Nitric oxide administration after the ventilator: evaluation of mixing conditions

Background: Because of the potential toxicity of nitric oxide (NO) and its oxidising product nitrogen dioxide (NO₂), any system for the delivery of inhaled NO must aim at stable and predictable levels of NO and as low concentrations as possible of NO₂.
Methods: In a laboratory set-up, we have evaluated mixing conditions in a system where NO is added after the ventilator with continuous flow. Mixing was studied by using carbon dioxide (CO₂) as a tracer gas since capnography has a short response time (360 ms) in comparison with measurements of NO with electrochemical fuel cells (response time of 18s). CO₂ (in volumes corresponding to an ideal mixture of 1,3 and 6%) was fed, after the ventilator, either into plain breathing tubing, into one or two soda lime absorbers, or into an empty and a soda lime-filled canister, at different ventilatory rates and different I: E ratios. Samples were drawn from the inspiratory limb close to the Y-piece. NO was added in the same way and in the same volume as the highest concentration of CO₂.
Results: CO₂ added to plain tubing resulted in peak levels up to five times the set levels, while addition to a mixing box with an empty and a soda lime-filled canister resulted in even mixing with gas concentrations close to the ideal. When NO was fed into plain tubing, low levels were measured at the Y-piece, indicating poor mixing. Gas supply to a mixing chamber resulted in even concentrations.
Conclusions: Even and predictable levels of NO can be obtained with continuous flow of NO to the inspiratory limb, after the ventilator, if a mixing chamber is used. To obtain adequate mixing, the volume of the mixing box should be greater than the tidal volume.     

The role of soda lime during administration of inhaled nitric oxide

We have studied the ability of three commercially availablepreparations of soda lime to act as nitrogen dioxide scavengersduring administration of inhaled nitric oxide. Soda lime, witha green to brown colour change (indicator=potassium permanganate),markedly reduced concentrations of nitrogen dioxide, but alsomarkedly reduced inhaled concentrations of nitric oxide. Theother varieties of soda lime, with colour changes from pinkto white (indicator=kenazol yellow) or white to violet (indicator=ethylviolet), produced little effect on concentrations of nitrogendioxide. None of the above soda limes can be recommended foruse as a nitrogen dioxide scavenger during administration ofinhaled nitric oxide.     

Inhaled nitric oxide administration during one-lung ventilation in patients undergoing thoracic surgery

OBJECTIVE: To evaluate the effects of inhaled nitric oxide (iNO) on hemodynamics and oxygenation during one-lung ventilation (OLV) in the lateral decubitus position in patients undergoing elective thoracic surgery. DESIGN: Prospective study. SETTING: University hospital. PARTICIPANTS: Thirty consecutive patients scheduled for thoracotomy. INTERVENTIONS: Anesthesia consisted of thoracic epidural analgesia combined with general anesthesia (isoflurane, fentanyl, and vecuronium bromide). Systemic and pulmonary circulations were monitored with a radial artery catheter and a pulmonary artery catheter. Inhaled NO, 40 ppm, was administered during OLV, and the inhaled gas mixture was monitored for NO and nitrogen dioxide (NO2). Hemodynamic and oxygenation data were collected before and during inhaled NO administration. MEASUREMENTS AND MAIN RESULTS: Inhaled NO caused a reduction of pulmonary vascular resistance index from 249 +/- 97.6 dyne. sec. cm(-5) to 199.3 +/- 68.9 dyne. sec. cm(-5) (p < 0.05), without effects on systemic hemodynamics or impairment of oxygenation. A stratification of the patients according to values of QS/QT (< 30%, 30% to 44%, > or = 45%), PaO(2)/fraction of inspired oxygen (> or = 200, 100 to 199, < 100), and pulmonary hypertension (mean pulmonary arterial pressure < 24 or > or = 24 mmHg) showed that inhaled NO causes a significant reduction of mean pulmonary artery pressure in patients with pulmonary hypertension, mainly as a result of a reduction of pulmonary vascular resistance index, and improves oxygenation by reducing intrapulmonary shunt in patients with severe hypoxemia during OLV. CONCLUSIONS: Inhaled NO administration neither significantly decreased mean pulmonary arterial pressure in patients with normal pulmonary artery pressure nor improved oxygenation in nonhypoxic patients. Nevertheless, inhaled NO is effective in patients with pulmonary hypertension and hypoxemia during OLV.     

