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CHAPTER 51: Ventilator-Induced Lung Injury 447

volumes on outcome were disappointing. 115-117 There was even a sug- The Lung Open Ventilation (LOV) clinical trial was conducted pur-
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gestion that tidal volume restriction was harmful, as it was associated suing an “open-lung” ventilation strategy characterized by high levels of
with a greater use of neuromuscular blockers, a greater need for dialysis PEEP using a fixed PEEP/Fi O 2 combination table. The PEEP values were
), and a trend slightly higher compared to those of the previous ALVEOLI study. The
( perhaps related to the lower pH from a higher Pa CO 2
toward higher mortality. In the study by Stewart and associates, the conventional arm received levels of PEEP comparable to the ARMA
mortality in the tidal volume restriction arm was 50% compared to study. At the end of the study, 985 patients were enrolled; 85% had
the control arm mortality of 47%, while in the study by Brochard and severe lung injury (P/F ratio <200). The study failed to demonstrate any
colleagues, the mortality was 47% and 39%, respectively. 115,117 However, difference in mortality in the two groups (36.4% and 40.4% in the treat-
the NIH-sponsored multicenter study of patients with ARDS (ARMA) ment and control groups, respectively). Moreover, the two study groups
has confirmed many of the earlier animal studies and clinical trials. differed only for the rescue therapy and death for refractory hypoxemia
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In this trial, patients were randomized to receive either “conventional” rates, which were less in the LOV—high PEEP group.
tidal volumes (12 mL/kg PBW; V was reduced for Pplat >50 cm H O), A national French multicenter randomized control trial (EXPRESS
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or a lower V (4-6 mL/kg PBW, and maintenance of Pplat between 25 study) addressed the superiority of an open-lung approach compared
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and 30 cm H O). The trial was stopped early after an interim analysis to a protective ventilation strategy limiting only tidal volume. In the
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demonstrated a survival benefit in the group with low V . Mortality was interventional arm of the study, PEEP was titrated to the highest value
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reduced by 9% from 40% in the conventional arm to 31% in the low V possible keeping Pplat <28 to 30 cm H O. In the control arm, PEEP was
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arm (CI 2.4%-15.3% difference between the groups). The benefit of a set between 5 and 9 cm H O. In both groups V was <6 mL/kg PBW.
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lung-protection strategy seemed to be independent of the severity of After enrolling 768 patients, the study failed to demonstrate a significant
the lung compliance at baseline. In addition to a mortality effect, the difference in hospital, 28-day and 60-day mortality. However, patients
number of days alive and free of mechanical ventilation was higher in ventilated with higher PEEP levels had significantly more ventilator-free
the intervention arm. The degree of benefit did not appear to be related days and organ failure–free days. Interestingly patients with the more
to the underlying risk factor for ARDS. Interestingly, the plasma IL-6 severe lung injury (P/F <200) ventilated with higher PEEP tended to
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concentration was decreased compared to the control group, supporting have lower 28-day mortality compared to patients treated with lower
the notion that a lung-protection strategy achieved its benefit through a PEEP. The authors suggested that in clinical practice, PEEP should be
reduction in the systemic release of inflammatory mediators and reduc- cautiously applied to mild forms of ALI and that higher levels of PEEP
tion in severity of multiple system organ failure. be considered only for patients with more severe lung injury. This
Following the trial, concerns regarding the safety of the ventilation impression was corroborated from the results of a robust meta-analysis
trials conducted in patients with ARDS was raised. In a review of the that incorporated trials (from 1996 to January 2010) comparing higher
controlled trials of mechanical ventilation in ARDS, Eichacker and versus lower levels of PEEP. The meta-analysis concluded that there is
associates presented the argument that 12 mL/kg PBW was potentially no difference in mortality applying lower versus higher levels of PEEP
excessive, and that the use of this V as the reference intervention in all ALI patients. However, in a subgroup of ARDS patients with more
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was inappropriate, placing patients in the control arm at risk. The severe forms of lung injury, edema and atelectasis, there may be a benefit
