Selected Recommendations from International Guidelines on Obstructive Sleep Apnoea

Obstructive sleep apnoea (OSA) is increasingly seen as a major health threat globally. However, it is still underdiagnosed mainly among Asian population partly due to lack of understanding on the pathophysiology, and limited access to the diagnostic and management aspect of the disease. Recurring complete and/or partial collapses of the upper airways define OSA. Based on the number of apnoeas and/or hypopnoeas per hour of sleep, OSA is categorized as mild, moderate and severe. Both the American Association of Sleep Medicine (AASM) and American College of Physicians (ACP) has published guidelines regarding the management of OSA in adults. Three recommendations have been suggested by the guidelines which can be used to tailor the management of OSA. The aim of this article is to select relevant recommendations from these guidelines in epidemiology, pathophysiology, diagnostic procedures and treatment for proper management of OSA, while considering specific patient populations, such as hypertensive, diabetic, obese and Asian patients.


INTRODUCTION
Obstructive sleep apnoea (OSA) is increasingly seen as a major health threat globally.Affecting approximately 2% of women and 4% of men in Western population [6], it is considered a frequent medical condition.
Recurring complete and/or partial collapses (apnoea and hypopnoea respectively) of the upper airways defined OSA.Based on the number of apnoeas and/or hypopnoeas per hour of sleep, known as the apnoea-hypopnoea index (AHI), OSA is categorized as mild, moderate and severe.Polysomnography (PSG) is the best tool to diagnose OSA [1].Well known risk factors for OSA include obesity, aging, male sex, smoking and alcohol intake [2][3][4][5].
Excessive daytime sleepiness (EDS) or insomnia, nocturia and morning headaches, are common complaints of OSA patients, but some patients may be asymptomatic.Berlin Questionnaire [2] and Epworth Sleepiness Scale (ESS) [3], are examples of clinically helpful questionnaires available to detect high risk OSA patients.
OSA is still underdiagnosed mainly among Asian population partly due to lack of understanding on the pathophysiology, and limited access to the diagnostic and management facility [6].The aim of this article is to focus on the current state-of-the-art in epidemiology, pathophysiology, diagnostic procedures and treatment selections for proper management of OSA, while considering specific patient populations, such as hypertensive, diabetic, obese and Asian patients.

OSA diagnosis
The diagnosis of OSA is often missed due to its complexity and unavailability of diagnostic modalities in certain centres.In order to standardize the diagnostic criteria for OSA, The American Association of Sleep Medicine (AASM) has come up with a guideline on how to diagnose obstructive sleep apnoea [24].
The document was developed by the AASM committees which consist of renowned authorities in sleep medicine field.Individuals with unexplained daytime sleepiness should be the target for OSA assessment.Appraisal of the common symptoms and risk factors for OSA should be included in the assessment [7][8][9][10].Obesity is the best-documented risk factor for OSA.Accidental sleep episodes during wakefulness, daytime drowsiness, unrefreshing sleep, lethargy, insomnia, and snoring are amongst clinical symptoms for OSA [11][12][13][14][15][16].In patients presenting with daytime drowsiness, which is a well-known OSA symptom most responsive to treatment, further evaluation for OSA may be warranted if other causes such as thyroid disease, gastro-oesophageal reflux disease, or other respiratory diseases have been ruled out.In assessing the symptom severity of OSA, sleepiness questionnaires, such as the ESS may assist, but it cannot assess the AHI due to its lack of sensitivity and specificity compared to PSG [22][23][24][25][26][27][28][29].
AASM and the Center for Medicare & Medicaid Services have considered AHI score of at least 15 events per hour or at least 5 events per hour with symptoms (such as daytime somnolence and fatigue) as criteria for OSA diagnosis.Type II, III, and IV monitors differ from PSG in terms of AHI estimation.For OSA prediction in various AHI cutoff levels, these monitors have a high positive likelihood ratio and low negative likelihood ratio.Performances are better in monitors with more channels compared to those with fewer channels.Type IV monitors are limited by their inability to distinguish obstructive from central sleep apnoea.Indirect data from studies comparing PSG monitors recommended that performances are better with type III monitors compared to type IV monitors in expecting AHI scores indicative of OSA.3% to 20% data loss of has been observed for type III and IV monitors [22].Inadequate clarification of results from the usage of type III monitors has been described in 13% to 20% of the evaluations, resulting from inadequate data [23].There is no verified study on the usefulness of transportable monitors for complicated patients with serious comorbid settings, such as chronic lung issues, cardiomyopathies, or brain disorders.Data is also lacking on head-to-head comparison on one monitor with the other [30].

