Early detection of acute lung injury uncoupled to hypoxemia in pigs using ultrasound lung comets

OBJECTIVE: Oleic acid-induced lung injury is an established experimental model of acute lung injury in pigs and is considered to reproduce the early exudative phase of acute respiratory distress syndrome. Ultrasound lung comets are an echographic sign of extravascular lung water, originating from thickened interlobular septa. The objective of this study was to evaluate the timing and relationship between the number of ultrasound lung comets, the Pao2/Fio2 ratio, and the static respiratory compliance in an experimental model of oleic acid-induced lung injury in pigs. DESIGN: Laboratory experiment. SETTING: Research institute. SUBJECTS: Ten anesthetized pigs. INTERVENTIONS: Acute lung injury was induced by injection of oleic acid (0.1 mL/kg, intravenously). Ultrasound lung comets, Pao2/Fio2, and static respiratory compliance were measured at baseline and at 15, 30, 60, and 90 mins after the injection of oleic acid. We evaluated ultrasound lung comets by transthoracic echography (7.5-MHz vascular probe), scanning on right and left hemithoraxes at 12 predefined scanning sites. MEASUREMENTS AND MAIN RESULTS: Acute lung injury/acute respiratory distress syndrome was present in all pigs at 90 mins. The number of ultrasound lung comets increased over time and was consistently earlier than the decrease in Pao2/Fio2. At 15 mins, ultrasound lung comets were markedly increased, but no significant changes in Pao2/Fio2 were observed. Accordingly, static respiratory compliance was dramatically reduced at 15 mins compared with baseline (17.04 +/- 1.82 vs. 34.84 +/- 2.62 mL/cm H2O, p < .05). CONCLUSIONS: Ultrasound lung comets, assessed by transthoracic echography, detected extravascular lung water accumulation very early in the course of the oleic acid lung injury in pigs, in the presence of a normal Pao2/Fio2. These results suggest that ultrasound lung comets could be a very early, noninvasive, and simple method to detect and quantify pulmonary edema in acute lung injury.     

Acute oxygenation response to inhaled nitric oxide when combined with high-frequency oscillatory ventilation in adults with acute respiratory distress syndrome

OBJECTIVE: To prospectively evaluate the oxygenation effect of inhaled nitric oxide (INO) delivered during high-frequency oscillatory ventilation in adult patients with the acute respiratory distress syndrome and oxygenation failure. DESIGN Prospective, clinical study. SETTING: Intensive care unit of a university teaching hospital. PATIENTS: A total of 23 adults (14 women, 9 men, 44.9 +/- 17.5 yrs, Acute Physiology and Chronic Health Evaluation II score of 28.6 +/- 7.1) with acute respiratory distress syndrome (lung injury score, 3.5 +/- 0.4) with Fio2 of > or = 0.6 and mean airway pressure of >or=28 cm H2O. INTERVENTIONS: INO was initiated at a dose of 5 ppm, and subsequently titrated according to a protocol, to determine the dose (5, 10, or 20 ppm) resulting in the greatest increase in Pao2/Fio2. Blood gas measurements were obtained 10-15 mins after initiation or any increase in INO dosage to assess the effect on Pao2/Fio2. MEASUREMENTS AND MAIN RESULTS: Arterial blood gases and ventilator settings were recorded at four time points: during conventional ventilation just before initiating high-frequency oscillatory ventilation, during high-frequency oscillatory ventilation just before initiating INO, after 30 mins on the optimal dose of INO, and 8-12 hrs after starting INO. Oxygenation index ([Fio2 x mean airway pressure x 100]/Pao2) and Pao2/Fio2 ratios were calculated at the same time intervals. At 30 mins after INO initiation, 83% of patients had a significant increase in blood oxygen tension, defined as > or = 20% increase in Pao2/Fio2. The mean change in Pao2/Fio2 at 30 mins was 38%. In these 19 patients, Pao2/Fio2 was highest at 20 ppm in four patients, at 10 ppm in eight patients, and at 5 ppm in seven patients. Compared with baseline measurements, Pao2/Fio2 improved significantly at both 30 mins (112 +/- 59 vs. 75 +/- 32, p=.01) and 8-12 hrs after INO initiation (146 +/- 52 vs. 75 +/- 32, p<.0001). In addition, oxygenation index was reduced at 8-12 hrs compared with baseline measurements (26 +/- 13 vs. 40 +/- 17, p=.08). CONCLUSIONS: INO delivered at doses of 5 to 20 ppm during high-frequency oscillatory ventilation increases Pao2/Fio2 and may be a safe and effective rescue therapy for patients with severe oxygenation failure.     

Immediate application of positive-end expiratory pressure is more effective than delayed positive-end expiratory pressure to reduce extravascular lung water

OBJECTIVE: To determine by the measurement of extravascular lung water (EVLW) whether the timing of positive-end expiratory pressure (PEEP) application influences the intensity of lung injury. DESIGN: Animal experimental study. SETTING: Animal experimental laboratory. SUBJECTS: Mixed-breed pigs (n = 18), aged 4 to 5 mos, weighing 25 to 30 kg. INTERVENTIONS: The animals were anesthetized and tracheotomized, after which a permeability pulmonary edema was instigated by infusing oleic acid (0.1/kg) into the central vein. All animals were then randomly divided into three groups. In group 1 (n = 5), 10 cm H2O of PEEP was applied immediately after the oleic acid infusion and maintained throughout the 6 hrs of the experiment. Group 2 (n = 7) received the same level of PEEP 120 mins after the insult for 4 hrs. Group 3 (n = 6), the control group, was ventilated without PEEP for the six hrs of the experiment. MEASUREMENTS AND MAIN RESULTS: At the end of the experiment, EVLW was calculated by gravimetric method. EVLW in group 1 (11.46+/-2.00 mL/kg) was significantly less than in group 2 (19.12+/-2.62 mL/kg) and group 3 (25.81+/-1.57 mL/kg), (p<.0001). Oxygenation also showed important differences by the end of the experiment when the Pao2/Fio2 ratio was significantly better in group 1 (467+/-73) than in group 2 (180+/-82) and group 3 (39+/-9), (p<.0001). CONCLUSIONS: The application of 10 cm H2O of PEEP reduces EVLW in a time-dependent manner and maximum protective effect is achieved if it is applied immediately after lung injury production.     

