Effect of ventilatory rate on airway cytokine levels and lung injury

doi:10.1016/S0022-4804(03)00195-1

Journal of Surgical Research

Volume 113, Issue 1, July 2003, Pages 139-145

https://doi.org/10.1016/S0022-4804(03)00195-1 Get rights and content

Abstract

Background

Controversy exists regarding the effect of large-volume mechanical ventilation (MV), as a sole stimulus, on the pulmonary cytokine milieu. We used a well described experimental model of ventilator-induced lung injury (VILI) to examine the impact of large volume ventilation on pulmonary cytokines in vivo and to study the effect of respiratory rate (RR) variation on these levels.

Materials and methods

Sixty rats (410 ± 47 g) were randomized to: 1) non ventilated control; 2) V_t = 40 ml/kg, RR = 40 bpm; 3) V_t = 40 ml/kg, RR = 20 bpm; 4) V_t = 7 ml/kg, RR = 40 bpm; or 5) V_t = 7 ml/kg, RR = 20 bpm. After 1 h of MV, bronchoalveolar lavage (BAL) and serum were collected. BAL was analyzed for urea, protein, lactate dehydrogenase (LDH), tumor necrosis factor (TNF)α and interleukin (IL)-6. Epithelial lining fluid volume (ELF) was calculated.

Results

Regardless of RR, animals ventilated at 7ml/kg did not differ from control in any outcome. In contrast, MV at 40 ml/kg V_t with 40 bpm produced lung injury characterized by significant elevations of BAL TNFα, IL-6, protein, ELF, and LDH. At 40ml/kg V_t, RR reduction (20 bpm) significantly reduced all injury measures.

Conclusion

This study confirms that large-volume MV, as a sole stimulus, produces lung injury and cytokine release. Whereas increasing RR at low V_t has little impact on injury parameters, RR reduction under VILI-promoting conditions significantly limits lung injury.

Introduction

More than three decades of investigation have provided us with a wealth of evidence that ventilatory assistance, particularly with large tidal volumes, can be injurious 1, 2, 3, 4. The clinical relevance of ventilator-induced lung injury (VILI) and the importance of ventilatory technique have been clearly established with the publication of a large clinical trial demonstrating a 22% reduction in mortality associated with limitation of tidal volume [5].

The isolated effects of primary lung injury and superimposed VILI can be difficult to separate, as the hallmarks of both include generalized inflammation, diffuse alveolar damage, and exudative edema 1, 3, 4, 6, 7. Several investigators have observed elevated levels of proinflammatory cytokines in the alveolar fluids and sera of animals subjected to experimental lung injury and patients with the acute respiratory distress syndrome (ARDS) 8, 9, 10. Although it has been suggested that mechanical ventilation (MV) as a sole stimulus may alter the pulmonary cytokine milieu and therefore play a central role in pulmonary inflammation and potentially in multiple system organ dysfunction (MSOD) 11, 12, this basic issue remains controversial 12, 13.

An inclusive understanding of the events responsible for VILI remains elusive. In contrast to the symmetrical and diffuse radiographic appearance of lungs affected by ARDS, computerized axial tomography reveals a distinctly inhomogeneous pattern of injury [14]. Dependent lung is preferentially consolidated, while there remains relative preservation and aeration of nondependent regions [15]. It has been suggested based on these observations that MV may contribute to lung injury either by overdistending aerated nondependent lung or by allowing the repetitive collapse and re-expansion of potentially surfactant-deficient dependent alveoli 16, 17, 18, 19. It can, therefore, be hypothesized that both the magnitude of tidal volume and the frequency of ventilation may contribute to VILI. Furthermore, respiratory rate variation can have significant impact on mean airway pressure and the duration of exposure to both peak and end- inspiratory pressures, all factors thought to be instrumental in producing MV-associated alveolar distention.

Based on these concepts of potential sources of VILI, we hypothesized that a relative reduction in respiratory rate during large-volume/high-pressure MV would limit lung injury. In the current study, we employed a well described rat model of VILI to examine the effect of respiratory rate limitation on the resultant elaboration of proinflammatory pulmonary cytokines and markers of lung injury. Furthermore, we examined the effect of respiratory rate variation during MV at comparatively smaller tidal volumes.

Section snippets

Animals

Sixty adult male Sprague-Dawley rats (weight 410 ± 47 g) were obtained from Harlan (Indianapolis, IN). All experimental procedures and protocols were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of North Carolina at Chapel Hill.

