Severe Asthma Exacerbation

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60 Severe Asthma Exacerbation

Thomas C. Corbridge, Susan J. Corbridge

Magnitude of the Problem

Each year in the United States, acute asthma accounts for approximately 1.8 million emergency department visits, 497,000 hospitalizations, and 3800 deaths.¹ All too commonly, failure to achieve adequate outpatient control lies at the crux of the problem. Asthma control is achieved in a minority of patients, largely due to the underuse of antiinflammatory agents, and poor control is a risk factor for asthma exacerbation.² More than half of current asthmatics had one or more attacks during the preceding year, and there appears to be a subset of patients who are prone to exacerbations. Factors underlying the exacerbation-prone phenotype include cigarette smoking, medication nonadherence, psychosocial factors, poverty, obesity, and alterations in host cytokine response to viral infections.³ The rate of asthma death is higher in blacks than whites and in patients aged 65 and older. Patients who require mechanical ventilation for asthma have a mortality rate of less than 10% and are most likely to die of tension pneumothorax or nosocomial infection.⁴ Fortunately, the rate of asthma death (which had increased from 1980 to 1995) has decreased each year since 2000. Risk factors for fatal or near-fatal asthma are listed in Table 60-1.

TABLE60-1 Risk Factors for Fatal or Near-Fatal Asthma

Pathophysiology of Acute Airflow Obstruction

Less than 15% of asthmatics have rapid-onset exacerbations. These are predominantly bronchospastic events resulting in significant airflow obstruction within minutes to a few hours. They occur from exposure to an allergen or irritant, stress, inhalation of illicit drugs, or the use of a nonsteroidal antiinflammatory agent or beta-blocker in susceptible patients. The trigger is generally not infectious and may remain unidentified.

Asthma attacks most commonly evolve over 24 hours and are associated with increasing airway wall inflammation and mucus plugs. These exacerbations are commonly triggered by viral infections (e.g., rhinovirus, influenza virus, respiratory syncytial virus) or mycoplasma and take longer to resolve.

Regardless of the tempo of the attack, acutely ill asthmatics develop critical airflow obstruction. The time available for expiration (less than 2 seconds in a patient breathing 30/min) is insufficient for full exhalation, resulting in gas trapping and dynamic lung hyperinflation (DHI). Trapped gas elevates alveolar volume and pressure relative to mouth pressure at end-expiration, a state referred to as auto-PEEP.⁵ Auto-PEEP must be overcome by forcefully lowering pleural pressure during spontaneous inspiration, which increases the inspiratory work of breathing. At the same time, dynamic hyperinflation increases elastic work of breathing. Dynamic hyperinflation also decreases diaphragm force generation by placing the diaphragm in a mechanically disadvantageous position. Dynamic hyperinflation may be self-limiting because increases in lung volume increase lung elastic recoil pressure and airway diameter to augment expiratory flow. In the end, an imbalance between increased respiratory system load (both resistive and elastic) and decreased respiratory muscle strength may result in respiratory failure.⁶

Hypoxemia results from decreased ventilation () to perfused () alveolar-capillary units. The severity of hypoxemia roughly tracks the severity of obstruction, but in recovering patients, airflow rates may improve faster than PaO₂ and inequality, indicating that larger airways recover faster than smaller airways. Multiple inert gas elimination technique (MIGET) analysis also demonstrates small areas of high relative to and slightly increased physiologic dead space in acute asthma. This may result from decreased blood flow to hyperinflated lung units. Elevated dead space and decreased minute ventilation in the critically hyperinflated and fatiguing patient underlie the development of hypercapnia in severe exacerbations.

Large swings in intrathoracic pressure accentuate the normal inspiratory fall in systolic blood pressure, a phenomenon referred to as pulsus paradoxus. During vigorous inspiration, intrathoracic pressure falls, lowering right atrial and right ventricular pressures and thereby augmenting right ventricular (RV) filling. Enhanced right-sided filling shifts the intraventricular septum leftward, causing a conformational change in the left ventricle (LV), LV noncompliance, and incomplete LV filling. Furthermore, LV filling may be impeded by dynamic hyperinflation, causing tamponade-like physiology; LV emptying is impaired by large negative pleural pressures and increased LV afterload.

