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- Status Asthmaticus -

9/12/05 re: Details of acute asthma treatment
Q.

A 17 year old male was admitted to the emergency dept. with a 2 day history of wheezing and shortness of breath. Previous admissions for this patient confirmed a diagnosis of moderately severe asthma. The emergency dept. physician writes the following order: Aerosol therapy with albuterol and flovent. What additional information would be needed about the order before treating the patient? What additional patient information would be important to obtain before delivering the aerosol treatment?

A.

Some of the information I would want to know about the patient prior to initiating therapy include:

1) On chronic corticosteroid (CS) therapy? If so, how much?
2) How much inhaled albuterol or other short acting beta agonist has the patient been taking in the hours/days prior to treatment in the E.D.?
3) Independent cardiac disease? Arrythmia?
4) Other medications currently taken? Drug allergies?
5) In pre-treatment exam -

Vital signs (particularly evidence of irregular heart rhythm), lungs, pulse-ox. Evidence of dehydration. Spirometry if patient can carry this out. Otherwise, measure PEFR.

Orders for nebulized albuterol. Flovent: obviously what is missing in your description is the amount and frequency of dosing of each agent. Monitor vital signs, pulse-ox and spirometry/PEFR frequently.

9/9/05 re: Value of PEFR in monitoring acute asthma exacerbations
Q.

I am trying to establish the use of the NAEPP guidelines Management of Asthma Exacerbation: Emergency Department Care, in our Pediatric Emergency Center and I developed standing orders in reference to the guidelines published in 2002 which suggest performing PERF on known asthmatics, to assess their respiratory status, along with a complete respiratory assessment. I presented these standing orders to our pediatric and adult pulmonologist at our hospital and neither of them wants the PERF to be part of the orders. Both say that PERF show little or no value when evaluating a patient's respiratory status and that it's not "current best practice", yet, the latest recommendations by the NAEPP guidelines recommend them. I am looking for recent literature to either prove or disprove the use of PERF on an acute exacerbation of asthma.

A.

To help respond to your question, I obtained input from Dr. Stanley Szefler of the National Jewish Medical and Research Center in Denver. Dr. Szefler is an expert in asthma, including the evaluation of acute asthma exacerbations. Dr. Szefler participated in the Expert Panel that constructed the NAEPP guidelines (sponsored by the NHLBI, NIH) to which he refers in his comments. I believe that part of the controversy about the value of PEFR monitoring, particularly in acute asthma exacerbations, may be related to the variability in repeated measurements of this very effort-dependent PEFR approach. As Dr. Szefler points out, spirometry seems preferable to PEFR in monitoring acute asthma exacerbations. You can obtain the updated NAEPP guidelines to get more information in this regard by accessing them through a link from this AADMC website. Go to the website ( www.aaaai.org/aadmc ), click on the Current Literature section, then click on "updated asthma guidelines"

Dr. Szefler's comments:

The question we addressed in the NAEPP guidelines update was in regards to the value of PEF in routine monitoring. We could find no evidence to support their regular use but still felt they could be useful for individuals as a guide to monitoring. This was discussed in detail in the 2002 update.

Certainly, in a pulmonary clinic, spirometry would be the preferable route to assess patient status regarding exacerbations.

6/24/05 re: Salmeterol use for acute asthma
Q.

Although I am an RN and work in disease management of asthma patients, I have not been able to locate information regarding the use of serevent vs albuterol during an asthma flare up. A physician recommended that a child with worsening asthma symptoms stop his advair when symptoms were worse and use only flovent - in other words - stop the serevent. As I understand it, the reason was because the albuterol would be more effective without the serevent because the serevent occupies the receptor sites needed by the albuterol, and therefore the child would not require albuterol as often. I had never heard of this previously and would like to know if you have any feedback regarding this practice.

A.

As you likely know, salmeterol (Serevent) is not recommended by the manufacturer for the treatment of acute asthma flares. Rather use of short-acting beta agonists such as albuterol is recommended (see page 1622 of the current edition of the PDR for the statements from GlaxoSmithKline). This recommendation is likely related to the relatively slower onset of bronchodilating effect of salmeterol (about 30 minutes). There have also been concerns about use of salmeterol for the treatment of acute asthma because of findings about asthma fatalities in the SMART study (also described in the discussion of Serevent in the current PDR). However, a recent analysis found that long-term use of short-acting beta agonists , but not long-acting beta agonists (LABA), was a significant risk factor for asthma fatalities (see my review of that report for the Current Literature section of this AADMC website, enclosed below).

You raised the question whether there would be decreased efficacy of inhaled albuterol in acute asthma because of concomitant salmeterol therapy. Previous studies have shown that pulmonary function was not decreased significantly during chronic therapy with LABA. However, there was a significant decrease in the acute bronchodilatory effect of inhaled albuterol in individuals treated daily with LABA for at least 2 weeks. It is not clear whether the latter effect was due to occupancy by salmeterol on receptors for beta agonists or the down-regulation of the expression of such receptors. Although the clinical significance of such decreased responsiveness to albuterol is still not certain, such findings have prompted some asthma experts to express concern about continued use of salmeterol during worsening asthma. That is likely the situation to which your physician referred. It may be advisable to with hold salmeterol when albuterol is being used for acute worsening asthma.

