A cover 1 - 2012 - aots.sanita.fvg.it€¦ · Several inflammatory markers, such as TNF- , PCR,...

Shortness of Breath 2012; 1 (1): 1 1

Editorial

Come gather !round peopleWherever you roamAnd admit that the watersAround you have grownAnd accept it that soonYou"ll be drenched to the bone.If your time to youIs worth savin"Then you better start swimmin"Or you"ll sink like a stoneFor the times they are a-changin".

[Bob Dylan]

Shortness of breath (SoB) is a common symptom in respiratory medicine, but it is also an expression of concern andworrying. Shortness of Breath (SoB) is a new online journal aimed first of all to be read. Favorite readers will be physi-cians, respiratory and critical care ones, but not only them, with the ambition to be timely for the readers, but also mov-ing to the next future.Bob Dylan sang the song “Times they are a changin" “ just on the night President JF Kennedy was killed, and it immedi-ately became the song of a new generation which accompanied the hopes and the changes of the following years. At thebeginning, the journal will privilege mini-reviews on scientific and daily practice topics, and clinical cases. Quarterly SoBwill cover respiratory medicine, with emphasis on clinical medical practice, but also translational medicine, innovation inrespiratory and critical care. We are deeply convinced that medicine is a rapidly changing multidisciplinary field of knowl-edge based on Life Sciences. Current medical care could not exist without a constant referral to knowledge area just fewdecades ago not involved into traditional references of pathology and clinics, such as biotechnology, molecular biology (the“omics” and beyond), bioinformatics, GRID computing, nanotechnology, economics, safety and quality evaluation, and soon. Systems biology is giving its aid to medicine moving from a reductionist to a personalized approach to the patient. Amajor paradigm of changing point of view in medicine is the dominant role of Internet not only for training and learning, butalso for medical practice (e.g. ‘googling’ for diagnosis) and patient-physician relationship. Even if medicine is even morescience of life than a physician centred discipline, relationship among humans remains the core of medicine, attention willbe also paid to “medical humanities”, a section of the journal hosting non-medical papers concerning the complexity of hu-man factor in health and illness status. In this first issue of the journal we have the privilege to host the contribution of thefamous writer and newspaper columnist Claudio Magris. The Italian-French artist Marco Ceruti will help the journal to stayyoung and pleasing by means of cartoons and paintings in the New Yorker’s magazine stlyle.We claim for contributions from physicians (pneumologists, critical care physicians, but not only them), and scientists.Each contribution will be peer reviewed in an attempt to ensure that articles meet the journal’s standards of quality, andscientific validity. The journal SoB is coming out in changing times, characterized by the global economic crisis, climatechange, social and religious conflicts: it should be easier to follow the “Zeitgeist”, the spirit of the times, and to be wor-ried and concerned. Nevertheless, we will collect in a section of SoB called “Land of hope and dreams” any news fromthe scientific literature that may carry hope for positive changes of patient care in a next future1. Respiratory medicineand science of life are for the progress and wellness of human being, so they have a bet on better times, anyway. Hop-ing this spirit of SoB will be shared by Authors and readers too.All articles published by “Shortness of Breath” are made freely and permanently accessible online immediately uponpublication, without subscription charges or registration request. Full-text of each article is deposited immediately andpermanently archived in PubMed Central.

Marco Confalonieri, MD

Editor in Chief of “Shortness of Breath“Director of Pneumology&Critical Care Department

University Hospital of Cattinara, Trieste, Italy

1 Bruce Springsteen “Land of hope and dreams”, at http://www.youtube.com/watch?v=XWOZotnFhLA accessed on December 9th, 2012.

Shortness of Breath (SoB): Times They Are A Changin!, isn’t it?

2 Shortness of Breath 2012; 1 (1): 2-6

Mini-review

Andrea Bianco1,2

Viviana Turchiarelli1,2

Federica Fatica1,2

Ersilia Nigro3

Gianluca Testa2

Carolina Vitale1

Theodoros Thanassoulas1

Olga Scudiero3,4

Aurora Daniele3,5

1 Chair of Diseases of the Respiratory Apparatus, Univer-sity of Molise, Campobasso, Italy

2 Department of Medicine and Health Sciences, Univer-sity of Molise, Campobasso, Italy

3 CEINGE - Advanced Biotechnologies ‘Scarl’, Napoli,Italy

4 Department of Biochemistry and Medical Biotechnolo-gies, University of Napoli “Federico II”, Napoli, Italy

5 Department of Sciences and Environmental, Biologicaland Pharmaceutical Technologies, II University ofNapoli, Caserta, Italy

Address for correspondence:Andrea Bianco, MD, PhDDepartment of Medicine and Health Sciences University of Molise Via de Sanctis 86100 Campobasso, ItalyE-mail: [email protected]

Summary

Metabolic disorders are common conditions associ-ated to chronic obstructive pulmonary disease(COPD) contributing to lung function impairment andmortality. Evidence suggests that systemic inflamma-tion may be the link between COPD and metabolic al-terations, but this issue is still poorly investigated.This review focuses on the adipocyte-derived cy-tokine adiponectin which has been shown to have arole in the airway patho-physiology and thereforerepresents an attractive marker to link COPD andmetabolic disorders.

KEY WORDS: COPD; adiponectin; metabolic disorders;inflammation.

Background

Chronic obstructive pulmonary disease (COPD) is a com-plex inflammatory disorder characterized by progressiveairflow limitation (1). There is a growing awareness that

COPD is a lung disease with heterogeneous systemic in-flammatory consequences and extrapulmonary comor-bidities. Like other complex diseases, COPD is due to a variety ofprocesses that contribute to the onset and progression ofthe disease including immune response, influence of hor-mones and environmental factors that represent both ini-tiators and causative agents. Extrapulmonary comorbidities are common and signifi-cantly impact disease severity and mortality. Cardiovas-cular disease, hypertension, musculoskeletal disorders,lung cancer, diabetes mellitus II, and metabolic disor-ders are among the most prevalent and relevant, al-though the molecular mechanisms linking COPD and itscomorbidities are still poorly understood (2). Unexplained weight loss, changes in body composition aswell as alterations in caloric intake, basal metabolic rateand intermediate metabolism are commonly reported inCOPD. In parallel, a consistent number of COPD pa-tients experience overweight and obesity, although the na-ture of this association remainsto be clarified (3). A close association betweenmetabolic syndrome biomark-ers and impairment of respi-ratory function as been re-cently reported, suggesting akey role for systemic inflam-mation in development ofboth metabolic disorders andlung function impairment. In this regard, scientific interesthas been recently focused on adipocyte-derived cytokinesincluding adiponectin whose receptors have been identi-fied on lung tissue.

Airway epithelium, environmental factors and inflammation

Airway epithelium represents a critical site for the mech-anisms involved in the complex interaction between en-vironmental triggers, airway inflammation (4-6) and spe-cific metabolic pathways. In addition to environmental air pollution, smoking habit isthe most relevant risk factor not only for COPD but alsofor many other chronic diseases. Smoking triggers a lo-cal inflammatory response throughout the whole tracheo-bronchial tree and pathological changes characteristic ofCOPD are found in the proximal large airways, peripheralsmall airways, lung parenchyma and pulmonary vascula-ture. Evidence indicates that airway inflammatory celltrafficking at epithelium level is mainly coordinated byadhesion molecules expression (7-10). The cellular pat-tern is quite heterogeneous, involving macrophages, neu-trophils, T and B lymphocytes and mast cells. Besidethese local effects, smoking may significantly contribute

COPD and metabolic disorders: role of adiponectin

Adiponectin is anadipocyte-derivedcytokine whose re-ceptors have beenidentified on lungtissue.


Shortness of Breath 2012; 1 (1): 2-6 3

to systemic inflammation, acting on the stimulation of thehematopoietic system and the consequent release ofpolymorphonuclear leukocytes and generation of sys-temic oxidative stress. These systemic effects of smokingcould explain why patients with COPD often concomi-tantly suffer from other chronic diseases such as cardio-vascular diseases or metabolic disorders with or withoutother risk factors such as arterial hypertension, hyperlipi-demia and obesity (2). The chronicity of the inflammatorystate in COPD is sustained by an increased production ofseveral pro-inflammatory cytokines at both serum and air-way levels. Indeed, C-reactive protein (CRP), fibrinogen,IL-1 , TNF- , MCP-1, IL-8, IL-6 have been associatedwith disease progression and exacerbation (11, 12), whilstan inverse correlation between anti-inflammatory cytokineIL-10 and COPD has been demonstrated.

Inflammation and metabolic disorders

Around 50% of patients with severe COPD and chronicrespiratory failure and 10 to 15% of patients with mild tomoderate disease experience unexplained weight loss(13, 4).It has been suggested that the potential causative factors ofcachexia are energy imbalance, disuse athrophy of the mus-cles, arterial hypoxiaemia and hormonal insufficiency (14). In addition, it has been reported that COPD patientspresent an increased basal metabolism leading to proteincatabolism, resistance to anabolic hormones (insulin)and to increased levels of catabolic molecules (cortisol,glucagon and catecholamines) (15). This so called “Hy-percatabolic syndrome” (HS) has the consequence ofskeletal and cardiac muscle protein breakdown (16-18)and loss of fat mass contributing to a lesser extent, al-though body composition alterations can occur also in theabsence of clinically significant weight loss (13).Systemic inflammation has become the primary focus tolink COPD and cachexia (13, 19, 20, 14) and to explainthe development of COPD as a syndrome in susceptiblesubjects (2). Several inflammatory markers, such as TNF- , PCR, IL-6, IL-8, Fas, Fas-L, Lipopolysaccharide Binding Proteinhave receiving great attention for their role in increasedmetabolism, weight loss and asthenia (21), although thereis still no direct evidence for a cause-and-effect relation-ship between them (14). Whilst weightloss has been the traditional nutritional con-cern in patients with COPD, a great number of COPD pa-tients is affected by overweight and obesity, but the na-ture of this association remains to be clarified (3). Clinical evidence indicates that in any given individualobesity decreases chest wall and lung compliance, re-duces the diaphragm motility and increases work and oxy-gen cost of breathing (22, 23).On the other side, COPD patients are at increased risk ofdeveloping obesity because of reduced level of physicalactivities in daily life and the repeated courses of systemicglucocorticosteroids, which cause truncal obesity as a re-sult of glucocorticoid mediated redistribution of storedenergy. (24). However, the pathophysiological interac-tions that occur when both COPD and obesity coexist inthe same individual are still poorly understood. It has been recently shown that the metabolic syndromecan precede reductions in lung function. The results by

Naaved et al. indicate that dyslipidemia, elevated heartrate, elevated insulin resistance and leptin levels were in-dependent risk factors of sub-sequent FEV1 decline withinsix months of World TradeCenter irritant exposure (13).However, evidence also indi-cates a possible protectiverole of obesity in COPD mor-tality. In mild and moderateCOPD patient, the low-gradesystemic inflammation associated with visceral fat accu-mulation contributes to develop cardiovascular complica-tions and type 2 diabetes and may contribute to mortal-ity; in contrast, in severe COPD obese patients mortalityrisk is reduced: this condition is described as “ObesityParadox” (24, 25). Systemic inflammation may represent a common back-ground for abnormal adipose tissue function and lungfunction impairment and may provide new insight into thepathogenesis and reversibility of systemic involvement ofCOPD (26). Recent studies have provided evidence for a link be-tween adipose tissue and circulating concentrations ofTNF- , IL-6, leptin and adiponectin that play a part inmetabolic changes associated with COPD andreduced/impaired lung function (17).

Adiponectin as a potential target for COPD-related metabolic disorders

In physiologic condition, adipose tissue synthesizes andsecretes a variety of proteins known as “adipokines” in-volved in several biological functions as immunity, insulinresistance, lipid and glucose metabolism, inflammation.Among the adipokines, adiponectin is a proteic hormonthat structurally belongs to the complement 1q familyand is found at high concentrations (~0.01% of the totalprotein) in serum of healthy individuals (25). Adiponectinis synthetized and secreted by adipose tissue as a 30KDa monomer that, due to post-translational modifica-tions, forms characteristic homomultimers. A peculiarstructural feature of adiponectin is its ability to assembleinto several characteristic oligomeric multimers includingtrimers known ad low molecular weight (LMW), hexamersknown ad medium molecular weight (MMW), and higher-molecular weight (HMW) multimeric complexes. Growingevidences associate the oligomerization process withmultiple biological activities of adiponectin. In humans, the gene encoding adiponectin (ACDC) is lo-cated on chromosome 3q27; single-nucleotide polymor-phisms (SNPs) and haplotypes in ACDC gene have beenassociated with obesity as well as with metabolic syn-drome (MS) and CAD (26-28). Adiponectin acts throughbinding and activation of two receptors, AdipoR1 andAdipoR2 that are ubiquitous expressed in several or-gans, tissues and cell lines (29-31). In particular, it is re-ported that AdipoR1 is mainly implicated in the meta-bolic functions of adiponectin, whereas AdipoR2 is moreinvolved in anti-inflammatory and anti stress-oxidativeactivities (32, 33). Downstream of these two receptors, thebiological effects of adiponectin are mediated by differentsignal pathways involving the following molecules: AMPK,ERK, AKT and P38 (34).

Adiponectin mayplay a role in me-tabolic changesassociated withCOPD.

Adiponectin plays an important role in energy homeosta-sis, regulating both glucose and lipid metabolism. Inhumans, down regulation of adiponectin and its recep-tors are associated with obesity, metabolic syndrome, in-sulin resistance, hyperinsulinemia, and type 2 diabetes,as well as with cardiovascular diseases (25, 35, 36).Moreover, adiponectin seems implicated in the develop-ment and progression of several local and systemic in-flammatory processes. In fact, it has been recently out-lined that adiponectin could play an important role inanti-inflammatory responses in several tissues and cellcultures such as pancreatic beta cells and endothelialcells (37, 38). Mouse models of adiponectin deficiencydevelop lung function impairment and systemic inflam-mation. In fact, Summer et al. reported a protective roleof adiponectin on lung through inhibition of alveolarmacrophage function and vascular homeostasis regula-tion (39, 40). On the other hand, it was also reported thatadiponectin plays an important pro-inflammatory role inexperimental tobacco smoke-induced COPD (29). Allthese in vitro and in vivo evidences support the idea ofan anti-inflammatory role of adiponectin. Furthermore, inseveral pathological conditions, adiponectin serum lev-els have been found elevated: osteoarthritis, rheumatoid

arthritis, lupus erythemato-sus, Crohn’s disease, cysticfibrosis, pulmonary emphy-sema, myotonic distrophyand COPD (41, 42). In allthese diseases, adiponectinlevels correlated with in-creased inflammatory cy-tokines (TNF-! IL-6, IL-1!and CRP) suggesting thatadiponectin attenuates ormodulates inflammation.Additionally, while the role

of adiponectin in energy me-tabolism has been studied in several tissues, organs andcells, little is known about its role in inflammatory lungdiseases. While the role of adiponectin in energy metabolism hasbeen widely studied, little is known about its role in in-flammatory processes of lung (25). Different studies in-dicate that adiponectin can exert pro-inflammatory ratherthan anti-inflammatory lung properties. Recent data haverevealed an anti-inflammatory role in the lung: micelacking adiponectin spontaneously develops a COPD-like phenotype with extrapulmonary effects, includingsystemic inflammation, body weight loss and osteoporo-sis. This finding highlights the key role of adiponectin inlung pathologies and the novel link between COPD andmetabolic disorders (43, 44). In humans, adiponectinserum levels are elevated in COPD patients but the bi-ological effects of adiponectin and of its oligomers on hu-man lung and even less in lung diseases are not fullyclear (42). In fact, it is known that low levels of totaladiponectin are present in smokers without COPD, whilehigh levels are observed in COPD patients (45-47). Re-cently, different studies showed that total serum levels ofadiponectin represent a significant diagnostic and prog-nostic marker of COPD. Recently, it has demonstratedthat the oligomerization pattern of adiponectin is alteredin COPD; in particular the higher levels of adiponectinare associated with a specific increase of HMW, the

most biologically active isoforms (42). Protective anti-in-flammatory role of HMW oligomers has been demon-strated both in vivo and in vitro studies (48). Pajavani re-ported that HMW oligomers improve insulin sensitivity,suppress apoptosis in endothelial cells, and their levelsare inversely correlated to cardiovascular events and tothe severity of coronary artery disease (49). Further-more, in vitro evidences indicate that HMW oligomers arealso involved in TNF- suppression. Daniele et al. foundno detectable TNF- values in normal subjects and inCOPD patients suggesting that the high levels ofadiponectin and HMW could be involved in reducing theincrease of circulating levels of this pro-inflammatorycytokine. As COPD is a disease characterized by inflam-matory process and impairment of endothelial functions,the high levels of HMW found in this study may exert aprotective role on both pathogenic mechanisms. Theseobservations suggest that total levels of adiponectin andHMW oligomers can be considered useful complemen-tary criteria to improve prognostic and therapeutic strate-gies for lung diseases (42). The specific biological role of adiponectin in lung functionsderives also from the observation that both AdipoRs areexpressed in COPD and tumour lung (29, 50). Petridou etal. reported the presence of AdipoR1 and AdipoR2 incancerous lungs and the association of AdipoR2 expres-sion with the progression of lung cancer, while Miller et al.showed that only AdipoR1 was expressed in healthy andCOPD lungs (29, 50).A recent study demonstrated the expression of AdipoR1and AdipoR2 at mRNA level as well as at protein levelin lung tissues from COPD and from non small cell lungcancer (NSCLC) with a AdipoR1 expression higher thanAdipoR2 in COPD suggesting a specific signaling path-way of adiponectin in this disease (42). The downregu-lation of AdipoR2 could be responsible for the worsen-ing of inflammation state in COPD and related to lungNSCLS cancer. Accordingly, it was reported that AdipoR2 signaling pathway is mainly involved inadiponectin inhibition effects on inflammation and oxida-tive stress (32). Furthermore, epidemiologic as well asin vitro studies have associated adiponectin and Adi-poRs with several malignancies (51). In fact, adiponectinhas been shown to suppress tumor growth in mice andcell growth in various cell lines (52, 53). In contrast,adiponectin stimulated colonic epithelial cell proliferationand breast carcinoma cell lines (54, 55). Besides, be-cause serum adiponectin is not significantly influencedby smoking status, it is a very promising biomarker ofcardiovascular outcomes in COPD (56). The adiponectin concentration and oligomeric isoformdistribution, and the modulation of receptors add complex-ity to adiponectin system.

Conclusions

New insight into mechanisms underlying systemic in-flammatory consequences and extrapulmonary comor-bidities in COPD will contribute to identification of poten-tial targets for new diagnostic and therapeuticapproaches. Adiponectin appears to be an attractivebiomarker in COPD and represents a promising dis-ease indicator with implications for the treatment ofCOPD.

A. Bianco et al.


In humans, adipo-nectin serum le-vels are elevatedin COPD patientsbut the biologicaleffects of adipo-nectin on humanlung are not yetfully clarified.

References

1. World Health Organization. The GOLD global strat-egy for the management and prevention of COPD.www.goldcopd.com. Date accessed: 2011.

2. Nussbaumer-Ochsner Y, Rabe Klaus F. SystemicManifestations of COPD. Chest 2011;139;165-173.

3. van den Bemt L, van Wayenburg CAM, Smeele IJM,Schermer TRJ. Obesity in patients with COPD, anundervalued problem? Thorax 2009;64;640.

4. Mazzarella G, Ferraraccio F, Prati MV, Annunziata S,Bianco A, Mezzogiorno A, et al. Effects of diesel ex-haust particles on human lung epithelial cells: an invitro study. Respir Med 2007;101(6):1155-62.

5. Mazzarella G, Esposito V, Bianco A, Ferraraccio F,Prati MV, Lucariello A, et al. Inflammatory effects onhuman lung epithelial cells after exposure to dieselexhaust micron sub particles (PM 1.0) and pollen al-lergens. Environ Pollut 2012;161:64-69.

6. Esposito V, Lucariello A, Savarese L, Cinelli MP,Ferraraccio F, Bianco A, et al. Morphology changesin human lung epithelial cells after exposure to dieselexhaust micron sub particles (PM1.0) and pollen al-lergens. Environ Pollut 2012;171:162-7.

