"Low-" versus "high"-frequency oscillation and right ventricular function in ARDS. A randomized crossover study

Abstract

Background: Recent, large trials of high-frequency oscillation (HFO) versus conventional ventilation (CV) in acute respiratory distress syndrome (ARDS) reported negative results. This could be explained by an HFO-induced right ventricular (RV) dysfunction/failure due to high intrathoracic pressures and hypercapnia. We hypothesized that HFO strategies aimed at averting/attenuating hypercapnia, such as "low-frequency" (i.e., 4 Hz) HFO and 4-Hz HFO with tracheal-gas insufflation (HFO-TGI), may result in an improved RV function relative to "high-frequency" (i.e., 7 Hz) HFO (which may promote hypercapnia) and similar RV function relative to lung protective CV.

Methods: We studied 17 patients with moderate-to-severe ARDS [PaO2-to-inspiratory O2 fraction ratio (PaO2/FiO2) < 150]. RV function was assessed by transesophageal echocardiography (TEE). Patients received 60 min of CV for TEE-guided, positive end-expiratory pressure (PEEP) "optimization" and subsequent stabilization; 60 min of 4-Hz HFO for "study mean airway pressure (mPaw)" titration to peripheral oxygen saturation ≥ 95%, without worsening RV function as assessed by TEE; 60 min of each tested HFO strategy in random order; and another 60 min of CV using the pre-HFO, TEE-guided PEEP setting. Study measurements (i.e., gas exchange, hemodynamics, and TEE data) were obtained over the last 10 min of pre-HFO CV, of each one of the three tested HFO strategies, and of post-HFO CV.

Results: The mean "study HFO mPaw" was 8-10 cmH2O higher relative to pre-HFO CV. Seven-Hz HFO versus 4-Hz HFO and 4-Hz HFO-TGI resulted in higher mean ± SD right-to-left ventricular end-diastolic area ratio (RVEDA/LVEDA) (0.64 ± 0.15 versus 0.56 ± 0.14 and 0.52 ± 0.10, respectively, both p < 0.05). Higher diastolic/systolic eccentricity indexes (1.33 ± 0.19/1.42 ± 0.17 versus 1.21 ± 0.10/1.26 ± 0.10 and 1.17 ± 0.11/1.17 ± 0.13, respectively, all p < 0.05). Seven-Hz HFO resulted in 18-28% higher PaCO2 relative to all other ventilatory strategies (all p < 0.05). Four-Hz HFO-TGI versus pre-HFO CV resulted in 15% lower RVEDA/LVEDA, and 7%/10% lower diastolic/systolic eccentricity indexes (all p < 0.05). Mean PaO2/FiO2 improved by 77-80% during HFO strategies versus CV (all p < 0.05). Mean cardiac index varied by ≤ 10% among strategies. Percent changes in PaCO2 among strategies were predictive of concurrent percent changes in measures of RV function (R2 = 0.21-0.43).

Conclusions: In moderate-to-severe ARDS, "short-term" 4-Hz HFO strategies resulted in better RV function versus 7-Hz HFO, partly attributable to improved PaCO2 control, and similar or improved RV function versus CV.

Trial registration: This study was registered 40 days prior to the enrollment of the first patient at ClinicalTrials.gov, ID no. NCT02027129, Principal Investigator Spyros D. Mentzelopoulos, date of registration January 3, 2014.

Keywords: Adult; Echocardiography; Heart ventricles; High-frequency ventilation; Hypercapnia; Respiratory distress syndrome; Transesophageal.

