Paediatric Respiratory Reviews 14 (2013) 7885

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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
Paediatric Intensive Care, Middelheim Ziekenhuis, Lindendreef 1, Antwerp, Belgium
2
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: Recent literature on paediatric status asthmaticus (PSA) confirms an increasing percentage of admissions
Paediatric status asthmaticus
to paediatric intensive care units. PSA is a medical emergency that can be fatal and needs careful and
Pathophysiology
prompt intervention. The severity of PSA is mainly determined by clinical judgement of signs and
Assessment
Treatment symptoms. Peak flow 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 inflammation 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 9.6%. The prevalence in children is higher than in adults (9.6%

Paediatric status asthmaticus (PSA) is a medical emergency
warranting prompt recognition and intervention. A status asth-
maticus or severe asthma exacerbation is defined 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 definition between authors.13 In other definitions,
need for hospitalisation, emergency room visit or decline in peak
expiratory flow (PEF) is also taken into account. PSA can result in
respiratory insufficiency 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).
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
classification asthma was subdivided in intrinsic, extrinsic and
chronic obstructive asthma. The ICD-10 classification 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
 M. Koninckx et al. / Paediatric Respiratory Reviews 14 (2013) 7885
Figure 1. Number and rate* of asthma deaths, by year and International Classification
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 influenced
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
inflammation, 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 psy-
chological 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. Mean-
while, the process of inflammation and oedema continues due to
inadequate treatment. Only a small increase in oedema or
inflammation can be fatal. Given the state of maximal broncho-
dilation, 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
79
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 inflammation.3,12 In contrast, Type I cases demonstrate
mainly neutrophilic inflammation. 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 demon-
strated 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 emphy-
sema 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 non-
invasive 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 flow. 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 neuromus-
cular 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 defining 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 defining
severity of PSA can be used to assess the effect of therapeutic
interventions. Peak flow measurements, serial lung function
measurements, pulse oximetry and clinical examination and
asthma scoring systems are tools that can be potentially helpful.
Peak flow measurements and serial lung function measurements
Peak expiratory flow rates (PEFR) or forced exipiratory volume
in one second (FEV1) are difficult 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 flow records can be
present despite severe bronchial hyperresponsiveness resulting in
fatal asthma.19 Thus, it is not recommended to rely on peak flow
measurements for assessing severity.
80 M. Koninckx et al. / Paediatric Respiratory Reviews 14 (2013) 7885

Pulse oximetry are wheezing, work of breathing and prolongation of expiration.

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 inflammation with a low
degree of intrapulmonary shunting.
Clinical scoring systems
Severity is predominantly assessed by applying clinical judge-
ment, based on different signs and symptoms, including respira-
tory 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 findings 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
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 defining the need for intensive care have
been identified. A history of three or more emergency presenta-
tions 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
inflammation and bronchoconstriction, and in a later phase also of
relieving mucus plugging if necessary. The initial goal is correction
of significant hypoxaemia and reversal of the airflow 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. predniso-
lone) and magnesium sulphate.

Table 1
Clinical judgement

Classification of severity of an asthma exacerbation

Symptoms Mild Moderate Severe Imminent Respiratory

Arrest

Dyspnoea When walking During speech (infant-softer At rest (infant: Gasping

or shorter crying; stops drinking)
difficulty drinking
Talks in: Sentences Shorter sentences Words None
Alertness: Can be agitated Most often agitated Most often agitated Decreased or confused
Signs at physical examination
Breathing frequency Increased Increased Often > 30/minute
(awake patient) Normal breathing
frequency in children
Age Normal frequency:
(mean)
< 2 months < 48/minute
2-12 months < 42/minute
1-5 years < 28/minute
6-8 years < 24/minute

Use of auxiliary muscles; Most often not Often Usually Paradoxal thoracoabdominal
Sternal retractions movements
Wheeze Moderate, most often Loud, whole expiration Mostly loud in- Absent
end-exiratory and expiratory
Pulse rate/minute < 100 100-120 > 120 Bradycardia
Normal pulse rate in children
Age Normal pulse:
212 months 80180
13 years 75150
412 years 60120

