Management of refractory chronic obstructive pulmonary disease

Endobronchial valve placement for severe emphysema (August 2018)

Endobronchial valves (EBVs) are placed bronchoscopically in a lung region with severe
emphysema, so air can exit but not re-enter the bronchus. This promotes atelectasis of the
distal emphysematous lung and thereby improves ventilation of less diseased areas.
Previously published randomized trials in patients with severe emphysema have reported
modest improvements in symptoms and lung function after placement of EBVs [1,2]. Based
on these trials, the US Food and Drug Administration (FDA) has approved use of the
Zephyr EBV [3]. Thus, for patients with hyperinflation due to severe emphysema who remain
symptomatic despite optimal medical therapy and pulmonary rehabilitation, we suggest
placement of EBVs in the lung region with the most emphysematous destruction and little to
no collateral ventilation. Placement of EBVs requires specialized training and equipment and
carries a high risk of pneumothorax, and thus continuing current therapy is a reasonable
alternative. (See "Management of refractory chronic obstructive pulmonary disease", section
on 'Endobronchial valves'.)

estimated global prevalence of almost 12 percent in adults over age 30. COPD is the fourth
leading cause of death . Some patients with COPD have refractory symptoms of dyspnea,
exercise limitation, and cough over a period of months or continue to have exacerbations
despite therapy with appropriate long-acting muscarinic agent (LAMA, ), long-acting beta
agonist, and inhaled glucocorticoid therapies.

Evaluation : confirm proper technique and adherence to prescribed inhalers/ re-evaluate

pulmonary function tests /chest radiograph/echocardiogram with Doppler to assess for
pulmonary hypertension and high resolution computed tomography (HRCT) to assess the
extent and distribution of emphysema and determine whether a new process (eg, interstitial
lung disease, lung cancer) has developed./ assess for exercise-related oxygen desaturation
using pulse oximetry during ambulation.

Assess for comorbid or concomitant disease processes including coronary heart disease,
heart failure, metabolic syndrome, lung cancer, skeletal muscle dysfunction, anxiety and
depression, chronic nasal/sinus disease, and gastroesophageal reflux. Pulmonary cachexia is
associated with advanced lung disease and can contribute to peripheral skeletal and
respiratory muscle weakness, fatigue, and poor exercise tolerance.

For patients who continue to have symptoms or repeated exacerbations of COPD despite
therapy with a long-acting muscarinic agent (LAMA), a long-acting beta agonist (LABA),
plus an inhaled glucocorticoid, potential pharmacologic options include optimizing inhaler
therapy, a trial of theophylline, and, in patients with recurrent exacerbation, roflumilast or
chronic azithromycin.

Adherence to COPD medication regimens is suboptimal, and lower adherence is associated

with more frequent hospitalization . Inhaler technique can be challenging, especially as the
techniques for using pressurized metered dose inhalers (pMDIs), dry powder inhalers (DPIs),
and soft mist inhalers (SMIs) are quite different. For patients who are unable to achieve
adequate technique despite a trial of different devices and a chamber device for metered dose
inhalers, an alternative may be to switch to nebulized medications such as albuterol,
arformoterol, levalbuterol, ipratropium, and budesonide, realizing that they may need to be
administered more often. The LAMA glycopyrrolate (glycopyrronium) is available by
nebulization for maintenance treatment in patients with moderate to very severe COPD The
medication requires a specialized closed nebulizer; the dose is one vial (25 microg) twice
daily. DPIs have the advantage of being breath actuated and thus less subject to problems
with actuation-inhalation coordination. On the other hand, DPIs require a threshold
inspiratory flow, which patients with advanced COPD may be unable to generate. Alternative
choices that are less dependent on inspiratory flow include pMDIs and SMIs.

The oral bronchodilator theophylline, which is only modestly effective is occasionally used
for patients with refractory COPD. Its mechanisms are controversial and numerous (eg,
enhanced respiratory muscle function), but modest bronchodilation certainly plays a role.
In general, patients with COPD can be adequately treated with serum levels in the 8 to 12
mcg/mL range. Long-acting extended-release preparations are available. Use of such a
preparation at night may reduce nocturnal decrements in respiratory function and morning
respiratory symptoms . Theophylline can be toxic. Theophylline is metabolized in the liver
and any process that interferes with liver function can rapidly change theophylline levels.
theophylline clearance decreases with age. close monitoring of drug levels and awareness of
potential interactions is essential.

