Josette Dall'ava-Santucci

Endogenous pulmonary nitric oxide production measured from exhaled air is increased in patients with severe cirrhosis

BACKGROUND/AIMS Endogenous pulmonary nitric oxide production may be increased in severe cirrhosis and contribute to pulmonary vasodilation. This study assessed pulmonary nitric oxide production by measuring nitric oxide in the exhaled air in patients with severe cirrhosis and examined the relationship between exhaled nitric oxide and pulmonary hemodynamics in these patients. METHODS Nitric oxide concentrations and production were measured in the exhaled air in six Child-Pugh class C patients with cirrhosis and 21 non-smoking healthy controls. Systemic and pulmonary hemodynamics were measured in patients only. RESULTS Nitric oxide concentration (32.0 +/- 1.7 (mean +/- SEM) vs. 8.9 +/- 1.0 ppb) and production (9.2 +/- 1.3 vs. 3.1 +/- 0.3 nmol/min) in exhaled air were significantly higher in patients than in controls. Patients had high cardiac output (8.5 +/- 0.9 l/min), low pulmonary and systemic vascular resistance (57 +/- 10 and 767 +/- 93 dyn.s.cm-5, respectively) under baseline conditions. A significant negative correlation was found between pulmonary vascular resistance and exhaled nitric oxide production (r=0.943, p=0.05) but not between cardiac output or systemic vascular resistance and nitric oxide measured in exhaled air. CONCLUSIONS Endogenous pulmonary nitric oxide production measured from exhaled air is increased in patients with cirrhosis and liver failure. Increased in patients with cirrhosis and liver failure. Increased nitric oxide production may also contribute to cirrhosis-induced pulmonary vasodilatation.

Exhaled nitric oxide during acute changes of airways calibre in asthma

It has been shown that endogenous nitric oxide (NO), measured in exhaled air, is increased in asthmatic subjects and after allergen challenge in sensitized animals. NO is also a paracrine molecule with some, though weak, bronchodilator effects. However, whether the amount of endogenous NO that originates in the lungs can reflect the degree of bronchial tone and airways calibre in asthmatic subjects has not yet been investigated. The aim of this study was, therefore, to determine whether NO production could be modified by acute changes of airways calibre in mild, nonatopic, asthmatic subjects. NO output was measured in the exhaled air of 14 steroid-free asthmatics, 8 steroid-treated asthmatics and 21 control subjects. In seven steroid-free asthmatics, exhaled NO was measured after methacholine challenge, and then after salbutamol-induced bronchial dilatation. Exhaled tidal breathing was collected for 30 s and NO in the exhaled air was measured with a chemiluminescence analyser. Both NO concentration and its output were significantly higher in the steroid-free asthmatic patients (15.6 +/- 1.5 parts per billion (ppb) and 6.3 +/- 0.7 nmol.min-1, respectively) as compared with the control subjects (8.9 +/- 1.0 ppb and 3.5 +/- 0.3 nmol.min-1, respectively; p < 0.001 for both) and with the steroid-treated asthmatic patients (11.3 +/- 3.3 ppb and 3.7 +/- 0.9 nmol.min-1, respectively; p < 0.05 for both). Neither methacholine-induced bronchial obstruction nor salbutamol-induced bronchial dilatation caused a significant change in exhaled NO. We conclude that NO production is higher in steroid-free than in steroid-treated asthmatics and in control subjects. Furthermore, NO production is not affected by acute pharmacologically-induced changes of airways calibre in asthmatic subjects. Our results suggest that NO production is a marker of airways inflammation rather than an endogenous modulator of bronchial tone in asthma.