However, there is evidence that the situation may be different with use of formoterol, another LABA. As you likely know, formoterol has an unique pattern of bronchodilating effect with onset as rapid as that of albuterol (1-3 minutes) and duration as long as salmeterol (8-12 hours, maybe even longer). In a recent report by O'Byrne et al (Amer J Respir Crit Care Med 2005;171:129-36), these experienced asthma investigators studied a group of asthmatics treated chronically with a combination inhaler containing formoterol and budesonide, an inhaled steroid. They found that when the asthma worsened acutely in such patients, they actually did better when the dosage of this combination was increased than when they were continued on the standing doses of the combination medications plus prn use of albuterol.The authors suggested that the combination formoterol/budesonide inhaler (now marketed as Symbicort) could be used as both maintenance controller and rescue treatment for acute asthma. I suggest that you read this report to see the details of this study. Another recent study found similar (mild) degrees of adverse effects of formoterol vs albuterol (Pulm Pharmacol Ther 2005;18:229-34)

Bronchodilator use and deaths from asthma

Summary
Background - There is a continuing debate whether chronic use of inhaled beta agonist bronchodilators is a risk factor for fatal outcomes in asthma. Based on findings in several studies, concerns have been raised about the chronic use of all inhaled beta agonist agents in asthma treatment.

Findings - Anderson et al of St. George's Hospital Medical School in London, UK carried out a case control study comparing prescription records in: 1) 532 asthmatics with fatal outcomes and in 2) 532 control subjects hospitalized with asthma flares during the same time period without fatal outcomes. They found no association of asthma fatalities with chronic use of any asthma medication during 4-12 months before the index date. However, there was a significant association of asthma fatalities with chronic use of inhaled short acting beta agonists during the period 1-5 years prior to the index date (Odds Ratio - 2.05). This association appeared to be mainly in patients 45-64 years old. If anything, there was a somewhat inverse relation between chronic use of inhaled long acting beta agonists (LABA) and asthma fatalities.

Reference - BMJ 2005;33:117

Editor's Comments
The findings in this study suggest that the risk for fatal asthma outcomes associated with inhaled short acting beta agonist use comes only with use of such agents for at least one year. This finding could support the contention that some cumulative toxic effect of agents such as albuterol is involved. While this is possible, my personal view has been that chronic use of inhaled short acting beta agonists as monotherapy frequently gives short term relief of asthma symptoms while the patients ignores the steadily deteriorating state of the asthmatic bronchial inflammation. Eventually, the airways pathology is so advanced that the risk of a fatal outcome is increased. The fact that chronic use of LABA was not associated with asthma fatalities in this analysis is reassuring in view of the extensive use of such agents along with inhaled corticosteroids in the management of moderate to severe persistent asthma. However, findings in the recent SMART study showed an increased frequency of asthma fatalities in those using salmeterol (an LABA agent) for persistent asthma. These findings have prompted the FDA to require a warning about the chronic use of salmeterol in persistent asthma, particularly in African-Americans.

8/19/04 re: Use of aminophylline in acute, severe asthma
Q.

Should aminophylline be used for severe asthma? I have a patient who is 14 years old and is in PICU in mechanical ventilator--it is recommended? May you send information to share with my pediatric residents? It has been controversial.

A.

You are correct that the use if I.V. aminophylline in acute severe asthma is controversial. Theoretically, aminophylline should be helpful in such situations because it induces bronchodilation for a longer duration than does albuterol, may dilate smaller airways and enhance diaphragmatic muscle strength in respiration. Indeed, theophyllines, including aminophylline, were considered a staple of the treatment of moderate/severe asthma in the 1970's-1980's. However, more recent asthma treatment guidelines such as those of the National Asthma Education and Prevention Program (NIH) Expert Panel, published in 1997 (and updated since then) have concluded that theophyllines are not first-line treatment for acute asthma. This reduced enthusiasm for use of theophyllines relates to the concerns about toxicity with a relatively narrow difference between the theophylline levels required to benefit acute severe asthma and those levels causing toxic effects (sometimes very severe) in some asthmatics. The situation is complicated by frequent interactions of theophyllines with other drugs leading to higher (or lower) serum theophylline levels than one would have predicted. Thus, serum theophylline levels must be closely monitored in the use of these agents in acute asthma. A meta-analysis of controlled studies concluded that the addition of aminophylline to full doses of inhaled beta-agonists conferred no additional benefit, while increasing the likelihood of toxicity in the treatment of acute asthma (2). Thus, most asthma experts feel that aminophylline treatment should be reserved only for severe acute asthma cases persisting despite intensive use of standard approaches (injected epinephrine frequent inhalation of beta agonists such as albuterol, parenteral corticosteroids, fluid replacement).

One may also consider some additional approaches when standard therapy is not sufficient. These include anti-cholinergic agents (3), MgSO4 (reviewed in 4) and maybe heliox (5)-controversial). You are likely familiar with the use of mechanical approaches in status asthmatics, including so-called controlled mechanical hypoventilation (6).

References

  1. NIH Publication #97-4051
  2. Cochrane Database Syst Rev 2000;CD002742
  3. NIH Publication #97-4051.
  4. Cochrane Database Syst Rev 2000; CD 001490
  5. Chest 2000;117:1212-1213
  6. Clin Rev Allergy Immunol 2001;20:385-397
7/15/04 re: Role of magnesium sulfate treatment in acute asthma
Q.

I recently completed the EMT-Intermediate program. I have been on several asthma calls since. We follow our protocols as approved by our medical director which includes using Albuterol, EPI, and Solumedrol for treating asthma. I went to the state-wide EMS conference this last weekend and one of the seminars I attended was on the emergency treatment for asthma. In the program, presented they included the use of Mag Sulfate in the treatment algorithm. We were not taught anything about this in our I program and our instructor was sitting right next to me in the seminar and she said she had not heard of using mag. My question to you is, is mag an accepted treatment for asthma and, if so, how does it work?

A.

The efficacy of magnesium sulfate (MgSO4) as add-on treatment in the therapy of acute asthma exacerbations has been debated in recent years. Most of the studies I have reviewed for this AADMC website (see my reviews below) and have concluded that any additional benefit of MgSO4 is relatively modest, generally confined to cases of more severe asthma exacerbation. Also enclosed is my review of a Commentary article in Lancet in 2003 which tried to put these findings in perspective. However, more impressive improvement in mild-moderate asthma was reported very recently (see enclosed abstract).

