Tips from Other Journals
Distinguishing Benign From Malignant Endometrial Findings
Transvaginal ultrasonography (US) identifies abnormal pathologic conditions in the endometrium as diffuse or focal areas of thickening. Transvaginal hysterosonography is useful when further evaluation of endometrial thickening or better visualization is needed. However, little is known about how well the latter technique can distinguish benign abnormalities from malignancies. Dubinsky and associates established criteria for classifying benign and suspicious lesions viewed with transvaginal hysterosonography. They applied these criteria prospectively to radiographic interpretations and correlated all cases with histopathologic findings obtained at hysterectomy or at dilatation and curettage (D&C) to evaluate the predictive values of transvaginal hysterosonography in diagnosing malignant endometrial disease.
Women between 25 and 81 years of age who sought medical attention at a Houston gynecology clinic for significant vaginal bleeding were eligible for the study. Patients with negative findings on aspiration biopsy of the endometrium were referred for transvaginal US.
Results of the transvaginal hysterosonographic examinations were interpreted prospectively, and the pathology reports of patients who had had either a D&C or a hysterectomy within one month of the examination were reviewed retrospectively. A benign endometrial appearance was defined as an endometrial thickness of less than 4 mm, the presence of a smoothly echogenic mass in the endometrial lumen or a diffusely thickened endometrium of greater than 4 mm. A suspicious endometrial appearance was defined as a focal nonhomogenous mass projecting into the lumen or focal endometrial thickening of greater than 4 mm. Sensitivity, specificity and predictive values for predicting malignant disease were then calculated.
Eighty-eight women met the study criteria and underwent transvaginal hysterosonography, followed by D&C (37 patients) or hysterectomy (51 patients). Of the 37 women who underwent D&C, 30 had benign-appearing endometria, and 28 had diffuse, smooth endometrial thickening that was benign on histology. Two patients had a thin endometrium at hysterosonography, despite an appearance on transvaginal US that suggested a thickening. D&C in these two patients revealed an inactive endometrium. Seven patients had pedunculated homogenously echogenic luminal masses identified on hysterosonography, and all of these patients underwent hysterectomy. Histology revealed six adenomatous polyps and one focus of carcinoma in situ in a polyp.
Of the 51 women who underwent hysterectomy, eight had endometrial carcinoma, 24 had adenomatous polyps, five had hyperplasia, 11 had fibroids and three had endometritis, which was subsequently cultured and found to be positive for Chlamydia.
The proposed classification system for detecting endometrial carcinoma with transvaginal hysterosonography had a sensitivity of 89 percent, a specificity of 46 percent, a positive predictive value of 16 percent and a negative predictive value of 97 percent.
The authors conclude that transvaginal hysterosonography is useful in identifying benign pathologic conditions of the endometrium and indicating when biopsy is warranted. Most endometrial abnormalities, including carcinoma, appear as a focal mass with this examination. The authors' criteria were highly predictive for benign processes, particularly endometrial thickening. However, because many pathologic conditions had a suspicious appearance, the positive predictive value of transvaginal hysterosonography for carcinoma was low. Therefore, women with multifocal or sessile lesions should undergo a guided biopsy, and any benign-appearing polyps should be removed to rule out carcinoma. Transvaginal hysterosonography should be used to identify patients who need more invasive therapy if an endometrial lesion is detected or to provide medical therapy if no lesion is present.
BARBARA APGAR, M.D., M.S.
Dubinsky TJ, et al. Prediction of benign and malignant endometrial disease: hysterosonographic-pathologic correlation. Radiology February 1999;210:393-7.
EDITOR'S NOTE: One major limitation of this study was the use of D&C to obtain the endometrial sample. This procedure is now considered a blind sampling technique, not the gold standard it once was. Of note, however, is that the histologic samples obtained with D&C were consistently abnormal in patients whose transvaginal hysterosonogram showed a focal mass.
B.A.
Detection of Tuberculosis Despite Normal Chest Films
Chest radiographs may be normal in some patients with pulmonary tuberculosis, an occurrence that has been noted with increasing frequency. To characterize the clinical features in patients with pulmonary tuberculosis and normal chest radiographs, Marciniuk and colleagues performed a retrospective study of 25 patients with normal chest films and culture-positive pulmonary tuberculosis.
The authors reviewed the records of a tuberculosis control program in Saskatchewan, Canada, to identify patients with culture-positive tuberculosis. Between 1988 and 1997, 518 cases of tuberculosis were diagnosed. Of these, 25 patients had normal findings on chest films, for an incidence of 4.8 percent.
The mean age of the patients with normal chest films was 26 ± 13 years (age range: six months to 59 years). In 22 cases, tuberculosis was diagnosed by positive sputum cultures. In the remaining three cases, the diagnosis was made by gastric washings. The results of the Mantoux skin test were recorded in 23 patients; the mean size of induration was 19 mm. However, four patients had no evidence of induration. (In the 493 patients with abnormal radiographic findings, no induration was found in 5 percent.)
The most common symptoms exhibited by the patients with normal chest films were cough (76 percent), sputum production (64 percent) and night sweats (24 percent). Anorexia was present in 20 percent, fever of more than one week's duration in 20 percent and weight loss in 16 percent. Twenty-four of the patients were noted to have a cough for more than one month, fever for more than one week or a skin-test conversion after contact with a person known to have active tuberculosis. Only two patients reported no symptoms; they were identified by contact tracing.
To examine whether the number of patients with tuberculosis who have normal chest films is increasing, the authors analyzed the data from three periods. The incidence of negative chest films and culture-positive pulmonary tuberculosis was 0.7 percent for 1988-89, 3.5 percent for 1990-91 and 10 percent for 1996-97.
The authors conclude that in their population, the occurrence of normal chest films in patients with active tuberculosis is not uncommon. A likely explanation for the increased incidence of this type of presentation may be improved detection of early disease. The authors believe the results suggest that sputum smear and culture for Mycobacterium tuberculosis should be obtained in patients who have normal chest films but present with a cough lasting for more than one month or fever lasting for more than one week or who have a documented skin-test conversion less than two years after exposure to infectious tuberculosis.
JEFFREY T. KIRCHNER, D.O.
Marciniuk DD, et al. Detection of pulmonary tuberculosis in patients with a normal chest radiograph. Chest February 1999;115:445-52.
EDITOR'S COMMENT: This is a provocative study, but the results must be interpreted within the clinical context. The patients were members of a highly select group who had been referred to a centralized tuberculosis program in Canada. The authors mention in their discussion that one reason for the observed increased incidence of normal chest radiography in patients with tuberculosis may have been the development in the mid-1990s of improved techniques for isolating and growing M. tuberculosis. Obtaining sputum cultures in all patients who present with only one of the three clinical features in this study may not as a general rule be clinically prudent or cost-effective. The appropriateness of such an approach would depend on the patient population. On the other hand, earlier diagnosis of tuberculosis leads to fewer contacts, decreased morbidity and usually better outcomes.
J.T.K.
When to Operate on Intracranial Aneurysms?
Subarachnoid hemorrhage (SAH) is a potentially fatal but rare event occurring in approximately 10 per 100,000 population each year. Most cases of SAH are believed to be caused by rupture of intracranial aneurysms. In a review of the International Study of Unruptured Intracranial Aneurysms, Kirkpatrick notes that approximately 5 percent of the population will develop an aneurysm, although very few ever become symptomatic.
Physicians now face a dilemma when cerebral aneurysms are identified in asymptomatic patients. In this study of 2,621 patients, the risk of rupture from small aneurysms (less than 10 mm diameter) was estimated to be 0.05 percent per year. The risk increased to 0.5 percent per year if the patient had previously bled from another aneurysm. For aneurysms greater than 10 mm in diameter, the annual risk of rupture was approximately 1 percent. Giant aneurysms (diameter over 25 mm) are rare but have a 6 percent risk of rupture within one year of diagnosis.
The risk of rupture for all aneurysms increases with patient age and location; areas such as the basilar tip are particularly vulnerable to rupture. The study concluded that most intracranial aneurysms are at extremely low risk of rupture, and that characteristics such as size, location, previous SAH and patient age indicated those aneurysms that are at increased risk of SAH.
Conversely, surgical treatment of aneurysms has significant morbidity and mortality. The mortality within one year of surgery was 3.8 percent; 12.0 percent of patients had significant morbidity. Morbidity and mortality increased with patient age. Rates of complications varied greatly between centers, emphasizing the role of clinical experience and the need for increased audit.
ANNE D. WALLING, M.D.
Kirkpatrick PJ. Time to reconsider treatment options for intracranial aneurysms. Lancet March 20, 1999;353:942-3.
