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Original Article

September 2001

ACUTE SEVERE ASTHMA: A STEPWISE APPROACH TO THERAPY Author:

Thomas Corbridge, MD. Associate Professor of Medicine. Northwestern University Medical School Director, Medical Intensive Care Unit. Northwestern Memorial Hospital. Chicago, IL. USA. e-mail: tcc734@nwu.edu

Pubmed:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=9792570

Introduction
Therapy of acute severe asthma is intended to restore a state of unlabored breathing --without complication. Fortunately this goal is often achieved by pharmacotherapy alone. Refractory patients may require intubation and mechanical ventilation to prevent respiratory arrest and anoxic brain injury. Importantly patients with acute asthma should receive a comprehensive asthma program with components of education, peak expiratory flow rate (PEFR) monitoring, environmental control, anti-inflammatory therapy, and a written action plan to decrease risk of future exacerbation, hospitalization, and death.

How to use a peak flow meter. Jain P, et al. Clev Clin J Med 1997; 64: 195-202.

ACUTE SEVERE ASTHMA: A STEPWISE APPROACH TO THERAPY

Spirometric data expressed as a function of clinical observations. Data expressed as mean SEM. Leatherman J. Clin Chest Med 1994; 15: 453-479.

In this brief paper I will review a stepwise approach to therapy of the acutely ill asthmatic with attention to pharmacotherapy and mechanical ventilation. I would like to begin with a review of pathophysiology insofar as it provides the rationale for drug and ventilator management.

Pathophysiology
The basic problem in acute severe asthma is critical airway narrowing stemming from variable combinations of bronchospasm, airway wall inflammation and mucus plugging. In sudden asphyxic asthma, severe airflow obstruction develops in less than 3 hours. This condition results primarily from smooth-muscle mediated bronchospasm. More often, airflow obstruction worsens over a longer period of time due to combinations of bronchospasm and airway wall edema and inflammation. Airway obstruction delays expiratory gas flow and results in incomplete alveolar gas emptying. In severe cases, inspiration (whether spontaneous or assisted) occurs before complete expiration. This elevates lung volume; a state referred to as dynamic lung hyperinflation (DHI). DHI is self-limiting in a spontaneously breathing patient because DHI increases lung elastic recoil pressure and airway diameter, factors favoring expiratory airflow. A new steady state occurs when expiratory airflow is adequate to exhale the inspired breath at the larger lung volume. Elevated alveolar volume and pressure at end-exhalation is called auto positive end expiratory pressure (auto-PEEP). Auto-PEEP is a threshold pressure that must be overcome before inspiratory flow can occur. This load is imposed on a diaphragm that is placed in a mechanically disadvantageous position by DHI, predisposing to ventilatory failure. Dead space increases in acute severe asthma, presumably due to hypoperfusion of regions of hyperinflated lung. An increase in the dead space to tidal volume ratio (VD/VT) favors hypercapnia. Nevertheless, mild (early)

ACUTE SEVERE ASTHMA: A STEPWISE APPROACH TO THERAPY

acute asthma results in acute respiratory alkalosis because of increased minute ventilation (VE). As airflow obstruction increases or fatigue develops, PaCO2 increases due to inadequate alveolar ventilation (VA) (which reflects an increase in VD/VT and a decrease in VE as the patient nears respiratory arrest). Importantly, the lack of hypercapnia does not exclude impending respiratory arrest; conversely, hypercapnia alone is not an indication for intubation. Airway obstruction causes maldistribution of alveolar ventilation relative to perfusion (low V/Q) -- not shunt. Therefore, correction of hypoxemia requires minimal enrichment of inspired oxygen (1-3 L/min by nasal cannula). If more oxygen support is required, then other conditions should be considered such as pneumonia, aspiration, acute lobar atelectasis, or pneumothorax. Hypoxemia resulting from peripheral airway obstruction may occur sooner and/or resolve later than airflow rates that predominantly reflect large airway function. Circulatory changes in acute severe asthma include tachycardia and a widened pulsus paradoxus. The latter reflects decreased left ventricular (LV) stroke volume resulting from decreased LV compliance and increased LV afterload caused by wide swings in pleural pressure. Hypotension occurs when high intrathoracic pressure and hypovolemia decrease venous return to the right atrium.

