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K. G. Correa and L. E. Eggert
Studies have not shown a benet of using nebulizers over MDIs; however, MDIs are more cost effective [9]. More doses of an MDI are required to reach an equivalent dosage of medication in a nebulized solution [9]. A meta-analysis and systematic review evaluated the benet of addition of SAAC to SABA monotherapy in acute asthma. The results consistently demonstrated that combination usage of SABA/ SAAC, at single or multiple doses, was more effective at reducing the risk for hospi­talization and improving lung function than either medication alone [10, 11]. Dosages and frequencies for inhaled medications varied in the studies; however, ranges included albuterol 2.5–5 mg from hourly to several times per hour, and ipratropium 0.5mg with similar frequency. In the ICU, inhaled bronchodilators are usually started as a continuous nebulization and then are spaced out as the patient improves clinically.
7.3.2 Indications forAntibiotics
Bacterial infections as triggers for asthma exacerbations only make up as small number of total exacerbations [12]. However, starting empiric antibiotics remains a common practice among providers [12]. Several studies have been published inves­tigating whether the addition of antibiotics to the standard of care improves out­comes in asthma exacerbations. These studies excluded patients with conrmed bacterial infections warranting antibiotics. In a meta-analysis and systematic review of these studies, there was limited evidence to suggest that the addition of empiric antibiotics improved symptoms or airow obstruction [12, 13]. The antibiotic classes that were studied included macrolides and penicillins, and there was no dif­ference in outcomes by antibiotic class. However, like prior studies, patients admit­ted to the ICU were excluded from these studies. In cases of severe asthma requiring ICU admission, antibiotic coverage is usually initiated empirically, and then the decision to continue is readdressed after reviewing preliminary data to better rule in or rule out infection.
In addition to white blood cell count and culture data, serum procalcitonin mea­surements have been explored in asthma to guide the initiation and discontinuation of antibiotics. Procalcitonin, a pre-hormone to calcitonin, rises with bacterial infections but not with viral infections and has been studied extensively in relation to airway infections [5]. In one randomized, controlled trial, the procalcitonin level was used to decide whether to initiate and when to discontinue antibiotics versus clinician discre­tion. The group where procalcitonin levels were used to guide decisions on antibiotics had reduced the use of antibiotics without differences in clinical outcomes [14]. While it is not available in all health systems, serum procalcitonin may be of assistance when making decisions regarding antibiotic initiation and/or discontinuation.
7 Acute Asthma Exacerbation intheIntensive Care Unit
161

