The outcomes of acute respiratory distress syndrome (ARDS) management remain insufficient with poor results, most probably due to patients’ diversity and incompatibility of the applied methods with the pathophysiology and biophysics of the respiratory pump.
In contrast, the result of this study proved the feasibility and effectiveness of a circulatory flow restoration (CFR) device as a potential therapeutic method in ARDS. For the first time in the literature, we have shown that a low-pressure extracorporeal pulsatile device could induce a nearly physiological arterial pressure curve (Fig.5C) in cardiac arrest models, regardless of heartbeats. This means that the device's vest which is also served as a non-invasive mechanical ventilator, provided efficient cardiac compression and recoil of chest wall and promoted ESS of the respiratory pump. Similarly, the alternating pulsations delivered by the infradiaphragmatic element at the stagnant hepatic-splanchnic venous capacitance increased RV preload, during the vest inspiratory phase, and decreased pulmonary afterload. These were confirmed by significant improvements in hemodynamics data, the cutaneous microcirculation, myocardial apoptosis and urine output which required compensation with IV fluids, despite the state of cardiac arrest.
Endothelial Shear Stress Versus Conventional Therapy In ARDS
Most of ARDS patients present endothelial dysfunction comorbidities with increased pulmonary and systemic vascular resistances. A situation that most commonly worsen with conventional treatment such as vasopressors and steady-flow CADs like ECMO . Yet, the immobilization of the respiratory pump and transformation of the respiratory tract into a closed pressurized hydraulic circuit by mechanical ventilators besides their interference with coronary perfusion flow are the principles causes of hemodynamic and metabolic deterioration in ARDS [21,22].
We have been previously reported the benefits of ESS applications in hemodynamic improvement with different pulsatile CAD tested in acute cardiogenic shock induced in thirty- six pediatric piglets divided equally (n=6) between groups, as follows (Table 1): Acute PAH, created with surgical aortopulmonary shunt ; Acute myocardial infarction (MI) , following permanent ligation of left anterior descending coronary artery (LAD) and Acute right ventricular failure (RVF) , following surgical disruption of pulmonary valve. As shown in (Table 2), there were significant improvement of hemodynamics and reduction of the pulmonary vascular resistances, within few minutes of device pulsations and without any pharmacological supports. In preclinical studies, low-pressure pulsatile devices, e.g. pulsatile trousers and mask prototypes, were tested on healthy volunteers, showed enhancement of the cutaneous microcirculation has also been observed, measured with a laser flowmeter (PeriFlux System 5000; Perimed) in an area remote from the pulsed zone (e.g. tip of the nose in mask trials, and fingertip with trousers) and increased cerebral blood flow (measured with carotid Doppler echo) after 20 min of un-synchronized pulsations (mask) [9,26].
Right-Heart Versus Left-Heart Endothelium
Contrary to historical consideration of endothelium as a homogenous cell layer, heterogeneity of the pulmonary endothelium is apparent and has been proven in literature from different disciplines . In general, left heart side endothelial functions are most frequently explored and stimulated with devices, e.g., the intra-aortic balloon pump (IABP), etc. In the long-term, these left-heart side CAD usually show tolerant effects with further deterioration, rather than restoration, of endothelial function . In contrast, our studies results proved the hypersensitivity of the pulmonary endothelium, which is a part of the right-heart, to shear stress stimuli. A few minutes of intrapulmonary catheter pulsations were more than enough to decrease a systolic PAP from ≥ 45 mmHg to approximately 9 mmHg within a few minutes (approximately 10) , which is contrary to IABP experience at the left heart side. Similar observations were obtained with the acute myocardial ischemia model . However, in acute RV failure, an external pulsatile trouser, decreased RV pressure and PVR, albeit in a slightly longer time frame (approximately 20 min) .
Pulmonary Versus Systemic Vascular Resistance
Clinical applications of vasopressors to increase systemic vascular resistance for acute PAH management is currently recommended by intensivists . A similar phenomenon is also observed with tetralogy of Fallot (TOF) cyanotic spells because the patient usually takes the advantage of the overriding aorta and assumes a squatting position to temporarily increase SVR in order to increase pulmonary flow dynamics of ESS to decrease PVR. However, hemodynamically that could be improved physiologically in a TOF patient, whose system may be deteriorated due to vasopressors (e.g., tachyarrhythmia, renal failure, multiple organ failure, etc.) .
In the previous studies, the effect of intrapulmonary shear stress enhancement was immediate on both SVR and PVR in the pulsatile group. Compared with vasopressors, there was evidence of increased renal flow without associated tachyarrhythmia, e.g., heart rate was 69 ± 19 bpm.
Endothelial Shear Stress-Microcirculation Interdependency
Endothelial shear stress (ESS)-microcirculation interdependency constitutes the cornerstone of the proposed concept.
While maintaining a full respiratory pump function, microcirculation behavior adapts to all circumstances of hematological disorders to ensure adequate tissue oxygenation by all means. For example, with a low or high hematocrit, the microcirculation exhibits a behavior that approximates that of Bernoulli's law, as interpreted by the Fahraeus-Lindqvist effect , in which plasma stuck at the inner vascular boundary layers while erythrocytes move faster at the center. This could explain the absence of cyanosis in anemic patients with low hematocrit, unlike those patients with high hematocrit, as erythrocytes aggregations at microcirculations induce cyanosis with clinical signs of finger clubbing (drumsticks fingers).
