Effects of nitric oxide inhalation on pulmonary serial vascular resistances in ARDS

The pulmonary vasculature site of action of nitric oxide (NO) in patients with acute respiratory distress syndrome (ARDS) is still unknown. Seven patients were studied during the early stage of ARDS. The bedside pulmonary artery single-occlusion technique, which allows estimation of the pulmonary capillary pressure (Pcap) and segmental pulmonary vascular resistance, was used without NO or with increasing inhaled NO concentrations (15 and 25 parts per million [ppm]). Systemic circulatory parameters remained unaltered during 15 ppm NO inhalation, whereas 25 ppm NO inhalation slightly decreased mean systemic arterial pressure from 76.7 +/- 5.1 (mean +/- SEM) to 69 +/- 5.2 mm Hg (p < 0.01). Mean pulmonary arterial pressure (Ppam) and mean pulmonary capillary pressure (Pcapm) fell during 25 ppm NO inhalation from 27.4 +/- 3.5 to 21 +/- 2.2 mm Hg (p < 0.001) and from 14.8 +/- 1.5 to 10.7 +/- 1.4 mm Hg (p < 0.001) respectively, the total pulmonary resistance decreased by 28% (p < 0.01). The resistance of the capillary-venous compartment fell during 25 ppm NO inhalation from 100 +/- 16 to 47 +/- 16 dyn x s x m(2) x cm(-5) (p < 0.01), whereas the pulmonary arterial resistance was unchanged. In these patients NO inhalation during the early stage of ARDS reduces selectively Ppam and Pcapm by decreasing the pulmonary capillary-venous resistance. This latter effect may reduce the filtration through the capillary bed and hence alveolar edema during ARDS.     

Effectiveness of nitric oxide inhalation in septic ARDS

STUDY OBJECTIVE: To evaluate the percentage of nitric oxide (NO) responders in septic shock patients with ARDS. Additionally, to investigate long-term NO effects on cardiac performance and oxygen kinetic patterns in NO responders vs nonresponders. DESIGN: Prospective cohort study. SETTING: ICU of a university hospital. PATIENTS: Twenty-five consecutive patients with a diagnosis of septic shock and established ARDS requiring inotropic and vasopressor support. INTERVENTIONS: After diagnosis of ARDS, NO was administered at 18 or 36 ppm. Patients demonstrating a NO-induced rise of arterial oxygen tension of 20% or more and/or a fall in mean pulmonary artery pressure of 15% or more were grouped as NO responders; others were grouped as nonresponders. MEASUREMENTS AND RESULTS: Ten patients (40%) were NO responders, while 15 patients (60%) were nonresponders. Mortality was 40% in NO responders and 67% in nonresponders (NS). NO responders developed a significantly lower mean pulmonary artery pressure (28 +/- 6 vs 33 +/- 6 mm Hg; p < 0.05), lower pulmonary vascular resistance (PVR: 258 +/- 73 vs 377 +/- 163 dyne.s.cm-5.m-2; p < 0.05), and higher PaO2/FIO2 ratio (192 +/- 85 vs 144 +/- 74 mm Hg; p < 0.05) within the study period. In responders, NO-induced afterload reduction resulted in increased right ventricular ejection fraction (RVEF: 40 +/- 7 vs 35 +/- 9%; p < 0.05), significantly higher cardiac index (CI: 4.5 +/- 1.1 vs 4.0 +/- 1.2 L.min-1.m-2; p < 0.05) and oxygen delivery (DO2: 681 +/- 141 vs 599 +/- 160 mL.min-1.m-2; p < 0.05) compared with nonresponders. In NO nonresponders, RVEF was correlated with PVR, CI, DO2, mixed venous oxygen saturation (SvO2), and oxygen extraction ratio (O2ER) (r = +/- 0.60 to +/- 0.69; p < 0.05). No significant correlation between RVEF and any of these parameters was observed in responders. SvO2 (75 +/- 7 vs 69 +/- 8%; p < 0.05) and O2ER (0.24 +/- 0.06 vs 0.27 +/- 0.06; p < 0.05) were significantly different between responders and nonresponders, while no difference in oxygen consumption was observed (161 +/- 41 vs 153 +/- 43 mL.min.m-2). CONCLUSIONS: Inhaled NO is effective in only a subgroup of septic ARDS patients, with a higher, but insignificantly different percentage of survivors in the responder group. NO responders were characterized by increased RVEF accompanied by higher CI, DO2, and lower O2ER. In nonresponders, RVEF remained depressed, with a close correlation between RVEF and CO as well as DO2 and O2ER. Thus, nonresponders seem to suffer from impaired cardiac reserves and correspondingly lower oxygen transport variables.     

