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.

The POOR Get POORer: A Hypothesis for the Pathogenesis of Ventilator-induced Lung Injury.

Protective ventilation strategies for the injured lung currently revolve around the use of low Vt, ostensibly to avoid volutrauma, together with positive end-expiratory pressure to increase the fraction of open lung and reduce atelectrauma. Protective ventilation is currently applied in a one-size-fits-all manner, and although this practical approach has reduced acute respiratory distress syndrome deaths, mortality is still high and improvements are at a standstill. Furthermore, how to minimize ventilator-induced lung injury (VILI) for any given lung remains controversial and poorly understood. Here we present a hypothesis of VILI pathogenesis that potentially serves as a basis upon which minimally injurious ventilation strategies might be developed. This hypothesis is based on evidence demonstrating that VILI begins in isolated lung regions manifesting a Permeability-Originated Obstruction Response (POOR) in which alveolar leak leads to surfactant dysfunction and increases local tissue stresses. VILI progresses topographically outward from these regions in a POOR-get-POORer fashion unless steps are taken to interrupt it. We propose that interrupting the POOR-get-POORer progression of lung injury relies on two principles: 1) open the lung to minimize the presence of heterogeneity-induced stress concentrators that are focused around the regions of atelectasis, and 2) ventilate in a patient-dependent manner that minimizes the number of lung units that close during each expiration so that they are not forced to rerecruit during the subsequent inspiration. These principles appear to be borne out in both patient and animal studies in which expiration is terminated before derecruitment of lung units has enough time to occur.

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.

Biological Response to Time-Controlled Adaptive Ventilation Depends on Acute Respiratory Distress Syndrome Etiology.

OBJECTIVES: To compare a time-controlled adaptive ventilation strategy, set in airway pressure release ventilation mode, versus a protective mechanical ventilation strategy in pulmonary and extrapulmonary acute respiratory distress syndrome with similar mechanical impairment. DESIGN: Animal study. SETTING: Laboratory investigation. SUBJECTS: Forty-two Wistar rats. INTERVENTIONS: Pulmonary acute respiratory distress syndrome and extrapulmonary acute respiratory distress syndrome were induced by instillation of Escherichia coli lipopolysaccharide intratracheally or intraperitoneally, respectively. After 24 hours, animals were randomly assigned to receive 1 hour of volume-controlled ventilation (n = 7/etiology) or time-controlled adaptive ventilation (n = 7/etiology) (tidal volume = 8 mL/kg). Time-controlled adaptive ventilation consisted of the application of continuous positive airway pressure 2 cm H2O higher than baseline respiratory system peak pressure for a time (Thigh) of 0.75-0.85 seconds. The release pressure (Plow = 0 cm H2O) was applied for a time (Tlow) of 0.11-0.18 seconds. Tlow was set to target an end-expiratory flow to peak expiratory flow ratio of 75%. Nonventilated animals (n = 7/etiology) were used for Diffuse Alveolar Damage and molecular biology markers analyses. MEASUREMENT AND MAIN RESULTS: Time-controlled adaptive ventilation increased mean respiratory system pressure regardless of acute respiratory distress syndrome etiology. The Diffuse Alveolar Damage score was lower in time-controlled adaptive ventilation compared with volume-controlled ventilation in pulmonary acute respiratory distress syndrome and lower in time-controlled adaptive ventilation than nonventilated in extrapulmonary acute respiratory distress syndrome. In pulmonary acute respiratory distress syndrome, volume-controlled ventilation, but not time-controlled adaptive ventilation, increased the expression of amphiregulin, vascular cell adhesion molecule-1, and metalloproteinase-9. Collagen density was higher, whereas expression of decorin was lower in time-controlled adaptive ventilation than nonventilated, independent of acute respiratory distress syndrome etiology. In pulmonary acute respiratory distress syndrome, but not in extrapulmonary acute respiratory distress syndrome, time-controlled adaptive ventilation increased syndecan expression. CONCLUSION: In pulmonary acute respiratory distress syndrome, time-controlled adaptive ventilation led to more pronounced beneficial effects on expression of biomarkers related to overdistension and extracellular matrix homeostasis.

Acute lung injury: how to stabilize a broken lung.

