Toxicity and complications of inhaled nitric oxide

The extent of toxicity and adverse effects resulting from inhaled NO is poorly understood. Presumably, toxicity is low and adverse effects are rare at the doses commonly used to treat acute respiratory failure. Much remains to be learned about this important topic, however.     

Electrochemical nitric oxide and nitrogen dioxide analyzer for use with inhaled nitric oxide

The use of inhaled nitric oxide (NO) in research and clinical applications requires the monitoring of NO and its autooxidation product nitrogen dioxide (NO2) in inspired gas and in the ambient environment. We describe an inexpensive electrochemical NO and NO2 analyzer that uses a critical orifice constant-flow controller and a microprocessor crossover correction for the measurement of NO and NO2 in the concentration range relevant to the use of inhaled NO. The analyzer proved to have good accuracy and precision for NO and NO2 in the range of concentrations relevant to studies of inhaled NO. In this range, the performance was similar to that of a chemiluminescence analyzer, and the response characteristics were not affected by varying the O2 concentration of the mixtures analyzed.     

Treatment of septic shock in rats with nitric oxide synthase inhibitors and inhaled nitric oxide

OBJECTIVE: To evaluate the effect of treatment with a combination of nitric oxide synthase inhibitors and inhaled nitric oxide on systemic hypotension during sepsis. DESIGN: Prospective, randomized, controlled study on anesthetized animals. SETTING: A cardiopulmonary research laboratory. SUBJECTS: Forty-seven male adult Sprague-Dawley rats. INTERVENTIONS: Animals were anesthetized, mechanically ventilated with room air, and randomized into six groups: a) the control group (C, n=6) received normal saline infusion; b) the endotoxin-treated group received 100 mg/kg i.v. of Escherichia coli lipopolysaccharide (LPS, n=9); c) the third group received LPS, and 1 hr later the animals were treated with 100 mg/kg i.v. Nw-nitro-L-arginine (LNA, n=9); d) the fourth group received LPS, and after 1 hr, the animals were treated with 100 mg/kg i.v. aminoguanidine (AG, n=9); e) the fifth group received LPS and 1 hr later was treated with LNA plus 1 ppm inhaled nitric oxide (LNA+NO, n=7); f) the sixth group received LPS and 1 hr later was treated with aminoguanidine plus inhaled NO (AG+NO, n=7). Inhaled NO was administered continuously until the end of the experiment. MEASUREMENTS AND MAIN RESULTS: Systemic mean blood pressure (MAP) was monitored through a catheter in the carotid artery. Mean exhaled NO (ENO) was measured before LPS (T0) and every 30 mins thereafter for 5 hrs. Arterial blood gases and pH were measured every 30 mins for the first 2 hrs and then every hour. No attempt was made to regulate the animal body temperature. All the rats became equally hypothermic (28.9+/-1.2 degrees C [SEM]) at the end of the experiment. In the control group, blood pressure and pH remained stable for the duration of the experiment, however, ENO increased gradually from 1.3+/-0.7 to 17.6+/-3.1 ppb after 5 hrs (p< .05). In the LPS treated rats, MAP decreased in the first 30 mins and then remained stable for 5 hrs. The decrease in MAP was associated with a gradual increase in ENO, which was significant after 180 mins (58.9+/-16.6 ppb) and reached 95.3+/-27.5 ppb after 5 hrs (p< .05). LNA and AG prevented the increase in ENO after LPS to the level in the control group. AG caused a partial reversal of systemic hypotension, which lasted for the duration of the experiment. LNA reversed systemic hypotension almost completely but only transiently for 1 hr, and caused severe metabolic acidosis in all animals. The co-administration of NO with AG had no added benefits on MAP and pH. In contrast, NO inhalation increased the duration of the reversal in MAP after LNA, alleviated the degree of acidosis, and decreased the mortality rate (from 55% to 29%). CONCLUSIONS: In this animal model, LPS-induced hypotension was alleviated slightly and durably after AG, but only transiently after LNA. Furthermore, co-administration of NO with AG had no added benefits but alleviated the severity of metabolic acidosis and mortality after LNA. We conclude that nitric oxide synthase (NOS) inhibitors, given as a single large bolus in the early phase of sepsis, can exhibit some beneficial effects. Administration of inhaled NO with NOS inhibitors provided more benefits in some conditions and therefore may be a useful therapeutic combination in sepsis. NO production in sepsis does not seem to be a primary cause of systemic hypotension. Other factors are likely to have a major role.     

