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29 June 2012 No. 21 Status Asthmaticus - Waiting to Exhale J Kanjee Commentator: NZ Dube Moderator: S Pershad Department of Anaesthetics CONTENTS INTRODUCTION ................................................................................................... 3 EPIDEMIOLOGY .................................................................................................. 4 PATHOPHYSIOLOGY .......................................................................................... 4 CLINICAL PRESENTATION ............................................................................... 12 4.1 Clinical features and assessment ......................................................... 14 INVESTIGATIONS .............................................................................................. 15 MANAGEMENT .................................................................................................. 17 6.1 Admission to ICU ................................................................................... 17 6.2 Mechanical Ventilation........................................................................... 21 6.2.1 Non-invasive Positive Pressure Ventilation ......................................... 21 6.2.2 Invasive Positive Pressure Ventilation ................................................ 22 6.3 Aerosol drug delivery during mechanical ventilation ....................... 26 Adjuvant Therapy .............................................................................................. 27 8.1 Extracorporeal membrane oxygenation in Status asthmaticus ......... 31 8.2 Cardiac Arrest in the Asthmatic Patient ............................................... 31 CONCLUSION .................................................................................................... 31 REFERENCES.................................................................................................... 32 Page 2 of 35 STATUS ASTHMATICUS - WAITING TO EXHALE INTRODUCTION Asthma is a disease of predominantly reversible airway obstruction characterized by a triad of bronchial smooth muscle contraction, airway inflammation, and increased secretions1. Its prevalence has increased worldwide and is the most common chronic lung disease. It is estimated to affect 300 million people and is implicated in one of every 250 deaths45. Outcomes of severe acute exacerbations are improving, with fewer complication rates and in-hospital deaths46. However, recognizing and managing it remains a challenge and morbidity and mortality are most often associated with failure to appreciate the severity of an acute exacerbation (by patient or clinician), resulting in inadequate emergency treatment and delay in referring to hospital, or to the intensive care unit (ICU). Generally the majority of acute asthma exacerbations presenting to an emergency department are well managed. Patients that develop status asthmaticus, defined as a life-threatening form of asthma in which progressively worsening reactive airways are unresponsive to usual appropriate therapy such as β-agonists that leads to pulmonary insufficiency will require escalation of therapy in a high care setting or ICU. Adequate patient history and clinical records can help clinicians determine those at risk of developing status asthmaticus (Table 1). Table 1. Risk factors for the development of status asthmaticus Previous severe exacerbation (requiring ICU admission/intubation) Two or more hospitalizations for asthma in the previous year Three or more emergency department visits for asthma in the previous year Hospitalization or emergency department visits for asthma in the previous month Use of two or more pumps(canisters) of short acting β2-agonists per month Current or recent use of corticosteroids Difficulty interpreting symptoms/severity of acute exacerbations Low socio-economic status, major psychosocial problems, illicit drug use, urban dwelling Severe co-morbidities (cardiovascular, chronic lung disease, or psychiatric disease) Page 3 of 35 EPIDEMIOLOGY Acute severe asthma accounts for approximately 2% of ICU admissions, with a female to male ratio of 2:1. The reported mortality of asthmatic patients requiring ICU admission is around 7–8%, although this figure varies widely, ranging from 040%8. PATHOPHYSIOLOGY The primary pathophysiology includes the triad of: Bronchial smooth muscle spasm Airway inflammation Mucous secretion The initiation of acute bronchospasm and airway inflammation culminating in status asthmaticus is usually precipitated by exposure to a triggering agent. These triggers (Table 2) vary for different individuals and exposure may occur in or out of hospital. Table 2. Common Asthma triggers. Environmental Native - - - Air pollutants Pollens and dust/other allergens including Latex Cleaning and industrial chemicals Animal dander (cat, dog, dust mite, cockroach) Tobacco Cold air/changes in weather - Increased secretions Vagal-sympathetic tone imbalance Acute respiratory tract infection/sinusitis/rhinitis Exercise Drugs Other - - NSAIDS Neuromuscular blocking agents Antibiotics B-blockers Protamine Opioids Drug preservatives Ester local anaesthetics - - Page 4 of 35 Polyposis Gastro-oesophageal reflux disease Pregnancy Poor treatment compliance/inadequate therapy Premenstrual syndrome The mechanism of acute airflow limitation varies according to the stimulus. Allergen-induced bronchospasm results from the IgE-dependant release of mediators from airway mast cells, including histamine, leukotrienes, and prostaglandins12. Triggering agents inducing bronchospasm in hyper-reactive airways may be related to the release of inflammatory cells and stimulation of central and local neural reflexes. Edematous swelling of the airway wall with or without smooth muscle contraction results in airflow obstruction. There is also an increase in microvascular permeability, and leakage results in mucosal thickening and swelling of the airway outside the smooth muscle12. Autopsy reports from patients who died from asthma revealed gross features of13: - airway narrowing diffuse plugging of the airways with mucous and inflammatory infiltrates hyperinflation atelectasis Microscopic examination revealed: - exudation of plasma proteins mucosal and submucosal edema hypertrophy and hyperplasia of the microvasculature and bronchial smooth muscle denudation of the epithelium thickening of the subepithelial collagen layer Progressive narrowing of the airway due to inflammation and/or the increased tone of bronchiolar smooth muscle are the key features