Time-Controlled Adaptive Ventilation (TCAV): a personalized strategy for lung protection

Abstract

Acute respiratory distress syndrome (ARDS) alters the dynamics of lung inflation during mechanical ventilation. Repetitive alveolar collapse and expansion (RACE) predisposes the lung to ventilator-induced lung injury (VILI). Two broad approaches are currently used to minimize VILI: (1) low tidal volume (LV_T) with low-moderate positive end-expiratory pressure (PEEP); and (2) open lung approach (OLA). The LV_T approach attempts to protect already open lung tissue from overdistension, while simultaneously resting collapsed tissue by excluding it from the cycle of mechanical ventilation. By contrast, the OLA attempts to reinflate potentially recruitable lung, usually over a period of seconds to minutes using higher PEEP used to prevent progressive loss of end-expiratory lung volume (EELV) and RACE. However, even with these protective strategies, clinical studies have shown that ARDS-related mortality remains unacceptably high with a scarcity of effective interventions over the last two decades. One of the main limitations these varied interventions demonstrate to benefit is the observed clinical and pathologic heterogeneity in ARDS. We have developed an alternative ventilation strategy known as the Time Controlled Adaptive Ventilation (TCAV) method of applying the Airway Pressure Release Ventilation (APRV) mode, which takes advantage of the heterogeneous time- and pressure-dependent collapse and reopening of lung units. The TCAV method is a closed-loop system where the expiratory duration personalizes V_T and EELV. Personalization of TCAV is informed and tuned with changes in respiratory system compliance (C_RS) measured by the slope of the expiratory flow curve during passive exhalation. Two potentially beneficial features of TCAV are: (i) the expiratory duration is personalized to a given patient's lung physiology, which promotes alveolar stabilization by halting the progressive collapse of alveoli, thereby minimizing the time for the reopened lung to collapse again in the next expiration, and (ii) an extended inspiratory phase at a fixed inflation pressure after alveolar stabilization gradually reopens a small amount of tissue with each breath. Subsequently, densely collapsed regions are slowly ratcheted open over a period of hours, or even days. Thus, TCAV has the potential to minimize VILI, reducing ARDS-related morbidity and mortality.

Keywords: APRV; ARDS; ARMA; Acute respiratory distress syndrome; Alveolar opening and collapse time constants; Driving pressure; Dynamic alveolar mechanics; Open lung approach; Regional alveolar instability; Stress-multipliers; TCAV; Tidal volume; VILI; Ventilator-induced lung injury; Viscoelastic.

Fig. 1

An ever-shrinking, baby lung, known as a VILI Vortex has been used to describe the evolution of ventilator-induced lung injury (VILI) [28]. Upper left: The ‘patient’ with mostly open lung tissue (pink) and a lesser amount of collapsed tissue (red) defined as Mild ARDS is placed on ARDSnet LV_T ventilation. The LV_T and low airway pressures strategy is designed to ‘rest’ the ‘baby lung’, however, this ventilation method allows the acutely injured tissue to continually collapse pushing it into the VILI Vortex. Lung pathogenesis moves from Mild to Moderate ARDS as normal tissue progressively shrinks (pink → red), Disease progression into Severe ARDS is inevitable if unchecked at which point rescue methods such as extracorporeal membrane oxygenation (ECMO) may be necessary. ARDS causes the lung to become time and pressure dependent. This means that it will take more time for the alveoli to open and less time for them to collapse at any given airway pressure. Thus, the alveolar opening can be accelerated by an extended inspiratory time, and alveolar collapse minimized by a short expiratory time. The brief time at inspiration is not adequate to open collapsed alveoli while the extended time at expiration will not prevent alveolar collapse using the ARDSnet approach (Upper left Protect the Lung, Ventilator Monitor blue Pressure/Time curve). The open lung approach to rapidly reopen the lung (seconds or minutes) using recruitment maneuvers and higher PEEP has not been successful at reducing ARDS-related mortality. Using inspiratory and expiratory duration in addition to pressure to open and stabilize alveoli has been shown very effective and lung protective by our group and others [, , –91]. An extended inspiratory time will progressively recruit alveoli and a brief expiratory time will prevent re-collapse. A correctly set time-controlled ventilator method will stabilize alveoli (Center, Stabilize the Lung, Ventilator Monitor blue Pressure/Time curve) using a short expiratory time pulling the lung from the Vortex. Once progressive lung collapse is halted, collapsed tissue can be reopened slowly (Red lung tissue turning pink) over hours or days depending on the level of lung pathophysiology [, , –91]. This figure depicts the ability of TCAV to be used after ARDS has developed or as a rescue mode but if applied early during mild ARDS movement of the lung into the Vortex could be prevented. Reproduced from Reference [29], under terms of the Creative Commons Attribution 4.0 International License

