Noninvasive mechanical ventilation in acute respiratory failure

European Respiratory Journal

Volumn 9, Issue 4, 1996, Pages 795-807

  Ambrosino, N ^a  

^a IRCCS   (Italy)

Author keywords

Chronic obstructive pulmonary disease; chronic respiratory failure; endotracheal intubation; respiratory muscles; tracheostomy

Indexed keywords

ACUTE RESPIRATORY FAILURE; ARTIFICIAL VENTILATION; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL ARTICLE; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; ENDOTRACHEAL INTUBATION; HUMAN; INTENSIVE CARE; PATIENT SELECTION; POSITIVE END EXPIRATORY PRESSURE; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; REVIEW; SURVIVAL RATE; TRACHEOSTOMY; TREATMENT INDICATION; TREATMENT OUTCOME;

ACIDOSIS; CLINICAL TRIALS; COMPLIANCE; EQUIPMENT DESIGN; HUMANS; INTENSIVE CARE UNITS; INTUBATION, INTRATRACHEAL; LUNG DISEASES, OBSTRUCTIVE; RESPIRATION, ARTIFICIAL; RESPIRATORY INSUFFICIENCY; SEVERITY OF ILLNESS INDEX; VENTILATOR WEANING;

EID: 0029938462     PISSN: 09031936     EISSN: None     Source Type: Journal    
DOI: 10.1183/09031936.96.09040795     Document Type: Review

References (116)

