Several key features of ARDS have been identified over the past 10 to 15 years to aid clinicians in their efforts to blunt the devastating morbidity and associated mortality currently reported to range from 30-65%. In the mid-1980s, Montgomery, et al. reported that death from intractable hypoxic respiratory failure in ARDS was uncommon and that on-going systemic inflammation with progression to multiple organ dysfunction syndrome was primarily responsible for mortality [3]. In the early 1990s, Gattinoni and associates utilizing thoracic CT scans defined ARDS as a heterogeneous and not homogenous process as previously suspected [4]. The consolidated infiltrates of the disease were found predominantly in the most dependent regions of the lung. Consequently, ARDS is perceived to represent a heterogeneous process with portions of the lung maintaining normal compliance, gas exchange, and tissue weight. It is important to recognize that substantial portions of the lung in ARDS appear to be recruitable by manipulation of patient position and ventilation. The current interest and ongoing evaluation of prone positioning for ARDS, permissive hypercapnia, and lung protection strategies originated from these observations [5].

Application of high volume ventilation (10-15 cm/kg) and inadequate or inappropriate levels of PEEP were hypothesized to increase barotrauma and volutrauma from resultant shearing of the pulmonary alveolocapillary surface and precipitate ventilator-induced lung injury (VILI). VILI has also been hypothesized to increase pulmonary and systemic cytokine production and play a role in the development of MODS. Recently, multiple studies have begun to examine whether ALI/ARDS can be caused by large tidal volume ventilation and whether established ARDS worsens when high tidal volume ventilation is applied to maintain gas exchange.

Ventilator-induced lung injury (VILI) was first observed in animal models and is currently the subject of intense investigation in humans. Ranieri and colleagues reviewed that VILI appears to develop as a consequence of pathologic neutrophil (PMN) infiltration; increased cytokine levels in bronchoalveaolar lavage fluid (BAL); and increased cytokine levels in the systemic circulation. Over a three-year period, their two-center study randomized 44 patients to a standard ventilatory strategy group [control (C)] vs. a lung-protection strategy group (LP). The two groups were well matched for demographics and severity of illness. Both groups received similar sedation and mechanical ventilation with a Servo 300 at 10-15 breaths /min with an I:E of 2 and underwent BAL at the time of admission and at 36 hours after study inception. In the control group, conventional therapy using a plateau pressure <35 to achieve gas exchange goals of PaC02 of 35 � 40 and Sa02 of 90% (PEEP was adjusted to optimize Sa02 without worsening of cardiac output). In the LP group, the tidal volume was set just below the upper inflexion point of the pressure volume curve. This is reported to represent where some units of the lung are overdistended. PEEP was set just above the lower inflection point of the pressure volume curve, this allegedly represents the pressure level required to open collapsed lung [6].

Patients had a mean tidal volume of 11.1 ml/kg (C) vs. 7.6 ml/kg (LP), end-inspiratory plateau pressure of 31 (C) vs. 24.6 cm H20 (LP), PEEP 6.5 (C) vs. 14.8 cm H20 (LP), and Fi02 0.9 (C) vs. 0.7 (LP) to obtain gas exchange goals. LP patients had significantly lower BAL levels of PMNs and the following cytokines, TNF-alpha, interleukin (IL) �8, and IL-6. Control patients had significantly elevated levels of IL-6. Finally in a post hoc review, patients who received the PL strategy had improved survival at 28 days [6].

In the superb accompanying editorial, Hudson reviews the potential pathologic interface between the mode of ventilation, PEEP, and outcome in patients with ARDS [7]. The small size of the study and the post-hoc survival analysis not withstanding, he offers collaborative and supportive evidence for this as Ranieri et al's findings are complimented by exciting recent data from the ARDS Network.

In 1994, the National Institutes of Health (NIH) established the 10-center ARDS Network. Thus far, this group of leading academic centers has evaluated ketaconazole and lysofylline in ARDS, both of which were unsuccessful. Since 1997, the network has been evaluating the effects of glucocorticoid therapy in ameliorating the progression of the fibroproliferative phase of ARDS. The Network is currently initiating pathogenesis studies to further elucidate biological markers in ARDS as a means to identify those at risk and the progression of the disease. Additional studies are being proposed to evaluate a wide range of issues pertinent to the care of ALI/ARDS patients, including a multicenter study on the clinical utility of the pulmonary artery catheter in the syndrome. For additional information contact the Network at their Website (http://hedwig.mgh.harvard.edu/ardsnet/index.shtml).

