Introduction
Obstructive sleep apnea (OSA) is a sleep-related respiration dysfunction characterised by repeated collapse of the higher airway, which induces intermittent episodes of apnea or hypopnea throughout sleep regardless of an ongoing respiratory effort. The worldwide prevalence of OSA is about 13% in males and 6% in females;1 it was estimated at 8.5% in Vietnam2 and at present rising with the event of weight problems. A current examine confirmed that the estimated prevalence of OSA recognized with an apnea-hypopnea index (AHI) ≥ 15/hour within the inhabitants aged from 30 to 69 years may as much as 34.4%.3 OSA can be thought of an unbiased threat issue for cardio-vascular/cardiovascular ailments reminiscent of hypertension, arrhythmia, or stroke.4 The therapy of OSA with steady constructive airway stress (CPAP) in hypertensive sufferers, particularly for individuals who are proof against antihypertensive remedy, may lower cardiovascular dangers5 The well-known penalties of OSA embody arousals and intermittent hypoxia. Intermittent hypoxia can be a mechanism of oxidative stress, irritation, and metabolic dysfunctions in OSA sufferers.6 Following some earlier research, cardiovascular morbidities normally develop with OSA severity. Thus, evaluating pulmonary irritation as a result of oxidative stress could also be helpful for early detection of sufferers with extreme OSA earlier than going ahead with polysomnography or respiratory polygraphy for making the prognosis and therapeutical choices.
Nitric oxide (NO) performs an necessary position each as a physiological modulator of vascular tone and a pathological pro-inflammatory biomarker implicated in several respiratory issues.7 NO will be simply measured within the exhaled air. Hypotheses assist the implication of exhaled NO (eNO) within the two principal pathological processes noticed in OSA, together with pulmonary or native irritation and endothelium dysfunction.8 Methods for measuring eNO provide a noninvasive, dependable, and straightforward approach to assess the irritation inside the higher airway and bronchial system by the fraction of NO within the airway compartment (FENO). Nonetheless, the OSA associated modifications in FENO have been reported in earlier examine with controversial findings.9–12 Some authors noticed an elevated eNO in OSA sufferers in contrast with non-OSA topics, whereas others demonstrated a decreased worth of this marker. These variations could be associated to the measured end result (as FENO is delicate to many confounding components), or the construction of the studied inhabitants (distribution of OSA severities among the many sufferers). FENO values are usually increased in topics with OSA than in wholesome topics.13
Due to this fact, we carried out this examine on an in-hospital inhabitants to guage the connection between eNO markers and OSA severity, and to confirm the modifications in eNO profiles amongst Delicate, Reasonable, and Extreme OSA subgroups.
Members and Strategies
Members
Consecutive sufferers assembly the inclusion standards have been prospectively recruited for the current examine after signing a written consent kind. All sufferers had been referred to the Division of Respiratory Illnesses of Cho Ray Hospital from October 2017 to October 2019 due to medical signs suggestive of OSA and underwent respiratory polygraphy.
Inclusion standards: adults with suspected signs of OSA (loud night breathing or choking throughout sleep, daytime sleepiness, nocturia, headache within the morning, or daytime tiredness); being able to doing laboratory assessments and respiratory polygraphy underneath technicians’ directions, and accepting to signal the consent kind.
Exclusion standards: an acute infectious illness with respiratory signs; recognized bronchial asthma or bronchial asthma like signs; persistent obstructive pulmonary illness (COPD); recognized lung fibrosis or pulmonary hypertension; decompensation of cardiovascular ailments; psychological or bodily deficits; different comorbidities reminiscent of systemic sclerosis, lupus, and polyarthritis; topics who at present use systemic corticosteroids or inhaled corticosteroids have been additionally excluded from the examine.
Ethics Assertion
This examine was authorised by the Institutional Overview Board of Cho Ray Hospital and the College of Medication and Pharmacy of Ho Chi Minh metropolis (192/ĐHYD-HĐ; June, twenty sixth 2016). All sufferers have been knowledgeable in regards to the function of the examine, and that it was carried out in accordance with the Declaration of Helsinki.
