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.     

Safety aspects of delivery and monitoring of nitric oxide during mechanical ventilation

In the presence of oxygen NO is oxidised to NO₂, which is toxic in higher concentrations.
In this technical investigation, we evaluated a dosage system, modified from Stenqvist et al. 1993 (1), regarding NO and NO₂ levels. NO was administered before the ventilator and NO₂ scavenged using a soda lime absorber in the inspiratory limb close to the ventilator. NO/NO₂ levels were measured using fuel cell technique. We tested the duration of soda lime scavenging, put in additional soda lime absorbers, used charcoal as absorber and exchanged tubing material. NO was delivered after the ventilator and we studied effects of interruption of ventilation.
With concentrations of NO at or below 40 parts per million (ppm) at F₁O₂ 0.9, NO₂ levels were 1.2 pprn or lower. Corresponding values for 20 and 10 ppm were 0.4 and 0.2 ppm, respectively. Duration of the soda lime absorber was at least 72 hours. Additional soda lime absorbers did not further reduce NO₂ levels. Charcoal absorbers reduced NO₂, but also NO by 45% from set value. Tubing materials had no influence on NO and NO₂ levels. When administering NO at the Y-piece, levels of NO were increased by 35–60% and NO₂ levels by 110–230%, compared to set values.
Oxidation of NO to NO₂ is continuously taking place in the breathing system. Doses of up to 40 pprn NO should be considered safe regarding NO₂ levels. Administration of NO at the Y-piece gives high and unpredictable levels of NO₂.     

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.     

一氧化氮合酶对精索静脉曲张患者精子功能的影响

为探讨一氧化氮、一氧化氮合酶对精索静脉曲张（VC）患者精子功能的影响,本文测定15例VC不育患者外周静脉血清、精索静脉血清和精浆中一氧化氮（NO）及一氧化氮合酶（NOS）,并与12例有生育能力的对照组进行了对比研究。结果显示VC组精索静脉血清和精浆中NO含量及NOS活性,不仅高于其外周静脉血清（P＜0．01）,而且高于对照组（P＜0．01）,但两组外周静脉血清中两项指标无显著性差异（P＞0．05）。提示VC时可能是由于曲张精索静脉血和精浆中NOS的产生增加导致精子生成障碍或（和）精子活力下降,从而导致不育症。     

Administration of nitric oxide into open lung regions: delivery and monitoring

Background. Pulsed administration of nitric oxide has proveneffective in relieving pulmonary hypertension and in improvingoxygenation. With this delivery method the nitric oxide administrationto low ventilated lung regions is avoided with subsequent enhancementin oxygenation. This study presents (i) pulsed administrationtechnique for nitric oxide during artificial ventilation, (ii)evaluation of the delivery in an animal model, and (iii) validationof the delivery device in a laboratory setting. Methods. Nitric oxide was delivered in four different pulsevolumes synchronously with inspiration. The delivery was monitoredwith a fast responding high sensitivity nitric oxide monitorand nitric oxide uptake was calculated. Pulse delivery doserange, accuracy of the delivered dose, and stability of successivedoses were analysed in a laboratory setting. Results. Uptake of the delivered nitric oxide was 87–92%.Measured nitric oxide pulse concentration was 1.6-fold the deliveryconcentration, calculated as the ratio of nitric oxide flowto inspiration flow. Dose accuracy and stability were both 5%or 3 nmol in the validated range of 3–1000 nmol. Conclusion. With pulsed administration nitric oxide therapycan be directed to well-ventilated lung regions. Avoiding administrationto the anatomic dead space eliminates nitric oxide exhalationeffectively, which makes the method optimal for nitric oxidetherapy in a rebreathing circuit. The required dose range frompaediatric to adult is covered by the delivery device with asingle nitric oxide gas supply. Br J Anaesth 2003; 90: 338–42     

Nitric oxide: description of a pipeline delivery system

We describe a pipeline system suitable for the delivery of nitric oxide gas to an 18-bed intensive care unit. The pipeline was developed and installed according to the current UK regulations HTM 2022, which relates to the supply of piped medical gases. Where HTM 2022 did not specify the appropriate standard, we consulted widely to achieve a safe solution. We continue to monitor all aspects of the performance of the pipeline to ensure safe operating practices and recommend changes to the standards.     

