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1. Nitric oxide
• Is Nitric oxide inhalation for treating acute
respiratory distress syndrome ?
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2. outline
• Introduction to nitric oxide
• Introduction to acute respiratory distress
syndrome
• Result of clinical study
• Summery
• Recommendation
• References
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3. What is Nitric oxide? ( its donors)
• Nitric oxide is an autacoid produced
from arginine in the body, and the active
metabolite of drugs that release it (NO
donors); it is available as a drug in itself (NO
gas). It interacts with iron in hemoglobin and
can be inhibited by hemoglobin.
(Keefer, L. K,2010)
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4. Classification of nitric oxide
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5. Continued…
• Nitric oxide (NO) is a product of the
metabolism of arginine in many tissues. It is
thought to be an important
paracrine vasodilator, and it may also play a
role in cell death and in neurotransmission; it
therefore qualifies as an autacoid. NO is also
released from several important vasodilator
drug molecules.
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6. Continued…
• Many human diseases are associated with insufficient
NO production like Alzheimer’s disease, pulmonary
hypertension, penile erection, angiogenesis, wound.
• Most of the disease conditions associated with NO
insufficiency is due to dysfunctional NOS or enhanced
scavenging of NO once produced or a combination of
both.
• Strategies or therapeutics designed to restore or
enhance NO production will have a profound impact on
human disease and public health(Moncada S
et.al,2013).
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7. Continued…
• It is appreciated that too little NO is associated
with a number of human conditions but also too
much NO produced under chronic inflammatory
conditions is toxic and harmful.
• Although there are several conditions where
inhibition of NO production may have therapeutic
utility such as sepsis, and ulcerative collitis, and
even some neurological disorders, my focus is
the therapeutic effects of NO
enhancement(Stryer Lubert,2009).
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8. NO donors
• A common feature of all of these compounds is
that they can relax isolated blood vessels in vitro
(hence, the older designation, ‘nitrovasodilators’)
and, depending on their mode and rate of
biotransformation, are principally capable of
enhancing blood flow and lowering blood
pressure in vivo.
• Nitrovasodilators are used in the management of
various acute and chronic cardiovascular
pathologies.
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9. Continued…
• Their pharmacological effects are mediated
biochemically via the release of NO in the
vasculature independent of endogenous eNOS
• Once liberated, NO activates sGC in the
smooth muscle, increases the concentrations
of the secondary messenger cGMP, alters
calcium flux and ultimately causes relaxation
(Katsuki S, et.al ,2011)
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10. Continued…
• Clinically available NO donors approved for
use in patients with cardiovascular disease
include nitroglycerin (GTN), isosorbide
dinitrate (ISDN), isosorbide mononitrate (IS-
5N), amyl nitrite and sodium nitroprusside
(SNP).
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11. Continued….
• The beneficial pharmacological effects of
nitrovasodilators are severely limited by the
rapid development of tolerance to their
vasodilatory effects .
• In order for organic nitrates to maintain their
vasodilatory effects when used clinically, an 8 -
- 12 h nitrate-free period needs to be
incorporated.(Daiber A, et.al ,2012)
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12. Mechanism for NO or its donors
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13. Continued…
• NO is released from several important drugs,
including nitroprusside , nitrates ,
and nitrites.
• Release from nitroprusside occurs
spontaneously in the blood in the presence
of oxygen, whereas release from nitrates and
nitrites is intracellular and requires the
presence of the mitochondrial enzyme ALD2
and thiol compounds such as cysteine .
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14. Continued..
• Rise of CGMP causes smooth muscle
relaxation and platelet aggregation inhibition,
presumably by a decrease in intracellular Ca2+
concentration.
• Tolerance may develop to nitrates and nitrites
if endogenous thiol compounds are
depleted.(Moncada S et.al,2013)
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15. Acute respiratory distress syndrome
• It is a state of acute, diffuse alveolar damage
characterized by increased capillary
permeability, pulmonary edema and
refractory hypoxemia.
• It is characterized by acute onset of severe
hypoxemia , signs of respiratory distress
(dyspnoea, tachypnoea), diffuse bilateral
infiltrates in the CXR and no evidence of left
atrial hypertension (Villar J,2011).
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16. Incidence
• ARDS accounts for 10-15% of all ICU
admissions
• ARDS mortality in trauma patients is 10-15%
and in medical ICU patients is 60%.
(Sulemanji D.,et.al , 2016)
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17. Pathophysiology
• ARDS is a very diverse pathology that is an
important clinical outcome to many pathological
insults including: sepsis, shock, lung injury,
polytrauma, and others insults which cause
excessive activation of inflammation and
coagulation cascades .
• The key feature of ARDS is damage to the alveolar
epithelial and capillary endothelial cells, resulting
in increased permeability. (Ware L, et.al,2013)
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18. Continued…
• Approximately 60% of ARDS deaths occur
within the first 14 days after diagnosis (11).
• However, the majority of ARDS deaths seem
not to be attributed directly to the presence
of a fibrotic lung or hypoxemia, but rather to
multi organ failure (MOF) from a systemic
inflammatory response syndrome (SIRS) due
to the lung injury (Ambros A, et al,2014).
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19. Treatment modality for ARDS
• mechanical ventilation can be used as the
mainstay of treatment in ARDS.
• As with all ICU patients, fluid management is
crucial.
• Pharmacological Treatments (adjuvants to
mechanical ventilation):
• Neuromuscular blocking agents (NMBA) have
been employed in the treatment of ARDS.
• Most frequently they are used in conjunction with
sedation to facilitate patient-ventilator synchrony
(Arroliga A, et al,2013).