My "bottom line" impression at this time is that MgSO4 may be worth consideration as add-on treatment in cases of severe, acute asthma not responding sufficiently to standard therapy. However, one should not expect too much of this approach with considerable variability among patients in responsiveness to MgSO4.

Current Lit Item
More about IV Magnesium Sulfate in the treatment of acute asthma

Summary
The role of magnesium sulfate (Mg SO4) in the treatment of acute asthma continues to be debated because of mixed findings. Silverman et al of the Long Island Jewish Medical Center in New Hyde Park, NY carried out a multi-center randomized trial of IV Mg SO4 2.0 Gm or placebo in the ED treatment of acute severe asthma in 248 adults (1). All patients received IV methylprednisolone and inhaled albuterol at regular intervals. After 240 minutes, the mean FEV1 was modestly better in those who received Mg SO4 than in those who received placebo (mean difference = 4.7%, p=0.045). However, the mean Mg SO4 placebo difference in FEV-1 was greater (9.7%) in those asthmatics with more severe impairment of FEV-1 (< 25%) to begin with. Overall, the use of MgSO4 did not reduce the rate of in-patient admission in these patients. Rowe et al of the Univ. of Alberta in Canada previously carried out a systematic review of medical literature dealing with the effects of IV Mg SO4 in acute asthma (2). They concluded that, overall, IV Mg SO4 treatment did not lead to significantly greater improvement in PEFR and FEV-1. However, there was a modest, but significant added benefit of IV Mg SO4 treatment in those who presented with more severe acute asthma flares. The IV Mg SO4 was well tolerated.

References
1. Chest 2002; 122:489-497
2. Ann Emerg Med 2001; 36:181-90

Editor's Comments
This large multi-center study by Silverman (1) came to conclusions fairly similar to that in the review by Rowe et al (described above) of previous studies of IV Mg SO4 therapy in acute asthma. Occasional earlier studies have found benefit of IV MgSO4 in acute asthma (J Asthma 1998; 129-130.). However, very modest, if any, significant added benefit of Mg SO4 to pulmonary function was demonstrated if one considers all asthmatics being so treated in all the studies reviewed. However, in those with more severe acute asthma flares (FEV-1 < 25% of predicted) a more impressive improvement in FEV-1 was noted. Nevertheless, the rate of hospitalization after treatment in the ED was not reduced significantly. Because the IV MgSO4 treatment was generally well tolerated, Rowe et al (2) suggested “Current evidence does not clearly support routine use of intravenous magnesium sulfate in all patients with acute asthma presenting to the ED. However, magnesium sulfate appears to be safe and beneficial for patients who present with severe acute asthma.” Recent controlled studies have found no significant added benefit of inhaled MgSO4 in the treatment of acute mild to moderate asthma (Ann Emerg Med 2002;39:585-91). A recent review of the treatment of acute severe asthma flares in children concluded that MgSO4 treatment “has no clear advantage.” My “bottom line” impression at this time is that IV MgSO4 may have a limited role in selected cases of acute asthma.


Current Lit Item
Role of inhaled magnesium in acute asthma treatment

Summary
Intravenous magnesium sulfate (MgSO4) has been found to enhance the response to standard treatment of acute severe asthma (but not mild-moderate asthma) flares. It is uncertain whether such therapy reduces the in-patient admission rate for asthma flares. Less is known about the effects of nebulized MgSO4 (neb MgSO4) in the treatment of acute asthma. This subject was reviewed in a recent editorial by Bucca and Rolla of the Univ. of Torino in Italy . Some studies have shown that the bronchodilating effect of nebulized MgSO4 was similar to that of inhaled albuterol in acute asthma flares. The addition of neb MgSO4 to standard therapy of acute severe asthma allows a significant reduction in the dose of inhaled albuterol needed to induce a bronchodilating effect with no change in the maximum bronchodilating effect. In contrast, the addition of neb MgSO4 to albuterol provided no significant added benefit when compared to inhaled albuterol alone in the treatment of mild to moderate asthma. The authors described a study by Hughes et al in the same issue of Lancet that showed an enhanced bronchodilating response when isotonic neb MgSO4 was used as an adjuvant to inhaled albuterol in the treatment of acute severe asthma.

Reference - Lancet 2003;361:2095-96

Editor's Comments
The findings reviewed here suggest that neb MgSO4 enhances the bronchodilating response to inhaled albuterol in standard doses in severe but probably not in mild to moderate acute asthma. MgSO4 is thought to act by competing with Ca++ ions at the voltage- dependent Ca++ ion channels in airway smooth muscle resulting in an anti-bronchoconstrictor effect. However, it is somewhat surprising that both IV and neb MgSO4 exert this beneficial effect in severe acute asthma since drugs, such as diltiazem and verapamil, which potently block this voltage- dependent Ca++ ion channel have variable and generally unimpressive bronchodilating effects.


J Emerg Med. 2004 Jul;27(1):21-5.
Comparison of nebulized magnesium sulfate plus albuterol to nebulized albuterol plus saline in children with acute exacerbations of mild to moderate asthma.
Mahajan P, Haritos D, Rosenberg N, Thomas R.
Division of Pediatric Emergency Medicine, Children's Hospital of Michigan, Detroit, Michigan, USA.

A prospective, randomized, double blinded study was conducted to determine whether a combination of nebulized magnesium sulfate and albuterol as a single dose adds any benefit in management of children with mild to moderate asthma when compared to nebulized albuterol with saline. The difference in FEV1 was significant at 10 and 20 minutes after a single dose of the combined treatment with magnesium and albuterol when compared with the albuterol and saline group (1.41 L +/- 0.53 vs. 1.13 L +/- 0.34, respectively, p = 0.03). The addition of magnesium to albuterol seems to provide short-term benefits in children with acute exacerbations of mild to moderate asthma.

