ARDSnet – the mechanical ventilation trial

“Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome” – the Acute Respiratory Distress Syndrome Network, May 4, 2000, The New England Journal of Medicine

Introduction

Since its inception in the late 1920s with the Iron Lung, mechanical ventilation has been an invaluable therapeutic intervention available to physicians treating almost every kind of severe illness. Mechanical ventilation, usually achieved by placing an endotracheal tube directly into the trachea of the patient, establishes a direct sealed connection with the lungs down to the terminal alveoli, where gas exchange occurs. The lung is little more than air tracts with alveolar gas exchange units, so mechanical ventilation essentially gives the operator total physiologic control over the respiratory system. No other organ system in the body can be modulated this way, and the vital importance of the lungs in terms of providing oxygen and removing carbon dioxide make mechanical ventilation remarkable.

In Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS), lung collapse and excess inflammatory fluid in the lungs reduces the amount of lung that is aerated. As a result, traditional tidal volumes were kept large to retribute. The investigators of this trial were interested in studying whether these high tidal volumes caused further lung injury by stretching out the lungs, and whether lower tidal volumes with associated decreased ventilation would be provide a mortality benefit without an associated detriment due to reduced carbon dioxide removal and ventilation.

Results

The tidal volumes in the low tidal volume group were maintained around 6.2 mL/kg body weight, while the traditional group received 11.8 mL/kg. The associated peak airway pressures were 25 and 33 cmH20, respectively. One hundred eighty day mortality was improved in the low tidal volume group (31% vs 39%), and probability of discharge home without breathing assistance was increased. The number of ventilator-free days was higher in the low tidal volume group, as was the number of days without organ failure. Plasma IL-6 levels were found to be lower and drop faster in the low tidal volume group. The trial was stopped after interim analysis due to the finding that use of low tidal volumes was efficacious in terms of mortality and a stringent significance threshold had been reached.

Why We Do What We Do

ARDS and ALI carried about a 40-50% mortality rate at the time that these investigators initiated their study. Their hypothesis that high tidal volumes cause barotrauma was supported by the increased levels of IL-6, a marker of inflammation, in the high tidal volume group. However, as previous theory had predicted, lower tidal volumes also led to higher blood CO2 levels and lower pH in this trial. Low tidal volumes were also correlated with increased respiratory rate, increased fraction of oxygen percentage in inspired air (FiO2) and increased positive end-expiratory pressure (PEEP – a back pressure used at the end of a breath to keep airways from collapsing) during this study, most likely to maintain oxygenation given a lower ventilation volume. The most important result, however, is that mortality was decreased in patients receiving lower tidal volumes.

In most medical interventions, there is always a cost-benefit trade off. In this case, the cost was higher CO2 levels and acidemia in patients with ARDS or ALI with the benefit of reducing further inflammation due to increased pressures on the lung parenchyma. The trade off was beneficial in this case. Some may argue that the provisions of PEEP and increased FiO2 skewed the results by providing the low tidal volume group with added benefit. These adjustments are, however, commonly used (in both arms of the study) and carry a trade off as well, all of which was factored into the primary mortality outcome.

The ARDSnet trial, as this is known, is not only remarkable because of the drastic improvements in mortality in dismal diseases such as ARDS and ALI or the implications it has in ventilator management today, but also in how it used basic physiologic principles of volume-pressure relationships to hypothesize a result and then show evidence to support the hypothesis. This trial is a true example of translational medicine – using basic science principles to directly impact and improve patient care. The elegance of thought and execution are an example for every clinician-researcher to strive for.