key: cord-0979916-qam7tlex authors: Maracaja, Luiz; Kumar Khanna, Ashish; Royster, Roger; Maracaja, Danielle; Lane, Magan; Jordan, James Eric title: Selective Lobe Ventilation and a Novel Platform for Pulmonary Drug Delivery date: 2021-05-04 journal: J Cardiothorac Vasc Anesth DOI: 10.1053/j.jvca.2021.04.041 sha: 83eb896687c43a66e5f0aa80c27c0e8557fa3337 doc_id: 979916 cord_uid: qam7tlex The current methods of mechanical ventilation and pulmonary drug delivery do not account for the heterogeneity of acute respiratory distress syndrome (ARDS), or its dependence on gravity. The severe lung disease caused by SARS-CoV-2-2019 is one of the many causes of ARDS. SARS-CoV-2 has caused more than 2.7 million deaths world-wide and has challenged all therapeutic options for mechanical ventilation. Thus, new therapies are necessary to prevent deaths and long-term complications of severe lung diseases and prolonged mechanical ventilation. We have developed a novel device that allows selective lobe ventilation, selective lobe recruitment and provides a new platform for pulmonary drug delivery. A major advantage of separating lobes that are mechanically heterogeneous is to allow customization of ventilator parameters to match the needs of segments with similar compliance, for better overall ventilation perfusion relationship (V/Q) and prevention of ventilator induced lung injury (VILI) of more compliant lobes. This device accounts for lung heterogeneity and is a potential new therapy for acute lung injury by allowing selective lobe mechanical ventilation using two novel modes of mechanical ventilation (differential positive end-expiratory pressure and asynchronous ventilation) and two new modalities of alveolar recruitment (selective lobe recruitment and continuous positive airway pressure of lower lobes with continuous ventilation of upper lobes). We report initial experience with this novel device which includes a brief overview of device development, the initial in vitro, ex-vivo and in-vivo testing, layout future research, potential benefits, new therapies, and expected challenges prior to uniform implementation in clinical practice. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the many causes of acute respiratory distress syndrome (ARDS). SARS-CoV-2 has caused more than 3 million deaths world-wide [1] and has challenged all therapeutic options for mechanical ventilation. Poor outcomes have led clinicians to question the need, and best modality, for mechanical ventilation in these patients with severe respiratory failure and clinically significant hypoxemia [2] [3] [4] . ARDS is a non-cardiogenic form of pulmonary edema that results in bilateral parenchymal infiltrates. The disease is now recognized to have biologic and mechanical heterogeneity with significant differences in compliance, opening pressure, and time-constant between different lung segments [5] [6] [7] [8] [9] . Such differences make the selection of parameters for mechanical ventilation very challenging, and finding one parameter to fit all the different lung segments may not be possible. The highly perfused gravity dependent zones are usually the most severely involved lung regions in ARDS [6, [9] [10] [11] . Ventilation with elevated airway pressure invariably results in preferential inspiratory flow to more compliant non-gravity dependent zones [12] , resulting in alveolar hyper distension and causing ventilator induced lung injury (VILI) [13] [14] [15] . Importantly, the current methods of mechanical ventilation and pulmonary drug delivery do not account for the mechanical heterogeneity of ARDS, its dependence on gravity, or difference in alveolar time constant. Therefore, innovation in mechanical ventilation and new therapies are necessary to prevent deaths, and the long-term complications of severe lung diseases and prolonged mechanical ventilation in ARDS. We have developed a novel device that promotes effective and safe selective lobe ventilation, selective lobe recruitment and that provides a new platform for selective pulmonary delivery of medical gases and drugs. This device better accounts for lung heterogeneity and is a potential new therapy for acute lung injury by allowing selective lobe mechanical ventilation using two novel modes of mechanical ventilation, (i) differential positive end-expiratory pressure (DPeeP) and (ii) asynchronous reverse cycle ventilation (ARCV) of upper and lower lung lobes; and two new modalities of alveolar recruitment, (i) selective lobe recruitment (SLRec) and (ii) continuous lower lobe positive airway pressure (CLLPAP). Here we report our preliminary experience with this novel device which includes a brief overview of device development, the initial in vitro, ex-vivo and in-vivo testing, layout future research, potential benefits, new therapies, and expected challenges prior to uniform implementation in clinical practice. Device development: The rationale for development of the device was based on the premise that gravity dependent zones are mostly located in the lower lung lobes. This relationship becomes more evident during mechanical ventilation with patients in supine position and some degree of head elevation, where oblique lung fissures assume a more horizontal position. A major advantage of separating lobes that are mechanically heterogeneous is to allow customization of ventilator parameters to match the needs of segments with