Nitric Oxide and OSA Fix

Nitric Oxide (NO) and Obstructive Sleep Apnea (OSA)
Presentan : dr. Anton, dr. Raymos, dr. Rizal, dr. Haves

Supervisor : Prof. Dr. dr. Teti Madiadipoera, Sp.THT-KL(K),
FAAAAI
Departement of Otorhinology Head and Neck Surgery

Faculty of Medicine – Universitas Padjajaran
Hasan Sadikin General Hospital
Bandung - 2022
Nitric oxide (NO)
• regulatory function in most tissue  involved in the causes of
obstructive sleep apnea (OSA)
• It is used by the pathways that control the patency of the airway, both
muscular and nervous, as well as by the tissues that sense the effects
of that obstruction
Haight, J.S.J., Djupesland, P.G. Nitric Oxide (NO) and Obstructive Sleep Apnea (OSA). Sleep Breath 7, 53–61 (2003).
https://doi.org/10.1007/s11325-003-0053-4
Obstructive sleep apnea (OSA)
• sleep-breathing disorder characterized by momentary episodes of
either 80–100% reductions in airflow for periods of ten seconds or
more (apnea) or 50–80% reductions (hypopnea) caused by a
collapsed or obstructed upper airway
• Risk factors : obesity, craniofacial abnormalities, smoking, male

gender, short neck, and menopause in women
Badran, M., Golbidi, S., Ayas, N., & Laher, I. (2015). Nitric oxide bioavailability in obstructive sleep apnea: Interplay of
asymmetric dimethylarginine and free radicals. Sleep Disorders, 2015, 1–10. https://doi.org/10.1155/2015/387801
four aspects of NO function that seem most
pertinent to sleep apnea
(1) its aerocrine function;
(2) REM atonia, when sleep apnea is at its worst;
(3) arousals, an index of severity and a major contributor to the failure
of sleep apnea to relieve sleepiness;
(4) O2 desaturations, another index of severity and probably
responsible in large measure for its long-term complications.
https://doi.org/10.1007/s11325-003-0053-4
• THE AEROCRINE FUNCTION OF NO IN SLEEP
• Increased NO in awake sleep correlated with degree of blood oxygen
desaturation while asleep
• NO is generated in nasal, NO at low concentrations is an important dilator of
the pulmonary vasculature.
• NO inspired in lung  reduce ventilation-perfusion mismatching  y increase
oxygenation and reduce pulmonary pressure
inhalation of high concentrations of NO is currently used therapeutically to

induce pulmonary vasodilation
https://doi.org/10.1007/s11325-003-0053-4
• THE RESPIRATORY MUSCLES
• various pharyngeal muscles exhibit activity in different phases of the
respiratory cycle, timing of the contraction of these muscles is critical
• role of NO in skeletal muscle varies in different muscles and between
isometric and isotonic contraction
• In Osa : the diaphragm sucks the airway closed while the pharyngeal
muscles attempt to maintain its patency
• Possible advantage of improvement in pharyngeal muscle tone

