Acute Exacerbations of Chronic Obstructive Pulmonary Disease: Diagnosis, Management, and Prevention in Critically Ill Patients Deepali Dixit,1,2,* Mary Barna Bridgeman,1,3 Liza Barbarello Andrews,1,4 Navaneeth Narayanan,1,5 Jared Radbel,6 Amay Parikh,6 and Jag Sunderram6 1
Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Critical Care, Robert Wood Johnson University Hospital, New Brunswick, New Jersey; 3Internal Medicine, Robert Wood Johnson University Hospital, New Brunswick, New Jersey; 4Critical Care, Robert Wood Johnson University Hospital Hamilton, Hamilton, New Jersey; 5Infectious Disease, Robert Wood Johnson University Hospital, New Brunswick, New Jersey; 6Division of Pulmonary and Critical Care Medicine, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 2
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death and is a substantial source of disability in the United States. Moderate-to-severe acute exacerbations of COPD (AECOPD) can progress to respiratory failure, necessitating ventilator assistance in patients in the intensive care unit (ICU). Patients in the ICU with AECOPD requiring ventilator support have higher morbidity and mortality rates as well as costs compared with hospitalized patients not in the ICU. The mainstay of management for patients with AECOPD in the ICU includes ventilator support (noninvasive or invasive), rapid-acting inhaled bronchodilators, systemic corticosteroids, and antibiotics. However, evidence supporting these interventions for the treatment of AECOPD in critically ill patients admitted to the ICU is scant. Corticosteroids have gained widespread acceptance in the management of patients with AECOPD necessitating ventilator assistance, despite their lack of evaluation in clinical trials as well as controversies surrounding optimal dosage regimens and duration of treatment. Recent studies evaluating the safety and efficacy of corticosteroids have found that higher doses are associated with increased adverse effects, which therefore support lower dosing strategies, particularly for patients admitted to the ICU for COPD exacerbations. This review highlights recent findings from the current body of evidence on nonpharmacologic and pharmacologic treatment and prevention of AECOPD in critically ill patients. In addition, the administration of bronchodilators using novel delivery devices in the ventilated patient and the conflicting evidence surrounding antibiotic use in AECOPD in the critically ill is explored. Further clinical trials, however, are warranted to clarify the optimal pharmacotherapy management for AECOPD, particularly in critically ill patients admitted to the ICU. KEY WORDS pulmonary, intensive care unit, COPD, severe acute exacerbation, chronic obstructive pulmonary disease. (Pharmacotherapy 2015;35(6):631–648) doi: 10.1002/phar.1599
*Address for correspondence: Deepali Dixit, Clinical Assistant Professor, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854; e-mail: [email protected]. Ó 2015 Pharmacotherapy Publications, Inc.
COPD is the third leading cause of death in the United States.1 The economic burden of COPD continues to be staggering, with the total estimated cost of COPD management at $49.9 billion in 2010 and $29.5 billion spent directly on health care expenditures.1 A significant percentage (50–70%) of the direct health care costs
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associated with COPD is attributed to exacerbations.1,2 Goals of COPD management are to optimize pulmonary function, prevent disease progression, prevent and reduce the frequency and severity of exacerbations, and improve quality of life.2 Recommended strategies for preventing acute exacerbations of COPD (AECOPD) include optimal pharmacologic therapy, smoking cessation, pulmonary rehabilitation, and influenza and pneumococcal vaccination. Despite the lack of conclusive data for the management of the critically ill population with AECOPD, this comprehensive review will update clinicians on the current literature regarding nonpharmacologic and pharmacologic interventions.
goals of exacerbation therapy are to minimize the impact of the current exacerbation and prevent subsequent exacerbations.2 Exacerbations requiring hospitalization are associated with a mortality rate of approximately 10%, whereas severe exacerbations necessitating ventilator support in the intensive care unit (ICU) are associated with a mortality rate of 37–64%.2,5,6 Patients with moderate-to-severe AECOPD can progress to respiratory failure requiring ICU admission and mechanical intubation. Nearly 10% of patients with AECOPD require mechanical ventilation.7 The need for ICU admission is based on the severity of respiratory insufficiency.
Literature Review
Pathogenesis
A literature search of the MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations databases was performed (1996 through February 2015). Search terms included chronic obstructive pulmonary disease exacerbation, COPD, pharmacologic, and critical illness. All published articles pertaining to AECOPD in critically ill patients were reviewed. Available English-language data from reviews, abstracts, presentations, and clinical trials were evaluated, and relevant clinical data were selected and included. Bibliographic citations of research articles were also reviewed for comprehensive identification of pertinent literature.
Airflow obstruction, which defines COPD, is created by a combination of airway narrowing and interstitial tissue destruction. Emphysema results from an imbalance of destructive serine proteinases such as neutrophil elastase and tissue protectors such as a-antitrypsin.2,8 The consequent tissue degradation leads to a loss of alveolar septal tethering of small airways and subsequent airway collapsibility on exhalation.8 Aside from emphysematous degeneration, inflammation, fibrosis, goblet cell metaplasia, and smooth muscle hypertrophy also increase airflow obstruction in the terminal bronchioles.8 AECOPD are a result of increased airway inflammation that worsens airflow obstruction by increasing bronchial tone, bronchial wall edema, and mucus production.2,9 This increased inflammation may be due to increased neutrophils, eosinophils, CD-8 lymphocytes, regulated upon activation normal T cell-expressed and secreted chemokine (RANTES), tumor necrosis factor alpha (TNF), chemokine (C-X-C motif) ligand 5 (CXCL5), granulocyte-macrophage colony stimulating factor (GM-CSF), and interleukins 6 and 8.9 As the degree of airway obstruction increases, the FEV1 decreases, leading to air trapping and hyperinflation. As a consequence, there is a progressive increase in ventilation-perfusion (V/Q) mismatch and physiological dead space, which combined with decreased respiratory drive, can lead to carbon dioxide retention.2,9 The resultant impairment of oxygenation and ventilation results in increased work of breathing. Ventilatory failure occurs once the patient’s respiratory muscles can no longer sustain the resultant increased work of breathing.