Test Characteristics of Markers for MI Based on Time From Onset of Symptoms
Marker
Early diagnosis
(6 hours)
Late diagnosis
(22 hours)
CK-MB subforms Sensitivity 91.5 53.1 Specificity 89.0 92.2 Myoglobin Sensitivity 78.7 42.9 Specificity 89.4 91.3 Troponin T Sensitivity 61.7 85.7 Specificity 96.1 94.6 Troponin I Sensitivity 57.5 89.8 Specificity 94.3 94.2 Conventional CK-MB Sensitivity 66.0 95.7 Specificity 100.0 99.1
MI=myocardial infarction; CK-MB=creatine kinase-MB subform.
Adapted with permission from Zimmerman J, et al. Diagnostic Marker Cooperative Study for the diagnosis of myocardial infarction. Circulation 1999;99: 1671-7.
Diagnostic Markers for Detection of Myocardial Infarction
Only 10 to 15 percent of patients who present with acute chest pain have a myocardial infarction (MI). Symptoms cannot be used to differentiate those who have had an MI from those who have not. Further, the electrocardiogram is diagnostic for myocardial ischemia in only 40 percent of patients. Cardiac enzyme assays have formed the basis for making this critical determination. Unfortunately, the standard creatine kinase-MB (CK-MB) assay is not reliable in excluding infarction until 10 to 12 hours after the onset of chest pain. Earlier diagnosis would have very specific advantages with regard to fibrinolytic therapy and triage. Studies have been undertaken to assess the utility of newer markers, such as troponin I, troponin T, creatine kinase-MB "subforms" and myoglobin. Zimmerman and associates present the results of the Diagnostic Marker Cooperative Study (DMCT), which was used to assess each of these enzyme assays.
The DMCT was a prospective, multicenter, double-blind study of 955 consecutively enrolled patients who presented to an emergency department with chest pain. Sensitivity and specificity were determined for conventional CK-MB, CK-MB "subforms," myoglobin, troponin T and troponin I.
Patients underwent each test at hours 2, 4, 6, 10, 14, 18 and 22. The results are shown in the accompanying table. The most reliable marker for early diagnosis (within six hours of onset of symptoms) was the CK-MB subform, with a sensitivity of 91.5 percent. This was followed by myoglobin, conventional CK-MB, troponin T and troponin I. The most reliable marker for late diagnosis (at 22 hours) was the conventional CK-MB, with a sensitivity of 95.7 percent. This was followed by troponin I, troponin T, CK-MB subforms and myoglobin.
Based on the results of this study, physicans can better discern the reliability of tests in ruling out myocardial ischemia. The authors found that CK-MB subforms were the most reliable marker for myocardial damage in the first six hours of symptom onset, a conclusion reached by Puleo and colleagues in an earlier article (Puleo PR, et al. Use of a rapid assay of subforms of creatine kinase MB to diagnose or rule out acute myocardial infarction. N Engl J Med 1994;331:561-6).
JIM NUOVO, M.D.
Zimmerman J, et al. Diagnostic Marker Cooperative Study for the diagnosis of myocardial infarction. Circulation April 6, 1999;99:1671-7.
A Novel Method of Treating Secondary Amenorrhea in Athletes
Secondary amenorrhea commonly affects women who participate in competitive and recreational sports, particularly running and dance. Women of reproductive age with this condition require estrogen replacement and, often, additional cyclic progestin to prevent excessive growth of the endometrium. Some of the most commonly used synthetic oral and transdermal progestins produce undesirable side effects related to the liver, making natural progesterone a better alternative. In addition, orally administered progesterone can cause dizziness and drowsiness; therefore, a transvaginal delivery method may be the only practical route. Warren and associates evaluated the safety and effectiveness of cyclic vaginal natural progesterone gel in women with secondary amenorrhea.
Women of reproductive age with confirmed secondary amenorrhea were eligible for the study. The study period consisted of three consecutive 28-day treatment cycles during which all patients received either 0.625 mg daily of conjugated estrogen or approximately 0.05 mg of transdermal estradiol daily. Patients were then randomized to receive 1.125 g of either 4 percent (45 mg) or 8 percent (90 mg) transvaginal progesterone gel every other day starting on day 15 of cycles two and three, for a total of six applications per cycle. Ultrasound examinations and laboratory studies were obtained before progesterone gel therapy was started to document that the endometrium had been adequately estrogenized. Efficacy was based on endometrial biopsy findings and the presence of withdrawal bleeding.
Of the 127 women enrolled in the study, 62 received 4 percent gel and 65 received 8 percent gel. Demographic data were similar between groups. Biopsy results showed that all patients in the higher dosage group had progestational changes in their endometrium, compared with 92 percent of patients in the lower dosage group. None of the patients had endometrial hyperplasia. Withdrawal bleeding occurred with equal frequency (about 82 percent) in the active drug treatment groups. Sixty-three percent of patients (17 of 27) who received the estradiol transdermal system experienced withdrawal bleeding compared with 69 percent (69 of 100) who received oral conjugated estrogen. Most patients experienced withdrawal bleeding 10 to 12 days after the initial placement of the progesterone gel.
The incidence of side effects, particularly psychologic effects, bloating and nausea, decreased significantly after patients began taking the progesterone gel, compared with estrogen alone. Headaches decreased significantly in the higher dosage group. Vaginal discharge increased significantly in frequency in the lower dosage group but decreased significantly in the higher dosage group. Cramping increased in both groups after initiation of gel therapy.
The authors conclude that progesterone vaginal gel is safe and effective in providing hormone replacement therapy in women with secondary amenorrhea. Transvaginal progesterone gel resulted in withdrawal bleeding in 81 percent of estrogenized women with hypothalamic amenorrhea or premature ovarian failure. Results also indicated that some women might require the higher dosage to maximize progestogenic effects on the endometrium. Psychologic side effects diminished with the combination of estrogen and progesterone, compared with estrogen alone. In fact, unexpected improvement in the feeling of well-being was observed when estradiol and natural progesterone were combined.
BARBARA APGAR, M.D., M.S.
Warren MP, et al. A new clinical option for hormone replacement therapy in women with secondary amenorrhea: effects of cyclic administration of progesterone from the sustained-release vaginal gel Crinone (4% and 8%) on endometrial morphologic features and withdrawal bleeding. Am J Obstet Gynecol January 1999;180(1 pt 1):42-8.
Newer Indications for Use of Permanent Pacemakers
Indications for the use of permanent pacemakers have extended beyond sinus node dysfunction and atrioventricular block. The third revision of the American College of Cardiology (ACC) and the American Heart Association (AHA) guidelines for indications for permanent pacing were published in 1998. Hayes summarizes the latest indications for permanent cardiac pacing.
Improvement of hemodynamics is the newest area of interest for the use of pacing. In patients with hypertrophic obstructive cardiomyopathy with significant left ventricular outflow obstruction gradient, pacing may reduce symptoms of angina and dyspnea, and improve exercise tolerance. Long-term outcomes are less clear. Patients with symptomatic first-degree atrioventricular block, or those with type 1 second-degree atrioventricular block with hemodynamic compromise associated with atrioventricular dyssynchrony and not necessarily bradycardia, may be considered for permanent pacing.
Patients with neurally mediated syncope (defined as syncope induced by a head-up tilt test) are generally not helped by pacing because the lack of atrioventricular synchrony aggravates the peripheral vasodilation that usually accompanies this condition. However, patients with subtypes of neurally mediated syncope that occur with significant bradycardia or asystole that is greater than three seconds may benefit from pacing. The North American Vasovagal Pacemaker Study was a randomized trial that demonstrated a relative risk reduction of 85 percent for syncopal spells in patients with frequent syncope and a positive head-up tilt test result with use of a dual-chamber pacemaker.
Atrial fibrillation and atrial flutter may be controlled with dual-site atrial pacing. Pacing for the prevention of atrial fibrillation is currently investigational. Pacing after cardiac transplantation is useful in patients with sinus node dysfunction.
The author concludes that indications for permanent pacing continue to evolve. The ACC/AHA guidelines provide an update on the use of pacing to improve hemodynamic function.
RICHARD SADOVSKY, M.D.
Hayes DL. Evolving indications for permanent pacing. Am J Cardiol March 11, 1999;83:161D-5D.
