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Folic Acid for the Prevention of Neural Tube Defects
The prevalence of major neural tube defects in the United States is estimated to be one per 1,000 births, equivalent to approximately 2,500 affected infants annually. International studies investigating the dramatic differences between the occurrence of neural tube defects in different populations concluded that the folic acid intake of mothers immediately before conception was a critical factor. Locksmith and Duff reviewed recent evidence to make recommendations regarding the optimal intake of supplemental folic acid to prevent neural tube defects.
The authors conducted a MEDLINE search using the terms "folic acid" and "neural tube defects" to identify 55 articles published between 1990 and 1997, including reviews, official recommendations, theoretical papers and studies of several different designs. Evidence that folic acid can prevent neural tube defects comes from results of large trials in countries where there is a high prevalence of neural tube defects. A British study of women who had previously given birth to children with neural tube defects demonstrated a 72 percent reduction in recurrence using 4 mg folic acid supplementation beginning four weeks before conception and continuing through the first trimester. In a Hungarian study of unselected women, there were no cases of neural tube defects in 2,104 infants born to mothers receiving 0.8 mg of folic acid, compared with six infants born with the defect in 2,052 mothers receiving a placebo.
Although the mechanism of action of folic acid in preventing neural tube defects is not well understood, it is believed to relate to homocysteine metabolism. With inadequate metabolism of folic acid, teratogenic levels of homocysteine could accumulate. Another theory suggests that folic acid acts by inducing the spontaneous abortion of fetuses with neural tube defects.
Folic acid is present in a variety of foods such as leafy green vegetables, legumes, liver, citrus fruits and whole wheat bread, but it is estimated that only 8 percent of adult women consume at least 0.4 mg of folic acid daily. Food sources must be converted in the upper small intestine for absorption; synthetic folic acid supplements actually offer better bioavailability than natural forms. The authors concur with official recommendations that women who may potentially become pregnant should consume at least 0.4 mg of folic acid daily. This may be achieved by taking a daily multivitamin supplement. It is recommended that women with previous offspring affected by neural tube defect take 4 mg of folic acid beginning at least one month before conception and continuing for the first three months of pregnancy. However, prenatal vitamins should not be the source for such a large dosage of folic acid because the number of tablets required would contain potentially dangerous levels of other components, especially vitamin A. Although they are at higher risk of having infants with neural tube defects, it is not recommended that women who are taking valproic acid or carbamazepine, or who have type 1 diabetes or a family history of neural tube defects take the higher dosage because the mechanism of their increased risk is unclear.
Since many pregnancies are unplanned and only one third of women consume multivitamins containing folic acid, fortification of flour has been considered as a way of preventing neural tube defects. Whether to expose the entire population to an intervention that would benefit relatively few women is an important consideration.
The authors conclude that women who plan to become pregnant should take folic acid supplements to reduce their risk of having infants with neural tube defects; however, the optimal dosage, timing and vehicle have yet to be established. For most women, a daily multivitamin with 0.4 to 0.8 mg of folic acid, beginning at least one month before conception and continuing through the first trimester, would be well advised.
ANNE D. WALLING, M.D.
Locksmith GL, Duff P. Preventing neural tube defects: the importance of periconceptional folic acid supplements. Obstet Gynecol June 1998;91:1027-34.
Treatment of Depression In Older Ambulatory Patients
Although five published meta-analysis studies and a consensus conference have concluded that pharmacologic and psychologic treatments for depression in the elderly are effective, the studies were performed on psychiatric inpatients with far more severe depression than is usually observed in the outpatient setting. McCusker and associates performed a meta-analysis to determine the effectiveness of acute pharmacologic and psychologic treatments of depression in older ambulatory patients.
A total of 40 quality ratings were performed on 37 studies (26 quality ratings were of pharmacologic treatments and 14 were of psychologic treatments). Most of the studies were performed in the United States. Among 12 comparisons of a heterocyclic drug with placebo, nine were statistically significant. Buspirone was significantly more effective than placebo in decreasing depressive symptoms, but alprazolam was not. Overall, antianxiety drugs were not significantly better than placebo and there was no significant heterogeneity. Among other randomized comparisons, significant benefits were found for fluoxetine, trazodone and phenelzine.
In the drug-drug comparisons, the mean differences were smaller than those in the placebo comparisons, and none was statistically significant. Significant heterogeneity was noted among the five comparisons of selective serotonin reuptake inhibitors (SSRIs) and heterocyclic drugs. With regard to the comparison of psychologic treatments and controls, none of the four comparisons of emotive treatments with untreated controls was significant. Five of the six comparisons of rational treatments with untreated controls were significant. Overall, rational treatments performed significantly better than untreated controls.
This meta-analysis demonstrated that in comparison with placebo, only heterocyclic drugs and SSRIs are effective in older ambulatory patients. The evidence for SSRIs is based on one study and is therefore less convincing than the evidence for heterocyclic drugs.
Most of the evidence of the effectiveness of SSRIs comes from comparisons with active treatment control subjects who received heterocyclic drugs. In the latter studies, the two classes of drugs appeared to be equally effective. However, these results must be tempered by the absence of a significant post-treatment difference in the severity of depression. Only three drug-placebo trials have been conducted in the primary care setting, only one of which found a treatment (fluoxetine) to be even marginally effective. For the psychologic treatments, rational therapies (cognitive or behavioral therapy) appeared more effective than emotive therapies. It seems that much of the effects of psychologic treatment can be attributed to the nonspecific effects of paying extra attention to older ambulatory patients during the sessions.
The authors conclude that heterocyclic antidepressants and rational psychologic therapies appear to be more effective treatments in older ambulatory patients with mild to moderate depression. Both SSRIs and heterocyclic drugs are effective, although the significance of the effectiveness is modest. Caution should be maintained because of the limitations of the quality and quantity of studies using active drug therapy, and physicians may want to consider using psychologic or attention interventions, particularly in patients with mild depressive symptoms.
BARBARA APGAR, M.D., M.S.
McCusker J, et al. Effectiveness of treatments of depression in older ambulatory patients. Arch Intern Med April 13, 1998;158:705-12.
Bisphosphonates and HRT for Postmenopausal Osteoporosis
Hormone replacement therapy is currently accepted as treatment for postmenopausal osteoporosis, with a 50 percent reduction in fractures, especially of the hip, related to this condition. Bisphosphonates are also known to increase bone mass. Wimalawansa conducted this randomized controlled trial to determine if there was a synergistic effect on bone mineral density when hormone replacement therapy and etidronate, a bisphosphonate, were used together in women with established postmenopausal osteoporosis.