Pharmacotherapy Beta2-agonists
Short-acting inhaled beta-agonists are the drugs of choice to treat smooth-muscle mediated bronchospasm in acute asthma. These drugs may result in rapid improvement in sudden asphyxic asthma; in attacks of longer duration, airway wall inflammation and intraluminal mucus may interfere with bronchodilator responsiveness.

ACUTE SEVERE ASTHMA: A STEPWISE APPROACH TO THERAPY

Comparison of epinephrine (0,3 mg subcutaneously every 20 min x 3) isoproterenol (2,5 mg by nebulization every 20 min x 3) and aminophilline (5,6 mg/kg intravenously over 20 min, then 0,9 mg/kg/hr) in acute asthma. Rossing TH, et al. Am Rev Respir Dis 1980; 122: 365-371. Albuterol (salbutamol) is preferred because of its greater b2-adrenoreceptor selectivity and longer duration of action than metaproternol. Levalbuterol, the active R enantioner of albuterol, has recently become commercially available. This formulation provides effective bronchodilation with fewer adverse effects than albuterol, but it is more expensive and has yet to be studied adequately in acute asthma. Long-acting b2-agonists are not indicated for immediate relief of bronchospasm because of their delayed onset of action.

Three principles should govern b2-agonist dosing: 1.Doses and dosing intervals should be individualized according to severity and response. 2.Higher and more frequent doses of albuterol are required in acute asthma, warranting a strategy of repeated (or continuous) delivery until there is a response or adverse affects limit further administration. 3.PEFR monitoring should be used to assess response. Importantly, data suggest that the initial response to albuterol in the emergency department (ED) is a better predictor of the need for hospitalization than the severity of the attack on presentation. Valid predictions regarding admission can generally be made after 30 minutes of therapy (1). There are 2 dose response patterns to high and cumulative doses of albuterol. Approximately two-thirds of patients respond to inhaled albuterol in a dose-dependent fashion, generally allowing discharge home from the ED (2). In these patients 1.2 - 2.4 mg delivered by MDI with spacer or 5 7.5 mg by nebulizer in the first hour is effective. In the remaining onethird of patients, albuterol, even in high doses, has minimal effect, presumably because of airway wall inflammation and mucus plugging. Recommendations from the National Asthma Education and Prevention Program Expert Panel Report 2 (EPR-2) from the National Institutes of Health (NIH) in the United States are to deliver albuterol 2.5 5 mg by nebulizer for three doses or 4 8 puffs (90 100 mcg/puff) every 20 minutes by MDI with spacer (3). This is an appropriate starting point. Subsequent dosing frequency, however, depends upon patient response. A substantial body of evidence has shown that albuterol may be delivered equally well by MDI with spacer or by nebulizer. In general, there is equivalency between 4-12 puffs of albuterol delivered by MDI with spacer and one 2.5 mg dose of albuterol by nebulizer (4). Many clinicians prefer nebulizers because fewer instructions are needed, less coordination is required and less supervision is needed. There is no advantage to subcutaneous or intravenous therapy in most cases. Subcutaneous b2-agonists are indicated when patients can not comply with inhaled therapy (such as those with altered mental status) or when there is unresponsiveness to inhaled therapy and the patient is nearing respiratory arrest. Caution should be exercised in older patients and when there is coronary artery disease. Intravenous b2-agonists are not recommended. Data have demonstrated that inhaled therapy is equal to or better than IV therapy in treating airflow obstruction, and causes less cardiac toxicity (5).

ACUTE SEVERE ASTHMA: A STEPWISE APPROACH TO THERAPY

Ipratropium bromide
Ipratropium bromide competitively inhibits acytelcholine, relaxing airway smooth muscle in large, central airways. A series of systematic reviews have demonstrated that combining this drug with albuterol improves lung function and reduces hospitalization rates when compared to albuterol alone (6-8). These effects have been demonstrated with single, small doses of ipratropium. The effects of high and cumulative doses of b2-agonists and anticholinergics are less well known. In one study, the combination of albuterol and high-dose ipratropium bromide (4 puffs each by MDI with spacer every 10 minutes for 3 hours) was compared to albuterol alone (9). Combination therapy resulted in a 48% greater improvement in FEV1 and fewer hospitalizations than albuterol alone. Based on these data, I use ipratropium bromide 4 puffs by MDI with spacer with every albuterol MDI treatment or add a unit-dose vial of ipratropium (0.5 mg in 2.5ml) to albuterol concentrate during each nebulizer treatment in difficult cases.

