Acute status asthmaticus is a fragile thing which, most ICU specialists would agree, is a good reason to get out of bed and drive to the hospital. These people tend to die rather readily, typically of cardiac arrest due to dynamic hyperinflation and the resulting loss of preload. This is made worse by the fact that the excellent outpatient management of asthma has filtered out the mild and moderate patient groups, and left only the incredibly brittle severe asthmatics. Only these are the people who ever get admitted to ICU for mechanical ventilation. Thankfully, even the ICU management of these people is improving, and in spite of an overall worsening severity of their illness, their ICU mortality has been steadily improving.
Severe asthma is very popular with the CICM examiners. Past paper SAQs on this topic include the following:
- Question 1 from the first paper of 2015
- Question 28 from the first paper of 2014
- Question 27 from the second paper of 2012
- Question 2 from the second paper of 2010
- Question 4 from the first paper of 2006
- Question 2 from the second paper of 2001
In brief summary, the management of severe asthma:
- Use the largest tube possible.
- Use lowest FiO2 to achieve SpO2 of 90-92%
- Use a small tidal volume, 5-7ml/kg
- Use a slow respiratory rate, 10-12 breaths per minute (or even less!)
- Use a long expiratory time, with I:E ratio 1:3 or 1:4
- Increase inspiratory flow rate to maximum. .
- Reset the pressure limits (i.e. ignore high peak airway pressures). .
- Use heavy sedation.
- Use neuromuscular blockade.
- Minimise the duration of neuromuscular blockade.
- Use a volume-control mode of ventilation.
- Use minimal PEEP.
- Keep the Pplat below 25cmH2o to prevent dynamic hyperinflation.
- Titrate PEEP to work of triggering once the patient is breathing spontaneously.
First-tier therapies with strong supporting evidence
- Humidified oxygen titrated to SpO2 90-92%
- Nebulised beta-agonist bronchodilators
- Nebulised anticholinergic drugs
- Steroids: IV hydrocortisone or oral prednisone
Second-tier therapies with weak supporting evidence
- Intravenous beta-agonist bronchodilators for refractory bronchospasm
- Nebulised adrenaline
- Magnesium sulfate
- Helium-oxygen mixture
Third-tier therapies without any supporting evidence
- Volatile anaesthetics
- ECMO in asthma
Now, in great detail:
What qualifies as "severe" asthma
There is a fairly well-defined set of features which qualifies asthma as "severe".
- Previous intubation
- Frequent admissions
- Agitation or delirium
- Use of accessory muscles
- Intercostal recession
- Tracheal tug
- Silent chest
- Inability to speak
- Pulsus paradoxus in excess of 15mmHg
- Heart rate in escess of 120
Pulmonary function test data:
- FEV1 less than 1L
- PEFR less than 100L/min (or less than 60% predicted)
- Hypercapnea and respiratory acidosis (PaCO2more than 45mmHg) is a good reliable marker.
Risk factors for ICU admission as an episode of "Severe" asthma
How do you get yourself admitted to the ICU as a severe asthmatic?
Well. There are several physiological behavioural and environmental features which seem common.
- Underestimation of severity: "its not that bad"
- Poor treatment compliance
- Previous treatment with bronchodilators without steroids
- Low socioeconomic status
- Genetic polymorphism: IL4RA 576R allele
Features which mandate immediate ICU admission
- Respiratory arrest
- Delirium or decreased level of consciousness
- Evidence of myocardial ischaemia
...But this list is not exclusive. Its not as if you would keep a severe asthmatic puffing away in the emergency department, waiting for these features to develop.
Physiological consequences of bronchospasm
Auto-PEEP, the trapping of pressurised gas inside the chest, is repsonsible for most of the problems in acute severe asthma.
- Dynamic hyperinflation - manifesting as Auto-PEEP - is discussed in detail elsewhere; suffice to say that (as all excessively positive intrathoracic pressure) it has unfortunate consequences for cardiac preload, and is thus viewed as a Terrible Thing. Consider the normal cardiovascular responses to positive intrathoracic pressure, and amplify them.
