High VT Research Articles

Impact of Different Tidal Volume Levels at Low Mechanical Power on Ventilator-Induced Lung Injury in Rats.

Tidal volume (VT) has been considered the main determinant of ventilator-induced lung injury (VILI). Recently, experimental studies have suggested that mechanical power transferred from the ventilator to the lungs is the promoter of VILI. We hypothesized that, as long as mechanical power is kept below a safe threshold, high VT should not be injurious. The present study aimed to investigate the impact of different VT levels and respiratory rates (RR) on lung function, diffuse alveolar damage (DAD), alveolar ultrastructure, and expression of genes related to inflammation [interleukin (IL)-6], alveolar stretch (amphiregulin), epithelial [club cell secretory protein (CC)16] and endothelial [intercellular adhesion molecule (ICAM)-1] cell injury, and extracellular matrix damage [syndecan-1, decorin, and metalloproteinase (MMP)-9] in experimental acute respiratory distress syndrome (ARDS) under low-power mechanical ventilation. Twenty-eight Wistar rats received Escherichia coli lipopolysaccharide intratracheally. After 24 h, 21 animals were randomly assigned to ventilation (2 h) with low mechanical power at three different VT levels (n = 7/group): (1) VT = 6 mL/kg and RR adjusted to normocapnia; (2) VT = 13 mL/kg; and 3) VT = 22 mL/kg. In the second and third groups, RR was adjusted to yield low mechanical power comparable to that of the first group. Mechanical power was calculated as [(Δ/Est,L)/2]× RR (ΔP,L = transpulmonary driving pressure, Est,L = static lung elastance). Seven rats were not mechanically ventilated (NV) and were used for molecular biology analysis. Mechanical power was comparable among groups, while VT gradually increased. ΔP,L and mechanical energy were higher in VT = 22 mL/kg than VT = 6 mL/kg and VT = 13 mL/kg (p < 0.001 for both). Accordingly, DAD score increased in VT = 22 mL/kg compared to VT = 6 mL/kg and VT = 13 mL/kg [23(18.5–24.75) vs. 16(12–17.75) and 16(13.25–18), p < 0.05, respectively]. VT = 22 mL/kg was associated with higher IL-6, amphiregulin, CC16, MMP-9, and syndecan-1 mRNA expression and lower decorin expression than VT = 6 mL/kg. Multiple linear regression analyses indicated that VT was able to predict changes in IL-6 and CC16, whereas ΔP,L predicted pHa, oxygenation, amphiregulin, and syndecan-1 expression. In the model of ARDS used herein, even at low mechanical power, high VT resulted in VILI. VT control seems to be more important than RR control to mitigate VILI.

Influence of tidal volume and positive end-expiratory pressure on ventilation distribution and oxygenation during one-lung ventilation

Objective: The aim of the study was to explore the feasibility of titrating tidal volume (VT) and positive end-expiratory pressure (PEEP) during one-lung ventilation (OLV) based on ventilation distribution and oxygenation. Approach: Twenty-four consecutive patients requiring intubation with a double-lumen tube and subsequent OLV for thoracic surgical procedures were examined prospectively in lateral posture. Electrical impedance tomography (EIT), blood gases, respiratory mechanics were successfully measured in 21 patients at various combinations of VT (4 ml kg−1, 6 ml kg−1, 8 ml kg−1 body weight) and PEEP (0 cm H2O, 4 cm H2O, 8 cm H2O) during OLV. Main results: Low VT and low PEEP resulted in low global respiratory system compliance (Crs). Arterial partial pressure of O2 (PaO2) decreased with falling VT. Regional Crs measured with EIT showed high values at high VT and high PEEP in all but two patients. Regional Crs in mid and most dependent regions indicated tidal recruitment/derecruitment in eight patients at 8 ml kg−1 of VT and 4 cm H2O of PEEP; in four patients at 8 ml kg−1 and 0 cm H2O; in one patient at 6 ml kg−1 and 8 cm H2O. The changes in regional Crs induced by decreasing PEEP from 8 to 4 cm H2O were much smaller than those from 4 to 0 cm H2O. Ventilation distribution was most inhomogeneous with VT of 8 ml kg−1. All measures differed significantly among various VT and PEEP steps (p < 0.05). Significance: By using EIT in combination with PaO2, it is feasible to titrate VT and PEEP at the bedside during OLV.

A dual Vt disturb-free subthreshold SRAM with write-assist and read isolation

This paper presents a new dual Vt 8T SRAM cell having single bit-line read and write, in addition to Write Assist and Read Isolation (WARI). Also a faster write back scheme is proposed for the half selected cells. A high Vt device is used for interrupting the supply to one of the inverters for weakening the feedback loop for assisted write. The proposed cell provides an improved read static noise margin (RSNM) due to the bit-line isolation during the read. Static noise margins for data read (RSNM), write (WSNM), read delay, write delay, data retention voltage (DRV), leakage and average powers have been calculated. The proposed cell was found to operate properly at a supply voltage as small as 0.41 V. A new write back scheme has been suggested for half-selected cells, which uses a single NMOS access device and provides reduced delay, pulse timing hardware requirements and power consumption. The proposed new WARI 8T cell shows better performance in terms of easier write, improved read noise margin, reduced leakage power, and less delay as compared to the existing schemes that have been available so far. It was also observed that with proper adjustment of the cell ratio the supply voltage can further be reduced to 0.2 V.