of an acute asthma attack. This leads to an increase in resistance to air flow, pulmonary hyperinflation, and ventilation/perfusion (V/Q) mismatching. Respiratory failure results as a consequence of the increased work of breathing, inefficient gas exchange, and respiratory muscle fatigue12. Clinicians should be aware of related complications (Table 3) that may occur as disease worsens or with the initiation of treatment. Page 5 of 35 Table 3. Complications of severe asthma:- Respiratory Tension pneumothorax Atelectasis Pneumonia Pulmonary oedema Subcutaneous emphysema Pulmonary interstitial emphysema Tracheoesophageal fistula (in the mechanically ventilated) Cardiovascular Hypotension, tachycardia Myocardial ischaemia/infarction Cardiac arrhythmias Pneumopericardium Treatment related Theophylline toxicity Lactic acidosis Electrolyte disturbances (hypokalaemia, hypophosphataemia, hypomagnesemia) Hyperglycaemia Myopathy 3.1 Effects on Lung mechanics and Gas-trapping The airflow obstruction during an asthmatic attack has important physiological effects. There is an increase in the functional residual capacity (FRC), total lung capacity and residual volume. Tidal breathing tends to occur near predicted total lung capacity. Bronchoconstriction, airway oedema and mucous plugging increase the work of breathing. The normally passive process of expiration becomes active in an attempt to force the inspired gas out of the lungs 14, and inspiratory work increases due to high airway resistance and hyperinflation. Obstruction to airflow during expiration slows the expiratory flow rate, prolonging the time to exhale the inspired volume. If the next inspiration occurs before complete expiration, gas-trapping occurs (Figure 1). As a consequence of gas-trapping, there is a positive pressure remaining in the lungs at the end of expiration. This pressure is referred to as auto or intrinsic PEEP (PEEPi) and is similar to the PEEP we set on ventilated patients. The term Dynamic hyperinflation describes this phenomenon, and is directly proportional to the minute ventilation and to the degree of airflow obstruction. Page 6 of 35 Hyperinflation causes the lungs and chest wall to operate on a suboptimal portion of their pressure –volume curves (ie. they are over stretched), resulting in increased work to stretch them further in an attempt to ventilate adequately14. It may be so severe that lung volumes approach total lung capacity and increase the risk of barotrauma. Figure 1. Development of gas trapping14 Consequences of dynamic hyperinflation14: 1. 2. 3. 4. 5. 6. Shifts normal tidal breathing to a less compliant part of the respiratory-system pressure-volume curve resulting in an increased work of breathing Flattening of the diaphragm resulting in poorer contraction(& increase use of accessory muscles) Increase in dead space ventilation and therefore an increase in minute volume to maintain adequate ventilation Increased risk of a pneumothorax Hypotension due to decreased venous return Possible reduction in diaphragmatic blood flow. These combined effects have a detrimental effect on the respiratory function, causing an increase in the load, elastance and the minute volume. Persistence of these effects as seen in status asthmaticus results in fatigue of the respiratory muscles and ventilatory failure. Page 7 of 35 Measuring gas trapping Tuxen et al measured the total exhaled volume (VEI) from a paralyzed patient during a 20-60second period of apnoea. VEI represented the sum of the tidal volume and the volume at end exhalation above FRC (figure 2). VEI values above 20mls/kg (1.4L in an average adult) predicted complications of hypotension and barotrauma 36, 37. However further studies are required to validate this and is limited by the need for paralysis. Figure 2. Measuring VEI - the volume of gas above FRC36.37 (VT=tidal vol.; VEE=end exhalation vol.) As explained above, if inspiration begins before complete exhalation then gas-trapping occurs. This may be seen on the flow-time graph on the ventilator. End expiratory plateau pressure (Pplat) and PEEPi can also be used to measure the degree of hyper-inflation. Pplat is an average of end-inspiratory alveolar pressure and is determined by stopping flow at end-inspiration (Figure 3). This reflects the respiratory system pressure change resulting from the delivery of the tidal volume which is added onto the PEEPi. The American College of Chest Physicians consensus conference on mechanical ventilation concluded that Pplat is the best predictor of hyperinflation in ventilated asthmatic patients and recommends that Pplat must be kept lower than 35 cmH2O43. Page 8 of 35 Figure 3. Measuring Pplat- End-inspiratory Alveolar Pressure41(The dotted line indicates a high peak-to-plateau gradient observed in status asthmaticus). PEEPi is the lowest average alveolar pressure reached during the respiratory cycle and is obtained by an end –expiratory hold manoeuvre (Figure 4).In the nonobstructed patient, alveolar pressure (PALV) equals pressure at the airway opening (PAO) both at end inspiration and end expiration. In the severely obstructed patient, PALV may increase because of air trapping, and at end expiration PALV does not equal PAO. If an expiratory hold manoeuvre is performed, PAO will rise, reflecting the degree of lung hyperinflation4. Page 9 of 35 Figure 4. Measuring intrinsic positive end-expiratory pressure41 3.2 Effects on Gas Exchange As a result of inadequate alveolar ventilation status asthmaticus patients develop varying degrees of hypoxaemia, hypercapnia and lactic acidosis. Studies of patients with respiratory failure secondary to acute severe asthma using multiple inert gas-elimination techniques have shown that bimodality of V/Q distributions with little shunt is a characteristic feature of their gas exchange; these studies demonstrated a substantial fraction of perfusion is associated with areas of lung with low V/Q ratio42. Thus, regional V/Q inequality, (usually <0.1) is the most important mechanism of hypoxemia. Part of the carbon dioxide retention observed can also be a consequence of V/Q abnormalities. Page 10 of 35 Although V/Q mismatch may be severe, intrapulmonary shunt is minor even in the most severe conditions. This may reflect three important pathophysiological observations40: 1. 2. 