Robert H Demling

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Professor of Surgery, Harvard Medical School, Brigham and Women s Hospital, Boston, Massachusetts


The acute respiratory distress syndrome, ARDS, remains a common, often lethal form of acute lung injury prevalent in both surgical and medical patients. The term ARDS was recently converted from adult to acute respiratory distress because children are also affected. The definition describes a severe acute lung injury characterized by progressive hypoxemia, increased pulmonary shunt fraction, decreased lung compliance, and diffuse bilateral lung infiltrates in the presence of a normal pulmonary artery wedge pressure. An increase in lung water is also seen due to increased lung capillary permeability. The degree of shunt, however, is not directly correlated with the degree of increased water content as would be the case with cardiogenic edema. The lung insult is very complex with a significant parenchymal, interstitial, and airway component to the disease process.

The common practice of referring to ARDS as one specific clinical entity probably results in more confusion than clarification. There are probably several distinct ARDS states, each with a different initiating cause but with a common pulmonary response.

In addition, a number of qualifying statements must be added when making the diagnosis. Since ARDS is an acute syndrome, chronic states such as idiopathic pulmonary fibrosis or lymphatic spread of lung cancer are not considered to be ARDS despite similar physiologic changes.

Incidence and Outcome

The incidence today appears to be comparable to that reported several decades ago, being 65 cases per 100,000 person years. The current incidence is actually three times greater than initially predicted. This fact is of interest because avoiding risk factors such as overresuscitation and high airway pressures during ventilation is now a standard of care, which should have decreased incidence. One explanation would be that there is an increase in risk factors for ARDS now present in the critically ill population. These include an increasingly older patient population and an increase in the severity of illness. Also of interest is the fact that the mortality rate of 40 to 60 percent, described with the initial characterization of the disease, has remained at this level until very recently. Several recent studies do report a decline in mortality to about 35 percent. Possible explanations for this recent decrease in mortality include the adoption of better supportive care of critically ill patients, especially those with early signs of acute lung injury. In addition, prevention and early treatment of sepsis should attenuate the disease process.

Patients surviving ARDS typically have some degree of lung dysfunction for a number of months, often attributed to the time required to resolve residual alveolar consolidation and fibrosis. The vast majority of survivors demonstrate improvement in the 10 to 14 days after the onset of illness. However, in severe cases significant chronic lung dysfunction can develop.

Mortality 30 years ago was due mainly to progressive respiratory failure. Today however, due in part to better lung support techniques, most patients who die with ARDS have developed multisystem organ failure and a resulting refractory hemodynamic instability that is the eventual cause of death. There is a smaller group of patients who die from progressive respiratory failure as a result of an obliterative alveolar fibrosis or from recurrent pneumonia.

There are two types of clinical disorders that can lead to acute lung injury and ARDS. These include either a direct

Table I Common Causes of ARDS.

Indirect lung injury


Severe nonpulmonary trauma Soft tissue damage Shock

Multiple transfusions Acute pancreatitis Fat emboli

Direct Lung Injury Pneumonia, usually bilateral

Lung contusions


Inhalation injury lung injury or more commonly an indirect lung injury caused by a systemic insult (Table I). The most common systemic insult is sepsis (Table I). Both types of insults lead to a generalized lung inflammation and a similar diffuse microvascular and alveolar injury.

Other systemic risk factors include a preexisting lung dysfunction or other organ dysfunction, especially involving the liver.


Acute Lung Injury

It is well established that the initial lung damage is the result of inflammatory mediators attacking the alveolar-capillary membrane. First endothelial cell damage occurs, leading to increased lung microvascular permeability and the leak of protein-rich fluid into the interstitium. A number of clinical studies have verified the increased protein content of edema and bronchoalveolar fluid, verifying animal studies that clearly indicate an increase in permeability. As the ARDS progresses, the alveolar epithelial cells are damaged. First the flat type I cells are damaged, leading to alveolar edema, by disrupting the normal epithelial fluid transport. This process is followed by damage to the more injury-resistant and complex type II cuboidal cells whose functions include ion transport, surfactant production, and differentiation of type I cells. Surfactant production is decreased, leading to an alveolar stability and microatelectasis. The normal local immune defenses are also severely impaired, and nosocomial pneumonia is a common complication of the later stages of ARDS.

