Inhaled cigarette smoke selectively reverses human hypoxic vasoconstriction.

The acute effects of the inhaled gas phase of cigarette smoke on pulmonary (PAP) and systemic (SAP) arterial pressures and on plasma arterial cGMP content were compared with those of inhaling 10, 20 and 80 ppm nitric oxide (NO) in one healthy adult volunteer spontaneously breathing a hypoxic gas mixture. Hypoxia (FIO2 0.12) induced a sustained, stable pulmonary vasoconstriction. Inhaled NO induced a dose-dependent fall in PAP; plasma cGMP rose from 39.4 (hypoxia) to 164 pmol/ml (hypoxia plus 80 ppm NO). Exposure to cigarette smoke induced a rapid, consistent and reversible fall in PAP; plasma cGMP rose from 45.5 (hypoxia) to 138 pmol/ml (hypoxia plus cigarette smoke). Neither NO nor cigarette smoke inhalation induced any change in SAP. These data suggest that exposure to cigarette smoke is able selectively to reverse acute hypoxic vasoconstriction in humans without causing systemic vasodilation, an effect likely mediated through the NO-cGMP pathway.

The impact of respiratory variables on mortality in non-ARDS and ARDS patients requiring mechanical ventilation.

OBJECTIVES: Primarily, to determine if respiratory variables, assessed on a daily basis on days 1-6 after ICU admission, were associated with mortality in non-ARDS and ARDS patients with respiratory failure requiring mechanical ventilation. Secondarily, to determine non-respiratory factors associated with mortality in ARDS and non-ARDS patients. DESIGN: Prospective multicentre clinical study. SETTING: Seventy-eight intensive care units in Sweden and Iceland. PATIENTS: Five hundred twenty non-ARDS and 95 ARDS patients. MEASUREMENTS AND RESULTS: Potentially prognostic factors present at inclusion were tested against 90-day mortality using a Cox regression model. Respiratory variables (PaO2/FIO2, PEEP, mean airway pressure (MAP) and base excess (BE)) were tested against mortality using the model. Primary aim: in non-ARDS a low PaO2/FIO2 on day 1, RR (risk ratio) = 1.17, CI (95% confidence interval) (1.00; 1.36), day 4, 1.24 (1.02; 1.50), day 5, 1.25 (1.02; 1.53) and a low MAP at baseline, 1.18 (1.00; 1.39), day 2, 1.24 (1.02; 1.52), day 3, 1.33 (1.06; 1.67), day 6, 2.38 (1.11; 5.73) were significantly associated with 90-day death. Secondary aim: in non-ARDS a low age, RR = 0.77 (0.67; 0.89), female gender, 0.85 (0.74; 0.98), and low APS (acute physiologic score), 0.85 (0.73; 0.99), were associated with survival; chronic disease, 1.31 (1.12; 1.52), and non-pulmonary origin to the respiratory failure, 1.27 (1.10; 1.47), with death. In ARDS low age, RR = 0.65 CI (0.46; 0.91), and low APS, 0.65 (0.46; 0.90), were associated with survival. CONCLUSIONS: No independent significant association was seen between 90-day mortality and degree of hypoxaemia, PEEP, MAP or BE for the first full week of ICU care in either ARDS or non-ARDS. In a sub-group of non-ARDS a lower PaO2/FIO2 and MAP tended to influence mortality where a significant association was seen for 3 of 7 study days. Age, gender, APS, presence of a chronic disease and a pulmonary/non-pulmonary reason for the respiratory failure were associated with mortality in non-ARDS, while only age and APS showed a similar association in ARDS.

Response to nitric oxide inhalation in early acute lung injury.

OBJECTIVE: To evaluate the dose response of inhaled nitric oxide (NO) on gas exchange and central haemodynamics in patients with early acute lung injury (ALI). DESIGN: Prospective, multicentre clinical study. SETTING: General ICUs in university and regional hospitals. PATIENTS: 18 Patients with early ALI according to specified criteria. INTERVENTIONS: During controlled ventilation an inhalation system was used to deliver NO (1000 ppm in N2) and O2/air to the low pressure fresh gas inlet of a Siemens 900C ventilator. Haemodynamics and pulmonary gas exchange variables were measured at baseline and at stepwise increased inspiratory NO concentrations of 0.1, 0.3, 1, 3, 10, 30 and 100 ppm, each dose being maintained for 15 min. Dose testing was repeated the next day, and the response to prolonged (2 h) NO inhalation at 1 and 10 ppm was also tested. MEASUREMENTS AND RESULTS: Inhalation of NO produced a significant increase in PaO2 (P < 0.0025). The degree of response, as well as the optimal NO dose varied in individual patients and between different days. Venous admixture (QVA/QT) was reduced (P < 0.02) from 38% (31-46%) to 33% (26-41%). In our patients with early acute lung injury and only a moderate elevation in pulmonary arterial pressure NO inhalation did not reduce mean pulmonary artery pressure significantly, being 27.0 (21-30) mmHg at baseline and 26.0 (21-30) mm Hg at 100 ppm. CONCLUSIONS: This study shows that improvements in arterial oxygenation in response to inhaled NO may show great inter- as well as intraindividual variability, and that improvements in arterial oxygenation occur without any measurable lowering of the pulmonary artery pressure.

