1. Inhaled Nitric Oxide Therapy in
Adults
Authors: Mark J.D. Griffiths, M.R.C.P., Ph.D., and Timothy W. Evans, M.D., Ph.D
From: NEJM 353;25 December 22, 2005
Presenter: R5 謝廣宇
Supervisor: Dr. VS 陳奇祥
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2. Introduction
 NO and endothelium-derived relaxing factor
→modulating vascular tone through stimulated
formation of cyclic guanosine 3',5'-
monophosphate
 NO is formed from semiessential amino acid L-
arginine by one of three (neural, inducible, and
endothelial) isoforms of nitric oxide synthase
 In 1991, inhaled NO →selective pulmonary
vasodilator in patients with pulmonary
hypertension, as well as in animals with
pulmonary hypertension induced by drugs or
hypoxia.

3.  NO in ARDS →↓ pulmonary vascular
resistance without affecting BP and ↑
oxygenation by redistributing pulmonary
blood flow toward ventilated lung
units….BUT →licensed indications are
restricted to pediatric practice
 This review → biologic actions of inhaled
NO , clinical indications in adults, possible
future developments

5. chemical reactions of inhaled nitric
oxide
 Atmospheric concentrations →between 10
and 500 parts per billion but may reach
1.5 parts per million (ppm) in heavy
traffic12 and 1000 ppm in tobacco smoke
 NO is potentially cytotoxic, and covalent
nitration of tyrosine in proteins by reactive
nitrogen species has been used as a
marker of oxidative stress

7.  NO is rapidly inactivated by hemoglobin in blood
by haptoglobin–hemoglobin complexes in
plasma → forms nitrosylhemoglobin ; in lung
→methemoglobin and nitrate on reaction with
oxyhemoglobin →reduced to ferrous hemoglobin
by NADH–cytochrome b5 reductase in
erythrocytes
 70 % inhaled NO is excreted as nitrate in the
urine within 48 hours

8.  >100 proteins, including hemoglobin and
albumin, contain reduced sulfur (thiol) →
react reversibly with NO to form S-
nitrosothiols → vasodilators that inhibit
platelet aggregation, also “store” nitric
oxide within the circulation

9. physiologic effects of inhaled nitric oxide
on the cardiovascular system

10.  Inhaled NO relaxes pulmonary vessels →
↓pulmonary vascular resistance,
pulmonary arterial pressure, and right
ventricular afterload
 rapid hemoglobin-mediated inactivation of
NO
 biventricular cardiac failure →inhaled NO
→ ↑ pulmonary blood flow →↑pulmonary
edema

12.  positive effect of inhaled NO on gas exchange
depends on the extent to which pulmonary
vasoconstriction and ventilation–perfusion
mismatching are contributing to impaired
oxygenation → study of mountaineers
 vascular selectivity →disproportionate arterial,
as opposed to venous →dilatation
→↑pulmonary-capillary pressure→ may ↑risk of
pulmonary edema ( but NO 40 ppm induced
venodilatation→ ↓pulmonary edema)

13.  NO decreasing inflammation and helping
maintain the integrity of the alveolar-
capillary membrane in animal studies
 inhaled NO has no effect on systemic
circulation… BUT experimental studies
have demonstrated ↓systemic vascular
resistance, restoration of mesenteric
perfusion after inhibition of NO synthase

14.  rapid withdrawal may induce rebound
pulmonary hypertension and hypoxemia
→↓endothelial NO synthase activity →↑
plasma concentrations of endothelin-1..
BUT large clinical studies didn’t support it

15. direct cytotoxicity and effects
on inflammation
 protective effects →specific effects on
neutrophil function→ attenuation of the
respiratory burst and neutrophil-derived
oxidative stress, ↓neutrophils in the
pulmonary vasculature and air space in
animal models of ALI, NO derived from
neutrophils acts as an autocrine
modulating factor in infiltration of
neutrophils into the lungs during sepsis

