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SHORT REPORTS Inhaled nitric oxide

as a cause

of selective pulmonary vasodilatation in pulmonary

hypertension

The acute effects of inhaled nitric oxide (NO) (40 ppm in air) on pulmonary (PVR) and systemic (SVR) vascular resistance were compared with those of an intravenous infusion of prostacyclin (24 µg/h) in 8 patients with severe pulmonary hypertension and 10 cardiac patients with normal values of PVR. 10 healthy volunteers were studied non-invasively. In the patients with pulmonary hypertension, PVR fell significantly after inhaled NO and after prostacyclin. PVR also fell significantly in the cardiac patients after inhaled NO. Although SVR fell substantially after prostacyclin in patients with pulmonary hypertension, inhaled NO had no effect on SVR in any patient or volunteer. Inhaled NO therefore seems to be both a selective and effective pulmonary vasodilator.

Nitric oxide (NO) has been identified as the powerful endothelium-derived relaxing factor (EDRF).l Isolated human pulmonary arteries relax with No2but investigation in vivo is difficult because NO is the most rapidly binding ligand of haemoglobin.3 Since NO is inactivated by haemoglobin, its vasorelaxant effects are restricted to the abluminal surface of the endothelium.1 This obstacle can be overcome in the lungs if NO is inhaled, thereby reaching resistance pulmonary arteries abluminally. Such arteries are closely associated with bronchioli and alveoli and are involved in the rapid uptake of inhaled NO in the lungs in much the same way as carbon monoxide uptake.4

In 10 normal volunteers, Q was measured non-invasively with a transthoracic impedance method (NCCOM-3 Bomed Medical Manufacturing, Irvine, California, USA). Mean SAP was measured with a sphygmomanometer. The effects of inhaled NO (40 ppm in air) and infused prostacyclin (PGI2) (24 j-ig/h) were investigated in patients with pulmonary hypertension, whereas only inhaled NO was studied in the cardiac and volunteer groups. The mixture of NO (about 40 ppm) in air was made from 5 litres of 1000 ppm NO in nitrogen (Air Products, Walton on Thames, UK), and added to 120 litres of air in a Douglas bag.4 The NO/air mixture was made 15 min before use, the concentration of NO being measured immediately before and after each study (chemiluminescence analyser, Chemlab, Homchurch, UK). Each subject, wearing a nose clip, breathed through a mouthpiece connected to a two-way valve and a switch to two Douglas bags, one containing air and the other the NO/air mixture. Operators and subjects were unaware of the content of the two bags. After baseline measurements, subjects spent four 5 min periods breathing from one bag then the other; the order of first bag use was random. Measurements were repeated at the end of each 5 min period. This time was chosen because in preliminary studies the effects of NO on pulmonary vascular resistance (PVR) had lasted less than 2 min. During the same catheterisation, PG 12 was infused intravenously in the pulmonary hypertension patients. Cumulative dose-response was assessed after baseline measurements with a stepwise increase of rate of infusion of PG 12 solution (05 mg in 250 ml) at 4, 8, and 12 ml per h at 10 min intervals.’ Haemodynamic measurements were made towards the end of each step. The order ofPGI2 infusion and NO/air inhalation was randomised, and 20 min elapsed between studies since the effects of PG 12 last for 10 min.5 Before and after breathing NO/air, venous blood samples were obtained in the volunteer group for measurements of methaemoglobin (IL282CO-oximeter Instrumentation Laboratory, Lexington, Massachusetts, USA). All results were expressed as mean (SEM). Analysis of variance was used to compare effects of NO/air and PGI2 on baseline pulmonary haemodynamics. The hospital ethics committee gave approval, and written and informed consent was obtained.

