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How should exacerbations of COPD be managed in the intensive care unit?
SECTION 3 Non-ARDS and Noninfectious Respiratory Disorders
11 How Should Exacerbations of COPD Be Managed in the Intensive Care Unit? Christina Campbell, Tara Cahill, and Anthony O’Regan
PREVALENCE OF COPD The Global Burden of Disease (GBD) project ranked chronic obstructive pulmonary disease (COPD) 8th of the 315 causes of the Global Burden of Disease in 2015.1 It estimated 3.2 million people died from COPD worldwide in 2015; this is an increase of 11% from 1990, despite a decrease in the overall age-standardized death rate of 42%. The prevalence of COPD increased by 44% in the same period. Worldwide, COPD affects 105 million males and 70 million females, with an age-standardized prevalence of 3% in males and 2% in females. However, age-standardized disability-adjusted life years (DALYs) rates in males are almost double the rates in females, which reflects a higher male-to-female ratio for mortality than prevalence.1 Smoking and exposure to ambient particulate matter are the main risk factors for development of COPD, followed by household air pollution, occupational exposures, ozone, and environmental tobacco smoke.1 In countries with a higher sociodemographic index (SDI), smoking contributes to 69% of COPD burden, whereas environmental risks are more prevalent in lower SDI countries, contributing to 58% of COPD cases.1 A significant proportion of COPD remains unexplained. The GBD group plan to expand their data to include a personal history of pulmonary tuberculosis as a risk factor, given the emergence of evidence for a causal relationship.1–3 A 2011 French study had demonstrated that exacerbations of COPD contribute to 1.6–2.6% of all medical admissions.4 Of these admissions, in-hospital mortality were 6–8%, with the mortality rates in males being significantly higher than in females (6–9% vs. 5–7%, respectively). The rates of COPD admission increased by 38% from 1998 to 2007, despite a drop in inpatient lethality from 7.6% to 6%.5 The US National Hospital Discharge Survey reported an increase in admissions between 1990 and 1999.5 Data from Italy, Australia, and Canada show similar trends.5–7 This may reflect improving care, leading to longer life expectancy and thus more admissions. 74
As expected, admission rates increase with age, particularly over 45 years and show a definite seasonal pattern, related to the peaks of prevalence of influenza-like illnesses.4 Acute episodes of respiratory failure in patients with COPD are estimated to account for between 5% and 10% of acute emergency hospital medical admissions. Failure of first-line medical treatment is a common source of intensive care unit (ICU) referrals, accounting for 2–3% of non-surgical ICU admissions.8 In a cohort of 1016 patients who were hospitalized for acute exacerbations, half of whom required intensive care, the in-hospital mortality rate was 11%.9 The 6-month and 1-year mortality rates 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 not completely understood but may be precipitated by any condition that increases the work of breathing. 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 believed to reflect problems with respiratory drive as suggested by the concept of “pink puffers and 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 pathophysiology, the presence of hypercapnea and the need for assisted ventilation identify patients that have high initial (up to 27%) and 12-month mortality (up to 50%).10
CLINICAL PRECIPITANTS OF RESPIRATORY FAILURE It has been shown that viral and bacterial infections account for between 50% and 70% of acute exacerbations and the
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majority of cases of acute respiratory failure in COPD.11,12 Numerous viral and bacterial agents have been implicated, but rhinoviruses, respiratory syncytial virus, Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae are the most common pathogens.12–15 Pseudomonas aeruginosa, Enterobacteriaceae, and Stenotrophomonas spp. are also frequently isolated, particularly from patients with severe COPD and those requiring mechanical ventilation.16 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. There is growing body of evidence that gastroesophageal reflux disease contributes to acute exacerbations in the COPD population,17 particularly those not on acid suppressive therapies.18 For many other cases the etiology of acute exacerbations is not 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 Towards 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%. A further study has demonstrated patients are at a higher risk of myocardial infarction or stroke following an exacerbation of COPD, possibly due to higher rates of systemic inflammation following exacerbations of COPD.19 Pulmonary embolism (PE) can be an occult cause of acute respiratory failure in COPD. A systematic review found that 16% of patients with an exacerbation of COPD had a PE, but other studies report a lower incidence at presentation to hospital.20 Signs of infection were seen less commonly with PE, with pleuritic chest pain and cardiac failure being more common.20
PROGNOSTIC INDICATORS IN PATIENTS WITH ACUTE EXACERBATIONS OF COPD There are several potential prognostic indicators that should be considered when admitting a patient to 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 UK in 2012: dyspnea, eosinophilia, consolidation, acidemia, and atrial fibrillation.21 As a combined score, this has been shown to be a stronger predictor of mortality than the CURB-65 score in patients with COPD and pneumonia, and as such, is a useful triage tool. Other factors commonly cited in literature include patients’ age, their forced expiratory volume in 1 second (FEV1), 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
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mortality, leading to a faster decline in lung function and quality of life.22 The 2-year mortality after a COPD exacerbation is approximately 50%. Finally, a patient who has failed adequate treatment for a COPD exacerbation over 48 hours (“late failure”) has a very poor prognosis in the setting of escalation to invasive mechanical ventilation.23 Patients with chronic hypercapnic 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 hypercapnia (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.24 They also found that in a cohort of COPD patients sent home from hospital on NIV, the 5-year survival rate was 26.4%, with deaths predominantly from respiratory causes (73.8%). A recent study demonstrated that domiciliary NIV following an exacerbation prolongs time to next admission if patients are selected for persistent hypercapnia at 4 weeks post discharge and NIV is titrated to normalize pCO2.25
MANAGEMENT OF COPD The treatment guidelines for management of acute exacerbation of COPD requiring admission to ICU are broadly similar to those principles employed 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. Compensated chronic respiratory failure can rapidly decompensate due to poor chest wall mechanics, suboptimal respiratory muscle function, malnutrition, obesity, and myopathy. Reducing the work of breathing using NIV to improve oxygenation, 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 (confusion, drowsiness, or coma), persistent or worsening hypoxemia, and/or severe or worsening hypercapnia, acidosis, or hemodynamic instability.26
Corticosteroids A number of randomized controlled trials (RCTs) have shown that for patients hospitalized with acute exacerbations of COPD, systemic corticosteroids administered for up to 2 weeks are helpful.27 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.28 Corticosteroids also reduce the duration of hospital stay.29 The optimal dose and need for tapering, route of administration, and length of treatment are uncertain. Most recent guidelines suggest intravenous corticosteroids should be given to patients who present with 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
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SECTION 3
Non-ARDS and Noninfectious Respiratory Disorders
heart failure). Nonetheless, if tolerated, oral corticosteroid administration is equally effective as intravenous.30 There appears to be no benefit to prolonged treatment beyond 2 weeks.31 There is a significant side-effect profile, the most common side effect being hyperglycemia occurring in approximately 15%.31 Studies have shown that nebulized steroid therapy is superior to placebo but not better than parenteral therapy.32
Bronchodilators Inhaled short-acting beta-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. RCTs have consistently demonstrated their efficacy.27 Parenteral or subcutaneous injection of short-acting beta-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 via a nebulizer or a metered dose inhaler (MDI) with a spacer device; however, despite evidence that neither method has been shown to be superior, physicians tend to favor the nebulized route, due to the ease of administration. Patients should revert to appropriate inhaled preparations as soon as possible. Anticholinergic bronchodilators, such as ipratropium, are equally efficacious,33 and some studies have found that combination therapy with inhaled beta-agonists provides better bronchodilation than either alone.34 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. These dual bronchodilators have been shown to improve symptoms and lung function in COPD patients where single bronchodilators may be insufficient,35 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 meta-analysis of four RCTs recommend that theophylline should not be used in the acute setting, as efficacy beyond that induced by inhaled bronchodilator and glucocorticoid therapy has not been demonstrated. In addition to lack of efficacy, methylxanthines have caused significantly more nausea and vomiting than placebo and trended toward more frequent tremor, palpitations, and arrhythmias.36
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.37 Other studies show inconsistent benefit from antibiotics, but the decision to withhold antimicrobials is difficult and potentially risky in severe exacerbations. Unfortunately, early
investigations using inflammatory markers such as procalcitonin have not shown a reduction in antibiotic use.38 Current guidelines suggest the use of antimicrobials with a spectrum of activity to cover beta-lactamase-producing organisms. While choice is somewhat dependent on the local streptococcal resistance patterns, amoxicillin–clavulanic acid, second-generation cephalosporin, or macrolides are all acceptable. A treatment of 3–7 days is recommended (GOLD).39 Wider-spectrum antibiotics such as fluoroquinolones or beta-lactam with antipseudomonal activity should be used in those at risk of resistant gram-negative infections (i.e., recent hospitalization, previous colonization, previous severe exacerbation or ,4 exacerbations per year) or prior culture for pseudomonas.