Impact of delivered tidal volume on the occurrence of intraventricular haemorrhage in preterm infants during positive pressure ventilation in the delivery room

Background and objectivesDelivery of inadvertent high tidal volume (VT) during positive pressure ventilation (PPV) in the delivery room is common. High VT delivery during PPV has been associated with haemodynamic...

The respiratory mechanics of the yacare caiman (Caiman yacare).

The structure and function of crocodilian lungs are unique compared with those of other reptiles. We examined the extent to which this and the semi-aquatic lifestyle of crocodilians affect their respiratory mechanics. We measured changes in intratracheal pressure in adult and juvenile caiman (Caiman yacare) during static and dynamic lung volume changes. The respiratory mechanics of juvenile caiman were additionally measured while the animals were floating in water and submerged at 30, 60 and 90deg to the water's surface. The static compliance of the juvenile pulmonary system (2.89±0.22 ml cmH2O-1100 g-1) was greater than that of adults (1.2±0.41 ml cmH2O-1100 g-1), suggesting that the system stiffens as the body wall becomes more muscular and keratinized in adults. For both age groups, the lungs were much more compliant than the body wall, offering little resistance to air flow (15.35 and 4.25 ml cmH2O-1100 g-1 for lungs, versus 3.39 and 1.67 ml cmH2O-1100 g-1 for body wall, in juveniles and adults, respectively). Whole-system dynamic mechanics decreased with increasing ventilation frequency (fR), but was unaffected by changes in tidal volume (VT). The vast majority of the work of breathing was required to overcome elastic forces; however, work to overcome resistive forces increased proportionally with fR Work of breathing was higher in juvenile caiman submerged in water at 90deg because of an increase in work to overcome both elastic and flow resistive forces. The lowest power of breathing was found to occur at high fR and low VT for any given minute ventilation (V̇E) in caiman of all ages.

Role and mechanism of mitochondrial DNA mediated Toll-like receptor 9-myeloid differentiation factor 88 signaling pathway activation in rats with ventilator-induced lung injury

To investigate the role and mechanism of mitochondrial DNA (mtDNA) in rats with ventilator-induced lung injury (VILI) via Toll-like receptor 9 (TLR9)-myeloid differentiation factor 88 (MyD88) signaling pathway. Thirty adult male Sprague-Dawley (SD) rats were randomly divided into three groups (each n = 10): spontaneous breathing group, normal tidal volume (VT) group (NVT group, VT = 8 mL/kg), and high VT group (HVT group, VT = 40 mL/kg). Rats in the NVT group and HVT group were ventilated mechanically with a positive end-expiratory pressure (PEEP) of 0 and the fraction of inspired oxygen (FiO2) at 0.50. After 4 hours of ventilation, the blood from the rats' hearts was collected and the rats were sacrificed, the levels of interleukins (IL-6, IL-1β) and tumor necrosis factor-α (TNF-α) in serum were determined with enzyme-linked immune sorbent assay (ELISA). The bronchoalveolar lavage fluid (BALF) was collected for a determination of total protein by using the bicinchoninic acid (BCA) assay. The lung tissues were harvested to determine the wet/dry (W/D) ratio. The changes in pathobiology of lung tissue were observed with hematoxylin and eosin (HE) staining. The protein expression levels of mtDNA-encoded cytochrome C oxidase subunit IV (COX-IV), TLR9, MyD88 and nuclear factor-κB p65 (NF-κB p65) in lung tissues were determined by immunohistochemistry. The histopathology of lung tissues indicated that lungs from animals ventilated with HVT developed marked lung inflammation changes, whereas no major histological change was observed in animals ventilated with NVT or spontaneously breathing. The pathological score in HVT group was significantly higher than that of spontaneous breathing group and NVT group (3.50±0.41 vs. 0.25±0.09, 0.33±0.10, both P < 0.05). Compared with spontaneous breathing group and NVT group, the ratio of W/D in the HVT group was significantly increased (6.42±0.41 vs. 4.14±0.04, 4.28±0.11, both P < 0.05), the contents of total proteins in BALF were significantly increased (g/L: 0.43±0.04 vs. 0.13±0.01, 0.14±0.01, both P < 0.05), and serum IL-6, IL-1β and TNF-α levels were also increased [IL-6 (μg/L): 1.15±0.17 vs. 0.42±0.10, 0.46±0.04; IL-1β (μg/L): 6.73±0.38 vs. 2.08±0.90, 2.19±0.18; TNF-α (μg/L): 4.10±0.11 vs. 1.12±0.10, 1.14±0.04; all P < 0.05]. Immunohistochemistry results demonstrated that the proteins of COX-IV, TLR9, MyD88 and NF-κB p65 in HVT group were shown in brown, which meant strongly expressed. However, these proteins in spontaneous breathing group and NVT group were uncolored or shown in buff, which meant unexpressed or weakly expressed. The results of quantitative analysis indicated that the immunoreactive scores (IRS) of COX-IV, TLR9, MyD88 and NF-κB p65 in HVT group were significantly higher than those in spontaneous breathing group and NVT group (COX-IV IRS: 8.80±2.17 vs. 0.80±0.45, 1.40±0.55; TLR9 IRS: 8.40±2.51 vs. 1.00±0.71, 1.20±0.84; MyD88 IRS: 9.40±1.52 vs. 1.40±0.55, 1.60±0.55; NF-κB p65 IRS: 9.80±2.05 vs. 1.00±0.71, 1.20±0.84; all P < 0.05). There was no significant difference in all of the parameters between spontaneous breathing group and NVT group (all P > 0.05). mtDNA contributes significantly to VILI by activating the TLR9-MyD88 signaling pathway, resulting in subsequent secretion of NF-κB p65 and the proinflammatory cytokines, which induce acute inflammatory injury of lung tissue.

