Download Using Cardiopulmonary Exercise Test to Differentiate Dyspnea

Using Cardiopulmonary Exercise Test to Differentiate Dyspnea Patients
莊銘隆 醫師
Abstract
The cardiopulmonary exercise test (CPET) is an important physiological investigation that can aid
clinicians in their evaluation of exercise intolerance and dyspnea. Maximal oxygen consumption () is
the gold-standard measure of aerobic fitness and is determined by the variables that define oxygen
delivery in the Fick equation ( = cardiac output × arterial-venous O2 content difference). In healthy
subjects, of the variables involved in oxygen delivery, it is the limitations of the cardiovascular system
that are most responsible for limiting exercise, as ventilation and gas exchange are sufficient to
maintain arterial O2 content up to peak exercise. Patients with lung disease can develop a pulmonary
limitation to exercise which can contribute to exercise intolerance and dyspnea. In these patients,
ventilation may be insufficient for metabolic demand, as demonstrated by an inadequate breathing
reserve, expiratory flow limitation, dynamic hyperinflation, and/or retention of arterial CO2. Lung
disease patients can also develop gas exchange impairments with exercise as demonstrated by an
increased alveolar-to-arterial O2 pressure difference. CPET testing data, when combined with other
clinical/investigation studies, can provide the clinician with an objective method to evaluate
cardiopulmonary physiology and determination of exercise intolerance.
ICS should be used in long term treatment of COPD: Pro and Cons
Pros: 王耀東
醫師
Cons: 劉旭崇
醫師
The short-term use of corticosteroids as part of the treatment for an acute exacerbation of COPD
is well established and not in question. The question here is whether ICSs should be given as
maintenance treatment for COPD. The rationale for using maintenance ICS therapy in COPD is that it
reduces the frequency of acute exacerbations, which are major events both medically and financially.
ICSs also improve health-related quality of life, but have only a slight and nonsignificant effect on
improvement in spirometry values. However, they have never been shown to decrease the rate of
decline of lung function.
ICSs have well-documented adverse effects that include a small but definite increase in the
frequency of pneumonia and a decrease in bone density. Reversible changes due to ICS use include
oral thrush, dysphonia, and easy bruising. Unfortunately, corticosteroids, whether administered
systemically or by inhalation, have only a marginal effect on airway inflammation, unlike in asthma. No
medications have been shown to address the type of inflammation that is present in COPD.[2]
One might conclude from the present, well-conducted trial that maintenance ICS use adds little or
nothing to the use of a combination of a LAMA and a LABA. In patients who have never experienced an
acute exacerbation, that would be a reasonable conclusion. The present trial was therefore
appropriately limited to persons who had experienced at least one acute exacerbation.
Before concluding that use of an ICS was ineffective and could be avoided when patients are
already receiving a LABA and a LAMA, one needs to consider the pitfalls of the present study. First, the
protocol was not how one uses an ICS in practice in COPD: We do not administer an ICS and then
withdraw it. Perhaps, therefore, use of the ICS at its full dose for 6 weeks to maximize therapy and
then slowly removing it over the next 3 months was sufficient to protect the airways from acute
exacerbations for the next 9 months.
The ICS that was used, fluticasone propionate, is one of the most potent ICSs available, and its
dosage, 500 µg twice daily, is twice that approved in the United States. In addition, the change in
trough FEV1 from baseline began as soon as the ICS dose is decreased and continued stepwise
throughout the remaining study period. Perhaps, therefore, if the study duration had been longer (as
would be the case in clinical practice), there would have been an increase in acute exacerbations and a
clinically significant decline in trough FEV1 after, say, 18 months without ICS use. In addition, a
different and less potent ICS may have revealed a different result.
The authors and the accompanying editorial[3] do not recommend any change in maintenance
therapy for COPD at present. However, it remains the case that an inhaled corticosteroid should not be
used in COPD until and unless the patient starts to experience acute exacerbations, or if there is an
asthmatic component to the patient's disease.