7.3.3 Potential Adjunctive Therapies

7.3.3.1 Inhaled Corticosteroids (ICSs)
ICSs are the mainstay of the management of outpatient asthma; however, they play a limited role in the management of acute asthma exacerbations [2, 15]. This is largely due to the use of enteral or intravenous corticosteroids that are at doses much higher than the inhaled form can deliver. However, one argument that is made for the use of ICS is immediate delivery to the affected region [15]. Previous studies evaluating the use of ICS in acute asthma exacerbations have primarily looked at the use of adjunctive ICS to prevent hospitalization, and in most studies, the need for ICU admission or status asthmaticus was an exclusion criterion. In a pooled meta­analysis addition to systemic corticosteroids, resulted in decreased hospital admissions [15]. Further studies analyzing the benet of ICS on other important outcomes and in more severe exacerbations are needed. Adjunctive ICS use combined with systemic corticosteroids should be considered for use in patients with severe asthma exacer­bations in the ICU in addition to standard-of-care therapy, especially since they are generally well tolerated with minimal potential for adverse effects.
and systematic review, ICS use in acute asthma, either versus placebo or in
7.3.3.2
venous (IV) Magnesium Sulfate (MgSO
Intra
)
4
The use of IV magnesium sulfate has been well described as an adjunctive treatment for severe asthma when there is clinical deterioration despite the initiation of standard- of-care medications [5, 16]. Its mechanism of action is still unclear, but it is believed that magnesium sulfate promotes bronchial wall smooth muscle relax­ation and may also mitigate airway inammation [16]. In a meta-analysis of placebo- controlled trials evaluating the efcacy of a one-time bolus of IV magne­sium sulfate, its use resulted in a reduced need for hospital admission and improved lung function [16]. Of the studies available, only one study evaluated the effect of IV magnesium sulfate on the need for admission to the ICU, which did not show any signicant difference compared to placebo [16]. Nonetheless, a one-time bolus of IV magnesium sulfate should be considered in all patients being admitted to the ICU for severe asthma given potential benets and lack of signicant adverse effects.
7.3.3.3 Inhaled Magnesium Sulfate (MgSO
)
4
While the use of IV magnesium sulfate is well described and frequently used in clinical practice, the use of inhaled magnesium sulfate is less common. The nebu­lized solution is prepared by diluting the IV formulation or dissolving MgSO4 into sterile water; however, there are no FDA-approved formulations of nebulized mag­nesium sulfate currently available [17]. The use of inhaled magnesium sulfate has
162
K. G. Correa and L. E. Eggert
been investigated in asthma refractory to the initial standard of care. In a review of trials investigating the benet of inhaled magnesium sulfate in addition to SABA/ SAAC, doses of inhaled magnesium sulfate ranged from one to three (spaced out by 30-min intervals) [17]. Another meta-analysis of seven studies showed varying results, and the authors concluded that there may be a small benet to the addition of inhaled magnesium sulfate, with a low condence level [17]. Given the relative safety of the medication, its use could be considered in life-threatening circum­stances in areas where it is available for use.
7.3.3.4 Intravenous (IV) Aminophylline
Aminophylline belongs to the drug class of methylxanthines, which includes theoph­ylline. Both medications have historically been used for the treatment of chronic asthma for their weak bronchodilator effects. They have since been mostly replaced by stronger bronchodilators such as inhaled beta2-agonists [18]. IV aminophylline has been proposed as an adjunct to inhaled beta2-agonists in the treatment of acute asthma. A meta-analysis of 17 studies did not show any signicant improvement in airow or need for systemic corticosteroids with the use of IV aminophylline [18]. Additionally, patients treated with aminophylline experienced a higher incidence of nausea, vomit­ing, palpitations, and/or arrhythmias [18]. Because of these potential side effects and minimal evidence for benet, IV aminophylline should be avoided in patients experi­encing severe asthma requiring ICU admission. Nausea and vomiting may increase the risk for aspiration in patients and may also predispose them to dangerous arrhythmias when used in combination with SABAs.
7.3.3.5 Intravenous (IV) Beta2-Agonists
The use of inhaled beta
-agonists is the standard of care in acute asthma; however,
2
the IV formulations of these drugs, such as bedoradrine and terbutaline, are rarely used. These drugs have mostly been studied in pediatric patients, in which there was no difference in the rates of ICU admissions with or without the drug [19]. Only one study has looked at the addition of IV beta2-agonists to the standard of care in adult patients, and it did not lead to a reduction in hospital admissions [19].
7.3.3.6 Leukotriene Antagonists (LTRAs)
LTRAs such as montelukast are commonly used in the outpatient setting for the management of allergic asthma [2]. Production of leukotrienes by the immune sys­tem as a response to allergic triggers leads to bronchoconstriction and subsequent asthma symptoms [20]. Several studies have evaluated the impact of LTRAs in acute asthma as adjuncts to standard-of-care therapy. A meta-analysis showed a small improvement in airow but no signicant difference in hospital admission
7 Acute Asthma Exacerbation intheIntensive Care Unit