No person coughed while breathing the NO/air mixture and none could distinguish air from NO/air. In the

5 women and 3 men, mean age 38 (SD13) years, with severe pulmonary hypertension of 9-60 months’ duration, which was unexplained by cardiac or pulmonary disease, were investigated. All had normal pulmonary function but some were hypoxaemic (mean [SD] arterial oxygen tension, 8-6 [0’9] kPa). Each underwent diagnostic right heart catheterisation while supine (triple-lumen Swan-Ganz catheter, model SP 5107H, Abbott Laboratories, UK). Recordings were made of mean right atrial pressure (RAP), mean pulmonary artery pressure (PAP), and pulmonary wedge pressure (PWP), and mean systemic arterial pressure (SAP) was measured

through a radial artery cannula. Cardiac output (Q) was measured in triplicate by

the thermodilution

technique (Gould cardiac computer, Gould Medical, California, USA). 3 female and 7 male cardiac patients, mean age 59 (9) years, were investigated during diagnostic right and left heart catheterisation. 7 had mitral valve disease and 3 ischaemic heart disease. They had normal pulmonary function. Haemodynamic measurements were as for the pulmonary hypertension group.

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"- B....... II

.. - I .- 11 ...I

Haemodynamic effects of infused PGI2 and inhaled NO Comparison of effects on pulmonary (PVR) and systemic (SVR) vascular resistance of an intravenous infusion of prostacyclin (PGI2) (05 mg in 250 ml) at rates of 4, 8, and 12 ml/h, and mhalation of NO (40 ppm in air) with baseline (BL) values in 8 patients with pulmonary hypertension. Means and SEM are shown *p < 005, **p < 0-01.

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volunteer group, methaemoglobin rose from 0-33% (0-04) when breathing air to 0-42% (0-06) on NO/air (p < 0-05). In the pulmonary hypertension patients, baseline PVR ranged from 6-8 to 27-6 mm Hg/1 per min and 6 of the 8 patients showed a dose-dependent pulmonary vasodilatation to PGI2, with PVR falling by more than 30% from baseline (figure). SVR fell but PWP did not change. PVR fell with NO/air (range 37-52 ppm) in all 8 patients-by 5-68% from baseline. This was not associated with a fall in SVR (figure). There were no differences between baseline PVR values before infusion ofPGI2 (15[2’1] mm Hg/1 per min) and inhalation of NO (145 [2’2] mm Hg/1 per min). The cardiac patients had baseline values of PVR ranging from 0-9 to 2-9 mm Hg/1 per min, and PVR fell from 19 (0-2) when breathing air to 1 -5 (0-2) mm Hg/1 per min when breathing NO/air (p < 0-05). In these patients, SVR did not change with NO/air (20-7 [1’5] vs 20-2 [1’3] mm Hg/1 per min). The same can be inferred for the volunteers, in whom there was no change in cardiac index (3-8 [0.3] vs 3-8 [0.3] 1/min per m2), nor in SAP (82-9 [1’6] vs 82-4 [1-3] mm Hg), when comparing air with NO/air. There was only a small but significant (p < 0-05) rise in methaemoglobin concentration in the volunteers when breathing NO/air. NO reacts with oxyhaemoglobin to form methaemoglobin, nitrites, and nitrates.6 We have previously demonstrated similar methaemoglobin concentrations both in smokers, who are chronically exposed to NO in cigarette smoke, and non-smokers.7 Endogenous NO probably accounts for most methaemoglobin. Although NO is unstable compared with the kinetics of NO uptake in the lungs, oxidation to nitrogen dioxide under normoxic conditions is about 700 times slower. 3 h of continuously

breathing NO/air (80 ppm) substantially reverses hypoxic pulmonary vasoconstriction but does not cause any lung injury in sheep.9 Infusion ofPGI2 enables the capacity for vasodilatation to be tested in patients with pulmonary hypertension.5 However, at the later stages of disease, in which irreversible structural abnormalities predominate, only a small capacity to reduce the PVR is seen. 10 Patients with severe pulmonary hypertension who responded to PG 12 also responded to breathing NO/air. These comparable effects indicate strongly that inhalation of NO (40 ppm) is an effective way to cause pulmonary vasodilatation. The presence of pulmonary hypertension is not necessary since in the cardiac patients a small but significant fall in PVR was also noted with NO. NO, when inhaled, acts selectively on the pulmonary vasculature, since it causes no change in SVR. The absence of systemic vasodilator effects is a result of rapid inactivation of NO by haemoglobin. By contrast, infusion of cumulative doses of PG 12 led to similar falls in PVR and SVR in pulmonary hypertension patients. Our results suggest that inhaled NO might be an effective and selective pulmonary vasodilator. Although it might offer an alternative treatment for pulmonary hypertensive patients in whom intravenous or non-selective vasodilator treatment is either contraindicated or without effect, further investigation of the development of tolerance and toxicity in man would be of value. We thank Mrs Alison Croker and Mrs Marion Jones for secretarial assistance, Mr Ben Milstein for his editorial advice, Dr John Scott and Mr Charles Glanville for their help with clinical measurements, and Dr Salvador Moncada (Wellcome Research Laboratories, Beckenham, Kent) for his helpful advice and discussion. J. P.-Z. is supported by the Cystic Fibrosis Research Trust, and A. T. D.-X. by the British Heart Foundation.