Effect of inhaled nitric oxide on pulmonary hemodynamics after acute lung injury in dogs

Increased pulmonary vascular resistance (PVR) and mismatch in ventilation-to-perfusion ratio characterize acute lung injury (ALI). Pulmonary arterial pressure (Ppa) decreases when nitric oxide (NO) is inhaled during hypoxic pulmonary vasoconstriction (HPV); thus NO inhalation may reduce PVR and improve gas exchange in ALI. We studied the hemodynamic and gas exchange effects of NO inhalation during HPV and then ALI in eight anesthetized open-chest mechanically ventilated dogs. Right atrial pressure, Ppa, and left ventricular and arterial pressures were measured, and cardiac output was estimated by an aortic flow probe. Shunt and dead space were also estimated. The effect of 5-min exposures to 0, 17, 28, 47, and 0 ppm inhaled NO was recorded during hyperoxia, hypoxia, and oleic acid-induced ALI. During ALI, partial beta-adrenergic blockade (propranolol, 0.15 mg/kg i.v.) was induced and 74 ppm NO was inhaled. Nitrosylhemoglobin (NO-Hb) and methemoglobin (MetHb) levels were measured. During hyperoxia, NO inhalation had no measurable effects. Hypoxia increased Ppa (from 19.8 +/- 6.1 to 28.3 +/- 8.7 mmHg, P < 0.01) and calculated PVR (from 437 +/- 139 to 720 +/- 264 dyn.s.cm-5, P < 0.01), both of which decreased with 17 ppm NO. ALI decreased arterial PO2 and increased airway pressure, shunt, and dead space ventilation. Ppa (19.8 +/- 6.1 vs. 23.4 +/- 7.7 mmHg) and PVR (437 +/- 139 vs. 695 +/- 359 dyn.s.cm-5, P < 0.05) were greater during ALI than during hyperoxia. No inhalation had no measureable effect during ALI before or after beta-adrenergic blockade. MetHb remained low, and NO-Hb was unmeasurable. Bolus infusion of nitroglycerin (15 micrograms) induced an immediate decrease in Ppa and PVR during ALI.(ABSTRACT TRUNCATED AT 250 WORDS)     

Minimizing the inhaled dose of NO with breath-by-breath delivery of spikes of concentrated gas

BACKGROUND: Pulmonary vasodilatation with a 100 ppm concentration of NO given as a short burst of a few milliliters at the beginning of each breath (NOmin) was compared with conventionally inhaled NO, in which a full breath of 40 ppm of NO was inhaled (NOCD). METHODS AND RESULTS: NOmin was studied in 16 patients with severe pulmonary hypertension and in 16 isolated porcine lungs with experimentally induced pulmonary hypertension. We compared volumes of 8 to 38 mL of 100 ppm NO in N2 injected at the beginning of each breath with conventional inhalation of 40 ppm NO in air. NOCD and NOmin were studied in 4 pigs after inhibition of NO synthase with NG-nitro-L-arginine methyl ester (1 to 2 mg/kg IV) had raised the pulmonary vascular resistance index (PVRI) from 4.4+/-0.8 to 10. 0+/-1.6 mm Hg. L-1. min-1. kg-1. A similar comparison was made in 7 isolated porcine lungs after the thromboxane analogue U46619 (10 pmol. L-1. min-1) increased the mean PVRI from 4.6+/-0.8 to 12.2+/-1. 3 mm Hg. L-1. min-1. kg-1. Patients' mean PVRI was reduced from 29. 2+/-3.7 to 24.0+/-3.1 with NOmin and 24.5+/-3.3 mm Hg. L-1. min-1. m-2 (mean+/-SEM) with NOCD. In isolated porcine lungs, there was the same reduction of PVRI for NOmin and NOCD between 12.7% and 34.8%. CONCLUSIONS: A small volume of NO inhaled at the beginning of the breath was equally effective as NOCD but reduced the dose of NO per breath by 40-fold, which ranged from 1.2x10(-8) (0.4 microg) to 1. 6x10(-7) mol/L (4.8 microg) compared with 5.3x10(-7) (16 microg) to 1.2x10(-6) mol/L (36 microg) per breath with NOCD.     

Partitioning of pulmonary vascular resistance in primary pulmonary hypertension

OBJECTIVES: This study sought to determine the site of increased pulmonary vascular resistance (PVR) in primary pulmonary hypertension by standard bedside hemodynamic evaluation. BACKGROUND: The measurement of pulmonary vascular pressures at several levels of flow (Q) allows the discrimination between active and passive, flow-dependent changes in mean pulmonary artery pressure (Ppa), and may detect the presence of an increased pulmonary vascular closing pressure. The determination of a capillary pressure (Pc') from the analysis of a Ppa decay curve after balloon occlusion allows the partitioning of PVR in an arterial and a (capillary + venous) segment. These approaches have not been reported in primary pulmonary hypertension. METHODS: Ppa and Pc' were measured at baseline and after an increase in Q induced either by exercise or by an infusion of dobutamine, at a dosage up to 8 microg/kg body weight per min, in 11 patients with primary pulmonary hypertension. Reversibility of pulmonary hypertension was assessed by the inhalation of 20 ppm nitric oxide (NO), and, in 6 patients, by an infusion of prostacyclin. RESULTS: At baseline, Ppa was 52+/-3 mm Hg (mean value+/-SE), Q 2.2+/-0.2 liters/min per m2, and Pc' 29+/-3 mm Hg. Dobutamine did not affect Pc' and allowed the calculation of an averaged extrapolated pressure intercept of Ppa/Q plots of 34 mm Hg. Inhaled NO had no effect. Prostacyclin decreased Pc' and PVR. Exercise increased Pc' to 40+/-3 mm Hg but did not affect PVR. CONCLUSIONS:ns. These findings are compatible with a major increase of resistance and reactivity at the periphery of the pulmonary arterial tree.     