Phosphodiesterase-4 (PDE-4) inhibition decreases inflammation and may promote airway

smooth muscle relaxation . Roflumilast is an oral, PDE-4 inhibitor that is approved to reduce
the risk of COPD exacerbations in patients with severe COPD associated with chronic
bronchitis and a history of frequent COPD exacerbations (eg, at least two per year or one
requiring hospitalization) despite maximally tolerated inhaled therapies.

Initiating treatment with roflumilast 250 mcg once daily for four weeks and then increasing to
500 mcg once daily may reduce the rate of treatment discontinuation. However, the lower
dose is subtherapeutic and not intended for long-term use. Roflumilast interacts with inducers
of CYP3A4 (eg, rifampicin, phenobarbital, carbamazepine) and dual inhibitors of CYP3A4
and CYP1A2 (eg, erythromycin, ketoconazole, cimetidine); concomitant use with the latter
will increase roflumilast systemic exposure and may cause adverse effects. Roflumilast has a
limited benefit on lung function. Thus, the medication should be used as a maintenance
therapy to prevent exacerbations rather than to improve other COPD outcomes /roflumilast
may be associated with an increase in adverse psychiatric reactions and should be used with
caution in patients with a history of depression. Other adverse effects include insomnia,
diarrhea, nausea, vomiting, weight loss, and dyspepsia.

Chronic antibiotic therapy is not indicated for the majority of patients with stable COPD (eg,
emphysema, chronic bronchitis). However, certain antibiotics, macrolides in particular, may
have antiinflammatory effects in addition to their antibiotic effect. For patients who continue
to have frequent exacerbations despite optimal therapy for COPD with bronchodilators and
antiinflammatory agents, we suggest antibiotic prophylaxis with azithromycin. Azithromycin
can be given as 250 mg daily or at a lower dose of 250 to 500 mg three times per week. We
often use 250 mg three times per week to reduce adverse effects. Azithromycin should be
avoided in patients with a long QT interval. Hearing should be assessed periodically as
macrolides were associated with hearing loss in clinical trials. Patients whose COPD is
associated with bronchiectasis may benefit from chronic antibiotic therapy.

— Oral mucolytic agents and chronic systemic glucocorticoids are rarely used in patients
with refractory COPD due to lack of evidence of efficacy.
Mucoactive agents — Thick, tenacious secretions can be a major problem in COPD, but there
is little evidence that thinning or increasing the clearance rate of secretions induces clinical
improvement. While some evidence supports a modest benefit from oral thiol derivatives,
other mucoactive agents, such as oral expectorants, iodine preparations, inhaled dornase alfa
(DNase), hydration, and inhaled hypertonic saline, are not accepted as routine care for
patients with stable COPD. There are no data to support mucolytic agents in patients with
COPD refractory to triple inhaler therapy.

Thiol derivatives such as N-acetylcysteine (NAC), erdosteine and carbocysteine, are

mucolytic agents designed to sever disulfide bonds of mucoproteins and DNA, possibly
leading to reduced mucus viscosity. NAC also have antioxidant effects. For patients with
bothersome sputum production that is refractory to smoking cessation, routine therapies for
COPD, and a course of antibiotics (when indicated), an oral thiol preparation (eg, N-acetyl
cysteine [NAC], 600 mg twice daily) can be initiated on a trial basis and continued if there is
symptomatic improvement. The use of inhaled NAC has no effect on sputum volume, can
induce significant bronchoconstriction, and should not be a part of routine COPD
Oral expectorants, such as guaifenesin, bromhexine, ipecac, and iodine preparations have
limited clinical benefits in COPD and may have substantial adverse effects. Their use in
COPD is not recommended. DNase, exogenous surfactant, various proteolytic agents, and
various detergents have not been adequately studied in COPD and are not recommended

Increasing fluid intake to reduce sputum viscosity is of no value unless a patient is

hypovolemic. Nebulized water or hypertonic saline is without documented benefit in COPD
and may irritate the airways and induce bronchospasm. On the other hand, hypertonic saline
may be of benefit in patients with concurrent bronchiectasis.

Systemic glucocorticoids have long been used to treat exacerbations in patients with COPD,
but are only rarely indicated for chronic use. In brief, long-term systemic glucocorticoids are
not recommended, even for severe COPD, because of the significant side effects and
evidence of increased morbidity and mortality with this therapy. In the uncommon
circumstance when discontinuing systemic glucocorticoids after a COPD exacerbation is
repeatedly met with recurrent symptoms, systemic glucocorticoids should be reduced to the
lowest dose possible. Objective measures of improvement (eg, spirometry, walk test) must be
used to justify ongoing therapy, as emotional and euphoric effects of systemic
glucocorticoids can cloud a patient's perception of benefit.

