Effects of Duration and Amount of Lung Stretch at Biophysical, Biochemical, Histological, and Transcriptional Levels in an In Vivo Rabbit Model of Mild Lung Injury

ABSTRACT

The purpose of this study was to characterize the effects of doubling minute ventilation (either by doubling ventilator frequency [Freq] or tidal volume [Vt]) and of normal minute ventilation prolonged to 12-fold duration, synchronously at biophysical, biochemical/cellular, histological, and transcriptional levels in a model of mild lung injury. A prospective, randomized study was performed on adolescent New-Zealand white rabbits. The rabbits were randomly assigned to one of the following groups: control (normal minute ventilation for 0.5 hours); 1 × Vt, 12-fold prolongation at normal Vt (normal minute ventilation for 6 hours [12 × 0.5 hours]); 2 × Freq at normal Vt (double minute ventilation for 6 hours); and 2 × Vt at normal Freq (double minute ventilation for 6 hours). Normocapnia was maintained throughout the experiment. At the biophysical level, gas exchange (alveolar-arterial O₂-tension difference [aaDo ₂]) deteriorated by 23, 51, and 95%, and respiratory compliance decreased by 6.0, 18.4, and 26% in the 1 × Vt, 2 × Freq, and 2 × Vt group, respectively, during 6 hours of ventilation. Concomitantly, at the biochemical-cellular level, interleukin-8 (IL-8) in the bronchoalveolar lavage fluid increased 44-fold, 150-fold, and 275-fold (p = 0.02), respectively. The white blood cell count decreased significantly in all three intervention groups. At the histological level, the influx of leukocytes as well as the tissue water content increased in proportion to the degree of injury. At the transcriptional level, lung IL-8 mRNA expression increased 11-fold in the 2 × Vt group (p = 0.002), 9-fold (p = 0.02) in the 2 × Freq group, and 4-fold in the 1 × Vt group as compared with control. Not only doubling Vt, but also doubling Freq at normal Vt injures the lung significantly, although to a lesser extent. A concept of weighted risk for increases of Vt and Freq is proposed.

KEYWORDS

Ventilator-induced lung injury - inflammation - interleukins - gene transcription - animals

