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critically ill patients, one observational study found that treatment with lower dose
glucocorticoids (<240 mg/day of methylprednisolone equivalent) compared to
higher dose (>240mg/day) in the rst 2days of treatment did not inuence mortality but was associated with shorter days mechanically ventilated, ICU LOS, and
overall hospital LOS [69, 73, 74]. Increasing evidence supports using personalized
and more moderate doses of glucocorticoids rather than xed or high doses during
severe COPD exacerbations. As such, a thorough review of an individual’s past
response to glucocorticoids can inform future decisions about treatment regimens.
When this information is unknown or not available, we recommend a dose equivalent of prednisone 40mg daily for the vast majority of exacerbations; however, if
patients are on chronic glucocorticoids, clinically deteriorating, or failing to
improve, higher doses such as methylprednisolone 60mg up to every 6hours should
be considered. Ongoing work is exploring the role of possible biomarkers, such as
peripheral eosinophilia, to inform methods to decrease patient exposure to systemic
glucocorticoids given their potential for signicant side effects, which are addressed
in greater detail below [75–78].
6.4.2.4 Duration
Data on the preferred duration of glucocorticoid treatment in critically ill patients
with ECOPD is limited. The REDUCE trial (Reduction in the Use of Corticosteroids
in Exacerbated COPD) showed that among non-ICU patients, a 5-day regimen is
not inferior to a 14-day regimen, which is supported by subsequent systematic
reviews [63, 79]. Based on this literature, several societies have adopted these
shorter courses into their treatment guidelines for non-critically ill patients with
ECOPD [23, 63, 80]. For critically ill patients, we again favor a personalized
approach, relying on patients’ past responses to not only glucocorticoid dosing but
also duration. In our practice, courses of 5–14days are generally considered standard, with longer courses being reserved for sicker patients [58].
Once the decided course is completed, the glucocorticoids can typically stop
altogether. However, in severe cases when patients have not fully recovered, tapers
can be considered to prevent abrupt worsening of respiratory symptoms; tapers are
not generally indicated to prevent acute adrenal insufciency.
6.4.2.5
Adv
erse Effects
Even brief courses of glucocorticoids are linked to heightened risks of pneumonia,
sepsis, and mortality [81]. Corticosteroids cause hyperglycemia, hypernatremia,
and uid retention (due to their mineralocorticoid effects). Further, they are associated with delirium, development of ICU-acquired weakness, gastrointestinal bleeding, uncontrolled hypertension, and hospital-acquired infections [82]. Many of
these effects are dose and duration dependent, highlighting the importance of ongoing efforts to reduce patients’ overall exposure to systemic glucocorticoids. In the
6 Acute Exacerbations ofChronic Obstructive Pulmonary Disease
131
interim, it is important to proactively mitigate as well as monitor for these potential
side effects. Examples of this include administering the medication earlier in the
day to avoid sleep–wake cycle disruption. To prevent gastrointestinal bleeding,
patients with a history of peptic ulcer disease, concurrent use of nonsteroidal antiinammatory drugs (NSAIDs), or therapeutic anticoagulation, or those who otherwise meet ICU stress ulcer prophylaxis recommendations, should receive a proton
pump inhibitor for the duration of systemic glucocorticoid therapy [83].
6.4.3 Antimicrobials
6.4.3.1 Antibiotic Patient Selection
It is recommended that antibiotics only be given to patients who are most likely to
have a bacterial infection or those who are the most ill [23]. About half of patients
presenting with a COPD exacerbation have sputum cultures that grow bacteria;
however, it can be challenging to distinguish infection from bacterial colonization,
as up to 30% of patients with stable COPD also have bacterial colonization of their
airways [84, 85]. In order to identify the patients most likely to benet from antibiotics, the GOLD guidelines recommend providing empiric antibiotics to patients
with increased sputum purulence if the patient also has associated dyspnea and/or
increased sputum volume. Guidelines also recommend providing empiric antibiotics to any patient who requires invasive or noninvasive mechanical ventilation [23,
26, 86]. In critically ill patients who require mechanical ventilation, antibiotic ther-
apy is associated with decreased mortality, duration of mechanical ventilation, and
length of hospital stay [87, 88].