3. airway occlusion is not complete collateral ventilation preserves ventilation in distal alveolar units hypoxic pulmonary vasoconstriction minimizes the extent of V/Q mismatch and therefore, hypoxemia The implication of these observations is important in the management of hypoxaemia, as it can be easily corrected with supplemental oxygen. However if there is no improvement other abnormalities such as shunt or pneumonia should be sought. The development of lactic acidosis is not fully understood, possible explanations include41: - use of high dose β2-adrenergic agonists anaerobic metabolism of the ventilatory muscles and overproduction of lactic acid coexisting tissue hypoxia intracellular alkalosis decreased lactate clearance by the liver from hypo-perfusion 3.3 Effects on the Cardiovascular System Dynamic hyperinflation and increased respiratory muscle activity can also greatly affect cardiovascular performance. Lung hyperinflation increases afterload on the right ventricle by increasing the length of pulmonary vessels and by direct compressive effects12. With extreme inspiratory and expiratory muscle effort, large differences in pleural pressure result. During forced expiration, increases in intrathoracic pressure diminish venous return and right ventricular filling. During forceful inspiratory efforts against obstructed airways, venous return and right ventricular filling increase, and this increase may be so pronounced that the intraventricular septum may shift toward the left ventricle, creating a conformational change of the left ventricle, impairing filling resulting in diastolic dysfunction12. Large negative pleural pressure changes may also impair left ventricular function by increasing afterload. The aggregate effect of these cyclical Page 11 of 35 respiratory events is to accentuate inspiratory increases in stroke volume and expiratory decreases in stroke volume. This can be measured as an increase in the pulsus paradoxus (PP), the difference between the maximal and minimal systolic arterial BP during the respiratory cycle12. A variation greater than 12- 14 mmHg in systolic blood pressure between inspiration and expiration represents a sign of severity in asthmatic crisis. This value is patient dependant and, in advanced stages, when ventilatory muscle fatigue, PP will decrease or disappear. This might falsely be interpreted as an improvement in airflow obstruction, therefore assessment of PP is no longer recommended. Finally, if the surrounding pressure of the heart continues to rise with progressive hyperinflation, there can also be mechanical compression of the heart and coronary vessels that can lead to myocardial ischemia and deterioration in cardiac function12. CLINICAL PRESENTATION Many terms have been used to describe severe acute asthma exacerbations, such as rapid-onset asthma attack, near-fatal asthma, acute asphyxic asthma, acute severe asthma, hyper-acute asthma, and even explosive asthma5! The British Thoracic Society (BTS)47 publishes a treatment guideline for acute asthma and also classifies the severity of acute asthma exacerbations at different levels (Table 4). Page 12 of 35 Table 4. BTS levels of severity of acute asthma47 Patients requiring an escalation of therapy after receiving a trial of the usual appropriate therapy in the emergency department are referred to as having status asthmaticus. Life-threatening asthma tends to occur as two sub-types (Table 5):1. Most common, 80-90% of cases, predominantly females. Includes those with severe or poorly controlled asthma (therefore considered preventable). Usually there is a history of progressive worsening of symptoms over several days or weeks, including recent onset nocturnal dyspnoea. Page 13 of 35 As a result of greater bronchial inflammation (typically esoinophilic) and mucous secretion, this group tends to respond more slowly to treatment, and therefore they are more prone to status asthmaticus. In contrast, a smaller sub-group, more frequently male, present with a rapidly progressive condition with highly reactive airways. These patients have intense bronchospasm and a neutrophilic inflammation that often responds more rapidly to bronchodilator therapy1,33 2. Table 5. Differential patterns of life threatening asthma12 Type 1: Slow Progression Type 2: Sudden Progression - - - 4.1 Progressive deterioration: > 6hrs (usually days or weeks) 80 to 90% patients who presented to an ED Female predominance More likely to be triggered by upper respiratory tract infections Less severe obstruction at presentation Slow response to treatment and higher hospital admissions Airflow inflammation mechanism - Rapid deterioration: < 6 hrs 10 to 20% patients who presented to an ED Male predominance More likely to be triggered by respiratory allergens, exercise and psychosocial stress More severe obstruction at presentation Rapid response to treatment and lower hospital admissions Bronchospastic mechanism of deterioration Clinical features and assessment Immediate assessment of patients with status asthmaticus includes: - the degree of respiratory dysfunction (ability to speak, respiratory rate, use of accessory respiratory muscles, air entry, intercostals recessions) the degree of hypoxia (SpO2, cyanosis, level of consciousness, diaphoresis) cardiovascular stability (arrhythmias, blood pressure) With deterioration, wheezing, accessory muscle usage, tachypnoea and pulsus paradoxus may diminish. An absence of wheezing could represent extreme airflow obstruction with reduced respiratory excursion and poor air movement. Also, the intensity and tone of wheezing does not necessarily correspond to the degree of airflow obstruction in an asthma attack5. Page 14 of 35 Many other diseases can cause wheezing (Table 6), and mimic acute asthmatic exacerbation. Differentiation can be challenging, although a history of asthma and physical examination assists. Table 6. Differential diagnosis-Not all that wheezes is asthma Pulmonary oedema Pneumonia Chronic obstructive pulmonary disease Anaphylaxis Foreign bodies Bronchiectasis Subglottic masses Vocal cord dysfunction Laryngeal malignancy INVESTIGATIONS Although helpful in directing and confirming response to therapy, investigations should not delay initiating treatment. Peak expiratory flow rate (PEFR) or the forced expiratory volume in 1 second (FEV1) –if possible to perform, these measurements can be used to measure the degree of airway obstruction, and the response to therapy. PEFR, using a peak flow meter is easier to perform in the acute setting, and should be compared to the patients’ baseline which may be obtained from the patient (asthma education) or from clinical records. Spirometry which is used to measure the FEV1 is regarded as ‘gold standard’ in asthma assessment may not be readily available. Symptoms of airway obstruction usually become apparent