Acute effects of inhaled nitric oxide in children

At present, there are only two laser Doppler perfusion imaging systems (LDIs) manufactured for medical applications: a 'stepwise' and a 'continuous' scanning LDI. The stepwise scanning LDI has previously been investigated and compared with coloured microsphere determined standardised flow. The continuous scanning LDI is investigated and compared with the stepwise scanning LDI for its ability to measure in vivo, hypoaemic, ligament tissue blood flow changes. The continuous scanning system was supplied with two lasers, red and near infrared (NIR), allowing for additional assessment of the effect of wavelength on imaging ligament perfusion. Perfusion images were obtained from surgically exposed rabbit medial collateral ligaments (MCL). Continuous and stepwise LDI scans were compared using correlation and linear regression analysis of image. averages and standard deviations. Using the same method of analysis, LDI measurements using red and NIR lasers indicated a high degree of correlation, at least over the ranges of perfusion assessed, indicating that red and NIR lasers measure similar regions of flow in the rabbit MCL. These experiments confirm that both LDI techniques provide a valid in vivo measure of dynamic changes in connective tissue perfusion and could have significant impact on the understanding and treatment of joint injury and arthritis.     

Hantavirus pulmonary syndrome treated with inhaled nitric oxide

BACKGROUND: A retrospective study was done to assess the correlation between endometrial cells on routine cervical cytology and carcinoma of the endometrium. METHODS: In a 4-year period, endometrial cells of some type were identified on the Papanicolaou (Pap) smears of 61 women, of whom 52 had further diagnostic evaluation of the endometrium. Data were analyzed with a multivariate stepwise logistic regression. RESULTS: The results indicated an association of endometrial cells in Pap smears with carcinoma of the endometrium in seven patients (13.5%). In 45 patients (86.5%), the final diagnosis was benign. Factors that impacted the diagnosis of carcinoma were the findings of atypical or cancerous endometrial cells on Pap smear and abnormal vaginal bleeding. CONCLUSIONS: These data indicate the importance of further diagnostic evaluation with endometrial sampling in postmenopausal patients with endometrial cells seen in Pap smears, especially those with abnormal bleeding.     

Effects of inhaled nitric oxide and oxygen in high-altitude pulmonary edema

BACKGROUND: High-altitude pulmonary edema (HAPE) is characterized by pulmonary hypertension, increased pulmonary capillary permeability, and hypoxemia. Treatment is limited to descent to lower altitude and administration of oxygen. METHODS AND RESULTS: We studied the acute effects of inhaled nitric oxide (NO), 50% oxygen, and a mixture of NO plus 50% oxygen on hemodynamics and gas exchange in 14 patients with HAPE. Each gas mixture was given in random order for 30 minutes followed by 30 minutes washout with room air. All patients had severe HAPE as judged by Lake Louise score (6.4+/-0.7), PaO2 (35+/-3. 1 mm Hg), and alveolar to arterial oxygen tension difference (AaDO2) (26+/-3 mm Hg). NO had a selective effect on the pulmonary vasculature and did not alter systemic hemodynamics. Compared with room air, pulmonary vascular resistance fell 36% with NO (P<0.001), 23% with oxygen (P<0.001 versus air, P<0.05 versus NO alone), and 54% with NO plus 50% oxygen (P<0.001 versus air, P<0.005 versus oxygen and versus NO). NO alone improved PaO2 (+14%) and AaDO2 (-31%). Compared with 50% oxygen alone, NO plus 50% oxygen had a greater effect on AaDO2 (-18%) and PaO2 (+21%). CONCLUSIONS: Inhaled NO may have a therapeutic role in the management of HAPE. The combined use of inhaled NO and oxygen has additive effects on pulmonary hemodynamics and even greater effects on gas exchange. These findings indicate that oxygen and NO may act on separate but interactive mechanisms in the pulmonary vasculature.     

Extra-pulmonary effects of inhaled nitric oxide in swine with and without phenylephrine

Whether radiofrequency (RF) fields are carcinogenic is controversial; epidemiological data have been inconclusive and animal tests limited. The aim of the present study was to determine whether long-term exposure to pulse-modulated RF fields similar to those used in digital mobile telecommunications would increase the incidence of lymphoma in E mu-Pim1 transgenic mice, which are moderately predisposed to develop lymphoma spontaneously. One hundred female E mu-Pim1 mice were sham-exposed and 101 were exposed for two 30-min periods per day for up to 18 months to plane-wave fields of 900 MHz with a pulse repetition frequency of 217 Hz and a pulse width of 0.6 ms. Incident power densities were 2.6-13 W/m2 and specific absorption rates were 0.008-4.2 W/kg, averaging 0.13-1.4 W/kg. Lymphoma risk was found to be significantly higher in the exposed mice than in the controls (OR = 2.4. P = 0.006, 95% CI = 1.3-4.5). Follicular lymphomas were the major contributor to the increased tumor incidence. Thus long-term intermittent exposure to RF fields can enhance the probability that mice carrying a lymphomagenic oncogene will develop lymphomas. We suggest that such genetically cancer-prone mice provide an experimental system for more detailed assessment of dose-response relationships for risk of cancer after RF-field exposure.     