1. Derenne JP, Fleury B, Pariente R. Acute respiratory failure of chronic obstructive pulmonary disease. Am Rev Respir Dis 1988; 138: 1006-1033.
2. Petty TL. Chronic airflow obstruction. In: Petty TL ed. Intensive and Rehabilitative Respiratory Care. Philadelphia, Lea and Febiger, 1982; pp. 222-245.
3. Tobin MJ. Mechanical ventilation. N Engl J Med 1994; 130: 1056-1061.
4. Pingleton S. Complications of acute respiratory failure. Am Rev Respir Dis 1988; 137: 1463-1493.
5. Rashkin MC, Davis T. Acute complications of endotracheal intubation. Chest 1986; 89: 165-167.
6. Heffner JE, Miller KS, Sahn SA. Tracheostomy in the intensive care unit. Part 2. Complications. Chest 1986; 90: 430-436.
7. Criner G, Make B, Celli B. Respiratory muscle dysfunction secondary to chronic tracheostomy tube placement. Chest 1987; 91: 139-141.
8. Deutschman CS, Wilton P, Sinow J, Dibbell D, Konstantinides FN, Cerra FB. Paranasal sinusitis associated with nasotracheal intubation: a frequently unrecognized and treatable source of sepsis. Crit Care Med 1986; 14: 11-114.
9. Torres A, Aznar R Gatell JM, et al. Incidence, risk and prognosis factors of nosocomial pneumonia in mechanically ventilated patients. Am Rev Respir Dis 1990; 142: 523-528.
10. Fagon JY, Chastre J, Hance A, Montravers P, Novara A, Gibert C. Nosocomial pneumonia in ventilated patients: a cohort study evaluating attributable mortality and hospital stay. Am J Med 1993; 94: 281-287.
11. Kingston GW, Phang PT, Leathley MJ. Increased incidence of nosocomial pneumonia in mechanically-ventilated patients with subclinical aspiration. Am J Surg 1991; 161: 589-592.
12. Shapiro M, Wilson RK, Casar G, Bloom K Teague RB. Work of breathing through different sized endotracheal rubes. Crit Care Med 1986; 14: 1028-1031.
13. Le Bourdelles G, Vires N, Bockzowki, Seta N, Pavolovic D, Aubier M. Effects of mechanical ventilation on diaphragmatic contractile properties in rats. Am J Respir Crit Care Med 1994; 149: 1539-1544.
14. Tobin MJ, Alex CG. Discontinuation of mechanical ventilation. In: Tobin MJ (ed). Principles and Practice of Mechanical Ventilation. NY, McGraw-Hill, 1994; pp. 1177-1206.
15. Hill N. Clinical applications of body ventilators. Chest 1986; 90: 897-905.
16. Ambrosino N, Rampulla C. Negative pressure ventilation in COPD patients. Eur Respir Rev 1992; 2: 353-356.
17. Nava S, Ambrosino N, Zocchi L, Rampulla C. Diaphragmatic rest during negative pressure ventilation by pneumowrap: assessment in normal and COPD patients. Chest 1990; 98: 857-865.
18. Beck GJ, Seanor HE, Barach AL, Gats D. Effects of pressure breathing on venous pressure: a comparative study of positive pressure breathing applied to the upper respiratory passageway and negative pressure to the body of normal individuals. Am J Med Sci 1952; 224: 169-173.
19. Ambrosino N, Cobelli F, Torbicki, et al. Hemodynamic effects of negative-pressure ventilation in patients with COPD. Chest 1990; 97: 850-856.
20. Levy RD, Cosio MG, Gibbons L, Macklem PT, Martin JG. Induction of sleep apnoea with negative pressure ventilation in patients with chronic obstructive lung disease. Thorax 1992; 47: 612-615.
21. Marino WD, Pitchumoni CS. Reversal of negative pressure ventilation-induced lower esophageal sphincter dysfunction with metoclopramide. Am J Gastroenterol 1992; 87: 190-194.
22. Zibrak JD, Hill NS, Federman EC, Kwa SL, O'Donnell C. Evaluation of intermittent long-term negative pressure ventilation in patients with severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1988; 138: 1515-1518.
23. Shneerson JM. Noninvasive and domiciliary ventilation: negative pressure techniques. Thorax 1991; 46: 131-135.
24. Levine S, Henson D. Negative pressure ventilation. In: Tobin MJ, ed. Principles and Practice of Mechanical Ventilation. NY: McGraw-Hill, 1994; pp. 393-411.
25. Corrado A, Bruscoli G, Messori A, et al. Iron Lung treatment of subjects with COPD in acute respiratory failure: evaluation of short- and long-term prognosis. Chest 1992; 101: 692-696.
26. Montserrat JM, Martos JA, Alarcon A, Celis R Plaza V, Picado C. Effect of negative pressure ventilation on arterial blood gas pressures and inspiratory muscles strength during an exacerbation of chronic obstructive lung disease. Thorax 1991; 46: 6-8.