at 40-50% or less of the predicted value. Arterial blood gas analysis(ABG)- Sampling of the arterial blood may be necessary in the severe acute crisis when the SpO2 falls below 90%, or when there is no response to treatment or deterioration in condition. Initially, analysis may reveal: - severe hypoxaemia with a PaO2 < 60mmHg hypocapnia respiratory alkalosis with or without metabolic compensation Page 15 of 35 Later, as the severity of the airflow obstruction increases, the PaCO2 first normalizes then subsequently increases because of patient’s exhaustion, inadequate alveolar ventilation and/or an increase in physiologic dead space. This is an important sign of impending respiratory failure and the possible need for mechanical ventilation, although some patients at this stage may still respond to aggressive medical therapy. If the deterioration in the patient’s clinical status lasts for a few days there may be some compensatory renal bicarbonate secretion, which manifests as a normal anion gap metabolic acidosis4. Chest radiograph- Although usually normal in the majority of patients4, common findings include: - features of hyperinflation (flattened diaphragms and narrowing of mediastinal shadows) localised atelectasis bronchial cuffing consolidation The physician must also be attentive to the presence of infective changes, foreign bodies, pneumothorax, or pneumomediastinum. Evaluation of the cardiac silhouette and pulmonary vasculature may suggest pulmonary edema due to decompensated heart failure5. Electrocardiography (ECG) – as a result of stress and airflow obstruction findings can include: - sinus tachycardia right axis deviation right ventricular hypertrophy(chronic) and strain These features thus usually resolve as the airflow improves and gas exchange normalizes. Aggressive β-agonist therapy can also provoke supra-ventricular arrhythmias, hypokalaemia and cause prolongation of the QTc interval13. Continuous electrocardiography monitoring is recommended in all patients who may have an arrhythmia and in older patients with underlying coronary artery disease5. White cell count – may be raised in patients with a respiratory tract infection. This can be correlated with patients that are febrile or have productive purulent sputum. Page 16 of 35 Electrolytes –monitor levels of potassium, magnesium and phosphate as they may be altered during therapy with β -agonists and corticosteroids. Hypokalaemia is common and may be exaggerated by fluid resuscitation. Blood glucose levels – hyperglycaemia may result from B-agonist and corticosteroid use. Serum theophylline levels – especially if the patient has been on it and requires further dosing as toxicity may occur (see Methlyxanthines below). MANAGEMENT Initial management includes following the basic principles of assessing and managing the airway, breathing and circulation. The primary goals of management of acute severe asthma are the rapid reversal of bronchial smooth muscle constriction, inhibiting the inflammatory response, and the correction of severe hypoxaemia and hypercapnia. If possible, removal or control of triggering agents should be undertaken in order to prevent ongoing stimulation of the hyper-reactive airways. The routine use of antibiotics is not recommended in status asthmaticus and should only be considered in selected cases. While the majority of infective precipitants are of viral origin, it may be prudent to have a low threshold to treat bacterial infections (and prevent a secondary infection). The decision should be based on close examination of the CXR, blood results, presence of purulent sputum and fever. A broad spectrum penicillin or macrolide may be appropriate until specific cultures and specificity are identified. Status asthmaticus patients are also often dehydrated and intravenous fluids should be administered to correct this. 6.1 Admission to ICU Admission to an intensive care unit should be considered in patients not responding to treatment or continue to deteriorate despite adequate therapy. These include patients that have: - <10-20% improvement in PEFR signs of respiratory arrest (RR≥30/minute, increased PaCO2), severe cardiovascular instability (arrhythmias, hypotension, ischaemia), an altered mental status significant co-morbidities Page 17 of 35 Admission to ICU facilitates monitoring of physiological variables and the rapid provision of invasive procedures such as intubation or insertion of intercostals drains. The first line of therapy started in the emergency department or ICU that is used in the management of status asthmaticus includes the use of oxygen, β2-agonists, corticosteroids, and frequently anticholinergics. 1. Oxygen Hypoxaemia due to V/Q mismatching is a frequent cause of death and should not be underestimated. All patients with acute severe asthma should therefore receive supplemental oxygen to maintain SpO2 >92%. After the initial bronchospasm, as the disease progresses, hypoxic pulmonary vasoconstriction causes shunting of blood away from poorly ventilated alveoli. Initial therapy with β2-agonists may worsen the V/Q mismatch as the vascular smooth muscle presumably dilates first causing intra-pulmonary shunting and a transient desaturation. This drop in SpO2 quickly resolves as bronchial constriction improves. Rodrigo et al35 performed a randomized controlled trial on the effects of using either 28 or 100% oxygen on 76 patients with acute severe asthma. They demonstrated that patients receiving 28% oxygen tended towards a fall in the PaCO2, and those receiving 100% had an increase in the PaCO2. Hypercarbia related to hyperoxia can be explained by regional hypoxic pulmonary vasoconstriction. The FiO2 should be titrated accordingly, though 0.4-0.6 is usually sufficient. Unlike patients with established COPD, the majority of asthmatics do not chronically retain CO2 so the danger of supplemental O2-induced hypercarbia is minimal. 