eligible for thrombolytic therapy. Possible answers were (1) yes; (2) no, because of hemorrhage; and (3) no, because of acute infarction. Each physician was given a list of findings that were contraindications to thrombolytic therapy (hemorrhage, early hypodensity, mass effect and shift) and findings that were not contraindications (calcification, atrophy and old infarction) to remind them of the criteria for this study. Physicians were shown two difficult hemorrhages, one intermediate acute infarction, one normal CT and one "imposter" scan. Physicians who correctly interpreted all of these scans were then placed in the advanced track, where they interpreted 10 more scans at a higher level of difficulty. Those who did not read all of the initial CT scans correctly were placed in the standard track and read 10 more scans.
A total of 29 neurologists, 36 radiologists and 38 emergency physicians participated in the study. Most (78 percent) failed to achieve correct readings on at least one of the five initial scans. Even the 21 physicians who were placed in the advanced track had a substantial number of incorrect readings overall. Neurologists and radiologists were 100 percent accurate in identifying easy hemorrhages; 94 percent of emergency physicians were also able to correctly interpret these scans. For scans classified as difficult hemorrhages, 80 percent of radiologists were correct in their interpretation compared with 78 percent of neurologists and 56 percent of emergency physicians. The average correct score by all three groups of physicians on all scans was 77 percent. The overall score for radiologists was 83 percent; the overall score was 83 percent for neurologists and 67 percent for emergency physicians.
The authors conclude that many physicians who are routinely called on to determine whether a CT scan precludes the use of recombinant TPA do not possess the skills needed to recognize hemorrhage on cranial CT scans. They note that the three-hour time limit imposed on administering recombinant TPA to a patient with an acute ischemic stroke mandates skillful interpretation of cranial CT scans. The authors suggest advanced training in CT scan interpretation or more widespread use of teleradiography to improve the accuracy of cranial CT scan interpretations.
GRACE BROOKE HUFFMAN, M.D.
Schriger DL, et al. Cranial computed tomography interpretation in acute stroke. Physician accuracy in determining eligibility for thrombolytic therapy. JAMA April 22, 1998;279:1293-7.
Association Between H. pylori and Ischemic Heart Disease
Several previous studies have shown a significant association between ischemic heart disease and various infective agents including Cytomegalovirus and Chlamydia pneumoniae. However, information regarding the association between Helicobacter pylori and ischemic heart disease has been contradictory. This might be explained by the genetic polymorphism of H. pylori. The more virulent strains of H. pylori bear the cytotoxin-associated gene-A (CagA), which is associated with severe forms of gastroduodenal diseases, including peptic ulcer and gastric cancer. Pasceri and associates conducted a controlled study to assess the prevalence of infection by the more virulent strains of H. pylori bearing the CagA antigen in patients with ischemic heart disease.
A total of 88 consecutive patients with severe unstable angina (27 patients), acute myocardial infarction (34 patients) or chronic stable angina (27 patients) for longer than one year were included in the study. All patients had angiographically confirmed ischemic heart disease. Eighty-eight control subjects were also recruited. Specific antiH. pylori was measured by use of a commercial enzyme-linked immunosorbent assay (ELISA). AntiH. pylori IgGs were detected in 55 of 88 patients with ischemic heart disease, compared with 35 of 88 control subjects. The prevalence of infection with H. pylori was similar in patients with acute myocardial infarction, unstable angina and chronic stable angina. A total of 38 of 88 patients and 15 of 88 control subjects were infected by CagApositive H. pylori. CagA negative strains of H. pylori had a similar prevalence in both groups and were not associated with increased risk of ischemic heart disease.
Results indicate that infection with more virulent CagApositive strains of H. pylori is significantly associated with ischemic heart disease, whereas CagAnegative strains have a similar prevalence in both patients and control subjects. The possible mechanisms are unknown, but recent studies have demonstrated that the presence of an inflammatory response has a prognostic value in patients with unstable angina and may predict the long-term risk of cardiovascular events in patients with chronic stable angina and in healthy men. The results suggest that CagApositive H. pylori cannot directly induce coronary atherosclerosis but may need the presence of other cofactors to stimulate progression of ischemia.
The authors conclude that an association between ischemic heart disease and chronic infection with virulent strains of a microorganism is apparent. This finding supports the hypothesis that the pathogenetic link between chronic infections and ischemic heart disease may be the chronic inflammatory response caused by these infections.
