Right over left ventricular end-diastolic area relevance to predict hemodynamic intolerance of high-frequency oscillatory ventilation in patients with severe ARDS

Abstract

Background

High-frequency oscillatory ventilation (HFOV) does not improve the prognosis of ARDS patients despite an improvement in oxygenation. This paradox may partly be explained by HFOV hemodynamic side-effects on right ventricular function. Our goal was to study the link between HFOV and hemodynamic effects and to test if the pre-HFOV right over left ventricular end-diastolic area (RVEDA/LVEDA) ratio, as a simple parameter of afterload-related RV dysfunction, could be used to predict HFOV hemodynamic intolerance in patients with severe ARDS.

Methods

Twenty-four patients were studied just before and within 3 h of HFOV using transthoracic echocardiography and transpulmonary thermodilution.

Results

Before HFOV, the mean PaO2/FiO2 ratio was 89 ± 23. The number of patients with a RVEDA/LVEDA ratio >0.6 significantly increased after HFOV [11 (46 %) vs. 17 (71 %)]. Although HFOV did not significantly decrease the arterial pressure (systolic, diastolic, mean and pulse pressure), it significantly decreased the cardiac index (CI) by 13 ± 18 % and significantly increased the RVEDA/LVEDA ratio by 14 ± 11 %. A significant correlation was observed between pre-HFOV RVEDA/LVEDA ratio and CI diminution after HFOV (r = 0.78; p < 0.0001). A RVEDA/LVEDA ratio superior to 0.6 resulted in a CI decrease >15 % during HFOV with a sensitivity of 80 % (95 % confidence interval 44-98 %) and a specificity of 79 % (confidence interval 49-95 %).

Conclusion

The RVEDA/LVEDA ratio measured just before HFOV predicts the hemodynamic intolerance of this technique in patients with severe ARDS. A high ratio under CMV raises questions about the use of HFOV in such patients.

Trial registration: ClinicalTrials.gov: NCT01167621

Ursulet et al. Ann. Intensive Care (2015) 5:25 DOI 10.1186/s13613-015-0068-6

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Web End = Lionel Ursulet1, Arnaud Roussiaux1, Dominique Belcour1, Cyril Ferdynus2, BernardAlex Gauzere1, David Vandroux1 and Julien Jabot1*

Abstract

Background: Highfrequency oscillatory ventilation (HFOV) does not improve the prognosis of ARDS patients despite an improvement in oxygenation. This paradox may partly be explained by HFOV hemodynamic sideeects on right ventricular function. Our goal was to study the link between HFOV and hemodynamic eects and to test if the preHFOV right over left ventricular enddiastolic area (RVEDA/LVEDA) ratio, as a simple parameter of afterload related RV dysfunction, could be used to predict HFOV hemodynamic intolerance in patients with severe ARDS.

Methods: Twentyfour patients were studied just before and within 3 h of HFOV using transthoracic echocardiogra phy and transpulmonary thermodilution.

Results: Before HFOV, the mean PaO2/FiO2 ratio was 89 23. The number of patients with a RVEDA/LVEDA ratio >0.6

signicantly increased after HFOV [11 (46 %) vs. 17 (71 %)]. Although HFOV did not signicantly decrease the arterial pressure (systolic, diastolic, mean and pulse pressure), it signicantly decreased the cardiac index (CI) by 13 18 %

and signicantly increased the RVEDA/LVEDA ratio by 14 11 %. A signicant correlation was observed between

preHFOV RVEDA/LVEDA ratio and CI diminution after HFOV (r = 0.78; p < 0.0001). A RVEDA/LVEDA ratio superior to

0.6 resulted in a CI decrease >15 % during HFOV with a sensitivity of 80 % (95 % condence interval 4498 %) and a specicity of 79 % (condence interval 4995 %).

Conclusion: The RVEDA/LVEDA ratio measured just before HFOV predicts the hemodynamic intolerance of this tech nique in patients with severe ARDS. A high ratio under CMV raises questions about the use of HFOV in such patients.

Trial registration: ClinicalTrials.gov: NCT01167621Keywords: Acute respiratory distress syndrome, Highfrequency oscillatory ventilation, Hemodynamic monitoring,

Acute right ventricular dysfunction, Echocardiography, Transpulmonary thermodilution

Background

In severe acute respiratory distress syndrome (ARDS), alternative therapies are indicated [1] when protective conventional mechanical ventilation (CMV) fails to maintain efficient gas exchange. High-frequency

oscillatory ventilation (HFOV) is a non-CMV technique that could improve alveolar recruitment and achieve protective ventilation with the most severe cases of ARDS using very low tidal volume (VT) and relatively high mean airway pressure (mPaw) as a surrogate for positive end-expiratory pressure (PEEP). Previous studies have clearly shown an improvement in oxygenation with HFOV [2] and even suggest a reduction in mortality [3, 4] although the level of improvement in oxygenation

*Correspondence: [email protected]

1 Medical Surgical Intensive Care Unit, Saint Denis University Hospital, Saint Denis, Reunion Island, FranceFull list of author information is available at the end of the article

