Vaporized Perfluorohexane Attenuates Ventilator-induced Lung Injury in Isolated, Perfused Rabbit Lungs

Background: The authors tested the hypothesis that administration of vaporized perfluorohexane may attenuate ventilator-induced lung injury.

Methods: In isolated, perfused rabbit lungs, airway pressure-versus-time curves were recorded. At baseline, peak inspiratory pressure and positive end-expiratory pressure of mechanically ventilated lungs were set to obtain straight pressure-versus-time curves in both the lower and upper ranges, which are associated with less collapse and overdistension, respectively. After that, peak inspiratory pressure and positive end-expiratory pressure were set at 30 cm H2O and 0, respectively, and animals were randomly assigned to one of two groups: (1) simultaneous administration of 14% perfluorohexane vapor in room air (n = 7) and (2) control group-ventilation with room air (n = 7). After 20 min of cycling collapse and overdistension, tidal volume and positive end-expiratory pressure were set back to baseline levels, administration of perfluorohexane in the therapy group was stopped, and mechanical ventilation was continued for up to 60 min. Lung weight, mean pulmonary artery pressure, and concentration of thromboxane B2 in the perfusate were measured. In addition, the distribution of pulmonary perfusate flow was assessed by using fluorescent-labeled microspheres.

Results: Significantly higher peak inspiratory values developed in control lungs than in lungs treated with perfluorohexane. In addition, upper ranges of pressure-versus-time curves were closer to straight lines in the perfluorohexane group. Lung weight, mean pulmonary arterial pressure, and release of thromboxane B2 were significantly higher in controls than in perfluorohexane-treated lungs. Also, redistribution of pulmonary perfusate flow from caudal to cranial zones was less important in the treatment group.     

One-lung ventilation with high tidal volumes and zero positive end-expiratory pressure is injurious in the isolated rabbit lung model

We tested the hypothesis that one-lung ventilation (OLV) with high tidal volumes (VT) and zero positive end-expiratory pressure (PEEP) may lead to ventilator-induced lung injury. In an isolated, perfused rabbit lung model, VT and PEEP were set to avoid lung collapse and overdistension in both lungs, resulting in a straight pressure-time (P-vs-t) curve during constant flow. Animals were randomized to (a) nonprotective OLV (left lung) (n = 6), with VT values as high as before randomization and zero PEEP; (b) protective OLV (left lung) (n = 6), with 50% reduction of VT and maintenance of PEEP as before randomization; and (c) control group (n = 6), with ventilation of two lungs as before randomization. The nonprotective OLV was associated with significantly smaller degrees of collapse and overdistension in the ventilated lung (P < 0.001). Peak inspiratory pressure values were higher in the nonprotective OLV group (P < 0.001) and increased progressively throughout the observation period (P < 0.01). The mean pulmonary artery pressure and lung weight gain values, as well as the concentration of thromboxane B(2), were comparatively higher in the nonprotective OLV group (P < 0.05). A ventilatory strategy with VT values as high as those used in the clinical setting and zero PEEP leads to ventilator-induced lung injury in this model of OLV, but this can be minimized with VT and PEEP values set to avoid lung overdistension and collapse. IMPLICATIONS: One-lung ventilation with high tidal volumes and zero positive end-expiratory pressure (PEEP) is injurious in the isolated rabbit lung model. A ventilatory strategy with tidal volumes and PEEP set to avoid lung overdistension and collapse minimizes lung injury during one-lung ventilation in this model.     

Comparative effects of vaporized perfluorohexane and partial liquid ventilation in oleic acid-induced lung injury

BACKGROUND: It is currently not known whether vaporized perfluorohexane is superior to partial liquid ventilation (PLV) for therapy of acute lung injury. In this study, the authors compared the effects of both therapies in oleic acid-induced lung injury. METHODS: Lung injury was induced in 30 anesthetized and mechanically ventilated pigs by means of central venous infusion of oleic acid. Animals were assigned to one of the following groups: (1) control or gas ventilation (GV), (2) 2.5% perfluorohexane vapor, (3) 5% perfluorohexane vapor, (4) 10% perfluorohexane vapor, or (5) PLV with perfluorooctane (30 ml/kg). Two hours after randomization, lungs were recruited and positive end-expiratory pressure was adjusted to obtain minimal elastance. Ventilation was continued during 4 additional hours, when animals were killed for lung histologic examination. RESULTS: Gas exchange and elastance were comparable among vaporized perfluorohexane, PLV, and GV before the open lung approach was used and improved in a similar fashion in all groups after positive end-expiratory pressure was adjusted to optimal elastance (P < 0.05). A similar behavior was observed in functional residual capacity (FRC) in animals treated with vaporized perfluorohexane and GV. Lung resistance improved after recruitment (P < 0.05), but values were higher in the 10% perfluorohexane and PLV groups as compared with GV (P < 0.05). Interestingly, positive end-expiratory pressure values required to obtain minimal elastance were lower with 5% perfluorohexane than with PLV and GV (P < 0.05). In addition, diffuse alveolar damage was significantly lower in the 5% and 10% perfluorohexane vapor groups as compared with PLV and GV (P < 0.05). CONCLUSIONS: Although the use of 5% vaporized perfluorohexane permitted the authors to reduce pressures needed to stabilize the lungs and was associated with better histologic findings than were PLV and GV, none of these perfluorocarbon therapies improved gas exchange or lung mechanics as compared with GV.     