27. Sauret JM, Guitart AC, Rodriguez-Frojan G, Cornudella R. Intermittent short-term negative pressure ventilation and increased oxygenation in COPD patients with severe hypercapnic respiratory failure. Chest 1991; 100: 455-459.
28. Libby DM, Briscoe WA, Boyce B, Smith JP. Acute respiratory failure in scoliosis of kyphosis: prolonged survival and treatment. Am J Med 1982; 73: 532-538.
29. Lassen HCA. A preliminary report on the 1952 epidemic of poliomyelitis in Copenhagen with special references to treatment of acute respiratory insufficiency. Lancet 1953: 1: 37-41.
30. Marks A, Bocles J, Morganti L. A new ventilatory assister for patients with respiratory acidosis. N Engl J Med 1963; 268: 61-67.
31. Corrado A, Bruscoli G, De Paola E, Ciardi-Duprè GF, Baccini A, Taddei M. Respiratory muscle insufficiency in acute respiratory failure of subjects with severe COPD: treatment with intermittent negative pressure ventilation. Eur Respir J 1990; 3: 644-648.
32. Calverley PMA. Domiciliary ventilation in chronic obstructive lung disease. Thorax 1992; 47: 334-336.
33. MacIntyre N. Nishima M, Usada Y, Tokioka H. Takezawa J, Shimada Y. The Nagoya conference on system design and patient-ventilator interactions during pressure support ventilation. Chest 1990; 97: 1463-1466.
34. Hill NS, Eveloff SE, Carlisle CC, Goff SG. Efficacy of nocturnal nasal ventilation in patients with restrictive thoracic disease. Am Rev Respir Dis 1992; 145: 365-371.
35. Strumpf DA, Millman RP, Carlisle CC, et al. Nocturnal positive-pressure ventilation via nasal mask in patients with severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1991; 144: 1234-1239.
36. Waldhorn RE. Nocturnal nasal intermittent positive pressure ventilation with Bi-level positive airway pressure (BiPAP®) in respiratory failure. Chest 1992; 145: 365-371.
37. Carrey Z, Gottfried S, Levy R. Ventilatory muscle support in respiratory failure with nasal positive pressure ventilation. Chest 1990; 97: 150-158.
38. Belman MJ, Soo Hoo GW, Kuei JH, Shadmer R. Efficacy of positive vs negative pressure evaluation in unloading the respiratory muscles. Chest 1990; 98: 850-856.
39. Nava S, Ambrosino N, Rubini F, et al. Effect of nasal pressure support ventilation and external PEEP on diaphragmatic activity in patients with severe stable COPD. Chest 1993; 103: 143-150.
40. Brochard L, Isabey D, Piquet J, et al. Reversal of acute exacerbations of chronic obstructive lung disease by inspiratory assistance with a face mask. N Engl J Med 1990; 323: 1523-1530.
41. Appendini F, Patessio A, Zanaboni S, et al. Physiological effects of positive end-expiratory pressure and mask pressure support during exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1994; 149: 1069-1076.
42. Ambrosino N, Nava S, Bertone P, Fracchia C, Rampulla C. Physiologic evaluation of pressure support ventilation by nasal mask in patients with stable COPD. Chest 1992; 101: 385-391.
43. Ambrosino N, Nava S, Torbicki A, et al. Hemodynamic effects of pressure support ventilation and PEEP by nasal route in patients with chronic hypercapnic respiratory insufficiency. Thorax 1993; 48: 523-528.
44. Meduri GU, Conoscenti CC, Menashe PH, Nair S. Noninvasive face mask ventilation in patients with acute respiratory failure. Chest 1989; 95: 865-870.
45. Ambrosino N, Nava S, Rubini F. Noninvasive mechanical ventilation in the treatment of acute respiratory failure in chronic obstructive pulmonary disease. Monaldi Arch Chest Dis 1993; 48: 144-154.
46. Elliott M, Moxham J. Noninvasive mechanical ventilation by nasal or face mask. In: Tobin MJ, ed. Principles and practice of mechanical ventilation. NY, McGraw-Hill, 1994; pp. 427-453.
47. Meyer TJ, Hill NS. Noninvasive positive pressure ventilation to treat respiratory failure. Ann Intern Med 1994; 120: 760-770.
48. Sassoon CSH. Noninvasive positive pressure ventilation in acute respiratory failure: review of reported experience with special attention to use during weaning. Respir Care 1995; 40: 282-288.