Nitric oxide pathways in circular muscle of the rat jejunum before and after small bowel transplantation

Previous studies suggest that nitric oxide synthase is upregulated after small bowel transplantation which may have implications in enteric dysfunction after small bowel transplantation. The aim of this study was to determine the role of nitric oxide in nonadrenergic, noncholinergic inhibitory function after small bowel transplantation in rat jejunal circular muscle. The following four groups of rats (n =≥8 rats per group) were studied: Neurally intact control animals; 1 week after anesthesia and sham celiotomy, and either 1 week or 8 weeks after isogeneic, orthotopic small bowel transplantation. Full-thickness jejunal circular muscle strips were evaluated under isometric conditions for spontaneous contractile activity, response to electrical field stimulation, and effects of exogenous nitric oxide and nitric oxide antagonists. Spontaneous activity did not differ among groups. Electrical field stimulation inhibited activity similarly in all groups. Exogenous nitric oxide, N^G-monomethyl L-arginine monoacetate salt (a nitric oxide synthase inhibitor), and methylene blue (cGMP antagonist) had no effect on spontaneous activity. Neither nitric oxide antagonist altered the inhibitory response to neural excitation by electrical field stimulation in any group. Nitric oxide, a known inhibitory neurotransmitter in other gut smooth muscle, has no apparent role in rat jejunal circular muscle before or after small bowel transplantation. Supported by grant DK 39337 from the National Institutes of Health, United States Public Health Service, the Mayo Foundation, the Swiss National Foundation, and the Department of Visceral and Transplantation Surgery, University of Bern, Switzerland. Part of this study was presented at a poster session at the Fortieth Annual Meeting of The Society for Surgery of the Alimentary Tract, Orlando, Fla., May 16–19, 1999. An abstract of this work was published in Gastroenterology 116:A1349, 1999.     

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.     

Nitric oxide synthase in the external urethral sphincter of the sheep: immunohistochemical and functional study

PURPOSE: We studied the distribution of neuronal nitric oxide synthase (nNOS) and the effects of nitric oxide (NO) modulating drugs on contractile function of the external urethral sphincter of lambs. Gender differences were evaluated. MATERIALS AND METHODS: Longitudinal and transverse sections of the external urethral sphincter from 10 female and 10 male lambs were studied using reduced nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry and nNOS immunocytochemistry. Isometric contractile responses to electrical field stimulation were recorded from external urethral sphincter preparations from 47 female and 45 male lambs and the effects of NO modulating drugs were evaluated. RESULTS: We detected nNOS in the sarcolemma of some but not all striated fibers, where nNOS seems to be concentrated at the neuromuscular junction. In addition, nNOS was present in nerve fibers and intramural ganglia. The density of innervation decreased toward the distal part of the external urethral sphincter and was higher in male preparations. No significant functional effects of the NOS inhibitor NG-nitro-L-arginine (10 mM.) or the NO donors diethylamine and spermine NONOate (Sigma Chemical Co., St. Louis, Missouri) (5 mM. each) on external urethral sphincter isometric contractility were found in either gender. CONCLUSIONS: Despite the evidence for nNOS at the sarcolemma and nerve fibers of the external urethral sphincter the physiological relevance of these immunohistochemical findings remains to be determined.     

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.     

The design and evaluation of a novel low-cost portable ventilator

Modern mechanical ventilator technologies broadly consist of digitally-controlled electronic devices and analogue systems driven by compressed gas sources. Drawbacks such as high cost, complex maintenance and the need for cumbersome sources of compressed driving gas hinder adoption in pre-hospital and low-resource environments. We describe the evaluation and testing of a simple, low-cost alternative ventilator that uses a novel pressure-sensing approach and control algorithm. This is designed to provide portable positive-pressure mechanical ventilation at a reduced cost, while autonomously monitoring patient condition and important safety parameters. A prototype ventilator was constructed and evaluated using an anaesthetic test-lung as a patient surrogate. Using a modifiable test-lung and digital pressure sensor, we investigated ventilation pressure waveform circuit leak detection, and compliance and resistance change detection. During intermittent positive-pressure ventilation to the test-lung, the prototype system showed acceptable pressure waveform parameters: all simulated circuit leaks ≥ 6 mm² in size were detected; compliance changes were detected between 10 ml.cmH₂O⁻¹, 20 ml.cmH₂O⁻¹ and 50 ml.cmH₂O⁻¹; and resistance changes were detected across the available simulated range. These results show this prototype technology has the potential to provide safe emergency ventilation without the use of any complex digital sensors or software while its construction and design enables significant reductions in cost and complexity. The study suggests further work is now justified in progressing the technology to clinical trials.     

Nitric oxide added to the sweep gas of the oxygenator during cardiopulmonary bypass in infants: A pilot randomized controlled trial

Our objective was to assess the effect of nitric oxide added to the sweep gas of the oxygenator during cardiopulmonary bypass (CPB) in infants on platelet count, platelet function, clinical outcomes, and safety. A randomized, double‐blinded, placebo‐controlled clinical trial in infants less than a year of age undergoing cardiac surgery requiring CPB was undertaken. Nitric oxide at a dose of 20 ppm was added to the sweep gas in the treatment group. Blood was collected at baseline and prior to separation from CPB to measure platelet count and function as determined by responsiveness to specific agonists. Clinical outcomes were observed through hospital discharge. Methemoglobin levels were measured preoperatively, at the conclusion of CPB, and upon admission to the ICU. Forty patients consented and were randomized in the trial. Eighteen patients were randomized to the treatment group and 22 were included in the placebo group. The groups were similar in terms of age, weight, gender, and surgical complexity. No significant differences were found in measures of platelet count, platelet response to agonist, or clinical outcomes. Patients in the treatment group had higher methemoglobin levels after receiving nitric oxide, but no levels approached toxicity (maximum 2.4%). Nitric oxide added to the sweep gas of the oxygenator during CPB in infants did not have an appreciable effect on the preservation of platelet count, platelet responsiveness to agonist, or clinical outcomes. Methemoglobin levels were increased after receiving nitric oxide but were far below a toxic level of 15%.     