7. Floreani AA, Wyatt TA, Stoner J, Sanderson SD,Thompson EG, Allen-Gipson D, Heires AJ. Smokeand C5a induce airway epithelial intercellular adhe-sion molecule-1 and cell adhesion. Am J Respir CellMol Biol 2003;29(4):472-82. Epub 2003 Apr 24.

8. Whiteman SC, Bianco A, Knight RA, Spiteri MA. Hu-man rhinovirus selectively modulates membranousand soluble forms of its Intercellular Adhesion Mole-cule-1 (ICAM-1) receptor to promote epithelial cell in-fectivity. J Biol Chem 2003;278(14):11954-11961.

9. Bianco A, Whiteman SC, Sethi SK, Allen JT, KnightRA, Spiteri MA. Expression of Intercellular AdhesionMolecule-1 (ICAM-1) in nasal epithelial cells of atopicsubjects: a mechanism for increased rhinovirus infec-tion? Clin Exp Immunol 2000;121(2):339-45.

10. Bianco A, Sethi SK, Allen JT, Knight RA, Spiteri MA.Th2 cytokines exert a dominant influence on epithe-lial cell expression of the Major group Human Rhi-novirus Receptor, ICAM-1. European RespiratoryJournal 1998;12:619-62.

11. Corsonello A, Antonelli Incalzi R, Pistelli R, PedoneC, Bustacchini S, Lattanzio F. Comorbidities ofchronic obstructive pulmonary disease. Current Opin-ion in Pulmonary Medicine 2011;17(suppl 1):S21-S28.

12. Agusti A. Systemic Effects of Chronic ObstructivePulmonary Disease. What We Know and What WeDon’t Know (but Should). Proc Am Thorac Soc2007;4:522-525.

13. Naveed B, Weiden Michael D, Kwon S, Gracely Ed-ward J, Comfort Ashley L, Ferrier N, KasturiarachchiKusali J, Cohen Hillel W, Aldrich Thomas K, RomWilliam N, Kelly K, Prezant David J, Nolan A. Meta-bolic Syndrome Biomarkers Predict Lung FunctionImpairment A Nested Case-Control Study. Am JRespir Crit Care Med 2012;185(4): 392-399.

14. Wagner PD. Possible mechanisms underlying thedevelopment of cachexia in COPD. Eur Respir J2008;31:492-501.

15. Baldi S, Aquilani R, Pinna GD, et al. Fat-free masschange after nutritional rehabilitation in weight losing

COPD: role of insulin, C-reactive protein and tissuehypoxia. International Journal of COPD 2010;5:29-39.

16. Pasini E, Aquilani R, Dioguardi FS, D’Antona G,Gheorghiade M, Taegtmeyer H. Hypercatabolic syn-drome: molecular basis and effects of nutritional sup-plements with amino acids. Am J Cardiol 2008 Jun2;101(11A):11E-15E.

17. Pansarasa O, Flati V, Corsetti G, et al. Oral aminoacid supplementation counteracts age-induced sar-copenia in elderly rats. The American Journal of Car-diology 2008.02.07.

18. Dal Negro RW, Aquilani R, Bertacco S, et al. Com-prehensive effects of supplemented essential aminoacids in patients with severe COPD and sarcopenia.Monaldi Archives for Chest Disease 2010 Mar;73(1):25-33.

19. Anant RC Patel, John R Hurst. Extrapulmonary co-morbidities in chronic obstructive pulmonary dis-ease: state of the art. Expert Rev Respir Med 2011;5(5):647-662.

20. Holguin F. The Metabolic Syndrome as a Risk Fac-tor for Lung Function Decline. American Journal ofRespiratory and Critical Care Medicine 2012;Vol 185.

21. Yang Yi-meng, Sun Tie-ying, Liu Xin-min. The role ofserum leptin and tumor necrosis factor-" in malnutri-tion of male chronic obstructive pulmonary diseasepatients. Chin Med J 2006;119(8):628-633.

22. Collins LC, Hoberty PD, Walker JF, et al. The effectof body fat distribution on pulmonary function tests.Chest 1995;107:1298-302.

23. Thomas PS, Cowen ER, Hulands G, et al. Respira-tory function in the morbidly obese before and afterweight loss. Thorax 1989;44:382-6.

24. Vestbo J, Prescott E, Almdal T, et al. Body mass, fat-free body mass, and prognosis in patients withchronic obstructive pulmonary disease from a ran-dom population sample: Findings from the Copen-hagen city heart study. Am J Respir Crit Care Med2006;173:79-83.

25. Landbo C, Prescott E, Lange P, et al. Prognosticvalue of nutritional status in chronic obstructive pul-monary disease. Am J Respir Crit Care Med 1999;160:1856-1861.

26. Franssen FME, O’Donnell DE, Goossens GH, BlaakEE, Schols AMWJ. Obesity and the lung: 5. Obesityand COPD. Thorax 2008;63;1110-1117.

27. Wert Susan E. Does adiponectin play a role in pul-monary emphysema? Am J Physiol Lung Cell MolPhysiol 2008;294:L1032-L1034.

28. Daniele A, Cammarata R, Pasanisi F, Finelli C, Sal-vatori G, Calcagno G, Bracale R, Labruna G, NardelliC, Buono P, Sacchetti L, Contaldo F, Oriani G. Mo-lecular analysis of the adiponectin gene in severelyobese patients from southern Italy. Ann Nutr Metab2008;53(3-4):155-61.

29. Daniele A, Cammarata R, Masullo M, Nerone G, Fi-namore F, D’Andrea M, Pilla F, Oriani G. Analysis ofadiponectin gene and comparison of its expressionin two different pig breeds. Obesity (Silver Spring)2008;16(8):1869-74.

30. Gable DR, Matin J, Whittall R, Cakmak H, Li KW,Cooper J, Miller GJ, Humphries SE. HIFMECH inves-tigators. Common adiponectin gene variants showdifferent effects on risk of cardiovascular disease



and type 2 diabetes in European subjects. Ann HumGenet 2007;71(Pt 4):453-66.

31. Miller M, Youn Cho J, Pham A, et al. Adiponectin andFunctional Adiponectin Receptor 1 Are Expressed byAirway Epithelial Cells in Chronic Obstructive Pul-monary Disease. J Immunol 2009;182;684-691.

32. Buechler C, Wanninger J, Neumeier M. Adiponectinreceptor binding proteins-recent advances in eluci-dating adiponectin signalling pathways. FEBS Lett2010;22;584(20):4280-6.

33. Petridou ET, Mitsiades N, Gialamas S, AngelopoulosM, Skalkidou A, Dessypris N, Hsi A, Lazaris N, Poly-zos A, Syrigos C, Brennan AM, Tseleni-Balafouta S,Mantzoros CS. Circulating adiponectin levels andexpression of adiponectin receptors in relation tolung cancer: two case-control studies. Oncology2007;73(3-4):261-9.

34. Yamauchi T, Nio Y, Maki T, Kobayashi M, TakazawaT, Iwabu M, Okada-Iwabu M, Kawamoto S, KubotaN, Kubota T, Ito Y, Kamon J, Tsuchida A, Kumagai K,Kozono H, Hada Y, Ogata H, Tokuyama K, TsunodaM, Ide T, Murakami K, Awazawa M, Takamoto I,Froguel P, Hara K, Tobe K, Nagai R, Ueki K, Kad-owaki T. Targeted disruption of AdipoR1 and Adi-poR2 causes abrogation of adiponectin binding andmetabolic actions. Nat Med 2007;13(3):332-9.

35. De Rosa, et al. Domestic animal 2012; in press.36. Kadowaki T, Yamauchi T. Adiponectin and adiponectin

receptors. Endocr Rev 2005;26(3):439-51.37. Koichi Tomoda, Masanori Yoshikawa, Takefumi Itoh,

Shinji Tamaki, Atsuhiko Fukuoka, Kazuyuki Komeda,and Hiroshi Kimura. Elevated Circulating PlasmaAdiponectin in Underweight Patients With COPD.Chest 2007;132(1).

38. Giannessi D, Maltinti M, Colotti C, Del Ry S. L’adipo-nectina: un nuovo indicatore di rischio cardiovasco-lare (Rassegna). LigandAssay 2007;12(2).

39. Wijesekara N, Krishnamurthy M, Bhattacharjee A,Suhail A, Sweeney G, Wheeler MB. Adiponectin-in-duced ERK and Akt phosphorylation protects againstpancreatic beta cell apoptosis and increases insulingene expression and secretion. J Biol Chem2010;285(44):33623-31.

40. Zhao HY, Zhao M, Yi TN, Zhang J. Globularadiponectin protects human umbilical vein endothe-lial cells against apoptosis through adiponectin recep-tor 1/adenosine monophosphate-activated proteinkinase pathway. Chin Med J (Engl) 2011;124(16):2540-7.

41. Summer R, Little FF, Ouchi N, Takemura Y, Apra-hamian T, Dwyer D, Fitzsimmons K, Suki B, Para-meswaran H, Fine A, Walsh K. Alveolar macrophageactivation and an emphysema-like phenotype inadiponectin-deficient mice. Am J Physiol Lung CellMol Physiol 2008;294(6):L1035-42.

42. Summer R, Fiack CA, Ikeda Y, Sato K, Dwyer D,Ouchi N, Fine A, Farber HW, Walsh K. Adiponectindeficiency: a model of pulmonary hypertension asso-ciated with pulmonary vascular disease. Am J Phys-iol Lung Cell Mol Physiol 2009;297(3):L432-8.

43. Daniele A, De Rosa A, De Cristofaro M, MonacoML, Masullo M, Porcile C, Capasso M, Tedeschi G,Oriani G, Di Costanzo A. Decreased concentration ofadiponectin together with a selective reduction of itshigh molecular weight oligomers is involved in meta-

bolic complications of myotonic dystrophy type 1.Eur J Endocrinol 2011;165(6):969-75.

44. Daniele A, De Rosa A, Nigro E, Scudiero O, CapassoM, Masullo M, de Laurentiis G, Oriani G, Sofia M,Bianco A. Adiponectin oligomerization state andadiponectin receptors airway expression in chronic ob-structive pulmonary disease. The International Journalof Biochemistry & Cell Biology 2012;44:563-569.

45. Agustí AG, Noguera A, Sauleda J, Sala E, Pons J, Bus-quets X. Systemic effects of chronic obstructive pul-monary disease. Eur Respir J 2003 Feb; 21(2):347-60.

46. Takeda Y, Nakanishi K, Tachibana I, Kumanogoh A.Adiponectin: A Novel Link Between Adipocytes andCOPD. Vitam Horm 2012;90:419-35.

47. Chan KH, Yeung SC, Yao TJ, Ip MS, Cheung AH,Chan-Yeung MM, Mak JC. COPD Study Group of theHong Kong Thoracic Society. Elevated plasmaadiponectin levels in patients with chronic obstructivepulmonary disease. Int J Tuberc Lung Dis 2010;14(9):1193-200.

48. Tomoda K, Yoshikawa M, Itoh T, Tamaki S, FukuokaA, Komeda K, Kimura H. Elevated circulating plasmaadiponectin in underweight patients with COPD.Chest 2007;132(1):135-40.

49. Krommidas G, Kostikas K, Papatheodorou G, Kout-sokera A, Gourgoulianis KI, Roussos C, KoulourisNG, Loukides S. Plasma leptin and adiponectin inCOPD exacerbations: associations with inflammatorybiomarkers. Respir Med 2010;104(1):40-6.

50. Tomizawa A, Hattori Y, Kasai K, Nakano Y.Adiponectin induces NF-kappaB activation that leadsto suppression of cytokine-induced NF-kappaB acti-vation in vascular endothelial cells: globularadiponectin vs. high molecular weight adiponectin.Diab Vasc Dis Res 2008;5(2):123-7.

51. Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW,Schulthess T, Engel J, Brownlee M, Scherer PE.Structure-function studies of the adipocyte-secretedhormone Acrp30/adiponectin: Implications for meta-bolic regulation and bioactivity. J Biol Chem2003;278:9073-9085.

52. Petridou ET, Mitsiades N, Gialamas S, AngelopoulosM, Skalkidou A, Dessypris N, Hsi A, Lazaris N, Poly-zos A, Syrigos C, Brennan AM, Tseleni-Balafouta S,Mantzoros CS. Circulating adiponectin levels andexpression of adiponectin receptors in relation tolung cancer: two case-control studies. Oncology2007;73(3-4):261-9.

53. Lang K, Ratke J. Leptin and Adiponectin: new play-ers in the field of tumor cell and leukocyte migration.Cell Commun Signal 2009;7:27.

54. Bråkenhielm E, Veitonmäki N, Cao R, Kihara S, Mat-suzawa Y, Zhivotovsky B, Funahashi T, Cao Y.Adiponectin-induced antiangiogenesis and antitu-mor activity involve caspase-mediated endothelialcell apoptosis. Proc Natl Acad Sci U S A 2004;101(8):2476-81.

55. Grossmann ME, Nkhata KJ, Mizuno NK, Ray A,Cleary MP. Effects of adiponectin on breast cancercell growth and signaling. Br J Cancer 2008;98(2):370-9.

56. Ho Il Yoon, Yuexin Li, S.F. Paul Man, Donald Tash-kin, Robert A. Wise, John E. Connett, et al. TheComplex Relationship of Serum Adiponectin toCOPD Outcomes. Chest October!2012;Vol 142:No.4.

A. Bianco et al.


Mini-review

Daniel MoralesFranco Laghi

Division of Pulmonary and Critical Care Medicine, EdwardHines Jr. Veterans Administration Hospital, and LoyolaUniversity of Chicago Stritch School of Medicine, Hines,Illinois, USA

Address for correspondence:Franco Laghi, MDDivision of Pulmonary and Critical Care MedicineEdward Hines, Jr. VA Hospital, 111N5th Avenue and Roosevelt RoadHines, IL 60141 - USAPhone: (708) 2022705Fax: (708) 2027907E-mail: [email protected]

Summary

Mechanical ventilation is necessary in most patientsaffected by the acute respiratory distress syndrome(ARDS). Unfortunately, mechanical ventilation itselfcan cause lung damage as a result of ventilator-in-duced lung injury (VILI). The cyclical recruitment andde-recruitment of atelectatic lung regions (atelec-trauma), lung overdistension (volutrauma) and de-novo inflammation caused by a combination of thetwo (biotrauma) are likely participants in the develop-ment of VILI. Increasing experimental evidence sug-gests that the risk of VILI may be decreased by care-ful titration of ventilator support guided by monitoringpulmonary mechanics. Airway pressure (Paw) is thesimplest signal available to monitor mechanics inARDS. In combination with measurements of lungvolume, Paw allows to plot volume-pressure curves(VP curves) and to record end-expiratory pressureand end-inspiratory pressure during zero flow (Pplat).In the past it was assumed that VP curves could giveaccurate information on lung recruitment andoverdistension. Those assumptions, however, havebeen proven incorrect. Similarly, it is incorrect toconsider Pplat an accurate index of overdistension.In this review we will examine some of the availabletools to monitor pulmonary mechanics in ARDS. Thecritical interpretation of the data recorded with thesetools, their limitations and the potentials use of thesedata in setting the ventilator will be discussed aswell.

KEY WORDS: Acute Respiratory Distress Syndrome;monitoring; respiratory mechanics; Ventilator-InducedLung Injury.

Introduction

The acute respiratory dis-tress syndrome (ARDS) isa form of noncardiogenicpulmonary edema that re-sults from acute damage tothe alveoli (1). Most pa-tients with this syndromewill die if they do not re-ceive supplemental oxygenand mechanical ventilation(2, 3). By reversing life-threatening hypoxemia andalleviating the work ofbreathing, mechanical ven-tilation buys time for the lungsto heal (3). Mechanical ventilation can also cause lungdamage by several mechanisms, including alveolar rup-ture and alveolar hemorrhage, especially when high air-way pressures are used for ventilation (4, 5). In these pa-tients, the damage to the lungs caused by mechanicalventilation is known as ventilator-induced lung injury (VILI)(5). Mounting experimental evidence suggests that therisk of VILI may be decreased by a careful titration of ven-tilator support guided by monitoring pulmonary mechan-ics in ARDS (5-8).

Pressure Volume curves in ARDS

A useful first step in understanding the impact of monitor-ing pulmonary mechanics in ARDS is to examine thepressure-volume relationship of the respiratory system inthese patients. As shown inFigure 1, the pressure-vol-ume curve in patients withARDS can have a sigmoidshape with two discretebends (9). The lower bendis called lower inflectionpoint (LIP) and the upperbend is called upper inflec-tion point (UIP) (9). In the past the LIP wasthought to be the criticalpressure needed to reopenmost of previously col-lapsed airways and alveoli.The UIP was thought to be the critical pressure beyondwhich alveolar overdistension occurs. That meant thattidal ventilation was thought to be safe as long as it wasdelivered within these two points. We now know thatthese are oversimplifications because recruitment ofcollapsed lung units continues above LIP (10) and aboveUIP (11).

Measuring respiratory mechanics in ARDS


Ventilator-inducedlung injury (VILI) maybe considered as a"de-novo" biotraumacaused by cyclicalrecruitment and de-recruitment of atelec-tatic lung regions(atelectrauma), andlung overdistension(volutrauma).

Examination of pres-sure-volume (P-V)curves is the firststep of monitoringpulmonary mecha-nics in ARDS. Howe-ver, P-V curves aredifficult to interpretdue to many con-founders.

D. Morales et al.


Ventilation that continues beyond the UIP can cause lunginjury (5). This type of lung injury is known as “baro-trauma” or lung trauma caused by excessive pressure ap-plied to the lungs (5). Some investigators, however, pre-

fer the term “volutrauma” (lung trauma caused by exces-sive distension of the lungs) because – they note – it isnot the pressure at the airway opening that causes lunginjury but the distention of the lung (12). Ventilation that starts below the LIP is associated with cycli-cal collapse and reopening of lung units. This cyclical col-lapse and reopening causes a type of lung damage knowas “atelectrauma” (13). In addition to biophysical injury (vo-lutrauma and atelectrauma), investigators now posit that in-jurious ventilatory strategies associated with overdisten-sion of the lung and with repeated recruitment andde-recruitment of collapsed lung units can also lead to therelease of inflammatory mediators, including TNF- , inter-leukin-6, prostaglandins, leukotrienes and reactive oxygenspecies (13). According to those investigators, these inflam-matory mediators cause a biochemical injury termed “bio-trauma” (13). At a local level inflammatory mediators canlead to recruitment of a number of cells, including neu-trophils (14). In addition, inflammatory mediators can translo-cate from the lung into the systemic circulation and this maylead to distal organ dysfunction and death (4, 13). At one time, investigators advocated obtaining pressure-volume curves to properly select ventilator settings inpatients with ARDS (15). Unfortunately, pressure-volumecurves are difficult to generate because they requireheavy sedation and paralysis (16). In addition they cancause hypoxemia at low lung volumes, derecruitment atlow levels of positive end-expiratory pressure (PEEP)and hemodynamic compromise (decrease of venous re-turn) (16). Pressure volume curves are also difficult to in-terpret due to many confounders. These confounders in-clude expiratory flow limitation (17), abnormal chest-wallmechanics (18), continuous recruitment of collapsed lungunits above LIP (10) and above UIP (11) and focal vs.non-focal distribution of ARDS (6, 19). Not surprisingly,most experts around the world use pressure-volumecurves only for research purposes but not in clinical prac-tice (Figure 2).

Figure 1 - Schematic representation of a pressure-volumecurve of the respiratory system in a patient with ARDS. Inthese patients, the pressure-volume curve can have a sig-moid shape with two discrete bends above functional resid-ual capacity. The lower bend is called lower inflection pointand an upper bend is called upper inflection point. In 1995,Roupie et al. (AJRCCM 1995;152:121) reported that usingconventional tidal volumes (9-12 mL/kg), and a mean PEEPof 10 cm H2O, more than 70% of patients with ARDS had anend-inspiratory plateau airway pressure exceeding upper in-flection point. Reducing tidal volumes to 6 mL/kg brought theend-inspiratory plateau airway pressure below upper inflec-tion point. This was the first study to demonstrate the rele-vance of reduction in tidal volume for lung protection.

