Nebulized nitric oxide/nucleophile adduct reduces pulmonary vascular resistance in mechanically ventilated septicemic sheep

OBJECTIVE: To study the effects of a novel, intermittently administered, aerosolized nitric oxide donor, methyl-N-2-dimethylaminoethyl-3-aminoproprionid/nitric oxide (DMDE-NO), on pulmonary hemodynamic responses to sepsis. DESIGN: Prospective, randomized, controlled study in awake sheep. SETTING: Investigational intensive care unit of a university medical center. SUBJECTS: Thirteen instrumented merino ewes weighing 36 +/- 0.9 kg underwent a hemodynamic study 1 wk postoperatively. INTERVENTIONS: On the day of the experiment, the sheep received a tracheotomy and mechanical ventilation was subsequently started. Pseudomonas aeruginosa bacteria were infused intravenously, beginning at time 0 hrs and continuing throughout the 48-hr experiment. The animals were randomly assigned to receive nebulized DMDE-NO 1 mg/kg, dissolved in 8 mL of saline (DMDE-NO group, n = 7), or nebulized saline alone (control group, n = 6) delivered by a nebulizer. The nebulizations started at 2, 6, 20, 24, and 43 hrs after the baseline, each time lasting for 1 hr. MEASUREMENTS AND MAIN RESULTS: Inhaled aerosolized DMDE-NO reversibly reduced the sepsis-induced increase in pulmonary artery pressure by 13-17% and pulmonary vascular resistance index by 21-31% compared with the values registered before the administration of the drug. Systemic hemodynamics underwent an early hypodynamic phase followed by a gradual increase in cardiac index and a decrease in both mean arterial pressure and systemic vascular resistance index, but with no significant difference between groups. Gas exchange variables and plasma nitrite/nitrate did not differ significantly between groups either. CONCLUSIONS: In sheep, inhaled nebulized DMDE-NO reduces sepsis-induced changes in pulmonary hemodynamics with no change in systemic hemodynamics or gas exchange.     

Aerosol delivery of diethylenetriamine/nitric oxide, a nitric oxide adduct, causes selective pulmonary vasodilation in perinatal lambs.

Postnatal adaptation of the pulmonary circulation is mediated partly by endothelium-derived nitric oxide (NO). Recent studies have demonstrated that inhaled NO causes selective and sustained vasodilation in infants with persistent pulmonary hypertension of the newborn. Because the short half-life of NO limits its clinical application, we hypothesized that aerosol delivery of an NO-adduct, diethylenetriamine (DETANO), can cause sustained and selective pulmonary vasodilation. To test the acute effects of DETANO, we studied the pulmonary vascular response of late-gestation fetal lambs (n = 8; age = 138 days; term = 147) to aerosolized DETANO in the presence of an endothelium-derived NO inhibitor, nitro-L-arginine. To determine whether DETANO has a sustained effect, fetal lambs were ventilated with FiO2 0.10 before and 15 minutes after they were treated with aerosolized DETANO. Fetal lambs were acutely prepared. Nitro-L-arginine (1 mg/min x 30 minutes) was infused into the left pulmonary artery before ventilation with FiO2 1.00 for 30 minutes, followed by continued ventilation with FiO2 0.10 for 10 minutes. This represented the control period. Ventilation was continued with FiO2 1.00, and aerosolized DETANO was given in doses of 0.1, 0.4, and 1.0 mg. Fifteen minutes after the last dose of DETANO was administered, animals were ventilated with FiO2 0.10. In the control period, during ventilation with FiO2 0.10, left pulmonary artery flow was 122+/-33 mL/min and decreased to 104+/-22 mL/min. Aerosol delivery of DETANO increased left pulmonary artery flow to 176+/-26 mL/min (P<.05) and had no effect on aortic pressure or heart rate. After DETANO was administered, ventilation with FiO2 0.10 did not cause any change in left pulmonary artery flow. We conclude that DETANO can cause selective fetal pulmonary vasodilation. Aerosol delivery of DETANO may increase the clinical applications of NO.     