Bodily Examination and Sleep Questionnaires
All topics underwent an in depth medical interview with the questionnaires for signs of sleep problem respiration, medical historical past, sleep habits, and different sleep issues, in addition to the Epworth sleepiness scale (ESS).14 The ESS assesses the final stage of daytime sleepiness by having people consider the probability of drowsiness throughout eight totally different daytime conditions. Scores ≥11 are thought of extreme daytime sleepiness (EDS), in any other case, to be non-EDS (scores 0–10). Self-evaluation of sleepiness was measured by visible analog scale (0–10). PICHOT scale was used to measure the severity of tiredness (0–32).15 The final info was recorded, reminiscent of age, intercourse, physique mass index (BMI), stomach circumference (AC), and neck circumference (NC). The waist circumference was measured with a measuring tape in a horizontal aircraft across the stomach on the stage of the iliac crest and the tip of a standard expiration of the topic. The neck circumference was measured at mid-neck, between the mid-cervical backbone and the mid-anterior neck, on points standing upright and going through forwards, with shoulders relaxed.
Respiratory Polygraphy and Parameters
Every topic underwent in a single day respiratory polygraphy (RP) in a sleep laboratory (CareFusion; Germany). The next parameters have been repeatedly recorded oxygen saturation (pulse oximeter). Respiratory effort was measured by thoracoabdominal pressure gauges and nasal airflow (thermistor indicators and stress cannula), place with a suprasternal sensor.
Apnea was outlined as really useful by the American Academy of Sleep Medication (AASM) because the cessation of airflow for at the very least 10 seconds; hypopnea was outlined if all the following standards have been met: (1) peak sign excursions drop by at the very least 30% of pre-event baseline, (2) period of the at the very least 30% drop in sign tour was ten or extra seconds, and (3) there was 3% or higher oxygen desaturation from pre-event baseline.16,17
All of the RP have been completed on the hospital underneath supervising sleep technicians by way of digicam remark throughout the evening. The RP was switched on or off by sleep technicians on obligation and relied on sufferers’ sleep onset or awake standing. The sleep diary was additionally completed for every affected person throughout the current examine.
Exhaled NO Measurements
Exhaled nitric oxide was measured at a number of circulate charges (50 mL/s, 100 mL/s, 150 mL/s, and 350 mL/s) after RP (6:00 AM) utilizing an electrochemical-based analyzer (FeNO+; Medisoft-MGCD, USA). Technical measurement of exhaled NO was carried out in accordance with producer’s directions and as described beforehand and really useful by the European Respiratory Society.10,18 The maximal bronchial manufacturing price of NO (J’awNO) and alveolar focus of NO (CANO) have been routinely decided utilizing the two-compartment mannequin by Tsoukias and George: VNO = J’awNO + CANO × VE by way of Expair’s software program.
Biochemical Testing
On the finish of the sleep check within the following day, blood exams have been taken from every topic, and the next assessments have been completed: fasting glucose and lipid profile (HDL-c, LDL-c, Triglyceride). The fasting glucose and lipid profiles have been completed by utilizing the Aptio® Automation programs of Siemens Healthineers –Germany.
Spirometry
All sufferers underwent customary spirometry (KoKo; nSpire; UK). For every pulmonary perform check, three maximal flow-volume loops have been taken to find out FVC and FEV1; the biggest one was retained to calculate the ratio of FEV1 to FVC (FEV1/FVC).
Knowledge Evaluation
Knowledge have been analyzed utilizing a scientific computing bundle (scipy) within the Python programming language. The evaluation plan consists of three steps: First, the traits of comorbidities, anthropometric, cardiovascular and respiratory perform have been described for 3 medical sub-groups. The distinction within the distribution of sleepiness rating and polygraphy metrics amongst OSA severity ranges was additionally evaluated. Subsequent, we explored the connection between exhaled nitric oxide markers (FENO, J’AWNO, CANO) and the standard OSA markers, reminiscent of sleepiness rating, AHI, and SpO2 based mostly indices, Spearman correlation evaluation.