OSA treatment
The guideline by the American College of Physicians (ACP) is intended to provide clinicians with evidencebased recommendations that will have positive, longterm effects on patients' cardiovascular risk, as well overall health and quality of life [20].Three recommendations have been suggested by the guidelines which can be used to tailor our OSA management.
First recommendation is to encourage weight loss in all overweight and obese patients diagnosed with OSA.There is strong evidence showing how weight loss interventions can reduce the apnoea/hypopnoea index (AHI) and improve symptoms.OSA severity can be categorized as mild, moderate and severe.In which, mild means having 5-14 events per hr, moderate means 15-30 events per hr, and severe means having more than 30 events per hr.In patients with mild OSA, weight loss alone can be sufficient to normalize the apnoea/hypopnoea index, thereby reducing the need for continuous positive airway pressure (CPAP).In those with persistent OSA, weight loss may reduce the amount of positive airway pressure required, which can increase tolerance of and adherence to CPAP.However, weight loss alone may not be sufficient to reduce OSA in all patients.In obese patients, weight loss must be encouraged with another primary treatment.In a meta-analysis of 12 published trials, weight loss produced substantial reductions in apnoea/hypopnoea index, however, almost all of the patients continued to have persistent OSA after significant weight reduction.So, while weight loss must always be urged in OSA patients, it should not be assumed that this intervention alone will be sufficient; patients need to be reassessed to determine whether OSA persists and if so, CPAP should be continued.
Second recommendation is to prescribe CPAP as the first-line treatment for OSA patients.CPAP is as critical as it is effective not only in reducing the AHI but also in improving sleep continuity and architecture and decreasing the sleep hypoxia that is associated with OSA.Because of the lack of adherence to CPAP, many new features have been added including heated humidification, broad pressure adjustments, and expiratory pressure relief.Again, it is critical that each patient's needs be taken into consideration.Some patients, particularly those with mild forms of OSA, may not need CPAP and may benefit from positional therapy or weight loss.Other therapy such as surgery or mandibular advancement devices (MADs) may be better suited for some patients despite their lesser effectiveness when compared with CPAP [33].
Third recommendation suggests that for OSA patients who favour MAD or for those with side effects due to CPAP, MAD can be considered as an alternate therapy to CPAP.MADs can be considered for patients with moderate to severe OSA, those with apnoea/hypopnoea index values between 18-40 events/hour, and for individuals who experienced adverse events on CPAP or who can't tolerate using it.While CPAP is still considered to be primary therapy, for those who must use a mandibular advancement device, it can often be very effective.Patients may find it easier to be compliant with MAD than with CPAP.One group of researchers observed that MADs were able to provide appropriate decrease in obstructive events in 70% of patients with mild OSA, 48% of those with moderate OSA, and 42% of those with severe OSA [21].The ACP concluded that, without sufficient evidence, it is unclear which patients will benefit from MADs.Data from several studies show that patients who are younger and thinner, with less severe OSA, may benefit more from the use of MADs.Although the ACP does not recommend surgery or pharmaceutical therapy for OSA, the ACP does acknowledge that it may work for certain patients.However, the documented efficacy rate ranges from 20%-100%, thereby making it challenging to determine its true effect [29].

OSA in hypertensive patients
There is a rising trend in the incidence of OSA in patients with hypertension.20%-40% of OSA patients have been detected amongst drug resistant hypertensives patients [25][26][27][28].Since the earliest description of PSG, acute changes in cardiovascular parameters are known to accompany OSA events at night.Wide fluctuations of blood pressure (BP) and heart rate, are well known acute effects which have been contributed by alternating obstructive apnoea and hyperventilation episodes during sleep [5].
Possible influence of OSA to the progression of resistant hypertension have been looked into by several studies.In OSA patients, refractory hypertension is primarily systolic and relatively more prominent at night [7][8][9].Nocturnal raises in systolic BP due to OSA may have particular adverse influences in patients with refractory hypertension, since nighttime systolic BP forecasts cardiovascular morbidity and mortality more precisely than daytime systolic BP.
In patients with resistant hypertension, OSA evaluation should emphasize on recognizing causative factors and excluding other causes of secondary (resistant) hypertension [24][25][26][27].In patients with significant signs of catecholamine excess in whom a catecholamine-producing tumour cannot be recognized, a diagnosis of OSA should be considered.A tailored and personalized diagnostic evaluation for other identifiable causes for each individual should be steered by their respective signs and symptoms [30].
A seemingly resistant hypertension, usually due to a "white coat hypertension" or "isolated office hypertension'' state (blood pressure raised in the office environment but normalized out of the office) must be differentiated from exact resistant hypertension.Serious overestimation of blood pressure might be caused by inability to use proper and correct cuffs on OSA patients with large arms [32].