Oxygen
The degree of hypoxemia roughly correlates with the severity of airflow obstruction, however there is no spirometric cutoff value that predicts accurately the severity of hypoxemia or need for supplemental oxygen. Thus, pulse oximetry should be used routinely to guide oxygen use in acutely ill patients. Arterial blood gas measurements should be reserved for the sickest patients who are not responding quickly to bronchdilator therapy. As previously mentioned, hypoxemia can be corrected by low flow supplemental oxygen. Oxygen should be delivered to maintain a saturation of > 90% (> 95% in pregnant or coronary artery disease patients) in the majority of patients. Oxygen should also be used to drive nebulizer treatments since b2-agonists cause pulmonary vasodilation and may further worsen ventilation/perfusion mismatching.

Corticosteroids
Airway inflammation is important in most cases of acute severe asthma. Systemically administered corticosteroids are the most potent and effective treatment of this inflammation, justifying their use in most cases.

ACUTE SEVERE ASTHMA: A STEPWISE APPROACH TO THERAPY

Effect of intravenous hydrocortisone (2 mg/kg followed by 0.5 mg/kg/hr for 24 hours) versus placebo in acute asthma. % D FEV, is the percent-age change in FEV, from the initial value. Time 0 is when patients received the test infusions. Data expressed as mean SEM. Fanta CH, et al. Am J Med 1983; 74: 845-851. One exception may be a mild attack that responds completely to initial b2-agonists. In this case, adding an inhaled corticosteroid for home use may enough. Anti-inflammatory therapy should be intensified at the first signs of acute asthma. Unfortunately this is often not the case; most patients seen in the ED have used high doses of b-agonists, but not corticosteroids (10). Corticosteroids should be given quickly in the ED to all but the mildest cases because anti-inflammatory effects do not occur for hours. This delay explains the results of several studies demonstrating that corticosteroid use in the ED does not decrease hospitalization rates. In one study to the contrary, methylprednisolone 125 mg IV on presentation to the ED did decrease hospitalizations (11). Corticosteroids improve the speed of acute asthma resolution, the number of relapses in the first week or two after treatment, and the risk of asthma death (12). The optimal dose has not been established; indeed it is not entirely clear that there is a doseresponse relationship in acute asthma. EPR-2 recommendations are to deliver 120 to 180 mg/d of either prednisone or methylprednisolone in 3 or 4 divided doses for 48 hours, then 60 to 80 mg/d until PEFR reaches 70% of predicted or the patients personal best. It matters little whether the drugs are given by mouth or by vein; IV drug is preferred in asthmatics at risk for intubation to minimize stomach contents. Although crucial in the home management of persistent asthma, inhaled cortiosteroids are not routinely used in the management of acute severe asthma. One recent study, however, deserves comment. In this study, combination of high dose flunisolide and albuterol improved airflow rates at 90 through 180 minutes compared to albuterol alone (13). Patients with a longer duration of attack who received flunisolide had improved airflow rates at 120 through 180 minutes and fewer hospitalizations compared with controls. This early benefit to corticosteroids suggests mechanism separate from inflammation such as inhibition of mucosal edema and constriction of the microcirculation.

Other Therapies
1.There is substantial evidence that adding Theophylline to high-dose b2-agonists does not confer additional benefit in the first few hours of acute asthma management (14). A fewer number of studies show the reverse --- that adding theophylline to inhaled bronchodilators improves airflow rates in the first several hours of management (15) and decreases hospitalization rates (16). Theophylline started in the ED may result in a delayed benefit during subsequent hospitalization. Thus it is difficult to make strong recommendations regarding theophylline in acute severe asthma. In our practice, we use theophylline sparingly when other therapies fail. 2.Several prospective studies have failed to show a benefit to use of IV Magnesium Sulfate in an ED population of acute asthmatics (17). However, in one of these studies (18), subgroup analysis showed improved airflow and decreased hospitalizations in magnesium treated patients with an FEV1 < 25% of predicted. Premenopausal women may also respond better to magnesium sulfate because estrogen augments the effects of magnesium to relax smooth muscle (19). Until more definitive data are available, I suggest magnesium sulfate 2 grams IV over 20 minutes in severely obstructed patients who are not responding to standard therapy. This practice is inexpensive and safe, although it may result in transient flushing and mild sedation.