Inhaled nitric oxide down-regulates intrapulmonary nitric oxide production in lipopolysaccharide-induced acute lung injury

OBJECTIVE: To examine whether inhaled nitric oxide (NO) affected the intrapulmonary production of NO, reactive oxygen species, and nuclear factor-kappaB in a lipopolysaccharide (LPS)-induced model of acute lung injury. DESIGN: Prospective, randomized, laboratory study. SETTING: Experimental laboratory at a biomedical institute. SUBJECTS: Twenty male rabbits weighing 2.5-3.5 kg. INTERVENTIONS: Saline or LPS (5 mg/kg of body weight) was administered intravenously with or without NO inhalation (10 ppm) in each group of five rabbits. MEASUREMENTS AND MAIN RESULTS: LPS increased the lung leak index, the neutrophils and NO levels in bronchoalveolar lavage fluid, and NO levels produced by resting and stimulated alveolar macrophages. Inhaled NO decreased the lung leak index, the neutrophils and NO levels as measured by nitrite levels in the lavage fluid, and NO produced by the resting and stimulated alveolar macrophages. Inhaled NO also blocked the activities of reactive oxygen species and nuclear factor-kappaB binding to DNA in lavage cells and in alveolar macrophages. CONCLUSION: Inhaled NO attenuates LPS-induced acute lung injury, possibly by decreasing NO production in the lungs. The mechanism of reducing NO production resulting from inhaled NO may involve, in part, the activities of reactive oxygen species and/or nuclear factor-kappaB.     

Response to nitric oxide inhalation in early acute lung injury

Objective To evaluate the dose response of inhaled nitric oxide (NO) on gas exchange and central haemodynamics in patients with early acute lung injury (ALI).Design Prospective, multicentre clinical study.Setting General ICUs in university and regional hospitals.Patients 18 patients with early ALI according to specified criteria.Interventions During controlled ventilation an inhalation system was used to deliver NO (1000 ppm in N₂) and O₂/air to the low pressure fresh gas inlet of a Siemens 900C ventilator. Haemodynamics and pulmonary gas exchange variables were measured at baseline and at stepwise increased inspiratory NO concentrations of 0.1, 0.3, 1, 3, 10, 30 and 100 ppm, each dose being maintained for 15 min. Dose testing was repeated the next day, and the response to prolonged (2 h) NO inhalation at 1 and 10 ppm was also tested.Measurements and results Inhalation of NO produced a significant increase in PaO₂ (P<0.0025). The degree of response, as well as the optimal NO dose varied in individual patients and between different days. Venous admixture (Q_VA/Q_T) was reduced (P<0.02) from 38% (31–46%) to 33% (26–41%). In our patients with early acute lung injury and only a moderate elevation in pulmonary arterial pressure NO inhalation did not reduce mean pulmonary artery pressure significantly, being 27.0 (21–30) mmHg at baseline and 26.0 (21–30) mm Hg at 100 ppm.Conclusions This study shows that improvements in arterial oxygenation in response to inhaled NO may show great inter- as well as intraindividual variability, and that improvements in arterial oxygenation occur without any measurable lowering of the pulmonary artery pressure.     

Role of nitric oxide in acute lung inflammation: lessons learned from the inducible nitric oxide synthase knockout mouse