Oxygen Therapy Adequate oxygenation can be achieved in most patients with acute exacerbations of COPD. Ventilation–perfusion mismatch is usually improved by 24–28% oxygen. There appears to be a tendency to develop CO2 retention at FiO2 . 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. Controlled or titrated oxygen therapy has been shown to significantly reduce hypercapnia, acidosis, and mortality.40 In critical care, the use of high-flow facemasks or nasal devices provides better titration of oxygen therapy compared to simple facemasks or nasal cannulae, Venturi masks or other variable performance devices.
Assisted Ventilation Recognition of need for assisted ventilation is essential and should be considered in any patient with type 2 or hypercapnic respiratory failure. NIV is definitely indicated if the pH remains ,7.32 and probably indicated if the pH remains ,7.36. Studies have shown that pH and degree of hypercapnia are better predictors of need for mechanical ventilation than hypoxia.41 There are a number of absolute and relative contraindications to NIV: • Respiratory arrest • Impaired level of consciousness • Cardiovascular collapse • Profound hypoxemia (ARDS) • Vomiting or very high aspiration risk due to excessive secretions • Uncooperative patient • Extreme obesity • Recent facial surgery • Burns A number of RTCs have validated the use of NIV in the setting of acute hypercapnic respiratory failure in COPD42 and indeed several studies have demonstrated the superiority of NIV over tracheal intubation and mechanical ventilation. NIV reduces intubation by up to 42%42 and appears to reduce nosocomial complications and mortality.42,43 Some studies have also found that patients with COPD who were randomly assigned to NIV had a shorter stay in the ICU. The use of
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NIV has certainly improved care for many COPD sufferers 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 5–20%. Studies have shown that staff training and experience are more important than location in regards to NIV, and can be given effectively outside of the ICU.44 However, when patients are admitted to intensive care, presumably in worse clinical condition, the failure rate is up to 60%.43,45 This is particularly problematic in patients who present late with advanced respiratory failure, and mortality is higher compared with patients who receive NIV at an earlier stage.10 There are many reasons for failing NIV, including patient intolerance, inadequate augmentation of tidal volume, and problems with triggering. The response to NIV treatment needs to be closely monitored using arterial blood gases, respiratory rate, hemodynamics, and overall degree of respiratory distress. Patients who respond within 1–4 hours are consistently shown to have better outcomes.46 An initial reduction in respiratory rate is generally a good indicator of a positive response to NIV. Failure of or contraindications to NIV, or imminent cardiorespiratory arrest, should prompt endotracheal intubation and mechanical ventilation. Ideally this should be performed in the controlled setting of ICU, as intubation can precipitate a cardiovascular collapse in the setting of significant air trapping.8 Once intubation has been performed, hypoxemia can be corrected, usually with modest FiO2. Subsequently, respiratory acidosis is corrected slowly using low rates and tidal volumes guided by air pressures and expiratory phase. This approach is to limit auto-PEEP from air trapping, which can result in significant hemodynamic compromise and can be difficult to detect.47 In the first 12–24 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 the need for high inflation pressures to achieve tidal volume. High mean airway pressures may lead to a number of serious problems, including circulatory collapse, pneumothorax, or barotrauma. It is unclear whether pressure-controlled or pressure-limited ventilation is safer than volume control. Nevertheless, efforts should be made to minimize auto-PEEP and end inspiratory stretch.47 Weaning can pose problems in ventilated COPD patients, with 20–30% of those patients meeting the traditional extubation criteria failing trial of weaning.8 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.32 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.48 The study demonstrated improved outcomes in the noninvasive
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group, 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. Ornico and colleagues demonstrated a significant reduction of reintubation rates and in-hospital mortality when nasal NIV was commenced after planned extubation, as compared with continuous oxygen therapy.49 Risk factors for postextubation respiratory failure includes an age over 65 years, cardiac failure as a cause for respiratory distress, an APACHE 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 over 48 hours of mechanical ventilation and hypercapnea during a spontaneous breathing trial. If patients do develop postextubation respiratory distress, they should be reintubated, as persisting with NIV in this setting may worsen outcomes.50 High-flow nasal cannula (HFNC) oxygen therapy was recently been shown to be at least as effective as NIV in reducing reintubation rates (see below).
HFNC Oxygen Therapy HFNC oxygen therapy is now widely used for the treatment of both hypoxic and hypercapnic respiratory failure in COPD. HFNC delivers humidified and heated air at flows up to 60 L/min and FiO2 from 21% to 100%. HFNC is postulated to reduce anatomical dead space and provide 4–5 cm H2O of positive end-expiratory pressure (PEEP).51 HFNC has been shown to significantly decrease dyspnea in patients with acute respiratory failure, when compared with conventional therapy.52 In the FLORALI trial, HFNC was noninferior to NIV in preventing intubation of patients with hypoxic respiratory failure, but patients that were intubated spent less time on mechanical ventilation and had significantly reduced 90-day mortality.53 HFNC has also been shown to reduce the rates of reintubation, when compared with conventional therapy and NIV.54,55 The use of HFNC in hypercapnic respiratory failure is expanding. Kim and colleagues51 retrospectively examined a small cohort of patients who presented principally with pneumonia, hypercarbia, and hypoxemia over a 2-year period. Compared with conventional oxygen therapy, which increased PaCO2, HFNC was associated with a reduction in PaCO2 by 4.2 6 5.5 and 3.7 6 10.8 mm Hg at 1 and 24 hours, respectively.51 Lee and colleagues compared HFNC oxygen therapy to NIV in hypercapnic respiratory failure in 92 patients. They found no difference in 30-day mortality or intubation rates between both groups,56 nor in pH, PaO2 or PaCO2 after 24 hours. Jeong et al. showed that HFNC reduced hypercapnia but did not prevent progression to NIV or invasive ventilation.57 Finally, a study of 604 patients found that HFNC was not inferior to NIV for preventing postextubating respiratory failure.55 Although these are small studies, HFNC could be used as an adjunct in patients with respiratory failure, particularly as an alternative to conventional oxygen therapy, particularly those failing NIV and after extubation. It is worth noting that many of these trials are not specific to COPD and further research is required.
