1
ON LINE SUPPLEMENT FOR
INTERMITTENT RECRUITMENT WITH HIGH-FREQUENCY
OSCILLATION/TRACHEAL GAS INSUFFLATION IN ARDS
AUTHORS: Spyros D. Mentzelopoulos, MD, PhD,
Sotiris Malachias, MD, Elias Zintzaras, PhD,
Stelios Kokkoris, MD, Epaminondas Zakynthinos, MD, PhD,
Dimosthenis Makris, MD, PhD, Eleni Magira, MD, PhD,
Vassiliki Markaki, MD, Charis Roussos, MD, PhD,
Spyros G. Zakynthinos, MD, PhD
2 eMETHODS Patients The major inclusion criterion was early ARDS [1] (i.e. diagnosis established within the preceding 72 hours) and severe oxygenation disturbances {i.e. PaO2/FiO2<150 mmHg for >12 consecutive hours with positive end-expiratory pressure (PEEP)≥8 cmH2O}. Full eligibility criteria are presented in eTable 1. For eligible patients, written next-of-kin consent for study enrollment was requested. Participating patients were informed of the study and their right to withdraw, as soon as clinically feasible. Patient monitoring included electrocardiographic lead II, hemodynamics {continuous intraarterial and central-venous pressure, and cardiac output/index by pulse-induced contour cardiac output (PiCCO)-plus (Pulsion Medical Systems, Munich, Germany)}, and peripheral oxygen saturation (SpO2). Sedation, and neuromuscular blockade Deep sedation (i.e. Ramsay sedation score=6) [2,3] with propofol (Diprivan; AstraZeneca, Halandri, Attica, Greece) and/or midazolam (Dormicum; Roche Hellas, S. A., Maroussi, Attica, Greece), analgesia [3] with fentanyl (Fentanyl; Janssen-Cilag Pharmaceutical, S. A. C. I., Athens, Greece) and/or remifentanil (Ultiva; Abbott Laboratories, Athens, Greece), and intermittent neuromuscular blockade [2,4] with cisatracurium (Nimbex, GlaxoSmithKline, Halandri, Attica, Greece) were used. eFigure 1 illustrates the protocolized management of sedation and neuromuscular blockade. In essence, this protocol constitutes an adaptation of recent guidelines [3,4] for ARDS, and reflects mainly standard intensive care practice in both study centers. It was expected that on study enrollment, severe ARDS patients would have been already deeply sedated and/or paralyzed by their attending physicians. This corresponds to the first and second “YES” options of eFigure 1. Nevertheless, in eFigure 1, we present the total of the options of the sedation/paralysis protocol. The pre-enrollment application of this clinically adopted sedation/paralysis protocol was in concordance with the indication of facilitating the achievement and maintainance the gas-exchange and plateau pressure targets of our clinically standardized, lung- protective conventional mechanical ventilation (CMV) strategy (see also Table 1 of main manuscript). Gas-exchange targets were PaO2=60-80 mmHg or SpO2=90-95%, and arterial pH (pHa)=7.20-7.45 (to be achieved through ventilatory control of PaCO2). Target end-inspiratory plateau pressure was 30 cmH2O. Besides the achievement and maintenance of the CMV gas-exchange/plateau pressure targets, the main indication for starting a continuous infusion of cisatracurium was the presence of patient-ventilator dyssynchrony. Dyssynchrony was defined as patient spontaneous breathing efforts resulting in periodic increases of ≥5 cmH2O in CMV peak pressures [4,5]. These peak pressure changes were referred to the peak pressures of preceding and/or subsequent mandatory breaths with no detectable patient breathing effort on ventilator screen-displayed pressure and flow waveforms; there were 7 study-dedicated, screen-equipped, conventional ventilators [either Siemens 300C (Siemens, Berlin, Germany), or Galileo Gold ventilator (Hamilton Medical, Bonaduz, Switzerland]. Just prior to a scheduled set of physiological measurements (see Methods of main manuscript), an extra bolus of 0.1- 0.2 mg/kg of cisatracurium was also given to deeply sedated patients who triggered CMV breaths without causing dyssynchrony. During the sessions of high frequency oscillation (HFO) and tracheal gas insufflation (TGI), we elected to use continuous neuromuscular blockade, in order to minimize the probability of spontaneous breathing efforts interfering with the lung- recruiting effectiveness of the HFO-TGI algorithm (see also below and Figure 1 and 3
Methods of main manuscript). However, after each HFO-TGI session, the infusion of cisatracurium was to be stopped (at least temporarily), in order to assess the need for its continued use [2,4]. The need for paralysis was also clinically assessed [5] on a daily basis in all CMV group patients and in HFO-TGI group patients no longer requiring HFO-TGI. Cisatracurium was considered as "unnecessary" if CMV gas-exchange/plateau pressure targets were achievable and dyssynchrony was absent for 60 min after the onset of the daily assessment. This assessment was undertaken by the attending physicians, and was started within ~30 min after the interruption of an infusion or the administration of a bolus (see also above) of cisatracurium. In patients achieving PaO2/FiO2>150 mmHg at PEEP8 cmH2O for >12 consecutive hours, the infusions of sedatives and/or analgesics were stopped on a daily basis to assess the need for their continued use {eFigure 1 [3]}. According to our standard clinical practice, additional criteria for the interruption of sedation and/or analgesia included absence of significant use of vasopressors/inotropes (i.e. norepinehrine >0.1 μg/kg/min and/or dobutamine >5μg/kg/min), intracranial pressure >15 mmHg, any evidence for acute myocardial ischemia, and clinically obvious factors mandating pain control {refers to opioid infusions in cases of trauma or surgery within the preceding 48-72 hours, or invasive procedure(s) such as tracheostomy within the preceding 12-24 hours}. After sedation interruption, a bolus of midazolam (0.1-0.2 mg/kg) or propofol (0.5-1.0 mg/kg) could be given just prior to a scheduled assessment of respiratory mechanics (see also Methods of main manuscript), provided that patients were still on CMV (eFigure 1). Following a daily interruption, attending physicians restarted the sedation in case of 1) patient agitation or restlessness (i.e. Ramsay score=1); and/or 2) respiratory rate increase to >40/min for >30 min due to patient-triggered breaths; and/or 3) patient- ventilator dyssynchrony, with or without failure to achieve the CMV gas-exchange targets (see above) at the current ventilatory settings. In such cases, sedation was retitrated to a Ramsay score of 2-4. The daily interruptions and retitrations of the sedatives were continued until patients fulfilled the criteria for partial ventilatory support (see below). Any administered sedation was to be stopped before the initiation of the weaning protocol (see below). Weaning from mechanical ventilation In both groups, weaning from CMV was initiated according to the concurrent fullfilment of objective criteria indicating 1) "some reversal" of the underlying cause of the respiratory failure [6], i.e., maintenance of a PaO2 of >60 mmHg at an FiO2 of ≤50% and a PEEP of <8 cmH2O; 2) absence of any significant respiratory acidosis, i.e., pHa>7.30, or electrolyte imbalance [6]; 3) hemodynamic stability [6], i.e., mean arterial pressure>70 mm Hg without using vasopressors (see also below); 4) no clinical or laboratory evidence for any new septic complication, i.e., hospital-acquired infection with systemic manifestations [7-10]; 5) a hemoglobin level of >6.5 g/dL, which is close to the 7.0 g/dL threshold for transfusion used in the context of a restricted transfusion strategy [11] adopted by both participating centers; and 6) patient sedation status compatible with adequate mentation [6], i.e., discontinuation of sedation for 24 hours before the initation of the weaning protocol, or discontinuation of sedation within the preceding 24 hours and Ramsay sedation score of 2-3. eFigure 2 illustrates the weaning algorithm applied in both groups by the attending investigators. The weaning procedure comprised the use of pressure-supported ventilation (PSV) with an initial PSV level of 20 cmH2O above PEEP and a PEEP level of 5 cmH2O (Step I). This PEEP level was maintained throughout the PSV 4 period. If the patients tolerated the initial PSV level for 60 min, the PSV level was reduced by 2.5-5.0 cmH2O/h until it reached 10 cmH2O (Step II). If the latter PSV level could be tolerated for 60 min (Step III), patients were disconnected from the ventilator for a spontaneous breathing trial (SBT) of 60 min (Step IV). If all four steps were successful, orotracheally intubated patients were extubated and trachesostomized patients remained disconnected from the ventilator and scheduled for tracheostomy closure. A recent multicenter trial employed a similar algorithm of decremental PSV- level followed by an SBT [12]. Weaning procedure steps were deemed as successful according to the concurrent fullfilment of the following objective criteria of patient tolerance: 1) stable ventilatory pattern [6], i.e., a respiratory rate of <35 breaths/min; 2) cardiovascular stability [6], i.e., a heart rate of <140 beats/min and a systolic arterial pressure of >90 mmHg and <180 mmHg; and 3) gas-exchange acceptability [6], i.e., an SpO2 of >90%. In case of patient intolerance at any of the aforementioned algorithmic steps, the weaning procedure was considered as unsuccessful. Subsequently and according to attending physician preference, patients were returned either to the preceding, volume assist/control CMV, or the 20-cmH2O PSV level for 12-24 hours. During this period, potentially reversible causes of weaning failure were to be identified and treated [6]. The weaning procedure was to be repeated on the next day [13], provided that patients still fullfiled the criteria for its initiation. Additional features of the protocolized use of recruitment maneuvers (RMs) RMs {continuous-positive airway pressure of 45 cmH2O for 40 s at an FiO2 of