coupled with diaphragmatic sparing
https://doi.org/10.1007/s11325-003-0053-4
• REM ATONIA
• Cholinergic stimulation of the forebrain can block atonia
• Cholinergic cells in the pons synthesize NO
• NO modulates Ach release
• NO donors induce REM sleep
• AROUSALS
• NO is also involved in the reinitiation of sleep
• NO synthase inhibition by L-NAME (NG-Nitro L-arginine methyl ester) that
induces daytime somnolence
https://doi.org/10.1007/s11325-003-0053-4
THE CARDIOVASCULAR
CONSEQUENCES OF SLEEP APNEA
• Hypoxia and NO Suppression :
• Reduced circulation NO  suggesting impaired function of the vascular
endothelial cells
• Role of NO Suppression in Sleep Related Myocardial Infarction and
Stroke :
• reduction in circulating NO increases platelet aggregation and
vasoconstriction
• reduction in NO by hypoxia may predispose to the known long-term
cardiovascular
https://doi.org/10.1007/s11325-003-0053-4
THE CARDIOVASCULAR
CONSEQUENCES OF SLEEP APNEA
• Role of NO Suppression in Sleep Related Cardiac Ischemia
• NO serves a protective function by inhibiting abnormal smooth muscle
proliferation
• The Role of Sleep-Related NO Suppression in Hypertension
• Hypertension might result from NO deficiency.
• Pharmacological inhibition of endogenous NO synthesis in humans will induce
a rise in blood pressure.
• The Role of Sleep-Related NO Suppression in Atherosclerosis
• NO serves a vasoprotective functionby acting as an antioxidant and because it
inhibits leukocyte adhesion
https://doi.org/10.1007/s11325-003-0053-4
nitric oxide (NO) and asymmetric
dimethylarginine (ADMA)
• NO relaxes smooth muscles despite the high levels of calcium and
activated myosin
• ADMA competes with L-arginine for the binding site in the active
center of nitric oxide synthase (NOS) enzymes  ADMA are able to
interfere with the substrate availability of NOS
• Elevated ADMA levels occur in patients with chronic kidney failure
and were proposed to act as possible endogenous inhibitors of NO
synthesis
• ADMA in OSA
• ADMA has the potential to exacerbate cardiovascular disease
• ADMA levels are higher in OSA patients
• Treatment with CPAP for 4 weeks lowered ADMA levels in patients with OSA
while also improving forearm mediated dilation (FMD)
• Oxidative Stress in OSA
• oxidative stress leads to an imbalance between prooxidant/antioxidant
reactions related to oxygen metabolism.
• ROS can oxidize lipids, protein, or DNA, so inhibiting their function and
disturbing many cellular processes
• Sources of ROS/RNS in OSA
• Due to hypoxia, there is an increase in ROS production as a result of excessive
mitochondrial reduction
• increased production of ROS in stimulated neutrophils and monocytes from
OSA patients
• Markers of Oxidative Stress in OSA
• Oxidative stress markers : lipid peroxidation, protein carbonylation, DNA
oxidation
• TBARS levels were significantly higher in severe OSA
• Endothelial Dysfunction in OSA
• Decreased endothelium-dependent vasodilation has been reported in several
studies
• Suggested mechanisms for endothelial dysfunction :
• (1) interaction between NO and superoxide anion leading to increased formation of a highly
unstable RNS peroxynitrite,
• (2) decreased expression and/or uncoupling of endothelial nitric oxide synthase (eNOS), and
• (3) increased levels of endogenous eNOS inhibitors such as ADMA
• ADMA as a Treatment Target
• Treatment with CPAP decreases ADMA levels and improves endothelial function.
• Supplementation with L-arginine can displace ADMA from its receptor and
improve NO bioavailability
Measurement of exhaled nitric
oxide concentration in patients
with obstructive sleep apnea
Introduction
• Obstructive sleep apnea (OSA) : common sleep disorder characterized by repetitive episodes of
upper airway obstruction during sleep leading to significant hypoxemia and frequent arousals
• Previous studies : OSA Patients present with airway inflammation because of the mechanical
trauma of recurrent snoring and oxidative stress  assessment of respiratory inflammation might
be a predictor of OSA and its complication
• Exhaled nitric oxide (eNO) levels have been suggested as a simple, noninvasive, and reproducible
marker of respiratory inflammation
• (FENO) : bronchial NO production and diffusion
• Maximum airway wall flux of NO (J’awNO) : NO from the airway tree
• alveolar NO (CANO): the steady-state alveolar NO concentration
Aim of study : evaluate the potential association between OSA and eNO levels.
Zhang, D., Luo, J., Qiao, Y., Xiao, Y., Huang, R., & Zhong, X. (2017). Measurement of exhaled nitric oxide concentration in patients
with obstructive sleep apnea. Medicine, 96(12). https://doi.org/10.1097/md.0000000000006429
Materials and methods
Data sources and study selection
Data extraction and

