AnesthesiaWeb - Lit Reviews- Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome

July 2000

Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.
ARDS Network. New Engl J Med 2000; 342:1301-1308
[see abstract below]

Culmination of an era in research on the acute respiratory distress syndrome.
Tobin MJ. New Engl J Med 2000; 342:1360-61
[see abstract below]

Medical progress: The acute respiratory distress syndrome.
Ware LB, Matthay NA. New Engl J Med 2000; 342:1334-49
[see abstract below]

Return to the Current Literature Review Front Page

Commentary by Douglas Coursin, M.D.

The Acute Respiratory Distress Syndrome (ARDS) continues to be a major cause of significant morbidity and mortality to our medical and surgical patients. These patients frequently require the care of anesthesiologists and intensivists and present a wide variety of clinical challenges. For a long time after the first description of ARDS in 1967, few interventions had significant positive impact on survival of this all too devastating process. These three articles include a positive original investigation by the ten center, 24 hospital ARDS network comparing two different ventilatory strategies in the treatment of patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). This is accompanied by a timely commentary on the state of ARDS research by Martin J. Tobin, MD, Professor and Chief of Pulmonary Critical Care Medicine at Loyola School of Medicine in Chicago. The final article is a state-of-the-art review by Drs. Ware and Mathay, two leading investigators from the University of California at San Francisco, on the current definition, pathophysiology, diagnosis, and treatment of ARDS.

Some simple issues in dealing with ALI/ARDS included establishment of a definition, determination of the incidence, and identification of patients at risk. In 1994, there was a combined meeting of leading pulmonary and critical care investigators from the United States and Europe. At that time, they presented a consensus definition of ARDS [1]. The group defined ARDS as:

acute onset;
bilateral infiltrates on chest radiography;
pulmonary artery wedge pressure = 18 mmHg or the absence of clinical evidence of left atrial hypertension;
acute lung injury considered to be present if PaO₂:FiO₂ = 300; acute respiratory distress syndrome considered to be present if PaO₂:FiO₂ = 200.

These criteria are felt to be simple, easy to use and recognize a reasonable spectrum of the clinical illness of ARDS. However, they do not identify the specific cause of ARDS nor do they consider the presence or absence of multiple organ dysfunction syndrome, known to significantly increase morbidity and mortality. Finally, the radiographic findings are nonspecific.

Historically, the incidence of ARDS was reported at ~150,000 patients per year in the United States. Later studies stated that it is far lower than this, more in the neighborhood of 15-25,000, but current opinion from the NEJM review of ARDS places the incidence in the neighborhood of 50 to 100,000 patients per year. Patients felt to be at particular risk include those with:

Direct lung injury		Indirect injury

Common etiologies

Pneumonia		Sepsis
Aspiration		Severe trauma

Less common etiologies

Pulmonary contusion		Cardiopulmonary bypass
Fat emboli syndrome		Drug overdose
Near-drowning		Acute pancreatitis
Reperfusion injury after lung transplantation or resection of PE		Multiple transfusions

Study rationale
The basis for the ARDS Network study was to determine if low volume ventilation with lower plateau pressures was associated with decreased morbidity and improved survival in ARDS patients. Previous experimental data revealed excessive airway distention, and opening and closing of airways could result in ventilator-induced lung injury from volutrauma with shearing of endothelium and biotrauma from an exaggerated inflammatory mediator production. Data from previous smaller uncontrolled human studies had reported both improvement in survival or no change in survival in patients ventilated with a low volume strategy.

The ARDS Network study was performed over three years, from 3/96 - 3/99, and included 861 patients. Patients had to meet the criteria for ARDS listed above and undergo randomization within 36 hours of onset of ARDS. The investigators used standard exclusion criteria, as well as the following:

morbid obesity (weight > 1 kg/cm height)
COPD
intracranial hypertension
pregnancy
sickle cell disease
neuromuscular disease that impaired normal respiration
burns > 30% of BSA
patient had undergone bone marrow or lung transplantation
chronic liver disease (Child-Pugh class C)
predicted mortality > 50% within the next 6 months

Patients were enrolled into one of two groups.

The control group received "traditional" tidal volume ventilation

~12 ml/kg of predicted body weight,
Plateau pressure < 50 cm H₂0
Respiratory rate adjusted to maintain a pH of 7.3 - 7.45
Oxygenation goal of Pa02 of 55 - 80 mm Hg
I:E ratio of 1:1 - 1:3
Applied PEEP determined by Fi02

The study group received "low" tidal volume ventilation

6ml/kg with
Plateau pressure < 30 cm H₂0
Same pH, Pa02, I:E ratio and PEEP criteria as the control patients

Both groups received volume-assist-control ventilation. Survival and ventilator-free days, defined as the number of days within the first 28 days on which a patient breathed without assistance, were the primary study endpoints. The number of days without organ system failure and incidence of barotrauma were secondary endpoints. Surrogate markers that were evaluated included the number of non-pulmonary organ systems that failed and the measurement of interleukin 6 (IL-6) as a marker of inflammations.