REFERENCES 1. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327: 524-26. 2. Dinh-Xuan AT, Higenbottam TW, Clelland CA, et al. Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease. N Engl J Med 1991; 324: 1539-47. 3. Gibson QH, Roughton FJW. The kinetics and equilibria of the reactions of nitric oxide with sheep haemoglobin. J Physiol 1957; 136: 507-26. 4. Borland CDR, Higenbottam TW. A simultaneous single breath measurement of pulmonary diffusing capacity with nitric oxide and carbon monoxide. Eur Respir J 1989; 2: 56-63. 5. Jones DK, Higenbottam TW, Wallwork J. Treatment of primary pulmonary hypertension with intravenous epoprostenol (prostacyclin). Br Heart J 1987; 57: 270-78. 6. Yoshida K, Kasama K, Kitabatake M, Okuda M, Imai M. Metabolic fate of nitric oxide. Int Arch Occup Environ Health 1980; 46: 71-77. 7. Borland CDR, Harmes K, Cracknell N, Mack D, Higenbottam TW. Methemoglobin levels in smokers and non-smokers. Arch Environ Health 1985; 40: 330-33. 8. Meyer M, Piiper J. Nitric oxide (NO), a new test gas for study of alveolar-capillary diffusion. Eur Respir J 1989; 2: 494-96. 9. Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM. Inhaled nitric oxide, a selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991; 83: 2038-47. 10. Reeves JT, Groves BM, Turkevich D. The case for treatment of selected patients with primary pulmonary hypertension. Am Rev Respir Dis 1986; 134: 342-46.

ADDRESSES: Department of Respiratory Physiology (J. PepkeZaba, MD, T W. Higenbottam, FRCP, A. T. Dinh-Xuan, MD); Department of Cardiology (D. Stone, MD); and Department of Cardiothoracic Surgery (J. Wallwork, FRCS); Papworth Hospital, Cambridge, UK. Correspondence to Dr T W Higenbottam, Department of Respiratory

Physiology, Papworth Hospital, Papworth Everard, Cambridge CB3 8RE, UK.

Central-nervous-system demyelination after immunisation with recombinant hepatitis B vaccine 2 patients had neurological symptoms and signs, with evidence of central-nervous-system 6 weeks after administration of demyelination, recombinant hepatitis B vaccine. 1 had known multiple sclerosis but the other had no history of neurological disease; both had HLA haplotypes DR2 and B7, which are associated with multiple sclerosis. A causal link between vaccination and demyelination cannot be established from these 2 case-reports, but the time interval would fit a proposed immunological mechanism. Guillain-Barre syndrome, optic neuritis, and transverse myelitis have been reported after administration of plasmaderived hepatitis B vaccines.1 Few such incidents have been associated with the use of recombinant vaccines, although there have been 2 reports of optic neuritis and 1 of Guillain-Barré syndrome.2 We describe 2 patients, 1 with known multiple sclerosis and 1 with no history of neurological disease, in whom magnetic resonance imaging showed central-nervous-system demyelination after immunisation with recombinant hepatitis B vaccine. A health-care worker had a history of relapsing-remitting sclerosis since 1984. Relapses consisted of incomplete transverse myelitis, paresis of the right arm, and sensory symptoms in the left arm; all were followed by good recovery. Her

multiple

Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension.

The acute effects of inhaled nitric oxide (NO) (40 ppm in air) on pulmonary (PVR) and systemic (SVR) vascular resistance were compared with those of a...
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