Review

A review of the use of

adjunctive therapies in severe
acute asthma exacerbation in
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by University of Queensland on 10/14/14

critically ill children

Expert Rev. Respir. Med. 8(4), 423–441 (2014)

Judith JM Wong1, Asthma is a common and potentially life threatening childhood condition. Asthma involves
Jan Hau Lee*2,3, not only chronic airway remodeling, but may also include frequent exacerbations resulting
David A Turner4 and from bronchospasm, edema, and mucus production. In children with severe exacerbations,
standard therapy with b2-agonists, anti-cholinergic agents, oxygen, and systemic steroids may
Kyle J Rehder4
fail to reverse the severe airflow obstruction and necessitate use of adjunctive therapies.
1
Department of Paediatric Medicine, These therapies include intravenous or inhaled magnesium, inhaled helium-oxygen mixtures,
KK Women’s and Children’s Hospital,
Singapore, Singapore intravenous methylxanthines, intravenous b2-agonists, and intravenous ketamine. Rarely, these
2
Children’s Intensive Care Unit, measures are not successful and following the initiation of invasive mechanical ventilation,
For personal use only.

KK Women’s and Children’s Hospital, inhaled anesthetics or extracorporeal life support may be required. In this review, we discuss
Singapore, Singapore
3 the mechanisms and evidence for adjunctive therapies in the setting of severe acute asthma
Office of Clinical Sciences, Duke-NUS
Graduate Medical School, Singapore, exacerbations in children.
Singapore
4
Division of Pediatric Critical Care KEYWORDS: b2-agonist • children • critical asthma • extracorporeal life support • heliox • inhaled anesthetics
Medicine, Department of Pediatrics, • ketamine • magnesium • methylxanthine • pediatric • status asthmaticus
Duke Children’s Hospital, Durham,
NC, USA
*Author for correspondence: Asthma, affecting more than 300 million production [9]. The airway epithelium is a
[email protected] people, is one of the most common chronic target for infectious, noxious and environmen-
diseases worldwide [1]. Prevalence varies accord- tal insults that cause injury by influx of
ing to geographical regions, with highest preva- proinflammatory cells and cytokines. Proin-
lence (10.9–18.4%) in countries like the UK, flammatory cytokines, chemokines as well as
Australia, Canada, the USA and Brazil. Th2 lymphocytes, eosinophils and mast cells
However, highest mortality from asthma have distinct roles in asthma pathogenesis.
(20.8–36.7 per 100,000 patients) comes from Asthma is also characterized by structural air-
regions with low asthma prevalence (e.g., China, way remodeling in the epithelium, which
Russia, Uzbekistan and Albania) [2,3]. Data from includes mucous gland hyperplasia, epithelial
the US CDC demonstrate an increase in inci- basement membrane thickening, sub-basement
dence of pediatric asthma and continued rise in membrane fibrosis, bronchial smooth muscle
healthcare resource utilization over the past hypertrophy and angiogenesis [9].
10 years [4]. Despite the continued rising inci- Though most children have mild-to-moder-
dence, mortality rates from asthma in the USA ate asthma, these children remain at risk for
have fallen from 0.21 to 0.14 per 1000 persons developing a severe acute exacerbation that may
in the past decade [5]. Among children present- necessitate admission to the PICU. ‘Severe acute
ing with a severe exacerbation of asthma, asthma exacerbation’, also termed ‘status
approximately 8–16% require pediatric inten- asthmaticus’, is defined as an asthma exacerba-
sive care unit (PICU) admission and <2% tion that does not respond to repetitive or
require invasive mechanical ventilation [6–8]. continuous administration of short-acting
The pathophysiology of an acute asthma inhaled b2-adrenergic receptor agonists [2]. The
exacerbation involves three main mechanisms: terms ‘fatal asthma’, ‘near-fatal asthma’ and
bronchospasm, inflammation and edema of ‘catastrophic asthma’ describe the presence
the bronchial mucosa and increased mucus of hypercapnia, hypoxemia and impending

informahealthcare.com 10.1586/17476348.2014.915752  2014 Informa UK Ltd ISSN 1747-6348 423

 Review Wong, Lee, Turner & Rehder

First tier therapies: Inhaled β-2 agonist Level 1a

(in addition to Inhaled anti-cholinergic Level 1a
oxygen therapy) Systemic corticosteroids Level 1a

ventilation if clinically indicated

Intubation and mechanical
Second tier therapies: iv. magnesium loading Level 1a
iv. aminophylline infusion Level 1a
iv. salbutamol infusion† Level 1b
Non-invasive ventilation Level 2b
Heliox‡ Level 2b
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by University of Queensland on 10/14/14

Inhaled magnesium§ Level 2b

iv. magnesium continuous infusion Level 4

Third tier therapies:

iv. ketamine infusion¶ Level 4
Inhaled anesthetics Level 4
ECMO Level 4

Figure 1. Proposed algorithm for escalation of therapy in acute severe asthma in children. Level of evidence adapted from the
Centre for Evidence-Based Medicine, www.cebm.net.
†
Evidence of benefit comes from two randomized controlled trials with overlapping patient population.
‡
For those with severe baseline pulmonary function impairment.
§
The evidence for inhaled magnesium derives from a single randomized controlled trial’s subanalysis of patients with SpO2 <92% and
For personal use only.

within 6 h of symptom onset.

{
iv. ketamine at adequate dose 20–60 mg/kg/min for infusion.
ECMO: Extracorporeal membrane oxygenation; iv.: Intravenous.

respiratory arrest in the setting of a severe exacerbation [3]. ‘Acute randomized controlled trials (RCTs) (1a) and individual RCTs
asphyxial asthma’ is characterized by a sudden onset that may (1b) form the highest level of evidence. Studies that unequivo-
rapidly progress to a near-arrest state [10]. Kenyon et al. proposed cally demonstrate survival of patients after instituting a therapy
the term ‘critical asthma syndrome’ to encompass all of these for a condition previously lethal constitutes level 1c evidence.
entities [11]. Critical asthma syndrome is used to describe any Systematic reviews of cohort studies (2a) and individual cohort
child or adult at risk of physical exhaustion from the overwhelm- studies (2b) form the next hierarchy. The next hierarchy
ing work of breathing, which may lead to respiratory arrest and involves systematic reviews of case–control studies (3a) and
death from hypoxia or related complications from asthma. individual case–control studies (3b). Level 4 evidence derives
The first-line treatment strategies for acute asthma exacerba- from case series and level 5 from expert opinion. For each
tions include supplemental oxygen, inhaled short-acting b2-ago- adjunctive therapy, we described studies that constitute the
nists in combination with anticholinergics, and systemic highest level of evidence. For all studies, we critically appraised
steroids [12]. Occasionally, despite aggressive treatment with the strengths and limitations, and downgraded the level of evi-
these conventional therapies, children with asthma will have dence for several therapies due to significant risk of bias, incon-
persistent and severe airflow obstruction. In these circumstan- sistency and indirect results (FIGURE 1).
ces, a combination of adjuvant therapies may be attempted
with or without the initiation of invasive or non-invasive Intravenous & inhaled magnesium sulfate
mechanical ventilation. Adjunctive therapies should be consid- Magnesium facilitates uptake of calcium into the sarcoplasmic
ered when conventional treatment fails and signs and symp- reticulum, inhibits slow inward calcium current and impedes
toms of deteriorating airflow and respiratory muscle fatigue are calcium-induced calcium release, which causes a decrease in
developing. These adjunctive therapies are the focus of this intracellular calcium, leads to smooth muscle relaxation and
review and they include intravenous (iv.) or inhaled magnesium bronchodilation [14]. Magnesium also inhibits mast cell degran-
sulfate, inhaled helium-oxygen mixtures (heliox), iv. aminoph- ulation, thus reducing histamine and prostaglandin release [15].
ylline/theophylline, iv. b2-agonists, inhaled anesthetics and iv. In addition, magnesium decreases the amount of acetylcholine
ketamine. liberated at motor nerve endings, which results in decreased
We used the Oxford Centre for Evidenced Based Medicine muscle fiber excitability [16]. Magnesium has been shown to
(2009) hierarchy of best evidence to evaluate and describe the produce a bronchodilator effect in a dose-dependent manner in
levels of evidence of available studies [13]. Systematic reviews of patients with mild-to-severe asthma [17].

