As we prepare for the potential of a novel H1N1 Influenza A pandemic this winter, we should consider that we may be challenged by an increased number of predominantly younger patients who present with severe lung injury.1-5 The adult respiratory distress syndrome was first described more than 40 years ago by Ashbaugh and colleagues.6 At that time, positive end-expiratory pressure (PEEP) was not a universal feature of mechanical ventilators and the mortality rates were extremely high, often approaching 90%.7,8 Today, we readily recognize the clinical presentation, classic radiographic appearance, and physiologic abnormalities of patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), and we are all familiar with the definition provided by the American-European Consensus Conference in 1994.9

The definition used to diagnosis ARDS has a dramatic effect on the reported incidence. Depending on the definition, which has changed over time, the incidence of ARDS has ranged from 1.5 per 100,000 in the Canary Islands Conference in 1985 to as high as 64.0 per 100,000 from the Seattle study reported by Rubenfeld et al in 2005.10-12 One of the difficulties with the current American-European Consensus Conference definition is the ambiguity of determining the presence of bilateral infiltrates on chest radiographs. When 21 experts reviewed and interpreted 28 chest x-rays, agreement was present only 43% of the time.13 This resulted in a range of ARDS diagnosis from 36% to 71%. Another controversy centers on the discrepancy between the clinical and the pathological manifestations of ARDS. Spanish investigators evaluated autopsy findings from patients who died with suspected ARDS compared to patients who died from other causes.14 The characteristic histologic finding of ARDS (diffuse alveolar damage) was not present in one third of the patients clinically suspected of having ARDS. More disturbing was the finding of diffuse alveolar damage in 11% of the patients who died, but were not diagnosed with ARDS.

This discussion will briefly review lung-protective ventilatory support for patients with ARDS and will also discuss some strategies to improve oxygenation. The interested reader is referred to a number of excellent reviews on the topic of ARDS for a more in-depth discussion of pathophysiology and management.10,15-22

Management Strategies

The management of patients with acute lung injury and ARDS has predominantly been one of support. The cornerstone of supportive management is the provision of mechanical ventilatory support, and recent data has demonstrated a significant survival benefit from the use of a lung-protective ventilatory support protocol.23 The primary goal of this support is to improve oxygenation and ensure that the lung is allowed to heal, while avoiding augmentation of the lung injury from “overstretching” or injuring alveoli and avoiding the recurrent opening and closing of distal airways. Ventilator induced lung injury (VILI) may involve volutrauma, barotrauma, biotrauma, mechanotrauma, and/or translocation.24,25

The NHLBI ARDS Network prospective, controlled, clinical trial of low versus high stretch management of patients with acute lung injury and ARDS (ARMA) compared low tidal volumes (6 ml/kg ideal body weight [IBW]) against conventional tidal volumes (12 ml/kg ideal body weight).23 The trial used a nomogram that governed the use of PEEP according to the FIO2 required to meet the oxygenation goal. There was also a weaning protocol once the patient was on a reduced amount of ventilatory support. This study was prematurely stopped after enrolling 861 patients when investigators observed a 22% reduction in mortality associated with the use of low tidal volume (39.5% versus 30.4%) on an interim analysis. The use of lung-protective ventilation significantly improved length of stay, ventilator days, and the development of multiple organ dysfunction syndrome. There was no difference in the development of barotrauma between the two strategies. Patients managed with high tidal volume had an earlier improvement in oxygenation, but this improvement did not translate into improved outcome. Additional support for this strategy was provided by Ranieri and colleagues who demonstrated increased serum and BAL proinflammatory cytokine levels in patients who were managed with large tidal volumes compared to lung-protective tidal volumes.26 Subsequent studies by the ARDS Network found that there was no survival benefit to the use of high levels of PEEP compared to the level of PEEP in the nomogram, no benefit to recruitment maneuvers, and outcome was similar when fluids were managed with the use of a pulmonary artery catheter versus a central venous catheter.27-29 Another study did demonstrate that use of a conservative fluid management strategy was associated with a shorter time on the ventilator and less organ dysfunction, even though there was not a survival benefit in comparison to a liberal fluid strategy.30 The use of liberal fluid resulted in approximately 7 liters of positive fluid balance after 1 week.30 A recent small pilot trial has demonstrated a potential survival benefit associated with using esophageal pressure measurements to guide PEEP dosing in patients with ALI and ARDS.31

