This pilot study focuses on a select group of patients with a severe lung injury and concomitant oxygenation failure. Moreover, this small group of patients all had an indwelling PAC for guidance of intravascular volume and/or pressor support of oxygen delivery. All of the patients had normal lactate levels and cardiac indices that exceeded 3 l/min perm2 BSA. These values were taken as acceptable markers of adequate perfusion and thorough resuscitation, thus establishing a patient population that was believed to be relatively stable. The causes of the severe lung injuries in the patients were diverse, as one may expect in a mixed medical-surgical ICU, which attests to the protean nature of the underlying disorders that may result in lung injury. The primary questions that the present study addresses are as follows: whether patients with a severe lung injury requiring inverse ratio PCV may be safely transitioned to APRV; whether APRV allows patients with a severe lung injury on IRV-PCV and neuromuscular blockade to be safely ventilated without neuromuscular blockade; whether transitioning to APRV allows patients to be treated with less sedation as compared with IRV-PCV; and whether APRV improves hemodynamic performance in patients with severe ALI/ARDS as compared with IRV-PCV.
An early trial in open-heart surgery patients  documented that patients on other forms of CPAP ventilation may be safely switched to APRV. However, the result from that study may not be directly applicable to patients with severe lung injury. The present trial clearly demonstrates that such transitioning is safe and well tolerated, even by patients with inverse ratios approaching 4:1. Importantly, such a transition is better tolerated by many patients than was the original mode of mechanical ventilation with regard to systemic oxygen delivery (Table 1). A more recent trial  evaluated ARPV in patients with ARDS who were sufficiently well to be supported entirely on pressure support ventilation. This group and the one studied here share similar findings, despite the differences in the degree of lung injury when APRV was instituted. In both studies, hemodynamics were improved by APRV. Importantly, we found that the beneficial effects of APRV were related to the spontaneous breathing component as demonstrated by improved alveolar recruitment.
Because APRV is a modified form of CPAP, spontaneous breathing is an essential characteristic of the mode. Otherwise, APRV becomes nothing more than PCV with rather long inspiratory times and huge inspiratory : expiratory ratios. It is not uncommon to establish an 'inspiratory : expiratory ratio' of 13:1 using APRV. The inspiratory : expiratory ratio, however, is misleading during spontaneous breathing on APRV. This is because the patient may breathe throughout the entire phase time for each alternation of Thigh and Tlow at their respective pressures (Fig. 1). Thus, neuromuscular blockade should be eliminated to achieve the full potential benefits of APRV. These benefits will principally include avoiding the muscular decondition-ing that is associated with neuromuscular blockade, and improving matching of recruitable lung volume with gas volume. In this manner APRV does not result in overdistension, because the patient can simply exhale or inhale to decrease or increase delivered gas volume to match the available lung volume. We were able to virtually eliminate neuromuscular blockade in this study after transitioning to APRV. It is currently unclear whether treating all ALI/ARDS patients with APRV will decrease duration of stay in ICU as a result of eliminating or minimizing the use of neuromuscular blocking agents. A prospective randomized study is certainly warranted on this aspect of care, given the current financial imperatives under which we practice.
Intuitively, APRV should be a more comfortable mode of ventilation than any of the volume-limited or pressure-limited modes, because APRV is simply a CPAP derivative that allows spontaneous breathing. Therefore, one might expect to be able to decrease the amount of sedative agents used to achieve patient comfort and 'synch' with the ventilator. Our data support this hypothesis. Sedative use markedly decreased with the transition to APRV. The reduced dosage of sedative that is required to maintain a constant stimulated BIS value objectively support increased comfort (or decreased discomfort) with the transition to APRV. This aspect of care may potentially be characterized by the use of any of the numerous scales available to quantify patient comfort, and should be incorporated into future investigations.
There were real benefits realized using APRV in this patient population, namely improved oxygen delivery with reduced pressor requirements. We titrated pressor infusions to achieve a mean arterial pressure of 75 mmHg or greater, warm extremities, and resolution of lactic acidosis (in combination with volume loading for volume-recruitable cardiac performance). Mean arterial pressure is an important parameter, because it is a physiologic end-point that the body defends with vigor. It should be noted that pressors are not used to treat hyperlactatemia that is not associated with acidemia. Almost half of the patients were successfully weaned off pressors when transitioned to APRV. The probable explanation for the enhanced cardiac performance with reduced pressor requirements stems from reduced peak and mean airway pressures. The reduction in intratho-racic pressure manifested as decreased central venous pressure. It is likely that these related reductions resulted in improved venous return and cardiac output.
Patients were not further volume loaded or transfused packed red blood cells during the study period. Therefore, the increase in cardiac performance cannot be readily explained by volume-recruited cardiac performance or changes in oxygen-carrying capacity. With enhanced venous return, cardiac output increased as an expected result of increased left ventricle end-diastolic volume. Real-time trans-esophageal echocardiographic documentation of an altered left ventricular chamber size may document this process in the future. The improved hemodynamic profile led to a 36% improvement in oxygen delivery in this subgroup of patients relative to their oxygen delivery while on PCV. The present study does not address whether such a hyperdynamic state is beneficial. However, it is clear that if such a state is appropriate for a given individual, then APRV may represent a lower oxygen cost method (relative to pressors) for enabling the body to achieve that oxygen delivery.