424 Expert Rev. Respir. Med. 8(4), (2014)

 Review: adjunctive therapies for severe acute asthma exacerbation in critically ill children Review

A total of six RCTs have examined the use of iv. magnesium combined adult and pediatric data concluded that there is cur-
in emergency care for children with moderate-to-severe exacer- rently no evidence for improved pulmonary function or
bations (TABLE 1) [18–23]. A meta-analysis including five of these reduced hospital admissions in children with asthma who are
studies found that iv. magnesium decreased hospital admission treated with nebulized magnesium [33]. The largest RCT of
rate (odds ratio [OR]: 0.290; 95% CI: 0.143–0.589; nebulized magnesium to date was published recently and
p = 0.0006), with a number needed to treat of 4 (95% CI: involved 502 children with moderate-to-severe exacerbations of
3–8). Other secondary outcomes that improved with iv. mag- asthma [34]. This investigation demonstrated that nebulized
nesium include short-term lung function (OR of persistently magnesium improved the Asthma Severity Score at 1 h (mean
low peak expiratory flow rate <60% was 0.155; 95% CI: difference after adjusting for baseline severity -0.25 [95% CI:
0.057–0.422; p = 0.0003) and clinical symptom scores (clinical -0.48 to -0.02]; p = 0.034), but this result did not meet the
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by University of Queensland on 10/14/14

asthma symptom score or pulmonary index score) [18,19,21,22]. predetermined clinically relevant difference of 0.5. Subgroup
This meta-analysis also found that iv. magnesium was generally analysis investigating treatment-covariate interactions found
safe and there were no major side effects, including hypoten- that those with lower initial oxygen saturation (<92%) and
sion [24]. The sixth RCT, performed by Torres et al., found those who were able to initiate nebulized magnesium therapy
that iv. magnesium sulfate within the first hour of admission in early (<6 h into the exacerbation) had greater response. This
children with acute severe asthma significantly reduced the subgroup of patients had a greater improvement in Asthma
need for mechanical ventilation (5 vs 33%; p = 0.001), PICU Severity Scores at 1 h post-randomization. The doses of nebu-
length of stay (LOS) (2 vs 10 days; p = 0.0367) and hospital lized magnesium used in all four studies ranged from 2 to
LOS (7 vs 19 days; p = 0.046) [25]. An important consideration 2.5 ml of isotonic magnesium sulfate or heptahydrate nebulized
is that the documented efficacy of iv. magnesium in these over 10–15 min with or without repeated doses (dosage and
studies should be interpreted in conjunction with the concur- concentration included in TABLE 2). Only one study reported
rent use of b2-agonists and clinical context. All six studies adverse effects, which were flushing, vomiting, headache and
were conducted in the emergency department (ED) and only transient hypotension in children treated with nebulized mag-
three of the six studies (TABLE 1) had a clear protocol for the nesium, but these findings were not statistically significant
For personal use only.

use of bronchodilators. when compared with controls [34].

Of note, all studies utilized a single dose of iv. magnesium In summary, iv. magnesium reduces hospital admission
sulfate between 25 and 75 mg/kg over 20 min early in the rates, LOS and intubation rates when administered early in
course of treatment. None of these investigations studied the the course of illness, but there is little evidence for its contin-
benefits of a continuous infusion after the single bolus dose, ued use in the PICU. Studies examining the efficacy of con-
despite pharmacokinetic studies in pediatric asthma that report tinuous magnesium infusion therapy are needed to clarify the
safety in using a continuous infusion of magnesium sulfate at a potential benefit of this therapy. Data to support the benefit
dose of 14.6–40 mg/kg/h [26–28]. One retrospective study from nebulized magnesium are not robust and come from
described the use of a continuous infusion of magnesium sul- analysis of small subgroup of asthmatic patients. In addition,
fate in 40 PICU patients [27]. The mean serum magnesium lev- we do not have data to support the use of nebulized magne-
els achieved were 3.8 mg/l in this cohort. A separate case series sium beyond the ED, and more studies are required to define
described 19 PICU patients who were treated with a loading the role of this therapy in the management of acute asthma
dose of iv. magnesium followed by a continuous infusion for exacerbations.
4 h. A mean serum magnesium level of 4.4 ± 0.8 mg/dl was
achieved in this case series [28]. However, both these studies did Heliox (helium–oxygen mixtures)
not report the clinical effects of the treatment, and there are no Helium is an odorless, tasteless, inert gas that is substituted for
established dosing regimens or target serum magnesium or ion- nitrogen and delivered at concentrations of more than 50% for
ized magnesium concentrations for the optimal treatment of medical use [35]. It has no direct pharmacologic or biologic
patients with asthma [28]. Even though there is a lack of defini- effects and does not have bronchodilatory or anti-inflammatory
tive evidence for the use of iv. magnesium in the PICU, it is properties [36]. Heliox refers to a gas mixture combining
one of the more commonly utilized adjunctive therapies in helium and oxygen in either 70:30 or 80:20% ratios. This
the pediatric critical care setting [7]. The Pediatric Health mixture is less dense compared with air and air/oxygen mix-
information System reported the use of iv. magnesium in tures and results in decreased resistance to gas flow in turbu-
20% of non-ventilated patients and 40% of ventilated lent systems [36]. Decreased gas density also transitions
patients admitted into the PICU, and the Collaborative Pedi- turbulence to a laminar flow state, creating a lower resistance
atric Critical Care Research Network reported an overall situation [36]. This decrease in density with heliox is linear as
40% use in their cohort [7,8]. the proportion of helium is increased. While higher fractions
Nebulized magnesium has also been investigated in this con- of helium are preferred to minimize gas density and improve
text, and four RCTs have been published examining the effi- flow, lower proportions of helium may have some efficacy.
cacy of nebulized magnesium in children with mixed results Thus, an improvement in spirometry measurements and work
(TABLE 2) [29–32]. A Cochrane meta-analysis in 2012 that of breathing may be anticipated with the use of heliox [37–39].

informahealthcare.com 425
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426

Review
Table 1. Summary of studies on the use of intravenous magnesium sulfate for asthma.
Study (year) Participants, Methods Outcomes Adverse Comments Level of Ref.
n (age range) effects evidence
Ciarallo et al. n = 31 Design: RCT • Improved PEFR None Therapy initiated after 3 b-agonist 1b [20]