Figure 2 - Pressure vol-ume curves are difficultto generate and to inter-pret. This is why mostinternational experts donot use them in theirdaily clinical practice(Franco Laghi, personalcommunication, Novem-ber 2010).

Monitoring pulmonary mechanics to limit overdistension (Volutrauma)

Following the seminal study of Amato et al. (15), theARDS Network published the result of a large multicen-ter trial of 861 patients with ARDS (20). In the study, onegroup of patients was randomized to mechanical ventila-

tion with small tidal volumes(6 ml/kg of ideal body weightor IBW) and a plateau air-way pressure (Pplat)recorded following an inspi-ratory pause of 0.5 secondsof 30 cm H2O or less. A sec-ond group of patients wasrandomized to traditionaltidal volumes (12 ml/kgIBW) and a Pplat of 50 cmH2O or less (20). The trialwas stopped when an in-terim analysis revealed that

lowering tidal volume andPplat decreased mortality by 22%. In a subsequent meta-analysis, Eichacker et al. (21) concluded that the most im-portant aspect in setting the tidal volume in ARDS is touse tidal volumes that produce a Pplat between 28 and32 cm H2O. Pplat is used to estimate transpulmonary pressure (lungstretching). A high Pplat usually signifies excessive lungstretching, and a low Pplat signifies less lung stretching.Unfortunately, the value of Pplat is determined not onlyby the stiffness of the lung but it is also determined bythe stiffness of the chest wall. In some patients, includ-ing those who are obese, pregnant or who have tenseascites, the stiffness of the chest wall can be significant.In these patients, Pplat may be very high without this sig-nifying that the lungs are truly overdistended (volu-trauma). That is, in patients with a chest wall that isstiffer than normal the simple measurement of Pplatwill cause physicians to grossly overestimate lungstretching. In these patients it may necessary to meas-ure transpulmonary pressure using esophageal pressuretracings (see below). Transpulmonary pressure is calculated by subtractingalveolar pressure from pleural pressure (Figure 3). Inclinical practice, it is unrealistic to perform direct measure-ments of alveolar pressure and direct measurements ofpleural pressure. Instead, airway pressure is used as asubstitute of alveolar pressure, and esophageal pres-sure is used as a substitute of pleural pressure. If a clinician wants to know the extent of lung stretching atend-inhalation he/she will have to record Pplat plus thecorresponding esophageal pressure at end-inhalation. Ofnote, the value of Pplat already comprises any externalPEEP applied to the patient and any intrinsic PEEP the pa-tient may have. This means that it would be wrong to in-clude in the calculation of transpulmonary pressure anycorrection for external PEEP or intrinsic PEEP. It has beenreasoned that in patients with ARDS, tidal volume shouldbe titrated to keep the transpulmonary pressure in thephysiologic range – i.e., transpulmonary pressure <25 cmH2O while the patient is in the supine position (7, 22). The use of small tidal volumes in ARDS causes a reduc-tion of CO2 clearance and a reduction in lung recruit-ment. These phenomena are responsible for an initial

worsening in lung compliance and ventilation/perfusionmatching when instituting low-tidal volume ventilation(20). In other words, permissive hypercapnia and permis-sive atelectasis/hypoxemia are the trade-offs we have toaccept to improve the outcome of patients with ARDS(20). Of interest, new experimental evidence suggeststhat permissive hypercapnia may itself be lung-protective(23). Hypercapnia causes intracellular acidosis, which, inturn, has many potential protecting effects on injuredalveolar cells. These potential protecting effects includethe inhibition of xanthine oxidase (with consequent de-crease in the production of free radicals), inhibition of theactivity of NF-kB (with consequent decrease in cytokineproduction) and inhibition of capsase-3 that results inless apoptosis (23).

Monitoring pulmonary mechanics to limit cyclical recruitment-derecruitment (Atelectrauma)

The central question here is “what aspects of pulmonarymechanics should we monitor to avoid atelectrauma?”.Stated differently the question is “what aspects of pul-monary mechanics should we monitor to set PEEP inARDS?”. This is a difficult question that can be answeredonly tentatively. The various strategies used to set PEEP in ARDS include:1. Monitoring oxygenation and using a sliding-scale

(table) developed by a panel of experts to adjustPEEP and FiO2 in discrete steps to maintain ade-quate arterial oxyhemoglobin saturation (24, 25).

2. Monitoring respiratory system compliance while titrat-ing PEEP (optimal PEEP defined as the PEEP asso-ciated with maximal compliance) (26, 27).



Figure 3 - Transpulmonary pressure or PL (lung stretching) iscalculated by subtracting alveolar pressure (PA) from pleu-ral pressure (Ppl). In clinical practice, airway pressure (Paw)substitutes alveolar pressure and esophageal pressure sub-stitutes pleural pressure.

Plateau airway pres-sure (Pplat) is usedto estimate trans-pulmonary pressure(lung stretching). Insome patients a hi-gher stiffness of thechest wall may cau-se grossly overesti-mation of lung stret-ching.

3. Monitoring the shapeof the airway pressuresignal during lung in-flation with constantairflow (optimal PEEPdefined as the PEEPassociated with a lin-ear rise in airwaypressure or “stress in-dex = 1”) (6).

4. Monitoring Pplat whiletitrating PEEP (opti-mal PEEP defined asthe highest PEEP as-sociated Pplat of 28-30 cm H2O) (28).

5. Monitoring an esti-mate of transpulmonary pressure measured with anesophageal balloon (optimal PEEP defined as thePEEP associated with positive transpulmonary pres-sure at end-exhalation while keeping transpul-monary pressure in the physiologic range of <25 cmH2O) (7).

Except for the first strategy listed above, all the otherstrategies are based on two ideas, first, to monitor the me-chanical characteristics of the individual patient withARDS and, second, set PEEP accordingly. Investigators have reported encouraging results (ten-dency to improve survival) in patients with ARDS venti-lated with a tidal volume of 6 ml/kg IBW in whom PEEPwas titrated according to the mechanical characteristicsof each individual patient (7, 28). In contrast, titratingPEEP using a sliding-scale (table) designed to adjustPEEP and FiO2 in discrete steps to maintain adequate ar-terial oxyhemoglobin saturation has not improved survival(24, 25).

Monitoring pulmonary mechanics to limit biotrauma

To posit that monitoring a particular aspect of pulmonarymechanics can give an insight to the risk of developingbiotrauma implies the existence of a not yet well identifiedlink between pulmonary mechanics and biotrauma. Mon-itoring tools that have triggered interest in this regard in-clude the quantification of the end-inspiratory strain of thelung (29, 30) and the computation of the so-called drivingpressure (31). 1. End-inspiratory strain: according to continuum me-

chanics, a branch of classic mechanics that dealswith solids and fluids, the transformation of a bodyfrom a reference configuration to a current configu-ration is called deformation. This is quantified as thedisplacement between particles in the body relativeto a reference length or strain. In the case of thelungs undergoing mechanical ventilation end-inspira-tory strain is defined as the change in lung volumerelative to the resting volume (29, 30). This meansthat to calculate the end-inspiratory strain of the lungit is necessary to measure the end-expiratory lungvolume and tidal volume (30). In mechanically ven-tilated patients, measurements of end-expiratory lungvolume can be performed using the helium dilutiontechnique, the nitrogen washout/washin technique

and with spiral computed tomography (32, 33).(Whether strain should be calculated while patientsare on PEEP or not remains controversial) (34).Cyclical end-inspiratory strain associated with infla-tion to total lung capacity is injurious to healthy lungs(29). This occurs when the resting lung volume (thebaby lung in case of ARDS) is increased by two-foldto three-fold (29, 35). In patients with ARDS damagehas been reported with end-inspiratory strains wellbelow this upper limit (29). Such observation impliesthe presence of inhomogeneous distribution of localend-inspiratory strain (29).

2. Driving pressure: thispressure is calculatedas the difference be-tween Pplat andPEEP. This meansthat one of the deter-minants of drivingpressure is end-inspi-ratory lung strain: thegreater the strain thegreater the drivingpressure. Post-hoc analysis ofseveral clinical inves-tigations suggeststhat driving pressuresabove 15-20 cm H2Oare conducive to increased mortality in ARDS (Fig-ure 4) (4, 7, 15, 20, 24, 25, 28, 36-40). It would betempting to speculate that the excess mortality inthose studies was due, at least in part, to excessivestrain and biotrauma. For several reasons such spec-ulation cannot be either accepted or refuted. First, thelink between strain and driving pressure is indirect.Second, the value of Pplat required to calculate driv-ing pressure is not only a function of lung mechan-ics but it is also a function of chest wall mechanics(see section on volutrauma). Third, no study hasprospectively determined the impact of different driv-ing pressures on ARDS outcome. Fourth, ventilatorsettings (such ventilator mode, as PEEP, respira-tory rate, FiO2) in the investigations summarized inFigure 4 varied from study to study (4, 7, 15, 20, 24,25, 28, 36-40). This makes it impossible to dissectthe effect of driving pressure from other ventilatorvariables on patient outcome. In other words, whileit would seem reasonable to aim for a driving pres-sure below 15-20 cm H2O (5, 15, 41) it is necessaryto bear in mind that such threshold is based on con-jecture, biological plausibility and post hoc analysisof studies not designed to identify the ideal drivingpressure to use in patients with ARDS.

Conclusion

In patients with ARDS mechanical ventilation can be life-saving yet it can also exacerbate lung injury (VILI). Cur-rent knowledge suggests that preventing VILI during me-chanical ventilation requires avoidance of cyclical openingand closing of unstable lung units and avoidance of ex-cessive stretching of lung parenchyma. Growing experi-mental evidence suggests that these goals may be

D. Morales et al.


Investigators havereported encoura-ging results (ten-dency to improvesurvival) in patientswith ARDS ventila-ted with a tidal volu-me of 6 ml/kg IBW inwhom PEEP was ti-trated according tothe mechanical cha-racteristics of eachindividual patient.

The quantificationof the end-inspira-tory strain of thelung and the com-putation of the so-called driving pres-sure has been sug-gested to limit bio-trauma, but the linkbetween pulmonarymechanics and bio-trauma has not yetbeen identified.

achieved by a careful titration of ventilator support guidedby monitoring pulmonary mechanics (5-8).

Acknowledgements and disclosures

The article is supported by grants from the Veterans Ad-ministration Research Service.

References

1. Ranieri VM, Rubenfeld GD, Thompson BT, FergusonND, Caldwell E, Fan E, et al. Acute respiratory dis-tress syndrome: the Berlin Definition. JAMA2012;307:2526-33.

2. Laghi F, Siegel JH, Rivkind AI, Chiarla C, De GaetanoA, Blevins S, et al. Respiratory index/pulmonary

shunt relationship: quantification of severity and prog-nosis in the post-traumatic adult respiratory distresssyndrome. Crit Care Med 1989;17:1121-28.

3. Tobin MJ. Culmination of an era in research on theacute respiratory distress syndrome. N Engl J Med2000;342:1360-61.

4. Ranieri VM, Suter PM, Tortorella C, De Tullio R, Da-yer JM, Brienza A, et al. Effect of mechanical venti-lation on inflammatory mediators in patients withacute respiratory distress syndrome: a randomizedcontrolled trial. JAMA 1999;282:54-61.

5. Marini JJ. Mechanical Ventilation in the Acute Res-piratory Distress Syndrome, In: Tobin MJ, editor.Principles and Practice of Mechanical Ventilation, 2ed. New York: McGraw Hill; 2006. p. 625-48.

6. Grasso S, Stripoli T, De Michele M, Bruno F, Mo-schetta M, Angelelli G, et al. ARDSnet ventilatory pro-tocol and alveolar hyperinflation: role of positive end-expiratory pressure. Am J Respir Crit Care Med2007;176:761-67.

7. Talmor D, Sarge T, Malhotra A, O’Donnell CR, Ritz R,Lisbon A, et al. Mechanical ventilation guided byesophageal pressure in acute lung injury. N Engl JMed 2008;359:2095-104.

8. Briel M, Meade M, Mercat A, Brower RG, Talmor D,Walter SD, et al. Higher vs lower positive end-expi-ratory pressure in patients with acute lung injury andacute respiratory distress syndrome: systematic re-view and meta-analysis. JAMA 2010;303:865-73.

9. Tobin MJ. Advances in mechanical ventilation. NEngl J Med 2001;344:1986-96.

10. Jonson B, Richard JC, Straus C, Mancebo J,Lemaire F, Brochard L. Pressure-volume curves andcompliance in acute lung injury: evidence of recruit-ment above the lower inflection point. Am J RespirCrit Care Med 1999;159:1172-78.

11. Hickling KG. The pressure-volume curve is greatlymodified by recruitment. A mathematical model of ARDSlungs. Am J Respir Crit Care Med 1998;158:194-202.

12. Dreyfuss D, Ricard JD, Saumon G. On the physio-logic and clinical relevance of lung-borne cytokinesduring ventilator-induced lung injury. Am J RespirCrit Care Med 2003;167:1467-71.

13. Slutsky AS. Ventilator-induced lung injury: from baro-trauma to biotrauma. Respir Care 2005;50:646-59.

14. Rivkind AI, Siegel JH, Littleton M, De Gaetano A, Ma-mantov T, Laghi F, et al. Neutrophil oxidative burst ac-tivation and the pattern of respiratory physiologicabnormalities in the fulminant post-traumatic adultrespiratory distress syndrome. Circ Shock1991;33:48-62.

15. Amato MB, Barbas CS, Medeiros DM, Magaldi RB,Schettino GP, Lorenzi-Filho G, et al. Effect of a pro-tective-ventilation strategy on mortality in the acuterespiratory distress syndrome. N Engl J Med1998;338:347-54.

16. Terragni PP, Rosboch GL, Lisi A, Viale AG, RanieriVM. How respiratory system mechanics may help inminimising ventilator-induced lung injury in ARDSpatients. Eur Respir J Suppl 2003;42:15s-21s.

17. Koutsoukou A, Bekos B, Sotiropoulou C, KoulourisNG, Roussos C, Milic-Emili J. Effects of positiveend-expiratory pressure on gas exchange and expi-ratory flow limitation in adult respiratory distress syn-drome. Crit Care Med 2002;30:1941-49.



Figure 4 - Mortality of patients with ARDS plotted against driv-ing pressure in twelve clinical studies designed to comparesome type of conventional ventilation against different lung-protective strategies (4, 7, 15, 20, 24, 25, 28, 36-40). For eachstudy, the circle indicates the combination of mortality anddriving pressure recorded with protective strategy and the starindicates the combination of mortality and driving pressurerecorded with conventional ventilation. In blue are studieswhere there was no difference in mortality between protec-tive strategy and conventional ventilation. In red are studieswere the mortality with conventional ventilation was greaterthan with protective strategy. In most instances, mortality wasthe highest when driving pressure of the conventional venti-lation group was more than 20 cm H2O and it was the lowestwhen driving pressure of the lung-protective strategy groupwas less than 15 to 20 cm H2O (Modified from Bugedo andBruhn) (41).

18. Mergoni M, Martelli A, Volpi A, Primavera S, ZuccoliP, Rossi A. Impact of positive end-expiratory pressureon chest wall and lung pressure-volume curve inacute respiratory failure. Am J Respir Crit Care Med1997;156:846-54.

19. Constantin JM, Grasso S, Chanques G, Aufort S, Fu-tier E, Sebbane M, et al. Lung morphology predictsresponse to recruitment maneuver in patients withacute respiratory distress syndrome. Crit Care Med2010;38:1108-17.

20. Ventilation with lower tidal volumes as comparedwith traditional tidal volumes for acute lung injuryand the acute respiratory distress syndrome. TheAcute Respiratory Distress Syndrome Network. NEngl J Med 2000;342:1301-08.

21. Eichacker PQ, Gerstenberger EP, Banks SM, Cui X,Natanson C. Meta-analysis of acute lung injury andacute respiratory distress syndrome trials testing lowtidal volumes. Am J Respir Crit Care Med2002;166:1510-14.

22. Colebatch HJ, Greaves IA, Ng CK. Exponentialanalysis of elastic recoil and aging in healthy malesand females. J Appl Physiol 1979;47:683-91.

23. Ismaiel NM, Henzler D. Effects of hypercapnia andhypercapnic acidosis on attenuation of ventilator-as-sociated lung injury. Minerva Anestesiol 2011;77:723-33.

24. Brower RG, Lanken PN, MacIntyre N, Matthay MA,Morris A, Ancukiewicz M, et al. Higher versus lowerpositive end-expiratory pressures in patients withthe acute respiratory distress syndrome. N Engl JMed 2004;351:327-36.

25. Meade MO, Cook DJ, Guyatt GH, Slutsky AS, ArabiYM, Cooper DJ, et al. Ventilation strategy using lowtidal volumes, recruitment maneuvers, and high pos-itive end-expiratory pressure for acute lung injuryand acute respiratory distress syndrome: a random-ized controlled trial. JAMA 2008;299:637-45.

26. Ward NS, Lin DY, Nelson DL, Houtchens J, SchwartzWA, Klinger JR, et al. Successful determination oflower inflection point and maximal compliance in apopulation of patients with acute respiratory distresssyndrome. Crit Care Med 2002;30:963-68.

27. Suter PM, Fairley B, Isenberg MD. Optimum end-ex-piratory airway pressure in patients with acute pul-monary failure. N Engl J Med 1975;292:284-89.

28. Mercat A, Richard JC, Vielle B, Jaber S, Osman D,Diehl JL, et al. Positive end-expiratory pressure set-ting in adults with acute lung injury and acute respi-ratory distress syndrome: a randomized controlledtrial. JAMA 2008;299:646-55.

29. Gattinoni L, Carlesso E, Caironi P. Stress and strainwithin the lung. Curr Opin Crit Care 2012;18:42-47.

30. Gattinoni L. Counterpoint: Is low tidal volume me-chanical ventilation preferred for all patients on ven-tilation? No. Chest 2011;140:11-13.

31. Marini JJ. Point: Is pressure assist-control preferredover volume assist-control mode for lung protectiveventilation in patients with ARDS? Yes. Chest2011;140:286-90.

32. Chiumello D, Cressoni M, Chierichetti M, Tallarini F,Botticelli M, Berto V, et al. Nitrogen washout/washin,helium dilution and computed tomography in the as-sessment of end expiratory lung volume. Crit Care2008;12:R150.

33. Olegard C, Sondergaard S, Houltz E, Lundin S, Sten-qvist O. Estimation of functional residual capacity atthe bedside using standard monitoring equipment: amodified nitrogen washout/washin technique requir-ing a small change of the inspired oxygen fraction.Anesth Analg 2005;101:206-12, table.

34. Graf J. Bedside lung volume measurement for esti-mation of alveolar recruitment. Intensive Care Med2012;38:523-24.

35. Protti A, Cressoni M, Santini A, Langer T, Mietto C,Febres D, et al. Lung stress and strain during me-chanical ventilation: any safe threshold? Am J RespirCrit Care Med 2011;183:1354-62.

36. Villar J, Kacmarek RM, Perez-Mendez L, Aguirre-Jaime A. A high positive end-expiratory pressure,low tidal volume ventilatory strategy improves out-come in persistent acute respiratory distress syn-drome: a randomized, controlled trial. Crit Care Med2006;34:1311-18.

37. Kallet RH, Jasmer RM, Pittet JF, Tang JF, CampbellAR, Dicker R, et al. Clinical implementation of theARDS network protocol is associated with reducedhospital mortality compared with historical controls.Crit Care Med 2005;33:925-29.

38. Stewart TE, Meade MO, Cook DJ, Granton JT, Hod-der RV, Lapinsky SE, et al. Evaluation of a ventilationstrategy to prevent barotrauma in patients at high riskfor acute respiratory distress syndrome. Pressure-and Volume-Limited Ventilation Strategy Group. NEngl J Med 1998;338:355-61.

39. Brower RG, Shanholtz CB, Fessler HE, Shade DM,White P Jr, Wiener CM, et al. Prospective, random-ized, controlled clinical trial comparing traditionalversus reduced tidal volume ventilation in acute res-piratory distress syndrome patients. Crit Care Med1999;27:1492-98.