100%; patient pre-oxygenated at an FiO2 of 100% for ≥5 min [14]} were performed during CMV and sessions of HFO-TGI in patients with a systolic blood pressure of 100-200 mmHg and a heart rate of 70-140 beats/min [15], and a pulse-pressure variation of <15% [16]. In case of hypotension (systolic or mean arterial pressure <90 or <60 mmHg, respectively) or desaturation (SpO2≤85% or absolute SpO2-decrease exceeding 5%), RMs were aborted and withheld for 12 hours. Hypotension lasting for >1 min was to be treated with a 300-500-mL bolus of crystalloid and/or norepinephrine. The pre-specified duration of the RM protocols of both groups is reported in the text, Figure 1, and footnote of Table 1 of the main manuscript. Additional RMs were to be performed after suction procedures in both groups. The pre-RM use of 100% FiO2 was aimed at minimizing the potential risk of hypoxemia during the subsequent RM [14,15]. Potential nonresponders to RMs [17] secondary to low lung recruitability during high PEEP application [18,19; Tables 1 and 4 of main manuscript] and/or collapsed lung tissue opening pressures of >45 cmH2O could experience mainly overdistention of aerated lung regions during an RM, with consequent adverse cardiorespiratory effects [20]. Arguably, the employed pre-oxygenation could have also predisposed to resorption atelectasis. At 100% FiO2, atelectasis develops within 5 min when no PEEP is used [21]. However, this potential risk was minimized by the present study’s concurrent high PEEP application, which prevents the pure oxygen-associated derecruitment [22]. Furthermore, the FiO2 was always re-decreased to its original level preceding the pre-oxygenation maneuver within 1 min after non-aborted RMs. Additional features of the HFO-TGI recruitment protocol The algorithmic interventions of the HFO-TGI protocol are illustrated in Figure 1 and described in the Methods section of the main manuscript. Termination of recruitment period. The recruitment period could last from 60 min to several hours, depending on whether it was extended by the use of the "Additional Recruitment Algorithm." The reason for such extension was a PaO2/FiO2 of <150 5 mmHg within 60-90 min of HFO-TGI initiation. For example, after 60 min of HFO- TGI with an initial mean airway pressure (mPaw) of 28 mmHg, physiological measurements are performed and PaO2/FiO2 remains below 150 mmHg. An RM is performed and mPaw is increased by 2 cmH2O, but PaO2/FiO2 is still <150 mmHg after another 60 min (step 1 of the "Additional Recruitment Algorithm"). Finally, PaO2/FiO2 exceeds 150 mmHg after another 5 consecutive steps of the "Additional Recruitment Algorithm". This corresponds to an "Additional Recruitment Algorithm" time of 6 hours, a mPaw rise to 40 cmH2O, and a recruitment period of 1.0 + 6.0=7.0 hours. Study Intervention Failure. If at 60 min after the setting of mPaw at 40 cmH2O, PaO2/FiO2 were still below 150 mmHg, the HFO-TGI session was to be considered as a "Study Intervention Failure." If PaO2/FiO2 were ≥60 mmHg, the HFO-TGI settings were to be maintained unchanged until PaO2/FiO2 exceeded 150 mmHg. The latter would result in transition to the stabilization period (eFigure 3). In contrast, a PaO2/FiO2 of <60 mmHg would trigger further algorithmic titration of mPaw to the highest achievable PaO2/FiO2, and consideration of additional interventions [i.e., prone positioning and inhaled nitric oxide (eFigure 3)]. One or both of these interventions could be combined with HFO-TGI. Alternatively, these interventions could be preceded by a trial of standard HFO (i.e. HFO without TGI); in the case of improvement in PaO2/FiO2 with standard HFO vs. HFO-TGI, the additional interventions were to be combined with standard HFO. An arterial blood gas analysis was to be performed at 30 min after every change in high-frequency ventilator mPaw, or use of TGI, or use of an additional intervention. For the case of "Study Intervention Failure," all the pre-specified, possible actions were aimed at ultimately achieving return to the study protocol (eFigure 3). The latter actions did not include RMs, as long as mPaw exceeded 40 cmH2O. However, RMs were to be performed when mPaw was ≤40 cmH2O (eFigure 3). TGI and FiO2. Following study enrollment, orotracheal tubes were cut-down to 25- 26 cm. During HFO-TGI sessions, continuous, forward-thrust TGI was administered through a rigid-wall catheter (Vygon, Ecouen, France; inner diameter=1.0 mm, outer diameter=2.0 mm) passed through the angled side-arm of a 4.8-cm long circuit adapter {Smiths Medical International, Watford, UK (eFigures 4A and 4B)}. Adhesive tape was placed around the proximal ends of the TGI catheter and the side- arm of the adapter, in order to minimize any potential, independent oscillatory motion of the TGI catheter relative to the tracheal tube (eFigure 4B). The length of the TGI- catheter was tailored to the placement of its tip at 0.5-1.0 cm beyond the tip of the tracheal tube [23]. Before clinical use, the positioning of the tip of the TGI-catheter was tested in vitro in an identical tracheal tube [23-27]. This was done on a case-by- case basis for each one of the HFO-TGI group patients. Furthermore, during laboratory testing of HFO-TGI performed in the context of a prior physiological study [23], we confirmed that at all possible combinations of oscillation frequencies of 3, 4, 5, 6, and 7 Hz and oscillatory pressure amplitudes of 60, 70, 80, 90, and 100 cmH2O, there was no visually identifiable change in the positioning of the tip of the TGI catheter relative to the inner wall of the distal end of the tracheal tube. This was reconfirmed in laboratory measurements of tracheal tube resistance performed in the context of a recent physiological study [27]. eFigure 4C displays an example of laboratory evaluation of the positioning of the TGI catheter tip during HFO-TGI. During HFO-TGI sessions, the TGI-catheter was proximally connected to a variable-orifice O2 flowmeter (eFigure 4A), which provided pure, humidified O2 at room temperature. TGI-flow was set at 50% of the minute ventilation of the preceding 6
CMV [23]. Throughout the recruitment period, during the 15-min periods [28] preceding the physiological measurements of the stabilization period (Figure 1 of main manuscript), and during the 5-6-min periods of the latter measurements (and any subsequent RMs), high-frequency ventilator FiO2 was set at 100% [29] (i.e. computed PaO2/FiO2=PaO2). During the rest of each session (Figure 1 of main manuscript), ventilator-FiO2 was reduced to 80%, 70%, and 60%, if the PaO2 of the immediately preceding physiologic measurement was 150-200, 200-300, and >300 mmHg, respectively. After the FiO2 adjustment, the SpO2 had to be maintained >95% for ≥15 min [28], in order to allow for the subsequent reduction of mPaw according to the study protocol (Figure 1 and Methods of main manuscript). Determinations of mean tracheal pressure. Mean tracheal pressure was measured via the TGI catheter with Direc218B software (Raytech Instruments, Vancouver, Canada; pressure transducer specifications: DCXL01DN ultra low pressure sensors, Honeywell, Columbus, Ohio, USA) during 3-min periods that 1) preceded the transition from CMV to HFO; 2) followed the placement of the tracheal tube cuff leak (at the start of the recruitment period of the HFO-TGI sessions, prior to TGI initiation); and 3) followed TGI discontinuation in the weaning period of the HFO- TGI sessions, while patients were receiving standard HFO (Figure 1 and Methods of main manuscript). During the aforementioned 3-min-lasting measurements, readouts of mean tracheal pressure were continuously displayed on a personal computer- screen; readout-values were recorded every 10-15 s for 2-min periods and averaged. Patient safety. During HFO-TGI sessions, we were vigilant for potential HFO-TGI- associated complications [30-33]. Any drop in cardiac output/index of >10% [34] for ≥5 min was treated with 300-500 mL of normal saline and/or upward titration of norepinephrine infusion. Brief fiberoptic endoscopy was performed by a study- independent physician after every 12-24 hours of HFO-TGI to rule out tracheal mucosal damage [23,26], and verify the correct positioning of the tracheal tubes. This procedure lasted <1 min. In HFO-TGI sessions lasting ≤24 hours, the procedure was performed during standard HFO, just prior to the return to CMV, and just after confirming that PaO2/FiO2 was >150 mmHg (Figure 1 of main manuscript). In HFO- TGI sessions exceeding 24 hours, the procedure was carried out every 24 hours during a brief (i.e. <1 min) discontinuation of TGI, provided that PaO2/FiO2 was >150 mmHg. Potential bronchoscopic findings comprising a hemorrhagic tracheal mucosa and/or presence of thrombotic material within the lower trachea or at the orifices of the main bronchi (Grade IIIA), or localized necrosis and/or presence of necrotic slough within the lower trachea (Grade IIIB and Grade IIIC) were to be considered as suggestive of TGI-related mucosal damage. This was to cancel any further use of TGI. A detailed presentation of the pre-specified grading of the potential bronchoscopic findings is provided in eTable 2. In case of Grade III findings, solely standard HFO was to be used instead of HFO-TGI during any remaining time of the study intervention period (i.e. the period of use of intermittent recruitment with HFO-TGI). TGI-catheters were discarded after 6 hours of use. Definitions Study-intervention period: the number of days of HFO-TGI use following randomization; Study intervention failure: inability to achieve PaO2/FiO2>150 mmHg during HFO-TGI after raising mPaw to 40 cmH2O for 1 hour (Figure 1 of main manuscript); Study protocol-related complication: any complication associated with a pre-specified, study protocol intervention (example: bronchoscopic evidence of TGI- related tracheal mucosal damage); RM-associated hypotension: RM-induced drop in systolic or mean arterial pressure to <90 or <60 mmHg, respectively; RM-associated 7
desaturation: RM-induced drop in SpO2 to ≤85% or absolute SpO2-decrease exceeding 5%); Refractory hypoxemia: sustained (i.e. for 60 min) drop of PaO2/FiO2 to <50 mmHg, not responsive to rescue oxygenation interventions; Ventilator-free: breathing without assistance for ≥48 consecutive hours; Weaning-failure: inability to maintain unassisted breathing for at least 48 consecutive hours; Recurrence of ventilatory failure: any inability to maintain unassisted breathing throughout post- randomization hospital stay; Circulatory failure: inability to maintain mean arterial pressure>70 mm Hg without using vasopressors [35] after volume loading [8]; Respiratory failure: PaO2/FiO2<200 mmHg [35]; Coagulation failure: platelet count≤50x103/μL (50x109/L) [35]; Hepatic failure: serum bilirubin≥6mg/dL (102.6 μmol/L) [35]; Renal failure: serum creatinine≥3.5mg/dL (309.4 μmol/L) [35] and/or requirement of renal-replacement therapy; Neurologic failure: Glasgow Coma Score≤9 [35], without sedation; Multiple organ failure (MOF): ≥3 concurrent organ/system failures; Barotrauma: any new pneumothorax, pneumomediastinum, or subcutaneous emphysema, or pneumatocele of >2 cm; Sepsis and infections were defined according to standard criteria [7-10]; Paresis: inability for muscular movement against a slight resistance. Rescue oxygenation therapies For the CMV group, the criteria for the implementation of rescue therapies were a PaO2/FiO2 of 50 to 60 mmHg for ≥60 min or a PaO2/FiO2 of <50 mmHg for ≥15 min, not associated with a "promptly reversible" factor (e.g. pneumothorax, malpositioning or obstruction of the tracheal tube, or ventilator malfunction). Available options included standard HFO, prone positioning, and inhaled nitric oxide. Decisions concerning the selection of rescue therapies were made by the attending physicians. Furthermore, in both centers, a consensus was reached between the ICU physicians and the investigators that weaning from the rescue therapy would be attempted on the achievement of a PaO2/FiO2 of >100 mmHg. This issue was addressed separately in each one of the 2 participating centers before the initiation of patient enrollment.
