吸入一氧化氮治疗对内毒素所致急性肺损伤肺泡液体清除影响的实验研究

目的 观察吸入不同浓度一氧化氮(NO)对急性肺损伤(ALI)时肺水肿形成、肺泡液体清除和渗出的影响,并探讨其治疗机制,为临床选择吸入NO(iNO)治疗ALI及其治疗方式提供理论依据.方法 健康雄性新西兰大耳白兔18只,建立内毒素脂多糖(LPS)所致肺损伤模型(0 h).将动物随机均分成3组:①机械通气(MV)组:行容积控制通气(VCV),潮气量(VT)15 ml/kg,呼气末正压(PEEP)5 cm H2O(1 cm H2O=0.098 kPa),通气频率40次/min;②高iNO(HNO)组:在MV组治疗基础上给予40×10-6 NO吸入;③低iNO(LNO)组:在MV组基础上加10×10-6 NO吸入.检测通气后不同时间点各组大鼠血流动力学、血气分析、呼吸力学等指标.通气4 h后放血处死动物,计算肺湿/干重(W/D)比值,并观察肺泡液体渗出情况.结果 ①治疗后0.5 h,HNO组和LNO组的氧合指数(PaO2/FiO2)显著高于MV组,并维持到实验结束(P均＜0.05).②治疗后0.5、2和4 h,LNO组气道峰压(Ppeak)和平台压(Pplat)较MV组下降(P＜0.05或P＜0.01);HNO组4 h时的Ppeak、2 h和4 h的Pplat低于MV组(P＜0.05或P＜0.01);LNO组2 h和4 h时的Pplat明显低于HNO组(P均＜0.01).③HNO组和LNO组肺泡液体渗出少于MV组(F=22.756,P＜0.01),肺泡液体清除多于MV组(F=3.965,P＜0.05),肺组织W/D比值MV组＞HNO组＞LNO组(F=11.740,P＜0.01).④HNO组和LNO组的肺损伤评分好于MV组,但差异无统计学意义.结论 ALI早期iNO治疗可显著促进肺泡液体清除、改善肺泡液体渗出、减轻肺水肿、改善氧合和降低气道压,相对较低浓度(10×10-6)吸入治疗可能更有益.     

Combining partial liquid ventilation with nitric oxide to improve gas exchange in acute lung injury

Objective: To assess the effects of increasing concentrations of inhaled nitric oxide (NO) during incremental dosages of partial liquid ventilation (PLV) on gas exchange, hemodynamics, and oxygen transport in pigs with induced acute lung injury (ALI). Design: Prospective experimental study. Setting: Experimental intensive care unit of a university. Subjects: 6 pigs with induced ALI. Interventions: Animals were surfactant-depleted by lung lavage to a partial pressure of oxygen in arterial blood (PaO₂) < 100 mmHg. They then received four incremental doses of 5 ml/kg perflubron (LiquiVent). Between each dose the animals received 0, 10, 20, 30, 40, and 0 parts per million (ppm) NO. Measurements and main results: Blood gases, hemodynamic parameters, and oxygen delivery were measured after each dose of perflubron as well as after each NO concentration. Perflubron resulted in a dose-dependent increase in PaO₂. At each perflubron dose, additional NO inhalation resulted in a further significant (ANOVA, p < 0.05) increase in PaO₂, with a maximum effect at 30 ± 10 ppm NO. The 5 ml/kg perflubron dose led to a significant decrease in mean pulmonary artery pressure, which decreased further with higher NO concentrations. Conclusions: PLV can be combined with NO administration and results in a cumulative effect on arterial oxygenation and to a decrease in pulmonary artery pressure, without having any deleterious effect on measured systemic hemodynamic parameters. Received: 29 April 1996 Accepted: 24 October 1996     

Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration

Objective Meconium aspiration induces acute lung injury (ALI) and subsequent pulmonary arterial hypertension (PAH) which may lead to right ventricular failure. Increase of endothelin-1, thromboxane-A, and phosphodiesterases are discussed molecular mechanisms. We investigated the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration. Design Animal study. Setting University-affiliated research laboratory. Subjects White farm pigs. Interventions Acute lung injury was induced in 24 pigs by instillation of meconium. Animals were randomly assigned to four groups to receive either intravenous tezosentan, inhalational iloprost, or combined tezosentan and iloprost, or to serve as controls. Measurements and results After meconium aspiration-induced lung injury each treatment increased oxyhemoglobin saturations (TEZO: 88 ± 6% (p = 0.02), ILO: 85 ± 13% (p = 0.05), TEZO-ILO: 89 ± 6% (p = 0.02), control: 70 ± 18%). TEZO but not ILO significantly decreased pulmonary arterial pressure and pulmonary vascular resistance (both p < 0.01). ILO alone decreased intrapulmonary shunt blood flow (p < 0.01). Compared with control, TEZO-ILO yielded the highest arterial partial pressure of oxygen (70 ± 6 torr vs.49 ± 9 torr, p = 0.04), although it decreased arterial blood pressure (change from 71 ± 13 mmHg to 62 ± 12 mmHg vs.85 ± 14 mmHg to 80  ± 11 mmHg (p = 0.01). Conclusions Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration. Inhaled ILO improves gas exchange only, thereby reducing intrapulmonary shunt blood flow. Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