Protective effects of anti-O polysaccharide and anti-lipid A monoclonal antibodies on pulmonary hemodynamics.

Monoclonal antibodies (MAbs) directed to endotoxin can protect in some animal models against the pathophysiological effects of endotoxin infusion. When 0.02 microgram/kg of lipopolysaccharide (LPS) derived from Escherichia coli O111:B4 was incubated in vitro for 2 h with the murine immunoglobulin G MAb, 5B10, directed against the O-polysaccharide antigenic domain of E. coli O111:B4 and then the mixture was infused into sheep, we noted significant protection. The second temperature peak was decreased (P < 0.05 vs. LPS control). The acute pulmonary arterial pressure elevation was diminished (mean peak pulmonary arterial pressure 23.2 +/- 2.5 mmHg, P < 0.05 vs. LPS control), and the peak plasma thromboxane B2 level was reduced (mean peak thromboxane B2 level 0.50 +/- 0.15 ng/ml, P < 0.05 vs. LPS control). In contrast, preincubation of the LPS with a human immunoglobulin M MAb, HA-1A, directed against the core glycolipid of the LPS molecule provided no protective effects in this sheep model. This finding is in agreement with recent studies reporting HA-1A may bind to antibiotic-treated bacteria but not to purified smooth LPS.

Induction of chromosome aberrations in peripheral blood lymphocytes after short time inhalation of nitric oxide.

INTRODUCTION: inhalation of nitric oxide (INO) leads to vasodilation of pulmonary vasculature in ventilated regions of the lung. The clinical use of INO, although not formally approved as a drug, is widespread. NO may rapidly form nitrogen dioxide (NO2) in an oxygen containing gas mixture. NO2 has been shown to induce chromosome aberrations and mutations in both animal and bacterial test systems. We investigated whether a 2-h exposure to NO would increase frequencies of cells with chromosome aberrations in peripheral blood lymphocytes of human volunteers. METHODS: 10 volunteers were exposed to inhaled NO 40 parts per million (ppm) for 2 h. Pre- and post-exposure blood samples were analysed. RESULTS: no statistically significant differences (p

Lung lymph drainage.

This presentation was intended as a brief review of two principally different approaches to studies on pulmonary lymphatic drainage. When selecting an experimental model, we have to choose between either sampling of pure lung lymph thereby sacrificing information about whole organ fluid balance, or emphasize dynamic fluid balance for the whole lung at the expense of obtaining pure lung lymph. Both approaches can be seen as fruitful and complementary strategies to obtain relevant information on pulmonary pathophysiology.

Delivery characteristics of a combined nitric oxide nasal continuous positive airway pressure system.

BACKGROUND: Nitric oxide (NO), when inhaled, has a synergistic effect with airway recruitment strategies such as positive endexpiratory pressure (PEEP) or continuous positive airway pressure (CPAP) in improving oxygenation in lung injury. METHODS: We modified a commercially available nasal CPAP (nCPAP) system to enable the concomitant delivery of inhaled NO (iNO) and nCPAP to neonates and term babies. Oxygen, NO and nitrogen dioxide (NO2) concentrations were measured, comparing the effects of using 50 or 1000 parts per million (p.p.m.) NO stock gas cylinders. RESULTS: Stable and accurate delivery of iNO was found for both stock gas concentrations. Using a 50 p.p.m. NO stock gas resulted in limited NO2 formation, with a maximum inspired NO2 concentration of < or = 0.3 p.p.m. (dose range up to 37 p.p.m. iNO), which was interpreted as the result of progressive dilution with nitrogen. In contrast, using a 1000 p.p.m. NO stock gas cylinder, inspired NO2 levels increased nonlinearly as expected with an increasing inspired concentration of NO. CONCLUSIONS: Inhaled NO can be safely and reliably delivered by the system we describe. The NO2 levels generated by the system are low, at least up to a dose of 37 p.p.m. NO, regardless of a stock gas concentration of 50 or 1000 p.p.m. NO. Using a 50 p.p.m. NO stock gas concentration, up to 80% oxygen can be given at 10 p.p.m. iNO.

