Recombinant Human Deoxyribonuclease Shortens Ventilation Time in Young, Mechanically Ventilated Children†
Corresponding Author
Joachim Riethmueller MD
Department of Pediatrics, University Children's Hospital, Tübingen, Germany
Department of Pediatrics, Tübingen University Children's Hospital, Hoppe-Seyler-Str. 1, D-72076 Tübingen, Germany.Search for more papers by this authorThomas Borth-Bruhns MD
Department of Pediatrics, University Children's Hospital, Tübingen, Germany
Search for more papers by this authorMatthias Kumpf MD
Department of Pediatrics, University Children's Hospital, Tübingen, Germany
Search for more papers by this authorReinhard Vonthein MD
Department of Medical Biometry, University of Tübingen, Tübingen, Germany
Search for more papers by this authorJakub Wiskirchen MD
Department of Radiology, University of Tübingen, Tübingen, Germany
Search for more papers by this authorMartin Stern MD
Department of Pediatrics, University Children's Hospital, Tübingen, Germany
Search for more papers by this authorMichael Hofbeck MD
Department of Pediatrics, University Children's Hospital, Tübingen, Germany
Search for more papers by this authorWinfried Baden MD
Department of Pediatrics, University Children's Hospital, Tübingen, Germany
Search for more papers by this authorCorresponding Author
Joachim Riethmueller MD
Department of Pediatrics, University Children's Hospital, Tübingen, Germany
Department of Pediatrics, Tübingen University Children's Hospital, Hoppe-Seyler-Str. 1, D-72076 Tübingen, Germany.Search for more papers by this authorThomas Borth-Bruhns MD
Department of Pediatrics, University Children's Hospital, Tübingen, Germany
Search for more papers by this authorMatthias Kumpf MD
Department of Pediatrics, University Children's Hospital, Tübingen, Germany
Search for more papers by this authorReinhard Vonthein MD
Department of Medical Biometry, University of Tübingen, Tübingen, Germany
Search for more papers by this authorJakub Wiskirchen MD
Department of Radiology, University of Tübingen, Tübingen, Germany
Search for more papers by this authorMartin Stern MD
Department of Pediatrics, University Children's Hospital, Tübingen, Germany
Search for more papers by this authorMichael Hofbeck MD
Department of Pediatrics, University Children's Hospital, Tübingen, Germany
Search for more papers by this authorWinfried Baden MD
Department of Pediatrics, University Children's Hospital, Tübingen, Germany
Search for more papers by this authorConflict of interest statement: J.R. has participated as a speaker in scientific meetings or courses organized and financed by Hoffmann La Roche, Grenzach.
Abstract
Recombinant human deoxyribonuclease I (dornase alfa) is currently used as an inhaled mucoactive agent in the treatment of cystic fibrosis. In a randomized, placebo-controlled, double-blind clinical study in 100 infants, we investigated whether the therapeutic use of dornase alfa can be extended to ventilated, fluid-restricted children to reduce reintubation rate, ventilation duration, pediatric intensive care unit (PICU) stay, and ventilation complications. While reintubation rates were similar for dornase alfa 7% vs. placebo 9% (odds ratio, 0.77; confidence interval, 0.11–4.9), the incidence of atelectasis (6 vs. 17, respectively; P-value 0.051), median ventilation time (2.2 vs. 3.4 days, respectively; P-value 0.043), median length of PICU stay (7 vs. 8 days, respectively; P-value 0.051), and mean costs (€4,830 vs. €6,320, respectively) were lower in the dornase alfa group. No adverse effects were observed, even in critically ill patients. We found that dornase alfa was beneficial and safe. Our findings also indicate that dornase alfa is possibly of value from the first day of mechanical ventilation onward, particularly when longer ventilation (>3 days) is expected in fluid-restricted children after cardiac surgery. Pediatr Pulmonol. © 2005 Wiley-Liss, Inc.
REFERENCES
- 1 Kondo CS, Macchionne M, Nakagawa NK, Ribeiro de Carvalho CR, King M, Saldiva PHN, Lorenzi-Filho G. Effects of intravenous furosemide on mucociliary transport and rheological properties of patients under mechanical ventilation. Crit Care Med 2002; 6: 81–87.