Doxycycline Is Cost-Effective for Community-Acquired Pneumonia
Patients with community-acquired pneumonia (CAP) typically receive empiric antibiotic therapy until a causative microbiologic organism is definitively identified. The most commonly detected organisms are Streptococcus pneumoniae, followed by Legionella, Chlamydia and Mycoplasma agents. However, if no organism is identified, as in most cases, and the clinical response to therapy is good, the course of treatment is completed with the initial antibiotic. Doxycycline has been shown to be highly effective against common respiratory pathogens and is frequently used for outpatient therapy of CAP. Ailani and associates evaluated the effectiveness of intravenous doxycycline as empiric treatment of hospitalized patients who had mild to moderately severe CAP.
Patients with clinical and radiologic diagnosis of CAP before hospital admission were eligible for the study. Patients under 18 years of age, those who were pregnant and those who had other serious medical conditions were excluded from the study. Patients were randomized to receive either intravenous doxycycline in a dosage of 100 mg every 12 hours or a medication regimen chosen by their primary physician. Demographic information, clinical condition and laboratory profiles were similar between groups. In addition, 40 percent of the patients in both groups had documented underlying lung disease. Study parameters included time until resolution of morbidity, length of hospital stay, cost of antibiotics and hospitalization, adverse effects of the medication and the number of antibiotics used per patient.
Of the 87 patients enrolled in the study, 43 were randomized to the doxycycline group and 44 to the control group. While patient age varied widely, few (23 percent) were older than 60 years of age. Patients in the doxycycline group used fewer antibiotics and responded to treatment faster; therefore, they required less time in the hospital. As a result, the median costs of antibiotic therapy and total hospitalization were significantly less than costs for the control group. Adverse effects and the need to change medications also occurred much less frequently in the doxycycline group than in the control group.
The authors conclude that doxycycline is effective in the empiric treatment of hospitalized patients with mild to moderately severe CAP. Besides being effective and relatively inexpensive, doxycycline is associated with fewer adverse effects than other, more complex regimens involving two or more medications.
BARBARA APGAR, M.D., M.S.
Ailani RK, et al. Doxycycline is a cost-effective therapy for hospitalized patients with community-acquired pneumonia. Arch Intern Med February 8, 1999;159:266-70.
Using Pravastatin to Reduce Risk of Stroke After MI
Although the importance of the cholesterol level has been established in the prevention of coronary artery disesase, it is less certain whether cholesterol reduction helps prevent strokes. The Cholesterol and Recurrent Events (CARE) trial was a secondary prevention trial designed to see if, after an acute myocardial infarction, HMG-CoA reductase inhibitors could reduce the incidence of fatal and nonfatal coronary events or strokes. Plehn and colleagues performed a review of the cerebrovascular events in the CARE study to determine if pravastatin lowered the patient's chances of a stroke in addition to reducing chances of myocardial infarction.
The study population included 4,159 patients, most of them men, between 21 and 75 years of age who had suffered a myocardial infarction in the previous three to 20 months. Patients were included in the study if they had a total cholesterol level of 240 mg per dL (2.4 g per L) or less, a low-density lipoprotein (LDL) level between 115 and 174 mg per dL (2.95 and 4.50 mmol per L) and fasting triglyceride levels of 350 mg per dL or less. Also enrolled were patients who had a fasting blood glucose level of 220 mg per dL (12.2 mmol per L) or less and a left ventricular ejection fraction of 25 percent or more, with absence of symptomatic congestive heart failure. Patients were randomized to receive either pravastatin, in a dosage of 40 mg per day, or placebo. Eighty-three percent of study participants were taking aspirin; 2 percent were taking other platelet inhibitors. About 3 percent of patients were taking warfarin. A small percentage of patients had a history of previous stroke or transient ischemic attack.
Patients in the pravastatin group experienced a 20 percent decrease in total cholesterol levels, a 32 percent decrease in LDL cholesterol levels and a 5 percent increase in high-density cholesterol levels. All patients were followed for a median of five years. During that time, 76 patients in the placebo group had a first stroke, compared with only 52 patients in the pravastatin group. This represents a 32 percent relative risk reduction (4 to 52 percent; P=0.03). Likewise, 124 patients in the placebo group had either a transient ischemic attack or a stroke, compared with 92 patients in the pravastatin group, resulting in a relative risk reduction of 27 percent (4 to 44 percent; P=0.02). The results held up when controlled for age, sex, hypertension, smoking, diabetes, ejection fraction, history of cerebrovascular event and baseline lipid values. The divergence of the treatment arms became apparent about three and one-half years into the study. Patients with higher baseline LDL cholesterol levels had a greater risk reduction. However, this trend did not reach the level of statistical significance.
The authors conclude that further studies should be performed to see if similar results can be achieved in other at-risk populations.
CLARISSA C. KRIPKE, M.D.
Medical Editing FellowPlehn JF, et al. Reduction of stroke incidence after myocardial infarction with pravastatin. Circulation January 19, 1999;99:216-23.
EDITOR'S NOTE: The number needed to treat for this study represents the number of patients with recent myocardial infarction who would need to be treated with pravastatin, in a dosage of 40 mg per day, to prevent one stroke or transient ischemic attack over approximately five years. In this study, the number needed to treat is 64.5 patients.
C.C.K.
Treating Dryness Associated with Sjögren's Syndrome
Sjögren's syndrome is a chronic autoimmune rheumatic disorder characterized primarily by dry mouth (xerostomia) and dry eyes (xerophthalmia). Hypofunction of the salivary and lacrimal glands causes discomfort and serious side effects, including increased susceptibility to infection. Over-the-counter saliva and tear substitutes provide only short-term relief and often fail to prevent long-term complications. Pilocarpine has been used successfully to treat the signs and symptoms of radiation-induced dry mouth, but not the dryness symptoms associated with Sjögren's syndrome. Vivino and associates evaluated the safety and effectiveness of pilocarpine tablets in treating dry mouth and eyes in patients with Sjögren's syndrome.
Patients eligible for the study had a primary or secondary diagnosis of Sjögren's syndrome, with significant dry mouth and eyes. Before entry into the study, patients were required to stop using any electric device to produce saliva and to discontinue using any medications that caused dry mouth. Patients with clinically significant cardiac, renal or gastrointestinal conditions, diabetes mellitus or multiple sclerosis were excluded from the study. Those who met the study criteria were randomized to receive either 2.5 mg or 5 mg of pilocarpine, or placebo tablets four times daily for 12 weeks. Efficacy was measured by response to questionnaires and measurements of salivary flow obtained at follow-up visits six and 12 weeks after initiation of the study. Safety was evaluated based on results of laboratory and diagnostic studies.
Of the 373 predominantly female patients enrolled in the study, 121 were in the 2.5-mg group, 127 were in the 5-mg group and 125 were in the placebo group. Demographic characteristics were similar across groups. Within six to 12 weeks after pilocarpine therapy was initiated, patients in the 5-mg group reported significant overall improvements in the symptoms of eye and mouth dryness compared with the other groups. These patients also slept better and reported improvements in dry skin and nasal dryness. Salivary flow also increased significantly in this group compared with the other groups. No serious drug-related adverse effects were reported, although some patients reported mild or moderate sweating, flushing and urinary frequency.
The authors conclude that treatment with the higher dosage of pilocarpine significantly improved the dryness associated with Sjögren's syndrome and that these benefits clearly outweighed the mild to moderate adverse cholinergic activity. Almost any patient with some degree of exocrine gland dysfunction in association with Sjögren's syndrome could potentially benefit from this treatment.
BARBARA APGAR, M.D., M.S.
Vivino FB, et al. Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjögren syndrome. Arch Intern Med January 25, 1999:159:174-81.
Vaginal Preparations May Compromise Condom Integrity
The use of condoms has risen dramatically in the past few years. When used correctly and consistently, condoms are inexpensive and highly effective in preventing pregnancy and decreasing the risk of infection with sexually transmitted diseases. Condoms are classified as a medical device and are randomly regulated and tested by the U.S. Food and Drug Administration. Condom failure is usually attributable to either inappropriate use or product deterioration. One possible cause of condom deterioration is exposure to oily substances. Many people are aware of this danger and avoid using lubricants that contain mineral oil or vegetable oil. Rosen and Rosen observed the potential risk for condom rupture after short exposures to common over-the-counter vaginal preparations.
Fresh latex condoms from the same manufacturer's lot number were used in the study. An air pump that tested condom rupture time was set to deliver a constant pressure of 4 psi. Each of the vaginal preparations was placed on the condoms for five minutes and then washed off with tap water. The condoms were air-dried before the test. A control group of condoms that were not exposed to the vaginal preparations was also used.
