Chronic Obstructive Pulmonary Disease Prevalence
It is estimated that 80 million people worldwide and up to 10% of the U.S. population have chronic obstructive pulmonary disease (COPD) (World Health Organization [WHO] ). It is the fifth leading cause of death and chronic morbidity in the United States and accounted for 5% of total deaths worldwide in 2005 (WHO). Prevalence and mortality are increasing and are likely to continue to do so because of continued high smoking prevalence. Significantly, COPD is the only leading cause of death that is rising, and it is predicted to be the third leading cause of mortality by 2030.
Acute episodes of respiratory failure in patients with COPD are estimated to account for between 5% and 10% of acute emergency hospital admissions. Failure of first-line medical treatment is a common source of intensive care unit (ICU) referrals, accounting for 2% to 3% of nonsurgical ICU admissions. In a cohort of 1016 patients who were hospitalized for acute exacerbations, half of whom required intensive care, the in-hospital mortality was 11%. The 6-month and 1-year mortality were 33% and 43%, respectively. Those who survived the first hospitalization had a 50% rate of rehospitalization within 6 months after discharge.
Respiratory Failure
The pathophysiology of acute respiratory failure in COPD is incompletely understood, but it may be precipitated by any condition that increases the work of breathing or, less commonly, decreases the respiratory drive. Respiratory failure may be predominantly hypoxic (type 1) or hypercapnic (type 2). The mechanism of hypercapnea in COPD is not clear, but it is no longer thought to reflect problems with respiratory drive as suggested by the concept of “pink puffer/blue bloaters.” Gas exchange abnormalities appear to predominantly reflect ventilation-perfusion mismatching due to airflow limitation, and progressive respiratory failure reflects a combination of severe airflow obstruction, hyperinflation, and respiratory muscle fatigue. Regardless of the cause, hypercapnea and the need to assist ventilation identify patients with high initial (up to 27%) and 12-month mortality (up to 50%).
Clinical Precipitants of Respiratory Failure
It has been shown that viral and bacterial infections account for between 50% and 70% of acute exacerbations and by inference a large proportion of cases of acute respiratory failure in COPD. Numerous viral and bacterial agents have been implicated, but rhinoviruses, respiratory syncytial virus, Haemophilus influenzae , Moraxella catarrhalis , and Streptococcus pneumoniae are the frequent pathogens. Pseudomonas aeruginosa , Enterobacteriaceae spp., and Stenotrophomonas spp. are also isolated, particularly from patients with severe COPD and those requiring mechanical ventilation. Therefore, although still uncommon, clinicians should consider more resistant gram-negative organisms in patients requiring ICU care with COPD exacerbations. The prevalence of atypical organisms such as Mycoplasma and Chlamydia is less well defined.
Up to 10% of COPD flares are caused by environmental pollution and airway irritants such as smoke or fumes. For the remainder of cases, the etiology is not always clear. Medical conditions can mimic or cause COPD exacerbations, and patients with COPD have higher rates of comorbid illnesses, in part reflecting exposure to cigarette smoke. This is supported by results from the Toward a Revolution in COPD Health (TORCH) trial ; only 35% of deaths were adjudicated as due to pulmonary causes, with cardiovascular disease being the other major cause of death at 27% and cancer third at 21%.
Important differential diagnoses for patients with COPD who have increased respiratory symptoms and decreased lung function include the following:
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Cardiovascular disease : myocardial ischemia, heart failure, pulmonary embolism
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Central nervous system depression : head trauma or injudicious use of sedatives, opioids, tranquilizers, or oxygen (O 2 ) therapy
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Endocrine and metabolic disorders : myxedema or metabolic alkalosis
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Thoracic abnormalities : chest trauma, pneumothorax, or thoracic or abdominal surgery
Pulmonary embolism can be an occult cause of acute respiratory failure in COPD. A prospective cohort study in 2006 reported that 22% of patients with a severe COPD exacerbation of unknown etiology had coexisting pulmonary emboli. A subsequent study of all patients in the emergency department with COPD exacerbations found the overall prevalence of clinically unsuspected pulmonary embolism to be relatively low at 1.3%, suggesting that systematic examination for those with uncomplicated presentations is probably not useful but that a high index of suspicion is warranted in those without other apparent precipitants.