Study patients were well matched for demographic characteristics as well as presenting illnesses and severity of illness by APACHE III. As expected, the low volume ventilated patients had lower pH and required higher respiratory rates but their minute ventilation was the same. However, they required lower levels of applied PEEP and a lower Fi02. This group required fewer days of ventilation than the control group and less non-pulmonary organ failure. In addition, the IL-6 levels dropped to significantly lower levels by day 3 in the study group. The study was discontinued after the fourth interim analysis because of statistically significant improvement in survival in study patients who received the low volume ventilation protocol. This group had an overall survival of 69%, which was a 22% higher rate of survival than for the control patients (survival rate of 60.2%) who received conventional volume ventilation. These are impressive survival results since the historical mortality has frequently been in excess of 50%.

In addition to this sentinel study, the National Institutes of Health sponsored ARDS network has completed several other studies, has additional on-going studies, and has future studies planned. A recent ARDS network study in the April 19, 2000 issue of JAMA reported that ketoconazole was not effective in improving survival in ARDS. Full information on these trials can be downloaded at http//:www.ardsnet.org/.

Several of the trials now in progress deserve comment.

A Phase II/III, randomized, double-blind, placebo-controlled trial of lisofylline in patients with ALI and ARDS. This on-going study was part of the NEJM low volume study cited and discussed above. The last 20% of patients in that trial were randomized to receive either lisofylline, a known inhibitor of tumor necrosis factor alpha mRNA transcription, and placebo. This study was designed to test whether the early administration of lisofylline reduces mortality and morbidity after the onset of ALI or ARDS. Results are pending as the study continues.

Late Steroid Rescue Study Rescue Trial (LaSRST). The late phase of ARDS is often characterized by excessive fibroproliferation of connective tissue and pneumocytes. This results in abnormal gas exchange and decreased compliance. A study in the late 1980s by Bernard and others reported that high dose corticosteroids are not effective in early ARDS, but several case reports and uncontrolled case series in the later 1990s suggested that corticosteroids may be useful in the management of late-phase ARDS. The LSRST study tests this hypothesis with a randomized, double-blinded trial comparing methylprednisolone to placebo in severe, late-phase ARDS after seven days to determine if steroids reduce morbidity and mortality. As of mid-May, 2000, 75 patients had been enrolled.

A prospective, randomized, multi-center trial of higher end-expiratory lung volume/lower FiO₂ versus lower end-expiratory lung volume/higher FiO₂ ventilation in ALI and ARDS. The objective of the study is to determine if mortality from ALI/ARDS can be reduced using a mechanical ventilation strategy that is designed to prevent lung injury from repeated collapse of bronchioles and alveoli at end-expiration. The study calls for recruitment of up to 750 patients.

A prospective, randomized, multi-center trial of Pulmonary Artery Catheter (PAC) vs. Central Venous Catheter (CVC) utilization in the management of ALI/ARDS.

A prospective, randomized, multi-center trial of "Fluid Conservative" vs. "Fluid Liberal" management of ALI and ARDS. These trials will attempt to answer questions raised by the controversial study by Connors and others in JAMA 1996; 276:889-897. See the Pulmonary Artery Catheter clinical outcomes (PACCO) workshop consensus statement and Dr. Jesse Hall's editorial commentary in JAMA 2000; 283(19):2568-72 and 2577-78 for further background on the on-going PACCO educational and research program.

The PAC trials will attempt to determine if the "less invasive" CVP can be used in place of the PAC and whether different degrees of fluid therapy impact on survival. Upwards of 1,000 patients will be enrolled. Patients will be randomized to receive either a CVP or PAC for 3 - 7 days. They will be randomized and treated with a specific fluid management strategy for 7 days or until unassisted ventilation, whichever occurs first. Patients randomized to PAC will utilize this catheter for at least 3 days and up to 7 days (depending on protocol defined stability criteria) or until unassisted ventilation, whichever occurs first. If the PAC is discontinued according to protocol between day 3 and day 7, the fluid management strategy will continue and will be guided by the CVC. Patients randomized to CVC will utilize this catheter for 7 days or until unassisted ventilation, whichever occurs first. Ten additional centers are being recruited for the ARDS network to assist in patient enrollment into these studies.

The low tidal volume ventilation strategy study will probably become a landmark report. It will hopefully be the foundation for future multicenter, high quality studies that aid us in extending our knowledge of the natural history of lung injury, combating ALI/ARDS, improving outcome, and appropriately directing our potent therapeutic arsenal.