1970-2000: Does rescue medicine make asthma worse?

The 1970s saw a third spike in asthma related deaths, and this time the location was isolated to New Zealand.  This prompted researchers to further investigate the relationship between asthma rescue medicine and asthma morbidity and mortality.

According to Ann Janet Woolcock, data from death certificates were investigated from Australia, New Zealand, U.S.A., West Germany, Canada, Japan, Britain and Wales.  Regarding these results, she said:

Deaths were lowest in about 1975 in all countries and then increased somewhat (dramatically in new Zealand) until about 1985, but since then, and especially since 1990, mortality has decreased or remained steady in all the countries shown.  There has been much speculation about the reasons for the fluctuations, but it is difficult to draw conclusions about these figures in the absence of accurate data about the prevalence and severity of the disease, and methods of treatment used in this age group (which was 4-34) in each country.

So did the same medicines that were supposed to make life better or asthmatics cause the rise in morbidity and mortality.  Lawrence K. Altmon suggests that perhaps Dr. Parkinson, in 1995, may have been right on when he suggested that morbidity and mortality was negligible prior to the arrival of adrenaline (epinephrine) in 1902.  (8, page 8)

 Altmon said:

Dr. parkinson wrote that it is "possible that mortality from asthma first appeared when adrenaline (epinephrine) became available.  It was identified in 1902.  Theoretically, lethal asthma could be the result of adrenal medullary suppressoin secondary tothe exogenous administration of its own hormones." (8, page 8)

 "The pattern of events of no adrenaline, no deaths; some adrenaline, some deaths; powerful adrenaline analogues prescribed generously, an epidemic of deaths; withdrawal of the more potent drugs, the epidemic disappears; and supports the thesis of iatrogenic adrenal medullary suppression.  (8, page 8)

There was no doubt that by review trends from New Zealand, rises in asthma morbidity and mortality rates corresponded with the sales of fenoterol.  Sales started to spike when the medicine was introduced to the market in the mid 1970s, and they began to decline when the product was pulled from the market in the early 1990s.

The trend was similar to that of which occurred during the 1940s when asthma morbidity and mortality rates spiked in New Zealand, Australia, Britain and Wales as sales of isoprenaline forte increased.  When the medicine was later pulled from the market, the death rate likewise declined.

Statistics showed similar trends for the rest of the nation, although the rise in morbidity and mortality was more subtle and gradual.  There was a gradual increase following the introduction of isoprenaline solution in the 1940s and again following the introduction of the the rescue inhaler in 1957.

There were now two questions researchers set out to answer:

1. Do beta adrenergics make asthma worse
2. If so, why?

The neat thing about this latest spike in asthma morbidity and mortality was, unlike those that occurred in the 1940s and 1960s, the experts now had an array of data to learn from.

The following were the theories to explain the rise in morbidity:

1.  High doses of beta agonists increases the risk for cardiac arrest.  The was especially the case with non-specific B2 agonists such as epinephrine and isopreterenol.  The high dosing provided by use of this medicine was suspected of  of  overworking the heart, thus causing cardiac arrest.  Beasley, Pearce and Crane suspect this to be most likely to be the case in cases "relating to their overuse in the situation of a life-threatening attack of asthma, in which the cardiac side effects are likely to be particularly harmful in the presence of severe hypoxia." (1, page 20)

Janet Woolcock suggests that "there is little evidence that it (fatal asthma or near fatal asthma) results from a cardiovascular event).  Likewise, she also suggests that "on the other hand, drugs such as albuterol, terbutaline, and salmeterol are partial beta-agonists (specific to the lungs only), and there is no substantial evidence that they increase the risk of death from asthma."  (2, page 190)

2.  High doses use of beta agonists increase tolerance to the medicine:  This subject was taken up by Benoy, Fellah, and Schneider in 1975.  They said that: (11)

The longer animals were pretreated and the higher the dose of bronchodilator given (isoprenaline or adrenaline) the greater was the degree of tolerance developed in the isolated lungs.  Tolerance could develop to such a degree that regardless of the dose of bronchodilator used to challenge the lungs (adrenaline, isoprenaline or aminophylline) no significant bronchodilation was produced.(11, pages 551-552)