similar compliance, for better overall ventilation perfusion relationship (V/Q) and prevention of ventilator induced lung injury (VILI) of more compliant lobes. Multiple criteria and design specifications were taken into consideration to build a mechanical airway apparatus with at least three lumens of different lengths that could pass and fit into the airway, achieve final position using flexible bronchoscopy, and provide functional isolation and effective ventilation of the different lobes. The prototype developed starts with a single lumen tube, we named the "Shuttle" tube, with a special contour and collapsed sheath in the posterior wall. The sheath is located outside of the posterior tube wall but inside of a cuff creating an internal channel to allow placement of the distal lobar tubes (Fig1). Computer assist design software, SolidWorks ® (Dassault Systèmes, Waltham, MA, USA), was used for the design. Multiple iterations of design concepts, molds, connectors and the anatomical model were 3D printed using Formlabs 3D printer (Formlabs, Somerville, MA, USA). Tubes, cuffs, cuff lines, and the sheath were purchased from different vendors and modified according to the design needs. We systematically approached several criteria for feasibility and clinical utility of the device and designed specific features to fulfill such criteria. (Table 1 ). In-vitro testing with a 3D printed anatomical model of the human tracheal bronchial tree allowed evaluation of the placement, interaction, and positioning of the three separate tubes and the initial instructions for device instrumentation was created. Device instrumentation: We have performed laryngoscopy, videolaryngoscopy and intubation in a high quality airway mannequin (Anesthesia Human Patient Simulator, CAE Healthcare, Sarasota, FL, USA) with the Shuttle, the single lumen tube, and the double lumen tube of various sizes. Placement was successful and we believe the level of difficulty was similar to a single lumen tube and easier than a double lumen tube. Shuttle placement is aimed to be performed by direct laryngoscopy, or alternatively After tracheal insertion the tube is rotated ninety degrees (clockwise or counter clockwise) to achieve anteroposterior orientation. After intubation and two lung ventilation is established, a 3.8 mm diameter or smaller flexible bronchoscope is used to confirm and adjust position of the distal tip at least 3 cm proximal to the main carina. The placement of the secondary tubes into lung lobes are also guided by the same size bronchoscope. The final position of the lobar tubes on the main stem bronchi allows for one lung ventilation (OLV) or further advancing to a lung lobe allows for selective lobe ventilation (SLV). If bilateral selective lower lobe ventilation is desired, placement of the right lower tube should be done before the left lower to facilitate placement and to prevent the lobar tubes from becoming crossed or kinked inside the sheath. Inflation of the cuffs on the lobar tubes can also be confirmed by bronchoscopy proximal to the cuffs to prevent over-inflation and cuff herniation. The ex-vivo testing was performed on a swine model. (Video.1). In comparing with human anatomy, the main macroscopic anatomical differences of the swine respiratory system are: the trachea is approximately 15 to 20 cm longer than human trachea, the right lung is divided into four lobes (upper, accessory, middle and lower), the right upper lobe bronchi comes directly from the trachea very proximal to the carina and the accessory lobe is a small lobe located retro cardiac with a high take off from the right mainstem bronchi [16] . For the sake of simplicity and comparison with the human lungs we considered the middle lobe as non-dependent all together with the upper lobes and did not consider the accessory lobe due to the small size, location and high takeoff. Placement of the device and selective ventilation of separate lung lobes without the surrounding chest wall showed the dynamics and differences in regional ventilation in separate lobes of new ventilation and recruitment modalities such as differential PEEP, selective lobe recruitment, continuous CPAP and asynchronous ventilation. The tracheal portion of the device was connected to one ventilator (Aestiva 5, Datex-Ohmeda, WI, USA) and the two lobar tubes were advanced to the right and left lower lobes. The proximal end of the secondary tubes are attached to a "Y" connector then connected to a second ventilator with same specifications. This configuration divides the lung segments into two compartments; one is a less gravity dependent compartment containing the upper lobes of both lungs and right middle lobe, and the second is a more gravity dependent compartment encompassing the bilateral lower lobes. Protocol (A20-150) was approved by the Wake Forest Institutional Animal Care and Use Committee (IACUC) to test this new respiratory apparatus in a double hit injury model of ARDS. In this model, after general anesthesia, ARDS was induced by 1) lung lavage to deplete surfactant then 2) intravenous oleic acid to cause endothelial lesions. Bronchoscopy with successful positioning of the apparatus in swine lungs was performed with 3.8mm flexible bronchoscope. (BFlex TM Scope) and imaging acquisition was performed using Glide Scope ® Core unit (Verathon, WA, USA) (Fig.2) . The preliminary results suggest that better ventilation and