Computed tomographic scanning has indicated that alveolar edema and atelectasis are seen mainly in dependent areas of the lung. However, selective bronchoalveolar lavage indicates that all areas of the lung are inflamed and contain protein-rich fluid.

Table II Inflammatory Mediators in ARDS.

Proinflammatory cytokines

Products of neutrophils and macrophages

Oxygen radicals and lipid peroxides

Neutrophil proteases


Activated coagulation cascade

Products of cyclo-oxygenase and lipoxygenase cascades

Causes of Injury

A number of inflammatory cells and inflammatory mediators have been described which appear to cause the lung damage in ARDS. The most common causes are described in Table II.

Neutrophil-Dependent Lung Injury

Neutrophil sequestration, first along the microvascular membrane, then in the alveoli, is characteristically seen in ARDS. Adhesion molecules on the neutrophil, known as neutrophil integrins, are known to be increased in ARDS, facilitating the binding of neutrophils to endothelium. The neutrophils are then activated by cytokines or other inflammatory agents, releasing proteases and toxic oxygen radicals that damage endothelial and epithelial cells.

Modulation of these adhesion molecules using antiadher-ence agents has been reported in animals to decrease the initial neutrophil sequestration and the degree of acute lung injury. However, long-term studies in humans have not been performed, because of the risk of impairing lung and systemic immune defenses by impeding the neutrophils' ability to control infection.

Some new evidence would suggest that the presence of neutrophils may be the result rather than the cause of the lung injury. In addition, ARDS has been reported in neutropenic patients. This latter finding may help explain why anti-inflammatory strategies aimed at suppressing neu-trophil activity have largely been unsuccessful.

Proinflammatory Cytokines

Proinflammatory cytokines, especially tumor necrosis factors (TNF) and interleukin-8 have been shown to be produced and released by the increased numbers of lung inflammatory cells, thereby amplifying the lung inflammatory response. This self-perpetuating inflammatory response then becomes autodestructive. However, selective inhibition of specific proinflammatory cytokines has not been shown to be beneficial in preventing or treating ARDS in humans. A number of new inhibitors of the proinflammatory cytokines are now available for study in ARDS. These include soluble tumor necrosis factor receptor and antibodies against tumor necrosis factor.

Oxidants and Antioxidants

Oxidant damage to the lung, measured by increased levels of lipid peroxides in lung tissue and bronchoalveolar lavage, has been well described. Also, endogenous antioxidant levels have been reported to be decreased with acute lung injury, altering the oxidant-antioxidant balance in favor of excess oxidant activity. Infusion of N-acetylcysteine, a precursor of the antioxidant glutathione, in patients with ARDS did transiently improve a number of hemodynamic parameters as well as lung compliance. However, there was no significant improvement in the severity of the ARDS in humans. To date, antioxidant therapy has not been shown to modify the course of ARDS.

Coagulation Activation

Activation of the coagulation cascade, with evidence of a consumptive or disseminated intravascular coagulation, is frequently evident in patients with ARDS. Microaggregates of fibrin platelets are well described in lung microvessels, suggesting a causal relationship with the lung dysfunction. in addition, specific fibrin degradation products have been reported to be toxic to the lung microcirculation. Also, thrombosis of pulmonary arterioles has been reported, all reflecting the role of coagulation and clotting in the patho-physiology. However, anticoagulant therapy has not been shown to be effective in attenuating ARDS.

Pathophysiology and Course

The course of ARDS can be divided into a number of phases as the disease progresses through early acute lung injury to end-stage ARDS or to resolution. It is important to point out that the early phases can resolve and do not necessarily progress to severe ARDS (Table III). The potential for resolution is often dependent on the severity and longevity of the initiating insult.

Early pathologic findings are described in Table III and shown in Figure 1. An acute inflammatory response is invariably present, with increased numbers of neutrophils marginated along the endothelium as well as migrating into the interstitium and alveoli. Fibrin-platelet aggregates are also frequently found in the microvessels. At this stage, the ARDS process is reversible but only if the initiating factor, such as a septic focus, is controlled.

