Open lung ventilation improves gas exchange and attenuates secondary lung injury in a piglet model of meconium aspiration

OBJECTIVE: Previous studies failed to show clear benefits of high-frequency ventilation compared with conventional positive pressure ventilation (PPV(CON)) in experimental meconium aspiration syndrome. However, none of these studies applied an open lung ventilation strategy (OLC), which aims to reduce intrapulmonary shunt due to alveolar collapse. We hypothesized that, if combined with an open lung strategy, both high-frequency oscillatory ventilation (HFOV(OLC)) and positive pressure ventilation (PPV(OLC)) would improve gas exchange and attenuate ventilator-induced lung injury in experimental meconium aspiration syndrome. DESIGN: Prospective, randomized animal study. SETTING: Research laboratory of a large university. SUBJECTS: Forty-two newborn piglets. INTERVENTIONS: Thirty minutes after intratracheal meconium instillation, 36 newborn piglets were assigned to one of three ventilation groups-PPV(OLC), HFOV(OLC), or PPV(CON)-and ventilated for 5 hrs. In both OLC groups, collapsed alveoli were actively recruited and thereafter stabilized using the lowest possible airway pressures. During PPV(CON), ventilator settings were adjusted to prevent critical hypoxia (Pao2 <60 torr [8 kPa]). Six animals served as saline controls. MEASUREMENTS AND MAIN RESULTS: Compared with the PPV(CON) group, arterial oxygenation and lung mechanics were superior in both OLC groups and the saline controls. Analysis of the bronchoalveolar lavage fluid obtained after 5 hrs of ventilation showed increased myeloperoxidase activity in the PPV(CON) group compared with both OLC groups and saline controls. Alveolar protein influx was not different between the groups. Histologic analysis revealed a higher lung injury score in the PPV(CON) group compared with the PPV(OLC) and the HFOV(OLC) groups. CONCLUSIONS: Application of the OLC during PPV and HFOV is feasible in experimental meconium aspiration syndrome and results in superior oxygenation and less ventilator-induced lung injury compared with PPV(CON).     

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.     

At surfactant deficiency, application of "the open lung concept" prevents protein leakage and attenuates changes in lung mechanics

OBJECTIVE: To evaluate whether mechanical ventilation using "the open lung concept" during surfactant depletion can attenuate the deterioration in pulmonary function. DESIGN: Experimental, comparative study. SETTING: Research laboratory of a large university. SUBJECTS: Eighteen adult male Sprague-Dawley rats, weighing 280-340 g. INTERVENTIONS: Twelve rats were anesthetized, mechanically ventilated with 100% oxygen, and randomly divided into two groups (n = 6 each). The open lung group underwent six saline lavages at different ventilator settings that prevented alveolar collapse. The settings (expressed as frequency/peak inspiratory pressure/positive end-expiratory pressure/inspiratory:expiratory ratio) were 30/26/6/1:2 during the first lavage, 100/27/10/1:1 during the next two lavages, and 100/33/15/1:1 during the last three lavages and during the remaining ventilation period. The ventilated control group underwent six saline lavages with settings at 30/26/6/1:2. After the lavages, peak inspiratory pressure and positive end-expiratory pressure were increased in this group by 2 cm H2O each for the remaining study period. An additional group of six animals were killed immediately after induction of anesthesia and served as healthy controls. Blood gases were measured before lavage, immediately after the last lavage, and thereafter hourly. At the end of the 4-hr study period, we constructed pressure-volume curves from which we determined total lung capacity at a distending pressure of 35 cm H2O (TLC35). Subsequently, total lung volume at a distending pressure of 5 cm H2O (V5) was determined, followed by bronchoalveolar lavage. RESULTS: In the ventilated control group, PaO2, V5, and TLC35 were significantly decreased and protein concentration of bronchoalveolar lavage was significantly increased compared with the healthy control group. In the open lung group, PaO2 did not decrease after the lavage procedure, and V5, TLC35, and the protein concentration of bronchoalveolar lavage were comparable with the healthy controls. CONCLUSION: We conclude that application of the open lung concept during surfactant depletion attenuates deterioration in pulmonary function.     