2. Inhaled ß2-Agonists eg. Salbutamol The use of inhaled B2-agonists is the corner stone in the management of status asthmaticus. It has a very rapid onset of action of 5 minutes, with a long duration of activity of up to 6 hours. The duration of activity and effectiveness is inversely related to the severity of the bronchoconstriction. Long acting β-agonists are not recommended in the acute setting because of their long onset time. Page 18 of 35 There are 4 areas of concern with regard to the use of B2-agonists:A. B. C. D. 3. Route – Intravenous vs. Inhaled The intravenous route has a theoretical advantage of bypassing obstructed airways. However a met analysis by Travers et al44 do not recommended its use. Greater adverse effects than clinical improvement were observed. The IV route should be reserved for when inhaled therapy has failed or is not practical. The inhaled route has a quicker onset time, fewer side effects, and may be more effective than systemic routes. Dosing and Intervals The administered dose depends on the patient’s lung volume and inspiratory flow rates, therefore the same dose can be used in most patients regardless of age or size7. Usually, 2.5-5mg of salbutamol is nebulized every 15-20minutes or 10-15mg/hour as continuous nebulization until clinical improvement or escalation of therapy is required. Higher doses are required in the mechanically ventilated patients because of aerosol losses in the ventilator circuit. Metered-dose inhalers (MDI) with a spacer vs. small-volume nebulizers A Cochrane meta-analysis showed no overall difference between the effects of salbutamol delivered by MDI- spacer or nebulizer, however, MDI-spacer administration can be difficult in patients in severe distress20. Continuous vs. Intermittent nebulization12 In a review 6 adult studies16 and 1 paediatric study17 showed no difference in the effects of continuous versus intermittent administration of nebulized salbutamol. Corticosteroids Patients who remain dyspnoeic and continue to wheeze despite adequate β2agonist therapy most likely have persistent airflow obstruction due to airway inflammation and plugging. Clinical improvement appears to slow down after the first hour or so of treatment, since airway oedema, cellular infiltration and mucous hypersecretion resolve slower than the bronchospasm (ref). Systemic glucocorticiods help speed the rate of improvement by suppressing airway inflammation. They exert a dose-dependent down-regulatory effect on cellar function including eosinophils, neutrophils, lymphocytes, and the production of growth factors8. Having no bronchodilating effects themselves, they influence the sensitivity and number of β2-receptors (permissive role). Page 19 of 35 Controversy exits as to the efficacy, route and dosage. Two systematic reviews21, 22 have suggested the following:1. 2. 3. Systemic corticosteroids require 6-24 hours to improve lung function (allowing time for gene transcription and new protein synthesis, therefore should be given early). Intravenous versus Oral (if no impairment of swallowing or absorption) therapy have equivalent effects. Precise dose-response relationships are not well described. It seems that medium to high doses are associated with a more rapid improvement, although there is a ceiling effect at very high doses (>400mg/day hydrocortisone). The use of inhaled corticosteroids (ICS) is beneficial, having a topical effect causing airway mucosa vasoconstriction. A meta-analysis concluded that ICS compared with placebo reduced hospital admission rates in patients with acute asthma, but it is unclear if there is a benefit of inhaled corticosteroids when used in comparison or in addition to systemic corticosteroids23. Tapering doses of oral prednisone may be commenced once the patient is stabilized and able to swallow. In addition to the common side effects of corticosteroids –hyperglycaemia, hypertension, hypokalaemia, immune compromise- patients who are mechanically ventilated are susceptible to myopathy especially if combined with neuromuscular blocking agents. 4. Anticholinergics The underlying principle for the use of anticholinergic therapy in patients with status asthmaticus is the assumption of an increased airway vagal tone. Acetylcholine release stimulates the muscarinic receptors (M1-3) resulting in bronchoconstriction and mucous secretion, therefore its inhibition theoretically lowers bronchial vagal tone. Increased vagal tone is also associated with nocturnal asthma and the down regulation of β-receptors as seen with viral infections. The most commonly used anticholinergic is Ipratropium bromide. It has a slow onset time of 20 minutes with a prolonged duration of action, and is associated with a 15% improvement in PEFR. It is therefore often used as a second line agent, particularly in patients not responding to β2-agonist therapy. According to a meta-analysis, combining an anti-cholinergic agent with nebulised β2-agonist has been shown to produce greater bronchodilatory benefit compared to β2-agonist alone28. It has minimal systemic absorption when delivered via inhalation and few side effects. Page 20 of 35 6.2 Mechanical Ventilation This may be in the form of either non-invasive positive pressure ventilation (NIPPV) or invasive positive pressure ventilation (IVPPV) 6.2.1 Non-invasive Positive Pressure Ventilation The purpose of NIPPV is to decrease the work of breathing by unloading fatigued respiratory muscles while improving alveolar ventilation, and minimizing the adverse effects of sleep on ventilation and airway resistance. It also avoids the risks and discomfort associated with an endotracheal tube. NIPPV may be delivered either in the form of continuous positive airway pressure (CPAP), or as mechanically assisted breaths (bi-level positive airway pressure, BiPAP).BiPAP allows for separate control of inspiratory and expiratory pressures. Numerous studies in patients with chronic obstructive pulmonary disease have shown that NIPPV decreases the need for endotracheal intubation, duration of hospital stay and in-hospital mortality. However, there have been limited studies for its use in patients with acute severe asthma, hence the indications for initiating NIPPV are not clearly defined and its use controversial. Nevertheless, there is a small group of patients that may derive benefit from an initial trial of NIPPV for 1-2 hours, provided there are no contraindications (Table 7). Table 7. Contraindications to NIPPV 1. 2. 3. 4. 5. 6. 