Overview Patients with COPD experience exacerbations during the natural course of their disease, requiring a primary care physician visit, emergency department visit, or hospital admission. The frequency and severity of exacerbations are among the factors that determine the prognosis of COPD. Available data suggest that patients with moderate COPD experience an average of 1.3 exacerbations per year; those with severe COPD experience an average of 2 exacerbations per year.3 Patients with frequent exacerbations have an accelerated decline in both lung function (measured as forced expiratory volume in 1 second [FEV1]) and quality of life as well as an increased risk of death.2,4 The standard of care for acute exacerbation management in patients with moderate-to-severe COPD includes provision of supplemental oxygen, mechanical ventilation, short-acting inhaled bronchodilators, systemic corticosteroids, and antibiotics. The
MANAGEMENT OF ACUTE EXACERBATIONS OF COPD IN THE ICU Dixit et al Etiology and Risk Factors The most common etiologies of COPD exacerbations are bacterial and viral infections as well as air pollution.9 Bacterial infections may account for as many as 50% of exacerbations and, compared with nonbacterial exacerbations, result in increased airway inflammation.10 In fact, potentially infectious bacteria have been found in up to 72% of patients with AECOPD who require mechanical ventilation.11 However, the presence of bacterial infections in this population does not worsen FEV1, Acute Physiology and Chronic Health Evaluation II score on presentation, or partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio, or increase the duration of mechanical ventilation, ICU stay, or hospital stay.11 Viruses as a sole pathogen have been isolated in 33% of patients with COPD who require ventilation.12 When viral infections are coexistent with bacterial infections, exacerbations are more severe, as evidenced by increased inflammatory markers.10 Although these etiologies are the most commonly implicated, the actual cause of exacerbation is unknown in up to one-third of severe exacerbations.2 Clinical risk factors that have been described for exacerbations of COPD are increased severity and duration of COPD, old age, prior exacerbations, presence of productive cough, gastrointestinal comorbidities, poor quality of life, current smoking, increased white blood cell count, and use of antibiotics, corticosteroids, or theophylline.13, 14 The correlation of antibiotic, corticosteroid, and theophylline use with exacerbations may be a explained by the fact that patients who are already susceptible to exacerbation are more likely to be receiving these medications.14 The majority of patients admitted to the ICU for an exacerbation have Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage III and IV disease, and are mostly males with an average age of 70 years.15 Clinical Presentation and Diagnostics Patients with AECOPD have worsening of already-present symptoms such as dyspnea, wheezing, cough, and/or changes in sputum volume or purulence.2,9 These changes should be acute and beyond the patient’s normal variation in symptoms.2 Signs of exacerbation on physical examination range from a spectrum of increased expiratory wheezes, rhonchi, and increased
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accessory muscles of respiration use to paradoxical breathing and decreased breath sounds. In addition, the patient may have changes in mental status as serum carbon dioxide (CO2) levels increase. Severe exacerbations of COPD require a diagnostic work-up to guide management. In exacerbations leading to respiratory failure, guidelines suggest obtaining oxygen saturations, arterial blood gases (ABG), a chest radiograph, a complete cell count, serum electrolyte levels, renal function indexes, sputum gram stain and culture, and an electrocardiogram (ECG).16 The ABG quantifies the limitation of oxygenation by measuring the PaO2, which allows for calculation of the alveolar concentration of oxygen to arterial concentration of oxygen (A-a) gradient. It also demonstrates the degree and acuity of hypercapnia when used along with pH and venous bicarbonate measures. Oxygen saturation measured with a pulse oximeter can give realtime measurements of the patient’s response to supplemental oxygen. Chest radiographs are used to evaluate for new infiltrates. Respiratory cultures can be useful in patients with less pulmonary reserve, who often require intensive care monitoring, because they are at increased risk for resistant organisms such as Pseudomonas aeruginosa.2,10,11,13 Finally, the ECG is useful in evaluating for coexisting cardiac pathology.2 Cardiac ischemia, arrhythmias, pulmonary embolism, or pulmonary hypertension are all diagnoses that may alter treatment or dictate additional therapies. Nonpharmacologic Management Ventilator Support Classic presentations of AECOPD include hypercapnic respiratory failure with a partial pressure of CO2 in arterial blood (PaCO2) > 45 mm Hg and/or a pH < 7.35.2 Nonpharmacologic treatment of AECOPD in the ICU includes ventilatory and oxygen support. The goal of such treatments is to decrease the patient’s work of breathing and provide support until the exacerbation subsides. Noninvasive support may be provided through noninvasive positive pressure ventilation (NIPPV) via face mask, nasal prongs, or nasal mask. NIPPV should be considered early in the treatment course of AECOPD.17 A Cochrane review of 14 randomized controlled trials comparing NIPPV plus usual care versus usual care alone showed
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that the use of NIPPV resulted in a decreased need for intubation (relative risk [RR] 0.44, 95% confidence interval [CI] 0.33–0.44), with a number needed to treat (NNT) of 4. This was associated with decreased mortality (RR 0.52, 95% CI 0.35–0.76) and NNT of 10.18 The low NNTs suggests that the positive effect of NIPPV can be demonstrated even with use in relatively few patients. Initial settings for support may consist of an inspiratory pressure of 8–12 cm of water with a positive end-expiratory pressure (PEEP) of 3–5 cm H20. The amount of PEEP aids in oxygenation, whereas the difference between the inspiratory pressure and PEEP provides ventilator support. Settings may be titrated to achieve resolution of dyspnea and patient-ventilator synchrony. Response to noninvasive ventilatory support should be seen within 30 minutes of therapy initiation, with a reduction in respiratory rate to < 30 breaths/minute while maintaining adequate minute ventilation. Repeat blood gas measurements should show an improvement in hypercarbia and pH. In addition, utilization of NIPPV to wean a patient off mechanical ventilation may decrease ventilator-associated events and mortality without increasing the risk of reintubation.19, 20 When noninvasive ventilator support fails to improve the PaCO2 despite titration, mechanical ventilation should be considered. Indications for both noninvasive and invasive ventilation are included in Table 1. Mechanical ventilation is indicated when patients fail to respond, or do not tolerate or have contraindications to noninvasive ventilator support. In addition, prolonged use of NIPPV increases the risk of aspiration with enteral nutrition.2,16 Tachypnea, accessory muscle use, altered mental status, and paradoxical motion of the rib cage and abdomen should prompt immediate intubation. Other indications include hypoxemia that has not corrected with supplemental oxygen or severe respiratory acidosis that has not corrected with NIPPV.2 Standard indications for intubation still apply, including, but not limited to, respiratory arrest, inability to remove respiratory secretions, change in mental status, and hemodynamic instability.2 In addition to improving oxygenation and reducing the work of breathing, mechanical ventilation should prevent hyperinflation. Hyperinflation may lead to barotrauma and further acute lung injury, which may prolong the duration of mechanical ventilation. Other nonpharmacologic maneuvers to optimize mechanical ventilation include reduction in
Table 1. Criteria for Noninvasive and Invasive Ventilatory Assistance2,16 Noninvasive Mechanical Ventilation Respiratory acidosis (arterial pH < 7.35 and PaCO2 > 6–8 kPa [45–60 mm Hg]) or dyspnea (> 24 breaths/min) in combination with clinical signs indicating increased work of breathing and/or respiratory muscle fatigue
Invasive Mechanical Ventilation Unable to tolerate, or fail to respond or have contraindications to noninvasive ventilator support Severe acidosis (pH < 7.25) and hypercapnia (PaCO2 > 60 mmHg) Life-threatening hypoxemia Tachypnea > 35 breaths/min Respiratory arrest Cardiovascular instability (hypotension, arrhythmias, myocardial infarction) Impaired mental status or inability to cooperate Persistent incapacity to remove respiratory secretions with high risk for aspiration Recent facial or gastrooesophageal surgery Severe obesity
PaCO2 = partial pressure of CO2 in arterial blood.
respiratory rate and/or tidal volume, raising the inspiratory flow rate, and application of extrinsic PEEP.21 Volume-limited modes of mechanical ventilation are advantageous in COPD given that a predetermined minute volume can be set, especially in COPD in which air resistance may be high. One may achieve the goals of mechanical ventilation using assist control or pressure-regulated volume control (PRVC). Pressure support ventilation would not be appropriate if the patient is not spontaneously breathing or if the desire is to lessen the work of breathing. Similar to NIPPV, the FiO2 is set to keep the PaO2 > 60 mm Hg or the arterial blood oxygen saturation of hemoglobin > 92%.16 Although the benefit in COPD is unknown, low tidal volumes (6–8 ml/kg based on ideal body weight) may be used as initial settings due to the concern for air trapping.16, 21 Respiratory rate is set to achieve a goal minute ventilation. Incomplete exhalation due to decreased expiratory time and air trapping (auto-PEEP) results in hyperinflation. The presence of high intrathoracic pressures due to autoPEEP can result in a reduction in preload and a drop in blood pressure. If hypotension is significant and auto-PEEP is high, taking the patient off the ventilator briefly to allow for exhalation of trapped air can be lifesaving. A number of other maneuvers need to be considered when