Studies have investigated whether acute-phase reactants (such as CRP and procalcitonin) can help identify patients who should receive antibiotics, but results are
inconclusive to date. One study found that when CRP was low (<20mg/L), there
was a reduction in antibiotic use without an increase in treatment failure [89, 90].
Conversely, in ICU patients with a COPD exacerbation, the use of a procalcitoninbased
algorithm (with a procalcitonin cutoff of 0.1μg/L) to decide whether to initiate or stop antibiotics was associated with higher 3-month mortality [91]. A
systematic review further elaborated that measuring procalcitonin in patients hospitalized with a COPD exacerbation did not signicantly reduce antibiotic exposure
[92]. Overall, more studies are needed to dene the role of acute-phase reactants in
informing antibiotic use in ECOPD.
Antibiotic Selection andDuration
6.4.3.2
Empiric antibiotic choice should be informed by any available historical patient
microbiologic data and patient risk factors for Pseudomonas infection and based on
local antibiograms. The most common bacterial pathogens triggering COPD
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L. C. McNamara et al.
exacerbations in hospitalized patients include Haemophilus inuenzae, Moraxella
catarrhalis, Streptococcus pneumoniae, and Staphylococcus aureus. While less
common, atypical pathogens, such as Chlamydophila pneumoniae and Mycoplasma
pneumoniae, can also lead to exacerbations. As such, standard therapy should target
these pathogens specically. Potential options include but are not limited to
amoxicillin- clavulanate, a third-generation cephalosporin, or a macrolide, tetracycline, or respiratory quinolone [23]. Whenever possible, antibiotic selection should
be further tailored based on updated results from the patient’s current
hospitalization.
In severe exacerbations, and thus for patients requiring ICU admission,
Pseudomonas or other gram-negative bacilli should be considered [93–95]. The
greatest predictor for Pseudomonas infection is the isolation of Pseudomonas on
prior cultures [96]. Other risk factors include FEV1 <30% predicted, active tobacco
use, bronchiectasis on chest imaging, antibiotic use in the last 3months, and chronic
systemic glucocorticoid use [97–99]. For these patients, anti-pseudomonal agents,
such as ciprooxacin, levooxacin, piperacillin-tazobactam, ceftazidime, or
cefepime, should be initiated depending on local susceptibility patterns [94]. At any
point in the presentation, if the patient has clinical signs and/or symptoms suggestive of pneumonia, antibiotics should be tailored to those specic treatment guidelines [100, 101].
Prior studies have shown that initiating antibiotics within the rst 2days of hospitalization is associated with decreased risks of treatment failure, in-hospital mortality, and 30-day readmission [102, 103]. It is recommended to evaluate clinical
response at 48–72hours, and the total duration of antibiotics should be 5–7days
[104, 105]. There are preliminary data to support shortening antibiotic duration further, though it is likely too early to implement this broadly, particularly in critically
ill patients, and thus further prospective trials are warranted [106].
The decision regarding the route of antibiotic administration should be based
on the patient’s ability to tolerate oral medications and the pharmacokinetic properties of the antibiotic, though generally speaking there is no difference in efcacy [23].
6.4.3.3
Anti
virals
Just as rates of bacterial infection approach 50% in patients with ECOPD, viral
infections are just as prevalent, with some patients even experiencing bacterial and
viral co-infection. The majority of viral infections are caused by rhinovirus, though
human metapneumovirus, inuenza, coronavirus, parainuenza, and respiratory
syncytial virus have also been implicated [84, 93]. Early treatment with oseltamivir
(within 48hours of symptom onset) in all critically ill patients infected with inuenza is associated with improved survival and may be associated with shorter ICU
LOS and duration of mechanical ventilation [107]. In patients presenting later, the
clinical trajectory should guide treatment. Oral agents, such as oseltamivir, are
recommended, but inhaled zanamivir can increase airway reactivity and subsequently worsen exacerbations [108]. Regarding other respiratory viruses, current
6 Acute Exacerbations ofChronic Obstructive Pulmonary Disease
133
guidelines suggest that patients with COPD exacerbations triggered by SARSCoV-2 infections should be treated with the same standard of care as other
COVID-19 patients, including consideration of antivirals (i.e., remdesivir), glucocorticoids (i.e., dexamethasone), IL-6 receptor blockers (i.e., tocilizumab), and/or
JAK inhibitors (i.e., baricitinib) according to current evidence and recommendations [23]. In general, treatment of respiratory syncytial virus (RSV) with antivirals
is not universally recommended for adults, as opposed to for children, and should
only be considered on a case-by-case basis in severely immunocompromised
patients [109].
