Claes Frostell

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

BackgroundNitric 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. MethodsNine 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. ResultsThe 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 Pa02 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 en-dothelinlike Immunoreactlvlty concentrations did not change either during hypoxia or hypoxia with NO inhalation. ConclusionsInhalation of 40 ppm NO selectively induced pulmonary vasodilation and reversed hypoxic pulmonary vasoconstriction in healthy humans without causing systemic vasodilation.

Inhalation of nitric oxide in acute lung injury: results of a European multicentre study

Objective: To determine whether inhalation of nitric oxide (INO) can increase the frequency of reversal of acute lung injury (ALI) in nitric oxide (NO) responders. Design: Prospective, open, randomised, multicentre, parallel group phase III trial. Setting: General ICUs in 43 university and regional hospitals in Europe. Patients: Two hundred and sixty-eight adult patients with early ALI. Interventions: NO responders were patients whose PaO2 increased by more than 20 % when receiving 0, 2, 10 and 40 ppm of INO for 10 min within 96 h of study entry. Responders were randomly allocated to conventional treatment with or without INO. INO, 1–40 ppm, was given at the lowest effective dose for up to 30 days or until an end point was reached. The primary end point was reversal of ALI. Clinical outcome parameters and safety were assessed in all patients. Results: Two hundred and sixty-eight patients were recruited, of which 180 were randomised NO responders. Frequency of reversal of ALI was no different in INO patients (61 %) and controls (54 %; p > 0.2). Development of severe respiratory failure was lower in the INO (2.2 % ) than controls (10.3 %; p < 0.05). The mortality at 30 days was 44 % for INO patients, 40 % for control patients (p > 0.2 vs INO) and 45 % in non-responders. Conclusions: Improvement of oxygenation by INO did not increase the frequency of reversal of ALI. Use of inhaled NO in early ALI did not alter mortality although it did reduce the frequency of severe respiratory failure in patients developing severe hypoxaemia.

Bronchodilator action of inhaled nitric oxide in guinea pigs.

The effects of inhaling nitric oxide (NO) on airway mechanics were studied in anesthetized and mechanically ventilated guinea pigs. In animals without induced bronchoconstriction, breathing 300 ppm NO decreased baseline pulmonary resistance (RL) from 0.138 +/- 0.004 (mean +/- SE) to 0.125 +/- 0.002 cmH2O/ml.s (P less than 0.05). When an intravenous infusion of methacholine (3.5-12 micrograms/kg.min) was used to increase RL from 0.143 +/- 0.008 to 0.474 +/- 0.041 cmH2O/ml.s (P less than 0.05), inhalation of 5-300 ppm NO-containing gas mixtures produced a dose-related, rapid, consistent, and reversible reduction of RL and an increase of dynamic lung compliance. The onset of bronchodilation was rapid, beginning within 30 s after commencing inhalation. An inhaled NO concentration of 15.0 +/- 2.1 ppm was required to reduce RL by 50% of the induced bronchoconstriction. Inhalation of 100 ppm NO for 1 h did not produce tolerance to its bronchodilator effect nor did it induce substantial methemoglobinemia (less than 2%). The bronchodilating effects of NO were additive with the effects of inhaled terbutaline, irrespective of the sequence of NO and terbutaline administration. Inhaling aerosol generated from S-nitroso-N-acetylpenicillamine also induced a rapid and profound decrease of RL from 0.453 +/- 0.022 to 0.287 +/- 0.022 cmH2O/ml.s, which lasted for over 15 min in guinea pigs broncho-constricted with methacholine. Our results indicate that low levels of inhaled gaseous NO, or an aerosolized NO-releasing compound are potent bronchodilators in guinea pigs.

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 lungs 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.

Contribution from upper and lower airways to exhaled endogenous nitric oxide in humans

Endogenous nitric oxide (NO) is thought to regulate many biological functions, including pulmonary circulation and bronchomotion, and it has been found in exhaled air. Our aim was to study the excretion of NO in different parts of the respiratory system.

Inhaled nitric oxide therapy in adults: European expert recommendations.

BackgroundInhaled nitric oxide (iNO) has been used for treatment of acute respiratory failure and pulmonary hypertension since 1991 in adult patients in the perioperative setting and in critical care.MethodsThis contribution assesses evidence for the use of iNO in this population as presented to a expert group jointly organised by the European Society of Intensive Care Medicine and the European Association of Cardiothoracic Anaesthesiologists.ConclusionsExpert recommendations on the use of iNO in adults were agreed on following presentation of the evidence at the expert meeting held in June 2004.

Endogenous nitric oxide in the upper airways of healthy newborn infants.

