- Asthma - 12/7/05 re: Adverse effects of long-acting beta agonists (LABA) More and more patients are hearing reports regarding the safety of long acting bronchodilators with respect to cardiac concerns. We have known for some time that all patients need to be on accompanying inhaled steroids and that African-Americans seem to be at highest risk, but is there something new that we have to be concerned about or is this simply media hype? I assume that you are referring to the recent concerns about the increased incidence of asthma fatalities in asthmatics using the LABA agent salmeterol regularly as an add on therapy in the SMART study supported by GlaxoSmithKline (GSK). Enclosed with my response is a copy of a recent Letter to the Editor of Lancet from the formerly Nader-associated group accusing GSK of manipulating the data presentation to make the increased risk of regular salmeterol use less prominent than if only the first 28 day study period had been described. Also enclosed is a reply from the GSK representative. I think that this correspondence summarizes that SMART study situation at present. Another, possibly related, issue is the question whether chronic use of LABA agents induces some type of tolerance to the bronchodilating effects of short acting beta agonists such as albuterol. I have enclosed an abstract of a thoughtful review in 2003 of existent studies dealing with this question. Also enclosed is an abstract of a recent review of LABA by Sears, one of the leading investigators who had previously raised concerns about the chronic use of short acting beta agonists and the now-discontinued LABA fenoterol. As you can see, Sears appears a bit more muted now in his concerns about chronic use of LABA as regular therapy. A recent case-control study by Anderson et al from the UK found an increased association of asthma fatalities with heavy use of short-acting beta agonists but not with use of LABA (see enclosed abstract). Where does that leave the clinician? There appears to be a general agreement that individuals using LABA regularly for as little as 7-10 days are protected less by albuterol pre-treatment before inhaling a bronchospastic stimulus such as methacholine or adenosine. This could be clinically relevant in asthmatic individuals encountering irritant vapors, etc. Also, some studies have shown less bronchodilating effects of albuterol in asthmatics treated chronically with formoterol (another LABA) and possibly with salmeterol. The clinical significance of such hypo-responsiveness to albuterol is still debated. There may be a genetic-based predisposition to such hypo-responsiveness. However, if it present, the asthmatic might be induced to use albuterol too frequently in an attempt to obtain symptom relief during an acute asthma flare with potential for adverse cardiac effects. The situation may be further complicated by the findings in some recent studies that formoterol/inhaled steroid combination can be used effectively as a rescue medication as well as a maintenance therapy. My personal feeling is that it is reasonable to use LABA along with an adequate dose of inhaled steroid as controller therapy for persistent asthma. However, in the event of an acute asthma flare, if there is not a prompt adequate symptomatic response to inhaled albuterol, the patient should not keep using the albuterol frequently but rather contact their physician right away. In patients able to handle instructions adequately, one can consider using formoterol/budesonide combination for rescue as well as maintenance use (see enclosed at the bottom an abstract of a report describing this approach). Am J Respir Med. 2003;2(4):287-97. Related Articles, Links Adverse effects of beta-agonists: are they clinically relevant? Abramson MJ, Walters J, Walters EH. Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, Australia. Inhaled beta(2)-adrenoceptor agonists (beta(2)-agonists) are the most commonly used asthma medications in many Western countries. Minor adverse effects such as palpitations, tremor, headache and metabolic effects are predictable and dose related. Time series studies suggested an association between the relatively nonselective beta-agonist fenoterol and asthma deaths. Three case-control studies confirmed that among patients prescribed fenoterol, the risk of death was significantly elevated even after controlling for the severity of asthma. The Saskatchewan study not only found an increased risk of death among patients dispensed fenoterol, but also suggested this might be a class effect of beta(2)-agonists. However, in subsequent studies, the long-acting beta(2)-agonist salmeterol was not associated with increased asthma mortality. In a case-control study blood albuterol (salbutamol) concentrations were found to be 2.5 times higher among patients who died of asthma compared with controls. It is speculated that such toxic concentrations could cause tachyarrhythmias under conditions of hypoxia and hypokalemia. The risk of asthma exacerbations and near-fatal attacks may also be increased among patients dispensed fenoterol, but this association may be largely due to confounding by severity. Although salmeterol does not appear to increase the risk of near-fatal attacks, there is a consistent association with the use of nebulized beta(2)-agonists. Nebulized and oral beta(2)-agonists are also associated with an increased risk of cardiovascular death, ischemic heart disease and cardiac failure. Caution should be exercised when first prescribing a beta-agonist for patients with cardiovascular disease. A potential mechanism for adverse effects with regular use of beta(2)-agonists is tachyphylaxis. Tachyphylaxis to the bronchodilator effects of long-acting beta(2)-agonists can occur, but has been consistently demonstrated only for formoterol (eformoterol) a full agonist, rather than salmeterol, a partial agonist. Tachyphylaxis to protection against induced bronchospasm occurs with both full and partial beta(2)-agonists, and probably within a matter of days at most. Underlying airway responsiveness to directly acting bronchoconstricting agents is not increased when the bronchodilator effect of the regular beta(2)-agonist has been allowed to wear off, although there may be an increase in responsiveness to indirectly acting agents. While there has been speculation that underlying airway inflammation in asthma may be made worse by regular use of short-acting beta(2)-agonists, in contradistinction, a number of studies have shown that long-acting beta(2)-agonists have positive anti-inflammatory effects. An Australian Cochrane Airways Group systematic review of the randomized, controlled trials of short-acting beta-agonists found only minimal and clinically unimportant differences between regular use and use as needed. Regular short-acting treatment was better than placebo. However, a subsequent systematic review has found that regular use of long-acting beta-agonists had significant advantages over regular use of short-acting beta-agonists. More studies and data are needed on the regular use of beta(2)-agonists in patients not taking inhaled corticosteroids, and in potentially vulnerable groups, such as the elderly and those with particular genotypes for the beta-receptor, who might be more prone. Respir Med. 2005 Feb;99(2):152-70. Related Articles, Links Past, present and future--beta2-adrenoceptor agonists in asthma management. Sears MR, Lotvall J. Department of Medicine, McMaster University and Firestone Institute for Respiratory Health, St Joseph's Hospital, Hamilton, Ont, L8N 4A6 Canada. The beta-adrenoceptor agonists (beta-agonists) have been used to relieve bronchoconstriction for at least 5000 years. beta-agonists are based on adrenaline and early forms, such as isoprenaline, Lacked bronchial selectivity and had unpleasant side effects. Modern beta-agonists are more selective for the beta2 adrenoceptors (beta2-receptors) located in bronchial smooth muscle and have less cardiotoxicity. Traditional beta2-adrenoceptor agonists (beta2-agonists), such as salbutamol, terbutaline and fenoterol, were characterized by a rapid onset but relatively short duration of action. While valuable as reliever medication, their short duration gave inadequate night-time relief and limited protection from exercise-induced bronchoconstriction. beta2-agonists with longer durations of action, formoterol and salmeterol, were subsequently discovered or developed. When combined with inhaled corticosteroids they improved lung function, and reduced symptoms and exacerbations more than an increased dose of corticosteroids. However, tolerance to the bronchprotective effects of long-acting beta2-agonists and cross-tolerance to the bronchodilator effects of short-acting beta2-agonists is apparent despite use of inhaled corticosteroids. The role of beta2-receptor polymorphisms in the development of tolerance has yet to be fully determined. Formoterol is unique in having both a long-lasting bronchodilator effect (> 12 h) and a fast onset of action (1-3min from inhalation), making it effective both as maintenance and reliever medication. The recent change in classification from short- and long-acting beta2-agonists to rapid-acting and/or long-acting agents reflects the ongoing evolution of beta2-agonist therapy. BMJ. 2005 Jan 15;330(7483):117. Epub 2004 Dec 23. Related Articles, Links Bronchodilator treatment and deaths from asthma: case-control study. Anderson HR, Ayres JG, Sturdy PM, Bland JM, Butland BK, Peckitt C, Taylor JC, Victor CR. Department of Community Health Sciences, St George's Hospital Medical School, London SW17 0RE. OBJECTIVE: To investigate the association between bronchodilator treatment and death from asthma. DESIGN: Case-control study. SETTING: 33 health authorities or health boards in Great Britain. PARTICIPANTS: 532 patients under age 65 who died from asthma and 532 controls with a hospital admission for asthma matched for period, age, and area. MAIN OUTCOME MEASURES: Odds ratios for deaths from asthma associated with prescription of bronchodilators and other treatment, with sensitivity analyses adjusting for age at onset, previous hospital admissions, associated chronic obstructive lung disease, and number of other drug categories. RESULTS: After full adjustment, there were no significant associations with drugs prescribed in the 4-12 months before the index date. For prescriptions in the 1-5 years before, mortality was positively associated with inhaled short acting beta2 agonists (odds ratio 2.05, 95% confidence interval 1.26 to 3.33) and inversely associated with antibiotics (0.59, 0.39 to 0.89). The former association seemed to be confined to those aged 45-64, and the association with antibiotics was more pronounced in those under 45. Significant age interactions across all periods suggested inverse associations with oral steroids confined to the under 45 age group. An inverse association with long acting beta2 agonists and a positive association with methylxanthines in the 1-5 year period were non-significant. CONCLUSION: There was no evidence of adverse effects on mortality with medium to long term use of inhaled long acting beta2 agonist drugs. The association with short acting beta(2) agonists has several explanations, only one of which may be a direct adverse effect. Pulm Pharmacol Ther. 2005 Jul 8; [Epub ahead of print] Related Articles, Links Efficacy and safety of budesonide/formoterol compared with salbutamol in the treatment of acute asthma. Balanag VM, Yunus F, Yang PC, Jorup C. Lung Center of The Philippines, Quezon City 1100, The Philippines. This study compared the efficacy and safety of budesonide/formoterol (Symbicort((R)) Turbuhaler((R))) with salbutamol pressurized metered-dose inhaler (pMDI) with spacer for relief of acute bronchoconstriction in patients with asthma. In this randomized, double-blind, parallel-group study, patients (n=104 allocated to treatment; n=103 received treatment; mean age 45 years) seeking medical attention for acute asthma (mean FEV(1) 43% of predicted) received two doses repeated at t=-5 and 0min of either budesonide/formoterol (320/9mug, two inhalations) or salbutamol (100mugxeight inhalations); total doses 1280/36mug and 1600mug, respectively. All patients received prednisolone 60mg at 90min and FEV(1) was assessed over 3h. FEV(1) 90min after dosing (primary variable) increased compared with pre-dose FEV(1) by an average of 30% and 32% for budesonide/formoterol and salbutamol, respectively (P=0.66), with similar increases at all time points from 3 to 180min for both groups. Mean pulse rate over 3h was significantly higher in the salbutamol group versus the budesonide/formoterol group (92 vs. 88bpm; P<0.01). No treatment differences were seen for other vital signs, including ECG. High-dose budesonide/formoterol was effective and well tolerated for the treatment of acute asthma, with rapid onset of efficacy and a safety profile over 3h similar to high-dose salbutamol. Ann Pharmacother. 