FLU VACCINE DOES NOT EXACERBATE ASTHMA

The influenza vaccine does not induce acute asthma exacerbations and should not be withheld from children with asthma, a large retrospective cohort analysis by Kramarz et al suggests. The researchers obtained computerized medical and vaccination records of children (age 1 to 6 years) from four large health maintenance organizations located on the West Coast of the United States. Data were available on 22,231 children during the 1993-1994 influenza season, 38,669 children during the 1994-1995 season, and 70,753 children during the 1995-1996 season.

After controlling for asthma severity, Kramarz et al found no increase in the incidence of acute asthma exacerbations within two days or two weeks of vaccination. In fact, during all three seasons, the researchers found a decrease in the incidence of asthma exacerbations during the two weeks after vaccination (as compared with that during other periods in the same group of children). This difference, although small each year, reached statistical significance in the 1993-1994 season. In addition, a separate analysis of children with severe asthma did not show an increased risk of exacerbations following vaccination.

"The results raise the question [of] whether influenza vaccination may cause a decrease in the incidence of asthma attacks beyond the two weeks (ie, vaccination may provide long-term protection against asthma exacerbations)," the researchers noted.

Kramarz P, DeStefano F, Gargiullo PM, et al. Does influenza vaccination exacerbate asthma? Analysis of a large cohort of children with asthma. Arch Fam Med. 2000;9:617-623.

CORTICOSTEROID WITHDRAWAL IN COPD PATIENTS

Patients with chronic obstructive pulmonary disease (COPD) who stop taking oral corticosteroids on a daily basis do not appear to experience an increase in COPD exacerbations or a worsening of dyspnea, subjective health ratings, or spirometric values, according to a recent placebo-controlled trial. The findings showed that discontinuation of daily corticosteroids reduced the patients' total exposure to systemic corticosteroids and their body weight.

Thirty-eight male COPD patients who had been taking oral prednisone at a dose of 5 mg/d or higher for at least six months were randomized to continue with their usual prednisone dose or to taper off prednisone at a rate of 5 mg/wk. Patients in both groups were given prednisone as needed for COPD exacerbations. The two groups were similar in regard to age, spirometric values, bronchodilator response, duration and dose of prior oral corticosteroid treatment, and use of inhaled corticosteroids.

During six months of follow-up, the groups had a similar number of COPD exacerbations per patient (2.5 with continuous treatment and 2.7 following treatment cessation). Measurements of dyspnea, quality of life, forced expiratory volume in one second, and forced vital capacity were similar in the two groups and did not change significantly from baseline levels.

Patients who continued daily treatment gained a mean of 0.5 kg, while patients who took prednisone only during exacerbations lost a mean of 4.8 kg; this difference was statistically significant. In addition, the mean daily systemic corticosteroid dose was significantly higher in the former group than in the latter group (10.7 mg vs 6.3 mg).

Rice KL, Rubins JB, Lebahn F, et al. Withdrawal of chronic systemic corticosteroids in patients with COPD. A randomized trial. Am J Respir Crit Care Med. 2000;162:174-178.

TWO IS BETTER THAN ONE IN APNEA DETECTION

Because apnea-hypopnea and microarousal indexes vary from night to night, a second polysomnographic recording may be required to detect apnea in patients with negative findings on first testing.

A total of 243 patients suspected of having sleep apnea underwent polysomnography on two consecutive nights. A classic first-night effect was found; patients had a shorter sleep period time and total sleep time, less sleep efficiency, longer sleep-onset latency, more wake time after sleep onset, a higher awakening index, less rapid eye movement (REM) sleep time, and a longer REM sleep latency on night 1 than on night 2. These differences were statistically significant. The nonrespiratory microarousal index was also markedly higher on night 1 than on night 2.

In terms of sleep respiratory events, the polysomnographic recording on night 1 showed significantly less evidence of obstructive apnea, total apnea, hypopnea, and combined apnea-hypopnea than did the recording on night 2 (Table 1). The number of desaturations of 3% or more was lower on night 1, while the index of desaturations of 3% or more was lower on night 2.

