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Tips from Other Journals
Review of Diagnosis and Treatment of TMJ Disorders
Approximately 70 percent of adults have at least one sign of a temporomandibular joint (TMJ) disorder, but only 25 percent report symptoms and only about 5 percent seek medical intervention. Dimitroulis reviews the clinical features of TMJ and the role of conservative treatment measures.
The most common type of TMJ disorder is myofascial pain and dysfunction, usually the result of bruxism or jaw clenching. These habits may be related to stress, anxiety, depression or chronic pain. Less commonly, TMJ is due to mechanical problems or osteoarthrosis.
The three cardinal features of TMJ are orofacial pain, restricted jaw function and noise in the joint. Patients may also report pain in the ear, neck and shoulder, tinnitus and generalized headaches, as well as stress-related symptoms, especially insomnia. Jaw movement is usually described as "a tightness." Patients who describe the jaw suddenly "sticking" or "catching" usually have mechanical dysfunction of the joint. A classic presentation is pain in front of the tragus, with radiation to the ear, lower jaw, cheek and temple. Pain is usually worse in the morning and may occur in cyclical episodes. Patients may also report clicking or grating sounds during chewing and progressive limitation of mouth opening.
Tenderness around the joint may be found on physical examination. The joint should be examined during opening, closing and lateral excursion of the mandible. Joint clicking may be detected by palpation or by placing a stethoscope in front of the tragus. Radiographs or even magnetic resonance imaging may be useful if joint derangement is suspected. A careful physical examination is required to exclude causes of pain in the ear, teeth, mouth, neck, jaw and salivary glands. Pain from disorders of these structures may mimic TMJ.
Conservative therapy is effective in over 80 percent of cases. It is essential to thoroughly explain the condition and educate the patient about it. Patients should be advised to identify and address sources of stress and to modify chewing and other habits that cause excessive jaw movement. Massage, application of local moist heat and exercises are all important recommendations. Nonsteroidal anti-inflammatory drugs are useful if pain is due to synovitis or myositis. Low dosages of tricyclic antidepressants or tranquilizers have been used to reduce stress if this is a significant contributor to TMJ syndrome. All drugs should be prescribed in a specified regimen for a defined period of time. The use of "as-needed" medications is unlikely to be successful and may lead to dependency or overuse. Occlusal dental devices are commonly prescribed for TMJ and are reported to alleviate symptoms in over 70 percent of patients. In selected patients, physical therapy, behavioral therapy or psychotherapy may be indicated. Surgical intervention is usually required in fewer than 5 percent of patients with TMJ disorders.
ANNE D. WALLING, M.D.
Dimitroulis G. Temporomandibular disorders: a clinical update. BMJ July 18, 1998;317:190-4.
Nonpharmacologic Steps to Improve Sleep in Older Adults
Elderly persons are susceptible to sleep disturbances during hospitalization because of age-related changes in sleep patterns, environmental disruptions, pain and anxiety. Sedative-hypnotic medications commonly used to treat these sleep problems are associated with adverse effects such as delirium, falls and respiratory depression. McDowell and colleagues conducted this prospective study to determine whether a nonpharmacologic approach to treating sleep disturbances in elderly hospitalized patients is feasible and effective.
Nonpharmacologic Sleep Protocol* Part 1. Back rub: a five-minute back massage consisting of slow, rhythmic stroking on both sides of the spinous processes from the crown of the head to the sacral area, with patient in side-lying position. Part 2. Warm drink: patient's choice of herbal tea or milk. Part 3. Relaxation tapes: classical music or nature sounds played on either a headset or bedside cassette tape player.
*--Nurse allows one hour to assess for effectiveness. If, ineffective, proceed to usual care.
Reprinted with permission from McDowell JA, Mion LC, Lydon TJ, Inouye SK. A nonpharmacologic sleep protocol for hospitalized older patients. J Am Geriatr Soc 1998;46:701.
Patients who were at least 70 years old were included in the study if they spoke English and either requested a sleep medication or complained of difficulty in getting to sleep on at least one night during hospitalization.
The hospital nursing staff received education about the nonpharmacologic sleep protocol (see the accompanying table). If the patient refused the protocol or was still awake one hour after an intervention, the usual care was offered, including a sedative-hypnotic (defined as any benzodiazepine, minor tranquilizer or sedative antihistamine), if ordered. General sleep hygiene measures (such as avoiding caffeine in the evening) were followed. Quality of sleep was assessed by daily patient interview. Patients were asked to rate their overall sleep of the night before as "poor," "fair" or "good." Records were reviewed to determine the number of patients receiving sedative hypnotic medications and the level of adherence to the sleep protocol.
A total of 111 patients were enrolled in the study. The sleep protocol was used for a total of 539 patient-days. At least one part of the nonpharmacologic sleep protocol was adhered to 74 percent of the time. The back-rub portion of the protocol had the highest adherence rate at 52 percent, with warm drink adherence at 49 percent and use of relaxation tapes at 36 percent. Patients were most likely to refuse the relaxation tapes (48 percent) and least likely to refuse the back rub (30 percent). The quality of sleep improved as the number of portions of the sleep protocol increased. One half of the patients reported "good" sleep when they received all three portions of the protocol versus about one quarter who reported "good" sleep when they received only one or two parts of the protocol. There was a significant reduction in the number of sedative hypnotic medications used after the nonpharmacologic protocol was put into place, compared with pre-protocol use of these medications (31 percent of patients received medications at least once during the study period compared with 54 percent of patients during the pre-study period).
The authors conclude that the use of simple nonpharmacologic interventions (specifically, back rub, warm drink and relaxation tapes) can improve sleep and reduce the use of sedative-hypnotic drugs in hospitalized elderly patients.
GRACE BROOKE HUFFMAN, M.D.
McDowell JA, et al. A nonpharmacologic sleep protocol for hospitalized older patients. J Am Geriatr Soc June 1998;46:700-5.
Breast Feeding and Mothers Who Smoke: Infant Exposure
Exposure to cigarette smoke in utero and in infancy has been linked to numerous adverse health outcomes, including prematurity, growth restriction, asthma and sudden infant death syndrome. Exposure through breast feeding has recently been scrutinized because studies have shown that breast-fed infants of mothers who smoke have urine cotinine levels from two to 10 times higher than bottle-fed infants who were exposed to environmental tobacco smoke. Mascola and colleagues performed a study to compare the urine cotinine levels in breast-fed and bottle-fed infants of mothers who smoked. They also examined the effects of breast feeding on urine cotinine levels in infants whose mothers did not smoke but who had environmental exposure to other household members who smoked. Finally, the authors examined whether restricting the location of smoking in the house affected the degree of infant exposure.
A cohort of 330 mother-infant pairs were selected from a longitudinal study of the effects of prenatal and postnatal smoking on respiratory illnesses and pulmonary function in children. Detailed information was obtained from the mothers, including age, race, medical and obstetric history, past and current smoking history and tobacco smoke exposure from other household members. Mothers who smoked included those who admitted to having at least one cigarette per day or whose corrected urine cotinine levels exceeded 200 ng per mg creatinine (1,135 nmol per L), a level unlikely to represent environmental exposure). Infants were considered to be breast-fed if the mothers reported any current breast-feeding, regardless of supplementation. The infants were considered to be environmentally exposed to tobacco smoke if they lived with a person who smoked or spent more than two hours twice weekly with a person who smoked. Urine specimens were collected from the infants at one or more visits during the first year of life. The specimens were analyzed for cotinine concentration by radioimmunoassay.
There were no significant differences among the infant-mother pairs in maternal age, education level, percentage of households with smokers, percentage of mothers who breast-fed, infant birth weights or length, or infant age at entry into the study. Urine cotinine levels were significantly higher in the infants whose mothers smoked compared with infants whose mothers did not smoke. Furthermore, breast-fed infants of mothers who smoked had median levels of cotinine that were 10-fold higher than those in bottle-fed infants of mothers who smoked. This finding was independent of the number of cigarettes smoked daily. Infants whose mothers reportedly smoked in the same room had increases in urine cotinine levels, regardless of feeding type, compared with infants whose mothers always smoked in rooms away from the infant.
The authors conclude that breast-fed infants of mothers who smoke have urine cotinine levels 10-fold higher than bottle-fed infants whose mothers smoke. Their findings suggest that the degree of exposure to nicotine through breast milk is much more substantial than was previously thought. The study also indicates that efforts to restrict smoking to certain areas of the home may have only a negligible effect on the child's exposure to environmental tobacco smoke. Physicians should encourage mothers to stop smoking both prenatally and after birth, and should inform them that harmful chemicals from cigarettes can be transmitted to their infants from the environment and through breast milk.
JEFFREY T. KIRCHNER, D.O.
Mascola MA, et al. Exposure of young infants to environmental tobacco smoke: breast-feeding among smoking mothers. Am J Public Health June 1998;88:893-6.
Administration and Dosage of a New Human Rabies Vaccine
A new human rabies vaccine, RabAvert, is prepared from purified chick embryo cell culture (PCEC) and marketed for pre- and postexposure prophylaxis against rabies infection. Although rabies is rare in the United States, thousands of persons receive postexposure prophylaxis each year. All rabies vaccines for human use are prepared in cell culture and are much safer than the rabies vaccine prepared from infected animal brains, which is used in some countries. The widely used HDCV vaccine is associated with a 6 percent incidence of serum-sicknesslike (type III) hypersensitivity reactions to booster doses given months or years after the primary series. Consultants for the Medical Letter reviewed the procedure for pre- and postexposure prophylaxis of rabies infection.
The wounds of patients exposed to rabies should be thoroughly washed, and human rabies immune globulin should be given in a dosage of 20 IU per kg. As much of the dose as possible should be infiltrated at the site of the wound, with the remainder given intramuscularly at a site distant from the vaccine injection. At the same time, a 1-mL dose of rabies vaccine (HDCV, RVA or PCEC) should be given intramuscularly in the deltoid (or the anterolateral thigh in children) and repeated on days 3, 7, 14 and 28 after the initial dose. Persons previously immunized with a cell-culture vaccine or those who have had a documented antibody response to other rabies vaccine do not need to receive rabies immune globulin and should be given only two doses of rabies vaccine, on day zero and day 3. The PCEC vaccine has been shown to be 100 percent effective in preventing rabies in patients with high-risk exposures.