2005 May;39(5):931-8. Epub 2005 Apr 5. Related Articles, Links What is new with the beta2-agonists: issues in the management of asthma. Kelly HW. Department of Pediatrics, Pediatrics/Pulmonary, MSC10-5590, 1 University of New Mexico, Albuquerque, NM 87131-0001, USA. OBJECTIVE: To review the more recent literature addressing the issue of whether beta2-agonists can worsen asthma and/or increase the risk of severe exacerbations and death from asthma. DATA SOURCES: PubMed was searched (2001-December 2004), along with the Food and Drug Administration and Cochrane Library Web sites. In addition, the bibliographies of recent reviews of the subject were assessed. STUDY SELECTION AND DATA EXTRACTION: Randomized clinical trials, retrospective and prospective cohort studies, and meta-analyses published in the past 3 years were reviewed. Studies assessing the potential for beta2-agonists to worsen outcomes in asthma as well as long-term studies assessing asthma outcomes that included an arm with regular administration of short- or long-acting inhaled beta2-agonists (LABAs) were selected. Worsening asthma was defined as a decline in lung function, an increase in bronchial hyperresponsiveness, exacerbations, or death. Studies older than 3 years selected from the bibliographies of the primary articles that addressed background perspective were also included where appropriate. DATA SYNTHESIS: The studies fell into 3 primary categories with some overlap: those assessing toxicity of the S-enantiomer of albuterol, those evaluating the risk of specific genotypes regarding worsening asthma, and those assessing asthma outcomes with LABA therapy. CONCLUSIONS: The current data on the use of beta2-agonists continue to support the national and international guidelines for the treatment of asthma. That is, short-acting inhaled beta2-agonists should only be used as needed for symptoms and prevention of exercise-induced bronchospasm, and LABAs should only be used regularly as adjunctive therapy with inhaled corticosteroids in patients whose asthma is not controlled with low to medium doses of the inhaled corticosteroid. 11/7/05 re: Exercise effect on asthma I have a patient that has asthma due to allergies. She asked me about the effects of exercise with this type of asthma - positive or negative. I didn't think there was much of a correlation, but I wanted to check with the experts so I am able to give her the most accurate information possible. The answer to your question is somewhat complex, depending on the type of exercise, the degree of control of the underlying asthma and the state of physical conditioning of the individual patient. Most patients with active asthma will exhibit increased symptoms during running-type exercises, particularly in cold temperatures. This appears to be due to increasing drying and chilling effects of air inhaled through the mouth on the bronchial mucosa. Also, the mouth breathing during exercise enhances penetration of offending aeroallergens (pollens, molds, etc) to the lower airways if such allergens are present outdoors and the patient is allergic to them. For this reason, swimming in a relatively warm, humid indoor swimming pool is generally better tolerated than running exercises by asthmatics. However, that does not mean that asthmatics should not exercise. Exercise can have real beneficial effects in asthmatics as in most people. However, some precautions should be taken: 1) get the asthma in as good control as feasible using controller medications such as inhaled corticosteroids with/without long-acting inhaled beta agonists (LABA) such as salmeterol or formoterol; 2) pre-treat before exercise. If the exercise is short-duration, inhaled albuterol 15 minutes prior to exercise. If the exercise is longer duration, consider inhaled formoterol if the patient has not already taken a combination of inhaled corticosteroids and LABA; 3) another pre-exercise treatment option is Singulair taken about 1 hour prior to exercise; 4) the exercise should start at a low level, increased gradually as tolerated. Increasing exercise tolerance should enhance respiratory reserve independent of the asthma. 11/7/05 re: Sulfites in generic propofol I am an anesthesiologist and have a question on the sodium metabisulfite in the generic propofol. First, is there any cross reactivity in patients with a sulfa allergy? Second, is it worth avoiding the generic propofol in asthmatic patients or even smokers? To respond to your questions, I obtained input from Dr. Ronald Simon of the Scripps Clinic in La Jolla, CA. Dr. Simon is an expert in sulfite sensitivity. His response is enclosed below. As you know, allergy to "sulfa" (sulfonamide) antibiotics has nothing to do with sulfite sensitivity. There have been concerns about the sulfite in generic propofol above and beyond the asthmatic issue (see: Am J Anesth, 2000; 27:1.). I would recommend to not give generic propofol to a sulfite-sensitive asthmatic. We recommend to not give it to any persistent asthmatic either. Being a smoker is not an issue per se insofar as tolerance of sulfite-containing agents. 10/5/05 re: Treatment of asthma and renal failure Would you please tell me how to manage a patient having renal failure and asthma? Your question involves a very large area of discussion not permitted by the limited space in this format. Therefore, I will try to give a brief discussion of any adjustment in the usual management of asthma needed because of the presence of renal failure. Even there, my discussion would vary depending on whether the renal failure is relatively mild (glomerular filtration rates of about 40-50) or severe (glomerular filtration rates of 10 or less).1) The treatment of persistent asthma with small-moderate doses of inhaled corticosteroids steroids (ICS) would not be changed since this is little systemic effect of any of the more recent ICS such as budesonide or fluticasone which is absorbed from the lungs into the circulation. If ciclesonide, a recently released ICS, is available in your region, that agent would be of particular safety in that regard.2) However, one has to use systemic corticosteroid therapy with caution because of salt-retaining and other possible adverse effects. Use it only for acute asthma exacerbations in as low a dose and for as short a time period as needed to control the asthma flare.3) Use of an inhaled long-acting beta agonists (LABA) such as formoterol or salmeterol in usual doses (twice daily) should be tolerated adequately unless there is severe hypertension and/or underlying significant cardiac disease. Use of LABA along with an ICS will generally allow a significant reduction in the ICS dose needed for asthma control. Avoid excessive use of short-acting beta agonists such as salbutamol. 4) Fluid and electrolyte replacement is an important supportive measure when asthmatic patients have become dehydrated because of fluid loss during hyperventilation and sweating. However, the rate of such replacement has to be watched more carefully than usual in individuals with renal failure to avoid fluid overloading and possible congestive failure.5) Of course, the dosage of certain antibiotics and other systemic therapy must be adjusted if there is normally significant renal excretion of such agents. 8/18/05 re: Use of nebulized fluticasone in infants Can you kindly clarify whether inhaled fluticasone (Flixotide) can be used in infants (8 months) by nebulization. There is an article, Persistent wheezing in infants with an atopic tendency responds to inhaled fluticasone, by R J Chavasse, Y Bastian-Lee, H Richter, T Hilliard, P Seddon in Arch Dis Child 2001;85:143-148 (August). At the same time the guidelines in GINA is quite vague about the use of inhalational corticosteroid in this age group. There is concern that early use of Inhaled corticosteroid in infancy may impair lung growth or enhance the development of the TH2-type immune response, thus promoting, rather than suppressing, the development of asthma. Is this concern valid? Is there any study which supports this fear? I cannot respond to your question specifically about nebulized fluticasone since fluticasone preparations for use in a nebulizer are not currently available for usual clinical practice in the USA. However, there is experience using nebulized budesonide in infants. This was recently reviewed by Berger and Shapiro, respected asthma investigators (see enclosed abstract). I suggest that you read the whole article. There is a potential concern about inhaled corticosteroids affecting lung growth in childhood. However, several groups have recently concluded that uncontrolled asthma in early childhood is itself a risk factor for decreased lung growth later in childhood. In the large, multi-institutional CAMP study, there was no significant difference in the "lung growth" as determined by the post-bronchodilator FEV-1 in children treated with inhaled budesonide vs placebo or nedocromil (Engl J Med. 2000;343:1054-63). Ann Allergy Asthma Immunol. 2004 Apr;92(4):387-399; quiz 399-402, 463. The use of inhaled corticosteroids for persistent asthma in infants and young children. Berger WE, Shapiro GG. Allergy and Asthma Associates of Southern California, Mission Viejo, California 92691, USA. weberger@gsm.uci.edu OBJECTIVE: To review pediatric trials of inhaled corticosteroid (ICS) therapy and summarize data on the pediatric use of devices to facilitate delivery of ICSs. DATA SOURCES: Relevant articles regarding ICS treatment of persistent asthma in children younger than 5 years were identified from MEDLINE and reference lists of review articles. STUDY SELECTION: Key articles were selected by the authors. RESULTS: Clinical trials from the United States and Europe consistently demonstrated that ICS therapy is the most favorable treatment option with regard to safety and efficacy for infants and young children with persistent asthma. This contention is supported by numerous trials of budesonide inhalation suspension in children ranging from 6 months through 8 years of age and data from older children treated with fluticasone propionate. CONCLUSIONS: As the only corticosteroid available in the United States as a nebulized formulation and the only ICS product extensively studied in young children and infants, budesonideinhalation suspension is an appropriate first-line therapy for treatment of persistent asthma in this population. 8/1/05 re: Association of pulmonary emboli and asthma I am an RN, CNA and would like to know if any correlation has been found between a long history of asthma and pulmonary emboli. Does lung tissue in an asthmatic patient make them more vulnerable to PE with a jolt - but not direct trauma to the chest - from an auto accident? The major association between pulmonary emboli (PE) and asthma of which I am aware is the fact that an acute PE may sometimes be confused with acute, new onset asthma because wheezing and cough may be occasionally prominent in the presentation of a PE. Although there are occasional case reports of PE occurring in a patient with asthma, I am not aware of any increased frequency of PE in asthma unless there are other risk factors present (e.g., immobility, marked dehydration, recent abdominal surgery, congenital blood disorder leading to an increased tendency to clotting, each of which predisposes to increased occurrence of deep vein thrombosis). In contrast, there appears to be an increased risk for PE in those with chronic obstructive pulmonary disease (COPD-see enclosed abstract). I am not aware of a jolting type occurrence in an auto accident without direct trauma to the chest as a frequent trigger of an acute PE. One must rule out the development of deep vein thrombosis in the lower extremities or pelvic veins secondary to trauma in that area since these thromboses are the source of most PE. Ann Epidemiol. 2005 Jul 20; [Epub ahead of print] Related Articles, Links Cardiovascular Disease in Patients with Chronic Obstructive Pulmonary Disease, Saskatchewan Canada Cardiovascular Disease in COPD Patients. Curkendall SM, Deluise C, Jones JK, Lanes S, Stang MR, Goehring E Jr, She D. From Cerner Health Insights (S.M.C.); Global Epidemiology, Pfizer, Inc. (C.D.); the Degge Group, Ltd. (J.K.J.); Boehringer-Ingelheim Pharmaceuticals, Inc. (S.L.); Population Health Branch, Saskatchewan Health (M.R.S.); and EMMES Corporation (D.S.). PURPOSE: To measure prevalence, incidence, and mortality of cardiovascular outcomes among persons with chronic obstructive pulmonary disease (COPD) and to assess the extent these outcomes differ from persons without COPD. METHODS: Retrospective cohort study in longitudinal health care databases maintained by the government of Saskatchewan , Canada . Subjects were persons age 40 years or older who were diagnosed with COPD during 1997-2000 and who received two or more prescriptions for bronchodilators within 6 months of diagnosis. Each subject was matched by age and sex to two controls without COPD or asthma. RESULTS: Of COPD patients (n=11,493), 54% were male, and 74% were 65 years or older. Prevalence of all cardiovascular diseases was higher in the COPD group than in the comparison group. After adjusting for cardiovascular risk, odds ratios of prevalence were: arrhythmia 1.76 (confidence interval [CI]: 1.64-1.89), angina 1.61 (CI: 1.47-1.76), acute myocardial infarction 1.61 (CI: 1.43 1.81), congestive heart failure 3.84(CI: 3.56-4.14), stroke 1.11 (CI: 1.02-1.21),pulmonary embolism 5.46 (CI: 4.25-7.02). Risk of hospitalization due to each cardiovascular cause was elevated in the COPD group. The risk ratio for cardiovascular mortality was 2.07 (CI: 1.82-2.36) and all cause mortality was 2.82 (CI: 2.61-3.05). CONCLUSIONS: Persons with diagnosed and treated COPD are at increased risk for hospitalizations and deaths due to cardiovascular diseases. 