Abstract
In acute respiratory distress syndrome (ARDS), recruitment sessions of high-frequency oscillation (HFO) and tracheal gas insufflation (TGI) with short-lasting recruitment manoeuvres (RMs) may improve oxygenation and enable reduction of subsequent conventional mechanical ventilation (CMV) pressures. We determined the effect of adding HFO-TGI sessions to lung-protective CMV on early/severe ARDS outcome.
We conducted a prospective clinical trial, subdivided into a first single-centre period and a second two-centre period. We enrolled 125 (first period, n=54) patients with arterial oxygen tension (Pa,O2)/inspiratory oxygen fraction (FI,O2) of <150 mmHg for >12 consecutive hours at an end-expiratory pressure of ≥8 cmH2O. Patients were randomly assigned to an HFO-TGI group (receiving HFO-TGI sessions with RMs, interspersed with lung-protective CMV; n=61) or CMV group (receiving lung-protective CMV and RMs; n=64). The primary outcome was survival to hospital discharge.
Pre-enrolment ventilation duration was variable. During days 1–10 post-randomisation, Pa,O2/FI,O2, oxygenation index, plateau pressure and respiratory compliance were improved in the HFO-TGI group versus the CMV group (p<0.001 for group×time). Within days 1–60, the HFO-TGI group had more ventilator-free days versus the CMV group (median (interquartile range) 31.0 (0.0–42.0) versus 0.0 (0.0–23.0) days; p<0.001), and more days without respiratory, circulatory, renal, coagulation and liver failure (p≤0.003). Survival to hospital discharge was higher in the HFO-TGI group versus the CMV group (38 (62.3%) out of 61 versus 23 (35.9%) out of 64 subjects; p=0.004).
Intermittent recruitment with HFO-TGI and RMs may improve survival in early/severe ARDS.
High-frequency oscillation (HFO) is suggested for adults with severe acute respiratory distress syndrome (ARDS) [1, 2]. During HFO, tidal volumes of <3.5 mL·kg−1 predicted body weight are administered at ≥3 Hz and mean airway pressure (P̄aw) ranges 22–40 cmH2O [1–3]. Animal lung injury data favour HFO over lung-protective conventional mechanical ventilation (CMV) [4]. The low HFO tidal volumes minimise volutrauma and the high HFO P̄aw limits atelectrauma [2, 5].
When combined with 40-s recruitment manoeuvres (RMs), HFO improves oxygenation versus lung-protective CMV, probably through lung recruitment [6–8]. The short-term addition of tracheal gas insufflation (TGI) to HFO may further improve oxygenation versus HFO without TGI and lung-protective CMV [7, 8]. TGI may promote lung recruitment by exerting a positive end-expiratory pressure (PEEP) effect and augmenting HFO-dependent distal gas mixing [7–10].
We reasoned that a lung-protective, CMV-based ventilatory strategy employing extended (i.e. ≥6 h) and repetitive (according to pre-specified criteria) recruitment sessions of HFO-TGI with RMs could result in a progressively sustained oxygenation improvement, with minimal concurrent risk of long-term HFO-TGI-related adverse effects [2, 7, 10]. This should enable rapid reduction of subsequent CMV pressures to noninjurious levels [11]. A reduced lung end-inspiratory stretch could attenuate ventilator-associated lung injury [12, 13] and improve outcome [14]. Thus, we compared the effect of two recruitment strategies during lung-protective CMV, namely HFO-TGI sessions with short-lasting RMs versus short-lasting RMs alone, on the survival of patients with early/severe ARDS.
METHODS
Patients
The study was approved by the Scientific Committees of Evaggelismos Hospital (Athens, Greece) and Larissa University Hospital (Larissa, Greece). Informed, written next-of-kin consent was obtained for patients fulfilling the eligibility criteria presented in eTable 1 of the online supplementary material. Patients had early (onset within ≤72 h) ARDS [15] and severe oxygenation disturbances: arterial oxygen tension (Pa,O2)/inspiratory oxygen fraction (FI,O2) <150 mmHg for >12 consecutive hours with a PEEP of ≥8 cmH2O; ARDS mortality increases at Pa,O2/FI,O2 <150 mmHg [16]. We employed deep sedation and intermittent neuromuscular blockade with cisatracurium [12]. The sedation/paralysis and weaning (from CMV) protocols are detailed in the online supplementary material.
