Discontinuation Of Nitric Oxide Research Articles

Impact of Inhalation of Nitric Oxide and Extubation on Hemodynamics of Right Heart in Acute Phase after Left Ventricular Assist Device Implantation

Right ventricular failure (RVF) is one of the major complications after LVAD implantation. In acute phase after LVAD implantation, inhalation of nitric oxide (NO) and mechanical respiratory support and extubation causes hemodynamic changes on right heart dramatically. Although perioperative management is crucial to prevent RVF, there was no study which analyzed the impact of NO, mechanical respiratory support and extubation on hemodynamics of right heart in detail. Between December 2014 and September 2018, consecutive 102 patients underwent LVADs implantation in Osaka University Hospital. Patients below 18 years were excluded. Patients with right ventricular assist device support, and/or tracheostomy without trying of extubation after LVAD implantation were also excluded. Finally, 75 patients were included in this study (mean age, 45 ± 14 years; 30% were women). We used 5 different types of LVADs. We assessed the perioperative course of central venous pressure (CVP), pulmonary vascular resistance (PVR), and cardiac index (CI) before and after discontinuation of NO and extubation. Mean duration of NO inhalation was 2.0(0-3.3) days and final concentration of NO was 5ppm. The changes of CVP and CI before and after discontinuation of NO were not significantly (CVP: 10.0±2.7 to 10±2.7 mmHg, p=0.436, CI: 2.8±0.6 to 2.6±0.4 l/min/m2, p=0.999). Mean duration of intubation was 2.7(1.8-6.2) days. Just before extubation, respiratory rate was 17±4rpm and PaO2/FiO2 ratio was 341±71 under 5 cmH20 of positive end-expiratory pressure. The changes of CVP, PVR and CI before and after extubation were significantly (CVP: 9.1±2.9 to 8.2±3.0 mmHg, p=0.001, PVR: 1.1±0.4 to 1.2±0.5 wood, p=0.014, CI: 2.8±0.6 to 3.0±0.6 l/min/m2, p=0.004). Furthermore, patients with elevated CVP(≧10mmHg, n=31) also increased their CI significantly after extubation (CI:2.9±0.5 to 3.1±0.6 l/min/m2, p=0.007). Among adult patients with LVAD, discontinuation of NO inhalation caused minor decrease of CI but not significant. Extubation improves CI even patients with elevated CVP, who are higher risk for suffering from RVF. These analysis of hemodynamic changes imply that after respiratory condition become stable, extubation could be one important choice to improve hemodynamics even in patients with higher risk for RVF.

Combined therapy with inhaled nitric oxide and intravenous epoprostenol (prostacyclin) for critical pulmonary perfusion after the Fontan procedure

J Thorac Cardiovasc Surg 2003;125:437-9

A preliminary study of the effect of inhaled nitric oxide on lung mechanics in the standing horse with histamine-induced bronchoconstriction.

The effect of inhaled nitric oxide on pulmonary mechanics was studied in normal standing horses with histamine-induced bronchoconstriction. The respiratory health status of 6 normal horses was established on the basis of history, clinical and bronchoalveolar lavage examination. Intrathoracic pressures were estimated using distal oesophageal pressures. Respiratory gas flows were measured using a heated pneumotachograph. Pulmonary mechanics variables were determined from these measurements on a breath by breath basis. Bronchoconstriction was induced by nebulizing a 0.75% w/v solution of histamine over 5 min. Pulmonary function was assessed during 4 periods: 1) while breathing room air prior to histamine challenge; 2) 5 min post histamine challenge; 3) 10 min post histamine challenge and while breathing 5 ppm nitric oxide; and 4) 14 min post histamine challenge while breathing room air. Statistical analysis included Friedman's nonparametric repeated measures analysis of variance followed by Dunn's multiple comparisons tests, where appropriate. Criteria for demonstration of nitric oxide effect on pulmonary mechanics variables were taken as a return of the variable value following nitric oxide administration towards control value and subsequent restoration of the value toward post histamine levels with discontinuation of nitric oxide. Five variables (dynamic compliance, airway resistance, maximum developed pressure, work of breathing, and peak expiratory flow) had significant changes in response to histamine. Three variables (dynamic compliance, airway resistance, and maximum developed pressure) met the above criteria, but only dynamic compliance and airway resistance showed statistical significance (P < 0.05). These results suggest that nitric oxide partly dilates small airways constricted by histamine.