Conflict of interest statement

This study was approved by the Evaggelismos Hospital Scientific Committee (approval no. 271-30-10-2013; Chairman, Athanassios Skoutelis, MD, PHD, Professor of Internal Medicine), and written informed consent was obtained from the next-of-kin of all participating patients.Surrogates who provided informed consent for study participation also granted permission to the sharing of de-identified study data with persons authorized by the principal investigator and first author.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Schematic representation of the study protocol. CV1 first period of lung protective conventional ventilation, PEEP positive end-expiratory pressure, TEE transesophageal echocardiography, SM safety measurement, RVEDA right ventricular end-diastolic area, LVEDA left ventricular end-diastolic area, FiO2 inspiratory oxygen fraction, RM recruitment maneuver, mPaw mean airway pressure, SpO2 peripheral oxygen saturation, HFO high-frequency oscillation, TGI tracheal gas insufflation, CV2 second (study protocol concluding) period of lung-protective conventional ventilation. *Continuous positive airway pressure of 45 cmH2O for 40 s; the HFO breathing circuit was pressurized with the oscillator piston off. †During the first study TEE SM (measurement duration, < 5 min), an RVEDA/LVDEA ratio of > 0.8 triggered a PEEP decrease by 2–3 cmH2O. ‡Performed within 15–20 min after a protocol-mandated decrease in PEEP (see above); this (second) TEE SM was not performed whenever RVEDA/LVEDA did not exceed 0.8 at the first TEE SM. §Includes saved midesophageal four-chamber views and, transgastric, two-chamber, short-axis views, and hemodynamic and gas exchange data during all ventilator strategy testing periods; quasistatic respiratory compliance data were also obtained during CV1 and CV2; each time, the study protocol measurements were to be completed within 10 min. ║During HFO-TGI, the mPaw was set at 2–3 cmH2O lower than the “study HFO mPaw” to counterbalance an estimated, TGI-associated increase of similar magnitude in HFO tracheal pressure; see also text, reference [15] and Additional file 1

Fig. 2

Examples of transesophageal echocardiographic (TEE) determination of two primary study outcome variables. Upper panel: determination of the right-to-left ventricular end-diastolic area ratio (RVEDA/LVEDA). Lower panel: determination of the end-diastolic eccentricity index (EDECCIx). The left vertical pair of images was obtained from study participant no. 12 during conventional ventilation (CV), the middle pair of images was obtained from participant no. 7 during 7-Hz high-frequency oscillation (HFO), and the right pair of images was obtained from participant no. 13 during 4-Hz HFO. In the lower panel (short-axis, transgastric views), “2” corresponds to the diameter of the left ventricle (LV) that was perpendicular to and bisecting the interventricular septum, whereas “1” corresponds to the diameter that was perpendicular to “2.” TEE measurements were repeated and averaged over 2–4 consecutive cardiac cycles (see also Additional file 1); EDECCIx was calculated as diameter “1”/diameter “2.” Description of figure modifications performed with Photoshop CC (Adobe Systems): upper panel, enhancement of the periphery of the right ventricle (RV) and LV using the “pen” tool and the “stroke path” command and enhancement of contrast of the middle image using the “adjust levels” command; lower panel, enhancement of diameter “1”/diameter “2” using the “line” tool. The original versions of the stored pairs of images are also provided in Additional file 1: Figure S1

Fig. 3

Individual patient data on two primary study outcomes and major determinants of right ventricular function. a Primary outcome no. 1, the right-to-left ventricular end-diastolic area ratio (RVEDA/LVEDA). b Primary outcome no. 2, the end-diastolic eccentricity index. c Determinant of right ventricular function no. 1, the arterial carbon dioxide tension (PaCO2). d Determinant of right ventricular function no. 2, the mean airway pressure. CV1 first period of conventional ventilation, HFO high-frequency oscillation, TGI tracheal gas insufflation, CV2 second period of conventional ventilation (see also “Methods” and Fig. 1). Numbers (from 1 to 17) just above the colored lines that connect the data points (triangles) indicate patient no.; the color of each “data-point-connecting line” is unique for each one of the patients. Horizontal black bars correspond to mean values. For each ventilatory strategy, summary data are also reported as mean ± SD. “Effect of Strategy” corresponds to the level of significance of the effect of the fixed, within-subjects factor (i.e., ventilatory strategy) in linear mixed-model analysis (see also the “Statistical Analysis” subsection); additional mixed-model data: a Percent variation explained 87, calculated as 100 × R2 value of bivariate linear regression between observed and mixed model-predicted values; b percent variation explained, 72; c percent variation explained, 74. *p < 0.05 versus CV1. †p < 0.05 versus 4-Hz HFO. ‡p < 0.05 versus 4-Hz HFO-TGI. §p < 0.05 versus 7-Hz HFO. Actual p values of pairwise comparisons are reported in Additional file 2