The first clinical trial completed by the Network was a randomized, controlled trial of Ketoconazole versus placebo in patients with acute lung injury and ARDS. It enrolled participants. The LARMA study was a randomized, double-blind, placebo-controlled multi-center study with where each patient was randomized between Lisofylline and Placebo. It was designed to test whether the administration of lisofylline early after the onset of ALI or ARDS would reduce mortality and morbidity. The late phase of ARDS is often characterized by excessive fibroproliferation leading to gas exchange and compliance abnormalities.
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The acute respiratory distress syndrome ARDS is an inflammatory disease of the lungs characterized clinically by bilateral pulmonary infiltrates, decreased pulmonary compliance and hypoxemia. Although supportive care for ARDS seems to have improved over the past few decades, few studies have shown that any treatment can decrease mortality for this deadly syndrome. The implications of this study with respect to clinical practice, further ARDS studies and clinical research in the critical care setting are discussed.
ARDS is an inflammatory disease of the lungs characterized clinically by bilateral pulmonary infiltrates, decreased pulmonary compliance and hypoxemia [ 1 , 2 ]. Despite intense research for decades, the mortality rate in patients with ARDS remains very high, although there is some evidence that these rates might be decreasing [ 3 ]. Interestingly, although the major initial physiological abnormalities are often pulmonary in origin, patients who go on to die of their acute illness usually die of multiple system organ failure MSOF rather than a respiratory death ie hypoxemia.
Virtually all patients with ARDS require mechanical ventilation to provide adequate oxygenation; this therapy is supportive, providing time for the lungs to heal.
As with any therapy, there are side effects of mechanical ventilation; for decades our understanding of these complications was largely limited to the gross air leaks induced by the large transpulmonary pressures - so-called barotrauma. Over the past decade we have learned about more subtle detrimental sequelae of mechanical ventilation, based largely on basic studies on mechanisms of injury [ 4 ].
These studies have demonstrated that mechanical ventilation can induce injury manifested as increased alveolar-capillary permeability due to overdistension of the lung volutrauma [ 5 ], can worsen lung injury by the stresses produced as lung units collapse and re-open atelectrauma [ 6 , 7 ], and can lead to even more subtle injury manifested by the release of various mediators biotrauma [ 8 , 9 ].
The latter provides a putative mechanism to explain the high mortality rate in patients with ARDS: if the mediators released by the lung owing to the increased pulmonary stresses enter the circulation it could lead to distal organ dysfunction, and ultimately organ failure [ 10 ].
Ironically, although mechanical ventilation is life-saving, a logical conclusion of the large body of data on ventilator-induced lung injury VILI is that it might be causing or perpetuating the pulmonary inflammation, preventing or delaying the recovery process. The results of the most recently completed trial were presented in the 4 May issue of New England Journal of Medicine [ 12 ]. This landmark paper answers a key question in relation to the supportive therapy of patients with ARDS but, as with any exciting research, raises a number of interesting questions, which will be addressed in this Commentary.
These beneficial results seemed to hold across a wide spectrum of patients, including septic and non-septic patients, and also those with different degrees of lung dysfunction as assessed by respiratory system compliances.
The study is very important from a clinical perspective, but also raises a large number of questions on the mechanisms underlying the decreased mortality, on the optimal way to ventilate patients with ARDS, and more broadly on the conduct of clinical trials in the critical care setting. This was not the first trial to assess a lung protective strategy in patients with acute lung injury or ARDS; in fact there were three previous negative trials [ 13 , 14 , 15 ], but this was the first large trial that showed a decrease in mortality by simply addressing the injury imposed by overstretching the lung.
Why was this trial positive when other similar trials were negative? One possible reason could be the relative power of the various studies; the ARDSNet trial enrolled patients compared with the patients enrolled in the three previous studies. Another possible explanation for the lack of efficacy in the previous trials might be related to the different approaches used to control respiratory acidosis.