Study design and randomisation
We conducted a prospective, randomised, unblinded, parallel-group controlled trial, temporally subdivided into a first single-centre and a second two-centre period for feasibility reasons (online supplementary material). The 37-bed intensive care unit (ICU) of Evaggelismos Hospital participated during both periods. The 10-bed ICU of Larissa hospital participated in the second period. Following consent, patients were allocated to the intervention (HFO-TGI) or control (CMV) group according to computer-generated odd and even random numbers, respectively.
The HFO-TGI group received recruitment sessions of HFO-TGI with RMs according to pre-specified oxygenation criteria. HFO-TGI sessions were interspersed with lung-protective CMV without RMs (table 1). The CMV group received lung-protective CMV and RMs for days 1–4 post-randomisation (table 1); the likelihood of sustained, RM-induced oxygenation improvement decreases and the risk of RM haemodynamic complications increases with CMV time [17]. In the HFO-TGI group, RMs were used after day 4 as part of the HFO-TGI protocol; RM-related oxygenation benefits are maintained when RMs are followed by HFO, even when HFO-time exceeds 4 days [6]. During days 1–4, minimum RM frequency was four per day in both groups. Figure 1 illustrates the study protocol.
Algorithmic representation of the study protocol. During high-frequency oscillation (HFO) tracheal gas insufflation (TGI), recruitment manoeuvres (RMs) were performed with TGI turned off and the tracheal tube cuff inflated. Target arterial oxygen saturation measured by pulse oximetry (Sp,O2) was >95% for all periods (see online supplementary material); at any period, an Sp,O2 of <88% for >5 min was the trigger for immediate transition to the additional recruitment algorithm, or to its next step if the desaturation occurred during its application. Note that any transition to the additional recruitment algorithm resulted in mean airway pressure (P̄aw) increase of ≥2 cmH2O, which had to be reversed after the subsequent transition to the stabilisation period. This resulted in extension of the stabilisation period by ≥1 h. CMV: conventional mechanical ventilation; Pa,O2: arterial oxygen tension; FI,O2: inspiratory oxygen fraction; CPAP: continuous positive airway pressure; iNO: inhaled nitric oxide; P̄tr: mean tracheal pressure; ΔP: oscillatory pressure amplitude; Pa,CO2: arterial carbon dioxide tension; I:E, inspiratory-to-expiratory time ratio; V′E: minute ventilation. #: temporal distance between any measurement and a preceding RM was ≥2 h. ¶: corresponds to the timing of the first set of daily physiological measurements performed during CMV, prior to HFO-TGI initiation; by design, these measurements were to be performed at 09:00 h unless the patient was already on HFO-TGI at that particular time (see online supplementary material). +: frequency and ΔP were adjusted to maintain an arterial blood pH of ≥7.20 by means of two consecutive arterial blood gas analyses performed within the first 30 min of the recruitment period. §: high-frequency ventilator FI,O2 was initially set at 100%; for further details regarding the management of FI,O2 see the Methods section. ƒ: corresponds to the timing of physiological measurements during the HFO-TGI session; in HFO-TGI sessions exceeding 6 h, one additional set of physiological measurements was obtained for every additional 2–4 h. ##: the corresponding, pre-specified management technique is presented in detail in the subsection “Additional features of the HFO-TGI protocol” of the eMethods in the online supplementary material; RMs were not performed at P̄aw >40 cmH2O; one RM was performed every 1–2 h during periods with P̄aw of 35–40 cmH2O. ¶¶: corresponds to the timing of physiological measurements performed during CMV, after weaning from TGI and HFO.
HFO-TGI recruitment protocol
HFO was provided using a 3100B high-frequency ventilator (Sensormedics, Yorba Linda, CA, USA). The goal of each HFO-TGI session was to increase Pa,O2/FI,O2 to >150 mmHg by using a high initial P̄aw (recruitment period), and then maintain the oxygenation benefit during a gradual P̄aw reduction to 6 cmH2O below its initial value (stabilisation period) and during weaning from TGI and HFO (weaning period). Additional protocol features are described in online supplementary material.