Sixty-two patients had higher apnea-hypopnea indexes on night 2; only 32 had higher numbers on night 1. "This finding underscores the larger proportion of subjects having more severe respiratory events on night 2," Le Bon et al reported. The study researchers also found that severe apnea-hypopnea indexes occurred more often on night 2--when sleep quality was better.

Le Bon O, Hoffmann G, Tecco J, et al. Mild to moderate sleep respiratory events: one negative night may not be enough. Chest. 2000;118:353-359.

PREDICTORS OF NEAR-FATAL AND FATAL ASTHMA

Nearly half of near-fatal and fatal asthma attacks occur suddenly and unexpectedly, outside of the hospital, and in stable, young, atopic patients who use corticosteroids on a daily basis. These findings are based on survey responses from 400 asthma specialists who submitted information on 25 cases of near-fatal asthma and 20 cases of fatal asthma.

Among patients with near-fatal asthma, the mean age at the time of the episode was 29.4 years. The event occurred suddenly (ie, in less than three hours) in 60% of cases. All of the patients had been using short-acting inhaled ß-agonists, and 88% had been taking inhaled corticosteroids on a daily basis. Compliance with these therapies was rated as good to excellent in 60% of patients.

Precipitating factors for near-fatal asthma included overuse of inhaled ß-agonists in six patients and a delay in initiation of oral corticosteroids in five patients. In the 20 patients with fatal asthma, the mean age at the time of death was 21.7 years. All of the patients had been using short-acting inhaled ß-agonists, 80% had been taking inhaled corticosteroids on a daily basis, and 30% had also been using oral corticosteroids. Sixty percent of the patients were believed to have good to excellent compliance with corticosteroid therapy.

Precipitating factors of fatal asthma included overuse of inhaled ß-agonists in nine patients and a delay in initiating oral corticosteroids in four patients. Risk factors for fatal asthma included exercising in cold weather, overreliance on home nebulizers, inadvertently ingesting nuts or peanuts, and a delay in seeking medical care on holiday weekends.

Predisposing psychosocial factors were noted in 44% of patients with near-fatal asthma and 45% of those who died from asthma. These factors included self-denial and/or poor care, depression, drug abuse, and loss of a loved one.

Hannaway PJ. Demographic characteristics of patients experiencing near-fatal and fatal asthma: results of a regional survey of 400 asthma specialists. Ann Allergy Asthma Immunol. 2000;84:587-593.

INTRANASAL MIDAZOLAM FOR FEBRILE SEIZURES

Intranasal midazolam is a safe and effective treatment for febrile seizures in children and may be used in general practice as well as by parents at home, according to the results of a recent study. While time from administration to seizure control was faster with intravenous diazepam than with intranasal midazolam, the latter treatment (which is administered more quickly) showed a faster time to cessation of seizures.

Lahat et al compared the effects of 0.2 mg/kg intranasal midazolam and 0.3 mg/kg intravenous diazepam in the treatment of 52 prolonged febrile seizures (ie, those that lasted 10 minutes or more) in 44 children age 6 months to 5 years. The patient groups had similar clinical characteristics.

The proportion of seizures that responded to treatment was similar in both groups (88% with midazolam and 92% with diazepam). Time to cessation of seizure after receipt of the drug was significantly faster in the diazepam group than in the midazolam group (2.5 minutes vs 3.1 minutes, respectively).

On the other hand, time to cessation of seizure after arrival at the hospital was significantly faster among those patients who received midazolam than among those who were given diazepam (6.1 minutes vs 8.0 minutes, respectively). "This is because midazolam was administered earlier and the administration of diazepam requires an intravenous line," explained Gideon Koren, MD, in an accompanying editorial.

None of the children developed side effects. "In conclusion, intranasal midazolam could be provided not only in medical centres but, with appropriate instruction, by the parents of children with febrile seizures at home," Lahat et al noted.

Koren G. Intranasal midazolam for febrile seizures. A step forward in treating a common and distressing condition. BMJ. 2000;321:64-65.
Lahat E, Goldman M, Barr J, et al. Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study. BMJ. 2000;321:83-86.

