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Background: There have been few reports of clinical pathway (CP) for treatment of asthma attack, because patients with asthma always admit emergently and the severity varies. We introduced CP so that standard asthma treatment can be widely used, and investigated its clinical usefulness., Methods: We designed a new CP for treating asthma attack according to the guideline (Japanese guideline (JGL) and Global Initiative for Asthma (GINA)). 136 patients who admitted to our hospital due to asthma attack from January 1999 to November 2006, were enrolled our study. Excluding cases complicated with pneumonia, COPD or cardiac failure, we evaluated 46 cases treated with the CP comparing with 19 cases treated without the CP. The clinical evaluations include systemic and inhaled steroid use, FEV1.0%, history of asthma, and the duration of asthma attack. Furthermore, we investigated difference between cases with and without prolonged admission., Results: While the rates of systemic and inhaled steroid use in cases without the CP were 57.9% and 52.6% respectively, those in cases with the CP were approximately 100%. Employing the CP, FEV 1.0% at discharge time was elevated from 71.7% to 76.3% and the duration of hospitalization was shortened from 14.2 days to 11.5 days. Mean age of the cases with prolonged admission was higher than the rest., Conclusion: The asthma CP is an effective way for the standard treatment according to the guideline to be used widely even by doctors who are not familiar with asthma treatment. It improves the efficacy of in-hospital treatment.

Background: The efficacy of systemic corticosteroids for infants and toddlers with acute severe asthma has been inadequately evaluated., Objective: The purpose of this study was to evaluate the additive efficacy of intravenous prednisolone in a randomized controlled study in the management of infants and toddlers with acute severe asthma., Methods: Sixty-two patients (aged 8 to 70 months) hospitalized with status asthmaticus were studied. They were randomized into two groups. One group received intravenous prednisolone treatment (1 approximately 3 mg/kg/day, 3 days); the other group served as a control. Each group received continuous aminophylline infusion and low-dose continuous isoproterenol inhalation by an Inspiron nebulizer. They were monitored their heart rate, respiratory rate and symptoms (Wood's clinical score)., Results: Each group showed rapid improvement in heart rate, respiratory rate and clinical score by low-dose continuous isoproterenol inhalation. There were no significant differences in the time course of these clinical indexes or the duration of aminophylline infusion, continuous isoproterenol inhalation and hospital stay., Conclusion: This study failed to confirm the additive benefit of intravenous prednisolone in the management of infants and toddlers with acute severe asthma.

Status asthmaticus is defined as an attack of bronchial asthma that resists conventional treatment and continues for more than 24 hours. We report here about patients with status asthmaticus who were successfully treated with isoflurane inhalation. Of the 19 patients who were transferred to the intensive care unit (ICU) and underwent mechanical ventilation from January 1996 to May 2001, eleven patients who were first treated by isoflurane inhalation were targeted in this study. Their improvement was assessed 6 and 24 hours after anesthesia compared with their condition before anesthesia. The tidal volume, pH, and PaCO2 improved within 6 hours after anesthesia. For the next step, among the patients who were transferred to the critical care center soon after an attack of bronchial asthma and underwent mechanical ventilation, 8 patients who were treated by isoflurane inhalation anesthesia (Group I) and another 4 patients who were not treated by isoflurane (Group NI) were compared to assess the usefulness of isoflurane inhalation therapy. The patients in Group I stayed in the ICU and underwent mechanical ventilation for a shorter period. These patients had hypotension and liver dysfunction after the inhalation anesthesia, but these symptoms were improved by decreasing the concentration of isoflurane. Isoflurane inhalation therapy seemed useful for intractable status asthmaticus, and earlier introduction of this therapy is expected to achieve a greater therapeutic effect.

Recently, it has been recognized that airway inflammation is the most important pathogenesis of bronchial asthma, and inhaled corticosteroids therapy is effective for childhood asthma. However, using metered dose inhalers (MDI) of beclomethasone dipropionate (BDP) is difficult for infants. In this study, we administered BDP inhalation therapy with a new spacer, Babyhaler, for five cases of early childhood with severe infantile asthma that we could not control even by combination of theophylline round the clock (RTC) therapy and disodium cromoglycate (DSCG) + beta 2 stimulant (beta 2) regular use. We compared symptom score of asthma attack between the pre-treatment period (prior 2 weeks) and post-treatment period (following 8 weeks) of BDP inhalation therapy with Babyhaler. As a result, symptom score decreased significantly within 4 weeks after treatment of BDP with Babyhaler as compared with the score before treatment of BDP. These findings suggest that Babyhaler is useful for BDP inhalation therapy in infantile asthma.