2015 Ursulet et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/

Web End =http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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is unpredictable and HFOV can indeed worsen oxygenation in some patients [5]. Alveolar recruitmentand thus improvement in gas exchangeseems to depend on the level of mPaw [6, 7] and a high mPaw (around 30cm H2O) for a period of several days seems to give the best results [6]. Unfortunately, two large, multicenter, randomized controlled trials recently raised doubts about the safety of HFOV: the rst [8] showed no signicant eect on 30-day mortality and, troublingly, the second [9] was prematurely discontinued following a nonsignicant but constant increase in mortality at each interim analysis. This paradoxan improvement in oxygenation in most cases on the one hand but no mortality reduction on the othermay partly be explained by the hemodynamic side-eects of HFOV. Indeed, a retrospective study [5] involving 190 patients treated by HFOV reported a high rate of hemodynamic complications (27 %). A study involving only nine patients with high mPaw HFOV showed a decrease in cardiac index (CI), probably due to airway pressure-related preload reduction [10]. Finally, a study involving 16 patients demonstrated that HFOV could worsen right ventricular function [11]. Therefore, our goal was to monitor hemo-dynamic eects during the rst 3 h with high mPaw HFOV using transthoracic echocardiography (TTE) and transpulmonary thermodilution (TPTD) and to assess if afterload-related RV dysfunction measured just before HFOV like the right over left ventricular end-diastolic area (RVEDA/LVEDA) ratio could predict hemodynamic intolerance during HFOV.

Methods

Patients

This observational prospective study was approved by the ethics committee of Bordeaux University Hospital (Comit de Protection des Personnes Sud-Ouest et Outre-Mer III, no. 2010-A00338-31).Written informed consent was obtained from each patients next of kin.

In our 18-bed intensive care unit (ICU), VMC therapy for ARDS was set according to a standardized protocol for maximal alveolar recruitment: protective CMV consisted of a volume-controlled mode with a VT of 6 mL kg1 of predicted body weight (PBW), maximal PEEP without exceeding a plateau airway pressure of 30 cmH2O [12], controlled sedation for a Ramsay Score>5 [13] followed by continuous infusion of cis-atracurium [14] and systematic use of a heated humidier and a closed endotracheal suction catheter [15]. All patients were hemodynamically optimized according to TPTD monitoring PiCCO2 (Pulsion Medical Systems, Munich, Germany) and/or TTE monitoring [16, 17].

In our unit, refractory ARDS was dened as follows:

Life-threatening hypoxemia (PaO2/FiO2<70mmHg) at any time during the rst 12h of CMV for maximal alveolar recruitment

When one of more of the following criteria are met after 12 h of CMV: arterial blood oxygen saturation <90 % with fraction of inspired oxygen (FiO2) = 1; PaO2/FiO2 ratio <120; hypercap

nia>55mmHg or pH<7.20 despite a respiratory rate of 35 min1, plateau airway pressure >30 cm H2O with a tidal volume of 6mLkg1 of PBW and a 5 cm H2O minimal PEEP.

When a patient exhibited these criteria for refractory ARDS, rescue therapies were considered (i.e., HFOV, prone positioning [18] or extra-corporeal membrane oxygenation (ECMO) [19]). Patients undergoing HFOV were enrolled in the study from May 2010 to November 2012 if the following criteria were met:

Refractory ARDS

HFOV used as an alternative therapy to CMV

A TPTD device used for hemodynamic monitoring

Hemodynamic stability during the 10 min prior to HFOV (mean arterial pressure stable and between 65 and 85mmHg, no CI variation of more than 10% given by the PiCCO2 beat-to-beat pulse contour analysis, no change in norepinephrine dose).

Exclusion criteria were:

Age<18years

Moribund status

Contraindications to HFOV (head injury, pneumothorax or persistent air leak despite chest tube insertion)

Hemodynamic instability before HFOV

Poor echogenicity preventing appropriate echocardiographic assessment by TTE.

HFOV

Initial settings andparameter adjustment

At inclusion, HFOV (3100B SensorMedics ventilator, Yorba Linda, CA, USA) was initially set as follows: FiO2

1; frequency 6 Hz; bias ow 40 L min1; mPaw 10 cm H2O above the CMV mPAw up to a maximum of 30 cm

H2O and pressure amplitude of oscillation 80%. During the 3-h protocol, mPaw and bias ow were not modied; other parameters were adjusted as follows:

FiO2 adjusted to obtain a PaO2 of 6085mmHg

Frequency and pressure amplitude of oscillation adjusted to obtain a pH>7.25 and a PCO2<55mmHg

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HFOV failure criteria

HFOV was dened as a failure if at least one of the following occurred:

Oxygen saturation fell below 90% despite a FiO2 1

PaO2/FiO2 ratio<70

Hypercapnia>55mmHg and/or pH<7.20 despite a frequency of 3.5Hz and pressure amplitude of oscillation of 100%

Occurrence of a new pneumothorax.

We dened HFOV-associated hemodynamic failure as major hemodynamic instability linked to HFOV: signi-cant arterial hypotension (systolic arterial pressure under 90mmHg or a decrease>30% of initial systolic pressure) and/or CI decrease>30%.

When HFOV failure was ascertained, CMV was removed leading to the termination of the study and an alternative method of oxygenation (prone positioning or ECMO) was initiated. If systolic arterial pressure was under 90mmHg, the norepinephrine dose was increased during the HFOVCMV transfer process.

Hemodynamic measurements

The study began at patient inclusion, i.e., under CMV during a 10-min period before initiation of HFOV, and ended 3h later. The dierent stages of the study were:

Just before initiation of HFOV (CMVpre)

Connection to HFOV (HFOV connection)

After 1h of HFOV (H1 HFOV)

After 3h of HFOV (H3 HFOV)

In each sequence, heart rate, arterial pressure, catecholamine and sedation dose rates and TTE and TPTD data were recorded.