Exogenous surfactant reduces ventilator-induced decompartmentalization of tumor necrosis factor alpha in absence of positive end-expiratory pressure

OBJECTIVE: To determine the effect of pretreatment with exogenous surfactant on ventilator-induced decompartmentalization of TNF-alpha. DESIGN AND SETTING: Prospective, randomized, animal study in the experimental laboratory of a university. SUBJECTS AND INTERVENTIONS: Male Sprague-Dawley rats (n=102) received lipopolysaccharide either intratracheally or intraperitoneally to stimulate TNF-alpha production; one-half of the animals were pretreated with surfactant. Animals were ventilated for 20 min with a peak inspiratory pressure/positive end-expiratory pressure (PEEP) ratio of either 45/0 or 45/10 (frequency 30 bpm, I/E ratio 1:2, FIO(2)=1). MEASUREMENTS AND RESULTS: Blood gas tension and arterial pressures were recorded 1, 10, and 20 min after the start of mechanical ventilation. After the animals were killed pressure-volume curves were recorded, and bronchoalveolar lavage was performed for assessment of protein content and the small/large surfactant aggregate ratio. TNF-alpha was determined in serum and bronchoalveolar lavage. Pretreatment with surfactant decreased decompartmentalization of TNF-alpha during 45/0 ventilation. Addition of a PEEP level of 10 cm H(2)O reduced decompartmentalization even further. In addition, surfactant prevented deterioration in oxygenation and decreased accumulation of protein in the bronchoalveolar lavage in the zero-PEEP group. CONCLUSIONS: An excess of active surfactant decreases transfer of cytokines across the alveolar-capillary membrane similar to PEEP. The combination of PEEP and surfactant reduces decompartmentalization of TNF-alpha even further.     

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.     

Methylprednisolone does not enhance the surfactant effects on oxygenation and histology in paraquat-induced rat lung injury

OBJECTIVE: To investigate whether exogenous surfactant would improve gas exchange and lung histology and methylprednisolone pretreatment would enhance the surfactant effect in a rat model of paraquat-induced lung injury. SETTING: University research facility. SUBJECTS: Thirty-three adult male Sprague-Dawley rats. INTERVENTIONS: All rats received intraperitoneal paraquat injection (35 mg/kg) and were assigned randomly to one of four groups: the control group received no further treatment; the methylprednisolone group received a concomitant intraperitoneal methylprednisolone injection (30 mg/kg); the surfactant group received intratracheal Survanta (100 mg/kg) at the start of ventilation; and the methylprednisolone + surfactant group received both methylprednisolone and surfactant treatments. MEASUREMENTS AND MAIN RESULTS: Three days after paraquat injection, every rat was ventilated for 90 min, a static pressure-volume curve and bronchoalveolar lavage were performed and postmortem histology was examined. Treatment with surfactant and methylprednisolone + surfactant improved oxygenation relative to the control group and produced significantly higher lung volumes than the control and methylprednisolone groups. Treatment with surfactant resulted in a significant decrease in total cell and neutrophil counts relative to the control group. Surfactant with methylprednisolone pretreatment significantly decreased total cell, macrophage and neutrophil counts when compared with the surfactant group. The histological appearance of the lungs was better in the two surfactant-treated groups. CONCLUSION: Intratracheal instillation of surfactant improves gas exchange, ameliorates lung inflammation and results in less lung damage in paraquat-induced rat lung injury. Surfactant with methylprednisolone pretreatment decreases inflammatory cell infiltration, but cannot further improve oxygenation and lung histology.     

肺表面活性物质稀释剂延迟肺灌洗治疗烟雾吸入性损伤

目的 探讨外源性肺表面活性物质(PS)稀释剂延迟肺灌洗对大鼠严重烟雾吸入伤后内源性PS功能障碍和急性呼吸衰竭的治疗效果.方法 90只Wistar大鼠随机分为5组:Ⅰ组,正常对照(n=14);Ⅱ组,烟雾吸入(n=27);Ⅲ组,烟雾+PS灌洗+机械通气(MV),n=21;Ⅳ组,烟雾+盐水灌洗+MV,n=10;V组,烟雾+MV,n=18.伤后2 h经气管插管注入含PS(100ms/ks)的等渗盐水30 ml/kg或等量盐水行肺灌洗,MV 4 h,观察24 h;检测动脉血气、肺水量、静态肺顺应性(Cst)、支气管肺泡灌洗液(BAIF)蛋白含量、BALF表面张力特性和24 h病死率等.结果 致伤动物伤后立即出现严重缺氧和一氧化碳中毒;Ⅱ组发生急性呼吸衰竭、高通透性肺水肿和PS功能障碍;Ⅲ组Cst和BALF表面张力特性显著改善(P<0.05),但氧合能力、肺水量和BALF蛋白含量无明显好转(P>0.05).Ⅳ、V组疗效不佳.结论 外源性PS稀释剂延迟肺灌洗可一定程度恢复烟雾吸入所致内源性PS功能抑制,改善肺功能,但不能显著减轻高通透性肺水肿和呼吸衰竭,不能降低早期病死率.     

