WE know that medicine cannot always be a provided

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1 Acta Anaesthesiol Scand 2004; 48: Copyright # Acta Anaesthesiol Scand 2004 Printed in Denmark. All rights reserved ACTA ANAESTHESIOLOGICA SCANDINAVICA Review Article From ventilator-induced lung injury to physician-induced lung injury: Why the reluctance to use small tidal volumes? J. VILLAR 1,R.M.KACMAREK 2 and G. HEDENSTIERNA 3 1 Hospital Universitario N.S. de Candelaria, Tenerife, Canary Islands, Spain; Adjunct Scientist, Research Center, St. Michael s Hospital, Toronto, Ontario, Canada, 2 Harvard Medical School, and Director, Respiratory Care, Massachusetts General Hospital, Boston, MA, and 3 Department of Medical Sciences, Clinical Physiology, Uppsala University, Stockholm, Sweden From lung research to pulmonary and critical care practice WE know that medicine cannot always be a provided by a protocol. Unlike drugs and medical devices, which cannot be sold unless their effectiveness has been documented, actual treatment in critical care medicine is often dictated by authority, personal experience, and bias. To effectively practise modern critical care medicine, clinicians must be knowledgeable of the complete spectrum of clinical disease and the safety and efficacy of all treatments for any disease. Training critical care physicians requires avoiding confusing opinions with evidence or personal ignorance with scientific uncertainty (1). The better we understand the quality of the evidence we use to make clinical decisions, the better we are able to judge whether new scientific evidence should be incorporated into our practice. But, how can we ensure that the current generation of physicians are trained to make clinical decisions based on the judicious use of the current best evidence-based practice? Practising evidence-based medicine relies on making evidence from clinical research available to support medical practice (2). In other words, critically ill patients should be treated by evidence-based clinical practice guidelines as standards of care. If medicine is not based on scientific evidence, one must wonder on what it is based. The fact that we generally do a poor job of translating research into practise is well documented (3). There is the perception that the lack of educational initiatives at the departmental level in Supported in part by the Fondo de Investigación Sanitaria, Spain (#00/0564). many teaching hospitals around the world prevents us from implementing interventions that can improve clinically relevant outcomes. Instead, many of us still practise medicine based on our personal experiences during training and from treating patients over the years (4). Although many randomized controlled trials in critically ill patients have been conducted over the last 20 years, some procedures that are well documented have still not become part of standard practice (5, 6). Physicians seem to be unwilling to change their practice (7, 8). Insufficient evidencebased medical education, scientific ignorance, bias, and lack of financial incentives or lack of belief in the research evidence are among some of the factors that may explain this attitude among critical care physicians (2, 8). As a result, a gap remains between what the evidence recommends and what is practised. In this commentary, we discuss the evidence regarding the impact of mechanical ventilation on outcome in acute respiratory distress syndrome (ARDS) and its implementation or more precisely lack of implementation. The case for ventilator-induced lung injury Acute respiratory distress syndrome is the most severe form of acute lung injury (ALI) and it is one of the most challenging problems in critical care medicine. The diffuse alveolar damage observed in ARDS reflects the effects of injurious stimuli and the complex interactions of inflammatory mediators on alveolar epithelial and capillary endothelial cells. Although there is a spectrum to the extent of lung involvement 267

2 J. Villar et al. in patients with diffuse alveolar damage, the factors determining which patients will develop the most severe form of lung injury are poorly understood. Despite current therapeutic advances, the prognosis of patients with ALI and ARDS is poor, with a rate of about 50% (9). It is important to emphasize that reported rates in randomized controlled trials do not represent the true ARDS. Among other considerations, those studies do not include all consecutive ARDS patients admitted into the intensive care unit. Approximately 90% of all deaths in ARDS patients occur within 2 3 weeks after the onset of the syndrome. Death has traditionally been attributed to the underlying disease, the presence of sepsis and the failure of vital organ systems other than the lung. Althoughinthepasttwodecadeswehavesubstantially increased our knowledge about pathophysiological aspects of ALI and ARDS that contribute to decreased morbidity and, it has been suggested that the reported reduction in observed in some recent clinical trials are the result of differences in patient selection, severity of the underlying disease, clinical expertise in the management of acute respiratory failure, or therapeutic changes (9). Mechanical ventilation is the most important aspect of life support for patients with respiratory failure. However, mechanical ventilation interferes with normal physiologic processes. The clinician is often applying levels and patterns of pressure, tidal volume, concentration of inspired oxygen and ventilatory rate well beyond the levels that normal lung usually experiences, making mechanical ventilation a potentially dangerous tool. Evidence from wellperformed experimental studies suggests that these abnormal pressures and volumes can cause or aggravate lung injury (10). Referred to as ventilator-induced lung injury (VILI), this condition resembles ALI and ARDS, and is difficult to identify in humans because its appearance overlaps the underlying disease (11). The recognition of VILI has prompted a number of investigators to suggest that ALI/ARDS may in part be a product of our therapy rather than the progression of the underlying disease, supporting the assumption that mechanical ventilation not only can save lives, but also extends the severity of pre-existent lung injury. Experimental and clinical studies (10, 12 18) have shown that cyclic stress caused by ventilating the lungs with high inspiratory volumes or low positive end-expiratory pressures (PEEP) leads to VILI which is accompanied by the development of a pulmonary and systemic inflammatory response with release of cytokines from a variety of lung cells. This ventilatorinduced inflammatory response can cause and/or worsen lung injury and offset outcome by altering cellular pathways that are important for the normal function of tissues and organs. It is now clear that animals with normal or diseased lungs ventilated with prolonged, cyclic overexpansion or cyclic re-expansion and collapse of the lung develop structural pulmonary damage identical to ARDS. In patients with ARDS, mechanical ventilation with large tidal volumes and no PEEP induces bronchiolar and alveolar distension (16). By contrast, experimental studies and clinical trials have shown that the application of so-called protective ventilatory strategies are associated with decreased serum cytokine levels(14, 15, 18), decreased extrapulmonary organ dysfunction (14, 15), and decreased (17, 18). In addition, some authors have hypothesized that the non-judicious use of mechanical ventilation is responsible for the development or progression of the multiple system organ dysfunction that very often is present in ARDS patients and is the main cause of death (19). Mechanical ventilation: The evidence for small tidal volumes! How can we ensure that all patients benefit from the mode of mechanical ventilation they actually receive? The ARDS Network study published in 2000 demonstratedareduced(from40to31%) ina mixed population of patients with ALI and ARDS ventilated with half the tidal volume of the control group (18). However, 3 years later, even in participating centres, clinicians are not routinely using a low VT strategy for patients with severe respiratory failure (20). Thirty-five years after the first description of ARDS, many investigators and experts in the field (20 23) still apply essentially the same ventilatory strategy (tidal volume greater than 10 ml kg 1 and PEEP levels less than 10 cmh 2 O) as in the original description of ARDS (24). Classically, patients with ARDS have been ventilated with tidal volumes of ml kg 1 b.w., and peak airway pressures have been allowed to increase above 50 cmh 2 O (16). However, as a general pattern, all mammals are similarly scaled (Fig. 1) and have a normal tidal volume of about 6.3 ml kg 1 ideal b.w. (25, 26). However, until recently this information has never found a place in clinical practice. In the early 60s, anaesthesiologists and critical care pioneers showed that small tidal volume ventilation caused a 268

