Management of Status Asthmaticus in Children Muriel Konickx 2013

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YPRRV-903; No. of Pages 8

Paediatric Respiratory Reviews xxx (2013) xxxxxx
Contents lists available at SciVerse ScienceDirect
Paediatric Respiratory Reviews
Mini-Symposium: Respiratory Emergencies in Children
Management of status asthmaticus in children

Muriel Koninckx 1,*, Corinne Buysse 2, Matthijs de Hoog 2
1
2
Paediatric Intensive Care, Middelheim Ziekenhuis, Lindendreef 1, Antwerp, Belgium

Paediatric Intensive Care, Sophia Childrens Hospital, Dr Molewaterplein 60 Rotterdam, The Netherlands
EDUCATIONAL AIMS
The reader will be able to:
Understand the pathophysiology of paediatric status asthmaticus
Assess the severity of an asthma exacerbation,
Implement different treatment strategies for severe asthma.
A R T I C L E I N F O
S U M M A R Y
Keywords:
Paediatric status asthmaticus
Pathophysiology
Assessment
Treatment
Recent literature on paediatric status asthmaticus (PSA) conrms an increasing percentage of admissions
to paediatric intensive care units. PSA is a medical emergency that can be fatal and needs careful and
prompt intervention. The severity of PSA is mainly determined by clinical judgement of signs and
symptoms. Peak ow measurements and serial lung function measurements are not reliable in PSA.
Validated clinically useful instruments are lacking. The three main factors that are involved in the
pathophysiology of PSA, bronchoconstriction, mucus plugging and airway inammation need to be
addressed to optimise treatment. Initial therapies include supplementation of oxygen, repetitive
administration of rapid acting b2-agonists, inhaled anticholinergics in combination with systemic
glucocorticosteroids and intravenous magnesium sulphate. Additional treatment modalities may include
methylxanthines, DNase, ketamine, sodium bicarbonate, heliox, epinephrine, non-invasive respiratory
support, mechanical ventilation and inhalational anaesthetics.
2013 Elsevier Ltd. All rights reserved.
INTRODUCTION
Paediatric status asthmaticus (PSA) is a medical emergency
warranting prompt recognition and intervention. A status asthmaticus or severe asthma exacerbation is dened as an acute
episode that does not respond to standard treatment with short
acting b2-agonists and corticosteroids, although a large variation
exists in this denition between authors.13 In other denitions,
need for hospitalisation, emergency room visit or decline in peak
expiratory ow (PEF) is also taken into account. PSA can result in
respiratory insufciency as well as circulatory failure and is
potentially life-threatening. The incidence of PSA has to be viewed
against the background of the total number of asthmatic patients.4
In the United States, the number of patients with asthma
increased from 20.3 million to 25 million between 2009 and 2011.
In 2009 the prevalence among children (less than 18 years old) was
* Corresponding author. Tel.: +0032/496068751; fax: +0032/2810292.
E-mail address: murielkoninckx@gmail.com (M. Koninckx).
9.6%. The prevalence in children is higher than in adults (9.6%

versus 7.7%). Mortality in children is lower compared to adults.
Asthma was linked to 3,447 deaths including 5.4% children (about
9 per day) in 2007.5 The prevalence of asthma is increasing,
however, mortality is decreasing. This might, in part, be due to a
coding change from ICD-9 to ICD-10 (Fig. 1). In the ICD-9
classication asthma was subdivided in intrinsic, extrinsic and
chronic obstructive asthma. The ICD-10 classication uses the
descriptors of mild, moderate and severe asthma.
The increasing prevalence of asthma is seen mainly in
developed countries. Environmental factors play an important
role in this disease, next to genetic predisposition.6 Data on the
incidence or prevalence of PSA are scarce. In a New Jersey cohort,
admission for status asthmaticus between 1992 and 2006
approximately halved from 1.92 to 0.93 per 1000 children. In
contrast, ICU care related to asthma increased from 0.09 to 0.31 per
1000 patients. A much higher percentage of children admitted
to hospital for status asthmaticus received ICU care, but the rate
of children needing mechanical ventilation was the same
1526-0542/$ see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.prrv.2013.03.003
Please cite this article in press as: Koninckx M, et al. Management of status asthmaticus in children. Paediatr. Respir. Rev. (2013), http://
dx.doi.org/10.1016/j.prrv.2013.03.003
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M. Koninckx et al. / Paediatric Respiratory Reviews xxx (2013) xxxxxx
Figure 1. Number and rate* of asthma deaths, by year and International Classication
of Diseasesy (ICD) United States, 1980-2004.
(0.02/1000).7 In Finland about 1% of the hospital admissions for