The association between tidal volume and neurological outcome following in-hospital cardiac arrest

AimsPrior investigation has found that mechanical ventilation with lower tidal volumes (Vt) following out-of-hospital cardiac arrest is associated with better neurologic outcomes. The relationship between Vt and neurologic outcome following in-hospital cardiac arrest (IHCA) has not previously been explored. In the present study, we investigate the association between Vt and neurologic outcome following IHCA. MethodsThis was an observational study using a prospectively collected database of IHCA patients at a tertiary care hospital in the United States. The relationship between time-weighted average Vt per predicted body weight (PBW) over the first 6- and 48 h after cardiac arrest and neurologic outcome were assessed using propensity-score adjusted logistic regression. Measurements and main resultsOf 185 IHCA patients who received invasive mechanical ventilation within 6 h of return of spontaneous circulation (ROSC), the average Vt over the first 6 h was 7.7 ± 2.0 ml/kg and 68 (36.8%) patients received an average Vt > 8.0 ml/kg. Of 121 patients who received mechanical ventilation for at least 48 h post-ROSC, the average Vt was 7.6 ± 1.5 ml/kg and 46 (38.0%) patients received an average Vt > 8.0 ml/kg. There was no relationship between Vt/PBW over the first 6- or 48 h post-ROSC and neurologic outcome (OR 0.99; 95%CI 0.84–1.16; p = 0.89; OR 1.03; 95%CI 0.78–1.37; p = 0.83 respectively). ConclusionsThis study did not identify a relationship between Vt and neurologic outcome following IHCA. This contrasts with results in OHCA, where higher Vt has been associated with worse neurologic outcome. Additional investigation is needed with respect to other potential benefits of low-Vt post IHCA.

Adverse Heart-Lung Interactions in Ventilator-induced Lung Injury.

In the original 1974 in vivo study of ventilator-induced lung injury, Webb and Tierney reported that high Vt with zero positive end-expiratory pressure caused overwhelming lung injury, subsequently shown by others to be due to lung shear stress. To reproduce the lung injury and edema examined in the Webb and Tierney study and to investigate the underlying mechanism thereof. Sprague-Dawley rats weighing approximately 400 g received mechanical ventilation for 60 minutes according to the protocol of Webb and Tierney (airway pressures of 14/0, 30/0, 45/10, 45/0 cm H2O). Additional series of experiments (20 min in duration to ensure all animals survived) were studied to assess permeability (n = 4 per group), echocardiography (n = 4 per group), and right and left ventricular pressure (n = 5 and n = 4 per group, respectively). The original Webb and Tierney results were replicated in terms of lung/body weight ratio (45/0 > 45/10 ≈ 30/0 ≈ 14/0; P < 0.05) and histology. In 45/0, pulmonary edema was overt and rapid, with survival less than 30 minutes. In 45/0 (but not 45/10), there was an increase in microvascular permeability, cyclical abolition of preload, and progressive dilation of the right ventricle. Although left ventricular end-diastolic pressure decreased in 45/10, it increased in 45/0. In a classic model of ventilator-induced lung injury, high peak pressure (and zero positive end-expiratory pressure) causes respiratory swings (obliteration during inspiration) in right ventricular filling and pulmonary perfusion, ultimately resulting in right ventricular failure and dilation. Pulmonary edema was due to increased permeability, which was augmented by a modest (approximately 40%) increase in hydrostatic pressure. The lung injury and acute cor pulmonale is likely due to pulmonary microvascular injury, the mechanism of which is uncertain, but which may be due to cyclic interruption and exaggeration of pulmonary blood flow.