Persons at high risk, such as veterinarians, animal control workers, wildlife professionals, people working with the rabies virus and travelers visiting rabies-endemic areas, should receive three 1-mL injections of rabies vaccine intramuscularly in the deltoid on days zero, 7 and either 21 or 28. Only the HDCV vaccine has been shown to be effective in a dosage of 0.1 mL when given intradermally. Persons with risk of frequent rabies exposure should have their antibody titers checked or receive a booster dose every two years.
Changing from one rabies vaccine to another during a pre- or postexposure series is not recommended because effectiveness data is lacking. Use of PCEC as a booster has been shown to produce a marked anamnestic response in antibody titers when HDCV was used as the primary vaccination. Certain medications, including antimalarial agents, corticosteroids and other immunosuppressive drugs, may interfere with antibody response to rabies vaccine.
Mild erythema, swelling and pain may occur at the site of injection of the PCEC vaccine. Serum-sickness hypersensitivity reactions like those associated with booster doses of HDCV have not been reported with PCEC. Although rare, anaphylaxis and severe neurologic symptoms have been reported temporally with PCEC. Persons with severe egg allergy should not be given the PCEC vaccine.
Medical Letter consultants report that the new rabies vaccine appears to be as effective as previously available rabies vaccines. Unlike the other vaccines, however, it does not appear to cause the serum-sicknesslike hypersensitivity reactions associated with booster doses of the HDCV vaccine.
BARBARA APGAR, M.D., M.S.
Medical Letter consultants. A new rabies vaccine. Med Lett Drugs Ther June 19, 1998:40(1029):64-5.
Sequential vs. Simultaneous Antiretroviral HIV Therapy
Antiretroviral therapy that consists of a combination of two nucleoside analog reverse transcriptase inhibitors and either a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor has been shown to suppress viral load in patients with human immunodeficiency virus (HIV) infection. The success of this combination therapy has prompted its endorsement by the International AIDS SocietyUSA and the U.S. Department of Health and Human Services as the preferred treatment for HIV infection. However, 30 to 66 percent of patients whose therapy includes protease inhibitorcontaining antiretroviral regimens fail to maintain viral suppression. A possible explanation is that sequential or simultaneous initiation of the three-drug regimen results in incomplete viral suppression. Gulick and colleagues conducted a multicenter, randomized, double-blind study to compare the antiretroviral effect of a three-drug regimen started simultaneously or sequentially in patients with established HIV infection.
Ninety-seven patients with HIV infection were initially randomized to receive indinavir alone, a combination of zidovudine and lamivudine, or all three drugs for 52 weeks. However, when the three-drug regimen proved to be superior in a preliminary analysis, the study was amended, and all patients were offered the three-drug regimen after 24 weeks. After at least 100 weeks from the time of initial randomization, the effects of the three-drug therapy were compared among the groups. Changes in each patient's HIV RNA level and CD4 cell count were recorded periodically for 100 weeks and compared with baseline characteristics.
The group that originally received the three-drug therapy experienced a median decrease in serum HIV RNA levels of 2.0 log10 after eight weeks, a level that was sustained through the entire 100-week study period. CD4 cell counts at 100 weeks also increased in this group, with a median increase of 0.209 per mm3 (0.209 3 109 per L). Patients who originally received indinavir alone experienced a median decrease in HIV RNA levels of 1.4 log10 and a median increase in CD4 cell count of only 0.163 per mm3 (0.163 3 109 per L). Patients who originally received zidovudine and lamivudine experienced a median decrease in HIV RNA levels of 1.3 log10 at week 100, and a median increase in CD4 cell count of 0.101 per mm3 (0.101 3 109 per L). Seventy-eight percent of the simultaneous-initiation group experienced a reduction in viral load to less than 500 copies per mL, compared with only 30 to 45 percent of patients in the sequential initiation groups.
The authors conclude that their study supports current guidelines recommending simultaneous introduction of at least two or, preferably, three antiretroviral agents, one of which is a protease inhibitor, for the greatest degree of viral suppression in patients with HIV infection. This three-drug regimen is also recommended when changing a failing antiretroviral therapy course. Sequential initiation of the three drugs is much less effective than simultaneous introduction.
GRACE BROOKE HUFFMAN, M.D.
Gulick RM, et al. Simultaneous vs sequential initiation of therapy with indinavir, zidovudine, and lamivudine for HIV-1 infection. 100-week follow-up. JAMA July 1, 1998; 280:35-41.
Prevention and Management of Diabetic Nephropathy
Diabetic nephropathy is now the leading cause of renal failure in the Western world. Cooper reviews the natural history of diabetic nephropathy and discusses interventions that may prevent its development and progression.
Strategy for screening and management of microalbuminuria in patients with diabetes. The schema is based on various position statements and consensus guidelines. (ACE=angiotensin converting enzyme) 
Reprinted with permission from Cooper ME. Pathogenesis, prevention, and treatment of diabetic nephropathy. Lancet 1998;352:213-9.The initial changes of glomerular hyperfiltration and hyperperfusion are followed by the development of subtle morphologic changes, including thickening of the glomerular basement membrane, glomerular hypertrophy and mesangial expansion. The first clinically detectable indication of incipient diabetic neuropathy is microalbuminuria, which manifests only after these changes are well established. Microalbuminuria is accompanied by other signs of diabetic microvascular damage and a modest rise in blood pressure (about 3 mm Hg per year). If untreated, the condition progresses to overt proteinuria and, eventually, to renal failure.
Although the basic process is believed to be glucose-induced tissue injury, hypertension and other factors exacerbate renal damage. Genetic factors may play a role through variations in the renin-angiotensin system that may mediate renal injury. A family history of hypertension has been linked with an increased risk of diabetic nephropathy.
The prevention and management of diabetic nephropathy is based on control of blood glucose levels and hypertension. Early studies showed benefits from tight glycemic control only before the stage of microalbuminuria. More recent studies, however, have reported reduced progression of renal impairment, even in proteinuric patients, when glycemic control was improved. While studies have conclusively demonstrated that control of blood pressure delays the onset of renal failure, the optimal therapy remains controversial.
Patients with type 1 (formerly known as insulin-dependent, or IDDM) diabetes mellitus and microalbuminuria should be treated with angiotensin converting enzyme (ACE) inhibitors even if the blood pressure is normal; studies have confirmed the renoprotective effect of these drugs. Some experts now advocate the use of ACE inhibitors even in the absence of microalbuminuria, because as many as 40 percent of patients with type 1 diabetes eventually develop nephropathy. Although early studies have shown benefits from early use of ACE inhibitors, more evidence is needed before this recommendation is widely advocated.
As shown in the accompanying algorithm, other classes of antihypertensive drugs may be required to maintain blood pressure control and to keep urinary protein excretion in target ranges. Patients receiving the combination of a calcium channel blocker (verapamil or nifedipine) and an ACE inhibitor have shown an improvement in renal function that may signify a delay in the development of diabetic nephropathy.
The role of dietary protein restriction for the prevention of diabetic nephropathy is not clear. Meta-analysis of data on the effects of dietary protein restriction in patients with diabetes suggests that protein restriction may have a beneficial effect on glomerular filtration rate, creatinine clearance and albuminuria. Long-term studies are needed to establish the efficacy of protein restriction. Problems with compliance, however, may limit this approach.
The importance of periodically screening for microalbuminuria in patients with diabetes is now clearly established. Early therapy with ACE inhibitors, particularly in hypertensive patients, has been proved to delay the onset of diabetic neuropathy and may reduce the risk of cardiovascular and retinal complications. The author emphasizes that screening and early therapy are potentially life-saving and can provide incalculable benefits to patients with diabetes.
ANNE D. WALLING, M.D.
Cooper ME. Pathogenesis, prevention, and treatment of diabetic nephropathy. Lancet July 18, 1998;352:213-9.
Treatment Options for the Patient with Acne Vulgaris
Acne vulgaris is a common skin disorder with a peak incidence around 18 years of age. The condition should not be underestimated in terms of its negative psychosocial consequences. Brown and Shalita review the range of treatment options and stress the importance of individualizing patient therapies.
Patients with acne have high rates of sebum secretion, providing a lipid-rich growth medium for Propionibacterium acnes. High sebum production may reflect increased production of adrenal and gonadal androgens. In most women with acne, serum androgen concentrations are not higher than normal; however, some women may respond to antiandrogen therapy. Patients with acne also have abnormally adherent desquamated cornified cells that may plug the follicular canal instead of shedding from the skin surface. The combination of plugged follicular canals and excessive sebum production leads to the development of comedones. As P. acnes proliferates in this medium, it contributes to the inflammatory process, leading to the typical papules, pustules and nodules of acne vulgaris.
In patients with mild to moderate acne or noninflammatory comedones, topical therapy is indicated. Tretinoin reduces the formation of comedones by reversing the abnormal keratinization process. Because topical tretinoin is irritating and photosensitive, therapy usually begins with the lowest-strength cream or gel, increasing the formulation strength until the desired result is achieved. Other topical agents include salicylic acid, adapalene, azelaic acid and isotretinoin, but not all of these preparations are currently available in the United States. Topical benzoyl peroxide targets P. acnes and is available in gels, lotions, creams and soaps. Local irritation may be reduced by using the lower-strength preparations or by applying the product less frequently. Topical bacteriostatic antibiotics such as clindamycin, tetracycline and erythromycin are effective in acne vulgaris but may induce resistant strains of P. acnes. Combination topical therapy is commonly used in the treatment of acne, because concurrent therapy with several agents has a synergistic antimicrobial effect. Benzoyl peroxide, topical antibiotics and tretinoin may be used concurrently. Several agents may be combined in one preparation, but an alternating schedule of application of individual agents may be less irritating. The choice of vehicle depends on the patient's skin type. Non-greasy gels and solutions tend to dry the skin and may be preferred by patients with oily skin. Creams and lotions may be more cosmetically acceptable.
Oral antibiotics such as tetracycline, doxycycline, minocycline, erythromycin and co-trimoxazole are used in patients with mild to moderate disease, those with affected areas that cannot be adequately covered with topical medications and those with a high potential for scarring or substantial pigmentary changes. These medications act primarily by inhibiting bacterial growth, although some also have anti-inflammatory properties. The potential benefits and side effects should be weighed when choosing an agent. Treatment with oral antibiotics should generally be continued for four to six months; maximal clinical improvement may not be apparent before three months of therapy. If acne worsens during antibiotic therapy, bacterial resistance may have developed.