Inflammatory response during simulated extracorporeal circulation with addition of nitric oxide

BACKGROUND: Heart operations performed with extracorporeal circulation (ECC) are associated with an inflammatory response. This response is partially due to granulocyte activation. Leukocyte derived free radicals are involved in tissue injury. The purpose of this study was to observe whether nitric oxide influence the inflammatory response during simulated ECC. METHODS: In a model of simulated extracorporeal circulation, fresh whole human blood mixed with Ringer's solution was circulated through a heart-lung machine for three hours. In five circuits NO was added to oxygen/air mixture (group N), while five other circuits were ventilated with oxygen/air mixture (group C). The methods for estimating the inflammatory response were determination of oxygen free radicals production capacity, using chemiluminescence, and measurements of concentration of granulocyte derived proteins (myeloperoxidase and human neutrophil lipocalin). RESULTS: All measured parameters were similarly independent of additional supply of nitric oxide almost throughout extracorporeal circulation time. The sole significant difference between the two groups was found at an early stage of extracorporeal circulation, when luminol-enhanced chemiluminescence in whole blood was higher in the N group (1,500, 1,470-1,950 vs 1,038, 750-1,050 in the control group; medians with quartiles). A similar tendency was observed in lucigenin-enhanced chemiluminescence at 60 min of extracorporeal circulation (625, 560-875 in the N group vs 400, 360-525 in the control group; medians with quartiles). CONCLUSIONS: Nitric oxide supply does not influence inflammatory response during three hours long extracorporeal circulation, although some protective effect on hydrogen peroxide production in whole blood was detected in the initial phase of extracorporeal circulation.     

Feasibility of nitric oxide administration by neonatal helmet-CPAP: a bench study

Background: Inhaled nitric oxide (NO) may have a role in the treatment of preterm infants with respiratory failure. We evaluated the feasibility of administering NO therapy by a new continuous positive airway pressure (CPAP) system (neonatal helmet‐CPAP). Methods: While maintaining a constant total flow of 8, 10, and 12 l·min⁻¹, NO concentrations were progressively increased to 5, 10, 20, and 40 p.p.m. in the neonatal helmet‐CPAP pressure chamber (5 cmH₂O). NO, NO_2, and O₂ concentrations were measured in the pressure chamber and the immediate external environment. Results: In the chamber, NO₂ levels remained low (≤0.8 p.p.m.) at inhaled therapeutic NO concentrations (5, 10, 20, and 40 p.p.m.). The lower O₂ concentrations were 95% at 40 p.p.m. NO levels. Leakage of NO and NO₂ to the surrounding environment was negligible. Conclusions: NO administration is safe and feasible using the neonatal helmet‐CPAP system. This method allows the delivery of accurate NO levels and high O₂ concentrations avoiding NO₂ accumulation. Further experimental and clinical studies are needed.     

Combined administration of nitric oxide gas and iloprost during cardiopulmonary bypass reduces platelet dysfunction: a pilot clinical study

