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5 Acute Respiratory Distress Syndrome
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119
Chapter 6
Acute Exacerbations ofChronic
Obstructive Pulmonary Disease
LauraC.McNamara, AlyseReichheld, andCamilleR.Petri
6.1 Introduction/Epidemiology
Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease marked by classic symptoms of dyspnea and cough, with objective
evidence of airow limitation. Despite these nearly universal ndings, patients with
COPD have heterogeneous lung disease, and thus a wide spectrum of clinical phenotypes exist. Proposed risk factors for this condition include tobacco use, genetic
predisposition (i.e., alpha-1 antitrypsin deciency), long-standing asthma, environmental pollution, and various occupational exposures, such as burning biomass fuel
and several types of mining [1]. In light of these risk factors, the prevalence, already
estimated to be at least 9–12% of the global population, is expected to increase over
time [2–5].
The natural history of COPD is marked by episodic worsening of patients’ respiratory symptoms, also referred to as COPD exacerbations (ECOPD). The severity
of these exacerbations can vary, ranging from mild cases that can be effectively
managed in the outpatient setting to severe cases necessitating admission to the
intensive care unit. Studies estimate that between 15 and 30% of patients admitted
with severe COPD exacerbation do not survive the hospitalization [6, 7]. As a result,
COPD and its sequelae require signicant healthcare resources and pose a major
threat to patients’ longevity and quality of life [8–10].
Herein, we provide a wholistic overview of COPD exacerbations. We describe
the pathophysiology of COPD exacerbations to offer the context for proposed
L. C. McNamara · A. Reichheld
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
C. R. Petri (
Division of Pulmonary and Critical Care, Department of Medicine, Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston, MA, USA
e-mail: cpetri@bidmc.harvard.edu
Switzerland AG 2025
Y. Alzaidi, M. A. Gebily (eds.), The Pharmacist’s Expanded Role in Critical
Care Medicine, https://doi.org/10.1007/978-3-031-77335-8_6
*)
121© The Author(s), under exclusive license to Springer Nature
122
L. C. McNamara et al.
treatments and potential complications. Caring for these patients in the ICU requires
a multidisciplinary approach, one in which pharmacists play an essential role.
6.2 Physiology
6.2.1
Basic Pulmonary Physiology ofCOPD
The diagnosis of COPD requires a constellation of clinical signs and symptoms in
concert with specic pulmonary function abnormalities. Common subjective ndings include cough, shortness of breath, and phlegm production. In order to make a
diagnosis of COPD, patients must have these symptoms as well as characteristic
changes on pulmonary function testing. Based on current best practices for spirometry interpretation, patients meet the criteria for obstruction when the ratio of forced
expiratory volume in 1s (FEV1) to forced vital capacity (FVC) (FEV1/FVC ratio) is
less than the predicted fth percentile, which is considered the lower limit of normal. Bronchodilator testing must also be negative; that is, neither FEV1 nor FVC
improve meaningfully after bronchodilator administration, indicating that the
obstruction is nonreversible.
The hallmarks of pulmonary physiology in patients with COPD include this nonreversible airway obstruction, increased lung compliance (i.e., ability of the lung to
stretch and expand), and gas exchange limitations. Risk factors (such as cigarette
smoking or environmental exposures) trigger chronic inammation and subsequent
airway remodeling. This pathophysiology develops insidiously over time and is
often progressive [11, 12]. In COPD, there is also heterogeneous distal airway and
alveolar destruction, which is termed emphysema. Proposed mechanisms for this
destruction include an imbalance between protease and antiprotease activity in the
lung parenchyma as well as apoptosis of pneumocytes [13].
The nonreversible obstruction often develops as a result of thickened, yet poorly
supported, airway walls, as well as reduced numbers of small airways [14]. Although
not universal for all patients with COPD, many also have goblet cell mucus hypersecretion, which predisposes to occlusion of terminal airways, and characteristics of
chronic bronchitis [15]. Together, these features combine to increase airway resistance, such that on spirometry, patients have a reduced FEV
, leading to reduced
1
expiratory airow and obstruction.
Emphysema also contributes to a reduction in the elastic recoil of the lungs.
