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Pediatric Anesthesia ISSN 1155-5645
SPECIAL INTEREST ARTICLE
Volatile anesthetics for status asthmaticus in pediatric
patients: a comprehensive review and case series
1,2 & Thomas Anthony Anderson1
Sabrina Carrie
1 Massachusetts General Hospital Department of Anesthesia, Critical Care and Pain Medicine, Boston, MA, USA
2 McGill University Health Center, Department of Anesthesia, Montreal, QC, Canada
Keywords
pediatrics; asthma; status asthmaticus;
volatile anesthetics; refractory asthma;
isoflurane for status asthmaticus
Correspondence
, Department of Anesthesia,
Dr. S. Carrie
McGill University, 687, Avenue des Pins,
Ouest Montreal, QC H3A 1A1, Canada
Email: [email protected]
Section Editor: Brian Anderson
Accepted 24 October 2014
doi:10.1111/pan.12577
Summary
Status asthmaticus is an acute, intractable asthma attack refractory to standard interventions that can lead to progressive respiratory failure. Successful
management requires a fundamental understanding of the disease process, its
clinical presentation, and proper evaluation. Treatment must be instituted
early and is aimed at reversing the airway inflammation, bronchoconstriction,
and hyper-reactivity that often lead to lower airway obstruction, impaired
ventilation, and oxygenation. Most patients are effectively treated with standard therapy including beta2-adrenergic agonists and corticosteroids. Others
necessitate adjunctive therapies and escalation to noninvasive ventilation or
intubation. We will review the pathophysiology, evaluation, and treatment
options for pediatric patients presenting with status asthmaticus with a particular focus on refractory status asthmaticus treated with volatile anesthetics.
In addition, we include a proven approach to the management of these
patients in the critical care setting, which requires close coordination between
critical care and anesthesia providers. We present a case series of three
patients, two of which have the longest reported cases of continuous isoflurane use in status asthmaticus. This series was obtained from a retrospective
chart review and highlights the efficacy of the volatile anesthetic, isoflurane,
in three pediatric patients with refractory life-threatening status asthmaticus.
Introduction
Asthma is a chronic respiratory disease characterized by
intermittent, varying degrees of airway inflammation,
bronchoconstriction, and hyper-reactivity to stimuli,
which can lead to lower airway obstruction (1). A lifethreatening asthma exacerbation or status asthmaticus
(SA) is generally defined as an acute, intractable asthma
attack. This condition is usually characterized by progressive respiratory failure, which is refractory to standard therapeutic treatments. Some patients with SA do
not respond to the more commonly used medications
including inhaled beta2-agonists, anticholinergics, steroids, magnesium, and even older medications such as
the methylxanthines. The decision to use invasive or
noninvasive ventilation is based on the patient’s signs
and symptoms. Patients with SA may respond to less
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commonly used bronchodilators such as propofol, ketamine, or volatile anesthetics (VAs). This article reviews
the epidemiology, pathophysiology, evaluation, and
treatment options of SA with a particular focus on the
use of VAs; three illustrative cases will also be described.
While other reviews of VAs for SA have been published,
no article was located that details the practical approach
to using a VA in the intensive care setting nor describes
patients requiring VAs for >2 weeks.
Epidemiology
Asthma is a serious public health problem especially in
children. The World Health Organization estimates that
~300 million individuals worldwide suffer from asthma.
A further increase in ~400 million is expected by 2025
owing in part to increasing industrialization and
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pollution in urban areas (2). Children are at greater risk
with 9.6% compared to 7.7% adults currently diagnosed
with asthma in the United States (US). A rise in prevalence of 1.4% per year was noted from 2001 to 2010 (3).
In fact, asthma has become the leading childhood illness
in industrialized countries and a major cause of childhood hospitalization and admission to the intensive care
unit (ICU).
In the US in 2008, almost 60% of children aged 5–17
with asthma missed one or more school days because of
this illness, a total of 10.5 million school days (3). In
2009 alone, there were 2.1 million asthma-related emergency department (ED) visits and over 479 000 hospitalizations in the US. Children had a higher ED visit rate
compared to adults (10.7 vs 7.0/100 persons with
asthma). ICU admissions have increased, but the rate of
invasive mechanical ventilation secondary to asthma has
decreased. While the prevalence of asthma is rising,
mainly in the developing world, mortality is decreasing
but still remains high. There are 1.9 deaths per 10 000
adults with asthma compared to 0.3 deaths per 10 000
children with asthma (3).
Pathophysiology
The proper management of SA requires a clear understanding of the underlying inflammatory process combined with airway hyper-reactivity, bronchial smooth
muscle constriction, mucosal edema, and increased
mucus production (1). These features lead to increased
airway resistance, limitation of airflow and dynamic
hyperinflation, increased work of breathing leading to
ventilation perfusion (V/Q) mismatch from heterogeneous ventilation, hypoxemia, and eventual hypercarbia.
