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Mechanical Ventilatory Support: The Expanding Evidence Base

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Concept of Ventilator-Induced Lung Injury (VILI)

Numerous animal studies have shown that the lung is subject to physical injury during mechanical ventilation. At least 2 mechanisms appear important in producing this injury. The first is a physical stretch injury resulting from lung regions being inflated beyond their physiologic maximum. This produces a tissue injury characterized by inflammation, edema formation, hyaline membranes, and the release of inflammatory mediators into the circulation. Lungs with a heterogeneous distribution of disease are at particular risk for this injury because healthier regions will be preferentially overdistended when a positive pressure breath is delivered. The second mechanism is a shearing injury from repeated opening and closing of atelectatic alveoli in an injured lung. The use of a low tidal volume and/or expiratory pressure to prevent alveolar derecruitment can ameliorate this injury. A third mechanism, tidal stretch above the normal tidal stretch (4-6 mL/kg), even if maximal stretch is limited, is more controversial but also could contribute to VILI.

To minimize this injury potential, mechanical ventilation goals should be twofold. The first goal should be to provide enough positive end expiratory pressure (PEEP) to recruit the "recruitable" alveoli while at the same time not applying so much PEEP that healthier regions are unnecessarily overdistended. The second goal should be to avoid a PEEP-tidal volume (Vt) combination that unnecessarily overdistends lung regions at end inspiration. These goals embody the concept of a "lung protective" mechanical ventilatory strategy.

The NIH ARDS Network Small Tidal Volume Study Revisited

From 1996-1999, the National Institutes of Health Acute Respiratory Distress Syndrome (ARDS) Network study of ventilator management randomized over 800 patients to receive either a low stretch strategy (Vt =6 mL/kg) or a high stretch strategy (Vt=12 mL/kg).[1] The results showed a statistically significant 25% reduction in mortality in the low stretch group despite the fact that the low stretch group actually had a lower PaO2/FiO2 ratio during the first 2 days of the trial. Also of note was that fact that there were fewer other organ failures and inflammatory cytokine values were lower in the low stretch group. This study provided compelling evidence that ventilator management strategies designed to prevent overdistention not only protect the lung from injury but also reduce systemic inflammation and improve mortality.

An ongoing controversy following this trial has focused on whether it was the tidal volume reduction (reduced tidal stretch) or the plateau pressure reduction (reduced maximal stretch) that provided the benefit. The clinical corollary to this question is whether tidal volumes should always be set to 6 mL/kg or whether it is simply enough to just reduce the plateau pressure (Pplat) to < 30-35 cm H2O, the maximal transpulmonary pressure at total lung capacity in normal human lungs.

Addressing this question, Deans and colleagues[2] analyzed outcomes in the eligible but not randomized patients in the original ARDS Network study and found a mortality rate similar to the small tidal volume group. They argued that these patients likely had tidal volumes "titrated" to Pplat limits based upon the prerandomization ventilator settings in the enrolled subjects. Their conclusion was thus that Pplat limitation should be the important clinical goal, not tidal volume reduction. Hager and colleagues[3] countered this by reanalyzing the ARDS Network results by quartiles of lung injury. Using this approach, they could identify the "healthier" patients in whom both the large and small tidal volumes produced Pplat values well below the 30-cm H2O threshold. Although the reduced sample size did not allow for adequate statistical analysis, there was good evidence from this study that tidal volume reduction was beneficial even when the Pplat was low. The "take home" message from this controversy seems to be that both mechanisms are likely important, and clinicians should aim to keep both low.

Ventilator-Induced Diaphragmatic Dysfunction

Ventilator induced diaphragmatic dysfunction (VIDD) describes ventilatory muscle abnormalities induced by mechanical ventilatory support strategies that suppress or eliminate spontaneous ventilatory muscle activity. Under circumstances of no (or minimal) neural input or muscle loading, a number of changes have been described in the ventilatory muscles that include atrophy, fibre transformation, myofibrillar loss, mitochondrial abnormalities, protein breakdown, and vacuole formation. These changes can be amplified by derangements in muscle resting length and blood flow, both of which are affected by mechanical ventilation support settings. Small animal studies and observations in neonates have shown that VIDD can develop in less than 24-48 hours of controlled mechanical ventilation (CMV).

A key clinical question is how much muscle activity must be present to prevent or reduce VIDD? A recent study[4] on rats mechanically ventilated for 24 hours analyzed muscle function after using 1 of 4 ventilator strategies: CMV, CMV with four 60-minute spontaneous breathing (SB) periods; CMV with five 5-minute SB periods, and SB alone. A control group without MV was also studied. Diaphragm physiologic and protein expression patterns were significantly impaired in the CMV group, consistent with VIDD. Of note, both groups with CMV with intermittent SB had less impairment but were still abnormal compared with control or rats receiving SB. Until VIDD is better understood, it would seem reasonable to avoid controlled modes of ventilation as much as possible and perhaps use interactive breaths (eg, pressure support, pressure assist, proportional assist) as soon as patients can tolerate these.

How Does a Clinician Select PEEP?

The application of PEEP in patients with ALI/ARDS prevents alveolar derecruitment, thereby improving gas exchange and lung mechanics. Preventing derecruitment might also reduce lung injury from repetitive open-close stresses on adjacent lung units.

Approaches to setting the right amount of PEEP, however, are controversial. Mechanical approaches (best compliance techniques, static pressure volume measurements) attempt to set PEEP on the deflation limb of the lung's pressure volume relationship just above the point when large scale derecruitment would occur. These mechanical approaches, however, are difficult to do, and the observed data are often "noisy" and difficult to interpret. The more common approach is to use gas exchange to guide the PEEP selection. This approach has been modified in recent years to target an "acceptable" PO2 rather than a maximal PO2 to prevent excessive PEEP that might open some sicker alveoli but end up overdistending healthier regions.

