VT Ventilation Research Articles

High Tidal Volume Ventilation Activates Smad2 and Upregulates Expression of Connective Tissue Growth Factor in Newborn Rat Lung

High tidal volume (V(T)) ventilation plays a key role in ventilator induced lung injury and bronchopulmonary dysplasia. However, little is known about the effect of high V(T) on expression of growth factors that are critical to lung development. In a previous study, we demonstrated that connective tissue growth factor (CTGF) inhibits branching morphogenesis. In this study, we investigated the effect of high V(T) on CTGF expression in newborn rat lungs. Newborn rats were ventilated with normal V(T) (10 mL/kg) or high V(T) (25 mL/kg) for 6 h. Nonventilated animals served as controls. We found that high V(T) upregulated CTGF expression. To identify the potential signaling pathways mediating high V(T) induction of CTGF, newborn rats were ventilated with high V(T) for 1 or 3 h. Temporal expression of TGF-betas, p-Smad2, Smad7, and CTGF was analyzed. High V(T) ventilation did not change gene expression of TGF-betas and Smad7 but induced rapid and sustained expression of p-Smad2 that precedes increased CTGF expression. CTGF and p-Smad2 were localized in bronchiolar epithelial cells, alveolar walls and septa. These data suggest that high V(t) ventilation activates the Smad2 pathway, which may be responsible for downstream induction of CTGF expression in newborn rat lungs.

Effects of reduced tidal volume ventilation on pulmonary function in mice before and after acute lung injury

We investigated the influence of load impedance on ventilator performance and the resulting effects of reduced tidal volume (Vt) on lung physiology during a 30-min ventilation of normal mice and 10 min of additional ventilation following lavage-induced injury at two positive end-expiratory pressure (PEEP) levels. Respiratory mechanics were regularly monitored, and the lavage fluid was tested for the soluble E-cadherin, an epithelial cell adhesion molecule, and surfactant protein (SP) B. The results showed that, due to the load dependence of the delivered Vt from the small-animal ventilator: 1) uncontrolled ventilation in normal mice resulted in a lower delivered Vt (6 ml/kg at 3-cmH(2)O PEEP and 7 ml/kg at 6-cmH(2)O PEEP) than the prescribed Vt (8 ml/kg); 2) at 3-cmH(2)O PEEP, uncontrolled ventilation in normal mice led to an increase in lung parenchymal functional heterogeneity, a reduction of SP-B, and an increase in E-cadherin; 3) at 6-cmH(2)O PEEP, ventilation mode had less influence on these parameters; and 4) in a lavage model of acute respiratory distress syndrome, delivered Vt decreased to 4 ml/kg from the prescribed 8 ml/kg, which resulted in severely compromised lung function characterized by increases in lung elastance, airway resistance, and alveolar tissue heterogeneity. Furthermore, the low Vt ventilation also resulted in poor survival rate independent of PEEP. These results highlight the importance of delivering appropriate Vt to both the normal and injured lungs. By leaving the Vt uncompensated, it can significantly alter physiological and biological responses in mice.

Brief, Large Tidal Volume Ventilation Initiates Lung Injury and a Systemic Response in Fetal Sheep