Instrumentation, Randomization, and Experimental Ventilation Protocols

Following a 72-h period of acclimation, animals were randomized to experimental groups based on a series of random-number-generated sealed envelopes. Following randomization, animals were anesthetized with pentobarbital (50 mg/kg

Results

All experimental animals survived the 1-h period of MV although subjects ventilated with the V₄₀RR₄₀ strategy manifested marked mucosal cyanosis and copious pink edema fluid was present within endotracheal tubes. As anticipated, peak inspiratory pressures (PIP) varied within groups in a manner generally consistent with the administered tidal volume (see Table 1). Notably, PIP was greatest in the V₄₀RR₄₀ group and significantly higher than the V₄₀RR₂₀ group. During large-volume MV at the higher

Discussion

This study supports the growing body of experimental evidence demonstrating that large-volume/high-pressure MV produces or contributes to lung injury. Additionally, we found that large-volume MV, as a sole stimulus in otherwise normal lungs, results in the local pulmonary release of proinflammatory cytokines. Furthermore, we demonstrated that VILI as measured by alveolar edema, protein leak, LDH release, and increased air way concentrations of TNFα and IL-6 is dependent on respiratory rate.

Conclusion

This animal study supports a large body of evidence that large-volume/high pressure MV is injurious to the lungs and confirms that injurious ventilation, as a sole stimulus, can significantly alter the local cytokine milieu of the lung. Furthermore, this study demonstrates that VILI, as measured by increased alveolar external cellular lysis, and the elaboration of the proinflammatory cytokines TNFα and IL-6, is dependent on respiratory rate under conditions that promote alveolar distention.

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With the addition of time, the contribution to potential lung injury caused by repeated insults, is then included, which may not be accounted for when only static parameters are obtained. With growing evidence that the rate of respiration,11,12 air flow,13 and the strain14,15 may play an essential role in the pathogenesis of VILI, it has been postulated that it is necessary to include these factors in strategies to optimize lung-protective ventilation. Considering this, there is a growing interest in using the concept of mechanical power in lung-protective ventilation strategy in an attempt to combine dynamic rate of change factors with the static pressures.
Mechanical ventilation is a potentially life-saving therapy for patients with acute lung injury, but the ventilator itself may cause lung injury. Ventilator-induced lung injury (VILI) is sometimes an unfortunate consequence of mechanical ventilation. It is not clear however how best to minimize VILI through adjustment of various parameters including tidal volume, plateau pressure, driving pressure, and positive end expiratory pressure (PEEP). No single parameter provides a clear indication for onset of lung injury attributable exclusively to the ventilator. There is currently interest in quantifying how static and dynamic parameters contribute to VILI. One concept that has emerged is the consideration of the amount of energy transferred from the ventilator to the respiratory system per unit time, which can be quantified as mechanical power. This review article reports on recent literature in this emerging field and future roles for mechanical power assessments in prospective studies.
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This may in part be explained by atelectasis, which impairs gas exchange because of pulmonary shunt and increases the vulnerability for more severe respiratory complications.27 Several experimental studies have shown harmful effects of high-respiratory-rate ventilation,9–14 but data on the effects of mechanical ventilation with high ventilatory frequencies in humans are limited, especially concerning the perioperative period. In a secondary analysis of the LUNG SAFE (Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE) cohort study, increased ventilatory frequency, low PEEP, and high peak inspiratory and driving pressures were associated with higher mortality in patients with acute respiratory distress syndrome.28
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^☆: This study was funded in part by grants from the National Institute of Health (1 K08 HL72836-01) and from the University of North Carolina Research Council.

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Regular articleEffect of ventilatory rate on airway cytokine levels and lung injury☆

Abstract

Background

Materials and methods

Results

Conclusion

Introduction

Section snippets

Animals

Instrumentation, Randomization, and Experimental Ventilation Protocols

Results

Discussion

Conclusion

Clin. Chest Med.

Chest

Chest

Chest

Chest

Lancet

Chest

Lancet

Chest

The mechanical ventilatora potentially dangerous tool

Minerva Anestesiol.

Ventilator-associated lung injury

Int. Anesthesiol. Clin.

Ventilator-induced injuryfrom barotrauma to biotrauma

Proc. Assoc. Am. Physicians

Ventilator-induced lung injuryLessons from experimental studies

Am. J. Respir. Crit. Care Med.

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.

The acute respiratory distress syndrome

N. Engl. J. Med.

Mechanical ventilation affects local and systemic cytokines in an animal model of acute respiratory distress syndrome

Am. J. Respir. Crit. Care Med.

Injurious ventilation induces widespread pulmonary epithelial expression of tumor necrosis factor α and interleukin-6 messenger RNA

Crit. Care Med.

Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model

J. Clin. Invest.

Production of inflammatory cytokines in ventilator-induced lung injurya reappraisal

Am. J. Respir. Crit. Care Med.

ARDS: the non-homogeneous lung, facts and hypothesis

Intensive Care Digest

Pressure-volume curve of total respiratory system in acute respiratory failure. Computed tomographic scan study

Am. Rev. Respir. Dis.

Adverse effects of large tidal volume and low PEEP in canine acid aspiration

Am. Rev. Respir. Dis.

Open up the lung and keep the lung open

Intensive Care Med.

Barotrauma and alveolar recruitment

Intensive Care Med.

Regular article
Effect of ventilatory rate on airway cytokine levels and lung injury☆