oxygenation can be achieved with the selective lobe ventilation strategy when compared to the current protective lung strategy, but we require more experiments to achieve statistical power and hopefully translate to clinical significance. (v) Expected challenges prior to uniform implementation in clinical practice: The use of this device in clinical practice will require continued pre-clinical in-vitro, ex-vivo and in-vivo animal model testing then a clinical trial to confirm safety and effectiveness in humans. The current plan is to continue pre-clinical work and test if the novel device is equivalent to or better than the currently available double lumen tubes. An important challenge to address is the need for two ventilators for one patient in order to implement selective lobe ventilation. We've considered that the need for two ventilators is not an ideal option, and if selective lung therapies prove to have clinical bennefit in the near future; we will need to design new respiratory circuits, new drug delivery systems and likely new ventilators. The lung lesions caused by SARS-CoV-2 show variable stages of inflammation, fluid accumulation and decreased perfusion which culminates with the clinical picture of ARDS. It also appears SARS-CoV-2 develops fibroproliferative lung damage in the most severe cases with progressive worsening of lung function, especially in cases with prolonged hospitalization and mechanical ventilation [17] . Now more than ever before, there is a need to explore new therapeutic options and potential improvements in the care of patients with severe lung injury. ARDS is an acute, diffuse, inflammatory form of lung injury [18] with non-cardiogenic pulmonary edema characterized by bilateral lung infiltrates and hypoxemia, caused by multiple etiologies. Before 2019, the incidence of ARDS in intensive care units was approximately 10 to 15% of admitted patients and up to 23% of mechanically ventilated patients [19] . The mortality rates of ARDS is 27%, 32%, and 45% for mild, moderate, and severe disease, respectively [19] . Mechanical ventilation with elevated airway pressures results in ventilator-induced lung injury (VILI) [20, 21] . Protective ventilation strategies with low tidal volumes reduce complications but have no significant impact on mortality [22] . In particular, heterogeneity constitutes a problem since the current methods of mechanical ventilation do not allow for regional ventilation of lung zones with different mechanical properties. Customization of ventilator parameters based on regional ventilation imaging by chest CT or electrical Selective lobe ventilation is an interesting and appealing concept. However, placing multiple tubes in the airway seems unpractical in particular in patients with low physiologic reserve where significant work within the airway may be risky. Moreover, having multiple ventilators seems to be clinically challenging and maybe not feasible in during ventilator shortages. On the other hand, the pandemic and ventilator shortages have forced clinicians to create means to perform split ventilation with different PEEP levels to help more than one patient [27, 28] . The idea of split ventilation may now have a long term application for patients who could benefit from selective lobe ventilation. The design achieved for the apparatus allows the Shuttle to work as single lumen tube, and placing one secondary tube in the main stem bronchi would allow OLV. If selective lobe ventilation is desired, one or more of the secondary tubes can be advanced to the respective lung lobe(s). Compared to the current double lumen tubes used for thoracic surgery, the Shuttle is more malleable and has a smaller profile which may be beneficial in patients with difficult airways. The placement of secondary tubes can be performed with no interruption of ventilation and the secondary tubes slide inside the Shuttle sheath, preventing tracheal injuries. The double lumen feature can be simply converted to single lumen by removing the secondary tube, without having to perform a tube exchange, which may also be a useful feature for extensive thoracic procedures such as esophagectomy and lung transplants. The ex-vivo test has shown different possibilities for ventilation, lung recruitment, delivery of medical gases and drug delivery. The selection of mechanical ventilation parameters, such as PEEP, minute ventilation, I:E ratio, upper and lower lobe respiratory cycle synchrony deserve special consideration. Differential PEEP- Having a higher peep on gravity dependent lobes provides better recruitment and having lower PEEP on nongravity dependent would prevent over distension and avoid VILI of more compliant segments. There is also evidence from OLV studies, that differential PEEP can shift perfusion between gravity dependent and nongravity dependent lungs, and that higher PEEP on the diseased affected segments could also shift perfusion to non-dependent segments improving V/Q relationship [29, 30] . Equipment dead space is an important factor to be considered especially when mechanically ventilating stiff lungs with limited tidal volumes [31] . Using the novel apparatus in a modified configuration will potentially eliminate equipment dead space. By placing the secondary tubes in the trachea, removing the "Y" piece from the respiratory circuit, and connecting one limb directly to the Shuttle and the other limb to