49. Meduri GU, Abou-Shala N, Fox RC, Jones CB, Leeper KV, Wunderink RG. Noninvasive face mask mechanical ventilation in patients with acute hypercapnic respiratory failure. Chest 1991; 100: 445-454.
50. Foglio C, Vitacca M, Quadri A, Scalvini S, Marangoni S, Ambrosino N. Acute exacerbations in severe COLD patients: treatment using positive pressure ventilation by nasal mask. Chest 1992; 101: 1533-1538.
51. Benhamou D, Girault C, Faure C, Portier F, Muir JF. Nasal mask ventilation in acute respiratory failure: experience in elderly patients. Chest 1992; 102: 912-917.
52. Vitacca M, Rubini F, Foglio K, Scalvini S, Nava S, Ambrosino N. Noninvasive modalities of positive pressure ventilation improve the outcome of acute exacerbations in COLD patients. Intens Care Med 1993; 19: 450-455.
53. Bott J, Carroll MP, Conway JH, et al. Randomized controlled trial of nasal ventilation in acute ventilatory failure due to chronic obstructive airways disease. Lancet 1 993; 341: 1555-1557.
54. Fernandez R Blanch LI, Valles J, Baigorri F, Artigas A. Pressure support ventilation via face mask in acute respiratory failure in hypercapnic COPD patients. Intens Care Med 1993; 19: 456-161.
55. Kramer N, Meyer TJ, Meharg J, Cece RD, Hill NS. Randomized, prospective trial of noninvasive positive pressure ventilation in acute respiratory failure. Am J Respir Crit Care Med 1995; 151: 1799-1806.
56. Brochard L, Mancebo J, Wysocki M, et al. Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1995; 333: 817-822.
57. Elliott MW, Steven MH, Phillips GD, Branthwaite MA. Noninvasive mechanical ventilation for acute respiratory failure. Br Med J 1990; 300: 358-360.
58. Confalonieri M, Aiolfi S, Gandola L, Scartabellati A, Della Porta R, Parigi P. Severe exacerbations of chronic obstructive pulmonary disease treated with BiPAP by nasal mask. Respiration 1994; 61: 310-316.
59. Meecham Jones DJ, Paul EA, Grahame-Clarke C, Wedzicha JA. Nasal ventilation in acute exacerbations of chronic obstructive pulmonary disease: effect of ventilator mode on arterial blood gas tensions. Thorax 1994; 49: 1222-1224.
60. Rossi A, Polese G, Brandi G, Conti G. Intrinsic positive end-expiratory pressure (PEEPi). Intens Care Med 1995; 21: 522-536.
61. Smith TC, Marini JJ. Impact of PEEP on lung mechanics and work of breathing in severe airflow obstruction. J Appl Physiol 1988; 65: 1488-1499.
62. Petrof BJ, Legare M, Goldberg P, Milic-Emili J, Gottfried SB. Continuous positive airway pressure reduces work of breathing and dyspnea during weaning from mechanical ventilation in severe chronic obstructive airway disease. Am Rev Respir Dis 1990; 141: 281-289.
63. De Lucas P, Tarancon C, Puente L, Rodriguez C, Tatay E, Monturiol JM. Nasal continuous positive airway pressure in patients with COPD in acute respiratory failure: a study of the immediate effects. Chest 1993; 104: 1694-1697.
64. Miro AM, Shivaram U, Hertig I. Continuous positive airway pressure in COPD patients in acute hypercapnic respiratory failure. Chest 1993; 103: 266-268.
65. Rossi A, Ranieri M. Positive end-expiratory pressure. In: Tobin MJ, ed. Principles and Practice of Mechanical Ventilation. New York, McGraw-Hill, 1994; pp. 259-303.
66. Vitacca M, Clini E, Rubini F, Foglio K Nava S, Ambrosino N. Noninvasive mechanical ventilation in severe COLD and acute respiratory failure: short- and long-term prognosis. Intens Care Med 1996; (in press).
67. Bardsley PA, Tweney J, Morgan N, Howard P. Oral almitrine in treatment of acute respiratory failure and cor pulmonale in patients with an exacerbation of chronic obstructive airways disease. Thorax 1991; 46: 493-498.
68. Jeffrey AA, Warren PM, Flenley DC. Acute hypercapnic respiratory failure in patients with chronic obstructive lung disease: risk factors and use of guidelines for management. Thorax 1992; 47: 34-40.
69. Nunn JF, Milledge JS, Singaraya J. Survival of patients ventilated in an intensive therapy unit. Br Med J 1979; 1: 1525-1527.
70. Gillespie DJ, Marsh HMM, Divertie MB, Meadows JA. Clinical outcome of respiratory failure in patients requiring prolonged (>24 hours) mechanical ventilation. Chest 1986; 90: 364-369.
71. Spicher JE, White DP. Outcome and function following prolonged mechanical ventilation. Arch Intern Med 1987; 147: 421-425.
