Chapter 39. Acute-on-Chronic Respiratory Failure

• Acute-on-chronic respiratory failure (ACRF) occurs when relatively minor, although often multiple, insults cause acute deterioration in a patient with chronic respiratory insufficiency.
• ACRF is usually seen in patients known to have severe chronic obstructive pulmonary disease (COPD), but occasionally it manifests as cryptic respiratory failure or postoperative ventilator dependence in a patient with no known lung disease.
• The wide variety of causes of ACRF may be compartmentalized into causes of incremental load, diminished neuromuscular competence, or depressed drive, superimposed on a limited ventilatory reserve.
• Intrinsic positive end-expiratory pressure (PEEPi) is a central contributor to the excess work of breathing in patients with ACRF.
• The most important therapeutic interventions are administration of oxygen, bronchodilators, and corticosteroids, and noninvasive positive pressure ventilation (NIPPV).
• NIPPV can be used in most patients to avoid intubation and has been shown to improve survival.
• The decision to intubate a patient with ACRF benefits from clinical judgment and a bedside presence. Hypotension and severe alkalemia commonly complicate the immediate periintubation course, but they are usually avoidable.
• Ventilator settings should mimic the patient's breathing pattern, with a relatively rapid rate (e.g., 20/min) and small tidal volume (e.g., 450 mL); some positive end-expiratory pressure (e.g., 5 cm H2O) should be added.
• Prevention of complications such as gastrointestinal hemorrhage, venous thrombosis, and nosocomial infection is a crucial component of the care plan.
• The key to liberating the patient from the ventilator is to increase neuromuscular competence while reducing respiratory system load.
• In selected patients, extubation to NIPPV despite failed spontaneous breathing trials reduces ventilator and ICU days and further improves survival.

In the past three decades, mortality from chronic obstructive pulmonary disease (COPD) has risen dramatically, making COPD the fourth leading cause of death in 2000.1 Compared with people with normal lung function, subjects with severe COPD (forced expiratory volume in 1 second [FEV1] <50% predicted) followed for 22 years as part of the National Health and Nutrition Examination Survey (NHANES I) had a 2.7-fold increased risk of death (95% CI 2.1 to 3.5) in an adjusted analysis.2 This trend is apparent in men and women, more prominent in black Americans, and clearly related to cigarette smoking. For the first time, in 2000 more women than men died of COPD in the U.S.1 Admissions to ICUs for exacerbations of COPD account for a substantial portion of bed-days,3 since these patients often require prolonged ventilatory support. In surgical ICUs, COPD is an important problem as well, since it is one of the more common reasons for a prolonged postoperative recovery. An approach to this disease is an essential component of the intensivist's armamentarium.

This chapter describes the pathophysiology and management of patients with chronic pulmonary disease (most with COPD) who require intensive care for decompensation of their normally precariously balanced ventilatory state. This acute deterioration superimposed on stable disease is termed acute-on-chronic respiratory failure (ACRF). Patients may present to the ICU with worsening dyspnea, deteriorating mental status, or respiratory arrest. Especially when there is a preexisting diagnosis of lung disease, the diagnosis of ACRF can be made easily. However, it is important to remember that not all patients with severe COPD will have been so identified. In many patients with respiratory distress, congestive heart failure or pulmonary thromboembolism is considered first; making a correct diagnosis of ACRF requires a high index of suspicion. On occasion the disease is even more occult, for example in a postoperative patient who fails extubation and then is noted to have hyperinflation on the chest radiograph. Since optimal therapy depends on accurate diagnosis, underlying COPD should be part of the differential diagnosis for most patients with dyspnea or inability to sustain unassisted ventilation.

A severe exacerbation of COPD is characterized by a sustained worsening from the stable state that is acute in onset and requires hospitalization.4 The typical symptoms are dyspnea that has been worsening over days, often with increased cough and sputum production. Physical examination typically demonstrates respiratory distress, accessory muscle use, a prolonged expiratory time, recruitment of expiratory muscles, and wheezing. As discussed below, the absence of respiratory distress is not necessarily reassuring and when associated with somnolence is a grave and ominous sign of impending respiratory arrest. The chest radiograph is usually abnormal, reflecting the chronic lung disease, but only in 15% to 20% of cases reveals a finding (eg, pneumonia, pneumothorax, pulmonary infarction, or pulmonary edema) that results in a change of management.5 Sometimes there are indicators of acute infection, such as purulent sputum, fever, leukocytosis, and a new radiographic infiltrate. Typical initial arterial blood gas values on room air show a partial oxygen pressure (PO2) of 35 to 45 mm Hg and a partial arterial carbon dioxide pressure (PaCO2) of 60 to 70 mm Hg. Comparison with values obtained when the patient is stable can be useful, as many patients have compensated metabolic acidosis with chronically elevated PaCO2 at baseline. Electrocardiography (ECG) may show signs of right atrial enlargement or right ventricular hypertrophy and strain. P-wave amplitude >1.5 mm is universal in patients with acute exacerbation of COPD (but not necessarily ACRF), although classic P pulmonale (P-wave amplitude in leads II, III, and/or aVF >2.5 mm) is uncommon. Resolution of the exacerbation is associated with an amplitude reduction of approximately 0.8 mm.6 Thus serial ECGs may be useful in assessing response to therapy.

Although the short-term risk of death is high for ACRF, the prognosis for patients with ACRF is not uniformly poor despite severe underlying pulmonary impairment. In a prospective analysis of 250 admissions (180 patients) to an ICU for acute respiratory failure complicating COPD, hospital mortality was 21% and was strongly associated with the development of extrapulmonary organ failures.7 One-year survival following ACRF ranges from 22% to 72%.8,9 Some patients will return to an acceptable quality of life, and some even go back to work. In a cohort of 1016 patients admitted with a COPD exacerbation and a PaCO2 >50 mm Hg, 1-year survival was 47%, but only 26% of the patients rated their quality of life as good or better when surveyed at 6 months.3 Other than the underlying cause of chronic respiratory failure, predictors of poor survival include premorbid functional status, baseline dyspnea, lower body mass index,3 older age,3 lower ratio of oxygen pressure to fraction of inspired oxygen (PO2:FiO2)3, history of congestive heart failure, presence of serious comorbid disease,10 development of extrapulmonary organ failures,7 serum albumin level,3,11 cor pulmonale,3 and requirement for >72 hours of ventilation,10 but these indicators are not refined enough to allow accurate prognostication for individual patients.

Critical care resource utilization and costs for ACRF and COPD are substantial. Ely and coworkers calculated that respiratory care costs were almost twice as much for patients with COPD compared with non-COPD–related respiratory failure ($2422 [$1157 to $6100] vs. $1580 [$738 to $3322]) respectively; p = 0.01, 1996 dollars), despite similar ICU lengths of stay and mechanical ventilation days.12

Ideally, patients followed in the clinic with known severe COPD will be encouraged to discuss with their physicians their wishes regarding intensive care before acute deterioration. Unfortunately this is only occasionally accomplished. It is our approach to fully support patients with ACRF who believe their quality of life is acceptable, especially since most will be successfully managed with noninvasive ventilation, and most of those intubated will eventually be successfully liberated from the ventilator and survive to hospital discharge.8,13 On the other hand, when mechanical ventilation seems excessive to the patient or physician, defining the goals of care as the provision of comfort and relief from dyspnea and pain is appropriate. We urge clinicians caring for COPD patients with compensated respiratory failure to address advance directives and desire for life-sustaining therapies during routine ambulatory clinic appointments when informed and deliberate decision making can be shared by the patient and their loved ones.