TTE measurements

TTE were performed by a single experienced echocardiographer. Images were acquired using an EnVisor Philips HD 11XE (Philips Medical System, Andover, MA, USA) scanner and a 3MHz transducer. Two-dimensional (2D) imaging examinations were performed in the standard apical four- and two-chamber views (4C- and 2C-views). Tissue harmonic imaging was used to enhance 2D image quality. Left ventricular ejection fraction (LVEF) was measured either by the biplane or monoplane Simpson method [20]. The velocitytime integral in the left ventricular outow tract (LVOT VTI) was measured using pulsed wave Doppler in the apical ve-chamber view. LVEDA and RVEDA were measured in the 4C-view. Echocardiographic patterns of acute cor pulmonale (ACP) associating RVEDA/LVEDA ratio>0.6 and systolic

septal dyskinesia on a short-axis view were looked for [21]. LV lling parameters were assessed in the 4C-view and using pulsed wave and tissue Doppler imaging in accordance with the current standards [22, 23]. All TTE studies were recorded over three consecutive cardiac cycles independently of the respiratory cycle and averaged. In patients with non-sinus rhythm, measurements were collected over 57 heartbeats.

TPTD measurements

Injection of 15 mL of cold saline through the central venous line was performed in triplicate, and the values of the dierent TDTP parameters [CI, stroke volume index (SVI), global end-diastolic index (GEDI) and cardiac function index (CFI)] were averaged [24].

Respiratory measurements

For each sequence, ventilator settings, respiratory system mechanical parameters, arterial blood gas analysis, extravascular lung water index (ELWI) and pulmonary vascular permeability water index (PVPI) obtained by TPTD were collected [25, 26].

Statistical analysis

Qualitative variables were described in frequencies and proportions. Quantitative variables were described in means and standard deviations. Evolution of hemo-dynamic and respiratory levels during the study was assessed using a linear mixed model adjusted for time. A rst-order autoregressive variancecovariance matrix was specied, to account for the correlated repeated time data. All multiple comparisons were performed using the Schee adjustment. The receiver operating characteristics curve was constructed to assess the ability of an RVEDA/LVEDA ratio at inclusion to predict a decrease in CI>15% with HFOV. Spearman rank correlation analysis was used to assess the relationship between RVEDA/ LVEDA ratio at inclusion and changes in CI on HFOV. Statistical analysis was performed using the SAS 9.2 software (SAS Institute, Cary, NC, USA). All hypotheses were tested at the 2-tailed 0.05 signicance level.

Results

Twenty-four patients (7 women and 17 men) were included in the study. None of them had a history of chronic respiratory failure. The mean time between ICUCMV and HFOV was 9 4 h. Twenty-three patients were still under HFOV at H1 (one patient was withdrawn for hemodynamic failure), and 19 at H3 (two patients were withdrawn for respiratory failure and two more for hemodynamic failure).

On admission, the Simplied Acute Physiology Score II (SAPS II) and the Sequential Organ Failure Assessment

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(SOFA) were, respectively, 6017 and 123. Mortality at D28 was 46 %. Causes of ARDS were pulmonary for 75% of patients (n=18) (thirteen cases of infectious pneumonia, four aspiration pneumonia and one drowning accident), and extra-pulmonary for 25% of patients (n = 6). At baseline, 21 patients (82 %) were receiving norepinephrine and three dobutamine. The respiratory variables during CMV at baseline are summarized in Table1.

Hemodynamic parametersRate andcause ofhemodynamic failure

Hemodynamic failure was reported in three patients (12 %), occurring within the rst 90 min after HFOV. These three patients had an ACP echocardiographic pattern not only during CMV but also after HFOV.

Hemodynamic eects ofHFOV

As shown in Table2, although HFOV did not signicantly decrease arterial pressure (systolic, diastolic, mean and pulse pressure), it signicantly decreased CI by 1311%

from 3.71.1 Lmin1m2 at baseline and LVOT VTI by 1312% from 175cm at baseline. SVI, GEDI, CFI,

LVEF and E/A ratio also signicantly decreased, whereas the RVEDA/LVEDA ratio increased by 1411%, from

0.610.15 at baseline. The number of patients with an RVEDA/LVEDA ratio>0.6 and with an ACP echocardio-graphic pattern signicantly increased during HFOV [11 (46%) vs. 17 (71%) and 5 (21%) vs. 11 (46%), respectively]. For each patient, RVEDA/LVEDA ratio on inclusion was compared with the percentage change in TDTP CI between inclusion and HFOV. When considering these 24 pairs of measurements, a signicant inverse correlation was observed (r = 0.78; p < 0.0001) (Fig. 1).

An RVEDA/LVEDA ratio superior to 0.6 predicted a decrease in CI>15% during HFOV with a sensitivity of 80% (95% condence interval 4498%) and a specicity of 79% (condence interval 4995%) (Fig.2).

Hemodynamic changes duringthe rst 3h ofHFOV

There was no hemodynamic change during the rst 3h with the exception of E-wave, E/A ratio, RVEDA/LVEDA ratio and numbers of ACP echocardiographic patterns (Table2).

