Paul Visintainer

Duration of antibiotic therapy for early Lyme disease. A randomized, double-blind, placebo-controlled trial.

Context Optimal antibiotic treatment for patients with early Lyme disease is unclear. Contribution This single-center randomized, double-blind, placebo-controlled trial found that patients with erythema migrans given any of the follwoing regimens had high response rates, defined as resolution of erythema migrans and symptoms at 30 months: 20 days of doxycycline, 83.9%; 10 days of doxycycline, 90.3%; and 10 days of doxycycline plus a single intravenous dose of ceftriaxone, 86.5%. Patients given doxycycline plus ceftriaxone more often had diarrhea than patients given doxycycline alone. Implications Oral doxycycline alone for 10 days is sufficient treatment for patients with early Lyme disease that manifests as erythema migrans. The Editors Although Lyme disease is the most common vector-borne disease in the United States (1), the appropriate duration of treatment for its most common manifestation, erythema migrans, remains unclear. A small open-label prospective study reported in 1983 found that outcome did not improve when tetracycline therapy was extended from 10 days to 20 days (2). However, most recent treatment trials have used antibiotic regimens of approximately 3 weeks (3-5), and some authorities recommend 20 to 30 days of therapy (6). This change in practice has occurred in the absence of additional prospective studies on the duration of treatment and is a source of ongoing controversy. Another uncertain issue in the management of patients with erythema migrans is whether Borrelia burgdorferi, the etiologic agent, has disseminated to the central nervous system at the time of presentation (7). If so, the outcome of therapy might be enhanced by treatment with a parenteral agent such as ceftriaxone, which readily crosses the bloodbrain barrier. To address these concerns, we conducted a placebo-controlled study comparing 10 days of doxycycline with both 10 days of doxycycline plus one dose of ceftriaxone and 20 days of doxycycline. Methods Patients at least 16 years of age who had erythema migrans and satisfied the U.S. Centers for Disease Control and Preventions surveillance definition of Lyme disease (an annular erythematous skin lesion 5 cm in diameter) (8) entered the study between 1992 and 1994. Volunteers were recruited primarily through the walk-in Lyme Disease Diagnostic Center at the Westchester Medical Center, Valhalla, New York. Exclusion criteria included pregnancy or lactation, allergy to a tetracycline or a -lactam antibiotic, receipt of antibiotic treatment for Lyme disease for more than 48 hours before enrollment, meningitis or advanced heart block, or any underlying conditions that might interfere with evaluability or follow-up. All patients gave written informed consent, and the institutional review board at New York Medical College approved the study protocol. Patients were randomly assigned to one of three treatment groups: 1) a single 2-g dose of intravenous ceftriaxone followed by 10 days of oral doxycycline capsules twice daily, then by 10 days of oral placebo capsules [cornstarch], identical in appearance to the doxycycline capsules, twice daily; 2) a placebo injection [5% dextrose] followed by 10 days of oral doxycycline, 100 mg twice daily, and then by 10 days of oral placebo twice daily; or 3) a placebo injection followed by 20 days of oral doxycycline twice daily. Since ceftriaxone is yellow, infusion bags were kept covered to maintain masking. The pharmacy dispensed study medications in accordance with a randomization schedule that was based on a computer-generated random-number code with a permuted block size of 9. Clinical staff involved in recruitment of participants or in assessing clinical outcomes were isolated from the allocation process and blinded to treatment assignment. Randomization was stratified by whether patients were symptomatic (defined as having any systemic symptoms or having multiple erythema migrans lesions) or asymptomatic (defined as having a single erythema migrans lesion and no systemic symptoms). This was done to ensure that patients who may have had dissemination of B. burgdorferi were equally represented in the three treatment groups. Evaluation Trained study personnel interviewed participants and performed physical examination at baseline and 10 days, 20 days, 3 months, 6 months, 12 months, 24 months, and 30 months after initiation of therapy. If appointments were missed, patients were interviewed by telephone; however, this occurred in fewer than 5% of patient interactions. A neurologist performed complete neurologic examination at baseline, 20 days, 3 months, 12 months, 24 months, and 30 months. At 18 months, an evaluation was conducted by telephone. Structured questionnaires using both closed- and open-ended questions were used. Symptom scores were recorded on a visual analogue scale (9). A blood sample was obtained for serologic testing (enzyme-linked immunosorbent assay) at all