Pulsed delivery of inhaled nitric oxide to patients with primary pulmonary hypertension: an ambulatory delivery system and initial clinical tests

BACKGROUND: Inhaled nitric oxide (NO) has been shown to be a selective pulmonary vasodilator in certain patients with primary pulmonary hypertension (PPH). ObJECTIVES: The purpose of this study was to design and test a system for delivery of NO to awaken, ambulatory patients with PPH and to evaluate this system in the home setting. METHODS: The ambulatory delivery system consisted of a tank of 80 ppm of NO (balance N2), a modified gas-pulsing device, and nasal cannulas. The pulsing device was set to deliver NO for 0.1 s at the beginning of each inspiration. RESULTS: Using this system, eight patients with PPH were studied with pulmonary artery catheters in place. Inhalation of NO led to significant reductions in both mean pulmonary arterial pressure (PAPm) (51 +/-12 to 43 +/- 10 mm Hg; p=0.001) and pulmonary vascular resistance (PVR) (790 +/- 285 to 620 +/- 208 dyne x s x cm-5; p=0.01). Three of the eight patients had both greater than 20% and greater than 30% decreases in PAPm and PVR, respectively. No exhaled NO or N02 was detectable in any of the eight patients. One patient was discharged home from the hospital on a regimen of inhaled NO. At 9 months, no adverse effects were noted and the system was working well. CONCLUSIONS: Pulsed delivery of inhaled NO to ambulatory patients with PPH, via nasal prongs, is feasible and, in some patients, leads to significant improvement in pulmonary hypertension. Inhaled 09NO, therefore, may have a role in the long-term treatment of patients with PPH.     

Acute hypoxic pulmonary vasoconstriction in man is attenuated by type I angiotensin II receptor blockade

OBJECTIVES: We examined the hypothesis that angiotensin II (ANG II) is a modulator of acute hypoxic pulmonary vasoconstriction (HPV) by looking at the effect of losartan, a selective type 1 ANG II receptor antagonist, on acute HPV in man. METHODS: Ten normal volunteers were studied on two separate days. They either received pre-treatment with losartan 25, 50, 100, 100 mg respectively on four consecutive days or matched placebo. They were then rendered hypoxaemic, by breathing an N2/O2 mixture for 20 min to achieve an SaO2 of 85-90% adjusted for a further 20 min to achieve an SaO2 of 75-80%. Pulsed wave Doppler echocardiography was used to measure mean pulmonary artery pressure (MPAP), cardiac output and hence pulmonary vascular resistance (PVR). RESULTS: Baseline MPAP and PVR (during normoxaemia) were unaffected by losartan pre-treatment compared with placebo. However, losartan significantly reduced MPAP at both levels of hypoxaemia compared with placebo: 14.7 +/- 0.7 vs 19.0 +/- 0.7 mmHg at an SaO2 85-90% (P < 0.01) and 20.0 +/- 0.7 vs 25.7 +/- 0.8 mmHg at an SaO2 75-80% (P < 0.05) respectively. Similarly losartan significantly reduced PVR compared to placebo: 191 +/- 9 vs 246 +/- 10 dyne.s.cm-5 at an SaO2 85-90% (P < 0.005) and 233 +/- 12 vs 293 +/- 18 dyne.s.cm-5 at an SaO2 75-80% (P < 0.05), respectively. Pre-treatment with losartan, however, had no significant effect on systemic vascular resistance although losartan compared to placebo resulted in a significant (P < 0.05) reduction in mean arterial pressure at an SaO2 75-80%: 78 +/- 2 vs 87 +/- 2 mmHg. CONCLUSIONS: Losartan had no effect on baseline pulmonary haemodynamics but significantly attenuated acute hypoxic pulmonary vasoconstriction, suggesting that angiotensin II plays a role in modulating this response in man via its effects on the type 1 angiotensin II receptor.     

