Vanillic acid-based pro-coagulant hemostatic shape memory polymer foams with antimicrobial properties against drug-resistant bacteria.

Uncontrolled bleeding is the primary cause of trauma-related death. For patients that are brought to the hospital in time to receive treatment, there is a great risk of contracting drug-resistant bacterial wound infections. Therefore, low-cost hemostatic agents with procoagulant and antibacterial properties are essential to reduce morbidity and mortality in patients with traumatic wounds. To that end, we introduced vanillic acid (VA) into shape memory polymer (SMP) foams through a dual incorporation mechanism to make dual vanillic acid (DVA) foams. The dual mechanism increases VA loading while allowing burst and sustained delivery of VA from foams. DVA foams exhibit antimicrobial and antibiofilm properties against native and drug-resistant Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis. Also, DVA foams inhibit the growth rate of both methicillin-sensitive and -resistant S. aureus colonies to limit their size and promote small colony variants. DVA SMP foams induced primary and secondary hemostasis in in vitro blood interaction studies. As a proof of concept, we demonstrated easy delivery and rapid clotting in a porcine liver injury model, indicating DVA foam feasibility for use as a hemostatic dressing. Thus, the inexpensive production of DVA SMP foams could enable a cost-effective procoagulant hemostatic dressing that is resistant to bacterial colonization to improve short- and long-term outcomes for hemorrhage control in traumatically injured patients. STATEMENT OF SIGNIFICANCE: Uncontrolled bleeding is the primary cause of preventable death on the battlefield. Of patients that survive, ∼40 % develop polymicrobial infections within 5 days of injury. Drug-resistant infections are anticipated to cause more deaths than all cancers combined by 2050. Therefore, novel non-drug-based biomaterials strategies for infection control in wound care are increasingly important. To that end, we developed hemostatic polyurethane foams that include antimicrobial and pro-coagulant vanillic acid, a plant-based antimicrobial species. These foams provide excellent protection against native and drug-resistant bacteria and enhanced coagulation while remaining cytocompatible. In a pilot porcine liver injury model, vanillic acid-containing foams stabilized a bleed within <5 min. These biomaterials provide a promising solution for both hemorrhage and infection control in wound care.

Effects of Lung Injury and Abdominal Insufflation on Respiratory Mechanics and Lung Volume During Time-Controlled Adaptive Ventilation.

BACKGROUD: Lung volume measurements are important for monitoring functional aeration and recruitment and may help guide adjustments in ventilator settings. The expiratory phase of airway pressure release ventilation (APRV) may provide physiologic information about lung volume based on the expiratory flow-time slope, angle, and time to approach a no-flow state (expiratory time [TE]). We hypothesized that expiratory flow would correlate with estimated lung volume (ELV) as measured using a modified nitrogen washout/washin technique in a large-animal lung injury model. METHODS: Eight pigs (35.2 ± 1.0 kg) were mechanically ventilated using an Engström Carescape R860 on the APRV mode. All settings were held constant except the expiratory duration, which was adjusted based on the expiratory flow curve. Abdominal pressure was increased to 15 mm Hg in normal and injured lungs to replicate a combination of pulmonary and extrapulmonary lung injury. ELV was estimated using the Carescape FRC INview tool. The expiratory flow-time slope and TE were measured from the expiratory flow profile. RESULTS: Lung elastance increased with induced lung injury from 29.3 ± 7.3 cm H2O/L to 39.9 ± 15.1cm H2O/L, and chest wall elastance increased with increasing intra-abdominal pressures (IAPs) from 15.3 ± 4.1 cm H2O/L to 25.7 ± 10.0 cm H2O/L in the normal lung and 15.8 ± 6.0 cm H2O/L to 33.0 ± 6.2 cm H2O/L in the injured lung (P = .39). ELV decreased from 1.90 ± 0.83 L in the injured lung to 0.67 ± 0.10 L by increasing IAP to 15 mm Hg. This had a significant correlation with a TE decrease from 2.3 ± 0.8 s to 1.0 ± 0.1 s in the injured group with increasing insufflation pressures (ρ = 0.95) and with the expiratory flow-time slope, which increased from 0.29 ± 0.06 L/s2 to 0.63 ± 0.05 L/s2 (ρ = 0.78). CONCLUSIONS: Changes in ELV over time, and the TE and flow-time slope, could be used to demonstrate evolving lung injury during APRV. Using the slope to infer changes in functional lung volume represents a unique, reproducible, real-time, bedside technique that does not interrupt ventilation and may be used for clinical interpretation.