163
rates with IV or oral LTRAs. There was a slight, although nonsignicant, trend towards a reduction in hospital admissions in the IV group [20]. However, there are currently no FDA-approved IV LTRAs available commercially.
7.3.3.7 Intramuscular (IM) or IV Epinephrine
As highlighted in the earlier sections, anaphylaxis may mimic a severe asthma exac­erbation. Untreated, both have a high mortality rate, and early recognition and appropriate treatment are paramount. IM epinephrine is the standard-of-care treat­ment for anaphylaxis. Epinephrine activates both alpha- and beta-adrenergic recep­tors and therefore could potentially be used in acute asthma exacerbations. A previous meta-analysis included studies in which epinephrine was administered in any formulation to patients with acute asthma exacerbations [21]. Epinephrine was found to be similarly efcacious to selective beta2-agonists, but epinephrine had more side effects, and there was no clinical benet when any form of epinephrine was added to inhaled beta2-agonists in acute asthma [21]. Therefore, there is no data to support the use of epinephrine for severe asthma in the ICU aside from in patients with concomitant conrmed or suspected anaphylaxis.
7.3.3.8 Inhaled Anesthetics
Inhalational anesthetics such as isourane have been studied in patients with severe asthma requiring invasive mechanical ventilation [22]. Inhalational isourane stim­ulates the beta-adrenergic receptor leading to bronchial wall smooth muscle relax­ation and bronchodilation [22]. In the limited number of cases in which isourane has been used, patients had generally already received many of the adjunctive thera­pies previously discussed. Clinical improvement was reported in all patients receiv­ing isourane therapy, with a duration of therapy ranging from 16 to 34hours [22]. Pursuant to local hospital policy, the presence of an anesthesiologist may be required when using inhaled isourane.
7.3.3.9
Inhaled Helium-Oxygen (Heliox)
The combination of oxygen-helium mixtures has long been used for patients with se
vere asthma exacerbations given that it reduces airway resistance [23, 24]. It has been studied in both mechanically ventilated patients and non-ventilated patients. For patients with acute asthma exacerbations not requiring mechanical ventilation, placebo-controlled trials have not demonstrated improved outcomes with heliox [23]. However, the primary outcomes in many of these studies were limited to rates of hospital admission and did not assess more seriously ill patients. One prospective observational study evaluated heliox in patients requiring mechanical ventilation for asthma or COPD exacerbations (high airway resistance states), without demonstra­ble improvement in measures of airway resistance [24].
164
7.3.3.10 Intravenous Ketamine
Ketamine has been used as an adjunct for severe asthma when there is clinical deterioration despite standard-of-care therapy [25]. Ketamine has many properties with potential benet in severe asthma. It acts as a direct bronchodilator, stimulat­ing beta2-adrenergic receptors, and has indirect bronchodilator effects through the inhibition of vagal stimulation that leads to bronchoconstriction [25]. Data support­ing the use of IV ketamine as an adjunctive therapy for severe asthma in the ICU come primarily from case reports. There is some data that ketamine, when given as an infusion, reduced the risk for requiring mechanical ventilation. In mechanically ventilated patients who received ketamine, improvement in clinical status and decreased airway resistance have been reported [25]. The limited data available suggests that IV ketamine is one of the few adjunctive therapies which may be particularly benecial in patients with severe asthma requiring ICU admissions. High-quality studies are needed to validate these benets. Also, this is another medication which may require the presence of an anesthesiologist for administration.
K. G. Correa and L. E. Eggert
7.3.4 Emerging andInvestigational Therapies
7.3.4.1 Subcutaneous (SC) Biologics
Biologics in asthma are a relatively new therapy. These monoclonal antibodies tar­get cytokines in the Th2 inammatory pathway and are used in the outpatient setting to treat patients with uncontrolled asthma symptoms or frequent exacerbations despite maximal inhaler therapy [26]. The role of these therapies in acute asthma is unknown. In one patient case, the biologic dupilumab was used as an adjunct for an asthma exacerbation that did not respond to the standard of care. Following SC administration of dupilumab, there was notable patient improvement [26]. Given the low side effect prole and potential benets of these medications in acute asthma exacerbations, further studies are needed evaluating these therapies in the acute setting.
7.4 Airway Management ofExacerbations
ICU admission and the need for mechanical ventilation are associated with increased morbidity and mortality in patients with severe asthma exacerbations [27]. Therefore, it is crucial to promptly identify patients at risk for progressive respiratory failure. Asthma is a disease of the airways, and hypoxemia is not typically present in most asthma exacerbations [5]. In many cases, patients do
7 Acute Asthma Exacerbation intheIntensive Care Unit
165
not require high amounts of supplemental oxygen, and providers should aim to keep oxygen saturation >92% [5]. Impending respiratory failure is often signaled by respiratory muscle fatigue, mental status changes, lethargy, or hypercapnia and should be promptly treated with noninvasive or invasive ventilatory sup­port [5].

