Gerard J. Canny

Prediction of Mortality in Patients with Cystic Fibrosis

BACKGROUND The majority of patients with cystic fibrosis die in early adulthood of lung disease. Lung transplantation is a treatment option for patients with advanced pulmonary disease, although the waiting period for organs may be as long as two years. Our purpose was to determine whether the risk of death due to respiratory failure could be predicted one or two years in advance on the basis of pulmonary function, blood gas levels, and nutritional status. METHODS The study cohort consisted of 673 patients followed between 1977 and 1989. In each patient, pulmonary function, blood gas levels, nutritional status, and vital status were assessed between 1977 and 1987. Cox proportional-hazards regression analysis was used to compute the relative risk of death within one or two years after particular measurements. The effects of age and sex on mortality were also included in the analysis. RESULTS One hundred ninety patients (28 percent) died during the study period. Overall, patients with a forced expiratory volume in one second (FEV1) less than 30 percent of the predicted value, a partial pressure of arterial oxygen below 55 mm Hg, or a partial pressure of arterial carbon dioxide above 50 mm Hg had two-year mortality rates above 50 percent. Among the laboratory measurements, the FEV1 was the most significant predictor of mortality, but age and sex were also significant in predicting risk. After adjustment for age and sex, the relative risk of death within two years was 2.0 (95 percent confidence interval, 1.9 to 2.2) for each decrement in the FEV1 of 10 percent below the predicted value. Among patients with the same FEV1, the relative risk of death was 2.0 (95 percent confidence interval, 1.5 to 2.6) in patients 10 years younger than other patients, and 2.2 (1.6 to 3.1) in female patients as compared with male patients. CONCLUSIONS Patients with cystic fibrosis should be considered candidates for lung transplantation when the FEV1 falls below 30 percent of the predicted value. Female patients and younger patients may need to be considered for transplantation at an earlier stage.

A Comparison of Inhaled Fluticasone and Oral Prednisone for Children with Severe Acute Asthma

BACKGROUND Inhaled corticosteroids are effective in the treatment of children with asthma. It is uncertain how inhaled corticosteroids compare with oral corticosteroids in the management of severe acute disease. METHODS We performed a double-blind, randomized trial involving 100 children five years of age or older who had severe acute asthma (indicated by a forced expiratory volume in one second [FEV1] that was less than 60 percent of the predicted value) and in whom the results could be evaluated. All were treated with an aggressive bronchodilator regimen and received one dose of either 2 mg of inhaled fluticasone through a metered-dose inhaler with a spacer or 2 mg of oral prednisone per kilogram of body weight. They were assessed hourly for up to four hours. RESULTS The mean (+/-SD) base-line FEV1 as a percentage of the predicted value was 46.3+/-12.5 in the fluticasone group (51 subjects) and 43.9+/-9.9 in the prednisone group (49 subjects). The FEV1 increased by a mean of 9.4+/-12.5 percentage points in the fluticasone group and by 18.9+/-9.8 percentage points in the prednisone group four hours after therapy (P< 0.001). None of the children in the prednisone group had a reduction in FEV1 as a percentage of the predicted value from base line to four hours, as compared with 25 percent of those in the fluticasone group (P<0.001). Sixteen (31 percent) of the children treated with fluticasone were hospitalized, as compared with five (10 percent) of those treated with prednisone (P=0.01). CONCLUSIONS Children with severe acute asthma should be treated with oral prednisone and not with inhaled fluticasone or a similar inhaled corticosteroid.

