Flow-Controlled Ventilation May Reduce Mechanical Power and Increase Ventilatory Efficiency in Severe Coronavirus Disease-19 Acute Respiratory Distress Syndrome

doi:10.21203/rs.3.rs-1438128/v1

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Flow-Controlled Ventilation May Reduce Mechanical Power and Increase Ventilatory Efficiency in Severe Coronavirus Disease-19 Acute Respiratory Distress Syndrome

https://doi.org/10.21203/rs.3.rs-1438128/v1

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published 28 Feb, 2023

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Background. The prevention of ventilator-induced lung injury is the mainstay of the management of mechanical ventilation in patients with acute respiratory distress syndrome (ARDS). Reducing mechanical power during invasive mechanical ventilation may be beneficial. Flow-controlled ventilation (FCV) (Evone^®, Ventinova Medical, Eindhoven, The Netherlands) is a ventilatory mode providing low and controlled flow rates throughout both inspiration and expiration. We hypothesize that FCV would reduce mechanical power and ventilatory ratio, by allowing the reduction of minute ventilation, in coronavirus disease (COVID)-19 patients developing refractory hypoxemia despite optimization of conventional constant-flow volume-targeted mechanical ventilation (CMV) and prone positioning.

Methods. The study was performed in the intensive care unit of the Vittorio Veneto Hospital (Italy). We included 10 sedated and paralyzed patients with ARDS secondary to COVID-19, with arterial partial pressure of oxygen to inspired oxygen fraction ratio (PaO2/FiO2) < 150 mmHg during CMV while in prone position for at least 12 consecutive hours. All measurements were obtained in CMV prior to switching to FCV (CMV1), after 4 hours of FCV, and then again after 4 hours of CMV (CMV2).

Results. During FCV inspiratory flow rate, respiratory rate, and minute ventilation were significantly lower than with both CMV1 and CMV2. Mechanical power was 10.8 (9.9-13.4) J/min, as opposed to CMV1 [22.7 (20.3-25.6) J/min (p=0.006)] and CMV2 [20.1 (19.0-24.0) J/min (p=0.006)]. Ventilatory ratio also significantly decreased to 1.40 (1.28-1.44) from CMV1 [2.22 (1.90-2.56) (p=0.006)] and then increased again during CMV2 [2.20 (1.79-2.57) (p=0.006)]. Arterial partial pressure of carbon dioxide, pH, and PaO2/FiO2 were not significantly different among the three conditions.

Conclusions. FCV reduced mechanical power and increased ventilatory efficiency in severely hypoxemic COVID-19 patients receiving CMV and prone positioning.

COVID-19

Respiratory Insufficiency

Respiration

Artificial

Ventilator-Induced Lung Injury

The prevention of ventilator-induced lung injury (VILI) is the mainstay of the management of mechanical ventilation in patients with acute respiratory distress syndrome (ARDS) [1]. Official guidelines have focused on tidal volume, plateau pressure (Pplat), positive end-expiratory pressure (PEEP), and driving pressure (DP), i.e., the difference between Pplat and PEEP, to identify lung-protective mechanical ventilation strategies [2]. However, even values of tidal volumes and Pplat that are normally considered safe may result in injurious ventilation as these settings may not be adequate surrogates for lung stress and strain [3].

Mechanical power represents the total energy transferred from the mechanical ventilator to the lungs during inflation and includes dynamic variables such as inspiratory flow rate and breathing frequency [3]. Some studies suggest that mechanical power may be predictive of mortality in ARDS patients [4] and that higher inspiratory flow rates increase the risk of VILI in patients with mild to moderate ARDS [5].

The lungs of patients with coronavirus disease (COVID)-19 related ARDS are characterized by parenchymal heterogeneity, leading to regional differences in pulmonary mechanical properties [6]. Consequently, higher velocities of lung inflation may drive a greater fraction of tidal volume to alveolar units with shorter time constant and unevenly amplify lung stress in some regions [3]. Therefore, reducing flow rates might be beneficial.