7/29/05 re: What type of pulmonary function equipment to use for asthmatic children I am a pediatrician in the community and have been investigating the feasibilty and recommendations on office based spirometry in pediatrics. So far evidence I have collected has been favorable (although sparse), but I am having a difficult time researching different portable office based spirometers that may be appropriate. Do you have any suggestions on products that are affordable, easy to interpret (preferably computer interpreted) and meet ATS requirements? Do you agree with office based testing as noted in Stanley Szefler M.D.'s update from the AAAAI for pediatrics? We are constantly trying to improve our asthma care and believe this is an area that could be greatly improved, especially with various factors that make it difficult to get families to follow through with the traditional spirometry lab. I do agree with the recommendations made by Dr. Szefler. I have known Dr. Szefler for a number of years and have found him to be a very thoughtful and "down to earth" investigator of childhood asthma.I contacted Dr. Szefler about your question concerning which type of pulmonary function equipment to use in your pediatric practice. Dr. Szefler referred the question to his colleague, Dr. Wayne Morgan, Chief of Pediatric Pulmonary in the Univ. of Arizona . I have enclosed Dr. Morgan's response to me below. I have also enclosed below an abstract of a very nice review article co-authored by Dr Morgan with Dr. Gary Larsen of the National Jewish Medical and Research Center . I suggest that you read the whole article to obtain more information about evaluation of pulmonary function in children. Dr Morgan's comments Clearly the key issue is that the company demonstrates that their equipment meets ATS standards which most do. For kids it is key to have a good flow volume loop display in real time and also the ability to quickly recycle a bad test into a new attempt to avoid the kid getting bored Clinically we have been very happy with Jaeger and with KOKO   J Allergy Clin Immunol. 2005 Apr;115(4):657-66. Assessing respiratory function in young children: Developmental considerations. Larsen GL, Kang JK, Guilbert T, Morgan W. National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA. larseng@njc.org The purpose of this review is to provide practitioners and clinical investigators with an update on methods of assessing respiratory function in young children. The importance of this topic is presented in light of the natural history of asthma, as well as maturational changes that occur early in life in terms of airway development. Models of disease are cited to support the concept that injury of the mammalian airway early in postnatal life might have far-reaching consequences in terms of control of airway caliber and responsiveness. The methods currently available to measure respiratory function in our younger patients are outlined. The ability of children to perform the maneuvers necessary for this testing is considered as a function of age. Areas in which research and development are needed are highlighted. 7/18/05 re: Respiratory allergies and respiratory infections Please advise whether there is any evidence that an allergic reaction characterized by respiratory symptoms in any way predisposes the patient to subsequent respiratory infection.. The relationship between respiratory allergies and respiratory infections is complex. Space limitations here do not permit a full discussion of this subject. I suggest that you read reviews written by Dr. Robert Lemanske of the Univ of Wisconsin about the interaction of virus infections and asthma (see abstracts enclosed below).I will state a few of my impressions based on my understanding of recent findings: 1) Certain viral infections, particularly with respiratory syncytial virus (RSV) in infancy, may play a pathogenic role in the initiation of asthma;. RSV infection is also not unusual in older individuals and was found to be linked to about 7% of acute asthma flares requiring emergent care (see enclosed abstract) 2) Respiratory virus infections, particularly with one of the many rhinovirus (RV) strains, are among the most common triggers of acute asthma flares; 3) Chronic asthmatics may not be more susceptible to RV infections of the upper respiratory tract. However, such patients have more frequent lower respiratory tract RV infections and suffer more from the consequences of such infections, possibly because an impaired immunity to RV leads to decreased clearance of RV from the respiratory tract (see enclosed abstract). A recent study showed that 24% of children hospitalized for viral infections of the lower respiratory tract had pre-existent asthma (see enclosed abstract). The relationship of bacterial infections to asthma is less clear-cut. There is no convincing evidence that bacterial infections are a common trigger of acute asthma flares. However: 1) there is an increased incidence of recurrent/chronic sinusitis in those with perennial allergic rhinitis. Some of these individuals have persistent asthma as well; 2) a recent study found a significantly increased incidence of invasive pneumococcal disease in asthmatics (see enclosed abstract) J Allergy Clin Immunol. 2005 Apr;115(4):668-74; Effects of viral respiratory infections on lung development and childhood asthma. Gern JE, Rosenthal LA, Sorkness RL, Lemanske RF Jr. Department of Pediatrics, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI 53792-9988, USA. Viral infections are closely linked to wheezing in infancy, and those children with recurrent virus-induced wheezing episodes are at great risk for chronic childhood asthma. Infancy is a time of increased susceptibility to viral infections, and this stage is also characterized by pulmonary alveolar multiplication and extensive remodeling of the airways to accommodate growth. This coincidence, together with the observation that children with asthma can have structural lung changes and functional deficits at an early age, suggests that viral infections could adversely affect lung development. Inflammatory mediators induced by viral infection are known to have effects on the remodeling process, suggesting a plausible mechanism to support this theory. Furthermore, animal models of viral infection during lung growth and development suggest that developmental factors are important in determining the consequences of infection on long-term lung function. Greater understanding of the effects of viral infections on lung development and growth in early childhood might lead to the discovery of additional strategies for the prevention of recurrent wheezing and chronic asthma. J Pediatr. 2003 Feb;142(2 Suppl):S3-7; Viruses and asthma: Inception, exacerbation, and possible prevention. Lemanske RF Jr. Division of Pediatric Allergy, Immunology, and Rheumatology, Department of Pediatrics, University of Wisconsin Medical School, Madison 53792, USA. Viral respiratory tract infections have been epidemiologically associated with asthma in at least 3 ways. First, during infancy, certain viruses have been implicated in the inception of the asthmatic phenotype. Second, in patients with established asthma, particularly children, viral upper respiratory tract infections play a significant role in producing acute exacerbations of airway obstruction, often resulting in outpatient visits or hospitalizations. This increased propensity of viral infections to produce lower airway symptoms in asthmatic persons may be related, at least in part, to interactions among allergic sensitization, allergen exposure, and viral infections-all acting as cofactors in the induction of acute episodes of airflow obstruction. Third, and perhaps counterintuitively, certain infections may actually prevent the development of allergic respiratory tract diseases, including asthma. This review discusses these associations as they pertain to both the pathogenesis and treatment of childhood asthma N Engl J Med. 2005 Apr 28;352(17):1749-59. Respiratory syncytial virus infection in elderly and high-risk adults. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. Department of Medicine, Rochester General Hospital, Rochester, NY 14621, USA. BACKGROUND: Respiratory syncytial virus (RSV) is an increasingly recognized cause of illness in adults. Data on the epidemiology and clinical effects in community-dwelling elderly persons and high-risk adults can help in assessing the need for vaccine development. METHODS: During four consecutive winters, we evaluated all respiratory illnesses in prospective cohorts of healthy elderly patients (> or =65 years of age) and high-risk adults (those with chronic heart or lung disease) and in patients hospitalized with acute cardiopulmonary conditions. RSV infection and influenza A were diagnosed on the basis of culture, reverse-transcriptase polymerase chain reaction, and serologic studies. RESULTS: A total of 608 healthy elderly patients and 540 high-risk adults were enrolled in prospective surveillance, and 1388 hospitalized patients were enrolled. A total of 2514 illnesses were evaluated. RSV infection was identified in 102 patients in the prospective cohorts and 142 hospitalized patients, and influenza A was diagnosed in 44 patients in the prospective cohorts and 154 hospitalized patients. RSV infection developed annually in 3 to 7 percent of healthy elderly patients and in 4 to 10 percent of high-risk adults. Among healthy elderly patients, RSV infection generated fewer office visits than influenza; however, the use of health care services by high-risk adults was similar in the two groups. In the hospitalized cohort, RSV infection and influenza A resulted in similar lengths of stay, rates of use of intensive care (15 percent and 12 percent, respectively), and mortality (8 percent and 7 percent, respectively). On the basis of the diagnostic codes of the International Classification of Diseases, 9th Revision, Clinical Modification at discharge, RSV infection accounted for 10.6 percent of hospitalizations for pneumonia, 11.4 percent for chronic obstructive pulmonary disease, 5.4 percent for congestive heart failure, and 7.2 percent for asthma. CONCLUSIONS: RSV infection is an important illness in elderly and high-risk adults, with a disease burden similar to that of nonpandemic influenza A in a population in which the prevalence of vaccination for influenza is high. An effective RSV vaccine may offer benefits for these adults Pediatr Infect Dis J. 2004 Nov;23(11 Suppl):S188-92. Epidemiology of respiratory infections in young children: insights from the new vaccine surveillance network. Griffin MR, Walker FJ, Iwane MK, Weinberg GA, Staat MA, Erdman DD; New Vaccine Surveillance Network Study Group.Department of Preventive Medicine and Vanderbilt Center for Education and Research on Therapeutics, Vanderbilt University Medical Center, and the Geriatrics Research and Education and Clinical Center, Nashville, TN, USA. BACKGROUND: The New Vaccine Surveillance Network, funded by the Centers for Disease Control and Prevention, was established to provide longitudinal data to help measure the impact of vaccines that decrease the burden of acute respiratory illness in children younger than 5 years of age. Currently 140,000 children younger than 5 years of age, nearly 1% of the U.S. population, are under surveillance in 3 urban counties, which include Nashville, TN, Rochester, NY, and Cincinnati, OH. Prospective, active, population-based surveillance of children hospitalized with respiratory symptoms or fever began in 2000, and outpatient surveillance began in 2002 in selected winter months. RESULTS: During the first year of surveillance, the admission rate for acute respiratory illness/fever in children younger than 5 years of age in the surveillance areas was 180 per 10,000 children. In 61% of these hospitalizations, a respiratory virus was identified. Respiratory syncytial viruses, influenza viruses and parainfluenza viruses were identified in 30%, and other respiratory viruses were identified in 36%. Approximately one-third of children hospitalized had identified high risk conditions, primarily asthma (24%). About one-half of the children hospitalized were younger than 6 months of age. Polymerase chain reaction doubled the diagnostic yield of culture for respiratory syncytial viruses, influenza and parainfluenza virus combined.Preliminary data on influenza admissions during the 4 years indicated considerable variation in admission rates by season and site. Annually the mean admission rates during the study period were 43 per 10,000 children younger than 6 months of age, 9 per 10,000 children 6-23 months of age and 4 per 10,000 children 24-59 months of age. CONCLUSION: These data provide ongoing surveillance of hospitalizations and other medically attended visits for respiratory viral illness in children younger than 5 years of age. Evaluation of influenza vaccine effectiveness, the epidemiology of respiratory viruses in children and the impact of the pediatric influenza vaccination program are in progress Curr Opin Pulm Med. 2005 Jan;11(1):21-6. Viruses in asthma exacerbations. Tan WC. Department of Medicine, National University Hospital, Singapore. PURPOSE OF REVIEW: Respiratory viruses are well recognized as major triggers of acute exacerbations of asthma in children and adults, resulting in frequent outpatients visits and hospitalizations. Clinical and epidemiologic evidence supports this association. The application of molecular diagnostic methods has improved understanding of viral epidemiology and the pathophysiological mechanisms involved in viral induced acute asthma. This article reviews