Premature infants are exposed to potentially injurious ventilation in the delivery room. Assessments of lung injury are confounded by effects of subsequent ventilatory support. To evaluate the injury response to a brief period of large tidal volume (Vt) ventilation, simulating neonatal resuscitation in preterm neonates. Preterm lambs (129 d gestation; term is150 d) were ventilated (Vt = 15 ml/kg, no positive end-expiratory pressure) for 15 minutes to simulate delivery room resuscitation, either with the placental circulation intact (fetal resuscitation [ FR]) or after delivery (neonatal resuscitation [NR]). After the initial 15 minutes, lambs received surfactant and were maintained with either ventilatory support (FR-VS and NR-VS) or placental support (FR-PS) for 2 hours, 45 minutes. A control group received no resuscitation and was maintained with placental support. Samples of bronchoalveolar lavage fluid, lung, and liver were analyzed. Inflammatory cells and protein in bronchoalveolar lavage fluid, heat shock protein-70 immunostaining, IL-1beta, IL-6, IL-8, monocyte chemotactic protein-1, serum amyloid A (SAA)-3, Toll-like receptor (TLR)-2, and TLR4 mRNA in the lungs were increased in the FR-PS group compared with control animals. There were further elevations in neutrophils, IL-6, and IL-8 mRNA in the FR-VS and NR-VS groups compared with FR-PS. SAA3, TLR2, and TLR4 mRNA increased in the liver in all resuscitation groups relative to control animals. Ventilation for 15 minutes with a Vt of 15 ml/kg initiates an injurious process in the preterm lung and a hepatic acute-phase response. Subsequent ventilatory support causes further increases in some injury indicators.

Higher Urine Nitric Oxide Is Associated with Improved Outcomes in Patients with Acute Lung Injury

Nitrogen oxide (NO) species are markers for oxidative stress that may be pathogenic in acute lung injury (ALI). We tested two hypotheses in patients with ALI: (1) higher levels of urine NO would be associated with worse clinical outcomes, and (2) ventilation with lower VT would reduce urine NO as a result of less stretch injury. Urine NO levels were measured by chemiluminescence in 566 patients enrolled in the National Heart Lung and Blood Institute Acute Respiratory Distress Syndrome Network trial of 6 ml/kg versus 12 ml/kg VT ventilation. The data were expressed corrected and uncorrected for urine creatinine (Cr). Higher baseline levels of urine NO to Cr were associated with lower mortality (odds ratio, 0.43 per log(10) increase in the ratio), more ventilator-free days (mean increase, 1.9 d), and more organ-failure-free days (mean increase, 2.3 d) on multivariate analysis (p < 0.05 for all analyses). Similar results were obtained using urine NO alone. NO to Cr levels were higher on Day 3 in the 6 ml/kg than in the 12 ml/kg VT group (p = 0.04). Contrary to our hypothesis, higher urine NO was associated with improved outcomes in ALI at baseline and after treatment with the 6 ml/kg VT strategy. Higher endogenous NO may reflect less severe lung injury and better preservation of the pulmonary and systemic endothelium or may serve a protective function in patients with ALI.

Choosing the frequency of deep inflation in mice: balancing recruitment against ventilator-induced lung injury

Low tidal volume (Vt) ventilation is protective against ventilator-induced lung injury but can promote development of atelectasis. Periodic deep inflation (DI) can open the lung, but if delivered too frequently may cause damage via repeated overdistention. We therefore examined the effects of varying DI frequency on lung mechanics, gas exchange, and biomarkers of injury in mice. C57BL/6 males were mechanically ventilated with positive end-expiratory pressure (PEEP) of 2 cmH2O for 2 h. One high Vt group received a DI with each breath (HV). Low Vt groups received 2 DIs after each hour of ventilation (LV) or 2 DIs every minute (LVDI). Control groups included a nonventilated surgical sham and a group receiving high Vt with zero PEEP (HVZP). Respiratory impedance was measured every 4 min, from which tissue elastance (H) and damping (G) were derived. G and H rose progressively during LV and HVZP, but returned to baseline after hourly DI during LV. During LVDI and HV, G and H remained low and gas exchange was superior to that of LV. Bronchoalveolar lavage fluid protein was elevated in HV and HVZP but was not different between LV and LVDI. Lung tissue IL-6 and IL-1beta levels were elevated in HVZP and lower in LVDI compared with LV. We conclude that frequent DI can safely improve gas exchange and lung mechanics and may confer protection from biotrauma. Differences between LVDI and HV suggest that an optimal frequency range of DI exists, within which the benefits of maintaining an open lung outweigh injury incurred from overdistention.