Therapeutic interventions bythe attending physicians

During the 3-h study, no volume expansion was administered to patients and there was no signicant change in doses of catecholamines, sedative drugs or cisatracurium. Therapeutic interventions were carried out only on the three patients with HFOV-associated hemodynamic failure.

Respiratory parameters

Respiratory parameter changes are summarized in Table3. The comparison of PaO2/FiO2 ratios revealed a signicant increase of 90% or more between the HFOV sequences and CMVpre sequence.

At H1 HFOV, the PaO2/FiO2 ratio increased from the baseline value by more than 100% for 39% of patients and by more than 30% for 61% of patients.

At H3 HFOV, the PaO2/FiO2 ratio increased from the baseline value by more than 100% for 47% of patients and by more than 30% for 74% of patients.

During the study, there was no signicant dierence between the mean PaO2/FiO2 ratios of the 18 patients with pulmonary ARDS and the 6 patients with extra-pulmonary ARDS (91 22 vs. 83 27 at inclusion, 180104 vs. 147119 at H1 and 18681 vs. 158131 at H3, respectively).

Discussion

To our knowledge, this study is the largest that focuses specically on hemodynamic changes during HFOV. It conrms the signicant CI decrease linked to HFOV. It also suggests that the initial pre-HFOV RVEDA/LVEDA ratio can predict the hemodynamic intolerance induced by HFOV.

Table 1 Respiratory variables atbaseline

Ventilator settings

VT (mL kg1 PBW) 5.8 0.6 Respiratory rate (cycles min1) 29 3

PEEP (cm H2O) 11 3 FiO2 (%) 97 9

Respiratorysystem mechanics

Plateau airway pressure (cm H2O) 29 2 mPaw (cm H2O) 19 3

Respiratory system compliance (mL cm H2O1) 22 9 Results of ABG measurements

pH 7.24 0.14 P/F ratio 89 23

PaO2 (mmHg) 86 22 PaCO2 (mmHg) 53 15

Bicarbonate (mmol L1) 24 5 Base excess (mmol L1) 6 6

TDTP respiratory parameters

ELWI (mL kg1 PBW) 19 7 PVPI 5.1 1.7

Results are given as meanSDABG arterial blood gas, TPTD transpulmonary thermodilution, VT tidal-volume,

PBW predicted body weight, PEEP positive end-expiratory pressure, FiO2 fraction of inspired oxygen, mPawmean airway pressure, P/F ratio of arterial oxygen concentration to the fraction of inspired oxygen, PaCO2 partial pressure of arterial carbon dioxide, PaO2 partial pressure of arterial oxygen, ELWI

extravascular lung water index, PVPI pulmonary vascular permeability index

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Table 2 Evolution ofthe hemodynamic characteristics duringthe study

CMVpre HFOV connection H1 HFOV H3 HFOV

Concerned patients number 24 24 23 19

Heart rate (beats/min) 102 22 102 23 102 23 102 24 Systolic arterial pressure (mmHg) 120 18 119 23 119 19 116 17

Diastolic arterial pressure (mmHg) 62 11 63 12 65 11 62 11 Mean arterial pressure (mmHg) 81 11 81 13 80 14 80 12

Pulse pressure (mmHg) 57 13 56 17 54 17 54 13 Cardiac index (L min1 m2) (TPTD) 3.7 1.1b,c,d 3.3 1.3a 3.3 1.2a 3.1 1.1a

SVI (mL min1 m2) (TPTD) 36 11b,c,d 33 14a 33 14a 32 14a GEDI (mL min1 m2) (TPTD) 680 140b,c,d 634 134a 646 126a 625 112a

CFI (min1) (TPTD) 5.5 1.8b,c,d 5.2 1.9a 5.0 1.8a 5.0 1.5a LVEF (%) (TTE) 53 16b,c,d 50 17a 49 15a 49 13a

RVEDA/LVEDA ratio (TTE) 0.61 0.15b,c,d 0.70 0.18a 0.72 0.18a 0.67 0.14a RVEDA/LVEDA ratio >0.6 [n (%)] 11 (46)b,c 17 (71)a,d 17 (74)a,d 10 (53)b,c

ACP echocardiographic pattern [n (%)] 5 (21)b,c 11 (46)a,d 10 (43)a,d 6 (32)b,c

LVOT VTI (cm) (TTE) 17 5b,c,d 14 5a 14 5a 14 5a Ewave (cm s1) (TTE) 90 23c 86 20c 80 21a,b,d 91 22c

Awave (cm s1) (TTE) 57 16 58 12 54 12 57 15 E (cm s1) (TTE) 14 5 14 5 14 4 15 5

DTE (ms) (TTE) 207 51 204 44 213 38 205 46

E/A (TTE) 1.8 0.5b,c 1.6 0.6a 1.6 0.5a 1.8 0.7b,c

E/E (TTE) 8.3 2.9 8.4 2.9 7.4 3.6 8.0 3.0 Norepinephrine (g kg1 min1) 0.59 0.78 0.59 0.78 0.58 0.78 0.53 0.69

