Effect of inhaled nitric oxide in combination with almitrine on ventilation-perfusion distributions in experimental lung injury

Objective: To investigate a possible additive effect of combined nitric oxide (NO) and almitrine bismesylate (ALM) on pulmonary ventilation-perfusion (V˙._A/Q˙) ratio.¶Design: Prospective, controlled animal study.¶Setting: Animal research facility of a university hospital.¶Interventions: Three conditions were studied in ten female pigs with experimental acute lung injury (ALI) induced by repeated lung lavage: 1) 10 ppm NO, 2) 10 ppm NO with 1 μg/kg per min ALM, 3) 1 μg/kg per min ALM. For each condition, gas exchange, hemodynamics and V˙._A/Q˙ distributions were analyzed using the multiple inert gas elimination technique (MIGET).¶Measurement and results: With NO + ALM, arterial oxygen partial pressure (PaO₂) increased from 63 ± 18 mmHg to 202 ± 97 mmHg while intrapulmonary shunt decreased from 50 ± 15 % to 26 ± 12 % and blood flow to regions with a normal V˙._A/Q˙ ratio increased from 49 ± 16 % to 72 ± 15 %. These changes were significant when compared to untreated ALI (p < 0.05) and NO or ALM alone (p < 0.05), although improvements due to NO or ALM also reached statistical significance compared to ALI values (p < 0.05).¶Conclusions: We conclude that NO + ALM results in an additive improvement of pulmonary gas exchange in an experimental model of ALI by diverting additional blood flow from non-ventilated lung regions towards those with normal V˙._A/Q˙ relationships.     

吸入一氧化氮对急性呼吸窘迫综合征患儿肺动脉压力的影响

目的观察吸入一氧化氮（NO）在急性呼吸窘迫综合征（ARDS）治疗中对肺动脉压力的影响。方法 20例确诊ARDS患儿在进行药物治疗、机械通气的同时均进行吸入外源性NO治疗,NO初始治疗浓度为10×10^-6,通过多普勒超声心动图分别计算吸入NO前,吸入后0.5、1、12、24、48小时等不同时刻的肺动脉压力（PAP）,直至某个时刻NO治疗效果不明显时,则将治疗浓度减为原浓度的50%,每2小时递减50%,直至停用,分别记录各时间点的PAP值。结果吸入前PAP均值为59.20 mmHg（1 mmHg=0.133 kPa）,吸入NO后0.5、1、12、24、48小时PAP均值分别为53.40 mmHg、48.10 mmHg、42.80 mmHg、36.60 mmHg、35.30 mmHg,与吸入前比均明显下降（P〈0.05）。在吸入NO后48小时内PAP平均值呈递减趋势,但吸入后24小时与48小时相比,差异无统计学意义（P〉0.05）;50小时吸入NO浓度减为原来的50%后PAP平均值为37.70 mmHg,与48小时相比,PAP增高且两组差异有统计学意义（P〈0.05）,52小时NO浓度再减为50%后与50小时相比,PAP差异无统计学意义（P〉0.05）,54小时停止吸入后PAP（平均值为40.30 mmHg）虽较前反弹但仍较吸入前明显减低。结论 NO对ARDS导致的肺动脉压力增高有治疗作用,吸入浓度为10×10^-6的NO,24小时内可有效减低PAP,维持原浓度继续吸入则无明显效果。     

Time-course and dose-response of nitric oxide inhalation for systemic oxygenation and pulmonary hypertension in patients with adult respiratory distress syndrome

Abstract. Inhalation of nitric oxide (NO), an endoge-neous vasodilator, was recently described to reduce pulmonary vascular resistance, and to improve arterial oxygenation by selective vasodilation of ventilated areas in patients with adult respiratory distress syndrome (ARDS). We describe the time-course and dose-response of initial short-term NO inhalation in 12 patients with ARDS. Enhanced oxygenation was achieved within 1–2 min after starting NO inhalation; after inhalation, baseline conditions were re-achieved within 5–8 min. Effective doses for improvement of oxygenation [baseline: P_aO₂= 10.2±2.5 KPa (76.4±18.7 mmHg)] were low: ED₅₀ was about 100 ppb—a concentration similar to the atmosphere. NO doses of more than 10 ppm [10 ppm NO: P_aO₂=17.3 ± 3.3 KPa (129.4 ± 25.1 mmHg)] re-worsen the arterial oxygenation. The ED₅₀ for reduction of mean pulmonary artery pressure was 2–3 ppm. This indicates that inhalation of NO for improvement of oxygenation in severe ARDS should be performed using lower doses, with lower risk of toxic side effects.     