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PROGNOSIS AND OUTCOMES Despite reasonable survival to hospital discharge, the decision to admit to the ICU in advanced cases is difficult and there is no consensus. One has to take into account expected prognosis, comorbidities and estimate likely quality of life assuming survival to hospital discharge. Factors affecting the decision to mechanically ventilate include cultural attitudes towards disability, perceived impact of treatment, financial resources, the availability of ICU and longterm ventilator beds, local medical practice, and patient wishes. Past perception has been that survival following ICU admission was poor, especially in those deemed to have severe or end-stage disease. However, short-term survival following invasive mechanical ventilation ranges from 63% to 86%, more than would be expected in unplanned medical admissions.58 In addition, survival following mechanical ventilation has been shown to be better in the absence of a major precipitating cause for acute deterioration, perhaps as shorter periods of assisted ventilation are required and thus length of ICU stay and associated complications are lessened.59 However, a difficulty still remains in identifying those patients most likely to derive benefit from aggressive management. Longterm survival rates are not quite as encouraging as survival to discharge figures. Rates of 52%, 42%, and 37% at 1, 2, and 3 years, respectively, were reported in one UK study60 and similar numbers have been reported from other centers. Poor prognostic indicators include: • Increased age; presence of severe respiratory disease • Increased length of stay in hospital before ICU admission • Cardiopulmonary resuscitation within 24 hours before admission • Low Pao2/FiO2 gradient • Hypercapnea • Low serum albumin • Low body mass index (BMI) • Cardiovascular organ failure; neurologic organ failure; and renal organ failure While all of these factors have been associated with increased in-hospital mortality,61 there is currently no reliable or definitive method for identifying patients at high risk of inpatient or 6-month mortality. Therefore, these parameters should not influence decisions about instituting, continuing, or withdrawing life-sustaining treatment. A small 2001 study of 166 COPD patients requiring mechanical ventilation found that absence of comorbid condition more than halved in-hospital mortality rates (28% vs. 12%).62 A higher mortality rate among those patients who required .72 hours of mechanical ventilation (37% vs. 16%), those without previous episodes of mechanical ventilation (33% vs. 11%), and those with a failed extubation attempt (36% vs. 11%) was also noted. Further larger studies would be helpful to assist in decision making. While the above material can guide treatment decisions, patient preference represents an essential component of our
assessment. A prospective cohort study carried out in 92 ICUs and 3 respiratory high dependency units in the UK examined outcomes in patients with COPD admitted to the ICU for decompensated hypercarbic respiratory failure, including survival and quality of life at 180 days.63 Of the survivors, 73% considered their quality of life to be the same as or better than it had been in the stable period before they were admitted, and 96% would choose similar treatment again. The GOLD guidelines state that acute mortality among COPD patients is lower than patients ventilated for nonCOPD causes. However, there is evidence that patients are denied admission to intensive care for intubation due to excessive prognostic pessimism.64 Taking all of this into account, current treatment guidelines suggest that failure of NIV in most cases should be followed by a short trial of invasive mechanical ventilation. Early reevaluation is then recommended. Patient wishes play an important role in this decision and advances directives based on discussion, ideally occurring during a medically stable period, regarding risks and complications of invasive ventilation are advocated.
END-OF-LIFE DECISIONS IN SEVERE COPD In the severe and end-stage COPD patient population, decisions regarding end-of-life care and palliation should be addressed. Factors that may lead to an end-of-life discussion include65: • FEV1 below 30% predicted • Oxygen dependence • Requirement of domiciliary NIPPV (noninvasive positive pressure ventilation) • One or more hospital admissions in the past year with an acute exacerbation of COPD • Weight loss or cachexia • Decreased functional status/decreased independence • Age over 70 years • On maximal medical management A retrospective study performed in the Mayo Clinic,66 involving 591 patients admitted to ICU with an acute exacerbation of COPD, found that the factors most associated with a poor 1-year mortality were age and length of hospital stay. These patients may benefit from early communication regarding end of life and palliation, prior to their next hospital admission. As COPD is a chronic progressive disease, there is opportunity to have the discussion early, with the knowledge that in severe and end-stage COPD patients, they will likely require more aggressive care (e.g., mechanical ventilation), with a possibly fatal outcome in an unpredictably acute setting. Given the opportunity, three primary end-of-life topics can be discussed32: • Their disease course and likely prognosis • Establishing a ceiling of care • Symptom management and control Knowing their own disease course allows patients to participate in their management strategy and provides context for the acute decisions made during an exacerbation. When discussed early in the course of the disease, it may improve
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compliance with therapy, and towards more end-stage disease, it allows patients to know what to expect and make informed end-of-life decisions, including establishing the ceiling of care and whether or not to be admitted to intensive care for ventilation. In a French study regarding patients with COPD admitted to intensive care, only 56% of patients had discussed intensive care as a possibility with their physician.67 A ceiling of care can be established by considering the patient’s comorbidities and prognosis, but it is also important to consider the patient’s quality of life, the functionality of activities of daily living, and their wishes with regards to their treatment. In particular, deciding whether the patient should be for mechanical ventilation in an ICU or for a trial of noninvasive ventilation should be established if possible. The SUPPORT trial published in 2000 compared patients with stage III and IV lung cancer with severe COPD, and found that 60% of patients in each group wanted comfort-focused care.68
AUTHORS’ RECOMMENDATIONS • COPD accounts for a large proportion of medical ICU admissions; 25% of COPD patients will require ICU at some stage in their disease. Half of those will not survive 1 year. • The majority of acute exacerbations of COPD are associated with viral or bacterial infection. • The DECAF (Dyspnea, Eosinophilia, Consolidation, Acidemia, and Atrial Fibrillation) score may be used to predict mortality. • Oxygen therapy, corticosteroids, beta-adrenoceptor agonists and anticholinergic agents continue to be the mainstay of therapy. Methylxanthines are probably ineffective. • Noninvasive ventilation (NIV) is effective and economical in moderate to severe cases and is associated with reduced mortality, reduced invasive ventilation, and nosocomial complications. • In severe cases intubation is necessary, and extreme care is required to control dyssynchrony, auto-PEEP, and end-inspiratory lung stretch. • Weaning and liberation can be difficult. Extubation to NIV may shorted duration of ICU and hospital stay. • High-flow nasal cannula oxygen therapy may be a useful adjuvant for patients with hypoxic or hypercapnic respiratory failure, failing NIV or postintubation. • Advanced age, low body weight, cardiovascular disease, and multiple previous ICU admissions predict poor outcomes in COPD, although no specific scoring system exists. Advanced directives and treatment limitation planning should be undertaken.