Thus, the lungs are more compliant, putting patients at risk of developing air trapping and hyperination [16]. This can be recognized clinically on chest imaging
(i.e., loss of diaphragm convexity as demonstrated in Fig.6.1) or on physical exam
(i.e., barrel deformity of the chest wall) but is formally diagnosed with lung volume
testing [17, 18].
With the destruction of terminal airways, alveoli, and their adjacent pulmonary
capillaries, patients also develop gas exchange limitations and ventilation/perfusion
(V/Q) mismatch, with resultant chronic hypoxemic and/or hypercapnic respiratory
6 Acute Exacerbations ofChronic Obstructive Pulmonary Disease
Fig. 6.1 Posterior–anterior and lateral chest radiographs demonstrating attening of the diaphragm, suggestive of hyperination
123
failure. This multilevel destruction of the lung anatomy also predisposes patients to
pulmonary hypertension.
6.2.2 Physiology During COPD Exacerbation
An acute worsening of underlying airway inammation, often incited by some additional insult, is thought to precipitate exacerbations of COPD.The most common
triggers include viral infections (of which rhinovirus is the most common), bacterial
infections, and environmental exposures (i.e., increases in air pollution or tobacco
use), though pulmonary emboli and cardiac conditions should also be considered
(see Sect. 6.3.1) [19].
This acute on chronic airway inammation results in increased airway edema,
smooth muscle tone, and mucus production. Together, these aggravate the underlying pathophysiology of V/Q mismatch and increased airway resistance, leading to
the common clinical ndings of worsened hypoxemia, hypercapnia, tachypnea,
increased sputum production, and dyspnea.
The dyspnea and increased ventilatory demand that patients experience during
an exacerbation can also have harmful pathophysiologic consequences, particularly
during a severe exacerbation. More specically, as minute ventilation increases during an exacerbation, patients will have reduced expiratory time [16]. In the context
of concurrent expiratory ow limitation, patients experience incomplete exhalation,
which leads to serial increases in end-expiratory lung volume with each breath, a
124
Fig. 6.2 Dynamic hyperination volume-time curve (showing increasing end-expiratory lung volumes during tachypnea, resulting in sequentially higher lung volumes). FRC functional residual
capacity (lung volume achieved at rest, after passive exhalation)
phenomenon referred to as “dynamic hyperination” (Fig.6.2). Dynamic hyperination may further impair respiratory function through the following mechanisms:
1. Increasing the patient’s work of breathing (by virtue of initiating a breath at a
higher resting lung volume).
2. Worsening mechanics of the respiratory system (due to reduced lung and chest
wall compliance at higher lung volumes, which forces the patient to exert greater
effort to successfully inspire).
3. Decreasing ventilatory efciency (by changing the geometric conguration and
length of the respiratory muscles, putting them in a disadvantaged position).
4. Increasing intrathoracic pressure (i.e., “intrinsic positive end-expiratory pressure
[PEEP]”), thereby risking impaired right ventricular lling and cardiac output
[20–22].
L. C. McNamara et al.
6.3 Diagnosis ofCOPD Exacerbation
6.3.1
While specic criteria dening a COPD exacerbation vary according to different
sources, all agree that it is marked by an acute episode of worsened respiratory
symptoms [23–25]. The hallmark features include increased dyspnea, cough,
phlegm production, and/or sputum purulence. These symptoms often develop
within 2weeks prior to presentation and most commonly after an inciting trigger
that leads to airway inammation (see below in Sect. 6.2.2 for further details on this
pathophysiology) [23, 24].
Denition
6.3.2 Differential Diagnoses andEvaluation
Essential to the diagnosis of ECOPD is a thorough workup to exonerate other potential causes of the patient’s respiratory symptoms. In particular, other pulmonary
conditions, such as pulmonary embolism, pneumonia, aspiration, and
6 Acute Exacerbations ofChronic Obstructive Pulmonary Disease
125
pneumothorax, and cardiac diseases, such as congestive heart failure, myocardial
infarction, and arrhythmias, should be considered as alternative diagnoses. Patients
with COPD are at increased risk for many of these conditions and are also susceptible to ECOPD triggered by them [26]. Nevertheless, it can be diagnostically challenging to determine the primary culprit of respiratory symptoms in patients with
underlying COPD and associated comorbidities. The management of ECOPD
should include a search for an inciting trigger, as patients often require treatment for
this trigger in addition to COPD-directed treatments.