asthma need intensive care, but numbers vary between 1 to 15%.
Since indications for PICU admission vary between countries these
numbers are hard to compare.8 The number of children that need
mechanical ventilation is decreasing and varies between 8 and 33%
of the PSA related PICU admissions.9 This may be due to the
increasing use of non-invasive respiratory support for severe
asthma. It can be concluded that more children with PSA are
admitted to the ICU but the need for invasive mechanical
ventilation seems to have decreased, although this is inuenced
by admission criteria. Mechanical ventilation in PSA is a risk factor
for mortality in the 10 years after discharge and close follow up is
suggested.8,9
PATHOPHYSIOLOGY OF STATUS ASTHMATICUS
The three main factors that are involved in the pathophysiology
of asthma are bronchoconstriction, mucus plugging and airway
inammation, with the exacerbation usually induced by a viral
infection.10 The relative contribution of these factors determines
the targets for optimal therapy. Some patients underestimate the
severity of airway obstruction: they have a reduced sensation of
dyspnoea while breathing with increased airway resistance and
have decreased hypoxic ventilatory drive, resulting in little reserve
at presentation.11 These are patients that are predisposed to near
fatal asthma.
In fatal and near fatal asthma we can distinguish two different
classes: type I or slow onset fatal asthma and type II or rapid onset
fatal asthma.12 Predisposing factors in type I are inadequate
therapy, inadequate compliance, inappropriate control and psychological factors. Type II can occur epidemically (soybean, castor
bean or unknown) or sporadically (NSAID, allergen, sulphites, food
or unknown).13
Type I is a progressive obstruction of the airways in patients
already constantly using bronchodilators. These patients are
usually undertreated with inhaled corticosteroids. Bronchodilating
medications cause a maximal smooth muscle relaxation. Meanwhile, the process of inammation and oedema continues due to
inadequate treatment. Only a small increase in oedema or
inammation can be fatal. Given the state of maximal bronchodilation, further use of short acting b2-agonists will not have much
additive effect and cannot reverse the bronchial obstruction. These
patients are at risk for severe therapy resistant PSA. Airway
plugging is demonstrated and secretions are characterised by
eosinophils in pathological examinations.14 In a prospective study
of the characteristics of (near) fatal asthma, about 80% belong to

type I.15 These exacerbations are preventable with extensive
asthma control and administration of adequate doses of inhaled
corticosteroids.
Type II is a rapid onset type, also called sudden asphyxial
asthma. It is an acute and sudden onset form where death can
follow in only a few hours after start of the clinical symptoms.
Severe bronchospasm occurs with little or no mucus plugging and
airway inammation.3,12 In contrast, Type I cases demonstrate
mainly neutrophilic inammation. In this type there is a higher
incidence of respiratory arrest, impaired consciousness level, a
lower pH and a silent chest reported. Clinical improvement is
directly related to improvement of bronchoconstriction. These
patients can deteriorate very rapidly, but with appropriate
interventions recovery can be accomplished swiftly, as demonstrated by a shorter length of hospital stay and fewer hours of
mechanical ventilation.15
The previously described mechanisms cause an occlusion of the
airway lumen with reduced ventilation leading to low ventilation/
perfusion(V/Q) ratios and gas exchange abnormalities. The
distribution of areas with reduced ventilation and hypoxic
vasoconstriction is widespread through the bronchial tree and
interspersed with areas of better V/Q.
An important complication of PSA is airleak which may manifest
with pneumothorax, pneumomediastinum, subcutaneous emphysema and pneumopericardium due to increased intrathoracic
pressure.4 This is mainly seen in PSA patients ventilated with high
peak pressures and is one of the drivers for the increasing use of noninvasive ventilation in the acute setting.4 Myocardial infarction,
hardly seen in children, is possible due to hypotension and elevated
inthrathoracic pressures. This increases left ventricular afterload
which can in turn decrease coronary blood ow. Mucus plugging can
provoke atelectasis. Electrolyte disturbances including hypokalemia
caused by salbutamol are possible. Myopathy and rhabdomyolysis
are described when giving steroids in combination with neuromuscular blockers.16 Lactic acidosis and anoxic brain injury have also
been described.17 These problems warrant close monitoring and
speedy intervention in a PICU.
DETERMINATION OF ASTHMA SEVERITY

