All patients with bronchial asthma are at risk of developing an acute episode with a progressive severity that is poorly responsive to standard therapeutic measures, regardless of disease severity or phenotypic variant. This is also known as status asthmaticus.
If not recognized and managed appropriately, asthmaticus portends risk of acute ventilatory failure and even, death.
In spite of advances in pharmacotherapy and access to early diagnosis and treatment of asthma itself, it remains one of the most common causes of visits to the emergency department. No single clinical or diagnostic index has been known to predict clinical outcome in status asthmaticus. Hence, a multi-pronged and time-sensitive approach combining symptoms and signs, assessment of airflow and blood gas, and a rapid escalation of treatment based on initial treatment response are favored to diagnose and manage the condition.
The time course of progression, as well as the severity of airway obstruction, follows 2 distinct patterns.
Eighty percent to 85% of asthma fatalities are in the subgroup of slow onset asthma exacerbation, perhaps reflecting an inadequate disease control over time. In contrast to the sudden onset exacerbation phenotype, which presents mostly with clear airways, slow onset exacerbation patients have extensive airway inflammation and mucus plugging.
According to the Center for Disease Control and Prevention (CDC), about 10% of world population suffers from asthma, with a 15% increase in disease burden in the United States over last 2 decades. Five percent of them are classified as severe asthma.
An estimated 3% to 16% of hospitalized adult asthmatic patients progress to respiratory failure requiring ventilatory support, although the statistics might be lower in children. Afessa et al. have reported mortality of around 10% in intensive care unit (ICU) patients admitted with status asthmaticus.
Increasing standardization of low tidal volume ventilation strategies, avoidance of prolonged neuromuscular blockade, and assist control mode ventilation hopefully helped reduce this trend even further over the past decade. In a retrospective review of 280 hospitalizations over a period of 30 years in the University of Texas, Health Science Center, San Antonio, 61.2 % patients required intubation and mechanical ventilation. Mortality rate was about 0.35%.
Multiple observational studies have reported a higher incidence in women, among African Americans and in subjects with adult-onset asthma, which developed after an age of 17 years.
At a physiological level, premature airway closure during exhalation causes an increase in functional residual capacity and air trapping. Heterogeneous distribution of air trapping results in ventilation-perfusion mismatch and hypoxemia- triggering anaerobic metabolism and lactic acidosis. It is offset initially by respiratory alkalosis and is compounded once respiratory fatigue and respiratory acidosis ensue.
Increasing understanding of the pathophysiology of asthma at the histological level over last 2 decades has emphasized airway inflammation as the primary player, over and above smooth muscle contraction and airway hyperresponsiveness. An interplay of mast cells, T lymphocytes, and epithelial cells result in a circulatory surge of inflammatory cells as well as cytokines. Histamines, leukotrienes, and platelet-activating factors are found in increased concentrations locally and systemically. Lymphocytic and eosinophilic submucosal infiltrates in tracheal and bronchial biopsy specimens have been reported to be associated with poorer outcomes in adult asthmatics.
Destruction of cilia and epithelial denudation render nerve endings irritable resulting in hyperreactivity. Inflammation also causes hypertrophy and hyperfunctioning of goblet cells and mucous glands resulting in mucus plugging.
The scheming of the catastrophe in cellular level is orchestrated by a dysregulated parasympathetic overdrive, mediated through pulmonary vagus innervation in the parasympathetic ganglia of small bronchi. The release of postganglionic acetylcholine causes bronchoconstriction and hypersecretion through muscarinic receptors while the inhibitory M2 receptors are often dysfunctional in individuals with atopy, sustained exposure to allergens, viral infection and chronic inflammation.
Physical Examination 
Brenner and colleagues demonstrated certain hemodynamic traits in patients who assumed an upright position than supine. They tend to have a significantly higher heart and respiratory rate along with pulsus paradoxes, a significantly lower PaO2 and lower peak expiratory flow rate (PEFR). However, the progressive decline in clinical and mental status in late presentation of status asthmaticus may also counter-intuitively lead patients to assume a supine position. That alone should not be a decision maker. After initial treatment, a diaphoretic patient, preferring to sit upright, unable to speak complete sentences or using accessory muscles of respiration all point toward status asthmaticus.