publications since October 2002 for an update of the role of viruses in exacerbations of asthma. RECENT FINDINGS: Respiratory viruses are present in most patients hospitalized for life-threatening asthma and acute non life-threatening asthma. Rhinovirus is the most common, but coinfection with other viruses may be important. Patients with asthma are not more susceptible to upper respiratory tract rhinovirus infections than healthy people but suffer from more severe consequences of the lower respiratory tract infection. Recent epidemiologic studies suggest that viruses provoke asthma attacks by additive or synergistic interactions with allergen exposure or with air pollution. An impaired antiviral immunity to rhinovirus may lead to impaired viral clearance and hence prolonged symptoms. Respiratory viral infections cause asthmatic exacerbations by triggering recruitment of Th2-type cells into the lungs. There is no specific antiviral strategy for prevention of respiratory-triggered asthma exacerbations, although clinical trials of potential antiviral agents are ongoing. Indirect prevention strategies focus on the reduction of overall airway inflammation to reduce the severity of the host response to respiratory viral infections. SUMMARY: Respiratory viral infections are a major cause of morbidity and mortality in asthma. There is a lack of specific antiviral strategies in the prevention or reduction of viral-triggered asthma exacerbations. Recent advances in understanding of the epidemiology and immunopathogenesis of respiratory viral infection in asthma provide opportunities or identification of specific targets for antiviral agents and strategies for management and prevention. N Engl J Med. 2005 May 19;352(20):2082-90. Asthma as a risk factor for invasive pneumococcal disease. Talbot TR, Hartert TV, Mitchel E, Halasa NB, Arbogast PG, Poehling KA, Schaffner W, Craig AS, Griffin MR. Department of Medicine, Vanderbilt University School of Medicine, Nashville, USA. BACKGROUND: The risk of invasive pneumococcal disease among persons with asthma is unknown. METHODS: We conducted a nested case-control study to examine the association between asthma and invasive pneumococcal disease. The study population included persons 2 to 49 years of age who were enrolled in Tennessee 's Medicaid program (TennCare) for more than one year during the study period (1995 through 2002) and who resided in counties participating in a prospective laboratory-based program of surveillance for invasive pneumococcal disease. For each subject with invasive pneumococcal disease, 10 age-matched controls without invasive pneumococcal disease were randomly selected from the same population. TennCare files were queried to identify the presence of coexisting conditions that confer a high risk of pneumococcal disease. For the purpose of our study, asthma was defined by documentation of one or more inpatient or emergency-department diagnoses of asthma, two outpatient diagnoses, or the use of asthma-related medications. High-risk asthma was defined as asthma requiring admission to a hospital or a visit to an emergency department, the use of rescue therapy or long-term use of oral corticosteroids, or the dispensing of three or more prescriptions for beta-agonists within the year before enrollment in the study. RESULTS: A total of 635 persons with invasive pneumococcal disease and 6350 controls were identified, of whom 114 (18.0 percent) and 516 (8.1 percent), respectively, had asthma. Persons with asthma had an increased risk of invasive pneumococcal disease (adjusted odds ratio, 2.4; 95 percent confidence interval, 1.9 to 3.1) as compared with controls. Among those without coexisting conditions, the annual incidence of invasive pneumococcal disease was 4.2 episodes per 10,000 persons with high-risk asthma and 2.3 episodes per 10,000 persons with low-risk asthma, as compared with 1.2 episodes per 10,000 persons without asthma. CONCLUSIONS: Asthma is an independent risk factor for invasive pneumococcal disease. The risk among persons with asthma was at least double that among controls. 6/14/05 re: Significance of the a decreased FEF 25-75% I am an Asthma nurse at a pediatric clinic and we perform spirometry at every visit for our patients with asthma. We are discovering that there are several children who show evidence of small airway obstruction (FEF 25-75 less than 75%) and are asymptomatic. These children use their inhaler less than 1x/week, cough at night less than 2x/month, and maybe get respiratory infections 2-3 times a year. Is there a specific recommendation for treating asymptomatic small airway obstruction? A decreased FEF25-75% value may be seen in about 8% of all asthmatics. It is not unusual to find a decreased FEF 25-75 in asthmatics who are asymptomatic at the time and have FEV-1 values over 80% of predicted (usually considered within normal limits). However, one must be careful in interpreting such decreases in the FEF 25-75. As pointed out in a report on pulmonary function testing by the American Thoracic Society ( Am Rev Resp Dis 1991; 144:1202-1218) there is a wide variability (up to 20%) in repeated FEF 25-75 measurements in healthy individuals. The lower limit of normal appears to be closer to 50% of predicted rather than 75%. In a report by Bar-Yishay et al, (Chest 2003;123:731-5) they concluded that the peak expiratory flow at 50% of the vital capacity is preferable to the FEF 25-75 because it is directly measured and therefore subject to less technical variability. Therefore, in a recent review, Kim and Morgenthaler of the Mayo Clinic concluded that the FEF 25-75 is only suggestive of but not entirely specific for small airways disease. They stated that the FEF25-75 should not be used for routine clinical purposes ( J.Respir Diseases 2005;26:26-40). I suggest that you read the report of the American Thoracic Society noted above to get more details. I also suggest that you may wish to use the FEV-1/FVC ratio in addition to the FEV-1 alone (as a percentage pf predicted) in assessing asthma status. Several recent studies have found that decreases in the FEV-1/FVC ratio to be a more sensitive predictor of changes in asthma status than the FEV-1 value as a percentage of predicted. There may be other non-invasive ways of assessing the status of airways inflammation in asthma such as sputum eosinophilia and exhaled nitric oxide levels. These have been found to be helpful in assessing whether the dose of inhaled steroids should be changed in asthma treatment. However, such approaches are still mainly research tools. 5/3/05 re: Frequency of paradoxical bronchospasm I am a GP in UK with an asthmatic/allergic 4 year old son. For his + my patients benefit can you tell me the risk of parodoxical bronchospasm with nebulisation ie. how many people per 100/1000/10000 etc people nebulised will suffer it - I want to be able to quantify the risk - thanks! Some investigators believe that most of the so-called paradoxical responses to inhaled bronchodilator medications are due to a direct bronchoconstrictor effect of additives, particularly benzalkonium chloride (BAC) when present in above certain concentrations (see enclosed abstract- note that the term albuterol used in the USA is the same as salbutamol used in the UK). Therefore, an effort has been made to eliminate additives such as BAC and EDTA from nebulizer solutions. However, there may still be some use of BAC since this agent may enhance the delivery of the active agent in some studies (see enclosed abstract). Therefore, I would estimate that the incidence of paradoxic bronchospasm associated with use of inhaled bronchodilators should be very low (likely quite less than one per thousand cases) if the solutions used contain very low (preferably no) content of BAC and EDTA. In treating sulfite-sensitive asthmatics, one should avoid solutions containing sizable levels of sulfite as a preservative. As an aside, I might mention that several reviews have shown that use of an MDI with spacer can deliver bronchodilators as effectively as power nebulizers once the patient (or parent) can time the actuation of the MDI with the patient's inhalation (see enclosed below my review for this AADMC website of one of those reports). Therefore, you may wish to consider switching your child to the more portable and less expensive MDI/spacer delivery system when feasible. J Allergy Clin Immunol. 1999 Aug;104(2 Pt 2):S53-60. Bronchoconstrictor additives in bronchodilator solutions. Asmus MJ, Sherman J, Hendeles L. Department of Pharmacy Practice, College of Pharmacy, University of Florida, Gainesville 32610-0486, USA. Nebulized bronchodilator solutions are available in the United States as both nonsterile and sterile-filled products. Sulfites, benzalkonium chloride (BAC), or chlorobutanol are added to nonsterile products to prevent bacterial growth, but there have been reports of contaminated solutions containing preservatives. Ethylenediamine tetraacetic acid (EDTA) is added to some products to prevent discoloration of the solution. With the exception of chlorobutanol, all of these additives are capable of inducing bronchospasm in a concentration-dependent manner. However, it is rarely apparent to the patient or health care provider that the additive diminishes the bronchodilator effects. Older products (eg, isoproterenol and isoetharine) contain enough sulfites to produce bronchospasm in most patients with asthma, even in those without a prior history of sulfite sensitivity. Bronchoconstriction from inhaled BAC is cumulative, prolonged, and correlates directly with basal airway responsiveness. The multidose dropper bottle of albuterol contains 50 microg BAC/dose, which is below the threshold for bronchoconstriction whereas the screwcap unit-dose vial contains 300 microg/dose, which is above the threshold for many patients. If the screwcap product is used in the emergency department, a patient could receive as much as 1800 microg of BAC in the first hour. Three sterile-filled unit dose albuterol products contain no additives, whereas a fourth, (manufactured by Dey Laboratories) contains 300 microg of EDTA, which is also below the threshold dose for bronchoconstriction. Only additive-free sterile solutions should be used for hourly or continuous nebulization of albuterol. The multidose dropper bottle or the Dey product can be used when the interval between doses is longer, whereas the screwcap product should not be used for acute therapy. Ipratropium is available only as a sterile, additive-free unit-dose vial, as is levalbuterol. Chest. 1997 Jan;111(1):204-8. A comparison of pulmonary availability between Ventolin (albuterol) nebules and Ventolin (albuterol) Respirator Solution. MacNeish CF, Meisner D, Thibert R, Kelemen S, Vadas EB, Coates AL. Division of Respiratory Medicine, Montreal Children's Hospital-McGill Research Institute, Quebec, Canada. The two most common albuterol preparations used for nebulization are: (1) Ventolin (albuterol) respirator solution (Glaxo Canada Inc; Montreal, Canada) of which 2.5 mg (0.5 mL) is diluted with 2 mL of normal saline solution, and (2) the preservative-free, prediluted Ventolin (albuterol) Nebules PF (Glaxo) (2.5 mg/2.5 mL). The two preparations were compared using both a Hudson 1720 "T" up-draft Neb-U-Mist jet nebulizer and a Hudson 1730 "T" up-draft Neb-U-Mist II jet nebulizer (Hudson; Temecula, Calif), which were driven by a compressor (Pulmo-Aide; Devilbiss; Somerset, Pa) and by dry compressed air at 6 and 8 L/min. Particle size distribution was measured with a particle sizer (Malvern 2600; Malvern Instruments; Malvern, UK) and drug output for the nebulizer was calculated from the differences in predrug and postdrug volume and concentration. Drug availability was defined as the amount of drug carried in particles less than 5 microns in diameter. Drug availability was greater with the albuterol respiratory solution, due to the surface activity of the preservative benzalkonium chloride, for both nebulizers but particularly for the 1720. Differences in drug availability between nebulizers exceeded fourfold depending on the preparation, the nebulizer, and the nebulizing flow. These differences could not have been predicted from the manufacturer's specifications. The results suggest that prediction of drug availability must be based on measurements with the specific preparation and the specific nebulizer used.   