ACUTE SEVERE ASTHMA: A STEPWISE APPROACH TO THERAPY

3.Heliox is low denisty gas consisting of various blends of helium and oxygen; commonly 70-80% helium and 20-30% oxygen. The benefit of low density gas breathing increases with helium percentage, but this approach may be limited by the need to supplement oxygen. Mixtures containing less than 60% helium are ineffective. Breathing low-density gas through a tight-fitting, non-rebreathing face mask or through the inspiratory limb of the ventilator circuit in an intubated patient decreases the driving pressure for airflow and work of breathing.

The effect of heliox (mixture 60-70% and oxygen 30-40% by face mask) on pCO2. (Sxs: syntoms). Kass JE, et al. Chest 1995; 107: 757-760.

Data are inconclusive regarding the efficacy of heliox in acute asthma. In one study, heliox decreased the pulsus paradoxus and increased PEFR in adults treated in the ED (20). Other studies have failed to demonstrate this effect (21). Conflicting data similarly exist regarding the use of heliox as a driving gas for b2-agonist delivery. In my practice I restrict use of heliox to non-intubated patients failing usual therapies. If there is a convincing clinical response in the first few minutes of treatment, I continue heliox until anti-inflammatory/bronchodilatory therapy takes hold. Dramatic responses to heliox warrant consideration of upper airway obstruction, including vocal cord dysfunction. In mechanically ventilated patients, heliox decreases peak airway pressure and PaCO2. Use of heliox in this setting is rarely indicated and limited by the requirement of considerable expertise and planning with recalibration of gas blenders and flow meters to low-density gas use. 4.Data on the use of Leukotriene modifiers is acute asthma is limited. Silverman and colleagues reported a trend toward fewer admissions in asthmatics given 160 mg of Zafirlukast in addition to standard therapy in the ED (22). Additional studies are needed and are currently underway.

Non-invasive ventilation
Data supporting the use of non-invasive positive pressure ventilation (NPPV) in acute severe asthma are limited. In one small study nasal CPAP of 5 or 7.5 cmH2O decreased respiratory rate and dyspnea compared to placebo, presumably by helping to overcome the adverse effects of auto-PEEP and decreasing inspiratory work of breathing (23). In another observational study of 17 episodes of acute asthma, NPPV was delivered by full-face mask

ACUTE SEVERE ASTHMA: A STEPWISE APPROACH TO THERAPY

with initial settings of 0 cmH2O CPAP and 10 cmH20 pressure support (24). CPAP was increased to 3 to 5 cmH2O and pressure support was increased to achieve an exhaled tidal volume of 7 ml/kg or more and a respiratory rate < 25/min. This approach improved dyspnea, blood gases, heart rate and respiratory rate in most patients, results that are promising, but in need of confirmation by randomized trials.

Invasive Mechanical Ventilation Peri-intubation Management

Absolute criteria for intubation include cardio-pulmonary arrest, obtundation and a deteriorating mental status. In many cases, the decision to intubate is based upon the clinicians judgement that the patient is nearing cardiopulmonary arrest. In any event, once the decision has been made, intubation should proceed in a timely fashion by an experienced clinician. Oral intubation with a large endotracheal tube is preferred. This facilitates secretion clearance and decreases airway resistance. Nasal intubation is acceptable in an awake patient, but it requires a smaller tube and may be complicated by nasal polyps and sinusitis. Rapid sequence induction using a short-acting benzodiazepine or propofol often in combination with succinylcholine is a common choice in securing the airway.

Early after Intubation

The immediate concern is hypotension. It occurs for several reasons. First, there is loss of vascular tone due to sedation and loss of sympathetic activity. Second, many patients are hypovolemic because of high insensible losses and decreased fluid intake. Third, overzealous AMBU-bag ventilation can result in dangerous levels of DHI. When this occurs, patients are difficult to ventilate and breath sounds diminish. Blood pressure falls and heart rate increases. In this situation, a trial of apnea is both diagnostic and therapeutic for DHI. If hypotension improves over 40 to 60 seconds of apnea, a fluid bolus and purposeful hypoventilation are indicated. If hypotension does not resolve, consideration should be given to tension pneumothorax. Tension pneumothorax also causes tachycardia, deterioration in gas exchange, and patient agitation; and because of DHI tension pneumothorax may occur without complete lung collapse. Pneumothorax decreases lung compliance so that ventilation is preferentially delivered to the contralateral lung. This increases the risk of contralateral pneumothorax and development of bilateral tension pneumothoraces. Management consists of decreasing minute ventilation, volume challenge, and tube thoracostomy.