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

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 (LVT) with low-moderate positive end-expiratory pressure (PEEP); and (2) open lung approach (OLA). The LVT 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 VT and EELV. Personalization of TCAV is informed and tuned with changes in respiratory system compliance (CRS) 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.

The use of protective mechanical ventilation during extracorporeal membrane oxygenation for the treatment of acute respiratory failure.

Acute respiratory failure (ARF) strikes an estimated two million people in the United States each year, with care exceeding US$50 billion. The hallmark of ARF is a heterogeneous injury, with normal tissue intermingled with a large volume of low compliance and collapsed tissue. Mechanical ventilation is necessary to oxygenate and ventilate patients with ARF, but if set inappropriately, it can cause an unintended ventilator-induced lung injury (VILI). The mechanism of VILI is believed to be overdistension of the remaining normal tissue known as the 'baby' lung, causing volutrauma, repetitive collapse and reopening of lung tissue with each breath, causing atelectrauma, and inflammation secondary to this mechanical damage, causing biotrauma. To avoid VILI, extracorporeal membrane oxygenation (ECMO) can temporally replace the pulmonary function of gas exchange without requiring high tidal volumes (VT) or airway pressures. In theory, the lower VT and airway pressure will minimize all three VILI mechanisms, allowing the lung to 'rest' and heal in the collapsed state. The optimal method of mechanical ventilation for the patient on ECMO is unknown. The ARDSNetwork Acute Respiratory Management Approach (ARMA) is a Rest Lung Approach (RLA) that attempts to reduce the excessive stress and strain on the remaining normal lung tissue and buys time for the lung to heal in the collapsed state. Theoretically, excessive tissue stress and strain can also be avoided if the lung is fully open, as long as the alveolar re-collapse is prevented during expiration, an approach known as the Open Lung Approach (OLA). A third lung-protective strategy is the Stabilize Lung Approach (SLA), in which the lung is initially stabilized and gradually reopened over time. This review will analyze the physiologic efficacy and pathophysiologic potential of the above lung-protective approaches.

Ratchet recruitment in the acute respiratory distress syndrome: lessons from the newborn cry.

Patients with acute respiratory distress syndrome (ARDS) have few treatment options other than supportive mechanical ventilation. The mortality associated with ARDS remains unacceptably high, and mechanical ventilation itself has the potential to increase mortality further by unintended ventilator-induced lung injury (VILI). Thus, there is motivation to improve management of ventilation in patients with ARDS. The immediate goal of mechanical ventilation in ARDS should be to prevent atelectrauma resulting from repetitive alveolar collapse and reopening. However, a long-term goal should be to re-open collapsed and edematous regions of the lung and reduce regions of high mechanical stress that lead to regional volutrauma. In this paper, we consider the proposed strategy used by the full-term newborn to open the fluid-filled lung during the initial breaths of life, by ratcheting tissues opened over a series of initial breaths with brief expirations. The newborn's cry after birth shares key similarities with the Airway Pressure Release Ventilation (APRV) modality, in which the expiratory duration is sufficiently short to minimize end-expiratory derecruitment. Using a simple computational model of the injured lung, we demonstrate that APRV can slowly open even the most recalcitrant alveoli with extended periods of high inspiratory pressure, while reducing alveolar re-collapse with brief expirations. These processes together comprise a ratchet mechanism by which the lung is progressively recruited, similar to the manner in which the newborn lung is aerated during a series of cries, albeit over longer time scales.

First Stabilize and then Gradually Recruit: A Paradigm Shift in Protective Mechanical Ventilation for Acute Lung Injury.