However, the approach to increases in P a CO 2 differed substantially between studies. Specifically, the ARDSNet study was the most aggressive in terms of trying to maintain P a CO 2 relatively close to the normal range, employing higher respiratory rates as well as more liberal use of bicarbonate than the other studies. There are reasons to believe that hypercapnia might actually be beneficial in the context of VILI [ 17 , 18 ]; for example, acidosis attenuates a number of inflammatory processes, inhibits xanthine oxidase a key component in reperfusion injury , and attenuates the production of free radicals [ 18 ].
However, there are also potential detrimental effects such as increased catecholamine release [ 19 ] that might mitigate the potential beneficial effects of hypercapnia on lung injury. The higher respiratory rate that was used in the low- V t arm of the ARDSNet study to minimize hypercapnia might have had a fortuitous benefit, by leading to the development of auto-positive end-expiratory pressure auto-PEEP. Increased end-expiratory lung volume has been shown to be protective in terms of VILI by minimizing the injury due to recruitment and de-recruitment of lung units atelectrauma.
No results have yet been presented on the degree of auto-PEEP in the ARDSNet patients, but minute ventilation was virtually identical between the low- V t and high- V t groups, making this explanation less likely because, for any given respiratory mechanics, minute ventilation is the major determinant of auto-PEEP.
Furthermore, one could argue that the low- V t group might have been subject to more atelectrauma because the smaller V t would probably lead to reduced recruitment with each tidal cycle. Another explanation for the positive ARDSNet trial might be related to the greater spread in V t and plateau pressure P plat between the control arm and the protective strategy.
For example, the difference between the P plat on day 1 in this study was 8 cmH 2 O, compared with 4. Clearly, the greater the difference in the independent variable, the greater the signal:noise ratio, and the greater the likelihood of a positive finding if the therapy is efficacious.
Finally, there might be a threshold in P plat as a surrogate for overdistension above which injury due to mechanical ventilation might increase markedly.
This suggestion could also explain the results of Amato et al [ 21 ] in which the P plat over the first 36 h averaged It seems highly unlikely that there is a specific break point for every patient, especially when one considers the spatial heterogeneity in injury and the difficulty in interpreting a high P plat in the context of a stiff chest wall. This latter possibility brings up the issue of whether the intervention arm was really protective or whether the control arm was injurious because the V t used was too large.
The latter was approx. Thus, on the basis of measured body weight, the V t used in the control arm was approx. What are the messages from this landmark paper? From a clinical perspective there are a number of issues and still many unanswered questions. In applying the results of this study at the bedside, it is important to re-emphasize the fact that V t was calculated on the basis of predicted body weight; this must also be borne in mind when comparing the V t values used in the various ventilation trials, which used different definitions for calculating V t.
This question is difficult to answer given the results available. From a physiological standpoint, it seems reasonable to suggest that PCV with relatively low values of pressure is acceptable; however, from an evidence-based medicine perspective one could argue that this is not the strategy that the ARDSNet investigators used and thus PCV might not be appropriate.
There are cogent arguments on both sides. Physiologically, lung distension is minimized if P plat is kept reasonably low - arguing that a pressure limited strategy should be as good as a volume limited strategy. However, we have to acknowledge that there might be something specific to the ARDSNet strategy not incorporated by using pressure limitation.
Although this suggestion is somewhat unappealing, it might have some merit; for example, in a patient with a very stiff chest wall, limiting the P plat to 30 cmH 2 O might limit V t more than is necessary to minimize overdistension, and in fact might lead to under-recruitment of the lung, poor oxygenation and further de-recruitment. This might not have occurred if the hypothetical patient had been treated exactly as in the ARDSNet protocol.
This question is a central one because preventing recruitment and de-recruitment seems to be crucial in animal studies of VILI. Similarly, the large body of literature on VILI suggests that high-frequency ventilation HFV may be an ideal way of ventilating patents with ARDS because it can provide adequate gas exchange, while minimizing both overdistension and the recruitment and de-recruitment of the lung.