Initial Ventilator Settings

During mechanical ventilation, the expiratory time, tidal volume, and severity of airway obstruction determine the level of DHI (25). Since standard treatment for airway obstruction has usually been maximized, expiratory time (as determined by VE and inspiratory flow rate) and tidal volume are important variables during ventilator management. To avoid dangerous levels of DHI, initial VE should not exceed 115 ml/kg/min or approximately 8 L/m in a 70 kg patient (26). This is achieved by a respiratory rate between 12 and 14/min combined with a tidal volume between 7 and 8 ml/kg. The use of a relatively low tidal volume avoids excessive peak lung inflation, which may occur even when there is acceptably low VE.

ACUTE SEVERE ASTHMA: A STEPWISE APPROACH TO THERAPY

Mechanism of dynamic pulmonary hyperinflation in the setting of severe airflow obstruction. Levy BD, et al. Intensive Care Med 1998; 24: 105-117.

Shortening the inspiratory time by use of a high inspiratory flow rate also prolongs expiratory time. To this end, we favor a constant inspiratory flow rate of 80 L/m. High inspiratory flow rates increase peak airway pressure by elevating airway resistive pressure, but they do not per se correlate with morbidity or mortality. Rather it is the state of lung hyperinflation that predicts outcome. Lowering peak airway pressure through use of a lower constant flow rate or a decelerating flow regime shortens expiratory time and worsens DHI. There is no consensus as to which ventilator mode should be used in asthmatics. In paralyzed patients synchronized intermittent mandatory ventilation (SIMV) and assist-controlled ventilation (AC) are equivalent. In patients triggering the ventilator, SIMV is generally preferred because of the unproven concern that minute ventilation will be higher during AC since each triggered breath receives a guaranteed tidal volume. Advantages of volume-controlled ventilation (VC) over pressure-controlled ventilation (PC) include the ability to deliver a constant inspiratory flow and staff familiarity with its use. Ventilator-applied PEEP is not recommended in sedated and paralyzed patients because it may increase lung volume if used excessively. In spontaneously breathing patients, small amounts of ventilatorapplied PEEP (e.g., 5 cmH2O) decrease the pressure gradient required to overcome autoPEEP and thereby decrease inspiratory work of breathing.

Assessing Lung Inflation

Determination of the level of DHI is central to risk assessment and ventilator adjustment (27). Several methods have been proposed to measure DHI, including the volume at end-inspiration, termed VEI. This volume is determined by collecting expired gas from TLC to FRC during 40 to 60 seconds of apnea. A VEI greater than 20 ml/kg has been correlated with barotrauma (26). The clinical utility of this measure is limited by the need for paralysis and staff unfamiliarity with expiratory gas collection. Measurement of volume at end-expiration (VEE) and volume at end inspriation (VEI). VEI is the volume of gas that is passwely exhaled during a prolonged apnea introduced during steady-state tidal ventilation. VEI includes the tidal volume (V,) and the volume of trapped gas (VEE) that is exhaled. VEE is calculated as VEI-VT. Tuxen DV, et al. Am Rev Respir Dis 1987; 136:872-879. 9

ACUTE SEVERE ASTHMA: A STEPWISE APPROACH TO THERAPY

Alternate measures of DHI include the single-breath plateau pressure (Pplat) and auto-PEEP. These pressures are easy to measure when there is patient-ventilator synchrony and no patient effort. Paralysis is generally not required. Unfortunately both measures are problematic and neither pressure has been shown to predict complications of barotrauma. Pplat is affected by the entire respiratory system including lung tissue and chest wall; thus significant variations in DHI may occur from patient to patient at the same pressure. Still, experience suggests that a Pplat less than 30 cmH2O is generally safe. Auto-PEEP may underestimate the severity of DHI when severe airway narrowing limits communication between the alveolus and mouth. In this case, mouth pressure may not rise during an end-exhalation hold maneuver. Still, an auto-PEEP less than 12 cm H2O appears to be safe in most cases.

Ventilator Adjustments
I recommend initial ventilator settings of: SIMV, RR 12-14 breaths/min, TV 7-8 ml/kg, a constant inspiratory flow rate of 80 L/, 0 cmH2O PEEP, and FiO2 of 1.0. Subsequent ventilator adjustments depend upon the level of DHI and arterial blood gas measurements (see algorithm).