Neutrophil-derived S100A12 in acute lung injury and respiratory distress syndrome

OBJECTIVE: Both persistent accumulation and activation of neutrophils may contribute to the most severe form of acute lung injury, acute respiratory distress syndrome. We analyzed the expression of neutrophil-derived S100A12 and the proinflammatory receptor for advanced glycation end products (RAGE) in patients with acute respiratory distress syndrome. Additional in vivo and in vitro experiments were performed to further analyze the contribution of S100A12 to pulmonary inflammation. SUBJECTS: We included 14 patients with acute respiratory distress syndrome and eight controls. In addition, 16 healthy subjects were included in an experimental lipopolysaccharide challenge model. INTERVENTIONS: Concentrations of S100A12 and soluble RAGE were analyzed in bronchoalveolar lavage fluid. The expression of S100A12 and RAGE in lung biopsies from patients was analyzed by immunohistochemistry. S100A12 was also analyzed in bronchoalveolar lavage fluid from eight healthy subjects after challenge with lipopolysaccharide and compared with eight controls who received placebo inhalation. Effects of S100A12 on endothelial cells were analyzed in vitro. MAIN RESULTS: Patients with acute respiratory distress syndrome had significantly enhanced pulmonary S100A12 expression and higher S100A12 protein concentrations in bronchoalveolar lavage fluid than controls. Levels of soluble RAGE were not significantly elevated in acute respiratory distress syndrome. S100A12 concentrations decreased with time from disease onset. In healthy volunteers, S100A12 was elevated in bronchoalveolar lavage fluid after lipopolysaccharide inhalation. In vitro experiments confirmed strong proinflammatory effects of human S100A12. CONCLUSIONS: S100A12 and its receptor RAGE are found at high concentrations in pulmonary tissue and bronchoalveolar lavage fluid in acute lung injury. S100A12 expression may reflect neutrophil activation during lung inflammation and contribute to pulmonary inflammation and endothelial activation via binding to RAGE.     

超声雾化吸入前列腺素E1在单肺通气期间的肺保护作用

【目的】研究超声雾化吸入前列腺素E1（PGE1）对单肺通气（OLV）患者的肺保护作用。【方法】选择40例OLV手术患者，随机分为两组，P组雾化吸入PGE1，C组为对照组。分别于OLV前10min（T0）、OLV45min（T1）、OLV90min（T2）抽动脉血与混合静脉血行血气分析，并于相应时点测定通气侧肺泡灌洗液（BALF）TNF-α，IL-8，IL-10的浓度。【结果】OLV后两组氧合指数（OI）均下降，但P组较C组下降缓慢，且P组T2较T1有所回升；而Qs／Qt则成相反的趋势；OLV后两组TNF-α，IL-8的浓度均升高，但P组较C组升高较少；IL-10两组OLV后均降低，但P组较C组降低较少。【结论】OLV期间吸入PGE1能改善氧合，降低肺内分流；并能下调IL-8、TNF-α，上调IL-10减轻肺泡炎性反应。     

Bronchoalveolar lavage with a diluted surfactant suspension prior to surfactant instillation improves the effectiveness of surfactant therapy in experimental acute respiratory distress syndrome (ARDS)

