Physiological predictors of survival during high-frequency oscillatory ventilation inadults with acute respiratory distress syndrome

Patients with acute respiratory distress syndrome (ARDS) exhibit a highly inhomogeneous,compliance-dependent distribution of regional ventilation during conventional mechanicalventilation (CMV) [1]. Consequently, CMV can lead to further lung injury through tidalhyperinflation and shear stress injury, even when it is administered according to a'lung protective strategy' that limits tidal volumes and plateau pressure [2], and employs recruitment maneuvers to maximize the proportion of aeratedalveolar tissue [1]. High-frequency oscillatory ventilation (HFOV) can theoretically offereffective lung protective ventilation by delivering very low tidal volumes (1 to 3 mLKg^-1) around a fixed mean airway pressure at frequencies of 5 to 12 Hz(lower frequencies are used in adults). At high respiratory frequencies, the shortinspiratory time results in a distribution of ventilation which, compared to mechanicalventilation at conventional breathing rates, is more homogeneous and less dependent onthe distribution of regional lung compliance [3, 4]. This results in the protection of the recruited lung (with greatercompliance) from excessive cyclic variations in alveolar pressure. In addition, if thecontinuous distending pressure (CDP) is optimized following a stepwise recruitmentmaneuver, the more compliant lung regions are less susceptible to static hyperinflation [3, 5, 6], thereby reducing lung strain and ventilation-induced inflammation [7, 8].

HFOV improves gas exchange and reduces lung injury in animal models of ARDS [9‐11] and in human neonatal and pediatric populations [12‐15]. In adults the effects of HFOV are largely limited to observational studies [16‐24] and two randomized trials [25, 26]. Overall these studies show that HFOV might improve gas exchange andsurvival. However, data that provide clinical criteria for identification of patientslikely to benefit from HFOV are scarce [23, 24]. Large studies outside North America, utilizing different protocols arelacking, although the results of two multicenter clinical trials in the UK and Canada(OSCAR and OSCILLATE trials) are awaited [16, 27, 28].

In this study we aim to describe potential physiological predictors of survival duringHFOV in adults with severe ARDS admitted to an advanced respiratory failure center inthe United Kingdom.

We report the results on 102 consecutive ARDS patients who received HFOV. The median(IQR) duration of ARDS prior to HFOV was 48 hours (24 to 120 hours). The median (IQR)duration of CMV prior to HFOV was 45 hours (9 to 138 hours). Table 1 presents the baseline patient demographics, physiological variables andseverity scores at study entry. Table 2 summarizes patients'outcome and complications from HFOV.

Overall, HFOV was well tolerated with low incidence of new or worsening pneumothoraces,pneumomediastinum or subcutaneous emphysema (2%) and hemodynamic compromise. Twopatients (1.96%) suffered profound hypotension during HFOV.

This study aimed to identify potential predictors of survival in patients with severeARDS who received HFOV after failing lung-protective CMV. The key results of our studyare that: 1) an early improvement in PaO₂/FiO₂ ratio is apredictor of survival at 30 days; 2) patients with more severe disease and lowerrespiratory system compliance pre-HFOV show greater CO₂ clearance; and 3) ifthere is no improvement in gas exchange within three hours, patients can be consideredto have failed HFOV and perhaps should be considered for alternative treatment (forexample, extracorporeal support).

Despite theoretical beneficial effects on minimizing lung injury and improving gasexchange, HFOV is not widely utilized because of the lack of evidence supporting a clearsurvival benefit over CMV [25, 26, 34]. Furthermore, available clinical trials do not help the clinician decide whento consider HFOV and, importantly, how long HFOV should be continued to enhance patientsurvival. Our study has a similar scope to the series reported by Adhikari et al. [23]; however, there are important methodological differences in the HFOVprotocols and the type of recruitment maneuver (that is, a slow stepwise maneuver in ourstudy versus a sustained inflation in Adhikari et al.) used in the two studies.Furthermore, recruitment maneuvers were performed in all patients in our case series,whereas in the study by Adhikari et al only 49.5% of the patients received arecruitment maneuver. The rationale of the stepwise recruitment we used in this studywas similar to the stepwise recruitment used in neonates [35], in that it allowed for setting of the optimal CDP but it differed in twoaspects. First, we used a fixed FiO₂ of 1.0 and response to the recruitmentwas assessed as changes in PaO₂. Second, in order to allow time forequilibration of PaO₂ [36] and to minimize hemodynamic instability, our protocol required longer timesbetween changes in CDP (ten minutes during the incremental phase and five minutes duringthe decremental phase) compared to the recruitment used in neonates [35]. It is possible that the slower and early recruitment, as performed in thisstudy, can explain the early identification of responders to HFOV.