Sustained ventilatory capacity in a rat model of amyotrophic lateral sclerosis (ALS)

ALS causes motoneuron degeneration and, ultimately, patient death by respiratory failure. Thus, we investigated the capacity to increase ventilation in a transgenic rat model of ALS that over expresses a mutated form of superoxide dismutase-1 (SOD1G93A). Whole body plethysmography was used to measure ventilation in mutant (n=7) and wild type (n=7) rats during baseline conditions, and during inhalation of 5% and 7% CO2 in air, or 7% CO2 in 10% O2. Measurements were repeated weekly from 61±10 days old until end-stage (defined by 20% weight loss) at 123±14 days. We hypothesized that the capacity to increase breathing during chemoreceptor stimulation declines with disease progression, particularly tidal volume (VT). However, there were no significant differences in VT (ml), frequency (breaths/min), or minute ventilation (ml/min) between SOD1G93A and wild type rats at any age or level of chemoreceptor stimulation (p > 0.05). When VT (ml/100g) and minute ventilation (ml/min/100g) were normalized to body mass, both were greater in SOD1G93A versus wild type rats at all levels of chemoreceptor stimulation at end-stage (p<0.05); normalized ventilation was elevated most at higher chemoreceptor stimulation levels (p<0.05). Since phrenic motor output in these same rats decreased approximately 50% at end-stage (Nashold et al., ibid), we conclude that mutant rats compensate for lost diaphragmatic function by recruiting accessory inspiratory muscles, most likely via mechanisms of neuroplasticity. In conclusion, SOD1G93A rats withstand respiratory challenges until late stage disease. Supported by the ALS Association and NIH HL89209, HL65383 and HL07654.

Ventilator-induced lung injury is reduced in transgenic mice that overexpress endothelial nitric oxide synthase

Although mechanical ventilation (MV) is an important supportive strategy for patients with acute respiratory distress syndrome, MV itself can cause a type of acute lung damage termed ventilator-induced lung injury (VILI). Because nitric oxide (NO) has been reported to play roles in the pathogenesis of acute lung injury, the present study explores the effects on VILI of NO derived from chronically overexpressed endothelial nitric oxide synthase (eNOS). Anesthetized eNOS-transgenic (Tg) and wild-type (WT) C57BL/6 mice were ventilated at high or low tidal volume (Vt; 20 or 7 ml/kg, respectively) for 4 h. After MV, lung damage, including neutrophil infiltration, water leakage, and cytokine concentration in bronchoalveolar lavage fluid (BALF) and plasma, was evaluated. Some mice were given N(omega)-nitro-L-arginine methyl ester (L-NAME), a potent NOS inhibitor, via drinking water (1 mg/ml) for 1 wk before MV. Histological analysis revealed that high Vt ventilation caused severe VILI, whereas low Vt ventilation caused minimal VILI. Under high Vt conditions, neutrophil infiltration and lung water content were significantly attenuated in eNOS-Tg mice compared with WT animals. The concentrations of macrophage inflammatory protein-2 in BALF and plasma, as well as plasma tumor necrosis factor-alpha and monocyte chemoattractant protein-1, also were decreased in eNOS-Tg mice. L-NAME abrogated the beneficial effect of eNOS overexpression. In conclusion, chronic eNOS overexpression may protect the lung from VILI by inhibiting the production of inflammatory chemokines and cytokines that are associated with neutrophil infiltration into the air space.