We investigated the efficacy and side effects of "low-dose isoproterenol continuous nebulization" for childhood status asthmaticus, and compared them with those of "high-dose method". "Low-dose" is defined as 10 ml or less of 0.5% dl-isoproterenol solution diluted in 500 ml of normal saline. Subjects were 23 children who were hospitalized and underwent the nebulization therapy. The period of continuous nebulization was 26.3 +/- 12.5 hours. The Wood's clinical score clearly decreased in 22 cases, the average score changing from 7.3 +/- 1.2 to 2.8 +/- 1.5. Heart rate was not elevated significantly during the nebulization period, and decreased gradually (142 +/- 22/min at the start of the nebulization, 145 +/- 22/min at 1 hour, and 134 +/- 23/min at 3 hours, and 103 +/- 13/min at the cessation of the nebulization). Serum GOT, LDH, CPK, and potassium were decreased after the nebulization compared with the values before the treatment, the changes of the last 2 items being statistically significant. Two subjects who had vomited before the nebulization therapy complained nausea during the procedure, and one experienced transient finger tremor. We conclude that "low-dose isoproterenol continuous nebulization" is an effective and safe method for childhood status asthmaticus. We expect that this method will be familiar to all clinicians.

We investigated the efficacy and the side effects of "high-dose isoproterenol continuous nebulization" for childhood status asthmaticus. Subjects were 34 children who were hospitalized and underwent the nebulization therapy. The 50 ml solution of 0.5% dl-isoproterenol was diluted in 500 ml of normal saline and nebulized through an ultrasound nebulizer. The period of continuous nebulization was 25.5 +/- 16.0 hours. The Wood's clinical score clearly decreased in 32 cases, the average score changing from 7.7 +/- 0.8 to 2.9 +/- 1.3. Heart rate was elevated significantly during the first 3 hours (156 +/- 25/min at the start of the nebulization, 180 +/- 20/min at 1 hour, 171 +/- 23 at 3 hours), and then it decreased gradually to 122 +/- 25/min at the cessation of the nebulization. Serum GOT, LDH, CPK, and potassium were elevated after the nebulization compared with the values before the treatment, though the changes were not statistically significant. CPK-MB fraction after the nebulization was higher than normal range in 12 of 13 subjects. Of 34 subjects, 11 (32%) complained nausea or vomited, 2 showed arrhythmia on ECG (ventricular premature conduction), 1 developed myocardiac infarction, and 1 developed possible heart failure, some of which might be attributable to the pharmacological side effects of isoproterenol nebulization. We conclude that "high-dose isoproterenol continuous nebulization" is an effective method for childhood status asthmaticus, but there is some risk of serious side effects. This method was originally developed as a method indicated for the case of respiratory failure or threatened respiratory failure following status asthmaticus, and we should not extend the indication of this method thoughness.

From April 1992 we introduced beclomethasone dipropionate (BDP) inhalation therapy with a large spacer for patients with bronchial asthma who were admitted to the internal medicine department of our hospital because of an exacerbation of asthma. To investigate the influence of this BDP inhalation therapy on emergency room visits by patients with bronchial asthma, we studied the patients who were admitted to the emergency room at our hospital with asthmatic attacks from April 1991 to March 1994. A significant (p < 0.05) reduction in the number of patients who visited our emergency room with asthmatic attacks was found over the 3 years: from April 1991 to March 1992 (before the introduction of BDP inhalation therapy), 575 patients (47.9 +/- 7.5 patients/month) were admitted with asthmatic attacks; from April 1992 to March 1993, 341 patients (28.4 +/- 13.0 patients/month) were admitted, and from April 1993 to March 1994, 285 patients (25.1 +/- 9.2 patients/month). Among the patients who were admitted to our emergency room, the proportion of first-visit patient tended to increase. We studied 27 emergency-room-visit patients who attended our hospital regularly from one year before to one year after the introduction of BDP therapy. The therapy failed to control asthmatic symptoms in 12 patients on long courses of oral corticosteroids, on the other hand control of 15 patients without oral steroid was favorable. These results suggests that BDP inhalation therapy with a large spacer decreases the number of emergency room visits by patients with bronchial asthma.

