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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