Hudson's editorial reports that in March, 1999, the ARDS network terminated a randomized prospective, control study in ~850 patients which compared conventional ventilation (12ml/kg) to low tidal volume ventilation (6ml/kg) because of a significant benefit in the lung protective (low tidal volume) group (see http://www.hedwig.mgh.harvard.edu/html). The mortality in the high volume group was significantly worse, 39% vs. 31% in the low volume group. Although this study has not yet appeared in peer-review, it should be forthcoming in the near future. We will need to carefully evaluate the results to determine what respiratory parameters were used (peak inspiratory pressure, use of inflection point to identify pressure at which airways opened, and how PEEP was applied and adjusted). We will also need to see what role other therapies such as prone positioning, steroids, anti-inflammatory agents, newer surfactants and others may play.

Although preliminary, these two studies present exciting findings that if corroborated, suggest that ventilatory support plays a major role in the evolution and survival from ARDS. It chillingly reminds us that sometimes our standard therapeutic approaches (10-15 cc/kg) may create insult and that the cure can exacerbate or be worse than the disease. We will need to rethink our "conventional wisdom" regarding patient positioning, PEEP, and desired tidal volume. We will also hopefully be able to define the optimal level of PEEP and safest peak and mean airway pressure while we monitor on-going inflammatory makers. At long last, we may see further significant strides in caring for patients with this most challenging pathology.

1. Conference Summary. Acute Lung Injury (ALI).
AUTHORS: Mathay M.
SOURCE: Chest 1999;116:119S-126S.
ABSTRACT: Not available.

2. Report of the American-European Consensus conference on acute respiratory distress syndrome: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Consensus Committee.
AUTHORS: Bernard GR; Artigas A; Brigham KL; Carlet J; Falke K; Hudson L; Lamy M; LeGall JR; Morris A; Spragg R.
SOURCE: J Crit Care 1994 Mar;9(1):72-81
ABSTRACT:
The acute respiratory distress syndrome (ARDS), a process of nonhydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies, carries a high morbidity rate, mortality rate (10% to 90%), and financial cost. The reported annual incidence in the United States is 150,000 cases, but this figure has been challenged and may be different in Europe. Part of the reason for these uncertainties is the heterogeneity of diseases underlying ARDS and the lack of uniform definitions for ARDS. Thus, those who wish to know the true incidence and outcome of this clinical syndrome are stymied. The European American Consensus Committee on ARDS was formed to focus on these issues and on the pathophysiologic mechanisms of the process. It was felt that international coordination between North America and Europe in clinical studies of ARDS was becoming increasingly important to address the recent plethora of potential therapeutic agents for the prevention and treatment of ARDS.

3. Causes of mortality in patients with the adult respiratory distress syndrome.
AUTHORS: Montgomery AB; Stager MA; Carrico CJ; Hudson LD.
SOURCE: Am Rev Respir Dis 1985 Sep;132(3):485-9.
ABSTRACT:
This study analyzed the factors causing and contributing to death in patients with the adult respiratory distress syndrome (ARDS). Two hundred seven patients were prospectively identified as being at risk for development of ARDS. Forty-seven patients developed ARDS, and the remaining 160 patients were used as a comparison control group. The severity of dysfunction in 8 organ systems and the presence of sepsis syndrome were determined by chart review after discharge or death. Sepsis syndrome was specifically defined by signs and laboratory tests reflecting infection or inflammation plus evidence of a deleterious systemic effect (hypotension, reduced systemic vascular resistance, or unexplained metabolic acidosis). Mortality was 68% in the ARDS group compared to 34% in the control group (p less than 0.005). Only 16% (5 of 32) of deaths in the ARDS group were from irreversible respiratory failure. Most deaths in the first 3 days after entry into the study could be attributed to the underlying illness or injury. The majority of late deaths were related to sepsis syndrome. Of the 22 patients with ARDS who died after 3 days, 16 (73%) met our criteria for sepsis syndrome. There was a sixfold increase in sepsis syndrome after ARDS compared with that in the control group (p less than 0.001). When sepsis syndrome preceded the ARDS, the abdomen was the predominant source, but when sepsis syndrome occurred after the onset of ARDS there was usually a pulmonary source. Our findings indicate that sepsis syndrome, rather than respiratory failure, is the leading cause of death in patients with ARDS.