Leukotrienes in Acute Lung Injury

Leukotrienes in Acute Lung Injury

The Role of Hyaluronan Synthase 3 in Ventilator-induced Lung Injury

We recently found that low-molecular-weight hyaluronan was induced by cyclic stretch in lung fibroblasts and accumulated in lungs from animals with ventilator-induced lung injury. The low-molecular-weight hyaluronan produced by stretch increased interleukin-8 production in epithelial cells, and was accompanied by an upregulation of hyaluronan synthase-3 mRNA. We hypothesized that low-molecular-weight hyaluronan induced by high VT was dependent on hyaluronan synthase 3, and was associated with ventilator-induced lung injury. Effects of high VT ventilation in C57BL/6 wild-type and hyaluronan synthase-3 knockout mice were compared. Significantly increased neutrophil infiltration, macrophage inflammatory protein-2 production, and lung microvascular leak were found in wild-type animals ventilated with high VT. These reactions were significantly reduced in hyaluronan synthase-3 knockout mice, except the capillary leak. Wild-type mice ventilated with high VT were found to have increased low-molecular-weight hyaluronan in lung tissues and concomitant increased expression of hyaluronan synthase-3 mRNA, neither of which was found in hyaluronan synthase-3 knockout mice. We conclude that high VT induced low-molecular-weight hyaluronan production is dependent on de novo synthesis through hyaluronan synthase 3, and plays a role in the inflammatory response of ventilator-induced lung injury.

Neutrophil depletion attenuates interleukin-8 production in mild-overstretch ventilated normal rabbit lung.

Acute lung injury induced by lung overstretch is associated with neutrophil influx, but the pathogenic role of neutrophils in overstretch-induced lung injury remains unclear. To assess the contribution of neutrophils, we compared the effects of noninjurious large tidal volume (Vt) ventilation on lungs in normal and neutrophil-depleted animals. Research animal laboratory. Twenty-six male Japanese white rabbits. Animals were mechanically ventilated for 4 hrs with one of the three following protocols: large Vt (20 mL/kg), small Vt (8 mL/kg), and large Vt (20 mL/kg) with neutrophil depletion achieved by a single dose of vinblastine injection (0.75 mg/kg) intravenously 4 days before the experiment. Large Vt ventilation produced alveolar neutrophil influx compared with low Vt (p =.002) without evidence of edema or increased epithelial permeability. The neutrophil influx was accompanied by increases in interleukin-8 in bronchoalveolar lavage fluid (p =.04). Immunohistochemistry of large Vt lungs showed increased interleukin-8 staining in bronchial epithelial cells, alveolar epithelium, alveolar macrophages, and smooth muscles of pulmonary vessels. Neutrophil depletion attenuated the interleukin-8 increase in the lung. Large Vt did not increase plasma interleukin-8 or tumor necrosis factor-alpha in plasma and bronchoalveolar lavage fluid. No expression of p-selectin or intercellular adhesion molecule-1 was observed. Cyclic overstretching of normal rabbit lungs with noninjurious large Vt produced neutrophil influx and interleukin-8 increase in bronchoalveolar lavage fluid. Production of pulmonary interleukin-8 by lung overstretch might require the interaction between resident lung cells and migrated neutrophils. This study suggests that large Vt ventilation potentiates the predisposed, subclinical lung injury, such as nosocomial pneumonia or aspiration of gastric contents.

Ventilation-induced neutrophil infiltration depends on c-Jun N-terminal kinase.

Positive pressure ventilation with large VTs has been shown to cause release of cytokines, including macrophage inflammatory protein-2 (MIP-2), a functional equivalent of human interleukin-8. The mechanisms regulating ventilation-induced cytokine production are unclear. Based on our previous in vitro model of lung cell stretch, we hypothesized that high VT ventilation-induced MIP-2 production is dependent on the activation of the c-Jun N-terminal kinase (JNK). We exposed C57BL/6 mice to high VT (30 ml/kg) or low VT (6 ml/kg) mechanical ventilation for 5 hours. High VT ventilation-induced neutrophil migration into the lung, MIP-2 protein production, MIP-2 messenger RNA expression, and JNK activation. Large VT ventilation of JNK knockout mice and pharmacologic JNK inhibition with SP600125 attenuated neutrophil sequestration and blocked MIP-2 messenger RNA expression and MIP-2 production. We conclude that lung cell stretch in vivo results in increased lung neutrophil sequestration and increased MIP-2 production, which was, at least in part, dependent upon the JNK pathway.