During forced expiration, high intrathoracic pressures impede right-sided filling during asthma exacerbations. The net result of cyclical changes in pleural pressure is pulsus paradoxus. Importantly, however, an increase in pulsus paradoxus does not occur when decreased respiratory muscle strength limits the magnitude of pleural pressure change.

Clinical Features

Dyspnea, cough, wheeze, and increased work of breathing are the hallmarks of acute asthma. Patients with moderate to moderately severe attacks are tachypneic and in mild to moderate respiratory distress. They have expiratory phase prolongation, difficulty speaking in long sentences, and audible wheezes. Arterial blood gases commonly reveal hypoxemia and acute respiratory alkalosis. A more severe attack leads to upright positioning, diaphoresis, monosyllabic speech, respiratory rate above 30/min, accessory muscle use, pulse above 120/min, pulsus paradoxus greater than 25 mm Hg, hypoxemia, and normo- or hypercapnia. Depressed mental status, paradoxical respiration, bradycardia, absence of pulsus paradoxus from respiratory muscle fatigue, and a quiet chest signal an impending arrest. The emergence of wheezes in these patients is generally a good marker that airflow has improved. Thus posture, speech, and mental status allow for a quick appraisal of severity, response to therapy, and need for intubation.⁷

The common cardiac response to acute asthma is sinus tachycardia. Supraventricular and ventricular arrhythmias occur rarely. Severe exacerbations may also cause right heart strain and myocardial ischemia.

Differential Diagnosis

“All that wheezes is not asthma” is an adage worth remembering. In heavy smokers over the age of 40, consider an acute exacerbation of chronic obstructive pulmonary disease. In patients with congestive heart failure, bear in mind that elevated left atrial pressure can cause wheezing. Pulmonary embolism rarely causes wheeze, but this possibility should be considered when dyspnea is out of proportion to signs and measures of expiratory flow. Vocal cord dysfunction (and other causes of upper airway obstruction) should be considered when there is stridor, normal oxygenation, or resolution of airflow obstruction after intubation. Tracheal stenosis (e.g., subglottic stenosis from prior intubation or bronchogenic cancer) may also present with breathlessness and wheezing. Finally, foreign-body aspiration should be considered in the very young and old, in individuals with altered mental status or neuromuscular disease, and if symptoms developed after eating or dental work. Pneumonia should be considered in the febrile patient with cough and phlegm when there are localizing signs on physical examination, and hypoxemia does not correct with low-flow oxygen.

Peak Flow Measurements

To avoid underestimating the severity of an asthma exacerbation, it is important to objectively measure the degree of airflow obstruction. Clinicians often underestimate the degree of obstruction and may alter therapy after peak expiratory flow rate (PEFR) determination. Patients perform slightly better than clinicians at estimating severity, but there is still variability in perception. Peak flow measurements should be deferred in patients with severe exacerbations; the maneuver can worsen bronchospasm even to the point of arrest.

The change in PEFR or FEV₁ (forced expiratory volume in the first second of expiration) predicts the need for hospitalization. Several studies have demonstrated that failure of initial therapy to improve expiratory flow significantly after 30 to 60 minutes predicts a refractory course requiring continued treatment in the emergency department (ED) or hospitalization.

Acid-Base Status

Arterial blood gas determination is recommended in patients with severe attacks (e.g., when FEV₁ is less than 1 L or PEFR is less than 200 L/min). However, serial blood gases are generally not necessary unless the patient is mechanically ventilated. Hypoxemia and respiratory alkalosis are common in mild to moderate exacerbations. Eucapnia and hypercapnia indicate a severe exacerbation, but they are in and of themselves not sufficient reasons for intubation, because these patients may still respond adequately to pharmacotherapy. Conversely, the absence of hypercapnia does not preclude a life-threatening attack.

In response to acute respiratory alkalosis of sufficient duration, there may be renal wasting of bicarbonate and development of a post-hypocapnic metabolic acidosis. Lactic acidosis occurs, particularly in patients with labored breathing who receive parenteral β-agonists.