Formation of nitrogen dioxide from nitric oxide and their measurement in clinically relevant circumstances.

Therapy with inhaled nitric oxide in oxygen requires adequate monitoring of nitric oxide and nitrogen dioxide. The characteristics of chemiluminescence and electrochemical measurement techniques were determined by analysis of continuously flowing gas mixtures and comparisons with traceable gas standards. Gas mixtures were also diluted with mass flow controllers and in addition created in ventilator breathing systems. Factors influencing the formation of nitrogen dioxide were defined. Both techniques accurately measured nitric oxide (10-80 parts per million, ppm) and nitrogen dioxide (0.5-5 ppm) in normoxic and hyperoxic (90% oxygen) gas in the studied ranges. Nitrogen dioxide in hyperoxic gas had three origins: (1) from the premixing point of nitric oxide in nitrogen, (2) as a result of the mixing process, and (3) from post-mixing and time-dependent continuous formation of nitrogen dioxide in oxygen. We conclude that adequate monitoring is possible and that factors affecting nitrogen dioxide generation can be defined.

Inhalation of nitric oxide modulates adult human bronchial tone.

We studied whether nitric oxide (NO), added at 80 ppm to inspired gas, can exert a bronchodilatory effect in humans. Four groups were studied: (1) healthy adult volunteers (n = 6), (2) adult subjects with hyperreactive airways (n = 6) during provocation with inhaled methacholine (MCh), (3) patients with bronchial asthma (n = 13), and (4) patients with chronic obstructive pulmonary disease (COPD, n = 6). All subjects were studied in a body plethysmograph, measuring volume-corrected specific airway conductance (SGaw). No patient or volunteer reacted with bronchoconstriction during NO inhalation. Nitric oxide did not affect SGaw in healthy volunteers or in patients with COPD. Inhaled NO modulated the MCh-induced bronchoconstriction toward dilatation. In patients with bronchial asthma, SGaw increased (p < 0.05) from 0.4 +/- 0.1 to 0.6 +/- 0.2 (kPa.s)-1. In a succeeding test with inhalation of a beta 2-agonist immediately after NO inhalation, a more marked increase in SGaw was seen, to 1.2 +/- 0.3 (kPa.s)-1 (p < 0.001). We conclude that NO inhaled at 80 ppm has no effect on airway tone in healthy volunteers, but modulates the response to MCh provocation toward bronchodilation. It exerts a weak bronchodilatory effect in bronchial asthma, but not in COPD.

Inhaled nitric oxide selectively reverses human hypoxic pulmonary vasoconstriction without causing systemic vasodilation.

BACKGROUND: Nitric oxide (NO), an endothelium-derived relaxing factor, acts as a local vasodilator. The authors examined the effects of NO on pulmonary and systemic circulation in human volunteers. METHODS: Nine healthy adults were studied awake while breathing 1) air, 2) 12% O2 in N2, 3) followed by the same mixture of O2 and N2 containing 40 ppm of NO. Pulmonary artery and radial artery pressures were monitored. RESULTS: The PaO2 decreased from 106 +/- 4 (mean +/- standard error of the mean) while breathing air (21% O2) to 47 +/- 2 mmHg after 6 min of breathing 12% O2. Concomitantly, the pulmonary artery mean pressure (PAP) increased from 14.7 +/- 0.8 mmHg to 19.8 +/- 0.9 mmHg, and the cardiac output (CO) increased from 6.1 +/- 0.4 to 7.7 +/- 0.6 L/min. After adding 40 ppm NO to the inspired gas while maintaining the FIO2 at 0.12, the PAP decreased (P < 0.01, by analysis of variance) to the level when breathing air while the PaO2 and PaCO2 were unchanged. The dilation (or recruitment) of pulmonary vessels produced by inhaling NO during hypoxia was not accompanied by any alteration in the systemic vascular resistance or mean arterial pressure (MAP). The authors also examined the effects of inhaling NO while breathing air. Breathing 40 ppm NO in 21% O2 for 6 min produced no significant changes of PAP, CO, PaO2, MAP, or central venous pressure. Plasma endothelinlike immunoreactivity concentrations did not change either during hypoxia or hypoxia with NO inhalation. CONCLUSIONS: Inhalation of 40 ppm NO selectively induced pulmonary vasodilation and reversed hypoxic pulmonary vasoconstriction in healthy humans without causing systemic vasodilation.

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.

Respiratory tract colonization and infection in patients with chronic tracheostomy. A one-year study in patients living at home.

