Nitric oxide
Duncan Young BM DM FRCA FMedSci
Nitric oxide (NO) is one of the three common
oxides of nitrogen, along with nitrous oxide
(N2O) and nitrogen dioxide (NO2). It is present in the atmosphere, arising from oxidation
of nitrogen by lightening and combustion and
so increases in urban areas as a result of internal combustion engines. The combined quantities of nitric oxide and nitrogen dioxide in
the atmosphere (nitrogen oxides or NOx) is
used as one measure of atmospheric pollution.
Although the NOx concentrations may have
an effect chronically on health, the atmospheric concentrations of nitric oxide are not
pharmacologically active.
Biology of nitric oxide
Key points
Inhaled nitric oxide
reduces the use of extracorporeal membrane
oxygenation (ECMO) in
neonates with pulmonary
hypertension.
Healthy humans produce about 1 mM of
endogenous nitric oxide per day, using the
cationic amino acid L-arginine as a substrate.
The reaction is catalysed by a family of
enzymes called nitric oxide synthases (NOS)
whose three subtypes correspond to the three
main functions of endogenous nitric oxide.
Endothelial NOS is found in vascular endothelium and produces nitric oxide in response to
changes in blood velocity (shear stress). The
nitric oxide in turn causes smooth muscle
relaxation by activating the membrane-bound
enzyme guanylate cyclase and increasing the
concentration of the second messenger cGMP
which modulates calcium concentrations in the
vascular smooth muscle cell and hence tone.
This mechanism is primarily used to match
blood vessel calibre to flow, especially in arteries, and is one of the homeostatic mechanisms
controlling blood pressure. Systemic arteries
are always in a partially relaxed state because
of continuous nitric oxide production.
Neuronal NOS is found in both central and
peripheral neural tissue and produces nitric
oxide which acts as a neurotransmitter in nitrergic or non-adrenergic non-cholinergic
(NANC) nerves. Nitric oxide based neurotransmission may be involved in matching
cerebral blood flow to neural activity, memory and a range of other activities. There is also
an increasing body of experimental evidence
linking neuronal nitric oxide production with
susceptibility to general anaesthetic agents.
However, to date, there are no human data.
Duncan Young BM DM FRCA
FMedSci
Clinical Reader in Anaesthetics,
Nuffield Department of
Anaesthetics, Radcliffe Infirmary,
Woodstock Road,
Oxford OX2 6HE
Tel: 01865 224772
Fax: 01865 794191
E-mail: [email protected]
British Journal of Anaesthesia | CEPD Reviews | Volume 2 Number 6 2002
© The Board of Management and Trustees of the British Journal of Anaesthesia 2002
161
History of therapeutic use
The first therapeutic use of nitric oxide was
described by William Murrell in the Lancet in
1879. In a paper entitled Nitro-glycerine as a
remedy for angina pectoris, he described the
effect of a nitric oxide donor (nitroglycerine)
on patients and volunteers. The symptoms
arising from dilatation of the cerebral vascular
bed are particularly well described:
Mr AG Field ... described in detail the symptoms
he had experienced from taking two drops of
one percent nitroglycerine in alcohol. He noticed
a sensation of fullness in both sides of the neck,
succeeded by nausea. For a moment or two there
was a little mental confusion, accompanied by a
loud rushing noise in the ears, like steam passing
out of a tea kettle ... . The sensations were succeeded by a slight headache.
Over the next century, the vasodilating
effects of nitric oxide were established and a
range of nitric oxide donor drugs developed for
angina. However, it was not until 1987 that the
role of endogenously-produced nitric oxide as
a neurotransmitter and local messenger was
DOI 10.1093/bjacepd/02.06.161
established independently by Palmer and
Ignarro. Since then, there has been a major
increase in our understanding of nitric oxide
biology in both health and disease.
Inhaled nitric oxide in
adults with type 1 respiratory failure improves
PaO2 but may not alter
outcome.
Organic nitrates and
nitroprusside are nitric
oxide donors but have
different actions related
to the mode of nitric
oxide release.
Treatment of excess
nitric oxide production
in septic shock may not
prove beneficial.