MANAGEMENT OF ACUTE EXACERBATIONS OF COPD IN THE ICU Dixit et al auto-PEEP is present. Lowering respiratory rate is the most useful ventilator maneuver in increasing exhalation time and decreasing autoPEEP, as the expiratory time of a breath is determined by a patient’s breathing rate.16, 22 Use of sedation and analgesia may become necessary to correct auto-PEEP and to reduce the patient’s dyspnea and respiratory rate. In addition, sedation and analgesia during mechanical ventilation helps improve patient comfort and reduces work of breathing. Initial goals may be for moderate to deep sedation depending on the severity of the AECOPD. However, a goal of a Richmond Agitation-Sedation Scale score of 0 to –2 is appropriate as the acute exacerbation is improving. When auto-PEEP is present, the patient is required to exert additional effort to trigger a breath. As a result, extrinsic PEEP may be applied to reduce this effort.22 Similarly, inspiratory triggers to alert the ventilator that a breath is desired can also be adjusted (trigger sensitivity). When this setting is too sensitive, inappropriate breaths may be delivered to the patient. Conversely, if it is not sensitive enough, then the patient’s work of breathing may be increased. Finally, the inspiratory flow rate may be increased to decrease the time required for inspiration, with the resultant high flow rate allowing more time for exhalation. Oxygen Administration of supplemental oxygen in patients with AECOPD who are not on ventilatory support should target a pulse oxygenation of 88–92% or a PaO2 of 60–70 mm Hg.2,16 This corresponds to the point at which the oxygenhemoglobin dissociation curve plateaus. Administration of high concentrations of oxygen has been shown to worsen V/Q mismatch, depress the respiratory drive, and result in hypercapnia.16 Gradual titration of FiO2 while monitoring PaO2 and PaCO2 is important, as both hypoxemia and hyperoxemia have been associated with adverse events.23 Various devices are available to deliver oxygen. The nasal cannula can deliver up to 6 L/minute of oxygen flow (~40% FiO2); however, the amount of oxygen delivered may vary based on the amount of room air inhaled. Other options include a Venturi mask, which allows precise titration of the amount of FiO2 administered, and a non-rebreathing mask. The non-rebreathing mask contains a one-way valve that allows for up to 90% FiO2. A highflow nasal cannula can also be used, which
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allows more precise titration of FiO2 and some PEEP (between 1–5 cm H2O). In general, a high FiO2 is not required to correct the hypoxemia of AECOPD. High FiO2 requirements should prompt consideration of other mechanisms of hypoxic respiratory failure: pneumonia, pulmonary edema, ventilator-associated pneumonia, pulmonary embolism, or acute respiratory distress syndrome.24 Right ventricular structure and function may also need to be assessed by echocardiography in scenarios requiring increased FiO2. Pharmacologic Treatment Bronchodilators Bronchodilator therapy is often described as a cornerstone of COPD management. In stable disease, inhaled anticholingeric agents and b2-adrenoceptor agonists are often used in combination on either a routine and/or as-needed basis for symptom management. Long-acting inhaled bronchodilators, such as tiotropium and salmeterol, offer no advantages in AECOPD and are replaced with more frequently dosed short-acting inhaled bronchodilators (SABDs).2,16 b-Agonists antagonize smooth muscle bronchoconstriction by increasing intracellular cyclic adenosine monophosphate and are associated with several adverse effects (e.g., tremor, palpitations, tachycardia, blood pressure variations) that can be problematic in ICU patients.2,16 Anticholingerics cause bronchodilation through competitive inhibition of muscarinic pulmonary acetylcholine receptors and have less concerning adverse effects in this population (e.g., tremor, dry mouth, urinary retention).2,16 b-Agonists have a faster onset than anticholinergics and a slightly shorter duration of action. Since studies have not demonstrated a difference in efficacy between these two classes of drugs, b-agonists are used first due to their faster onset, with anticholinergics added if insufficient response results from b-agonist monotherapy.2,16 Methylxanthines have not demonstrated benefit in this setting and are associated with significant adverse effects (e.g., arrhythmias, seizures); thus, they do not have a routine role in AECOPD management.2,16 SABD administration for AECOPD often begins in the emergency department. Studies demonstrated that b2-agonists provide similar benefits to anticholinergic agents with regard to change in FEV1; however, optimal doses for AECOPD have
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not yet been defined.25 No benefit has been demonstrated in using the two classes combined.25 Although delivery via metered-dose inhalers (MDIs) with a spacer/holding chamber is equivalent to nebulization in this setting, several factors, including the patient’s disease severity and ability and willingness to comply with the instructions and technique, guide the choice of delivery method.26 Since many of these patients require long-term bronchodilator therapy, strategies for use in AECOPD include increasing the dose frequency (typically every 2– 4 hrs), using combination therapy to optimize bronchodilation mechanisms, and/or adjusting the delivery method to optimize drug delivery.16 Patients admitted to the ICU for treatment of severe AECOPD often require both positive pressure ventilation (PPV) and SABD therapy. Not enough evidence exists to compare MDIs and nebulized delivery of SABDs in NIPPV. During mechanical ventilation, aerosol delivery to the lower respiratory tract depends on several factors, including the delivery system used, size of aerosolized particles, ventilator circuit characteristics (e.g., heat, humidification, density of inhaled gas, position and method of connecting delivery system to circuit, and endotracheal tube size), and patient-specific factors, such as airway geometry, degree of airway responsiveness, and presence of mucus.27 When the appropriate technique is used, such as synchronization of inspiratory flow with MDIs and adjustment of inspiratory flow for nebulizer flow, as described in Tables 2 and 3, studies in mechanically ventilated patients support no difference between the methods.26, 27 An international survey represent-
Table 2. Technique for Administering Metered-Dose Inhalers in Mechanically Ventilated Adult Patients27 Step 1
2 3 4 5 6 7
Procedure Before beginning, ensure that tidal volume is > 500 ml during assisted ventilation. Target goal inspiratory time (excluding inspiratory pause) > 0.3 total breath duration. Ensure that patient’s inspiration in synchronized with ventilator breath Shake the metered-dose inhaler vigorously Insert the canister into the inspiratory limb of the ventilator circuit Actuate the metered-dose inhaler in synchrony with the onset of inspiration by the ventilator Allow a breath hold at end-inspiration for 3–5 sec Allow for passive exhalation Repeat actuation after 20–30 sec until total dose is delivered
Table 3. Technique for Administering Nebulizers to Mechanically Ventilated Adult Patients27 Step 1 2
3 4 5
Procedure Place drug solution in nebulizer, employing a fill volume (2–6 ml, depending on the manufacturer) that ensures greatest aerosol-generating efficacy Place nebulizer in the inspiratory line at least 30 cm from the patient. Although bypassing the humidifier may improve aerosol delivery, this is not recommended in routine treatments as it is associated with drying of the airway mucosa Ensure adequate airflow of 6–8 L/min based on ideal body weight through the nebulizer Ensure adequate tidal volumes of ≥ 500 ml, attempting to use duty cycle > 0.3 when possible Adjust the minute volume to compensate for additional airflow through the nebulizer, if required
ing 854 critical care physicians found that few respondents clinically incorporated optimal technique or device selection routinely in their practice, suggesting a need for improved education and bench-to-bedside translation of research to ensure optimal aerosol drug delivery during mechanical ventilation.28 In recent years, MDI formulations have been adjusted to phase out chlorofluorocarbons (CFCs) in accordance with the Montreal Protocol on Substances that Deplete the Ozone Layer, an international treaty designed to limit CFC impact on the environment.29 CFC-free MDIs increasingly include dose counters designed to support outpatient compliance with obtaining refills. This presents a challenge for use during mechanical ventilation as these canisters with counters are rarely compatible with the ventilator circuit. These regulatory requirements have also spurred the development of newer drug delivery devices, such as the propellant-free Respimat delivery system (Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT) that delivers a slow moving mist. Both issues have impacted selection of SABD administration methods in mechanically ventilated patients, including those treated for AECOPD. Data are limited to guide dosing and administration of SABDs with the Respimat delivery system using an adapter in the mechanically ventilated patient. As the newest system, guidelines and reviews for SABD administration in the mechanically ventilated patient currently do not address delivery from this device.26,30 This is potentially concerning, as studies with MDIs have demonstrated the need to deliver more puffs through mechanical ventilation circuits to
MANAGEMENT OF ACUTE EXACERBATIONS OF COPD IN THE ICU Dixit et al overcome drug deposition along the circuit and provide adequate intrapulmonary drug delivery.31 Only one in vitro study is currently providing some insight into appropriate dosing using the commercially available adapter.32 Applicability of these data to mechanically ventilated patients is difficult given that the methods used a size 8.0 cuffed tracheostomy tube that was held in a 90-degree bend to simulate anatomical placement in humans. Endotracheal tube size is a known factor affecting aerosol drug delivery, and extrapolating these data presents problems. This study used a larger diameter and shorter length tube than applied in average mechanically ventilated patients and was additionally placed at an angle not consistent with usual endotracheal tube placement. As a result, the optimal dose for delivery of bronchodilators via Respimat in patients with severe COPD is unknown at this time and requires additional investigation. Measuring effectiveness of bronchodilation during mechanical ventilation is markedly different than during stable COPD in that FEV1 and forced vital capacity (FVC) are not obtainable. Therefore, investigators have used changes in peak pressures, PEEP, and airway resistance as relative markers of varying degree of bronchodilation.27 Use of SABDs in mechanically ventilated patients treated for severe COPD is guided both by these ventilator parameters as well as clinical status. For patients developing acute lung injury/ acute respiratory distress syndrome, bronchodilator therapy can be complicated by the addition of inhaled vasodilators such as epoprostenol and nitric oxide.33 Although nitric oxide has one commercially available closed-loop delivery system that is ventilator compatible, no such system exists for epoprostenol, although there are several established delivery methods. Formulation considerations (such as the viscous glycine buffer in epoprostenol) can contribute to ventilator clogging and auto-PEEP.33 In addition, adjustments in gas flow rate and other parameters are often required to maximize drug delivery. Adjustment of these settings, as described earlier, can affect delivery of aerosol delivery of both SABDs and vasodilators. When using SABDs in mechanically ventilated patients, practitioners should carefully consider their drug delivery choice and the implications of its use, including administration technique and impact on ventilator settings to ensure optimal delivery in AECOPD.
