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Editorial Views  |   July 2004
Mechanical Ventilation–induced Lung Release of Cytokines: A Key for the Future or Pandora’s Box?
Author Affiliations & Notes
  • Didier Dreyfuss, M.D.
    *
  • Jean-Jacques Rouby, M.D., Ph.D.
  • * Service de Réanimation Médicale Hôpital Louis Mourrier, Colombes, University of Paris, Paris, France. † Service de Réanimation Chururgicale Hôpital Pitié-Salpêtrière, Paris, University of Paris, Paris, France.
Article Information
Editorial Views
Editorial Views   |   July 2004
Mechanical Ventilation–induced Lung Release of Cytokines: A Key for the Future or Pandora’s Box?
Anesthesiology 7 2004, Vol.101, 1-3. doi:
Anesthesiology 7 2004, Vol.101, 1-3. doi:
IN this issue of Anesthesiology, Whitehead et al.  1 bring experimental evidence suggesting that a high tidal volume ventilation can markedly reduce the release of inflammatory cytokines in response to intratracheal lipopolysaccharide. They attribute this paradoxical effect to a reduction of the alveolar macrophage population and hypothesize that injurious ventilation may increase susceptibility to infection, a detrimental effect that may participate in ventilator-induced lung injury.
Clinicians have long known some of the risks of mechanical ventilation. The classic and well-known manifestations of gross barotrauma (air leaks) and the adverse hemodynamic effects of high pressure/volume mechanical ventilation were described shortly after the generalization of mechanical ventilators in intensive care units. More recently, severe histologic distension of bronchoalveolar structures,2 lung overinflation,3–6 large air cysts, and extended bronchiectasis7,8 have been reported in acute respiratory distress syndrome (ARDS) patients mechanically ventilated with high tidal volumes and pressures. One of the most important breakthroughs in the ventilatory management of such patients was the recognition of another iatrogenic potential of mechanical ventilation, which has been termed ventilator-induced lung injury  (VILI). The concept was derived from animal studies that clearly showed that mechanical ventilation with high airway pressure and tidal volume rapidly caused a permeability-type pulmonary edema with diffuse alveolar damage and was accompanied by severe lung inflammation when protracted.9 High lung volume rather than pressure was identified as responsible for these abnormalities, hence the term volutrauma  .
In the 1970s, the recommendation was to deliver generous tidal volumes in the range of 15–20 ml/kg to patients with acute lung injury10,11 to provide adequate carbon dioxide elimination and counterbalance the formation of atelectasis with ensuing development of lung regions with low ventilation/perfusion ratios.12 In the following years, practices progressively moved toward a reduction of tidal volume to values lower than 10 ml/kg,13 and, interestingly, a decrease in ARDS mortality was simultaneously observed.14 These progressive changes in ventilation modalities over time were supported by solid pathophysiologic foundations that form the concept of VILI. Definite proof of a causal relation between mortality and ventilatory strategy was given by the results of a multicenter randomized controlled trial that showed better survival in patients ventilated with a 6-ml/kg rather than a 12-ml/kg tidal volume.15 
In addition to the permeability alterations and diffuse alveolar damage observed during VILI, the possibility that lung cell overstretching induced a biochemical reaction was soon investigated. Indeed, lung cell stretch elicits many responses, including opening of ion channels,16 increased lipid trafficking in cell membranes,17 and CXC chemokine release.18 The release of many cytokines by lungs subjected ex vivo  to injurious ventilatory modalities was also reported.19 These findings led to the hypothesis that the multiple organ system dysfunction observed in many patients with ARDS was the result of uncontrolled production of inflammatory cytokines by the lungs and their systemic diffusion because of the alveolocapillary barrier alterations produced by injurious ventilation.20,21 Should this hypothesis prove to be true, it would offer both an interesting explanation for the reduced mortality observed with lung-protective ventilation strategies during ARDS and an exciting avenue for the search for newer treatments for this deadly disease. Some authors strongly advocated the use of antiinflammatory therapies during mechanical ventilation of patients with ARDS to decrease the risk and severity of associated organ failure.20,22,23 Given the high costs of such therapies and their potential for adverse effects,24 their administration should be based on strong and concordant experimental and clinical data. This may not be the case for the time being.