Patients were excluded from the study if they had surgically-induced menopause or secondary osteoporosis, or if they had previously used medications that affect calcium metabolism. All 72 patients were encouraged to engage in mild exercise and to make lifestyle modifications as needed. All patients received 1 g of elemental calcium and 400 units of vitamin D daily. Three treatment groups and a control group were included in the study. The hormone replacement therapy group received 0.625 mg of premarin and 150 mg of norgestrel daily for 12 days each month; the etidronate group received 400 mg of etidronate daily for 14 days every 12 weeks; and the combined therapy group received hormone replacement therapy and etidronate in the above dosages.
To determine bone mineral density, patients had radiograph absorptiometric measurements of the spine and hip at baseline and at two and four years after beginning treatment. Lateral radiographs of the spine were also taken at baseline and at four years, to determine the occurrence of new vertebral fractures. Patients in the control group lost 0.9 percent of spinal bone mineral density at two years and 2.5 percent at four years. Patients in the hormone replacement therapy group and the etidronate group experienced no significant increases in spinal bone mineral density. In contrast, the combined therapy group showed a significant increase in spinal bone mineral density at year two and year four. Similarly, the patients in the combined treatment group had significant increases in hip bone mineral density at four years over the control and treatment groups. The combined treatment group also had a much lower fracture rate (17 per 1,000 patient years) when compared with the control group (89 per 1,000 patient years).
The author concludes that the combination of hormone replacement therapy plus etidronate can increase spinal and hip bone mineral density and prevent vertebral fractures in postmenopausal women with known osteoporosis. A long-term study is necessary to assess the impact on fracture rates.
GRACE BROOKE HUFFMAN, M.D.
Wimalawansa SJ. A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis. Am J Med March 1998;104:219-26.
Inaccuracies in Interpretation of Tuberculin Skin Tests
The tuberculin skin test is considered to be the best method of detecting tuberculosis in patients who have no clinical signs or symptoms of disease. The recommended test is the intradermal Mantoux test, which should be read by a health care professional 48 to 72 hours after application. The Centers for Disease Control and Prevention (CDC), the American Thoracic Society (ATS) consider a positive test to be one with an induration of 15 mm or more in patients with no identifiable risk factors for tuberculosis. The AAP concurs, except in children four years of age or younger. In these children, the American Academy of Pediatrics (AAP) requires an induration of 10 mm or greater. Kendig and colleagues performed an observational study to evaluate the ability of health care professionals to accurately interpret tuberculin skin tests.
An intermediate-strength Mantoux tuberculin skin test was applied to the forearm of an adult man with a history of pulmonary tuberculosis who was known to have a positive skin test. Approximately 64 hours after the Mantoux test was applied, 107 health care professionals were asked to interpret the patient's skin test. The readers were told nothing about the patient's history and assumed they were reading the skin test of a healthy person who "converted" after exposure to a patient with active tuberculosis. They were provided with a tape measure, a ruler and a ball-point pen and were asked to record the results, their initials and their professional designations.
The "gold standard" used for interpretation of the patient's skin test was an induration of 15 mm or more. Of the 52 pediatricians who read the test, 17 (33 percent) interpreted the induration as less than 10 mm. The readings ranged from 5 to 15 mm (median: 10 mm). Of the 33 pediatric residents, 10 (30 percent) read the test as less than 10 mm (range: 5 to 15 mm; median: 10 mm). Of the 12 registered nurses participating in the study, four (33 percent) read the test as less than 10 mm, and three read it as 15 mm or greater. Of the 10 participating academicians, four (40 percent) read the tuberculin skin test as less than 10 mm. Of all the participants, only eight (7 percent) correctly charted an induration of 15 mm or more.
The authors conclude that there is a marked tendency on the part of health care professionals to underread tuberculin skin tests. Even if the previous cutoff level of 10-mm induration had been used, 33 percent of the study participants would have failed to identify this patient's positive tuberculosis skin test. The authors suggest this tendency to underread raises some questions about the decision of the ATS, the CDC and the AAP to increase the positive induration measurement to 15 mm in low-risk adults and children.
In an accompanying editorial, Reichman regards the study as uncovering a "scandalous incompetence" and demands emergent intervention on the part of professional associations and regulatory bodies.
JEFFREY T. KIRCHNER, D.O.
Kendig EL Jr, et al. Underreading of the tuberculin skin test reaction. Chest May 1998;113:1175-7, and Reichman LB. A scandalous incompetence [Editorial]. Chest May 1998; 113:1153.
EDITOR'S NOTE: The results of this study should be quite disturbing, particularly to physicians who take care of high-risk patients or practice in areas where the prevalence of tuberculosis is high. Many offices and clinics depend on non-physician personnel to interpret the Mantoux tests of patients who return 48 to 72 hours after the test is applied. If health care workers are indeed missing up to 30 percent of patients with a positive test, the public health ramifications are significant. Many of these patients are theoretically at risk for progressing to active tuberculosis and may be candidates for isoniazid prophylaxis.--j.k.
Repaglinide: An Oral Agent for the Treatment of Type 2 Diabetes
Repaglinide, a new oral glucose-lowering agent for the treatment of type 2 diabetes, has received approval for use as a single agent or in combination with metformin. Medical Letter consultants review the current data on this drug.
While repaglinide is structurally different from sulfonylureas, it also binds to adenosine triphosphatesensitive potassium channels on pancreatic beta cells and increases the secretion of insulin. The drug is well absorbed when taken in the fasting state or with meals and reaches peak plasma levels within 30 to 60 minutes. It is rapidly metabolized in the liver and excreted mainly in the bile. Higher plasma concentrations may occur in patients with impaired hepatic function. As the serum repaglinide concentration increases, the plasma insulin level rises and usually returns to baseline before the next meal.
A clinical study of repaglinide therapy in patients already receiving a sulfonylurea demonstrated that the mean glycemic control was equivalent but that fasting glucose levels were lower with glyburide and postprandial peaks were lower with repaglinide. Repaglinide has been shown to be more effective when used with metformin than when either drug is used alone. Unpublished data indicate that 1 to 4 mg of repaglinide before meals lowers glycosylated hemoglobin by 1.3 to 1.9 percent.
Although no serious drug interactions have been reported with repaglinide, coadministration with ketoconazole, erythromycin and other drugs that are inhibitors of the cytochrome P450 3A4 enzyme system may increase serum concentrations of repaglinide.
The agent should also be used with caution in patients with impaired liver function. Although data are limited, repaglinide may not accumulate in patients with impaired renal function. Safety in pregnancy has not been determined.
Repaglinide is available as 0.5-, 1.0- and 2.0-mg tablets. The recommended starting dosage in patients who have not previously taken oral hypoglycemic drugs is 0.5 mg before each meal. If oral hypoglycemic agents have been used previously, the starting dosage may be 1 or 2 mg. The maximum dosage is 4 mg per meal for a maximum of four meals daily. If a meal is missed, that dose of repaglinide should be omitted.
BARBARA APGAR, M.D., M.S.
Medical Letter consultants. Repaglinide for type 2 diabetes mellitus. Med Lett Drugs Ther May 22, 1998; 40(1027):55-6.