8/20/01 re: I.V. furosemide for childhood asthma
Q. I am a pediatric nurse working at Flagstaff Medical Center in Arizona. I am caring for a 3-year-old male patient who was admitted for acute exacerbation of asthma. His physician has added intravenous furosemide to his drug therapy, which consisted of albuterol, atrovent and solumedrol. He also discontinued his intravenous fluids. I am unfamiliar with the use of diuretic therapy for asthma and am unable to find relevant research. I located some studies, but they were primarily about the use of inhaled furosemide with adult subjects. I would appreciate any feedback.
A. I am aware of reports about trials of furosemide in adult asthmatics but have not heard about the use of this agent in children. Because I have not participated in the care of children with asthma for many years, I consulted Dr. Susan Schuval, a highly experienced Pediatric Allergist who is a member of the Medical Advisory Committee for this AADMC website. Dr. Schuval's response is enclosed below. As she notes, the mechanism proposed for any effect of inhaled furosemide is a local action in the airways. Therefore, I think that any trials of furosemide would be by inhalation and not systemic administration. The latter may lead to further dehydration in-patients where dehydration is already a frequent problem because of excessive fluid loss due to hyperpnea.

INHALED FUROSEMIDE FOR ASTHMA

Furosemide is a loop diuretic that interferes with ion and water transport. Although furosemide has long been used for treatment of bronchopulmonary dysplasia in infants, it is not currently approved for treatment of either pediatric or adult asthma. It is regarded as an alternative therapy for steroid-dependent asthma (1).

In a 1989 NEJM article, Bianco et al reported that inhaled furosemide had a protective effect on the allergen-induced early and late phase asthmatic reactions. This double blind, placebo-controlled, randomized crossover study involved 11 adult patients with mild allergic asthma (2). Previous studies had shown that inhaled furosemide protected against exercise-induced asthma (3). The mechanism of bronchoprotection was postulated to involve either an anti-inflammatory effect via changes in the osmotic or ionic environment of epithelial cells or an effect on sensory nerves rather than direct bronchodilatation. Inhaled furosemide was subsequently shown to attenuate bronchoconstriction secondary to other stimuli such as hypertonic salt and adenosine but not to methacholine or histamine (1).

Bianco's study provided the impetus for further study of inhaled furosemide in the treatment of allergic asthma. A 1997 study by Melo et al. examined the efficacy of inhaled furosemide in the treatment of exercise-induced asthma (EIA) in children. Furosemide was found to have comparable efficacy to cromolyn in the prevention of EIA (4). In 1999, Yuensrigul et al showed that children with mild asthma receiving inhaled furosemide had modest improvement in their pulmonary function tests (5). The authors were able to demonstrate that furosemide had an anti-inflammatory effect in that it reduced cytokine production (IL-8, IL-6, TNF-alpha) by stimulated peripheral blood mononuclear cells. Furosemide was also shown to reduce production of the enzyme phospholipase A2 involved in the arachidonic acid pathway (6).

In summary, although inhaled furosemide seems to hold some promise for future treatment of asthma, it should not be routinely administered to children with asthma.

REFERENCES:

1. Moss RB. Alternative pharmaco therapies for steroid-dependent asthma. Chest 1995;107(3):817-825.

2. Bianco S, et al. Protective effect of inhaled furosemide on allergen-induced early and late asthmatic reactions. N Engl J Med 1989;321:1069-73.

3. Bianco S, et al. Prevention of exercise-induced bronchoconstriction by inhaled furosemide. Lancet 1988;2:252-5.

4. Melo RE, et al. Comparative efficacy of inhaled furosemide and disodium cromoglycate in the treatment of exercise-induced asthma in children. J Allergy Clin Immunol 1997;99:204-9.

5. Yuengsrigul A, et al. Immunosuppressive and cytotoxic effects of furosemide on human peripheral blood mononuclear cells. Annals of Allerg 1999;83(6):559-566.

6. Helfrich U et al. In vitro effects of theophylline and furosemide on PLA2 activity (Abstract). Anesth Analgesia 1998;86(2S):543S.

 
5/25/01 re: Role for hydration in asthma therapy
Q. I am the clinical director of a disease management organization that provides education to patients regarding their asthma. A question has arisen from some of our nurses regarding the need for hydration in asthma. I have delved back into the guidelines and searched the literature, with very little success in addressing the issue. I have found only one article that speaks to hydration and asthma, and that is regarding EIA. Would you please clarify the role of hydration in the management of asthma, and it's importance or role in educating patients.
A. It is generally stated in textbook chapters and reviews that hydration is an important component of the management of acute asthma flares, particular when the latter are severe. I believe that this philosophy dates from the known rapid fluid loss from the airways during hyperpnea and previous observations of the of excessively thick airway secretions, sometimes forming a solid cast within the bronchial lumen, in cases of fatal or near-fatal asthma. However, I agree with you that there is little published evidence to support the concept that large amounts of intravenous fluids lead to hydration of such excessively thick airway secretions. In some patients, there is evidence of systemic dehydration, sometimes to the point of hypotension. In one study (see enclosed abstract) this dehydration was considered of modest degree and fluid replacement at a rate of 50 ml/kg/hour was considered reasonable in children. In another study, vascular volume expansion was thought to decrease the physiologic dead space in asthmatics (see enclosed abstract) In the well-known allergy text by Middleton et al. Eds. The asthma treatment section suggest dextrose in half-normal saline (with K+ added as needed) at a rate of 100-150ml/hr. but cautions against excessively rapid fluid replacement because of the hazard of inducing pulmonary edema in occasional individuals. I personally have used the vital signs, lab evidence of hemoconcentration, and urinary output (or lack of it) to assess how much fluid to give IV and the rate of administration. What may be more effective at times is hydration of the inspired air, particularly when supplemental oxygen is given. Again, one has to avoid excessively high humidity of this inspired air since it may trigger coughing in some asthmatics with marked bronchial hyper-reactivity. Previous attempts at obtaining more rapid clearing of the thick mucous plugs in the airway by bronchial lavage have been pretty much discontinued because of technical difficulties and adverse effects during the procedure.

