ResearchVentilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury : a preventive randomized controlled trial

Introduction: Recent cohort studies have identified the use of large tidal volumes as a major risk factor for development of lung injury in mechanically ventilated patients without acute lung injury (ALI). We compared the effect of conventional with lower tidal volumes on pulmonary inflammation and development of lung injury in critically ill patients without ALI at the onset of mechanical ventilation. Methods: We performed a randomized controlled nonblinded preventive trial comparing mechanical ventilation with tidal volumes of 10 ml versus 6 ml per kilogram of predicted body weight in critically ill patients without ALI at the onset of mechanical ventilation. The primary end point was cytokine levels in bronchoalveolar lavage fluid and plasma during mechanical ventilation. The secondary end point was the development of lung injury, as determined by consensus criteria for ALI, duration of mechanical ventilation, and mortality. Results: One hundred fifty patients (74 conventional versus 76 lower tidal volume) were enrolled and analyzed. No differences were observed in lavage fluid cytokine levels at baseline between the randomization groups. Plasma interleukin-6 (IL-6) levels decreased significantly more strongly in the lower-tidal-volume group ((from 51 (20 to 182) ng/ml to 11 (5 to 20) ng/ml versus 50 (21 to 122) ng/ml to 21 (20 to 77) ng/ml; P = 0.01)). The trial was stopped prematurely for safety reasons because the development of lung injury was higher in the conventional tidal-volume group as compared with the lower tidal-volume group (13.5% versus 2.6%; P = 0.01). Univariate analysis showed statistical relations between baseline lung-injury score, randomization group, level of positive end-expiratory pressure (PEEP), the number of transfused blood products, the presence of a risk factor for ALI, and baseline IL-6 lavage fluid levels and the development of lung injury. Multivariate analysis revealed the randomization group and the level of PEEP as independent predictors of the development of lung injury. Conclusions: Mechanical ventilation with conventional tidal volumes is associated with sustained cytokine production, as measured in plasma. Our data suggest that mechanical ventilation with conventional tidal volumes contributes to the development of lung injury in patients without ALI at the onset of mechanical ventilation. Trial registration: ISRCTN82533884 Introduction Mechanical ventilation is a life-saving strategy in patients with acute respiratory failure. Nevertheless, unequivocal evidence from both experimental and clinical studies indicates that mechanical ventilation has the potential to aggravate lung injury [1-3]. Data from three randomized controlled clinical trials confirmed the existence of venti* Correspondence: m.j.schultz@amc.uva. nl 1 Department of Intensive Care Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands See related commentary by Villar and Slutsky, http://ccforum.com/content/14/1/120 © 2010 Determann et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Determann et al. Critical Care 2010, 14:R1 http://ccforum.com/content/14/1/R1 Page 2 of 14 lator-associated lung injury in patients with acute lung injury (ALI) or its more-severe form, acute respiratory distress syndrome (ARDS), by showing reduced morbidity and mortality in the lower tidal-volume arm [3-6]. As a result of these studies, current guidelines now clearly support the use of lower tidal volume in patients with ALI/ARDS [7]. In contrast, little evidence supports the use of lower tidal volume in critically ill patients without ALI/ARDS, partly because of a lack of randomized controlled trial evidence on the best ventilator strategies in these patients [8]. Pneumonia, aspiration, sepsis, trauma, shock, and multiple blood transfusions are well-described risk factors for ALI/ARDS [9]. Animal studies demonstrate that mechanical ventilation with conventional tidal volume not only may aggravate, but also may initiate lung injury [1,2]. The role of tidal-volume size as a contributor to the development of lung injury in humans is, however, less clear. One study on reduced tidal volume and pressure settings did not show a reduction in mortality but suggested more side effects of lower tidal-volume ventilation in patients at high risk for ALI/ARDS [10]. Conversely, pulmonary procoagulant changes and increased systemic cytokine production were observed in patients without preexisting lung injury receiving conventional-tidal-volume mechanical ventilation during surgery [11,12]. Other studies have challenged these findings [13,14]. Results from cohort studies suggest that mechanical ventilation with conventional tidal volumes may cause or contribute to development of lung injury in critically ill patients who did not have