Comparative Effects of Vaporized Perfluorohexane and Partial Liquid Ventilation in Oleic Acid- induced Lung Injury

Background: It is currently not known whether vaporized perfluorohexane is superior to partial liquid ventilation (PLV) for therapy of acute lung injury. In this study, the authors compared the effects of both therapies in oleic acid-induced lung injury.

Methods: Lung injury was induced in 30 anesthetized and mechanically ventilated pigs by means of central venous infusion of oleic acid. Animals were assigned to one of the following groups: (1) control or gas ventilation (GV), (2) 2.5% perfluorohexane vapor, (3) 5% perfluorohexane vapor, (4) 10% perfluorohexane vapor, or (5) PLV with perfluorooctane (30 ml/kg). Two hours after randomization, lungs were recruited and positive end-expiratory pressure was adjusted to obtain minimal elastance. Ventilation was continued during 4 additional hours, when animals were killed for lung histologic examination.

Results: Gas exchange and elastance were comparable among vaporized perfluorohexane, PLV, and GV before the open lung approach was used and improved in a similar fashion in all groups after positive end-expiratory pressure was adjusted to optimal elastance (P < 0.05). A similar behavior was observed in functional residual capacity (FRC) in animals treated with vaporized perfluorohexane and GV. Lung resistance improved after recruitment (P < 0.05), but values were higher in the 10% perfluorohexane and PLV groups as compared with GV (P < 0.05). Interestingly, positive end-expiratory pressure values required to obtain minimal elastance were lower with 5% perfluorohexane than with PLV and GV (P < 0.05). In addition, diffuse alveolar damage was significantly lower in the 5% and 10% perfluorohexane vapor groups as compared with PLV and GV (P < 0.05).     

Nitric oxide and thromboxane A2-mediated pulmonary microvascular dysfunction

OBJECTIVES: To examine whether the lung releases nitric oxide (NO) in response to thromboxane A2 and to examine the local release of NO as a protective compensatory mechanism by which the lung responds to the proinflammatory and vasoactive effects of thromboxane A2. DESIGN: The lungs of anesthetized Sprague-Dawley rats were perfused in vitro with Krebs-Henseleit buffer that contained an inhibitor of NO synthase (nitroglycerinenitro-L-arginine methyl ester [L-NAME]) (10(-4) mol/L), an NO donor (sodium nitroprusside) (10(-8) mol/L), or perfusate alone. Following equilibration, the thromboxane A2 receptor agonist 9,11-dideoxy-11alpha, 9alpha-epoxymethanoprostaglandin F2alpha(U-46619) (7.1 X 10(-8) mol/L) was added to the perfusate. Fifteen minutes later, the capillary filtration coefficient, pulmonary arterial pressure, and vascular resistance were measured. Pulmonary NO release was assessed by quantitating the release of cyclic guanosine monophosphate into the perfusate. RESULTS: The capillary filtration coefficient of lungs exposed to U-46619 was 3.5 times greater than that of lungs perfused with buffer alone (P<.05). The addition of sodium nitroprusside reduced the increase in capillary filtration coefficient associated with U-46619 by 50% (P<.05) whereas L-NAME had no effect. The addition of U-46619 to the perfused lung caused a 3.0+/-0.4 mm Hg increase in pulmonary artery pressure (P<.01) with a corresponding rise in total vascular resistance (P<.05). This effect was exacerbated by L-NAME (P<.05) and inhibited by sodium nitroprusside (P<.05). Exposure of the isolated lungs to U-46619 caused a 4-fold increase in cyclic guanosine monophosphate levels within the perfusate. CONCLUSION: These data are consistent with the hypothesis that NO release may be an important protective mechanism by which the lung responds to thromboxane A2.     