- Distorted mechanics of respiration - due to hyperinflation of the chest, the normal mechanics of respiration are grossly abnormal. Consider that normally the diaphragm hangs between the ribs as a dome-shaped structure, and by contraction increases the intrathoracic volume. Consider now what would happen if this dome-like structure were to flatten.
That flattening, which is a typical radiological feature of the asthmatic, makes is very difficult to generate a normal tidal volume. At its limits already, the poor diaphram has nowhere else to go. By expending a massive amount of effort, it can only generate a relatively small tidal volume. Oh's Manual describes this as "a severe mechanical disadvantage".
When this pathophysiological feature takes center stage in the presentation of an asthmatic, one tends to find extremely high PaCO2 values, and a silent chest.
- Deranged gas exchange - due to several factors. There is a V/Q mismatch, for which both the V and the Q are responsible.
Ventilation is lacking, to be sure - some parts of the lung are not getting any air movemewnt at all, be it due to severe airway closure, or merely because the hyperinflation creates minimal air movement (as in the case of the apices).
Perfusion is also impaired, and this is largely an Auto-PEEP associated thing. Consider that Auto-PEEP can be as high as 30-35 cm H2O - this is pressure which directly opposes pulmonary perfusion. Consequently, the areas where this Auto-PEEP is greatest will receive the least blood flow.
Humidified oxygen titrated to SpO2 90-92%
Hyperoxia, it turns out, is harmful in asthmatics - for reasons completely divorced from CO2 retention.
Consider the hyperinflated alveolus. It, sitting there full of pressurised gas, is slowly filling up with CO2, and emptying of oxygen. Its ventilation is terrible, and the normal mechanism of hypoxic vasoconstriction has intelligently diverted blood flow from this useless cavity, to collect oxygen from better ventilated regions.
Now, see what happens when you blow extra oxygen into this intermittently ventilated alveolus. Suddenly, the burst of extra oxygen reverses the hypoxic vasoconstriction, and blood is diverted away from well-ventilated regions. The well-ventilated regions will still participate in gas exchange, to be sure - but now, CO2 clearance will be impaired, because the CO2-containing blood is being diverted to regions from which expoiratory gas escape is impossible.
On top of that, there is probably some contribution from the Haldane effect, which describes the affinity of hemoglobin for CO2. In brief, hyperoxic environments degrade this carrying capacity, decreasing the exchange of CO2 at the alveolus.
Is there any evidence for the validity of these fancy theories? Yes there is. Perrin et al published a trial in Thorax which compared liberal untargeted oxygen therapy with conservative targets (for 93-95% saturation). Turns out, the liberally oxygenated patients became hypercapneic.
This phenomenon is analogous to the need for careful O2 control in patients with COPD, and elsewhere in this site there is an exploration of the empirical evidence for the changes in CO2 with excessive oxygen administration. Thugh data of this sort is not available for asthma, one could surmise that it would be the same sort of relationship, if not worse.
Nebulised beta-agonist bronchodilators
Even though probably less than 10% of the nebulised drug reaches the lung, salbutamol nebs are the mainstay of treatment. Whether to nebulise the drugs with a continuous flow of oxygen, or to administer via spacer - there seems to be no real difference in effectiveness.
Intravenous beta-agonist bronchodilators for refractory bronchospasm
Now, here is controversy. These tend to have a massive excess of adverse effects, for comparatively little clinical benefit. The general consensus is that these should be avoided unless absolutely necessary.
What would make them "absolutely necessary"? Well, for one, in order for nebulised bronchodilators to be effective, they would need to have access to the bronchi. A patient in a state of near-total respiratory arrest is unlikely to be moving enough air to get any mist to its site of action. In these people, IV salbutamol may be the right choice. In effect, any nebs administered to them will nly be having effect by absorbing directly into the bloodstream via the oral mucosa.
Thus, it is generally held that IV bronchodilators should be started when it is clear the the patient is not responding to the nebulised administration. In general we tend not to give doses higher than 10μcg/min. Lactic acidosis and hypokalemia reward the overvigorous salbutamol user.
Nebulised anticholinergic drugs
Ipratropium nowadays gets used for all acute asthmatics, because of its suspected benefit, and absence of harm. The anticholinergics seem to be useless on their own, but potent in combination with beta-agonists.
