October - December 2007: 
Volume 20, Issue 4

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ARDS: Forty Years Later A short look on the history of understanding the pathogenesis and treatment of the syndrome
As to diseases, make a habit of two things - to help, or at least do not harm Hippocrates, Epidemics the first II, 11
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In 1967, a new clinical entity was described in twelve patients, in an article published in Lancet and the authors called it «acute respiratory distress in adults». This syndrome was characterized by acute onset, tachypnea, diffuse infiltrates on chest roentgenogram and hypoxemia refractory to supplemental O2. Seven patients died (mortality 60%) and autopsy findings revealed dense infiltration of the lungs with leukocytes and proteinaceous material1. The article recognized for the first time that the syndrome indicated a severe lung injury as a result of a wide variety of unrelated insults - for example blunt trauma, fat embolism, pancreatitis, pneumonia, gastric aspiration and drug ingestion. In 1971 Petty and Ashbaugh, in another publication, used the term «adult respiratory distress syndrome» probably to address the perception of ARDS as an adult version of the previously described infant respiratory distress syndrome (IRDS). The ARDS, a new kind of non cardiac pulmonary edema, had been no longer emerged in the fore of the Intensive Care Units and it was going to step with them.

Mechanical ventilation using positive end expiratory pressure (PEEP) for prevention of atelectasis and correction of hypoxemia was from the outset the therapy of choice for the ARDS. Since that, PEEP was inseparably linked with the ARDS concept. A typical treatment during this period included modest PEEP 5-10 cm H2O, FiO2 as low as possible, and VT 12-15 ml/kgr to keep the PaCO2 in normal range. A Ppl of 100 mmHg was not unusual during this period!

In 1972, Suter et al introduced the concept of the best PEP2. This was a landmark paper because for the first time the interactions of lung mechanics and hemodynamics were considered together, clearly indicating that the oxygenation of patients with ARDS was not simply focused on the PaO2 values.

In the decade of the 1970s the ARDS became increasingly recognized but hydrostatic causes were difficult to rule out. The potential for confusion was so great that the measurements of pulmonary capillary wedge pressure (PCWP) became a very common means of diagnosis3. Nowadays, this routine measurement is much less frequent because there are usually other clinical data and historical clues that allow fairly secure diagnosis of ARDS apart from volume overload to be made. Thus, a PCWP greater than 18 mmHg does not exclude the diagnosis of ARDS since a concurrent illness could raise this setting. Even when a PAOP is less than 18 mmHg one cannot confirm that edema is the result of altered permeability because reduced colloid oncotic pressure promotes edema in the absence of permeability changes.

In the same period, a sophisticated treatment such as extracorporeal membrane oxygenation (ECMO) failed to reduce the mortality of patients with ARDS4.

In the decade of 1980s computerized tomography demonstrated that bilateral infiltrates are patchy or asymmetric. They are predominantly distributed in dependent lung zones whereas other areas of the lung may be relatively spared5. Pleural effusions are common, making the diagnosis of ARDS indistinguishable from that of cardiac pulmonary oedema6,7.

In 1988, an expanded definition was proposed by J Murray et al that quantified the physiologic respiratory impairment through the use of a four-point lung-injury scoring system that was based on the level of PEEP, the PaO2/FiO2, the static lung compliance, and the degree of infiltration evident on chest radiographs. Other factors included in the assessment were the inciting clinical disorder and the presence or absence of non-pulmonary organ dysfunction8. Although the lung-injury score (LIS) has been widely used to quantify the severity of lung injury in both basic research and clinical trials, it has limited clinical usefulness because it cannot predict outcome whereas there are no specific criteria for excluding diagnosis of cardiac pulmonary edema9.

In 1992 the American European Consensus Conference (AECC) was charged with developing a standardized definition for ARDS in order to assist clinical and epidemiologic research. The AECC recommended that a new designation, acute lung injury (ALI), be defined as “a syndrome of inflammation and increased permeability that is associated with a constellation of clinical, radiologic, and physiologic abnormalities that cannot be explained by, but may coexist with, left atrial or pulmonary capillary hypertension” and “is associated most often with sepsis syndrome, aspiration, primary pneumonia, or multiple trauma and less commonly with cardiopulmonary bypass, multiple transfusions, fat embolism, pancreatitis, and others” 10. The consensus definition has two advantages. First, it recognizes that the severity of clinical lung injury varies: patients with less severe hypoxemia (as defined by a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of 300 or less) are considered to have acute lung injury, and those with more severe hypoxemia (as defined by a ratio of 200 or less) are considered to have the acute respiratory distress syndrome. The recognition of patients with acute lung injury may facilitate earlier enrolment of affected patients in clinical trials. Second, the definition is simple to apply in the clinical setting9. However, this simplicity is also a disadvantage, since factors that influence the outcome, such as the underlying cause and whether other organ systems are affected, do not need to be assessed11. In addition, the criterion for the presence of bilateral infiltrates on chest radiography consistent with the presence of pulmonary oedema is not sufficiently specific to be applied consistently by experienced clinicians12.