In our Department, continuous isoproterenol inhalation therapy has been conducted on status asthmatics over the last 10 years. In the present study, we investigated whether there are any differences in the therapeutic efficacy of continuous inhalation of isoproterenol in the presence or absence of respiratory infections which may induce or aggravate asthma attacks. The treatment period was significantly longer in patients with pneumonia. Further prolongation of the treatment period was noted in patients with atelectasis. However, there were no apparent differences in therapeutic efficacy according to age or the severity of attacks. These findings suggest that continuous inhalation of isoproterenol is very effective for status asthmatics if respiratory infections are thoroughly controlled.

The bronchodilatory response to procaterol delivery by a metered dose inhaler with a spacer device (Volumatic) and a corniced extension tube was studied in a double blind manner in 18 asthmatic children, who were brought to our emergency room with acute attacks. The mean percent increase in forced expiratory volume in 1 second (FEV1) with the Volumatic was 55.6 +/- 39.3%, and 46.2 +/- 37.4% with the extension tube. There were no significant differences in the mean percent increase in FEV1, forced vital capacity (FVC), maximal flow rate at 50% of vital capacity (V50), maximal flow rate at 25% of vital capacity (V25) and peak expiratory flow rate (PEFR) between the two devices. It is concluded that there is no difference in the bronchodilatory effects of the two devices. The corniced extension tube has the advantage of being less expensive and more convenient to carry around.

Serial changes of circulating immune complexes and anti-mite specific IgG antibody in the peripheral blood were measured eight times in six status asthmatics treated with high doses of methylprednisolone (MPS). Circulating immune complexes decreased to normal levels three hours after MPS administration. By contrast, anti-mite specific IgG antibody increased to beyond the normal range 14 days after MPS administration. Serum levels of IgE and allergen specific IgG4 antibody did not show any significant changes. In vitro experiments, circulating immune complexes in the sampled sera were decreased by an absorption test with anti-mite specific IgG antibody, and increased by reaction with an adequate volume of mite allergen. These facts indicate that circulating immune complexes are an anti-complementary factor working on the complement system, as previously reported, and that mite allergen and anti-mite IgG antibody relate to their conformation in status asthmatics. Clinically, MPS might possess an inhibitory effects on the formation of immune complexes and/or accelerate complement-dependent solubilization of antigen-antibody complexes, so that anti-mite specific IgG antibody increased markedly in the peripheral blood.

Complement system was investigated in 7 patients with status asthmatics treated with large doses of methylprednisolone (MPS). Complement hemolytic activities, complement protein profile, complement fragments and circulating immune complexes were measured before, 3 and 8 hours after and 14 days after MPS administration. MPS normalized C4 and C1INH activities 6 hours after administration. MPS also decreased ACH50 6 hours after administration and D activity 3 and 6 hours after, but these activities recovered to their previous normal range within 14 days. P and H were decreased at each measurement time, and C1s was transiently decreased 6 hours after MPS administration. Complement fragment iC3b was increased at each measurement time, but fragment Bb tended to be decreased 14 days after MPS administration. The increment of anaphylatoxin C3a recovered to normal 14 days after MPS administration. In vitro experiments, MPS inhibited D and C1s activation directly, and decreased the decay of B and C4. Inhibition of C1s might also increase C1INH activity clinically. These results clarified that the alternative complement pathway was activated, and suggested that the C1 bypass pathway might be also activated in status asthmatics. It was further considered that these anti-complementary effects induced by MPS, brought about an improvement in asthmatic symptoms. Studies to identify the complement activators continued, and circulating immune complexes may possibly be one of those agents activating complement cascade.