secondary tubes, would technically result in moving the "Y" piece into the airway. By reducing unnecessary dead space, it increases effective ventilation, reduces the work of breathing and promotes more effective CO2 elimination. The combination of high perfusion, and collapsed alveoli creates a problem for the delivery of any pulmonarydelivered therapy for heterogeneous lung diseases. Drugs administered though tracheal injections or nebulized particles will take the path of least resistance to normal or less injured lung parenchyma where they will be systemically absorbed. Therefore, treatment will either not reach the diseased tissue in need of therapy or will not have had sufficient exposure time to have significant impact. This is likely the reason why surfactant administration has not shown benefit in treating adult ARDS [32] . Certain therapies such as lung lavage may temporarily worse oxygenation by removing surfactant from normally ventilated areas. This novel apparatus allows delivery of therapies to specific lobes that are injured and likely not contributing very much, simultaneously with normal ventilation of the remaining lobes to maintain gas exchange. Drugs that increase pulmonary perfusion such as prostaglandin and nitric oxide would likely to improve oxygenation if delivered to the alveoli that is not shunting. Heliox or liquid ventilation could be an interesting option for lung zones difficult to achieve aeration. Finally, the device has potential to be a novel delivery platform for drugs, medical gases and biologics. Media 1-Video content with different ex-vivo experiment using the apparatus for selective lobe ventilation and pulmonary drug delivery. Initial images of the shuttle tube, two lobar tubes, bronchoscope and 3D printed tracheal bronchial tree. Placement of the shuttle, right lower lobe tube, left lower lobe tube. Bronchoscope placed on the tracheal lumen. Connectors for tracheal, lobar and sheath. Selective lobe ventilation, right lower lobe, left lower lobe, and upper lobes (including right middle lobe). Differential PEEP ventilation, lower lobes with PEEP=20cmH2O and Upper lobes with zero PEEP. Differential PEEP ventilation, lower lobes with PEEP=12cmH2O and Upper lobes with PEEP=5cmH2O. Selective lower lobe recruitment with 30cmH2O on left lower lobe with continuous ventilation. TV=650ml and PEEP=5cmH2O. Lower lobes CPAP=20cmH2O and controlled ventilation with PEEP=5cm H2O on the upper lobes. Asynchronous ventilation-inspiration and expiration of upper and lower lobes ventilating in different times of the respiratory cycle. Lower lobes PEEP=12cmH2O and upper lobes PEEP=8cmH2O. PEEP=positive end expiratory pressure, Is the Prone Position Helpful During Spontaneous Breathing in Patients With COVID-19? Noninvasive Versus Invasive Ventilation in COVID-19: One Size Does Not Fit All! Anesthesia and analgesia Early Self-Proning in Awake, Non-intubated Patients in the Emergency Department: A Single ED's Experience During the COVID-19 Pandemic Lung Metabolic Activation as an Early Biomarker of Acute Respiratory Distress Syndrome and Local Gene Expression Heterogeneity Clinical and biological heterogeneity in acute respiratory distress syndrome: direct versus indirect lung injury Embracing the Heterogeneity of ARDS Understanding a Heterogeneous Syndrome Progression of regional lung strain and heterogeneity in lung injury: assessing the evolution under spontaneous breathing and mechanical ventilation Acute Respiratory Distress Syndrome Acute Respiratory Distress Syndrome Respiratory Mechanics of COVID-19-versus Non-COVID-19-associated Acute Respiratory Distress Syndrome Ventilator-induced Lung Injury Ventilator-induced lung injury Ventilator-Induced Lung Injury: Classic and Novel Concepts Anatomy and bronchoscopy of the porcine lung. A model for translational respiratory medicine Tracking the time course of pathological patterns of lung injury in severe COVID-19 Acute respiratory distress syndrome: new definition, current and future therapeutic options Incidence, clinical course, and outcome in 217 patients with acute respiratory distress syndrome Ventilator-induced lung injury: historical perspectives and clinical implications Quantifying unintended exposure to high tidal volumes from breath stacking dyssynchrony in ARDS: the BREATHE criteria Lung protective ventilation strategy for the acute respiratory distress syndrome. The Cochrane database of systematic reviews Use of computed tomography scanning to guide lung recruitment and adjust positive-end expiratory pressure Overview of current lung imaging in acute respiratory distress syndrome Electrical impedance tomography in acute respiratory distress syndrome Hemodynamic effects of lung recruitment maneuvers in acute respiratory distress syndrome. BMC pulmonary medicine A novel inline PEEP valve design for differential multi-ventilation. The American journal of emergency medicine Differential Ventilation Using Flow Control Valves as a Potential Bridge to Full Ventilatory Support during the COVID-19 Crisis Approaches to hypoxemia during single-lung ventilation Ventilation and perfusion of each lung during differential ventilation with selective PEEP Dead space: the physiology of wasted ventilation Effect of surfactant administration on outcomes of adult patients in acute respiratory distress syndrome: a meta-analysis of randomized controlled trials. BMC pulmonary medicine