Download Intratracheal recombinant human deoxyribonuclease in acute life

British Journal of Anaesthesia 84 (4): 505–7 (2000)
Intratracheal recombinant human deoxyribonuclease in acute
life-threatening asthma refractory to conventional treatment
A. Patel, E. Harrison, A. Durward* and I. A. Murdoch
Department of Paediatric Intensive Care, Guy’s Hospital, St Thomas Street, London SE1 9RT, UK
*Corresponding author
Recombinant human deoxyribonuclease (rhDNase) is a mucolytic agent used to relieve
peripheral airway obstruction in patients with cystic fibrosis. We report dramatic sustained
improvement following the intratracheal administration of rhDNase to a 3-yr-old boy with
acute life-threatening asthma in whom 48 h of aggressive therapy had failed.
Br J Anaesth 2000; 84: 505–7
Keywords: complications, asthma; children; enzymes, recombinant human deoxyribonuclease
Accepted for publication: November 1, 1999
Cystic fibrosis is characterized by chronic airway inflammation caused by infection of thick secretions. The increased
viscosity of these secretions is caused by a large content
of extracellular deoxyribonucleic acid (DNA), from the
migration and death of neutrophils associated with the
inflammatory process.1 By altering sputum from a thick
viscous gel to a flowing liquid, recombinant human DNase
(rhDNase) can relieve peripheral airway obstruction and
improve respiratory symptoms and lung function in patients
with cystic fibrosis.2 In severe asthma, airflow obstruction
that does not respond to bronchodilators may be caused by
occlusion of the airways by mucous plugs and inflammatory
exudate. Elevated sputum DNA levels have been reported
in patients with acute asthma (with or without infection),3
so rhDNase may be effective as a mucolytic agent in
the treatment of patients with acute asthma. We describe
dramatic sustained improvement in airflow obstruction
following the intratracheal administration of rhDNase in a
child with acute life-threatening asthma that did not
respond to conventional treatment.
Case report
A 3-yr-old 15-kg boy with six previous hospital admissions
for asthma presented to his local hospital with a 24-h
history of wheeze and coryzal symptoms. His regular
medications were inhaled budesonide 400 µg and terbutaline twice daily. At the local hospital he failed to respond
to treatment with nebulized salbutamol 2.5 mg hourly,
hydrocortisone 60 mg i.v. 6-hourly and infusions of aminophylline 1 mg kg–1 h–1 and salbutamol 1 µg kg–1 min–1 i.v.
The patient deteriorated and after 9 h had respiratory arrest,
followed by tracheal intubation and mechanical ventilation.
Arterial blood gas analysis after intubation showed
pH 7.10, PaCO2 12.0 kPa, PaO2 12.3 kPa and base excess –
4.0 mmol litre–1 with manual ventilation, and FIO2 of 1.0. He
was transferred to the regional paediatric intensive care unit,
where mechanical ventilation was difficult and respiratory
acidosis persisted. The chest radiograph revealed marked
hyperinflation without segmental atelectasis. The blood leukocyte count was 24.3 ⫻ 109 litre–1 (neutrophils 22.4 ⫻ 109
litre–1) and Streptococcus pneumonii sensitive to all antibiotics was cultured from the bronchoalveolar lavage
performed on admission. He was treated with cefuroxime
300 mg i.v. 8-hourly. The patient was sedated with morphine
40 µg kg–1 h–1 and muscle relaxation was achieved with
vecuronium 100 µg kg–1 h–1. A lung protective strategy using
a Servo 900C ventilator with permissive hypercapnia was
adopted. Peak airway pressure was limited to 46 cm H2O,
with tidal volume from 76 ml (5.1 ml kg–1) to 97 ml (6.4 ml
kg–1) and a ventilation rate from 10 to 14 breath min–1. At
these settings, the severity of the airway obstruction was
evident from a marked decrease in inspiratory pause pressure
to 17–21 cm H2O. Over the subsequent 24 h, although oxygenation was adequate (PaO2 8.2–15.6 kPa, FIO2 0.6–0.8), the
respiratory acidosis persisted (pH 7.04–7.16, PaCO2 10.6–
17.5 kPa). Salbutamol therapy was increased to 6 µg kg–1
min–1, ketamine infusion was started at 30 µg kg–1 min–1 i.v.,
and magnesium sulphate 1 g given i.v. to achieve bronchodilation, but this was unsuccessful. General anaesthesia using
isoflurane for bronchodilation also failed to relieve airflow
obstruction. The expired concentration of isoflurane was
maintained at 1%, monitored via a connection from the
DATEX AS/3TM gas analyser placed between the Y connector
and endotracheal tube.
With no improvement in ventilation after 48 h of this
therapy and physiotherapy with saline lavage (0.9% saline
5 ml), we decided to give intratracheal rhDNase in an attempt
to reverse the airflow obstruction.
RhDNase 2.5 mg was dissolved in 0.9% saline 10 ml and
© The Board of Management and Trustees of the British Journal of Anaesthesia 2000
Patel et al.
Fig 1 Expiratory tidal volume (closed circles) and arterial PCO2 (open
circles) against time from admission.
half of this volume (5 ml) was given via an 8F feeding catheter
into the trachea with the patient placed in the right lateral
position. Manual ventilation was carried out during the procedure, the peak airway pressure not exceeding 45 cm H2O.
After 15 min of manual ventilation and vigorous physiotherapy, the procedure was repeated with the patient in the left
lateral position. Tracheal suction was performed after 30 min
and clear loose secretions were removed. Within 30 min
a dramatic, sustained improvement in ventilation occurred,
allowing a reduction in the peak airway pressure from 44 to
less than 26 cm H2O with a corresponding increase in expired
tidal volume from 93 to 196 ml (Fig. 1). The arterial blood
gas improved, with an increase in pH from 7.17 to 7.41 and
a decrease in PCO2 from 13.8 to 7.6 kPa within 3 h of the
procedure. This improvement was sustained; the tracheal tube
was removed 72 h after rhDNase therapy and the patient
made an uneventful recovery.