visits. Complete blood count was determined and serum chemistries were performed at baseline, day 10, and day 20. Electrocardiography was done at baseline and was repeated if results were abnormal. Patients were considered unevaluable if they did not adhere to study medication. Nonadherence was defined as taking fewer than 90% of prescribed capsules or not returning pill containers at the 10- or 20-day visit, receiving an intercurrent antibiotic within the first 20 days, not meeting study inclusion criteria, or not attending follow-up visits after the baseline visit. Patients who had an intercurrent episode of erythema migrans due to reinfection were considered unevaluable from that point onward. Outcome was characterized as complete response, partial response, or failure. Early treatment response was assessed at 20 days. At this time, complete response was defined as resolution of erythema migrans and associated symptoms and return to preLyme disease health status. Partial response was defined as resolution of erythema migrans but incomplete resolution or development of subjective symptoms. Failure was defined as the occurrence of any one of the following during the first 20 days: no clinical improvement by day 10; recurrence of erythema migrans; recurrence of fever attributed by the study physician to Lyme disease; development of new objective rheumatologic, cardiac, or neurologic manifestations of Lyme disease that were not present within the first 10 days; or the occurrence of meningitis, advanced heart block, or other objective manifestation of Lyme disease requiring intravenous therapy. Late response was evaluated at 3 months, 12 months, and 30 months. Complete response was defined as no recurrence of erythema migrans or associated symptoms and the continued absence of objective rheumatologic, cardiac, or neurologic manifestations of Lyme disease, with return to preLyme disease health status. Partial response was defined as no recurrence of erythema migrans and the continued absence of objective manifestations of Lyme disease, but incomplete resolution or development of subjective symptoms of uncertain cause. Failure was defined as the occurrence of objective manifestations of Lyme disease. Safety Assessment Drug safety was monitored by recording adverse events (solicited by open-ended semi-structured interview) and results of laboratory tests during treatment. Neurocognitive Evaluation At baseline, 12 months, and 30 months, a psychologist performed neurocognitive testing consisting of the Booklet Categories Test, the California Verbal Learning Test, the Wechsler Memory ScaleRevised, the Block Design Test, the Trail Making Test (Parts A and B), the Boston Naming Test, the Symbol Digit Modalities Test (written and oral), the Beck Depression Inventory, and the Symptom Checklist-90Revised. Healthy volunteers without a history of Lyme disease were recruited to serve as controls for the psychiatric interview and the neuropsychological testing. Spouses were preferred as controls since they were usually similar to the patients in age, socioeconomic level, and place of residence. Controls were 27 persons with a mean age (SD) of 42.6 15.2 years; 22% were men. Statistical Analysis Groups were compared by using one-way analysis of variance for continuous variables and the chi-square test for categorical variables (two-tailed). Data were analyzed both for participants who adhered to the study protocol and on an intention-to-treat basis. Patient blinding was evaluated at the 30-month visit by using the chi-square test and the statistic (10). For the neuropsychological tests, analysis of variance techniques were used to examine differences among treatment and control groups. For analysis of raw test scores, analysis of covariance was used, controlling for the effects of age, sex, and education. Test scores that were normalized to population standards (11-19) were analyzed by using one-way analysis of variance. For all analysis of variance models, residual plots were generated to verify adequate model fit. In the few situations in which test scores were not normally distributed or model fit was questionable, nonparametric procedures (the KruskalWallis test) or conventional transformations were applied. For categorical results, the chi-square test or the Fisher exact test was used. If the treatment variable in the global tests achieved the liberal cut-point of a P value less than 0.10, pairwise comparisons were conducted. In these instances, the Bonferroni adjustment was applied to the P value to control for multiple comparisons. Sample size was based on the estimated frequency of postLyme disease syndrome, defined as an array of subjective symptoms, such as fatigue, arthralgias, or myalgias, that may occur after infection. It was assumed that 30% of patients receiving the least effective treatment would develop postLyme disease syndrome. A more effective treatment was assumed to reduce the rate to 5%. Using an level of 0.05, two-tailed testing, and a Bonferroni multiple compari