Wong, Lee, Turner & Rehder

(1996) (6–18 years) Intervention: 25 mg/kg • Improved FEV1 nebulizations
iv. MgSO4 (max 2 g) • Reduced hospital Use of b-agonists after randomization left to
Control: NS admission discretion of treating physicians. Reported as
Setting: ED no difference between both groups
Devi et al. n = 47 Design: RCT • Improved CAS Epigastric Therapy initiated after 3 b-agonist 1b [21]
(1997) (1–12 years) Intervention: 0.2 ml/kg • Improved PEFR warmth, nebulizations
of iv. 50% MgSO4 • Improved SaO2 epigastric pain, Same protocol for use of b-agonists after
Control: NS • Reduced hospital tingling and randomization for both groups
Setting: ED length of stay numbness over
the infusion
site – transient
Gurkan et al. n = 20 Design: RCT • Improved PEFR Not reported Therapy initiated after 3 b-agonist 2b [22]
(1999) (6–16 years) Intervention: 40 mg/kg • Improved CAS nebulizations
iv. MgSO4 (max 2 g) Use of b-agonists after randomization left to
Control: NS discretion of treating physicians. Reported as
Setting: ED no difference between both groups
Scarfone et al. n = 54 Design: RCT • PI – no difference None Excluded mildly (PI £ 7) and severely (PI ‡ 14) 1b [18]
(2000) (1–18 years) Intervention: 75 mg/kg • Hospitalization ill children
iv. MgSO4 (max 2.5 g) rate – no difference Therapy initiated after 2 b-agonist
Control: NS • Time to discharge – nebulization
Setting: ED no difference Same protocol for use of b-agonists after
randomization for both groups
Ciarallo et al. n = 30 Design: RCT • Improved PEFR None High dose of MgSO4 utilized. 1b [19]
(2000) (6–17.9 years) Intervention: 40 mg/kg • Improved FEV1 Therapy initiated after 3 b-agonist
iv. MgSO4 (max 2 g) • Improved FVC nebulizations
Control: NS • Reduced hospital Use of b-agonists after randomization left to
Setting: ED admission discretion of treating physicians. Reported as
• Improved CAS no difference between both groups
Torres et al. n = 143 Design: RCT • Reduced use of None Not placebo controlled 1b [25]
(2012) (2–15 years) Intervention: 25 mg/kg invasive and non- Not blinded
Expert Rev. Respir. Med. 8(4), (2014)

iv. MgSO4 (max 2 g) invasive ventilation Same protocol for use of b-agonists after
Control: standard • Reduced PICU length randomization for both groups
protocol Setting: ED of stay
• Reduced hospital
length of stay
CAS: Clinical asthma score; ED: Emergency department; FEV1: Forced expiratory volume in 1 s; FVC: Forced vital capacity; iv.: Intravenous; MgSO4: Magnesium sulfate; NS: Normal saline; PEFR: Peak expiratory flow rate;
PI: Pulmonary index; PICU: Pediatric intensive care unit; RCT: Randomized controlled trial.
 Review: adjunctive therapies for severe acute asthma exacerbation in critically ill children Review

Ref.

[34]

[31]

[32]

[29]
The conducting airways provide the
dominant component of flow resis-
tance and are the region where turbu-

evidence

applicable
Level of
lent or near-turbulent flows occur.

ASS: Asthma severity score; ED: Emergency department; FEV1: Forced expiratory volume in 1 s; MgSO4: Magnesium sulfate; NS: Normal saline; PEF: Peak expiratory flow; RCT: Randomized controlled trial.
This results in entrainment of aerosols

Not
2b

2b

2b
that are often administered in the
management of an asthma exacerba-

Intervention arm
publication only
response to 1 h
of conventional
tion. Therefore, another additional

did not receive

Comments

started if no
mechanism of action of heliox is

Magnesium

salbutamol
nebulized
increased delivery of aerosolized drugs

Abstract
therapy
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deeper into the lungs [40]. In addition,

carbon dioxide (CO2) diffuses four- to
five-times faster through helium than

headache, transient
air, leading to increased clearance of

Flushing, vomiting,

hypotension – not
Adverse effects
CO2 [36].
To date, five RCTs have examined

statistically
significant
the use of heliox in children with
asthma (TABLE 3) [37,40–43]. A meta-

None

None

None
analysis involving both adults and chil-
dren concluded that heliox improves
pulmonary function only in the sub-

• Reduced oxygen supplementation

– Greater response when started

• Davis-Leffert-Dabbous respiratory
group of patients with the most severe

• Adverse effects – no difference

• Respiratory distress scores – no

• Admission rate – no difference

• Improved FEV1 (but effect not
– Greater clinical response in

oxygen saturation (<92%)

impairment of baseline pulmonary

• Hospital length of stay – no

patients with lower initial

early (<6 h) during the

function [44]. This meta-analysis only

For personal use only.

Table 2. Summary of studies on the use of nebulized magnesium for asthma.

included three out of the five pediatric

• Subgroup analysis:

RCTs. One RCT was excluded

exacerbation

because of incomplete data and the

• Improved ASS

distress score
use of an unvalidated clinical score, difference
difference

sustained)
Outcomes

and the patients in this RCT treated

in the PICU were not described in
detail [41]. The other RCT that was • PEF
not included was published after the
completion of the meta-analysis [42].

Intervention: nebulized 2.5 ml of

isotonic MgSO4 (250 mmol/l) for

Intervention: nebulized 2 ml of
MgSO4 (concentration unclear)

In this study, 34 patients were treated

Intervention: nebulized 2.5 ml

Intervention: nebulized 2.5 ml

Control: nebulized salbutamol

in the PICU and the authors found no

isotonic 6.3% magnesium

Design: multicenter RCT

difference in the time to achieve a clin-

Control: nebulized NS

Control: nebulized NS

Control: nebulized NS
MgSO4 (280 mmol/l)

ical asthma score <3 in the heliox

group compared with the control
2.5 mg in 2.5 ml
Setting: unclear

Setting: unclear

group (24.4 ± -2.8 vs 23.7 ± 5 h,

heptahydrate
Design: RCT

Design: RCT

Design: RCT
three doses

Setting: ED

respectively; p = 0.34) [42]. These Setting: ED

Methods

PICU patients also demonstrated no

difference in duration of continuous
nebulized albuterol administration in
both groups (25.6 ± 4.6 vs 24.3 ±
intervention arm
and 11 years in

5.8 h, respectively; p = 0.51).

Participants

10.6 years in

control arm)
(2–16 years)

(5–17 years)

While two RCTs reported

3.55 years)
(mean age

(mean age
n = 508

improvement in surrogate markers

n = 40

n = 40

n = 62

(e.g., pulsus paradoxus, clinical scores

(n)

and spirometry parameters) [40,41],

none of the studies demonstrated ben-
Khashabi et al.

Mahajan et al.

efits in clinical outcomes such as

Study (year)

Powell et al.

Meral et al.

admission rate, LOS and intubation

rate. Of note, there were no adverse
(2013)

(2008)

(1996)

(2004)

effects from this therapy reported in

any of the studies.

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428

Review
Table 3. Summary of studies on the use of heliox for asthma.
Study (year) Participants Methods Outcomes Adverse Comments Level of Ref.
(n) effects evidence

Wong, Lee, Turner & Rehder

Kudukis et al. n = 18 Design: RCT • Less pulsusparadoxus None Heliox was initiated 2b [41]
(1997) (6 months– Intervention: heliox (80% • Reduced DI within 30 min after
16 years) helium: 20% oxygen mixture) • Improved PEF conventional treatment
Control: air–oxygen mixture if respiratory distress
Setting: ED or PICU was still evident

