一氧化氮和一氧化氮合成酶在急性肺损伤的作用

急性肺损伤(acute lung injury,ALI)是一种发病率和死亡率都很高的常见临床疾病. 目前,对ALI病理生理学基础和临床研究方面的了解越来越多,但并没有提出新的治疗策略能够明显改善ALI的治疗.在ALI的动物模型和患者中,一氧化氮合成酶(nitric oxide synthases,NOS)表达及活性增强和一氧化氮(NO)的增多在ALI的病理生理过程中有重要作用;但临床抑制NO生成以及选择性抑制NOS并没有对ALI的治疗有明显效果.目前提出了不同细胞源性NO的概念,这种NO的细胞源性差异可能对ALI的治疗有潜在的意义.现综述NO和NOS在ALI中的作用.     

丙泊酚镇静对急性肺损伤/急性呼吸窘迫综合征患者血液动力学及氧合的影响

目的观察丙泊酚镇静对急性肺损伤(ALI)/急性呼吸窘迫综合征(ARDS)患者行机械通气时血液动力学和肺氧合功能的影响。方法18例实施机械通气的ALI/ARDS患者随机分为丙泊酚组(P组,镇静诱导和维持用丙泊酚)和咪唑安定组(M组,镇静诱导和维持用咪唑安定)。根据Ramsay分级标准调整两组用药量。记录两组患者镇静诱导前即刻(T0)、镇静诱导后1h(T1)、5h(T2)、9h(T3)和12h(T4)血液动力学变化,同时采集上述各时点中心静脉血、股动脉血测定血气,计算肺内动静脉分流率(Qs/Qt)和氧合指数(OI)。结果(1)与T0时比较,T1～T4时两组患者MAP、HR下降(P<0.05);(2)与M组比较,T2～T4时P组Qs/Qt下降、OI升高(P<0.05)。结论丙泊酚镇静有利于改善机械通气时ALI/ARDS患者氧合,可为其病因治疗和肺损伤的修复赢得时间。     

急性肺损伤/急性呼吸窘迫综合征液体治疗策略

背景 高通透性肺水肿是急性肺损伤/急性呼吸窘迫综合征(acute lung injury/acute respiratory distress syndrome,ALI/ARDS)的基本病理生理特征,其程度与ALI/ARDS的预后密切相关.目的 对ALI/ARDS患者合理的液体管理,有助于改善ALI/ARDS患者的肺水肿,降低该病病死率.内容 回顾了ALI/ARDS液体治疗策略探索过程中存在争议的问题(如限制性或开放性的液体治疗策略及治疗液体种类的选择),总结了该领域近年来的研究进展(如ALI/ARDS病程不同阶段的差异化治疗及液体治疗的监测指标).趋向 今后将进一步探索该病在不同的病理生理状态下特异性的液体治疗方法,寻求高效敏感的监测指标,指导液体治疗策略的选择和调整.     

Uptake of inhaled nitric oxide in acute lung injury

Background: Despite the widespread use of inhaled nitric oxide (NO), little is known of its pulmonary uptake in patients with acute respiratory failure.
Methods: Fourteen patients with acute lung injury (ALI) and ongoing NO therapy were studied. Three doses of NO (5, 10 and 40 ppm) were given for 20 min and at each dose level the following parameters were recorded: minute ventilation, inspiratory NO cone, mixed expired NO cone, end-tidal NO cone, mixed expired CO₂ cone, end-tidal CO₂ cone and arterial CO₂ tension. Total uptake was calculated and correlated to the total amount of NO inhaled, the amount of NO administered to the alveolar space, and the amount of NO administered to the perfused alveolar space.
Results: About 35% of the total amount of NO delivered is taken up by the lungs, 70% of NO administered to the alveolar space is taken up, and 95–100% of the NO administered to perfused alveolar space is taken up. The size of the alveolar dead space varied between 10 and60% of the alveolar space. At 40 ppm of inhaled NO there was no difference between inspired and mixed expired NO₂ concentration, indicating that there is no significant NO₂ formation taking place in the lungs during NO inhalation at the concentrations studied.
Conclusions: Practically all NO administered to the perfused alveolar space is taken up. The total uptake differs from that of healthy persons probably because of differences in the alveolar dead space.     