Recruitment period: initial setting of HFO P̄aw
A rigid-wall catheter (inner diameter 1.0 mm, outer diameter 2.0 mm) was introduced during CMV. In each patient, catheter length was tailored to catheter tip placement at 0.5–1.0 cm beyond tracheal tube tip. CMV mean tracheal pressure (P̄tr) was determined through the catheter with Direc218B (Raytech Instruments, Vancouver, Canada) over 3-min periods preceding transition to HFO. Patients were connected to the high-frequency ventilator and an RM was performed. Subsequently, a tracheal tube cuff-leak of 3–5 cmH2O was placed and P̄tr was re-measured. High-frequency ventilator-displayed P̄aw (HFO-P̄aw) was titrated to an HFO-P̄tr that exceeded preceding CMV-P̄tr by 3 cmH2O. This resulted in an average HFO-P̄aw of 8–9 cmH2O above the preceding average CMV-P̄aw, because the average high-inspiratory flow-related drop [8] in HFO-P̄aw along the tracheal tube was ∼6 cmH2O.
TGI initiation
Following setting of the initial HFO-P̄aw, the catheter was proximally connected to a variable-orifice oxygen flow meter providing pure, humidified oxygen at room temperature. Continuous, forward-thrust TGI was initiated through the catheter (TGI-flow 50% of preceding CMV minute ventilation [10]). TGI initiation caused a 1–2-cmH2O increase in HFO-P̄aw, which was reversed by adjusting the P̄aw valve [10].
Recruitment period duration
If, at 60–90 min after HFO-TGI initiation, Pa,O2/FI,O2 exceeded 150 mmHg, we proceeded to the stabilisation period. Otherwise, the additional recruitment algorithm was applied, and the recruitment period extended until Pa,O2/FI,O2 exceeded 150 mmHg and/or P̄aw reached 40 cmH2O (fig. 1). The high-frequency ventilator FI,O2 was kept at 100% throughout this period.
Stabilisation period: targeted HFO-P̄aw reduction
P̄aw was gradually reduced (rate 1–2 cmH2O·h−1) to 3 cmH2O below its initially set value. If Pa,O2/FI,O2 remained >150 mmHg, an RM was performed and P̄aw was decreased by another 3 cmH2O at 1–2 cmH2O·h−1. If Pa,O2/FI,O2 was still >150 mmHg, we proceeded to weaning period. Whenever these downward P̄aw titrations resulted in a Pa,O2/FI,O2 of <150 mmHg, the additional recruitment algorithm was followed (fig. 1). The pre-specified minimum duration of the stabilisation period was 240 min.
Ventilator FI,O2 was reduced to 80, 70 or 60% if the Pa,O2/ FI,O2 of the immediately preceding physiological measurement was 150–200, 200–300 or >300 mmHg, respectively. Prior to and during each subsequent physiological measurement, ventilator FI,O2 was set at 100% (for 20 min). This enabled precise determination of Pa,O2/FI,O2 during ongoing TGI.
Weaning period: discontinuation of TGI and HFO
An RM was performed and TGI was discontinued over 30 min; the associated HFO-P̄aw reduction of 1–2 cmH2O was reversed by adjusting the P̄aw valve. Patients were ventilated with standard HFO for a further 30 min and if Pa,O2/FI,O2 was >150 mmHg, they were returned to CMV. If Pa,O2/FI,O2 was <150 mmHg, patients were returned to the additional recruitment algorithm (fig. 1).
HFO-TGI session duration
The minimum time from HFO initiation to HFO termination was 6 h. Each transition to the additional recruitment algorithm (fig. 1) extended the session by ≥2–3 h. After every 12–24 h of HFO-TGI, a brief bronchoscopic inspection of the carina was performed to rule out TGI-induced tracheal mucosal damage.
Return to HFO-TGI
The criterion for return to HFO-TGI was Pa,O2/FI,O2 <150 mmHg sustained for >12 consecutive hours, while on CMV. Patients were assessed for return to HFO-TGI at 12 and 24 h after return to CMV, and then at the beginning of each day until day 10 post-randomisation.
Definitions
Definitions of organ/system failures according to a corresponding Sequential Organ Failure Assessment (SOFA) subscore ≥3 [18], infections and other complications are provided in the online supplementary material. Multiple organ failure (MOF) was defined as three or more concurrent organ/system failures [19].