BACKGROUND: Thrombocytopenia and platelet dysfunction are major mechanisms of cardiopulmonary bypass-induced postoperative hemorrhage. This study evaluated the effects of low amounts of nitric oxide, iloprost (prostacyclin analog), and their combination administered directly into the oxygenator on platelet function, platelet-leukocyte interactions, and postoperative blood loss in patients undergoing coronary artery bypass grafting. METHODS: Blood samples from 41 patients randomized to the control, nitric oxide (20 ppm), iloprost (2 ng x kg -1 x min -1 ), or nitric oxide plus iloprost groups were collected during cardiopulmonary bypass. Platelets and leukocytes were enumerated. Platelet membrane glycoprotein Ib and glycoprotein IIb/IIIa, P-selectin, platelet-derived microparticles, leukocyte CD11b/CD18 (Mac-1), and platelet-leukocyte aggregate were quantified by means of flow cytometry. Collagen and thrombin receptor-activating peptide-induced platelet aggregation in whole blood was analyzed by means of aggregometry. RESULTS: Both nitric oxide or iloprost attenuated cardiopulmonary bypass-induced thrombocytopenia, reduction of glycoprotein Ib and glycoprotein IIb levels, translocation of P-selectin, microparticle formation, Mac-1 upregulation, and suppression of collagen-induced aggregation. Nitric oxide plus iloprost was significantly more effective in preventing thrombocytopenia, microparticle formation, and P-selectin translocation. Moreover, this treatment preserved thrombin receptor-activating peptide-induced aggregation, which was not rescued by single treatments. Both nitric oxide and nitric oxide plus iloprost attenuated postoperative blood loss. CONCLUSIONS: Nitric oxide plus iloprost reduced the deleterious effects of cardiopulmonary bypass, such as thrombocytopenia, platelet activation, platelet-leukocyte aggregate formation, and suppression of platelet aggregative responses. The reduced postoperative bleeding observed with this treatment suggests that this is a new and clinically feasible therapeutic option for patients subjected to cardiopulmonary bypass.     

Inhalation administration of nitric oxide during selective pulmonary ventilation decreases the intrapulmonary shunt]

OBJECTIVE: To assess the effects of inhaled nitric oxide (NO) on oxygenation and hemodynamics in patients undergoing lung resection surgery during one-lung ventilation (OPV). PATIENTS AND METHODS: Prospective study of 16 patients aged 62 +/- 10 years scheduled for chest surgery under combined general and epidural anesthesia. During ventilation of only one lung, NO was administered for 15 minutes. Arterial blood and mixed venous blood samples were taken for analysis of blood gases and the calculation of intrapulmonary shunt. Pulmonary and systemic hemodynamic variables were also recorded using a Swan-Ganz catheter at three times: baseline (ventilation of both lungs), OLV, and with OLV plus NO (OLV NO). RESULTS: The most relevant data consisted of a significant decrease in shunt after start of NO inhalation in comparison with the level during OLV (31.1 +/- 0.5% versus 36 +/- 0.6%; p < 0.05). Arterial oxygen pressure decreased significantly during OLV and increased after start of NO (118.9 +/- 53.6 versus 155.4 +/- 78.5 mmHg; p < 0.05). Mean pulmonary artery pressure, pulmonary and systemic vascular resistances, and cardiac index did not change with inhalation of NO. CONCLUSIONS: Inhalational administration of NO during OLV significantly improves arterial oxygenation and decreases intrapulmonary shunt during OLV, without causing hemodynamic or systemic effects.     

Preoperative and postoperative response to inhaled nitric oxide

The preoperative dose response to inhaled nitric oxide (NO) was compared with the need for and response to NO after cardiac surgery in patients with congenital heart defect and secondary pulmonary hypertension. In a preoperative vasodilator test with inhaled NO 20, 40 and 80 ppm and oxygen, mean pulmonary artery pressure (PAP) was at least 40 mmHg and/or the pulmonary vascular resistance index (PVRI) 4 Wood units. Preoperatively, NO 40 ppm and FiO2 0.9 reduced systolic pulmonary/systemic arterial pressure (PAPs/SAPs) from 0.89 (SD 0.10) to 0.80 (0.18) and pulmonary/systemic vascular resistance (PVR/SVR) from 0.26 (0.13) to 0.13 (0.08). Haemodynamic assessment was repeated in 11 patients postoperatively. NO treatment was started if PAPs/SAPs rose to 0.8 or the pulmonary oximetry fell below 40%. Postoperatively, eight of 11 patients, including 6 patients with Down's syndrome, needed NO. PAPs/SAPs decreased more than preoperatively: 48.5% vs 11.2, p = 0.0045. Pulmonary oximetry increased by 15.7%, p = 0.02. The degree of preoperative response to NO did not differ between the patients with postoperative pulmonary hypertension and the other children. Patients with early pulmonary hypertensive crisis (first 24 h; n = 6) had a higher PVRI (7.6 vs 4.4 Um2; p = 0.003) and PVR/SVR (0.34 VS 0.17; p = 0.02) preoperatively. Two patients died in pulmonary hypertensive crisis.     