40. Brochard L, Roudot-Thoraval F, Roupie E, DelclauxC, Chastre J, Fernandez-Mondejar E, et al. Tidalvolume reduction for prevention of ventilator-inducedlung injury in acute respiratory distress syndrome.The Multicenter Trail Group on Tidal Volume reduc-tion in ARDS. Am J Respir Crit Care Med1998;158:1831-38.

41. Bugedo G, Bruhn A. Ventilacion mecanica en el sin-drome de distres respiratorio agudo, In: Andersen M,editor. Manual de Medicine Intensiva. Santiago,Chile: Editorial Mediterraneo Ltda 2010:77-89.

D. Morales et al.


Mini-review

Vincenzo Patruno1

Orietta Coletti1

Nicola Montano2

1 Division of Pulmonary Rehabilitation, I.M.F.R., Udine,Italy

2 Department of Clinical Sciences, Internal Medicine II,University of Milan, “L. Sacco” Hospital, Milano, Italy

Address for correspondence:Vincenzo Patruno, MDDivision of Pulmonary Rehabilitation, I.M.F.R.Via Gervasutta 4833100 Udine, Italy E-mail: [email protected]

Summary

Sleep breathing disorders (SBD) are commonly di-vided in three syndromes: obstructive sleep apneasyndrome (OSA), central sleep apnea-hypopnea syn-drome (CSA) and Cheyne-Stokes breathing syndrome(CSR), the latter two both characterized by cyclicnon-obstructive breathing patterns.Because the prevalence of CSA-CSR in chronic heartfailure (CHF) population has been reported from 40%to 60%, CSA-CSR is the more frequent respiratoryconsequence of such cardiovascular illness. CSA-CSR has been associated with increased mortality inheart failure patients, but a causal role for CSA-CSRin the morbidity and mortality of heart failure awaitsmore definitive evidence. In fact, it is not yet known whether CSA-CSR is anepiphenomenon in the setting of heart failure orwhether it may itself lead to increased risk or progres-sion of heart failure.CPAP is the most studied form of treatment for CSA-CSR. However, in randomized trials of long term du-ration, several forms of non-invasive positive airwaypressure, including CPAP, bi-level, adaptive pressuresupport ventilation and nocturnal oxygen therapy,have been shown to alleviate CSA-CSR in heart fail-ure patients.Nevertheless, at present, none therapeutic approachwas ideal with respect to both efficacy and tolerance,nor has any available therapy been demonstrated toimprove survival. In CHF patients with CSA-CSR,standard employment of CPAP cannot be recom-mended at present, though the post hoc analysis ofthe CANPAP study is intriguing and suggests thatCPAP responders may benefit prognostically. Fur-thermore, the results of the CANPAP study should notbe extrapolated to heart failure patients with OSA,

which is much more effectively suppressed by CPAP.Finally, there is a need to examine novel treatment op-tions for CSA-CSR in patients with CHF, as these pa-tients appear to have the worst prognosis and there-fore the most to gain if successful treatment ofCSA-CSR improves survival.

KEY WORDS: Cheyne-Stokes; Central Sleep Apnea;Heart Failure.

Introduction

One of the most recentand intriguing develop-ments in the field of car-diovascular medicineoriginated from the ob-servations that somesleep disorders, such asobstructive sleep ap-noea-hypopnoea syn-drome (OSA), maycause or worsen cardiacdisease and, in turn, thatcertain cardiac diseases,like chronic heart failure(CHF), may bring onsleep disorders such ascentral sleep apnoea-hy-popnoea syndrome (CSA) and Cheyne-Stokes breathingsyndrome (CSR). This review will mainly focus on the cur-rent treatment options of CSR-CSA in CHF. First we willexplore the physiopathology and clinical significance ofCSA-CSR in CHF and then we will examine the up-to-date knowledge on the effects of treatment of centralsleep disordered breathing in patients with CHF.

Cheyne-Stokes Respiration/Central Sleep Apnoea in Heart Failure

Sleep breathing disor-ders (SBD) are com-monly divided (1) inthree syndromes: ob-structive sleep apnoeasyndrome, central sleepapnoea-hypopnoea syn-drome and Cheyne-Stokes breathing syn-drome, the latter twoboth characterized bycyclic non-obstructive breathing patterns.CSA-CSR is a form of periodic breathing characterized byoscillation of ventilation between apnoea and tachypnea,

Treatment of Cheyne-Stokes Respiration and Central Sleep Apnoea in Chronic Heart Failure


Respiratory sleep dis-orders may cause orworsen cardiac disea-se. Moreover, cardiacdiseases leading tochronic heart failure(CHF) may cause respi-ratory sleep disorderssuch as central sleepa p n o e a - h y p o p n o e asyndrome (CSA) andCheyne-Stokes brea-thing syndrome (CSR).

Patients with heart fai-lure and CSA-CRS havea significantly lower Pa-CO2, while awake andasleep, when comparedwith patients with simi-lar ejection fraction butno CSA-CSR.

V. Patruno et al.

with a crescendo-decrescendo pattern in the depth of res-pirations (Figure 1). Central sleep apnoea is a manifes-tation of respiratory instability and is particularly prone tooccur during sleep when the respiratory system becomescritically dependent on the metabolic control system. Oneof the most well-known mathematical models proposes anexplanation to CSA-CSR (2) based on three basic com-ponents: a controlling system, a controlled system and afeedback loop. The controlled variables are PaO2 andPaCO2. Prolonged circulation time, which is a hallmark ofheart failure, promotes a delayed response that may pro-mote respiratory instability. However, it is generally agreedthat this mechanism may contribute to the generation ofCSA-CSR, but is not alone sufficient (3). The high sensi-tivity of ventilatory chemoreceptors promotes a strongventilatory response and blood gas instability. Increasedcontroller gain is well-documented and it is thought to playa central role in the genesis of CSA-CSR in patients withheart failure (4, 5). Plant gain is dependent on lung gasstores, on body stores of oxygen and carbon dioxide, andon the metabolic rate (Figure 2). Reduction in lung vol-umes increases plant gain because smaller volumes areless effective at damping out changes in PaCO2 andPaO2, thus favouring instability (6), and that may explainthe increased propensity to CSA-CSR in the supine po-sition (7). Low PaCO2 levels play a central role in the gen-esis of apnoeas and hypopneas. Patients with heart fail-ure and CSA-CRS have a significantly lower PaCO2,

while awake and asleep, when compared with patientswith similar ejection fraction but no CSA-CSR. It hasbeen shown that the first apnoea is regularly preceded byhyperventilation (4), which caused PaCO2 to reach thevalue below the apnoeic threshold; this proved to be thekey element in triggering central apnoea (8). Severalmechanisms were proposed to explain why patients withheart failure tend to hyperventilate. PaCO2 levels corre-late negatively with pulmonary capillary wedge in pa-tients with HF submitted to cardiac catheterization (9).Therefore, the development of CSA-CSR by state of hy-perventilation may be explained as a consequence of pul-monary congestion due to tonic stimulation of pulmonaryvagal afferents (10). However, the observation of CSA-CSR in one patient submitted to lung transplantation (11),suggests that other mechanisms, such as cardiac vagalafferents, may also be important. Hyperventilation may becaused by an elevated sympathetic activity upon centraland peripheral chemoreceptors (12). While OSA hasbeen identified as a possible independent risk factor forthe development of heart and vascular disease, CSA-CSR is a more frequent consequence of such cardiovas-cular illness. However it is not yet known whether CSA-CSR is an epiphenomenon in the setting of heart failureor whether it may itself lead to increased risk or progres-sion of heart failure (13-16). Lanfranchi et al. (13), whilestudying a variety of baseline patient characteristics, in-cluding New York Heart Association class, left ventricular

Figure 1 - Polysomnographic example of CSA-CSR (180 sec). On flow trace # 7, Cheyne-Stokes respiration with typical “wax-ing and waning” pattern and central apnoea with concomitant absent movements of chest (trace # 8) and abdomen (trace #9). Arousal occurred at the top of “crescendo” flow.


ejection fraction, and exercise capacity, found that the leftatrial area and the apnoea/hypopnoea index (AHI)emerged as the two most potent predictors of mortality.Other studies suggested that the higher rates of deathand cardiac transplantation seen in patients with heart fail-ure, along with low diastolic BP and severe right ventric-ular dysfunction (17), were proportional to the frequencyof central apnoeic events (15). Another issue that shouldbe stressed is that central and obstructive events are notindependent phenomena, in fact they often coexist in pa-tients with heart failure, who may convert OSA to CSAduring the course of a single night (18) and over a longerperiod of time (19).

Treatment of central sleep disordered breathing in chronic heart failure

CPAP is the most studied form of treatment for CSA-CSR.Nevertheless, in randomized trials of long term duration,several forms of non-invasive positive airway pressure, in-cluding CPAP, bi-level, and adaptive pressure supportservo-ventilation, have been shown to alleviate CSA-CSR in heart failure patients (20-22). The mechanisms bywhich CPAP exerts the beneficial effects in HF without ob-struction of the upper airways during sleep are not com-pletely understood, but the primary effect may be on thecardiovascular system by reducing the preload and after-load (23). This may be due to the increase of the intratho-racic pressure and the decrease of the transmural pres-sure of the intrathoracic structures.

CPAP also reduces the work of breathing in patientswith HF (24). In randomized trials, nightly application ofCPAP for three months increased left ventricular ejectionfraction, reduced mitral regurgitation and nocturnal uri-nary and daytime plasma nor-epinephrine, and improvedquality of life (24, 25). Sin et al. (16) studied patients withHF and CSA-CSR and reported a significant improve-ment in LVEF and transplant-free survival in those ran-domized to CPAP therapy, if they complied with treat-ment, compared to control with no CPAP. Bradley et al.(26) carried out the largest randomized prospective studyon the use of nasal CPAP therapy in 258 HF patients withCSA-CSR (CANPAP study). They found no difference in2-year survival or atrial natriuretic peptide plasma leveldespite significant improvements in LVEF, lower nor-adrenaline levels and increased mean 6-minute walktest distance in patients randomized to CPAP. The au-thors suggested that current medical therapies for HF(particularly beta-blockers) led to significant improve-ment in prognosis, with a fall in the mortality of both con-trol and treatment groups which reduced the study’spower to detect a treatment difference. In addition, themean reduction of AHI in the treatment arm was to a levelabove the inclusion AHI threshold of 15. Moreover, the is-sues of compliance and efficacy may be relevant. Atone year, CPAP was used for 3.6 hours per night and at-tenuated AHI by 50%, indicating only a partial reductionin “apnoea burden”. A recent post hoc analysis of CAN-PAP study showed that responders to CPAP had a sig-nificant improvement in LVEF and transplant-free survivalcompared to non-responders or controls (27). Although



Figure 2 - Schematic representation of loop gain (see text for details).

this was a post hoc analysis, it is hypothesis generatingand provides directions for future research on CPAP inHF patients with CSA-CSR responsive to CPAP becausebetter-tolerated and more effective treatment of CSA-CSR might have resulted in improved survival (27-29). Another point of interest regards the theoretical possibil-ity that other forms of non-invasive ventilation able toabolish CSA-CSR may be effective in the treatment of thecardiovascular consequences associated with CSA-CSR.Because CPAP is not effective in reducing CSA-CSR ina significant number of patients, other forms of non-inva-sive ventilation, including bi-level positive airway pressure(BiPAP) and adaptative pressure support ventilation(ASV), have been proposed as alternative.Bi-level positive airway pressure (BiPAP) is a ventilatorymode that delivers two pressure levels, a higher inspira-tory pressure and a lower expiratory pressure. BiPAPhas been postulated to be superior to CPAP in HF patientsbecause the typically lower expiratory pressure may notimpede stroke volume in patients with low cardiac fillingpressures, as may occur with CPAP (30). Despite the gen-eral concern that these patients already hyperventilate,and further increasing ventilation may not necessarily bea good approach, possibly leading to hypocapnic alkaloticglottic closure, recently Khayat et al. (31), in moderate-se-vere HF patients randomly assigned to CPAP or BiPAPtreatment, found that LVEF improved significantly in theBiPAP group but not the CPAP group. Previously, on theother hand, Konhnlein et al. (32) in a random, crossover

study design concludedthat both CPAP and Bi-PAP treatments equallyand effectively improveCheyne-Stokes respira-tion in HF patients. Atany rate, it’s important tohighlight the setting val-ues of the bi-level de-vices employed in afore-mentioned studies (31,32) because the verylow span used (mean 3cmH2O) between inspi-ratory and expiratory

pressure really suggest aCPAP-like effect more than a pressure support ventilation.One interesting and relatively new format of treatment isthe adaptive pressure support ventilation (ASV). This is anovel form of bi-level PAP in which the flow generator pro-vides a fixed end expiratory pressure that should betitrated to abolish upper airway obstructive events. The in-spiratory pressure support level then varies in accor-dance to an algorithm that aims at stabilizing ventilationat an approximate 80% of the baseline minute ventilation.Adaptive pressure support ventilation results in acutesuppression of CSA-CSR (21) that is more effective thanCPAP and may result in better compliance and a greaterimprovement in heart function (22).A prospective study used a randomized parallel design intreating 26 CSA-CSR in heart failure patients, comparingone month of therapeutic and sub therapeutic ASV (33).Active treatment attenuated daytime sleepiness (primaryend point), plasma brain natriuretic peptide and urinenor-adrenaline (secondary end points). Despite thesepromising results, further studies are needed to clarify the

optimal ventilation strategy for patients with CSA-CSRand HF.As an alternative ap-proach nocturnal oxygentherapy has been re-ported to improve CSAin patients with systolicheart failure (34-36).Hanly et al. (35) shouldbe credited for the firstrandomized, placebocontrolled study. In ninesubjects with systolic heart failure, the authors showedthat the administration of nasal oxygen for one night(when compared to nasal air) improved CSA-CSR, sleeparchitecture (i.e. decreased arousals and shifted sleep todeep stages), and arterial oxyhaemoglobin desaturation.Two studies of Andreas et al. (37) and Staniforth (38) etal. indicated that in systolic heart failure, oxygen de-creases sympathetic activity due to CSA. Another studyof Sasayama (39) showed that supplemental nocturnaloxygen therapy for three months, compared to control,significantly improved CSA-CSR, LVEF and quality of lifein patients with HF and central sleep breathing disor-ders. Oxygen administration decreased periodic breathing withthe most significant effect on CSA. While the patientswere receiving oxygen, desaturation was virtually elimi-nated. Unfortunately not all patients with heart failureand CSA-CSR have a complete reversal of sleep apnoeawith oxygen. It was noted (40) that in patients fully respon-sive to oxygen therapy the PaCO2 values of the subjectswere within the normal range while in patients which oxy-gen therapy resulted in only partial response, the PaCo2

values of the subject were lower than normal range. Themechanisms of the therapeutic effects of oxygen on CSAare multifactorial. These include a rise in PCO2 and, pre-sumably, a widening of the difference between the eucap-nic PCO2 and the PCO2 at the apnoeic threshold, thesuppression of ventilatory response to hypercapnia, andan increase in the body stores of oxygen. Taken together,this should dampen the respiratory loop-gain (change ofventilation for a given change of ventilation) (41) and de-crease the likelihood of ventilatory instability promotingCSA-CSR. It was speculated (40) that subjects that re-sulted as only partial responders to oxygen therapy havesuch an intense non-chemical ventilatory stimuli that oxy-gen failed to raise their baseline PCO2 in the transitionfrom wakefulness to sleep. Because oxygen decreasessympathetic activity and eliminates desaturation, long-term therapy may potentially decrease the morbidity andmortality of subjects with HF. Nevertheless, careful, ran-domized, placebo controlled, multicenter studies withmortality as the end point are required to prove nocturnaloxygen therapy as a long-term helpful treatment modal-ity in HF with CSA-CSR.In accordance to point of view that CSA-CSR is a conse-quence of a failing heart, all therapies able to ameliorateheart function may be helpful in reducing CSA-CSR.In effect CSA-CSR was abolished in patients underwentto heart transplant for CHF (42). Some, but not all, stud-ies indicate that beta-blockers and furosemide ameliorateCSA-CSR (43, 44). Also theophylline (45), acetazolamide(46), administration of carbon dioxide (47) and addition ofdead space (48) can reduce CSA-CSR; however there is

V. Patruno et al.


CPAP, and several mo-de of nocturnal nonin-vasive ventilation havebeen shown to alleviateCSA-CSR, but despitepromising results, fur-ther studies are neededto establish this treat-ment for respiratorysleep disorders in pa-tients with CHF.

Nocturnal oxygen the-rapy decreases perio-dic breathing, but failedto show complete re-versal of sleep apnea inpatients with CHF.

a general concern that to use drugs or devices with astrong stimulatory effect on respiratory drive in patientswith CHF and CSA/CSR, already hyperventilate, maynot to beneficial.Cardiac resynchronization therapy also appears to im-prove CSA-CSR in HF, but only in those patients whosecardiac function improved with the resynchronization ther-apy (24), suggesting that improved cardiac function mayhave reduced the severity of CSA-CSR. Changes in CSA-CSR seemed to be associated with CRT-inducedchanges in mitral regurgitation but further studies are re-quired to confirm these early results, to determine the ex-act mechanisms by which CRT might improve CSA-CSR,and to identify which CSA-CSR patients with heart failurewould benefit from such interventions.

Conclusions

Although CSA-CSR has been associated with increasedmortality in CHF patients, a causal role for CSA-CSR inthe morbidity and mortality of heart failure awaits more de-finitive evidence. A number of treatment strategies forCSA have been tested, but presently none is ideal with re-spect to both efficacy and tolerance, nor has any availabletherapy been demonstrated to improve survival. For CSA-CSR, use of CPAP cannot be recommended at present,though the post hoc analysis of the CANPAP study (27)is intriguing and suggests that CPAP responders maybenefit prognostically. Furthermore, the results of theCANPAP study should not be extrapolated to heart failurepatients with OSA, which is much more effectively sup-pressed by CPAP. Finally, there is a need to examinenovel treatment options for CSA-CSR in patients withHF, as these patients appear to have the worst progno-sis and therefore the most to gain if successful treat-ment of CSA-CSR improves survival.


All Authors have no financial or other potential conflicts ofinterest to disclose.

References

1. Sleep-related breathing disorders in adults: recom-mendations for syndrome definition and measure-ment techniques in clinical research. The Report ofan American Academy of Sleep Medicine Task Force.Sleep 1999; 22:667-89.

2. Khoo MC, Kronauer RE, Strohl KP, Slutsky AS. Fac-tors inducing periodic breathing in humans: a generalmodel. J Appl Physiol 1982;53:644-59.

3. Lorenzi-Filho G, Genta PR, Figueiredo AC, Inoue D.Cheyne-Stokes respiration in patients with conges-tive heart failure: causes and consequences. Clinics(Sao Paulo) 2005;60:333-44.

4. Naughton M, Benard D, Tam A, Rutherford R,Bradley TD. Role of hyperventilation in the pathogen-esis of central sleep apneas in patients with conges-tive heart failure. Am Rev Respir Dis 1993;148:330-8.

5. Solin P, Roebuck T, Johns DP, Walters EH, Naughton

MT. Peripheral and central ventilatory responses incentral sleep apnea with and without congestiveheart failure. Am J Respir Crit Care Med2000;162:2194-200.

6. Carley DW, Shannon DC. Relative stability of humanrespiration during progressive hypoxia. J Appl Phys-iol 1988;65:1389-99.

7. Szollosi I, Roebuck T, Thompson B, Naughton MT.Lateral sleeping position reduces severity of centralsleep apnea / Cheyne-Stokes respiration. Sleep2006;29:1045-51.

8. Lorenzi-Filho G, Rankin F, Bies I, Douglas Bradley T.Effects of inhaled carbon dioxide and oxygen oncheyne-stokes respiration in patients with heart fail-ure. Am J Respir Crit Care Med 1999;159:1490-8.

9. Lorenzi-Filho G, Azevedo ER, Parker JD, BradleyTD. Relationship of carbon dioxide tension in arterialblood to pulmonary wedge pressure in heart failure.Eur Respir J 2002;19:37-40.

10. Roberts AM, Bhattacharya J, Schultz HD, ColeridgeHM, Coleridge JC. Stimulation of pulmonary vagal af-ferent C-fibers by lung edema in dogs. Circ Res1986;58:512-22.