Follow-up
Baseline patient data were recorded within 2 h pre-randomisation. Daily recordings included physiological/laboratory data (days 1–28 post-randomisation), intervention-associated complications (days 1–10; e.g. RM-induced hypotension or desaturation), mechanical ventilation-associated barotrauma (study-independent radiologists assessed chest radiographs for pathological gas collection(s), e.g. pneumothorax), data on organ/system failures and medication (days 1–60), episodes of failure to maintain unassisted breathing and various complications (until hospital-discharge or death; e.g. infections and heparin-induced thrombocytopenia). Investigators were unblinded to patient outcomes. Adherence to the protocol was overseen by the Data Monitoring Committee (see Acknowledgements section for details).
During days 1–10, sets of physiological measurements were obtained as follows. 1) CMV group: three measurements per day, starting at 09:00 h. 2) HFO-TGI group: just before, during and 6 h after HFO-TGI, and as in CMV group if no longer requiring HFO-TGI. Measurements included arterial/central-venous blood-gas analysis, haemodynamics and respiratory mechanics while on CMV [7, 12]. For between-group comparisons, we used CMV data obtained between 09:00 and 10:00 h in both groups.
Outcome measures
Primary
The primary outcome was survival to hospital-discharge, i.e. “patient discharged home, while breathing without assistance.”
Secondary
The secondary outcomes were: ventilator-free and organ/system failure-free days up to day 28 and 60, i.e. follow-up days within days 1–28 and 1–60, minus days on a ventilator or days with organ/system failure (for survivors, minimum follow-up was 60 days); mechanical ventilation-associated barotrauma; TGI-related tracheal mucosal injury; and evolution of oxygenation, plateau pressure and respiratory compliance during the period of HFO-TGI use.
Statistical analysis
Additional details are provided in the online supplementary material. According to the pilot cohort data, the predicted survival rate to hospital discharge was 66 and 40% for the HFO-TGI group and CMV group, respectively. For an α-value of 0.05 and a power of 0.80, a total sample size of 124 patients was required. Interim analyses were conducted at the completion of the follow-up of the 84th and 104th patient; stopping rules were p<0.001 for efficacy and p>0.1 for futility. All study personnel were masked from interim analyses results.
An intention-to-treat analysis was performed with SPSS version 12.0 (SPSS, Chicago, IL, USA) and SAS version 9.0 (SAS Institute, Cary, NC, USA). Data are reported as mean±sd, median (interquartile range) or n (%), unless otherwise specified. Dichotomous and categorical variables were compared using Fisher’s exact test. Continuous variables were compared using a two-tailed, independent-samples t-test or the Mann–Whitney exact U-test. The Bonferroni correction was used for multiple comparisons. For days 1–10, the effects of group, time and group×time on physiological variables were determined by mixed-model analysis. Survival was analysed with the Kaplan–Meier method, and survival data were compared by Fisher’s exact test and the log-rank test. Cox regression was used to determine independent predictors of death. The effect of centre was assessed by between-centre comparisons for study end-points. Reported p-values are two-sided. Significance was accepted at p<0.05.
RESULTS
The study was conducted from July 1, 2006 to September 29, 2007 (first period; n=54) and from March 10, 2008 to May 30, 2009 (second period; n=71). From 171 potentially eligible patients, 125 were randomised (HFO-TGI group, n=61; CMV group, n=64) and their data analysed (fig. 2). 16 (34.8%) out of the 46 excluded patients survived to hospital discharge.
Study flow chart. ARDS: acute respiratory distress syndrome; HFO: high-frequency oscillation; TGI: tracheal gas insufflation; RM: recruitment manoeuvre; CMV: conventional mechanical ventilation. #: definition provided in the footnote of eTable 1 in the online supplementary material; additional pre-specified exclusion criteria not met by anyone of the 171 potentially eligible patients were active air leak or recent severe air leak, obstructive or interstitial lung disease, lung surgery on current admission, pregnancy, and dependency on prone positioning or inhaled nitric oxide (eTable 1); the lower limits for age and body weight were 18 yrs and 40 kg, respectively. ¶: the patient was transferred to another hospital not participating in the study on day 31 post-randomisation; the data from this patient were included in the intention-to-treat analysis, assuming that he died, because at the time-point of transfer the patient was not discharged home and was not breathing without assistance (see the main text for the definition of “hospital discharge”).