REFERENCES

• 1 Tremblay L N, Slutsky A S. Ventilator-induced injury: from barotrauma to biotrauma.  Proc Assoc Am Physicians. 1998;  110 482-488
• 2 Dreyfuss D, Soler P, Basset G et al.. High inflation pressure pulmonary edema. Respective effects of high airway pressure, high tidal volume, and positive end-expiratory pressure.  Am Rev Respir Dis. 1988;  137 1159-1164
• 3 Bjorklund L J, Vilstrup C T, Larsson A et al.. Changes in lung volume and static expiratory pressure-volume diagram after surfactant rescue treatment of neonates with established respiratory distress syndrome.  Am J Respir Crit Care Med. 1996;  154 918-923
• 4 Tremblay L, Valenza F, Ribeiro S P et al.. Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model.  J Clin Invest. 1997;  99 944-952
• 5 Torday J S, Sanchez-Esteban J, Rubin L P. Paracrine mediators of mechanotransduction in lung development.  Am J Med Sci. 1998;  316 205-208
• 6 Liu M, Tanswell A K, Post M. Mechanical force-induced signal transduction in lung cells.  Am J Physiol. 1999;  277 L667-L683
• 7 Tremblay L N, Miatto D, Hamid Q et al.. Injurious ventilation induces widespread pulmonary epithelial expression of tumor necrosis factor-alpha and interleukin-6 messenger RNA.  Crit Care Med. 2002;  30 1693-1700
• 8 Simonson D A, Adams A B, Wright L A et al.. Effects of ventilatory pattern on experimental lung injury caused by high airway pressure.  Crit Care Med. 2004;  32 781-786
• 9 Hernandez L A, Peevy K J, Moise A A et al.. Chest wall restriction limits high airway pressure-induced lung injury in young rabbits.  J Appl Physiol. 1989;  66 2364-2368
• 10 Peevy K J, Hernandez L A, Moise A A et al.. Barotrauma and microvascular injury in lungs of nonadult rabbits: effect of ventilation pattern.  Crit Care Med. 1990;  18 634-637
• 11 Ricard J D, Dreyfuss D, Saumon G. Production of inflammatory cytokines in ventilator-induced lung injury: a reappraisal.  Am J Respir Crit Care Med. 2001;  163 1176-1180
• 12 Keszler M, Abubakar K. Volume guarantee: stability of tidal volume and the incidence of hypocarbia.  Pediatr Pulmonol. 2004;  38 240-245
• 13 Luyt K, Wright D, Baumer J H. Randomised study comparing extent of hypocarbia in preterm infants during conventional and patient triggered ventilation.  Arch Dis Child Fetal Neonatal Ed. 2001;  84 F14-F17
• 14 Graziani L J, Spitzer A R, Mitchell D G et al.. Mechanical ventilation in preterm infants: neurosonographic and developmental studies.  Pediatrics. 1992;  90 515-522
• 15 Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network.  N Engl J Med. 2000;  342 1301-1308
• 16 Heicher D A, Kasting D S, Harrod J R. Prospective clinical comparison of two methods for mechanical ventilation of neonates: rapid rate and short inspiratory time versus slow rate and long inspiratory time.  J Pediatr. 1981;  98 957-961
• 17 Pohlandt F, Saule H, Schroder H et al.. Decreased incidence of extraalveolar air leakage or death prior to air leakage in high versus low rate positive pressure ventilation: results of a randomised seven-centre trial in preterm infants.  Eur J Pediatr. 1992;  151 904-909
• 18 Bland R D, Kim M H, Light M J et al.. High frequency mechanical ventilation in severe hyaline membrane disease: an alternative treatment?.  Crit Care Med. 1980;  8 275-280
• 19 Bollen C W, Uiterwaal C S, van Vught A J. Cumulative metaanalysis of highfrequency versus conventional ventilation in premature neonates.  Am J Respir Crit Care Med. 2003;  168 1150-1155
• 20 Thome U H, Pohlandt F. High-frequency ventilation.  N Engl J Med. 2003;  348 1181-1182
• 21 Tschumperlin D J, Oswari J, Margulies A S. Deformation-induced injury of alveolar epithelial cells. Effect of frequency, duration, and amplitude.  Am J Respir Crit Care Med. 2000;  162 357-362
• 22 Wilson M R, Choudhury S, Goddard M E et al.. High tidal volume upregulates intrapulmonary cytokines in an in vivo mouse model of ventilator-induced lung injury.  J Appl Physiol. 2003;  95 1385-1393
• 23 Copland I B, Martinez F, Kavanagh B P et al.. High tidal volume ventilation causes different inflammatory responses in newborn versus adult lung.  Am J Respir Crit Care Med. 2004;  169 739-748
• 24 Swenson E R, Robertson H T, Hlastala M P. Effects of inspired carbon dioxide on ventilation-perfusion matching in normoxia, hypoxia, and hyperoxia.  Am J Respir Crit Care Med. 1994;  149 1563-1569