BARBARA APGAR, M.D., M.S.
Pasceri V, et al. Association of virulent Helicobacter pylori strains with ischemic heart disease. Circulation May 1998;97:1675-9.
Community-Acquired Pneumonia and Use of Macrolide Antibiotics
Prospective studies suggest that 10 to 25 percent of cases of community-acquired pneumonia are caused by atypical pathogens such as Legionella pneumophila, Chlamydia species and Mycoplasma pneumoniae. Guidelines from the American Thoracic Society for the management of community-acquired pneumonia, however, do not recommend routine testing for atypical pathogens. The recommended empiric therapy for hospitalized patients who are not severely ill includes a second- or third-generation cephalosporin or a beta lactam beta lactamase inhibitor with or without a macrolide. To evaluate the role of atypical pathogens and macrolide antibiotics in community-acquired pneumonia, Mundy and colleagues conducted a retrospective study of patients hospitalized because of community-acquired pneumonia between 1990 and 1991.
Routine sputum and blood cultures were obtained in all patients. Patients were also evaluated for the presence of atypical pathogens, including L. pneumophila, Chlamydia pneumoniae, Chlamydia psittaci and M. pneumoniae. The empiric antibiotic treatment was reviewed to determine which agents were used and if the selection had any impact on the outcome. Of the 385 patients with community-acquired pneumonia, 31 (8 percent) had pneumonia caused by atypical pathogens. Sixteen of the atypical cases also had a second common pathogen. In most cases of pneumonia caused by atypical pathogens, the pathogen was identified after patients were discharged from the hospital. On the basis of the American Thoracic Society guidelines, 260 patients were classified as severely ill, but only 57 were admitted to the intensive care unit. Only four of the patients with an atypical pathogen received a seven-day course of erythromycin or tetracycline. No patient in whom an atypical pathogen was detected died. None of the patients received macrolide therapy.
The authors conclude that early establishment of the causative agents for community-acquired pneumonia is problematic. Only 8 percent of the patients in this study had atypical pathogens, and most were identified after the patients were discharged. The fact that no macrolides were used suggests that routine administration of these antibiotics in all patients with community-acquired pneumonia is not necessary. The authors note that patients who are seriously ill and require admission to an intensive care unit should receive a macrolide antibiotic with one of the other recommended antibiotics, in accordance with the American Thoracic Society guidelines.
KARL MILLER, M.D.
Mundy LM, et al. Implications for macrolide treatment in community-acquired pneumonia Chest May 1998;113: 1201-6.
Transvaginal Sonohysterography in Postmenopausal Bleeding
Although endometrial biopsy is a relatively sensitive method for identifying endometrial cancer and its precursors, it is unreliable for identifying endometrial polyps and submucous fibroids. The addition of hysteroscopy increases the sensitivity for finding intraluminal masses. To perform sonohysterography, sterile saline solution is instilled into the uterus to increase the visualization of intraluminal masses. O'Connell and associates conducted a prospective, controlled trial to compare the diagnostic reliability of transvaginal sonohysterography and endometrial biopsy with fractional curettage and hysteroscopy in the initial evaluation of postmenopausal bleeding.
The study included 100 postmenopausal women with abnormal uterine bleeding who ranged in age from 42 to 80 years (mean age: 59.7 years). An endometrial biopsy was performed at the time of initial evaluation in all patients. Transvaginal ultrasonography was then performed to measure endometrial stripe thickness, the uterus and ovaries. This was immediately followed by sonohysterography to evaluate the endometrial wall thickness and identify any intraluminal masses. A fractional curettage at the time of operative hysteroscopy was used to obtain a histologic sample. The histologic results were compared with the diagnoses obtained by endometrial biopsy and sonohysterography. Histopathologic examination revealed atrophic or proliferative changes in 52 percent of the patients. Five patients had endometrial cancer.
The mean endometrial thickness for the entire group was 7.6 mm. It was significantly thinner (4.4 mm) in patients with endometrial atrophy. Conversely, endometrial thickness was 10.0 mm in patients diagnosed with submucosal fibroids and 17.7 mm in patients diagnosed with adenocarcinoma.
