The Acute Respiratory Distress Syndrome

The Acute Respiratory Distress Syndrome* Historic Perspective Thomas L. Petty, M.D., F.C.C.P.

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dramatic clinical catastrophe results from acute lung injury from a variety of precipitating causes . The clinical syndrome that results has been termed the acute respiratory distress syndrome (ARDS). The purpose of this brief review is to present a historic perspective on the description and characterization of ARDS, with emphasis, in chronologie order, on the contributions of the Denver group. Before reciting the recent exciting history of ARDS, it is important to recognize that sudden pulmonary collapse was known to military physicians following battlefield casualties during World War 1. 1 The description of the pathologic picture accompanying major trauma was previously described. 2·3 But the clinical state and pathophysiological features of ARDS and its treatment were first described by the Denver group in 1967.4 In the mid1960s, our small group of clinicians, consisting of a pulmonologist, a surgeon, two pulmonary fellows, and supporting staff including a blood gas technician and a respiratory nurse specialist, recognized a unique form of acute respiratory failure which was different from that associated with asthma, COPD, and neuromuscular disorders, and most postoperative states where mechanical ventilation was required. At the bedside, we observed the sudden emergence of tachypnea, obvious respiratory distress with use of accessory muscles of respiration, the presence of diffuse bilateral and usually symmetrical pulmonary infiltrates on chest x-ray films, and refractory hypoxemia in a series of 12 consecutive patients that we encountered in our newly developed respiratory care service and units beginning in 1964. We also found that reduced thoracic compliance was present in these patients who all required mechanical ventilatory assistance for this disorder. We learned that refractory hypoxemia could be improved with the use of positive end-expiratory pressure (PEEP). Five of these patients recovered. Lungs from the seven patients who died demonstrated remarkably consistent pathologic findings with hyaline membrane formation and inflammatory cellular debris. A surfactant abnormality was identified in two patients. These first 12 patients with ARDS were identified from a series of 272 consecutive patients who had received mechanical ventilatory support for all causes in the medical and surgical intensive care units of our university hospital in that era.• Our first report on acute respiratory distress in adults 4 was read by surgeons involved in the Vietnam War. The similarity between our description of ARDS in the civilian population appeared virtually identical to that which was occurring in the Southeast Asian conflict. This caused *From the Presbyterian-St. Luke's Center for Health Sci7~ces Education, and the University of Colorado School of Med1cme,

Denver. Reprint requests: Dr. Petty, 1719 East 19th Avenue, Denver

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military leaders to quickly convene a conference which was organized by the American Association for the Surgery of Trauma. The conference was sponsored by the National Academy of Sciences-National Research Council. This meeting was held in Washington in April 1968 and resulted in the publication of the proceedings in September of that year.s Here, on behalf of our group, I presented the central theme of ARDS with congested and collapsed alveolar units, a surfactant abnormality, the exudation of proteinase material, and destructive enzymes in the lungs of the patients who had died.6 I restated the pathophysiologic features of ARDS and the blood gas response to PEEP at this conference (although we had not yet coined the term at that time).' Later, we expanded on the clinical features, the factors influencing prognosis, and the emerging principles of management of ARDS . We titled this second article the "Adult Respiratory Distress Syndrome."8 In retrospect, this was a mistake because in our original series, the youngest patient was 11 ; the oldest was 58 (mean age of 27.3 years) . The principles of management which we developed and tested were supportive care designed to maintain oxygenation via a volume-cycled ventilator, a tracheostomy, control of the inspired oxygen fraction, and the use of PEEP in the range of 5 to 12 em Hp to prevent alveolar collapse. Further strategies were designed to mitigate additional injury from high oxygen concentrations and fluid overload. Antibiotics were used primarily for specific infections. It was felt that corticosteroids would likely be beneficial, and we initially recommended their use in ARDS. 8 Today, our approach to management remains similar to those principles established in the late 1960s and early 1970s. A tracheostomy remains the ideal airway for the management of patients who require ventilatory support for more than 1 week. A tracheostomy is much more comfortable than an endotracheal tube, and it allows for better mouth care. It also allows the patient to eat and to talk if the occluding balloon is slightly deflated. Our original use of high tidal volume ventilation, however, is now being reconsidered, and it is likely that patients should be ventilated at lower tidal volumes than we previously believed.8 Subsequent to our original support, controlled clinical trials have failed to show that corticosteroids either prevent or are effective in established ARDS. 9 • 11 Whether or not corticosteroids will be valuable in the fiberproliferative and recovery phase of ARDS remains the subject of current study. 12 Two classic x-ray patterns are often major indicators of the emergence of ARDS . The pulmonary edema pattern has a normal cardiac silhouette, a normal vascular pedicle, and slow clearing. 13 A second roentgenographic picture has been termed "galloping pneumonia." 13 Although this 36th Annual Aspen Lung Conference

