Nitric Oxide Ventilation
in ARDS
Muhammad Asim Rana
► Nitric
oxide was formerly known as endotheliumderived relaxing factor (EDRF). It is one of the
nitrogen oxides ("NOx") and is synthesized within
cells by an enzyme NO synthase (NOS). This
enzyme catalyses the oxidation of L-arginine to Lcitrulline, producing NO, which diffuses into
vascular smooth muscle, activating guanylate
cyclase which in turn converts guanosine
triphosphate into cyclic guanosine monophosphate
(cGMP), causing vascular relaxation.
NOS is present in two forms:
►
The constitutive form (eNOS)
Present in vascular, neuronal, cardiac tissue, skeletal muscle
and platelets, producing small quantities of NO
continuously. Here NOS is Ca2+/calmodulin dependant and is
stimulated by cGMP.
►
The inducible form (iNOS)
Present in endothelium, myocytes, macrophages and neutrophils,
which produces relatively large quatities of NO after exposure to
endotoxins in sepsis. Following induction high levels of NO produced
may form cytotoxic radicals and cause capillary leakage.
Effects
Cardiovascular
Nitric oxide is a potent vasodilator. Shear
stresses in vessels increase NO production
and may account for flow dependant
vasodilatation. Endothelial NO inhibits
platelet aggregation. In septic shock the
overproduction of NO results in hypotension
and capillary leak. NOS inhibitors have
been investigated experimentally in the
treatment of sepsis.
Respiratory
► Important
basal vasodilatation in pulmonary
vessels is provided by endogenous NO and
this may be reversed in hypoxia. Nitric
oxide inhibits hypoxic pulmonary
vasoconstriction and preferentially increases
blood flow through well-ventilated areas of
the lung, thereby improving ventilation:
perfusion relationships.
Neuronal
► Nitric
oxide appears to have a physiological role as
a neurotransmitter within the autonomic and
central nervous system. Proposed roles include
modulation of the state of arousal, pain
perception, apoptosis and long term neuronal
depression and excitation whereby neurones may
“remember” previous signals. Peripheral neurones
containing NO control regional blood flow in the
corpus cavernosum.
Gastrointestinal
► NO
is a determinant of gastrointestinal
motility and appears to modulate morphineinduced constipation.
Genitourinary
► Nitric
oxide may play a role in sodium
homeostasis in the kidney.
Immune
► Macrophages
and neutrophils synthesize NO
which can be toxic to certain pathogens and
may be important in host defence
mechanisms.
Hematological
Platelet aggregation is inhibited by NO.
Basic Concept
► One
hallmark of ARDS is severe hypoxemia
caused by physiologic shunting and
ventilation/perfusion (V/Q) mismatching.
Inhaled vasodilators, particularly nitric oxide
can selectively dilate vessels that perfuse
well ventilated lung zones, resulting in
improved V/Q matching, better oxygenation,
and amelioration of pulmonary
hypertension.
MECHANISM OF ACTION
► Nitric
oxide relaxes vascular smooth muscle by
binding to the heme moiety of cytosolic guanylate
cyclase, activating guanylate cyclase and
increasing intracellular levels of cyclic guanosine
3',5'-monophosphate, which leads to vasodilation.
When inhaled, pulmonary vasodilation occurs and
an increase in the partial pressure of arterial
oxygen results. Dilation of pulmonary vessels in
well ventilated lung areas redistributes blood flow
away from lung areas where ventilation/perfusion
ratios are poor.
Inhaled vasodilators
►
Inhaled vasodilators
(green circles)
preferentially dilate the
pulmonary vessels that
perfuse functioning alveoli
(white circles), recruiting
blood flow away from
poorly ventilated units
(black circles). The net
effect is improved
ventilation/perfusion
matching.
► In
addition, inhaled vasodilators have few
systemic effects and rarely cause
hypotension because they act locally and
have short half-lives.
► Inhaled
Nitric oxide (NO) has been wellstudied in patients with acute lung injury
and ARDS.
► Inhaled NO has beneficial physiological
effects, but there is little evidence that
patient outcome improves. This is illustrated
by the following clinical trials:
►A
well-designed multicenter trial randomly
assigned 385 patients with moderate to severe
acute lung injury (P/F ratio ≤ 250 mmHg) to either
placebo or inhaled NO at 5 ppm. The acute lung
injury was not caused by sepsis, and significant
nonpulmonary organ dysfunction was absent.