Benson &Periman (1948) and Laurence & Moulton (1960) reported that tolerance developed in the brochodilator effect of adrenaline after excessive use of this drug in man...(11, page 552)

These results suggest that asthmatic patients who are heavy users of bronchodilators may become resistant to these drugs.  the valueof these drugs in relieving mild asthmatic attacks in such patients becomes less.  In an extreme case, a patient may die because the drug he is using has become completely ineffective.  A young asthmatic has been found dead clutching an empty bronchodilator aerosol container (Pickvance, 1967).  The same conclusion was reached by  Herxheimer (1973)...(11, page 552 )

Conolly et al. (1971)... suggested that in asthmatic patients who use sympathomimetic pressurized aerosols excessively cross-resistance developsto both exogenous sympathomimetic amines and to the natural transmiter release by the adrenergic nerves, and that this may lead to a deterioration of the asthmatic state and explain the rise in the asthma mortality rate.  The cross tolerance experiments described here may exlain the good results which were obtained only after the withdrawal of adrenergic bronchodilator therapy from some asthmatic patients (Keighley, 1966, Reisman, Friedman & Arbesman, 1968)...(11, page 553 )

The work described in this paper has demonstrated that the tolerance which developed as a result of the repeated administration of isoprenaline or adrenaline remained for periods of upto three weeks after the last administration of isoprenaline or adrenaline to guinea-pigs. (11, page 553)

Developing a tolerance to rescue medicine may result in worsening severity.

3.  High doses of beta agonists increase severity of asthma.  Some studies showed that high doses of beta adrenergics may increase the severity of asthma.  This may result from high dose beta adrenergics such as isoprenaline forte and fenoterol, or from frequent use of regular doses of beta adrenergics such as isoprenaline.  Later studies showed that frequent use of epinephrine, terbulatine, metaproterenol, and albuterol also resulted in increased severity.  (2, pages 189-190)(3, pages 468-470) Some experts have gone as far to suggest that albuterol should not be used on a regular frequency, and should only be used as a rescue medicine as needed.

Regarding these studies, Malcolm R. Sears said the following:

These studies suggest a class efectof regular B-agonists which is likely to be more evident if higher doses of more potent B-agonists are given, and perhaps also more evident in patients with more severe asthma. If this is so, then the natural  tendency to use higher doses of B-agonist in subjects with worsening asthma, and to change to more potent B-agonists for those patients when a new drug is marketed, would escalate the adverse effects (developing a vicious circle of worsening asthma), leading to increased opportunity for a fatality in disadvantageous circumstances. (2, page 469)

The "more potent B-agonists" being referenced to here would be isopreterenol forte and fenoterol. Sears further notes that:

"Strong support for the hypothesis that B-agonists increase the severity of asthma ocmes from the abrupt reversal of both morbidity and mortality in New Zealand in 1990, when, on advice from the drug regulatory agency, fenoterol was effectively withdrawn from use over a period of a few months." (2, page 469)

Other evidence that supports this theory is the decline in asthma morbidity and mortality following increased warnings regarding the risks of isoprenaline forte that resulted in decreased sales(1, page 18) Likewise, following warnings regarding the overuse of the medihaler epi and medihaler iso, morbidity and mortality declined as well.

4.  Over reliance on beta agonists results in delay in seeking help.  Various studies showed that those asthmatics who were found dead with a rescue inhaler clutched in their grasp may have had a false sense of security, and a belief that the medicine would eventually make their asthma better.  Buy the time they realized this was not true it was too late. (2, pages 471-473)

5.  Lack of use of inhaled corticosteroids:  Woolcock said that some patients may develop worsening asthma and have an increased risk of death, "but the lack of inhaled coticosteroids (ICS).  Where salbutamol and ICS are used otgether, there is no increased risk.  One message that is clear an dcan be used in educational campaigns is that increasing frequency of use of beta-agonists such as albuterol is a sign of increasing severity of asthma and thus of increased risk of death. (2, page 190)

These continue to be theories debated by the medical community. Albert L. Schefler, the editor of Fatal Asthma, sums up

A recent study in this regard explored the effect of regular beta agonist use on the bronchoprotective effect of beta agonists. Among a small group of persons with mild, stable asthma, subjects were randomly assigned to use either albuterol or placebo 2 puffs four times daily; both groups could use as-needed albuterol for "rescue." Although the bronchodilator effect of albuterol was not changed by regular use of albuterol, the bronchoprotective effect of albuterol was reduced. Albuterol did not blunt methacholine- or allergen-induced bronchoconstriction as effectively after regular beta-agonist inhalation for two weeks as it did in the placebo group. Tolerance to the bronchoprotective effect of beta agonists may be one way in which overuse of inhaled beta agonists might contribute to fatal outcomes in asthma.