ADDITIONAL STUDY DESIGN AND STATISTICAL DETAILS Apriori design for two study periods After considering the minimum number of investigators required for study conduct and the actual, projected investigator availability, we decided to conduct the trial in 2 periods: a single-center first period [36] of 50-54 patients (average estimate=52 patients), starting on July 2006 and having a projected duration of 12-13 months; and a two-center final period of at least 70 patients, starting on March 2008 and having a projected duration of 14-15 months. The Evaggelismos Scientific Committee approved the first period of the trial on May 30, 2006 and the second period of the trial on September 19, 2007 (i.e. before actual completion date of the first period, which occurred on September 29, 2007). The Scientific Committee of the Larissa hospital approved the trial on June 6, 2008. Regarding Evaggelismos, both trial periods were planned apriori as integral parts of a single study ultimately aimed at assessing in-hospital mortality. In both periods, the applied methodology was identical and the principal investigators were the same. The study was interrupted for approximately 5.5 months mainly because of a temporary manpower inadequacy, and the sole between-period difference was the participation of a second center. Accordingly, in the analysis of our results, we addressed the effect of center by means 8 of between-center comparisons for all the pre-specified outcome measures. Methodology of important, specific analyses Physiological variables and sequential organ failure assessment (SOFA) score during days 1-10. We used linear mixed-model analysis to determine the effects of group, time, and grouptime, on the physiological variables, the hemodynamic support, and the patient daily SOFA scores. We analyzed data obtained through measurements performed during CMV at baseline (i.e. within 2 hours before randomization) and in the morning (i.e. within 9:00-10:00 a.m.) of each one of the days of the HFO-TGI recruitment intervention (i.e. days 1-10 post-randomization). For the HFO-TGI group, we substituted morning CMV data missing due to a "poor response to HFO-TGI" {i.e. CMV data missing because patients required prolonged HFO-TGI session(s) of >12 hours according to study protocol} by using the "last value carried forward" method [37]. For both groups, we did not substitute data missing due to patient death, or data missing because patients were on partial ventilatory support or breathing spontaneously, or data "missing at random" [37]; in Table 4 of the main manuscript, we report the total of the missing observations for each one of the aforementioned variables as percentage of the maximum possible HFO-GI group (n=671) and CMV group (n=704) morning observations of days 1-10. We also assessed the effect of center on PaO2/FiO2, oxygenation index, plateau pressure, respiratory compliance, and SOFA score. We analyzed the data by fitting a linear model using the PROC MIXED procedure in the Statistical Analysis System (SAS) version 9.0 (SAS Institute Inc., Cary, North Carolina, USA). The variable “time” was considered as repeated effect. The model included as explanatory terms the intervention, the time, their interaction and the center. The center was declared as random effect. We assumed an unstructured covariance model, i.e., non-equal variances across time periods. The estimation method used was the restricted maximum likelihood. The denominator degrees of freedom for the performed tests were calculated according to Kenward and Roger [38]. We determined fixed-effects significance with the F-test. For both groups, analyzed data corresponded to 11 consecutive time points, i.e., the baseline and the morning of each one of the first 10 days post-randomization. For between-group comparisons at each time point, we used the Bonferroni correction, i.e., we multiplied the obtained P values by 11. Furthermore, the 11 time points resulted in a total of 55 within-group pairwise comparisons. Consequently, we multiplied P values from within-group comparisons by 55. Physiological data of HFO-TGI sessions. In 217 of the 223 HFO-TGI sessions (97.3%), the pre-specified oxygenation target of "PaO2/FiO2>150 mmHg" was achieved. For these sessions, we grouped the airway pressure {i.e. mPaw and determined or estimated tracheal pressure (see below)}, gas-exchange and hemodynamic data according to the following 5 time points: 1) pre-session CMV; 2) end of the recruitment period (defined as the time point of transition into the stabilization period); 3) end of the stabilization period; 4) end of the weaning period; and 5) post-session CMV (i.e. 6 hours after weaning from HFO-TGI; see also Figure 1 of main manuscript). We did not substitute the missing weaning period data of 1 patient, because we considered them as "missing at random" [37]. Six of the 223 sessions (2.7%), corresponding to 6 patients, fulfilled the criteria for "Study Intervention Failure" (see also "eMethods" and eFigure 3). In 2 of these sessions, apart from HFO-TGI, we used once standard HFO for 30-60 min. There was no use of prone positioning or inhaled nitric oxide (eFigure 3). For these sessions, we corresponded the end of the recruitment period to the highest employed mPaw of 9
HFO-TGI, and the end of the stabilization period to the lowest employed mPaw of HFO-TGI. We then grouped the respective gas-exchange and hemodynamic data for the purpose of analysis. Furthermore, all 6 patients died while still on HFO-TGI (see also footnote of Table 3 of main manuscript) and there was no weaning period in any of these sessions. The weaning period data were missing, primarily because PaO2/FiO2 had never reached the pre-specified level of 150 mmHg. This could introduce a bias (i.e. artificially improved results on the weaning period) due to poor responders to HFO-TGI having missing values [37]. Thus, for these cases, we adopted the "last value carried forward" approach [37]. The values corresponding to the end of the stabilization period were considered as "last values." Indeed, according to the HFO-TGI recruitment protocol, the physiological measurements of the end of the weaning period are preceded by the physiological measurements of the end of the stabilization period. Lastly, the post-session CMV data of these HFO-TGI sessions were also missing due to "poor response to HFO-TGI." We substituted these missing CMV data, again with the method of "last value carried forward". On this occasion, the "last values" were those of the pre-session CMV. For all the 223 HFO-TGI sessions, we used linear mixed-model analysis to determine the effect of time on gas-exchange and hemodynamics. The 5 time points resulted in a total of 10 within-group pairwise comparisons. Consequently, we multiplied the P values from within-group comparisons by 10. Furthermore, we used the paired t test to compare the pre-session with the post-session values of end- inspiratory plateau airway pressure and respiratory compliance. Cox regression analyses. We used multivariate Cox regression analysis (Method: "Enter") to determine independent predictors of death, and respective proportional hazards and their 95% confidence intervals. Tested covariates included assignment to CMV group, study center, and baseline simplified acute physiology score II [39], arterial blood lactate [40], oxygenation index [41], and plateau pressure [42]. An additional Cox regression analysis with the same covariates was performed to determine the independent predictors of achieving unassisted breathing for ≥48 hours. Post hoc analyses Additional, important, post hoc analyses of the study data included the determination of the effect of the "use or no use" of RMs after day 4 on study outcomes, and the study outcome results of the subgroup of patients with pulmonary contusion-induced ARDS. eRESULTS Physiological effects of HFO-TGI Oxygenation and lung mechanics. Relative to pre-HFO-TGI CMV, PaO2/FiO2 and oxygenation index exhibited significant improvements during and after the HFO-TGI sessions (eFigure 5A and 5B; effect of time, P<0.001). Furthermore, during post- HFO-TGI CMV, there were significant drops in plateau pressure and rises in respiratory compliance compared to pre-HFO-TGI CMV (eFigure 5C and 5D). Lastly, in eFigure 5E, we present the patient-by-patient data on the physiological endpoints at 6 hours after the end of the last HFO-TGI session vs. just before the initiation of the first HFO-TGI session. This shows the beneficial, cumulative effect of the total of the recruitment sessions of HFO-TGI on respiratory physiology. mPaw and mean tracheal pressure. On HFO initiation and before the addition of TGI, we determined a mPaw drop of 6.1±1.6 cmH2O along the tracheal tubes. This mPaw drop was reconfirmed at the end of the weaning period of the HFO-TGI sessions (Figure 1 of main manuscript). The drop in mPaw was probably due to the 10 high inspiratory flows of HFO and the associated, resistive inspiratory pressure drops along the tracheal tubes [27]. Indeed, at a frequency of 4 Hz, and an oscillatory pressure amplitude of 80-90 cmH2O, HFO tidal volume can reach 150-200 mL [43]. In the present study, we used an initial frequency of 4 Hz, an initial oscillatory pressure amplitude of 78.7±8.8 cmH2O, and an inspiratory-to-expiratory time ratio of 1:2. Hence, at 4 Hz, inspiratory time=1 / (3 x 4 respiratory cycles/s) or approximately 0.08 s/respiratory cycle, and mean inspiratory flow=tidal volume / inspiratory time=0.15-0.20 L / 0.08 s=1.9-2.5 L/s. In a recent physiological study [27], we showed that at inspiratory flows of 2.0-2.5 L/s, the resistive inspiratory pressure drops can exceed 20 cmH2O, even along orotracheal tubes with internal diameters of 9.0 mm. Furthermore, we showed that the placement of a TGI catheter increases the inspiratory pressure drop by up to 20% [27]. Lastly, the addition of a TGI flow of 6.7±0.7 L/min reduced a mPaw-drop along the tracheal tube of 5.9±1.8 cmH2O by 1.5±0.6 cmH2O [27]. This TGI-induced change in mPaw-drop was relatively minor, probably because of the concurrent use of a tracheal tube cuff leak of 4-5 cmH2O [27]. Indeed, the cuff leak reduces the expiratory resistance at the level of the trachea by widening the expiratory pathway [44]; this probably resulted in reduced expiratory pressure for any level of expiratory flow. In the present study, we used an average TGI flow of 6.5±0.8 L/min, a cuff leak of 3-5 cmH2O, and average HFO settings were comparable to those we employed in our recent physiological study [27]. Therefore, for the end of the present study’s recruitment and stabilization period, we estimated the mean tracheal pressure by 1) subtracting the initially determined mPaw-drop from the respective ventilator- displayed mPaws, and 2) adding 1.5 cmH2O to the obtained result, in order to account for the effect of TGI [23,27]. In addition, the measured mean tracheal pressure of pre- HFO-TGI CMV exceeded the ventilator-displayed mPaw by 0.4±0.1 cmH2O. Thus, we also estimated the mean tracheal pressure of post-HFO-TGI CMV by adding 0.4 cmH2O to the ventilator-displayed mPaw. eFigures 6A and 6B display respectively the evolution of mPaw and mean tracheal pressure before, during, and after the HFO-TGI sessions (effect of time, P<0.001). The average of all the mPaw recordings of the HFO-TGI sessions and the average mPaw of the end of the recruitment and stabilization period were approximately identical (29.1±3.6 and 29.3±3.7 cmH2O, respectively). Relative to pre-HFO-TGI CMV, the (estimated) mean tracheal pressure was approximately 6.8 cmH2O higher at the end of the recruitment period, and approximately 1.2 cmH2O lower at the end of the stabilization period. Thus, the (estimated) average mean tracheal pressure of the end of the recruitment and stabilization period was just 2.7 cmH2O higher vs. pre- HFO-TGI CMV (i.e., 24.5±5.5 cmH2O vs. 21.8±3.0 cmH2O, P<0.001). This relatively small, estimated difference in tracheal pressure may partly explain the below- presented results on hemodynamics. Hemodynamics. The average hemodynamics of the HFO-TGI sessions were similar vs. pre-HFO-TGI CMV, (cardiac index: 4.2±1.2 vs. 4.1±1.2 L/min/m2 body surface area, P=0.29; mean arterial pressure: 83.6±13.8 vs. 83.0±13.6 mmHg, P>0.99; and central venous pressure: 12.9±4.0 vs. 12.3±4.1 mmHg, P=0.08). eFigures 6C, 6D, and 6E display the evolution of hemodynamics before, during, and after the HFO-TGI sessions (effect of time, P<0.001). The high mPaw-associated hemodynamic changes of the recruitment period of HFO-TGI were reversed at the end of the stabilization and weaning period (eFigures 6C-6E). This was at least partly due to the reduction in mPaw (and in mean tracheal pressure) according to the study 11 protocol (eFigures 6A and 6B). At the end of the weaning period, the measured mean tracheal pressure was ~2.9 cmH2O lower vs. pre-HFO-TGI CMV. Other factors contributing to the similar average hemodynamic status of HFO-TGI vs. preceding CMV could include 1) the reversal of RM-associated hypotension with a bolus of crystalloid and a temporary increase in the infusion rate of norepinephrine (see relevant subsections of eMethods and eResults, and footnote of eTable 3); 2) the overall positive fluid balance of days 1-10 (see Table 4 of main manuscript); and 3) the similar PaCO2 [45] of HFO-TGI and preceding CMV (eFigure 5F). PaCO2. The average PaCO2 of the HFO-TGI sessions was similar vs. pre-HFO-TGI CMV (50.2±11.2 vs. 49.0±9.6 mmHg, P=0.19). The discontinuation of the TGI in the weaning period caused a minor but significant increase in PaCO2 vs. the end of the stabilization period (52.3±11.6 vs. 49.8±11.2 mmHg, P=0.004), which was reversed during post-HFO-TGI CMV (eFigure 6F; effect of time, P<0.001). RM-related complications A detailed presentation is provided in eTable 3. These complications included mainly adverse hemodynamic effects and desaturation associated with the use of RMs. Effective and prompt reversal was most frequently achieved solely by RM discontinuation. Major complications and corresponding treatment (eTable 3 and corresponding footnote) are also reported in the Results section of the main manuscript. eTable 3 also includes data on the frequency of obstruction of TGI catheters by secretions. Effect of RMs on oxygenation in the CMV group During days 1-4, post-recruitment SpO2/FiO2 [46] increased, remained unchanged, and decreased at 15 min after 178 (91.3%), 13 (6.7%), and 4 (2.1%) of the 195 RMs performed in-between 7:00 and 7:30 a.m. On days 1, 2, 3, and 4, there was a minor but significant improvement in SpO2/FiO2 at 15 min post-recruitment. On days 2, 3, and 4, the early rise in SpO2/FiO2 was no longer present at 2 hours post-recruitment (eTable 4). After 86 (44.1%) RMs, PEEP could be increased by 2 cmH2O without concurrent plateau pressure rise to >30 cmH2O. In 62 (72.1%) of the aforementioned cases, SpO2 rose to >95% and PEEP and FiO2 were re-titrated to an SpO2 of 90-95% within the next 60 min. Overall, there were only slight changes in the ventilatory settings from the start to the end of the 2-hour observation period (detailed data not shown). The early SpO2/FiO2 rise was greater in cases of increased vs. unchanged post-recruitment PEEP (4.1±3.5 vs. 3.1±3.0 points, P=0.04). Effect of the "use or no use" of RMs after day 4 on physiological endpoints and survival During days 5-10, 19 HFO-TGI group patients received ≥1 RM as part of the HFO- TGI algorithm. For the purpose of this post hoc analysis, these patients were included in the RMs 1-10 group, whereas the remaining 109 patients of the study population were included in the RMs 1-4 group. During days 1-10, the RMs 1-10 group received more RMs vs. the RMs 1-4 group {30.2±12.3 (range=8-58) vs. 17.4±6.8 (range=0- 42); P<0.001}. eTable 5 displays results of between-group and within-group comparisons with respect to the physiological endpoints and SOFA scores. The mixed model-estimated [47], overall means for PaO2/FiO2 (152.8 vs. 124.0 mmHg) and oxygenation index (22.3 vs. 17.8) were respectively lower and higher in the RMs 1-10 group vs. the RMs 1-4 group (P=0.03 for both). There was no significant effect of group on plateau pressure, and respiratory compliance. The survival to hospital discharge was not significantly different in the RMs 1-10 group vs. the RMs 1-4 group 12/19, 63.2% vs. 49/106, 46.2%; P=0.22 by Fisher’s exact test. In bivariate 12
Cox regression, there was no significant association between the "use or no use" of recruitment maneuvers after day 4 and survival to hospital discharge: hazard ratio (HR)=0.61, 95% confidence interval (CI)=0.28-1.34, P=0.22. In addition, there was no significant association between the total number of RMs within days 1-10 and survival to hospital discharge: HR=1.02, 95% CI=0.99-1.06, P=0.17. Consequently, the interpretation of the favorable results of the HFO-TGI group cannot be based solely on the "use or no use" of RMs after day 4 and/or the total use of RMs during days 1-10. Indeed, the present study’s results indicate that only the combination of RMs and HFO-TGI according to the intermittent HFO-TGI recruitment protocol can improve outcome. The 19 patients of the RMs 1-10 group received HFO-TGI sessions including RMs within days 5-10, because their severe oxygenation disturbances persisted after day 4. The 63.2% survival rate of these patients was very close to the survival rate of the HFO-TGI group patients, who did not receive HFO-TGI after day 4. The latter patients did not experience severe oxygenation disturbances after day 4 and their survival rate was 26/42 (61.9%; P>0.99 vs. the RMs 1-10 group). The sole, plausible interpretation of these results is that the use of HFO-TGI and RMs according to the intermittent HFO-TGI recruitment protocol was equally effective with respect to survival in HFO-TGI group patients with and in HFO-TGI group patients without severe oxygenation disturbances after day 4. Patients with Contusions In a preceding, uncontrolled clinical trial [48,49], 32 trauma patients were treated with a recruitment strategy using high-frequency (median respiratory rate=80/min), inverse ratio, pressure-cycled ventilation and RMs. All patients had lung injury secondary to pulmonary contusions, and their long-term survival rate was 30/32 (93.8%). Furthermore, in the subgroup with available computerized tomographic (CT) data (n=17) and 100% long-term survival, 9 patients (52.9%) had a PaO2/FiO2 of <150 mmHg. In the same subgroup, the reported, median, external PEEP level was 10 cmH2O [49]. In the present study, from 34 trauma patients with pulmonary contusion-induced ARDS, 22 (64.7%) were assigned to the HFO-TGI group and just 12 (35.3%) were assigned to the CMV group (Table 2 of main manuscript). On the basis of this apparent randomization imbalance, one could argue that our overall results were primarily driven by the expectedly good outcomes of HFO-TGI group patients with contusions. However, as reported in the footnote of Table 2 of the main manuscript, 7 HFO-TGI group patients and 2 CMV group patients with contusions had a concurrent, microbiologically documented, hospital-acquired pneumonia (HAP) at baseline. Consequently, the proportions of patients with exclusively bilateral, contusion- induced, severe ARDS were 15/61 (24.6%) and 10/64 (15.6%) in the HFO-TGI group and CMV group, respectively. A recent, multicenter, CT study showed that patients with pneumonia-induced lung injury exhibit a higher amount of potentially recruitable lung as compared to patients with sepsis-induced lung injury [19]. In the present study, the proportions of patients with pneumonia- and/or contusion-induced ARDS were approximately identical in the 2 groups {HFO-TGI group, 42/61 (68.9%); CMV group, 44/64 (68.8%)}. This indicates that there was no randomization imbalance with respect to a current literature-supported, higher likelihood of increased lung recruitability. In addition to the above arguments, a post hoc, contusion subgroup analysis failed to reveal a significant difference in long-term survival {HFO-TGI group vs. CMV group: 13/22 (59.1%) vs. 8/12 (66.7%), P=0.72}. Accordingly, within days 1-60, 13
HFO-TGI group vs. CMV group had comparable ventilator-free days {26.5 (0.0-47.6) vs. 28.5 (1.3-36.8), P=0.96}, and days without respiratory {32.5 (0.0-52.0) vs. 39.5 (3.5-54.8), P=0.35}, coagulation {58.5 (5.5-60.0) vs. 60.0 (35.5-60.0), P=0.45}, liver {60.0 (6.8-60.0) vs. 60.0 (35.3-60.0), P=0.53}, circulatory {38.0 (0.8-54.3) vs. 50.0 (4.3-54.5), P=0.65}, renal {38.5 (3.8-60.0) vs. 60.0 (35.3-60.0), P=0.15}, and nonpulmonary organ failure {30.5 (0.0-46.0) vs. 36.5 (2.0-48.3), P=0.46}; results were similar for days 1-28 (data not shown). During days 1-10, the mixed-model estimated [49], overall mean for respiratory compliance was higher in HFO-TGI group vs. CMV group (38.2 vs. 31.9 mL/cmH2O, P=0.03). However, the evolution of the other major physiological variables and the SOFA score was similar in the 2 groups (eTable 6). In HFO-TGI group vs. CMV group, patients with contusions had respectively an age of 40.916.4 vs. 40.014.6 years (P=0.87), a pre-enrollment CMV duration of 3.72.1 vs. 3.01.8 days (P=0.35), a baseline SAPS II score of 39.413.3 vs. 36.710.6 (P=0.54), and a SOFA score decrease of 2.14.6 vs. 2.23.9 during days 1- 10 (P=0.94); twenty (90.9%) vs. 11 (91.7%) patients had acute lung injury or ARDS [1] on ICU admission (P>0.99). In bivariate Cox regression, there was no significant association between the presence of contusions and death before hospital discharge: HR=0.64, 95% CI=0.35-1.17, P=0.17. In the HFO-TGI contusion subgroup, 6 patients (27.2%) had a very severe, early clinical course with a SOFA score increase of 1.23.6 from a baseline value of 13.12.0. At baseline, 2 patients had concurrent HAP. Study intervention failure and death occurred in all 6 patients within days 4-9 (see also footnote of Table 3 of main manuscript). Intervention failure (see also above and eFigure 3) meant that a PaO2/FiO2 of >150 mmHg could not be achieved during the last and prolonged (duration=67.128.6 hours) HFO-TGI session, despite the use of an average mPaw of 37.91.3 cmH2O, a TGI flow of 7.10.9 L/min, and a per-session RM frequency of 12.311.6. All 6 patients died while still on HFO-TGI (1 of hypoxemia, 4 of MOF, and 1 of iatrogenic pneumothorax). One patient who died of MOF also experienced an RM-associated pneumothorax, which was treated by chest tube drainage ~4 hours before his death (see also Results of main text and eTable 3). Also, 3 patients had concurrent diffuse brain injury and swelling and developed post-randomization, treatment-refractory intracranial hypertension (eTable 1); in these patients, intracranial pressure was controlled with a continuous thiopental infusion of 5-7 mg/kg/hour, which likely aggravated their coexisting circulatory failure [50]. Judging from the overall favorable response to HFO-TGI, we speculate that all 6 patients would have required rescue oxygenation if they had been assigned to the CMV group, and also that their outcome would have been the same. The HFO-TGI contusion subgroup also included a patient who was transferred to another hospital not participating in the study on day 31 post-randomization. The data from this patient were included in the intention-to-treat analysis, assuming that he died before hospital discharge (see also legend of Figure 2 of main manuscript). The above-presented facts suggest that the randomization imbalance with respect to contusions actually resulted in the assignment of more patients with a subsequently anyway fatal clinical course to the HFO-TGI group. Nevertheless, there was no stratification of randomization according to ARDS etiology and the sizes of the contusion subgroups were unequal and small. Thus, we cannot draw any specific conclusion on the efficacy of intermittent recruitment with HFO-TGI and RMs in contusion-induced ARDS. Results of bronchoscopies 14
During days 1-10, 111 brief bronchoscopic evaluations of the trachea were performed. Twenty (18.0%) revealed Grade I findings, 88 (79.3%) revealed Grade II findings, and 3 (2.7%) revealed Grade IIIA findings (see also eTable 2). In 2 of the latter 3 cases, the hemorrhagic tracheal mucosa was attributable to tracheostomy performed within the preceding 6-24 hours. In 2 of the 6 HFO-TGI sessions with intervention failure, bronchoscopy was not performed, because of a persistently low PaO2/FiO2 of <100 mmHg. During the other 4 of these HFO-TGI sessions, the bronchoscopic evaluation was undertaken once within 24-72 hours of HFO-TGI initiation at PaO2/FiO2s of 127.9-149.1 mmHg. Bronchoscopy performed in 1 patient at the end of the HFO-TGI session of day 10 revealed Grade IIIA findings suggestive of tracheal mucosal damage, i.e., a hemorrhagic posterior tracheal mucosa. This patient was tracheostomized before study enrollment. For that particular time point, the discontinuation of intermittent HFO-TGI was anyway pre-specified by the study protocol, and the patient was returned to CMV. During the intervention period, the patient had received 118.3 hours of intermittent HFO-TGI. During days 8-10, the patient’s platelet count exhibited a drop from 59x109/L to 19x109/L, and then rose to 66x109/L by day 12. This hemorrhagic complication could be due to the concurrent thrombocytopenia and potential impact of the TGI jet stream on the tracheal mucosa. During days 16-20, the patient suffered 2 episodes of acute hypoxemia (i.e. abrupt SpO2 drop to 80-82%). On both occasions, he was effectively treated by bronchoscopic removal of thrombotic material mixed with inspissated mucous from the orifice of the left main bronchus. The patient was discharged from the ICU on day 43, and from the hospital on day 102. Rescue Oxygenation Therapies In the CMV group, rescue oxygenation was used in 6 of the 64 patients (9.4%). More specifically, standard HFO, in conjunction with RMs [14,23,27], was used for 3-18 hours on days 3, 8, and 24 post-randomization in 1, 2, and 1 patients, respectively. Two patients were returned to CMV when PaO2/FiO2 rose to >100 mmHg, and did not again require rescue oxygenation (see also above); the 1 patient died on day 9 of MOF, and the other patient died on day 16 after suffering a spontaneous pneumothorax during CMV. The other 2 patients suffered cardiac arrest and died, while PaO2/FiO2 was ≤47 mmHg. Lastly, on days 1 and 2, another 2 hypoxemic patients were proned but died within 16-20 hours thereafter, while their PaO2/FiO2 was ≤45 mmHg. Following pronation, both patients received 2 RMs [51] during transient PaO2/FiO2 improvements to 55 mmHg; however, in the 1 patient, both RMs were aborted within the first 15-20 s (once due to desaturation and once due to hypotension), and in the other patient the 1 RM was aborted within the first 20 s due to desaturation. Clinical course data Organ failure free and ventilator free days. Full data on organ failure free and ventilator free days within days 1-28 and 1-60 post-randomization are presented in eTable 7. Medical treatment. During days 1-10, the prescribed treatment with norepinephrine (data reported in Table 4 of main manuscript), and with sedatives, opioids, cisatracurium, and furosemide did not differ significantly between the 2 groups, with respect to either the number of patients treated, or the average daily infusion rates, or the total daily doses (eTable 8); the same was true with respect to the number of patients treated with corticosteroids, although the mixed-model estimated [47], overall mean for hydrocortisone total daily dose was slightly higher (268 vs. 242 mg, 15