Lastly, we carried out a non-parametric ANOVA (Kruskal–Wallis H-test) and pair-wise comparability utilizing Conover post-hoc check to confirm the modifications in exhaled NO profiles amongst Delicate, Reasonable, and Extreme OSA subgroups. Null-hypothesis testing was based mostly on a significance threshold of p < 0.05.
Outcomes
Traits of the Studied Inhabitants
From January 2017 to December 2019, 123 sufferers with a confirmed prognosis of OSA have been consecutively included – within the examine and accomplished the examine; six different sufferers have been excluded from the examine as a result of being unable to do the repeated exhaled NO measurements. In line with the AASM severity grading system, most of those sufferers (67.5%) have extreme OSA, whereas the Delicate and Reasonable OSA sufferers occupied respectively 13.8% and 18.7%. Their medical traits are proven in Table 1. Briefly, there have been important variations in LDL stage, BMI, neck, and waist circumferences amongst three severity subgroups, which point out an affiliation between weight problems as a threat issue and the severity of OSA. Nonetheless, no important distinction has been discovered for blood glucose, HDL, and triglycerides.
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Desk 1 Traits of the OSA Sufferers in 3 Severity Sub-Teams |
Among the many cardiovascular comorbidities, solely hypertension was considerably related to OSA severity. Although the frequency of ischemic coronary heart illness was comparatively excessive inside the Extreme OSA group in contrast with Delicate or Reasonable teams, such distinction was not statistically important.
The distributions of 25 numeric variables, stratified by three severity subgroups are proven in Figure 1. As anticipated, the AHI was usually distributed inside every group. All morphometric parameters, in addition to blood stress and sleepiness scores have a standard distribution. Nonetheless, a skewed distribution with massive dispersion characterizes different physiological metrics, reminiscent of FEV1, FENO, J’AWNO, CANO, and SpO2. Among the many studied parameters, solely BMI, SpO2, FENO 350, J’AWNO, and CANO confirmed comparatively easy distinction amongst three subgroups, suggesting a possible affiliation between these parameters and the OSA severity.
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Determine 1 Distribution of 25 parameters amongst 3 medical subgroups. Abbreviations: Sys_BP, systolic blood stress; Dia_BP, diastolic blood stress; BMI, physique mass index; HDL, excessive density lipid; LDL, low density lipid; FEV1, compelled expiratory quantity in a single second; FVC, compelled important capability; FENO, fractional exhaled nitric oxide; J’AWNO, bronchial nitric oxide circulate; CANO, alveolar focus of nitric oxide; ppb, half per billion; ESS, Epworth sleepiness scale; VAS, visible analog scale; HDL, excessive density lipid; LDL, low density lipid; SpO2, pulse oxygen saturation. Notes: Every panel consists of a stratified Kernel density plot, visualizing the distribution of a numeric variable inside 3 OSA severity subgroups (Delicate in inexperienced, Reasonable in orange and Extreme in crimson). |
In our examine, medical features of OSA have been evaluated utilizing each subjective and goal strategies. These outcomes are represented in Table 2. The subjective method consists of utilizing the questionnaires reminiscent of Epworth, EVA, and PICHOT; none of them confirmed a big distinction. In distinction, all the target measurements, together with AHI and SpO2 indices, confirmed an evident disparity amongst three OSA severity subgroups.
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Desk 2 Sleepiness Rating and Polygraphy Metrics Amongst 3 OSA Severity Sub-Teams |
Exhaled Nitric Oxide within the Affiliation Community with Different Scientific Parameters
Within the current examine, we measured the exhaled nitric oxide at a number of sampling circulate charges. This maneuver permits an evaluation of nitric oxide variation at totally different places within the respiratory system, together with CANO and FENO 350 for the distal compartment (alveoli, alveolar duct and bronchioles), and J’AWNO, FENO50-150 for the proximal airway (bronchi and tracheal tube).
Earlier than focusing on these parameters as a surrogate marker in OSA, we carried out a pair-wise linear correlation evaluation. The affiliation community (Figure 2) permits an summary of the connection between exhaled nitric oxide parameters and different medical metrics.
