Thirty-one isolates from France and Spain were genotyped using a published method analyzing DNA s... more Thirty-one isolates from France and Spain were genotyped using a published method analyzing DNA sequence variation in open reading frame (ORF) 22, together with an evaluation of three well-characterized single nucleotide polymorphisms (SNP) in ORF 38, 54, and 62. Nineteen were allocated to the European (E) genotype, six were mosaic-1 (M1), and two were mosaic-2 (M2). Four strains were assigned to a new genotype, mosaic-4 (M4). All isolates were wild type, with no Oka vaccine-associated markers. No isolates of the mosaic-3 (M3) or Japanese (J) genotype were observed. We also evaluated 13 selected isolates of E, J, M1, and M2 strains (9 of the 31 described above) using an alternative genotyping method based on the assessment of multiple SNP located in ORF 1, 9, 10, 21, 31, 50, 54, 62, and 68. This method assigns wild-type varicella-zoster virus (VZV) strains to seven genotypes: A1, A2, J1, B1, B2, C, and C1. VZV isolates identified as E (ORF22 method) had the genetic signature of genotype C VZV strains, M1 strains were A1, and M2 were A2. No J strains were detected, but parental Oka and vaccine Oka (genotype J) corresponded to genotype J1. M4 isolates (B) share the SNP array observed for M1 and E viruses, and probably represent recombinants between African-Asian (M1) and European (E) viruses. The two genotyping methods, using entirely different genomic targets, produced identical clusters for the strains examined, suggesting robust phylogenetic linkages among VZV strains circulating in Europe.
Thirty-one isolates from France and Spain were genotyped using a published method analyzing DNA s... more Thirty-one isolates from France and Spain were genotyped using a published method analyzing DNA sequence variation in open reading frame (ORF) 22, together with an evaluation of three well-characterized single nucleotide polymorphisms (SNP) in ORF 38, 54, and 62. Nineteen were allocated to the European (E) genotype, six were mosaic-1 (M1), and two were mosaic-2 (M2). Four strains were assigned to a new genotype, mosaic-4 (M4). All isolates were wild type, with no Oka vaccine-associated markers. No isolates of the mosaic-3 (M3) or Japanese (J) genotype were observed. We also evaluated 13 selected isolates of E, J, M1, and M2 strains (9 of the 31 described above) using an alternative genotyping method based on the assessment of multiple SNP located in ORF 1, 9, 10, 21, 31, 50, 54, 62, and 68. This method assigns wild-type varicella-zoster virus (VZV) strains to seven genotypes: A1, A2, J1, B1, B2, C, and C1. VZV isolates identified as E (ORF22 method) had the genetic signature of genotype C VZV strains, M1 strains were A1, and M2 were A2. No J strains were detected, but parental Oka and vaccine Oka (genotype J) corresponded to genotype J1. M4 isolates (B) share the SNP array observed for M1 and E viruses, and probably represent recombinants between African-Asian (M1) and European (E) viruses. The two genotyping methods, using entirely different genomic targets, produced identical clusters for the strains examined, suggesting robust phylogenetic linkages among VZV strains circulating in Europe.
Thirty-one isolates from France and Spain were genotyped using a published method analyzing DNA s... more Thirty-one isolates from France and Spain were genotyped using a published method analyzing DNA sequence variation in open reading frame (ORF) 22, together with an evaluation of three well-characterized single nucleotide polymorphisms (SNP) in ORF 38, 54, and 62. Nineteen were allocated to the European (E) genotype, six were mosaic-1 (M1), and two were mosaic-2 (M2). Four strains were assigned to a new genotype, mosaic-4 (M4). All isolates were wild type, with no Oka vaccine-associated markers. No isolates of the mosaic-3 (M3) or Japanese (J) genotype were observed. We also evaluated 13 selected isolates of E, J, M1, and M2 strains (9 of the 31 described above) using an alternative genotyping method based on the assessment of multiple SNP located in ORF 1, 9, 10, 21, 31, 50, 54, 62, and 68. This method assigns wild-type varicella-zoster virus (VZV) strains to seven genotypes: A1, A2, J1, B1, B2, C, and C1. VZV isolates identified as E (ORF22 method) had the genetic signature of genotype C VZV strains, M1 strains were A1, and M2 were A2. No J strains were detected, but parental Oka and vaccine Oka (genotype J) corresponded to genotype J1. M4 isolates (B) share the SNP array observed for M1 and E viruses, and probably represent recombinants between African-Asian (M1) and European (E) viruses. The two genotyping methods, using entirely different genomic targets, produced identical clusters for the strains examined, suggesting robust phylogenetic linkages among VZV strains circulating in Europe.
Two cumulative doses of salbutamol delivered by metered dose inhaler (MDI) with a pear-shaped spa... more Two cumulative doses of salbutamol delivered by metered dose inhaler (MDI) with a pear-shaped spacer were compared (400 I~g vs 600 I~g at 10-minute intervals). Twenty-two patients (mean age 35.1 -+ 11.1 years) with acute exacerbation of asthma were randomly assigned, in a doubleblind fashion, to receive salbutamol delivered with MDI into a spacer device in 4 puffs at 10-minute intervals (100 I~g or 150 Fg per actuation) during 3 hours (1200 t~g or 1800 I~g each 30 minutes). Mean peak expiratory flow rate (PEFR) and forced expiratory volume in the first second (FEVl) improved significantly over baseline values for both groups (P < .001). Nevertheless, there were no significant differences between both groups for PEFR and FEVI at any time point studied. A significant net reduction of heart rate was observed in the 400 ~g group (P < .01). On the other hand, a significant increase in heart rate was observed in the 600 iLg group (P < .001). The QTc interval did not show a significant prolongation, and the two groups presented moderate decreases of serum potassium levels. There was a significant dose-related increase (P = .027) in Sao2. Additionally, the 600 ~g group generated a serum glucose level increase from 0.85 + 0.12 mg/100 mL to 1.04 + 0.25 mg/100 mL (P = .02). At the end of treatment, the salbutamol plasma levels were 10.0 -+ 1.67 ng/mL for the 400 I~g group, and 14.0 + 2.17 for the 600 Izg group (P = .001). Finally, the overall symptom score in patients in the 600 ~g group was significantly greater than the score in the low dose group (P = ,02), with a higher incidence in 4 symptoms (tremor, headache, palpitations, and anxiety). These data support the notion that the treatment of acute asthma patients in the emergency department setting with salbutamol, 2.4 rag/h, delivered by MDI and spacer (4 puffs at 10-minute intervals) produces satisfactory bronchodilation, low serum concentration, and minimal extrapulmonary effects, However, an increase of 50% of the dose (600 p,g at 10-minute intervals) produced a nonsignificant, slightly better therapeutic response but with greater side effects, probably related to higher salbutamol levels.