Obstetric antecedents of intraventricular hemorrhage and periventricular leukomalacia in the low-birth-weight neonate☆☆☆★

OBJECTIVE Neonatal intraventricular hemorrhage and periventricular leukomalacia have a strong correlation with eventual neurologic deficit. Our objective was to correlate obstetric factors with the development of these lesions. STUDY DESIGN Seven hundred forty-five consecutive inborn neonates with birth weights from 500 to 1750 gm were divided into three clinical groups: premature rupture of membranes, refractory preterm labor with intact membranes, and delivery initiated by the physician for maternal or fetal indications. Neonatal neurosonography was performed on days 3 and 7 of life and results were described as normal or abnormal. Abnormal scans included intraventricular hemorrhage seen within 3 days and echodense or echolucent periventricular leukomalacia seen within 7 days of life. Major abnormalities included intraventricular hemorrhage grades 3 and 4, intraventricular hemorrhage with periventricular leukomalacia, and echolucent periventricular leukomalacia. Abnormal scans were correlated with groups of origin and clinical and histologic chorioamnionitis. RESULTS Abnormal scans occurred in 33% of cases of premature rupture of membranes and in 38.9% of cases of preterm labor compared with 17.7% of physician-initiated cases (p < 0.000001). Major lesions occurred in 17.6% of cases of premature rupture of membranes, 21.4% of cases of preterm labor, and 1.1% of physician-initiated cases (p < 0.0000001). Clinical chorioamnionitis occurred in 19.7% of cases of premature rupture of membranes, 11.9% of cases of preterm labor, and 1.1% of physician-initiated cases (p < 0.001) and was associated with a significant increase in the incidence (p < or = 0.005) and severity (p < or = 0.007) of these lesions. Histologic chorioamnionitis occurred in 59.9% of cases of premature rupture of membranes, 43.2% of cases of preterm labor, and 8% of physician-initiated cases and did not correlate significantly with the incidence or severity of abnormal scans. These findings were independent of gestational age. CONCLUSIONS The incidence and severity of intraventricular hemorrhage and periventricular leukomalacia were significantly increased in premature rupture of membranes and preterm labor compared with the physician-initiated cases. Clinical chorioamnionitis increased the incidence and severity of these lesions.

High Flow Nasal Cannulae Therapy in Infants with Bronchiolitis

OBJECTIVES To determine whether the introduction of heated humidified high-flow nasal cannulae (HFNC) therapy was associated with decreased rates of intubation for infants <24 months old with bronchiolitis admitted to a pediatric intensive care unit (PICU). STUDY DESIGN A retrospective chart review of infants with bronchiolitis admitted before and in the season after introduction of HFNC. RESULTS In the season after the introduction of HFNC, only 9% of infants admitted to the PICU with bronchiolitis required intubation, compared with 23% in the prior season (P=.043). This 68% decrease in need for intubation persisted in a logistic regression model controlling for age, weight, and RSV status. HFNC therapy resulted in a greater decrease in respiratory rate compared with other forms of respiratory support, and those infants with the greatest decrease in respiratory rate were least likely to be intubated. In addition, median PICU length of stay for children with bronchiolitis decreased from 6 to 4 days after the introduction of HFNC. DISCUSSION We hypothesize that HFNC decreases rates of intubation in infants with bronchiolitis by decreasing the respiratory rate and work of breathing by providing a comfortable and well-tolerated means of noninvasive ventilatory support.