一氧化氮吸入对羊感染性急性呼吸窘迫综合征血液动力学和肺氧合功能的影响

目的：探讨一氧化氮（NO）吸入对羊感染性急性呼吸窘迫综合征（ARDS）血流动力学和肺氧合功能的影响。方法：静脉注入小剂量内毒素诱导羊感染性ARDS模型。随机分为两组：（1）NO组（n=6）为ARDS建立后，在容量控制通气基础上持续吸入40ppmNO 3h；（2）对照组（n=6)为ARDS一单纯容量控制通气，观察3h以确定模型的稳定性并与NO组比较，通过肺动脉导管和动脉血气分析，测定各组每小时肺气体交换和血流动力学参数，3h结束实验时，检测血中高铁血红蛋白（MetHb）浓度。结果：静脉注入小剂量内毒素能够诱导稳定的羊感染性ARDS模型，该模型的平均肺动脉压（MPAP）较基础值明显升高（P＜0．01），体循环血液动力学则能维持稳定。NO组各时点MPAP均较治疗前和同时点的对照组低（P＜0．01），动脉氧分压（PaO2）则明显增加（P＜0．01），肺泡动脉血氧分压差（PA－aO2)和肺内分流（Qs/Qt)明显低于治疗前和同时点的对照组（P＜0．01）。两组平均动脉压（MAP）和心排量（CO）各时点及治疗前后比较均无明显变化（P＞0．05），MetHb未见明显升高，结论：吸入NO选择性降低肺动脉压，改善肺氧合，无明显毒副作用。     

去甲肾上腺素对山羊急性呼吸窘迫综合征吸入一氧化氮疗效的影响

目的 观察去甲肾上腺素(NE)对山羊感染性急性呼吸窘迫综合征(ARDS)吸入一氧化氮(NO)疗效的影响。方法 静脉注入小剂量内毒素诱导山羊感染性ARDS模型6只,在吸入体积分数为40×10-6的NO 30 min后,联合静脉泵入NE 0.5μg·kg-1·min-1治疗。通过肺动脉导管、动脉和混合静脉血气分析,测定基础、ARDS时、NO吸入治疗30 min和联合NE静脉泵入治疗30 min后血流动力学指标和肺气体交换参数。结果 NO吸入治疗能显著降低ARDS山羊的平均肺动脉压(MPAP),增加动脉氧分压(PaO2),减少肺泡动脉氧分压差[P(A-a)O2]和肺内分流率(Qs/Qt);联合NE静脉泵入不影响吸入NO后降低的MPAP,增加吸入NO后升高的PaO2,降低NO吸入后减少的P (A-a)O2和Qs/Qt,升高吸入NO后无改变的平均动脉压(P<0.05或P<0.01);吸入NO及联合应用NE治疗均不改变ARDS山羊的心排血量。结论静脉注入NE能增强吸入NO后改善感染性ARDS肺气体交换的疗效。     

Miliary tuberculosis presenting as adult respiratory distress syndrome

We report the history of a 27-year-old Caucasian girl who died of adult respiratory distress syndrome secondary to miliary tuberculosis (MTB), after treatment with antibiotics to which the organism was sensitive, and a long period of ventilation. This case emphasises the importance of considering MTB as the cause of respiratory failure when another aetiology is not apparent.     