Influence of tidal volume on pulmonary NO release, tissue lipid peroxidation and surfactant phospholipids

Mechanical stress during ventilation may cause or aggravate acute lung injury. This study investigates the influence of low vs. high tidal volume (Vt) on factors known to play key roles in acute lung injury: nitric oxide release, eNOS and iNOS gene expression, lipid peroxidation (LPO), and surfactant phospholipids (PL). Isolated rabbit lungs were subjected to one of three ventilation patterns for 135 min (Vt-PEEP): 6 ml/kg–0 cm H2O. 12 ml/kg–0 cm H2O 6 ml/kg–5 cm H2O, 12 ml/kg–0 cm H2O, and 6 ml/kg–5 cm H2O resulted in comparable peak inspiratory pressure (PIP). This allowed comparing low and high Vt without dependence on PIP. Ventilatory patterns did not induce changes in pulmonary artery pressure, vascular permeability (Kf,c), PIP or pulmonary compliance. High Vt in comparison with both of the low Vt groups caused an increase in BALF-nitrite (30.6±3.0* vs. 21.4±2.2 and 16.2±3.3 μM), BALF-PL (1110±19* vs. 750±68 and 634±82 μg/ml), and tissue LPO product accumulation (0.62±0.051* vs. 0.48±0.052 and 0.43±0.031 nmol/mg), *P<0.05 each. Perfusate nitrite and BALF-PL composition (assessed by use of 31P-NMR spectroscopy and MALDI-TOF mass spectrometry) did not differ among the groups. High Vt ventilation reduced eNOS gene expression but did not affect iNOS expression. The increased release of NO and the accumulation of LPO products may represent early lung injury while elevated BALF-PL may reflect distension-induced surfactant secretion.

High tidal volume upregulates intrapulmonary cytokines in an in vivo mouse model of ventilator-induced lung injury.

Mechanical ventilation has been demonstrated to exacerbate lung injury, and a sufficiently high tidal volume can induce injury in otherwise healthy lungs. However, it remains controversial whether injurious ventilation per se, without preceding lung injury, can initiate cytokine-mediated pulmonary inflammation. To address this, we developed an in vivo mouse model of acute lung injury produced by high tidal volume (Vt) ventilation. Anesthetized C57BL6 mice were ventilated at high Vt (34.5 +/- 2.9 ml/kg, mean +/- SD) for a duration of 156 +/- 17 min until mean blood pressure fell below 45 mmHg (series 1); high Vt for 120 min (series 2); or low Vt (8.8 +/- 0.5 ml/kg) for 120 or 180 min (series 3). High Vt produced progressive lung injury with a decrease in respiratory system compliance, increase in protein concentration in lung lavage fluid, and lung pathology showing hyaline membrane formation. High-Vt ventilation was associated with increased TNF-alpha in lung lavage fluid at the early stage of injury (series 2) but not the later stage (series 1). In contrast, lavage fluid macrophage inflammatory protein-2 (MIP-2) was increased in all high-Vt animals. Lavage fluid from high-Vt animals contained bioactive TNF-alpha by WEHI bioassay. Low-Vt ventilation induced minimal changes in physiology and pathology with negligible TNF-alpha and MIP-2 proteins and TNF-alpha bioactivity. These results demonstrate that high-Vt ventilation in the absence of underlying injury induces intrapulmonary TNF-alpha and MIP-2 expression in mice. The apparently transient nature of TNF-alpha upregulation may help explain previous controversy regarding the involvement of cytokines in ventilator-induced lung injury.

Future research directions in acute lung injury: summary of a National Heart, Lung, and Blood Institute working group.

Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are syndromes of acute respiratory failure that result from acute pulmonary edema and inflammation. The development of ALI/ARDS is associated with several clinical disorders including direct pulmonary injury from pneumonia and aspiration as well as indirect pulmonary injury from trauma, sepsis, and other disorders such as acute pancreatitis and drug overdose. Although mortality from ALI/ARDS has decreased in the last decade, it remains high. Despite two major advances in treatment, low VT ventilation for ALI/ARDS and activated protein C for severe sepsis (the leading cause of ALI/ARDS), additional research is needed to develop specific treatments and improve understanding of the pathogenesis of these syndromes. The NHLBI convened a working group to develop specific recommendations for future ALI/ARDS research. Improved understanding of disease heterogeneity through use of evolving biologic, genomic, and genetic approaches should provide major new insights into pathogenesis of ALI. Cellular and molecular methods combined with animal and clinical studies should lead to further progress in the detection and treatment of this complex disease.

Systemic microvascular leak in an in vivo rat model of ventilator-induced lung injury.

Positive pressure mechanical ventilation has significant systemic effects, but the systemic effects associated with ventilator-induced lung injury (VILI) are unexplored. We hypothesized that VILI would cause systemic microvascular leak that is dependent on nitric oxide synthase (NOS) expression. Rats were ventilated with room air at 85 breaths/minute for 2 hours with either VT 7 or 20 ml/kg. Kidney microvascular leak, which was assessed by measuring 24-hour urine protein and Evans blue dye, was used as a marker of systemic microvascular leak. A significant microvascular leak occurred in both lung and kidney with large VT (20 ml/kg) ventilation. Injection of 0.9% NaCl corrected the hypotension and the decreased cardiac output related to large VT, but it did not attenuate microvascular leak of lung and kidney. Serum vascular endothelial growth factor was significantly elevated in large VT groups. Endothelial NOS expression significantly increased in the lung and kidney tissue with large VT ventilation but not inducible NOS. The NOS inhibitor, N-nitro-L-arginine methyl ester, attenuated the microvascular leak of lung and kidney and the proteinuria with large VT ventilation. Endothelial NOS may mediate the systemic microvascular leak of the present model of VILI.

Ventilation with lower tidal volumes versus traditional tidal volumes in adults for acute lung injury and acute respiratory distress syndrome.

Patients with acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) require mechanical ventilatory support. ALI/ARDS is further complicated by ventilator-induced lung injury. Lung-protective ventilation strategies may lead to improved survival. To assess the effects of ventilation with lower tidal volume (Vt) on morbidity and mortality in adults patients affected by ALI/ARDS. A secondary objective was to determine whether the comparison between low and conventional Vt is different if a plateau airway pressure of greater than 30 to 35 cm H20 was used. We searched The Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library issue 3, 2002; MEDLINE (1966 to June 2002); EMBASE and CINAHL (1982 to June 2002); intensive care journals and conference proceedings; databases of ongoing research, reference lists and 'grey literature'. Randomized trials comparing ventilation using lower Vt and/or low airway driving pressure (plateau pressure 30 cm H2O or less), resulting in Vt of 7 ml/kg or less versus ventilation that uses Vt in the range of 10 to 15 ml/kg, in adults (16 year-old or greater). Two reviewers independently assessed trial quality and extracted data. Wherever appropriate, results were pooled. Fixed and random effects models were applied. Five trials, involving 1202 patients, were eligible. The test for heterogeneity gave a P-value of 0.12. Ventilation with lower Vt was associated with a decreased mortality at the end of the follow up period for each trial: 216/605 (35.7%) versus 249/597 (41.7%), relative risk (RR) 0.85 (CI 0.74 to 0.98). The effect of the intervention was not statistically significant when a random effects model was used: RR 0.91 (CI 0.72 to 1.14). Mortality at day 28 was significantly reduced by lung-protective ventilation: RR 0.74 (CI 0.61 to 0.88). The comparison between low and conventional Vt was not significantly different if a plateau pressure less than or equal to 31 cm H2O in control group was used: RR 1.13 (CI 0.88 to 1.45). There was insufficient evidence about morbidity and long term outcomes. Clinical heterogeneity, such as different lengths of follow up and higher plateau pressure in control arms in two trials make the interpretation of the combined results difficult. Mortality is significantly reduced at day 28 and the effects on long term mortality are uncertain, although the possibility of a clinically relevant benefit cannot be excluded. There is no evidence that low Vt ventilation is beneficial in patients where hypercapnia is potentially harmful.