Modified from: Corbridge TC, Hall JB. Am J Respir Crit Care Med 1995; 151: 1310.

Whether respiratory rate can be safely increased in hypercapneic patients to lower PaCO2 and elevate pH depends on the degree of DHI. If Pplat is less than 30 cmH2O, respiratory rate can be increased until Pplat nears that threshold pressure. If the Pplat is greater than 30 cmH2O, a further decrease in respiratory rate is indicated until this goal is achieved. Fortunately, in some cases, lowering minute ventilation does not cause the expected rise in PaCO2, possibly because less DHI lowers dead space. If pH is less than 7.20 and minute ventilation can not be safely increased, we consider a slow infusion of sodium bicarbonate, although there are no data that this improves outcome.

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ACUTE SEVERE ASTHMA: A STEPWISE APPROACH TO THERAPY

This strategy favors hypercapnia over severe hyperinflation. Fortunately hypercapnia, even with a PaCO2 as high as 90 mmHg, is generally well tolerated as long as a sudden rise in PaCO2 does not occur (28). Permissive hypercapnia should be avoided when there is anoxic brain injury or myocardial dysfunction because hypercapnia causes cerebral vasodilation, decreased myocardial contractility, and pulmonary vasoconstriction.

Evolution of arterial pCO2, pH, pO2/FiO2 and minute ventilation during the first 24 hours of hospitalization. Adnet F, et al. Intensive Care Med 1998; 24: 1335-1338.

Sedation and Paralysis

Sedation is indicated in patients to improve comfort, safety and patient-ventilator synchrony. This is particularly true when hypercapnia serves as a stimulus to respiratory drive. Some patients improve quickly allowing for extubation within hours. In these patients, propofol is attractive because it allows for quick and reliable reversal of sedation. Benzodiazopines, such as lorazepam and midazolam, are cheaper alternatives that are also appropriate for sedation of intubated patients. Time to awakening after discontinuation of these drugs is longer and less predictable than with propofol. In order to provide the best combination of amnesia, sedation, analgesia and suppression of respiratory drive, we recommend the addition of a narcotic given by continuous infusion to either propofol or a benzodiazopine. Ketamine, an IV anesthetic with sedative, analgesic, and bronchodilating properties, is reserved for patients with severe bronchospasm that precludes safe mechanical ventilation. Ketamine must be used with caution because of its sympathomimetic effects and ability to cause delirium.

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ACUTE SEVERE ASTHMA: A STEPWISE APPROACH TO THERAPY

When safe mechanical ventilation cannot be achieved by sedation alone, consideration should be given short-term muscle paralysis. We prefer cis-atracurium because it is essentially free of cardiovascular effects, does not release histamine, and does not require intact hepatic and renal function for clearance. Of concern during parlysis is the development of acute myopathy (29) . Strongly implicated risk factors include the concurrent use of corticosteroids and paralytics, and the duration of paralysis. Acute myopathy is rare in patients paralyzed for less than 24 hours. The best treatment is prevention; thus paralytics should be restricted to patients who have failed deep sedation. Paralytics should be discontinued as soon as possible.

Bronchodilator Delivery during Mechanical Ventilation

b2-agonists may be delivered equally well by nebulization or by meter dose inhalers (MDI) with a spacer (30). In general, nebulizers should be placed close to the ventilator manifold and in-line humidification systems should be stopped during treatments. Inspiratory flow should be reduced to 40 L/m during treatments to minimize turbulence (care must be taken to avoid worsening DHI during the period of low inspiratory flow). Patient-ventilator synchrony is crucial to optimize drug delivery. Higher b2-agonist doses are required during mechanical ventilation because of poor drug delivery and because these patients demonstrate a flat dose-response relationship. Drug dosage should be titrated to a fall in the peak-to-plateau airway pressure gradient or to the development of toxic effects. When no measurable drop in airway resistance occurs, it is important to exclude other causes of elevated airway resistance such as a bent or plugged endotracheal tube. Bronchodilator non responders might be considered for a drug holiday. This refers to withholding of medication (in this case because of medication unresponsiveness) possibly allowing for upregulation of b2-receptors.