The mean burst time for each group was obtained by averaging the individual burst times of 20 condoms using the air pump. The mean burst time for the control group was 59.8 seconds. Pure mineral oil reduced the burst time to 11.2 seconds. Vaginal preparations that did not contain mineral or vegetable oil did not affect the burst time. In addition, two commonly used anti-pruritic preparations (Vagisil and Vagicaine) that contained mineral oil did not significantly reduce the burst time. Agents that reduced the burst time included one vaginal moisturizer (Replens), and miconazole antifungal creams and suppositories.
Women regularly use various over-the-counter vaginal preparations, especially antifungal preparations. Because these are no longer prescription medications, a significant number of women have used the products. If women are relying on condom integrity for prevention of pregnancy or provision of "safe sex," the use of preparations that contain mineral or vegetable oil can have a significant impact on the integrity of the condom.
The authors conclude that patients should be cautioned about the simultaneous use of condoms and over-the-counter vaginal preparations.
KARL MILLER, M.D.
Rosen AD, Rosen T. Study of condom integrity after brief exposure to over-the-counter vaginal preparations. Southern Med J March 1999;92:305-7.
Cardioversion of Paroxysmal Atrial Fibrillation
Symptoms of uncontrolled atrial fibrillation include palpitations and poor cardiac performance, with resultant worsening of coronary artery disease, congestive heart failure and possible sudden death. Patients presenting with new-onset atrial fibrillation are usually admitted to the hospital for evaluation of cardiac pathology and to monitor for complications. Anti-arrhythmic therapy may require extended cardiac monitoring because of proarrhythmic complications. Cardioversion is generally safe if patients present within 48 hours of the start of atrial fibrillation. With a longer duration of symptoms, patients should undergo three weeks of anticoagulation therapy before cardioversion is attempted. Recently, the need for hospitalization in low-risk patients with new-onset atrial fibrillation has been questioned. Michael and associates reviewed the postcardioversion management of low-risk patients who presented with symptoms of atrial fibrillation lasting for less than 48 hours.
During the 18-month study period, 168 low-risk patients made 289 visits to the emergency department. Atrial fibrillation was one of the discharge diagnoses in all of the study subjects. The average age of the participants was 64 years. Seventy-two percent had a previous history of atrial fibrillation.
Seventy-five percent of the patients who received medication to control heart rate had a rate reduction to less than 120 beats per minute, with diltiazem providing the highest rate of success and adenosine and digoxin being least helpful. Ninety of 180 attempts at chemical cardioversion were successful. Intravenous procainamide was used in 98 percent of these cases. Ninety-nine percent of the patients who had a successful chemical cardioversion were discharged home from the emergency department. Eighty patients underwent electric cardioversion; in most of these patients, chemical cardioversion had failed. Patients who were successfully converted were discharged home. Ten percent of patients unexpectedly returned to the emergency department within seven days, although none of the patients had complications associated with cardioversion.
The authors conclude that, assuming patients presenting with new-onset atrial fibrillation are at low risk, most patients (97 percent) treated in the emergency department with either heart rate control, chemical cardioversion or electric cardioversion do not require hospitalization. Rates of short-term complications appear to be very low, but long-term complications require further study.
RICHARD SADOVSKY, M.D.
Michael JA, et al. Cardioversion of paroxysmal atrial fibrillation in the emergency department. Ann Emerg Med April 1999;33:379-87.
A New Tool That Specifically Diagnoses Pemphigus Vulgaris
Pemphigus vulgaris (PV) is an autoimmune blistering disease of the skin and mucous membranes, characterized by the appearance of flaccid blisters and erosions that usually arise on normal-appearing skin and mucosa. PV is caused by antibodies directed against desmoglein 3 (Dsg3), an epidermal glycoprotein of the cadherin family. In animal studies, anti-Dsg3 antibodies have been shown to induce loss of cell adhesion, suggesting that Dsg3 plays an important role in disease pathogenesis. Traditionally, pemphigus antibodies are detected by direct or indirect immunofluorescence (IIF) testing, but this method tends to be subjective and often fails to distinguish PV from other bullous diseases. However, recent success in cloning the Dsg3 gene has led to the development of a specific, sensitive, enzyme-linked immunosorbent assay (ELISA) that detects PV autoantibodies. Lenz and associates compared ELISA values with autoantibody titers obtained by classic IIF in patients with PV and other dermatologic conditions to determine the specificity and sensitivity of ELISA in diagnosing PV.
Serum samples obtained from 11 patients with confirmed PV were tested for anti-Dsg3 reactivity. Forty-five patients with other bullous or nonbullous conditions were also included in the study to evaluate the specificity of ELISA and to determine whether ELISA was prone to false-positive results. In addition, 10 healthy persons were included in the analysis to serve as the control group. The Dsg3 protein used in this study was produced in the authors' laboratory.
Of the 52 PV serum samples evaluated in the study, 47 were positive by Dsg3-ELISA, for a sensitivity of 93 percent. The sensitivity increased to 98 percent when IIF-negative PV samples were excluded, suggesting that both tests have similar sensitivity. Results of ELISA were negative in 51 of the 55 non-PV serum samples. Only four of these samples were positive by ELISA, resulting in a specificity of 93 percent. These results suggest a positive correlation between Dsg3-ELISA and IIF titer. ELISA values paralleled IIF titers and, more importantly, results of both tests increased at the time of disease relapse and decreased after treatment-induced remission. ELISA values increased earlier and were more pronounced when compared with IIF titers, possibly reflecting a higher sensitivity of ELISA in detecting anti-Dsg3 antibodies.
The authors conclude that Dsg3-ELISA is a highly sensitive and specific test for detecting pathogenic Dsg3 antibodies and should be considered an additional diagnostic tool in the routine evaluation and monitoring of patients with PV.
BARBARA APGAR, M.D., M.S.
Lenz P, et al. Desmoglein 3-ELISA. A pemphigus vulgarisspecific diagnostic tool. Arch Dermatol February 1999;135:143-8.
The Differential Diagnosis of Diverticulitis vs. Colon Cancer
Computed tomographic (CT) scans are often used to establish a diagnosis of suspected colon cancer or colonic diverticulitis. Although CT images are generally effective in identifying these conditions, the imaging appearance overlaps in about 10 percent of patients. Chintapalli and associates sought to identify specific signs on CT scan to help distinguish diverticulitis from colon cancer. They conducted a retrospective review of CT images from patients with confirmed diverticulitis or colon cancer to establish diagnostic criteria. These criteria were then compared prospectively with CT images from another series of patients with the same suspected diagnoses.
To establish the criteria, 58 CT images were obtained from a series of patients diagnosed with diverticulitis or colon cancer and evaluated retrospectively by five radiologists for the presence or absence of previously reported CT findings. The findings were correlated with the final clinical or histologic diagnosis. These initial CT findings were then compared prospectively with a series of 72 CT scans from different patients and evaluated by the same five radiologists. Each new scan was evaluated on a confidence scale of one to five, ranging from "definitely diverticulitis" to "definitely malignant." Individual CT diagnoses were correlated with final clinical diagnoses. The combinations of readings from the five radiologists were tabulated to identify the overlap in each of the categories on the confidence scale. CT findings for which the accuracy of diagnosis was the highest were determined.
In the retrospective part of the study, 27 patients were diagnosed with diverticulitis and 31 were diagnosed with colon cancer. The findings most specific for diverticulitis were pericolonic inflammation and a length of segment longer than 10 cm. The presence of lymph nodes and a luminal mass were most specific for colon cancer. The presence of pericolonic edema suggested diverticulitis, but the results were not statistically significant in this portion of the study.
In the prospective part of the study, 40 patients were diagnosed with diverticulitis and 32 were diagnosed with colon cancer. Eighty-three readings were rated definite diverticulitis and, of these, 80 were diverticulitis and three were colon cancer. Ninety-six readings were rated definite colon cancer and, of these, 92 were cancer and four were diverticulitis. The individual readings of the CT images were 96 percent accurate in making a correct, unequivocal diagnosis, suggesting a very low rate of interpretive mistakes.
Additional analysis showed that fluid at the root of the mesentery, pericolonic edema and pericolonic inflammation had the highest specificity for diverticulitis. The presence of pericolonic lymph nodes, shoulder formation and a luminal mass had the highest specificity for colon cancer. Although the presence of pericolonic edema was not significant in the retrospective review, it became highly significant in the prospective study. The presence of lymph nodes with or without pericolonic edema resulted in a sensitivity of 90 percent and a diagnostic accuracy of 79 percent for colon cancer.
The authors conclude that the specificity of the CT findings in identifying diverticulitis and colon cancer is so high that, depending on the radiologist's experience, an unequivocal diagnosis carries an accuracy of up to 100 percent for both diverticulitis and colon cancer. In this situation, no additional diagnostic work-up is necessary, and further evaluation for surgical planning may be initiated.