Efficacy of Low Tidal Volume Ventilation in Patients with Different Clinical Risk Factors for Acute Lung Injury and the Acute Respiratory Distress Syndrome

In patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), a recent ARDS Network randomized controlled trial demonstrated that a low tidal volume (VT) mechanical ventilation strategy (6 ml/kg) reduced mortality by 22% compared with traditional mechanical ventilation (12 ml/kg). In this study, we examined the relative efficacy of low VT mechanical ventilation among 902 patients with different clinical risk factors for ALI/ARDS who participated in ARDS Network randomized controlled trials. The clinical risk factor for ALI/ARDS was associated with substantial variation in mortality. The risk of death (before discharge home with unassisted breathing) was highest in patients with sepsis (43%); intermediate in subjects with pneumonia (36%), aspiration (37%), and other risk factors (35%); and lowest in those with trauma (11%) (p < 0.0001). Despite these differences in mortality, there was no evidence that the efficacy of the low VT strategy varied by clinical risk factor (p = 0.76, for interaction between ventilator group and risk factor). There was also no evidence of differential efficacy of low VT ventilation in the other study outcomes: proportion of patients achieving unassisted breathing (p = 0.59), ventilator-free days (p = 0.58), or development of nonpulmonary organ failure (p = 0.44). Controlling for demographic and clinical covariates did not appreciably affect these results. After reclassifying the clinical risk factors as pulmonary versus nonpulmonary predisposing conditions and infection-related versus non-infection-related conditions, there was still no evidence that the efficacy of low VT ventilation differed among clinical risk factor subgroups. In conclusion, we found no evidence that the efficacy of the low VT ventilation strategy differed among clinical risk factor subgroups for ALI/ARDS.

Ventilatory Mechanics and Gas Exchange during Exercise before and after Lung Volume Reduction Surgery

Many patients with emphysema are able to meet ventilatory demands during resting conditions, but they show severe limitations during exercise. To examine the effect of lung volume reduction (LVR) surgery on exercise performance and the mechanism of possible improvement, we measured ventilatory mechanics (pulmonary resistance [RL], work of breathing [WOB], dynamic intrinsic positive end-expiratory pressure [PEEPi,dyn], peak expiratory flow rate [PEFR]), breathing pattern, oxygen uptake (V O2), and carbon dioxide removal (V CO2) at rest and during cycle ergometry in eight patients before and 3 mo after LVR surgery. Ventilatory mechanics were evaluated assessing esophageal pressure and air flow. Three months after LVR surgery, the tolerated workload was doubled when compared with the preoperative value (p < 0.0005), associated with a reduction of RL (p < 0.05), PEEPi,dyn (p < 0.005), and WOB (p < 0. 005) at comparable workloads. Maximal ventilatory capacity and maximal tidal volume (VT) increased significantly (p < 0.01). Maximal V O2 increased from 474 +/- 23 to 601 +/- 16 ml/min (p < 0. 005) and maximal V CO2 from 401 +/- 13 to 558 +/- 21 ml/min (p < 0. 005), though no significant difference at comparable workloads could be observed. In conclusion, emphysema surgery leads to an improvement of ventilatory mechanics at rest and during exercise. Higher maximal VT and minute ventilation were observed, resulting in improvement of maximal V O2 and V CO2 and exercise capacity.