Acute respiratory distress syndrome (ARDS) is associated with a heterogeneous pattern of injury throughout the lung parenchyma that alters regional alveolar opening and collapse time constants. Such heterogeneity leads to atelectasis and repetitive alveolar collapse and expansion (RACE). The net effect is a progressive loss of lung volume with secondary ventilator-induced lung injury (VILI). Previous concepts of ARDS pathophysiology envisioned a two-compartment system: a small amount of normally aerated lung tissue in the non-dependent regions (termed "baby lung"); and a collapsed and edematous tissue in dependent regions. Based on such compartmentalization, two protective ventilation strategies have been developed: (1) a "protective lung approach" (PLA), designed to reduce overdistension in the remaining aerated compartment using a low tidal volume; and (2) an "open lung approach" (OLA), which first attempts to open the collapsed lung tissue over a short time frame (seconds or minutes) with an initial recruitment maneuver, and then stabilize newly recruited tissue using titrated positive end-expiratory pressure (PEEP). A more recent understanding of ARDS pathophysiology identifies regional alveolar instability and collapse (i.e., hidden micro-atelectasis) in both lung compartments as a primary VILI mechanism. Based on this understanding, we propose an alternative strategy to ventilating the injured lung, which we term a "stabilize lung approach" (SLA). The SLA is designed to immediately stabilize the lung and reduce RACE while gradually reopening collapsed tissue over hours or days. At the core of SLA is time-controlled adaptive ventilation (TCAV), a method to adjust the parameters of the airway pressure release ventilation (APRV) modality. Since the acutely injured lung at any given airway pressure requires more time for alveolar recruitment and less time for alveolar collapse, SLA adjusts inspiratory and expiratory durations and inflation pressure levels. The TCAV method SLA reverses the open first and stabilize second OLA method by: (i) immediately stabilizing lung tissue using a very brief exhalation time (≤0.5 s), so that alveoli simply do not have sufficient time to collapse. The exhalation duration is personalized and adaptive to individual respiratory mechanical properties (i.e., elastic recoil); and (ii) gradually recruiting collapsed lung tissue using an inflate and brake ratchet combined with an extended inspiratory duration (4-6 s) method. Translational animal studies, clinical statistical analysis, and case reports support the use of TCAV as an efficacious lung protective strategy.

Protective ventilation in a pig model of acute lung injury: timing is as important as pressure.

Ventilator-induced lung injury (VILI) is a significant risk for patients with acute respiratory distress syndrome (ARDS). Management of the patient with ARDS is currently dominated by the use of low tidal volume mechanical ventilation, the presumption being that this mitigates overdistension (OD) injury to the remaining normal lung tissue. Evidence exists, however, that it may be more important to avoid cyclic recruitment and derecruitment (RD) of lung units, although the relative roles of OD and RD in VILI remain unclear. Forty pigs had a heterogeneous lung injury induced by Tween instillation and were randomized into four groups (n = 10 each) with higher (↑) or lower (↓) levels of OD and/or RD imposed using airway pressure release ventilation (APRV). OD was increased by setting inspiratory airway pressure to 40 cmH2O and lessened with 28 cmH2O. RD was attenuated using a short duration of expiration (∼0.45 s) and increased with a longer duration (∼1.0 s). All groups developed mild ARDS following injury. RD ↑ OD↑ caused the greatest degree of lung injury as determined by [Formula: see text]/[Formula: see text] ratio (226.1 ± 41.4 mmHg). RD ↑ OD↓ ([Formula: see text]/[Formula: see text]= 333.9 ± 33.1 mmHg) and RD ↓ OD↑ ([Formula: see text]/[Formula: see text] = 377.4 ± 43.2 mmHg) were both moderately injurious, whereas RD ↓ OD↓ ([Formula: see text]/[Formula: see text] = 472.3 ± 22.2 mmHg; P < 0.05) was least injurious. Both tidal volume and driving pressure were essentially identical in the RD ↑ OD↓ and RD ↓ OD↑ groups. We, therefore, conclude that considerations of expiratory time may be at least as important as pressure for safely ventilating the injured lung.NEW & NOTEWORTHY In a large animal model of ARDS, recruitment/derecruitment caused greater VILI than overdistension, whereas both mechanisms together caused severe lung damage. These findings suggest that eliminating cyclic recruitment and derecruitment during mechanical ventilation should be a preeminent management goal for the patient with ARDS. The airway pressure release ventilation (APRV) mode of mechanical ventilation can achieve this if delivered with an expiratory duration (TLow) that is brief enough to prevent derecruitment at end expiration.

Unshrinking the baby lung to calm the VILI vortex.