analysis
• patients with OSA were compared with
more than 1 group of control patients
(e.g., obese and nonobese controls)
only the one that was a better match
for the patients with OSA in the study
was included in the meta-analysis
Zhang, D., Luo, J., Qiao, Y., Xiao, Y., Huang, R., & Zhong, X. (2017).
Measurement of exhaled nitric oxide concentration in patients with
obstructive sleep apnea. Medicine, 96(12).
https://doi.org/10.1097/md.0000000000006429
Results
• Search results and study characteristics
• 5 were cross-sectional trials (CSTs) and 11 were case–control trials
• mean age of participants ranged from 37 to 66 years in both groups
• FENO
• FENO levels in the OSA group were 6.39 ppb (95% confidence interval [CI] 4.46–
8.33, P<0.001) higher than in control group
• in patients with OSA, the overnight increase of FENO levels was larger than that
in non-OSA controls
• CANO and J’awNO
• there was no statistical difference in the CANO and J’awNO levels between the
OSA groups and control groups.
• Publication bias
• The bias might have been caused by the inclusion of subjects with allergies.
• Sensitivity analysis
• No single trial, when removed, significantly affected the overall estimate of the effects
of the 3 eNO measures  FENO levels were always increased significantly
• Meta-regression analysis
• Meta-regression analyses were performed to evaluate the effect of age, BMI, AHI, and
minimum pulse oxygen saturation (SpO2) on the levels of FENO.
• The FENO levels were not significantly correlated with the age, BMI, the AHI and
minimum SpO2
• The analyses of CANO levels and J’awNO levels were not reanalyzed by meta-
regression because of the limited number of studies included
Discussion
• inducible NOS (iNOS) can produce a large amount of NO for longer
periods of time after activation by stimuli; it plays a role in
pathophysiological processes such as inflammation.
• Exhaled NO levels are elevated in conditions associated with airway
inflammation
• There was an increase in FENO levels in subjects with OSA; however,
CANO and J’awNO were not significantly different between the
patients with OSA and the controls.
• FENO levels were significantly increased on waking up in patients with
OSA
• An increased FENO might be linked to the overexpression of iNOS,
which was partially reversible after long-term CPAP treatment
oropharyngeal
amplifying the
increased upper inspiratory muscle
Mechanical stress produces oxygen upper airway
airway dysfunction and
on the mucosa free radicals narrowing and
inflammation progressive local
collapsibility
neurogenic lesions
FENO can be used as a simple, noninvasive marker of upper

airway inflammation in patients with OSA
• other exhaled markers : increase of interleukin 6, interleukin 10, 8-
isopentane in adult OSA patients
• a significantly higher percentage of neutrophils in sputum of OSA
patients
• characteristics (age and BMI) and OSA severity (AHI and minimum
SpO2) had no correlation with the increased FENO levels.
• mechanical damage may play a more important role in the upper
airway inflammation than that of hypoxemia.
• extent of inflammation processes was not enough to alter the
concentration of CANO  lack of a significant difference in CANO
levels between the OSA and control subjects.
• patients with OSA and healthy subjects showed a circadian pattern of
FENO with a decrease of values across the day, suggesting that the
time of measurement may be a confounder
• Limitations
• available literature is largely low-level evidence;
• different techniques and instruments were used for the measurement of exhaled NO
• there was also heterogeneity across the sample populations
• Conclusion
• OSA was significantly associated with elevated FENO levels, especially after waking
up
• long-term CPAP therapy can reduce FENO levels
• FENO levels might be a noninvasive marker of upper airway inflammation in patients
with OSA
• NO and CANO are not useful markers of airway inflammation for patients with OSA
Methods
A. Research design
- Medical record who were admitted to the respiratory sleep center at chao yang hospital in beijing
- Included who are diagnosed OS
- Collecting data: medical history, clinical examination results, FENO, and upper airway computed
tomographic (UACT) findings.
B. Patient
- OSA hypopnea >5 based on a polysomnographic study who had SDB (sleep disorder breathing)
- Characteristics : snoring, witnessed apneas, excessive daytime sleepiness based on International
Criteria of Sleep Disorder
Feng, X., Guo, X., Lin, J., Zhao, Z. and Tong, Z., 2020. Risk factors and fraction of exhaled nitric oxide in obstructive sleep apnea in adults. Journal of
International Medical Research, 48(7), p.030006052092601.
C. Determination of NO content
- Portable electro-chemistry-based machine detect Feno before
polysomnography
- Feno detected : breathing for 10 s under a situation of constant
flow (50 mL/s) and pressure (10 cm H2O).
D. Statistical Analysis
- Mean ± standard deviation
- Repeat: 3 times
RESULT
• TOTAL PATIENT : 181 patient SDB
Ordinal logistic regression analysis of risk factor
Male sex, age, BMI, FENO, the narrowest transverse diameter of the upper airway,
and tonsil size were associated with OSA (all P<0.05).
Relationship between Feno and upper airway inflammation based on UACT