Open-ring imaging sign Highly specific for atypical brain demyelination

Objective: To test the specificity for demyelination of a new neuroimaging sign: contrast enhancement shaped as an open ring or a crescent circumscribed to the white matter. Background: Brain demyelination can cause ring enhancement mimicking neoplasm or infection on CT or MRI. Methods: A MEDLINE search of pathology-proved demyelination yielded 32 illustrated cases of ring-enhancing lesions published between 1981 and 1995. Controls consisted of the same number of published images of neoplasms and infections, pathology proved, and matched by year of publication, and age and gender of the patient. Two neuroradiologists read the images twice independently 1 year apart. Results: Interrater agreement was good (κ = 0.64 and 0.66 for either reading). Test-retest reliability was high (κ = 0.75 and 0.74 for either rater). The open-ring sign clearly distinguished demyelinating lesions from neoplasms and infections. For demyelination versus neoplasm or infection, the specificity of the reading by the first neuroradiologist was 93.8 (95% CI, 86 to 98), and that of the second was 84.4 (95% CI, 74 to 92). The likelihood ratio of demyelination versus neoplasm averaged 5.2, and versus infection, 17.2. That is, if the lesions had the same incidence in the population, in the presence of an open-ring sign demyelination would be five times more likely than neoplasm and 17 times more likely than infection. However, given the much higher incidence of neoplasms and infections, these lesions are still frequently responsible for open-ring enhancement. Conclusions: The open-ring sign is often present in large, contrast-enhancing demyelinating lesions and helps to differentiate them from neoplasms and infections.

Histologic chorioamnionitis, antenatal steroids, and perinatal outcomes.

Objective To determine the perinatal effects of histologic chorioamnionitis on preterm neonates and the effectiveness of antenatal steroids in the presence of histologic chorioamnionitis. Methods We studied neonates at our institution who weighed 1750 g or less at birth from January 1990 through December 1997. The population was stratified primarily by presence of histologic chorioamnionitis and secondarily by exposure to antenatal steroids. Subgroups were compared by various perinatal outcomes and confounding variables. Student t test, χ2, Fisher exact test, and logistic regression were used for analysis. Results Among 1260 neonates entered, the placentas of 527 had evidence of histologic chorioamnionitis and 733 did not. Those with histologic chorioamnionitis had a lower mean gestational age, lower birth weight, and higher rate of major neonatal morbidities than those without it. After adjusting for confounding variables, histologic chorioamnionitis independently associated with lower gestational age, lower birth weight, and neonatal death. Among neonates exposed to antenatal steroids who had histologic chorioamnionitis, there was a significantly lower incidence of low Apgar scores (18% compared with 33.5%, P < .001), respiratory distress syndrome (RDS) (39.6% compared with 55.9%, P < .001), intraventricular hemorrhage and periventricular leukomalacia (21.9% compared with 36.9%, P < .001), major brain lesions (7.7% compared with 18.4%, P < .001), patent ductus arteriosus (14.8% compared with 23.7%, P = .018), and neonatal death (8.3% compared with 16.2%, P = .02), with no increase in rate of proven neonatal sepsis (18.3% compared with 14%, P = .24). Conclusion Histologic chorioamnionitis increases major perinatal morbidity through its association with preterm birth and is independently associated with neonatal death. In the presence of histologic chorioamnionitis, antenatal steroids significantly decreased the incidence of RDS, intraventricular hemorrhage and periventricular leukomalacia, major brain lesions, and neonatal mortality, without increasing neonatal sepsis.

Increased Risk for Anaphylactoid Reaction from Contrast Media in Patients on β-Adrenergic Blockers or with Asthma