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Determine 2 Correlation community of 25 parameters. Abbreviations: Sys_BP, systolic blood stress; Dia_BP, diastolic blood stress; BMI, physique mass index; HDL, excessive density lipid; LDL, low density lipid; FEV1, compelled expiratory quantity inone second; FVC, compelled important capability; FENO, fractional exhaled nitric oxide; J’AWNO, bronchial nitric oxide circulate; CANO, alveolar focus of nitric oxide; ppb, half per billion; ESS, Epworth sleepiness scale; VAS, visible analog scale; HDL, excessive density lipid; LDL, low density lipid; SpO2, pulse oxygen saturation. Notes: On this correlation community, every node (in orange) signifies a medical or practical parameter, the node dimension is proportional to variety of important correlations between that parameter to others. |
The AHI, and SpO2 have a central position on this community, as they bought the best variety of affiliation hyperlinks to different parameters. The six exhaled nitric oxide parameters (FENO50, 100, 150, J’AWNO, and CANO) fashioned a cluster with dense co-relationships amongst them.
The one connection that may very well be established between OSA severity and exhaled nitric oxide markers was by J’AWNO (bronchial maximal diffusing price, rho=0.25, p=0.02) and CANO (alveolar focus, rho= 0.18, p=0.04). There was no important correlation between FENO measured at three totally different circulate charges and the OSA severity. We additionally discovered a weak however important correlation between FENO 100 and averaged SpO2 (rho = 0.07, p= 0.03).
Adjustments in Exhaled NO Profiles Amongst Three Ranges of OSA Severity
Subsequent, we evaluated the modifications in 6 nitric oxide markers amongst 3 OSA severity subgroups utilizing a non-parametric evaluation of variance and pair-wise comparisons. The outcomes are offered in Tables 3 and 4.
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Desk 3 Distribution of Exhaled NO Metrics Inside 3 OSA Severity Sub-Teams |
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Desk 4 Outcomes of Pair-Smart Comparability for Exhaled NO Parameters |
Although the general evaluation of variance confirmed no important distinction within the distribution profile of FENO markers, the pair-wise comparability reveals that the FENO measured at a medium sampling circulate price (100–150 mL/s) did change considerably between reasonable and Extreme OSA (p = 0.03).
The median worth of bronchial maximal NO manufacturing price (J’AWNO) was considerably elevated in proportion with the OSA severity (11.2 vs 33.9 vs 36.2, p=0.01). After making use of a Bonferroni adjustment, we discovered that the change in J’AWNO was comparatively weak however important and primarily situated between Delicate versus Reasonable, however not important between Reasonable and Extreme ranges. We might differentiate the Extreme versus Reasonable and Delicate OSA by J’AWNO with p-values of 0.021.
The alveolar focus of NO (CANO) additionally represents a big variation amongst 3 severity teams (p=0.015); nevertheless the variation sample was not linear: the sufferers with reasonable OSA had increased CANO than that in gentle OSA (7.79 ppb vs 6.49 ppb), however the CANO was decreased in extreme OSA group (5.2 ppb). The pair-wise comparisons indicated that CANO permits considerably differentiate between Delicate versus Reasonable, Reasonable versus Extreme, and Extreme versus Reasonable or Delicate OSA (p values = 0.04, 0.004, and 0.037, respectively).
Every sampling flowrate (50, 100, 150 and 350 mL/s) permits to the measurement of a selected worth of FENO, and each represents a combination of NO from totally different origins, together with alveolar focus (CANO) – the primary compartment and contribution of NO manufacturing from epithelial tissues to various depths of the bronchial tube. Due to this fact, stand-alone FENO metrics could not characterize nitric oxide manufacturing price in every compartment. Making use of a easy linear regression mannequin, as proposed by Georges and Tsoukias in 1998, we might decide the J’AWNO and CANO from a mix of three or extra FENO values measured at totally different sampling circulate charges. As proven in Figure 3, there’s a clear differentiation between the regression line in Reasonable OSA teams, in comparison with that within the different 2 OSA severity teams. The regression line of Reasonable OSA has increased intercept and slopes, indicating increased values of J’AWNO and CANO, respectively.