Expression of endothelin-1 and effects of an endothelin receptor antagonist, TAK-044, at reperfusion after cold preservation in a canine lung transplantation model

BACKGROUND: Rapid increase of pulmonary vascular resistance (PVR) early after reperfusion remains a major issue in clinical lung transplantation. A potent vasoconstrictor peptide, endothelin- plays an important role in various pulmonary pathophysiologic conditions and might induce increased PVR. We investigated the expression and influence of endothelin-1, and the effects of an ETA and ETB nonselective endothelin receptor antagonist, TAK-044, at reperfusion after cold preservation in a canine lung transplantation model. METHODS: Left single lung allotransplantation procedures were performed in three groups of animals. In group I (n=5) lungs were preserved for 12 hours; in group II (n=5) lungs were preserved for 18 hours; and in group III (n=6) lungs were also preserved for 18 hours, and TAK-044 (5 mg/kg) was administered just before reperfusion. All donor lungs were flushed and preserved with low-potassium dextran glucose solution at 4 degrees C. RESULTS: Six hours after reperfusion, arterial oxygen tension (mm Hg, inspired oxygen fraction=1.0) was 512.9+/-34.7 in group I, 152.4+/-46.7 in group II, and 509.6+/-29.0 in group III; PVR index (dyne x sec x cm(-5) x m2) was 1130+/-142 in group I, 1820+/-142 in group II, and 1287+/-191 in group III. Plasma endothelin-1 level was elevated significantly, and endothelin-1-like immunoreactivity was found in a variety of pulmonary vascular tissue and was seen less with immunohistochemical evaluation in group II in bronchial tissue. Conclusions: These results suggest that endothelin-1 is expressed as a result of ischemia-reperfusion injury and may worsen early graft function. TAK-044 is beneficial in protecting the graft from high pulmonary vascular resistance and pulmonary edema during the early posttransplantation stage.     

Inhaled nitric oxide inhibits human platelet aggregation, P-selectin expression, and fibrinogen binding in vitro and in vivo

BACKGROUND: Recent data suggest that inhaled NO can inhibit platelet aggregation. This study investigates whether inhaled NO affects the expression level and avidity of platelet membrane receptors that mediate platelet adhesion and aggregation. METHODS AND RESULTS: In 30 healthy volunteers, platelet-rich plasma was incubated with an air/5% CO2 mixture containing 0, 100, 450, and 884 ppm inhaled NO. ADP- and collagen-induced platelet aggregation, the membrane expression of P-selectin, and the binding of fibrinogen to the platelet glycoprotein (GP) IIb/IIIa receptor were determined before (t0) and during the 240 minutes of incubation. In addition, eight patients suffering from severe adult respiratory distress syndrome (ARDS) were investigated before and 120 minutes after the beginning of administration of 10 ppm inhaled NO. In vitro, NO led to a dose-dependent inhibition of both ADP-induced (3+/-3% at 884 ppm versus 70+/-6% at 0 ppm after 240 minutes; P<.001) and collagen-induced (13+/-5% versus 62+/-5%; P<.01) platelet aggregation. Furthermore, P-selectin expression (36+/-7% of t0 value; P<.01) and fibrinogen binding (33+/-11%; P<.01) were inhibited. In patients with ARDS, after two who did not respond to NO inhalation with an improvement in oxygenation had been excluded, an increase in plasma cGMP, prolongation of in vitro bleeding time, and inhibition of platelet aggregation and P-selectin expression were observed, and fibrinogen binding was also inhibited (19+/-7% versus 30+/-8%; P<.05). CONCLUSIONS: NO-dependent inhibition of platelet aggregation may be caused by a decrease in fibrinogen binding to the platelet GP IIb/IIIa receptor.     

The fetoplacental pressor effects of low-dose acetylsalicylic acid and angiotensin II in the ex vivo cotyledon model

OBJECTIVE: Our purpose was to investigate perfusion pressure changes ex vivo induced by angiotensin II on fetoplacental vasculature pretreated with low-dose acetylsalicylic acid. STUDY DESIGN: Two cotyledons from each of 12 placentas were perfused. The intervillous space of one cotyledon was infused with acetylsalicylic acid (5 x 10(-5) mol/L) similar to the serum concentration of women receiving daily low-dose aspirin therapy (60 to 81 mg). The control cotyledon was infused with an equivalent amount of normal saline solution. Two doses of angiotensin II, 1 x 10(-11.5) and 1 x 10(-10) moles, were injected as boluses into the chorionic arteries of each cotyledon. A 3 x 10(-7) mole dose of angiotensin II was also injected into the intervillous space. Statistical analysis was performed with analysis of variance, and results are expressed as mean pressure change in millimeters of mercury +/- SEM. RESULTS: Perfusion pressure response did not vary between cotyledons pretreated with acetylsalicylic acid and control cotyledons when 3 x 10(-7) moles of angiotensin II was injected into the intervillous space (8.0 +/- 1.9 mm Hg vs 9.8 +/- 1.6 mm Hg, p = 0.59). There were no differences between cotyledons in pressure response to 1 x 10(-11.5) moles of angiotensin II injected into the fetal circuit (5.9 +/- 0.8 mm Hg vs 6.7 +/- 0.9 mm Hg, p = 0.51). However, in the cotyledons pretreated with acetylsalicylic acid there was a decrease in the pressor response to 1 x 10(-10) moles of angiotensin II (14.1 +/- 1.4 mm Hg vs 21.5 +/- 3.3 mm Hg, p = 0.05). CONCLUSIONS: Low-dose aspirin infused into the intervillous space decreases vasoconstriction elicited by angiotensin II in the fetoplacental compartment. This suggests that maternal low-dose aspirin therapy has effects in the fetoplacental circulation in addition to its effects in the maternal 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.     