In the middle of 1990s there were reports in the literature of decreasing mortality in patients with ARDS although no new therapies with proven efficacy in ARDS patients had become available13. Perhaps, our overall strategies in caring for critically ill patients have improved, that is, better infection surveillance, more rapid attention to resuscitation, and more improved techniques and vigilance for prophylaxis against secondary problems such as stress ulcers, deep venous thrombosis and nosocomial pneumonias.

Moving towards the millennium a large number of new experimental and clinical data had been accumulated, indicating that large tidal volumes used during conventional mechanical ventilation can damage the lungs (volotrauma). This is more common in patients with ARDS leading to overdistention of alveoli in the non dependent areas and to the development of tissue stress and shearing forces in the middle and lower zones of the lung. Closure of small airways and alveolar units occurs at low end-expiratory pressure and high inspiratory pressure repeatedly subjects these tissues to forces that may be several folds higher than those experienced in the free wall of alveoli that remain inflated throughout the tidal cycle. From theoretical standpoint shear stresses at the junction of open and closed tissue will rise to high levels that may mechanically disrupt epithelial or endothelial membranes and/or incite inflammation (some times referred as biotrauma). The resulting clinical condition is strikingly similar to ARDS and it is known as ventilatorinduced lung injury (VILI)14.

According to the above mentioned data, the reversal of atelectasis (by opening of closed small airways and alveoli) not only improves oxygenation but also may reduce damaging tissue stress. The implementation of a more lung-protective (lower than traditional used tidal volumes) strategy, taking care to keep the lung “open” (using a suitable PEEP) throughout the tidal cycle, was the primary rationale. A total of 5 clinical trials compare mechanical ventilation with low tidal volumes (usually 6 ml/kgr) and conventional tidal volumes (usually 12 ml/kgr) in patients with ARDS15-19. In two trials, low tidal volumes were associated with reduced mortality and in 3 trials there was no survival benefit associated with low tidal volumes20. The pooled results of all five trials showed a benefit with low tidal volumes particularly when the end-inspiratory plateau pressure (which correlates with the risk of volotrauma) is lower than 30 cm H2O. The most successful trial of low tidal volume ventilation in ARDS was conducted by the ARDS Clinical Network and, despite the criticism, it was what changed our daily practice, on implementation of mechanical ventilation in patients with ALI/ARDS19.

During the last decade an intense research is ongoing worldwide extended from the understanding of the pathogenesis of ALI/ARDS in microcellular level until to its epidemiologic background. The complexity of the pathogenesis of the syndrome, the meaning of interaction between inflammation and coagulation and the role of genetic polymorphism in its final expression are only some issues expected to be clarified by basic research. In 2002, the NHLBI convened a working group to consider future directions in ALI/ARDS research and the conclusions were that there are major unanswered questions that will required continued major multidiscipline research efforts mainly in the era of basic sciences21.

Today, forty years after its first description, there are more than 5000 articles in PupMed concerning the ALI/ARDS. As many of us implicated in the fascinating field of Intensive Care Medicine, we think the ALI/ARDS as «our disease» not only for historical reasons (it was born together with critical care) but mainly because it is the ideal model of multi-organ dysfunction in witch the complex interactions between the acute respiratory failure and the de-arrangements in circulation, inflammation, coagulation and metabolism are all present simultaneously in this syndrome22. In other words the ALI/ARDS is the epitome of the Intensive Care Medicine.

Despite the tremendous progress in understanding its pathogenesis only one therapeutic manipulation has proven effective in improving survival in ALI/ARDS: the use of mechanical ventilation with low tidal volumes. This is not really a specific therapy for ALI/ARDS but is a lessening of the harmful effects of mechanical ventilation on the lungs. Τhis conclusion makes the Hippocrates saying in the beginning of this article, for the 40 years of ALI/ARDS, absolutely timely.


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3. Swan HJC, Ganz W, Forrester JS, Marcus H, Diamond J, Chonette D. Catheterization of the heart in man with use of a flow-directed balloon-tipped catheter N Engl J Med 1970; 283:447-51.
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8. Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988; 138:720-723.
9. Ware LB, Matthay MA. The acute respiratory Distress Syndrome. N Engl J Med 2000;342:1334-1349
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17. Brochard L, Roudot-Thoraval F, Roupie E et al. Tidal volume reduction for prevention of ventilator –induced lung injury in the acute respiratory distress syndrome Am j Respir Crit Care Med 1998; 158:1831-1838
18. Brower RG, Shanholtz CB, Fessler HE et al. Prospective randomized controlled clinical trial comparing traditional vs reduced tidal volume ventilation in ARDS patients Crit Care Med 1999; 27:1492-1498
19. The ARDS Network: Ventilation with lower tidal volumes as compared with traditional volumes for acute lung injury and the acute respiratory distress syndrome N Engl J Med 2000; 342:1301-1308.
20. Fan E, Needham DM, Stewart TE. Ventilator management of acute lung injury and acute respiratory distress syndrome JAMA 2005; 294:2889-2896.
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22. Gattinoni L, Carlesso E, Valenza F et al. Acute respiratory distress syndrome, the critical care paradigm: what we learned and what we forgot. Curr Opin Crit Care Med. 2004; 10:272-278.