P=0.004) in the steroid-treated CMV group patients vs. the steroid-treated HFO-TGI group patients. During days 1-60, there were no significant differences between the 2 groups in the cumulative doses of (or the numbers of patients treated with) sedatives, analgesics, and cisatracurium (eTable 9); the same was true for furosemide, corticosteroids, antibiotics, anticoagulants, antiepileptic drugs, bronchodilators, cardiovascular drugs (i.e. dobutamine, amiodarone and other antiarrhythmics, and antihypertensives), and insulin (data not shown). Cisatracurium was administered as continuous infusion of 0.1-0.2 mg/kg/h in 221 of the 223 HFO-TGI sessions (99.1%). Neuromuscular blockade infusion was discontinued for ≥6 hours after 84 of the 223 HFO-TGI sessions (37.7%). During the first 2 days post-randomization [12], cisatracurium was not used at all or its average daily use was 8 hours/day in 14/61 (23.0%) and 22/64 (34.4%) patients of the HFO- TGI group and the CMV group, respectively (P=0.17); in all the remaining patients of both groups, cisatracurium was infused continuously throughout days 1 and 2. Within days 1-60, cisatracurium was used for 4.0 (3.0-7.0) vs. 4.0 (2.0-9.0) days in HFO-TGI group vs. CMV group (P=0.54). In HFO-TGI group vs. CMV group, there were 12/2781 (0.6%) vs. 19/2017 (0.9%) patient days without a study protocol- indicated use of cisatracurium (P=0.04); there was no recorded case of any protocol- unindicated cisatracurium use (see also above and eFigure 1). Furthermore, HFO-TGI group vs. CMV group patients received respectively at least 1 sedative for 11.0 (6.0- 23.0) vs. 12.0 (7.0-24.8) days (P=0.92), 1 opioid for 6.0 (1.5-19.5) vs. 8.0 (2.0-16.8) days (P=0.94), and 1 sedative and/or opioid for 18.5±13.5 vs. 18.0±14.8 days (P=0.84). HFO-TGI group vs. CMV group patients had 2.0 (0.5-4.0) vs. 1.5 (0.0-5.0) sedation interruptions (P=0.68). In HFO-TGI group vs. CMV group, there were 52/2781 (1.9%) vs. 19/2017 (0.9%) patient days without a study protocol-indicated sedation interruption (P=0.01). Despite the slight, between-group differences in the scarce violations of the protocolized use of cisatracurium and sedatives and/or opioids, our relevant, combined results (see above and eTables 8 and 9) indicate accurate and very similar application of the sedation/paralysis protocol in both groups. Our results on study outcomes cannot be interpreted by any systematic, between-group difference in sedation use arising from potentially more frequent, oxygenation-driven interruptions of sedation, and leading to more frequent attempts at weaning from CMV. Admittedly, as in a recent multicenter study [52], both sedation interruption and weaning procedures were partly oxygenation-driven (eFigures 1 and 2). However, in contrast to that study [52], in the present study, sedation interruption was not necessarily coupled to a weaning attempt. Indeed, apart from oxygenation, the actual initiation of a weaning procedure in a nonsedated or lightly sedated patient was also dependent on the absence of circulatory failure, disturbances of the acid-base and electrolyte balance, and any new evidence of sepsis (eFigure 2). Consequently, our results of earlier and more frequent successful weaning in the HFO-TGI group (see Results of main manuscript) can be much more plausibly interpreted by a superior ventilatory treatment-associated, prompt and effective reversal of the respiratory failure [6], leading to improved, overall vital organ/system function {[53]; see also Discussion of main manuscript}. Complications recorded throughout hospital stay did not differ significantly between the 2 groups (eTable 10). Regarding barotrauma, it manifested mainly as new pneumothorax requiring chest tube drainage in both groups: HFO-TGI group vs. CMV group: 6/61 (9.8%) vs. 9/64 (14.1%), P=0.59. In each one of the afflicted 16 patients of the HFO-TGI group and CMV group, the pneumothorax occurred once at 16.2±10.9 (range, 5-36) and 18.2±13.4 (range, 5-43) days post-randomization, respectively (P=0.76). In 1 HFO-TGI group patient, there was a preceding diagnosis of a pneumatocele of >2 cm (see below). Furthermore, the HFO-TGI group vs. CMV group had a comparable frequency of radiologic findings indicating concurrent presence of pneumothorax and pneumomediastinum [54]: 2/61 (3.3%) vs. 4/64 (6.3%), P=0.68; suspected, isolated pneumomediastinum [54]: 3/61 (4.9%) vs. 4/64 (6.3%), P>0.99; and subcutaneous emphysema persisting for >24 hours following chest tube insertion for pneumothorax 0/61 (0.0%) vs. 2/64 (3.1%), P=0.26. Regarding isolated pneumomediastinum, 4 (HFO-TGI group, n=2) of the 7 patients underwent a CT of the thorax within 3-5 days after its initial, possible radiologic detection. The chest CT scans did not demonstrate any pathologic collection of gas in the mediastinum in any case, implying a preceding, radiologic Mach band effect [54,55]; in 3 scans (CMV group, n=2), there were bilateral emphysematous cysts with diameters not exceeding 1.5 cm. The assessing, study-independent radiologists (see also Methods of main manuscript) also opined that the chest x-rays of 2 HFO-TGI group patients and 2 CMV group patients were suggestive of the presence of pneumatoceles. The subsequent thoracic CT scans revealed a left anteromedial pneumatocele of >2 cm in 1 HFO-TGI group patient, lung abscesses in 1 HFO-TGI group patient, and bilateral bullae with diameters not exceeding 2 cm in 2 CMV group patients. eTable 11 displays the causes of death and the 14-day, 28-day, 60-day, 90-day, and 150-day mortality rates. The 150-day mortality rates were confirmed through telephone communication with the 61 hospital-discharged patients, or their families. Within ≤3 hours before death, patients who died of MOF in HFO-TGI group (n=8) vs. CMV group (n=22) had respectively a PaO2/FiO2 of 89.4±32.6 vs. 71.0±13.8 mmHg (P=0.16) at an FiO2 of 92.5±13.9% vs. 93.2±9.5% (P=0.36), a mean arterial pressure of 59.2±18.3 vs. 57.9±5.1 mmHg (P=0.85), a central venous pressure of 15.6±2.9 vs. 14.5±2.1 mmHg (P=0.25), and were receiving norepinephrine at a rate of 0.80±0.27 vs. 0.74±0.16 μg/kg/min (P=0.46); death occurred at 6.6±4.0 vs. 8.3±4.5 days post- randomization (P=0.36), while 5 HFO-TGI group patients (62.5%) were still on HFO- TGI (see also above and footnote of Table 3 of main manuscript). In the remaining 3 HFO-TGI group patients and the 22 CMV group patients, PEEP was set at 14.0±5.3 and 16.7±2.3 cmH2O, respectively. In 7 HFO-TGI group patients vs. 17 CMV group patients, cardiac index was 2.6±0.3 vs. 2.8±0.5 L/min/m2 body surface area (P=0.35). In HFO-TGI vs. CMV group, 6 vs. 20 (P=0.28), 2 vs. 5 (P>0.99), and 0 vs. 3 (P=0.55) patients were respectively receiving stress-dose hydrocortisone, additional epinephrine (rate=0.15-0.27 μg/kg/min) or vasopressin (rate=0.03 units/min), and dobutamine (rate=5-7 μg/kg/min) [8]. Independent predictors of in-hospital death were the assignment to CMV group, the baseline arterial blood lactate and the SAPS II score; full multivariate Cox regression results are reported in eTable 12. The sole independent predictor of succesfull weaning from CMV (see also Results of main manuscript) was the assignment to the CMV group (see legend of Figure 3F of main manuscript). In bivariate Cox regression, the occurrence of ventilator- associated pneumonia (VAP) was not significantly associated with the achievement of successful weaning (HR=0.70, 95% CI=0.43-1.13; P=0.15). Regarding the subgroups with successfull weaning, VAP occurred in 22 of the 42 HFO-TGI group patients (52.4%) vs. 18 of the 26 CMV group patients (69.2%) (P=0.21). In the HFO-TGI group, the time to weaning was 25.3±9.3 days in patients who had ≥1 episode of VAP 17 post-randomization vs. 17.2±9.0 days in patients who remained VAP-free (P=0.006); the respective times to weaning of the CMV group were 33.8±11.4 vs. 24.3±13.9 days (P=0.08). Finally, regarding the effect of center, between-center comparisons with respect to study outcomes did not reveal any significant difference (data not shown). The timely participation of the second center (see also the above-provided subsection "Apriori design for two study periods") enabled the demonstration of the "transferability" of our relatively complex HFO-TGI protocol after a short-term training period of 50 hours (see also Results of the main manuscript).
eAPPENDIX Derived physiological variables These variables were derived according to the following formulas: 1. Oxygenation index = 100 x mPaw x FiO2 / PaO2 2. Quasistatic respiratory system compliance = Vt / (P2,aw – PEEPTOTAl) 3. CaO2 = Hgb x 1.36 x SaO2 / 10 + 0.003 x PaO2 4. CcvO2 = Hgb x 1.36 x ScvO2 / 10 + 0.003 x PcvO2 5. PAO2 = PiO2-PACO2 x [FiO2 -(1-FiO2) / R]; PiO2 = FiO2 x (PB-47); PACO2 ~ PaCO2; R = (FEY of carbohydrate intake) x 1.0 + (FEY of protein intake) x 0.8 + (FEY of lipid intake) x 0.7. 6. CcO2 = Hgb x 1.36 / 10 + 0.003 x PAO2 7. Shunt fraction = (CcO2-CaO2) / (CcO2-CcvO2) 8. O2 delivery index = CI x CaO2 Where mPaw = mean airway pressure (cmH2O); Vt = tidal volume (mL); P2,aw = end-inspiratory plateau airway pressure (cmH2O); PEEPTOTAL = end-expiratory plateau airway pressure (cmH2O); FiO2 = inspired O2 fraction; Pa, Pcv, PA, and Pi = arterial, central-venous, alveolar, and inspired gas partial pressure (mmHg), respectively; CaO2, CcvO2, and CcO2 = O2 content in arterial, central-venous, and pulmonary end-capillary blood (mL), respectively; Hgb = hemoglobin concentration (g/L); 1.36 = O2 combining power of 1 g of hemoglobin (mL); SaO2 and ScvO2 = arterial and central-venous O2 saturation as determined by the blood-gas analyzer, respectively; 0.003 = O2 solubility coefficient at 37 C (mL x mmHg/dL); R = respiratory quotient; PB = barometric pressure (mmHg); 47 = H2O saturated vapor pressure at 37 C (mmHg); FEY = fractional energy yield relative to total of prescribed nutritional support; CI = cardiac index (L/min/m2 body surface area). For the computation of shunt fraction, we used blood gas values obtained from the central-venous blood, because all patients of both groups had central venous catheters [19], whereas only 11 patients had Swan Ganz pulmonary artery catheters for ≤72 hours during the study intervention period. 1 mmHg = 0.133 kPa.
18
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eTable 1. Eligibility criteria.
Inclusion criteria Exclusion Criteria
Age 18-75 years Active air leak or recent severe air leak *
Body weight >40 kg Severe hemodynamic instability †
Diagnosis of ARDS established within preceding 72 hours Significant heart disease ‡
Endotracheal intubation, mechanical ventilation, and need for deep Significant COPD or asthma §
sedation with or without neuromuscular blockade
Severe Oxygenation Disturbance: PaO2/FiO2 <150 mm Hg sustained Uncontrollable intracranial hypertension ║
for >12 hours, despite being ventilated with PEEP ≥8 cmH2O
CILD associated with bilateral pulmonary infiltrates
Lung biopsy or resection on current admission
Immunosuppression **
Inability to wean from prone positioning or iNO
Pregnancy or morbid obesity ††
Enrollment in another interventional study
ARDS, acute respiratory distress syndrome; FiO2, inspired oxygen fraction; PEEP, positive end-expiratory pressure; COPD, chronic obstructive pulmonary disease; CILD, chronic interstitial lung disease; iNO, inhaled nitric oxide. *, Defined as >1 chest tube per hemithorax with persistent gas leak for >72 hours. 24
†, Defined as systolic arterial pressure <90 mmHg, despite volume loading and norepinephrine infusion at ≥0.5 μg/kg/min. ‡, Defined as ejection fraction <40 %, and/or history of pulmonary edema, and/or active coronary ischemia or myocardial infarction §, Defined as previous admissions for COPD/asthma, chronic corticosteroid therapy for COPD/asthma, and documented chronic CO2 retention leading to a baseline PaCO2 of >50 mmHg (for COPD). ║, Defined as intracranial pressure >20 mmHg despite deep sedation, analgesia, hyperosmolar therapy, and minute ventilation titrated to PaCO2 = 35 mmHg. **, Caused by 1) neutropenia, i.e., polymorphonuclear leukocyte count <1.0 x 103/μL (1.0 x 109/L) after chemotherapy or bone marrow transplantation for hematologic cancers; or 2) corticosteroid or cytotoxic therapy for a nonmalignant disease; or 3) the acquired immunodeficiency syndrome. ††, Defined as body mass index >40 kg/m2. 1 mmHg = 0.133 kPa; 1 cmH2O = 0.098 kPa.