Relationship between shedding of syndecan-4 in lung tissues and ventilator-induced lung injury in rats

Objective To evaluate the relationship between the shedding of syndecan-4 (SDC-4) in lung tissues and ventilator-induced lung injury in rats. Methods Thirty pathogen-free healthy adult male Wistar rats, weighing 220-250 g, were divided into 3 groups (n=10 each) using a random number table: control group (group C), mechanical ventilation with traditional tidal volume (VT) group (group T-VT) and mechanical ventilation with high VT group (group H-VT). The animals were anesthetized with pentobarbital sodium and tracheostomized.The rats kept spontaneous breathing in group C. The rats were mechanically ventilated for 4 h with the VT set at 6 ml/kg in group T-VT and with the VT set at 40 ml/kg in group H-VT.Blood samples were collected immediately after the end of ventilation for measurement of serum SDC-4 concentrations by enzyme-linked immunosorbent assay.The left lung was lavaged, and broncho-alveolar lavage fluid was collected for determination of interleukin-1beta (IL-1β), IL-18, tumor necrosis factor-alpha and SDC-4 concentrations by enzyme-linked immunosorbent assay.The lungs were removed for determination of the wet to dry weight ratio and expression of SDC-4 protein and mRNA in lung tissues (by Western blot and real-time polymerase chain reaction, respectively) and for examination of the pathological changes.The lung injury scores were recorded. Results Compared with group C, the wet to dry weight ratio, lung injury scores, concentrations of IL-1β, IL-18, tumor necrosis factor-alpha and SDC-4 in broncho-alveolar lavage fluid and concentrations of SDC-4 in serum were significantly increased, the expression of SDC-4 mRNA was up-regulated, and the expression of SDC-4 was down-regulated in group H-VT (P 0.05). Marked pathological changes of lung tissues were found in group H-VT. Conclusion A large shedding of SDC-4 in lung tissues may be involved in the pathophysiological mechanism of ventilatior-induced lung injury in rats. Key words: Syndecan-4; Respiration, artificial; Respiratory distress syndrome, adult

Effects of regional perfusion block in healthy and injured lungs

BackgroundSevere hypoperfusion can cause lung damage. We studied the effects of regional perfusion block in normal lungs and in the lungs that had been conditioned by lavage with 500 ml saline and high VT (20 ml kg−1) ventilation.MethodsNineteen pigs (61.2 ± 2.5 kg) were randomized to five groups: controls (n = 3), the right lower lobe block alone (n = 3), lavage and high VT (n = 4), lung lavage, and high VT plus perfusion block of the right (n = 5) or left (n = 4) lower lobe. Gas exchange, respiratory mechanics, and hemodynamics were measured hourly. After an 8-h observation period, CT scans were obtained at 0 and 15 cmH2O airway pressure.ResultsPerfusion block did not damage healthy lungs. In conditioned lungs, the left perfusion block caused more edema in the contralateral lung (777 ± 62 g right lung vs 484 ± 204 g left; p < 0.05) than the right perfusion block did (581 ± 103 g right lung vs 484 ± 204 g left; p n.s.). The gas/tissue ratio, however, was similar (0.5 ± 0.3 and 0.8 ± 0.5; p n.s.). The lobes with perfusion block were not affected (gas/tissue ratio right 1.6 ± 0.9; left 1.7 ± 0.5, respectively). Pulmonary artery pressure, PaO2/FiO2, dead space, and lung mechanics were more markedly affected in animals with left perfusion block, while the gas/tissue ratios were similar in the non-occluded lobes.ConclusionsThe right and left perfusion blocks caused the same “intensity” of edema in conditioned lungs. The total amount of edema in the two lungs differed because of differences in lung size. If capillary permeability is altered, increased blood flow may induce or increase edema.

Evaluation of Simulated Ventilation Techniques With the Upright and Conventional Self-Inflating Neonatal Resuscitators.

The study assessed the impact of simulated ventilation techniques using upright and conventional self-inflating neonatal resuscitators on delivered tidal volume (VT) and pressure. We analyzed videos of participants ventilating a manikin using an upright (upright, n = 33) and a conventional resuscitator (conventional, n = 32) under normal and low lung compliance. Mask hold, number of fingers squeezing the bag, and degree of bag squeeze were compared with VT and peak inspiratory pressure (PIP). VT and PIP values were higher when using the upright resuscitator than when using the conventional resuscitator. With low compliance, differences in VT were insignificant except with the use of the OK/C hold, (upright, 29.6 ± 4.0 mL, vs conventional, 24.8 ± 6.0 mL, P = .02). PIP was significantly higher when using the upright resuscitator with the OK hold (upright, 36.3 ± 4.4 mL, vs conventional, 30.3 ± 6.6 mL, P = .009) and when the bag was squeezed by more than half (upright, 33.8 ± 16.3 mL, vs conventional, 29.3 ± 9.5 mL, P = .046). With normal compliance, VT was high with both resuscitators, being significantly higher when using the upright resuscitator with the OK hold (upright, 64.3 ± 9.5 mL, vs conventional, 45.8 ± 9.4 mL; P < .001), and when the bag was squeezed using more than 2 fingers (upright, 58.0 ± 17.2 mL, vs conventional, 45.7 ± 12.6 mL, P = .01) and by more than half (upright, 58.7 ± 16.6 mL, vs conventional, 45.8 ± 12.2 mL, P = .004). PIP, too, was significantly higher when using the upright resuscitator with the OK hold (upright, 29.3 ± 3.5 mL, vs conventional, 21.5 ± 4.0 mL, P = <.001) and when the bag was squeezed using more than 2 fingers (upright, 27.2 ± 7.0 mL, vs conventional, 21.6 ± 5.7 mL, P = .005), and by more than half (upright, 27.6 ± 6.6 mL, vs conventional, 21.7 ± 5.4 mL, P = .001). Improved mask design, larger bag volume, and upright orientation of the upright resuscitator likely contributed to higher VT and PIP. However, high VT was observed with both resuscitators, possibly due to excessive squeezing of the bag, especially during low compliance. Thus, the design of the resuscitator and manner in which the device is utilized can both significantly influence the VT and PIP attained.