If the process continues to progress over the next several days, established ARDS develops, characterized by evidence of acute respiratory failure necessitating mechanical ventilation and an increased fractional oxygen concentration to treat hypoxia.

A hypermetabolic, catabolic state is also characteristically seen with the onset of ARDS. The lung inflammation, as well as any systemic inflammatory or septic foci, produces a maladaptive endocrine environment known as the

Table III Pathophysiologic Changes in Acute Respiratory Distress Syndrome.

Radiographic change

Clinical finding

Physiologic change pathologic change

Phase I (Early Changes) Normal radiograph

Dyspnea, tachypnea, normal chest examination

Mild pulmonary hypertension, normoxemic or mild hypoxemia, hypocarbia

Neutrophil sequestration, no clear tissue damage

Phase 2 (Onset of Parenchymal Changes)

Patchy alveolar infiltrates beginning Dyspnea, tachypnea, in dependent lung No perivascular cuffs (unless a component of high-pressure edema is present) Normal heart size cyanosis, tachycardia, coarse rales

Pulmonary hypertension, normal wedge pressure, increased lung permeability, increased lung water, increasing shunt, progressive decrease in compliance, moderate-to-severe hypoxemia

Neutrophil infiltration, vascular congestion, fibrin strands, platelet clumps, alveolar septal edema, intra-alveolar protein, type i epithelial damage

Phase 3 (Acute Respiratory Failure with Progression, over 2—10 days)

Diffuse alveolar infiltrates Air bronchograms Decreased lung volume Normal heart

Tachypnea, tachycardia, hyperdynamic state, sepsis syndrome, signs of consolidation, diffuse rhonchi

Progression of symptoms, increasing shunt fraction, further decrease in compliance, increased minute ventilation, impaired oxygen extraction of hemoglobin

Alveolar consolidation from alveolar exudates and protein-rich fluid, type II cell damage, beginning fibroblast proliferation, thromboembolic occlusion

Phase 4 (Pulmonary Fibrosis—Pneumonia with Progression, > 10 days)

Persistent diffuse infiltrates Superimposed new pneumonic infiltrates Recurrent pneumothorax Normal heart size Enlargement with cor pulmonale

Symptoms as above, recurrent sepsis, evidence of multiple system organ failure

Recurrent pneumonia, progressive lung restriction, impaired tissue oxygenation, impaired oxygen extraction, multiple system organ failure

Type ii cell hyperplasia, interstitial thickening, infiltration of macrophages, fibroblasts, loculated pneumonia and/or interstitial fibrosis, medial thickening and remodeling of arterioles

Figure 1 ARDS: Acute phase. Intense lung congestion and inflammation is evident in the interstitial and intra-alveolar space. (see color insert)

Figure 2 ARDS: Late phase. Macrophage infiltration and increased collagen (pink) is evident. Macrophages release inflammatory cytokines that increase the inflammatory response. These cytokines can produce both lung and systemic organ injury. Increased fibroblasts are also present as precursors to later lung fibrosis. (see color insert)

Figure 2 ARDS: Late phase. Macrophage infiltration and increased collagen (pink) is evident. Macrophages release inflammatory cytokines that increase the inflammatory response. These cytokines can produce both lung and systemic organ injury. Increased fibroblasts are also present as precursors to later lung fibrosis. (see color insert)

"stress response." The increase in catabolic cytokines and hormones leads to a progressive decrease in body protein. The increase in circulatory catechols produces an increase in metabolic rate comparable to that seen with major trauma or sepsis.

Pathologically, the lungs are much more cell dense with an increasing interstitial population of mononuclear cells and fibroblasts (Figure 2). An alveolar inflammatory exu-dates persists, and type II cell damage with compensatory proliferation is evident. Thrombotic or thromboembolic occlusion of precapillary arteries and loss of capillary surface area is a common finding.

The cause of death during this late phase is usually from a progressive multisystem organ failure. The mechanism of this systemic process remains unclear but it is likely due to the release of cytokines and inflammatory mediators from the lung into the systemic circulation. The lung changes from the organ being injured to being the focus of systemic organ injury. Approximately 50 percent of patients with established ARDS develop multiple system organ failure.