A number of studies are currently re-evaluating this approach in the context of VILI. The study also raises broader questions with regard to clinical trials in the context of the ICU setting. For many years there has been an uneasy feeling in the critical care community that perhaps it would not be possible to prove that any therapy is beneficial in patients with ARDS or sepsis. This pessimism was based on the large number of negative phase III type randomized, large n , multicentered clinical trials in the treatment of these diseases.
There are a number of possible reasons for the large number of negative trials, including of course the possibility that the tested therapy was indeed not effective.
However, the major concern was that we might never obtain a positive trial even if a therapy was effective, because of the tremendous heterogeneity in the patient population, multiple co-morbidities, widely differing underlying diseases, difficulty in controlling co-interventions, and so on. The trial is a role model of the way in which clinical trials should be conducted in the ICU; however, it required a large number of patients, took a long time to complete, and was extremely expensive.
If studies this large, long, and costly are to be performed to evaluate all changes in management of our patients with or without ARDS, it will be extremely difficult to prove almost anything definitively in the ICU setting, other than interventions that are extremely effective.
How, then, will it be possible to evaluate the use of inhaled nitric oxide, HFV, the prone position, less restrictive V t values, optimal PEEP levels and a whole host of changes in management?
We do not have any definitive answers to these questions; ideally other networks such as the ARDSNet should be set up to answer some of these questions with large-scale trials. In addition, it would be wonderful if a reasonably robust, yet less expensive both in monetary terms and in the numbers of patients required study designs could be developed. Perhaps for some questions we should accept less stringent P values when assessing a mortality endpoint.
After all, a P value of less than 0. This is particularly true for therapies for which there is no physiological or biological concern a priori concerning the toxicity of the intervention. In this regard, it has been argued that physiological also called intermediate endpoints might be useless, and even grossly misleading.
Results such as this have been used to suggest that studies that use physiological endpoints should not be used to change clinical practice. We would argue that physiological endpoints might be useful but should be used advisedly.
For example, we know that higher mean airway pressures, as would be observed with higher V t values, usually lead directly to higher P a O 2 values; the use of inhaled nitric oxide also leads directly to increases in P a O 2. Because these endpoints are a direct consequence of the intervention, they might not give us clues to potential detrimental effects of the interventions and hence might not be ideal endpoints for outcome studies.
However, endpoints that are further downstream and are correlated with mortality might be suitable; an example of such an endpoint within the context of ventilation trials might be changes in inflammatory cytokines with different ventilatory strategies. It is tempting to speculate that it might have been related to the greater decrease in serum cytokines interleukin-6 was measured in the present study. As discussed above, it had previously been suggested that injurious forms of mechanical ventilation could lead to an increase in various mediators in the lung biotrauma and, owing to the increased alveolar-capillary permeability, that these mediators might enter the circulation and cause organ dysfunction.
This hypothesis is attractive and has some indirect experimental support data [ 22 ], but it is extremely difficult to prove - at the moment all we have is tantalizing correlative results, but a definitive answer to this question might require a study that specifically targets these mediators and examines changes in outcome.
Indeed, if this hypothesis is correct, it would suggest possible novel approaches to the assessment and treatment of patients at risk for VILI. Ideally, one should apply ventilatory strategies that are relatively non-injurious, but in patients with severe ARDS this might be extremely difficult, if not impossible, because of the spatial heterogeneity of their lung disease [ 23 ].
A strategy that maintains a given lung unit open might lead to the overdistension of other units. In situations such as this, anti-inflammatory therapies such as anti-cytokine therapies might prove to be useful adjuncts to lung protective strategies [ 24 , 25 ], possibly by preventing distal organ injury. Admittedly this approach is purely conjectural at the moment, but if it turns out to be correct, how might we decide which patients would benefit from these therapies?