Severe nodular acne is best treated with isotretinoin. Therapy usually continues for 20 weeks. About 15 percent of cases relapse after a single course, but most patients who relapse show enhanced results from a second course of treatment. Further courses of isotretinon are seldom necessary. Clinical improvement may continue for up to five months following a course of therapy, so retreatment should not be attempted within six months. Isotretinoin has several serious potential side effects, particularly spontaneous abortion and congenital malformations. Stringent methods of contraception are mandatory when this drug is used in women with childbearing potential.
Other possible therapies for acne include hormonal manipulation to reduce androgens and spironolactone, which blocks androgen receptors and has antiandrogenic effects.
ANNE D. WALLING, M.D.
Brown SK, Shalita AR. Acne vulgaris. Lancet June 20, 1998;351:1871-6.
Comparison of Albuterol Dosage in Asthma Attacks
Current standard management of an acute asthma attack calls for use of an aerosolized beta2 agonist, generally in a dosage of 2.5 mg of albuterol given every 20 minutes for one hour. However, the assumption that this dosage is optimal for terminating an attack has never been rigorously tested. McFadden and associates conducted a prospective study to compare the effectiveness of a 5.0-mg dose of albuterol given twice during a 40-minute period with the standard 2.5-mg dose given three times during a 60-minute period in patients with acute exacerbations of asthma.
Adult patients with asthma who presented to an emergency department with an acute exacerbation of asthma were included in the study. Medical history, symptoms and medication use were recorded, peak expiratory flow (PEF) was measured and pulse oximetry was performed. One group of patients received 2.5 mg of aerosolized albuterol every 20 minutes for one hour. The other group received 5.0 mg of aerosolized albuterol every 20 minutes for two doses. Peak expiratory flow was measured after each treatment. Length of stay in the emergency department, clinical resolution and improvements in pulmonary function were assessed.
Eighty patients received the standard dosage of albuterol and 80 patients received the high dosage. Mean pretreatment PEF was less than 40 percent of normal at baseline. Patients receiving the high dosage (two doses of 5.0 mg) of albuterol had significantly more improvement in mean PEF after each treatment. These patients were well enough to be discharged from the emergency department after just one treatment more often than the patients receiving the standard dosage. Recurrence rates were similar in the two groups, with three patients in the standard-dosage group and four patients in the high-dosage group requiring additional treatment within 24 hours of discharge from the emergency department. Charges to third-party payers were 24 percent lower for patients who received the high-dosage therapy.
The authors conclude that the use of two 5.0-mg doses of aerosolized albuterol is as effective as the standard regimen of three 2.5-mg doses and has the advantage of more rapid improvement in lung function and more rapid discharge from the emergency department. A patient who fails to respond to 5.0 mg of albuterol with an increase in PEF to at least 40 to 45 percent of predicted levels should be hospitalized.
GRACE BROOKE HUFFMAN, M.D.
McFadden ER, et al. Comparison of two dosage regimens of albuterol in acute asthma. Am J Med July 1998;105: 12-7.
Evaluating the Risk of Fetal Loss Following Amniocentesis
An increased rate of fetal loss following amniocentesis has been reported by some studies; however, their findings have not been confirmed. This uncertainty complicates advising families at risk of having a child with chromosomal or developmental abnormalities about the risks and benefits of prenatal diagnosis. The issue is difficult to study because of ethical problems and the fact that patients are selected for amniocentesis based on complications of pregnancy or increased risk of fetal abnormality. Tongsong and colleagues conducted a controlled study to ascertain the true risk of fetal loss attributable to second-trimester amniocentesis.
More than 2,000 women who were at risk of having a child with chromosomal abnormalities but who were healthy, had confirmed gestational age, early antenatal care and no contraindication to amniocentesis were included in the study. The most common indication for amniocentesis was advanced maternal age (35 years or older), but 5 percent of the study participants had given birth previously to children with trisomy. Each study subject was matched with a control subject of the same age, parity and socioeconomic status who also met study entry criteria except for the risk of abnormality. The study subjects underwent amniocentesis between 15 and 24 weeks of gestation, and both study subjects and control subjects were monitored until delivery. All fetal losses were autopsied and tested for chromosomal abnormalities.
A total of 2,045 matched pairs completed the study. Pregnancy outcomes such as fetal loss, preterm rupture of the membranes, abruptio placentae, pregnancy-induced hypertension and cesarean delivery rates were comparable between the groups. The rates of spontaneous abortion before 28 weeks and of intrauterine fetal death were higher in the study group; the differences were not statistically significant and occurred in fewer than 2 percent of pregnancies.
The authors conclude that second-trimester amniocentesis is probably not associated with an increased rate of fetal loss in the absence of other conditions that could adversely influence pregnancy outcome.
ANNE D. WALLING, M.D.
Tongsong T, et al. Amniocentesis-related fetal loss: a cohort study. Obstet Gynecol July 1998;92:64-7.
Predicting Recovery from Post-Traumatic Vegetative State
Caring for patients in a persistent vegetative state is one of the most demanding duties faced by families and health care professionals. An estimated 10,000 to 25,000 adult patients are in a persistent vegetative state in the United States; medical care for these patients may cost up to $7 billion annually. Predicting which patients with severe brain damage will progress to a persistent vegetative state is extremely important, as crucial decisions about life support, resuscitation, tube feeding and other issues have to be faced. Unfortunately, vegetative states may be misdiagnosed in up to 43 percent of patients, and one half of patients in post-traumatic vegetative states may recover within one year. Neurodiagnostic tests such as evoked potentials, electroencephalograms and computed tomographic (CT) scanning have failed to predict the probability of recovery. Kampfl and colleagues studied the ability of magnetic resonance imaging (MRI) to predict recovery from a post-traumatic vegetative state.
The study included 80 patients who were admitted to a trauma and rehabilitation center as a result of closed head injury between 1988 and 1996. The patients were in a subacute vegetative state that continued for at least six to eight weeks following the injury. Full clinical assessment with MRI was performed six to eight weeks after the injury. Clinical assessment, including documentation of the patient's score on the Glasgow Coma Scale, was repeated at two, three, six, nine and 12 months following the injury. International diagnostic criteria were used to define vegetative state; persistent vegetative state was defined as a vegetative state that had endured for at least 12 months following injury. MRIs were interpreted by three independent neuroradiologists who were unaware of the clinical findings or medical histories of the patients.
The most common cause of head injury was motor vehicle accident. Patients who remained in a persistent vegetative state did not differ from those who recovered in terms of age, sex or initial score on the Glasgow Coma Scale. The two groups were also comparable in terms of medical complications or surgical intervention for evacuation of subdural or epidural hematoma. Of the 38 patients who recovered, 24 patients showed signs of recovery within three months, and 36 patients showed signs of recovery within six months of the injury. One half of those who recovered from vegetative states had a moderate disability. In general, better outcomes were associated with earlier signs of recovery.
Patients who developed a persistent vegetative state had a significantly higher frequency of MRI-detected lesions in the corpus callosum and corona radiata. Corpus callosum injury was documented in 98 percent of patients who developed a persistent vegetative state, compared with only 24 percent of those who recovered. Differences in injury to the corona radiata were less dramatic (57 percent in patients with persistent vegetative state, compared with 26 percent of those who recovered) but were still statistically significant. Patients in a persistent vegetative state also had significantly more injuries to the dorsolateral upper brain stem than patients who recovered.
The authors conclude that obtaining cerebral MRI on patients with closed head injury within eight weeks of the injury can predict outcome. They developed a model that correctly predicted outcome at one year in over 87 percent of cases. The most significant lesions determining outcome appeared to be those of the corpus callosum, followed by lesions on the dorsolateral brainstem. This finding is in contrast to studies that have documented the inability of various neurodiagnostic tests and CT scanning to predict outcome in these cases.
ANNE D. WALLING, M.D.
Kampfl A, et al. Prediction of recovery from post-traumatic vegetative state with cerebral magnetic-resonance imaging. Lancet June 13, 1998;351:1763-7.
EDITOR'S NOTE: Assisting a family that is trying to cope with the aftermath of severe trauma is a demanding part of family practice. Although each case is unique, studies like this help to stabilize an overwhelming situation and provide some reasonably scientific data on which families can base decisions. Hope must never be lost, but pragmatic actions have to be taken concerning such issues as long-term placement, the use of ventilation, gastrostomy feeding and level of intervention in treating medical complications. Families may receive conflicting advice and prognoses from multiple specialists, and the primary care physician can be a powerful advocate and counselor. Family physicians need to be able to provide reliable probabilities and "quantitative" information, as well as counseling and support, in the care of these patients and their families.
A.D.W.
Induction of Labor at Term Following Membrane Rupture
Ten percent of pregnancies beyond 36 weeks' gestation are complicated by spontaneous premature rupture of membranes. Multiple studies have compared the use of expectant management with the use of active labor induction in women who do not begin spontaneous labor following membrane rupture. Traditionally, labor is induced to prevent chorioamnionitis and neonatal sepsis. The use of intravenous oxytocin and the incidence of cesarean delivery are lower when prostaglandins are applied to ripen the cervix. Misoprostol, a synthetic prostaglandin E1 analog, has been shown to be as effective in inducing labor as dinoprostone. Wing and Paul prospectively compared vaginally administered misoprostol with intravenous oxytocin for labor induction in women with ruptured membranes who have not begun labor.
A total of 197 women were randomized to treatment: 98 women received misoprostol and 99 received oxytocin. A 25-µg dose of misoprostol was placed in the posterior vaginal fornix. If adequate uterine contraction frequency was not demonstrated, a single repeat dose of misoprostol was administered six hours later. Oxytocin was given intravenously by an incremental infusion protocol to a maximum of 20 mU per minute.
The mean estimated gestational age of the patients in both groups was 38 weeks. A similar percentage of subjects in both treatment groups had a treatment success. A total of 76 percent of the misoprostol-treated group and 74 percent of the oxytocin-treated group delivered vaginally within 24 hours of treatment initiation. Parity influenced the success of labor induction, regardless of the treatment arm. In the misoprostol group, 63 percent of nulliparous women and 86 percent of multiparous women were delivered within 24 hours. In the oxytocin group, 60 percent of the nulliparous patients and 86 percent of the multiparous group were delivered in the same time period. The duration from induction to delivery in both groups was similar. Thirty of the women who were treated with misoprostol required two doses. Uterine hyperstimulation did not occur in either treatment group. Abnormal fetal heart rate monitor tracings occurred equally in both groups.