The inflammatory cascade of asthma is triggered by a
wide variety of irritants, infections, stress, exercise, cold
air, aspirin, and nonsteroidal anti-inflammatory drugs
(NSAIDs). Allergens have been shown to stimulate Th2
lymphocytes and the release of a wide variety of IgEdependent factors from mast cells; these include histamine, leukotrienes, prostaglandins, and tryptase which
in turn lead to smooth muscle contraction and activation of other inflammatory cells (4). Furthermore, the
bronchial wall undergoes structural remodeling of the
submucosal basement membrane, smooth muscles,
mucous glands, and associated capillaries (4). Although
asthma is traditionally known to have reversible airway
obstruction, the structural remodeling can render airflow limitation of asthma partially irreversible or fixed
and refractory to treatment.
Severe asthma attacks typically fall into two
categories: ‘slow-onset, late-arrival’ (type I) and ‘sudden-onset fatal asthma’ (type II) (5,6). Type I asthma
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exacerbations are characterized by slowly progressive
airway obstruction. Type I events occur usually from
inadequate asthma control, treatment, and/or compliance in older patients who worsen over at least 6 h.
These children are usually overusing bronchodilators,
with maximally relaxed smooth muscle, but are otherwise undertreated with continued inflammation and airway edema. Additional beta2-agonists will not result in
improvement, as bronchoconstriction is not the underlying problem. Such patients usually present with airway
plugging and secretions with eosinophilic infiltration.
Type I events lead to the majority of asthma fatalities
and can be prevented with improved treatment such as
adding an inhaled corticosteroid.
Type II asthma exacerbations or sudden asphyxial
asthma results from the sudden onset of severe bronchospasm. Type II events usually occur rapidly without preceding deterioration and are secondary to a specific
allergen. There is very little airway inflammation, and
neutrophilic infiltration is prominent. As opposed to
children with Type I attacks who are maximally bronchodilated from chronic bronchodilator use, patients
with Type II attacks typically respond rapidly to bronchodilators. The latter is more likely to have respiratory
arrest, acidemia, and altered mental status (5). However,
they improve more quickly with appropriate treatment,
generally spend less time on mechanical ventilation, and
are discharged earlier (7). The distinction between the
two types is an important one to make on history including a thorough review of medication use, as the treatment is guided by the appropriate diagnosis.
Evaluation
Evaluation of the child with SA must be performed
quickly and thoroughly. The child may exhibit wheezing, coughing, irritability, increased work of breathing,
tachypnea, and tachycardia. In more severe cases, diaphoresis, cyanosis, inability to phonate, decreased or
absent air entry, pulsus paradoxus, and altered mental
status can be seen (8). The first step is always to assess
the ABCs [(airway (normal or abnormal anatomy),
breathing (retractions, wheezing, or absence of wheezing
(most severe), and circulation (pulse oximetry, heart
rate, NIBP)]. The assessment should elicit a history that
confirms the diagnosis and defines the severity of underlying asthma including the frequency of exacerbations,
underlying symptom control, and previous responses to
treatment. Laboratory analysis can be helpful to assess
for leukocytosis as a marker of bacterial infection, but
in a child receiving steroids, an increased white blood
cell may be secondary to demargination (9). The process
of demargination happens when leukocytes are released
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Volatile anesthetics for status asthmaticus
from the endothelial lining of blood vessels and effectively increase the white blood cell count in circulation
(10). Children receiving steroids and beta2-agonists may
have hyperglycemia, which should be appropriately
assessed and treated.
Objective measurement of CO2 and O2 partial pressures can be helpful in a child who is not responding to
escalating treatment. However, arterial blood gas
(ABG) sampling is not routinely performed in pediatric
asthma patients and does not predict outcome. ABG
sampling is mostly obtained in ventilated patients to
quantify the level of hypoxemia, hypoventilation, and/
or hyperventilation (1). In nonventilated patients at high
risk of respiratory failure, venous and capillary samples
can provide an accurate assessment of the serum partial
pressure of carbon dioxide and pH and can be used in
conjunction with oximetry for assessment of oxygenation (11–13). In children older than five who are also
cooperative, peak expiratory flow can be measured and
a trend followed overtime. However, one study showed
that only 65% of children between six and eighteen were
able to sufficiently perform peak expiratory flow rate
measurements (14). Furthermore, peak flow measurements alone should not be used to assess the severity of
asthma, as they can be stable despite severe bronchial
constriction. There is also a wide interindividual variability, and therefore, these measurements should be
interpreted in light of the patient’s previous known best
measurement. Forced expiratory volume in 1s (FEV1) is
more reliable but may not be easily available in an ED.
A chest radiograph is not usually necessary unless there
is concern for pneumonia, atelectasis, foreign body aspiration, pneumothorax, or if the child requires ICU
admission.
Treatment
Status asthmaticus usually improves with first-line treatments including oxygen, continuous albuterol nebulizer,
and corticosteroids. Second-line therapies are used in an
escalating fashion only when initial treatments fail. Oxygen is usually the initial treatment as asthma fatality is
secondary to hypoxia. Inhaled SABAs are the most
commonly used medication in asthma to reverse bronchoconstriction. These agents act locally via adrenergic
receptors resulting in smooth muscle relaxation but
must reach the affected areas to work properly. In
patients with copious secretions, mucous plugging, and
low tidal volumes, these medications may not reach the
areas most affected. One study showed that continuous
albuterol nebulization was more efficacious than intermittent nebulization in children with SA and imminent
respiratory failure (15).