Chest Radiography

In classic cases of acute asthma, the chest x-ray rarely affects management. A chest x-ray should be obtained when there are localizing signs on examination, concerns regarding barotrauma, or questions regarding diagnosis. Chest x-rays are also indicated in intubated patients to confirm proper endotracheal tube position.

Emergency Department Disposition

Asthmatic patients with inadequate response to albuterol in the ED invariably require hospital admission or prolonged treatment in an ED holding area (see later).⁸ Approximately one-third of patients are nonresponders to albuterol (Figure 60-1), which is not necessarily explained by prior heavy use of this medication. Rather, nonresponsiveness suggests a significant component of airway wall inflammation and the presence of intraluminal mucus. Albuterol nonresponders have negligible (i.e., <10%) changes in their PEFR after 30 to 60 minutes of therapy. These patients should be admitted to the hospital, as should patients with other markers of a severe attack such as a PEFR less than 40% of predicted or personal best PEFR, or deterioration despite ED treatment. Patients with respiratory failure, need for frequent albuterol treatments, fatigue, altered mental status, and cardiac arrhythmias require intensive care unit admission. Patients with an incomplete response to treatment in the ED, defined by improved but persistent symptoms and a PEFR or FEV₁ between 40% and 69% of predicted, should be considered for admission, although selected patients safely return home with appropriate treatment and follow-up. Patients with a good response to treatment may be discharged home with appropriate instructions for anti-inflammatory therapy. These patients have a PEFR ≥ 70% an hour after their last treatment, a clear chest, and are in no distress.

Figure 60-1 Dose-response relationship to albuterol 4 puffs (400 µg) every 10 minutes in 116 acute asthmatics. Sixty-seven percent of patients obtained discharge criteria after administration of 2.4 mg albuterol within 1 hour; half of responders met discharge criteria after 12 puffs. Patients with a blunted cumulative dose-response relationship were hospitalized.

(Reproduced with permission from Rodrigo C, Rodrigo G. Therapeutic response patterns to high and cumulative doses of salbutamol in acute severe asthma. Chest. 1998;113:593.)

Oxygen

Supplemental oxygen should be provided to maintain arterial oxygen saturations greater than 90% (>95% in pregnancy). This improves oxygen delivery to tissue beds including the respiratory muscles and reverses hypoxic pulmonary vasoconstriction. Oxygen further protects against β-agonist-induced pulmonary vasodilation and increased blood flow to low units. Oxygen saturation should be monitored until there is clear clinical progress, remembering that improved oxygenation may lag behind improved airflow rates.

Pharmacologic Management

Selected drugs used in the treatment of acute asthma are presented in Table 60-2. Brief discussions of a few of the more common therapeutic agents employed to treat severe asthma exacerbation follow.

TABLE60-2 Selected Drugs Used in the Treatment of Acute Asthma

Albuterol	2.5 mg in 2.5 mL normal saline by nebulization every 15-20 min × 3 in the first hour or 4-8 puffs by MDI with spacer every 10-20 min for 1 hour, then as required; for intubated patients, titrate to physiologic effect and side effects.
Levalbuterol	1.25 mg by nebulization every 15-20 min × 3 in the first hour, then as required.
Epinephrine	0.3 mL of a 1 : 1000 solution subcutaneously every 20 min × 3. Terbutaline is favored in pregnancy when parenteral therapy is indicated. Use with caution in patients older than age 40 and in patients with coronary artery disease.
Corticosteroids	Methylprednisolone IV or prednisone PO 40-80 mg/d in 1 or 2 divided doses until PEFR reaches 70% of predicted or personal best.
Anticholinergics	Ipratropium bromide 0.5 mg (with albuterol) by nebulization every 20 min, or 8 puffs by MDI with spacer (with albuterol) every 20 min.
Magnesium sulfate	2 g IV over 20 minutes, repeat once as required (total dose 4 g, unless hypomagnesemic).

IV, intravenous; MDI, metered-dose inhaler; PEFR, peak expiratory flow rate; PO, per os (oral).