A gold standard for the assessment of the severity of an asthma
exacerbation does not exist. Similar to adults, there is a lack of
validated instruments to determine asthma severity in children.
The primary importance of dening severity is to determine
further patient management. Depending on severity patients can
be divided into life threatening asthma, necessitating immediate
therapy and PICU admission, slow responding forms that need
hospital admission and patients that can be discharged directly
from the emergency department. Second, a tool for dening
severity of PSA can be used to assess the effect of therapeutic
interventions. Peak ow measurements, serial lung function
measurements, pulse oximetry and clinical examination and
asthma scoring systems are tools that can be potentially helpful.
Peak ow measurements and serial lung function measurements
Peak expiratory ow rates (PEFR) or forced exipiratory volume
in one second (FEV1) are difcult to reliably perform in children
with acute asthma, especially in those under 5 years of age. In
children aged between 6 and 18 years, only 64% were able to
perform PEFR adequately.18 Stable peak ow records can be
present despite severe bronchial hyperresponsiveness resulting in
fatal asthma.19 Thus, it is not recommended to rely on peak ow
measurements for assessing severity.
dx.doi.org/10.1016/j.prrv.2013.03.003
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Pulse oximetry
Measuring SaO2 is an important tool to determine asthma
severity, but always in combination with other parameters. Initial
SaO2 <91% or SaO2 unresponsive to oxygen treatment are related
to hospital admission and outcome.20,21 The cut-off value of 91% is
somewhat arbitrary and needs to be seen in the context of the
whole patient.21 Low oxygen saturations and hypoxia are the
consequence of V/Q mismatch caused by mucus plugging,
bronchoconstriction and bronchial inammation with a low
degree of intrapulmonary shunting.
Clinical scoring systems
Severity is predominantly assessed by applying clinical judgement, based on different signs and symptoms, including respiratory effort, pulse rate and the presence of pulsus paradoxus in
combination with measurements of gas exchange (Table 1).
Warning signs of imminent respiratory arrest should be observed
closely and warrant immediate PICU care and intervention.
A clinically useful and simple (but unvalidated) tool to assess
severity of PSA is shown in Table 2.22 This tool results in a score
between 5 and 15 which can be repeated on a regular basis and can
help assess the effect of therapy. The paediatric asthma severity
score (PASS) is based on assessment of three clinical ndings and
validated in children.23 It is a three item score where every item is
scored as none or mild (0 points), moderate (1 point) or severe (2
points). Minimum score is 0, maximum score is 6. The items scored
are wheezing, work of breathing and prolongation of expiration.