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Corticosteroid Use in Hospitalized Patients Several studies suggest that corticosteroids improve symptoms and FEV1, reduce risk of treatment failure and relapse, and reduce the length of hospital stay.2,34,35 Conversely, these studies also showed a high rate of adverse events, namely hyperglycemia, and did not exhibit a reduction in the mortality rate related to COPD exacerbation.2,34,35 A series of recent studies suggested that lower-dose oral corticosteroids and shorter treatment duration were associated with a lower incidence of treatment failures and a lower rate of serious adverse effects.34–36 The most recently updated GOLD guidelines, which recommend oral prednisone 40 mg daily for 5 days, are based on the findings from a large observational analysis and the Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial.2,35,36 The REDUCE trial was a prospective, randomized, noninferiority, multicenter study that included 314 patients with a mean age of 69.8 years and who were current or past smokers (≥ 20 pack-yrs); over 50% of the participants in both groups (prednisone 40 mg daily for 5 days or 14 days) had moderate-severity disease (GOLD stage IV), and many of the patients had experienced prior exacerbations.36 The primary endpoint was time to next COPD exacerbation within 6 months. The investigators found that a 5-day course of prednisone 40 mg daily was noninferior to a 14-day course with respect to reexacerbation within 6 months. Notably, the subgroup analysis of different severities of COPD (i.e., GOLD stage) demonstrated that there was no evidence of heterogeneity across all subgroups. In addition, there was no increase in need for mechanical ventilation between the treatment regimens, suggesting that perhaps the 5-day regimen may be adequate in this population. However, further investigation in clinical trials is required to confirm benefits in critically ill. In light of the recent robust body of evidence, it appears that the optimal corticosteroid regimen in hospitalized patients may be a low-dose, short course of oral prednisone 40 mg/day for 5 days, concurrently reducing the risks associated with steroid exposure. Corticosteroid Use in ICU Patients Literature supporting the efficacy and safety of corticosteroids among critically ill patients with AECOPD on ventilator support is scarce. Thus
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far, nearly all studies have excluded patients with respiratory failure severe enough to require mechanical ventilation or ICU admission for AECOPD; it is therefore unclear whether results from previous studies are applicable to patients receiving ventilator support. Nevertheless, extrapolation of study data from non-ICU AECOPD has led to corticosteroid use in critically ill patients with AECOPD. Despite recent evidence indicating that higher doses are not superior to lower doses in hospitalized patients for AECOPD,36 anecdotal observations and a recent retrospective cohort study suggest that critically ill patients admitted to the ICU for AECOPD are treated with higher doses of corticosteroids than hospitalized non-ICU patients, predisposing such patients to adverse effects, without a clear benefit.37 Clinically significant adverse effects associated with high-dose corticosteroids include muscle weakness, ICU-acquired myopathy leading to prolonged duration on ventilator and increased length of stay (LOS), immune suppression, hyperglycemia, and other metabolic disorders.38 It is also important to keep in mind that older patients may be at risk for dose- and/or duration-related acute psychiatric disturbances that can be confused with ICU delirium, posing further dilemma in critically ill patients who are receiving concomitant sedation.38 In addition, it is well documented that hyperglycemic episodes are clearly associated with poor outcomes, including noninvasive ventilation failure, especially in patients with COPD.39,40 Given the aforementioned adverse effects, it critical for clinicians to consider the risks and benefits of administering high doses of steroids in ICU patients experiencing AECOPD. To date, only two small randomized clinical trials have evaluated the efficacy of corticosteroids in patients with COPD exacerbations requiring mechanical ventilation.41,42 The first study of mechanically ventilated patients suffering from severe COPD exacerbations was a multicenter, double-blind, placebo-controlled, randomized study undertaken to evaluate the efficacy and safety of corticosteroid treatment in patients with AECOPD who were receiving invasive or noninvasive ventilatory support.41 A total of 354 ICU patients underwent screening from 8 hospitals in 4 countries, of which 271 (76%) were excluded; thus, 83 mechanically ventilated patients were randomized to receive intravenous methylprednisolone 0.5 mg/kg every 6 hours for 72 hours followed by 0.5 mg/kg every 12 hours on days 4–6 and 0.5 mg/kg/day on days 7–10,
or placebo. Primary outcomes were duration of mechanical ventilation, length of ICU stay, and need for intubation in patients receiving noninvasive mechanical ventilation. Secondary outcomes were length of hospital stay and ICU mortality. Overall, a significant benefit was observed in the corticosteroid cohort versus placebo, with shorter median duration on mechanical ventilation (3 days vs 4 days, p=0.04), a trend toward shorter median ICU LOS (6 days vs 7 days, p=0.09), and a decreased rate of noninvasive ventilation failure (0% vs 37%, p=0.04). The investigators found no significant difference in mortality between the two groups, and the rate of hyperglycemia in the corticosteroid group was twice the rate in the placebo group (46% vs 25%, p=0.04). Despite these important findings, noteworthy limitations included questionable blinding of the investigators and inability to detect primary outcomes and rare risks associated with steroids, as the study was underpowered due to a strict exclusion criterion of recent exposure to steroids. The second prospective, randomized, controlled trial was conducted in two ICUs in Tunisia,42 which included 217 patients with severe COPD exacerbations requiring ventilator support (noninvasive or invasive). Investigators compared the open-label use of prednisone 1 mg/kg/day (oral or via enteral tube) for a maximum of 10 days or usual care. Usual care was defined as receiving ventilator support, nebulized ipratropium, and b2-agonists; antibiotics were given if clinically warranted. The primary endpoint was ICU mortality, and secondary endpoints were days on ventilator support and ICU LOS. No significant differences were noted between the prednisone versus the usual care groups in ICU mortality (15% vs 14%, p=0.81), median duration of ventilation (6 days vs 6 days, p=0.87), noninvasive ventilation failure (16% vs 13%, p=0.59), or ICU LOS (9 days vs 8 days, p=0.88). The rate of hyperglycemia requiring insulin treatment was significantly higher in patients receiving prednisone (50% vs 33%, p=0.01). These results suggest that prednisone does not improve ICU mortality or patientcentered outcomes in patients with COPD experiencing severe exacerbations. However, similar to the previous study,41 this study did not reach the intended enrollment due to an exclusion criterion of recent steroid exposure and was therefore underpowered to detect differences in outcomes between the groups. Despite this limitation, the results are noteworthy and offer
MANAGEMENT OF ACUTE EXACERBATIONS OF COPD IN THE ICU Dixit et al some insight into steroid treatment for critical care patients, but continue to raise questions about the efficacy of steroids in severe AECOPD. A reasonable explanation for the conflicting results observed between the two studies may be due to the fact that patients in the first study41 received higher doses of steroids for the first few days of admission compared with the second study.42 The initial higher dose of intravenous steroids may have contributed to the difference seen in mechanical ventilation duration. Another striking difference between the studies was that the first42 reported similar rates of noninvasive ventilation failure between the prednisone and usual care arms (16% and 13%, respectively), whereas the second41 reported disparate noninvasive ventilation failure rates for the steroid and placebo arms (0% and 37%, respectively). The conflicting results make it difficult to draw concrete conclusions regarding steroid efficacy in ICU patients with AECOPD on ventilator support. Although both studies offer some insight into efficacy and treatment regimens for critically ill patients with AECOPD, change in clinical practice is unlikely to occur based on these findings. Another multicenter, observational cohort study examined the effectiveness and safety of lower versus higher doses of corticosteroids in critically ill patients with AECOPD.37 This study included 17,239 patients (77% aged > 60 years; 31% tobacco users), using a quality and health care use database from 400 U.S. hospitals between 2003 and 2008. Critically ill patients were included if they were admitted with a diagnosis of AECOPD and received oral or intravenous steroids within the first 2 days of admission. The study population was divided into two groups according to their steroid dosing regimen: high dose (> 240 mg/day methylprednisolone equivalent) and low dose (≤ 240 mg/day methylprednisolone equivalent). The primary endpoint was hospital mortality. Secondary endpoints were ICU and hospital LOS, and total hospital costs. Clinical outcomes included initiation and length of noninvasive ventilation or invasive ventilation at day 2, and readmission for AECOPD within 30 days. In addition, corticosteroid-associated adverse effects, such as hyperglycemia, fungal infection, and myopathy, were also assessed. Patients in the two groups were matched by propensity scoring. The analysis included 11,083 (64%) in the high-dose group and 6156 (36%) in the low-dose group.