The aim of this study was to evaluate the efficacy of continuous isoproterenol inhalation therapy for severe asthma attacks in younger children, compared with its efficacy in older children. We used l-body isoproterenol (Proternol L) in 31 children with 42 episodes of severe attacks. They were divided into two group according to age: 20 cases under 6 years old (Group A), and 22 cases over 7 years old (Group B). All of the patients except for one in Group B, eventually improved with this therapy. Wood's clinical scores for Group A were significantly higher than those for group B (p < 0.01). In 22 cases whose scores were 5-6, their SpO2 values at the onset of this therapy were 90.8 +/- 3.17 in group A and 92.4 +/- 3.82% in group B. The improvement time of group A (13.6 +/- 16.2 hours) was significantly longer than that of group B (2.5 +/- 5.66, p < 0.01). The nebulized isoproternol doses for group A were 0.47 +/- 0.168 and for group B 0.26 +/- 0.096 mg/kg/saline 500 ml. The dose for group A was significantly higher than that for group B (p < 0.01). We concluded that continuous isoproterenol inhalation therapy was effective even in younger children. But the degree of efficacy was slightly lower in younger children, although they inhaled higher doses of isoproterenal than older children.

The aim of this study was to evaluate the efficacy and safety of continuous isoproterenol inhalation therapy for asthma attacks in children. We used l-body isoproterenol (Proternol L) in 22 children with 32 episodes of severe attacks. One of them did not respond to this therapy, and two had complications (atelectasis and pneumothorax). Twenty-nine cases were divided into three subgroups according to their clinical scores; A) scores less than or equal to 4, which meant that they were in the early stage of severe attack (n = 9), B) scores 5-6, which meant impending respiratory failure (n = 17), C) scores greater than or equal to 7, which meant respiratory failure (n = 3). The values of SpO2 at the start of this therapy were 94.8, 91.5, 82.0%, respectively. The more severe their attacks were, the lower their SpO2 levels were. The periods until their scores became zero were 0.78, 6.3, 17.2 hours, respectively. There were significant differences between each period respectively (p less than 0.001, p less than 0.01). Heart rates decreased when their symptoms improved, and other adverse effects were not detected. These results suggest that this therapy is effective and safe for children with severe asthma attacks, especially in the early stage.

We performed inhalation anesthetic therapy in an attempt to produce improvement in cause of life-threatening asthma, which were standard pharmacological therapy. We analysed the results obtained in 6 cases given inhalation anesthetic therapy (4 cases were treated with halothane and 2 cases with enflurane). The following observations were made: 1) The criteria for starting inhalation anesthetic therapy were persistent hypoxycemia or hypercapnia, persistently high inspiratory intra-airway pressure, clinical exhaustion and bronchial toilet with bronchofiberscope. 2) We treated the patients with halothane concentrations of between 1.0 and 2.0% and enflurane concentrations of between 1.0 to 4.2%. 3) No major complications were observed in inhalation anesthetic therapy.

A 56-year-old male with non-atopic bronchial asthma was admitted to our hospital due to status asthmaticus. His asthma attacks could not be controlled by oral and/or inhalation therapy, but only by intravenous theophylline therapy with corticosteroid. A theophylline absorption test was performed on him after over night fasting. 500 mg of theophylline was administered. The maximum serum theophylline concentration was only 4.0 micrograms/ml at 30 minutes and the urinary one was 13.0 micrograms/ml at 360 minutes after starting the test. The threshold level of absorption from the intestinal tract was higher than the usual level in this patient. We conclude that among patients with intractable bronchial asthma there may be some who have problems with orally administered theophylline. Continuous theophylline therapy at home is recommended for such intractable asthmatics.

I made microcomputer software for the pharmacokinetic calculation of appropriate administration doses of aminophylline for the treatment of status asthmaticus. It consists of three programs for determination of initial doses, four for determination of maintenance doses, and four for calculation of the pharmacokinetics parameters (Vd, Ke, CL, T1/2). The parameters were estimated 376 times during 151 attacks in 84 patients with bronchial asthma. Vd, Ke, and CL were calculated as below, and the wide variation in the values suggests that individual programs for theophylline therapy should be made for each patient. I concluded that these microcomputer programs were useful in creating an individual administration program. Distribution volume (Vd): 385 +/- 106 ml/kg (n = 115) Elimination rate constant (Ke): 0.155 +/- 0.0878/h (n = 176) Clearance (CL): 61.8 +/- 14.3 ml/kg.h (n = 85)