Effects of Ultrasound Treatment in Carpal Tunnel Syndrome
The use of splints, local corticosteroid injections and surgical decompression has limited effectiveness in the treatment of carpal tunnel syndrome. Ultrasound therapy applied to the wrist may induce an anti-inflammatory effect that could provide relief of symptoms of carpal tunnel syndrome. Ebenbichler and colleagues conducted a controlled clinical trial to evaluate the use of ultrasound therapy in patients with mild to moderate bilateral carpal tunnel syndrome.
Patients in the study had been referred to an outpatient clinic for symptoms of carpal tunnel syndrome. The diagnosis was confirmed by clinical and electrophysiologic criteria, and other potential causes for the symptoms were excluded. Patients were randomly assigned to receive either active ultrasonic therapy or "sham" treatment under identical conditions. A total of 34 patients completed the study.
Ultrasound therapy was administered daily for 10 days, followed by twice-weekly treatments for five weeks. Corticosteroids and nonsteroidal anti-inflammatory drugs were prohibited, but analgesics were permitted for pain relief during the course of treatment. Discomfort was assessed with visual analog scales, and electroneurographic measurements were used to assess the effectiveness of therapy.
At the end of treatment, satisfactory improvement or complete remission of symptoms was noted in 23 of 34 wrists (68 percent) treated with ultrasound and in 13 of 34 wrists (38 percent) receiving sham treatment. Thirty of the 34 patients completed the six-month follow-up assessment. At that time, satisfactory improvement or complete relief of symptoms was noted in 74 percent of the actively treated wrists (22 of 30 wrists). This degree of improvement was noted in 20 percent of the wrists receiving sham treatment (six of 30 wrists).
Motor distal latency and velocity of sensory nerve conduction were both significantly improved in the active treatment group but remained unchanged in the sham group. Hand grip, finger-pinch strength and the patients' overall impressions were significantly better in the active treatment group, both immediately following therapy and at the six-month assessment. No side effects were reported, and use of analgesics was low.
The authors conclude that ultrasound therapy provides good short-term relief of symptoms in patients with moderate carpal tunnel syndrome and that the beneficial effects persist for at least six months. The authors state that further research is needed to determine optimal treatment schedules and to discover whether ultrasound treatment is superior to other forms of nonsurgical treatment, either alone or in combination with one of the nonsurgical treatments, or whether early decompression provides better long-term results.
ANNE D. WALLING, M.D.
Ebenbichler GR, et al. Ultrasound treatment for treating the carpal tunnel syndrome: randomised "sham" controlled trial. BMJ March 7, 1998;316:731-5.
Hepatitis C Virus Infection: Diagnosis and Treatment
Infection with the hepatitis C virus is often asymptomatic until liver disease has progressed to cirrhosis or hepatocellular carcinoma. The causative agent for hepatitis C virus was discovered in 1989. Recent studies show the overall prevalence of hepatitis C virus infection in the United States to be approximately 1.4 percent. About 89 percent of persons with hemophilia and about 0.5 percent of blood donors are infected with hepatitis C virus. Morton and Kelen discuss issues encountered in identification and treatment of patients with hepatitis C virus infection.
Hepatitis C is usually transmitted parenterally. The prevalence among intravenous drug users has been reported to be as high as 97 percent in some populations. Other modes of parenteral infection include tattoo needles, organ transplants, intravenous immuneglobulin and occupational exposure. Up to 40 percent of infected patients have no apparent parenteral risk factor. Transmission is thought to occur by sexual contact or by vertical transmission from mother to child. Transmission by simple household contact appears to be very rare.
About 2,200 health care workers seroconvert annually following occupational exposure. Four to 10 percent of persons who sustain a stick with a needle containing hepatitis Cinfected blood become infected with the virus. Antibodies to the proteins of hepatitis C virus allow diagnosis of infection using serologic assays. The variation in genotypes accounts for the possibility that a person may have multiple exposures to the hepatitis C virus, even to the original inoculum, and exhibit signs of acute hepatitis each time. Hepatic cellular damage during viral illness results from immunologic and, possibly, direct cytopathic effects.
The enzyme-linked immunosorbent assay (ELISA) has several limitations. Sensitivity was found to be only 81 to 89 percent, and seroconversion was detected an average of 15 to 20 weeks after exposure. Sensivity and specificity of the second-generation ELISA2 is much improved over the first-generation test, and seroconversion can be detected within one to six weeks after exposure. The second-generation recombinant immunoblot assay (RIBA2) is used as a confirmation test and correlates well with active viral activity. A third-generation RIBA test seems to offer a small improvement in accuracy. The best available diagnostic test for hepatitis C virus infection is reverse transcriptasePCR, which detects very low levels of virus in tissue and serum, and has a high sensitivity and specificity. However, this test is quite expensive and not widely available for routine diagnosis. Problems with reproducibility among laboratories has become a major issue. Flawless technique is key to the accuracy of results. Methods for quantitation of hepatitis C RNA recently became available. Currently, the best technique appears to be a combination of ELISA2 to diagnose and RIBA2 to confirm infection. Patients at high risk for hepatitis C virus infection and those with unexplained elevation of alanine transaminase levels should be evaluated.
Interferon-alfa2b is the current therapy for patients with hepatitis C infection, but long-term remission is achieved in fewer than 25 percent of those treated. Positive prognostic indicators include low total viral titer, less severe liver damage and fibrosis, low total body iron, and positive early response to interferon. Current dosage regimens are 3 million to 6 million U administered subcutaneously three times per week for six to 12 months. Ribavirin is another treatment that has been tried with variable success. When used in combination with interferon, it appears to delay relapse but does not appear to effect long-term clearance of hepatitis C virus. Although liver transplantation may eventually be required, reinfection occurs universally. Post-exposure prophylaxis with intravenous immune globulin shows no benefit. Currently, vaccination against hepatitis C virus does not exist.
RICHARD SADOVSKY, M.D.
Morton TA, Kelen GD. Hepatitis C. Ann Emerg Med March 1998;31:38190.
EDITOR'S NOTE: Screening for hepatitis C virus infection is clearly appropriate in high-risk persons and in persons with evidence of unexplained liver inflammation. Screening of asymptomatic lower-risk patients needs to be individualized. Benefits of screening include the possibility of counseling patients about healthier lifestyles, avoiding transmission and instituting appropriate monitoring for liver inflammation. These benefits must be balanced against patient anxiety and insurability. Universal screening for pregnant patients is not recommended because there is no available management plan that would reduce the rate of vertical transmission.
R.S.
Effects of Epidural Analgesia and Meperidine During Labor
Epidural analgesia has been associated with slower rates of cervical dilatation, longer labor and more frequent use of oxytocin augmentation, with increased rates of operative delivery. The American College of Obstericians and Gynecologists defines prolonged second stage of labor differently if epidural analgesia is used. Alexander and associates measured the effects of epidural analgesia compared with boluses of meperidine, using the same cohort from a previous similar trial.
