ARDSnet — Lower Tidal Volumes (NEJM 2000)

Background Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome. We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients. Methods Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter, randomized trial. The trial compared traditional ventilation treatment, which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.

5-second pause at the end of inspiration (plateau pressure) of 50 cm of water or less, with ventilation with a lower tidal volume, which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less. The first primary outcome was death before a patient was discharged home and was breathing without assistance. The second primary outcome was the number of days without ventilator use from day 1 to day 28. Results The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31. 0 percent vs. 39. 8 percent, P=0.

007), and the number of days without ventilator use during the first 28 days after randomization was greater in this group (mean [±SD], 12±11 vs. 10±11; P=0. 007). The mean tidal volumes on days 1 to 3 were 6. 2±0. 8 and 11. 8±0. 8 ml per kilogram of predicted body weight (P<0. 001), respectively, and the mean plateau pressures were 25±6 and 33±8 cm of water (P<0. 001), respectively. Conclusions In patients with acute lung injury and the acute respiratory distress syndrome, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use.

T HE mortality rate from acute lung injury and the acute respiratory distress syndrome1 is approximately 40 to 50 percent. 2-4 Although substantial progress has been made in elucidating the mechanisms of acute lung injury,5 there has been little progress in developing effective treatments. Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight. 6 These volumes are larger than those in normal subjects at rest (range, 7 to 8 ml per kilogram), but they are frequently necessary to achieve normal values for the partial pressure of arterial carbon dioxide and pH.

Since atelectasis and edema reduce aerated lung volumes in patients with acute lung injury and the acute respiratory distress syndrome,7,8 inspiratory airway pressures are often high, suggesting the presence of excessive distention, or “stretch,” of the aerated lung. In animals, ventilation with the use of large tidal volumes caused the disruption of pulmonary epithelium and endothelium, lung inflammation, atelectasis, hypoxemia, and the release of inflammatory mediators. 9-14 The release of inflammatory mediators could increase lung inflammation and cause injury to other organs.

10,15 Thus, the traditional approach to mechanical ventilation may exacerbate or perpetuate lung injury in patients with acute lung injury and the acute respiratory distress syndrome and increase the risk of nonpulmonary organ or system failure. The use of lower tidal volumes during ventilation in patients with acute lung injury and the acute respiratory distress syndrome may reduce injurious lung stretch and the release of inflammatory mediators. 16-18 However, this approach may cause respiratory acidosis16,17 and decrease arterial oxygenation19,20 and may therefore require changes in the priority of some objectives in the care of these patients.

With the traditional approach, the attainment of normal partial pressure of arterial carbon dioxide and pH is given a higher priority than is protection of the lung from excessive stretch. With an approach that involves lower tidal volumes, the reverse is true. Uncontrolled studies suggested that the use of a lower tidal volume would reduce mortality in patients with acute lung injury and the acute respiratory distress syndrome,17 but the results of four randomized trials of lungprotecting ventilation strategies have been conflicting. 21-24 The present trial was conducted to determine whether the use of a lower tidal volume with mechanical ventilation would improve important clinical outcomes in such patients.

Patients

Patients were recruited from March 1996 through March 1999 at the 10 university centers of the Acute Respiratory Distress Syndrome Network of the National Heart, Lung, and Blood Institute (the centers are listed in the Appendix). The protocol was approved by the institutional review board at each hospital, and informed consent was obtained from the patients or surrogates at all but one hospital, where this requirement was waived. A complete description of the methods is available on the World Wide Web (at www. ardsnet. org) or from the National Auxiliary Publications Service (NAPS).

* Patients who were intubated and receiving mechanical ventilation were eligible for the study if they had an acute decrease in the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen to 300 or less (indicating the onset of hypoxemia; values were adjusted for altitude in Denver and Salt Lake City), bilateral pulmonary infiltrates on a chest radiograph consistent with the presence of edema, and no clinical evidence of left atrial hypertension or (if measured) a pulmonary-capillary wedge pressure of 18 mm Hg or less.