Table 2 presents baseline characteristics. 85 (68.0%) patients (HFO-TGI group, n=40) had MOF. The HFO-TGI intervention period extended to day 10 post-randomisation. Table 3 presents data on daily HFO-TGI; session duration ranged 6.0–102.2 h.
Physiological variables during intervention period
Physiological variables during the intervention period are summarised in table 4. There were no significant between-group differences in haemodynamics, arterial blood lactate or haemodynamic support. Measures of oxygenation ((Pa,O2/FI,O2) and oxygenation index) and lung mechanics (plateau pressure and respiratory compliance) improved substantially over days 1–10 in the HFO-TGI group (table 4 and fig. 3a–d).
Data for a–d) major physiological variables, e) Sequential Organ Failure Assessment (SOFA) score and f) probability of achieving unassisted breathing for ≥48 h. a–d) Circles represent means of measurements obtained during conventional mechanical ventilation (CMV), within 2 h before randomisation (baseline (BL)) and between 09:00 and 10:00 h on days 1–10 post-randomisation. e) Circles represent the mean SOFA score at baseline and at the time-points of the aforementioned physiological measurements, and numbers represent surviving patients. One CMV group patient achieved unassisted breathing from day 6 onward. One, two, two and one high-frequency oscillation (HFO) tracheal gas insufflation (TGI) group patients achieved unassisted breathing from days 4, 7, 9 and 10 onward, respectively, and one and one HFO-TGI group patients achieved unassisted breathing for 72 h starting from day 9 and unassisted breathing solely during day 9, respectively (table 3). The significant between-group difference observed on days 9 and 10 was partly due to the more frequent development of post-randomisation multiple organ failure in the CMV group (see main text for details). a–e) Error bars represent sd. Summary results for a) arterial oxygen tension (Pa,O2)/inspiratory oxygen fraction (FI,O2), b) oxygenation index, c) plateau pressure, d) compliance and e) SOFA score are presented in table 4. Between-group (*) and within-group (#,¶,+) comparisons were subjected to the Bonferroni correction (see footnote of table 4 and the online supplementary material). *: p<0.05 versus CMV group at that particular time-point; #: p<0.05 versus baseline maintained from this point onward; ¶: p<0.05 versus baseline; +: p<0.05 versus day 2 maintained from this point onward. f) p<0.001 by log-rank test, which compares the probability of achieving unassisted breathing for ≥48 h within days 1–60 post-randomisation. Assignment to CMV group was an independent predictor of unassisted breathing for ≥48 h within days 1–60 (hazard ratio 0.37, 95% CI 0.22–0.61; p<0.001).
Response to HFO-TGI
Mean±sd pre-session Pa,O2/FI,O2 rose from 110.6±32.0 to 256.1±93.1 mmHg during the recruitment period (maximum duration 8.5 h). Oxygenation improvement was primarily due to the high P̄aw, RMs and TGI (fig. 1) [7, 8]. Subsequently, Pa,O2/FI,O2 fell to 221.0±82.3 mmHg (end of stabilisation period) and to 172.2±33.4 mmHg (weaning period, 30 min after TGI discontinuation; eFigure 5 in the online supplementary material). The initial P̄aw was reduced by 6 cmH2O within 5.5±0.6 and 16.3±14.4 h in 124 and 93 out of 223 HFO-TGI sessions, respectively. HFO-TGI resulted in significant improvements in post- versus pre-session oxygenation and lung mechanics, and did not affect haemodynamics or arterial carbon dioxide tension versus the preceding CMV (details provided in the text and eFigure 6 of the online supplementary material). Intervention failure (fig. 1) occurred in six sessions (online supplementary material).
