Summary of Clinical Trials of Mechanical Ventilation in ARDS

in ARDS

R. G. Brower and G. D. Rubenfeld

Introduction

Acute respiratory distress syndrome (ARDS) is characterized pathophysiologically by increased intrapulmonary shunt and ventilation-perfusion imbalances, in- creased intrapulmonary dead space, and decreased respiratory system compliance.

Most ARDS patients experience hypoxemia while ventilating spontaneously, even with high fractions of inspired oxygen (FiO

). Many patients cannot sustain ade- quate ventilation, leading to hypercapnia, respiratory acidosis, and worsening hypoxemia. Without mechanical ventilation, death may occur within a short time.

With mechanical ventilation, adequate ventilation and oxygenation can be sus- tained in most patients, providing more time for administration of specific treat- ments such as antibiotics for infections and for natural healing. However, mechani- cal ventilation may also cause acute lung injury (ventlation-associated or ventila- tor-induced lung injury, VILI). Thus, our primary means of respiratory support, which is critical for survival of most patients with ARDS, may paradoxically prevent recovery of some patients.

Many studies in experimental animal models suggested that some specific aspects of mechanical ventilation techniques are responsible for VILI, and that modifications of mechanical ventilation approaches could decrease or prevent VILI [1–9]. However, these modifications could also have adverse effects on respi- ratory or circulatory function which could be detrimental to recovery of ARDS patients. Therefore, clinical trials were necessary to demonstrate the value of different mechanical ventilation strategies for improving important clinical outcomes. This chapter summarizes the rationale for the modified mechanical ventilation strategies and the results of several randomized clinical trials designed to compare clinical outcomes among patients who received different mechanical ventilation approaches.

Traditional Approach to Mechanical Ventilation in ARDS

Positive pressure ventilation techniques were developed by anesthesiologists in the

first half of the 20

century to support general anesthesia during thoracic surgery

[10]. Ventilation with small, physiologic tidal volumes (V

) led to progressive

hypoxemia during several hours of volume-cycled ventilation, presumably from

progressive atelectasis. Ventilation with generous V

of 10-15 ml/kg was adopted

because this approach was associated with lower alveolar-arterial oxygen gradients and decreased intrapulmonary shunt [11, 12].

Positive pressure ventilation was used with increasing frequency in patients with acute respiratory failure in the 1950s. Many aspects of the techniques devel- oped by anesthesiologists for support of general anesthesia were adopted for use in critically ill patients. Two aspects of these techniques probably contributed to VILI.

VILI from Ventilation with High Volumes and High Pressures

Because dead space is increased in ARDS, the generous V

approach was useful for maintaining near-normal PaCO

and pH. Moreover, the generous V

approach was also useful for preventing or decreasing atelectasis and reversing some of the intrapulmonary shunt caused by atelectasis or intraalveolar filling [13, 14]. How- ever, much of the ARDS lung is not available for ventilation because of consolidation, atelectasis, and alveolar filling [15, 16]. Therefore, most of the V

is delivered to the less diseased or normal lung regions. This may cause overdistention in the aerated lung tissue. Numerous studies in experimental animal models have demonstrated that overdistention can cause increased pulmonary vascular permeability, decreased sur- factant function, hemorrhage, inflammation, and hypoxemia [1, 4, 7, 17, 18]. Venti- lation with smaller V

may decrease mechanical stresses in the aerated lung regions and attenuate this form of acute lung injury (ALI). However, the smaller V

approach is less effective for maintaining gas exchange than the traditional approach that used generous V

. Some ARDS patients experience hypercapnia and acidosis while receiving ventilation with small V

[19, 20]. Therefore, it was not clear that the smaller V

approach would lead to improved clinical outcomes in ARDS patients.

VILI from Ventilation with Low End-Expiratory Volume and Pressure

VILI occurred in experimental animal models of ALI when positive pressure ventilation was delivered with low end-expiratory volumes and airway pressures [1, 8, 9]. At least three mechanisms for this form of VILI have been suggested:

1. Low volume/low pressure VILI may occur if there is some atelectasis at end-ex- piration, which is more likely when low end-expiratory airway pressures are applied. This may allow repeated opening and closing of small bronchioles and alveoli, which could involve injurious mechanical stresses [8].