Nitric oxide
The third nitric oxide synthase isoform (inducible NOS) is
produced in response to inflammation and probably aids host
defence by acting as an antimicrobial, chemotactic agent and
promoter of the vasodilation associated with inflammation. It
is also possible that induction of this isoform of NOS is
responsible for the vasodilatation and tissue dysoxia (anaerobic metabolism in spite of high oxygen delivery) seen in septic shock. In vivo, nitric oxide is oxidised to nitrite and nitrate
ions and renally excreted.
Nitric oxide donors
In clinical medicine, 2 types of nitric oxide donors are used
(Table 1). The direct-acting nitric oxide donors release nitric
oxide spontaneously, the indirect-acting donors require an
enzymic or other chemical reaction to release the gas. All
nitric oxide donors are used for their vasodilating actions.
The only directly acting nitric oxide donor in common use is
sodium nitroprusside. It has a very short half-life and is used as an
infusion to control malignant hypertension or to induce controlled
hypotension during anaesthesia. It is equipotent as a venous and
arterial dilator and so reduces filling pressures as well as systemic
vascular resistance. There are a number of problems that limit its
use. The drug itself can undergo photolysis after reconstitution and
infusion sets need to be shielded from light. The drug contains 5
cyanide moieties for every nitric oxide moiety so the possibility of
cyanide toxicity exists with prolonged treatment. Monitoring of the
cyanide concentration or base excess is advised. Direct arterial
blood pressure monitoring is required. Like virtually all vasodilators, nitroprusside reverses hypoxic pulmonary vasoconstriction
and so worsens ventilation/perfusion inequalities in the lungs, leading to a widening of the alveolar–arterial oxygen difference. The
reduction in arterial pressure in some patients may lead to a reflex
tachycardia, limiting the hypotensive effect. In these cases, βblockers are often used.
The indirect nitric oxide donors in clinical use are all organic
nitrates (polyol esters of nitric acid). Commonly used drugs
include glyceryl trinitrate, isosorbide dinitrate, isosorbide-5mononitrate, erythrityl tetranitrate and, historically, amyl nitrate.
They are used primarily as coronary vasodilators, to relieve
angina. However, their venodilating action is also used extensively to reduce venous pressure and cardiac filling pressures in
heart failure and anaesthesia for cardiac surgery. Glyceryl trinitrate is given by infusion, transdermally, sub-lingularly or via
the buccal mucosa as it undergoes extensive first-pass metabolism in the liver. The other nitrates are usually given as slow
release oral preparations for the control of angina. They all
162
Table 1 Nitric oxide donors and related drugs
Direct
Indirect (requires
thiol moiety)
Inhaled
NO release
from
endothelium
Sodium
nitroprusside
Glyceryl trinitrate
Isosorbide dinitrate
Isosorbide mononitrate
Erythrityl tetranitrate
Amyl nitrate
Nitric
oxide
gas
Acetylcholine
Bradykinin
Adenosine
require the presence of thiol (sulphydryl or R–SH) groups to
release nitric oxide at the tissue level. This requirement for
thiol groups explains some of the pharmacological differences
between sodium nitroprusside and the organic nitrates.
Venous myocytes may have more thiol groups available.
Therefore, organic nitrates are more potent venodilators than
arteriodilators, unlike nitroprusside which is equally potent on
both sides of the circulation. Thiol depletion may account for
the phenomenon of ‘nitrate tolerance’ where patients develop
tachyphylaxis to organic nitrates. Therefore, a ‘nitrate-free
interval’ is recommended for patients on nitrate infusions or
chronic transdermal nitrates. Surprisingly, although indirect
nitric oxide donors that include thiol groups have been developed, they do not seem to improve the tachyphylaxis.
There are also compounds that cause the release of endogenous nitric oxide from endothelial cells which might be
classed as ‘indirect’. These include acetylcholine, bradykinin
and adenosine, all of which have been used experimentally
but are not in common clinical use. Hydroxyarginine is an
intermediate in the arginine to nitric oxide reaction and is broken down by cytochromes to release nitric oxide.
Nitric oxide gas
Cigarette smoke was known to be a pulmonary vasodilator
long before the discovery of endogenous nitric oxide production. The vasoactive component of cigarette smoke is nitric
oxide which is present in very high concentrations.