大鼠肝缺血／再灌注后肝组织一氧化氮和不同亚型一氧化氮合酶的变化

目的探讨一氧化氮（NO）和一氧化氮合成酶（NOS）在肝缺血／再灌注（I／R）过程中的变化和作用。方法健康雄性SD大鼠24只，随机分为3组（每组8只）：①正常对照组，术中只分离肝周围韧带，不做肝门阻断及再灌注。②I/R组，进行45min的部分肝门阻断及60min的再灌注。③L-精氨酸（L—Arg）组，缺血前20min经阴茎背静脉注射L—Arg（300mg／kg），余同②组。实验结束后，取下腔静脉血2ml，并迅速切取缺血肝组织。检测血清丙氨酸转氨酶（ALT）、门冬氨酸转氨酶（AST）、乳酸脱氢酶（LDH）；测定肝组织中超氧化物歧化酶（SOD）、丙二醛（MDA）、黄嘌呤氧化酶（XOD）、一氧化氮（NO）和一氧化氯合成酶（NOS）等指标；观察光镜和电镜下肝组织学变化。结果与正常对照组相比，I／R组iNOS升高，NO降低；L-Arg组NO、eNOS均高于I／R组。2、3组比1组大鼠的肝组织病理损害重、肝功能差，L—Arg组病理损害较I／R组明显减轻、肝功能改善。结论NO对大鼠肝I／R损伤具有保护作用．不同亚型NOS的变化参与其中。     

Placebo-controlled study of inhaled nitric oxide to treat hypoxaemia during one-lung ventilation

The aim of this prospective, placebo-controlled study was to assess if unilaterally inhaled nitric oxide 20 ppm could treat hypoxaemia during one-lung ventilation. Sixty patients undergoing pulmonary resection using a lateral thoracotomy were allocated randomly to a control or nitric oxide group (NO group). During one-lung ventilation in the lateral decubitus position, the lungs were ventilated mechanically with 90% oxygen--10% nitrogen. After randomization, if PaO2 decreased to less than 9.3 kPa during one-lung ventilation, nitric oxide 20 ppm or nitrogen was added to the inspired gas. The criterion for treatment efficacy was an increase in PaO2 to greater than 9.3 kPa after gas administration. Eight patients in the control group and eight in group NO experienced hypoxaemia during one-lung ventilation. PaO2 was not significantly different in the two groups at the time of gas administration (control group mean 8.0 (SD 0.6) kPa; NO group 8.5 (0.5) kPa). The efficacy criterion was reached in two of eight patients in the control and NO groups. The results of this study showed that inhaled nitric oxide 20 ppm, administered in the dependent lung, was not superior to nitrogen in the treatment of hypoxaemia during one-lung ventilation. Nitric oxide should not be recommended as an alternative to conventional management of hypoxaemia in this condition.      

Evaluation of Mapleson systems for administration of inhaled nitric oxide

To assess the safety of nitric oxide (NO) inhalation during manual-controlled ventilation using Mapleson A, D, and F systems, we examined nitrogen dioxide (NO₂) production using a chemiluminescence analyzer. The NO concentration was changed from 0 to 19 parts per million (ppm), and at each level of NO the oxygen (O₂) concentration was changed from 21% to 100%. The NO₂ concentration was observed to increase when either the O₂ or NO concentration was increased. The maximum NO₂ concentrations (mean ± standard deviation) of the Mapleson A, D, and F systems were 0.20±0.03, 0.15±0.03, and 0.17±0.02 ppm, respectively, when the concentrations of NO and O₂ were 19 ppm and 100%, respectively. The NO₂ concentrations of the Mapleson A system were significantly higher than those of either the Mapleson D or F system at 4, 8, and 12 ppm NO and 100% O₂, and than that of the Mapleson D system at 19 ppm NO and 100% O₂. From the viewpoint of NO₂ production, we suggest that the Mapleson D and F systems are safer than the Mapleson A system when manual-controlled ventilation is required.     