Perhaps patients with a genetic predisposition to the development of high levels of pro-inflammatory mediators would be those who require these novel adjunctive anti-inflammatory therapies. These are exciting times for basic scientists, clinical researchers and physicians caring for patients with ARDS.
Basic discoveries in the laboratory have been translated into randomized controlled trials, demonstrating decreases in mortality in patients with ARDS by changes in ventilatory strategy that are relatively easy to implement in all ICUs.
Furthermore, there is now the hope that a number of other ventilatory and non-ventilatory interventions that are currently under intense study recruitment maneuvers, higher PEEP levels, prone positioning, high-frequency ventilation, liquid ventilation will be found to decrease mortality further in ARDS patients. Finally, as our understanding of the molecular consequences of VILI increases, and as our understanding of genetic DNA-sequence variants increases, novel approaches to anti-inflammatory therapies of VILI will certainly emerge.
This work was supported in part by the Medical Research Council of Canada grant no. National Center for Biotechnology Information , U. Journal List Respir Res v. Respir Res. Published online Aug Author information Article notes Copyright and License information Disclaimer.
Corresponding author. Arthur S Slutsky : ac. This article has been cited by other articles in PMC. Abstract The acute respiratory distress syndrome ARDS is an inflammatory disease of the lungs characterized clinically by bilateral pulmonary infiltrates, decreased pulmonary compliance and hypoxemia. Keywords: acute lung injury, artificial respiration, barotrauma, biotrauma, iatrogenic, respiratory failure.
Introduction ARDS is an inflammatory disease of the lungs characterized clinically by bilateral pulmonary infiltrates, decreased pulmonary compliance and hypoxemia [ 1 , 2 ]. Why was this trial positive when three previous trials were negative? Summary These are exciting times for basic scientists, clinical researchers and physicians caring for patients with ARDS. Acute respiratory distress in adults. The acute respiratory distress syndrome.
N Engl J Med.
NHLBI ARDS Network
Low tidal volume ventilation also led to an increase in ventilator-free days and a decrease in the number of days with systemic organ failure. There was no change in the incidence of barotrauma between the two groups. Patients assigned to lower tidal volume ventilator settings initially required a higher PEEP to maintain arterial oxygenation and were more likely to develop respiratory acidosis, although the difference disappeared by day 7. However, studies in animals showed that higher tidal volumes were associated with increased lung inflammation and injury. There was no difference in barotrauma between the two groups. Of note, patients in the lower tidal volume group required higher PEEP and had a slight, but significant, respiratory acidosis, both of which resolved after 7 days.
Acute Respiratory Distress Syndrome Clinical Network (ARDSNet)
The acute respiratory distress syndrome ARDS is an inflammatory disease of the lungs characterized clinically by bilateral pulmonary infiltrates, decreased pulmonary compliance and hypoxemia. Although supportive care for ARDS seems to have improved over the past few decades, few studies have shown that any treatment can decrease mortality for this deadly syndrome. The implications of this study with respect to clinical practice, further ARDS studies and clinical research in the critical care setting are discussed. ARDS is an inflammatory disease of the lungs characterized clinically by bilateral pulmonary infiltrates, decreased pulmonary compliance and hypoxemia [ 1 , 2 ]. Despite intense research for decades, the mortality rate in patients with ARDS remains very high, although there is some evidence that these rates might be decreasing [ 3 ].
Mechanical ventilation: lessons from the ARDSNet trial
Study record managers: refer to the Data Element Definitions if submitting registration or results information. Despite 20 years of research into the mechanisms that cause this syndrome and numerous developments in the technology of mechanical ventilation, the mortality has remained greater than 50 percent. Many of the patients are young, and to the tragic loss of human life can be added the cost to society because these patients spend an average of 2 weeks in intensive care units and require multiple high tech procedures. Because of the overwhelming nature of the lung injury once it is established, prevention would appear to be the most effective strategy for improving the outlook in this condition.