This score might have limited clinical use, since these three items
do not easily detect subtle changes in the clinical situation.
For clinical purposes, at this point in time, treatment will be
mainly driven by clinical signs and symptoms rather than results
from lung function testing.
PICU admission is necessary in a minority of PSA patients.
Several predicting factors dening the need for intensive care have
been identied. A history of three or more emergency presentations in the previous year, an elevated serum IgE level, oxygen
saturations of 91% or less on presentation or a longer duration of
asthma can predict the need for intensive care admission.24
Next to these factors, PICU admission in PSA patients was
recently related to allergies, active or passive smoking, earlier
hospitalization for asthma and non-sanitized homes.25
THERAPY
Choices in treatment of PSA are made taking the underlying
pathophysiology into account. Treatment is directed at reversal of
inammation and bronchoconstriction, and in a later phase also of
relieving mucus plugging if necessary. The initial goal is correction
of signicant hypoxaemia and reversal of the airow obstruction as
soon as possible. Initial therapies for PSA are supplementation of
oxygen, repetitive administration of rapid-acting b2-agonists (e.g.
salbutamol), inhaled anti-cholinergics (e.g. ipratropium bromide)
in combination with systemic glucocorticosteroids (e.g. prednisolone) and magnesium sulphate.
Table 1
Clinical judgement
Classication of severity of an asthma exacerbation
Symptoms
Mild
Moderate
Severe
Imminent Respiratory
Arrest
Dyspnoea
When walking
At rest (infant:
stops drinking)
Gasping
Talks in:
Alertness:
Signs at physical examination
Breathing frequency
(awake patient)
Sentences
Can be agitated
During speech (infant-softer

or shorter crying;
difculty drinking
Shorter sentences
Most often agitated
Words
Most often agitated
None
Decreased or confused
Increased
Often > 30/minute
Use of auxiliary muscles;

Sternal retractions
Wheeze
Pulse rate/minute
Pulsus paradoxus
Fluctuation of pulse pressure
between in- and expiration.
Gas exchange
SaO2 (room air)
PaCO2
PaO2
Increased
Normal breathing
frequency in children
Age
< 2 months
2-12 months
1-5 years
6-8 years
Normal frequency:
(mean)
< 48/minute
< 42/minute
< 28/minute
< 24/minute
Most often not
Often
Usually
Moderate, most often

end-exiratory
< 100
Normal pulse rate in children
Age
212 months
13 years
412 years
Loud, whole expiration
Mostly loud inand expiratory

> 120
Normal pulse:
80180
75150
60120
Absent
< 10 mm Hg
Can be present
1025 mm Hg
Often
2040 mm Hg (child)
> 95%
< 5.6 kPa
Normal
91-95%
< 5.6 kPa
> 8 kPa
< 91%
>= 5.6 kPa
< 8 kPa: possible cyanosis
100-120
Paradoxal thoracoabdominal
movements
Absent
Bradycardia
Absence suggests exhaustion
>= 5.6 kPa

< 8 kPa: possible cyanosis
C.A. Camargo, G. Rachelefsky, M. Schatz. Managing asthma exacerbations in the emergency department. Summary of the national asthma education and prevention program
expert panel report 3 guidelines for the management of asthma exacerbations. Proc Am Thoracic Society 2009;6: 357366.83
The presence of several parameters, not necessarily all, gives an indication of the severity of status asthmaticus.
Many of these parameters have not been studied systematically, they only serve as guidance.
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Table 2
Asthma score
VARIABLE
ASTHMA SCORING
1 point
2 points
3 points
34
30
26
23
>95 with room air
3539
3135
2730
2427
9095 with room air
Auscultation
normal breathing or end

expiratory wheezing
expiratory wheezing
Retractions
Dyspnoea
none or intercostal
Speaks in sentences
or coos and babbles
SEVERITY OF ASTHMA
intercostal and substernal

speaks in partial sentences
or utters short cries
40
36
31
28
<90 with room air or
supplemental oxygen
Inspiratory and expiratoy
wheezing, diminished breath
sounds or both
Intercostal, substernal and supraclavicular
speaks in single words or short
phrases or grunts
MILD
MODERATE
SEVERE
Peak expiratory ow rate (% of predicted value*)

Asthma score
>70
57
5070
811
<50
1215
Respiratory rate (Breaths/min)