The pulmonary vasodilating effect of inhaled nitric oxide was
first demonstrated in patients with primary pulmonary hypertension and in volunteers given reduced inspired oxygen to induce
hypoxic pulmonary vasoconstriction. Very small amounts are
needed; the effect can often be seen with inhaled concentrations
as low as 0.5 parts per million (ppm) by volume and the maximal
effect is usually seen at 10–20 ppm. Nitric oxide is absorbed from
the alveoli into the outer surface of pulmonary arterioles, causing
British Journal of Anaesthesia | CEPD Reviews | Volume 2 Number 6 2002
Nitric oxide
vasodilatation and a reduction in pulmonary vascular resistance.
No systemic effects are seen, as any nitric oxide that is absorbed
into the vessel rapidly reacts with haemoglobin to form nitrite
and methaemoglobin and is inactivated before it reaches the systemic circulation.
The combination of pulmonary vasodilation and no systemic effects makes inhaled nitric oxide a totally selective pulmonary vasodilator. This made it an ideal drug to treat
neonates with conditions that increase pulmonary vascular
resistance, e.g. primary pulmonary hypertension of the newborn (PPHN). In these conditions, the increased pulmonary
vascular resistance increases the right ventricular and atrial
pressures, re-opening the foramen ovale and causing right-toleft intracardiac shunting. The resulting hypoxaemia may
result in re-opening of the ductus arteriosus and further shunting. Treatment involved intravenous alkali and hyperventilation to induce an alkalosis that causes some vasodilatation.
Semi-selective pulmonary vasodilators (e.g. tolazoline) were
also used but their effectiveness was limited by the systemic
hypotension they caused which worsened right-to-left shunting. Inhaled nitric oxide avoided these problems. Clinical trials have shown that inhaled nitric oxide in PPHN considerably reduces the number of babies requiring salvage treatment
with extra-corporeal membrane oxygenation (ECMO).
In adults, inhaled nitric oxide is used as a pulmonary
vasodilator in a range of acute conditions. Following cardiopulmonary bypass for mitral valve replacement, the right
ventricle is sometimes compromised by high pulmonary vascular resistance which can be reduced to some degree by nitric
oxide. A similar situation occasionally occurs after heart transplantation. Inhaled nitric oxide is sometimes used during cardiac catheterisation to determine how much pulmonary hypertension is reversible and anecdotal evidence suggests it may
reduce acute rejection following lung transplantation.
A practical system for long-term nitric oxide delivery to
patients with chronic pulmonary hypertension has now been
developed and may prove an alternative to long-term prostacyclin infusions used at present. Not surprisingly, inhaled
nitric oxide can markedly reduce the pulmonary hypertension
that leads to high altitude pulmonary oedema but it is unclear
if it has any benefit over oxygen or altitude reduction.
The main interest in adults has centred around those patients
with severe type 1 (hypoxaemic) respiratory failure. Twothirds of these patients, when given inhaled nitric oxide,
increase their arterial oxygenation by 25% or more and, in
some cases, the increases are very much more dramatic. This
increased arterial oxygenation occurs because nitric oxide
improves the ventilation/perfusion relationships within the
lungs. Nitric oxide gas is delivered in the inhaled gas and,
therefore, preferentially to areas of high ventilation. The
resulting vasodilatation shifts blood flow towards the better
ventilated areas, reducing ventilation/perfusion mismatch and
increasing arterial oxygenation. There is usually an associated
reduction in pulmonary vascular resistance. As nitric oxide is
Maximum change (%)
100
50
Arterial PO2
0
–50
–100
Pulmonary artery
pressure
0
0.01
0.1
1
10
100
Log nitric oxide dose (ppm)
Fig. 1 The log dose-response for inhaled nitric oxide. Both PaO2 and mean pulmonary artery pressure are shown. Note how an excess of nitric oxide continues to reduce the pulmonary artery pressure but reverses the improvement in PaO2.The solid line represent data from a clinical trial, the grey lines are a
modelling study.The graphs are redrawn from data in Gerlach et al. Eur J Clin Invest 1993; 23: 499 and Frasch et al. Anesthesiology 1995; 83:3A.