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3. Lee CH, Lee MC, Lin HH, et al. Pulmonary tuberculosis and delay in anti-tuberculous treatment are important risk factors for chronic obstructive pulmonary disease. PLoS One. 2012;7(5):e37978. 4. Fuhrman C, Roche N, Vergnenègre A, Zureik M, Chouaid C, Delmas MC. Hospital admissions related to acute exacerbations of chronic obstructive pulmonary disease in France, 1998-2007. Respir Med. 2011;105(4):595-601. 5. Public Health Agency of Canada. Life and breath: respiratory disease in Canada. 2007. Available at http://publications.gc.ca/ pub?id59.690355&sl50. Accessed October 10, 2018. 6. Trerotoli P, Bartolomeo N, Moretti AM, Serio G. Hospitalisation for COPD in Puglia: the role of hospital discharge database to estimate prevalence and incidence. Monaldi Arch Chest Dis. 2008;69(3):94-106. 7. Wilson DH, Tucker G, Frith P, Appleton S, Ruffin RE, Adams RJ. Trends in hospital admissions and mortality from asthma and chronic obstructive pulmonary disease in Australia, 1993-2003. Med J Aust. 2007;186(8):408-411. 8. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (Gold Report). 2018. Available at http://www.goldcopd.com. Accessed October 10, 2018. 9. Davidson AC. The pulmonary physician in critical care: 11: critical care management of respiratory failure resulting from COPD. Thorax. 2002;57(12):1079-1084. 10. Chandra D, Stamm JA, Taylor B, et al. Outcomes of noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease in the United States, 1998-2008. Am J Respir Crit Care Med. 2012;185(2):152-159. 11. Papi A, Bellettato CM, Braccioni F, et al. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med. 2006;173(10):1114-1121. 12. Soler N, Torres A, Ewig S, et al. Bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation. Am J Respir Crit Care Med. 1998;157(5 Pt 1):1498-1505. 13. Monsó E, Ruiz J, Rosell A, et al. Bacterial infection in chronic obstructive pulmonary disease: a study of stable and exacerbated outpatients using the protected specimen brush. Am J Respir Crit Care Med. 1995;152(4 Pt 1):1316-1320. 14. Rutschmann OT, Cornuz J, Poletti PA, et al. Should pulmonary embolism be suspected in exacerbation of chronic obstructive pulmonary disease? Thorax. 2007;62(2):121-125. 15. Snow V, Lascher S, Mottur-Pilson C, et al. Evidence base for management of acute exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. 2001;134(7):595-599. 16. Wood-Baker RR, Gibson PG, Hannay M, Walters EH, Walters JA. Systemic corticosteroids for acute exacerbations of chronic obstructive airway disease. Cochrane Database Syst Rev. 2005;(1): CD001288. 17. Bigatao AM, Herbella FAM, Del Grande LM, Nascimento OA, Jardim JR, Patti MG. Chronic obstructive pulmonary disease exacerbations are influenced by gastroesophageal reflux disease. Am Surg. 2018;84(1):51-55. 18. Ingebrigtsen TS, Marott JL, Vestbo J, Nordestgaard BG, Hallas J, Lange P. Gastro-esophageal reflux disease and exacerbations in chronic obstructive pulmonary disease. Respirology. 2015; 20(1):101-107. 19. Donaldson GC, Hurst JR, Smith CJ, Hubbard RB, Wedzicha JA. Increased risk of myocardial infarction and stroke following exacerbation of COPD. Chest. 2010;137(5):1091-1097.
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20. Aleva FE, Voets LWLM, Simons SO, de Mast Q, van der Ven AJAM, Heijdra YF. Prevalence and localization of pulmonary embolism in unexplained acute exacerbations of COPD: a systematic review and meta-analysis. Chest. 2017;151(3):544-554. 21. Steer J, Gibson J, Bourke SC. The DECAF Score: predicting hospital mortality in exacerbations of chronic obstructive pulmonary disease. Thorax. 2012;67(11):970-976. 22. Anzueto A. Impact of exacerbations on COPD. Eur Respir Rev. 2010;19(116):113-118. 23. Lightowler JV, Elliott MW. Predicting the outcome from NIV for acute exacerbations of COPD. Thorax. 2000;55(10):815-816. 24. Budweiser S, Jörres RA, Riedl T, et al. Predictors of survival in COPD patients with chronic hypercapnic respiratory failure receiving noninvasive home ventilation. Chest. 2007;131(6):1650-1658. 25. Murphy PB, Rehal S, Arbane G, et al. Effect of home noninvasive ventilation with oxygen therapy vs oxygen therapy alone on hospital readmission or death after an acute COPD exacerbation: a randomized clinical trial. JAMA. 2017;317(21):2177-2186. 26. Tillie-Leblond I, Marquette CH, Perez T, et al. Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease: prevalence and risk factors. Ann Intern Med. 2006;144(6):390-396. 27. de Jong YP, Uil SM, Grotjohan HP, Postma DS, Kerstjens HA, van den Berg JW. Oral or IV prednisolone in the treatment of COPD exacerbations: a randomized, controlled, double-blind study. Chest. 2007;132(6):1741-1747. 28. Nouira S, Marghli S, Belghith M, Besbes L, Elatrous S, Abroug F. Once daily oral ofloxacin in chronic obstructive pulmonary disease exacerbation requiring mechanical ventilation: a randomized placebo-controlled trial. Lancet. 2001;358(9298):2020-2025. 29. O’Driscoll BR, Taylor RJ, Horsley MG, Chambers DK, Bernstein A. Nebulised salbutamol with and without ipratropium bromide in acute airflow obstruction. Lancet. 1989;1(8652):1418-1420. 30. Barr RG, Rowe BH, Camargo Jr CA. Methylxanthines for exacerbations of chronic obstructive pulmonary disease: metaanalysis of randomized trials. BMJ. 2003;327(7416):643. 31. Falagas ME, Avgeri SG, Matthaiou DK, Dimopoulos G, Siempos II. Short- versus long-duration antimicrobial treatment for exacerbations of chronic bronchitis: a meta-analysis. J Antimicrob Chemother. 2008;62(3):442-450. 32. Dean MM. End-of-life care for COPD patients. Prim Care Respir J. 2008;17(1):46-50. 33. Karpel JP. Bronchodilator responses to anticholinergic and beta-adrenergic agents in acute and stable COPD. Chest. 1991; 99(4):871-876. 34. Maltais F, Ostinelli J, Bourbeau J, et al. Comparison of nebulised budesonide and oral prednisolone with placebo in the treatment of acute exacerbation of COPD: a randomized control trial. Am J Respir Crit Care Med. 2002;165(5):698-703. 35. Bateman ED, Ferguson GT, Barnes N, et al. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur Respir J. 2013;42(6):1484-1494. 36. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone: an 85-day multicenter trial. COMBIVENT Inhalation Aerosol Study Group. Chest. 1994;105(5):1411-1419. 37. Vollenweider DJ, Frei A, Steurer-Stey CA, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2018;29;10:CD010257. 38. Huang DT, Yealy DM, Filbin MR, et al. Procalcitonin-guided use of antibiotics for lower respiratory tract infection. N Engl J Med. 2018;379(3):236-249.
39. Global Initiative for Chronic Obstructive Lung Disease (2019 report). Available at https://goldcopd.org/wp-content/ uploads/2018/11/GOLD-2019-v1.7-FINAL. 40. Austin MA, Wills KE, Blizzard L, Walters EH, Wood-Baker R. Effect of high flow oxygen on mortality in chronic obstructive pulmonary disease patients in prehospital setting: randomised controlled trial. BMJ. 2010;341:c5462. 41. Antonelli M, Conti G, Rocco M, et al. A comparison of noninvasive positive-pressure ventilation and conventional mechanical ventilation in patients with acute respiratory failure. N Engl J Med. 1998;339(7):429-435. 42. Brochard L, Mancebo J, Wysocki M, et al. Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med. 1995;333(13):817-822. 43. Moretti M, Cilione C, Tampieri A, Fracchia C, Marchioni A, Nava S. Incidence and causes of non-invasive mechanical ventilation failure after initial success. Thorax. 2000;55(10): 819-825. 44. Elliott MW, Confalonieri M, Nava S. Where to perform noninvasive ventilation? Eur Respir J. 2002;19(6): 1159-1166. 45. Alvesi V, Romanello A, Badet M, Gaillard S, Philit F, Guérin C. Time course of expiratory flow limitation in COPD patients during acute respiratory failure requiring mechanical ventilation. Chest. 2003;123(5):1625-1632. 46. Nevins ML, Epstein SK. Predictors of outcome for patients with COPD requiring invasive mechanical ventilation. Chest. 2001;119(6):1840-1849. 47. Plant PK, Elliott MW. Chronic obstructive pulmonary disease. 9. Management of ventilatory failure in COPD. Thorax. 2003; 58(6):537-542. 48. Nava S, Ambrosino N, Clini E, et al. Noninvasive mechanical ventilation in the weaning of patients with respiratory failure due to chronic obstructive pulmonary disease. A randomized, controlled trial. Ann Intern Med. 1998;128(9): 721-728. 49. Ornico SR, Lobo SM, Sanches HS, et al. Noninvasive ventilation immediately after extubation improves weaning outcome after acute respiratory failure: a randomized controlled trial. Crit Care. 2013;17(2):R39. 50. Esteban A, Frutos-Vivar F, Ferguson ND, et al. Noninvasive positive-pressure ventilation for respiratory failure after extubation. N Engl J Med. 2004;350(24):2452-2460. 51. Kim ES, Lee H, Kim SJ, et al. Effectiveness of high-flow nasal cannula oxygen therapy for acute respiratory failure with hypercapnia. J Thorac Dis. 2018;10(2):882-888. 52. Lenglet H, Sztrymf B, Leroy C, Brun P, Dreyfuss D, Ricard JD. Humidified high flow nasal oxygen during respiratory failure in the emergency department: feasibility and efficacy. Respir Care. 2012;57(11):1873-1878. 53. Frat JP, Thille AW, Mercat A, et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med. 2015;372(23):2185-2196. 54. Hernández G, Vaquero C, González P, et al. Effect of postextubation high-flow nasal cannula vs conventional oxygen therapy on reintubation in low-risk patients: a randomized clinical trial. JAMA. 2016;315(13):1354-1361. 55. Hernández G, Vaquero C, Colinas L, et al. Effect of postextubation high-flow nasal cannula vs noninvasive ventilation on reintubation and postextubation respiratory failure in highrisk patients: a randomized clinical trial. JAMA. 2016;316(15): 1565-1574.