The Effect of Prolonged Inhaled Nitric Oxide on Pulmonary Vasoconstriction in Rats

Down-regulation of the endogenous nitric oxide (NO) pathway may explain rebound pulmonary hypertension after discontinuation of inhaled NO. We determined whether the prolonged administration of inhaled NO increases pulmonary vasoconstriction, which may occur from decreased endogenous NO. Rats were placed in normoxic (N; 21% O2) or hypoxic (H; 10% O2) chambers with or without inhaled NO (20 ppm) for 1 or 3 wk. Immediately after or 24 h after discontinuation of NO, vasoconstrictive responses were determined in isolated lungs to acute hypoxia (HPV; 0% O2 for 6 min), angiotensin II (0.05 [micro sign]g), and the thromboxane analog U-46619 in the presence and absence of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 100 [micro sign]M). Inhaled NO did not alter HPV or angiotensin II vasoconstriction in the N group immediately after or 24 h after discontinuation of NO. In the H group, inhaled NO decreased HPV but had no effect on the angiotensin II vasoconstriction compared with H alone. Inhaled NO did not alter the response to L-NAME. Inhaled NO did not alter, whereas L-NAME significantly decreased, the dose of U-46619 required to increase the pulmonary pressure by 10 mm Hg. In conclusion, prolonged inhaled NO decreased or did not alter HPV and did not alter vasoconstriction secondary to angiotensin II, U-46619, or L-NAME in N and H rats. These results suggest that prolonged inhaled NO does not increase pulmonary vasoconstriction, as would be expected from down-regulation of endogenous NO. Implications: High pulmonary pressure has been observed clinically after discontinuation of inhaled NO. This rat study suggests that 1-3 wk of inhaled NO does not increase pulmonary vasoconstriction, as would be expected from decreasing the endogenous vasodilator NO. (Anesth Analg 1998;87:1285-90)

The effect of prolonged inhaled nitric oxide on pulmonary vasoconstriction in rats.

Down-regulation of the endogenous nitric oxide (NO) pathway may explain rebound pulmonary hypertension after discontinuation of inhaled NO. We determined whether the prolonged administration of inhaled NO increases pulmonary vasoconstriction, which may occur from decreased endogenous NO. Rats were placed in normoxic (N; 21% O2) or hypoxic (H; 10% O2) chambers with or without inhaled NO (20 ppm) for 1 or 3 wk. Immediately after or 24 h after discontinuation of NO, vasoconstrictive responses were determined in isolated lungs to acute hypoxia (HPV; 0% O2 for 6 min), angiotensin II (0.05 microg), and the thromboxane analog U-46619 in the presence and absence of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 100 microM). Inhaled NO did not alter HPV or angiotensin II vasoconstriction in the N group immediately after or 24 h after discontinuation of NO. In the H group, inhaled NO decreased HPV but had no effect on the angiotensin II vasoconstriction compared with H alone. Inhaled NO did not alter the response to L-NAME. Inhaled NO did not alter, whereas L-NAME significantly decreased, the dose of U-46619 required to increase the pulmonary pressure by 10 mm Hg. In conclusion, prolonged inhaled NO decreased or did not alter HPV and did not alter vasoconstriction secondary to angiotensin II, U-46619, or L-NAME in N and H rats. These results suggest that prolonged inhaled NO does not increase pulmonary vasoconstriction, as would be expected from down-regulation of endogenous NO. High pulmonary pressure has been observed clinically after discontinuation of inhaled NO. This rat study suggests that 1-3 wk of inhaled NO does not increase pulmonary vasoconstriction, as would be expected from decreasing the endogenous vasodilator NO.