A hallmark of ARDS is progressive shrinking of the 'baby lung,' now referred to as the ventilator-induced lung injury (VILI) 'vortex.' Reducing the risk of the VILI vortex is the goal of current ventilation strategies; unfortunately, this goal has not been achieved nor has mortality been reduced. However, the temporal aspects of a mechanical breath have not been considered. A brief expiration prevents alveolar collapse, and an extended inspiration can recruit the atelectatic lung over hours. Time-controlled adaptive ventilation (TCAV) is a novel ventilator approach to achieve these goals, since it considers many of the temporal aspects of dynamic lung mechanics.

Assessment of Heterogeneity in Lung Structure and Function During Mechanical Ventilation: A Review of Methodologies.

The mammalian lung is characterized by heterogeneity in both its structure and function, by incorporating an asymmetric branching airway tree optimized for maintenance of efficient ventilation, perfusion, and gas exchange. Despite potential benefits of naturally occurring heterogeneity in the lungs, there may also be detrimental effects arising from pathologic processes, which may result in deficiencies in gas transport and exchange. Regardless of etiology, pathologic heterogeneity results in the maldistribution of regional ventilation and perfusion, impairments in gas exchange, and increased work of breathing. In extreme situations, heterogeneity may result in respiratory failure, necessitating support with a mechanical ventilator. This review will present a summary of measurement techniques for assessing and quantifying heterogeneity in respiratory system structure and function during mechanical ventilation. These methods have been grouped according to four broad categories: (1) inverse modeling of heterogeneous mechanical function; (2) capnography and washout techniques to measure heterogeneity of gas transport; (3) measurements of heterogeneous deformation on the surface of the lung; and finally (4) imaging techniques used to observe spatially-distributed ventilation or regional deformation. Each technique varies with regard to spatial and temporal resolution, degrees of invasiveness, risks posed to patients, as well as suitability for clinical implementation. Nonetheless, each technique provides a unique perspective on the manifestations and consequences of mechanical heterogeneity in the diseased lung.

Effects of time-controlled adaptive ventilation on cardiorespiratory parameters and inflammatory response in experimental emphysema.

The time-controlled adaptive ventilation (TCAV) method attenuates lung damage in acute respiratory distress syndrome. However, so far, no study has evaluated the impact of the TCAV method on ventilator-induced lung injury (VILI) and cardiac function in emphysema. We hypothesized that the use of the TCAV method to achieve an expiratory flow termination/expiratory peak flow (EFT/EPF) of 25% could reduce VILI and improve right ventricular function in elastase-induced lung emphysema in rats. Five weeks after the last intratracheal instillation of elastase, animals were anesthetized and mechanically ventilated for 1 h using TCAV adjusted to either EFT/EPF 25% or EFT/EPF 75%, the latter often applied in acute respiratory distress syndrome (ARDS). Pressure-controlled ventilation (PCV) groups with positive end-expiratory pressure levels similar to positive end-release pressure in TCAV with EFT/EPF 25% and EFT/EPF 75% were also analyzed. Echocardiography and lung ultrasonography were monitored. Lung morphometry, alveolar heterogeneity, and biological markers related to inflammation [interleukin 6 (IL-6), CINC-1], alveolar pulmonary stretch (amphiregulin), lung matrix damage [metalloproteinase 9 (MMP-9)] were assessed. EFT/EPF 25% reduced respiratory system peak pressure, mean linear intercept, B lines at lung ultrasonography, and increased pulmonary acceleration time/pulmonary ejection time ratio compared with EFT/EPF 75%. The volume fraction of mononuclear cells, neutrophils, and expression of IL-6, CINC-1, amphiregulin, and MMP-9 were lower with EFT/EPF 25% than with EFT/EPF 75%. In conclusion, TCAV with EFT/EPF 25%, compared with EFT/EPF 75%, led to less lung inflammation, hyperinflation, and pulmonary arterial hypertension, which may be a promising strategy for patients with emphysema.NEW & NOTEWORTHY The TCAV method reduces lung damage in ARDS. However, so far, no study has evaluated the impact of the TCAV method on ventilator-induced lung injury and cardiac function in experimental emphysema. The TCAV method at EFT/EPF ratio of 25%, compared with EFT/EPF of 75% (frequently used in ARDS), reduced lung inflammation, alveolar heterogeneity and hyperinflation, and pulmonary arterial hypertension in elastase-induced emphysema. TCAV may be a promising and personalized ventilation strategy for patients with emphysema.

Hemostatic shape memory polymer foams with improved survival in a lethal traumatic hemorrhage model.