Efficacy of albuterol administered by nebulizer versus spacer device in children with acute asthma

The aim of this study was to compare the response to inhaled albuterol after administration by nebulizer with the response after administration by a metered-dose inhaler and spacer device (MDI-spacer) to children with acute asthma. In a double-blind fashion, 33 children (6 to 14 years of age) with forced expiratory volume in 1 second (FEV1) between 20% and 70% of predicted values, and who were seen in the emergency department with acute asthma, were studied. They were treated with aerosolized albuterol or placebo by MDI-spacer, followed immediately by albuterol or placebo administered by nebulizer with oxygen. The dose ratio for albuterol by MDI-spacer versus nebulizer was 1:5. Outcome measures included a clinical score, respiratory rate, arterial oxygen saturation, and FEV1, measured before and 10, 20, and 40 minutes after treatment. With the exception of heart rate (which increased in the nebulizer group and decreased in the MDI-spacer group (p < 0.05), no difference in the rate of improvement of clinical score, respiratory rate, arterial oxygen saturation, or FEV1 was noted during the 40-minute study period between children who received albuterol by nebulizer and those who received it by MDI-spacer. We conclude that spacers and nebulizers are equally effective means of delivering beta 2-agonists to children with acute asthma.

Energy expenditure of patients with cystic fibrosis

Resting energy expenditure was measured by open-circuit indirect calorimetry in 71 patients, aged 8.9 to 35.5 years, with cystic fibrosis who had no recent history of acute lung infection. Pulmonary function and nutritional status were studied simultaneously. In most patients, resting energy expenditure was above normal (range 95% to 153% of predicted values for age, sex, and weight as derived from the Harris Benedict equations), and was negatively correlated with pulmonary function (P less than 0.01) and nutritional status (P less than 0.01) when expressed as a percentage of body fat. Pulmonary status was positively correlated with nutritional status (P less than 0.01). We conclude that resting energy expenditure in patients with cystic fibrosis exceeds normal values and that the increase correlates with a deterioration in lung function and nutritional status.

Nebulized albuterol in acute bronchiolitis

In a double-blind, placebo-controlled trial, 40 infants between 6 weeks and 24 months of age who had a first episode of wheezing and other signs and symptoms of bronchiolitis were randomly assigned to receive either nebulized albuterol (0.15 mg/kg/dose) or placebo (saline solution) for two administrations 1 hour apart. The albuterol therapy resulted in a significantly greater improvement in the accessory muscle score (decreases 0.70 vs decreases 0.30; p = 0.03), oxygen saturation (increases 0.71% vs decreases 0.47%; p = 0.01) after one dose, and in the accessory muscle score (decreases 0.86 vs decreases 0.37; p = 0.02), respiratory rate (decreases 19.6% vs decreases 8.0%; p = 0.016), and oxygen saturation (increases 0.76% vs decreases 0.79%; p = 0.015) after two doses of the drug. The response to therapy was similar in infants younger and those older than 6 months of age. The heart rate rose slightly more in the albuterol group (increases 7.76 from baseline) versus the placebo group (decreases 6.79). There were no other side effects of the treatment. Of the 34 children from whom nasal specimens were obtained by swab for viral identification, 24 had positive test results (21 for respiratory syncytial virus, 1 for parainfluenza, 1 for paramyxovirus, and 1 for influenza A). We conclude that nebulized albuterol constitutes a safe and effective treatment of infants with bronchiolitis.

Frequent administration by inhalation of salbutamol and ipratropium bromide in the initial management of severe acute asthma in children

A study was performed to compare the efficacy and safety of two therapeutic regimens for the treatment of children presenting to the emergency department with acute asthma. A regimen of inhaled salbutamol alone was compared to inhaled salbutamol combined with ipratropium bromide. Twenty-five children ranging in age from 5 to 15 years were enrolled in the study. Children with FEV1 less than or equal to 55% predicted were eligible to participate in the study. Subjects were randomized in a double-blind fashion into one of two treatment groups. Both groups received an initial dose of salbutamol by nebulizer of 150 micrograms/kg (0.03 cc/kg), followed by six consecutive doses of 50 micrograms/kg (0.01 cc/kg) at 20-minute intervals. In one group of subjects, 250 micrograms (1.0 ml) of ipratropium bromide respirator solution was added to the salbutamol administered at the time of the initial inhalation, and at 40 and 80 minutes, whereas the remaining subjects received a placebo with salbutamol at those times. Formal one-way statistical ANOVA with change in percent predicted FEV1 as a response variable confirmed there was a statistically significant difference at all time points caused by drug regimen during the 150-minute observation period. There was no significant difference in side effects reported in the two groups. Significant additional bronchodilation achieved with salbutamol and ipratropium bromide together indicates that there is likely a substantial cholinergic element to the bronchospasm observed in acute exacerbations of asthma in the pediatric age group.