Pulmonary gas distribution during ventilation with different inspiratory flow patterns in experimental lung injury -- a computed tomography study

BACKGROUND: There is still controversy about the optimal inspiratory flow pattern for ventilation of patients with acute lung injury. The aim of this study was to compare the effects of pressure-controlled ventilation (PCV) with a decelerating inspiratory flow with volume-controlled ventilation (VCV) with constant inspiratory flow on pulmonary gas distribution (PGD) in experimentally induced ARDS. METHODS: Sixteen adult sheep were randomized to be ventilated with PCV or VCV after surfactant depletion by repeated bronchoalveolar lavage. Positive end-expiratory pressure (PEEP) was increased in a stepwise manner from zero end-expiratory pressure (ZEEP) to 7, 14 and 21 cm H(2)O in hourly intervals. Respiratory rate, inspiration-to-expiration ratio and tidal volume were kept constant. Central hemodynamics, gas exchange and airway pressures were measured. Electron beam computed tomographic (EBCT) scans of the entire lungs were performed at baseline (preinjury) and each level of end-expiratory pressure during an inspiratory and expiratory hold maneuver. The lungs were three-dimensionally reconstructed and volumetric assessments were made separating the lungs into four subvolumes classified as overinflated, normally aerated, poorly aerated and nonaerated. RESULTS: Pressure-controlled ventilation led to a decrease in peak airway pressure and an increase in mean airway pressure. No differences between groups were found regarding plateau pressures, hemodynamics and gas exchange. Recruitment, defined as a decrease in expiratory lung volume classified as nonaerated, was similar in both groups and predominantly associated with PEEP. Overinflated lung volumes were increased with PCV. CONCLUSIONS: In this model of acute lung injury, ventilation with decelerating inspiratory flow had no beneficial effects on PGD when compared with ventilation with constant inspiratory flow, while the increase in overinflated lung volumes may raise concerns regarding potential ventilator-associated lung injury.     

Perfluorohexane vapor has only minor effects on spatial pulmonary blood flow distribution in isolated rabbit lungs

We tested the hypothesis that administration of perfluorohexane (PFH) vapor does not significantly affect the relative pulmonary blood flow (Qrel) distribution in isolated rabbit lungs. Fourteen isolated rabbit lungs were perfused with a Krebs-Henseleit buffer solution (flow 150 mL/min). Pulmonary afterload was set to 3 mm Hg. The lungs were ventilated with 4% CO(2) in room air using a small animal ventilator (respiratory rate, 30 breaths/min; tidal volume, 12 mL/kg body weight; positive end-expiratory pressure, 2 cm H(2)O). After a steady-state period, 18 vol. % of PFH vapor was administered to 9 lungs for 30 min. In a second set of experiments five lungs served as controls. Change in (Qrel) distribution was assessed using fluorescent-labeled microspheres. The unpaired Student's t-test was used to compare variables between groups. The paired Student's t-test, the one-sample Student's t-test, the Anderson-Hauck test of equivalence, and Pearson correlation were used to analyze changes within groups. The mean correlation coefficients of (Qrel) were 0.564 +/- 0.182 for the PFH group and 0.502 +/- 0.295 for the control group, respectively. No significant changes in (rel) distribution over time and between groups were found. However, in the PFH group a tendency towards redistribution of (Qrel) to more ventral lung areas was noted. Our results suggest that PFH vapor has no significant effects on redistribution of (Qrel) in isolated rabbit lungs.     

Regional gas exchange and cellular metabolic activity in ventilator-induced lung injury

BACKGROUND: Alveolar overdistension and repetitive derecruitment-recruitment contribute to ventilator-induced lung injury (VILI). The authors investigated (1) whether inflammatory cell activation due to VILI was assessable by positron emission tomography and (2) whether cell activation due to dynamic overdistension alone was detectable when other manifestations of VILI were not yet evident. METHODS: The authors assessed cellular metabolic activity with [(18)F]fluorodeoxyglucose and regional gas exchange with [(13)N]nitrogen. In 12 sheep, the left ("test") lung was overdistended with end-inspiratory pressure of 50 cm H(2)O for 90 min, while end-expiratory derecruitment of this lung was either promoted with end-expiratory pressure of -10 cm H(2)O in 6 of these sheep (negative end-expiratory pressure [NEEP] group) or prevented with +10 cm H(2)O in the other 6 (positive end-expiratory pressure [PEEP] group) to isolate the effect of overdistension. The right ("control") lung was protected from VILI. RESULTS: Aeration decreased and shunt fraction increased in the test lung of the NEEP group. [(18)F]fluorodeoxyglucose uptake of this lung was higher than that of the control lung and of the test lung of the PEEP group, and correlated with neutrophil count. When normalized by tissue fraction to account for increased aeration of the test lung in the PEEP group, [(18)F]fluorodeoxyglucose uptake was elevated also in this group, despite the fact that gas exchange had not yet deteriorated after 90 min of overdistension alone. CONCLUSION: The authors could detect regional neutrophil activation in VILI even when end-expiratory derecruitment was prevented and impairment of gas exchange was not evident. Concomitant end-expiratory derecruitment converted this activation into profound inflammation with decreased aeration and regional shunting.     

