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Traditionally, the goals of mechanical ventilation have been to maintain adequate tissue oxygenation (generally accepted as a saturation greater than 90%, with a reasonable cardiac output) and adequate ventilation to achieve normocarbia and maintain normal blood pH. To achieve these goals, patients with acute respiratory failure were often ventilated using a standard ventilation cocktail consisting of variable levels of PEEP and oxygen, and a tidal volume in the range of 10 to 15 mL/kg. This strategy was often employed with little regard for the underlying cause of respiratory failure. However, based on the forgoing discussion, adopting such a strategy may be deleterious. Consequently clinical trials and experimental endeavors have focused on the development of lung-protective strategies. The principal objectives of a lung-protective strategy are to limit alveolar distention and maintain alveolar patency. A lung-protective strategy should be implemented early in the course of respiratory failure to prevent the development of VILI.
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There are four potential strategies, none of which are mutually exclusive, to reduce alveolar overdistention. The first strategy is to limit inflation pressure. Current opinion and recommendations from a consensus conference on mechanical ventilation in ARDS recommend that plateau pressure be kept below 35 cm H2O in patients with ARDS. However, as emphasized in a review by Brower,90 a strategy that focuses on plateau pressure alone may still produce potentially injurious tidal volumes. Conversely, another limitation of using airway pressure as an indicator of lung inflation is that this method assumes that chest wall (including abdominal) compliance is normal. Patients with ARDS and conditions such as obesity or ascites may have a significantly reduced abdominal compliance. Consequently, high airway pressures may not be a reflection of overdistention. A second strategy to prevent lung overdistention is to limit tidal volume. This strategy is attractive because it is simple and eliminates concerns about changes in thoracic or abdominal compliance. In addition, this method was shown to be effective in decreasing mortality compared to conventional lung volumes.2 The potential difficulty with limiting volume is that the tidal volume used is still rather arbitrary and does not take into account the severity of lung injury. In fact, the ARDS Network study2 used a protocol that limited tidal volume to 6 mL/kg predicted body weight (PBW) and limited plateau pressures to less than 30 cm H2O. It is clear based on this study that tidal volumes of 12 mL/kg are excessive. What is not known at present is whether 6 mL/kg PBW volumes are superior to larger volumes (8 to 10 mL/kg). Whether 6 mL/kg is superior or inferior to 8 mL/kg remains a matter of debate. However, until evidence to support the contrary emerges, 6 mL/kg PBW should be considered the standard of care. It is worth emphasizing that the ARDS Network trial based tidal volumes on the patient's PBW, and not measured body weight. In this study a tidal volume of 6 mL/kg based on predicted body weight was on average equivalent to a tidal volume of 5 mL/kg measured body weight.
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The Pressure-Volume Curve in Acute Respiratory Distress Syndrome
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Some argue that ventilator settings should be individualized based on the pressure-volume (P-V) curve (see Fig. 37-3).24 Examination of the P-V relationship of the lungs of patients with ARDS provides a good conceptualization of the changes that occur during ARDS, and has been instrumental in the development of strategies of mechanical ventilation to reduce lung injury in these patients. Indeed one approach to optimize ventilation in patients with ARDS makes use of the shape of the P-V curve, in order to maintain lung inflation between the upper and lower inflection points. With a progressive increase in static airway pressure, there is a gradual increase in lung volume, which depends on the compliance of the respiratory system. As lung inflation approaches total lung capacity, a similar increase in airway pressure produces less lung inflation, and the P-V curve begins to flatten. This is often referred to as the upper inflection point. Continued inflation beyond this point results in overdistention of alveoli and increases the risk for macroscopic and microscopic lung injury. Similarly (although more controversial a notion) the lower inflection point is felt to reflect opening of atelectatic regions of the lung. It has been suggested that the level of PEEP be maintained above this level to avoid cyclic injury (atelectrauma) to the lung. However, this attractive approach has a number of problems. First, use of PEEP a few cm H2O above the lower inflection curve does not ensure that the lung is recruited; indeed recruitment takes place over the entire steep portion of the P-V curve.91–93 Secondly, the upper inflection point may indicate the completion of recruitment, rather than the development of overdistension.93 Furthermore, for the practicing intensivist, determining the lower inflection point may not be practical. Some guidance is provided by studies that suggest that in most patients with ARDS, PEEP levels above 15 cm H2O are generally required to maintain lung inflation above the lower inflection point.24,94
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Permissive Hypercapnia
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Permissive hypercapnia was first described in patients with asthma who were being mechanically ventilated. In an attempt to reduce dynamic hyperinflation and gas trapping, minute ventilation was decreased to allow sufficient expiratory time for the lung to empty via the obstructed airways. Relative to historical controls, patients managed in this manner had much better outcomes, with less barotrauma and less time spent receiving mechanical ventilation.95,96 The concept of permissive hypercapnia was extended to the management of patients with ARDS, and follows occasionally from a mechanical ventilation strategy that demands a restriction in tidal volume. It should be emphasized that permissive hypercapnia does not represent a method of mechanical ventilation per se. Rather, it is the consequence of a strategy that limits lung volume excursions in an attempt to minimize alveolar overdistention and hence VILI. In an uncontrolled study, Hickling and associates described the use of a pressure-limited strategy and permissive hypercapnia in patients with advanced ARDS. Mortality was significantly lower than that which would have been predicted from the APACHE II score alone.97 This was subsequently confirmed by some of the same authors in a prospective uncontrolled study in patients with ARDS.98 These were landmark studies, but used historical controls, the method of ventilation was not well defined, and efforts were made concurrently to limit oxygen toxicity. Therefore, these studies suggested, but did not conclusively prove, that a pressure-limited strategy and disregard for the partial arterial pressure of carbon dioxide (PaCO2) improved outcome. Importantly, serious side effects of an elevation of PaCO2 were not observed in either study.
