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Tidal volumes expressed in ml/kg of a measured body weight, dry body weight, c ideal body

Tidal volumes expressed in ml/kg of a measured body weight, dry body weight, c ideal body weight, or d predicted body weight.

Mechanical Ventilation

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.

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.

Four of the clinical trials summarized in Table 1 tested the value ofventilation with small Vt 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 Vt ventilation [33, 34] were stopped early at an interim analysis because it was very unlikely that a beneficial effect of the lower Vt approach could be demonstrated if the trial continued to its original planned enrollment (futility). The NIH trial [36] and also the trial of combined lower VT/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 Vt approach. The two studies that stopped early for efficacy are more likely to be biased in favor of the beneficial effects of the small Vt 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 smallest. 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 differences in outcomes among these trials is variation by chance alone.

Differences in the Vt used in the study groups

The mean difference in Vt 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 Vt between the study groups in the three other trials that tested low Vt ventilation [33-35]. Direct comparisons of the Vt used in the NIH trial and those used in two of the other studies are possible because these studies used explicit formulae for setting Vt [34-36]. In the fourth trial that tested ventilation with low Vt, the Vt were set according to dry body weight, which required a clinical estimation of weight gain from extravascular fluid accumulation [33]. To compare the Vt 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 Vt that were set according to explicit formulae [38].

The values for Vt for the three studies that did not show a beneficial effect of Vt 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 Vt between study groups in the NIH study appears to be due to both the use of lower Vt in the lower Vt study group of the NIH study and higher Vt in the higher Vt 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 PaCO2 andpH. There maybe deleterious effects of respiratory acidosis [39-42]. Beneficial effects of Vt 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 important clinical outcomes in ARDS patients remains to be demonstrated.

High Frequency Ventilation

High frequency ventilation uses very small Vt at very high rates [45, 46]. The rationale for using very small Vt is, as explained earlier, to prevent lung injury from overdistention. With very high respiratory rates, adequate CO2 clearance can be achieved despite Vt 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 associated 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 neonatal 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 Vt of approximately 10 ml/kg predicted body weight. These Vt 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 Vt 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.

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