Steroids: IV hydrocortisone or oral prednisone
From internship, one recalls the tendency for these asthmatic people to be put on 100mg qid of hydrocortisone, which equates to about 100mg of oral prednisolone. There are many benfits:
- ablation of IgE-mediated inflammatory response
- increased responsiveness of the smooth muscle to beta-2 agonists
- decreased mucus secretion
However, it seems oral agents are at least as effective as intravenous agents, and that there is no benefit in giving truly massive doses (eg. over 800mg/day of hydrocortisone).
Aminiphylline is the only one available in Australia. Its use tends to be reserved for patients refractory to the first tier of therapies.
In general, the current opinion of aminophylline is that it ...
- is a poor bronchodilator
- is associated with a prohibitive toxicity
- has a narrow therapeutic range and needs monitoring (levels should not get above 200 10μmol/L)
There is also an entire population of patients in whom it should ever be even considered:
- Heart failure
Additonally, aminophylline interacts with a whole host of drugs, making its use a fiddly and complicated affair. It can even decrease the sedating effects of propofol.
Some might say that the vasoconstricting effects of adrenaline are beneficial in asthma because they address the inflamed vascular engorgement of the bronchial lining. In early studies, it had compared favourably. However, well-designed trials which followed had demonstrated that it is no different to salbutamol in efficacy, and that salbutamol has fewer adverse events.
IV or nebulised adrenaline is one of the things you try when you are truly stuck, and have nothing else to add to the management.
The use of magnesium sulfate in asthma is controversial; generally speaking everybody knows that "thats what you give for severe asthma" but when one examines the evidence, there is actually nothing to support its routine use in anything but the most desperate situations. The recent MAGNETIC trial has demonstrated that nebulised magneisum sulfate may actually have a little bit of benefit in children with severe asthma, and a 2013 meta-analysis has confirmed that IV magnesium has a statistically significant influence on resiratory function among adults.
Oh's Manual only gives it a lukewarm recommendation.
ketamine is generally though to be a bronchodilator by a variety of mechanisms, the chief of which is probably sympathomimetic. This all sounds very nice, but the evidence for its use in adults is not very strong, and a recent meta-analysis has demonstrated that it has no benefit in acutely asthmatic children. In its support, we only have case series of questionable quality.
That said, I think nobody should die of asthma without having had a trial of ketamine.
Heliox, the trade name of the 70% helium - 30% oxygen mixture, is another measure one may consider when faced with a comletely impenetrable bronchospasm. This therapy, in contrast to such baddies as adrenaline and aminophylline, remains on the menu purely because it has so few adverse effects (and who cares about the lack of benefit, right?)
The theory behind it is well summarised in the 2006 paper by Wigmore and Stachowski. Characteristically of these authors, interesting details of physics are offered, including a table of the physical properties of gases at room temperature and pressure. One immediately notices that the density of helium is vastly lower than the density of oxygen, or all the other atmospheric gases for that matter. This leads to an improvement in the flow of gas through narrow cylinders; laminar flow occurs in tight spaces where turbulence would otherwise appen.
Thus, the benefit of this therapy lies in the decreased effort of breathing. This seems to have some benefit in the setting of severe asthma (but, as expected, the mild and moderate asthmatics get nothing out of it). Ther are really very few risks - helium is very well tolerated. The major risk is hypoxia, because the ideal mixture of gases has only 30% FiO2, and not every asthma patient can tolerate this.
Like ketamine, these are only described in small case series. There is an inherent difficulty in fitting a volatile vapouriser to the ICu ventilator. That said, it seems they are potent bronchodilators, and can make all the difference in an intubated severely bronchospastic patient. In essence, this therapy should be brought into the equation as a prelude to ECMO.
Evidence for the use of non-invasive ventilation in asthma
NIV has a number of theoretical benefits in asthma:
- Extrinsic PEEP decreases the work of breathing by helping overcome Auto-PEEP
- Extrinsic inspiratory positive pressure (IPAP) may increase tidal volume by decreasing the work done against airway resistance
- Shorter inspiratory times may increase tidal volumes without causing any extra dynamic hyperinflation
- NIV may be able to prevent intubation in a selected group of patients.
NIV also has a number of theoretical disadvantages.