Surfactant and corticosteroid effects on lung function in a rat model of acute lung injury.

OBJECTIVES: To evaluate pulmonary responses to intratracheal administration of surfactant with and without dexamethasone in rats with paraquat-induced lung injury. DESIGN: Prospective, randomized, controlled study. SETTING: University research facility. SUBJECTS: Adult male Sprague Dawley rats. INTERVENTIONS: Rats were anesthetized and underwent a tracheostomy and arterial catheter insertion 3 days after intraperitoneal injection of paraquat (35 mg/kg). The rats were ventilated for 90 mins after sequential designation as controls or as recipients of intratracheal surfactant alone (50 or 100 mg/kg) or surfactant (50 or 100 mg/kg) plus dexamethasone (0.5 mg/kg). MEASUREMENTS AND MAIN RESULTS: Arterial blood gases were determined at 15, 30, 60, and 90 mins. After 90 mins of ventilation, a static pressure-volume curve was performed, and inflammatory cells, total protein content, and cytokines were measured in bronchoalveolar lavage fluid. Postmortem histology was then examined. Treatment with 50 mg/kg dexamethasone/Survanta and 100 mg/kg Survanta with and without dexamethasone significantly increased oxygenation shortly after instillation when compared with the control group, with the response maintained throughout the study period. Static pressure-volume curves showed that the group receiving 100 mg/kg dexamethasone/Survanta had significantly higher lung volumes than the control group. Total cell, neutrophil, and macrophage counts were decreased significantly in the animals treated with 100 mg/kg dexamethasone/Survanta compared with untreated control rats. Total protein recovered from bronchoalveolar lavage fluid in the animals treated with 100 mg/kg Survanta with and without dexamethasone was decreased significantly compared with control animals. The histologic appearance of the lungs was markedly better in the groups treated with surfactant with or without dexamethasone. CONCLUSIONS: Results suggest that the combined administration of high doses of intratracheal surfactant and dexamethasone improves gas exchange, ameliorates lung inflammation, and alleviates lung damage after paraquat-induced lung injury. Surfactant alone and lower doses of surfactant plus dexamethasone had a lesser effect on these measures.     

Partial liquid ventilation in severely surfactant-depleted, spontaneously breathing rabbits supported by proportional assist ventilation

OBJECTIVE: We hypothesized that partial liquid ventilation (PLV) would improve oxygenation in nonparalyzed, surfactant-deficient rabbits breathing spontaneously while supported by proportional assist ventilation (PAV). This ventilation mode compensates for low pulmonary compliance and high resistance and thereby facilitates spontaneous breathing. DESIGN: Randomized trial. SETTING: University animal research facility. SUBJECTS: Twenty-six anesthetized New Zealand white rabbits weighing 2592 +/- 237g (mean +/- sd). INTERVENTIONS: After pulmonary lavage (target Pao2 <100 mm Hg on mechanical ventilation with 6 cm H2O of positive end-expiratory pressure [PEEP] and an Fio2 of 1.0), rabbits were randomized to PAV (PEEP of 8 cm H2O) with or without PLV. PLV rabbits received 25 mL/kg of perfluorocarbon by intratracheal infusion (1 mL/kg/min). Pao2, Paco2, tidal volume, respiratory rate, minute ventilation, mean airway pressure, arterial blood pressure, heart rate, pulmonary compliance, and airway resistance were measured. Evaporated perfluorocarbon was refilled every 30 mins in PLV animals. After 5 hrs, animals were killed and lungs were removed. Lung injury was evaluated using a histologic score. MAIN RESULTS: Pao2 and compliance were significantly higher in PLV rabbits compared with controls (p <.05, analysis of variance for repeated measures). All other parameters were similar in both groups. CONCLUSIONS: PLV improved oxygenation and pulmonary compliance in spontaneously breathing, severely surfactant-depleted rabbits supported by PAV. The severity of lung injury by histology was unaffected.     

Local effect of lung contusion on lung surfactant composition in multiple trauma patients.