16.  endogenously produced NO contributes to
control and killing of multiple pathogens and
malignant cells.
 NO–derived reactive nitrogen species contribute
to epithelial damage after a variety of insults
→unpredictable and probably depend on the
relative local concentrations →↑oxidative
products of NO in airway-lining fluid of patients
with ARDS and MAYBE may be further
increased by inhalation of NO

17.  In rodents, inhalation of nitric oxide (20
ppm) did not increase protein nitration
unless hyperoxia was superimposed
 Endogenous NO inhibits adhesion of
platelets to endothelial cells and
subsequent aggregation → inhalation NO
not certain

18.  Reactive nitrogen species →↓ functions of
surfactant →animals receiving inhaled
high-dose nitric oxide (80 to 100 ppm) had
↓ capacity to lower surface tension…. But
inhaled NO ↑surfactant proteins in four-
week-old lambs, NOT certain in human
 Inhaled NO has a dose-dependent
bronchodilator effect →nitric oxide–
derived S-nitrosothiols

19. administration of inhaled nitric oxide
to adults
 Limiting mixing of NO with high concentrations of
inspired oxygen ,and mixture of NO and nitrogen
into inspiratory limb of ventilator tubing as near
to patient as possible , synchronizing injection of
the mixture with inspiration →↓risk of adverse
effects resulting from formation of nitrogen
dioxide
 a massive overdose of inhaled NO (500 to 1000
ppm) is rapidly fatal →< 40 ppm for up to 6
months…. Safe in animals

20.  < 40 ppm of inhaled NO administered clinically
should not cause methemoglobinemia →check
methemoglobin within 6 hours after initiation of
NO therapy and after each increase in the
dose( UK guideline)
 environmental concentrations of NO and NO2
should not exceed a time-weighted average of
25 ppm and 2 ppm, respectively, over an 8
hours period----The Control of Substances
Hazardous to Health Regulations -----( unlikely
in a well-ventilated room)

21. Dose–Response Relationship
 higher doses were required to treat
pulmonary hypertension than to improve
oxygenation
 a minority of patients have no response
when a response is defined as a 20
percent increase in oxygenation →No
radiologic or physiological variables
predict a response

22.  30 % ↓pulmonary vascular resistance
during inhalation of NO (10 ppm for 10
minutes) has been used to identify an
association with vascular responsiveness
to agents that can be helpful in the long
term (like calcium-channel blockers)

23.  Dose–response relationships ( NO, 0 to 100
ppm) were constructed in the two groups on
days 0, 2, and 4 → first, the dose– response
curves for changes in oxygenation and mean
pulmonary pressure were shifted to left only in
patients who inhaled nitric oxide (10 ppm)
continuously. Second, “supramaximal” doses of
NO were associated with worsening
oxygenation------- Gerlach H, et al.
Dose-response characteristics during long-term inhalation of nitric
oxide in patients with severe acute respiratory distress syndrome: a
prospective, randomized, controlled study. Am J Respir Crit Care
Med 2003;167:1008-15.

24. clinical indications for administering
inhaled nitric oxide to adults
 failed to determine the therapeutic role of
inhaled nitric oxide in patients with acute
respiratory failure
 no decrease in duration of mechanical
ventilation or the mortality rate----similar at 30
days (European multicenter study enroll 600
subjects enrolled 268 patients with early ALI)
 ↑oxygenation (specifically in the partial pressure
of arterial oxygen) lasted only for the first day of
therapy

26.  why are the effects of inhaled NO so short-
lived?------↑sensitivity to NO during its inhalation
may diminish its beneficial effects and increase
toxicity, constant inhalation may lead to
equilibration of vasodilator effect between
ventilated and nonventilated areas
 any continued benefit may depend on use of
other therapeutic approaches such as
maintaining alveolar recruitment

27.  if clinical benefits are real, why do they not
translate into improved outcome?-----ARDS is a
heterogeneous condition with multiple causes
requiring different interventions that
independently affect outcome, very large
numbers of patients would be required for a
study to demonstrate benefit------many large
studies evaluating modes of ventilation and
prone positioning in patients with ARDS have
shown no correlation between improved
oxygenation and the outcome----majority die
from multiorgan failure