Flow-controlled ventilation (FCV) (Evone®, Ventinova Medical, Eindhoven, The Netherlands) is a ventilatory mode where both inspiratory and expiratory flow rates are maintained constant and < 20 L/min throughout the respiratory cycle. Briefly, an ejector-based flow reversal device applies the same constant flow, positive during inspiration and negative during expiration, by regulating in both phases of the respiratory cycle tracheal pressure, as measured by means of a dedicated lumen opening at the distal end of the endotracheal tube [7]. During FCV, the inspiratory flow rate, inspiratory to expiratory ratio, peak inspiratory pressure (Ppeak), end-expiratory pressure (EEP), and the inspiratory concentration of oxygen are pre-set, whereas tidal volume and respiratory rate vary depending on ventilator settings and the patient’s respiratory system mechanical properties. Some studies observed improved lung recruitment, more homogeneous lung aeration, better gas exchange, and attenuated experimental lung injury with FCV, compared to conventional constant-flow volume-targeted mechanical ventilation (conventional mechanical ventilation, CMV) [7, 8].

The present study aims at assessing difference in respiratory rate, minute ventilation, gas exchange, ventilatory ratio, and mechanical power during FCV, as opposed to CMV. We hypothesize that FCV would reduce mechanical power and increase ventilatory efficiency, i.e., ventilatory ratio, in COVID-19 patients developing refractory hypoxemia despite optimization of CMV and prone positioning.

The study was performed in the intensive care unit (ICU) of the Vittorio Veneto Hospital (Italy) in 10 sedated and paralyzed patients with ARDS secondary to COVID-19, with arterial partial pressure of oxygen to inspired oxygen fraction ratio (PaO2/FiO2) < 150 mmHg during CMV while in prone position for at least 12 consecutive hours [2]. The study was approved by the Local Ethical Committee (protocol n. 0235105/21) and was conducted in accordance with the principles of the Helsinki Declaration. Informed consent was obtained according to the national regulation.

Inspiratory and expiratory flow rates were initially set at 15 L/min with inspiratory to expiratory ratio 1:1, while EEP was equal to PEEP and Ppeak to Pplat during CMV, thereby maintaining approximately the same DP and consequently similar tidal volumes. All measurements were collected as part of our routine clinical practice and were obtained in CMV prior to switching to FCV (CMV1), after 4 hours of FCV, and then again after 4 hours of CMV (CMV2).

During CMV, plateau pressure (Pplat) and total PEEP were measured at the points of zero flow during an end-inspiratory and end-expiratory pause, respectively, while during FCV Pplat is displayed every 10 cycles after an automatic pressure drop in the pressure curve. DP was computed as the difference between Pplat and total PEEP, during CMV, and the difference between Ppeak and EEP, during FCV. The compliance of the respiratory system was calculated as the ratio between tidal volume and driving pressure. Inspiratory flow during CMV was calculated as the ratio between tidal volumes and inspiratory time, while inspiratory flow during FCV is set on the ventilator. Mechanical power was calculated as already proposed [9].

All variables are reported as median (interquartile range) and compared using the Friedman test, followed by pairwise comparison with Wilcoxon signed-rank test and post-hoc Bonferroni correction, when indicated. The Kendall's W value was calculated as effect size estimate. All statistical tests were two-tailed and statistical significance was defined as p < 0.05.

Patient age was 59 (55–57) years, the predicted body weight (PBW) 65 (59–68) kg and the body mass index 30 (27–33) kg/m². Five patients were obese, two patients suffered from arterial hypertension, and one patient was diabetic. The duration of symptoms before ICU admission was 7 (6–9) days. Nine (90%) patients survived the hospital stay.