Evidence of intra-amniotic infection was equal in both groups (about 27 percent). Neonatal sepsis was suspected in 21 percent of infants born to misoprostol-treated women and in 27 percent of infants born to oxytocin-treated women. Approximately 86 percent of women receiving misoprostol were delivered vaginally, compared with 83 percent of women treated with oxytocin. In the misoprostol-treated group, 13 women had cesarean deliveries; in the oxytocin-treated group, 17 women had cesarean deliveries. Neonatal outcomes did not differ between treatment groups.
The authors conclude that vaginal administration of misoprostol is an effective alternative to oxytocin infusion for labor induction. Because the majority of cesarean deliveries in the misoprostol-treated women were performed for labor dystocia rather than for failed induction, misoprostol appears to be effective in causing cervical dilatation and effacement, and in inducing labor when premature rupture of the membranes has occurred.
BARBARA APGAR, M.D., M.S.
Wing DA, Paul RH. Induction of labor with misoprostol for premature rupture of membranes beyond thirty-six weeks' gestation. Am J Obstet Gynecol July 1998;179:94-9.
Prostate Cancer Screening Beliefs and Recommendations
It is a long-held belief in the United States that early detection and treatment of prostate cancer can lead to lower rates of metastasis and death. However, findings from some well-designed studies do not support this belief. The American Urologic Association and the American Cancer Society recommend routine screening for prostate specific antigen (PSA) in men older than 50 years of age, whereas the U.S. Preventive Services Task Force recommends against this screening. Fowler and colleagues conducted two national surveys of physicians to determine if primary care physicians and urologists had similar beliefs about early detection of prostate cancer and the effectiveness of different therapies for patients with prostate cancer at various stages.
Two survey instruments were developed, one for primary care physicians and the other for urologists. Both surveys asked about diagnosis of and treatment practices for benign prostatic hyperplasia and prostate cancer. Specifically, primary care physicians were asked how often they performed digital rectal examinations (DRE) and PSA tests and how often they recommended biopsy in patients with PSA levels of 4 to 10 ng per mL (4 to 10 mg per L). Urologists were asked if they thought primary care physicians should routinely perform DRE and PSA tests, and if they would recommend biopsy in patients with PSA levels of 4 to 10 ng per mL (4 to 10 mg per L). All of the physicians surveyed were asked if they thought radical prostatectomy and radiation therapy offered a survival benefit in patients with more or less than 10 years of life expectancy, or if watchful waiting was the more appropriate approach.
Of the 870 primary care physicians eligible for the study, 444 responded (response rate: 51 percent). Of the 582 urologists surveyed, 394 (68 percent) responded. The authors stress that primary care physicians' responses were compared with urologists' responses not because the latter's answers were necessarily "right," but because urologists are the subspecialists most likely to treat patients with prostate cancer. Almost all (90 percent) of the primary care physicians included DRE as part of routine examinations in men between 50 and 80 years of age. Urologists concurred that DRE should be part of the routine care for men in this age group. In addition, urologists were almost unanimous in recommending that primary care physicians perform DREs routinely in men between 50 and 75 years of age and that PSA testing be performed in men between 50 and 70 years of age. Eighty-eight percent of urologists also recommended routine PSA testing in men between 70 and 74 years of age. PSA testing was rarely recommended in men older than 80 years of age.
The pattern of PSA testing reported by primary care physicians did not change with patient age as sharply as the recommendations reported by the urologists. Most primary care physicians reported that they still routinely order PSA tests in men older than 80 years.
Most urologists (80 percent) recommend prostate biopsy in patients younger than 60 years of age if their PSA levels are between 4 and 10 ng per mL (4 to 10 mg per L). Only one third of urologists would recommend biopsy in patients 70 to 74 years of age. In contrast, primary care physicians said they routinely referred patients in this age group for biopsy. All physicians agreed that radical prostatectomy offered little benefit to patients with a life expectancy of less than 10 years. Most physicians believed that "watchful waiting" was appropriate in these patients.
In an accompanying editorial, Wilt offers several reminders: routine DRE has not been shown to reduce prostate cancer mortality; PSA testing is unlikely to benefit patients with a life expectancy of less than 10 years and surgical treatment for prostate cancer is associated with a high risk of cardiopulmonary complications in the month after surgery in men older than 65 years. He recommends that men requesting PSA testing should be educated about the risks and potential benefits of such screening, and that PSA testing should not be done if a patient's life expectancy is less than 10 years. He further states that the best treatment for clinically localized prostate cancer is currently not known.
GRACE BROOKE HUFFMAN, M.D.
Fowler FJ Jr, et al. Prostate cancer screening and beliefs about treatment efficacy: a national survey of primary care physicians and urologists. Am J Med June 1998; 104:526-32, and Wilt TJ. Prostate cancer screening: practice what the evidence preaches [Editorial]. Am J Med June 1998;104:602-4.
EDITOR'S NOTE: The American Academy of Family Physicians currently does not recommend routine prostate cancer screening. The editorial clearly underscores the need to use available evidence, not just plausible assumptions, as the basis for medical practice. This step may require extensive education of patients and will certainly require more randomized trials.
G.B.H.
New AAP Recommendations for Blood Lead Screening in Children
In 1991, the value for an elevated blood lead level was redefined to 10 µg per dL (0.48 µmol per L) or greater; treatment was recommended at levels of 15 µg per dL (0.73 µmol per L) or greater. Based on these changes, in 1993, the American Academy of Pediatrics (AAP) issued recommendations on screening for elevated blood lead levels and preventing lead poisoning. The AAP has recently updated its recommendations for screening and prevention of elevated blood lead levels.
The well-known toxic effects of lead include cognitive deficits. Specifically, a two- to three-point average loss in IQ has been reported in children with blood lead levels averaging 20 µg per dL (0.97 µmol per L), compared with IQ scores in children whose levels average 10 µg per dL (0.48 µmol per L). Other effects associated with lead exposure include aggression, decreased attention, somatic complaints and antisocial or delinquent behavior. Elevated blood lead levels may also be associated with abnormal balance, poor eye-hand coordination and sleep disturbances, although the data for these associations are less consistent than the data for cognitive deficits.
The physician's role in providing anticipatory guidance to prevent lead exposure cannot be overemphasized. Educating parents about potential sources of lead is essential, as is providing information about proper nutrition and the importance of dietary iron. Removal of environmental lead sources is also important.
Universal screening of all children is recommended if the prevalence of elevated blood lead levels in a community is unknown or if more than 27 percent of the housing in the community was built before 1950. Targeted screening is recommended in areas where the prevalence of elevated lead levels in children is less than 12 percent or where fewer than 27 percent of the houses were built before 1950.
A simple at-risk questionnaire can be useful for determining which children should be screened for elevated blood lead levels. Management of elevated blood lead levels proceeds according to a specific scheme. A blood lead level of 10 mg per dL (0.48 mmol per L) or greater requires confirmatory testing, with the urgency of the second test depending on the initial value. Patients with blood lead levels of 70 mg per dL (3.38 mmol per L) or higher must be hospitalized immediately.
The recommendations include the following strategies: anticipatory guidance should be provided to parents of infants and toddlers; children at risk should be screened for the first time at nine to 12 months of age and again at about 24 months of age; the possibility of lead exposure history should be assessed periodically, beginning at age six months and continuing until six years of age. The recommendations state that further research is needed to identify which strategies are best for treating elevated lead levels and educating the public about the risks of lead toxicity.
GRACE BROOKE HUFFMAN, M.D.
American Academy of Pediatrics Committee on Environmental Health. Screening for elevated blood lead levels. Pediatrics June 1998;101:1072-8.
Effects of Missing the First Oral Contraceptives in a Cycle
Within their first year of using oral contraceptive pills, at least 50 to 60 percent of women report irregular pill taking. Based on this high rate of missed oral contraceptive pills, it seems that contraceptive reliability may be compromised. The finding that follicular development begins initially during the pill-free interval of seven days has led to the idea that missing the first pills of the cycle (thus extending the pill-free interval) would be critical in terms of escape ovulation. Possibly this concern would increase if the woman were using a triphasic combination. Elomaa and associates conducted a study to test the hypothesis that omitting the first three pills of the oral contraceptive pill cycle leads to escape ovulation.
The 99 study subjects were randomly assigned to receive one of the following treatments: 75 µg of monophasic gestodene and 30 µg of ethinyl estradiol, a triphasic gestodeneethinyl estradiol combination or 150 µg monophasic desogestrel and 20 µg of ethinyl estradiol. Noncompliance was simulated by extending the pill-free period from seven days (study period 1) to 10 days (study period 2). After the 21-day cycle was completed, follicular size was measured by ultrasonography, and hormonal levels were analyzed.
During or after the standard seven-day pill-free interval, the leading follicle grew up to or beyond 13 mm in 9 percent, 6 percent and 27 percent of the subjects in the monophasic gestodene, triphasic gestodene and monophasic desogestrel groups, respectively. During or after the extended pill-free interval, follicular growth of 13 mm or more occurred in 41 percent, 47 percent and 70 percent of patients in each respective group. In study period 1, statistically significant differences were noted between the monophasic gestodene and monophasic desogestrel groups, and between the triphasic gestodene and monophasic desogestrel groups. In study period 2, the monophasic desogestrel group differed significantly from the monophasic gestodene group.
Normal ovulation was not observed in any of the patients after either a seven- or a 10-day pill-free period. The diameter of the largest follicle on the third day of treatment was 12 mm. Two days later it was 15 mm, and it grew to 21 mm by treatment day 7. This finding provides strong evidence against normal ovulation but is consistent with a luteinized unruptured follicle. Serum progesterone levels did not indicate normal ovulation. The level of follicle stimulating hormone reached a maximal concentration in most women during the first pill-free period, indicating complete pituitary recovery. Increases in estradiol levels were experienced by all patients, although variability was marked. Results indicated that no normal ovulation occurred in this study of 98 standard oral contraceptive pill cycles and 98 cycles covering the pill-free extended period of 10 days.
The authors conclude that extending the pill-free interval to 10 days does not alone compromise the efficacy of combination oral contraceptive pills. This seems to be true whether monophasic or triphasic oral contraceptive pills are used. However, ovarian recovery as evidenced by estradiol concentrations and follicular growth is significantly more rapid in women using an oral contraceptive pill with only 20 µg of ethinyl estradiol.
The practical consequences of this study, in terms of patient counseling, come from the low risk of ovulation after a patient forgets the first three pills of the new cycle. If no additional pills are missed, ovulation is unlikely to occur. If the woman cannot remember the intake of the pills, she should be advised to use an additional barrier method of contraception for one week.