Data from studies using the factor analysis technique have shown that asthma appears to be multid... more Data from studies using the factor analysis technique have shown that asthma appears to be multidimensional and that most of the subjective and objective measures utilized in the assessment of asthma patients represent a much smaller number of underlying dimensions. Additionally, several investigators have emphasized that evaluation of acute asthma is an ongoing process, as the degree and time course of the response to therapy vary considerably between patients. The aim of this study was to examine the usefulness of the most common clinical and objective measures in the evaluation of acute asthma in the emergency department (ED) for predicting the outcome of acute episodes in adults.
This randomized, double-blind trial was designed to determine the benefit of high and cumulative ... more This randomized, double-blind trial was designed to determine the benefit of high and cumulative doses of flunisolide added to salbutamol in patients with acute asthma in the emergency room (ER). Ninety-four patients who presented to an ER for treatment of an acute exacerbation of asthma were assigned in a randomized, double-blind fashion to receive salbutamol and placebo (n = 47) or salbutamol combined with flunisolide (n = 47). Both drugs were administered successively through a metered-dose inhaler and spacer at 10-min intervals for 3 h (400 microg of salbutamol and 1 mg of flunisolide every 10 min). In both groups, FEV1 and peak expiratory flow rate (PEFR) improved significantly over baseline values (p &amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). Results in the flunisolide group were significantly different from those in the placebo group at 90, 120, 150, and 180 min. Data analyzed separately in accord with the duration of the attack before presenting at the ER (&amp;amp;amp;amp;amp;amp;amp;amp;lt; 24 or &amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 24 h) showed that the placebo &amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 24 h group produced a significantly lower FEV1 at 120, 150, and 180 min (p = 0.041) than did the remaining groups. Our data support the theory that high and cumulative doses of inhaled flunisolide administered by metered-dose inhaler with spacer and added to salbutamol are an effective therapy for patients with acute asthma and a prolonged duration of symptoms before ER presentation.
Current Therapeutic Research-clinical and Experimental, 1993
Abstract In severe acute asthma, beta-agonist bronchodilator aerosols are the standard first line... more Abstract In severe acute asthma, beta-agonist bronchodilator aerosols are the standard first line of treatment. More controversial are the method of delivery and the dose. The purpose of this study was to compare the efficacy of salbutamol delivered by jet nebulizer with that of ...
Two cumulative doses of salbutamol delivered by metered dose inhaler (MDI) with a pear-shaped spa... more Two cumulative doses of salbutamol delivered by metered dose inhaler (MDI) with a pear-shaped spacer were compared (400 I~g vs 600 I~g at 10-minute intervals). Twenty-two patients (mean age 35.1 -+ 11.1 years) with acute exacerbation of asthma were randomly assigned, in a doubleblind fashion, to receive salbutamol delivered with MDI into a spacer device in 4 puffs at 10-minute intervals (100 I~g or 150 Fg per actuation) during 3 hours (1200 t~g or 1800 I~g each 30 minutes). Mean peak expiratory flow rate (PEFR) and forced expiratory volume in the first second (FEVl) improved significantly over baseline values for both groups (P < .001). Nevertheless, there were no significant differences between both groups for PEFR and FEVI at any time point studied. A significant net reduction of heart rate was observed in the 400 ~g group (P < .01). On the other hand, a significant increase in heart rate was observed in the 600 iLg group (P < .001). The QTc interval did not show a significant prolongation, and the two groups presented moderate decreases of serum potassium levels. There was a significant dose-related increase (P = .027) in Sao2. Additionally, the 600 ~g group generated a serum glucose level increase from 0.85 + 0.12 mg/100 mL to 1.04 + 0.25 mg/100 mL (P = .02). At the end of treatment, the salbutamol plasma levels were 10.0 -+ 1.67 ng/mL for the 400 I~g group, and 14.0 + 2.17 for the 600 Izg group (P = .001). Finally, the overall symptom score in patients in the 600 ~g group was significantly greater than the score in the low dose group (P = ,02), with a higher incidence in 4 symptoms (tremor, headache, palpitations, and anxiety). These data support the notion that the treatment of acute asthma patients in the emergency department setting with salbutamol, 2.4 rag/h, delivered by MDI and spacer (4 puffs at 10-minute intervals) produces satisfactory bronchodilation, low serum concentration, and minimal extrapulmonary effects, However, an increase of 50% of the dose (600 p,g at 10-minute intervals) produced a nonsignificant, slightly better therapeutic response but with greater side effects, probably related to higher salbutamol levels.