72. Kaelin RM, Assimacopoulos A, Chevrolet JC. Failure to predict six month survival of patients with COPD requiring mechanical ventilation by analysis of simple indices: a prospective study. Chest 1987; 92: 971-978.
73. Menzies R Gibbons W, Goldberg P. Determinants of weaning and survival among patients with COPD who require mechanical ventilation for acute respiratory failure. Chest 1989; 95: 398-405.
74. Gracey DR Naessens JM, Krishan I, Marsh HMM. Hospital and posthospital survival in patients mechanically-ventilated for more than 29 days. Chest 1992; 101: 211-214.
75. Stauffer JL, Fayter N, Graves B, Cromb M, Lynch JC, Goebel P. Survival following mechanical ventilation for acute respiratory failure in adult men. Chest 1993; 104: 1222-1229.
76. Ambrosino N, Foglio K Rubini F, Clini E, Nava S, Vitacca M. Noninvasive mechanical ventilation in acute respiratory failure due to chronic obstructive pulmonary disease: correlates for success. Thorax 1995; 50: 755-757.
77. Brochard L (Editorial). Noninvasive ventilation: practical issues. Intens Care Med 1993; 19: 431-432.
78. Le Gall JR, Loirat P, Alperovitch A, et al. A simplified acute physiology score for ICU patients. Crit Care Med 1984; 12: 975-977.
79. Knaus WA, Draper EA, Wagner DP, et al. Apache II: a severity of disease classification system. Crit Care Med 1985; 13: 818-829.
80. Soo Hoo GW, Santiago S, Williams A. Nasal mechanical ventilation for hypercapnic respiratory failure in chronic obstructive pulmonary disease: determinants of success and failure. Crit Care Med 1994; 22: 1253-1261.
81. Elliot MW (Editorial). Noninvasive ventilation in chronic obstructive pulmonary disease. N Engl J Med 1995; 333: 870-871.
82. Wysocki M, Tric L, Wolff MA, Gertner J, Millet H, Herman B. Noninvasive pressure support ventilation in patients with acute respiratory failure. Chest 1993; 103: 907-913.
83. Wysocki M, Tric L, Wolff MA, Millet H, Herman B. Noninvasive pressure support ventilation in patients with acute respiratory failure: a randomized comparison with conventional therapy. Chest 1995; 107: 761-768.
84. Pennock BE, Crawshaw L, Kaplan PD. Noninvasive nasal mask ventilation for acute respiratory failure: institution of a new therapeutic technology for routine use. Chest 1994; 105: 441-444.
85. Nava S, Rubini F, Zanotti E, et al. Survival and prediction of successful ventilator weaning in COPD patients requiring mechanical ventilation for more than 21 days. Eur Respir J 1994; 7: 1645-1652.
86. Petheram IS, Branthwaite MA. Mechanical ventilation for pulmonary disease: a six year survey. Anesthesia 1980; 35: 467-473.
87. Swinburne AJ, Fedullo AJ, Bixby K Lee DK, Wahl GW. Respiratory failure in the elderly: analysis of outcome after treatment with mechanical ventilation. Arch Intern Med 1993; 153: 1657-1662.
88. Rieves RD, Bass D, Carter RR, Griffith JE, Norman JR. Severe COPD and acute respiratory failure: correlates for survival at the time of tracheal intubation. Chest 1993; 104: 854-860.
89. Rello J, Ausina V, Ricart M, Castella J, Prats G. Impact of previous antimicrobial therapy on the etiology and outcome of ventilator-associated pneumonia. Chest 1993; 104: 1230-1235.
90. Warren PM, Flenley DC, Millar JS, Avery A. Respiratory failure revisited: acute exacerbations of chronic bronchitis between 1961-1968 and 1970-1976. Lancet 1980 1: 467-471.
91. Craven DE, Kunches LM, Kilinsky V, Lichtenberg DA, Make BJ, McCabe WR. Risk factors for pneumonia and fatality in patients receiving continuous mechanical ventilation. Am Rev Respir Dis 1986; 133: 792-796.
92. Sluiter HJ, Blokzijil EJ, Vandijl W, et al. Conservative and respirator treatment of acute respiratory insufficiency in patients with chronic obstructive lung disease: a reappraisal. Am Rev Respir Dis 1972; 105: 932-943.
93. Potgieter PD, Rosenthal E, Benatar SR. Immediate and long-term survival in patients admitted to a respiratory ICU. Crit Care Med 1985; 13: 798-802.
94. Sukulmachantra Y, Dinakara P, Williams MH. Prognosis of patients with chronic obstructive pulmonary disease after hospitalization for acute ventilatory failure: a 3 year follow-up study. Am Rev Respir Dis 1966; 93: 215-222.