OBJECTIVE: The aim of this study was to investigate the direct influence of lung contusion on pulmonary surfactant in multiple trauma patients. DESIGN: Prospective, nonrandomized study. SETTING: University hospital, trauma intensive care unit. PATIENTS: Eighteen multiple trauma patients with unilateral lung contusions and Injury Severity Scores >19 were studied prospectively. INTERVENTIONS: Bronchoalveolar lavage was performed daily until either day 7 or extubation. Samples from the side of lung contusion (n = 62) and the contralateral, uninjured side (n = 62) were obtained at the same time in 14 patients. Total phospholipids, total phospholipid classes, and surfactant apoprotein A were quantified. Additionally, surfactant function was measured with a pulsating bubble surfactometer in four patients. All data are presented as mean +/- SEM. Statistical analyses were performed using programs of SPSS for Windows 6.1.3 (SPSS Inc., Chicago, IL) (Student's t-test; p < .05). MEASUREMENTS AND MAIN RESULTS: Total phospholipids were significantly increased on the side of lung contusion (contusion side, 40+/-7 microg/mL; contralateral side, 21+/-3 microg/mL; p = .004). The percentage contents of phosphatidylcholine (contusion side, 87.1%+/-1.0%; contralateral side, 84.3%+/-1.0%; p = .04) and sphingomyelin (contusion side, 2.9%+/-0.3%; contralateral side, 1.9%+/-0.2%; p = .004) were significantly higher. In contrast, the percentage content of phosphatidylglycerol was significantly decreased (contusion side, 4.1%+/-0.1%; contralateral side, 6.9%+/-0.6%; p = .001). No alterations were found for the relative contents of phosphatidylethanolamine (contusion side, 2.4%+/-0.2%; contralateral side, 2.2%+/-0.2%; p = .47), phosphatidylinositol (contusion side, 3.5%+/-0.4%; contralateral side, 4.6%+/-0.5%; p = .06), and surfactant apoprotein A (contusion side, 7177+/-1404 ng/mL; contralateral side, 4513+/-787 ng/mL, p = .10). There was no statistical difference for minimal surface tension measured with the pulsating bubble surfactometer after 5 mins of oscillation (contusion side, 29.5+/-2.3 mN/m; contralateral side, 23.7+/-2.1 mN/m; p = .08). CONCLUSIONS: Direct damage of lung parenchyma by lung contusion alters the composition of surfactant. No additional changes in surfactant function were observed that would argue in favor of functional compensation.     

Topical inhibition of nuclear factor-kappaB enhances reduction in lung edema by surfactant in a piglet model of airway lavage

OBJECTIVE: Acute respiratory distress syndrome is occasionally seen in newborn infants due to a severe inflammatory process in the lungs that affects capillary-alveolar permeability, epithelial integrity, and type I and II pneumocyte function. The aim of this study was to investigate the effect of a topically applied nuclear factor-kappaB inhibitor (IkappaB kinase-NF-kappaB essential modulator binding domain [IKK-NBD] peptide) on gas exchange, lung function, lung fluids, and inflammation in a piglet model of repeated airway lavage that is characterized by surfactant deficiency, lung edema, and an inflammatory response. DESIGN: Prospective, randomized, controlled animal study. SETTING: Research laboratory of a university children's hospital. SUBJECTS: A total of 24 anesthetized, mechanically ventilated newborn piglets. INTERVENTIONS: Repeated airway lavage was carried out until both the Pao2 decreased to approximately 40 mm Hg, while ventilating the piglets with an Fio2 of 0.6, and a peak inspiratory pressure of >/=18 cm H2O was needed to maintain tidal volume at 6 mL/kg. One group of piglets served as a control (n = 8), a second group (S, n = 8) received a porcine surfactant preparation (Curosurf), and a third group received IKK-NBD peptide admixed to surfactant (S+IN, n = 8). MEASUREMENTS AND MAIN RESULTS: After 6 hrs of mechanical ventilation after intervention, S+IN group piglets showed decreased extravascular lung water (S+IN vs. S, 20 +/- 3 vs. 28 +/- 10 mL/kg; p < .05) and a lesser protein content in the epithelial lining fluid (S+IN vs. S, 38 +/- 5 vs. 50 +/- 5 mg/L; p < .05). Functional residual capacity (S+IN vs. S, 16.7 +/- 6.3 vs. 12.2 +/- 4.3 mL/kg; p < .05), alveolar volume (S+IN vs. S, 5.4 +/- 1.8 vs. 4.6 +/- 1.5 mL/kg; p < .05), and lung mechanics were improved. Bronchoalveolar lavage showed a lesser percentage of polymorphonuclear leukocytes (S+IN vs. S, 70% +/- 6% vs. 82% +/- 3%; p < .01) and a reduction in the chemokine leukotriene B4 (S+IN vs. S, 2.0 +/- 0.6 vs. 3.5 +/- 1.4 pg/mL; p < .01). CONCLUSIONS: A topically applied nuclear factor-kappaB inhibitor improves lung edema and lung volumes and reduces inflammation in this newborn piglet model of airway lavage.     

Effects of endothelin receptor antagonism on acute lung injury induced by chlorine gas

OBJECTIVE: To test the hypothesis that the endothelin system is involved in chlorine gas-induced lung injury. DESIGN: Experimental study. SETTING: Academic research laboratory. SUBJECTS: Twenty-four domestic juvenile pigs. INTERVENTIONS: Anesthetized, ventilated pigs were exposed to chlorine gas (400 parts per million in air) for 20 mins and then randomly allocated to four groups (n=6 in each group). The tezosentan pretreatment group received the dual endothelin receptor antagonist tezosentan 20 mins before and hyperoxic gas (Fio2 0.6) after chlorine gas exposure. The tezosentan postinjury treatment group received hyperoxic gas after chlorine gas exposure and tezosentan 60 mins later. Animals in the oxygen group received hyperoxic gas after chlorine gas exposure. Pigs in the fourth group (air) were ventilated with room air (Fio2 0.21) throughout the experiment. MEASUREMENTS AND MAIN RESULTS: Hemodynamics, gas exchange, lung mechanics, and plasma endothelin-1 were evaluated for 6 hrs. Chlorine gas exposure induced an increase in circulating endothelin-1 by 90% (p<.05). The acute chlorine gas-induced rise in pulmonary vascular resistance was partly blocked by tezosentan pretreatment (p<.001). Tezosentan postinjury treatment also decreased pulmonary vascular resistance to levels significantly lower than in the air and oxygen groups (p<.001). Recovery of peak airway pressure was better in the tezosentan-treated groups than in the air group. There were significant linear relationships between circulating endothelin-1 and pulmonary vascular resistance (r=.47, p<.001) and endothelin-1 and peak airway pressure (r=.41, p<.001). These relationships were modified by tezosentan. CONCLUSIONS: Tezosentan modified chlorine gas-induced pulmonary dysfunction, indicating that the endothelin system is involved in this mode of acute lung injury.     