We conducted a randomized, double-blind, placebo-controlled study to determine if intravenous ami... more We conducted a randomized, double-blind, placebo-controlled study to determine if intravenous aminophylline adds any benefit to high doses of inhaled salbutamol in patients who presented for treatment of acute asthma. We studied 94 patients (mean age, 35.6 +/- 11.2 years) with moderate to severe acute asthma. All patients received therapy with salbutamol delivered with metered-dose inhaler (MDI) into a spacer device (Volumatic) in four puffs (400 micrograms) at 10-min interval, and intravenous hydrocortisone (500 mg). Patients were randomly assigned to receive either a loading dose of intravenous aminophylline followed by a routine infusion (n = 45) or an equal volume of placebo as a loading dose and infusion (n = 49). The two groups showed no differences in measurements of peak expiratory flow, FEV1, and FVC at baseline and at the end of treatment. However, the patients treated with aminophylline had significantly more adverse effects (p &amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). There were no differences in the final mean dose of salbutamol (6.3 +/- 44.5 mg for the placebo group and 5.8 +/- 4.2 mg for the aminophylline group), hospital admission rate (10.2 percent for the placebo group and 9.0 percent for the aminophylline group), and mean duration of Emergency Department treatment (2.5 +/- 1.83 h for the placebo group and 2.37 +/- 1.75 h for the aminophylline group). The results were similar when the patients were divided in accord with the degree of respiratory obstruction (baseline FEV1 &amp;amp;amp;amp;amp;amp;amp;amp;lt; 30 percent of predicted) and theophylline level at 30 min of treatment (placebo group patients with theophylline level &amp;amp;amp;amp;amp;amp;amp;amp;lt; 10 mg/L vs aminophylline group patients with theophylline level &amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 10 mg/L). We conclude that intravenous aminophylline adds to the toxicity but not the efficacy of inhaled salbutamol in the treatment of acute exacerbations of asthma.
Data from studies using the factor analysis technique have shown that asthma appears to be multid... more Data from studies using the factor analysis technique have shown that asthma appears to be multidimensional and that most of the subjective and objective measures utilized in the assessment of asthma patients represent a much smaller number of underlying dimensions. Additionally, several investigators have emphasized that evaluation of acute asthma is an ongoing process, as the degree and time course of the response to therapy vary considerably between patients. The aim of this study was to examine the usefulness of the most common clinical and objective measures in the evaluation of acute asthma in the emergency department (ED) for predicting the outcome of acute episodes in adults.
To examine the main therapeutic response patterns to high doses of salbutamol and to determine th... more To examine the main therapeutic response patterns to high doses of salbutamol and to determine the factors that contribute to outcome in acute severe asthma. The emergency department (ED) of a large, urban hospital with primary and referral care responsibilities. One hundred sixteen consecutive patients with acute exacerbations of asthma were enrolled in the trial, using a prospective sequential design. All patients were treated with salbutamol delivered with a metered-dose inhaler into a spacer device in four puffs (400 microg) at 10-min intervals. The protocol involved 3 h of this treatment (1,200 microg each 30 min). A dose-response increase in pulmonary function was found, but only 70% improved sufficiently to be discharged. Of these, almost 70% required &amp;amp;amp;amp;amp;amp;amp;amp;lt; or =2.4 mg of the drug within 1 h to reach the discharge threshold, whereas the remainder 30% need &amp;amp;amp;amp;amp;amp;amp;amp;gt; or =3.6 mg. In 30% of subjects, salbutamol was ineffective. These patients were characterized by a more severe disease as judged by previous beta2-agonist use, larger duration of attack before ED visit, and a more severe obstruction at presentation. However, the most important predictors of outcome were peak expiratory flow rate (PEFR) as percent of predicted, PEFR as liters per minute, and PEFR variation over baseline value, all at 30 min. This study described two different therapeutic response patterns to salbutamol. Almost 70% of patients were sensitive to salbutamol (good response pattern), and in this group, 2.4 to 3.6 mg represents optimal treatment. In the remainder 30% of patients (poor response pattern), salbutamol in high doses had little effect. However, the outcome was not determined by the intensity of the initial symptoms or by the value of the presenting PEFR, but rather by the early (30 min) short-term response to treatment.
This randomized, double-blind trial was designed to determine the benefit of high and cumulative ... more This randomized, double-blind trial was designed to determine the benefit of high and cumulative doses of flunisolide added to salbutamol in patients with acute asthma in the emergency room (ER). Ninety-four patients who presented to an ER for treatment of an acute exacerbation of asthma were assigned in a randomized, double-blind fashion to receive salbutamol and placebo (n = 47) or salbutamol combined with flunisolide (n = 47). Both drugs were administered successively through a metered-dose inhaler and spacer at 10-min intervals for 3 h (400 microg of salbutamol and 1 mg of flunisolide every 10 min). In both groups, FEV1 and peak expiratory flow rate (PEFR) improved significantly over baseline values (p &amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). Results in the flunisolide group were significantly different from those in the placebo group at 90, 120, 150, and 180 min. Data analyzed separately in accord with the duration of the attack before presenting at the ER (&amp;amp;amp;amp;amp;amp;amp;amp;lt; 24 or &amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 24 h) showed that the placebo &amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 24 h group produced a significantly lower FEV1 at 120, 150, and 180 min (p = 0.041) than did the remaining groups. Our data support the theory that high and cumulative doses of inhaled flunisolide administered by metered-dose inhaler with spacer and added to salbutamol are an effective therapy for patients with acute asthma and a prolonged duration of symptoms before ER presentation.
The objectives of this study were to compare the efficacy of salbutamol delivered by either meter... more The objectives of this study were to compare the efficacy of salbutamol delivered by either metered-dose inhaler plus spacer (MDl-spacer) or by wet nebulization (NEB), and to determine the relationships between physiologic responses and plasma salbutamol concentrations. Asthmatic patients presenting to the emergency department (ED) with acute severe asthma (forced expiratory volume in the first second [FEV1] less than 50% of predicted) were enrolled in a randomized, double-blind, parallel-group study. The MDl-spacer group received salbutamol, delivered via MDI into a spacer device, in four puffs actuated in rapid succession at 10-minute intervals (2.4 mg/h). The NEB group was treated with nebulized salbutamol, 1,5 mg, via nebulizer at 15-minute intervals (6 mg/h). Doses were calculated on the basis of the percentage of total dose that reaches the lower airway with both methods. The protocol involved 3 hours of this treatment. Mean peak expiratory flow rate (PEFR) and FEV1 improved significantly over baseline values for both groups (P = .01). However, there were no significant differences between both groups for PER and FEV1 at any point studied. The examination of the relationships between cumulative dose of salbutamol and change in FEV~ showed a significant linear relationship (P = .01) for both methods (MDI r = ,97; NEB r = .97). The regression equations showed that for every 1 mg of salbutamol by MDI-spacer, 2.5 mg are needed from nebulization to have equal therapeutic response. At the end of treatment, the salbutamol plasma levels were 10.1 _+ 1.6 ng/ml for the aDI-spacer group and 14.4 + 2.3 ng/ml for the NEB group (P = .0003). Both groups showed a nonsignificant heart rate decrease. A significant group-by-time interaction means that differences between groups increased with time (P = .04). Additionally, the NEB group presented a higher incidence of tremor (P = .03) and anxiety (P--.04), reflecting larger systemic absorption of salbutamol. These data indicate that when doses used are calculated on the basis of the percentage of total drug that reaches the lower airway, there was equivalent bronchodilatation after salbutamol administered by either MDI-spacer or nebulization in patients with acute severe asthma. However, nebulizer therapy produced greater side effects related to the increase in salbutamol absorption and higher plasma level. (Am J Emerg Med 1998;16:637-642.