One of the circulatory consequences of status asthmaticus apart from tachycardia and tachypnea is also a large respiratory phase variation in pleural pressure. The increased inspiratory effort against obstructed airway results in augmented negative intrathoracic pressure. This results in reduced left ventricular filling and outflow due to a combination of (1) septal deviation to the left due to an enlarged RV, (2) increased LV afterload, and (3) increased RV afterload due to increase in pulmonary arterial pressure. Systolic blood pressure, therefore, tends to fall at the height of inspiration. Pulsus paradoxus is the difference between end-expiratory and end-inspiratory systolic blood pressure. It is augmented to more than 12 mm Hg in status asthmaticus, although may paradoxically decline in late-stage with increasing fatigability and loss of respiratory drive.
Tachycardia greater than 120 can be an indicator of disease severity as well as treatment response to beta agonists. Grossman et al. demonstrated that successful treatment results in a 24-hour drop in heart rate from 120 per minute to 105 per minute. Sinus tachycardia is the predominant rhythm, although supraventricular and ventricular arrhythmias have also been reported.
Classic wheezing, as an indicator of bronchospasm, is poorly reliable, as the extent of alveolar airflow is so significantly impaired in these subsets of patients that it cannot generate a wheeze before bronchodilation.
Measurement of airflow obstruction can be challenging to perform but is best achieved at the bedside with an assessment of PEFR than FEV1. Reduction of both values by 50% from personal best of the patient is an indicator of status. The absolute value of PEFR less than 120 L per minute and FEV1 less than 1 L corresponds with the proportional reduction. These absolute numbers should prompt an assessment of arterial blood gas (ABG) immediately. Initial blood gas results indicate respiratory alkalosis with hypoxemia. Therefore, developing respiratory acidosis or elevated PCO2 is indicators of status asthmaticus that is indicative of the need for ventilatory support.,, However, it should not be the lone decision maker and should be coupled with a serial physical examination, evidence of worsening mentation, and fatigability or hemodynamic alterations.
Mountain and colleagues, in their study of 229 hospitalized patients with acute asthma, detected a 28% incidence of anion gap metabolic acidosis, caused by rising lactate.
ECG may also show transient and reversible signs of right heart strain including peaked p wave or right axis deviation.
Chest radiography has little role to play in predicting the course of status asthmaticus, other than ruling out alternate etiologies or associated complicating diagnoses.
Indication for Hospitalization and ICU
Serial measurement of PEFR is a practical and reliable predictor of severity and need for hospitalization. Stein and Cole found that a significant improvement in PEFR, 2 hours after treatment predicted the need for hospitalization, even though initial PEFR on presentation did not (improvement noted from a median of 250 L per minute to 330 L per minute). Rodrigo and Rodrigo demonstrated a similar pattern with treatment response in FEV1, although it may not be the most practical approach at the bedside.,,
A favorable response to initial treatment of status asthmaticus should be a visible improvement in symptoms which sustains 30 minutes or beyond the last bronchodilator dose, and a PEFR greater than 70% of predicted.
On the other hand, patients with evidence of continuing clinical decline or less than 10% improvement in PEFR or less than 40% of predicted, should be considered for admission to the intensive care unit. Anyone with worsening evidence of respiratory failure, alteration of mental status, arrhythmia, cardiac or respiratory arrest, or complications like pneumothorax or pneumomediastinum naturally requires ICU admission along with aggressive resuscitation measures if consistent with their goals of care.
FEV1 or PEFR between 40% to 70% of predicted after initial treatment in the emergency room is considered as “inadequate response." Duration of management in the hospital does play a role in these subsets of patients. Kelsen and colleagues showed a 50% relapse rate in patients treated for 2 hours or less in a facility as opposed to 4% in those treated and observed for an additional 2 to 4 hours. The consensus, therefore, varies anywhere between 4 to 6 hours of treatment in a facility in this group of patients before deciding on admission versus discharge. A poor psychosocial makeup or a hostile home environment with obvious exposure to triggers may tilt the decision in favor of hospitalization.
Pharmacological Management 
Short-acting inhaled beta-agonists are the drug of first choice in acute asthma. Albuterol is preferred over metaproterenol in that class because of its higher beta 2 selectivities and longer duration of action. The dose-response curve and duration of action of these medications are adversely affected by a combination of patient factors including preexisting bronchoconstriction, airway inflammation, mucus plugging, poor patient effort, and coordination. Therefore, larger and more frequent dosing than conventional therapy is necessary. Initial treatment consists of 2.5 mg of albuterol (0.5 mL of a 0.5% solution in 2.5 mL normal saline) by nebulization every 20 minutes for 60 minutes (three doses) followed by treatments hourly during the first several hours of therapy. Interestingly, Idris and colleagues demonstrated that even in patients with severe disease, 4 puffs of albuterol (0.36 mg) delivered with a metered dose inhaler (MDI) and spacer was as effective as a 2.5-mg dose by nebulization. In an ER setting, a nebulizer is still preferred because of less need for supervision, coordination and continued instructions.