Results are given as meanSDCMV conventional mechanical ventilation, HFOV high frequency oscillation ventilation, TPTD transpulmonary thermodilution, SVI stroke volume index, GEDI global end diastolic index, CFI cardiac function index, LVEF left ventricular ejection fraction, TTE transthoracic echocardiography, LVEDA left ventricular end diastolic area, RVEDA right ventricular end diastolic area, LVOT VTI velocitytime integral in the left ventricular outow tract, DTE E-wave deceleration time

a p<0.05 for all data as compared to CMVpre

b p<0.05 for all data as compared to HFOV Connection

c p<0.05 for all data as compared to H1 HFOV

d p<0.05 for all data as compared to H3 HFOV

Fig. 1 Inverse correlation between the right over left ventricular end diastolic area at inclusion and changes in cardiac index during HFOV. Line linear regression line

Although right heart dysfunction is a commonly reported side-eect of ARDS protective ventilation [27], only two prospective studies have specically focused on the hemodynamic eects of HFOV, with both transesophageal echocardiography (TEE) and right heart catheterization monitoring. David et al. reported a clinically signicant decrease in CI and SVI thought to be related to a preload decrease [10]. Guervilly etal. described a right ventricular dysfunction in HFOV proportional to the mPaw setting level [11].

Our results are in accordance with those two studies, since HFOV led to a 13% decrease in CI and to a 14% increase of RVEDA/LVEDA. The proportion of patients with a ratio above 0.6 (46 %) is comparable with that reported by Guervilly etal. (56%) [11].

The initial pre-HFOV RVEDA/LVEDA ratio is a good predictive factor of HFOV hemodynamic intolerance, as shown by the strong correlation of 78 % (r2 = 0.61)

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Fig. 2 Receiver operating characteristic curve showing the ability of the right over left ventricular enddiastolic area at inclusion to detect a cardiac index decrease 15 % during HFOV. RVEDA right ventricular

end diastolic area, LVEDA left ventricular end diastolic area

between the pre-HFOV ratio and the CI decrease induced by HFOV and the sensitivity (80%) and specicity (79%) values found to predict a decrease in 15% CI by a CMV pre-HFOV RVEDA/LVEDA superior to 0.6.

Such results underline the value of performing an echo-cardiography before HFOV to assess the RVEDA/LVEDA ratio and the risk of right ventricular dysfunction. In our study, the exact pathophysiology of right ventricular dys-function cannot be explained given the lack of pulmonary vascular resistance monitoring.

Although our denition of refractory ARDS is neither published nor consensual, these patients had severe ARDS after 12h of CMV maximum alveolar recruitment with a mean PaO2/FiO2 ratio of 8923. This new practice of delaying ARDS severity ranking is of key importance as it precludes inclusion of initially severe ARDS patients showing rapid improvement with CMV once set to maximal alveolar recruitment. Although our study was designed before the new Berlin denition for ARDS [28], its HFOV utilization is very close to that proposed by experts [29]. The early and very brief use of HFOV for 3h for severe ARDS patients improved oxygenation in 66% of cases. These data are consistent with a recent retrospective study [30] in which the early response to HFOV (an improvement of more than 38% in the PaO2/

FiO2 ratio) was identied as a predictor for survival at day 30. Therefore, HFOV could be used in the future as a recruitment technique, possibly applied sequentially as for prone positioning. This new approach is currently being studied in our ICU.

It must be said that the two recently published large randomized controlled trials, OSCILLATE [9] and

Table 3 Evolution ofthe respiratory andgazometric parameters duringthe study

CMVpre HFOV connection H1 HFOV H3 HFOV

Concerned patients number 24 24 23 19

mPaw (cm H2O) 19 3b,c,d 29 1a 28 1a 29 1a Frequency (Hz) NA 6.0 0.0d 6.0 0.0d 5.2 1.3b,c

Amplitude (cm H2O) NA 88 13 86 12 85 12 Pressure amplitude of oscillation (%) NA 80 0 79 4 79 5pH 7.24 0.14d NA 7.25 0.16 7.30 0.17a

PaCO2 (mmHg) 53 15d NA 49 19a 47 15a Bicarbonate (mmol L1) 24 5 NA 23 6 24 4

Base excess (mmol L1) 6 6d NA 6 7d 4 5a,c P/F ratio 89 23c,d NA 171 106a 177 96a

OI 26 8d NA 26 17d 23 15a,c ELWI (mL/kg PBW) 19 7 19 7 19 7 17 6

PVPI 5.1 1.7 5.2 1.8 5.1 1.5 5.1 1.7

Results are given as meanSDCMV conventional mechanical ventilation, HFOV high frequency oscillation ventilation, mPaw mean airway pressure, FiO2 fraction of inspired oxygen, P/F ratio of arterial oxygen concentration to the fraction of inspired oxygen, OI oxygenation index calculated as (mean airway pressure FiO2)/PaO2, ELWI extravascular lung

water index, PBW predicted body weight, PVPI pulmonary vascular permeability index

a p<0.05 for all data as compared to CMVpre

b p<0.05 for all data as compared to HFOV connection

c p<0.05 for all data as compared to H1 HFOV

d p<0.05 for all data as compared to H3 HFOV

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OSCAR [8] comparingHFOVwith a conventional lung-protective ventilation, casted doubt over HFOV, suggesting no benet or even a worse outcome on adults with HFOV with early moderate to severe ARDS. But despite strong compliance with current recommendations of protective ventilation from the ARDS network [31] and prompt initiation of HFOV in these two studies, randomization was performed on patients with moderate to severe ARDS (PaO2/FiO2<200), not severe ARDS patients only. Furthermore, the randomization was conducted regardless of early clinical evolution under CMV and the use of muscle relaxants was practitioner dependant. In the OSCILLATE study [9], the use of very high mPaw, without ruling out risk of potential hemodynamic failure, may have led to an excess mortality in the HFOV arm of this study. These two studies have given rise to three recent meta-analyses including 6 RCTs for 1608 patients [32], 5 RCTs for 1580 patients [33] and 7 RCTs for 1759 patients [34] without conrming better survival or higher mortality with HFOV.