OBJECTIVE: Acute lung inflammation is characterized by complex interactions among cytokines, chemokines, adhesion molecules, leukocytes, and other mediators. Proinflammatory cytokines have been implicated in the up-regulation of the inducible form of nitric oxide synthase (iNOS), which produces large amounts of nitric oxide (NO). Conversely, in some systems, NO regulates the expression of cytokines to affect leukocyte recruitment. Thus, the role of NO both exogenously administered and endogenously produced by iNOS in acute lung inflammation has not been fully elucidated. The current studies suggest a proinflammatory role for inhaled NO in a compartmentalized model of lung injury, whereas blocking of iNOS afforded protection. These results and other previous investigations have been complicated by the use of nonselective blockers of the iNOS isoform. MEASUREMENTS AND MAIN RESULTS: In an attempt to circumvent this, we examined the response of the lung to direct endotoxin challenge in mice in which iNOS had been genetically deleted (iNOS-/-). We observed a significant decrease in the inflammatory response in the iNOS-/- mice compared with wild-type mice as characterized by decreases in neutrophil accumulation and cytokine expression. Additionally, the lung cytokine response in the iNOS-/- mice was characterized by a significant increase in interleukin-12 and an inability to up-regulate interleukin-10. CONCLUSIONS: Induction of NO may be a key mediator in driving the cytokine response to endotoxin toward an increased type-2 (interleukin-10) response and a diminished type-1 (interleukin-12) response.     

Markers of lung disease in exhaled breath: nitric oxide

Management of airway inflammation requires proper monitoring and treatment to improve long-term outcomes. However, achieving this goal is difficult, as current methods have limitations. Although nitric oxide (NO) was first identified 200 years ago, its physiological importance was not recognized until the early 1980s. Many studies have established the role of NO as an essential messenger molecule in body systems. In addition, studies have demonstrated a significant relationship between changes in exhaled NO levels and other markers of airway inflammation. The technique used to measure NO in exhaled breath is noninvasive, reproducible, sensitive, and easy to perform. Consequently, there is growing interest in the use of exhaled NO in the management of asthma and other pulmonary conditions. The purpose of this review is to promote a basic understanding of the physiologic actions of NO, measurement techniques, and ways that research findings might translate to future application in clinical practice. Specifically, the article will review the role of exhaled NO in regard to its historical background, mechanisms of action, measurement techniques, and implications for clinical practice and research.     

Inhalation of nitric oxide in severe lung failure

Despite intensive therapeutic efforts, adult respiratory distress syndrome (ARDS) is still associated with a lethality ranging from 50 to 80%. Besides hypoxemia, fatal outcome is caused by myocardial insufficiency due to a progressive decrease in pulmonary vascular conductance. Inhalation of NO can selectively dilate pulmonary vessels in ventilated lung regions, thus increasing mean pulmonary artery conductance and decreasing venous admixture. This study determines the effects of NO inhalation in patients with severe ARDS on pulmonary gas exchange, haemodynamics and mortality. Twenty surgical patients (mean age 50.3 +/- 9.25 years) with severe ARDS (Murray score 3.4 +/- 0.3) were treated with variable concentrations of NO during mechanical ventilation with continuous positive pressure. Pulmonary artery catheters were used to measure pressures, flow and venous admixture. Mortality with NO inhalation was compared with that of previous ARDS patients (n = 20) who had not received NO. Mean duration of NO inhalation was 120.1 +/- 33.12 hours (n = 20) (range 40 to 254 hours). Mean NO concentration during the first hour of delivery was 18.5 +/- 3.88 ppm. Sixteen patients had FiO2 of 1.0 when NO was started. Within the first hour of NO inhalation, the PaO2/FiO2 ratio increased from 82.1 +/- 10.28 to 124.6 +/- 28.18. Eighteen patients were responders. Mean ventilatory pressure was lowered. Oxygenation improvement was most marked during the first 36 hours and then gradually declined. Despite the significant increase in NO related oxygenation, pulmonary artery pressures did not consistently decrease. Sixteen patients in the NO group died. In the group without NO 15 patients died. Compared with ARDS patients of similar severity not receiving NO, the NO-treated patients had the same lethality. In severe ARDS, oxygenation significantly improves with the initiation of NO inhalation, but this effect declines over time. With NO, FiO2 and ventilatory pressures can be lowered. Whether the theoretically reduced oxygen toxicity and the reduced invasiveness of mechanical ventilation with NO reduces patient mortality must be determined in larger patient groups.     