Reduction of NO-induced methemoglobinemia requires extremely high doses of ascorbic acid in vitro.

The objective of the present study was to investigate the treatment of nitric oxide (NO)-induced methemoglobinemia by ascorbate and its consequences on red blood cell (RBC) glutathione in vitro. RBC were obtained from five healthy volunteers. The following experiments were carried out: (1) After methemoglobin generation by NO, ascorbate was added (2) RBC were simultaneously exposed to NO and ascorbate (3) Methemoglobin was generated by NO, ascorbate was added and incubation with NO continued. (1) After discontinuation of NO, the mean half life for methemoglobin was reduced from 195 min (controls) to 60 min (10 mM ascorbate) in a dose-dependent manner. (2) Methemoglobin formation after 3 h of NO exposure was 2.7 +/- 0.3% in controls and 1.8 +/- 0.1% with 10 mM ascorbate (p < 0.01). (3) Further methemoglobin formation was inhibited only by 10 mM ascorbate (p < 0.001). NO incubation did not affect RBC glutathione (86.5 +/- 19.6 and 86.5 +/- 19.6 mg/l, respectively). Treatment with 10 mM ascorbate significantly decreased glutathione (p < 0.002). In vitro, NO-induced methemoglobin formation is significantly decreased only by a high (10 mM) ascorbate concentration. Glutathione, critical for ascorbate activity, is not influenced by NO.

Methaemoglobinaemia after inhalation of nitric oxide in infant with pulmonary hypertension

A 41-week baby girl was delivered by emergency caesarean section because of severe fetal distress. Because she was covered with thick meconium and immediate suctioning via endotracheal tube produced meconium, the trachea was washed with surfactant. Apgar scores were 2 and 7. On admission to the neonatal unit her arterial blood gas determination revealed pH 6·89, pO2 10·6 kPa, pCO2 9·4 kPa, HCO3 10 mmol/L, base excess –24 mmol/L. We started mechanical ventilation (Hamming II, Senko-ikakikai, Tokyo, Japan) and infusion of dopamine, dobutamine, morphine, and a volume expander, and instilled surfactant into the endotracheal tube. Blood oxygen saturation fluctuated 40–100% by pulse oximeter and that at the leg was more than 20% lower than that at the arm. She showed severe cyanosis despite bagging with 100% oxygen. A working diagnosis of persistent pulmonary hypertension of the newborn (PPHN) was made. At 4 h of age nitric oxide (NO) was started from an intended dose of 20 parts per million (ppm). Effective peak inspiratory concentrations of NO were monitored with Ecoline Plus (Nichion-Irikakikai, Chiba, Japan). At 24 h of age, on discontinuing the NO the oxygen saturation dropped immediately, then NO was restarted and increased up to 80 ppm. From 36 h urination was obtained and transcutaneous oxygen pressure began to stabilise at 13·3 kPa but oxygen saturation still fluctuated. At 50 h of age, however, she developed deep central cyanosis although arterial blood gas analysis revealed pH 7·5, pO2 50·7 kPa, and an oxygen saturation of 100%. A methaemoglobin level was 40%. Then NO was decreased and discontinued after 1 h and 1 mg/kg of methylene blue was infused over 8 min, resulting in a reduction in the methaemoglobin concentration to 3·9% over the next 20 min. Blood oxygen saturation transiently decreased from 90 to 65% during the methylene blue infusion (figure), urine of the patient dyed blue for 3 days, and the skin looked dark brown for 1 month. However, discontinuation of NO did not lead to rebound hypoxia or pulmonary hypertension and there were no further episodes of methaemoglobinaemia. Cranial magnetic resonance imaging at 4 weeks of age revealed no finding suggestive of hypoxic damage. She can hold her head up in the supine position at 4 months of age.