BARBARA APGAR, M.D., M.S.
Chintapalli KN, et al. Diverticulitis versus colon cancer: differentiation with helical CT findings. Radiology February 1999;210:429-35.
Clinical Findings in Patients with Ectopic Pregnancy
The role of the history and physical examination in the diagnostic evaluation of patients presenting with symptoms of ectopic pregnancy has become less defined with the use of other modalities such as ultrasonography, quantitative ß human chorionic gonadotropin (ß-hCG) and progesterone assays, laparoscopy and endometrial sampling. Yet each of these testing modalities has limitations. Identifying reliable findings from the history or physical examination would help increase the specificity and sensitivity of diagnostic studies. Dart and associates conducted a prospective study of patients presenting to an emergency department with abdominal pain or bleeding during the first trimester to identify historical or clinical findings that may predict ectopic pregnancy.
Of the 438 patients in the study, 57 (13 percent) were found to have an ectopic pregnancy. Of the remaining patients, 214 had a normal intrauterine pregnancy, and 167 had an abnormal intrauterine pregnancy.
Analysis of the data revealed three groups with a less than 10 percent frequency of ectopic pregnancy. The first of these groups included patients with no pain or only mild pain and no risk factors for ectopic pregnancy. In this group, 10 of 182 (5.5 percent) patients had ectopic pregnancy. The second group included patients with moderate to severe pain but no cervical motion tenderness, peritoneal signs or risk factors; ectopic pregnancy was diagnosed in 10 of 115 (8.5 percent) patients with these findings. The third group included patients with moderate to severe pain and cervical motion tenderness but an open cervical os. No case of ectopic pregnancy was found in the five patients with these clinical findings. The remaining 52 patients did not fit into any of these groups and had a high incidence (23 patients, 44 percent) of ectopic pregnancy.
Patients with ectopic pregnancy were more likely to have moderate to severe, sharp pain, lateral or bilateral tenderness on abdominal or pelvic examination, a uterus smaller than eight weeks in size, and cervical motion tenderness. Peritoneal signs, although not common, were highly predictive of ectopic pregnancy. Risk factors found to be predictive of ectopic pregnancy included a history of infertility or use of an intrauterine device, a prior tubal ligation and pelvic surgery.
Neither tachycardia nor hypertension were predictive of ectopic pregnancy. Other findings that were not predictive of ectopic pregnancy included the presence of an adnexal mass, a history of ectopic pregnancy, a history of pelvic inflammatory disease, the amount of vaginal bleeding and an open cervical os.
The authors conclude that although predictive variables can be identified, clinicians cannot reliably exclude ectopic pregnancy on the basis of the history and physical examination findings alone. The authors state that one possible role for the history and physical examination is to determine the need for emergency ultrasonography at hospitals where this study is not readily available at any hour. The need for additional emergent diagnostic testing to identify ectopic pregnancy may be determined by the presence or absence of risk factors.
RICHARD SADOVSKY, M.D.
Dart RG, et al. Predictive value of history and physical examination in patients with suspected ectopic pregnancy. Ann Emer Med March 1999;33:283-90.
EDITOR'S NOTE: The diagnosis of ectopic pregnancy is not straightforward. Serial quantitative ß-hCG determinations are enhanced by the clinical examination, although a 48-hour interval is required between measurements. Abdominal or transvaginal ultrasonography is useful in identifying whether the pregnancy is intrauterine or ectopic. Reassurance must be provided to the anxious patient during evaluation, and a specific diagnostic protocol is useful in providing absolute reassurance that the pregnancy is viable.
R.S.
Lorazepam Prevents Recurrence of Alcohol-Related Seizures
Alcohol abuse has been linked to seizures in adults, although the reason for this is not well established. Theories that may explain the link include a seizure-inducing effect of alcohol, an exacerbation of preexisting epilepsy or the presence of structural abnormalities in the brain related to chronic alcohol intake. Phenytoin is not effective in preventing the recurrence of these seizures, but benzodiazepines have been shown to be effective in the management of acute alcohol syndromes, including the primary prevention of seizures. D'Onofrio and colleagues conducted a randomized, double-blind trial to evaluate the use of lorazepam to prevent recurrent alcohol-related seizures in patients who initially present with a seizure.
Patients enrolled in the trial were adults with a known history of alcohol abuse. They presented to one of two urban emergency departments after having a witnessed generalized seizure and had consumed one or more drinks in the previous 72 hours. An alcohol-related seizure was diagnosed on the basis of a history of alcohol use, no history of recent trauma and review of the patient's medical record. Patients were excluded from the trial if they were found to have another possible cause for the seizures, including hyponatremia, hypoglycemia, hypocalcemia or hypomagnesemia. Patients who were found to have used cocaine or phenobarbital were also excluded because of the anticonvulsant effect of these agents. Patients had computed tomographic scans of the head and an electroencephalogram, if clinically indicated.
Patients who were eligible to participate in the trial were randomly assigned to receive either 2 mg of lorazepam in 2 mL of saline or 4 mL of saline intravenously. The patients and all care providers were unaware of the treatment assignments. In addition, all patients were given fluids, 100 mg of thiamine, 2 g of magnesium and 1 ampule of intravenous multivitamins. The observation period ended if a second seizure occurred in the emergency department or six hours after lorazepam or placebo was administered.
Initially, 229 patients were enrolled, 43 of whom were excluded on the basis of established criteria. Almost all of the patients were men, and the average age was 45 years in the lorazepam group and 44 years in the placebo group. Researchers found that 85 percent of the patients drank at least one pint of distilled alcohol per day for more than 10 years and that 90 percent had the first seizure seven to 48 hours after their last drink. One hundred patients received lorazepam and 86 patients were given placebo.
Twenty-four percent of patients in the placebo group had a second seizure compared with 3 percent in the lorazepam group. When additional patients were excluded after enrollment, the percentages remained essentially the same--27 percent of the patients taking placebo had a second seizure compared with 3 percent of patients taking lorazepam. Thirty-six patients in the placebo group and 29 patients in the lorazepam group were admitted to the hospital. Researchers were able to determine readmission to the emergency department (within 48 hours after discharge) with a seizure by reviewing ambulance records. Seven patients from the placebo group and one patient from the lorazepam group were readmitted, although in the case of the latter patient, it happened only 2.5 hours after discharge.
The authors conclude that lorazepam is safe and effective in preventing recurrent alcohol-related seizures. It may also decrease the number of hospitalizations after a second observed alcohol-related seizure. This is significant, as many hospitals require admission of a patient who has had a second seizure. The study also used logistic-regression analysis to determine if there were any independent predictors for recurrent seizures. The authors found no statistically significant association with age, sex, serum ethanol level, number of years of alcohol use or time since the last drink.
JEFFREY T. KIRCHNER, D.O.
D'Onofrio G, et al. Lorazepam for the prevention of recurrent seizures related to alcohol. N Engl J Med March 25, 1999;340:915-9.
Use of Antibiotic Prophylaxis in the Intensive Care Unit
The use of prolonged courses of prophylactic antibiotics in the intensive care unit may have both financial and health costs. Namias and associates evaluated the use of prophylactic antibiotic therapy in a surgical intensive care unit during a one-year period.
Over 60 percent of all patients (346 of 572) received prophylactic antibiotic therapy for more than one day. Nontransplant patients were less likely to receive prophylactic antibiotics (47 percent, or 151 of 325 patients). A variety of agents were used, with ampicillin/sulbactam being the most commonly prescribed antibiotic for all patients and cefazolin the most common agent for nontransplant patients.
Transplant patients who received more than four days of antibiotic therapy were more likely to have had clean-contaminated surgery than clean surgery and were less likely to have malignant disease. In the nontransplant patients, these distinctions did not occur. Bacteremia and line infection were more frequent in all patients receiving more than four days of prophylactic antibiotics.
The use of prophylactic antibiotics in clean cases is widespread. Their use should be limited to one preoperative dose plus, optionally, two or three postoperative doses, not to exceed 24 hours of treatment. Delays in termination of prophylactic antibiotics were often related to determinations made by physicians from the primary service. Previous studies have demonstrated that limiting the course of perioperative antibiotics could save 18 to 50 percent of associated costs. The occurrence of more line infections and bacteremias in patients receiving more than four days of prophylactic antibiotic therapy may be associated with an increased susceptibility to infection caused by suppression of endogenous flora and selection of pathogens or with some other predisposition to infection. Data were not complete enough to evaluate the second possibility, although there was no difference in patient age, degree of contamination of operation or frequency of malignancy.