Arch Dis Child 1991 Feb;66(2):216-9
Hydration in severe acute asthma.
Potter PC, Klein M, Weinberg EG.
Department of Clinical Science and Immunology, University of Cape Town, South Africa.

Twenty children were studied during severe attacks of acute asthma to find out how dehydrated they were on admission to hospital. Mean body weight on admission was 97.8% of their reference stable weight seven to 10 days after the attack and in only three children was it less than 95% of the stable weight. Bedside assessment of dehydration was unreliable. The mean packed cell volume was significantly higher on admission than 7-10 days later (0.44 compared with 0.42, difference 0.02 SE 0.01). Serum sodium and potassium concentrations and osmolality on admission were within normal ranges. The degree of dehydration correlated best with a fall in blood pH. There was no association between the degree of dehydration and the recovery of the peak expiratory flow rate during the first 24 hours or thereafter. We conclude that mild dehydration is common in severe acute childhood asthma. Fluid given at a rate of 50 ml/kg/24 hours was safe and appropriate for these children 

Chest 1997 Sep;112(3):843-6
The effect of volume infusion on dead space in mechanically ventilated patients with severe asthma. 
Manthous CA, Goulding P. 
Pulmonary and Critical Care Division, Bridgeport Hospital and Yale University School of Medicine, Conn, USA.

Mechanical ventilation of patients with severe asthma is associated with elevated airway pressures that may contribute to increased physiologic dead space. To our knowledge, no previous reports have considered the effect of intravascular volume status on dead space fraction. We herein describe three patients whose dead space decreased by a mean of 4.2% in response to intravascular volume expansion with 250 or 500 mL of normal saline solution administered as part of their routine treatment. No significant changes in CO2 production, minute volume, or airway pressures occurred over the time interval. We conclude with a brief discussion of potential mechanisms to explain these findings and their potential clinical application.  
5/01/01 re: Albuterol dosing for acute, severe asthma episode
Q. How frequently should we give ventolin nebulization in acute severe asthma in children and in adults? What is the role of steroid nebulization in acute severe asthma?
A.

A number of regimens using varying doses and frequency of inhaled albuterol (Alb, salbutamol) have been reported. The NAEPP Expert Panel Guidelines and The Joint Task Force Practice Parameters do not contain detailed recommendations concerning dosing of Alb in acute asthma episodes. Therefore, I have enclosed abstracts of several recent articles describing their approaches in adults and children.. Note that some groups add an inhaled anti-cholinergic agent to the treatment regimen. I have also enclosed the responses in this area which I had previously solicited from 2 highly experienced pediatric asthma specialists (since I am an internist who does not care for small children).

I should mention that reviews of comparisons between the use of nebulizers and MDI with spacers have shown no significant differences in clinical efficacy except where the patients cannot manipulate the MDI correctly (e.g.young children). See the enclosed review I had written about about a meta-analysis of these comparisons.

Ann Emerg Med 2000 Sep;36(3):198-203
Comment in: Ann Emerg Med. 2000 Sep;36(3):236-8
Continuous versus intermittent nebulization of salbutamol in acute severe asthma: a randomized, controlled trial.
Besbes-Ouanes L, Nouira S, Elatrous S, Knani J, Boussarsar M, Abroug F. 
Intensive Care Unit and Emergency Department, Centre Hospitalo-Universitaire Fattouma Bourguiba, Monastir, Tunisia.

Study Objective: This study was conducted to compare the clinical and spirometric effects of continuous and intermittent nebulization of salbutamol in acute severe asthma.
Methods: Forty-two consecutive patients presenting to the emergency department for acute severe asthma (peak expiratory flow [PEF] mean+/-SD, 24%+/-12% predicted) were prospectively randomly assigned to receive 27.5 mg of salbutamol by either continuous or intermittent nebulization over a 6-hour period. The continuous nebulization group received 15 mg of salbutamol during the first hour and 12.5 mg over the next 5 hours. The intermittent nebulization group received 5 mg of salbutamol every 20 minutes during the first hour and 2.5  mg hourly over the next 5 hours. All participants received oxygen and intravenous hydrocortisone. Clinical and spirometric assessment was performed at baseline, 40 minutes, 60 minutes, and at 3 and 6 hours after the start of the nebulization. Secondary endpoints were the respective rates of hospitalization and treatment failure. 
Results: A significant clinical and spirometric improvement was observed in both groups over baseline as soon as the 40th minute and was sustained thereafter (absolute PEF increase at the sixth hour 30%+/-18% and 32%+/-22% in the continuous and intermittent nebulization groups, respectively; P <.01 over baseline). PEF and the clinical score evolved similarly in both groups. There was no difference between the groups regarding the failure rate of the initial bronchodilator treatment to terminate the asthma attack (3 [14%] in the continuous nebulization group and 2 [9.5%] in the intermittent nebulization group, absolute difference 4.5% [95% confidence interval -14% to 23%]). Eight (38%) patients and 9 (43%) patients from the continuous and intermittent nebulization groups, respectively, required hospitalization according to predefined criteria (absolute difference 4.8% [95% confidence interval -24% to 34%]). 
Conclusion: We did not observe an appreciable difference between continuous and intermittent nebulization of salbutamol in acute severe asthma. The decision to use one of these nebulization methods should be based on logistical considerations.