7. Poor patient cooperation Inability to clear secretions from the respiratory tract Inability to deliver medications Need for definitive control of the airway Excessive gastric distention with the increased risk of aspiration Patients may feel claustrophobic Lack of experienced staff and/or a high dependency area For patients with a moderately increased work of breathing, or a relatively mild-moderate degree of hypoxaemia (SpO2 >92%, with FiO2 0.25-0.7) or hypercarbia (PaCO2 45-50mmHg), CPAP can be initiated at a pressure of 5 cm H2O. For patients with a more marked increase in the work of breathing, or sever hypoxaemia (requiring FiO2 > 0.7) and hypercarbia (PaCO2 >50mmHg), Page 21 of 35 BiPAP may be should be instituted as it offers a greater level of support and decreases the work of breathing more efficiently. Initiation of BiPAP should start of low and then titrated to patient comfort and improvement in gas exchange. Inspiratory pressures can be titrated from 8- 12 cm H2O, and the expiratory pressures from 5- 8 cm H2O. In a study by Meduri et al9, low levels of CPAP and pressure support of 10– 19 cm H2O in acute severe asthma improved gas exchange and prevented endotracheal intubation in all but two of 17 hypercapnic patients. However, the rate of intubation in patients with acute asthma, even in the presence of hypercapnia, is low at 3–8%10,11. There is a risk that CPAP may worsen lung hyperinflation, and it may not on its own improve ventilation in hypercapnic patients. If patients are intolerant of the mask or do not demonstrate improvement, CPAP should be withdrawn. Deciding when to initiate NIPPV or when a trial has failed and optimizing NIPPV in the setting of status asthmaticus requires considerable expertise. Additional studies are therefore necessary to support the use of this technique. 6.2.2 Invasive Positive Pressure Ventilation It is important to try to prevent intubation and ventilation in patients with status asthmaticus as mortality and morbidity starts to increase once the need arises. Indications for endotracheal intubation and mechanical ventilation are:- coma respiratory or cardiac arrest severe refractory hypoxaemia Relative indications include - an adverse course of response to initial management fatigue and somnolence, cardiovascular compromise the development of a pneumothorax Hypercapnia per se is not an indication for mechanical ventilation so long as the patient is fully conscious and does not seem exhausted. Clinical judgement is important for this determination. Intubation should generally be by direct laryngoscopy following a rapid sequence induction. It is advisable to avoid nasal intubation due to the high incidence of sinusitis and nasal polyps in asthmatics. Page 22 of 35 Choice of induction agents and dosages should be considered carefully inpatients that are haemodynamically unstable. Status asthmatic patients are often volume depleted and induction may result in a loss of sympathetic tone and cardiovascular instability. In addition, dynamic hyperinflation and inappropriate ventilator settings may contribute to circulatory collapse The largest bore endotracheal tube possible should be used for two reasons: it represents a resistance in series with the obstructed airways, thus dynamic hyperinflation tends to worsen after intubation and this can be avoided to some extent by selecting a larger tube. Secondly, it is common for patients to mobilize large mucous plugs during recovery, which has a greater potential for causing acute obstruction in small endotracheal tubes12. Once intubated, manually hand-bag ventilating the patient may give the clinician a subjective assessment of the severity of the airflow obstruction. The major complication of manual ventilation is the development of dynamic hyperinflation and its related complications (barotrauma, volutrauma) and haemodynamic compromise from the decrease in venous return. There have been concerns with regard to the humidification of inspired gases. Although not recommended in the guidelines, a small trial investigated whether airway dehydration occurs in patients with acute severe asthma and its potential implication; the authors demonstrated that significant dehydration of expired air is present in patients with an asthma attack, and that bronchoconstriction triggered by dry-air challenge in the laboratory can be prevented by humidifying the inspired air. Thus, these findings suggest that full humidification of the inspired gases should be recommended for patients with status asthmaticus12, 15. Adequate humidification prevents thickening of secretions and drying of airway mucosa which could perpetuate the bronchoconstriction. The goals of mechanical ventilation:1. 2. 3. Avoid dynamic hyperinflation Achieve adequate oxygenation – by titrating FiO2 Allow permissive hypercapnia (until pharmacological improvement in airflow) In order to avoid or reduce dynamic hyperinflation minute ventilation should be reduced. Decreasing the respiratory rate has a greater effect as it will allow for the adjustment of the inspiratory: expiratory (I:E) ratio so that proportionately more time can provided for exhalation. I:E ratios of ≥ 1:4 and Page 23 of 35 inspiratory flow rates of 70-100l/minute are commonly used. Elimination of an inspiratory pause also helps to reduce dynamic hyperinflation. Reducing the tidal volume means less volume to exhale and may be appropriate, but is limited by the increase in the fraction of dead space ventilation. Expiratory flow resistance can also be decreased by suctioning of airways frequently. Table 8.Shows the recommended initial ventilatory settings in status asthmaticus. Table 8 Initial ventilator settings in status asthmaticus 1. 2. 3. 4. 5. 6. 7. 8. Tidal volume 5-6mls/kg Respiratory rate 6-8 breaths/minute Increased expiratory time (I:E ratio > 1:2) Reduced external PEEP ≤ 5cm H2O Limit peak inspiratory pressure to < 40cmH2O Target plateau pressure <20cmH2O FiO2 –titrate to SpO2 > 92% Humidification Permissive hypercapnia – by reducing the minute ventilation, retention of CO2 occurs. This is generally well tolerated amongst patients with status asthmaticus when pH is maintained above 7.2 or the PaCO2 ≤90 mmHg.Anoxic brain injury and severe myocardial dysfunction are contraindications because of the potential for hypercapnia to dilate cerebral vessels, constrict pulmonary vessels, and decrease myocardial contractility51. Permissive hypercapnia should also be avoided in pregnancy due to its effects on uterine blood flow. The use of sedation, muscle paralysis, analgesics and anti-pyretics often used to achieve patient-ventilator synchrony will also decrease CO2 production and hence the need for very low minute volumes. External PEEP (PEEPe) – use is controversial as it may increase total PEEP and exacerbate gas-trapping. In a study by Tuxen52, gradual increase in PEEPe from 5 to 15 cmH2O induced a proportional and significant increase in end-inspiratory volume and of functional residual capacity, paralleled by an elevation in Pplat. In addition, an elevation in both esophageal and central venous pressures with a concomitant reduction in cardiac output and blood pressure was observed. Therefore it is not recommended in the acute setting of status asthmaticus.If profound hypotension does occur when assisted ventilation has been initiated, one should consider