Immunoreactive trypsin in the adult respiratory distress syndrome

With the purpose of studying the role of proteinases in the development of ARDS, plasma levels of immunoreactive trypsin (IRT) and amylase were measured in 43 intensive care patients at risk of developing ARDS (22 polytrauma, seven abdominal surgery, four burns, two DIC and eight pancreatitis). Twenty four of these 43 patients developed ARDS and 31 presented abnormal IRT values (above 70 g/L). Twenty-one of these 31 patients had ARDS; a significant correlation thus appeared between ARDS and abnormal IRT values. In nine patients, IRT values were higher than 800 g/L and remained high for 3 to 4 days. A statistically significant correlation also appeared between abnormal IRT and septic phenomena: 20 patients with high IRT values presented septic problems. When IRT values were high, amylase values were often also abnormal: 12 of 23 patients with high IRT had abnormal amylase levels (the eight patients with documented pancreatitis were excluded); no other clinical signs or symptoms of pancreatitis were present in these patients. IRT could be one of the mediators of ARDS in septic patients. It is not clear that the pancreas is the origin of IRT in all cases.     

Use of prostacyclin and ultrafiltration in adult respiratory distress syndrome

A primigravida with severe kyphoscoliosis developed cardio-respiratory failure in pregnancy. Cardiac arrest occurred 10 days after Caesarean section; gastric acid was aspirated then and was followed by the development of adult respiratory distress syndrome. Initial recovery, with clearing of peripheral oedema, was followed by a recurrence of respiratory distress associated with infection. Profound hypoxaemia and oliguria unresponsive to diuretics were relieved by the infusion of prostacyclin combined with fluid removal by ultrafiltration. This treatment may be of value in the management of respiratory distress syndrome when pulmonary oedema is the dominant feature.     

一氧化氮吸入治疗新生儿呼吸窘迫综合征临床观察

目的观察一氧化氮(NO)吸入对新生儿呼吸窘迫综合征(NRDS)治疗作用及其有关影响因素。方法将49例NRDS患儿随机分为两组,对照组24例,采用综合治疗、肺表面活性物质(PS)替代疗法及氧疗等常规治疗;吸入NO(iNO)组25例,在常规治疗基础上加用NO吸入治疗,NO与机械通气同步使用,吸入浓度从10ppm开始,最高不超过30ppm,持续吸入时间24~36h,同时动态观察血气主要指标的变化。结果治疗后(24h)pH、PaO2、PaCO2、PaO2/FiO2、SaO2及肺泡动静脉氧分压差(A-a)PO26项血气指标的改善,iNO组优于对照组(P<0.01或0.05);iNO组在治疗后不同时期(1、12、24及36h)6项血气指标均有较好改善,与治疗前相比,除治疗后1h差异无统计学意义(P>0.05)外,治疗后12、24及36h各项指标差异均有统计学意义(P<0.05或0.01),且血气指标改善情况与吸入时间相关;iNO组在治愈率、死亡率及并发症发生率等转归方面均优于对照组(均P<0.05)。结论吸入NO治疗NRDS,尤其是重症和早产患儿,能够显著改善氧合功能,增加通气/血流比值,从而明显缓解临床症状,改善患儿的预后。对吸入NO的最有效时间,尚需进一步研究。     

Atrial natriuretic peptide infusion and nitric oxide inhalation in patients with acute respiratory distress syndrome

Aim  

To study the effects of infusion of atrial natriuretic peptide (ANP) versus the inhalation of nitric oxide (NO) in patients with an early acute respiratory distress syndrome (ARDS).     

Long-term inhalation with evaluated low doses of nitric oxide for selective improvement of oxygenation in patients with adult respiratory distress syndrome