Current Therapeutic Research-clinical and Experimental, 1993
Abstract In severe acute asthma, beta-agonist bronchodilator aerosols are the standard first line... more Abstract In severe acute asthma, beta-agonist bronchodilator aerosols are the standard first line of treatment. More controversial are the method of delivery and the dose. The purpose of this study was to compare the efficacy of salbutamol delivered by jet nebulizer with that of ...
To review the literature to determine whether inhaled ipratropium bromide provides additive benef... more To review the literature to determine whether inhaled ipratropium bromide provides additive benefits to adults with acute asthma who are being treated with beta-agonists in an emergency department. SUBJECTS AND METHODS: English-language studies, both published (1978 to 1999) and unpublished, were retrieved using Medline, Science Citation Index, Current Contents, bibliographic reviews of primary research, review articles, consultation with experts, and the register of Medical Editors' Trial Amnesty. Only randomized, double-blind, controlled trials that enrolled patients having an exacerbation of asthma were included. The main outcome measure was pulmonary function; hospital admission rate was also evaluated. RESULTS: Ten studies including 1,483 adults with acute asthma were selected (mean age 32 Ϯ 13 years, 36% men). The overall effect size in SD units of pulmonary function showed a significant benefit from ipratropium (effect size 0.14, 95% confidence interval [CI]: 0.04 to 0.24, P ϭ 0.008).
We conducted a randomized, double-blind, placebo-controlled study to determine if intravenous ami... more We conducted a randomized, double-blind, placebo-controlled study to determine if intravenous aminophylline adds any benefit to high doses of inhaled salbutamol in patients who presented for treatment of acute asthma. We studied 94 patients (mean age, 35.6 +/- 11.2 years) with moderate to severe acute asthma. All patients received therapy with salbutamol delivered with metered-dose inhaler (MDI) into a spacer device (Volumatic) in four puffs (400 micrograms) at 10-min interval, and intravenous hydrocortisone (500 mg). Patients were randomly assigned to receive either a loading dose of intravenous aminophylline followed by a routine infusion (n = 45) or an equal volume of placebo as a loading dose and infusion (n = 49). The two groups showed no differences in measurements of peak expiratory flow, FEV1, and FVC at baseline and at the end of treatment. However, the patients treated with aminophylline had significantly more adverse effects (p &amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). There were no differences in the final mean dose of salbutamol (6.3 +/- 44.5 mg for the placebo group and 5.8 +/- 4.2 mg for the aminophylline group), hospital admission rate (10.2 percent for the placebo group and 9.0 percent for the aminophylline group), and mean duration of Emergency Department treatment (2.5 +/- 1.83 h for the placebo group and 2.37 +/- 1.75 h for the aminophylline group). The results were similar when the patients were divided in accord with the degree of respiratory obstruction (baseline FEV1 &amp;amp;amp;amp;amp;amp;amp;amp;lt; 30 percent of predicted) and theophylline level at 30 min of treatment (placebo group patients with theophylline level &amp;amp;amp;amp;amp;amp;amp;amp;lt; 10 mg/L vs aminophylline group patients with theophylline level &amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 10 mg/L). We conclude that intravenous aminophylline adds to the toxicity but not the efficacy of inhaled salbutamol in the treatment of acute exacerbations of asthma.
To examine the main therapeutic response patterns to high doses of salbutamol and to determine th... more To examine the main therapeutic response patterns to high doses of salbutamol and to determine the factors that contribute to outcome in acute severe asthma. The emergency department (ED) of a large, urban hospital with primary and referral care responsibilities. One hundred sixteen consecutive patients with acute exacerbations of asthma were enrolled in the trial, using a prospective sequential design. All patients were treated with salbutamol delivered with a metered-dose inhaler into a spacer device in four puffs (400 microg) at 10-min intervals. The protocol involved 3 h of this treatment (1,200 microg each 30 min). A dose-response increase in pulmonary function was found, but only 70% improved sufficiently to be discharged. Of these, almost 70% required &amp;amp;amp;amp;amp;amp;amp;amp;lt; or =2.4 mg of the drug within 1 h to reach the discharge threshold, whereas the remainder 30% need &amp;amp;amp;amp;amp;amp;amp;amp;gt; or =3.6 mg. In 30% of subjects, salbutamol was ineffective. These patients were characterized by a more severe disease as judged by previous beta2-agonist use, larger duration of attack before ED visit, and a more severe obstruction at presentation. However, the most important predictors of outcome were peak expiratory flow rate (PEFR) as percent of predicted, PEFR as liters per minute, and PEFR variation over baseline value, all at 30 min. This study described two different therapeutic response patterns to salbutamol. Almost 70% of patients were sensitive to salbutamol (good response pattern), and in this group, 2.4 to 3.6 mg represents optimal treatment. In the remainder 30% of patients (poor response pattern), salbutamol in high doses had little effect. However, the outcome was not determined by the intensity of the initial symptoms or by the value of the presenting PEFR, but rather by the early (30 min) short-term response to treatment.