Carter et al. n = 11 Design: RCT cross-over trial • PI score and Dyspnea None Heliox was initiated 2b [37]
(1996) (5–18 years) Intervention: heliox (70% score – no difference after conventional
helium: 30% oxygen mixture) • FEV1 – no difference therapy for 6 h if
Control: air-oxygen mixture • FVC – no difference respiratory distress was
Setting: inpatient unit • Improved FEF 25–75 still evident
After 15 min, the groups • Improved PEFR
crossed over and
measurements were repeated
Kim et al. n = 31 Design: single-blind RCT Improved PI score None Convenience sample 2b [40]
(2005) (2–18 years) Intervention: heliox (70% Not double-blinded
helium : 30% oxygen) heliox initiated after
Control: oxygen 20 min of
Setting: ED conventional therapy
regardless clinical
status
Bigham et al. n = 42 Design: RCT • CAS – no difference None Excluded patients who 2b [42]
(2010) (2–21 years) Intervention: heliox (70% • Hospital length of had clinical asthma
helium: 30% oxygen) stay – no difference score <3
Control: air–oxygen mixture • PICU length of Randomization
Setting: ED, inpatient unit or stay – no difference occurred
PICU • Albuterol approximately 10 h
nebulizations – no after attendance to
difference the ED
Rivera et al. n = 41 Design: RCT • Modified DI score – None Convenience sample 2b [43]
Expert Rev. Respir. Med. 8(4), (2014)

(2006) (3–16 years) Intervention: heliox (helium no difference Time to start heliox
70%:30% oxygen mixture) • Admission rate – no therapy unclear
Control: air–oxygen mixture difference
Setting: ED
CAS: Clinical asthma score; DI: Dyspnea index; ED: Emergency department; FEV1: Forced expiratory volume in 1 s; FEF 25–75: Forced expiratory flow during mid-portion (25–75%) of FVC; FVC: Forced vital capacity; PEF:
Peak expiratory flow; PI: Pulmonary index; PICU: Pediatric intensive care unit; RCT: Randomized controlled trial.
 Review: adjunctive therapies for severe acute asthma exacerbation in critically ill children Review

It is difficult to form a definitive conclusion with regard to the Only one study included in the meta-analysis specifically
utility of heliox based on current studies because of the heteroge- studied patients admitted within 2 h to the PICU (regardless
neity of patient groups, degrees of illness, timing of intervention of duration since first presentation) with status asthmaticus [50].
and outcome measures [36]. The currently available investigations The investigators found no differences in the primary outcome
also were underpowered to detect a difference in clinical out- (clinical asthma score) over time: all groups (iv. theophylline,
comes. There are no data to support routine use of heliox in iv. terbutaline and iv. theophylline and terbutaline) had similar
acute asthma; however, this therapy is based on sound physio- improvement in clinical asthma scores at study completion.
logic principles, can be safely administered and may provide ben- Four patients did not complete the study protocol for various
efit for patients with severe impairment of lung function. reasons. If these patients were excluded from the analysis, the
length of time to clinical asthma score £3 was significantly
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Intravenous methylxanthine shorter in group one compared with groups two and three
Theophylline is a dimethylated xanthine that has been used as (24.2 ± 12.1, 51.6 ± 33.3, 47.1 ± 38.3 h, respectively;
a bronchodilator for both acute and chronic reversible airway p < 0.05). There was no improvement in secondary outcome
disease [45]. Aminophylline is the ethylene diamine salt of the- measures such as length of PICU stay (4.4 ± 2.3 vs 4.9 ±
ophylline and is more commonly used in the treatment of criti- 3.0 vs 4.8 ± 3.0 days, respectively) and progression to mechani-
cal asthma, because it has higher water solubility for iv. cal ventilation (no patients required mechanical ventilation).
administration [45]. Methylxanthine derivatives reduce the rate The authors concluded that iv. theophylline was as effective as
of degradation of cAMP by inhibition of phosphodiesterase [46]. iv. terbutaline in critically ill children with status asthmaticus.
Other potential mechanisms of action are associated with Nine of the 10 available RCTs used an age- or weight-based
changes in intracellular calcium, prostaglandins and adenosine loading dose followed by a continuous infusion [56]. All
receptors [47,48]. Methylxanthines may also increase respiratory 10 studies monitored serum levels of theophylline or aminoph-
drive and diaphragmatic contractions, promote mucociliary ylline and targeted a level of 5–20 mg/ml. Patients receiving
clearance and inhibit late inflammatory response [45,49,50]. Criti- aminophylline were three-times more likely to experience
cally ill patients may also benefit from aminophylline’s poten- vomiting compared with placebo [54]. Serious side effects like
For personal use only.

tial reduction in excess alveolar fluid through diuresis and seizures and glycosuria were not statistically significant
lowered microvascular permeability [51]. Aminophylline also between groups and there were no incidences of arrhythymias
decreases airflow obstruction without adversely affecting ventila- or death [55,59].
tion–perfusion mismatch, as opposed to salbutamol, which par- In conclusion, aminophylline can improve lung function and
tially inhibits hypoxic pulmonary vasoconstriction, thereby oxygen saturation in children with severe asthma exacerbations.
adversely affecting ventilation–perfusion mismatch and reducing However, there are no definitive data to demonstrate an
arterial partial pressure of oxygen [52,53]. However, aminophyl- improvement in other clinical outcomes, and the decision to
line has a narrow therapeutic index and can cause serious side use aminophylline use must be balanced against the risks for
effects such as nausea, vomiting, headache, seizures, arrhythy- side effects.
mias and death [45,49].
A Cochrane meta-analysis in 2009 included seven pediatric Intravenous b2-agonists
RCTs and concluded that the addition of aminophylline to In acute asthma, penetration of nebulized drugs into the
standard therapy significantly improved forced expiratory vol- small airways is impeded by progressive airway inflamma-
ume in one second (FEV1) and persistently low peak expiratory tion [60,61]. As such, systemic administration of drugs that are
flow rate compared with placebo in children with severe asthma commonly used via the aerosolized route may bring about
exacerbation [54]. The effect of aminophylline occurs within 6 h faster clinical response [62]. One such example is iv. b2-ago-
and lasts up to 24 h, and these improvements were derived nists (TABLE 5).
from a single study, albeit the largest and of strongest method- Browne et al. compared iv. salbutamol used in conjunction
ology [55]. The Cochrane review also concluded that there was with inhaled salbutamol versus inhaled salbutamol alone, and
no benefit for other clinical outcomes such as hospital LOS, demonstrated that iv. salbutamol shortened time to recovery
frequency of nebulization administration and need for mechan- (defined as time to cessation of every 30 min inhaled salbuta-
ical ventilation. Three additional RCTs have been published in mol; 4 vs 11.1 h; p = 0.03), reduced need for oxygen supple-
addition to those included in the meta-analysis (TABLE 4). These mentation (14 vs 53%; p = 0.05), shortened time to
three RCTs had unique features that made them clinically het- discharge from the ED (11.5 vs 21.2 h; p = 0.02) and
erogeneous and not appropriate to be pooled: one included all improved pulmonary index scores at 2 h (43 vs 93% of
patients with ‘broncho-obstructive crisis’ (i.e., wheezing patients having persistent moderate-to-severe asthma scores;
infants), another used two loading doses of aminophylline and p < 0.001) [62]. Browne and Lam later performed another
did not titrate to a therapeutic range, and the last study pro- larger study (with some overlap of patients from the prior
vided a very different ‘standard care’ (e.g., subcutaneous epi- study) that demonstrated similar findings [63]. These benefits
nephrine, nebulized isoproterenol, nebulized phenylephrine and were associated with increased incidence of tremors
antibiotics) [56–58]. (p < 0.02). Recent studies have also demonstrated elevated

informahealthcare.com 429
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430

Review
Table 4. Summary of studies on the use of intravenous methylxanthine for asthma.
Study (year) Participants, n Methods Outcomes Adverse effects Comments Level of Ref.
evidence
Carter et al. n = 21 Design: RCT • FEV1 – no difference Not statistically significant Those in respiratory 1b [49]