25
eTable 2. Pre-specified grading of bronchoscopic findings
Grade Bronchoscopic Findings Interpretation Action
I Pink and glistening tracheal mucosa Normal; No TGI-related complication None
II Reddened and/or swollen mucosa Probable respiratory infection during mechanical None
with/without presence of purulent secretions ventilation; No TGI-related complication
III A. Hemorrhagic mucosa and/or presence of thrombotic material* Possible mucosal pealing, in conjunction with Dicontinue
B. Limited localized necrosis, especially at the carina †, and/or mechanical erosion of the submucosal vessels by the TGI §
presence of necrotic mucosal slough TGI jet stream; Suggests TGI-related complication §
C. Extensive localized necrosis, especially at the carina †, and/or
presence of necrotic mucosal slough
TGI, tracheal gas insufflation. *, Any concurrent bleeding diathesis / coagulopathy could constitute an independent contributory factor. †, Considered as the probable site of impact of the TGI jet stream. §, Exception: Grade IIIA findings attributable to tracheostomy performed within the preceding 6-24 hours. 26
eTable 3. Study protocol-related complications.
HFO-TGI Group CMV Group P-value
(n=61) (n=64)
Days 1-10 post-randomization
Sustained proportional drop of >10% in cardiac index during HFO-TGI - no. (%) * 10 (16.7) Not applicable
Prolonged absolute drop in SpO2 of >5% - no. (%) † 3 (4.9) 2 (3.1) 0.68
TGI catheter blocked by secretions - no. (%) ‡ 5/469 (1.1) Not applicable
RMs, days 1-4 post-randomization
Aborted due to hypotension - no. (%) § 46/1111 (4.1) 46/1122 (4.1) >0.99
Systolic pressure before the RM (mmHg) 103.2±2.1 103.3±3.2 0.82
RM-associated proportional decrease in systolic pressure - (%) 16.9±5.5 15.9±2.4 0.30
Cardiac index before the recruitment maneuver – L/min/m2 4.0±1.0 4.2±0.7 0.23
RM-associated proportional decrease in cardiac index - (%) 11.1±1.4 7.6±0.2 0.02
Aborted due to desaturation - no. (%) § 27/1111 (2.4) 19/1122 (1.7) 0.24
SpO2 before the recruitment maneuver – (%) 97.5±3.2 90.2±8.1 <0.001
RM-associated absolute decrease in SpO2 – (%) 10.5±3.6 8.4±1.7 0.02
RMs, days 5-10 post-randomization
Aborted due to hypotension - no. (%)║ 12/194 (6.2) Not applicable
Systolic pressure before the recruitment maneuver (mmHg) 105.1±4.3
RM-associated proportional decrease in systolic pressure - (%) 19.8±9.1
Cardiac index before the recruitment maneuver – L/min/m2 4.1±1.4
RM-associated proportional decrease in cardiac index - (%) 14.8±10.2
Aborted due to desaturation - no. (%) ║ 20/194 (10.3) ** Not applicable
SpO2 before the recruitment maneuver – (%) 95.5±2.1
RM-associated absolute decrease in SpO2 – (%) 11.4±2.7
CMV, conventional mechanical ventilation; HFO, high-frequency oscillation; TGI, tracheal gas insufflation; SpO2, peripheral oxygen saturation, RM, recruitment maneuver. Values are number (percentage), or mean±SD. *, In all 10 patients, the complication was observed once during the recruitment period of HFO-TGI and within 5 min after a recruitment maneuver aborted due to hypotension {i.e., drop in systolic 27 pressure to 75.1±5.4 mmHg (average drop=28.0±7.2%)}; in 9 of the 10 cases (90.0%), hemodynamic status was restored within 10 min with 300-500 mL of normal saline and temporary increase of the norepinephrine infusion rate by 0.04-0.06 μg/kg/min; norepinephrine infusion rate was readjusted to its pre-HFO-TGI levels within another 30 min; in 1 of the 10 cases (day 8 post-randomization), there was a precipitous drop in cardiac index secondary to tension pneumothorax, which was effectively treated with emergency placement of a thoracostomy tube; pulse oximetry was interrupted during the procedure due to unwanted displacement of the oximeter. †, Reversed within 3-5 min after RM discontinuation in all cases; no additional intervention was required apart from RM discontinuation in any case. ‡, Number referred to a total of 469 TGI catheters used in the study; upon removal, the patency of the TGI catheters was always confirmed by the unobstructed injection of 5 mL of normal saline through their lumen. §, Number referred to a total of 1111 and 1122 recruitment maneuvers administered to the HFO-TGI group and CMV group within days 1-4, respectively; hypotension (and the concurrent transient cardiac output drop of >10%) was reversed in 83 of the 90 cases (92.2%) within <1min, and desaturation was reversed in 41 of the 44 cases (93.2%) within <3 min and without any additional intervention. ║, Number referred to a total of 194 recruitment maneuvers administered to the HFO-TGI group within days 5-10; hypotension (and the concurrent transient cardiac output drop of >10%) was reversed in 9 of the 12 cases (75.0%) within <1 min, and desaturation was reversed in 18 of the 20 cases (90.0%) within <3 min and without any additional intervention. **, P<0.001 versus desaturation-related abort rates of days 1-4.
28
eTable 4. Effect of the first daily recruitment maneuver (RM) on the peripheral
O2 saturation (SpO2) to inspired O2 fraction (FiO2) ratio in the conventional
mechanical ventilation group.
Baseline 15 min 120 min P value for the
post-RM post-RM Effect of Time
SpO2/FiO2 response to first RM of day 1 127.9 ± 25.4 131.9 ± 26.4 * 131.5 ± 25.9 * 0.003
SpO2/FiO2 response to first RM of day 2 133.9 ± 35.7 137.8 ± 35.3 * 134.5 ± 35.6 † <0.001
SpO2/FiO2 response to first RM of day 3 136.1 ± 39.3 139.6 ± 39.0 * 136.2 ± 39.2 † <0.001
SpO2/FiO2 response to first RM of day 4 142.2 ± 43.1 144.9 ± 42.3 * 142.6 ± 43.0 † <0.001
Values are mean±SD. Baseline corresponds to the time point just before the initiation of the RM. For days 1, 2, 3, and 4, the effects of 51, 50, 48, and 46 RMs were evaluated, respectively. *, P<0.05 vs. Baseline. †, P<0.05 vs. 15 min post-RM.
29
eTable 5. Effect of the temporal distribution (i.e. use vs. no use after day 4) of the recruitment maneuvers (RMs), of time, and of their interaction on the
physiological endpoints and sequential organ failure assessment (SOFA) score.
VARIABLE BASELINE DAY 1 DAY 5 DAY 10 P-VALUES, EFFECT OF
Group Time Group*Time
PaO2/FiO2– mmHg; RMs 1-10 Group 99.3±30.9 104.5±31.4 123.0±50.0 160.3±78.6 †,‡ 0.03 <0.001 0.03
RMs 1-4 Group 102.2±29.9 105.2±30.3 162.0±72.8 †,‡ 203.2±101.6 †,‡,§
Oxygenation index; RMs 1-10 Group 24.9±13.6 23.8±13.8 19.5±9.1 21.5±23.1 0.045 <0.001 0.14
RMs 1-4 Group 23.5±11.3 22.5±11.2 15.6±9.5 †,‡ 12.1±8.1 †,‡
Plateau pressure - cmH2O; RMs 1-10 Group 30.7±4.7 30.6±4.7 28.3±2.6 29.2±5.5 0.10 <0.001 0.03
RMs 1-4 Group 30.3±3.4 30.1±3.5 27.7±4.5 †,‡ 25.0±4.8 †,‡,§
Compliance – mL/cmH2O; RMs 1-10 Group 30.2±9.4 30.4±9.4 34.2±9.7 33.7±8.0 † 0.48 <0.001 0.82
RMs 1-4 Group 29.4±6.3 29.1±6.5 32.6±9.4 †,‡ 37.1±13.0 †,‡,§
SOFA score- (no. of surviving patients); RMs 1-10 Group 10.8±2.4 (19) 10.4±2.3 (19) 11.5±3.3 (19) 8.5±4.7 (76) 0.74 <0.001 0.004
RMs 1-4 Group 12.1±2.7 (106) 12.0±2.7 (106) 11.0±4.2 (90) 8.6±4.4 †,‡,§ (15)
RMs 1-10 Group, group of patients who received RMs during days 1-10; RMs 1-4 Group, group of patients who received RMs during days 1-4. Values are mean±SD. Data originate from physiologic measurements performed during conventional mechanical ventilation in each one of the 125 patients (intention-to-treat analysis), within 2 hours before randomization (baseline), and in-between 9:00 and 10:00 a.m. of days 1-10 post-randomization; between-group and within-group multiple comparisons were subjected to the Bonferroni correction (see also relevant subsection of Statistical Methodology). †, P<0.05 versus baseline. ‡, P<0.05 versus Day 1. §, P<0.05 versus Day 5. 30
eTable 6. Evolution of the main physiological variables and sequential organ failure assessment (SOFA) score in patients with pulmonary contusions.
VARIABLE BASELINE DAY 1 DAY 5 DAY 10 P-VALUES, EFFECT OF
Group Time Group*Time
PaO2/FiO2– mmHg; HFO-TGI Group 94.2±25.7 95.8±26.7 149.3±63.2 228.0±103.1 †,‡,§ 0.64 <0.001 0.005
CMV Group 110.2±10.2 113.6±32.2 153.0±59.0 193.9±86.6 †,‡
Oxygenation index; HFO-TGI Group 25.4±9.2 252±9.7 16.1±10.1 11.0±5.7 †,‡ 0.40 <0.001 0.77
CMV Group 20.6±9.5 19.6±10.2 14.7±6.9 11.2±7.2
Plateau pressure - cmH2O; HFO-TGI Group 29.8±3.6 30.6±4.5 26.4±4.1 23.8±5.3 †,‡ >0.99 <0.001 0.25
CMV Group 30.3±3.4 29.5±4.0 27.1±4.3 25.5±4.7 †,‡
Compliance – mL/cmH2O; HFO-TGI Group 32.3±8.2 32.1±8.2 41.6±11.5 †,‡ 44.4±10.7 †,‡ 0.03 <0.001 0.02
CMV Group 30.8±6.7 31.5±8.1 32.1±5.0 35.4±11.2
SOFA score- (no. of surviving patients); HFO-TGI Group 11.6±2.6 (22) 11.3±2.4 (22) 10.0±2.8 (17) 6.7±4.0 †,‡,§ (14) 0.41 <0.001 0.006
CMV Group 10.8±2.4 (12) 11.1±2.3 (12) 9.6±2.8 (11) 8.4±3.4 †,‡,§ (11)
CMV, conventional mechanical ventilation; HFO, high-frequency oscillation; TGI, tracheal gas insufflation. Values are mean±SD. Data originate from physiologic measurements performed during conventional mechanical ventilation in each one of the 34 patients (intention-to-treat analysis), within 2 hours before randomization (baseline), and in-between 9:00 and 10:00 a.m. of days 1-10 post-randomization; between-group and within-group multiple comparisons were subjected to the Bonferroni correction (see also relevant subsection of Statistical Methodology). †, P<0.05 versus baseline. ‡, P<0.05 versus Day 1. §, P<0.05 versus Day 5.
31
eTable 7. Organ or system failure free and ventilator free days during follow-up.