Regional Gas Exchange and Cellular Metabolic Activity in Ventilator-induced Lung Injury

Background: Alveolar overdistension and repetitive derecruitment-recruitment contribute to ventilator-induced lung injury (VILI). The authors investigated (1) whether inflammatory cell activation due to VILI was assessable by positron emission tomography and (2) whether cell activation due to dynamic overdistension alone was detectable when other manifestations of VILI were not yet evident.

Methods: The authors assessed cellular metabolic activity with [18F]fluorodeoxyglucose and regional gas exchange with [13N]nitrogen. In 12 sheep, the left ("test") lung was overdistended with end-inspiratory pressure of 50 cm H2O for 90 min, while end-expiratory derecruitment of this lung was either promoted with end-expiratory pressure of -10 cm H2O in 6 of these sheep (negative end-expiratory pressure [NEEP] group) or prevented with +10 cm H2O in the other 6 (positive end-expiratory pressure [PEEP] group) to isolate the effect of overdistension. The right ("control") lung was protected from VILI.

Results: Aeration decreased and shunt fraction increased in the test lung of the NEEP group. [18F]fluorodeoxyglucose uptake of this lung was higher than that of the control lung and of the test lung of the PEEP group, and correlated with neutrophil count. When normalized by tissue fraction to account for increased aeration of the test lung in the PEEP group, [18F]fluorodeoxyglucose uptake was elevated also in this group, despite the fact that gas exchange had not yet deteriorated after 90 min of overdistension alone.     

Pressure-time curve predicts minimally injurious ventilatory strategy in an isolated rat lung model

BACKGROUND: We tested the hypothesis that the pressure-time (P-t) curve during constant flow ventilation can be used to set a noninjurious ventilatory strategy. METHODS: In an isolated, nonperfused, lavaged model of acute lung injury, tidal volume and positive end-expiratory pressure were set to obtain: (1) a straight P-t curve (constant compliance, minimal stress); (2) a downward concavity in the P-t curve (increasing compliance, low volume stress); and (3) an upward concavity in the P-t curve (decreasing compliance, high volume stress). The P-t curve was fitted to: P = a. tb +c, where b describes the shape of the curve, b = 1 describes a straight P-t curve, b < 1 describes a downward concavity, and b > 1 describes an upward concavity. After 3 h, lungs were analyzed for histologic evidence of pulmonary damage and lavage concentration of inflammatory mediators. Ventilator-induced lung injury occurred when injury score and cytokine concentrations in the ventilated lungs were higher than those in 10 isolated lavaged rats kept statically inflated for 3 h with an airway pressure of 4 cm H2O. RESULTS: The threshold value for coefficient b that discriminated best between lungs with and without histologic and inflammatory evidence of ventilator-induced lung injury (receiver-operating characteristic curve) ranged between 0.90-1.10. For such threshold values, the sensitivity of coefficient b to identify noninjurious ventilatory strategy was 1.00. A significant relation (P < 0.001) between values of coefficient b and injury score, interleukin-6, and macrophage inflammatory protein-2 was found. CONCLUSIONS: The predictive power of coefficient b to predict noninjurious ventilatory strategy in a model of acute lung injury is high.     

Extracorporeal membrane oxygenation for neonatal respiratory failure. A report of 50 cases