Differential role of endothelium-derived nitric oxide in the modulation of the systemic and pulmonary circulation in lambs

We have studied the differential role of endothelium-derived nitric oxide (EDNO) in the regulation of the systemic and pulmonary circulations of the lamb. Hemodynamic effects of NG-nitro-L-arginine methyl ester (L-NAME, 1 mg/kg i.v.), an inhibitor of NO synthesis, were determined in juvenile (6 +/- 1 weeks old) lambs, under conditions of basal and elevated vasomotor tone. Under basal conditions, L-NAME raised both systemic (SVR) and pulmonary vascular resistances (PVR) by 20-30% (increasing SVR from 0.318 +/- 0.013 to 0.385 +/- 0.015 mm Hg.min.ml-1.kg and PVR from 0.050 +/- 0.003 to 0.067 +/- 0.010 mm Hg.min.ml-1.kg). When tone was elevated in the pulmonary circulation with hypoxia (PVR was elevated by 60%, from 0.059 +/- 0.010 to 0.094 +/- 0.019 mm Hg.min.ml-1.kg), L-NAME treatment resulted in an augmented increase in PVR (PVR increased by greater than 50% to 0.140 +/- 0.024 mm Hg.min.ml-1.kg). However, when tone was elevated to a comparable degree in the systemic circulation with angiotensin infusion (SVR was elevated by 60%, from 0.432 +/- 0.065 to 0.065 to 0.634 +/- 0.113 mm Hg.min.ml-1.kg), the response to L-NAME was not augmented. Our data suggest that the role of EDNO in the modulation of the pulmonary circulation is dependent on the level of vasomotor tone, whereas its role in the systemic circulation is small and is independent of the level of vasomotor tone.     

The effect of low-dose inhalation of nitric oxide in patients with pulmonary fibrosis

The aim of this study was to determine whether low-dose inhalation of nitric oxide (NO) improves pulmonary haemodynamics and gas exchange in patients with stable idiopathic pulmonary fibrosis (IPF). The investigation included 10 IPF patients breathing spontaneously. Haemodynamic and blood gas parameters were measured under the following conditions: 1) breathing room air; 2) during inhalation of 2 parts per million (ppm) NO with room air; 3) whilst breathing O2 alone (1 L.min-1); and 4) during combined inhalation of 2 ppm NO and O2 (1 L.min-1). During inhalation of 2 ppm NO with room air the mean pulmonary arterial pressure (Ppa 25 +/- 3 vs 30 +/- 4 mmHg) and the pulmonary vascular resistance (PVR 529 +/- 80 vs 699 +/- 110 dyn.s.cm-5) were significantly (p < 0.01) lower than levels measured whilst breathing room air alone. However the arterial oxygen tension (Pa,O2) did not improve. The combined inhalation of NO and O2 produced not only a significant (p < 0.01) decrease of Ppa (23 +/- 2 vs 28 +/- 3 mmHg) but also, a remarkable improvement (p < 0.05) in Pa,O2 (14.2 +/- 1.2 vs 11.7 +/- 1.0 kPa) (107 +/- 9 vs 88 +/- 7 mmHg)) as compared with the values observed during the inhalation of O2 alone. These findings suggest that the combined use of nitric oxide and oxygen might constitute an alternative therapeutic approach for treating idiopathic pulmonary fibrosis patients with pulmonary hypertension. However, further studies must first be carried out to demonstrate the beneficial effect of oxygen therapy on pulmonary haemodynamics and prognosis in patients with idiopathic pulmonary fibrosis and to rule out the potential toxicity of inhaled nitric oxide, particularly when used in combination with oxygen.     