The pathophysiology of acute respiratory distress syndrome (ARDS) results in heterogeneous lung collapse, edema-flooded airways and unstable alveoli. These pathologic alterations in alveolar mechanics (i.e. dynamic change in alveolar size and shape with each breath) predispose the lung to secondary ventilator-induced lung injury (VILI). It is our viewpoint that the acutely injured lung can be recruited and stabilized with a mechanical breath until it heals, much like casting a broken bone until it mends. If the lung can be "casted" with a mechanical breath, VILI could be prevented and ARDS incidence significantly reduced.

Bayesian inference of the lung alveolar spatial model for the identification of alveolar mechanics associated with acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is acute lung failure secondary to severe systemic inflammation, resulting in a derangement of alveolar mechanics (i.e. the dynamic change in alveolar size and shape during tidal ventilation), leading to alveolar instability that can cause further damage to the pulmonary parenchyma. Mechanical ventilation is a mainstay in the treatment of ARDS, but may induce mechano-physical stresses on unstable alveoli, which can paradoxically propagate the cellular and molecular processes exacerbating ARDS pathology. This phenomenon is called ventilator induced lung injury (VILI), and plays a significant role in morbidity and mortality associated with ARDS. In order to identify optimal ventilation strategies to limit VILI and treat ARDS, it is necessary to understand the complex interplay between biological and physical mechanisms of VILI, first at the alveolar level, and then in aggregate at the whole-lung level. Since there is no current consensus about the underlying dynamics of alveolar mechanics, as an initial step we investigate the ventilatory dynamics of an alveolar sac (AS) with the lung alveolar spatial model (LASM), a 3D spatial biomechanical representation of the AS and its interaction with airflow pressure and the surface tension effects of pulmonary surfactant. We use the LASM to identify the mechanical ramifications of alveolar dynamics associated with ARDS. Using graphical processing unit parallel algorithms, we perform Bayesian inference on the model parameters using experimental data from rat lung under control and Tween-induced ARDS conditions. Our results provide two plausible models that recapitulate two fundamental hypotheses about volume change at the alveolar level: (1) increase in alveolar size through isotropic volume change, or (2) minimal change in AS radius with primary expansion of the mouth of the AS, with the implication that the majority of change in lung volume during the respiratory cycle occurs in the alveolar ducts. These two model solutions correspond to significantly different mechanical properties of the tissue, and we discuss the implications of these different properties and the requirements for new experimental data to discriminate between the hypotheses.

Enhanced liver autophagic activity improves survival of septic mice lacking surfactant proteins A and D.

Autophagy is a protective cellular mechanism in response to various stresses, including sepsis. Sepsis is defined as systemic inflammation by infection. Surfactant protein A and D (SP-A and SP-D) are involved in host defense, regulation of inflammation, and homeostasis, but their roles in the autophagic activity and relevant gene expression in sepsis are unclear. In this study, mice lacking SP-A and SP-D (SP-A/D KO mice) and background-matched wild-type (WT) C57BL/6 mice underwent either cecal ligation and puncture (CLP) or sham surgery. The results showed that SP-A/D KO mice had lower mortality than WT mice in CLP sepsis. Liver tissues showed marked pathological changes in both septic SP-A/D KO and WT mice 24 hrs after CLP treatment; and quantitative analysis of liver histopathology revealed significant difference between septic SP-A/D and septic WT mice. SP-A/D KO mice had higher basal and sepsis-induced level of autophagy than WT mice (p < 0.05), as judged by Western blot and electron microscopic analyses. The expression of 84 autophagy-related genes revealed differential basal and sepsis-induced gene expression between SP-A/D KO and WT mice. The expression increased in three genes and decreased in four genes in septic WT mice, as compared to septic SP-A/D KO mice (p < 0.05). Furthermore, differential responses to sepsis between SP-A/D KO and WT mice were found in six signaling pathways related to autophagy and apoptosis. Therefore, enhanced autophagic activity improves the survival of septic SP-A/D KO mice through the regulation of liver autophagy/apoptosis-related gene expression and signaling pathway activation.

Identification of collaborative cross mouse strains permissive to Salmonella enterica serovar Typhi infection.