卡托普利对急性肺损伤大鼠肺气体交换的影响

目的:探讨卡托普利对急性肺损伤(ALI)大鼠肺气体交换的影响。方法:36只Wistar大鼠随机平均分成对照组、烟雾致伤组(ALI组)和卡托普利干预组(CAP组)。CAP组腹腔注射卡托普利(5mg/kg),对照组和ALI组腹腔注射等量生理盐水。15min后复制烟雾吸入性ALI模型。致伤后5min、5h分别采动脉血行血气分析,光镜观察肺病理变化。结果:ALI组血氧分压(PaO2)、动脉血氧饱和度(SaO2)及氧合指数(PaO2/FiO2)呈进行性下降,与对照组相比差异有显著性(P<0.01),肺病理改变明显。CAP组致伤后5hPaO2及PaO2/FiO2较5min显著改善(P<0.01),与ALI组相比差异有显著性(P<0.01),肺病理改变较轻。结论:卡托普利能明显改善ALI时肺的气体交换。     

控制性肺膨胀对急性肺损伤患者肺气体交换及氧代谢的影响

目的　通过观察控制性肺膨胀 (SI)同小潮气量通气模式结合对急性肺损伤 (ALI)患者肺气体交换及氧代谢的影响 ,探讨SI的疗效及其最佳压力值。方法　选择严重创伤并发ALI的患者 31例 ,确诊ALI后 2 4h内入重症监护室 (ICU)予机械通气治疗。先予小潮气量通气模式 (基础阶段 )通气 1h ,然后分别给予 2 0cmH2 O× 30s(SI1 )、30cmH2 O× 30s(SI2 )、40cmH2 O× 30s(SI3)、50cmH2 O× 30s(SI4 )的SI各通气 1h ,在基础通气 1h、SI后 1h以及回到基础通气 1h各时点监测肺气体交换及氧代谢指标。结果　与基础通气模式相比 ,SI1 及SI2 后各指标无明显变化 ,SI3和SI4 后氧分压 (PaO2 )显著提高 ,分别由(92 0± 1 4 2 )mmHg上升至 (1 2 1 3± 1 6 9)mmHg和 (1 2 0 4± 1 7 0 )mmHg ,P <0 0 1 ,氧输送指数 (DO2 I)也显著提高 ,肺内分流率(Qs/Qt)显著减少 ,而当SI结束后 ,所有数据均回到基础通气状态。并且我们发现SI3和SI4 对氧合的改善作用无显著性差异。结论　SI同小潮气量通气模式结合治疗ALI患者时 ,可显著改善肺气体交换及氧合功能。 40cmH2 O为SI的最佳压力值     

High-dose furosemide alters gas exchange in a model of acute lung injury

Furosemide is often used to reduce edema in patients with acute respiratory distress syndrome (ARDS). It was hypothesized that furosemide would reduce lung water and improve gas exchange in a phorbol-myristate acetate (PMA) model of acute lung injury. Two groups of mongrel dogs received PMA (25 to 30 μ/kg) and continuous saline at 10 mL/kg/h; one group received PMA plus two 1-mg/kg doses of furosemide at 1 and 2 hours after PMA. Arterial blood gases on F₁O₂ = 1.0 and double-dilution lung water were measured at intervals over 7 hours. In dogs receiving PMA + furosemide, AaDO₂ and shunt fraction increased compared with dogs receiving PMA only (AaDO₂, P = .014; shunt, P = .017). There were no significant differences between the groups in lung water (P = .34) during the experiment or in wet/dry weight postmortem. Urine flow was markedly reduced in both groups; the kidneys appeared unresponsive to the diuretic effects of furosemide. Significant elevations in hematocrit and pulmonary vascular resistance were seen in furosemide-treated compared with PMA-only dogs. In this model of ARDS, which results in the absence of effective kidney function and multiple organ failure, furosemide compromises alveolar-capillary gas exchange and fails to influence the time course of lung water accumulation. The results suggest that the nondiuretic affects of furosemide cannot explain its purported clinical utility in ARDS.     