Wong, Lee, Turner & Rehder

(1993) (5–18 years) Intervention: iv. aminophylline • PI score – no difference failure were excluded
1 mg/kg loading followed by an • Albuterol
infusion titrated to achieve a nebulizations – no
serum theophylline level of difference
10–20 mg/ml for 36 h • Length of hospital
Control: placebo stay – no difference
Setting: inpatient unit
Strauss et al. n = 31 Design: RCT • PEFR – no difference Nausea, vomiting, Those admitted to the 1b [45]
(1994) (5–18 years) Intervention: iv. aminophylline • Length of hospital abdominal pain, PICU were excluded
7 mg/kg loading followed by an stay – no difference headache.
infusion
• 1.2 mg/kg/h for <9 years
• 1 mg/kg/h for 9–12 years
• 0.75 mg/kg/h for >12 years
Target serum theophylline level
10–20 mg/ml
Control: dextrose 5%
Setting: inpatient unit
Yung and n = 163 Design: RCT • Improved FEV1 Nausea, vomiting. 1b [55]
South (1998) (1–19 years) Intervention: iv. 10 mg/kg • Improved mid-expiratory Headache, irritability,
aminophylline loading over 1 h, volume tremor, seizures – not
followed by an infusion • Improved PEFR statistically significant
• 1.1 mg/kg/h for <10 years • Improved oxygen
• 0.7 mg/kg/h for >10 years saturation
Target serum theophylline level • Reduced oxygen
14.5–20 mg/ml supplementation
Control: sterile water • Improved ASS
Setting: inpatient unit • Reduced intubation
• Length of hospital
stay – no difference
Bien et al. n = 39 Design: RCT • PI scores – no difference Nausea, vomiting, 1b [109]
Expert Rev. Respir. Med. 8(4), (2014)

(1995) (2–10 years) Intervention: loading dose • Nebulizations – no insomnia.

followed by an infusion difference Headache, irritability – not
targeting serum theophylline • Oxygen statistically significant
level 10–20 mg/ml supplementation – no
Control: Dextrose 5% difference
Setting: inpatient unit
CAS: Clinical asthma score; ED: Emergency department; FEV1: Forced expiratory volume in 1 s; FVC: Forced vital capacity; iv.: Intravenous; OR: Odds ratio; NS: Normal saline; PEFR: Peak expiratory flow rate;
PI: Pulmonary index; PICU: Pediatric intensive care unit; RCT: Randomized controlled trial.
 Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by University of Queensland on 10/14/14
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Table 4. Summary of studies on the use of intravenous methylxanthine for asthma (cont.).
Study (year) Participants, n Methods Outcomes Adverse effects Comments Level of Ref.
evidence
Nuhoglu et al. n = 36 Design: RCT • Nebulizations – no Nausea, vomiting and 1b [59]

Review: adjunctive therapies for severe acute asthma exacerbation in critically ill children
(1998) (2–16 years) Intervention: iv. 6 mg/kg difference glycosuria – not
aminophylline over 30 min • CAS – no difference statistically significant
followed by an infusion
• 1 mg/kg/h for 2–9 years
• 0.8 mg/kg/h for >9 years
Target serum theophylline level
10.5–14.3 mg/ml
Control arm: NS
Setting: inpatient unit
Vieira et al. n = 43 Design: RCT • Length of ED stay – no Not reported Included younger 2b [57]
(2000) (1–7 years) Intervention: iv. 6 mg/kg difference children <2 years
aminophylline followed by an • Hospital admission – no May have included
infusion 1.2 mg/kg/h throughout difference diagnosis other than
the protocol • Discharge rate – no asthma (bronchiolitis)
Control: NS difference
Setting: ED • Wood–Downes
score – no difference
D’Avila et al. n = 60 Design: RCT • Length of hospital Not reported Used two loading 1b [56]
(2008) (2–5 years) Intervention: Two doses of iv. stay – no difference doses of iv.
5 mg/kg aminophylline over • Oxygen aminophylline (serum
20 min 6 h apart supplementation – no aminophylline levels
Control: NS difference fell below 10–20
Setting: ED • Nebulizations – no mg/ml range)
difference
• Hospital or PICU
admission – no
difference
Needleman n = 42 Design: RCT • Length of hospital Not reported 1b [110]
et al. (1995) (2–18 years) Intervention: stay – no difference
• iv. 8 mg/kg loading of iv. • CAS – no difference
theophylline followed by an
infusion 1 mg/kg/h for <12 years
• iv. 6 mg/kg loading of iv.
theophylline followed by an
infusion of 0.8 mg/kg/h for
>12 years
Titrated to maintain a serum

Review
level 10–20 mg/ml
Control: dextrose and NS
Setting: inpatient unit
431

CAS: Clinical asthma score; ED: Emergency department; FEV1: Forced expiratory volume in 1 s; FVC: Forced vital capacity; iv.: Intravenous; OR: Odds ratio; NS: Normal saline; PEFR: Peak expiratory flow rate;
PI: Pulmonary index; PICU: Pediatric intensive care unit; RCT: Randomized controlled trial.
 Review Wong, Lee, Turner & Rehder

[111]
Ref.

[58]

CAS: Clinical asthma score; ED: Emergency department; FEV1: Forced expiratory volume in 1 s; FVC: Forced vital capacity; iv.: Intravenous; OR: Odds ratio; NS: Normal saline; PEFR: Peak expiratory flow rate;
markers of cardiac toxicity and lactic acidosis
with prolonged administration (>72 h) of iv.
terbutaline [64,65].
evidence
Level of

A recent Cochrane meta-analysis identified

two RCTs in children investigating the effec-
1b

2b
tiveness of iv. b2-agonists [66]. They found
only limited evidence from the study by

injections of epinephrine

isoproterenol, nebulized

systemic corticosteroids
asthmaticus defined by
Browne et al. to support the use of iv. b2-ago-

(0.01 ml/kg of 1:1000)

phenylephrine, fluids,
failure to respond to
three subcutaneous
Patients with status

included nebulized
nists in children with severe exacerbation. The

Standard therapy
second RCT in the meta-analysis was the

and antibiotics
were recruited
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Comments

only study that had examined a cohort of

patients admitted to the PICU (n = 46) [67].
This study found no statistical significance
between iv. b2-agonists and placebo with
regard to improvement in clinical asthma
scores, length of PICU stay, duration of con-
statistically significant

tinuous nebulized albuterol and need for addi-

Adverse effects

tion of theophylline [67].

Vomiting, tremor,
tachycardia – not

When comparing the efficacy of iv. b2-ago-

Table 4. Summary of studies on the use of intravenous methylxanthine for asthma (cont.).

nists against methylxanthines, a recent meta-

analysis (total four studies) concluded that
None

there was no difference in clinical outcomes

between the two groups [68]. Roberts et al.
studied a loading dose of iv. salbutamol versus
For personal use only.

• Time to discharge – no

loading dose and infusion of aminophyl-

supplementation – no
• CAS – no difference

line [69]. This investigation demonstrated that

• Nebulizations – no

the salbutamol group had increased need for

• Improved FEV1
• Improved FVC

oxygen and a longer duration of hospital stay.

difference
difference

difference
Outcomes

Wheeler et al. compared three groups of ther-

• Oxygen

apies in the PICU: loading and continuous

infusion of theophylline, terbutaline and the-
ophylline and terbutaline [50]. This study
demonstrated that the theophylline group was
PI: Pulmonary index; PICU: Pediatric intensive care unit; RCT: Randomized controlled trial.
20 min theophylline followed by
Intervention: iv. 4.8 mg/kg over

associated with reduced healthcare cost and

continuous infusion of 0.4 mg/
Intervention: iv. aminophylline
Targeting serum theophylline

7 mg/kg loading followed by

• 0.68 mg/kg/h for >9 years
• 0.8 mg/kg/h for 2–9 years

the combination group (theophylline and ter-

kg/h for 24 h (not titrated)

butaline) reported increased side effects. Ham-

Setting: inpatient unit

Setting: inpatient unit

bleton and Stone reported no statistical

Target range unclear

difference in clinical scores or respiratory rate

level 12–20 mg/ml
Control: dextrose

between salbutamol and aminophylline, but

Design: RCT

Design: RCT

Control: NS

iv. salbutamol was associated with more

an infusion
Methods

tachycardia [70].
Despite the paucity of data supporting the
effectiveness of iv. b2-agonists as adjunctive
therapy, their use is common (23.0–87.2%)
Participants, n

Age: 2–16 years

in children with critical asthma [7,8]. Indeed,

(5–17 years)

the British Thoracic Society and Scottish

Intercollegiate Guidelines Network have advo-
n = 29

n = 23

cated early addition of a single bolus dose of

iv. salbutamol (15 mg/kg over 10 min) in
severe cases, where the patient has not
responded to initial inhaled therapy [71].
Study (year)

DiGiulio et al.