Alveolar ventilation is maintained by the central nervous system, which acts through nerves and the respiratory muscles to drive the respiratory pump. The three subsets of ventilatory failure are loss of adequate drive, impaired neuromuscular competence, and excessive respiratory load. This concept is elucidated in Fig. 39-1. The central nervous system drives the inspiratory muscles via the spinal cord and phrenic and intercostal nerves. Inspiratory muscle contraction lowers pleural pressure, thereby inflating the lungs. The pressure generated by the inspiratory muscles (neuromuscular competence) must be sufficient to overcome the elastance of the lungs and chest wall (elastic load), as well as the flow resistance of the airways (resistive load). Spontaneous ventilation can be sustained only as long as the inspiratory muscles are able to maintain adequate pressure generation.14

Relatively few patients develop ventilatory failure from loss of drive. Most often this occurs in the setting of drug or alcohol overdose or physician-directed sedation. Typically these patients present little challenge, requiring only supportive care until the drug can be reversed or metabolized. One exception is the group of patients with undiagnosed sleep-disordered breathing. Although sleep-disordered breathing is no more common in people with mild COPD than in healthy controls,15 many patients with chronic respiratory failure have a significant component of central apnea with nocturnal desaturation. Specific therapy directed at relief of their sleep disorder, including nocturnal bilevel pressure support and supplemental oxygen, may be required. Far more common and difficult are patients who have adequate drive but have inadequate neuromuscular function, excessive load, or both.

A useful approach to understanding the pathophysiology of ACRF is that inspiratory muscle fatigue is a primary determinant.16 A muscle is fatigued when it can no longer develop the degree of tension possible before fatigue, no matter what the degree of stimulation, yet the muscle recovers with rest. Skeletal muscles fatigue when their rate of energy consumption exceeds the energy supplied by blood flow.17 Similarly, for the respiratory muscles, endurance time during inspiratory resistive loading is closely tied to the oxygen cost of breathing (V̇O2resp).18 The primary determinants of V̇O2resp are the time-tension index, work rate, and lung volume.19 Several experiments in humans indicate that the intensity required of the contracting respiratory muscles, as well as their strength, is a crucial factor in determining fatigue.20 In contrast to patients with ACRF, patients with stable, moderately severe COPD do not demonstrate low frequency diaphragmatic fatigue after maximal exercise effort when measured with a nonvolitional magnetic coil–induced twitch,21,22 despite excessive muscle loading manifest by significant slowing of the respiratory muscle maximal relaxation rate after a volitional sniff maneuver.23 This would suggest that the superimposition of infection, heart failure, or other precipitants potentiates muscle fatigue. Once fatigue of the respiratory muscles is established, neuromuscular competence is unable to sustain the mechanical load imposed on the respiratory system, and ventilatory failure ensues. The intensivist must therefore address both the precipitant and resultant respiratory muscle fatigue for treatment to be successful.

In health, neuromuscular function far exceeds that necessary to sustain ventilation against the normally small load. Dramatic increments in load (as in status asthmaticus) or decrements in strength (as in the Guillain-Barré syndrome) are required to cause hypoventilation. In patients with COPD, however, the respiratory system load as judged by the V̇O2resp is elevated to 17% to 46% of the total body volume of oxygen utilization (V̇O2), owing to abnormal airway resistance and increased elastance.24 The increase in airway resistance is caused by bronchospasm, airway inflammation, and physical obstruction by mucus and scarring.

The most significant contributor to the elastic load is dynamic hyperinflation. Airflow obstruction, compounded by decreased elastic recoil in patients with emphysema, leads to prolongation of expiration. When the rate of alveolar emptying is slowed, expiration cannot be completed before the ensuing inspiration. Rather than reaching the normal static equilibrium of lung and chest wall recoil at functional residual capacity (FRC) at the end of each breath, the respiratory system empties incompletely. Expiration terminates at this higher, dynamically determined FRC. At end expiration, there remains a positive elastic recoil pressure, which is called intrinsic positive end-expiratory pressure (PEEPi). Accordingly, alveolar pressure remains positive with respect to end-expiratory pressure at the airway opening, such that a greater effort must be generated by the inspiratory muscles on the subsequent breath. This adds a threshold load to spontaneous inspiration, and in mechanically ventilated patients makes triggering of assisted breaths more difficult.25 Determinants of the magnitude of PEEPi include the degree of expiratory obstruction (including both patient and ventilator), elastic recoil, minute ventilation, and expiratory time (and therefore the respiratory rate, inspiratory flow rate, and inspiratory flow profile). PEEPi of about 10 cm H2O is present in most, if not all, COPD patients with acute ventilatory failure,26,27 and PEEPi can be measured in many ambulatory outpatients as well.28 As discussed more fully below, counterbalancing this PEEPi with external positive end-expiratory pressure (PEEP) provides a means by which to lower the work of breathing (or the work of triggering). The impact of PEEPi on the work of breathing is illustrated in Fig. 39-2.

At the same time that the respiratory system load is elevated, the inspiratory muscles are poorly able to tolerate it. The hyperexpansion that occurs during COPD forces the inspiratory muscles to operate in a disadvantageous portion of their force-length relationship. Diaphragm strength (measured by sniff esophageal pressure) in patients with severe but stable COPD is only two-thirds that of normal individuals, virtually all of this ascribable to the diaphragm position rather than to inherent muscle weakness.29 Still, patients presenting with ACRF may have not only worsening hyperinflation but also other conditions (e.g., protein-calorie malnutrition30 or steroid myopathy31) that cause intrinsic muscle weakness. Even when patients with severe COPD are in a state of compensation, the increased load and diminished neuromuscular competence are precariously balanced. Only minor additional decrements in strength or increments in load are sufficient to precipitate inspiratory muscle fatigue and respiratory failure. It is this incremental deterioration in the balance of neuromuscular competence and respiratory system load that defines ACRF. Its many potential contributors are enumerated in Fig. 39-3.

Additional Causes of Decreased Neuromuscular Competence

Depressed Drive

In the usual patient who is dyspneic, tachypneic, diaphoretic, and using accessory muscles of respiration, impairment of drive is clearly not the cause of ACRF. When drive has been assessed in this setting it is greatly elevated,32 as it is in most patients who fail to be weaned from mechanical ventilation.33 Nevertheless, there are patients in whom new central nervous system (CNS) insults or drug effects contribute to respiratory failure. Even small doses of sedatives or narcotics may cause respiratory failure when superimposed on chronic ventilatory insufficiency; a careful history is essential to exclude this possibility. Occult hypothyroidism is not rare in the elderly, particularly in women. Thyroid function testing should be part of the routine screening of patients with ventilatory failure attributed to decreased drive.

It has been proposed that central depression of drive contributes to the terminal stages of respiratory failure, regardless of the precipitating factor. According to this “central wisdom” hypothesis, overworked respiratory muscles reach a threshold of loading at which point muscle injury results in the elaboration of inhibitory signals, which feedback to the CNS to reduce drive, thereby protecting the muscles from fatigue.34–36 The relevance of this mechanism to respiratory failure remains to be demonstrated.

Failed Neuromuscular Transmission

In order to effect adequate ventilation, the CNS must transmit drive to the working muscles via the spinal cord and peripheral nerves. Therefore causes of neuromuscular failure such as spinal cord lesions, primary neurologic diseases, and neuromuscular blocking drugs, may produce ACRF. Aminoglycosides37 and procainamide38 act as mild neuromuscular blockers, a feature unimportant in the great majority of patients, but relevant in those with neuromuscular diseases such as myasthenia gravis. The clinical setting may be a clue to one of the unusual causes, such as phrenic nerve injury following cardiopulmonary bypass. This occult lesion may be induced by direct trauma to the nerve, or more indirectly by cold cardioplegia.

Muscle Weakness

The most important causes of decreased neuromuscular competence fall into the category of muscle weakness. In patients with COPD, respiratory muscle changes represent a balance between factors capable of impairing respiratory muscle function and metabolic adaptation of the diaphragm (Table 39-1).