OBJECTIVE To determine whether greater risk for anaphylactoid reaction from intravenous urographic contrast media exists in patients receiving beta-adrenergic blockers or in asthmatic patients. DESIGN Case-control study. SETTING Tertiary care, referral-based medical center. PATIENTS Of 28,978 intravenous urographic contrast media procedures done from July 1987 to June 1988, 49 patients experienced moderate to severe anaphylactoid reaction. Medical records from these 49 reactors were compared with those from a control group matched for gender, age, and date and type of contrast study who received intravenous urographic contrast media without adverse reaction. MAIN RESULTS Patients exposed to beta-adrenergic blockers or with asthma comprised 39% (19 of 49) of reactors, compared to 16% (13 of 83) of matched controls (odds ratio, 3.43; 95% CI, 1.45 to 8.15; P = 0.005). Exposure to beta-blockers was 27% among reactors and 12% in matched controls (odds ratio, 2.67; CI, 1.01 to 7.05; P = 0.036). Asthma was found in 12% of reactors and 4% of controls; after correction for beta-blocker use, asthma was also associated with increased risk for anaphylactoid reaction (odds ratio, 4.54; CI, 1.03 to 20.05; P = 0.046). Compared with nonasthmatic patients not taking beta-blockers, asthmatic patients were at greater risk for anaphylactoid reaction with bronchospasm (P = 0.02). Five of 13 reactors receiving beta-blockers became hypotensive, and three needed hospitalization. Compared with nonasthmatic patients not taking beta-blockers, patients exposed to beta-blocking drugs were almost nine times (odds ratio, 8.7; CI, 0.81 to 93.5; P = 0.075) more likely to be hospitalized after an anaphylactoid reaction. CONCLUSION Increased risk for moderate to severe anaphylactoid reaction from intravenous urographic contrast media exists in patients receiving beta-adrenergic blockers or with asthma. These patients are appropriate target populations for efforts to reduce risk before intravenous urographic contrast media are administered.

Association of necrotizing enterocolitis with anemia and packed red blood cell transfusions in preterm infants

Objective:To determine association of anemia and red blood cell (RBC) transfusions with necrotizing enterocolitis (NEC) in preterm infants.Study Design:A total of 111 preterm infants with NEC ⩾stage 2a were compared with 222 matched controls. In all, 28 clinical variables, including hematocrit (Hct) and RBC transfusions were recorded. Propensity scores and multivariate logistic regression models were created to examine effects on the risk of NEC.Result:Controlling for other factors, lower Hct was associated with increased odds of NEC (odds ratio (OR)=1.10, P=0.01). RBC transfusion has a temporal relationship with NEC onset. Transfusion within 24 h (OR=7.60, P=0.001) and 48 h (OR=5.55, P=0.001) has a higher odds of developing NEC but this association is not significant by 96 h (OR=2.13, P=0.07), post-transfusion.Conclusion:Anemia may increase the risk of developing NEC in preterm infants. RBC transfusions are temporally related to NEC. Prospective studies are needed to better evaluate the potential influence of transfusions on the development of NEC.

Clinical and hematologic effects of hydroxyurea in children with sickle cell anemia

PURPOSE This open-label pilot study was designed (1) to determine the effect of hydroxyurea on the hemoglobin level in children with sickle cell anemia, (2) to evaluate the toxicity of hydroxyurea, and (3) to assess any impact of hydroxyurea on the frequency of vaso-occlusive crises (VOCs). PATIENTS AND METHODS Ten children (group 1) with three or more VOCs of the extremities or two or more VOCs of the lungs (acute chest syndrome) in the preceding 12 months, and five children (group 2) with hemoglobin levels less than 70 gm/L were treated with hydroxyurea in doses of 20 to 35 mg/kg per day. The frequency of VOCs before hydroxyurea therapy was compared with the frequency during therapy, and the peak hemoglobin levels during hydroxyurea therapy were compared with the pretreatment values. RESULTS One patient in group 1 was removed from the study within 1 month because of nausea. Seven of the remaining nine patients in group 1 had a decrease in the frequency of VOCs. The number of VOCs per patient-year for all 14 patients decreased from 2.5 before hydroxyurea therapy to 0.87 during hydroxyurea therapy, a decrease of 65% (p < 0.00001). Two of five patients in group 2 had an increase in hemoglobin of 27 gm/L and 34 gm/L over the baseline. The median rise in hemoglobin was 19 gm/L (range, 7 to 37) for all 14 patients. Nine patients are still receiving hydroxyurea for a median period of 23 months (range, 18 to 59). CONCLUSIONS Hydroxyurea decreases the severity of anemia in some patients, and it may decrease the frequency of VOC. Its short-term hematologic toxicity is minimal.