Pierson et al.

According to data from the PREDICT

research network (11 centers in Australia and
(1993)

(1971)

New Zealand), all constituent sites had local

clinical practice guidelines advocating for the

432 Expert Rev. Respir. Med. 8(4), (2014)

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Table 5. Summary of studies on the use of intravenous b-agonists for asthma.

Study (year) Participants, n Methods Outcomes Adverse effects Comments Level of Ref.
evidence
Browne et al. n = 29 Design: RCT • Reduced time to Tremor Therapy initiated 1b [62]

Review: adjunctive therapies for severe acute asthma exacerbation in critically ill children
(1997) (1–12 years) Intervention: single dose iv. recovery† after 1 b-
15 mg/kg salbutamol • Reduced length of agonist
Control: normal saline stay in the ED nebulizations
Setting: • Reduced oxygen
• Phase I (initial 2 h) in ED supplementation
• Phase II (subsequent 22 h) • Improved PI
in the inpatient unit
Browne et al. n = 55 Design: RCT • Reduced time to Increased plasma Therapy initiated 2b [112]
(2002) (1–14 years) Three arms: recovery glucose and after 1 b-
• Group 1 – single dose iv. • Reduced oxygen decreased serum agonist
15 mg/kg salbutamol and supplementation in potassium at 2 h nebulizations
nebulized saline group 1 compared with 1 h
• Group 2 – iv. normal saline • Reduced length of
and nebulized ipratropium hospital stay in
250 mg group 1
• Group 3 – single dose iv.
15 mg/kg salbutamol over
10 min and nebulized
ipratropium 250 mg
Setting: as above
Browne et al. n = 84 Design: reanalysis of the • Earlier clinical Nausea, vomiting, Therapy initiated 2b [63]
(2002) (1–14 years) above two RCTs. improvement abdominal pain, after 1 b-
Intervention: iv. 15 m g/kg • Reduced oxygen tremor, dizziness, agonist
salbutamol supplementation nervousness, nebulizations
Control: NS • Reduced headache – not Variable
Setting: as above nebulizations statistically proportion of
• Reduced time to significant intervention and
discharge from ED control arm
• Reduced length of receiving
hospital stay ipratropium
nebulization
Bogie et al. n = 49 Design: RCT • CAS – no difference Elevated troponin Therapy initiated 1b [67]
(2007) (2–17 years) Intervention: iv. 10 mg/kg/min • Nebulizations – no levels and after 3 b-
terbutaline loading followed difference electrocardiogram agonist
by an infusion of 1–4 • Length of PICU changes - not nebulizations
mg/kg/min stay – no difference statistically and requiring
Control: placebo significant PICU admission

Review
Setting: ED and PICU
†
Time to recovery refers to time taken for cessation of every 30 min nebulized salbutamol.
CPK: Creatine phosphokinase; CK-MB: Creatine kinase muscle brain; ED: Emergency department; iv.: Intravenous; MgSO4: Magnesium sulfate; NS: Normal saline; PI: Pulmonary index; PICU: Pediatric intensive care unit;
433

RCT: Randomized controlled trial.

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434

Table 5. Summary of studies on the use of intravenous b-agonists for asthma (cont.).

Review
Study (year) Participants, n Methods Outcomes Adverse effects Comments Level of Ref.
evidence
Roberts et al. n = 44 Design: RCT • Increased length of Nausea, vomiting, Therapy initiated 1b [69]
(2003) (1–16 years) Two groups: hospital stay in the abdominal after 3 b-

Wong, Lee, Turner & Rehder

• Salbutamol group – single salbutamol group pain – not agonist
iv. bolus 15 mg/kg followed • ASS – no difference statistically nebulizations
by saline infusion • Longer duration of significant Studied single
• Aminophylline group – iv. inpatient treatment iv. bolus of
5 mg/kg aminophylline in the salbutamol salbutamol vs iv.
followed by an infusion group bolus and
0.9 mg/kg/h infusion of
Setting: unclear aminophylline
Wheeler et al. n = 40 Design: RCT • CAS – no difference Group 3 had more 1b [50]
(2005) (3–15 years) Three arms: • Length of PICU tremor and nausea.
• Group 1 – theophylline and stay – no difference Hyperglycemia,
placebo • Reduced hospital hypokalemia, CPK
• Group 2 – terbutaline and cost in group 1 elevation, CK-MB
placebo elevation, vomiting,
• Group 3 – terbutaline and palpitations,
theophylline headache,
Setting: PICU dysrhythymia – not
Theophylline dosing – 6.4 statistically
mg/kg loading followed by significant
an infusion of
• 0.96 mg/kg/h for 3–8 years
• 0.8 mg/kg/h for 9–12 years
• 0.64 mg/kg/h for 12–15
years
Targeting serum theophylline
level 12.1–15.9 mg/ml
Terbutaline dosing – 20 mg/
kg loading followed by
infusion of 0.4 mg/kg/
min – titrated to CAS
Hambleton and n = 18 Design: RCT • Clinical score – no Salbutamol group Baseline therapy 2b [70]
Stone (1979) (1.5–7 years) Intervention: difference had more unclear
Expert Rev. Respir. Med. 8(4), (2014)

Two groups: • Respiratory rate – no tachycardia including if the

• iv. salbutamol 4 mg/kg difference patients
loading followed by 0.6 received any
mg/kg/h infusion inhaled
• iv. aminophylline 4 mg/kg b-agonist
loading followed by
0.6 mg/kg/h infusion
Setting: inpatient unit
†
Time to recovery refers to time taken for cessation of every 30 min nebulized salbutamol.
CPK: Creatine phosphokinase; CK-MB: Creatine kinase muscle brain; ED: Emergency department; iv.: Intravenous; MgSO4: Magnesium sulfate; NS: Normal saline; PI: Pulmonary index; PICU: Pediatric intensive care unit;
RCT: Randomized controlled trial.
 Review: adjunctive therapies for severe acute asthma exacerbation in critically ill children Review

Ref.

[113]

CPK: Creatine phosphokinase; CK-MB: Creatine kinase muscle brain; ED: Emergency department; iv.: Intravenous; MgSO4: Magnesium sulfate; NS: Normal saline; PI: Pulmonary index; PICU: Pediatric intensive care unit;
use of iv. salbutamol [72]. From our review, iv. b2-agonists may
be considered for use as second-line therapy, but must be
Not applicable weighed against the risk of significant side effects.

