Suter, P.M.

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Received: 27 December 2001Accepted: 28 December 2001Published online: 9 February 2002© Springer-Verlag 2002P.M. Suter (✉)Surgical intensive care, University Hospitals, 1211 Genève 14, Switzerlande-mail: peter.suter@hcuge.chIntensive Care Med (2002) 28:383–385DOI 10.1007/s00134-002-1226-5 E D I T O R I A LP.M. Suter MV causes lung inflammation and systemic immune depressionA balance of fire and iceThe lung is a unique immunologic organ, responding toinfectious, antigenic or toxic insults with specific humor-al, cellular, and tissular mechanisms while maintainingits primary biologic functions [1]. It has been recognizedmore recently that other types of aggression lead to asignificant activation of inflammatory mechanisms with-in the lung. For instance, direct or indirect severe traumaresults in acute inflammation of the pulmonary paren-chyma in a significant proportion of patients. Thesechanges are characterized by massive leukocyte segrega-tion in lung capillaries and interstitial space, as well as amarked leak of plasma and blood cells into the interstiti-um. This inflammatory reaction is associated with signif-icant changes in pro- and anti-inflammatory cytokinelevels in bronchoalveolar lavage (BAL) fluid [2]. Thesemediators seem to play essential roles in the lung tissuechanges, as their local concentrations are significantlyhigher than in the systemic circulation. A few exceptionsexist, however: in ARDS secondary to septic shock dueto an extrapulmonary infection, for instance, serum lev-els of proinflammatory cytokines can increase as muchas intrapulmonary values [3]. The inflammatory tissuereaction can be of short duration and self-limiting, prob-ably due to a subtle autoregulation and balance betweenpro- and anti-inflammatory mediators and repair mecha-nisms. The resulting features of cellular infiltration, tis-sue remodelling, and healing seem to be quite similar toother types of wounds and their healing [4]. In relativelyrare cases, lung inflammation can persist for weeks, evenwithout clear-cut superinfection, and persistently highBAL and/or plasma levels of proinflammatory cytokinesseem to indicate a poor outcome [5].The latest addition to the list of identified agents ca-pable of inducing significant inflammatory lung injury ismechanical ventilation (MV), above all if higher tidalvolumes and lower positive end-expiratory pressure(PEEP) levels are used [6, 7]. Although it has beenknown for a long time that damage to pulmonary tissueand airways can occur during prolonged MV, it has onlybecome clear during recent years that not only are me-chanical forces responsible for alveolar rupture and air-way dilatation, but also acute inflammation is involved.MV with “normal” or high tidal volumes leads to ac-tivation of leukocytes such as macrophages, monocytes,and polymorphonuclear cells, but possibly also to stimu-lation of alveolar pneumocytes I and airway epithelialcells, with a consecutive production of cytokines of theTNFα, IL-1β, IL-6 or IL-8 type, and a number of others.Stretching cultured human macrophages in a plasticchamber by positive pressure ventilation results in a sig-nificant production of pro-inflammatory cytokines whenendotoxin is present [8]. MV of isolated perfused lungsproduces increased pulmonary cytokines and transloca-tion of nuclear factor-κB, which are effects similar tothese observed after endotoxin infusion [7, 9].From earlier work in humans, i.e., critically ill pa-tients requiring MV, it seems clear that marked changesin cytokine levels and leukocyte count can be observedin BAL over a time period of 1–3 days [10]. Less isknown about shorter periods of MV, both in terms oflung injury and inflammatory changes.This gap in knowledge is beginning to be filled bywork such as the one published in this issue of IntensiveCare Medicine by Frans B. Plötz and his colleagues [11].These authors have studied twelve infants undergoing di-agnostic cardiac catheterization. The short-term effectsof MV using a VT of 10 ml/kg and a PEEP of 4 cmH2Oon intrapulmonary levels of pro- and anti-inflammatorymediators were assessed, as well as the associatedchanges in the capacity of leukocytes collected from thesystemic circulation to produce interferon IFNγ, TNFα,and IL-6, and finally the killing activity of systemic nat-ural killer (NK) cells. The authors observed an increasein TNFα and IL-6 levels in BAL, but no significantchanges in IL-8 and the anti-inflammatory cytokines IL-10 and IFNγ. In systemic blood, the capacity of lympho-cytes to produce IFNγ was decreased and, after LPSstimulation, monocytes released less IL-6 and TNFα; inaddition, the killing activity of NK cells was decreased.How do these findings fit into the concept of the re-sponse of the lung tissue to insults such as trauma orMV? First, the results reported by Plötz et al. confirmthe early inflammatory reaction to positive pressure ven-tilation seen in isolated lungs [7, 9], experimental ani-mals subjected to high VT and low PEEP ventilation[12], and