Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome (ARDSNET)
Summary by Joseph Kirollos, MD and Lama Almadhyani, MD 2.29.24
https://www.nejm.org/doi/full/10.1056/nejm200005043421801
Clinical Hypothesis: In patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) who are mechanically ventilated, use of low tidal volumes (6 ml per kg with plateau pressure of 30 cm water or less) compared to larger tidal volumes (12 ml per kg with plateau pressure of 50 cm water or less) would result in reduced mortality before discharge (or 180-day mortality), increased incidence of breathing without assistance by day 28, and increased ventilator-free days (during days 1-28).
Take Home Message:
In patients with ALI/ARDS, mechanical ventilation with low tidal volumes resulted in significantly decreased mortality before discharge and increased days without ventilator use compared to larger traditional tidal volumes.
The use of low tidal volumes also resulted in significantly decreased plasma interleukin-6 (an inflammatory marker) and significantly more days without non-pulmonary organ or system failure, circulatory failure, coagulation failure, and renal failure in ALI/ARDS patients compared to larger traditional tidal volumes.
Summary:
Background: At the time of the study, the mortality rates of ALI and ARDS patients were approximately 40-50%. The traditional approach to mechanical ventilation at this time involved the use of large tidal volumes of 10-15 ml per kg. Animal studies have suggested that large tidal volumes could result in disruption of pulmonary epithelium/endothelium, lung inflammation, atelectasis, hypoxemia, and release of inflammatory mediators. These findings led to the hypothesis that the use of large tidal volumes in ALI/ARDS patients could result in increased lung injury/inflammation as well as injury to other organ systems which could influence mortality. Thus, this trial sought to elucidate whether lower tidal volumes in ALI/ARDS patients could prevent this theoretical lung injury and inflammation and thus reduce mortality and improve outcomes in these patients.
Study Design: Multicenter randomized controlled trial
Methods: Patients with clinical criteria for ALI/ARDS (see inclusion/exclusion criteria) were randomized by a centralized interactive voice system from 10 university centers to receive volume-assist-control mechanical ventilation with traditional tidal volumes (12 ml per kg with a plateau pressure of 50 cm water or less) or low tidal volumes (6 ml per kg with a plateau pressure of 30 cm water or less). Patients were started at tidal volumes of 12 ml or 6 ml (respectively) per kg predicted body weight and adjusted per a standardized protocol to maintain the plateau pressures between 45-50 cm water for the traditional group and 25-30 cm water for the low tidal volume group. Plateau pressures were measured at 4-hour intervals and after changes in tidal volumes. Physiologic, radiographic, and medication data were recorded on day 0 and days 1, 2, 3, 4, 7, 14, 21, and 28. Patients were followed until day 180 or until they were discharged and breathing on their own at home. Data were transmitted weekly to the network coordinating center and used to analyze differences in the primary and secondary outcomes (see below) between the two groups using multiple statistical analyses including student’s t-test, fisher’s exact test, analysis of covariance, Wilcoxon’s test, or chi-squared test depending on the variables being compared.
Inclusion criteria: Patients intubated and receiving mechanical ventilation, diagnosis of ALI/ARDS ≤36h before enrollment (acute decrease in PaO2/FiO2 ratio to ≤300, bilateral pulmonary infiltrates on CXR consistent with the presence of edema, PCWP of ≤18mmHg without evidence of left atrial HTN)
Exclusion criteria: Age less than 18 years, participation in other trials within 30 days, pregnancy, increased ICP, neuromuscular disease that could impair spontaneous breathing, sickle cell disease, or severe chronic respiratory disease, weight more than 1kg/cm of height, burns more than 30% of BSA, estimated 6-month mortality rate >50%, hx of bone marrow or lung transplant, Child-Pugh class C liver disease.
Primary outcomes: Mortality before discharge home or 180-day mortality, number of ventilator-free days during days 1-28, breathing without assistance by day 28.
Secondary outcomes: Number of days (during days 1-28) without each of the following individual outcomes: non-pulmonary organ or system failure, circulatory failure, coagulation failure, renal failure.
Incidence of barotrauma (defined as new pneumothorax, pneumomediastinum, subcutaneous emphysema, pneumatocele).
Mean log-transformed plasma interleukin-6 value on day 3 and decrease in mean log-transformed plasma interleukin-6 values from day 0 to day 3.
Results:
Lower tidal volumes resulted in a significantly lower mortality rate before discharge (31% vs 39.8%, P=.007), a significantly larger number of ventilator-free days (12 vs 10, P=.007), and a significantly higher percentage of patients breathing without assistance by day 28 (65.7% vs 55%, P=<.001) compared to the traditional tidal volume group.
Lower tidal volumes also resulted in significantly more days without non-pulmonary organ or system failure (15 vs 12, P=.006), circulatory failure (19 vs 17, P=.004), coagulation failure (21 vs 19, P=.004), and renal failure (20 vs 18, P=.005) compared to the traditional tidal volume group.
Lower tidal volumes did not result in a significantly lower incidence of barotrauma as defined by this study (10% vs 11%, P=.43) compared to the traditional tidal volume group.
Lower tidal volumes resulted in a significantly lower mean log-transformed plasma interleukin-6 value on day 3 compared to traditional tidal volumes (P=.002) as well as a significantly greater decrease in this value from day 0 to day 3 (P<.001).
Discussion/conclusion:
This study demonstrated that patients with ALI/ARDS treated with lower tidal volumes had reduced mortality before discharge and more ventilator-free days compared to those treated with traditional larger tidal volumes. However, the similarity in the number of days of ventilator use among the survivors in both groups suggests that the higher number of ventilator-free days in the group treated with lower tidal volumes likely resulted from reduced mortality rather than from a reduced number of days of ventilation among the survivors. Furthermore, patients treated with the lower tidal volumes had significantly lower plasma interleukin-6 (an inflammatory marker) as well as more days without non-pulmonary organ or system failure, circulatory failure, coagulation failure, renal failure compared to the traditional tidal volume group, potentially reflecting a reduced systemic inflammatory response to lung injury. Of note, a slightly higher PEEP was necessary in the lower tidal volume group during the first few days to maintain arterial oxygenation at a level similar to that in the traditional tidal volume group which could have further prevented lung injury by preventing the repeated opening and closing of small airways, potentially confounding the isolated benefit of low tidal volumes. Overall, this study supports the use of a low tidal volume approach to mechanical ventilation in ALI/ARDS patients to reduce mortality and improve several important clinical outcomes.