Intravenous ketamine
evidence
Level of

Ketamine hydrochloride is an anesthetic agent reported to

relieve bronchospasm and improve chest compliance in the
operating room [73–75]. It has a high bioavailability following
iv. or intramuscular administration. The onset of action is
rapid, and peak plasma concentrations are seen within 60 s of
included if they

3 nebulizations
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by University of Queensland on 10/14/14

of salbutamol
Abstract only

administration. The duration of action after a single bolus

Comments

respond to

injection is 10–15 min and distribution half-life is 7–11 min.

including
standard
failed to
Subjects

therapy

Ketamine is cleared via hepatic route with a half-life of 2–

3 h [76].
In asthma, the proposed mechanisms of action of ketamine
involve the following pathways: inhibition of NMDA-receptor-
vomiting in 27% of
hypokalemia in 6%

induced bronchoconstriction, downregulation of inducible

Adverse effects

the aminophylline
of the terbutaline

nitric oxide synthetase in pulmonary tissue, suppression of

Symptomatic

macrophage function (including recruitment, oxidative ability

Nausea and

and inflammatory cytokine production), reversal of histamine-

group.

group

induced bronchoconstriction and enhanced adrenaline-induced

Table 5. Summary of studies on the use of intravenous b-agonists for asthma (cont.).

bronchodilation [76–82]. Ketamine is also hypothesized to

increase synaptic catecholamine levels by blocking the re-uptake
of norepinephrine into presynaptic sympathetic neurons and
For personal use only.

score £ 4 at 1 h) was

exert anticholinergic effects on bronchial smooth muscle by

better in the MgSO4

CAS score lowest in

group (97 vs 70 vs
Treatment success

the MgSO4 group

inhibiting vagal outflow [74,76]. Arterial partial pressure of oxy-

(defined as CAS

gen to fraction of inspired oxygen ratio and dynamic compli-

Outcomes

ance have been demonstrated to improve in mechanically

ventilated patients with asthma who received ketamine infu-
70%)

sion [81]. Ketamine is a relatively safe drug owing to its prop-

erty for preservation of airway reflexes. However, it can
increase airway secretions, thus necessitating the use of anti-
Time to recovery refers to time taken for cessation of every 30 min nebulized salbutamol.

sialogogues (e.g., atropine and glycopyrrolate) in some

loading followed by 0.1 mg/

• iv. aminophylline (5 mg/kg

patients [76]. Disorientation, sensory and perceptual illusions

• iv. terbutaline (10 mg/kg
• iv. MgSO4 (50 mg/kg)

and vivid dreams upon recovery may also occur, but these
0.9 mg/kg/h infusion)
loading followed by

effects are less likely in children and can be ameliorated with

kg/min infusion)

Setting: unclear

co-administration of benzodiazepines [76].

A Cochrane meta-analysis in 2012 identified only one
Three groups
Intervention:
Design: RCT
Methods

RCT involving non-intubated patients, which did not show

a significant benefit and concluded that more studies need
to be performed to form a firm conclusion [83]. In this
RCT, researchers utilized a relatively small dose of ketamine
in non-intubated patients in the ED [84]. In contrast to pre-
Participants, n

vious doses reported in the literature (1–2 mg/kg for iv.

bolus and 20–60 mg/kg/min for infusion), this study investi-
(1–12 years)

gated the efficacy of ketamine with the following dose

n = 100

regime: 0.2 mg/kg bolus and 8.33 mg/kg/min infusion for

RCT: Randomized controlled trial.

2 h [84]. It involved a convenience sample (enrollment

occurred only if the primary investigator was available) of
68 patients between age 2 and 18 years. No differences were
noted in mean pulmonary index score and hospital admis-
Study (year)

Singhi et al.

sion rate. A prospective single-arm study of 10 children aged

5–18 years in the ED showed improved clinical asthma
(2011)

score, respiratory rate, oxygen saturation and PEF at 1 h

after administration of ketamine 1 mg/kg over 15 min
†

informahealthcare.com 435
 Review Wong, Lee, Turner & Rehder

followed by continuous infusion of 12.5 mg/kg/min for pressure of CO2 (PCO2) were 7.13 (6.89–7.41) and
1 h [85]. However, due to the small sample size and observa- 87 mmHg (50–160), respectively. Within 4 h of initiation
tional nature, it is difficult to determine if effects seen were of isoflurane, there was significant improvement in pH
due to the study drug or the concurrent first-line therapies. 7.24 (6.95–7.45) and PCO2 64 (35–134) from baseline. The
Reported side effects included skin flushing, visual hallucina- dose of isoflurane was titrated at the discretion of the clinical
tions and hypertension. All were transient and resolved on team, but generally aimed to achieve minimal alveolar concen-
discontinuation of the ketamine infusion. tration of approximately 0.5–1.0%. Hypotension was a com-
Evidence favoring the use of ketamine in severe asthma mon side effect, with 77% of children requiring vasopressors.
exacerbations derives largely from small prospective observa- Other significant side effects include arrhythymias, neurologic
tional studies and case series/reports. The majority of studies symptoms and air leaks. Another smaller case series involving
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by University of Queensland on 10/14/14

involving ketamine were conducted in intubated patients 10 patients also reported improvements in arterial blood pH
with severe asthma in the PICU [74,81,86]. These studies and PCO2, with use of isoflurane for life-threatening
reported benefits in clinical signs (improvement in respira- asthma [89]. Consistent with other series, 80% of the patients
tory rate, wheezing, chest excursion, peak inspiratory treated with isoflurane developed hypotension and required a
pressures, tidal volumes, dynamic compliance) and arterial vasopressor infusion.
blood gas measurements. Adverse reactions with the use of A retrospective chart review from the Pediatric Health
ketamine included increased oral and airway secretions [74,81]. information System group of hospitals revealed that inhaled
In summary, there is only a low level of evidence that anesthetics were used as rescue therapy in only 3% of venti-
ketamine may be beneficial in patients with severe asthma lated patients with severe asthma exacerbations [90]. The use
exacerbations who are mechanically ventilated. Further of inhaled anesthetics was variable and driven by staff experi-
investigations are needed to determine the impact of keta- ence, presence of anesthetist and availability of scavenging
mine in intubated and non-intubated patients with status system. Inhaled anesthetics are associated with increased
asthmaticus. monitoring with blood gases and radiographs, prolonged
LOS and increased hospital costs. Patients who were treated
For personal use only.