The combination of endometrial biopsy and transvaginal sonohysterography had a 95 percent positive correlation with the surgical pathologic findings. The use of this approach to evaluate women with postmenopausal vaginal bleeding was 94 percent sensitive and 96 percent specific, with positive and negative predictive values of 96 and 94 percent, respectively. In only five of the 100 patients did the ultrasonographic report not correlate with the surgical findings.
Data revealed a disproportionate number of false-negative and false-positive results among the eight patients receiving tamoxifen. If these patients were excluded from the analysis, the positive correlation increased to 97 percent and the sensitivity and specificity to 95 and 98 percent, respectively.
Neither endometrial biopsy nor measurement of endometrial thickness was reliable as a single diagnostic approach. However, endometrial biopsy did have a high specificity with a high positive predictive value. Transvaginal sonohysterography had a sensitivity of 86 percent and a specificity of 100 percent for identification of an intraluminal mass. However, sensitivity would have been noticeably hampered without an endometrial biopsy.
The authors conclude that transvaginal sonohysterography accurately identifies intraluminal uterine masses. Although some studies have suggested that endometrial thickness can be used as a means of excluding cancer, nine patients in this study with an endometrial thickness of less than 5 mm had significant endometrial pathologic findings, including adenocarcinoma. If these patients had been treated expectantly on the basis of benign findings on endometrial biopsy and an endometrial thickness of less than 5 mm, it is likely that they would have experienced continued bleeding. Neither transvaginal ultrasonography nor endometrial biopsy by themselves appear to be reliable tools for evaluating postmenopausal vaginal bleeding. Endometrial biopsy combined with sonohysterography was an accurate means of identifying patients who did not require further surgical intervention.
BARBARA APGAR, M.D., M.S.
O'Connell LP, et al. Triage of abnormal postmenopausal bleeding: a comparison of endometrial biopsy and transvaginal sonohysterography versus fractional curettage with hysteroscopy. Am J Obstet Gynecol May 1998:178: 956-61.
EDITOR'S NOTE: Although uterine curettage has been considered the "gold standard" for the evaluation of abnormal uterine bleeding, its limitations must be realized. Blind sampling of the endometrium can miss intraluminal masses. If postmenopausal women with vaginal bleeding are to be managed expectantly, the clinician must have a reliable method of identifying the etiology of the bleeding to confidently allow medical management rather than surgical intervention.
B.A.
Effectiveness of Ring Block for Neonatal Circumcision
Many newborn males continue to undergo neonatal circumcision without anesthesia in spite of evidence that the procedure causes pain and distress. Several anesthetic techniques have been described for neonatal circumcision, but ring block of the penis has mainly been used in older children and adults. Hardwick-Smith and colleagues studied the effectiveness of penile ring block in reducing the indicators of distress during and after neonatal circumcision.
Forty healthy infants scheduled for circumcision were included in the study and were randomly assigned to receive either a penile ring block or no anesthesia after obtaining informed parental consent. The ring blocks were each performed by the same researcher using a standard technique. After a three-minute waiting period, circumcision using a Gomco clamp was also performed by the same operator on all infants. Indices of perceived pain including behavior, heart rate, respiratory rate and oxygen saturation percentage were recorded at baseline, at 10 intervals during the procedure and at two hours after circumcision. Behavior was assessed using a standardized six-point scale of degree of arousal. Crying time was documented by tape recordings, and other indices were monitored.
The two groups of infants were comparable in demographic, behavioral and other characteristics before the procedure. Infants receiving the block had a mean reduction of approximately two minutes in crying time (36 percent, compared with control subjects) and a significantly decreased arousal state. Anesthetized infants had returned to basal levels of arousal within two minutes of the procedure, but the control infants remained significantly aroused. Non-anesthetized infants showed significantly increased heart and respiratory rates during the procedure. A trend toward greater oxygen desaturation was documented in these infants. Both groups had returned to baseline levels within two hours of the circumcision.
The authors conclude that ring block provides safe and effective short-term anesthesia for neonatal circumcision. The fascia is not pierced, so there is less potential for hematoma formation and other bleeding than with the dorsal penile nerve block. The technique was easy for the clinician to learn and perform, and no complications were encountered in this study.
ANNE D. WALLING, M.D.
Hardwick-Smith S, et al. Ring block for neonatal circumcision. Obstet Gynecol June 1998;91:930-4.
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