Results of the previous study by this group were challenged because of the multiplicity of confounding variables such as parity, use of oxytocin and self-selection of the method of analgesia. These variables were minimized in the current trial. All of the 199 patients in the study were managed on a low-risk unit and delivered spontaneously at term. All of the women were nulliparous and received oxytocin for labor augmentation before the initiation of analgesia. Epidural analgesia was administered in 126 of the women; 73 women received bolus doses of meperidine. The two analgesia groups had the same cervical dilatation on admission (3.3 cm) and at the time of analgesia (4.1 cm), indicating similar progress of labor before oxytocin was initiated. All of the study subjects started at the same juncture of labor, were managed similarly and ended with the same method of delivery. However, the active phase of labor, the duration of the second stage and the admission-to-delivery intervals were all significantly prolonged in women who received epidural analgesia compared with those who received meperidine.
The pelvic examination at the time of epidural administration in the epidural group indicated that cervical dilatation was less than in patients at the time of oxytocin administration. Cervical dilatation was significantly more advanced in the epidural group before oxytocin augmentation than in the meperidine group. However, women with epidural analgesia received oxytocin for longer intervals and required more oxytocin to achieve each centimeter of cervical dilatation. All infants were live-born, and no deaths occurred during the neonatal period in either study group. Apgar scores, umbilical cord blood pH measurements and admission to the intensive care unit did not differ between the two analgesia groups.
Results demonstrated that uterine performance was reduced by epidural analgesia. This was reflected in the longer first and second stages of labor and an increased oxytocin requirement per centimeter of cervical dilatation. Although this study included women who self-selected their methods of analgesia, the analysis after removing these patients did not affect the results. Controlling for other variables known to be related to labor progression, such as parity, progress of labor up to administration of analgesia, oxytocin use and surgical intervention in labor, still demonstrated that epidural analgesia diminishes uterine performance and slows the progress of labor.
The authors conclude that the expectation of labor duration and rate of cervical dilatation should be modified when epidural analgesia is used. They indicate that perhaps when epidural analgesia is used, guidelines for management of the first stage of labor should be modified as they already have been for the second stage of labor. Modifying labor expectations as such may help to reduce the excessive rate of cesarean delivery associated with epidural analgesia.
BARBARA APGAR, M.D., M.S.
Alexander JM, et al. The course of labor with and without epidural analgesia. Am J Obstet Gynecol March 1998; 178:516-20.
EDITOR'S NOTE: Although epidural analgesia is associated with a longer duration of labor, increased use of oxytocin and increased dystocia, patient satisfaction is high because of the significant reduction in pain after epidural analgesia administration. Given the recent criticism that epidural analgesia increases the rate of operative delivery, it may be that readjusting our expectations for labor progress will allow more women to deliver vaginally with less pain.
B.A.
Neurologic Complications of Carotid Sinus Massage
Carotid sinus massage is recommended in the routine investigation of all older patients who have syncope, dizziness or unexplained falls. Twenty-three percent of unexplained falls are attributed to carotid sinus hypersensitivity, an abnormal response to carotid sinus massage characterized by either a significant heart rate slowing (more than three seconds asystole; cardioinhibitory type), a decrease in systolic blood pressure (more than 50 mm Hg; vasodepressor type) or a combination of both (mixed carotid sinus hypersensitivity). The massage technique involves applying longitudinal digital pressure at the bifurcation of the internal and external carotid artery for five seconds. This procedure is applied first to the right and then to the left side after 120 seconds. It is performed using a tilt table, with the patient in a supine position and tilted to 70 degrees. The risk of carotid sinus hypersensitivity increases with age. Davies and Kenny present incidence data of neurologic and cardiologic complications of carotid sinus massage in a large series of older patients evaluated for syncope or falls.
A total of 4,000 patients were evaluated using the technique described previously. Contraindications to carotid sinus massage include the presence of a carotid bruit, stroke or myocardial infarction within the previous six months, and a history of serious cardiac arrhythmia, ventricular tachycardia or ventricular fibrillation.
During the study, 11 patients had neurologic complications and no patients had a cardiac complication. Of the patients who experienced neurologic complications, 10 developed hemiparesis, three developed expressive dysphasia and one developed a hemianopia. Complications occurred within five minutes of massage in five patients, and at 10 minutes, 30 minutes and two hours after massage in the remaining patients. Computed tomographic head scan revealed new brain lesions in only two patients. A carotid Doppler ultrasound examination was performed in nine of the patients after the procedure; two patients showed greater than 70 percent contralateral diameter stenosis and another two patients showed greater than 30 percent contralateral diameter stenosis. Seven of the 11 patients had carotid sinus hypersensitivity. All had a significant vasodepressor response and one had a cardioinhibitory response. Nine patients made a full functional recovery, and seven of these patients recovered within 24 hours. Full recovery occurred in two patients within one month. Hemiparesis persisted in two patients.
The authors conclude that the incidence of neurologic complications following carotid sinus massage is low (0.28 percent) and that most patients make a full functional recovery.
RICHARD SADOVSKY, M.D.
Davies AJ, Kenny RA. Frequency of neurologic complications following carotid sinus massage. Am J Cardiol May 15, 1998;81:12567.
Four Criteria for Use in Detecting Stress Incontinence
Although the symptom complex alone is unreliable in the diagnosis of stress incontinence, a full urodynamic assessment may be distressing for patients and may cost more than $4,000. Videla and Wall conducted a retrospective chart review to evaluate the correlation between clinical findings and multichannel urodynamic testing to determine if simple criteria could be used to make a diagnosis of stress urinary incontinence.
The authors reviewed the charts of 652 women who presented for evaluation of symptoms suggestive of pelvic organ prolapse and urinary tract dysfunction. Four criteria were used to make a diagnosis of stress incontinence: urine loss during episodes of raised intra-abdominal pressure (sneezing, coughing or exercising); positive cough stress-test (observed spurt of urine on coughing); postvoiding residual bladder capacity of up to 50 mL; and functional bladder capacity of at least 400 mL. Women who met the criteria then underwent provocative multichannel urodynamic testing to confirm the diagnosis.
Of the 74 women who fulfilled these four criteria, 72 (97 percent) had stress incontinence demonstrated by urodynamic testing. One patient had normal test results, and one had uninhibited detrusor contractions.
The authors conclude that simple criteria based on history and clinical assessment are highly reliable in the diagnosis of stress urinary incontinence. They suggest that the role of complex urodynamic testing be re-examined.
ANNE D. WALLING, M.D.
Videla FL, Wall LL. Stress incontinence diagnosed without multichannel urodynamic studies. Obstet Gynecol June 1998;91:965-8.