BARBARA APGAR, M.D., M.S.
Elomaa K, et al. Omitting the first oral contraceptive pills of the cycle does not automatically lead to ovulation. Am J Obstet Gynecol July 1998;179:41-6.
Corticosteroid Use For the Treatment of Herpes Zoster
Antiviral agents are clearly beneficial in the treatment of herpes zoster, but the role of corticosteroids is not as well defined. MacFarlane and colleagues conducted a literature review to determine, in an evidence-based manner, the safety, tolerability and effectiveness of corticosteroids in the treatment of herpes zoster.
Although theoretic concerns have been posed that corticosteroid-induced immunosuppression may cause a patient to be at increased risk of viral dissemination, the authors found that these concerns are not borne out by randomized clinical trials of patients with no underlying immunosuppression.
With regard to the tolerability of these agents, the Collaborative Antiviral Study Group reported that the most frequent adverse effects in patients receiving corticosteroids were nausea, vomiting and hyperglycemia. However, these effects occurred with placebo and antiviral agents as well. Another study demonstrated that patients receiving prednisolone in combination with acyclovir for seven to 21 days had a higher incidence of dyspepsia, edema and flushing compared with patients who received acyclovir alone. The difference, however, was not statistically significant. This study also showed that laboratory abnormalities occurred more frequently in patients receiving corticosteroids, but the values returned to normal after the steroid dosage was tapered. Most clinical trials of the use of cortisteroids, however, have excluded patients with other medical problems, and it is these patients who may be more likely to develop side effects.
One study showed that patients receiving corticosteroids in combination with antiviral agents had a greater reduction in pain at seven and 14 days than did patients receiving antiviral agents alone. However, no significant differences were detected in the incidence or severity of postherpetic neuralgia at six months. The Collaborative Antiviral Study Group found that quality of life in the month following the onset of herpes zoster was improved in patients receiving corticosteroids. While the extreme pain associated with postherpetic neuralgia has led physicians to prescribe corticosteroids for treatment of herpes zoster, the authors found no evidence in the literature that corticosteroids reduce the incidence or duration of postherpetic neuralgia.
The authors conclude that recent clinical trials support the use of corticosteroid therapy in patients with herpes zoster. Combined with antiviral therapy, corticosteroid therapy helps reduce acute zoster pain and improves quality of life in the month following the outbreak. The authors note, however, that clinical trials often excluded patients with concomitant conditions such as hypertension, diabetes, peptic ulcer disease, osteoporosis and renal insufficiency, but they believe corticosteroid therapy is a reasonable approach in the treatment of herpes zoster in patients with well-controlled chronic disease, as long as the chronic conditions are carefully monitored. The cost of a three-week course of tapering corticosteroids is less than $10.
GRACE BROOKE HUFFMAN, M.D.
MacFarlane LL, et al. The use of corticosteroids in the management of herpes zoster. J Am Board Fam Pract May-June 1998;11:224-8.
Differentiating Benign and Malignant Lymph Nodes
Color Doppler ultrasonography is the only accurate method of displaying the angioarchitecture of lymph nodes. A distorted angioarchitecture has been described as occurring more frequently in malignant lymph nodes. Tschammler and associates evaluated reactive and malignant lymphadenopathy using Doppler ultrasonographic studies of intranodal blood vessels.
Doppler ultrasonography of 117 lymph nodes was performed in 100 consecutive patients with lymphadenopathy before surgical biopsy, neck dissection or high-speed core biopsy. The intranodal architecture was assessed by color Doppler. At least one lymph node from each patient was studied. Most lymph nodes were located in the cervical, submandibular or supraclavicular regions. After excision, the size and shape of the nodes were compared with the ultrasound results to ensure that exactly the same nodes were assessed by both ultrasonography and histology. Specific criteria for the angioarchitecture were established to allow precise differentiation of benign and malignant findings.
Histologic examination yielded 48 reactive lymph nodes, 56 lymph node metastases and 13 malignant lymphomas. Malignant lymph nodes had larger diameters in all axes than did reactive lymph nodes. A missing echogenic center and a round shape were further signs of malignancy. Of the 69 malignant lymph nodes, 96 percent met at least one criterion of malignancy in the assessment of the intranodal angioarchitecture. Of the 48 reactive lymph nodes, 25 percent showed no perfusion, 52 percent had normal angioarchitectural features, and 23 percent were classified as false-positives.
Lymph nodes that were classified as malignant on the basis of color Doppler ultrasonography had an average of 2.6 criteria of malignancy. The negative predictive value was 93 percent, and the positive predictive value was 86 percent when at least one criterion of malignancy was present. If all four criteria of malignancy were present, the positive predictive value increased to 94 percent. The echogenicity of the center of the lymph nodes representing interfaces between tissue and vessels was the only sonomorphologic criterion that was correlated with the angioarchitecture.
Results of this study showed that if intranodal vessels are assessed carefully, reactive lymph nodes display the same angioarchitecture known from histopathologic studies. The false-positive results were most likely due to overinterpretation of peripheral flow signals depicted on the high-resolution equipment. One of the three false-negative results showed a low-grade non-Hodgkin's lymphoma. The two others occurred in cases of metastases of squamous cell carcinoma. It is suggested that the false negativity was caused by regressive tissue alterations that yielded low perfusion.
The authors conclude that the use of color Doppler ultrasonography in the assessment of intranodal angioarchitecture in superficial lymph nodes is a reliable and reproducible method of differentiating between reactive and malignant lymphadenopathy. With color Doppler ultrasonography, a total of 88 percent of nodes were classified correctly, resulting in a specificity of 77 percent and a sensitivity of 96 percent.
BARBARA APGAR, M.D., M.S.
Tschammler A, et al. Lymphadenopathy: differentiation of benign from malignant disease--color Doppler US assessment of intranodal angioarchitecture. Radiology July 1998;208:117-23.
Beta Blockers for Heart Failure Due to Coronary Artery Disease
New York Heart Association Classification of Heart Disease Class I No symptoms Class II Mild symptoms; patient can tolerate strenuous physical activity Class III Moderate symptoms; patient can only tolerate mild to moderate activity Class IV Severe symptoms; patient is symptomatic at rest Beta-adrenergic blockers are generally considered to be contraindicated in patients with heart failure because of their negative inotropic effect. Sympathetic activation, however, is associated with an adverse prognosis in patients with heart failure. This observation has led to studies of the role of beta blockers in this population. Haim and associates evaluated the long-term effects of beta-blocker therapy in patients with coronary artery disease and heart failure in New York Heart Association (NYHA) functional classes II and III (see the accompanying table).
Using a population from the registry for a trial of the lipid-lowering agent bezafibrate, the authors compared a group of 1,109 patients in NYHA classes II and III who were receiving beta-blocker therapy at the time of enrollment with a group of 2,116 patients in NYHA classes II and III who were not receiving beta blockers. The beta-blocker dosages were not recorded.
The four-year mortality rate in the patients treated with beta blockers was 9 percent, significantly lower than the 17 percent mortality rate in patients not receiving beta blockers. The cardiac mortality rate was 5 percent in patients treated with beta blockers, compared with a rate of 11 percent in patients not receiving beta blockers. Multivariate analysis revealed that the lower mortality risk associated with beta blockers remained highly significant after adjusting for concomitant therapy with digoxin, diuretics, nitrates or angiotensin converting enzyme (ACE) inhibitors. The lower mortality rates were significant regardless of the patient's sex, history of previous myocardial infarction or NYHA class (II or III).
The authors conclude that patients with ischemic heart failure (NYHA functional classes II and III) who were treated with beta blockers had a 38 percent lower risk for all-cause mortality and a 39 percent lower risk for cardiac mortality than their counterparts who were not treated with beta blockers.
RICHARD SADOVSKY, M.D.
Haim M, et al. Effect of beta-blocker therapy in patients with coronary artery disease in New York Heart Association Classes II and III. Am J Cardiol June 15, 1998; 81:1455-60.
EDITOR'S NOTE: The deterioration of cardiac function that occurs with heart failure is secondary to compensatory mechanisms, including neurohormonal activation involving the sympathetic nervous system and the renin-angiotensin-aldosterone hormonal axis. Such protracted alterations lead to ventricular dilatation, increased myocardial energy demand, impaired diastolic function, systemic vasoconstriction, arrhythmias and heart failure. Halting these events with ACE inhibitors slows the progression of heart failure. Beta-adrenergic blockers may do the same, as well as exert antiarrhythmic effects.
Compared with first-generation beta blockers, second-generation agents selective for beta1 receptors, which include metoprolol, atenolol, bisoprolol and betaxolol, are not as likely to produce systemic vasoconstriction. Thus, they may be of benefit in patients with heart failure when they are used in combination with ACE inhibitors. Third-generation beta blockers, which include carvedilol, labetolol, pindolol and sotalol, may have even better myocardial protective properties. Slow titration of beta-blocker therapy is important in these patients, and symptomatic improvement, possibly preceded by a period of decompensation, may require up to three months. It is becoming clear that selected beta blockers can be used in combination with ACE inhibitors in the treatment of mild to moderate heart failure. This approach may delay progression of heart failure and improve survival.
R.S.
Methylprednisolone for Acute Respiratory Distress Syndrome
Acute respiratory distress syndrome (ARDS) is a frequent cause of hypoxemic respiratory failure and is associated with a mortality rate higher than 50 percent. Previous studies have not shown a benefit from a short course of treatment with high-dose methylprednisolone in patients with ARDS. However, long-term therapy with this agent may improve lung function and general outcome if treatment is started before end-stage fibrosis develops. Meduri and associates conducted a randomized, double-blind, placebo-controlled trial to evaluate the safety and effectiveness of long-term therapy with methylprednisolone in improving lung function and decreasing mortality in patients with unresolving ARDS.
Patients in an adult intensive care unit were included in the study if they had been diagnosed with ARDS, had no evidence of untreated infection and had been on mechanical ventilation for at least seven days with a lung injury score (LIS) of at least 2.5 and less than one point of improvement since the original diagnosis of ARDS. Patients were excluded if they had ARDS for three weeks or more, had extensive burns or a history of recent major gastrointestinal bleeding, were pregnant or terminally ill, or required methylprednisolone therapy for another medical condition. Patients were randomized to receive either a placebo or methylprednisolone in a loading dose of 2 mg per kg by intravenous push every six hours, then a single oral daily dose once oral intake was restored. For the next two weeks, patients received 2 mg per kg of methylprednisolone daily. The daily doses were reduced by one half every seven days until patients were taking only 0.125 mg per kg on the last two days of the study. Patients whose LIS failed to improve after 10 days were crossed over to the other intervention. Patients were also monitored for the development of infections or gastrointestinal bleeding. Improvements in lung function and mortality were the main outcome measures.