Objective To evaluate the lowest dose of inhaled nitric oxide (NO) in patients with adult respiratory distress syndrome (ARDS), which is able to improve arterial oxygenation more than 30% compared to baseline data.Design Prospective, clinical study.Setting Anesthesiological ICU in a university hospital.Patients 3 consecutive patients with severe ARDS according to clinical and radiological signs.Interventions Pressure-controlled ventilation with positive endexpiratory pressure of 8–12 cm H₂O. Inhalation of NO was performed with a blender system and a Servo 300 ventilator. The lowest effective NO dose was defined by titrating the inspiratory NO dose until reaching a 30% improvement of PaO₂/FiO₂. This dose was used for the following continuous long-term NO inhalation; controls of efficacy by investigation of hemodynamics and blood gas exchange were performed initially and 2 times per patient after intervals of 3–5 days.Measurements and results Initial NO concentrations were found to be effective at 60, 100, and 230 parts per billion (ppb). In all measurements, arterial oxygenation was found to be elevated by NO inhalation with the initially evaluated dose compared to baseline data; in parallel, the venous admixture was reduced. The O₂ delivery increased, although O₂ consumption and hemodynamics did not change. In 1 patient, interruption of NO inhalation caused remarkable increase of pulmonary resistance.Conclusions The improvement of oxygenation by NO inhalation in ARDS does not require reduction of pulmonary resistance and can be performed using low doses in the ppb range, which has to be considered as probably non-toxic.The studies were supported by the Deutsche Forschungsgesellschaft (DFG), Grants Fa 139/1-3 and Fa 139/2-3. Dr. H. Gerlach completed this work during the tenure of a VTG Scientific Award     

Miliary tuberculosis and adult respiratory distress syndrome

Although, miliary tuberculosis is an unusual cause of severe acute respiratory failure, we describe nine patients with miliary tuberculosis who developed adult respiratory distress syndrome. This complication occurred in seven patients despite treatment with antituberculous drugs. In two patients who developed the syndrome, miliary tuberculosis was diagnosed only at postmortem. The presence of pulmonary hypertension in all cases and disseminated intravascular coagulation in seven cases suggests a possible pathophysiologic relationship with severe pulmonary vascular damage. The high mortality rate (88.8%) was associated with nonpulmonary organ system failure. Miliary tuberculosis should be considered in patients with adult respiratory distress syndrome of unknown etiology, and simple diagnostic procedures such as sputum, bronchial brushing, and gastric examination should be followed by invasive diagnostic procedures to confirm this etiology. Since untreated miliary tuberculosis is usually fatal, early recognition of this disease is of great importance, and specific therapy may play a lifesaving role.     

吸入一氧化氮联合反比通气治疗感染性急性呼吸窘迫综合征

目的 :观察吸入一氧化氮 (NO)联合反比通气 (IRV)对感染性急性呼吸窘迫综合征 (ARDS)羊血流动力学、肺气体交换和机械力学的影响。方法 :静脉注入小剂量内毒素诱导的羊感染性 ARDS模型 12只 ,随机均分为两组。 NO组吸入 4 0× 10 - 6 NO,复合组联合容量控制反比通气 (VC IRV)和吸入 4 0× 10 - 6 NO。通过肺动脉导管、动脉和混合静脉血气分析 ,测定基础、ARDS和治疗 30 m in后肺气体交换和血流动力学参数 ,记录相应时间点的气道峰压 (PIP)、平均气道压 (Pm)和内源性呼气末正压 (PEEPi)。结果 :NO组和复合组治疗期间平均肺动脉压较 ARDS时均显著降低 (P均 <0 .0 1) ,动脉血压和心排血量则无明显变化 ;治疗 30 m in后 ,两组均能明显提高 ARDS的 Pa O2 (P均 <0 .0 1) ,减少肺泡动脉氧分压差〔 P( A a) O2 〕和肺内分流 (Qs/ Qt,P均 <0 .0 1) ,复合组更为显著 (P均 <0 .0 5 ) ;NO组各监测时间点 PIP、Pm均无明显变化 ,复合组的 Pm较治疗前及NO组对应时间点高 (P均 <0 .0 5 ) ,PIP则低 (P均 <0 .0 5 )。复合组治疗时 ,PEEPi为 (2 .5± 0 .5 ) cm H2 O(1cm H2 O=0 .0 98k Pa)。结论 :吸入 NO复合 IRV可协同改善 ARDS肺氧合 ,不影响体循环。     

Atrial and brain natriuretic peptide concentrations and the response to inhaled nitric oxide in patients with acute respiratory distress syndrome

Purpose

The response to inhaled nitric oxide (iNO) is inconsistent in patients with acute respiratory distress syndrome (ARDS). We sought to determine whether the response to iNO, defined as 20% Pao₂/Fio₂ increase from baseline, depends on the level of cardiac natriuretic peptides.