disconnecting the patient Page 24 of 35 from the circuit (possibly with the addition of pressure on the chest wall to assist expiratory flow) to allow full passive expiration Sedation and the use of Neuromuscular blocking drugs (NMBD) The use of sedation improves patient tolerance of the endotracheal tube, ventilator synchrony, and prevents agitation and self extubation. It also lessens the need for neuromuscular blocking drugs. Benzodiazepines are frequently sufficient. Opioids are not usually recommended for sedation in asthmatics because of their potential to induce hypotension through a combination of direct vasodilation, histamine release, and vagally-mediated bradycardia. Opioids also induce nausea and vomiting, decrease gut motility, and depress ventilatory drive4. The rationale for the use of NMBD in the intubated and mechanically ventilated patient is to optimize ventilation by:- Creating ventilator synchrony, Decreasing the risk of barotrauma, Decreasing oxygen demand and CO2 production, and Decreasing lactate accumulation. NMBD may be administered as bolus doses or as an infusion. Consideration should be given to the use of a nerve stimulator and to stopping an infusion every 4-6hrs to prevent accumulation. Prolonged use is associated with myopathy and muscle weakness, with an incidence of about 30%31, 32. This is usually correlated with the duration of NMDB usage and can occur with or without the concomitant use of corticosteroids. Although reversible, it may take a few weeks to fully resolve; therefore their use is recommended to be kept to a minimum (usually <24 hours), and only in those patients in which sedation alone is inadequate to control ventilation. In addition, allergic reactions and histamine release may exacerbate the bronchospasm. Page 25 of 35 Modes of ventilation Pressure controlled ventilation is discouraged because53: 1. Variable changes in airway resistance and PEEPi subject the patient to fluctuations in tidal volume, with the risk of unacceptably low alveolar ventilation. 2. Respiratory alkalosis may develop once airway resistance subsides rapidly Volume controlled ventilation is therefore currently preferred as it obviates these disadvantages, but mandates careful monitoring of airway pressures. Normally a period of 24hrs is required to rest the respiratory muscles and allow for medical therapy to take effect. Once the patient improves and begins to breathe, spontaneously triggered modes of ventilation such as pressure support ventilation can be introduced. Weaning Once dynamic hyperinflation has settled and there is an improvement in clinical condition based on - ABG assessment, lack of wheezing, clinical judgement, and PEEPi < 5cm H2O – weaning may be commenced. A trial of pressure support ventilation is initiated, followed if well tolerated by a standard weaning procedure53. Weaning is normally rapidly achieved in status asthmaticus and should not be prolonged as the endotracheal tube may be a trigger for bronchospasm. 6.3 Aerosol drug delivery during mechanical ventilation Mechanical ventilation, either invasive or non-invasive, may compromise the delivery of inhaled bronchodilators. A variety of factors including the type of nebuliser, driving gas flow, ventilator tubing and the diameter of the endotracheal tube influence the amount of drug able to reach the distal airways. Drug delivery may vary between 0-42 % in ventilated patients39. Details of drug delivery are beyond the scope of this text. Table 9 shows the methods commonly employed. Page 26 of 35 Table 9. Aerosol drug delivery to mechanically ventilated patients2 Metered dose inhaler spacer or holding chamber place in inspiratory limb rather than Y-piece briefly discontinue humidification activate during lung inflation large bore endotracheal tube prolonged inspiratory time Jet nebulisation mount in inspiratory limb delivery improved by inspiratory triggering increase inspiratory time and decrease respiratory rate use a spacer high flow to generate aerosol high volume fill stop humidification consider continuous nebulisation Ultrasonic nebulisation Position in inspiratory limb prior to a spacer device Use high power setting Use a high volume fill Maximise inspiratory time Drugs must be stable during ultrasonic nebulisation Adjuvant Therapy Adjuvant therapy used in status asthmaticus 1. 2. 3. 4. 5. 6. 7. 8. Magnesium sulphate Methylxanthines Adrenaline Inhalation anaesthetic agents Heliox Ketamine Nitric oxide Leukotriene antagonists Page 27 of 35 1. Magnesium sulphate The potential role of magnesium sulphate in status asthmaticus:- bronchodilation by inducing smooth muscle relaxation prevents the release of histamine from mast cells and acetylcholine from nerve endings enhances β2-agonist effects attenuates potentially deleterious neutrophil oxidative bursts Intravenous magnesium is generally considered safe (barring the hypotension associated with rapid administration, and that toxicity may worsen respiratory muscle weakness), however, its routine use in status asthmaticus remains inconclusive. Two meta-analyses concluded that magnesium sulfate might be most beneficial in severe attacks where the PEF is less than 30–40% predicted and where a failed response to initial conventional treatment is evident25, 26. Currently, the BTS guidelines recommend using a single IV bolus of 1.2-2.0g of MgSO4 as an infusion over 20 min27. 2. Methylxanthines Aminophylline is a methylxanthine derivative, which contains 80% theophylline. It is a non-selective phosphodiesterase inhibitor that results in an increase in intracellular cAMP and possibly cGMP. They also interfere with the translocation of calcium into smooth muscle, inhibit the degranulation of mast cells and potentiate prostaglandin synthetase activity. In addition they may also directly release noradrenaline from sympathetic nerve terminals and synergistically act with catecholamine to increase cAMP. Its role in status asthmaticus is thought to induce bronchodilation, improve diaphragmatic function and ventilatory drive, and enhance mucocilliary clearance. Methylxanthines have a narrow therapeutic index, and toxicity (arrhythmias, vomiting, convulsions and restlessness) results easily, hence its use as a first line agent has diminished in recent years. The outcomes of two systematic reviews have shown that intravenous aminophylline in severe acute asthma does not cause additional bronchodilation above the use of β2-agonist and corticosteroids29, 30. However it is still used in patients not responding to standard therapy. The BTS/SIGN guideline suggests that a loading dose of 5 mg/kg body weight of aminophylline administered intravenously over 20 min (unless already on oral treatment), followed by an infusion of 0.5 mg/kg/hour. Regular Page 28 of 35 blood level monitoring is an important part of using this drug. The therapeutic range is 55–110 mmol/l (10–20 mg/l). 