Twenty-four patients were included in the study. Sixteen patients were randomized to the methylprednisolone group and eight to the placebo group. All patients in the treatment group showed significant improvement in lung function after 10 days, including ratio of Pao2 (partial pressure of arterial oxygen) to Fio2 (percentage of inspired oxygen), LIS, static lung compliance and mean pulmonary artery pressure. None of these variables improved in the placebo group during the first 10 days of treatment; four of the control subjects crossed over to the treatment group because of failure to improve. Two patients in the placebo group improved by day 10, and two patients died. Those who crossed over from placebo to methylprednisolone had a significantly higher mortality rate than those who had received methylprednisolone from the beginning of the study. Eighty-seven percent of the patients in the methylprednisolone group survived to discharge from the intensive care unit, compared with 37 percent of patients in the placebo group.
The authors conclude that lung injury scores and mortality rates can be improved in patients with ARDS through the prolonged use of methylprednisolone therapy.
In a related editorial, Brun-Buisson and Brochard note that the sample size in this study was quite small, making the confidence interval wide. Larger trials are needed to confirm the findings of this study and to determine the optimal dosage, duration and timing of methylprednisolone therapy in patients hospitalized with ARDS.
GRACE BROOKE HUFFMAN, M.D.
Meduri GU, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome. A randomized controlled trial. JAMA July 8, 1998;280:159-65, and Brun-Buisson C and Brochard L. Corticosteroid therapy in acute respiratory distress syndrome. Better late than never? [Editorial] JAMA July 8, 1998;280:182-3.
Garlic Therapy for Treatment of Hypercholesterolemia?
Garlic has been advocated as a remedy for the treatment and prevention of a variety of health problems. Its cardioprotective effects seem worthy of study; however, previous studies appear to have been flawed or poorly designed. Berthold and associates conducted a randomized, double-blind trial to determine the effect of a garlic oil preparation on serum lipoprotein levels and cholesterol metabolism.
Patients were included in the study if they had not taken any medications to decrease serum lipid levels during the previous eight weeks and if their total cholesterol levels were between 240 and 348 mg per dL (6.22 and 9.01 mmol per L) and their triglyceride levels were less than 265 mg per dL (3.0 mmol per L). Patients remained eligible for the study if they took antihypertensive medication, thyroid hormones or hormone replacement medications. Twenty-five people were included in the study.
The patients were advised to follow their usual diets but were not allowed to take additional garlic or other food supplements during the study. They were randomized to receive either a placebo or 5 mg of garlic oil (equaling 4 or 5 g of fresh garlic cloves) per day. During the first four weeks of the study, all patients were given placebo. For the next 12 weeks, they received either the placebo or the garlic preparation. This regimen was followed by a four-week placebo washout period. The patients then entered a 12-week cross-over period. High-density lipoprotein and low-density lipoprotein cholesterol levels were calculated at the beginning and end of each phase.
The garlic preparation was well tolerated by all 25 patients included in the study, and no patients experienced adverse effects. Compliance was good for both the placebo and garlic preparations. The garlic preparation had no significant effect on lipoprotein fractions and no effect on parameters of cholesterol metabolism (including cholesterol absorption and cholesterol synthesis).
The authors conclude that the evidence does not support use of garlic oil products to lower serum lipid levels.
GRACE BROOKE HUFFMAN, M.D.
Berthold HK, et al. Effect of a garlic oil preparation on serum lipoproteins and cholesterol metabolism. A randomized controlled trial. JAMA June 17, 1998;279:1900-2.
Evaluating a Shorter Course of Therapy for Acute Otitis Media
Antibiotic treatment has been shown to speed resolution of the symptoms of acute otitis media in children, but since there is no significant difference in long-term outcomes among children who are treated and children who are not treated, some clinicians advocate not prescribing antibiotics at all. There is, however, a reluctance on the part of American physicians to adopt this practice. Kozyrskyj and associates conducted a meta-analysis to determine if a short course of antibiotic treatment was as efficacious as a traditional longer course of therapy for acute otitis media in children.
Clinical trials were included if their study populations were between four weeks and 18 years of age, had a diagnosis of acute otitis media, had been randomly assigned to receive a short or long course of antibiotic treatment and were assessed to see if the acute otitis media had resolved. Treatment failure was defined as lack of clinical resolution, or relapse, or recurrence within one month. Middle ear effusion was not considered a treatment failure.
The literature search yielded 32 trials: 17 were trials of short-acting antibiotics, 11 were trials of azithromycin and four were trials of ceftriaxone. Fourteen of these studies could be used for evaluation of the main outcome measures. A total of 1,031 children were treated for five days with an antibiotic, and 1,084 children were treated for eight to 10 days. There were no significant differences in primary outcomes between the two groups. Evaluation at 30 days after initiation of therapy showed that a 10-day course of antibiotics was not significantly different from a five-day course of antibiotics; however, at 20 days there was a slight increase in relapse or reinfection (odds ratio: 1.52) in those treated with a shorter course of antibiotics. The difference in short-term risk of failure was 7.8 percent. In other words, to prevent one treatment failure with the short course of therapy, 13 children would need to receive the longer course of antibiotics.
The authors conclude that a five-day course of antibiotic treatment for uncomplicated acute otitis media in children is effective, costs less and is associated with greater compliance than the longer course of therapy that is typically prescribed.
In a related editorial, Pichichero states that many children are overdiagnosed with acute otitis media if tympanocentesis is not performed. He stresses that diagnostic accuracy must be improved, particularly by tympanocentesis. Tympanocentesis should be used in patients whose tympanic membrane is bulging and in patients who appear toxic or have a high fever. Long (10-day) courses of antibiotic therapy should be reserved for use in patients who have perforated tympanic membranes, those with chronic or recurrent otitis media and those with underlying medical conditions who may be at higher risk of treatment failure.
GRACE BROOKE HUFFMAN, M.D.
Kozyrskyj AL, et al. Treatment of acute otitis media with a shortened course of antibiotics. A meta-analysis. JAMA June 3, 1998;279:1736-42, and Pichichero ME. Changing the treatment paradigm for acute otitis media in children [Editorial]. JAMA June 3, 1998;279:1748-50.
Continuous Fluconazole for Oropharyngeal Candidiasis
Fluconazole has been widely used to treat oropharyngeal candidiasis in patients with human immunodeficiency virus (HIV) infection. Resistance to fluconazole is becoming a serious problem, particularly with continuous low-dose use and multiple short courses of therapy. Revankar and colleagues conducted a prospective, randomized study to determine the frequency of oropharyngeal candidiasis and the development of resistance with intermittent or continuous use of fluconazole in patients infected with HIV.
HIV-infected patients with active oropharyngeal candidiasis were eligible for this study if their CD4 counts were less than 350 per mm3 (350 3 106 per L) and they were not currently taking any azole compound. Forty-four patients were randomized to receive continuous therapy or intermittent therapy with fluconazole. Patients were treated with 200 mg of fluconazole on day 1 and then with 100 mg per day for seven days or until complete resolution of the candidiasis. Patients assigned to the continuous treatment group continued to receive prophylaxis of 200 mg of fluconazole per day, whereas the patients assigned to the intermittent group received fluconazole only during a recurrence of candidiasis. Cultures were obtained every three months, and weekly during episodes of thrush. Resistance to fluconazole was evaluated in all of the culture samples. Other outcomes measured included occurrence of relapses and clinical failure.
All patients were followed for at least three months. The mean follow-up for the 16 patients who received continuous treatment was 11 months compared with 10.5 months in the 28 patients who received intermittent therapy. Symptomatic relapses occurred in 25 percent of patients receiving continuous therapy compared with 82 percent of patients receiving intermittent therapy. However, two thirds of the relapses that occurred in the continuous treatment group were associated with short breaks in the fluconazole regimen. Development of clinical resistance occurred in 13 percent of patients in the continuous group and 18 percent of patients in the intermittent group.
The authors also compared costs of the two regimens. The cost of continuous therapy was higher than that of intermittent therapy; however, for patients who had frequent relapses of candidiasis and needed higher dosages and longer courses of treatment, the cost of intermittent therapy approached that of continuous therapy.
The authors conclude that HIV-infected patients who have recurrent infections with oropharyngeal candidiasis may benefit from continuous suppressive therapy with fluconazole. They found no significant difference in the development of resistance, microbiologically or clinically, in either the intermittent or the continuous treatment groups. Further studies are needed to determine if patients at high risk for recurrences can be identified.
GRACE BROOKE HUFFMAN, M.D.
Revankar SG, et al. A randomized trial of continuous or intermittent therapy with fluconazole for oropharyngeal candidiasis in HIV-infected patients: clinical outcomes and development of fluconazole resistance. Am J Med July 1998;105:7-11.
Hypertension, Blood Pressure Levels and Aspirin Therapy
Even after undergoing treatment, hypertensive patients remain at increased risk for morbidity and mortality from cardiovascular disease. The principal reason for this is believed to be inadequate therapy, since at least two thirds of patients with treated hypertension have blood pressure levels persistently higher than 140/90 mm Hg. Many authors have expressed concern that lowering blood pressure excessively may be hazardous, and the optimal target levels for blood pressure reduction have never been established. In addition, the role of aspirin therapy in hypertensive patients has not been defined. The controversy concerning aspirin centers on balancing its benefits in preventing stroke and myocardial infarction against the increased risk of cerebral hemorrhage. The international Hypertension Optimal Treatment trial conducted by Hansson and colleagues assessed the optimal reduction in blood pressure and the role of aspirin in the management of hypertension.
The study involved 18,790 patients in 26 countries. Participants were 50 to 80 years of age (mean age: 61.5 years) and had confirmed hypertension with diastolic pressures between 100 and 115 mm Hg. All patients were treated with felodipine, with the dosage adjusted or additional agents (angiotensin converting enzyme inhibitors or beta blockers) added to achieve target diastolic blood pressures of less than 90 mm Hg (6,264 patients), less than 85 mm Hg (6,264 patients) or less than 80 mm Hg (6,262 patients). All blood pressures were measured using standardized and stringent criteria. The mean follow-up time was 3.8 years. Only 2.6 percent of patients were lost to follow-up and, at the end of the study, 78 percent of patients were still taking the medication.