BOSETAN IN PULMONARY HYPERTENSION

Intravenous bosentan, an endothelin receptor antagonist, reduced pulmonary resistance in patients with isolated pulmonary hypertension in a recent study, but the drug was not selective for the pulmonary vasculature at the doses tested. Furthermore, bosentan caused systemic hypotension and other adverse events that may limit its use in patients with severe pulmonary hypertension, Williamson et al reported.

The study consisted of two parts. The first part was an open-label, dose-ranging trial that was designed to examine the safety and efficacy of intravenous bosentan in patients with isolated pulmonary hypertension. The seven patients enrolled received 50-mg, 150-mg, and 300-mg infusions of the drug at two-hour intervals.

In the second part, the patients who had been given the three infusions were randomized to receive either bosentan or placebo as part of an eight-week, double-blind, placebo-controlled trial. However, the study was ended early because many of the patients experienced serious adverse events.

In the first part of the study, bosentan was found to cause dose-dependent reductions in mean pulmonary artery pressure and total pulmonary resistance. At the highest doses, these measurements fell by 10.6% and 20.0%, respectively; however, only the decrease in total pulmonary resistance was significant. Furthermore, the vasodilative effects of this drug were not limited to the pulmonary vasculature. Systemic vascular resistance fell by 26.2% and mean arterial pressure dropped by 19.8%. The researchers also noted a slight rise in the cardiac index and a dose-dependent increase in endothelin-1 levels.

The study was terminated early after two patients died within 36 hours of randomization to placebo. Both of these subjects had a very poor exercise tolerance. Sepsis could not be excluded as a cause of death in one of the patients. No specific cause other than pulmonary hypertension was found in the second patient. A third subject, who was also randomized to receive placebo, showed no adverse cardiorespiratory effects.

Of the four patients who were randomized to bosentan, only one completed the eight-week treatment protocol before the study was terminated. Among the serious adverse events experienced by these subjects were increasing dyspnea, peripheral edema, respiratory tract infection with significant cardiac decompensation, Clostridium difficile diarrhea with metabolic acidosis, and severe hypoxemia (in a patient who was also treated for a urinary tract infection). Other adverse events included hypotension, peripheral edema, headache, and urinary tract infections.

"These observations should suggest caution in further studies of long-term oral administration," Williamson et al warned. The researchers noted that the high doses used in the trial may have contributed to the high rate of adverse events. They also recommended that patients with significantly elevated right atrial pressures or severely impaired exercise tolerance be excluded from future trials.

Williamson DJ, Wallman LL, Jones R, et al. Hemodynamic effects of bosentan, an endothelin receptor antagonist, in patients with pulmonary hypertension. Circulation. 2000;102:411-418.

MONOXIDINE EFFECTIVE FOR HYPERTENSION AND PULMONARY DISEASE

The new antihypertensive agent moxonidine has been found to be as effective as ramipril in the treatment of patients with hypertension and obstructive pulmonary disease, according to research by Feuring et al. However, moxonidine does not appear to have any effect on lung function.

The researchers randomized 104 adults to eight weeks of treatment with either moxonidine (0.2 or 0.4 mg/d) or the angiotensin-converting enzyme inhibitor ramipril (2.5 or 5 mg/d). All of the patients had essential hypertension in addition to bronchitis or moderate chronic airway obstruction.

Both groups experienced small changes in arterial oxygen tension. Forced expiratory volume in one second remained constant in the moxonidine group but decreased slightly in the ramipril group.

The drugs achieved a similar reduction in systolic and diastolic blood pressure. Treatment with moxonidine did not alter any other indexes of lung function or blood gases.

Furthermore, a similar proportion of patients in each group experienced drug-related adverse effects (13.5% with moxonidine and 11.5% with ramipril). Both drugs were generally well tolerated, according to Feuring et al.

"The results of this study suggest that moxonidine may be recommended as an effective antihypertensive drug in the long term therapy of patients with arterial hypertension and concomitant pulmonary disease," the researchers concluded.

Feuring M, Cassel W, Thun B, et al. Moxonidine and ramipril in patients with hypertension and obstructive pulmonary disease. Clin Drug Invest. 2000;20:19-24.

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