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Nitric oxide
a totally selective pulmonary vasodilator, it does not cause any
reduction in systemic vascular resistance. There is often a trivial reduction in arterial carbon dioxide tension in patients on
ventilators but this is of no clinical consequence. The normal
dose range is 0.5–20 ppm; increasing the dose can cause a
paradoxical reduction in arterial oxygenation as the poorly
ventilated areas of the lung start to receive a pharmacologically active dose (Fig. 1).
A number of studies have shown clinically useful increases
in arterial oxygenation with nitric oxide. However, to date,
there are no clinical randomised controlled studies showing a
reduction in mortality in adults treated with nitric oxide.
Inhaled nitric oxide seems devoid of major side-effects.
Methaemoglobinaemia occurs but is not normally clinically
significant. Some patient groups (American Indians, neonates,
congenital methaemoglobinaemia) may be at increased risk of
methaemoglobinaemia because they have reduced or absent
methaemoglobin reductase activity. If nitric oxide is suddenly
stopped, rebound pulmonary hypertension and hypoxaemia
may occur. Therefore, slow weaning and back-up equipment
is required. If patients with New York Heart Association
(NYHA) grade IV heart failure are given nitric oxide, an
increase in left atrial pressure occurs which may decompensate their circulation. Appropriate monitoring of inhaled nitric
oxide and nitrogen dioxide concentrations is required.
Nitric oxide is usually supplied as 1000 ppm in nitrogen (it
oxidises slowly in contact with oxygen). A variety of devices
are available to add the nitric oxide to the inspired gas. The
best systems adjust the nitric oxide/nitrogen mixture flow rate
to keep a constant inspired concentration even if the minute
ventilation is altered.
Septic shock and nitric oxide
Initial animal studies strongly suggested excess nitric oxide
production was the cause of the vasodilatation and hypotension seen in septic shock. These models showed induction of
(inducible) nitric oxide synthase in vessel walls and a marked
increase in nitric oxide metabolites in the plasma. Inhibitors of
164
nitric oxide synthase reversed the shock. However, evidence
that the same situation applies to humans is still not conclusive. Human septic shock results in only modest increases in
nitric oxide metabolites and, to date, the studies looking for
induced nitric oxide synthase in vessel walls or endothelium
have produced conflicting results. The only large-scale randomised controlled trial of a specific nitric oxide synthase
antagonist in human septic shock was stopped because of an
increased mortality rate in the treatment group and a large
study of ketaconazole (which has anti-nitric oxide as well as
antifungal effects) showed no benefit in terms of mortality in
patients with the adult respiratory distress syndrome (ARDS).
In human septic shock, excess nitric oxide production may
yet turn out to be the cause of the tissue dysoxia as nitric oxide
is an inhibitor of cytochrome oxidases. However, inducible
nitric oxide synthase is clearly raised in tissue affected by
chronic inflammatory conditions such as asthma, rheumatoid
arthritis and Crohn’s disease. Exhaled nitric oxide, generated
by the inflammatory process within the lungs, is already used
as a marker of asthma severity and to monitor treatment. The
future of drugs that modulate the inducible NOS isoform may
be away from the ICU.
Key references
Cuthbertson BH, Dellinger P, Dyar OJ, Evans TE, Higenbottam T, Latimer
R et al. UK guidelines for the use of inhaled nitric oxide therapy in
adult ICUs. American–European Consensus Conference on
ALI/ARDS. Intensive Care Med 1997; 23: 1212–8
Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endotheliumderived relaxing factor produced and released from artery and vein
is nitric oxide. Proc Natl Acad Sci USA 1987; 84: 9265–9
Kinsella JP, Neish SR, Shaffer E, Abman SH. Low-dose inhalation nitric
oxide in persistent pulmonary hypertension of the newborn. Lancet
1992; 340: 819–20
Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the
biological activity of endothelium-derived relaxing factor. Nature
1987; 327: 524–6
Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992; 340:
818–9
See multiple choice questions 105–107.
British Journal of Anaesthesia | CEPD Reviews | Volume 2 Number 6 2002