A reasonable practical guide to PEEP settings are the 2 PEEP-FiO2 tables used in the ARDS Network. Both of these tables target a PO2 of 55-80 mm Hg and have a maximum of 24 cm H2O PEEP. They differ in that one table has a minimum of 5 cm H2O while the other has a minimum of 12 cm H2O. Of note, in a direct comparison of these 2 approaches,[5] the higher PEEP strategy provided better recruitment but offered no survival or ventilator-free-day advantage. Two explanations for this "disconnect" between physiologic improvement and outcome have been offered. First, the benefits of a higher PEEP strategy may have been countered by injury from additional overdistention. Second, in the setting of a reduced tidal volume that limits the magnitude of the open-close stresses, further recruitment of sicker lung units may simply offer no additional benefit.

New Modes for Managing Respiratory Failure

Airway Pressure Release Ventilation

Airway pressure release ventilation (APRV; also known as biphasic ventilation, bilevel ventilation, and BIPAP) is a time-cycled, pressure-targeted form of ventilatory support. It differs from conventional pressure targeted modes in that a pressure release mechanism allows spontaneous breathing to occur during both the inflation and deflation phases. Generally, APRV is used in a strategy of long inspiratory time ventilation -- similar in concept to older forms of inverse ratio ventilation. The putative advantages of this approach are that: (a) the long inflation phase recruits more slowly filling alveoli and raises mean airway pressure without increasing tidal volume or applied PEEP (although intrinsic PEEP can develop with short deflation periods); and (b) the additional unassisted spontaneous efforts during the inflation may enhance both recruitment and cardiac filling as compared with other controlled forms of support. Animal work and small observational human trials have demonstrated that these APRV mechanical concepts are sound.

APRV has been evaluated in 2 randomized clinical trials. In one,[6] ventilator days were shorter with APRV. However, the control group in this trial was placed on an unusual pressure controlled mode that required paralysis for 3 days and that dramatically worsened their PO2/FiO2 ratio compared with the prerandomization baseline. Thus, the data are difficult to interpret. In a second study,[7] the control group strategy was a more conventional SIMV-pressure support mode, and the outcomes (survival and ventilator days) were identical in both the control group and the APRV group.

It is important to remember that with APRV, the set inflation pressure ("P high") is NOT necessarily the maximal stretching pressure across the lungs. Any negative pleural pressure generated to effect spontaneous tidal volumes during the inflation period must be added to the applied pressure to calculate the true end-inspiratory transpulmonary pressure (and thus the risk of overdistention VILI). Given this risk and the lack of meaningful supportive clinical data to date, additional trials are clearly needed to justify widespread application of APRV.

High-Frequency Ventilation

High-frequency ventilation (HFV) uses very high breathing frequencies (120-900 breaths per minute in the adult) coupled with very small tidal volumes (often less than anatomic dead space) to provide gas exchange in the lungs. Gas transport under these seemingly unphysiologic conditions involves such mechanisms as Taylor dispersion, coaxial flows, and augmented diffusion.

The putative advantages to HFV are that substantial mean airway pressures can be applied for recruitment but overdistention is limited because of the very small tidal volume and pressure changes in the alveolar regions. Indeed, HFV behavior in the alveolar regions has been described as "CPAP with a wiggle."

Clinical experience with HFV has been most extensive in the neonatal and pediatric arenas, where it has been shown in many studies to reduce long-term lung dysfunction in survivors of various forms of respiratory failure. In the only adult HFV study to date,[8] Derdak and colleagues compared a 300-breaths-per-minute HFV strategy with a control group receiving a conventional mode of support using 10 mL/kg tidal volumes. The HFV group had a 53% vs 38% survival rate advantage over the control group, but the P value was above the conventional significance threshold at .057. Larger, better powered trials are needed to firmly establish the role of HFV in adult respiratory failure.

References

  1. ARDS Network. A trial of low versus high tidal volume mechanical ventilation in patients with ALI/ARDS. N Engl J Med. 2000;342: 1301-1308. Abstract
  2. Deans KJ, Minneci PC, Cui X, Banks SM, Natanson C, Eichacker PQ. Mechanical ventilation in ARDS: one size does not fit all. Crit Care Med. 2005;33:1141-1143. Abstract
  3. Hager DN, Krishnan JA, Hayden DL, Brower RG; ARDS Clinical Trials Network. Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med. 2005;172:1241-1247. Abstract
  4. Gayan Ramirez G, Testelmans D, Maes K, et al. Intermittent spontaneous breathing protects the rat diaphragm from mechanical ventilation effects. Crit Care Med. 2005;33:2804-2810. Abstract
  5. ARDS Network. A trial of higher vs. lower PEEP in patients with ARDS. N Engl J Med. 2004;351:4-11.
  6. Putensen C, Zech S, Wrigge H, et al. Long-term effects of spontaneous breathing during ventilatory support in patients with acute lung injury. Am J Respir Crit Care Med. 2001;164:43-49. Abstract
  7. Varpula T, Valta P, Niemi R, Takkunen O, Hynynen M, Pettila VV. Airway pressure release ventilation as a primary ventilatory mode in acute respiratory distress syndrome. Acta Anaesth Scand. 2004;48:722-731. Abstract
  8. Derdak S, Mehta S, Stewart TE, et al. High-frequency oscillatory ventilation for acute respiratory distress syndrome in adults: a randomized, controlled trial. Am J Respir Crit Care Med. 2002;161:801-808.
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