Changes in chest wall geometry and diaphragm position are particularly important and adversely affect the muscles of inspiration (diaphragm and intercostal muscles) and expiration (abdominal muscles). The inspiratory muscles are poorly able to tolerate the maximal loading that occurs in emphysema. Hyperexpansion forces them to operate on a disadvantageous portion of their force-length curve. The piston-like displacement of the diaphragm is compromised and expansion of the lower thoracic cage is disturbed. In addition, a flattened diaphragm generates less transmural pressure for a given tension than the normally curved one, as described above. Electrolyte disturbances such as hypokalemia, hypophosphatemia,39 and hypomagnesemia40 may potentiate muscle weakness. Disturbances of the myofibrillar contractile unit have been demonstrated in humans41 and in animal models of loaded resistive breathing that simulates ACRF. Disturbances of the sarcomere length/tension relationship, activation of proteolytic enzymes such as calpain that can degrade actin and intercellular adhesions,42 oxidative stress, and elaboration of proinflammatory cytokines have also been proposed to play a role.43

Hypophosphatemia may be exacerbated by many of the drugs used to treat ventilatory failure, such as methylxanthines, β-adrenergic agonists, corticosteroids, and diuretics, accounting for its striking prevalence in COPD patients (about 20%).44 Malnutrition, which is present in 40% to 50% of hospitalized patients with emphysema,45 has been suggested to be associated with respiratory muscle weakness,44 yet one study demonstrated that diaphragmatic strength was comparable between stable COPD patients with reduced body mass index (BMI; 17.3 kg/m2) and those with normal BMI.46 Short-term refeeding can improve indices of respiratory muscle function30 and immune response.

Myopathy due to corticosteroids may also contribute.31,47 Rarely, other myopathies such as an adult variant of acid maltase deficiency or mitochondrial myopathy may cause cryptic respiratory failure due to muscle weakness. Cellular and molecular adaptations of the respiratory musculature differ between the diaphragm and the intercostal muscles. The diaphragmatic myocytes adopt an “aerobic” type I phenotype with prolonged loading (see Table 39-1). By contrast the intercostal muscles undergo relatively greater glycolytic adaptation to chronic loading.48

As discussed above, muscle fatigue is the reversible loss of force generation despite adequate neural stimulation. Fatigue is itself a cause of muscle weakness and can be short-lasting (high-frequency fatigue), or long-lasting (low-frequency fatigue) which can persist for days to weeks. To the extent that fatigue is central to the development of respiratory failure, it may be caused by an inadequate supply of nutrients, excess generation of metabolites such as lactate or hydrogen ion, or depletion of muscle glycogen. Evidence to support the importance of blood supply in the genesis of fatigue comes from studies of respiratory failure in animals with hemorrhagic, cardiogenic, or septic shock.49,50 In these animals, fatigue is hastened by circulatory insufficiency. The magnitude of blood flow to the respiratory muscles seems to be important beyond aerobic needs, as demonstrated by experiments in which flow was manipulated independently of oxygen delivery.51 Hypoperfusion states, hypoxemia, and severe anemia have the potential to contribute to muscle fatigue and thereby hasten respiratory failure. Although fatigue is likely to contribute to the precipitation of an ACRF event, systematic evaluation has failed to demonstrate that low-frequency fatigue contributes to prolonged mechanical ventilation and failure to liberate. For example, none of 17 “weaning-failure” patients developed objective fatigue (transdiaphragmatic pressure changes with phrenic nerve stimulation), despite three quarters of patients having a diaphragmatic tension-time index (TTdi) greater than 0.15—a level associated with diaphragmatic fatigue by several other investigators.52

Additional Causes of Increased Load

Increased Resistive Load

In patients with COPD, the respiratory system load is chronically elevated owing to abnormal airway resistance and increased elastance. The increase in airway resistance is caused by bronchospasm, airway inflammation, and physical obstruction by mucus and scarring. One common cause of increased flow resistance, and the one most amenable to pharmacologic intervention, is bronchospasm. The disease course in most patients with COPD includes an asthmatic component, and bronchial hyperreactivity to provocation may be as common in COPD as in asthma.53 Exacerbations of bronchospasm increase resistive workload, precipitating ACRF. Superimposed heart failure may also cause increased airway resistance, mimicking asthma (“cardiac asthma”). Upper airway obstruction is much less common, but since these patients frequently have a history of prior intubation, tracheal stenosis should be considered. Finally, sleep-disordered breathing, which commonly coexists with COPD, may need to be excluded. Especially once the patient is intubated, clues to this underlying cause of dynamic upper airway obstruction (e.g., snoring) may be impossible to discern. In the proper setting (an obese, hypersomnolent patient), this possibility should be vigorously pursued. The endotracheal tube (ETT) itself presents a significant resistive workload, especially when a small size (<7.5 mm internal diameter) is chosen.54 The angulation and length of the tube and the presence of secretions also affect flow resistance. Additionally, ventilator circuit heat and moisture exchangers (HME filters) impose significantly greater dead space and tube resistance than heated humidifiers in ventilated ACRF patients.55 Automatic tube compensation (ATC) algorithms available on some modern ventilators are designed to maintain airway pressure by continuously calculating pressure drop across the ETT during inspiration and to decrease airway pressure during expiration to maintain constant alveolar pressure. However, ATC may be insufficient to compensate fully for the imposed resistive load of the ETT.56

Increased Lung Elastic Load

Contributors to lung stiffness include pulmonary edema (cardiogenic and noncardiogenic), pneumonia, interstitial fibrosis or inflammation, tumor, and atelectasis. As noted above, bronchospasm not only causes increased flow resistance, but simultaneously worsens the elastic load by augmenting PEEPi.

Increased Chest Wall Elastic Load

The chest wall includes the thorax, diaphragm, and abdomen. Therefore obesity, rib fracture, pneumothorax, pleural effusion, ascites, chest wall abnormalities, and abdominal distention (see Chap. 42) contribute to the work of breathing. These factors are particularly relevant in the postoperative setting.

Minute Ventilation Loads

Dividing the work of breathing into resistive and static components is a useful way of analyzing the effort of each breath. However, even if the work of each breath remains constant, an increase in respiratory rate increases the load. Increased minute ventilation (V̇e) requirements can be divided into those due to excess carbon dioxide production (V̇CO2) and those from worsened dead space. The first category includes excessive caloric intake, fever, agitation, muscular exertion (including shivering and respiratory distress), and hypermetabolism due to injury or infection. New dead space may be caused by pulmonary embolism, hypovolemia, PEEP (including PEEPi), or shallower breathing (which raises the dead space fraction, Vds/Vt). Partitioning of the lung mechanics into resistive and static components in the intubated COPD patient may be inaccurate if the end-inspiratory pause maneuver is too short and if there is a rapid spontaneous respiratory rate.57

Multifactorial Respiratory Failure

In order to analyze respiratory failure in a way that facilitates management, it is important to dissect the very complex real-life patient into simple components of deranged neuromuscular competence and load. However, the patient with ACRF due to isolated rib fracture or hypokalemia is uncommon. More often numerous contributors to both decreased strength and increased load are implicated. For example, a patient admitted with pneumonia and worsening bronchospasm may also have hypophosphatemia, heart failure, and malnutrition. Aspiration at the time of intubation, abdominal distention related to attempts to feed enterally, and overzealous parenteral nutrition complete the picture of multifactorial ACRF. Although the situation in such a patient may seem overwhelmingly complex, we caution against a “shotgun” approach to evaluation and management of patients with multifactorial respiratory failure. Despite the temptation to provide all possible interventions for these very ill patients, a systematic approach to each component of respiratory failure leads logically to a plan for treatment.

Failure to aggressively treat mild to moderate acute exacerbations of COPD prior to the development of ACRF and other organ failure is associated with an increased risk of emergency hospitalization and delayed recovery.58 The unequivocal role of noninvasive positive pressure mechanical ventilation (NIPPV) justifies its position as the cornerstone in the therapeutic approach to critically ill patients with ACRF (see Chap. 33). We consider NIPPV to be the “bookends” in the therapeutic library of therapy for ACRF, providing firm support on either end of an exacerbation of ACRF. This approach is discussed below, but it incorporates early initiation of NIPPV to avoid mechanical ventilation (MV) and improve survival, and later use of this tool for early liberation from MV. We describe below three phases of management of the ACRF patient: early ACRF, late ACRF requiring intubation for MV, and liberation from the ventilator.