Materials and methods

This is a prospective cohort study including 11 consecutive patients with ARDS who were eligible to receive iNO. Measurements of plasma concentrations of atrial natriuretic peptide (ANP), N-Terminal-Pro-B-Type Natriuretic Peptide (NT-pro-BNP) and 3′,5′-cyclic guanosine monophosphate were obtained before initiating iNO and 30 minutes later during iNO. Baseline cardiac peptides, oxygenation, and hemodynamic variables and their change during iNO were compared among responders and nonreponders to iNO.

Results

Baseline ANP and NT-pro-BNP concentrations were higher in patients that responded to iNO and tended to decrease during iNO in responders only. 3′,5′-Cyclic guanosine monophosphate concentrations were not different among responders and nonresponders and were unchanged during iNO. Baseline ANP was strongly correlated with change in intrapulmonary shunt, and baseline NT-pro-BNP and its change were correlated with the change in cardiac output.

Conclusions

High ANP and NT-pro-BNP concentrations are associated with the response to iNO. These data suggest that cardiac peptides have the potential to identify a subgroup of patients with ARDS who might derive clinical benefit from iNO.     

An index to predict outcome in adult respiratory distress syndrome

Thirty patients with adult respiratory distress syndrome required intermittent positive pressure ventilation;15 survived. In 25 the syndrome followed bacterial infection or multiple injuries. From the peak upper airway pressure,the oxygen gradient and the age of the patient, an index was obtained which discriminated between the survivours and those who died from the pulmonary lesion of the syndrome.     

一氧化氮吸入复合呼气末正压治疗羊感染性急性呼吸窘迫综合征

目的　观察一氧化氮 (NO)吸入复合呼气末正压 (PEEP)通气对羊感染性急性呼吸窘迫综合征 (ARDS)血流动力学、肺气体交换和机械力学的影响。方法　静脉注入小剂量内毒素诱导的羊感染性ARDS模型 12只 ,随机均分为两组 ,NO组 :吸入 40ppmNO ;复合组 :PEEP(6cmH2 O)通气复合吸入 40ppmNO。通过肺动脉导管和动脉血气分析 ,测定基础、ARDS和治疗 3 0min后肺气体交换和血流动力学参数 ,记录相应时点的气道峰压 (PIP)、平均气道压 (Pm)。结果　NO组和复合组治疗期间平均肺动脉压较ARDS时显著降低 (P <0 0 1) ,动脉血压和心输出量则无明显变化 ;治疗 3 0min后 ,两组ARDS的PaO2 均明显升高 (P <0 0 1) ,肺泡动脉氧分压差 (P(A -a)O2 )和肺内分流 (Qs/Qt)显著减少 (P <0 0 1) ,复合组比NO组更为显著 (P<0 0 5 ) ;NO组各监测时点PIP、Pm均无明显变化 ,复合组的PIP、Pm较治疗前明显增高 (P <0 0 5 )。结论　吸入NO复合PEEP通气协同改善ARDS肺氧合 ,不影响体循环     

一氧化氮吸入对感染性休克并发急性呼吸窘迫综合征患者氧合功能的作用及血流动力学的安全性研究

目的 :评估吸入低浓度一氧化氮 (NO)治疗感染性休克并发急性呼吸窘迫综合征 (ARDS)患者的有效性及对患者血流动力学的影响。方法 :对 17例感染性休克并发 ARDS患者行机械通气 ,Swan Ganz导管检查 ,观察吸入 10 m mol/ L NO前后氧合功能和血流动力学的变化。结果 :吸入 NO后 ,患者动脉血氧分压、血氧饱和度及氧合指数分别由 (8.6 7± 2 .15 ) k Pa(1k Pa=7.5 mm Hg) ,0 .86± 0 .0 8和 (9.6 3± 3.0 7) k Pa上升至(17.74± 8.82 ) k Pa,0 .95± 0 .0 8和 (2 5 .33± 11.36 ) k Pa(P均 <0 .0 0 1) ;肺内分流率由 (4 7.4± 13.3) %下降至(2 8.1± 12 .7) % (P<0 .0 0 1) ;血流动力学参数 :平均动脉压、平均肺动脉压、心输出量、心脏指数、体肺循环阻力指数、中心静脉压及肺动脉楔压均无明显变化 (P均 >0 .0 5 )。结论 :吸入低浓度 NO对感染性休克并发ARDS患者的氧合功能、血气指标有明显改善且血流动力学稳定 ,安全有效     