Ventilator settings, mechanical properties of the respiratory system, and outcome variables are reported in the Table. During FCV inspiratory flow rate was decreased to 15 (14–15) L/min, compared to both CMV1 and CMV2 [26 (23–26) and 22 (22–26) L/min, respectively (p = 0.006 for both)]. Respiratory rate was significantly lower with FCV [17 (16–18) breaths/min] than with both CMV1 [26 (24–28) breaths/min] and CMV2 [25 (22–26] breaths/min) (p = 0.017 for both). Minute ventilation also significantly decreased to 7.7 (7.1–8.2) L/min from 11.8 (10.2–12.8) L/min (p = 0.006) and from 10.8 (9.6–12.1) L/min (p = 0.006), compared to both CMV1 and CMV2, respectively. As depicted in the Figure, in FCV the mechanical power was 10.8 (9.9–13.4) J/min, as opposed to CMV1 [22.7 (20.3–25.6) J/min (p = 0.006)] and CMV2 [20.1 (19.0–24.0) J/min (p = 0.006)]. Ventilatory ratio also significantly decreased to 1.40 (1.28–1.44) from CMV1 [2.22 (1.90–2.56) (p = 0.006)] and then increased again during CMV2 [2.20 (1.79–2.57) (p = 0.006)]. Arterial partial pressure of carbon dioxide, pH, and PaO2/FiO2 were not significantly different among the three conditions. No patients displayed intrinsic PEEP during CMV.

Our pilot study evaluating a series of 10 patients affected by COVID-19 with refractory hypoxemia while receiving CMV, despite prone positioning, suggests that FCV may be associated with some advantages. First, the application of FCV resulted in decreased mechanical power, as a consequence of lower inspiratory flow rates and breathing frequencies, potentially reducing the dissipated energy [10]. Indeed, FCV has been shown to attenuate VILI through this mechanism in a porcine model [8]. Worth remarking, however, the calculation of mechanical power only relates to the inspiratory phase, while, because of its viscoelastic mechanical behavior, the lung dissipates energy when inflated and deflated, which may also cause lung injury [3]. Therefore, the decrease in mechanical power might underestimate the lung-protective potential of FCV.

Second, our results are in keeping with preclinical and clinical studies, demonstrating higher ventilatory efficiency, likely related to improved intrapulmonary distribution of ventilation with FCV [7, 8]. Indeed, the lower constant inspiratory flow rate and the higher mean airway pressure may contribute to enhance ventilation of lung units with higher resistance, while the linear decline of expiratory pressure might limit small airway and alveolar collapse [7].

Our study has some limitations. First of all, the small sample size makes our findings hypothesis-generating. Worth remarking, however, only a few case reports have been published insofar in the critical care setting and, to the best of our knowledge, this is the largest clinical investigation assessing this novel ventilatory mode in the ICU. Also, the generalizability of our findings to patients with acute respiratory failure of different etiology needs to be assessed. Furthermore, we cannot rule out that different dead space of the ventilator apparatus may have contributed to the improvement of ventilatory ratio with FCV. However, this is unlikely to have occurred because we always used an active humidifier before the Y-piece of the respiratory circuit during CMV, whereas during FCV we used a heat and moisture exchange filter, as recommended by the manufacturer. Finally, during FCV it is presently impossible to determine the occurrence of intrinsic PEEP as no expiratory hold maneuver can be performed on the ventilator. Nonetheless, considering that no intrinsic PEEP was detected during CMV and the expiratory time was longer during FCV in all patients, the potential occurrence of intrinsic PEEP can be reasonably excluded.

In conclusion, FCV reduced mechanical power and increased ventilatory efficiency in severely hypoxemic COVID-19 patients receiving CMV and prone positioning. Larger prospective physiological studies are undoubtedly necessary to confirm these results and build solid ground for clinical studies ascertaining the impact of FCV on clinical outcomes.

