BJA Advance Access published July 24, 2013

British Journal of Anaesthesia Page 1 of 4

doi:10.1093/bja/aet257

Sevoflurane therapy for life-threatening asthma in children

D. Schutte 1*, A. M. Zwitserloot 2, R. Houmes 3, M. de Hoog3, J. M. Draaisma 2 and J. Lemson 1

1
Department of Intensive Care Medicine and 2 Department of Paediatrics, Radboud University Nijmegen Medical Centre, PO Box 9101
Nijmegen, 6500 HB, The Netherlands
3
Department of Paediatric Intensive Care, Erasmus MC-Sophia Childrens Hospital, Rotterdam, The Netherlands
* Corresponding author. E-mail: [email protected]

Background. Asthma is a common disease in children and often develops early in life. This
Editors key points multicentre retrospective case series describe the use and effectiveness of sevoflurane
Children with inhalation therapy in a series of children with severe asthma in the paediatric intensive care
life-threatening asthma unit (PICU).
are successfully treated Methods. Seven children ranging from 4 to 13 yr of age admitted to the PICU of two tertiary
with sevoflurane care hospitals in the Netherlands were included. They all were admitted with the diag-
inhalation therapy nosis of severe asthma requiring invasive mechanical ventilation and were treated with
without serious sevoflurane inhalation therapy.

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side-effects.
Results. The median (range) PCO2 level at the start, after 2 h, and at the end of sevoflurane
Sevoflurane treatment were 14 (5.1 24.8), 9.8 (5.4 17.0), and 6.2 (4.5 11.4) kPa (P0.05) while the
administration corrects median (range) pH was 7.02 (6.97 7.36), 7.18 (7.04 7.35), and 7.43 (7.15 7.47) kPa
high levels of PCO2 and (P0.01), respectively. The median (range) peak pressure values declined from 30 (23 56)
provides clinical to 20.4 (14 33) cm H2O (P0.03). No severe adverse effects besides hypotension, with
improvement within the sufficient response to norepinephrine treatment, were seen.
first hours.
Conclusions. Sevoflurane inhalation corrects high levels of PCO2 and provides clinical
Prospective research is improvement in mechanically ventilated children with life-threatening asthma who fail to
required to further explore respond to conventional treatment.
the position of
sevoflurane as rescue Keywords: anesthetics, inhalation; asthma; pediatrics; sevoflurane
medication. Accepted for publication: 5 June 2013

Asthma is a common disease in children and often develops of life-threatening asthma in children.4 8 10 These agents
early in life. It is a chronic inflammation of the airways, with provide a reversal of bronchospasm in humans as well, but
reversible airflow obstruction and enhanced bronchial re- the exact mechanism of its effect is not clear.11 The proposed
activity.1 In Western Europe, the prevalence is 9.7% in children mechanisms include lowering of vagal tone, direct relaxation
from 6 to 7 yr old and 15.8% in children from 13 to 14 yr old.2 Of of smooth muscle tissue, inhibition of the release of broncho-
these children, respectively, 12.6 and 15.2% have severe constrictive mediators, and synergy with catecholamines.4 11
asthma; 9% of the children with asthma visit an emergency Sevoflurane is a newer volatile anaesthetic agent, and is fre-
department while 2% need hospitalization.2 3 A severe asthma quently used in children for the induction and maintenance
attack requiring hospitalization is treated with oxygen, corti- of anaesthesia. It has a low blood to gas solubility coefficient
costeroids, and b2-agonists, either nebulized or i.v., in combin- and for this reason provides a rapid and smooth inhaled induc-
ation with anticholinergic agents and magnesium sulphate. tion.12 An animal study showed the beneficial effect of sevo-
Life-threatening asthma requires invasive interventions like flurane on asthmatic bronchoconstriction, which was later
mechanical ventilation and can even be fatal.4 5 There is a posi- confirmed in humans.13 15 We describe a multicentre retro-
tive correlation between asthma prevalence in children and spective case series of the use of sevoflurane therapy in chil-
the amount of hospital admissions and mortality rate.6 It dren with asthma on the paediatric intensive care unit (PICU).
seems, therefore, important to develop more efficient therap-
ies to prevent death in children because of this disease. In 2004,
an animal study demonstrated that volatile agents reverse Methods
bronchoconstriction in sensitized guinea pigs.7 For several In the PICU database with all patient admission data of two
years, inhalation of volatile anaesthetics, such as halothane university teaching hospitals, children admitted with asthma
and isoflurane, have been used as last resort for the treatment over a period of 10 yr (2002 2012) were collected. Children

& The Author [2013]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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BJA Schutte et al.

who did not receive mechanical ventilation were excluded.