Pumpless extracorporeal lung assist for protective mechanical ventilation in experimental lung injury

OBJECTIVE: To test the hypothesis that ventilation with 3 mL/kg tidal volume combined with extracorporeal CO2 removal by arteriovenous interventional lung assist reduces ventilator-associated organ injury in experimental acute lung injury when compared with ventilation with 6 mL/kg tidal volume without interventional lung assist. DESIGN: Prospective, randomized, controlled trial. SETTING: A university research laboratory. SUBJECTS: A total of 14 pigs weighing 46 +/- 4 kg (mean +/- sd). INTERVENTIONS: Acute lung injury was induced by repeated lung lavages until Pao2 was <100 mm Hg, with Fio2 of 1.0 and positive end-expiratory pressure of 5 cm H2O, for 1 hr without additional lavages. Animals were randomized to an interventional group with a tidal volume of 3 mL/kg with interventional lung assist (n = 7) or to a control group with a tidal volume of 6 mL/kg without interventional lung assist (n = 7) for 24 hrs. Organ function in vivo was determined by laboratory analyses, including calculations of pulmonary ventilation/perfusion distribution. Histologic assessment of organ injury was performed post mortem after 24 hrs. MEASUREMENTS AND MAIN RESULTS: In both groups, gas exchange improved in the course of the study (p < .05). However, in contrast to control animals, animals with lower tidal volumes and interventional lung assist had severe ventilation/perfusion mismatch, as indicated by increased perfusion to lung areas with a low ventilation/perfusion ratio (p < .05). Other variables of organ function in vivo and results of histologic examination post mortem did not reveal any statistical difference between groups. CONCLUSIONS: Combined ventilation with lower tidal volumes and extracorporeal CO2 removal as compared with traditional low tidal volumes without extracorporeal CO2 removal is not associated with differences in organ injury. Obviously, ventilation with tidal volumes of <6 mL/kg may cause pulmonary de-recruitment when positive end-expiratory pressure is not adequately increased.     

Recruitment maneuvers during prone positioning in patients with acute respiratory distress syndrome

OBJECTIVE: To evaluate the interaction of recruitment maneuvers and prone positioning on gas exchange and venous admixture in patients with early extrapulmonary acute respiratory distress syndrome ventilated with high levels of positive end-expiratory pressure. We hypothesized that a sustained inflation performed after 6 hrs of prone positioning would induce sustained improvement in oxygenation (Pao2/Fio2) and venous admixture. DESIGN: Prospective, interventional study. SETTING: Tertiary care, postoperative intensive care unit. PATIENTS: Fifteen patients with early extrapulmonary acute respiratory distress syndrome. INTERVENTIONS: After 6 hrs of prone positioning, a sustained inflation was performed with 50 cm H2O maintained for 30 secs. Data were recorded in supine position, after 6 hrs of prone positioning, at 3, 30, and 180 mins following the sustained inflation. MEASUREMENTS AND MAIN RESULTS: A response to prone positioning was observed in nine of 15 patients leading to an improvement of Pao2/Fio2 (147 +/- 37 torr vs. 225 +/- 77 torr, p = .005) and venous admixture (35.4 +/- 8.3% vs. 28.9 +/- 9.8%, p = .001). Six patients did not respond to prone positioning. Following the sustained inflation, the responders to prone positioning showed a further increase of Pao2/Fio2 and decrease of venous admixture at 3 mins (Pao2/Fio2, 225 +/- 77 torr vs. 368 +/- 90 torr, p = .018; venous admixture, 28.9 +/- 9.8% vs. 18.9 +/- 6.7%, p = .05). In all six nonresponders to prone positioning, an improvement of Pao2/Fio2 and venous admixture occurred at 3 mins following the sustained inflation (128 +/- 18 torr vs. 277 +/- 59 torr, p = .03; venous admixture, 34.2 +/- 6.0% vs. 23.8 +/- 6.3%, p = .05). The beneficial effects of the sustained inflation remained significantly elevated over 3 hrs in responders and nonresponders to prone positioning. CONCLUSION: In patients with early extrapulmonary acute respiratory distress syndrome, a sustained inflation performed after 6 hrs of prone positioning induced further and sustained improvement of oxygenation and venous admixture in both responders and nonresponders to prone positioning.     