4. Body position changes redistribute lung computed-tomographic density in patients with acute respiratory failure.
AUTHORS: Gattinoni L; Pelosi P; Vitale G; Pesenti A; D'Andrea L; Mascheroni D.
SOURCE: Anesthesiology 1991 Jan;74(1):15-23.
ABSTRACT:
Ten patients with parenchymal acute respiratory failure (ARF) underwent computed tomography (CT) scans while in the supine and prone positions. At equal levels of positive end-expiratory pressure, the authors measured the changes of CT density in dorsal and ventral basilar lung regions induced by the change of position as well as alterations of gas exchange. The level of venous admixture did not change with body position. The CT scan image of each lung was fractionated into ten levels from dorsal to ventral, each constituting 10% of the lung height. After measuring each lung fraction, the volume, the average CT number, its frequency distribution, and the expected normal value, we computed the lung tissue mass, the excess tissue mass, and the fraction of normally inflated tissue (excess tissue mass = amount of "tissue," which includes edema, cells, and blood in excess of the expected normal value). We also estimated the superimposed hydrostatic pressure on each lung region. We found that the excess lung tissue mass is independent of position. However, in patients in the supine position, lung CT density increased and regional inflation decreased from ventral to dorsal, suggesting progressive deflation of gas-containing alveoli along the gravity gradient. A similar ventral-dorsal deflation pattern occurred within 10 min in patients in the prone position. We conclude that the lung in patients with ARF behaves like an elastic body with a diffusely increased mass; dependent lung regions are compressed by the pressure of overlying structures.(ABSTRACT TRUNCATED AT 250 WORDS)

5. AUTHORS: Kacmarek RM.
SOURCE: Inter Anesth Clin 1999; 37:47-64.

6. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial.
AUTHORS: Ranieri VM; Suter PM; Tortorella C; De Tullio R; Dayer JM; Brienza A; Bruno F; Slutsky AS.
SOURCE: JAMA 1999 Jul 7;282(1):54-61
ABSTRACT:
CONTEXT: Studies have shown that an inflammatory response may be elicited by mechanical ventilation used for recruitment or derecruitment of collapsed lung units or to overdistend alveolar regions, and that a lung-protective strategy may reduce this response.

OBJECTIVE: To test the hypothesis that mechanical ventilation induces a pulmonary and systemic cytokine response that can be minimized by limiting recruitment or derecruitment and overdistention.

DESIGN AND SETTING: Randomized controlled trial in the intensive care units of 2 European hospitals from November 1995 to February 1998, with a 28-day follow-up. PATIENTS: Forty-four patients (mean [SD] age, 50 [18] years) with acute respiratory distress syndrome were enrolled, 7 of whom were withdrawn due to adverse events.

INTERVENTIONS: After admission, volume- pressure curves were measured and bronchoalveolar lavage and blood samples were obtained. Patients were randomized to either the control group (n = 19): tidal volume to obtain normal values of arterial carbon dioxide tension (35-40 mm Hg) and positive end-expiratory pressure (PEEP) producing the greatest improvement in arterial oxygen saturation without worsening hemodynamics; or the lung-protective strategy group (n = 18): tidal volume and PEEP based on the volume-pressure curve. Measurements were repeated 24 to 30 and 36 to 40 hours after randomization.

MAIN OUTCOME MEASURES: Pulmonary and systemic concentrations of inflammatory mediators approximately 36 hours after randomization. RESULTS: Physiological characteristics and cytokine concentrations were similar in both groups at randomization. There were significant differences (mean [SD]) between the control and lung- protective strategy groups in tidal volume (11.1 [1.3] vs 7.6 [1.1] mL/kg), end-inspiratory plateau pressures (31.0 [4.5] vs 24.6 [2.4] cm H2O), and PEEP (6.5 [1.7] vs 14.8 [2.7] cm H2O) (P<.001). Patients in the control group had an increase in bronchoalveolar lavage concentrations of interleukin (IL) 1beta, IL-6, and IL-1 receptor agonist and in both bronchoalveolar lavage and plasma concentrations of tumor necrosis factor (TNF) alpha, IL-6, and TNF-alpha, receptors over 36 hours (P<.05 for all). Patients in the lung-protective strategy group had a reduction in bronchoalveolar lavage concentrations of polymorphonuclear cells, TNF-alpha, IL-1beta, soluble TNF-alpha receptor 55, and IL-8, and in plasma and bronchoalveolar lavage concentrations of IL-6, soluble TNF-alpha receptor 75, and IL-1 receptor antagonist (P<.05). The concentration of the inflammatory mediators 36 hours after randomization was significantly lower in the lung-protective strategy group than in the control group (P<.05). CONCLUSIONS: Mechanical ventilation can induce a cytokine response that may be attenuated by a strategy to minimize overdistention and recruitment/derecruitment of the lung. Whether these physiological improvements are associated with improvements in clinical end points should be determined in future studies.

7. Progress in understanding ventilator-induced lung injury.
AUTHORS: Hudson LD.
SOURCE: JAMA. 1999 Jul 7;282(1):77-8.
ABSTRACT: Not available.