11. Solin P, Snell GI, Williams TJ, Naughton MT. Centralsleep apnoea in congestive heart failure despite va-gal denervation after bilateral lung transplantation.Eur Respir J 1998;12:495-8.

12. Heistad DD, Wheeler RC, Mark AL, Schmid PG, Ab-boud FM. Effects of adrenergic stimulation on venti-lation in man. J Clin Invest 1972;51:1469-75.

13. Lanfranchi PA, Somers VK, Braghiroli A, Corra U,Eleuteri E, Giannuzzi P. Central sleep apnea in leftventricular dysfunction: prevalence and implicationsfor arrhythmic risk. Circulation 2003;107:727-32.

14. Lanfranchi PA, Braghiroli A, Bosimini E, et al. Prog-nostic value of nocturnal Cheyne-Stokes respirationin chronic heart failure. Circulation 1999;99:1435-40.

15. Hanly PJ, Zuberi-Khokhar NS. Increased mortalityassociated with Cheyne-Stokes respiration in pa-tients with congestive heart failure. Am J Respir CritCare Med 1996;153:272-6.

16. Sin DD, Logan AG, Fitzgerald FS, Liu PP, BradleyTD. Effects of continuous positive airway pressure oncardiovascular outcomes in heart failure patientswith and without Cheyne-Stokes respiration. Circula-tion 2000;102:61-6.

17. Javaheri S, Shukla R, Zeigler H, Wexler L. Centralsleep apnea, right ventricular dysfunction, and low di-astolic blood pressure are predictors of mortality insystolic heart failure. J Am Coll Cardiol 2007;49:2028-34.

18. Tkacova R, Niroumand M, Lorenzi-Filho G, BradleyTD. Overnight shift from obstructive to central apneasin patients with heart failure: role of PCO2 and circu-latory delay. Circulation 2001;103:238-43.

19. Tkacova R, Wang H, Bradley TD. Night-to-night al-terations in sleep apnea type in patients with heartfailure. J Sleep Res 2006;15:321-8.

20. Naughton MT, Liu PP, Bernard DC, Goldstein RS,Bradley TD. Treatment of congestive heart failure andCheyne-Stokes respiration during sleep by continu-ous positive airway pressure. Am J Respir Crit CareMed 1995;151:92-7.

21. Teschler H, Dohring J, Wang YM, Berthon-Jones M.



Adaptive pressure support servo-ventilation: a noveltreatment for Cheyne-Stokes respiration in heart fail-ure. Am J Respir Crit Care Med 2001;164:614-9.

22. Philippe C, Stoica-Herman M, Drouot X, et al. Com-pliance with and effectiveness of adaptive servoven-tilation versus continuous positive airway pressure inthe treatment of Cheyne-Stokes respiration in heartfailure over a six month period. Heart 2006;92:337-42.

23. Naughton MT, Rahman MA, Hara K, Floras JS,Bradley TD. Effect of continuous positive airwaypressure on intrathoracic and left ventricular trans-mural pressures in patients with congestive heartfailure. Circulation 1995;91:1725-31.

24. Oldenburg O, Faber L, Vogt J, et al. Influence of car-diac resynchronisation therapy on different types ofsleep disordered breathing. Eur J Heart Fail 2007;9:820-6.

25. Tkacova R, Liu PP, Naughton MT, Bradley TD. Effectof continuous positive airway pressure on mitral re-gurgitant fraction and atrial natriuretic peptide in pa-tients with heart failure. J Am Coll Cardiol 1997;30:739-45.

26. Bradley TD, Logan AG, Kimoff RJ, et al. Continuouspositive airway pressure for central sleep apnea andheart failure. N Engl J Med 2005;353:2025-33.

27. Arzt M, Floras JS, Logan AG, et al. Suppression ofcentral sleep apnea by continuous positive airwaypressure and transplant-free survival in heart failure:a post hoc analysis of the Canadian ContinuousPositive Airway Pressure for Patients with CentralSleep Apnea and Heart Failure Trial (CANPAP). Cir-culation 2007;115:3173-80.

28. Olson LJ, Somers VK. Treating central sleep apneain heart failure: outcomes revisited. Circulation2007;115:3140-2.

29. Somers VK. Sleep-a new cardiovascular frontier. NEngl J Med 2005;353:2070-3.

30. Bradley TD, Hall MJ, Ando S, Floras JS. Hemody-namic effects of simulated obstructive apneas in hu-mans with and without heart failure. Chest2001;119:1827-35.

31. Khayat RN, Abraham WT, Patt B, Roy M, Hua K, Jar-joura D. Cardiac effects of continuous and bilevelpositive airway pressure for patients with heart fail-ure and obstructive sleep apnea: a pilot study. Chest2008;134:1162-8.

32. Kohnlein T, Welte T, Tan LB, Elliott MW. Assisted ven-tilation for heart failure patients with Cheyne-Stokesrespiration. Eur Respir J 2002;20:934-41.

33. Pepperell JC, Maskell NA, Jones DR, et al. A ran-domized controlled trial of adaptive ventilation forCheyne-Stokes breathing in heart failure. Am JRespir Crit Care Med 2003;168:1109-14.

34. Walsh JT, Andrews R, Starling R, Cowley AJ, JohnstonID, Kinnear WJ. Effects of captopril and oxygen onsleep apnoea in patients with mild to moderate con-gestive cardiac failure. Br Heart J 1995;73:237-41.

35. Hanly PJ, Millar TW, Steljes DG, Baert R, Frais MA,Kryger MH. The effect of oxygen on respiration andsleep in patients with congestive heart failure. Ann In-tern Med 1989;111:777-82.

36. Andreas S, Clemens C, Sandholzer H, Figulla HR,Kreuzer H. Improvement of exercise capacity withtreatment of Cheyne-Stokes respiration in patientswith congestive heart failure. J Am Coll Cardiol1996;27:1486-90.

37. Andreas S, Bingeli C, Mohacsi P, Luscher TF, Noll G.Nasal oxygen and muscle sympathetic nerve activ-ity in heart failure. Chest 2003;123:366-71.

38. Staniforth AD, Kinnear WJ, Starling R, Hetmanski DJ,Cowley AJ. Effect of oxygen on sleep quality, cogni-tive function and sympathetic activity in patients withchronic heart failure and Cheyne-Stokes respiration.Eur Heart J 1998;19:922-8.

39. Sasayama S, Izumi T, Seino Y, Ueshima K, Asanoi H.Effects of nocturnal oxygen therapy on outcomemeasures in patients with chronic heart failure andcheyne-stokes respiration. Circ J 2006;70:1-7.

40. Javaheri S. Pembrey’s dream: the time has come fora long-term trial of nocturnal supplemental nasaloxygen to treat central sleep apnea in congestiveheart failure. Chest 2003;123:322-5.

41. Khoo MC. Determinants of ventilatory instability andvariability. Respir Physiol 2000;122:167-182.

42. Mansfield DR, Solin P, Roebuck T. The effect of suc-cessful heart transplant treatment of heart failure oncentral sleep apnoea. Chest 2003;124:1675-1681.

43. Tamura A, Kawano Y, Naono S. Relationship be-tween beta-blocker treatment and the severity ofcentral sleep apnea in chronic heart failure. Chest2007;131:130-135.

44. Solin P, Bergin P, Richardson M. Influence of capil-lary wedge pressure on central apnea in heart failure.Circulation 1998;97:2154-2159.

45. Javaheri S. Parker TJ, Wexler L. Effect of theo-phylline on sleep disordered breathing in heart fail-ure. N Engl J Med 1996;335:562-567.

46. Javaheri S. Acetazolamide improves central sleepapnea in heart failure. A double blind prospective trial.Am J Respir Crit Care Med 2006;173:234-237.

47. Lorenzi-Filho G, Rankin F, Bies I. Effects of inhaledcarbon dioxide and oxygen on Cheyne-Stokes res-piration in patiemts with heart failure. Am J Respir CritCare Med 1999;159:1490-1498.

48. Khayat RN, Xie A, Patel AK. Cardiorespiratory effectsof added dead space in patients with heart failure andcentral sleep apnea. Chest 2001;123:1551-1560.

V. Patruno et al.


Mini-review

Giulio RossiElena Tagliavini Riccardo ValliAlberto Cavazza

Anatomic Pathology Unit, Hospital “Arcispedale SantaMaria Nuova - IRCCS”, Reggio Emilia, Italy

Address for correspondence:Giulio Rossi, MDAnatomic Pathology Unit Hospital “Arcispedale Santa Maria Nuova - IRCCS”Viale Risorgimento 80 42123 Reggio Emilia, ItalyPhone: +39 0522 295656Fax: +39 05222 96945E-mail: [email protected]

Summary

Lymphomatoid granulomatosis (LYG) is a rare B-celllymphoproliferative disorder predominantly involvingthe lungs, but poorly-recognized among cliniciansand pathologists. It is an Epstein-Barr virus (EBV)-driven disease mimicking several other diseases onclinical and radiological grounds, generally showingmultiple, bilateral nodular, ill-defined infiltrates of thelungs tending to coalescence and/or cavitation. LYGoften affects middle-aged males with an underlyingimmunodeficiency and commonly involves skin andcentral nervous system during disease progression.Diagnosis requires a generous biopsy and a carefulhistologic examination with immunohistochemicalstains and molecular demonstration of EBV genomein large atypical B-cells. LYG is graded as I to IIIbased on the number of large EBV-positive B-cellsand grade II/III are now considered as a peculiar vari-ant of T-cell rich diffuse large B-cell lymphoma. In this brief review clinical, radiologic and pathologicfeatures of LYG will be analyzed discussing differen-tial diagnosis, the most appropriate treatment andprognosis.

KEY WORDS: lung; lymphoma; EBV; immunohistochem-istry; immunodeficiency.

Introduction

Lymphomatoid granulomatosis (LYG) is a misnomer coinedby Liebow in 1972 (1) actually designating a rare Epstein-Barr virus (EBV)-driven lymphoproliferative disorder withdifferent aggressiveness, ranging from low-grade to high-

grade angiocentric andangiodestructive lym-phoma (2-8). The lungsare the most commonlyinvolved organ, but theskin and nervous systemare also frequently af-fected (7, 8). The diseasemainly affects middle-aged patient with a male prevalence,clinical outcome is generally poor and an effective therapyis lacking (7-14). Imaging work-up generally reveal multi-ple, bilateral nodules tending to central cavitation (15-21).At histology, LYG appears as a polymorphic lymphoprolif-erative, angiogentric and necrotic process with a predom-inant T-cell rich infiltrate obscuring large lymphomatous B-cells (1-8, 22, 23). Diagnosis is almost impossible oncytology and rarely feasible on small biopsies, most oftenrequiring a generous amount of pathologic tissue as a sur-gical specimen (22, 23). Demonstration of EBV RNAgenome is the crucial point for the correct diagnosis andLYG is graded from I to III based on the rate of EBV-posi-tive large B-cells (3-8, 22, 23). From practical purposes,LYG is suggested to represent a EBV-driven T-cell rich dif-fuse large B-cell lymphoma (22, 23).In this brief report, the main clinico-radiologic and patho-logic findings of LYG are reviewed in order to highlight themost helpful diagnostic features to be kept in mind in rou-tine practice when dealing with this controversial and dif-ficult entity.

Methods

Clinical featuresLYG has a predilection for men in a 2:1 ratio and may af-fect children and elderly, with a prevalence in the forth andfifth decades of life (2, 3, 7, 8, 10-14). The disease morecommonly occurs in patients with immunodeficiency orpredisposing conditions, as Wiskott-Aldrich syndrome,human immunodeficiency virus infection (HIV), allogenicorgan transplantation, common variable immunodefi-ciency, X-linked hypo- or agammaglobulinemia, rheuma-toid arthritis, previous history of solid or hematologic neo-plasms, and chronic treatment with methotrexate (Table1) (2, 3, 7-14, 22-27). The mean time from onset of symp-toms to diagnosis is about 8 months (2, 3, 7-14). It is a common view that LYG may derive from a deficit ofCD8 T lymphocytes that cannot control EBV-specific im-munity (3, 7, 8, 10-14, 22, 23). LYG may be localized tothe lungs or rather presents as a systemic disease involv-ing skin (50%), central nervous system (25%) and lesscommonly kidneys (3, 7-14). Of note, lymph nodes, bonemarrow and spleen are rarely involved (3, 7-14). Cough,chest pain and dyspnoea are the main pulmonary symp-toms, while haemoptysis usually indicates cavitation of theparenchymal nodules (3, 7-14-16, 28-30). However, pa-

Lymphomatoid granulomatosis: a poorly-recognized lymphoproliferative disorder of the lung


Lymphomatoid granu-lomatosis (LYG) is a ra-re Epstein-Barr virus(EBV)-driven lympho-proliferative disorder.

G. Rossi et al.

tients with LYG often suffer from systemic symptoms in-cluding fever, asthenia, night sweats and weigh loss (11-16, 28-30).Cutaneous involvementoften occur in the armsand legs with a very het-erogeneous manifesta-tion, ranging from anerythematous macu-lopapular eruption tosubcutaneous noduleswith non confluent rash(11-16, 28-30). Neuro-logic presentation may pres-ent as an isolated peripheral or cranial neuropathy, as acentral mass lesion, or with seizures (11-16, 28-30).

Predictors of poor prognosis are central nervous system in-volvement, high grade, young age at diagnosis (less than25 years), leukocytosis and hepatomegaly (11-16, 28-30).

Imaging studiesThe most common radi-ographic feature is multi-ple lung nodules, occur-ring in approximately80% of the cases, pre-dominantly involving thelung bases (15-21). Thelesions can progress rapidly, coalesce and commonlycavitate, therefore mimicking Wegener’s granulomato-sis or metastases (Figure 1) (15-21, 26). Dee et al. (18)described two distinct radiographic manifestations ofLYG. In their series of five patients, diffuse reticulonodu-lar opacities correlated microscopically with angiocentricgranulomatous infiltration without pulmonary infarction,whereas larger mass-like opacities corresponded tobiopsy-proven pulmonary infarcts (18). There is a widerange in the number (5-60) and diameter of the nodules(up to 6.5 cm) but generally they measure 1 cm and tendto be located along the bronchovascular bundles and in-terlobular septa (15-21). Less common radiological ap-pearances include coarse linear opacities along the bron-chovascular bundles and thin-walled cysts (15, 18).Nodules can disappear or migrate spontaneously, andmay display central ground-glass opacity surrounded bydenser consolidation at least 2 mm thick – the so called‘‘reversed halo sign’’ (20). However, this is a non-specificsign, most commonly seen in organising pneumonia.Differential diagnosis at imaging presentation may bevery challenging and includes several other, more com-mon diseases, including metastases, lymphocytic inter-stitial pneumonia (LIP), sarcoidosis, Wegener’s granulo-matosis, and cryptogenic organizing pneumonia (Table 2)(15-21). In contrast with other lymphomas involving thethoracic region, mediastinal lymphadenopathy is veryuncommon in LYG (15-21).

Table 1 - Conditions associated with lymphomatoidgranulomatosis.

Hematological disordersLeukemia (acute lymphoblastic; chronic lymphocytic)Hodgkin lymphomaNon-Hodgkin lymphomaMyelofibrosis

Wiskott-Aldrich syndromeCommon variable immunodeficiencyAcquired immune deficiency syndromeSolid tumorsRenal transplantationAutologous stem-cell transplantationRheumatoid arthritisSarcoidosisBiliary cirrhosisChronic hepatitisRetroperitoneal fibrosisPsoriasisDermatitis herpetiformis

The disease morecommonly occurs inpatients with immuno-deficiency, e.g. CD8+lymphocytopenia thatcannot control EBV-specific immunity.

Diagnosis requires agenerous amount ofpathologic tissue as asurgical specimen.

Figure 1 - Chest CT showing atdiagnosis several ill-definednodular opacities along thebronchovascular bundles.


Histology, immunohis-tochemistry and mo-lecular analysisHistology is character-ized by poorly-definedpulmonary nodules (Fig-ure 2, A) along the bron-chovascular bundles andinterstitial inflammatory infiltrates consisting of lympho-cytes, plasma cells, histiocytes and intermediate-to-large

centroblast-like lymphoid cells (Figure 2, B, C) (1-8, 22,23). Vascular and bronchiolar involvement by lymphoid in-filtrates is frequently noted. In fact, venous and arteriousvessels tend to be infiltrated by a mixture of small sizedand large atypical lymphocytes justifying the peculiar an-giocentric involvement (Figure 2, D) (1-8, 22, 23). At theperiphery of lymphoid proliferation, lung parenchyma com-monly shows an acute lung injury with fibrin and jalinemembranes (Figure 2, E) (14, 27). At immunohistochem-istry, there is a background of small T-lymphocytes (CD3+)predominantly with helper phenotype (CD4+) (Figure 3, A)and CD68+ histiocytes intermingled by a population oflarge B-cells (CD20+, PAX5+, CD79a+) (Figure 3, B, C)with high proliferative index by Ki67/MIB-1 (Figure 3, D) (3-8, 22, 23). In-situ hybridization for EBV-encoded RNA(EBER) reveals a consistent number of EBV-positive largeB-cells (Figure 3, E), while molecular analyses generallydemonstrate B-cell clonality by immunoglobulin heavychain gene rearrangement (3-8, 10-13, 16, 22, 23). Despite the misnomer, no granulomas or multinucle-ated giant cells are observed in LYG. According to theWHO classification criteria based on the number ofEBV-positive large atypical B-cells, 3 grades are recog-nized in LYG. Grade I is very rare and shows a polymor-phous infiltrate with minimal angiocentric lesions andfewer than 5 EBV-positive large B-cells x high-power-field (hpf) (3, 8, 22, 23). Grade II had more than 5 andfewer than 20 EBV-positive atypical B-cells x hpf, whilegrade III LYG contains aggregates of EBV positive largeB-cells (more than 20 x hpf), prominent angiocentric le-sions and necrosis (3, 8, 22, 23).

Treatment and prognosisNo standard therapy has been so far established, andtreatment is controversial and problematic, basically de-pending on disease grade (7, 9, 10-13, 30-37). Severalregimens have been considered in the past, from obser-vation to cyclophosphamide plus prednisone or combina-tion chemotherapy with different agents with variablesuccess (10).

Lymphomatoid granulomatosis


Table 2 - Main pathologic conditions mimicking LYG in the lungs.

NeoplasmsPrimary lung carcinomarMetastatic tumorsLymphoproliferative disease (i.e., leukaemia)

InfectionsFungalMycobacterialNocardiaActinomycesParagonomiasis

Autoimmune diseasesWegener’s granulomatosisChurg-Strauss syndromeMicroscopic polyangiitisRheumatoid arthritisIgG4 syndrome

SarcoidosisAmyloidosisLIPCOPPneumoconioses

Abbreviations: LYG, lymphomatoid granulomatosis; LIP,lymphocytic interstitial pneumonia; COP, cryptogenic or-ganizing pneumonia.

Demonstration of EBVRNA genome is thecrucial point for thecorrect diagnosis andLYG.

Figure 2 - Histology showingsurgical lung specimens withseveral “blue” nodules (A).Higher magnification shows apolymorphous mononuclear in-filtrate (B, C) with vascular in-volvement (D) and areas of dif-fuse alveolar damage (E).

However, the outcome is poor and most patients with LYGsuccumb to the disease after a short period of time. In ad-dition, patients often respond initially, but relapse is verycommon and the immunosuppressive effects of therapymay actually worsen the condition. During therapy, aclose follow-up for possible superimposed infections is re-quired.Since this is an EBV-driven process, grade I LYG is oftentreated with interferon alpha (starting dose of 7.5 millionunits subcutaneously administered 3 times per week,then dose-escalation to best response or complete remis-sion and therapy continued at that dose for a year be-yond) (7, 10-13). By contrast, grade II and III should beconsidered high-grade lymphomas, requiring a more ag-gressive treatment including cyclophosphamide, doxoru-bicin, vincristine and prednisone (CHOP) combined withthe anti-CD20 monoclonal antibody rituximab (R-CHOP).Etoposide, prednisone, vincristine, cyclophosphamidedoxorubicin and rituximab (DAEPOCH-R) was also con-sidered an effective treatment strategy in grade III LYG (7,10-13, 30-37).Of note, patients with grade I LYG can relapse withgrade II or grade III disease, but this is sampling-depen-dant due to the presence of discordant disease at differ-ent sites. Re-biopsy should then be highly recom-mended in patients who are progressing on therapy inorder to switch in treatment strategy. At a median follow-up time of 5 years, the progression-free survival (PFS)of patients with grade I LYG was 56% with a median timeto remission of 9 months (7, 10-13). Almost all deathsare recorded in the first 36 months after diagnosis.Grade II-III disease at diagnosis treated with immuno-chemotherapy, PFS was 40% with a median follow-up of28 months (7, 10-13).