Inhaled nitric oxide in infants with developing or established chronic lung disease.

The effect on gas exchange of increasing concentrations of nitric oxide (0-60 parts per million) added to the inspired gases of nine ventilator-dependent infants (median postnatal age = 4 weeks; range 2-16 weeks) with chronic lung disease and pathological oxygenation index values was studied by means of arterial or transcutaneous PO2/PCO2. A significant improvement of oxygenation, indicated by a reduction of oxygenation index, was found (p < 0.014). The optimal nitric oxide concentration and the individual response varied between patients. PO2 returned to baseline values after the discontinuation of nitric oxide in all patients except one. No effect on PCO2 could be identified. Methaemoglobin values only increased marginally during the nitrous oxide exposition (pre-nitric oxide: 0.56% +/- 0.27; post-nitric oxide: 0.78 +/- 0.08; p = ns). Systemic blood pressure and heart rate were unaffected in all patients. Before inhaled nitric oxide can be considered for prolonged use in this patient category further studies regarding long-term efficacy and safety are needed.

Severity of hypoxia predicts response to nitric oxide in a porcine pulmonary hypertension model

Although inhaled nitric oxide (NO) has been variably successful in resolving pulmonary hypertension in neonates, children, and adults, no parameters predictive of response to this therapy have been elucidated. We conducted an animal study to determine if severity of hypoxia can predict magnitude and sustenance of response to inhaled NO therapy. Seven Yorkshire swine weighing 11 to 20 kg underwent 16 experiments, each consisting of four phases: Phase 1: Control period of ventilation on F io 2 .3; phase 2: Hypoxic period on F io 2 .10 to .15, establishing pulmonary hypertension; phase 3: Treatment period with NO starting at five parts per million (ppm), doubling dose every 10 min to 80 ppm; phase 4: Posttreatment observation period after discontinuation of NO while maintaining hypoxia for 1 hour or until circulatory failure or pulmonary hypertension of pre-NO magnitude developed. Each animal underwent a maximum of three experiments in random order of hypoxia severity before sacrifice with pentobarbital overdose. Continuous hemodynamic parameters, intermittent cardiac output and pulmonary capillary wedge pressure, and intermittent arterial blood gas analyses were obtained through pulmonary and systemic artery catheters placed by femoral cutdown. Pulmonary and systemic vascular resistances (PVR and SVR) were calculated by standard formulas. Experiments were divided into two groups (n = 8 in each): group 1 with severe hypoxia (Pa o 2, 25 to 35) and group 2 with moderate hypoxia (Pa o 2, 36 to 65). Data for all hemodynamic parameters were expressed as mean percentage change from baseline (phase 1) ± SEM under each set of conditions, and the two groups were compared by two-way analysis of variance and covariance adjusted for order of experimentation. The severely hypoxic group showed significantly less improvement than the moderately hypoxic group in mean pulmonary artery pressure during treatment with NO (17 ± 3% versus −2 ± 3%, P = .005) and after discontinuing the drug (55 ± 11% versus 21 ± 7%, P = .03). The severely hypoxic group also experienced a significant elevation in cardiac output during NO therapy when compared with the moderately hypoxic group (26 ± 6% versus 3 ± 4%, P = .02). Furthermore, there were no incidents of circulatory failure after discontinuing NO during moderate hypoxia versus three incidents (38%) during severe hypoxia, all of which were immediately reversed by restarting NO. In a porcine hypoxic pulmonary hypertension model, severe hypoxia predicts weaker improvement in the pulmonary hypertension during NO therapy and stronger recurrence after discontinuing the drug. Nitric oxide may also have a hemodynamic supportive role during severe hypoxia by enhancing cardiac output and preventing acute cor pulmonale.

