Since its proposal by Alan K. Laws in Toronto in the late 1960s, and subsequent publication , there have been many descriptions of the titration of PEEP. For the bedside clinician, PEEP is utilized in an attempt to increase the FRC, and has the potential to achieve the following goals:
• Improved oxygenation (permitting lowered FiO2)
• Improved compliance
• Improved hemodynamic status (reduced pulmonary vascular resistance, reduced left ventricular afterload)
• Reduced stretch-induced lung injury (and concomitant lung-to-systemic release of inflammatory factors)
• Elimination of auto-PEEP
While these goals are admirable, they need to be weighed in the context of the potential deleterious effects of excessive PEEP including:
• Reduced compliance (if over-inflated)
• Impaired hemodynamic status (reduced right - and maybe left - ventricular preload)
The effects of PEEP on oxygenation and hemodynamics occur rapidly with changes in PEEP, and, therefore, are well appreciated by any bed-side intensivist. An early attempt to titrate the beneficial effects of PEEP on oxygenation against the deleterious effects on hemodynamics represented one of the first attempts to integrate several key ICU parameters in ICU patients . In terms of clinical trials of the application of PEEP in ARDS, three studies are especially important. Amato et al demonstrated that maintenance of PEEP at a level greater than the LIP in a PV curve, as well as utilizing small Vt, was associated with a significantly better survival compared with a strategy consisting of lower PEEP plus higher Vt . Application of 'prophylactic' PEEP was not associated with improved outcome in ARDS , and preliminary data from a recently completely study suggest that use of PEEP to induce recruitment is not associated with improved outcome 10. The full data from this study are not yet available, and it is not clear that the applied PEEP resulted in lung recruitment 10.
However, several issues have become prominent since then. First, patients with ARDS represent a heterogeneous population in terms of the etiology of their respiratory failure, as well as the 'morphology' of the lung injury. Although most acute forms of lung injury are similar at a microscopic (i.e., histologic) level, wider utilization of bedside respiratory mechanics and Ct scanning  has increased our appreciation of different categories of ARDS . Indeed Gattinoni et al. have suggested that the etiology of ARDS is related to the characterization of the subsequent lung mechanics, wherein 'pulmonary' etiology (e.g., aspiration, primary pneumonia) results in ARDS associated with consolidated, non-recruitable lung, whereas 'non-pulmonary' etiology (e.g., sepsis) results in recruitable lung . Second, the protection against stretch-induced lung injury afforded by PEEP is largely accepted in the laboratory literature, spanning multiple experimental models of VILI [42,43]. However, this is far from obvious in the clinical environment, given the mixed outcomes from clinical studies. In this context, timing may be extremely important. A recent clinical study , demonstrated that the ability to recruit lungs depends on the timing of the efforts: recruitment is easier in the setting of early lung injury, and is more difficult when injury is more established.
In a recent provocative article, Rouby et al. developed a paradigm for characterizing patients with ARDS . In that paper, the authors outline the importance of early assessment of CT-based morphology and bedside compliance in patients with ARDS. Following this, they outline an approach to optimization of PEEP, based on the slope of the PV curve, as well as the values of the lower and upper inflection points . The rationale for this approach is largely based on their division of ARDS into two basic populations. In cases with diffuse hyperdensities accompanied by a 'high' LIP (>5 cmH2O) and a 'non-compliant' PV curve (slope <<50 ml/cmH2O), higher levels of PEEP are likely to be necessary, and are unlikely to cause problematic hyperinflation. Conversely, where the hyperdensities are focal and accompanied by a 'low' LIP (<5 cmH2O) and a 'compliant' PV curve (slope >50 ml/cmH2O), lower levels of PEEP are likely to be optimal; however, higher levels are likely to cause hyperinflation with the potential for barotrauma.
Finally, the 'titration' of PEEP against either oxygenation (or recruitment) must take into account the experimental findings of Rimensberger et al.  who confirmed theoretical predictions based on the differences between the inspiratory vs. expiratory limbs of the PV curve. They reported that whereas high levels of airway pressure (PEEP or continuous positive airway pressure [CPAP]) may be required to 'open' collapsed lungs in an experimental model, far lower levels of PEEP are required to maintain this opened -'recruited'- state. Thus, the early need for high levels of PEEP may not be maintained. Thus, one should not set a high level of PEEP and leave the bedside. Rather, one should apply a high level of PEEP or CPAP (sometimes to very high levels as tolerated by the hemodynamic status), and when improved oxygenation is attained, convert to a lower (but still elevated) level of PEEP, and thereafter titrating downwards to a 'stable' level of PEEP. This process may need to be repeated to progressively higher levels of 'stable' PEEP if oxygenation deteriorates during downward titration of 'stable' PEEP. The clinician will only discover this for each patient by regular - and repeated - titration.
In summary, if oxygenation is the chosen surrogate for recruitment, regular titration of PEEP should be commenced early in the ICU course, and be guided by the morphology and mechanics.