Intervention-associated complications
On days 1–4, HFO-TGI group and CMV group patients received 4.7±3.5 and 4.7±1.5 RMs per day, respectively (p=0.79); RM abort rates due to hypotension or desaturation were ∼6% in both groups (online supplementary material). On days 5–10, 19 HFO-TGI group patients received 2.0±2.2 RMs per day and the RM abort rate was 16.5%; this exclusive RM use had no significant effect on study outcomes (online supplementary material). On HFO-TGI initiation, 10 (16.7%) patients experienced one RM-associated, major drop in systolic pressure to 75.1±5.4 mmHg (average drop 28.0±7.2%) and cardiac index to 2.4±0.6 L·min−1·m−2 (average drop 26.0±11.4%). In nine patients, haemodynamic status was restored within ≤10 min with fluids and vasopressors. In one patient, a chest tube was inserted for tension pneumothorax. Five patients (three of whom were in the HFO-TGI group) experienced one RM-associated, prolonged (duration 3–5 min) desaturation (maximum absolute drop in oxygen saturation 7–17%), which was reversed within ≤5 min after RM discontinuation. In one patient, day 10 bronchoscopy revealed a haemorrhagic posterior tracheal mucosa, suggesting TGI-induced mucosal damage (online supplementary material).
Clinical course data
On days 1–60, the HFO-TGI group had more ventilator-free days versus the CMV group (median (interquartile range) 31.0 (0.0–42.0) versus 0.0 (0.0–23.0) days; p<0.001), and more days without respiratory (46.0 (2.0–54.0) versus 5.0 (0.0–33.8) days; p=0.001), coagulation (60.0 (21.5–60.0) versus 17.0 (5.3–60.0) days; p=0.003), liver (60.0 (28.5–60.0) versus 24.5 (6.3–60.0) days; p=0.003), circulatory (43.0 (2.0–55.0) versus 6.5 (0.0–39.0) days; p=0.001), renal (60.0 (12.0–60.0) versus 15.5 (2.0–60.0) days; p=0.001) and nonpulmonary organ failure (29.0 (0.0–46.5) versus 0.0 (0.0–30.8) days; p=0.001); results were similar for days 1–28 (online supplementary material).
On days 1–10, SOFA score improved in the HFO-TGI group (table 4 and fig. 3e). On days 1–60, the HFO-TGI group had more follow-up days versus the CMV group (60.0 (28.5–60.0) versus 24.5 (7.0–60.0) days; p=0.001), lower proportions of follow-up days with MOF (11.7% (1.7–69.1%) versus 51.0% (11.3–100.0%); p=0.002), less frequent MOF occurrence in patients without MOF at baseline (seven (33.3%) out of 21 versus 15 (78.9%) out of 19 subjects; p=0.005) (respective times of occurrence mean±sd 4.7±5.1 versus 8.5±6.6 days post-randomisation; p=0.20), similar absolute number of days on ventilator (20.1±13.3 versus 20.4±15.9 days; p=0.90), and more patients (42 (68.9%) out of 61 versus 26 (40.6%) out of 64 patients; p=0.002) achieving unassisted breathing for ≥48 h (i.e. successful weaning) in a shorter time (21.4±10.0 versus 30.9±12.8 days; p=0.001) (fig. 3f).
Throughout the study period, the HFO-TGI group, versus the CMV group, had 24.3±20.9 versus 22.3±20.0 total days on a ventilator (p=0.60) and 35.0 (18.0–61.5) versus 21.0 (7.0–57.3) total days of in-hospital follow-up (p=0.07). The HFO-TGI group had comparable percentages of patients with an occurrence of barotrauma as a new pneumothorax versus the CMV group (six (9.8%) out of 61 versus nine (14.1%) out of 61 patients; p=0.59), and one or more episodes of ventilator-associated pneumonia (VAP) (49.2% versus 50.0%; p>0.99), catheter-related bacteraemia (21.3% versus 18.8%; p=0.82), Gram-negative sepsis (59.0% versus 48.4%; p=0.28), renal (32.8% versus 37.5%; p=0.71), coagulation (24.6% versus 26.6%; p=0.84), hepatic (9.8% versus 9.4%; p>0.99) and neurological failure (52.5% versus 46.9%; p=0.59), heparin-induced thrombocytopenia (16.4% versus 18.8%; p=0.82), failure to maintain unassisted breathing (47.5% versus 32.8%; p=0.10), and paresis (18.0% versus 15.6%; p=0.81). VAP occurrence was not a predictor of successful weaning but prolonged the mean time to its achievement by ∼8–9 days in both groups (online supplementary material). Further details on complications, and data on administered medication and rescue oxygenation (used in six (9.4%) out of 64 CMV group patients) are provided in the online supplementary material.