CHAPTER 11 56. Lee MK, Choi J, Park B, et al. High flow nasal cannulae oxygen therapy in acute-moderate hypercapnic respiratory failure. Clin Respir J. 2018;12(6):2046-2056. 57. Jeong JH, Kim DH, Kim SC, et al. Changes in arterial blood gases after use of high-flow nasal cannula therapy in the ED. Am J Emerg Med. 2015;33(10):1344-1349. 58. Seneff MG, Wagner DP, Wagner RP, Zimmerman JE, Knaus WA. Hospital and 1-year survival of patients admitted to intensive care units with acute exacerbation of chronic obstructive pulmonary disease. JAMA. 1995;274(23):1852-1857. 59. Breen D, Churches T, Hawker F, Torzillo PJ. Acute respiratory failure secondary to chronic obstructive pulmonary disease treated in the intensive care unit: a long term follow up study. Thorax. 2002;57(1):29-33. 60. Sapey E, Stockley RA. COPD exacerbations. 2: aetiology. Thorax. 2006;61(3):250-258. 61. Wildman MJ, Harrison DA, Brady AR, Rowan K. Case mix and outcomes for admissions to UK adult, general critical care units with chronic obstructive pulmonary disease: a secondary analysis of the ICNARC Case Mix Programme Database. Crit Care. 2005;9(suppl 3):S38-S48. 62. Nevins ML, Epstein SK. Predictors of outcome for patients with COPD requiring invasive mechanical ventilation. Chest. 2001;119(6):1840-1849.
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63. Wildman MJ, Sanderson CF, Groves J, et al. Survival and quality of life for patients with COPD or asthma admitted to intensive care in a UK multicentre cohort: the COPD and Asthma Outcome Study (CAOS). Thorax. 2009;64(2):128-132. 64. Wildman MJ, Sanderson C, Groves J, et al. Implications of prognostic pessimism in patients with chronic obstructive pulmonary disease (COPD) or asthma admitted to intensive care in the UK within the COPD and asthma outcome study (CAOS): multicentre observational cohort study. BMJ. 2007;335(7630):1132. 65. Patel K, Janssen DJ, Curtis JR. Advance care planning in COPD. Respirology. 2012;17(1):72-78. 66. Batzlaff CM, Karpman C, Afessa B, Benzo RP. Predicting 1-year mortality rate for patients admitted with an acute exacerbation of chronic obstructive pulmonary disease to an intensive care unit: an opportunity for palliative care. Mayo Clin Proc. 2014;89(5):638-643. 67. Schmidt M, Demoule A, Deslandes-Boutmy E, et al. Intensive care unit admission in chronic obstructive pulmonary disease: patient information and the physician’s decision-making process. Crit Care. 2014;18(3):R115 68. Claessens MT, Lynn J, Zhong Z, et al. Dying with lung cancer or chronic obstructive pulmonary disease: insights from SUPPORT. Study to understand prognoses and preferences for outcomes and risks of treatments. J Am Geriatr Soc. 2000;48(suppl 5):S146-S153.
e1 Abstract: Chronic obstructive pulmonary disease (COPD) is increasing in prevalence and accounts for up to 10% of acute emergency medical hospital admissions and 2% of nonsurgical referrals to the intensive care unit (ICU). Acute admission with COPD is associated with as high as an 11% acute mortality and 43% 1-year m ortality, and a 50% readmission rate within 6 months. While it is difficult to predict the acute outcome of ICU admissions in COPD, late failure of ward-based care, comorbidities and severe disease may aid in establishing appropriate ceilings of care. Pharmacologic treatment remains corticosteroids, nebulized bronchodilators, and anti biotics. Oxygen should be titrated in a controlled manner in COPD to oxygen saturation of 88–90%. This has been shown to reduce mortality. Noninvasive ventilation has evolved into the most effective treatment for acute hypercapnic respiratory
failure, with better outcome in mortality and length of stay compared with invasive ventilation. Clinicians must be aware of barotrauma and dynamic hyperinflation when using positive pressure ventilation in COPD. High-flow nasal oxygen is evolving as an effective therapy to assist extubation as well as treat acute respiratory failure in COPD. Further studies are required. End-of-life decisions can be assisted by early discussion in those with severe disease, especially with comorbid illness, and in those with prolonged intubation over 72 hours and failed extubation. Some studies have shown that patients with COPD describe same or improved quality of life after invasive ventilation in the ICU; so it can be difficult to predict impact and outcomes. Keywords: COPD exacerbation, noninvasive ventilation, high-flow oxygen, prevalence, mortality
11 How Should Exacerbations of COPD Be Managed in the Intensive Care Unit? Christina Campbell, Tara Cahill, and Anthony O’Regan
PREVALENCE OF COPD The Global Burden of Disease (GBD) project ranked chronic obstructive pulmonary disease (COPD) 8th of the 315 causes of the Global Burden of Disease in 2015.1 It estimated 3.2 million people died from COPD worldwide in 2015; this is an increase of 11% from 1990, despite a decrease in the overall age-standardized death rate of 42%. The prevalence of COPD increased by 44% in the same period. Worldwide, COPD affects 105 million males and 70 million females, with an age-standardized prevalence of 3% in males and 2% in females. However, age-standardized disability-adjusted life years (DALYs) rates in males are almost double the rates in females, which reflects a higher male-to-female ratio for mortality than prevalence.1 Smoking and exposure to ambient particulate matter are the main risk factors for development of COPD, followed by household air pollution, occupational exposures, ozone, and environmental tobacco smoke.1 In countries with a higher sociodemographic index (SDI), smoking contributes to 69% of COPD burden, whereas environmental risks are more prevalent in lower SDI countries, contributing to 58% of COPD cases.1 A significant proportion of COPD remains unexplained. The GBD group plan to expand their data to include a personal history of pulmonary tuberculosis as a risk factor, given the emergence of evidence for a causal relationship.1–3 A 2011 French study had demonstrated that exacerbations of COPD contribute to 1.6–2.6% of all medical admissions.4 Of these admissions, in-hospital mortality were 6–8%, with the mortality rates in males being significantly higher than in females (6–9% vs. 5–7%, respectively). The rates of COPD admission increased by 38% from 1998 to 2007, despite a drop in inpatient lethality from 7.6% to 6%.5 The US National Hospital Discharge Survey reported an increase in admissions between 1990 and 1999.5 Data from Italy, Australia, and Canada show similar trends.5–7 This may reflect improving care, leading to longer life expectancy and thus more admissions. 74
As expected, admission rates increase with age, particularly over 45 years and show a definite seasonal pattern, related to the peaks of prevalence of influenza-like illnesses.4 Acute episodes of respiratory failure in patients with COPD are estimated to account for between 5% and 10% of acute emergency hospital medical admissions. Failure of first-line medical treatment is a common source of intensive care unit (ICU) referrals, accounting for 2–3% of non-surgical ICU admissions.8 In a cohort of 1016 patients who were hospitalized for acute exacerbations, half of whom required intensive care, the in-hospital mortality rate was 11%.9 The 6-month and 1-year mortality rates 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 not completely understood but may be precipitated by any condition that increases the work of breathing. 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 believed to reflect problems with respiratory drive as suggested by the concept of “pink puffers and 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 pathophysiology, the presence of hypercapnea and the need for assisted ventilation identify patients that have high initial (up to 27%) and 12-month mortality (up to 50%).10
CLINICAL PRECIPITANTS OF RESPIRATORY FAILURE It has been shown that viral and bacterial infections account for between 50% and 70% of acute exacerbations and the