Inhaled nitric oxide lowers pulmonary capillary pressure and changes longitudinal distribution of pulmonary vascular resistance in patients with acute lung injury

In acute lung injury (ALI), where pulmonary microvascular permeability is increased, transvascular fluid filtration depends mainly on the hydrostatic capillary pressure. In the presence of intrapulmonary vasoconstriction pulmonary capillary pressure (PCP) may increase thereby promoting transvascular fluid filtration and lung oedema formation. We studied the effect of 40 ppm inhaled nitric oxide (NO) on PCP and longitudinal distribution of pulmonary vascular resistance (PVR) in 18 patients with ALI.
PCP was estimated by visual analysis of the pressure decay profile following pulmonary artery balloon inflation. Contribution of venous pulmonary resistance to total PVR was calculated as the percentage of the pressure gradient in the pulmonary venous system to the total pressure gradient across the lung.
Inhalation of 40 ppm NO produced a prompt decrease in mean pulmonary artery pressure (PAP) from 34.1 6.8 to 29.65.7 (s.d.) mmHg; ( P < 0.0001). PCP declined from 24.86.2 to 21.65.2 mmHg; ( P < 0.0001) while pulmonary artery wedge pressure (PAWP) did not change. PVR decreased from 16673 to 12850 dyn sec cm^-5; ( P < 0.0001). Pulmonary venous resistance (PVRven) decreased to a greater extent (from 7641 to 5028 dyn. sec. cm^-5; ( P < 0.001) than pulmonary arterial resistance (PVRart) (from 9036 to 7929 dyn sec cm^-5; ( P < 0.01). The contribution of PVRven to PVR feU from 44.310.8 to 37.811.9%; ( P < 0.01). Cardiac output (CO) remained constant. The findings demonstrate that NO has a predominant vasodilating effect on pulmonary venous vasculature thereby lowering PCP in patients with ALI.     

Combination of inhaled nitric oxide therapy and inverse ratio ventilation in patients with sepsis-associated acute respiratory distress syndrome

Inverse ratio ventilation (IRV) is a ventilatory technique that uses an inspiratory to expiratory ratio (I:E) greater than 1:1. We studied the effects of mechanical ventilation with an I:E of 1:3, 1:1, and 2:1 on arterial oxygenation in 10 patients with sepsis-associated acute respiratory distress syndrome (ARDS). At each I:E, patients received 0 and 4 ppm of inhaled nitric oxide (INO) in random order for 30 min. Respiratory and cardiovascular parameters were measured. Of the 10 patients studied, 7 responded to IRV and 3 did not. An increase in the I:E and the addition of INO significantly improved arterial oxygenation in the responders (p < 0. 0001 and p < 0.006, respectively). The combination of an increase in the I:E and INO had an additive effect on arterial oxygenation. The combined use of IRV and INO is a more effective method of avoiding hypoxemia than either INO or IRV alone.     

肝移植术后急性肺损伤/急性呼吸窘迫综合征的研究进展

急性肺损伤/急性呼吸窘迫综合症（ALI/ARDS）是肝移植术后常见的并发症,可延长受者术后重症监护室入住时间,影响肝移植手术疗效,病情严重可致受者死亡,临床中引起了肝移植外科医师的高度重视。肝移植术后ALI/ARDS可由肺源性因素（例如机械通气相关肺损伤、肺部感染、误吸等）直接导致,也可由非肺源性因素（例如肺部以外的严重感染、输血、缺血-再灌注损伤等）间接导致。本文对肝移植术后ALI/ARDS的诊断标准及发生情况、发生机制、危险因素、实验室及临床诊断方法以及治疗方法等进行综述,加深对肝移植围手术期ALI/ARDS的理解与认知,以期为肝移植术后ALI/ARDS的诊治提供借鉴。     