6.4.4 Symptomatic Treatment ofDyspnea + Anxiolysis
6.4.4.1 Nonpharmacologic Interventions
The American Thoracic Society recommends that symptomatic treatment of COPD
exacerbations should focus on both the psychological and physical components of
dyspnea. Dyspnea may be improved with supplemental oxygen, if the patient is
hypoxemic, or blowing cool air on the patient’s face with a fan [110].
6.4.4.2 Opioids
If nonpharmacologic interventions are insufcient or if sedation is required in the
context of invasive mechanical ventilation, opioids can be given to improve dyspnea. Although nebulized opioids have been anecdotally reported as a treatment for
dyspnea, systemic reviews have shown no difference between nebulized opioids and
placebo, so oral or intravenous administration is preferred [109, 111]. Further, for
dyspnea relief, studies have not shown that any certain opioid is superior [112–114].
Opioids should be titrated to the effect of relieving dyspnea with frequent reassessment given that higher doses of opioids may lead to respiratory depression, a signicant consequence amidst signicant ECOPD. As such, opioid use should be of
limited duration, provided at the lowest effective dose and weaned as able. Chronic
opioid use for dyspnea palliation can be considered in patients otherwise optimized
after acknowledging the risks and shared decision-making between patient and provider [115].
6.4.4.3
Benzodiazepines
Benzodiazepines can be considered in cases of distressing breathlessness, when
opioids are not sufciently effective, when they are contraindicated, or when the
patients are in the last days of life. Overall, the evidence does not suggest signicant
benets for these symptoms, so caution is advised due to potential side effects such
as delirium and drowsiness as well as respiratory depression [116–118].
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L. C. McNamara et al.
6.4.4.4 Dexmedetomidine
Dexmedetomidine, a continuous intravenous infusion often limited to the ICU setting, may improve dyspnea as it offers analgesic and anxiolytic properties without
causing signicant respiratory depression. It can be used as a potential alternative to
respiratory depressing anxiolytics (i.e., benzodiazepines) for the management of
dyspnea [119]. In patients with refractory dyspnea due to end-stage cancer, one
retrospective study found that dexmedetomidine safely relieves symptoms [120].
Though its use in the ECOPD setting is not yet established in clinical guidelines,
dexmedetomidine is an appealing option for the management of anxiolysis to help
patients better tolerate noninvasive or invasive ventilation support.
6.4.4.5 Ketamine
By inhibiting catecholamine reuptake and decreasing production of inammatory
cytokines, ketamine can cause airway relaxation and alleviate bronchospasms
[121–123]. Prior studies have reported that continuous ketamine infusion in patients
with asthma improved gas exchange and chest compliance [124]. One prospective
study, in patients with underlying COPD undergoing thoracic surgery with singlelung ventilation, demonstrated improved oxygenation and decreased shunt fraction
[125]. However, a different RCT found that ketamine did not improve respiratory
mechanics in mechanically ventilated patients with COPD exacerbation or status
asthmaticus when compared to fentanyl infusion [126]. In light of these variable
results, we consider ketamine as an alternative sedative when typical analgesia and
sedation regimens are not effective for ECOPD patients requiring invasive mechanical ventilation. Nevertheless, more studies are needed to further explore the potential
role of ketamine in the management of COPD exacerbations in critically ill patients.
6.4.5 Adjunctive Therapies
6.4.5.1 Magnesium
For patients with severe exacerbations, we recommend intravenous magnesium sulfate. It is thought that magnesium causes bronchodilation by inhibiting calcium
inux into airway smooth muscle cells [127]. A systematic review showed that
magnesium sulfate reduced hospital admissions for patients with acute COPD exacerbation [128]. Two milligrams dosed once intravenously is likely sufcient to
achieve these desired effects.