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authors argued that there should have been a control group that better from higher levels of PEEP. 122
reflected “conventional” treatment. What tidal volume this control group Moreover, higher PEEP levels and lung recruitment maneuvers asso-
would have actually been managed with is speculative. The reader is ciated with reduced V seem to be beneficial also in clinical condition
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referred to an excellent review of the controversy and its consequences different from ARDS such as in the care of potential organs donor. In
by Steinbrook. Although this controversy has raised important a recent RCT, including 118 potential organ donors, Mascia et al dem-
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discussions regarding the use of a “one-size-fits-all” approach to onstrated that protective ventilation (V 6-8 mL/kg) and higher PEEP
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mechanical ventilation the ARDSNet strategy for ventilation of ARDS (8-10 cm H O) compared to conventional ventilation (V 10-12 mL/kg)
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patients remains the accepted standard to which all other clinical trials and lower PEEP (3-5 cm H O) resulted in a markedly higher number of
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are compared. eligible and harvested lungs. 123
In addition to lung overdistention, VILI also incorporates the concept
that underdistension of alveolar units can also lead to injury. Several RESCUE THERAPIES FOR LIFE-THREATENING
clinical trials have been conducted in the past decade to evaluate the HYPOXIA MINIMIZING VILI
effects of an “open-lung” approach to patients with ARDS. In two
randomized studies, Amato and colleagues, and Villar and colleagues An alternative method to recruiting the lung is to ventilate patients while
examined the effect of a multifaceted strategy that (1) minimized tidal they are in the prone position. This strategy basically uses gravity to
volume, (2) recruited alveoli through a sustained inflation, (3) used a recruit the lung and improve ventilation perfusion matching. Prone posi-
level of PEEP above the closing pressure of the lung, and (4) utilized tioning has been demonstrated to improve oxygenation, 124-126 and decrease
a pressure-volume curve to define the optimum lung volume and the incidence of VAP in patients with acute hypoxic respiratory failure.
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PEEP. 103,104 Consequently, the specific effects of maintaining alveolar However, none of the studies demonstrated that this approach improved
patency cannot be determined from this trial. Nonetheless, using this mortality. In the most recent clinical trial, prone ventilation was associated
strategy they demonstrated a reduction in mortality. However, the major with a nonsignificant decrease (37.8% vs 46.1%) in 28-day mortality in
criticism of these studies is that the control groups were significantly the subgroup of patients with severe hypoxemia. This finding led to the
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disadvantaged by a protocol that allowed for significant overventilation, conduct of a larger clinical trial in patients with severe respiratory failure.
and that the observed results may not have been due to a benefit in the The results of this study are pending at the time of writing. At present,
treatment arm, but rather a detrimental outcome in the control group. however, there are conflicting results as to whether prone ventilation
The ARDS Network performed a second large clinical trial comparing may be beneficial in reducing ARDS mortality based on the most recent
lower versus higher levels of PEEP (the ALVEOLI study). The trial was meta-analysis. 127,128 Suffice to say that expert opinion recommends prone
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stopped early for futility. One limitation of this study was that the mean ventilation as rescue therapy in severe respiratory failure (as indicated by
age of the high PEEP arm was higher (54 ± 17 vs 49 ± 17; p <0.05), Pa O 2 /Fi O 2 <100) after maximization of conventional therapy. 129
was lower (151 ± 67 vs 165 ± 77; p <0.05), and Compared to conventional mechanical ventilation, high-frequency
the mean Pa O 2 /Fi O 2
there was a trend to higher APACHE III scores, at baseline. A second oscillation ventilation (HFOV) is theoretically an ideal modality to
limitation was that the effectiveness of the PEEP levels in preventing minimize VILI. This ventilation strategy embraces many of the prin-
atelectrauma was not assessed. Thus, the optimal level of PEEP and ciples of lung protection, as it delivers extremely small tidal volumes
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the best method used to set PEEP have not been definitively established. around a relatively high mean airway pressure, at high respiratory

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