3. Adrenaline Adrenaline has been used both as a nebulized solution and intravenously. There are theoretical advantages to the preferential use of IV adrenaline as opposed to pure β2-agonists in acute severe asthma. Although bronchoconstriction is the major pathology in asthma, airway oedema might also make a significant contribution. Both the α-agonist and β-agonist effects of adrenaline might be beneficial, with the α-effect decreasing oedema and the β-effect responsible for bronchodilation. Currently there are no recommendations regarding adrenaline. Its use would be reasonable as a rescue therapy in severe asthma complicated by hypotension that is not secondary to dynamic hyperinflation. 4. Inhalation anaesthetic agents After intubation, inhaled anaesthetic agents might be useful because of their potent direct bronchodilatory effect and their ability to decrease airway responsiveness. The benefits of the use of these agents must be balanced against the risk of inducing myocardial depression and arrhythmias, and the logistical problems associated with their use. Scavenging and agent monitoring are absolute requirements. The anaesthesia conserving device (AnaConDaTM) is a modified heat and moisture exchanger which allows the delivery of volatile anaesthetic agents directly into a standard breathing circuit. Volatile agent is continuously infused into the patient side of the device via a volatile agent compatible syringe and giving set (supplied with the device) and a standard infusion pump. A reflective filter within the device maintains the volatile agent on the patient side and therefore conserves the volatile agent. Ninety-five percent of the anaesthetic vapour is conserved, allowing for very low volatile infusion rates. End tidal agent monitoring is mandatory and allows titration of the volatile agent infusion according to a normogram. Sample gases passing through the volatile agent monitor may be returned to the breathing system or scavenged. The successful use of volatile anaesthetic agents as bronchodilators has been previously documented in studies more than a decade old. Traditionally, halothane has been the agent of choice. Isoflurane and sevoflurane have been shown to be as effective as halothane and beneficial in acute severe asthma. Page 29 of 35 5. Heliox (HeO2) Heliox is a mixture of helium and oxygen, usually a 70:30 helium to oxygen ratio. By substituting helium for nitrogen the physical properties of the inhaled gas mixture changes, (ie. by decreasing the gas density, airway resistance can be decreased in the absence of any anatomical change), which is the theoretical rationale for its use. Decreasing airway resistance improves the work of breathing and gas exchange. Heliox has been shown to improve the delivery and deposition of nebulized salbutamol. Although recent metaanalysis of 4 clinical trials did not support the use of heliox in the initial treatment of patients with acute asthma, it may be useful for asthma that is refractory to conventional therapy. The heliox mixture requires at least 70% helium for effect, so if the patient requires >30% oxygen, the heliox mixture cannot be used. Flow meters and nebulizer generator systems must be adapted for heliox use in ventilated patients. The use of heliox to prevent intubation has not been studied, but dyspnoea scores were improved in one study, possibly by reducing the work of breathing2. 6. Ketamine Ketamine is a general anaesthetic agent that has bronchodilatory and sedative properties. One case series suggested substantial effectiveness, but the single randomized trial published to date showed no benefit of ketamine when compared with standard care50. One of the drawbacks is that it stimulates copious bronchial secretions. 7. Nitric oxide(NO) NO exerts a weak bronchodilator effect. It dilates pulmonary arteries and, when inhaled, may improve ventilation/perfusion matching2. 8. Leukotriene antagonists Leukotriene antagonists improve lung function and decrease the need for short-acting β-agonists during long-term asthma therapy, but their effectiveness during acute exacerbations of asthma is unproven7. In one study, the intravenous agent, montelukast, given to patients in the emergency department with an acute exacerbation resulted in improved FEV1 within 20 minutes of administration48. Patients tended to receive less βagonist and had fewer treatment failures than patients receiving placebo. The authors concluded that montelukast combined with standard therapy Page 30 of 35 produces rapid benefit and is well tolerated in adults who have acute asthma48. In another study Silverman et al49 demonstrated that oral zafirlukast resulted in a significant improvement in FEV1 and dyspnoea within 60 minutes of administration in the emergency department. Further research is required to validate this, but it may be prudent to consider it as adjuvant therapy. 8. OTHER ISSUES OF STATUS ASTHMATICUS 8.1 Extracorporeal membrane oxygenation in Status asthmaticus Case reports of the use of extra-corporeal membrane oxygenation in lifethreatening asthma suggest that this may be successful, but its limited availability and the risk profile limit its applicability. In contrast, the development of less complex systems of extra pulmonary gas exchange that facilitate CO2 clearance (e.g. Novalung) brings extra-corporeal CO2 removal (ECCO2R) within bounds. Their use should be considered particularly where the control of hypercarbia is imperative1. 8.2 Cardiac Arrest in the Asthmatic Patient When the asthmatic patient experiences a cardiac arrest, the provider may be concerned about modifications to the ACLS guidelines. There is inadequate evidence to recommend for or against the use of heliox during cardiac arrest (Class Indeterminate). There is insufficient evidence to recommend compression of the chest wall to relieve gas trapping if dynamic hyperinflation occurs7. CONCLUSION Acute severe exacerbations of asthma are a common medical emergency. Proper identification of risk factors and markers of severity with the appropriate management helps prevent the development of status asthmaticus. However there are a number of patients that will require referral to ICU for escalation of therapy. 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