Despite the survival benefit associated with lung-protective ventilatory support, there has not been universal adoption of this technique. Reasons for the slower than expected adoption of this strategy into daily practice are many and varied, and certainly go beyond lack of awareness. Young and coworkers reported that the tidal volume used to ventilate ARDS patients at three large New England university hospitals averaged 12.3 ml/kg predicted body weight (9.8 ml/kg measured body weight) prior to publication of the ARMA results and only dropped to 10.6 ml/kg predicted body weight (8.0 ml/kg measured body weight) after the publication and education of the house staff.32 This observation underscores the importance of actually measuring what is done in your institution and not assuming that things are done according to the latest evidence.

Improving Oxygenation Abnormalities

When using lung-protective ventilatory support strategies, it is not uncommon to have elevated PACO2 (often termed permissive hypercapnia or controlled hypoventilation), which may be associated with a decrease in oxygenation.33,34 To improve oxygenation in patients who have significant hypoxemia despite high levels of PEEP and FIO2, a number of strategies have been investigated.35 These strategies include recruitment maneuvers, prone positioning, sighs, surfactant replacement therapy, partial liquid ventilation, inhaled nitric oxide, enhanced edema clearance, corticosteroid treatment, and even extracorporeal membrane oxygenation (ECMO).28,36-68 In addition, innovative ventilatory support techniques, such as high-frequency oscillation and airway pressure release ventilation, are currently under evaluation to determine their benefit in ARDS patients.35 An in-depth discussion of these techniques is beyond the scope of this review, and it is important to remember that these techniques are currently investigational and need to undergo rigorous evaluation to determine their ability to improve outcome for patients with ALI and ARDS. As a reminder, the use of higher tidal volumes (12 ml/kg IBW) in the ARDS Network trial was associated with an improvement in oxygenation, but a significantly decreased survival.23

Recruitment Maneuvers

Recruitment maneuvers represent an attempt to open the atelectatic distal airways and alveoli on the border of the collapsed flooded alveoli using sustained increases in airway pressure.36,37 Some believe that this maneuver should precede the provision of PEEP and ventilator support in the early phase of acute lung injury.37 The maneuver is accomplished by increasing the PEEP to 35 to 60 cm H2O and holding that level of pressure for approximately 30 seconds. The ARDS Network randomly assigned 43 patients with ARDS to a recruitment maneuver with 35 to 40 cm H2O for 30 seconds versus a sham maneuver.28 The improvement in oxygenation related to recruitment was assessed by the ability to titrate PEEP/FIO2 based on the network algorithm and changes in lung compliance. There was no significant difference in the magnitude or duration of the oxygenation effect, compliance, or change in PEEP/FIO2 titration. The use of a recruitment maneuver was associated with a greater decrease in blood pressure during the maneuver. To date, there is no evidence that a recruitment maneuver results in an improvement in outcome for patients with ARDS and ALI.

Positioning in ARDS

The prone position has been shown to improve oxygenation in some patients with ARDS.38,42-44 This position is felt to be more physiologic for most mammals and results in improved secretion removal, ventilation perfusion matching, and better aeration of the dorsal lung units.43,44 The prone position may also prevent the heart from collapsing the left lower lobe and enhance the recruitment effects of PEEP by stabilizing the more flexible ventral chest wall. While a number of reports have demonstrated an improvement in oxygenation during and after the proning maneuver, the survival benefit remains controversial.39-41 Despite some reports of improved survival with proning, the mortality rate is higher than the mortality rate seen with lung-protective ventilatory support.23 A number of potential complications can result from the proning process such as tube/catheter malposition/problems, pressure sores, blindness, and difficulty with patient assessment and resuscitation.39 Based on current data, I do not recommend the routine use of proning despite the noted improvement in oxygenation and its theoretical value. I would reserve this technique for rescue treatment.

Inhaled Nitric Oxide

Inhaled nitric oxide (NO) is a bronchial and vascular smooth muscle dilator that also decreases platelet adherence and aggregation.58,59 Nitric oxide improves oxygenation by improving ventilation/perfusion relationships in the lung.58,59 Nitric oxide also reduces pulmonary artery pressure and pulmonary vascular resistance.62 There are minimal systemic effects from the inhaled NO since it is rapidly inactivated by the red blood cells in the pulmonary vessels. Two prospective, randomized, placebo-controlled clinical trials failed to demonstrate an improvement in survival despite the early improvement in oxygenation associated with the administration of inhaled NO.60,61 Inhaled NO is another rescue or salvage technique for those patients with significantly impaired oxygenation.