J Pediatr 2001 Jan;138(1):51-58  
Ipratropium bromide plus nebulized albuterol for the treatment of hospitalized children with acute asthma.
Craven D, Kercsmar CM, Myers TR, O'riordan MA, Golonka G, Moore S. 
Division of Pediatric Pulmonology, Department of Pediatrics, University Hospitals of Cleveland, Rainbow Babies and Childrens Hospital, Case Western Reserve University, Cleveland, Ohio 44106, USA.

Objective: To determine whether the addition of repeated doses of nebulized ipratropium bromide (IB) to a standardized inpatient asthma care algorithm (ACA) for children with status asthmaticus improves clinical outcome.
Study Design: Children with acute asthma (N = 210) age 1 to 18 years admitted to the  ACA were assigned to the intervention or placebo group in randomized double-blind fashion. Both groups received nebulized albuterol, systemic corticosteroids, and oxygen according to the ACA. The intervention group received 250 microg IB combined with 2.5 mg albuterol by jet nebulization in a dosing schedule determined by the ACA phase. The placebo group received isotonic saline solution substituted for IB. Progression through each ACA phase occurred based on assessments of oxygenation, air exchange, wheezing, accessory muscle use, and respiratory rate performed at prescribed intervals. 
Results: No significant differences were observed between treatment groups in hospital length of stay (P =.46), asthma carepath progression (P =.37), requirement for additional therapy, or adverse effects. Children >6 years (N = 70) treated with IB had shorter mean hospital length of stay (P =.03) and more rapid mean asthma carepath progression (P =.02) than children in the placebo group. However, after adjustment was done for baseline group differences, the observed benefit of IB therapy in older children no longer reached statistical significance.
Conclusion: The routine addition of repeated doses of nebulized IB to a standardized regimen of systemic corticosteroids and frequently administered beta-2 agonists confers no significant enhancement of clinical outcome for the treatment of hospitalized children with status asthmaticus.

J Allergy Clin Immunol 2000 Sep;106(3):472-8
Efficacy of adding multiple doses of oxitropium bromide to salbutamol delivered by means of a metered-dose inhaler with a spacer device in adults with acute severe asthma.
Nakano Y, Enomoto N, Kawamoto A, Hirai R, Chida K.   
Department of Internal Medicine, Hamamatsu Rosai Hospital, Hamamatsu, Japan.

Background: The efficacy of combination therapy adding multiple doses of anticholinergics to beta(2)-agonists to improve outcome has not been established in adults with acute severe asthma. 
Objective: This study was undertaken to compare the outcome of adults with acute severe asthma treated with 4 puffs of salbutamol (100 microg/actuation) every 20 minutes for 3 doses plus 4 puffs of oxitropium bromide (100 microg/actuation) with each of the 3 salbutamol doses versus salbutamol alone administered by means of a metered-dose inhaler with a spacer device. 
Methods: A randomized, single-blind, placebo-controlled study was performed in 74 patients between 18 and 55 years old presenting to the emergency department (ED) for treatment of acute asthma with a peak expiratory flow (PEF) of 50% or less than the normal predicted value. The primary endpoint was improvement in PEF over the course. The secondary endpoint was the need for additional ED treatment at 120 minutes. 
Results: The  increase in PEF over the course was significantly greater in the oxitropium plus salbutamol treatment group (P <.0001). The mean absolute difference in PEF at 120 minutes for combination therapy compared with salbutamol alone was 37.8 L/min (P =.001). In addition, the proportion of need for additional ED treatment was less in the combination group than the group receiving salbutamol alone (odds ratio, 0.32; 95% confidence interval, 0.11-0.90). 
Conclusion: Adding multiple doses of oxitropium bromide to salbutamol delivered by means of a metered-dose inhaler with a spacer device for acute severe asthma produces a significant improvement in lung function and reduces the need for additional ED treatment.

Response to a previous similar Ask the Expert question:
Dosing of albuterol in kids is erratic. It is true that hospitals do tend to give much larger doses than is done as routine outpatient dosing. CHOP is very aggressive in inpatient management - we will go up to 1 cc of albuterol which is total of 5 mg for one treatment. I am not aware of anyone going higher than that. There was a recent article in one of the pediatric journals regarding inpatient protocol for Johns Hopkins, (see Harriet Lane guidelines enclosed below). For outpatient management, the recommendation is up to .5 cc (2.5mg) as pointed out in the guidelines. It does get a little confusing with the use of xopenex (the recently released albuterol stereoisomer), because then the dosage gets halved. I have been using a good bit of the xopenex when I have to give frequent treatments with exacerbations associated with URI's. Anecdotally, the episodes don't resolve any quicker but I do believe we are seeing less of the jitteriness that is commonly associated with the use of frequent albuterol. In the recent survey published in the lay publication from the Mothers of Asthmatics group, under 50% of parents comply with giving full doses of albuterol because of side effect profile. My concern is that the more you give, the less likely parents will comply with outpatient recommendations because of the side effects. Not related to above, but I heard Peter Barnes this week and he was an advocate of low dose theophylline as option for second controller medication after inhaled  steroids.   