Table. Ventilator settings, mechanical properties of the respiratory system, and outcome variables
Variable	CMV1	FCV	CMV2	p-value^a	Kendall’s W
Ventilatory settings
Respiratory rate (breaths/min)	26 (24–28)	17 (16–18)^bc	25 (22–26)	< 0.001	0.930
Tidal volume (mL/kg PBW)	6.9 (6.8–7.3)	6.8 (6.5–7.3)	6.8 (6.5–7.2)	0.968	0.003
Minute ventilation (L/min)	11.8 (10.2–12.8)	7.7 (7.1–8.2)^de	10.8 (9.6–12.1)	< 0.001	0.830
Peak pressure (cmH2O)	27 (25–28)	23 (20–25)^bc	26 (25–28)	< 0.001	0.810
Plateau pressure (cmH2O)	21 (20–23)	21 (19–23)	22 (21–23)	0.015	0.420
PEEP (cmH2O)	9 (8–10)	9 (7–10)	9 (8–10)	0.772	0.030
Inspiratory flow (L/min)	26 (23–26)	15 (14–15)^de	22 (22–26)	< 0.001	0.800
Gas exchanges
pH	7.37 (7.30–7.42)	7.39 (7.36–7.42)	7.34 (7.27–7.42)	0.280	0.130
PaCO2 (mmHg)	49 (43–51)	45 (42–48)	51 (45–56)	0.275	0.130
PaO2/FiO2 (mmHg)	128 (116–134)	136 (115–147)	134 (106–152)	0.275	0.150
Ventilatory ratio	2.22 (1.90–2.56)	1.40 (1.28–1.44)^de	2.20 (1.79–2.57)	< 0.001	0.770
Mechanical properties of the respiratory system
Crs (mL/cmH2O)	36 (34–38)	35 (34–40)	36 (33–39)	0.704	0.040
Driving pressure (cmH2O)	13 (12–13)	12 (11–13)	13 (12–14)	0.331	0.110
Mechanical power (J/min)	22.7 (20.3–25.6)	10.8 (9.9–13.4)^de	20.1 (19.0–24.0)	< 0.001	0.760
All measurement were obtained in CMV prior to switching to FCV (CMV1), after 4 hours of FCV and then again after 4 hours of CMV (CMV2). Abbreviations: CMV, conventional mechanical ventilation; FCV, flow-controlled ventilation; PBW, predicted body weight; PEEP, positive end-expiratory pressure; PaCO2, arterial partial pressure of carbon dioxide; PaO2/FiO2, arterial partial pressure of oxygen to fraction of inspired oxygen ratio; Crs, compliance of the respiratory system. Variables are reported as median (interquartile range) and were compared using the Friedman two-way analysis of variance, followed by pairwise comparison with Wilcoxon signed-rank test and post-hoc Bonferroni correction, when indicated. The Kendall's W value is the effect size estimate for Friedman test and ranges from 0.1–0.3 (small effect) to > 0.5 (large effect). ^ap-value from the Friedman two-way analysis of variance. ^bp<0.05 between FCV and CMV1 after post-hoc Bonferroni correction. ^cp<0.05 between FCV and CMV2 after post-hoc Bonferroni correction. ^dp<0.01 between FCV and CMV1 after post-hoc Bonferroni correction. ^ep<0.01 between FCV and CMV2 after post-hoc Bonferroni correction.

Acknowledgments

We feel indebted to all personnel working in the intensive care unit of the Vittorio Veneto Hospital who made this work possible.

Authors' contributions

Concept and design: AG, TP. Acquisition of the data: AG, TP, FB, FB, RC, SD, MP, AV. Analysis of the data: AG, TP, MDP, NS. Interpretation of the data: All authors. Drafting of the manuscript: AG, TP, PN. Critical revision of the manuscript for important intellectual content: All authors. All authors have approved the submitted version and have agreed both to be personally accountable for their own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.

Funding

None declared.

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The study was approved by the Local Ethical Committee (Comitato Etico di Sperimentazione Clinica ULSS 2 Marca Trevigiana, protocol n. 0235105/21) and was conducted in accordance with the principles of the Helsinki Declaration. Informed consent was obtained according to the national regulation.

Consent for publication

Informed consent was obtained according to the national regulation.

Competing interests

PN research lab received grants/research equipment by Draeger, Intersurgical SPA, and Gilead. PN receives royalties from Intersurgical SPA for Helmet Next invention. He also received speaking fees from Getinge, Intersurgical SPA, Gilead, MSD, Draeger, and Medicair. PN has no Conflict of Interest to declare in relation to this manuscript. The other authors have no competing interests to declare.

Authors details

¹Anesthesia and Intensive Care, Vittorio Veneto Hospital, Vittorio Veneto, Italy

²Institute of Anesthesiology and Intensive Care, Padua University Hospital, Padua, Italy

³Department of Medicine, University of Padua, Padua, Italy

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No competing interests reported.

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Journal Publication

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Flow-Controlled Ventilation May Reduce Mechanical Power and Increase Ventilatory Efficiency in Severe Coronavirus Disease-19 Acute Respiratory Distress Syndrome

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