Too many inconsistencies and contradictions exist that preclude making a straightforward link between cell responses to stress, VILI, organ failure, and their putative treatments.25 Detailing these conceptual problems is beyond the scope of this editorial, but several aspects deserve mentioning. Pulmonary and systemic cytokine release was found highly variable during experimental VILI, even when experiments were performed under the same conditions and by the same team. For example, the concentration of tumor necrosis factor α in bronchoalveolar lavage was found higher than 1,000 pg/ml after ventilating isolated nonperfused lungs with a high tidal volume19 but 10 pg/ml under the same conditions at another institution.26 Similarly, the level of interleukin 6 was more than 1,500 pg/ml in the perfusate (indicating the systemic release of lung borne cytokine) of isolated perfused mice lungs subjected to injurious high-volume ventilation,27 whereas it was less than 100 pg/ml (a value lower than that observed during normal tidal volume ventilation in the former article) in a subsequent experiment conducted under the same conditions by the same team.28 
To their own surprise, Whitehead et al.  1 found that injurious ventilation can markedly reduce the release of inflammatory cytokines in response to intratracheal lipopolysaccharide challenge. This is different from the results of a recent experimental study showing that injurious ventilation promotes the release of inflammatory cytokines in rats with mesenteric ischemia–reperfusion (a two-hit lung injury).29 It is also worth noting that the study by Whitehead et al.  1 also confirms the highly variable release of cytokines observed during experimental injurious ventilation. They found no increase in the chemokine macrophage inflammatory protein 2 (the rodent equivalent of interleukin 8) in the bronchoalveolar lavage fluid of preparations ventilated with an injurious modality (high tidal volume, zero end-expiratory pressure) as compared with those ventilated with a protective lung strategy (low tidal volume, positive end-expiratory pressure), whereas in a previous article, using the same experimental settings, they reported a marked increase in this mediator.19 The authors ascribe this discrepancy to minor protocol changes.1 Similarly, they report that most of cytokine release in their study was due to alveolar macrophages, whereas in an earlier work, they concluded that pulmonary epithelium was a major contributor of cytokine production during injurious ventilation and may play an important role in the pathogenesis of lung injury.30 
These discrepancies are at the heart of the problem of the relation between mechanical ventilation and cytokine release and balance toward inflammation or antiinflammation. Whatever their origin, it is quite difficult to draw a comprehensive theory linking mechanical ventilation and systemic inflammation and organ failure and even more difficult to derive any therapeutic conclusion because, depending on the study, one may conclude that injurious ventilation does not affect cytokine balance26,31 or promotes either inflammation19,23 or antiinflammation, as in the study by Whitehead et al.  1 Clinical studies are as puzzling. One concluded that injurious ventilation orientates lung and systemic cytokine balance toward inflammation,32 whereas another showed that this balance was oriented toward antiinflammation.33,34 
What can clinicians conclude? Obviously, lung cells are challenged by multiple aggressions in critically ill patients (infection, hyperoxia, mechanical ventilation). There is no doubt that their response to these potentially injurious stimuli involves a cascade of mediators, including cytokines, whose complexity is fantastic. However, the variability of the biochemical response observed in extraphysiologic experimental conditions (isolated nonperfused lungs as in the current study1) must be balanced against the well-defined and easy-to-evidence morphologic alterations observed in ARDS patients ventilated for prolonged periods of time with high pressure/volume mechanical ventilation.2–8 In addition, VILI is certainly not solely the result of mechanical injury9 and may be worsened by hyperoxia, lung infection, and malnutrition.2 In the past decade, the prognosis of ARDS markedly improved because of a comprehensive physiologic approach of the effects of positive-pressure mechanical ventilation,35 and it may further improve as a result of the considerable amount of basic research on cytokines and VILI, including that presented in the article by Whitehead et al.  1 However, we should remain modest before drawing definitive theoretical and, more importantly, therapeutic conclusions, and avoid playing the sorcerer’s apprentice. Some exciting hypotheses turned out to be catastrophic for the patients.36 
* Service de Réanimation Médicale Hôpital Louis Mourrier, Colombes, University of Paris, Paris, France. † Service de Réanimation Chururgicale Hôpital Pitié-Salpêtrière, Paris, University of Paris, Paris, France.
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