- 2 Thomas KMA, Habibi P, Britto J, Owens CM. Distribution and pathophysiology of acute lobar collapse in the pediatric intensive care unit. Crit Care Med 1999; 27: 1594–1597.
- 3 Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, Rosenstein BJ, Smith AL, Wohl ME, for the Pulmozyme Study Group. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with Cystic Fibrosis. N Engl J Med 1994; 331: 637–642.
- 4 Aitken ML, Burke W, McDonald G, Shak S, Montgomery AB, Smith A. Recombinant human DNase inhalation in normal subjects and patients with cystic fibrosis. A phase 1 study. JAMA 1992; 267: 1947–1951.
- 5
Harms HK,
Matouk E,
Tournier G,
von der Hardt H,
Weller PH,
Romano L,
Heijerman HG,
Fitzgerald FX,
Richard D,
Strandvik B,
Kolbe J,
Kraemer R,
Michalsen H.
Multicenter, open-label study of recombinant human DNase in cystic fibrosis patients with moderate lung disease. DNase International Study Group.
Pediatr Pulmonol
1998;
26:
155–161.
10.1002/(SICI)1099-0496(199809)26:3<155::AID-PPUL1>3.0.CO;2-K CAS PubMed Web of Science® Google Scholar
- 6 Quan JM, Tiddens HAWM, Sy JP, McKenzie SG, Montgomery MD, Robinson PJ, Wohl MEB, Konstan MW. A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities. J Pediatr 2001; 139: 813–820.
- 7 Rochat T, Pastore FD, Schlegel-Häuter SE, Filthuth I, Auckenthaler R, Belli D, Suter S. Aerosolized rhDNase in cystic fibrosis: effect on leucocyte proteases in sputum. Eur Respir J 1996; 9: 2200–2206.
- 8
Dasgupta B,
King M.
Reduction in viscoelasticity in cystic fibrosis sputum in vitro using combined treatment with nacystelyn and rhDNase.
Pediatr Pulmonol
1996;
22:
161–166.
10.1002/(SICI)1099-0496(199609)22:3<161::AID-PPUL4>3.0.CO;2-S CAS PubMed Web of Science® Google Scholar
- 9 Kirchner KK, Wagener JS, Khan TZ, Copenhaver SC, Accurso FJ. Increased DNA levels in bronchoalveolar lavage fluid obtained from infants with cystic fibrosis. Am J Respir Crit Care Med 1996; 154: 1426–1429.
- 10 Shah PL, Scott SF, Knight RA, Marriott C, Ranashina C, Hodson ME. In vivo effect of rhDNase I on sputum in patients with cystic fibrosis. Thorax 1996; 51: 119–125.
- 11 O'Donnell AE, Barker AF, Ilowite JS, Fick RB. Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I. RhDNase Study Group. Chest 1998; 113: 1329–1334.
- 12 Wills PJ, Wodehouse T, Corkery K, Mallon K, Wilson R, Cole PJ. Short-term recombinant human DNase in bronchiectasis. Effect on clinical state and in vitro sputum transportability. Am J Respir Crit Care Med 1996; 154: 413–417.
- 13 Touleimat BA, Conoscenti CS, Fine JM. Recombinant human DNase in management of lobar atelectasis due to retained secretions. Thorax 1995; 50: 1319–1321.
- 14
Boeuf B,
Prouix F,
Morneau S,
Marton D,
Lacroix J.
Safety of endotracheal rhDNase for treatment of pulmonary atelectasis in mechanically ventilated children.
Pediatr Pulmonol
1998;
26:
147.
10.1002/(SICI)1099-0496(199808)26:2<147::AID-PPUL14>3.0.CO;2-1 CAS PubMed Web of Science® Google Scholar
- 15 Voelker KG, Chetty KG, Mahutte CK. Resolution of recurrent atelectasis in spinal cord injury patients with administration of recombinant human DNase. Intensive Care Med 1996; 22: 582–584.