辛伐他汀纳米粒通过调节诱导型一氧化氮合酶/内皮型一氧化氮合酶系统对小鼠脓毒症相关急性肺损伤的影响

目的探讨辛伐他汀纳米粒对脓毒症相关急性肺损伤小鼠肺组织中诱导型一氧化氮合酶（iNOS）/内皮型一氧化氮合酶（eNOS）平衡的调节以及对脓毒症小鼠预后的影响。 方法将90只C57 / BL6小鼠分为假手术组、脓毒症组、灌胃组、静脉制剂组及纳米粒组,每组各18只。采用盲肠结扎穿孔术（CLP）建立脓毒症小鼠模型;灌胃组小鼠通过灌胃针,给予辛伐他汀口服制剂灌胃治疗后进行CLP术;静脉制剂组及纳米粒制剂组小鼠CLP术后,立即分别通过尾静脉注射预配置好的辛伐他汀静脉制剂和辛伐他汀纳米粒制剂。其中每组12只小鼠用于7 d生存评估,另外6只用于24 h时间点标本采集。每24小时观察小鼠的生存情况,然后记算各组小鼠每日生存情况。采用苏木素-伊红（HE）染色观察5组小鼠病理变化并计算肺损伤病理评分,免疫组织化学法检测5组小鼠肺组织iNOS、eNOS表达水平。 结果Kaplan-Meier生存曲线结果显示,5组小鼠7 d生存情况比较,差异有统计学意义（χ² = 3.780,P < 0.001）。进一步两两比较发现,脓毒症组及灌胃组小鼠的7 d生存情况均较假手术组明显下降（P均< 0.001）,而纳米粒组小鼠的7 d生存情况显著优于脓毒症组（P = 0.001）。HE染色结果显示,假手术组小鼠肺组织未见明显病理征象;脓毒症组小鼠肺组织弥漫性中性粒细胞浸润、肺泡腔变小、肺泡间中隔增厚、肺间质弥漫性水肿、细胞排列紊乱、部分肺组织完整性遭破坏;灌胃组小鼠病理所示与脓毒症组相似;静脉制剂组及纳米粒组小鼠中性粒细胞渗出均较脓毒症组损伤减少、肺泡完整性较好、损伤程度较轻。5组小鼠肺损伤病理评分、iNOS及eNOS表达水平比较,差异均有统计学意义（F = 889.200、9.633、6.918,P均< 0.05）。进一步两两比较发现,脓毒症组小鼠的肺损伤病理评分、iNOS及eNOS表达水平与假手术组比较,差异均有统计学意义（P均< 0.05）;静脉制剂组及纳米粒组小鼠病理评分、iNOS及eNOS表达水平与脓毒症组比较,差异均有统计学意义（P均< 0.05）,且纳米粒组小鼠的肺损伤病理评分较静脉制剂组显著降低（P < 0.05）。 结论不同的辛伐他汀制剂具有不同的效应,其中纳米粒制剂对于脓毒症相关的肺损伤最具保护价值,建立eNOS与iNOS之间的平衡,可以成为具有保护效应的重要处理位点。     

Burn-induced lung damage in rat is mediated by a nitric oxide/cGMP system

This study was conducted to demonstrate the burn-induced lung neutrophil deposition and damage in rats is affected by the nitric oxide (NO)-dependent downstream cGMP signaling. In experiment 1, 1H-[1,2,4] oxadiazolo [4,3-alpha] quinoxalin-1-one (ODQ) was given (20 mg/kg i.p.) to specific pathogen-free Sprague-Dawley rats immediately postburn to suppress the guanylate cyclase (GC) activity. At 8 h after burn, blood was assayed for the peroxynitrite-mediated dihydrorhodamine 123 (DHR 123) oxidation and lung tissues were harvested for myeloperoxidase (MPO) determination and histological studies. Pulmonary microvascular dysfunction was quantified by measuring the extravasations of Evans blue dye. In experiment 2, Sodium nitroprusside (SNP) was given (2 mM, i.p.) to elevate cGMP levels and ODQ (20 mg/kg, i.p.) or methylene blue (100 microM, i.p.) or saline was given. The animals were sacrificed 4 h after injection and lung tissues were harvested for iNOS mRNA study. The MPO activity in lung, blood DHR 123 oxidation level, and lung permeability increased up to 2-fold, 4-fold, and 2.5-fold after burn. Inhibition of GC by ODQ administration significantly decreased MPO activity, blood DHR 123 oxidation, and lung permeability by 55%, 66%, and 53%, respectively, and markedly decreased the thermal injury-induced perivascular and interstitial inflammatory cell infiltration and septum edema. The protective effects of ODQ were comparable to the use of selective iNOS inhibitor as demonstrated previously. Furthermore, ODQ decreased the burn or SNP-induced iNOS mRNA levels at 4 h after burn. These findings suggest that burn-induced lung dysfunction is mediated by the NO/cGMP system because it is abolished by application of either iNOS inhibitor or GC inhibitor. Also, the beneficial effect of ODQ is partly due to the attenuation of burn-induced iNOS expression by GC inhibition.     