Postoperative Cognitive Dysfunction in Elderly Patients
Although not extensively studied, both short- and long-term postoperative cognitive dysfunction are well-recognized problems in elderly patients. To evaluate the frequency of these problems and to identify possible risk factors, Moller and colleagues conducted a multicenter study to determine the occurrence of long-term postoperative cognitive dysfunction in patients 60 years of age and older.
The study included 1,218 elderly patients who underwent major abdominal or orthopedic surgery at 13 hospitals in eight European countries and the United States. The operations were performed between 1994 and 1996. Priority was given to patients undergoing elective abdominal and noncardiac thoracic surgery, and no more than one quarter of the cases from each hospital could be orthopedic. Patients were excluded if they had diseases of the central nervous system or low scores on the Mini-Mental State examination, were taking psychotropic medications or were not expected to be able to participate in follow-up assessments three months following surgery.
Neuropsychologic testing was performed on the day before surgery, one week after surgery or on discharge from the hospital (whichever was earlier) and three months after the surgery. Extensive demographic and physiologic data were collected on each patient, including continuous pulse oximetry data collected the night before and continuing for three days after the surgery. Blood pressure was measured every three minutes during surgery and every 15 to 30 minutes for 24 hours following surgery.
One week after surgery, cognitive dysfunction was documented in 266 of the patients (26 percent). At the second assessment three months after surgery, cognitive dysfunction was present in 94 of the patients (10 percent).
Factors that showed significant relationships to postoperative cognitive dysfunction at one week were increased age, a long duration of anesthesia, a low educational level, postoperative infection, respiratory complications and a second operation. Only increased age was related to dysfunction that persisted at least three months after surgery.
Although episodes of hypoxia and hypotension were frequently documented, no relationship was found between postoperative cognitive function and different degrees or durations of hypotension or hypoxia. Similarly, postoperative cognitive dysfunction was not related to factors such as the patient's physical status, lung disease, heart disease, hypertension, smoking status or sex. Nor was an association found between cognitive dysfunction and procedure-related variables such as type of anesthesia, use of an intensive care unit, amount of blood loss, type of procedure or drugs used.
The authors conclude that major surgical procedures cause cognitive decline in a significant proportion of elderly patients and that the risk increases with age. Even though relatively healthy persons were included in the study, significant cognitive decline was documented in 26 percent of the patients one week after surgery and in 10 percent three months after surgery. None of the variables studied except age appeared to be related to the occurrence of cognitive decline. The authors speculate that anesthetic effects on central neurotransmission, such as cholinergic and glutamatergic function, may be among the causes of cognitive dysfunction after major surgery in elderly patients.
ANNE D. WALLING, M.D.
Moller JT, et al. Long-term postoperative cognitive dysfunction in the elderly: ISPOCD1 study. Lancet March 21, 1998;351:857-61.
EDITOR'S NOTE: This study validates the frequent observation by patients and families that "they aren't quite as sharp as they were before the surgery." Many elderly patients have little margin of safety in maintaining daily survival in the community, and any cognitive decline can tip the balance into dependency. The finding that 10 percent of the patients had a measurable decline in cognitive function three months after surgery is very worrisome, especially since the study selected relatively healthy patients undergoing elective noncardiac surgery. Most worrisome of all is the lack of correlation with hypoxia and other conditions associated with cerebral circulation. The entire topic of subtle postoperative effects on patients of all ages warrants much further study. This study had a high dropout rate and provides relatively little information about the types or severity of cognitive decline. Ethically, do we now tell elderly patients considering hip replacement, for example, that there might be a 10 percent chance of a decline in cognition, or do we wait for further studies?
A.D.W.
Spontaneous Vaginal Delivery and Risk of Erb's Palsy
Erb's palsy results from injury to the fifth and sixth cervical nerve roots and is commonly associated with shoulder dystocia. Although approximately 80 percent of Erb's palsies resolve in three to six months, the 1 to 5 percent of cases that persist one year after delivery are usually the focus of litigation. Because Erb's palsy may occur without shoulder dystocia, the risk factors are not defined. Gherman and associates evaluated cases of Erb's palsy occurring in the absence of shoulder dystocia to see if they differ from those occurring after shoulder dystocia.
During the two-year study period, 126 cases of shoulder dystocia were identified among 9,071 vaginal deliveries. Among vertex-presentation fetuses, 40 cases of Erb's palsy were found. Seventeen cases of Erb's palsy without shoulder dystocia were compared with 23 cases associated with shoulder dystocia. Among the fetuses with shoulder dystocia, the risk of Erb's palsy was 18.3 percent (of which 1.6 percent had permanent injury). The only variable that differed between the two study groups was an increased incidence of second-stage length greater than 15 minutes among those without antecedent shoulder dystocia.
Neonates with Erb's palsy not associated with shoulder dystocia displayed a trend toward smaller birth weights and were more likely to have clavicular fractures. The affected Erb's palsy was more likely to occur in the anterior delivered shoulder with an identified shoulder dystocia, compared with the posterior arm when there was no shoulder dystocia. Erb's palsies without shoulder dystocia took longer to resolve and were more likely to persist at one year of age. Six of the seven persistent injuries occurred in infants weighing less than 4,000 g (8 lb, 13 oz). Both permanent injuries occurred in term macrosomic fetuses. The first case was associated with a four-hour second stage.
Results of this study demonstrate that most "no-shoulder" Erb's palsies do not represent underreporting of shoulder dystocia, and that not all cases are related to excessive traction on the nerve roots. The most important study result was the significantly higher rate of persistence found among cases of Erb's palsy without shoulder dystocia. There were also two instances of transient facial nerve palsy associated with brachial plexus injury. These observations suggest that pressure of the fetal cheek and shoulder against the symphysis pubis produced the injuries, rather than traction on the fetal head; as many as 50 percent of brachial plexus injuries can result from unavoidable intrapartum or antepartum events.
The authors concluded that Erb's palsy occurring without shoulder dystocia is a distinct entity and demonstrated that permanent brachial plexus injuries may occur before actual delivery of the fetal head. Attempts to recognize the at-risk fetus may not be successful.
BARBARA APGAR, M.D., M.S.
Gherman RB, et al. Spontaneous vaginal delivery: a risk factor for Erb's palsy? Am J Obstet Gynecol March 1998;178:423-7.
Review of Antibacterial Drugs for Treatment of Infections
Medical Letter consultants last reviewed the antimicrobial agents for treatment of bacterial infections in 1996. Because new drugs have emerged and new information about older agents is now available, recommendations are discussed again.
Pneumonia. In some areas of the United States, more than 30 percent of isolates of S. pneumoniae, the most common cause of community-acquired pneumonia, are relatively or highly resistant to penicillin and sometimes to cephalosporins. Haemophilus influenzae, Klebsiella pneumoniae, legionellae and tuberculosis infection should be considered in the differential diagnosis. In hospitalized patients, cefotaxime, ceftriaxone or high doses of penicillin administered intravenously are reasonable first choices.