95. Martin JG, Shore S, Engel LA. Effect of continuous positive airway pressure on respiratory mechanics and pattern of breathing in induced asthma. Am Rev Respir Dis 1982; 126: 812-817.
96. Schivaram U, Miro AM, Cash ME, et al. Cardiopulmonary responses to continuous positive airway pressure in acute asthma. J Crit Care 1993; 8: 87-92.
97. Branthwaite MA. An update on mechanical ventilation for severe acute asthma. Clin Intens Care 1990; 1: 4-6.
98. Meduri GU, Fox RC, Abou-Shala N, Leeper KV, Wunderink RG. Noninvasive mechanical ventilation via face mask in patients with acute respiratory failure who refused endotracheal intubation. Crit Care Med 1994; 22: 1584-1590.
99. Freichels TA. Palliative ventilatory support: use of noninvasive positive pressure ventilation in terminal respiratory insufficiency. Am J Crit Care 1994; 3: 6-10.
100. Robert D, Gaussorgues P, Leger P, et al. Ventilation mécanique au masque dans les poussées d'insuffisance respiratoire chronique. Réan Soins Intens Méd Urg 1989; 5: 401-406.
101. Pennock BE, Kaplan PD, Carlin BW, Sabangan JS, Macgovem JA. Pressure support ventilation with a simplified ventilatory support system administered with a nasal mask in patients with respiratory failure. Chest 1991; 100: 1371-1376.
102. Marino W. Intermittent volume cycled mechanical ventilation via nasal mask in patients with respiratory failure due to COPD. Chest 1991; 99: 681-684.
103. Bersten AD, Holt AW, Vedig AE, Skowronski GA, Baggley CJ. Treatment of severe cardiogenic pulmonary edema with continuous positive airway pressure delivered by face mask. N Engl J Med 1991; 325: 1825-1830.
104. Lapinski SE, Mount DB, Mackey D, Grossman RF. Management of acute respiratory failure due to pulmonary edema with nasal positive pressure support. Chest 1994: 105: 229-231.
105. Piper AJ, Parker S, Torzillo PJ, Sullivan CE, Bye PTP. Nocturnal nasal EPPV stabilizes patients with cystic fibrosis and hypercapnic respiratory failure. Chest 1992; 102: 846-850.
106. Lin M, Yang Y, Chiang H, Chang M, Chiang BN, Chitlin MD. Reappraisal of continuous positive airway pressure therapy in acute cardiogenic pulmonary edema: short-term results and long-term follow-up. Chest 1995; 107: 1379-1386.
107. Gachot B, Clair B, Wolff M, Regnies B, Vachon F. Continuous positive airway pressure by face mask or mechanical ventilation in patients with human immunodeficiency virus infection and severe Pneumocystis carinii pneumonia. Intens Care Med 1992; 18: 155-159.
108. Ambrosino N, Rubini F, Callegari G, Nava S, Fracchia C. Noninvasive mechanical ventilation in the treatment of infectious complications of lung transplantation. Monaldi Arch Chest Dis 1994; 49: 311-314.
109. Brochard L, Rauss A, Benito S, et al. Comparison of three methods of gradual withdrawal from ventilatory support during weaning from mechanical ventilation. Am J Respir Crit Care Med 1994; 150: 896-903.
110. Esteban A, Frutos F, Tobin MJ, et al. A comparison of four methods of weaning patients from mechanical ventilation. N Engl J Med 1995; 332: 345-350.
111. Udwadia ZF, Santis GK Steven MH, Simonds AK. Nasal ventilation to facilitate weaning in patients with chronic respiratory insufficiency. Thorax 1992; 47: 715-718.
112. Goodenberger DM, Couser JI Jr, May JJ. Successful discontinuation of ventilation via tracheostomy by substitution of nasal positive pressure ventilation. Chest 1992; 102: 1277-1279.
113. Restrick LJ, Scott AD, Ward EM, Feneck RO, Cornwell WE, Wedzicha JA. Nasal intermittent positive pressure ventilation in weaning intubated patients with chronic respiratory disease from assisted intermittent, positive pressure ventilation. Respir Med 1993; 87: 199-204.
114. Criner GJ, Travaline JM, Brennan KJ, Kreimer DT. Efficacy of a new full face mask for noninvasive positive pressure ventilation. Chest 1994; 106: 1109-1111.
115. Chevrolet JC, Jolliet P, Abajo B, Toussi A, Louis M. Nasal positive pressure ventilation in patients with acute respiratory failure: difficult and time-consuming procedure for nurses. Chest 1991; 100: 775-782.
116. Sacks H, Chalmers TC, Smith H Jr. Randomized versus historical controls for clinical trials. Am J Med 1982; 72: 233-240.