OSA in diabetic patients
Among OSA patients, type 2 diabetes mellitus (T2DM) have been postulated to be one of the main driver that increased risk of cardiovascular morbidity.A cross-sectional correlation between OSA severity and T2DM prevalence have been identified from community and sleep laboratory-based populations data [12,13].A recent cross-sectional study assessing the correlations between OSA severity and T2DM prevalence in a vast multinational population involving 6,616 patients in the European Sleep Apnoea Cohort (ESADA) analysis have shown that T2DM prevalence increased with OSA severity [11,33].
This study also found out that Diabetic patients with severe OSA had poorer glycaemic control, with adjusted mean HbA1c levels 0.72% higher compared to those without sleep-disordered breathing (P <0 .001).They also concluded that worsening OSA severity is directly correlated with increased likelihood of having concomitant T2DM and worse diabetic control in subjects with T2DM [11].
Another study done amongst 544 participants without any pre-existing diabetes assessed in a Yale sleep clinic by Botros et al suggested a possible contributory role for OSA in propagating the development of T2DM.This population-level data showed that a OSA diagnosis conversed a significantly increased risk of emerging T2DM over a mean followup period of 2.7 years, despite modification for confounding demographic and clinical factors (HR 1.43 per quartile of OSA severity) [14].

OSA amongst obese patients
The prevalence of OSA is noted to be rising among obese patients, given that obesity is the most common risk factor in OSA.OSA is closely linked with the metabolic syndrome, and it is proposed that OSA propagate cardiometabolic dysfunction, and ultimately vasculopathy as suggested by recent data.Well-known pathophysiological triggers in OSA include alternating hypoxia and sleep disturbances.Few possible ways of OSA-obesity-metabolic syndrome correlations have been proposed, which include activation of sympathetic nervous system, presence of oxidative stress, inflammatory changes and neurohumoral activation involving adiponectin and leptin [32,33].
The data from human and animal/cell studies of intermittent hypoxia to describe these pathways are accumulating [28][29][30][31].A balanced and healthy food intake accompanied by proper lifestyle adjustments play important roles in managing metabolic syndrome and are equally important as CPAP usage in OSA management as a whole [10,30].

OSA in Asian patients
Despite being reported as a common disease in Western population, surprisingly, the data on OSA prevalence in Asian population are still lacking.A systematic review on OSA prevalence in Asian population by Mirrakhimov et al [6] which included 24 articles, covering 47, 957 patients have shown that OSA prevalence were observed to range from 3.7% to 97.3%.Several risk factors have been associated with OSA among Asian patients, which include male sex, elderly patient, high BMI and waist to hip ratio, larger neck circumference, presence of arterial hypertension, smoking habits, snoring events and daytime drowsiness.Differences in prevalence rates among previous Asian studies can be explained by different sample size, different study populations and different inclusion criteria (some studies included subjects with a high pre-test probability of OSA).The prevalence of snoring, witnessed apnoea, EDS and insomnia, rather than OSA diagnosis have been reported by few other studies.Thailand has been reported to have the lowest snoring prevalence of 4.6% [18] while Taiwan has been reported to have the highest prevalence of 59.1% [17].A much higher number of women have been included in the study from Thailand [18] and the younger subjects were included in the study from Taiwan and China [17].Taiwan was reported to have the lowest 2.6% [17], and Malaysia was reported to have the highest prevalence of witnessed apenas of 15.2% [19].,In Turkish studies, EDS symptoms ranged from 3.85% [16] to 24% [15].Different sample sizes and populations studied explained the difference in EDS prevalence findings The results of many published studies on Asian population evaluated subjects with high pre-test probability of OSA; hence their findings may overemphasize the exact load of the disease.More researches with larger samples are required in order to expand our understanding on OSA amongst Asian population.

CONCLUSION
Obstructive sleep apnoea (OSA) is a progressively evolving health threat in both developed and developing nations.Major recommendations have been suggested for OSA diagnosis and treatment.Early identification and management of OSA is paramount in reducing cardio metabolic risks in global population.Some aspects of pathophysiology and correlations of OSA remain unexplored.Future research with larger study population are needed to establish the OSA correlations and its long-term effect especially in specific population.

Sixth recommendation: if the first PSG result is negative or inconclusive, a repeat PSG is needed.
The guidelines have outlined six recommendations, in which four of them were strong recommendations.

Table 1
Four modes of sleep study available in the market: Type I, Type II, Type III and Type IV Mode Definition Type I Type I is the standard recommended overnight PSG for OSA diagnosis, in which the test was done in a proper sleep lab, attended by sleep technician.Type II Type II is defined by a test whereby the full PSG with its monitoring devices can be done outside of the sleep laboratory, without the presence of sleep technician.
Type III Type III device channels only measure four physiologic variables which include cardiac variable (eg, heart rate or an electrocardiogram), respiratory variables (eg, respiratory movement and airflow), and arterial oxygen saturation.Signals needed to determine sleep stages or sleep disruption were not recorded by the device.Type IV Type IV is also known as continuous single or dual bioparameter devices.This device can only record one or two variables and it can work without a technician.The channels usually measure arterial oxygen saturation and airflow.