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The physiologic consequences of hypercapnia and respiratory acidosis have been reviewed extensively.99,100 At present, the only absolute contraindication to a rise in PaCO2 is increased intracranial pressure, although acute hypercarbia may have adverse effects on the fetus in gravid individuals. In patients with critical illness and impaired oxygen delivery, there have been concerns about effects on cardiovascular performance. However, the potential myocardial depressant effects are usually short-lived owing to the buffering capacity of myocytes and the increase in sympathetic activity and decrease in afterload that accompany hypercapnia.101 Caution, however, is warranted in patients with evidence of myocardial dysfunction. A final concern surrounds the increase in pulmonary arterial pressures that develops with hypercapnic acidosis. This response is likely mediated by a reduction in nitric oxide and has been shown to be reversible with nitric oxide inhalation.102 In the face of these concerns hypercapnia has been shown to be protective in a variety of settings.103–106 Indeed it has been postulated that hypercapnia may attenuate the severity of acute lung injury, or at the very least that the development of hypocapnia may be harmful.100,103,107,108 Hypercapnic acidosis has been shown to attenuate protein leakage, lung edema, lung lavage inflammatory mediators, and lung injury score, and preserve oxygenation and lung compliance in several models of lung injury (Fig. 37-5).1,108–110
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More controversial is whether the resulting respiratory acidosis should be corrected by the infusion of a buffer solution. Although some advocate the use of a bicarbonate infusion, in the setting of impaired ventilation the additional CO2 generated during the buffering of H+ with bicarbonate might worsen intracellular pH. Second, as pointed out by Feihl and Perret, very large doses of bicarbonate are required to produce a significant improvement in pH during hypercapnia, owing to the large volume of distribution of the bicarbonate ion, to renal bicarbonate losses, and to conversion of bicarbonate to CO2.99 In addition, although extracellular pH is low, intracellular pH is rapidly corrected and seldom becomes critical. Consequently, the slow bicarbonate infusion recommended by some studies is not likely to be of benefit, and the routine administration of bicarbonate during permissive hypercapnia remains controversial. Indeed Laffey and coworkers demonstrated that correction of hypercapnic acidosis worsened lung function in an ischemia-reperfusion lung injury model.107 Other buffers such as Carbicarb may theoretically be more efficacious in the setting of hypercapnia.99,111
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Based on the foregoing discussions several controlled clinical trials have evaluated the effects of a lung protective strategy on outcome in ARDS (Table 37-3). However, initial randomized clinical trials evaluating the effect of lower tidal volumes on outcome were disappointing.112–114 There was even a suggestion that tidal volume restriction was harmful, as it was associated with a greater use of neuromuscular blockers, a greater need for dialysis (perhaps related to the lower pH from a higher PaCO2), and a trend toward higher mortality. In the study by Stewart and associates, the mortality in the tidal volume restriction arm was 50% compared to the control arm mortality of 47%, while in the study by Brochard and colleagues, the mortality was 47% and 39%, respectively.112,114 However, the NIH-sponsored multicenter study of patients with ARDS has vindicated many of the earlier animal studies and clinical trials.2 In this trial patients were randomized to receive either “conventional” tidal volumes (12 mL/kg PBW; tidal volume was reduced if plateau pressure was greater than 50 cm H2O), or a lower tidal volume (6 mL/kg PBW, and maintenance of a plateau pressure between 25 and 30 cm H2O). The trial was stopped early after an interim analysis demonstrated a survival benefit in the group with low tidal volume (Fig. 37-6). Mortality was reduced by 22% from 40% in the conventional arm to 31% in the low-lung-volume arm (CI 2.4 to 15.3 percent difference between the groups). The benefit of a lung-protection strategy seemed to be independent of the severity of the lung compliance at baseline. In addition to a mortality effect, the number of days alive and free of mechanical ventilation was lower in the intervention arm. However, this effect was solely due to the reduction in mortality, as the median duration of mechanical ventilation was 8 days for survivors in both groups. The benefit did not appear to differ when patients were stratified based on their risk factor for ARDS.115 Interestingly the number of days with nonpulmonary organ failure was lower in the intervention arm, and the plasma interleukin-6 concentration was decreased compared to the control group. This again supported the notion that a lung protection strategy achieved its benefit through a reduction in the systemic release of inflammatory mediators and reduction in severity of multiple system organ failure. Unlike previous studies, however, there was no difference in the use of neuromuscular blockers.