Our study has several limitations. Its observational design with non-consecutive patients could engender a selection bias. The study population is small given the monocentric screening and the stringent inclusion criteria. Even if only a single experienced operator performed TTE, a post hoc analysis by an independent expert could have conrmed the hemodynamic data obtained by blinded practitioners. Similarly, data were obtained by TTE and not TEE, which, in the context of HFOV, could cast doubts on the accuracy of the results. Yet, TTE-obtained data are consistent with those found by TPTD (e.g., LVOT VTI and TPTD CI both decreased by 13 % on HFOV) and comparable to those obtained by Guervilly etal. with TEE [11]. Another limitation of the study is the lack of assessment of a potential preload decrease during HFOV. The only way to test this would have been a comparison of the passive leg raising results at inclusion and during HFOV since pulse pressure variation, stroke volume variation, vena cava variations and tele-expiratory occlusion test cannot be used with HFOV. Unfortunately, this test is very difficult to implement with HFOV and would have slowed and complicated the protocol. Lastly, it is unfortunate that we could not compare TTE data with those obtained by a pulmonary artery catheter (PAC) to better assess right ventricular function. However, our study was strictly observational and we routinely use TPTD and not PAC for monitoring patients with severe ARDS. This enables us to better assess the risk/benet ratio of volume expansion based on ELWI and PVPI rather than on pulmonary capillary pressure [35, 36]. In this context, we considered it unethical to insert a PAC in addition to a TPTD device only for the purpose of the study.

Conclusion

This study suggests that the RVEDA/LVEDA ratio measured just before HFOV is a predictor of the hemodynamic intolerance of this technique in patients with severe ARDS. A high value of this ratio observed under CMV should question the use of HFOV in such patients.

Abbreviations

ARDS: acute respiratory distress syndrome; CMV: conventional mechanical ventilation; HFOV: highfrequency oscillatory ventilation; MPaw: mean airway pressure; CI: cardiac index; TTE: transthoracic echocardiography; TPTD: transpulmonary thermodilution; RVEDA/LVEDA: right over left ventricular enddiastolic area; ICU: intensive care unit; PBW: predicted body weight; PEEP: positive endexpiratory pressure; 2D: two dimensional; 2Cview: twochamber view; 4Cview: fourchamber view; LVEF: left ventricular ejection fraction; LVOT VTI: velocitytime integral in the left ventricular outow tract; ACP: acute cor pulmonale; ELWI: extravascular lung water index; PVPI: pulmonary vascular permeability water index; SVI: stroke volume index; GEDI: global enddiastolic index; CFI: cardiac function index; SAPS II: Simplied Acute Physiology Score II; SOFA: sequential organ failure assessment; PAC: pulmonary artery catheter.

Authors contributions

LU collected the data, participated in the study design and helped to draft the manuscript. AR collected the data and helped to draft the manuscript. DB collected the data. CF performed the statistical analysis. BAG helped to draft the manuscript. DV participated in the study design and helped to draft the manuscript. JJ collected the data, performed all the TTEs, conceived the study, participated in its design and coordination and helped to draft the manuscript. All authors read and approved the nal manuscript.

Author details

1 Medical Surgical Intensive Care Unit, Saint Denis University Hospital, Saint Denis, Reunion Island, France. 2 Methodological Support and Biostatistics Unit, Saint Denis University Hospital, Saint Denis, Reunion Island, France.

Acknowledgements

We thank Didier Drouet for his help during the conception of the study and Fidline Filleul from the methodological support unit of the Saint Denis University Hospital for her help during the request for authorization by the Ethics Committee.

Compliance with ethical guidelines

Competing interests

The authors declare that they have no competing interests.

Received: 15 May 2015 Accepted: 8 September 2015

References

1. Ferguson ND, Fan E, Camporota L, Antonelli M, Anzueto A, Beale R,et al. The Berlin denition of ARDS: an expanded rationale, justication, and supplementary material. Intensive Care Med. 2012;38:157382. doi:http://dx.doi.org/10.1007/s00134-012-2682-1

Web End =10.1007/s0013401226821 .

2. Niwa T, Hasegawa R, Ryuge M, Kawase M, Kondoh Y, Taniguchi H. Benets and risks associated with the R100 high frequency oscillatory ventilator for patients with severe hypoxaemic respiratory failure. Anaesth Intensive Care. 2011;39:11119.

3. Mentzelopoulos SD, Malachias S, Zintzaras E, Kokkoris S, Zakynthinos E, Makris D, et al. Intermittent recruitment with highfrequency oscillation/ tracheal gas insufflation in acute respiratory distress syndrome. Eur Respir J. 2012;39:63547. doi:http://dx.doi.org/10.1183/09031936.00158810

Web End =10.1183/09031936.00158810 .4. Sud S, Sud M, Friedrich JO, Meade MO, Ferguson ND, Wunsch H, et al. High frequency oscillation in patients with acute lung injury and acute

Ursulet et al. Ann. Intensive Care (2015) 5:25

Page 8 of 8

respiratory distress syndrome (ARDS): systematic review and metaanaly

sis. BMJ. 2010;340:c2327.5. Adhikari NKJ, Bashir A, Lamontagne F, Mehta S, Ferguson ND, Zhou Q, et al. Highfrequency oscillation in adults: a utilization review. Crit Care Med. 2011;39:263144. doi:http://dx.doi.org/10.1097/CCM.0b013e318226675e

Web End =10.1097/CCM.0b013e318226675e .