From February 1985 through June 1987, 50 newborn infants in whom maximal ventilator therapy failed (80% predicted mortality) were treated with extracorporeal membrane oxygenation (ECMO) according to the following inclusion criteria: arterial oxygen tension less than 50 torr (alveolar-arterial oxygen gradient greater than 630 torr) for 2 hours or arterial oxygen tension less than 60 torr (alveolar-arterial oxygen gradient greater than 620 torr) for 8 hours. Criteria for exclusion from ECMO therapy included birth weight less than 2000 gm, gestational age less than 35 weeks, presence of intracranial hemorrhage, presence of other major congenital anomalies including cyanotic heart disease, and high levels of ventilatory support for more than 7 days. Mean birth weight was 3.28 +/- 0.56 kg, mean gestational age was 39.6 +/- 1.7 weeks, and mean age at the start of ECMO was 48.6 +/- 36.9 hours. Meconium aspiration, usually associated with persistent pulmonary hypertension, was the most common cause of pulmonary failure (62%). Mean pre-ECMO arterial oxygen tension during maximal ventilatory and pharmacologic support was 34.5 +/- 14.5 torr. Mean ventilatory support immediately before the institution of ECMO was as follows: peak inspiratory pressure 46.8 +/- 9.9 cm H2O, positive end-expiratory pressure 4.6 +/- 1.6 cm H2O, and intermittent mandatory ventilation rate 101.0 +/- 22.7 breaths/min with all patients receiving an inspired oxygen fraction of 1.0. Lung management to prevent pulmonary atelectasis during ECMO consisted of moderate levels of positive end-expiratory pressure (mean 10.3 +/- 2.6 cm H2O, range 8 to 14 in 94% of patients. Other mean ventilator parameters during ECMO were as follows: peak inspiratory pressure 22.8 +/- 1.6 cm H2O, intermittent mandatory ventilation rate 11.8 +/- 2.9, and inspired oxygen fraction 0.21. The overall long-term patient survival rate was 90%. Mean values for arterial blood gases and ventilator settings immediately after the discontinuation of ECMO were as follows: oxygen tension 78.4 +/- 22.1 torr, pH 7.39 +/- 0.10, carbon dioxide tension 37.4 +/- 10.7 torr, peak inspiratory pressure 25.2 +/- 3.9 cm H2O, positive end-expiratory pressure 5.6 +/- 1.2 cm H2O, and intermittent mandatory ventilation rate 41.3 +/- 12.6 with an inspired oxygen fraction of 0.42 +/- 0.17. Despite slightly higher levels of ventilator support (peak inspiratory pressure 46.8 versus 45.0 cm H2O, not significant) mean pre-ECMO oxygen tension was significantly lower than that reported from the National ECMO Registry (34.5 versus 42.0 torr, p less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)     

Pressure-Time Curve Predicts Minimally Injurious Ventilatory Strategy in an Isolated Rat Lung Model

Background: We tested the hypothesis that the pressure-time (P-t) curve during constant flow ventilation can be used to set a noninjurious ventilatory strategy.

Methods: In an isolated, nonperfused, lavaged model of acute lung injury, tidal volume and positive end-expiratory pressure were set to obtain: (1) a straight P-t curve (constant compliance, minimal stress); (2) a downward concavity in the P-t curve (increasing compliance, low volume stress); and (3) an upward concavity in the P-t curve (decreasing compliance, high volume stress). The P-t curve was fitted to: P =a [middle dot] t b +c, where b describes the shape of the curve, b = 1 describes a straight P-t curve, b < 1 describes a downward concavity, and b > 1 describes an upward concavity. After 3 h, lungs were analyzed for histologic evidence of pulmonary damage and lavage concentration of inflammatory mediators. Ventilator-induced lung injury occurred when injury score and cytokine concentrations in the ventilated lungs were higher than those in 10 isolated lavaged rats kept statically inflated for 3 h with an airway pressure of 4 cm H2O.

Results: The threshold value for coefficient b that discriminated best between lungs with and without histologic and inflammatory evidence of ventilator-induced lung injury (receiver-operating characteristic curve) ranged between 0.90-1.10. For such threshold values, the sensitivity of coefficient b to identify noninjurious ventilatory strategy was 1.00. A significant relation (P < 0.001) between values of coefficient b and injury score, interleukin-6, and macrophage inflammatory protein-2 was found.     

Experimental studies on lung mechanics, gas exchange and oxygen delivery under open lung conditions Mechanical ventilation with decelerating versus constant inspiratory flow