β₂-agonists

Inhaled short-acting β₂-agonists (SABAs) are the preferred drugs to treat the bronchospastic component of acute asthma. They should be delivered in a repetitive or continuous fashion depending on clinical response and side effects. A commonly recommended strategy is albuterol, 2.5 mg by nebulization, every 20 minutes during the first hour of ED management. In severe asthma exacerbations, continuous administration (same total dose) may be slightly superior to repetitive dosing, although there is little difference between the two strategies in most cases. Albuterol can be delivered effectively by metered dose inhaler (MDI); 4 to 8 puffs of albuterol by MDI with a spacer is equivalent to a 2.5-mg nebulizer treatment. MDIs with spacers are cheaper and faster; hand-held nebulizers require less supervision and coordination. Treatment frequency after the first hour depends on clinical response and side effects.

Although albuterol is the most widely used SABA, other SABAs are available, including levalbuterol, bitolterol, and pirbuterol. Levalbuterol in one-half the milligram dose of albuterol provides comparable efficacy and safety but has not been studied by continuous administration. Bitolterol and pirbuterol have not been studied in severe asthma exacerbations.

There is no advantage to subcutaneous epinephrine or terbutaline in the initial management of acute asthma unless the patient is unable to comply with inhaled therapy. In refractory cases, however, subcutaneous treatment in the absence of contraindications may confer additional benefit. β-Agonists are generally well tolerated in younger patients; tremor and tachycardia are common, but serious toxicity is rare. Subcutaneous injections are riskier and should be used with caution in older patients at risk for coronary artery disease. Long-acting β₂-agonists (LABAs) are not recommended for treatment of acute asthma, although limited data demonstrate formoterol (which has acute onset of action) is effective and safe in this setting. Combination therapy with a LABA and an inhaled corticosteroid (ICS) may be initiated or continued in hospitalized patients receiving rescue therapy. LABA/ICS combination therapy may be required to achieve adequate outpatient asthma control and decrease the risk of future attacks.

Ipratropium Bromide

The modest bronchodilator properties of ipratropium bromide preclude its use as a single agent in acute asthma. However, ipratropium bromide added to albuterol appears to be more effective than albuterol alone. The expert panel of the National Institutes of Health recommends adding ipratropium bromide to albuterol, particularly in patients with severe exacerbations, to improve flow rates and decrease hospitalizations. For nebulization in adults, 0.5 mg of ipratropium bromide is added to 2.5 mg of albuterol; by MDI, 8 puffs of ipratropium bromide are added to 4 to 8 puffs of albuterol by MDI. If a combination albuterol/ipratropium bromide inhaler is used, the recommended dose is 8 puffs every 20 minutes for the first 1 to 3 hours as guided by clinical response and toxicity.

Corticosteroids

Most acutely ill asthmatics are not taking corticosteroids (either inhaled or oral) prior to ED arrival. In the ED, systemic corticosteroids are recommended for all patients save the rare patient who has a marked immediate and durable response to initial SABA therapy (who should invariably be started on an ICS before ED discharge).

Corticosteroids treat the inflammatory component of asthma by promoting new protein synthesis. Their effects are typically delayed, underlining the importance of early initiation. If initiated early in the ED, systemic corticosteroids decrease hospitalization rates. They also decrease the chance of relapse after discharge. In hospitalized patients, systemic corticosteroids improve the rate of recovery.

Oral steroids are as effective as parenteral steroids. Single-dose formulations of an intramuscular preparation should be considered in an ED patient who is deemed unlikely to take oral corticosteroids after discharge.

Various dosing regimens have been studied, and debate continues regarding the optimal dosing strategy. For hospitalized adults, the Expert Panel Report 3 recommends 40 to 80 mg/d of prednisone, methylprednisolone, or prednisolone in 1 or 2 divided doses until PEFR reaches 70% of predicted or the patient’s personal best. For outpatients, a common strategy is to use prednisone, 40 mg/d for 5 to 10 days, with early follow-up to judge clinical response and optimize the outpatient regimen.

There is no established role for high-dose ICSs in acute asthma. However, ICSs play a pivotal role in achieving outpatient asthma control. Patients discharged from the ED or hospital after an asthma attack should be started on an ICS-based treatment program combined with adequate education regarding ICS use.