Sustained pulmonary vasodilation after inhaled nitric oxide for hypoxic pulmonary hypertension in swine

It has been shown that pulmonary vasodilation is sustained after discontinuation of inhaled nitric oxide (INO) during moderate hypoxic pulmonary hypertension (HPH) in swine. The present investigations demonstrated how INO dose, hypoxia duration, and endogenous NO production influence this important phenomenon. Fifteen adolescent Yorkshire swine were randomly assigned to three groups (n = 5 each) and underwent the following phasic experimental protocol: (I) Baseline ventilation (FIO2 = .3); (II) Initiating HPH (FIO2 = .16 to .18, PaO2 = 45 to 55 mm Hg); (III) INO at 10 ppm; (IV) Posttreatment observation; (V) INO of 80 ppm; and (VI) Posttreatment observation. Phase II (pretreatment hypoxia) lasted 30 minutes in group A (short hypoxia) and 120 minutes in group B (long hypoxia). N-nitro-L-arginine methyl ester (NAME) was used to inhibit nitric oxide synthase (NOS) throughout the experiment in group C (short hypoxia + NAME). Hemodynamics and blood gases were monitored by systemic and pulmonary artery catheters placed by femoral cutdown. Analysis of variance with post-hoc adjustment was used to compare groups at each phase, and the paired t test was used for comparisons within a group. With respect to baseline mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance (PVR), there were no significant differences among the three groups. MPAP and PVR were significantly higher in group C than in group A during phase II, (MPAP, 76% +/- 8% v 33% +/- 2%; PVR, 197% +/- 19% v 78% +/- 10%; P < .05). There were no significant differences in MPAP or PVR during phases III through VI. When MPAP was expressed as percent dilation, 80 ppm caused significantly more dilation than did 10 ppm in all three groups. Groups A and C had significantly higher sustained pulmonary artery dilation after 80 ppm than after 10 ppm (A, 82% +/- 31% v 17% +/- 11%; C, 68% +/- 10% v 42% +/- 12%; both P < .05), but group B did not (43% +/- 15% v 30% +/- 9%; P = .25). High dose results in stronger vasodilation than low dose during and after INO for moderate HPH of short duration. Long hypoxia blunts this high-dose advantage. Endogenous NO inhibition augments HPH but does not decrease pulmonary vasodilation during or after INO.     

Polygraphic validation of distraction tasks in clinical differential tremor diagnosis

We studied the effect of inhaled nitric oxide (NO) on 80 patients who had undergone cardiac surgery in our center. The indications for receiving NO inhalation and the number of patients were as follows: Pp/Ps > 0.5 for pulmonary hypertension (PH) (n = 32; 21 children and 11 adults), severe PH crisis (n = 9), high pulmonary vascular tone (Glenn pressure more than 18 mm Hg after bidirectional Glenn operation) or arterial oxygen saturation (SaO2) less than 70% despite an FiO2 of 1.0 after Blalock-Taussig shunt (n = 6), mean pulmonary artery pressure (PAP) > 15 mm Hg and transpulmonary gradient (TPG) (mean PAP - left atrial pressure [LAP]) > 8 mm Hg after Fontan-type operation (n = 18), elevated pulmonary vascular tone (mean PAP > 30 mm Hg and left ventricular assist system [LVAS] flow rate < 2.5 L/min/m2) in patients with LVAS (n = 3), and impaired oxygenation (PaO2/FiO2 < 100 under positive end-expiratory pressure [PEEP] > 5 cm H2O) (n = 12). Low dose inhaled NO (10 ppm) had the following effects. In adult PH patients, it significantly reduced the mean PAP (from 37.3 to 27.0 mm Hg; average values are given) and increased the mean systemic arterial pressure (SAP) (64.7 to 75.3 mm Hg). In infant PH patients, it increased the mean SAP (51.8 to 56.1 mm Hg). In patients with a PH crisis, it significantly reduced the central venous pressure (CVP) (13.3 to 8.8 mm Hg) while increasing both the mean SAP (49.4 to 57.9 mm Hg) and PaO2/FiO2 (135 to 206). In patients after a Fontan-type operation, it significantly reduced the mean PAP (16.8 to 13.8 mm Hg) and TPG (9.5 to 5.8 mm Hg). In patients under LVAS, it reduced the CVP (11.7 to 8.0 mm Hg) and mean PAP (32.0 to 24.7 mm Hg). In impaired oxygenation patients, PaO2/FiO2 was increased (75 to 106). Sixty-five patients were all followed for 2.0-4.3 years (average, 3.1 years). All 65 patients remained free from oxygen requirement, and possible chronic adverse effects including the occurrence of malignant tumors or chronic inflammation in the respiratory tract were not observed.     

Intravenous almitrine combined with inhaled nitric oxide for acute respiratory distress syndrome. The NO Almitrine Study Group