6.4.5.2
Diuretics are commonly used in the management of heart failure, which often can
coexist with COPD.When clinically indicated, one can consider using diuretics to
further optimize a patient’s respiratory status by decreasing cardiac preload and
Diur
etics
6 Acute Exacerbations ofChronic Obstructive Pulmonary Disease
135
subsequently reducing pulmonary edema. When prescribing diuretics, it is important to monitor for potential adverse effects, including electrolyte imbalances and
impaired renal function.
6.4.5.3 Vitamin D
Vitamin D has immune modulator effects and may attenuate inammatory responses
to viral and bacterial infections [129, 130]. A meta-analysis showed that vitamin D
supplementation can reduce the rate of moderate or severe COPD exacerbations in
decient patients (<25nmol/L) without an effect in those with higher levels, but
more recent studies did not demonstrate this benet [131, 132]. GOLD guidelines
recommend screening all hospitalized patients with COPD exacerbation for vitamin
D deciency and supplementing when identied.
6.4.5.4 Venous Thromboembolism Prophylaxis
All patients who are hospitalized with acute COPD exacerbations, and with respiratory failure more generally, are at risk for the development of deep venous thrombosis and subsequent pulmonary embolism [27]. We recommend pharmacologic
thromboprophylaxis for patients who do not have other contraindications [23, 133].
6.4.5.5 Smoking Cessation
For patients who use tobacco, hospitalizations provide an opportunity to promote
smoking cessation, which, in addition to other systemic benets, can improve
COPD prognosis and risk of future exacerbations [134]. All patients who currently
smoke should be offered nicotine replacement therapy (such as nicotine patches or
nicotine lozenges) to decrease the risk of nicotine withdrawal, which can affect even
patients receiving sedation with mechanical ventilation [23, 135–137].
6.4.5.6 Bowel Regimen
Although data is limited, constipation and abdominal bloating may interfere with
diaphragmatic excursion and worsen feelings of breathlessness in COPD exacerbations [138]. We recommend monitoring for constipation and starting a gentle bowel
regimen for patients admitted with COPD exacerbation.
6.4.5.7
Mucolytics
We do not recommend a standardized approach to the use of mucolytic agents (i.e.,
thiol or thiol-based derivatives such as nebulized -acetylcysteine), which may help
address the mucus hypersecretion seen in ECOPD.Given limited prospective data
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L. C. McNamara et al.
on these medications, we favor an individualized approach based on the patient’s
presenting symptoms and clinical ndings [139].
6.4.5.8 Nutrition
Low body mass index in patients with COPD has been associated with worse outcomes, including mortality, exacerbations, and quality of life. For patients presenting with ECOPD, a thorough nutritional assessment and as-needed supplementation
are essential not only to their immediate recovery but also to potentially reducing
their risk for future exacerbations [140–142].
6.4.5.9 Post-Discharge Adjuncts
Efforts should be made to ensure that patients receive appropriate post-discharge
follow-up for discussion of further measures to reduce the risk of subsequent exacerbation. This includes but is not limited to immunizations, smoking cessation as
discussed above, and evaluation of candidacy for nocturnal NPPV, pulmonary rehabilitation, chronic suppressive antibiotics (i.e., azithromycin), and phosphodiesterase- 4 inhibitors (i.e., roumilast) [23].
6.5 ICU-Level Interventions
Respiratory support is a key pillar in the treatment of patients presenting with severe
ECOPD who require admission to an ICU.Here, we describe an evidence-based
approach to these types of support and their indications and contraindications. The
rst step is to determine if the patient’s respiratory failure is driven by hypoxemia,
hypercapnia, or a combination of both, as this will guide which type of support or
device should be utilized. The second step is to titrate the device settings to objective markers of oxygenation and ventilation. Given the inaccuracies reported with
pulse oximetry, particularly in individuals with darker skin tones, we recommend
the additional use of arterial blood gas sampling to assist with clinical decisions
regarding oxygen titration [143, 144]. Alternatively, venous blood gas sampling,
which is less painful for the patient, logistically easier to obtain, and a reasonably
accurate measure of pH, PaCO
of ventilatory support [145, 146]. In addition to blood gas analysis, close monitoring of patient’s mental status, work of breathing, and device measurements (e.g.,
minute ventilation) should inform NPPV adjustments.