2. Low volume/low pressure VILI may occur from excessive stress in the parenchy- mal attachments between atelectatic and aerated lung units [21].

3. Low volume/low pressure VILI may occur if there is substantial atelectasis or

alveolar filling, leading to maldistribution of the V

to the aerated lung units,

causing overdistention[22, 23]. Several studies in experimental models demon-

strated decreased VILI when higher levels of positive end-expiratory pressure

(PEEP) were applied, to raise end-expiratory lung volume by recruiting atelectasis

or flooded alveoli [1, 8, 9]. Higher levels of PEEP were recommended by some

investigators to prevent this form of VILI in ARDS patients [24, 25]. However,

higher levels of PEEP may cause higher levels of end-inspiratory pressure and volume, which could cause VILI from overdistention. Moreover, higher levels of PEEP may cause circulatory depression [26, 27]. Therefore, it was not clear that modifying traditional mechanical ventilation approaches with higher PEEP would improve clinical outcomes.

Schemes for Prioritizing Competing Clinical Objectives

Surveys of physicians’ use of mechanical ventilation in ARDS demonstrated great variability in practices [28–30]. Some physicians used generous V

with higher airway pressures. This approach gave high priority to traditional goals of maintaining gas exchange and breathing comfort; it gave lower priority to preventing VILI from overdistention. Other physicians used moderate or small V

with lower airway pressures. This approach gave higher priority to preventing VILI from overdistention;

it gave lower priority to maintaining gas exchange and breathing comfort. There was also great variability in physicians’ use of PEEP [28]. These differences in physi- cians’ practices reflect disparity in physicians’ estimations of the risks and benefits of the different approaches to setting V

and levels of PEEP. Randomized clinical trials were necessary to provide clinically relevant information to guide clinician practice.

Clinical Trials of Mechanical Ventilation Strategies Clinical Trials Using Conventional Mechanical Ventilation

Five different randomized trials were conducted in the 1990s to test modified

mechanical ventilation strategies in ARDS patients (Table 1). One of these trials

compared clinical outcomes in ARDS patients randomized to receive either a

conventional approach with generous V

and relatively low levels of PEEP to those

randomized to receive small V

and relatively high levels of PEEP [31]. Patients in

the small V

/higher PEEP group also received recruitment maneuvers (continuous

positive pressure airway pressure [CPAP] of 40 cmH

O for 40 seconds) to reverse

atelectasis. Oxygenation was substantially improved with the small V

/high PEEP

approach. Thus, higher levels of PEEP can compensate for the deleterious effects of

the small V

approach on oxygenation. The small V

/higher PEEP approach was also

associated with respiratory acidosis, as expected. However, the small V

/higher

PEEP approach was associated with substantially improved survival. These striking

results demonstrated that the approach to mechanical ventilation could alter clinical

outcomes and suggested that mechanical ventilation approaches should be modified

from those that were used in the past. However, it was not clear if the improved

outcomes were attributable to the use of smaller V

, higher PEEP, recruitment

maneuvers, or the possibility of some unrecognized imbalances between the study

groups [32]. Moreover, because this was a relatively small trial that involved many

patients with causes of ARDS that are uncommon in other intensive care environ-

ments, it was important to confirm the findings.

Fig. 1. Relative risks of mortality (± 95% confidence intervals) for the study groups that received lung-protective mechanical ventilation strategies relative to those that received conventional, standard, or traditional mechanical ventilation strategies. The mortality estimates from the two trials that stopped early for efficacy [31, 36] may be biased in favor of beneficial effects. The two studies that stopped early for futility [33–35] may be biased against beneficial effects of the lung protective approach. The confidence intervals shown overlap, suggesting that the differences could be from chance variation.

Table 1. Clinical trials of lung-protective mechanical ventilation strategies in patients with ARDS.

Values shown for tidal volumes are as reported in the studies.

Study Tidal volumes (ml/kg) Mortality (%)

Higher Lower Higher Lower

Amato et al.[31]^a ~12 ~6 71 38

Brochard et al. [33]^b ~10 ~7 38 47

Stewart et al. [35]^c ~11 ~7 47 50

Brower et al. [34]^d ~10 ~7 46 31

NIH Network [36]^d ~12 ~6 40 31

Tidal volumes expressed in ml/kg of^ameasured body weight,^bdry body weight,^cideal body weight, or^dpredicted body weight.