Discussion
In acute severe asthma, airflow obstruction is caused
by bronchospasm, airway inflammation and mucous
plugging.4 5 Conventional treatment aims to decrease
bronchospasm with bronchodilator therapy and airway
inflammation with steroid therapy, and provide supportive
care with mechanical ventilation. In most patients conventional treatment is effective, although a small number of
patients may fail to improve, deteriorate and eventually die
from asphyxia due to severe airflow obstruction.5 Post mortem examinations of patients who have died from severe
asthma have shown widespread severe mucous plugging of
the airways.6
This patient failed to respond to conventional treatment
with bronchodilator therapy with i.v. salbutamol, corticosteroids, magnesium sulphate, ketamine and isoflurane. Following the use of the mucolytic agent rhDNase, a dramatic
sustained improvement was observed in ventilation, with
resolution of the respiratory acidosis. This improvement
appeared to be directly related to the intratracheal administration of rhDNase and not simply the result
of the vigorous physiotherapy that had been performed at
regular intervals without effect. Sudden responsiveness to
bronchodilator therapy would be unusual after 48 h of maximum medical treatment that included steroids. Manual alveolar recruitment is also unlikely to explain the
improvement because the airway pressures used during the
instillation of rhDNase were similar to those used during
conventional mechanical ventilation.
A role for mucolytic therapy in refractory status
asthmaticus has been suggested, with the use of the mucolytic
agent acetylcysteine.4 However, this is irritant and can
aggravate bronchospasm, making its use in a patient with
severe ventilatory difficulties questionable. Nebulized
rhDNase has also been proposed as a mucolytic in nonintubated asthmatic patients with lobar atelectasis.7 Direct
administration of rhDNase by bronchoscopy into regions of
mucous plugging has been reported in intubated,
mechanically ventilated asthmatic patients.8 9 In both of these
cases lobar atelectasis cleared completely within hours of
administration. In the absence of clinical or radiological evidence of segmental atelectasis, bronchoscopy was not
attempted in our patient. Bronchoscopy can help in the management of refractory status asthmaticus with mucous plugging, although its efficacy in diffuse small airway mucous
plugging is unknown.4
In contrast to all previous reports,7–9 this case, to our knowledge, is the first to describe an improvement in airflow obstruction in the absence of lobar atelectasis. This may
be of importance in those asthmatic patients who
do not respond to conventional treatment because of
unrecognized diffuse small airway mucous plugging. The
proposed mechanism of action of rhDNase in acute asthma
is a reduction in the viscoelastic properties of mucous plugs,
by the hydrolysis of extracellular DNA derived from degenerating leucocytes and epithelial debris.9 Other factors that may
also be important include the alteration of mucous clearance
mechanisms by enhanced ciliary function and the mobilization of secretions.10 We found rhDNase to be well tolerated
and without side-effects, as have previous reports,7–9 although
dose-dependent mucosal airway damage with haemoptysis
due to increased airway protease activity may occur.1 11
Despite advances in the medical management of acute
asthma and improved ventilatory strategies, a small number
of patients still develop life-threatening airflow obstruction
refractory to therapy. In such patients the potential benefits
and apparent safety of rhDNase may be preferred to other
options, such as extracorporeal membrane oxygenation.
In summary, we describe dramatic reversal of airflow obstruction following the intratracheal administration
of rhDNase in a ventilated child with refractory status asthmaticus.
References
506
1 Ramsey B, Dorkin HL. Consensus Conference: Practical
applications of pulmozyme. Paediatr Pulmonol 1994; 17: 404–8
2 Geddes DM, Shah PL. Where are we now with rhDNase? Lancet
1999; 353: 1727
rhDNase in life-threatening asthma
3 Fahy JV, Liu J, Wong H, Boushey HA. Cellular and biochemical
analysis of induced sputum from asthmatic and healthy patients. Am
Rev Resp Dis 1993; 147: 1126–31
4 Henke CA, Hertz M, Gustafson P. Combined bronchoscopy
and mucolytic therapy for patients with severe refractory
status asthmaticus on mechanical ventilation: a case
report and review of the literature. Crit Care Med 1994; 22:1880–3
5 Benatar SR. Fatal asthma. N Engl J Med 1986; 314: 423–9
6 Hogg JC. Varieties of airway narrowing in severe and fatal asthma.
J Allergy Clin Immunol 1987; 80: 417–9
7 Puterman AS, Weinberg EG. rhDNase in acute asthma. Paediatr
Pulmonol 1997; 23: 316–31
8 Greally P. Human recombinant DNase for mucous plugging in
status asthmaticus. Lancet 1995; 346: 1423–4
9 Durward A, Forte V, Shemie S. Resolution of mucous plugging and
atelectasis after intratracheal rhDNase therapy in a mechanically
ventilated child with refractory status asthmaticus. Crit Care Med
2000; 27: 560–2
10 Puchelle E, Zahm JM, de Bentzman S, Grosskopf C, Shak S, Mongel
D, Pohn JM. Effects of rhDNase on purulent airway secretions in
chronic bronchitis. Eur Respir J 1996; 9: 765–6
11 Rochat T, Pastore FD, Schlegel-Hauter SE, Filthuth I, Auckenthaler
R, Bell D, Suter S. Aerosolized rhDNase in cystic fibrosis: Effect
on leucocyte proteases in sputum. Eur Respir J 1996; 9: 2200–20
507