Salmonella enterica serovar Typhi is the causative agent of typhoid fever restricted to humans and does not replicate in commonly used inbred mice. Genetic variation in humans is far greater and more complex than that in a single inbred strain of mice. The Collaborative Cross (CC) is a large panel of recombinant inbred strains which has a wider range of genetic diversity than laboratory inbred mouse strains. We found that the CC003/Unc and CC053/Unc strains are permissive to intraperitoneal but not oral route of S. Typhi infection and show histopathological changes characteristic of human typhoid. These CC strains are immunocompetent, and immunization induces antigen-specific responses that can kill S. Typhi in vitro and control S. Typhi in vivo. Our results indicate that CC003/Unc and CC053/Unc strains can help identify the genetic basis for typhoid susceptibility, S. Typhi virulence mechanism(s) in vivo, and serve as a preclinical mammalian model system to identify effective vaccines and therapeutics strategies.

A two-compartment mathematical model of endotoxin-induced inflammatory and physiologic alterations in swine.

OBJECTIVE: To gain insights into individual variations in acute inflammation and physiology. DESIGN: Large-animal study combined with mathematical modeling. SETTING: Academic large-animal and computational laboratories. SUBJECTS: Outbred juvenile swine. INTERVENTIONS: Four swine were instrumented and subjected to endotoxemia (100 µg/kg), followed by serial plasma sampling. MEASUREMENTS AND MAIN RESULTS: Swine exhibited various degrees of inflammation and acute lung injury, including one death with severe acute lung injury (PaO(2)/FIO(2) ratio µ200 and static compliance µ10 L/cm H(2)O). Plasma interleukin-1ß, interleukin-4, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-α, high mobility group box-1, and NO(2)/NO(3) were significantly (p µ .05) elevated over the course of the experiment. Principal component analysis was used to suggest principal drivers of inflammation. Based in part on principal component analysis, an ordinary differential equation model was constructed, consisting of the lung and the blood (as a surrogate for the rest of the body), in which endotoxin induces tumor necrosis factor-α in monocytes in the blood, followed by the trafficking of these cells into the lung leading to the release of high mobility group box-1, which in turn stimulates the release of interleukin-1ß from resident macrophages. The ordinary differential equation model also included blood pressure, PaO(2), and FIO(2), and a damage variable that summarizes the health of the animal. This ordinary differential equation model could be fit to both inflammatory and physiologic data in the individual swine. The predicted time course of damage could be matched to the oxygen index in three of the four swine. CONCLUSIONS: The approach described herein may aid in predicting inflammation and physiologic dysfunction in small cohorts of subjects with diverse phenotypes and outcomes.

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.

Jack of all trades: pleiotropy and the application of chemically modified tetracycline-3 in sepsis and the acute respiratory distress syndrome (ARDS).

Sepsis is a disease process that has humbled the medical profession for centuries with its resistance to therapy, relentless mortality, and pathophysiologic complexity. Despite 30 years of aggressive, concerted, well-resourced efforts the biomedical community has been unable to reduce the mortality of sepsis from 30%, nor the mortality of septic shock from greater than 50%. In the last decade only one new drug for sepsis has been brought to the market, drotrecogin alfa-activated (Xigris™), and the success of this drug has been limited by patient safety issues. Clearly a new agent is desperately needed. The advent of recombinant human immune modulators held promise but the outcomes of clinical trials using biologics that target single immune mediators have been disappointing. The complex pathophysiology of the systemic inflammatory response syndrome (SIRS) is self-amplifying and redundant at multiple levels. In this review we argue that perhaps pharmacologic therapy for sepsis will only be successful if it addresses this pathophysiologic complexity; the drug would have to be pleiotropic, working on many components of the inflammatory cascade at once. In this context, therapy that targets any single inflammatory mediator will not adequately address the complexity of SIRS. We propose that chemically modified tetracycline-3, CMT-3 (or COL-3), a non-antimicrobial modified tetracycline with pleiotropic anti-inflammatory properties, is an excellent agent for the management of sepsis and its associated complication of the acute respiratory distress syndrome (ARDS). The purpose of this review is threefold: (1) to examine the shortcomings of current approaches to treatment of sepsis and ARDS in light of their pathophysiology, (2) to explore the application of COL-3 in ARDS and sepsis, and finally (3) to elucidate the mechanisms of COL-3 that may have potential therapeutic benefit in ARDS and sepsis.