Thirty-one isolates from France and Spain were genotyped using a published method analyzing DNA s... more Thirty-one isolates from France and Spain were genotyped using a published method analyzing DNA sequence variation in open reading frame (ORF) 22, together with an evaluation of three well-characterized single nucleotide polymorphisms (SNP) in ORF 38, 54, and 62. Nineteen were allocated to the European (E) genotype, six were mosaic-1 (M1), and two were mosaic-2 (M2). Four strains were assigned to a new genotype, mosaic-4 (M4). All isolates were wild type, with no Oka vaccine-associated markers. No isolates of the mosaic-3 (M3) or Japanese (J) genotype were observed. We also evaluated 13 selected isolates of E, J, M1, and M2 strains (9 of the 31 described above) using an alternative genotyping method based on the assessment of multiple SNP located in ORF 1, 9, 10, 21, 31, 50, 54, 62, and 68. This method assigns wild-type varicella-zoster virus (VZV) strains to seven genotypes: A1, A2, J1, B1, B2, C, and C1. VZV isolates identified as E (ORF22 method) had the genetic signature of genotype C VZV strains, M1 strains were A1, and M2 were A2. No J strains were detected, but parental Oka and vaccine Oka (genotype J) corresponded to genotype J1. M4 isolates (B) share the SNP array observed for M1 and E viruses, and probably represent recombinants between African-Asian (M1) and European (E) viruses. The two genotyping methods, using entirely different genomic targets, produced identical clusters for the strains examined, suggesting robust phylogenetic linkages among VZV strains circulating in Europe.
Thirty-one isolates from France and Spain were genotyped using a published method analyzing DNA s... more Thirty-one isolates from France and Spain were genotyped using a published method analyzing DNA sequence variation in open reading frame (ORF) 22, together with an evaluation of three well-characterized single nucleotide polymorphisms (SNP) in ORF 38, 54, and 62. Nineteen were allocated to the European (E) genotype, six were mosaic-1 (M1), and two were mosaic-2 (M2). Four strains were assigned to a new genotype, mosaic-4 (M4). All isolates were wild type, with no Oka vaccine-associated markers. No isolates of the mosaic-3 (M3) or Japanese (J) genotype were observed. We also evaluated 13 selected isolates of E, J, M1, and M2 strains (9 of the 31 described above) using an alternative genotyping method based on the assessment of multiple SNP located in ORF 1, 9, 10, 21, 31, 50, 54, 62, and 68. This method assigns wild-type varicella-zoster virus (VZV) strains to seven genotypes: A1, A2, J1, B1, B2, C, and C1. VZV isolates identified as E (ORF22 method) had the genetic signature of genotype C VZV strains, M1 strains were A1, and M2 were A2. No J strains were detected, but parental Oka and vaccine Oka (genotype J) corresponded to genotype J1. M4 isolates (B) share the SNP array observed for M1 and E viruses, and probably represent recombinants between African-Asian (M1) and European (E) viruses. The two genotyping methods, using entirely different genomic targets, produced identical clusters for the strains examined, suggesting robust phylogenetic linkages among VZV strains circulating in Europe.
Thirty-one isolates from France and Spain were genotyped using a published method analyzing DNA s... more Thirty-one isolates from France and Spain were genotyped using a published method analyzing DNA sequence variation in open reading frame (ORF) 22, together with an evaluation of three well-characterized single nucleotide polymorphisms (SNP) in ORF 38, 54, and 62. Nineteen were allocated to the European (E) genotype, six were mosaic-1 (M1), and two were mosaic-2 (M2). Four strains were assigned to a new genotype, mosaic-4 (M4). All isolates were wild type, with no Oka vaccine-associated markers. No isolates of the mosaic-3 (M3) or Japanese (J) genotype were observed. We also evaluated 13 selected isolates of E, J, M1, and M2 strains (9 of the 31 described above) using an alternative genotyping method based on the assessment of multiple SNP located in ORF 1, 9, 10, 21, 31, 50, 54, 62, and 68. This method assigns wild-type varicella-zoster virus (VZV) strains to seven genotypes: A1, A2, J1, B1, B2, C, and C1. VZV isolates identified as E (ORF22 method) had the genetic signature of genotype C VZV strains, M1 strains were A1, and M2 were A2. No J strains were detected, but parental Oka and vaccine Oka (genotype J) corresponded to genotype J1. M4 isolates (B) share the SNP array observed for M1 and E viruses, and probably represent recombinants between African-Asian (M1) and European (E) viruses. The two genotyping methods, using entirely different genomic targets, produced identical clusters for the strains examined, suggesting robust phylogenetic linkages among VZV strains circulating in Europe.
Two cumulative doses of salbutamol delivered by metered dose inhaler (MDI) with a pear-shaped spa... more Two cumulative doses of salbutamol delivered by metered dose inhaler (MDI) with a pear-shaped spacer were compared (400 I~g vs 600 I~g at 10-minute intervals). Twenty-two patients (mean age 35.1 -+ 11.1 years) with acute exacerbation of asthma were randomly assigned, in a doubleblind fashion, to receive salbutamol delivered with MDI into a spacer device in 4 puffs at 10-minute intervals (100 I~g or 150 Fg per actuation) during 3 hours (1200 t~g or 1800 I~g each 30 minutes). Mean peak expiratory flow rate (PEFR) and forced expiratory volume in the first second (FEVl) improved significantly over baseline values for both groups (P < .001). Nevertheless, there were no significant differences between both groups for PEFR and FEVI at any time point studied. A significant net reduction of heart rate was observed in the 400 ~g group (P < .01). On the other hand, a significant increase in heart rate was observed in the 600 iLg group (P < .001). The QTc interval did not show a significant prolongation, and the two groups presented moderate decreases of serum potassium levels. There was a significant dose-related increase (P = .027) in Sao2. Additionally, the 600 ~g group generated a serum glucose level increase from 0.85 + 0.12 mg/100 mL to 1.04 + 0.25 mg/100 mL (P = .02). At the end of treatment, the salbutamol plasma levels were 10.0 -+ 1.67 ng/mL for the 400 I~g group, and 14.0 + 2.17 for the 600 Izg group (P = .001). Finally, the overall symptom score in patients in the 600 ~g group was significantly greater than the score in the low dose group (P = ,02), with a higher incidence in 4 symptoms (tremor, headache, palpitations, and anxiety). These data support the notion that the treatment of acute asthma patients in the emergency department setting with salbutamol, 2.4 rag/h, delivered by MDI and spacer (4 puffs at 10-minute intervals) produces satisfactory bronchodilation, low serum concentration, and minimal extrapulmonary effects, However, an increase of 50% of the dose (600 p,g at 10-minute intervals) produced a nonsignificant, slightly better therapeutic response but with greater side effects, probably related to higher salbutamol levels.