The endogenous production of nitric oxide (NO) in the upper airways was studied in healthy newborn infants within the first minutes after delivery(N = 2) and at postnatal ages of 1 and 24 h (N = 13). Measurements were made in infants born vaginally or by cesarean section and at various times after the rupture of membranes. Gas was sampled from the nose and pharynx, and NO concentrations were determined by a fast response chemiluminescence analyzer. Sampling from the nose at a constant flow of 20 mL/min gave 0.27 ± 0.01 parts per million (mean ± SEM, ppm) of NO, independent of age and mode of delivery (vaginal delivery and cesarean section). Allowing NO to accumulate in the nose for 15-120 s yielded peak concentrations up to 4.6 ppm. A 30% increase was noted between 1 and 24 h of age. We conclude that nasal peak NO concentrations in the ppm range can be demonstrated in the healthy newborn infant within the first hour after birth. Consequently autoinhalation of endogenously produced upper airway NO may play a role in the adaptation of the respiratory system to postnatal life in the human.

Measurement of extravascular lung water by thermal-dye dilution technique: Mechanisms of cardiac output dependence

The extent to which extravascular lung water (EVLW) is dependent on cardiac output was analysed in anaesthetized and mechanically ventilated pigs. EVLW was measured by thermal-dye dilution technique, by a fibreoptic thermistor catheter system (system 1), and by a thermistor catheter-external optical cuvette system (system 2). During baseline conditions, at which cardiac output was 3.65 l/min, EVLW was 11.7 and 7.7 ml/kg b. w. with systems 1 and 2 respectively. A reduction of cardiac output to a mean of 1.90 l/min by the addition of halothane to the inspired gas did not significantly affect EVLW with system 1 (−50%) but increased EVLW by 39% (p<0.05) with system 2. An increase of cardiac output to a mean of 4.78 l/min by intravenous infusion of isoproterenol caused a small increase in EVLW with system 1 (14%;p<0.05) and a decrease with system 2 (10%;p<0.05). The dependence on cardiac output was the same whether the catheters were positioned centrally (aortic root) or peripherally (abdominal aorta). With system 1 the CO dependence was due to different time constants in thermistor and optical systems, and with appropriate phasing the dependence could be eliminated. With system 2 a large overestimation of the mean transit time difference between the two indicators was seen when cardiac output was low, resulting in overestimation of EVLW. It is concluded that the dependence of EVLW volume on cardiac output is an artefact due to technical problems in the design of the recording equipment rather than a reflection of pulmonary or vascular effects.

Differential release of matrix metalloproteinase‐9 and nitric oxide following infusion of endotoxin to human volunteers

Background: Roughly 400 000 cases of sepsis occur every year in the United States only and this is associated with a very high mortality. Bacterial lipopolysaccharide (LPS) triggers systemic inflammatory reactions in sepsis. However, down‐stream cellular cascade initiated by LPS is still being elucidated. Nitric oxide (NO) and matrix metalloproteinases‐2 and ‐9 (MMP‐2 and MMP‐9) are known to be induced by LPS. We have investigated the release of NO, MMP‐2 and MMP‐9 following infusion of LPS to volunteers.

Nitric Oxide Modulation of Pulmonary Blood Flow Distribution in Lobar Hypoxia

Background Nitric oxide, endogenously produced or inhaled, has been shown to play an important role in the regulation of pulmonary blood flow. The inhalation of nitric oxide reduces pulmonary arterial pressure in humans, and the blockade of endogenous nitric oxide production increases the pulmonary vascular response to hypoxia. This study was performed to investigate the hypothesis that intravenous administration of an nitric oxide synthase inhibitor and regional inhalation of nitric oxide can markedly alter the distribution of pulmonary blood flow during regional hypoxia. Methods Hypoxia (5% Oxygen2) was induced in the left lower lobe of the pig, and the blood flow to this lobe was measured with transit‐time ultrasound. Nitric oxide was administered in the gas ventilating the hypoxic lobe and the hyperoxic lung regions with and without blockade of endogenous nitric oxide production by means of Nomega ‐nitro‐L‐arginine methyl ester (L‐NAME). Results Hypoxia in the left lower lobe reduced blood flow to that lobe to 27 plus/minus 3.9% (mean plus/minus SEM) of baseline values (P < 0.01). L‐NAME caused a further reduction in lobar blood flow in all six animals to 12 plus/minus 3.5% and increased arterial oxygen tension (Pa sub O2) (P < 0.01). Without L‐NAME, the inhalation of nitric oxide (40 ppm) to the hypoxic lobe increased lobar blood flow to 66 plus/minus 5.6% of baseline (P < 0.01) and, with L‐NAME, nitric oxide delivered to the hypoxic lobe resulted in a lobar blood flow that was 88 plus/minus 9.3% of baseline (difference not significant). When nitric oxide was administered to the hyperoxic lung regions, after L‐NAME infusion, the blood flow to the hypoxic lobe decreased to 2.5 plus/minus 1.6% of baseline and PaO2 was further increased (P < 0.01). Conclusions By various combinations of nitric oxide inhalation and intravenous administration of an nitric oxide synthase inhibitor, lobar blood flow and arterial oxygenation could be markedly altered during lobar hypoxia. In particular, the combination of intravenous L‐NAME and nitric oxide inhalation to the hyperoxic regions almost abolished perfusion of the hypoxic lobe and resulted in a PaO2 that equalled the prehypoxic values. This possibility of adjusting regional blood flow and thereby of improving PaO2 may be of value in the treatment of patients undergoing one‐lung ventilation and of patients with acute respiratory failure.