Device characteristics of enhancement mode double heterostructure DH‐HEMT with boron‐doped GaN gate cap layer for full‐bridge inverter circuit

AbstractThis paper reports a systematic theoretical study of Al0.23Ga0.77N/GaN/AlxGa1‐xN double‐heterojunction high electron mobility transistors (DH‐HEMTs) with a boron‐doped GaN cap layer under the gate. Boron containing GaN is a desired replacement for Schottky gate in DH‐HEMT to improve the resistivity and surface qualities of GaN cap with good structural properties, and the influence of polarization field in the GaN cap layer can be used to lift up the conduction band for normally OFF operation of the device. This study shows that the B‐doped GaN cap layer offers excellent device characteristics such as high threshold voltage VT of 1.92 V, steep subthreshold slope of ~ 72 mV/dec, high ON/OFF drain current ratio of ~ 107, extremely low subthreshold drain current Ids,LL ~ 10−9 A/mm, and low gate leakage current, Igs,LL less than 10−15 A/mm. For an Al0.07Ga0.93N back‐barrier/buffer, a high OFF‐state breakdown voltage (VBR,OFF) of 865 V is achieved at Ids = 1 mA/mm and Vgs = 0 V with substrate grounded and gate‐to‐drain distance and gate field plate length of 10 and 5 μm, respectively. The simulated high VT and VBR,OFF values are achieved due to the presence of increased back‐barrier height of the AlxGa1‐xN buffer and high Schottky barrier between the Boron‐doped GaN cap and gate metal. Finally, a DC to AC full‐bridge inverter circuit is designed to evaluate the benefit of B‐doped DH‐HEMTs based switching devices for an ultra‐low‐loss inverter circuit.

Effects of couple based coping intervention on self-efficacy and quality of life in patients with resected lung cancer

ObjectiveWe aimed to assess the couple based coping intervention (CBCI) for self-efficacy and quality of life in patients with resected lung cancer, compared with individual coping intervention (ICI). MethodsFrom October to December 2015, 132 consecutive patients with resected lung cancer who were married/lived in a stable relationship were randomly assigned to the ICI group and the CBCI group. ResultsThe CBCI group had higher GSES compared with the ICI group at 2 month after operation, and at 6 month after operation (P<0.05). The CBCI group had higher VT, SF, RE, and MH score of SF-36 compared with the ICI group at 2 month after operation, and at 6 month after operation (P<0.05), but no significant differences were found in RP, PF, BP, and GH score of SF-36 compared between two groups (P>0.05) in these 2 time points. ConclusionCouple based coping intervention is more effective than individual coping intervention for improving the self-efficacy and the quality of life in patients with resected lung cancer. Practice implicationsPractitioners might like to consider using couple based coping intervention strategy to improve self-efficacy and quality of life in patients with resected lung cancer.

Epidemiology, practice of ventilation and outcome for patients at increased risk of postoperative pulmonary complications: LAS VEGAS - an observational study in 29 countries.

Limited information exists about the epidemiology and outcome of surgical patients at increased risk of postoperative pulmonary complications (PPCs), and how intraoperative ventilation was managed in these patients. To determine the incidence of surgical patients at increased risk of PPCs, and to compare the intraoperative ventilation management and postoperative outcomes with patients at low risk of PPCs. This was a prospective international 1-week observational study using the 'Assess Respiratory Risk in Surgical Patients in Catalonia risk score' (ARISCAT score) for PPC for risk stratification. Adult patients requiring intraoperative ventilation during general anaesthesia for surgery in 146 hospitals across 29 countries. The primary outcome was the incidence of patients at increased risk of PPCs based on the ARISCAT score. Secondary outcomes included intraoperative ventilatory management and clinical outcomes. A total of 9864 patients fulfilled the inclusion criteria. The incidence of patients at increased risk was 28.4%. The most frequently chosen tidal volume (VT) size was 500 ml, or 7 to 9 ml kg predicted body weight, slightly lower in patients at increased risk of PPCs. Levels of positive end-expiratory pressure (PEEP) were slightly higher in patients at increased risk of PPCs, with 14.3% receiving more than 5 cmH2O PEEP compared with 7.6% in patients at low risk of PPCs (P < 0.001). Patients with a predicted preoperative increased risk of PPCs developed PPCs more frequently: 19 versus 7%, relative risk (RR) 3.16 (95% confidence interval 2.76 to 3.61), P < 0.001) and had longer hospital stays. The only ventilatory factor associated with the occurrence of PPCs was the peak pressure. The incidence of patients with a predicted increased risk of PPCs is high. A large proportion of patients receive high VT and low PEEP levels. PPCs occur frequently in patients at increased risk, with worse clinical outcome. The study was registered at Clinicaltrials.gov, number NCT01601223.