Vancomycin may be required for highly resistant strains. In ambulatory patients, an oral macrolide (erythromycin, azithromycin or clarithromycin), doxycycline or a fluoroquinolone such as levofloxacin is recommended. Hospital-acquired bacterial pneumonia, often caused by gram-negative bacilli such as Klebsiella, should be initially treated with a third-generation cephalosporin, cefepime, ticarcillin/clavulanic acid or imipenem--with or without an aminoglycoside. In the intensive care unit, where Pseudomonas aeruginosa is common, imipenem or meropenem plus an aminoglycoside would be a good first choice of therapy.
Meningitis. The organisms most commonly responsible for bacterial meningitis are Streptococcus pneumoniae and Neisseria meningitidis. In adults and children older than two months, cefotaxime or ceftriaxone is recommended, plus vancomycin (with or without rifampin) to cover resistant pneumococci. Vancomycin and rifampin are stopped if the organism is found to be susceptible to cephalosporins. In patients who are allergic to penicillin, vancomycin (with or without rifampin) can be used for treatment of resistant pneumococci. In children, administration of dexamethasone before or at the same time as the first dose of antibiotics to decrease the incidence of hearing loss and neurologic complications remains a matter of controversy. However, it is recommended if the meningitis is due to H. influenzae. Because of the high incidence of group B streptococci in newborns, ampicillin plus cefotaxime, with or without gentamicin, is usually recommended.
Sepsis Syndrome. The third- or fourth-generation cephalosporins can be used to treat sepsis caused by many strains of gram-negative bacilli. The initial treatment should include either a third- or fourth-generation cephalosporin, ticarcillin/clavulanic acid, piperacillin/tazobactam, imipenem or meropenem--each with an aminoglycoside. If methicillin-resistant staphylococci are suspected, vancomycin is often recommended. If anaerobes are suspected in intra-abdominal or pelvic infections, treatment with ticarcillin-clavulanic acid, ampicillin-sulbactam, or cefoxitin or cefotetan, each with or without an aminoglycoside, is recommended.
Urinary Tract Infection. Uncomplicated urinary tract infections can be effectively treated with oral trimethoprim-sulfamethoxazole or fluoroquinolone. A three-day course is usually sufficient. For repeated infections, a fluoroquinolone, oral amoxicillin-clavulanic acid or an oral third-generation cephalosporin can be effective. Hospitalized patients may need an aminoglycoside in addition to the standard regimens.
BARBARA APGAR, M.D., M.S.
Medical Letter consultants. The choice of antibacterial drugs. Med Lett Drugs Ther March 27, 1998;40(1023): 33-42.
EDITOR'S NOTE: Medical Letter has produced a comprehensive guide to the antibacterial agents used to treat common infections. A list of trade names is included. For each of the infecting organisms, the drug of choice and alternatives are recommended. A cost analysis is also presented. It is a handy reference for any clinician.
B.A.
Preexposure Vaccination Regimens to Prevent Rabies
Adequate preexposure vaccination for rabies allows persons who may later be exposed to rabies virus to be protected by receiving only two postexposure doses of vaccine. Although the World Health Organization and the Centers for Disease Control and Prevention recommend a three-dose preexposure series of vaccinations, countries such as Britain and France have introduced two-dose vaccination schedules. Strady and colleagues conducted a prospective study to determine the long-term immunity results of both two- and three-dose schedules for the two most commonly used rabies vaccines.
The study included 312 French volunteers who were at risk for rabies because of their profession. After screening for contraindications to vaccination, the participants were randomly assigned to receive either the human diploid cell rabies vaccine or the purified Vero cell rabies vaccine. Each vaccine group was further divided into a two-injection group or a three-injection group. Persons in the two-injection group were vaccinated on days zero and 28. The three-injection protocols included an additional vaccination on day seven. All patients received a booster vaccination at one year. Blood was drawn for antibody levels before the first injection and at day 42. Antibody levels were also checked one year after the primary series, 14 days following the booster dose and once per year for 10 years to assess the evolution of immunogenicity.
The only significant difference in the four study groups at baseline was the mean age of participants. However, this was not believed to influence the immunogenicity of the vaccines. All subjects seroconverted by day 42. The mean antibody titer was significantly higher in patients on the three-dose schedules than in those on the two-dose schedules. Both vaccines performed well when given in three-dose schedules, and there were no significant differences between the different vaccines in the three-injection schedule. When the two-dose schedules were compared, workers receiving purified Vero cell rabies vaccine had significantly lower mean antibody titers and more rapid decline in titers. Workers who received the three-injection schedules plus a booster at one year developed protective antibodies for at least 10 years. For both types of vaccines, the three-shot schedule plus a booster given at one year provided protection for up to 10 years in 96 percent of patients who were followed. Patients who did not develop such protection could be reliably identified by measurement of their antibody responses two weeks after the one-year booster injection (day 379).
The authors recommend that high-risk patients receive either type of rabies vaccination using a schedule of three injections plus a booster at one year. Antibody testing should be performed two weeks after the booster dose, and patients with antibody levels of less than 30 IU per mL should receive booster rabies vaccination every three years. High-risk patients with antibody levels of 30 IU per mL or greater following the booster dose may be revaccinated every 10 years.
ANNE D. WALLING, M.D.
Strady A, et al. Antibody persistence following preexposure regimens of cell-culture rabies vaccines: 10-year follow-up and proposal for a new booster policy. J Infect Dis May 1998;177:1290-5.
Fenoldopam for Parenteral Treatment of Severe Hypertension
Fenoldopam, a peripheral dopamine-1 agonist, is labeled by the U.S. Food and Drug Association for parenteral treatment of severe hypertension. The drug induces arteriolar vasodilation mainly through stimulation of dopamine-1 receptors. Fenoldopam leads to an increase in renal blood flow. It also has direct natriuretic and diuretic properties mediated through effects on renal tubular cells, particularly in patients with hypertension. Medical Letter consultants review the information on this agent.
An intravenous infusion of fenoldopam produces effects in about five minutes, and plasma concentrations reach a steady state in about 20 minutes. The drug is metabolized in the liver and excreted in the urine. The plasma elimination half-life is about five minutes.
In a randomized trial of 153 patients, fenoldopam was found to be as effective as sodium nitroprusside in the treatment of severe hypertension (patients with diastolic pressure of 120 mm Hg or higher). Fenoldopam produced a dose-response reduction in arterial pressure for up to 24 hours, without evidence of tolerance, rebound on withdrawal of the agent or significant changes in the heart rate. However, partial tolerance over time has been observed in smaller studies. Fenoldopam has been shown to improve renal function in some patients with severe hypertension and renal impairment. Other studies have demonstrated that fenoldopam maintained or increased urine output better than nitroprusside in patients with postoperative hypertension following cardiac and noncardiac surgery.