Prone positioning ventilation for treatment of acute lung injury and acute respiratory distress syndrome

Patients who are diagnosed with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) usually have ventilation-perfusion mismatch, severe decrease in lung capacity, and gas exchange abnormalities. Health care work-ers have implemented various strategies in an attempt to compensate for these pathological alterations. By rotating patients with ALI/ARDS between the supine and prone position, it is possible to achieve a significant improvement in PaO2/FiO2, decrease shunting and therefore improve oxy-genation without use of expensive, invasive and experimen-tal procedures.     

The role of nitric oxide in cardiac surgery

The release of nitric oxide (NO) from coronary endothelial cells is impaired following reperfusion; however, several experimental studies have found that it exerts a cardioprotective effect during myocardial ischemiareperfusion. Thus, attempts have been made to supplement NO production exogenously during reperfusion when endogenous NO release may be diminished. Conversely, other studies suggest that NO exacerbates reperfusion injury by inducing the production of peroxynitrite. NO has also been reported to provide beneficial effects as a selective pulmonary vasodilator to relieve pulmonary hypertension. A loss of NO-mediated relaxation caused by the dysfunction of endothelial cells is characteristic of intimal hyperplasia, and nitrosovasodilators have proven efficient against atherosclerotic coronary heart disease, which may be attributable to their antiplatelet effects as well as to vasodilation. Furthermore, protamine sulfate, which is rich inl-arginine, is thought to augment NO production by supplying exogenousl-arginine, or to act on endothelial cell receptors to stimulate the production of NO. This review summarizes the current role of NO in cardiac surgery.     

Combined effects of inhaled nitric oxide and positive end-expiratory pressure during mechanical ventilation in acute respiratory distress syndrome

We studied the combined effects of inhaled nitric oxide (INO) and positive end expiratory pressure (PEEP) during mechanical ventilation in patients with acute respiratory distress syndrome (ARDS). Eleven patients received 0 and 4 parts per million of INO in random order for 30 min at PEEP levels of 0, 5, and 10 cm H2O. Respiratory and cardiovascular parameters were measured. The addition of INO and PEEP significantly improved arterial oxygenation (p < 0.005 and p < 0.0001, respectively). The combined effect of INO and PEEP on arterial oxygenation was remarkable during 10 cm H2O PEEP. There was synergistic effect on arterial oxygenation by combining INO and 10 cm H2O PEEP. The present study showed that the combination of INO and 10 cm H2O PEEP enhanced arterial oxygenation in patients with ARDS.     

Effect of Radix Paeoniae Rubra on the expression of HO-1 and iHOS in rats with endotoxin-induced acute lung injury

Objective ： To investigate the effect of Radix Paeoniae Rubra （RPR） on the expression of heme oxygenase （ HO- 1 ） and induced nitric oxide synthase （ iNOS ） in endotoxin- induced acute lung injury in rats and its protective mechanism. Methods： Forty Wistar rats were divided randomly into 5 groups with 8 rats in each group： saline control group （NS group ）, lipopolysaccharide group （LPS group）, RPR-treatment group, RPR-prevention group and Hemin group. The effect of RPR on protein content, the ratio of neutrophiles in bronchoalveolar lavage fluid, malondialdehyde （MDA） content in the lung and the activity of serum NO were observed. Arterial blood was drawn for blood-gas analysis. The expression of HO-1 and iNOS in lung tissues was detected by immunohistochemitry and morphometry computer image analysis. The histological changes of the lung were observed under fight microscope. Results： Compared with that in NS group, the expression of HO-1 and iNOS was markedly increased in LPS group （P 〈0.01）. In RPR-treatment, RPR-prevention, and Hemin groups, the expression of iNOS was significantly lower, while the expression of HO-1 was higher than that in LPS group （P〈0.05）. The protein content, the ratio of neutrophiles in bronchouiveolar lavage fluid, the content of MDA and the activity of serum NO in LPS group were significantly higher than those in NS group （ P〈0.01 ）. There was a significant decrease in the level of arterial bicarbonate and partial pressure of oxygen in the LPS group （P 〈0.01）; these parameters of lung injury however, were significantly lower in RPR-treatment, RPR- prevention, and Heroin groups than LPS group （P〈0.05 or P〈0.01 ）. The pathologic changes of lung tissues were substantially attenuated in RPR-treatment, RPR- prevention, and Hemin groups than LPS group. Conclusions ： The high expression of HO-1 reflects an important protective function of the body during lipopolysaccharide-induced acute lung injury. The acute lung injury is related to the inhibition of iNOS expression and the induction of HO-1 expression.     