Molecular studies of the beta-agonist receptor have revealed polymorphisms in the general and asthmatic populations. Some genetically determined beta-receptor types may be more susceptible to phosporylation and thereby to down-regulation, a potential mechanism for the development of tolerance to the bronchoprotective effects of beta agonists. An estimated 5-10% of the population have this particular phenotypic expression of their beta receptor and may as a result be at increased risk for severe, potentially fatal asthma. 

The message here is not that beta agonists are dangerous. Used properly, they can be life- saving. The key point is that their role in asthma is as rescue medication for relief of acute asthmatic symptoms. We do no longer prescribe albuterol for regular use on a Q.I.D. basis. Frequent use of albuterol (more than one cannister [=200 puffs]/month should be a warning sign for poorly controlled asthma requiring an intensification of anti-inflammatory therapy. (10)

6.  Rescue medicine by metered dose inhaler (MDI)  causes inert bronchospasm:  A 1985 study by J. Yarbrough, L.E. Lansfield, and S. Ting concluded that the alupent inhaler was likely to cause bronchoconstriction in the smallest air passages of the lungs. They concluded that high doses from frequent use may worsen some cases of asthma.  (12)

7.  Socioeconomic status:  Some studies suggest that asthma is more likely to be uncontrolled and more severe in people who live in poor economic conditions.  The following have been shown by various studies:

• The asthma mortality rate is 5.6 higher in blacks compared to whites (13, page 238)
• Studies in Chicago showed that the highest mortality rates are among a city's poorest neighborhoods (13, page 238)(3, page 471)
• The highest death rates were in the nations poorest communities (13, page 238)
• Morbitity and mortality were highest among the nations least educated (13, page 239)
• Impoverished people are more likely to be exposed to their asthma allergens, such as dust mites, cockroaches, etc. (3, page 472)  
• Impoverished people (including children) are more likely to be exposed to cigarette smoke
• Studies in Philadelphia showed that that areas of the city with the highest percentage of minorities (particularly African Americans) had the greatest chance of using beta agonist medicine as the sole Treatment, as compared to beta agonists combined with inhaled corticosteroid therapy.  (3, page 472)
• Crowding increases risk of severe asthma, perhaps due to increased risk of being exposed to viruses that have been shown to worsen asthma (13, page 239, 244)
• Impoverished people are less likely to have the educational knowledge to adequately care for their own, or their child's, asthma.  (13, page 247)
• Poor children are 40% less likely to visit a doctor, compared to non-poor children (13, page 247)
• Poor children are 40% more likely to require hospitalization, compared to non-poor children (13, page 247)
• Poor children are "more likely to utilize the emergency department." (13, page 247)
• A study in Boston showed that minority children were "less likely to have been on preventative therapy prior to hospitalization, and were less likely to receive a nebulizer at discharge. These differences were not explained by source of payment.  Instead, the racial diferences in outpatient medication use were attributed to practice site, with hospital-based clinics and neighborhood health centers differing from private practices." (13, page 249)

It has also been established that poverty makes it unlikely for an asthmatic to:

• Escape from potential asthma triggers (mainly from poorly maintained homes) (13, page 244)
• Afford asthma medicines, either rescue or preventative
• Afford to see a physician (i.e. family practice, internist)
• Afford to see an asthma specialist (allergist, pulmonologist, etc.)
• Have access to well located medical clinics, hospitals (i.e. physician), resulting in delayed treatment. This increases the risk of near fatal and fatal asthma. 
• Be educated on the proper management of asthma (i.e. have an asthma action plan, the need for 
• Escape from family conflicts, single parent families, substance abuse, crime, etc., all of whihc have been linked with worsening asthma. (13, page 245)
• Escape inner city pollution that has been linked with worsening asthma (13, page 245)
• Escape "psychosocial variables associated with asthma death."  This is particularly true for impoverished asthma children (emotion due to family dysfunction, separation from parents or one parent, etc. (13, page 245)

So it is possible that worsening asthma morbidity and mortality due to socioeconomic status may skewer statistics, making it appear as though asthma is getting worse in a particular nation overall. 