Although the mortality rate at this stage is greater than 50 percent, complete resolution can occur over the subsequent weeks if further lung insults can be avoided.

If resolution or death does not occur, a fourth phase develops. This phase is characterized by progressive respiratory failure with pulmonary fibrosis and/or recurrent pneumonia. If progressive pulmonary fibrosis develops, there will be a significant increase in barotrauma-related complications. Increased collagen production in the interstitium and the alveoli actually begins in the earlier phases. Increased deposition of type III collagen is usually present by day 4 or 5. Also, destruction of the more elastic collagens, which are usually found in the basement membrane of the alveolar capillary junction, is well documented. The rate of collagen deposition is very rapid in ARDS as compared with other forms of pulmonary fibrosis.

The mortality rate of this phase is greater than 80 percent, again with death usually due to multiple system organ failure and systemic hemodynamic instability. The majority of patients with multiple system organ failure develop ARDS as the initial organ failure.


Improved strategies in supportive care have developed in response to a better understanding of the pathogenesis of the lung injury in ARDS (Table IV). It is now well accepted that support modalities, especially ventilator support and fluid management, can further increase damage if not performed properly. Although current pharmacologic strategies have in large part been unsuccessful, new approaches are being developed to help correct the underlying acute lung damage (Table IV).

Mechanical Ventilation

A large number of modes of mechanical ventilation have been used over the past several decades (Table IV). Until recently, a high tidal volume (12 to 15mL/kg) has been considered as standard for supportive treatment of ARDS, with a resultant increase in peak and mean airway pressures. More recently, lower tidal volumes (6 to 8mL/kg) have been used to decrease airway pressure. This approach has been found to significantly reduce ARDS mortality, with a decrease in mortality from 40 percent to 31 percent in one series. A higher respiratory rate is usually required along with some permissive hypercapnia.

Fluid Management and the Level of Oxygen Delivery

Because of the report several decades ago, that oxygen consumption VO2 was increased and was oxygen delivery dependent (DO2) in ARDS, an approach of increasing DO2 until VO2 peaked was attempted in order to avoid a hidden oxygen debt. This approach was an attempt to deliver supernormal levels of oxygen in order to prevent multisystem organ failure. Both blood volume and systemic perfusion

Table IV ARDS Treatment Modalities.

Ventilator support Pharmacotherapy

Type Outcome Type Outcome

High-level PEEP No benefit Glucocorticoids (early) No benefit

High-frequency jet vent No benefit Glucocorticoids (during fibrosis) Improved (small study)

Pressure control inverse Inconclusive Glucocorticoids (rescue doses) Inconclusive

I:E ratio

Low tidal volume Improvement Surfactant No benefit to date

Inhaled nitric oxide No benefit

Prone position ventilation Inconclusive Antioxidants No benefit

Cyclo-oxygenase inhibition No benefit have been increased by using inotropes. Recent data indicate that this approach is not advantageous and may actually be harmful. Currently the approach of fluid restriction, maintaining a low to normal filling pressure, is being tested. The degree of lung edema appears to be decreased. No increase in MSOF has been reported with this approach.

Anti-Inflammatory Support

Since the lung injury is in large part inflammation induced, attempts have been made at pharmacologic anti-inflammatory therapy. The use of glucocorticoids has been the most popular. Past studies have demonstrated no benefit with high-dose glucocorticoid treatment, the exception being in progressive lung fibrosis where some benefit has been shown. Short courses of corticosteroids may be of benefit as "rescue therapy" to control excessive inflammation and allow recovery. Current trials are pursuing this approach. Other anti-inflammatory agents that have been tested have also not been found to be effective (Table IV). These include the use of anti-endotoxin antibody, a number of proinflammatory cytokine inhibitors as well as anti-neutrophil adherence agents.

Surfactant Therapy

Abnormalities in the production and composition of alveolar surfactant are well recognized in ARDS and are likely due to damage to the type II alveolar cells as well as deacti-vation of surfactant by oxidants. This decrease likely contributes to the microatelectasis and decreased lung compliance.