An area that needs clarity is the appropriate mode of delivery of these inhaled medications in a ventilated patient. So far consensus prevails over a higher dosage required to achieve physiologic benefits compared to non-intubated patients. However, there is an ongoing debate about the use of MDI versus nebulizers, the appropriate mode of ventilation, the exact site of the connection of the delivery device on the ventilator circuit among others. The optimal delivery device has been a point of polarizing opinion. Mcintyre and colleagues demonstrated that only 2.9% of a radioactive aerosol was deposited in the lungs when delivered by a small volume nebulizer. They, therefore, advocated use of MDI via an adapter attached to the inspiratory limb of the ventilator circuit. However, their findings were refuted by a subsequent study by Manthous and colleagues demonstrating a poor effect on inspiratory flow-resistive pressure by MDI as opposed to nebulized albuterol. Assessment of airway peak to pause pressure gradient can be a rational indicator to use when either one of the delivery modes is used. A 15% or greater decline in the gradient is considered to be a favorable response to be aimed for, with repetitive doses, monitoring for toxicity.
Subcutaneous epinephrine or terbutaline, used in the past, have fallen out of favor due to their toxicity profile, as has direct endotracheal instillation of epinephrine due to lack of demonstrated efficacy and evidence-based studies.
Intravenous beta agonists are not routinely recommended although there are reports of center-specific use in younger patients with status asthmaticus, nonresponsive to inhaled therapy demonstrating persistent severe hyperinflation of airways.
There have been more recent concerns with several studies showing a correlation between asthma mortality and use of inhaled beta-agonists. Suissa and colleagues demonstrated that risk of asthma mortality increases drastically with use of 1.4 canisters per month or more of inhaled beta-agonists.
The Executive Committee of the American Academy of Allergy and Immunology published a position statement on the use of inhaled beta-agonists in asthma.
However significant the concerns are regarding their long-term use, the use of short-acting inhaled beta agonists should not be withheld or underdosed during acute attacks, and they remain the drug of first choice under those circumstances.
Most available data support a distinct benefit of corticosteroids in status asthmaticus in an emergency setting. Rowe et al. in their meta-analysis of 30 RCT concluded that use of steroids in emergency department significantly reduces rates of admission and number of future relapses in subsequent 7 to 10 days. Route of administration did not make a difference, and McFadden based on analysis of available data came up with a recommended dose of 150 to 225 mg per day of prednisone or its equivalent to reach maximum therapeutic benefit. Littenberg and Gluck also demonstrated a significant reduction in hospitalization with a methylprednisolone dose of 125 mg intravenously on presentation in the emergency room. Currently available data, therefore, support the approach of 60 to 125 mg methylprednisolone intravenously every 6 hours for the initial 24 hours of treatment of status asthmaticus. Oral steroids are usually required for the next 10 to 14 days.
In a physiologic level, steroids not only reduce airway inflammation and mucus production but also potentiates beta-agonist activity in smooth muscles and reduces beta agonists tachyphylaxis in patients with severe asthma.
Anticholinergics have a variable response in acute exacerbation with a somewhat underwhelming bronchodilatory role. However, they can be useful in patients with bronchospasm induced by beta-blockade or severe underlying obstructive disease with FEV1 less than 25% of predicted.
Bryant and Rogers demonstrated that 0.25 mg of ipratropium bromide with 5 mg of albuterol by nebulizer resulted in greater improvement in FEV1 than albuterol alone. The response time was also much faster than corticosteroids with a detectable change in FEV1 within 19 minutes. Nebulized glycopyrrolate can also be an alternative although it is not as much in vogue in the United States. Available data and practice still recommend anticholinergics as second-line agents in status asthmaticus patients with inadequate response to beta agonists or steroids. A 0.5-mg dose of Ipratropium by nebulization in conjunction with albuterol is the consensus choice.
Magnesium inhibits calcium-mediated smooth muscle constriction, decreases acetylcholine release in the neuromuscular junction, and affects respiratory muscle force generation.