Discussion

LYG is an angiocentric large B-cell lymphoproliferative dis-order due to a defective immune response to EBV and

characterized by a mixed polymorphic mononuclear infil-trate with small and large lymphocytes, plasma cells andhistiocytes arranged in ill-defined nodules with transmuralangiocentric infiltration leading to an angiodestructiveprocess (7, 10-13, 22, 23). The disease generally occursin middle-aged patients (mean, 40-50 years; range, 2-85years) with systemic symptoms (fever, malaise, arthralgia,weight loss) mimicking infections (especially tuberculosisand acute histoplasmosis), vasculitides (Wegener’s gran-ulomatosis) or malignancies (7, 10-13, 16, 22, 23). Giventhe rarity of LYG and the non-specific symptoms, correctdiagnosis is frequently delayed, requiring a mean time of8 months from disease onset (14, 30). When LYG is re-stricted to lungs, fever is the main and often unique symp-tom, followed by general malaise, weight loss, arthralgia,but clinical manifestations are mainly organ-related (skin,central nervous system, kidney) (7, 10-13). Lungs are al-most always involved by LYG, but respiratory symptomsmay be absent in 20% of cases, while imaging studies in-variably show parenchymal nodules, opacities or poorly-defined masses with a peculiar tropism for bronchoalve-olar bundles and interlobular septa without mediastinallymphadenopathy (15-21). Otherwise, LYG may appearas pulmonary cystic disease, pleural-based mass orprominent interstitial process (15, 18). Patients with LYGshould be investigated for alterations of cytotoxic T-cellfunction, since a significant association between LYGand immunodeficiencies has been well-demonstrated(i.e., AIDS, Wiskott-Aldrich, post-transplantation, colla-gen-vascular diseases treated with methotrexate, sar-coidosis, hematologic and solid malignancies, chronicliver and cutaneous diseases, medications) (3, 7, 8, 10-13, 24, 25, 27). Interestingly, recent observations by Ya-mashita et al. (38) suggested that some cases of EBV-negative grade 1 LYG are indistinguishable frompulmonary IgG4-related sclerosing disease, an autoim-mune disorder affecting several organs and characterizedby elevated serum IgG4 titer, increased IgG4-positiveplasma cells in tissues with vascular involvement and dra-matic clinical response to steroids.

G. Rossi et al.


Figure 3 - Immunohistochem-istry displaying a backgroundof scattered CD3+ T-cells (A)with CD20+ (B) and PAX-5+(C) large atypical B-cells show-ing high proliferative rate byKi67 (D) and nuclear positivityfor EBV-RNA (E, EBER probe,in-situ hybridization).

Diagnosis of LYG obligatorily requires an accuratehistopathologic examination on generous biopsies. Bron-choalveolar lavage cytology does not permit a confidentdiagnosis, basically evidencing a non-specific mixed in-flammatory infiltrate. Transbronchial or transthoracic CT-guided biopsies may be diagnostic when sampling alarge amount of pathologic tissue and in the hands of ex-pert pathologists. By the way, in the majority of cases di-agnosis is performed on surgical specimens and tissuesampled should be entirely analyzed, since correct diag-nosis mainly depends on a careful examination of variousareas of the pathologic process coupled to adequate im-munohistochemical stains and molecular analysis (22,23). In other words, LYG may actually show grade I andgrade III disease in different pathologic areas of the samecase. Based on the number of EBV-positive large B-cellcounted x high-power-field, LYG is subdivided in III grades(7, 8). According to recent observations by Katzenstein etal. (22) and Colby (23), grade I LYG is a formidable chal-lenging diagnosis and probably represent a early or poorlysampled lymphoma. Grade II/III LYG likely raise the sus-picion of a malignant lymphoproliferative disease even inthe hands of general pathologist. Sharing these compli-cated cases with more expert colleagues and performingEBER-EBV analysis on multiple sections or blocks isvery helpful in discriminating LYG from other mimickingprocesses. Differential diagnosis at histology includes other lympho-proliferative (primary or secondary) and inflammatory dis-eases (22, 23). Knowledge of a previous diagnosis of lym-phoma (Hodgkin or large B-cell lymphomas) is mandatorybefore performing a diagnosis of LYG. Since post-trans-plant lymphoproliferative disorder and iatrogenic immun-odeficiency-associated lymphoproliferative disorder arequite similar to LYG, such a diagnosis should be posed

with caution in patients receiving organ transplant orthose heavily treated with methotrexate or other immuno-suppressive agents (7, 22).The main differentials is with Wegener’s granulomatosis(WG). However, WG shows a true granulomatous in-flammation with scattered multinucleated giant cells, dirty“blue” necrosis and/or granulocytic microabscesses. Neu-trophils, plasma cells and eosinophils represent the ma-jor cellular components in the necrotic background (1, 2,22, 23). Vascular infiltration of WG takes the form of a in-flammatory necrotizing vasculitis with a mixture of gran-ulocytes and mononuclear cells with or without giant cellsleading to at least segmental vessel wall necrosis (1, 2,22, 23).Special stains for mycobacteria and fungi should be per-formed in all cases before considering a diagnosis ofLYG. Spontaneous remission or waxing-and-waning coursehas been reported in grade I LYG, while grade II and IIILYG are basically a unique variant of “T-cell-rich diffuselarge B-cell lymphoma”, mortality ranging from 50% to90% with an overall median survival of 14 months (3, 7,8, 10-13, 22, 23). No standard therapies are available atnow for patients with LYG. Monotherapy using steroids,rituximab or interferon-alpha has been adopted mainly ingrade I LYG (10). Combined chemotherapy with CHOP ±rituximab in patients with grade II-III LYG seems to rep-resent the best therapeutic option at now (3, 10-14, 29,30, 32, 34).


The Authors have no conflicts of interest or funding to dis-close.



TAKE HOME MESSAGES

! LYG is an EBV-driven lymphoproliferative disease, ranging from grade I to grade II and III, these latter being conside-red as a form of diffuse large B-cell lymphoma (“T-cell rich diffuse large B-cell lymphoma”). LYG primarily occurs inthe lungs, less frequently involving skin and central nervous system.

! Mean age at diagnosis is 48 years with a male prevalence. Cough, dyspnoea, fever and malaise are the mainsymptoms.

! CT key features: bilateral, round, poorly defined nodules ranging from 0.5 to 8 cm in diameter with basal predominan-ce and peribronchovascular distribution. The nodules may coalesce and cavitate, and even show “reversed halosign’’, while “migratory’’ nodules due to ‘‘waxing and waning’’ may occur.

! Diagnosis always relies on histology and cannot be made on cytology. Morphologic examination requires the presen-ce of a polymorphic, angiocentric lymphoid proliferation including a background of T-cells, plasma cells and histiocy-tes intermingled by varying numbers of large B-cells. Necrosis may be focal to extensive and surrounding parenchy-ma frequently shows acute lung injury. Demonstration of EBV genome in large B-cells is mandatory and determinesthe grade of disease. Grade II and III contain clusters of EBV-positive large B-cells. Of note, grade I is very rare andusually represents an unsampled or poorly sampled grade II or III lymphoma.

! Prognosis in grade II and III is dismal, median survival ranging from 14 months to 4 years from the diagnosis. Morta-lity rate ranges from 53% to 64%.

! Therapy depends on disease grade. Grade I is usually treated with immunomodulators, namely interferon alpha, whi-le grade II and III require immunochemotherapy combining chemotherapeutic agents with rituximab.

References

1. Liebow AR, Carrington CR, Friedman PJ. Lym-phomatoid granulomatosis. Hum Pathol 1972;3:457-558.

2. Katzenstein AL, Carrington CB, Liebow AA. Lym-phomatoid granulomatosis: a clinicopathologic studyof 152 cases. Cancer 1979;43:360-373.

3. Jaffe ES, Harris NL, Stein H, Vardiman JW, eds.Pathology and Genetics of Tumours of theHaematopoietic and Lymphoid Tissues. WHO Clas-sification of Tumours. IARC Press, Lyon, 2001.

4. Katzenstein AL, Peiper SC. Detection of Epstein-Barr virus genomes in lymphomatoid granulomatosis:analysis of 29 cases by the polymerase chain reac-tion technique. Mod Pathol 1990;3:435-441.

5. Guinee D Jr, Jaffe E, Kingma D, et al. Pulmonarylymphomatoid granulomatosis: evidence for a prolif-eration of Epstein-Barr virus infected B-lymphocyteswith a prominent T-cell component and vasculitis. AmJ Surg Pathol 1994;18:753-764.

6. Myers JL, Kurtin PJ, Katzenstein AL, et al. Lym-phomatoid granulomatosis: evidence of immunophe-notypic diversity and relationship to Epstein-Barrvirus infection. Am J Surg Pathol 1995;19:1300-1312.

7. Jaffe ES, Wilson WH. Lymphomatoid granulomato-sis: pathogenesis, pathology and clinical implica-tions. Cancer Surv 1997;30:233-48.

8. Travis WD, Brambilla E, Muller-Hermelink HK, Har-ris CC, eds. Tumours of the lung, pleura, thymus andheart. Pathology and Genetics. WHO Classificationof Tumours. IARC Press, Lyon, 2004.

9. Fauci AS, Haynes BF, Costa J, Katz P, Wolff SM.Lymphomatoid granulomatosis: prospective clinicaland therapeutic experience over 10 years. N Engl JMed 1982;306:68-74.

10. Dunleavy K, Roschewski M, Wilson WH. Lymphoma-toid Granulomatosis and Other Epstein-Barr VirusAssociated Lymphoproliferative Processes. Curr He-matol Malig Rep 2012;7:208-215.

11. Calfee CS, Shah SJ, Wolters PJ, Saint S, King, Jr.TE. Anchors Away. N Engl J Med 2007;356:504-9.

12. Hochberg EP, Gilman MD, Hasserjian RP. CaseRecords of the Massachusetts General Hospital.Case 17-2006: a 34-yer-old man with cavitary lung le-sions. N Engl J Med 2006;354:2485-93.

13. Dolgonos L, Janssen WJ. A 75-year-old woman withdyspnea and a sore throat. Chest. 2008;133:1014-20.

14. Rossi G, Marchioni A, Guicciardi N, Bertolini F, Valli R,Cavazza A. A rare cause of fever and PET-positivenodules in the lungs. Clin Respir J 2009;3:118-120.

15. Lee JS, Tuder R, Lynch DA. Lymphomatoid granulo-matosis: radiologic features and pathologic correla-tions. Am J Roentgenol 2000;175:1335-39.

16. Pisani RJ, DeRemee RA. Clinical implications of thehistopathologic diagnosis of pulmonary lymphoma-toid granulomatosis. Mayo Clin Proc 1990;65:151-63.

17. Hicken P, Dobie JC, Frew E. The radiology of lym-phomatoid granulomatosis in the lung. Clin Radiol1979;30:661-4.

18. Dee PM, Arora NS, Innes DJ Jr. The pulmonarymanifestations of lymphomatoid granulomatosis. Ra-diology 1982;143:613-8.

19. Sheehy N, Bird B, O’Briain DS, Daly P, Wilson G.Synchronous regression and progression of pul-monary nodules on chest CT in untreated lymphoma-toid granulomatosis. Clin Radiol 2004;59:451-4.

20. Benamore RE, Weisbrod GL, Hwang DM, Bailey DJ,Pierre AF, Lazar NM, et al. Reversed halo sign in lym-phomatoid granulomatosis. Br J Radiol 2007;80:e162-6.

21. Hare SS, Souza CA, Bain G, Seely JM, Gomes MM,Quigley M. The radiological spectrum of pulmonarylymphoproliferative Disease. The British Journal ofRadiology 2012;85:848-864.

22. Katzenstein AL, Doxtader E, Narendra S. Lympho-matoid granulomatosis. Insights gained over 4decades. Am J Surg Pathol 2010;34:e35-e48.

23. Colby TV. Current histological diagnosis of lym-phomatoid granulomatosis. Modern Pathology2012;25, S39-S42.

24. Sebire NJ, Haselden S, Malone M, Davies EG, Ram-say AD. Isolated EBV lymphoproliferative disease ina child with Wiskott-Aldrich syndrome manifesting ascutaneous lymphoid granulomatosis and responsiveto anti-CD20 immunotherapy. J Clin Pathol2003;56:555-557.

25. Haque AK, Myers JL, Hudnall SD, et al. Pulmonarylymphomatoid granulomatosis in acquired immunod-eficiency syndrome: lesions with Epstein-Barr virusinfection. Mod Pathol 1998;11:347-356.

26. McCloskey M, Catherwood M, McManus D, Todd G,Cuthbert R, Riley M. A case of lymphomatoid gran-ulomatosis masquerading as a lung abscess. Thorax2004;59:818-819.

27. Kameda H, Okuyama A, Tamaru J, Itoyama S, IizukaA, Takeuchi T. Lymphomatoid granulomatosis and dif-fuse alveolar damage associated with methotrexatetherapy in a patient with rheumatoid arthritis. ClinRheumatol 2007;26:1585-1589.

28. Jaffre S, Jardin F, Dominique S, et al. Fatal haemop-tysis in a case of lymphomatoid granulomatosistreated with rituximab. Eur Respir J 2006;27:644-646.

29. Erickson BW, Cripe L, Rieger K, Cummings OW,Wilkes D. A Woman with Facial Papules and Pul-monary Nodules. Respiration 2007;74:471-474.

30. Vahid B, Salerno DA, Marik PE. Lymphomatoid gran-ulomatosis: a rare cause of multiple pulmonary nod-ules. Respir Care 2008;53:1227-29.

31. Johnston A, Coyle L, Nevell D. Prolonged remissionof refractory lymphomatoid granulomatosis after au-tologous hemopoietic stem cell transplantation withposttransplantation maintenance interferon. LeukLymphoma 2006;47:323-328.

32. Jung KH, Sung HJ, Lee JH, et al. A case of pul-monary lymphomatoid granulomatosis successfullytreated by combination chemotherapy with rituximab.Chemotherapy 2009;55:386-390.

33. Wilson WH, Kingma DW, Raffeld M, et al. Associa-tion of lymphomatoid granulomatosis with Epstein-Barr viral infection of B lymphocytes and response tointerferon-alpha 2b. Blood 1996;87:4531-4537.

34. Drasga RE, Williams SD, Wills ER, Roth LM, EinhornLH. Lymphomatoid granulomatosis: successful treat-ment with CHOP combination chemotherapy. Am JClin Oncol 1984;7:75-80.

35. Raez LE, Temple JD, Saldana M. Successful treat-

G. Rossi et al.


ment of lymphomatoid granulomatosis using cy-closporin-A after failure of intensive chemotherapy.Am J Hematol 1996;53:192-195.

36. Zaidi A, Kampalath B, Peltier WL, Vesole DH. Suc-cessful treatment of systemic and central nervoussystem lymphomatoid granulomatosis with rituximab.Leuk Lymphoma 2004;45:777-780.

37. Wilson WH, Kingma DW, Raffeld M, et al. Associa-

tion of lymphomatoid granulomatosis with Epstein-Barr viral infection of B lymphocytes and response tointerferon-alpha 2b. Blood 1996;87:4531-4537.

38. Yamashita K, Haga H, Kobashi Y, et al. Lung in-volvement in IgG4-related lymphoplasmacytic vas-culitis and interstitial fibrosis. Report of 3 cases andreview of the literature. Am J Surg Pathol2008;32:1620-1626.



Mini-review

Daniel MoralesFranco Laghi

Division of Pulmonary and Critical Care Medicine, EdwardHines Jr. Veterans Administration Hospital, and LoyolaUniversity of Chicago Stritch School of Medicine, Hines,Illinois, USA

Address for correspondence:Franco Laghi, MDDivision of Pulmonary and Critical Care MedicineEdward Hines, Jr. VA Hospital, 111N5th Avenue and Roosevelt RoadHines, IL 60141 - USAPhone: (708) 2022705Fax: (708) 2027907E-mail: [email protected]

Summary

Mechanical ventilation is necessary in most patientsaffected by the acute respiratory distress syndrome(ARDS). Unfortunately, mechanical ventilation itselfcan cause lung damage as a result of ventilator-in-duced lung injury (VILI). The cyclical recruitment andde-recruitment of atelectatic lung regions (atelec-trauma), lung overdistension (volutrauma) and de-novo inflammation caused by a combination of thetwo (biotrauma) are likely participants in the develop-ment of VILI. Increasing experimental evidence sug-gests that the risk of VILI may be decreased by care-ful titration of ventilator support guided by monitoringpulmonary mechanics. Airway pressure (Paw) is thesimplest signal available to monitor mechanics inARDS. In combination with measurements of lungvolume, Paw allows to plot volume-pressure curves(VP curves) and to record end-expiratory pressureand end-inspiratory pressure during zero flow (Pplat).In the past it was assumed that VP curves could giveaccurate information on lung recruitment andoverdistension. Those assumptions, however, havebeen proven incorrect. Similarly, it is incorrect toconsider Pplat an accurate index of overdistension.In this review we will examine some of the availabletools to monitor pulmonary mechanics in ARDS. Thecritical interpretation of the data recorded with thesetools, their limitations and the potentials use of thesedata in setting the ventilator will be discussed aswell.

KEY WORDS: Acute Respiratory Distress Syndrome;monitoring; respiratory mechanics; Ventilator-InducedLung Injury.

Introduction

The acute respiratory dis-tress syndrome (ARDS) isa form of noncardiogenicpulmonary edema that re-sults from acute damage tothe alveoli (1). Most pa-tients with this syndromewill die if they do not re-ceive supplemental oxygenand mechanical ventilation(2, 3). By reversing life-threatening hypoxemia andalleviating the work ofbreathing, mechanical ven-tilation buys time for the lungsto heal (3). Mechanical ventilation can also cause lungdamage by several mechanisms, including alveolar rup-ture and alveolar hemorrhage, especially when high air-way pressures are used for ventilation (4, 5). In these pa-tients, the damage to the lungs caused by mechanicalventilation is known as ventilator-induced lung injury (VILI)(5). Mounting experimental evidence suggests that therisk of VILI may be decreased by a careful titration of ven-tilator support guided by monitoring pulmonary mechan-ics in ARDS (5-8).

Pressure Volume curves in ARDS

A useful first step in understanding the impact of monitor-ing pulmonary mechanics in ARDS is to examine thepressure-volume relationship of the respiratory system inthese patients. As shown inFigure 1, the pressure-vol-ume curve in patients withARDS can have a sigmoidshape with two discretebends (9). The lower bendis called lower inflectionpoint (LIP) and the upperbend is called upper inflec-tion point (UIP) (9). In the past the LIP wasthought to be the criticalpressure needed to reopenmost of previously col-lapsed airways and alveoli.The UIP was thought to be the critical pressure beyondwhich alveolar overdistension occurs. That meant thattidal ventilation was thought to be safe as long as it wasdelivered within these two points. We now know thatthese are oversimplifications because recruitment ofcollapsed lung units continues above LIP (10) and aboveUIP (11).



Ventilator-inducedlung injury (VILI) maybe considered as a"de-novo" biotraumacaused by cyclicalrecruitment and de-recruitment of atelec-tatic lung regions(atelectrauma), andlung overdistension(volutrauma).

Examination of pres-sure-volume (P-V)curves is the firststep of monitoringpulmonary mecha-nics in ARDS. Howe-ver, P-V curves aredifficult to interpretdue to many con-founders.