Effects of FTY720 pretreatment on ventilator-induced lung injury in rats

Objective To study the effects of FTY720 pretreatment on ventilator-induced lung injury (VILI) in rats in order to explore the role of sphingosine-1-phosphate receptor 1 (S1PR1). Methods Forty healthy adult male SD rats weighing 300-350 g were randomly (randlom number)divided into 4 groups (n=10 each): group CV (conventional tidal volume VT = 8 mL/kg), group HV (high tidal volume VT= 40 mL/kg), group HF and group HFW. The rats in group HF received intra-gastric administration of FTY720 10 mg·kg-1·d-1for 7 days, while additional dose of W146 (S1PR1 antagonist) 1 mg·kg-1·d-1 was administrated in group HFW before high tidal volume ventilation. After 4-hour mechanical ventilation, arterial blood samples were obtained for blood gas analysis before the animals were sacrificed. The lungs were harvested for histopathologic observation. Apoptosis rate in lung tissue was determined with flow cytometry. W/D lung weight ratio, pulmonary permeability index (PPI), total protein, and TNF-α, IL-1β in bronchoaveolar lavage fluid (BALF) were measured. All data were analyzed by one-way analysis of variance (ANOVA), The intergroup comparisons were analyzed by the least-significant-difference (LSD) test by using SPSS version 20.0 software. Differences were considered statistically significant if P<0.05. Results Compared with group CV, the level of PaO2 [(73.6± 8.9) vs.(50.5± 6.0)] was decreased, the levels of W/D [(3.12± 0.27)vs. (5.12± 0.56)], PPI [(0.08±0.03)vs.(0.30 ± 0.06)], apoptosis rate [(10.6±2.9)vs.(48.5±6.7)], total protein [(5.8±2.1)vs.(15.4±5.6)] and TNF-α [(24.3±5.7) vs. (108.4±16.0)] and IL-1β [(90.6±14.1) vs.(338.5±44.3)] were increased in group HV (P 0.05). Compare with group CV, The histopathologic damage of lung tissue was obvious in group HV and group HFW, it was attenuated by pretreatment with FTY720 in group HF. Conclusions FTY720 pretreatment provides protective effects against ventilation-induced lung injury in rats, and S1PR1 may mediate the protection through reducing apoptosis rate and inflammatory reaction. Key words: Receptions, Lysosphingolipid; Respiration, artificial; Respiratory distress syndrome, adult; Apoptosis; Inflammatory response; Rats

Nintedanib reduces ventilation-augmented bleomycin-induced epithelial-mesenchymal transition and lung fibrosis through suppression of the Src pathway.

Mechanical ventilation (MV) used in patients with acute respiratory distress syndrome (ARDS) can increase lung inflammation and pulmonary fibrogenesis. Src is crucial in mediating the transforming growth factor (TGF)‐β1‐induced epithelial–mesenchymal transition (EMT) during the fibroproliferative phase of ARDS. Nintedanib, a multitargeted tyrosine kinase inhibitor that directly blocks Src, has been approved for the treatment of idiopathic pulmonary fibrosis. The mechanisms regulating interactions among MV, EMT and Src remain unclear. In this study, we suggested hypothesized that nintedanib can suppress MV‐augmented bleomycin‐induced EMT and pulmonary fibrosis by inhibiting the Src pathway. Five days after administrating bleomycin to mimic acute lung injury (ALI), C57BL/6 mice, either wild‐type or Src‐deficient were exposed to low tidal volume (VT) (6 ml/kg) or high VT (30 ml/kg) MV with room air for 5 hrs. Oral nintedanib was administered once daily in doses of 30, 60 and 100 mg/kg for 5 days before MV. Non‐ventilated mice were used as control groups. Following bleomycin exposure in wild‐type mice, high VT MV induced substantial increases in microvascular permeability, TGF‐β1, malondialdehyde, Masson's trichrome staining, collagen 1a1 gene expression, EMT (identified by colocalization of increased staining of α‐smooth muscle actin and decreased staining of E‐cadherin) and alveolar epithelial apoptosis (P < 0.05). Oral nintedanib, which simulated genetic downregulation of Src signalling using Src‐deficient mice, dampened the MV‐augmented profibrotic mediators, EMT profile, epithelial apoptotic cell death and pathologic fibrotic scores (P < 0.05). Our data indicate that nintedanib reduces high VT MV‐augmented EMT and pulmonary fibrosis after bleomycin‐induced ALI, partly by inhibiting the Src pathway.