Objective: To assess whether bronchoalveolar lavage (BAL) with a diluted surfactant suspension prior to surfactant instillation prevents the only transient improvement in lung function as reported after surfactant instillation in severe acute respiratory distress syndrome (ARDS). Design: Randomized, prospective, experimental study. Setting: Laboratory and animal facility of a large university. Materials: Adult male Sprague-Dawley rats (280 ± 30 g). Interventions: All animals underwent repetitive whole lung saline lavage to induce acute lung injury. Then, animals were randomly divided into seven study groups: the first group received surfactant (150 mg/kg) within 10 min after the last lavage (early treatment), whereas in the other six groups mechanical ventilation was continued for 3 h before treatment (late treatment). Treatment consisted of: surfactant instillation at a dose of 150 mg/kg; at a dose of 250 mg/kg; BAL with saline; BAL with a diluted surfactant suspension (2.5 mg/ml); BAL with saline, immediately followed by surfactant instillation (150 mg/kg) and BAL with a diluted surfactant suspension (2.5 mg/kg), immediately followed by surfactant instillation (150 mg/kg). Measurements and results: Blood gases were measured for 6 h and then BAL was performed to measure the protein concentration and surface tension properties. Mean PaO₂ values increased immediately after surfactant instillation to pre-lavage values but remained stable only in the group that received surfactant immediately after the lavage procedure and the group that underwent BAL with a diluted surfactant suspension prior to surfactant instillation. Conclusion: BAL with a diluted surfactant suspension prior to surfactant instillation at a later time point in lung injury resulted in a stable improvement of lung function. This improvement is comparable with the results seen after surfactant instillation immediately after lung lavage.     

肺表面活性物质和吸入一氧化氮治疗感染性急性肺损伤

目的　研究肺表面活性物质 (Surf)和吸入一氧化氮 (iNO)治疗幼猪感染性腹膜炎诱发急性肺损伤 (ALI)的作用及疗效。方法　健康雄性幼猪 (7 5± 0 5 )kg 30只 ,随机分为 5组 ,每组 6只 :正常组 (N组 ) ,对照组 (C组 ) ,吸入一氧化氮组 (NO组 ) ,肺表面活性物质组 (Surf组 ) ,联合应用Surf和吸入NO组 (SNO组 )。正常组腹腔注射无菌生理盐水后 ,单纯机械通气 ;其余动物腹腔注射标准大肠杆菌菌株诱发ALI后再随机分为四组进行治疗。监测血气 ,呼吸力学 ,支气管肺泡灌洗液 (BALF)成分分析和肺病理改变。结果　腹腔注射大肠杆菌后 4～ 6h动物出现ALI,C组动脉血氧合 (PaO2 /FiO2 )和呼吸系统动态顺应性 (Cdyn)显著性下降 ,治疗后SNO组有较高的PaO2 /FiO2 和Cdyn (与C组比较P <0 0 1) ,肺组织病理损害较轻 ;与SNO组相比 ,单独应用Surf效果稍差 ;NO组对Cdyn肺组织病理损害改善不明显。结论　联合应用Surf和吸入NO能明显改善氧合、肺功能 ,减轻肺病理损害 ,延缓肺损伤的进展     

Open lung ventilation improves functional residual capacity after extubation in cardiac surgery

OBJECTIVE: After cardiac surgery, functional residual capacity (FRC) after extubation is reduced significantly. We hypothesized that ventilation according to the open lung concept (OLC) attenuates FRC reduction after extubation. DESIGN: A prospective, single-center, randomized, controlled clinical study. SETTING: Cardiothoracic operating room and intensive care unit of a university hospital. PATIENTS: Sixty-nine patients scheduled for elective coronary artery bypass graft and/or valve surgery with cardiopulmonary bypass. INTERVENTIONS: Before surgery, patients were randomly assigned to three groups: (1) conventional ventilation (CV); (2) OLC, started after arrival in the intensive care unit (late open lung); and (3) OLC, started directly after intubation (early open lung). In both OLC groups, recruitment maneuvers were applied until Pao2/Fio2 was >375 Torr (50 kPa). No recruitment maneuvers were applied in the CV group. MEASUREMENTS AND MAIN RESULTS: FRC was measured preoperatively and 1, 3, and 5 days after extubation. Peripheral hemoglobin saturation (Spo2) was measured daily till the third day after extubation while the patient was breathing room air. Hypoxemia was defined by an Spo2 value < or =90%. Averaged over the 5 postoperative days, FRC was significantly higher in the early open lung group and tended to be higher in the late open lung group, in comparison with the CV group (mean +/- sem: CV, 1.8 +/- 0.1; late open lung,1.9 +/- 0.1; and early open lung, 2.2 +/- 0.1l). In the CV group, 37% of the patients were hypoxic on the third day after extubation, compared with none of the patients in both OLC groups. CONCLUSIONS: After cardiac surgery, earlier application of OLC resulted in a significantly higher FRC and fewer episodes of hypoxemia than with CV after extubation.     