Although there are many hemostatic agents available for use on the battlefield, uncontrolled hemorrhage is still the primary cause of preventable death. Current hemostatic dressings include QuikClot® Combat Gauze (QCCG) and XStat®, which have inadequate success in reducing mortality. To address this need, a new hemostatic material was developed using shape memory polymer (SMP) foams, which demonstrate biocompatibility, rapid clotting, and shape recovery to fill the wound site. SMP foam hemostatic efficacy was examined in a lethal, noncompressible porcine liver injury model over 6 h following injury. Wounds were packed with SMP foams, XStat, or QCCG and compared in terms of time to bleeding cessation, total blood loss, and animal survival. The hemostatic material properties and in vitro blood interactions were also characterized. SMP foams decreased blood loss and active bleeding time in comparison with XStat and QCCG. Most importantly, SMP foams increased the 6 h survival rate by 50% and 37% (vs. XStat and QCCG, respectively) with significant increases in survival times. Based upon in vitro characterizations, this result is attributed to the low stiffness and shape filling capabilities of SMP foams. This study demonstrates that SMP foams have promise for improving upon current clinically available hemostatic dressings and that hemostatic material properties are important to consider in designing devices for noncompressible bleeding control. STATEMENT OF SIGNIFICANCE: Uncontrolled hemorrhage is the leading cause of preventable death on the battlefield, and it accounts for approximately 1.5 million deaths each year. New biomaterials are required for improved hemorrhage control, particularly in noncompressible wounds in the torso. Here, we compared shape memory polymer (SMP) foams with two clinical dressings, QuikClot Combat Gauze and XStat, in a pig model of lethal liver injury. SMP foam treatment reduced bleeding times and blood loss and significantly improved animal survival. After further material characterization, we determined that the improved outcomes with SMP foams are likely due to their low stiffness and controlled shape change after implantation, which enabled their delivery to the liver injuries without inducing further wound tearing. Overall, SMP foams provide a promising option for hemorrhage control.

Mechanical Ventilation in Pediatric and Neonatal Patients.

Pediatric acute respiratory distress syndrome (PARDS) remains a significant cause of morbidity and mortality, with mortality rates as high as 50% in children with severe PARDS. Despite this, pediatric lung injury and mechanical ventilation has been poorly studied, with the majority of investigations being observational or retrospective and with only a few randomized controlled trials to guide intensivists. The most recent and universally accepted guidelines for pediatric lung injury are based on consensus opinion rather than objective data. Therefore, most neonatal and pediatric mechanical ventilation practices have been arbitrarily adapted from adult protocols, neglecting the differences in lung pathophysiology, response to injury, and co-morbidities among the three groups. Low tidal volume ventilation has been generally accepted for pediatric patients, even in the absence of supporting evidence. No target tidal volume range has consistently been associated with outcomes, and compliance with delivering specific tidal volume ranges has been poor. Similarly, optimal PEEP has not been well-studied, with a general acceptance of higher levels of F i O2 and less aggressive PEEP titration as compared with adults. Other modes of ventilation including airway pressure release ventilation and high frequency ventilation have not been studied in a systematic fashion and there is too little evidence to recommend supporting or refraining from their use. There have been no consistent outcomes among studies in determining optimal modes or methods of setting them. In this review, the studies performed to date on mechanical ventilation strategies in neonatal and pediatric populations will be analyzed. There may not be a single optimal mechanical ventilation approach, where the best method may simply be one that allows for a personalized approach with settings adapted to the individual patient and disease pathophysiology. The challenges and barriers to conducting well-powered and robust multi-institutional studies will also be addressed, as well as reconsidering outcome measures and study design.

Time-Controlled Adaptive Ventilation Versus Volume-Controlled Ventilation in Experimental Pneumonia.