Inhaled nitric oxide (iNO), a selective pulmonary vasodilator and intravenously administered almitrine, a selective pulmonary vasoconstrictor, have been shown to increase PaO2 in patients with acute respiratory distress syndrome (ARDS). This prospective study was undertaken to assess the cardiopulmonary effects of combining both drugs. In 48 consecutive patients with early ARDS, cardiorespiratory parameters were measured at control, after iNO 5 ppm, after almitrine 4 micrograms. kg-1. min-1, and after the combination of both drugs. In 30 patients, dose response to 2, 4, and 16 micrograms. kg-1. min-1 of almitrine with and without NO was determined. Almitrine and lactate plasma concentrations were measured in 17 patients. Using pure O2, PaO2 increased by 75 +/- 8 mm Hg after iNO, by 101 +/- 12 mm Hg after almitrine 4 micrograms. kg-1. min-1, and by 175 +/- 18 mm Hg after almitrine combined with iNO (p < 0.001). In 63% of the patients, PaO2 increased by more than 100% with the combination of both drugs. Mean pulmonary artery pressure (Ppa) increased by 1.4 +/- 0.2 mm Hg with almitrine 4 micrograms/kg/ min (p < 0.001) and decreased by 3.4 +/- 0.4 mm Hg with iNO and by 1.5 +/- 0.3 mm Hg with the combination (p < 0.001). The maximum increase in PaO2 was obtained at almitrine concentrations <= 4 micrograms. kg-1. min-1, whereas almitrine increased Ppa dose-dependently. Almitrine plasma concentrations also increased dose-dependently and returned to values close to zero after 12 h. In many patients with early ARDS, the combination of iNO 5 ppm and almitrine 4 micrograms. kg-1. min-1 dramatically increases PaO2 without apparent deleterious effect allowing a rapid reduction in inspired fraction of O2. The long-term consequences of this immediate beneficial effect remain to be determined.     

Fetoplacental vascular tone during fetal circuit acidosis and acidosis with hypoxia in the ex vivo perfused human placental cotyledon

OBJECTIVES: Our purpose was to determine the effects of acidosis and acidosis-hypoxia on fetoplacental perfusion pressure and its response to angiotensin II. STUDY DESIGN: Perfused cotyledons from 14 placentas were studied with either an acidotic fetal circuit perfusate (n = 7) or an acidotic-hypoxic fetal circuit perfusate (n = 7). Each cotyledon's fetal vasculature was initially perfused under standard conditions and bolus injected with 1 x 10(-10) moles of angiotensin II. Fetoplacental perfusate was then replaced with either an acidotic medium (pH 6.90 to 7.00 and Po2 516 to 613 mm Hg) or an acidotic-hypoxic medium (pH 6.90 to 7.00 and Po2 20 to 25 mm Hg) followed by an angiotensin II injection. The vasculature was subsequently recovered with standard perfusate and again injected with angiotensin II. Perfusion pressures within each group were compared by one-way analysis of variance, and results were expressed as mean pressure +/- SEM. RESULTS: Resting fetoplacental perfusion pressure did not change when the fetal circuit perfusate was made acidotic (28 +/- 1 mm Hg vs 25 +/- 2 mm Hg) or acidotic-hypoxic (26 +/- 2 mm Hg vs 25 +/- 2 mm Hg). The maximal fetoplacental perfusion pressure achieved in response to angiotensin II did not differ with an acidotic perfusate (41 +/- 2 mm Hg vs 38 +/- 1 mm Hg) or with an acidotic-hypoxic perfusate (39 +/- 2 mm Hg vs 36 +/- 2 mm Hg). CONCLUSIONS: In the perfused placental cotyledon fetoplacental perfusion pressure and pressor response to angiotensin II are not affected by fetal circuit acidosis or acidosis-hypoxia. This suggests that neither fetal acidosis nor fetal acidosis combined with hypoxia has a direct effect on fetoplacental vascular tone.     

Low-dose sodium nitroprusside reduces pulmonary reperfusion injury

BACKGROUND: Reperfusion injury is a significant cause of early allograft dysfunction after lung transplantation. We hypothesized that direct pulmonary arterial infusion of an intravascular nitric oxide donor, sodium nitroprusside (SNP), would ameliorate pulmonary reperfusion injury more effectively than inhaled nitric oxide without causing profound systemic hypotension. METHODS: Using an isolated, ventilated, whole-blood-perfused rabbit lung model, we studied the effects of both inhaled and intravascular nitric oxide during lung reperfusion. Group I (control) lungs (New Zealand White rabbits, 3 to 3.5 kg) were harvested en bloc, flushed with Euro-Collins solution, and then stored inflated for 18 hours at 4 degrees C. Lungs were then reperfused with whole blood and ventilated with 60% oxygen for 30 minutes. Groups II, III, and IV received pulmonary arterial infusions of SNP at 0.2, 1.0, and 5.0 micrograms.kg-1.min-1, respectively, whereas group V was ventilated with 60% oxygen and nitric oxide at 80 ppm during reperfusion. RESULTS: Pulmonary arterial infusions of SNP even at 0.2 microgram.kg-1.min-1 (group II) showed significant improvements in pulmonary artery pressure (31.35 +/- 0.8 versus 40.37 +/- 3.3 mm Hg; p < 0.05) and pulmonary vascular resistance (38,946 +/- 1,269 versus 52,727 +/- 3,421 dynes.s/cm-5; p < 0.05) when compared with control (group I) lungs after 30 minutes of reperfusion. Infusions of SNP at 1.0 microgram.kg-1.min-1 (group III) showed additional significant improvements in dynamic airway compliance (1.98 +/- 0.10 versus 1.46 +/- 0.02 mL/mm Hg; p < 0.05), venous-arterial oxygenation gradient (116.00 +/- 24.4 versus 34.43 +/- 2.5 mm Hg; p < 0.05), and wet-to-dry ratio (6.9 +/- 0.9 versus 9.1 +/- 2.2; p < 0.05) when compared with control (group I) lungs. Lungs that received inhaled nitric oxide at 80 ppm (group V) were significantly more compliant (1.82 +/- 0.13 versus 1.46 +/- 0.02 mL/mm Hg; p < 0.05) than control (group I) lungs. CONCLUSIONS: Pulmonary arterial infusion of low-dose SNP during lung reperfusion significantly improves pulmonary hemodynamics, oxygenation, compliance, and edema formation. These effects were achieved at doses of SNP that did not cause profound systemic hypotension. Direct intravascular infusion of SNP via pulmonary arterial catheters could potentially abate reperfusion injury immediately after allograft implantation.     