Comparison of transesophageal echocardiographic, fick, and thermodilution cardiac output in critically ill patients

PURPOSE Recent observations have highlighted errors in the thermodilution technique of measuring cardiac output. Thus, cardiac output measurements using transesophageal echocardiography and the Fick method were compared with simultaneous thermodilution measurements. METHODS In 13 mechanically ventilated critically ill patients, cardiac output was determined simultaneously using (1) transesophageal echocardiography (COTEE, (2) the Fick method (COFICK, and (3) thermodilution (COTD immediately before and after a rapid infusion of 500 mL of saline. Left ventricular end-diastolic and end-systolic areas were measured using the transesophageal echocardiographic transgastric short axis view, and COTEE was calculated from the corresponding volumes. Absolute cardiac output values and the changes from before to after saline infusion (delta CO) were compared using analysis of variance, linear regression, and the Bland and Altman method. RESULTS There were no significant differences between COTEE (8.0 +/- 3.4), COFICK (8.4 +/- 3.3), and COTD (8.3 +/- 3.0) or between delta COTEE, delta COFICK, and delta COTD using analysis of variance. However, correlations between COTEE and COTD (r2 = 0.46; P < .00001), COFICK and COTD (r2 = 0.46; P < .0001), and COTEE and COFICK (r2 = 0.42; P < .0001) were only moderately good. Using the method of Bland and Altman, the mean difference (+/-2 standard deviations) between COTEE and COTD was 0.3 +/- 4.3 L/min, between COFICK and COTD was -1.0 +/- 3.8 L/min, and between COTEE and COFICK was 0.6 +/- 5.6 L/min, whereas the difference between delta COTEE and delta COTD was 0% +/- 26%, between delta COFICK and delta COTD was 9% +/- 46%, and between delta COTEE and delta COFICK was 8% +/- 39%. CONCLUSIONS There are substantial differences in cardiac output as measured by these three methods, best demonstrated using the method of Bland and Altman. The variability of cardiac output and its derivatives (eg, oxygen delivery) should be borne in mind when making clinical decisions on individual patients.

Small hemodynamic effect of typical rapid volume infusions in critically ill patients

OBJECTIVES To determine what volumes are commonly used for rapid volume infusions in critically ill patients admitted to the intensive care unit (ICU) for > 12 hrs; and to determine the effectiveness of a typical rapid volume infusion in producing hemodynamic change and increasing left ventricular end-diastolic volume. DESIGN A prospective survey of clinical practice (part 1) and a prospective clinical investigation (part 2). SETTING Two hospital ICUs (11 and six beds) of which one is university affiliated. PATIENTS Critically ill patients admitted to the ICU for > 12 hrs. INTERVENTIONS Infusion of 500 mL of normal saline over 5 to 10 mins. MEASUREMENTS AND MAIN RESULTS For 1 month, we recorded the volume and composition of all volume infusions given as a rapid bolus in patients admitted to the ICU for > 12 hrs. We then measured the effected the median rapid volume infusion in a subset of 13 patients by measuring hemodynamics (using arterial and pulmonary artery flotation catheters) and left ventricular end-diastolic area (using transgastric short-axis views from transesophageal echocardiograms). During 470 patient days, 159 rapid volume infusions were administered. The average rapid volume infusion administered was 390 +/- 160 mL (median 500; interquartile range 250 to 500). Crystalloid solutions were used for two thirds of the rapid volume infusions and colloid solutions were used for one third of the rapid volume infusions. The rapid volume infusion of 500 mL of saline did not significantly increase mean arterial pressure (78.0 +/- 11.9 to 79.3 +/- 14.6 mm Hg), cardiac index (4.3 +/- 1.7 to 4.6 +/- 1.8 L/min/m2), right atrial pressure (11.1 +/- 3.8 to 12.4 +/- 3.3 mm Hg), left ventricular end-diastolic area (8.6 +/- 1.7 to 9.1 +/- 1.8 cm2/m2), or left ventricular end-systolic area (3.5 +/- 1.5 to 3.6 +/- 1.5 cm2/m2). Pulmonary artery occlusion pressure increased slightly but significantly from 12.9 +/- 3.4 to 14.7 +/- 3.3 mm Hg (p < .05). CONCLUSIONS After patients are admitted to the ICU for > 12 hrs, rapid volume infusions are common therapeutic interventions but the rapid volume infusions are typically small. The effect of a typical rapid volume infusion on hemodynamics and left ventricular areas in these patients is surprisingly small.