Intravenous Magnesium sulfate has therefore been a useful adjunct in patients with acute status asthmaticus refractory to beta agonists. The benefit does not seem to isolate patients with low serum magnesium levels although 50% of patients with acute asthma tend to present with hypomagnesemia. In spite of its widespread use in Emergency department setting, 2 large prospective studies failed to demonstrate any statistically significant improvement in lung function in severe asthma exacerbation. However, it is relatively cheap and harmless and has been proposed to have a trend towards female responsiveness, as estrogen potentiates bronchodilator effects of magnesium. At the commonly used dose of 2 gm intravenously (IV) in 2 separate doses over 20 minutes, side effects of hypotension or hyporeflexia are fairly uncommon.
Heliox and Oxygen
True shunt in acute asthma averages only 1.5% of pulmonary blood flow. Therefore, oxygen supplementation need in status asthmaticus is infrequent and low dose. Refractory hypoxemia in status asthmaticus should trigger a search for complications like pneumonia, atelectasis or barotrauma. Heliox as a mixture of 70:30 or 60:40 helium:oxygen decreases airway resistance and turbulence, and therefore reduces work of breathing and inspiratory muscle fatigue. There is a demonstrated reduction in pulsus paradoxus and enhancement in peak flow. However, its routine use is hindered by the prohibitive cost, infrequent indication and need for recalibration of gas blenders and flow meters when used with mechanical ventilation.
Graham et al. conducted a randomized double-blinded trial and demonstrated no difference in improvement in symptom score, spirometry or length of hospitalization with routine use of antibiotics in status asthmaticus. That does not mean that patients with clinical signs of infection should not be treated with antimicrobials or due diligence should not be pursued in obtaining respiratory culture specimens early on.,
Mechanical Ventilation and Sedation
The decision to intubate a patient presenting with status asthmaticus is a clinical one and does not unequivocally require a blood gas assessment.
Immediate indications for intubation include:
If a patient continues to deteriorate in spite of initial pharmacologic treatment, a bedside assessment around the time window of response needs to be made.
Clinical findings that tilt a decision in favor include:
In patients who are not significantly encephalopathic, and has no excessive secretions, noninvasive ventilation with CPAP or BIPAP can be a useful modality to support ventilation, and avoid the need for anesthesia and sedation, as well as the risk of nosocomial infection with endotracheal intubation. It is increasingly being used in the first 24 hours, at pressure support titrated to reduce respiratory rate below 25 per minute and generate tidal volume above 7 ml/kg body weight. Beyond that, there might be an increased risk of aspiration, facial pressure necrosis and suboptimal ventilation to reconsider invasive mechanical ventilation.,
Once a decision to intubate is made, choice of sedation agent is of paramount importance.
Ketamine has sedative, analgesic, anesthetic and bronchodilatory properties and has been increasingly recommended for emergency intubation in status asthmaticus along with succinylcholine. The usual dose is 1 to 2 mg/kg given intravenously at a rate of 0.5 mg/kg per minute to provide 10 to 15 minutes of general anesthesia without significant respiratory depression (as opposed to bolus doses).
Potential risks to consider before deciding in favor of ketamine include:
Propofol is an equally preferred initial agent due to its rapid onset of action and east titratability, ability to achieve deep sedation without paralytics and mild bronchodilatory effects. However prolonged propofol administration in this subset of patients raises the risk of increased carbon dioxide (CO2) production, as it is constituted in a fat-based diluent.
Thus for ongoing sedation needs, lorazepam is preferred with caution to minimize sedation to a level to maintain ventilator synchrony and allow response to stimulation.
For patients who continue to remain desynchronized with the ventilator in spite of sedation, and has a risk of generating auto-PEEP or barotrauma, paralytics may need to be considered. Atracurium is the agent of choice because of the lower risk of myopathy although it can cause bronchoconstriction due to histamine release. Vecuronium is an alternative in such circumstances.
Conditions that can mimic an asthma attack should always be considered in physical examination, particularly, if the response to initial resuscitation is not as expected.
Some of these conditions can also be a complication of an actual asthma attack.