Conclusion:  Keep in mind that all of these theories based on just a few studies, and further studies are definitely indicated.  Experts continue to wonder whether the results from the studies listed above are isolated to particular beta adrenergic medicine studies (such as adrenaline and isopreterenol only) or if they are indicative of a class action effect of the medicine.

Ann Janet Woolcock said the following:

On the other hand, drugs such as albuterol, terbutaline, and salmeterol are partial beta agonists specific only to the lungs, and not the heart), and there is no substantial evidence that they increase the risk of death from asthma. Regular use of albuterol did not increase the severity of disease in patients with mild asthma. (2, page 190)

 I added the emphasis there. Albuterol is specific to beta 2 adrenergic receptors in the lungs only, and not to beta 2 adrenergic receptors in the heart.  Is it possible, therefore, that this makes albuterol exempt from all the studies mentioned above?

"Regular use of albuterol did not increase the severity of disease in patients with mild asthma."

Albuterol is the best selling asthma medicine of all time, and part of the reason is that it relieves asthma symptoms and it comes with essentially negligible side effects.  Some studies do suggest, however, that high doses due to frequent use of albuterol may increase asthma severity.  Further studies are ongoing to determine if this is true, and, if so, to determine the reason why.

References.

1. Beasley, Charles Richard William Beasley, Neil Edward Pearce, Julian Crane, authors of chapter two in the book "Fatal Asthma" edited by Albert L. Sheffer, 1998, New York, Hong Kong, Marcel Dekker, Inc. Chapter two is titled "Worldwide trends in asthma mortality during the twentieth century." 
2. Woolcock, Ann Janet, author of chapter 14 of the book, "Fatal Asthma," edited by Albert L. Sheffer, 1998, New York and Hong Kong, Marcel Dekker, Inc. Chapter 14 is titled "Natural Histor of Fatal Asthma." 
3. Sears, Malcolm R., "author of chapter 29 in the book "Fatal Asthma," edited by Albert L. Sheffer, 1998, New York and Hong Kong, Marcel Dekker, Inc.  Chapter 29 is titled "Role of B-Agonists in Asthma Fatalities." 
4. Jackson, Mark, "Asthma: The Biography," 2009, New York, Oxford University Press 
5. Bisgaard, Hans, Chris O'Callaghan, Gerald S. Smaldone, editors, "Drug Delivery to the Lung," 2001, New York, Marcel Dekker, Inc 
6. Mittman, Gregg, "Breathing Space," 
7. Speizer, F.E., R. Doll, P. Heaf, "Observations on Recent Increase in Mortality from Asthma," British Medical Journal, February 10, 1968, 1, pages 335-339 
8. Altman, Lawrence K., "The Public Perception of Asthma," Chapter one of the book "Fatal Asthma," edited by Albert L. Sheffer, New York, Marcel Dekker, Inc, pages 3 and 11 
9. Speizer, F.E., R. Doll, P. Heaf, and B. Strang, "Investigation into use of drugs preceding death from asthma," British Medical Journal, 1968, 1, 339-343Sheffer, Albert L, "Partner Asthma Center's Grand Rounds," asthma.partners.org, http://www.asthma.partners.org/newfiles/ShefferFatalAsthma.html, accessed 10/5/13 
10. Bendy, Christine J., E.L-Fellah, R. Schneider, "Tolerance to sympathomimetic bronchodilators in guinea-pig isolated lungs following chronic administration in vivo," 1975, British Journal of Pharmacology, 55, pages 547-554 
11. Yarbrough, J., L.E. Lansfield, and S. Ting, "Metered dose inhaler induced bronchospasm in asthma patients," , Annals of Allergy, Asthma and Immunology," July, 1985, (55)1, pages 25-27 
12. Grant, Evalyn N., Kevin B. Weiss, "Socioeconomic risk factors for asthma mortality," chapter 17 of the book, Fatal Asthma," edited by Albert L. Sheffer, 1998, New York, Hong Kong, Marcel Dekker, Inc.