Natural inhibitors of neutrophil function in acute respiratory distress syndrome

OBJECTIVE: Neutrophils play a key role in the physiopathogenesis of acute lung injury in general and acute respiratory distress syndrome (ARDS) in particular. To identify the anti-inflammatory mediators with a protective effect on lung tissue damage in ARDS, we correlated the concentration of the Clara cell 16-kD protein (CC16; an inhibitor of neutrophil chemotaxis), angiogenin (an inhibitor of degranulation), and the total radical oxygen neutralizing activity with the amount of elastase (a marker of neutrophil activation) and with the Pao2/Fio2 ratio, which is inversely related to lung injury. SETTING: University hospital. PATIENTS: Patients with ARDS (n = 12) and patients at risk for developing ARDS (n = 14). INTERVENTIONS: Patients underwent bronchoalveolar lavage 12 hrs after diagnosis of ARDS or at-risk status. MEASUREMENTS AND MAIN RESULTS: The amount of CC16 and radical oxygen neutralizing activity was not significantly different in patients with or at risk for ARDS. In contrast, the amount (mean +/- sem) of angiogenin in the bronchoalveolar lavage of ARDS patients (45 +/- 14 ng/mL, n = 12) was increased 11-fold (p <.05) compared with patients at risk for ARDS (4 +/- 1 ng/mL, n = 14). In patients with ARDS, the amount of protein and angiogenin in bronchoalveolar lavage increased with decreasing concentration of CC16 (p <.05). In addition, CC16 correlated with the Pao2/Fio2 ratio (p <.05) and inversely with the amount of elastase (p <.05) and thus may be regarded as a reliable protective agent for lung injury. CONCLUSION: A high concentration of CC16, a natural inhibitor of neutrophil function, decreases neutrophil-mediated lung damage of patients with ARDS. Strategies to increase natural anti-inflammatory agents, and thus influence the disruption of the balance between natural inflammatory and anti-inflammatory or protective factors, could be useful to modulate the tissue destruction and the course of ARDS.     

Comparison of prone positioning and high-frequency oscillatory ventilation in patients with acute respiratory distress syndrome

OBJECTIVE: Both prone position and high-frequency oscillatory ventilation (HFOV) have the potential to facilitate lung recruitment, and their combined use could thus be synergetic on gas exchange. Keeping the lung open could also potentially be lung protective. The aim of this study was to compare physiologic and proinflammatory effects of HFOV, prone positioning, or their combination in severe acute respiratory distress syndrome (ARDS). DESIGN:: Prospective, comparative randomized study. SETTING: A medical intensive care unit. PATIENTS: Thirty-nine ARDS patients with a Pao2/Fio2 ratio <150 mm Hg at positive end-expiratory pressure > or =5 cm H2O. INTERVENTIONS: After 12 hrs on conventional lung-protective mechanical ventilation (tidal volume 6 mL/kg of ideal body weight, plateau pressure not exceeding the upper inflection point, and a maximum of 35 cm H2O; supine-CV), 39 patients were randomized to receive one of the following 12-hr periods: conventional lung-protective mechanical ventilation in prone position (prone-CV), HFOV in supine position (supine-HFOV), or HFOV in prone position (prone-HFOV). MEASUREMENTS AND MAIN RESULTS: Prone-CV (from 138 +/- 58 mm Hg to 217 +/- 110 mm Hg, p < .0001) and prone-HFOV (from 126 +/- 40 mm Hg to 227 +/- 64 mm Hg, p < 0.0001) improved the Pao2/Fio2 ratio whereas supine-HFOV did not alter the Pao2/Fio2 ratio (from 134 +/- 57 mm Hg to 138 +/- 48 mm Hg). The oxygenation index ({mean airway pressure x Fio2 x 100}/Pao2) decreased in the prone-CV and prone-HFOV groups and was lower than in the supine-HFOV group. Interleukin-8 increased significantly in the bronchoalveolar lavage fluid (BALF) in supine-HFOV and prone-HFOV groups compared with prone-CV and supine-CV. Neutrophil counts were higher in the supine-HFOV group than in the prone-CV group. CONCLUSIONS: Although HFOV in the supine position does not improve oxygenation or lung inflammation, the prone position increases oxygenation and reduces lung inflammation in ARDS patients. Prone-HFOV produced similar improvement in oxygenation like prone-CV but was associated with higher BALF indexes of inflammation. In contrast, supine-HFOV did not improve gas exchange and was associated with enhanced lung inflammation.     

Open lung ventilation preserves the response to delayed surfactant treatment in surfactant-deficient newborn piglets

OBJECTIVE: Delayed surfactant treatment (>2 hrs after birth) is less effective than early treatment in conventionally ventilated preterm infants with respiratory distress syndrome. The objective of this study was to evaluate if this time-dependent efficacy of surfactant treatment is also present during open lung ventilation. DESIGN: Prospective, randomized controlled animal study. SETTING: University-affiliated research laboratory. SUBJECTS: Thirty-eight newborn piglets. INTERVENTIONS: Following repeated whole-lung lavage, animals were randomly allocated to conventional positive pressure ventilation (PPVCON) using a positive end-expiratory pressure (PEEP) of 5 cm H2O and a tidal volume of 7 mL/kg or open lung positive pressure ventilation (PPVOLV). During PPVOLV, collapsed alveoli were actively recruited and thereafter stabilized with sufficient PEEP. Within each ventilation group, animals received surfactant (25 mg/kg) either after 2 hrs (PPVCON-2 and PPVOLV-2) or after 4 hrs (PPVCON-4 and PPVOLV-4) of ventilation. A control group received surfactant immediately after lung lavage. Following surfactant administration, all animals were conventionally ventilated for an additional 2 hrs. MEASUREMENTS AND MAIN RESULTS: Two hours after surfactant treatment, both oxygenation and lung mechanics showed a clear deterioration in the PPVCON-4 group compared with PPVCON-2 and the control group. However, this deterioration of the surfactant response over time was not observed during PPVOLV. Analysis of the bronchoalveolar lavage fluid obtained at the end of the experiment showed that the protein concentration and the conversion of large to small aggregate surfactant was significantly higher in the PPVCON-4 group compared with the PPVCON-2 group while comparable in both PPVOLV groups. In addition, interleukin-8 and myeloperoxidase levels tended to be higher in the PPVCON-4 group compared with the PPVOLV-4 group. CONCLUSIONS: In contrast to conventional ventilation, open lung ventilation preserves the response to delayed surfactant treatment in surfactant-deficient newborn piglets. This sustained response is accompanied by an attenuation of secondary lung injury.     