Inhaled anesthetics with inhaled anesthetics were also less likely to be given
Halothane, isoflurane and sevoflurane are volatile anesthetics inhaled b2-agonist and inhaled anticholinergics, which are
that have been used as rescue therapy for both adults and well-established therapies. However, a limitation of this study
children with life-threatening asthma [87]. These inhaled anes- is that it was based on administrative data and did not ana-
thetic agents produce bronchodilatory effects, decrease airway lyze severity of illness, physiologic parameters or laboratory
responsiveness and attenuate histamine-induced broncho- variables. The use of inhaled anesthetics is only possible for
spasm [87]. The mechanism of action of these agents is intubated patients and the clinical benefit relative to other
thought to be b-adrenergic receptor stimulation leading to an therapies remains controversial.
increase in intracellular cAMP, which has a direct bronchial
muscle relaxing effect [88]. Increased cAMP may also bind Extracorporeal membrane oxygenation
free calcium within bronchial myoplasm and cause relaxation Extracorporeal membrane oxygenation (ECMO) in an asth-
by negative feedback. cAMP may also impede antigen-anti- matic patient allows for lung rest, providing time for bronchio-
body-mediated enzyme production and the release of hista- lar relaxation, aggressive pulmonary toilet and even controlled
mine from leukocytes. Halothane and isoflurane are agents bronchoscopy, if needed for plastic bronchitis [91]. The Extra-
that have more frequently been utilized in the setting of corporeal Life Support Organization (ELSO) registry reported
asthma. However, sevoflurane has more pronounced bron- 64 cases of ECMO during the period from 1986 to 2007 for
chodilator effects than halothane and isoflurane and is as refractory severe asthma, with a survival of 94% [92]. Of these
effective as halothane in preventing the methacoline-induced cases, two-thirds of reports came from 2002 to 2007 and one-
increase in airway resistance [87]. Unfortunately, long-term third from the preceding 16 years, indicating a significant
use of sevoflurane may cause organ dysfunction such as renal increase in the reported use of ECMO for asthma. In a more
tubular injury, hepatotoxicity and neuropathy. A key concern detailed, albeit single-center description, Hebbar et al. reported
with the use of volatile agents in the PICU is the scavenging 13 children (median age 10 [range 1–16] years) with severe
of the exhaust agents that is necessary to prevent anesthetic asthma supported with ECMO. Patients generally received
exposure of PICU staff [87]. aggressive use of medical and anesthetic therapies before cannu-
To date, there are no RCTs examining the effects of inhaled lation, including iv. b2-agonists and ketamine infusions.
anesthetics in children with severe asthma exacerbations. The Median arterial PCO2 was 130 (range 102–186) mmHg before
evidence supporting the use of anesthetics in asthma is derived cannulation and serum pH 6.89 (range 6.75–7.03). The
from retrospective case series, the largest of which involved median time of ECMO support was 95 (range 42–395) h, and
31 patients [88]. Isoflurane was started at a mean of 13 h after all 13 children survived without neurological sequelae [93]. For
institution of invasive mechanical ventilation and continued for severe refractory respiratory failure secondary to asthma,
a mean duration of 54.5 h. The mean baseline pH and partial ECMO remains an important therapeutic option, and further

436 Expert Rev. Respir. Med. 8(4), (2014)

 Review: adjunctive therapies for severe acute asthma exacerbation in critically ill children Review

data are needed to determine the optimal timing of ECMO Following intubation, inhaled anesthetics and extracorporeal
implementation relative to mechanical ventilation or other support should be considered as potential rescue therapies
invasive therapies. [93,102]. Based the current data, we propose an evidenced-
based algorithm for therapy progression (FIGURE 1). This pro-
Expert commentary tocol should be adapted according to latest evidence, along
Due to the absence of definitive data, critical care management with local resources and expertise available at respective
of severe asthma in children is often variable and inconsis- centers.
tent [7,8,94], with the use of adjunctive therapies depending on
local practices, resource availability and provider preferences [95]. Five-year view
All children with acute asthma exacerbation should receive Over the next 5 years, we expect more data to emerge from
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by University of Queensland on 10/14/14

first-line treatment per established guidelines [12,96]. Those chil- ongoing studies. We eagerly await the results of a recently com-
dren who do not respond sufficiently to initial measures should pleted RCT testing the efficacy of iv. terbutaline for the treat-
be admitted to the PICU and adjunctive therapies should be ment of status asthmaticus in the PICU [103]. In this study, iv.
considered at that time. Importantly, adjunctive therapies repre- terbutaline or placebo was added to standard asthma treatment.
sent an addition to first-line strategies rather than a replace- The dose of terbutaline or placebo was titrated according to
ment for these approaches. severity of illness as quantified by the clinical asthma score.
Despite the lack of evidence supporting the efficacy of Outcomes compared in this study include LOS, lung function
these adjunctive therapies for patients with severe asthma in and side effects. Another upcoming RCT studying the efficacy
the PICU, their use is relatively common. Iv. magnesium has of nebulized magnesium sulfate versus placebo in addition to
been reported to be used in 32–40% of patients intubated standard therapy in the ED is expected to complete in
for asthma [7,8]. Reports from the USA and Australia quote 2017 [104]. The primary outcome in this trial is the hospitaliza-
frequencies of usage of iv. methylxanthine and iv. b2-agonists tion rate, and secondary outcomes are Pediatric Respiratory
to be approximately 44 and 17–87.2%, respectively [7,8]. Assessment Measure, respiratory rate, oxygen saturation and
Use of iv. ketamine and inhaled heliox ranged between blood pressure from randomization baseline to 240 min in the
For personal use only.

37–47 and 18–22%, respectively [7,8]. Given the lack of two groups.
definitive data, clinicians must use his/her clinical judgment The impact of genetic constitution on asthma severity and
to determine the potential benefit of adjunctive therapies on exacerbations will also continue to be explored. Genetic varia-
a case-by-case basis, with avoidance of invasive mechanical tions of the b2-adrenergic receptor have been shown to affect
ventilation an important priority due to air trapping and sig- response to b2-agonist therapy in the population patients who
nificant morbidity and mortality for intubated asthmatic develop critical asthma [105]. Some investigators hypothesize
patients. Side effects of these therapies, including tachycardia that a child’s b2-adrenergic receptor genotype is associated
and tremor with iv. methylxanthines and b2-agonists and with the development of a near-fatal asthma exacerbation and
nausea with these therapies and magnesium, must also be have conducted a case–control study examining this genotype
considered. Non-invasive positive pressure ventilation is also among inpatient asthmatics, outpatient asthmatics and healthy
a feasible option for patients with moderate lower airway controls [106].
obstruction and can be considered along with these adjunc- In addition, with continued refinements and new develop-
tive therapies [97–99]. ments in extracorporeal support [107,108], the use of ECLS in
Despite the risks, for patients with severe airway obstruc- severe asthma may increase over the coming years. ECLS pro-
tion, markedly increased work of breathing, hypoxemia and vides the opportunity to ‘rest’ the lungs and may allow for
impending respiratory arrest, timely intubation and invasive implementation of a lung protective ventilatory strategy while
mechanical ventilation should be instituted [10]. Ventilatory awaiting the reversal of inflammatory changes in an acute
support may be necessary and is beyond the scope of this exacerbation of asthma.
report, but we refer the reader to a number of other excel-
lent available publications on non-invasive respiratory sup- Financial & competing interests disclosure
port and invasive mechanical ventilation in severe asthma The authors have no relevant affiliations or financial involvement with
[97,99–101]. Intubation of a patient with severe asthma exacer- any organization or entity with a financial interest in or financial con-
bation must be approached with caution, given the difficulty flict with the subject matter or materials discussed in the manuscript.
in matching the patient’s native respiratory drive, the risk This includes employment, consultancies, honoraria, stock ownership or
for worsening air-trapping and complex cardiorespiratory options, expert testimony, grants or patents received or pending or
interactions seen with the transition from extremely negative royalties.
to positive pressure ventilation. For intubation, iv. ketamine No writing assistance was utilized in the production of this
may be useful as both a bronchodilator and sedative. manuscript.

informahealthcare.com 437
 Review Wong, Lee, Turner & Rehder

Key issues
• All children with acute asthma exacerbation should receive first-line treatment as per published guidelines. Those who do not respond
sufficiently to these measures should be admitted and adjunctive therapies considered, in addition to (not to replace) first-line
treatment strategies.
• Intravenous (iv.) magnesium use in the emergency department reduces hospital admission rate, LOS and intubation rate, but there is
little evidence for its continued use in the PICU. There are limited data to support the use of nebulized magnesium in the
emergency department.
• Iv. b-agonists and iv. methylxanthines may be used as second-tier therapies, but these agents are associated with significant side effects.
• Inhaled heliox can be safely administered and may improve pulmonary function in severe asthma exacerbations.
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by University of Queensland on 10/14/14

• Inhaled anesthetics and iv. ketamine have bronchodilatory and anesthetic/sedative effects. These agents may be considered in children
with severe asthma who require mechanical ventilation.
• The use of extracorporeal membrane oxygenation in refractory severe asthma has been increasing over the past two decades and
despite disease severity, survival in this group remains high.

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