Close attention to the physical exam (e.g., looking for signs of volume overload)
and thoughtful diagnostic workup can help identify confounding diagnoses and/or
triggers. All patients should undergo chest imaging according to local resource
availability. Chest radiograph and/or lung ultrasound can be useful in identifying
pneumonia, pneumothoraces, pulmonary edema, and pleural effusions. We also recommend evaluating for infection with viral testing and sputum sample for gram
stain and bacterial culture, as these results can be diagnostically relevant and can
also help guide treatment (see below in Sect. 6.4.3 for further details on antimicrobials). The breadth of these tests should be guided by local resources and other epidemiologic considerations, such as seasonal variations of different respiratory
pathogens. While C-reactive protein (CRP) and procalcitonin levels may help guide
antibiotic usage, they have yet to be incorporated into COPD guidelines, and there
is still signicant debate regarding how they should best be used in this population
(see below in Sect. 6.4.3 for further details on these acute-phase reactants). Because
patients with COPD are at increased risk for pulmonary emboli, all patients should
undergo a probability assessment to determine further workup with a d-dimer or CT
pulmonary angiogram as clinically indicated, particularly when no other trigger has
been identied [27]. Cardiac workup should include electrocardiogram, cardiac
biomarkers with troponin and NT-pro BNP, and consideration of an
echocardiogram.
6.3.3 Classication ofExacerbation Severity
Recent work aims to better characterize the severity of an individual’s COPD exacerbation, both for guiding clinical care and advancing research. For example, the
Rome Proposal integrates several objective clinical variables, specically measures of dyspnea (using the validated visual analog score [VAS] for dyspnea),
respiratory rate, heart rate, hypoxemia, hypercapnia, and inammation (using the
serum CRP), to classify patients as having either a mild, moderate, or severe exacerbation (Fig. 6.3) [24]. Other studies have looked at the relationship between
eosinophilia, both in the sputum and peripheral blood, and COPD exacerbations.
While results are limited and sometimes conicting, there is a suggestion that
peripheral eosinophilia is associated with an increased risk of moderate-to-severe
exacerbations, but also improved short-term outcomes during an exacerbation
[28, 29].
126
Fig. 6.3 Severity grading for ECOPD [24]. SaO2 oxygen saturation of arterial blood, RR respira-
tory rate, HR heart rate, ABG arterial blood gas, PCO
with permission of the American Thoracic Society. Copyright © 2024 American Thoracic Society.
All rights reserved [24]. The American Journal of Respiratory and Critical Care Medicine is an
ofcial journal of the American Thoracic Society
partial pressure of carbon dioxide. Reprinted
2
L. C. McNamara et al.
6.3.4 Indications forICU Admission
The treatment setting for patients with ECOPD should be determined by the severity of their presentation as well as local resources and practice patterns. In general,
patients with features of severe exacerbation, such as those described in Fig.6.3,
should be considered for ICU admission. Other features that suggest life- threatening
respiratory failure and warrant ICU admission include altered mental status, refractory hypoxemia (i.e., requiring fraction of inspired oxygen [FiO2] ≥0.4) or hypercarbia (i.e., PaCO2>60mmHg or above the patient’s baseline), severe acidemia
(i.e., pH ≤7.25), refractory increased work of breathing (i.e., accessory muscle use
and tachypnea), hemodynamic instability, and/or need for noninvasive or invasive
mechanical ventilation [23].
6.4 Pharmacologic Treatment
6.4.1 Bronchodilators
6.4.1.1 Mechanism
The recommended initial bronchodilators for COPD exacerbations are short-acting
beta-agonists (SABAs), either alone or in combination with short-acting muscarinic
antagonists (SAMAs) [23]. SABAs stimulate beta2 receptors, causing relaxation of
airway smooth muscle and subsequent improvement in expiratory airow. SAMAs
block muscarinic cholinergic receptors, leading to decreased contraction of these
6 Acute Exacerbations ofChronic Obstructive Pulmonary Disease
127
smooth muscles as well as reducing the airway mucus hypersecretion that accompanies ECOPD [23, 30].