Impact of Low Tidal Volumes During One-Lung Ventilation. A Meta-Analysis of Randomized Controlled Trials

The link between ventilation strategies and perioperative outcomes remains one of the fundamental paradigms of thoracic anaesthesia. During one-lung ventilation (OLV), one lung is excluded from gas exchange and ventilation is directed at the dependent lung. The authors hypothesised that the use of low tidal volumes (VT) during OLV provides adequate gas exchange and improves postoperative outcome. Meta-analysis of randomized clinical trials. Thoracic surgery. Patients undergoing OLV. None. The authors performed a meta-analysis of all randomized trials on low versus high VT during OLV in patients undergoing thoracic surgery. Outcomes of the study were gas exchange and airway pressures during and after OLV, postoperative pulmonary complications (PPCs), and hospital stay (HLOS). Fourteen randomized trials were selected, but only a few of them contained one outcome of interest. Low VT was associated with lower arterial oxygen tension, lower airway pressures, and higher arterial carbon dioxide tension at specific time points during OLV. Low VT was associated with preserved gas exchange after OLV, lower incidence of pulmonary infiltrations, and acute respiratory distress syndrome. Incidences of PPCs and HLOS were similar. The use of low VT reduces airway pressure but worsens gas exchange during OLV. Preservation of postoperative oxygenation and reduction in infiltrates suggest a lung-protective modality with no demonstrable impact on PPCs and HLOS.

Partial Neuromuscular Blockade during Partial Ventilatory Support in Sedated Patients with High Tidal Volumes.

Controlled mechanical ventilation is used to deliver lung-protective ventilation in patients with acute respiratory distress syndrome. Despite recognized benefits, such as preserved diaphragm activity, partial support ventilation modes may be incompatible with lung-protective ventilation due to high Vt and high transpulmonary pressure. As an alternative to high-dose sedatives and controlled mechanical ventilation, pharmacologically induced neuromechanical uncoupling of the diaphragm should facilitate lung-protective ventilation under partial support modes. To investigate whether partial neuromuscular blockade can facilitate lung-protective ventilation while maintaining diaphragm activity under partial ventilatory support. In a proof-of-concept study, we enrolled 10 patients with lung injury and a Vt greater than 8 ml/kg under pressure support ventilation (PSV) and under sedation. After baseline measurements, rocuronium administration was titrated to a target Vt of 6 ml/kg during neurally adjusted ventilatory assist (NAVA). Thereafter, patients were ventilated in PSV and NAVA under continuous rocuronium infusion for 2 hours. Respiratory parameters, hemodynamic parameters, and blood gas values were measured. Rocuronium titration resulted in significant declines of Vt (mean ± SEM, 9.3 ± 0.6 to 5.6 ± 0.2 ml/kg; P < 0.0001), transpulmonary pressure (26.7 ± 2.5 to 10.7 ± 1.2 cm H2O; P < 0.0001), and diaphragm electrical activity (17.4 ± 2.3 to 4.5 ± 0.7 μV; P < 0.0001), and could be maintained under continuous rocuronium infusion. During titration, pH decreased (7.42 ± 0.02 to 7.35 ± 0.02; P < 0.0001), and mean arterial blood pressure increased (84 ± 6 to 99 ± 6 mm Hg; P = 0.0004), as did heart rate (83 ± 7 to 93 ± 8 beats/min; P = 0.0004). Partial neuromuscular blockade facilitates lung-protective ventilation during partial ventilatory support, while maintaining diaphragm activity, in sedated patients with lung injury.

MECHANICAL VENTILATION IN PATIENTS BITTEN BY BUNGARUS CANDIDUS

Background: Bungarus candidus is a common accident, leading to respiratory failure due to respiratory muscle paralysis. Artificial ventilation is an essential intervention to cure. Objective: Assess results of artificial ventilation in patients bitten by Bungarus candidus. Subjects and Methods: The ventilation method is volume control with 2 different Vt levels: Vt 8-10ml/kg with PEEP 5cmH2O versus Vt 12-15ml/kg with out PEEP. To describe figures of ventilation, complication and microbiology causes of pneumonia. Results: 64 patients were put on ventilation. Average time of artificial ventilation was 9.8±7.1 days. Complications were due to ventilator-associated pneumonia (59.4%), the most common is Acinetobater baumanii 45%, followed by P. aeruginosa, K. pneumoniae, S. and Candida albicans. Complete recovery is 94%, sequelae is 3% and mortality is 3%. Sequelae and mortality mainly is due to respiratory failure and complications associated with mechanical ventilation. Conclusion: High Vt 12-15ml/kg mode is less atalectasis than Vt 8-10ml/kg with PEEP 5cmH2O. Complications mainly related to ventilator-associated pneumonia, the most common etiology is A.baumanii. Key words: Bungarus candidus, mechanical ventilation, respiratory muscle paralysis, complications.