Prognostic Indicators in Patients with Acute Exacerbations of COPD
There are several potential prognostic indicators that should be considered when admitting a patient to the ICU with an acute exacerbation of COPD. The DECAF score has been developed to predict mortality. It is based on the five strongest predictors of mortality in a study from the United Kingdom in 2012: Dyspnea, Eosinophilia, Consolidation, Acidemia, and Atrial Fibrillation. As a combined score, this has been shown to be a stronger predictor of mortality than the CURB-65 ( C onfusion of new onset, blood U rea nitrogen, R espiratory rate, B lood pressure, age 65 or older) score in patients with COPD and pneumonia, and as such it is a useful triage tool. Other factors commonly cited in literature would include a patient’s age, the patient’s forced expiratory volume in 1 second (FEV 1 ), the degree of hypoxemia or hypercapnea, the presence of other comorbidities such as cardiovascular disease, or a history of prior or frequent exacerbations. Frequent exacerbations accelerate disease progression and mortality, leading to a faster decline in lung function and quality of life. The 2-year mortality after a COPD exacerbation is approximately 50%. Finally, a patient who has failed adequate treatment for a COPD exacerbation over 3 to 5 days (“late failure”) has a very poor prognosis in the setting of escalation to mechanical ventilation.
Patients with chronic hypercapneic respiratory failure are particularly high risk, and, as a result, noninvasive ventilation (NIV) at home is being increasingly used. Base excess, which represents a metabolic response to chronic hypercapnea (increased bicarbonate, reduced chloride) was found to be one of the strongest prognostic indicators in this setting, as reported in a study published in 2007 by Budweiser and colleagues. They also found that in a cohort of COPD patients sent home from the hospital and undergoing NIV, the 5-year survival rate was 26.4%, with deaths predominantly from respiratory causes (73.8%).
Management of COPD
The treatment guidelines for management of acute exacerbations of COPD requiring admission to the ICU are broadly similar to those principles used in patients without respiratory failure, although significantly more attention must be paid to safe and appropriate gas exchange. Addressing the issue of poor respiratory mechanics due to dynamic hyperinflation, loss of alveolar volume, and impaired ventilation is fundamental to COPD management. Clinically compensated chronic respiratory failure can rapidly become decompensated respiratory failure because of poor chest wall mechanics, suboptimal respiratory muscle function, malnutrition, obesity, and myopathy. Reducing the work of breathing with noninvasive positive pressure ventilation (NIPPV) to improve oxygenation, improve rest muscles, and manage hyperinflation has become key in the management of COPD.
Indications for referral to ICU include dyspnea that does not respond to emergency treatment; changes in mental status (e.g., confusion, drowsiness, or coma); persistent or worsening hypoxemia; and/or severe or worsening hypercapnia, acidosis, or hemodynamic instability.
Corticosteroids
Several randomized controlled trials have shown that for patients hospitalized with acute exacerbations of COPD, systemic corticosteroids administered for up to 2 weeks are helpful. Treatment of an exacerbation of COPD with oral or parenteral corticosteroids increases the rate of improvement in lung function and dyspnea over the first 72 hours. Corticosteroids also reduce the duration of hospital stay. The optimal dose and need for tapering, route of administration, and length of treatment are uncertain.
Most recent guidelines suggest that intravenous corticosteroids should be given to patients who have a severe exacerbation, including all those requiring ICU admission or those who may have impaired absorption due to decreased splanchnic perfusion (e.g., patients in shock or congestive heart failure). Nonetheless, if tolerated, oral corticosteroid administration is equally effective as intravenous administration. There appears to be no benefit to prolonged treatment beyond 2 weeks. There is a significant side effect profile, the most common being hyperglycemia occurring in approximately 15%. Studies have shown that nebulized steroid therapy is superior to placebo but not better than parenteral therapy.