- Scan using high-speed 64-channel spiral CT scanner.
- Univariate analysis showed that FENO, soft palate thickness, soft palate length,
upper airway stenosis, sinusitis, and upper airway stenosis were directly
proportional to disease severity (all P<0.05).
Discussion
• Research found that various factors, including male sex, age, BMI, the smoking
index, alcohol consumption, FENO, soft palate thickness, soft palate length, upper
airway stenosis, and sinusitis, were risk factors for SDB and disease severity.
• Factor that susceptibility to OSA: age, obesity, menopause, craniofacial
deformity, male sex, family history of OSA, smoking, and drinking
• In this research: male sex, age, BMI, the smoking index, alcohol consumption,
FENO, thickness of the soft palate, length of the soft palate, the narrowest
transverse diameter of the upper airway, tonsil size, and nasal sinusitis were risk
factors for OSA and might be associated with disease severity.
• Further analysis: Logistic regression to evaluate: age, male sex, BMI, FENO, the
narrowest transverse diameter of the upper airway, and normal tonsil size were
significantly associated with OSA and disease severity.
• Older patient : the risk is increase exponentially
• There is close relationship between increased BMI and high risk of OSA. Obesity
makes narrowing of upper airway
• Relationship between OSA and male sex. It caused by different in structure and
function of airway
• In the study, found that anatomical factors, such as the thickness of the soft palate,
the length of the soft palate, the narrowest transverse diameter of the upper airway,
tonsil size, and nasal sinusitis, were closely associated with the severity of OSA.
• Increased Feno level relates with upper airway inflammation in SDB. Airway
and systematic inflammation have crucial role in pathophysiology of OSA
• Elevated Feno levels in OSA indicate the prescence of inflammation in the
bronchial and upper airway
• NO --> main factor for vasodilation --> depend on occurence and
degradation of oxygen free radicals and oxidative free radicals.
• Enhanced release of oxygen free radicals caused by hypoxia–reoxygenation
exceeds the physiological antioxidant ability in OSA --> reduce NO synthesis
--> synthesis of more superoxide radicals and peroxynitrite
• Nitric oxide plays an important role both as a physiology
modulator of vascular tone and and a pathological pro
inflammatory biomarker implicated in different respiratory
disorders
• Can be easily measured in exhaled air
• Hypotheses : implicatino of exhaled NO in the two principal
pathological process observed in OSA
Dang-Thi-Mai, K., Le-Dong, N., Le-Thuong, V., Tran-Van, N. and Duong-Quy, S., 2021. Exhaled Nitric Oxide as a Surrogate Marker for Obstructive Sleep Apnea
Severity Grading: An In-Hospital Population Study. Nature and Science of Sleep, Volume 13, pp.763-773.
Methods
• Participant • Exclusion criteria:
- Acute infectious disease with respiratory
- Signing a written consent form
symptoms
- Had been referred to the - Diagnosed astma or asthma like symptoms
departement of respiratory of
ChoRay Hospital (Oct 2017-2019) - Chronic obstructive pulmonary disease
because of suggestive OSA and - Diagnosed lung fibrosis or pulmonary
underwent respiratory polygraphy hypertension
- Inclusion criteria: - decompensation of cardiovascular diseases
- mental or physical deficits
1. Adult with suspected symptoms
of OSA - other comorbidities such as systemic
sclerosis, lupus, and polyarthritis
2. Capable of doing lab test and
- subjects who currently use systemic
respiratory polygraphy under
technicians instruction corticosteroids or inhaled corticosteroids
were also excluded from the study.
3. Accepting to sign the consent
form
Methods