LAMA combined ICS could be better than LABA combined ICS in control of
asthma: Pros & Cons
Pros:
林彥甫
醫師
Cons:
林縵婷
醫師
Abstract
Poorly controlled asthma and preventable exacerbations place a significant strain on healthcare,
often requiring additional medications, hospital stays or treatment in the emergency
department.Long-acting beta2-agonists (LABA) are the preferred add-on treatment for adults with
asthma whose symptoms are not well controlled on inhaled corticosteroids (ICS), but have important
safety concerns in asthma. Long-acting muscarinic antagonists (LAMA) have confirmed efficacy in
chronic obstructive pulmonary disease and are now being considered as an alternative add-on therapy
for people with uncontrolled asthma.
To assess the efficacy and safety of adding a LAMA to ICS compared with adding a LABA for adults
whose asthma is not well controlled on ICS alone.
We searched the Cochrane Airways Group's
Specialised Register (CAGR) from inception to April 2015, and imposed no restriction on language of
publication. We searched additional resources to pick up unpublished studies, including
ClinicalTrials.gov, World Health Organization trials portal, reference lists of primary studies and existing
reviews, and manufacturers' trial registries. The most recent search was conducted in April 2015.
We searched for parallel and cross-over RCTs in which adults whose asthma was not well controlled
with ICS alone were randomised to receive LAMA add-on or LABA add-on for at least 12 weeks. Two
review authors independently screened the electronic and additional searches and extracted data from
study reports. We used Covidence for duplicate screening, extraction of study characteristics and
numerical data, and risk of bias ratings.The pre-specified primary outcomes were exacerbations
requiring oral corticosteroids (OCS), quality of life and serious adverse events.
We included eight studies meeting the inclusion criteria, but four double-blind, double-dummy
studies of around 2000 people dominated the analyses. These four trials were between 14 and 24
weeks long, all comparing tiotropium (usually Respimat) with salmeterol on top of medium doses o f
ICS.Studies reporting exacerbations requiring OCS showed no difference between the two add-ons, but
our confidence in the effect was low due to inconsistency between studies and because the confidence
intervals (CI) included significant benefit of either treatment (odds ratio (OR) 1.05, 95% CI 0.50 to 2.18;
1753 participants; 3 studies); three more people per 1000 might have an exacerbation on LAMA, but
the CIs ranged from 29 fewer to 61 more. Imprecision was also an issue for serious adverse events and
exacerbations requiring hospital admission, rated low (serious adverse events) and very low quality
(exacerbations requiring hospital admission), because there were so few events in the analyses.People
taking LAMA scored slightly worse on two scales measuring quality of life (Asthma Quality of Life
Questionnaire; AQLQ) and asthma control (Asthma Control Questionnaire; ACQ); the evidence was
rated high quality but the effects were small and unlikely to be clinically significant (AQLQ: mean
difference (MD) -0.12, 95% CI -0.18 to -0.05; 1745 participants; 1745; 4 studies; ACQ: MD 0.06, 95% CI
0.00 to 0.13; 1483 participants; 3 studies).There was some evidence to support small benefits of LAMA
over LABA on lung function, including on our pre-specified preferred measure trough forced expiratory
volume in one second (FEV1) (MD 0.05 L, 95% CI 0.01 to 0.09; 1745 participants, 4 studies). However,
the effects on other measures varied, and it is not clear whether the magnitude of the differences
were clinically significant.More people had adverse events on LAMA but the difference with LABA was
not statistically significant.
Direct evidence of LAMA versus LABA as add-on therapy is currently limited to studies of less than
six months comparing tiotropium (Respimat) to salmeterol, and we do not know how they compare in
terms of exacerbations and serious adverse events. There was moderate quality evidence that LAMAs
show small benefits over LABA on some measures of lung function, and high quality evidence that
LABAs are slightly better for quality of life, but the differences were all small. Given the much larger
evidence base for LABA versus placebo for people whose asthma is not well controlled on ICS, the
current evidence is not strong enough to say that LAMA can be substituted for LABA as add-on
therapy.The results of this review, alongside pending results from related reviews assessing the use of
LAMA in other clinical scenarios, will help to define the role of these drugs in asthma and it is
important that they be updated as results from ongoing and planned trials emerge
Management of severe asthma using anti-IgE
Pros & Cons
Pros:
戴芳詮
醫師
Cons:
陳世彬
醫師
Pros:
It is well known that immunoglobulin E (IgE) antibodies, Th2 derived cytokines and eosinophils
play a major role in the development of chronic airway inflammation, which is observed even in
subjects with mild disease. Airway inflammation plays a central role in the pathogenesis of bronchial
asthma and is associated with an increase in airway responsiveness to several trigger factors such as
aeroallergens which induce bronchoconstriction in atopic asthma patients, acting sometimes in
cooperation with other trigger factors such as viruses and air pollution. The development of
inflammation in asthma involves a complex array of several inflammatory mediators that promote the
recruitment and activation of various different immune cells and regulate inflammatory cell trafficking
into the lungs.