Pulsus paradoxus Absent Can be present Often Absence suggests exhaustion

Fluctuation of pulse pressure < 10 mm Hg 1025 mm Hg 2040 mm Hg (child)
between in- and expiration.
Gas exchange
SaO2 (room air) > 95% 91-95% < 91%
PaCO2 < 5.6 kPa < 5.6 kPa >= 5.6 kPa >= 5.6 kPa
PaO2 Normal > 8 kPa < 8 kPa: possible cyanosis < 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.
 M. Koninckx et al. / Paediatric Respiratory Reviews 14 (2013) 7885
Table 2
Asthma score
VARIABLE ASTHMA SCORING
1 point
Respiratory rate (Breaths/min)
23 yr "34
45 yr "30
612 yr "26
>12 yr "23
Oxygen saturation (%) >95 with room air
Auscultation normal breathing or end
expiratory wheezing
Retractions none or intercostal
Dyspnoea Speaks in sentences
or coos and babbles
SEVERITY OF ASTHMA
MILD
Peak expiratory flow rate (% of predicted value*) >70
Asthma score 57
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 five 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 flow 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 first line therapy in acute severe (life-threatening)
asthma in the hospital setting.26 Oxygen also has a broncho-
dilating 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 salbuta-
mol 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 sympatho-
mimetic agents with adrenergic effects like smooth muscle
relaxation resulting in bronchodilation. Inhaled short acting b2-
agonists have a local effect on the b-receptors in the bronchial
smooth muscle cells if air entry is sufficient. 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 con-
tinuous or repeated intermittent nebulised short acting b2-
agonists 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 significantly
shorter length of stay in the emergency department for the first
81
2 points 3 points
3539 #40
3135 #36
2730 #31
2427 #28
9095 with room air <90 with room air or
supplemental oxygen
expiratory wheezing Inspiratory and expiratoy
wheezing, diminished breath
sounds or both
intercostal and substernal Intercostal, substernal and supraclavicular
speaks in partial sentences speaks in single words or short
or utters short cries phrases or grunts
MODERATE SEVERE
5070 <50
811 1215
group.32,33 Conversely, nebulisation has the added advantage of
delivering high flow oxygen. Comparison of the different studies is
difficult 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 pharmaco-
dynamics 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 min-
utes.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 non-
significant 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 adminis-
tered according to a severity related dosing algorithm, it led to
shorter PICU length of stay.40 Although the use of intravenous b2-
agonists 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 specific b2
adrenoreceptor genotypes are related to shorter ICU length of
stay and shorter duration of continuous b2-agonist therapy in
children.41
82 M. Koninckx et al. / Paediatric Respiratory Reviews 14 (2013) 7885
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 benefit 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 absorp-
tion, 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
inflammation. 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 difficult to administer. In mild to
moderate exacerbations a single dose of intramuscular dexa-
methasone 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 fluticasone
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 hyperten-
sion, 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. Conflicting
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
inflammation55 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 beneficial in patients with severe acute asthma when
added to bronchodilators.56 Three studies in children demon-
strated that early administration of intravenous magnesium
sulphate is beneficial 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 flushing 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
inflammatory cells. They result in bronchodilation, improved
mucociliary clearance and down-regulation of inflammation
and immune cell infiltration. 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 adminis-
tered 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 inflammation 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 mechani-
cally 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.
 M. Koninckx et al. / Paediatric Respiratory Reviews 14 (2013) 7885
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 benefit 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
beneficial. Administration of sodium bicarbonate in 17 patients
with life threatening asthma admitted to the PICU showed a
significant decrease in mean pCO2 and a significant 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 insufficient to sufficiently improve oxygenation in
hypoxic children. Heliox reaches lower and obstructed airways
more easily because of a lower resistance and less turbulent flow.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 insufficient
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
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, inflammation and mucus production
because of its effect on a-receptors. Intramuscular administration
of epinephrine is the first 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 significant decline in heart rate, respiratory rate
and clinical asthma score was demonstrated during the first
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
83
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, sevoflurane and isoflurane are inhalational anaes-
thetic 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 difficult given that most caregivers in paediatric
ICUs are not familiar with the equipment.79 The positive effect of
isoflurane 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
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
insufficient 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: methyl-
xanthines, rhDNase, ketamine, sodium bicarbonate, heliox, epi-
nephrine, 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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