7.4.1 Noninvasive Ventilation (NIV)

The use of NIV in severe asthma may help to provide enough respiratory support to stave off the need for intubation and mechanical ventilation. NIV can assist with alleviating the patient’s work of breathing and correcting hypercapnia that may lead to CO2 narcosis—a common cause of intubation in delayed presentations of severe asthma exacerbations [4]. Modalities of NIV include continuous positive-pressure ventilation (CPAP) and bilevel positive pressure ventilation (BiLevel). For severe asthma exacerbations, bilevel pressure support ventilation is preferred and titrated at the discretion of the intensivist to augment ventilation [4, 27]. Support for the use of NIV in severe asthma exacerbations is mostly coopted from the literature sup­porting the use of NIV in COPD exacerbations, which are similar physiologically to asthma exacerbations [27]. A large, multicenter, cohort study evaluating outcomes of NIV use in severe asthma exacerbations found that its use was associated with a reduction in the need for invasive mechanical ventilation and also a small mortality benet [27]. NIV should be considered for appropriately selected patients with severe asthma exacerbations in the ICU.

7.4.2 Invasive Mechanical Ventilation (IMV)

Progression of an asthma exacerbation to IMV is concerning and indicates severe disease. This severe state is notable for high airway resistance (P tion [28, 29]. Intensivists and respiratory therapists should closely monitor the air­way resistance and auto-PEEP, a marker for hyperination [29, 30]. Medication adjuncts can be considered if there is limited response to standard of care while patients receive IMV. Downstream complications of uncontrolled hyperination and high airway resistance include barotrauma, pneumothorax, and hypotension [29, 30]. Deep sedation may be required to address ventilator dyssynchrony until improvement in respiratory dynamics. If unable to obtain ventilator synchrony despite sedation, paralytics may be considered [29]. Once improved from a respira­tory status, mechanical support and sedation should be weaned as tolerated by the patient. Extubation should be considered once there has been signicant improve­ment in disease state (Fig.7.3).
) and hyperina-
peak
166
Fig. 7.3 Ventilator screen demonstrating obstruction and auto-PEEPing in an asthmatic patient
K. G. Correa and L. E. Eggert
7.5 Extracorporeal Membrane Oxygenation (ECMO)
inExacerbations
ECMO is a form of mechanical circulatory support that can be used to support patients with profound hypoxemic respiratory failure and/or cardiovascular failure. It functions by removing blood via a drainage cannula inserted either in a central vein or in an artery, passing it through an oxygenator and pump and then delivered back into the body via a return cannula [31]. The conguration of ECMO is deter­mined by the disease state and the amount of support required by the patient [31]. The use of ECMO for refractory severe asthma is rare; however, it has been described in the literature as salvage therapy when invasive mechanical ventilation was insuf­cient. There is limited evidence to support the use of ECMO as salvage therapy. A retrospective, cohort study evaluating 127 asthma exacerbations requiring ECMO support demonstrated an association with lower mortality in the ECMO group ver­sus propensity-matched models [31]. While further studies are required to explore this subject, ECMO as a rescue modality can be considered if there is further clini­cal deterioration despite maximal patient optimization following the initiation of invasive mechanical ventilation.
7 Acute Asthma Exacerbation intheIntensive Care Unit
167
7.6 De-escalation ofCare
As an asthma exacerbation improves, the patient will note improved work of breath­ing, reduced cough, resolution of wheezing, and improved air movement on auscul­tation. Corticosteroids should be transitioned to oral when tolerated and continued until at least discharge, if not continued as a slow taper through outpatient follow­ up. Use of SABAs and SAACs should be spaced out from continuous to every few hours and then used on an as-needed basis. Near discharge, patients should be restarted on their home ICS if not continued during hospitalization. If a patient was not previously on an ICS, this should be started prior to discharge and continued until outpatient follow-up. The GINA guidelines are a helpful resource for identify­ing an ideal inhaler regimen for a patient. Inhaler teaching should occur with a respiratory therapist before discharge, and patients should be given a spacer if appropriate and instructed on its use.

7.6.1 Outpatient Follow-Up

Patients who require admission for an asthma exacerbation should be referred to a pulmonologist as an outpatient [5]. Inhalers and medications should be reconciled based on symptoms, and triggers should be reviewed to prevent future exacerba­tions. In certain cases, patients with severe asthma exacerbations are discharged on a tapered oral corticosteroid regimen that should be carefully discontinued. Symptoms may return if corticosteroids are weaned too quickly. If asthma symp­toms remain persistent and severe despite maximal inhaler therapy requiring oral steroids, addition of biologics should be considered.

7.7 Summary

Asthma is an inammatory disease of the respiratory airways that results in symp­toms of shortness of breath, wheezing, and cough. Mainstay therapy of outpatient asthma is through inhaled corticosteroids and bronchodilators. An asthma exacerba­tion is dened by acute worsening of asthma symptoms, and it requires escalation of care to properly manage. Exacerbations can be triggered by infectious and non­infectious etiologies. The standard of care in an asthma exacerbation is centered around corticosteroids and frequent administration of bronchodilators. Exacerbations can be severe and progress to profound respiratory failure requiring the ICU.Several adjunct therapies have been studied in severe asthma that does not initially respond to the standard of care, each with varying levels of efcacy. Respiratory status should be closely monitored with the goal to avoid invasive mechanical ventilation
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K. G. Correa and L. E. Eggert
as it carries an increased risk for mortality. Studies show some mortality benets with using noninvasive ventilation to prevent the need for invasive mechanical ven­tilation. Once improved and discharged, patients with a history of an asthma exac­erbation requiring ICU admission are considered high risk and should have close outpatient pulmonology follow-up.

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