Phase 1: Early Acute‐on-Chronic Respiratory Failure

The goals of management in the patient not yet intubated are to avoid MV whenever possible and to recognize progressive respiratory failure when it is not. The proven efficacy of NIPPV, that its use can avert mechanical ventilation in about 75% of patients with ACRF, is one of the most important developments in the management of these patients, because it buys time for the physician to treat precipitants of ACRF and for the patient to improve.

Current guidelines recommend NIPPV as definitive and first-line therapy for COPD-related ACRF.59,60 Most centers use a face or nasal mask and pressure-support ventilation, although helmet interfaces, poncho wraps, and other ventilator modes can support NIPPV. A tight-fitting mask allows substantial ventilatory assistance yet provides for brief periods off the ventilator during which patients can speak, inhale nebulized medications, expectorate, and swallow liquids. NIPPV has been systematically evaluated in several large studies. The outcomes from these studies have been synthesized in a Cochrane meta-analysis of 14 randomized controlled studies of NIPPV versus usual medical care (UMC) that enrolled a total of 758 patients with ACRF.61 Age ranged from 63 to 76 years, admission pH was 7.26 to 7.34, admission partial pressure of arterial carbon dioxide (PaCO2) was 57 to 87 mm Hg, admission PaO2 was 39 to 73 mm Hg, and the FEV1 ranged from 0.68 to 1.03 L. The eight largest studies enrolled 40 or more patients. The combined analysis demonstrated that: treatment failure was less likely with NIPPV than UMC (RR 0.48; 95% CI 0.37, 0.63) with a number needed to treat (NNT) of 5 (95% CI 4, 6), and mortality was reduced by 48% (RR for death 0.52; 95% CI 0.35, 0.76; NNT 10; 95% CI 7, 20). Notably, the mortality reduction was evident regardless of whether ACRF was treated in an ICU or in a general ward. Additionally, there was a 60% reduction in requirement for intubation with NIPPV, and rapid improvements in respiratory rate, PaCO2 and pH. Hospital length of stay (LOS) was reduced by 3.24 days, although the trend to reduced ICU LOS (4.71 fewer days) did not reach significance.61 Interestingly, the improvement in PaO2 was heterogeneous between studies and was not significantly different at 1 hour after initiation of treatment. The finding of another meta-analysis revealed essentially similar findings for survival and clinical improvement, but subgroup analysis suggested that the benefit was limited to patients with severe but not mild ACRF. This hypothesis has not been tested in a prospective stratified fashion.62

NIPPV has been used for prolonged periods (more than 1 week) and has been shown to relieve symptoms, reduce respiratory rate, increase tidal volume, improve gas exchange,63 and to lessen the amplitude of both the diaphragmatic electromyogram and the transdiaphragmatic pressure.64 Complications of the mask have been minor and few;61 local skin breakdown has been attributed to the tight-fitting mask, but can be avoided by applying a patch of wound care dressing. Only a few patients cannot tolerate face or nasal masks, and some of these patients respond to judicious and carefully monitored use of anxiolytics. Aspiration of gastric contents has only rarely been noted in these patients, even when a nasogastric tube is not routinely placed; however, impaired mentation probably increases this risk.

Careful patient selection is essential for successful NIPPV in ACRF and is summarized in Table 39-2.65 Although a nasal mask is objectively as effective and well tolerated as a full face mask,66 we typically begin therapy with a full face mask held lightly against the face. Positive pressure of 5 to 8 cm H2O is delivered using a pressure limited mode on a noninvasive ventilator until the patient is able to tolerate the mask comfortably and synchronize with the ventilator.67 After applying head straps, we aim to achieve an expiratory positive pressure of 2 to 5 cm H2O (to counterbalance PEEPi) and an inspiratory positive pressure of 15 to 18 cm H2O (equivalently, 2 to 5 cm H2O PEEP with 13 to 16 cm H2O pressure support) to assist alveolar ventilation. Higher pressures can sometimes be used, but they tend to be limited by air leak or mask discomfort. The PEEP component of NIPPV is important68 and does not usually cause incremental hyperinflation.69 Indeed, continuous positive airway pressure (CPAP) alone (without ventilatory assistance) reduces the work of breathing, improves gas exchange, leads to subjective benefit, and sometimes can avert intubation70–72 when applied to patients with ACRF. When PEEP was added to pressure-support ventilation in ventilated patients with COPD, inspiratory effort fell another 17%, and patient-ventilator synchrony improved.45

NIPPV is not uniformly successful in patients with ACRF.73 Essential to successful patient-NIPPV synchrony are trigger settings for inspiration, pressurization rates (rapid pressurization reduces diaphragm work but results in increased leakage), and inspiratory-to-expiratory cycling (mask leaks can result in delayed cycling). These aspects are reviewed in detail in Chap. 33. A salutary response is typically evident within 10 minutes of beginning NIPPV, as indicated by a falling respiratory rate and heart rate as well as by the patient's subjective assessment. Occasional patients feel claustrophobic and may show objective worsening with NIPPV. Although we occasionally use pharmacologic anxiolytic therapy with success, this course has obvious attendant risks and should only be undertaken with appropriate safeguards.

A risk of NIPPV that is not often discussed is its potential to lull the physician-nurse-respiratory therapist team into a sense of comfort while the patient continues to worsen. In these patients, time spent trying NIPPV may potentially lead to a later, more urgent intubation in a more exhausted patient with significantly greater tissue hypoxia.

Avoiding intubation and conventional mechanical ventilation nearly always depends on discerning the cause of ACRF and reversing it. Thus while NIPPV is initiated, each of the potential causes enumerated in Fig. 39-3 should be reviewed in light of the clinical presentation. On occasion, impending respiratory failure can be averted by a specific intervention targeted to one precipitant, such as rib fracture (intercostal) nerve block or pulmonary edema (diuresis or afterload reduction). More often, several contributors are identified, such as worsened bronchospasm, electrolyte derangement, and infection, and treatment must be broad-based. The treatments of many of these precipitants are discussed elsewhere in this text; here, the use of oxygen and drugs will be discussed.

Oxygen

One of the most pervasive myths surrounding the treatment of ACRF is that these patients rely on hypoxic drive to breathe. Physicians are often hesitant to supply oxygen, fearing that patients will stop breathing, necessitating intubation. Since these patients are typically hypoxemic on presentation (PO2 is usually about 30 to 40 mm Hg), failure to supply adequate oxygen is a potentially devastating treatment error. Unrelieved hypoxemia in the face of acidemia, fatiguing respiratory muscles, and an often failing right ventricle risks arrhythmia, myocardial infarction, cerebral injury, renal failure, and respiratory arrest.

In several studies performed over the past decade, patients with COPD have been convincingly shown to nearly maintain V̇e despite treatment with even 100% oxygen,74,75 and to augment their drive in response to hypercarbia.76 When oxygen is given, the PCO2 typically rises, but this effect is attributed largely to worsened matching of ventilation and perfusion and the Haldane effect, not to hypoventilation. In one series, patients with ACRF had a mean initial PO2 of 38 mm Hg and PCO2 of 65 mm Hg.17 They were then placed on 100% oxygen, which caused a rise in the mean PO2 to 225 mm Hg, while the mean PCO2 plateaued at 88 mm Hg. V̇e fell by a small amount, and drive remained supranormal. Three further studies have confirmed that worsened respiratory acidosis is modest and manageable in ACRF patients receiving O2 therapy titrated to a functional oxygen saturation (SpO2) of 90%.77–79 Our point is not to claim that hypoxic drive in patients with ACRF does not exist—it clearly does80—but to emphasize that oxygen should nevertheless be given. High concentrations of inspired oxygen are not usually necessary in ACRF, unless pneumonia or pulmonary edema is present, since hypoxemia is due largely to ventilation-perfusion (V̇/Q̇) mismatching, not to shunting. Nevertheless, we believe that the risks of oxygen therapy have been greatly overstated,81 often leading physicians to withhold a potentially life-saving therapy. The goal of oxygen therapy is to maintain 90% saturation of an adequate amount of circulating hemoglobin. This goal can usually be attained with a face mask at 30% to 35% or a nasal cannula at 3 to 5 L/min. A rise in PCO2 is likely, but that in itself is of little importance. Patients may progress to respiratory failure despite oxygen therapy, but not because of it. For this reason, careful serial assessments by the ICU team of the physician, nurse, and respiratory therapist are essential.