• 25 Tsukimoto K, Arcos J P, Schaffartzik W et al.. Effects of inspired CO2, hyperventilation, and time on VA/Q inequality in the dog.  J Appl Physiol. 1992;  72 1057-1063
• 26 Domino K B, Swenson E R, Polissar N L et al.. Effect of inspired CO2 on ventilation and perfusion heterogeneity in hyperventilated dogs.  J Appl Physiol. 1993;  75 1306-1314
• 27 Chiumello D, Pristine G, Slutsky A S. Mechanical ventilation affects local and systemic cytokines in an animal model of acute respiratory distress syndrome.  Am J Respir Crit Care Med. 1999;  160 109-116
• 28 Guyton A C. Analysis of respiratory patterns in laboratory animals.  Am J Physiol. 1947;  150 78-83
• 29 Thome U H, Schulze A, Schnabel R et al.. Partial liquid ventilation in severely surfactant-depleted, spontaneously breathing rabbits supported by proportional assist ventilation.  Crit Care Med. 2001;  29 1175-1180
• 30 Rimensberger P C, Cox P N, Frndova H et al.. The open lung during small tidal volume ventilation: concepts of recruitment and “optimal” positive end-expiratory pressure.  Crit Care Med. 1999;  27 1946-1952
• 31 Simbruner G. Inadvertent positive end-expiratory pressure in mechanically ventilated newborn infants: detection and effect on lung mechanics and gas exchange.  J Pediatr. 1986;  108 589-595
• 32 Smith P K, Krohn R I, Hermanson G T et al.. Measurement of protein using bicinchoninic acid.  Anal Biochem. 1985;  150 76-85
• 33 Imai Y, Kawano T, Iwamoto S et al.. Intratracheal anti-tumor necrosis factor-alpha antibody attenuates ventilator-induced lung injury in rabbits.  J Appl Physiol. 1999;  87 510-515
• 34 Zhou Z H, Sun B, Lin K et al.. Prevention of rabbit acute lung injury by surfactant, inhaled nitric oxide, and pressure support ventilation.  Am J Respir Crit Care Med. 2000;  161 581-588
• 35 Thome U H, Schulze A, Schnabel R et al.. Partial liquid ventilation in severely surfactant-depleted, spontaneously breathing rabbits supported by proportional assist ventilation.  Crit Care Med. 2001;  29 1175-1180
• 36 Lista G, Colnaghi M, Castoldi F et al.. Impact of targeted-volume ventilation on lung inflammatory response in preterm infants with respiratory distress syndrome (RDS).  Pediatr Pulmonol. 2004;  37 510-514
• 37 Makhoul I R, Kugelman A, Garg M et al.. Intratracheal pulmonary ventilation versus conventional mechanical ventilation in a rabbit model of surfactant deficiency.  Pediatr Res. 1995;  38 878-885
• 38 Hotchkiss Jr J R, Blanch L, Murias G et al.. Effects of decreased respiratory frequency on ventilator-induced lung injury.  Am J Respir Crit Care Med. 2000;  161 463-468
• 39 Laffey J G, O'Croinin D, McLoughlin P et al.. Permissive hypercapnia- role in protective lung ventilatory strategies.  Intensive Care Med. 2004;  30 347-356
• 40 Fu Z, Costello M L, Tsukimoto K et al.. High lung volume increases stress failure in pulmonary capillaries.  J Appl Physiol. 1992;  73 123-133
• 41 Egan E A. Response of alveolar epithelial solute permeability to changes in lung inflation.  J Appl Physiol. 1980;  49 1032-1036
• 42 Parker J C, Ivey C L, Tucker A. Phosphotyrosine phosphatase and tyrosine kinase inhibition modulate airway pressure-induced lung injury.  J Appl Physiol. 1998;  85 1753-1761
• 43 Carlton D P, Cummings J J, Scheerer R G et al.. Lung overexpansion increases pulmonary microvascular protein permeability in young lambs.  J Appl Physiol. 1990;  69 577-583
• 44 Verbrugge S J, Lachmann B. Mechanisms of ventilation-induced lung injury: physiological rationale to prevent it.  Monaldi Arch Chest Dis. 1999;  54 22-37
• 45 Parker J C, Hernandez L A, Longenecker G L et al.. Lung edema caused by high peak inspiratory pressures in dogs. Role of increased microvascular filtration pressure and permeability.  Am Rev Respir Dis. 1990;  142 321-328
• 46 Watson P A. Function follows form: generation of intracellular signals by cell deformation.  FASEB J. 1991;  5 2013-2019
• 47 Chu E K, Whitehead T, Slutsky A S. Effects of cyclic opening and closing at low- and high-volume ventilation on bronchoalveolar lavage cytokines.  Crit Care Med. 2004;  32 168-174
• 48 Ricard J D, Dreyfuss D. Cytokines during ventilator-induced lung injury: a word of caution.  Anesth Analg. 2001;  93 251-252