The authors conclude that there is poor compliance with the principle of stopping prophylactic antibiotics at 24 hours in the intensive care unit. Prolonged prophylaxis may result in more bacteremias and line infections, as well as increased financial costs.
RICHARD SADOVSKY, M.D.
Namias N. Cost and morbidity associated with antibiotic prophylaxis in the ICU. J Am Coll Surg March 1999;188: 225-30.
Two Regimens in the Treatment of Q Fever Endocarditis
Q fever endocarditis is a serious and often fatal condition caused by the gram-negative bacterium Coxiella burnetii. Nonspecific cardiac findings, evidence of infection and detection of specific antibodies on blood culture confirm the diagnosis. Eradicating C. burnetii is difficult, making Q fever endocarditis fatal in 25 to 60 percent of patients. Combination therapy with tetracycline and a quinolone increases survival, but patients often must take the medication for the rest of their lives. This treatment regimen is the longest of any bacterial disease. Raoult and associates compared the effectiveness of the standard combination therapy with that of doxycycline and hydroxychloroquine to assess whether the latter resulted in a shorter period of treatment.
Patients with confirmed C. burnetii infection and endocarditis were enrolled in the 10-year study. During the first five years, patients were given combination therapy consisting of 100 mg of doxycycline twice daily and 200 mg of ofloxacin three times daily. During the next five years, patients received the same dosage of doxycycline and 200 mg of hydroxychloroquine three times a day. Patients were evaluated monthly for overall physical condition, blood chemistry and plasma levels of hydroxychloroquine, and dosages were adjusted accordingly. Patients were considered cured, and treatment was discontinued when their IgG antibodies to C. burnetii were lower than 1/800, and their IgM and IgA antibodies were lower than 1/50. Follow-up was performed at specified intervals after treatment was discontinued.
Thirty-five patients were enrolled in the study, 14 of whom were given doxycycline and ofloxacin. Of these patients, one died, seven experienced a relapse and were either re-treated or switched to the new regimen, five were cured and one was undergoing evaluation. All patients reported photosensitivity during the summer months. The mean duration of treatment for patients considered cured was 55 months. No patients treated for longer than four years experienced a relapse, and only one patient experienced a relapse after three years of treatment.
Twenty-one patients received the combination of doxycycline and hydroxychloroquine. Of these, two had increased IgG antibodies and discontinued treatment within 10 months. However, both experienced relapses within six months and were re-treated. At that time, treatment for all patients was extended to a minimum of 18 months. Fifteen patients were cured with no relapse, two experienced a relapse and were re-treated and cured, two were still being treated, one was being evaluated and one died. These patients also reported photosensitivity. The mean duration of treatment for patients considered cured was 31 months. Only two patients were treated for longer than four years.
Mortality rates, the need for valve surgery, and drug tolerance were similar between groups. However, patients in the doxycycline-hydroxychloroquine group had a shorter period of treatment and experienced fewer relapses. Patients treated with the standard combination for more than 48 months were still undergoing treatment and, of the four patients who switched to the doxycycline-hydroxychloroquine regimen, three were cured.
The authors conclude that treatment with doxycycline-hydroxychloroquine was more effective and resulted in a shorter duration of treatment than the standard regimen. Doxycycline and ofloxacin should be given for at least four years, whereas doxycycline-hydroxychloroquine requires a period of no less than 18 months but no longer than four years.
BARBARA APGAR, M.D., M.S.
Raoult D, et al. Treatment of Q fever endocarditis. Comparison of 2 regimens containing doxycycline and ofloxacin or hydroxychloroquine. Arch Intern Med January 25, 1999:159:167-73.
Gynecologic Care, Health Issues for Lesbian Patients
Lesbians are members of all ethnic, age and socioeconomic groups. These women report a wide range of sexual identities (celibate, bisexual, homosexual), and up to 80 percent have a history of heterosexual activity. In general, lesbians are often of lower socioeconomic status than homosexual men, may have restricted family benefits such as health insurance and use health care services relatively infrequently. Carroll addresses the issues of health care for these women.
The disclosure of sexual identity can be very difficult, especially for adolescents. Medical histories should be based on gender-neutral statements and nonjudgmental attitudes to encourage patients to discuss sexual orientation, history and concerns.
The risk of sexually transmitted disease in lesbian patients depends on sexual practices, number of partners and use of prophylaxis. Vaginal insertion of fingers or objects can transmit pathogens, particularly if anal penetration is also practiced. Little is known about transmission of human immunodeficiency virus (HIV) infection during lesbian sexual activity, but woman-to-woman transmission has been documented, and the virus has been isolated from menstrual fluid, cervical biopsies and vaginal secretions. Women who use insemination to attempt pregnancy should be cautioned about the possibility of acquiring sexually transmitted diseases from donated body fluids. Studies have not shown any differences in sexual or gender identity, personality traits or intelligence in children raised by lesbians compared with children of heterosexual parents.
Lesbian patients may have an increased risk for certain cancers. Vulnerability to ovarian cancer may be increased because of low pregnancy rates and reduced exposure to oral contraceptive agents. Low fertility combined with an increased prevalence of smoking and alcohol use, and a decreased use of preventive health services contributes to an increased risk for cancers of the lung, breast and uterus. These factors also predispose lesbians to cardiovascular disease and diabetes.
Although it is generally believed that Papanicolaou screening is not indicated in lesbian patients, data from clinics serving lesbian populations indicate that significant pathology is frequently detected, particularly in patients with a history of first coitus at an early age, incest or sexual abuse, or other risk factors. Annual Pap screening should be considered for all women.
ANNE D. WALLING, M.D.
Carroll NM. Optimal gynecologic and obstetric care for lesbians. Obstet Gynecol April 1999;93:611-3.
A Simplified Scale for Evaluating Stroke Patients
Appropriate use of thrombolytic therapy in patients with acute ischemic stroke requires rapid medical evaluation. Patients must be treated within 180 minutes of symptom onset for treatment to be effective. Having prehospital or emergency medical personnel notify the hospital of potentially treatable stroke patients seems to reduce evaluation time by prompting team preparation. Kothari and associates developed a three-item scale to be used by prehospital providers to identify potentially treatable stroke patients.
The Cincinnati Prehospital Stroke Scale (CPSS) was derived from a simplification of the 15-item National Institutes of Health (NIH) Stroke Scale. The CPSS evaluates facial palsy, asymmetric arm weakness and speech abnormalities (see the accompanying table). Patients with stroke or symptoms similar to stroke were identified from the neurology service and the emergency department. Study subjects were then evaluated using the CPSS, first by one of two physicians certified in the use of the NIH Stroke Scale and, immediately following, by a group of paramedics and emergency medical technicians (prehospital care providers) who were trained briefly about how to perform and score the CPSS. Only verbal instruction was given to the prehospital providers.
Cincinnati Prehospital Stroke Scale Evaluation Criteria
Facial droop (the patient shows teeth or smiles) Normal: Both sides of the face move equally. Abnormal: One side of face does not move as well as the other. Arm drift (the patient closes eyes and extends both arms straight out for 10 seconds) Normal: Both arms move the same, or both arms do not move at all. Abnormal: One arm either does not move, or one arm drifts down compared with the other. Speech (the patient repeats, "The sky is blue in Cincinnati.") Normal: The patient says correct words with no slurring of words. Abnormal: The patient slurs words, says the wrong words or is unable to speak.
NOTE: Items are scored as either normal or abnormal.
Adapted with permission from Kothari RU, et al. Cincinnati prehospital stroke scale: reproducibility and validity. Ann Emerg Med April 1999;33:373-8.
Excellent reproducibility was observed among prehospital care providers for total score and for each of the three scale items. There was also excellent correlation between the total scores compiled by the physician and the prehospital providers. The CPSS correctly identified 21 of the 24 patients with anterior circulation stroke. The three patients who were missed had minimal or atypical symptoms.
The authors conclude that the CPSS, which can be taught in approximately 10 minutes and performed in less than one minute, is a valid tool for identifying stroke patients, especially those with anterior circulation stroke, who may be candidates for thrombolytic therapy.
In an editorial in the same issue, Marler strongly supports rapid identification of treatable stroke patients, recommending a "door-to-needle" time of one hour, since full-dose thrombolytic therapy does not occur until four hours after initiation of treatment. Careful interpretation of computed tomographic scans remains essential for identification of patients with intracerebral hemorrhage before initiating thrombolytic therapy.
RICHARD SADOVSKY, M.D.
Kothari RU, et al. Cincinnati prehospital stroke scale: reproducibility and validity. Ann Emerg Med April 1999;33:373-8, and Marler JR. Early stroke diagnosis saves time [Editorial]. Ann Emerg Med April 1999;33:450-1.