Data from studies using the factor analysis technique have shown that asthma appears to be multid... more Data from studies using the factor analysis technique have shown that asthma appears to be multidimensional and that most of the subjective and objective measures utilized in the assessment of asthma patients represent a much smaller number of underlying dimensions. Additionally, several investigators have emphasized that evaluation of acute asthma is an ongoing process, as the degree and time course of the response to therapy vary considerably between patients. The aim of this study was to examine the usefulness of the most common clinical and objective measures in the evaluation of acute asthma in the emergency department (ED) for predicting the outcome of acute episodes in adults.
This randomized, double-blind trial was designed to determine the benefit of high and cumulative ... more This randomized, double-blind trial was designed to determine the benefit of high and cumulative doses of flunisolide added to salbutamol in patients with acute asthma in the emergency room (ER). Ninety-four patients who presented to an ER for treatment of an acute exacerbation of asthma were assigned in a randomized, double-blind fashion to receive salbutamol and placebo (n = 47) or salbutamol combined with flunisolide (n = 47). Both drugs were administered successively through a metered-dose inhaler and spacer at 10-min intervals for 3 h (400 microg of salbutamol and 1 mg of flunisolide every 10 min). In both groups, FEV1 and peak expiratory flow rate (PEFR) improved significantly over baseline values (p &amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). Results in the flunisolide group were significantly different from those in the placebo group at 90, 120, 150, and 180 min. Data analyzed separately in accord with the duration of the attack before presenting at the ER (&amp;amp;amp;amp;amp;amp;amp;amp;lt; 24 or &amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 24 h) showed that the placebo &amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 24 h group produced a significantly lower FEV1 at 120, 150, and 180 min (p = 0.041) than did the remaining groups. Our data support the theory that high and cumulative doses of inhaled flunisolide administered by metered-dose inhaler with spacer and added to salbutamol are an effective therapy for patients with acute asthma and a prolonged duration of symptoms before ER presentation.
Current Therapeutic Research-clinical and Experimental, 1993
Abstract In severe acute asthma, beta-agonist bronchodilator aerosols are the standard first line... more Abstract In severe acute asthma, beta-agonist bronchodilator aerosols are the standard first line of treatment. More controversial are the method of delivery and the dose. The purpose of this study was to compare the efficacy of salbutamol delivered by jet nebulizer with that of ...
Two cumulative doses of salbutamol delivered by metered dose inhaler (MDI) with a pear-shaped spa... more Two cumulative doses of salbutamol delivered by metered dose inhaler (MDI) with a pear-shaped spacer were compared (400 I~g vs 600 I~g at 10-minute intervals). Twenty-two patients (mean age 35.1 -+ 11.1 years) with acute exacerbation of asthma were randomly assigned, in a doubleblind fashion, to receive salbutamol delivered with MDI into a spacer device in 4 puffs at 10-minute intervals (100 I~g or 150 Fg per actuation) during 3 hours (1200 t~g or 1800 I~g each 30 minutes). Mean peak expiratory flow rate (PEFR) and forced expiratory volume in the first second (FEVl) improved significantly over baseline values for both groups (P < .001). Nevertheless, there were no significant differences between both groups for PEFR and FEVI at any time point studied. A significant net reduction of heart rate was observed in the 400 ~g group (P < .01). On the other hand, a significant increase in heart rate was observed in the 600 iLg group (P < .001). The QTc interval did not show a significant prolongation, and the two groups presented moderate decreases of serum potassium levels. There was a significant dose-related increase (P = .027) in Sao2. Additionally, the 600 ~g group generated a serum glucose level increase from 0.85 + 0.12 mg/100 mL to 1.04 + 0.25 mg/100 mL (P = .02). At the end of treatment, the salbutamol plasma levels were 10.0 -+ 1.67 ng/mL for the 400 I~g group, and 14.0 + 2.17 for the 600 Izg group (P = .001). Finally, the overall symptom score in patients in the 600 ~g group was significantly greater than the score in the low dose group (P = ,02), with a higher incidence in 4 symptoms (tremor, headache, palpitations, and anxiety). These data support the notion that the treatment of acute asthma patients in the emergency department setting with salbutamol, 2.4 rag/h, delivered by MDI and spacer (4 puffs at 10-minute intervals) produces satisfactory bronchodilation, low serum concentration, and minimal extrapulmonary effects, However, an increase of 50% of the dose (600 p,g at 10-minute intervals) produced a nonsignificant, slightly better therapeutic response but with greater side effects, probably related to higher salbutamol levels.