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Corticosteroids are used to control the inflammatory
response. Children presenting with moderate to severe
asthma exacerbation who received corticosteroids within
75 min of triage have been shown to have a lower rate
of hospital admission and shorted length of active treatment (16). The incidence of side effects including hyperglycemia, hypertension, and mood changes is difficult to
quantify but are usually transient with short-term treatment. Given the lack of studies, the optimal route and
dose of corticosteroids for effective treatment of asthma
without increasing side effects in children are not known
(17).
Anticholinergic agents are often used to supplement
first-line therapies. Anticholinergic agents, such as
inhaled ipratropium, act via the parasympathetic nervous system to relax bronchial smooth muscle. Studies
suggest that anticholinergic agents have an additional
bronchodilating action when used in conjunction with
SABAs and can be helpful in severe asthma attacks
(18,19).
Magnesium sulfate is thought to relieve bronchoconstriction by inhibition of uptake and release of calcium
from bronchial smooth muscle, inhibition of mast cell
degranulation leading to decreased histamine, and
decreased excitability of membranes by decreased acetylcholine release at the motor end plate. Intravenous magnesium appears to be helpful in moderate to severe acute
asthma in children by improving peak expiratory flow
rate (PEFR), FEV1, and forced vital capacity (FVC)
with doses from 25–75 mgkg 1 (20,21).
Second-line therapies include intravenous beta2-agonists, which may be effective when the severity of airflow
obstruction limits the delivery of inhaled agents. Intravenous beta2-agonists may improve outcome in patients
with severe asthma but should be closely monitored for
arrhythmias (22,23).
Methylxanthines nonselectively inhibit phosphodiesterase and antagonize adenosine receptors in smooth
muscle and inflammatory cells. Studies on the use of
methylxanthines in critically ill children with SA have
shown mixed results with some showing no difference in
outcome (24,25) and another showing benefit over intravenous beta2-agonists (26,27). Methylxanthines should
be considered in critically ill children with refractory SA
with close attention to potential toxicity.
Noninvasive positive pressure ventilation (NIPPV)
should be considered early in severe SA to reduce the
work of breathing. Its benefits include stabilization of
heart and respiratory rate, and improvement of clinical
asthma score in the first 48 h after initiation (28). However, NIPPV is contraindicated in children with copious
secretions, altered mental status, severe agitation, and
an inability to cooperate.
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Rescue therapies include inhaled helium–oxygen mixture (Heliox) and ketamine. Heliox generally contains
60–80% helium with 20–40% oxygen. Heliox has a
lower density than oxygen alone. Therefore, it can theoretically reach lower and obstructed airways more efficiently and with less turbulence. This property of heliox
can potentially help deliver nebulized beta2-agonist
agents to distal airways; however, studies have shown
mixed benefits. One randomized study showed improvement in peak flow and decreased dyspnea index and pulsus paradoxus (29). However, another randomized
study showed no significant difference in hospital length
of stay or clinical asthma scores (30). Furthermore, to
significantly lower its density, the concentration of oxygen is often as low as 20%, thus limiting heliox to nonhypoxemic children with SA.
Ketamine is an intravenous anesthetic with noncompetitive N-methyl-D-aspartate receptor antagonist properties used primarily for its analgesic property and
stable hemodynamic effect. Ketamine has a dissociative
effect and can potentially increase bronchial secretions;
however, it also has bronchodilator properties (31).
Studies in pediatric patients with SA have shown mixed
results on pulmonary status (32–34). Given the lack of
well-designed studies on ketamine use in SA and the
paucity of information on optimum dose, ketamine is
often reserved for refractory cases or mechanically ventilated patients with SA.
Propofol is an intravenous hypnotic anesthetic used
mostly for induction and maintenance of anesthesia as
well as sedation in the ICU. Propofol has been shown in
vitro to have direct bronchial smooth muscle relaxation
properties (35). Propofol is useful for patients with SA
that may be candidates for extubation within a few
hours of intubation such as type II asthma patients as it
can be titrated easily and is metabolized quickly after
discontinuation of the infusion. However, propofol can
cause hypotension through a negative inotropic effect
and decreased systemic vascular resistance. Furthermore, prolonged use of propofol infusions has led to
propofol infusion syndrome (PIS) especially in children
(36).
Other treatment options that have been proposed
include nebulized epinephrine and recombinant human
deoxyribonuclease (DNase). Epinephrine has both betaand alpha-adrenergic activity, which contribute to bronchodilation and can potentially decrease edema through
vasoconstriction. Several studies have shown subcutaneous epinephrine to be equivalent to albuterol in improving respiratory function in asthma exacerbation but
given its numerous side effects compared to inhaled
SABAs including hypertension, tachycardia, and arrhythmias, and its use is often limited to the prehospital
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setting (37,38). Nebulized epinephrine has been postulated to be a safer route for administration and potentially beneficial in patients who do not respond to
selective beta2-agonist treatment (39).