Passive Smoking and Arterial Endothelial Dysfunction
Regular exposure to environmental tobacco smoke is associated with early arterial injury and an increased risk of coronary disease in nonsmokers. The reversibility of these harmful cardiovascular effects would encourage the development of healthier environments. Raitakari and associates compared endothelial responses in three matched groups of healthy young adults: nonsmokers, passive smokers and former passive smokers.
Sixty healthy young adults were studied, comprising a control group of 20 lifelong nonsmokers, a group of 20 nonsmokers who had been exposed to environmental tobacco smoke for at least one hour per day for two or more years (with this exposure ceasing at least one year before the study began) and a group of 20 nonsmokers who were currently exposed to environmental tobacco smoke. During the study visit, brachial arterial reactivity and flow were measured ultrasonographically at rest, during reactive hyperemia and after sublingual administration of nitroglycerin. Vessel diameter was measured in each study subject by two independent observers who were blinded as to the participant's smoking status. This measurement technique has demonstrated accuracy for detection of small changes in arterial diameter.
Endothelial-dependent dilatation was significantly better in the former passive smokers than in the current passive smokers, although compared with nonsmoking control subjects, both groups were impaired. In the former passive smoking group, endothelial function was most severely impaired in participants whose last exposure to environmental tobacco smoke was two years before the study or less, compared with those in whom exposure ended two or more years before the study visit.
The authors conclude that endothelial function, a marker of arterial health, is significantly better in young adults who do not have regular exposure to environmental tobacco smoke, with maximal improvement at two years after cessation of passive smoking. Neither group with exposure to tobacco smoke had normal function, suggesting only partial reversibility of the arterial damage associated with passive smoking. The observed partial recovery of the arteries' ability to produce nitric oxide after cessation of passive smoking may indicate disease reversibility. Whether clinical benefit may be obtained by withdrawing from exposure to passive smoke requires further study, but the current data support avoidance of smoke-filled environments.
RICHARD SADOVSKY, M.D.
Raitakari OT. Arterial endothelial dysfunction related to passive smoking is potentially reversible in healthy young adults. Ann Intern Med April 6, 1999;130:578-81.
Comparison of Drugs Used to Treat Chronic Hypertension
Physicians today have a variety of drugs from which to choose when treating a patient with hypertension. These medications must be carefully chosen to fit the patient's needs, and even then, responses will vary. The Medical Letter recently outlined the most common drugs prescribed for hypertension in the United States. All categories of drugs were reviewed, except for those used in hypertensive emergencies.
Angiotensin-converting enzyme (ACE) inhibitors are considered generally effective and well tolerated but appear to be less effective in black patients. ACE inhibitors prolong survival in patients with heart failure or left ventricular dysfunction after acute myocardial infarction. They may also preserve renal function in patients with diabetes or nondiabetic nephropathies. However, patients who are volume depleted, have bilateral renovascular disease or congestive heart failure should not take ACE inhibitors. In addition, pregnant women should not use ACE inhibitors because of the risk of fetal injury and death, but exposure at the time of conception or early in pregnancy does not appear to produce adverse outcomes.
Beta blockers are also considered to be generally effective and, like ACE inhibitors, they appear to be less effective in black patients. Beta blockers alone appear to be less effective than diuretics alone in treating hypertension in the elderly. The cardioselective beta blockers, including metoprolol, acebutolol and betaxolol, have a greater effect on cardiac adrenergic receptors than on receptors in the bronchi and blood vessels. However, they become less selective with increased dosages, and even low dosages of cardioselective beta blockers can cause bronchospasm in patients with asthma.
Calcium-channel blockers cause vasodilatation, which decreases peripheral resistance. The heart's response to this action varies, depending on the specific medication given. Some classes of calcium-channel blockers actually slow the heart rate, affecting atrioventricular conduction, and should be used with caution in patients taking beta blockers concurrently. Calcium-channel blockers should also be used with caution in patients with heart failure. Short-acting calcium-channel blockers, particularly nefedipine, should not be used for treatment of hypertension.
Diuretics decrease mortality in patients with hypertension. Many thiazide diuretics used in the treatment of isolated systolic hypertension have also been shown to reduce the incidence of stroke and cardiovascular events in elderly patients. One advantage to using diuretics is that small dosages are very effective. Dosages as low as 6.25 mg daily can enhance the effectiveness of other drugs and minimize adverse effects such as hypokalemia.
Central alpha-adrenergic agonists do not inhibit reflex responses as completely as sympatholytic drugs that act peripherally. However, they can produce adverse effects such as sedation, dry mouth and depression.
Alpha-adrenergic blocking agents cause less tachycardia than vasodilators but often cause postural hypotension, particularly after the first dose. Unlike beta blockers and diuretics, these drugs do not adversely affect serum lipid levels; rather, they may increase the ratio of high-density lipoprotein (HDL) to total cholesterol. While they may relieve the symptoms of prostatism in men, they may cause stress incontinence in women.
Direct vasodilators often cause reflex tachycardia but rarely cause orthostatic hypotension as do alpha blockers. Vasodilators are typically given in combination with a beta blocker or a centrally acting drug to minimize the reflex increase in heart rate and cardiac output. A loop diuretic should also be given in conjunction with vasodilators to avoid sodium and water retention. Patients with coronary artery disease should not be given vasodilators.
The authors conclude that diuretics, beta blockers, ACE inhibitors, angiotensin receptor antagonists and calcium-channel blockers are the agents best tolerated in the treatment of hypertension. Some, but not all, of the consultants believe that use of calcium-channel blockers should be reserved for patients who do not respond to or cannot tolerate diuretics, beta blockers or ACE inhibitors.
BARBARA APGAR, M.D., M.S.
Medical Letter consultants. Drugs for hypertension. Med Lett Drugs Ther March 12, 1999;41(1048):23-8.
Is CPAP Effective Against Obstructive Sleep Apnea?
Continuous positive airway pressure (CPAP) is widely used to treat obstructive sleep apnea; however, there is little evidence to support the idea that it improves outcomes. CPAP does not cure the underlying illness; rather, it prevents the periodic collapse of the upper airway during sleep. Maintaining the airway with CPAP decreases the intermittent hypoxia resulting from airway obstruction that disrupts normal sleep patterns. Because CPAP is expensive and uncomfortable, better evidence is needed to demonstrate that it improves quality of life to justify its use. Ballester and colleagues compared the effectiveness of conservative management alone and in combination with CPAP in improving symptoms, daytime function, and self-perceived health status.
Patients with an established diagnosis of sleep apnea/hypopnea syndrome were eligible for the study. Inclusion criteria consisted of severe clinical symptoms and an apnea/hypopnea index score of greater than 15 without symptoms or greater than 30 with symptoms. Patients were randomized into two groups in a ratio of two patients in the treatment group for every one patient in the control group. Patients with unstable cardiovascular disease or hazardous jobs were excluded from the study. Patients in the control group followed conservative measures alone, including completing enough hours of sleep every night, sleeping on their side, avoiding sedatives and alcohol, and losing weight by following a home diet. Those in the treatment group followed the same conservative measures and were fitted for CPAP. Patients in the latter group attended a full-day training program, were fitted with the mask and took a short test nap in the sleep unit so they could be monitored by staff. Titration was performed with the automatic Rescare AutoSet system under staff supervision.
Patients completed questionnaires before treatment was initiated and then three months later. Questions about sleepiness, apnea symptoms, and daytime function were included in the assessment. Perceived health status was assessed using the Nottingham Health Profile questionnaire.
Although both groups showed improvement with treatment on all scales, the CPAP group showed significantly more improvement on key items. The Nottingham Health Profile is a generic instrument with six domains. In the more relevant domains, such as energy, the CPAP group showed significant improvement. In fact, the analysis using the most relevant questionnaires showed that only 35 percent of patients showed improvement in the conservative group, while 78 percent of patients showed improvement in the CPAP group. The odds of group 2 showing improvement over group 1 were 6.52 (CI: 95 percent).
The authors conclude that treating patients with CPAP plus conservative measures improves outcomes compared with use of conservative measures alone in patients with moderate to severe obstructive sleep apnea.
CLARISSA C. KRIPKE, M.D.
Medical Editing FellowBallester E, et al. Evidence of the effectiveness of continuous positive airway pressure in the treatment of sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med February 1999;159:495-501.