23 yr
45 yr
612 yr
>12 yr
Oxygen saturation (%)
F Qureshi, J Pestian, P Davis, A Zaritsky. Effect of nebulized ipratropium on the hospitalization rates of children with asthma. N Engl J Med 1998; 339: 10305.22
The overall asthma score (range 5 to 15 points) was calculated by adding the scores for each of ve variables: respiratory rate, oxygen saturation, auscultation, retractions and
dyspnoea. The overall asthma score was used to stratify children according to the severity of the disease.
*
When peak expiratory ow rate was known and reliable, it, rather than the asthma score, was used to stratify the children according to severity.
Oxygen
Asthma fatality is related to hypoxia. As respiratory arrest in
asthma has been associated with hypoxic asphyxia, oxygen is
advised as rst line therapy in acute severe (life-threatening)
asthma in the hospital setting.26 Oxygen also has a bronchodilating effect.17 Loss of respiratory drive through oxygen
delivery, associated with chronic hypercapnia, is very rare in
children and should not delay oxygen treatment. There are small
studies in children demonstrating that nebulisation of salbutamol without oxygen can cause profound hypoxaemia from
increased V/Q mismatch, but this could not be found in adult
studies.27
Short acting b2-agonists
Reversal of bronchoconstriction can be achieved by short acting
b2-agonists like salbutamol or terbutaline which are sympathomimetic agents with adrenergic effects like smooth muscle
relaxation resulting in bronchodilation. Inhaled short acting b2agonists have a local effect on the b-receptors in the bronchial
smooth muscle cells if air entry is sufcient. In cases of severe
bronchoconstriction, with mucus plugging and low tidal volumes,
the drug will not be able to reach the most affected areas. Even in
healthy subjects only a small fraction of the dose administered will
reach the bronchial receptors because of deposition in the pharynx
and swallowing with intestinal absorption leading to detectable
concentrations in plasma.28 Recent guidelines recommend continuous or repeated intermittent nebulised short acting b2agonists combined with oxygen in cases of severe hypoxaemia.29
Continuous nebulisation might be slightly better than intermittent
nebulisation, since it led to a shorter duration of hospital stay and a
decrease in bedside respiratory therapy care in one study.30
However, this study included only 17 patients. Depending on age
the dose of nebulised salbutamol is 2.5 mg (4 years) or 5 mg (>4
years) for intermittent administration. A metered dose inhaler
with spacer is equally effective as nebulisation, with the dose being
six inhalations [total of 600 mcg] or twelve inhalations [1200 mcg]
via spacer respectively.31 However, in contrast to adults, a recent
Cochrane review shows some advantages of an inhalation device
with holding chamber compared to a nebuliser, with a signicantly
shorter length of stay in the emergency department for the rst
group.32,33 Conversely, nebulisation has the added advantage of