In patients with stable COPD, there are different oxygen saturation goals depending on the presence or absence of hypercapnia. In all patients with ECOPD though,
supplemental oxygen should be titrated to achieve oxygen saturations of 88–92%
(or PaO
60–70 mmHg). This has been associated with improved respiratory
2
, and HCO3−, can and should be utilized for titration
2
6 Acute Exacerbations ofChronic Obstructive Pulmonary Disease
137
acidosis and mortality compared to higher oxygen saturation targets in this population [147–149]. Compared to oxygen targets, the decisions about PaCO2 targets are
more nuanced. They are dictated by the patient’s baseline PaCO2, as well as the
patient’s lung mechanics and other factors contributing to overall acid-base status.
6.5.1 Noninvasive Positive-Pressure Ventilation
Noninvasive positive-pressure ventilation (NPPV) is the delivery of ventilatory support with air or a combination of air and oxygen to a patient without an endotracheal
tube. Ventilatory support is provided via a face mask that is tightly tted with straps
over the patient’s head to ensure an adequate seal around the patient’s mouth and
nose. Colloquially, both bilevel positive airway pressure (BPAP) and continuous
other forms of NPPV that are outside of the scope of this and are best managed by
providers and respiratory therapists trained in acute and chronic respiratory failure.
BPAP, which can treat both hypercapnia and hypoxemia, is considered the mode of
choice for patients with ECOPD; therefore, the majority of our discussion will center there [150]. CPAP in general can be helpful in hypoxemic respiratory failure, but
has limited benet in hypercapnic respiratory failure, and therefore is not considered rst line for ventilatory support in patients with ECOPD [151].
As opposed to continuous airway pressure that is delivered in CPAP, bilevel
NPPV delivers both a higher inspiratory positive airway pressure (IPAP) and a
lower expiratory positive airway pressure (EPAP). By providing pressure during
inspiration, the IPAP is able to reduce the patient’s work of breathing required to
achieve a particular tidal volume. With pressure provided during exhalation, the
EPAP stents open the airways and alveoli and over time counteract the high work of
breathing that occurs during ECOPD (see Sect. 6.2.2). The difference between IPAP
and EPAP values, referred to as the delta PAP, inuences the resultant tidal volume
). As such, a larger delta PAP should lead to a greater Vt and greater minute ven-
(V
t
tilation, and thus more ventilatory support [152]. In addition to these parameters,
providers can set the delivered FiO2 and a backup mandatory respiratory rate.
The indications for bilevel NPPV in ECOPD include the following:
1. Hypercapnic Respiratory Failure (PaCO2>45mmHg and pH <7.35).
Evidence: A Cochrane review of 17 studies showed improved mortality and risk
of endotracheal intubation when NPPV with usual care was compared to usual
care alone in patients presenting with ECOPD and respiratory acidosis (dened by
the above laboratory values) [150]. In light of these benets, many guidelines suggest usage of bilevel NPPV in patients with acute or acute on chronic hypercapnic
respiratory failure due to ECOPD in an effort to prevent endotracheal intubation.
It can also be considered as an alternative to endotracheal intubation if the patient
is not acutely deteriorating, though this is a nuanced decision and requires a
wholistic view of the patient and subsequent close monitoring [153]. We
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L. C. McNamara et al.
recommend reassessing no more than 2hours after initiation of BPAP. Data suggests that if the pH remains <7.25 after 2hours of BPAP, then the need for intubation is likely [154].
Comments: In ECOPD with hypercapnia but a normal pH, NPPV has not been
shown to be benecial. Given potential harms, many agree that it should not be
offered in this clinical setting; instead, medical management and as-needed oxygen
support should be prioritized [153]. Conversely, if intubation is not within a patient’s
care preferences, BPAP should be discussed and offered as an alternative treatment
for ECOPD if the need arises.
2. Respiratory Distress or Hypoxemic Respiratory Failure.
Evidence: Brochard and colleagues looked at NPPV plus usual care compared to
usual care alone in patients with ECOPD. To be included, patients had to have
hypercapnic respiratory failure or meet at least two of the following criteria: tachypnea (respiratory rate >30 breaths per minute), hypoxemia (PaO
<45mmHg), or
2
acidemia (pH <7.35) on room air. This study found improvement in respiratory rate,
need for endotracheal intubation, as well as hospital LOS and in-hospital mortality
in the NPPV arm [155].