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.     

Effects of ventilatory pattern on exhaled nitric oxide in mechanically ventilated rabbits

BACKGROUND: Nitric oxide [NOexp] is present in exhaled air in many species. During experiments on pressure-controlled inverse ratio ventilation (PCIRV) in rabbits, increased [NOexp] was observed during PCIRV. The present study was undertaken to clarify which component of PCIRV increased [NOexp]. METHODS: Three groups of six New Zealand White rabbits were anaesthetised and mechanically ventilated. Exhaled nitric oxide, lung mechanics and gas exchange were measured using an experimental protocol designed to assess the effects of variations in 1) flow profile, 2) inspiratory time and 3) time-weighted tidal volume. Ventilator settings used were volume and pressure control ventilation at I:E ratios of 1:2 and 4:1. RESULTS: Constant and decelerating flow gave comparable [NOexp] levels (20.0 +/- 6.4 vs. 21.9 +/- 7.7 ppb, n.s.) when time-weighted tidal volume was kept constant. Using conventional (I:E 1:2) or inverted (I:E 4:1) I:E ratios in combination with decelerating flow and constant time-weighted tidal volumes did not alter [NOexp] (26.0 +/- 3.6 vs. 24.0 +/- 5.8 ppb, n.s.). An increased time-weighted tidal volume produced by pressure control with an I:E ratio of 4:1 increased [NOexp] (29.6 +/- 7.4) in comparison to constant (19.3 +/- 4.1, P < 0.05) and decelerating flow ventilation (19.6 +/- 3.6, P < 0.05) with I:E ratios of 1:2. CONCLUSION: The exhaled NO concentration was affected by ventilator setting. Increased levels of [NOexp] were observed with increases in time-weighted tidal volume, whereas changes in flow pattern and inspiratory time did not seem to influence airway NO production or release.     

Nitric oxide and skeletal muscle reperfusion injury: current controversies (research review)

Nitric oxide (NO) has been implicated in a large number of disease processes, including ischemia-reperfusion injury following the restoration of oxygenated blood to previously ischemic muscle, which is a recognized significant complication of vascular surgery. Altered metabolism of NO is implicated in the endothelial dysfunction that forms part of the pathophysiology of ischemia-reperfusion injury. However, NO can demonstrate either protective or cytotoxic effects during reperfusion injury. The use of transgenic mice, either NO synthase (NOS) gene knockout animals, or animals that over-express NOS isoforms, along with direct NO measurements and NO donor or inhibitor studies, have all demonstrated a role for NO in skeletal muscle reperfusion injury. There appears to be an initial stimulation of NO production in the first 20-min of ischemia, with a gradual decline through early reperfusion and a second higher peak of NO commencing in the later stages of reperfusion. The absolute levels of NO in the reperfused tissue and its regulation by the subtle interplay with superoxide and the subsequent production of the highly toxic peroxynitrite anion, are important factors in determining whether NO, in the context of ischemia-reperfusion injury, has damaging or protective effects in the body.     

Nitric oxide and superoxide in rat mesangial cells: modulation by C-reactive protein

Background: C-reactive protein (CRP) has been linked to cardiovascular and renal disease. We evaluated the effects of CRP on the production of nitric oxide (NO) and superoxide by rat mesangial cells (RMC) and the impact on cell function. Methods and Results: RMC were incubated with cytokines (IFN-γ, IL-1β, and LPS) and CRP (10–100 μg/ml) for 24–72 h. Exposure to CRP resulted in a time- and dose-dependent reduction in NO accumulation (p<0.05). Although inducible nitric oxide synthase (iNOS) protein expression was unaltered after 48 h, CRP stimulated expression of HSP90. Steady state abundance of iNOS mRNA increased nearly threefold after a 24-h exposure to CRP. Incubation with 100 μg/ml CRP for 60–120 min resulted in a 272% increase in superoxide production that was prevented by diphenyleneiodium chloride but not L-NAME (p<0.0001). Conclusion: CRP enhances superoxide release in RMC, which in turn inactivates NO and reduces net production. The functional relevance of these CRP-induced changes is supported by increased expression of HSP90 in RMC exposed to the mediator. These findings suggest that systemic inflammation, which contributes to the pathogenesis of atherosclerosis, may play a role in the progression of kidney disease.