Although our study is not a randomized comparative study, we believe it identifiesclinically important predictors of clinical outcome within the first few hours ofinitiation of HFOV, possibly in response to the initial SRM. Our study populationincluded, as might be expected for a rescue study, patients with more severe ARDS thanin the MOAT trial where patients received HFOV as a primary ventilation mode [26] and similar to that of the EMOAT trial [25] and the recent case series[23].

In contrast to other published reports [17, 18], in our study gas exchange variables (PaO₂/FiO₂, andOI) improved significantly only in survivors, and change in PaO₂/FiO₂ remained significantly different between the two outcome groups after adjustingfor baseline confounding factors. Although the CDP on HFOV was higher than the CDP onCMV, there was no difference in CDP between survivors and non-survivors. Despite similarlevels of CDP, the response to HFOV within the first three hours could identify patientswith a favorable outcome based on PaO₂/FiO₂ and OI.

An important factor for the response to HFOV may be played by the proportion of patientswith pulmonary versus extra-pulmonary ARDS. Indeed, in this study we show that thelargest change in PaO₂/FiO₂ post HFOV was seen for extra-pulmonaryARDS whereas little difference in PaO₂/FiO₂ was seen in pulmonaryARDS. This is consistent with the findings reported by Pachl et al. that showthat oxygenation and recruitment during HFOV are more pronounced in patients withextra-pulmonary ARDS [37]. However, Pachl et al. studied changes in oxygenation undernormocapnic conditions; therefore, no data on the different behavior of PaCO₂ in the two types of ARDS are available for comparison with our data. The otherimportant finding of our study is the effect of HFOV on PaCO₂. In our study,in contrast to other reports [19, 26], the PaCO₂ decreased significantly throughout the duration of HFOVin parallel to an increase in PaO₂/FiO₂ despite similar settingsof frequency, power and amplitude. We found that in survivors there was both an increasein PaO₂/FiO₂ and a decrease in PaCO_2. In addition,patients who had at least a 38% increase in their PaO_2//FiO₂ (asidentified by the ROC curve), also showed greater reductions in PaCO₂ allowing for a reduction in delta pressure. Patients with a greater diseaseseverity (higher PaCO_2, lower compliance and worse gas exchange), showed ahigher rate of clearance in PaCO₂ during the first six hours of HFOV. Thesechanges in physiological variables have been described in patients with severe ARDS andhigher potential for lung recruitment [38].

The increase in intra-thoracic pressure generated during a SRM could have caused areduction in cardiac output and pulmonary blood flow, leading to a decrease in venousadmixture and to an apparent improvement in PaO₂/FiO₂ in theabsence of true alveolar recruitment [39, 40]. However, this mechanism seems less likely as an explanation for the changesseen in our study, as the cardiac output and oxygen delivery were unchanged followingthe SRM, and therefore the combined improvement in PaO₂/FiO₂ andPaCO₂ leads us to speculate that HFOV facilitated lung recruitment in amanner similar to that described for patients responding to prone positioning [41].

The 30-day mortality in this study was 56%, comparable to the mortality rate reported inother uncontrolled studies (61.7% [23, 42], 66% [18], 53% [17]) but higher than the studies using HFOV as primary intervention (43% [25] and 37% [26]) and studies of trauma patients [16]. Multivariate analysis shows that changes in PaO₂/FiO_2, age, days with ARDS prior to HFOV and baseline pH are independent predictivefactors of mortality. Lung injury is positively associated with duration of mechanicalventilation in both animal and human studies: increased lung injury is associated withreduced likelihood of pulmonary recruitment

In conclusion, this study shows that HFOV is effective in improving oxygenation in someadults with ARDS, particularly when instituted early. This study also shows that changesin PaO₂/FiO₂ are sensitive criteria to predict survival and thechange in PaCO₂ may identify patients with a greater proportion ofrecruitable lung more likely to benefit from HFOV. Patients who do not show improvementin PaO₂/FiO₂ ratio and oxygenation index within six hours oncommencing HFOV should be considered for extracorporeal support. These data are ofpotential value in aiding decision making.

Further randomized controlled trials powered to detect a difference in survival betweenHFOV strategies are expected. Interpretation of these comparisons will also need to takeinto consideration the number, the duration, and the type of recruitment maneuverscarried out during HFOV and CMV (for example, slow stepwise RMs, as employed in thisstudy versus traditional RMs, with continuous positive airway pressure (CPAP) of 40cmH₂O for 40 seconds). The identification of patients likely to benefitfrom HFOV and the identification of physiological variables associated with thepotential for lung recruitment will prove essential to ensure the best use of HFOV inadults with ARDS.