The angiotensin receptor antagonist 2-ethoxy-1-[[2'-(1H- tetrazol-5-yl) biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (CV11974) attenuates the tubuloglomerular feedback response during NO synthase blockade in rats

Nitric oxide (NO) produced in the juxtaglomerular apparatus may regulate the tubuloglomerular feedback (TGF) response. The inhibition of intrinsic NO results in significant renal hemodynamic changes, a phenomenon similar to that observed after angiotensin II (A-II) administration. We measured stop-flow pressure (Psf) during loop perfusion with artificial tubular fluid in Sprague-Dawley rats to establish whether alterations in TGF responsiveness during NO inhibition depend on the action of endogenous A-II. The NO synthase blocker N omega-nitro-L-arginine-methyl-ester (L-NAME: 10 mg/kg i.v.) significant increased TGF responsiveness, defined as the change in Psf on increasing loop flow from 0 to 40 nl/min compared with control (delta Psf: -21.3 +/- 2.6 vs. -9.7 +/- 0.6 mm Hg, P < .001). After concomitant treatment with the nonpeptide A-II type 1 receptor antagonist 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxic acid (CV11974: 1 mg/kg i.v.) and L-NAME, the TGF response was attenuated significantly (delta Psf: -7.6 +/- 1.9 mm Hg, P < .001). On the other hand, Psf in the absence of loop perfusion was increased similarly by L-NAME treatment in the presence (53.7 +/- 2.2 mm Hg) or absence of CV11974 (Psf 50.7 +/- 3.2 mm Hg). These results suggest that augmentation of the TGF response by endogenous NO inhibition depends, at least in part, on the intrinsic A-II activity.     

Baroreflex control of heart rate and cardiac hypertrophy in angiotensin II-induced hypertension in rabbits

The cardiac hypertrophy observed in hypertension is thought to be responsible for the accompanying deficiency in the baroreflex control of heart rate. In this study, we assessed the baroreflex relationship between heart rate and arterial pressure on a group of seven rabbits during a normotensive period, during the early phase of angiotensin II (Ang II)-induced hypertension II week) (50 ng/kg per minute i.v. via osmotic minipumps), after 7 weeks of continuous hypertension, then 2 days after Ang II was stopped, and finally 7 days after Ang II. Left ventricles were weighed for measurement of left ventricular weight-body weight ratio. One week of intravenous Ang II infusion produced hypertension (mean arterial pressure from 80 +/- 2 up to 115 +/- 8 mm Hg), with significantly increased heart rate and hematocrit. The heart rate-arterial pressure baroreflex curve was shifted to the right, with a significant 45% reduction in the gain of the reflex (-6.4 +/- 1.5 to -3.5 +/- 0.2 beats per minute/mm Hg). After 7 weeks of Ang II, arterial pressure was still elevated (112 +/- 4 mm Hg) and the gain of the baroreflex curve still somewhat attenuated, although it was no longer markedly different from normotensive levels (gain, -5.09 +/- 0.95, 20% reduction from normotensive level). Two days after the Ang II infusion was stopped, arterial pressure had returned to normotensive levels, although hematocrit and heart rate remained elevated. At this time, the baroreflex curve was similar to prehypertensive control levels, with no further changes when measured again 7 days after Ang II. Cardiac hypertrophy was present when measured at 7 days after angiotensin (left ventricular weight-body weight ratio: 1.78 +/- 0.05 versus 1.35 +/- 0.04 g/kg, hypertensive versus normotensive, P < .05). Thus, although Ang II infusion produced an initial deficit in the baroreflex control of heart rate, this effect became less as the hypertension continued. Furthermore, although cardiac hypertrophy developed, its presence did not appear to be sufficient to produce a decrease in barosensitivity independent of raised arterial pressure.