Small-dose nitric oxide improves oxygenation during one-lung ventilation: an experimental study

Inhaled nitric oxide (NO) at 20 or 40 ppm does not improve arterial oxygenation during one-lung ventilation (OLV). The authors hypothesized that NO at smaller concentrations might improve oxygenation. Twelve piglets weighing 26 to 32 kg were studied. When PaO(2) had reached a plateau during OLV, NO at doses of 4, 8, 16, and 32 ppm were randomly administered for 30 min. Hemodynamic data were determined by invasive monitoring. Blood gas analysis and, in six animals, ventilation-perfusion analysis by the multiple inert gas elimination technique were used to characterize pulmonary gas exchange. NO at 4, 8, 16, and 32 ppm improved PaO(2) during OLV. NO at 4 ppm had a more intense effect on arterial oxygenation than doses of 8, 16, and 32 ppm (DeltaPaO(2), 42 +/- 35 mm Hg versus 22 +/- 20 mm Hg, 13 +/- 18 mm Hg, and 15 +/- 16 mm Hg; P < 0.05). NO at 4 ppm reduced intrapulmonary shunt flow, whereas a larger concentration exhibited no statistically significant effect. The authors conclude that NO improves arterial oxygenation more effectively at smaller doses than at larger doses. This dose-dependent effect remains to be confirmed in acute hypoxemia during OLV. IMPLICATIONS: Inhaled nitric oxide at 4 ppm improves arterial oxygenation during one-lung ventilation to a greater extent than larger doses, and this effect is caused by a reduction in intrapulmonary shunt.     

Production of nitrogen dioxide during nitric oxide therapy using the Servo Ventilator 300 during volume-controlled ventilation

BACKGROUND: Inhaled nitric oxide may be useful in the treatment of pulmonary hypertension and hypoxaemia. Nitric oxide is rapidly oxidized to nitrogen dioxide, which is toxic and may adversely affect the airways of the patient. The aim of the present investigation was to examine factors that may affect the concentration of nitrogen dioxide, using the Servo Ventilator 300 nitric oxide delivery system, where nitric oxide is flow-proportionally mixed with the main ventilatory flow in the proximal part of the inspiratory limb. METHODS: In this experimental study nitric oxide and nitrogen dioxide levels were measured at the inspiratory site of a Y-piece with a chemiluminescence analyzer and electrochemical fuel cells. The effects of different concentrations of nitric oxide and oxygen, minute volume, different tube lengths, a soda lime absorber, and a humidifier placed in the inspiratory limb were evaluated. RESULTS: The concentration of nitrogen dioxide was dependent on the concentrations and residence time of nitric oxide with oxygen and the minute volume ventilation used. A soda lime absorber reduced concentrations of nitrogen dioxide at the expense of almost corresponding reductions in inhaled concentrations of nitric oxide. A humidifier increased the concentration of nitrogen dioxide, to an extent depending on the water volume and temperature used. CONCLUSION: Concentrations of nitric oxide and oxygen, minute volume ventilation, and residence time in the inspiratory part of the ventilatory circuit were factors that affected the generation of nitrogen dioxide. A soda lime absorber in this system is not recommended.     