Surfactant treatment impairs gas exchange in a canine model of acute lung injury

The effectiveness of surfactant (SURF) treatment in acute lung injury in the adult is controversial. In this study, we tested the effectiveness of early surfactant treatment in a commonly used animal model of acute lung injury, phorbol-myristate acetate (PMA), to see if it would attenuate the progression of lung injury. We measured the effect on lung compliance and whether positive end-expiratory pressure (PEEP) (10 cm H2O) during SURF administration had a synergistic effect. METHODS: Four groups of anesthetized dogs were studied: a) normals; b) PMA injury only; c) PMA injury + SURF; and d) PMA + SURF + PEEP. Lung injury was induced with 25-30 microg/kg of PMA. Responses were measured over 7 hrs. Surfactant was administered in the form of Survanta, 4 x 25 mg/kg doses via tracheal instillation 2.5 hrs after PMA. For the group receiving PEEP, 10 cm H2O PEEP was begun 1.5 hrs after PMA, 1 hr before SURF. Postmortem, the left lung was excised and inflated three times to total lung capacity (volume at 30 cm H2O) and expiratory compliance was measured with 25-100 mL volume increments. The trachea was then clamped and trapped volume was determined by water displacement. RESULTS: PMA-induced lung injury significantly reduced expiratory compliance and total lung capacity (p < .05 from normal). Wet/dry lung weights did not differ between groups. SURF without PEEP further decreased lung compliance as compared with PMA only. CONCLUSIONS: SURF administration after PMA injury causes marked reductions in lung compliance when no PEEP is coadministered. However, the loss of static expiratory lung compliance appears partly ameliorated by application of PEEP + SURF. Given that tracheal instillation of SURF is known to acutely elevate lung impedance in the first few hours after administration, coadministration of PEEP appears to be critically important in counteracting these early effects of surfactant instillation on the lung.     

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).     

Nitric oxide inhalation increases alveolar gas exchange by decreasing deadspace volume

OBJECTIVE: To test the hypothesis that nitric oxide inhalation facilitates CO2 elimination by decreasing alveolar deadspace in an ovine model of acute lung injury. DESIGN: Prospective, placebo-controlled, randomized, crossover model. SETTING: University research laboratory. SUBJECTS: Eleven mixed-breed adult sheep. INTERVENTIONS: To induce acute lung injury, hydrochloric acid was instilled into the tracheas of paralyzed sheep receiving controlled mechanical ventilation. Each sheep breathed 0 ppm, 5 ppm, and 20 ppm nitric oxide in random order. MEASUREMENTS AND MAIN RESULTS: Estimates of alveolar deadspace volumes and arterial-to-end tidal CO2 partial pressure differences were used as indicators of CO2 elimination efficiency. At a constant minute ventilation, nitric oxide inhalation caused dose-independent decreases in Paco2 (p <.05), alveolar deadspace (p <.01), and arterial-to-end tidal CO2 partial pressure differences (p <.01). We found that estimates of arterial-to-end tidal CO2 partial pressure differences may be used to predict alveolar deadspace volume (r2 =.86, p <.05). CONCLUSIONS: Estimates of arterial-to-end tidal CO2 partial pressure differences are reliable indicators of alveolar deadspace. Both values decreased during nitric oxide inhalation in our model of acutely injured lungs. This finding supports the idea that nitric oxide inhalation facilitates CO2 elimination in acutely injured lungs. Future studies are needed to determine whether nitric oxide therapy can be used to reduce the work of breathing in selected patients with cardiopulmonary disorders.     

Decelerating inspiratory flow waveform improves lung mechanics and gas exchange in patients on intermittent positive-pressure ventilation

The effects of two inspiratory flow waveforms (WFs), decelerating and constant have been studied in 14 patients undergoing intermittent positive-pressure ventilation (IPPV). With tidal volume (VT), inspiratory time, inspiratory-expiratory (I/E) ratio and frequency being kept constant, the decelerating waveform produced statistically significant reduction of peak pressure, total respiratory resistance, work of inspiration, ratio of dead space to tidal volume (VD/VT) and alveolar-arterial gradient for oxygen (A-a)PO2. There was significant increase in total static and kinetic compliances and PaO2, with no significant changes in PaCO2, in cardiac output (CO) and in other haemodynamic measurements.     

The contribution of arterio-venous extracorporeal lung assist to gas exchange in a porcine model of lavage-induced acute lung injury

This prospective large-animal study was performed to evaluate the contribution of arterio-venous extracorporeal lung assist (AV-ECLA) to pulmonary gas exchange in a porcine lavage-induced acute lung injury model. Fifteen healthy female pigs, weighing 50.3 +/- 3.8 kg (mean +/- SD), were included. After induction of general anaesthesia and controlled ventilation, an arterial line and a pulmonary artery catheter were inserted. Saline lung lavage was performed until the PaO2 decreased to 51 +/- 16 mmHg. After a stabilization period of 60 min, the femoral artery and vein were cannulated and a low-resistance membrane lung was interposed. Under apnoeic oxygenation, variations of sweep-gas flow were performed every 20 min in order to evaluate the membrane lung's efficacy, in terms of carbon dioxide (CO2) removal and oxygen (O2) uptake. Although AV-ECLA is highly effective in eliminating CO2, if combined with apnoeic oxygenation, normocapnia was not achievable. AV-ECLA's contribution to oxygenation during severe hypoxemia was antagonized by a significant increase in the pulmonary shunt fraction.     