Activation of chemokine receptors triggers multiple cascades of intracellular signaling events that
lead to recruitment and activation of immune effector cells. The inhibition of specific chemokines and
receptors could prevent the excessive recruitment of leukocytes to sites of inflammation. Elevated
serum levels of specific IgE towards common environmental allergens are a key component in the
pathogenesis of allergic asthma. IgE antibodies cause chronic airway inflammation through effector
cells such as mastcells, basophils etc, activated via high-affinity (FcϵRI) or low-affinity (FcϵRII) IgE
receptors.
Current treatment for asthma suggested by Global Initiative for Asthma (GINA) guidelines includes
several reliever and controller drugs, in particular corticosteroids which reduce recruitment and
activation of inflammatory cells in the airways. The available anti-asthma treatments are effective for
most of these patients. However, there are asthmatic subjects who continue to experience severe
debilitating disease, since their bronco-obstruction is incompletely controlled by inhaled or systemic
corticosteroids associated with other drugs such as beta-2 agonist bronchodilators (short and
long-acting), antileukotrienes etc. Moreover, increased asthma severity is not only associated with
enhanced recurrent hospitalisation and mortality within one year of initial hospitalisation, but also
with higher economical and social costs
IgE antibodies have been viewed as a target for immunological drug development in asthma, and
a number of strategies aimed at inhibiting its proinflammatory action have been developed, despite an
increase in recent years in the availability of drugs used for asthma therapy.
Results of several large randomized trials have established omalizumab as an effective and well
tolerated treatment for use as add-on therapy in patients with severe persistent allergic asthma.
Several trials have demonstrated that this therapy is well tolerated and significantly improves
symptoms and disease control, reducing asthma exacerbations and improving quality of life of asthma
patients.
Cons:
Asthma is a common heterogeneous disease with a complex pathophysiology. Current therapies
based on inhaled corticosteroids and longacting β2 agonists are effective in controlling asthma in most,
but not all patients, with a few patients falling into the severe asthma category. Severe asthma is
characterised by poor asthma control, recurrent exacerbations, and chronic airflow obstruction despite
adequate and, in many cases, high-dose treatments. There is strong evidence supporting the role for
interleukins derived from T-helper-2 (Th2) cells and innate lymphoid cells, such as interleukins 4, 5,
and 13, as underlying the eosinophilic and allergic inflammatory processes in nearly half of these
patients. An anti-IgE antibody, omalizumab, which binds to circulating IgE, a product of B cells from the
actions of interleukin 4 and interleukin 13, is used as treatment for severe allergic asthma. Studies
examining cytokine blockers such as anti-interleukin-5, anti-interleukin-4Rα, and anti-interleukin-13
monoclonal antibodies in patients with severe asthma with recurrent exacerbations and high blood
eosinophil counts despite use of inhaled corticosteroids have reported improved outcomes in terms of
exacerbations, asthma control, and forced expiratory volume in 1 s. The US Food and Drug
Administration's recommendation to use an anti-interleukin-5 antibody for the treatment of severe
eosinophilic asthma suggests that there will be a therapeutic place for these anti-Th2 agents.
Biomarkers should be used to identify the right patients for such targeted approaches. More guidance
will be needed as to which patients should receive each of these classes of selective antibody-based
treatments. Currently, there is no treatment that targets the cytokines driving asthma associated with
non-eosinophilic inflammation and low Th2 expression.