On days 1–28, CMV protocol violations corresponded to 6.3% versus 3.8% of the follow-up time in the HFO-TGI group and CMV group, respectively (p=0.004). The HFO-TGI algorithm was applied without deviation in 202 (90.1%) sessions. The CMV group RM protocol was accurately applied in 98.8% of the corresponding patient-days. There was no between-group crossover. Study centre did not affect study outcomes (data not shown).
Survival
Survival to hospital discharge was higher in the HFO-TGI group versus the CMV group (38 (62.3%) out of 61 versus 23 (35.9%) out of 64 patients; p=0.004 by Fisher’s exact test) (figure 4). There was no significant between-group difference in the ICU and hospital stays of survivors and nonsurvivors (table 5), or the survival of patients with pulmonary contusion-associated ARDS (HFO-TGI group versus CMV group: 13 (59.1%) out of 22 versus eight (66.7%) out of 12 patients; p=0.72) (online supplementary material). Death attributable to MOF [19] was less frequent in the HFO-TGI group versus the CMV group (eight (13.1%) out of 61 versus 22 (34.4%) out of 64 patients; p=0.006) (online supplementary material). Independent predictors of in-hospital mortality included assignment to the CMV group (hazard ratio (HR) 2.64, 95% CI 1.51–4.61; p=0.001), baseline arterial blood lactate (HR 1.16, 95% CI 1.06–1.28; p=0.002) and baseline Simplified Acute Physiology Score (SAPS) II (HR 1.04, 95% CI 1.00–1.06; p=0.003).
Survival to hospital discharge. p=0.002 by log-rank test; p=0.004 by Fisher’s exact test. HFO: high-frequency oscillation; TGI: tracheal gas insufflation; CMV; conventional mechanical ventilation. #: p=0.002 by Fisher’s exact test for 28-day survival. ¶: p=0.001 by Fisher’s exact test for 60-day survival. +: for patients with hospital stays of ≥60 days, follow-up was terminated at the time-point of hospital discharge; the actual range of hospital stay was 17–137 days; patients discharged before day 60 (HFO-TGI group, n=25; CMV group, n=11) were followed as outpatients until day 60; the surviving status of all 61 discharged patients at 150 days post-randomisation was reconfirmed through telephone communication.
DISCUSSION
We showed an increased efficacy of intermittent HFO-TGI recruitment sessions in early (exhibiting high likelihood of lung recruitability) and severe ARDS. During the recruitment period, the 2.3-fold average Pa,O2/FI,O2 rise was consistent with enhanced lung recruitment [6–10, 20]. This enabled reduction of the initial respiratory system distending pressure by 6 cmH2O (stabilisation period), with maintenance of ∼85% of the oxygenation benefit. The evolution of compliance (fig. 3d) suggests progressive increase in aerated lung volume [20], which explains the concurrent plateau-pressure reduction (fig. 3c). These changes imply prompt inhibition of the injurious mechanical stresses to the lung [13, 21], leading to prevention of biotrauma-associated organ injury [21] and improved survival.
In the CMV group, the absence of physiological improvements (fig. 3a–d) was associated with prolonged and multiple organ dysfunction during follow-up and a long-term mortality of 64.1% [19]. In a recent multicentre study [22], ARDS patients with similar baseline SAPS II scores and oxygenation disturbances had similar evolution of their respiratory variables and SOFA scores during early follow-up, and a long-term mortality of 63.2%.
Previous trials evaluated continuous HFO [23, 24], prone positioning [22, 25, 26] and high PEEP with/without RMs [27–29]. Positive findings comprised improved oxygenation [22, 24–29], improved respiratory mechanics [26, 27, 29], lower rates of refractory hypoxaemia [28, 29], and more ventilator-free and organ failure-free days [29]. However, results on mortality were inconclusive. In contrast, our results on both physiology and outcome favour intermittent recruitment with HFO-TGI and RMs. This suggests improved lung protection throughout the early phase of ARDS through a more effective method of periodic lung recruitment.
We compared a recruitment strategy of combined HFO, TGI and short-lasting RMs to short-lasting RMs alone during lung-protective CMV. Theoretically, longer-lasting RMs could have produced different results. However, the best way to perform RMs still remains undetermined. Also, TGI usefulness is still unproven, and similar outcome results might have been obtained with an HFO-RM recruitment protocol. Nevertheless, three physiological studies suggest a TGI-related, gas-exchange and/or lower lung recruitment benefit [7, 8, 30]. Furthermore, the present study’s potentially nonprotective HFO settings may augment lung base recruitment [8, 30].