- May delay intubation
- Inappropriate settings may increase the effort of breathing
- Increased positive airway pressure increases risk of pneumothorax
- Addition of extrinsic PEEP which is higher than intrinsic PEEP will exacerbate dynamic hyperinflation
- NIV makes it more difficult to clear secretions if there is a strong infective component.
The evidence for the use of NIV in asthma is not as strong as the evidence for its use in COPD, but among the experts the general opinion is that NIV in asthma is useful. So what if there haven't been enough trials to confirm the improvement in mortality?
- It seems to prevent intubation
- It decreases the length of ICU stay
- It accelerates the return of normal lung function
- It improves the delivery of nebulised drugs
However, the evidence has significant limitations:
- Trials are small, ~ 30 people! The most recent meta-analysis of such RCTs (Lim et al, 2012) ended up scraping together five studies - which only had n=206 in total.
- The data has so far failed to demonstrate a clear mortality benefit, but this is mainly because the groups of patients enrolled into these studies have not been very sick. For an example, let us take endotracheal intubation. Of the 90-or so patients in two RCTs analysed by Lim et al, only two required intubation. There were no deaths in either group. How can you demonstrate a mortality benefit if nobody is dying?..
- A recent systematic review by Green et al (2017) found the available studies (13 met criteria) had such heterogeneity that no recommendations could be made.
Practical use of NIV in the acute severe asthmatic
Indications for NIV in the acute asthmatic are thought to be:
- severe dyspnoea
- use of accessory muscles
- respiratory rate greater than 25
Full face masks are usually best.
No "routine" pressure settings can be recommended; it is best to stand at the bedside and adjust the pressures until the patient feels their breathing is getting easier. Oh's Manual suggests initial settings of 5cmH2O EPAP, and 8-10cmH2O of pressure support on top of this (i.e. an IPAP of 13-15 cmH2O).
Predictors of failure in using NIV for the acute severe asthmatic
If n=206 was depressing, then you're going to love this area. It seems we have only this conference abstract to work with (Samaria et al, 2011). In this n=54 prospective cohort, NIV failure was defined as the need for intubation. The following features identified patients who would go on to be intubated after a trial of NIV (as defined by an hour of continuous NIV)
- High APACHE II score at presentation
- High respiratory rate after 1 hour of NIV
- Tachycardia after 1 hours of NIV
- persistently high CO2 after 1 hour of NIV
A gradual course of onset makes you think the patient will fail NIV. If the asthma attack has been going for days, the patient arrives to the ED when they are already exhausted.
When to intubate the asthmatic patient
Another way of asking the question about the predictors of NIV failure is to ask which criteria one would use to intubate the asthmatic patient. This is not a consequence-free decision. It is possible to cause worsening bronchospasm, and to inadvertantly cause pneumothorax or worsening hyperinflation.
The following criteria are "consensus indications for intubation" listed in an article by Brenner et al (2009 - see Table 2).
- Progressive respiratory exhaustion (rising PaCO2)
- Decreasing level of consciousness, altered sensorium
- Severe hypoxemia
- Silent chest
- Respiratory arrest (or cardiac arrest)
Mechanical ventilation of the intubated asthmatic
There are several principles to abide by:
- Use the largest tube possible: this will decrease the airway resistance and the peak airway pressures, not that hey are especially important. The machine will alarm less frequently.
- Use lowest FiO2 to achieve SpO2 of 90-92%
- Use a small tidal volume, 5-7ml/kg
- Use a slow respiratory rate, 10-12 breaths per minute (or even less!)
- Use a long expiratory time, with I:E ratio 1:3 or 1:4
- Increase inspiratory flow rate to maximum. You want a short inspiratory time and maximal expiratory time for CO2 clearance. In order to achieve the desired tidal volume within an unaturally shortened inspiratory time, the inspiratory flow must be very high. Ventilators may offer either a percentage (% of inspiratory phase), an actual time (eg. 0.2 to 0.5 seconds) or an actual flow rate (eg. 100L/min). Crank this as high as it will go.
- Reset the pressure limits (i.e. ignore high peak airway pressures). Given that the airway resistance will be high, with a maximised inspiratory flow rate one expects a high peak airway pressure, and cares little about it. One cares more about the plataeu pressure.