delivering high ow oxygen. Comparison of the different studies is
difcult because of the variation in outcome measures and severity
of asthma exacerbations.
If nebulisation fails, salbutamol can also be given intravenously,
on the assumption that with little air entry only a small amount of
the drug reaches the target airway receptors. In children, well
conducted studies concerning pharmacokinetics and pharmacodynamics of intravenous salbutamol are lacking. An early study
found that 69% of the patients responded satisfactorily after a
loading dose of 10 mg/kg, followed by a continuous infusion of
0.2 mg/kg/min, which was increased by 0.1 mg/kg every 15 minutes.34 This study included only 14 children and the outcome
parameter was a decrease of the pCO2, which gives only scarce
information about the clinical condition. Another double blind
randomized study in 29 children with severe acute asthma
compared a loading dose of 15 mg/kg intravenous salbutamol to
nebulised ipratropium bromide or a combination of both. Bolus
salbutamol was more effective, leading to earlier cessation of
nebulisation, less oxygen need and earlier discharge from
hospital.35 Dosing of intravenous salbutamol in children varies
between 0.1 and 15 mg/kg/min and there is no consensus if a
loading dose is needed.36,37
Terbutaline is also used as short acting b2-agonist. When added
to continuous nebulisation, intravenous terbutaline showed a nonsignicant decrease in clinical asthma scores, duration of
continuous nebulisation and PICU length of stay compared to
saline.38 A terbutaline dose of 0.41 mg/kg/min was shown to
lower diastolic blood pressure.39 When terbutaline was administered according to a severity related dosing algorithm, it led to
shorter PICU length of stay.40 Although the use of intravenous b2agonists varies between countries, it is normally only started after
failure of continuous nebulisation. The relationship between dose
and effect has not been studied in children. The drugs are also
known for many side effects including hypokalemia, tachycardia,
hyperglycaemia and hypotension, warranting close monitoring,
most often in the PICU setting. Some children are not as responsive
to b2-agonists as others; this could be explained by genetic
polymorphisms. Recent studies suggested that specic b2
adrenoreceptor genotypes are related to shorter ICU length of
stay and shorter duration of continuous b2-agonist therapy in
children.41
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Anticholinergic agents
These agents can decrease secretions, mucosal oedema and
reduce bronchomotor tone. Anticholinergic agents such as
ipratropium bromide give less bronchodilation and the effect
is slower compared to short acting b2-agonists. Adding multiple
doses of anticholinergics in moderate and severe acute asthma in
children to short acting b2-agonists has an additive effect. There
is a benet in terms of lung function and hospital admission.42
Recommended doses are 250-500 mg every 20 minutes for up to
three times, followed by administration every three hours if
necessary.43 In cases where salbutamol is given intravenously,
addition of ipratropium bromide does not have an additive
effect.44,45 Ipratropium bromide has a very low rate of absorption, implying that systemic side effects are rare. There are
reported cases of bronchoconstriction, but this adverse effect has
not been described when current isotonic ipratropium bromide
nebuliser solutions are used.46 In summary, ipratropium bromide
has no additional value when it is used in combination with
intravenous short acting b2-agonists in the intensive care
setting, but it can have a positive effect in the emergency
department.44,45
Steroids
In most cases of PSA, especially with failure to respond to
repeated short acting b2-agonists, steroids are added. Their most
important effect is controlling, suppressing and reversal of
inammation. They also potentiate the effect of b2-agonists on
smooth muscle relaxation, decrease b-agonist tachyphylaxis,
mucus production and microvascular permeability.47,48 The onset
of action of steroids is two to four hours with a maximum effect
after twelve hours. It is important to administer steroids early in
the disease course of PSA because this can lead to earlier discharge
and fewer relapses.49 Recommended doses of oral prednisone are
1-2 mg/kg/day with a maximum dose of 60 mg for 5 to 10 days.
Methylprednisolone is dosed 2 to 4 mg/kg/day with a maximum of
125 mg per day. Higher doses are not associated with better
effects.50 The same effect is achieved whether steroids are given
intravenously or orally, although in severely ill and dyspnoeic
children, the oral form is often difcult to administer. In mild to
moderate exacerbations a single dose of intramuscular dexamethasone has the same effect as a 5 day oral course with
prednisone.51
A study in 100 children with PSA that were randomised either
to oral prednisone 2 mg/kg or a single dose of 2 mg uticasone
through inhalation showed a higher FEV1 and a lower rate of
hospitalisation in the prednisone group.52 In children, adding high
doses of budesonide (1200-2000 mg) to systemic prednisone
(1 mg/kg) and nebulised albuterol can prevent or shorten
hospitalization.53 A more recent study concluded that adding a
single dose of 2 mg of budesonide to standard treatment of PSA did
not have a positive effect on asthma severity score or short term
outcome.54 Adverse effects of a short course treatment with
systemic steroids are mostly transient and can include hypertension, hyperglycaemia and mood disorders among others. These
reactions are especially described in high dose steroid pulse
therapy and chronic use. Overall in PSA, addition of systemic
steroids is recommended orally or intravenously. Conicting
results were reported on the addition of inhaled budesonide to
standard treatment of PSA.
Magnesium
Magnesium sulphate has a proven effect in status asthmaticus.
It works through smooth muscle relaxation secondary to inhibition
of calcium uptake leading to bronchodilation. Magnesium can also