The open lung concept: pressure controlled ventilation is as effective as high frequency oscillatory ventilation in improving gas exchange and lung mechanics in surfactant-deficient animals

Objective: To demonstrate in experimental animals with respiratory insufficiency that under well-defined conditions, commercially available ventilators allow settings which are as effective as high frequency oscillatory ventilators (HFOV), with respect to the levels of gas exchange, protein infiltration, and lung stability. Design: Prospective, randomized, animal study. Setting: Experimental laboratory of a university. Subjects: 18 adult male Sprague-Dawley rats. Interventions: Lung injury was induced by repeated whole-lung lavage. Thereafter, the animals were assigned to pressure-controlled ventilation (PCV) plus The Open Lung Concept (OLC) or HFOV plus OLC (HFO_OLC). In both groups, an opening maneuver was performed by increasing airway pressures to improve the arterial oxygen tension/fractional inspired oxygen (PaO₂/FIO₂) ratio to L 500 mm Hg; thereafter, airway pressures were reduced to minimal values, which kept PaO₂/FIO₂ L 500 mm Hg. Pressure amplitude was adjusted to keep CO₂ as close as possible in the normal range. Measurements and results: Airway pressure, blood gas tension, and arterial blood pressure were recorded every 30 min. At the end of the 3-h study period, a pressure-volume curve was recorded and bronchoalveolar lavage was performed to determine protein content. After the recruitment maneuver, the resulting mean airway pressure to keep a PaO₂/FIO₂ L 500 mm Hg was 25 ± 1.3 cm H₂O during PCV_OLC and 25 ± 0.5 cm H₂O during HFOV_OLC. Arterial oxygenation in both groups was above L 500 mm Hg and arterial carbon dioxide tension was kept close to the normal range. No differences in mean arterial pressure, lung mechanics and protein influx were found between the two groups. Conclusions: This study shows that in surfactant-deficient animals, PCV, in combination with a recruitment maneuver, opens atelectatic lung areas and keeps them open as effectively as HFOV. Received: 14 October 1998 Final revision received: 11 April 1999 Accepted: 25 June 1999     

猪肺表面活性物质治疗兔油酸型急性呼吸窘迫综合征

目的：探讨肺表面活性物质（PS）对实验性急性呼吸窘迫综合征（ARDS）的治疗作用。方法：油酸诱发新西兰兔ARDS模型后分组（n＝9）治疗4h：1）对照组；2）气管内滴入PS100mg／kg（PS组）。测定动态肺顺应性（Cdyn）、动脉血气和灌洗液的总磷脂（TPL）、总蛋白（TP）、饱和卵磷脂（DSPC）、最小表面张力（STmin）、肺湿干重比（W／D）。结果：治疗后PS组各时点Cdyn和PaO2／FiO2较治疗前和同时点的对照组显著升高，TPL、DSPC／TPL和DSPC／TP较对照组显著增加，STmin和肺W／D明显降低。结论：PS对油酸型ARDS有效，可作为ARDS综合治疗的重要措施之一。     

High frequency oscillatory ventilation attenuates the activation of alveolar macrophages and neutrophils in lung injury

BACKGROUND: Recent investigations have shown that leukocyte activation is involved in the pathogenesis of ventilator-associated lung injury. This study was designed to investigate whether the inflammatory responses and deterioration of oxygenation in ventilator-associated lung injury are attenuated by high-frequency oscillatory ventilation (HFO). We analyzed the effects of HFO compared with conventional mechanical ventilation (CMV) on the activation of pulmonary macrophages and neutrophils in 10 female rabbits. RESULTS: After surfactant depletion, the rabbits were ventilated by CMV or HFO at the same mean airway pressure. Surfactant-depletion followed by 4 h mechanical ventilation hindered pulmonary oxygenation in both groups. Impairment of oxygenation was less severe in the HFO group than in the CMV group. In the HFO group the infiltration of granulocytes into alveolar spaces occurred more readily than in the CMV group. Compared with CMV, HFO resulted in greater attenuation of beta2-integrin expression, not only on granulocytes, but also on macrophages. CONCLUSIONS: In the surfactant-depleted lung, the activation of leukocytes was attenuated by HFO. Reduced inflammatory response correlated with decreased impairment of oxygenation. HFO may reduce lung injury via the attenuation of pulmonary inflammation.     