Effect of HRT on Thickness of the Left Ventricular Wall
Postmenopausal estrogen replacement therapy appears to reduce the risk of coronary artery disease as well as the mortality associated with cardiovascular disease. The mechanisms for this effect are unclear, although postmenopausal hormone replacement therapy (HRT) reduces low-density lipoprotein cholesterol and increases high-density lipoprotein cholesterol by 10 to 15 percent. A beneficial effect on endothelial function has also been observed. Lim and associates studied the effects of long-term HRT on left ventricular (LV) wall thickness in women.
Twenty women who had been receiving HRT for more than 10 years were compared with 19 healthy control subjects. All of the women were white and postmenopausal. The study excluded women with previously identified heart disease or high blood pressure, or those being treated with cardiac medications. The study subjects and control subjects were matched for age. Complete medical histories were obtained, as well as vital signs and transthoracic echocardiography to measure LV dimensions.
Members of the control group were found to have a significantly greater LV mass adjusted for height. A statistically significant difference between the groups was found in the size of the posterior wall and the septum. Even after adjusting for age, alcohol consumption, body mass index and systolic hypertension, HRT remained a statistically significant variable. There was a nonsignificant trend for more regular exercise among the women who were taking HRT.
The authors conclude that LV dimensions were reduced by 19.7 percent in a small group of women taking HRT for more than 10 years compared with control subjects. Since LV hypertrophy has been shown to be an independent risk factor for mortality associated with cardiovascular causes, this protective effect may explain a part of the beneficial effects of HRT in the reduction of cardiac mortality in women.
RICHARD SADOVSKY, M.D.
Lim WK, et al. Effect of hormone replacement therapy on left ventricular hypertrophy. Am J Cardiol April 1, 1999 83:1132-4.
Fomepizole for the Treatment of Ethylene Glycol Poisoning
Ethylene glycol, a solvent found in antifreeze, may result in metabolic acidosis, renal failure, nervous system damage and even death when ingested by humans. Standard therapy includes high dosages of oral or intravenous ethanol and hemodialysis. Ethanol inhibits alcohol dehydrogenase, but because it must be used at intoxicating dosages, it may cause hepatotoxicity and hypoglycemia. Fomepizole (4-methylpyrazole) is an inhibitor of alcohol dehydrogenase but does not appear to have the adverse effects of ethanol. Brent and associates studied the efficacy of fomepizole in the treatment of ethylene glycol poisoning.
Twenty-three patients at least 12 years of age who presented with confirmed or suspected ethylene glycol poisoning were enrolled in the study. Criteria for poisoning included one of three characteristics: (1) a plasma ethylene glycol level of at least 20 mg per dL (3 mmol per L); (2) suspected ingestion of ethylene glycol along with three of four laboratory findings, including an arterial pH of less than 7.3, a bicarbonate level of less than 20 mEq per L, an osmolar gap of greater than 10 mOsm per L and oxaluria; (3) suspected ingestion of ethylene glycol within the preceding hour and a serum osmolar gap of greater than 10 mOsm per L.
Patients were given intravenous fomepizole, in a loading dose of 15 mg per kg of body weight followed by 10 mg per kg every 12 hours for 48 hours. This regimen was followed by a repeat dosing of 15 mg per kg every 12 hours to compensate for increased fomepizole metabolism. The patients were treated until their ethylene glycol level was less than 20 mg per dL.
After the loading dose of fomepizole, patients underwent hemodialysis if the initial ethylene glycol level was 50 mg per dL (8 mmol per L) or greater, if the arterial pH dropped below 7.1, if the arterial pH dropped below 7.3 despite intravenous bicarbonate, if the serum creatinine level increased by at least 1 mg per dL (88 mmol per L) above baseline or if the creatinine level was more than 3 mg per dL (265 mmol per L). Continuous cardiac monitoring, assessment of urinary output and frequent laboratory studies were performed in all patients. The main end points of the study were development of renal injury, additional production of ethylene glycol metabolites (including urinary excretion of oxalate) and the development of cranial neuropathies.
After initial enrollment, four of the 23 patients were found to have plasma ethylene glycol concentrations less than 20 mg per dL or did not meet other criteria for entry and were excluded from the study. Of the remaining 19 patients, 14 were determined to have ingested antifreeze as the source of the ethylene glycol. On presentation, seven patients were comatose, seven were awake, three were inebriated and two were lethargic. Based on the previously noted criteria, 17 patients required hemodialysis. The average number of doses of fomepizole was 3.5, with a range of one to seven. The plasma glycolate levels decreased progressively in all patients, and the pH and bicarbonate levels concurrently increased. None of the patients showed deterioration in mental status from baseline, and there were no episodes of hypoglycemia.
Concerning other outcomes, 18 of the 19 patients survived. The patient who died suffered a myocardial infarction before enrollment and had a baseline pH of 7.05. There were no cases of cranial neuropathy. Ten patients had a normal creatinine level at entry, and none sustained renal injury during treatment with fomepizole. Of the nine patients who had an elevated creatinine level at baseline, all showed worsening renal function during treatment. However, the creatinine level normalized in six of the patients and in the other three, it ranged from 1.5 to 3.8 mg per dL (132 to 335 mmol per L) at the time of discharge. All patients with renal injury had initial ethylene glycol levels of 98 mg per dL (16 mmol per L) or greater. The only adverse events possibly related to treatment with fomepizole were transient bradycardia (heart rate of 50 to 60 beats per minute) in two patients, headaches in two patients and brief seizures that occurred 15 minutes after the first dose of medication but not with subsequent dosing in two patients.
The authors conclude that fomepizole is a safe and effective treatment for patients who have ingested ethylene glycol. When given early, it prevents renal injury and does not appear to cause hypoglycemia or mental status changes, problems that are seen when ethanol is used for treatment.
JEFFREY T. KIRCHNER, D.O.
Brent J, et al. Fomepizole for the treatment of ethylene glycol poisoning. N Engl J Med March 18, 1999; 340:832-8.
Celecoxib for Patients with Arthritis and Osteoarthritis
The anti-inflammatory effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is due primarily to inhibition of the enzyme cyclooxygenase (COX), a compound required for synthesis of prostaglandins and thromboxanes. Of the two COX isoforms identified, COX-1 is expressed constitutively in most tissues, whereas COX-2 is expressed in the brain, the kidneys and at sites of inflammation. Both isoforms appear in the synovial fluid of patients with arthritis. Older NSAID formulations block both isoforms. Celecoxib, a selective COX-2 inhibitor, has been labeled for treatment of osteoarthritis and rheumatoid arthritis, and in therapeutic doses does not inhibit COX-1. Medical Letter consultants reviewed the data on celecoxib.
Celecoxib is available in 100- and 200-mg capsules and is more expensive than generic diclofenac, naproxen, and ibuprofen. It is rapidly absorbed, reaching peak levels in about three hours, is metabolized in the liver by CYP2C9, and excreted in the feces and urine. CYP2C9 inhibitors, including zafirlukast, fluconazole and fluvastatin, may increase serum concentrations of celecoxib. Because no clinical trials of celecoxib have been published, data about its effectiveness are available from the manufacturer, reports of meetings and U.S. Food and Drug Administration submission logs. Celecoxib taken in dosages ranging from 100 to 400 mg appears to be more effective than placebo and just as effective as 500 mg of naproxen in treating rheumatoid arthritis. However, other trials have shown celecoxib to be less effective than higher dosages of naproxen or ibuprofen in relieving postsurgical dental pain.
Adverse effects include abdominal pain, diarrhea and dyspepsia, and increases in aminotransferase. As with other NSAIDs, renal toxicity has also been reported. However, the incidence of gastrointestinal ulcers is lower than with agents such as diclofenac, naproxen and ibuprofen. Unlike other NSAIDs, celecoxib does not inhibit platelet aggregation or increase bleeding time. Large doses of celecoxib given to pregnant animals decreased fetal survival.
The authors conclude that celecoxib appears to be as effective as older NSAIDs in treating osteoarthritis and rheumatoid arthritis, but it may be less effective as an analgesic for acute pain. Short-term study data indicate that celecoxib is associated with fewer gastrointestinal ulcers than older NSAIDs and does not increase bleeding time. However, whether serious gastrointestinal bleeding will occur less frequently with celecoxib is still unknown.
BARBARA APGAR, M.D., M.S.
Medical Letter consultants. Celecoxib for arthritis. Med Lett Drugs Ther January 29, 1999;4(1045):11-2.
EDITOR'S NOTE: The subsequent issue of The Medical Letter stated that celecoxib is also contraindicated in patients allergic to sulfonamides.
B.A.
"Tips from Other Journals" are written by the medical editors of American Family Physician.
Copyright © 1999 by the American Academy of Family Physicians.
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