Other Therapies

Aminophylline does not confer additional bronchodilation in adults compared to standard care with β₂-agonists. It increases the frequency of adverse effects such as tachyarrhythmias, and therefore should only be used by seasoned clinicians facing refractory cases.

Prospective trials have yielded conflicting results regarding the use of magnesium sulfate (MgSO₄) in acute asthma. The general consensus is that intravenous (IV) MgSO₄ is not effective in mild to moderate exacerbations. In patients with severe exacerbations, however, MgSO₄ is safe and may improve airflow rates. The dose in adults is 2 gm by vein over 20 minutes. Additional, albeit limited, data support the use of inhaled MgSO₄ in acute asthma.

There are insufficient data to recommend leukotriene modifiers in acute asthma. The most compelling data come from randomized trials of IV montelukast in adults, but the IV formulation is not available in the United States.

Studies of heliox have been plagued by methodological differences, small patient numbers, and failure to control for concurrent upper airway obstruction (e.g., vocal cord dysfunction). Taken in sum, the available data do not support its routine use in acute asthma. However, heliox can be conditionally recommended in patients with severe asthma attacks as a way to potentially decrease work of breathing. The gas is easily administered by tight-fitting face mask, and its effects (or lack thereof) can be determined within seconds to minutes after administration. Limited data further support the use of heliox as a driving gas during albuterol nebulization to improve bronchodilator delivery.

Noninvasive Ventilation

Noninvasive ventilation (NIV) has not been studied extensively in acute asthma. There are no large, well-designed randomized trials to inform its use in this setting, but a recent systematic review of the available literature suggests it may be beneficial in selected patients with respiratory failure, perhaps by decreasing work of breathing. Data also suggest that the coupling of albuterol nebulization with noninvasive positive-pressure ventilation (NPPV) may be superior to nebulization alone in acute asthma.

Noninvasive ventilation includes the use of low levels of nasal continuous positive airway pressure (CPAP) of 5 to 7.5 cm H₂O or, more commonly, bilevel positive airway pressure (BiPAP). One approach to BiPAP use is to start with 8 cm H₂O inspiratory pressure support and 3 cm H₂O of expiratory positive airway pressure. These pressures can be adjusted as required to 15 cm H₂O for inspiration and 5 cm H₂O during expiration to achieve common endpoints of improved patient comfort, RR below 25 and tidal volume above 7 mL/kg.⁹ Noninvasive ventilation should only be used in alert, cooperative, and hemodynamically stable patients who do not need an endotracheal tube for airway protection or secretion clearance.

Intubation and Mechanical Ventilation

Respiratory arrest or impending respiratory arrest (e.g., extreme exhaustion, a quiet chest, progressive hypercapnia, and altered mental status) are indications for intubation. Oral intubation is preferred because it allows for a larger endotracheal tube, which lowers airway resistance and helps remove mucus plugs. Nasal intubation is not recommended because it necessitates a smaller tube and may be complicated by nasal polyps and sinusitis.

Postintubation Hypotension

The time immediately after intubation can be difficult for patients with severe airflow obstruction, and care must be taken to stabilize the patient by the thoughtful use of sedatives, paralytics, bronchodilators, intravenous fluids, and positive-pressure ventilation. A common problem in the immediate postintubation period is hypotension which stems from loss of vascular tone with sedation or paralysis, hypovolemia, tension pneumothorax, and—importantly—overzealous mechanical ventilation.

Inappropriately fast respiratory rates during mechanical ventilation result in inadequate exhalation time and dangerous levels of dynamic hyperinflation. Clues to this condition include (1) excessive efforts required to deliver manual breathes during Ambu bag ventilation and high airway pressures and (2) hypotension and tachycardia. When critical dynamic hyperinflation is suspected, a trial of hypopnea (2-3 breaths/min) or apnea in a well-oxygenated patient for 30 to 60 seconds is both diagnostic and therapeutic. This maneuver lowers lung volumes and airway pressures and increases cardiac preload to help regain cardiopulmonary stability. However, close inspection of the chest radiograph is mandatory in all hypotensive patients to rule out pneumothorax, which invariably requires tube thoracostomy (unilateral or bilateral as required).