Evaluation of a new system for ventilatory administration of nitric oxide

A new system for delivery of nitric oxide (NO) to inspiratory gas consisting of two mass flow regulators and a soda–lime absorber for scavenging of nitrogen dioxide (NO₂) is described. The system was evaluated using three different techniques for NO analysis (infrared, chemi–luminescence and electro–chemical fuel cell technique). The electro–chemical fuel cell was less sensitive to humidity in the sample and is suitable for clinical routine use. The infrared analyser was very sensitive to humidity and the gas sample must be dried by silica gel, which absorbs NO₂ and will cause falsely low NO₂ values. NO₂ was analysed with ultra–violet methodology. NO₂ is highly toxic and the highest recommended occupational health and safety level for inhalation is 5 ppm. The highest values of NO₂ in our system were detected before the absorber in the inspiratory limb of the breathing system, being 5 ppm at 100% oxygen and 100 ppm NO using “infant” respiratory settings (3 1/min in ventilation, frequency of 30/min). The corresponding value for “adult” respiratory settings (10 1/min in ventilation, frequency of 15/min) was 3.2 ppm. The absorber reduced these levels to well below 1 ppm. When clinically relevant levels of NO were used (20 ppm), no NO₂ could be detected after the absorber, irrespective of oxygen concentration in the breathing gas. It was observed that gas cylinders with NO mixed in nitrogen may initially have a high NO₂ concentration (around 12 ppm) and should be flushed thoroughly before use.     

Evaluation of a delivery system and monitors for ventilator administration of nitric oxide

The aim of this study was to compare nitric oxide (NO) and nitrogen dioxide (NO₂) measurements obtained by chemiluminescence and electrochemical monitors using a delivery system for ventilator administration of NO. The formation of NO₂ in this system and the efficacy of a soda-lime absorber to scavenge NO₂ from inspiratory gas were also evaluated. Various concentrations of NO without and with soda lime were administered to a model lung via a Servo ventilator 900C with controlled ventilation by setting mass-flow regulators to maintain desired concentrations of NO in 80% O₂. Close correlations were found between NO concentrations, as well as NO₂ concentrations, measured using electrochemical monitors (TM100; 1002, PACII) and a chemiluminescence monitor (CLA-510SS). Soda-lime removed NO₂ almost completely during administration of 0–25 p.p.m. NO, although a high concentration of NO₂ appeared in the breathing circuit without soda lime. Four hundred grams of soda lime continued to absorb NO₂ effectively during long-term administration of inhaled NO. These findings suggest that electrochemical monitoring is accurate and clinically useful for measurements of NO and NO₂ concentrations, and that low doses of inhaled NO can be administered safely and reliably with the NO delivery system using a soda-lime absorber and mass-flow regulators.     

A single-blind study of combined pulse oximetry and capnography in children

This single-blind study examined four levels of monitoring in 402 pediatric cases. Patients were randomly assigned to one of four groups: 1) oximeter and capnograph; 2) only oximeter; 3) only capnograph; or 4) neither oximeter nor capnograph data available to the anesthesia team. An anesthesiologist, not involved in patient care, observed all cases and continuously recorded hemoglobin oxygen saturation (Spo2), ECG, expired CO2, and the oximeter plethysmographic output. Mean age, weight, ASA physical status, airway management (mask or endotracheal tube), and anesthetic technique were similar in each group. Two-hundred sixty problems were documented in 153 patients. Fifty-nine events in 43 patients resulted in "major" desaturation (Spo2 less than or equal to 85% for greater than or equal to 30 s). Fifteen "major" capnograph events (esophageal intubation, disconnection, accidental extubation, or obstructed endotracheal tube) were observed in 11 patients; 8 of these also developed varying degrees of desaturation. One-hundred thirty "minor" desaturation events (Spo2 less than or equal to 95% for greater than 60 s) and 79 "minor" desaturation events (hypercarbaria or hypocarbia) were observed. A number of problems fulfilled criteria in multiple categories. Infants less than or equal to 6 months of age had the highest incidence of major desaturation events (18 of 65 [27%]) compared to toddlers 7-24 months of age or children greater than 24 months of age (P less than 0.001). Blinding the oximeter data increased the number of patients (12 vs. 31) experiencing major desaturation events (P = 0.003); blinding the capnograph data altered neither the frequency of desaturation events nor the incidence of major capnograph events.(ABSTRACT TRUNCATED AT 250 WORDS)