Download J Kanjee STATUS ASTHMATICUS - Waiting to Exhale

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
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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)
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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
-
-
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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).
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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.
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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.
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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
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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.
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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
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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.
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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. The intensive care physician plays a vital role in the prevention of
morbidity and mortality provided there is an understanding of the disease process,
timely intervention when required and knowledge of first line and adjuvant therapy.
Prevention of complications and appropriate ventilatory management is of key
importance in improving outcomes in patients with status asthmaticus.
Page 31 of 35
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