Mucolytic agents such as DNase are more commonly
used in cystic fibrosis patients (40). There are several
case reports of positive results with intratracheal administration of DNase in patients with SA that are mechanically ventilated (41–43). Without high level of evidence
supporting its use, DNase is administered during bronchoscopy to theoretically cleave the DNA found in
mucus plugs to reduce viscosity and help with clearance.
Despite optimal pharmacological treatment, about
2% of children with severe SA will require mechanical
ventilation (44). The clinical status is the main determinant of the need for invasive ventilation. Intubation,
however, may exacerbate bronchospasm, while positive
pressure ventilation can cause lung disruption including
barotrauma, volutrauma, atelectrauma from cyclic atelectasis, and biotrauma from alveolar inflammatory
response to stretch. In children that have SA severe
enough to warrant intubation, inhaled anesthetics can
be life saving.
Rarely, extracorporeal membrane oxygenation
(ECMO) is used as a temporizing measure in SA when
adequate gas exchange or systemic circulation is unable
to be maintained with other treatments. Based on the
extracorporeal life support registry, the survival rate for
patients with SA on ECMO is estimated at 83% (45).
However, ECMO is an expensive and invasive therapy
fraught with complications including serious bleeding,
infections, and neurological events such as strokes and
seizures. Despite the lack of comparative studies,
ECMO should be used only as a rescue therapy (46)
when all other treatments have failed including VAs.
Inhaled anesthetics
The treatment of children with severe SA and respiratory failure with volatile anesthetics (VAs) is another
useful alternative. The VAs have been shown in asthma
to rapidly reverse bronchoconstriction, markedly
improve gas exchange and peak inspiratory pressure,
and possibly decrease the incidence of ventilatorinduced lung injury (8,47–50). In a retrospective review
from a tertiary care children’s hospital, 10 children with
11 episodes of severe asthma refractory to conventional
medical management were successfully treated with isoflurane over a 5-year period (8). In another retrospective
review at a single institution, 31 pediatric patients with
severe asthma were successfully treated over a 15-year
period (47). In this series, isoflurane led to a significant
improvement in pH and PCO2 within 4 h of initiation
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and there were no lasting side effects (47). Other case
reports at other institutions exist describing the dramatic
reversal of severe refractory asthma with the use of VAs
with minimal side effects in smaller numbers of patients
(48,49,51).
There are several proposed mechanisms of action for
VAs including beta-adrenergic receptor activation,
direct bronchial smooth muscle relaxation by inhibition
of acetylcholine and histamine, and hindrance of hypocapnic bronchoconstriction (8). After institution of firstand second-line treatments as previously discussed, the
management of intubated children with refractory SA
can remain problematic. Heavy sedation and paralysis
may facilitate ventilation, but using a VA can provide
excellent sedation with the added benefit of reversing the
underlying bronchoconstriction. However, the use of
VAs outside the operating room is still uncommon, and
most pediatric intensivists are not familiar with nor have
access to the equipment necessary to deliver and scavenge these agents. Pediatric anesthesiologists can therefore play an important role in the use of VAs in
treatment of refractory SA in the ICU.
All of the available VAs, halothane, isoflurane, sevoflurane, and desflurane, have been used to treat refractory SA (52,53). However, given that desflurane has
been shown to increase airway resistance in children
with high airway susceptibility (54), caution should be
taken when considering its use in the pediatric patient
with SA. Given its low cost, high potency, and the ability to use low gas flows without the accumulation of
breakdown products, isoflurane is attractive in this setting. On a practical level, isoflurane requires the fewest
number of reservoir refills over time. The retrospective
review of 31 children treated with isoflurane reported 24
patients (77%) with hypotension, three with neurologic
side effects including two with abnormal movements
during treatment, and one with withdrawal symptoms;
three patients had transient arrhythmia without hemodynamic compromise (47). As opposed to the older
anesthetic halothane, isoflurane and sevoflurane do not
produce life-threatening arrhythmias. Hypotension from
arterial and venous smooth muscle relaxation is the
most common side effect, but is usually transient and
responsive to fluid and vasopressor administration
(49).To minimize unwanted side effects, it is important
to wean intravenous beta2-agonists upon initiation of
VAs. While beta2-agonists are proven for asthma treatment, as previously mentioned, patients with a type I
asthma are unlikely to benefit from further treatment
with beta2-agonists. Additionally, these agents may
cause tachycardia, arrhythmias, and troponin elevation.
Once traditional treatment options have failed and a VA
has been shown to completely or partially reverse
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hypoxemia and hypercarbia, agents that did not
improve respiratory failure but may have unwanted side
effects should be weaned.
Some animal studies have demonstrated that prolonged exposure to VAs leads to neuroapoptosis in neonatal mice brains and subsequent memory deficit (55).
Although these findings raise concern for the use of VAs
in the pediatric population, long-term neurological
effects have not been shown in clinical practice. VAs
may also raise serum inorganic fluoride concentration;
however, there have been no reports of fluoride toxicity
or adverse effect on renal function (56,57). Although
nitrous oxide has been shown to suppress vitamin B12
and impair DNA synthesis in bone marrow cells, this
has not been demonstrated with other VAs (58). A retrospective review of 1558 patients at 40 hospitals who
received mechanical ventilation for treatment of asthma,
not SA, did not show an improvement in outcome.