Effect of Radix Paeoniae Rubra on the expression of HO-1 and iNOS in rats with endotoxin-induced acute lung injury

Objective: To investigate the effect of Radix Paeoniae Rubra (RPR) on the expression of heme oxygenase (HO-1) and induced nitric oxide synthase (iNOS) in endotoxin-induced acute lung injury in rats and its protective mechanism. Methods: Forty Wistar rats were divided randomly into 5 groups with 8 rats in each group: saline control group (NS group), lipopolysaccharide group ( LPS group), RPR-treatment group, RPR-prevention group and Hemin group. The effect of RPR on protein content, the ratio of neutrophiles in bronchoalveolar lavage fluid, malondialdehyde ( MDA ) content in the lung and the activity of serum NO were observed. Arterial blood was drawn for blood-gas analysis. The expression of HO-1 and iNOS in lung tissues was detected by immunohistochemitry and morphometry computer image analysis. The histological changes of the lung were observed under light microscope. Results: Compared with that in NS group, the expression of HO-1 and iNOS was markedly increased in LPS group (P<0.01). In RPR-treatment, RPR-prevention , and Hemin groups, the expression of iNOS was significantly lower, while the expression of HO-1 was higher than that in LPS group (P<0.05). The protein content, the ratio of neutrophiles in bronchoalveolar lavage fluid, the content of MDA and the activity of serum NO in LPS group were significantly higher than those in NS group (P<0.01). There was a significant decrease in the level of arterial bicarbonate and partial pressure of oxygen in the LPS group (P<0.01); these parameters of lung injury however, were significantly lower in RPR-treatment. RPR-prevention, and Hemin groups than LPS group (P<0. 05 or P< 0.01). The pathologic changes of lung tissues were substantially attenuated in RPR-treatment, RPR-prevention, and Hemin groups than LPS group. Conclusions: The high expression of HO-1 reflects an important protective function of the body during lipopolysaccharide-induced acute lung injury. The protective effect of RPR on lipopolysaccharide-induced acute lung injury is related to the inhibition of iNOS expression and the induction of HO-1 expression.     

Preventive influence of inhaled nitric oxide on lung ischemia-reperfusion injury

n = 9). The control group was not administered NO (group II, n = 8). Severe ischemia-reperfusion injury occurred as evidenced by hypoxia and lung edema. PaO₂ at 120 min after reperfusion was 325 ± 41 mmHg in group I and 40 ± 6 mmHg in group II. The pulmonary blood flow of the left lung at 120 min after reperfusion was 51% ± 3% in group I and 20% ± 5% in group II. The wet-to-dry weight ratio was 5.5 ± 0.2 for the right lungs, 5.8 ± 0.8 for the left lung in group I, and 6.1 ± 0.4 for the left lung in group II. Histopathologically, marked hemorrhage, hyaline membrane formation, and leukocyte infiltration were observed in group II but not in group I. These data suggested that inhaled NO reduced warm ischemia-reperfusion injury in the lung, and also contributed to a better preserved lung function. (Received for publication on July, 13, 1998; accepted on Mar. 11, 1999)     

The effect of inhaled nitric oxide in acute respiratory distress syndrome in children and adults: a Cochrane Systematic Review with trial sequential analysis