- Use heavy sedation, because the respiratory acidosis will generate a powerful respiratory drive and you dont want this to interfere with your carefully planned ventilation strategy
- Use neuromuscular blockade to defeat patient-ventilator dyssynchrony and to remove the contribution of respiratory muscles to the respiratory circuit resistance.
- Minimise the duration of neuromuscular blockade: wean it as soon as possible; the combination of steroids and NMJ blockers leads to the hideous complication of acute necrotising myopathy. The most important predictor of this is the duration of paralysis.
- Use a volume-control mode of ventilation: There is no evidence to help recommend one mode of ventilation over another. Oh's Manual recommends SIMV with volume support ventilation, because it features a square flow waveform. Because of this, the initial high flow rate generates a short inspiratory time, which decreases the risk of dynamic hyperinflation. Pressure-controlled modes have the advantage of controllable peak pressures, but in asthma the high peak airway pressure is wholely due to the airway resistance, and the plateau pressure is typically modest.
- Use minimal PEEP. One does not have a work of breathing to decrease in the sedated paralysed asthmatic, and so there is no need to overcome Auto-PEEP with intrinsic PEEP. Rather, one should instead make no effort to contribute to the existing Auto-PEEP. Back in the day, we used to ventilate patients with a PEEP of 0 (ZEEP). Now, it would appear that some small level of PEEP is actually beneficial - the theory is that it splints the spastic bronchi open, and thus actually improves the clearance of CO2 (as those little airways were otherwise going to collapse in expiration).
- Keep the Pplat below 25cmH2o to prevent dynamic hyperinflation. With an arterial line, respiratory changes in pulse pressure variation can be obvious, and this will alert you to the increase in Auto-PEEP. Additionally, one can observe a number of waveform-plotted parameters:
- End-tidal CO2 has a characteristic sawtooth pattern in dynamic hyperinflation.
- The flow waveform fails to reach the zero line in dynamic hyperinflation.
- An inspiratory hold manoeuvre can be performed to assess the plateau airway pressure (Pplat). This is a direct measure of alveolar hyperinflation. In general, this number should be below 25cm H2O. Empirical evidence demonstrates that this correlates with an end expiratory lung volume of around 20ml/kg (on top of the FRC!), which approaches total lung capacity. Beyond this level, complications due to dynamic hyperinflation will ensue.
- An expiratory hold manoeuvre can be performed which measures auto-PEEP, but this manoeuvre tends to underestimate its true extent, as by the time expiration happens, many of the most bronchospastic airways have closed, and only the least bronchspastic airways remain open.
- If one observes that dynamic hyperinflation is taking place, one may want to disconnect the patient from the ventilator, and manually decompress the chest - the "status asthmaticus hug". One will likely be rewarded with a nice increase in MAP and a nice fall in CVP.
- Titrate PEEP to work of triggering: once the patient is triggering spontaneously on pressure support, you may titrate the CPAP to the minimum level at which the patient is able to flow-trigger the ventilator without undue effort. This reduces the work of breathing, and enhances the process of weaning.
Inspiratory time and expiratory time
Though various highly reputable sources (Stather & Stewart, 2005; Leatherman et al, 2015; Laher et al, 2018) might recommend "to shorten inspiratory time as much as possible", there is obviously a limit to this recommendation. For instance, it does not mean that in all status asthmaticus scenarios one should reduce the inspiratory time to the shortest possible duration permitted by the ventilator. Thinking along those lines might lead to absurd ventilator settings; for instance, the Siemens SERVO-i can deliver a maximum flow rate of 3.33L/sec, and so could theoretically blow a 500ml tidal volume over an I-time of 0.15 seconds. Obviously no sane person would ever leave the patient on those settings. So, there must be some safe (short) inspiratory time which everybody is comfortable with, and which still maximises expiratory time.