• Ethics statement Each subject underwent overnight
Approved by the Institutional Review repiratory polygraphy in a sleep laboratory
Board of Cho Ray Hospital and the Following parameters  recorded oxygen
University of Medicine and Pharmacy of Ho saturation
Chi Minh City Respiratory effort was measured by
• Physical Examination and Sleep thoracoabdominal strain gauges and nasal
Questionnaires airflow, position with a suprasternal sensor
All subjects underwent clinical interview
General information: age, sex, BMI,
abdomen circumference and neck
circumference
• Respiratory Polygraphy and Parameters
Methods
• Exhaled NO measurements
Exhaled nitric oxide was measured at multiple flow rates (50 mL/s, 100 mL/s, 150 mL/s, and 350
mL/s) after RP (6:00 AM) using an electrochemical-based analyzer (FeNO+; MedisoftMGCD, USA)
• Biochemical testing
At the end of the sleep test in the following day, blood exams were taken from each subject, and
the following tests were done: fasting glucose and lipid profile (HDL-c, LDL-c, Triglyceride).
• Spirometry
All patient underwent spirometry
Methods
• Data analysis
- Using a scientific computing package in Python programming
language
- Analysis plan:
1. Characteristics of comorbidities
2. Anthropometric
3. Cardiovascular and respiratory function
Results
Dang-Thi-Mai, K., Le-Dong, N., Le-Thuong, V., Tran-Van, N. and Duong-Quy, S., 2021. Exhaled Nitric Oxide as a Surrogate Marker for Obstructive Sleep Apnea Severity Grading: An In-Hospital Population Study. Nature and Science of Sleep, Volume 13,
Results
Results
Dang-Thi-Mai, K., Le-Dong, N., Le-Thuong, V., Tran-Van, N. and Duong-Quy, S., 2021. Exhaled Nitric Oxide as a Surrogate Marker for Obstructive Sleep Apnea Severity Grading: An In-Hospital Population Study. Nature and Science of Sleep, Volume 13, pp.763-773.
Discussion
The key findings in the study:
(1) There is a weak but significant relationship between the bronchial production rate of NO and
alveolar concentration of NO and OSA severity;
(2) The bronchial NO rate would increase in proportional as AHI values increase, while the CANO
increases in mild to moderate OSA, but decreases in patients with severe OSA
- Increased FENO might suggest an eosinophilic inflammation within the upper and/lower airways.
- OSA-related inflammation does not imply the eosinophil cells
- Local inflammation due to mechanic stress might explain the increased level of exhaled NO in
snorer and OSA patients.
Conclusion
• Represents eNO derived from the central airway, is proportionally
increased in more severe OSA, whilst eNO from alveolar space,
indicated by CANO, was also associated with OSA severity and
relatively lower in the most severe OSA patients.
• In contrast, stand-alone FENO metrics did not show a clear difference
among the three severity subgroups. Therefore, it’s recommended
measure exhaled NO at multiple sampling flow rates for evaluating
pathological changes in airway inflammation and/or endothelial
dysfunction, which differentiate the most severe patients from those
who have moderate or mild OSA.
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Nitric Oxide and OSA Fix

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Nitric Oxide (NO) and Obstructive Sleep Apnea (OSA)

Presentan : dr. Anton, dr. Raymos, dr. Rizal, dr. Haves

Departement of Otorhinology Head and Neck Surgery

• Risk factors : obesity, craniofacial abnormalities, smoking, male

inhalation of high concentrations of NO is currently used therapeutically to

• Possible advantage of improvement in pharyngeal muscle tone

Data extraction and

FENO can be used as a simple, noninvasive marker of upper

Relationship between Feno and upper airway inflammation based on UACT

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