OBJECTIVES: We hypothesized that a time-controlled adaptive ventilation strategy would open and stabilize alveoli by controlling inspiratory and expiratory duration. Time-controlled adaptive ventilation was compared with volume-controlled ventilation at the same levels of mean airway pressure and positive end-release pressure (time-controlled adaptive ventilation)/positive end-expiratory pressure (volume-controlled ventilation) in a Pseudomonas aeruginosa-induced pneumonia model. DESIGN: Animal study. SETTING: Laboratory investigation. SUBJECTS: Twenty-one Wistar rats. INTERVENTIONS: Twenty-four hours after pneumonia induction, Wistar rats (n = 7) were ventilated with time-controlled adaptive ventilation (tidal volume = 8 mL/kg, airway pressure release ventilation for a Thigh = 0.75-0.85 s, release pressure (Plow) set at 0 cm H2O, and generating a positive end-release pressure = 1.6 cm H2O applied for Tlow = 0.11-0.14 s). The expiratory flow was terminated at 75% of the expiratory flow peak. An additional 14 animals were ventilated using volume-controlled ventilation, maintaining similar time-controlled adaptive ventilation levels of positive end-release pressure (positive end-expiratory pressure=1.6 cm H2O) and mean airway pressure = 10 cm H2O. Additional nonventilated animals (n = 7) were used for analysis of molecular biology markers. MEASUREMENTS AND MAIN RESULTS: After 1 hour of mechanical ventilation, the heterogeneity score, the expression of pro-inflammatory biomarkers interleukin-6 and cytokine-induced neutrophil chemoattractant-1 in lung tissue were significantly lower in the time-controlled adaptive ventilation than volume-controlled ventilation with similar mean airway pressure groups (p = 0.008, p = 0.011, and p = 0.011, respectively). Epithelial cell integrity, measured by E-cadherin tissue expression, was higher in time-controlled adaptive ventilation than volume-controlled ventilation with similar mean airway pressure (p = 0.004). Time-controlled adaptive ventilation animals had bacteremia counts lower than volume-controlled ventilation with similar mean airway pressure animals, while time-controlled adaptive ventilation and volume-controlled ventilation with similar positive end-release pressure animals had similar colony-forming unit counts. In addition, lung edema and cytokine-induced neutrophil chemoattractant-1 gene expression were more reduced in time-controlled adaptive ventilation than volume-controlled ventilation with similar positive end-release pressure groups. CONCLUSIONS: In the model of pneumonia used herein, at the same tidal volume and mean airway pressure, time-controlled adaptive ventilation, compared with volume-controlled ventilation, was associated with less lung damage and bacteremia and reduced gene expression of mediators associated with inflammation.

Mechanical Ventilation Lessons Learned From Alveolar Micromechanics.

Morbidity and mortality associated with lung injury remains disappointingly unchanged over the last two decades, in part due to the current reliance on lung macro-parameters set on the ventilator instead of considering the micro-environment and the response of the alveoli and alveolar ducts to ventilator adjustments. The response of alveoli and alveolar ducts to mechanical ventilation modes cannot be predicted with current bedside methods of assessment including lung compliance, oxygenation, and pressure-volume curves. Alveolar tidal volumes (Vt) are less determined by the Vt set on the mechanical ventilator and more dependent on the number of recruited alveoli available to accommodate that Vt and their heterogeneous mechanical properties, such that high lung Vt can lead to a low alveolar Vt and low Vt can lead to high alveolar Vt. The degree of alveolar heterogeneity that exists cannot be predicted based on lung calculations that average the individual alveolar Vt and compliance. Finally, the importance of time in promoting alveolar stability, specifically the inspiratory and expiratory times set on the ventilator, are currently under-appreciated. In order to improve outcomes related to lung injury, the respiratory physiology of the individual patient, specifically at the level of the alveolus, must be targeted. With experimental data, this review highlights some of the known mechanical ventilation adjustments that are helpful or harmful at the level of the alveolus.

A Physiologically Informed Strategy to Effectively Open, Stabilize, and Protect the Acutely Injured Lung.

