Writing Group for the PReVENT Investigators IMPORTANCE It remains uncertain whether invasive ventilation should use low tidal volumes in critically ill patients without acute respiratory distress syndrome (ARDS).OBJECTIVE To determine whether a low tidal volume ventilation strategy is more effective than an intermediate tidal volume strategy.

BackgroundIt is uncertain whether lung-protective mechanical ventilation using low tidal volumes should be used in all critically ill patients, irrespective of the presence of the acute respiratory distress syndrome (ARDS). A low tidal volume strategy includes use of higher respiratory rates, which could be associated with increased sedation needs, a higher incidence of delirium, and an increased risk of patient-ventilator asynchrony and ICU-acquired weakness. Another alleged side-effect of low tidal volume ventilation is the risk of atelectasis. All of these could offset the beneficial effects of low tidal volume ventilation as found in patients with ARDS.Methods/DesignPReVENT is a national multicenter randomized controlled trial in invasively ventilated ICU patients without ARDS with an anticipated duration of ventilation of longer than 24 hours in 5 ICUs in The Netherlands. Consecutive patients are randomly assigned to a low tidal volume strategy using tidal volumes from 4 to 6 ml/kg predicted body weight (PBW) or a high tidal volume ventilation strategy using tidal volumes from 8 to 10 ml/kg PBW. The primary endpoint is the number of ventilator-free days and alive at day 28. Secondary endpoints include ICU and hospital length of stay (LOS), ICU and hospital mortality, the incidence of pulmonary complications, including ARDS, pneumonia, atelectasis, and pneumothorax, the cumulative use and duration of sedatives and neuromuscular blocking agents, incidence of ICU delirium, and the need for decreasing of instrumental dead space.DiscussionPReVENT is the first randomized controlled trial comparing a low tidal volume strategy with a high tidal volume strategy, in patients without ARDS at onset of ventilation, that recruits a sufficient number of patients to test the hypothesis that a low tidal volume strategy benefits patients without ARDS with regard to a clinically relevant endpoint.Trial registrationThe trial is registered at www.clinicaltrials.gov under reference number NCT02153294 on 23 May 2014.

Respiratory viruses are frequently detected in acutely admitted and invasively ventilated patients. Rhinovirus and human metapneumovirus are more frequently found in severe acute respiratory infection patients. Detection of respiratory viruses is not associated with worse clinically relevant outcomes in the studied cohort of patients.

Strategies that increase the ability of human hematopoietic stem and progenitor cells to repair alkylator-induced DNA damage may prevent the severe hematopoietic toxicity in patients with cancer undergoing high-dose alkylator therapy. In the context of genetic diseases, this approach may allow for selection of small numbers of cells that would not otherwise have a favorable growth advantage. No studies have tested this approach in vivo using human hematopoietic stem and progenitor cells. Human CD34(+) cells were transduced with a bicistronic oncoretrovirus vector that coexpresses a mutant form of O(6)-methylguanine DNA methyltransferase (MGMT(P140K)) and the enhanced green fluorescent protein (EGFP) and transplanted into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Mice were either not treated or treated with O(6)-benzylguanine (6BG) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). At 8-weeks postinjection, a 2- to 8-fold increase in the percentage of human CD45(+)EGFP(+) cells in 6BG/BCNU-treated versus nontreated mice was observed in the bone marrow and was associated with increased MGMT(P140K)-repair activity. Functionally, 6BG/BCNU-treated mice demonstrated multilineage differentiation in vivo, although some skewing in the maturation of myeloid and B cells was observed in mice transplanted with granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood compared to umbilical cord blood. Expansion of human cells in 6BG/BCNU-treated mice was observed in the majority of mice previously transplanted with transduced umbilical cord blood cells. In addition, a significant increase in the number of EGFP(+) progenitor colonies in treated versus nontreated mice were observed in highly engrafted mice indicating that selection and maintenance of human progenitor cells can be accomplished by expression of MGMT(P140K) and treatment with 6BG/BCNU.