We conducted a randomized, double-blind, placebo-controlled study to determine if intravenous ami... more We conducted a randomized, double-blind, placebo-controlled study to determine if intravenous aminophylline adds any benefit to high doses of inhaled salbutamol in patients who presented for treatment of acute asthma. We studied 94 patients (mean age, 35.6 +/- 11.2 years) with moderate to severe acute asthma. All patients received therapy with salbutamol delivered with metered-dose inhaler (MDI) into a spacer device (Volumatic) in four puffs (400 micrograms) at 10-min interval, and intravenous hydrocortisone (500 mg). Patients were randomly assigned to receive either a loading dose of intravenous aminophylline followed by a routine infusion (n = 45) or an equal volume of placebo as a loading dose and infusion (n = 49). The two groups showed no differences in measurements of peak expiratory flow, FEV1, and FVC at baseline and at the end of treatment. However, the patients treated with aminophylline had significantly more adverse effects (p &amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). There were no differences in the final mean dose of salbutamol (6.3 +/- 44.5 mg for the placebo group and 5.8 +/- 4.2 mg for the aminophylline group), hospital admission rate (10.2 percent for the placebo group and 9.0 percent for the aminophylline group), and mean duration of Emergency Department treatment (2.5 +/- 1.83 h for the placebo group and 2.37 +/- 1.75 h for the aminophylline group). The results were similar when the patients were divided in accord with the degree of respiratory obstruction (baseline FEV1 &amp;amp;amp;amp;amp;amp;amp;amp;lt; 30 percent of predicted) and theophylline level at 30 min of treatment (placebo group patients with theophylline level &amp;amp;amp;amp;amp;amp;amp;amp;lt; 10 mg/L vs aminophylline group patients with theophylline level &amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 10 mg/L). We conclude that intravenous aminophylline adds to the toxicity but not the efficacy of inhaled salbutamol in the treatment of acute exacerbations of asthma.
Data from studies using the factor analysis technique have shown that asthma appears to be multid... more Data from studies using the factor analysis technique have shown that asthma appears to be multidimensional and that most of the subjective and objective measures utilized in the assessment of asthma patients represent a much smaller number of underlying dimensions. Additionally, several investigators have emphasized that evaluation of acute asthma is an ongoing process, as the degree and time course of the response to therapy vary considerably between patients. The aim of this study was to examine the usefulness of the most common clinical and objective measures in the evaluation of acute asthma in the emergency department (ED) for predicting the outcome of acute episodes in adults.
To examine the main therapeutic response patterns to high doses of salbutamol and to determine th... more To examine the main therapeutic response patterns to high doses of salbutamol and to determine the factors that contribute to outcome in acute severe asthma. The emergency department (ED) of a large, urban hospital with primary and referral care responsibilities. One hundred sixteen consecutive patients with acute exacerbations of asthma were enrolled in the trial, using a prospective sequential design. All patients were treated with salbutamol delivered with a metered-dose inhaler into a spacer device in four puffs (400 microg) at 10-min intervals. The protocol involved 3 h of this treatment (1,200 microg each 30 min). A dose-response increase in pulmonary function was found, but only 70% improved sufficiently to be discharged. Of these, almost 70% required &amp;amp;amp;amp;amp;amp;amp;amp;lt; or =2.4 mg of the drug within 1 h to reach the discharge threshold, whereas the remainder 30% need &amp;amp;amp;amp;amp;amp;amp;amp;gt; or =3.6 mg. In 30% of subjects, salbutamol was ineffective. These patients were characterized by a more severe disease as judged by previous beta2-agonist use, larger duration of attack before ED visit, and a more severe obstruction at presentation. However, the most important predictors of outcome were peak expiratory flow rate (PEFR) as percent of predicted, PEFR as liters per minute, and PEFR variation over baseline value, all at 30 min. This study described two different therapeutic response patterns to salbutamol. Almost 70% of patients were sensitive to salbutamol (good response pattern), and in this group, 2.4 to 3.6 mg represents optimal treatment. In the remainder 30% of patients (poor response pattern), salbutamol in high doses had little effect. However, the outcome was not determined by the intensity of the initial symptoms or by the value of the presenting PEFR, but rather by the early (30 min) short-term response to treatment.
This randomized, double-blind trial was designed to determine the benefit of high and cumulative ... more This randomized, double-blind trial was designed to determine the benefit of high and cumulative doses of flunisolide added to salbutamol in patients with acute asthma in the emergency room (ER). Ninety-four patients who presented to an ER for treatment of an acute exacerbation of asthma were assigned in a randomized, double-blind fashion to receive salbutamol and placebo (n = 47) or salbutamol combined with flunisolide (n = 47). Both drugs were administered successively through a metered-dose inhaler and spacer at 10-min intervals for 3 h (400 microg of salbutamol and 1 mg of flunisolide every 10 min). In both groups, FEV1 and peak expiratory flow rate (PEFR) improved significantly over baseline values (p &amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). Results in the flunisolide group were significantly different from those in the placebo group at 90, 120, 150, and 180 min. Data analyzed separately in accord with the duration of the attack before presenting at the ER (&amp;amp;amp;amp;amp;amp;amp;amp;lt; 24 or &amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 24 h) showed that the placebo &amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 24 h group produced a significantly lower FEV1 at 120, 150, and 180 min (p = 0.041) than did the remaining groups. Our data support the theory that high and cumulative doses of inhaled flunisolide administered by metered-dose inhaler with spacer and added to salbutamol are an effective therapy for patients with acute asthma and a prolonged duration of symptoms before ER presentation.
The objectives of this study were to compare the efficacy of salbutamol delivered by either meter... more The objectives of this study were to compare the efficacy of salbutamol delivered by either metered-dose inhaler plus spacer (MDl-spacer) or by wet nebulization (NEB), and to determine the relationships between physiologic responses and plasma salbutamol concentrations. Asthmatic patients presenting to the emergency department (ED) with acute severe asthma (forced expiratory volume in the first second [FEV1] less than 50% of predicted) were enrolled in a randomized, double-blind, parallel-group study. The MDl-spacer group received salbutamol, delivered via MDI into a spacer device, in four puffs actuated in rapid succession at 10-minute intervals (2.4 mg/h). The NEB group was treated with nebulized salbutamol, 1,5 mg, via nebulizer at 15-minute intervals (6 mg/h). Doses were calculated on the basis of the percentage of total dose that reaches the lower airway with both methods. The protocol involved 3 hours of this treatment. Mean peak expiratory flow rate (PEFR) and FEV1 improved significantly over baseline values for both groups (P = .01). However, there were no significant differences between both groups for PER and FEV1 at any point studied. The examination of the relationships between cumulative dose of salbutamol and change in FEV~ showed a significant linear relationship (P = .01) for both methods (MDI r = ,97; NEB r = .97). The regression equations showed that for every 1 mg of salbutamol by MDI-spacer, 2.5 mg are needed from nebulization to have equal therapeutic response. At the end of treatment, the salbutamol plasma levels were 10.1 _+ 1.6 ng/ml for the aDI-spacer group and 14.4 + 2.3 ng/ml for the NEB group (P = .0003). Both groups showed a nonsignificant heart rate decrease. A significant group-by-time interaction means that differences between groups increased with time (P = .04). Additionally, the NEB group presented a higher incidence of tremor (P = .03) and anxiety (P--.04), reflecting larger systemic absorption of salbutamol. These data indicate that when doses used are calculated on the basis of the percentage of total drug that reaches the lower airway, there was equivalent bronchodilatation after salbutamol administered by either MDI-spacer or nebulization in patients with acute severe asthma. However, nebulizer therapy produced greater side effects related to the increase in salbutamol absorption and higher plasma level. (Am J Emerg Med 1998;16:637-642.