However, once the pulmonary production of ESS is compromised due to pathological conditions of the contractile structures of the respiratory pump, patients exhibit symptoms and signs such as tachycardia, tachyarrhythmia, orthopnea, ... which are pathophysiological accelerators of pulmonary ESS induction by the respiratory pump to improve microcirculation.
Endothelial Shear Stress Versus Conventional PAH Therapy
Current PAH management includes pharmacological supports such as: the nitrous oxide (NO)– cGMP pathway and the prostacyclin–cAMP and endothelin receptors antagonists ; inhalational NO (iNO) ; phosphodiesterase-5 (PDE5) inhibitors [34,35]. Nonpharmacological supports, along with the employment of mechanical-assist devices and/or surgical procedures, may be needed in critical hemodynamic cases .
Unfortunately, current PAH therapies remain insufficient linked with a dismal prognosis comparable with that of advanced cancer [37,38,39]. For example, iNO, which relaxes arterial smooth muscle in the absence of parenchymal lung disease, could increase endothelin-1 levels and decrease endogenous nitric oxide synthase (eNOS) activity . Abrupt discontinuation of iNO can result in rebound PAH with further deterioration of hemodynamic [41, 42]. Similarly, inhaled iloprost, may cause acute bronchoconstriction [43,44]. These drawbacks of inhalational PAH therapies may be explained by the different behavior of the extra-alveolar and alveolar endothelial cells due to their different embryological origins .
The employment of CAD for PAH management is still linked with controversial results . Unfortunately, CAD could aggravate hemodynamics, leading to multiple-organ failure due to factors linked to the devices themselves (e.g., momentum energy losses) or indirectly due to patient-related factors (e.g., age, sex, right or left heart failure, etc.). For example, devices that unload and bypass the left ventricle are less successful when used at the RV, which is preload dependent.
In fact, PAH is an endothelial dysfunction disease, treated with pharmacological options which are functionally simulating what could be obtained naturally from the endothelium, but with side effects. Accordingly, we have induced ESS enhancement for PAH management with new generation of pulsatile circulatory assist devices (CAD) to reduce PVR and improve hemodynamics in a nearly physiological manner and without pharmacological supports.
Practically, a human body (Soma) can be divided into three imaginary hemorheological spheres : A, B, and C (Somarheology theory), wherein A stands for the amount of fluids, that could be compressible Newtonian (e.g., air), or incompressible non-Newtonian (e.g., blood) fluids, surrounded by B, the barriers of cells (e.g., vascular endothelium, alveolar epithelium), overlapped by C, the covering tissues (e.g., vascular vessels, parenchyma, muscles, etc.). Therefore, reduction of pulmonary vascular resistances (PVR) could be induced with a pulsatile device internally through sphere (A) and/or externally e.g., through sphere (C) to create ESS at sphere (B), and in correspondence to the Dana Point (PAH) classification , as depicted in (Fig.7) .
For example, in group (C), e.g., Covid-19 patients with parenchymal congestion, delivery of ESS should be induced externally through sphere (C) with a pulsatile device adapted to patients’ pathophysiological requirements.
As depicted in (Fig.3) the (CFR) device can induce ESS through several endothelial surrounding covering layers (C): parenchymal, mediastinal, thoracic cage muscles and the diaphragm.
As a result, the device stimulates the massive natural pulmonary and hepatic endothelial stocks, inducing plenty of mediators to restore hemodynamics and metabolic processes.
Contrarily to noninvasive ventilation (NIV), which is only considered in the early stages of SARS, the device can be used effectively in severe ARDS .
Unlike the iron lung , it is a low-pressure pulsatile device (0.1-0.5 bar), that can mobilize both supra and infradiaphragmatic structures of the respiratory pump that makes it suitable for all ages and genders without side effects, e.g., rib fractures, mammary glands hematoma,
The device is an automated assembly that could be easily tilted at the request of clinicians, e.g., physiotherapists. Therefore, it could be an exclusive therapeutic tool for ARDS and achievement of current concept-based trials that showed some hope, but still remain without major impacts, e.g., prone position, low-dose neuromuscular blockades, thrombolytics therapies… .
We have been confronted with some technical difficulties that include the use of two separate mal-synchronized pneumatic generators. A tissue prototype, which is less rigid at its outer part that makes the body compression less efficient particularly, with the morphological difference between the dog and the pig that required specific prototypes for each model.
We have planned to continue the development pathway of the CFR, as has been figured recently from the United States Food and Drug Administration , with preclinical studies for out of hospital cardiac arrest management. We have planned a PAH study in hypoxic piglets’ model. Both programs are in standby for logistic, unscientific reasons.
Nevertheless, given the current pandemic with the shortage and/or controversial results of ventilators worldwide, in review with the FINER criteria for a good research question and the phases of evaluation of new therapies [52,53], we consider a low-pressure noninvasive device is ease of manufacture, safe for use to promotes endothelial shear stress to improve hemodynamic, tissues oxygenation and metabolic processes, which significantly will improve the outcomes of critically ill Covid-19 patients.