Fig. 2

A Pressure/Time and Flow/Time curves = generated by the ARDSnet method to set and adjust the Volume Assist-Control mode. Key features include an inspiratory: expiratory ratio of 1:3 where the peak/plateau inspiratory pressure is brief. A set positive end-expiratory pressure (Set-PEEP) and FiO₂ are adjusted using oxygenation as the trigger for change [20]. B Pressure/Time and Flow/Time curves for the Time Controlled Adaptive Ventilation (TCAV) method to set and adjust the Airway Pressure Release Ventilation (APRV) mode. Key features include an inspiratory: expiratory ratio of ~ 12:1, where. the continuous positive airway pressure (CPAP) Phase is ~ 90% of each breath. A tidal volume (V_T), which is measured as the volume of gas released during the Release Phase (brown arrow), is not set but is influenced by changes in (i) respiratory system compliance (C_RS), (ii) the CPAP Phase pressure, and (iii) the duration of the Release Phase. The Release Phase is determined by the Slope of the Expiratory Flow Curve (red arrowhead), which is a breath-to-breath measure of C_RS. The lower the C_RS, the faster the lung recoil, the steeper the slope, and the shorter the Release Phase, further reducing V_T. Thus, the V_T will be low in a non-compliant, injured lung and will increase in size only when the lung recruits and C_RS increases. Since a change in C_RS directs the Release Phase duration, which in turn adjusts the V_T and the time-controlled PEEP (TC-PEEP) the TCAV method is both personalized and adaptive as the patient’s lung gets better or worse [104]. Reproduced from Reference [104], under terms of the Creative Commons Attribution 4.0 International License

Fig. 3

The ability of the TCAV method to stabilize and then open the lung is based on opening and collapse time constants, which are greatly altered if pulmonary surfactant is deactivated, and the viscoelastic system by which the lung changes volume. A Viscoelastic lung volume change. EXPIRATION (Lung Derecruitment): Viscoelastic volume change can be modeled using the spring connected in parallel with a dashpot. When airway pressure begins to fall during the Release Phase (Fig. 2B), there is a very short time delay before alveolar collapse begins, followed by rapid collapse (spring), and then a gradual, continual collapse over time (dash moving slowing through the pot). INSPIRATION (Lung Recruitment): When airway pressure is reapplied during the CPAP Phase (Fig. 2B, CPAP Phase), the reverse sequence of events occurs during lung opening: slight delay → rapid recruitment → gradual progressive recruitment. B Diagram of viscoelastic lung opening and collapse over time. If the expiratory time is very brief (≤ 0.5 s), lung tissue will not have time to collapse (green box). Lung tissue will continue to recruit without a change in airway pressure for as long as the CPAP Phase is applied. (yellow boxes). C A ventilator monitor showing typical TCAV method Pressure/ Flow/ Volume/ Time curves. Using the TCAV method the extended CPAP Phase continually 'nudges' the lung open over time (yellow boxes) (Additional file 3, Additional file 4) and establishes durable lung recruitment by not giving the lung sufficient time to collapse during the brief Release Phase (green boxes). D A blow-up of the expiratory and inspiratory flow curves is seen on the ventilator monitor (black box). The animal being ventilated had ARDS so the slope of the expiratory flow curve (Slope_EF) was very steep (ARDS, yellow line) as compared to the Slope_EF in a healthy lung (NORMAL, blue dashed line). At the termination of the brief Release Phase (green star) the lung is rapidly reinflated to the set CPAP Pressure. Panel A Adapted from Reference [29], under terms of the Creative Commons Attribution 4.0 International License

Fig. 4

Expiratory Gas Flow/Time curve using the TCAV method to set T_Low, the duration of the Release Phase (Fig. 2B, Release Phase). As lung injury increases from Normal Lung to Moderate and Severe ARDS, the respiratory system compliance (C_RS) decreases, increasing the collapse recoil of the lung. The increased lung recoil causes faster gas flow during expiration resulting in a steeper slope of the expiratory flow curve (Slope_EF). a Using the Slope_EF to set the Release Phase duration (Fig. 2B, Release Phase), the Normal Lung has a release time of 0.5 s, Moderate ARDS 0.4 s, and Severe ARDS 0.3 s. Expiratory flow is terminated (red arrowhead) by the clinician by adjusting the T_Low, following which the lung is rapidly reinflated to the CPAP Phase (Fig. 2B, CPAP Phase). Thus, using the TCAV method personalizes and adapts the Release Phase (T_Low) according to the patient’s lung physiology. b Calculation of the termination point on the expiratory flow curve using the TCAV method. Termination of expiratory flow (TEF) is calculated as 75% of the peak expiratory flow (PEF) (PEF 50L/min × 0.75 = TEF 37.5L/min). Adapted from Reference [104], under terms of the Creative Commons Attribution 4.0 International License

Fig. 5

Closed-loop systems for both the VILI Vortex and TCAV personalized lung protection (Fig. 1). VILI Vortex—injury collapses lung tissue and reduces respiratory system compliance (C_RS) → redistributing a fixed tidal volume into a heterogeneously damaged lung → leads to maldistribution of gas within the lung damaging alveoli by both atelectrauma and volutrauma → causing progressive lung collapse (VILI Vortex) → further reducing C_RS. TCAV—injury collapses lung tissue and reduces C_RS → changes in C_RS are manifest as a change in the slope of the expiratory flow curve (Slope_EF) → the Slope_EF is used to set the duration of the Release Phase and is thus directed by changes in the patient’s C_RS (Fig. 2B, Release Phase) → directed by changes in the patient’s C_RS the Release Phase is set sufficiently short to prevent alveolar collapse resulting in a gradual lung recruitment → lung recruitment increases C_RS. The slope of the expiratory flow curve (Slope_EF) can be used as a dynamic feedback signal to adaptively change the expiratory duration necessary to maintain lung stability. Changes in the Slope_EF will identify if C_RS is low or high and used to personalize and adaptively adjust the Expiratory Duration (T_Low) necessary to maintain an open and stable lung, regardless of lung injury severity. The left side of the figure does not have this feedback mechanism which may lead to further alveolar collapse. On the right side of the figure the change in SlopeEF allows a stop and brake and adjustments made to T-low to halt the VILI Vortex