Current Therapeutic Research-clinical and Experimental, 1993
Abstract In severe acute asthma, beta-agonist bronchodilator aerosols are the standard first line... more Abstract In severe acute asthma, beta-agonist bronchodilator aerosols are the standard first line of treatment. More controversial are the method of delivery and the dose. The purpose of this study was to compare the efficacy of salbutamol delivered by jet nebulizer with that of ...
To review the literature to determine whether inhaled ipratropium bromide provides additive benef... more To review the literature to determine whether inhaled ipratropium bromide provides additive benefits to adults with acute asthma who are being treated with beta-agonists in an emergency department. SUBJECTS AND METHODS: English-language studies, both published (1978 to 1999) and unpublished, were retrieved using Medline, Science Citation Index, Current Contents, bibliographic reviews of primary research, review articles, consultation with experts, and the register of Medical Editors' Trial Amnesty. Only randomized, double-blind, controlled trials that enrolled patients having an exacerbation of asthma were included. The main outcome measure was pulmonary function; hospital admission rate was also evaluated. RESULTS: Ten studies including 1,483 adults with acute asthma were selected (mean age 32 Ϯ 13 years, 36% men). The overall effect size in SD units of pulmonary function showed a significant benefit from ipratropium (effect size 0.14, 95% confidence interval [CI]: 0.04 to 0.24, P ϭ 0.008).
We conducted a randomized, double-blind, placebo-controlled study to determine if intravenous ami... more We conducted a randomized, double-blind, placebo-controlled study to determine if intravenous aminophylline adds any benefit to high doses of inhaled salbutamol in patients who presented for treatment of acute asthma. We studied 94 patients (mean age, 35.6 +/- 11.2 years) with moderate to severe acute asthma. All patients received therapy with salbutamol delivered with metered-dose inhaler (MDI) into a spacer device (Volumatic) in four puffs (400 micrograms) at 10-min interval, and intravenous hydrocortisone (500 mg). Patients were randomly assigned to receive either a loading dose of intravenous aminophylline followed by a routine infusion (n = 45) or an equal volume of placebo as a loading dose and infusion (n = 49). The two groups showed no differences in measurements of peak expiratory flow, FEV1, and FVC at baseline and at the end of treatment. However, the patients treated with aminophylline had significantly more adverse effects (p &amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). There were no differences in the final mean dose of salbutamol (6.3 +/- 44.5 mg for the placebo group and 5.8 +/- 4.2 mg for the aminophylline group), hospital admission rate (10.2 percent for the placebo group and 9.0 percent for the aminophylline group), and mean duration of Emergency Department treatment (2.5 +/- 1.83 h for the placebo group and 2.37 +/- 1.75 h for the aminophylline group). The results were similar when the patients were divided in accord with the degree of respiratory obstruction (baseline FEV1 &amp;amp;amp;amp;amp;amp;amp;amp;lt; 30 percent of predicted) and theophylline level at 30 min of treatment (placebo group patients with theophylline level &amp;amp;amp;amp;amp;amp;amp;amp;lt; 10 mg/L vs aminophylline group patients with theophylline level &amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 10 mg/L). We conclude that intravenous aminophylline adds to the toxicity but not the efficacy of inhaled salbutamol in the treatment of acute exacerbations of asthma.
To examine the main therapeutic response patterns to high doses of salbutamol and to determine th... more To examine the main therapeutic response patterns to high doses of salbutamol and to determine the factors that contribute to outcome in acute severe asthma. The emergency department (ED) of a large, urban hospital with primary and referral care responsibilities. One hundred sixteen consecutive patients with acute exacerbations of asthma were enrolled in the trial, using a prospective sequential design. All patients were treated with salbutamol delivered with a metered-dose inhaler into a spacer device in four puffs (400 microg) at 10-min intervals. The protocol involved 3 h of this treatment (1,200 microg each 30 min). A dose-response increase in pulmonary function was found, but only 70% improved sufficiently to be discharged. Of these, almost 70% required &amp;amp;amp;amp;amp;amp;amp;amp;lt; or =2.4 mg of the drug within 1 h to reach the discharge threshold, whereas the remainder 30% need &amp;amp;amp;amp;amp;amp;amp;amp;gt; or =3.6 mg. In 30% of subjects, salbutamol was ineffective. These patients were characterized by a more severe disease as judged by previous beta2-agonist use, larger duration of attack before ED visit, and a more severe obstruction at presentation. However, the most important predictors of outcome were peak expiratory flow rate (PEFR) as percent of predicted, PEFR as liters per minute, and PEFR variation over baseline value, all at 30 min. This study described two different therapeutic response patterns to salbutamol. Almost 70% of patients were sensitive to salbutamol (good response pattern), and in this group, 2.4 to 3.6 mg represents optimal treatment. In the remainder 30% of patients (poor response pattern), salbutamol in high doses had little effect. However, the outcome was not determined by the intensity of the initial symptoms or by the value of the presenting PEFR, but rather by the early (30 min) short-term response to treatment.
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