The major cardiovascular events were lowest at a blood pressure level of 138.5/82.6 mm Hg. For myocardial infarction, no defined minimum blood pressure could be established, but the optimal systolic blood pressure was calculated to be 142.2 mm Hg. For all types of cardiovascular mortality, the risk was lowest at 138.8/86.5 mm Hg. For stroke, the optimal systolic blood pressure was 142.2 mm Hg, and the optimal diastolic blood pressure was below 80 mm Hg.
In addition to blood pressure reduction agents, over 9,000 patients were randomly assigned to receive either placebo or aspirin, 75 mg per day. Aspirin therapy was associated with a 15 percent reduction in major cardiovascular events and, most significantly, a 36 percent reduction in myocardial infarction. No difference was observed in stroke or in fatal bleeding events, but the aspirin group had 129 major events, which was significantly greater than the 70 nonfatal bleeding events in the group receiving placebo.
The authors conclude that lowering blood pressure with medication was highly beneficial to hypertensive patients, with the optimal effect at 140/85 mm Hg or lower. The addition of small dosages of aspirin reduced the risk of myocardial infarction. The benefits were particularly marked in patients with diabetes.
ANNE D. WALLING, M.D.
Hansson L, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet June 13, 1998;351:1755-62.
Hormone Replacement Therapy and Risk of Hip Fracture
Postmenopausal hormone replacement therapy (HRT) is known to reduce the incidence of both osteoporosis and hip fractures. However, many questions remain regarding the specific characteristics of HRT, such as the optimal dosage and duration of treatment, the influence of the patient's age when therapy is initiated or discontinued, and the effectiveness of alternative regimens of HRT. Michaëlsson and colleagues conducted a case-control study to assess the risk of hip fracture in patients receiving HRT. The study focused specifically on whether dosage and duration of therapy, route of administration and addition of progestins to the regimen have any influence on the incidence of hip fracture.
The authors used hospital discharge records to identify all female residents of six Swedish counties who were born after 1914 and treated for fractures of the proximal femur any time between 1993 and 1995. A total of 1,610 women were included in the study. Exclusion criteria included incorrect diagnosis, old fracture, blindness, birth outside of Sweden, a diagnosis of severe alcohol misuse, senile dementia or psychosis, death within three months of the fracture, or fracture attributable to severe trauma or malignancy. Data on demographics, reproductive history, use of HRT, dietary habits and smoking history were collected using a comprehensive questionnaire that was completed an average of 95 days after the fracture occurred. Hormone replacement therapy regimens were categorized by dosage. Dosages of 1 mg of estradiol, 0.325 mg of conjugated estrogens, 5 µg of ethinyl estradiol or 25 µg of transdermal estradiol were considered low-dose regimens. Higher amounts were classified as high-dose regimens. Each study patient was matched with two control subjects from the same county of residence.
Complete data were obtained from 1,328 (82.5 percent) of the study patients and 3,312 (81.6 percent) of the control subjects. Use of HRT was associated with a 6 percent (range: 3 to 9 percent) reduction in risk for hip fracture for every year of HRT, regardless of type. Current users of any type of HRT had a 9 percent (range: 5 to 13 percent) reduction in risk of hip fracture. For current users, regimens that combined estrogen and progestin provided the greatest reduction in risk (8 to 24 percent) compared with estrogen therapy alone (1 to 12 percent). In addition, current users of combination therapy experienced a substantial protective effect compared with those who had never received HRT. However, the benefit of combination therapy over estrogen therapy alone was less apparent among former users. The odds ratios showed a substantial net reduction in the risk of hip fracture. Current users of estrogen alone had an odds ratio of 0.48, and former users had an odds ratio of 0.76.
Both oral and transdermal routes of administration appeared to be equally effective. Hormone replacement therapy that was started up to nine years after menopause provided the same protective effect in reduction of hip fracture as therapy started much sooner. However, this protective effect diminished when HRT was discontinued. After five years without HRT, the protective effect diminished by up to 48 percent.
The authors conclude that HRT provides substantial protection against hip fracture in women. Protection appears to be dosage-related and increases with duration of therapy. The minimally effective dosage of estrogen without progestin to prevent postmenopausal bone loss in most women is 2 mg of estradiol, 0.625 mg of conjugated estrogens or the equivalent daily. Initiating therapy several years after menopause is effective, but protection diminishes when therapy is discontinued.
ANNE D. WALLING, M.D.
Michaëlsson K, et al. Hormone replacement therapy and risk of hip fracture: a population based case-control study. BMJ June 20, 1998;316:1858-63.
Enalapril for Attenuating Renal Function Decline in Diabetes
Albuminuria in persons with diabetes mellitus is a risk factor for the development of nephropathy and for cardiovascular morbidity. Angiotensin converting enzyme (ACE) inhibitors have been shown in previous studies to attenuate progression of nephropathy in both types of diabetes in hypertensive and normotensive patients with microalbuminuria. ACE inhibitors also lower urinary albumin excretion in normotensive and normoalbuminuric patients with type 1 diabetes, although the relationship between albuminuria and later nephropathy in these patients has not been established. Ravid and associates evaluated the effects of early introduction of the ACE inhibitor enalapril in the management of normotensive, normoalbuminuric patients with type 2 diabetes.
The randomized, double-blind, placebo-controlled study included 156 patients younger than 60 years of age who were diagnosed with type 2 diabetes when they were 40 years of age or older. All of the patients had a baseline mean blood pressure of less than 107 mm Hg and albuminuria (albumin excretion: 30 mg per 24 hours or less [30 mg per day]). Patients were randomly assigned to receive either 10 mg of enalapril daily or a placebo and remained in the study for six years.
At semiannual visits, hemoglobin A1c, serum creatinine, serum electrolyte and urinary creatinine levels, and 24-hour albumin excretion were measured. Blood pressure was also monitored; if the systolic pressure dropped below 100 mm Hg, the enalapril dosage was reduced by one half. Evidence of retinopathy was evaluated by an ophthalmologist.
Transition to microalbuminuria after six years differed significantly in the treatment and placebo groups. Microalbuminuria was found in five (6.5 percent) of the 77 patients in the enalapril group compared with 15 (19.0 percent) of the 79 patients in the placebo group. The absolute risk reduction with enalapril was 12.5 percent. The placebo group also had a greater decrease in creatinine clearance by the fifth and sixth years.
Annual funduscopic examinations revealed 15 new cases of retinopathy in the placebo group (19 percent) and six new cases in the enalapril group (7.8 percent). Enalapril was associated with an absolute risk reduction of 11.2 percentage points for the development of retinopathy during the course of six years.
The mean blood pressure of the enalapril group was significantly lower than the placebo group only during the fifth year of the study.
The authors conclude that enalapril appears to offer a modest renal protective effect in normotensive, normoalbuminuric patients with type 2 diabetes. The population in this study was at low risk for development of diabetic nephropathy, making the recommendation of universal use of ACE inhibitors in all normotensive, normoalbuminuric patients with well-controlled diabetes inappropriate at this time. Further studies are needed to identify which low-risk patients are likely to benefit from such therapy and to establish if the onset of overt diabetic nephropathy will be delayed with such therapy.
RICHARD SADOVSKY, M.D.
Ravid M, et al. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med June 15, 1998;128:982-8.
Extended Period of Excretion May Follow Rotavirus Infection
Rotaviruses are a major cause of severe diarrheal illness in children, who frequently require hospital admission because of the severity of symptoms. Since clinically significant infection can result from the ingestion of just one plaque-forming viral unit, it is important to determine the time period during which virus particles may be shed by children recovering from acute infection. Richardson and colleagues evaluated the length of time that rotavirus was excreted following severe acute infection in children.
Thirty-seven children aged one to 39 months were included in the study. All of the study subjects were admitted to an Australian hospital because of severe confirmed rotavirus infection but were otherwise healthy, with normal serum immunoglobulin levels. Fecal specimens were examined for rotavirus using molecular biologic techniques with very high sensitivity and specificity. Specimens were collected daily for 14 days following admission to the hospital and then weekly for at least 100 days. Approximately 26 specimens were collected from each child.
Although the median duration of viral excretion was 10 days, the range was four to 57 days. In 16 children (43 percent), viral shedding ceased within 10 days of hospital admission. In 11 children (30 percent), viral excretion was detectable for 22 to 57 days. Many of the children with extended periods of viral excretion had intermittent viral shedding. It was not possible to predict which children would have long periods of viral shedding on the basis of age, duration of diarrhea or symptom severity. Children with extended excretion showed different patterns of IgA antibody response to infection and had more frequent recurrence of diarrhea during convalescence.
The authors conclude that approximately one third of immunocompetent children with severe rotavirus infection continue to secrete potentially infective virus particles for at least three weeks following hospital admission. In some cases, excretion may continue for up to 57 days. Children who secrete virus for prolonged periods cannot be easily distinguished from other children with rotavirus infection and could be important sources of infection in the community.
ANNE D. WALLING, M.D.
Richardson S, et al. Extended excretion of rotavirus after severe diarrhoea in young children. Lancet June 20, 1998;351:1844-8.
Efficacy of a Vaccine for the Prevention of Lyme Disease
A total of 10,000 new cases of Lyme disease are reported each year to the Centers for Disease Control and Prevention, making it the most common vector-borne disease in the United States. Steere and colleagues, of the Lyme Disease Vaccine Study Group, report the results of a multicenter, randomized, double-blind, placebo-controlled phase III trial of a vaccine for the prevention of Lyme disease.
The 10,936 subjects were enrolled in the study at 31 sites in 10 states in which Lyme disease is endemic. The mean age of the study participants was 46 years (range: 15 to 70 years). Immunization against Lyme disease consisted of three injections of recombinant Borrelia burgdorferi outer-surface lipoprotein A (OspA) with adjuvant. Two additional injections were administered one month and 12 months later. Patients were excluded if they had active Lyme disease or were treated for Lyme disease within three months before the study began.
Blood samples for measurement of antibody to B. burgdorferi were drawn at baseline and again two, 12 and 20 months later. Only Western blot testing was performed because enzyme-linked immunosorbent assay would likely yield positive results in patients who received the Lyme disease vaccine. Serologic evidence for the diagnosis of Lyme disease was based on the demonstration of seroconversion between baseline and the acute phase of the illness or between the acute phase and convalescence.