inhibit mast cell degranulation and in this way mitigate
inammation55 and decrease acetylcholine release from nerve
terminals. A recent Cochrane review does not support routine use
of intravenous magnesium sulphate in patients with acute asthma
presenting to the emergency department. However, it can be used
safely and is benecial in patients with severe acute asthma when
added to bronchodilators.56 Three studies in children demonstrated that early administration of intravenous magnesium
sulphate is benecial on hospital admission, lung function and
clinical symptom score in children treated with bronchodilators
and steroids.5759 Doses vary between 25 mg/kg and 75 mg/kg.
Possible adverse effects are muscle weakness, hypotension,
tachycardia, skin ushing and fatigue but these are mostly
negligible.
ADDITIONAL TREATMENT MODALITIES
Standard treatment of PSA in the emergency department
should include oxygen, short acting b2-agonists and steroids.
In case of further deterioration intravenous salbutamol in
combination with anticholinergics and intravenous magnesium
sulphate should be considered. When there is no improvement
despite these therapies there are still some less frequently
used options. Most of these therapies are not evidence
based and (large) randomised controlled trials are not available.
These therapies warrant close monitoring preferably in a
PICU.
Methylxanthines
Methylxanthines (theophylline, aminophylline) act through
non-selective inhibition of a phosphodiesterase [enzyme]
and antagonise adenosine receptors in smooth muscle and
inammatory cells. They result in bronchodilation, improved
mucociliary clearance and down-regulation of inammation
and immune cell inltration. In children, the addition of
aminophylline to short acting b2-agonists and corticosteroids
in an acute asthma exacerbation improves lung function (FEV1
and PEF), but there is no reduction in symptoms, number of
nebulised treatments and length of hospital stay.60 In critically
ill children with status asthmaticus admitted to the intensive
care unit with impending respiratory failure, intravenous
theophylline is as safe and effective as intravenously administered terbutaline.61 Methylxanthines have a small therapeutic
window with many side-effects including headache, nausea,
palpitations and anxiety.62 High theophylline concentrations can
result in severe toxicity and in cardiac arrhythmias, hypotension,
seizures and even death. Given the small clinical effect,
methylxanthines should be used with caution and only in
refractory PSA.
Deoxyribonuclease (DNase)
Mucus plugging and atelectasis are an important clinical
problem in PSA. Since inammation might lead to a high DNA
content in mucus, the use of recombinant human (rh) DNase as
treatment modality has been hypothesized. In children there are
only a few case reports (but no good evidence) which described
positive effects after intratracheal delivery of DNase in mechanically ventilated asthmatic children.63,64 There is no place for
routine addition of nebulised rhDNase to conventional treatment
in children with PSA presenting at the emergency department.65
Treatment with rhDNase might rarely have a place in the PICU for
patients with refractory PSA, sometimes in combination with
bronchoscopy.
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Ketamine
Ketamine has bronchodilating properties through increasing
circulating catecholamines after inhibition of the re-uptake of
noradrenaline in the presynaptic neurons. Ketamine was
successfully used to prevent intubation in two children with
status asthmaticus who received a loading dose of ketamine
(2 mg/kg) followed by continuous infusion of ketamine (2 mg/
kg/h).66 However, a study in 68 paediatric patients could not
demonstrate an additional benet of ketamine over conventional
emergency department therapy in PSA. A rather low loading
dose of 0.2 mg/kg followed by continuous infusion of 0.5 mg/kg/
h was used in this study.67 In refractory PSA ketamine might
have a place, especially when sedation and/or intubation are
considered.
Sodium bicarbonate
Respiratory or metabolic acidosis can be seen in PSA. The
presence of acidosis can diminish the effect of catecholamines.
Therefore, treatment of acidosis with sodium bicarbonate could be
benecial. Administration of sodium bicarbonate in 17 patients
with life threatening asthma admitted to the PICU showed a
signicant decrease in mean pCO2 and a signicant increase of
mean pH. Clinical improvement of respiratory distress and level of
consciousness was seen in individual patients.68 This small
retrospective study suggests sodium bicarbonate could be
considered in life threatening asthma with severe acidosis (pH
<7.2).
Heliox
Heliox is a mixture of 60% to 80% helium with 20 to 40% oxygen,
which often is insufcient to sufciently improve oxygenation in
hypoxic children. Heliox reaches lower and obstructed airways
more easily because of a lower resistance and less turbulent ow.69
In this way it can help to bring small particles, like salbutamol/
albuterol to the distal airways. A randomised controlled trial in 29
children with moderate to severe asthma exacerbations that
compared heliox driven continuous albuterol delivery to a 100%
oxygen driven delivery demonstrated that the heliox group had
better asthma scores.70 Other studies, however, showed opposite
results. A Cochrane review concluded that there is insufcient
evidence for the use of heliox in the standard treatment of acute
non-intubated asthma patients though it has proven its effect in
certain circumstances.71
2 hours after start of non-invasive positive pressure ventilation