Comparison of "open lung" modes with low tidal volumes in a porcine lung injury model.

BACKGROUND: Ventilator strategies that maintain an "open lung" have shown promise in treating hypoxemic patients. We compared three "open lung" strategies with standard of care low tidal volume ventilation and hypothesized that each would diminish physiologic and histopathologic evidence of ventilator induced lung injury (VILI). MATERIALS AND METHODS: Acute lung injury (ALI) was induced in 22 pigs via 5% Tween and 30-min of injurious ventilation. Animals were separated into four groups: (1) low tidal volume ventilation (LowVt -6 mL/kg); (2) high-frequency oscillatory ventilation (HFOV); (3) airway pressure release ventilation (APRV); or (4) recruitment and decremental positive-end expiratory pressure (PEEP) titration (RM+OP) and followed for 6 h. Lung and hemodynamic function was assessed on the half-hour. Bronchoalveolar lavage fluid (BALF) was analyzed for cytokines. Lung tissue was harvested for histologic analysis. RESULTS: APRV and HFOV increased PaO(2)/FiO(2) ratio and improved ventilation. APRV reduced BALF TNF-α and IL-8. HFOV caused an increase in airway hemorrhage. RM+OP decreased SvO(2), increased PaCO(2), with increased inflammation of lung tissue. CONCLUSION: None of the "open lung" techniques were definitively superior to LowVt with respect to VILI; however, APRV oxygenated and ventilated more effectively and reduced cytokine concentration compared with LowVt with nearly indistinguishable histopathology. These data suggest that APRV may be of potential benefit to critically ill patients but other "open lung" strategies may exacerbate injury.

A clinically applicable porcine model of septic and ischemia/reperfusion-induced shock and multiple organ injury.

BACKGROUND: Although many sepsis treatments have shown efficacy in acute animal models, at present only activated protein C is effective in humans. The likely reason for this discrepancy is that most of the animal models used for preclinical testing do not accurately replicate the complex pathogenesis of human sepsis. Our objective in this study was to develop a clinically applicable model of severe sepsis and gut ischemia/reperfusion (I/R) that would cause multiple organ injury over a period of 48 h. MATERIALS AND METHODS: Anesthetized, instrumented, and ventilated pigs were subjected to a "two-hit" injury by placement of a fecal clot through a laparotomy and by clamping the superior mesenteric artery (SMA) for 30 min. The animals were monitored for 48 h. Wide spectrum antibiotics and intravenous fluids were given to maintain hemodynamic status. FiO(2) was increased in response to oxygen desaturation. Twelve hours following injury, a drain was placed in the laparotomy wound. Extensive hemodynamic, lung, kidney, liver, and renal function measurements and serial measurements of arterial and mixed venous blood gases were made. Bladder pressure was measured as a surrogate for intra-peritoneal pressure to identify the development of the abdominal compartment syndrome (ACS). Plasma and peritoneal ascites cytokine concentration were measured at regular intervals. Tissues were harvested and fixed at necropsy for detailed morphometric analysis. RESULTS: Polymicrobial sepsis developed in all animals. There was a progressive deterioration of organ function over the 48 h. The lung, kidney, liver, and intestine all demonstrated clinical and histopathologic injury. Acute lung injury (ALI) and ACS developed by consensus definitions. Increases in multiple cytokines in serum and peritoneal fluid paralleled the dysfunction found in major organs. CONCLUSION: This animal model of Sepsis+I/R replicates the systemic inflammation and dysfunction of the major organ systems that is typically seen in human sepsis and trauma patients. The model should be useful in deciphering the complex pathophysiology of septic shock as it transitions to end-organ injury thus allowing sophisticated preclinical studies on potential treatments.

Functional pathophysiology of SARS-CoV-2-induced acute lung injury and clinical implications.