Nitric oxide synthase 1 as a potential modifier gene of decline in lung function in patients with cystic fibrosis

Background: The severity of lung disease varies widely in patients with cystic fibrosis (CF) who have the same type of mutations of the cystic fibrosis transmembrane regulator (CFTR) gene, suggesting involvement of “modifier” genes. The nitric oxide synthase 1 (NOS1) gene is a candidate for this role because exhaled nitric oxide (NO) is reduced in patients with CF and NOS1 activity contributes to transepithelial ionic transport, immune defence, and non-specific inflammation of the airways. Methods: Dinucleotide GT repeat polymorphism was studied in the 5′ untranslated region of the NOS1 gene, immediately upstream from the transcription initiation site, in 59 patients with CF and 59 healthy controls. Results: Nineteen alleles of the NOS1 gene were identified according to the number of GT repeats (from 18 to 36) in the 5 untranslated region. Exhaled NO levels were significantly correlated with the number of GT repeats. Patients with CF who had the NOS1 genotype associated with high NO production had a slower decline in lung function during the 5 year follow up period. There was no confounding effect of age, chronic bacterial colonisation of the airway, or CFTR genotype. Conclusions: These data suggest a possible link between the NOS1 gene locus and the rate of decline in lung function in patients with CF.

Nasal airway ion transport is linked to the cystic fibrosis phenotype in adult patients.

Background: This study was conducted to determine whether the major nasal airway ion transport abnormalities in cystic fibrosis (that is, defective cAMP regulated chloride secretion and basal sodium hyperabsorption) are related to the clinical expression of cystic fibrosis and/or to the genotype. Methods: Nasal potential difference was measured in 79 adult patients with cystic fibrosis for whom clinical status, respiratory function, and CFTR genotype were determined. Results: In univariate and multivariate analysis, patients with pancreatic insufficiency were more likely to have low responses to low chloride (odds ratio (OR) 8.6 (95% CI 1.3 to 58.5), p = 0.03) and isoproterenol (OR 11.2 (95% CI 1.3 to 93.9), p = 0.03) solutions. Similarly, in univariate and multivariate analysis, patients with poor respiratory function (forced expiratory volume in 1 second <50% of predicted value) were more likely to have an enhanced response to amiloride solution (OR 3.7 (95% CI 1.3 to 11.0), p = 0.02). However, there was no significant relationship between nasal potential difference and the severity of the genotype. Conclusions: Nasal epithelial ion transport in cystic fibrosis is linked to the clinical expression of the disease. The pancreatic status appears to be mostly related to the defect in epithelial chloride secretion whereas the respiratory status is mostly related to abnormal sodium transport and the regulatory function of the CFTR protein.

Role of NO in the pulmonary artery hyporeactivity to phenylephrine in experimental biliary cirrhosis

The aim of this study was to see whether increased activity of nitric oxide (NO) might account for decreased pulmonary vascular tone seen in the hyperdynamic circulation of cirrhosis. We compared the pulmonary vascular reactivity of isolated pulmonary arteries (PA) from control rats (n = 10), and rats with biliary cirrhosis (n = 10) induced by chronic bile duct ligation (4 weeks). The responses of PA rings to cumulative concentrations of phenylephrine, acetylcholine, and sodium nitroprusside were studied, and also the effects of inhibition of synthesis of NO by the L-arginine analogue, N omega-nitro-L-arginine (L-NOARG) in PA rings challenged with cumulative concentrations of phenylephrine and acetylcholine. The contractile response to phenylephrine was significantly reduced in cirrhotic PA rings as compared with controls. Pretreatment with L-NOARG (10(-4) M) significantly increased the contractile response to phenylephrine in PA rings from cirrhotic rats but not in control PA rings. Furthermore, L-NOARG restored the response to phenylephrine in cirrhotic PA rings back to normal. There was no difference in the relaxation of PA rings from both groups in response to acetylcholine and sodium nitroprusside. We conclude that in vitro pulmonary artery ring hyporeactivity to phenylephrine results from increased nitric oxide production in the pulmonary circulation of cirrhotic rats and might account for the hepatopulmonary syndrome.