Pharmacotherapy

Bronchodilators are an essential part of the early management of these patients (Table 39-3). While much of the airflow obstruction of COPD is irreversible, most patients have some reversible component.82,83 In stable COPD, combinations of a β-agonist and ipratropium have been demonstrated to be superior to either drug alone.84 However, in a meta-analysis of four randomized studies, combination therapy for acute exacerbations of COPD does not result in greater short-term bronchodilation compared with either albuterol or ipratropium alone.85 Despite these data, current practice continues to support combination therapy if airflow obstruction persists despite maximal doses of β-agonists or if treatment-limiting tachycardia is experienced. Respiratory stimulants would be predicted not to work in this setting, since drive is already supranormal. Indeed, doxapram and similar drugs are now rarely used since their toxicity is substantial and their efficacy minimal,86,87 particularly when compared with NIPPV.88 We believe there is no role for these drugs. Similarly there is no evidence to support routine use of mucolytic agents or chest percussion.

Beta-Agonists

Inhaled β2-selective agents (albuterol, bitolterol, terbutaline, or metaproterenol) should be given by metered-dose inhaler (MDI), unless patient distress makes that impractical, since this route seems to be equally efficacious in nonventilated patients.5 Administration may be facilitated by the use of a chamber device. Higher doses than usual can be given, such as 4 to 10 (or more) puffs every 20 to 60 minutes, although there is no clear benefit from frequent doses. A hand-held nebulizer (0.5 mL albuterol or 0.3 mL metaproterenol mixed with 2.5 mL saline solution) may be useful in patients who cannot use an MDI reliably, but otherwise this route confers no additional efficacy. Parenteral agents (e.g., epinephrine 0.3 mL subcutaneously) and their accompanying toxicity can nearly always be avoided. The longer-acting β2-agonist formoterol (but not salmeterol) has a fast onset of action and has been demonstrated to provide equally effective bronchodilation in mild COPD exacerbations when administered in high doses.89 However, because of concerns about activity as a partial receptor antagonist, significant additional cost, and therapeutic equivalence, we do not recommend long-acting inhaled β2-agonist agonists for ACRF.

Ipratropium

The anticholinergic agent ipratropium bromide is as effective as metaproterenol in the treatment of ACRF,85,90 and may even be better in stable COPD. An additional advantage of this drug is that compared to metaproterenol, its use is associated with a small rise in PaO2 rather than the small decline usually seen with β-agonists. The addition of ipratropium to a regimen containing inhaled β-agonists yields incremental benefit in patients with stable COPD,84 but as discussed above, does not result in improved bronchodilation in acute exacerbations. The usual dose of ipratropium in ACRF is three puffs every 30 to 60 minutes. Much higher doses (400 μg) have been shown to be optimal in stable patients with COPD, but this question has not been examined in ACRF.91

Tiotropium

Tiotropium, a recently released long-acting inhaled anticholinergic, has demonstrated great promise in patients with stable COPD by reducing symptoms, the decline in FEV1, and frequency of exacerbations. Preliminary evidence of its potential efficacy in patients with acute exacerbations was suggested by a randomized prospective study conducted by a Veterans Administration collaborative involving 1829 men with severe COPD (FEV1 1 L, 36% predicted) at risk for exacerbations.92 Significantly fewer patients treated with once-daily tiotropium experienced exacerbations (27.9% vs. 32.3%; p = 0.037) that were associated with 26% fewer hospital days (p = 0.001). To date, however, there is no published experience with tiotropium as a specific therapy for ACRF.

Phosphodiesterase Inhibitors

Aminophylline

Aminophylline is a mildly effective nonselective phosphodiesterase (PDE) inhibitor in patients with COPD. In addition to its actions as a bronchodilator, aminophylline has salutary effects on the diaphragm in experimental settings. These include inotropy and resistance to fatigue seen in patients on this agent, although the clinical relevance of these findings has yet to be demonstrated, and recent studies have challenged the underpinnings of these clinical trials.93 Whether aminophylline should be given to patients with ACRF is controversial, and recent trends show it falling out of favor. A controlled trial in patients hospitalized for an acute exacerbation of COPD failed to show any benefit of aminophylline when added to a standard regimen of β-agonists and corticosteroids.94 On the other hand, theophylline causes demonstrable (although generally minor) physiologic improvement in stable COPD patients, even when superimposed on a regimen of a β-agonist83 or on a combination of a high-dose inhaled β-agonist plus ipratropium.95 Meta-analysis of four randomized controlled trials including 169 patients demonstrated no improvement in bronchodilation or hospital LOS in patients with acute exacerbations. However, not all patients had severe ACRF.96 Toxicity of these drugs is substantial, including arrhythmogenesis and CNS effects. In the meta-analysis, there were fivefold greater odds of gastrointestinal symptoms occurring in theophylline-treated patients.96 Daily serum level measurement is necessary for safe use, especially in light of the significant interactions with other drugs. Even when serum levels are considered to be therapeutic, aminophylline may have important toxicity. In a multivariate analysis of 100 patients receiving theophylline, drug level was the most important predictor of arrhythmia,97 ahead of age and gender. Both atrial and ventricular arrhythmias were seen and correlated with theophylline level. In the group with therapeutic levels 48% had arrhythmias. Particularly worrisome was the finding of multifocal atrial tachycardia in patients on theophylline, including those with nontoxic levels. Two of six patients with this rhythm disturbance died suddenly during hospitalization, without antecedent ventricular ectopy.

Consistent with guidelines from expert panels,59,98 we rarely use intravenous aminophylline, and then only as an adjunct to other, more effective management (standard bronchodilators and steroids). Aminophylline is initiated as a loading dose of 5 mg/kg infused over 30 minutes, then continued as an intravenous infusion at a rate of 0.5 mg/kg per hour. In patients who are already taking an oral methylxanthine, intravenous loading and maintenance dosing should be guided by serum levels. Given the minor efficacy of the drug and its substantial toxicity, it is difficult to justify empirical partial loading doses.

Selective Phosphodiesterase Inhibitors

Selective inhibitors of type IV PDE (such as cilomilast) are likely to have a major impact on the management of patients with stable COPD with recent studies (unpublished at the time of this writing) demonstrating modest improvements in lung function compared to placebo and a significant reduction in acute exacerbations. However, as for many newer therapies, PDE-IV inhibitors have not been evaluated in the treatment of COPD exacerbations. Additionally, a single dose of cilomilast appears to confer no additional bronchodilatory effect in stable COPD patients who respond to albuterol or ipratropium.82

Corticosteroids

Patients with ACRF given methylprednisolone 0.5 mg/kg every 6 hours, in addition to standard bronchodilators, show greater improvement in spirometric values than patients who do not receive this drug.99 This benefit is demonstrable at least as early as 12 hours, and in some studies of patients with asthma possibly after 1 hour. In another study of patients with ACRF, 0.8 mg/kg of prednisolone given intravenously reduced the inspiratory resistance and PEEPi when measured at 90 minutes.100 A meta-analysis that included 537 patients in 7 randomized controlled studies yielded an aggregate beneficial effect of steroid treatment that translated into an early FEV1 improvement of 120 mL (95% CI; 5 mL to 190 mL) compared with controls, an effect that persisted for 3 to 5 days.101 Although there was no survival benefit derived from the addition of steroids, treatment failure and hospital LOS were significantly reduced. Although there is significant debate about the optimal dose and duration of steroids,5 current guidelines recommend methylprednisolone 0.5 to 1 mg/kg every 6 hours. Since these drugs have important detrimental effects on metabolic, muscular, and immune function, their continued use should be re-evaluated after the first 72 hours with a transition to oral therapy when tolerated. Although no effect of corticosteroids on respiratory muscle function can be shown in the short term (<2 weeks102), they do contribute to muscle weakness in the long term.31 No additional benefit is derived from prolonging steroid therapy beyond 2 weeks. A possible alternative may be to use high doses of the nebulized steroid budesonide (2 mg every 6 hours), which may be as effective as an oral steroid regimen in patients with a COPD exacerbation.103 Notably, hyperglycemia was less common in the budesonide-treated patients. However, this approach is significantly more expensive.