Hypoxemic reperfusion after 120 mins of intestinal ischemia attenuates the histopathologic and inflammatory response

OBJECTIVE: It has been suggested that reactive oxygen species play a pivotal role in the initial organ-tissue injury during reperfusion, eliciting inflammatory reaction and multiple organ failure. It was investigated if hypoxemic reperfusion attenuates tissue injury and inflammatory response. DESIGN: Randomized animal study. SETTING: Medical school laboratory. SUBJECTS: Twenty-five male pigs weighing 25-28 kg. INTERVENTIONS: Pigs were subjected to 120 mins of intestinal ischemia by clamping the superior mesenteric artery. Upon declamping, the animals were randomly assigned to receive either hypoxemic reperfusion (HR group, n = 9) reperfused with a Pao2 = 30-35 or normoxemic reperfusion (control group, n = 16) reperfused with a Pao2 = 100 mm Hg for 120 mins. Fluids without inotropes were given to combat circulatory shock during reperfusion. MEASUREMENTS AND MAIN RESULTS: Portal blood and intestinal and lung biopsies were collected at baseline, end of ischemia, and end of reperfusion. Histopathologic changes were scored, and interleukin-1beta, qualitative Limulus amebocyte, lysate test, and Pao2/Fio2 were measured. Eight of 16 animals of the control group and seven of nine of the HR group survived (p = .22). At the end of reperfusion, the intestinal (p = .004) and lung (p = .028) pathologic scores were lower in the HR group compared with controls. The only significant difference in concentration of interleukin-1beta in the portal blood between the two animal groups occurred 120 mins after reperfusion (p = .006). The number of HR animals with a positive Limulus test was significantly smaller compared with controls at 60 (p = .041) and 120 (p = .07) mins of reperfusion. During the period of ischemia, the Pao2/Fio2 decreased similarly in the control and HR group, whereas after 120 mins of reperfusion the rate was significantly higher in the HR group. CONCLUSIONS: Hypoxemic reperfusion represents an intervention that may attenuate the triggering of multifactorial cascade and organ tissue injury.     

Repeated derecruitments accentuate lung injury during mechanical ventilation

OBJECTIVE: This study was performed to test the hypothesis that derecruitment itself might accentuate lung injury during mechanical ventilation. SETTING: Randomized, controlled trial. SETTING: Experimental laboratory. SUBJECTS: New Zealand White rabbits (2.8-3.5 kg). INTERVENTION: Twenty-four rabbits were ventilated in pressure-controlled mode with constant tidal volume (10 mL/kg). After lung injury was induced by repeated saline lavage (PaO2 <100 torr, 13.3 kPa), a pressure-volume curve was drawn to calculate the lower inflection point (Pflex), and randomization was done. The control group (n = 8) received ventilation with positive end-expiratory pressure (PEEP) fixed at Pflex for 3 hrs. The nonderecruitment group (n = 8) was ventilated at PEEP of 2 mm Hg (2.7 cm H2O) for the initial hour and then PEEP of Pflex for the remaining 2 hrs. The derecruitment group (n = 8) was ventilated for 3 hrs with six 30-min cycles consisting of 10 mins at PEEP of 2 mm Hg (2.7 cm H2O) and 20 mins at PEEP of Pflex to induce repeated derecruitments. MEASUREMENTS AND MAIN RESULTS: Variables of gas exchange, mechanics, and hemodynamics were measured, and histologic evaluation was done. In the control group, Pao2 remained >500 torr (66.7 kPa) for 3 hrs. In the nonderecruitment group, PaO2 was 40 +/- 16 (mean +/- SD) torr (5.3 +/- 2.1 kPa) at 1 hr but increased to >500 torr (66.7 kPa) for the remaining 2 hrs after increase in PEEP to Pflex. In the derecruitment group, there was progressive decline in Pao2 with each derecruitment to 220 +/- 130 torr (29.3 +/- 17.3 kPa) at 3 hrs (p <.05 compared with other groups). Histologically there was more hyaline membrane formation in the derecruitment group compared with control (p <.05) and significantly higher mean bronchiolar injury score in the derecruitment group (1.92 +/- 0.78) than both control (0.50 +/- 0.50) and nonderecruitment (0.78 +/- 0.42) groups (p <.05). CONCLUSION: Repeated derecruitments can accentuate lung injury during mechanical ventilation.     