雾化吸入氯胺酮对哮喘大鼠肺组织一氧化氮及一氧化氮合酶的影响

目的通过建立大鼠支气管哮喘模型,观察不同浓度氯胺酮对哮喘大鼠肺组织iNOS活性及NO含量的影响。方法SD大鼠随机分成对照组(N组)、哮喘模型组(A组)、不同浓度氯胺酮预处理组(分别为K1组、K2组)和地塞米松组(D组),每组8只。A组大鼠用卵白蛋白辅以百日咳杆菌菌苗和氢氧化铝为佐剂注射致敏,2周后雾化吸入卵蛋白激发哮喘;氯胺酮处理组大鼠用同样方法致敏,但在激发前分别给予雾化吸入氯胺酮25 g/L(K1组)和50 g/L(K2组);D组在激发前给予雾化吸入0.01%地塞米松;N组用生理盐水替代卵蛋白进行注射和吸入。每组分别测定其肺组织NO2-/NO3-水平、肺组织诱导型NOS(iNOS)和原生型NOS(cNOS)活性水平,并用免疫组织化学法观察iNOS在大鼠哮喘模型肺组织中的分布。结果A组肺组织中NO2-/NO3-和iNOS水平升高,iNOS和肺组织NO2-/NO3-水平呈高度正相关;K1、K2组肺组织中NO2-/NO3-和iNOS水平低于A组(P<0.05);D组肺组织中NO2-/NO3-和iNOS水平亦低于A组(P<0.05)。结论25 g/L或50 g/L的氯胺酮雾化吸入可抑制哮喘大鼠肺组织iNOS活性,降低NO含量,减轻大鼠肺部炎症。     

Nebulized morphine for relief of dyspnea due to chronic lung disease

OBJECTIVE: To evaluate the efficacy and safety of nebulized morphine for the management of dyspnea in chronic pulmonary diseases. DATA SOURCES: MEDLINE (1966-May 2004), EMBASE (1980-May 2004), and International Pharmaceutical Abstracts (1970-May 2004) searches were performed. Key search terms included morphine, dyspnea, and inhalation. DATA SYNTHESIS: Nine studies have evaluated the efficacy of nebulized morphine in relieving dyspnea. Three trials had positive results, but the rest failed to show improvement after treatment with doses ranging from 1 to 40 mg nebulized morphine. The small number of subjects, variety of disease states, and different outcome measures limit interpretation of the studies. CONCLUSIONS: Results from several small studies do not support the use of nebulized morphine for treatment of dyspnea; however, several positive case reports have been published.     

The role of nitric oxide synthase/nitric oxide in vascular smooth muscle control

Vascular compliance is dependent on endogenous and exogenous sources of nitric oxide (NO). In a discussion of therapeutics and NO derived via nitric oxide synthase (NOS) enzymes, it is necessary to examine the pathways of each drug to provide the clinical perfusionist with a greater understanding of the role of NOS/NO in vascular function. Endothelial-derived NO is a contributor in the vasoregulation of vascular smooth muscle. Therapeutics seek to mimic the vasodilatory effects of the endogenous NO. The therapeutics included in this review are nitroglycerin, nitroprusside, amyl nitrite, and inhalation of NO. L-Arginine supplementation provides additional substrate for the endogenous pathway that can augment NO production. NO is a small bioactive molecule involved in various biochemical pathways. Dysregulation of NO production can impair normal physiologic control of vascular compliance. Therefore, the purpose of this review is to provide the perfusionist with an understanding of the biochemical and pharmacological aspects of NOS/NO associated with vascular function.     