Providing exogenous surfactant by aerosol has been shown to be beneficial in treating neonatal respiratory distress syndrome. However, studies to date have not shown any benefit in the adult population with ARDS. This failure may be due to the aerosol delivery system being used as less than 5 percent of the surfactant actually reaches the surfactant-depleted alveoli using this approach. Newer preparations using more efficient delivery systems are being tested.

Vasodilator Therapy

Since increased pulmonary artery pressures are characteristically present, especially with severe ARDS, the use of a variety of pulmonary vasodilators has been attempted. Unfortunately, recent trials with inhaled nitrous oxide, an approach that does not produce systemic vasodilation, have not demonstrated a decrease in mortality. Other vasodilator agents such as prostacyclin and prostaglandin-E have also not demonstrated long-term benefit.

Nutritional Support

A major advance in the management of ARDS is the recognition of the need for nutritional support and early implementation by the enteral route. Providing the increased calorie, protein, and micronutrient needs is essential to avoid an energy deficit and the excess erosion of lean body mass. This process will lead to the impairment of immune and lung function defenses, especially the strength of the respiratory muscles needed for coughing and for weaning from mechanical support.


The acute respiratory distress syndrome remains a common source of respiratory failure and mortality. Its incidence does not appear to be decreasing and its high mortality rate has only recently been reported to be improving. Its etiology appears to be due to the combination of a variety of inflammatory mediators activated either directly by a source of lung inflammation or indirectly through a systemic focus. Activation of the various inflammatory cascades occurs, with the lung being the target organ.

The current advances in treatment appear to be focused on avoiding further lung damage caused by therapy. Low-volume mechanical ventilation and adoption of an approach to avoiding an increase in blood volume appear to be beneficial. Early aggressive nutritional support is also of benefit. The formation of an NIH-supported Multicenter Acute

Respiratory Distress Syndrome Research Team has provided the impetus for the evaluation of current treatment modalities and the development of new therapeutic strategies. Attempts at pharmacologically modifying the degree of acute destructive inflammation have as yet not been successful. However, it can be stated that prevention of further septic episodes or lung infection will lead to a more rapid resolution of an acute lung injury or established ARDS.


Cytokines: Hormone-like low-molecular-weight proteins, secreted by many cell types, which regulate many aspects of the inflammatory immune and healing responses.

Oxidant: An unstable metabolite of oxygen that leads to oxidation of local compounds.

Syndrome: An aggregate of signs and symptoms associated with any morbid process and constituting the description of the disease.


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study group on ARDS. Current projects are discussed as well as a sneak preview of future directions in management.

Parodo, I., Kajikawa, O., and De Perrot, M. (2003). Injurious mechanical ventilation and end organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA 289, 2104-2112.

Puybasset, L., Grosman, P., Muller, J., Cluzel, P., Conat, P., and Rouby, J. (2000). Regional distribution of gas and tissue in acute respiratory distress syndrome. Consequences of the effects of positive end expiratory pressure. CT scan ARDS study group. Intensive Care Med. 26, 1215-1227.

Shanna, S., and Kimar, A. (2003). Septic shock, multiple organ failure and acute respiratory distress syndrome. Curr. Opin. Pulm. Med. 9, 199-209.

Sprint, M., Nemery, B., and Decramer, M. (2003). Survivors of the acute respiratory distress syndrome. N. Engl. J. Med. 348, 2149-2150.

Steinbrook, R. (2003). How best to ventilate? Trial design and patient safety in studies of the acute respiratory distress syndrome. N. Engl. J. Med. 348, 13293-13401. This review describes the variety of techniques used for mechanical ventilation in ARDS. Each approach is then analyzed as to its pros and cons.

Ware, L., and Matthay, M. (2000). The acute respiratory distress syndrome. N. Engl. J. Med. 342, 1334-1342. This review presents an up-to-date discussion of the current status of ARDS. Incidence, pathophysiology, and treatment modalities are described.

Capsule Biography

Dr. Demling is a Professor of Surgery at Harvard Medical School. The focus of his clinical and research activity has been critical care with emphasis on respiratory distress and the "stress response" to injury. He is the director of the Trauma, Burn, Critical Care Division of the Brigham and Women's Hospital.

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