The worldwide pandemic caused by the SARS-CoV-2 virus has resulted in over 84,407,000 cases, with over 1,800,000 deaths when this paper was submitted, with comorbidities such as gender, race, age, body mass, diabetes, and hypertension greatly exacerbating mortality. This review will analyze the rapidly increasing knowledge of COVID-19-induced lung pathophysiology. Although controversial, the acute respiratory distress syndrome (ARDS) associated with COVID-19 (CARDS) seems to present as two distinct phenotypes: type L and type H. The "L" refers to low elastance, ventilation/perfusion ratio, lung weight, and recruitability, and the "H" refers to high pulmonary elastance, shunt, edema, and recruitability. However, the LUNG-SAFE (Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure) and ESICM (European Society of Intensive Care Medicine) Trials Groups have shown that ∼13% of the mechanically ventilated non-COVID-19 ARDS patients have the type-L phenotype. Other studies have shown that CARDS and ARDS respiratory mechanics overlap and that standard ventilation strategies apply to these patients. The mechanisms causing alterations in pulmonary perfusion could be caused by some combination of 1) renin-angiotensin system dysregulation, 2) thrombosis caused by loss of endothelial barrier, 3) endothelial dysfunction causing loss of hypoxic pulmonary vasoconstriction perfusion control, and 4) hyperperfusion of collapsed lung tissue that has been directly measured and supported by a computational model. A flowchart has been constructed highlighting the need for personalized and adaptive ventilation strategies, such as the time-controlled adaptive ventilation method, to set and adjust the airway pressure release ventilation mode, which recently was shown to be effective at improving oxygenation and reducing inspiratory fraction of oxygen, vasopressors, and sedation in patients with COVID-19.

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.

Toll-like receptor 2 deficiency results in impaired antibody responses and septic shock during Borrelia hermsii infection.

Overwhelming bacteremia is a leading cause of death. To understand the mechanisms involved in protective antibody and pathological inflammatory responses during bacteremia, we have been studying the murine model of Borrelia hermsii infection. Toll-like receptor (TLR) signaling plays an important role in generating the rapid anti-B. hermsii antibody responses required for the resolution of bacteremia. Using NF-κB reporter assays, we found that B. hermsii activates TLR2 and TLR9. However, TLR2(-/-) TLR9(-/-) mice exhibited an impairment in anti-B. hermsii antibody responses similar to that of TLR2(-/-) mice. Moreover, the impairment in the antibody responses of TLR2(-/-) mice or TLR2(-/-) TLR9(-/-) mice coincides with an order-of-magnitude-higher bacteremia, and death results from septic shock, as evidenced by a dysregulated systemic cytokine response and characteristic organ pathology. Since TLR2 appears to be the major extracellular sensor stimulated by B. hermsii, we hypothesized that during elevated bacteremia the activation of intracellular sensors of bacteria triggers dysregulated inflammation in TLR2(-/-) mice. Indeed, blocking the internalization of B. hermsii prevented the induction of inflammatory cytokine responses in TLR2-deficient cells. Furthermore, we found that B. hermsii activates the cytoplasmic sensor nucleotide-binding oligomerization domain 2 (NOD2). Macrophages deficient in both TLR2 and NOD2 have impaired cytokine responses to B. hermsii compared to cells lacking TLR2 alone, and B. hermsii-infected TLR2(-/-) NOD2(-/-) mice exhibited improved survival compared to TLR2(-/-) mice. These data demonstrate that TLR2 is critical for protective immunity and suggest that, during heightened bacteremia, recognition of bacterial components by intracellular sensors can lead to pathological inflammatory responses.

Titration of mean airway pressure and FiO2 during high frequency oscillatory ventilation in a porcine model of acute lung injury.

BACKGROUND: High frequency oscillatory ventilation (HFOV) is frequently utilized for patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, precise criteria to titrate mean airway pressure (mPaw) and FiO(2) as the patient's condition improves are lacking. We hypothesized that reducing mPaw and FiO(2) too quickly after reaching target arterial oxygen saturation levels would promote ventilator induced lung injury (VILI). MATERIALS AND METHODS: ALI was induced by instilling 3% Tween 20. Pigs were placed supine and received 30 min of nonprotective ventilation. Pigs were separated into two groups: HFOV constant (HFOVC, n = 3) = constant mPaw and FiO(2) for the duration; HFOV titrated (HFOVT, n = 4) = FiO(2) and/or mPaw were reduced every 30 min if the oxygen saturation remained between 88%-95%. Hemodynamic and pulmonary measurements were made at baseline, after lung injury, and every 30 min during the 6-h study. Lung histopathology was determined by quantifying alveolar hyperdistension, fibrin, congestion, atelectasis, and polymorphonuclear leukocyte (PMN) infiltration. RESULTS: Oxygenation was significantly lower in the HFOVT group compared to the HFOVC group after 6 h. Lung histopathology was significantly increased in the HFOVT group in the following categories: PMN infiltration, alveolar hyperdistension, congestion, and fibrin deposition. CONCLUSIONS: Rapid reduction of mPaw and FiO(2) in our ALI model significantly reduced oxygenation, but, more importantly, caused VILI as evidenced by increased lung inflammation and alveolar hyperdistension. Specific criteria for titration of mPaw and inspired oxygen are needed to maximize the lung protective effects of HFOV while maintaining adequate gas exchange.