D. Morales et al.


Ventilation that continues beyond the UIP can cause lunginjury (5). This type of lung injury is known as “baro-trauma” or lung trauma caused by excessive pressure ap-plied to the lungs (5). Some investigators, however, pre-

fer the term “volutrauma” (lung trauma caused by exces-sive distension of the lungs) because – they note – it isnot the pressure at the airway opening that causes lunginjury but the distention of the lung (12). Ventilation that starts below the LIP is associated with cycli-cal collapse and reopening of lung units. This cyclical col-lapse and reopening causes a type of lung damage knowas “atelectrauma” (13). In addition to biophysical injury (vo-lutrauma and atelectrauma), investigators now posit that in-jurious ventilatory strategies associated with overdisten-sion of the lung and with repeated recruitment andde-recruitment of collapsed lung units can also lead to therelease of inflammatory mediators, including TNF- , inter-leukin-6, prostaglandins, leukotrienes and reactive oxygenspecies (13). According to those investigators, these inflam-matory mediators cause a biochemical injury termed “bio-trauma” (13). At a local level inflammatory mediators canlead to recruitment of a number of cells, including neu-trophils (14). In addition, inflammatory mediators can translo-cate from the lung into the systemic circulation and this maylead to distal organ dysfunction and death (4, 13). At one time, investigators advocated obtaining pressure-volume curves to properly select ventilator settings inpatients with ARDS (15). Unfortunately, pressure-volumecurves are difficult to generate because they requireheavy sedation and paralysis (16). In addition they cancause hypoxemia at low lung volumes, derecruitment atlow levels of positive end-expiratory pressure (PEEP)and hemodynamic compromise (decrease of venous re-turn) (16). Pressure volume curves are also difficult to in-terpret due to many confounders. These confounders in-clude expiratory flow limitation (17), abnormal chest-wallmechanics (18), continuous recruitment of collapsed lungunits above LIP (10) and above UIP (11) and focal vs.non-focal distribution of ARDS (6, 19). Not surprisingly,most experts around the world use pressure-volumecurves only for research purposes but not in clinical prac-tice (Figure 2).

Figure 1 - Schematic representation of a pressure-volumecurve of the respiratory system in a patient with ARDS. Inthese patients, the pressure-volume curve can have a sig-moid shape with two discrete bends above functional resid-ual capacity. The lower bend is called lower inflection pointand an upper bend is called upper inflection point. In 1995,Roupie et al. (AJRCCM 1995;152:121) reported that usingconventional tidal volumes (9-12 mL/kg), and a mean PEEPof 10 cm H2O, more than 70% of patients with ARDS had anend-inspiratory plateau airway pressure exceeding upper in-flection point. Reducing tidal volumes to 6 mL/kg brought theend-inspiratory plateau airway pressure below upper inflec-tion point. This was the first study to demonstrate the rele-vance of reduction in tidal volume for lung protection.

Figure 2 - Pressure vol-ume curves are difficultto generate and to inter-pret. This is why mostinternational experts donot use them in theirdaily clinical practice(Franco Laghi, personalcommunication, Novem-ber 2010).

Monitoring pulmonary mechanics to limit overdistension (Volutrauma)

Following the seminal study of Amato et al. (15), theARDS Network published the result of a large multicen-ter trial of 861 patients with ARDS (20). In the study, onegroup of patients was randomized to mechanical ventila-

tion with small tidal volumes(6 ml/kg of ideal body weightor IBW) and a plateau air-way pressure (Pplat)recorded following an inspi-ratory pause of 0.5 secondsof 30 cm H2O or less. A sec-ond group of patients wasrandomized to traditionaltidal volumes (12 ml/kgIBW) and a Pplat of 50 cmH2O or less (20). The trialwas stopped when an in-terim analysis revealed that

lowering tidal volume andPplat decreased mortality by 22%. In a subsequent meta-analysis, Eichacker et al. (21) concluded that the most im-portant aspect in setting the tidal volume in ARDS is touse tidal volumes that produce a Pplat between 28 and32 cm H2O. Pplat is used to estimate transpulmonary pressure (lungstretching). A high Pplat usually signifies excessive lungstretching, and a low Pplat signifies less lung stretching.Unfortunately, the value of Pplat is determined not onlyby the stiffness of the lung but it is also determined bythe stiffness of the chest wall. In some patients, includ-ing those who are obese, pregnant or who have tenseascites, the stiffness of the chest wall can be significant.In these patients, Pplat may be very high without this sig-nifying that the lungs are truly overdistended (volu-trauma). That is, in patients with a chest wall that isstiffer than normal the simple measurement of Pplatwill cause physicians to grossly overestimate lungstretching. In these patients it may necessary to meas-ure transpulmonary pressure using esophageal pressuretracings (see below). Transpulmonary pressure is calculated by subtractingalveolar pressure from pleural pressure (Figure 3). Inclinical practice, it is unrealistic to perform direct measure-ments of alveolar pressure and direct measurements ofpleural pressure. Instead, airway pressure is used as asubstitute of alveolar pressure, and esophageal pres-sure is used as a substitute of pleural pressure. If a clinician wants to know the extent of lung stretching atend-inhalation he/she will have to record Pplat plus thecorresponding esophageal pressure at end-inhalation. Ofnote, the value of Pplat already comprises any externalPEEP applied to the patient and any intrinsic PEEP the pa-tient may have. This means that it would be wrong to in-clude in the calculation of transpulmonary pressure anycorrection for external PEEP or intrinsic PEEP. It has beenreasoned that in patients with ARDS, tidal volume shouldbe titrated to keep the transpulmonary pressure in thephysiologic range – i.e., transpulmonary pressure <25 cmH2O while the patient is in the supine position (7, 22). The use of small tidal volumes in ARDS causes a reduc-tion of CO2 clearance and a reduction in lung recruit-ment. These phenomena are responsible for an initial

worsening in lung compliance and ventilation/perfusionmatching when instituting low-tidal volume ventilation(20). In other words, permissive hypercapnia and permis-sive atelectasis/hypoxemia are the trade-offs we have toaccept to improve the outcome of patients with ARDS(20). Of interest, new experimental evidence suggeststhat permissive hypercapnia may itself be lung-protective(23). Hypercapnia causes intracellular acidosis, which, inturn, has many potential protecting effects on injuredalveolar cells. These potential protecting effects includethe inhibition of xanthine oxidase (with consequent de-crease in the production of free radicals), inhibition of theactivity of NF-kB (with consequent decrease in cytokineproduction) and inhibition of capsase-3 that results inless apoptosis (23).

Monitoring pulmonary mechanics to limit cyclical recruitment-derecruitment (Atelectrauma)

The central question here is “what aspects of pulmonarymechanics should we monitor to avoid atelectrauma?”.Stated differently the question is “what aspects of pul-monary mechanics should we monitor to set PEEP inARDS?”. This is a difficult question that can be answeredonly tentatively. The various strategies used to set PEEP in ARDS include:1. Monitoring oxygenation and using a sliding-scale

(table) developed by a panel of experts to adjustPEEP and FiO2 in discrete steps to maintain ade-quate arterial oxyhemoglobin saturation (24, 25).

2. Monitoring respiratory system compliance while titrat-ing PEEP (optimal PEEP defined as the PEEP asso-ciated with maximal compliance) (26, 27).



Figure 3 - Transpulmonary pressure or PL (lung stretching) iscalculated by subtracting alveolar pressure (PA) from pleu-ral pressure (Ppl). In clinical practice, airway pressure (Paw)substitutes alveolar pressure and esophageal pressure sub-stitutes pleural pressure.

Plateau airway pres-sure (Pplat) is usedto estimate trans-pulmonary pressure(lung stretching). Insome patients a hi-gher stiffness of thechest wall may cau-se grossly overesti-mation of lung stret-ching.

3. Monitoring the shapeof the airway pressuresignal during lung in-flation with constantairflow (optimal PEEPdefined as the PEEPassociated with a lin-ear rise in airwaypressure or “stress in-dex = 1”) (6).

4. Monitoring Pplat whiletitrating PEEP (opti-mal PEEP defined asthe highest PEEP as-sociated Pplat of 28-30 cm H2O) (28).

5. Monitoring an esti-mate of transpulmonary pressure measured with anesophageal balloon (optimal PEEP defined as thePEEP associated with positive transpulmonary pres-sure at end-exhalation while keeping transpul-monary pressure in the physiologic range of <25 cmH2O) (7).

Except for the first strategy listed above, all the otherstrategies are based on two ideas, first, to monitor the me-chanical characteristics of the individual patient withARDS and, second, set PEEP accordingly. Investigators have reported encouraging results (ten-dency to improve survival) in patients with ARDS venti-lated with a tidal volume of 6 ml/kg IBW in whom PEEPwas titrated according to the mechanical characteristicsof each individual patient (7, 28). In contrast, titratingPEEP using a sliding-scale (table) designed to adjustPEEP and FiO2 in discrete steps to maintain adequate ar-terial oxyhemoglobin saturation has not improved survival(24, 25).

Monitoring pulmonary mechanics to limit biotrauma

To posit that monitoring a particular aspect of pulmonarymechanics can give an insight to the risk of developingbiotrauma implies the existence of a not yet well identifiedlink between pulmonary mechanics and biotrauma. Mon-itoring tools that have triggered interest in this regard in-clude the quantification of the end-inspiratory strain of thelung (29, 30) and the computation of the so-called drivingpressure (31). 1. End-inspiratory strain: according to continuum me-

chanics, a branch of classic mechanics that dealswith solids and fluids, the transformation of a bodyfrom a reference configuration to a current configu-ration is called deformation. This is quantified as thedisplacement between particles in the body relativeto a reference length or strain. In the case of thelungs undergoing mechanical ventilation end-inspira-tory strain is defined as the change in lung volumerelative to the resting volume (29, 30). This meansthat to calculate the end-inspiratory strain of the lungit is necessary to measure the end-expiratory lungvolume and tidal volume (30). In mechanically ven-tilated patients, measurements of end-expiratory lungvolume can be performed using the helium dilutiontechnique, the nitrogen washout/washin technique

and with spiral computed tomography (32, 33).(Whether strain should be calculated while patientsare on PEEP or not remains controversial) (34).Cyclical end-inspiratory strain associated with infla-tion to total lung capacity is injurious to healthy lungs(29). This occurs when the resting lung volume (thebaby lung in case of ARDS) is increased by two-foldto three-fold (29, 35). In patients with ARDS damagehas been reported with end-inspiratory strains wellbelow this upper limit (29). Such observation impliesthe presence of inhomogeneous distribution of localend-inspiratory strain (29).

2. Driving pressure: thispressure is calculatedas the difference be-tween Pplat andPEEP. This meansthat one of the deter-minants of drivingpressure is end-inspi-ratory lung strain: thegreater the strain thegreater the drivingpressure. Post-hoc analysis ofseveral clinical inves-tigations suggeststhat driving pressuresabove 15-20 cm H2Oare conducive to increased mortality in ARDS (Fig-ure 4) (4, 7, 15, 20, 24, 25, 28, 36-40). It would betempting to speculate that the excess mortality inthose studies was due, at least in part, to excessivestrain and biotrauma. For several reasons such spec-ulation cannot be either accepted or refuted. First, thelink between strain and driving pressure is indirect.Second, the value of Pplat required to calculate driv-ing pressure is not only a function of lung mechan-ics but it is also a function of chest wall mechanics(see section on volutrauma). Third, no study hasprospectively determined the impact of different driv-ing pressures on ARDS outcome. Fourth, ventilatorsettings (such ventilator mode, as PEEP, respira-tory rate, FiO2) in the investigations summarized inFigure 4 varied from study to study (4, 7, 15, 20, 24,25, 28, 36-40). This makes it impossible to dissectthe effect of driving pressure from other ventilatorvariables on patient outcome. In other words, whileit would seem reasonable to aim for a driving pres-sure below 15-20 cm H2O (5, 15, 41) it is necessaryto bear in mind that such threshold is based on con-jecture, biological plausibility and post hoc analysisof studies not designed to identify the ideal drivingpressure to use in patients with ARDS.

Conclusion

In patients with ARDS mechanical ventilation can be life-saving yet it can also exacerbate lung injury (VILI). Cur-rent knowledge suggests that preventing VILI during me-chanical ventilation requires avoidance of cyclical openingand closing of unstable lung units and avoidance of ex-cessive stretching of lung parenchyma. Growing experi-mental evidence suggests that these goals may be

D. Morales et al.


Investigators havereported encoura-ging results (ten-dency to improvesurvival) in patientswith ARDS ventila-ted with a tidal volu-me of 6 ml/kg IBW inwhom PEEP was ti-trated according tothe mechanical cha-racteristics of eachindividual patient.

The quantificationof the end-inspira-tory strain of thelung and the com-putation of the so-called driving pres-sure has been sug-gested to limit bio-trauma, but the linkbetween pulmonarymechanics and bio-trauma has not yetbeen identified.

achieved by a careful titration of ventilator support guidedby monitoring pulmonary mechanics (5-8).


The article is supported by grants from the Veterans Ad-ministration Research Service.

References

1. Ranieri VM, Rubenfeld GD, Thompson BT, FergusonND, Caldwell E, Fan E, et al. Acute respiratory dis-tress syndrome: the Berlin Definition. JAMA2012;307:2526-33.

2. Laghi F, Siegel JH, Rivkind AI, Chiarla C, De GaetanoA, Blevins S, et al. Respiratory index/pulmonary

shunt relationship: quantification of severity and prog-nosis in the post-traumatic adult respiratory distresssyndrome. Crit Care Med 1989;17:1121-28.

3. Tobin MJ. Culmination of an era in research on theacute respiratory distress syndrome. N Engl J Med2000;342:1360-61.

4. Ranieri VM, Suter PM, Tortorella C, De Tullio R, Da-yer JM, Brienza A, et al. Effect of mechanical venti-lation on inflammatory mediators in patients withacute respiratory distress syndrome: a randomizedcontrolled trial. JAMA 1999;282:54-61.

5. Marini JJ. Mechanical Ventilation in the Acute Res-piratory Distress Syndrome, In: Tobin MJ, editor.Principles and Practice of Mechanical Ventilation, 2ed. New York: McGraw Hill; 2006. p. 625-48.

6. Grasso S, Stripoli T, De Michele M, Bruno F, Mo-schetta M, Angelelli G, et al. ARDSnet ventilatory pro-tocol and alveolar hyperinflation: role of positive end-expiratory pressure. Am J Respir Crit Care Med2007;176:761-67.

7. Talmor D, Sarge T, Malhotra A, O’Donnell CR, Ritz R,Lisbon A, et al. Mechanical ventilation guided byesophageal pressure in acute lung injury. N Engl JMed 2008;359:2095-104.

8. Briel M, Meade M, Mercat A, Brower RG, Talmor D,Walter SD, et al. Higher vs lower positive end-expi-ratory pressure in patients with acute lung injury andacute respiratory distress syndrome: systematic re-view and meta-analysis. JAMA 2010;303:865-73.

9. Tobin MJ. Advances in mechanical ventilation. NEngl J Med 2001;344:1986-96.

10. Jonson B, Richard JC, Straus C, Mancebo J,Lemaire F, Brochard L. Pressure-volume curves andcompliance in acute lung injury: evidence of recruit-ment above the lower inflection point. Am J RespirCrit Care Med 1999;159:1172-78.

11. Hickling KG. The pressure-volume curve is greatlymodified by recruitment. A mathematical model of ARDSlungs. Am J Respir Crit Care Med 1998;158:194-202.

12. Dreyfuss D, Ricard JD, Saumon G. On the physio-logic and clinical relevance of lung-borne cytokinesduring ventilator-induced lung injury. Am J RespirCrit Care Med 2003;167:1467-71.

13. Slutsky AS. Ventilator-induced lung injury: from baro-trauma to biotrauma. Respir Care 2005;50:646-59.

14. Rivkind AI, Siegel JH, Littleton M, De Gaetano A, Ma-mantov T, Laghi F, et al. Neutrophil oxidative burst ac-tivation and the pattern of respiratory physiologicabnormalities in the fulminant post-traumatic adultrespiratory distress syndrome. Circ Shock1991;33:48-62.

15. Amato MB, Barbas CS, Medeiros DM, Magaldi RB,Schettino GP, Lorenzi-Filho G, et al. Effect of a pro-tective-ventilation strategy on mortality in the acuterespiratory distress syndrome. N Engl J Med1998;338:347-54.

16. Terragni PP, Rosboch GL, Lisi A, Viale AG, RanieriVM. How respiratory system mechanics may help inminimising ventilator-induced lung injury in ARDSpatients. Eur Respir J Suppl 2003;42:15s-21s.

17. Koutsoukou A, Bekos B, Sotiropoulou C, KoulourisNG, Roussos C, Milic-Emili J. Effects of positiveend-expiratory pressure on gas exchange and expi-ratory flow limitation in adult respiratory distress syn-drome. Crit Care Med 2002;30:1941-49.



Figure 4 - Mortality of patients with ARDS plotted against driv-ing pressure in twelve clinical studies designed to comparesome type of conventional ventilation against different lung-protective strategies (4, 7, 15, 20, 24, 25, 28, 36-40). For eachstudy, the circle indicates the combination of mortality anddriving pressure recorded with protective strategy and the starindicates the combination of mortality and driving pressurerecorded with conventional ventilation. In blue are studieswhere there was no difference in mortality between protec-tive strategy and conventional ventilation. In red are studieswere the mortality with conventional ventilation was greaterthan with protective strategy. In most instances, mortality wasthe highest when driving pressure of the conventional venti-lation group was more than 20 cm H2O and it was the lowestwhen driving pressure of the lung-protective strategy groupwas less than 15 to 20 cm H2O (Modified from Bugedo andBruhn) (41).

18. Mergoni M, Martelli A, Volpi A, Primavera S, ZuccoliP, Rossi A. Impact of positive end-expiratory pressureon chest wall and lung pressure-volume curve inacute respiratory failure. Am J Respir Crit Care Med1997;156:846-54.

19. Constantin JM, Grasso S, Chanques G, Aufort S, Fu-tier E, Sebbane M, et al. Lung morphology predictsresponse to recruitment maneuver in patients withacute respiratory distress syndrome. Crit Care Med2010;38:1108-17.

20. Ventilation with lower tidal volumes as comparedwith traditional tidal volumes for acute lung injuryand the acute respiratory distress syndrome. TheAcute Respiratory Distress Syndrome Network. NEngl J Med 2000;342:1301-08.

21. Eichacker PQ, Gerstenberger EP, Banks SM, Cui X,Natanson C. Meta-analysis of acute lung injury andacute respiratory distress syndrome trials testing lowtidal volumes. Am J Respir Crit Care Med2002;166:1510-14.

22. Colebatch HJ, Greaves IA, Ng CK. Exponentialanalysis of elastic recoil and aging in healthy malesand females. J Appl Physiol 1979;47:683-91.

23. Ismaiel NM, Henzler D. Effects of hypercapnia andhypercapnic acidosis on attenuation of ventilator-as-sociated lung injury. Minerva Anestesiol 2011;77:723-33.

24. Brower RG, Lanken PN, MacIntyre N, Matthay MA,Morris A, Ancukiewicz M, et al. Higher versus lowerpositive end-expiratory pressures in patients withthe acute respiratory distress syndrome. N Engl JMed 2004;351:327-36.

25. Meade MO, Cook DJ, Guyatt GH, Slutsky AS, ArabiYM, Cooper DJ, et al. Ventilation strategy using lowtidal volumes, recruitment maneuvers, and high pos-itive end-expiratory pressure for acute lung injuryand acute respiratory distress syndrome: a random-ized controlled trial. JAMA 2008;299:637-45.

26. Ward NS, Lin DY, Nelson DL, Houtchens J, SchwartzWA, Klinger JR, et al. Successful determination oflower inflection point and maximal compliance in apopulation of patients with acute respiratory distresssyndrome. Crit Care Med 2002;30:963-68.

27. Suter PM, Fairley B, Isenberg MD. Optimum end-ex-piratory airway pressure in patients with acute pul-monary failure. N Engl J Med 1975;292:284-89.

28. Mercat A, Richard JC, Vielle B, Jaber S, Osman D,Diehl JL, et al. Positive end-expiratory pressure set-ting in adults with acute lung injury and acute respi-ratory distress syndrome: a randomized controlledtrial. JAMA 2008;299:646-55.