Participants were asked to notify the investigative site if they developed any symptoms suggestive of Lyme disease. Cultures and laboratory tests for B. burgdorferi DNA by polymerase chain reaction (PCR) were performed on biopsy specimens from erythema migrans lesions. PCR testing was also done on joint fluid or cerebrospinal fluid if the test was clinically indicated.
During the first year after vaccination, 1,109 subjects were evaluated for possible Lyme disease, and in 89 percent, other diagnoses were made. During the second year, 808 subjects were evaluated for possible Lyme disease, and 82 percent were diagnosed with an illness other than Lyme disease. In both years, a diagnosis other than Lyme disease was made in nearly an equal number of subjects in the placebo and the vaccine groups.
In the first year, after two injections, 22 subjects in the vaccine group and 43 subjects in the placebo group had definite Lyme disease. The vaccine efficacy was calculated to be 49 percent after two injections. In the second year, after the third injection, 16 subjects in the vaccine group and 66 subjects in the placebo group contracted Lyme disease, which translates to a vaccine efficacy of 76 percent.
During the first year, two subjects in the vaccine group and 13 subjects in the placebo group had asymptomatic IgG seroconversion. However, in the second year, 15 placebo recipients had asymptomatic IgG seroconversion compared with none of the subjects in the vaccine group. This translates to a vaccine efficacy of 83 percent in the first year and 100 percent in the second year in this subset of participants.
Evaluation of antibody responses to the protective epitope of OspA demonstrated that 95 percent of the recipients had measurable antibody titers one month after the second injection. After the third injection, 99 percent had measurable antibody titers.
Adverse effects such as redness, swelling and soreness at the injection site and myalgias, aches, fever or chills were reported by 63 percent of the vaccine recipients and 53 percent of the placebo recipients. The symptoms tended to occur within 48 hours of vaccination and lasted about three days.
The authors conclude that three injections of the Lyme disease vaccine induced a high level of protective antibody against B. burgdorferi infection. The authors believe this vaccine is an important step in the prevention of Lyme disease.
JEFFREY T. KIRCHNER, D.O.
Steere AC, et al. Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. N Engl J Med July 23, 1998; 339:209-15.
Five-Day vs. 10-Day Course of Cefuroxime for GABHS
Tonsillopharyngitis is usually viral in children younger than three years of age, but between the ages of five and 10, group A beta-hemolytic streptococci (GABHS) account for more than 25 percent of cases. Failure to eradicate the infection with penicillin is becoming more frequent, probably because of the presence of beta-lactamaseproducing pathogens such as Haemophilus influenzae, Moraxella catarrhalis and Staphylococcus aureus, tolerance of GABHS to penicillin and poor compliance. GABHS is susceptible to cefuroxime, a broad-spectrum cephalosporin, as are the beta-lactamaseproducing pathogens such as H. influenzae, S. aureus and M. catarrhalis. Mehra and associates compared the efficacy of a five-day course of cefuroxime axetil suspension with that of the standard 10-day regimen in children with GABHS tonsillopharyngitis.
The open, randomized, multicenter study included children from three to 13 years of age. After GABHS infection was verified by throat cultures, the children were randomly assigned to receive cefuroxime axetil suspension in a dosage of 10 mg per kg twice daily, for either five days or 10 days (taken after food when possible).
Eradication of infection was similar in the two treatment groups. In the five-day group, the eradication rate was 88 percent (177 of 201 patients); in the 10-day group, the eradication rate was 92 percent (189 of 205 patients). Post-treatment evaluation revealed clinical cure in 96 percent of patients in the five-day treatment group and 98 percent of patients in the 10-day treatment group.
The most common drug-related adverse events were nausea, vomiting, diarrhea and gastrointestinal discomfort. Drug-related adverse events occurred in 5 percent of the children in each group.
The authors conclude that a five-day course of cefuroxime is clinically and bacteriologically equivalent to a 10-day course in children with GABHS tonsillopharyngitis.
RICHARD SADOVSKY, M.D.
Mehra S, et al. Short course therapy with cefuroxime axetil for group A streptococcal tonsillopharyngitis in children. Pediatr Infect Dis J June 1998;17:452-7.
Detecting Protruding Aortic Plaques as a Source of Stroke
With the increased use of transesophageal echocardiography (TEE), systemic emboli from atheromas in the thoracic aorta are being identified more often. Recent studies have suggested that protruding aortic plaques may be an important source of iatrogenic stroke and embolic events in elderly patients. TEE is a semi-invasive method that usually requires anesthesia and is unsuitable for screening potentially high-risk patients. It also does not reliably visualize the upper part of the ascending aorta and the proximal aortic arch. Tenenbaum and associates compared the effectiveness of TEE with that of unenhanced dual-helical computed tomography (CT) in diagnosing protruding aortic atheromas.
Thirty-two consecutive patients at least 50 years of age who had recent ischemic strokes, systemic emboli, or both were included in the study. All patients underwent assessment with both TEE and dual-helical CT.
TEE revealed a protruding aortic atheroma in 15 of the patients (47 percent). Dual-helical CT revealed protruding atheromas in 13 of the 15 patients with positive TEE scans (87 percent). The two remaining patients had negative CT scans.
In patients without evidence of atheromas on TEE, CT revealed the absence of atheromas (in areas defined as visible at TEE) in 14 patients and the presence of atheromas in three. Dual-helical CT had a sensitivity of 87 percent and a specificity of 82 percent, with an overall accuracy of 84 percent.
Of the 36 protruding aortic atheromas depicted with TEE, 34 were correctly identified with CT. Two noncalcified plaques remained undetected. Three nonprotruding aortic plaques depicted on TEE were diagnosed as protruding atheromas on CT. Of the 34 atheromas correctly identified with CT, 13 were located in the arch and 21 in the descending aorta.
The main finding of this study is the potential of CT to enable detection of a protruding aortic atheroma, particularly in the ascending aorta and the arch. Using dual-helical CT instead of the widely used single-section CT provides acquisition of data twice as quickly. The rapid CT technique enables examination of the ascending aorta and the arch during the holding of a single breath, preventing respiratory motion artifacts. This is critical for measuring and defining protruding atheromas.
The advantages of CT over TEE include its noninvasive character, its suitability for screening large populations and the possibility of complete visualization of the ascending aorta and the proximal arch. This permits evaluation of the location and extent of the plaque. Obvious disadvantages include the inability of CT to detect intracardiac sources of emboli. The authors suggest that positive unenhanced dual-helical CT should be followed by contrast material injection or TEE.
The authors conclude that despite some limitations, unenhanced dual-helical CT may become complementary and occasionally superior to TEE in the rapid, noninvasive detection of protruding aortic atheromas in areas not well visualized with TEE.
BARBARA APGAR, M.D., M.S.
Tenenbaum A, et al. Dual-helical CT for detecting aortic atheromas as a source of stroke: comparison with transesophageal echocardiography. Radiology July 1998; 208:153-8.
Estimation of Uterine Size by Bimanual Examination
Up to 40 percent of women of reproductive age in the United States develop uterine leiomyomas. This condition is reported to be the principal indication for approximately one third of all hysterectomies. The size of the uterus is the major determinant of symptoms, probability of surgery and choice of surgical procedure. The traditional assessment of uterine size relies on bimanual examination. Ultrasound examination is commonly used to confirm bimanual assessments, but it is not clear if ultrasound studies add to clinical information. Cantuaria and colleagues compared bimanual and ultrasonographic assessment of uterine size in patients with leiomyomas to clarify the role of ultrasonography.
A total of 111 women who underwent ultrasound examination before hysterectomy for uterine leiomyomas were retrospectively studied. Before the ultrasound examination, uterine size was estimated by bimanual examination performed by a senior resident and confirmed by an attending physician. The results of the bimanual examination were reported in terms of equivalent gestational size. Uterine dimensions on ultrasound were converted to equivalent gestational size using an established formula. Each uterus was weighed and measured after surgery.
On bimanual examination, uterine size estimations ranged from six to 25 weeks. In four patients, bimanual estimations were not possible because of obesity. The correlation between bimanual and ultrasound estimations was highly significant. Body mass index did not influence this correlation. Both bimanual and ultrasound estimates correlated with the actual size of pathologic specimens.
The authors conclude that routine ultrasound examination is not indicated when bimanual assessment of uterine leiomyomas is performed by an experienced examiner. Ultrasonography may provide useful information when bimanual examination and assessment are difficult, as in the case of extremely obese patients.
ANNE D. WALLING, M.D.
Cantuaria GH, et al. Comparison of bimanual examination with ultrasound examination before hysterectomy for uterine leiomyoma. Obstet Gynecol July 1998;92:109-12.
Use of Human Albumin in Critically Ill Patients
Human albumin is used in a range of medical and surgical patients in whom urgent restoration of blood volume is needed. Although human albumin is much more expensive than alternative solutions (twice the cost of hydroxyethyl starch and 30 times the cost of crystalloid solutions), it may help maintain the serum albumin concentration in critically ill patients. Previous studies have shown that the serum albumin concentration is inversely related to mortality. Each decrease of 2.5 g per L (3,790 µmol per L) in serum albumin concentration is associated with an increased risk of death of 24 to 56 percent. Because of concerns about the high cost and limited availability of human albumin, the Cochrane Injuries Group Albumin Reviewers performed an analysis of randomized clinical trials to quantify the effect on mortality of administering human albumin or plasma protein fraction during management of critically ill patients.
The reviewers identified 30 randomized controlled trials that met acceptable standards of quality. The studies included over 1,000 patients with burns, hypovolemia or hypoalbuminemia. The principal outcome measured was death.
Death occurred in 98 of 596 patients who received albumin, compared with 58 of 608 patients who received placebo. For pooled data, the relative risk of death after use of albumin was 1.68 (1.26 to 2.23). The relative risk of death was higher in each of the patient groups receiving human albumin but was highest in patients with burns. The relative risk of death was 2.40 (1.11 to 5.19) in burn patients receiving albumin solution, followed by patients with hypoalbuminemia, with a relative risk of death of 1.69 (1.07 to 2.67), and those with hypovolemia, with a relative risk of death of 1.46 (0.97 to 2.22) associated with albumin administration.
The authors conclude that the use of albumin may increase mortality in critically ill patients. The overall risk of death in patients who received albumin was increased by 6 percent. The authors found no evidence to support the previously reported protective effect of albumin, and they call for the use o