Improvement in oxygenation by prone position and nitric oxide in patients with acute respiratory distress syndrome

Objective: Inhaled nitric oxide (NO) and prone position improve arterial oxygenation in patients with the acute respiratory distress syndrome. This study was undertaken to assess the combined effects of NO and prone position in these patients. Design: Prospective clinical study. Setting: General intensive care service in a community teaching hospital. Patients: 14 mechanically ventilated adult patients with the acute respiratory distress syndrome (mean lung injury score 3.23 ± 0.27). Measurements and results: We measured hemodynamic and oxygenation parameters in the supine position and 2 h later in the prone position, before and during inhalation of 10 ppm NO. A positive response in oxygenation was defined as a ≥ 20 % increment in the arterial oxygen tension/fractional inspired oxygen ratio (PaO₂/FIO₂). In the prone position PaO₂/FIO₂ increased significantly (from 110 ± 55 to 161 ± 89 mmHg, p < 0.01) and venous admixture decreased (from 38 ± 12 to 30 ± 7 %, p < 0.01) compared to the supine position. Ten of the 14 patients were responders in the prone position. In the supine position, inhalation of NO improved oxygenation to a lesser extent, increasing PaO₂/FIO₂ to 134 ± 64 mmHg (p < 0.01) and decreasing venous admixture to 35 ± 12 %, (p < 0.01). Five of the 14 patients responded to NO inhalation supine and 8 of 14 responded prone (p = 0.22). The combination of NO therapy and prone positioning was additive in increasing PaO₂/FIO₂ (197 ± 92 mmHg) and decreasing venous admixture (27 ± 8 %) (p < 0.01). This combination also showed a positive oxygenation response on compared to the supine value without NO in 13 of the 14 patients (93 %). NO-induced changes in PaO₂/FIO₂ were correlated to changes in pulmonary vascular resistance only in the prone position. Conclusions: In patients with the acute respiratory distress syndrome, the combination of NO and prone position is a valuable adjunct to mechanical ventilation. Received: 15 June 1998 Final revision received: 13 October 1998 Accepted: 30 October 1998     

Endothelin production in sepsis and the adult respiratory distress syndrome

Objective Septic shock is characterised by a decrease in systemic vascular resistance. Nevertheless, regional increases in vascular resistance can occur which may predispose to organ dysfunction, including the adult respiratory distress syndrome (ARDS). Because endothelial damage is a major feature of acute lung injury, we examined whether the potent endothelial vasoconstrictor peptide endothelin-1 plays a pathophysiological role in sepsis of ARDS.Design Plasma endothelin was measured in mixed venous, pulmonary capillary and arterial blood, and the relationship with outcome measures was determined.Setting The intensive care unit of a university teaching hospital.Patients and participants A consecutive series of well-characterised patients with sepsis syndrome, both with (n=11) and without (n=15) ARDS, and ventilated controls without sepsis or ARDS (n=7).Measurements and results Plasma endothelin was significantly elevated in patients with sepsis alone and in patients with sepsis and ARDS. Plasma endothelin did not differ among mixed venous, pulmonary capillary and systemic arterial blood. On multiple regression analysis, plasma endothelin correlated positively with organ failure score and with oxygen consumption, and negatively with the P_aO₂FiO₂ ratio. There was no correlation with plasma creatinine, suggesting that decreased renal clearance did not account for the high plasma endothelin concentrations.Conclusions Although the lung does not appear to be the major site of endothelin production in critically ill patients with sepsis, increased endothelin production may contribute to regional increases in vacular resistance, hypoperfusion, and the development of organ failure, including ARDS, in patients with sepsis.