Poor Prognostic Factors
Acute Hypotension on Mechanical Ventilation
Acute hypotension beyond the initial period of sedation and paralytic effect post-intubation needs immediate bedside intervention in status asthmaticus patients. The first and most time-sensitive pathology to be ruled out is tension pneumothorax. If bedside clinical examination, ultrasound or chest x-ray support so, it needs to be managed immediately with tube thoracostomy. Apart from sedation and hypovolemia as other potential causes, a common etiology of hypotension in mechanically ventilated asthma patients is dynamic hyperinflation causing air trapping and auto-PEEP generation. It can be detected by observing flow pattern in ventilator graphics and inability to return airflow to baseline. It is confirmed by measuring total PEEP with expiratory breath hold and then managed by increasing exhalation time, either by reducing the tidal volume or respiratory rate. Sometimes deeper sedation or paralysis may also be necessary.
Ventilator applied PEEP should be kept in moderation in status asthmaticus patients because of the risk of barotrauma and hypotension as well.
In patients without raised intracranial pressure or severely depressed myocardial function, purposeful hypoventilation and permissive hypercapnia is, therefore, an often practiced strategy for above reasons. More importance is paid to a ph target than a target PCO2, and ph greater than 7.25 is generally well tolerated.
High peak pressure with stable plateau pressure on the ventilator should also prompt effort at clearance of airway and endotracheal tube from secretion as it tends to be thick and tenacious in this subgroup of patients. Larger lumen endotracheal tube (7.5 or 8 Fr) is preferred due to higher airway resistance and the need for airway clearance.
Apart from complications related to neuromuscular blockade and those that are outcome of the pathophysiology of asthma itself, other commonly reported complications are electrolyte abnormalities, hypotension, and dysrhythmias.
Severe hypotension and respiratory acidosis in refractory cases have resulted in myocardial infarction, hypoxic and anoxic encephalopathy and death.
Incidence and prevalence of severe asthma are increasing in both adults and children. Such episodes may progress to a status of progressive respiratory failure refractory to standard therapeutic measures. Early recognition of such severe episodes, based on clinical signs, lab data, and follow-up evaluation at close intervals can be life-saving. An initial aggressive treatment trial of beta-agonist, corticosteroids, and anticholinergics has to be tried followed by adjunct measures which may not be based on robust guidelines but evidence. Although initially avoided mechanical ventilation is indicated for certain specific situations including alteration of consciousness, respiratory fatigue, or cardiopulmonary arrest. There have been recent advances in ventilation strategies to protect against barotrauma, alveolar trauma, and neuromyopathy.
Finally, once resolved, attention needs to be paid to measures for avoidance of future severe episodes for which the patient carries an increased risk.
Preventing Future Attacks and an Interprofessional Team Approach
Beyond the period of recovery from an acute episode of status asthmaticus, the management goal should shift to an interprofessional team approach to help prevent future severe attacks. It should start with extensive patient education from nurses, respiratory therapists, nurse practitioners, physician assistants, and physicians about the pathophysiology of asthma, warning signs and symptoms, elimination and avoidance of triggers, and early identification and treatment of attacks. Inpatient education by respiratory therapists or nursing team about asthma action plan, tools of self-assessment of severity with peak flowmetry, the appropriate technique of inhaler use, and relevant numbers to call for specialist help. Maintenance inhaler therapy should be appropriately addressed along with assessment for the need for advanced immunotherapy based on asthma phenotype and allergy profile.,
Patients should be well-versed in detecting early warning signs at home and be well equipped to detect and address, based on the asthma action plan.
A 20% drop in PEFR below predicted, or personal best is a good objective indicator.
Finally, patients with a history of anaphylaxis or sudden asphyxic asthma presentation should also be equipped with Epipen for immediate subcutaneous use if needed.
Health systems across the United States are endorsing the role of outpatient pharmacy in monitoring for patient compliance, as well as, an increase in disease severity based on prescription refills. Bluetooth enabled monitors to inhaler devices can be an answer to remote monitoring of rescue inhaler needs and effective use for physicians. An example of a similar sensor-enabled smart inhaler is the San Francisco based propeller health devices.
Outcomes and Evidence-based Medicine
Over the years several protocols and guidelines have been developed to manage patients with status asthmaticus. Overall, when the patient is brought to the emergency room and quickly managed according to a streamlined protocol, the outcomes are good. (Level E) However, when the patient does require mechanical ventilation, the outcomes vary from moderate to severe. (Level C) Mortality is not an uncommon event in these patients. The reason for the high morbidity and mortality is due to nosocomial pneumonia while on the ventilator. Thus, the importance of educating the family on bringing the patient immediately to the ER at the first signs of respiratory distress.
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