ICU patients [10]. Second, the data presentedindicate that 2 h of MV is sufficient in these children toinitiate significant changes in the local and systemic im-mune status. Third, their work suggests that further stud-ies in children and adults are warranted – not only toconfirm the results reported here, but also to define ifdifferent techniques of MV (e.g., lower tidal volume,higher PEEP) lead to a different pulmonary and systemicimmune response. In addition, the specific roles of MV,anesthesia, and other interventions such as surgeryshould be investigated further.There is another important consideration which shouldbe included in this discussion. Indeed, the effects of a lo-cal inflammatory reaction on systemic immune status arenot well explored. On the one hand, an overflow or atranslocation of mediators and activated cells from thesite of inflammation into the systemic circulation and todistant organs have been observed, inducing systemicsigns of inflammation such as fever, hyperdynamic car-diovascular state, and leukocytosis as well as vital organdysfunctions [13]. On the other hand, it has been suggest-ed that local inflammation could be coordinated with sys-temic antiinflammation, thereby allowing the body to lo-calize activated leukocytes at the injured local site [14].This reaction could protect uninvolved organs and tissuesfrom the damaging effects of mediators and activatedcells, but it may also be immunosuppressive.There are some data confirming a strong local pro-inflammatory activity in acute lung injury, assessed byBAL, whereas no such activity was detected in systemicblood [15]. Another clinical example of systemic immu-nosuppression (also called immune paralysis) occurs inthe trauma patient: lymphocyte function can be impairedand these patients are at increased risk for infection, sep-sis, and death [16]. In critically ill patients undergoingnon-protective methods of MV and presenting with in-creased signs of intrapulmonary inflammation as as-sessed by BAL fluid, higher plasma levels of IL-6 (a cy-tokine considered to have significant antiinflammatorycharacteristics), more vital organ dysfunctions and ahigher mortality have been observed [17, 18].Any therapeutic consequences? If confirmed, the dataof the present [11] and further studies could change themethods and techniques of MV used to allow short- orlonger-term diagnostic or therapeutic interventions underanesthesia. It could be possible that even short-term MVshould be conducted using a lung-protective strategy. Onthe other hand, millions of patients undergo MV duringgeneral anesthesia each week around the world, and littleclinical evidence is available suggesting this is harmfulfor subsequent respiratory and other organ function. Re-cently, a clinical study did not reveal an increase in plas-ma levels of pro- or antiinflammatory cytokine levels af-ter 1 h of mechanical ventilation with 15 or 6 ml/kg bwtidal volume [19].However, the absence of clinically visible harmful ef-fects of MV with normal tidal volume should not stopclinical investigators from looking into mechanisms pro-ducing acute lung inflammation and systemic depressionof immune defences, because superinfection is a well-recognized complication after this type of intervention.The susceptibility and mechanisms of infection havebeen clarified to some extent, but more work must bedone to improve our understanding, and thereby themeans for prevention.In conclusion, Plötz et al. report important changes inthe immune response in children after only 2 h of MV – fire in the lung and icy peripheral leukocytes – a con-firmation of a systemic immunosuppression in responseto acute lung inflammation?384References1. 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International consensusconferences in intensive care medicine:ventilator-associated lung injury inARDS (1999) Am J Respir Crit CareMed 160:2118–21247. Tremblay L, Valenza F, Ribeiro SP, LiJ, Slutsky AS (1997) Injurious ventila-tory strategies increase cytokines andc–fos m–RNA expression in an isolat-ed rat lung model. J Clin Invest 99:1–98. Pugin J, Dunn I, Jolliet PH, Tassaux D,Magnenat JL, Nicod P, Chevrolet JC(1998) Activation of human macro-phages by mechanical ventilation invitro. Am J Physiol 19:L 1040–L 10509. Held HD, Boettcher S, Hamann L,Uhlig S (2001) Ventilation – inducedchemokine and cytokine release is as-sociated with activation of nuclear fac-tor – kB and is blocked by steroids.Am J Respir Crit Care Med163:711–71610. Ranieri VM, Suter PM, Tortorella C,De Tullio R, Dayer JM, Brienza A,Bruno F, Slutsky AS (1999) Effect ofmechanical ventilation on inflammato-ry mediators in patients with acute res-piratory distress syndrome. A random-ized controlled trial. 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MV causes lung inflammation and systemic immune depression: A balance of fire and ice

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MV causes lung inflammation and systemic immune depression: A balance of fire and ice

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