Current Lit Item Inhaled beta agonists administered by MDI/spacer vs nebulization for acute asthma exacerbations in young children Summary Background - The delivery of inhaled beta agonist such as albuterol (Alb) of acute asthma exacerbations in young children has typically been by power nebulizers. However, some (but not all) studies in recent years have shown equal efficacy in acute asthma flare when albuterol is inhaled by the child using either a nebulizer or a meter dose inhaler (MDI) with a valved spacer (holding chamber). Are the two methods of delivering inhaled Alb in young children really equally effective? Findings - Castro-Rodriguez and Rodrigo of the Univ. of Chile in Santiago carried out a meta-analysis of reports of randomized, prospective, controlled trials comparing nebulized Alb vs Alb delivered by MDI plus valved hold chamber (VHC) in the treatment of acute asthma exacerbations in children < 5 years old. In 6 trials involving 491 patients obtained from databases which met the authors criteria for inclusion, children who received Alb by MDI + VHC actually were admitted subsequently because of uncontrolled asthma less frequently than children of the same age treated with nebulized Alb (Odds Ratio (OR) = 0.42; p=0.002). This decreased admission rate following MDI + VHC treatment was even more striking in those children treated for moderate to severe asthma exacerbations (OR=0.27; p=0.003). The mean reduction in severity of asthma symptoms was also significantly greater in those treated with MDI + VHC than in those treated with nebulized Alb (p=0.0003). Conclusions - The use of MDI + VHC was more effective than nebulization in delivery of inhaled beta-agonists to children <5 years old with moderate to severe acute asthma flares in terms of improving clinical scores and decreasing the need for hospitalization. Reference J Pediatr 2004;45:172-7 Editor's Comments As a non-pediatrician, I have been puzzled by the somewhat conflicting results of previous studies comparing nebulization with MDI + VHC in the delivery of inhaled beta agonists in acute childhood asthma. Following discussion with a highly experienced Pediatric Allergist/Immunologist I now realize that there are a number of variables, which differ among these studies than can affect the authors' conclusions. For example: 1) the type of VHC used (most children < 5 years of age cannot adequately time activation of MDI with inhalation); 2) the number of MDI puffs inhaled in a treatment. The "standard" 2 puff MDI treatment is not equivalent to the delivery of Alb, 5 mg/ml by nebulizer; 3) the use of a facial mask vs "blow by" in nebulization; 4) the outcome measure assessed (no mention of pulmonary function findings in the meta-analysis above. It would not be surprising if MDI + VHC (with adequate number of puffs inhaled) was as effective as nebulization. What was surprising is that children treated with MDI + VHC did that much better, at likely a considerably reduced cost! 3/24/05 re: Reactions to sulfites in propofol solution I am a CRNA . Was wondering whether you have found an increase in untoward respiratory effects when propofol with methylbisulfite preservative has been used in asthmatic patients without known sulfite allergy As you may know, it is the generic formulation of propofol that contains bisulfites as a preservative. The branded product (Diprivan) contains EDTA instead of sulfites as a preservative (see abstract enclosed below). Propofol itself tends to inhibit bronchoconstriction (see enclosed abstract).To help respond to your question. I obtained input from Dr. Ronald Simon of the Scripps Clinic, an authority in the area of adverse reactions to sulfites. His response is enclosed immediately below. My impression from his comments is that the evidence of bronchoconstriction associated with use of generic propofol is mainly anectodal, including some cases where the patient had asthma without known adverse reactions to sulfites. Therefore, it would seem prudent to use Diprivan rather than generic propofol in individuals with pre-existent asthma. The presence of sulfites may also lead to alterations in the propofol molecule, affecting the actions of propofol, as noted below by Dr. Simon. Dr. Simon's comments: There have been (anecdotal, but around the country) reports of increased Bronchial reactions to generic propofol. However, such reactions are actually NEVER seen with branded Diprivan.While I believe the sulfite added (in place of EDTA in Diprivan) is related and would cause reactions in those already sulfite sensitive; that's not the (only) possible factor in the reported reactions. I believe it is due to the physiochemical difference in the propofol itself when in a sulfite suspension. There have also been issues of the quality of the anesthetic effect and stability of the product and other issues with the generic propofol. I suggest reading:Am J Anesth, 2000;27. The whole supplement is devoted to this issue. I participated in the preparation of the supplement and authored one of the articles. Anesth Analg. 2000 Oct;91(4):871-5. Bisulfite-containing propofol: is it a cost-effective alternative to Diprivan for induction of anesthesia? Shao X, Li H, White PF, Klein KW, Kulstad C, Owens A. Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-9068, USA. Propofol (Diprivan(TM); AstraZeneca, Wilmington, DE) is a commonly used drug forthe induction of general anesthesia in the ambulatory setting. With the availability of a new bisulfite-containing generic formulation of propofol, questions have arisen regarding its cost effectiveness and safety compared with Diprivan(TM). Two hundred healthy outpatients were randomly assigned, according to a double-blinded protocol, to receive either Diprivan(TM) or bisulfite-containing propofol 1.5 mg/kg IV as part of a standardized induction sequence. Maintenance of anesthesia consisted of either desflurane (4%-8% end- tidal) or sevoflurane (1%-2% end-tidal) in combination with a remifentanil infusion (0.125 microg x kg(-1) x min(-1) IV). Patient assessments included pain on injection, induction time, hemodynamic and bispectral electroencephalographic changes during induction, emergence time, and incidence of postoperative nausea and vomiting. The two propofol groups were comparable demographically, and the induction times and bispectral index values during the induction were alsosimilar. However, the bisulfite-containing formulation was associated with less severe pain on injection (5% vs 11%), with fewer patients recalling pain on injection after surgery (38% vs. 51%, P<0.05). None of the patients manifested allergic-type reactions after the induction of anesthesia. The acquisition cost (average wholesale price in US dollars) of a 20-mL ampoule of Diprivan(TM) was $15 compared with $13 for the bisulfite-containing propofol formulation. Therefore, we concluded that the bisulfite-containing formulation of propofol is a cost-effective alternative to Diprivan(TM) for the induction of outpatient anesthesia. Implications: Bisulfite-containing propofol and Diprivan(TM) (AstraZeneca, Wilmington , DE ) were similar with respect to their induction characteristics; however, the generic formulation was associated with a smaller incidence of injection pain. Assuming that the drug costs are similar, these data suggest that the bisulfite-containing formulation of propofol is a cost-effective alternative to Diprivan(TM) Anesthesiology. 2001 May;94(5):851-5; discussion 6A. Comment in: Anesthesiology. 2002 Jun;96(6):1529; author reply 1529-30. Anesthesiology. 2002 Mar;96(3):771-2; author reply 772-3. Efficacy of propofol to prevent bronchoconstriction: effects of preservative. Brown RH, Greenberg RS, Wagner EM. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore , Maryland 21205, USA. rbrown@welchlink.welch.jhu.edu BACKGROUND: The authors previously showed that propofol attenuates bronchoconstriction. Recently, a newer formulation of propofol with metabisulfite preservative has been introduced. metabisulfite causes airway narrowing in asthmatics. Therefore, we tested whether the preservative metabisulfite abolishes the ability of propofol to attenuate bronchoconstriction. The authors used a sheep model in which anesthetic agents could be directly administered to the airways via the bronchial artery. METHODS: After Internal Review Board approval, seven sheep were anesthetized (pentobarbital 20 mg x kg(-1) x h(-1)) and paralyzed (pancuronium 2 mg), and the lungs were ventilated. After left thoracotomy, the bronchial artery was cannulated and perfused. In random order, propofol with and without metabisulfite, lidocaine (5 mg/ml), or metabisulfite alone (0.125 mg/ml) was infused into the bronchial artery at a rate of 0.06, 0.2, or 0.6 ml/min. After 10 min, airway resistance (Raw) was measured before and after vagal nerve stimulation (30 Hz, 30-ms duration at 30 V for 9 s.) and methacholine challenge (2 microg/ml at 2 ml/min in the bronchial artery). Data were expressed as a percent of maximal response and analyzed by analysis of variance with correction and with significance accepted at P < or = 0.05. RESULTS: Raw at baseline was not significantly different among the four drugs (P = 0.87). Infusion of lidocaine and propofol without metabisulfite into the bronchial artery caused a dose- dependent attenuation of the vagal nerve stimulation-induced bronchoconstriction (P = 0.001). Propofol with metabisulfite had no effect on vagal nerve stimulation- induced bronchoconstriction (P = 0.40). There was a significant difference in the ability of propofol without metabisulfite compared with propofol with metabisulfite to attenuate vagal nerve stimulation-induced (P = 0.0001) and methacholine-induced bronchoconstriction (P = 0.0001). CONCLUSION: Propofol without metabisulfite and lidocaine attenuated vagal nerve stimulation- induced bronchoconstriction in a dose-dependent fashion. Propofol without metabisulfite also decreased direct airway smooth muscle constriction. The preservative used for propofol can have a dramatic effect on its ability to attenuate bronchoconstriction. Crit Care Med. 2003 Mar;31(3):787-92. Comment in: Crit Care Med. 2003 Mar;31(3):981-3. Free radical and drug oxidation products in an intensive care unit sedative: propofol with sulfite. Baker MT, Gregerson MS, Martin SM, Buettner GR. Department of Anesthesia, University of Iowa, Iowa City, USA. OBJECTIVES: Some propofol emulsion formulations contain EDTA or sodium metabisulfite to inhibit microbe growth on extrinsic contamination. EDTA is not known to react with propofol formulation components; however, sulfite has been shown to support some oxidation processes and may react with propofol. This study compared the oxidation of propofol and the formation of free radicals by electron paramagnetic resonance analysis in EDTA and sulfite propofol emulsions during a simulated intensive care unit 12-hr intravenous infusion. DESIGN: Controlled laboratory study. SETTING: University laboratory. MEASUREMENTS AND MAIN RESULTS: Propofol emulsions (3.5 mL) were dripped from spiked 50-mL vials at each hour for 12 hrs. Two propofol oxidation products, identified as propofol dimer and propofol dimer quinone, were detected in sulfite and EDTA propofol emulsions; however, sulfite propofol emulsion contained higher quantities of both compounds. After initiation of the simulated infusion, the quantities of propofol dimer and propofol dimer quinone increased in the sulfite propofol emulsion, but the lower levels in the EDTA propofol emulsion remained constant. Sulfite propofol emulsion began to visibly yellow at about 6-7 hrs. The EDTA propofol emulsion remained white at all times. The absorbance spectra of the propofol dimer and propofol dimer quinone extracted from sulfite propofol emulsion showed that propofol dimer did not absorb in the visible spectrum, but the propofol dimer quinone had an absorbance peak at 421 nm, causing it to appear yellow. Electron paramagnetic resonance analysis of the propofol emulsion containing metabisulfite revealed that the sulfite propofol emulsion yielded a strong free radical signal consistent with the formation of the sulfite anion radical (SO3*-). The EDTA propofol emulsion yielded no free radical signal above background. CONCLUSION: Sulfite from the metabisulfite additive in propofol emulsion creates an oxidative environment when these emulsions are exposed to air during a simulated intravenous infusion. This oxidation results in propofol dimerization and emulsion yellowing, the latter of which is caused by the formation of propofol dimer quinone. These processes can be attributed to the rapid formation of the reactive sulfite free radical. 