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Although there was only a trend toward reduction in hospital mortality in the low-dose group (odds ratio [OR] 0.85, 95% CI 0.71–1.01, p=0.06), it was associated with reductions in hospital LOS (–0.44 day, 95% CI 0.67 to 0.21, p
Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Critical Care, Robert Wood Johnson University Hospital, New Brunswick, New Jersey; 3Internal Medicine, Robert Wood Johnson University Hospital, New Brunswick, New Jersey; 4Critical Care, Robert Wood Johnson University Hospital Hamilton, Hamilton, New Jersey; 5Infectious Disease, Robert Wood Johnson University Hospital, New Brunswick, New Jersey; 6Division of Pulmonary and Critical Care Medicine, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 2
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death and is a substantial source of disability in the United States. Moderate-to-severe acute exacerbations of COPD (AECOPD) can progress to respiratory failure, necessitating ventilator assistance in patients in the intensive care unit (ICU). Patients in the ICU with AECOPD requiring ventilator support have higher morbidity and mortality rates as well as costs compared with hospitalized patients not in the ICU. The mainstay of management for patients with AECOPD in the ICU includes ventilator support (noninvasive or invasive), rapid-acting inhaled bronchodilators, systemic corticosteroids, and antibiotics. However, evidence supporting these interventions for the treatment of AECOPD in critically ill patients admitted to the ICU is scant. Corticosteroids have gained widespread acceptance in the management of patients with AECOPD necessitating ventilator assistance, despite their lack of evaluation in clinical trials as well as controversies surrounding optimal dosage regimens and duration of treatment. Recent studies evaluating the safety and efficacy of corticosteroids have found that higher doses are associated with increased adverse effects, which therefore support lower dosing strategies, particularly for patients admitted to the ICU for COPD exacerbations. This review highlights recent findings from the current body of evidence on nonpharmacologic and pharmacologic treatment and prevention of AECOPD in critically ill patients. In addition, the administration of bronchodilators using novel delivery devices in the ventilated patient and the conflicting evidence surrounding antibiotic use in AECOPD in the critically ill is explored. Further clinical trials, however, are warranted to clarify the optimal pharmacotherapy management for AECOPD, particularly in critically ill patients admitted to the ICU. KEY WORDS pulmonary, intensive care unit, COPD, severe acute exacerbation, chronic obstructive pulmonary disease. (Pharmacotherapy 2015;35(6):631–648) doi: 10.1002/phar.1599
*Address for correspondence: Deepali Dixit, Clinical Assistant Professor, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854; e-mail: [email protected]. Ó 2015 Pharmacotherapy Publications, Inc.
COPD is the third leading cause of death in the United States.1 The economic burden of COPD continues to be staggering, with the total estimated cost of COPD management at $49.9 billion in 2010 and $29.5 billion spent directly on health care expenditures.1 A significant percentage (50–70%) of the direct health care costs
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associated with COPD is attributed to exacerbations.1,2 Goals of COPD management are to optimize pulmonary function, prevent disease progression, prevent and reduce the frequency and severity of exacerbations, and improve quality of life.2 Recommended strategies for preventing acute exacerbations of COPD (AECOPD) include optimal pharmacologic therapy, smoking cessation, pulmonary rehabilitation, and influenza and pneumococcal vaccination. Despite the lack of conclusive data for the management of the critically ill population with AECOPD, this comprehensive review will update clinicians on the current literature regarding nonpharmacologic and pharmacologic interventions.
goals of exacerbation therapy are to minimize the impact of the current exacerbation and prevent subsequent exacerbations.2 Exacerbations requiring hospitalization are associated with a mortality rate of approximately 10%, whereas severe exacerbations necessitating ventilator support in the intensive care unit (ICU) are associated with a mortality rate of 37–64%.2,5,6 Patients with moderate-to-severe AECOPD can progress to respiratory failure requiring ICU admission and mechanical intubation. Nearly 10% of patients with AECOPD require mechanical ventilation.7 The need for ICU admission is based on the severity of respiratory insufficiency.
Literature Review
Pathogenesis
A literature search of the MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations databases was performed (1996 through February 2015). Search terms included chronic obstructive pulmonary disease exacerbation, COPD, pharmacologic, and critical illness. All published articles pertaining to AECOPD in critically ill patients were reviewed. Available English-language data from reviews, abstracts, presentations, and clinical trials were evaluated, and relevant clinical data were selected and included. Bibliographic citations of research articles were also reviewed for comprehensive identification of pertinent literature.
Airflow obstruction, which defines COPD, is created by a combination of airway narrowing and interstitial tissue destruction. Emphysema results from an imbalance of destructive serine proteinases such as neutrophil elastase and tissue protectors such as a-antitrypsin.2,8 The consequent tissue degradation leads to a loss of alveolar septal tethering of small airways and subsequent airway collapsibility on exhalation.8 Aside from emphysematous degeneration, inflammation, fibrosis, goblet cell metaplasia, and smooth muscle hypertrophy also increase airflow obstruction in the terminal bronchioles.8 AECOPD are a result of increased airway inflammation that worsens airflow obstruction by increasing bronchial tone, bronchial wall edema, and mucus production.2,9 This increased inflammation may be due to increased neutrophils, eosinophils, CD-8 lymphocytes, regulated upon activation normal T cell-expressed and secreted chemokine (RANTES), tumor necrosis factor alpha (TNF), chemokine (C-X-C motif) ligand 5 (CXCL5), granulocyte-macrophage colony stimulating factor (GM-CSF), and interleukins 6 and 8.9 As the degree of airway obstruction increases, the FEV1 decreases, leading to air trapping and hyperinflation. As a consequence, there is a progressive increase in ventilation-perfusion (V/Q) mismatch and physiological dead space, which combined with decreased respiratory drive, can lead to carbon dioxide retention.2,9 The resultant impairment of oxygenation and ventilation results in increased work of breathing. Ventilatory failure occurs once the patient’s respiratory muscles can no longer sustain the resultant increased work of breathing.
Overview Patients with COPD experience exacerbations during the natural course of their disease, requiring a primary care physician visit, emergency department visit, or hospital admission. The frequency and severity of exacerbations are among the factors that determine the prognosis of COPD. Available data suggest that patients with moderate COPD experience an average of 1.3 exacerbations per year; those with severe COPD experience an average of 2 exacerbations per year.3 Patients with frequent exacerbations have an accelerated decline in both lung function (measured as forced expiratory volume in 1 second [FEV1]) and quality of life as well as an increased risk of death.2,4 The standard of care for acute exacerbation management in patients with moderate-to-severe COPD includes provision of supplemental oxygen, mechanical ventilation, short-acting inhaled bronchodilators, systemic corticosteroids, and antibiotics. The
MANAGEMENT OF ACUTE EXACERBATIONS OF COPD IN THE ICU Dixit et al Etiology and Risk Factors The most common etiologies of COPD exacerbations are bacterial and viral infections as well as air pollution.9 Bacterial infections may account for as many as 50% of exacerbations and, compared with nonbacterial exacerbations, result in increased airway inflammation.10 In fact, potentially infectious bacteria have been found in up to 72% of patients with AECOPD who require mechanical ventilation.11 However, the presence of bacterial infections in this population does not worsen FEV1, Acute Physiology and Chronic Health Evaluation II score on presentation, or partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio, or increase the duration of mechanical ventilation, ICU stay, or hospital stay.11 Viruses as a sole pathogen have been isolated in 33% of patients with COPD who require ventilation.12 When viral infections are coexistent with bacterial infections, exacerbations are more severe, as evidenced by increased inflammatory markers.10 Although these etiologies are the most commonly implicated, the actual cause of exacerbation is unknown in up to one-third of severe exacerbations.2 Clinical risk factors that have been described for exacerbations of COPD are increased severity and duration of COPD, old age, prior exacerbations, presence of productive cough, gastrointestinal comorbidities, poor quality of life, current smoking, increased white blood cell count, and use of antibiotics, corticosteroids, or theophylline.13, 14 The correlation of antibiotic, corticosteroid, and theophylline use with exacerbations may be a explained by the fact that patients who are already susceptible to exacerbation are more likely to be receiving these medications.14 The majority of patients admitted to the ICU for an exacerbation have Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage III and IV disease, and are mostly males with an average age of 70 years.15 Clinical Presentation and Diagnostics Patients with AECOPD have worsening of already-present symptoms such as dyspnea, wheezing, cough, and/or changes in sputum volume or purulence.2,9 These changes should be acute and beyond the patient’s normal variation in symptoms.2 Signs of exacerbation on physical examination range from a spectrum of increased expiratory wheezes, rhonchi, and increased