Bronchodilators
Inhaled short-acting β-adrenergic agonists are the mainstay of therapy for an acute exacerbation of COPD because of their rapid onset of action and efficacy in producing bronchodilation. Several randomized control trials have consistently demonstrated their efficacy. Parenteral or subcutaneous injection of short-acting β-adrenergic agonists is reserved for situations in which inhaled administration is not possible. Parenteral use of these agents results in greater inotropic and chronotropic effects, which may cause arrhythmias or myocardial ischemia in susceptible individuals and is not generally recommended. These medications may be administered with a nebulizer or a metered dose inhaler with a spacer device; however, despite evidence that neither method has been shown to be superior, physicians tend to favor the nebulized route because of the ease of administration. Patients should revert to appropriate inhaled preparations as soon as possible.
Anticholinergic bronchodilators, such as ipratropium, are equally efficacious, and some studies have found that combination therapy with inhaled beta agonists provides better bronchodilation than either alone. The array of inhalers available for use in stable COPD patients is widening, and newer combination inhalers include a long-acting beta agonist with a long-acting anticholinergic, such as indacaterol and glycopyrronium. These dual bronchodilators have been shown to improve symptoms and lung function in COPD patients in which single bronchodilators may be insufficient, but there is no proven efficacy for their use in acute exacerbations.
Methylxanthines have a long history in the treatment of COPD; however, despite widespread clinical use, their role in the acute setting is controversial. Current guidelines based on a meta-analysis of four randomized control trials recommend that theophylline should not be used in the acute setting because efficacy beyond that induced by an inhaled bronchodilator and glucocorticoid therapy has not been demonstrated. In addition to a lack of efficacy, methylxanthines caused significantly more nausea and vomiting than placebo and trended toward more frequent tremors, palpitations, and arrhythmias.
Antibiotics
In patients with severe exacerbations requiring mechanical ventilation, antibiotic therapy is beneficial and has been shown to significantly decrease mortality (4% vs. 22%), the need for additional courses of antibiotics, the duration of mechanical ventilation, and the duration of hospital stay. This does not suggest that bacterial etiology is actually present, and the clinical decision to withhold antibiotics is difficult in hospitalized patients. Early investigations using inflammatory markers, such as procalcitonin, to distinguish bacterial infections from other causes are encouraging.
Current guidelines suggest use of antimicrobials with a spectrum of activity to cover β-lactamase–producing organisms. Although choice is somewhat dependent on the local streptococcal resistance patterns, amoxicillin–clavulanic acid, second-generation cephalosporin, or macrolides are all acceptable. Three to seven days of treatment is recommended ( G lobal Initiative for Chronic O bstructive L ung D isease [GOLD]). Wider spectrum antibiotics such as fluoroquinolones or β-lactam with antipseudomonal activity should be used in those at risk of resistant gram-negative infections such as Pseudomonas (e.g., recent hospitalization, previous colonization, previous severe exacerbation, or >4 exacerbations per year).
Oxygen Therapy
Adequate oxygenation can be achieved in most patients with acute exacerbations of COPD. Ventilation-perfusion mismatch is usually improved by 24% to 28% oxygen. There appears to be a tendency to develop CO 2 retention at a fraction of inspired oxygen (F io 2 ) greater than 30%. The mechanism is more likely to reflect a combination of ventilation-perfusion mismatching and the Haldane effect rather than any effect on hypoxic drive for ventilation. Nevertheless, controlled oxygen therapy is recommended. In critical care, the use of high-flow facemasks or nasal devices provides better titration of oxygen therapy compared with simple facemasks or nasal cannulae, venture masks, or other variable performance devices.