The treatment of patients with acute respiratory failure poses an ever-present clinical challenge since conventional ventilation sometimes causes further impairment of lung function. Thus, it is important to identify characteristics of different ventilatory patterns and ventilatory strategies that affect airway pressures, lung volumes, pulmonary gas exchange and hemodynamics. In order to mimic acute respiratory failure in the patient, we have used an experimental animal injury model, characterized by highly unstable alveoli. The basic prerequisite for this thesis was a positive end-expiratory pressure (PEEP) sufficient to keep the lung open throughout the whole ventilatory cycle. Different inspiratory flow patterns were studied by using a successful recruitment procedure together with ventilation performed using PEEP levels below, at, and above the inflection-point pressure. To elucidate the effect of prolonged inspiration time, sufficient PEEP was supplied to prevent end-expiratory collapse already during the reference mode with an inspiration/expiration ratio (I:E ratio) of 1:1. When an I:E ratio of 2:1 or above was used, both studies (one with mean airway pressure constant and the other with total PEEP constant) showed impaired hemodynamics, but displayed unaffected arterial oxygen tension. Decelerating inspiratory flow delivers the major part of the tidal volume during early inspiration under sustained constant inspiratory pressure. This reduces serial dead space and improves alveolar ventilation. In all studies, decelerating inspiratory flow showed increased carbon dioxide elimination, i.e. improved alveolar ventilation, but decelerating inspiratory flow was found to be no better for alveolar recruitment or in oxygenation. In an attempt to explain radiological observations when studying the relationship of pulmonary radiological appearance to end-expiratory pressure, Staubs' concept of quantal alveolar behavior was used. This states that the individual alveolus fills essentially independently of its neighbors and has a propensity to be either air-filled and expanded, or completely fluid-filled and collapsed. Stepwise sequential deflation of the lung from full expansion, followed by stepwise inflation of the lung, produced a pressure/attenuation loop. This hysteresis phenomenon implies that the attenuation of the lung relates to the set PEEP, but also to the immediately preceding structural status. For identical end-expiratory pressures the attenuation on the hysteresis down-slope invariably had a higher value than that of the up-slope. Thus, the pressure at which alveolar collapse takes place differs from that of expansion. In conclusion, ventilation with decelerating inspiratory flow revealed lower peak inspiratory and higher mean airway pressure than did constant inspiratory flow. No differences in end-inspiratory pressure were seen. Decelerating inspiratory flow delivers the major part of the tidal volume during early inspiration, which reduces serial dead space and improves alveolar ventilation. The decelerating inspiratory flow was found to be no better than constant inspiratory flow for alveolar recruitment or oxygenation. When the lung was ventilated with PEEP sufficient to prevent end-expiratory collapse, an inspiration-to-expiration ratio at and above 2:1 impaired hemodynamics. Our results suggest that, in order to obtain and maintain open lung conditions, the lung must be recruited and PEEP reduced to the level just above the alveolar collapse pressure.     

Exogenous Surfactant Preserves Lung Function and Reduces Alveolar Evans Blue Dye Influx in a Rat Model of Ventilation-induced Lung Injury

Background: Changes in pulmonary edema infiltration and surfactant after intermittent positive pressure ventilation with high peak inspiratory lung volumes have been well described. To further elucidate the role of surfactant changes, the authors tested the effect of different doses of exogenous surfactant preceding high peak inspiratory lung volumes on lung function and lung permeability.

Methods: Five groups of Sprague-Dawley rats (n = 6 per group) were subjected to 20 min of high peak inspiratory lung volumes. Before high peak inspiratory lung volumes, four of these groups received intratracheal administration of saline or 50, 100, or 200 mg/kg body weight surfactant; one group received no intratracheal administration. Gas exchange was measured during mechanical ventilation. A sixth group served as nontreated, nonventilated controls. After death, all lungs were excised, and static pressure-volume curves and total lung volume at a transpulmonary pressure of 5 cm H2 O were recorded. The Gruenwald index and the steepest part of the compliance curve (Cmax) were calculated. A bronchoalveolar lavage was performed; surfactant small and large aggregate total phosphorus and minimal surface tension were measured. In a second experiment in five groups of rats (n = 6 per group), lung permeability for Evans blue dye was measured. Before 20 min of high peak inspiratory lung volumes, three groups received intratracheal administration of 100, 200, or 400 mg/kg body weight surfactant; one group received no intratracheal administration. A fifth group served as nontreated, nonventilated controls.

Results: Exogenous surfactant at a dose of 200 mg/kg preserved total lung volume at a pressure of 5 cm H2 O, maximum compliance, the Gruenwald Index, and oxygenation after 20 min of mechanical ventilation. The most active surfactant was recovered in the group that received 200 mg/kg surfactant, and this dose reduced minimal surface tension of bronchoalveolar lavage to control values. Alveolar influx of Evans blue dye was reduced in the groups that received 200 and 400 mg/kg exogenous surfactant.     

The effects of thoracic epidural analgesia with bupivacaine 0.25% on ventilatory mechanics in patients with severe chronic obstructive pulmonary disease