Fenoldopam has been used in the treatment of congestive heart failure in a few patients. Although it decreased peripheral resistance and increased cardiac output in these patients, the increases in cardiac output were not accompanied by consistent reductions in pulmonary wedge pressure or right atrial pressure. The diuretic effects observed in hypertensive patients did not consistently occur in patients with congestive heart failure.
The most common adverse effects of fenoldopam are related to its vasodilatory properties. Hypotension, flushing, dizziness, headache and tachycardia have all occurred, along with nausea and hypokalemia. Fenoldopam increases intraocular pressure and should be used cautiously in patients with glaucoma.
Significant drug interactions have not been reported. Metabolism of fenoldopam does not involve the cytochrome P450 system. However, the natriuretic and diuretic properties could lead to worsening volume depletion, especially in some patients receiving diuretics. Concomitant use of beta-adrenergic blockers could inhibit reflex tachycardia in response to fenoldopam and result in severe hypotension. The safety of fenoldopam when used with beta blockers remains to be established.
Fenoldopam is diluted in normal saline or a 5 percent dextrose solution and given as a continuous infusion, usually for 48 hours or less, without a bolus dose. The effective dosage range is 0.1 to 1.6 µg per kg per minute. Although lower starting dosages produce less reflex tachycardia, the blood pressure response may be ineffective or only modestly effective. The dosage is titrated upward in increments of 0.05 to 0.1 µg per kg per minute at 15-minute intervals until blood pressure is controlled. The predominant effect of any dosage is usually apparent within 15 minutes. When blood pressure is stabilized, oral antihypertensive therapy can be started. The fenoldopam infusion can either be stopped abruptly or tapered.
BARBARA APGAR, M.D., M.S.
Medical Letter consultants. Fenoldopam--a new drug for parenteral treatment of severe hypertension. Med Lett Drugs Ther May 22, 1998;40(1027):57-8.
Features of Allergic Fungal Sinusitis on CT Scan
Allergic fungal sinusitis is considered to be the most common form of fungal sinusitis. Accurate diagnosis is important because treatment of allergic fungal sinusitis is substantially different from treatment of other types of fungal sinusitis. Mukherji and associates examined computed tomographic (CT) findings in patients with surgically proven allergic fungal sinusitis to further characterize the clinical features of this disease.
The diagnosis of allergic fungal sinusitis in these patients was based on accepted criteria. All of the patients had the characteristic endoscopic finding of allergic mucin and fungal hyphae identified by light microscopy. The presence of allergic mucin, primarily composed of eosinophils, is considered to be highly suggestive of the diagnosis. Of the 45 patients included in the study, 27 were male. Thirty-one patients lived in warm, humid climates, and 14 lived in drier climates. The presenting clinical complaints were nonspecific and consisted of symptoms of chronic sinusitis. Six of the patients had proptosis secondary to extension into the retrobulbar region.
Unenhanced CT scans in each patient revealed increased intrasinus attenuation within the mucosal opacification. Mucosal thickening was visualized in any of the sinuses, but the ethmoid sinus complex was the most commonly involved sinus. At least one ethmoid sinus complex demonstrated infection in 43 (96 percent) of the patients. The next most commonly involved region was the maxillary sinus, which harbored infection in 42 patients (93 percent). Only two patients had disease limited to one sinus.
Unilateral involvement was present in 22 patients (49 percent); the right side was affected in 15 of these patients and the left side in the remaining seven patients. Complete opacification of at least one sinus was found in 44 (98 percent) of the patients. Of these 44 patients, 41 (93 percent) had erosion of a sinus wall. Nine patients (20 percent) had evidence of disease extending into adjacent structures. Each of these nine patients had bony erosion, and three had both intraorbital and intracranial disease extension.
The authors conclude that the CT findings suggestive of a diagnosis of allergic fungal sinusitis included complete unilateral or bilateral opacification of multiple paranasal sinuses, extension beyond the sinus and erosion of a wall of the involved sinus and scattered areas of high attenuation amid mucosal thickening. Bilateral sinus involvement is common in patients with advanced disease. The authors note that the degree of bony erosion and extension beyond a sinus may mimic aggressive sinonasal neoplasms. The presence of increased internal attenuation on unenhanced CT scans may help to distinguish allergic fungal sinusitis from an invasive tumor. The presence of expansion and thinning of the sinus walls may help separate allergic fungal sinusitis from chronic sinusitis of other origins.
BARBARA APGAR, M.D., M.S.
Mukherji SK, et al. Allergic fungal sinusitis: CT findings. Radiology May 1998;207:417-22.
Evaluation of Unilateral Breast Masses in Men
Breast cancer in men is rare, accounting for approximately 1 percent of all cases of breast cancer. Differentiating cancer from the many other causes of breast enlargement in men is problematic, resulting in the usual recommendation to biopsy all lesions. Vetto and colleagues conducted a diagnostic test study and cost-effectiveness analysis to assess the combination of physical examination and fine-needle aspiration in the diagnosis of breast masses in men as an alternative to routine surgical biopsy.
The authors studied 51 men referred to three breast clinics between 1991 and 1996. Each patient was examined by at least two skilled physicians and underwent fine-needle aspiration in triplicate. Mammography was performed before referral in 13 of the patients. Patients with breast masses that were assessed as benign were followed for up to 60 months (mean: 19 months). Patients with masses suspicious for cancer were referred for open surgical biopsy. In 38 patients, all tests concurred that the lesion was benign. None of these patients developed cancer during the follow-up period. In six patients, the tests concurred that the lesion was malignant, and this finding was confirmed at open biopsy. In seven patients, physical examination and fine-needle aspiration provided different assessments. All of the masses were found to be benign at open biopsy. Fine-needle aspiration was more likely than physical examination to correctly predict the results of the open biopsy.
The authors conclude that the combination of physical examination and fine-needle aspiration performed by experienced physicians is diagnostically accurate, can significantly reduce the number of open biopsies and is associated with an average decrease in patient charges of $510 per patient.
ANNE D. WALLING, M.D.
Vetto J, et al. Accurate and cost-effective evaluation of breast masses in males. Am J Surg May 1998;175:383-7.
Immunization Guidelines for International Travelers
Each year more than 20 million Americans travel abroad to rural areas or developing countries. Assessing an international traveler's risks will ensure that the proper immunizations are given. Thanassi reviews a six-step approach (see the accompanying table) to the immunization consultation.