Aerosolized Prostacyclin Versus Inhaled Nitric Oxide in Children with Severe Acute Respiratory Distress Syndrome

Aerosolized Prostacyclin Versus Inhaled Nitric Oxide in Children with Severe Acute Respiratory Distress Syndrome

Continuous inhalation of nitric oxide protects against development of pulmonary hypertension in chronically hypoxic rats.

Exposure to hypoxia and subsequent development of pulmonary hypertension is associated with an impairment of the nitric oxide (NO) mediated response to endothelium-dependent vasodilators. Inhaled NO may reach resistive pulmonary vessels through an abluminal route. The aim of this study was to investigate if continuous inhalation of NO would attenuate the development of pulmonary hypertension in rats exposed to chronic hypoxia. In conscious rats previously exposed to 10% O2 for 3 wk, short-term inhalation of NO caused a dose-dependent decrease in pulmonary artery pressure (PAP) from 44 +/- 1 to 32 +/- 1 mmHg at 40 ppm with no changes in systemic arterial pressure, cardiac output, or heart rate. In normoxic rats, acute NO inhalation did not cause changes in PAP. In rats simultaneously exposed to 10% O2 and 10 ppm NO during 2 wk, right ventricular hypertrophy was less severe (P < 0.01), and the degree of muscularization of pulmonary vessels at both alveolar duct and alveolar wall levels was lower (P < 0.01) than in rats exposed to hypoxia alone. Tolerance to the pulmonary vasodilator effect of NO did not develop after prolonged inhalation. Brief discontinuation of NO after 2 wk of hypoxia plus NO caused a rapid increase in PAP. These data demonstrate that prolonged inhalation of low concentrations of NO induces sustained pulmonary vasodilation and reduces pulmonary vascular remodeling in response to chronic hypoxia.

Inhaled Nitric Oxide

Inhaled nitric oxide (NO), an endothelium-derived relaxing factor, is a selective pulmonary vasodilator. The authors investigated whether the pulmonary vasodilation resulting from 20 ppm inhaled NO is related to the degree of pulmonary hypertension or affected by cardiopulmonary bypass (CPB) or the presence of intravenous nitrates. In patients undergoing cardiac surgery (n = 20) or in whom the circulation was supported with a ventricular assist device (VAD; n = 5), the lungs were ventilated with 80% O2 and 20% N2 followed by the same gas concentrations containing 20 ppm NO for 6 min. Inhaled NO decreased (P < 0.05) the pulmonary artery pressure from 36 +/- 3 to 29 +/- 2 mmHg and 32 +/- 2 to 27 +/- 1 mmHg, before and after CPB, respectively, and from 68 +/- 12 to 55 +/- 9 mmHg in patients with a VAD. Similarly, the pulmonary vascular resistance (PVR) decreased (P < 0.05) from 387 +/- 44 to 253 +/- 26 dyne.cm.s-5 and 260 +/- 27 to 182 +/- 18 dyne.cm.s-5, before and after CPB, respectively, and from 1,085 +/- 229 to 752 +/- 130 dyne.cm.s-5 in patients with a VAD. Central venous pressure, cardiac output, systemic hemodynamics, and blood gases did not change after inhalation of NO before or after CPB, whereas arterial oxygen tension, mixed venous hemoglobin saturation, and mean arterial pressure increased (P < 0.05) in patients supported with a VAD. All hemodynamic and laboratory data returned to control 6 min after discontinuation of NO. The decrease in PVR was proportional to baseline PVR (delta PVR = -0.45 PVRb + 39.9) before CPB. The pre- and post-CPB slopes were identical despite possible damage to the endothelium resulting from CPB and the post-CPB presence of intravenous nitroglycerin (17 of 20 patients). This study demonstrates that 20 ppm inhaled NO is a selective pulmonary vasodilator in cardiac surgical patients before and after CPB and in patients in whom the circulation is supported with a VAD. Furthermore, NO-induced pulmonary vasodilation is proportional to PVRb and does not appear to be altered by CPB, the presence of a VAD, or infusion of nitrates.