Acute respiratory distress syndrome is associated with high mortality and morbidity. Inhaled nitric oxide has been used to improve oxygenation but its role remains controversial. Our primary objective in this systematic review was to examine the effects of inhaled nitric oxide administration on mortality in adults and children with acute respiratory distress syndrome. We included all randomised, controlled trials, irrespective of date of publication, blinding status, outcomes reported or language. Our primary outcome measure was all‐cause mortality. We performed several subgroup and sensitivity analyses to assess the effect of inhaled nitric oxide. There was no statistically significant effect of inhaled nitric oxide on longest follow‐up mortality (inhaled nitric oxide group 250/654 deaths (38.2%) vs. control group 221/589 deaths (37.5%; relative risk (95% CI) 1.04 (0.9–1.19)). We found a significant improvement in PaO₂/F_IO₂ ratio at 24 h (mean difference (95% CI) 15.91 (8.25–23.56)), but not at 48 h or 72 h, while four trials indicated improved oxygenation in the inhaled nitric oxide group at 96 h (mean difference (95% CI) 14.51 (3.64–25.38)). There were no statistically significant differences in ventilator‐free days, duration of mechanical ventilation, resolution of multi‐organ failure, quality of life, length of stay in intensive care unit or hospital, cost‐benefit analysis and methaemoglobin and nitrogen dioxide levels. There was an increased risk of renal impairment (risk ratio (95% CI) 1.59 (1.17–2.16)) with inhaled nitric oxide. In conclusion, there is insufficient evidence to support inhaled nitric oxide in any category of critically ill patients with acute respiratory distress syndrome despite a transient improvement in oxygenation, since mortality is not reduced and it may induce renal impairment.     

Pulmonary function in adult survivors of severe acute lung injury treated with inhaled nitric oxide

Background : Following an episode of acute respiratory distress syndrome (ARDS), some degree of measurable pulmonary impairment may be anticipated. ARDS is thought to be the more severe form of acute lung injury (ALI) and a recently proposed addition to conventional therapy in ALI/ARDS is inhaled nitric oxide (INO). We carried out a non-randomised follow-up study with pulmonary function tests on survivors of severe ALI/ARDS treated with INO.
Methods : Sixteen previously healthy pulmonary patients, survivors of severe ALI/ARDS, were evaluated with pulmonary function tests >8 months after the acute event. The tests included static and dynamic spirometry, diffusion capacity for carbon monoxide (DLCO), blood gas analysis and evaluation of a chest radiograph.
Results : The most common abnormality seen was a low DLCO in 69% of the patients. Abnormally low values were seen in forced vital capacity in 31%, in forced expiratory volume in 1 s in 13%, and in residual volume and total lung capacity in 6%. Blood gas data were within normal limits in 15/16 patients. All chest radiographs showed resolution of the interstitial and alveolar changes present during the acute event.
Conclusion : In this non-randomised follow-up study we conclude that a degree of measurable pulmonary impairment after INO treatment in severe ALI/ARDS was common, but did not differ markedly from other published studies on pulmonary function in similar patient material. No late unexpected major abnormalities due to the inhaled nitric oxide treatment could be identified in these survivors.     

Effect of NO donor sodium nitroprusside on lipopolysaccharide induced acute lung injury in rats