28. Targeting Pulmonary Vascular Resistance
 ↓expression of endothelial NO synthase in
pulmonary arteries of patients with chronic
primary and secondary pulmonary
hypertension→ possible therapeutic role
for nitric oxide →Inhaled NO improves
hemodynamic variables and exercise
tolerance in patients with chronic
pulmonary hypertension of various causes

29.  inhaled NO alleviates pulmonary HTN in severe
COPD but exacerbates hypoxemia at rest-----
BUT pulsed therapy (O2 with inhaled NO as a
bolus after the start of inspiration) markedly ↓
pulmonary arterial pressure and ↑ cardiac output
without impairing oxygenation (Vonbank K,et al.
Controlled prospective randomised trial on the effects on pulmonary
haemodynamics of the ambulatory long term use of nitric oxide and oxygen
in patients with severe COPD. Thorax 2003;58:289-93)
 During exercise, inhaled NO alleviates
pulmonary HTN without inducing hypoxemia

30. Lung Transplantation
 ischemia and reperfusion and oxidative
stress is an important cause of morbidity
and mortality after lung transplantation---
also ↓Endogenous NO activity-----
randomized, placebo-controlled trial of 84
transplant recipients, starting 10 minutes
after reperfusion and continuing for a
minimum of 6 hours, demonstrated no
benefit in terms of oxygenation, the time to
extubation, or the 30-day mortality rate.

31. Sickle Cell Disease
 results in widespread chronic inflammation
and recurrent ischemia–reperfusion injury
in organs such as the lungs and is caused
by microvascular occlusion by stiff
erythrocytes containing polymerized
deoxyhemoglobin S-----high-dose inhaled
NO (80 ppm for 1.5 hours) →↓scavenging
potential of hemoglobin within the
circulation (because of the weak
interaction of nitric oxide with
methemoglobin)

32. alternatives and adjuncts to inhaled
nitric oxide
 aerosolized sodium nitrite
 Epoprostenol, the most extensively studied
alternative to inhaled NO, also an endothelium-
derived vasodilator with antithrombotic effects---
longer half-life (three to six minutes), causing
recirculation ---- greater pulmonary and systemic
hypotensive effect, but causes less improvement
in oxygenation
 Inhaled NO and nebulized prostacyclin have
been observed to have additive effects

33.  Nebulized epoprostenol (10 to 50 ng per
kilogram per minute) , Iloprost, a long-
acting prostacyclin analogue (half-life, 20
to 30 minutes) , Inhaled prostaglandin E1
(6 to 15 ng per kilogram of body weight
per minute)

34. Adjunctive Therapies That Increase the Effectiveness
of Inhaled Nitric Oxide
 sildenafil, an inhibitor of phosphodiesterase type
5, is a selective pulmonary vasodilator, partially
because phosphodiesterase type 5 is highly
expressed in the lung ---- augmented pulmonary
vasodilatation induced by NO inhalation
 But zaprinast, predictably worsened oxygenation
through the attenuation of hypoxic pulmonary
vasoconstriction in an ovine model of acute lung
injury---most useful when pulmonary HTN rather
than respiratory failure

35.  Almitrine, an agonist at peripheral arterial
chemoreceptors, is a selective pulmonary
vasoconstrictor that specifically enhances
hypoxic pulmonary vasoconstriction
 PEEP , prone positioning, or ventilatory
maneuvers designed to inflate collapsed lung
 Partial liquid ventilation with perfluorocarbons
facilitates delivery of dissolved gases to alveoli
by enhancing recruitment of injured lung units

36. conclusions
and future directions
 Large clinical trials have indicated that
physiologic benefits are short-lived in
adults with acute lung injury or ARDS, and
no associated improvement in mortality
rates has been demonstrated-------
statistically underpowered to show a
decrease in mortality rates and have not
considered recent insights into effect of
continuous inhalation on dose– response
relationship of this agent

37.  On basis of evidence, inhaled NO is not
an effective therapeutic intervention in
patients with acute lung injury or ARDS,
and its routine use to achieve this end is
inappropriate-----may be useful as a short-
term adjunct therapy