During days 1–10, the study protocol was applied by subgroups of two investigators assigned to each patient of each group on a rotating 12-h basis. There was tighter tidal volume control (table 4) and accurate RM protocol application in the CMV group. Medical treatment (including sedation/paralysis) was similar in both groups (online supplementary material). Notable, but promptly/effectively treated, complications occurred in 13 (5.8%) out of the 223 HFO-TGI sessions (see Results section).
Limitations
Our sample size was relatively small, but the study was adequately powered to detect a substantial survival benefit. The study design was unblinded and the results originate from just two centres, thus warranting further multicentre confirmation. Also, the study was conducted over two periods, primarily for feasibility reasons (online supplementary material). Lastly, although the high CMV group mortality and small number of ventilator-free days may be justifiable by disease severity, a selection bias in favour of the HFO-TGI group cannot be totally excluded.
Another limitation was the lack of measurement of pro-inflammatory cytokines during the intervention period. However, the causal link among persistence of ARDS, systemic inflammation and development of multiple organ dysfunction/MOF is well-established [31]. Furthermore, our physiological and SOFA score results (fig. 3) are consistent with this sequence of events occurring more frequently in the CMV group, with a consequent increase in the probability of death [19].
Pre-enrolment duration of mechanical ventilation (DMV) was variable (table 2), with a potentially unpredictable impact on patient outcomes [30, 32]. Indeed, although pre-enrolment DMV exceeded 7 days [33] in just 12 (9.6%) patients (eight in the HFO-TGI group), the results of a recent multicentre trial imply that any difference in the overall management strategy of early ARDS might affect results for mortality [34].
Conclusions
Our two-centre results suggest that in early/severe ARDS, the addition of recruitment sessions of HFO-TGI with RMs to lung-protective CMV may improve survival to hospital discharge. This is supported by the associated improvements in respiratory physiology, ventilator-free days and nonpulmonary organ function.
Acknowledgments
First study period results (www.clinicaltrials.gov identifier NCT00416260) were presented in part at 1) the 11th State-of-the-Art Interdisciplinary Review Course (Athens, Greece; April 20–22, 2007), and 2) the 20th (Berlin, Germany; 2007) and 22nd (Vienna, Austria; 2009) annual congresses of the European Society of Intensive Care Medicine [35, 36]. Also, a lecture based on the aforementioned results was given at the 2008 International Symposium on Intensive Care and Emergency Medicine in Brussels, Belgium. The results of the first period have also been summarised in a recently published meta-analysis [37]. The Study Protocol can be accessed at the official website of the Scientific Society of Evaggelismos Hospital [38].
The Study Chairpersons were S.D. Mentzelopoulos (principal investigator), S. Malachias (principal investigator), S.G. Zakynthinos (study director), C. Roussos (study chair) and E. Zakynthinos (collaborating centre principal investigator). The members of the Independent Main Endpoint and Safety Monitoring Committee were P. Politis, E. Stamataki and Z. Mastora (all Evaggelismos Hospital), and Z. Daniil (Larissa University Hospital). Overall study and data quality assurance was performed by P. Politis, E. Stamataki, Z. Mastora and Z. Daniil.
We wish to thank to P. Zygoulis for his assistance with the study protocol and patient follow-up at Larissa University hospital. We also wish to thank M. Tzoufi (Dept of Intensive Care Medicine, Evaggelismos Hospital, Athens, Greece) for her assistance in the analyses and presentation of the study results. The representative of Sensormedics in Greece is Meditrust A.E.
Footnotes
This article has supplementary material available from www.erj.ersjournals.com
Clinical Trial
This study is registered at www.clinicaltrials.gov with identifier numbers NCT00416260 (first period) and NCT00637507 (second period).
Support Statement
This study was funded by the Thorax Foundation (Athens, Greece; www.thorax-foundation.gr) and the Project “Synergasia” (Cooperation) of the Greek Ministry of Education (09ΣYΝ-12-1075).
Statement of Interest
None declared.
- Received October 10, 2010.
- Accepted August 15, 2011.
- ©ERS 2012
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