6. Derdak S, Mehta S, Stewart TE, Smith T, Rogers M, Buchman TG, et al. Highfrequency oscillatory ventilation for acute respiratory distress syn drome in adults: a randomized, controlled trial. Am J Respir Crit Care Med. 2002;166:8018. doi:http://dx.doi.org/10.1164/rccm.2108052

Web End =10.1164/rccm.2108052 .

7. Papazian L, Gainnier M, Marin V, Donati S, Arnal JM, Demory D, et al. Comparison of prone positioning and highfrequency oscillatory ventila tion in patients with acute respiratory distress syndrome. Crit Care Med. 2005;33:216271.

8. Young D, Lamb SE, Shah S, MacKenzie I, Tunniclie W, Lall R, et al. High frequency oscillation for acute respiratory distress syndrome. N Engl J Med. 2013;368:80613. doi:http://dx.doi.org/10.1056/NEJMoa1215716

Web End =10.1056/NEJMoa1215716 .

9. Ferguson ND, Cook DJ, Guyatt GH, Mehta S, Hand L, Austin P, et al. High frequency oscillation in early acute respiratory distress syndrome. N Engl J Med. 2013;368:795805. doi:http://dx.doi.org/10.1056/NEJMoa1215554

Web End =10.1056/NEJMoa1215554 .

10. David M, von Bardeleben RS, Weiler N, Markstaller K, Scholz A, Karmrodt J, et al. Cardiac function and haemodynamics during transition to high frequency oscillatory ventilation. Eur J Anaesthesiol. 2004;21:94452.

11. Guervilly C, Forel JM, Hraiech S, Demory D, AllardetServent J, Adda M, et al. Right ventricular function during highfrequency oscillatory ventila tion in adults with acute respiratory distress syndrome. Crit Care Med. 2012;40:153945. doi:http://dx.doi.org/10.1097/CCM.0b013e3182451b4a

Web End =10.1097/CCM.0b013e3182451b4a .

12. Mercat A, Richard JCM, Vielle B, Jaber S, Osman D, Diehl JL, et al. Positive endexpiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299:64655. doi:http://dx.doi.org/10.1001/jama.299.6.646

Web End =10.1001/jama.299.6.646 .

13. Van Dishoeck AM, van der Hooft T, Simoons ML, van der Ent M, Scholte OP, Reimer WJM. Reliable assessment of sedation level in routine clinical practice by adding an instruction to the Ramsay Scale. Eur J Cardiovasc Nurs. 2009;8:1258. doi:http://dx.doi.org/10.1016/j.ejcnurse.2008.10.004

Web End =10.1016/j.ejcnurse.2008.10.004 .

14. Papazian L, Forel JM, Gacouin A, PenotRagon C, Perrin G, Loundou A, et al. Neuromuscular blockers in early acute respiratory distress syn drome. N Engl J Med. 2010;363:110716. doi:http://dx.doi.org/10.1056/NEJMoa1005372

Web End =10.1056/NEJMoa1005372 .

15. Morn I, Bellapart J, Vari A, Mancebo J. Heat and moisture exchangers and heated humidiers in acute lung injury/acute respiratory distress syndrome patients. Eects on respiratory mechanics and gas exchange. Intensive Care Med. 2006;32:52431. doi:http://dx.doi.org/10.1007/s00134-006-0073-1

Web End =10.1007/s0013400600731 .

16. Allyn J, Allou N, Dib M, Tashk P, Desmard M, Dufour G, et al. Echocardiog raphy to predict tolerance to negative uid balance in acute respira tory distress syndrome/acute lung injury. J Crit Care. 2013;28:100610. doi:http://dx.doi.org/10.1016/j.jcrc.2013.07.044

Web End =10.1016/j.jcrc.2013.07.044 .

17. Isakow W, Schuster DP. Extravascular lung water measurements and hemodynamic monitoring in the critically ill: bedside alternatives to the pulmonary artery catheter. Am J Physiol Lung Cell Mol Physiol. 2006;291:L111831. doi:http://dx.doi.org/10.1152/ajplung.00277.2006

Web End =10.1152/ajplung.00277.2006 .

18. Gurin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368:215968. doi:http://dx.doi.org/10.1056/NEJMoa1214103

Web End =10.1056/NEJMoa1214103 .

19. Richard C, Argaud L, Blet A, Boulain T, Contentin L, Dechartres A, et al. Extracorporeal life support for patients with acute respiratory distress syn drome: report of a Consensus Conference. Ann Intensive Care. 2014;4:15. doi:http://dx.doi.org/10.1186/2110-5820-4-15

Web End =10.1186/21105820415 .

20. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA,et al. Recommendations for chamber quantication: a report from the American Society of Echocardiographys Guidelines and Standards Committee and the Chamber Quantication Writing Group, developed in conjunction with the European Association of Echocardiograph. J Am Soc Echocardiogr. 2005;18:144063. doi:http://dx.doi.org/10.1016/j.echo.2005.10.005

Web End =10.1016/j.echo.2005.10.005 .