Effectiveness of antenatal steroids in obstetric subgroups

OBJECTIVE To determine the effectiveness of antenatal steroids in the reduction of neonatal morbidity and mortality in obstetric subgroups of preterm labor with intact membranes, preterm premature rupture of membranes (PROM), and pregnancy-associated hypertension. The secondary objective was to determine the effect of antenatal steroids in appropriate for gestational age (AGA) and growth-restricted neonates. METHODS We studied the neonatal outcomes for all women who delivered infants weighing 1750 g or less at birth between January 1990 and July 1997 at our institution. The study population was divided primarily into three clinical groups: preterm labor with intact membranes, PROM, and pregnancy-associated hypertension. Secondarily, the total population was divided based on birth weight and gestational age into AGA and growth-restricted neonates. Within each obstetric subgroup, neonates exposed to antenatal steroids were compared with unexposed neonates for respiratory distress syndrome (RDS), intraventricular hemorrhage and periventricular leukomalacia, the incidence of major brain lesions, necrotizing enterocolitis, proved neonatal sepsis, patent ductus arteriosus, and neonatal death. The subgroups were also compared for gestational age at delivery, birth weight, birth weight percentile, Apgar scores, postnatal surfactant exposure, and clinical and histologic chorioamnionitis. Descriptive statistics, Student t test, chi2, Fisher exact test, and logistic regression were used for analysis. RESULTS A total of 1148 neonates weighing 1750 g or less were delivered during the study period. There were 447 and 410 neonates delivered after preterm labor with intact membranes and PROM, respectively, and 245 neonates born to mothers with pregnancy-associated hypertension. Nine hundred twenty-eight neonates were AGA and the remaining 220 neonates were growth restricted. Antenatal steroids significantly decreased the incidence of RDS, the incidence and severity of intraventricular hemorrhage and periventricular leukomalacia, necrotizing enterocolitis, and neonatal mortality in preterm labor with intact membranes. In the presence of PROM, it significantly decreased the incidence and severity of intraventricular hemorrhage and periventricular leukomalacia and decreased neonatal mortality, with no apparent effect on the incidence of RDS. Antenatal steroids did not show any beneficial effect in pregnancy-associated hypertension and fetal growth restriction (FGR). Additionally, a significant increase was observed in the incidence of proved neonatal sepsis when antenatal steroids were used in pregnancy-associated hypertension. CONCLUSION The effectiveness of antenatal steroids varies with the obstetric population studied. Antenatal steroids significantly decreased the incidence of major neonatal morbidity and mortality in the AGA preterm neonate delivered after preterm labor with intact membranes. Antenatal steroids did not show any benefit in cases of pregnancy associated with maternal hypertension or FGR. Its effect in the presence of PROM is limited to a significant reduction in the incidence and severity of intraventricular hemorrhage and periventricular leukomalacia and in neonatal death.

The open ring. A new imaging sign in demyelinating disease.

Because demyelinating disease of the brain occasionally presents with large ring‐enhancing lesions on computed tomography (CT) scans and magnetic resonance images (MRis), the authors sought to determine whether the ring pattern differed from that found in other common brain lesions with ring enhancement. Published MRI and CT scans of patients with adrenoleukodystrophy (23), and multiple sclerosis or similar demyelinating disorders (21), as well as a variety of tumors (44) and infections (44) matched to the demyelinating lesions by year of publication, in which ring enhancement was evident, were photographed. Photographs without diagnostic identification were presented randomly to two independent observers. The observers rated the contrast enhancement pattern as (1) open ring, with enhancement in the border of the lesion abutting the white matter; (2) closed ring; or (3) uncertain. For all diagnostically certain cases (n = 112), interrater agreement was excellent (κ = 0.75). As an average of the two reviewers, scans for 11 of 132 cases were read as uncertain; 89% of adrenoleukodystrophy cases, 41% of the multiple sclerosis cases, 3% of tumors, and 9% of infections were classified as having the open‐ring pattern. Overall, 66% of demyelinating lesions had an open‐ring pattern compared with 7% of the nondemyelinating lesions (χ2 = 41.2, p < 0.0001 ). An open‐ring pattern of enhancement is more likely to be associated with demyelinating lesions than with nondemyelinating lesions .