Edward Abraham, MD
Professor and Chairman
Department of Medicine
The University of Alabama at Birmingham
Birmingham, Alabama

In accordance with the Accreditation Council for Continuing Medical Education Standards for Commercial Support, Dr. Abraham does not have any conflicts of interest to disclose.

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Recent studies of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) - the more severe subset of injury - estimate that almost 200,000 Americans a year suffer from these devastating and frequently fatal inflammatory lung conditions. Despite advances in patient management, mortality remains at approximately 30%.

ALI and ARDS are medical emergencies and patients require substantial health care resources for intensive care and advanced life support. "Individual and economic costs are high," says UAB Department of Medicine Chair Edward Abraham, MD, an internationally known pulmonary and critical care medicine investigator who recently joined UAB from University of Colorado at Denver Health Sciences Center. "Patients often spend 10 to 12 days or longer on a ventilator in an intensive care unit (ICU), which can cost as much as $10,000 a day. This translates into billions of dollars a year in direct health care expenditures."

ALI/ARDS survivors also face a significant risk of prolonged functional limitations, he says. “Some patients experience pulmonary dysfunction, but many more have overall reduced quality of life, including muscle weakness, sleep disorders, and cognitive problems. It may take years for these individuals to recover fully, and some never regain complete function.”

ALI is characterized by bilateral infiltrates on a chest radiograph and hypoxemia without evidence of volume overload or left ventricular dysfunction. Inflammation damages alveolocapillary membranes, and the resulting interstitial and alveolar fluid buildup inhibits oxygen exchange and makes lungs edematous and stiff, limiting their ability to expand.

Consensus guidelines define ALI as acute onset of bilateral infiltrates on chest radiography and a ratio of partial pressure of arterial oxygen (PaO2) to fraction of inspired oxygen (FIO2) <300; for ARDS, the PaO2/FIO2 ratio is <200 (Am J Respir Crit Care Med. 1994;149:818-824). Many processes can lead to ALI/ARDS, but the most common cause is severe infection; most frequently, pneumonias, Abraham says. “Severe traumatic injury — especially multiple fractures — and blood transfusions, also are significant causes, as are sepsis and systematic inflammatory response syndrome. Burns, acute pancreatitis, inhalation injuries, aspiration (including near-drowning) and drug overdose also can lead to acute lung injury.”

Diagnosis and Treatment

Individuals who develop acute lung injury typically initially present in emergency departments with infection or trauma and then progress to severe respiratory distress. Some patients are already hospitalized and develop pneumonia or other infections leading to ALI/ARDS. Symptoms usually appear within 12 to 48 hours of the original insult.

Patients may have tachypnea, low blood pressure, and cyanosis. Rales heard on auscultation are common but may not predict severity of radiographic findings. Clinical findings of volume overload are absent, ruling out congestive heart failure. An echocardiogram can exclude cardiac causes, although clinical examination usually suffices, Abraham says.

There are no specific therapies for ALI/ARDS. Care is primarily supportive and aimed at improving oxygenation, avoiding barotrauma, and reducing excessive inflammation and edema, while preventing complications, which can include pneumothorax, ventilator-associated pneumonia, and peptic ulcers.

“Most patients require ventilatory support and supplemental oxygen,” he says. “PaO2 should be maintained at 60 mm Hg or higher. Low tidal volumes — 6 mL/kg based on ideal body weight — improve mortality. Plateau airway pressure should not exceed 30 cm H2O. If airway pressure rises above 30 cm H2O, tidal volumes should be decreased to less than 6 mL/kg.”

ALI/ARDS patients require a broad management approach that goes beyond ventilatory support. “Physicians should identify and control underlying causes, protect patients against peptic ulcers, and provide nutritional support. Recent studies do not support use of corticosteroids, showing no benefit for patients and a possible increase in complications,” Abraham says.

In the absence of evidence-based protocols, critical care experts have disagreed about the best supportive strategies for ALI/ARDS. The National Heart, Lung, and Blood Institute formed the ARDS Clinical Research Network in 1994 to address this deficiency and bring effective therapies to the bedside. The network, with its 18 clinical sites at 42 hospitals across the nation, provides a sufficient population for meaningful study and is generating crucial patient-management information.

The network’s 2 most recent studies offer important answers to long-debated issues of optimal catheter selection (pulmonary artery catheter [PAC] versus central venous catheter [CVC]) and fluid management (liberal versus conservative).

Abraham notes the standard of care had leaned toward using PACs, which also drove aggressive fluid management. “These approaches increase delivery of oxygen to tissues and cardiac output, which helps keep organs perfused, particularly the kidneys,” he says. “Although extra fluid makes the lungs more edematous, this was balanced by the belief that preserving organ perfusion offered an overall benefit.”

Before joining UAB, Abraham served as principal investigator for University of Colorado’s site of the Fluid and Catheter Treatment Trial. Two simultaneous studies at 20 clinical sites randomized 1000 patients to conservative or liberal fluid management with either a PAC or a CVC.

The studies show conservative fluid management and the less-invasive CVC produce equivalent survival rates compared with the other approaches, while reducing patients’ time on mechanical ventilation and in the ICU. “There are clear clinical and economic benefits from patients spending less time on ventilators, as well as associated psychological bene-fits from decreasing time on life support measures,” Abraham says.

In the fluid management study, the target for conservative fluid replacement was central venous pressure <4 mm Hg compared with 10 to 14 mm Hg for liberal replacement. Patients receiving less fluid had improved lung function and no increase in organ failure risk compared with those given liberal fluids. After 60 days, investigators saw no differences in numbers of deaths among patients receiving conservative fluid management versus those receiving more fluid (N Engl J Med. 2006;354:2564-2575).

The interrelated catheter study also challenged conventional thinking by showing that while PACs provide hemodynamic data not available with CVCs, the extra information does not outweigh risks posed by the more-invasive device. Compared with CVCs, PACs did not improve survival or organ function. After 28 days, participants in PAC and CVC groups had similar ICU- and ventilator-free days, but those with PACs had twice as many catheter-related complications (N Engl J Med. 2006;354:2213-2224).

Previous ARDS network clinical trials also altered standards of care for patients with severe lung injuries. Investigators called an early halt to the network’s first trial, a ventilator management study, when data showed 25% fewer deaths among patients receiving small rather than large tidal volumes of air from mechanical ventilators (N Engl J Med. 2000;342:1301-1308). A more recent study found corticosteroids do not improve survival in persistent ARDS and may increase the risk of death when given more than 2 weeks after ARDS onset (N Engl J Med. 2006;354[16]:1671-84). Network research is now evaluating nutritional and additional pharmacologic strategies for ALI/ARDS patients.

Identifying factors that increase risk for ALI/ARDS is the most promising path to improved patient survival, says Abraham, who recently found a genetic abnormality that leads to poor outcomes. About 25% of the population has a genetic alteration in the interleukin-1 receptor-associated kinase. The abnormality provokes increased transcription of inflammatory genes and production of their proteins, driving an inflammatory cascade that damages lungs and other organs, a recent paper by Abraham and colleagues reports (Am J Respir Crit Care Med. 2006;173:1335-1341).

“Patients with an overly exuberant inflammatory response stay on the ventilator longer, have a higher incidence of shock and hypotension, and decreased survival,” he says. “Other genetic abnormalities interface with the inflammatory cascade and increase release of inflammatory mediators. Finding genetic factors and cellular abnormalities that confer risk for poorer outcomes in acute lung injury may allow us to identify vulnerable patients early and prevent them from developing these conditions.”

For more information:

Dr. Edward Abraham
1-800-UAB-MIST
mist@uabmc.edu

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