Patients treated with VAs had a longer length of hospital stay and greater hospital costs (59). Thus, selection
of patients for VA use is important. We suggest using
VA for patients with severe asthma who are refractory
to traditional asthma therapies.
The beneficial effects of volatile anesthetics are illustrated in Table 1 below at the MassGeneral Hospital for
Children. We report the use of isoflurane in three pediatric patients with life-threatening SA. Two of these three
cases represent the longest reported use of isoflurane in
the setting of SA when compared to available published
data (8,17,47,49,51,57,60–66).
Patient 1, a 13-year-old female with a history of
asthma presented with acute onset of cough, dyspnea,
fever, and headache. She was diagnosed with H1N1
and developed SA. She became refractory to albuterol, terbutaline, magnesium sulfate, and heliox and
developed theophylline toxicity. Her condition deteriorated rapidly requiring intubation and mechanical
ventilation. Isoflurane was titrated to an end-expiratory concentration of 1.5%, with dramatic improvement in arterial blood CO2 and exhaled tidal
volumes. Within 24 h of isoflurane initiation, her
PaCO2 dropped from the 90–100s mmHg to 70–80s
and her arterial pH increased from 7.2s to 7.3s. She
remained intubated and required isoflurane for
17 days before successful weaning.
Patient 2, a 3-year-old male with a tracheostomy secondary to severe tracheomalacia was admitted with SA
refractory to pulse steroids, continuous albuterol, terbutaline, heliox, and magnesium sulfate. Isoflurane was
titrated to an end-expiratory concentration of 1.2%,
and he was rapidly weaned to his baseline ventilator settings. Within 24 h of isoflurane initiation, his EtCO2
dropped from the 120s to the 90s mmHg, his O2
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Volatile anesthetics for status asthmaticus
saturation improved from the low 90s to high 90s with a
decreased FiO2, and his fentanyl and midazolam
requirements were decreased by 33% and 50%, respectively. He remained ventilated and isoflurane dependent
for 16 days.
Patient 3, a previously healthy 2-year-old male with
respiratory syncytial virus developed life-threatening
SA. After emergent intubation in the operating room,
he responded to conventional treatment. However, he
subsequently developed acute respiratory distress with
an oxygen saturation as low as 8%. He was started on
isoflurane at an end-expiratory concentration of 1.1%
with a marked improvement in ventilation. Within 24 h
of isoflurane initiation, the peak airway pressures
required for adequate ventilation and oxygenation fell
from the mid-20s cmH2O to the low 20s cmH2O and
oxygenation improved from PaO2 in the 70s mmHg to
the 90s mmHg using the same FiO2. He was on isoflurane for 3 days before it was successfully weaned off, and
he was extubated.
Successful use of VAs in the ICU requires a coordinated effort between the intensive care and anesthesia
Table 1 Three cases of pediatric patients with SA successfully treated with inhalation of isoflurane
Days
on
VA
Complication
from VA*
Previous
treatment failed
13 y/o F history of
asthma, presents with
SA in setting of H1N1
17
None
3 y/o M, history of
chronic bronchiectasis
and tracheostomy for
tracheomalacia
presents with SA
16
None
2 y/o M previously
healthy presents with
SA in setting of RSV
infection—taken to OR
directly for intubation in
setting of severe
hypoxemia
3
Mild
Hypotension
Albuterol
Terbutaline
Magnesium
Sulfate
Heliox
Theophylline
(with toxicity)
Steroids
Continuous
albuterol—
complicated by
SVT
Terbutaline
Heliox
Magnesium
Sulfate
Albuterol
Patient
*Isoflurane titrated in all cases to an end-expiratory concentration
between 1 and 1.5% with dramatic improvement in arterial blood
CO2 and exhaled tidal volumes.
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Pediatric Anesthesia 25 (2015) 460–467
teams. As the ICU ventilators are not equipped with
vaporizer for the delivery of anesthesia gasses, a standard anesthesia machine with a vaporizer or alternatively, an AnaConDa (Anesthetic Conserving Device),
must be used. The AnaConDa is placed in the ventilator
circuit between the patient and the ICU ventilator and
delivers VAs via syringe pump injection into the ventilator circuit (67). The standard ICU monitoring should
always be in place including 1 : 1 nursing care with frequent assessment of clinical status and vitals signs. In
addition, a self-inflating bag-valve-mask resuscitator
should always be at the bedside in case of ventilator failure. Ventilator parameters should also be adjusted to
include a prolonged expiratory time, and the ventilator
capnograph and pressure waveforms should be evaluated frequently to assess for continued obstruction,
breathing stacking, and carbon dioxide retention. For
optimal patient care, a pediatric anesthesiologist should
round at least twice daily and be on call at all times in
case of an emergency. Additionally, an anesthesia technician should check twice a day for proper equipment
function, fill the VA vaporizer, and change the CO2
absorbent as needed. A backup circuit should also be
available near the machine in case of excess condensation in the circuit (‘rain-out’).