As the physician noted in the inquiry, the general tendency in pediatrics has been to really push the dosage for sick kids in hospital. One of the things that I have been doing for years, is use terbutaline sometimes as substitute, and will go up to 3 mg for treatment. We do see more musculoskeletal side effects with the terbutaline, but less tachycardia. What CHOP has been doing as a routine now for a few months is use atrovent with albuterol on the inpatient side. I am not convinced that it makes a major difference by adding the atrovent, at least in pediatrics with pure asthma 

  1. Package insert for Albuterol sulfate inhalation solution 0.5%: Says to titrate dose to reach desired clinical effect:        
    2-12 year old children: 0.1-0.15 mg/kg/dose to a maximum of (1.25 mg) 0.25mL 
    >12 years : 2.5 mg (0.5 ML) 

  2. 2000 Physician's Desk Reference: Proventil solution for inhalation 0.5%: Only lists a dose for children > age 12 (2.5 mg=0.5 mL); Ventolin inhalation solution 0.5%: 0.1-0.15 mg/kg/dose to a maximum of 2.5 mg in children between the ages of 2 years to 12 years

  3. Harriet Lane Handbook (15th Ed., 2000)  
    Albuterol nebulization solution 0.5%: 
    Kids < 1 year: 0.05-0.15 mg/kg/dose 
    1-5 years: 1.25-2.5 mg/dose 
    5-12 yrs: 2.5 mg/dose 
    >12 years: 2.5-5 mg/dose (With a note that in "acute exacerbations more aggressive dosing may be employed)>

  4. Pediatric Pharmacology and Therapeutics-Textbook (Radde IC, MacLeod SM. Mosby 1993. Chicago).
    Salbutamol: starting dose: 0.04 ml/KG of body weight increase to 0.1 ml/kg or "until a significant increase from the basal heart rate is seen" 

  5. Mosby's GenRx: 2000 (10th ed.)
    children 2 yrs- 12 yrs: 0.1 to 0.15 mg/kg/dose to a maximum of 2.5 mg

Another Opinion:
At our institution, we generally use the 0.1-0.15 mg/kg/dose for nebulization of hospitalized asthmatics.

Nebulized corticosteroids in the treatment of asthmatic patients

Summary
Some clinicians who believe that machine-powered nebulization is a more effective means of delivering inhaled anti-asthma medications than MDI have been pleased to see the current availability of the steroids, budesonide and fluticasone, in nebulizer solutions in some parts of the world. But is their use really advantageous? This subject was reviewed by Hill of the Northern General Hospital in Sheffield, UK. On the basis of a literature review, she has concluded that the most likely group to be prescribed nebulized corticosteroids (NCS) are the minority of asthmatics who require very high doses of inhaled corticosteroids (ICS) by MDI and/or frequently used oral steroids. There is little evidence from controlled studies that NCS is more effective than high dose ICS in this group. There may be less side effects from either NCS or high dose ICS than from oral steroids used in doses yielding the same beneficial anti-asthma effects. A few, small studies have shown that NCS are as effective as oral steroids in acute severe exacerbations of asthma. Larger, randomized controlled studies are needed for all these comparisons. Meanwhile, one cannot ignore the much higher cost and time involved in nebulized treatment than in oral steroid therapy. 

Reference
Thorax 1999;54:661-63

Editor's Comments
There is strong belief by some clinicians that power nebulization should deliver steroids more effectively to the lower airways than do MDI or dry powder inhalers (DPI). The evidence summarized by Hill does not make a strong case for major advantages of NCS therapy with the exception of use in those (e.g. young children) in whom effective MDI or DPI use is not feasible.
6/23/00 re: Stages of acute asthma
Q. What are the stages of acute asthma attacks by biochemical stages, clinically and by treatment.
A. Space limitations do not permit the required discussion of the subject of the complex events which transpire in acute asthma exacerbations. This has generally required at least a monograph for complete discussion. Therefore, we have to ask you to focus your question more. For example, are you asking about biochemical changes that occur at different time periods during the acute asthma flare, or as categorized by the degree of severity of symptoms?

Below are references to several review articles dealing with the acute asthma exacerbation to give you an idea of the thinking in this area. This subject is also discussed well in the recent editions of textbook (e.g.-Allergy, Principles and Practice by Middleton et al, Eds; Pulmonary Diseases by Fishman et al, Eds). If you have specific questions after reading these (and preferably the whole articles), please re-submit such questions.

REFERENCES: www.medline.com 

  • Arch Pediatr 2000 Mar;7 Suppl 1:27S-32S
  • Acad Emerg Med 2000 Apr;7(4):327-34
9/14/99 re: Value of Heliox in acute asthma
Q. I am trying to find studies on Heliox usage in asthmatics. I can personally vouch for the use of it. I have seen children come into the ER on high FiO2's and wheezing terribly to be weaned to 25-30% O2 and better aeration from breathing Heliox mixtures. I am most interested in finding some concrete studies ( or proof on paper) so that my argument is more convincing..
A. Recent reports have come to varying conclusions about the value of Heliox in acute asthma. Henderson et al found no greater improvement in PEFR after Heliox than after standard O2 administration in 205 episodes of mild to moderate asthmatic exacerbation (1). Verbeek and Chopra found no improvement in FEV1 after Heliox treatment in a small study (n=13) (2). On the other hand, Browne and Cassidy found improved PEFR, decreased dyspnea and pulsus paradoxicus following Heliox treatment of a small group of children in status asthmaticus (3). In a review, Levy et al of the Brigham and Women's Hospital in Boston, stated that Heliox treatment in status asthmaticus has its advocates but is not recommended as part of routine care of status asthmaticus.

These findings suggest that Heliox may be inconsistently beneficial, possibly varying among patients. Therefore, it may be necessary to consider its use on a case by case basis.