ALI/ARDS at the onset of mechanical ventilation [15,16]. The inconclusive results from the studies in surgical patients may arise from the fact that these patients were ventilated for only a short period, whereas the patients of the larger cohort studies were critically ill patients who had been ventilated for a longer period. As ALI/ARDS is characterized by a profound production of inflammatory mediators, it might be expected that if conventional tidal volumes contribute to development of lung injury, the injury also may be associated with increased production of cytokines. We therefore conducted a trial to determine whether mechanical ventilation with conventional or lower tidal volume would be associated with different cytokine patterns in the lungs and the plasma of critically ill patients without ALI at onset of mechanical ventilation. Secondary end points were development of lung injury, duration of mechanical ventilation, and mortality. Materials and methods Participants From January 2005 until December 2007 patients were recruited in the intensive care departments of one academic and one regional teaching hospital in the Netherlands. The academic ICU is a 28-bed "closed format" department where medical/surgical patients (including neurosurgery/neurology, cardiothoracic surgery, and cardiology patients) were under the direct care of the ICU team. The ICU team comprised 10 full-time ICU physicians, eight subspecialty fellows, 12 residents, and occasionally one intern. The regional teaching ICU is an eightbed "open format" department with medical/surgical patients (not including neurosurgery and cardiothoracic surgery patients). The ICU team comprised three fulltime ICU physicians, five physicians who participate in evening and night shifts, and one resident. The two ICUs had similar standards of practice in terms of mechanicalventilation and sedation protocols. Patients were eligible for the study if they did not meet the consensus criteria for ALI/ARDS [17] and needed mechanical ventilation for an anticipated duration of more than 72 hours. Patients had to be randomized less than 36 hours after the onset of mechanical ventilation. Exclusion criteria were age younger than 18 years, participation in other clinical trials, pregnancy, increased uncontrollable intracranial pressure, chronic obstructive pulmonary disease (defined as a forced expiratory volume in 1 second to a forced vital capacity ratio less than 0.64 and daily medication), restrictive pulmonary disease (evidence of chronic interstitial infiltration on chest radiograph), use of immunosuppressive agents (100 mg hydrocortisone per day was allowed), pulmonary thromboembolism, previous pneumectomy or lobectomy, and previous randomization in this study. Randomization was performed by using sealed opaque envelopes in blocks of 50 patients. Each study center had its own randomization block. The protocol was approved by the medical ethics committees of both hospitals, and written informed consent was obtained from the patient or closest relatives before entry in the study. All procedures were done in compliance with the Helsinki declaration. Interventions The volume-controlled mode was used for mechanical ventilation. To calculate tidal volume, predicted body weight was used, as described [3]. The target tidal volume in the conventional group was 10 ml/kg of predicted body weight, which was routine practice at the time of the conduct of the study. Patients from the intervention group were ventilated at tidal volumes of 6 ml/kg of predicted body weight. In case patients were randomized to 6 ml/ kg, the attending physician was allowed to increase tidalDetermann et al. Critical Care 2010, 14:R1 http://ccforum.com/content/14/1/R1 Page 3 of 14 volume size to 7 to 8 ml/kg if patients had severe dyspnea, as identified by increased respiratory rate (more than 35 to 40 breaths per minute) accompanied by increasing levels of discomfort (with or without need for more sedation). Levels of PEEP were set, together with the level of inspired oxygen (FiO2) depending of the PaO2 according to a local protocol. The ventilator was routinely (3 times/day) switched to the pressure support mode. If the pressure support mode was tolerated, this mode was used for further mechanical ventilation. Toleration of pressure support mode was assessed at the discretion of the attending physician. The pressure support was adjusted to reach the target tidal volumes. In case the attending physician preferred pressure-support ventilation in a patient randomized to the lower-tidal-volume group, and the applied tidal volume exceeded the target tidal volume because of high levels of pressure support, then this was accepted. Such patients were kept in their original randomization group in the statistical analyses. As soon as patients were ready to be weaned from the ventilator, the pressure-support level