Additional Considerations
Rarely, the above strategies are insufficient to stabilize the ventilated patient. In this situation, consideration should be given to additional therapies including the use of inhalational anesthetic bronchodilators, low-density gas (heliox) ventilation, and bronchoalveolar lavage. These therapies require institutional expertise and careful planning.

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Dose-response relationship between Rmax (Maximun Respiratory Resistance), Rmin (Minimum Respiratory Resistance), Crs (Respiratory System Compliance) and isoflurane concentration. Maltais F, et al. Chest 1994; 106: 1401-1406.

Extubation
Patient improvement is evident by a fall in airway resistance (we like to see Raw < 20 cmH2O/L/sec) and normalization of the PaCO2 at a safe level of minute ventilation. Once this occurs we stop sedation. If the patient is awake and able to maintain spontaneous ventilation on pressure support of 5 to 8 cm H2O (or a T-piece) without worsening bronchospasm we extubate quickly. We monitor the patient for an additional 24 hours before transfer out of the ICU.

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12.Rowe BH, Keller JL, Oxman AD: Effectiveness of steroid therapy in acute exacerbations of asthma: a meta-analysis. Am J Emerg Med 1992; 10:301. 13.Rodrigo G, Rodrigo C: Inhaled flunisolide for acute severe asthma. Am J Resp Crit Care Med 1998; 157:698. 14.Rodrigo C, Rodrigo G: Treatment of acute asthma: Lack of therapeutic benefit and increase of the toxicity from aminophylline given in addition to high doses of salbutamol delivered by metered-dose inhaler with a spacer. Chest 1994; 106:1071. 15.Yung M, South M: Randomised controlled trial of aminophylline for severe acute asthma. Arch of Disease in Childhood 1998; 79:405. 16.Wrenn K, Slovis CM, Murphy F, Greenberg RS. Aminophylline therapy for acute bronchospastic disease in the emergency room. Ann Intern Med 1991; 115:241-47. 17.Tiffany BR, Berk W, Todd IK, et al.: Magnesium bolus or infusion fails to improve expiratory flow in acute asthma exacerbations. Chest 1993; 104:831. 18.Bloch H, Silverman R, Mancherje N, et al.: Intravenous magnesium sulfate as an adjunct in the treatment of acute asthma. Chest 1995; 107:1576. 19.Murray P, Corbridge T. Pharmacotherapy of acute asthma. In: Hall, Corbridge, Rodrigo, Rodrigo (eds): Acute Asthma: Assessment and Management. McGraw-Hill, New York, New York, 2000; pp 139-160. 20.Manthous CA, Hall JB, Caputo ME, et al.: The effect of heliox on pulsus paradoxus and peak flow in non-intubated patients with severe asthma. Am J Resp Crit Care Med 1995: 151:310. 21.Verbeek PR, Chopra A: Heliox does not improve FEV1 in acute asthma patients. J Emerg Med 1998; 16:545-8. 22.Silverman RA, Miller CJ, Chen Y, et al. Zafirlukast reduces relapses and treatment failures after an acute asthma episode. Chest 1999; 116:296S. 23.Shivaram U, Miro AM, Cash ME, et al.: Cardiopulmonary responses to continuous positive airway pressure in acute asthma. J Crit Care 1993; 8:87. 24.Meduri GU, Abou-Shala N, Fox RC, et al.: Noninvasive face mask mechanical ventilation in patients with acute hypercapnic respiratory failure. Chest 1991; 100:445. 25.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 Respir Dis 1987; 136:872. 26.Williams TJ, Tuxen DV, Scheinkestel CD, et al.: Risk factors for morbidity in mechanically ventilated patients with acute severe asthma. Am Rev Respir Dis 1992; 146:607. 27.Tuxen DV, Williams TJ, Scheinkestel CD, et al.: Use of a measurement of pulmonary hyperinflation to control the level of mechanical ventilation in patients with acute severe asthma. Am Rev Respir Dis 1992; 146:1136.

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28.Feihl F, Perret C: State of the art: Permissive hypercapnia: how permissive should we be? Am J Resp Crit Care Med 1994; 150:1722. 29.Leatherman JW, Fluegel WL, David WS, et al.: Muscle weakness in mechanically ventilated patients with severe asthma. Am J Resp Crit Care Med 1996; 153:1686. 30.Manthous CA, Hall JB, Schmidt GA, et al.: Metered-dose inhaler versus nebulized albuterol in mechanically ventilated patients. Am Rev Respir Dis 1993; 148:1567.

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