Inhaled nitric oxide during partial liquid ventilation shifts pulmonary blood flow to the non-dependent lung regions

Objective: To elucidate the change in pulmonary blood flow brought about by nitric oxide (NO) inhalation during partial liquid ventilation (PLV).¶Design: Prospective, controlled study.¶Setting: A research laboratory at a university medical center.¶Subjects: Fourteen Japanese white rabbits (3.2 ± 0.05 kg body weight).¶Interventions: Animals were mechanically ventilated in the right decubitus position. Following saline lung lavage, PLV was started with perflubron (15 ml/kg). In the NO group (n = 7), PLV was supplemented by a 30-min challenge of NO inhalation (10 ppm) from 30 min after the initiation of PLV. In the control group (n = 7), PLV was continued for 60 min.¶Measurements and main results: For the pulmonary blood flow analysis, colored microspheres were administered from the right atrium at 30 min (T_PLV1) and 60 min (T_PLV2) after the initiation of PLV. The percentage of the left lung blood flow in the total pulmonary blood flow (%Q_L/Q_T) was significantly increased by NO inhalation in the NO group (p = 0.0164), while that in the control group was significantly decreased during the same period (p = 0.0107). PaO₂ in the NO group was significantly increased by NO inhalation (p = 0.0153), but not in the control group (p = 0.7911).¶Conclusion: Inhaled NO during PLV shifted the pulmonary blood flow to the non-dependent region and improved pulmonary gas exchange. This result suggested that inhaled NO took effect predominantly in the non-dependent region during PLV.     

Mixed expired nitric oxide in primary pulmonary hypertension in relation to lung diffusion capacity

The mixed expired nitric oxide (NO) production of the lungsof patients with primary pulmonary hypertension (PPH) and normalsubjects was measured to determine the relationship betweenNO production and the diffusion capacity of the lung (KCO).Expired air was collected from eight patients with PPH and 20healthy volunteers for analysis by a chemluminescent analyser.Mean pulmonary artery pressure in the PPH patients was 59.5± 6.45 mmHg and their mean cardiac output was 2.95 ±0.35 l/min. All patients and subjects underwent measurementsof FEV1, VC and KCO. The rate of production of NO in mixed exhaledair was lower in the PPH group compared to the controls (2.85± 0.7 vs. 4.69 ± 0.35 nM/min; p<0.05). Therewas a good correlation of expired NO with the KCO (r=0.7; n=30;p<0.001). When corrected, KCO differences in exhaled NO werenot significant (p=0.09). We conclude that the low exhaled NOobserved in PPH patients is a reflection of the reduced bloodcapillary volume in these patients rather than a decreased basalproduction of NO.     

Enhanced nitric oxide concentrations and expression of nitric oxide synthase in acupuncture points/meridians