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Determine 3 Affect of OSA severity on the results of multi-flow exhaled NO measurement. Notes: This regression plot reproduces the SC Georges’s bi-compartment linear mannequin: VNO = J’AWNO + CANO *VE, exploring the exhaled nitric oxide manufacturing price (VNO, nl/min) to the sampling circulate price (VE). Primarily based on this mannequin, we decide the J’AWNO (bronchial nitric oxide circulate) because the intercept of the regression line, and CANO (alveolar focus of nitric oxide) because the regression slope. The graph illustrates how OSA (obstructive sleep apnea) severity (gentle in inexperienced, reasonable in orange, and extreme crimson) modifies the J’AWNO and CANO values. |
Dialogue
Our examine gives for the primary time a complete evaluation of all 6 exhaled nitric oxide metrics as surrogate markers at totally different severity grades of OSA. In contrast to the earlier research that implied a case-control design, our examine focused gentle to extreme sufferers as a substitute of evaluating OSA and non-OSA subgroups.
The important thing findings in our examine: (1) There’s a weak however important relationship between the bronchial manufacturing price of NO and alveolar focus of NO and OSA severity; (2) the bronchial NO price would improve in proportional as AHI values improve, whereas the CANO will increase in gentle to reasonable OSA, however decreases in sufferers with extreme OSA. Collectively, these outcomes point out that J’AWNO and CANO drove from a multi-flow exhaled; NO measurement may very well be used as potential surrogate markers for distinguishing amongst 3 severity ranges of OSA.
The potential utility of exhaled NO in OSA was beforehand demonstrated in case-control research, which reported a considerably increased stage of FENO between OSA and non-OSA sufferers. Some authors have additionally reported a correlation between OSA severity and FENO.10,19,20 Physiologically, elevated FENO may counsel an eosinophilic irritation inside the higher and/decrease airways.7 Nonetheless, not like bronchial asthma, OSA-related irritation doesn’t indicate the eosinophil cells. Earlier research demonstrated that many inflammatory cells, together with neutrophils and lymphocytes within the sputum, mucosa, and muscular layer of the higher airway in OSA sufferers.21–23
Loud night breathing is a crucial symptom of OSA. Native irritation as a result of mechanic stress may clarify the elevated stage of exhaled NO in snorer and OSA sufferers.24 Intermittent hypoxia and its shut relationship with oxidative stress may also clarify the correlation between exhaled NO metrics and OSA severity.25
In our examine, J’AWNO and CANO have been correlated with AHI, the important thing metric for OSA severity grading. Although the FENO values by themselves weren’t related to OSA severity, a FENO measurement utilizing at the very least three sampling flowrate ranges is required to acquire J’AWNO and CANO. Within the current examine, all of the measurement of exhaled NO have been completed in duplicates, and which one with increased assured coefficients completed by Hypair FeNO+ machine was chosen for evaluation. Beforehand, Lazar et al confirmed that some sufferers couldn’t ship dependable measurements of exhaled NO with a number of flows.26 Nonetheless, as compared with Lazar’s examine, the place the measurements of CANO have been completed in asthmatic sufferers, which was in our examine was completed in topics with out persistent respiratory illness, and all topics accomplished the measurements of exhaled NO with none issue.
Our findings counsel {that a} measurement of FENO at a number of circulate charges could be extra helpful than a traditional single circulate measurement (FENO 50 mL/s) for monitoring native irritation related to OSA severity in a inhabitants of gentle to extreme OSA sufferers. The truth that J’AWNO was elevated in additional extreme OSA means that although the fraction of NO can be constantly excessive inside the mouth and tracheal tube of all sufferers, those that have extra extreme OSA have been characterised by the next bronchial NO manufacturing price, which is unbiased to the sampling flowrate. A persistent excessive price of NO biosynthesis inside the bronchial tissues is an indicator of persistent airway irritation, contributing to illness worsening or improvement in OSA, as prompt by Culla et al.19 Excessive J’AWNO was additionally properly correlated with nadir SpO2, suggesting an affiliation between intermittent hypoxia mixed with micro-arousal and airway irritation.