Antibiotics

Bacterial bronchitis is a common precipitant of ACRF. Nevertheless the efficacy of antibiotics is controversial. Since benefit has been demonstrated in several studies and a trend towards benefit in some others,5 an inexpensive oral broad-spectrum antibiotic (e.g., ampicillin, doxycycline, or trimethoprim-sulfamethoxazole) should be provided in the absence of clinical features of pneumonia. Community-acquired pneumonia should be treated with a cephalosporin-macrolide combination or a high-dose single-agent fluoroquinolone.

Anabolic Steroids

Inflammation is not limited to the lungs during an acute exacerbation of COPD. Peripheral and diaphragmatic skeletal muscle weakness is pronounced during ACRF and is associated with markers of systemic inflammation such interleukin-6 and interleukin-8.104 A combination of anabolic steroids (nandrolone decanoate 25 to 50 mg IM every 2 weeks) and caloric supplementation (420 kcal/d supplement) raised the mouth pressure during a maximal static inspiratory maneuver in patients with clinically stable COPD.105 Similarly, COPD patients treated with oxandrolone experienced a significant increase in lean body mass.106 However, this effect may only be clinically useful in patients receiving long-term oral steroids.107 We are aware of no trials showing clinically important benefits in patients with ACRF.

Arrhythmias

Arrhythmias are common in the setting of respiratory failure. Fortunately, they are rarely a serious problem, but they can serve to distract the physician from more important issues, may limit the dose of bronchodilating drugs, and sometimes are significant in themselves. The most common rhythms are sinus tachycardia, atrial fibrillation, atrial flutter, multifocal atrial tachycardia, and ventricular premature beats. β-Agonists, macrolides, and electrolyte disturbances can cause transmural dispersion of repolarization abnormalities such as QT prolongation, T-wave alternans, and P-wave dispersion as precursors to serious arrhythmias. It can be difficult to judge the contributions of hypoxemia, cor pulmonale, metabolic derangements, underlying coronary artery disease, and drug toxicity to arrhythmogenesis. Treatment should focus on rectifying the underlying respiratory failure, since doing so usually has a beneficial impact on arrhythmias. Hypoxemia and electrolyte abnormalities should be corrected as a first priority. Monitoring should be initiated, and if arrhythmias continue despite correction of apparent exacerbating factors, myocardial ischemia should be excluded. Atrial fibrillation can be controlled with a calcium channel blocker or digoxin (see Chap. 24). β-Blockers should generally be avoided for fear of worsening lung function, although short-acting selective drugs have occasionally been used with success. Multifocal atrial tachycardia often responds to verapamil, sometimes with restoration of sinus rhythm,108 and there appears to be a role for parenteral magnesium as well (see Chap. 24).

Recognizing Impending Respiratory Failure

Despite aggressive attempts to find and reverse the causes of ACRF, some patients will progress to frank respiratory failure. The decision to intubate requires clinical judgment and is best assessed by a physician present at the bedside (Table 39-4). Assessment of respiratory failure based solely on results of arterial blood gas studies is fraught with error. Certainly a rising PaCO2 in a patient with progressively worsening symptoms and signs of distress should be interpreted as heralding respiratory arrest. However, the absolute level of the PaCO2, isolated from other clinical data, may be less useful. We have taken care of a small number of patients in whom the PaCO2 rose to 150 mm Hg while the patients were alert and conversing, and mechanical ventilation did not become necessary. On the other hand, many patients with ACRF will progress to respiratory arrest long before progressive hypercarbia is clearly documented. Patients who have had an unsuccessful attempt at stabilization with NIPPV are at particular risk for underappreciated clinical instability. Those patients may have very little tissue oxygen reserve, low effective circulating volume, and are at substantial risk of cardiopulmonary arrest if transition to intubation is delayed. Respiratory arrest may be complicated by aspiration or cardiovascular instability, compromising future efforts to return the patient to spontaneous breathing. Indeed, the survival of patients who are allowed to progress to respiratory arrest is significantly lower than that of patients ventilated for acute deterioration of COPD who are intubated electively prior to arrest. The goal at this stage of management is to intubate the patient electively once mechanical ventilation becomes unavoidable. In some cases this will require foregoing NIPPV and opting for immediate airway intubation for mechanical ventilation to avoid respiratory arrest.

Useful bedside parameters of impending respiratory arrest include respiratory rate, mentation, pattern of breathing, and the patient's own assessment. The patient may be able to tell the physician whether improvement is occurring or not; the degree of dyspnea over time is a useful guide to the likelihood of success without intubation. Most patients with ACRF are tachypneic, reflecting their excessive drive. A rate that remains above 35 to 40 breaths/min, or a rate that continues to rise despite therapy and NIPPV is predictive of respiratory failure. Deterioration of mentation commonly precedes respiratory arrest. Patients become confused, less able to converse, then poorly rousable. Thoracoabdominal paradox and respiratory alternans are rarely seen and are probably not useful signs.

Phase 2: Late Acute‐on-Chronic Respiratory Failure Requiring Intubation

This phase consists of the immediate peri-intubation management and the first few days of mechanical ventilation. In many respects, treatment begun in the preintubation phase (bronchodilator administration in particular) is continued, but several additional concerns become relevant. Care consists of stabilizing the patient on the ventilator, ensuring rest of the patient and respiratory muscles, improving neuromuscular competence, reducing load, and giving prophylaxis against complications, while optimizing definitive therapy for any precipitant such as infection. Optimal treatment at this time is likely to facilitate eventual liberation from mechanical ventilation.

Peri-Intubation Risks

There are two common pitfalls in the immediate postintubation period: life-threatening alkalosis and hypotension. Both are related to overzealous ventilation, and both are avoidable by taking the patient's own ventilatory pattern prior to intubation into consideration. Hypotension is a consequence of escalating PEEPi following intubation. The degree of dynamic hyperinflation is proportional to V̇e. PEEPi has the same deleterious consequences on venous return as externally applied PEEP and can cause serious hypoperfusion. This can be particularly prominent in patients with ineffective circulating volumes (preload) and concomitant right heart dysfunction when vasodilatory and sympatholytic sedatives are used for intubation. The key to avoiding this pitfall is to prevent excessive ventilation, particularly during bag-valve-mask preoxygenation before intubation attempts. When hypotension occurs, the circulation can usually be promptly restored by simply ceasing ventilation for 30 seconds, then reinstituting ventilation along with measures to reduce PEEPi and restore circulating volume. It is also our practice in patients without decompensated left heart failure to administer a fluid bolus immediately prior to sedation for intubation.