Closed-loop mechanical ventilation for lung injury: a novel physiological-feedback mode following the principles of the open lung concept

Adherence to low tidal volume (V_T) ventilation and selected positive end-expiratory pressures are low during mechanical ventilation for treatment of the acute respiratory distress syndrome. Using a pig model of severe lung injury, we tested the feasibility and physiological responses to a novel fully closed-loop mechanical ventilation algorithm based on the “open lung” concept. Lung injury was induced by surfactant washout in pigs (n?=?8). Animals were ventilated following the principles of the “open lung approach” (OLA) using a fully closed-loop physiological feedback algorithm for mechanical ventilation. Standard gas exchange, respiratory- and hemodynamic parameters were measured. Electrical impedance tomography was used to quantify regional ventilation distribution during mechanical ventilation. Automatized mechanical ventilation provided strict adherence to low V_T-ventilation for 6 h in severely lung injured pigs. Using the “open lung” approach, tidal volume delivery required low lung distending pressures, increased recruitment and ventilation of dorsal lung regions and improved arterial blood oxygenation. Physiological feedback closed-loop mechanical ventilation according to the principles of the open lung concept is feasible and provides low tidal volume ventilation without human intervention. Of importance, the “open lung approach”-ventilation improved gas exchange and reduced lung driving pressures by opening atelectasis and shifting of ventilation to dorsal lung regions.     

Purine in bronchoalveolar lavage fluid as a marker of ventilation-induced lung injury.

OBJECTIVE: To investigate in a rat model of ventilation-induced lung injury whether metabolic changes in the lung are reflected by an increased purine concentration (adenosine, inosine, hypoxanthine, xanthine, and urate; an index of adenosine-triphosphate breakdown) of the bronchoalveolar lavage fluid and whether purine can, thus, indirectly serve as a marker of ventilation-induced lung injury. DESIGN: Prospective, randomized, controlled trial. SETTING: Research laboratory. SUBJECTS: Forty-two male Sprague-Dawley rats. INTERVENTIONS: Five groups of Sprague-Dawley rats were subjected to 6 mins of mechanical ventilation. One group was ventilated at a peak inspiratory pressure of 7 cm H2O and a positive end-expiratory pressure of 0 cm H2O. A second group was ventilated at a peak inspiratory pressure of 45 cm H2O and a positive end-expiratory pressure of 10 cm H2O. Three groups of Sprague-Dawley rats were ventilated at a peak inspiratory pressure of 45 cm H2O without positive end-expiratory pressure. Before mechanical ventilation, two of these groups received intratracheal administration of saline or exogenous surfactant at a dose of 100 mg/kg and one group received no intratracheal administration. A sixth group served as the nonventilated controls. MEASUREMENTS AND MAIN RESULTS: Bronchoalveolar lavage fluid was collected in which both purine concentration (microM; mean +/- SD) and protein concentration (mg/mL; mean +/- SD) were determined. Statistical differences were analyzed using the one-way analysis of variance (ANOVA) with a Student-Newman-Keul's post hoc test. Purine and protein concentrations were different between groups (ANOVA p value for purine and protein, <.0001). Both purine and protein concentrations in bronchoalveolar lavage fluid were increased in Group 45/0 (3.2 +/- 1.9 and 4.2 +/- 1.6, respectively) compared with Group 7/0 (0.4 +/- 0.1 [p < .05] and 0.4 +/- 0.2 [p < .001]) and controls (0.2 +/- 0.2 [p < .01] and 0.2 +/- 0.1 [p < .001]) and in Group 45/Na (5.8 +/- 2.5 and 4.2 +/- 0.5) compared with Group 7/0 (purine and protein, p < .001) and the controls (purine and protein, p < .001). Positive end-expiratory pressure prevented an increase in purine and protein concentrations in bronchoalveolar lavage fluid (0.4 +/- 0.3 and 0.4 +/- 0.2, respectively) compared with Group 45/0 (purine, p < .01; protein, p < .001) and Group 45/Na (purine and protein, p < .001). Surfactant instillation preceding lung overinflation reduced purine and protein concentration in bronchoalveolar lavage fluid (2.1 +/- 1.6 and 2.7 +/- 1.0) compared with Group 45/Na (purine, p < .001; protein (p < .01). Surfactant instillation reduced protein concentration compared with Group 45/0 (p < .01). CONCLUSIONS: This study shows that metabolic changes in the lung as a result of ventilation-induced lung injury are reflected by an increased level of purine in the bronchoalveolar lavage fluid and that purine may, thus, serve as an early marker for ventilation-induced lung injury. Moreover, the study shows that both exogenous surfactant and positive end-expiratory pressure reduce protein infiltration and that positive end-expiratory pressure decreases the purine level in bronchoalveolar lavage fluid after lung overinflation.     