OBJECTIVES: The objectives of this study were to examine the distributions of nitric oxide (NO) in the skin points (acupoints)/meridian regions and determine whether neuronal nitric oxide synthase (nNOS) protein levels were associated with NO concentrations in the areas. DESIGN: Low skin resistance points (LSRP) on the skin surface in response to electrical stimuli were performed in anesthetized adult rats. The skin together with subcutaneous tissue was isolated in meridian regions from PC 2 to 6, BL 36 to 57, CV 3 to 22, and GV 2 to 14. Control skin tissues were obtained in the areas close to related meridians without containing LSRP. Concentrations of nitrite (NO(2)(-)), nitrate (NO(3)(-)), and total NO(2)(-) plus NO(3)(-) (NO(x)(-)) were quantified in the skin tissues, micropunches of brain nuclei, and blood vessels in a blinded fashion. Western blots were also conducted using polyclonal anti-nNOS and anti-endothelial nitric oxide synthase (eNOS) antibody in the skin tissues. RESULTS: NO(x)(-) and NO(3)(-) concentrations were higher (45 +/- 8% and 43 +/- 7% in the CV, 47 +/- 7% and 51 +/- 9% in the BL, and 47 +/- 8% and 45 +/- 6% in the PC) than those in control regions (p < 0.05, n = 6). NO(x)(-) concentrations are 2- to 3-fold greater in skin tissues than those in brain regions and blood vessels (p < 0.05, n = 6-8). nNOS protein levels were consistently increased in the skin regions of BL, PC, and GV meridians compared with their controls (p < 0.05, n = 5-7) but endothelial NO synthase expression was not changed. CONCLUSION: This is the first evidence showing that NO contents and nNOS expression are consistently higher in the skin acupoints/meridians associated with low electric resistance. The results suggest that enhanced NO in the acupoints/meridians is generated from multiple resources including neuronal NOergic system, and NO might be associated with acupoint/meridian functions including low electric resistance.     

Inhaled nitric oxide reduces lung edema during fluid resuscitation in ovine acute lung injury

OBJECTIVE: Fluid resuscitation in sepsis-related lung injury is limited by aggravation of pulmonary edema. Hypovolemia, however, may compromise tissue perfusion and contribute to organ dysfunction. We hypothesized that inhaled nitric oxide would reduce edema formation during fluid therapy. DESIGN AND SETTING: Prospective laboratory investigation in a university research laboratory. PARTICIPANTS: Eighteen chronically instrumented sheep. INTERVENTIONS: The animals were randomly assigned to one of three groups and received endotoxin (S. typhi, 10 ng kg(-1) min(-1)) for 30 h. After 24 h the sheep were anesthetized (ketamine/midazolam), mechanically ventilated with oxygen, and received 0.1 ml kg(-1) oleic acid: oxy group (n=6), an infusion of Ringer's lactate was restricted to 1 ml kg(-1) h(-1); fluid/oxy group (n=6), a bolus of 10 ml kg(-1) Ringer's lactate plus 10 ml kg(-1) h(-1) was given; fluid/NO group (n=6), the sheep were treated as in the fluid/oxy group, except that they inhaled nitric oxide (20 ppm). MEASUREMENTS AND RESULTS: The extravascular lung water index was measured using thermodye dilution. Oleic acid increased extravascular lung water, impaired oxygenation, and reduced cardiac index at 26 h in all groups. After 30 h the extravascular lung water in the fluid/NO group was not higher than in the oxy group and significantly than in the fluid/oxy group. While cardiac index returned to the level of sepsis baseline in fluid/NO and fluid/oxy, it was reduced in the oxy group after 30 h. There were no significant differences in cardiac index between groups. CONCLUSIONS: Inhaled nitric oxide may be an option for reducing edema formation secondary to fluid resuscitation in acute lung injury.     

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     

Carboxyhemoglobin formation secondary to nitric oxide therapy in the setting of interstitial lung disease and pulmonary hypertension

Carbon monoxide (CO) has been widely recognized as an exogenous poison, although endogenous mechanisms for its formation involve heme-oxygenase (HO) isoforms, more specifically HO-1, in the setting of oxidative stress such as acute respiratory distress syndrome, sepsis, trauma, and nitric oxide use have been studied. In patients with refractory hypoxemia, inhaled nitric oxide (iNO) therapy is used to selectively vasodilate the pulmonary vasculature and improve ventilation-perfusion match. Inhaled nitric oxide is rapidly inactivated on binding to hemoglobin in the formation of nitrosyl- and methemoglobin in the pulmonary vasculature. Hence, inhaled nitric oxide has minimal systemic dissemination. Several experimental design studies involving lab rats have demonstrated increased levels of carboxyhemoglobin and exhaled CO as a result of nitric oxide HO-1 induction.