Intratracheal Pulmonary Ventilation at Low Airway Pressures in a Ventilator-Induced Model of Acute Respiratory Failure Improves Lung Function and Survival

The pulmonary parenchyma in patients with acute respiratory failure (ARF) is commonly not involved in a homogenous disease process. Conventional mechanical ventilation (MV) at elevated positive end-expiratory pressure (PEEP) and peak inspiratory pressure (PIP) aims at recruiting collapsed or nonventilated lung units. Invariably, those pressures are also transmitted to the healthiest regions, with possible extension of the disease process (barotrauma). During intratracheal pulmonary ventilation (ITPV), a continuous flow of fresh gas is delivered directly at the carina, bypassing the dead space proximal to the catheter tip. In healthy sheep, it allows lowering tidal volume (VT) to as low as 1.0 mL/kg, at respiratory rates (RR) up to 120 breaths/min, while maintaining normocapnia. In a model of ventilator-induced lung injury, we wished to explore whether ITPV, applied at low VT and low PEEP and tailored to ventilate the healthiest regions of the lungs, could provide adequate oxygenation and alveolar ventilation, without any attempt to recruit lungs. Randomized study in sheep. Animal research laboratory. We induced ARF in 12 sheep following 1 to 2 days of MV at a PIP of 50 cm H2O, except that 5 to 8% of lungs were kept on apneic oxygenation of 5 cm H2O, sparing those regions from the injury process. Sheep were randomized to volume-controlled MV (control group) (n = 6) with VT of 8 to 12 mL/kg, PEEP of 5 to 10 cm H2O, or to ITPV (n = 6) at PEEP of 3 to 5 cm H2O, VT of 2.5 to 4 mL/kg, PIP of <20 cm H2O, at RRs sufficient to sustain normocapnia. Hemodynamic status in the ITPV group progressively improved, and all six sheep were weaned to room air within 83+/-54 h. Sheep in the control group had progressively deteriorating conditions and all animals died after a mean of 50+/-39 h. Barotrauma and postmortem histopathologic changes were more pronounced in the control group. In this model of ventilator-induced lung injury, low PEEP-low VT ventilation with ITPV sustained normocapnia and prevented further lung injury, allowing weaning to room air ventilation.

Immediate response to inspiratory resistive loading in anesthetized patients with kyphoscoliosis: spirometric and neural effects.

In kyphoscoliosis (KS), lung volumes are reduced, respiratory elastance and resistance are increased, and breathing pattern is rapid and shallow, attributes that may contribute to defense of tidal volume (VT) in the face of inspiratory resistive loading. The control of ventilation of 12 anesthetized patients about to undergo corrective spinal surgery was compared to that of 11 anesthetized patients free of cardiothoracic disease during quiet breathing and the first breath through one of three linear resistors. Mean forced vital capacity (FVC) of the KS group was 48% that of the controls (C). Passive elastance (Ers) and active elastance and resistance (E'rs and R'rs, respectively) were computed according to previously described techniques (Behrakis PK, Higgs BD, Baydur A, Zin WA, Milic-Emili J (1983) Active inspiratory impedance in halothane-anesthetized humans. J Appl Physiol 54: 1477-1481). Baseline tidal volume VT, inspiratory duration Tl, expiratory duration TE, duration of total breathing cycle TT, and inspiratory duty cycle TI/TT were significantly reduced, while VE was slightly decreased in the KS. Ers, E'rs, and R'rs, were, respectively, 72, 69, and 89% greater in the KS. Driving pressure (Pmus) was derived from the equation of motion, using active values of respiratory elastance. With resistive loading, there was greater prolongation of TI in the C, while percent reduction in VT and minute ventilation VE was less in KS. Compensation in both groups was achieved through three changes in the Pmus waveform. (1) Peak amplitude increased. (2) The duration of the rising phase increased. (3) The rising Pmus curve became more concave to the time axis. These changes were most marked with application of the highest resistance in both groups. Peak driving pressure and mean rate of rise of Pmus were greater in the KS. Increased intrinsic impedance, Pmus, and differences in changes in neural timing in anesthetized kyphoscoliotics contribute to modestly greater VT defense, compared to that of anesthetized subjects free of cardiorespiratory disease.