21. VieillardBaron A, Schmitt JM, Augarde R, Fellahi JL, Prin S, Page B, et al. Acute cor pulmonale in acute respiratory distress syndrome submitted to protective ventilation: incidence, clinical implications, and prognosis. Crit Care Med. 2001;29:15515. doi:http://dx.doi.org/10.1097/00003246-200108000-00009

Web End =10.1097/0000324620010800000009 .

22. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr. 2009;10:16593. doi:http://dx.doi.org/10.1093/ejechocard/jep007

Web End =10.1093/ http://dx.doi.org/10.1093/ejechocard/jep007

Web End =ejechocard/jep007 .

23. Paulus WJ, Tschpe C, Sanderson JE, Rusconi C, Flachskampf FA, Rade makers FE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J. 2007;28:253950. doi:http://dx.doi.org/10.1093/eurheartj/ehm037

Web End =10.1093/eurheartj/ehm037 .

24. Sakka SG, Reuter DA, Perel A. The transpulmonary thermodilu tion technique. J Clin Monit Comput. 2012;26:34753. doi:http://dx.doi.org/10.1007/s10877-012-9378-5

Web End =10.1007/ http://dx.doi.org/10.1007/s10877-012-9378-5

Web End =s1087701293785 .

25. Sakka SG, Rhl CC, Pfeier UJ, Beale R, McLuckie A, Reinhart K, et al. Assessment of cardiac preload and extravascular lung water by single transpulmonary thermodilution. Intensive Care Med. 2000;26:1807.

26. Monnet X, Anguel N, Osman D, Hamzaoui O, Richard C, Teboul JL. Assessing pulmonary permeability by transpulmonary thermodilution allows dierentiation of hydrostatic pulmonary edema from ALI/ARDS. Intensive Care Med. 2007;33:44853. doi:http://dx.doi.org/10.1007/s00134-006-0498-6

Web End =10.1007/s0013400604986 .

27. VieillardBaron A, Price LC, Matthay MA. Acute cor pulmonale in ARDS. Intensive Care Med. 2013;39:18368. doi:http://dx.doi.org/10.1007/s00134-013-3045-2

Web End =10.1007/s0013401330452 .

28. Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, et al. Acute respiratory distress syndrome: the Berlin denition. JAMA. 2012;307:252633. doi:http://dx.doi.org/10.1001/jama.2012.5669

Web End =10.1001/jama.2012.5669 .

29. Ferguson ND, Fan E, Camporota L, Antonelli M, Anzueto A, Beale R,et al. The Berlin denition of ARDS: an expanded rationale, justication, and supplementary material. Intensive Care Med. 2012;38:157382. doi:http://dx.doi.org/10.1007/s00134-012-2682-1

Web End =10.1007/s0013401226821 .

30. Camporota L, Sherry T, Smith J, Lei K, McLuckie A, Beale R. Physiological predictors of survival during highfrequency oscillatory ventilation in adults with acute respiratory distress syndrome. Crit Care. 2013;17:R40. doi:http://dx.doi.org/10.1186/cc12550

Web End =10.1186/cc12550 .

31. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syn drome. The acute respiratory distress syndrome network. N Engl J Med. 2000;342:13011308. doi:http://dx.doi.org/10.1056/NEJM200005043421801

Web End =10.1056/NEJM200005043421801 .

32. Gu XL, Wu GN, Yao YW, Shi DH, Song Y. In adult acute respiratory distress syndrome patients, is highfrequency oscillatory ventilation more eective and safer than conventional protective ventilation? A metaanalysis of randomized controlled trials. Crit Care. 2014;18:R111. doi:http://dx.doi.org/10.1186/cc13900

Web End =10.1186/cc13900 .

33. Huang CT, Lin HH, Ruan SY, Lee MS, Tsai YJ, Yu CJ. Efficacy and adverse events of high frequency oscillatory ventilation in adult patients with acute respiratory distress syndrome: a metaanalysis. Crit Care. 2014;18:R102. doi:http://dx.doi.org/10.1186/cc13880

Web End =10.1186/cc13880 .

34. Maitra S, Bhattacharjee S, Khanna P, Baidya DK. Highfrequency ventila tion does not provide mortality benet in comparison with conventional lungprotective ventilation in acute respiratory distress syndrome: a metaanalysis of the randomized controlled trials. Anesthesiology. 2014;. doi:http://dx.doi.org/10.1097/ALN.0000000000000306

Web End =10.1097/ALN.0000000000000306 .

35. Kushimoto S, Taira Y, Kitazawa Y, Okuchi K, Sakamoto T, Ishikura H, et al. The clinical usefulness of extravascular lung water and pulmonary vascular permeability index to diagnose and characterize pulmonary edema: a prospective multicenter study on the quantitative dierential diagnostic denition for acute lung injury/acute. Crit Care. 2012;16:R232. doi:http://dx.doi.org/10.1186/cc11898

Web End =10.1186/cc11898 .

36. Tagami T, Nakamura T, Kushimoto S, Tosa R, Watanabe A, Kaneko T, et al. Earlyphase changes of extravascular lung water index as a prognostic indicator in acute respiratory distress syndrome patients. Ann Intensive Care. 2014;4:27. doi:http://dx.doi.org/10.1186/s13613-014-0027-7

Web End =10.1186/s1361301400277 .