Initial Ventilator Settings

Expiratory time (Te), tidal volume (VT), and the severity of airway obstruction determine the level of dynamic hyperinflation during mechanical ventilation (Figure 60-2).^10,¹¹ Expiratory time is determined by minute ventilation (RR × VT) and the inspiratory flow rate. To illustrate this point, consider the following hypothetical ventilator settings: RR 15/min; VT 1000 mL, and an inspiratory flow rate of 60 LPM (or 1 LPS). In this example, the respiratory cycle time (the total amount of time allowed for one complete breath) is 4 seconds (Figure 60-3). Inspiratory time (Ti) is 1 second, and Te is 3 seconds, resulting in an I : E of 1 : 3. If these settings caused critical dynamic hyperinflation, lowering RR to 10/min would prolong respiratory cycle time to 6 seconds and Te to 5 seconds (I : E of 1 : 5), thus providing additional exhalation time. Granted, the additional volume of gas emptied by this strategy may be small because of low expiratory flow rates, but even small changes in lung volume may be clinically relevant. Now consider the effect of increasing inspiratory flow. If inspiratory flow is increased from 60 LPM to 120 LPM, then Ti would decrease to 0.5 seconds, and with a RR of 15/min, Te would increase from 3 seconds to 3.5 seconds. High inspiratory flow rates, however, increase peak airway pressures, and though high peak airway pressures themselves do not correlate with outcome, they might worsen patient-machine synchrony. Furthermore, high inspiratory flow rates may have the untoward effect of increasing respiratory rate in spontaneously breathing patients, thereby decreasing Te. On the other hand, if too low an inspiratory flow is used, Te falls and dynamic hyperinflation increases.

Figure 60-2 Effects of ventilator settings on airway pressures and lung volumes during normocapnic ventilation of eight paralyzed asthmatic patients. V_EE, lung volume at end-expiration; V_EI, lung volume at end-inspiration; P_pk, peak airway pressure; P_plat, end-inspiratory plateau pressure, V_E, minute ventilation, V_I, inspiratory flow. The numerals 7 and 8 are patient numbers. The numerals < 0.001, < 0.01, and < 0.02 are P values. A, As inspiratory flow is decreased from 100 L/min to 40 L/min at the same V_E, P_pk falls, but hyperinflation increases due to dynamic gas trapping. B, Dynamic hyperinflation is reduced by low respiratory rates and high tidal volumes (as long as V_E is decreased), but high tidal volumes result in high P_plat.

(Reproduced with permission from Tuxen DV, Lane S. The effects of ventilatory pattern on hyperinflation, airway pressures and circulation in mechanical ventilation of patients with severe air-flow obstruction. Am Rev Resp Dis. 1987;136:872.)

Figure 60-3 Effects of changing respiratory rate (RR) on expiratory time (Te) with a VT of 1000 mL and a constant inspiratory flow rate of 60 LPM (1 LPS). Note that with RR of 15/min (solid line), total cycle time (amount of time allowed for one complete breath) is 4 seconds. Inspiratory time (Ti) is 1 second, and Te is 3 seconds, resulting in an I : E of 1 : 3. By lowering RR to 10/min (dotted line) total cycle time increases to 6 seconds, and Te is 5 seconds, resulting in an I : E of 1 : 5. Lower RR allows for greater exhalation of the delivered breath and lower end-expiratory plateau pressure (not shown), although effects are modest because of low end-expiratory flow rates.