(NIPPV).76 A recent study also demonstrated the advantages of NIV
compared to standard treatment with a greater improvement in
clinical asthma score and a decrease in respiratory rate in the NIV
group.77 The advantages of NIV are that spontaneous breathing,
especially expiration, can remain as well as productive coughing
and swallowing. In addition, it leads to better patient comfort,
fewer lower airway infections and less need for sedation. All in all,
NIV is certainly feasible although its precise position in treatment
of PSA has not been determined as yet.
Mechanical ventilation
In severe PSA about 8% to 33% of cases need mechanical
ventilation9 which is associated with several risks. The clinical
condition of the patient is the main determinant in the decision to
start ventilation. Next to severe hypoxia, deterioration in mental
state and progressive exhaustion, cardiac and respiratory arrest are
indications to intubate.78 Intubation can trigger bronchospasm and
is a risk factor in the development of barotrauma. Fluid
resuscitation and a cuffed tube are often necessary during this
procedure. The preferred method of intubation is with rapid acting
muscle relaxants and ketamine as a sedative because of its
bronchodilating effect.2
Inhalational anaesthetics
Halothane, sevourane and isourane are inhalational anaesthetic agents that can be used to treat severe therapy resistant
asthma. They have a bronchodilating effect through relaxation of
bronchial smooth muscle cells, lowering of vagal tone and a
synergistic effect with catecholamines. They can result in
haemodynamic compromise with hypotension and delivery in
the ICU is often difcult given that most caregivers in paediatric
ICUs are not familiar with the equipment.79 The positive effect of
isourane in the setting of refractory PSA has been described in two
case series.80,81
Extracorporeal membrane oxygenation (ECMO)
This is a possible rescue therapy in life threatening asthma. The
outcome in 24 adults receiving ECMO with respiratory failure due
to status asthmaticus was better compared to adults with
respiratory failure due to other causes.82 ECMO has been
anecdotally used in children with success.83
CONCLUSION
Epinephrine (Adrenaline)
Epinephrine nebulisation was frequently used in asthma
patients in the 20th century. It has a b2-agonist effect with
relaxation of the bronchial smooth muscle cells. Additionally, it can
decrease airway oedema, inammation and mucus production
because of its effect on a-receptors. Intramuscular administration
of epinephrine is the rst choice in case of anaphylactic
asthma.72,73
Non-invasive respiratory support
Non-invasive ventilation (NIV) is increasingly used in PSA. In 72
episodes of NIV with PSA only 5 patients needed intubation. In the
other patients a signicant decline in heart rate, respiratory rate
and clinical asthma score was demonstrated during the rst
48 hours after start of NIV.74,75 Another randomised controlled
trial in children with lower airway obstruction also demonstrated
an improvement in clinical asthma score and respiratory rate
PSA is a frequent presentation in the emergency department

and PICU. Standard therapy includes oxygen, inhalation of short
acting b2-agonists, anticholinergics and systemic steroids. If
insufcient improvement is achieved, magnesium sulphate and
intravenous short acting b2-agonists have to be considered and
intensive care admission will be necessary. Besides these therapies
there are additional treatment modalities including: methylxanthines, rhDNase, ketamine, sodium bicarbonate, heliox, epinephrine, non-invasive ventilation, mechanical ventilation and
inhalational anaesthetics to be considered. Solid data on the effect
of these therapies in children are lacking.
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YPRRV-903; No. of Pages 8

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Paediatric Respiratory Reviews

Mini-Symposium: Respiratory Emergencies in Children