Acute respiratory distress syndrome (ARDS) causes a heterogeneous lung injury and remains a serious medical problem, with one of the only treatments being supportive care in the form of mechanical ventilation. It is very difficult, however, to mechanically ventilate the heterogeneously damaged lung without causing secondary ventilator-induced lung injury (VILI). The acutely injured lung becomes time and pressure dependent, meaning that it takes more time and pressure to open the lung, and it recollapses more quickly and at higher pressure. Current protective ventilation strategies, ARDSnet low tidal volume (LVt) and the open lung approach (OLA), have been unsuccessful at further reducing ARDS mortality. We postulate that this is because the LVt strategy is constrained to ventilating a lung with a heterogeneous mix of normal and focalized injured tissue, and the OLA, although designed to fully open and stabilize the lung, is often unsuccessful at doing so. In this review we analyzed the pathophysiology of ARDS that renders the lung susceptible to VILI. We also analyzed the alterations in alveolar and alveolar duct mechanics that occur in the acutely injured lung and discussed how these alterations are a key mechanism driving VILI. Our analysis suggests that the time component of each mechanical breath, at both inspiration and expiration, is critical to normalize alveolar mechanics and protect the lung from VILI. Animal studies and a meta-analysis have suggested that the time-controlled adaptive ventilation (TCAV) method, using the airway pressure release ventilation mode, eliminates the constraints of ventilating a lung with heterogeneous injury, since it is highly effective at opening and stabilizing the time- and pressure-dependent lung. In animal studies it has been shown that by "casting open" the acutely injured lung with TCAV we can (1) reestablish normal expiratory lung volume as assessed by direct observation of subpleural alveoli; (2) return normal parenchymal microanatomical structural support, known as alveolar interdependence and parenchymal tethering, as assessed by morphometric analysis of lung histology; (3) facilitate regeneration of normal surfactant function measured as increases in surfactant proteins A and B; and (4) significantly increase lung compliance, which reduces the pathologic impact of driving pressure and mechanical power at any given tidal volume.

Prevention and treatment of acute lung injury with time-controlled adaptive ventilation: physiologically informed modification of airway pressure release ventilation.

Mortality in acute respiratory distress syndrome (ARDS) remains unacceptably high at approximately 39%. One of the only treatments is supportive: mechanical ventilation. However, improperly set mechanical ventilation can further increase the risk of death in patients with ARDS. Recent studies suggest that ventilation-induced lung injury (VILI) is caused by exaggerated regional lung strain, particularly in areas of alveolar instability subject to tidal recruitment/derecruitment and stress-multiplication. Thus, it is reasonable to expect that if a ventilation strategy can maintain stable lung inflation and homogeneity, regional dynamic strain would be reduced and VILI attenuated. A time-controlled adaptive ventilation (TCAV) method was developed to minimize dynamic alveolar strain by adjusting the delivered breath according to the mechanical characteristics of the lung. The goal of this review is to describe how the TCAV method impacts pathophysiology and protects lungs with, or at high risk of, acute lung injury. We present work from our group and others that identifies novel mechanisms of VILI in the alveolar microenvironment and demonstrates that the TCAV method can reduce VILI in translational animal ARDS models and mortality in surgical/trauma patients. Our TCAV method utilizes the airway pressure release ventilation (APRV) mode and is based on opening and collapsing time constants, which reflect the viscoelastic properties of the terminal airspaces. Time-controlled adaptive ventilation uses inspiratory and expiratory time to (1) gradually "nudge" alveoli and alveolar ducts open with an extended inspiratory duration and (2) prevent alveolar collapse using a brief (sub-second) expiratory duration that does not allow time for alveolar collapse. The new paradigm in TCAV is configuring each breath guided by the previous one, which achieves real-time titration of ventilator settings and minimizes instability induced tissue damage. This novel methodology changes the current approach to mechanical ventilation, from arbitrary to personalized and adaptive. The outcome of this approach is an open and stable lung with reduced regional strain and greater lung protection.

Surfactant delivery in rat lungs: Comparing 3D geometrical simulation model with experimental instillation.

Surfactant Replacement Therapy (SRT), which involves instillation of a liquid-surfactant mixture directly into the lung airway tree, is a major therapeutic treatment in neonatal patients with respiratory distress syndrome (RDS). This procedure has proved to be remarkably effective in premature newborns, inducing a five-fold decrease of mortality in the past 35 years. Disappointingly, its use in adults for treating acute respiratory distress syndrome (ARDS) experienced initial success followed by failures. Our recently developed numerical model has demonstrated that transition from success to failure of SRT in adults could, in fact, have a fluid mechanical origin that is potentially reversible. Here, we present the first numerical simulations of surfactant delivery into a realistic asymmetric conducting airway tree of the rat lung and compare them with experimental results. The roles of dose volume (VD), flow rate, and multiple aliquot delivery are investigated. We find that our simulations of surfactant delivery in rat lungs are in good agreement with our experimental data. In particular, we show that the monopodial architecture of the rat airway tree plays a major role in surfactant delivery, contributing to the poor homogeneity of the end distribution of surfactant. In addition, we observe that increasing VD increases the amount of surfactant delivered to the acini after losing a portion to coating the involved airways, the coating cost volume, VCC. Finally, we quantitatively assess the improvement resulting from a multiple aliquot delivery, a method sometimes employed clinically, and find that a much larger fraction of surfactant reaches the alveolar regions in this case. This is the first direct qualitative and quantitative comparison of our numerical model with experimental studies, which enhances our previous predictions in adults and neonates while providing a tool for predicting, engineering, and optimizing patient-specific surfactant delivery in complex situations.