Long-term supplemental oxygen therapy is recommended for chronic hypoxemia (arterial

oxygen tension [PaO2] ≤55 mmHg or pulse oxygen saturation [SpO2] ≤88 percent).

Nocturnal noninvasive ventilation — Noninvasive ventilatory support is sometimes useful in

patients with chronic respiratory failure due to COPD manifest by daytime hypercapnia and
nocturnal hypoxemia not due to obstructive sleep apnea and not responsive to supplemental
oxygen during sleep, especially those who derived benefit from noninvasive ventilation
during an exacerbation of COPD.

Carefully selected patients with advanced COPD and refractory dyspnea may benefit from
an intervention, such as bronchoscopic lung volume reduction (LVR) using endobronchial
valves, lung volume reduction surgery (LVRS), or lung transplantation. Bronchoscopic LVR
is nonsurgical.
Bronchoscopic LVR — A number of techniques have been proposed for bronchoscopic LVR,
including endobronchial placement of one-way valves, plugs and blockers, endobronchial
instillation of biologic sealants, thermal airway ablation, and airway stents for decompression
of bullae. Endobronchial valves (EBV) are placed in the most diseased lung region after
specific assessment to ensure little to no collateral ventilation in that region For patients with
hyperinflation due to severe emphysema who remain symptomatic despite optimal medical
therapy and pulmonary rehabilitation , we suggest placement of EBV in the lung region with
the most emphysematous destruction and little to no collateral ventilation. As placement of
EBV requires specialized training and equipment and carries a high risk of pneumothorax,
continuing current therapy is a reasonable alternative .Placement of endobronchial valves
does not preclude subsequent LVRS or lung transplant.

Lung volume reduction surgery — LVRS entails wedge excisions of emphysematous tissue
to remove poorly functioning lung tissue and reduce hyperinflation. It is generally reserved
for patients with severe dyspnea due to COPD despite optimal medical therapy, pulmonary
rehabilitation, longer than six months of smoking cessation, and a diffusing capacity for
carbon monoxide (DLCO) that is NOT less than 20 percent predicted. LVRS appears less
promising for patients with COPD due to severe deficiency of alpha-1 antitrypsin (AAT)
deficiency, than for those without AAT deficiency.

Lung transplantation — Guidelines for timing a referral for a transplant evaluation for
patients with COPD and emphysema due to alpha-1 antitrypsin deficiency include the
following ●Progressive disease despite maximal treatment including medication, pulmonary
rehabilitation, and oxygen therapy●Patient is not a candidate for surgical or endoscopic
LVRS●BODE index 5 to 6 ●Post-bronchodilator FEV1 <25 percent of predicted●Resting
hypoxemia, defined as arterial oxygen tension (PaO2) <60 mmHg (8 kPa)●Hypercapnia,
defined as carbon dioxide tension (PaCO2) >50 mmHg (6.6 kPa)

The following are suggested criteria for placing a patient with COPD on the transplant list
(presence of one criterion is sufficient) ●BODE index ≥7 (calculator 3)●FEV1 <15 to 20
percent of predicted●Three or more severe exacerbations in the preceding year●One severe
exacerbation with acute hypercapnic respiratory failure●Moderate to severe pulmonary
hypertension

Palliative care Patients with advanced lung disease are frequently troubled by dyspnea, but
are also prone to other symptoms that may benefit from palliative care, such as cough,
sputum production, anxiety, depression, fatigue, insomnia, muscle weakness, and pain.
General steps to ameliorate the experience of dyspnea include pulmonary rehabilitation (eg,
exercise training, pursed-lip breathing and other breathing strategies), ergonomics, and
accommodation strategies (eg, relaxation, modification of activity level, use of a fan to blow
air on the face). Opiates may be of benefit for relief of dyspnea in selected patients

— Advance care planning (ACP), defined as "planning for and about preference-sensitive
decisions often arising at the end-of-life,"

Hospice and end-of-life care / palliative care that is offered to patients with a terminal disease
who are at the end of life (generally with an estimated life expectancy of six months or less)
when curative or life-prolonging therapy is no longer the focus of treatment.