Surfactant Replacement Therapy

In the infant respiratory distress syndrome, there is a lack of effective surfactant related to immaturity of the type II epithelial cells. Surfactant abnormalities may be present in patients with ALI and ARDS related to decreased production, inactivation by alveolar proteins and proteolytic enzymes, and dilution by the alveolar fluid.54 To counter these abnormalities, surfactant replacement has been evaluated in patients with ARDS. Anzueto and colleagues reported no difference in hemodynamic function, oxygenation, length of stay, duration of mechanical ventilation, and survival in 725 sepsis-induced ARDS patients who were prospectively randomized into a placebo controlled trial of Exosurf (artificial surfactant) versus placebo.55 It was felt that the lack of associated surfactant proteins might account for the lack of efficacy. Subsequent trials using recombinant forms of surfactant replacement that include surfactant proteins have also had disappointing results and, while demonstrating improvement in oxygenation, have not been shown to improve survival.56

Enhanced Edema Clearance

Fluid in the alveolus may worsen gas exchange and pulmonary mechanics, and increase the work of breathing. Specific trials have been designed to evaluate the ability of various agents to improve edema clearance either using aquaporins or increasing the activity of the Na/K ATP pump in patients with ALI and ARDS. The BALTI (Beta-Agonist Lung Injury) trial evaluated the use of intravenous salbutamol in patients with ALI and demonstrated a significant decrease in extravascular lung water at day 7, lower end-inspiratory plateau pressures, and a trend toward a lower Murray Lung Injury Score.63 Salbutamol treatment was also associated with more supraventricular arrhythmias. Low oncotic pressures associated with hypoalbuminemia may also be a cause of increased lung edema. Martin and colleagues conducted a randomized controlled trial in 40 hypoproteinemic patients with ALI comparing albumin plus furosemide to furosemide alone to evaluate the effect on edema clearance.64 The albumin-treated patients had an improvement in oxygenation, total protein, and net fluid loss, and had an increased number of shock-free days and less hypotension. While this is a small pilot study, it suggests a potential benefit for hypoproteinemic ALI/ARDS patients. Further studies are currently under way to determine the benefit of edema clearance strategies in the management of acute lung injury patients.

New Techniques

In the 1970s, it was felt that the lungs just needed rest and they would adequately heal from ARDS. The use of extracorporeal membrane oxygenation was evaluated in a clinical trial versus conventional mechanical ventilation in an NIH-sponsored trial conducted in patients with severe lung injury.7 Both strategies were associated with mortality rates exceeding 90%. The use of ECMO did not get abandoned, however, and was used in neonates and pediatric patients with lung injury with reasonable success.67 A recent report from the United Kingdom has renewed interest in ECMO for selected patients with ARDS. The CESAR (Conventional Ventilation or ECMO for Severe Adult Respiratory Failure) trial compared ECMO performed at a single referral center in England to conventional ventilatory support in 180 patients.68 All patients were supposed to be managed with lung-protective ventilatory support strategies, but they were more often employed in the ECMO allocated group. The patients allocated in the consideration of ECMO group had a greater 6-month survival without disability (63%) versus the conventional support group (47%). The authors recommend considering the use of ECMO for adult patients with potentially reversible ARDS who have a Murray Lung Injury Score greater than 3 or a pH <7.20 on conventional ventilatory support therapy.

Prognosis in Acute Lung Injury

Using lung-protective ventilation strategies and avoiding complications of critical illness have resulted in a significant reduction in mortality rate from ARDS.69-73 Current trials report mortality rates in the range of 30% to 60% in comparison to the 60% to 90% mortality rates of older studies. The 30-day mortality rate in the NIH-sponsored ECMO trial of the 1970s was 91% with both conventional and ECMO treatment.7 Older reports from large tertiary referral centers documented mortality rates of 90% for patients with gram-negative septic shock and ARDS.8 A large multicenter trial of inhaled surfactant in septic-induced ARDS reported in the mid 1990s observed survival rates of 60% at 28 days in both the treatment and the control groups.55 The ARDS Network ARMA trial of lung-protective ventilatory support was associated with a mortality rate of approximately 30%.23 The observed mortality rate from ALI/ARDS depends on the cause of the injury, the patient’s underlying disease status and age, and institutional factors. The most common cause of death in patients with ARDS continues to be from multiple organ failure and recurrent sepsis.10,11 Less than 20% of patients die because of the inability to adequately oxygenate or ventilate the patient.10