REFERENCES

  1. Ann Emerg Med 1999;33:141-6
  2. J Emerg Med 1998;16:545-8
  3. Ped Nurs 1997;23:479-82
  4. Intens Care Med 1998;24:105-17
4/27/99 re: Nature of sudden fatal asthma
Q. I am a CNS on a Med/Surg floor - we recently had a case of status asthmaticus which resulted in patient demise. It has been suggested that this patient experienced "sudden fatal status asthmaticus" a well-known syndrome that presents with little warning, progressing to asphyxiation over a few minutes or in less than 1 hour. I am unfamiliar with this syndrome and have had little success in finding any information on same.
A. Sudden death (SD) during an asthma exacerbation of short duration (e.g. - less than 1-2 hours) is a relatively rare event. Recent studies suggest a different respiratory pathologic profile in such SD cases, as compared to that seen in chronic asthmatics and in those who died after more prolonged asthmatic flares, with more prominent neutrophils and mucus gland hyperactivity and possibly less prominent eosinophil accumulation. One study reported increased CD8+ T lymphocytes in SD cases. Another report described adrenal gland atrophy in 18% of cases, likely related to prior chronic higher dose steroid therapy.

The clinical background/characteristics of SD cases is less clearly distinguished from those individuals who died after more prolonged asthma flares. Overall, fatal asthma has occurred in those with more severe asthma, often requiring high dose steroid therapy and common (but not universal) histories of previous repeated hospitalizations, including a previous episode of a near fatal asthma exacerbation. There is often a denial of asthma severity by the patient. Most of the data does not suggest that SD has been associated with an acute toxic effect of medications employed. Therefore, much has to be learned about these tragic events.

Several helpful references are listed below, including a review of asthma mortality in general (Ref. #1).

  1. Annals Intern Med 1997;127:142-7
  2. Am J Resp Crit Care Med 1998;157:394-402
  3. Eur Resp J 1996;9:709-715
2/17/99 re: Information regarding early albuterol nebulizer in treatment of asthma
Q. Patient status asthmaticus possible aspiration pneumonia with edema to facial and neck distention with remarkable swelling. intubated resumes on mechanical ventilator what is this edema or swelling due to. history of severe asthma.
A. A good place to start getting recent information about treatment of acute asthma is in the Practice Parameters for Asthma composed by a national task force of asthma specialists. You can access this through a linkage by opening the Current Literature section of this AADMC web site and choose "Practice Parameters".

Without knowing more about your question, several considerations have to be kept in mind before administering continuous nebulization of beta 2 agents, including:

Any medical contraindications - e.g. arrhythmias, active coronary artery disease.

Cannot control adequately with frequent use of inhaled beta-2 agents by MDI?
2/17/99
Q. I have been searching the web to find risk factors that predispose people with asthma for acute or even fatal attack. The commonly known risks appear to be previous hospital admission or ED use for asthma episodes, age, allergies, exposure to triggers, non use of anti inflammatory drugs (either due to pt non compliance or poor management) viral URIs? I appreciate your help, the information will be used for nursing education, if you happen to know publications that mention the risks or studies of the risk factors, it would be most appreciated. I am not looking for the
advanced models of risk quantification, just the commonly accepted and known risk factors, for both adults and children. (ethnic status does not help us, since we do not collect that information.) F.e. is comorbidity of diabetes seen as additional risk? (glucose metabolism/cortisone), how about conditions that limit ability to exercise?
A. A number of studies have attempted to determine retrospectively the clinical characteristics of those asthmatics who experience fatal or near-fatal episodes. You have described several of those characteristics as part of your question. Another characteristic which has turned up in several studies is under-recognition by the patient of the severity of his/her asthma. The levels of such recognition may differ between males and females (see review of a study of this subject in the Current Literature section of this AADMC site). This may be a factor in the well-recognized factor of poor compliance with treatment in fatal asthma. Many of the patients dying in asthmatic flares had histories of near-fatal previous asthmatic episodes.

You mentioned that ethnic factors were not considered by you. However, there is still debate whether the increased incidence of severe/fatal asthma in inner city minority populations is related mainly to decreased compliance with treatment, environmental allergen/air pollutant exposure or genetic factors. The subject of fatalities in asthma is reviewed in he Asthma Summary Statements of the Practice Parameters of the Joint Task Force on Allergy, Asthma and Immunology which may be accessed through a link from the Current Literature Section of this AADMC web site, or published in the J Allergy Clin Immunol, November 1995.
2/16/99 re: Cause of neck/facial edema in status asthmaticus
Q. Patient status asthmaticus possible aspiration pneumonia with edema to facial and neck distention with remarkable swelling. Intubated resumes on mechanical ventilator what is this edema or swelling due to history of severe asthma.
A. The first considerations that come to my mind in a status asthmaticus patient on mechanical ventilation who then develops marked facial/neck swelling would be:
  1. Pneumomediastinum with dissection of air into neck and subcutaneous tissues of the face. Generally easily detected in plain x-rays.
  2. Some mechanical obstruction of the superior vena cava leading to the SVC syndrome.
  3. Spread of infection from lungs to subcutaneous tissues.
  4. Angioedema secondary to a reaction to a medication, particularly ACE inhibitors.
3/19/98 re: systemic symptoms in severe asthma
Q. I am a first year medical student. For my problem based learning class I
am looking up information on general systemic effects and signs one sees in a
severe asthma attack. For example, would one see muscle cramping? Would it
be more in the extremities than all over? Is nausea common? If you could highlight some of these signs for me I would appreciate it.
A. Besides the typical respiratory symptoms seen during an acute asthmatic flare, some patients exhibit systemic symptoms. These are mainly fatigue from excessive, prolonged respiratory efforts and signs of dehydration (due to excess fluid loss from the respiratory tract). It is conceivable that blood pCO2 levels in a hyper-ventilating asthmatic patient may decrease to the point of respiratory alkalosis with resultant muscle spasms. However, in most cases, the decrease in pCO2 is slow enough so that compensatory renal mechanisms prevent such severe alkalosis.

Vomiting may follow prolonged, pronounced coughing, effects of some anti-asthma medications (theophyllines and possibly other agents), and possibly other factors.

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