Nitric oxide (NO) donor-sodium nitroprusside (SNP) mitigates acute lung injury (ALI), but the mechanism of this protection is incompletely known. We investigated the effect of SNP on lipopolysaccharide (LPS)-induced ALI in rats. Forty-eight male Wistar rats were randomly assigned into six groups: the sham-operation group (S group), the LPS instillation group (LPS group), the haemin, a haeme oxygenase-1 (HO-1) inducer, pretreatment group (HM group), the haemin pretreatment plus LPS instillation group (HM+LPS group), the SNP alone and SNP plus LPS treatment groups. Macroscopic and histopathological examinations and immunohistochemistry analysis were performed for the lung specimens 8h after LPS instillation. Intratracheal administration of LPS induced significant expressions of the inducible isoform of NO synthase (iNOS) and HO-1, while both haemin pretreatment and SNP treatment increased the expression of HO-1 and prevented the expression of iNOS. In the LPS group, the wet-dry weight ratio (W/D), bronchoalveolar lavage fluid (BALF) protein, and lung malondialdehyde (MDA) content were significantly higher than those in the sham-operation group, which were reversed by the pretreatment with haemin or administration of SNP. These results suggest that HO-1 plays a protective role against LPS-induced acute lung injury, which may be achieved at least in part, via inactivating the iNOS/NO system that is involved in the pathophysiological process of LPS-induced acute lung injury. The nitric oxide (NO) donor-SNP ameliorates LPS-induced ALI, which may be related to the induction of HO-1 and the subsequent inhibition of iNOS.     

Early treatment with arteriovenous extracorporeal lung assist and high-frequency oscillatory ventilation in a case of severe acute respiratory distress syndrome

BACKGROUND: Lung protective ventilation can reduce mortality in acute respiratory distress syndrome (ARDS). However, many patients with severe ARDS remain hypoxemic and more aggressive ventilation is necessary to maintain sufficient gas exchange. Pumpless arteriovenous extracorporeal lung assist (av-ECLA) has been shown to remove up to 95% of the systemic CO(2) production, thereby allowing ventilator settings and modes prioritizing oxygenation and lung protection. High-frequency oscillatory ventilation (HFOV) is an alternative form of ventilation that may improve oxygenation while limiting the risk of further lung injury by using extremely small tidal volumes (VT). METHODS: We discuss the management of a patient suffering from severe ARDS as a result of severe bilateral lung contusions and pulmonary aspiration. RESULTS: Severe ARDS developed within 4 h after intensive care unit admission. Conventional mechanical ventilation (CV) with high-airway pressures and low VT failed to improve gas exchange. Av-ECLA was initiated to achieve a less aggressive ventilation strategy. VT was reduced to 2-3 ml/kg, but oxygenation did not improve and airway pressures remained high. HFOV (8-10 Hz) was started using a recruitment strategy and oxygenation improved within 2 h. After 5 days, the patient was switched back to CV uneventfully and av-ECLA was removed after 8 days. CONCLUSION: The combination of two innovative treatment modalities resulted in rapid stabilization and improvement of gas exchange during severe ARDS refractory to conventional lung protective ventilation. During av-ECLA, extremely high oscillatory frequencies were used minimizing the risk of baro- and volutrauma.     

Glycyrrhizin treatment is associated with attenuation of lipopolysaccharide-induced acute lung injury by inhibiting cyclooxygenase-2 and inducible nitric oxide synthase expression

Glycyrrhizin (GL), a major active constituent of licorice root, has been attributed numerous pharmacologic effects, including anti-inflammatory, anti-viral, anti-tumor, and hepatoprotective activities. In this study, we investigated the anti-inflammatory effect of GL on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. ALI was induced in Balb/c mice by intratracheal instillation of LPS (1 mg/kg). Before 1 h of LPS administration, the mice received intraperitoneal injection of GL at varied doses (10, 25, and 50 mg/kg). The severity of pulmonary injury was evaluated 12 h after LPS administration. GL pretreatment led to significant attenuation of LPS induced evident lung histopathologic changes, alveolar hemorrhage, and neutrophil infiltration with evidence of reduced myeloperoxidase (MPO) activity. The lung wet/dry weight ratios, as an index of lung edema, were markedly reduced by GL pretreatment. The concentrations of pro-inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α were elevated in bronchoalveolar lavage fluid (BALF) after LPS administration, which were significantly inhibited by GL pretreatment. GL pretreatment also reduced the concentrations of nitric oxide (NO) in lung tissues. Furthermore, the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) was suppressed by GL pretreatment. In conclusion, GL potently protected against LPS-induced ALI, and the protective effects of GL may attribute partly to the suppression of COX-2 and iNOS expression.