3/14/05 re: Cause and treatment of reactive airways disease Ever since I moved to Albuquerque NM I am having problems with Sinus infections and RAD, I moved on 9/04. I ran for the first time on my life on the cold on 10/04. On 11/04 before my first RAD I was outside watching my colleagues running in a very cold environment, I coughed for the whole 30minutes. I could not leave because it was an order given by a superior. I did not run but the next day I started to cough very bad, I developed asinus infection and Bronchitis with SOB on small activities such as shorts walks, my peak flow was 450, I was treated with Albuterol for 48 hrs, did not get better, I started prednisone 40 mg po qd for 5 days. The prednisoe acted wonderfully, no SOB, no cough after three days of Tx. No problems after that. On 2/14/05 I have another sinus infection plus another RAD, I was out for 4 days, again same treatment I got better but since then I am having a everyday cough, the cough responds well to Albuterol, but still there until today. I have two normal PFTs, my best peak flow now is 710, however in the night time I feel some SOB and the cough increased too, the peak flow at night is about 550 to 600 before Albuterol. After I used it it increase to 700. I am on prednisone 40 mg x 4 days, 30 mg x 3 days and then 20 mg for 3 days. The use of Albuterol it decreased with the prednisone, before it was every 3 to four hrs, now its two to three times a day, except on exercise days; the cough at night is been once over the past four days. No symptoms for GER, no symptoms for postnasal drip. No headaches. The pulmonologist had mentioned that I might have this cough for about six weeks; it is almost four and its very annoying, I cough at least every 10 minutes if I don't use Albuterol and the effect of the medicine its about 3 to 4 hrs. He Do me with EIA but no asthma yet. He thinks I have bronchial hyper reactivity. He stated to try the prednisone and to do a methacholin test after six wks. I tried Salmeterol before but the effect it lasted for 6 hrs so I had to use the Albuterol about noon every day. While I was on prednisone the salmeterol lasted for about 10 hrs. The pulmonologist discontinued the salmeterol and told me to stick with the Albuterol only. PMHx: Few wheezing episodes after URIs as a child. No hx of exerciseinduced asthma during adolescent yrs. I had always lived at sea level. I had never use Albuterol before coming to Albuquerque . No smoker. My past URI it lasted the usual 5 to 7 days with no use of Albuterol or prednisone before. Two times use of prednisone in the last four months I can run and exercise without problems inside doors. Now after my last episode of RAD I do use Albuterol before exercise. I cough once or twice after exercise but not during exercise. I think I do have asthma because of the variance on the peak flows, the decrease peak flow at night, and the response to Albuterol, please give me your valuable opinion My questions are: For how long should I be having this bronchial hyper reactivity? Can you have normal PFTs and still have asthma? Do you think the dry and cold weather contributes to my illness? Any other different approaches to my problem? The fact that my first RED episode was because I stood outside in the cold, without doing any exercise activities, I am afraid to do exercises in a cold environment. Any advice about that? Your description sounds as if you have reactive airways disease (RAD). This could be a residual effect of a certain type of viral infection in a pre-disposed individual (noted by your history of wheezing in chiklhood) in which case you may have bronchial hyper-responsiveness (BHR) lasting up to as long as 6 months. However, it is also possible that you have adult-onset asthma. I have seen a number of patients with histories of recurrent wheezing in childhood which is “outgrown” in late childhood/adolescence, only to recur in the 20's-30's age. To respond directly to your questions: 1) Duration of BHR- up to 6 months after certain viral infections. But longer duration if you have chronic asthma. It sounds as if you have more than just exercise-induced asthma. 2) In intermittent asthma, the usual screening PFT may be normal at times. Be sure that the FEV-1/.FVC ratio has been calculated. This ratio is often a more reliable predictor of wheezing recurrence than is the FEV-1 alone as a % of normal predicted. The PEFR is a less sensitive, more variable measure because it may not take into account obstruction in the smaller airways which persists in asthma even after the FEV-1 returns to normal. Almost all individuals with asthma have abnormal methacholine challenge responses,even when the PFT are normal. 3) Inhalation of cold, dry air is a potent stimulus of airflow obstruction in those with BHR. Indeed, some groups find it as sensitive a stimulus as methacholine in inhalational challenge studies. Some patients find that use of a “cold weather” mask (in which there is partial re-breathing of previously warmed air) will reduce the symptoms in cold air exposures. It would be worth seeing whether your symptoms, including response to outdoors exercise, improve during a stay in a warmer, slightly moister environment. 4) Another possible factor in the onset of your symptoms since your move to this location is that you have developed allergies to a locally prominent aeroallergen. This possibility would be greater if you had also manifested nasal symptoms when exercising out of doors. An allergy evaluation may be indicated. 5) I think that you may be benefited by inhalation of a combination therapy with an inhaled corticosteroid (ICS) and a long-acting beta agonist (LABA). Advair is the most commonly used combination. However, because you find that salmeterol , the LABA in Advair, helps you for only 6 hours, I would try formoterol, a unique LABA with onset of action as rapid as albuterol and yet duration of bronchodilation up to 12 hours . Along with this, use inhaled budesonide, a potent ICS, in a dose of 400 mcg . These two agents should be used b.i.d. The dose of budesonide can be tapered somewhat once there is persistent improvement. A combination inhaler containing formoterol and budesonide is available (as Symbicort) in Europe but not yet in the USA so you would have to use two inhalers. I have enclosed below my reviews for this AADMC website of two recent reports describing these effects of ormoterol/budesonide. Budesonide/formoterol combination therapy as both maintenance and reliever.treatment in asthma. A number of recent studies have shown that adding inhaled long-acting beta agonists (LABA) to low-medium doses of inhaled corticosteroids (ICS) improves asthma control However, acute asthma flares do occur occasionally in individuals treated with such combination therapy, generally treated with inhaled short-acting beta agonists (SABA) such as albuterol or terbutaline. This study was carried out in 2,760 asthmatics on maintenace therapy with an inhaled combination of budesonide (an ICS) and formoterol ( a LABA) in doses of 80/4.5 mcg bid). The authors then compared the effects of adding to this maintenance therapy either: 1) inhaled terbutaline (0.4 mg) or 2) additional doses of the budesonide/formoterol combination when there were signs of worsening asthma.They found that asthmatics using additional doses of budesonide/formoterol had better symptomatic control and 46% fewer asthma exacerbations than those using terbutaline as added therapy (p<0.001). There was also a longer interval before such asthma exacerbations occurred in those using additional doses of budesonide/formoterol as needed. Indeed, this use as needed of additional budesonide/formaterol doses led to better asthma control than did maintenance therapy with budesonide 320 mcg bid with added SABA as needed. These findings suggest that the combination of budesonide/formoterol can be used as both maintenance and reliever treatment in asthma O'Byrne et al Am. J Respir Crit Care Med 2005;171:129-136   Safety and tolerability of inhaled high-dose formoterol and salbutamol in persistent asthma. Summary Background – Formoterol (Form) is a long acting beta agonist with a very rapid onset of bronchodilating action, as fast as the commonly used albuterol (salbutamol) when inhaled. Therefore, some investigators have recently suggested that inhaled Form can be used both as:1) an acute symptom reliever and 2) a component of long-term controller therapy in persistent asthma (PA), (Am J Resp CC Med 2005;171:129-36). But is such a use of Form safe? Findings – Kruse et al of PARAXEL International in Berlin , Germany compared the safety/tolerability of inhaled Form (36 microg t.i.d.) by aerolizer vs salbutamol 600 microg t.i.d. in a double-blind, double-dummy, crossover study in 16 adults with mild/moderate PA. They found mild adverse effects thought to be not clinically relevant of similar degree during the both the Form and salbutamol therapy. No treatment was discontinued because of treatment- related adverse effects. Reference Pulm Pharmacol Ther 2005;18:229-34 Editor's Comments I have been impressed with the considerable advantage of using Form, with its rapid onset of bronchodilating action (within 1-2 minutes) and long duration of such effect (8-12 hours). However, concerns have been raised whether there would be a cumulative adverse effect if Form were used every few hours as an acute asthma reliever. The findings described above give some reassurance that such adverse effects are relatively 3/14/05 re: Child with increased serum IgE levels Thanks for your response. I have completed your survey form. The IGE level of the child is 198 I.U. Please let us know if any vaccine is available for the virus you have mentioned in you mail? Is there any way to normalize the IGE Level or it is a life time problem. Please suggest some prophylaxis measures. A serum IgE of 198 IU in a child of this age is quite compatible with someone who has had atopic dermatitis and now has respiratory allergies. The serum IgE will remain in this range (or somewhat higher) as long as the allergies are uncontrolled. My suggestions are these:1) Thorough evaluation for allergies to aeroallergens (inhalants). 2) If the atopic dermatitis (eczema) is still active, evaluation for food allergies. Such food allergies play a role in about 60% of children with atopic dermatitis Appropriate allergen avoidance (and allergen immunotherapy if indicated) should significantly reduce allergies and asthma. The most cost effective way to do this is usually through consultation with a certified allergist. If such a specialist is not available, you can obtain levels of IgE antibodies against inhalants and perhaps foods from a reliable lab in your area (one has to choose such a lab carefully since there are some questionable operations). The lab findings have to be carefully correlated with the clinical history. Cautious food challenges may be necessary. In response to your question, there are many strains of the rhinovirus family that can cause respiratory infections. Therefore, a vaccine that is truly protective is not yet available. 1/26/05 re: Significance of candida in asthma I am a nurse practitioner in Iowa. I have a 50ish female patient who has severe asthma. Over the course of the past year her severe exacerbations have been treated with oral prednisone and antibiotics. She is also on nebulizer at home. She is convinced that candida is her primary issue. She feels the treatment for her asthma worsens her presumed candida intolerance. A local pulmonoligist and allergist both are not impressed with her theory. I just want to get her to a specialist who has an interest in this area. I noted the work done with chronic sinusitis and it seems intriguing. Please send me any info on May researchers or specialists if possible. Candida is a relatively low invasive yeast that presents potential problems only in those with depressed immune/host defense problems. It is not unusual to find candida on the posterior pharynx in those receiving corticosteroids either systemically or by bronchial inhalation. However, there is no evidence that candida in this location spreads into the lower airway in immunocompetent individuals. Thus, there is no convincing evidence that candida plays a role in the pathogenesis of asthma. Perhaps your patient has come across some material on the Internet or elsewhere about the “yeast connection”. About 15-20 years ago there was an unproven theory that colonization of the body by candida could be responsible for a variety of ailments and symptoms. This theory was based predominantly on a book which I believe was called “The Yeast Connection”. As I recall, this book contained a collection of case anecdotes without any evidence from true scientific studies. Nevertheless, this book and the theory it espoused received a lot of attention in the lay media at the time. One hears much less about candida in this regard in recent years since several scientific studies to see if there is a role of candida in asthma and several other disorders came up with negative findings. Therefore, in this patient I would concentrate on using an appropriate aggressive treatment with inhaled corticosteroids, possibly along with an inhaled long-acting beta agonist (such as fluticasone/salmeterol or budesonide/formoterol) rather than trying to eliminate candida from the body. One should also look for and then treat possible co-morbid conditions such as smoking, G-E reflux (GERD), active sinusitis, ongoing allergies, cardiac disease that may make asthma control moredifficult. However, if there is heavy candida colonization in the posterior pharynx causing local symptoms, one should take appropriate steps to reduce such colonization. This includes use of an appropriate spacer/holding chamber with the MDI, rinsing with water /spitting out after each treatment with inhaled corticosteroids, and use of an anti-fungal gargle. 11/1/04 re: Asthma in athlete I have a 21-year-old collegiate female runner who has developed asthma (progressively worsening) over the past 2 years. She has been to a pulmonary specialist who did not find anything other than to document that her peak flow varied from 280-380. He prescribed Intal and Albuterol and Singular. She did not see any improvement. Because the pulmonary specialist could not determine a problem or course of action, I referred her to an allergy specialist. He did pin prick testing for allergens and found she had a reaction to grass, mold, and dust mites. He put her Pulmacort and a nasal spray for allergies. The new medications seemed to help over the first week (peak flow up to 380), but the second week deteriorated to 300ish again. (We are from Northern Minnesota, and the weather has gotten progressively colder over this time but not below 30 degrees.) The allergist insists now that he cannot help her. Two years ago the athlete could push herself extremely hard as a distance runner and run 10+ miles. Now she cannot run more than 1/2 mile without breathing extremely hard/asthma attack. She simply cannot breath every day. Is there an expert out there, particularly one who was a runner or who has worked with athletes and understands that a peak flow of 300 can't possibly be normal for a competitive college runner? To obtain more information regarding your question, I contacted Dr. John Weiler, Chair of the American Academy of Allergy, Asthma and Immunology Sports Medicine Committee. Dr. Weiler's response is enclosed below. Dr. Weiler's Comments: What other studies were performed by the pulmonary specialist and the allergist? Without knowing what has been done to evaluate her, it is difficult to narrow the possible diagnoses. Is the diagnosis of asthma confirmed? In my opinion, she needs: 1. Full spirometry pre- and post-bronchodilator. Peak expiratory flow rates do not provide much information. She needs to have FEV1, FVC, and flow loop (inspiratory and expiratory) before and after bronchodilator. Depending on the result of these tests I would then consider: 1. Lung volumes. 