The intensive care team should be trained on the use
of anesthesia machine including delivered gas concentration; however, major changes in delivered gasses should
be performed with strict guidance and direct consultation with the anesthesia service. Although sedation level
does not equate with bronchodilation effect, a bispectral
index (BIS) monitor can be helpful in assessing sedation
and avoid an excessive inhaled VA concentration. In
general, the concentration of endtidal VA should be closely monitored. The endtidal concentration of isoflurane
should not generally exceed 1.5% without consultation
with an anesthesiologist. While the inhaled concentration of volatile agent necessary for bronchodilation may
be less than required for complete sedation in the intubated child, use of VAs should allow a significant reduction in the need for intravenous sedatives. In fact, given
the side effects associated with infusions of other sedative agents (68), it may be useful to minimize the use of
other agents when a volatile agent is used in this situation.
Conclusions
While most asthma exacerbations resolve with treatment
by SABAs and corticosteroids, ICU admissions for
refractory SA continue to increase. Inhaled VAs, as
illustrated, can be life saving for those who do not
improve with standard treatments. VAs have a rapid
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onset and produce sustained bronchodilatation that can
quickly reverse severe respiratory failure. Our experience, and that of others, has shown that VAs may be an
important addition to treatment options for SA. However, given that there are no randomized controlled trials for the use of VAs, we emphasize that they should be
use with caution and only with the support of anesthesiologists. Future studies on efficacy, safety, and costeffectiveness are warranted as well as the timing of their
initiation.
Financial disclosure
This research was carried out without funding.
Conflict of interest
No conflict of interest to declare.
References
1 Cohen NH, Eigen H, Shaughnessy TE. Status asthmaticus. Crit Care Clin 1997; 13:
459–476.
2 Masoli M, Fabian D, Holt S et al. The global burden of asthma: executive summary of
the GINA Dissemination Committee report.
Allergy 2004; 59: 469–478.
3 Moorman JE, Akinbami LJ, Bailey CM
et al. National surveillance of asthma: United States, 2001-2010. Vital Health Stat 3.
2012:1–67.
4 Busse WW, Lemanske RF Jr. Asthma. N
Engl J Med 2001; 344: 350–362.
5 Koninckx M, Buysse C, de Hoog M. Management of status asthmaticus in children.
Paediatr Respir Rev 2013; 14: 78–85.
6 Papiris SA, Manali ED, Kolilekas L et al.
Acute severe asthma: new approaches to
assessment and treatment. Drugs 2009; 69:
2363–2391.
7 Plaza V, Serrano J, Picado C et al. Frequency and clinical characteristics of rapidonset fatal and near-fatal asthma. Eur Respir
J 2002; 19: 846–852.
8 Shankar V, Churchwell KB, Deshpande JK.
Isoflurane therapy for severe refractory status asthmaticus in children. Intensive Care
Med 2006; 32: 927–933.
9 Nakagawa M, Terashima T, D’Yachkova
Y et al. Glucocorticoid-induced granulocytosis: contribution of marrow release and
demargination of intravascular
granulocytes. Circulation 1998; 98: 2307–
2313.
10 Neonatal Hematology. Pathogenesis, Diagnosis and Management, of Hematologic
Problems. Alarcon P, ed. London: Cambridge University Press; 2013: 255–256
11 Yildizdas D, Yapicioglu H, Yilmaz HL et al.
Correlation of simultaneously obtained capillary, venous, and arterial blood gases of
patients in a paediatric intensive care unit.
Arch Dis Child 2004; 89: 176–180.
12 Harrison AM, Lynch JM, Dean JM et al.
Comparison of simultaneously obtained arterial and capillary blood gases in pediatric
intensive care unit patients. Crit Care Med
1997; 25: 1904–1908.
466
13 Chu YC, Chen CZ, Lee CH et al. Prediction
of arterial blood gas values from venous
blood gas values in patients with acute respiratory failure receiving mechanical ventilation. J Formos Med Assoc 2003; 102: 539–
543.
14 Gorelick MH, Stevens MW, Schultz T
et al. Difficulty in obtaining peak expiratory flow measurements in children with
acute asthma. Pediatr Emerg Care 2004;
20: 22–26.
15 Papo MC, Frank J, Thompson AE. A prospective, randomized study of continuous
versus intermittent nebulized albuterol for
severe status asthmaticus in children. Crit
Care Med 1993; 21: 1479–1486.
16 Bhogal SK, McGillivray D, Bourbeau J et al.
Early administration of systemic corticosteroids reduces hospital admission rates for
children with moderate and severe asthma
exacerbation. Ann Emerg Med 2012; 60: 84–
91.e3.
17 Smith M, Iqbal S, Elliott TM et al. Corticosteroids for hospitalised children with acute
asthma. Cochrane Database Syst Rev. 2003:
(2) Cd002886.
18 Goggin N, Macarthur C, Parkin PC. Randomized trial of the addition of ipratropium
bromide to albuterol and corticosteroid therapy in children hospitalized because of an
acute asthma exacerbation. Arch Pediatr
Adolesc Med 2001; 155: 1329–1334.
19 Schuh S, Johnson DW, Callahan S et al. Efficacy of frequent nebulized ipratropium bromide added to frequent high-dose albuterol
therapy in severe childhood asthma. J pediatr
1995; 126: 639–645.