After recovery from acute lung injury, the prognosis appears to be reasonably good. The majority of survivors return to near baseline pulmonary function status within 3 to 6 months.74-76 The major residual abnormality in pulmonary function is a restrictive pulmonary defect and a reduction in the carbon monoxide diffusion capacity.74 These alterations may result in exercise desaturation in some patients. A recent report used health-related quality of life questionnaires to evaluate the outcome of survivors of ARDS against a severity of illness matched group of septic and traumatic patients who did not have ARDS and survived their critical illness.77 The ARDS survivors had a clinically significant reduction in their physical function and increased pulmonary complaints in comparison to matched survivors of critical illness. A review of ALI/ARDS survivors has demonstrated an overall decrease in quality of life, and increase in respiratory and health issue complaints, and increased anxiety, insomnia, and depression. Posttraumatic stress disorder is also seen in about a quarter of the survivors of ALI/ARDS.77 Survivors of ARDS have reduced overall function as manifested by a decrease in 6 minute walk distance as compared to survivors of non-ARDS critical illness.78 As we learn more about the long-term clinical, physiological, and psychological impact of the injury on survivors of ALI and ARDS, we have realized that there are significant effects on these individuals and their ability to return to their past quality and type of life.

Summary

As our understanding of the injury process and the molecular aspects of the mechanisms that govern a patient’s response to injury, repair, and cell death becomes clear, this information will likely help determine optimum future management strategies for patients with ALI and ARDS. Currently, we know that certain genetic polymorphisms govern TNF production, surfactant proteins A and B, and the type of superoxide dismutase that is produced; and all of these can have an impact on a patient’s likelihood of developing ALI and ARDS.10 Future research will undoubtedly identify patients at increased risk of developing ALI and ARDS based on their genetic profile. Similar information may direct the provision of optimum management based on a patient’s genetic makeup or the biologic response. There may also be the opportunity to change outcome by inserting selected genes or modifying the transcription or function of various regulatory proteins.

Despite some controversy concerning the diagnostic criteria we use to define ALI/ARDS, the current clinical definition appears to serve our purpose to identify patients who benefit from lung-protective ventilatory support strategies. Clearly, the future will no doubt bring us a specific biomarker of lung epithelial cell or pulmonary vascular endothelial cell injury that more specifically defines the ALI/ARDS injury process. For now, the current definition appears to be adequate despite the apparent disconnect with pathology. The National Institutes of Health-supported ARDS Network has given us important clinical management knowledge to help ensure the best possible outcomes for our ALI/ARDS patients. The data clearly show that these patients should be managed with a lung-protective ventilatory support protocol and the use of PEEP dosing by nomogram. Careful attention to the prevention of the complications of critical illness and prevention of multiple organ dysfunction syndrome are also important goals to help us achieve good outcomes. The use of corticosteroids for the fibroproliferative phase of injury remains controversial, with conflicting data at the present time. The clinician must carefully consider the individual patient and clinical circumstances to determine if this therapy is warranted in the particular patient. We must always keep in mind that survivors of ALI/ARDS often have persistent health, respiratory, and neurocognitive abnormalities. Some exciting future data may be forthcoming concerning improved ways to utilize PEEP, perhaps guided by esophageal pressure monitors. The future may also include rescue measures to improve oxygenation issues when standard measures fail. Some of these rescue therapies may include ECMO, steroids, high-frequency oscillation, or some currently undiscovered form of specific treatment for lung injury. Future work will likely identify high-risk genotypes that may be more susceptible to the development of ALI/ARDS and possibly more responsive to an effective preventive and/or reparative strategy. Repair of the acutely injured lung, whether from the initial event, the ventilator, or complicating infection, is an important target and may be more achievable than attempting to prevent the initial injury or intervening early enough to prevent the development of ARDS.

Robert A. Balk, MD, is J. Baily Carter, MD, Professor of Medicine, Rush Medical College and Rush University Medical Center, Chicago. For further information, contact [email protected].

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