Four of the clinical trials summarized in Table 1 tested the value of ventilation with small V

with limited inspiratory airway pressures [33–36]. Three of these trials did not demonstrate improved clinical outcomes with the volume and pressure limited approach [33–35]. However, the trial conducted by the NIH ARDS Network demonstrated improved mortality, more ventilator-free days, and more organ failure- free days with the volume and pressure limited approach [36]. There are several possible explanations for the different results among the four trials.

Chance variation

Risk ratios for mortality for each of the five clinical trials summarized in Table 1 are shown in Figure 1. The 95% confidence intervals for the mortality estimates are inversely proportional to the sizes of the clinical trials. In other words, we have less confidence in the mortality estimates from the smaller clinical trials.

Mortality estimates for some of the trials shown in Figure 1 may also be biased because the trials stopped earlier than had been originally planned. Two of the studies that did not show a beneficial effect of lower V

ventilation [33, 34] were stopped early at an interim analysis because it was very unlikely that a beneficial effect of the lower V

approach could be demonstrated if the trial continued to its original planned enrollment (futility). The NIH trial [36] and also the trial of com- bined lower V

/higher PEEP [31] stopped earlier than was originally planned because there was convincing evidence for efficacy of the modified ventilation approaches.

The mortality estimates from clinical trials that stop early tend to be biased in favor of the early stopping rules [37]. The two studies that stopped early for futility are more likely to be biased towards over-estimating harmful effects or underestimating beneficial effects of the lower V

approach. The two studies that stopped early for efficacy are more likely to be biased in favor of the beneficial effects of the small V

approach. These biases, if present, tend to be proportional to the fraction of the planned enrollment that was actually enrolled in the studies. The NIH trial enrolled a greater proportion (86%) of the planned enrollment than the two trials that stopped early for futility. Moreover, the NIH trial was the largest of the trials, and, therefore, the confidence intervals around the mortality estimate from this study are the small- est. These considerations support a higher level of confidence in the mortality estimate from the NIH trial than in the other trials. Most importantly, the confidence intervals for all of the trials overlap. Thus, one plausible explanation for the differ- ences in outcomes among these trials is variation by chance alone.

Differences in the V

used in the study groups

The mean difference in V

between the two study groups in the NIH trial was 5.6 ml/kg of predicted body weight [36]. This difference was probably greater than the difference in V

between the study groups in the three other trials that tested low V

ventilation [33–35]. Direct comparisons of the V

used in the NIH trial and those used in two of the other studies are possible because these studies used explicit formulae for setting V

[34–36]. In the fourth trial that tested ventilation with low V

, the V

were set according to dry body weight, which required a clinical estima- tion of weight gain from extravascular fluid accumulation [33]. To compare the V

in this study to those in the other studies requires some estimations and assumptions

regarding the relationships of dry body weight to the body weights and V

that were set according to explicit formulae [38].

The values for V

for the three studies that did not show a beneficial effect of V

reduction [33–35] suggest that the separation between the study groups was smaller than 5.6 ml/kg, as used in the NIH study (Table 1). The greater separation in V

between study groups in the NIH study appears to be due to both the use of lower V

in the lower V

study group of the NIH study and higher V

in the higher V

study group of the NIH study.

Other differences in the study protocols

There were several other methodologic differences between the study protocols used in the trials. One difference between the NIH study and the three studies that did not show a beneficial effect was in the management of respiratory acidosis. The NIH trial utilized higher respiratory rates to maintain near-normal arterial PaCO

and pH. There may be deleterious effects of respiratory acidosis [39–42]. Beneficial effects of V

reduction could be counteracted by adverse effects of respiratory acidosis. On the other hand, respiratory acidosis has been shown to reduce ALI in experimental animal models [43,44]. The net effect of respiratory acidosis on impor- tant clinical outcomes in ARDS patients remains to be demonstrated.