6.4.1.2 Evidence-Based Regimen andDosing
The SABA-SAMA combination of albuterol and ipratropium results in greater spirometric improvements compared to albuterol alone in stable COPD, but evidence for
acute exacerbations is scarce, with no additional benet in pulmonary function
observed after 90min [31, 32]. Nevertheless, the combination is frequently utilized
to treat COPD exacerbations [31, 33, 34]. It is further recommended that all patients
either continue long-acting bronchodilators (LABAs, LAMAs, or a combination)
during an acute exacerbation or start long-acting agents before hospital discharge [35].
Systematic reviews have demonstrated no difference in FEV
between short-
1
acting bronchodilators delivered via metered-dose inhaler (MDI) and nebulizer
[36]. Acutely symptomatic patients may be unable to adequately perform proper
MDI technique, such that nebulized delivery of bronchodilators is preferred.
Nebulizers are also a convenient and more effective medication delivery method for
patients requiring noninvasive positive-pressure ventilation (NPPV) or high-ow
nasal cannula (HFNC), as the medications can be delivered through these circuits
without interruption of respiratory support [37, 38]. Conversely, in patients receiving invasive mechanical ventilation, if the appropriate technique is used by those
administering the medication, MDIs are a safe and effective option [39].
For severe exacerbations, patients should typically receive a dose of short-acting
bronchodilator, according to local pharmacy formulary, every hour for 2–3hours.
Examples of this include, but are not limited to, 1–2 puffs of albuterol MDI or a 3cc
nebulized solution of ipratropium 0.5mg/albuterol 2.5mg. Depending on the clinical response, time between treatments may be extended to every 2–3hours [23]. If
the patient is not responding to treatment, some clinicians will start continuous
nebulized treatments, commonly albuterol monotherapy, although this practice is
not recommended by the Global Initiative for Chronic Obstructive Lung Disease
(GOLD) guidelines, likely given logistical challenges and a lack of robust data to
support this practice [40, 41].
Methylxanthines, such as aminophylline and theophylline, provide bronchodilatory effects via nonselective phosphodiesterase inhibition. These agents should be
avoided in exacerbations, however, as they disproportionately increase the risk of
adverse effects, such as nausea, vomiting, tremors, and palpitations/arrhythmias,
while providing only modest and inconsistent benet in lung function [23, 42].
Adv
erse Effects
6.4.1.3
While practitioners should be aware of potential adverse effects, they rarely preclude the use of SABA and SAMA bronchodilators during a COPD exacerbation,
given the clear benets of bronchodilators in this setting. Due to the activation of
128
L. C. McNamara et al.
beta2 adrenergic receptors, SABAs may cause tremors, sinus tachycardia, and
even arrhythmias in certain patients [43]. Physiologically, albuterol can also
decrease serum potassium levels and produce lactic acidosis, particularly when
administered at high doses or continuously [44–47]. These metabolic effects are
transient and are rarely of clinical signicance. The main adverse effect of SAMAs
is dry mouth; some patients report a bitter metallic taste. Prior studies have
reported a small increase in cardiovascular events in COPD patients treated with
ipratropium, but larger clinical trials did not nd an effect on cardiovascular event
risk [48–53].
6.4.2 Glucocorticoid Therapy
6.4.2.1 Mechanism
The anti-inammatory effects of glucocorticoids, which complement bronchodilators to improve airway resistance, are a key component in the treatment of moderateto- severe ECOPD [54].