roentgenographic presentation of ARDS is not common, occasionally bacterial lobar pneumonia results in the subsequent development of diffuse bilateral symmetrical infiltrations, probably due to activation of humoral and cellular mechanisms that are involved in the pathogenesis of ARDS . Our early studies of whole excised human lungs from patients who died of ARDS indicated that the acute lung injury was partly focal in nature , thus allowing some possibility of maintaining adequate arterial oxygenation via remaining functional lung units with mechanical ventilation and PEEP. Later computed tomography scan studies by Gattinoni and Presenti 14 demonstrated the focal nature of lung injury in ARDS most convincingly. The uninjured or partially injured regions of the lung allow for survival, while the most injured zones must "regenerate" and thus re-establish the air-blood interface. Since the uninjured part of the lung represents a relatively small volume for ventilation, it is prudent to utilize mechanical ventilation strategies which can minimize damage to these regions. Thus, high tidal volumes, high inflation pressures, and high PEEP should be avoided if possible. Accordingly, newer concepts of mechanical ventilation strategies are presently emerging. These newer mechanical ventilation strategies include pressure limited ventilation and permissive compensated C0 2 retention.15 The epidemiology of ARDS focuses on risk factors which include bacteremia, cardiopulmonary bypass, hypertransfusion , major burns , intensive care unit pneumonias, aspiration, long bone or pelvic fractures , or diffuse intravascular coagulation. When these risk factors were present in 936 consecutive cases, 54 patients with ARDS resulted. 16 When 2 or more of these risk factors were present (in 57 patients), 14 additional patients with ARDS resulted. In 1 year in university hospitals, there were 88 patients from a series of 34,865 patients, including 20 patients where no identifiable risk factor was present. 16 More recently the concept of sepsis syndrome has emerged as a major clinical scenario with the highest risk of ARDS. 17 Since many patients with sepsis syndrome have no evidence of an infectious pathogen, the term systemic inflammatory responses syndrome (SIRS) has emerged to refer to a multiorgan response to an inflammatory insult. 18 Later studies by our group demonstrated both a qualitative and quantitative surfactant abnormality in patients who die of ARDS, along with reduced compliance of the whole, fresh, excised human lungs, compared with normal control subjects. l9.2o These observations have spawned "the surfactant hypotheses" in the pathogenesis of ARDS . The concept is presented in Figure l. This hypothesis suggests that following a variety of indirect or direct injuries to the lungs, alveoli become flooded by proteolytic and/or oxidative agents, which results in surfactant damage which in turn leads to alveolar instability and in turn an increase in hydrostatic forces favoring pulmonary edema. Thus, a vicious cycle is set in action . Numerous mediators of inflammation in ARDS have been identified. These include a long list of possibilities such as complement activation, the effect of lipopolysac-

charides from endotoxin, leukocytic aggregation and sequestration in the lung with the release of elastases and toxic oxygen species. platelet and endothelial factors , other mediators such as tumor necrosis factor, interleukin IL-l , IL-6, and IL-8, and interactions between these various factors. 21 Carrying the surfactant hypothesis further, it is interesting that all of these putative mechanisms can attack the surfactant system of the lung resulting in high surface tension pulmonary edema and damage and necrosis of the air-blood interface. Certainly the polymorphonuclear leukocyte plays an important role in the pathogenesis of ARDS in most, but not all, cases.22 Neutrophils are found in the bronchial alveolar lavage of patients in early stages of ARDS and before pulmonary edema is very severe. Which chemoattractive factors result in this neutrophilic alveoli tis remain unknown , but there are many suggestions including the mediators of acute lung injury listed above . It is important to emphasize the fact that ARDS is an inflammatory pulmonary edema. This sets it apart from other forms of permeability pulmonary edema, such as high altitude, postictal, and drug-associated pulmonary edema, where inflammation and damage and destruction at the air-blood interface is not present. The time from the original insult to full-blown ARDS ranged from 1 to 96 h in our original report} In the comprehensive study on epidemiology,16 slightly more than 80 percent of ARDS cases had developed within 48 h of the initial injury and 90 percent by 80 h following the original insult. 16 This latent phase offers a window of