Changes of vasoactive peptides and effects of inhaled nitric oxide after pneumonectomy

To clarify the role of vasoactive peptides in the physiologic response to pneumonectomy, we investigated the changes of atrial (A-type) natriuretic peptide (ANP). C-type natriuretic peptide (CNP), and endothelin-1 (ET-1) levels in the lung and blood after pneumonectomy and the effects of inhaled nitric oxide (NO; 5 ppm) after pneumonectomy in beagle dogs. The concentrations of these peptides in the lung and blood were measured by radioimmunoassay. The dogs in group A (n = 10) were observed without NO inhaling after right pneumonectomy, and the dogs in group B (n = 5) were observed with NO inhaling from 120 to 180 min after right pneumonectomy. After the thoracotomy, right lung tissue was resected for the pre-operative histological control. Tissue from the left lung was obtained at 120 min (5 dogs in group A), at 180 min (5 dogs in group A), and after 60 min of NO inhalation (group B) for the post-operative histological material. Peripheral blood was collected from the femoral artery. The pulmonary arterial pressure (PAP) was significantly increased after pneumonectomy, but rapidly decreased to the same level as the pre-operative stage after NO inhalation. Increases of plasma ANP, lung ANP and lung CNP levels occurred after pneumonectomy, while the ET-1 level was unchanged. Inhaled NO rapidly reduced the plasma ANP, lung ANP and lung CNP. These results indicate that both ANP and CNP act to maintain normotensive homeostatic balance in the pulmonary circulation.     

Acute effects of inhaled nitric oxide in adult respiratory distress syndrome

This study evaluated the dose-response effect of inhaled nitric oxide (NO) on gas exchange, haemodynamics, and respiratory mechanics in patients with adult respiratory distress syndrome (ARDS). Of 19 consecutive ARDS patients on mechanical ventilation, eight (42%) responded to a test of 10 parts per million (ppm) NO inhalation with a 25% increase in arterial oxygen tension (Pa,O2,) over the baseline value. The eight NO-responders were extensively studied during administration of seven inhaled NO doses: 0.5, 1, 5, 10, 20, 50 and 100 ppm. Pulmonary pressure and pulmonary vascular resistance exhibited a dose-dependent decrease at NO doses of 0.5-5 ppm, with a plateau at higher doses. At all doses, inhaled NO improved O2 exchange via a reduction in venous admixture. On average, the increase in Pa,O2, was maximal at 5 ppm NO. Some patients, however, exhibited maximal improvement in Pa,O2 at 100 ppm NO. In all patients, the increase in arterial O2 content was maximal at 5 ppm NO. The lack of further increase in arterial O2 content above 5 ppm partly depended on an NO-induced increase in methaemoglobin. Respiratory mechanics were not affected by NO inhalation. In conclusion, NO doses < or =5 ppm are effective for optimal treatment both of hypoxaemia and of pulmonary hypertension in adult respiratory distress syndrome. Although NO doses as high as 100 ppm may further increase arterial oxygen tension, this effect may not lead to an improvement in arterial O2 content, due to the NO-induced increase in methaemoglobin. It is important to consider the effect of NO not only on arterial oxygen tension, but also on arterial O2 content for correct management of inhaled nitric oxide therapy.     

Evaluation of nitrogen dioxide scavengers during delivery of inhaled nitric oxide

Tissue hypoxia is an important cause for the development of multisystem organ failure in the critically ill. Achieving adequate haemodynamic support of oxygen demand is the mainstay of treatment in these patients. Controversies regarding therapeutic end-points do exist but in general maintaining oxygen delivery by ensuring adequate cardiac output, oxygen saturation and haemoglobin is important in the critically ill.     

Site of pulmonary vasodilation by inhaled nitric oxide in microembolic lung injury

The double free-muscle transfer technique has restored prehension in patients following complete avulsion of the brachial plexus. This achievement was almost inconceivable as recently as several years ago and has now given new hope for these patients to be able to use their otherwise useless limbs.     