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majority of cases of acute respiratory failure in COPD.11,12 Numerous viral and bacterial agents have been implicated, but rhinoviruses, respiratory syncytial virus, Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae are the most common pathogens.12–15 Pseudomonas aeruginosa, Enterobacteriaceae, and Stenotrophomonas spp. are also frequently isolated, particularly from patients with severe COPD and those requiring mechanical ventilation.16 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. There is growing body of evidence that gastroesophageal reflux disease contributes to acute exacerbations in the COPD population,17 particularly those not on acid suppressive therapies.18 For many other cases the etiology of acute exacerbations is not 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 Towards 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%. A further study has demonstrated patients are at a higher risk of myocardial infarction or stroke following an exacerbation of COPD, possibly due to higher rates of systemic inflammation following exacerbations of COPD.19 Pulmonary embolism (PE) can be an occult cause of acute respiratory failure in COPD. A systematic review found that 16% of patients with an exacerbation of COPD had a PE, but other studies report a lower incidence at presentation to hospital.20 Signs of infection were seen less commonly with PE, with pleuritic chest pain and cardiac failure being more common.20
PROGNOSTIC INDICATORS IN PATIENTS WITH ACUTE EXACERBATIONS OF COPD There are several potential prognostic indicators that should be considered when admitting a patient to 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 UK in 2012: dyspnea, eosinophilia, consolidation, acidemia, and atrial fibrillation.21 As a combined score, this has been shown to be a stronger predictor of mortality than the CURB-65 score in patients with COPD and pneumonia, and as such, is a useful triage tool. Other factors commonly cited in literature include patients’ age, their forced expiratory volume in 1 second (FEV1), 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
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mortality, leading to a faster decline in lung function and quality of life.22 The 2-year mortality after a COPD exacerbation is approximately 50%. Finally, a patient who has failed adequate treatment for a COPD exacerbation over 48 hours (“late failure”) has a very poor prognosis in the setting of escalation to invasive mechanical ventilation.23 Patients with chronic hypercapnic 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 hypercapnia (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.24 They also found that in a cohort of COPD patients sent home from hospital on NIV, the 5-year survival rate was 26.4%, with deaths predominantly from respiratory causes (73.8%). A recent study demonstrated that domiciliary NIV following an exacerbation prolongs time to next admission if patients are selected for persistent hypercapnia at 4 weeks post discharge and NIV is titrated to normalize pCO2.25
MANAGEMENT OF COPD The treatment guidelines for management of acute exacerbation of COPD requiring admission to ICU are broadly similar to those principles employed 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. Compensated chronic respiratory failure can rapidly decompensate due to poor chest wall mechanics, suboptimal respiratory muscle function, malnutrition, obesity, and myopathy. Reducing the work of breathing using NIV to improve oxygenation, 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 (confusion, drowsiness, or coma), persistent or worsening hypoxemia, and/or severe or worsening hypercapnia, acidosis, or hemodynamic instability.26
Corticosteroids A number of randomized controlled trials (RCTs) have shown that for patients hospitalized with acute exacerbations of COPD, systemic corticosteroids administered for up to 2 weeks are helpful.27 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.28 Corticosteroids also reduce the duration of hospital stay.29 The optimal dose and need for tapering, route of administration, and length of treatment are uncertain. Most recent guidelines suggest intravenous corticosteroids should be given to patients who present with 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
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Non-ARDS and Noninfectious Respiratory Disorders
heart failure). Nonetheless, if tolerated, oral corticosteroid administration is equally effective as intravenous.30 There appears to be no benefit to prolonged treatment beyond 2 weeks.31 There is a significant side-effect profile, the most common side effect being hyperglycemia occurring in approximately 15%.31 Studies have shown that nebulized steroid therapy is superior to placebo but not better than parenteral therapy.32
Bronchodilators Inhaled short-acting beta-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. RCTs have consistently demonstrated their efficacy.27 Parenteral or subcutaneous injection of short-acting beta-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 via a nebulizer or a metered dose inhaler (MDI) with a spacer device; however, despite evidence that neither method has been shown to be superior, physicians tend to favor the nebulized route, due to the ease of administration. Patients should revert to appropriate inhaled preparations as soon as possible. Anticholinergic bronchodilators, such as ipratropium, are equally efficacious,33 and some studies have found that combination therapy with inhaled beta-agonists provides better bronchodilation than either alone.34 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. These dual bronchodilators have been shown to improve symptoms and lung function in COPD patients where single bronchodilators may be insufficient,35 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 meta-analysis of four RCTs recommend that theophylline should not be used in the acute setting, as efficacy beyond that induced by inhaled bronchodilator and glucocorticoid therapy has not been demonstrated. In addition to lack of efficacy, methylxanthines have caused significantly more nausea and vomiting than placebo and trended toward more frequent tremor, palpitations, and arrhythmias.36
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.37 Other studies show inconsistent benefit from antibiotics, but the decision to withhold antimicrobials is difficult and potentially risky in severe exacerbations. Unfortunately, early
investigations using inflammatory markers such as procalcitonin have not shown a reduction in antibiotic use.38 Current guidelines suggest the use of antimicrobials with a spectrum of activity to cover beta-lactamase-producing organisms. While choice is somewhat dependent on the local streptococcal resistance patterns, amoxicillin–clavulanic acid, second-generation cephalosporin, or macrolides are all acceptable. A treatment of 3–7 days is recommended (GOLD).39 Wider-spectrum antibiotics such as fluoroquinolones or beta-lactam with antipseudomonal activity should be used in those at risk of resistant gram-negative infections (i.e., recent hospitalization, previous colonization, previous severe exacerbation or ,4 exacerbations per year) or prior culture for pseudomonas.
Oxygen Therapy Adequate oxygenation can be achieved in most patients with acute exacerbations of COPD. Ventilation–perfusion mismatch is usually improved by 24–28% oxygen. There appears to be a tendency to develop CO2 retention at FiO2 . 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. Controlled or titrated oxygen therapy has been shown to significantly reduce hypercapnia, acidosis, and mortality.40 In critical care, the use of high-flow facemasks or nasal devices provides better titration of oxygen therapy compared to simple facemasks or nasal cannulae, Venturi masks or other variable performance devices.