Study on Rac1/MAPK/ERK pathway mediated mechanism and role in rats with ventilator induced lung injury

To investigate the role of Ras-related C3 botulinum toxin substrate 1/mitogen-activated protein kinase/extracellular signal-regulated kinase (Rac1/MAPK/ERK) signal pathway in rats with ventilator induced lung injury (VILI) and its mechanism. Thirty Sprague-Dawley (SD) rats were randomly divided into spontaneous respiration group, normal tidal volume (VT) group and high VT group with 10 rats in each group. The rats in spontaneous respiration group were kept their spontaneous breathing. The rats in normal VT group and high VT group were performed tracheal intubation after tracheostomy, and underwent mechanical ventilation on bilateral lungs with 6 mL/kg and 40 mL/kg VT respectively with maintenance anesthesia. After 4-hour ventilation, heart blood, bronchoalveolar lavage fluid (BALF) and lung tissues were harvested. The levels of interleukins (IL-1β, IL-6), tumor necrosis factor-α (TNF-α), myeloperoxidase (MPO) and macrophage inflammatory protein-2 (MIP-2) in serum and BALF were determined by enzyme linked immunosorbent assay (ELISA). Lung wet/dry radio (W/D) was determined. The lung tissues were stained with hematoxylin and eosin (HE), and pathological changes were observed, and pathological scores were evaluated. The ultra structure changes in type II alveolar epithelial cells (AEC II) were observed with transmission electron microscope. The positive expressions of phosphorylation of extracellular signal-regulated kinase (p-ERK) were determined by immunohistochemistry, and those of Rac1 and F-actin were determined by immunofluorescence. The mRNA expressions of ERK and Rac1 were determined by real-time fluorescent quantitation reverse transcription-polymerase chain reaction (RT-qPCR), and protein expressions of Rac-1, p-ERK and F-actin were determined by Western Blot. (1) Compared with spontaneous breathing group, lung W/D in both mechanical ventilation groups was significantly increased, with more significant increase in the high VT group (6.64±0.88 vs. 1.79±0.36, P < 0.01). (2) There was no obvious pathological changes in the lung tissue and AEC II of the spontaneously breathing group. In the normal VT group, there was slight edema and infiltration of inflammatory cells; AEC II had less lamellar bodies and uniform distribution of the villi of the alveolar epithelium. In the high VT group, the edema of the lung tissue, the widening of the pulmonary septum, the alveolus congestion, the infiltration of inflammatory cells, and alveolar structure disorder were found; and AEC II was irregular, the number of lamellar bodies in the plastids was decreased and was unevenly distributed. The pulmonary histopathological score in the high VT group was significantly higher than that in the spontaneous breathing group and the normal VT group (12.00±2.00 vs. 6.00±1.51, 8.50±0.53, both P < 0.01). (3) Compared with spontaneous breathing group, IL-1β, IL-6, TNF-α, MPO, and MIP-2 in serum and BALF in both mechanical ventilation groups were significantly increased, with more significant increase in the high VT group [serum IL-1β (ng/L): 104.2±15.1 vs. 20.3±8.3, IL-6 (ng/L): 46.6±11.5 vs. 22.7±7.5, TNF-α (ng/L): 39.4±6.5 vs. 5.4±1.9, MPO (ng/L): 0.66±0.24 vs. 0.06±0.03, MIP-2 (ng/L): 109.2±25.8 vs. 22.8±8.4; BALF IL-1β (ng/L): 121.5±25.6 vs. 24.0±7.5, IL-6 (ng/L): 136.7±32.7 vs. 31.4±10.5, TNF-α (ng/L): 98.0±14.8 vs. 10.1±2.6, MPO (ng/L): 0.80±0.31 vs. 0.08±0.04, MIP-2 (ng/L): 144.4±28.9 vs. 41.2±20.7; all P < 0.01]. (4) There were only a few p-ERK, Rac1 and F-actin positive expressions in the spontaneous breathing group. The positive expressions in normal VT group were increased. In high VT group, the positive expression of p-ERK was significantly increased; Rac1 and F-actin were mainly distributed in the cell membrane and cytoplasm respectively, the positive expressions were further enhanced. (5) The gene expressions of ERK and Rac1, and protein expressions of p-ERK, Rac1 and F-actin in the high VT group were significantly higher than those in the spontaneous breathing group and normal VT group [ERK mRNA (2-ΔΔCt): 8.23±2.83 vs. 1, 3.02±1.38, p-ERK protein (gray value): 1.15±0.36 vs. 0.61±0.23, 0.88±0.22; Rac1 mRNA (2-ΔΔCt): 4.45±2.26 vs. 1, 1.22±0.39, Rac1 protein (gray value): 0.91±0.16 vs. 0.48±0.11, 0.55±0.10; F-actin protein (gray value): 0.70±0.09 vs. 0.49±0.08, 0.55±0.04; all P < 0.01]. F-actin expression in lung tissue was up-regulated in rats with VILI, which resulted in reconstruction of AEC II cyto-skeleton, and variation of cell membrane permeability through Rac1/MAPK/ERK signaling pathway during VILI.