2. DLCO 3. Chest x-ray Depending on these results, I would then consider: 1. An exercise challenge. 2. A gas exchange study, possibly. 3. Evaluation of the upper airway by rhinoscopy during exercise The range of diagnostic possibilities is high. It is not clear to me that asthma is responsible for these symptoms and lack of responsiveness to adequate therapy suggests another diagnosis. There are a variety of pulmonary and even cardiac disorders that could be responsible for her problems. For example, she could have collapse of the posterior arytenoids which could masquerade as asthma. Clearly, she needs an evaluation by a physician trained in evaluating sports medicine respiratory disorders. Finally, asthma can coexist with another disorder. 10/13/04 re: Esophagectomy in an asthmatic I am a thoracic surgeon in the Hebei province of China. We admitted a male patient of 56 years old with esophageal cancer and allergic asthma. The patient still looks well. We want to perform esophagectomy through a left thoracic incision. But we are afraid his asthma may get worse or even fatal during or after the operation. May you tell me if asthma is a contraindication for esophagectomy? If not, could you give me some advice to avoid the risks in perioperation period? Someone with active asthma is at an increased risk for complications during and after major, prolonged surgery such as esophagectomy. Whether this surgery is absolutely contra-indicated would depend in part on: 1) The patient's pulmonary function at the time of surgery 2) The training and experience of the anesthesiologist in dealing with prolonged surgery in an asthmatic 3) The chance for a cure by the surgery. I assume that you have found no evidence of tumor away from the primary tumor site in a careful evaluation. 4) The patient's desire or reluctance to have the surgery Particular concerns that I would have include: 1) Increased airways hyper-reactivity in active asthma which might make the patient more susceptible to adverse effects of anesthesia and other inhalational agents 2) Possible aspiration problems and related pneumonitis 3) Pleural fluid-particularly bleeding 4) Diaphragmatic paresis One can reduce risk by intensive pre-operative treatment of the asthma to get pulmonary function and exercise tolerance to normal or very close to normal. However, special precautions would still be necessary, particularly during prolonged anesthesia and the immediate post-op period. 10/11/04 re: Asthma in post-op patient I am a 46 year old RN who works in the PACU. Recently I had a patient who had a Thyroidectomy (Total) and who has developed Stressed Induced Asthma post op. Could you tell me the correlation between the two, if any, and if this is treatable or reversible or could this be permanent damage from the surgery? Patient does have a long hx of sinusitis. Now the patient, with the least bit of exertion of talking, develops shortness of breath. The patient is three weeks post-op and has now been put on Proventil Inhaler. The first question that comes to my mind in trying to respond to your question is whether there is solid documentation by pulmonary function tests that the patient truly has asthma at this time. I say this because some other conditions that may be triggered by thyroid surgery can mimic some of the symptoms of asthma. For example, vocal cord dysfunction (VCD) can be manifest as episodic dyspnea and even something that sounds like wheezing. However, in VCD, there are frequently vocal symptoms (e.g.-hoarseness) sometimes inspiratory distress, and a pattern on pulmonary function testing (spirometry) that does not suggest asthma. Patients with VCD also do not exhibit impressive improvement after albuterol inhalation. Another condition to consider if there is no clear-cut evidence of asthma is whether there is some form of laryngeal nerve dysfunction that occurred as a result of local trauma related to the thyroidectomy. If this is a possibility, it should be investigated by a careful laryngoscopy by an experienced observer. However, if this patient now has well documented asthma (and nothing to suggest asthma pre-op) it is possible that someone with chronic sinusitis may have a pre-disposition to asthma (bronchial hyper-reactivity). Occasionally, the use of certain inhalational anesthetics can trigger asthma in such a pre-disposed individual. If this is the case, the situation may be relatively transient, lasting weeks to several months. However, inhaled albuterol may not be effective in reducing the local inflammatory reaction that leads to the bronchial hyper-reactivity. Daily use of an inhaled corticosteroid such as Flovent or Pulmocort (about 400 mcg/day for 4-6 weeks) for the average sized adult may “calm” the local reactivity. If the patient has obtained impressive improvement from albuterol inhalation (both symptomatic and by comparing the FEV-1 before and after the albuterol treatment), one may wish to try Advair instead of Flovent. Although there are occasional case reports suggesting that the “stress of surgery” may trigger asthma, I think that this possibility is much less likely than the other conditions I mentioned above. 10/7/04 re: Bone marrow donation by an asthmatic I am a general internist. I would like to compliment you on your very informative site. I would like to elicit your expert opinion on a matter of public health policy regarding asthmatics of which I recently became aware. Since I am myself an asthmatic, this question is of both personal and professional interest to me. I recently completed an application to become a member of the National Bone Marrow Registry. Although I have been registered as an organ donor for years, I had overlooked participating in the bone marrow registry and wished to correct this oversight. I was very surprised to learn that any level of asthma other than exercise-induced automatically disqualifies one from registering as a potential donor. No consideration is given to level of control, use of rescue medications or history of complications. The rationale provided for this NBMR policy is that many medical centers that harvest bone marrow still prefer to use a general anesthetic with intubation. Since the donor doesn't “benefit” personally (health-wise) from the donation, the risk/benefit ratio is thus determined to be unsatisfactory for the asthmatic donor. I have been unable to locate any evidence-based literature which provides information on the risk of general anesthesia in a well-controlled asthmatic (no history of hospitalizations or ER usage, no oral corticosteroids in >10 years, infrequent use of rescue inhaler) for non-abdominal, non-thoracic surgeries. I would appreciate any information or references which you could provide. Is it appropriate to exclude 17 million Americans from registering for the National Bone Marrow Registry because they have a diagnosis of asthma, without consideration of the level of control? I hope you can help me with this question. It is true that the majority of bone marrow donations are apparently still carried out under general anesthesia. Such anesthesia presents the potential, if not actual, use of intubation. When such general anesthesia is carried out by highly experienced anesthesiologists in asthmatics, particularly well-controlled asthmatics, the risk should not be greater than in otherwise matched individuals without asthma (see enclosed abstracts). However, I think that such tolerance of general anesthesia may be very dependent on the experience and skill of the anesthesiologist in dealing with asthmatic subjects. It may be that such level of expertise is not always available in the anesthesiologists assigned to bone marrow donation procedures (since the procedures are considered as “less risky” when healthy donors are the subjects). I admire your altruistic desire to be of help with tissue donations. I suggest that you consider getting involved in being a peripheral blood cytapharesis donor instead of a bone marrow donor. This procedure (generally involving cytokine treatment of the donor) has assumed increasing popularity because it is preferred by donors (see enclosed abstracts). There is also a lower frequency of peri-procedure donor morbidity with this approach than with bone marrow donation. The element of less frequent/prolonged fatigue may be particularly important if your asthma becomes active. J Investig Allergol Clin Immunol. 1993 Jan-Feb;3(1):53-5. Anasthesiol Intensivmed Notfallmed Schmerzther. 2000 Sep;35(9):545-58. [Anesthesia in bronchial asthma] Bremerich DH. Klinik fur Anasthesiologie, Intensivmedizin und Schmerztherapie, Zentrum der Anasthesiologie und Wiederbelebung, Klinikum der Johann Wolfgang Goethe-Universitat Frankfurt / Main. Asthma is defined as a chronic inflammatory airway disease in response to a wide variety of provoking stimuli. Characteristic clinical symptoms of asthma are bronchial hyper-reactivity, reversible airway obstruction, wheezing and dyspnea. Asthma presents a major public health problem with increasing prevalence rates and severity worldwide. Despite major advances in our understanding of the clinical management of asthmatic patients, it remains a challenging population for anesthesiologists in clinical practice. The anesthesiologist's responsibility starts with the preoperative assessment and evaluation of the pulmonary function. For patients with asthma who currently have no symptoms, the risk of perioperative respiratory complications is extremely low. Therefore, pulmonary function should be optimized preoperatively and airway obstruction should be controlled by using steroids and bronchodilators. Preoperative spirometry is a simple means of assessing presence and severity of airway obstruction as well as the degree of reversibility in response to bronchodilator therapy. An increase of 15% in FEV1 is considered clinically significant. Most asymptomatic persons with asthma can safely undergo general anesthesia with and without endotracheal intubation. Volatile anesthetics are still recommended for general anesthetic techniques. As compared to barbiturates and even ketamine, propofol is considered to be the agent of choice for induction of anesthesia in asthmatics. The use of regional anesthesia does not reduce perioperative respiratory complications in asymptomatic asthmatics, whereas it is advantageous in symptomatic patients. Pregnant asthmatic and parturients undergoing anesthesia are at increased risk, especially if regional anesthetic techniques are not suitable and prostaglandin and its derivates are administered for abortion or operative delivery. Bronchial hyper-reactivity associated with asthma is an important risk factor of perioperative bronchospasm. The occurrence of this potentially life-threatening condition in anesthesia practice varies from 0.17 to 4.2%. The anesthesiologists' goal should be to minimize the risk of inciting bronchospasm and to avoid triggering stimuli. As increases in airway resistance are noticed, therapy should be directed towards optimizing oxygenation and proper diagnosis needs to be established. With deepening anesthesia level and aggressive pharmacological management utilizing both, beta-agonists and steroids, respiratory failure may be properly controlled. Br J Anaesth. 1996 Aug;77(2):200-2. Effect of anaesthesia on lung function in children with asthma. May HA, Smyth RL, Romer HC, Martin PH, Bowhay AR , Heaf DP. Department of Paediatric Anaesthesia, Royal Liverpool Children's NHS Trust. Spirometry was performed before operation, soon after recovery (“early”) and the day after (“late”) general anaesthesia for elective surgery in 20 children with asthma and 20 matched children without asthma. Pulse oximetry was recorded on the first postoperative night. The mean early peak expiratory flow rate (PEFR) decreased in the asthmatics by 19.91 (95% confidence intervals (CI) 10.84-28.97) % and in the controls by 19.25 (10.70-27.80)%. The mean early FEV1decreased in the asthmatics by 16.02 (9.29-22.75) % and in the controls by 11.03 (2.86-19.19) %. The mean late decrease from baseline PEFR for the asthmatics was18.55 (11.23-25.87) % but only 14.93 (7.89-21.97) % for the controls. The mean late FEV1 was 8.2 (0.83-15.56) % below baseline in the asthmatics but only 6.82 (-0.79 to 14.42) % in the controls. There were no differences in overnight pulse oximetry. We conclude that healthy children exhibited a decrease in FEV1 and PEFR after general anaesthesia for elective surgery, but this decline did not appear to be any greater in well controlled asthmatic children compared with children who did not have asthma. Curr Opin Hematol. 