Optimal analgesia is important after thoracotomy in pulmonary-limited patients to avoid pain-related pulmonary complications. Thoracic epidural anesthesia (TEA) can provide excellent pain relief. However, potential paralysis of respiratory muscles and changes in bronchial tone might be unfavorable in patients with end-stage chronic obstructive pulmonary disease (COPD). Therefore, we evaluated the effect of TEA on maximal inspiratory pressure, pattern of breathing, ventilatory mechanics, and gas exchange in 12 end-stage COPD patients. Pulmonary resistance, work of breathing, dynamic intrinsic positive end-expiratory pressure, and peak inspiratory and expiratory flow rates were evaluated by assessing esophageal pressure and airflow. An increase in minute ventilation (7.50 +/- 2.60 vs 8.70 +/- 2.10 L/min; P = 0.04) by means of increased tidal volume (0.46 +/- 0.16 vs 0.53 +/- 0.14 L/breath; P = 0.003) was detected after TEA. These changes were accompanied by an increase in peak inspiratory flow rate (0.48 +/- 0.17 vs 0.55 +/- 0.14 L/s; P = 0.02) and a decrease in pulmonary resistance (20.7 +/- 9.9 vs 16.6 +/- 8.1 cm H(2)O. L(-1). s(-1); P = 0.02). Peak expiratory flow rate, dynamic intrinsic positive end-expiratory pressure, work of breathing, PaO(2), and maximal inspiratory pressure were unchanged (all P > 0.50). We conclude that TEA with bupivacaine 0.25% can be used safely in end-stage COPD patients. IMPLICATIONS: Thoracic epidural anesthesia with bupivacaine 0.25% does not impair ventilatory mechanics and inspiratory respiratory muscle strength in severely limited chronic obstructive pulmonary disease patients. Thus, thoracic epidural anesthesia can be used safely in patients with end-stage chronic obstructive pulmonary disease.     

Changes in respiratory mechanics and gas exchange during the acute respiratory distress syndrome

BACKGROUND: The time course of impairment of respiratory mechanics and gas exchange in the acute respiratory distress syndrome (ARDS) remains poorly defined. We assessed the changes in respiratory mechanics and gas exchange during ARDS. We hypothesized that due to the changes in respiratory mechanics over time, ventilatory strategies based on rigid volume or pressure limits might fail to prevent overdistension throughout the disease process. METHODS: Seventeen severe ARDS patients {PaO2/FiO2 10.1 (9.2-14.3) kPa; 76 (69-107) mmHg [median (25th-75th percentiles)] and bilateral infiltrates} were studied during the acute, intermediate, and late stages of ARDS (at 1-3, 4-6 and 7 days after diagnosis). Severity of lung injury, gas exchange, and hemodynamics were assessed. Pressure-volume (PV) curves of the respiratory system were obtained, and upper and lower inflection points (UIP, LIP) and recruitment were estimated. RESULTS: (1) UIP decreased from early to established (intermediate and late) ARDS [30 (28-30) cmH2O, 27 (25-30) cmH2O and 25 (23-28) cmH2O (P=0.014)]; (2) oxygenation improved in survivors and in patients with non-pulmonary etiology in late ARDS, whereas all patients developed hypercapnia from early to established ARDS; and (3) dead-space ventilation and pulmonary shunt were larger in patients with pulmonary etiology during late ARDS. CONCLUSION: We found a decrease in UIP from acute to established ARDS. If applied to our data, the inspiratory pressure limit advocated by the ARDSnet (30 cmH2O) would produce ventilation over the UIP, with a consequent increased risk of overdistension in 12%, 43% and 65% of our patients during the acute, intermediate and late phases of ARDS, respectively. Lung protective strategies based on fixed tidal volume or pressure limits may thus not fully avoid the risk of lung overdistension throughout ARDS.     

Sodium Nitrite Mitigates Ventilator-induced Lung Injury in Rats

BACKGROUND:: Nitrite (NO2) is a physiologic source of nitric oxide and protects against ischemia-reperfusion injuries. We hypothesized that nitrite would be protective in a rat model of ventilator-induced lung injury and sought to determine if nitrite protection is mediated by enzymic catalytic reduction to nitric oxide. METHODS:: Rats were anesthetized and mechanically ventilated. Group 1 had low tidal volume ventilation (LVT) (6 ml/kg and 2 cm H2O positive end-expiratory pressure; n = 10); group 2 had high tidal volume ventilation (HVT) (2 h of 35 cm H2O inspiratory peak pressure and 0 cm H2O positive end-expiratory pressure; n = 14); groups 3-5: HVT with sodium nitrite (NaNO2) pretreatment (0.25, 2.5, 25 μmol/kg IV; n = 6-8); group 6: HVT + NaNO2 + nitric oxide scavenger 2-(4-carboxyphenyl)-4,5dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3oxide(n = 6); group 7: HVT + NaNO2 + nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (n = 7); and group 8: HVT + NaNO2 + xanthine oxidoreductase inhibitor allopurinol (n = 6). Injury assessment included physiologic measurements (gas exchange, lung compliance, lung edema formation, vascular perfusion pressures) with histologic and biochemical correlates of lung injury and protection. RESULTS:: Injurious ventilation caused statistically significant injury in untreated animals. NaNO2 pretreatment mitigated the gas exchange deterioration, lung edema formation, and histologic injury with maximal protection at 2.5 μmol/kg. Decreasing nitric oxide bioavailability by nitric oxide scavenging, nitric oxide synthase inhibition, or xanthine oxidoreductase inhibition abolished the protection by NaNO2. CONCLUSIONS:: Nitrite confers protection against ventilator-induced lung injury in rats. Catalytic reduction to nitric oxide and mitigation of ventilator-induced lung injury is dependent on both xanthine oxidoreductase and nitric oxide synthases.     