3 Ventilator-induced lung injury to physician-induced lung injury Lung volume (L) Rat Mouse Shrew Bat SLOPE = 1.02 Rabbit Marmot Dog Racoon Cat Guinea Pig Manatee Bear Cow Pig Porpoise Goat MAN Monkey Armadillo Dugong Lung Volume = 6.3% BW Tidal Volume = 6.3 ml kg Body weight (kg) 1000 Whale Fig. 1. Scaling of the lung in mammals (adapted from [25,26]). gradual loss of lung volume and hypoxaemia due to right-to-left shunting through regions with poor ventilation. As a result, the one-tidal volume fits-all approach was formulated and inspiratory volumes of ml kg 1 were recommended and, for the next 20 years, experts and pioneers of critical care medicine continued ventilating patients with ALI and ARDS with large tidal volumes and high inspiratory pressures (27). In 1967 the hallmark paper on ARDS by Ashbaugh et al. (24) showed that the application of PEEP was associated with a lower rate in patients with severe lung injury. In the early 70s, Webb and Tierney (28) demonstrated for the first time that high peak alveolar pressure can severely damage the lung and that PEEP can attenuate that damage. There are now considerable experimental and clinical evidence showing that the application of high levels of PEEP in the initial phase of ARDS protect against alveolar flooding and support gas exchange by maintaining collapsed alveoli open, increasing end expiratory lung volume and improving compliance. Although PEEP is an important tool used to facilitate lung recruitment and minimize further injury (12, 14, 29 31), most critical care physicians are still reluctant to use PEEP levels above 10 cmh 2 O (23), despite the fact that a low tidal volume can induce alveolar derecruitment (29, 30). In 1994, a Consensus Conference on mechanical ventilation (32) concluded with a set of recommendations based on three important pieces of information. First, in the acutely injured lung, only 30 50% of the lung contributes to gas exchange (baby lung concept). The diseased lung in patients with ARDS is heterogeneous with collapsed and consolidated units mainly in the dependent regions and more aerated units in the non-dependent regions (33). Second, experimental animal data demonstrated that it is not the high pressure per se but the relatively large regional tidal volumes (volutrauma) overstretching compliant areas of the lung, and the shear forces associated with the opening and closing of unstable lung regions that damage the lung (10). Third, the goal of mechanical ventilation should be to maintain adequate gas exchange rather than maintaining blood gases values within the normal or supra-normal range. However, following the Consensus Conference on Mechanical Ventilation little change in ventilator practice occurred around the world, as most of its recommendations on how to ventilate ARDS patients were not the result of any specific randomized, controlled clinical trial. If the amount and quality of information regarding mechanical ventilation in acutely injured lung is so much greater now than that in 1967, why is there the current tendency towards therapeutic nihilism? Although most would agree that we have not reached the culmination of an era in research on ARDS, clinical studies do demonstrate a decrease in over the years as tidal volumes have decreased (18, 34) (Fig. 2). However, additional research on ARDS is still needed. We have not clearly defined the role of PEEP in ARDS outcome. There is increasing laboratory evidence that ventilating ARDS models with relatively low tidal volumes and high levels of PEEP is clinically beneficial. A recent experimental study has demonstrated that the application of high levels of PEEP, independent of tidal volume, had a direct VT (ml kg 1 ) % % 40% VT (ml kg 1 ) 30% Fig. 2. Schematic representation of the relationship between the temporal reduction of tidal volume and the reported of patients with ARDS throughout the last 25 years. Data have been compiled from [9, 17, 18, 34]. 269

4 J. Villar et al. effectontheimmuneresponseofthelunginaseptic animal model (14). Although the NIH trial (18) did not address formally the question of whether VILI occurs more frequently from repetitive collapse and re-expansion of injured lung or from overdistension of persistently aerated lung units, an urgent issue is to demonstrate whether a recruited lung using high levels of PEEP is preferable to a collapsed lung rested with low PEEP. In addition, there is still controversy over the concept of a safe end inspiratory plateau pressure. In summary, we cannot definitively say what tidal volume, plateau pressure, or PEEP has the most impact on outcome. However, what we can say without reservation is that small tidal volumes in ARDS save lives (17, 18). The era of large tidal volume ventilation should be over. If ARDS outcome depends on ventilatory settings, our patients require that we proceed with the translational process of applying the results of clinical research on mechanical ventilation without undue scepticism. Let us insure we do the most to decrease in our ARDS patients by incorporating the evidence into our daily practice! References 1. Naylor CD. Grey zones of clinical practice: some limits to evidence-based medicine. Lancet 1995; 345: Kalassian KG, Dremsizov T, Angus DC. Translating research evidence into clinical practice: new challenges for critical care. Crit Care 2002; 6: McLaughlin TJ, Soumerai SB, Wilson DJ et al. Adherence to National guidelines for drug treatment of suspected acute myocardial infarction: evidence for undertreatment in women and the elderly. Arch Intern Med 1996; 156: Pronovost PJ, Berenholtz SM, Dorman T, Merrit WT, Martinez EA, Guyatt GH. Evidence-based medicine in Anesthesiology. Anesth Analg 2001; 92: Torres A, Serra-Batlles J, Ros E et al. Pulmonary aspiration of gastric contents in patients receiving mechanical ventilation: the effect of body position. Ann Intern Med 1992; 116: Hebert PC, Wells G, Blajchman MA et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999; 340: Taubes G. Looking for the evidence in medicine. Science 1996; 272: Whitcomb ME. Research in medical education: what do we know about the link between what doctors are taught and what they do? Acad Med 2002; 77: Villar J, Slutsky AS. Is the outcome from acute respiratory distress syndrome improving? Curr Opin Crit Care 1996; 2: Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med 1998; 157: Pinhu L, Whitehead T, Evans T, Griffiths M. Ventilatorassociated lung injury. Lancet 2003; 361: Muscedere JG, Mullen JBM, Gan K, Slutsky AS. Tidal Volume at low airway pressures can augment lung injury. Am Rev Respir Dis 1994; 149: Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS. Injurious ventilatory strategies increase cytokines and c-fos mrna expression in an isolated rat lung model. J Clin Invest 1997; 99: Herrera MT, Toledo C, Valladares F et al. Positive end-expiratory pressure modulates local and systemic inflammatory responses in a sepsis-induced lung injury model. Intensive Care Med 2003; 29: Ranieri VM, Suter PM, Tortorella C et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 1999; 282: Rouby JJ, Lherm T, Martin de Lassale E, Bodin L, Callard P, Viars P. Histologic aspects of pulmonary barotrauma in critically ill patients with acute respiratory failure. Intensive Care Med 1993; 19: Amato MB, Barbas CS, Medeiros DM et al. Effect of a protective-ventilation strategy on in the acute respiratory distress syndrome. N Engl J Med 1998; 338: The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342: Imai Y, Parodo J, Kajikawa O et al. Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA 2003; 289: Weinert CR, Gross CR, Marinelli WA. Impact of randomized trial results on acute lung injury ventilator therapy in teaching hospitals. Am J Respir Crit Care Med 2003; 167: Gattinoni L, Tognoni G, Pesenti A et al. Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med 2001; 345: Hirschl RB, Croce M, Gore D et al. Prospective, randomized, controlled pilot study of partial liquid ventilation in adult acute respiratory distress syndrome. Am J Respir Crit Care Med 2002; 165: Esteban A, Anzueto A, Frutos F et al. Characteristics and outcomes in adult patients receiving mechanical ventilation: a 28-day international study. JAMA 2002; 287: Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress syndrome. Lancet 1967; II: Tenney SM, Remmers JE. Comparative quantitative morphology of the mammalian lung: diffusing area. Nature 1963; 197: Schmidt-Nielsen K. Body size and problems of scaling. In: How Animals Work. New York: Cambridge University Press, 1972: Suter PM, Fairley HB, Isenberg MD. Optimum end-expiratory pressure in patients with acute pulmonary failure. N Engl J Med 1975; 292: Webb H, Tierney D. Experimental pulmonary edema due to intermittent positive pressure ventilation with high inflation pressures. Am Rev Respir Dis 1974; 110: Takeuchi M, Goddon S, Dolhnikoff Shimaoka M, Hess D, Amato MBP, Kacmarek RM. Set positive end-expiratory 270

5 Ventilator-induced lung injury to physician-induced lung injury pressure during protective ventilation affects lung injury. Anesthesiology 2002; 97: Richard JC, Brochard L, Vandelet P et al. Respective effects of end-expiratory and end-inspiratory pressures on alveolar recruitment in acute lung injury. Crit Care Med 2003; 31: Villar J. Positive end-expiratory pressure or no positive endexpiratory pressure: is that the question to be asked? Crit Care 2003; 7: Slutsky AS. Consensus conference on mechanical ventilation. Intensive Care Med 1994; 20: Gattinoni L, Pesenti A. ARDS: the non-homogeneous lung; facts and hypothesis. Intensive Care Digest 1987; 6: Jardin F, Fellahi J, Beauchet A, Vieillard-Boron A, Loubieres Y, Page B. Improved prognosis of acute respiratory distress syndrome. Intensive Care Med 1999; 25: Address: Dr Jesús Villar, Director Research Institute Hospital NS de Candelaria Carretera del Rosario s/n, Santa Cruz de Tenerife Canary Islands Spain jesus.villar@canarias.org 271