Assisted Ventilation Recognition of need for assisted ventilation is essential and should be considered in any patient with type 2 or hypercapnic respiratory failure. NIV is definitely indicated if the pH remains ,7.32 and probably indicated if the pH remains ,7.36. Studies have shown that pH and degree of hypercapnia are better predictors of need for mechanical ventilation than hypoxia.41 There are a number of absolute and relative contraindications to NIV: • Respiratory arrest • Impaired level of consciousness • Cardiovascular collapse • Profound hypoxemia (ARDS) • Vomiting or very high aspiration risk due to excessive secretions • Uncooperative patient • Extreme obesity • Recent facial surgery • Burns A number of RTCs have validated the use of NIV in the setting of acute hypercapnic respiratory failure in COPD42 and indeed several studies have demonstrated the superiority of NIV over tracheal intubation and mechanical ventilation. NIV reduces intubation by up to 42%42 and appears to reduce nosocomial complications and mortality.42,43 Some studies have also found that patients with COPD who were randomly assigned to NIV had a shorter stay in the ICU. The use of
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NIV has certainly improved care for many COPD sufferers 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 5–20%. Studies have shown that staff training and experience are more important than location in regards to NIV, and can be given effectively outside of the ICU.44 However, when patients are admitted to intensive care, presumably in worse clinical condition, the failure rate is up to 60%.43,45 This is particularly problematic in patients who present late with advanced respiratory failure, and mortality is higher compared with patients who receive NIV at an earlier stage.10 There are many reasons for failing NIV, including patient intolerance, inadequate augmentation of tidal volume, and problems with triggering. The response to NIV treatment needs to be closely monitored using arterial blood gases, respiratory rate, hemodynamics, and overall degree of respiratory distress. Patients who respond within 1–4 hours are consistently shown to have better outcomes.46 An initial reduction in respiratory rate is generally a good indicator of a positive response to NIV. Failure of or contraindications to NIV, or imminent cardiorespiratory arrest, should prompt endotracheal intubation and mechanical ventilation. Ideally this should be performed in the controlled setting of ICU, as intubation can precipitate a cardiovascular collapse in the setting of significant air trapping.8 Once intubation has been performed, hypoxemia can be corrected, usually with modest FiO2. Subsequently, respiratory acidosis is corrected slowly using low rates and tidal volumes guided by air pressures and expiratory phase. This approach is to limit auto-PEEP from air trapping, which can result in significant hemodynamic compromise and can be difficult to detect.47 In the first 12–24 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 the need for high inflation pressures to achieve tidal volume. High mean airway pressures may lead to a number of serious problems, including circulatory collapse, pneumothorax, or barotrauma. It is unclear whether pressure-controlled or pressure-limited ventilation is safer than volume control. Nevertheless, efforts should be made to minimize auto-PEEP and end inspiratory stretch.47 Weaning can pose problems in ventilated COPD patients, with 20–30% of those patients meeting the traditional extubation criteria failing trial of weaning.8 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.32 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.48 The study demonstrated improved outcomes in the noninvasive
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group, 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. Ornico and colleagues demonstrated a significant reduction of reintubation rates and in-hospital mortality when nasal NIV was commenced after planned extubation, as compared with continuous oxygen therapy.49 Risk factors for postextubation respiratory failure includes an age over 65 years, cardiac failure as a cause for respiratory distress, an APACHE 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 over 48 hours of mechanical ventilation and hypercapnea during a spontaneous breathing trial. If patients do develop postextubation respiratory distress, they should be reintubated, as persisting with NIV in this setting may worsen outcomes.50 High-flow nasal cannula (HFNC) oxygen therapy was recently been shown to be at least as effective as NIV in reducing reintubation rates (see below).
HFNC Oxygen Therapy HFNC oxygen therapy is now widely used for the treatment of both hypoxic and hypercapnic respiratory failure in COPD. HFNC delivers humidified and heated air at flows up to 60 L/min and FiO2 from 21% to 100%. HFNC is postulated to reduce anatomical dead space and provide 4–5 cm H2O of positive end-expiratory pressure (PEEP).51 HFNC has been shown to significantly decrease dyspnea in patients with acute respiratory failure, when compared with conventional therapy.52 In the FLORALI trial, HFNC was noninferior to NIV in preventing intubation of patients with hypoxic respiratory failure, but patients that were intubated spent less time on mechanical ventilation and had significantly reduced 90-day mortality.53 HFNC has also been shown to reduce the rates of reintubation, when compared with conventional therapy and NIV.54,55 The use of HFNC in hypercapnic respiratory failure is expanding. Kim and colleagues51 retrospectively examined a small cohort of patients who presented principally with pneumonia, hypercarbia, and hypoxemia over a 2-year period. Compared with conventional oxygen therapy, which increased PaCO2, HFNC was associated with a reduction in PaCO2 by 4.2 6 5.5 and 3.7 6 10.8 mm Hg at 1 and 24 hours, respectively.51 Lee and colleagues compared HFNC oxygen therapy to NIV in hypercapnic respiratory failure in 92 patients. They found no difference in 30-day mortality or intubation rates between both groups,56 nor in pH, PaO2 or PaCO2 after 24 hours. Jeong et al. showed that HFNC reduced hypercapnia but did not prevent progression to NIV or invasive ventilation.57 Finally, a study of 604 patients found that HFNC was not inferior to NIV for preventing postextubating respiratory failure.55 Although these are small studies, HFNC could be used as an adjunct in patients with respiratory failure, particularly as an alternative to conventional oxygen therapy, particularly those failing NIV and after extubation. It is worth noting that many of these trials are not specific to COPD and further research is required.
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Non-ARDS and Noninfectious Respiratory Disorders
PROGNOSIS AND OUTCOMES Despite reasonable survival to hospital discharge, the decision to admit to the ICU in advanced cases is difficult and there is no consensus. One has to take into account expected prognosis, comorbidities and estimate likely quality of life assuming survival to hospital discharge. Factors affecting the decision to mechanically ventilate include cultural attitudes towards disability, perceived impact of treatment, financial resources, the availability of ICU and longterm ventilator beds, local medical practice, and patient wishes. Past perception has been that survival following ICU admission was poor, especially in those deemed to have severe or end-stage disease. However, short-term survival following invasive mechanical ventilation ranges from 63% to 86%, more than would be expected in unplanned medical admissions.58 In addition, survival following mechanical ventilation has been shown to be better in the absence of a major precipitating cause for acute deterioration, perhaps as shorter periods of assisted ventilation are required and thus length of ICU stay and associated complications are lessened.59 However, a difficulty still remains in identifying those patients most likely to derive benefit from aggressive management. Longterm survival rates are not quite as encouraging as survival to discharge figures. Rates of 52%, 42%, and 37% at 1, 2, and 3 years, respectively, were reported in one UK study60 and similar numbers have been reported from other centers. Poor prognostic indicators include: • Increased age; presence of severe respiratory disease • Increased length of stay in hospital before ICU admission • Cardiopulmonary resuscitation within 24 hours before admission • Low Pao2/FiO2 gradient • Hypercapnea • Low serum albumin • Low body mass index (BMI) • Cardiovascular organ failure; neurologic organ failure; and renal organ failure While all of these factors have been associated with increased in-hospital mortality,61 there is currently no reliable or definitive method for identifying patients at high risk of inpatient or 6-month mortality. Therefore, these parameters should not influence decisions about instituting, continuing, or withdrawing life-sustaining treatment. A small 2001 study of 166 COPD patients requiring mechanical ventilation found that absence of comorbid condition more than halved in-hospital mortality rates (28% vs. 12%).62 A higher mortality rate among those patients who required .72 hours of mechanical ventilation (37% vs. 16%), those without previous episodes of mechanical ventilation (33% vs. 11%), and those with a failed extubation attempt (36% vs. 11%) was also noted. Further larger studies would be helpful to assist in decision making. While the above material can guide treatment decisions, patient preference represents an essential component of our
assessment. A prospective cohort study carried out in 92 ICUs and 3 respiratory high dependency units in the UK examined outcomes in patients with COPD admitted to the ICU for decompensated hypercarbic respiratory failure, including survival and quality of life at 180 days.63 Of the survivors, 73% considered their quality of life to be the same as or better than it had been in the stable period before they were admitted, and 96% would choose similar treatment again. The GOLD guidelines state that acute mortality among COPD patients is lower than patients ventilated for nonCOPD causes. However, there is evidence that patients are denied admission to intensive care for intubation due to excessive prognostic pessimism.64 Taking all of this into account, current treatment guidelines suggest that failure of NIV in most cases should be followed by a short trial of invasive mechanical ventilation. Early reevaluation is then recommended. Patient wishes play an important role in this decision and advances directives based on discussion, ideally occurring during a medically stable period, regarding risks and complications of invasive ventilation are advocated.