ORGAN OR SYSTEM ORGAN FAILURE FREE DAYS WITHIN 28 P value ORGAN FAILURE FREE DAYS WITHIN 60 P value
DAYS POST-RANDOMIZATION DAYS POST-RANDOMIZATION
HFO-TGI Group (n=61) CMV Group (n=64) HFO-TGI Group (n=61) CMV Group (n=64)
Respiratory 15.0 (1.0-22.0) 1.0 (0.0-7.75) 0.001 46.0 (2.0-54.0) 5.0 (0.0-33.75) 0.001
Coagulation 28.0 (15.0-28.0) 17.0 (5.25-28.0) 0.008 60.0 (21.5-60.0) 17.0 (5.25-60.0) 0.003
Liver 28.0 (26.0-28.0) 24.5 (6.25-28.0) 0.004 60.0 (28.5-60.0) 24.5 (6.25-60.0) 0.003
Circulatory 18.0 (1.0-23.0) 3.5 (0.0-13.75) 0.003 43.0 (2.0-55.0) 6.5 (0.0-39.0) 0.001
Central nervous * 11.8 1.4 10.1 1.5 0.41 37.3 2.7 31.0 3.3 0.14
Renal 28.0 (7.25-28.0) 14.0 (2.0-28.0) 0.007 60.0 (12.0-60.0) 15.5 (2.0-60.0) 0.001
Nonpulmonary organs 0.0 (0.0-16.5) 0.0 (0.0-2.0) 0.01 29.0 (0.0-46.5) 0.0 (0.0-30.75) 0.001
Unassisted breathing 0.0 (0.0-12.5) 0.0 (0.0-0.0) <0.001 31.0 (0.0-42.0) 0.0 (0.0-23.0) <0.001
CMV, conventional mechanical ventilation; HFO, high-frequency oscillation; TGI, tracheal gas insufflation. For variables with skewed distributions, values are median (interquartile range); for variables with normal distributions values are meanSEM. *, Data are from 45 HFO-TGI-group patients and from 37 CMV-group patients, in whom it was feasible to obtain at least 1 daily Glasgow Coma Scale Score; neurological evaluation was not feasible before the occurrence of death in 16 HFO-TGI-group patients and 27 CMV-group patients; in these patients, sedation/neuromuscular blockade could not be discontinued due to the concomitant severe respiratory failure; the proportions of patient-days without neurological evaluation to day 60 were 715/2781 (25.7%) in the HFO-TGI group and 502/2017 (24.9%) in the CMV group (P=0.52).
32
eTable 8. Sedatives/analgesics, neuromuscular blockers, diuretics, and corticosteroids administered at baseline, day 1, day 5, and day 10 post-randomization.
BASELINE DAY 1 DAY 5 DAY 10 P-VALUES, EFFECT OF
Group Time Group*Time
Midazolam - mg/kg/h – no. (% of surviving patients); HFO-TGI Group 0.27±0.09; 54 (88.5) 0.27±0.10; 54 (88.5) 0.27±0.10; 41 (74.5) 0.23±0.11; 26 (52.0) 0.07 <0.001 0.02
CMV Group 0.24±0.08; 56 (87.5) 0.24±0.07; 56 (87.5) 0.22±0.07; 44 (80.0) 0.22±0.11; 26 (63.4)
Propofol - mg/kg/h; – no. (% of surviving patients); HFO-TGI Group 1.8±0.9; 46 (75.4) 1.9±0.8; 44 (72.1) 1.7±0.8; 39 (70.9) 1.6±0.6; 22 (44.0) 0.48 0.16 0.38
CMV Group 1.7±0.5; 45 (70.3) 1.6±0.5; 45 (70.3) 1.6±0.8; 39 (70.9) 1.7±0.7; 27 (65.9)
Fentanyl - μg/kg/h; – no. (% of surviving patients); HFO-TGI Group 1.1±0.6; 16 (26.2) 1.1±0.6; 16 (26.2) 0.9±0.6; 14 (25.5) 1.1±0.6; 8 (16.0) 0.14 0.001 0.001
CMV Group 1.1±0.5; 15 (23.4) 1.1±0.5; 15 (23.4) 0.8±0.6; 11 (20.0) 0.6±0.3; 5 (12.2)
Remifentanil - μg/kg/min; – no. (% of surviving patients); HFO-TGI Group 0.08±0.02; 13 (21.3) 0.08±0.02; 15 (24.6) 0.08±0.03; 18 (32.7) 0.13±0.09; 14 (28.0) 0.52 <0.001 >0.99
CMV Group 0.07±0.04; 11 (17.2) 0.07±0.04; 11 (17.2) 0.11±0.07; 13 (23.6) 0.15±0.09; 10 (24.4) †
Cis-atracurium - mg/kg/h for 24 h; – no. (% of surviving patients); HFO-TGI Group 0.22±0.05; 40 (65.6) 0.20±0.06; 45 (73.8) 0.22±0.07; 22 (40.0) 0.21±0.09; 10 (20.0) 0.20 0.04 0.38
CMV Group 0.23±0.03; 40 (62.5) 0.23±0.04; 40 (62.5) 0.22±0.05; 26 (47.3) 0.19±0.09; 14 (34.1)
Cis-atracurium - mg/kg/h for ≤8 h #; – no. (% of surviving patients); HFO-TGI Group 0.00±0.00; 21 (34.4) 0.06±0.02 *,†; 16 (26.2) 0.00±0.01 ‡; 33 (60.0) 0.00±0.00 ‡; 40 (80.0) 0.08 <0.001 0.006
CMV Group 0.00±0.00; 24 (37.5) 0.03±0.04 †; 24 (37.5) 0.01±0.04; 29 (52.7) 0.00±0.00 ‡; 27 (65.9)
Furosemide – mg/day; – no. (% of surviving patients); HFO-TGI Group 107±87; 17 (27.9) 160±118; 18 (29.5) 188±135; 28 (50.9) 120±126; 21 (42.0) 0.84 <0.001 0.03
CMV Group 82±47; 17 (26.6) 86±70; 13 (20.3) 144±122; 24 (43.6) 196±166; 16 (39.0)
Hydrocortisone – mg/day; – no. (% of surviving patients); HFO-TGI Group 289±57; 28 (45.9) 300±0; 34 (55.7) 158±84; 37 (67.3) †,‡ 220±63; 10 (20.0) †,‡ 0.004 <0.001 0.08
CMV Group 300±0; 26 (40.6) 300±0; 30 (46.9) 206±100; 33 (60.0) †,‡ 242±79; 12 (29.3) †,‡
33
CMV, conventional mechanical ventilation; HFO, high-frequency oscillation; TGI, tracheal gas insufflation. Results are mean±SD of patient recordings of days 1, 5, and 10, and number (percentage) of surviving patients treated at the aforementioned time points. For furosemide, and hydrocortisone, baseline data refer to the cumulative dose over the preceding 24 hours. For all other drugs, baseline data refer to infusion rates just prior to study enrollment. #, For the purpose of analysis, when given for ≤8 hours, cisatracurium total daily dose (in mg/kg) was always divided by 8, thus yielding the equivalent 8-hour infusion rate. Between-group and within-group multiple comparisons were subjected to the Bonferroni correction (see also "Additional Statistical Details"). Data on norepinephrine are presented in Table 4 of the main manuscript. *, P<0.05 vs. CMV group †, P<0.05 versus baseline. ‡, P<0.05 versus day 1. §, P<0.05 versus day 5.
34
eTable 9. Cumulative doses of and numbers of patients treated with sedatives,
opioids, and cisatracurium during days 1-60.
HFO-TGI Group CMV Group P value
(n=61) (n=64)
Midazolam (mg) 4383±2862 3911±2563 0.35
No. of patients treated (% of total patients) 58 (95.1) 59 (92.2) 0.72
Propofol (mg) 50865±40572 45672±34904 0.48
No. of patients treated (% of total patients) 53 (86.9) 53 (84.1) 0.80
Fentanyl (mg) 225±249 122±190 0.15
No. of patients treated (% of total patients) 19 (31.1) 21 (32.8) 0.85
Remifentanil (mg) 157 (50-238) 124 (43-285) 0.47
No. of patients treated (% of total patients) 40 (65.6) 46 (71.9) 0.56
Cisatracurium (mg) 1176 (517-2590) 1393 (635-3411) 0.25
No. of patients treated (% of total patients) 61 (100.0) 60 (93.8) 0.12
CMV, conventional mechanical ventilation; HFO, high-frequency oscillation; TGI, tracheal gas insufflation. Data are mean±SD, or median (interquartile range), or number (percentage). In addition to the presented results, 4 HFO-TGI group patients (6.6%) and 3 CMV group patients (4.7%) (P=0.71) developed post-randomization, treatment-refractory, intracranial hypertension (see also eTable 1 and text), which was effectively controlled with thiopental infused at a rate of 5-7 mg/kg/h, the respective total dose of thiopental was within 13.4-40.0 g and 16.0-67.2 g; 1 HFO-TGI group patient and 2 CMV group patients survived to hospital discharge; the data from all 7 patients were included in the intetnion-to-treat analysis
35
eTable 10. Complications recorded throughout hospital stay.
No. – (%) of Patients No. – (%) of Patients P value
with Complication, with Complication,
HFO-TGI Group (n=61) CMV Group (n=64)
New pneumothorax * 6 (9.8) 9 (14.1) 0.59
Ventilator-associated pneumonia; 1 episode 30 (49.2) 32 (50.0) >0.99
2 episodes 9 (14.8) 11 (17.2) 0.81
Catheter-related bacteremia; 1 episode 13 (21.3) 12 (18.8) 0.82
2 episodes 1 (1.6) 1 (1.6) >0.99
Gram negative sepsis / septic shock †; 1 episode 36 (59.0) 31 (48.4) 0.28
2 episodes 11 (18.0) 9 (14.1) 0.63
Renal failure; attributed to sepsis 16 (26.2) 17 (26.6) >0.99
non-septic etiology 4 (6.6) 7 (10.9) 0.53
Coagulation failure; attributed to sepsis 9 (14.8) 11 (17.2) 0.81
non-septic etiology 6 (9.8) 6 (9.4) >0.99
Hepatic failure § 6 (9.8) 6 (9.4) >0.99
Neurologic failure; septic encephalopathy 24 (39.3) 25 (39.1) >0.99
non-septic etiology 8 (13.1) 5 (7.8) 0.39
Heparin-induced thrombocytopenia 10 (16.4) 12 (18.8) 0.82
Weaning failure / Recurrence of ventilatory failure ‡;
1 episode 29 (47.5) 21 (32.8) 0.10
2 episodes 14 (23.0) 10 (15.6) 0.37
3 episodes 5 (8.2) 3 (4.7) 0.49
Paresis║ 11 (18.0) 10 (15.6) 0.81
Other ** 16 (26.2) 10 (15.6) 0.19
CMV, conventional mechanical ventilation; HFO, high-frequency oscillation; TGI, tracheal gas insufflation; ARDS, acute respiratory distress syndrome. *, The complication was treated with chest tube drainage in all cases; for results on other forms of barotrauma see subsection "Clinical course data" of eResults. †, On study enrollment, 46 of the 60 HFO-TGI-group patients (75.4%) and 46 of the 64 CMV-group patients (71.9%) (P=0.69) had already clinical manifestations of sepsis/septic shock, which was subsequently microbiologically confirmed through blood culture positivity (all respective blood samples were taken before enrollment); this episode was not considered as a post-randomization complication. §, Complication confirmed at 16.7±20.7 (range, 2-57) and 16.0±20.1 (range, 2-56) days post- randomization in the HFO-TGI group and CMV group, respectively (P=0.96); the hepatic failure was associated with multiple organ failure in all cases. 36
‡, Weaning failure: inability to maintain spontaneous breathing for ≥48 hours following cessation of mechanical ventilatory support / Recurrence of ventilatory failure: any inability to maintain unassisted breathing throughout post-randomization hospital stay; in the presented results, the occurrence of either of the aforementioned complications corresponds to 1 episode. ║, Defined as inability for muscular movement against a slight resistance; the presence of paresis could not be evaluated in 17 HFO-TGI group patients (27.9%) and 27 CMV-group patients (42.2%) (P=0.13), because of inability to discontinue the sedation before the occurrence of death. **, Includes 4 cases of surgical wound infection (2 in the HFO-TGI group and 2 in the CMV group), and iatrogenic pneumothorax (2 in the HFO-TGI group and 1 in the CMV group); 2 cases of acalculus cholecystitis (1 in each group), candidemia (1 in each group), intrapulmonary hemorrhage (1 in each group), myositis ossificans (1 in each group), and empyema secondary to pulmonary abscess rupture (both in the HFO-TGI group; the presence of abscesses was confirmed by computerized tomography performed prior to study enrollment in 1 of the 2 patients and after study enrollment in the other patient); and 1 case of soft tissue infection (CMV group), hemorrhagic cystitis (HFO-TGI group), splenic abscess (HFO-TGI group), sinusitis (HFO-TGI group), cerebral venous thrombosis (HFO-TGI group), accidental extubation (HFO-TGI group), aortic aneurysm rupture (CMV group), abdominal compartment syndrome (CMV group), and recurrent atelectasis/hypoxemia due to main bronchus occlusion by mucous plugs/thrombotic material (HFO-TGI group).