Time-controlled adaptive ventilation (TCAV) accelerates simulated mucus clearance via increased expiratory flow rate.

BACKGROUND: Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in intensive care units. Distal airway mucus clearance has been shown to reduce VAP incidence. Studies suggest that mucus clearance is enhanced when the rate of expiratory flow is greater than inspiratory flow. The time-controlled adaptive ventilation (TCAV) protocol using the airway pressure release ventilation (APRV) mode has a significantly increased expiratory relative to inspiratory flow rate, as compared with the Acute Respiratory Distress Syndrome Network (ARDSnet) protocol using the conventional ventilation mode of volume assist control (VAC). We hypothesized the TCAV protocol would be superior to the ARDSnet protocol at clearing mucus by a mechanism of net flow in the expiratory direction. METHODS: Preserved pig lungs fitted with an endotracheal tube (ETT) were used as a model to study the effect of multiple combinations of peak inspiratory (IPF) and peak expiratory flow rate (EPF) on simulated mucus movement within the ETT. Mechanical ventilation was randomized into 6 groups (n = 10 runs/group): group 1-TCAV protocol settings with an end-expiratory pressure (PLow) of 0 cmH2O and PHigh 25 cmH2O, group 2-modified TCAV protocol with increased PLow 5 cmH2O and PHigh 25 cmH2O, group 3-modified TCAV with PLow 10 cmH2O and PHigh 25 cmH2O, group 4-ARDSnet protocol using low tidal volume (LTV) and PEEP 0 cmH2O, group 5-ARDSnet protocol using LTV and PEEP 10 cmH2O, and group 6-ARDSnet protocol using LTV and PEEP 20 cmH2O. PEEP of ARDSnet is analogous to PLow of TCAV. Proximal (towards the ventilator) mucus movement distance was recorded after 1 min of ventilation in each group. RESULTS: The TCAV protocol groups 1, 2, and 3 generated significantly greater peak expiratory flow (EPF 51.3 L/min, 46.8 L/min, 36.8 L/min, respectively) as compared to the ARDSnet protocol groups 4, 5, and 6 (32.9 L/min, 23.5 L/min, and 23.2 L/min, respectively) (p < 0.001). The TCAV groups also demonstrated the greatest proximal mucus movement (7.95 cm/min, 5.8 cm/min, 1.9 cm/min) (p < 0.01). All ARDSnet protocol groups (4-6) had zero proximal mucus movement (0 cm/min). CONCLUSIONS: The TCAV protocol groups promoted the greatest proximal movement of simulated mucus as compared to the ARDSnet protocol groups in this excised lung model. The TCAV protocol settings resulted in the highest EPF and the greatest proximal movement of mucus. Increasing PLow reduced proximal mucus movement. We speculate that proximal mucus movement is driven by EPF when EPF is greater than IPF, creating a net force in the proximal direction.

The time-controlled adaptive ventilation protocol: mechanistic approach to reducing ventilator-induced lung injury.

Airway pressure release ventilation (APRV) is a ventilator mode that has previously been considered a rescue mode, but has gained acceptance as a primary mode of ventilation. In clinical series and experimental animal models of extrapulmonary acute respiratory distress syndrome (ARDS), the early application of APRV was able to prevent the development of ARDS. Recent experimental evidence has suggested mechanisms by which APRV, using the time-controlled adaptive ventilation (TCAV) protocol, may reduce lung injury, including: 1) an improvement in alveolar recruitment and homogeneity; 2) reduction in alveolar and alveolar duct micro-strain and stress-risers; 3) reduction in alveolar tidal volumes; and 4) recruitment of the chest wall by combating increased intra-abdominal pressure. This review examines these studies and discusses our current understanding of the pleiotropic mechanisms by which TCAV protects the lung. APRV set according to the TCAV protocol has been misunderstood and this review serves to highlight the various protective physiological and mechanical effects it has on the lung, so that its clinical application may be broadened.