29. Gattinoni L, Carlesso E, Caironi P. Stress and strainwithin the lung. Curr Opin Crit Care 2012;18:42-47.

30. Gattinoni L. Counterpoint: Is low tidal volume me-chanical ventilation preferred for all patients on ven-tilation? No. Chest 2011;140:11-13.

31. Marini JJ. Point: Is pressure assist-control preferredover volume assist-control mode for lung protectiveventilation in patients with ARDS? Yes. Chest2011;140:286-90.

32. Chiumello D, Cressoni M, Chierichetti M, Tallarini F,Botticelli M, Berto V, et al. Nitrogen washout/washin,helium dilution and computed tomography in the as-sessment of end expiratory lung volume. Crit Care2008;12:R150.

33. Olegard C, Sondergaard S, Houltz E, Lundin S, Sten-qvist O. Estimation of functional residual capacity atthe bedside using standard monitoring equipment: amodified nitrogen washout/washin technique requir-ing a small change of the inspired oxygen fraction.Anesth Analg 2005;101:206-12, table.

34. Graf J. Bedside lung volume measurement for esti-mation of alveolar recruitment. Intensive Care Med2012;38:523-24.

35. Protti A, Cressoni M, Santini A, Langer T, Mietto C,Febres D, et al. Lung stress and strain during me-chanical ventilation: any safe threshold? Am J RespirCrit Care Med 2011;183:1354-62.

36. Villar J, Kacmarek RM, Perez-Mendez L, Aguirre-Jaime A. A high positive end-expiratory pressure,low tidal volume ventilatory strategy improves out-come in persistent acute respiratory distress syn-drome: a randomized, controlled trial. Crit Care Med2006;34:1311-18.

37. Kallet RH, Jasmer RM, Pittet JF, Tang JF, CampbellAR, Dicker R, et al. Clinical implementation of theARDS network protocol is associated with reducedhospital mortality compared with historical controls.Crit Care Med 2005;33:925-29.

38. Stewart TE, Meade MO, Cook DJ, Granton JT, Hod-der RV, Lapinsky SE, et al. Evaluation of a ventilationstrategy to prevent barotrauma in patients at high riskfor acute respiratory distress syndrome. Pressure-and Volume-Limited Ventilation Strategy Group. NEngl J Med 1998;338:355-61.

39. Brower RG, Shanholtz CB, Fessler HE, Shade DM,White P Jr, Wiener CM, et al. Prospective, random-ized, controlled clinical trial comparing traditionalversus reduced tidal volume ventilation in acute res-piratory distress syndrome patients. Crit Care Med1999;27:1492-98.

40. Brochard L, Roudot-Thoraval F, Roupie E, DelclauxC, Chastre J, Fernandez-Mondejar E, et al. Tidalvolume reduction for prevention of ventilator-inducedlung injury in acute respiratory distress syndrome.The Multicenter Trail Group on Tidal Volume reduc-tion in ARDS. Am J Respir Crit Care Med1998;158:1831-38.

41. Bugedo G, Bruhn A. Ventilacion mecanica en el sin-drome de distres respiratorio agudo, In: Andersen M,editor. Manual de Medicine Intensiva. Santiago,Chile: Editorial Mediterraneo Ltda 2010:77-89.

D. Morales et al.


26 Shortness of Breath 2012; 1 (1): 26

Two recent studies opened new exciting avenues of re-search, respectively in the field of regenerative medicineand new treatment for airways diseases.The first study (1) tested a method to stimulate organ tis-sue repair without complicated procedures. The secondstudy (2) identified molecular pathway responsible forexcess mucus production in airways suggesting newdrugs that inhibit that pathway. Giacca’s team at Trieste’sInternational Centre for Genetic Engeneering and Biology(ICGEB) screened a library of human miRNAs to identifythose inducing cardiomyocites proliferation. They trans-fected rat neonatal cardiomyocytes in vitro with different200 miRNAs and measured proliferation and cell division.Fluorescence microscopy showed that rat neonatal car-diomyocytes proliferated in response to miRNA injection,and 12 days after injection, mouse neonatal hearts wereenlarged, but without showing signs of cell enlargement,indicating an increased number of cells in the organ. Im-portantly, hearts of adult rats administered the miRNAs im-mediately after induced heart attack showed reduceddamage and preserved function compared to the heartsof rats that didn’t receive the therapy. Cardiac cells losemost of their capacity for proliferation and regenerationshortly after birth, making it difficult for hearts to recoverfrom damage later in life. But researchers have identifiedfour human microRNAs that can stimulate proliferation ofadult rodent cardiac cells in culture and help protectagainst damage during heart attack in vivo, according toa study published in Nature. If the microRNAs work sim-ilarly in human cardiac cells, they may have potential asregenerative therapies after heart damage.Holtzman et al. (2) have described the molecular pathwayresponsible for excess mucus in airway cells and haveused that information to design a series of new drugs thatinhibit that pathway. As part of the new research, the sci-entists discovered that a critical signaling molecule,CLCA1, has a special role in the mucus pathway. Theyshowed that CLCA1 allows a protein known as IL-13 toturn on the major mucus gene in airway cells. The re-searchers also showed that CLCA1 needs help from anenzyme called MAPK13. Although there were no existingdrugs that acted against MAPK13, there were several thatinhibit a similar enzyme known as MAPK14, which differsslightly in structure. MAPK13 inhibitor drugs may have apossible role in related conditions with excess mucusproduction, like COPD, asthma, cystic fibrosis and eventhe common cold.

1) Functional screening identifies miRNAs inducingcardiac regeneration. Eulalio A, Mano M, Dal Ferro M, Zentilin M, Sinagra G,Zacchina S, Giacca M

Nature doi:10.1038/nature11739AbstractIn mammals, enlargement of the heart during embryonic

development is primarily dependent on the increase incardiomyocyte numbers. Shortly after birth, however,cardiomyocytes stop proliferating and further growth ofthe myocardium occurs through hypertrophic enlarge-ment of the existing myocytes. As a consequence of theminimal renewal of cardiomyocytes during adult life, re-pair of cardiac damage through myocardial regenerationis very limited. Here we show that the exogenous admin-istration of selected microRNAs (miRNAs) markedlystimulates cardiomyocyte proliferation and promotescardiac repair. We performed a high-content mi-croscopy, high-throughput functional screening for hu-man miRNAs that promoted neonatal cardiomyocyteproliferation using a whole-genome miRNA library. FortymiRNAs strongly increased both DNA synthesis andcytokinesis in neonatal mouse and rat cardiomyocytes.Two of these miRNAs (hsa-miR-590 and hsa-miR-199a)were further selected for testing and were shown topromote cell cycle re-entry of adult cardiomyocytes exvivo and to promote cardiomyocyte proliferation in bothneonatal and adult animals. After myocardial infarctionin mice, these miRNAs stimulated marked cardiac re-generation and almost complete recovery of cardiacfunctional parameters. The miRNAs identified hold greatpromise for the treatment of cardiac pathologies conse-quent to cardiomyocyte loss.

2) IL-13–induced airway mucus production is attenu-ated by MAPK13 inhibition.Alevy YG, Patel CA, Romero AG, Patel DA, Tucker J,Roswit WT, Miller CA, Heier RF, Byers DE, Brett TJ,Holtzman MJ

J Clin Invest 2012;122:4555-68AbstractIncreased mucus production is a common cause ofmorbidity and mortality in inflammatory airway dis-eases, including asthma, chronic obstructive pul-monary disease (COPD), and cystic fibrosis. However,the precise molecular mechanisms for pathogenic mu-cus production are largely undetermined. Accordingly,there are no specific and effective anti-mucus thera-peutics. Here, we define a signaling pathway fromchloride channel calcium-activated 1 (CLCA1) toMAPK13 that is responsible for IL-13–driven mucusproduction in human airway epithelial cells. The samepathway was also highly activated in the lungs of hu-mans with excess mucus production due to COPD. Wefurther validated the pathway by using structure-baseddrug design to develop a series of novel MAPK13 in-hibitors with nanomolar potency that effectively re-duced mucus production in human airway epithelialcells. These results uncover and validate a new path-way for regulating mucus production as well as a cor-responding therapeutic approach to mucus overpro-duction in inflammatory airway diseases.

Land of hope and dreamsSelection of life science literature

by Marco Confalonieri


Medical humanities

H ow, when and to what extent is it acceptable, essen-tial or improper to tell the truth, a terrible truth, to a

sick person who is unaware of how quickly his or her con-dition is deteriorating? This dilemma impacts deeply andpainfully on the life and quality of life of many people. Ispeak from experience having had to cope with thispainful dilemma personally; the life I shared with MarisaMadieri, my wife for thirty-two years, lead me to share alsothis ordeal with her. For five years, day after day – the ex-perience of disease and of knowing the disease, the ex-perience of truth when truth is so difficult to accept, andthe liberating and devastating power of that truth. Everygeneral problem – as, in this case, informing patientsabout their condition and the manner and method of de-livering information involving the essence of their life andtheir death – is concretely endured by each person, byeach family. That was our experience, too. I say “we” evenif the protagonist of this story is Marisa, because it is shewho was stricken by cancer, who coped with it, fought itand eventually lost her battle, although she made this vic-tory an arduous one as she confronted and hit back at herenemy step by step, calmly, blow after blow.She is the protagonist, because she lived every aspect ofher story with her unceasing need to know the truth andwith her questions on how to ask for it, demand it and lis-ten to it – while the others, those who were questioned byher, certainly wondered how they could or should tellsuch truth. I am just a witness to this story, one who es-caped to tell it, as the Bible says. However, given the in-tensity of our relationship, I was directly involved, too, allthe time, second by second, step by step in this problemof requesting and delivering the truth – in this case aharmful and evil truth – and in the way of requesting andproviding this information.I can only describe what I lived through, without anyclaim to constructing a theory. Freud often quoted theGospel’s phrase “The truth shall make you free”, in whichhe believed firmly, as I do. Without truth, there is no free-dom, no intensity of life; the world cannot be crossedfreely. Like any other instrument of salvation, truth is dan-gerous because it has to do with the essence of life; thegreat Spanish Jesuit and baroque writer Gracian said thatnothing demands more caution than the truth: “’tis thelancet of the heart”. If this operation is carried out hastilyand driven by a rash albeit generous impulse, it coulddamage the aorta and kill the patient.It is one thing to love truth, it is quite another thing to befanatical and obsessive about truth – an attitude againstwhich the philosopher Benedetto Croce often warned.There are the right manners, forms, opportunities andtimes to tell the truth. If a person is ugly and ungainly,telling them outright is not love for truth. A humane actlies in how the truth is told, on how we care for the per-son to whom we are telling an unpleasant truth. In thiscase, too, we tell the truth not because we want todemonstrate our frankness (and that form of frankness

that may take the disguise of scientific language); weshould not be focused on ourselves, but on the otherperson.Moreover, we must be aware that given our finite condi-tion, an exchange of absolute truth can never be achievedbetween two people, even within the closest of relation-ships. It is impossible to tell all the truth, to convey all itsfacets and possible shades; this is impossible due to therelative, imperfect and delimited nature of the humancondition, and it would be wrong to believe that we cantell all the truth, that we can see everything clearly; as St.Paul maintains, we see “per speculum et in aenigmate”,through a mirror and in mystery, and it would be illusiveto see ourselves as omniscient as God. Yet, we can tellalmost all the truth, and this almost – if taken to its furthestpossible extreme – is our all. When it comes to diseases(or news about diseases) that are serious, distressing andoften fatal like cancer frequently is, there are people –Marisa, for example, or other people I was close to in sim-ilar circumstances now concluded, for the best or for theworst – who have by their intimate constitution a moralneed, an existential, total, almost physical need to knowand be told the truth, even a terrible truth about their con-dition. They need the truth to fight it, but they also needit to be able to live. Not knowing, ignoring, fearing to bedeceived, even if for noble reasons, means to move in an-guish through the mist, in an ambiguous darkness thaterodes their life and destroys any opportunity for joy,pleasure, beneficial forgetfulness and abandonment thatcan be achieved in spite of the difficult or dramatic expe-rience.However, there are other people – as I have personallyseen with other friends stricken by the disease – who donot want to know the truth, who try to hide it in every pos-sible way, who manage not to read and understand eventhe most evident signs, who misunderstand even themost clearly worded communication. I have seen rationalpeople, even deeply religious people, who would normallyanalyze reality and try to grasp its meaning, choose to de-ceive themselves about their tumor even though theywere experiencing the burden of the disease day by day,actually manage to deceive themselves until the end. Ina situation like this, I think that physicians are faced witha terrible dilemma: telling the truth or not revealing it, hid-ing it, softening it.As I see it, there is no definite answer: of course, assum-ing that the protagonist is the patient, that his or herrights must be considered and not general principles andpre-defined behavioral models, and that the physicianshould pay attention to the patient’s requests, then it is (itshould be) more appropriate to lie to a sick person whoclearly asks for a lie, because this is what he or shewants and a doctor is there to serve the sick person, notto comply to a strict behavioral rule. It is a question forwhich I am not able to provide an answer, because aphysician’s duty is not only to serve the sick person and

Telling the truthClaudio Magris

C. Magris


to meet his or her requests, but also to understand the in-nermost, real needs of the patient. If a person with livercirrhosis asks for a bottle of whisky which he is really crav-ing for, I do not think a doctor should give it to him, as adoctor knows better than his patient what the true needsof the person and of the patient as a whole are, from apsychological and physical point of view. And yet, there isa terrible implication (a necessary, but nonetheless terri-ble implication): that another person knows better thanyou what is best for your life, and has the power to makedecisions for you according to his opinion.As far as I am concerned, this attitude would be uncon-ceivable; I need the truth, like Marisa did. Not because Iam a brave person – Marisa was brave, much more thanI am, and not only regarding diseases or death – but be-cause truth is like a shield to me, the comfortable warmthof life against my fears or my weaknesses.Marisa always wanted to be told the truth, and in fact shewas always aware of the truth, all the truth, about hercondition. I am sure of this, because at each visit Ispoke at length with her doctors and I witnessed the con-versations she had with them: I know what she askedthem and what they replied. When, on a couple of occa-sions, we went to different hospitals from usual, evenabroad, after every conversation with her doctor or doc-tors, Marisa would write a brief yet detailed and ex-haustive description of her condition and of the state ofher disease, and then show her report to the doctor tobe sure that she had not written inaccuracies. And I canconfirm that her report was perfectly in line with what hertreating physicians wrote to describe her case to theircolleagues. It is not without reason that she was a greatwriter, whose books are appreciated in many countries,

and one of her characteristics was the clear-cut, accu-rate style, the ability to use the most appropriate wordsthat reflect true poetry.Throughout the five years of her illness – five yearsmarked by alternating phases, with tumor exacerbationsthat were very hard to manage followed by long periodsof good health and vitality – I have seen this continuingprocess of truth, as those years were characterized by fre-quent clinical tests, examinations, procedures, visits withdoctors, questions and answers. I could see that thiscontinuous “link”, as I call it, with Marisa’s own truth wasan anti-anxiety factor for her, a sort of safety net (the lit-tle safety remaining under those circumstances), a sort ofguarantee of normality.Marisa managed, for herself and for the others who livedwith her, to keep a “normal” atmosphere until the end; shedid not allow the disease (which she fought strenuously)to control all her life, to become a nightmare or a fixedthought that would make her life a black hole. She de-voted the necessary time and energy to her fight againstthe disease, but then she moved on to other things, andeven if at times she certainly was scared and sad abouther probable death, she never projected her anxiety ontothe rest of her life; she did not become neurotic, did notlose her taste for life or interest in the personal and col-lective affairs of others; she kept her love for the sea andfor all other pleasures or passions until the end. Not tomention her loving relationship with our two children, withher friends, and with me. I think that this knowledge of thetruth, this gazing into the face of Medusa, this tearing offthe mask of a terrible disease and looking it in the eyewithout fear or humble submission, allowed her to deprivethe disease not of its destructive and ultimately triumphant

“Red shoes” by Marco Ceruti.

Telling the truth


power, but of its dark nature. And it is darkness that moreoften and most of all scares us.This attitude was also made possible by the health pro-fessionals we were so lucky to encounter: humane peo-ple, who showed their wisdom and great ability in tellingthe truth. Not because they softened it, but because theyplaced it, frankly but very tactfully, within the general con-text of her condition, with an emphasis on all possible op-tions available. To be specific, I can quote the words of one of her doc-tors, Guido Tuveri. A month or two before the end, whenher condition was rapidly worsening with the insurgenceof an ascites, he described the likely fatal consequencesto us – I was present with Marisa – without complacency,just the bare truth. Then he added “All this can happen anhour from now, in six months’ time or perhaps even never.It is unlikely, most unlikely, that it will never happen, butit is not to be excluded”.He had told the truth, because he had yes given thebare facts of the new threat, but also because it wasquite true that the devastating effect of the ascitescould have occurred at any time or even, based onmedical history, never – because not only in life itself,but also in those processes which threaten to destroythat life, or do destroy it, nothing can be absolutelycertain. Of course, that ‘never’ was improbable com-pared to the other two possibilities; Dr. Tuveri did not

hide the fact that these were more probable, but histone when enumerating the three possibilities did con-vey the sense that after all ‘perhaps’ (perhaps never)was faint but not impossible. He was able to tell the un-veiled truth in such a way that the dreadfulness of it wasclear yet not totally damning.I believe those words are an example of how a negativeand destructive truth can and should be told to a patient;with no omissions but without brutality, with delicacy butwithout reserve. Perhaps, also, it is only right to clarify thetruth, as it does not only regard the disease or the ther-apy or the psychotherapy, but existence itself; the truth inknowing that we die anyway – even without a fatal illnesswe are destined to die – but that we also live. Life is adeadly disease, but it is possible to live it happily, withoutdwelling too much on death, without letting the GrimReaper cast too long a shadow.That was how Marisa lived her life in those five difficultyears, allowing those around her to live a better life too,and this, I believe, was due to her capacity and need forthe truth but also to the ability of those who knew just howto impart that truth.

Reproduced with the permission of “The Wylie Agency”LA STORIA NON È FINITA

Copyright © 2006, Claudio MagrisAll rights reserved

Claudio Magris (born April 10, 1939, Trieste) is an Italian scholar, translator and writer. Ma-gris graduated from the University of Turin, where he studied German studies, and has beena professor of modern German literature at the University of Trieste since 1978. He is an essayist and columnist for the Italian newspaper Corriere della Sera and for otherEuropean journals and newspapers.His numerous studies have helped to promote an awareness in Italy of Central Europeanculture and of the literature of the Habsburg myth.Magris is a member of several European academies and served as senator in the ItalianSenate from 1994 to 1996.His first book on the Habsburg myth in modern Austrian literature rediscovered central Eu-ropean literature. His journalistic writings have been collected in “Behind Words”, 1978 and“Ithaca and Beyond”, 1982. He has written essays on E.T.A. Hoffmann, Henrik Ibsen, ItaloSvevo, Robert Musil, Hermann Hesse and Jorge Luis Borges. His novels and theatre pro-ductions, many translated into several languages, include Inferences from a Sabre (1984),Danube: A Sentimental Journey from the Source to the Black Sea (1986), Stadelmann(1988), A different sea (1991), and Microcosms (1997).

His breakthrough was Danube (1986), which is a magnum opus. In this book (said by the author to be an “drowned novel”),Magris tracks the course of the Danube from its sources to the sea. The whole trip evolves into a colorful, rich canvas of themulticultural European history.Magris won the Bagutta Prize in 1987 for Danube and the Strega Prize in 1997 for Microcosms. He was also awarded theErasmus Prize in 2001 and a Prince of Asturias Award for Literature in 2004. On July 31, 2006 he won the Austrian State Prizefor European Literature. On October 18, 2009 he received the Peace Prize of the German Book Trade during the FrankfurtBook Fair. He received in 2009 the Prix Européen de l!Essai Charles Veillon to honor his work.

Date post:	16-Jul-2020
Category:	Documents
Upload:	others
View:	0 times
Download:	0 times

A cover 1 - 2012 - aots.sanita.fvg.it€¦ · Several inflammatory markers, such as TNF- , PCR,...

Documents