PRO: Routine intraoperative PLV has been shown to improve outcome in patients affected by ALI/ARDS

N. Petrucci, MD MSc
Consultant in Anaesthesia and Intensive Care
Dept. of Anaesthetics
Desenzano (BS) - Italy

Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are known to be associated with abnormal mechanical properties of the respiratory system with hallmark features of reduction in static compliance.1 As a result of this low compliance, high pressures are needed to obtain a sufficient tidal volume (Vt). The larger the Vt, the higher the pressure required which may lead to barotrauma, that is, alveolar rupture and radiological evidence of extra-alveolar air. In patients with ALI/ARDS mechanical ventilation (MV) could lead to injury resulting from barotrauma and overdistension. This results from the distribution of the increased Vt to the high-compliance regions, causing stretching and sheer forces on the alveolar wall (volutrauma).2,3 Pressure- and volume-limited ventilation with high level of end-expiratory pressure (PEEP), known as protective lung ventilation (PLV), has been proposed as ventilatory support for ALI/ARDS patients. Between 1998 and 2000 some RCTs were published to test PLV in ALI/ARDS patients, with controversial results.4,5,6,7 A large controlled trial showed that ventilation with lower Vt (6 ml/Kg ideal body weight, IBW) decreased mortality at day-180 by 22%, compared to higher Vt (12 ml/Kg IBW).8 A systematic review on this topic showed that mortality at day-28 was significantly reduced by PLV (RR 0.74; CI 0.61-0.88), whereas beneficial effect on hospital mortality was uncertain (RR 0.84; CI 0.68-1.05).9 Another finding of the review was that, as long as plateau pressure was kept below 31 cmH2O, there was no benefit from using lower Vt, suggesting that variations of trans-pulmonary pressure in the individual patient is an important variable to be measured when setting the ventilator. The high volume might induce lung damage when the resulting trans-pulmonary pressure is high. Conversely, when trans-pulmonary and airway pressure are within the safe limits, high or intermediate tidal ventilation (8-10 ml/Kg) could be used, thus avoiding potentially deleterious effects of low Vt. The uncertainty about the long-term benefit of higher Vt ventilation as a determinant of outcome has been recently confirmed in a prospective observational study.10

Biotrauma: Does MV induce pulmonary and systemic inflammation?

The answer is yes. Baseline plasma levels of cytokine markers of inflammation (IL-6, IL-8, IL-10) are associated with an increased risk of death in ALI/ARDS patients in a multivariate analysis.11 Clinical and experimental studies suggested that MV could alter inflammatory responses in patients with ALI/ARDS. In such patients, increased intra-alveolar and systemic levels of inflammatory mediators were associated with high Vt ventilation and low PEEP,12 whereas low Vt ventilation was associated with a more rapid attenuation of the inflammatory response.11 Systemic inflammatory response may culminate in multiple organ dysfunction syndrome (MODS). In a clinical prospective cross-over study, Stuber at al. demonstrated that switching from PLV to high Vt ventilation led to with a marked increase of measured plasma cytokines after one hour in a cohort of patients with ALI.13 Copland et al. reported that 30 min. of high Vt ventilation were sufficient to upregulate 10 genes encoding for transcription factors, stress proteins, and inflammatory mediators and to downregulate 12 genes mainly encoding for metabolic enzymes.14 Importantly, the recent published trial ALVEOLI showed that in ALI/ARDS patients treated with 6 ml/Kg IBW Vt, the clinical outcomes were similar whether lower or higher PEEP levels were used, meaning that levels of PEEP are not as crucial as tidal volume for determining the clinical outcome.15

Surgery and biotrauma
Interestingly, major abdominal and thoracic surgery have been associated with an increase in measured plasma interleukins over time.16 The cytokine response to lower abdominal surgery is characterized by an increase in IL-6 and IL-1b concentrations occurring later than cortisol and reaching its maximum in the postoperative period. A twelve-fold increase of IL-6 concentrations was measured one hour after surgery. In addition, IL-6 and IL-1b are known to stimulate the release of ACTH and cortisol, and could indirectly modulate their own secretion and change the perioperative response of the typical stress hormones.16 In patients with existing pulmonary and systemic inflammation, such as ALI/ARDS, who already have high plasma levels of cytokine markers, major surgery could further increase levels of inflammatory mediators. Therefore, since MV can affect the inflammatory response, intraoperative ventilatory strategy is a relevant issue and a potential determinant of outcome.

Three-hit model?
It is convenient to analyse the problem by referring to the two-hit model: according to this model, pulmonary inflammation must already be present (first hit) for injurious MV (second hit) to aggravate the inflammatory response.17 When patients with ALI/ARDS undergo surgery, a third-hit adds up. Therefore, it is reasonable to believe that intraoperative high Vt ventilation in ARDS patient aggravate lung injury, potentially facilitating development of multi-organ failure.

Is there clinical evidence showing that intraoperative PLV improve outcome in ALI/ARDS patients?

There are no clinical trials addressing this issue. Wrigge et al. studied whether PLV altered plasma mediators during major abdominal and thoracic surgery in adult healthy patients.18 This trial showed increase of all plasma mediators, but failed to demonstrate that PLV with 10 cmH2O PEEP decreases concentrations of pulmonary or systemic mediators compared with high tidal volume ventilation with zero PEEP. However, the study population did not include ALI/ARDS patients.

Experimental evidence To test whether MV may act as a second-hit to aggravate the inflammatory response, Tremblay et al. examined the effect of ventilation strategy in the presence and absence of a pre-existing inflammatory stimulus. This study showed that zero PEEP and high volume ventilation per se could alter lung cytokine and gene expression.19 The study showed that sepsis-induced lung injury was a significant co-stimulus. A recent controlled study tested whether, in anesthetized-paralyzed rabbits, ventilation with 10 ml/kg Vt and zero PEEP would result in lung injury during endotoxemia, compared to healthy lung. Endotoxemic animals treated with high ventilation had significantly more lung inflammation compared to endotoxemic animals that were endotoxemic and spontaneously breathing.20

Conclusions: ALI/ARDS, major surgery and MV may act in a synergistic manner, according to a three-hit model, leading the patient to an unfavorable outcome in the short term. The use of high volume ventilation in ALI/ARDS patients in the operating room may aggravate lung injury. Conversely, intraoperative PLV, by attenuating the pulmonary and systemic inflammatory response, can favourably influence outcome.

References

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