20 Cheuk DK, Chau TC, Lee SL. A meta-analysis on intravenous magnesium sulphate for
treating acute asthma. Arch Dis Child 2005;
90: 74–77.
21 Ciarallo L, Sauer AH, Shannon MW. Intravenous magnesium therapy for moderate to
severe pediatric asthma: results of a randomized, placebo-controlled trial. J Pediatr 1996;
129: 809–814.
22 Browne GJ, Penna AS, Phung X et al.
Randomised trial of intravenous salbutamol
23
24
25
26
27
28
29
30
31
in early management of acute severe asthma
in children. Lancet 1997; 349: 301–305.
Bogie AL, Towne D, Luckett PM et al.
Comparison of intravenous terbutaline versus normal saline in pediatric patients on
continuous high-dose nebulized albuterol for
status asthmaticus. Pediatr Emerg Care 2007;
23: 355–361.
Bien JP, Bloom MD, Evans RL et al. Intravenous theophylline in pediatric status asthmaticus. A prospective, randomized, doubleblind, placebo-controlled trial. Clin Pediatr
1995; 34: 475–481.
Strauss RE, Wertheim DL, Bonagura VR
et al. Aminophylline therapy does not
improve outcome and increases adverse
effects in children hospitalized with acute
asthmatic exacerbations. Pediatrics 1994; 93:
205–210.
Roberts G, Newsom D, Gomez K et al.
Intravenous salbutamol bolus compared with
an aminophylline infusion in children with
severe asthma: a randomised controlled trial.
Thorax 2003; 58: 306–310.
Wheeler DS, Jacobs BR, Kenreigh CA et al.
Theophylline versus terbutaline in treating
critically ill children with status asthmaticus:
a prospective, randomized, controlled trial.
Pediatr Crit Care Med 2005; 6: 142–147.
Mayordomo-Colunga J, Medina A, Rey C
et al. Non-invasive ventilation in pediatric
status asthmaticus: a prospective observational study. Pediatr Pulmonol 2011; 46: 949–
955.
Kudukis TM, Manthous CA, Schmidt GA
et al. Inhaled helium-oxygen revisited: effect
of inhaled helium-oxygen during the treatment of status asthmaticus in children. J Pediatr 1997; 130: 217–224.
Bigham MT, Jacobs BR, Monaco MA et al.
Helium/oxygen-driven albuterol nebulization
in the management of children with status
asthmaticus: a randomized, placebo-controlled trial. Pediatr Crit Care Med 2010; 11:
356–361.
Goyal S, Agrawal A. Ketamine in status
asthmaticus: a review. Indian J Crit Care
Med 2013; 17: 154–161.
© 2015 John Wiley & Sons Ltd
Pediatric Anesthesia 25 (2015) 460–467
and T.A. Anderson
S. Carrie
32 Petrillo TM, Fortenberry JD, Linzer JF et al.
Emergency department use of ketamine in
pediatric status asthmaticus. J Asthma 2001;
38: 657–664.
33 Maddox RP, Seupaul RA. Is ketamine effective for the management of acute asthma
exacerbations in children? Ann Emerg Med
2014; 63: 309–310.
34 Youssef-Ahmed MZ, Silver P, Nimkoff L
et al. Continuous infusion of ketamine in
mechanically ventilated children with refractory bronchospasm. Intensive Care Med
1996; 22: 972–976.
35 Ouedraogo N, Roux E, Forestier F et al.
Effects of intravenous anesthetics on normal
and passively sensitized human isolated airway smooth muscle. Anesthesiology 1998; 88:
317–326.
36 Bray RJ. Propofol infusion syndrome in children. Paediatr Anaesth 1998; 8: 491–499.
37 Becker AB, Nelson NA, Simons FE.
Inhaled salbutamol (albuterol) vs injected
epinephrine in the treatment of acute
asthma in children. J Pediatr 1983; 102:
465–469.
38 Sharma A, Madan A. Subcutaneous epinephrine vs nebulized salbutamol in asthma.
Indian J Pediatr 2001; 68: 1127–1130.
39 Wiebe K, Rowe BH. Nebulized racemic epinephrine used in the treatment of severe asthmatic exacerbation: a case report and
literature review. CJEM 2007; 9: 304–308.
40 Nair GB, Ilowite JS. Pharmacologic agents
for mucus clearance in bronchiectasis. Clin
Chest Med 2012; 33: 363–370.
41 Chia AC, Menzies D, McKeon DJ. Nebulised DNase post-therapeutic bronchoalveolar lavage in near fatal asthma exacerbation
in an adult patient refractory to conventional
treatment. BMJ Case Rep 2013; 2013. doi:
10.1136/bcr-2013-009661.
42 Hull JH, Castle N, Knight RK et al. Nebulised DNase in the treatment of life threatening asthma. Resuscitation 2007; 74: 175–177.
43 Durward A, Forte V, Shemie SD. Resolution
of mucus plugging and atelectasis after intratracheal rhDNase therapy in a mechanically
ventilated child with refractory status asthmaticus. Crit Care Med 2000; 28: 560–562.