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It is difficult to reconcile the difference in the results of the ARDSNet study with earlier clinical trials evaluating a lung volume restriction strategy, because the ARDSNet study differed in several ways, making direct comparisons difficult.116 First, the method of determining predicted body weight (and hence tidal volume) was different from earlier trials. Second, patients in the low-tidal-volume arm had higher respiratory rates that may have led to significant auto-PEEP, in turn leading to improved alveolar patency or recruitment. Third, the respiratory acidosis was more likely to be corrected with bicarbonate. This may have reduced the number of patients dialyzed, and could have reduced some of the yet to be determined effects of hypercapnic acidosis.
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A concern regarding the safety of the ventilation trials conducted in patients with ARDS has recently been raised. In a review of the controlled trials of mechanical ventilation in ARDS, Eichacker and associates presented the argument that 12 mL/kg was potentially excessive, and that the use of this tidal volume as the reference intervention was inappropriate, placing patients in the control arm at risk.117 The authors argued that there should have been a control group that better reflected “conventional” treatment. What tidal volume this control group would have actually been managed with is speculative. The reader is referred to an excellent review of the controversy and its consequences by Steinbrook.118 The implications for this issue for the design and conduct of subsequent trials remain to be seen, but at present the ARDSNet strategy for ventilation of ARDS patients should be viewed as the standard.
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In addition to lung overdistention, VILI also incorporates the concept that underdistention of alveolar units can also lead to injury. At present there are only two clinical trials that have evaluated the effects of an “open lung” approach to patients with ARDS. The first study by Amato and colleagues examined the effect of a multifaceted strategy that (1) minimized tidal volume, (2) recruited alveoli through a sustained inflation, (3) used a level of PEEP above the closing pressure of the lung, and (4) utilized a pressure-volume curve to define the optimum lung volume and PEEP.119 Consequently the specific effects of maintaining alveolar patency cannot be determined from this trial. Nonetheless, using this strategy they demonstrated an impressive reduction in mortality. However, the major criticism of this study is that the control group was significantly disadvantaged by a protocol that allowed for significant overventilation, and that the observed results were not due to a benefit in the treatment arm, but rather a detrimental outcome in the control group.
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In order to make specific recommendations about the optimum strategy, the relative effects of tidal volume reduction, alveolar recruitment, and level of PEEP need to be determined. To this end two multicenter trials are evaluating the effect of lung recruitment and high PEEP on outcome in ARDS. The ARDS Network has reported the results of their trial (ALVEOLI trial) that was closed after enrolling 550 patients, citing a finding of futility in the trial being able to determine a treatment effect during an interim analysis.124 In an ongoing Canadian trial over 800 patients will be randomized to either low tidal volumes (identical to the ARDSNet low stretch trial) or a low tidal volume with an open lung approach. The open lung approach will utilize both periodic sustained inflations to 40 cm H2O continuous positive airway pressure for 40 seconds and high levels of PEEP (up to 20 cm H2O). It is hoped that this strategy will ensure both alveolar recruitment and maintenance of alveolar patency, respectively. Preliminary evidence suggests that this strategy may lead to a significant improvement in oxygenation in a subset of patients with early ARDS and no impairment in chest wall mechanics.120 Whether this physiologic improvement and attendant reduction in atelectasis will lead to an improvement in survival has yet to be proven.
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High-frequency oscillation (HFO) may accomplish many of the goals of a lung-protective strategy. It utilizes small tidal volume excursions at a high mean airway pressure. Consequently lung overdistention may be prevented and alveolar patency may be maintained. In a study of HFO in 70 pediatric patients with ARDS, Arnold and associates reported an improvement in oxygenation and requirement for supplemental oxygen at 30 days in the HFO group.121 However there was no difference in duration of mechanical ventilation or survival. These observed improvements in physiologic parameters were also found in a study by Derdak and coworkers.122 In a multicenter randomized controlled trial of HFO compared to what was at that time a conventional ventilatory strategy, in 148 adults with ARDS they found no difference in survival or duration of mechanical ventilation. However the oxygenation was better in the HFO group during the study. These reports suggest that HFO is at least as safe as conventional mechanical ventilation, and may be associated with a more rapid improvement in oxygenation. However, both trials were hampered by the fact that the control group likely did not represent the current standard of care, namely tidal volumes of 6 mL/kg PBW. It remains to be seen if HFO is any more efficacious than a strategy that restricts tidal volume (with or without a strategy to maintain alveolar patency).
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Even in the face of overwhelming experimental evidence and convincing results of a large controlled study, one of the major challenges faced by intensivists seems to be implementing these recommendations in practice. Two studies have demonstrated that compliance with the ARDS Network tidal volume goals are poor, even in those centers that participated in the original trial. Clearly education and protocolization of care will need to occur to allow best evidence to be translated into clinical practice.3,116
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ARDS continues to be a common component of multisystem organ dysfunction and primary lung injury. Unfortunately, no pharmacologic intervention has proven to be efficacious in reducing mortality in patients with ARDS. An improved understanding of ARDS and the notion that prior ventilator strategies may have been injurious has led to rethinking how these patients should be supported.