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accessory muscles of respiration use to paradoxical breathing and decreased breath sounds. In addition, the patient may have changes in mental status as serum carbon dioxide (CO2) levels increase. Severe exacerbations of COPD require a diagnostic work-up to guide management. In exacerbations leading to respiratory failure, guidelines suggest obtaining oxygen saturations, arterial blood gases (ABG), a chest radiograph, a complete cell count, serum electrolyte levels, renal function indexes, sputum gram stain and culture, and an electrocardiogram (ECG).16 The ABG quantifies the limitation of oxygenation by measuring the PaO2, which allows for calculation of the alveolar concentration of oxygen to arterial concentration of oxygen (A-a) gradient. It also demonstrates the degree and acuity of hypercapnia when used along with pH and venous bicarbonate measures. Oxygen saturation measured with a pulse oximeter can give realtime measurements of the patient’s response to supplemental oxygen. Chest radiographs are used to evaluate for new infiltrates. Respiratory cultures can be useful in patients with less pulmonary reserve, who often require intensive care monitoring, because they are at increased risk for resistant organisms such as Pseudomonas aeruginosa.2,10,11,13 Finally, the ECG is useful in evaluating for coexisting cardiac pathology.2 Cardiac ischemia, arrhythmias, pulmonary embolism, or pulmonary hypertension are all diagnoses that may alter treatment or dictate additional therapies. Nonpharmacologic Management Ventilator Support Classic presentations of AECOPD include hypercapnic respiratory failure with a partial pressure of CO2 in arterial blood (PaCO2) > 45 mm Hg and/or a pH < 7.35.2 Nonpharmacologic treatment of AECOPD in the ICU includes ventilatory and oxygen support. The goal of such treatments is to decrease the patient’s work of breathing and provide support until the exacerbation subsides. Noninvasive support may be provided through noninvasive positive pressure ventilation (NIPPV) via face mask, nasal prongs, or nasal mask. NIPPV should be considered early in the treatment course of AECOPD.17 A Cochrane review of 14 randomized controlled trials comparing NIPPV plus usual care versus usual care alone showed
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that the use of NIPPV resulted in a decreased need for intubation (relative risk [RR] 0.44, 95% confidence interval [CI] 0.33–0.44), with a number needed to treat (NNT) of 4. This was associated with decreased mortality (RR 0.52, 95% CI 0.35–0.76) and NNT of 10.18 The low NNTs suggests that the positive effect of NIPPV can be demonstrated even with use in relatively few patients. Initial settings for support may consist of an inspiratory pressure of 8–12 cm of water with a positive end-expiratory pressure (PEEP) of 3–5 cm H20. The amount of PEEP aids in oxygenation, whereas the difference between the inspiratory pressure and PEEP provides ventilator support. Settings may be titrated to achieve resolution of dyspnea and patient-ventilator synchrony. Response to noninvasive ventilatory support should be seen within 30 minutes of therapy initiation, with a reduction in respiratory rate to < 30 breaths/minute while maintaining adequate minute ventilation. Repeat blood gas measurements should show an improvement in hypercarbia and pH. In addition, utilization of NIPPV to wean a patient off mechanical ventilation may decrease ventilator-associated events and mortality without increasing the risk of reintubation.19, 20 When noninvasive ventilator support fails to improve the PaCO2 despite titration, mechanical ventilation should be considered. Indications for both noninvasive and invasive ventilation are included in Table 1. Mechanical ventilation is indicated when patients fail to respond, or do not tolerate or have contraindications to noninvasive ventilator support. In addition, prolonged use of NIPPV increases the risk of aspiration with enteral nutrition.2,16 Tachypnea, accessory muscle use, altered mental status, and paradoxical motion of the rib cage and abdomen should prompt immediate intubation. Other indications include hypoxemia that has not corrected with supplemental oxygen or severe respiratory acidosis that has not corrected with NIPPV.2 Standard indications for intubation still apply, including, but not limited to, respiratory arrest, inability to remove respiratory secretions, change in mental status, and hemodynamic instability.2 In addition to improving oxygenation and reducing the work of breathing, mechanical ventilation should prevent hyperinflation. Hyperinflation may lead to barotrauma and further acute lung injury, which may prolong the duration of mechanical ventilation. Other nonpharmacologic maneuvers to optimize mechanical ventilation include reduction in
Table 1. Criteria for Noninvasive and Invasive Ventilatory Assistance2,16 Noninvasive Mechanical Ventilation Respiratory acidosis (arterial pH < 7.35 and PaCO2 > 6–8 kPa [45–60 mm Hg]) or dyspnea (> 24 breaths/min) in combination with clinical signs indicating increased work of breathing and/or respiratory muscle fatigue
Invasive Mechanical Ventilation Unable to tolerate, or fail to respond or have contraindications to noninvasive ventilator support Severe acidosis (pH < 7.25) and hypercapnia (PaCO2 > 60 mmHg) Life-threatening hypoxemia Tachypnea > 35 breaths/min Respiratory arrest Cardiovascular instability (hypotension, arrhythmias, myocardial infarction) Impaired mental status or inability to cooperate Persistent incapacity to remove respiratory secretions with high risk for aspiration Recent facial or gastrooesophageal surgery Severe obesity
PaCO2 = partial pressure of CO2 in arterial blood.
respiratory rate and/or tidal volume, raising the inspiratory flow rate, and application of extrinsic PEEP.21 Volume-limited modes of mechanical ventilation are advantageous in COPD given that a predetermined minute volume can be set, especially in COPD in which air resistance may be high. One may achieve the goals of mechanical ventilation using assist control or pressure-regulated volume control (PRVC). Pressure support ventilation would not be appropriate if the patient is not spontaneously breathing or if the desire is to lessen the work of breathing. Similar to NIPPV, the FiO2 is set to keep the PaO2 > 60 mm Hg or the arterial blood oxygen saturation of hemoglobin > 92%.16 Although the benefit in COPD is unknown, low tidal volumes (6–8 ml/kg based on ideal body weight) may be used as initial settings due to the concern for air trapping.16, 21 Respiratory rate is set to achieve a goal minute ventilation. Incomplete exhalation due to decreased expiratory time and air trapping (auto-PEEP) results in hyperinflation. The presence of high intrathoracic pressures due to autoPEEP can result in a reduction in preload and a drop in blood pressure. If hypotension is significant and auto-PEEP is high, taking the patient off the ventilator briefly to allow for exhalation of trapped air can be lifesaving. A number of other maneuvers need to be considered when
MANAGEMENT OF ACUTE EXACERBATIONS OF COPD IN THE ICU Dixit et al auto-PEEP is present. Lowering respiratory rate is the most useful ventilator maneuver in increasing exhalation time and decreasing autoPEEP, as the expiratory time of a breath is determined by a patient’s breathing rate.16, 22 Use of sedation and analgesia may become necessary to correct auto-PEEP and to reduce the patient’s dyspnea and respiratory rate. In addition, sedation and analgesia during mechanical ventilation helps improve patient comfort and reduces work of breathing. Initial goals may be for moderate to deep sedation depending on the severity of the AECOPD. However, a goal of a Richmond Agitation-Sedation Scale score of 0 to –2 is appropriate as the acute exacerbation is improving. When auto-PEEP is present, the patient is required to exert additional effort to trigger a breath. As a result, extrinsic PEEP may be applied to reduce this effort.22 Similarly, inspiratory triggers to alert the ventilator that a breath is desired can also be adjusted (trigger sensitivity). When this setting is too sensitive, inappropriate breaths may be delivered to the patient. Conversely, if it is not sensitive enough, then the patient’s work of breathing may be increased. Finally, the inspiratory flow rate may be increased to decrease the time required for inspiration, with the resultant high flow rate allowing more time for exhalation. Oxygen Administration of supplemental oxygen in patients with AECOPD who are not on ventilatory support should target a pulse oxygenation of 88–92% or a PaO2 of 60–70 mm Hg.2,16 This corresponds to the point at which the oxygenhemoglobin dissociation curve plateaus. Administration of high concentrations of oxygen has been shown to worsen V/Q mismatch, depress the respiratory drive, and result in hypercapnia.16 Gradual titration of FiO2 while monitoring PaO2 and PaCO2 is important, as both hypoxemia and hyperoxemia have been associated with adverse events.23 Various devices are available to deliver oxygen. The nasal cannula can deliver up to 6 L/minute of oxygen flow (~40% FiO2); however, the amount of oxygen delivered may vary based on the amount of room air inhaled. Other options include a Venturi mask, which allows precise titration of the amount of FiO2 administered, and a non-rebreathing mask. The non-rebreathing mask contains a one-way valve that allows for up to 90% FiO2. A highflow nasal cannula can also be used, which