HYPOTHESIS:

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..........J,.......... +

FLOODED Al VEOU /

(Proteolysis) \

HYDAOSTATIC FORCES FAYORIG~DEMA

SURFACT ANT DAMAGE

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Fi GUR E l. Hypothesis presents the notion that endothelial or epithelial damage can initiate a surfactant abnormality in ARDS, which in turn leads to unstable alveoli allowing flooding with proteolytic material which destroys or inactivates surfactant, resulting in hydrostatic forces which create increased elastic recoil and local edema formation promoting further inflammatory injury at the air-blood interface.

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opportunity for therapeutic interventions when effective blockers of the inflammatory process can be identified. Today, there is a massive search for circulating markers of acute lung injury which can be identified through bronchoalveolar lavage or in serum. 23 The survival in ARDS remains poor, approximately 40 percent in most large series. However, there is some suggestion that survival is improving in recent years. It is possible that surfactant replacement could prevent alveolar collapse and allow for mechanical ventilation at a lower inflation pressure than without surfactant. If this were the case and functional lung units could be recruited, adequate arterial blood gases might be achieved at lower inflation pressures and lower inspired oxygen concentrations, than without surfactant replacement. Very little has been written about the recovery phase of ARDS. For recovery to occur, the lung must respond to the injury by removing debris, repairing the basic membrane, and re-establishing the air-blood interface. Type II cells rapidly proliferate and become the stem cell for type I cells. Thus, type II cell proliferation is an essential step in the recovery process. 14 Whether or not corticosteroids can accelerate this process has been previously suggested and is the subject of the report by Dr. Meduri and colleagues included in this supplement. Treatment strategies in the recovery phase focus on the support of nutrition to be able to provide the "building blocks" for lung regeneration. It is best if nutrition can be given by the oral route in order to utilize the gastrointestinal tract and prevent gut atrophy. But when the gastrointestinal tract cannot be utilized, alimentation via intravenous feeding is a requirement. During recovery, the prevention and treatment of infections are everpresent challenges. Supportive mechanical ventilation strategies should employ the lowest possible inspired oxygen fraction and PEEP. Both high inspired oxygen fractions and PEEP can cause further lung injury during the recovery phase of ARDS. Psychosocial support is also critical to help keep patients focused on survival long enough to be able to recover, sometimes after weeks or months of mechanical ventilation.13 In summary, ARDS is both an endothelial and epithelial injury. The alveolar epithelium is critical in preventing edema and in the clearance of alveolar edema. The alveolar epithelium is key to the maintenance of the airblood interface. Supportive therapy is life-saving in approximately 40 to 50 percent of patients. Recovery in ARDS requires type II proliferation, differentiation, and remodeling of the lung. It is possible that surfactant can play a role in the early supportive phase of ARDS. The requirement for well-disciplined and controlled clinical trials in the management of ARDS has been emphasized,lll.J& as has the requirement for standardization of all facets of supportive care during the trial of any drug designed to prevent or treat the inflammatory factors that result in ARDS. Thus, the future of ARDS will focus upon better supporting care, controlled clinical trials, early identification and intervention with blockers of inflammatory mediators, and perhaps, surfactant replacement. Although the true numbers of patients with ARDS only

remain an estimate today, certainly large numbers of patients are encountered on a worldwide basis. ARDS has created an important biological concept and stimulated an immense amount of research into the mechanisms of acute lung injury and its repair. Many challenges remain for basic scientists who are studying the mechanisms in clinical models and in man. Simultaneously, clinical investigators must develop better methods of both preventive care and the best possible strategy for recovery. REFERENCES

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21 Fowler AA, Hyers TM, Fisher BJ, et al. The adult respiratory distress syndrome: cell populations and soluble mediators in the air spaces of patients at high risk. Am Rev Respir Dis 1987; 136:1225-31 22 Maunder RJ, Hackman RC, Riffe E, et al. Occurrence of the adult respiratory distress syndrome in neutropenic patients. Am Rev Respir Dis 1986; 133:313-16 23 Leff JA, Parsons PE, Day CE, et al. Serum antioxidants as predictors of adult respiratory distress syndrome in patients

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