6.4.2.2 Evidence forUse
Prior studies have demonstrated that systemic glucocorticoids reduce recovery time,
enhance lung function (FEV
specically), improve oxygenation, lower the risk of
1
treatment failure, and shorten hospital stays during COPD exacerbations [23,
55–57]. These studies, however, have primarily explored systemic glucocorticoids
in ambulatory or hospital settings, while often excluding ICU patients. Two randomized controlled trials (RCTs) have explored the use of systemic glucocorticoids
in critically ill patients with conicting results. Alía and colleagues compared systemic glucocorticoids versus placebo and demonstrated that glucocorticoids
decrease the duration of mechanical ventilation, reduce failure rates of noninvasive
mechanical ventilation, and shorten ICU length of stay (LOS) [58]. Abroug and colleagues, however, did not nd a signicant difference in these outcomes but saw
higher rates of clinically relevant hyperglycemia with glucocorticoid use [59]. Of
note, these studies used different formulations of glucocorticoids, which will be
addressed in further detail below, and neither study met their enrollment targets due
to difculty identifying patients not already started on glucocorticoids. A metaanalysis found that systemic glucocorticoids seem to have greater treatment success
for non-critically ill patients compared to critically ill patients [60]. Nevertheless,
considering this efcacy in less severe ECOPD, systemic glucocorticoids remain
essential in managing COPD exacerbations in critically ill patients. As an aside,
although it is widely accepted that the use of glucocorticoids in patients with inuenza pneumonia results in higher mortality, use in patients with ECOPD triggered
by inuenza is still recommended [61, 62].
6 Acute Exacerbations ofChronic Obstructive Pulmonary Disease
129
6.4.2.3 Dose andFormulation
In non-critically ill patients with ECOPD, there is evidence to support the use of
oral prednisone 40mg daily or its equivalent [23, 63]. Limited data exist regarding
the optimal medication, dose, and route for systemic glucocorticoids in patients
with COPD exacerbations requiring ICU admission. Alía and colleagues, who conducted the previously mentioned trial that showed a benet of systemic glucocorticoids in critically ill patients with COPD exacerbations, used high doses of
methylprednisolone (0.5mg/kg every 6hours for 72hours, 0.5mg/kg every 12hours
on days four through six, and 0.5mg/kg/day on days seven through day ten) [58].
Limited data exists regarding which glucocorticoid should be used in ECOPD in
critically ill patients, though, as discussed above, Alía and colleagues did show benet with methylprednisolone compared to placebo [64]. In non-ICU patients, studies have shown similar efcacy with methylprednisolone, prednisone, and
prednisolone [55, 65]. There have not been head-to-head trials between different
glucocorticoids in critically ill patients, but for non-ICU patients, methylprednisolone is equivalent to hydrocortisone in terms of treatment failure rate, length of
emergency department stays, and dyspnea, but patients treated with hydrocortisone
experience lower FEV1, lower peak expiratory ow rates, and increased hyperglycemia [66]. Another study, also in non-ICU patients, comparing methylprednisolone
to dexamethasone, found that those treated with dexamethasone had less improvement in FEV1 and a longer duration of symptoms [67]. As such, when available,
methylprednisolone, prednisolone, or prednisone should be the preferred systemic
glucocorticoids in the treatment of ECOPD.
In terms of route of administration, the bioavailability of oral versus intravenous
glucocorticoids is nearly equivalent, and thus efcacy is equivalent in non-critically
ill patients [68, 69]. In critically ill patients, data is limited, but it is important to
note that the previously mentioned positive clinical trial, by Alía etal., used intravenous methylprednisolone, while the negative trial, by Abroug etal., used oral prednisone [58, 59]. In our practice, it is common to use intravenous formulations for
more severe exacerbations, for patients who are failing to respond to oral glucocorticoids, for patients with impaired gastrointestinal absorption, or for patients with
inadequate oral access, such as those who are receiving noninvasive positivepressure v
entilation (NPPV). Prior studies have shown that in outpatients and hospitalized patients, high-dose nebulized budesonide seems to be non-inferior to oral
or intravenous glucocorticoids, though its use in lieu of systemic glucocorticoids
has not been studied in ICU patients and therefore is not recommended for this
population presently [57, 70–72].
There is data to support a personalized approach to glucocorticoid dosing. One
study utilized patient characteristics, symptoms, and laboratory analysis to create a
personalized, severity-dependent dose for study participants and found that this
approach led to higher initial doses of glucocorticoids and reduced in-hospital treatment failure compared to a xed-dose approach, without an impact on hospital
length of stay. As such, it is common for clinicians to use higher dosing for more
severe exacerbations. There are limits to this approach, however. For example, in