2000 May;7(3):150-5. Granulocyte colony-stimulating factor versus granulocyte-macrophage colony-stimulating factor for collection of peripheral blood progenitor cells from healthy donors. Fischmeister G, Gadner H. St. Anna Children's Hospital and Children's Cancer Research Institute, Vienna, Austria. The harvesting of peripheral blood progenitor cells (PBPCs) after granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor stimulation instead of bone marrow in healthy donors has become increasingly popular. Donors, given the choice between bone marrow and PBPC donation, often prefer cytapheresis because of the easier access, no necessity for general anesthesia, and no multiple bone marrow punctures. In addition, accelerated engraftment and immunomodulation by granulocyte colony-stimulating factor-mobilized PBPCs are advantageous for the recipient. However, because of donor inconvenience and poor mobilization, there is a need to develop improved procedures. Aspects such as durability of hematopoietic engraftment, characterization of the earliest stem cell, and composition of PBPCs are not yet well defined, and international donor registration and follow-up must be considered when evaluating long-term safety profiles in healthy donors. This review concentrates on the most significant developments on mobilization of PBPCs published during the past year. Bone Marrow Transplant. 2004 Apr;33(7):709-13. Mobilized blood cells vs. bone marrow harvest: experience compared in 171 donors with particular reference to pain and fatigue. Karlsson L, Quinlan D, Guo D, Brown C, Selinger S, Klassen J, Russell JA. Alberta Bone Marrow Transplant Program and Department of Medicine, Tom Baker Cancer Centre, Calgary, Alberta, Canada. This prospective study compared the donor experience of blood cell (BC) mobilization and leukapheresis (n=116) with that of bone marrow (BM) harvest (n=55). Internal jugular catheters were inserted electively in 89% of BC donors. Most (80%) BM donors had a harvest with general anesthesia; 20% had epidural or spinal anesthesia. Pain and fatigue were frequent with both procedures and were compared in responses to questionnaires. A total of 85% of BM donors reported moderate or severe pain compared with 68% of BC donors (P=0.02). The median duration of pain was 14 days for BM donors compared with 3 days after BC mobilization (P<0.0001). More BM donors had pain for more than 7 days (75% vs. 0%, P<0.0001). Severe fatigue was experienced by more BM donors (49 vs. 16%, P<0.0001). Fatigue lasted significantly longer in BM donors (median 11 vs. 4 days, P<0.0001) and more BM donors were fatigued for more than 1 week (69 vs. 0%, P<0.0001). A total of 11 donors had both BM and BC collection; seven preferred the latter. Simply considered with respect to pain and fatigue, BC donation appears better tolerated by donors. However, there are other sequelae of both influencing the acceptability for individual donors. 8/2/04 re: Percentage of asthma which are allergic Can you advise what proportion of all asthma cases are considered to be allergic asthma (i.e. IgE-mediated)? Further, what is the breakdown of IgE-mediated asthma in adults and in children? I haven't been able to find any definitive answers in the published literature and though you may have more up to date data. I believe that the confusion you may have experienced in reviewing different reports reflects the fact that asthma is a multi-factorial disease in which usually genetically predisposed individuals are affected by certain environmental exposures (with the particular exposures not always the same from case to case). Allergic factors may play important roles in many, if not most asthmatics but are often not the only factor in the individual patient. The answer to your question also depends on when the wheezing started in life and age of the group studied. Therefore, I believe that there is no one simple answer to your question. However, a brief description of certain trends may help your understanding. 1) Recurrent wheezing is very common in early childhood. In many cases, such wheezing occurs only with certain respiratory infections. Perhaps the strongest risk factor for childhood wheezing is a strong parental history of asthma. 2) The majority of wheezing young children no longer wheeze after age 5 years. However, if there is evidence of atopy (IgE-mediated allergies, including food allergies), atopic dermatitis, and/or more severe or earlier onset wheezing in early childhood, wheezing is much more likely to persist past age 5 years. Thus, studies have shown that up to 80% of asthma in such school-age children has a significant allergic component, most commonly sensitivity to indoor allergens such as the dust mite. 3) Recent total population studies have shown that about 25% of children who are asthmatic at age 9 years will have persistent or recurrent asthma at age 26 years (see enclosed abstract). Early onset of wheezing in childhood, mite allergy, smoking and female gender are risk factors for such persistent asthma. Indeed those with more severe asthma in childhood are much more likely to have persistent asthma at age 42 years (Horak et al Longitudinal study of childhood wheezy bronchitis and asthma: outcome at age 42.BMJ. 2003 Feb 22;326(7386):422-3) 4) Asthma starting in adulthood is more difficult to classify because of confounding factors such as diagnostic overlap with COPD (mainly in smokers), occupational exposures (thought responsible for about 10% of adult asthma), GERD effects, etc. Nevertheless, allergic factors probably play significant roles in up to 60% of adult asthmatics, including those with asthma starting in childhood. Asthma which truly starts for the first time past the age of 40 years is unlikely to have a major allergic component although there are certainly such cases seen occasionally. However, it should be noted that a very sizable percentage of adult asthmatics have concomitant rhinitis (allergic or non-allergic). N Engl J Med. 2003 Oct 9;349(15):1414-22. A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. Sears MR, Greene JM, Willan AR, Wiecek EM, Taylor DR, Flannery EM, Cowan JO, Herbison GP, Silva PA, Poulton R. Firestone Institute for Respiratory Health, Department of Medicine, McMaster University and St. Joseph 's Healthcare, Hamilton, Ont., Canada. Background: The outcome of childhood asthma in adults has been described in high-risk cohorts, but few population-based studies have reported the risk factors for persistence and relapse. Methods: We assessed children born from April 1972 through March 1973 in Dunedin, New Zealand, repeatedly from 9 to 26 years of age with questionnaires, pulmonary-function tests, bronchial-challenge testing, and allergy testing. Results : By the age of 26 years, 51.4 percent of 613 study members with complete respiratory data had reported wheezing at more than one assessment. Eighty-nine study members (14.5 percent) had wheezing that persisted from childhood to 26 years of age, whereas 168 (27.4 percent) had remission, but 76 (12.4 percent) subsequently relapsed by the age of 26. Sensitization to house dust mites predicted the persistence of wheezing (odds ratio, 2.41; P=0.001) and relapse (odds ratio, 2.18; P=0.01), as did airway hyper-responsiveness (odds ratio for persistence, 3.00; P<0.001; odds ratio for relapse, 3.03; P<0.001). Female sex predicted the persistence of wheezing (odds ratio, 1.71; P=0.03), as did smoking at the age of 21 years (odds ratio, 1.84; P=0.01). The earlier the age at onset, the greater the risk of relapse (odds ratio, 0.89 per year of increase in the age at onset; P<0.001). Pulmonary function was consistently lower in those with persistent wheezing than in those without persistent wheezing. Conclusions: In an unselected birth cohort, more than one in four children had wheezing that persisted from childhood to adulthood or that relapsed after remission. The factors predicting persistence or relapse were sensitization to house dust mites, airway hyper-responsiveness, female sex, smoking, and early age at onset. These findings, together with persistently low lung function, suggest that outcomes in adult asthma may be determined primarily in early childhood.   8/2/04 re: Percentage of asthma which are allergic Can you advise what proportion of all asthma cases are considered to be allergic asthma (i.e. IgE-mediated)? Further, what is the breakdown of IgE-mediated asthma in adults and in children? I haven't been able to find any definitive answers in the published literature and though you may have more up to date data. I believe that the confusion you may have experienced in reviewing different reports reflects the fact that asthma is a multi-factorial disease in which usually genetically predisposed individuals are affected by certain environmental exposures (with the particular exposures not always the same from case to case). Allergic factors may play important roles in many, if not most asthmatics but are often not the only factor in the individual patient. The answer to your question also depends on when the wheezing started in life and age of the group studied. Therefore, I believe that there is no one simple answer to your question. However, a brief description of certain trends may help your understanding. 1) Recurrent wheezing is very common in early childhood. In many cases, such wheezing occurs only with certain respiratory infections. Perhaps the strongest risk factor for childhood wheezing is a strong parental history of asthma. 2) The majority of wheezing young children no longer wheeze after age 5 years. However, if there is evidence of atopy (IgE-mediated allergies, including food allergies), atopic dermatitis, and/or more severe or earlier onset wheezing in early childhood, wheezing is much more likely to persist past age 5 years. Thus, studies have shown that up to 80% of asthma in such school-age children has a significant allergic component, most commonly sensitivity to indoor allergens such as the dust mite. 3) Recent total population studies have shown that about 25% of children who are asthmatic at age 9 years will have persistent or recurrent asthma at age 26 years (see enclosed abstract). Early onset of wheezing in childhood, mite allergy, smoking and female gender are risk factors for such persistent asthma. Indeed those with more severe asthma in childhood are much more likely to have persistent asthma at age 42 years (Horak et al Longitudinal study of childhood wheezy bronchitis and asthma: outcome at age 42.BMJ. 2003 Feb 22;326(7386):422-3) 4) Asthma starting in adulthood is more difficult to classify because of confounding factors such as diagnostic overlap with COPD (mainly in smokers), occupational exposures (thought responsible for about 10% of adult asthma), GERD effects, etc. Nevertheless, allergic factors probably play significant roles in up to 60% of adult asthmatics, including those with asthma starting in childhood. Asthma which truly starts for the first time past the age of 40 years is unlikely to have a major allergic component although there are certainly such cases seen occasionally. However, it should be noted that a very sizable percentage of adult asthmatics have concomitant rhinitis (allergic or non-allergic). N Engl J Med. 2003 Oct 9;349(15):1414-22. A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. Sears MR, Greene JM, Willan AR, Wiecek EM, Taylor DR, Flannery EM, Cowan JO, Herbison GP, Silva PA, Poulton R. Firestone Institute for Respiratory Health, Department of Medicine, McMaster University and St. Joseph 's Healthcare, Hamilton, Ont., Canada. Background: The outcome of childhood asthma in adults has been described in high-risk cohorts, but few population-based studies have reported the risk factors for persistence and relapse. Methods: We assessed children born from April 1972 through March 1973 in Dunedin, New Zealand, repeatedly from 9 to 26 years of age with questionnaires, pulmonary-function tests, bronchial-challenge testing, and allergy testing. Results : By the age of 26 years, 51.4 percent of 613 study members with complete respiratory data had reported wheezing at more than one assessment. Eighty-nine study members (14.5 percent) had wheezing that persisted from childhood to 26 years of age, whereas 168 (27.4 percent) had remission, but 76 (12.4 percent) subsequently relapsed by the age of 26. Sensitization to house dust mites predicted the persistence of wheezing (odds ratio, 2.41; P=0.001) and relapse (odds ratio, 2.18; P=0.01), as did airway hyper-responsiveness (odds ratio for persistence, 3.00; P<0.001; odds ratio for relapse, 3.03; P<0.001). Female sex predicted the persistence of wheezing (odds ratio, 1.71; P=0.03), as did smoking at the age of 21 years (odds ratio, 1.84; P=0.01). The earlier the age at onset, the greater the risk of relapse (odds ratio, 0.89 per year of increase in the age at onset; P<0.001). Pulmonary function was consistently lower in those with persistent wheezing than in those without persistent wheezing. Conclusions: In an unselected birth cohort, more than one in four children had wheezing that persisted from childhood to adulthood or that relapsed after remission. The factors predicting persistence or relapse were sensitization to house dust mites, airway hyper-responsiveness, female sex, smoking, and early age at onset. These findings, together with persistently low lung function, suggest that outcomes in adult asthma may be determined primarily in early childhood.   6/9/04 re: Pleuritic pain in an asthmatic I am a pediatric resident with a difficult asthmatic adolescent. He is 19 years old with severe atopy. As a child, he was a severe persistent asthmatic with multiple hospita