Insulin attenuates endotoxin-induced acute lung injury in conscious rats

OBJECTIVES: To investigate the effects of insulin on the acute lung injury induced by lipopolysaccharide using a conscious rat model. DESIGN: Prospective, randomized, controlled animal study. SETTING: University research laboratory. SUBJECTS: A total of 190 adult male Sprague-Dawley rats weighing 250-300 g. INTERVENTIONS: Endotoxemia was induced by intravenous infusion of lipopolysaccharide. Lipopolysaccharide at various doses (0, 1, 5, 10, 20, and 30 mg/kg, n=10 for each dose) was administered intravenously in 20 mins. Insulin infusion at doses of 0.5, 1, and 5 microU/kg/min was given 5 mins before lipopolysaccharide administration. Plasma glucose was clamped at 90-110 mg/dL by infusion of 10-80% glucose solution. Insulin and glucose infusion (0.01 mL/min) was started 5 mins before lipopolysaccharide and continued for 120 mins. The rats received a total of 60, 120, and 600 microU/kg insulin as well as 0.12, 0.36, and 0.96 g of glucose in respective groups. The animals were then observed for 4 hrs. MEASUREMENTS AND MAIN RESULTS: The extent of acute lung injury was evaluated by lung weight/body weight ratio, lung weight gain, protein concentration in bronchoalveolar lavage, and exhaled nitric oxide. We also measured plasma nitrate/nitrite and methyl guanidine. In addition, histopathologic changes of the lung were examined. Lipopolysaccharide caused systemic hypotension and severe acute lung injury with increases in plasma nitrate/nitrite and methyl guanidine. Pretreatment with insulin infusion at doses of 0.5, 1, and 5 microU/kg/min mitigated or prevented systemic hypotension and the development of acute lung injury, depending on the dose. Insulin also attenuated the lipopolysaccharide-induced increases in nitrate/nitrite and methyl guanidine. CONCLUSIONS: Insulin is effective in reducing or preventing the lipopolysaccharide-induced increases in plasma nitrate/nitrite and methyl guanidine and the occurrence of acute lung injury.     

Response to exogenous surfactant is different during open lung and conventional ventilation

OBJECTIVE: Previous studies have shown that the efficacy of exogenous surfactant is dose-dependent during conventional positive pressure ventilation (PPVCON). The present study aimed to determine whether this dose-dependent relationship is also present during open lung (OLC) ventilation. We also explored the effect of exogenous surfactant on the ventilation pressures applied during ventilation. DESIGN: Animal study. SETTING: University-affiliated research laboratory. SUBJECTS: Seventy-two newborn piglets. INTERVENTIONS: After repeated whole lung lavage, animals were randomly allocated to two surfactant groups receiving either 100 mg/kg surfactant (S100) or 25 mg/kg surfactant (S25) or to a control group receiving a bolus of air. Within each group, animals were randomly assigned to either PPVCON, open lung PPV (PPVOLC), or open lung high-frequency oscillatory ventilation (HFOVOLC) and ventilated for 5 hrs. MEASUREMENTS AND MAIN RESULTS: The ventilation pressures decreased in a dose-dependent way, showing the largest reduction in the S100 group. In both OLC groups, oxygenation, lung mechanics, and polymorphonuclear neutrophils analyzed in bronchoalveolar lavage were independent of the surfactant dose. In the PPVCON group, however, there was a clear dose-dependency, resulting in a deterioration of oxygenation and lung mechanics and an increase in polymorphonuclear neutrophils as the surfactant dose decreased. Although comparable between the three ventilation groups, bronchoalveolar lavage interleukin-8 concentrations significantly increased in all ventilation groups as the surfactant dose increased. Alveolar protein influx and conversion of large to small aggregate surfactant were higher during PPVCON compared with both OLC groups. There were no differences in the surfactant treatment response between PPVOLC and HFOVOLC. CONCLUSION: Exogenous surfactant enables a reduction in ventilation pressures. Compared with PPVCON, the efficacy of surfactant treatment is less dose-dependent during open lung ventilation. Surfactant conversion during open lung ventilation is reduced compared with PPVCON. Exogenous surfactant seems to up-regulate bronchoalveolar lavage interleukin-8 concentrations, independent of the ventilation strategy.     

Alveolar recruitment in combination with sufficient positive end-expiratory pressure increases oxygenation and lung aeration in patients with severe chest trauma

OBJECTIVE: Investigation of oxygenation and lung aeration during mechanical ventilation according to the open lung concept in patients with acute lung injury or acute respiratory distress syndrome. DESIGN: Retrospective analysis. SETTING: Surgical intensive care unit of a university hospital. PATIENTS: We retrospectively identified 17 patients with acute lung injury/acute respiratory distress syndrome due to pulmonary contusion who had thoracic helical computed tomography scans before and after ventilation with the open lung concept. INTERVENTIONS: Baseline ventilation consisted of low tidal volumes (< or =6 mL/kg) and positive end-expiratory pressure (PEEP; 5-17 cm H2O). We briefly applied high inspiratory pressures for opening up collapsed alveoli. External PEEP and intrinsic PEEP were combined to keep recruited lung units open. We generated intrinsic PEEP by pressure-cycled high-frequency inverse ratio ventilation (80 min, inspiratory/expiratory ratio 2:1) and maintained our ventilatory strategy for 24 hrs. Then, after reducing total PEEP by decreasing respiratory rate, Pao2/Fio2 ratio was reevaluated. If it remained >300 mm Hg, weaning was started. If not, previous ventilator settings were resumed for another 24 hrs after recruiting the lungs once again. MEASUREMENTS AND MAIN RESULTS: Physiologic variables and ventilator settings were obtained from routine charts. Data from computed tomography before and after the open lung concept were analyzed for volumetric quantification of lung aeration and collapse. All results are presented as median and range. During baseline ventilation, PEEP was 10 (range, 5-17) cm H2O and after recruitment 21 (range, 18-26) cm H2O. Opening pressures were 65 (range, 50-80) cm H2O. After recruitment, Pao2/Fio2 ratio was higher in all patients. Total lung volume increased from 2915 (range, 1952-4941) to 4247 (range, 2285-6355) mL and normally aerated volume from 1742 (range, 774-2941) to 2971 (range, 1270-5232) mL. Atelectasis decreased significantly from 604 (range, 147-1538) to 106 (range, 0-736) mL. Hyperinflation increased significantly from 5 (range, 0-188) to 62 (range, 1-424) mL, whereas poor aeration did not change substantially from 649 (range, 302-1292) to 757 (range, 350-1613) mL. No hemodynamic problems occurred. CONCLUSIONS: Lung recruitment increased arterial oxygenation, normally aerated lung volume, and total lung volume while decreasing the amount of collapsed tissue. These results indicate that the open lung concept is a reasonable mode of ventilation for patients with severe chest trauma.     