One should note that the patients studied here had their sedative infusions titrated to an objective criteria - the BIS value. This value has been well correlated with improvements in time to awakening from sedation in the operating room, as well as with decreased recall phenomenon in the operating room and ICU. It is likely that the sedative need decreased as patient comfort improved during positive-pressure ventilation by transitioning to a spontaneous breathing mode. It is also possible that the increased cardiac performance resulted from increased catecholamine tone as the patients awoke. However, none of the patients were fully awake during the study period; they simply required less sedative to achieve the target BIS monitored level of sedation. Thus, the increased cardiac performance is probably not an expected commensal of awakening.
An earlier study in dogs with and without parenchymal lung injury  compared APRV with conventional positive-pressure ventilation, and assessed the hemodynamics. Unsurprisingly, conventional ventilation resulted in reduced blood pressure, stroke volume and cardiac performance, including systemic oxygen delivery. The results reported here closely support and buttress the animal data, although the ventilator modes were introduced in opposite orders. The lower airway pressures achieved with APRV have recently been cited [7,8] as an essential element in the care of neonates and pediatric patients with ARDS or congenital cardiac anomalies, and as an adjunctive support during extracorporeal membrane oxygenation therapy. Despite the recognition of reduced airway pressures (peak, plateau, mean), there has been relatively little data on the hemodynamic impact of APRV. The present study clearly documents the beneficial effects of APRV on cardiac performance in patients with severe ALI/ARDS.
It is unsurprising that lactate levels remained normal, because these were well-perfused patients whose mean arterial pressures were held relatively constant. However, it is important that the measured lactate declined with the transition to APRV. Concomitantly, the increased cardiac performance was also reflected in an increased urine output as an indicator of improved end-organ perfusion. Although the SvO2 values demonstrated an increased trend, the difference failed to reach statistical significance. Because SvO2 is a global measure and reflects an amalgam of oxygen consumptions and utilizations from all of the perfused organs, it may fail to reflect cardiac index increases in already hyperdynamic patients. Alternatively, the increased cardiac performance may have increased perfusion to areas that were not maximally utilizing the delivered oxygen. The increased extraction ratio of these segments may have offset the expected increase in SvO2. An increase in extraction ratio with additional work has been identified in patients who were ultimately destined to fail a weaning trial . Because the present study was performed for only a limited period, it is impossible to comment with any degree of certainty on whether this mechanism was operative in our patient population. Nonetheless, there was a small increase in SvO2 in the patients on APRV, although this was not statistically significant. This small increase correlates quite well with an identifiable and statistically significant increase in urine output.
It is useful to speculate on the potential financial implications of nearly eliminated neuromuscular blocking agent use, reduced sedative use, and diminished pressor use. Such cost savings may translate into real savings for a hospital. Additionally, nursing time is liberated, and may potentially be redirected to primary patient care and family liaison activities. Because a significant proportion of pressors utilized in this select patient population are used to support oxygen delivery, a PAC is also frequently utilized to guide such therapy. If the pressors are eliminated, then the PAC may also be unnecessary. This potential reduction in PAC utilization is probably real, because many PAC placement schemes require insertion of PAC for the evaluation of cardiac performance with high PEEP levels or elevated mean airway pressure levels. Each of these pressures are markers of increased intrathoracic pressure, increased pressure on the right atrium, and potentially reduced venous return and, hence, cardiac output. APRV may make such assessments a less frequent occurrence.
Treating patients with APRV may seem at odds with the recent US National Institutes of Health ARDSNet study , as well as the closely related study of Amato et al . Each of these studies holds forth the promise of increased survival using a combination of lower tidal volumes, reduced peak airway pressures, permissive hypercapnia, and the elimination of lower inflection points on the static pressure-volume curve (as a guide to optimal PEEP). The common denominator is matching gas delivery rates, volumes, and durations to an individual patient's unique lung dynamics, including the dynamics of their chest wall and heart size. Each of the factors that are patient specific impacts on the volume of available and recruitable lung. The strategies suggested above are designed to avoid overinflating a given lung, with resultant volutrauma and biotrauma, while maximizing the recruitment of available alveolar units.
This is the exact premise and promise behind APRV in a spontaneously breathing patient. The slow gas delivery rates and long Thigh times are designed to achieve better matching of regional time constant variations and to enable more uniform gas delivery to a greater number of alveolar units than is possible with conventional ventilation strategies. The patient's ability to exhale at any time ensures that, when the patient's lung volume is 'full', excess volume may be eliminated through an open and floating expiratory valve. In this way overdistension is avoided. A related strategy is constant flow ventilation, as championed by Slutsky and coworkers . However, constant-flow ventilation is hampered by difficulties related to carbon dioxide clearance in humans, and the resultant respiratory acidosis. This problem is eliminated by the release phase of APRV. Optimal recruitment of alveolar units is achieved by developing intrinsic PEEP with a short release phase, as well as through the principle of alveolar interdependency utilizing the pores of Kohn. Despite seeming disparity, APRV and the ARDSNet study have virtually identical goals that are achieved using different strategies.