Methacholine Inhalational Challenge in the Evaluation of Chronic Cough in Children

The medical records of 58 children (age range, 7 to 16 years) who presented with chronic cough were retrospectively analyzed to determine the value of methacholine (MCH) bronchial challenge in reaching a specific diagnosis. Baseline lung function tests were normal in all subjects, apart from an elevated residual volume/total lung capacity ratio (RV/TLC) in 11 patients, and a reduced midexpiratory flow rate (FEF25-75) in five of these patients. Thirty-one patients had a positive response to MCH, but these patients could not be identified on the basis of clinical criteria or spirometric parameters. MCH-positive patients did have a significantly higher RV/TLC than did MCH-negative patients. Twenty-seven of the 31 MCH-positive patients responded to a trial of bronchodilator therapy (albuterol/theophylline), confirming the diagnosis of cough variant asthma in these patients. We conclude that children with chronic cough should be considered for methacholine challenge in order to identify patients who are likely to benefit from specific bronchodilator therapy.

Renal calcium handling in cystic fibrosis: Lack of evidence for a primary renal defect

Because cystic fibrosis (CF) epithelia have ion transport abnormalities that may in part be regulated by intracellular calcium metabolism, and the kidney is actively involved in both ion transport and calcium homeostasis, we have investigated renal calcium handling in CF. Twenty-four-hour urine collections were analyzed in 34 CF patients (age 5 to 35 years) and kidney ultrasound studies were performed in 17 CF patients (age 6 months to 23 years). Renal histologic findings at postmortem examination of 14 CF patients (age 4 months to 23 years) were compared with those of 12 patients (age 11 months to 17 years) with other chronic illnesses (6 congenital heart disease, 6 malignancy). In 30 of the 34 CF patients urinary calcium excretion was normal (less than 4 mg (0.1 mmol)/kg/24 hr). Four CF patients had hypercalciuria (calcium excretion 4.4 to 8.8 mg (0.11 to 0.22 mmol)/kg/24 hr). However, these patients had other possible explanations for hypercalciuria, such as immobilization (n = 2), increased dietary sodium load (n = 1), and glucocorticoid therapy (n = 1). None of the 17 patients examined by renal ultrasonography had nephrocalcinosis. Five CF patients had histologic evidence of sparse nephrocalcinosis at autopsy. However, 6 of 12 autopsy kidney specimens from patients with other chronic illnesses and similar preterminal events also showed nephrocalcinosis. The hypercalciuria and nephrocalcinosis in CF and other chronic debilitating diseases may be explained by factors known to affect calcium handling. Our evidence does not support a primary renal defect as the basis of hypercalciuria and nephrocalcinosis in CF.

Pharmacokinetics of inhaled salbutamol in patients with cystic fibrosis versus healthy young adults

We studied the disposition of inhaled salbutamol in adolescents with cystic fibrosis (CF) and compared it with the pharmacokinetics of the drug given by the intravenous and inhaled routes in healthy adults. After inhalation of salbutamol, CF patients had a significantly larger area under the concentration-time curve derived from amounts of drug in the systemic circulation. The differences in serum concentration of salbutamol were not reflected in differences in change of heart rate. We conclude that the rate and extent of pulmonary absorption of inhaled salbutamol in patients with CF differ from those in healthy adults.

The role of corticosteroids in respiratory diseases of children

Glucocorticosteroids are potent anti-inflammatory agents and have an important role in a variety of respiratory diseases. Although their exact mode of action is unknown, it is thought that they exert their effects by binding to cytoplasmic glucocorticoid receptors. In certain conditions, such as asthma, the value of steroids cannot be questioned, and inhaled steroids have revolutionized management. In other situations, such as interstitial lung disease, the true role of steroids is still to be defined. In the management of diseases such as tuberculosis, the use of steroids is solely based on anecdotal experience.