44 Marquette CH, Saulnier F, Leroy O et al.
Long-term prognosis of near-fatal asthma. A
6-year follow-up study of 145 asthmatic
patients who underwent mechanical ventila-
© 2015 John Wiley & Sons Ltd
Pediatric Anesthesia 25 (2015) 460–467
Volatile anesthetics for status asthmaticus
45
46
47
48
49
50
51
52
53
54
55
tion for a near-fatal attack of asthma. Am
Rev Respir Dis 1992; 146: 76–81.
Zabrocki LA, Brogan TV, Statler KD et al.
Extracorporeal membrane oxygenation for
pediatric respiratory failure: survival and
predictors of mortality. Crit Care Med 2011;
39: 364–370.
Rehder KJ, Turner DA, Cheifetz IM. Extracorporeal membrane oxygenation for neonatal and pediatric respiratory failure: an
evidence-based review of the past decade
(2002-2012). Pediatric Crit Care Med 2013;
14: 851–861.
Turner DA, Heitz D, Cooper MK et al. Isoflurane for life-threatening bronchospasm: a
15-year single-center experience. Respir Care
2012; 57: 1857–1864.
Restrepo RD, Pettignano R, DeMeuse P.
Halothane, an effective infrequently used
drug, in the treatment of pediatric status
asthmaticus: a case report. J Asthma 2005;
42: 649–651.
Johnston RG, Noseworthy TW, Friesen EG
et al. Isoflurane therapy for status asthmaticus in children and adults. Chest 1990; 97:
698–701.
Maltais F, Sovilj M, Goldberg P et al. Respiratory mechanics in status asthmaticus.
Effects of inhalational anesthesia. Chest
1994; 106: 1401–1406.
Wheeler DS, Clapp CR, Ponaman ML et al.
Isoflurane therapy for status asthmaticus in
children: a case series and protocol. Pediatr
Crit Care Med 2000; 1: 55–59.
Tobias JD. Inhalational anesthesia: basic
pharmacology, end organ effects, and applications in the treatment of status asthmaticus. J Intensive Care Med 2009; 24: 361–371.
Vaschetto R, Bellotti E, Turucz E et al. Inhalational anesthetics in acute severe asthma.
Curr Drug Targets 2009; 10: 826–832.
von Ungern-Sternberg BS, Saudan S, Petak F et al. Desflurane but not sevoflurane
impairs airway and respiratory tissue
mechanics in children with susceptible
airways. Anesthesiology 2008; 108: 216–
224.
Kodama M, Satoh Y, Otsubo Y et al.
Neonatal desflurane exposure induces more
robust neuroapoptosis than do isoflurane
and sevoflurane and impairs working
memory. Anesthesiology 2011; 115: 979–
991.
56 Murray JM, Trinick TR. Plasma fluoride
concentrations during and after prolonged
anesthesia: a comparison of halothane and
isoflurane. Anest Analg 1992; 74: 236–240.
57 Best A, Wenstone R, Murphy P. Prolonged
use of isoflurane in asthma. Can J Anaesth
1994; 41: 452–453.
58 Amos RJ, Amess JA, Hinds CJ et al. Investigations into the effect of nitrous oxide anaesthesia on folate metabolism in patients
receiving intensive care. Chemioterapia 1985;
4: 393–399.
59 Char DS, Ibsen LM, Ramamoorthy C et al.
Volatile anesthetic rescue therapy in children
with acute asthma: innovative but costly or
just costly? Pediatric Crit Care Med 2013; 14:
343–350.
60 Miyagi T, Gushima Y, Matsumoto T et al.
Prolonged isoflurane anesthesia in a case of
catastrophic asthma. Acta paediatr Jpn 1997;
39: 375–378.
61 Takeyama K, Takaya T, Takiguchi M et al.
A case of status asthmatics relieved by longterm inhalation of isoflurane. Masui 1995;
44: 1559–1562.
62 du Peloux Menage H, Duffy S, Yates DW
et al. Reversible sensorimotor impairment
following prolonged ventilation with isoflurane and vecuronium for acute severe asthma.
Thorax 1992; 47: 1078–1079.
63 Parnass SM, Feld JM, Chamberlin WH et al.
Status asthmaticus treated with isoflurane
and enflurane. Anest Analg 1987; 66: 193–
195.
64 Arakawa H, Takizawa T, Tokuyama K et al.
Efficacy of inhaled anticholinergics and anesthesia in treatment of a patient in status asthmaticus. J Asthma 2002; 39: 77–80.
65 Rice M, Hatherill M, Murdoch IA. Rapid
response to isoflurane in refractory status asthmaticus. Arch Dis Child 1998; 78: 395–396.
66 Revell S, Greenhalgh D, Absalom SR et al.
Isoflurane in the treatment of asthma. Anaesthesia 1988; 43: 477–479.
67 Soro M, Badenes R, Garcia-Perez ML et al.
The accuracy of the anesthetic conserving
device (AnaConDa(c)) as an alternative to
the classical vaporizer in anesthesia. Anest
Analg 2010; 111: 1176–1179.
68 Tobias JD. Tolerance, withdrawal, and physical dependency after long-term sedation and
analgesia of children in the pediatric intensive
care unit. Crit Care Med 2000; 28: 2122–2132.
467