Plasma cGMP levels in air embolism-induced acute lung injury

Purpose: An impaired generation of cGMP may account for the pulmonary hypertension seen in acute lung injury (ALI). We investigated the hemodynamic changes and the plasma levels of cGMP during air embolism-induced ALI in two different models: venous air infusion (VAI) and massive air embolism (MAE). Materials and Methods: After a baseline hemodynamic evaluation, anesthetized dogs received a VAI (0.2 mL/kg/min, N = 10) or a bolus of air (MAE, 2.5 mL/kg, N = 10) intravenously. A group of control dogs (n = 5) received no further treatment. Hemodynamic evaluation was performed 5 to 60 minutes after the VAI was initiated or after the MAE. Blood samples were drawn for plasma cGMP determinations. Results: The VAI increased the pulmonary artery pressure (by 181%, P < .05) after 15 minutes of air infusion without changing the cardiac index. The MAE increased the pulmonary artery pressure (by 252%) and decreased the cardiac index (by 31%) 5 minutes after the air injection (both P < .05). These variables returned to baseline 15 to 30 minutes thereafter. The cGMP concentrations remained unaltered during the VAI. In contrast, cGMP levels increased 26% (P < .05) by 15 minutes after the MAE and returned to basal levels thereafter. Conclusion: These findings suggest that a lack of increase in the production of the cGMP may account for the pulmonary hypertension seen in air embolisminduced ALI. Additionally, the small increase in cGMP levels after the MAE may reflect the more severe hemodynamic derangement in this setting. Copyright © 2000 by W.B. Saunders Company     

高氧所致小鼠急性肺损伤时一氧化氮合成酶的表达

目的探讨一氧化氮合成酶(INOS,eNOS)在高氧所致急性肺损伤发病过程中的作用.方法将54只小鼠置于密闭的氧气室暴露于＞95%的高氧,另18只小鼠呼吸正常空气作为对照组;分别于24、48h和72 h取出小鼠,评价肺损伤程度同时进行支气管肺泡灌洗液细胞分类和计数;免疫组织化学测定肺组织iNOS和eNOS的表达及组织分布.结果高氧能引起急性肺损伤伴支气管肺汽灌洗液细胞总数、巨噬细胞、中性粒细胞数均明显增加;免疫组织化学研究显示iNOS和eNOS蛋白主要表达于气道上皮细胞、血管平滑肌细胞和巨噬细胞的胞浆中,它们在气道上皮细胞的表达在高氧环境下明显升高.结论在高氧环境下一氧化氮合成酶通过促进肺组织中一氧化氮合成从而在高氧所致的急性肺损伤过程中发挥重要作用.     

Dose-dependent effects of almitrine on hemodynamics and gas exchange in an animal model of acute lung injury

Objective: To determine the dose-response relationship of almitrine (Alm) on pulmonary gas exchange and hemodynamics in an animal model of acute lung injury (ALI).¶Design: Prospective, randomized, controlled study.¶Methods: Twenty anesthetized, tracheotomized and mechanically ventilated (FIO₂ 1.0) pigs underwent induction of ALI by repeated saline washout of surfactant. Animals were randomly assigned to either receive cumulating doses of Alm intravenously (0.5, 1.0, 2.0, 4.0, 8.0 and 16.0 μg · kg^–1· min^–1) for 30 min each (treatment; n = 10) or to receive the solvent malic acid (controls; n = 10).¶Measurements and results: Measurements of pulmonary gas exchange and hemodynamics were performed at the end of each infusion period. Alm < 4.0 μg · kg^–1· min^–1 improved arterial oxygen pressure (PaO₂) (105 ± 9 mmHg for Alm 1.0 vs 59 ± 5 mmHg) and decreased intrapulmonary shunt (Q_s/Q_t) (32 ± 4 % for Alm 1.0 vs 46 ± 4 %) (P < 0.05). Alm ≥ 8.0 μg · kg^–1· min^–1 did not improve pulmonary gas exchange compared to controls. When compared to low doses of Alm < 4.0 μg · kg^–1· min^–1, high doses ≥ 8.0 μg · kg¹· min^–1 decreased PaO₂ (58 ± 11 mmHg for Alm 16.0) and increased Q_s/Q_t (67 ± 10 % for Alm 16.0) (P < 0.05).¶Conclusions: In experimental ALI, effects of almitrine on oxygenation are dose-dependent. Almitrine is most effective when used at low doses known to mimic hypoxic pulmonary vasoconstriction.