Assisted Ventilation
Recognition of the need for assisted ventilation is often a clinical judgment as patients fail to improve on initial treatment. NIV is indicated after initial treatment if the pH remains less than 7.32. Studies have shown that pH and degree of hypercapnia are better predictors of need for mechanical ventilation than hypoxia. The following are several absolute and relative contraindications to NIPPV:
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Respiratory arrest
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Impaired level of consciousness
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Cardiovascular collapse
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Profound hypoxemia (acute respiratory distress syndrome)
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Vomiting or very high aspiration risk due to excessive secretions
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Uncooperative patient
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Extreme obesity
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Recent facial surgery
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Burns
Several randomized control trials have validated the use of NIV in the setting of acute hypercapnic respiratory failure in COPD ; indeed, several studies have demonstrated the superiority of NIV over tracheal intubation and mechanical ventilation. NIV reduces intubation by up to 42% and appears to reduce nosocomial complications and mortality. Some studies have also found that patients with COPD who were randomly assigned to NIV had a shorter stay in the ICU. Use of NIV has certainly improved care for many patients with COPD and allowed some to undergo a more intense level of treatment than perhaps may have been previously available to them.
NIV on respiratory care wards and intermediate care settings is highly efficacious, with a reported failure rate of 5% to 20%. However, when patients are admitted to intensive care, presumably in a worse clinical condition, the failure rate is up to 60%. This is particularly problematic in patients who present late with advanced respiratory failure, and mortality is higher than in patients who receive NIV at an earlier stage. There are a medley of reasons for failing NIV, which include patient intolerance, inadequate augmentation of tidal volume, and problems with triggering.
The response to NIV treatment needs to be closely monitored with arterial blood gases, respiratory rate, hemodynamics, and overall degree of respiratory distress. Those who respond within 1 to 4 hours are consistently shown to have better outcomes. An initial reduction in respiratory rate is generally a good indicator of a positive response to NIV. Failure of NIV, contraindications, or imminent cardiorespiratory arrest should prompt endotracheal intubation and mechanical ventilation. This should ideally be performed in the controlled setting of an ICU because intubation can precipitate a cardiovascular collapse.
Once intubation has been performed, hypoxemia can be corrected, usually with modest F io 2 . After this, respiratory acidosis is corrected slowly with low rates and tidal volumes guided by air pressures and the expiratory phase. This approach is to limit auto-positive end-expiratory pressure (auto-PEEP) from air trapping, which can result in significant hemodynamic compromise and can be difficult to detect.
In the first 12 to 24 hours, paralysis may be required to prevent ventilator dyssynchrony, which can increase airway resistance and decrease alveolar ventilation. Airway resistance and hyperinflation can both contribute to a need for high inflation pressures to achieve tidal volume. High mean airway pressures may lead to several serious problems, including circulatory collapse, pneumothorax, or barotrauma. It is unclear whether pressure-controlled or pressure-limited ventilation is safer than volume control. Irrespective efforts should be made to minimize auto-PEEP and end inspiratory stretch.
Weaning can pose problems in ventilated COPD patients, with 20% to 30% of those meeting the traditional extubation criteria failing a trial of weaning. Failure to wean raises the risks of the complications associated with prolonged ventilation. There is some evidence that expiratory flow limitation may predict successful extubation. Nava and colleagues randomly assigned patients with COPD who were intubated for 48 hours to extubation and NIV or to continued invasive ventilation and conventional liberation after an unsuccessful initial spontaneous breathing trial. The study demonstrated improved outcomes as measured by the percentage of patients in whom assisted ventilation could be discontinued, the duration of assisted ventilation, survival, the length of stay in the ICU, and the incidence of ventilator-associated pneumonia. More recently, this was validated by Ornico et al., who showed a significant reduction of re-intubation rates and in-hospital mortality when nasal NIV was commenced after planned extubation as compared with continuous oxygen therapy. Risk factors for postextubation respiratory failure include an age older than 65, cardiac failure as a cause for respiratory distress, an APACHE (Acute Physiology and Chronic Health Evaluation) score of 12 or greater at the time of extubation, the diagnosis of an acute exacerbation of COPD, or the presence of chronic respiratory disease with more than 48 hours of mechanical ventilation and hypercapnea during a spontaneous breathing trial. If patients do have postextubation respiratory distress, then they should undergo reintubation because persisting with NIV in this setting may worsen outcomes.
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