Comments: For patients with respiratory distress or hypoxemia refractory to
supplemental oxygen, bronchodilators, steroids, and IV magnesium, NPPV is a
helpful form of respiratory support. NPPV use, though, should not delay intubation if invasive mechanical ventilation is ultimately required and best for the
patient.
3. Post-extubation Support.
Evidence: Prospective randomized controlled trials have shown decreased risk of
post-extubation failure when patients with chronic lung conditions or hypercapnia,
and even more specically with COPD, are extubated to bilevel NPPV as opposed
to oxygen mask alone [156–158].
Comments: In patients with COPD exacerbations who are approaching extubation, BPAP should be utilized in the immediate post-extubation period to reduce the
risk of post-extubation respiratory failure [153]. Given the differences in study protocols utilized, the optimum duration of BPAP post-extubation is not clear; however, likely a minimum of 6–8hours per day for 1–2days is required to achieve
benet [153, 156–159].
Contraindications to NPPV include need for emergent intubation, conditions
that would place patients at risk of aspiration (e.g., copious secretions or emesis,
inability to protect airway), recent facial trauma or surgery, and recent upper
gastrointestinal surgery [160]. Altered mental status is a relative contraindication; if this is attributable to hypercapnia, it often improves with the ventilatory
support BPAP offers [161]. If a patient is unable to tolerate wearing the NPPV
mask, anxiolytic medications (as discussed further in Sect. 6.4.4) can be trialed,
though generally this is an indication to pursue another form of respiratory
support.
6 Acute Exacerbations ofChronic Obstructive Pulmonary Disease
139
6.5.2 High-Flow Nasal Canula
After BPAP, high-ow nasal canula (HFNC) is the second-line respiratory support
device for patients with a COPD exacerbation [162]. HFNC is a noninvasive device
that delivers a gas with titratable FiO2 at high ow rates (e.g., up to 70L per minute). Physiologically, there are several benets of this type of delivery system,
which we have summarized here:
1. Decreases air entrainment:
Air entrainment occurs when the patient inhales
ambient air, in conjunction with the gas provided by a given respiratory support
device. This mixing of gases, proportional to the ow rate of the device and
minute ventilation of the patient, has the effect of reducing the true FiO
of
2
inspired gas. This phenomenon is therefore common with lower ow oxygen
devices, like nasal cannula or simple face mask, such that there is a limit to the
amount of inspired oxygen that can be achieved. Because the airow provided
by HFNC matches or even exceeds the ventilatory demands of patients with
respiratory failure, the FiO2 of the gas delivered is not appreciably diluted by
ambient air, and thus the set FiO2 is delivered in full to the alveoli. Studies have
shown that HFNC improves oxygenation without up-titration of the set FiO2,
suggesting that the ow rate has a greater role [163].
2. Decreased dead-space ventilation: The adult respiratory tract has about 150cc of
anatomic dead space, where gas exchange does not occur due to the structure of
the nasal and oropharynx, larynx, and trachea [164]. The high airow delivered
by HFNC is able to wash out residual carbon dioxide from the respiratory tract
and thereby improve ventilation [165]. It is proposed that this improves patient
work of breathing as they no longer need to maintain as high of a minute ventilation [163].
3. Mild positive end-expiratory pressure (PEEP): At sufcient airow velocity,
HFNC is able to provide modest levels of PEEP.As the ow rate increases, so
too does the pressure in the alveoli at the end of expiration. However, this effect
likely does not exceed 5cm H2O [166].
Given these physiologic effects, the most robust evidence for HFNC use is in
patients with acute hypoxemic respiratory failure. In this broad population, not specic to ECOPD, HFNC has been shown to reduce risk of intubation and perhaps
even improve 90-day mortality [162, 167]. While these same benets have not been
reproduced in patients with hypercapnic respiratory failure, many of whom had
ECOPD, there still may be a role for its use [162]. In these patients, HFNC appears
to be non-inferior to NPPV in terms of gas exchange and work of breathing, and
actually superior with regard to patient comfort [167, 168].
In light of this evidence, in patients with ECOPD, we recommend the use of
HFNC under the following circumstances:
1. Intolerance of or failure of NPPV prior to consideration of endotracheal intuba-
tion and invasive mechanical ventilation.