Maturational changes of endothelial vasoactive factors and pulmonary vascular tone at birth

The aim of this study was to determine which endothelial factors were involved in the decrease of pulmonary vascular resistance at birth, and how they changed with maturation. Response of intrapulmonary artery rings precontracted with prostaglandin F2alpha were studied from piglets aged <2 h, 2-3 day, 10 day and adult pigs for pharmacological responses to acetylcholine (ACh) and cromakalim (CMK) in the presence and the absence of the nitric oxide synthase (NOS) inhibitor, N(omega)-nitro-L-arginine (L-NA), the adenosine triphosphate sensitive potassium (K(ATP)) channel blocker, glibenclamide and the endothelin (ET)-A receptor antagonist, BQ123. In situ hybridization and immunochemistry studies were performed in lung tissues of the same animals in order to determine the expression of NOS and ET. There was a small contractile effect of ACh in the newborn. Relaxation to ACh, which was blocked by L-NA and reduced by glibenclamide, only appeared from the age of 3 days. The significantly greater relaxation to CMK in rings without endothelium (p<0.05) was abolished by BQ123 in the newborn, and then disappeared by 2 days of age. Glibenclamide had a greater inhibitory effect on relaxation induced by CMK at 10 days than in the newborn and 2 days old piglets. NOS expression was low in pulmonary arteries of the newborn and increased by 2 days of age whereas the converse was seen with ET expression. It is concluded that: 1) relaxant response to acetylcholine was absent at birth and appeared at 2 days; 2) the reduced relaxant response to cromakalin in rings with endothelium at birth could be blocked by BQ123; and 3) the expression of endothelin decreased whereas the expression of nitric oxide synthase increased from birth to 2 days of age.

Silver/silver chloride electrodes for measurement of potential difference in human bronchi

BACKGROUND An easy and reliable method to measure potential difference (PD) in the lower airways would be of interest in the field of cystic fibrosis. We have developed silver/silver chloride (Ag/AgCl) electrodes to measure PD in the lower airways. METHODS To validate this technique the nasal PD measured with Ag/AgCl electrodes and with conventional perfused electrodes was compared in 16 patients. The range of PD measured with Ag/AgCl electrodes in the lower airways during fibreoptic bronchoscopy was determined in 14 adult patients and in nine the reproducibility of this technique was examined. RESULTS Nasal PD values measured with Ag/AgCl and perfused electrodes were highly correlated (r = 0.985, p<0.0001) and the limits of agreement (mean ±2SD of the difference) between the two methods were –1.91 mV and 1.53 mV. In the lower airways a progressive and slight decrease in PD values with decreasing airway diameter was observed in most patients. The mean (2SD) of the differences between the two tracheal measurements was 0.21 (1.73) mV. CONCLUSIONS The use of Ag/AgCl electrodes gives a reliable and reproducible measurement of PD in the lower airways in humans.

Role of tyrosine phosphatase in the modulation of pulmonary vascular tone

In the vascular system, synthesis of the potent vasodilator nitric oxide (NO) is tightly regulated by the constitutively expressed endothelial NO synthase (eNOS). Activity of eNOS is controlled by Ca2+/calmodulin and various seryl/threonyl protein kinases. Less is known about the importance of phosphorylation and dephosphorylation of tyrosyl residues. Therefore the role of tyrosine phosphatase on the modulation of isolated rat pulmonary artery tone has been assessed. Inhibition of tyrosine phosphatase by sodium orthovanadate (SOV, 1×10−6 M) significantly: 1) increased phenylephrine-induced vasoconstriction and 2) decreased endothelium-dependent relaxation to acetylcholine, but had no effect on endothelium-independent relaxation to the NO donor, sodium nitroprusside. In phenylephrine-precontracted pulmonary arterial rings, SOV (1×10−7–1×10−5 M) had no effect on vascular tone but significantly relaxed rings which were pretreated with the NO-synthase inhibitor, Nω‐nitro‐l‐arginine-methyl ester (l‐NAME). SOV-induced relaxation in the presence of l‐NAME was, however, abolished by glibenclamide. In conclusion, inhibition of tyrosine phosphatase altered pulmonary vascular tone by increasing vasoconstrictor response to phenylephrine and decreasing endothelium-dependent relaxation to acetylcholine. Furthermore, the tyrosine phosphatase inhibitor, sodium orthovanadate, exhibited original vasodilator properties which were only observed when nitric oxide synthesis was inhibited. Thus a new pathway involving the inhibitory effect of nitric oxide on a glibenclamide-sensitive diffusible relaxing factor, that might play an important role in the control of pulmonary vascular tone is described.