Nonetheless, the nonlinear sample of CANO in sufferers with reasonable to extreme OSA is harder to elucidate. Right here, we targeted on the decreased CANO when passing from Reasonable to Extreme OSA, as identification of such inhabitants can be useful for a call on OSA remedy and screening for cardiovascular comorbidities. CANO worth is decided by a dynamic equilibration between the NO stage between alveolar area and pulmonary circulation. A decreased CANO worth may very well be defined by inhibiting alveolar eNOS underneath the hypoxic burden, or elevated uptake by hemoglobins inside the pulmonary capillary circulation.
Girgis et al reported that lowered CANO may very well be attributable to an harm of alveolar endothelium and elevated reactive oxidative species manufacturing in leukocytes in peripheral airspace.27 Oxidative stress as a result of intermittent hypoxia inhibits phosphorylation of endothelial nitric oxide synthase (eNOS) and reduces NO ranges.28 These processes are in keeping with the pathological sample in extreme OSA, representing extra systemic irritation than gentle, reasonable OSA. As well as, alveolar NO diffuses quickly after its biosynthesis throughout the air-blood barrier for its lipid-soluble function. Liu Jie et al reported of their examine that in alveoli, NO serves as a compensatory mechanism contributing to the regulation of pulmonary circulation, This course of occurred quickly and consistently as a result of NO might bind to hemoglobin and oxidize it shortly.29 Past that, a protracted improve of inflammatory cytokines, adhesion molecules, and microparticles in OSA have been proved to be liable for native irritation and endothelial dysfunction.30
Thus, it will be affordable if each excessive J’AWNO and low CANO may very well be noticed in extreme OSA, in contrast with gentle or reasonable OSA. Although CANO correlated with AHI, airway obstruction, and age, neither COPD nor Tiffeneau (FEV1/VC) index was related to OSA severity. We might exclude the impact of persistent lung ailments on the change of exhaled NO in our sufferers. Due to this fact, OSA might be the important attribution of airway irritation. Though the evaluation of exhaled NO is a non-invasive, innocent, and nonetheless not absolutely standardized methodology to research the pathophysiology of OSA,13,31–33 based mostly on our findings, CANO may very well be used as marker of endothelial dysfunction for differentiating sufferers from wholesome topics. Nonetheless, the contradictions with the CANO worth measured utilizing the easy linear mannequin must be thought of the limitation of this system. A earlier examine demonstrated by Fortuna et al confirmed that extreme OSA sufferers had decrease CANO ranges, and these have been restored to regular after CPAP therapy. A current meta-analysis completed by Zhang et al prompt that OSA was considerably related to elevated FENO ranges. Nonetheless, J’awNO and CANO ranges weren’t very totally different between the OSA teams and management teams.32 Inversely, Duarte et al came upon the FENO values have been comparable amongst topics with and with out OSA −0.610); nevertheless, this examine didn’t measure CANO ranges in OSA sufferers. Lastly, the current examine additionally has another limitations relating to the dearth of a management group and respiratory polygraphy as a substitute of PSG. As well as, the results of exhaled NO values, particularly for CANO, was not offered in adjusting on cofounders, together with age, intercourse and BMI. Though one of many exclusion standards was having a present persistent respiratory illness reminiscent of bronchial asthma or persistent obstructive pulmonary illness, two topics had a medical historical past of childhood bronchial asthma. It was positive that the restricted variety of points in every subgroup additionally contributed to the examine limitation.
Conclusion
The current examine confirmed that J’AWNO, which represents eNO derived from the central airway, is proportionally elevated in additional extreme OSA, while eNO from alveolar area, indicated by CANO, was additionally related to OSA severity and comparatively decrease in probably the most extreme OSA sufferers. In distinction, stand-alone FENO metrics didn’t present a transparent distinction among the many three severity subgroups. Due to this fact, it’s really useful measure exhaled NO at a number of sampling circulate charges for evaluating pathological modifications in airway irritation and/or endothelial dysfunction, which differentiate probably the most extreme sufferers from those that have reasonable or gentle OSA.
Disclosure
The authors declare no conflicts of curiosity.
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