Medical records of the remaining children were analysed. Chil- 7.6
dren who were treated with sevoflurane inhalation therapy
7.5
with a dedicated anaesthesia system were identified and
reviewed. Patient characteristic data, medical history, provoca- 7.4

tion factor for the current asthma attack, and medication 7.3
before hospitalization were gathered. To determine the effect

pH (kPa)
7.2
of sevoflurane therapy, blood gas and mechanical ventilation
7.1
parameters, other medication used, and the dose and duration
7
of sevoflurane therapy were collected. Outcomes included
clinical improvement of the patient as a subjective measure. 6.9
Objective measures were improvement of blood gas and 6.8
mechanical ventilation parameters, and duration of PICU
6.7
stay. Statistical analysis of the changes in blood gas and mech- Start First assessment End
anical ventilation parameters after administration of sevoflur-
Patient 1 Patient 2 Patient 3
ane was performed with the Mann Whitney U-test and a Patient 4 Patient 5 Patient 6
P-value of ,0.05 was considered statistically significant. Patient 7

Results

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Fig 1 pH values per patient before, after a first assessment, and at
the end of treatment with sevoflurane. The dashed line shows the
A total of seven children (age range 413 yr) were included.
patient who did not respond to sevoflurane therapy.
One patient presented with a first exacerbation of asthma
and had not been previously diagnosed with this disease. All
other patients used daily asthma medication, varying from
beclomethason, fluticasone, salmeterol in combination with
fluticasone, and montelukast, in combination with salbutamol
when necessary. Five patients had no history of hospitalization 30
for asthma exacerbations, and in six children, the asthma
attack was triggered because of a viral or bacterial infection. 25
All patients received oxygen and multiple inhalations with
20
salbutamol and ipratropium bromide, followed by i.v. prednis-
PCO2 (kPa)

olone, salbutamol, and magnesium sulphate. They showed

15
no improvement of oxygenation and ventilation with the con-
ventional treatment. Because of life-threatening respiratory 10
muscle fatigue or altered mental status, the patients were
sedated and intubated with a varying combination of propofol, 5
morphine, rocuronium, esketamine, and midazolam. Sevoflur-
ane treatment was indicated because of respiratory acidosis 0
Start First assessment End
(n5), hypoxaemia (n1), or a combination (n1). Sevoflur-
Patient 1 Patient 2 Patient 3
ane was administered for a median duration of 24 h, with a
Patient 4 Patient 5 Patient 6
range of 0.590 h. The peak concentration of sevoflurane
Patient 7
ranged from 1 to 8%. Six patients showed an immediate clinical
improvement and a progressive correction of blood gas para-
meters and peak pressures. In Figures 13, individual improve- Fig 2 PCO2 values per patient before, after a first assessment, and at
ment of blood gas parameters is displayed. The first the end of treatment with sevoflurane. The dashed line shows the
assessment point is 23 h after the start of the treatment, patient who did not respond to sevoflurane therapy.

except for the patient who only received 0.5 h sevoflurane.

The endpoint in the figures varies from 0.5 to 90 h. There was
a significant improvement in PaCO2 , pH, and peak pressure at sevoflurane treatment; afterwards, he was diagnosed with
the end of treatment compared with the start. The median acute respiratory distress syndrome (ARDS). Five patients
(range) PaCO2 levels at the start, at the first assessment, and developed hypotension; of which, four received norepineph-
at the end of sevoflurane treatment were 14 (5.1 24.8), 9.8 rine (0.1 0.6 mg kg h) as vasoactive support, effectively
(5.4 17.0), and 6.2 (4.5 11.4) kPa (P0.05) while the median increasing the arterial pressure. One patient had pupils unre-
(range) pH was 7.02 (6.97 7.36), 7.18 (7.04 7.35), and 7.43 active to light for a short period. There was no evidence of
(7.15 7.47) kPa (P0.01), respectively. The median (range) other complications. The length of PICU stay ranged from
peak pressure values normalized from 30 (23 56) to 20.4 3 to 10 days. All patients survived and were discharged from
(14 33) cm H2O (P0.03). One patient failed to respond to the hospital within 14 days.

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Sevoflurane therapy for life-threatening asthma BJA
In the treatment of our patients, there was a variation in the
50 dose of sevoflurane from 1 to 8%; the duration of adminis-
45
tration varied from 0.5 to 90 h. This variation can be explained
by patient factors, such as the age, severity of and duration of
40
the asthma attack, and by preference or experience of the
Peak pressure (cm H2O)

35
treating physician. Dose and duration should be individually
30 titrated to effect. High-dose sevoflurane can have several
25 adverse effects. Epileptiform activity is seen in electroence-
20 phalograms, which is occasionally accompanied by clinical
15 manifestation of seizures, however without clinical sequalae.11
10 Furthermore, there can be a dose-related effect on arterial
pressure and heart rate. Theoretically, sevoflurane is asso-
5
ciated with nephrotoxicity related to the release of fluoride
0
Start End during metabolism, but clinical signs of nephrotoxicity are
Patient 1 Patient 2 Patient 3
rare.8 Hepatotoxicity is an important adverse effect of the
Patient 4 Patient 5 Patient 6 other volatile anaesthetics, related to immune-mediated
Patient 7 hepatitis caused by trifluoroacetic acid (TFA), a metabolic
product. Sevoflurane is metabolized in a different way than
the other agents and does not produce TFA and thereby does