High Frequency Ventilation

High frequency ventilation uses very small V

at very high rates [45, 46]. The rationale for using very small V

is, as explained earlier, to prevent lung injury from overdistention. With very high respiratory rates, adequate CO

clearance can be achieved despite V

that are smaller than traditional estimations of dead space.

Moreover, with this approach, lung volumes can be maintained at higher levels to achieve greater recruitment and aeration; to prevent VILI from low volume/low pressure ventilation [47].

An early trial of high frequency jet ventilation in ARDS patients was not associ- ated with improved clinical outcomes [48]. However, using refined high frequency ventilation approaches (high frequency oscillatory ventilation, HFOV), some clinical trials demonstrated modest improvements in clinical outcomes in infants with neo- natal respiratory distress [49–52]. In other studies there were no apparent beneficial effects of HFOV in neonates [53,54].

In a recent clinical trial, ARDS patients were randomized to receive HFOV or a conventional mechanical ventilation approach [55]. Mortality was lower in the study group that received HFOV, although this difference was not statistically significant. Patients randomized to receive the conventional mechanical ventilation approach received V

of approximately 10 ml/kg predicted body weight. These V

were not as small as those used in the NIH trial, and they were associated with inspiratory airway pressures that were higher than those used in the lower V

approach as in the NIH study [36]. Therefore, although the results of this trial were

promising for HFOV, the investigators acknowledged that additional studies were

needed to compare important clinical outcomes among patients who receive HFOV

to those that receive the best conventional ventilator-based lung protective strategies.

Summary

Each of the clinical trials summarized in this chapter compared clinical outcomes among ARDS patients who received mechanical ventilation according to different schemes for prioritizing competing clinical objectives. The NIH trial demonstrated that a prioritization scheme that gave higher priority to preventing high vol- ume/high pressure VILI would yield better clinical outcomes than a prioritization scheme that gave higher priority to maintaining traditional goals with respect to gas exchange and comfort.

The NIH trial was not designed to demonstrate the best mechanical ventilation strategy. However, the results of this trial strongly suggest that V

of 12 ml/kg predicted body weight and higher should be avoided unless there are compelling reasons to use this approach in some patients. Some investigators have suggested that the use of V

that are intermediate between 6 and 12 ml/kg will yield better clinical outcomes than the use of 6 ml/kg [56]. Also, it has been suggested that an inspiratory plateau pressure of 3032 cmH

O may be a safe limit [56, 57]; that reductions of V

to achieve lower inspiratory plateau pressures are not necessary.

However, subset and multiple logistic regression analyses of the NIH study database suggest that better outcomes result from V

reduction to achieve lower inspiratory plateau pressures [58].

Numerous studies in experimental animals strongly suggest that higher levels of end-expiratory lung volume are beneficial to prevent low volume/low pressure VILI. The clinical trial in which improved clinical outcomes were associated with the “open-lung approach” [31] is consistent with the animal studies. However, it is not yet clear that higher levels of end-expiratory lung volume can improve clinical outcomes in patients already receiving mechanical ventilation with small V

and limited inspiratory airway pressures. Three multi-center clinical trials were initiated between 1999 and 2002 to assess the value of higher levels of end-expiratory pressure and recruitment maneuvers in patients with ARDS receiving small V

. Preliminary analysis of one of the trials, which concluded in 2002, suggests that raising PEEP may not alter clinical outcomes. The other two trials continue to enroll patients. We do not yet know the answer to this question.

Conclusion

Mechanical ventilation is necessary for the survival of most ARDS patients. How-

ever, traditional approaches to mechanical ventilation may have prevented recov-

ery of some patients. Mechanical ventilation with a volume and pressure limited

approach appears to improve clinical outcomes relative to a mechanical ventilation

approach that utilizes generous V

and inspiratory airway pressures. Further

improvements in clinical outcomes may result from mechanical ventilation ap-

proaches designed to prevent low volume/low pressure VILI. This may be possible

using conventional mechanical ventilation, but definitive evidence for this ap-

proach awaits conclusion of the current clinical trials. HFOV is a promising

lung-protective approach that must be further developed and proven in relation to conventional mechanical ventilation lung protective approaches.

Acknowledgement. Supported in part by National Institutes of Health/National

Heart, Lung, and Blood Institute grants NO1-HR 46054–64 and HLR0167939

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