END-OF-LIFE DECISIONS IN SEVERE COPD In the severe and end-stage COPD patient population, decisions regarding end-of-life care and palliation should be addressed. Factors that may lead to an end-of-life discussion include65: • FEV1 below 30% predicted • Oxygen dependence • Requirement of domiciliary NIPPV (noninvasive positive pressure ventilation) • One or more hospital admissions in the past year with an acute exacerbation of COPD • Weight loss or cachexia • Decreased functional status/decreased independence • Age over 70 years • On maximal medical management A retrospective study performed in the Mayo Clinic,66 involving 591 patients admitted to ICU with an acute exacerbation of COPD, found that the factors most associated with a poor 1-year mortality were age and length of hospital stay. These patients may benefit from early communication regarding end of life and palliation, prior to their next hospital admission. As COPD is a chronic progressive disease, there is opportunity to have the discussion early, with the knowledge that in severe and end-stage COPD patients, they will likely require more aggressive care (e.g., mechanical ventilation), with a possibly fatal outcome in an unpredictably acute setting. Given the opportunity, three primary end-of-life topics can be discussed32: • Their disease course and likely prognosis • Establishing a ceiling of care • Symptom management and control Knowing their own disease course allows patients to participate in their management strategy and provides context for the acute decisions made during an exacerbation. When discussed early in the course of the disease, it may improve
CHAPTER 11
compliance with therapy, and towards more end-stage disease, it allows patients to know what to expect and make informed end-of-life decisions, including establishing the ceiling of care and whether or not to be admitted to intensive care for ventilation. In a French study regarding patients with COPD admitted to intensive care, only 56% of patients had discussed intensive care as a possibility with their physician.67 A ceiling of care can be established by considering the patient’s comorbidities and prognosis, but it is also important to consider the patient’s quality of life, the functionality of activities of daily living, and their wishes with regards to their treatment. In particular, deciding whether the patient should be for mechanical ventilation in an ICU or for a trial of noninvasive ventilation should be established if possible. The SUPPORT trial published in 2000 compared patients with stage III and IV lung cancer with severe COPD, and found that 60% of patients in each group wanted comfort-focused care.68
AUTHORS’ RECOMMENDATIONS • COPD accounts for a large proportion of medical ICU admissions; 25% of COPD patients will require ICU at some stage in their disease. Half of those will not survive 1 year. • The majority of acute exacerbations of COPD are associated with viral or bacterial infection. • The DECAF (Dyspnea, Eosinophilia, Consolidation, Acidemia, and Atrial Fibrillation) score may be used to predict mortality. • Oxygen therapy, corticosteroids, beta-adrenoceptor agonists and anticholinergic agents continue to be the mainstay of therapy. Methylxanthines are probably ineffective. • Noninvasive ventilation (NIV) is effective and economical in moderate to severe cases and is associated with reduced mortality, reduced invasive ventilation, and nosocomial complications. • In severe cases intubation is necessary, and extreme care is required to control dyssynchrony, auto-PEEP, and end-inspiratory lung stretch. • Weaning and liberation can be difficult. Extubation to NIV may shorted duration of ICU and hospital stay. • High-flow nasal cannula oxygen therapy may be a useful adjuvant for patients with hypoxic or hypercapnic respiratory failure, failing NIV or postintubation. • Advanced age, low body weight, cardiovascular disease, and multiple previous ICU admissions predict poor outcomes in COPD, although no specific scoring system exists. Advanced directives and treatment limitation planning should be undertaken.
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Non-ARDS and Noninfectious Respiratory Disorders
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63. Wildman MJ, Sanderson CF, Groves J, et al. Survival and quality of life for patients with COPD or asthma admitted to intensive care in a UK multicentre cohort: the COPD and Asthma Outcome Study (CAOS). Thorax. 2009;64(2):128-132. 64. Wildman MJ, Sanderson C, Groves J, et al. Implications of prognostic pessimism in patients with chronic obstructive pulmonary disease (COPD) or asthma admitted to intensive care in the UK within the COPD and asthma outcome study (CAOS): multicentre observational cohort study. BMJ. 2007;335(7630):1132. 65. Patel K, Janssen DJ, Curtis JR. Advance care planning in COPD. Respirology. 2012;17(1):72-78. 66. Batzlaff CM, Karpman C, Afessa B, Benzo RP. Predicting 1-year mortality rate for patients admitted with an acute exacerbation of chronic obstructive pulmonary disease to an intensive care unit: an opportunity for palliative care. Mayo Clin Proc. 2014;89(5):638-643. 67. Schmidt M, Demoule A, Deslandes-Boutmy E, et al. Intensive care unit admission in chronic obstructive pulmonary disease: patient information and the physician’s decision-making process. Crit Care. 2014;18(3):R115 68. Claessens MT, Lynn J, Zhong Z, et al. Dying with lung cancer or chronic obstructive pulmonary disease: insights from SUPPORT. Study to understand prognoses and preferences for outcomes and risks of treatments. J Am Geriatr Soc. 2000;48(suppl 5):S146-S153.
e1 Abstract: Chronic obstructive pulmonary disease (COPD) is increasing in prevalence and accounts for up to 10% of acute emergency medical hospital admissions and 2% of nonsurgical referrals to the intensive care unit (ICU). Acute admission with COPD is associated with as high as an 11% acute mortality and 43% 1-year m ortality, and a 50% readmission rate within 6 months. While it is difficult to predict the acute outcome of ICU admissions in COPD, late failure of ward-based care, comorbidities and severe disease may aid in establishing appropriate ceilings of care. Pharmacologic treatment remains corticosteroids, nebulized bronchodilators, and anti biotics. Oxygen should be titrated in a controlled manner in COPD to oxygen saturation of 88–90%. This has been shown to reduce mortality. Noninvasive ventilation has evolved into the most effective treatment for acute hypercapnic respiratory
failure, with better outcome in mortality and length of stay compared with invasive ventilation. Clinicians must be aware of barotrauma and dynamic hyperinflation when using positive pressure ventilation in COPD. High-flow nasal oxygen is evolving as an effective therapy to assist extubation as well as treat acute respiratory failure in COPD. Further studies are required. End-of-life decisions can be assisted by early discussion in those with severe disease, especially with comorbid illness, and in those with prolonged intubation over 72 hours and failed extubation. Some studies have shown that patients with COPD describe same or improved quality of life after invasive ventilation in the ICU; so it can be difficult to predict impact and outcomes. Keywords: COPD exacerbation, noninvasive ventilation, high-flow oxygen, prevalence, mortality