How long does the inspiratory time have to be, and for what scientific reason does it need to be longer than 0.15 seconds? There are two main reasons. For most conventional ventilation scenarios, a prolonged I-time allows the recruitment of lung units with longer time-constants, which favours oxygenation by increasing the available gas exchange surface, and by decreasing shunt by defeating the typical tendency of mechanically ventilated patients to develop atelectasis in their lung bases. These matters are less relevant in the context of severe status asthmaticus. For one, the lung units with the long time constants tend remain recruited throughout the respiratory cycle by autoPEEP. Atelectasis does not tend to be a major feature of severe acute asthma, and oxygenation is rarely the problem. The more important benefit of a longer inspiratory time in asthma is the tendency of short time constant units to fill quickly, taking much of the volume and therefore becoming the most hyperinflated during inspiration. A longer inspiratory time is therefore likely to result in a more even inflation among heterogeneous lung units, and therefore a reduced risk of pneumothorax. Sarnaik et al (2004) used this argument to support the use of a pressure-controlled mode of ventilation for asthamtic children.
Another relevant benefit of a longer inspiratory time is the reduced flow rate. Using a "square" constant flow pattern, one could deliver the 500ml volume over 0.15 seconds with a flow rate of around 200L/min, or over 1.0 seconds with a flow rate of 30L/min. In severely bronchospastic highly resistant airways, flow rate will be directly related to the peak inspiratory pressure; the lower flow rate will produce much lower peak pressures, and fewer ventilator alarms.
The better question to ask is, how much good does it do to shorten inspiratory time to a minimum? Turns out, the benefit from it is probably minor, when compared to decreasing the respiratory rate. Tuxen & Lane (1987) found that changes to the respiratory rate and minute volume were by far the more effective. The ultimate benefit is from the increased expiratory time; removing extra breaths from a minute of ventilation increases the total expiratory time by a much large value than decreasing the inspiratory time of each breath from 1.0 to 0.5 seconds.
In summary, the strategy of shortening the inspiratory time should be viewed as second fiddle to the strategy of decreasing the respiratory rate. It should be resorted to only in those scenarios where one cannot possibly decrease the respiratory rate any further, and but still wishes to have some additional minor advantage. Another minor advantage is passing the CICM fellowship exam, where this topic comes up frequently, and where the official college answers (eg. in Question 27 from the second paper of 2012 and Question 4 from the first paper of 2006 ) occasionally mention "minimise inspiratory time) as one of the strategies. In order to score full marks, one would be expected to join the examiners in being inaccurate.
Tenacious mucus plugging is a major problem and historically people have viewed mucolytics +/- bronchoscopy as either a major curative strategy or a end-of-the-line last ditch rescue therapy for intubated severe asthma patients. A representative article from the heyday of this strategy is Henke et al (1996), whose team tended to give 3ml of an N-acetylcysteine/salbutamol mixture into each lobe of the lung via a bronchoscope and then suctioned the resulting mucus.
The options for mucolytic agent are
- Recombinant human DNase (rhDNase)
- Hypertonic saline
This practice is far from dead. A more recent survey of British intensivists found that "recombinant human DNase (rhDNase) does get administered by 63% of clinicians, with 54% and 19% that administer hypertonic saline or N-acetylcysteine, respectively" (Snoek et al, 2015). Case reports with miraculous rescues exist (eg. Hull et al, 2010).
The largest part of the literature on this topic comes in the from of observational studies and case reports. The rest is evidence extrapolated from cystic fibrosis patients, burns patients, surgical patients and other non-asthma territories. For these reasons, most authors do not recommend mucolytics. In their chapter (Ch 5, Acute Exacerbations of Asthma) for Pulmonary Emergencies (2016), Bhakta and Lazarus placed mucolytics into the "Therapies without supporting evidence" table. Irwin and Rippe (p 708, section 4) also could not recommend either rhDNAse or N-acetylcysteine. In fact, even in cystic fibrosis the benefits of rhDNAse were not statistically significant (seems antibiotics and chest physiotherapy did all the work). The most recent consensus guidelines (Expert Panel Report 3, 2007) do not support the routine use of mucolytics.
When all else fails, patients who are dying from this reversible condition should be offered ECMO wherever it is available. A publication from 2003 details a series of case reports, which support the use of ECMO in near-fatal asthma. If hypercapnea is what ails you, CO2 removal alone by ECCOR is also an option. Obviously, owing to the extreme potential complications, and the violently invasive nature of this treatment, it should probably be reserved for patients in whom all other management strategies have failed.