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allows more precise titration of FiO2 and some PEEP (between 1–5 cm H2O). In general, a high FiO2 is not required to correct the hypoxemia of AECOPD. High FiO2 requirements should prompt consideration of other mechanisms of hypoxic respiratory failure: pneumonia, pulmonary edema, ventilator-associated pneumonia, pulmonary embolism, or acute respiratory distress syndrome.24 Right ventricular structure and function may also need to be assessed by echocardiography in scenarios requiring increased FiO2. Pharmacologic Treatment Bronchodilators Bronchodilator therapy is often described as a cornerstone of COPD management. In stable disease, inhaled anticholingeric agents and b2-adrenoceptor agonists are often used in combination on either a routine and/or as-needed basis for symptom management. Long-acting inhaled bronchodilators, such as tiotropium and salmeterol, offer no advantages in AECOPD and are replaced with more frequently dosed short-acting inhaled bronchodilators (SABDs).2,16 b-Agonists antagonize smooth muscle bronchoconstriction by increasing intracellular cyclic adenosine monophosphate and are associated with several adverse effects (e.g., tremor, palpitations, tachycardia, blood pressure variations) that can be problematic in ICU patients.2,16 Anticholingerics cause bronchodilation through competitive inhibition of muscarinic pulmonary acetylcholine receptors and have less concerning adverse effects in this population (e.g., tremor, dry mouth, urinary retention).2,16 b-Agonists have a faster onset than anticholinergics and a slightly shorter duration of action. Since studies have not demonstrated a difference in efficacy between these two classes of drugs, b-agonists are used first due to their faster onset, with anticholinergics added if insufficient response results from b-agonist monotherapy.2,16 Methylxanthines have not demonstrated benefit in this setting and are associated with significant adverse effects (e.g., arrhythmias, seizures); thus, they do not have a routine role in AECOPD management.2,16 SABD administration for AECOPD often begins in the emergency department. Studies demonstrated that b2-agonists provide similar benefits to anticholinergic agents with regard to change in FEV1; however, optimal doses for AECOPD have
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not yet been defined.25 No benefit has been demonstrated in using the two classes combined.25 Although delivery via metered-dose inhalers (MDIs) with a spacer/holding chamber is equivalent to nebulization in this setting, several factors, including the patient’s disease severity and ability and willingness to comply with the instructions and technique, guide the choice of delivery method.26 Since many of these patients require long-term bronchodilator therapy, strategies for use in AECOPD include increasing the dose frequency (typically every 2– 4 hrs), using combination therapy to optimize bronchodilation mechanisms, and/or adjusting the delivery method to optimize drug delivery.16 Patients admitted to the ICU for treatment of severe AECOPD often require both positive pressure ventilation (PPV) and SABD therapy. Not enough evidence exists to compare MDIs and nebulized delivery of SABDs in NIPPV. During mechanical ventilation, aerosol delivery to the lower respiratory tract depends on several factors, including the delivery system used, size of aerosolized particles, ventilator circuit characteristics (e.g., heat, humidification, density of inhaled gas, position and method of connecting delivery system to circuit, and endotracheal tube size), and patient-specific factors, such as airway geometry, degree of airway responsiveness, and presence of mucus.27 When the appropriate technique is used, such as synchronization of inspiratory flow with MDIs and adjustment of inspiratory flow for nebulizer flow, as described in Tables 2 and 3, studies in mechanically ventilated patients support no difference between the methods.26, 27 An international survey represent-
Table 2. Technique for Administering Metered-Dose Inhalers in Mechanically Ventilated Adult Patients27 Step 1
2 3 4 5 6 7
Procedure Before beginning, ensure that tidal volume is > 500 ml during assisted ventilation. Target goal inspiratory time (excluding inspiratory pause) > 0.3 total breath duration. Ensure that patient’s inspiration in synchronized with ventilator breath Shake the metered-dose inhaler vigorously Insert the canister into the inspiratory limb of the ventilator circuit Actuate the metered-dose inhaler in synchrony with the onset of inspiration by the ventilator Allow a breath hold at end-inspiration for 3–5 sec Allow for passive exhalation Repeat actuation after 20–30 sec until total dose is delivered
Table 3. Technique for Administering Nebulizers to Mechanically Ventilated Adult Patients27 Step 1 2
3 4 5
Procedure Place drug solution in nebulizer, employing a fill volume (2–6 ml, depending on the manufacturer) that ensures greatest aerosol-generating efficacy Place nebulizer in the inspiratory line at least 30 cm from the patient. Although bypassing the humidifier may improve aerosol delivery, this is not recommended in routine treatments as it is associated with drying of the airway mucosa Ensure adequate airflow of 6–8 L/min based on ideal body weight through the nebulizer Ensure adequate tidal volumes of ≥ 500 ml, attempting to use duty cycle > 0.3 when possible Adjust the minute volume to compensate for additional airflow through the nebulizer, if required
ing 854 critical care physicians found that few respondents clinically incorporated optimal technique or device selection routinely in their practice, suggesting a need for improved education and bench-to-bedside translation of research to ensure optimal aerosol drug delivery during mechanical ventilation.28 In recent years, MDI formulations have been adjusted to phase out chlorofluorocarbons (CFCs) in accordance with the Montreal Protocol on Substances that Deplete the Ozone Layer, an international treaty designed to limit CFC impact on the environment.29 CFC-free MDIs increasingly include dose counters designed to support outpatient compliance with obtaining refills. This presents a challenge for use during mechanical ventilation as these canisters with counters are rarely compatible with the ventilator circuit. These regulatory requirements have also spurred the development of newer drug delivery devices, such as the propellant-free Respimat delivery system (Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT) that delivers a slow moving mist. Both issues have impacted selection of SABD administration methods in mechanically ventilated patients, including those treated for AECOPD. Data are limited to guide dosing and administration of SABDs with the Respimat delivery system using an adapter in the mechanically ventilated patient. As the newest system, guidelines and reviews for SABD administration in the mechanically ventilated patient currently do not address delivery from this device.26,30 This is potentially concerning, as studies with MDIs have demonstrated the need to deliver more puffs through mechanical ventilation circuits to
MANAGEMENT OF ACUTE EXACERBATIONS OF COPD IN THE ICU Dixit et al overcome drug deposition along the circuit and provide adequate intrapulmonary drug delivery.31 Only one in vitro study is currently providing some insight into appropriate dosing using the commercially available adapter.32 Applicability of these data to mechanically ventilated patients is difficult given that the methods used a size 8.0 cuffed tracheostomy tube that was held in a 90-degree bend to simulate anatomical placement in humans. Endotracheal tube size is a known factor affecting aerosol drug delivery, and extrapolating these data presents problems. This study used a larger diameter and shorter length tube than applied in average mechanically ventilated patients and was additionally placed at an angle not consistent with usual endotracheal tube placement. As a result, the optimal dose for delivery of bronchodilators via Respimat in patients with severe COPD is unknown at this time and requires additional investigation. Measuring effectiveness of bronchodilation during mechanical ventilation is markedly different than during stable COPD in that FEV1 and forced vital capacity (FVC) are not obtainable. Therefore, investigators have used changes in peak pressures, PEEP, and airway resistance as relative markers of varying degree of bronchodilation.27 Use of SABDs in mechanically ventilated patients treated for severe COPD is guided both by these ventilator parameters as well as clinical status. For patients developing acute lung injury/ acute respiratory distress syndrome, bronchodilator therapy can be complicated by the addition of inhaled vasodilators such as epoprostenol and nitric oxide.33 Although nitric oxide has one commercially available closed-loop delivery system that is ventilator compatible, no such system exists for epoprostenol, although there are several established delivery methods. Formulation considerations (such as the viscous glycine buffer in epoprostenol) can contribute to ventilator clogging and auto-PEEP.33 In addition, adjustments in gas flow rate and other parameters are often required to maximize drug delivery. Adjustment of these settings, as described earlier, can affect delivery of aerosol delivery of both SABDs and vasodilators. When using SABDs in mechanically ventilated patients, practitioners should carefully consider their drug delivery choice and the implications of its use, including administration technique and impact on ventilator settings to ensure optimal delivery in AECOPD.