Loss of airway pressure during HFOV results in an extended loss of oxygenation: a retrospective animal study.

BACKGROUND: Patients with acute respiratory distress syndrome (ARDS) are often ventilated with high airway pressure. Brief loss of airway pressure may lead to an extended loss of oxygenation. While using high frequency oscillatory ventilation (HFOV) in a porcine acute lung injury model, two animals became disconnected from the ventilator with subsequent loss of airway pressure. We compared the two disconnected animals to the two animals that remained connected to determine causes for the extended reduction in oxygenation. METHODS: ARDS was induced using 5% Tween. Thirty min of nonprotective ventilation (NPV) followed before placing the pigs on HFOV. Measurements were made at baseline, after lung injury, and every 30min during the 6-h study. Disconnections were treated by hand-ventilation and a recruitment maneuver before being placed back on HFOV. The lungs were histologically analyzed and wet/dry weights were measured to determine lung edema. RESULTS: Hemodynamics and lung function were similar in all pigs at baseline, after injury, and following NPV. The animals that remained connected to the oscillator showed a continued improvement in PaO(2)/FiO(2) (P/F) ratio throughout the study. The animals that experienced the disconnection had a significant loss of lung function that never recovered. The disconnect animals had more diffuse alveolar disease on histologic analysis. CONCLUSIONS: A significant fall in lung function results following disconnection from HFOV, which remains depressed for a substantial period of time despite efforts to reopen the lung. Dispersion of edema fluid is a possible mechanism for the protracted loss of lung function.

Plateau and transpulmonary pressure with elevated intra-abdominal pressure or atelectasis.

BACKGROUND: ARDSnet standards limit plateau pressure (Pplat) to reduce ventilator induced lung injury (VILI). Transpulmonary pressure (Ptp) [Pplat-pleural pressure (Ppl)], not Pplat, is the distending pressure of the lung. Lung distention can be affected by increased intra-abdominal pressure (IAP) and atelectasis. We hypothesized that the changes in distention caused by increases in IAP and atelectasis would be reflected by Ptp but independent of Pplat. METHODS: In Yorkshire pigs, esophageal pressure (Pes) was measured with a balloon catheter as a surrogate for Ppl under two experimental conditions: (1) high IAP group (n=5), where IAP was elevated by CO2 insufflation in 5 mm Hg steps from 0 to 30 mm Hg; and (2) Atelectasis group (n=5), where a double lumen endotracheal tube allowed clamping and degassing of either lung by O2 absorption. Lung collapse was estimated by increases in pulmonary shunt fraction. RESULTS: High IAP: Sequential increments in IAP caused a linear increase in Pplat (r2=0.754, P<0.0001). Ptp did not increase (r2=0.014, P=0.404) with IAP due to the concomitant increase in Pes (r2=0.726, P<0.0001). Partial Lung Collapse: There was no significant difference in Pplat between the atelectatic (21.83+/-0.63 cm H2O) and inflated lung (22.06+/-0.61 cmH2O, P<0.05). Partial lung collapse caused a significant decrease in Pes (11.32+/-1.11 mm Hg) compared with inflation (15.89+/-0.72 mm Hg, P<0.05) resulting in a significant increase in Ptp (inflated=5.97+/-0.72 mm Hg; collapsed=10.55+/-1.53 mm Hg, P<0.05). CONCLUSIONS: Use of Pplat to set ventilation may under-ventilate patients with intra-abdominal hypertension and over-distend the lungs of patients with atelectasis. Thus, Ptp must be used to accurately set mechanical ventilation in the critically ill.