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Fig 3 Peak pressure values per patient before and at the end of
not cause hepatotoxicity.11 The only adverse effect we
treatment with sevoflurane. The dashed line shows the patient
who did not respond to sevoflurane therapy. observed was hypotension but that was successfully treated
with norepinephrine. One patient had pupils unreactive to
light for a short period; no other symptoms of neuropathy
occurred. We cannot explain this symptom, but it is known
that nebulized ipratropium bromide sometimes causes this
Discussion effect.19 20 The patient received multiple doses of nebulized
This study shows that children with life-threatening asthma ipatropium and salbutamol as first treatment modality.
are successfully treated with sevoflurane inhalation therapy One drawback for the use of sevoflurane is the introduction
without serious side-effects. These results are consistent with of an anaesthesia machine on the PICU. Most PICUs do not
published single cases.14 15 Almost all patients showed a have the equipment needed for the safe delivery of sevoflur-
clinical improvement within an hour after administration of ane, the technology is often not known to the PICU personnel,
sevoflurane. Improved blood gas parameters and peak pres- and exhaled gas evacuation is mandatory. All PICUs should
sures after 2 h confirm this improvement. All other medication consider procuring such options and cooperate with the local
was continued after administration of sevoflurane in equal anaesthesia department. There has been a report where sevo-
dosages; therefore, it is very likely that the observed positive flurane is used in combination with non-invasive ventilation.21
effect was induced by sevoflurane. It seems sensible to de- However, since children with very severe asthma are already
crease the dose of sedative drugs during sevoflurane therapy intubated, this will not be possible in these children. On the
guided by sedation scoring. other hand, in less severe cases, it is questionable if the cost
One patient in our study did not respond to the therapy. He benefit of administering sevoflurane by a face mask is more
was afterwards judged to have ARDS related to pneumonia; beneficial compared with salbutamol inhalation or i.v. therapy.
gas exchange in this patient indeed improved with the inhal- Although there are limitations of our study, like the
ation of nitric oxide. retrospective nature, the chance of missing a few patients
In the past, older volatile anaesthetics have shown to be because of the retrospective nature, and the small number of
lifesaving for children with life-threatening asthma with persist- patients, we conclude that sevoflurane should be considered
ent hypercapnia, hypoxaemia, and respiratory acidosis.4 7 8 as rescue therapy in children with life-threatening asthma
Sevoflurane is a newer anaesthetic, and is safely used in children who fail to respond to conventional treatment.
for the induction and maintenance of anaesthesia. Habre and
colleagues described a negative effect of sevoflurane in children
with asthma receiving sevoflurane as induction of anaesthesia, Authors contributions
it increased the respiratory system resistance.12 However, D.S. designed the study, collected the data, performed all statis-
others described beneficial effects in which sevoflurane tics, wrote the manuscript, and approved the final manuscript
caused a greater decrease in airway resistance compared with as submitted. A.M.Z. assisted in the design of the study and
halothane or isoflurane.16 18 Furthermore, sevoflurane pro- assisted in the writing of the manuscript, reviewed and revised
vides a favourable haemodynamic profile, a lower metabolic the manuscript, and approved the final manuscript as submitted.
rate, and most importantly increased bronchodilator prop- M.H. provided the data of some of the patients, reviewed and
erties and less adverse effects than the older anaesthetic revised the manuscript, and approved the final manuscript as
volatile agents.9 13 16 18 submitted. R.H. provided the data of some of the patients,

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BJA Schutte et al.

reviewed and revised the manuscript, and approved the final 9 Shankar V, Churchwell KB, Deshpande JK. Isoflurane therapy for
manuscript as submitted. J.M.D. reviewed and revised the manu- severe refractory status asthmaticus in children. Intensive Care
script, and approved the final manuscript as submitted. J.L. Med 2006; 32: 927 33
assisted in the writing of the manuscript, supervised the study, 10 Turner DA, Heitz D, Cooper MK, Smith PB, Arnold JH, Bateman ST. Iso-
flurane for life-threatening bronchospasm: a 15-year single-center
reviewed and revised the manuscript, and approved the final
experience. Respir Care 2012; 57: 185764
manuscript as submitted.
11 Tobias JD. Inhalation anesthesia: basic pharmacology, end organ
effects, and applications in the treatment of status asthmaticus.
Declaration of interest J Int Care Med 2009; 24: 36171
12 Habre W, Scalfaro P, Sims C, Tiller K, Sly PD. Respiratory mechanics
None declared.
during sevoflurane anesthesia in children with and without asth-
ma. Anesth Analg 1999; 89: 117781
Funding 13 Burburan SM, Xisto DG, Ferreira HC, et al. Lung mechanics and hist-
No external funding was obtained for this study. ology during sevoflurane anesthesia in a model of chronic allergic
asthma. Anesth Analg 2007; 104: 631 7
14 Watanabe K, Mizutani T, Yamashita S, Tatekawa Y, Jinbo T, Tanaka M.
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Handling editor: M. M. R. F. Struys

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