Extravascular lung water determined with single transpulmonary thermodilution correlates with the severity of sepsis-induced acute lung injury

OBJECTIVE: To find out if the extravascular lung water index (EVLWI) and the derived permeability indexes determined by the single transpulmonary thermodilution technique are associated with markers of acute lung injury in human septic shock. DESIGN: Prospective, observational study. SETTING: Mixed intensive care unit of a 900-bed university hospital. PATIENTS: Thirty-eight consecutive adult patients with septic shock and acute lung injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The variables were assessed over a 72-hr period and included hemodynamics, EVLWI, and pulmonary vascular permeability indexes determined with the single indicator transpulmonary thermodilution technique, lung compliance, oxygenation ratio (Pao2/Fio2), lung injury score, cell counts, and the plasma concentration of endothelin-1. At day 1, EVLWI was elevated (>or=7 mL/kg) in 28 (74%) patients and correlated with lung compliance (r=-.48, p=.002), Pao2/Fio2 (r=-.50, p=.001), lung injury score (r=.46, p=.004), roentgenogram quadrants (r=.39, p=.02), and platelet count (r=-.43, p=.007). At day 3, EVLWI correlated with compliance (r=-.51, p=.002), Pao2/Fio2 (r=-.49, p = .006), and lung injury score (r=.53, p=.003). At day 3, EVLWI and pulmonary vascular permeability indexes were higher in nonsurvivors (p<.05). The plasma concentration of endothelin-1 (mean+/-sd) was significantly higher in patients with elevated EVLWI (>or=7 mL/kg) (3.85+/-1.40 vs. 2.07+/-0.38 pg/mL, respectively). Twenty-two (59%) patients died before day 28. CONCLUSIONS: In human septic shock, EVLWI demonstrated moderate correlation with markers of acute lung injury, such as lung compliance, oxygenation ratio, roentgenogram quadrants, and lung injury score. In nonsurvivors, EVLWI and permeability indexes were significantly increased at day 3. Thus, EVLWI might be of value as an indicator of prognosis and severity of sepsis-induced acute lung injury.     

High-frequency oscillatory ventilation of the perfluorocarbon-filled lung: dose-response relationships in an animal model of acute lung injury

OBJECTIVE: To examine dose-response relationships regarding the efficiency of gas exchange and hemodynamic function during high-frequency oscillation and partial liquid ventilation (HFO-PLV) of the perfluorocarbon (PFC)-treated lung in a model of acute lung injury. SETTING: An animal research laboratory in a university medical center. DESIGN: A prospective, randomized study comparing animals receiving varying doses (0, 5, 15, and 20 mL/kg) of perflubron during high-frequency oscillatory ventilation (HFOV) with mean airway pressure (Paw) optimized to achieve a minimal percutaneous oxygen saturation (Spo2). SUBJECTS: Nineteen healthy swine (mean weight 28.9 kg) with saline lavage-induced acute lung injury. METHODS: Animals were treated with repetitive saline lavage to achieve a uniform degree of acute lung injury (Spo2 < or =90% on an Fio2 of 1.0). After lung injury, subjects were converted to HFOV, and lung volume was optimized. HFO-PLV was initiated by instillation of perflubron at a rate of 0.5 mL.kg-1.min-1 to achieve total doses of 5, 15, and 20 mL/kg. After PFC dosing, the only experimental manipulation consisted of adjustment of Paw to achieve an Spo2 of 90% +/- 2% with Fio2 of 0.6. Gas exchange, hemodynamic variables, and pulmonary mechanics data were collected over a 1-hr period. Five control animals were not dosed with perflubron and remained on HFOV for the 1-hr period of data collection. MEASUREMENTS AND MAIN RESULTS: After lung volume recruitment with HFOV, the initiation of HFO-PLV was best tolerated with the two lower doses in our protocol. There were essentially no changes in Paco2 or pH between groups over the dosing interval. After dosing, analysis of variance demonstrated a PFC dose-dependent effect for oxygenation index (p =.01) only; the lowest oxygenation index was found in the 15 mL/kg group (p =.01). In the 15 mL/kg group, the Paw decreased steadily from 20.6 +/- 3.4 cm H2O at the end of dosing to 18.0 +/- 4.9 cm H2O at 60 mins. The Pao2 increased from 113 +/- 51 torr (15.06 +/- 6.79 kPa) to 134 +/- 49 torr (17.86 +/- 6.53 kPa) during this period and was associated with a decreasing oxygenation index (from 11.4 +/- 2.0 to 9.3 +/- 1.5). The cardiac index and pulmonary vascular resistance did not change significantly during the dosing period and were relatively stable after the completion of dosing. CONCLUSIONS: The combination of HFOV and perflubron administration was well tolerated hemodynamically and was not associated with deterioration of gas exchange during dosing. Our data suggest that the optimal dose of perflubron to achieve the lowest oxygenation index during HFO-PLV is between 5 and 15 mL/kg. The combination of HFOV and perflubron administration is a novel strategy in the treatment of acute lung injury that shows some promise and merits additional investigation. We hope in future studies to address the histopathologic effects of varying perflubron doses during HFOV in a long-term study of the lung-protective effects of HFO-PLV.