Recent clinical trials have provided contradictory results relating to the optimal Vt, plateau pressure, and associated PEEP [14, 17, 19, 47, 48]. Whereas three of these studies found no impact of ventilatory strategy on outcome, two studies did. The clearest evidence of effect has been provided by the studies of Amato et al.  and the ARDSnet group . The study by Amato et al. reported that relatively low VT combined with relatively high levels of PEEP resulted in significantly reduced mortality . The ARDnet study reported that a 'low tidal volume' vs. a 'high tidal volume' strategy (as part of a comprehensive ventilatory management protocol that dictated FiO2, plateau airway pressure, and PEEP) was associated with improved patient survival . These two studies are the only randomized controlled trials that demonstrate that mechanical ventilation has an impact on mortality in ARDS, and as such, constitute critically important contributions to the critical care literature. Applying the 'best available' evidence, a clinician might be tempted to conclude that 'on aggregate', lower Vt is generally better than higher Vt. However, titration of Vt in ARDS based on such suppositions may be dangerous for three reasons. First, each of the studies had two experimental groups (only), so that the results are 'binary'. Therefore, we have no clinical basis for interpolation about 'intermediate' ventilatory targets, or for extrapolating towards extremes of Vt. Second, a recent meta-analysis  of these studies casts (disputed ) doubt on the reliability of the validity of the concerns about 'high' Vt (as opposed to high plateau pressure) and the benefits of 'low' Vt . Finally, a large-scale Australian study of outcome in ARDS, reported (without presenting the data) that there was no correlation between Vt and mortality .
In summary, if the alternatives available to a clinician are either of the four treatment groups in the studies by Amato et al.  or the ARDSnet , then the clinician should definitely opt for one of the respective 'low stretch' group options. This is never the case, however, and the clinician should not at this stage decide that lower Vt is necessarily better for all ranges of Vt; therefore, Vt should not be continually titrated downwards in the absence of due regard to lung recruitment or adequacy of ventilation. Instead, avoidance of high Vt that result in elevated plateau pressures appears appropriate.
Since the late 1960s it has been recognized that lung stretch results in release of inflammatory mediators , and this was proposed as a mechanism of hemodynamic depression resulting from mechanical ventilation . Recent work from multiple laboratories has suggested that adverse forms of mechanical ventilation are associated with pulmonary  or systemic  release of cytokines or bacterial products [56, 57]. From the clinical perspective, these findings have been confirmed, at least in principle. The ARDSnet study reported that systemic circulating interleukin (IL)-6 was higher in the 'high stretch' group , and an additional smaller study demonstrated that high PEEP combined with lower Vt resulted in lesser elevations in lung and circulating cytokine release . Nonetheless, not all experimental evidence concurs with the hypothesis that adverse ventilatory strategy results in elevated cytokines .
Our group has recently reported that cytokine gene activation is associated with high stretch ventilation, but that such activation occurs well before the development of measurable physiologic lung impairment or before the appearance of pathologic changes in lung histology . Taken together, these data suggest that in the future, plasma cytokine profile might provide an early-warning signal of impending stretch-induced lung injury, thereby mandating a change in ventilatory strategy. In such a way circulating (or bronchoalveolar lavage) cytokines or bacterial products could function as a target for ventilatory titration.
Much of the foregone discussion has focussed on respiratory issues, or on the integrated physiology of O2 delivery and CO2 control. However, it is increasingly clear that patients do not die from hypoxia perse , or indeed from any particular impingement of pulmonary function, including overt barotrauma . Furthermore, the overall ICU mortality from ARDS appears to be fairly consistent over the last decade, and pending a radical change in approach to mechanical ventilation or a new biologically driven therapy, it is difficult to envisage how mortality could improve significantly beyond the current range. Thus, clinicians should expand their focus from mortality statistics to the broader issues of morbidity and quality of life in those patients - the majority - who survive ARDS. Several groups have investigated these issues, and several pertinent findings have been described. The key causes of long-term morbidity disability relate to acquired neuromuscular impairment . In addition, long-term depression and post-traumatic stress disorder may be associated with increased use of sedative or neuromuscular blocking drugs . Finally, the use of low Vt -although associated with less mortality [14, 17] - does not appear to translate into less morbidity in survivors of ARDS . Thus, it will be important for future investigators to explore the biologic basis for long-term disability, and investigate therapeutic and preventive approaches.
Conclusion: Trading Multiple Targets Against Each Other
Although we are rapidly accumulating knowledge about specific questions in critical care, we do not - and will never - have the answers to all possible clinical questions in ventilatory care, much less in critical care in general. Thus, randomized clinical trials will answer isolated questions, and the individual clinician will have to weigh the evidence as applied to specific scenarios. However, frameworks can be constructed to address clinical situations. In terms of targeting parameters in mechanical ventilation, the following approach might be useful:
1. Decide on the single most important immediate issue for the patient, and consider the following (illustrative) examples:
- If the SpO2 is less than 85%, then correction of hypoxemia would be the first priority.
- On the other hand, if the PaCO2 is 11 kPa in the setting of elevated intracranial pressure, then reduction of PaCO2 would be a very high priority.
2. Prioritize among the following parameters or targets (oxygenation, PaCO2, plateau pressure or Vt, hemodynamic depression, lung recruitment, patientventilator synchrony) and rank them in order of importance for the patient.
3. Decide on which parameters will be selected for clinical titration
In summary, the clinician needs to decide which parameter is of immediate - and subsequent - importance, and which scientific literature is applicable. In addition, he/she must decide on which 'trade-offs' are appropriate for the patient in question, and atwhat stage the benefits oftargets such as oxygenation, perfusion, recruitment are worth the cost to the patient of attaining them.
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