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20. Continued….
• It is found that early use of cistracurium in
severe (<150 PaO2) ARDS improved 90 day
survival and increased time off the ventilator
without increasing muscle weakness .
• Sedation use in ARDS such as midazolam and
propofol facilitates ventilator-patient
synchrony, patient comfort and somnolence,
lower opioid use, and is necessary for
mechanical ventilation(Silva P, et.al ,2015).
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21. Result of Clinical study
• In 83% of the patients, NO increased the ratio of
arterial Po2 to the fraction of inspired 0 2
(Pa0z/Fio2) by 2::10 mm Hg; in 87 %, NO reduced
venous admixture (QvA / QT) by 2::10%, and in
63 %, NO decreased mean pulmonary artery
pressure (PAP) by 2::3 mm Hg.
• Daily short interruption of continuous inhalation
of NO for a duration of 17 ± 2.4 days was
consistently associated with a decrease in
Pa0z/Fio2 by 81 ± 4 mm Hg .
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22. Continued…
• QvA / QT increased by 8.3 ± 0.4% and PAP by
5.3±0.3 mm Hg .
• Over time, they observed neither
tachyphylaxis nor a more pronounced effect of
inhaled NO.
• Survival rates in patients treated with NO did
significantly differ from survival rates in
patients not treated with NO.
• ( Rossaint, et.al ,2017)
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23. Mechanism of NO inhalation for
ARD
• inhalation of low concentrations of the gaseous
vasodilator nitric oxide (NO) has been described
to cause selective pulmonary vasodilation. (1,2)
• This phenomenon is explained on the one hand
by the inhalation strategy allowing NO to dilate
lung vessels and on the other hand by the
immediate inactivation of NO by binding to
hemoglobin as soon as NO enters the
bloodstream .
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24. Continued…
• Inhaled NO (iNO) can provide selective
pulmonary vasodilatation in well-ventilated
lung units, improve ventilation–perfusion
mismatch, and subsequently reduce the
elevated pulmonary vascular resistance and
pulmonary hypertension seen in ARDS.
• (Frostell C. et al,2016)
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25. Summery
• Beneficial effects of NO inhalation can be
observed in most patients with severe ARDS.
• in some cases, this study showed patients
with great improvement pulmonary gas
exchange or to reduce pulmonary
hypertension without obvious explanation.
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26. Recommendation
• To demonstrate reliability of this study, large
randomized prospective trials are required.
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27. References
• Villar J(2011). What is the acute respiratory distress syndrome? Respiratory care.
;56(10):1539--‐45.
• Sulemanji D.,et.al , (2016). The acute respiratory distress syndrome: incidence and
mortality, has it changed? Current opinion in critical care. ;20(1):3--‐9.
• Tomashefsk J(2012). Pulmonary pathology of acute respiratory distress syndrome.
Clinics in chest medicine. ;21(3):435--‐66.
• Ware L, et.al(2013). The acute respiratory distress syndrome. The New England
journal of medicine. ;342(18):1334--‐49.
• Martin T(2011). Lung cytokines and ARDS: Roger S. Mitchell Lecture. Chest.;116(1
Suppl).
• Greene K, et.al(2010). Serial changes in surfactant--‐associated proteins in lung
and serum before and after onset of ARDS. American journal of respiratory and
critical care medicine. 1999;160(6):1843--‐50.
• Ambros A, et al(2014). The ALIEN study: The incidence and outcome of acute
respiratory distress syndrome in the era of lung protective ventilation. Intensive
care medicine. 2011;37(12):1932--‐41.
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28. Continued..
• Stryer Lubert(2009). Biochemistry. 4th ed. New York, W. H. Freeman and Company. 732
• Keefer, L. K(2010). “Nitric oxide-releasing compounds: From basic research to promising drugs.”
Modern Drug Discovery. 20-29.
• Moncada S et.al(2013). NO physiology, pathophysiology and pharmacology, Pharmachol.Rev, 2 vol
43, nr.2, p.109 – 42.
• Collier JG, et.al(2014). Comparison of effects of tolmesoxide (RX71107), diazoxide, hydrallazine,
prazosin, glyceryl trinitrate and sodium nitroprusside on forearm arteries and dorsal hand veins of
man. Br J Clin Pharmacol ; 5: 35-44.
• Rolf Rossaint, et.al (2017).Efficacy of Inhaled Nitric Oxide in Patients With severe ARCS. CHEST I 107
, 1113-19
• Frostell C, et al(2016). Inhaled nitric oxide: a selective pulmonary vasodilator reversing hypoxic
pulmonary vasoconstriction. Circulation ; 83:2038-47
• Katsuki S, et.al (2011). Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin and
nitric oxide in various tissue preparations and comparison to the effects of sodium azide and
hydroxylamine. J Cyclic Nucleotide Res;3:23-35
• Daiber A, et.al (2012). Organic nitrates and nitrate tolerance--state of the art and future
developments. Adv Pharmacol ;60:177-227
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29. Continued..
• Cauwels A, et.al (2014). Extracellular ATP drives systemic
inflammation, tissue damage and mortality. Cell death &
disease.;5.
• Arroliga A, et al(2013). Use of sedatives And neuromuscular
blockers in a cohort of patients receiving mechanical
ventilation. Chest. ;128(2):496--‐506.
• Silva P, et.al (2015). Fluids in acute respiratory distress
syndrome: pros and cons. Current opinion in critical care.
;20(1):104--‐12.
• Marieb E. N(2007). Human Anatomy and Physiology. 4th
ed. California, Benjamin/Cummings Science Publishing.
391, 826-27, 533, 859
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