Effects of peak inspiratory flow on development of ventilator-induced lung injury in rabbits

BACKGROUND: A lung-protecting strategy is essential when ventilating acute lung injury/acute respiratory distress syndrome patients. Current emphasis is on limiting inspiratory pressure and volume. This study was designed to investigate the effect of peak inspiratory flow on lung injury. METHODS: Twenty-four rabbits were anesthetized, tracheostomized, ventilated with a Siemens Servo 300, and randomly assigned to three groups as follows: 1) the pressure regulated volume control group received pressure-regulated volume control mode with inspiratory time set at 20% of total cycle time, 2) the volume control with 20% inspiratory time group received volume-control mode with inspiratory time of 20% of total cycle time, and 3) the volume control with 50% inspiratory time group received volume-control mode with inspiratory time of 50% of total cycle time. Tidal volume was 30 ml/kg, respiratory rate was 20 breaths/min, and positive end-expiratory pressure was 0 cm H2O. After 6 h mechanical ventilation, the lungs were removed for histologic examination. RESULTS: When mechanical ventilation started, peak inspiratory flow was 28.8 +/- 1.4 l/min in the pressure regulated volume control group, 7.5 +/- 0.5 l/min in the volume control with 20% inspiratory time group, and 2.6 +/- 0.3 l/min in the volume control with 50% inspiratory time group. Plateau pressure did not differ significantly among the groups. Gradually during 6 h, Pao2 in the pressure regulated volume control group decreased from 688 +/- 39 to a significantly lower 304 +/- 199 mm Hg (P < 0.05) (mean +/- SD). The static compliance of the respiratory system for the pressure regulated volume control group also ended significantly lower after 6 h (P < 0.05). Wet to dry ratio for the pressure regulated volume control group was larger than for other groups (P < 0.05). Macroscopically and histologically, the lungs of the pressure regulated volume control group showed more injury than the other groups. CONCLUSION: When an injurious tidal volume is delivered, the deterioration in gas exchange and respiratory mechanics, and lung injury appear to be marked at a high peak inspiratory flow.     

Low-dose phosphodiesterase inhibition improves responsiveness to inhaled nitric oxide in isolated lungs from endotoxemic rats

BACKGROUND: Inhalation of nitric oxide (NO) and inhibition of phosphodiesterase type 5 (PDE5) selectively dilate the pulmonary circulation in patients with acute lung injury (ALI) associated with pulmonary hypertension. PDE5 inhibitors administered at doses that decrease pulmonary artery pressures have been shown to worsen arterial oxygenation. We investigated the efficacy of doses of PDE5 inhibitors that do not reduce pulmonary artery pressure alone (subthreshold doses) to improve the response to inhaled NO in an animal model of ALI. MATERIALS AND METHODS: Adult Sprague-Dawley rats were pre-treated with 0.5 mg/kg Escherichia coli 0111:B4 endotoxin and 16 to 18 h later, their lungs were isolated perfused and ventilated. The thromboxane mimetic U46619 was used to induce pulmonary hypertension. After the determination of subthreshold doses of two different PDE5 inhibitors, either 50 microg zaprinast or 10 ng sildenafil was added to the perfusate and the decrease of pulmonary artery pressure measured in the presence and absence of inhaled NO. RESULTS: In the presence of 4 or 10 ppm NO, zaprinast (-1.6 +/- 0.4 and -2.9 +/- 0.6 mmHg, respectively) and sildenafil (-1.9 +/- 0.4 and -2.4 + 0.3 mmHg, respectively) improved responsiveness to inhaled NO compared to lungs from rats treated with LPS only (0.7 +/- 0.1 and -1.0 +/- 0.1 mmHg, respectively; P<0.05). Neither zaprinast nor sildenafil prolonged the pulmonary vasodilatory response to inhaled NO. CONCLUSIONS: Subthreshold doses of PDE5 inhibitors improved responsiveness to inhaled NO. Combining inhaled NO with subthreshold doses of PDE5 inhibitors may offer a therapeutic strategy with minimal side-effects in ALI associated with pulmonary hypertension.