Most patients with ACRF have a minute ventilation of 10 L/min or less and breathe at tidal volumes of about 300 mL. Physicians commonly choose ventilator settings with a higher tidal volume and a correspondingly lower ratio of dead space to tidal volume. In addition, a minute ventilation higher than 10 L/min often is employed, particularly during the first few minutes of manual-assisted ventilation. Finally, as the work of breathing is assumed by the ventilator, V̇CO2 drops by as much as 20%. All of these factors join to dramatically lower the patient's PaCO2 once assisted ventilation begins. Since preexisting compensatory metabolic alkalosis is the rule, life-threatening alkalemia (pH >7.7) can easily be achieved. This scenario can be avoided by simply aiming for a more reasonable minute ventilation, approximating the patient's own pattern of breathing. Typical initial ventilator settings are described below. There is no need to attempt to normalize pH, a maneuver that merely serves to waste the bicarbonate that has been so vigorously conserved during the evolution of respiratory failure.

We generally recommend head-up intubation with a large-diameter endotracheal tube, not laryngeal mask. Depolarizing muscle relaxants should be avoided and if necessary, short-acting nondepolarizing agents such as rocuronium or cisatracurium should be considered.

Initial Ventilator Settings

We generally initiate ventilation using the assist-control mode, since one of the goals in this phase is to rest the loaded respiratory muscles (see Chap. 36). Tidal volumes of about 5 to 7 mL/kg are used (about 350 to 500 mL) with a respiratory rate of 20 to 24 breaths/min. As discussed above, PEEPi presents an inspiratory threshold load to the patient with ACRF. The patient must generate enough force to counterbalance PEEPi before the breathing effort results in any inspiratory flow and before it can trigger the ventilator. This difficulty cannot be sidestepped by lowering the triggering sensitivity on the ventilator or by using flow triggering. Applying external PEEP that is roughly equal to the PEEPi does reduce the work of breathing (and triggering) by a significant amount, as depicted in Fig. 39-2.68,109 In some patients, externally applied PEEP causes additional hyperinflation, with detrimental hemodynamic effects and a potentially increased risk of barotrauma.110,111 However, most patients with ACRF demonstrate flow limitation so that external PEEP (in amounts up to about 85% of the PEEPi) has no significant impact on the expiratory flow-volume relationship, lung volume, or hemodynamics.112,113 Strategies to shorten ventilator inflation time are not generally helpful unless inspiratory flow is inordinately low (we typically use 60 L/min), although PEEPi can be reduced modestly.114

Ensuring Rest and Recovery

Following intubation, most patients are exhausted and will sleep for the first day and experience significant diuresis. Little or no sedation is typically necessary, although close monitoring for delirium and alcohol or substance withdrawal may be required. The respiratory muscles will require 48 to 72 hours for full recovery, so that resumption of breathing efforts before that point is counterproductive and is likely to lead to recurrence of respiratory muscle fatigue.115 However, as discussed below this does not preclude extubation to NIPPV if there is convincing evidence that extrapulmonary organ dysfunction has stabilized and cognitive function has improved. We continue to encourage rest by maintaining ventilation, adding sedation and antidelirium agents when necessary. Rest can be achieved using any mode of ventilation, including bilevel NIPPV, as long as settings are chosen that minimize patient effort. It is important to emphasize that having the patient connected to a ventilator is no guarantee that the patient is relieved of the work of breathing. Even when the ventilator is set at a very sensitive trigger point, the presence of PEEPi causes the patient to have to make a substantial inspiratory effort to get a breath, even on volume assist-control mode. For example, with a triggered sensitivity of 1 cm H2O and PEEPi of 10 cm H2O, the patient must lower his airway pressure by 11 cm H2O to trigger a breath. It is incumbent on the physician to ensure that the patient is in fact rested. We evaluate inspiratory muscle activation, synchrony, and the presence of PEEPi by palpating the epigastric area during the respiratory cycle116 while monitoring the pressure-time and flow-time waveforms on the mechanical ventilator. When optimal ventilatory rest is achieved, respiratory muscle strength usually improves demonstrably over the first few days.

Improving Neuromuscular Competence

Each of the factors discussed in phase 1 (and shown in Fig. 39-3) that contribute to depressed neuromuscular competence should be reviewed daily in the ventilated patient. In this phase the importance of nutrition must be recognized. Malnutrition is a common comorbidity of advanced COPD117 and may contribute to respiratory muscle dysfunction as well as to immune suppression. In a randomized trial of standard feeding versus supplementation (1000 kcal above usual), malnourished inpatients with COPD were shown to develop greater respiratory muscle endurance and strength in only 16 days when given extra calories.30 However, excessive refeeding should be avoided since unnecessarily high levels of carbon dioxide production (V̇CO2) may result. Harris-Benedict predictions of resting energy expenditure provide a reasonable estimate in stable COPD patients;117 however, detailed nutritional information including indirect calorimetry may be helpful to guide nutritional management in ACRF (see Chap. 11). When caloric requirements have been assessed, it is usually advisable to supply a large fraction (50% or more) of total calories in the form of lipids, to minimize the respiratory quotient (RQ) and hence V̇CO2. Especially with refeeding, hypophosphatemia commonly develops while the patient is in the ICU, and serum phosphate content should be assessed on a daily basis.

Once the respiratory muscles are rested, a program of exercise should be initiated in conjunction with daily evaluations of readiness for liberation from mechanical ventilation. The goal is to encourage muscle power, tone, and coordination by allowing the patient to assume nonfatiguing respirations, possibly in combination with inspiratory resistive training. This can be achieved by progressively lowering the triggered sensitivity on assist-control, lowering the inspiratory pressure on pressure-support, or through graded T-piece sprints. After a period of work, the patient is returned to full rest to facilitate sleep at night. As strength improves, the amount of exercise can be increased in stepwise fashion until the breathing can be sustained and the patient passes a trial of spontaneous breathing.

During this phase, meticulous attention should be paid to harm reduction and risk avoidance. Prevention and early recognition of venous thromboembolism, gastrointestinal stress ulceration, ventilator-associated pneumonia, integument breakdown (including nasal bridge integrity in NIPPV patients), corneal desiccation, drug side effects, drug-drug interactions, substance withdrawal, and delirium are recommended.

Decreasing Load

Efforts to decrease load should continue. Once the patient is ventilated, it becomes possible to apportion the load into resistive and elastic components (see Chap. 36). These determinations may provide insight into the precipitants of respiratory failure and serve to guide therapy. For example, if the resistive load and PEEPi are minimal, but the elastic load is excessive, there is little to be gained from more aggressive use of bronchodilators. Rather, the source of the elastic load (lung, chest wall, or abdomen; see Fig. 39-3) should be determined and corrected.

It is important to continue treatment with bronchodilators, but whether MDIs and nebulizers are equally effective is controversial.60,118 On the one hand, in a study of drug deposition in ventilated patients, a MDI (plus a holding chamber) was more efficient than a nebulizer.119 In another trial of ventilated patients, MDIs were completely ineffective, despite a cumulative dose in 1 hour of 100 puffs.120 The magnitude and duration of effectiveness of medications given via an MDI and a nebulizer appear to be similar.118 There may be substantial differences related to the method of administration or to the specific equipment used to deliver the drug. We recommend that these drugs be given to effect, whether by MDI or nebulizer. If MDIs are used, the usual number of puffs should be doubled as a starting point to compensate for the reduced delivery of drug to the patient, and the dose increased as needed until bronchodilation is achieved (as assessed by determining respiratory mechanics).