- 16 Desai M, Weller PH, Spencer DA. Clinical benefit from nebulized human recombinant DNase in Kartagener's syndrome. Pediatr Pulmonol 1995; 20: 307–308.
- 17 Puterman AS, Weinberg EG. RhDNase in acute asthma. Pediatr Pulmonol 1997; 23: 316–317.
- 18 Puchelle E, Zahm JM, de Nentzmann S, Grosskopf C, Shak S, Mougel D, Polu JM. Effects of rhDNase on purulent airway secretions in chronic bronchitis. Eur Respir J 1996; 9: 765–769.
- 19 Nasr SZ, Strouse PJ, Soskolne E, Maxvold NJ, Garver KA, Rubin BK, Moler FW. Efficacy of recombinant human deoxyribonuclease I in the hospital management of respiratory syncytial virus bronchiolitis. Chest 2001; 120: 203–208.
- 20 Reiter PD, Townsend SF, Velasquez R. Dornase alfa in premature infants with severe respiratory distress and early bronchopulmonary dysplasia. J Perinatol 2000; 20: 530–534.
- 21 Spiegelhalter D, Thomas A, Best N, Lunn D. WinBUGS user manual, version 1.4.1. http://www.mrc-bsu.cam.ac.uk/bugs [September 13, 2004].
- 22 O'Hagan A, Luce BR. A primer on Bayesian statistics in health economics and outcomes research. Sheffield: CHEBS; 2003.
- 23 Green JD. Pharmaco-toxicological expert report. Pulmozyme rhDNase, Genentech, Inc. Hum Exp Toxicol [Suppl] 1994; 13: 1–42.
- 24 Bloomfield FH, Teele RL, Voss M, Knight DB, Harding JE. Inter- and intra-observer variability in the assessment of atelectasis and consolidation in neonatal chest radiographs. Pediatr Radiol 1999; 29: 45–462.
- 25 Peroni DG, Boner AL. Atelectasis: mechanisms, diagnosis and management. Paediatr Respir Rev 2000; 1: 274–278.
- 26 van Kaam AH, Lachmann RA, Herting E, De Jaegere A, van Iwaarden F, Noorduyn LA, Kok JH, Haitsma JJ, Lachmann B. Reducing atelectasis attenuates bacterial growth and translocation in experimental pneumonia. Am J Respir Crit Care Med 2004; 169: 1046–1053.
- 27 Brix-Christensen V. The systemic inflammatory response after cardiac surgery with cardiopulmonary bypass in children. Acta Anaesthesiol Scand 2001; 45: 671–679.
- 28 Massoudy P, Zahler S, Becker BF, Braun SL, Barankay A, Meisner H. Evidence for inflammatory responses of the lungs during coronary artery bypass grafting with cardiopulmonary bypass. Chest 2001; 119: 31–36.
- 29
Martin GS.
Fluid balance and colloid osmotic pressure in acute respiratory failure: emerging clinical evidence.
Crit Care [Suppl]
2000;
4:
21–25.
10.1186/cc966 Google Scholar
- 30 Reising CA, Chendrasekhar A, Wall PL, Paradise NF, Timberlake GA, Moorman DW. Continuous dose furosemide as a therapeutic approach to acute respiratory distress syndrome (ARDS). J Surg Res 1999; 82: 56–60.
- 31 Bancalari E, Jesse MJ, Gelband H, Gracia M. Lung mechanics in congenital heart disease with increased and decreased pulmonary blood flow. Pediatrics 1977; 90: 192–195.
- 32 Howlett G. Lung mechanics in normal infants and infants with congenital heart disease. Arch Dis Child 1972; 47: 707–715.
- 33
Yau K,
Fang L,
Wu M.
Lung mechanics in infants with left-to-right shunt congenital heart disease.
Pediatr Pulmonol
1996;
21:
42–47.
10.1002/(SICI)1099-0496(199601)21:1<42::AID-PPUL7>3.0.CO;2-S CAS PubMed Web of Science® Google Scholar
- 34 Puchelle E, de Bentzmann S, Zahm JM. Physical and functional properties of airway secretions in cystic fibrosis—therapeutic approaches. Respiration [Suppl] 1995; 62: 2–12.