A reasonable compromise is to choose an inspiratory flow rate of 60 LPM and an initial minute ventilation of 7 to 8 L/min in a 70-kg patient to avoid dangerous levels of dynamic hyperinflation.¹² This can be achieved by setting the RR between 12 and 14/min and VT between 7 and 8 mL/kg. In spontaneously breathing patients, low levels of machine-set PEEP (e.g., 5 cm H₂O) decrease inspiratory work of breathing by decreasing the pressure gradient required to overcome auto-PEEP, without aggravating lung inflation. There are no randomized trials of ventilator mode in acute asthma. In paralyzed patients and other patients not breathing above the set respiratory rate, synchronized intermittent mandatory ventilation (SIMV) and assist-controlled ventilation (AC) are identical. In patients triggering the ventilator, AC may increase Ve more than SIMV, but SIMV may increase work of breathing. Depending on the institution, volume-controlled ventilation (VC) may be recommended over pressure-controlled ventilation (PC) because of greater staff familiarity with its use. Pressure control offers the advantage of limiting peak airway pressure to a predetermined set value (e.g., 30 cm H₂O) and has been used successfully in children with severe asthma exacerbation. During PC, VT is inversely related to auto-PEEP, and Ve is not guaranteed, requiring appropriate use of minute ventilation/tidal volume alarms.

Assessing Lung Inflation

In concept, the degree of dynamic hyperinflation is central to ventilator adjustments, but there are inherent problems with measuring the degree of hyperinflation in clinical practice. The only validated method is to measure the volume gas at end-inspiration, termed Vei, by collecting expired gas from total lung capacity (TLC) to functional residual capacity (FRC) during 40 to 60 seconds of apnea. Although Vei may underestimate air trapping in the presence of slowly emptying lung units, a Vei greater than 20 mL/kg correlates with barotrauma. The utility of this measure is limited by the need for paralysis and staff expertise with expiratory gas collection. Alternate measures of lung inflation include the single-breath plateau pressure (Pplat) and auto-PEEP. Accurate measurements of Pplat and auto-PEEP require patient-ventilator synchrony and the absence of patient interference. Paralysis is generally not required. However, neither pressure has been validated as a predictor of outcome. Pplat (or lung distension pressure) is an estimate of average end-inspiratory alveolar pressure that is determined by briefly stopping flow at end-inspiration (Figure 60-4), but Pplat is also affected by properties of the chest wall and abdomen. For example, Pplat will be higher in a patient with abdominal distension or obesity for the same degree of hyperinflation. Nevertheless, experience suggests that a Pplat less than 30 cm H₂O generally correlates with favorable outcomes.

Figure 60-4 Pressure-time tracing during mechanical ventilation demonstrating measurement of peak inspiratory pressure (Ppk), plateau pressure (Pplat), and auto-PEEP. While delivering a constant inspiratory flow (not shown), airway pressure (Paw) increases to Ppk, the sum of airway resistive pressure and Pplat. Airway resistive pressure and Pplat are determined by an end-inspiratory hold maneuver during which inspiratory flow is temporarily stopped during one breath to eliminate airway resistive pressure, allowing Paw to fall from Ppk to Pplat. If inspiratory flow is set at 60 L/min, the resistance pressure drop equals airway resistance (Raw) in units of cm H₂O/L/sec. An end-expiratory hold maneuver is performed to measure auto-PEEP. During this maneuver, Paw increases by the amount of auto-PEEP present. Note that end-inspiratory and end-expiratory hold maneuvers are performed on different breaths.

Auto-PEEP is the lowest average alveolar pressure achieved during the respiratory cycle. It is obtained by measuring airway opening pressure during an end-expiratory hold maneuver (Figure 4) and does not estimate end-inhalation volume or pressure. Persistence of expiratory gas flow at the beginning of inspiration (which can be detected by auscultation or flow tracings) also suggests auto-PEEP (Figure 60-5). As with Vei, auto-PEEP may underestimate the severity of dynamic hyperinflation when there is poor communication between the alveoli and airway opening. In general, however, auto-PEEP less than 15 cm H₂O is likely acceptable.

Figure 60-5 Flow-time tracings in a normal subject and a patient with asthma during mechanical ventilation. Note that peak expiratory flow rates are diminished in asthma because of increased airway resistance and that increased expiratory time is required to exhale the tidal breath. In the asthmatic patient, expiratory flow persists at the time of the next delivered breath (as demonstrated by failure of the exhalation flow tracing to return to baseline or zero flow), suggesting the presence of auto-PEEP.