Selective pulmonary vasodilation by inhaled nitric oxide is due to hemoglobin inactivation

BACKGROUND: Inhaled nitric oxide gas selectively decreases pulmonary artery pressure without affecting systemic arterial pressure. To determine if the selective pulmonary vasodilating effect of inhaled nitric oxide gas is due to inactivation by hemoglobin, we studied the ability of whole blood to inhibit the vasodilator activity of effluent from isolated lungs exposed to inhaled nitric oxide. METHODS AND RESULTS: The effluent from ventilated, Krebs-perfused rabbit lungs was passed directly over 3- to 4-mm rabbit aortic rings. Inhaled nitric oxide (150 ppm for 3 minutes) reduced pulmonary perfusion pressure, elevated by a continuous infusion of U46619, by 35 +/- 7% (mean +/- SEM, n = 5). Lung effluent from this series of experiments caused 40 +/- 13% relaxation of phenylephrine-preconstricted aortic rings. When blood was added to the combined lung/ring perfusion cascade (final hemoglobin concentration, 1 g/dL), inhaled nitric oxide again significantly reduced pulmonary perfusion pressure, but the effluent now failed to relax the aortic rings (30 +/- 6% [control] versus 1.5 +/- 1% [blood]). Both reduction in pulmonary perfusion pressure and relaxation of the rings during nitric oxide exposure were unchanged from control values after discontinuing the blood infusion. CONCLUSIONS: The presence of hemoglobin, even in extremely small amounts, restricts the vasodilating effect of inhaled nitric oxide gas to the pulmonary circulation.     

Controversies in the use of inhaled nitric oxide therapy in the newborn

Because of the increasing incidence of tuberculosis consequent on the increasing number of patients with drug-related or HIV-induced immunosuppression, the problems of the invasive or noninvasive treatment of osteoarticular tuberculosis have come up again. While the approach aimed at the elimination of infectious foci with an adequate combination of medical therapy with a conservative treatment or surgery is still valid, the advanced technology of osteosynthesis systems and prosthetic replacement for spinal, hip and knee involvement respectively, with suitable indications, affords new solutions of surgical technique. The objective is to achieve surgical procedures that preserve at best the physiology of locomotor apparatus.     

The use of inhaled nitric oxide in a wide variety of clinical problems

Inhaled nitric oxide (NO) clearly decreased pulmonary vascular resistance in pediatric patients with pulmonary hypertension, regardless of the underlying origin of the pulmonary hypertension. In persistent pulmonary hypertension of the neonate (PPHN) and CHD, the use of inhaled NO appears to improve the outcome of these patients. In acute respiratory distress syndrome (ARDS) and surfactant deficiency the role of inhaled NO therapy remains unclear. The use of inhaled NO is safe in a carefully monitored setting with a delivery system designed to minimize the generation of NO2.     

Hemodynamic effect of inhaled nitric oxide in dilated cardiomyopathy patients on LVAD support

Recently it has been shown that inhaled nitric oxide (NO), which has been proven to contribute to improvement in critical pulmonary hypertension, may provide a favorable effect early after left ventricular assist device (LVAD) support. To improve right ventricular function, inhalation of NO was added to treatment with conventional catecholamines for four consecutive dilated cardiomyopathy (DCM) patients following institution of LVAD. In two patients 1 hr after inhalation of NO, central venous pressure (CVP), mean pulmonary arterial pressure (PAm), and pulmonary vascular resistance (PVR) were improved. These results led to better LVAD output and resulted in an adequate cardiac index. On the other hand, a right VAD (RVAD) was implemented in one patient whose high CVP, PAm, and PVR continued; he was weaned after 8 days of RVAD support. Another patient who had a high CVP but normal PAm and PVR before and after inhalation of NO had no improvement in his hemodynamic state. These data suggest that inhaled NO may improve systemic circulation by reducing right ventricular afterload and may become a promising and convenient therapy before placing RVAD in DCM patients under LVAD support. RVAD should be conducted in patients with right ventricular failure or when pulmonary hypertension is associated with impaired right ventricular reserve, even after inhalation of NO.     

In pigs, inhaled nitric oxide (NO) counterbalances PAF-induced pulmonary hypertension

In 6 anesthetized mechanically ventilated pigs we have studied the effects of inhalation of 80 ppm of nitric oxide (NO) before and after platelet-activating factor (PAF) administration (50 ng/kg iv). Our results show that NO inhalation causes a decrease in pulmonary arterial pressure and in heart rate without affecting other circulatory parameters. PAF administration causes a pulmonary hypertension and a prompt and brief decrease in systemic pressure. Inhalation of NO reduces the pulmonary hypertension, without completely reversing PAF-dependent vasoconstriction. PAF administration to pigs pretreated with indomethacin produces a lesser increase in pulmonary vascular pressure. In this case, NO inhalation can restore to baseline values. Pretreatment of 3 of the 6 pigs with NG-nitro-L-arginine-methyl-ester did not prevent the prompt and brief PAF-induced systemic hypotension. In conclusion, our results show that NO reduces basal pulmonary vascular tone, acts as a pulmonary vasodilator on PAF-preconstricted vessels and is not involved in the brief systemic hypotension consequent to PAF administration.