Six-Step Approach to Assessing the Immunization Needs of International Travelers
- Special needs of the traveler
- Routine childhood immunization status
- Routine travel immunization status
- Entry requirements of the country being visited
- Geographically indicated vaccinations
- Immunizations indicated for an extended stay abroad
Information from Thanassi WT. Immunizations for international travelers. West J Med 1998;168:197-202.When evaluating the special immunization needs of travelers, consideration must be given to older people, pregnant women, children and immunocompromised persons. For healthy elderly persons, as well as for travelers with chronic obstructive pulmonary disease and asthma, a one-time pneumococcal vaccine and an annual influenza immunization should be administered. Older adults who are taking gastric acid blockers should be considered for cholera vaccination when traveling to an endemic area. In pregnant or immunocompromised travelers, live-virus vaccines (such as those for measles, mumps, rubella [MMR], oral polio and yellow fever) and attenuated live vaccines (such as oral typhoid) are contraindicated. Immunization requirements for children are similar to those for adults, although it is important to remember that yellow fever vaccine is absolutely contraindicated in children younger than four months of age and generally contraindicated in those younger than nine months.
Adults who have not completed their routine series of childhood immunizations should receive "catch-up" vaccinations for tetanus-diphtheria, MMR and poliovirus. Vaccination for varicella is appropriate for nonimmune travelers. A tetanus booster should be given to any traveler who has not been appropriately vaccinated within five years. A one-time adult polio booster is appropriate for travelers to developing countries in the Eastern Hemisphere.
The three most common tropically acquired febrile illnesses in returning travelers are hepatitis A, typhoid fever and malaria. Influenza also carries a high morbidity. Immunization for hepatitis A should be provided to travelers going outside developed areas. Typhoid vaccine should be administered to those staying in endemic areas for over two weeks. Influenza vaccine is appropriate when travelers are visiting an area during its influenza season.
Entry requirements of the country to be visited may require yellow fever vaccination, which is strongly recommended for travelers to South America and rural areas of equatorial Africa. A booster is needed only once every 10 years. Geographically indicated immunizations include cholera for persons traveling to tropical Africa, Asia and South America (although the cholera vaccine is only 50 percent effective) and meningococcus for those traveling to Nepal, northern India, Saudi Arabia and the "meningitis belt" across sub-Saharan Africa. Tick-borne encephalitis, which occurs in the forests of Europe and the former Soviet Union, can be contracted from a carrier tick between April and August. Immunization for this condition is not available in the United States but can be obtained in Europe. For overseas stays of more than one month, the traveler should consider immunization against hepatitis B, Japanese encephalitis, rabies and, in certain circumstances, the plague (Yersinia pestis).
The author concludes that general guidelines for immunization of international travelers are helpful, but that the individual needs of specific travelers vary.
RICHARD SADOVSKY, M.D.
Thanassi WT. Immunizations for international travelers. West J Med March 1998;168:197-202.
EDITOR'S NOTE: Recommendations for vaccination before travel vary depending on the source. Cholera risk, for example, is very low, and this vaccine is generally not recommended for most tourists. The availability of both an oral typhoid vaccine as well as a parenteral preparation gives clinicians more choices in administration routes. More detailed information is available in Health Information for International Travel, published biannually by the Centers for Disease Control and Prevention (CDC). Up-to-date automated information is available from the CDC (telephone: 888-232-3228) or on the Internet at www. cdc.gov under "Traveler's Health."
R.S.
Cost-effective Immunization Against Hemophilus Influenzae
The incidence of invasive infection attributed to Hemophilus influenzae type b (Hib) has been dramatically reduced in industrialized countries as a result of immunization with conjugate vaccines. Because a single dose of Hib vaccine costs more than the combined cost of all other vaccines routinely given in the first two years of life, protocols reducing the cost without compromising the efficacy of Hib immunization are important, particularly in developing countries. Lagos and colleagues conducted a randomized trial comparing the immunogenic response in Chilean infants given vaccination regimens other than the three standard doses of Hib vaccine.
The study included healthy infants presenting to public clinics for immunization. Infants with low birth weight (less than 2,500 g [5 lb, 8 oz]), a major chronic disease, a congenital condition, a known immunologic disorder or contraindication to vaccination were excluded from the study. Two Hib vaccines that were commercially available in Chile were used: polysaccharide-tetanus toxoid conjugate vaccine (PRP-T) and oligosaccharide-diphtheria mutant toxoid conjugate vaccine (PRP-CRM). The infants were randomly allocated to one of eight vaccination regimens. The regimens included three full doses, three fractional doses consisting of one half or one third of the full dose, and a regimen of two full doses. The infants in the three-dose regimens were vaccinated at two, four and six months of age, and the infants in the two-dose regimens were vaccinated at four and six months of age. For each of the Hib vaccines, approximately 78 infants received two full doses, 78 infants received three full doses, 78 infants received three vaccinations containing one half of the standard dose and 78 infants received three vaccinations containing one third of the standard dose. Levels of antibody to type b capsular polysaccharide were measured in all infants at eight months of age. Levels of 0.15 µg per mL or higher were regarded as seroprotective.
All four regimens of the PRP-T vaccines produced seroprotective levels in at least 93 percent of the infants. The highest geometric mean antibody concentration, 6.3 µg per mL, resulted from the two full-dose regimen, followed by 5.3 µg per mL for the three one-half dose regimen; 5.0 µg per mL for the three one-third dose regimen and 3.8 µg per mL for the standard three-dose regimen. Seroprotective antibody levels were achieved using the PRP-CRM vaccine in 93, 91 and 94 percent of the infants receiving three full doses, three one-half doses and three one-third doses, respectively. Two doses of full-strength vaccine produced seroprotection in 87 percent of the infants. The highest geometric mean antibody level for PRP-CRM vaccines was 3.2 µg per mL, occurring in infants receiving three full doses of the vaccine. Other levels were 3.1 µg per mL for infants receiving three half doses and 2.0 µg per mL for infants receiving two full doses. By 12 months of age, 84 to 93 percent of the infants who had received PRP-T vaccines and 77 to 92 percent of those receiving PRP-CRM vaccines still had seroprotective levels of antibodies, but the geometric mean antibody concentration had dropped substantially in all groups. When challenged with unconjugated PRP polysaccharide, antibody concentrations rose substantially, with the lowest rise being sixfold. These increases were particularly marked for nonstandard doses of PRP-T.
The authors conclude that three vaccinations with one half or one third of the standard dose provide equivalent or superior seroprotection against Hib compared with standard doses. This correlates with other studies, which stress that the optimal antigen dose must be neither too low nor too high, since excessive doses may cause "high tolerance." Two-dose regimens, although the least satisfactory, still provided substantial protection in this study and could be useful in endemic areas. The authors believe this study has implications for improving the efficacy and reducing the cost of immunization against Hib in all countries.
ANNE D. WALLING, M.D.
Lagos R, et al. Economisation of vaccination against Haemophilus influenzae type b: a randomised trial of immunogenicity of fractional-dose and two-dose regimens. Lancet May 16, 1998;351:1472-6.
"Tips from Other Journals" are written by the medical editors of American Family Physician.
Copyright © 1998 by the American Academy of Family Physicians.
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