Ventilator Adjustments

We offer the following approach to ventilator adjustments in severe asthma (Figure 60-6). This approach relies on Pplat as the measure of dynamic hyperinflation and arterial pH as a surrogate marker of ventilation. If initial ventilator settings result in Pplat above 30 cm H₂O, RR should be reduced to decrease Pplat below 30 cm H₂O. Decreasing RR may cause hypercapnia. Fortunately, hypercapnia is generally well tolerated in this patient population. Anoxic brain injury and myocardial dysfunction are contraindications to permissive hypercapnia because of the potential for hypercapnia to dilate cerebral vessels, decrease myocardial contractility, and constrict pulmonary vasculature. Lowering RR may not increase PaCO₂ as much as expected if it decreases the degree of hyperinflation and thereby lowers dead space. If hypercapnia results in a blood pH of less than 7.20, and RR cannot be increased because Pplat is at its limit, we consider an infusion of sodium bicarbonate, although bicarbonate has not been shown to improve outcome. If Pplat is less than 30 cm H₂O and pH is less than 7.20, RR can be safely increased until Pplat nears the 30 cm H₂O limit.

Figure 60-6 Recommendations for initial ventilator settings and subsequent ventilator adjustments based on Pplat (end-inspiratory plateau pressure) and arterial pH in patients with severe asthma exacerbation.

Sedation and Paralysis

Sedation improves comfort, safety, and patient-ventilator synchrony. In patients who may be extubated within hours (such as those with rapid onset asthma), propofol is recommended because it can achieve a deep level of sedation while allowing for rapid reversal after discontinuation. Benzodiazepines such as lorazepam and midazolam are less expensive alternatives, but time to awakening is less predictable.

To provide amnesia, sedation, analgesia, and suppress respiratory drive, morphine or fentanyl can be added by continuous infusion to either propofol or a benzodiazepine. For all patients, daily interruption of sedatives and analgesics avoids undue accumulation.

Ketamine is an IV anesthetic with sedative, analgesic, and bronchodilating properties. In most cases it is reserved for intubated patients with refractory and critical obstruction. Ketamine should be used with caution because of its sympathomimetic effects and ability to cause delirium.

When safe and effective mechanical ventilation cannot be achieved by sedation alone, consider short-term muscle paralysis. Cisatracurium is essentially free of cardiovascular effects, does not release histamine, and does not rely on hepatic and renal function for clearance. Pancuronium is a less expensive alternative, but it lasts longer and may increase heart rate. Pancuronium and atracurium both release histamine, but this is of unclear clinical significance in the setting of severe asthma exacerbations.

Paralytics may be given intermittently by bolus or continuous IV infusion. Continuous infusions mandate the use of a nerve stimulator (or interruption of drug every 4-6 hours) to avoid drug accumulation and prolonged paralysis. The use of paralytics has been associated with additional complications including myopathy, venous thromboembolism, and ventilator-associated pneumonia. Paralytics should be discontinued as soon as possible to minimize risk.

Use of Bronchodilators During Mechanical Ventilation

Additional controlled trials are needed to inform the optimal use of bronchodilators in intubated patients and to provide additional evidence for or against current recommendations. One consistent observation is that intubated patients require higher drug dosages to achieve a clinical effect. This may reflect the refractory nature of these patients or inadequate dose or delivery. Whether bronchodilators are delivered by MDI or nebulizer, there is little doubt that good patient-ventilator synchrony helps delivery. When MDIs are used during mechanical ventilation, a spacing device on the inspiratory limb of the ventilator is mandatory. When nebulizers are used, they should be placed close to the ventilator, and in-line humidifiers should be stopped during treatments. Dropping the inspiratory flow rate to approximately 40 L/min during nebulization helps minimize turbulence, but this strategy may worsen the extent of hyperinflation and should be time-limited.

Regardless of whether an MDI with spacer or nebulizer is used, higher drug dosages are required, and the dosage should be titrated to achieve a fall in the peak-to-pause airway pressure gradient (Figure 60-7). When no measurable drop in airway resistance occurs, other causes of elevated airway resistance such as a kinked or plugged endotracheal tube should be excluded. Moreover, it may be reasonable to consider a drug holiday in patients who do not demonstrate a physiologic response to appropriately delivered medications.