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Corticosteroid Use in Hospitalized Patients Several studies suggest that corticosteroids improve symptoms and FEV1, reduce risk of treatment failure and relapse, and reduce the length of hospital stay.2,34,35 Conversely, these studies also showed a high rate of adverse events, namely hyperglycemia, and did not exhibit a reduction in the mortality rate related to COPD exacerbation.2,34,35 A series of recent studies suggested that lower-dose oral corticosteroids and shorter treatment duration were associated with a lower incidence of treatment failures and a lower rate of serious adverse effects.34–36 The most recently updated GOLD guidelines, which recommend oral prednisone 40 mg daily for 5 days, are based on the findings from a large observational analysis and the Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial.2,35,36 The REDUCE trial was a prospective, randomized, noninferiority, multicenter study that included 314 patients with a mean age of 69.8 years and who were current or past smokers (≥ 20 pack-yrs); over 50% of the participants in both groups (prednisone 40 mg daily for 5 days or 14 days) had moderate-severity disease (GOLD stage IV), and many of the patients had experienced prior exacerbations.36 The primary endpoint was time to next COPD exacerbation within 6 months. The investigators found that a 5-day course of prednisone 40 mg daily was noninferior to a 14-day course with respect to reexacerbation within 6 months. Notably, the subgroup analysis of different severities of COPD (i.e., GOLD stage) demonstrated that there was no evidence of heterogeneity across all subgroups. In addition, there was no increase in need for mechanical ventilation between the treatment regimens, suggesting that perhaps the 5-day regimen may be adequate in this population. However, further investigation in clinical trials is required to confirm benefits in critically ill. In light of the recent robust body of evidence, it appears that the optimal corticosteroid regimen in hospitalized patients may be a low-dose, short course of oral prednisone 40 mg/day for 5 days, concurrently reducing the risks associated with steroid exposure. Corticosteroid Use in ICU Patients Literature supporting the efficacy and safety of corticosteroids among critically ill patients with AECOPD on ventilator support is scarce. Thus
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far, nearly all studies have excluded patients with respiratory failure severe enough to require mechanical ventilation or ICU admission for AECOPD; it is therefore unclear whether results from previous studies are applicable to patients receiving ventilator support. Nevertheless, extrapolation of study data from non-ICU AECOPD has led to corticosteroid use in critically ill patients with AECOPD. Despite recent evidence indicating that higher doses are not superior to lower doses in hospitalized patients for AECOPD,36 anecdotal observations and a recent retrospective cohort study suggest that critically ill patients admitted to the ICU for AECOPD are treated with higher doses of corticosteroids than hospitalized non-ICU patients, predisposing such patients to adverse effects, without a clear benefit.37 Clinically significant adverse effects associated with high-dose corticosteroids include muscle weakness, ICU-acquired myopathy leading to prolonged duration on ventilator and increased length of stay (LOS), immune suppression, hyperglycemia, and other metabolic disorders.38 It is also important to keep in mind that older patients may be at risk for dose- and/or duration-related acute psychiatric disturbances that can be confused with ICU delirium, posing further dilemma in critically ill patients who are receiving concomitant sedation.38 In addition, it is well documented that hyperglycemic episodes are clearly associated with poor outcomes, including noninvasive ventilation failure, especially in patients with COPD.39,40 Given the aforementioned adverse effects, it critical for clinicians to consider the risks and benefits of administering high doses of steroids in ICU patients experiencing AECOPD. To date, only two small randomized clinical trials have evaluated the efficacy of corticosteroids in patients with COPD exacerbations requiring mechanical ventilation.41,42 The first study of mechanically ventilated patients suffering from severe COPD exacerbations was a multicenter, double-blind, placebo-controlled, randomized study undertaken to evaluate the efficacy and safety of corticosteroid treatment in patients with AECOPD who were receiving invasive or noninvasive ventilatory support.41 A total of 354 ICU patients underwent screening from 8 hospitals in 4 countries, of which 271 (76%) were excluded; thus, 83 mechanically ventilated patients were randomized to receive intravenous methylprednisolone 0.5 mg/kg every 6 hours for 72 hours followed by 0.5 mg/kg every 12 hours on days 4–6 and 0.5 mg/kg/day on days 7–10,
or placebo. Primary outcomes were duration of mechanical ventilation, length of ICU stay, and need for intubation in patients receiving noninvasive mechanical ventilation. Secondary outcomes were length of hospital stay and ICU mortality. Overall, a significant benefit was observed in the corticosteroid cohort versus placebo, with shorter median duration on mechanical ventilation (3 days vs 4 days, p=0.04), a trend toward shorter median ICU LOS (6 days vs 7 days, p=0.09), and a decreased rate of noninvasive ventilation failure (0% vs 37%, p=0.04). The investigators found no significant difference in mortality between the two groups, and the rate of hyperglycemia in the corticosteroid group was twice the rate in the placebo group (46% vs 25%, p=0.04). Despite these important findings, noteworthy limitations included questionable blinding of the investigators and inability to detect primary outcomes and rare risks associated with steroids, as the study was underpowered due to a strict exclusion criterion of recent exposure to steroids. The second prospective, randomized, controlled trial was conducted in two ICUs in Tunisia,42 which included 217 patients with severe COPD exacerbations requiring ventilator support (noninvasive or invasive). Investigators compared the open-label use of prednisone 1 mg/kg/day (oral or via enteral tube) for a maximum of 10 days or usual care. Usual care was defined as receiving ventilator support, nebulized ipratropium, and b2-agonists; antibiotics were given if clinically warranted. The primary endpoint was ICU mortality, and secondary endpoints were days on ventilator support and ICU LOS. No significant differences were noted between the prednisone versus the usual care groups in ICU mortality (15% vs 14%, p=0.81), median duration of ventilation (6 days vs 6 days, p=0.87), noninvasive ventilation failure (16% vs 13%, p=0.59), or ICU LOS (9 days vs 8 days, p=0.88). The rate of hyperglycemia requiring insulin treatment was significantly higher in patients receiving prednisone (50% vs 33%, p=0.01). These results suggest that prednisone does not improve ICU mortality or patientcentered outcomes in patients with COPD experiencing severe exacerbations. However, similar to the previous study,41 this study did not reach the intended enrollment due to an exclusion criterion of recent steroid exposure and was therefore underpowered to detect differences in outcomes between the groups. Despite this limitation, the results are noteworthy and offer
MANAGEMENT OF ACUTE EXACERBATIONS OF COPD IN THE ICU Dixit et al some insight into steroid treatment for critical care patients, but continue to raise questions about the efficacy of steroids in severe AECOPD. A reasonable explanation for the conflicting results observed between the two studies may be due to the fact that patients in the first study41 received higher doses of steroids for the first few days of admission compared with the second study.42 The initial higher dose of intravenous steroids may have contributed to the difference seen in mechanical ventilation duration. Another striking difference between the studies was that the first42 reported similar rates of noninvasive ventilation failure between the prednisone and usual care arms (16% and 13%, respectively), whereas the second41 reported disparate noninvasive ventilation failure rates for the steroid and placebo arms (0% and 37%, respectively). The conflicting results make it difficult to draw concrete conclusions regarding steroid efficacy in ICU patients with AECOPD on ventilator support. Although both studies offer some insight into efficacy and treatment regimens for critically ill patients with AECOPD, change in clinical practice is unlikely to occur based on these findings. Another multicenter, observational cohort study examined the effectiveness and safety of lower versus higher doses of corticosteroids in critically ill patients with AECOPD.37 This study included 17,239 patients (77% aged > 60 years; 31% tobacco users), using a quality and health care use database from 400 U.S. hospitals between 2003 and 2008. Critically ill patients were included if they were admitted with a diagnosis of AECOPD and received oral or intravenous steroids within the first 2 days of admission. The study population was divided into two groups according to their steroid dosing regimen: high dose (> 240 mg/day methylprednisolone equivalent) and low dose (≤ 240 mg/day methylprednisolone equivalent). The primary endpoint was hospital mortality. Secondary endpoints were ICU and hospital LOS, and total hospital costs. Clinical outcomes included initiation and length of noninvasive ventilation or invasive ventilation at day 2, and readmission for AECOPD within 30 days. In addition, corticosteroid-associated adverse effects, such as hyperglycemia, fungal infection, and myopathy, were also assessed. Patients in the two groups were matched by propensity scoring. The analysis included 11,083 (64%) in the high-dose group and 6156 (36%) in the low-dose group.
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Although there was only a trend toward reduction in hospital mortality in the low-dose group (odds ratio [OR] 0.85, 95% CI 0.71–1.01, p=0.06), it was associated with reductions in hospital LOS (–0.44 day, 95% CI 0.67 to 0.21, p