37
eTable 11. Causes of death and mortality rates at 14, 28, 60, 90, and 150 days
post-randomization.
HFO-TGI Group CMV Group P-value
(n=61) (n=64)
Causes of death during days 1-14
Multiple organ failure - no. (%) * 7 (11.5) 20 (31.3) 0.009
Extrapulmonary Sepsis - no. (%) †, †† 2 (3.3) 2 (3.1) >0.99
Refractory Hypoxemia – no. (%) ‡ 1 (1.6) 3 (4.7) 0.62
Cardiac arrest after spontaneous pneumothorax during CMV- no. (%) 0 (0.0) 1 (1.6) >0.99
Cardiac arrest after iatrogenic pneumothorax - no. (%) 1 (1.6) 0 (0.0) 0.49
Mortality rate at day 14-no (%) 11 (18.0) 26 (40.6) 0.006
Causes of death during days 15-28
Multiple organ failure - no. (%) * 1 (1.6) 2 (3.1) >0.99
Extrapulmonary Sepsis - no. (%) §, †† 1 (1.6) 2 (3.1) >0.99
Refractory Hypoxemia – no. (%) ‡ 0 (0.0) 1 (1.6) >0.99
Cardiac arrest after spontaneous pneumothorax during CMV 1 (1.6) 1 (1.6) >0.99
Cardiac arrest after iatrogenic pneumothorax - no. (%) 0 (0.0) 1 (1.6) >0.99
Mortality rate at day 28-no (%) 14 (23.0) 33 (51.6) 0.002
Causes of death during days 29-60
Extrapulmonary Sepsis - no. (%)║,†† 4 (6.6) 5 (7.8) >0.99
Rupture of Aortic Aneurysm – no. (%) 0 (0.0) 1 (1.6) >0.99
Other ** 1 (1.6) 0 (0.0) 0.49
Mortality rate at day 60-no (%) 19 (31.1) 39 (60.9) 0.001
Causes of death during days 61-90
Extrapulmonary Sepsis - no. (%)║,†† 4 (6.6) 1 (1.6) 0.20
Mortality rate at day 90-no (%) 23 (37.7) 40 (62.5) 0.007
38
eTable 11. Causes of death and mortality rates at 14, 28, 60, 90, and 150 days
post-randomization (cont).
Causes of death during days 91-150
Extrapulmonary Sepsis - no. (%)║,†† 0 (0.0) 1 (1.6) >0.99
Mortality rate at day 150-no (%) ‡‡ 23 (37.7) 41 (64.1) 0.004
CMV, conventional mechanical ventilation; HFO, high-frequency oscillation; TGI, tracheal gas insufflation. Values are number (percentage). *, All patients had concurrent respiratory failure (i.e. PaO2/inspired O2 fraction <200 mmHg) and the multiple organ failure was likely causally related and/or aggravated by their severe acute respiratory distress syndrome [55]; for additional, clinical course details see text. †, With concurrent respiratory failure.
‡, Defined as sustained (i.e., for 60 min) drop of PaO2/FiO2 to <50 mmHg, not responsive to rescue oxygenation interventions. §, Without concurrent respiratory failure in 1 CMV group patient, and with concurrent respiratory failure in the remaining 2 patients. ║, Without concurrent respiratory failure in all patients. **, Patient assumed dead for the purpose of analysis, because at the time of transfer to another hospital not participating in the study, he did not fulfill the pre-specified criterion of "Hospital Discharge" (see also subsection "Outcome measures" of Methods and legend of Figure 2 of main manuscript). ††, Extrapulmonary septic complications according to group: HFO-TGI group: 7 patients had intraabdominal sepsis, 2 patients had catheter-related sepsis, 1 patient had empyema-related sepsis, and 1 patient had urosepsis; CMV group: 5 patients had intraabdominal sepsis, 4 patients had catheter- related sepsis, 1 patient had empyema-related sepsis, and 1 patient had mediastinitis. ‡‡, The "surviving status" of all the 61 discharged patients at 150 days post-randomization was reconfirmed though telephone communication.
39 eTable 12. Results of the Cox regression analysis.
Covariate Hazard Ratio95% CI P-value
Assignment to CMV group 2.64 1.51-4.61 0.001
Arterial blood lactate - mmol/L* 1.16 1.06-1.28 0.002
SAPS II * 1.04 1.01-1.06 0.003
Arterial pH* 0.14 0.06-2.87 0.20
Plateau Pressure - cmH2O* 1.05 0.96-1.15 0.27
Oxygenation index* 1.01 0.99-1.04 0.40
Study center (Evaggelismos hospital) 0.97 0.47-2.01 0.94
CI:, confidence interval; CMV, conventional mechanical ventilation; SAPS, simplified acute physiology score. *, Variable values were determined within 2 hours after randomization. 1 cmH2O = 0.098 kPa.
40
eFigure 1. The present trial’s protocolized use of sedation and paralysis. 41
ARDS, acute respiratory distress syndrome; HFO, high-frequency oscillation; CMV, conventional mechanical ventilation; TGI, tracheal gas insufflation; FiO2, inspired O2 fraction; PEEP, positive end- expiratory pressure. *, PaO2/FiO2<150 mmHg, despite being ventilated at PEEP≥8 cmH2O for >12 consecutive hours. †, In both study centers, the standard management of sedation and paralysis of patients with ARDS [1] is similar to the presented protocol. ‡, Refers mainly to trauma patients, and/or patients subjected to major surgery. §, The criteria for the "use or no use" of neuromuscular blockade are reported in the text. ║, Unless the patient is on HFO-TGI throughout that day. **, Additional, standard criteria for the interruption of sedation and/or analgesia are reported in the text. ††, The criteria for the restarting of the intravenous sedation are detailed in the text. §§, The criteria for partial ventilatory support are presented in the text and eFigure 2.
42
eFigure 2. Schematic representation of the weaning protocol. CMV, conventional mechanical ventilation; FiO2, inspired O2 fraction; PEEP, positive end-expiratory pressure; pHa, arterial-blood pH; SAP, systolic arterial pressure; SpO2, peripheral O2 saturation. Continuous lines correspond to the clinical evaluation detailed in the dedicated box. For steps I-III, the "transition to the next step" corresponds to successful gradual withdrawal of ventilatory support. The transition from step IV to step V corresponds to a successful spontaneous breathing trial. *, At the end of a successful spontaneous breathing trial confirm that PaO2>60 mmHg and pHa>7.30 by arterial blood gas analysis. †, In case of recurrence of respiratory failure, reintubate and consider tracheostomy. ‡, In case of patient failure to tolerate spontaneous breathing for 48 consecutive hours, return to Step I or CMV for 12-24 hours; following tracheostomy decannulation, consider interim placement of a minitracheostomy tube to facilitate suctioning of secretions. 1 cmH2O=0.098 kPa; 1 mmHg=0.133 kPa.
43
eFigure 3. Pre-specified algorithmic actions and options for the case of Study Intervention Failure. HFO, high-frequency oscillation; TGI, tracheal gas insufflation; mPaw, mean airway pressure; FiO2, inspired O2 fraction; SpO2, peripheral O2 saturation; iNO, inhaled nitric oxide. An arterial blood gas 44 analysis was to be performed and hemodynamic data were to be recorded at 30 min after every change in high-frequency ventilator mPaw, or TGI, or use of an additional intervention. *, If applicable, consider HFO without TGI after taking into account the oxygenation response to TGI discontinuation during the weaning period of the preceding HFO-TGI session. †, Defined as additional interventions; the use of these interventions had to be approved by the attending physicians. ‡, If applicable, return to the supine position from prone, or discontinue iNO, or both; if on HFO without TGI, restart TGI at its initial setting of 50% of the minute ventilation of the conventional mechanical ventilation that preceded the HFO-TGI session. §, If on HFO without TGI, follow all steps of the HFO-TGI protocol (apart from the discontinuation of TGI) as presented in Figure 1 of the main manuscript. ║, This time point corresponds to the end of the weaning period of the HFO-TGI session, i.e., 60 min after the reaching of the protocol-pre-specified target mPaw, which is 6 cmH2O lower than the initial mPaw used at the start of the HFO-TGI session (see also Figure 1 of main manuscript).
45
eFigure 4. The set-up for high-frequency oscillation (HFO) and tracheal gas insufflation (TGI). 46
A: AD, Smiths Medical circuit adapter with angled side arm; PTGI, proximal end of TGI catheter; VOF, variable orifice O2 flowmeter; the adhesive tape (see below) has just been removed, in order to replace the current TGI catheter by a new one (see also text). B: Adhesive tape is placed around the PTGI and the proximal end of the side arm (SA) of the AD, in order to minimize the independent oscillatory motion of the TGI catheter. C: Laboratory evaluation of the positioning of the distal end of the TGI catheter relative to the distal end of a Portex endotracheal tube (ETT; inner diameter=8.0 mm) during HFO-TGI (ventilator settings: bias flow=60 L/min, frequency=4 Hz, oscillatory pressure amplitude=100 cmH2O, inspiratory time=33% of total respiratory cycle time, inspired O2 fraction=100%, ventilator-displayed mean airway pressure=26 cmH2O; O2 flow through the TGI catheter=6 L/min); upper panel: photograph of the distal ends of the ETT and the TGI catheter taken just after the initiation of the experiment; lower panel: photograph of the distal ends of ETT and the TGI catheter taken 30 min after the initiation of the experiment; in both pictures, the black line is the axis of the distal orifice of the TGI catheter and the red line is the distance between the catheter-orifice axis and the midpoint of the distal end of the "blue line" of the ETT; in both pictures, the length of the red line is 6.5 mm.
47
eFigure 5. Effect of high frequency oscillation (HFO) and tracheal gas insufflation (TGI) on respiratory physiology. 48
FiO2, inspired O2 fraction. Data from cases of "Study Intervention Failure" (see text) are included in all panels. A-D: Effect of HFO-TGI sessions; circles correspond to individual patient values and bars show the level of the mean values. A and B: Evolution of PaO2/FiO2 and oxygenation index just before{pre- HFO-TGI conventional mechanical ventilation (CMV)}, during (end of recruitment, stabilization period, and weaning period), and at 6 hours after (post-HFO-TGI CMV) the HFO-TGI sessions; TGI was discontinued at 30 min before the end of the weaning period (see also Figure 1 of main manuscript); C and D: Plateau pressure and respiratory compliance before and after the HFO-TGI sessions. E: Effect of the total study intervention, i.e., physiological variables just before the first session and at 6 hours after the last session of HFO-TGI. "Before" corresponds to the first study measurements of pre- HFO-TGI CMV; these measurements were performed on day 1 of the intervention period, whereas "After" corresponds to the last study measurements of post-HFO-TGI CMV; these measurements were performed within days 2-11 of the intervention period, depending on the time point of the end of the last HFO-TGI session according to the oxygenation criterion of the study protocol (see also Figure 1 of main manuscript). Small circles correspond to individual patient values. Large, interconnected circles show the level of the mean values. *, P<0.05 vs. pre-HFO-TGI CMV. †, P<0.05 vs. the end of the recruitment period. ‡, P<0.05 vs. the end of the stabilization period. §, P<0.05 vs. the end of the weaning period. ║, P<0.05 vs. the first study measurement of pre-HFO-TGI CMV.
49
50
eFigure 6. Airway pressures, hemodynamics, and PaCO2, just before, during, and at 6 hours after the sessions of high frequency oscillation (HFO) and tracheal gas insufflation (TGI). Values are meanSD. Data from cases of "Study Intervention Failure" (see text) are included in all panels. Time points during HFO-TGI correspond to the end of recruitment, stabilization, and weaning period). A: Ventilator-displayed mean airway pressure; B: Actually measured mean tracheal pressure (before HFO-TGI and weaning period), and estimated mean tracheal pressure (recruitment and stabilization period, and after HFO-TGI); C, D, E, and F: Evolution of cardiac index, mean arterial pressure, central venous pressure, and PaCO2; E: The increase in central venous pressure after vs. before HFO-TGI, probably reflects the positive fluid balance of days 1-10 (see also Table 4 of main manuscript). *, P<0.05 vs. before HFO-TGI. †, P<0.05 vs. the end of the recruitment period. ‡, P<0.05 vs. the end of the stabilization period. §, P<0.05 vs. the end of the weaning period.