Inhaled NO induced short-term improvement of
oxygenation; however, there was no improvement
in the duration of mechanical ventilation, 28-day
mortality, or one-year survival.
► Another
multicenter double-blind trial randomly
assigned 177 with ARDS to receive increasing
concentrations of inhaled NO or placebo. Inhaled
NO improved oxygenation modestly, but was not
sustained. There was no difference in 28-day
mortality, although this was not a primary end
point. The modest improvement of oxygenation
detected in this trial caused some to argue that
further investigation of inhaled NO for ARDS is not
warranted, although this view is not universal.
It has also been hypothesized that NO may have benefits
unrelated to improved V/Q matching, including
1.antiinflammatory properties,
2.antiplatelet activity, and
3.effects which diminish vascular permeability
►
Dosing
► Inhaled
NO is typically administered at a dose
between 1.25 and 40 parts per million (ppm).
► It has been used continuously for days to weeks,
with interruptions or attempts to discontinue
therapy resulting in worsened oxygenation and
increased pulmonary artery pressure.
► However, there is evidence that patients treated
with continuous inhaled NO might become
sensitized, such that lower doses improve
oxygenation and continued higher doses have little
or no effect.
Metabolism
► Nitric
oxide combines with hemoglobin that is 60%
to 100% oxygenated. Nitric oxide combines with
oxyhemoglobin to produce methemoglobin and
nitrate. Within the pulmonary system, nitric oxide
can combine with oxygen and water to produce
nitrogen dioxide and nitrite respectively, which
interact with oxyhemoglobin to then produce
methemoglobin and nitrate. At 80 ppm the
methemoglobin percent is ~5% after 8 hours of
administration. Methemoglobin levels >7% were
attained only in patients receiving 80 ppm.
PHARMACODYNAMICS / KINETICS
► Absorption:
Systemic after inhalation
► Excretion: Urine (as nitrate)
► Clearance: Nitrate: At a rate approaching
the glomerular filtration rate.
Storage
► NO
is stored in aluminium or stainless steel
cylinders which are typically 40
litres. These contain 100/1000/2000 p.p.m.
nitric oxide in nitrogen. Pure NO is
corrosive and toxic.
Administration
► The
drug is injected via the patient limb of
the inspiratory circuit of a ventilator. The
delivery system is designed to minimise the
oxidation of nitric oxide to nitrogen dioxide.
Monitoring
► Chemiluminescence
and electrochemical
analysers should be used and are accurate
to 1 ppm.
Potential harms
► Inhaled
NO may produce toxic radicals.
However, it is unknown whether the toxic
radicals are more harmful than ongoing
exposure to high fractions of inspired
oxygen.
► Methemoglobin
and NO2 concentrations
may increase when high doses of NO are
given(500-2000 ppm of NO), and the
concentration of both should be monitored
frequently.
► Inhaled
NO is associated with renal
dysfunction.
► Inhaled NO has immunosuppressant
properties that, in theory, could increase the
risk of nosocomial infection.
► NO can cause DNA strand breaks and base
alterations, which are potentially mutagenic.
SUMMARY
► Management
of acute respiratory distress
syndrome (ARDS) is supportive, aimed at
improving gas exchange and preventing
complications while the underlying disease that
precipitated ARDS is treated.
► Potential ARDS-specific therapies like inhaled NO
have been studied; however, they have not been
shown to improve clinical outcome and, thus,
cannot be recommended for routine care.
Predictors when to use Inhaled NO
► Inhaled
NO does not improve oxygenation
in all patients and the factors that
determine responsiveness are uncertain.
► One
retrospective study found that patients
with septic shock responded to inhaled NO
less frequently than patients without sepsis
or septic shock.
► A different study reported that a high
baseline pulmonary vascular resistance and
responsiveness to positive end-expiratory
pressure (PEEP) predicted a positive
response.
► So
the decision lies with treating Intensivist
about starting a patient on inhaled NO
keeping in view the potential benefits and
harms of such therapy.
Acknowledgements
► Dr.
Mostafa Adel
► Dr. Omar Alsayed
► Dr. Ahmed fouad
► Dr. Ahmed Hossam
► Dr.
Ahmed Rajab
► Dr. Sameer Ibrahim
► Dr. Bashir Ahmed
► Dr. Sayed Afzal
Thank You