Bilateral lavage with diluted surfactant improves lung function after unilateral lung contusion in pigs

OBJECTIVE: This study evaluates the effects of bronchoalveolar lavage with diluted surfactant on unilateral lung contusion-induced lung dysfunction. DESIGN: Randomized prospective animal study. SETTING: An animal laboratory. SUBJECTS: Twenty adult pigs, weighing 25-35 kg. INTERVENTIONS: Animals were randomly assigned to controls and surfactant treatment. Bilateral lavage with surfactant treatment began 30 mins after unilateral lung contusion. Then 25 mg/kg of body weight diluted Curosurf (5 mg/mL) was applied in a volume of 5 mL/kg of body weight. Observation time was 8 hrs postinjury. MEASUREMENTS AND MAIN RESULTS: The Pao2/Fio2 ratio fell from 500 to 250 and then recovered gradually in controls and surfactant-treated pigs. After another 4 hrs, the Pao2/Fio2 ratio deteriorated again in controls, but not in surfactant-treated animals. Total compliance fell by 50% after injury but was completely restored by surfactant treatment. Lung contusion increased the median number of neutrophils in bronchoalveolar lavage fluid from 2% to 30% of total cells and peaked >60% at 480 mins in the contused lungs of control pigs. Surfactant-treated pigs had 40% neutrophils at 480 mins without reaching significant difference to controls. The leukocyte neutral proteinase inhibitor increased to 500 ng/mL at 30 mins postinjury in the contused lungs and increased to 2000 ng/mL after surfactant treatment. CONCLUSIONS: Bilateral bronchoalveolar lavage with diluted surfactant can effectively improve lung function after experimental unilateral lung contusion in pigs.     

Host response to intratracheally instilled bacteria in ventilated and nonventilated rats

OBJECTIVE: Pneumonia occurs in approximately 7% of hospitalized patients. Susceptibility to certain bacteria such as Pseudomonas aeruginosa increases in critically ill patients, particularly those requiring mechanical ventilation. Previous studies investigating this susceptibility have used injurious modes of ventilation. The objective of this study was to evaluate the host's response to intratracheal instillation of P. aeruginosa in the setting of noninjurious mechanical ventilation and compare this with normal, spontaneously breathing animals receiving bacteria. DESIGN: Randomized, controlled in vivo animal study. SETTING: Research laboratory at a university-affiliated institution. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: Rats were randomized into four groups: spontaneously breathing given saline, spontaneously breathing given bacteria, mechanically ventilated given saline, and mechanically ventilated given bacteria. The ventilation strategy used involved low stretch (tidal volume of 8 mL/kg) with a positive end-expiratory pressure of 5 cm H2O. MEASUREMENTS AND MAIN RESULTS: Lung compliance, bacterial recovery, surfactant, total cells, and cytokine concentrations in the lung lavage were analyzed after 4 hrs. Results showed that neither ventilation nor bacteria alone altered lung function, although the combination of ventilation and Pseudomonas significantly decreased arterial oxygenation and lung compliance. Increases in lavage cell counts, cytokines, and surfactant were observed in both groups administered bacteria compared with animals given saline. However, there were no significant differences in bacterial recovery, cell counts, cytokines, and surfactant measurements in the groups given bacteria. CONCLUSIONS: These data suggest that bacterial instillation with low-stretch ventilation had a significant effect on lung function but did not alter the inflammatory response to a bacterial challenge over this time course compared with spontaneously breathing animals.