Other contributors to increased load, such as congestive heart failure, pulmonary embolization, and respiratory infection, may be easier to discern once the patient is mechanically ventilated, and they should be sought during this phase. Congestive heart failure can usually be excluded by the physical examination and chest radiograph, although pulmonary edema may have an atypical appearance in patients with advanced emphysema. Only occasionally is the additional information from pulmonary artery catheterization useful. Pulmonary embolism (PE) is much more difficult to exclude. The incidence of PE as a precipitant of ACRF is unknown. The reported frequency of deep venous thrombosis ranges from 9% to 45%.17,121 Large pulmonary emboli are much less common, although the incidence of smaller emboli may not be. Nevertheless, PE is commonly found at autopsy. In patients with ACRF, pulmonary hypertension is virtually universal and diagnosis of PE is difficult. Ventilation-perfusion lung scanning nearly always gives abnormal results, and computed tomographic angiography has been incompletely evaluated in patients with underlying structural lung disease (see Chap. 27). Noninvasive leg studies have been challenged in this setting as well. Capnography has been suggested as a method for excluding PE in patients with ACRF.122

Phase 3: Liberation from the Ventilator

The fundamental principle that guides management in this phase is that successful liberation from the ventilator requires that the premorbid compensated relationship between neuromuscular competence and load be re-established. Therefore a strategy for successfully discontinuing mechanical ventilation emphasizes increasing the strength and decreasing the load, while avoiding sedatives that may impair drive. We use a nurse- or respiratory therapist–led protocol that emphasizes daily testing of readiness for spontaneous breathing, targeted sedation strategies with daily sedation withdrawal, formal spontaneous breathing trials, and triggers for liberation including early extubation to NIPPV as discussed below and reviewed in further detail in Chap. 44. This approach has been demonstrated to be particularly effective in achieving successful ventilator liberation.123 However, similar results may be achieved in well-staffed, well-organized closed-management ICUs where decisions to liberate are directed by expert intensivists.124 Therapy may be highly focused, by measures such as repleting inorganic phosphate, relieving a pneumothorax, addressing neuropsychiatric components including delirium, or managing right heart syndrome. More often a broad assault on many potential precipitants, namely bronchospasm, infection, electrolyte derangement, and fatigue, is used. In either case, when load has been reduced and neuromuscular competence promoted, the patient will be able to breathe free of assistance. On the other hand, if a compensated balance of strength and load cannot be restored, attempts at spontaneous breathing will be futile. A corollary is that the specifics of ventilator management, such as the mode chosen or the device used, are less important.125,126 Only the patient's improving physiology determines the ability to maintain ventilation as determined by the patient's ability to tolerate short periods of unassisted breathing (spontaneous breathing trial). This point has been confirmed by recent trials of weaning methods, which have shown that frequent T-piece trials are superior to intermittent mandatory ventilation (and in some cases, also to pressure-support ventilation), probably because they more readily demonstrate to the physician that the ventilator is no longer necessary.123,126–128 This issue is more fully elaborated in Chap. 44.

Respiratory parameters (negative inspiratory force [NIF], peak pressure [Ppk], plateau pressure [Pplat], and PEEPi; see Chaps. 32 and 36) have historically been used to evaluate the progress of the patient and resolution of the load-strength imbalance. However, the poor individual performance characteristics of these maneuvers make them unreliable for predicting sustained spontaneous breathing and successful liberation.129 However, by daily integrating respiratory parameters of load-strength balance with other validated parameters such as the frequency:tidal volume ratio, the readiness for a spontaneous breathing trial can be determined. Additionally, the impact of therapeutic maneuvers can be assessed by serially evaluating respiratory parameters. For example, while PEEPi remains at 10 cm H2O, there is little point in trying to make the patient breathe without assistance. Indeed, in such a circumstance efforts should be directed to attempting to reduce the work of breathing.130 On the other hand, when PEEPi has resolved and strength is adequate (usually when the NIF >30 cm H2O), mechanical ventilation is no longer necessary and the patient should be able to tolerate at least 30 minutes of spontaneous minimally-assisted breathing.

When discontinuation of mechanical ventilation is imminent, it is useful to anticipate the respiratory pattern that the patient will soon assume. We have been impressed that patients ventilated at supraphysiologic tidal volumes, such as 800 to 1000 mL, experience respiratory distress and agitation when they resume their usual pattern of 30 breaths/min at a tidal volume of 300 mL. By choosing a pattern of mechanical ventilation that more closely approximates spontaneous respiration (e.g., assist-control mode, tidal volume of 420 mL, and a rate of 20 breaths/minute), the transition from the ventilator is smoothed.

For patients that fail to re-establish load-strength balance within 72 hours of initiating therapy, there is a significant prospect of prolonged mechanical ventilation, tracheostomy, and complications that increase the attributable morbidity and mortality. A significant shift in approach involves elective extubation to NIPPV for patients who consistently fail spontaneous breathing trials after 48 to 72 hours. In a randomized controlled trial of NIPPV versus continued intubation and ventilation in 50 ACRF patients failing a T-piece trial at 24 to 36 hours of initial ventilation via an endotracheal tube, NIPPV reduced the period of mechanical ventilation (16.6 ± 11.8 days vs. 10.2 ± 6.8 days; p = 0.021), ICU days (24.0 ± 13.7 days vs. 15.1 ± 5.4 days; p = 0.005), the incidence of nosocomial pneumonia, and mortality at 60 days (8% NIPPV vs. 28% of those on invasive ventilation; p = 0.009), while increasing approximately fourfold the number of patients liberated from ventilation at day 21.131 These findings have been confirmed by others randomizing patients (75% of whom had ACRF) after three failed daily T-piece trials.132 In a meta-analysis of five studies involving 171 patients, extubation to NIPPV translated into an aggregate relative risk reduction of 0.41 [95% CI 0.22 to 0.76].133 NIPPV is likely to tide the patient over the additional days until the balance of neuromuscular competence and respiratory system load is re-established.

Even with appropriate institution of rest on the ventilator, rapid application of the algorithms given above or correction of abnormalities of neuromuscular competence and load, and progressive exercise of the patient, some patients require protracted periods of ventilator support. Indeed, with the wider use of NIPPV and the avoidance of intubation in all but the most severely impaired patients, it may be the case that in the future ICUs will encounter truly difficult-to-wean patients. The principles elaborated above still apply to this group, with a few additional comments. After approximately 7 days of ventilator dependence, we typically assess the patient for tracheostomy (see Chap. 35). If it appears that liberation from mechanical ventilation may succeed within another week, tracheostomy is usually not performed, and efforts continue to extubate the patient. If we judge that the course will be protracted, we prefer bedside percutaneous tracheostomy for purposes of patient comfort, communication, and avoidance of complications associated with translaryngeal intubation. If progress to liberation is likely to be very slow after the first couple of weeks, many ICUs will consider transferring the stable patient to a long-term acute care facility with dedicated expertise in pulmonary rehabilitation and liberation from mechanical ventilation. Despite the overall poor prognosis for such compromised patients, these facilities have demonstrated superior expertise in liberating a significant proportion even after long periods of ventilation for ACRF.134 Optimal results are achieved when a protocolized multidisciplinary care pathway involves specialist respiratory care, rehabilitation, nutrition, and physical therapy departments.

Following extubation, careful serial assessments are in order. Deterioration in the hours just following extubation suggests upper airway edema. In the uncomplicated patient, the respiratory rate falls slightly through the first day, most often into the mid-twenties to low thirties. Efforts to build strength and reduce load should continue in order to protect the gains that have been made. Once the patient is stable off the ventilator, a prompt transfer tothe more benign setting of the general ward should be encouraged.

Recurrence of respiratory failure is an ominous but not infrequent complication for which efforts to stave off intubation may prove fruitless and potentially harmful. When 221 patients with recurrent respiratory failure within 48 hours of initial ventilator liberation (only 12% had COPD) were randomized to either NIPPV or usual care, equal numbers progressed to intubation (48%), but the ICU mortality rate at an interim analysis was 25% in the NIPPV vs. 14% in the usual care arm (RR 1.78; 95% CI 1.03 to 3.20; p = 0.048).135

For many patients, liberation from prolonged mechanical ventilation is associated with a decision to change the goals of care from “treatment-for-cure” to “treatment-for-comfort.” Decisions to withhold and withdraw life-sustaining therapy entail extensive involvement of the patient, as well as their care providers, ICU staff, chaplaincy, hospital ethics, and social work support. Pertinent to the terminal care of the ACRF patient are meticulous attention to palliation of terminal dyspnea, pain, and delirium. This subject is covered in Chap. 17.