The high rate of complications, especially respiratory tract infection (RTI), reported in patients with chronic tracheostomy (CT) has discouraged physicians from using this method. However, previous studies of CT have concerned mainly hospitalized patients. We have followed the bacterial colonization patterns of the upper and lower respiratory tract and recorded all RTIs in 39 outpatients with CT during a 12-mo period. Patients were colonized with one or more potential pathogens at the stomal site and in the trachea in 95% and 83%, respectively, of all sampling occasions. Staphylococcus aureus, gram-negative enteric bacteria (GNEB), and Pseudomonas aeruginosa were the most common colonizing bacteria at these sites. Seventy percent of bronchial-protected brush cultures were negative, despite simultaneous heavy colonization of the stomal site or the trachea. Only 18 of 39 (46%) patients were treated with antibiotics because of RTIs on a total of 30 occasions during the study year. Of these, only five episodes of pneumonia in four patients were registered, corresponding to an incidence of about 10 per 100 person years. We conclude that outpatients with chronic tracheostomy can be managed with a low risk for developing severe RTIs, despite massive airway colonization with potentially pathogenic bacteria.

Near fatal pulmonary hypertension after surgical repair of congenital diaphragmatic hernia. Successful use of inhaled nitric oxide.

The addition of 10-20 parts per million nitric oxide to the inspired gas was successful in controlling near fatal pulmonary hypertension after surgical repair of a congenital diaphragmatic hernia in a neonate. A preceding prostacyclin infusion was unable to prevent the failure of pulmonary perfusion. No side effect of nitric oxide therapy was observed, and ventilatory support could be substantially reduced as a result of the treatment. On the basis of the striking and lifesaving effects of nitric oxide therapy demonstrated in this child, we believe that nitric oxide treatment will prove to be a major contribution to the management of postoperative pulmonary hypertensive crises.

Inhaled nitric oxide. A selective pulmonary vasodilator of heparin-protamine vasoconstriction in sheep.

Nitric oxide (NO) has recently been discovered to be an important endothelium-derived relaxing factor and produces profound relaxation of vascular smooth muscle. To learn if NO could be a potent and selective pulmonary vasodilator, NO was inhaled by 16 awake lambs in an attempt to reduce the increase in pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) induced by either the infusion of an exogenous pulmonary vasoconstrictor (the thromboxane analog U46619) or the endogenous release of thromboxane that occurs during the neutralization of heparin anticoagulation by protamine sulfate. Inhaling greater than or equal to 40 ppm of NO during a continuous U46619 infusion returned the PAP to a normal value, without affecting systemic blood pressure or vascular resistance. Pretreatment with the cyclooxygenase inhibitor indomethacin before infusing U46619 did not reduce the pulmonary vasodilatory effect of inhaled NO, and we conclude that the dilatory effect of NO on the lung's circulation is independent of cyclooxygenase products such as prostacyclin. Continuously inhaling NO at 180 ppm did not significantly reduce the mean peak thromboxane B2 concentration at 1 min after protamine injection; however, the mean values of pulmonary hypertension and vasoconstriction at 1 min were markedly reduced below the levels in untreated heparin-protamine reactions. Breathing NO at lower concentrations (40-80 ppm) did not decrease the mean peak PAP and PVR at 1 min after protamine but decreased the PAP and PVR values at 2, 3, and 5 min below those of control heparin-protamine reactions. Intravenous infusion of nitroprusside completely prevented the transient increase of PAP and PVR during the heparin-protamine reaction; however, marked concomitant systemic vasodilation occurred. Inhaled NO is a selective pulmonary vasodilator that can prevent thromboxane-induced pulmonary hypertension during the heparin-protamine reaction in lambs and can do so without causing systemic vasodilation.

Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland. The ARF Study Group.

To determine the incidence and 90-d mortality of acute respiratory failure (ARF), acute lung injury (ALI), and the acute respiratory distress syndrome (ARDS), we carried out an 8-wk prospective cohort study in Sweden, Denmark, and Iceland. All intensive care unit (ICU) admissions (n = 13,346) >/= 15 yr of age were assessed between October 6th and November 30th, 1997 in 132 of 150 ICUs with resources to treat patients with intubation and mechanical ventilation (I + MV) >/= 24 h. ARF was defined as I + MV >/= 24 h. ALI and ARDS were defined using criteria recommended by the American-European Consensus Conference on ARDS. Calculation to correct the incidence for unidentified subjects from nonparticipating ICUs was made. No correction for in- or out-migration from the study area was possible. The population in the three countries >/= 15 yr of age was 11.74 million. One thousand two hundred thirty-one ARF patients were included, 287 ALI and 221 ARDS patients were identified. The incidences were for ARF 77.6, for ALI 17.9, and for ARDS 13.5 patients per 100,000/yr. Ninety-day mortality was 41.0% for ARF, including ALI and ARDS patients, 42.2% for ALI not fulfilling ARDS criteria, and 41.2% for ARDS.