1 Patients were excluded if 36 hours had elapsed since they met the first three criteria; they were younger than 18 years of age; they had participated in other trials within 30 days before the first three criteria were met; they were pregnant; they had increased intracranial pressure, neuromuscular disease that could impair spontaneous breathing, sickle cell disease, or severe chronic respiratory disease; they weighed more than 1 kg per centimeter of height; they had burns over more than 30 percent of their body-surface area; they had other conditions with an estimated 6-month mortality rate of more than 50 percent; they had undergone bone marrow or lung transplantation; they had chronic liver disease (as defined by Child–Pugh class C)25; or their attending physician refused or was unwilling to agree to the use of full life support.

A centralized interactive voice system was used for randomization. Patients were randomly assigned to receive mechanical ventilation involving either traditional tidal volumes or lower tidal volumes. *See NAPS document no. 05542 for 15 pages of supplementary material. To order, contact NAPS, c/o Microfiche Publications, 248 Hempstead Tpk. , West Hempstead, NY 11552. 1302 · Ventilator Procedures The volume-assist–control mode was used for the ventilator until the patient was weaned from the device or for 28 days after randomization on day 0. Because normal lung volumes are predicted on the basis of sex and height, 26,27 a predicted body weight was calculated for each patient from these data.

28 The predicted body weight of male patients was calculated as equal to 50+ 0. 91(centimeters of height¡152. 4); that of female patients was calculated as equal to 45. 5+0. 91(centimeters of height¡152. 4). In the group treated with traditional tidal volumes, the initial tidal volume was 12 ml per kilogram of predicted body weight. This was subsequently reduced stepwise by 1 ml per kilogram of predicted body weight if necessary to maintain the airway pressure measured after a 0. 5-second pause at the end of inspiration (plateau pressure) at a level of 50 cm of water or less. The minimal tidal volume was 4 ml per kilogram of predicted body weight.

If the plateau pressure dropped below 45 cm of water, the tidal volume was increased in steps of 1 ml per kilogram of predicted body weight until the plateau pressure was at least 45 cm of water or the tidal volume was 12 ml per kilogram of predicted body weight. In the group treated with lower tidal volumes, the tidal volume was reduced to 6 ml per kilogram of predicted body weight within four hours after randomization and was subsequently reduced stepwise by 1 ml per kilogram of predicted body weight if necessary to maintain plateau pressure at a level of no more than 30 cm of water. The minimal tidal volume was 4 ml per kilogram of predicted body weight.

If plateau pressure dropped below 25 cm of water, tidal volume was increased in steps of 1 ml per kilogram of predicted body weight until the plateau pressure was at least 25 cm of water or the tidal volume was 6 ml per kilogram of predicted body weight. For patients with severe dyspnea, the tidal volume could be increased to 7 to 8 ml per kilogram of predicted body weight if the plateau pressure remained 30 cm of water or less. Plateau pressures were measured with a half-second inspiratory pause at four-hour intervals and after changes in the tidal volume or positive end-expiratory pressure.

Plateau pressures of more than 50 cm of water in the patients in the group treated with traditional tidal volumes and of more than 30 cm of water in patients in the group treated with lower tidal volumes were allowed if the tidal volume was 4 ml per kilogram of predicted body weight or if arterial pH was less than 7. 15. All other objectives and ventilation procedures, including weaning, were identical in the two study groups (Table 1). If a patient became able to breathe without assistance but subsequently required additional mechanical ventilation within a period of 28 days, the same tidal-volume protocol was resumed. Organ or System Failure Patients were monitored daily for 28 days for signs of the failure of nonpulmonary organs and systems.

29 Circulatory failure was defined as a systolic blood pressure of 90 mm Hg or less or the need for treatment with any vasopressor; coagulation failure as a platelet count of 80,000 per cubic millimeter or less; hepatic failure as a serum bilirubin concentration of at least 2 mg per deciliter (34 µmol per liter); and renal failure as a serum creatinine concentration of at least 2 mg per deciliter (177 µmol per liter). We calculated the number of days without organ or system failure by subtracting the number of days with organ failure from the lesser of 28 days or the number of days to death. Organs and systems were considered failure-free after patients were discharged from the hospital.

Plasma Interleukin-6 Concentrations Blood samples were obtained from 204 of the first 234 patients on day 0 and on day 3 for measurement of plasma interleukin-6 by immunoassay (R & D Systems, Minneapolis).

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